Essentials of Primary Care - Continuing Medical Education

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


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


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


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


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




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


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

11:10 am


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

Continental Breakfast


G Every Patient is an Athlete Carlin Senter, MD


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


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


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


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


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




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


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


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


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


G Management of Atrial Fibrillation 2013 Katherine A. Julian MD


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




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


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




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: 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,, 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: . 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:

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 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




High certainty of substantial net benefit



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



Moderate certainty that net benefit is small

Selectively offer/provide


No net benefit or harms outweigh benefits

Do not provide


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


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


• 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


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

Page 6

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*


• 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)

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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


• 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 (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

Page 13

USPSTF Annals IM 2008


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


• 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


– 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


• 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%

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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









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?


• 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?


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)


• 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 140/90) • Risk for poor control: Latinos, Blacks, age 1844 and ≥80, 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


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



0.64 (0.46 -0.95)

• NNT = 20 to prevent one stroke

CVA Death 6.5


0.55 (0.33 -0.93)

• NNT = 10 to prevent one CHF




0.28 (0.17 -0.48)

CV Death



0.73 (0.55 -0.97)

Any Death 47.2


0.72 (0.59-0.88)


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 90 • Drug treatment for all with DBP > 100 • If lifestyle fails, drugs for DBP > 90 • If lifestyle fails, drugs for SBP >140 • • • •


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


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


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 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 



Summary of  antihypertensive  drug treatment Step 1


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


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



CCB Beta Blockers

11.0/8.1 11.2/8.5


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


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



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%)


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


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



Vaccines for Special Populations  Plague

Key Website Centers for Disease Control and Prevention

 Tularemia  Smallpox

 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



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 10 years

Ward JL et al.  NEJM, 2005;353(13)



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 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.



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).



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)



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)



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)



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 


 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



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 (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



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)



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 


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


 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)



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



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 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 



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



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.





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) 90%

 

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


Nonanginal Chest Pain

Atypical angina

Typical angina



































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




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 


Exercise echo:  LR+ = 3.7 

b) c)

LR- = 0.19


(Fleischmann KE. et al. JAMA 1998) 


LR- = 0.42

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

AHA recommendation is to limit testing to intermediate risk patients 



ACE inhibitors (ARBs) Aspirin Beta blockers Statins

Exercise imaging:  

LR+ = 2.4 LR- = 0.20

(Fleischmann KE. et al. JAMA 1998)







+ (0.77)









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) 


LDL target 1 year without symptoms of muscle toxicity Beware of drug interactions


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


Difference in myopathy risk: 


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




% Lowered LDL-C

10 mg


20 mg


40 mg


80 mg


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  AIM-HIGH Investigators, NEJM 2011





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

AIM-HIGH Investigators, NEJM 2011



Do fibrates improve clinical outcomes?

27% lower risk of CVD events

Bruckert et al. Atherosclerosis 2010



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


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)


95% CI

P Value

Non-fatal coronary events



3 month duration of either:

Kidney failure (end-stage renal disease) Death

Other chronic disease:

 

Decreased kidney function (eGFR105 90-104 eGFR 75-89 (mL/min/ 60-74 1.73m2) 45-59 30-44 15-29 All *P 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.



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)


 

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- 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



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


 

ACR (mg/g)



< 30


Normal or mildly elevated



Moderately elevated



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


New CKD Staging 2013


Screening for CKD


Treatment of CKD

Introduction to Cystatin C

When to refer to nephrologist


ACE/ARB treatments Blood pressure control Glucose control Statins



ACE/ARB’s in Diabetic CKD

CKD Treatment 

Goals:  


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



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 150 (Peralta CA, Arch Intern Med, 2012) Guidelines on blood pressure control in CKD:  

JNC-7 target < 130 New KDIGO-CKD HTN guideline: suggests 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)



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)



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


  

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



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.


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


Advise and Assist  State your conclusion and recommendation clearly

“You are drinking more than is medically safe.”

image credit: Comstock







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





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






Example 2 -For patients who meet the criteria for


Advise and Assist Is the patient ready to commit to change at this time?


 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



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



Stages of Change from Transtheoretical Model


Mentality of the Stages

Lapse Precontemplation Contemplation



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



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 



“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?”


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”



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)



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



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



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





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)



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)



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



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



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



Thank You! 

Resources 

Local mutual help groups   (resources)

Substance Abuse Facility Treatment Locator Website


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


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 – (T65 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


• 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


• 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%


Take Home Message

• Osteoporosis would develop in 50 y/o as labrum degenerates naturally)



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 /hip‐pain/hip‐anatomy.aspx

Hip palpation • Abdomen • Pelvis – Iliac crest – ASIS – Inguinal canal • Lymph nodes

– Pubic tubercles _pelvis_disorders/hip_fracture_leg_external_rotation.htm

• Hip – Greater trochanter

• Back: SI joints, LS‐ 1098987346941.html



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°

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. atlas_of_human_anatomy/a/atlasbook/8



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 (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




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



Overall Number



Eligible for  analysis at first  screen



Eligible for  analysis at  second screen (5 years later) 



Attended second  screen



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) 



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




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.



PLCO Results Group








OC 212 (5.7) diagnosis

176 (4.7)



100 (2.6)


118 (3.1)



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



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?



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  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? 


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


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).



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 ( 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 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













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).



New Oral Anticoagulants

New Oral Anticoagulants XII

Oral Xa Inhibitors Rivaroxaban Apixaban





Approval Status



Fibrin Clot

Dabigatran (Pradaxa)

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

T ½ Hours








Substrate of p- Yes glycoprotein Antidote None






Anti Xa

Anti Xa

DVT Prevention DVT and PE treatment





Renal Metabolism




New Oral Anticoagulants


Nonvalvular • Nonvalvular Nonvalvular Afib Afib Afib

Oral IIa Inhibitor Dabigatran



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.



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%


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 CrCl50 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).



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



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)



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)


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



Screening for Diabetes 2013  BMI ≥25 plus other risk factors

Robert B. Baron MD MS Professor and Associate Dean UCSF School of Medicine


Low HDL or high TG

First degree relative


High-risk ethnicity

Acanthosis nigricans

Gestational DM



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


Robert Baron, MD, MS


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 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


Robert Baron, MD, MS


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


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

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