Essentials of Primary Care - Continuing Medical Education

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The Department of Medicine, Division of General Internal Medicine University of California, San Francisco School of Medicine presents

Essentials of Primary Care: A Core Curriculum for Adult Ambulatory Practice August 4-9, 2013 Resort at Squaw Creek North Lake Tahoe, California

Course Chair: Robert B. Baron, MD, MS Professor of Medicine; Associate Dean for Graduate and Continuing Medical Education University of California, San Francisco

University of California, San Francisco School of Medicine

Acknowledgement of Commercial Support

Exhibitor Bayer Samia Solutions

In-Kind Donations Brymill

ESSENTIALS OF PRIMARY CARE: A Core Curriculum for Adult Ambulatory Practice August 4-9, 2013 North Lake Tahoe, CA   SUNDAY, August 4, 2013 3:00 pm Registration 5:00

Welcome Robert B. Baron, MD, MS

5:10

G Cancer Screening 2013: Using Best Evidence to Guide Practice Judith M. E. Walsh, MD, MPH

6:00

G Current Strategies in Hypertension: Getting Ready for JNC 8 Robert B. Baron, MD, MS

6:50 pm Adjourn

MONDAY, August 5, 2013 Moderator: Robert B. Baron, MD, MS 7:00 am

Continental Breakfast

7:30

G Vaccinations in Adults and Adolescents Katherine A. Julian, MD

8:20

G Management of CAD: a Primary Care Perspective Michael G. Shlipak, MD, MPH

9:10

Break

9:30

G Preventing the Unintended: Update in Contraception Jody Steinauer, MD, MAS

10:20

G Assessment and Treatment of Common Dermatologic Problems Toby A. Maurer, MD

11:10 am

Adjourn

TUESDAY, August 6, 2013 Moderator: Robert B. Baron, MD, MS 7:00 am

Continental Breakfast

7:30

G Every Patient is an Athlete Carlin Senter, MD

8:20

G Detection and Treatment of Non-melanoma Skin Cancers Toby A. Maurer, MD

9:10

G Differentiating Pigmented Skin Lesions and Melanoma Toby A. Maurer, MD

10:00 Break 10:20 Concurrent Workshops (select one): G A: Physical Exam Skills and Office Procedures in Orthopaedics Carlin Senter, MD G B: Management of Obesity: a Systematic Approach Robert B. Baron, MD, MS

11:50 am Adjourn

WEDNESDAY, August 7, 2013 Moderator: Jody Steinauer, MD, MAS 7:00 am

Continental Breakfast

7:30

Cervical Dysplasia: Current Guidelines for Abnormal Pap and HPV Tests Jody Steinauer, MD, MAS

8:20

G Prevention and Treatment of Dementia Katherine A. Julian, MD

9:10

G Chronic Kidney Disease: What the Generalist Needs to Know Michael G. Shlipak, MD, MPH

10:00

Break

10:20

Concurrent Workshops (select one): G C: Mastering Office Gynecological Procedures Jody Steinauer, MD, MAS D: Substance Abuse Disorders in Primary Care: a Practical Approach Katherine A. Julian, MD

11:50 am Adjourn

THURSDAY, August 8, 2013 Moderator: Judith M.E. Walsh, MD, MPH 7:00 am

Continental Breakfast

7:30

G New Developments in Osteoporosis: Screening, Prevention and Treatment Judith M.E. Walsh, MD, MPH

8:20

G Common Knee Problems: What You "Knee'd" to Know Carlin Senter, MD

9:10

G Diagnosis and Management of Common Shoulder and Hip Complaints Carlin Senter, MD

10:00 Break 10:20 Concurrent Workshops (select one): E: Dermatologic Procedures in Primary Care Toby A. Maurer, MD F: Advances in Women’s Health 2013: a Critical Review of This Year’s Most Important Papers Judith M.E. Walsh, MD, MPH 11:50 am Adjourn

FRIDAY, August 9, 2013 Moderator: Katherine Julian, MD 7:00 am

Continental Breakfast

7:30

G Management of Atrial Fibrillation 2013 Katherine A. Julian MD

8:20

G Management of Diabetes: a Primary Care Perspective Robert B. Baron MD MS

9:10

Break

9:30

G Congestive Heart Failure: Effective Monitoring and Treatment Michael G. Shlipak, MD, MPH

10:20

Applying Best Evidence in Menopause Management Judith M. E. Walsh, MD, MPH

11:10

Adjourn

G

Geriatric Credit

University of California, San Francisco School of Medicine Presents

ESSENTIALS OF PRIMARY CARE: A CORE CURRICULUM FOR ADULT AMBULATORY PRACTICE Changing patterns of medical practice are placing greater responsibility on primary care clinicians. Increasingly difficult management decisions must now be made in the ambulatory setting. Primary care clinicians must be increasingly competent in office skills and procedures more commonly associated with specialist practice. At the same time, many specialty-trained physicians – particularly obstetrician gynecologists, traditionally trained internists and medical subspecialists are being asked to play an expanding role in primary care practice. Nurse practitioners and physician assistants are also playing an ever-increasing role. This course is designed to provide a comprehensive core curriculum in adult primary care. The course will serve as an excellent update and review for current primary care physicians and other primary care professionals, and as an opportunity for specialists to expand their primary care knowledge and skills. Particular emphasis will be placed on principles of primary care, office-based preventive medicine, practical management of the most common problems seen in primary care practice, and expanded skills in clinical examination and common office procedures. Special emphasis will be placed on examination and procedural skills in dermatology, gynecology and women’s health, and sports medicine. The course will utilize formal lectures, hands-on workshops, case discussions, an audience response system, and questions and answers. A detailed syllabus will be provided for all participants. This course is presented by the Division of General internal Medicine, Department of Medicine and is sponsored by the office of Continuing Medical Education, University of California, San Francisco School of Medicine.

Educational Objectives The purpose of this course is to increase competence and improve clinician practice in primary care. We specifically anticipate improvements in skills and strategies to: • Implement new guidelines in office-based preventive medicine including cancer screening, management of cardiac risk factors, and exercise; • Manage common problems in women’s health including contraception, abnormal pap tests, menopause, osteoporosis, and office gynecological procedures; • Develop strategies to care for common office problems including hypertension, CAD, CHF, chronic kidney disease, diabetes, atrial fibrillation, shoulder, knee and hip disorders, and dementia and delirium; • Diagnose and treat common skin disorders and skin cancer; • Counsel patients to lose weight, increase physical activity, and address issues of substance abuse; • Perform an effective problem-focused history and physical examination for evaluation and treatment of dermatologic, gynecologic, musculoskeletal and neurologic complaints; • Perform common office procedures in dermatology, gynecology, and orthopaedics; • Interpret the strengths and weaknesses of different types of clinical studies.

Accreditation The University of California, San Francisco School of Medicine (UCSF) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. This course is designated 20.25 AMA PRA Category Credits™. This activity has been reviewed and is acceptable for up to 20.25 prescribed credits by the American Academy of Family Physicians. The approved credits include 17.25 credits towards meeting the requirement under California Assembly Bill 1820 Geriatric Medicine.

General Information Attendance Verification/CME Certificates Please complete the sign‐in registration form located at the front desk area of the meeting. Make certain to indicate your total number of credits collected. Visit the below URL to complete the overall course evaluation and receive an electronic certificate immediately. EVALUATION – CME CERTIFICATE ACCESS: www.ucsfcme.com/evaluation Individual Faculty Evaluation Your cooperation in completing and returning the course evaluation is an important part of future course planning. The evaluation is the blue packet you received at registration. Please return your evaluation at course completion to the UCSF Registration Desk. Phone Messages Any messages during the conference can be left by calling (415) 913-9146 and asking for the UCSF Essentials of Primary Care. Messages will be posted at the registration desk. Security We urge caution with regard to your personal belongings and syllabus books. We are unable to replace these in the event of loss. Please do not leave any personal belongings unattended in the meeting room during breaks or overnight. Presentations PowerPoint presentations will be available on our website, www.cme.ucsf.edu, approximately 2-4 weeks post event. We will only post presentations for those authorized by the presenters. Going Green We are pleased to announce our efforts to ‘go green’. Currently all marketing materials such as brochures and syllabi are printed only on recycled paper. We need your help – if you would like to see this course provide only an electronic syllabus or make other changes please let us know via your evaluation.

Federal and State Law Regarding Linguistic Access and Services for Limited English Proficient Persons I. Purpose. This document is intended to satisfy the requirements set forth in California Business and Professions code 2190.1. California law requires physicians to obtain training in cultural and linguistic competency as part of their continuing medical education programs. This document and the attachments are intended to provide physicians with an overview of federal and state laws regarding linguistic access and services for limited English proficient (“LEP”) persons. Other federal and state laws not reviewed below also may govern the manner in which physicians and healthcare providers render services for disabled, hearing impaired or other protected categories II.

Federal Law – Federal Civil Rights Act of 1964, Executive Order 13166, August 11, 2000, and Department of Health and Human Services (“HHS”) Regulations and LEP Guidance. The Federal Civil Rights Act of 1964, as amended, and HHS regulations require recipients of federal financial assistance (“Recipients”) to take reasonable steps to ensure that LEP persons have meaningful access to federally funded programs and services. Failure to provide LEP individuals with access to federally funded programs and services may constitute national origin discrimination, which may be remedied by federal agency enforcement action. Recipients may include physicians, hospitals, universities and academic medical centers who receive grants, training, equipment, surplus property and other assistance from the federal government. HHS recently issued revised guidance documents for Recipients to ensure that they understand their obligations to provide language assistance services to LEP persons. A copy of HHS’s summary document entitled “Guidance for Federal Financial Assistance Recipients Regarding Title VI and the Prohibition Against National Origin Discrimination Affecting Limited English Proficient Persons – Summary” is available at HHS’s website at: http://www.hhs.gov/ocr/lep/ . As noted above, Recipients generally must provide meaningful access to their programs and services for LEP persons. The rule, however, is a flexible one and HHS recognizes that “reasonable steps” may differ depending on the Recipient’s size and scope of services. HHS advised that Recipients, in designing an LEP program, should conduct an individualized assessment balancing four factors, including: (i) the number or proportion of LEP persons eligible to be served or likely to be encountered by the Recipient; (ii) the frequency with which LEP individuals come into contact with the Recipient’s program; (iii) the nature and importance of the program, activity or service provided by the Recipient to its beneficiaries; and (iv) the resources available to the Recipient and the costs of interpreting and translation services. Based on the Recipient’s analysis, the Recipient should then design an LEP plan based on five recommended steps, including: (i) identifying LEP individuals who may need assistance; (ii) identifying language assistance measures; (iii) training staff; (iv) providing notice to LEP persons; and (v) monitoring and updating the LEP plan. A Recipient’s LEP plan likely will include translating vital documents and providing either on-site interpreters or telephone interpreter services, or using shared interpreting services with other Recipients. Recipients may take other reasonable steps depending on the emergent or nonemergent needs of the LEP individual, such as hiring bilingual staff who are competent in the skills required for medical translation, hiring staff interpreters, or contracting with outside public or private agencies that provide interpreter services. HHS’s guidance provides detailed examples of the mix of services that a Recipient should consider and implement. HHS’s guidance also establishes a “safe harbor” that Recipients may elect to follow when determining whether vital documents must be translated into other languages. Compliance with the safe harbor will be strong evidence that the Recipient has satisfied its written translation obligations.

In addition to reviewing HHS guidance documents, Recipients may contact HHS’s Office for Civil Rights for technical assistance in establishing a reasonable LEP plan. III. California Law – Dymally-Alatorre Bilingual Services Act. The California legislature enacted the California’s Dymally-Alatorre Bilingual Services Act (Govt. Code 7290 et seq.) in order to ensure that California residents would appropriately receive services from public agencies regardless of the person’s English language skills. California Government Code section 7291 recites this legislative intent as follows: “The Legislature hereby finds and declares that the effective maintenance and development of a free and democratic society depends on the right and ability of its citizens and residents to communicate with their government and the right and ability of the government to communicate with them. The Legislature further finds and declares that substantial numbers of persons who live, work and pay taxes in this state are unable, either because they do not speak or write English at all, or because their primary language is other than English, effectively to communicate with their government. The Legislature further finds and declares that state and local agency employees frequently are unable to communicate with persons requiring their services because of this language barrier. As a consequence, substantial numbers of persons presently are being denied rights and benefits to which they would otherwise be entitled. It is the intention of the Legislature in enacting this chapter to provide for effective communication between all levels of government in this state and the people of this state who are precluded from utilizing public services because of language barriers.”

The Act generally requires state and local public agencies to provide interpreter and written document translation services in a manner that will ensure that LEP individuals have access to important government services. Agencies may employ bilingual staff, and translate documents into additional languages representing the clientele served by the agency. Public agencies also must conduct a needs assessment survey every two years documenting the items listed in Government Code section 7299.4, and develop an implementation plan every year that documents compliance with the Act. You may access a copy of this law at the following url: http://www.spb.ca.gov/bilingual/dymallyact.htm

Faculty List Course Chair Robert B. Baron, MD, MS Professor of Medicine; Associate Dean for Graduate and Continuing Medical Education; Vice Chief, Division of General Internal Medicine

Course Faculty (University of California, San Francisco unless indicated) Katherine A. Julian, MD Professor of Medicine; Director, Primary Care Internal Medicine Residency Toby A. Maurer, MD Professor and Chief of Dermatology, San Francisco General Hospital Carlin Senter, MD Assistant Professor of Orthopaedics and of Medicine, UCSF Primary Care Sports Medicine Michael G. Shlipak, MD, MPH Chief, Division of General Internal Medicine; San Francisco VA Medical Center; ProfessorIn-Residence of Medicine, Epidemiology and Biostatistics Jody Steinauer, MD, MAS Associate Professor, Department of Obstetrics, Gynecology and Reproductive Sciences; Assistant Director, Family Planning Fellowship Judith M. E. Walsh, MD, MPH Professor of Medicine, Women’s Health Clinical Research Center

Disclosures The following faculty speakers, moderators, and planning committee members have disclosed they have no financial interest/arrangement or affiliation with any commercial companies who have provided products or services relating to their presentation(s) or commercial support for this continuing medical education activity: Robert B. Baron, MD, MS Katherine A. Julian, MD Toby A. Maurer, MD Carlin Senter, MD Michael G. Shlipak, MD, MPH Jody Steinauer, MD, MAS Judith M. E. Walsh, MD, MPH

This UCSF CME educational activity was planned and developed to: uphold academic standards to ensure balance, independence, objectivity, and scientific rigor; adhere to requirements to protect health information under the Health Insurance Portability and Accountability Act of 1996 (HIPAA); and, include a mechanism to inform learners when unapproved or unlabeled uses of therapeutic products or agents are discussed or referenced. This activity has been reviewed and approved by members of the UCSF CME Governing Board in accordance with UCSF CME accreditation policies. Office of CME staff, planners, reviewers, and all others in control of content have disclosed no relevant financial relationships.

Selected Controversies

Cancer Screening

• Breast Cancer Screening – Who should be screened? – Digital Mammography – MRI

Using Best Evidence to Guide Practice

• Colorectal Cancer

Judith M.E. Walsh, MD, MH

– What test and how often? – Are there new screening options?

Division of General Internal Medicine Women’s Health Center of Excellence University of California, San Francisco

Estimated New Cancer Cases* in the US in 2013

Selected Controversies • Lung Cancer – Does screening work? – Chest X-Ray? – Low dose CT? • Prostate Cancer – Should we screen?

Page 1

USPSTF

USPSTF Grades Grade

• Rigorous review of existing peer‐ reviewed evidence – Ratings reflect the strength of the  evidence on the harms and benefits of  a preventive service • Task Force does not consider the costs of  providing service or make recommendations  for coverage

Breast Cancer Screening

Evidence

Recommendation

A

High certainty of substantial net benefit

Provide

B

High certainty of moderate net benefit Moderate certainty of moderate/substantial net benefit

Provide

C

Moderate certainty that net benefit is small

Selectively offer/provide

D

No net benefit or harms outweigh benefits

Do not provide

I

Insufficient evidence regarding balance of benefits and harms

Harms Of Screening • False positives

• Breast cancer is the most common cancer in women and the second leading cause of cancer death

– Anxiety – Additional tests including biopsies – One-third of total screening cost

• Over-diagnosis

• Screening mammography reduces mortality from breast cancer

– Cancers diagnosed that never would cause symptoms: patients receive all the costs and harms of treatment – Estimates: 10% to 26% of invasive breast cancers and 34% of all breast cancers

• Younger women have lower breast cancer risk • Increased density of pre-menopausal breast tissue leads to decreased sensitivity

• Radiation exposure – One breast cancer for 3000 women screened annually for 10 years

Jorgensen, BMJ, 2009

Page 2

Case

Screening Mammography and Mortality

• Stella Skeptic is a 58 year old woman who doesn’t believe in “conventional medicine.” She has previously declined all your preventive recommendations, including screening mammography and CRC screening. She comes in today wanting to know what you think about ‘that new study” that shows that mammography really doesn’t work that well after all.”

• Screening should lead to diagnosis of earlier stage cancers • Early treatment of these detected cancers should lead to more benefit then treatment given at time of clinical presentation • Effective screening programs should lead to a reduction in the diagnosis of late stage cancers

The News

Methods

• Effect of three decades of screening mammography on breast cancer incidence –Bleyer and Welch, NEJM 2012

• SEER data (1976 to 2008) to evaluate trends in incidence of early stage breast cancer (DCIS and localized disease) and late stage breast cancer (regional and distant disease) among women aged 40 and over

• Aim: To quantify the expected increase in the incidence of early stage breast cancer and to determine the extent to which this has led to a corresponding decrease in the incidence of late stage cancer

• NHIS data on proportion of women undergoing screening mammography • Estimates adjusted for transient increase associated with hormone therapy use from 1990-2005

Page 3

Results • Screening mammography associated with a doubling in the number of cases of early stage breast cancer found annually – 112 to 234 cases/100,000 women • Rate of presentation with late stage breast cancer has decreased by 8% – 102 to 94 cases per 100,000 women • Assuming constant underlying disease burden, 8 of the additional 122 cancers detected expected to progress to advanced disease

Take Home Message

Results: Over-diagnosis

• Screening mammography has led to a substantial increase in the diagnosis of early stage breast cancers, with only a small reduction in the rate of late stage breast cancer

• Over-diagnosis: tumors detected by screening that would never have led to clinical symptoms • Adjusting for trends in breast cancer incidence, estimate for over-diagnosis –In 2008 over 70,000 women (31% of all breast cancers diagnosed)

• The reduction in mortality from screening appears to be smaller and the risk of overdiagnosis higher, than previously believed.

Page 4

Age and Mammography

USPSTF Guidelines Mammography

Meta-analysis: Nelson et al Ann Intern Med. 2009;151:727-737.

• Age 50-74: screening mammography every 2 years • Age 40-49: individualize decision to begin biennial screening according to patient’s context and values • Age ≥75: no recommendation (insufficient evidence)

Breast Exam • Clinical breast examination alone – insufficient evidence • Recommend against teaching women to perform routine breast self-examination – No mortality benefit – Higher rates of benign breast biopsies » USPSTF , 2009

Mammography and Age

Frequency of Mammography • Similar reduction in mortality with screening every one or two years

“Mammography screening at any age is a tradeoff of a continuum of benefits

• Every two years (compared to annually) maximizes benefits of screening & minimizing harms

and harms. The ages at which this tradeoff becomes acceptable to individuals and society are not clearly resolved by the available evidence.” USPSTF 19

20

Page 5

Mandelblatt, Annals IM, 2009

ACS Recommendations: Average Risk Women

Probability of False Positives

• Begin mammography at age 40

• Cohort study of 169.456 women who underwent first screening at age 40-59 and 4,492 women with incident invasive breast cancer

• Clinical breast exam – At least every three years for women in their 20s and 30s – Annually for women age 40 and over

• Women should be informed about the benefits and limitations of breast self examination (BSE)

• After 10 years, over half of women will have at least one false positive recall and 7-9% will have false positive biopsy recommendation

– Prompt reporting of any breast symptoms – Technique may reviewed, but it is acceptable not to do it

– Biennial screening decreases cumulative probability of false positives but may be associated with a small absolute increase in probability of late stage cancer diagnosis »

• Women should become informed about benefits, limitations and potential harms of routine screening

Hubbard, Annals Int Med, 2011

Newer Technologies

Digital mammography • Higher sensitivity, same specificity in women < 50 years old

• Digital Mammography

– Sensitivity 82% versus 76% film – Specificity 88%

• Breast MRI

• Cancer detection rates overall similar between film and digital mammography

• Ultrasound and Mammography

• Test characteristics better for women aged 40-49, dense breasts and estrogen receptor negative tumors » Kerlikowske, Ann Intern Med, 2011

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Mammography plus Ultrasound

MRI Screening

• Screening ultrasound may detect small cancers not seen on mammography

• Does MRI have a role for screening in high risk women?

• 2809 high risk women underwent mammography and ultrasound

– MRI is a very sensitive method of breast imaging and has been used as a diagnostic tool in women with breast cancer

• Mammography alone compared to mammography plus ultrasound

– Not influenced by breast density

• Adding an ultrasound will find 1.1 to 7.2 more cancers per 1,000 but with a significant increase in false positives

– Specificity is variable – Expensive

• Berg et al JAMA 2008

Mammography plus Annual Ultrasound or Single MRI

Impact For Clinical Practice

• 2,809 high risk women with dense breasts – Annual ultrasound and mammography for 3 years

• MRI may be useful in screening high risk women

– 612 of 703 women who had MRI had complete data • Adding MRI will find 14.7 more cancers per 1,000 but with many false positives

• The effect of MRI screening on mortality is not known

• Number of screens to detect one cancer – Mammography – Supplemental U/S

127 234

– Adding MRI*

68

• MRI is not currently recommended for screening average risk women

– *After mammogram and ultrasound negative – Berg, JAMA 2011

• Ultrasound adds little to mammography

Page 7

Bottom line • 40-49 informed consent

Lung Cancer Screening

• 50-74 screen every 2 years • 75+ informed consent - don’t if life expectancy less than 10 years • Don’t promote SBE • Digital mammography for women < 50 • BRCA equivalent: MRI

Lung Cancer Screening: Systematic Review of Chest X-rays

Question? • Mr. Nico Teen is a 69 year old man with a 50 packyear history of smoking and COPD. You have previously been unsuccessful in encouraging him to quit smoking. He comes in for a check-up, is worried about developing lung cancer and wants to know what test you think he should have. What do you recommend?

• 7 trials of lung cancer screening • Frequent screening with chest x-rays was associated with an increase in mortality – RR 1.11 (95% C.I. 1.00-1.23)

• No difference in chest X-ray plus cytology versus chest X-ray alone

– Chest X ray – Sputum cytology – Spiral CT – None of these tests

Manser, Thorax, 2003

Page 8

PLCO: Lung Cancer Screening

Low Dose Spiral Computed Tomography • Scans lung in < 20 seconds (single breath)

• PCLO randomly assigned 154,901 adults  aged 55 through 74 to annual CXR for 4  years vs. usual care 

• No IV contrast • More radiation exposure than CXR but less than conventional CT

• Followed for 13 years

• Can detect much smaller lesions than chest X-ray

• Cumulative lung cancer mortality  – 14.0/10,000 py screening group vs.  14.2/10,000 py control group – Rate ratio: 0.99 (95% CI 0.87‐1.22) Oken MM. JAMA 2011;306:1865

The National Lung Screening Trial (NLST)

Number needed to invite to screen

53,454 participants randomized to CT or CXR

• NNI to prevent one lung cancer death in 6.5 years = 320

- Current or former heavy smokers: ≥ 30 pack-years - Ages 55 to 74

• NNI to prevent one death from any cause in 6.5 years = 218

- Annual CT scans x 3 years. 6.5 years follow-up LDCT ∆

CXR RR (95% CI)

Lung Cancer Deaths

356 87

443 .80 (.73-.93)

Any death

1877 121

2000 .93 (.86-.98)

Page 9

Balanced by…

NLST Harms

• 75,000 CT scans • 18,146 positive tests

• False positives – At least 1 positive test in 39% CT

• 17,066 false positive tests

• Possible over diagnosis

• False positive results in 96% CT

• 673 thoracotomy / mediastinoscopy

– Higher cancer incidence with CT • 1060 vs. 941 cancers • Rate ratio 1.13 (95% CI 1.03‐1.23)

• 303 broncoscopies

• Radiation exposure

• 99 needle biopsies

• Incidental findings

• To prevent 62 deaths from lung cancer

Concern: Control = Chest x-ray • Screening with CXR was ineffective in 30,341  subjects in the PLCO meeting NSLT criteria – 30+ pack year, smoked within past 15 years – Cumulative lung cancer mortality was  36.1/10,000 py screening group vs.   38.3/10,000 py controls • Rate ratio: 0.94 (0.81‐1.10)

• Reasonable to conclude that CT screening is  more effective than usual care

Page 10

Health Policy not yet established

Guidelines and recommendations

• ~ 94 million current or former smokers in the U.S.

• Recommend for those meeting NLST entry criteria at specialized centers –ACCP / ASCP / ATS –ACS –ALA –NCCN –AATS

• ~ 7 million meet NLST criteria • Implementation issues –Multidisciplinary teams –Trained radiologist

• Expensive… $ $ $

The NLST Setting

Guidelines and recommendations

• 76% of sites were NCI designated cancer centers

• USPSTF recommendations – Screening: “I” insufficient evidence  (2004)

• 82% were large academic medical centers • All likely to have specialized thoracic radiologists and board certified thoracic surgeons on site

– Smoking cessation counseling: “A” (2009) • 85% of cancers among smokers attributed to  smoking

• CT scanners extensive quality control • Nodule management algorithm but not mandated

Page 11

Primary Prevention Of Lung Cancer

Implications

• Smoking cessation

• Smoking cessation

• Smoking cessation

• Strict adherence to NLST entry criteria

• Smoking cessation • Smoking cessation

– 55-74 years, 30+ pack years

• Smoking cessation

• Use experienced centers / demonstration projects to ensure quality and effectiveness

• Smoking cessation • Smoking cessation!!!!!

Question • What do you most commonly recommend for colorectal cancer screening?

Colorectal Cancer

– Fecal occult blood test (FOBT) – Sigmoidoscopy – Colonoscopy – Air contrast barium enema – Virtual Colonoscopy – Fecal DNA – Fecal immunochemical Test (FIT)

Page 12

Joint Guideline: ACS, ACR,…

Joint Guideline Recommendation

• FOBT annually • Clinicians should make patients aware of the full range of screening options

• Fecal immunochemical test annually • Flexible sigmoidoscopy every 5 years

• Offer patients a choice between a screening test that is effective at both early cancer detection and cancer prevention through the detection and removal of polyps and a test that is primarily effective at cancer detection

• DCBE every 5 years • CT colonography every 5 years • Colonoscopy every 10 years • Stool DNA testing (interval uncertain)

• CRC prevention should be the primary goal of screening

Levin, Gastroenterology, 2008

USPSTF

USPSTF (continued)

• USPSTF: “A” recommendation (2008)

• USPSTF: “A” recommendation (2008)

– Routine screening from age 50 until 75

– Acceptable modalities 

• Individualized decisions from 76 to 85 • No screening after 85

• Colonoscopy • Fecal blood test – Fecal immunochemical test, high‐sensitivity  hemoccult

• Flexible sigmoidoscopy

– Insufficient evidence for CT  colonography, fecal DNA USPSTF Annals IM 2008

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USPSTF Annals IM 2008

Colonoscopy

Colonoscopy: RCTs in progress • VA

• American College of Gastroenterology  guidelines for colorectal cancer  screening 

– Colonoscopy versus fecal immunochemical test  in reducing mortality from colorectal cancer

• Spain

(Rex DK. Am J Gastroenterol 2009;104:739)

– Colorectal cancer screening in average‐risk  population: immunochemical fecal occult blood  testing versus colonoscopy

– Colonoscopy… remains the preferred  CRC screening strategy

• Netherlands – Colonoscopy or colonography for screening

Sigmoidoscopy: New Evidence

Flexible Sigmoidoscopy

• PLCO Trial

• Reduced CRC incidence

• 154,890 average risk men and women aged 55-74 assigned to screening with FS with repeat at 3-5 years vs usual care

– Relative risk: 0.79 (95% CI 0.72‐0.85) – Absolute risk reduction: 3.3/10,000  person years

• 11.9 year follow up

• Number needed to invite to screening (NNI):  285 (95% CI 210‐427)

• Outcomes: CRC incidence and mortality – Schoen et al NEJM 2012

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Flexible Sigmoidoscopy

Flexible Sigmoidoscopy

• Reduced CRC mortality

• United Kingdom study showed one‐time  flex sig reduced CRC incidence by 23%  and mortality by 31% (Atkin WS. Lancet 

– Relative risk: 0.74 (95% CI 0.63‐0.87) – Absolute risk reduction: 1.0/10,000  person years

2010;375:1624)

• Fewer primary care physicians now  recommend flex  sig (Klabunde CN. Am J Prev Med 

• NNI: 871 (95% CI 567‐1874)

– Mortality reduction limited to distal  cancers

2009;37:8)

– 78% (2000) to 26% (2007)

Flexible Sigmoidoscopy

Newer Tests • Virtual Colonoscopy

• United Kingdom study showed one‐time  flex sig reduced CRC incidence by 23%  and mortality by 31% (Atkin WS. Lancet 

• Stool-based molecular testing – Fecal DNA

2010;375:1624)

• Fecal immunochemical tests

• Fewer primary care physicians now  recommend flex  sig (Klabunde CN. Am J Prev Med  2009;37:8)

– 78% (2000) to 26% (2007) – Colonoscopy recommendations  increased from 38% to 95%

Page 15

Computed Tomographic Colonography (Virtual Colonoscopy)

Laxative-Free CT Colonography

• Non-invasive radiological technique

• Low fiber diet, orally ingested contrast material and specialized processing software “electronic cleansing”

– Radiation dose similar to barium enema

• Bowel preparation similar to colonoscopy

• 605 adults underwent CTC and OC

– Prep-less technique is being evaluated

• CTC was more accurate in detecting adenomas 10 mm or larger and less so for smaller lesions

• Does not require sedation • Colon distended with carbon dioxide or air

– 91% sensiivity vs 70% for adenoma 8 mm or larger

• Breath holding for 20-50 seconds • Colonoscopy to remove polyps

• Patients preferred it » Zalis, Ann Intern Med, 2012

Potential Harms

Extra-colonic Findings • Extra-colonic findings common: 27 – 69%

• Radiation Exposure

• “High” clinical significance require surgical or medical treatment or intervention or further investigation

– 1/1000 could develop solid cancer or leukemia

• Procedure related harms

– 5 - 11%

– Perforation rate low

• 7-16% of individuals need additional evaluation for extra-colonic findings, but very few abnormalities ultimately required definitive treatment

• Extra-colonic findings

Page 16

Fecal DNA Testing

Fecal DNA Testing • Screening test in multi-center study

• PCR test for DNA mutations in the stool

• Fecal DNA test (23 mutations), FOBT, and colonoscopy

• Potential advantages – Non-invasive

• 4482 average risk adults

– No preparation

• Fecal DNA detects more neoplasms than FOBT, but with more false positive results

– Detection along entire length of the colon

• Expensive: $400 to $800 versus $3 to $40 for FOBT

Ahlquist, 2008

Fecal Immunochemical Testing (FIT)

Fecal Immunochemical Testing

• Uses labeled antibodies that attach to antigens of any human globin present in the stool

• FIT is more sensitive in detecting CRC and large adenomas (>1 cm) than FOBT

• Globin does not survive passage of the upper GI tract

• FIT is a little less specific than FOBT

• No dietary restrictions (easier than FOBT)

Page 17

Colorectal Cancer Screening

Screening Outcomes

• Randomized screening trial in Spain of  biennial FIT vs. one‐time colonoscopy  53,302 subjects ages 50 to 69  • Primary outcome is CRC mortality after  10 years • Interim report on participation rates and   diagnostic findings • (Quintero E. NEJM 2012;366:697) Quintero E. NEJM 2012;366:697

Colorectal Cancer Screening: Choices

Screening Completion

• Randomized trial offering colonoscopy,  FOBT, or choice of colonoscopy/FOBT • 997 subjects ages 50 to 79 • 12‐month follow up • (Inadomi JM. Arch Intern Med 2012;172:575)

• Recommending only  colonoscopy led to  lower adherence  Inadomi JM. Arch Intern Med 2012;172:575

Page 18

How Are We Doing? Year

FOBT in past year

2002

54%

2004

57%

2006

61%

2008

64%

Colorectal Cancer Screening: Conclusions • Any screening is better than no screening for reducing colorectal cancer mortality

or ever scope in 10?

• Increase awareness of the importance of colorectal cancer screening • Virtual colonoscopy and fecal DNA testing are included as options in the new joint guidelines but not in USPSTF guidelines

Rim, MMWR, 2011

Implications for Practice

Implications for Practice

 Offer screening

• Recognize importance of patient  preferences

 Testing modalities  Fecal immunochemical tests more acceptable and accurate than Hemoccult II  Flex sig no longer routinely performed  Colonoscopy RCT ongoing  CT colonography not reimbursed by Medicare

– “The best test is the one that gets  done” • Positive fecal blood tests must be  evaluated with diagnostic colonoscopy

Page 19

Prostate Cancer: Should We Screen?

QUESTION

• Disease has high prevalence – 10% lifetime risk – 30% of men have prostate cancer at autopsy

• What is your usual practice for PSA screening for men aged 50-70?

• Disease has serious consequences – Sometimes but may be a benign disease for many men

–Usually order PSA –Sometimes order PSA –Rarely order PSA –Never order PSA

• Detectable preclinical phase- ?? PSA • Treatment for preclinical disease is more effective? – Complications of prostate cancer treatment • 8.4% incontinence • 60% impotence » Prostate Cancer Outcomes Study 24 month follow up Screening • Screening reduces cancer mortality?

SCREENING TESTS: PSA

PLCO Cancer Screening Trial

• PSA testing has increased dramatically since 1988

• 76,693 men randomized to annual PSA for 6 years plus rectal examination for four years vs usual care

• Observational studies have had conflicting findings about the benefits of screening

• High rates of screening in the control group • No significant difference in death between the two groups at 7 year follow-up – 2.0 deaths per 10,000 person years in the screening group – 1.7 deaths per 10,000 person years in the controls

• Two large randomized controlled trials of PSA screening and mortality

• Similar results after 10 years – Andriole, NEJM 2009

Page 20

European Randomized Study of Screening for Prostate Cancer (ERSPC)

PSA SCREENING: CONCLUSIONS

• 182,160 men aged 50-74 in eight European countries

• PSA screening may lead to a modest reduction in mortality

• PSA screening at least once every four years vs no screening • During 9 year follow up, incidence was higher in the screened group – 8.2% vs 4.8%

• To achieve this mortality reduction, there is a substantial amount of over-diagnosis and over-treatment

• Mortality lower in the screened group – 7 fewer prostate cancers per 10,000 screened men • To prevent one prostate cancer death at 11 year follow up – 1,410 men needed to be screened – 48 additional prostate cancers treated – Schroder NEJM 2009; Schroder NEJM 2012

American Cancer Society

USPSTF RECOMMENDATIONS 2012 • Recommends against PSA based screening for prostate cancer

• Men with at least a 10 year life expectancy should have an opportunity to make an informed decision with their health care provider about whether to be screened

– PSA can detect early prostate cancer, but inconclusive evidence about whether early detection improves health outcomes. – Harms include frequent false positives and unnecessary anxiety, biopsies and potential complications of treatment of some cases of cancer that may never have affected a patient’s health. – Grade “D” recommendation

• Screening should not occur without an informed decision making process • Men at average risk should receive the information beginning at age 50 • Information should be provided at age 45 for men at higher risk – Age 40 for very high risk

– USPSTF 2012

• American Cancer Society, 2010

Page 21

American Cancer Society

American Cancer Society

• For men unable to decide, the decision can be left to the discretion of the health care provider

• For those who choose to be screened – PSA with or without DRE – Screening yearly for men whose PSA is 2.5 ng/ml or greater – If PSA <2.5 ng/ml, screening can be extended to every 2 years – PSA of 4.0 ng/ml or greater- referral – PSA of 2.5-4.0 ng/ml individualized risk assessment

• Men with less than a 10 year life expectancy should not be offered screening – At age 75, only half of men have a life expectancy of 10 years or more • Men without access to regular care should be tested only if high quality informed decision making is available through community based programs – Follow-up and counseling

• Age, African American, family history, previous negative biopsy

• ACS 2010

» ACS, 2010

American Urological Association Guidelines • May, 2012 News Release “AUA outraged at USPSTF’s failure to amend guidelines”

ACP Guidance Statement • Derived from an appraisal of available guidelines

• Men who choose to be screened should have both DRE and PSA

– ACPM, ACS, AUA, USPSTF

• The decision to use PSA testing should be individualized – Inform men of the potential benefits and risks

• Inform men aged 50-69 about limited potential benefits and substantial harms of screening for PSA

• Early detection and risk assessment for prostate cancer should be offered to all men aged 40 and older who wish to be screened and who have an estimated life expectancy of more than 10 years – American Urological Association, 2009

– Base decision on risk for prostate CA, discussion of benefits and harms, health and life expectancy and preferences – Do not screen in those who do not have a clear preference for screening

Page 22

ACP Guidance Statement

Prostate Cancer Screening: Summary

• Do not screen average risk men under age 50, over age 69 or with a life expectancy of less than 10-15 years

• PSA testing may reduce prostate cancer mortality but is not recommended by USPSTF • Risks of early detection and treatment • Shared decision making is key

Summary Of Recommendations

Summary Of Recommendations

• Women aged 50 to 74 should undergo mammography every 2 years

• Screening for lung cancer with low-dose CT reduces mortality

• Screening decisions for women in their forties and for women and for women aged 75 and older should be individualized

– Policy recommendations are still evolving

• Screening for prostate cancer may reduce mortality but there are significant risks and harms to early detection and treatment

• MRI screening for breast cancer may be useful in high risk women • All men and women aged 50 -75 should be screened for colorectal cancer – Any screening is better than no screening

Page 23

Thank you!

Questions?

Page 24

CURRENT STRATEGIES IN HYPERTENSION

Current Strategies in Hypertension: Getting Ready for JNC 8 Robert B. Baron MD Professor of Medicine Associate Dean for GME and CME

Declaration of full disclosure: No conflict of interest

Current Status of Hypertension • Prevalence 29%; Blacks 33.5% • About 72.5% treated; 53.5% uncontrolled (>140/90) • Risk for poor control: Latinos, Blacks, age 1844 and ≥80, <300% poverty, < college degree more uncontrolled BPBP control • Better control: Any insurance, ≥2 visits, and a usual source of care

Summary of Presentation • Update on recent studies • JNC 7 Review • Role of Lifestyle Change • Medication Choice • Recommendations

Hypertension Control by Cardiovascular Disease and Risk: NHANES, 2003-04 Condition Controlled

%HTN

%Rx

% Not

Average Risk

34

66

Diabetes

85

96

35 54

Chronic Kidney Disease 83

95

53

CHF

86

98

50

Cardiovascular Dis

85

95

51

Framingham Score ≥10

77

68

59

MMWR 2012;61: 703-709 Bertoia ML, Hypertension 2011

CURRENT STRATEGIES IN HYPERTENSION

Co-morbid Conditions and Hypertension Management • Clinicians are being “graded” for level of BP control • 140/90 held as standard • In primary care visit, other factors intervene with “control” • Retrospective cohort of 15,459 patients with uncontrolled HTN with 200 clinicians • 6 sites through EMR • Effect of 28 conditions on intensification

Co-morbid Conditions and Hypertension Control • Average of 2.2 unrelated conditions • Intensification of treatment decreased with number of conditions from OR = 0.85 for one to OR = 0.59 for 7 or more • Findings persisted at visit, clinician and patient levels • Quality of care measures need to consider co-morbid conditions Ann Internal Medicine 2008; 148: 578-586

Hypertension in the Very Elderly Trial (HYVET)

Hypertension Treatment after 80 y • No clinical trial showing clear benefit • Meta-analysis of 7 RCT, 1670 patients, 75% women showed a 3.3% absolute reduction in stroke (NNT = 30) and 2.1% reduction in CHF (NNT = 48) • Borderline trend to increase deaths from any cause in treated group • Observational data showed risk of death inversely related to BP level

• • • • • • •

3845 patients ≥ 80 y >160 mm Hg – goal of 150/80 mm Hg Indapamide SR 1.5 mg vs. placebo Added perindopril if needed Follow up of 2 years 60% women, age 83.6 y, BP = 173/91 12% with CV disease, 7% diabetes, 64% already treated for hypertension Beckett NS, NEJM 2008; 358: 1887-1898

CURRENT STRATEGIES IN HYPERTENSION

HYVET Study Results Beckett NS, NEJM 2008; 358: 1887-1898

Conclusions and Implications: Always Offer Treatment

End Point Meds

Placebo HR (95% CI)

• Benefits appear at 1 year of Rx

Stroke

17.7

0.64 (0.46 -0.95)

• NNT = 20 to prevent one stroke

CVA Death 6.5

10.7

0.55 (0.33 -0.93)

• NNT = 10 to prevent one CHF

CHF

5.3

14.8

0.28 (0.17 -0.48)

CV Death

23.9

30.7

0.73 (0.55 -0.97)

Any Death 47.2

59.6

0.72 (0.59-0.88)

12.4

SBP and Risk of Recurrent Stroke • 20,330 patients ≥50 y with CVA < 120 day followed for 2.5 years, 695 centers • Outcome: recurrent stroke any type • Predictors: SBP in mm Hg <120 8.0% 120-<130 7.2% 130 -<140 6.8% Optimal SBP 140 - <150 8.7% ≥150 14.1% Ovbiagele B, JAMA 2011; 306: 2137-44

• Not a specific drug effect • Never too old to treat SBP > 160 • Goal does not have to be < 140

Treatment Based on What Blood Pressure Measurement? • Home BP measurement leads to less intensive drug Rx & BP control • Identifies “white-coat” HTN • Ambulatory monitor measures – higher correlation with CVD • Office clinician measures are standard, used in trials, one point • Automated Office BP monitors may lead to more standard measures

CURRENT STRATEGIES IN HYPERTENSION

Clinic, Home and Ambulatory BP in Diagnosis of Hypertension • Systematic review comparing measures in initial diagnosis • 20 studies with 5683 patients, compared to ambulatory monitor daytime mean ≥135/85 Measure

Definition Sensitivity Specificity

Home

135/85 mean

85.7% 62.4% +LR = 2.28 –LR= 0.23

Clinic

140/90 mean

74.6% 74.6% +LR = 2.94 +LR = 0.34

Number of BP Measurements to Influence Decisions • Compare Home, Clinic and research BP measurements in VAMC setting • 444 patients, 92% men, inadequate control • Only 33% consistently categorized as being out of control • Clinic > Home > Research measures • Within patient Variance reduced by doing more –– plateau at 5-6 measures • Rarely should a decision to initiate or change treatment be based on one reading

Powers BJ, et al. Ann Intern Med 2011; 154: 781-788

Hodgkinson J, et al. BMJ 2011: 342: d3621

JNC 7 Classification of Blood Pressure Normal

and

<80

Pre-hypertension 120-139

<120

or

80-89

Hypertension Stage 1 Stage 2

or or

90-99 ≥100

140-159 ≥160

Risk of CVD doubles with each increment of 20/10 mm Hg – SBP more important risk factor

When to Treat Hypertension Lifestyle advice for all Initial lifestyle for stage 1 HTN Drug treatment for all with SBP > 160 Drug treatment for all with CV comorbidity and SBP > 140 or DBP > 90 • Drug treatment for all with DBP > 100 • If lifestyle fails, drugs for DBP > 90 • If lifestyle fails, drugs for SBP >140 • • • •

CURRENT STRATEGIES IN HYPERTENSION

Individual Lifestyle Modifications for Hypertension Control • Weight loss if overweight: 5-20 mm Hg/10-kg weight loss • Limit alcohol to ≤ 1 oz/day: 2-4 mm Hg • Reduce sodium intake to ≤100 meq/d (2.4 g Na): 2-8 mm Hg in SBP • DASH Diet: 6 mm alone; 14 mm plus Na • Physical activity 30 min/day: 4-9 mm Hg • Habitual caffeine consumption not associated with risk of HTN

Where is the salt? 80% in processed or pre‐ prepared foods

Sources: Mattes et al.

Salt and Public Policy • Coronary Heart Disease Policy Model to quantify benefits of 3 g salt/day reduction in US– average is 8-10 g/d • Benefit through a reduction in SBP from 19 mm Hg in selected populations • New cases of CHD decrease by 4.7 - 8.3 and stroke by 2.4 to 3.9 /10,000 • Regulatory change leads to wide benefit and is cost-effective Bibbins-Domingo K, et al. NEJM 2010

CURRENT STRATEGIES IN HYPERTENSION

Sources of salt in our grocery bags • 35% from cereal and cereal products 

Initial Drug Treatment of Hypertension Initial Drug Choices

– breads, cereals, pastries • 26% from meat & meat products • 8% from milk & milk products

Stage 1: Thiazides for most Stage 2: 2-drug combination for most – thiazides plus -blockers, ACE-I, ARB, CCB

– milk, cheese Based on randomized controlled trials

60 Year Old Man, BP=160/96; Which treatment first? 1) Thiazide diuretic 12.5 or 25 mg 2) Beta blocker of choice 3) Ace Inhibitor or ARB 4) Calcium Channel Blocker 5) Alpha-blocker 6) Intensify lifestyle

60 Year Old woman, BP=160/96, with diabetes? 1) Thiazide diuretic 12.5 or 25 mg 2) Beta blocker of choice 3) Ace Inhibitor or ARB 4) Calcium Channel Blocker 5) ACE/ARB plus Diuretic 6) ACE/ARB plus CCB

CURRENT STRATEGIES IN HYPERTENSION

Possible JNC 8 Recommendations

Compelling Indications for Drug Selection in Hypertension

• Medication choice menu: Thiazides, Ace Inhibitor or Ace Receptor Blocker, Calcium Channel Blocker • Beta blockers restricted to <60 years • Use urinary albumin to identify patients with diabetes and CKD for ACE/ARB Rx • Combination of ACE + CCB preferred over ACE + HCTZ in persons at highest risk • Coordinate with pharmacists to enhance adherence

• Low EF Heart Failure: Beta B, ACE-I or ARB, and aldosterone antagonist • Post ant MI: Beta Blocker, ACE-I • CAD Risk: BB or just lower SBP • Diabetes with proteinuria: ACE-I, ARB • Renal Disease: ACE-I, ARB • Recurrent stroke prevention: thiazide, ACE-I

NICE Guidance: Management of Hypertension • Guideline development in the UK • If BP 140/90, use amb monitor to confirm • Estimate CV risk, evaluate for target organ effects such as LVH, CKD, retinopathy • Treat stage 1 with meds only if target organ damage, known CVD, diabetes, 10year CV risk ≥ 20% • Offer meds to all at any age with stage 2 (>155/95) independent of other effects Krause T, et al, BMJ 2011; 343:d4891

Aged under 55 years

Aged over 55 years or  black person of African  or Caribbean family  origin of any age 

CCB

A – ACE/AR B

Summary of  antihypertensive  drug treatment Step 1

ACE/ARB + CCB

Step 2

ACE/ARB + CCB +  Thiazide

Step 3

Resistant hypertension

Step 4

A + C + D + consider further diuretic3, 4 or  alpha‐ or  beta‐blocker5 Consider seeking expert advice

CURRENT STRATEGIES IN HYPERTENSION

Chlorthalidone vs. HCTZ

Thiazide Diuretics Very effective for systolic BP Do not increase sudden death Most effective in LVH regression Lipid effects are short lasting (1 y) Hyperglycemia only in high doses Still effective in early chronic kidney disease (to GFR 40-45) • Erectile dysfunction in 20% • More effective in Blacks and older • • • • • •

Chlorthalidone Treatment in Systolic Hypertension

• • • •

Return of MRFIT 6441 men treated with either drug, 35-57 yrs, 88% White, primary prev Both drugs reduced CV events: CTD hazard ratio = 0.51 and for HCTZ, HR = 0.65 with overlapping CI CTD had fewer events in comparison to HCTZ; HR = 0.79 (0.68-0.92) Higher doses CTD and more potent drug at equivalent mg Dorsch MP et al, Hypertension 2011; 57: 689-694

Efficacy of HCTZ by Ambulatory Monitoring Messerli FH, et al, JACC 2011; 57: 590-600 Medication Class

• 2365 treated with CTD and 2371 with placebo in 4.5 y RCT • Outcomes determined at 22 years with national death index • CV Death reduced by 11%, but no difference in all-cause mortality • One month of treatment = 1 day life extension Kostis JB, et al, JAMA 2011; 306: 2588-93

Decrease in mm Hg

HCTZ 12.5 -25 mg HCTZ 50 mg ACE-I

6.5/4.5 12.0/5.4 12.9/7.7

ARB

13.3/7.8

CCB Beta Blockers

11.0/8.1 11.2/8.5

CURRENT STRATEGIES IN HYPERTENSION

Atenolol in hypertension: is it a wise choice?

Beta Blockers • More effective as mono-therapy in younger persons and Whites • Adverse effects limited: Do not cause depression or sexual dysfunction • Glucose elevation with A1C increase by 0.2% –– less with carvedilol • No lasting effect on lipids • Compelling evidence to use in CAD and systolic HF to decrease mortality • Less efficacy in stroke prevention among those older than 60 years

ACE–I or ARB • 30% reduction of ESRD (dialysis) and of doubling of serum creatinine; optimal with GFR 30-60, proteinuria • Not better tolerated than other drugs • Regression of LVH not more than other drugs–SBP reduction • Elevates K+ • Do not use in women < 50 y • Works less well in Blacks as 1 drug • Best choice in diabetes? • Infrequent need to combine

Bo Carlberg. LANCET 2004, Vol 364

No benefit to prevent MI or All‐cause mortality

Valsartan for Prevention of DM and CV Events in Patients with Pre-Diabetes • 9306 patients, 50% women, with pre-DM and CV risk factors or disease • Valsartan 160 mg or placebo plus lifestyle • Follow for 5 years, outcomes are new diabetes and CV events • Diabetes: 33.1% vs. 36.8% (HR= 0.86; 0.800.92) • No benefit on CV outcomes: 14.5% vs. 14.8% • DREAM Trial showed no benefit (ramipril) The Navigator Study Group. NEJM 2010; 362: 1477-1490

CURRENT STRATEGIES IN HYPERTENSION

Benazepril for CKD: Is it Ever Too Late to Try? • 442 patients randomized to benazepril or placebo and followed for 3.4 years • Creatinine 1.5 to 3: benazepril 20 mg (1) • Creatinine 3.1 to 5: benazepril vs. placebo • Outcomes: ESRD, 2X creatinine or death • 22% in group 1; 41% in group 2 on ACE vs. 60% on placebo • Similar AE; not mediated by SBP

Calcium Channel Blockers Effective in Blacks and elderly • Effective in preventing CV events • Do not reverse atherosclerosis • No increase risk of cancer • Short acting CCB may be harmful • Effective in systolic hypertension • Better outcomes in latest trials



NEJM 2006; 131-140

ACCOMPLISH

ACCOMPLISH Results

Calcium Blockers combined with ACE • Comparison of combinations: ACE-I + hctz vs. ACE-I + amlodipine for htn • RCT, 11,506 patients, ≥ 65 y, 60% men, 83% White, 60% diabetes, BMI = 31 • Outcomes: CV death, MI, stroke, hospitalization for angina, resuscitation after cardiac arrest, CABG or PCI • Follow-up 36 months • Funded by Novartis: USA and 4 N Europe Jamerson K, NEJM 2008; 359:2417-28

Primary Outcomes

Benazepril + Amlodipine N=5744

Benazepril + HCTZ N=5762

Hazard Ratio (95% CI)

All Events

552 (9.6%)

679 (11.8%) 0.80 (0.72-0.90)

CV Death

107 (1.9%)

134 (2.3%)

0.80 (0.62-1.03)

All MI

125 (2.2%)

159 (2.8%)

0.78 (0.62-0.99)

All Strokes 112 (1.9%)

133 (2.3%)

0.84 (0.65-1.08)

Revasc procedure

386 (6.7%)

0.86 (0.74-1.00)

334 (5.8%)

CURRENT STRATEGIES IN HYPERTENSION

What About Other Drugs?

ACCOMPLISH Conclusions • Combination of CCB and ACE was superior to ACE/HCTZ • BP differences of 1 mm only • Different populations may matter • Chlorthalidone vs. HCTZ? • Recommendation to change practice in highest risk patients – ACE and CCB may have special benefits

Take Home Points 1 Risk of CVD is linear to SBP level 120-139/80-89 is “pre-hypertension” and merits lifestyle modifications in all and may need drug treatment with co-morbidity of DM, CAD, CKD Set goal SBP and treat with drugs at any age for SBP >160 Goal SBP level is relative, not fixed

Spironolactone CNS sympatholytics: Clonidine No reason to use methyldopa Alpha-1 blockers: OK but inferior as single drug and tachyphylaxis • Labetalol good 5th or 6th choice • Direct vasodilators - hydralazine or minoxidil - need more diuretics • Peripheral adrenergic antagonists

• • • •

Take Home Points 2 • Most patients will need two or more

drugs to achieve goal SBP • Thiazides, ACE-I, ARB, and CCB are similar–combinations in almost all • Co-morbid condition and age considerations in selecting meds • Control only occurs with motivated patients who trust their clinician

7/23/2013

Katherine Julian, MD Professor of Clinical Medicine, UCSF August 5, 2013

Vaccines Generally Available in the  U.S.           

Tetanus Diptheria Pertussis Measles Mumps Rubella Varicella Meningococcus Pneumococcus Human Papillomavirus Influenza

 Hepatitis B  Hepatitis A  Haemophilus influenzae      

type B Rotovirus Inactivated polio Rabies Typhoid Yellow fever Japanese encephalitis

Vaccines Generally Available in the  U.S.           

Tetanus Diptheria Pertussis Measles Mumps Rubella Varicella Meningococcus Pneumococcus Human Papillomavirus Influenza

 Hepatitis B  Hepatitis A  Haemophilus influenzae      

type B Rotovirus Inactivated polio Rabies Typhoid Yellow fever Japanese encephalitis

1

7/23/2013

Vaccines for Special Populations  Plague

Key Website Centers for Disease Control and Prevention

 Tularemia  Smallpox

http://www.cdc.gov/vaccines

 Anthrax  Botulism  Tuberculosis – BCG  Adenovirus

Case I  45 yo woman here for regular visit.  PMH:  Healthy   SH: smoker    Vaccine history:  “all the regular vaccines  as a child”, but last vaccine was given “as a teen”.  What  vaccines should be given now?  1) Td  2) Tdap  3) Pneumovax  4) #1 and #3  5) #2 and #3 MMWR. Feb 1, 2013

2

7/23/2013

Pertussis…Not Just for Kids  Annual cases of pertussis have increased   41,880 pertussis cases and 14 infant deaths in 2012  Post‐tussive emesis and inspiratory “whoop”=  increased LR of pertussis  Residual immunity from prior vaccination may modify  the clinical presentation  Among adults, prolonged cough may be the only  manifestation of pertussis  13‐32% of adolescents/adults with cough >6 days have  serologic evidence of infection with pertussis ACIP.  MMWR, 2013;62 Cornia PB, et al.  JAMA, 2010;304(8)

Pertussis Vaccine  In 1980’s, acellular vaccine created  Contains purified, detoxified pertussis antigens  Childhood DTaP:  diptheria toxoid, tetanus toxoid, and  acellular pertussis (full dose)  Adult/adolescent Td and Tdap:  tetanus toxoid (full  dose) and reduced dose diptheria toxoid +/‐ reduced  dose acellular pertussis antigens

Pertussis…Not Just for Kids  Adults may act as reservoirs of the disease to  vulnerable populations  Since 2004, approx 20 deaths/year with majority in  infants <2 months  Highly contagious to home contacts  Immunity for pertussis wanes in adults 

after childhood vaccination

Hewlett EL et al.  NEJM, 2005;35:12

Pertussis Vaccine – How Effective?  2781 subjects aged 15‐65 randomized to reduced dose  of acellular pertussis vaccine or hepatitis A placebo  Followed for 2.5 years  Based on primary pertussis definition (cough and  positive culture/PCR), vaccine 92% effective

 Adacel:  age 11‐64  Boostrix:  >10 years

Ward JL et al.  NEJM, 2005;353(13)

3

7/23/2013

Tdap Recommendations  Adults >19 years:  Tdap regardless of interval since last  tetanus (if never had Tdap)  For adolescents, give Tdap instead of Td at routine 11‐ 12 year visit    Contraindication:  encephalopathy without a known  cause < 7 days after previous pertussis vaccination,  Guillain‐Barré syndrome < 6 weeks after previous  tetanus vaccine.

Tdap Recommendations  Other  Recommended for all >65 yo 

Does not depend on contact with young children

 Both Adacel and Boostrix appear to be 

immunogenic 

If a choice, give Boostrix for now

Tdap Recommendations

Tdap Recommendations

 If pregnant woman

 Recommended for healthcare workers with patient 

 Administer Tdap during EACH pregnancy, 

preferably during between 27‐36 weeks  If not administered during pregnancy, Tdap should  be administered immediately postpartum  Adolescents and adults with close contact with an  infant aged <12 months should receive a single dose  of Tdap if they have not received Tdap previously

contact  No current recommendations for Tdap booster  aside from pregnant women  Give once – then back to Td  Look for more on this soon…

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Pneumococcus ‐ Background

Pneumococcus ‐ Background

 Colonizes the upper respiratory tract  Gram + diplococcus, polysaccharide capsule  Over 90 serotypes  U.S. annual incidence of pneumococcal bacteremia is 15‐ 30 cases/100,000  Causes 40,000 deaths annually in the U.S.  Mainly transmitted by direct contact with 

 Risk factors for invasive disease  Age >65 or <2 years  People with chronic illness, immunocompromised  Crowding, PPI’s  Antecedent respiratory infection and recent Abx  Smokers

respiratory secretions (ex: household)

Pneumovax Polysaccharide  Vaccine (PPSV23)  23 purified capsular polysaccharide antigens of S.  pneumoniae  Represent at least 85‐90% of the serotypes that cause  invasive  pneumococcal infections   Shorter Ab duration  Good evidence it decreases pneumococcal bactermia  Retrospective cohort 47K people >65 yrs; HR 0.56  Likely no effect on PNA

Pneumovax Polysaccharide Vaccine  PPSV23 ‐ Recommendations  Age >65  People > 2 years old** with chronic illness  Chronic cardiovascular disease  Chronic pulmonary disease including ASTHMA  Chronic liver disease, ETOH  Diabetes  Immunocompromising conditions  Smokers  People aged 2‐64 living in environments in which the risk 

for invasive pneumococcal disease is increased (no longer  American Indians or Alaskan natives)

Jackson LA.  NEJM, 2003;348:18.

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Revaccination with  Pneumococcal Polysaccharide  Vaccine (PPSV23)  One‐time vaccination after 5 years for 

immunosupression, asplenia, renal  failure/nephrotic syndrome, long‐term  corticosteroids  If at least 65 yrs, one‐time revaccination if  vaccinated >5 yrs prior and age less than 65 yrs at  the time of initial vaccination

Pneumococcal 13‐Valent  Conjugate Vaccine for Adults  (PCV13)  Conjugates the bacterial capsular polysaccharide to a  carrier protein.  Longer Ab duration.  FDA data comparing PPSV23 vs. PCV13  Ab titers for PCV13 equal or higher in adults 60‐64 yrs  Adults  50‐59yrs given PPSV23 first had lower antibody  titers when given PCV13 booster compared to those  given PCV13 for 2 doses  Similar result for PPSV23 vs. PCV7 in HIV+ patients ACIP.  MMWR, 2012; 61(40).

Pneumococcal 13‐Valent   Conjugate Vaccine (PCV13)‐ Recommendations  Age >19 AND  Immunocompromising conditions 

  

HIV, Chronic renal failure, nephrotic syndrome,  malignancy, transplant Functional or anatomic asplenia CSF leaks Cochlear implants

Pneumococcal Boosters – More  Complicated…  No history of pneumovax  If indication for PCV13:  give PCV13 first and then  PPSV23 booster 8 weeks later 

Then give PPSV23 booster 5 years later

 Previous vaccination with PPSV23 AND indication for  PCV13:  Give PCV13 dose at least 1 year after previous pneumovax  People >65 years with chronic illness should get  PPSV23 booster 5 years after first vaccine dose (if first  dose was given before they were 65).

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Pneumovax…Future Changes?  13‐valent conjugate vaccine in all adults?  Prevnar 13 approved by the FDA Dec 2011 (for 

adults >50 years) but not yet recommended by  ACIP aside from immunocompromised  Functional antibody responses higher than for  polysaccharide vaccine  Need data on clinical efficacy against S. Pneumo PNA  May be more cost‐effective depending on  effectiveness

Case I  45 yo woman here for regular visit.  PMH:  Healthy    SH:  smoker    Vaccine history:  “all the regular  vaccines as a child”, but last vaccine was given “as a  teen”.  What vaccines should be given now?  1) Td  2) Tdap  3) Pneumovax  4) #1 and #3  5) #2 and #3

Smith KJ et al.  JAMA, 2012;307(8)

Bonus Question to Case I  What type of pneumovax should she have? 1) Polysaccharide vaccine (PPSV23)? 2) Conjugate vaccine (PCV13)?

Case 2 63 yo woman  PMH:  htn, DM Meds:  HCTZ, metformin SH:  Married, non‐smoker What vaccine(s) does she need? Hepatitis B Varicella (zoster) Seasonal Influenza #2 and #3 All of the above

1) 2) 3) 4) 5)

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Varicella ‐ Background  After primary VZV infection (chickenpox), latent  infection is established in the sensory‐nerve ganglion  Decline in cell‐mediated immunity with age predisposes  to zoster  Zoster develops in 30% of people over a lifetime   Post‐herpetic neuralgia 13‐40%; directly

correlated with age

Zoster Vaccine  Originally licensed as the “chickenpox vaccine”  Live attenuated virus vaccine  Older adults need higher titer of live attenuated virus  to produce a durable increase in cell‐mediated  immunity  Zoster vaccine contains more plaque‐forming  units/dose than the chickenpox vaccine  Vaccine “boosts” older adults’ waning immunity to  prevent reactivation of varicella

Kimberlin DW, et al.  NEJM, 2007;356(13).

Varicella Zoster Vaccine…The  Evidence  Randomized, double‐blind, placebo‐controlled trial of  38,546 adults > 60 yrs  Zoster vaccine vs. placebo  Primary endpoint:  “burden of illness” due to zoster 

Incidence, severity of pain, duration of pain

 Secondary endpoint:  incidence of post‐herpetic 

neuralgia (pain >120 days)

Oxman MN et al.  NEJM, 2005;352(22)

Varicella Zoster Vaccine…The  Evidence  Results:  followed median 3.12 years   Incidence of zoster reduced by 51.3%  Incidence  of post herpetic neuralgia decreased by  66.5%  Burden of illness due to zoster decreased by 61.1%  Higher efficacy ages 60‐70  Newer study shows efficacious in 75K community  dwellers  6.4/1000 person‐years vs. 13/1000 (HR 0.45) Oxman MN et al.  NEJM, 2005;352(22) Tseng  HF et al.  JAMA, 2011;305(2)

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Varicella Zoster Vaccine

Varicella Zoster Vaccine ‐ Contraindications

 Licensed in March 2011 for adults > 50 years  Study presented at IDSA meeting  

22K adults 50‐59 years followed 1 year Zostavax vs. placebo decreased risk of zoster by 69.8%  (CI 54.1‐80.6)

 ACIP:  recommended for >60 years due to vaccine 

production shortages  No need to determine if immune to chickenpox

 h/o anaphylaxis to gelatin, neomycin  Immunodeficiency or immunosuppressive therapy  OK if healthy HIV patient with CD4>200

 Pregnant women (for varicella vaccine)  Pts with active (untreated) TB

Schmader et al, Clin Infect Dis 2012;54

Varicella Zoster Vaccine  Frozen for storage, administered immediately after  reconstitution  Cost of vaccine approx $150  Can now be given concurrently with pneumovax  Cost per quality‐adjusted life‐year ranges from $14,877  to $34,852.  Vaccinate 17 people to prevent 1 case of zoster 

Varicella Zoster Vaccine  Remaining questions  What happens in the future with childhood 

varicella vaccine?  What is the efficacy of the vaccine in people who 

have had zoster? 

New evidence Olmstead County of 1669 people with  h/o zoster showing risk for recurrent zoster ~1/160 

Cost $3,330 for each case of zoster prevented

 Vaccinate  31 to prevent 1 case of postherpetic neuralgia 

Cost $6,405 for each case of postherpetic neuralgia Kimberlin DW.  NEJM, 2007;356

Yawn BP, et al.  Mayo Clin Proc, 2011;86(2)

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7/23/2013

Seasonal Influenza Vaccine  Types of vaccines  Inactivated influenza vaccine (IIV) given by injection    

IIV3 (Trivalent) IIV4 (Quadrivalent – approved for 2013‐2014 season) High‐dose  Intradermal

Seasonal Influenza Vaccine  Indications  All people older than 6 

months  Unless there is a 

contraindication…

 Live attenuated influenza vaccine (LAIV) – FluMist 

Quadrivalent approved 2/12

Influenza Vaccine Strains for  2013‐2014 Flu Season  A/California/7/2009 (H1N1‐like)‐‐‐same  Virus antigenically like A/Victoria/361/2011 (H3N2‐ like)‐‐‐similar to last year  B/Massachustetts/2/2012‐like (new)  For quadrivalent vaccine—2 A strains and 2 B strains  B/Brisbane/60/2008‐like

Seasonal Influenza Vaccine  Inactivated influenza vaccine (IIV3)  Given IM  Approved for all > 6 months  Live attenuated influenza vaccine (LAIV) ‐ FluMist  Same strains as IIV  Intra‐nasal vaccine; cold‐adapted, temp sensitive  Runny nose, congestion, HA, wheezing  Approved in the U.S. for healthy 2‐49 year‐olds

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Intradermal Influenza Vaccine High Dose TIV Vaccine

 Fluzone intradermal vaccine approved by FDA in 

 12/09 FDA licensed Fluzone High‐Dose for >65 yrs  Contains 60µg of hemagglutinin per strain virus vs. 15 µg  in regular TIV  May enhance immune response compared to standard  dose (phase 3 trials)  More local reactions  No trials yet of prevention of influenza…

 Developed in hopes of conserving vaccine supply

May 2011  Needle is about one‐tenth of standard length  Contains 9 mcg hemagglutinin per strain versus 

standard 15 mcg  Dose is 0.1 mL versus standard 0.5 mL

 Approved ages 18 – 64 years  Local reactions are more common

Seasonal Influenza Vaccine… The Evidence

Who Should NOT Get the Live  Attenuated Influenza Vaccine?

 In children, several studies suggest better efficacy of  LAIV compared to TIV

 Outside recommended age ranges (<2yrs  or >49yrs)

 In adults, studies suggest better efficacy of TIV  RCT of 1952 healthy adults age 18‐49 during 2007‐2008  flu season  Absolute efficacy of the inactivated vaccine to prevent  influenza A was 73% (positive =culture)  Absolute efficacy of the live vaccine was 51%

 Chronic medical conditions including  asthma 



Too few cases to determine efficacy of influenza B

Monto AS, et al.  NEJM, 2009;361.

 Pregnant women  History of Guillain‐Barré  Egg allergy (only hives):  give IIV  Anaphylaxis to eggs:  refer to allergist  Highly immunosuppressed  Contact with highly immunosuppressed

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New Vaccines…

Hepatitis B Vaccine

 LAIV Quadrivalent vaccine (FluMist quadrivalent)

 Since 1996, 29 outbreaks of HBV infection in long‐ term care facilities  25 involved adults with DM receiving assisted blood  glucose monitoring  Diabetics 23‐59 yrs without hep B risk factors 2.1x odds  of developing hep B compared to non‐diabetics  10/11 ACIP recommended all unvaccinated adults 19‐59  yrs with DM be vaccinated for hep B (rec category A)

 IIV4 Quadrivalent vaccine (Fluarix quadrivalent)  Recombinant Influenza Vaccine Trivalent (RIV3) – FluBok  Not grown in eggs  Inactivated trivalent vaccine (IIV3) Flucelvax  Canine kidney cell culture derived and not grown in  eggs

Hepatitis B Vaccine  3 doses:  0, 1, 6 months  Less protective immunogenic response with age  Post‐vaccination serologic testing recommended 1‐2  months after last injection for:  Healthcare workers (at high exposure risk)  Patients on hemodialysis  HIV/immunocompromised  Others at high risk of exposure  If not immune…re‐vaccinate Estimated cost per QALY saved was $75,100 for persons  aged 20‐59 yrs but increases with age

 Unvaccinated adults >60 with DM may be vaccinated  at discretion of treating clinician

Case 2 63 yo woman  PMH:  htn, DM Meds:  HCTZ, metformin SH:  Married, non‐smoker What vaccine(s) does she need? Hepatitis B Varicella (zoster) Seasonal Influenza #2 and #3 All of the above

1) 2) 3) 4) 5)

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Human Papillomavirus (HPV)  Background

Case 3 17 yo young woman getting ready to go to college and is  seeing you for a routine physical. She has not had a  vaccine since age 9 (when she had a tetanus shot).  What (if any) vaccines does she need?  

 40 million people currently infected with HPV  6.2 million new cases each year  Most HPV infections self‐limited

 Lifetime cervical cancer risk 3.6% 1) No vaccines are needed at this time 2) HPV vaccine 3) Meningococcal vaccine 4) Both 2 and 3

Human Papillomavirus (HPV)  Vaccine  Quadrivalent viral protein vaccine (Gardisil)   Contains major capsid protein L1 from types 6, 11 and 16,  18  Bivalent vaccine (Cevarix) contains proteins from  types 16 and 18  Efficacy nearly 100% in preventing infection of the virus  types included in the vaccine

HPV Vaccine Recommendations  IM in a 3‐dose schedule (0, 1‐2, 6 months)  Little effect on HPV infections present prior to 

vaccination

 Approved for girls as young as 9; focus on 11‐12 yo  Catch‐up vaccination for 13‐26 yo if not previously 

vaccinated

 h/o HPV NOT a contraindication to vaccination

 SE:  low‐grade fever, local reactions, fainting  Contraindicated in anyone with hypersensitivity to yeast 

or to the vaccine

Koutsky LA et al.  NEJM, 2002;347(21)

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HPV Vaccine in Boys/Men…  HPV4 recommended for males 13‐21 years who 

have not been vaccinated  Males 22‐26 may be vaccinated  MSM recommended to be vaccinated through age  26 yrs

HPV Vaccine in Boys/Men  HPV4 approved 2010 for prevention of anal 

cancer ages 9 – 26  602 MSM  Gardasil was 50% effective (ITT) vs. 78% effective (per 

protocol) in preventing HPV 16 and 18 related anal  intraepithelial neoplasia

 HPV4 decreases external anal/genital lesions  4065 males aged 16‐26 yrs RCT, f/u 2.9 yrs  ITT:  60.2% efficacious  Per‐protocol (n=2805):  efficacy 90.4%

NEJM, 2011;365 NEJM, 2011;364:401‐411

HPV Vaccine Questions

HPV Vaccine Questions

 What about women> 26 yrs?  3817 women aged 24‐45 yrs, randomized, placebo‐ controlled, double‐blind study

 Will non‐vaccine viral strains emerge?

 

 What is the durability of the immunity?

No h/o genital warts or cervical disease Quadrivalent vaccine vs. placebo – 3 doses  Outcome=disease/infection related  to HPV 6, 11, 16, 18  Per protocol efficacy 90.5%  ITT efficacy:  30.9% Munoz N, et al.  Lancet, 2009;373

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Meningococcus Background

Meningococcal Vaccine 

 Approximately 10% of adults carry N meningitidis in  the nasopharynx

 Tetravalent polysaccharide vaccine (MPSV4) ‐ Menomune  Contains polysaccharide antigens to capsular serogroups A, C, Y, W‐135  Stimulate a B cell immune response

 Rates of invasive disease  0.8‐1.3 cases/100,000  Case fatality rates range 3‐10%  13 serogroups of meningococci  A:  rare in U.S.  B, C, Y:  each cause approx 30% of meningococcal  disease in the U.S.

Meningococcal Conjugate Vaccine  Tetravalent polysaccharide conjugate vaccine (MCV4) – Menactra and Menveo  Conjugates the bacterial capsular polysaccharide to a  carrier protein (diptheria toxoid) 

Results in a T cell dependent immune response—longer Ab titers

 Contains antigens to serogroups A, C, Y, W‐135 (NOT B)  Menveo produced a statistically higher seroresponse than 

Menactra for serogroups A, W, and Y 

Clinical relevance is unknown

 Now approved 9 months‐55 years  (Menactra); Manveo approved ages 2‐55

 

Antibody response is short‐lived (1‐5 yrs) Not effective in age < 2; FDA approved for ages 2‐10 and >55

 Does NOT protect against serogroup B, which is the 

most prevalent in U.S.

Meningococcal Vaccine  Recommendations  Give conjugate to ages 11‐18 (ideally  at 11 to 12 year‐old  visit)  “Catch‐up” at high school or college entry if not given  at age 11‐12  Vaccinate those at increased risk  Military recruits  Travelers to areas with hyperendemic disease  Microbiologists  Cost effectiveness better for 2‐dose series 

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Meningococcal Conjugate  Vaccine—Summary Table Risk Group

Primary Series

Booster Dose

Age 11‐18

1 dose, preferred age 11‐12

• Age 16, if primary dose  age 11 or 12 • Age 16‐18, if primary  dose age 13‐15 • No booster if primary  dose on/after age 16

Also, 1st year college  students in dorms up to  age 21 2 doses, 2 months apart Age 2‐55 yrs with  complement deficiency or  functional/anatomic asplenia

Every 5 years

Age 2‐55 yrs with  prolonged increased risk  of exposure

• Age 2‐6; after 3 years • >7 yrs, after 5 years

1 dose

Coming Soon?  Meningococcal serogroup B vaccine 

(4CMenB) recently licensed in Europe

Case 3

Take Home Points…

17 yo young woman getting ready to go to college and is  seeing you for a routine physical. She has not had a  vaccine since age 9 (when she had a tetanus shot).  What (if any) vaccines does she need?  

 Don’t forget Tdap boosters ages 11+

1) No vaccines are needed at this time

 Zoster vaccine ages >60 (licensed for >50)

2) HPV vaccine

 Influenza vaccine everyone

3) Meningococcal vaccine

 HPV vaccine ages boys/girls 9‐26; continue pap smears

4) Both 2 and 3

 Meningococcal conjugate vaccine ages 11‐55

 Pneumococcus vaccine > 65, people with asthma,  chronic illness, and smokers  Pneumococcus conjugate vaccine  immunocompromised, asplenic, cochlear implants

 http://www.cdc.gov/vaccines

16

Vaccines Selected References Updated July 2, 2013

Advisory Committee on Immunization Practice. Interim recommendations: prevention and control of influenza with vaccines: recommendations of the advisory committee on immunization practices. MMWR, Feb 21, 2013. Advisory Committee on Immunization Practice. Licensure of 13-valent pneumococcal conjugate vaccine for adults aged 50 years and older. MMWR, 2012;61(21):394-395. Advisory Committee on Immunization Practice. Prevention and control of influenza with vaccines: recommendations of the advisory committee on immunization practices (ACIP). MMWR, 2012;61(32):613-618. Advisory Committee on Immunization Practice. Recommendations on the use of quadrivalent human papillomavirus vaccines in males. MMWR, 2011;60(50):1705-1708.

Advisory Committee on Immunization Practice. Recommended immunization schedule for adults aged 19 years and older – United States, 2013. MMWR, 2013;62(01):9-19. Advisory Committee on Immunization Practices. Updated recommendations for use of meningococcal conjugate vaccines—advisory committee on immunization practices. MMWR, January 28, 2011. Advisory Committee on Immunization Practices. Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) in adults aged 65 years and older. MMWR, 2012;61(25):468-470.

Advisory Committee on Immunization Practice. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions. MMWR, October 12, 2012 / 61(40);816-819. Advisory Committee on Immunization Practice. Update on herpes zoster vaccine: licensure for persons aged 50 through 59 years. MMWR, 2011;60(44):1528-1528. Advisory Committee on Immunization Practice. Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in pregnant women. MMWR, 2013;62(07);131-135. Advisory Committee on Immunization Practice. Use of hepatitis b vaccination for adults with diabetes mellitus. MMWR, 2011;60(50):1709-1711.

Advisory Committee on Immunization Practices. Use of influenza A (H1N1) 2009 monovalent vaccine. MMWR, 2009;58:1-8. Ashkenazi A, Vertrugen A, et al. Superior relative efficacy of live attenuated influenza vaccine compared with inactivated influenza vaccine in young children with recurrent respiratory tract infections. Ped Infec Dis J 2006; 25(10):870-879. Baden LR, Curfman GD, et al. Human papillomavirus vaccine- opportunity and challenge. N Engl J Med 2007; 356(19):1990-1991. Bilukha OO, Rosenstein N. Prevention of pneumococcal disease: recommendations of the advisory committee on immunization practices (ACIP). MMWR 1997; 46(RR-08):1-11. Bilukha OO, Rosenstein N. Prevention and control of meningococcal disease recommendations of the advisory committee on immunization practices (ACIP). MMWR 2005; 54(RR07):1-21. Center for Biologics Evaluation and Research. Update: guillain-barre syndrome among recipients of menactra meningococcal conjugate vaccine – United States, june 2005-july 2005. MMWR 2005; 54(40):1023-1025. Committee on Infectious Diseases. Meningococcal conjugate vaccines policy update: booster dose recommendations. Pediatrics, 2011;128:1213-1218. Cornia PB, Hersh AL, et al. Does this coughing adolescent or adult patient have pertussis? JAMA, 2010;304(8):890-896. Dayan GH, Quinlisk MP, et al. Recent resurgence of mumps in the United States. N Engl J Med 2008;358:1580-9. Dunne EF, Datta SD, et al. A review of prophylactic human papillomavirus vaccines: recommendations and monitoring in the US. Cancer Supplement, 2008;113(10):29953003. Erickson BK, et al. Human papillomavirus: what every provider should know. Am J Obstet Gynecol, 2013 Mar; 208(3):169-175. Fleming DM, Crovari P, et al. Comparison of the efficacy and safety of live attenuated cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adolescents with asthma. Ped Infec Dis J 2006; 25:860-869. French N. Use of pneumococcal polysaccharide vaccines: no simple answers. J Infec 2003; 46:78-86. Gardner P. Prevention of meningococcal disease. N Engl J Med 2006; 355(14):14661473.

Garland SM, Hernandez-Avila M, et al. Qualrivalent vaccine against human papillomavirus to prevent anogental diseases. N Engl J Med 2007; 356(19):1928-1943. Giuliano AR, Palefsky JM, et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med, 2011;364:401-411. Keyserling H, Papa T, et al. Safety, immunogenicity, and immune memory of a novel meningococcal (groups a, c, y and w-135) polysaccharide diphtheria toxoid conjugate vaccine (mcv-4) in healthy adolescents. Arch Pediatr Adolesc Med. 2005; 159:907-913. Kimberlin DW, Whitley RJ, et al. Varicella-zoster vaccine for the prevention of herpes zoster. N Engl J Med 2006; 355(24):1338-1343. Kroger AT, Atkinson WL, et al. Update: General recommendations on immunization. MMWR 2006; 55(RR15):1-48. Liddon N, Hood J, Wynn BA, et al. Acceptability of human papillomavirus vaccine for males: a review of the literature. J of Adolescent Health 2010;46:113-123. Middleton DB, Zimmerman RK, et al. Vaccine schedules and procedures. J Fam Prac 2007; 56(2):S47-S60. Monto AS, Ohmit SE, Petrie JG, et al. Comparitive efficacy of inactivated and live attenuated influenza vaccines. N Engl J Med, 2009;361:1260-1267. Muñoz N, Manalastas R, Pitisuttithum P, et al. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24-45 years: a randomized, double-blind trial. The Lancet, 2009;373:1949-1957. Oxman MN, Levin MJ, et al. A vaccine to prevent herpes zoster and posterpetic neuralgia in older adults. N Engl J Med 2005; 352(22):2271-2284. Oxman MN. Zoster vaccine: current status and future prospects. CID, 2010;51(2):197213. Pace D, Pollard AJ. Meningococcal a, c, y and w-135 polysaccharide-protein conjugate vaccines. Arch Dis Child 2007; 92:909-915. Pham H et al. Adult immunizations: update on recommendations. The American Journal of Medicine, 2011;124:698-701. Rambout L, Hopkins L. Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized controlled trials. CMAJ 2007; 177(5):469-479.

Rambout L, Hopkins L, et al. Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized controlled trials. CMAJ 2007; 177(5):469-479. Sawaya GF, Smith-McCune K, et al. Hpv vaccination – more answers, more questions. N Engl J Med 2007; 356(19):1991-1993. Singh M, Lingappan K. Whooping cough: the current scene. Amer Col CHEST Phys 2006; 130:1547-1553. Siston AM, Rasmussen SA, et al. Pandemic 2009 Influenza A (H1N1) virus illness among pregnant women in the United States. JAMA, 2010;303(15):1517-1525. Sullivan SJ, Jacobson RM, Dowdle WR, et al. 2009 H1N1 influenza. Mayo Clin Proc, 2010;85(1):64-76. Tseng HF, Smith N, et al. Herpes zoster vaccine in older adults and the risk of subsequent herpes zoster disease. JAMA, 2011;305(2):160-166. Vesikari T, Fleming DM, et al. Safety, efficacy and effectiveness of cold-adapted influenza vaccine-trivalent against community-acquired, cultured-confirmed influenza in young children attending day care. Amer Acad Pediatr 2006; 118(6):2298-2312. Villa LL, Perez G, et al. Quadivalent vaccine against human papillomarvirus to prevent high-grade cervical lesions. N Engl J Med 2007; 356(19):1915-1927. Ward JL, Cherry JD, et al. Efficacy of an acellular pertussis vaccine among adolescents and adults. N Engl J Med 2005; 353(15):1555-1563. Woo EJ, Ball R, et al. Update: guillain-barre syndrome among recipients of menactra meningococcal conjugate vaccine – United States, June 2005-September 2006. MMWR 2006; 55(41):1120-1124. Yawn BP, Wollan PC, et al. Herpes zoster recurrences more frequent than previously reported. Mayo Clin Proc, 2011;86(2):88-93. Zimmerman RK, Middleton DB, et al. Routine vaccines across the life span, 2007. J Fam Prac 2007; 56(2):S18-S37. Zimmerman RK, Middleton DB. Vaccines for persons at high risk, 2007. J Fam Prac 2007; 56(2):S38-S46.

7/23/2013

FEATURES

OF THIS

TALK

It’s a debut Covers a broad array of topics  Greatest attention to common challenges in decision making  All recommendations supported by the following Guideline: AHA Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease (Circulation, 2012) 

OUTPATIENT MANAGEMENT OF CAD- A PRIMARY CARE PERSPECTIVE Michael G. Shlipak, MD, MPH Professor of Medicine, Biostatistics, and Epidemiology Chief, General Internal Medicine August 5, 2013

QUESTION #1 Your patient is a 62yo man with history of controlled hypertension, mild overweight (BMI 29), and untreated LDL of 137mg/dL. He reports to you that for about 2 months he has experienced left-sided chest tightness after working up 2 flights of stairs . It is relieved by rest and is not progressing noticeably. The symptoms have not occurred at any other times. What is the probability that the patient’s symptoms are caused by CAD? a) <50% b) 60% c) 80% d) >90%



 

Class 1 indication: we should do this Class 2 indication: it’s reasonable to do this

PRETEST PROBABILITY OF CORONARY HEART DISEASE IN PATIENTS WITH CHEST PAIN ACCORDING TO AGE, GENDER, AND SYMPTOMS Age

Nonanginal Chest Pain

Atypical angina

Typical angina

Men

Women

Men

Women

Men

Women

30-39

4

2

34

12

76

26

40-49

13

3

51

22

87

55

50-59

20

7

65

31

93

73

60-69

27

14

72

51

94

86

AHA definitions: low risk ~10% or less high risk ~90% or higher intermediate risk- anything in between

Diamond GA et al., N Engl J Med 1979 Weiner DA et al., N Engl J Med 1979

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QUESTION #2: YOUR PATIENT IS CAPABLE OF WALKING AND HAS A NORMAL RESTING ECG. WHICH OF THE FOLLOWING TESTS SHOULD YOU ORDER NEXT? a) b) c) d) e)

Exercise only stress test Exercise with perfusion imaging Exercise echo Coronary angiography None of the above

If patient can exercise and has normal resting ECG, then exercise only stress test  If abnormal ECG, then exercise/imaging or exercise echo  If patient cannot exercise, then pharmacologic stress with imaging/echo

WHY DO WE ONLY TEST PATIENTS WITH CAD? Exercise only:  LR+ = 3.0 

a)

Exercise echo:  LR+ = 3.7 

b) c)

LR- = 0.19

d)

(Fleischmann KE. et al. JAMA 1998) 

QUESTION #3: WHICH OF THE FOLLOWING IS NOT CONSIDERED PART OF OPTIMAL MEDICAL THERAPY FOR A PATIENT WITH ANGINAL SYMPTOMS?

LR- = 0.42

(Gianrossi R. et al. Circulation, 1989) 

AHA recommendation is to limit testing to intermediate risk patients 

INTERMEDIATE PROBABILITY OF 

NON INVASIVE TESTING FOR DIAGNOSIS OF ISCHEMIC HEART DISEASE

ACE inhibitors (ARBs) Aspirin Beta blockers Statins

Exercise imaging:  

LR+ = 2.4 LR- = 0.20

(Fleischmann KE. et al. JAMA 1998)

-

+

(0.02)

(0.28)

0.1

(0.25)

+ (0.77)

0.5

-

+

(0.65)

(0.97)

0.9

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ASPIRIN All patients with CAD should use 81-162mg of aspirin (class 1)  Clopidigrel (plavix) should be offered to patients who cannot tolerate aspirin (class 1)  Aspirin + clopidigrel for severe patients is reasonable (class 2B) 

STATINS (MORE ON THIS TOPIC LATER)  

LDL target <100 mg/dL - class 1 LDL target <70 mg/dL - class 2A

BETA BLOCKERS 

Improved survival in patients with prior MI  



If patient has prior MI, BB is class 1 If MI >3 years ago, BB is class 2A

Best choice for angina symptoms

ACE INHIBITORS Not clearly indicated in patients with angina because no effect on symptoms  Considered a “reasonable choice” (2A)  ACE inhibitors (Class I) must be used for patients with: 

 

Reduced ejection fraction CKD with albuminuria

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CASE CONTINUED 

RISK PREDICTION

Your patient worries that something bad might happen with his heart. He asks you to assess the likelihood of him having a heart attack or dying from his heart disease. How do you determine risk in the secondary prevention setting?





 



Feared adverse outcomes in CAD patients:   





1.

3. 4.

Framingham risk factors are still important: •Blood pressure control

•Smoking cessation

•Weight loss

•Diabetes control

•Lipid management

•Encourage exercise

Patients who have CAD No risk score for ambulatory patients with established CAD Framingham risk score does not work

CARDIAC-SPECIFIC RISK PATIENTS WITH CAD 2.

Recurrent MI Heart failure Sudden death

Patients without CAD or CVD Framingham risk score

Secondary prevention: 

RISK FACTORS FOR ADVERSE OUTCOMES IN PATIENTS WITH CAD

CAD

Primary prevention: 



IN

5.

FACTORS IN

Exercise capacity Number and size of MIs Reduced ejection fraction BNP/NT-pro-BNP Troponin T

Although important, cardiac status matters more for prognosis than metabolic risk factors

Kragelund Omland T. C. N Engl N Engl J Med, J Med, 2009 2005

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TREATMENT OF ANGINAL SYMPTOMS RANKING ANTI-ISCHEMIC AGENTS (PER AHA GUIDELINES) 1. 2. 3. 4. 5.

BBs- top choice CCBs or long acting nitrites (if BB intolerant) Use combinations if necessary NTG (sl or spray) for immediate relief Ranolozine as lesser alternative (class 2A)

FOLLOW UP IN CAD PATIENTS Routine  Assess anginal symptoms and physical function  Assess signs of heart failure or arrythmia  Risk factor management  Lifestyle Situational  If heart failure signs or repeat MI echo  If new or worsening angina exercise testing

CASE STUDY FOLLOW UP 

Your patient is still frustrated by the concept of medical management and concerned that his symptoms indicate an impending heart attack. He asks you “why can’t I just get a stent and fix this problem?” This seems logical- why not proceed to PCI?

INTERVENTIONS

IN

STABLE ANGINA

Interventions should be limited to patients who fail optimal medical therapy  Currently, 85% of all percutaneous coronary intervention (PCI) procedures are elective in patients with stable angina  The COURAGE trial demonstrated that PCI does not improve outcomes 

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COURAGE OUTCOMES

COURAGE TRIAL Conducted to compare OMT with and without PCI in 2,287 patients with stable angina  Funded by the US VA R&D/Canadian Institutes of Health Research  Outcome: 

  

All-cause mortality Non-fatal MI

Average follow-up: 4.6 years

Boden et al. NEJM 2007

COURAGE RESULTS 

Your patient insists on talking with a specialist You refer to a cardiologist  The patient returns to your office 8 weeks later for a follow-up visit… 

19.0% in PCI group 18.5% in OMT group





HR PCI vs. no PCI:   



CASE STUDY FOLLOW UP

Adverse event rates: 



Boden et al. NEJM 2007

Composite death/MI/stroke: Hospitalization for ACS: Myocardial Infarction:

1.05, 0.87-1.27 1.07, 0.84-1.37 1.13, 0.89-1.43

PCI doesn’t reduce risk of death, MI, or other CV events when added to OMT in patients with stable angina

…after having received a stent. What happened?

Boden et al. NEJM 2007

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CARDIOLOGISTS’ USE OF PCI FOR STABLE CAD Design: focus groups of cardiologists in N. Cal Research Question: Why do cardiologists ignore COURAGE results?  Reasons given for performing PCI in stable angina: 

What are cardiologists thinking?



     

Belief in the benefits of treating ischemia Belief in the open artery hypothesis Potential regret (psychological and legal) for not intervening if a cardiac event could be averted Alleviation of patient anxiety “Oculostenotic reflex” Belief that referring PCP expects a procedure Lin et al. Arch Intern Med. 2007

CONCLUSIONS We need to fully implement OMT (β-blocker, statin, aspirin) first, before referring to cardiologists  We need to resist the urge to “fix” patients’ angina by stenting  We need to educate patients that stents do not prevent adverse outcomes  We need to be clear about our expectations prior to referring patients to cardiologists 

QUESTION 4 

Your patient returns for follow up. He has been taking 20mg simvastatin. LDL is 110mg, HDL 25mg. Which is the best next step? a) b) c) d) e)

↑ simvastatin Change to pravastatin Change to atorvastatin Add gemfibrozil Add niacin

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FDA RESTRICTS USE OF SIMVASTATIN June 8, 2011: FDA restricts use of 80mg simvastatin because of increased risk of myopathy  FDA recommends: 

  

 

No new patients on simvastatin 80mg Okay to maintain patients on 80mg if >1 year without symptoms of muscle toxicity Beware of drug interactions

SEARCH TRIAL: STUDY OF THE EFFECTIVENESS OF ADDITIONAL REDUCTIONS IN CHOLESTEROL AND HOMOCYSTEINE  

Funded by Merck 7-year RCT comparing: 

Simvastatin 80mg vs. 20mg

Subjects: 12,064 patients with prior MI  Outcome: major vascular events (coronary death, MI, stroke, arterial revascularization)  Results: no difference (RR 0.94, 95%CI 0.881.01) 

Was this an over-reaction? Is simvastatin different from other statins? SEARCH Study Group The Lancet, 2010

SEARCH TRIAL RESULTS 

Difference in myopathy risk: 

NEW LABEL ON SIMVASTATIN 

Myopathy (muscle weakness + CK >10x ULN)



80 mg: 52 patients (0.9%)  20 mg: 1 patient (0.02%)









Rhabdomyolysis (muscle weakness + CK>40x ULN)  

Simvastatin contraindicated in users of:

80 mg: 22 patients (0.4%) 20 mg: 0 patients

 

Risk 5-fold higher in year 1 compared with subsequent years  Key drug interactions noted 

Do not exceed 10mg simvastatin if using: 

Verapamil Diltiazem

Calcium channel blockers are very  Do not exceed 20mg simvastatin with: common in  Amlodipine primary care 

  SEARCH Study Group The Lancet, 2010

Antifungals Macrolide antibiotics Antiretrovirals Gemfibrozil

Ranolazine Amiodarone

FDA Safety Announcement, 6/8/2011

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7/23/2013

LDL-LOWERING EFFECTS OF SIMVASTATIN Simvastatin

% Lowered LDL-C

10 mg

30%

20 mg

38%

40 mg

41%

80 mg

47%

WHAT SHOULD WE DO? Myopathy risks appear higher with simvastatin compared with other statins  Don’t go beyond 20 mg, unless you have a good pharmacy or great memory  Simvastatin 20 mg equivalent to: 

  

Pravastatin 40 mg Lovastatin 40-80 mg

If simvastatin 20 mg gives inadequate  LDL, use atorvastatin or rosuvastatin

FDA Safety Announcement, 6/8/2011

QUESTION 5 You decide your patient should switch to atorvastatin. However, he has now stopped his statin due to adverse publicity and will not restart. He asks you for a different medication or a “natural option”. You recheck his lipids; his HDL is 24 mg/dL and his LDL is 140 mg/dL. Your best management option is: a) Inform the patient that statins are the only workable hyperlipidemia treatment, so he might as well take nothing b) Offer him niacin to treat his HDL and tell him it’ a “vitamin” c) Offer a fibrate (e.g. gemfibrozil), as it is an evidencebased treatment for patients like him d) Any of the above approaches is fine.

WHY IS NIACIN IN DISFAVOR? AIM-HIGH trial Participants: N=3,414 in US and Canada  Inclusion criteria:  

  

Prior CVD On a statin Low HDL and high TG

Design: Placebo-controlled RCT  Intervention: Niaspan – 2 g/day or placebo  Outcomes: CVD death, MI, CVA, ACS, revascularization  Follow-up: 36 months 

http://www.aimhigh-heart.com/ AIM-HIGH Investigators, NEJM 2011

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7/23/2013

NIACIN META-ANALYSIS OF PLACEBO-CONTROLLED RCTS

AIM-HIGH FINDINGS  

Trial stopped early Event rate was same in both groups

NIACIN PATIENTS NOT ON STATINS No recent trials  Recent meta analysis summarized11 RCTs 

(Brucker et al. Atherosclerosis 2010)

Coronary Drug Project (from the 1970s): only large-scale RCT  Other studies very small 



No benefit to adding niacin for statin-treated patients http://www.aimhigh-heart.com/

AIM-HIGH Investigators, NEJM 2011

SUMMARY OF RESULTS FOR CARDIOVASCULAR EVENTS Publication bias?

?

Do fibrates improve clinical outcomes?

27% lower risk of CVD events

Bruckert et al. Atherosclerosis 2010

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7/23/2013

EFFECTS OF FIBRATES ON CARDIOVASCULAR OUTCOMES Design: systematic review and meta-analysis Analysis: 18 RCTs from 1950-2010  Participants: N=45,058  

FIBRATE



For patients with low HDL:  



Statins are treatment of choice to decrease CVD risk, regardless of LDL No data to add either niacin or fibrates to statin treatment (AIM-HIGH, ACCORD trials)

For patients not on statins:   

Niacin may reduce CVD risk Fibrates appear to lower MI risk, but no other CVD endpoints According to the AHA guidelines, for statin untreated patients, either fibrates or niacin are “reasonable choices” (2A)

PLACEBO AND CVD RISK Relative Risk

95% CI

P Value

Non-fatal coronary events

0.81

0.75-0.89

<0.0001

Total stroke

1.03

0.91-1.16

0.69

Cardiovascular death

0.97

0.88-1.07

0.59

All-cause mortality

1.00

0.98-1.08

0.92

Outcome

Jun et al. The Lancet 2010

DATA SUMMARY

VS.

Jun et al. The Lancet 2010

CASE STUDY FOLLOW UP Now that your patient with stable CAD is on OMT, he has increased exercise, as you recommended.  However, he has developed persistent knee pain and wants to take “prescription-strength” ibuprofen. The label says to ask a doctor before use if you have heart disease.  Is the risk real? 

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7/23/2013

NSAIDS IN CAD PATIENTS

BEST EVIDENCE

Meta-analysis demonstrates increased risk for incident CAD (Trelle et al. BMJ 2011)  Are they clinically harmful in patients with established CAD?  No RCT evidence in CAD patients





FROM

DENMARK

National registry of MI patients and pharmacy data  Patients with first MI (1997-2009); N= 97,698  44% received NSAIDS; average age = 65  Follow-up for MI/CHD death

Schjerning AM et al. PLoS ONE. 2013

NSAIDS AND RISK CAD

FOR

RECURRENT

CONCLUSIONS MI risk from NSAIDS appears real NSAIDS should be used only short-term in CAD patients  American Geriatric Society recommended therapies include: 

Any NSAID HR= 1.42 (1.36-1.49)

Diclofenac



 

Tylenol, exercise, topical NSAIDs

NSAID CV risk RR of 1.5; in context: 4%

Statins  30%

3% 2%

NSAIDs  50%

1% 0% Schjerning AM et al. PLoS ONE. 2013

CV Risk

Schjerning Olsen et al. Circulation 2011

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THANK YOU! ANY QUESTIONS?

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7/23/2013

Disclosure Statement Using the Best Evidence to  Select the Best Contraceptive 

I have nothing to disclose.

Jody Steinauer, MD, MAS Dept. Ob/Gyn & Reproductive Sciences University of California, San Francisco

Are you familiar with the US Medical Eligibility  Criteria for Contraception? a. Yes b. No

How comfortable would you be offering a  nulliparous woman an IUD if she had a history  of Chlamydia and no current infection? a. Very comfortable b. Somewhat comfortable c. Uncomfortable

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7/23/2013

Objectives Would you offer a 20 year‐old woman with  migraine the combined oral contraceptive? a. Yes b. It depends c. No

To review contraceptive methods so that you can  prioritize contraceptive counseling and provision in  your practice To be comfortable using CDC Medical Eligibility Criteria  (MEC) to determine safety Review basics, controversies, myths and new updates  about contraceptive methods

6.4 Million U.S. Pregnancies Annually Jane is a 27 year‐old woman taking combined  oral contraceptive pills, who presents to your  clinic for an annual examination.  She reports  having missed two periods.  Her urine  pregnancy test is positive.  

25 % Unintended Despite method use

52 % Intended 23 % Unintended No method used Jones PSRH 2008 Mosher Vital Health Stat 2010

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7/23/2013

Why did Jane get pregnant? Jane ran out of pills last month. She tried to  schedule an appointment, but because she  was overdue for a pap smear the clinic staff  couldn’t call in refills. Today was the first day  she could get an appointment.

Provider Barriers to Contraception • Clinical Visit – BP check to initiate estrogen‐containing methods – No pap smear or other examination – Refill methods without seeing patient

• Remember birth control – 48% using D or X rx counseled on contraception1

• Knowledge about contraindications – US guidelines Schwarz Ann Intern Med, 2007.

Can my patient use this method?

Case: US Guidelines After Jane has completed her pregnancy she  returns to you for contraceptive counseling.  Jane has had migraine headaches since she  was a teen.  She has no aura and they have  not changed with the combined pill. Can she use the pill again?

US Medical Eligibility Criteria (MEC) 1 2

Can use the method Can use the method

3

Should not use method  unless no other method  is appropriate Should not use method

4

No restrictions Advantages generally  outweigh theoretical or  proven risks. Theoretical or proven risks  generally outweigh  advantages Unacceptable health risk

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7/23/2013

Birth Control Methods

Where do you find the US MEC?

Medical Condition

MEC Category

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7/23/2013

Migraine and Combined Hormonal  Contraception (CHC)

Migraine, COC*, and Stroke Synergistic effect of Migraine and COC OR 8.7 (95% CI 5.0‐15.0)

1

OR 13.9 (95% CI 5.5‐35.1) 2

*COC= combined oral contraceptive pills

WHO/US: Headaches and CHC*

WHO/US: Headaches and CHC* Initiate

Non‐migrainous Migraine (i) w/o focal neurologic symptoms Age < 35 Age > 35 (ii) w/ focal neurologic symptoms (at any age)

1

2 3 4

Etminan BMJ, 2005. Tzourio BMJ, 1995.

Non‐migrainous Migraine (i) w/o focal neurologic symptoms Age < 35 Age > 35 (ii) w/ focal neurologic symptoms (at any age)

Continue

1

2

2 3 4

3 4 4

Focal symptoms = AURA = vision changes, numbness, parasthesias

Focal symptoms = AURA = vision changes, numbness, parasthesias

Non‐focal = Prodrome, photo/phonophobia, N/V 

Non‐focal = Prodrome, photo/phonophobia, N/V 

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7/23/2013

Absolute Risk of Stroke  No COC

COC

Healthy

6 per 100,000 ♀ /yr

12 per 100,000 ♀ /yr

Migraine

12 per 100,000 ♀ /yr 19 per 100,000 ♀ /yr

Case: Counseling Issues After reviewing the US and WHO MEC you  decide Jane can use the pill again. But is it the best method for her?

Migraine + aura 18 per 100,000 ♀ /yr 30 per 100,000 ♀ /yr

Stroke in pregnancy: 34 per 100,000 ♀ / year 

Speroff & Darney Clinical Guide for Contraception 2005

Helping patients choose the best method

Safety

Efficacy

Always balance against the risk of pregnancy

Efficacy How effective is the combined oral  contraceptive for prevention of pregnancy? 

Perfect use efficacy Frequency of intervention Non-contraceptive benefits Future pregnancy plans

Patient Preference Convenience Side effects Efficacy

Typical use ≠ Perfect use

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7/23/2013

Oral Contraceptives 2010: Missed Pills Mean Pills Missed

How effective is the combined oral  contraceptive for prevention of pregnancy? 

8% failure rate in 1 year How many pills, on average, do women forget to take each month (not including placebo)?

Diary

6

EMD

←5 pills

5 4 3 2

← admit 1

1 0 1

2

Typical use ≠ Perfect use

3

Cycle Hou, Ob Gynecol, 2010

Contraception Methods

Contraceptive Method Use, U.S.*

Most effective

Least effective

40 35 30 25 20 15 10 5 0

10 million = 800,000 pregnancies each year 28%

Most effective Effective Least effective

<83%

>99%

Episodic Daily Weekly Monthly 3 Mo’s

Ring

OCPs

6.6%

Barrier

Patch

3 yrs

5 yrs

Progestin Implant DMPA (IM or SQ)

10 yrs

Copper IUD LNG-IUS

Permanent

BTL Hysteroscopic Vasectomy

EC

Method *Among the 38 million women currently using birth control

94%

92%

Mosher Vital Health Statistics, 2010 Alan Guttmacher Institute, Facts In Brief, 2010.

Combined Hormonal

Progestin Only

IUC

Sterilization

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7/23/2013

Natural Family Planning Failure Rate Perfect Use Typical Use

Contraceptive Method No Method Periodic Abstinence Standard Days Method®* Ovulation Method Symptothermal Two‐Day Method®

85%

85%

5% 3% 2% 3%

12% 22% 13‐20% 14%

Barrier Methods Failure Rate Perfect Use Typical Use Withdrawal 4 % 18 % Condoms 2 % 17 % Cervical Cap (parous/nullip) 26%/9% 32%/16% Sponge (parous/nulliparous) 20%/9% 32%/16% Female Condoms 5 % 27 % Diaphragm 6 % 16 % Contraceptive Method

* Including Cycle Beads National Center Health Statistics; Contraceptive Technology

National Center Health Statistics; Contraceptive Technology

Hormonal Methods Contraceptive Method Combined Hormonal Pills Progestin Only Pills Transdermal Patch Vaginal Ring 3‐Month Injection Implants Copper IUD/LNG IUS

Failure Rate Perfect Use Typical Use <1 % 8 % <1 % 8 % <1 % 8 % <1 % 8 % <1 % 3 % <1 % <1 % <1 % <1 %

National Center Health Statistics; Contraceptive Technology

http://www.fhi.org/nr/shared/enFHI/Resources/EffectivenessChart.pdf

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Frequency of Intervention • • • • • • • • •

Permanent: sterilization Every 10 years: IUD Every 5 years: IUD Every 3 years: implant Every 3 Months: injection Monthly: vaginal ring Weekly: patch Daily: pill, NFP Episodic: barrier methods, NFP

Daily: Natural Family Planning • Help women identify fertile days – Fertility window 6‐8 days – Failure rate 12‐22%

• Two‐day method® – Simple, accurate method – quicker to learn – Two questions

Increasing efficacy

Natural Family Planning: Two‐day Method® • Study of 450 women – 3,928 cycles • Failure rates:  – 14% typical use – 3% perfect use (no intercourse) – 6% semi‐perfect (barriers or withdrawal) – Half of pregnancies in first 3 months

• Did I note secretions today? • Did I note secretions yesterday? • If yes to either, consider fertile

Daily: Combined Oral Contraceptives • Estrogen + progestin • Traditional prescription flawed – Daily x 3 weeks / 1 week off

• Extended cycle may ↑efficacy

• Mean fertile window 12 days • High acceptability  Arevalo, Fertil Steril, 2004.

Baerwald, Contraception, 2004.

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7/23/2013

Extended Cycle:  Shortened hormone‐free week • 23, 24 or 26 days hormones + 2‐5 d placebo – Decreased ovarian activity at end of placebo – Shorter withdrawal bleeds

Extended Cycle: Fewer hormone‐free weeks • 12 weeks hormone/1 week off • Ethinyl estradiol and levonorgestrel – 84 days LNG 150 µg/EE 30 µg; 7 days placebo

– Similar breakthrough bleeding – Decreased breakthrough bleeding over time – 3 FDA‐approved products in US

Spona Contraception, 1996  Bachman Contraception, 2004  Endrikat Contraception, 2001.

Tricycle Breakthrough  Bleeding/Spotting

Anderson Contraception, 2003

Extended Cycle:  Continuous Use • Continuous for one year – Increased spotting in first six months – Median 1.5 days spotting in last trimester • FDA‐approved: ethinyl estradiol and levonorgestrel – 90 mcg levonorgestrel + 20 mcg EE 

Anderson FD, et al., Contraception, 2003.

Miller Obstetrics and Gynecology, 2003.   Kwiecen, Contraception, 2003.    Foidart, Contraception, 2006. 

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7/23/2013

Choosing a COC

VTE & oral progestin type

• Estrogen dose

• Desogestrel and drosperinone OCPs may  increase risk of VTE • BUT. . . Absolute risk remains low

– Low dose = < 50 mcg

• Progestin type – 1st‐generation: norethindrone – Second‐generation: levonorgestrel – Third‐generation: desogestrel – Drospirenone: spironolactone derivative

Non-pregnant, no COCs: 4.4 per 10,000 ♀- yrs Levonorgestrel COCs: 5.0 per 10,000 ♀- yrs Desogestrel COCs: 6.5 per 10,000 ♀- yrs Drosperinone COCs: 7.8 per 10,000 ♀- yrs PREGNANCY: 29 per 10,000 ♀- yrs Lidegaard 2009 BMJ Heinemann 2007 Contraception

Kemmeren BMJ 2001; Lidegaard BMJ 2009

Choosing a COC • Careful with very low‐dose estrogen – ↑ bleeding • Monophasic fine • No clear benefit of drospirenone

Jane no longer wants to take a pill every day.  She asks you about other birth control  methods which she doesn’t have to think  about as often.  What can you offer her? 

– PMDD: fewer sxs 6 months – equivalent at 2 yr – Acne: Equivalent to other pills  30 or 35 mcg EE + 2nd generation progestin Shortened or erased placebo week if possible Monophasic

Weekly

5‐10 years

3 months Monthly

3 years

VanViet Cochrane 2006 LaGuardia Contraception, 2003 Freeman Womens Health 2001 van Vloten Cutis 2002 

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7/23/2013

Daily: Progestin‐only Pills (POPs)

Weekly: Patch • Norelgestromin and EE 

• 35 mcg norethindrone DAILY

– 20mcg EE & 150mcg norelgestromin

– No hormone free interval!!

• Primary mechanism = cervical mucus thickening • Requires punctual dosing – If > 3 hours late, need back up x 48 hours

• One patch q week for 3 weeks, then no x 1 wk • Few side effects – comparable to pills except: – 20% skin irritation – 2% stopped method – More breast discomfort and spotting in first 2 cycles than pills – 3% detached –RCT 46% experience at least one  detachment in one cycle • Prescribe replacement patch Creinin Obstet Gynecol 2008 

Monthly:  Extended Cycle Ring

Monthly: Ring • Ethinyl estradiol and etonogestrel

• RCT of 561♀: 4wk, 8 wk, 12 wk, continuous:

– 15 mcg EE & 120 mcg desogestrel

• One ring each month:

– All regimens well‐tolerated

– Ring in x 3 wks – Ring out x 1 week

• Few side effects – comparable to pills except – – – –

Spotting: only 5% (significantly less in first month) Discharge: 1% stop method  Discomfort: 2.5% stop method  Expulsion: RCT: 20% expelled at least once during 3‐week  period Dieben Obstet Gynecol, 2002  Creinin Obstet Gynecol, 2008 

– Extended: ↓ bleeding days,  spotting days

• Potential for use on a monthly basis – Serum levels for 35 days

I instruct patients to remove ring the last 3‐4 days  of the month if they want withdrawal bleed. Miller Obstet Gynecol, 2005 

12

7/23/2013

Non‐oral HC and VTE 2 case‐control studies • No association‐ new users  – OR=1.1 (CI 0.6–2.1) 1 • Association‐ all users – OR=2.4 (CI 1.1‐5.5)2 Retro cohort, 9.4 m ♀‐yrs3

• Attributable risk:  – +7.6/10K (vs. non) – +3.5/10K (vs. COC)

EE Exposure with  combined hormonal contraception

Retro cohort, 9.4 m ♀‐yrs3 •

AUC (pg/ml):

Attributable risk:  – +5.7/10K (vs. non) – +1.5/10K (vs. COC)

Patch = 37.7 + 5.6 COC = 22.7 + 2.8 Ring = 11.2 + 2.7

• NNT (switch to COC): – 2000 ring users – 1250 patch users • No info on BMI, smoking, fam hx 1. Jick SS 2007 Contraception 2. Cole JA 2007 Obstet Gynecol 3. Lidegaard 2012 BMJ

Every 3 months: Progestin Injection • Medroxyprogesterone acetate 150 mg IM – One injection every 12‐13 weeks

• Very effective  – Typical use failure = 3%

• Side effects:  – Delayed return to fertility (9‐10 months) – Irregular bleeding, amenorrhea (50% at 1 yr)  – Weight gain (5 lbs at 1 year, 16 lbs at 5 yrs)

• SQ low‐dose (104 mg) version now available

van den Heuvel, Contraception 2005 (*30 mcg EE COC)

Progestin Injection & BMD • BMD decreases by 1‐2% per year • FDA: limit to 2 yrs. in young women – WHO & ACOG do not agree  – Bone loss reverses by 1 year after discontinuation.  – No evidence of increased fractures.

• No indication for DEXA • Weigh risks against risk of pregnancy Meier, J Clin Endocrin Metab, 2010.  Scholes Arch Pediatr Adolesc Med, 2005.; Scholes, Epidemiology, 2002; ACOG 2008 Com Opin 415.

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7/23/2013

Progestin Injection: Delay • Traditionally recommend caution after > 14  weeks from last DMPA injection  • WHO recommends 4‐week grace period – Repeat up to 16 weeks

Missed Hormonal Contraceptives:  New Recommendations • Guidelines for CHC and DMPA • For CHC:  – The hormone free interval (HFI) not > 7 days – In the 1st week • Back‐up should be used after >1 missed dose until 7 days of  use occur. Consider EC.

– In the 2nd and 3rd week • If < 3 days are missed,  eliminate the next HFI • If > 3 days are missed, back‐up contraception and  consideration of EC should be added Soc Ob GYN of Canada, JOGC 2008; 219:1050-62

Every 3 years: Single‐Rod Implant • Etonogestrel 60mcg/day • New version replaced old in 2011 – Identical but with radiopaque rod – Easier‐to‐use inserter – Must complete FDA‐approvedtraining

• Efficacy > 99% • 1 year continuation: 75%‐90%

Progestin Implant: Side Effects • Bleeding: “Irregularly irregular” (40%) – Amenorrhea: 22% – 7% frequent: > 5 B‐S episodes in 90‐day period – 18% prolonged: at least 1 B‐S episode > 14 days – 20% have B‐S for >50 days in first 90‐day period – Generally NOT heavy

• Treatment of bleeding

– Reasons for discontinuation:  Bleeding ( up to 40%) Blumenthal Eur J Contracept Reprod Health  Care, 2008

Blumenthal Eur J Contracept Reprod Health Care, 2008  Mansour Eur J Contracept Reprod Health Care 2008.

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7/23/2013

Every 3‐10 Years: Intrauterine Devices  (IUD, IUC, IUD, IUS)

Implant: Bleeding Treatment  Therapy

Evidence?

1. COC x 21d/7d (3 mo) or Estrogen alone  (0.5 mg estradiol x 21 d) (3 mo)

Minimal

2. Cyclic progestin (MPA 10bid) x 21d/7d  (3mo)

Anecdotal

3. POP daily up to 3 mo

Anecdotal

4. NSAIDs, COX‐2 inhibitors x 5‐10d Tranexamic acid 500 bid x 5d

Minimal Anecdotal

Copper T 380A IUD 0.8% failure (1 yr)

10 years

3‐5 years

Levonorgestrel Intrauterine  System (LNG‐IUS) • Levonorgestrel 20 mcg/day • 0.1% failure (1 yr) New LNG IUS – 13.5 mg/day • 3 years

Adapted from Mansour et al 2010, and 2011 Contraception

Lockhat Fertil Steril, 2005

IUD Review • Current IUDs do NOT cause PID!!! – Transient increased risk at time of insertion – STI at time of insertion increases risk – GC/CT screening can follow CDC guidelines – Okay to screen on insertion day – treat if +

• Beyond time of insertion • Overall decreased risk with LNG IUS  • No increased risk with Copper IUD

• Okay to treat for PID with IUD in place Svensson L, et al. JAMA. 1984; Sivin I, et al. Contraception. 1991. Farley T, et al. Lancet. 1992; Hubacher, NEJM,  2003.

Routine GC/CT screening NOT necessary! • Retrospective cohort, n=57,728 IUDs • Evidence‐based STI screening, treat if + test Overall PID risk = 0.54% All women: Risk of PID Non-screening = Screening OR= 1.05 (0.78, 1.43)

Women appropriately selected for non-screening Same  results  < 26 yo

Screened Women: Risk of PID Same day = Pre-insertion OR=.997 (.64, 1.54)

Most accurate screening time is day of insertion Sufrin et al In press, Obstet Gynecol

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7/23/2013

IUC, Nulliparity  & Infertility

Is Jane a candidate for an IUD?

• Nulliparity is not a contraindication – May have increased pain with insertion – May have increased risk of expulsion

Women of any reproductive age seeking  long‐term, highly effective contraception 

• IUDs do NOT cause infertility – Tubal factor 1° infertility  is not associated with  prior IUD use (OR=1)

Hubacher 2003 N Engl J Med

Permanent: Tubal Sterilization • Postpartum  salpingectomy • Silicone Band  (Yoon, Fallope) • Filshie Clip • Electrosurgical  dessication – unipolar  lowest failure

Permanent: Hysteroscopic Tubal Sterilization • Coils inserted into proximal tubes via  hysteroscopy – Induces scarring reaction in tubes

• Back‐up method x 3 mo, confirm w/ HSG

Failure risk 0.5‐1.8% Increases over time

• Low failure rate (0.26% at 5 yrs)  • Non‐invasive

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7/23/2013

Post‐exposure: Oral Emergency Contraception Levonorgestrel 120 mg x 1, up to 5 days Ulipristal Acetate • Selective progesterone receptor modulator • Proposed mechanism:1 – Delay follicular rupture

• Will not harm existing pregnancy • Dosing: 

Emergency Contraception:  Ulipristal Acetate Effectiveness:1,2 “Non‐inferior” to LNG: 1.4% vs. 2.2% Meta‐analysis of 3445 ♀ 120 hrs: OR = .55 (.32‐.93) 24 hrs: OR = .35 (.11‐.93)

Side effects: Headache (20%), nausea (12%)

30mg, FDA‐approved up to 5 days 1. Glasier 2010 Lancet 2. Creinin 2006 Obstet Gynecol

1. Brache 2010 Hum Reprod

Alternatives to LNG EC & Ulipristal acetate? • Copper IUD – VERY effective as EC up to 7 days! – More effective than LNG EC

• Mifepristone (10, 25 or 50 mg) – More effective than LNG

Jane • You counsel Jane about the other options  available, emphasizing those with high  efficacy that require less intervention. She  ends up choosing a highly effective IUD which  you place that same day.

• Yuzpe regimen – More side effects and less effective Cheng 2008 Cochrane Database

17

7/23/2013

Summary

References

• Unintended pregnancy remains a common  problem in the US. • We can minimize barriers to successful  contraception. • Consider including efficacy in your  contraception counseling in addition to other  priorities of the patient.

• Many easily accessible resources exist to help  solve contraception quandaries. . . . www.cdc.gov www.acog.org www.arhp.org

http://www.managingcontraception.com/ http://www.who.int/reproductivehealth/publications/family_planning

UCSF Family Planning Consult Service (415) 443-6318

http://www.cochrane.org/

Resources  • WHO and US Medical Eligibility Criteria for  Contraceptive Use – www.who.int – www.cdc.gov – www.reproductiveaccess.org

• A Pocket Guide to Managing Contraception • UCSF Family Planning Consult Service – (415) 443‐6318 Thanks to Carolyn Sufrin for sharing some slides. . .

18

7/23/2013

Acknowledgments • Thanks to all who have shared slides – Carolyn Sufrin  – Mike Policar – Phil Darney – Sarah Prager

19

Summary Chart of U.S. Medical Eligibility Criteria for Contraceptive Use Updated June 2012. This summary sheet only contains a subset of the recommendations from the US MEC. For complete guidance, see: http://www.cdc.gov/reproductivehealth/unintendedpregnancy/USMEC.htm

I C Menarche to <40=1 >40=2

Age

Anatomic abnormalities Anemias

Benign ovarian tumors Breast disease

a) Distorted uterine cavity b) Other abnormalities a) Thalassemia b) Sickle cell disease‡ c) Iron-deficiency anemia (including cysts) a) Undiagnosed mass b) Benign breast disease c) Family history of cancer d) Breast cancer‡ i) current ii) past and no evidence of current disease for 5 years a) < 1 month postpartum b) 1 month or more postpartum

Breastfeeding (see also Postpartum) Cervical cancer Awaiting treatment Cervical ectropion Cervical intraepithelial neoplasia Cirrhosis a) Mild (compensated) b) Severe‡ (decompensated) Deep venous a) History of DVT/PE, not on thrombosis anticoagulant therapy (DVT) i) higher risk for recurrent /Pulmonary DVT/PE embolism (PE) ii) lower risk for recurrent DVT/PE b) Acute DVT/PE c) DVT/PE and established on anticoagulant therapy for at least 3 months i) higher risk for recurrent DVT/PE ii) lower risk for recurrent DVT/PE d) Family history (first-degree relatives) e) Major surgery (i) with prolonged immobilization (ii) without prolonged immobilization f) Minor surgery without immobilization Depressive disorders Diabetes mellitus a) History of gestational DM only (DM) b) Non-vascular disease

1 2 1 1 2* 1 1

I C I C I C I C I C Menarche to Menarche to Menarche to Menarche to Menarche to <18=1 <18=2 <18=1 <20=2 <20=2 18-45=1 18-45=1 18-45=1 >20=1 >20=1 >45=1 >45=2 >45=1 4 4 2 2 1 1 1 1 2 1 1 1 1 2 1 1 1 1 2 1 1 1 1 1 2* 1 1

2* 1 1

2* 1 1

4 3

4 3

4 3

4 3

3* 2*

2* 1*

2* 1*

2* 1*

2 1 2

1 1 1

2 1 2

2 1 2

1 4

1 3

1 3

4

2

3 4

4*

2 1 1

1 1 1

4 3

4

2

4

2 1 1

1 3

1 3

1 1

2

2

2

1

2

2

2

2

1

2

2

2

2

2

2

2

2

2

2

2

2

2

2

2

2

1

1

1

1

1

2

2

Endometrial cancer‡ Endometrial hyperplasia Endometriosis Epilepsy‡ Gallbladder disease

Gestational trophoblastic disease 1 2

2

2

1

2

1

1

1

1

1

1

1

1

1

1

1

1*

1*

1*

1*

1*

1*

1

1

1

1

1

1

Headaches

History of bariatric surgery‡ History of cholestasis History of high blood pressure during pregnancy History of pelvic surgery HIV

Hyperlipidemias Hypertension

(i) non-insulin dependent (ii) insulin dependent‡ c) Nephropathy/ retinopathy/ neuropathy‡ d) Other vascular disease or diabetes of >20 years' duration‡

(see also Drug Interactions) a) Symptomatic (i) treated by cholecystectomy (ii) medically treated (iii) current b) Asymptomatic a) Decreasing or undetectable ß-hCG levels b) Persistently elevated ß-hCG levels or malignant disease‡ a) Non-migrainous b) Migraine i) without aura, age <35 ii) without aura, age >35 iii) with aura, any age a) Restrictive procedures b) Malabsorptive procedures a) Pregnancy-related b) Past COC-related

High risk HIV infected (see also Drug Interactions)‡ AIDS (see also Drug Interactions) ‡ Clinically well on therapy a) Adequately controlled hypertension b) Elevated blood pressure levels (properly taken measurements) (i) systolic 140-159 or diastolic 90-99 (ii) systolic ≥160 or diastolic ≥100‡ c) Vascular disease

C

I

C

I

C

I

Copper-IUD

LNG--IUD

Implant

Injection

Progestin-only pill

Combined pill, patch, ring

Sub-condition

I Diabetes mellitus (cont.)

1 1

3*

4

Condition

Implant

LNG--IUD

Copper-IUD

Most contraceptive methods do not protect against sexually transmitted infections (STIs). Consistent and correct use of the male latex condom reduces the risk of STIs and HIV.

Injection

Progestin-only pill

Combined pill, patch, ring

Sub-condition

No restriction (method can be used) Advantages generally outweigh theoretical or proven risks Theoretical or proven risks usually outweigh the advantages Unacceptable health risk (method not to be used)

Condition

Key: 1 2 3 4

C

I

C

I

2 2 2

C

2 2 3/4*

2 2 2

2 2 3

2 2 2

1 1 1

3/4*

2

3

2

1

1

1

1

1

1

1

1

1

1

1 1*

1 1*

1 1*

1 1*

1 1

2 1

2

2

2

2

2

1

3 3 2 1

2 2 2 1

2 2 2 1

2 2 2 1

2 2 2 3

1 1 1 3

1

1

1

1

4

4

2 4

1 2

4

2

1*

2*

1*

1*

1*

1*

1*

1*

1*

1*

1*

2* 3* 4*

3* 4* 4*

1* 1* 2*

2* 2* 3*

2* 2* 2*

2* 2* 3*

2* 2* 2*

2* 2* 3*

2* 2* 2*

2* 2* 3*

1 COCs: 3 P/R: 1 2 3 2

1 3

1 1

1 1

1 1

1* 1* 1* 1 1

1 2 1

1 2 1

1 2 1

1 2 1

1 1 1

1

1

1

1

1

1

1 1*

1 1*

1* 1*

1 1*

2 2

2 2

2 2

2 2

1*

1*

1*

1*

3

2*

3

2*

If on treatment, see Drug Interactions 2* 2* 2* 1* 2* 1*

2

2

2

2/3* 3*

2

2* 1

1* 1

3

1

2

1

1

1

4

2

3

2

2

1

4

2

3

2

2

1

(Ulcerative colitis, Crohn’s disease) Current and history of a) Benign i) Focal nodular hyperplasia ii) Hepatocellular adenoma‡ b) Malignant‡

Malaria Multiple risk (such as older age, smoking, factors for arterial diabetes and hypertension) cardiovascular disease Obesity a) >30 kg/m2 body mass index (BMI) b) Menarche to < 18 years and > 30 kg/m2 BMI Ovarian cancer‡ Parity Past ectopic pregnancy Pelvic inflammatory disease

Peripartum cardiomyopathy‡

Postabortion

Postpartum (see also Breastfeeding)

a) Nulliparous b) Parous

a) Past, (assuming no current risk factors of STIs) (i) with subsequent pregnancy (ii) without subsequent pregnancy b) Current a) Normal or mildly impaired cardiac function (i) < 6 months (ii) > 6 months b) Moderately or severely impaired cardiac function a) First trimester b) Second trimester c) Immediately post-septic abortion a) < 21 days b) 21 days to 42 days (i) with other risk factors for VTE (ii) without other risk factors for VTE c) > 42 days

Postpartum (in a) < 10 minutes after delivery of breastfeeding or the placenta non-breastfeeding b) 10 minutes after delivery of the women, including placenta to < 4 weeks post-cesarean c) > 4 weeks section) d) Puerperal sepsis Pregnancy Rheumatoid a) On immunosuppressive therapy arthritis b) Not on immunosuppressive therapy Schistosomiasis a) Uncomplicated b) Fibrosis of the liver‡ Severe dysmenorrhea Sexually a) Current purulent cervicitis or transmitted chlamydial infection or gonorrhea infections (STIs) b) Other STIs (excluding HIV and hepatitis)

C

I

2/3* 4

2 4 4 1 3/4*

C 2

2

C

I

2 3

2 3 3 1 2*

I

3

2 3 3 1 3*

C

I

1 2

C

I

1 3

2

2 3 3 1 2*

3

1

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1 1 1 1 1

1

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1* 1* 1*

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4

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4

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1 4 4*

1 4 4*

NA* 2

NA* 1

NA* 2/3*

NA* 1

2

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1 1 1

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4

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2

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C

I

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I

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1 2 3 4

1 1 1 1

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2/3*

Solid organ transplantation‡

a) Complicated b) Uncomplicated History of cerebrovascular accident a) Varicose veins b) Superficial thrombophlebitis

4 2* 4

2 2

2 2 3

2 2

3

1 2

1 1

a) Positive (or unknown) antiphospholipid antibodies b) Severe thrombocytopenia c) Immunosuppressive treatment d) None of the above

4

3

3

2 2 2 4*

2 2 2 2*

3 2 2

1

1

1* 1*

Thrombogenic mutations‡ Thyroid disorders Simple goiter/ hyperthyroid/hypothyroid Tuberculosis‡ a) Non-pelvic (see also Drug b) Pelvic Interactions) Unexplained (suspicious for serious condition) vaginal bleeding before evaluation Uterine fibroids Valvular heart a) Uncomplicated disease b) Complicated‡ Vaginal a) Irregular pattern without heavy bleeding bleeding patterns b) Heavy or prolonged bleeding Viral hepatitis a) Acute or flare b) Carrier/Chronic Drug Interactions Antiretroviral a) Nucleoside reverse therapy transcriptase inhibitors b) Non-nucleoside reverse transcriptase inhibitors c) Ritonavir-boosted protease inhibitors Anticonvulsant a) Certain anticonvulsants therapy (phenytoin, carbamazepine, barbiturates, primidone, topiramate, oxcarbazepine) b) Lamotrigine Antimicrobial a) Broad spectrum antibiotics therapy b) Antifungals c) Antiparasitics d) Rifampicin or rifabutin therapy

Copper-IUD

LNG--IUD

Implant

Injection

Progestin-only pill

Combined pill, patch, ring I

1

Systemic lupus erythematosus‡

2*

C

c) Vaginitis (including trichomonas vaginalis and bacterial vaginosis) d) Increased risk of STIs a) Age < 35 b) Age > 35, < 15 cigarettes/day c) Age > 35, >15 cigarettes/day

Superficial venous thrombosis

2 2 2

1* 2 4

I Sexually transmitted infections (cont.) Smoking

Stroke‡

1 2

4

2 2 2

Sub-condition

C 1

2

1 1

Condition

Copper-IUD

LNG--IUD

Implant

Injection

Progestin-only pill

Combined pill, patch, ring

Sub-condition

Condition

I Inflammatory bowel disease Ischemic heart disease‡ Liver tumors

C 2

I 2

C 2

2

2/3*

1 1 1

2 1 1 1

2

3

2

2 2

2 1

1 1

1 1

1 1

3

3

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4

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I = initiation of contraceptive method; C = continuation of contraceptive method; NA = Not applicable * Please see the complete guidance for a clarification to this classification: www.cdc.gov/reproductivehealth/unintendedpregnancy/USMEC.htm ‡ Condition that exposes a woman to increased risk as a result of unintended pregnancy.

7/23/2013

The Telederm Experiment Teledermatolgy and Primary Care Integrating common dermatology diseases into a system where  teledermatology triaging is used

Toby Maurer, MD University of California, San Francisco

• Obtains verbal consent from pt • Provider or assistant takes picture and uploads  picture • Question can be typed in on web based  template at the time of pt visit or later that  day, etc • Derm group answers question and primary  will get notification that derm report is ready

• California Health Care Foundation‐can we  make it happen in the Bay Area? • La Clinica‐first group in the Bay Area • Primary care provider has any derm question  or wants to refer to derm • ALL referrals go through telederm‐even if it is  a pt followed by derm in past

• Provider will get first pass advice‐what is it,  how to treat, when he/she should see pt back  or when to refer OR • Provider will be alerted that pt needs derm appointment and pt will be triaged within an  appropriate time to be seen in LIVE CLINIC. • Derm report is part of the electronic medical  record

1

7/23/2013

Results to date • Dermatologists from UCSF read the triage  consults and they also staff the live clinics at  the primary care providers site

• We have completed around 2000 consults • 85% of consults have been successfully  treated by primary provider with derm guidance‐the GPS system • 15% seen in live derm clinic • Wait time at San Mateo was 9 months to see  DERM.  Now we get consults back in 2 days  and live clinics booked within 1 month

Acne • Primary providers have learned  from one on  one consults • Primary providers have had to DO some  dermatology • Live dermatology clinic –difficult cases but  time has been properly apportioned to see  them

Primary care provider: Pt has recent onset of  bumps on face.What is this and how do I treat.  Has used Proactive with minimal change.

2

7/23/2013

Topicals

Primary Care Provider: Pt with acne –used  retin A but very irritating.  What is the next  step?

• BP 5% gel (10% ‐ more drying) • Retin A 0.025% ‐ 0.1% ( vehicle determines  strength ‐ start with crème) • Cleocin T or erythromycin topically – Use 1 qam and 1qhs – If NO success after 8 weeks, go to p.o.’s 

• Pt has cystic/scarring acne‐topicals won’t  work and in Asians‐Retin A is very irritating. • Start p.o. antibiotics

P.O. Antibiotics • • • •

TCN ‐ 500 bid x 8 weeks Doxycycline ‐ 100 bid x 8 weeks Minocycline ‐ 100 bid x 8 weeks Taper ‐ Do NOT STOP ABRUPTLY.  Once pt’s skin is clear, taper the dose in ½ fo another  month and then stop the medication

3

7/23/2013

Spiranolactone • Diuretic used in cirrhosis of liver • Also an anti‐androgen • Useful in females who have cysts around  menstruation • 50‐100 mg qday • Increased urination, don’t use during  pregnancy, ?electrolyte imbalance

• Pt told he has psoriasis‐used some crème in  Mexico‐can’t remember name. Worried that  his grandchildren could catch this.

Pt did not get better…… • Psoriasis is fast growing skin‐can’t get it from  anyone and can’t give it to anyone • What meds is he on? Certain meds might  unmask this like atenelol, lithium, NSAIDS • Start Clobetasol oint and dovonex crème  together.  Apply M‐F bid‐weekends off • Primary see pt again in 6 weeks.  If not better‐ send another telederm consult and we will  readvise or book pt in derm clinic

• New pictures show increased total body  surface area involvement • Dermatology triage: I see that pt has liver  disease (seen on EMR). First choice systemic  drug is acitretin.  Please order up baseline  LFT’s , fasting TG and cholesterol. • We will book pt for derm clinic in 2 weeks and  start him on acitretin 25 qd

4

7/23/2013

Psoriasis‐when topicals don’t work • Acitretin‐safer to use in liver disease‐monitor TG,  Chol • Methrotrexate‐titrate dose, follow LFT’s and CBC,  needs liver biopsy after 1.5 gm‐great drug if there  is psoriatic arthritis • TNF blockers‐good drugs, expensive, subcu injections, presecreen for TB and Hep B and  cancer risk • Ultraviolet light‐is pt able to spend the time; is it  accessible to pt?

Psoriasis‐What is it? • Fast growing skin‐takes 3 days to come to  surface and desquamate • Normal rate is 28 days • Psoriatic skin has a fast mitotic rate • Triggers an inflammatory response in and  around affected skin

Psoriasis‐Tx: • New onset often preceded by strep infection  (strep pharyngitis) especially in the younger  age group. • In older age group, drugs often unmask  psoriasis • Drugs: beta‐blockers, lithium, NSAIDS,  antimalarials, terbinafine, gemfibrozil‐pts on  these meds for 3‐6 months before onset of  psoriasis

• Decrease the MITOTIC  RATE of skin – Tar (LCD 5% in TAC 0.1% oint)  ( Tar emulsions) – topical retinoids (Tazarac)

• Decrease the  INFLAMMATORY Reaction  of the skin – Steroid Ointment (mid‐ potency‐1st line) – Calcipotriene (Dovonex  Creme)‐not on face or groin – Clobetasol/Dovonex  combination – Ultraviolet light

5

7/23/2013

NO PREDNISONE

Atopic Dermatitis Body Treatment • Topical steroids and antihistamines still mainstay of  treatment • Avoid prednisone (oral and injectable) • Clobetasol ointment qd for 5 days when severe then • Fluocininide (lidex) oint bid for 2 weeks then • Triamcinolone 0.1 % oint bid maintenance • FACE: HC or aclomethasone oint bid

Gentle Skin Care discussion

Atopic Dermatitis

• Steroids are okay to use‐not going to thin out  the skin  • Use steroids with grease‐bid • Bathing or showering 1‐2x’/wk and don’t even  dry off after bathing • Grease up immediately • Antihistamine (benadryl, atarax, doxepin) at  night so pt can sleep and break the  itch/scratch cycle

• Deeper exploration re: therapy particularly in  pediatrics group • Not sure whether it can be generalized to  adults • Dilute bleach baths decreased severity of  atopic derm in kids –on body‐not face Rx: ½ cup of bleach in full bathtub followed by  liberal use of emmolients‐once daily Anderson Curr Opin Ped 2009 Feb

6

7/23/2013

Do Bleach baths do anything to reduce  staph aureus carriage • Up to 90% of kids with atopic dermatitis  carry  staph aureus (usually not MRSA) • When the staph burden is great, thought is  that there is a flare of eczema • Standard treatment is 14 days of p.o. cephalosporin

• 3 treatment groups: 1) Bleach baths with mupiricin in nose 2) Plain bath water 3) Plain ointment ‐Group 1‐reduced staph aureus carriage rate to 4%  compared to controls at a rate of 75% ‐Group 1‐severity index of atopic derm reduced  Lofgren et al Curr Opin Ped 2001 Aug

Let’s go back in time

Nursing Education

• The old moist wraps: Used about 25 years ago Corticosteroid and ointment goes directly onto skin Moisten first layer‐kerlex, gauze, socks that are cut  open‐ring out for excess water Dry layer on top‐sleep in this overnight Can be done nightly for up to 2 weeks until gone OR Every 5 days‐watch for maceration of skin 

• Two nice studies: Great Britain and  Netherlands Atopic families who had the benefit of intense  nursing education did much better re: quality of  life and severity indices compared to families  who just saw the doctor. des Bes et al Acta DermatolVenereol 2011 Jan

7

7/23/2013

Food

Calcineurin inhibitors

• Not enough evidence to suggest that any  foods or categories of food contribute to  atopic dermatitis • Not enough evidence to suggest that breast  feeding reduces risk for developing atopic  dermatitis • Not enough evidence to suggest that holding  back on solids or milk after 4‐6 months of age  reduces risk for developing atopic dermatitis

• Tacrolimus (protopic ointment) and pimecrolimus ( elidel cream) • Being studied again against corticosteroids • Recommendation in children: do not use for  extended periods of time, especially in sun‐ exposed areas and in persons who are  immunosuppressed • My experience‐works best on face and stops  working after around 2 yrs of use Schmitt et al BJD 2011 Feb

Cutaneous Tinea • KOH is helpful in distinguishing tinea from eczema • Topical antifungals x 4‐6 weeks –your  formulary has econazole‐apply bid • Just say NO to Lotrisone PLEASE!

• Primary Care Provider: weird fungal infection?  Not responding to topical or oral antifungals. • Should I add topical steroids‐if so, which one? • Won’t I exacerbate the tinea?

8

7/23/2013

How to diagnose • This is corynebacterium‐ a bacterial infection  that causes pitted keratolysis of the foot and  has a very bad odor • Use topical erythromycin bid or oral  erythromycin for 10 days • You are right that antifungals won’t work – neither will steroids‐for this condition

• Not all dystrophic nails= onychomycosis • KOH‐difficult to do and operator dependent • CULTURE is gold standard but takes 3 weeks to grow  out. • Now PCR‐used in Scotland  with high sensitivity and  specificity • Cost effective and results in 72 hours Alexander et al Br. J Derm 2011 May

Onychomycosis • Topical treatment –use for the right type of  lesions • Naftin gel for small superficial lesions • Penlac (Ciclopirox 8%) reported to work 35‐ 52% of  the time

Right type of lesions for topicals • • • •

Lunula not affected Less than 5 nails affected No thickening of nails No separation of nail plate on sides

– cost: expensive

9

7/23/2013

Terbinafine (Lamisil) • Griseofulvin‐least hepatotoxic but lower  efficacy‐ 250 mg bid x 12‐18 months • Fluconazole‐ 150 mg qweek for more than 6  months  –July 2012 Dermat Tx Gupta AK et al

• Still the leader of the pack‐most effective in  terms of INITIAL and LONG‐TERM cure rate. • DOSE: 250 mg qd Continuously x 3 months  for fingernails and x4 months for toenails  (July 2012) i.e. no pulsing

• Itraconazole‐ can pulse it‐ 400 mg qd x 7 days  q month x 4 months

Onychomycosis A New Approach BASELINE        1 YR       5 YR Terbinafine   77%                   75%        50% Itraconazole   70%                  50%       13% Grispeg            41%                                         Fluconazole      ?                      ?               ?

• Toenails take 12‐18 months to grow • Pulse terbinafine 250 mg per day for 1 week  every 2‐3 months for one year • Booster dose at 9 months (250 mg qd x 1  month)

10

7/23/2013

Liver toxicity

What about laser?

• Transaminase elevation 0.4% to 1% with  terbinafine and intraconazole • Transaminase elevation does not predict liver  failure • Liver failure 1/100,000 • Terbinafine has gone generic

• Photo‐ inactivation laser and destructive  laser • Destructive laser‐reduced fungal elements  by 75‐85% but  long term?? • Photoinactivation‐mycologic cure at 9  months=38% (1 study) • No randomized controlled studies at this  point

• Pt notes changing mole‐also itchy.  Worried  she has melanoma

• Seborrheic keratosis‐reassure‐treatment not  covered by county services • You can apply cryotherapy 2 x 15 sec thaw  cycles or • Private derms in your county will do this for a  fee

11

7/23/2013

• 24 year old with new black bump • No others noted

• Looks like seb keratosis but that is unusual in   pt under the age of 29.  I want to biopsy this • We will contact pt for next live derm clinic • Cc scheduler‐book for live derm in 1 week

• Pt notes these get caught on shirt‐sometimes  get inflamed

• Skin tags‐benign • Primary can snip them off‐services not  covered by county

12

7/23/2013

• On pts back‐( I can see it  from  homunculous) • Sometimes wife squeezes out smelly  cheese –like material

• Epidermoid cyst‐not inflamed.  Does not  need to be excised unless repeatedly  inflamed. • Wife should stop squeezing this‐could  cause cyst contents to be released into  surrounding tissue‐causing inflammation • If pt wants this out‐please send to surgery  for excision

Inflamed Epidermoid Cysts • Primary Care Provider: pt came in with 2 day  history of enlarging lesion and increasing pain. • Started doxycyline

• Antibiotics‐USELESS‐this is abscessed‐6 papers and  metanalysis shows that antibiotics will not help where an I  and D should be • If just starting to become inflamed and cyst is small( < 1 cm),  can try intralesional Kenalog injection but see them back in  few days‐you can exacerbate the inflammation • This cyst is bigger than 1 cm • INCISE and DRAIN and PACK‐send to surgery or ER today • 6 weeks later, inspect for residual cyst and send pt for  excision to surgery

13

7/23/2013

Caution • We may not see this for a couple of days  (store and forward) so please don’t send  anything acute or if you must‐call or write an  email to personal account and we will pay  special attention

• 30 yr old HIV infected pt started septra 36 hrs ago‐looks like drug reaction.  I have stopped  the septra.  Should I give him prednisone?

Drug Reactions • This is toxic epidermal necrolysis. • Get him into the ICU with supportive nursing  care re: burn victim‐I will be by later today to  do the biopsy/frozen section • No evidence to support that prednisone is  helpful • Start IVIg NOW at high dose 2 mg/kg over 3  days‐qd infusion‐not a lot of evidence to  support that this works

• Thiazides known to give photodrug reaction • Calcium Channel blockers‐associated with non‐ specific eczematous reactions/itch in the elderly‐ starts on arms and legs‐if you can switch pt’s to  other drugs Summers et al JAMA Dermatol May 2013 • Allopurinol‐ rare drug reactions but 25%  mortality rate‐don’t use for hyperuricemia‐risk is  too high Kim et al Arthritis Care Res April 2013

14

7/23/2013

Total Body Redness: Drug • Drug Hypersensitivity Syndrome – – – – – – – – –

Allopurinol Dapsone Antiseizure medications Septra Nevirapine/Sustiva/Abacavir (+) fever (+) lymphadenopathy Check kidneys, check liver +/‐ Prednisone

• THE PROCEDURES!!!

• 30 yr old with multiple previous biopsies to  rule out melanoma.  Here for skin check. • No recent changes in moles • No family history of melanoma • Please see in live derm clinic • Agree and will book within 1‐2 months

Keloids • These are keloids • Did they come from acne‐if so‐look for other  acneiform lesions and let me know‐I can  discuss systemic acne treatment so that pt does not get new keloids after every acne  breakout. • Will need intralesional kenalog‐will book with  derm clinic for monthly injections‐book within  next two months

15

7/23/2013

Reply from practitioner • I like to inject keloids‐review with me

Alopecia areata • Non‐scarring alopecia‐we have no idea why it  starts and we don’t have preventive treatment  in terms of halting future episodes • Inject with intralesional kenalog 10mg/cc q  month for at least 6 months to see if there is  hair regrowth • Do you want to do this or do you want us to  do this in live derm clinic?

Alopecia Areata  Autoimmune  Occas assoc with atopic dermatitis  Stress?

Alopecia Areata Prognosis

Treatment

 Good: Short duration,  limited affected area

• No Rx alters prognosis

 Bad: long duration,  extensive involvement  & concomitant AD

• Local areas can be injected with  triamcinolone 10mg/ml (Kenalog®)

 Acute onset of well circumscribed, oval  patches of non‐scarring alopecia  No cure

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7/23/2013

• Pt has actinic keratosis • Can I freeze it with liquid nitrogen?

• Yes‐2 x 15 sec thaws –appropriate  treatment.  Please make sure that you have  looked at all sun‐exposed areas to rule out  non‐melanoma skin cancers • Please explain side effects • Please see pt back in 1 month‐if lesion not  resolved , please biopsy or send pt for  biopsy to live derm clinic • Other option‐we can book pt for live derm clinic in 4‐6 weeks‐please let me know

• Likely hyperkeratotic AK but book in derm clinic within 1 month‐I need to palpate to  r/o Squamous cell cancer

• Likely squamous cell cancer‐please book  with derm within next month for shave  biopsy Next steps: I will biopsy‐send pathology to dermatopath at UCSF If positive‐will send to plastics or dermsurgery for excision

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7/23/2013

• Pt notes hair loss and this bald spot x 3  months.  No other health problems.  Not on  any meds

• Hair loss‐will need live derm clinic  evaluation and possible biopsy for scarring  alopecia. • I suspect discoid lupus • Please order CBC and iron, Vit D, TSH,  VDRL, ANA • Book within 1 month

Discoid Lupus Erythematosis

• Pt with new lesions around nose‐thinks it  started when bacon fat hit face • No pain or itching

• Patchy Scarring Alopecia • Biopsy helpful • ANA –ve • Annual ANA if pt has DLE  under age 20‐5% chance of  SLE • Check ears, face & trunk • Rx: intralesional triamcinolone & antimalarials

18

7/23/2013

Cutanous Sarcoidosis • This is sarcoid • I want to make sure that she does not have  systemic involvement • Please order Cxray and PFT’s • Order a G6PD in case I need to start sytemic plaquenil • Start clobetasol oint qd to lesions • Would like to see within 2‐3 weeks

• As we manage patients in the upcoming years,  triage teledermatology allows primary care  providers and dermatologists to effectively  work together • Increased efficiency and access • Total cost of specialty service is less • Pt outcomes and satisfaction appear  to be  better

• Plum colored lesions around orifices • Has multiple morphologies and reaction patterns –less  common • Includes annular scaly patches on legs and erythema  nodosum • Can be only cutaneous but obligated to look for  systemic disease • Apply potent topical steroids, inject or use plaquinil,  MTX, azathioprine, thalidomide, accutane‐plaquinil will  not help with systemic disease • Prednisone used for systemic disease

Many Thanks!  

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7/23/2013

Every patient is an athlete:  Hot Topics in Sports Medicine 2013 Carlin Senter M.D. Primary Care Sports Medicine UCSF Internal Medicine and Orthopaedics

In 50 minutes you will know 1. The return to work/play progression for  concussion treatment. 2. 2 key radiographs for knee OA. 3. Updated treatment for knee OA. 4. The three pillars of the female athlete triad. 5. How to write an exercise prescription.

UCSF Essentials of Primary Care   August 6, 2013

Case #1 • 40 y/o woman presents to your office for ER follow‐up two  days after bike accident. • Slid out while crossing streetcar tracks on wet city streets.  • No loss of consciousness. • Taken by ambulance to ER. • Had trauma work‐up including head CT (‐). • Diagnosed with clavicle fracture, nonoperative tx by  orthopaedic surgeon, discharged home. • Has headache, fatigue, dizziness, light sensitivity. Trouble  staying focused at work, sleeping more than usual. • Normal neurologic exam.

Diagnosis: Concussion  • • • • • • •

H/o trauma Headache Fatigue Dizziness Light sensitivity Trouble staying focused at work Sleeping more than usual.

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Concussion definition

How would you treat the concussion? 1. Order urgent head CT to rule out subtle post  traumatic bleed, return to clinic after CT. 2. Rest from work and biking, return to clinic 1  week. 3. Return to work but rest from biking, return to  clinic in a month. 4. Return to work and biking (assuming cleared  by orthopaedic surgeon for clavicle fracture).

Blow to head, neck, body  force to brain Rapid onset of neurologic impairment Symptoms represent metabolic change in CNS Standard neuroimaging normal (CT, MRI) Graded set of clinical symptoms that may or may not  include loss of consciousness • Symptoms usually short‐lived and resolve  spontaneously but in some cases can be prolonged

• • • • •

Consensus statement on concussion in sport. Br J Sports Med. 2013 Apr;47(5):250-8

Concussion symptoms

Concussion pathophysiology

Physical

Sleep

Cognitive

Emotional

Force to  brain

Ion fluxes;  vasocon‐ striction

Need  glucose but  less blood  flow

Energy  crisis

Giza CC and Hovda DA, J of Athletic Training, 2001. Vespa et al, J Cerebral Blood Flow and Metabolism, 2005.

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Clinic concussion evaluation • History of injury

• Worsening headache • Does not recognize  people/places • Seizure • Increasing  • Increasing  confusion/irritability drowsiness • Weakness/numbness  • Focal neuro deficit arms or legs • Neck pain • Repeated vomiting • Loss of consciousness  • Slurred speech >30 seconds

http://www.cdc.gov/ncipc/tbi/Facts_for_Physicians_booklet.pdf.

– PMHx ADHD, anxiety, depression, head injury

• Neurological exam – – – – –

Mental status Cognitive functioning Strength, sensation, reflexes Balance Gait (tandem walk)

• Clinical status: improving or worsening since time  of injury? • Any need for emergent neuroimaging based on  hx or exam?

Accessed Nov. 9, 2008.

SCAT3: locker room or clinic

Concussion treatment • Cognitive rest • Physical rest – No same day return  to play

• Medication – Avoid aspirin and  ibuprofen – Tylenol OK

• Avoid alcohol • Avoid driving Consensus statement on concussion in sport. Br J Sports Med. 2013 Apr;47(5):250-8

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7/23/2013

Recovery time after sport concussion  in high school athletes 50% in 1 week 83% in 3 weeks 17% longer than 3 weeks (Collins MW et al, Neurosurgery, 2006.) High school athletes take longer to recover  based on neuropsychological testing  compared to college athletes (Field et al, J Pediatr, 2003.) • Prolonged symptoms: > 4 weeks. Consider  neurology or neuropsychology consult. • • • •

Return to work/play • Asymptomatic • Normal neurologic exam (SCAT2) – Cognitive – Balance

• Computerized neuropsychological testing

Guskiewitcz in SCAT2 Clin J Sports Med. July 2010.

Return to school/work • Increasing attention to need for cognitive rest  in concussion • First return to school/work, then return to  play • School/work note requesting  accommodations • Gradual return to school/work as symptoms  allow

Return to school progression Return to full  day of school

15 min cognitive  activity at a time No school.  Rest.

30 min schoolwork at a time until can do 1-2 hours

Return to ½ day of school

http://www.chop.edu/service/concussion-care-for-kids/returning-to-school.html

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Return to sports progression Clinician clearance

Asymptomatic

Light  aerobic  activity

Sport  specific  activity

Full  contact  practice

Game  play

Non‐ contact  training

Clinician clearance 2nd International Conference on Concussion in Sport (2004). 2005 Br J Sport Med 39:196.

New concussion statement 2012

Consensus statement on concussion in sport. Br J Sports Med. 2013 Apr;47(5):250-8

Case #2 • 65 y/o man presents for new patient  appointment. • Tired, lots of stress at work, doesn’t exercise  due to right knee pain. H/o meniscus surgery  in college due to football injury. • BP 135/80, 6’2”, 250# (BMI 32), HR 80

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7/23/2013

Case #2 history • • • • • • • • •

Onset Provocation Quality Radiation Severity Timing Locking Swelling Instability

Physical exam

Gradual Walking Generalized ache To thigh Worst at night, can prevent from  falling asleep, stiff in AM < 30 min • No • Yes, more if walks on the beach • When painful

• • • • •

Physical exam case #2 • I: large effusion, varus alignment of knees • P: tender medial joint line and above/below  medial joint line. Nontender patellar facets  and lateral joint line • R: 5‐110, limited 2/2 pain and swelling • Other Tests: (‐) laxity on ligament testing,  unable to perform McMurray due to limited  flexion

Diagnosis case #2 A. B. C. D. E.

Medial meniscus tear ACL tear Osteoarthritis Patellar dislocation Septic arthritis

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7/23/2013

Radiographs:  2 keys to ordering knee xrays 1. Minimum 2 views of every joint (AP and  lateral) 1. Knee has 2 articulations: want 2 views of each 1. Patella – femur 2. Femur‐ tibia

2. Weight‐bearing views to evaluate for arthritis – Arthritis is not painful if it’s not weight‐bearing.  Reproduce the painful situation to see the degree  of cartilage loss.

Lateral of the affected side

Flexion weight‐bearing PA view, aka  “Notch view” Patient standing, knees bent to 45 degrees.

• Evaluate medial and lateral compartments for OA • Fractures

Merchant view = axial view of the patella

• Patellofemoral compartment • Patellar fracture

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7/23/2013

Radiographic findings in osteoarthritis

Nonpharmacologic tx knee OA • YES: strongly recommended

1. Joint space  narrowing 2. Subchondral sclerosis 3. Osteophytosis

– Cardiovascular and/or resistance exercise • Land‐based • Aquatic

– Weight loss

• YES: conditionally recommended – Self‐management program – Physical therapy (manual + supervised exercise) – Tai chi

• DON’T KNOW http://www.hopkins-arthritis.org/arthritisnews/2009/Chondroitin-Sulfate-May-Act-as-aStructure-Modifying-Agent-in-KneeOsteoarthritis html

Pharmacologic tx for initial  management knee OA • YES : conditionally recommend – Acetaminophen, Oral NSAIDs, Topical NSAIDs – Tramadol – Intraarticular corticosteroid injections

• NO : conditionally do not recommend – Chondroitin sulfate – Glucosamine – Topical capsaicin

– Knee braces, manual therapy alone Hochberg et al. ACR 2012 Recommendations…in Osteoarthritis. Arthritis Care & Research, April 2012.

Nonpharmacologic tx for knee OA in  patient who cannot have TKA • Conditionally recommend – Acupuncture – Self use of transcutaneous electrical stimulation  (TENS unit)

• DON’T KNOW – Intraarticular hyaluronates – Duloxetine – Opioid analgesics Hochberg et al. ACR 2012 Recommendations…in Osteoarthritis. Arthritis Care & Research, April 2012.

Hochberg et al. ACR 2012 Recommendations…in Osteoarthritis. Arthritis Care & Research, April 2012.

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7/23/2013

Pharmacologic treatment for patient  who can’t have TKA • If not responding to initial recs, both non  pharmacologic and pharmacologic • Then – Strong recommendation: Opioid analgesics – Conditional recommendation: Duloxetine

Knee OA treatment summary 1. 2. 3. 4. 5. 6. 7. 8.

Exercise (water or land based) Weight loss Physical therapy (manual + supervised rehab) Tai Chi Self management Oral meds (acetaminophen or NSAID) Topical NSAID Injections (steroid up to 4x/year)

Hochberg et al. ACR 2012 Recommendations…in Osteoarthritis. Arthritis Care & Research, April 2012.

http://www.arthritis.org/conditions‐ treatments/disease‐center/osteoarthritis/

http://www.arthritis.org/resources/co mmunity‐programs/

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7/23/2013

Who needs surgery?

If conservative measures providing inadequate 1. Pain relief 2. Functional improvement

Locate the hip pain • Anterior groin = hip  joint, hip flexor • Buttock = SI joint,  lumbar spine • Lateral hip = greater  trochanteric bursitis,  gluteus tendinopathy • Radiating to thigh =  could be hip joint • Radiating to the foot =  lumbar spine

Case #3 • 20 y/o collegiate cross  country athlete • Presents to clinic with right  groin pain • Started a few weeks ago,  getting worse gradually • Still able to run but pain  gets worse the more she  runs, hard to lift her leg due  to pain

Differential diagnosis groin pain in young runner • Intraarticular hip  problem – Impingement – Labral tear – Femoral neck stress  fracture 

• Extraarticular hip  problem – Hip flexor strain – Sports hernia http://www.everydayhealth.co m/hip-pain/hip-anatomy.aspx

• GI/gyn problems Falvey EC et al, BJSM. 2007.

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Hip impingement

Hip labral tear

http://www.aafp.org/afp/1999/1015/p1687.html

Femoral neck stress fracture

5 questions for every athlete with  hip pain 1. Training: increased mileage? 2. Nutrition: Calories in versus calories out?  History of eating d/o? Dietary restrictions? 3. History of stress fractures? 4. Family history of osteoporosis? 5. Age of menarche? Amenorrhea?

http://www.eorthopod.com/content/stress-fracture-hip

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7/23/2013

Our patient – additional history

Our patient ‐ exam

• Increased mileage from 30 to 60 miles/week  in last month without increased caloric intake • No dietary restrictions or h/o eating d/o • (+) h/o tibial stress fracture in high school • No family history osteoporosis • Menses: menarche age 13. Regular periods  until college but none since freshman year (18  months) 

• Walking with right‐sided limp • Tender right inguinal region • Pain with passive ROM:  flexion, internal, and  external rotation of hip • Neurologically intact lower extremities but  pain with active hip flexion

Hip passive range of motion

What’s your leading diagnosis?

Flexion normal 120°

External rotation normal 40-60°

Internal rotation normal 30-40°

1. 2. 3. 4. 5.

Hip flexor strain Hip impingement or hip labral tear GI/gyn problems Sports hernia Femoral neck stress fracture

http://www.youtube.com/watch?v=5LNYdJIrWYo

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7/23/2013

High index of suspicion to prevent bad  outcome

Female athlete triad Low energy availability with or without eating d/o

Suboptimal energy availability

Healthy energy status OPTIMAL HEALTH Healthy bones

Low bone density

Healthy menstrual cycles

PATHOLOGY Irregular menses Osteoporosis

Amenorrhea

Nattiv A et al, ACSM Position Stand, 2007.

Female athlete triad treatment • Best treatment = prevention

• Cohort of 437 exercising women, mean age  18+/‐ 3 years and weight 127 lb. • Low BMD defined as Z score <‐1 and/or ≤‐2 • 2 most significant risk factors for low BMD  – Late menarche (≥ 15 yr) – Low BMI (≤ 18.5 kg/m²)

• More triad risk factors   increased risk low  bone mineral density

– Screen for risk factors – Finding 1 risk factor should prompt eval for others

• Increase energy availability  – Increase dietary intake – Decrease exercise – Can restore menses + increase bone mineral density

• Oral contraceptives: if increased energy availability does  not increase bone mineral density and/or restore menses • Multidisciplinary approach: primary care doctor,  nutritionist, psychologist, eating d/o specialist, athletic  trainer Nattiv A et al, ACSM Position Stand, 2007. Temme KE, Hoch AZ. Curr Sports Med Rep. 2013 May-Jun;12(3):190-9.

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Female athlete triad clinic tools high school physicals

Female athlete triad clinic tools detailed screening

• 4th Preparticipation evaluation monograph • http://www.aap.org/en‐us/professional‐resources/practice‐ support/Documents/Preparticipation‐Physical‐Exam‐Form.pdf

http://www.femaleathletetriad.org/

http://www.femaleathletetriad.org/for‐ professionals/information‐for‐physicians/

Female athlete triad detailed screening  questions

http://www.femaleathletetriad.org/~triad/wp‐ content/uploads/2008/11/ppe_for_website.pdf

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7/23/2013

Case #4

What treatment would most benefit  this patient now and in the long run?

• 55 y/o woman presents for routine annual exam. No  complaints but shocked that she gained 10# since  she saw you last year. Takes no medications. • BP 140/80, HR 80, Height: 5’3”, weight 170# (BMI 30) • Labs: – HgA1c 6.3% – Fasting glucose 104 – Total cholesterol 192, TG 119, HDL 50, LDL 118

Strong evidence that physical activity  associated with lower risk of • Coronary artery  disease • Stroke • High blood pressure • High cholesterol

• • • •

Type 2 diabetes Colon cancer Breast cancer Falls 

The exercise prescription:  What’s the right dose of activity?

Credit: Piotr Redlinski for The New York Times

US Dept Health and Human Services. Physical Activity Guidelines Advisory Committee Report, 2008: http://www.health.gov/paguidelines/guidelines/chapter2.aspx. Accessed 11/6/2011.

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Physical activity recommendations:  4 types of activities

•Frequency •Intensity •Time •Type

CV fitness Balance

Flexibility Strength

Estimating exercise intensity Heart rate Talk test

Low <50% max Can talk and  sing

Moderate 50‐70% max Can talk but  not sing

Physical activity recommendations:  components of each activity

Vigorous >70% max Can only say a  few words before pause  for breath

Exercise prescription: Combine activity with components

CV fitness Balance

Flexibility Strength

•Frequency •Intensity •Time •Type

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CV fitness recommendations Frequency

Intensity

Time

Type

5x/week

Moderate

30 minutes

Major muscle  groups

Balance recommendations Frequency

Intensity

Time

Type

2‐3d/week

Unknown

20 minutes

Heel‐toe walk,  stand on 1 foot,  Tai Chi

OR Frequency

Intensity

Time

Type

3x/week

Vigorous

20 minutes

Major muscle  groups

ACSM Position Stand on Prescribing Exercise, Med Sci Sports Ex, 2011.

Strength recommendations Frequency

Intensity

2‐3d/week

Novice: 40‐50% Unknown Experienced: 80%

Time

Type All major  muscle groups

ACSM Position Stand on Prescribing Exercise, Med Sci Sports Ex, 2011.

ACSM Position Stand on Prescribing Exercise, Med Sci Sports Ex, 2011.

Flexibility recommendations Frequency

Intensity

Time

Type

2‐3d/week

Stretch to  feeling of  tightness

Hold 10‐30 seconds

All major  muscle‐tendon  units

ACSM Position Stand on Prescribing Exercise, Med Sci Sports Ex, 2011.

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Action plan: Exercise is Medicine 1. Identify potential health benefits of exercise. 2. Is the patient healthy enough to begin  exercise? 3. Assess patient’s stage of change. 1. 2. 3. 4.

Precontemplation Contemplation Preparation Action and maintenance

4. Write the exercise prescription. http://exerciseismedicine.org/documents/HCPActionGuide.pdf. Accessed 11/6/11.

What makes a successful exercise  program? • Program characteristics  – Moderate intensity – Supervised activity by  experienced leader – Group support

• Individually tailored program – Goal‐setting – Reinforcement: social  support for behavioral  change – Problem‐solving

http://en.wikipedia.org/wiki/File:07-06_WtrAerob1a.jpg

Should we spend clinic time on this? • Small benefit of providing medium or high‐ intensity counseling on diet and exercise to  health patients – Healthy = no diabetes, heart disease,  hypertension, hyperlipidemia

• Spend clinic time… – Counseling patients who are less healthy – Counseling patients are motivated to change – Using community resources to motivate change Moyer VA; U.S. Preventive Services Task Force. Ann Intern Med. 2012 Sep 4;157(5):367-71.

Pedometers • Popular and effective for promoting physical activity • 10,000 steps/day was old recommendation • Update in 2011: – Pedometers don’t measure speed – May need <10,000 steps/day for sig health benefit – 100 steps/minute is rough estimate of moderate intensity  exercise – Recommend using steps/minute and the number of  minutes/session ACSM Position Stand on Prescribing Exercise, Medicine & Science in Sports & Exercise, 2011.

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Case • 55 y/o woman presents for routine annual exam. No  complaints but shocked that she gained 10# since  she saw you last year. Takes no medications. • BP 140/80, HR 80, Height: 5’3”, weight 170# (BMI 30) • Labs: – HgA1c 6.3% – FPG 104 – Total cholesterol 192, TG 119, HDL 50, LDL 118

Write the exercise prescription

CV fitness Balance

Flexibility Strength

•Frequency •Intensity •Time •Type

Exercise prescription resources

Stationary bike 5/10 intensity 10 minutes each time 3 times a week Carlin Senter, MD http://bleacherreport.com/articles/1189176-bay-tobreakers-2012-changes-the-race-must-make

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http://www.cdc.gov/physicalactivity/everyone/guidelines/index.html Accessed October 23, 2011.

http://go4life.niapublications.org/try-theseexercises#strength-exercises Accessed October 23, 2011.

http://go4life.niapublications.org/ Accessed October 23, 2011.

http://win.niddk.nih.gov/publications/walking.htm Accessed October 23, 2011.

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Thank you!

Carlin Senter, M.D. Primary Care Sports Medicine UCSF Internal Medicine and Orthopaedics

21

Detection and Treatment of NonMelanoma Skin Cancers Toby Maurer, MD University of California, San Francisco

• Sunscreens- Australian study randomized residents to daily use vs discretionary us between 1992 and 1996 • Risk for developing any melanoma reduced by 50% and invasive melanoma risk reduced by 73% • Same trial also showed reduction of risk of developing squamous cell cancer Green et al. J Clin Oncol 2011 Jan 20; 29:257

Basics of Skin Cancer • Large majority caused by sun exposure • Often sun exposure before age 20 • Persons who burn easily and tan poorly are at greatest risk

• Sunscreens- Australian study randomized residents to daily use vs discretionary us between 1992 and 1996 • Risk for developing any melanoma reduced by 50% and invasive melanoma risk reduced by 73% • Same trial also showed reduction of risk of developing squamous cell cancer Green et al. J Clin Oncol 2011 Jan 20; 29:257

1

Vitamin D controversy • Intermittant weekly UVB exposure is most convenient source of vit D. • Vit D-plays vital role in muscle and bone health • Decreased Vit D levels being implicated in more cancers/solid tumors • Right level of Vit D debated and oral doses and forms of vit D being worked out

Tanning Beds • International Agency for Research on Cancer • Comprehensive metaanlaysis found that risk of melanoma (skin and eye) increases by 75% when tanning begins before age 30. • Cite this to your young patients El Ghissassi et al. Lancet Oncol 2009 Aug 10:751

Bottom Line Recommendations • Sun exposure causes cancer • Supplement Vit D with food/vitamins until more is known

“I’m Here for a Skin Check” • Screening for skin cancer: an update from US preventive services task force: Annals of Internal Med 2009 Feb-Wolff T, et al. • Can screening by Primary MD reduce morbidity/mortality from skin cancer? • Hard to do study-need to follow 800,000 persons over long period of time to determine this-studies not done

2

Bottom line: • Not enough evidence for or against to advise that patients have routine full body exams BUT • Know risk factors and incorporate exam into full physical and teach patients what to look for

Basal Cell Carcinoma (BCC)

Non-Melanoma Skin Cancers • Basal cell carcinoma (BCC) • Actinic keratosis (AK) • Squamous cell carcinoma (SCC)

Diagnosis of BCC: Shave or Punch Biopsy

• Who is at Risk? – Age 20+ – Fair-skinned persons – Sun-exposed sites • over 50% on face

3

Recommended Treatment of BCC

Differential Diagnosis of BCC • • • • •

Intradermal Nevus Sebaceous hypersplasia Fibrous Papule (angiofibroma) Eczema Melanoma

Aldara (Imiquimod) • Topical therapy designed for wart treatment • Upregulates interferon/ down regulates tumor necrosis factor/works on toll like receptors • Seems to have efficacy in superficial BCC’s • Do Not use in BCC’s that are nodular or invasive • Biopsy to confirm diagnosis BEFORE treatment

• • • •

Surgical excision (head and neck) Curettage and desiccation (trunk) Radiation therapy (debilitated patient) Microscopically controlled surgery (Mohs) – Recurrent/sclerotic BCC’s – BCC’s on eyelid and nasal tip

Treatments NOT Recommended • Cryotherapy • Topical chemotherapy - 5 Fleurourical (Efudex) • Radiation therapy (good surgical candidate)

4

When to Refer • • • • •

It depends on your surgical skills > 1 cm Sclerotic BCC Recurrent BCC Eyelid BCC

Actinic Keratosis (AK) • Who is at risk? – Over age 35-40 – Fair-skinned persons – Sun-exposed sites • Face, forearms, hands, upper trunk

– History of chronic sun exposure

Diagnosis of AK

Clinical Features of AK • • • •

Red, adherent, scaly lesions, usually < 5mm Sandpapery, rough texture Tender when touched or shaved Thick, warty character (cutaneous horn)

• Diagnosis – Clinical features – Shave or punch biopsy

• Differential Diagnosis – BCC/SCC – Seborrheic keratosis – Wart

5

Treatment of AK • Cryotherapy-goal is 2x15 sec thaws • Topical chemotherapy/chemical peel – Efudex (5FU crème) 2x’s/day x 6 wks or Imiquimod3X’s /wk and 3 mos.

Photodynamic therapy • Place photosensitizer on skin and then use light therapy-increases absorbency of light • Evidence that it changes histologic features of photodamage and changes expression of oncogenes Uses in: • Actinic keratoses • Basal cell cancers • Superiority studies being evaluated • Bagazgoitia et al BJD 2011 July

Squamous Cell Carcinoma (SCC) • Who is at risk? – Age 50+ – Chronic sun exposure • Head, neck, lower lip, ears, dorsal hands, trunk

– Special circumstances • Immunosuppression (organ transplant) • Radiation therapy

Clinical Features of SCC • • • •

Papule, nodule or tumor Non-healing erosion or ulcer Cutaneous horn (wart-like lesion) Fixed, red, scaling patch/plaque (Bowen’sSCC-in-situ)

6

Differential Diagnosis of SCC • • • • •

Actinic keratosis Wart Seborrheic keratosis BCC Eczema or psoriasis

How to Diagnose • Punch or excisional/incisional biopsy • Shave biopsy for flat, non-elevated lesion

Treatment of SCC • Recommended treatment – Excision – Radiation therapy ( in debilitated patient)

• Treatments NOT recommended

When to Refer • • • •

SCC’s may metastasize Low threshold for biopsy and referral Regularly check draining lymph nodes High risk SCC’s

– Curettage and desiccation – Topical chemotherapy

7

High-risk SCC’s • • • •

Lip Temple Immunocompromised host (i.e. organ transplant) Area of previous radiation therapy

Keratoacanthomas • What are they?-self-healing SCC’s • Look like SCC’s but history is that they come up quickly • Biopsy to rule out SCC • Sometimes pathologist cannot tell the difference • Treat by injecting methotrexate, 5 FU-but close follow-up to make sure that tumor regression is evident-if not, excise like SCC

8

Risk Factors Distinguishing Pigmented Skin Lesions and Melanoma Toby Maurer, MD University of California, San Francisco

• Red/blond hair • Family history of melanoma • Sun exposure in childhood/intermittant sun exposure • Multiple nevi-typical and atypical in fair-skinned persons Melanoma- Miller AJ-NEJM July 2006-good review re: nevus to melanoma-what it takes

Survival • In 1940’s 5 year survival was 40%, now 90% • Survival assoc. with tumor thickness-early detection is what has changed statistic not the treatment

Specific Types of Melanoma • • • •

Lentigo maligna Nodular Melanoma Acral Melanoma Amelanotic Melanoma

1

How do we increase our chances of finding thin melanomas • Full body exam on everybody?-Not enough evidence to support Screening for skin cancer: an update from US preventive services task force: Annals of Internal Med 2009 Feb-Wolff T, et al.

• Concentrate on high risk folks and incorporate skin exam into physical exam-men 50 and olderlook at their backs

Ask these questions: 1) Personal or family history of melanoma? 2) History of atypical nevus that has been removed? 3) Presence of new or changing mole- i.e. change in size or color?

Factors Associated with physician discovery of early melanoma in middle-aged and older men. Arch Dermatol 2009 Apr Geller AC et al.

Melanoma • Melanoma may be INHERITED or occur SPORADICALLY • 10% of melanomas are of the INHERITED type Familial Atypical Multiple MoleMelanoma Syndrome (FAMMM)

Risk Factors for Sporadic (Nonhereditary) Melanoma • Numerous normal nevi, some atypical nevi • Sun sensitivity, excessive sun exposure

2

Clinical Features of FAMMM

Risk Categories (Lifetime Risk)

• Often numerous nevi (30-100+) • Nevi > 6mm in diameter • New nevi appear throughout life (after age 30) • Nevi in sun-protected areas (buttocks, breasts of females) • Family history of atypical nevi and melanoma

• Very low risk: pigmented races (Latino,African American ,Asian,etc.) • Low risk: Caucasian = 1% • Intermediate risk: Caucasian w/additional risk factors = 2% - 10% • High risk: FAMMM Syndrome up to 100%

Prevention • Self examination/spousal exam for low-risk individuals • Self examination/spousal exam and regular physician examination (yearly to every several years) for intermediate risk individuals • Self examination and examination by a dermatologist every 3-12 months for FAMMM kindred

• Take all nevi off-NO to “melanotomies” • Look for signature nevi and then identify ugly duckling Strategies for early melanoma detection Approaches to the patient with nevi-JAAD May 2009 Goodson A and Grossman D

3

If not sure: • Measure and see pt back in 3-6 months for reevaluation!!

Tools to improve the Art • Photography- available at pigmented nevus centers Involves mapping of nevi, far and close up photos Set of photos for pt and provider About $200.00

• Dermoscopy-magnified view of lesion-a science being developed and validated-needs lots of training; better developed in Europe • Confocal microscopy-looking at lesions in the human at the bedside • Genomic Hybridization-used by pathologists

Differential Diagnosis • • • • •

Seborrheic keratosis Nevus, blue nevus, halo nevus Solar (senile) lentigo Pigmented BCC Dermatofibroma

How to Diagnose • If melanoma is suspected, an excisional biopsy is recommended

4

Why Excisional Biopsy?

What to do if Melanoma

• The diagnosis and prognosis of melanoma is dependent on the depth of the lesion • Send your pathologist the whole thing

• Staging workup for melanomas > 1 mm in depth • Re-excise all melanomas with wider margins

What to Do if Melanoma Dx

If Melanoma:

• Depth is key – < 1 *mm *- Close clinical f/u and labs – > 1 *mm* - CT scans of chest, pelvis, MRI/PET scan brain & sentinel nodes to stage – Now also looking at mitoses to determine work-up – Melanoma center at least once (or call for latest guidelines) – Prognositc Importance of Sentinel Lymph Node in Thin Biopsies of MelanomaRanier JM et al. Ann Surg Oncol July 2006 – Management of Cutaneous Melanomas-Tsao, et al. NEJM Sept 2004-good review

• Re-excise area with larger surgical margins: size of reexcision dependent on the original depth of melanoma • Original melanoma in-situ-Excise 0.5 cm margin • Original melanoma < 1 mm-Excise 1.0 cm margin • Original melanoma >1 mm-Excise 2.0 cm margin • Coordinate with surgeon in the know and someone who can do nuclear scan/sentinal node at time of the reexcision if indicated.

5

Primary care follow-up

Follow-up for Melanomas

• For the first two years after diagnosis-see patient back q 6 months for total body exam • Looking for local recurrence, in-transit metastases, lymph node involvement and second melanomas. • Q yr CBC, LFT’s including LDH for lymph node involvement or ulcerative lesion • CXray-controversial

• Second melanomas 1% after 1 year, 2% at 5 yrs, 3% at 10 yrs and 5% at 20 yrs-regular f/u for LIFE (Cancer 97,2003) • Developing new risk trees for patients with thinner melanomas • Also look for non-melanoma skin cancer and nonHodgkin’s lymphoma (higher risk is those who had primary melanoma) • Melanoma risk is 5 x’s higher in renal transplant recipients

New Directions in Therapy • Surgical excision is our therapy • Very little to offer re: metastatic disease-6-9 month survival . Current chemo extends life to 1.3 yrs • Rational therapy that targets genes and interrupts signalling pathways for metastases Chudnovsky Y, Khavari P, Adams A. J. Clin Investigations April 2005

BRAF mutations and melanoma • Many melanomas have a BRAF mutationwithout chemotherapy, these may have a worse prognostic risk • There are many new therapies being developed which target this group of melanomas • vemurufinab-new therapy-extends life by 5.2 months-assoc with BCC’s and SCC’s • Ipilumibab-blocks BRAF immune responseincreased overall survival for metastatic melanoma but only by 4-6 months

6

Gene sequencing and melanoma • Many melanomas have identifiable mutationswithout chemotherapy, these may have a worse prognostic risk • There are many new therapies being developed which target this group of melanomas • Gleevac-CKIT mutation • PLX4032-new therapy for BRAF mutation • Ipilumibab-blocks BRAF gene expression-increased overall survival for metastatic melanoma but only by 4-6 months

Special Cases • Genital pigmented lesions • Congenital nevi • Pregnancy

Genital Pigmented Lesions • Follow the same rules as other pigmented lesions • 15% of genital melanoma pts had family history of melanoma

Congenital Nevi • • • •

< 1 cm - 1% Lifetime risk of melanoma 1-5 cm - Unknown risk > 5 cm - 10% Lifetime risk Have congenital nevi evaluated once by a dermatologist

7

Pregnancy • Nevi change during pregnancy • New ones appear • Should people who have had melanoma get pregnant? – Depends on depth of melanoma – Call Central Melanoma Center for advice

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7/23/2013

Physical Exam Skills and  Office Procedures in Orthopaedics

Outline • • • •

Knee exam  Knee aspiration and injection Shoulder exam Subacromial bursa injection

UCSF Essentials of Primary Care         August 14, 2012 Carlin Senter, M.D.

The quadriceps  muscles extend the  knee

Knee Anatomy

http://thefitcoach.wordpress.com/2012/04/07/267/

http://scientia.wikispaces.com/Thigh+and +Leg+‐+Lecture+Notes

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The quadriceps muscles merge to form the  quadriceps tendon… patellar tendon

The hamstrings flex the knee

www.hep2go.com

Pes anserine bursa

There are 4  main ligaments  in the knee

http://meded.ucsd.edu/clinicalmed/joints.htm

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7/23/2013

Meniscus

Musculoskeletal work‐up

• History • Inspection • Palpation • Range of motion • Other Tests

Knee exam

Common Causes of Knee Pain by Location of  Symptoms • Anterior: - Patellofemoral syndrome - Quadriceps tendinitis - Patellar tendinitis

• Medial

• Lateral: - Lateral jointline: meniscus tear or OA - IT band syndrome - LCL sprain (rare) - Fibular head: fracture (rare)

• Posterior - Hamstring tendinitis - Gastrocnemius strain - OA, meniscus tears, effusion, popliteal cyst….

- Medial joint-line: meniscus tear or OA - MCL sprain - Pes anserine bursitis

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7/23/2013

Inspection

http://doctorhoang.wordpress.com/20 10/09/06/valgus‐knee‐and‐bunion/

http://meded.ucsd.edu/cl inicalmed/joints.htm

Palpation of patella - supine

Palpation of joint line seated or supine

http://www.rheumors.com/kneeexam/palpation.html

Palpation of patellar facet

Ballottement

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7/23/2013

Knee range of motion

Other Tests: Lachman to evaluate ACL Sensitivity 75‐100%   Specificity 95‐100%

• ROM: normal 0‐135 – Determine if knee is locking or if ROM is limited due to  effusion – Locking: think bucket handle meniscus. • Urgent xrays, MRI • Urgent referral to sports surgeon for arthroscopy

Permission for use provided by  Dr. Charles Goldberg, UCSD

PCL: Posterior Drawer

Magee, DJ. Orthopaedic Physical Assessment, 5th ed. 2008.

MCL and LCL

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7/23/2013

Meniscus: McMurray

Meniscus: Thessaly

Sensitivity medial 65%, Specificity medial 93% Magee, DJ. Orthopaedic Physical Assessment, 5th ed. 2008.

Knee exam practice

Meniscus: Squat

• Standing: inspection – Varus or valgus

• Sitting: palpation – – – –

Joint line Femoral condyles Tibial plateau Fibular head

• Supine – – – –

Patellar facets Patellar grind ROM Special tests Lachman Posterior drawer Varus 0 and 30 Valgus 0 and 30 McMurray medial and  lateral • Thessaly • Squat • • • • •

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7/23/2013

Intra‐articular corticosteroid  injections: do they work for knee OA? • Good short‐term pain relief – Effect size 0.72 at 2 and 3 weeks

Knee aspiration and injection

• No significant effect on function – Effect size 0.06

• No evidence for long‐term pain relief • Clinical effect independent of degree of inflammation  present  – Don’t need to restrict injection just to those with effusion

• Frequency: general practice once every 3 months max – Concern for cartilage toxicity with more than 4/year

• AAOS: recommends for short‐term pain relief (level II) Zhang W et al. OARSI recommendations for the management of hip and  knee osteoarthritis: Osteoarthritis Cartilage. 2010 Apr;18(4):476‐99.

Superolateral approach • Patient supine • Extend knee • Bump under knee so  flexed 10‐20 degrees • Superior border patella • Lateral border patella • 1cm below • Mark with syringe cover  or tip of pen

Injection set‐up bucket • • • • •

Betadine Ethyl chloride Alcohol swabs 4x4 guaze Bandaids

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7/23/2013

Injection prep

Needles, syringes, meds

Corticosteroids

Why use local anesthetic with steroid  injection? • Dilute the steroid – Decrease likelihood of steroid atrophy – Decrease irritant nature of steroid crystals causing  post‐injection flare

• Pain relief – Diagnostic and therapeutic (subacromial more than  knee)

• Floculation: combining steroid and local  anesthetic can precipitate crystals. Carefully  inspect for precipitate before injection.

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7/23/2013

Why aspirate the effusion before  injection?

Aspiration

• Clinically – Decreased pain and stiffness because effusion gone – More effect of steroid because not diluted by effusion – Inspect fluid for inflammation/infection, send to lab if  question – Confirms that injxn was intra‐articular

• Significantly greater improvement in VAS for patients  who had joint aspirated at time of injection in knee OA  patients (Gaffney K et al, Ann Rheum Dis, 1995.) • Reduction in relapse for 6 months after injection in RA  patients (Weitoft T et al, Ann Rheum Dis, 2000.)

Post‐injection patient instructions • Rest: no definitive evidence‐based  recommendation – Recommendations in literature vary • No restrictions • Bed rest x 24 hours • Light activity x 7 days, no weight bearing exercise

• Avoid swimming, hot tub, bath x 24 hours

Contraindications to steroid injection Joint infection Fracture Prosthetic joint Hemarthrosis (theoretically higher risk of  infection) • Soft tissue infection overlying joint

• • • •

– Let injection site heal

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7/23/2013

Relative contraindications to steroid  injection • Corticosteroid injection within past 4 months • Coagulopathy (ok if on warfarin but check  recent INR, make sure not >> 3)  • Poorly controlled diabetes

Risks of steroid injection in the knee • Diabetics: increased blood sugar, 300 mg/dl starting as early as 2 hours  after, lasting 5 days • Suppression of hypothalamic pituitary adrenal axis, mild – Lasts 1‐3 days post‐injection

• Facial flushing: 10% with Kenalog – 19‐36 hours post‐injection

• Skin or fat atrophy • Post‐injection steroid flare: 1‐10% – Synovitis in response to injected crystals – Within hours ‐ 48 hours post‐injection – More common in soft tissue injections (20% of trigger points) than intra‐ articular injections

• Septic arthritis: 1/3000‐1/50,000 – 1‐2 days after injection

• Possible risk of chondrocyte toxicity with repeated injections Habib GS. Clin Rheumatol, 2009. UpToDate, “Joint aspiration or injection in adults,” 2010.

My current knee injection steps 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Knee injection

Patient supine with bump under knee Mark injection site (superior lateral) Betadine x 3 Alcohol x 1 Ethyl chloride for skin anesthesia Alcohol again 22g needle attached to 10cc syringe containing 5cc of 1%  lidocaine without epi Slowly advance and inject lidocaine, 1mm at a time Feel resistance give when in joint Aspirate, make sure fluid straw‐colored and clear Keep needle in place, switch syringe  Inject 1cc of 40mg kenalog

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7/23/2013

Underlying Anatomy ‐ Bones

Shoulder anatomy

Acromion Greater  Tuberosity

• Humerus • Scapula o Glenoid o Acromion o Coracoid o Scapular body • Clavicle • Sternum

Clavicle

Glenohumeral  Joint

Lesser  Tuberosity

The LABRUM is a fibrocartilaginous ring of tissue that attaches to the glenoid rim & deepens the glenoid fossa

Acromion

Spine of scapula is at the level of T3

Bottom of scapula is at level of T7

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7/23/2013

Supraspinatus (Abduction)

The Rotator Cuff Muscles (SITS) The tendons of the  rotator cuff muscles  reinforce the capsule  of the glenohumeral joint. 

Greater  Tubersosity

Posterior View

Lesser  Tuberosity

Anterior View

Subscapularis (Internal Rotation)

The Biceps Muscle

Infraspinatus (External rotation))

Teres Minor (External rotation)

Shoulder exam

• #1 Supination of the elbow (screwing, twisting) • #2 Flexion of the elbow

Long  head

3 attachments: • Radial tuberosity (distal) • Glenoid (long head) • Coracoid (short head) Short  head

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7/23/2013

Cervical Spine

Neck examination • • • •

• Neck extended • Head rotated toward affected shoulder • Axial load placed on the cervical spine • Reproduction of patient’s shoulder/arm pain indicates possible nerve root compression

Inspection Palpate CS FF and extension Spurlings

Shoulder examination

Shoulder examination • Inspection

• Inspection

• Palpation

– Patient in gown

• Palpation • ROM • Strength

• ROM • Strength – Supraspinatus – Infraspinatus &  Teres minor – Subscapularis

– Supra – Infra and teres minor – Subscapularis

• Other tests

Spurling’s Maneuver

http://meded.ucsd.edu/clinicalmed/joints 2.htm, permission granted by Dr. Charles  Goldberg, UCSD SOM

http://meded.ucsd.edu/clinic almed/joints2.htm,  permission granted by Dr.  Charles Goldberg, UCSD SOM

• Other tests

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7/23/2013

Range of motion

Range of motion

Internal  rotation

Abduction External rotation

Flexion

Other tests

Supine shoulder PROM • • • • •

Rotator cuff strength Impingement tests Biceps Labrum AC joint

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7/23/2013

Supraspinatus = abduction

Infraspinatus and teres minor =  external rotation

Supraspinatus

Infraspinatus

Teres minor

Empty can Photos from Dr. Christina Allen

Subscapularis = internal rotation

Photos from Dr. Christina Allen

Subscapularis = internal rotation

Subscapularis

Lift‐Off

Subscapularis

Belly press Photos from Dr. Christina Allen

Photos from Dr. Christina Allen

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7/23/2013

Impingement signs

Impingement syndrome • Inflammation of the  subacromial space

Subacromial bursa

Supraspinatus

– The area under the  acromion and above the  glenohumeral joint – Structures in this space • Supraspinatus • Subacromial/subdeltoid bursa

Hawkin’s Photos from Dr. Christina Allen

Biceps Tests: Speeds

Biceps Tests: Yergasons

Tests for biceps pathology  (tendinitis, tendinopathy,  tear)

Tests for biceps pathology  (tendinitis, tendinopathy,  tear)

Palms up, patient pushes  up against resistance  (resisted elbow flexion)

Patient supinates (twists  out) against resistance

+Test is pain at proximal  biceps tendon Sens = 54%, Spec = 81%

Neer’s

+Test is pain at proximal  biceps tendon Sens = 41%, Spec = 79%

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7/23/2013

O’Brien’s Test To r/o Labral Tear • Arm forward flexed to 90° • Elbow fully extended • Arm adducted 10° to 15° with thumb down • Downward pressure • Repeat with thumb up • Suggestive of labral tear if more pain with thumb down • Sens = 59-94%, Spec = 28-92%

• Tests for AC joint  osteoarthritis or  sprain • Can be done  passively by  patient or  physician • +Test is pain at  AC joint

Shoulder Exam Hands On Key Components of the  Shoulder Exam: ‐ Inspection ‐ Palpation  ‐ Range of Motion:  abduction, flexion, ER, IR ‐ Strength ‐ Neurovascular ‐ Special tests

Testing the AC Joint:  AC Crossover

Special Tests: • Spurling’s (cervical spine radiculopathy) • Job’s, aka Empty‐can (supraspinatus) • Lift‐off test (subscapularis) • Resisted external rotation  (infraspinatus) • Hawkins (impingement sign) • Neers (impingement sign) • Speeds (biceps) • Yergason’s (biceps) • O’briens (SLAP tear) • AC crossover (AC joint OA or sprain)

Subacromial injection for  impingement syndrome

http://www.youtube.com/watch?v=wr_FBVjHJY8

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7/23/2013

Impingement syndrome • Inflammation of the  subacromial space

Subacromial bursa

Approach Supraspinatus

1. Posterior 2. Lateral

– The area under the  acromion and above the  glenohumeral joint – Structures in this space • Supraspinatus • Subacromial/subdeltoid bursa

Slide courtesy of Anthony Luke, M.D.

Subacromial Injection Posterior approach Landmarks • Posterior and lateral  borders of acromion • Coracoid Technique • Insert needle at Posterior  “soft spot” • Aim parallel to angle of  lateral acromion to reach  subacromial bursa • Direct needle towards  opposite nipple

http://www.aafp.org/afp/2003/0315/p1271.html

Slide courtesy of Anthony Luke, M.D.

Subacromial Injection Lateral approach Landmarks • Lateral border of the  acromion  Technique • Inject 3 mm below lateral  border of the acromion • Angle needle parallel to  plane of the acromion Slide courtesy of Anthony Luke, M.D.

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7/23/2013

Subacromial Injection

Subacromial injection palpation

• 5 – 8 mL combination of local anesthetic  solutions • 1 – 2 mL steroid solution My preferred solution: • 5 mL 1% lidocaine with 1 mL 40 mg/mL  triamcinolone

Subacromial injection

Thank you

Questions?  [email protected]

19

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

You are serving as a delegate at the AMA House of Delegates. You are asked: Is obesity a disease?

Robert B. Baron MD MS Professor of Medicine Associate Dean for GME and CME

1. Yes 2. No

Director, UCSF Weight Management Program

Declaration of full disclosure: No conflict of interest

Prevalence of Obesity (Adults)  Obesity: 33.8%  Men: 32.2%

Men and Women Aged 40 to 59 Years in 1999-2000 and 2007-2008

Women: 35.5%

 Overweight + obesity: 68%  Men: 72.3% Women: 64.1% .

 Severe Obesity: 6% Flegal JAMA 2010

1

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

Prevalence of Obesity (Children)

Prevalence of Obesity and Trends in Body Mass Index Among US Children and Adolescents, 1999-2010

 Severe obesity (97 percentile): 11.9%  Obesity (95 percentile): 16.9%  Overweight (85 percentile): 31%  No increase from 1999 to 2008  (except severe obesity in boys) JAMA. 2012;307(5):483-490

Flegal JAMA 2010 Copyright © 2012 American Medical Association. All rights reserved.

Obesity Trends* Among U.S. Adults BRFSS, 2010

Obesity Disparities

(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

 Women, 40-59  Black: 52%, Hispanic: 47%, Whites: 36%  Teens  Black: 29%, Hispanic: 17.5%, Whites: 14.5%  Mental illness  Overweight + obese: 83% No Data

<10%

10%–14%

15%–19%

20%–24%

25%–29%

≥30%

Flegal JAMA 2010

2

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

For a 40 yo woman, with normal BP, lipids, and FBS which BMI is associated with the lowest allcause mortality? 1. 2. 3. 4. 5.

BMI (kg/m2)

I II III

<18.5 18.5 – 24.9 25.0 – 29.9 30.0 – 34.9 35.0 – 39.9 >40

Extreme Obesity

BMI AND MORTALITY: Overall

MORTALITY AND OBESITY Meta-analysis of 97 studies of 2.8M people, 270,000 deaths

Combined NHANES I, II, and III data set

<18.5 18.5-<25 25 to <30 30 to <35 ≥35

Obesity Class Underweight Normal Overweight Obesity

18 24 28 34 38

BMI

CLASSIFICATION OF OVERWEIGHT AND OBESITY BY BMI

25-59 y

60-69 y

≥70 y

1.38 1.00 0.83 1.20 1.83

2.30 1.00 0.95 1.13 1.63

1.69 1.00 0.91 1.03 1.17

Flegal, JAMA, 2005

BMI Below 25 (Normal) 25-30 (Overweight) Above 30 (Obese) *** 30-35 (Grade 1 Obesity) Above 35 (Grade 2/3 Obesity)

HR 1.0 0.94 1.18 0.95 1.29 Flegal, JAMA, 2013

3

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

For a 40 yo woman, with normal BP, lipids, and FBS which BMI is associated with the lowest allcause mortality? 1. 2. 3. 4. 5.

18 24 28 34 38

You are serving as a delegate at the AMA House of Delegates. You are asked: Is obesity a disease? 1. Yes 2. No

Epidemic of Inactivity 60% US adults don’t exercise regularly 25% are sedentary

EXERCISE FOR OBESITY Meta-analysis of 43 RCTs: 3476 participants • Exercise plus diet vs diet alone – -1.1 kg • Increased intensity of exercise – -1.5 kg • Exercise without weight loss – Reduced: BP, triglycerides, blood sugar Shaw, Cochrane, 2006

4

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

FITNESS AND MORTALITY Aerobics Center Longitudinal Study 25,714 men, 44 years old, 14 year observational study

Relative Risk* of Death According to Body Mass and Physical Activity Physical activity level

2.42

> 3.5 hours/week 1 – 3.4 hours/week

CV death (RR) normal Fit 1.0 Not fit 3.1

overweight 1.5 4.5

obese 1.6 5.0

Total death (RR) normal Fit 1.0 Not fit 2.2

overweight 1.1 2.5

obese 1.1 3.1

< 1 hour/week

** 1.18 1.00

< 25

1.91 1.64

1.55 1.28 1.33

25 – 29.9

> 30

Body mass index (BMI) * RR’s adjusted for age, smoking status, family history, menopausal status, hormone use, and other factors Wei, JAMA 1999

** Reference group = women with 3.5 or > hours/week of physical activity and BMI of 25 or less

Hu FB, et al. N Engl J Med 2004;351:2694

Estimating Calorie Needs To estimate calories for weight maintenance:  If you are moderately active, multiply current weight (pounds) x 15. To estimate calories for weight loss:  Subtract 500 calories to lose approximately 1.0 pound per week  A pound of fat is about 3500 kcals

5

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

COMPARISON OF ATKINS, ORNISH, WEIGHT WATCHERS, AND ZONE

COMPARISON OF ATKINS, ORNISH, WEIGHT WATCHERS, AND ZONE Weight loss associated with adherence, but not diet type

160 patients, randomly assigned Intention to treat at 1 year Wt Loss (kg) Completers (%)

Atkins 2.1 53

Ornish 3.3 50

WW 3.0 65

Zone 3.2 65

Ornish 6.6

WW 4.6

Zone 4.9

Completers at 1 year Wt Loss (kg)

Atkins 3.9

Each group: 25% lost 5%, 10% lost 10% of initial weight Each diet reduced LDL/HDL by 10% No significant effects on BP or glucose

Dansinger, JAMA 2005

COMPARISON OF WEIGHT LOSS DIETS WITH DIFFERENT MACRONUTRIENTS  RCT of 811 patients, 4 diets: fat/protein/carbs 20/15/65; 20/25/55; 40/15/45; 40/25/35  6 months: 6kg, 7% weight; at 2 years: completers lost 4kg; 15% lost 10% of weight  Results similar for:  15% pro v. 25% pro  20% fat v. 40% fat  35% carbs v. 65% carbs

Dansinger, JAMA, 2005

Heterogeneity of Response to Weight Loss Diets: Insulin Resistance  Insulin sensitive: low carb and high carb both effective for weight loss  Insulin resistant: low carb more effective

 Attendance highly correlated with weight loss; satiety, hunger, lipids, insulin all equal Sacks, NEJM, 2009

6

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

Very Low Calorie Diets (VLCD) vs Low Calorie Diets (LCD): Meta-analysis of 6 RCTs

• The type of diet does not really matter for weight loss.

• Trials with direct comparisons • Short-term: mean 12.7 weeks • Long-term: mean 1.9 years Weight loss (as % of initial weight): short-term long-term LCDs 9.7 5.0 VLCDs 16.1 6.3 (p)

(0.001)

WEIGHT LOSS DIET BOTTOM LINE

(0.2)

• Sticking to the diet does matter • Calories “trump” macronutrients • But, select healthy, nutrient rich foods

Tsai and Wadden, Obesity, 2006

Weight Loss Diet Tips • Ready to lose weight?

BEHAVIORAL ASPECTS OF WEIGHT LOSS

• Set realistic expectations.

Goal setting

• Choose diet that is easy to follow and compatible with lifestyle.

Self-monitoring

• Control portion size (plate method, etc).

Cognitive skills

Stimulus control

• Vegetables, fruit and whole grains • Maintaining the weight you lose is key.

7

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

40 yo woman, BMI 36. Much to your surprise (and satisfaction), she has lost 35 pounds. In order to maintain her new weight, her lifelong daily calorie intake should be: 1. 2 3 4. 5.

SUCCESSFUL WEIGHT LOSS MAINTENANCE  3000 subjects in National Weight Control Registry: 30-lb weight loss for 1-year  Average weight loss 33 kg (10 BMI units less), average weight maintenance 5.5 years  45 years old, 80% women, 97% Caucasian  46% overweight as child, 46% one parent obese, 27% both parents

2000 kcals 1800 kcals 1600 kcals 1400 kcals 1200 kcals

SUCCESSFUL WEIGHT LOSS MAINTENANCE • High levels of physical activity • Women 2545 kcal/week, men 3293 kcal/week • (1-hour moderate intensity per day • Only 9% report no physical activity

• Diet low in calories • 1381 kcal day • 4.87 meals or snacks/day • Fast food 0.74/week

• Regular self-monitoring of weight • 44% weigh once per day; 31% once per week

Wing, Am J Clin Nutr, 2005

8

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

40 yo woman, BMI 36. Much to your surprise, she has lost 35 pounds. In order to maintain her new weight, her lifelong daily calorie intake should be: 1. 2 3 4. 5.

2000 kcals 1800 kcals 1600 kcals 1400 kcals 1200 kcals

In the last year, I have prescribed a medication for weight loss.

1. Yes 2 No

The medication I have most commonly prescribed for weight loss is: 1. 2. 3. 4. 5. 6. 7.

Phentermine Orlistat (Xenical™, Alli™) Buproprion (Wellbutrin™) Exenatide (Byetta™, Bydureon™) Phentermine/topiramate (Qsymia™) Locaserin (Belviq™) Other

9

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

The Neuroendocrinology of Energy Balance

“LONG TERM” PHARMACOTHERAPY OF OBESITY Review of all RCT’s more than 36 weeks published since 1960 Weight loss in excess of placebo:

% of initial Phen-fen

SIBUTRAMINE AND CARDIOVASCULAR OUTCOMES (SCOUT)

 Outcomes MI, stroke, cardiac arrest, CV death  Results  Weight:  BP:  Combined outcome:  Nonfatal MI:  Nonfatal Stroke:  Death:

-1.7 kg 1.2 vs 1.4 mm Hg 11.4% vs. 10.0% (HR 1.16, p = 0.02) 4.1% vs. 3.1% (HR 1.28; p = 0.02) 2.6% vs 1.9% (HR 1.36; p = 0.03) No differences

kg’s 9.6 kg

Phentermine

8.1%

7.9 kg

Sibutramine

5.0%

4.3 kg

Orlistat

3.4%

3.4 kg

Dexfenfluramine

3.0%

2.5 Kg

Fluoxetine

-0.4%

-0.4 kg

Diethyproprion

-1.5%

-1.5 kg

LORCASERIN

 9804 patients, over 55, with CV disease or diabetes  Sibutramine vs. placebo, 3.4 year f/u

11.0%

Selective serotonin 2C receptor agonist RCT of 3,182 adults, 52 week study 45% vs. 55% drop-out (lorcaserin vs. placeb) 5.8±0.2 kg vs. 2.2±0.1 kg wt. loss Frequent adverse events: headache, dizziness, and nausea  No increase in valvulopathy     

James, NEJM 2010

Smith, NEJM, 2010

10

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

Weight Loss Medications: October, 2010 •

Sibutramine (Meridia™): withdrawn by Abbott







FDA panel approved after new round of studies



Industry sponsored study: 604 patients with type 2 diabetes • After 1 year, 3.1% more weight loss (criteria >5%) • 38% lost >5% weight vs. 16% on placebo



Lingering uncertainty re breast tumors, valvular heart disease, psychiatric issues



Approved June 2012. Trade name Belviq™

Lorcaserin (selective serotonin receptor agonist, more specific than fenfluramine): not approved by FDA





Increased risk of stroke and MI

Lorcaserin Update: May-June 2012

Animals with increased mammary adenocarcinoma

Phentermine/topiramate (Qnexa™): not approved by FDA

• • •

Psychiatric adverse events: sleep, anxiety depression: 21% vs 10% with placebo Increased heart rate Teratogenicity

Lorcaserin Update (Belviq™): June 2013

Phentermine/Topiramate Update: February-July 2012 •

FDA panel approved 20:2

• Classified as Schedule IV controlled



Industry sponsored study: 4323 subjects • 9.3% weight loss • Increased heart rate, increased cleft lip

• Available as of June 7, 2013



Recommend post-market monitoring for CV risk and recommendation against use in pregnancy



Company plans larger trial (16,000 subjects)



Approved July 2012. Trade name Qsymia™

substance

11

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

Phentermine/Topiramate (Qsymia™) Side Effects • Paraesthesia, dizziness, dysgeusia, insomnia,

constipation, dry mouth Fetal harm: cleft lip, cleft palate Mood disorders: anxiety and depression Suicidal thoughts or behavior Acute angle glaucoma Cognitive dysfunction: concentration memory, language Metabolic acidosis and renal failure Hypoglycemia (in association with diabeyes meds) Interactions with alcohol and sedatives

• • • • • • • •

Prescribing Phentermine/Topiramate (Qysmia™)



Two prescriptions: • 14 days on 3.75/23 and • 30 days on 7.5/46

• • • •

Need DEA # Fax to certified pharmacy Pharmacy will call patient Drug delivered to patient’s home



Local pharmacy availability soon

OTHER INVESTIGATIONAL DRUGS •

Buproprion/naltrexone (Contrave™): Approved by FDA panel 12/10; rejected by FDA 2/11 (concern re heart attacks and CV risk.)



Buproprion/zonisamide (Empatic™): Phase 3



Exenatide (Byetta™), Liraglutide (Victoza™: Phase 2/3



Pramlintide/metreleptin: Phase 2/3



Cetilistat: Phase 3 in Japan

PRINCIPLES OF DRUG THERAPY •

NIH: BMI > 30 kg/m2 or 27 kg/m2 with co-morbidity (but in practice almost never)



Motivated to begin structured exercise and low calorie diet



Begin medications at completion of one month successful diet and exercise



Continue medications only if additional weight loss achieved in first month with meds

12

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

Wouldn’t It Be Easier Just To Have Surgery ?

INDICATIONS FOR BARIATRIC SURGERY

Definition Normal Overweight Obese, class 1

BMI < 25 25-29.9 30-34.9

Obese, class 2 Obese, class 3 “Superobese”

35-39.9 with co-morbidity 40+ 60+

Restrictive and Mixed Procedures

Types of Surgery Restrictive • • • • •

Horizontal Gastroplasties Vertical Banded Gastroplasty (VGB) Silastic Ring Vertical Gastroplasty (SRVG) Adjustable Gastric Banding Sleeve Gastrectomy

SURGERY

VBG

Adjustable Gastric Banding

Roux-en-Y GB

Malabsorptive • • • •

Jejunoileal Bypass (JIB) Biliopancreatic Diversion (BPD) Duodenal Switch Long Limb Gastric Bypass

Restrictive with Malabsorptive Component •

Roux-en-Y Gastric Bypass (RYGPB)

13

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

Bariatric Surgery: Weight Change

Sleeve Gastrectomy

Years

LONG-TERM OUTCOMES OF LAP BAND • 151 patients, single center, 12 year f/u; 54.3% included

Sleeve Gastrectomy Indications  Very high risk of co-morbidities

(82/151) • Operative mortality: 0 • Mean weight loss: 20.75 kg (BMI decreased from 41.6 to 33.8) • 60% of patients satisfied; overall quality of life unchanged • 39% major complications; 60% required re-operation

Conclusion: Lap band results in poor long-term outcomes

 BMI >60  Possible non-compliance with meds (less risk of micronutrient deficiencies)  IBD, IBS, abdominal pain, SBO, adhesions, other GI morbidities

LABS Consortium, NEJM, 2009

14

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

Resolution of Comorbidities

Bariatric Surgery and Mortality Swedish Obese Subjects Study  4047 subjects, surgery vs. matched control. 10.9 years f/u Max weight loss % Control

Final weight loss % 2

Gastric bypass

32

25

Vertical banded Gastroplasty

25

16

Banding

20

14

Sjostrom, NEJM, 2007

35 yo woman, BMI 42 in good health, asks about bariatric surgery. Her surgeon suggests a laporoscopic roux-n-y. Her risk of mortality, DVT, reintervention, or prolonged hospital stay is: 1. 2. 3. 4. 5.

1 in 200 1 in 100 1 in 50 1 in 25 1 in 10

BARIATRIC SURGERY OUTCOMES •

Ten sites, 4776 patients. 3/4 roux-en-y (87% lap); 1/4 lap band



30 Day overall mortality: 0.3%



-lap band

0.0%

-roux-en-y (lap)

0.2%

-roux-en-y (open)

2.1%

Composite (death, DVT, reintervention, 30 + days in hosp): 4.1% -lap band

1.0%

-roux-en-y (lap)

4.8%

-roux-en-y (open)

7.8% LABS Consortium, NEJM, 2009

15

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

35 yo woman, BMI 42 in good health, asks about bariatric surgery. Her surgeon suggests a laporoscopic roux-n-y. Her risk of mortality, DVT, reintervention, or prolonged hospital stay is: 1. 2. 3. 4. 5.

57 yo woman, BMI 42 with diabetes, hypertension, and creatinine 1.4 asks about bariatric surgery. Her risk of mortality 30 days post-op is 1. 2. 3. 4. 5.

1 in 200 1 in 100 1 in 50 1 in 25 1 in 10

1 in 200 1 in 100 1 in 50 1 in 25 1 in 10

Mortality After Surgery

Bariatric Surgery and Mortality

Community Medicare Data: 55-64 year old

Swedish Obese Subjects Study

30 days 2.0%

90 days 2.7%

1 Year 5.2%

Deaths HR

Rate

Control

129

0.063

25

47

Surgery

101 0.76 (p = 0.04)

0.050

13

29

NNT

MI deaths Cancer deaths

77 over 11 years (approx 850 per year)

Sjostrom, NEJM, 2007

16

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

Nutrition after Bariatric Surgery

Weight Loss Before Bariatric Surgery 881 patients with gastric bypass; 6 month program to achieve 10% weight loss; 2/3 lost 5%; 1/2 lost 10% Weight Change

Complications %

Gain 5%

28.4

Gain 0-5%

27.9

Loss 0-5%

23.5

Gastric Bypass

Lap Band

Mulitvitamin 2 daily

Mulitvitamin 1 daily

(400 mcg folate) Omeprazole 20 mg daily

Omeprazole 20 mg daily

Calcium (500mg TID)

Calcium (500mg TID) Vitamin D (500 IU TID)

Loss 6-10%

14.2

Vitamin D (200 IU TID)

Loss 10%

18.0

Iron sulfate 325mg daily

(p for trend = 0.004)

Benotti, Arch Surg, 2009

(women) Vitamin B12 500mcg SL daily

BARON’S FACTS ABOUT OBESITY 





Environmental changes work: YES Diets work, but not for long in most people: YES, BUT THEY DO FOR SOME Exercise improves health independent of weight change and aid in weight maintenance: YES

BARON’S FACTS ABOUT OBESITY 









Continuation of conditions that promote weight loss promotes weight maintenance: YES

For children, programs that involve parents and home promote greater weight loss: MAYBE Provision of meals and meal replacement products promote greater weight loss: IN THE SHORT TERM Medications can help achieve meaningful weight loss for as long as agents can be used: BUT WHAT ABOUT LONGER TERM CLINICAL OUTCOMES? Surgery results in long term weight loss and reductions of diabetes and mortality: WITH COMPLICATIONS IN SOME/MANY AND A HIGH Casazza, NEJM 2013 NNT

17

Robert Baron, MD, MS

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

GOALS OF MANAGEMENT 

Be as fit as possible at current weight



Prevent further weight gain



The Magic Formula

If successful at 1 and 2, begin weight loss

18

Cervical Cancer Screening Guidelines:  Updates and Controversies

I have no financial interests in any  product I will discuss today.

Jody Steinauer, MD, MAS University of California, San Francisco

Objectives • To understand the latest cervical cancer screening  guidelines (updated in 2012)  • To review HPV co‐testing and how to manage  HPV+ and cytology – • To know current CDC recommendations for HPV  vaccination of women

Background • ~12,000 cervical cancer cases and 4,200 deaths per  year in the US (ACS, 2010) • Most successful cancer screening program in US – 70% reduction in deaths over last 60 years

*Obstet Gynecol 94:307‐10

1

Can we do better?

Why does pap screening work? • Sensitivity and specificity of pap/cytology not  great BUT • The organ is easily accessible for screening • Natural history is favorable :  – precursor exists that is detectable and treatable;  – time course before cancer develops is long – many opportunities to detect . Even if one test is false negative, get  another chance. 

• Half occur in women who are not screened or  inadequately screened.  – Tend to be poor, uninsured, with lack of access to care – A more sensitive test (like many marketed directly to  the public eg Thin Prep), will not fix this problem!

• In poor countries, cervical cancer remains a huge  problem. 

• It is cost‐effective because many years of life are  saved because cancer is actually prevented.

SEER Cervical Cancer Rates: 2003‐2007

Can we do better? YES! • False +:  – False positives cause anxiety and cost. – Spacing the screening interval, starting screening later  and HPV typing used correctly in conjunction with  cytology, will reduce false +’s and colposcopies

• Over‐treatment: – Only 30% of untreated CIN3 becomes invasive cancer  (over 30 yrs).  – Destroying all CIN3 =over‐treatment. Main harm is  preterm delivery.  – Smart screening, biomarkers, risk‐based approaches and  less aggressive (but still evidence‐based) treatment  guidelines can help.  http://seer.cancer.gov/statfacts/html/cervix.html

2

From virus to cancer

Cytology Primer • ASC‐US: atypical squamous cells of  undetermined significance  • LSIL: low‐grade squamous intraepithelial lesion  • HSIL: high‐grade squamous intraepithelial lesion • AGC: atypical glandular cells of undetermined  significance (AGUS)

Schiffman and Wright NEJM 2003;348(6):489‐490

Histology Primer Cervical intraepithelial neoplasia (CIN) Graded based on proportion of epithelium involved • CIN 1: indicates active HPV infection; treatment  discouraged since spontaneous resolution is high • CIN 2: most are treated, but about 40% resolve over a  6‐month period; treatment may be deferred in young  women • CIN 3: proximal cancer precursor

US Guidelines: the Big 3 • American College of Obstetricians and Gynecologists (ACOG)  2012: Screening for Cervical Cancer. Number 131, November  2012. • American Cancer Society, American Society for Colposcopy and  Cervical Pathology, American Society of Clinical Pathologists  (ACS/ASCCP/ASCP)  • US Preventive Services Task Force (USPSTF) 2012  Cervical cancer screening. At  http://www.uspreventiveservicestaskforce.org/uspstf/uspscerv. htm

Guidelines do not apply to immunocompromised women  (HIV+), those with in utero DES exposure and those with  prior CIN 2 or 3.

3

Evidence Review

Evidence Based Practice Center:  Evidence Report, May 2011 • Liquid‐based and conventional cytology do not differ • HPV testing finds more precancerous lesions but has  unclear effects on cancer and on harms (e.g.,  additional colposcopies) • HPV positivity incurs short‐term adverse psychological  effects • Women with negative HPV tests and normal cytology  may be at particularly low risk

http://www.uspreventiveservicestaskforce.org/uspstf11/cervcancer/cervcanceres.pdf

Age to Begin Screening

Age to Begin Screening • ACOG (2012): same as ACS/ASCCP/ASCP  • ACS/ASCCP/ASCP (2012): begin at age 21 (“no  screening” under age 21) • USPSTF (2012): begin at age 21 “regardless of sexual  history”, “D” recommendation (don’t screen under  age 21)

All agree: do not screen before age 21 years

4

Why is it ok to delay screening  until  age 21? • Cervical cancer extremely rare in younger women • HPV infection very common immediately after onset of  intercourse and 90% is cleared by host within 2 yrs • When dysplasia does occur in adolescents, it tends to be  low grade and transient (90% regression at 3 yr).  – If persists, plenty of time to detect and treat because  long progression time of pre‐invasive lesions to invasive  cancer

Potential adverse effects of LEEP Preterm delivery  Low birth weight PPROM

70%  82%  169%  Lancet 2006 367:489‐98

Potential adverse effects of cold knife cone Perinatal mortality  187%  Severe preterm delivery  178%  Extreme low birthweight 186% 

• Excision of dysplasia associated with harm • Bottom Line: HPV infection typically cleared. Screening in  adolescents therefore leads to treatment that is largely  over‐treatment . Harms>>>Benefits

BMJ 2008 Sep 18;337

Caution: No randomized trials.

Screening Interval

Cervical Cytology Guidelines  ACOG  Practice Bulletin #109 (2009) Criteria

Recommendation



Women under 21 yrs old

Avoid screening (regardless of age  or other risk factors)



21‐29 years old

Screen every  2 years



30 to 65 or 70 years old

May screen every 3 years



65 or 70 years old and older

May discontinue screening

• • •

HIV‐positive Immunosuppressed Exposed in utero to DES

Screen annually

5

Triple A Guideline: ACS, ASCCP,  Am Society for Clinical Pathology

USPSTF Cervical Cytology Guidelines  March 2012

CA CANCER J CLIN March 2012 Age

Screening

<21

No screening

21‐29

Cytology alone every 3 years

30‐65

Preferred:    Cytology + HPV every 5 years* OR Acceptable: Cytology alone every 3 years*

>65

No screening, following adequate neg prior screens

After total  hysterectomy

No screening, if no history of CIN2+ in the past 20 years or  cervical cancer ever

*If cytology result is negative or ASCUS + HPV negative

Screening frequency: ages 21‐29 •

Criteria

Grade

Recommendation



Cytology only, 21 to 65 years old

A

Every 3 years



Cytology + HPV co‐testing, 30‐65 years  old

A

Every 5 years



Women under 21 yrs old

D

Avoid screening



Age >65 with adequate prior screening  and not high risk

D

Avoid screening



Total hysterectomy; benign disease

D

Avoid screening



HPV testing, alone or in combination, <  30 years old

D

Avoid screening

Screening frequency: ages 30‐65

ACOG (2012): same as ACS/ASCCP/ASCP • ACOG (2012): same as ACS/ASCCP/ASCP 



ACS/ASCCP/ASCP (2012): cytology every 3 years



USPSTF (2012): cytology every 3 years (“A”)

• ACS/ASCCP/ASCP (2012): screen every 3 years with cytology  alone or every 5 years with cytology plus HPV testing  (‘preferred’ strategy, but a ‘weak’ recommendation)

All agree: no annual screening  ACS/ASCCP/ASCP: “Women of any age should not be screened  annually by any screening method.”

• USPSTF (2012): screen every 3 years with cytology alone or every 5 years with cytology plus HPV testing (but only for  ‘women who want to lengthen the screening interval’)

All agree: no HPV testing for primary screening USPSTF: “D” recommendation women under 30

6

Why the difference between <30  and >30 yo? • HR‐HPV co‐testing becomes clinically useful after age  30 • In <30yo: HPV often positive, often transiently.  Therefore, HPV testing not clinically useful. • > Age 30: HPV positivity more likely to represent  persistent HPV which is a significant risk factor for  dysplasia/cancer. Conversely, HPV negativity is a  strong negative predictor. 

Summary of Important Guideline  Changes • 1st time that all 3 organizations involved with cervical cancer  prevention have endorsed equivalent guidelines • Co‐testing is “ready for prime time” for women > 30 – But, co‐testing every 5 years (NOT every 3 years) • Women 21‐29: cytology every 3 years (NOT 1 or 2) • “3 consecutive documented negatives” no longer required • Stop screening women under 21 years of age • Stop screening women 65 and older if negative results and   adequate prior screening

Common Questions About Cytology  Intervals • Do virginal women need Pap smears? • Are the intervals any different for women – With multiple sexual partners? – Using hormonal contraceptives, menopausal  hormone therapy? – Who only have female partners? – Who are pregnant? ACOG: “Speculum examinations for cervical cancer  screening should begin at age 21 years,  irrespective of sexual activity of the patient.”

Modeling False  positives

Colposcopies

CIN 2‐3

Cancers

Cancer deaths

Cytology q3  years, ages 21‐ 65

350

758

80

8.5

1.55

Cytology q3  years until age  30 then co‐ testing q5 years

281

625

85

7.1

1.29

Per 1000 women screened over a lifetime.

NB: Women with normal cytology and persistent HPV+ were returned to  routine screening if colposcopy was normal.

“Modeling studies support similar benefits of co‐testing every 5  years and cytology every 3 years, demonstrating small  differences in expected cancer cases and cancer deaths.”

ACOG Committee Opinion No. 534 August 2012 

7

Co‐testing caveats • HPV has decreased specificity so if we co‐screen more  often than q5 years, patients will incur greater harm  without benefit  – Before doing co‐test, ensure patient is willing to be screened  every 5 years

• HPV‐based strategies also lead to more positives  – Some women will need prolonged surveillance  – Some women who would otherwise be able to stop at age  65 will require continued screening beyond age 65

Cotesting: what to do with HPV  positive/Pap normal women? About 8‐11% of women ages 30‐55 in the US will have  a positive HPV test (HC2) and a normal Pap test (Ann  Int Med April, 2008) At Kaiser Northern CA, about 3‐7% of women ages 30‐ 55 have a positive HPV test (HC2) and a normal Pap  test (Obstet Gynecol March 2009)

• What to do with HPV+, cytology negative?

HPV positive/Pap normal women Recommendations by ASCCP and ACOG:  • Repeat co‐test at 12 months.  – If negative q 5yr screening – If still HPV+ or if >= LSIL AS‐CUScolposcopy.  2012 ASCCP Guidelines; ObstetGynecol, Apr 2013

Alternate recommendation by ASCCP: • Perform HPV genotype‐specific  typing for 16 or 16/18.  – if positive, perform colposcopy.  – If negative, repeat co‐test at 12 months.

Age to End Screening • ACOG (2012): same as ACS/ASCCP/ASCP  • ACS/ASCCP/ASCP (2012): end at age 65 in those with  adequate negative prior screening (see next slide)  Once ended, do not resume screening in women who  have new partners. • USPSTF (2012): end at age 65 in those with adequate  negative prior screening 

8

What is “adequate prior screening”? 3 consecutive negative cytology results or  2 consecutive negative co‐tests  within the 10 years before ceasing screening,  with the most recent test occurring within the  past 5 years

Ending screening: regardless of age • ACOG, ACS and USPSTF: all agree that screening  following total hysterectomy with removal of the cervix  for benign disease is not indicated.  USPSTF: “D” recommendation • ACOG (2003): If hysterectomy for CIN 2 or 3, may stop  screening after 3 normal tests.  • ACOG (2012): Continued routine screening (cytology  ever 3 years) recommended for 20 years.

ACOG: bimanual pelvic examinations

The Prostate, Lung, Colorectal and Ovarian Cancer  Screening Randomized Controlled Trial

• “No evidence supports the routine internal  examination of the healthy, asymptomatic patient  before age 21 years…” but • “Annual pelvic examination of patients 21 years of  age or older is recommended by the College.” • Recommendation based on expert opinion • “No evidence supports or refutes the annual pelvic  examination or speculum and bimanual  examination for the asymptomatic, low‐risk  patient.”

• Randomized trial of 78 216 women aged 55‐74 • Annual screening with CA‐125 for 6 years and  transvaginal U/S for 4 years (n=39 105) versus usual  care (n=39 111) • 10 US screening centers  • Followed a median of 12 years • Bimanual examination originally part of the screening  procedures but was discontinued

ACOG Committee Opinion No. 534 August 2012 

JAMA. 2011;305(22):2295‐2303

9

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial

Routine exams “The decision to perform an internal pelvic  examination, breast examination, or both should be  made by the physician and the patient after shared  communication and decision making.” “Concerns, such as individual risk factors, patient  expectations, or medical–legal concerns may influence  the decision to perform an internal pelvic examination  or clinical breast examination.”

More cancers found but no effect on mortality.

JAMA. 2011;305(22):2295‐2303

After removal of the uterus and ovaries  in asymptomatic, low‐risk* women “The decision to receive an internal examination  can be left to the patient…” “Annual examination of the external genitalia  should continue.”

*no history of vulvar intraepithelial neoplasia, cervical intraepithelial  neoplasia grade 2+, immunocompromise and in utero DES exposure

ACOG Committee Opinion No. 534 August 2012 

What’s Better: Pap or LBC?

Siebers, 2009

• N=89,784, cluster RCT – No difference in detection rate (sensitivity)  or PPV, fewer  unsatisfactory tests with LBC Conclusion: no difference

• 2nd RCT, different design, similar findings • Evidence based practice center & 2 reviews  conclude: no difference in relative or absolute  sensitivity or specificity

ACOG Committee Opinion No. 534 August 2012 

10

HPV Vaccination • CDC: HPV vaccine advised for females  ages 11‐26

Summary • No cytology screening prior to age 21 • Annual cytology not recommended for most women – Annual screening is recommended for high‐risk women:  immunocompromised (HIV+), in utero DES exposure and  prior CIN grade 2 or 3 – Annual screening recommended “for at least 20 years” in  those with prior CIN grade 2 or 3 (ACOG, ASC)

• Co‐testing (HPV plus cytology) every 5 years may be  equivalent to cytology every 3 years for women aged  30‐65 years

Summary • Women aged 30‐65 who are resistant to screening  every 5 years are poor candidates for co‐testing (HPV  plus cytology) • Screening with (conventional) cytology alone (without  HPV testing) every 3 years is still a great option (and  perhaps the least complicated)

Questions

11

Guidelines for Screening for Cervical Cancer and its Precursors, 2010 San Francisco General Hospital These are guidelines for use of cervical cytology in asymptomatic women as a screening tool for cervical cancer and its precursors. Tests performed in symptomatic women should be evaluated in clinical context. Screening guidelines do not apply to women with prior treatment of high-grade cervical dysplasia (CIN 2 or CIN 3) or cervical cancer; see other aspects of this guideline for surveillance after treatment. Age to begin screening Interval of screening

Age to end screening

Age 21 years; avoid screening within 3 years of becoming sexually active and in known virgins. Screen every 2 years with cytology. At or after age 30 years, women with 3+ prior consecutive, normal tests may be screened every 3 years. Screening may end at or after age 65 years if 3+ consecutive, normal cytology tests have been documented within the prior 10 years and there is no history of treated CIN 2, CIN 3, AIS or cervical cancer.

Special populations Pregnant women Women with HIV infection or immunocompromised

Screen as above; do not screen within 3 years of becoming sexually active. Annual screening after 2 normal cytology tests 6 months apart in the year following initial HIV diagnosis or immunocompromised state. Screening should not be performed.

After total hysterectomy in women with no prior history of CIN 2 or CIN 3 After total hysterectomy in Annual cytology. After 3 consecutive, normal tests, women with a prior history of screening may be performed every 3 years. CIN 2 or CIN 3 After diagnosis and treatment Surveillance as per gynecologic oncology protocols of cervical cancer CIN indicates cervical intraepithelial lesion.

1- Sawaya & Smith-McCune, August 2010

Guidelines for Initial Management of Abnormal Cervical Cytology, 2010 San Francisco General Hospital Cytology Interpretation Common Benign Findings Unsatisfactory Satisfactory, but no endocervical cells Benign-appearing endometrial cells Epithelial Cell Abnormalities Atypical squamous cells of undetermined significance (ASC-US)

ASC, cannot exclude HSIL (ASC-H) Low-grade SIL (LSIL)

High-grade SIL (HSIL) Squamous cell carcinoma Glandular Cell Abnormalities Atypical glandular cells (AGC) • endocervical • endometrial • not otherwise specified Adenocarcinoma in situ (AIS) Common Infections • shift in flora suggestive of bacterial vaginosis (BV) • fungal organisms consistent with Candida. • cellular changes consistent with herpes simplex virus (HSV) • Trichomonas vaginalis (TV)

Action Repeat cytology next available Repeat cytology in 12 months Pre-menopausal: No action. Post-menopausal: Endometrial biopsy. Three different strategies may be adopted, but colposcopy is the least preferred: 1. Repeat cytology at 6 and 12 months. If ASC-US+, colposcopy. After 2 normal cytology tests, resume routine screening. 2. HPV testing for high-risk types. If positive, colposcopy. If negative, repeat cytology in one year; do not do HPV testing in women age 20 or less. 3. Colposcopy† If age 20 or less, repeat cytology at 12 months (colposcopy if ASC-H or HSIL+) and at 24 months (colposcopy if ASC-US+). If normal, resume routine screening. For pregnant women age 21+, repeat cytology at 6 months; if ASC-US+, colposcopy 6 weeks post-partum. Colposcopy† Colposcopy† If age 20 or less, repeat cytology at 12 months (colposcopy if ASC-H or HSIL+) and at 24 months (colposcopy if ASC-US+). If normal, resume routine screening. For pregnant women age 21+, colposcopy may be deferred to 6 weeks postpartum. For post-menopausal women, LSIL may be managed identically to ASC-US. Colposcopy† Colposcopy†

Colposcopy† with endocervical curettage (ECC) Colposcopy† with ECC and EMB Colposcopy† with ECC; add EMB if abnormal bleeding, chronic anovulation or age 35+ Colposcopy† with ECC and EMB

Consider evaluation of and treatment for BV if symptomatic. Repeat cytology at appropriate screening interval. Consider evaluation of and treatment for yeast vaginitis if symptomatic. Repeat cytology at appropriate screening interval. Diagnostic of HSV. Finding may indicate other STIs. Repeat cytology at appropriate screening interval. Consider evaluation of and treatment for TV if symptomatic. Finding may indicate other STIs. Repeat cytology at appropriate screening interval. DEP indicates diagnostic excisional procedure (e.g., cone biopsy, loop excision). HSIL+ indicates HSIL, AGC, AIS and/or cancer. ASC-US + indicates ASC-US, ASC-H, LSIL and/or HSIL+. ECC indicates endocervical curettage. †ECC should be performed in all non-pregnant women with unsatisfactory colposcopy and in those with cytology interpreted as AGC, AIS and cancer. Vaginal colposcopy with Lugol’s solution should be performed in all women with no obvious lesion seen and cytology interpreted as HSIL, AGC, AIS or cancer. In pregnant women, ECC is contraindicated.

2- Sawaya & Smith-McCune, August 2010

Guidelines for Follow-up after Initial Colposcopy, 2010 San Francisco General Hospital These are guidelines for the most common clinical scenarios. Patients may be managed individually based on clinical judgment.

Referral Cytology (pre-colposcopy)

Findings at initial colposcopy No visible lesion

ASC-US once ASC-US twice (unknown HPV status) ASC-US, positive high-risk HPV Atypical squamous cells, cannot exclude HSIL (ASC-H)

Visible lesion, biopsy-proven CIN 1

Cytology in 12 months. If normal, resume routine screening; if ASC+, repeat colposcopy at the next available appointment. Cytology in 6 and 12 months. The 6-month cytology result should be managed as follows: • If ASC or LSIL, repeat colposcopy at the next scheduled appointment (6 months). • If ASC-H or HSIL+, repeat colposcopy at the next available appointment. • If normal, repeat cytology at the next scheduled appointment (6 months); if cytology is normal at that time (i.e., at the 12-month visit), resume routine screening; if ASC+, repeat colposcopy at the next available appointment.

Biopsy-proven CIN 2 or 3 See “Guidelines for Treatment of biopsyproven cervical intraepithelial neoplasia (CIN) 2 (moderate dysplasia) and CIN 3 (CIS, severe dysplasia)”

Low- grade SIL (LSIL) High-grade SIL (HSIL)

If colposcopy is satisfactory, ECC is normal Treatment is preferred. and the vagina has no lesions, colposcopy and cytology every 6 months for 1 year is acceptable. DEP may also be performed (non-pregnant women only); review of outside cytology suggested prior to DEP. If colposcopy is unsatisfactory, DEP is preferred (non-pregnant women only). Atypical glandular cells (AGC) Cytology in 6, 12, 18 and 24 months. Repeat colposcopy if ASC-US+. After 4 normal cytology tests, resume routine screening. If AGC recurs, perform cone biopsy. Pelvic sonogram to rule out adnexal malignancy is recommended in women with persistent AGC. Adenocarcinoma in situ, cancer Cone biopsy CIN indicates cervical intraepithelial neoplasia. SIL indicates squamous intraepithelial lesion. HSIL+ indicates HSIL, AGC, adenocarcinoma in situ and/or cancer. ASC-US + indicates ASC-US, ASC-H, LSIL and/or HSIL+. DEP indicates diagnostic excisional procedure (e.g., cone biopsy, loop excision).

Smoking cessation is advised in all patients. HIV testing should be offered in all women with biopsy-proven CIN 3. Additional information on colposcopy by UCSF authors can be found by typing “GLOWM” and “colposcopy” into your search engine.

3- Sawaya & Smith-McCune, August 2010

Guidelines for treatment of biopsy-proven cervical intraepithelial neoplasia (CIN) 2 (moderate dysplasia) and CIN 3 (CIS, severe dysplasia), 2010 San Francisco General Hospital • CIN 2 and 3 can be treated by either an ablative or an excisional procedure in non-pregnant women. • Ablative methods include laser and cryotherapy; excisional methods include loop excision and cone biopsy. • In adolescents and young women with satisfactory colposcopy, CIN 2 may be managed with colposcopy and cytology surveillance every 6 months; routine screening may resume after 2 normal cytology tests and colposcopic exams. If surveillance is chosen, CIN 2 may be followed for up to 24 months without treatment. Alternatively, ablative therapy (e.g., cryotherapy) is the preferred treatment.

Treatment Cryotherapy

Laser ablation Loop excision (aka LEEP)

Cone biopsy

Factors affecting choice Appropriate for CIN 2 or CIN 3 if following general criteria met: • Satisfactory colposcopy • No prior cervical treatment • Lesion(s) completely visible and <2 cm in diameter • Lesion(s) can be covered entirely with the cryoprobe Often used for large lesions (>2 cm) with or without vaginal extension. Candidacy same as for cryotherapy. Choose for CIN 2 or CIN 3 lesions in which cryotherapy is inappropriate (e.g., unsatisfactory colposcopy, endocervical curettage with dysplasia). Choose instead of loop excision if suspicion for malignancy or recurrent atypical glandular cells (AGC) on cytology and/or cervical architecture disrupted.

Guidelines for follow-up after treatment of CIN 2 and CIN 3 Treatment Follow-up Cryotherapy or laser ablation Loop excision (LEEP) or cone biopsy Dysplasia in specimen, negative endocervical margin No dysplasia in specimen Dysplasia in specimen, positive endocervical margin

Cytology in 6 and 12 months; colposcopy for ASC-US+. After 2 normal tests, annual cytology. Cytology in 6 and 12 months; colposcopy for ASC-US+. After 2 normal tests, annual cytology.

Cytology and ECC in 6 months; colposcopy for ASC-US+. Then, cytology alone in 12 months; colposcopy for ASC-US+. Repeat excision if HSIL+ at any time. After 2 normal tests, annual cytology. Hysterectomy Annual cytology. After 3 consecutive, normal tests, screening may be performed every 3 years. ECC indicates endocervical curettage. ASC-US indicates atypical squamous cell of undetermined significance. HSIL indicates high-grade squamous intraepithelial lesion. HSIL+ indicates HSIL, AGC, adenocarcinoma in situ and/or cancer. ASC-US + indicates ASC-US, ASC-H, LSIL and/or HSIL+.

Guidelines for treatment and follow-up of adenocarcinoma in situ Treatment Follow-up Hysterectomy (treatment of choice) Cone biopsy

Annual cytology. After 3 consecutive, normal tests, screening may be performed every 3 years. Cytology and ECC every 4 months for 2 years, then every 6 months until hysterectomy.

Smoking cessation is advised in all patients. HIV testing should be offered in all women with biopsy-proven CIN 3.

4- Sawaya & Smith-McCune, August 2010

Conflicts of Interest Update in the Diagnosis, Treatment and Prevention of Dementia*



No Conflicts of Interest

Katherine Julian, M.D. Professor of Clinical Medicine University of California, San Francisco August 7, 2013

Case EM is a 67 year-old woman with a h/o high blood pressure. Brought in by husband who is reporting that patient’s personality has changed over the last year. She is becoming more suspicious, and at times talks and “doesn’t make sense”.

Questions...





Does EM have dementia or Alzheimer’s Disease (AD)? How do I make the diagnosis?

1

Outline     

Clinical Presentation Diagnosis Updates in Treatment Updates in Prevention Resources

AD Prevalence 



 



AD estimated prevalence 24.3 million world-wide in 2001 Predicted rise to 42.3 million in 2020 81.1 million by 2040 Lifetime risk of dementia after age 65 is 17-20% Costs $150 billion/yr

Ferri CP, et al. Lancet 2005; Simmons BB et al. AAFP 2011

Dementia Types   

Alzheimer’s: most common, 70% Vascular dementia: approx 17% Other types: 13% Parkinson-related  Alcohol  Dementia with Lewy Bodies 

Pathophysiology of AD 

Neuritic plaques Amyloid precursor protein cleaved  Makes beta amyloid protein  Accumulation initiates cell death 



Neurofibrillary tangles 



Loss of neurons 



filaments of abnormally phosphorylated tau protein Cholinergic, noradrenergic, serotonergic neurotransmitters

Is it amyloid deposition that kills neurons OR are neurons being damaged by something else?

2

Risk Factors for AD/Dementia       

Age Down’s syndrome Head trauma Fewer years of formal education Female sex Family history Vascular risk factors (DM, htn, smoking)

Clinical Presentation of Dementia   

Cognitive changes Personality changes Changes in day-to-day functioning 

  

Psychiatric symptoms Problem Behaviors Dementia under-diagnosed  

Rapid Screening for Cognitive Impairment 



Routine screening not recommended; complete screen for those who screen positive Variety of office screening tests MMSE sens 80-85% 7-min screen sens 93%  MOCA sens 90%  Clock drawing sens 97%  

IADLs that require calculation/planning first to be impaired

High index of suspicion Ask caregivers/surrounding family and friends

Definitions of Dementia* by DSM5 Dementia No longer using the term “dementia”  Neurocognitive disorder 

 Due

to…

 Alzheimer’s

Disease Disease  Lewy Body, etc  Vascular

J Hort JT, et al. European Journal of Neurology, 2010

3

DSM5 Neurocognitive Disorders (NCD) 

Minor neurocognitive disorder 

Modest cognitive decline from a previous baseline   

DSM5 Neurocognitive Disorders (NCD) 

Major neurocognitive disorder 

Can be in any domain (ex: memory, language, executive function, etc) Based on pt’s concerns AND knowledgeable informant (or clinician) AND Decline in neurocognitive performance (1-2 SD below normal) on formal testing or equivalent clinical evaluation

 

Cognitive decline doesn’t interfere with independence but requires some compensation  Can’t occur due to delirium  Deficits can’t be from another mental disorder (ex: depression) 





American Academy of Neurology recommendations: Vitamin B12, thyroid, depression screen  Other tests as indicated: blood count, urine tests, liver tests, syphilis test, lumbar puncture  Neuro imaging (CT or MRI) 



Do we need to do this?

Based on pt’s concerns AND knowledgeable informant (or clinician) AND Decline in neurocognitive performance (>2 SD below normal) on formal testing or equivalent clinical evaluation

Cognitive decline is sufficient to interfere with independence (ex: requires assistance with IADLs or ADLs)  Can’t occur due to delirium  Deficits can’t be from another mental disorder 

Example: Mild cognitive impairment: impairment doesn’t affect function

Work-Up of Cognitive Impairment

Evidence of substantial cognitive decline in one or more domains

“Reversible” Dementias…do they exist? 

Meta-analysis in 2003 



5620 subjects; potentially reversible causes in 9%; 0.6% actually resolved

Causes of dementia in meta-analysis    

56% AD 20% vascular 1% metabolic 0.9% depression 0.1% medications 15% Other (NPH, subdural hematoma, B12, tumor, Parkinson’s disease, HIV, frontal lobe) Clarfield AM. Archives of Internal Medicine, 2003;163.

4

“Reversible” Dementias…do they exist? 

Most reversible dementias were in patients who:  





 



Were relatively young Had mild or atypical symptoms

Neuroimaging detected conditions in 2.2% 

Neuro-Imaging – Updates  



0.9% tumor, 1% NPH, 0.3% SDH Most did not change course of illness

AGS recommends imaging: age <60, rapid decline (weeks/months), CA, HIV, anti-coagulation

  



Medial temporal lobe atrophy in AD New studies looking at hippocampal and cortical thickness

PET with fluorodeoxyglucose measures glucose metabolism (18F-FDG-PET) 

Reversible dementias less common Must weigh costs/benefits of neuro-imaging 

Semi-quantitative MRI

Hypometabolism in temporal/parietal regions Approved in US for dx purposes of AD in early stages Sens/spec estimate 86% (wide variation) PET with beta-amyloid ligands will visualize beta-amyloid deposition

May overlap with other brain pathologies

Clarfield AM. Archives of Internal Medicine, 2003;163.

Example of 18F-FDG-PET

Diagnosis of AD – Updates 

Abnormal CSF biomarkers  





Low beta-amylod Increased tau/phosphotau concentrations No consensus on cutoff points for real practice

Perfusion SPECT 

Resolution less but less expensive

Alzheimer’s Disease Neuroimaging Initiative, Jan 2010

5

Diagnostic Instruments 

Diagnostic Instruments

Mini Mental Status Exam Maximum score 30  Score <24 suggests delirium or dementia 





MMSE  

Decline of 4 points over 1-4 years significant



Scores correlated with education level; inversely correlated with age  Not sensitive in people with higher levels of education 



Survey of 18,056 adults Scores relate to age 



Scores relate to educational level  

Montreal Cognitive Assessment

Median score 29 in those 18-24 years Median score 25 in those >80 years Median score 29 in those with >9 years schooling Median score 22 in those with 0-4 years schooling

Crum RM et al. JAMA, 1993;269(18)

Diagnostic Instruments…Take Home Points 

Caution in interpreting MMSE score  





Consider appropriate age/education median scores MMSE scores for age/education: http://www.angelfire.com/retro/michaelpoon168/mini_ mental_state_examination_normative%20data.htm (accessed 7/9/13) Median LR for positive result 6.3 (CI 3.4-47)

If positive initial screen, can consider further testing if appropriate

Diagnostic Instruments…Take Home Points 

Highly educated individuals 

Hopkins Verbal Learning Test  



Given 12 words; check recall on 3 different trials Decoy words given

Neuropsychological testing 

May be better in detecting early impairment in highly educated individuals

Holsinger T, et al. JAMA, 2007;297. Holsinger T, et al. JAMA, 2007;297.

6

Diagnostic Instruments…Take Home Points 



Tests not quite ready for “prime time”…  PET scanning (although approved)  MRI  CSF ß-amyloid  CSF tau  APOEε4 genotyping Not enough evidence for USPSTF to recommend screening for dementia in primary care

Treatment of AD 

Clarify goals Preserve function and independence  Maintain quality of life  Minimize excess disability and ensure safety  Make long-term decisions early 



Treatment Options Symptomatic treatment of memory disturbance Symptomatic treatment of behavioral disturbance  Disease-modifying treatment  

Case 78 year-old woman recently diagnosed with Alzheimer’s Disease. MMSE score is 19. What should you do next? 1) Start an acetylcholinesterase inhibitor (ex: donepezil or aricept) 2) Start memantine 3) Do not start any medications at this time 4) Discuss with the family/patient their wishes regarding treatment

Symptomatic Treatment of Memory Disturbance 

Cholinesterase Inhibitors delay degradation of acetylcholine at the synaptic cleft. Indicated for mildmoderate Alzheimer’s Disease  Donepezil (Aricept)--5-10mg/day  Rivastigmine (Exelon)--6-12mg/day  May cause weight loss  Galantamine (Razadyne)--24-32mg/day or patch 4.69.5mg  May cause weight loss

7

Cholinesterase Inhibitors…What’s the Data?

Cholinesterase Inhibitors 

Donepezil and Galantamine 





Studies range 12 weeks to 3 years 

Metabolized by cytochrome P450 system

ChEIs 



Vivid dreams: take in am Bradycardia, AV block



Outcome Clinician Interview Based Assessment of Change

Long-term donepezil treatment evaluated 565 patients with mild-mod AD randomly assigned to donepezil 5mg or placebo for 12-week run-in  Followed up to 3 years  End points: Institutionalization or progression of disability (loss of ADLs)

Statistically significant differences, but most do not show clinically significant changes

Symptomatic Memory Treatment? 



AD2000 Collaborative Group, Lancet 2004;363.

Average difference on ADAS-cog -4

Qaseem A, et al. Ann Intern Med, 2008;148.

What’s Clinically Significant? 

ADAS-cog evaluates memory, attention, language, orientation (score 0-70) 

Take with food  Interruption of meds = start back at lowest dose  If changing meds due to SE, washout period 7-14 days 



Common side effects: nausea, vomiting, diarrhea 



Pts on ChEIs compared to placebo

Long-term donepezil treatment No difference in rates of institutionalization or disability progression  No difference in care costs, unpaid caregiver time, behavioral/psychological symptoms 



Costs of drug not offset by any positive outcomes

AD2000 Collaborative Group, Lancet 2004;363.

8

Cholinesterase Inhibitors…Take Home Points 

Likely no disease modifying effects 



Modest cognitive improvement 



Delay progression 6mo-1yr Guidelines: “Base the decision to initiate therapy on individualized assessment”

Insufficient evidence regarding head-to-head comparisons; choose medication based on SE and dosing

Other Options in Memory Treatment? 

80 year-old woman with progression of her Alzheimer’s Disease. She is currently being treated with Aricept at 10mg/day. Her recent MMSE=11. Are there other treatment options?

Case 78 year-old woman recently diagnosed with Alzheimer’s Disease. MMSE score is 19. What should you do next? 1) Start an acetylcholinesterase inhibitor (ex: donepezil or aricept) 2) Do not start any medications at this time 3) Discuss with the family/patient their wishes regarding treatment

Other Options in Mod-Severe AD? 

Memantine (Namenda)  NMDA-receptor antagonist 

Glutamate stimulates NMDA receptor; overstimulation results in neuronal damage

 Pooled

estimate from 3 trials (vs. placebo) significant improvements on ADAS-cog scale but not clinically important Memantine combined with donepezil  Statistically



Qaseem A, et al. Ann Intern Med, 2008;148 Tariot PN et al. JAMA, 2004;291(3).

9

Other Options in Mod-Severe AD? 

New dose of donepezil 23mg daily approved for moderate-severe AD

Guidelines in Memory Treatment? 

Take Home Points…  First line therapy in mild-mod AD (if treatment decided) is cholinesterase inhibitors  If treatment failure/not tolerated, can either:  Change

to another ChEI memantine  Change to memantine (or increase donepezil)  Add



Disease-Modifying Treatment of AD

Guidelines in Memory Treatment? 

When to stop treatment? If quality of life benefits no longer possible (as determined by family, provider)  Pt dependent in all basic activities of daily living 

Consider memantine for moderate-to-severe dementia



Anti-inflammatories? Anti-oxidants?



Ginkgo biloba?





Vitamin E

10

Treatment of AD with Anti-Inflammatory Drugs 



AD brain with acute phase reactants and immune-related markers No evidence for NSAIDS to treat AD   

Prednisone vs. placebo Diclofenac/misoprostol Rofecoxib or naproxen vs. placebo

Treatment of AD Vitamin E 

Free radicals and oxidative damage contributes to neuronal death



Older study showing some benefit of vitamin E Cochrane review: no benefit of vitamin E





Scharf S, et al. Neurology, 1999;53. Aisen PS, et al. Neurology, 2000;54. ADAPT Research Group, Arch Neurol, 2008

Sano et al. NEJM, 1997;336 Issac MD et al. Cochrane Database Syst Review, 2008

Treatment of AD Ginkgo Biloba

Side Effects of Vitamin E? 



Can increase risk of bleeding—particularly in pts on coumadin Meta-analysis of 19 RCT  





135,967 patients on vitamin E (16.5-2000 IU/d) Dose >400 IU associated with increased mortality (Risk difference 39 per 10,000 people CI 3-74) Lower-dose vitamin E associated with decreased mortality

Vitamin E traps free radicals



Cochrane review of Ginkgo   

 

Most studies small, poor methodology Evidence=inconsistent benefit High doses: GI SE, may increase bleeding in patients on ASA/coumadin

Currently, not recommended Problem: lack of regulation with ginkgo

IOM now recommending dose <1000 IU/day Miller ER, et al. Ann Intern Med, 2005;142:37-46.

Birks J, et al. Cochrane Database of Systematic Reviews, 2007;2.

11

Disease-Modifying Treatments...Take Home Points 

No real evidence for Vitamin E 







(Old) guidelines 1000 IU BID; IOM 1000 IU daily Low-dose even better!

Insufficient evidence for antiinflammatories Insufficient evidence for ginkgo

New Directions for AD Treatment…  

 

Clearance of beta-amyloid through immunotherapy? Inhibit the enzymes that cleave amyloid pre-cursor protein? Anti-tau agents? Lower beta-amyloid levels?  Prelim evidence from RCT, double-blind placebocontrolled trial in 1684 patients with mild AD  No difference in outcomes  Other agents being studied Green RC, et al. JAMA, 2009;302(23)

Updates in Prevention Estrogen Replacement Therapy

Prevention of AD Case 60 year-old woman with strong family history of Alzheimer’s Disease. She is concerned about her own risk for dementia. What is the best prevention treatment can you offer? A) She should start ERT B) She should take a statin…forget about that package warning! C) She should start an NSAID D) She should exercise



Women’s Health Initiative Memory Study 

4532 healthy post-menopausal women (65-79)  



Randomized to estrogen/progestin or placebo Estrogen/progestin increased risk for probable dementia (HR 2.05)

2947 randomized to estrogen only or placebo Increased risk of development of probable dementia (HR 1.49; CI 0.83-2.66))  Pooled data increased risk (HR 1.76; CI 1.19-2.6) 

Shumaker SA, et al. JAMA, 2003;289(20). Shumaker SA, et al. JAMA, 2004;291(24).

12

More on Estrogen/Progesterone 

Estrogen/Progesterone

Cohort study from Olmsted County, MN 

All women 1950-1987 who underwent oophorectomy prior to menopause for noncancer indication 



Is there a “window of opportunity” when hormones are actually beneficial?

1,433 with unilateral; 1,824 with bilateral

Each cohort member matched to control  Median f/u 29.2 years  Oophorectomy before menopause: Increased risk of dementia compared to control (HR 1.46, CI 1.13-1.9) 

Rocca WA, et al. Neurology, 2007;69.

Updates in AD Prevention Should Statins be in the Water? 

RCT: Pravastatin vs. placebo in 5804 people aged 70-82 years 



RCT: Simvastatin vs. placebo in 20,536 people aged 40-80 



No difference in cognitive function after 3.2 years

No difference in incidence of dementia

No evidence statins prevent vascular dementia Shepard J, et al. Lancet, 2002;360. Heart Protection Study Collaborative Group. Lancet, 2002;360.



Reports that statins may worsen cognition



Review of all statin studies: benefits outweigh risks







Case reports (described in 60 adults) 1 RCT simvastatin impaired some measures of cognition compared to placebo Preliminary data: hydrophilic statins (ie, pravastatin and rosuvastatin) may be less likely to contribute to cognitive impairment due to limited penetration across the blood-brain barrier Rojas-Fernadez CH, et al. Ann Pharmacother, 2012.

13

Prevention of AD with Anti-Inflammatory Drugs 



Meta-analysis of observational studies NSAIDS >2yrs reduced risk by 73%  Confounding? 



Sleep-Disordered Breathing

RCT 

2528 volunteers >70 yrs with FH AD 



Naproxen vs. Celebrex vs. Placebo

Study stopped after 3 years: no evidence antiinflammatories prevent AD



 



Yaffe K, et al. JAMA, 2011

BMJ, 2003(327), Neurology 2007(68)

Obesity and Risk of AD 

Kaiser Permanente 6,583 members Sagittal abdominal diameter (SAD) measured 1964-1973 with medical records f/u 1994-2006  Marker for metabolic syndrome  Higher SAD associated with increased dementia risk 





298 older women without dementia followed prospectively 1 sleep study overnight  Sleep-disordered breathing=15 (or more) apneahypopnea events per hour of sleep Followed average 4.7 years Women with sleep-disordered breathing more likely to develop MCI or dementia (44.8% vs. 31.1% in controls) Adjusted for age, race, BMI, education level, baseline cognitive scores, sedating meds, DM/htn

Exercise and Dementia Prevention   



Meta-analysis 33,816 non-demented patients followed prospectively Subjects with high-level physical activity protected against cognitive decline (HR 0.62 CI 0.54-0.7) Low-moderate exercise also protective (HR 0.65; CI 0.57-0.75)

Highest quintile of SAD: HR for dementia 2.72 (CI 2.33-3.33)

Thigh adiposity didn’t increase dementia risk Whitmer RA, et al. Neurology, 2008

Sofi F et al. J Intern Med, 2011

14

Prevention of AD – Cognitive Reserve

Leisure Activities and Risk of AD 

775 older adults followed for 5 years Current and past cognitive activities rated  Higher rate of participation in cognitive activity was associated with reduced incidence of AD (HR 0.58) 



Evidence suggests that cognitive reserve is protective against AD Education Occupation  Mental activities  

Wilson RS, et al. Neurology, 2007;69

β-Amyloid 42/40, Cognitive Reserve and Cognitive Decline

Prevention of AD…Take Home Points       

Estrogen replacement therapy is out for now… Need more evidence regarding statins… Jury still out on NSAIDS Get out there and exercise! Be a “pear” rather than an “apple” Chess never hurt anyone Stay in school

Yaffe K, et al. JAMA, 2011;305(3)

15

60 year-old woman with strong family history of Alzheimer’s Disease. She is concerned about her own risk for dementia. What is the best prevention treatment can you offer? A) She should start ERT B) She should take a statin C) She should start an NSAID D) She should exercise

Prevention of AD – Stay Positive! • To estimate impact of risk factor reduction on AD prevalence for 7 modifiable factors:  Diabetes ▪ Mid-life hypertension  Mid-life obesity ▪ Depression  Physical inactivity ▪ Low education  Smoking • Population attributable risks (PARs) • Tools to estimate proportion of disease attributable to given risk factor, accounting for prevalence & strength of association • Calculations • Risk factor prevalence worldwide, U.S. • Relative risk from most recent/comprehensive meta-analysis or systematic review Barnes, DE and Yaffe K. Lancet Neurol, 2011;10

Prevention of AD – Stay Positive! Observational studies with increased dementia risk



  

Mid-life htn Current Smoking Diabetes

No evidence yet that treatment decreases dementia risk



Prevention of AD – Stay Positive 3,000,000 No. AD Cases Prevented, Worldwide

Prevention of AD Case

10% Reduction 25% Reduction 2,000,000

1,000,000

0

Barnes DE and Yaffe K. Lancet Neurol, 2011

16

Evaluation of Driving Risk in Dementia – Practice Parameter 

Resources

Patient is at increased risk for unsafe driving if:  

 

 

Clinical Dementia Rating Scale > 0.5 (level A) Caregiver rates patient’s driving ability as marginal or unsafe (level B) Pt has a h/o crashes/traffic citations (level C) Pt has reduced driving mileage or self-reported situational avoidance (level C) MMSE < 24 (level C) Pt with aggressive/impulsive personality characteristics (level C)



Alzheimer’s Disease Education and Referral (ADEAR) Center 800-438-4380



Alzheimer’s Association 800-272-3900  www.alz.org  Safe Return Program American Academy of Neurology







http://www.nia.nih.gov/alzheimers

http://www.aan.com/go/practice/guidelines

Iverson DJ, et al. Neurology, 2010;74.

17

Kathy Julian, M.D. Updated 7/9/13

Alzheimer’s Disease Selected References

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

21.

22. 23. 24.

25.

AD2000 Collaborative Group. Long-term donepezil treatment in 565 patients with alzheimer’s disease: randomized double-blind trial. Lancet, 2004;363:2105-2115. ADAPT Research Group. Cognitive function over time in the alzheimer’s disease anti-inflammatory prevention trail. Arch Neurol, 2008;65(7):896-905. Aisen PS, Davis KL, et al. A randomized controlled trial of prednisone in Alzheimer's disease. Alzheimer's Disease Cooperative Study. Neurology. 2000 Feb 8;54(3):588-93. Aisen PS, Schafer KA, et al. Effects of rofecoxib or naproxen vs. placebo on alzheimer disease progression. JAMA, 2003;289(21):2819-2826. Ballard C, et al. Alzheimer’s disease. Lancet, 2011;377:1019-1031. Barnes DE and Yaffe K. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol, 2011;10:819-828. Birks J, Gremley EJ. Ginkgo bilobe for cognitive impairment and dementia (review). Cochrane Library 2008; (2):1-68. Butcher J. Mind games: do they work? BMJ 2008; 336:246-248. Brown J, et al. Self administered cognitive screening test for detection of alzheimer’s disease: a cross sectional study. BMJ, 2009;338:b2030. Clarfield AM. The reversible dementias: do they reverse? Annals of Internal Medicine, 1988;476486. Clarfield AM. The decreasing prevalence of reversible dementias. Archives of Internal Medicine, 2003;163:2219-2229. Crum RM, et al. Population-based norms for the mini-mental state examination by age and educational level. JAMA, 1993;269(18):2386-2391. Cummings JL and Cole G. Alzheimer disease. JAMA, 2002;287(18):2335-2338. Cummings JL et al. Guidelines for managing alzheimer’s disease: Part I assessment. American family physician, 2002;65(11):2263-2272. Cummings JL et al. Guidelines for managing alzheimer’s disease: Part II treatment. American family physician, 2002;65(12):2525-2541. DeKosky ST, et al. Ginkgo biloba for prevention of dementia. JAMA, 2008;300(19):2253-2262. Doody RS et al. Practice parameter: management of dementia. Neurology, 2001;56:1154-1166. Etminan M et al. The role of lipid-lowering drugs in cognitive function: a meta-analysis of observational studies. Pharmacotherapy, 2003;23(6):726-730. Farlow M, Cummings J. Effective pharmacologic management of alzheimer’s disease. Amer J Med 2007; 120(5):388-397. Farlow MR, et al. Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer's disease: A 24-week, randomized, double-blind study. Clin Ther, 2010 Jul;32(7):1234-51. Feigin V, Ratnasabapathy Y, et al. Does blood pressure lowering treatment prevents dementia or cognitive decline in patients with cardiovascular and cerebrovascular disease? J Neuro Sci 2005; 151155. Feldman H et al. A 24-week, randomized, double-blind study of donepezil in moderate to severe alzheimer’s disease. Neurology, 2001;57:613-620. Green RC, et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease. JAMA, 2009;302(23):2557-2564. Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomized placebo-controlled trial. Lancet 2002; 360:7-22. Helzner EP, Scarmeas N, et al. Leisure activity and cognitive decline in incident alzheimer disease. Arch Nerurol 2007; 64(12):1749-1754.

26. Hogervorst E, Bandelow S. Should surgical menopausal women be with estrogens to decrease the risk of dementia? Neurol 2007; 69:1070-1071. 27. Holsinger T, Deveau J, et al. Does this patient have dementia? JAMA 2007; 297(21):2391-2404. 28. Issac MG, et al. Vitamin E for alzheimer’s disease and mild cognitive impairment. Cochrane Database Syst Review, 2008;(3):CD0022854. 29. J Hort JT, et al. EFNS guidelines for the diagnosis and management of alzheimer’s disease. European Journal of Neurology, 2010;17:1236-1248. 30. Jick H et al. Statins and the risk of dementia. Lancet, 2000;356:1627-1631. 31. Lautenschlager NT et al. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease. JAMA, 2008;300(9):1027-1037. 32. Lyketsos CG, Breitner JC, et al. Naproxen and celecoxib do not prevent ad in early results from a randomized controlled trial. Neurol 2007; 68:1800-1808. 33. Marin DB et al. Alzheimer’s disease: accurate and early diagnosis in the primary care setting. Geriatrics, 2002;57(2):36-40. 34. McGuinness B, et al. Statins for the treatment of dementia (review). The Cochrane Collaboration, 2010;8:1-32. 35. Miller ER, Pastor-Barriuso R, et al. Meta-analysis: high-dosage vitamin e supplementation may increase all-cause mortality. Ann Intern Med 2005; 142:37-46. 36. Mitchell SL, et al. The clinical course of advanced dementia. N Engl J Med, 2009;361:1529-38. 37. Middleton LE and Yaffe K. Promising strategies for the prevention of dementia. Arch Neurol, 2009;66(10):1210-1215. 38. Mohs RC et al. A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology, 2001;57:481-488. 39. Patterson C, Feightner JW, et al. Diagnosis and treatment of dementia: 1. risk assessment and primary prevention of alzheimer disease. CMAJ 2008; 178(5):548-56. 40. Patwardhan MB et al. Alzheimer disease: operating characteristics of PET—a meta-analysis. Radiology, 2004;231(1):73-80. 41. Petersen RC. Mild cognitive impairment. N Engl J Med, 2011;364:2227-2234. 42. Plassman BL, et al. Systematic review: factors associated with risk for and possible prevention of cognitive decline in later life. Ann Intern Med, 2010;153:182-193. 43. Qaseem A, Snow V, et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the american college of physicians and the american academy of family physicians. Ann Intern Med 2008; 148(5):370-378. 44. Rabins PV, Blacker D, et al. Practice guideline for the treatment of patients with alzheimer’s disease and other dementias. 2007, American Psychiatric Association. 45. Rafii MS, Galasko D. Primary care screening for dementia and mild cognitive impairment. JAMA 2008; 299(10):1132-1134. 46. Rapp SR et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women. JAMA, 2003;289(10):2663-2672. 47. Raskind MA, et al. Galantamine in AD. A six-month randomized, placebo-controlled trial with a 6month extension. Neurology, 2000;54:2261-2268. 48. Reisberg B et al. Memantine in moderate-to-severe alzheimer’s disease. NEJM, 2003;348:1333-41. 49. Rocca WA, Bower JH, et al. Increased rick of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurol 2007; 69:1074-1083. 50. Rojas-Fernadez CH, et al. Is statin-associated cognitive impairment clinically relevant? a narrative review and clinical recommendations. Ann Pharmacother, 2012;April 3. 51. Rosler M, et al. Efficacy and safety of rivastigmine in patient with alzheimer’s disease: international randomised controlled trial. BMJ, 1999;318:633-640. 52. Shepherd J, Blauw GJ, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360:1623-1630. 53. Shumaker SA et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. JAMA, 2003289(10):2651-2662. 54. Simmons BB et al. Evaluation of suspected dementia. AAFP, 2011;84(8):895-902. 55. Szekeley CA, Breitner JC, et al. Nsaid use and dementia risk in the cardiovascular health study* role of APOE and NSAID type. Neurol 2008; 70:17-24.

56. Szwast SJ, Hendrie HC, et al. Association of statin use with cognitive decline in elderly african americans. Neurol 2007; 69:1873-1880. 57. Tang-Wai DF et al. Comparison of the short test of mental status and the mini-mental state examination in mild cognitive impairment. Archives of Neurology, 2003;60:1777-1781. 58. Tariot PN et al. Memantine treatment in patients with moderate to severe alzheimer disease already receiving donepezil. JAMA, 2004;291:317-324. 59. Teri L et al. Exercise plus behavioral management in patients with alzheimer disease. JAMA, 2003;290:2015-2022. 60. Teri L et al. Nonpharmacologic treatment of behavioral disturbance in dementia. Medical Clinics of North America, 2002;86:641-656. 61. Verghese J, et al. Leisure activities and the risk of dementia in the elderly. NEJM, 2003;348(25):2508-2516. 62. Whitmer RA, Gustafson DR, et al. Central obesity and increased rick of dementia more than three decades later. Neurol 2008; Mar 26. 63. Wilson RS, Scherr PA, et al. Relation of cognitive activity to risk of developing alzheimer disease. Neurol 2007; 69:1911-1920. 64. Winblad B, Grossberg G, et al. A 6-month, double-blind, placebo-controlled study of the first skin patch for alzheimer disease. Neuro 2007; 69(Suppl 1):S14-S22. 65. Yaffe K et al. Association of plasma beta-amyloid level and cognitive reserve with subsequent cognitive decline. JAMA, 2011;305(3):261-266. 66. Yaffe K et al. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA, 1998;279(9):688-700. 67. Yaffe K et al. Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA, 2011;306(6):613-619.

7/23/2013

Outline

CHRONIC KIDNEY DISEASE UPDATE: WHAT THE GENERALIST NEEDS TO KNOW



Definition and Complications



New CKD Staging 2013

MICHAEL G. SHLIPAK, MD, MPH



Screening for CKD

CHIEF-GENERAL INTERNAL MEDICINE, SAN FRANCISCO VA MEDICAL CENTER PROFESSOR OF MEDICINE, EPIDEMIOLOGY AND BIOSTATISTICS, UCSF



Treatment of CKD



Introduction to Cystatin C



When to refer to nephrologist

August 7, 2013

Outline 

Definition and Complications



New CKD Staging 2013



Screening for CKD



Treatment of CKD



Introduction to Cystatin C



When to refer to nephrologist

Question 1: Which of these patients has CKD? a) b)

c)

d)

Heart failure patient in ED with creatinine of 2.0 Diabetes patient with albumin/creatinine of 100 mg/g, creatinine= 1.0 mg/dL 35 year old African American man with creatinine of 1.5 All of the above

1

7/23/2013

Introduction 

DEFINITION & CLASSIFICATION OF CHRONIC KIDNEY DISEASE

Chronic Kidney Disease (CKD):  Defined

in 2002 with original CKD staging

 Replaced

earlier terms “chronic renal insufficiency”, “chronic renal failure”, or “high creatinine”

KDIGO 2012 Clinical Practice Guideline (CPG) for the Evaluation and Management of Chronic Kidney Disease

 Previous

5 CKD stages were developed by an expert

panel

Kidney inter., Suppl. 2013; 3: 1–150

 Most

CKD epidemiology research has been conducted since the 5 stages were defined

Definition and Complications

Complications of CKD



Overall CKD definition unchanged





Chronic kidney disease: >3 month duration of either:



Kidney failure (end-stage renal disease) Death



Other chronic disease:

 



Decreased kidney function (eGFR<60) Injury/damage to the kidney (e.g. albuminuria, cysts, stones)



Etiology of CKD: a) b) c)

Common diseases treated by generalists: diabetes, hypertension, cardiovascular disease, heart failure Other systemic diseases typically treated by specialists: systemic lupus erythematosus, HIV, urological diseases Primary kidney disease: polycystic kidney disease, glomerular disease

    

Atherosclerotic Cardiovascular Disease Heart failure Osteoporosis/fracture Cognitive impairment/dementia Frailty

Treatment Complications:  

Medications Procedures

2

7/23/2013

Question 2: A 75 yr. old White male with CAD and HF has an eGFR= 25. What is he at most risk for? a)

Death

b)

Dialysis

Prognosis by eGFR and Albuminuria 

Key meta-analysis published in 2010 in Lancet



Evaluated prognosis by eGFR and albuminuria



21 studies, 1.2 million patients



Predictor:  



eGFR categories Albuminuria (ACR categories)

Outcome: mortality risk

CKD Complications Keith et al., Arch Int Med, 2004

•Design: Northwest Kaiser database •5 year follow-up •Death and ESRD outcomes eGFR 30-60 N= 11,278

eGFR 15-30 N= 777

Age

72

74

ESRD (%), 5 yrs

1

20

Death (%), 5 yrs

24

45

Albuminuria and eGFR grid Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality : a collaborative meta-analysis. Lancet 2010

AGE, SEX, RACE and CARDIOVASCULAR RISK FACTOR ADJUSTED HAZARD RATIO for All-cause Mortality Albuminuria Classes (mg/g)

Conclusion: CKD staging <10 must integrate and albuminuria 10-29 eGFR 30-300 >300 Alltogether >105 90-104 eGFR 75-89 (mL/min/ 60-74 1.73m2) 45-59 30-44 15-29 All *P<0.05

1.0

1.4

2.0

4.4

1.0 0.9 0.9 1.2 1.7 4.0 1.0

1.3 1.2 1.2 1.5 2.1 3.0 1.3

1.5 1.7 1.8 1.9 3.0 4.2 2.0

3.1 2.5 3.0 3.4 4.4 6.0 3.6

CKD by low GFR

1.2 1.0 by CKD 1.0 albuminuria 1.3 2.0 4.0 3.6

CKD Prognosis Consortium. Lancet: 2073-81. 2010

3

7/23/2013

Q3: What is the current definition of Stage 3 CKD?

Outline 

Definition and Complications



New CKD Staging 2013



Screening for CKD



Treatment of CKD



Introduction to Cystatin C



When to refer to nephrologist

CKD Stages and Prevalence CKD Stage

Estimated GFR (mL/min per 1.73 m2)

U.S. Prevalence N (1000’s) (%)

CKD Stage 1

90+*

CKD Stage 2

60-89*

6,500 (3.2)

CKD Stage 3

30–59

15,500 (7.7)

CKD Stage 4

15–29

700 (0.4)

CKD Stage 5

<15 (or dialysis)

400 (0.2)

a)

1+ proteinuria or ACR > 30

b)

GFR 30-60

c)

GFR 45-60

d)

There’s no such thing

Problems with Old Staging  

3,200 (1.6) 

Stages 1 and 2 were the same Stage 3 (30-60) was too broad; eGFR of 30-45 is very different from 45-60 Did not address levels of albuminuria; and only used albuminuria for Stages 1 and 2

*With evidence of kidney damage, e.g. albuminuria KDOQI Guidelines, AJKD, Feb. 2002

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7/23/2013

Classification of CKD

From Old to New Staging



CGA Staging (like TMN) replaces the prior 5 stages of CKD CKD Stage Cause

Estimated GFR GFR •“CKD” is 2 (mL/min per per 1.73 (mL/min 1.73 m m2))

CKD Stage 1 Diabetes Hypertension CKD Stage 2

Polycystic Disease CKD Stage 3

GN

Unknown CKD Stage 4 CKD Stage 5

U.S. Prevalence

G5 (< 15) <15 (or dialysis)

 

 

Definition and Complications



New CKD Staging 2013



Screening for CKD



Treatment of CKD



Introduction to Cystatin C



When to refer to nephrologist

This is collectively referred to as “CGA Staging” Represents a revision of the previous KDOQI CKD guidelines, which included staging only by level of GFR

400 (0.2)

Outline 

It is recommended that CKD be classified by: Cause GFR category  Albuminuria category

an inadequate N (1000’s) Albuminuria (%) descriptor (like diabetes) •Define C, G,3,200 A whenever (1.6)30) you G190+* (>90) A1 (ACR< mention CKD G260-89* (60-89) A2 (ACR(3.2) 6,500 •Hypertensive with30-300) eGFR= 50, G3a (45-59) ACR= 10 A3 (ACR > 300) 30–59 15,500 (7.7) G3b (30-44) •Diabetic CKD with eGFR= 75, ACR= 500 700 (0.4) G415–29 (15-29)

Screening for CKD 





CKD guidelines do not address when or how to screen Other guidelines have disease-specific recommendations (hypertension, diabetes, CVD) The following are my suggestions.

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7/23/2013

GFR Estimation from Creatinine

Who and When to Check Creatinine? 

Begin screening:



>40 lower-risk populations  Age >30 Blacks, Native Americans 



 No

risk factors: 3-5 years  Risk factors: 1-2 years 

Creatinine cost: $0.20

Question 4: Which of the following is true about creatinine GFR estimates? a)

b) c)

d)

 

Diagnosis of hypertension, diabetes, cardiovascular disease, heart failure Frequency of creatinine monitoring (no evidence)

Estimated GFR: Automatic reporting by most labs Equations are rough  <60 concerning for kidney disease, but not diagnostic of kidney disease  > 60- imprecise

 Age



3 equations in current use: Cockroft-Gault (Nephron, 1976)- used by FDA and pharmacies  MDRD (Annals, 1999)- used for most automated reporting  CKD-EPI (Annals, 2009)- favored by researchers 

Pros and Cons of Estimated GFR

More accurate in older populations than middleaged because prevalence of kidney disease is higher



They have been validated in most ethnic groups



They are more likely to be accurate in healthy persons than in persons with chronic illness All of the above

Pros:  Indexes  Forces

creatinine for demographic characteristics us to think in terms of GFR and kidney function

Cons:  Mostly

validated in younger patients with kidney disease  Huge assumption that demographic characteristics alone can define muscle mass  Only developed in Whites and Blacks  Estimated GFR ≠ GFR

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Who to Screen with Urine Albumin? 

Primary prevention screens: annual  Hypertension  Elderly

How to Measure Urine Albumin 

Often listed as “microalbumin panel”



Focus on albumin/creatinine ratio (ACR):

 Diabetes-



CKD Staging:  Urine

albumin will be important part of CKD staging  Should be measured and documented in all CKD patients  Repeat  every

annually in diabetics 2-3 years in non-diabetics

Outline

 

ACR (mg/g)

OLD

NEW

< 30

Normal

Normal or mildly elevated

30-300

Microalbuminuria

Moderately elevated

>300

Macroalbuminuria

Severely elevated

Dipstick: “trace” is abnormal If dipstick is abnormal, quantify ACR

Question 5: Which of the following treatment options will not slow the progression of kidney disease?



Definition and Complications

a)



New CKD Staging 2013

b)



Screening for CKD

c)



Treatment of CKD



Introduction to Cystatin C



When to refer to nephrologist

d)

ACE/ARB treatments Blood pressure control Glucose control Statins

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ACE/ARB’s in Diabetic CKD

CKD Treatment 

Goals:  



Prevention

Prevent progression to ESRD Prevent CKD complications



Diabetic CKD- nearly always has albuminuria



Diabetic CKD- ACE/ARB essential for:

Treatments:    

ACE/ARB therapy Blood Pressure Control Glucose Control in Diabetes Statins

 Type

I or II diabetes albuminuria (ACR 30-300)  Severe albuminuria (ACR > 300)  Moderate



ACE/ARB’s do not appear to be helpful to prevent onset of albuminuria

Shlipak, Clinical Evidence 2009

ACE/ARB’s in Non-Diabetic CKD 



Non-diabetic CKD- ACE benefit likely varies by proteinuria status (Jafer TH, Ann Intern Med, 2008)

Are ACE/ARB’s for All CKD Patients? 

 Subgroup

of ACE vs. other HTN agents



Overall RR 0.67 (0.53-0.84) for kidney outcomes



Subgroup analysis:  No

benefit in group without proteinuria (< 500 mg/g)

analysis of CKD (eGFR< 60) lisinopril, amlodipine, and chlorthalidone

 Compared

Meta-analysis- 1,860 CKD patients  RCTs

ALLHAT Hypertension Trial –





ACE not different from thiazides or CCB’s for kidney decline or ESRD (Rahman, Arch Intern Med, 2005) Low eGFR without albuminuria- choice of blood pressure agent may not matter

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ACE-I in Advanced CKD

ACE/ARB Combination?

Hou FF et al. NEJM 2006; 354:131-140



224 patients with creatinine 3.1-5.0 mg/dL



Mean eGFR 25; mean urine prot – 1.6g/day



Benazepril 20 mg daily vs. placebo



Primary end point: doubling of creatinine, ESRD, death

Findings: 

43% reduction in primary end point



52% reduction in proteinuria



Effects independent of blood pressure



Adverse events rare

Blood Pressure Target in CKD 



SBP control extremely important and often requires 3-4 meds at full dose Meta-analysis in non-diabetic CKD found SBP of 110-129 to be ideal (Jafer, Ann Intern Med, 2005).





Proteinuria reduction from ACE inhibitors and ARBs is similar. Combination of ACE/ARB has additional reductions in proteinuria. Meta-analysis Kunz, et al. Ann Int Med, 2008



However, ACE/ARB combination carries higher risk of adverse events Mann JF et al. Lancet, 2008



Given added risk of hyper-kalemia and uncertain benefit, I do NOT recommend combination therapy.

The Challenge of Blood Pressure Control in CKD 





Since CKD often in older patients with stiff arteries, an SBP<130 rarely attainable. In large health screening study, we found one-third of CKD patients had SBP > 150 (Peralta CA, Arch Intern Med, 2012) Guidelines on blood pressure control in CKD:  



JNC-7 target < 130 New KDIGO-CKD HTN guideline: suggests <130 recommends <140

Evidence-based treatment: <140 for most CKD patients

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Glycemic Control in Diabetic CKD 



Type I Diabetes- tight glucose control slows kidney disease progression: OR= 0.34 (0.20-0.58) Tight glucose control (HbAlc 6.5 vs. 7.3): 20% lower risk of “new or worsening nephropathy”  RR= 0.8; 4.1 vs. 5.2% (p = 0.006)





Meta-analysis, 26 studies, statins vs. placebos in CKD  cardiovascular  RR

Type II Diabetes- ADVANCE trial (NEJM, 2008, 2560-72) 



Statins in CKD- beneficial for CVD

In Type II Diabetes, risks of tight glucose control may offset kidney benefits

deaths (20 studies, 18,746 patients) 0.80 (95% CI: 0.70,0.90)

Navaneethan et al. Cochrane Review. April, 2009 

SHARP Trial: RCT of 9,500 patients with CKD  Simvastatin/ezetimide

vs. placebo- RR= 0.83 (95% CI: 0.74-

0.94) for CVD Baigent et al. The Lancet. June, 2011 

No benefits of statins in patients with ESRD

Tailor A1C treatment goal to the individual patient

Outline 

Definition and Complications



New CKD Staging 2013



Screening for CKD



Treatment of CKD



Introduction to Cystatin C



When to refer to nephrologist

Cystatin C 





Cystatin C is a blood test of kidney function that is an alternative to creatinine Because cystatin C is not related to muscle mass (or age, sex, and race), it has major advantages over creatinine Cystatin C is a reliable, standardized, and inexpensive ( $4/test) measure that is available for clinical use.

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GFR Equations using Cystatin C 

2 recent studies in major journals developed GFR equations for cystatin C CKD-EPI (NEJM July 2012)

1.   

eGFRcys, eGFRcys-cr Best GFR by creatinine + cystatin C Cystatin C has no race bias, so same eGFR formula for Blacks and Whites

Berlin Study (Ann Intern Med November 2012)

2.  

“Cystatin C versus Creatinine in Determining Risk based on Kidney Function” Shlipak et al, In Press, New England Journal of Medicine; 2013 •





Meta-analysis of all available observational studies and clinical trials with creatinine and cystatin C Compared associations of eGFRcr, eGFRcys, and eGFRcr-cys with death Determined proportions reclassified by cystatin C in each eGFRcr subgroup and impact on risk associations

In elderly persons, cystatin C much better than creatinine Best estimate also uses creatinine + cystatin C

eGFR Distributions and CKD Prevalence

All-Cause Mortality 12,351 events

CKD prevalence: 9.7% (eGFRcr) 13.7% (eGFRcys) 10.0% (eGFRcr-cys) 83 59

Shlipak MG. et al. In Press, N Eng J Med, 2013

88

Shlipak MG. et al. In Press, N Eng J Med, 2013

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Reclassification by eGFRcys and associated risk Mortality Associations 1.36 (1.24, 1.48)

1.0 Mortality Associations1.0 0.88 (0.76, 1.01)

KDIGO 2012 Clinical Practice Guideline (CPG) for the Evaluation and Management of Chronic Kidney Disease

= same 1.57 (1.39, 1.78)

1.0 1.0

= worse 0.66 (0.57, 0.77) 0.77 (0.61, 0.98)

1.67 (1.49, 1.88)

1.0 1.0

= better 1.0 1.0

0.60 (0.27, 1.36)

1.72 (1.24, 2.37)

Guideline Statements Relevant to Cystatin C

1.0

Adjusted for age, gender, race, smoking, systolic blood pressure, total cholesterol, diabetes, history of cardiovascular disease, body mass index, and albuminuria. Shlipak MG et al. In Press, N Eng J Med, 2013

KDIGO Suggestion #1 (2B) •

Estimating GFR: Use creatinine eGFR Are you confident that this is accurate? If no, use either:

1. 2. 3.  

Cystatin C Direct measure GFR

KDIGO Suggestions #2 (2C) Confirming CKD: •

Your patient’s eGFRcr is 45-60 and is not known to have kidney disease: 1. 2.

Measure cystatin C If eGFR <60 by cystatin C, CKD >60 by cystatin C, no CKD

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KDIGO Suggestion #3 (2C) •

When using cystatin C: • •



Use eGFR equation Use standardized measure

Outline 

Definition and Complications



New CKD Staging 2013



Screening for CKD



Treatment of CKD



Introduction to Cystatin C



KDIGO Recommendation (1C)

When to refer to nephrologist

For medical dosing of potentially toxic agents, use cystatin C or direct measure GFR

Reasons to Consider Referral to Nephrologist 

Combined hematuria and proteinuria



Estimated GFR< 30



Nephrotic proteinuria



Mineral metabolism management:



Anemia of CKD

 Indicates

 Need

to start planning for dialysis

 Potential

 High

concern for glomerulonephritis

for treatable condition

phosphate/high PTH

 Hemoglobin

target ~10

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Thank you! Any Questions?

14

Mastering Office Gynecological Procedures  Jody Steinauer, MD, MAS  University of California San Francisco     In this hands‐on workshop you will practice many gynecological procedures.  You will practice bimanual  examination, paracervical block, endometrial biopsy, IUD insertion, and implant placement.  You will also have  the opportunity to practice manual uterine aspiration on a papaya.  Finally, you can pose complex  contraception or gynecological cases for the group to discuss.     Objectives:  At the end of this workshop you will be able to:  1. Model a perfect bimanual examination.  2. List the risks of instrumenting a uterus.  3. Perform a paracervical block, endometrial biopsy, and IUD insertion (on a papaya).  4. List the contraindications to IUDs for contraception.  5. Aspirate and curette a papaya.  I. II.

III.

IV.

V.

VI. VII.

 

Uterine Anatomy: Papaya vs. Uterus  Bimanual Exam   A. What comes first: speculum or bimanual?  i.  Uterine position  ii. Perforation risks  B. Diagnosing pelvic pain  Orientation to Instruments / Techniques    A.  Review of tools    B.  No‐touch technique  Procedure: Endometrial Biopsy  A. Possible diagnoses and diagnostic tests  B. Techniques  i.  Tenaculum  ii. Paracervical blocks  Procedure: IUD Insertion  A. Who is a candidate for Intrauterine contraception?  B.   Paraguard (Copper T) and Mirena (LNG‐IUS)  C.   Order of procedure    i.  Place paracervical block    ii. Place tenaculum    iii. Sound uterus    iv. Place IUD  Procedure: Implant Placement  Procedure: Uterine/Papaya Aspiration    A.  Why aspirate?    B.  Manual Uterine Aspirator (MUA)      i.  Size of uterus; size of cannula      ii.  Electric vs. manual aspiration    C.  Miscarriage management in the ER or outpatient setting    D.  Elective Abortion 

7/23/2013

A Real Case… Substance Use Disorders in Primary Care:

Screening, Brief Interventions, Pharmacotherapy Katherine Julian, M.D. UCSF Division of General Internal Medicine August 7, 2013

Quiz…Your Clinic Panel In your clinic panel, what percentage of your current clinic patients would be classified with alcohol abuse or dependence? A. <1% B. 2-5% C. 6-9% D. 10% E. 20% 







31 yo man presenting to resident clinic for new patient appt Recently hospitalized with new onset atrial fibrillation. Resolved with cardioversion. Given coumadin and presenting to titrate this medication. Prompted to take an alcohol history→binge drinking with indications of alcohol dependence

Substance Use Issues are Highly Prevalent in Americans At Risk Drinking*

23%

Illicit Drug Use

8%

Substance Abuse/Dependence

9%

Alcohol

7%

Illicit Drugs

3%

SAMHSA, National Survey on Drug Use and Health, 2008 Ages 12+ in the United States

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Alcohol Use Disorders in Older Adults

Alcohol Use in Primary Care 



3439 primary care patients 11% had “at risk” drinking defined as any of the following:  



> 2 drinks/day > 2 episodes of 5+ drinks/day in 30 days Drinking and driving

 3%

17%

of men, 11% of women ages 50+ of all respondents ages 50-64 13% of all respondents ages 65+ 19%

 Binge

drinking was reported in:

20%

of men, 6% of women ages 50+ of all respondents ages 50-64 15% of all respondents ages 65+ 23%

Curry SJ, et al. Prev Med 2000;31(5):595-607

NSDUH, 2009 Blazer D, Wu L. Am J Psychiatry, 2009

Outline  Substance Use Disorders - Definitions  SBIRT  Screening: quickly assess use and severity of alcohol, illicit drugs, and prescription drug abuse  Brief Intervention: a 3-5 minute motivational intervention given to risky or problematic substance users  Referral to Treatment  Motivational Interviewing  ETOH and Opiate Substance Use Pharmacotherapy

met full criteria for an alcohol use disorder drinking was reported in:

 At-risk

Why SBIRT? The Evidence… 

Brief interventions can reduce alcohol use for at least 12 months in patients who are not alcohol dependent.



10-30 % of patients can be expected to change their drinking behaviors as a result of a brief intervention. Babor & Higgins-Biddle, 2000; Fleming and Manwell, 1999.

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Quiz… Which of the following is NOT considered to be “at risk” drinking? A. 45 yo woman who drinks 1-2 glasses of wine each night B. 70 yo man who drinks 1-2 beers each night C. 25 yo woman who drinks 4-5 drinks once a week when she goes out with friends D. 40 yo man who drinks 1-2 glasses of wine each night 

Quiz… Which of the following is NOT considered to be “at risk” drinking? A. 45 yo woman who drinks 1-2 glasses of wine each night B. 70 yo man who drinks 1-2 beers each night C. 25 yo woman who drinks 4-5 drinks once a week when she goes out with friends D. 40 yo man who drinks 1-2 glasses of wine each night 

Definition – At Risk Drinking 

Men • •



Women (and > than 65 yrs) • •



>4 drinks/day or >14 drinks/week >3 drinks/day or >7 drinks/week

Increased risk of alcohol-related problems

What is a Drink? A standard drink is any drink that contains about 14 grams of pure alcohol (about 0.6 fluid ounces or 1.2 tablespoons)

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7/23/2013

New DSM5 - Substance Use Disorder

New DSM5 - Substance Use Disorder 







No longer need to differentiate between substance abuse and substance dependence Each substance can be categorized as a disorder  Ex: Alcohol use disorder, stimulant use disorder, etc Substance use disorder: Mild, Moderate, Severe

Criteria for Substance Use Disorder (contd)        

   

Tolerance Withdrawal Using more than originally intended Persistent desire or unsuccessful efforts to cut-down Time spent obtaining/using substance or recovering from side effects Reduction of social/occupational activities Use despite physical/psychological problems Craving

Need 2 criteria for SUD 2-3 criteria =mild 4-5 = moderate >6 = severe

“Maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by 2 (or more) of the following, occurring within a 12-month period:”  



Failure to fulfill role obligations Recurrent substance use in situations that are physically hazardous Persistent use despite social/interpersonal problems

Screening Some key opportunities include:  As part of a routine examination  Before prescribing a medication that interacts with alcohol or other drugs  In the emergency department or urgent care center  When seeing patients who..  Are pregnant or trying to conceive  Have health problems that might be alcohol or drug induced/ related  Have a chronic illness not responding to treatment  Are likely to drink heavily NIAAA, 2005. Helping Patients Who Drink Too Much: A Clinician’s Guide (Updated)

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How to Screen?  Ask permission: “Would it be ok to spend the new few minute talking about alcohol?”

 Pre-screen: Do you sometimes drink beer, wine, or other alcoholic beverages?

 Single Alcohol Screen Question:

 Men: How many times in the past year have you had 5 or more drinks in one day?

 Women (or >65 yo): How many times in the past year have you had 4 or more drinks in one day?

How to Screen?  Single Drug Use Screen Question: How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?  Positive Screen=1 or more

 Positive Screen=1 or more

Smith PC, et al. J Gen Intern Med 2009;24(7); NIAAA Guidelines 2005

Smith PC, et al. J Gen Intern Med 2009;24(7); NIAAA Guidelines 2005

A Positive Screen…

Evidence for the Single Screen

 Single Question Screen

 Sensitivity/specificity: 88%/ 67% for alcohol use d/o  Sensitivity/specificity: 82%/79% for unhealthy use

 CAGE:  Sensitivity/specificity: 92%/ 48% for alcohol dependence

 AUDIT

  

1 or more heavy drinking days Any positive drug screen What to do next? Assess…  

 Sensitivity/specificity: 96%/ 57% for unhealthy use  Sensitivity/specificity: 90%/ 61% for alcohol use d/o

 Single Drug Screen  Sensitivity/ specificity: 100%/ 74% for drug disorder  Sensitivity/specificity: 71%/ 95% for use with consequences



Determine how many drinks/day in a week Ask which drugs the patient has been using Ask about negative impacts

The follow-up questions are to assess impact and whether or not use is serious enough to warrant a substance use disorder diagnosis.

Smith PC, JGIM 2009; Smith PC, Arch Intern Med 2010

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Determining “At Risk” vs. “Substance Use Disorder”  

Pts who meet criteria for “at-risk” should get a brief intervention Patients who meet substance use disorder criteria abuse should get a 





Brief intervention AND A referral to specialty care (if they are willing) AND Be considered for pharmacotherapy

What is a Brief Intervention?  



Advise and Assist the patient Short, 3-5 minute motivational interviews that encourage patients to create a plan of action (ex: reduce drinking) that is based on their willingness to change their behavior Feedback and recommendations are given respectfully in the form of useful information.

HOW TO HELP PATIENTS: A CLINICAL APPROACH: NIAAA 2005 Resource for Clinicians

Brief Intervention 

Non-judgmental but give direct, honest feedback



Provide advise on what a patient should do



Negotiate a concrete, realistic plan for behavioral change



If not ready to change→harm reduction



Plan for follow-up

AT-RISK DRINKING

Advise and Assist  State your conclusion and recommendation clearly

“You are drinking more than is medically safe.”

image credit: Comstock

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HOW TO HELP PATIENTS: A CLINICAL APPROACH

AT-RISK DRINKING

HOW TO HELP PATIENTS: A CLINICAL APPROACH

AT-RISK DRINKING

Advise and Assist

Advise and Assist

 State your conclusion and recommendation clearly

 State your conclusion and recommendation clearly  Gauge readiness to change drinking habits

Consider using the chart on page 25 to show increased risk.

“I strongly recommend that you cut down (or quit) and I’m willing to help.” image credit: Comstock

“Are you willing to consider making changes in your drinking?” image credit: Comstock

HOW TO HELP PATIENTS: A CLINICAL APPROACH

HOW TO HELP PATIENTS: A CLINICAL APPROACH

AT-RISK DRINKING

AT-RISK DRINKING

Advise and Assist

Advise and Assist

Is the patient ready to commit to change at this time? NO

Do not be discouraged. Ambivalence is common. Your advice has likely prompted a change in your patient’s thinking. With continued reinforcement, your patient may decide to take action. For now, restate your concern about his or her health.

Is the patient ready to commit to change at this time? NO

 Encourage reflection:

Ask patients to weigh what they like about drinking versus their reasons for cutting down. What are the major barriers to change? Reaffirm your willingness to help when he or she is ready. Don’t forget FOLLOW-UP

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HOW TO HELP PATIENTS: A CLINICAL APPROACH

AT-RISK DRINKING

HOW TO HELP PATIENTS: A CLINICAL APPROACH

Example 2 -For patients who meet the criteria for

ALCOHOL USE DISORDERS

Advise and Assist Is the patient ready to commit to change at this time?

YES

 Help set a goal to cut down to within maximum limits or abstain for a period of time. Agree on a plan, including— -What specific steps the patient will take -How drinking will be tracked -Who can help

Advise and Assist  State your conclusion and recommendation clearly. • Relate to the patient’s concerns

and medical findings, if present.

“I believe that you have an alcohol use disorder. You are drinking more than is medically safe. I’m concerned about your health. I strongly recommend that you quit drinking and I’m willing to help.”

image credit: Comstock

-How to manage high-risk situations

HOW TO HELP PATIENTS: A CLINICAL APPROACH

ALCOHOL USE DISORDERS

Advise and Assist  Negotiate a drinking goal: • Abstaining is the safest course for most patients with

AUDs. • Patients who have milder forms of alcohol abuse or dependence and are unwilling to abstain may be successful at cutting down.

Motivational Interviewing

If needed, refer for additional evaluation by Specialized Substance Abuse Services Consider recommending a mutual help (self-help) group, like AA. For patients with dependence, consider medically managed withdrawal vs. medications

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Stages of Change from Transtheoretical Model

Maintenance

Mentality of the Stages

Lapse Precontemplation Contemplation

Action

Preparation

Motivational Interviewing Principles

Motivational Interviewing  Specialized

skill set designed to help patients become ready and motivated to change health-related behaviors

  



Express empathy Develop discrepancy Roll with resistance – patients aren’t “resistant” (they just aren’t seeing things the way you do!) Support self-efficacy

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MI: Assess Readiness to Change 

Readiness Ruler



“On a scale of 0-10, how ready are you to stop drinking?”  “I would say about a 3” “So it sounds like you aren’t too interested right now. But I’m curious why you said ‘3’ rather than ‘0’.” OR “What would it take to move you to a 5?”  “Well, I know I should stop at some point.” “Can you say a bit more about why you think that you should stop?”





MI: Enhance Motivation 

Listen for “change talk” 





“I was worried there at first, but I don’t really think I have a problem.” “I don’t see why everyone is making such a fuss about this. I can handle it.”

MI: Enhance Motivation 

When you hear “change talk”, use MI skills (OARS) to respond 



Affirmations



Reflections





“On a scale of 1-10, how important is it to you to stop drinking (or cut back)? On a scale of 1-10, how confident are you that you can stop drinking (or cut back)?”  This will help guide your next steps

“I can see you really care a lot about your health” “You are really considering whether you should cut down”

Ask Importance/Confidence Questions 

“Why do you think everyone is making such a fuss?”





MI

Open-ended questions 

Small verbal cues that the patient has thought about changing/need to change or health consequences of their behavior



Ask about pros/cons of the behavior

Summary statements: tie together multiple points 

“I hear you saying that you don’t drink more than most people but everyone is making a fuss about your drinking”

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Continuum of Care for Substance Use Disorders

MI: Negotiating a Plan 

 

Plan should match the patient’s level of readiness to change It is concrete, specific and realistic Patient agrees to it and is able to repeat it back to you

 

• • •

   

Addiction Treatment Model: Treating Limbic Drive and Cortical Thinking Structures

Intensive outpatient - > 3x/wk Day treatment Usually group-based

Sober Housing (“Halfway House --can be unstaffed) Residential - brief (< 28 da) or extended, non-medical (“rehab”) Inpatient hospital for true medical detoxification Aftercare – usually low intensity 1/wk indiv or group

Substances for which Pharmacotherapy is Available   

Decision Making (Counseling)

Self-help (AA, etc) Outpatient – with our without sober housing

Opioids Alcohol Tobacco (nicotine dependence)

Substances for which Pharmacotherapy is Not Available     

From Pettinati, NIH 2006

Cocaine Methamphetamine Hallucinogens Cannabis Solvents/Inhalants

Limbic Drive (Pharmacotherapy)

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Alcohol Use Disorder Pharmacotherapy

Phases of Substance Use as Targets for Pharmacotherapy     

Two Phases of Alcohol Use Disoder Treatment:  Acute Alcohol Withdrawal  SubAcute/Chronic Treatment: Maintenance medications to reduce use or prevent relapse to alcohol use (FDA approved)

Intoxication/overdose Withdrawal/detoxification Abstinence initiation/use reduction Relapse prevention Sequelae (psychosis, agitation, etc.)

  





Most alcohol withdrawal is managed in an inpatient setting Meds typically include:   

 

Benzodiazepines Anticonvulsants Adjunctive Medications/supplements

  

Avoid outpatient detox; best to refer to specialized programs with close monitoring What’s the role of an outpatient provider? 

Refer for alcohol detox and ongoing substance abuse treatment

Minimum trial of 3 months (risk of relapse high 6-12 months)

Alcohol Relapse Prevention Meds: Disulfiram (Antabuse)

Alcohol Withdrawal 

Disulfiram Acamprosate Naltrexone (oral and injectable)



Blocks alcohol metabolism (prevents acetaldehyde→acetate); increase in blood acetaldehyde levels Antabuse reaction: flushing, weakness, nausea, tachycardia, hypotension (up to 2 weeks later!) VA Cooperative Study of Disulfuram in 605 men  No effect on number of patients maintained abstinence  Among non-abstinent, signif fewer drinking days  High rate of non-compliance: 80%  If adherent, more likely to be abstinent Works better if given in monitored fashion

Fuller RK, et al. JAMA, 1986;256

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Alcohol Relapse Prevention Meds: Disulfiram (Antabuse)   

Pt should avoid alcohol containing foods Clinical Dose: 250mg daily (range 125-500mg/d) SE: metallic taste, sulfur-like odor  

 

Rare: hepatotoxicity, neuropathy, psychosis Check LFTs before, q1mo X 3, then q3 mo

Contraindications: CAD, hypersen to rubber, varices, renal disease, severe hepatic dysfunction (LFTs> 3x upper level of nl) Encourage patient to attend substance abuse treatment where disulfiram could be administered by staff/family

Alcohol Relapse Prevention Meds: Acamprosate  Recommended length of treatment: 1 year  Effective in reducing relapse to alcohol use in studies

Alcohol Relapse Prevention Meds: Acamprosate  Acts on GABA and glutamate neurotransmitter systems  Impact is anti-craving, reduced protracted withdrawal  Dose: 2 g daily (6 pills/day= TWO 333 mg pills three times/d)

 SE: Diarrhea (up to 16%), nausea, itching (up to 4%)  Contraindications: severe renal disease (creat cl < 30 ml/min); dose adjust if CrCl 30-50

 Only approved for people who are abstinent

Naltrexone for Alcohol Use Disorder  

Similar structure to naloxone (Narcan) Potent inhibitor of Mu opioid receptor binding 

leading to FDA approval

abstinent at 6 months vs. 23% on placebo



 Not effective in Project COMBINE: 1383 patients  Only naltrexone signif increased % days abstinent and time to heavy drinking

 More severe dependence in European trials (acamprosate with greater effect in longer h/o dependence)?

May explain reduction of relapse 

 Meta-analysis of European trials: 36% on acamprosate

May explain reduced craving for alcohol 



because endogenous opioids involved in the reinforcing (pleasure) effects of alcohol because endogenous opioids may be involved in craving alcohol

Shown to reduce drinking in those who have cut down but not abstained (28% naltrexone vs. 43% placebo)

 Fewer abstinence days required to enter COMBINE Mann K et al. Alcohol Clin Exp Res, 2004 Anton RF et al. JAMA, 2006

Littleton & Zieglgansberger, (2003) Am J Addict 12[Suppl1]:S3-S11

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Naltrexone for Alcohol Use Disorder 

Cochrane Review of NTX (based on 50 RCT)  Reduced

risk of heavy drinking to 83% of the risk vs. placebo (RR 0.83; CI 0.76-0.90)  Decreased drinking days by 4%  Not significant for return to any drinking (RR 0.96; CI 0.92-1.00) 

Pharmacotherapy of Alcohol Dependence: Naltrexone 

Oral Naltrexone Hydrochloride



Extended-Release Injectable Naltrexone (Vivitrol)



 





Garbutt et al. JAMA, 2005

Naltrexone Safety



More effective if >7 days abstinence

Too little data to make conclusion if as effective as PO form (Cochrane review 2010)

Must be opioid-free for 7-10 days before starting

Srisurapanont & Jarusuraisin (2005) Cochrane Database Syst Rev. 2005 Jan 25;(1):CD001867

Can cause hepatocellular injury in very high doses (eg 5-10 times higher than normal)  Contraindicated in acute hepatitis or liver failure  Check liver function before, q1 month for 3 months, then q 3 months Caution about NSAIDS  May have additive hepatic effects

1 injection per month 624 patients 25% decrease in heavy drinking days vs. placebo 

Estimate…helps 1 out of 9…



DOSE: 50 mg per day

Naltrexone Safety 



Other contraindications 

Concomitant opioid analgesics



Opioid dependence or withdrawal



Medical conditions requiring opioid analgesics



Pregnancy (Category C)

Main adverse effects: 

Gastrointestinal: ab pain, N/V



Headache



Dizziness

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7/23/2013

Case Study

Summary – Alcohol Use Disorder 



A 42 year old man with a 14 year history of alcohol dependence relapsed to alcohol abuse 3 months ago. He currently reports drinking 3-5 drinks 4-5 times/wk, but states that he when he abstains for a day or two occasionally he does not experience alcohol withdrawal symptoms. However, his spouse is upset with his drinking and he now wants medication to help him to abstain. He tried naltrexone in the past, but says it ‘didn’t help much.’ He takes no other medications and has no known allergies.



What of the following would you recommend?  A. Liver function tests  B. Acamprosate 666 mg three times daily  C. Disulfiram 250 mg/d

If abstinent: Consider disulfiram as “insurance” (if monitored) Consider naltrexone for relapse prevention  Can consider acamprosate  



If still drinking 



Consider naltrexone

If on opioids 

Consider acamprosate

(from E. McCance-Katz, 2010)

A

Quiz…

Case Study: Answer

and C:

 This

patient has a long and difficult history of alcohol dependence.  He has failed naltrexone in the past and acamprosate is not likely to be helpful (the Combine Study showed it to be inferior to naltrexone).  He has significant consequences of his drinking; is motivated to quit;  If his liver functions indicate that he does not have significant impairment; a trial of disulfiram 250 mg daily might help.



Which of the following is the most commonly misused class of prescription drugs? A. B. C.

Opiates Stimulants Benzodiazepines

(from E. McCance-Katz, 2010)

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Rates of Prescription Narcotic Abuse  Prescription Narcotic Abuse Prevalence:  12th graders:  1992: 3.3% 2007: 9.2%   179% increase over 15 years  OxyContin Vicodin  8th 1.8% 8th 2.7%  10th 3.9% 10th 7.2% 12th 9.6%  12th 5.2%

Source Where Pain Relievers Were Obtained for Most Recent Nonmedical Use among Past Year Users Aged 12 or Older: 2006 Source Where Respondent Obtained Bought on Drug Dealer/ Internet 0.1% Stranger More than 3.9% One Doctor 1.6%

Other 1 4.9%

Free from Friend/Relative 55.7%

One Doctor 19.1%

Source Where Friend/Relative Obtained More than One Doctor 3.3% Free from Friend/Relative 7.3% One Doctor 80.7%

Bought/Took from Friend/Relative 14.8%

Bought/Took from Friend/Relative 4.9%

Other 1 2.2%

Drug Dealer/ Stranger 1.6%

Source: Monitoring the Future, 2007.

Pharmacotherapies for Opiate Dependence

Opioid Dependence Maintenance Therapy: Methadone 

  

Methadone Buprenorphine Naltrexone



Can only be prescribed through a registered “narcotic treatment program” Characteristics    



Long acting mu agonist Duration of action: 24-36 h 30-40 mg will block withdrawal, but not craving Illicit opiate use decreases with increasing methadone dose 80-100 mg is more effective at reducing opioid use than lower doses (e.g.: 40-50 mg/d) Strain EC, et al. JAMA, 1999

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Opioid Dependence Therapy: Methadone  Agonist therapy Prevention of Withdrawal Syndrome Induction of Tolerance

 

Opioid Dependence Maintenance Therapy: Methadone  Can interact with many commonly used medications

 Decreased methadone concentrations:     

 Who is appropriate for methadone therapy?  > 18 years

Greater than 1 year of opioid dependence Medical compromise Infectious disease Pregnancy

   

 Increased methadone concentrations:   

 ECG: methadone prolongs QT in approx 2% (CSAT 2005)

Opioid Dependence Maintenance Therapy: Buprenorphine  Mu Opioid receptor partial agonist  Binds opioid receptors; slow to dissociate  

If recent opioids, may withdraw OD can’t be reversed with standard dosing of naloxone

 Dosing may be daily, every other day or

Ciprofloxacin Fluvoxamine Discontinuation of inducing drug McCance-Katz et al. 2009

Opioid Dependence Maintenance Therapy: Buprenorphine 

To reduce diversion, combined with naloxone in 4:1 ratio 

  

three times weekly

 Average dose 8-16 mg daily  Little effect on respiration or

Pentazocine Phenytoin Carbamazepine Rifampin Many HIV meds



Cheaper price than buprenorphine alone!

Occas increase in LFTs SE: N/V (?if due to withdrawal) Equivalent to lower dose of methadone in reducing illicit opioid use (though 80mg methadone better) Primary care physicians may be providers of this treatment as well as addiction specialists

cardiovascular responses at high doses

McNicholas, 2004

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Opioid Dependence Maintenance Therapy: Buprenorphine  

Metabolized by cytochrome P450 Drug Interactions: Atazanavir/ritonavir: increases buprenorphine concentrations; rifampin: decreases buprenorphine concentrations; opiate withdrawal possible  Buprenorphine DEA certification required to prescribe (8 hrs of training)  Can treat up to 100 patients

Take Home Points  Ask, Assist, Advise, Refer: At-risk and substance use disorders common  Three medications FDA-approved for the maintenance treatment of alcoholism  Disulfiram: for those already abstaining  Naltrexone (oral daily or injectable once monthly): To reduce use in those still drinking

 Acamprosate: for those who can’t take Naltrexone

Opioid Dependence Therapy: Antagonist Treatment (Naltrexone)   

Prevent impulsive use of drug Relapse rates high (90%) following detoxification with no medication treatment Dose (oral): 50 mg daily, 100 mg every 2 days, 150 mg every third day  



Side effects: hepatotoxicity, monitor liver function tests every 3 months Biggest issue is lack of compliance

Injectable naltrexone not currently approved for opioid dependence, but likely to also be effective

Take Home Points  Three medications FDA-approved for treatment of opioid dependence  Methadone (must be given through a licensed narcotic treatment program)

 Buprenorphine/naloxone (Suboxone) available by prescription from qualified providers)

 Naltrexone: an opioid antagonist best for highly motivated patients

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7/23/2013

Thank You! 

Resources 

Local mutual help groups  

www.ncadi.samhsa.gov (resources) www.aa.org



Substance Abuse Facility Treatment Locator Website



http://www.niaaa.nih.gov/Pages/default.aspx



http://findtreatment.samhsa.gov/

19

Osteoporosis: Overview

New Developments in Osteoporosis: Screening, Prevention and Treatment

• • • • •

Judith Walsh, MD, MPH Departments of Medicine and Epidemiology and Biostatistics UCSF

Definitions Risk factors Screening and Monitoring Treatment Emerging Issues

Background

Osteoporosis: Definitions

• Osteoporotic fractures are increasing as the population ages • Hip and vertebral fractures are associated with premature mortality • More recent evidence shows that any fracture is associated with an increased risk of 5-10 year mortality • A subsequent fracture is associated with an increased mortality risk for 5 more years

• Normal: BMD no lower than 1 SD below mean for young adult women • Osteopenia (Low bone mass): BMD 1.0-2.5 SD below the mean for young adults



– (T=-1 to -2.5)

• Osteoporosis: BMD more than 2.5 SD below young adult mean – (T<-2.5)

Dubbo Osteoporosis Epidemiology study

Page 1

Osteoporosis: Definitions

Risk Factors

• T scores vs Z scores • T scores compare the patient with the average young adult female

• Age – Risk of hip fracture increases with age – Older women have a much higher fracture rate than younger women with the same bone density

– Useful for treatment decisions

• Vertebral fractures indicate very high risk

• Z scores compare the patient with an age matched female

– Even if asymptomatic – 20% risk of new fracture in the year following a fracture

– Useful for ruling out secondary causes of bone loss

• • • • • • • • • •

Risk Factors in the WHO Risk Factor Assessment Tool

Drugs Associated with an Increased Risk of Osteoporosis

Age Gender Personal history of fracture Femoral neck BMD Low body mass index Use of oral glucocorticoids Secondary osteoporosis Parental history of hip fracture Current smoking Alcohol intake of 3 or more drinks per day

• • • • • • •

Page 2

Thyroid hormone (over replacement) Aromatase inhibitors SSRIs PPIs Androgen deprivation agents Thiazolidinediones Anticonvulsants

BMD and Risk Factors

Screening and Monitoring

Cummings et al., NEJM 332(12):767-773, 1995

Question

Screening for Osteoporosis

• Which of the following women would you screen for osteoporosis? – – – – –

• Bone density is the single best predictor of future fracture

66 year old healthy woman 57 year old healthy woman who does not exercise 55 year old woman whose mother had a hip fracture 1 and 3 1, 2 and 3

– Hip BMD is best predictor of hip fracture

• Central dual x-ray absorptiometry (DXA) of spine, hip and body most commonly used and is preferred when available

Page 3

National Osteoporosis Foundation 2010

NOF Guidelines 2010

• Evidence based guidelines for screening and prevention • Recommend screening and treatment alternatives

• All postmenopausal women should receive at least 1,200 mg calcium per day, should engage in regular weight bearing exercise and should avoid smoking and excessive alcohol intake • Adults over age 50 should receive 800 IU of Vitamin D3 per day • Fall prevention – Consider hip protectors for high risk women

NOF: Who to Screen

Case

• All women >65 and men >70 • Younger postmenopausal women and men aged 50-70 about whom there is concern based on their clinical risk factor profile • Women in menopausal transition if there is a specific risk factor • Adults with a fracture after age 50 • Adults with a condition associated with low bone mass • Postmenopausal women discontinuing estrogen should be considered

• Bonnie Bony is a 68 year old woman who wants to know when she should have her next bone mineral density test. Her last BMD was 2 years ago and showed osteopenia with a t score of -1.8. What do you tell her?

Page 4

USPSTF Recommendations

Choices • • • •

• Screen all women age 65 and older

Let’s schedule it now We should do it in 2 years We should do it in 5 years I have no idea…when do you want to do it?

– Evidence for screening is indirect

• Screen younger women whose fracture risk is equal to or greater than a 65 year old white woman who has no additional risk factors • “Evidence is lacking about optimal intervals for repeated screening” – A minimum of 2 years may be needed to reliably measure a change in BMD – Longer intervals may be needed to improve fracture risk prediction – USPSTF 2011

The News

Methods

• Bone-density testing interval and transition to osteoporosis in older women.

• 4.597 women from the Study of Osteoporotic Fractures (SOF)

– Gourlay et al. NEJM 2012

• Aim: To determine how the BMD testing interval relates to the timing of the transition from normal BMD or osteopenia to the development of osteoporosis before a hip or vertebral fracture occurs

– Aged 65 and older, population based – Study examinations at year 2, 6, 8, 10 and 16

• Outcome: Estimated interval for 10% of individuals to make transition from normal BMD or osteopenia to osteoporosis before a hip or clinical vertebral fracture or treatment for osteoporosis

Page 5

Results/Competing Risk Analyses

Results

• Adjusted interval between baseline testing and the development of osteoporosis in 10% of study participants – Normal BMD 16.8 (11.5-24.6) yrs – Mild osteopenia 17.3 (13.9-21.5) yrs – Moderate osteopenia 4.7 (4.2-5.2) yrs – Advanced osteoopenia 1.1 (1.0-1.3) yrs

• Within each t score range, a percentage of women developed osteoporosis over 15 years – Normal » (-1.00 or higher) – Mild osteopenia » (-1.01 TO -1.49) – Moderate osteopenia » (-1.50 to -1.99) – Advanced osteopenia » (-2.00 to -2.49)

0.8% 4.6% 20.9% 62.3%

Conclusions

Take Home Message

• Osteoporosis would develop in <10% of individuals during rescreening intervals of 15 years for women with normal BMD or mild osteopenia, 5 years for women with moderate osteopenia and 1 year for women with advanced osteopenia

• Decisions about when to rescreen should be based on the results of initial screening • Few women with normal BMD will develop osteoporosis at 15 year follow-up

• Future screening recommendations will probably be based on likelihood of osteoporosis progression based on initial BMD

Page 6

BMD for Monitoring Treatment

Monitoring Treatment?

• Analysis of data from the FIT study • Over 3 year follow-up, comparison of between person variation (treatment) with within person variation (measurement) • Within person variation was greater than between person variation • 97.5% of individuals gained BMD with alendronate treatment • Routine monitoring in the first 3 years of bisphosphonate treatment is unnecessary

• Treatment should be continued in patients who lose BMD initially • Patients who have the largest increases during the first year are more likely to lose or have modest gains during the second year • If most women will gain BMD with treatment and since resistance to osteoporosis drugs has not been documented, there may not be value in monitoring BMD during treatment • Will monitoring reinforce adherence or change your management?

• BMJ 2009

Monitoring Guidelines • All recommend follow-up monitoring but no consensus on site and frequency • What is definition of “treatment failure?” • ISCD: DEXA spine and hip when expected change in BMD exceeds LSC expected on bone densitometer

OSTEOPOROSIS

– Typically every 1-2 years – Less often once stable

Absolute Risk Assessment

• AACE: DEXA spine and hip every 1-2 years until stability • NAMS: DXA hip every 2 years • Question: What are you going to do?

Page 7

WHO Fracture Risk Algorithm • FRAX • Calculate the 10 year probability of a hip fracture and the 10 year probability of any osteoporotic fracture • Includes femoral neck BMD and risk factors • Can be used only in previously untreated patients • Can be used with or without BMD • Algorithm adapted for the U.S. • Now available as an I phone app

www.shef.ac.uk/FRAX

WHO Fracture Risk Algorithm • Most useful in identifying individuals in the osteopenic range who are most likely to benefit from treatment • Treat when there is a 10 year risk of hip fracture ≥3% or a 10 year risk of a major osteoporosis-related fracture that is ≥20% based on the U.S. adapted WHO algorithm • In the future some BMD machines may be able to provide a report with absolute fracture risk

OSTEOPOROSIS TREATMENT

Page 8

Question

NOF: Who to Treat

• Mrs. P is a 66 year old woman who has no previous fracture or other risk factors. Her hip BMD t score is -1.9. She is on no medications. What are your next steps? • Discuss Calcium and Vitamin D intake • Start raloxifene 60 mg per day • Start alendronate 70 mg per week • 1 and 3

• Postmenopausal women and men age 50 and older – Hip or vertebral fracture – Other prior fractures and low bone mass (t score between -1.0 and -2.5) – T score <-2.5 after excluding secondary causes – Low bone mass (t score between -1.0 and -2.5) and secondary causes associated with a high risk of fracture – Low bone mass (t score between -1.0 and -2.5) and 10 year probability of hip fracture ≥3% or a 10 year probability of any major osteoporosis related fracture ≥20%

Non-pharmacologic Interventions

ACP: Who to Treat • Treat men and women with known osteoporosis and those who have had fragility fractures • Consider pharmacologic treatment in men and women at risk for osteoporosis • Choice of therapy should include risks, benefits and adverse effects of drug options for each individual

• • • • •

• Annals of Intern Med 2008

Page 9

Smoking cessation Avoid ETOH abuse Exercise has transient effect Avoid thyroid over-replacement Hip protectors (compliance)

USPSTF Recommendations February, 2013

Calcium/Vitamin D • Women should ideally get RDA for calcium and Vitamin D from diet • Previous studies have suggested that calcium/Vitamin D are necessary but not sufficient

• Evidence is insufficient to assess balance of benefits and harms – Vitamin D with or without calcium for cancer prevention – Vitamin D and calcium for primary prevention of fractures in postmenopausal women or men – Daily supplementation with >400 IU of Vitamin D3 and 1,000 mg of calcium for fracture prevention

– Even if a woman is receiving adequate calcium and Vitamin D, she may still be at risk for fracture – Additional therapies (eg anti-resorptive therapies) may also be necessary

• Recommends against daily supplementation with <400 IU of Vitamin D3 and 1,000 mg calcium for primary prevention of fractures in noninstitutionalized postmenopausal women

What do you most commonly use for treatment of osteoporosis?

Vitamin D and Falls • USPSTF concluded that Vitamin D supplementation is effective in preventing falls in community dwelling adults aged 65 and older who are at increased risk for falls

• • • • •

– Ages 51-70: 600 IU daily – Older than aged 70: 800 IU daily

Page 10

Weekly bisphosphonate Monthly bisphosphonate Annual bisphosphonate Selective estrogen receptor modulator PTH

FDA Approved Pharmacologic Therapies • • • • •

Estrogen 50% reduction in hip and other non-spine fractures in observational studies • In two RCTs of women with vertebral fractures, estrogen reduced the risk of new vertebral fractures by half • Women’s Health Initiative

Estrogen Bisphosphonates Calcitonin SERMs Parathyroid hormone

– Reduced hip fracture risk by 34%

• Approved non-estrogen treatments should first be carefully considered

Estrogen

Bisphosphonates

• USPSTF does not recommend the use of estrogen for the treatment of any chronic disease • Some women may be taking estrogen for other reasons

• Four approved: alendronate, risedronate, ibandronate, zolendronate – No head to head fracture studies

• Bind to bone and inhibit osteoclastic resorption • Increase BMD by 3% per year • Have been shown to reduce the risk of fracture – All reduce vertebral fracture – All but ibadronate reduced nonvertebral fracture (including hip fracture)

Page 11

Bisphosphonates: Adverse Effects

Bisphosphonates

• Atrial fibrillation

• Less frequent administration of bisphosphonates has improved compliance – – – –

– Some studies have showed increases and others have not

Weekly alendronate or risedronate Monthly Ibandronate or risedronate Ibandronate IV every 3 months Yearly zolendronate

• Osteonecrosis of the jaw • Femoral shaft fractures

• Therapeutic effects with 10 year use of alendronate • Gradual loss of effect with discontinuation of medication

Osteonecrosis of the Jaw

Osteonecrosis of the Jaw • Goals:

• More common with potent bisphosphonate use – 94% treated with IV zolendronate or ibandronate – 4% of cases have osteoporosis; most have cancer – 60% caused by tooth extraction

– Early identification – Conservative treatment

• Estimated risk in those treated for osteoporosis

• Risk factors – Meds: chemotherapy, steroids – Dental extractions, periodontal disease, dental trauma, use of dentures – – –

– 1/10,000 to 1/100,000 patient years

Pazianas M. Clinical Therapeutics 2007: 29 (2) Cartsos VM. JADA 2008: 139: 23-30 Grbic et al. JADA 2008: 139: 32-40

Page 12

Atypical femur fractures

Results

• Several case series have described an increased risk of atypical femoral shaft fractures in bisphosphonate users

• 284 hip or femur fractures in 14,195 women in 3 randomized trials – 12 were subtrochanteric or diaphyseal

• Relative hazards

– Subtrochanteric fracture makes up 2-4% of all hip fractures – No estimate of population prevalence

– RH 1.03 (95% C.I. 0.06, 16.46) for alendronate use in FIT – RH 1.50 (95% C.I. 0.25, 9.00) for zoledronic acid use in HORIZON-PFT – RH 1.33 (95% C.I. 0.12, 14.67) for continued alendronate use in FLEX

• In population based registries, fracture rates higher in alendronate users – Increased alendronate use in high risk individuals

• Re-analysis of data from 3 bisphosphonate trials • Black DM et al. NEJM 2010:362:1761-71

Conclusions

Atypical Fractures • Case-control study of all fractures in a single hospital • 39 patients with atypical fractures and 438 patients with classic fractures

• Fracture of subtrochanteric or diaphyseal femur was very rare even in women on bisphosphonates for up to 10 years • There was no significant increase in risk but confidence intervals were wide

– OR 66.9 (27.2-165.1) for treatment with bisphosphonates and atypical fracture – OR 0.5 (0.3-0.9) for treatment with bisphosphonate and classic fracture – Higher risk atypical fracture with longer duration of treatment

– Small number of events

• Absolute risk of atypical fracture – 32 cases per million person years – Meier et al. Arch Intern Med 2012:172: 930-936

Page 13

Bisphosphonates: Duration of Use

Impact for Practice

• Women who discontinued alendronate for 5 years had a decrease in BMD of 2.4% at hip and 3.7% at the spine but levels remained above pretreatment levels from 10 years earlier • Lower risk of clinically recognized vertebral fractures for those who continued • For many women, discontinuing alendronate after 5 years may not increase fracture risk • Those at high risk for clinical vertebral fractures may benefit from continuing more than 5 years

• Small risk of atypical fracture associated with bisphosphonate use must be weighed against the population benefits of overall reduction in hip fractures with bisphosphonates in women with osteoporosis

Bisphosphonates: Duration of Use

Bisphosphonates: Summary • Bisphosphonates reduce risk of vertebral and hip fracture in women with vertebral fracture or low BMD (T score <2.5) • May not reduce fracture risk in women without osteoporosis • Intermittent dosing appears to be affective • Best evidence of any osteoporosis treatment • After 5 years, some may stop

• FDA Meeting September 9, 2011 – Re-evaluate the efficacy of continuing bisphosphonates for more than 3-5 years

• “Bisphosphonates may be safely discontinued in some patients without compromising therapeutic gains but no adequate clinical trials have yet delineated how long the drugs’ benefits are maintained after cessation.” • New “Important Limitation of Use Statement”

– Who? – How to monitor? – How long?

– Optimal duration of use has not been determined – Periodic re-evaluation of continued need

Page 14

Impact for practice

Question: Choice of Drugs

• Patients at “low risk” may safely have bisphosphonates discontinued

• Bea Brittle is a 67 year old woman with a hip BMD with a t score of -2.8. She has severe GI side effects with weekly bisphosphonates. She is otherwise healthy, but had a DVT at the age of 33 when she was on birth control pills. What would you choose as the next step?

– Younger, , no fracture history, med was started for osteopenia, BMD approaching normal?

• Patients at “increased risk” may benefit from continued therapy – Older, history of fracture, BMD remaining in osteoporotic range?

– – – – –

• Decisions about when to restart? – Role of BMD and bone marker turnovers

Raloxifene

Start ibandonate monthly Start yearly intravenous zolendronate Start raloxifene 60 mg per day Start daily subcutaneous PTH Start intranasal calcitonin

Raloxifene

• Selective Estrogen Receptor Modulators • Ideally maximize bone and cardiovascular protective effects of estrogen, while minimizing negative effects (endometrial and breast cancers)

• Raloxifene reduces vertebral fractures, but has not been shown to reduce the risk of hip fracture • Increased risk of thromboembolic events • Effect similar to tamoxifen in preventing breast cancer • No effect on vaginal bleeding/endometrial cancer

Page 15

Lasofoxifene: Newer SERM

Calcitonin • FDA approved for women who are at least 5 years postmenopausal • Intranasal spray • Increased BMD 10-15% in two years • Fracture data limited and inconclusive • Analgesic effect • Oral calcitonin in studies

• Lasofoxifene (0.5 mg per day) reduced risk of vertebral and nonvertebral fractures • 85% reduction in ER-positive breast cancer • Reduced CHD and stroke • Increased DVT • Increased leg cramps, hot flushes, uterine polyps, endometrial hypertrophy, vaginal candidiasis and arthralgias with lasofoxifene • 38% increase in all cause mortality with lasofoxifene 0.25 mg; no increase with 0.5 mg dose • Approved in Europe, not yet U.S.

– Possible increased cancer risk

• Cummings et al. NEJM 2010: 362: 686-696

Parathyroid Hormone

PTH vs Bisphosphonates • They have not been compared head to head in a trial that evaluated fracture outcomes • PTH increased BMD more than alendronate • PTH is much more expensive • Long term safety of PTH?

• Pulsatile vs constant effect – Anabolic vs anti-resorptive

• PTH 1-34 and PTH 1-84 • Reduces vertebral fractures by 65% and nonvertebral fractures by 53% after 18 months • FDA approved for postmenopausal women at high risk for fracture • Safety and efficacy has been shown for 2 years – Most BMD gains occur in first few months

• Daily subcutaneous injection

Page 16

PTH: Adverse Effects

Combination Treatment

• Hypercalcemia and hypercalcuria • Concern for osteosarcoma

• PTH plus bisphosphonates – No additional benefit – Bisphosphonate may impair PTH stimulation of new bone formation

– Higher doses for longer duration increased risk in rats – Case reports of co-existing osteosarcoma in patients with primary hyperparathyroidism – Only one reported case in post-menopausal woman on PTH

• PTH plus SERMs – Does not suppress BMD response to PTH – No evidence that adding SERM is beneficial

• FDA currently recommends limiting PTH therapy to two years

• PTH plus hormone therapy – Small studies show an increase in BMD with combined therapy

– Post-marketing surveillance is ongoing

After PTH…

PTH: Summary

• PTH is recommended to be used for two years • Some BMD decline after discontinuing PTH • Some anti-resorptive therapy should be added after PTH discontinuation

• Big impact on BMD • Reduces spine and non-spine fractures compared with placebo – Hip fracture?

• Long term safety issues • Daily injection of an expensive drug • Consider use in severe osteoporosis when other agents have failed

– Bisphosphonate – Raloxifene is an alternative

Page 17

Denosumab: Background

Denosumab: FREEDOM trial

• Human monoclonal antibody against RANKL • RANKL is a cytokine essential to osteoclast function • Inhibits osteoclast mediated bone resorption

• 7,868 women with osteoporosis received denosumab 60 mg or placebo subcutaneously every 6 months for 36 months • Endpoints were new vertebral fractures at 6 months and time to first hip and nonvertebral fractures » Cummings SR et al.. NEJM 2009: 361: 756-65

Denosumab: FREEDOM Trial

Denosumab • FDA approved for the following groups

• Reduced risk of vertebral fractures – 2.3% in denosumab group vs 7.2% in placebo group – (Risk ratio: 0.32: 95% C.I. 0.26 to 0.41)

– High risk for fracture including androgen deprivation therapy for prostate cancer and aromatase inhibitor therapy for breast cancer – Treatment for osteoporosis in postmenopausal women at high risk for fracture

• Reduced risk of hip fracture – 0.7% in denosumab group vs 1.2% in placebo group – (Hazard ratio 0.60; 95% C.I. 0.37, 0.97)

• Reduced risk of nonvertebral fracture – 6.5% vs 8.0% in placebo group – (Hazard ratio 0.80: CI 0.67 to 0.95)

• Increased risk of cellulitis in denosumab group – No significant differences in overall infection or cancer

Page 18

NAMS Highlights

Osteoporosis Managament Guidelines

• Pharmacologic treatment: – Women with fractures or osteoporosis – Women with osteopenia who have a 10 year fracture risk of at least 20% and a 10 year hip fracture risk of at least 3%

• Management of osteoporosis in postmenopausal women: 2010 position statement of the North American Menopause Society

• Drug choices – Bisphosphonates are first line – Consider PTH for women with osteoporosis at high risk

• Menopause 2010: 17;25-54

• Highlights

• Fracture risk after discontinuing therapy has not been adequately evaluated

– Periodic review of calcium, Vitamin D and lifestyle – Assess fall risk annually and when physical/mental status changes

Summary: Osteoporosis Prevention • • • •

Summary • Measure bone mineral density in women aged 65 and older • Consider risk factors in measuring BMD in younger postmenopausal women • Any fracture increases the risk of subsequent fracture and mortality • WHO FRAX tool is useful for absolute risk assessment especially in women with low bone mass

Avoid or quit smoking Regular weight bearing exercise Calcium and vitamin D Fall prevention

Page 19

Choice of Pharmacologic Therapies

Choice of Pharmacologic Therapies • Calcitonin may be an option for women who decline or cannot tolerate other options or who desire analgesic effect • PTH may be an option for women who have failed other treatments

• The bisphosponates and estrogen* have been studied most extensively and should remain first line agents • Raloxifene, calcitonin and PTH should remain second line agents • Raloxifene can reduce breast cancer risk

– Treatment for 2 years should be followed by an antiresorptive therapy

• Denosumab FDA approved for women with breast cancer on Ais and for postmenopausal women with osteoporosis • Guidelines about when or whether to stop bisphosphonates in evolution

Thank you!

Questions?

Page 20

7/23/2013

Common Knee Problems:  What You “Knee’d” to Know

UCSF Essentials of Primary Care         August 8, 2013 Carlin Senter, M.D.

Learning objectives:  in 50 minutes you will be able to… 1. List the organizational scheme for any  musculoskeletal work‐up 2. List the 3 key knee history questions 3. Generate a differential diagnosis for acute knee  injury with effusion 4. Generate a differential diagnosis for chronic  anterior knee pain 5. Treat a patient with knee OA and meniscus tear 6. QUIZ

Musculoskeletal work‐up

• History • Inspection • Palpation • Range of motion • Other Tests

Knee history • Acute vs. Subacute‐ Chronic • Mechanism of injury – Direct fall onto patella • Patellar fracture or  cartilage damage

– Varus or valgus force to the  knee • MCL or LCL

– Noncontact with a pop • ACL

• Location of the pain

http://www.ski-injury.com/kneeanat.gif, Accessed 10/04/05. Accessed 10/4/05

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3 key knee injury questions 1. Locking = meniscus or intra‐articular loose  body 2. Instability = ligament 3. Swelling = intra‐articular derangement 1. Immediate: due to blood (ACL, fracture, patellar  dislocation) 2. Subacute: 8‐24 hours, due to synovial  inflammation (meniscus, MCL)

Case #1: House of Air • 35 y/o woman on trampoline half‐pipe.  Jumped down and felt a pop with immediate  knee pain and swelling. • Went to ER: placed in knee immobilizer and  given Vicodin for pain relief. • Now, 3d later, has posterior pain and tightness  with bending. • Knee feels unstable if not in the brace.

Ddx acute traumatic knee injury with  effusion

Musculoskeletal exam order

• History • Inspection • Palpation • ROM

• Intra‐articular  derangement – (+) instability  ligament – (+) locking  meniscus – Dislocation • Patella • Knee

• Other 

– Cartilage damage – Patellar or quad tendon  rupture

•T

ests

http://www.ski-injury.com/kneeanat.gif, Accessed 10/04/05. Accessed 10/4/05

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Knee exam case #1: Inspection

Significance of acute effusion • Intra‐articular derangement • You will likely be ordering xray +/‐ MRI • The patient will not be returning to sport  today

Knee exam case #1: Palpation

Ballottement

Palpation: patellar facet

Video courtesy of Dr. Anthony Luke

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Knee exam case #1: Palpation • Supine, knee fully extended – Ballotement to evaluate for effusion – Medial patellar facet (patellar dislocation) – Patellar apprehension (patellar dislocation)

• Straight leg raise intact – If not ‐ Quad tendon or patellar tendon rupture ‐> urgent ortho

• Knee flexed to 90 degrees – Joint line (meniscus) – Lateral femoral condyle (patellar dislocation) – Above and below medial and lateral joint lines (MCL, LCL)

• Our patient: tender medial joint line, can do straight leg  raise

Knee exam case #1 • ROM: 5‐90, limited due  to pain (normal 0‐135) – Determine if knee is  locking or if ROM is  limited due to effusion – Locking: think bucket  handle meniscus. • Urgent xrays, MRI • Urgent referral to sports  surgeon for arthroscopy

– Rules out patellar dislocation, LCL, tendon rupture

Knee exam case #1

Other Tests: Lachman to evaluate ACL

• Strength 5/5 hip flexion, knee extension, PF,  DF.   – (+) active knee extension rules out quad or  patellar tendon rupture

• 2+ dorsalis pedis pulses bilaterally • Sensation intact to light touch over legs  bilaterally • Reflexes 2+ at patella and achilles bilaterally Video courtesy of Dr. Anthony Luke

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PCL: Sag sign

PCL: Posterior Drawer

Video courtesy of Dr. Anthony Luke

MCL and LCL

Video courtesy of Dr. Anthony Luke

Meniscus: McMurray

Sensitivity medial 65%, Specificity medial 93% Magee, DJ. Orthopaedic Physical Assessment, 5th ed. 2008.

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Meniscus: Thessaly

Meniscus: squat

Video courtesy of Dr. Anthony Luke

Case #1 special tests • • • • • •

Case #1 diagnosis

(+) pain with medial McMurray, (‐) lateral (+) Thessaly – medial pain (+) Squat – medial pain (‐) laxity to varus or valgus at 0 and 30 (+) Lachman without endpoint (‐) Posterior drawer http://www.ski-injury.com/kneeanat.gif, Accessed 10/04/05. Accessed 10/4/05

1. Patellar tendon  rupture 2. Quad tendon  rupture 3. PCL tear 4. ACL tear 5. MCL tear 6. Fracture 7. Meniscus tear

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Case #1 treatment • Knee brace +/‐ crutches  depending on pain and  instability • Xrays to r/o fracture • MRI to confirm diagnosis • Pain medication • PT to restore normal  ROM, decrease swelling,  strengthen quad • Orthopaedic surgery  referral to discuss +/‐ reconstruction

Traumatic knee effusion red flags  urgent ortho referral • Locked knee: unable to fully extend compared  to other side – Bucket handle meniscus – Make non weight bearing w/crutches

• Fracture (tibial plateau, patella) • Unable to extend knee against gravity Segond fracture – avulsion of lateral tibial plateau in ACL tear

Case #2: Sketcher Shape‐Ups 40 y/o woman presents with sharp anterior  knee pain x 1 month. Might have some swelling.  No locking but the knee is popping. Feels  unstable when walking down stairs. Pain worse  up/down stairs. Painful when gets up from  sitting. Exercise: started a walking program for  New Year’s resolution, wearing new Sketcher  Shape‐Up shoes. No squats/lunges. Doesn’t  wear orthotics.

– Patellar or quadriceps tendon rupture – Needs urgent surgical repair

Subacute knee history • 3 key questions – Swelling – Locking – Instability

• Exercise and activity history: squats, lunges,  new training program, marathon? • Shoes: how old, what type • Orthotics: how old, why wearing them

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Ddx subacute‐chronic anterior knee  pain 1. 2. 3. 4.

Case #2: Inspection

Patellofemoral pain syndrome Patellar chondromalacia Osteochondral lesion Osteoarthritis of patellofemoral joint

Patellofemoral pain syndrome:  miserable malalignment syndrome • Femoral anteversion (inward rotation of  femur) • Squinting patella • Patella alta • Increased Q‐angle • Excessive outward tibial rotation

Palpation • Effusion: none • Joint line, patellar facets – Tender medial and  lateral patellar facets

http://www.kneeguru.co.uk/KNEEnotes/node/763

http://www.gla.ac.uk/ibls/US/fab/tutorial/biomech/akp3.html

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ROM • 0‐135 • (+) crepitus with flexion and extension as  patella moves across articular surface of femur

Other tests • Ligaments – Lachman – Posterior drawer – MCL – LCL

• Meniscus – McMurray

Other tests:  identify tightness and weakness

Ober part 1

• Ober (too tight?) • Hip abduction strength (weak?) • One‐legged standing squat (weak? Pain?)

Passive hip abduction and extension.  Hip extension  ITB positioned over greater  trochanter of femur.  http://www.youtube.com/watch?v=A0C0WBw4l4s&feature=player_detailpage

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Ober part 2

Lower the upper limb. If tight ITB then hip will  not adduct past neutral. Compare side to side.

Hip abduction strength

http://www.youtube.com/watch?v=9Iy‐QrcuGno&feature=player_detailpage

http://www.youtube.com/watch?v=A0C0WBw4l4s&feature=player_detailpage

One‐legged standing squat

One‐legged standing squat

• Patient standing on unaffected leg • Do 3 slow 1‐legged squats • Watch for stability, valgus angulation of knee,  ask about pain • Switch and perform on affected leg • Sign of weak hip abductors, weak core • Can bring out pain of patellofemoral pain

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Case #2: Sketcher Shape‐Ups Physical exam

One‐legged standing squat

Valgus angulation of the knees  No effusion Tender medial and lateral patellar facets ROM 0‐135, crepitus No laxity with lachman, posterior drawer, varus or valgus at 0 and 30 degrees • (+) Ober bilaterally • 4/5 hip abductor strength bilaterally • Unstable 1‐legged squat with valgus knee  angulation • • • • •

Case #2 diagnosis 1. 2. 3. 4.

Patellofemoral pain syndrome Patellar chondromalacia Osteochondral lesion Osteoarthritis

Case #2 treatment • Physical therapy rx – Strengthen hip abductors – Strengthen quadriceps – Stretch ITB, quads, hamstrings

• Correct alignment: consider OTC orthotics  with arch support if pes planus • Activity: avoid running, squats, lunges, stair‐ running, downhill hiking until improved.

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Case #3

Radiographs

• 55 y/o man with R knee h/o lateral meniscus  surgery.  • Lateral‐sided pain and swelling of the R knee  since hiking last week. • No locking, no instability • Exam: effusion, tender lateral joint line and  above/below lateral joint line, (+) lateral knee  irritation with lateral McMurray, (+) lateral pain  with squat and Thessaly, no ligamentous laxity • He brings with him xrays and MRI for your review

MRI  Lateral 

Medial

Lateral 

Diagnosis Medial

A. B. C. D. E.

Lateral meniscus tear ACL tear Osteoarthritis Patellar dislocation Septic arthritis

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Initial treatment A. Refer for arthroscopic debridement of  meniscus tear and lavage B. Nonoperative knee OA program C. Refer for total knee arthroplasty

Interventions • Control 

Results

• Arthroscopic surgery

– PT: 1 hour/week x 12  weeks – Home ex program  2x/day – Instruction on ADLs – Self management  arthritis education  reading + videotape – Medications (APAP,  NSAIDs, hyaluronic acid  injections)

– Irrigation with at least 1  L saline – 1 or more of the  following: • Debridement or excision  of degenerative meniscus  tears • Removal loose bodies,  chondral flaps, bone spurs

– Optimal medial and  physical therapy as  above

Kirkley et al. A Randomized Trial of Arthroscopic  Surgery for Osteoarthritis of the Knee, NEJM, 2008.

Kirkley et al. A Randomized Trial of Arthroscopic  Surgery for Osteoarthritis of the Knee, NEJM, 2008.

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Interventions • Control (PT) – Usually 6 weeks – 3‐stage program

• APAP, NSAIDs,  intraarticular steroid  injections as needed

Results

• Arthroscopic partial  meniscectomy (APM) – Trim damaged meniscus  back to stable rim – Remove loose cartilage  and bone

• PT protocol • APAP, NSAIDs,  intraarticular steroid  injections as needed

Katz JN et al. Surgery versus physical therapy for a meniscal tear and osteoarthritis.  N Engl J Med. 2013 May 2;368(18):1675‐84. 

Katz JN et al. Surgery versus physical therapy for a meniscal tear and osteoarthritis.  N Engl J Med. 2013 May 2;368(18):1675‐84. 

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Results

Conclusions • 30% crossed over from PT to APM at 6mo – These people had WOMACs that didn’t improve until  crossover

• No sig difference in adverse events • PT and APM are reasonable options with similar  outcomes for these patients (with allowed cross  over if not achieving relief with PT) • Starting with conservative approach is reasonable Katz JN et al. Surgery versus physical therapy for a meniscal tear and osteoarthritis.  N Engl J Med. 2013 May 2;368(18):1675‐84. 

Katz JN et al. Surgery versus physical therapy for a meniscal tear and osteoarthritis.  N Engl J Med. 2013 May 2;368(18):1675‐84. 

Meniscus tears are common if ≥ 50  years old

Osteoarthritis with meniscus tear

• Seen in 35% of all people – 66% medial, 24% lateral, 10% both

• Increased prevalence with increased age • 82% of people with OA had meniscus tears • 2/3 of patients with meniscus tears had no  symptoms in the prior month

• Meniscus tear is part of the natural history of  osteoarthritis • Treat as osteoarthritis initially • Consider arthroscopic meniscus surgery if PT not  helping

Englund M et al. Incidental meniscal findings on knee MRI in middle‐aged and elderly  persons. N Engl J Med. 2008 Sep 11;359(11):1108‐15. http://www.weddingbee.com/2009/07/20/rock‐paper‐scissors‐shoot/

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Caveats: Who to Refer • Younger patients • Bucket handle meniscus tears – Knee locked due to meniscus blocking joint  movement

• Mechanical symptoms: locking, catching • Failure of nonoperative knee OA treatment

Learning objectives:  in 1 hour you will be able to… 1. List the organizational scheme for any  musculoskeletal work‐up 2. List the 3 key knee history questions 3. Generate a differential diagnosis for acute knee  injury with effusion 4. Generate a differential diagnosis for chronic  anterior knee pain 5. Treat a patient with knee OA and meniscus tear

Quiz

List the organizational scheme for  any musculoskeletal work‐up

• History • Inspection • Palpation • Range of motion • Other Tests

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3 key knee history questions 1. Locking 2. Instability 3. Swelling

Ddx acute traumatic knee injury with  effusion • Intra‐articular  derangement – (+) instability  ligament – (+) locking  meniscus – Dislocation • Patella • Knee

– Cartilage damage – Patellar or quad tendon  rupture http://www.ski-injury.com/kneeanat.gif, Accessed 10/04/05. Accessed 10/4/05

Ddx chronic anterior knee pain 1. 2. 3. 4.

Patellofemoral pain syndrome Patellar chondromalacia Osteochondral lesion Osteoarthritis of patellofemoral joint

Treat a patient with knee OA and  meniscus tear 1. Physical therapy 1. Manual therapy 2. Strengthening 3. Home ex program

2. Offer APAP, NSAIDs, intraarticular steroid  injections 3. Patient education (www.arthritis.org) 4. Consider surgical consult if pain and function  not improving with above

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Thank you!

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Diagnosis and Management of  Common Shoulder and Hip  Complaints

UCSF Essentials of Primary Care         August 8, 2013 Carlin Senter, M.D.

At the end of this hour you will know 1. The differential diagnosis for patients with  decreased AROM and PROM of shoulder. 2. The key difference between impingement  syndrome and rotator cuff tear. 3. How to diagnose a shoulder labral tear. 4. The key exam finding in hip OA. 5. The 2 exam maneuvers to bring out hip  impingement and/or labral tear.

Musculoskeletal work‐up

• History • Inspection • Palpation • Range of motion • Other Tests

Shoulder Problems

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Shoulder keys

Shoulder examination • Inspection • Palpation • ROM

• History – Hand dominance – Occupation – H/o dislocation – Pain that wakes patient from sleep

– – – –

• Exam

Abduction Forward flexion ER IR

• Strength – Supra – Infra and teres minor – Subscapularis

– Always perform neck exam with shoulder – Inspection: gown tied under arms or shirt off – Always examine unaffected side 

• Other tests

Shoulder: diagnosis driven exam

Impingement RC tear Labral tear Biceps tendinitis AC joint OA

Case #1 • 50 y/o RHD woman with DM2 and  hypothyroidism presenting with R shoulder  pain. No injury. Waking up at night during  sleep.  Shoulder feels very stiff, having trouble  reaching behind and raising above head.

Active ROM Normal

http://www.aafp.org/afp/20000515/3079.html

Decreased

Passive ROM Normal Decreased

Frozen  shoulder

GH joint  OA

Xray Normal

Abnormal

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Range of motion

Range of motion

Internal  rotation

Abduction External rotation

Flexion

Supine shoulder PROM

External  rotation

Internal  rotation

Physical exam: AROM

Unable to lift  the shoulder  so uses entire  shoulder  girdle to  abduct and FF. http://www.belmarpt.com/newwordpress/wp-content/uploads/2009/03/img_0294.jpg

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Physical examination: PROM

Shoulder: diagnosis driven exam Active ROM Normal Impingement RC tear Labral tear Biceps tendinitis AC joint OA

Forward flexion

Abduction

Decreased

Passive ROM Normal Decreased

Frozen  shoulder

GH joint  OA

Xray Normal

Abnormal

http://www.youtube.com/watch?v=p52IdSVqvjo

Shoulder xrays

Weighted abduction: diagnose  glenohumeral joint OA

• Evaluate etiology of decreased passive and  active ROM

AP Glenohumeral joint

Scapular Y view

1# weight

No weight Xrays courtesy of Ben Ma.

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Case #1: decreased AROM, PROM, but  normal xrays A. B. C. D.

Shoulder: diagnosis driven exam

Adhesive capsulitis Rotator cuff tear Impingement syndrome Glenohumeral joint osteoarthritis

Active ROM Normal Impingement RC tear Labral tear Biceps tendinitis AC joint OA

Decreased

Passive ROM Normal Decreased

Frozen  shoulder

GH joint  OA

Xray Normal

Abnormal

Associated with

Adhesive capsulitis • • • • • • • •

Diabetes Hyper and hypothyroidism Hypoadrenalism Parkinson’s disease Cardiac disease Pulmonary disease Stroke Surgery (cardiac, cardiac cath, neurosurgery, radical neck dissection)

http://www.aurorahealthcare.org/healthgate/images/si55551230.jpg

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Adhesive capsulitis is a clinical  diagnosis

Active ER key finding

• No need for MRI • Xrays helpful to r/o GH joint OA 

3 stages of adhesive capsulitis

Freezing

3-9 months ↑ pain ↓ ROM Pain at rest, sleep

Frozen

4-12 months ↓ pain Stable, decreased ROM

• Pain control: NSAIDs, oral or injected corticosteroids (either in GH joint or subacromial bursa)

Thawing

12-42 months Gradual ↑ ROM

Treatment for adhesive capsulitis

• Resolution Average time to resolution: 1-3 years

Does not change disease course

• +/- physical therapy to help restore ROM • Capsular distention injections • Surgery • •

Manipulation under anesthesia Arthroscopic release and repair

Manske and Prohaska, Curr Rev Musculoskeletal Med, 2008.

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Case #2

Case #3 Exam

• 57 y/o RHD man presents with R shoulder pain  that started after he fell 3 months ago. Pain at  R deltoid. He tried physical therapy without  benefit. Waking at night from sleep due to  pain.

Shoulder: diagnosis driven exam

• I: no atrophy • P: mild ttp deltoid, nontender biceps and AC  joint • ROM: Unable to actively abduct past 120  degrees 2/2 pain. Full PROM. 

Rotator cuff anatomy

Active ROM Normal Impingement RC tear Labral tear Biceps tendinitis AC joint OA

Decreased

Passive ROM Normal Decreased

Frozen  shoulder

GH joint  OA

Xray Normal

Abnormal

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Rotator cuff anatomy Subscapularis

Supraspinatus = abduction

Supraspinatus Infraspinatus

Supraspinatus

Teres minor

Empty can Photos from Dr. Christina Allen

Infraspinatus and teres minor =  external rotation

Infraspinatus

Subscapularis = internal rotation

Subscapularis

Teres minor

Lift‐Off Photos from Dr. Christina Allen

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Subscapularis = internal rotation

Impingement • Inflammation of the  subacromial space

Subacromial bursa

Supraspinatus

– The area under the  acromion and above the  glenohumeral joint – Structures in this space

Subscapularis

Impingement signs

• Supraspinatus • Subacromial/subdeltoid bursa

Case #2 exam, continued • Other tests:  – 4/5 supraspinatus strength due to pain. – 5/5 infra and teres minor with pain. – 4/5 subscapularis with pain.  – (+) Neers, (+) Hawkins.

Hawkin’s Photos from Dr. Christina Allen

Neer’s

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Diagnosis A. B. C. D.

Adhesive capsulitis Rotator cuff tear Impingement syndrome Glenohumeral joint osteoarthritis

Rotator cuff tear more likely if… • Older patient • Traumatic mechanism • Weak on exam

Treatment

Rotator cuff disease spectrum

A. Order MRI, confirm tear, refer for  arthroscopic RTC repair B. Repeat trial of physical therapy, f/u 3 months. C. NSAIDs and activity modification, f/u 3  months D. Subacromial injection, f/u 3 months

• Stage I: < 25 y/o. Bursitis  • Stage II: 25‐40 y/o. Tendinitis and fibrosis of  rotator cuff • Stage III: > 40 y/o. Partial to complete tearing  of rotator cuff

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AP shoulder

Rotator cuff tear algorithm • If weak on testing of rotator cuff  order xrays and MRI  if (+) rotator cuff tear  refer. • Greater likelihood tear if >40 y/o • Surgical outcomes better if cuff tears fixed earlier  than later  – – – –

Reduced acromiohumeral interval

Smaller tear Less fatty infiltration Less muscle atrophy Less retraction

Saupe N, et al. AJR, 2006.

Differential diagnosis traumatic shoulder injury

Case #3 • 30 y/o RHD man fell off bike 9 months ago,  injured R shoulder • Went to PT but continues to have pain • Anterior shoulder • Only feels pain if moves shoulder in certain  directions quickly • Does not wake him from sleep at night

• • • • •

AC joint separation Labral tear Rotator cuff tear Shoulder dislocation Fracture – Humerus or clavicle

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Physical examination • No atrophy • Tender biceps tendon, nontender AC joint • AROM R shoulder – FF 0‐170 with pain at top – Abd 0‐170 with pain at top – ER 45, IR L1 (Same as L shoulder)

• Strength 5/5 rotator cuff • (‐) Neers and Hawkins • (+) O’Brien’s test

O’Brien’s Test To r/o Labral Tear • Arm forward flexed to 90° • Elbow fully extended • Arm adducted 10° to 15° with thumb down • Downward pressure • Repeat with thumb up • Suggestive of labral tear if more pain with thumb down • Sens = 59-94%, Spec = 28-92%

SLAP tears

Glenoid labrum

• Superior Labrum Anterior to Posterior – Many different types, classifications

• Diagnosis: MR arthrogram • Treatment: surgery – Debridement – Repair

• NOT a disease of older people (do not  consider as etiology for shoulder pain in most  >50 y/o as labrum degenerates naturally)

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7/23/2013

Locate the hip pain

Hip Problems

• Anterior groin = hip  joint, hip flexor • Buttock = SI joint,  lumbar spine • Lateral hip = greater  trochanteric bursitis,  gluteus tendinopathy • Radiating to thigh =  could be hip joint • Radiating to the foot =  lumbar spine

Hip inspection • Ecchymosis: fracture,  hematoma • Leg shortened and  externally rotated:  fracture • Gait‐ unable to weight  bear or sig limp:  fracture, inflammatory  arthritis

http://www.everydayhealth.com /hip‐pain/hip‐anatomy.aspx

Hip palpation • Abdomen • Pelvis – Iliac crest – ASIS – Inguinal canal • Lymph nodes

– Pubic tubercles http://www.emedx.com/emedx/diagnosis_information/hip _pelvis_disorders/hip_fracture_leg_external_rotation.htm

• Hip – Greater trochanter

• Back: SI joints, LS http://www.rush.edu/rumc/page‐ 1098987346941.html

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7/23/2013

Hip passive range of motion

Flexion normal 120°

External rotation normal 40‐60°

Hip passive range of motion: internal and external rotation

Internal rotation normal 30‐40°

http://www.youtube.com/watch?v=5LNYdJIrWYo

Hip neurovascular exam • Strength – – – – –

Signs of intra‐articular hip pathology • Pain with passive ROM • Most pain with IR of  affected hip

Hip flexion (T12‐L3) Knee extension (L2‐4) Plantar flexion (S1) Foot dorsiflexion (L4) Great toe extension (L5)

– Narrows joint space

• Decreased IR of  affected compared to  unaffected side

• Sensation to light touch • Reflexes: patellar (L4)  and achilles (S1) Netter online anatomy  atlas, UCSF library.

http://netterreference.com/ELSEVIER/netter_s_ atlas_of_human_anatomy/a/atlasbook/8

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7/23/2013

If pain with passive ROM be concerned  about hip emergencies • Septic arthritis – Xrays – Hip aspiration • Orthopaedics • Interventional radiology • Do not delay

Non‐emergent hip pathology • • • •

Osteoarthritis ( >50) Femoral acetabular impingement (< 50) Labral tear (< 50) Adductor strain

– Confirmed: to OR for washout

• Femoral neck fracture or stress fracture – Xrays – Make non weight bearing (crutches or wheelchair)

Case #1 69 y/o woman w/ L hip pain.  Pain worse when trying to  put shoes on, sitting, driving.  Better if takes ibuprofen.  Started a year ago, slowly  getting worse. Has noticed  that the left hip isn’t as  flexible as the right hip in  yoga.

Case #1 exam • I: no ecchymosis • P: mild tenderness L inguinal canal • ROM – R hip flexion 130, IR 40, ER 60 – L hip flexion 100 (limited 2/2 groin pain), ER 30  and IR 10 (limited 2/2 groin pain)

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7/23/2013

Xrays

Hip OA treatment • Pain control – Tylenol – NSAIDs

• Physical therapy – Gait training – Core strengthening

• Activity modification: avoid pain

Normal

Frontera: Essentials of Physical  Medicine and Rehabilitation, 2nd ed.

Hip osteoarthritis

Hip replacement • 6‐12 month recovery • Excellent pain relief  starting POD 1 • 10‐20 year minimum  duration

Case #2 • 29 y/o woman with R hip  pain • Localizes to R groin • Started when running on  sand  • Pain 2/10 sitting, 5/10  standing • Aleve helps • Groin pain can be sharp  with certain movements • Did PT but didn’t help http://www.aafp.org/afp /2009/1215/p1429.html

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7/23/2013

5 questions for every athlete with  hip pain 1. Training: increased mileage? 2. Nutrition: Calories in versus calories out?  History of eating d/o? Dietary restrictions? 3. History of stress fractures? 4. Family history of osteoporosis? 5. Menstrual history?

Case #2 exam • I: no ecchymosis • P: ttp R inguinal canal • ROM: bilateral flexion 130, IR 40 and ER 60  but R groin pain with flexion and IR. • OT: – FADIR and FABER R hip cause R groin pain – No pain with FADIR and FABER L hip

FADIR • • • •

FABER

Flexion Adduction Internal Rotation

• • • •

Flexion Abduction External Rotation

http://kurumiyama.web.fc2.com/PT/orthopedic_test.htm http://www.aafp.org/afp /2009/1215/p1429.html

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7/23/2013

Case #2 differential diagnosis 1. 2. 3. 4.

Femoroacetabular impingement (FAI)

Hip labral tear Hip impingement Labral tear and impingement Femoral neck stress fracture

FAI imaging

Hip labral tear

• Xrays to order – AP pelvis – Dunn view lateral • Hip flexed 90 and  abducted 20 degrees

– Lateral can miss  impingement

http://www.aafp.org/afp/2009/1215/p1429.html

http://www.aafp.org/afp/1999/1015/p1687.html

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7/23/2013

Hip labral tear imaging

Treatment FAI/labral tear

• Xrays: normal or impingement, r/o OA • MR arthrogram – Contrast injected into hip joint – 92% sensitivity (DeLee and Drez’s Orthpaedic Sports Medicine, 3

rd

ed)

• Physical therapy – Core strengthening – Hip muscle strengthening

• Activity modification • Corticosteroid injection – Short term pain relief – Confirm that provides pain relief (right diagnosis)

http://www.currentprotocols.com/Wi leyCDA/CPUnit/refId‐mia2602.html

Surgery for FAI/labral tear • Indications – – – –

Pain with flexion and IR Labral tear on MRI or MR arthrogram Relief of pain after injection Failed physical therapy

• Arthroscopy

At the end of this hour you will know 1. The differential diagnosis for patients with decreased  AROM and PROM of shoulder. 1.

1.

– Labral debridement or repair – Osteoplasty of femoral neck and/or acetabulum to restore  normal bony alignment – Higher pt satisfaction if no co‐existing hip cartilage damage  (chondropathy) – Impact of FAI and FAI surgery on development of hip OA is  unknown

Adhesive capsulitis and Glenohumeral joint OA

2. The key difference between impingement syndrome and  rotator cuff tear. RCT is weak

3. How to diagnose a shoulder labral tear. 1.

O’Brien’s test

4. The key exam finding in hip OA. 1.

Decreased hip PROM, particularly flexion and IR

5. The 2 exam maneuvers to bring out hip impingement  and/or labral tear. 1.

FADIR and FABER cause groin pain

Kemp JL et al, Br J Sports Med 2012; 46:632‐643.

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Thank you

Questions?   [email protected]

20

• Liquid nitrogen

Dermatologic Procedures Toby Maurer, MD University of California, San Francisco

• Intralesional steroids • KOH prep • Scabies prep • Unna Boots • Biopsies-snip, shave, punch

The Gun vs. The Q-Tip

Liquid Nitrogen • Thaw time is key

• Cost:

• Thawing destroys the cells

• Gun delivers more constant pressure

• Freeze to get sustained ice ball & adequate thaw time

• Gun is faster if you have the volume

• Thaw time - From time the lesion is white until it goes back to normal color • Always do 2 cycles of thawing

1

Liquid Nitrogen (cont’d) • Thaw times differ by location – Face/genital 2 x 15 sec. thaws and dorsal arms – Palms/soles 2 x 30-45 sec. thaws

• Thaw times differ by diagnosis

Know what you are freezing • Check that pt has resoltuion of lesiondocument that you told them or that you are bring them back

– Seborrheic keratoses - 15 sec. thaws – Actinic keratoses - 15 sec. thaws – Warts - need more & want to go 1mm around periphery

Side Effects • So cold it feels like a burn • Blister tonight then crust that will take 5 days to resolve (15 sec. thaws) vs. 10 days (30-45 sec. thaws) • Can break the blister • Warn re: hypo/hyperpigmentation in persons w/underlying pigment

WARTS • many different ways to treat warts • Liquid nitrogen • Electrocautery • Duct tape • Excision/laser • Aldara (imiquimod) • Liquid nitrogen PLUS podophylin (good for periungual warts and anal warts)

2

Molluscum • Ave number of treatments=12

• Usually self-limited but…..

• Every 3 weeks for destructive modalities

• Liquid nitrogen-light freeze • Toothpick technique-goode for home therapy • Cantheradine-not licnesed for use in the US • Imiquimod does not work

Intralesional Steroids • Used for keloids, hypertrophic scars, patches of alopecia areata • Trick is not to go into fat but stay in dermis(don’t want atrophy)

Keloids • Intralesional steroids-20-40 mg/cc • Pts will absorb steroids systemically so limit is 40 mg per month

• Warn patient and document potential side effects like pigment change and atrophy

• Anaesthetize surface with lidocaine and epinephrine using 30 gauge needle

• For alopecia areata -10 mg/cc; 1-3 cc per month

• Get into the right space and inject steroid with 22 gauge needle

• For Keloids-20-40 mg/cc; 1 cc per month

3

How to do a KOH • Scrape the area and GET LOTS of scale-use a 15 scalpel

• Heat the specimen not to point of boiling (Important to do when you have dry skin)

• Place cover slip on top of scale

• Use your pen to put pressure on cover slip to separate the cells

• Put a drop of KOH on the side of the cover slip and let it go under the slip by osmosis

• Bring your condensor all the way down • Use 4x power and MAX of 10 x power to look for hyphae

Scabies Prep • Why do it? Not everything that itches is scabies Tip: itchy nodules on penis=scabies

Juice and scale go on slide, place cover slip on top

• Don’t rely on finding a burrow but if you do, scrape it-high yield

Mineral oil is great but water will do

• Highest yield areas-between the fingers, wrists, scapula, lateral edge of the feet-look for papulovesicular lesions that are primary (not scratched)

Look at every part of slide and especially around cover slip edges

Bring condenser all the way up

4

Unna Boots

Unna Boots

• For venous ulcers when there is edema

• Never too tight

• Make sure there is no cellulitis before you cover an area

• Leave folds in place

• You will need:

• Start at mid foot and work up to the knee

Currette, +/- lidocaine (no epi), metrogel, duoderm, allevyn, unna boot

• Coban layer on outside

• Anchor joints

• If pt notes pain, take dressing off

Biopsy Tips • Pathologists are only as good as the clinician • REFER - If you have no idea what you are looking at, neither will the pathologist. • Must include history, location and DIFFERENTIAL diagnosis-what are you ruling out AT LEAST

• Give your pathologist an adequate and representative sample • Choose a lesion that has not yet evolved • Don’t crush the tissue • If your results don’t make sense, call the pathologist or a dermatologist for review • Billing: procedural code for biopsy (including closure)-neoplasm of uncertain behavior

5

Informed Consent

• NUMBING IS STANDARD OF CARE • 1% Lidocaine and epinephrine • Epi-okay to use on fingers, toes, and penis unless using large doses • Do not use Epi in Reynauds or other vascular problems (lower leg vascular insufficiency)

• Why are you doing this? • What could be done instead? • Risks involved

• EMLA in Kids followed by IL numbing

– Scar

• Lidocaine allergy

– Infection

• IL Benadryl

– Bleeding

Snip Biopsies/Excision • Scissor snip • Skin tags • AlCl for hemostasis • Send to pathology • Do NOT use silver nitrate or Monsels on visible skin

Shave Biopsies • Leave half of lesion behind so you know to where to return for definitive treatment • Puff up section with anesthetic and LIGHTLY pick up with forceps-scalpel cuts under skin • Al Cl for hemostasis • Petroleum jelly/bandaid

6

Punch Biopsies • Allows you to get to the top of the fat • You will get the epidermis and dermis • Use for diseases that go into the dermis from the epidermis or that originate in the dermis. (Hint: There is a palpable or papular/ nodular component.)

Punch Biopsy • Punch (sizes 2-6mm) – 2mm - Not enough info for pathologist – 3 mm - Use in cosmetically sensitive areas – 4mm - Standard – 5-6mm - Use to get around lesion or if submitting part of a biopsy for tissue culture

Punch Biopsy - You Will Need • Non-absorbable suture – 2mm & 3mm - one stitch

How to make a hole oval? • All in skin tension lines

– 4mm - two stitches – 5mm and 6mm - three stitches – GELFOAM

7

Suturing

Excisional Biopsies • You have control

• Interrupted adequate

• Go down to fat, through fat to fascia & beyond

• Double knot for first throw then 3 more single knot throws

• Lets you get around the lesion entirely

• Remove sutures in 3 days face, 7 days back, chest and 10-14 days limbs • Petroleum jelly/bandaid-keep wound dry

– Malignant melanoma – r/o Dysplastic nevus vs. malignant melanoma – Vasculitis – Panniculitis – Epidermoid cysts

• Mark it with pen before putting in anesthetic • 3:1 rule-measure lesion- If 1 cm, then will need total length to be 3 cm (1.5 cm on each side) for proper closure • Don’t bevel blade-should be perpendicular • Undermine edges for larger wounds-helps to close

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7/23/2013

Our Systematic Review Women’s Health: Year in Review Judith M.E. Walsh, MD, MPH Professor of Medicine UCSF Women’s Health Center of Excellence Conflicts of Interest: None

Sources Reviewed • • • • • • • • • • • • • • • • • • • •

New England Journal of Medicine Journal of the American Medical Association Annals of Internal Medicine Archives of Internal Medicine British Medical Journal Lancet Obstetrics and Gynecology American Journal of Obstetrics and Gynecology Journal of General Internal Medicine PLOS Medicine American Journal of Public Health Circulation Diabetes Cochrane database of systematic reviews Guideline Clearing House ACP Journal Club ACP Journal Wise Journal of Women’s Health Journal Watch Women’s Health Journal Watch



Review for ACP and SGIM – – –



Rachel Bonnema MD, MS Megan McNamara, MS, MSc Sarah Tilstra MD, MS

Reviewed all titles published in top journals –

January 1, 2012 to March 1, 2013



Evaluated potential impact on internists’ clinical practice



Consensus reached about those most worthy of your time today

Plan for today • Breast Cancer Risk Factors and Prevention • Cervical and Ovarian Cancer Screening • Issues for Reproductive Aged Women • Menopause and Beyond • Osteoporosis and Bone Health

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7/23/2013

Cancer Screening and Risk Factors

Breast Cancer Screening and Risk  Factors for Women in Their Forties

Screening Women in Their Forties

Case

• USPSTF recommends individualized, informed  decision making based on a woman’s values about  benefits and harms • Women with a two fold risk of breast cancer who  start biennial screening in their forties have similar  benefits and harms as average risk women who start  screening at age 50 • CISNET Microsimulation Models (Van Ravesteyn, 2012)

• Identifying women with at least a two fold increased  breast cancer risk could be useful in decision making  about mammography initiation before age 50

• Suzie Screening has just turned 40.  Her  gynecologist gave her a referral for a  mammogram but her best friend said that  her doctor told her not to have one.  Suzie’s  head is spinning because every day she  hears something different and she wants to  know what you, her primary care physician,  think.  What do you tell her? 

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7/23/2013

What do you recommend to Suzie?

The News

• Yes, of course.  All women should have their  first mammogram at age 40. • No, wait until you are 50. • Let’s talk about it (even though you are  already 20 minutes behind) • We can talk about this next time you come in  (maybe the guidelines will be more clear then) • I don’t know….what do you want to do? 

• Risk factors for breast cancer for women aged  40 to 49 years: a systematic review and meta‐ analysis

Methods: Systematic Review

Results

• Main outcome: – Incidence of invasive breast cancer at age 40‐49  – Combined outcome: invasive and non‐invasive breast cancer if  only available outcome • Risk factors: Race/ethnicity, BMI, physical activity, alcohol use,  smoking, family history of breast cancer, breast density, prior breast  procedures, reproductive factors • Included studies measuring at least one confounder • Data from Breast Cancer Surveillance Consortium (BCSC) to  supplement systematic review – 5 mammography registries and two affiliate sites – Some risk factors not reported in published studies

– Nelson et al. Ann Intern Med, 2012

• Aim: To determine which factors increase risk  for breast cancer in women aged 40 to 49 and  the magnitude of risk for each factor

• Personal Risk Factors: No association race,  ethnicity, BMI, physical activity, alcohol or  smoking • Family history – – – –

RR 2.14 (CI 1.92‐2.38) one first degree relative RR 3.84 (2.37‐6.220 with 2 relatives RR 12.05  (1.70‐85.16) for ≥3 relatives Risk higher if relative diagnosed at younger age

• Breast density (BI‐RADS category 2 as reference) – RR 1.62 (CI 1.51‐1.75) for BI‐RADS 3 – RR 2.04 (CI 1.84‐2.26) for BI‐RADS 4

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7/23/2013

Results: Reproductive Factors • Menarche at age 15 or older associated with reduced risk  compared with reference (13 years)  – RR 0.87 (CI: 0.78‐0.97)

• Reduced risk for women with 3 or more births (reference  nulliparous) – RR 0.73 (CI 0.61‐0.87) 

• Breast feeding associated with reduced risk – RR 0.87 (CI 0.77‐0.98) 

• Oral contraceptive use – No association in meta‐analysis – BCSC data showed higher risk for current OC use compared with  former or never use • RR 1.30 (CI: 1.13‐1.49) 

Results: Lower than Average Risk • • • • • • •

BMI of 25 kg/m2 or higher Low breast density Age 15 or older at menarche Birth of 3 or more children Breastfeeding Perimenopausal or postmenopausal Use of menopausal estrogen only hormone  therapy

Results: Magnitude of Risk • Greater than two fold increased risk – First degree relative with breast cancer – Extremely dense breasts on mammography

• 1.5 to 2.0 times increased risk – Prior benign breast biopsy result – Second degree relative with breast cancer – Heterogeneously dense breast tissue

• 1.0 to 1.5 times increased risk – – – –

Current use of OCPs Nulliparity First birth at age 30 or over Results differed by data sources (inconsistency) 

Take Home Message • High breast density and having a first degree  relative with breast cancer are factors that  could be useful in developing a personalized  approach to breast cancer screening.

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7/23/2013

Key Article • Institute of Medicine recently published a report  on environmental causes of breast cancer and  radiation from medical imaging • Two environmental factors most strongly  associated with breast cancer are exposure to  ionizing radiation and to combined  postmenopausal hormone therapy • Some lifestyle factors may modestly limit breast  cancer risk: – Limiting alcohol use, maintaining a healthy body  weight and reducing active smoking

IOM Report Conclusions • Current evidence based options for breast cancer  reduction are limited • Many risk factors are not modifiable • Avoiding and reducing exposure to medical  radiation is an evidence based strategy that could  reduce breast cancer risk – Radiation doses from CT are particularly high – Reducing unnecessary exposures

» IOM, 2011

Breast Cancer Prevention • Screening detects breast cancer early but does  not prevent it • For women at high risk, other preventive  strategies should be considered • Tamoxifen and raloxifene are two selective  estrogen receptor modifiers (SERMS) that  have been shown to decrease breast cancer  risk

USPSTF Draft Recommendations:  May, 2013 • Clinicians should engage in shared decision making with  women at increased risk for breast cancer regarding  medications to reduce their risk • For women at high risk for breast cancer and at low risk for  adverse medication effects, clinicians should offer to prescribe  risk reducing medications (Grade B) – “In general, women with an estimated 5‐year breast cancer risk  of 3% or greater are more likely to benefit from tamoxifen or  raloxifene”

• Routine use of medications such as raloxifene or tamoxifen for  risk reduction of primary breast cancer for women not at  increased risk for breast cancer is not recommended (Grade D) 

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7/23/2013

SERM Risk Benefit Ratio Likely To Be Favorable For … Age <50 Age >50 no uterus uterus intact

5 yr Gail >1.5 – >1.67%

Cervical Cancer Screening

>2.5% >5.0%

Cervical Cancer

The News

• Cervical cancer mortality has dramatically decreased with routine screening • Pap smear is a commonly used method for cervical cancer screening • The use of liquid based cytology for primary cervical cancer screening is widespread • HPV testing is recommended for the triage of abnormal Pap smears- use for screening has been controversial

• Human papillomavirus testing for the detection of  high‐grade cervical intraepithelial neoplasia and  cancer: final results of the POBASCAM  randomised controlled trial – Rijkaart et al, BMJ, 2012

• Aim: To determine whether HPV testing in the  first round of screening  can decrease the  detection of CIN Grade 3 or worse, CIN grade 2 or  worse and cervical cancer in the second round of  screening

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7/23/2013

Methods

Results: Participants

• Population based RCT in the Netherlands – Women enrolled as part of nationwide screening  program – Screening every 5 years age 30‐60 – HPV and cytology co‐testing vs cytology alone – At second screening HPV DNA and cytology co‐ testing done in both groups

• Primary endpoint: CIN3 or worse • Intention to screen analysis

Results • At baseline, more cases of CIN Grade 2 or worse  detected in intervention group – 267/19,999 vs 215/20,106 – RR 1.25 (95% C.I.: 1.05‐1.50)

• CIN Grade 3 or worse less common in intervention  group at second screen – 88/19,579 vs 122/19,731 – RR 0.73 (95% C.I.: 0.55‐0.96) 

• Cervical cancer less common in intervention group

Intervention

Control

Overall Number

22,420

22,518

Eligible for  analysis at first  screen

19,999

20,106

Eligible for  analysis at  second screen (5 years later) 

19.579

19.731

Attended second  screen

16,750

16,743

Results • Cumulative detection of CIN grade 3 or worse  and CIN grade 2 or worse did not differ  significantly between study arms nor for  subgroups including women invited for the  first time and differing age groups • Major component of effect was detection of  high grade cervical lesions caused by HPV16

– 4/19579 vs 14/19,731 – RR 0.29 (95% C.I.:0.10‐0.87) 

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7/23/2013

Take Home Message • Using HPV DNA testing for cervical cancer  screening leads to earlier detection of  clinically relevant CIN grade 2 or worse, which  when treated, then leads to improved  protection against CIN grade 3 or worse and  cervical cancer

Cervical Cancer  Screening Guidelines USPSTF 2012

ACS/American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology Joint Guidelines 2012

Pap smear every 3 years in women aged 21-65

Pap every 3 years in women aged 21-29

For women aged 30-65 who want to lengthen the For women aged 30-65 Pap plus HPV testing is the screening interval, screen with a combination of preferred method cervical cytology and HPV testing every 5 years Pap every 3 years is acceptable Discontinue in women over the age of 65 in whom smears have been consistently normal

Discontinue in women over the age of 65 in whom smears have been consistently normal Continue to screen women diagnosed with cervical pre-cancer

No HPV screening in women younger than 30

No HPV testing in women less than age 30 unless needed after an abnormal test result

No screening in women who have had a hysterectomy

No screening in women who have had a hysterectomy and have no history of cervical cancer or pre-cancer

Ovarian Cancer: What Test?

Question • Ms. O. is a 52 year old woman whose best friend was recently diagnosed with ovarian cancer. She is concerned about ovarian cancer and wants “whatever test you can give her” for it. What do you recommend?

• • • •

Bimanual Examination CA-125 Transvaginal ultrasound CA-125 and transvaginal ultrasound • None of these tests

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OVARIAN CANCER: SHOULD WE SCREEN?

Ovarian Cancer: Screening Techniques

• Lifetime risk of ovarian cancer – – – –

No affected relatives One affected relative 2 affected relatives Hereditary syndrome

1% 5% 7% 40%

• Serum CA-125 assay • Trans-vaginal ultrasound • Serum CA-125 plus ultrasound

• Ovarian cancer limited to the ovaries is associated with a much higher survival rate

Prostate, Lung, Colorectal and Ovarian (PLCO) Trial 2011 • AIM: To determine whether annual screening with CA-125 and transvaginal sonography can reduce ovarian cancer mortality

PLCO • 78,216 women aged 55-74 randomized to screening or usual care • Annual CA 125 plus ultrasound – CA 125 >35 or abnormal sono was positive

• Follow-up of positive screens by patients’ physicians • 12.4 years follow-up Buys S. et al. Effect of Screening on Ovarian Cancer Mortality. JAMA 2011;305(22):2295-2303.

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PLCO Results Group

Screen

Control

RR

n

39,105

39,111

--

OC 212 (5.7) diagnosis

176 (4.7)

1.2

Deaths

100 (2.6)

1.2

118 (3.1)

(1.0-1.5)

(0.8-1.7)

PLCO Results • 3285 women with false positive screens – 1080 surgical follow-up – 163 serious surgical complications Conclusion: “Annual screening for ovarian cancer…with simultaneous CA-125 and transvaginal ultrasound does not reduce disease-specific mortality in women at average risk for ovarian cancer but does increase medical procedures and associated harms.”

Ovarian Cancer (rate/10,000)

Primary Prevention of Ovarian Cancer • Oral contraceptives – 37% risk reduction

• Pregnancy • Breast feeding

USPSTF Recommendations • Reaffirmation September 2012 • Grade D recommendation • Do not screen for ovarian cancer

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Goals of “Annual Examination”

The Well Woman Exam

• • • •

Pelvic Examination • Inspection of external genitalia • Speculum examination of vagina and cervix • Bimanual Examination of uterus, cervix and  adnexa

Risk factor identification Screening Counseling Immunizations based on age and risk factors

Goals of Routine Pelvic Exam • • • •

Ovarian Cancer Screening? Evaluate uterus STI screening Detection of other abnormalities?

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Well Woman Exam:  ACOG 2012 Guidelines

Well Woman Exam:  ACOG 2012 Guidelines

• Annual pelvic exam in all women aged 21 and  older

• No evidence supports routine pelvic  examination in women <21 years of age • STI screening can be performed without doing  a pelvic examination • Young women with symptoms should be  evaluated accordingly

– “No evidence supports or refutes” – “Seems logical but lacks data to support specific  time frame or frequency” – Shared decision between patient and provider – Not needed before initiating OCPs

• Patients with any symptoms should be  evaluated accordingly

Case Issues for Reproductive Aged  Women

• Natasha is a 23 yo female who presents to  your office for vaginal discharge. You are  explaining to your medical student how to  collect an appropriate sample for STI testing.

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What Do You Tell Him? A. Place the probe at/in the cervical os B. Sample the entire vulvovaginal canal with the  swab C. Sample the entire vulvovaginal canal  and  then place the swab directly in the os

Testing for Chlamydia and  Gonorrhea • Several studies have shown that self‐collected  vulvovaginal swabs are as sensitive (if not  better?) as urethral or endocervical swabs for  detection of chlamydia; sensitivity for  gonorrhea is unclear • Current practice in the United States remains  endocervical sampling for detection of STIs  • Having to perform a gyne exam is a barrier to  appropriate screening for STIs, especially when  pap is not due Shafer et al. Clin Micro 2003; 41: 4395‐9. Schachter et al.  Sex Transm Dis 2005; 32: 725‐8 CDC.gov

Methods 

The News • Assessment of best single sample for finding  chlamydia in women with and without symptoms:  a diagnostic test study

• Women ≥16 yo were recruited from Centre for Sexual  Health at Leeds, UK

– Schoeman et al. BMJ 2012; 345:e8013.

• Assessment of self taken swabs versus clinician  taken swab cultures for diagnosing gonorrhoea in  women: single centre, diagnostic accuracy study

Self‐taken  vulvovaginal swab

Exam: Endocervical culture, urethral  culture, endocervical swab

Samples  analyzed for  Chlamydia and  Gonorrhea

– Stewart et al. BMJ 2012;345:e8107.

• Aim(s): Compare vulvovaginal swabs with  endocervical swabs and cultures (GC only) for  detection of Chlamydia and Gonorrhea 

Aptima Combo 2 assay, nucleic acid amplification test (NAAT), “gold standard” for testing ‐all positive/equivocal tests were confirmed using standard guidelines

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Results

Sensitivity of Vulvovaginal & Endocervical Swabs for  Detection of GC/CH

• 3973 women recruited by 42 separate  physicians, mean age 25, mostly white • Prevalence: – Chlamydia: 10.3% – Gonorrhea: 2.5% – Co‐infection:  1.4%

*p = 0.028

Conclusions

Take Home Messages

• Vulvovaginal testing (NAAT) is superior to  endocervical testing for detection of  chlamydia, regardless of symptoms • Vulvovaginal and endocervical samples are  equal and superior to culture in detecting  gonorrhea • Endocervical samples may miss asymptomatic  urethral gonorrhea infections

• Standard of care may be shifting away from  endocervical sample collection, especially  with better testing technology (NAATs) • Consider offering self‐vulvovaginal swabs  for STI screening in women who otherwise  would not need pelvic exam (i.e. pap is not  due)

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Case Natasha’s vulvovaginal swab collected by your  astute medical student during her exam returns  positive for gonorrhea. Chlamydia was negative.  What is the treatment that you would  recommend? 

The News • Since 2007, cephalosporins are the only  antibiotics recommended for gonorrhea  treatment • Increased resistance to cefixime has been  documented worldwide • Neisseria gonorrhoeae Treatment Failure and  Suceptability to Cefixime in Toronto, CA – Allen et al, JAMA 2013; 309(2): 163‐170.

• Aim: Assess risk of treatment failure of N  gonorrhoeae infections associated with cefixime use

Summary • Results: treatment failure rate for oral cefixime was 6.8%  (133/291, 46%) • Most of these (7/9) were associated with  increased minimum inhibitory concentrations  (MICs) to cefixime on initial culture • Of the 158 that did not return, 19.6% has  increased MICs and considered high risk for  failure

Gonorrhea Treatment:  CDC Update August 2012 • First‐line therapy:  – Ceftriaxone 250mg IM x1 PLUS azithromycin  1gm x1 OR doxycycline 100mg BID x 7days

• Second‐line:  – Cefixime 400mg orally x1 PLUS azithromycin  1gm x1 OR doxycycline 100mg BID x 7days – Azithromycin 2gm orally x1

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Gonorrhea Treatment Follow‐Up • All patients that do not complete first‐line  therapy need a test‐of‐cure in ONE WEEK – Consider NAAT swab and culture if still  symptomatic

• All patients that test positive should be re‐ screened in 3 months (high re‐infection  rate)

Screening for Intimate Partner  Violence • Approximately 1‐5 million women experience  IPV annually in the United States • IPV can result in injuries, death, STIs,  unintended pregnancies and mental health  issues • In 2004, the USPSTF indicated that evidence  was insufficient to support screening women  for IPV

CDC gonorrhea treatment guidelines Aug 2012 

The News • Effect of Screening for Partner Violence on  Women’s Quality of Life, A Randomized  Controlled Trial

Methods Group 1 N=909 Computerized Screen + IPV Resource List 1 positive answer  video + IPV Resource List negative answers  General Resource List

– Klevens et al. JAMA 2012; 308(7): 681‐689.

• Aim: To assess the effect of a computerized  IPV screening program and provision of IPV  resource list on the quality of life of women  seeking care in primary care clinics

Group 2  N= 893 No computerized screening +IPV Resource List + General Resource List

Group 3‐Control Group N= 898 No computerized screening No IPV Resource List + General Resource List

Outcomes assessed by phone interview at 1 year

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Results  • 2708 women randomized, 87% follow‐up • Average age 39,  55% African American women • ~15% reported IPV in the year before the study (no  difference among groups) Outcomes: QOL (SF‐12) Days lost from work/household duties Use of health services No statistical differences  Use of IPV resources among groups Recurrence of IPV

Conclusions • A computerized screening tool and provision  of an IPV resource did not effect outcomes  related to QOL  • Lack of efficacy may be related to brevity of  intervention or 1‐time occurrence • However, IPV remains an important WH  issue…. 

January 2013: USPSTF Updated  Recommendations for IPV Screening • “…Recommends that clinicians screen women of  childbearing age for IPV … and provide/refer women  who screen positive to intervention services” • Grade B recommendation • Based on:

Menopause and Beyond

– High prevalence‐ 31% of women some form of IPV  (underreported) – Good tools: HITS, OAS/OVAT, STaT, HARK, WAST, CTQ‐SF – Little harm – Decent interventions: counseling, safety plans – No comment on interval

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Case

Case

• Florence is a 68yo woman in for follow up of  hyperlipidemia and thyroid disease.  She  admits during ROS she has to wear a pad daily  and has difficulty “making it to the bathroom  in time.” She has tried minimizing her fluid  intake and scheduling bathroom breaks but  admits this has quite a negative impact on her  life.

• What do you advise as her next steps? A. Referral for pessary B. Begin trospium, there is clear benefit for  this medication over any other C. Begin a medication for urge incontinence,  whatever is first tier on her insurance plan D. Refer for pelvic floor muscle training

Background

The News

• Older women: urinary frequency and  urgency with or without urge incontinence • Initial treatments: lifestyle changes, bladder  retraining, pelvic floor strengthening • Several medications have been approved

• Benefits and Harms of Pharmacologic  Treatment for Urinary Incontinence in Women:  A Systematic Review

– Medications have high rates of anti‐cholinergic  side effects

• Previous reviews have not emphasized  continence or quality of life (QOL) as  outcome 

– Shamliyan T, et al. Ann Int Med. 2012; 156:861‐ 874. 

• Aim: To conduct a systematic literature review  of drugs for urgency urinary incontinence in  women

Hartmann, et al. Evid Rep Technol Assess. 2009:1‐120.

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Methods • Objectives: 1. Analyze efficacy, safety and comparative  effectiveness of drugs  for patient centered  outcomes 2. Analyze long‐term adherence to drug treatment 3. Analyze which characteristics of women can  modify treatment effects

Results  • Drugs were more effective, but with low  magnitude of effect

Methods • Defined clinically important improvement in UI  as ≥50% reduction in UI frequency – Calculated pooled RR and AR difference for efficacy  outcomes

• QOL according to minimal clinically important  differences in validated scales • Performed meta‐analysis of direct results from  head‐to‐head comparisons for comparative  effectiveness

Results  Continence with drugs for urgency urinary incontinence 

• Fewer than 200 cases/1000 treated were  attributable to drugs

• Absolute risk difference in continence was  <20% for all drugs • 21 head‐to‐head RCTs comparing drugs suggest  similar effectiveness

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Results 

Conclusions

Treatment discontinuation due to adverse effects

• Strong evidence that rates of continence and  clinically important improvement in UI were  greater with drugs than placebo – All drugs were better than placebo and had  similar effectiveness – Benefits from drugs are small

• Drugs caused treatment discontinuation due  to side effects

Key Article

Take Home Messages

• Urinary Incontinence in Young Nulligravid Women:  A Cross‐sectional Analysis

• Ask about UI—in all women • UI is associated with lower QOL • Medications have small magnitude of  benefit, side effects causing discontinuation  of treatment • All drugs for urgency UI have similar  effectiveness

– O’Halloran T, et al. Ann Int Med. 2012;157:87‐93.

• 1002 nulligravid women, mean age 22.5yrs • Rate of any UI: 12.6% (10.5‐14.7) – Ever sexually active, no COC use:  21.5% (16.7‐27.3) – Never sexually active, no COC use:  10.1% (7.0‐14.4)

• UI associated with poorer indexes of health‐ related QOL

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Case

Bone Health Dietary vs Supplemental Calcium

Choices A. Keep taking your calcium- it’s good for your bones B. As long as you are taking Vitamin D with it, it should be fine C. Good decision. Stay off the calcium. Just be sure you are drinking a lot of milk.

• Bonnie Bony is a 67 year old woman with hypertension and osteopenia comes in for an annual examination. As you review her medications with her, she tells you that she has stopped taking her calcium supplements because she heard that calcium might cause heart attacks. What do you tell her?

Calcium and Cardiovascular Disease: Background • Calcium supplements are widely recommended for bone health • Previous studies have shown that calcium is necessary but not sufficient for reducing osteoporosis risk • A 5 year randomized controlled trial in healthy older women, where CVD outcomes were prespecified showed possible increases in MI and cardiovascular events in women who took calcium – Bolland MI et al. BMJ 2008

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Background: 2010 Meta-analysis • 15 eligible trials • Calcium supplements were associated with a 30% increase in myocardial infarction and smaller, non-significant increases in stroke and mortality – MI risk was higher in those with a dietary calcium intake above the mean

• Findings consistent across trials • Did not include calcium co-administered with Vitamin D

WHI Outcomes • WHI reported no adverse CVD events in 7 year RCT of calcium/vitamin D supplementation – N=36,282

• 54% of participants were taking calcium on their own and 47% were taking vitamin D • Did personal use of calcium/vitamin D obscure an adverse effect on CVD risk? • WHI participants taking personal calcium and those not taking it were analyzed separately • Meta-analysis updated to include WHI women not taking personal calcium

– Bolland M et al. BMJ 2010

Results: WHI Subgroups • 16,718 women not taking personal calcium at baseline – Hazard Ratio MI 1.22 (1.00 to 1.50) – Other individual outcomes not significant

• 19,564 taking calcium at baseline – HR MI 0.92 (0.75 to 1.13)

Results: Meta-analysis • 20,090 participants from three trials of calcium plus vitamin D vs placebo – Two trials not published before previous metaanalysis and WHI Ca/D – Increased risk of MI with Ca/D – RR 1.21 (1.01 to 1.44)

– Increased risk of stroke with Ca/D – RR 1.20 (1.00 to 1.43)

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Take Home Message • Supplemental calcium with or without Vitamin D is associated with a small increased risk of cardiovascular events • Limitations – Post hoc sub group analyses – WHI accounted for most of the weighting in the meta-analyses

Dietary Calcium • Recent studies have suggested an increase in cardiovascular events with supplemental calcium, but the role of dietary calcium intake has been less clear

• Calcium supplements modestly increase BMD and may have a modest protective effect against fracture • \

The News • Associations of dietary calcium intake and calcium  supplementation with myocardial infarction and  stroke risk and overall cardiovascular mortality in  the Heidelberg cohort of the European  Prospective Investigation into Cancer and  Nutrition study (EPIC‐Heldelberg) – Li et al, Heart, 2012

• Aim: To examine the associations of dietary  calcium intake and calcium supplementation with  MI and stroke risk and overall CVD mortality

Methods • 25,540 residents of Heidelberg aged 35‐64  recruited in 1994‐8 – Excluded those with MI, stroke or TIA at baseline and  those with outlying nutritional intakes – 23,980 included in analysis

• Validated food frequency questionnaire  consumption of 148 items in preceding 12  months • Self reported supplement use • Self reported  cardiovascular events were verified

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Results

Results: Dietary Calcium

• Higher dietary calcium intake was  associated with younger age, higher  education, higher level of physical activity,  less likelihood of being overweight • Dietary calcium intake associated with  Vitamin D intake and likelihood of taking  calcium supplements • Average duration of follow‐up 11 years 

• Total of 354 MIs, 260 strokes and 267 CVD deaths • Third quartile of dietary calcium and dairy  calcium intake had a decreased risk of MI  compared with first quartile

Results: Calcium Supplements • Calcium supplement users had an increased  risk of MI compared with nonusers – HR 1.86 (95% C.I. 1.17 ‐2.96)  – HR 2.39 (95% C.I. 1.12‐5.12) for calcium only

• No association between calcium  supplements and other CV outcomes

– HR 0.69 (95% C.I. 0.50‐0.94) dietary – HR 0.68 (95% C.I. 0.50‐0.93) dairy – Trend was not significant

• Gender subgroup analyses – Men: HR 0.80 (95% C.I.: 0.56‐1.14)  – Women: HR 0.43 (95% C.I.: 0.22‐0.82)

Conclusions • Calcium supplements were associated with a  small increased risk of MI, but were not  associated with other cardiovascular  outcomes • Dietary calcium intake was not associated with  cardiovascular benefits

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Take Home Message • Encouraging adequate dietary calcium intake   should be an important goal • Consider judicious use of calcium supplements  in individuals at high risk for CVD. 

USPSTF Recommendations February, 2013 • Evidence is insufficient to assess balance of benefits  and harms – Vitamin D and calcium for primary prevention of fractures  in postmenopausal women or men – Daily supplementation with >400 IU of Vitamin D3 and  1,000 mg of calcium for fracture prevention

• Recommends against daily supplementation with  <400 IU of Vitamin D3 and 1,000 mg calcium for  primary prevention of fractures in  noninstitutionalized postmenopausal women

Case • Bonnie Bony  still does not know what to do  about her calcium supplements, but she  wants to know if you could please check her  Vitamin D level.  What do you say?

Question: Vitamin D • Order a Vitamin D level • Don’t order a Vitamin D level because you are not sure to do with the results • Don’t order it but start her on a Vitamin D supplement

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Screening for Vitamin D Deficiency

Background • The role of Vitamin D in human health has received widespread attention • Vitamin D clearly has a role in bone health but association with other health outcomes has been less clear • 25-OH Vitamin D levels are widely ordered and deficiency widely treated

• Endocrine Society recommends screening in  those “at high risk for deficiency” but do not  recommend population based screening – At risk may include infants, pregnant women and  the elderly

• Other organizations do not recommend  screening

CASE • Bonnie decides to start taking the Vitamin D supplement. What do you tell her about how much she needs?

Vitamin D • • • •

1.  1,000 IU per day 2.  2,000 IU per day 3.  50,000 IU once a week 4.  600 IU per day

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Key Article • New IOM guidelines for calcium and Vitamin D • www.iom.edu/reports/2010/Dietary-Reference-intakes-forCalcium-and-Vitamin-D

• RDA – 600 IU for women aged 9-70 – 800 IU for women over age 70 – Upper limit 4,000 IU per day

• 25-OH Vitamin D level of 20 ng/ml is the goal

USPSTF: Vitamin D and Falls • USPSTF recommends exercise or physical  therapy and Vitamin D supplementation to  prevent falls in community dwelling adults  aged 65 and older who are at increased risk  for falls – 600 IU daily for adults aged 51‐70 – 800 IU daily for adults over age 70

PPIS and Fracture Risk • PPIs among most commonly prescribed drugs  worldwide

PPIS and Fracture Risk

– OTC since 2003

• Prior studies have suggested an association  between PPI and hip fracture – Limitations: retrospective, inability to control for  confounders, ascertainment of PPI exposure

• FDA warning in May, 2010 about potential  association – More data needed

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The News • Use of proton pump inhibitors and risk of hip  fracture in relation to dietary and lifestyle  factors: a prospective cohort study – Khalili et al. BMJ 2012

• Aim: To examine the association between long  term PPI use and risk of hip fracture among  postmenopausal women in prospective cohort  in the context of dietary and other lifestyle  factors

Results • 893 incident hip fractures • Overall PPI use: – 6.7% in 2,000 – 18.9% in 2008

• Absolute risk of hip fracture – 2.02 per 1,000 person years in users vs 1.51  events per 1,000 person years in non‐users

• HR 1.36 (95% C.I. 1.13,1.63)  – Adjusted for multiple confounders

Methods • Nurses’ Health Study prospective cohort – 121,700 nurses receive questionnaire every 2 years – 79,899 postmenopausal women

• Outcome:  – Self reported hip fractures (low or moderate trauma) 

• Predictors: H2 blockers, PPIs, exercise, smoking,  BMI, alcohol, menopause and HT, calcium and  vitamin D intake, osteoporosis and osteoporosis  medications

Results • Risk increased with duration of use  • Hip fracture risk varied with history of  smoking – HR 1.51 (1.20,1.91) among current or former  smokers – HR 1.06 (0.77, 1.46) among those who never  smoked

• Estimates not affected by reason for PPI use

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Results: Meta‐analysis • Meta‐analysis to include all seven studies  included in FDA report and 4 additional  studies • 1,562,862 individuals included in 11 studies • Pooled odds ratio of hip fracture associated  with PPI use

Conclusions • Regular use of PPIs is associated with an  increased risk of hip fracture in  postmenopausal women • Strongest association in those with the longest  duration of use or with a history of smoking

– 1.28 (1.19, 1.37)

Take Home Message • Clinicians should periodically evaluate the  need for long term PPI use, especially in  current or former smokers

Conclusions • Mammographic density an important risk  factor in younger women • New cervical cancer screening guidelines  incorporate HPV testing • Ovarian cancer screening is not recommended • Standard of care for STI screening may be  shifting from endocervical sampling

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Conclusions • Screen women of childbearing age for IPV • All drugs for urinary incontinence have similar  efficacy • Jury is still out on supplemental calcium – USPSPF gives it a grade “I” recommendaiton

• Important to periodically reevaluate long term  PPI use in women

Questions?

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Management of Atrial Fibrillation in 2013



No financial disclosures

Katherine Julian, MD August 9, 2013

Epidemiology 

Most common arrhythmia in clinical practice 

Why Is This Important? 

AF associated with an increased risk of stroke

2.3 million people in North America



Average cost of $3600/patient/year





Accounts for 1/3 of all hospitalizations for cardiac rhythm disturbances  Prevalence: 0.4-1% in the general population and 8% in those older than 80 years

Six-fold increase in rate of ischemic stroke Rate of ischemic stroke in non-valvular AF approx 5%/year  AF accounts for 15% of all strokes





Associated with increased CHF and all-cause mortality

Singer DE, et al.  Chest, 2004;126.

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Atrial Fibrillation     

Work-Up Rate vs. Rhythm Control Treatment Options Anti-coagulation Future Treatment Options and What’s New

The EKG…

Case I 

 

55 yo woman being seen for a new patient visit. Asymptomatic. PMH: HTN (untreated) PE: 150/80, HR 125 Irregularly irregular

What Work-Up Does She Need? 1) 2) 3) 4) 5)

TSH ECHO r/o MI with troponins 1 and 2 All of the above

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What Work-Up Does She Need? 



Complete history and physical PIRATES

Secondary Causes of AF 

Other Secondary Causes Obesity – likely due to LA dilatation  ?Smoking  Familial  ?Inflammation 



Secondary Causes of AF 

PIRATES – secondary causes Pericarditis Pulmonary/pulmonary embolism  Ischemia  Rheumatic heart disease  Atrial myxoma  Thyrotoxicosis  Ethanol  Sepsis  

What Work-Up Does She Need? 

Complete history and physical exam Pulmonary/pulmonary embolism Ischemia  Ethanol  Sepsis  

Treat Underlying Etiology

Fuster et al. ACCF/AHA/HRS Practice Guidelines. J Am Coll Cardiol. 2011

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What Work-Up Does She Need? ECHO



 

Rheumatic heart disease Atrial myxoma

The real reason…



  

LVH Occult valvular disease Occult pericardial disease

What Work-Up Does She Need?     

Complete history and physical exam TTE EKG CXR Associated labs 



Other tests based on history…ex: event monitor Fuster et al. ACCF/AHA/HRS Practice Guidelines. J Am Coll Cardiol. 2011

Fuster et al. ACCF/AHA/HRS Practice Guidelines. J Am Coll Cardiol. 2011

What Work-Up Does She Need? 1) 2) 3) 4) 5)

TSH ECHO r/o MI with troponins 1 and 2 All of the above

TSH, (CBC, renal and hepatic function)

Classification 

Recurrent: 2 or more episodes  

 

Paroxysmal: arrhythmia terminates spontaneously Persistent: sustained beyond 7 days and is not selfterminating

Permanent: cardioversion has failed (or been foregone) Lone: patients <60 years without clinical/EKG evidence of cardiopulmonary disease (incl htn)

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Case I 

 

55 yo woman being seen for a new patient visit. Asymptomatic. PMH: HTN (untreated) PE: 150/80, HR 125 Irregularly irregular

What is the Next Step for Our Case? What should be our goal in treatment? 1) Convert her to sinus rhythm 2) Rate-control 3) Stroke prevention 4) #1 and #3 5) #2 and #3

Hemodynamic Consequences of AF 

Loss of atrial mechanical function 

  

Atrial fibrosis, loss of atrial muscle mass

Irregular ventricular response Elevated HR Results in: Reduction in diastolic filling, stoke volume, CO  Risk of cardiomyopathy (chronic > 130 bpm) 



Asymptomatic afib 12X more common…

Rate or Rhythm? 

AFFIRM Study 

Randomized 4070 patients with AF to rate-control vs. rhythm-control, F/U 3.5 years  



Rate-control = coumadin Rhythm-control = cardioversion/meds/coumadin

No difference in survival, stroke or QOL Trend towards increased survival in rate-control (P = .08) Pts > 65 yrs and pts without h/o CHF had better outcomes with rate-control therapy  More thrombotic events in rhythm arm  

AFFIRM Investigators, NEJM, 2002;347

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Rate or Rhythm? 

AFFIRM Study…the Caveats…   

No symptomatic patients Average age of enrollees: 70 yrs Only 63% of patients in control arm in sinus rhythm

Rate or Rhythm for CHF Patients 

 



Patients: 1376 patients with h/o afib, EF<35%, sx of CHF Intervention: RCT rate vs. rhythm Outcome: time to death from CV causes, followed 37 months Results    

27% in rhythm-control group died from CV causes 25% in rate-control group died from CV causes HR 1.06 Other outcomes similar (CVA, worse CHF, all-cause mortality)

AFFIRM Investigators, NEJM, 2002;347

Roy, et al. NEJM, 2008;358.

Rate Control

Rate Control Previous goal HR: 60-80 bpm at rest; 90-115 bpm during exercise  No evidence getting HR <80 vs. <110 any better for mortality  No benefit to strict control (if no sx and EF>40%) 

Van Gelder IC et al. NEJM 2010;362 Groenveld HF, et al. J Am Coll Cardiol 2013



What do I use? 

First choice: beta-blockers or calcium-channel blockers 

 

Don’t give if Wolf-Parkinson-White or other accessory pathways

OK to combine nodal-blocking agents Digoxin is second-line as it does not control HR during exercise

Fuster et al. ACCF/AHA/HRS Practice Guidelines. J Am Coll Cardiol. 2011

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What About Cardioversion?

Rhythm vs. Rate…Bottom Line 





Highly symptomatic or unstable: rhythm control If minimal symptoms: rate control is safe and appropriate (maintain goal HR <110) Anticoagulation therapy should be continued regardless of the strategy (rhythm vs. rate)



Electrical cardioversion preferred  

  

Most thrombi in atrial fibrillation arise from the LA appendage Cardioversion can reduce LA appendage function Peri-cardioversion period is particularly prothrombotic 

Electrial Cardioversion 

If AF < 48 hrs, can safely undergo cardioversion without anticoagulant therapy 









Anti-coagulate for at least 4 weeks afterward 

Anti-coagulate also for those who would not normally require coumadin

Fuster et al. ACCF/AHA/HRS Practice Guidelines. J Am Coll Cardiol. 2011

Other factors besides LA clot may affect stroke risk 

Must be documented!

Anti-coagulate X 3 weeks (therapeutic INR) before cardioversion TEE to r/o clot

Regardless of mode of cardioversion

Cardioversion – Thrombus Risk 

If AF > 48 hrs (or unknown duration) OR high-risk for stroke (h/o stroke/TIA, mechanical heart valve), then 2 choices: 

Most effective if within 7 days of AF onset Requires conscious sedation or anesthesia

 





Age DM LA flow velocity HTN

One study showed intra-atrial thrombus has been detected by TEE in 15% of patients with AF < 72 hours duration No difference in thrombus risk between electrical and pharmacologic cardioversion

Fuster et al. ACCF/AHA/HRS Practice Guidelines. J Am Coll Cardiol. 2011

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Pharmacologic Cardioversion – Stable Patients 

Pharmacologic cardioversion in AF < 7 days 

Type 1C  



Flecainide Propafenone

Type III Dofetilide  Ibutilide 



Pharmacologic cardioversion in AF > 7 days 

Proven efficacy: dofetilide, ibutilide, amiodarone

The Next Step… 55 yo woman being seen for a new patient visit. Asymptomatic. PMH: HTN (untreated) PE: 150/80, HR 125 Irregularly irregular Does she need anti-coagulation? 1) Yes, with coumadin 2) Yes, with ASA 3) Yes, with coumadin and ASA 4) Yes, with dabigatran (pradaxa) 5) No

Fuster et al. ACCF/AHA/HRS Practice Guidelines. J Am Coll Cardiol. 2011

Risk/Benefits of Coumadin

Key Point… 

A rhythm control strategy does not negate the need for anticoagulation therapy 

Assuming anticoagulation is indicated



Pooled analysis from five primary prevention trials in non-valvular AF Annual rate of stroke 4.3% in control group 1.4% risk of stroke in the warfarin group  20% of subjects >75 yrs; excluded pts at risk for bleed  Need to consider warfarin risks  

Symptomatic intracranial hemorrhage 0.4% with warfarin; 0.2% in control  Major bleeding: 2.2% with warfarin; 0.9% in control 

Bath PMW, et al. European Heart Journal, 2005

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Secondary Prevention of Stroke

What About Aspirin? 

Two randomized trials evaluated the use of ASA (75mg, 325mg) in primary stroke prevention 



 

Pooled data: Risk of stroke with ASA 4.2%; risk of stroke in controls 6.4%

ASA may be better in preventing noncardioembolic strokes and non-disabling strokes

EAFT Study Group, Lancet, 1993

Bath PMW, et al.  European Heart Journal, 2005

Anti-Platelets vs. Coumadin? 

Risk of stroke with warfarin 3.1%; placebo 10% Risk of stroke with ASA (300mg) 7.7%

Anti-Coagulation

ACTIVE-W trial 3335 patients with AF and at least 1 other risk factor for stroke  ASA + clopidogrel vs. coumadin  Outcomes: stroke, non-CNS systemic embolus, MI or vascular death  Stopped early because of superiority of warfarin in preventing vascular events (165 events vs. 234 events). Warfarin even better for those who entered the study already taking it. 

Active Writing Group. Lancet, 2006;367(9526)



Bottom line…anticoagulation with warfarin superior to ASA and superior to ASA + clopidogrel. Effective in the prevention of primary and secondary stroke.

Active Writing Group. Lancet, 2006;367(9526)

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Who Needs Anti-Coagulation in AF? 

CHADS2 used as accurate predictor of stroke 

Who Needs Anti-Coagulation in AF? 

1 point each for: CHF (or reduced systolic function) Htn  Age > 75 years  Diabetes

CHF/LV dysfunction = 1 pt Htn = 1 pt  Age >75 yrs = 2 pts  DM = 1 pt  Stroke/TIA/Thromboembolism = 2 pts  Vascular Disease (prior MI, PVD) = 1 pt  Age 65-74 yrs = 1 pt  Sex category (female) = 1 pt











2 points for: 

For low-risk paitents CHA2DS2-VASc outperformed CHADS2

History of stroke or TIA

0 pts: no treatment; >1 pt: anticoagulation  Problem: doesn’t account for other stroke RF 

Olesen JB et al. BMJ, 2011;342

Gage BF, et al.  JAMA, 2001;285.

Anticoagulation…Who Needs It? 

CHA2DS2-VASc 



Stroke rate (%/year based on cohort data) 0 points: 0 1 point: 1.3  2 points: 2.2  3 points: 3.2  4 points: 4.0  5 points: 6.7  

Anticoagulation…Who Needs It?

6 points: 9.8 7 points: 9.6  8 points: 6.7  9 points: 15.2

CHA2DS2-VASc 

No benefit of oral anticoagulation if patients lowrisk (score=0)



Neutral or positive benefit of anticoagulation for score >1



 

No treatment vs. ASA 81-325mg daily

Score of 1: ASA or anticoagulation (anticoagulation preferred)  Score >2: anticoagulation 

Lip GY et al.  Stroke, 2010;41(12).

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Back to Our Case… 

 

55 yo woman being seen for a new patient visit. Asymptomatic. PMH: HTN (untreated) PE: 150/80, HR 125 Irregularly irregular

Anti-Coagulation Special Considerations 

What about my 85 yo patient who falls? 



What about my patient with a remote h/o GIB? 







CHA2DS2-VASc score = 2 points; CHADS2 score=1 Offer anticoagulation

Predisposition to falling not considered a contraindication for warfarin Risk of recurrent bleeding 1.2% Resolved peptic ulcer disease bleeding (with H. Pylori testing/treatment) not a contraindication for warfarin

Man-Son-Hing M et al. Arch Intern Med, 2003;163.

Anti-Coagulation Special Considerations 

What are absolute contraindications to warfarin? Bleeding diathesis  Thrombocytopenia (<50K)  Untreated or poorly-controlled htn (> 160/90)  Non-compliance with INR monitoring 



Relative contraindications 

Significant ETOH use, NSAID use without PPI, activities predisposing to trauma

Man‐Son‐Hing M et al.  Arch Intern Med, 2003;163.

Anti-Coagulation Special Considerations 

What about stopping anti-coagulation for a procedure? Mechanical heart valve→heparin (UFH vs LMWH)…most of the time…  Non-valvular AF 

High-risk (CHADS 5 or 6) →heparin Medium-risk (CHADS 3 or 4) →heparin full or low-dose  Low-risk (CHADS 1 or 2) →ok to stop coumadin for <1 week  

Kraai EP et al. J Thromb Thrombolysis, 2009;28

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Prediction for Major Bleeding Risk – HAS-BLED 

HAS-BLED risk scheme for AF Hypertension  Abnormal renal function  Abnormal liver function  h/o Stroke/TIA  Bleeding history 

HAS-BLED Risk Classification 

Labile INR  Elderly (age>65 yrs)  Drugs (NSAIDs/steroids) or alcohol* concomitantly 

 

Validated using trial data; prelim evidence looks like it is best prediction model Max=9pts Risk of major bleeding=intracranial, transfusion, hospitalization

HAS-BLED score

Bleeds/100 patients

0

1.13

1

1.02

2

1.88

3

3.74

4

8.70

5

12.50

Lip GY, et al. J Am Coll Cardiol, 2011;57(2):173-180

What if warfarin is contraindicated? 

ACTIVE-A Trial 

7554 patients with afib at increased stroke risk, warfarin “unsuitable” RCT clopidogrel (75mg) + ASA vs. placebo + ASA Outcome: stroke, MI, embolism, vascular death  Median f/u 3.6 years  



Vascular events clopidogrel 6.8% vs. 7.6% (RR 0.89; CI 0.81-0.98)



Major bleeding 2% vs. 1.3% (RR 1.57; CI 1.29-1.92)



What if warfarin is contraindicated? 

Bottom line… Lessened stroke risk almost off-set by increased bleeding risk (but not quite)  AF Guidelines: Could consider in patients at highrisk for stroke who can’t take warfarin (**but consider dabigatran first) 



Need to ensure not at high-risk for bleeding

Mostly due to stroke reduction (2.4% vs. 3.3%)

ACTIVE Investigators. N Eng J Med, 2009;360.

ACTIVE Investigators. N Eng J Med, 2009;360. Wann et al. JACC, 2011;57(2).

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New Oral Anticoagulants

New Oral Anticoagulants XII

Oral Xa Inhibitors Rivaroxaban Apixaban

XI

IX

VII

II

Approval Status

IIa

Fibrin



Fibrin Clot



Dabigatran (Pradaxa)

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

T ½ Hours

12-17

5-9

8-15

CYP3A4

---

Yes

Yes

Substrate of p- Yes glycoprotein Antidote None

Yes

---

None

None

Monitoring

Anti Xa

Anti Xa

DVT Prevention DVT and PE treatment

Mechanism

DTI

Anti-Xa

Anti-Xa

Renal Metabolism

80%

30-60%

25%

New Oral Anticoagulants

PTT

Nonvalvular • Nonvalvular Nonvalvular Afib Afib Afib

Oral IIa Inhibitor Dabigatran

Xa

X

Dabigatran Rivaroxaban Apixaban (Pradaxa) (Xarelto) (Eliquis)

Dabigatran 





AF Guidelines: recommended as an alternative to warfarin for prevention of stroke and systemic thromboembolism (nonvalvular AF) Recommended by American College of Chest Physicians instead of warfarin Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY)  18,113 patients with afib and stroke risk (CHADS2 score mean 2.1)  RCT Dabigatran vs. warfarin  Dabigatran 110mg or 150mg BID (blinded) vs. unblinded adjusted warfarin Connolly SJ.  N Engl J Med, 2009;361.

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Dabigatran 

RE-LY Study  Primary outcome: stroke or embolism, F/U 2 years

Dabigatran 

Dyspepsia/gastritis GI bleeding increased with dabigatran  Increased MI’s in dabigatran groups (RR 1.38; CI 1.0-1.91 for high-dose)  Valvular AF excluded  Warfarin 64% in therapeutic range 

 1.69%

warfarin  1.53% for 110mg dabigatran (non-inferior)  1.11% for 150mg dabigatran (superior)  Rate



of major bleeding

 3.36%

warfarin dabigatran 110mg  3.11% dabigatran 150mg (p-value NS)  2.71%

Caveats…



As effective as coumadin post-cardioversion

Connolly SJ. N Engl J Med, 2009;361.; Nagarakanti R, et al. Circulation, 2011;123

Dabigatran  







Oral direct thrombin inhibitor Pros: No INR monitoring, fewer dietary/drug interactions Cons: BID, $200/one month supply, no antidote (is dialyzable), renally cleared Dosing: 150mg BID if CrCl>30 (75mg BID if CrCl 15-30). Not for CrCl<15 Substrate of transporter p-glycoprotein  

Starting Dabigatran   

Baseline labs: CBC, Cr, PTT (LFTs) Patient Education med guide Monitoring Adherence Adverse effects (GI)  Bleeding/Stroke  

Follow-Up 2 weeks 1 month 3 months Continue monthly check-in

P-gp inducers (St. John’s wart, rifampin) decrease levels P-gp inhibitors (ketoconazole) increase levels

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Rising Concerns with Dabigatran… 

Dec 7, 2011 FDA launches investigation into bleeding reports with pradaxa 



Rivaroxaban (Xarelto)  

Between March 2008 and October 31, 2011, 260 fatal bleeding events worldwide.

Meta-analysis: more coronary events 30,514 patients  OR 1.33 (CI 1.03-1.71) for MI or ACS

 





 

Uchino K and Hernandez AV. Arch of Intern Med, 2012

Rivaroxaban 

ROCKET AF trial 14,264 non-valvular afib pts at high risk for stroke (mean CHADS2=3.5)  Randomized: rvaroxaban 20mg/d or 15mg/d vs. warfarin  Endpoint: stroke or systemic embolism  Non-inferior to warfarin in AF patients 

1.7% rivaroxaban vs. 2.2% warfarin Bleeding rates overall equal but statistically fewer intracranial and fatal bleeding with rivaroxaban (more GIB)  Low rate of therapeutic INR (58%)  

Direct Xa inhibitor Once daily dosing 20mg qhs if CrCl >50 15mg if CrCl 15-50

Approved July 2011 for prevention of DVTs in knee/hip arthroplasty patients Approved Nov 2011 for non-valvular afib Beware CYP3a4 inhibitors: diltiazem, amiodarone, verapamil

The Next Step… 55 yo woman being seen for a new patient visit. Asymptomatic. PMH: HTN (untreated) PE: 150/80, HR 125 Irregularly irregular CHA2DS2-VASc score = 2 points; CHADS2 score=1

Does she need anti-coagulation? 1) Yes, with coumadin 2) Yes, with ASA 3) Yes, with coumadin and ASA 4) Yes, with dabigatran 5) No

Patel MR, et al. N Engl J Med, 2011;365(10).

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Apixaban  

Factor Xa inhibitor ARISTOTLE Trial

What’s “In” and What’s “Out”? 

Approved July 2009 for low-to intermed-risk pts with AF  Similar to amiodarone but noniodinated, thus no thyroid/pulm toxicity  Athena Trial: 

18,201 afib patients with 1 additional risk factor for stroke (mean CHADS2=2.1)  Randomized, double-blind apixaban 5mg BID (2.5mg BID in select pts) vs. warfarin  Outcomes: stroke, systemic embolism  Apixaban superior to warfarin in primary outcome 





4628 pts with afib Outcome: First hospitalization due to CV events or death  31.9% dronedarone vs. 39.4% in placebo group (HR 0.76; CI 0.69-0.84)  Reduction mostly due to afib hospitalization (no difference in death rate)  

Lower mortality and less bleeding

Approved Dec 2012

Hohnloser SH et al. NEJM, 2009;360.

Granger CB, et al. N Engl J Med, 2011;365.

Dronedarone in High-Risk Permanent Afib

Dronedarone in CHF  

ANDROMEDA trial Patients with symptomatic CHF RCT dronedarone vs. placebo 



Stopped early due to increased mortality in dronedarone group Mostly worsened CHF



 





Kober L, et al. NEJM, 2008;358.

What’s “Out”---Dronedarone

3236 patients >65 yrs with at least 6 mo h/o permanent afib and risk factors for major vascular events Dronedarone vs. placebo Outcome: stroke, MI, systemic embolism, death from CV causes Study stopped early for safety reasons (more stroke, CV deaths, CHF)  Post marketing reports of hepatocellular injury Bottom line…would avoid dronedarone in CAD/CHF pts Connolly SJ et al. NEJM, 2011:365;24

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What’s New?--Ablation 

Paroxysmal AF primarily emanates from the pulmonary veins 



Future Directions 

Edoxaban 

Less effective than ablation for SVT, a-flutter

Updated guidelines: ablation recommended (in experienced center) for pts with symptomatic, paroxysmal AF who have failed drug treatment

Studied in ENGAGE study  



Edoxaban vs. warfarin Awaiting results

Obliteration of left atrial appendage 

Where 90% of thrombi form

Wann et al. JACC, 2011;57(2).

Recap…Current Guidelines 

Paroxysmal 



Anticoagulate; treat if symptoms

Current Guidelines…To Maintain Sinus Rhythm 

Persistant Anticoagulate, rate control  Can then decide whether to accept permanent AF vs. antiarrythmic drug therapy +/- cardioversion









Recurrent paroxysmal Anticoagulate, rate control  If disabling symptoms, antiarrhythmic meds and ablation if this fails



If no response→amiodarone/or dofetilide or ablation

If heart disease→dofetilide or sotolol (dronedarone) 



Fuster et al. ACC/AHA/ESC Practice Guidelines. JACC, 2006;48(4).

No heart disease→flecainide, propafenone or sotolol (dronedarone)

If no response→amiodarone or ablation

If CHF→amiodarone or dofetilide 

If no response→ablation Wann LS, et al. Circulation, 2011;123(1)

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Current Guidelines…To Maintain Sinus Rhythm 

Hypertension with LVH→amiodarone



Hypertension and NO LVH →flecainide, propafenone, sotolol (dronedarone)





If no response→ablation

Thank You!!

If no response→amiodaroneor dofetilide or ablation

Wann LS, et al. Circulation, 2011;123(1)

18

Katherine Julian, MD July 2013

Atrial Fibrillation Selected References ACTIVE Writing Group of the ACTIVE Investigators, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events. Lancet, 2006;367(9526):1903-12. ACTIVE Writing Group of the ACTIVE Investigators, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009;360:2066-2078. The AFFIRM Investigators. Clinical factors that influence response to treatment strategies in atrial fibrillation: the atrial fibrillation follow-up investigation of rhythm management (AFFIRM) study. Amer Heart Jour 2004; 149(4):645-649. The AFFIRM Investigators. Relationships between sinus rhythm, treatment, and survival in the atrial fibrillation follow-up investigation of rhythm management (AFFIRM) Study. Circulation, 2004;109:1509-1513. Alboni P, Botto GL, et al. Outpatient treatment of recent-onset atrial fibrillation with the “pill-in-the-pocket” approach. N Engl J Med 2004; 351(23):2384-2390. Ansell J. New oral anticoagulants should not be used as first-line agents to prevent thromboembolism in patients with atrial fibrillation. Circulation 2012;125:165-170. Bath PM, Zhao L, et al. Current status of stroke prevention in patients with atrial fibrillation. Euro J Heart Fail 2005; 7(suppl C):C12-C18. Blaauw Y and Crijns HJGM. Treatment of atrial fibrillation. Heart, 2008;94:1342-1349. Camm AJ, Savelieva I, et al. Rate control in the medical management of atrial fibrillation. Heart 2006; 93:35-38. Caterina RD and Hylek EM. Stroke prevention in atrial fibrillation: current status and near-future directions. The American Journal of Medicine 2011;124:793-799. Connolly SJ, Cam AJ, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011;365:2268-2276. Connolly SJ, Ezekowitz MD, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-1151. Curtis AB. Update on the clinical management of atrial fibrillation: guidelines and beyond. Postgraduate Medicine 2011;123(6):7-19.

DiMarco JP, Flaker G, et al. Factors affecting bleeding risk during anticoagulant therapy in patients with atrial fibrillation: observations from the atrial fibrillation follow-up investigation of rhythm management (affirm) study. Am Heart J 2005; 149:650-656. Dwar RI, Lip GY. Identification, diagnosis and assessment of atrial fibrillation. Heart 2006; 93:25-28. Eagle KA, Cannom DS, Garcia DA. Management of atrial fibrillation: translating clinical trial data into clinical practice. The Am J of Med, 2011;124:4-14.

Flaker GC, Belew K, et al. Asymptomatic atrial fibrillation: demographic features and prognostic information from the atrial fibrillation follow-up investigation of rhythm management (AFFIRM) study. Am Heart J 2004; 149(4):657-663. Fuster V, Ryden LE, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines. Europace, 2006;8(9):651-745. Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 2011 Mar 15;57(11):e101-98 Gage BF, Walraven CV, et al. Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. J Amer Heart Assoc 2004; 110:2287-2292. Gage BF, Waterman A, et al. Validation of clinical classification schemes for predicting stroke. JAMA 2001; 285(22):2864-2870. Garcia D, Libby E and Crowther MA. The new oral anticoagulants. Blood 2010;115:1520. Granger CB, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-992. Granger CB and Armaganijan LV. Newer oral anticoagulants should be used as first-line agents to prevent thromboembolism in patients with atrial fibrillation and risk factors for stroke or thromboembolism. Circulation 2012;125:159-164.

Groenfeld HF, et al. Rate control efficacy in permanent atrial fibrillation: successful and failed strict rate control against a background of lenient rate control. J Am Coll Cardiol 2013;61:741–8 Groenveld HF, Crijns HJ, et al. Does intensity of rate control influence outcome in persistent atrial fibrillation? Am Heart J 2009;158:785-91. Gutierrez C, Blanchard DG. Atrial fibrillation: diagnosis and treatment. Am Fam Physician 2011;83(1):61-68. Jais P, Cauchemez B, et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation, 2008;118:2498-2505. Kalra L, Lip GY. Antithrombotic treatment in atrial fibrillation. Heart 2007; 93:39-44. Lafuente-Lafuente C, Mahe I and Extramiana F. Management of atrial fibrillation. BMJ 2010;340:40-45. Matchar DB, Jacobson A, et al. Effect of home testing of international normalized ratio on clinical events. NEJM 2010;363:1608-1620. Miller CS et al. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol 2012;110:453– 460. Nagarakanti R, et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation, 2011;123:131-136. Nattel S, Opie L. Controversies in atrial fibrillation. Lancet 2006; 367:262-272. Oral H, Pappone C, et al. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. N Engl J Med 2006; 354:934-941. Oral H, Scharf C, et al. Catheter ablation for parozysmal atrial fibrillation: segmental pulmonary vein ostial ablation versus left atrial ablation. J Amer Heart Assoc 2003; 108:2355-2360. Page R. Newly diagnosed atrial fibrillation. N Engl J Med 2004; 351:2408-2416. Pappone C, Rosanio S, et al. Mortality, morbidity, and quality of life after circumferential pulmony vein ablation for atrial fibrillation. J Amer Col Card 2003; 42(2):187-197. Patel MR, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-891.

Pellegrini CN, Vittinghoff E, et al. Statin use is associated with lower risk of atrial fibrillation in women with coronary heart disease: The HERS trial. Heart 2009;95:704708. Penugonda N, Mohmand-Borkowski A, et al. Dronedarone for atrial fibrillation: how does it compare with amiodarone? Cleveland Clinic Journal of Medicine, 2011;78(3):179-185. Perez-gomez F, Alegria E, et al. Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and nonvalvular atrial fibrillation. J Amer Col Card 2004; 44(8):1557-1566. Reddy VY, et al. Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation. Circulation, 2013;127:720-729.

Tapson VF, Hyers TM, et al. Antithrombotic therapy practices in us hospitals in an era of practice guidelines. Arch Intern Med 2005; 165:1458-1464. The Medical Letter. Dabigatran etexilate – a new oral anticoagulant. The Medical Letter. November 2010;52(1351). Wann LS, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updated on dabigatran). JACC 2011;57(11):1330-1337. Wann LS, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the american college of cardiology foundation/American heart association task force on practice guidelines. J Am Coll Cardiol 2011;57:223-242. Wazni OM, Marouche NF, et al. Radiofrequency ablation vs antiarrhythmic drugs at first-line treatment of symptomactic atrial fibrillation a randomized trial. JAMA 2005; 293:2634-2640. You JJ, et al. Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2012;141:e531s-e575s.

Robert Baron, MD, MS

CURRENT ISSUES IN DIABETES MANAGEMENT

CURRENT ISSUES IN DIABETES MANAGEMENT

Screening for Diabetes 2013  BMI ≥25 plus other risk factors

Robert B. Baron MD MS Professor and Associate Dean UCSF School of Medicine

Inactivity

Low HDL or high TG

First degree relative

PCOS

High-risk ethnicity

Acanthosis nigricans

Gestational DM

Hx CVD

HTN

Declaration of full disclosure: No conflict of interest

Diagnosis of Diabetes 2013

 Age 45 ADA Diabetes Care, 2013

Advantages of HbA1c as a Diagnostic Test

 A1C ≥ 6.5% (New, 2010)

 Non fasting

 FPG ≥ 126 mg/dl (7.0 mmol/L)

 Lower intra-individual variation

 2-h plasma glucose ≥ 200 during OGTT

 HbA1c: 2%

 Symptoms and random plasma glucose ≥200 mg/dl (11.1 mmol/L)

 FPG: 6.5%

 Need two separate measurements

 2 hour plasma glucose: 16-17%

ADA Diabetes Care, 2013

1

Robert Baron, MD, MS

CURRENT ISSUES IN DIABETES MANAGEMENT

Diagnosis of Pre-Diabetes 2013  A1C 5.7 – 6.4% (New, 2010)  FPG 100 - 125 mg/dl (5.6mmol/L - 6.9 mmol/L)  2-h plasma glucose 140 mg/dl – 199 mg/dl during OGTT (7.8mmol/L – 11.0 mmol/L)

Risk of Pre-Diabetes 2013  Increased risk of progression to diabetes  44,203 individuals; 16 studies, 5.6 years  A1C 5.5 – 6.0: risk of DM 9 - 25%  A1C 6.0 – 6.5: risk of DM 25 – 50%

ADA Diabetes Care, 2013

Treatment of Pre-Diabetes 2013  Weight loss 7%; physical activity 150 min/week  Metformin (but only metformin) may be considered, especially for those with BMI >35, age <60, and women with history of gestational DM ADA Diabetes Care, 2013

ADA Diabetes Care, 2013

2013 Practice Guidelines: ASA  ASA: only in those at increased CV risk (10 year risk >10%. (Typically men over 50, women over 60 with other risk factors) 2009:  ASA: over age 40 and for those with other CHD risk factors ADA Diabetes Care, 2013

2

Robert Baron, MD, MS

CURRENT ISSUES IN DIABETES MANAGEMENT

2013 Practice Guidelines: HTN and Lipids and Tobacco

Intensive BP Control in Type 2 DM: ACCORD • RCT of 4733 patients with type 2 DM • Compare BP less than 120 mm Hg vs 140

 BP: Goal less than 130 and less than 80  LDL: Goal less than 70 (with CVD); less than 100 (without CVD)

• • • • •

120 119 1.87% 1.28% 0.32% 3.3%

BP CV events plus death Mortality Stroke Adverse events

140 133 2.09% 1.19% 0.53% 1.3%

p .20 .55 .01 .001

In type 2 DM: treating to 120 mm Hg did not reduce the rate of composite fatal and non-fatal CV events

 Don’t forget tobacco ADA Diabetes Care, 2013

Case 1

ACCORD, NEJM 2010

Case 1 Her glycemic goal should be:

70 yo woman with type 2 diabetes, hypertension, and coronary heart disease (s/p MI in 2003). Meds: Metformin, glipizide, aspirin, lisinopril, metoprolol, and simvastatin Exam: BP 130/80, BMI 29 kg/m2 Normal exam

1. HbA1c <6.0% 2. HbA1c <6.5% 3. HbA1c <7.0% 4. HbA1c <7.5% 5. HbA1c <8.0%

3

Robert Baron, MD, MS

CURRENT ISSUES IN DIABETES MANAGEMENT

ACCORD Trial

Glycemic Control Update

NIH RCT in DM 2, 10,251 patients, known CVD or risk factors, mean A1c 8.1%

 3 newer trials  ADVANCE

Intensive vs. standard BP (120 v. 140) Lipid control (statins v. statins + fibrates Normalization v. standard BS control (A1c 6 v. 7-7.9) Outcomes: CV events. Also microvascular events, quality of life, others

 ACCORD  VA Diabetes Trial

ACCORD, NEJM, 2008

ACCORD Trial

ACCORD trial Intensive n=5,128

Standard n=5,123

A1c achieved:

6.5%

7.5%

-

1° outcome:

352

371

0.90 (0.78-1.04)

Total mortality

5.0%

3.1%

1.22 (1.01-1.46)

CVD mortality

2.6%

1.8%

1.35 (1.04-1.76)

HR (95% CI)

Hypoglycemia

10.5%

3.5%

-

Wt. gain>10 kg

27.8%

14.1%

-

Deaths

Standard

Intensive

203 11/1000/y

257 14/1000/y

Number Needed to Harm: 333 February 2008 (after 3.5 years): NIH stops this arm of study

4

Robert Baron, MD, MS

CURRENT ISSUES IN DIABETES MANAGEMENT

ACCORD Trial 5-Year Outcomes Additional follow-up of 1.5 years All subjects treated to HbA1c of 7-7.9% during this period Results: Mortality still higher in intensive group (7.6% vs 6.4%; HR 1.19) ACCORD, NEJM, 2011

Outcome of Intensive Glucose Lowering in Type 2 DM Over five year period: NNT to prevent one MI

117-150

Outcome of Intensive Glucose Lowering in Type 2 DM Meta-analysis of 13 RCTs in DM 2; 34,533 pts

All cause mortality CV death Non-fatal MI Microalbuminuria Severe hypoglycemia * P <0.001

RR 1.04 (0.91 – 1.19 1.11 (0.86 – 1.43) 0.85 (0.74 – 0.96)* 0.90 (0.85 – 0.96)* 2.33 (21.62 -3.36)* Boussageon, BMJ 2011

ORIGEN Trial RCT, 12,537 subjects; impaired FBS, IGT, or new diabetes, and high CV risk Mean FBS 131 mg/dl

NNT to prevent one microalbuminuria

32- 142

NNT to cause one episode of severe hypoglycemia

15-52 Boussageon, BMJ 2011

Glargine to FBS <95 mg/dl; 6.2 years Results: No difference in CV outcomes ORIGEN, NEJM, 2012

5

Robert Baron, MD, MS

CURRENT ISSUES IN DIABETES MANAGEMENT

Glycemic Control Summary  No consistent evidence that tight glycemic control reduces risk of CVD in DM 2  Possible subgroups with benefit: shorter diabetes duration, no CVD  Strong evidence to support decrease in microvascular disease outcomes with more intensive glucose control  More hypoglycemia and weight gain with more intensive regimens

2013 Practice Guidelines: Glucose Control  Goal A1C ≤7 for most  Goal A1C <6.5 for some: short duration, long life expectancy, and no CVD  Goal less stringent (≤8) for history of hypoglycemia, limited life expectancy, mico or macrovascular complications, comorbid conditions, and those in whom the goal is difficult to attain ADA Diabetes Care, 2013

Critically Ill patients? Meta-analysis of 29 RCTs (n=8,432 patients)

Glycemic Control Summary

Mortality Rates Tight

Usual

RR (95% CI)

Overall

21.6%

23.3%

0.93 (0.85-1.03)

Very tight, ≤110 mg/dl

23.0%

25.2%

0.90 (0.77-10.4)

Moderate, <150 mg/dl

17.3%

18.0%

0.99 (0.83-1.18)

Medical ICU

26.9%

29.7%

0.92 (0.82-1.04)

Surgical ICU

8.8%

10.8%

0.88 (0.63-1.22)

Med-Surg ICU

26.1%

27.0%

0.95 (0.80-1.13)

 No consistent evidence that tight glucose control improves mortality in hospitalized patients.

6

Robert Baron, MD, MS

CURRENT ISSUES IN DIABETES MANAGEMENT

2013 Practice Guidelines: Glucose Control in Hospital  Critically ill: Goal 140 - 180.

Case 1 Her glycemic goal should be: 1. HbA1c <6.0%

 IV protocol

2. HbA1c <6.5%

 Non-critically ill: premeal <140 if can be done safely; random < 180. Less stringent if severe comorbidities  Scheduled subcu insulin with basal, nutritional, and correction components

3. HbA1c <7.0% 4. HbA1c <7.5% 5. HbA1c <8.0%

ADA Diabetes Care, 2013

In my practice, I have initiated: 1. Exenatide (Byetta™) or Liraglutide (Victoza™) 2. Sitagliptin (Januvia™) or Saxagliptin (Onglyza™) 3. Both exenatide and sitagliptin 4. Pramlintide (Symlin™) 5. All three of the above 6. None of the above

7

Robert Baron, MD, MS

CURRENT ISSUES IN DIABETES MANAGEMENT

Case 2: 48 yo woman with DM, BMI 33, on diet and exercise and max dose metformin. HbA1C is now 8.5. Your next best step is:

Generic Oral Hypoglycemic Slide

1. Change from Drug A to B, C, or D

2. Begin a sulfonylurea 3. Begin pioglitizone 4. Begin NPH insulin or long-acting insulin analogue

Add Drug A to B, or B to A HgA1c Add Drug D

5. Begin exenatide (Byetta™), liraglutide (Victoza™), sitagliptin (Januvia™) or saxagliptin (Onglyza™)

Metformin: The Safest Hypoglycaemic Agent in Chronic Kidney Disease? “There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared with other oral hypoglycaemic treatments.” Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes. Cochrane Database Syst Rev 2010;4: CD002967.

Add Drug C

Time

Rosiglitazone vs Pioglitazone Observational study, FDA, 227,571 Medicare patients, over 3 years. Rosi/Pio HR MI Stroke CHF Death Composite

1.06 1.27 1.25 1.14 1.18

Number Needed to Harm with Rosiglitazone = 60 per year Graham et al, JAMA 2010

8

Robert Baron, MD, MS

CURRENT ISSUES IN DIABETES MANAGEMENT

Oral Agent “Failure” Why does this occur?

Relative Contributions of Fasting and Postprandial Plasma Glucose to Total Glycemic Excursions as a Function of A1C

Changing HbA1c goals Compliance, side effects Wrong diagnosis (LADA--latent autoimmune diabetes in adults 10%) Stress, diabetogenic medications Postprandial hyperglycemia Natural progression of the disease

Contribution (%)

80

Postprandial hyperglycemia Fasting hyperglycemia

60

40

20

0

1 (<7.3)

2 3 4 (7.3–8.4) (8.5–9.2) (9.3–10.2)

5 (>10.2)

A1C (%) Quintiles Monnier L et al. Diabetes Care. 2003;26:881-885.

Natural History of Type 2 Diabetes Obesity

Glucose (mg/dL)

IFG*

Diabetes

Natural History of Type 2 Diabetes Biguanide

Uncontrolled hyperglycemia

Lifestyle

350 300 250 200 150 100 50

Post-meal Glucose Fasting Glucose

250 200 Relative 150 Function 100 (%) 50 0

Glucose (mg/dL)

Insulin Resistance Insulin Level` Beta-cell failure

-10 *IFG = impaired fasting glucose

-5

0

5

10

Years of Diabetes

15

20

25

30

Relative Function (%)

350 300 250 200 150 100 50 250 200 150 100 50 0

Insulin

SU Post-meal Glucose

Fasting Glucose

Insulin Resistance Insulin Level

Beta-cell failure

-10

-5

0

5 10 15 Years of Diabetes

20

25

30

9

Robert Baron, MD, MS

CURRENT ISSUES IN DIABETES MANAGEMENT

Insulin Plus Oral Agents Introduction of insulin – Bedtime – Intermediate/Long-acting insulins • NPH, glargine, levemir • 10 units – Self-monitoring of blood glucose (hypoglycemia education)

When to go to > 1 shot per day  HgA1c >7

 Glucose in AM at goal but glucose before dinner >140 Options  Add premeal lispro/aspart  Add bid premixed insulin – 70/30, 75/25 Questions

Insulin plus other oral agent combinations (maintain effect on insulin sensitivity)

Function of Insulin in Regimens Meal coverage (carbohydrates)

 Continue metformin  ? Sulfonylurea, ? Thiazolidinedione (mostly not)

INCRETINS Gut factors that promote insulin secretion in response to nutrients

Basal insulin Major incretins: GLP-1, CCK, GIP Correction of high blood sugar

10

Robert Baron, MD, MS

CURRENT ISSUES IN DIABETES MANAGEMENT

Incretin Drugs

Oral Glucose Promotes More Insulin Release than IV Glucose - Indicating a Role for Incretins

GLP Agonists – Exenatide – Liraglutide – Exenatide Lar – Semaglutide – Aliglutide – Taspoglutide – Lixsenatide

DPP IV Inhibitors – Sitagliptin – Saxagliptin – Vildagliptin – Alogliptin – Linagliptin – Dutogliptin – Metogliptin

A1C (%) Effect (change from baseline)

Placebo BID

5 mcg exenatide BID

10 mcg exenatide BID

MET

0.1

-0.4

-0.8

SFU

0.1

-0.5

-0.9

MET+SFU

0.2

-0.6

-0.8

Changes in A1C from baseline vs placebo statistically significant

11

Robert Baron, MD, MS

CURRENT ISSUES IN DIABETES MANAGEMENT

Side Effects

Weight (change from baseline) & Hypoglycemia Placebo BID

5 mcg exenatide BID

10 mcg exenatide BID

Weight (kg)

-1.4

-3.1

-4.2

Hypoglycemia (%) MET SFU MET + SFU

5.3 3.3 1.26

4.5 14.4 19.2

5.3 35.7 27.8

GI – Nausea (44% vs 18% with placebo); incidence lessens over time; 3% dropout rate due to nausea – Vomiting (13% vs 4%) – Diarrhea (13% vs 6%) Headache (9% vs 6%) Hypoglycemia (see previous slide)

Open-label extension study to 90 weeks: persistence in weight loss and A1C

Improvements in HbA1C With Initial Co-administration of Sitagliptin and Metformin

Sitagliptin – adverse reactions Number of patients (%) Sitagliptin

Mean Baseline HbA1C = 8.8% N=1091 Placebo

HbA1C (%)*

-0.5 -1.0 -1.5 -2.0 -2.5

Sita 100 mg QD Met 500 mg BID

-0.8

Met 1000 mg BID

-1.0

Sita 50 mg BID + Met 500 mg BID Sita 50 mg BID + Met 1000 mg BID

-1.3 -1.6 -2.1

* Placebo-subtracted LS mean change form baseline at Week 24. Sita=sitagliptin; Met=metformin. Aschner P, et al. Oral presentation at the EASD 42nd Annual Meeting; 14-17 September 2006; Copenhagen.

Placebo

Monotherapy

n = 443

n = 363

Nasopharyngitis

23 (5.2)

12 (3.3)

+ pioglitazone

n = 175

n = 178

Upper resp. infection

11 (6.3)

6 (3.4)

Small increase in WBC – neutrophil count higher by 200 on Sitagliptin No nausea or vomiting No weight loss

12

Robert Baron, MD, MS

CURRENT ISSUES IN DIABETES MANAGEMENT

Increased Incidence of Pancreatitis and Cancer Among Patients Given Glucagon Like Peptide-1 Based Therapy  Sitagliptin or exenatide increased the odds ratio for pancreatitis 6-fold ( P <2 x 10 -16).  Pancreatic cancer was more commonly reported among patients that took sitagliptin or exenatide, ( P <0.033, P <2x10 -4)  All other cancers occurred more frequently among patients that took sitagliptin, ( P <1x10 -4)

SGLT2 Inhibitors Sodium-glucose cotransporter 2 Inhibitors

Inhibit glucose reabsorption in renal proximal tubule Potential advantages Weight loss, low risk of hypoglycemia, reduced BP

Potential disadvantages Polyuria, electrolyte disorders, UTI, fungal genital infections, ?

Gastroenterology (2011)

Natural History of Type 2 Diabetes Incretins/Others ? Thiazolidinedione ? - Biguanide Lifestyle

Glucose (mg/dL)

Relative Function (%)

250 200 150 100 50 0

Drug and Dose

Insulin

SU

350 300 250 200 150 100 50

Post-meal Glucose Fasting Glucose

Insulin Resistance

-5

0

5 10 15 Years of Diabetes

Cost/month

Glucose strips (2 per day) Sulfonylurea Generic Brand Rapaglinide 2 mg tid Acarbose 100 mg tid Metformin 1000 bid Generic Brand Rosiglitazone 8 mg qd Pioglitazone 45 mg/d Sitagliptin/Saxagliptin Exenatide 10 mcg/Liraglutide 1.2mg Glargine, 45 U/d

$66

$4-32 $161 $266 $245 $207/190 $271/280 $150

24 hour fitness Center YMCA

$35 $65

$4-14 $50 $193 $88

Insulin Level

Beta-cell failure

-10

Drug Cost Comparison

20

25

30

13

Robert Baron, MD, MS

CURRENT ISSUES IN DIABETES MANAGEMENT

Case 2: 48 yo woman with DM, BMI 33, on diet and exercise and max dose metformin. HbA1C is now 8.5. Your next best step is: 1. 2. Begin a sulfonylurea 3. Begin pioglitizone 4. Begin NPH insulin or long-acting insulin analogue 5. Begin exenatide (Byetta™), liraglutide (Victoza™), sitagliptin (Januvia™) or saxagliptin (Onglyza™)

Conclusions  Tight glycemic control not effective in lowering total mortality or CV mortality.  Many newer diabetes agents available, all with some side effects and higher costs…few with hard outcome data.  Glucose control may be more important early in diabetes  Good BP, lipid control, smoking cessation, and aspirin use is important throughout the diabetes life course

14

Chronic

Congestive^ Heart Failure:  Update on Effective  Monitoring and Treatment

Outline •

Diagnosis and Staging



Diastolic Heart Failure



ACE Inhibitors, ARBs, and Beta Blockers

Michael G. Shlipak, MD, MPH



Other Systolic Heart Failure Medications

Professor of Medicine, UCSF Chief, Division of General Internal Medicine, SFVA Medical Center August 9, 2013



Devices and End‐State Heart Failure

Heart Failure Epidemiology 2013 ACCF/AHA Guideline for the  Management of Heart Failure A Report of the American College of Cardiology  Foundation/American Heart Association Task Force on Practice Guidelines CIRCULATION, 2013



Only cardiovascular outcome that continues to increase



Lifetime risk ~20%



Complicated to manage with multiple other comorbidities



Treatments improve survival and reduce morbidity  substantially.



4 classes of medications improve survival



2 classes of medications improve symptoms

1

Why is Heart Failure Challenging to Manage? •

Patients are very complicated and often frail



CHF travels with many other comorbidities:  −

CAD, hypertension, diabetes, CKD



Polypharmacy



Diastolic heart failure becoming more common

Heart Failure is a Clinical Diagnosis

Question 1: Which of the following  establishes a HF diagnosis? a) b) c) d) e)

EF < 35% on echo BNP > 300 on blood test S3 on exam All of the above None of the above

Diastolic vs. Systolic Heart Failure Diastolic HF: 



Essential Symptoms: dyspnea, fatigue, orthopnea



Signs: rales, edema, JVD, S3





Physical exam: does not distinguish systolic vs.  diastolic 





Helpful features include:







Official term is “Heart Failure with Preserved  Ejection Fraction” Abbreviated as HFpEF Pronounced “huff‐puff”

Systolic HF:  −



Chest X‐Ray: pulmonary congestion



Elevated BNP or Nt‐proBNP





Echo showing diastolic or systolic dysfunction



Official term is “Heart Failure with Reduced  Ejection Fraction” Abbreviated as HFrEF Pronounced “huff‐ruff”

2

NYHA Functional Classes Classes assume a prior diagnosis of heart failure I.

No limitation on ordinary physical activity

II.

Slight limitation – ordinary physical activity

III.

Marked limitation‐ < ordinary physical activity

IV.

Symptoms or discomfort at rest Problems with these classes:  •Patients vary across stages, going up and down •All class 4 at time of hospitalization

Stages, Phenotypes and Treatment of HF

New AHA (2009) Classification of Heart  Failure  A.

Risk factors for heart failure‐ no clear  signs/symptoms

B.

Asymptomatic LV disease‐ LVH, diastolic  dysfunction, valve disease, low EF

Not  HF

C. Symptomatic heart failure‐ dyspnea at rest or  exertion, fluid retention Combines stages 1‐3 D. Advanced heart failure‐ inotrope requirement,  consideration for assist device or transplant •

Can only progress down the classes



Emphasizes prevention over staging

Strategies that apply to all CHF Patients •

Initial ECHO



Repeat only if major changes



Salt restriction



Daily weight monitoring



Exercise 



Diuretics for symptoms



Avoid NSAIDS



Monitor: −

Volume status



Electrolytes, renal function 

3

Outline

Question 2: Which of the following improve  survival in diastolic heart failure?



Diagnosis and Staging



Diastolic Heart Failure

b)



ACE Inhibitors, ARBs, and Beta Blockers

c)



Other Systolic Heart Failure Medications

e)



Devices and End‐Stage Heart Failure

f)

What is Diastolic Heart Failure? •

“Stiff heart syndrome”‐ heart cannot relax in diastole  to allow the left ventricle to fill



Causes increased pressure in the left atrium, and  pulmonary edema



Defined by EF, yet actual stroke volume may be same  as SHF



Same signs and symptoms as systolic HF



Especially common in women and elderly

a)

d)

ACE‐I ARB’s Beta blockers Ca‐channel blockers All of the above None of the above

Diastolic HF: Good and Bad News  Good news: •

More favorable prognosis than SHF



Simpler regime, as diuretics cornerstone of therapy

Bad news: •

Often progresses to SHF



No therapies improve DHF survival

4

ARBs/ACE‐Is Do Not  Improve Survival •

ACC/AHA Guidelines for DHF Treatment

I‐PRESERVE TRIAL

HR: 0.95 (0.86‐1.05) p= 0.35



BP control (SBP < 130)



Rate/rhythm control in AF



Diuretics for pulmonary congestion



Revascularization and other treatment for coronary  ischemia



European guideline recommends cardiac  rehabilitation, though limited evidence −

Guideline for Management of Chronic HF, Ann Intern Med, 2011

Massie B. et al., NEJM 2008

Outline

Question 3 : Which is the most  important treatment for heart failure?



Diagnosis and Staging

a)

ACE inhibitors



Diastolic Heart Failure

b)

Beta‐blockers



ACE Inhibitors, ARBs, and Beta Blockers

c)

They’re equally effective



Other Systolic Heart Failure Medications

d)

Neither 



Devices and End‐Stage Heart Failure

5

ACE Inhibitors • •

Meta‐Analysis of ACE Trials

Improve symptoms and reduce hospitalizations Decrease mortality risk for all heart failure stages



Class effect‐ all ACE inhibitors 



Aim for target dose (ATLAS finding)



30 RCTs‐ ACE‐I vs. placebo



N= 3,870 + 3,2,35



Mortality −



Death or hospitalization for heart failure −



Kidney Function and ACE Inhibitors  in Heart Failure 

0.77 (0.67‐0.88)

0.65 (0.57‐0.74)

Specific ACE‐I’s with benefits in RCT’s: −

Benzapril

‐Enalapril 



Captopril

‐Lisinopril

‐Ramipril

ARBs in Systolic Heart Failure

Clinical trials show benefit if estimated GFR > 30



Generally equivalent to ACE inhibitors



No evidence for lower GFR levels



Use for patients with cough on ACE inhibitors



Expect the creatinine to rise at least 30%



Combination of ACE and ARB?



Even creatinine doubling is OK‐ typically returns near  baseline



Worry about K increase (keep < 5.5); balance the K  with diuretic dose.





Continue ACE‐Is as eGFR declines unless cannot  control K.

Shlipak MG, Ann Intern Med 2003



Decreases hospitalization risk; increases adverse effect  risk (increased K)



No survival difference



Generally, not recommended, as safety probably lower  in actual practice Yusuf S. et al. Lancet 2003

6

Question 4 : Which of the following  beta blockers improves survival? a)

Atenodol

b)

Carvedilolol

c)

Metoprolol

d)

Proprendol

e)

B and C

f)

All of the above (class effect)

Heart Failure Survival

Beta Blockers in Systolic Heart Failure •

Beta blockers improve symptoms and increase ejection  fraction by 5‐10%



Beta blockers decrease mortality in systolic heart  failure, from both pump failure and arrhythmic causes



Unlike ACE inhibitors, not a class effect  



Metoprolol or Carvedilol (U.S.)



Bisoprolol in Europe

Challenge of Titrating Beta Blockers  in Heart Failure Patients •

Both metoprolol and carvedilol require subtle dose  increases at 2 week intervals



Can take up to 6 visits to reach target



Hypo‐tension is not a contra‐indication unless  symptomatic



Carvedilol may be more difficult to titrate dose up.



Benefit greatest at maximum dose



Unfortunately, many patients left at the low starting  dose

Ramani G et al., Mayo Clin Proc 2010

7

Outline

Other Therapies in Systolic Heart  Failure



Diagnosis and Staging



Diuretics



Diastolic Heart Failure



Aldosterone Antagonists‐ spironolactone, eplerenone

ACE Inhibitors, ARBs, and Beta Blockers



Hydralazine/Nitrates



Digoxin

• •

Other Systolic Heart Failure Medications



Devices and End‐Stage Heart Failure

Diuretics

Diuretic Refractory Patients



Rapid relief of dyspnea and fluid retention



Aim for lowest dose that reaches “dry weight”



e.g. 3x/week doses

Therapeutic goals:



watch for hypo‐Na+, hypo‐K+







Improved dyspnea and orthopnea



Minimal pre‐tibial edema

Patients can manage the dose and schedule 



Periodic thiazide (metolazone)



Change the loop diuretic‐ furosemide (Lasix),  bumetanide (Bumex), Torsemide (Demadex)



Long‐acting nitrates also useful for symptoms



Occasional IV diuretics may be required‐ intestinal  edema can block po absorption

8

Aldosterone Antagonists 

Enormous Rise in Spironolactone Use

(spironolactone, eplerenone)

Rales Trial •

Improve survival and  reduce hospitalization‐ RALES trial



Only studied in NYHA  class 3‐4 heart failure  patients on ACE  inhibitors



K allowed up to 5.6;  very few hyper‐K  complications



1/3 on beta blockers

HR = 0.70

Pitt B. et al., NEJM 1999

Epidemic of Hyper‐K Followed

Juurlink DN et al., NEJM 2004

Juurlink DN et al., NEJM 2004

What Happened? •

It’s in the fine print…



RALES methods‐ inclusion if patients Cr < 2.5



2005 and 2013 AHA Guidelines‐ spironolactone recommended in NYHA III heart failure if Cr < 2.5



RALES table 1‐ actual Cr levels 1.2 ± 0.3 −

~80% had Cr ≤ 1.5



~ all had Cr < 2.0



average furosemide dose of 80mg Shlipak MG et al., Ann Intern Med 2003

9

Case Details of Hyper‐K on  Spironolactone •

Case reviews of critical or fatal hyper‐K (≥ 6.5) Schepkers

Guideline Recommendations  on Aldosterone Antagonists



Caution in using spironolactone if eGFR < 45, or Cr ≥1.5

AHA HF guidelines (2005, 2009, 2013) have vascillated on aldosterone antagonists AHA Class I: • Recommended for HF patients EF< 35% • eGFR> 30; K < 5.0 AHA Class III (harmful): • eGFR< 30, K > 5.0



Stop spironolactone in acute illness

My recommendation: Use extreme caution if eGFR 30‐45

et al., Am J Med 2001



Mean Cr of 2.1; all on ACE‐I also



Often in setting of other illness‐ decreased oral intake



Lessons learned:



− −

Hydralazine and Nitrtes A‐HEFT TRIAL (Taylor AL. et al. N Engl J Med, 2004)

QOD dosing: cutting dose by ½  Advise patients to stop using when PO intake is reduced  or acutely ill

Hydralazine/Nitrates •

Recommended (Class I) for “self‐described”  African Americans − − −



Reduced EF Class III/IV symptoms Already treated with ACE, BB

Consider (Class 2A) in patients who cannot  tolerate ACE/ARB

•1,040 African American patients •Hydralazine

vs. Placebo

•Trial halted early •HR= 0.57, p= 0.01 

10

Digoxin in Systolic HF

Digoxin in Systolic HF



Remains widely used in heart failure, especially if  atrial fibrillation present



Often, digoxin‐induced bradycardia hinders use of  beta blockers.



DIG Study – huge trial of digoxin vs. placebo



In these cases, stop digoxin and initiate beta blockers.



When using digoxin, do not increase dose > 0.125mg;  attenuate day dosing in CKD.



AHA Guidelines: “clearly, if digoxin was a new drug,  it would not gain approval in HF”.



clearly no survival benefit; HR=0.99



Decreased risk of first hospitalization (28% lower)



Trial included both SHF and DHF patients



Trial conducted before beta blockers widely used in  heart failure

Outline •

agnosis and Staging



Diastolic Heart Failure



ACE Inhibitors, ARBs, and Beta Blockers



Other Systolic Heart Failure Medications



Devices and End‐Stage Heart Failure

Rationale for Implantable Cardiac  Defibrillators (ICDs) in CHF •

Ventricular arrythmia ‐ common cause of heart failure  death



ICDs can reverse VT/VF and save the patient



VT/VF risk is highest in end‐stage CHF patients; but  those patients unlikely to survive to gain benefit



Challenge for selecting ambulatory patients for ICDs: −

VT/VF risk high enough to benefit 



CHF moderate, so patient might live a few years

11

ICD’s in Secondary Prevention 

ICDs in Primary Prevention



Studied in Systolic HF patients



Risk/benefit tradeoff



Patients who survived prior sudden death or unstable  VT event



Recommended for patients with EF < 35% AND:



ICD’s clearly improve survival



Must be consistent with goals of care for  patient/family – critical role for the PCP •

Rationale for CRT  (Cardiac Resynchronization Therapy) •

Cardiac dys‐synchrony: −

Concern in patients with EF< 35%



RV and LV may not be in harmony



Suspect dyssynchrony in patients with persistent symptoms  despite ideal treatment 



moderate HF symptoms on appropriate treatment 



expectation of survival > 1 year



Not for class 4 HF ‐ prognosis too poor to benefit, unless  as a bridge to transplant

Prior MI patients appear to have higher SCD risk,  among those with Systolic HF

Ideal Candidates for CRT  •

EF < 35% and persistent symptoms



3 additional ECG criteria: −

Sinus rhythm



LBBB



QRS > 150mg



Causes: decrease ventricle filling, decrease EF, increase MR



CRT: activates LV/RV together with bi‐ventricular pacer



Class I: all 3 ECG criteria



Meta‐analysis:



Class 2A: 2 of 3 ECG criteria



Class 2B: 1 of 3 ECG criteria



decrease in mortality by 25%



detectable after 3 months

McAlister FA, JACC 2004

12

End‐Stage Heart Failure  European Definition of Class D/Advanced HF • Severe symptoms at rest or with minimal exertion • Hospitalized in last 6 months • Treatment already optimized • Poor functional status Clinical correlates of Advanced HF Weight loss Worsening kidney function • SBP<90 • Intolerance to ACE and/or BB • Na<133 • Increasing diuretic requirement • Frequent ICD shocks

Additional Support for End‐ Stage Heart Failure Patients

Consider: 

Specialized strategies (HF specialist): • Mechanical circulatory support • Inotrope infusions • Transplant or surgery referral

• •

Hospice/End‐of‐Life Care (Palliative care) • Comfort care •Turn off the ICD

Thank you!  Any Questions?

13

Overview

Applying Best Evidence to Menopause Management

Natural history of menopause Hormone therapy: Risks and Benefits Menopausal symptoms Current role of hormone therapy for menopausal symptoms Non-hormonal treatment of menopausal symptoms

Judith Walsh, MD, MPH Division of General Internal Medicine Women’s Health Center of Excellence UCSF

“Feminine Forever” Dr. Robert Wilson, 1966

MENOPAUSE IS NOT A DISEASE

Replacing estrogen is like diabetics replacing insulin Women “will be much more pleasant to live with and will not become dull and unattractive.” Wyeth-Ayerst funded all expenses

Page 1

Menopause Is A Positive Step

Natural History of Menopause Average age is 51 Predictors of age at menopause

Gallup poll 1997: Most middle aged American women “welcome menopause as a new and fulfilling life stage.” Goal: Support women in achieving a successful transition

– Genetics – Family history – Ethnicity » Earlier in Latino and later in Japanese American compared to Caucasians – Smoking: about two years earlier – Reproductive history » Never having children and shorter cycle length associated with earlier menopause

What do you tell her about when they will go away?

Vasomotor Symptoms Minnie Pause is a 53 year old woman who had her last menstrual period 18 months ago. She is still having hot flashes and awakens at least twice a night with them. She is considering taking estrogen but wants to know how much longer this will last. What do you tell her?

Average duration is about 2 years and so they should be gone in about 6 months. Average duration is about 4 years They will never go away

Page 2

Duration of Vasomotor Symptoms

Background Treatment for menopausal symptoms is based on their transitory nature Many clinical guidelines suggest that symptom duration is approximately 2 years

Politi MC et al. Revisiting the duration of vasomotor symptoms of menopause: a meta-analysis. JGIM 2008:23: 1507-13 Objective: to estimate the natural progression of menopausal symptoms

– Many studies do not follow women more than 2 years

Risks and benefits of hormone therapy depend on duration of use – “Use lowest dose for shortest duration”

Vasomotor symptoms

Results

Rigorous meta-analysis included 10 studies with over 35,000 participants Clear definition of vasomotor symptoms Assessed prevalence of symptoms and “bothersome symptoms”

Percent of women with symptoms increased in the two years before the final menstrual period (FMP) , peaked one year after the FMP and did not return to premenopausal levels until 8 years after the FMP 50% of women had symptoms during the 4 years after FMP 10% of women had symptoms up to 12 years after FMP

Page 3

Results: Bothersome Symptoms

Duration of Hot Flushes Most prior studies examined populations of older women Newer evidence suggests that these durations might be longer when younger women are included Counseling regarding duration of hot flushes may inform clinical decision making

Methods

The News

Penn Ovarian Aging Study - 436 premenopausal women, ages 35-47 years (not using hormonal therapy of any type); followed for 13 years

Duration of menopausal hot flushes and associated risk factors

– Analytic Subsample: 259 women did not report hot flushes at baseline but did experience mod/severe sx during follow-up

– Freeman, EW et al. Obstetrics and Gynecology, May 2011

Measures: validated menopausal symptom list embedded in structured interview, hormones Assessments made at 9-month intervals during study years 0-5, then annually until year 10, every other year until study completion

Aim: To estimate the duration of moderate-to-severe menopausal hot flushes and identify potential risk factors for hot flush duration.

Page 4

Results

Menopausal stages Premenopause: regular menstrual cycles 22-35 days long Late premenopause: change of more than 7 days in cycle length Early transition: changes in cycle length of 7 days or more in either direction for 2 consecutive menstrual cycles OR 60 days amenorrhea Late transition: 90 d to 11 months amenorrhea Postmenopause: 12 months or more amenorrhea Soules, et al. Climacteric 2001

Results – Hazard Ratio for Likelihood of Hot Flashes Ending Variable

HR (95% CI)

Menopausal Premenopausal or Late Premenopausal Early Transition Late Transition or Postmenopausal

Ref. 3.26 (1.78-5.97) 5.14 (2.70-9.77)

Age 39 or younger 40-44 45-49 50 or older

0.33 (0.14-0.78) 0.52 (0.30-0.91) Ref. 1.00 (0.54-1.87)

White Race (Ref: African American)

1.73 (1.11-2.68)

BMI 30 or more (Ref: BMI under 30)

1.94 (1.25-3.02)

Estradiol (mean)

0.82 (0.64-1.05)

Take Home Message In this population-based cohort, median duration of moderate-to-severe hot flushes was…10.2 years! – Adding mild hot flushes…duration was 11.6 years

Younger, thinner, African-American women are likely to have longer hot flush duration Effect of hormone therapy on hot flush duration was not evaluated Clinicians counseling patients about hot flash duration should be mindful that the earlier the hot flashes start, the longer they are likely to last!

Page 5

Hormone therapy is recommended for prevention of which of the following conditions?

Hormone Therapy

Osteoporosis CHD Colorectal Cancer 1 and 3 None of the above

What have we learned from the Women’s Health Initiative? What questions still remain unanswered? What is the current role of HT ?

Women’s Health initiative

WHI OUTCOMES

Aim was to determine the health risks and benefits of estrogen/progestin in healthy women 16,608 women aged 50-79 with a uterus – Randomized to estrogen/progestin or placebo

Primary outcomes – CHD (CHD death or non-fatal MI) – Invasive breast cancer • Writing Group for WHI JAMA 2002

E/P arm stopped at 5.2 years

Page 6

OTHER WHI PUBLICATIONS

HT and the Brain

Effects on the brain Effects on CHD Effects on breast cancer Effects on colorectal cancer Effects on osteoporosis Effects on venous thrombosis Effects on gallbladder disease Effects on incontinence Effects of estrogen alone

WHI Memory Study – Subgroup of WHI – Slight increase in dementia in hormone therapy group » Absolute number of cases was small – Greater decrease in modified mini mental status exam in hormone therapy group • Rapp, JAMA 2003; Shumaker, JAMA 2003

Increase in stroke in HT group – 1.8% vs 1.3% – Hazard ratio 1.31 (1.02, 1.68) • Wassertheil-Stoller, 2003

BREAST CANCER OUTCOMES: WHI

HT AND CHD: WHI

Final results of the effects of estrogen and progestin on CHD outcomes HT users had a hazard ratio for CHD higher than non-users

Since the WHI, use of hormone therapy (HT) in the U.S. has decreased Breast cancer incidence has also decreased in the U.S. What is the long term impact of HT on breast cancer?

– HR 1.24 (95% C.I. 1.00, 1.54)

Risk was highest in the first year – HR 1.81 (95% C.I. 1.09, 3.01) • Manson, NEJM 2003

Page 7

Adherent Participants in WHI: Invasive Breast Cancers by Group

Chlebowski RT et al: JAMA 2003; 289: 3243-3253

Figure 2. Incidence of Invasive Breast Cancer in the WHI Clinical Trial

Chlebowski, R. T. et al. JAMA 2010;304:1684-1692

Copyright restrictions may apply.

Breast Cancer Outcomes: WHI

OSTEOPOSIS RESULTS: WHI

Combined E+P therapy increases the cumulative risk of invasive breast cancer, and diagnosed cancers are more likely to be node-positive This risk becomes evident within about 4.7 years of randomization and is persistent through a total of 11 years of follow-up There were more breast cancer deaths in the combined E+P group

11.1% of placebo treated women compared with 8.6% of estrogen treated women had a fracture – Hazard ratio 0.76 (95% C.I. 0.69, 0.83)

Effects did not differ by age, BMI, smoking status, history of falls, family history of osteoporosis, past use of hormone therapy or BMD No global benefit even in high risk women

• Chlebowski JAMA 2010

» Cauley, JAMA 2003

Page 8

COLORECTAL CANCER: WHI

VTE Outcomes: WHI

Reduced rate of colorectal cancer in hormone therapy users

Risk increased overall in HT users – HR 2.06 (95% C.I. 1.57, 2.70)

– Hazard ratio 0.56; 95% C.I. 0.38, 0.81)

Risk higher in older women

Invasive cancers in the hormone group had a greater number of positive lymph nodes and were more advanced

– HR 4.28 (95% C.I. 2.38, 7.72) for women aged 60-69 – HR 7.46 (95% C.I. 4.32, 14.38) for women aged 70-79

Risk higher in obese women

» Chlebowski NEJM 2004

– HR 3.8 (95% C.I. 2.08, 6.94) for overweight – HR 5.61 (95% C.I. 3.12, 10.11) for obese

Factor V Leiden increased HT associated risk • Cushman, JAMA 2004

Gallbladder Disease: WHI

Urinary Incontinence: WHI

Increased risk of any gallbladder disease or surgery in hormone therapy users

HT has long been thought to relieve the symptoms of urinary incontinence HT increased the incidence of all types of urinary incontinence at 1 year among women who were continent at baseline Among women with UI at baseline, frequency worsened in hormone users Did not assess vaginal estrogens

– HR 1.67 (95% C.I.. 1.35, 2.06) in estrogen users – HR 1.59 (95% C.I. 1.28, 1.97) in estrogen/progestin users

Increased risk of cholecystitis, cholelithiasis, and cholecystectomy in both groups NNH – 323 for CEE – 500 for E plus P

» Hendrix JAMA 2005

• Cirillo JAMA 2005

Page 9

HT and Quality of Life

WHI: Estrogen Alone

In the WHI there were small improvements in quality of life among women who had vasomotor symptoms

10,739 postmenopausal women aged 50-79 with prior hysterectomy Intervention phase ended early after reviewing data through November, 2003 Average follow-up 6.8 years

Hormone therapy is associated with improvement in some quality of life measures in women with vasomotor symptoms and may improve sexual function and vitality • Hess, 2008; Welton, 2008

WHI: Estrogen Alone

WHI: Outcomes after Stopping CEE

Non-significant reduction in breast cancer

Follow-up after treatment with CEE

– RH 0.77 (95% C.I. 0.59, 1.01)

– CEE use median 5.9 years – Mean follow-up 10.7 years

No reduction in colon cancer – RH 1.08 (95% C.I. 0.75, 1.55)

No increase or decrease in CHD, DVT, stroke, hip fracture, CRC or total mortality Decreased risk of breast cancer continued

Non-significant increase in pulmonary embolism – RH 1.34 (95% C.I. 0.87, 2.06)

Lower risk of fractures

» LaCroix, JAMA 2011

– RH 0.70 (95% C.I. 0.63, 0.79)

Increased risk of stroke Global index not consistent with harm – RH 1.01 (95% C.I. 0.91, 1.12)

Page 10

Adherent Participants In WHI: Invasive Breast Cancers In E Alone Study

WHI OUTCOMES (E +P) Recently updated from all WHI studies Treat 10,000 women for a year – – – – – – – – – –

23% reduction in BC over 11 years with 6 years of CEE in women without a uterus.

9 strokes 9 P.E.s 12 DVTs 8 invasive breast cancers 5 more lung cancer deaths 6 fewer hip fractures 46 fewer fractures 22 cases of dementia 20 cases of gall bladder disease 872 cases or urinary incontinence – Nelson et al. Ann Intern Med 2012:157:104-113

LaCroix, JAMA, 2011

WHI Outcomes (E alone)

CLINICAL QUESTIONS

Recently updated from all WHI studies Treat 10,000 women for a year – – – – – – –

What about other estrogen/progestin combinations? What about younger women?

56 fewer fractures 8 fewer invasive breast cancers 2 fewer deaths 11 more strokes 7 more DVTs 33 more cases of gallbaldder disease 1,271 more cases of urinary incontinence

– Does it matter when you start HT?

What about symptomatic treatment?

– Nelson et al. Ann Inern Med 2012: 157:104-113.

Page 11

Transdermal Estrogen

Age at Initiation: Background

Transdermal estrogen avoids hepatic first pass metabolism Transdermal estrogen may be associated with a lower risk of VTE

RCTs and observational studies have found differing results of the effect of HT on CHD Observational studies have generally shown benefit

• Canonico, 2007

– Women in observational studies are generally younger and started HT closer to the time of menopause

Transdermal estrogen associated with a lower risk of stroke

Mean age of women in the WHI was 63

• Renoux BMJ 2010

Hormone Therapy in Younger Women

Hormone Therapy in Younger Women

Secondary analysis of WHI data Combined the women who received E plus P with the women who received E alone Risk for CHD with HT increased with increasing time since menopause – < 10 years: 0.76 (0.50, 1.16) – 10-19 years: 1.10 (0.84, 1.45) – 20 or more years 1.28 (1.03, 1.58) » P for trend=0.02

Hormone therapy increased risk of stroke regardless of age or years since menopause » HR 1.32 (1.12, 1.56)

Non-significant trend for the effects of hormone therapy on total mortality to be more favorable in younger women

• Roussow JAMA 2007

Page 12

Estrogen Alone: Results by Age at Enrollment

Take home message Statistically significant age interactions for CEE group – greater safety and benefit for women in 50s – potential harm among older women

Timing of HT initiation relative to age or menopause onset may influence CHD risk – Less underlying atherosclerosis in younger women?

Clinicians should counsel women differently based on age and hysterectomy status – Unlikely to change current recommendations for HT use

Statistically significant age interactions (greater safety and benefit for younger women, potential harm among older women) were shown for: CHD, total MI, colorectal CA, total mortality and the global index. La Croix et al. JAMA 2011

Danish Osteoporosis Study: CV Outcomes

Results

1006 healthy recently menopausal women aged 45-58 Open-label randomization to triphasic estradiol/norethisterone or placebo (hysterectomy: treatment with estradiol alone) for 10 years Outcomes:

WHI: mean age 63 WHI: 13% with increased lipids WHI: 36% with HTN

• Composite outcome of death or admission for myocardial infarction or heart failure • Individual components of primary endpoint, admission for stroke

WHI: 4% with DM

Schierbeck et al. BMJ 2012; 345:e6409.

Page 13

Primary endpoint and mortality for hormone replacement therapy

Take Home Messages The findings from this study substantiate the “timing theory” but… – Different type and dose of estrogen used – Underpowered to determine effect of Estrogen monotherapy – Unclear if primary composite outcome was prespecified

Minimal risk associated with therapy but… – Likely underpowered to detect differences in DVT/PE, CVA, and possibly breast CA

Overall: reassured about using HT in symptomatic healthy menopausal women, but would not prescribe for primary prevention

Schierbeck L L et al. BMJ 2012;345:bmj.e6409

Menopausal Symptoms: Prevalence

Hot flushes (50% or more) » Often with perspiration

Menopausal Symptoms

Night sweats (50% or more) Sleep disturbance (40-60%)

Page 14

OTHER SYMPTOMS Other symptoms happen at the time of menopause but are less clearly related to menopause – – – –

Treatment of Menopausal Symptoms

Mood changes Cognition Changes in sexual function Urinary complaints

What do you most commonly recommend for the treatment of severe vasomotor symptoms?

HT for Symptomatic Relief Any form of estrogen is highly effective Generally can be taken for a few years and gradually stopped A progestin should be added for women with a uterus Therapy can be tailored to a woman’s preference Decision should be made SEPARATELY from decision for disease prevention

Estrogen SSRI Venlafaxine Clonidine Gabapentin Lifestyle changes and/or complementary therapy

Page 15

Effective Dose Equivalents

Lower dose hormone therapy Lower doses have been effective in some trials Estimates of efficacy after 12 weeks

Dose that stops hot flashes in 80% of women – – – –

1 mg micronized 17 beta estradiol 50mcg/day transdermal 17 beta-estradiol 0.625 mg conjugated equine estrogens 1.25 mg piperazine estrone sulfate

– 38% placebo – 63% low dose estrogen – 83% standard dose estrogen

Lower doses may take longer for maximal symptom relief – 12 weeks vs 4-8 weeks

Less bleeding and breast tenderness and may require less progestin » Ettinger, Am J Med 2005

QUESTION

QUESTION

Estee Jenn is a 60 year old woman who has been on HT for 10 years. You have been trying to encourage her to stop it for a while but she has not wanted to do it. Her best friend has recently developed breast cancer; she has now decided to stop, and wants your advice on the best way to do it. What do you recommend?

Taper by decreasing the daily dose over 6-12 months Taper by decreasing the number of days a week HT is used over 6-12 months Just stop

Page 16

Discontinuing hormone therapy

Progestins

Symptoms will recur in up to 25% of women with stopping therapy Unclear if it is best to stop “cold turkey” or to taper Taper can be by daily dose or number of days per week Taper until mild symptoms

Concern about VTE and breast cancer risk High doses Oral megestrol (20-80 mg) has shown efficacy – Some weight gain • Goodwin J Clin Oncology 2008

High dose depo-MPA (400 mg) is also effective – Compared with venlafaxine

– Maintain that dose until symptoms resolve

• Loprinzi J Clin Oncol 2006

QUESTION

OTHER DRUG TREATMENTS

Estee has a resumption of her hot flashes after she stops her estrogen. What pharmacologic alternative do you suggest?

SSRIs Venlafaxine Desvenlafaxine Clonidine 50-67% reduction in hot flash frequency with these regimens Placebo effects generally large

– – – – –

Paroxitene Escitalopram Venlafaxine Clonidine Gabapentin

– Generally less than estrogen

Page 17

Paroxitene

Escitalopram

Paroxitene CR led to a significant decrease in hot flash score

Recent study of the efficacy of escitalopram Reduction in hot flash frequency

– 62% in 12.5 mg group – 65% in 25 mg group – 38% in placebo group

– 55% in escitalopram group – 36% in placebo group

Effective in African American and Caucasian women Effective regardless of coexisting anxiety or depression

Avoid in women receiving tamoxifen – Decreases active metabolite of tamoxifen – Cytochrome P450 CYP2D6

» Freeman, JAMA 2011

Venlafaxine

Desvenlafaxine

Significant reduction in hot flashes

Industry sponsored trial of metabolite of venlafaxine 700 women with severe hot flashes 64% reduction in hot flashes at 12 weeks

– 61% vs 27% in placebo (p<0.01)

150 mg no more effective than 75 mg • Lopinzi, Lancet 2000

– Vs 51% with placebo

Hot flashes less severe in desvenlafaxine group Not currently FDA approved for this indication • Speroff, 2008

Page 18

Alternatives for treatment of hot flushes

Clonidine and Gabapentin

Treatment

Clonidine – Start with 0.1 mg/day transdermal patch – 40% reduction in hot flashes – Side effects can be limiting

Gabapentin – 45% reduction in hot flashes vs placebo (29%) – 900 mg a day more effective than placebo – 300-600 mg at bedtime may help with hot flashes that awaken patients from sleep

Dosage (mg/day)

Efficacy (vs placebo)

Estrogen

0.625 CEE

80% vs 20-30%

Paroxitene

12.5 or 25

62% vs 38%

Escitalopram

10 to 20

55% vs 36%

Venlafaxine

37.5

37% vs 27%

Venlafaxine

75 or 150

61% vs 27%

Desvenlafaxine

100

64% vs 51%

Clonidine

0.1

38% vs 20%

Question

Background

Estee is tired of medications and would like to try an herbal therapy for treatment of her hot flashes. What treatment do you recommend? Evening primrose Ginseng Dietary soy Wild yam None of the above

Soy products have been proposed to provide comparable benefits to estrogen for treating menopausal symptoms, without the risks Epidemiologic studies on Asian women suggest that soy-containing foods are of benefit to the skeleton – Limited by short duration, low dose of soy isoflavones, few participants

Rapid bone loss occurs during the first 2 years of menopause

Page 19

SPARE Study: Soy isoflavones

Results No significant differences between soy and placebo group:

SPARE study (Soy Phytoestrogens As Replacement Estrogen) – parallel group, placebo controlled, double blind trial 248 women (early menopause) were randomly assigned to receive 200mg soy isoflavones or placebo Measures: – – – – –

– – – –

Spinal BMD Total hip BMD Femoral neck BMD NTx (N-telopeptide type I bone collagen)

Subgroup analyses by: race, BMI, estradiol, 25-OH Vit D – Women with low 25-OH vit D at baseline – soy group had lower decrease in spinal BMD than placebo

BMD change Menopausal symptoms Vaginal Maturation Lipids and thyrotropin Assessed at baseline, 12 mo, & 24 mo

Rate of hot flashes actually increased in soy isoflavone group – (48% vs 32%: p=0.02)

Lifestyle and Complementary Modalities

Summary Of Herbal Evidence Evidence: no benefit – Red Clover

– – – – – –

Dong quai Ginseng Evening primrose Wild yam Vitamin E Acupuncture

Evidence mixed – Soy – Black cohosh No data – Chasteberry – Licorice

Cooling body temperature Exercise Avoiding hot and spicy foods Relaxing therapies – Yoga, massage, mediation, slow breathing, baths

Mind-body therapies – Relaxation, biofeedback, paced respiration, hypnosis • NAMS

Some evidence that weight loss is beneficial

Page 20

Hot Flash: Self Help - Be Cool!

Relaxation

Keep house cool

Relaxation therapy

Avoid caffeine, alcohol, spicy foods, hot drinks

– 73% reduction HF

Dress in layers, cotton

Diaphragmatic breathing – Simple deep breathing when sense HF – > 50% reduction HF

Light bed linens Use fan, cool drinks Exercise

Wijma, 1997 Freedman 1995

Recommendations USPSTF: Harmful effects are likely to exceed the chronic disease prevention benefits in most women

Guidelines for Hormone Therapy Use

ACOG, AHA, and Canadian Task Force recommend against use of HT for prevention of chronic disease NAMS 2012: When alternative therapies not appropriate, extended use of HT appropriate for women at high risk of fracture

Page 21

NAMS 2012 Recommendations

Summary

Focuses on emerging differences between ET and EPT as varying ages and time intervals since menopause

Average duration of menopausal symptoms is approximately 4 years but seems to be longer in younger women Estrogen either alone or with a progestin is not recommended for chronic disease prevention in postmenopausal women Risks and benefits may differ in older and younger women

Individualization in decision to use HT :consider individual health, personal risk factors and quality of life priorities ET has a more favorable risk benefit profile which allows for more flexibility in duration of use EPT associated with an increased risk of breast cancer incidence and mortality after 3-5 years Premature menopause: HT until median age of natural menopause and then reassess – Menopause 2012:257-71

Summary Estrogen works best for menopausal symptoms – Use lowest dose for shortest duration

Best method for discontinuation is not known Start with lifestyle modifications and nonprescription remedies Other drug alternatives include venlafaxine, desvenlafaxine, paroxitene, escitalopram, gabapentin, and clonidine

Questions?

Page 22

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Essentials of Primary Care - Continuing Medical Education

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