Presented by the Division of General Internal Medicine, Department of Medicine, and the Department of Obstetrics, Gynecology & Reproductive Sciences University of California San Francisco
Hawaii’s Big Island Essentials of Women’s Health: An Integrated Approach to Primary Care and Office Gynecology
PROGRAM CHAIRS Robert B. Baron, MD, MS Associate Dean for Graduate and Continuing Medical Education
Rebecca Jackson, MD Chief, Obstetrics, Gynecology & Reproductive Sciences, San Francisco General Hospital
July 6-11, 2014 Hapuna Beach Prince Hotel Mauna Kea, Big Island, Hawaii ESSENTIALS OF WOMEN’S HEALTH: An Integrated Approach to Primary Care and Office Gynecology July 6– July 11, 2014 Big Island, Hawaii
SUNDAY, JULY 6, 2014 4:00 pm Course Registration and Check‐in 5:00 Welcome Robert B. Baron, MD, MS & Rebecca Jackson, MD 5:10 The “Choosing Wisely” Campaign: Women’s Health Recommendations (G) Michael S. Policar, MD, MPH 6:00 Cancer Screening 2014: Using Best Evidence to Guide Practice (G) Rebecca Jackson, MD 7:10 Adjourn
MONDAY, JULY 7, 2014 Moderator: Robert B. Baron, MD, MS 6:30 am Continental Breakfast 7:00 Management of Lipid Disorders: Implications of the New Guidelines (G) Robert B. Baron, MD, MS 7:50 Current and Emerging Strategies for Osteoporosis (G) Douglas Bauer, MD 8:40 Break 9:00 Contraception in Medically Complicated Women Jody Steinauer, MD, MAS 9:50 New Developments in Management of Sexually Transmitted Infections (G) Michael S. Policar, MD, MPH 10:40 Adjourn
TUESDAY, JULY 8, 2014 Moderator: Rebecca Jackson, MD 6:30 am Continental Breakfast 7:00 Understanding Amenorrhea and PCOS Rebecca Jackson, MD 7:50 Updated Guidelines for Managing Menopausal Symptoms Michael S. Policar, MD, MPH 8:40 Management of Diabetes Mellitus: A Primary Care Perspective (G) Robert B. Baron, MD, MS 9:30 Break 9:50 Concurrent Workshops (select one): A: Mastering Office Procedures in Women’s Health Rebecca Jackson, MD B: Critically Reading the Medical Literature: Tricks of the Trade Douglas Bauer, MD 11:20 Adjourn
G = Geriatric Credit
WEDNESDAY, JULY 9, 2014 Moderator: Douglas Bauer, MD 6:30 am Continental Breakfast 7:00 Diagnosis and Treatment of Common Thyroid Disorders (G) Douglas Bauer, MD 7:50 Modern Management of Hypertension (G) Robert B. Baron, MD, MS 8:40 Vaccinations for Adult and Adolescent Women (G) Katherine A. Julian, MD 9:30 Break 9:50 Concurrent Workshops (select one): C: Caring for Challenging Patients in Women’s Health: Insights into Empathy and Professionalism (G) Jody Steinauer, MD, MAS D: Hot Topics in Clinical Nutrition (D) Robert B. Baron, MD, MS 11:20 Adjourn
THURSDAY, JULY 10, 2014 Moderator: Katherine A. Julian MD 6:30 am Continental Breakfast 7:00 Atrial Fibrillation: New Guidelines and New Treatments for Women (G) Katherine A. Julian MD 7:50 Best Practices in Preconception Counseling Jody Steinauer, MD, MAS 8:40 Acute Pelvic Pain: Managing Torsion, Ruptured Cysts, and Pelvic Inflammatory Disease Rebecca Jackson, MD 9:30 Break 9:50 Concurrent Workshops (select one): E: Vulvovaginal Disorders: Photoquiz (G) Michael S. Policar, MD, MPH F: Evaluation and Treatment of Common Musculoskeletal Complaints (G) Katherine A. Julian MD 11:20 am Adjourn
FRIDAY, JULY 11, 2014 Moderator: Jody Steinauer, MD, MAS 6:30 am Continental Breakfast 7:00 Modern Management of Sleep Disorders (G) Douglas Bauer, MD 7:50 Updates in Diagnosis and Treatment of Dementia (G) Katherine A. Julian, MD CLOSING ADDRESS: 8:40 Early Pregnancy Loss and Abortion: Patient‐centered Counseling and Evidence‐ based Care Jody Steinauer, MD, MAS 9:30 Course Adjourns
G = Geriatric Credit
The Department of Medicine Division of General Internal Medicine, and The Department of Obstetrics, Gynecology & Reproductive Sciences present
Essentials of Women’s Health An Integrated Approach to Primary Care and Office Gynecology
July 6-11, 2014
Hapuna Beach Prince Hotel Big Island, Hawaii
Course Chairs Robert B. Baron, MD, MS Rebecca Jackson, MD
University of California, San Francisco School of Medicine
Exhibitors
Bayer
Hologic
University of California, San Francisco School of Medicine Presents
Essentials of Women’s Health: An Integrated Approach to Primary Care and Office Gynecology
OVERVIEW This program, designed for family physicians, internists, gynecologists, nurses, nurse practitioners, physician assistants, pharmacists, and all others involved in providing quality health care for women, will provide a practical update on a full range of common but controversial issues in women’s health. The course will serve to enhance the skills of those already working in women’s health as well as help develop new skills for those expanding their work to include more primary care and office gynecology. Developed and taught by UCSF faculty in both primary care internal medicine and obstetrics and gynecology, the course will present an integrated approach to women’s health. Emphasis will be placed on new developments in preventive care and cardiovascular risk factors in women, issues in reproductive health, and clinical strategies in the diagnosis and treatment of common gynecologic complaints and common medical problems of women. Special emphasis will be placed on office skills needed for modern day practice including: enhanced skills in physical examination, common office procedures, clinical nutrition, assessment of new medical technologies, and how to better read the medical literature. The course will use interactive lectures, clinical vignettes, hands-on workshops, small group discussions, questions and answers, and an online syllabus.
EDUCATIONAL OBJECTIVES The purpose of this course is to increase competence and improve clinician practice in women’s health. We specifically anticipate improvements in skills and strategies to: Implement new guidelines in office-based preventive medicine for prevention and early detection of cancer with clinical exam, pap tests, genetic testing and diagnostic imaging; Implement new guidelines for prevention and treatment of cardiovascular risk factors in women; Provide vaccinations to adults and adolescents; Diagnose and treat common problems in women's health including abnormal uterine bleeding, acute pelvic pain, sexually transmitted infections, amenorrhea, PCOS, vulvovaginal disorders, thyroid disorders, atrial fibrillation, hypertension, high blood cholesterol, diabetes, osteoporosis, sleep disorders and dementia; Facilitate counseling and informed decision-making in contraception and abortion; Examine patients and perform common office procedures in gynecology; Evaluate and treat common musculoskeletal complaints; Counsel patients about diet and nutritional supplements; Critically read the medical literature in women’s health; Provide empathic and professional communication with all patients; Increase quality and decrease costs in medical practice.
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.
UCSF designates this educational activity for a maximum of 19.75 AMA PRA Category 1 Credits™.
Physicians should claim only the credit commensurate with the extent of their participation in the activity.
This CME activity meets the requirements under California Assembly Bill 1195, continuing education and cultural and linguistic competency.
Geriatric Medicine: The approved credits shown above include 13.0 credits toward meeting the requirement under California Assembly Bill 1820, Geriatric Medicine.
Nurses: For the purpose of recertification, the American Nurses Credentialing Center accepts AMA PRA Category 1 Credits™ issued by organizations accredited by the ACCME.
Physician Assistants: AAPA accepts category 1 credit from AOACCME, Prescribed credit from AAFP, and AMA PRA category 1 credits™ from organizations accredited by the ACCME.
Pharmacy: The California Board of Pharmacy accepts as continuing professional education those courses that meet the standard of relevance to pharmacy practice and have been approved for AMA PRA Category 1 Credits™.
Family Physicians: This activity, Controversies in Women's Health, with a beginning date of December 6, 2012, has been reviewed and is acceptable for up to 19.50 Prescribed credits by the American Academy of Family Physicians. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Obstetricians and Gynecologists: The American College of Obstetricians and Gynecologists has assigned 20 cognate credits to this program.
General Information
Attendance Verification / CME Certificates Please remember to sign-in on the sign-in sheet when you check in at the UCSF Registration Desk on your first day. You only need to sign-in once for the course, when you first check in.
After the meeting, please visit this website to complete the online course evaluation: http://www.ucsfcme.com/evaluation
Upon completing the online evaluation, your CME certificate will be automatically generated and emailed to you.
Evaluation Your opinion is important to us – we do listen! We have two evaluations for this meeting. The speaker evaluation is the light blue hand-out you received when you checked in. Please complete this during the meeting and turn it in to the registration staff at the end of the conference.
The overall conference evaluation is online at: http://www.ucsfcme.com/evaluation
We request you complete this evaluation within 30 days of the conference in order to receive your CME certificate through this format.
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 lunch or breaks or overnight.
Exhibits Industry exhibits will be available outside the ballroom during breakfasts and breaks.
Phone Messages Any messages during the conference can be left by calling (808) 880‐1111 and asking for the UCSF “Women’s Health” course. Messages will be posted on the board near the registration desk.
Presentations Color PDFs of the final lectures will be available on our website, www.cme.ucsf.edu, approximately 2-4 weeks post event. We will only post presentations for those authorized by the presenters.
Federal and State Law Regarding Linguistic Access and Services for Limited English Proficient Persons
I. Purpose. This document is intended to satisfy the requirements set forth in California Business and Professions code 2190.1. California law requires physicians to obtain training in cultural and linguistic competency as part of their continuing medical education programs. This document and the attachments are intended to provide physicians with an overview of federal and state laws regarding linguistic access and services for limited English proficient (“LEP”) persons. Other federal and state laws not reviewed below also may govern the manner in which physicians and healthcare providers render services for disabled, hearing impaired or other protected categories
II. Federal Law – Federal Civil Rights Act of 1964, Executive Order 13166, August 11, 2000, and Department of Health and Human Services (“HHS”) Regulations and LEP Guidance. The Federal Civil Rights Act of 1964, as amended, and HHS regulations require recipients of federal financial assistance (“Recipients”) to take reasonable steps to ensure that LEP persons have meaningful access to federally funded programs and services. Failure to provide LEP individuals with access to federally funded programs and services may constitute national origin discrimination, which may be remedied by federal agency enforcement action. Recipients may include physicians, hospitals, universities and academic medical centers who receive grants, training, equipment, surplus property and other assistance from the federal government.
HHS recently issued revised guidance documents for Recipients to ensure that they understand their obligations to provide language assistance services to LEP persons. A copy of HHS’s summary document entitled “Guidance for Federal Financial Assistance Recipients Regarding Title VI and the Prohibition Against National Origin Discrimination Affecting Limited English Proficient Persons – Summary” is available at HHS’s website at: http://www.hhs.gov/ocr/lep/ .
As noted above, Recipients generally must provide meaningful access to their programs and services for LEP persons. The rule, however, is a flexible one and HHS recognizes that “reasonable steps” may differ depending on the Recipient’s size and scope of services. HHS advised that Recipients, in designing an LEP program, should conduct an individualized assessment balancing four factors, including: (i) the number or proportion of LEP persons eligible to be served or likely to be encountered by the Recipient; (ii) the frequency with which LEP individuals come into contact with the Recipient’s program; (iii) the nature and importance of the program, activity or service provided by the Recipient to its beneficiaries; and (iv) the resources available to the Recipient and the costs of interpreting and translation services.
Based on the Recipient’s analysis, the Recipient should then design an LEP plan based on five recommended steps, including: (i) identifying LEP individuals who may need assistance; (ii) identifying language assistance measures; (iii) training staff; (iv) providing notice to LEP persons; and (v) monitoring and updating the LEP plan.
A Recipient’s LEP plan likely will include translating vital documents and providing either on-site interpreters or telephone interpreter services, or using shared interpreting services with other Recipients. Recipients may take other reasonable steps depending on the emergent or non-emergent needs of the LEP individual, such as hiring bilingual staff who are competent in the skills required for medical translation, hiring staff interpreters, or contracting with outside public or private agencies that provide interpreter services.
HHS’s guidance provides detailed examples of the mix of services that a Recipient should consider and implement. HHS’s guidance also establishes a “safe harbor” that Recipients may elect to follow when determining whether vital documents must be translated into other languages. Compliance with the safe harbor will be strong evidence that the Recipient has satisfied its written translation obligations.
In addition to reviewing HHS guidance documents, Recipients may contact HHS’s Office for Civil Rights for technical assistance in establishing a reasonable LEP plan.
III. California Law – Dymally-Alatorre Bilingual Services Act. The California legislature enacted the California’s Dymally-Alatorre Bilingual Services Act (Govt. Code 7290 et seq.) in order to ensure that California residents would appropriately receive services from public agencies regardless of the person’s English language skills. California Government Code section 7291 recites this legislative intent as follows:
“The Legislature hereby finds and declares that the effective maintenance and development of a free and democratic society depends on the right and ability of its citizens and residents to communicate with their government and the right and ability of the government to communicate with them.
The Legislature further finds and declares that substantial numbers of persons who live, work and pay taxes in this state are unable, either because they do not speak or write English at all, or because their primary language is other than English, effectively to communicate with their government. The Legislature further finds and declares that state and local agency employees frequently are unable to communicate with persons requiring their services because of this language barrier. As a consequence, substantial numbers of persons presently are being denied rights and benefits to which they would otherwise be entitled.
It is the intention of the Legislature in enacting this chapter to provide for effective communication between all levels of government in this state and the people of this state who are precluded from utilizing public services because of language barriers.”
The Act generally requires state and local public agencies to provide interpreter and written document translation services in a manner that will ensure that LEP individuals have access to important government services. Agencies may employ bilingual staff, and translate documents into additional languages representing the clientele served by the agency. Public agencies also must conduct a needs assessment survey every two years documenting the items listed in Government Code section 7299.4, and develop an implementation plan every year that documents compliance with the Act. You may access a copy of this law at the following url: http://www.spb.ca.gov/bilingual/dymallyact.htm
Course Chairs
Robert B. Baron, MD, MS Professor of Medicine; Associate Dean for Graduate and Continuing Medical Education; Vice Chief, Division of General Internal Medicine University of California, San Francisco
Rebecca Jackson, MD Professor of Obstetrics, Gynecology & Reproductive Sciences, and of Epidemiology & Biostatistics, University of California, San Francisco; Chief, Obstetrics, Gynecology & Reproductive Sciences, San Francisco General Hospital
Course Faculty (University of California, San Francisco)
Douglas Bauer, MD Professor of Medicine and Epidemiology and Biostatistics
Katherine A. Julian, MD Professor of Medicine; Program Director, UCSF Primary Care General Internal Medicine Residency Program
Michael S. Policar, MD, MPH Professor; Medical Director, UCSF/ Family PACT Program Support and Evaluation, California Office of Family Planning, Sacramento, CA
Jody Steinauer, MD, MAS Associate Professor of Obstetrics, Gynecology, and Reproductive Sciences
Disclosures
The following faculty speakers, moderators and planning committee members have disclosed 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 Douglas Bauer, MD Rebecca Jackson, MD Katherine A. Julian, MD Michael S. Policar, MD, MPH Jody Steinauer, MD, MAS
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 UPCOMING UCSF PRIMARY CARE CME COURSES FALL IN SAN FRANCISCO Primary Care Medicine: Principles & Practice Hotel Nikko, San Francisco October 22-24, 2014 DECEMBER IN SAN FRANCISCO Controversies in Women’s Health Hotel Nikko, San Francisco December 11-12, 2014 APRIL IN HAWAII Primary Care Medicine: Update 2014 Wailea Marriott, Maui, Hawaii April 5-10, 2015 JULY IN HAWAII Essentials of Women’s Health: An Integrated Approach to Primary Care and Office Gynecology Hapuna Beach Prince Hotel, Hawaii’s Big Island July 5-10, 2015 AUGUST AT LAKE TAHOE Essentials of Primary Care: A Core Curriculum for Adult Ambulatory Practice Resort at Squaw Creek, North Lake Tahoe August 2-7, 2015
University of California San Francisco Essentials of Women’s Health Hapuna Beach Prince Hotel, Hawaii July 6, 2014 The “Choosing Wisely” Campaign: Women’s Health Recommendations
Michael S. Policar, MD, MPH Clinical Professor of Ob,Gyn, & RS UCSF School of Medicine [email protected]
• There are no relevant financial relationships with any commercial interests to disclose choosingwisely.org
The Choosing Wisely Campaign
• 53 leading specialty societies have created lists of “Things Physicians and Patients Should Question” • Encourages clinicians, patients and others to think and talk about medical tests and procedures that may be unnecessary, and may cause harm • Consumer Reports has developed, and is disseminating, materials for patients • The driver is to improve care, not only to save money – Payers are not involved, except to spread the word Choosing Wisely: Key Principles
• Order tests and prescribe medications based on best evidence – Unnecessary meds can cause unwanted side effects – Unnecessary testing can lead to further testing or harm • Use effective communication techniques to explain and reassure patients about why we are or are not recommending certain medications, tests or procedures • We have an obligation to our patients, profession and society to be responsible stewards of medical resources Key Skills: Provide Clear Information Based on Best Evidence
• Explain your recommendations using the guidelines as a reference • Keep explanations simple and avoid medical jargon • Acknowledge that guidelines are not a “one size fits all” • You may need to discuss key evidence about risks, benefits and research supporting the guidelines • Use written materials to support your recommendations
Evidentiary Rationales For the Choosing Wisely Lists Gilwa C, Pearson SD. JAMA. 2014 Apr 9;311(14):1443‐4
• Of the 135 “top 5” services – 49 (36%) were for diagnosis, prognosis, or monitoring – 46 (34%) for patient treatment – 40 (30%) for population screening • Rationale – 66 (49%) mentioned greater risks to patients – 33 (24%) mentioned higher costs – 21 (16%) mentioned both greater risk and higher cost – 57 (42%) mentioned neither Evidentiary Rationales for the Choosing Wisely Lists Gilwa C, Pearson SD. JAMA. 2014 Apr 9;311(14):1443‐4
• Specialty societies can enhance trust in the Choosing Wisely campaign by – Defining more clearly the types of potentially wasteful medical care they seek to eliminate – Providing a clear evidentiary justification for the selection of each service – Greater transparency in the selection process – Broadening reach and looking at emerging techniques Summary of 2012 Cervical Cancer Guidelines Under 21 21‐29 30‐65 >65 years old Hyst, years old years old Years old benign USPSTF [D] Every 3 yCo‐test: Q5 None** [D] 2012 Cytology: Q3 Triple A None Every 3 yCo‐test: Q5* None** None 2012 Cytology: Q3 ACOG “Avoid” Every 3 yCo‐test: Q5* None** None 2012 Cytology: Q3
* Preferred ** If adequate prior screening with negative results
Co‐test: cervical cytology plus hrHPV test Cytology: cervical cytology (Pap smear) alone Cervical Cytology in Special Groups
• Do not increase the screening interval beyond annual testing for women who are – HIV‐positive – Immunosuppressed (e.g., major organ transplant) – Were exposed in utero to diethylstilbestrol (DES) • Follow ASCCP Consensus Guidelines for women who have been treated for CIN 2 or 3 or adenocarcinoma‐in‐situ
ACOG Practice Bulletin No. 109, Dec 2009
Other Important Messages
• Women at any age should NOT be screened annually by any screening method • For women 65 and older – “Adequate screening” is defined as… • 3 consecutively negative results in prior 10 years, or • 2 negative co‐tests, most recently within 5 years – If screening stopped, do not restart for any reason • Women treated for CIN 2+ or AIS must be regularly screened for 20 years, even if 65 or older – After post‐treatment surveillance, with cytology alone every 3 years or HPV+ cytology Q5 years Case Study
• 28 year old woman is seen for a family planning health screening visit; prior visit was 14 months ago • She has been receiving screening every 12‐18 months since 20 years of age • Using LNG‐IUS for 2 years; intends to continue • When informed that she did not need rescreening for 22 months, she insisted …her mother had had a cone biopsy • What will you do??
Answer: Case Study
The client should be counseled that… • Intervals are designed to balance benefits and risks and that being screened too often may be harmful to her • Over‐screening results in an excess risk of false positive test results, which can lead to unnecessary colposcopy and biopsies, with anxiety and inconvenience • Cervical cancer is not a hereditary condition • You would be happy to see her for family planning health screening visits, but next cytology is not due for 22 months Michael Pollan: Healthy Cervical Cancer Healthy eating Screening Eat real food Start later, end sooner Not too much Not too often Mostly plants Every 3 or every 5 years
What doesn’t matter for screening intervals • Age of sexual debut • Prior HPV vaccination • New sexual partners or practices • Hormonal contraceptives or hormone therapy Cervical Cancer Screening: Take It Home
• Over‐screening minimally improves detection rates but results in an excess risk of false positive tests – Unnecessary colposcopy and biopsies – Attendant anxiety and inconvenience – Unnecessary costs to the patient and the health system • Expect quality metrics to evaluate your practice on… – Percentage of eligible women who are screened – The average interval between tests in women who should be screened routinely every 3 to 5 years
Ovarian Cancer Screening
• Options for screening – (Bimanual) Pelvic examination – Transvaginal pelvic ultrasound (TVS) – Serum Tumor Marker: CA‐125 • Not recommended for low risk asymptomatic women – Low sensitivity, specificity for early disease – Low prevalence of disease – High cost of evaluation Ovarian Cancer Screening
USPSTF (2012) • Screening asymptomatic women with ultrasound, tumor markers, or exam is not recommended [D] • Insufficient evidence to recommend for or against in asymptomatic women at increased risk [I]
The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial
• Randomized trial of 78,216 women aged 55‐74 • Annual screening with CA‐125 for 6 years + transvaginal U/S for 4 years (n=39,105) versus usual care (n=39,111) • 10 US screening centers • Followed a median of 12 years • Bimanual examination originally part of the screening procedures but was discontinued
JAMA. 2011;305(22):2295‐2303 Ovarian Cancers: PLCO Cancer Screening RCT
Cases Deaths
JAMA. 2011;305(22):2295‐2303 U.S. SPR: Exams And Tests Needed Before Contraceptive Method Initiation Examination Needed for Blood pressure OC, patch, ring Clinical breast examination None Weight (BMI) (weight [kg]/ height [m]2 Hormonal methods Bimanual examination, cervical inspection IUC, cap, diaphragm Glucose, Lipids None Liver enzymes None Thrombogenic mutations None Cervical cytology (Papanicolaou smear) None STD screening with laboratory tests None HIV screening with laboratory tests None
ACP Clinical Guideline: The Screening Pelvic Exam (SPE)
• Low diagnostic accuracy for detecting ovarian cancer or BV • The PLCO trial and cohort studies suggest that SPE rarely detects non‐cervical cancer and was not associated with improved health outcomes • No studies were identified that addressed the diagnostic accuracy of the SPE for other gynecologic conditions • Full pelvic examination with bimanual examinations is indicated in some non‐screening clinical situations
Qassem A, et al. Ann Intern Med. 2014;161:67-72 ACP Clinical Guideline: The SPE
• Harms – Low‐quality evidence for harms of fear, anxiety, embarrassment, pain, and discomfort…and possibly is an obstacle to care – False‐positive screening results can lead to unnecessary laparoscopies or laparotomies – SPE adds unnecessary costs ($2.6 billion/year) • Recommendation: ACP recommends against performing SPE in asymptomatic, nonpregnant, adult women (strong recommendation, moderate‐quality evidence)
Qassem A, et al. Ann Intern Med. 2014;161:67-72
Pelvic Exam at the Well‐Woman Visit ACOG Committee Opinion 534; August 2012
• Women younger than 21 years – Pelvic exam only when indicated by medical history – Screen for GC, chlamydia with vaginal swab or urine • Women aged 21 years or older – “ACOG recommends an annual pelvic examination” • No evidence supports or refutes routine exam if low risk – If asymptomatic, pelvic exam should be a “shared decision” • Individual risk factors, patient expectations, and medico‐ legal concerns may influence these decisions – If TAH‐BSO, decision “left to the patient” if asymptomatic SPE: Right, Wrong, or Rite?
• None of the studies evaluated the most important goal of the SPE cited by ObGyns — detecting noncancerous masses • SPE may have benefits (preventing surgical emergencies) and harms (surgery for asymptomatic fibroids), but little is known about the likelihood of either • Clinicians should be cognizant of the uncertainty of benefit and the potential to cause harm through a positive test result and the cascade of events that follow
Sawaya G Jacoby V, Ann Intern Med. 2014;161:78‐79 Krogsbøll LT, General Health Checks In Adults For Reducing Morbidity And Mortality From Disease: Cochrane Meta‐analysis BMJ. 2012;345:e7191
• General health exams (GHE) for adults 18‐65 years of age failed to improve overall or disease‐specific rates of mortality • GHEs failed to improve the risk for major health events, but increased the incidence of undiagnosed chronic disease • There were few data on whether the GHE affected the use of healthcare resources or rates of disability • The GHE among adults should focus on specific evidence‐based goals, and not broad reviews for potential disease • Decision‐support technology can make visits more effective 10‐Year Fracture Probability Age vs. Femoral Neck T‐score
46.2 42.7 35.5 26 30.8 29.4 15 23.9 50 16.8 19.4 19.1 10 15.6 -4 40 10.7 6.6 -3 30 10 11.8 12 Probability 6.7 -2 4.3 (%) 20 -1 T-score 4.1 6.3 7 7.4 2.8 0 10 4.2 4.5 1.8 2.6 4 1 0 45 55 65 75 85 Age Adapted from JA Kanis et al, Osteoporos.Int. 2001;12:989-995 NOF 2013 : BMD Screening
• Women age 65 and older, regardless of risk factors • Adults who have a low trauma fracture after age 50 • In postmenopausal women age 50 to 64 – Adults with a condition (e.g., RA) or taking a medication associated with low BMD or bone loss • ≥ 5 mg prednisone QD or equivalent for ≥ 3 months – Historical height loss of 1.5 inches or more (4 cm) – Prospective height loss of 0.8 inches or more (2 cm)
NOF, Clinician’s Guide to Prevention and Treatment of Osteoporosis, 2013
NOF 2013: Treatment Guidelines
Prior hip or vertebral fracture Other prior bone fracture, or Secondary medical condition, or Elevated 10 year fracture risk
No Risk Factors
0 -1.0 ‐1.5 ‐2.0 ‐2.5 ‐3.0 T‐Score WHO 10 Year Fracture Risk Assessment
• Current age . Alcohol >3 drinks/ day • Gender . Use of glucocorticoids • Femoral neck BMD . Secondary osteoporosis • Body mass index . Personal history of fracture • Current smoking . Parental history of hip fracture
. Treat if T score ‐1.0 to ‐2.5 and 10‐year probability of • Hip fracture >3%, OR • Any major OP fracture > 20%
NOF, Clinician’s Guide to Prevention and Treatment of Osteoporosis, 2013
http://www.shef.ac.uk/FRAX/ “Top 5” Lists Top $5 Billion Arch Intern Med. 2011;171(20):1858‐1859
Pap women <21 y.o. $50 million DEXA women 40‐64 y.o. $527 million
Take It Home: Choosing Wisely
• Recent studies have demonstrated that improper care is overutilized more than proper care is underutilized • Joining the Choosing Wisely initiative, more than 60 medical societies have now identified more than 200 medical actions that should be questioned, and the elimination of which can provide lower costs and better quality care • More numerous and courageous lists should be published, developed, and heeded Take It Home
• Be mindful of clinical indications when ordering multi‐test panels – Just because you can order a test doesn’t mean that you should! – The decision is up to you…not up to the lab!!! – Order only the tests that needed now for this patient • Feel empowered to discuss this information with your medical director and physician colleagues… “avoiding avoidable care” is a concept that is gaining wide acceptance • Stay up‐to‐date on the lists in your areas of practice
Additional References
• Committee on Practice Bulletins‐‐Gynecology. ACOG Practice Bulletin Number 131: Screening for cervical cancer. Obstet Gynecol. 2012 Nov;120(5):1222‐38 • CDC. Cervical cancer screening among women aged 18‐30 years ‐ United States, 2000‐2010. MMWR Morb Mortal Wkly Rep. 2013 Jan 4;61:1038‐42 • Saslow D, American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. Am J Clin Pathol. 2012 Apr;137(4):516‐42. • Moyer VA; Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012 Jun 19;156(12):880‐91 Cancer Screening for Women: Updates and Controversies
Rebecca Jackson, MD Professor, Ob/Gyn & Reproductive Sciences Epidemiology & Biostatistics University of California, San Francisco
Disclosures
I have no financial interests to disclose
However, I sometimes hike in Kapu areas….! Lecture Plan
• Major cancers: Cervix, breast, colon, lung, ovary • Not comprehensive: 1-2 questions for each one • Cervix: Why did USPSTF and other organizations change guidelines (interval, start and stop ages) • Colorectal: What is the best method for screening
Lecture Plan • Breast 1) Why USPSTF changed guidelines for 40-49 yo women from B to C 2) Evidence on newer screening techniques: U/S, MRI, digital mammography • Lung: Why does the USPSTF recommend screening even though there are so many false positives? •Ovary: Why can’t we effectively screen for ovarian cancer? Pap smears are the most effective screening test ever invented…. Cervical Cancer in US Why does pap screening work? • Sensitivity and specificity of pap/cytology not great BUT • The organ is easily accessible for screening • Natural history is favorable : – precursor exists that is detectable and treatable; – time course before cancer develops is long – many opportunities to detect . Even if one test is false negative, get another chance. • It is cost-effective because many years of life are saved because cancer is actually prevented.
Can we do better?
• Half of cervical cancers occur in women who are not screened or inadequately screened. These women tend to be poor, uninsured, with lack of access to care – A more sensitive test like HPV or Thin Prep (marketed directly to the public!) will not fix this problem!
• In poor countries, cervical cancer remains a huge problem. Can we do better? YES! • False +: Although colposcopy is not that morbid, false +’s still cause anxiety, labeling, and are costly. – Spacing the screening interval, starting screening later and HPV typing used correctly in conjunction with cytology, will reduce false +’s and colposcopies • Over-treatment: Only 30% of untreated CIN3 becomes invasive cancer (over 30 yrs). Destroying all CIN3 =over-treatment. Main harm is preterm delivery. • Smart screening, biomarkers, risk-based approaches and less aggressive (but still evidence- based) treatment guidelines can help.
2012 USPSTF Cx Ca
• STRONGLY RECOMMENDS (“A”) • Who? Women with cervix, regardless of sexual history • Begin: Start age 21 • Interval:. 21-29: cytology q 3yr; after 30: can do q 5yr with cyto+HPV or cont’d q 3 yr cyto alone • End: Age 65 if adequate prior screening (as per ACS/ASCCP) and not at high risk for cx cancer (HIV, DES, immunocompromised) • Other: Recommends against any HPV testing in <30yo (“D” grade) All US guidelines similar • All strongly recommend against starting before age 21 • None recommends annual screening • All recommend against HPV alone or as a co-test in women <30 (ok as a reflex test after abnormal pap per ACS/ASCCP) • All recommend no screening after hyst as long as no history of CIN2+ • All recommend stop at age 65 • None recommend changes in screening for those who’ve had HPV vaccine
What’s new/different?
• Co-test with HPV: – 1st time USPSTF has recommended co- testing with HPV (ok for women who want to extend interval to 5 yrs) – ACS/ASCCP/ASCP: prefers co-test with 5 yr interval; acceptable to do cyto alone q3yr • F/U after CIN2+: ACS/ASCCP: 20 yrs ACOG: 10 yrs, USPSTF vague • Criteria to end at age 65: ACS/ASCCP— clearer guidance than others Why is less screening now recommended?
Why is it ok to delay screening until age 21 • Cervical cancer extremely rare; HPV infection very common immediately after onset of intercourse. 90% cleared by host within 2 yrs • If persistent, we will pick up at age 21, still with plenty of time to treat because long progression time of pre- invasive lesions to invasive cancer Why is it ok to lengthen the screening interval • Large population based study showed safety of this approach. 1yr vs 3 yr screening: decrease lifetime risk of mortality by 2 per 100,000, increase in lifetime colpo rates from 760/1000 to 2000/1000 • The more tests you the do, the more false positives.
Why the difference between <30 and >30 yo? • HR-HPV co-testing becomes clinically useful after age 30 • In <30yo: HPV often positive, often transiently. Therefore, HPV testing not clinically useful. • > Age 30: HPV positivity more likely to represent persistent HPV which is a significant risk factor for dysplasia/cancer. Conversely, HPV negativity is a strong negative predictor. Role of HR-HPV co-testing • Better sensitivity, worse specificity, better reproducibility than pap/cytology • HPV tests may better forecast which women will develop CIN3+ and more sensitive for adeno-ca • Has potential for increased detection (more sensitive) and increased interval of screening (more predictive of CIN3 risk) • Harm=increased colpo/treatment. This can be mitigated by increasing interval to 5 yr
Co-testing caveats
• HPV has decreased specificity so if we co-screen more often than q5 years, patients will incur greater harm without benefit – Before doing co-test, ensure patient is willing to be screened every 5 years • HPV-based strategies also lead to more positives – Some women will need prolonged surveillance – Some women who would otherwise be able to stop at age 65 will require continued screening beyond age 65 • What to do with HPV+, cytology negative? ACS/ACSSP/ACP guidelines • Co-testing “preferred” method • Preferred by whom? – USPSTF: co-testing is an option “for women who want to lengthen the screening interval” • Looking more deeply into the “preferred” recommendation…. Supplemental page
Co-testing “preferred”
• Weak recommendation – “substantial uncertainty surrounding the balance of benefits and harms, and further research is needed to increase confidence in the results, or that benefits and harms are closely balanced, with decisions based largely on individual preferences and values” • Given these substantial reservations, it is puzzling that the guidelines did not disclose that the designation of co-testing as “preferred” was a weak recommendation. Beware guideline bias
• ACS/ASCCP/ACSP: Approximately 25% of committee members reported financial conflicts of interests with companies that make HPV tests
Now what?
• FDA approved Roche Cobas HPV test as primary screen (no pap) in >25yo Should we wait for more evidence? • Downside of waiting… Missing cancer? – our screening programs already work very well – most cancers occur in under-screened or those not followed up well after abnormal pap – chance of cervical cancer in 5 yrs after neg pap is 7.5/100,000, after neg HPV test is 3.8/100,000. • Downside of being early adopter? – Don’t know if it’s a better approach – Increased worry in women told they have hpv – Increased colposcopy in women who have no dysplasia Stout, Arch Int Med 2008
Conclusions: Cervical Cancer
• Cervical cancer screening in the US is already very successful at decreasing cervical cancer incidence and morbidity • Now the goal is to decrease harm by decreasing false + and over-treatment: – Start screening later (age 21) – Screen less often (q 3yr) – Use HPV co-test to extend interval to 5yr in patients who desire this Path to Mauna Kea Resort
• Part of Ala Kahakai Trail • 1.5 miles • Access to the right of Hapuna property—up on grassy area (not down on beach) • Mauna Kea=sister resort eg can use facilities, sign for Mai Tai’s • Wear closed-toed shoes Q1: 43 yo woman with normal mammo 2 yrs ago but with “extremely dense” breasts. No other breast cancer risk factors. She would like your recommendation re: screening.
A. Wait until age 50 and then get mammo B. Regular (film) mammo C. Digital mammo D. Mammo plus ultrasound E. Mammo plus MRI
2009 USPSTF recommendations • 50-74 yo: RECOMMENDS (“B”) • 40-49 yo: Individual decision (ie don’t offer routinely) (“C”) (was“B” in 2003) • What? Mammography with or without clinical breast exam • How often? Every 2 years (was every 1-2 years in 2003) • When stop? After age 75, evidence is insufficient to make recommendation (“I”)
USPSTF Rec’s: A=strongly recommends; B=recommends; C=no recommendation; D=Recommends against; I=insufficient evidence 2009 Meta-analysis by USPSTF
• 1 new trial specifically in women 40-49 • 1 trial with updated data
Nelson, Annals Int Med, 2009
Why the change? Conceptually…
In women 40-49 c/w older women… • Smaller number of deaths are prevented because: – Lower incidence of breast cancer – Lower sensitivity of mammography – Cancers often more aggressive, less treatable • More false positives – Lower specificity and prevalence lower positive predictive value & more false positives Why the change? Numerically….
Tice, Prim Care Clin Office Pract 2009
Why the change from B to C for 40-49 yo’s from 2003 to 2009?
Bottom Line: USPSTF uses absolute benefit, not relative benefit and strongly considers risk of harm to healthy women (which is subjective and debatable). The USPSTF notes that a "C" grade is a recommendation against routine screening of women aged 40 to 49 years. The Task Force encourages individualized, informed decision making about when to start... Other Guidelines
Given the lack of consensus, involve patient in the decision- making….
New Technologies
• Digital Mammography • Breast MRI • Ultrasound plus Mammography
• Thermography? Digital Mammography
• More sensitive for women<50, extremely dense breasts, ER negative breast cancer • Easier access, transmission and storage of images, lower average dose of radiation • Trade-off of slightly lower specificity • From BCSC: in 10,000, 2 additional breast cancers for 170 additional false positive results
Tipping the balance toward benefit in 40-49yo
• Digital mammography – Increased sensitivity in 40-49yo and women with dense breasts c/w film • Risk based screening – If limit the screened population to one with similar prevalence of cancer as older women, ratio of benefit to harm becomes more favorable – Who? women with >1 first degree relative w brst ca or brst density category >4 Caution: comparing detection rates…. • Studies of new techniques typically compare detection rates in observational studies • Key q is : does improved detection lead to overall benefit (decreased mortality/morbidity) • Observational studies prone to lead-time and length bias • Earlier detection/treatment may not be better than later – Ex: 10,000 50 yo’s followed for 20 yrs. Without mammo, 260 die of breast cancer. With mammo: 223 die. Screening averted 37 deaths per 10,000 over 20 years = 1 death saved/270 women for 20 years
Ultrasound + Mammo • Potentially useful in dense breasts? • No RCT’s of normal risk women or women with only risk being dense breasts • Meta-analysis in women with dense breasts: – 6 cohort studies, only 2 included adeq f/u (nec to know false + and -) – Studies small; few cancers detected (results unstable) – CONCLUSION—more study necessary
Nothacker BMC Cancer 2009 MRI + Mammo
• Only for high risk women (BRCA, personal h/o brst ca, lifetime risk >20%) • Systematic review Warner, Ann Int Med, 2008 – No RCT’s, no studies with long term f/u or mortality – MRI more sensitive (80-100%) vs 25-59%, less specific 73-93% (3-5 fold higher recall rate) – Mammo more sensitive for DCIS therefore need both – Concl: more study needed, unknown if lead time/ length bias or real benefit, screening doesn’t detect nor cure 100% therefore consider risk reducing strategies • ACS: Annual MRI + mammo for women with lifetime risk >20%
Q1: 43 yo woman with normal mammo 2 yrs ago but with “extremely dense” breasts. No other breast cancer risk factors. She would like your recommendation re: screening.
A. Wait until age 50 and then get mammo B. Regular (film) mammo C. Digital mammo D. Mammo plus ultrasound (evid insuff, esp in women with dense breasts as only rf) E. Mammo plus MRI (only for women with >20% risk of brst ca) Conclusions: Breast Cancer • 40-49 informed decision – Risk evaluation—recommend if risk 2x greater than general popln; Digital if decide to screen • 50-74 screen every 2 years – Best benefit/harm ratio from 50-65yo • Ultrasound + mammo for dense breasts… – More study needed. • MRI + mammo for very high risk…. – May be useful, longer f/u necessary to confirm benefit, ACS recommends if>20% lifetime risk
Ala Kahakai Trail
• Ancient Hawaiian Trail • Access it at left side of beach—walk inland along rocks and you will see it • Nice beach with trees/coves about 25 min away Q2: 55 yo woman with no symptoms or family history of colorectal cancer. What type of CRC screening do you typically recommend? A. FOBT or FIT B. Sigmoidoscopy C. Colonoscopy D. CT Colonography E. Any of the above F. None of the above
Colorectal cancer screening 3rd most common cause of cancer death in women Similar in many ways to cervical cancer screening: • Natural history is known: – Pre-invasive lesion exists (adenoma) – Orderly progression from simple adenoma to one with poor histologic features to carcinoma-in-situ to invasive cancer – Long time course for this progression (many years) • Treatment of the pre-invasive lesions is effective (~100%) at PREVENTING cancer Colorectal cancer screening: options • FOBT: fecal occult blood test * • Sigmoidoscopy * • Colonoscopy • Barium enema • CT colonography (virtual colonoscopy) • Various combinations of the above • Fecal DNA • FIT: Fecal immunochemical test * RCT evidence of benefit
Evidence of benefit • 4 large RCT’s of FOBT prove benefit (>320,000 people, up to 18 years follow-up) – Decreased CRC mortality of 16% – Absolute risk reduction: 0.8 - 4.6/1000 – One trial also showed decreased cancer incidence of 17-20% • 5 trials of sigmoidoscopy showed: – Decreased CRC mortality of 28% – Absolute risk reduction 1.6/1000 – Decreased cancer incidence of 18% Newer methods?
CT colonography: • No sedation needed, need bowel prep • Radiation exposure: 1/1000 risk of new cancer • Colonoscopy to remove polyps seen • Incidental extra-colonic findings in 27-69% – 5-15% require additional evaluation and medical or surgical intervention but few ultimately required definitive treatment
Newer methods? Fecal DNA: • Detects more neoplasms than FOBT, but with more false positive results • Expensive: $400 to $800 versus $3 to $20 for FOBT Fecal Immunochemical Testing (FIT): • Detects more neoplasms than FOBT, but with only slightly more false positive results • ~$20, only one sample needed, no dietary restrictions • Compliance improved compared with FOBT How Are We Doing?
• FOBT in past 2 years 27%
• Ever had a 53% sigmoidoscopy or colonoscopy
• Colonoscopy after 33% positive FOBT
BRFSS, 2004
CRC: slowly improving 70
60 28% Incidence decrease 50
40
30 per 100,000 per Mortality 20
10 44% decrease 0 What is the best test? • Any test that the patient will accept is the best test!
• USPSTF STRONGLY RECOMMENDS (“A”): – All men and women 50-75 yo – FOBT (or FIT) q 1 year – Sigmoidoscopy: q 5 years – Colonoscopy q 10 years • Joint ACS, ACR Task Force also recommends CT Colonography q5yr & fecal DNA (unknown timing)
Kawaihae Harbor: Lunch fish truck Ovarian Cancer Screening
PLCO RCT: Annual screening with CA-125 + TVUS for 6 yrs, 12 yr f/u (PLCO=pro, lung, colon, ovarian screening trial) Ovarian Cancer (rate/10,000) Screen Control RR (95% CI) 39,105 39,111 – Ov Ca 212 (5.7) 176 (4.7) 1.2 (1.0-1.5) Stage 3&4 77% 78% ns Deaths 118 (3.1) 100 (2.6) 1.2 (0.8-1.7)
20% increase in diagnosis AND death Buys S.JAMA 2011
PLCO Results
• 3285 women (8%) with false positive screens – 1080 surgical follow-up – 163 serious surgical complications (15%) • PPV=6% (94% of those with + test did NOT have cancer)
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.” Why can’t we screen for ovarian cancer?
1. No known histologic precursor lesions 2. Unknown time for development or for progression from Stage 1 to Stage 4 – mathematical models suggest 8 months for development which would be impossibly short to detect by screening 3. For false positives, about 1/3 undergo surgery as the confirmatory test which is more morbid than confirmatory tests for others types of cancer screening
Why can’t we screen for ovarian cancer?
4. Very low prevalence compared to other cancers – Peak prevalence(age 55), 50/100,000 (yearly incidence=14/100k) – Breast cancer: 6/1000; cervical dysplasia and colonic adenomas: ~4% 5. Given low prevalence, even if a test had a specificity of 99.5%, PPV would only be 7%. – Large number would undergo unnecessary surgery to detect 1 case of ovarian cancer – In practice, specificity always lower than in research studies CT for Lung Cancer Screening
• National Lung Cancer Screening Trial (2011) • Stopped early due to benefit • 53,000 smokers (>30pack-yr), 55-74yo, helical CT (low dose) vs CXR annually for 3 yrs, f/u 7 yrs • 354 vs 442 lung cancer deaths: ARR~3.3/1000 RR 0.80 (0.73-0.93). Any death: RR 0.93 (0.86-98) • 24% with positive CT during study— 95% were false positives with requirement for various tests, mostly imaging but sometimes lung biopsy or surgery to rule-in/rule out lung ca
To prevent 62 deaths from lung cancer..
Among 53,000 participants over 7 yrs, there were 309 deaths in cxr group and 247 in CT group (diff=62). This required: – 75,000 CT scans – 18,146 positive tests – 17,066 false positive tests – 673 thoracotomy / mediastinoscopy – 303 broncoscopies – 99 needle biopsies USPSTF 2013: B recommendation
Why does the USPSTF recommend it even though there are so many false positives?
Why do you think a B recommendation?
Comparing it to mammography in 40-49yo…. Mammo (C rec) LDCT (B rec)
Decr mortality 15% 20% False positives 10% per screening 24% over 3 rounds, round 96% false positive Baseline risk in popln Very low High to be screened ARR 0.5 per 1000 3 per 1000 NNS 1904 320 Case fatality (% with Very low Very high this cancer who die) Bottom Line: Lung Cancer Screening
• The only cancer screening trial with a statistically significant decrease in total mortality • “The personal and public health consequences of lung cancer are enormous, and even a small benefit from screening could save many lives.” USPSTF
Health Policy not yet established • ~ 94 million current or former smokers in the U.S.; ~ 7 million meet NLST criteria • Specificity of CT in practice will be lower than in research setting increased false positive rates • Instituting in practice more complex than other cancers: need primary care, radiology, IR, surgery, pulmonary to be involved. • Expensive… $ $ $ If only we could do a better job helping our patients quit smoking…..! Last words • Preventive interventions require a high burden of proof: the “do no harm” principle. • Comparing detection rates of newer technologies is insufficient b/c of lead-time and length bias. Need RCT showing better outcomes, not just more cancers detected. • Choose your guidelines carefully: beware vested interests in guideline groups. • Guidelines are designed to maximize population benefits and minimize population harms—this is hard to explain to individual patient.
Enjoy The Big Island! Robert Baron MD, MS
MANAGEMENT OF HIGH BLOOD CHOLESTEROL: IMPLICATIONS OF THE NEW GUIDELINES
Robert B. Baron MD MS Professor and Associate Dean UCSF School of Medicine
Declaration of full disclosure: No conflict of interest
EXPLAINING THE DECREASE IN DEATHS FROM CVD 1980 to 2000: death rate fell by approximately 50% in both men and women
2000 to 2010: Death still falling: down 31%
• About 1/2 from acute treatments, 1/2 from risk factor modification
• Reductions in cholesterol: 1/4
Go, Circulation, 2014 Robert Baron MD, MS
Placebo-Controlled Statin Trials
Reductions in Major Coronary Events Relative to Placebo
simva 20-40 mg prava 40 mg prava 40 mg simva 40 mg prava 40 mg lova 80 mg
Prevention Of CVD in Women
. Overwhelming majority of recommendations are the same for women and for men . Aspirin use is a notable exception . But…there are gender differences in the magnitude of the absolute potential benefits
Mosca, Circulation 2011 Robert Baron MD, MS
A 40 year women, in good health. In for a preventive visit. BMI, BP, diet and exercise all at ideal. What blood tests will you order to screen her for a lipid disorder?
1. Total cholesterol (fasting or non-fasting) 2. Total and HDL cholesterol (fasting or non-fasting) 3. LDL and HDL cholesterol (fasting) 4. LDL, HDL, and hs-CRP 5. No screening blood tests for lipids
USPSTF: Screening Recommendations
. Men: . age 35 and older, regardless of risk level . age 20 to 35, at increased risk
. Women: . age 20 and older at increased risk . If not at increased risk, no recommendation (I)
. Increased Risk: . tobacco use, diabetes, hypertension, obesity, and family history of premature CV disease.
USPSTF Robert Baron MD, MS
ACC/AHA Screening
. All adults age 21.
Stone, Circulation 2013
ACC/AHA CVD Risk: Ideal All of These
. Total cholesterol <200 mg/dL (untreated)
. BP <120/<80 mm Hg (untreated)
. Fasting blood glucose <100 mg/dL (untreated)
. Body mass index <25 kg/m2
. Abstinence from smoking
. Physical activity at goal for adults >20 y of age: 150 min/wk moderate intensity, 75 min/wk vigorous intensity, or combination
. Healthy (DASH-like) diet Mosca, Circulation 2011 Robert Baron MD, MS
A 40 year women, in good health. In for a preventive visit. BMI, BP, diet and exercise all at ideal. No prior lipid screen. What blood tests will you order to screen her for a lipid disorder?
1. Total cholesterol (fasting or non-fasting) 2. Total and HDL cholesterol (fasting or non-fasting) 3. LDL and HDL cholesterol (fasting) (MY CHOICE) 4. LDL, HDL, and hs-CRP 5. No screening blood tests for lipids
BARON TREATMENT CONCLUSIONS: OLD
Patients with CHD or CHD equivalent:
• Treat aggressively with statin independent of LDL level (to LDL <70 in most cases)
• Treat other risk factors aggressively as well, especially easy ones (HTN, Aspirin use)
• Little evidence that adding a second drug (if on statin) adds benefit
• Patients at high risk are undertreated. Maximize adherence and avoid clinical inertia Robert Baron MD, MS
BARON TREATMENT CONCLUSIONS: OLD Patients without CHD:
• Use medications at thresholds based on LDL and risk:
LDL goal LDL drug threshhold High Risk (>20%) <100 (<70 optional) ≥100 Mod high risk (10-20%) <100 ≥130 Moderate risk (<10%) <100 ≥160 Low risk (no risk factors) <100 ≥190
BARON TREATMENT CONCLUSIONS: OLD
Patients without CHD:
• Use medications at thresholds based on risk:
ASA STATIN High Risk (>20%) YES YES Mod high risk (10-20%) YES YES Moderate risk (<10%) NO Occasional YES Low risk (no risk factors)NO Usually NO Robert Baron MD, MS
2013 ACC/AHA Guidelines What is New?
. 4 groups of patients who benefit from statins . Identifies high and moderate intensity statins . No LDL treatment targets . Non-statin therapies no not provide acceptable risk reduction . Estimate 10-year ASCVD risk with new equation
Stone, Circulation 2013
Heart Protection Study: Vascular Events by Baseline LDL-C
No. Events
Baseline Statin Placebo Risk Ratio and 95% Cl Feature (10,269) (10,267) Statin better Statin worse
LDL (mg/dL) <100 285 360 ≥100 <130 670 881
≥130 1087 1365 24% reduction ALL PATIENTS 2042 2606 (p<0.00001) (19.9%) (25.4%)
0.4 0.6 0.8 1.0 1.2 1.4 Robert Baron MD, MS
2013 ACC/AHA Guidelines Four Groups of Patients Who Benefit From Statins
. Individuals with clinical ASCVD . Individuals with primary elevations of LDL ≥190 . Individuals age 40-75 with diabetes and LDL ≥ 70 . Individuals without ASCVD or diabetes, age 40-75, with LDL ≥ 70, and 10 year risk 7.5% or higher Stone, Circulation 2013
2013 ACC/AHA Guidelines What Statin for Each Group?
. Individuals with clinical ASCVD: . Treat with: high intensity statin, or moderate intensity statin if > age 75 . Individuals with primary elevations of LDL ≥190: . Treat with: high intensity statin
Stone, Circulation 2013 Robert Baron MD, MS
2013 ACC/AHA Guidelines What Statin for Each Group?
. Individuals 40-75 with diabetes and LDL ≥ 70: . Treat with: moderate intensity statin, or high intensity statin if risk over 7.5% . Individuals without ASCVD or diabetes, 40- 75, with LDL ≥ 70, and 10 year risk 7.5% or higher:
. Treat with: moderate-to-high intensity statin
Stone, Circulation 2013
2013 ACC/AHA Guidelines High Intensity vs. Moderate Intensity Statin
. High Intensity: lowers LDL by >50% . Atorvastatin 40 - 80 . Rosuvastatin 20 - 40 . Moderate Intensity: lowers LDL by 30-50% . Atorvastatin 10 - 20 . Rosuvastatin 5 – 10 . Simvastatin 20 - 40 . Pravastatin 40 – 80 . Lovastatin 40 Stone, Circulation 2013 Robert Baron MD, MS
TREATING TO NEW TARGETS (TNT)
• RCT of 10,001 patients with stable CHD; 35-75 yr
• LDL <130 mg/dl
• Atorvastatin 10 vs atorvastain 80
• Followed for 4.9 years
• Research question: safety and efficacy of lowering LDL below 100 mg/dl
Larosa NEJM, 2005
TREATING TO NEW TARGETS (TNT)
LDL Event % Death % LFTs % Atorv 10 101 10.9 2.5 0.2
Atorv 80 77 8.7 2.0 1.2 p value <0.001 0.09 Robert Baron MD, MS
How Best To Calculate 10 Year Risk? Old issues . Hard vs. hard + soft CHD end points (angina)
. CHD or CVD
. Include diabetes or not
. Include peripheral vascular disease or not
. Race/ethnicity (usually not)
. Include family history and hs-CRP (Reynolds)
. Ranges vs. exact numbers
. Paper vs. computer vs. phone
How Best To Calculate 10 Year Risk? Old issues
. Insufficient shared decision making Robert Baron MD, MS
How Best To Calculate 10 Year Risk? New
Pooled Cohort Risk Assessment Equations: hard CHD events and stroke
. http://my.americanheart.org/professional/StatementsGui delines/PreventionGuidelines/Prevention- Guidelines_UCM_457698_SubHomePage.jsp
. http://www.cardiosource.org/en/Science-And- Quality/Practice-Guidelines-and-Quality-Standards/2013- Prevention-Guideline-Tools.aspx
. http://clincalc.com/Cardiology/ASCVD/PooledCohort.asp x
Pooled Cohort Risk Assessment Equations
. Age
. Gender
. Race (White/African American)
. Total cholesterol (170 mg/dl)
. HDL cholesterol (50 mg/dl) . Systolic BP (110 mmHg . Yes/no meds for BP . Yes/no DM . Yes/no cigs . Outcome: 10-year risk of total CVD (fatal and non-fatal MI and stroke) Robert Baron MD, MS
Do the Pooled Cohort Risk Assessment Equations Overestimate Risk?
Ridker PM, Cook NR, Lancet Nov 19, 2013
How Best To Calculate 10 Year Risk? Baron approach April 2014
. Use both CHD (hard end points) calculator and new CV risk calculator . Include both in shared decision- making discussion Robert Baron MD, MS
63 yo woman; s/p MI
LDL 115 HDL 45 TG 160
The best next step in lipid management is:
1. Atorvastatin 40 mg 2. Rosuvastatin 10 mg 3. Pravastatin 40 mg 4. Simvastatin 40 mg 5. Lovastatin 40 mg 6. Whatever works to get her LDL below 70 mg/dl Robert Baron MD, MS
2013 ACC/AHA Guidelines What Statin for Each Group?
. Individuals with clinical ASCVD: . Treat with: high intensity statin, or moderate intensity statin if > age 75
Stone, Circulation 2013
The best next step in lipid management is:
1. Atorvastatin 40 mg 2. Rosuvastatin 10 mg 3. Pravastatin 40 mg 4. Simvastatin 40 mg 5. Lovastatin 40 mg 6. Whatever works to get her LDL below 70 mg/dl Robert Baron MD, MS
63 yo woman; s/p MI. On atorvastatin 80.
LDL 95 HDL 40 TG 200
The best next step in lipid management is:
1. Continue current therapy 2. Switch to rosuvastatin 40 mg 3. Add fenofibrate 4. Add fish oil 5. Add niacin 6. Add ezetimibe Robert Baron MD, MS
Summary Lipid-Lowering Drugs
• Statins are treatment of choice based on RCT to decrease risk
• No evidence to support adding niacin or fibrates to statins
• If completely statin-intolerant, niacin may reduce CVD risk (weak evidence)
• Fibrates appear to lower MI risk, but no other CVD endpoints
• Ezetimibe: just say no
2013 ACC/AHA Guidelines What Statin for Each Group?
. Individuals with clinical ASCVD: . Treat with: high intensity statin, or moderate intensity statin if > age 75
Stone, Circulation 2013 Robert Baron MD, MS
The best next step in lipid management is:
1. Continue current therapy 2. Switch to rosuvastatin 40 mg (Also potentially correct, but medication still on patent) 3. Add fenofibrate 4. Add fish oil 5. Add niacin 6. Add ezetimibe
63 yo woman, no traditional risk factors
LDL 155 HDL 55 TG 160 SBP 120 No BP meds No DM Nonsmoker Robert Baron MD, MS
The best next step in lipid management is to calculate 10 year risk and:
1. Continue current therapy (no meds) 2. Begin atorvastatin 40 3. Begin atorvastatin 10 4. Begin simvastatin 20 5. Begin sustained release niacin 6. Begin red yeast rice
2013 ACC/AHA Guidelines What Statin for Each Group?
. Individuals without ASCVD or diabetes, 40- 75, with LDL ≥ 70, and 10 year risk 7.5% or higher:
. Treat with: moderate-to-high intensity statin
Stone, Circulation 2013 Robert Baron MD, MS
63 yo woman, no risks
LDL 155, HDL 55, TG 160 SBP 120, No BP meds Nonsmoker, No DM
10 yr CHD risk (old calculator): 2%… 10 yr CV risk (new calculator): 4.5%…
Therefore no medication recommended
63 yo man, no traditional risk factors
LDL 155 HDL 55 TG 160 SBP 120 No BP meds No DM Nonsmoker Robert Baron MD, MS
The best next step in lipid management is to calculate 10 year risk and:
1. Continue current therapy (no meds) 2. Begin atorvastatin 40 3. Begin atorvastatin 10 4. Begin simvastatin 20 5. Begin sustained release niacin 6. Begin red yeast rice
2013 ACC/AHA Guidelines What Statin for Each Group?
. Individuals without ASCVD or diabetes, 40- 75, with LDL ≥ 70, and 10 year risk 7.5% or higher:
. Treat with: moderate-to-high intensity statin
Stone, Circulation 2013 Robert Baron MD, MS
63 yo man, no risks
LDL 155, HDL 55, TG 160 SBP 120, No BP meds Nonsmoker, No DM
10 yr CHD risk (old calculator): 10%… 10 yr CV risk (new calculator): 10.8%… “Toss-up.” Shared decision making. If start statin (per new guidelines), can start with moderate intensity statin
The best next step in lipid management is to calculate 10 year risk and:
1. Continue current therapy (no meds)- old (but toss-up) 2. Begin atorvastatin 40-new (but still close call) 3. Begin atorvastatin 10-new (but still close call) 4. Begin simvastatin 20-new (but still close call) 5. Begin sustained release niacin 6. Begin red yeast rice
Key is shared decision-making Robert Baron MD, MS
NSAIDs and CVD
Meta-analysis. 31 RCTs, 116, 429 patients MI: No increase naproxen, diclofenac . Ibuprofen 1.61; celecoxib 1.35
Stroke: All drugs increased . Naproxen 1.76, Ibuprofen 3.36, Diclofenac 2.86
CV death: No increase naproxen . Ibuprofen 2.39, diclofenac 3.98, celecoxib 2.07
Total death: All drugs increased . Naproxen 1.23, Ibuprofen 1.77, Diclofenac 2.31, celecoxib 1.50
Trelle S. BMJ 2011
NSAIDS and CVD
. Danish national study, 97,698 patients with prior MI. 44% received NSAIDS.
. NSAIDS associated with 42% increase in CV death (CI 1.36 – 1.49)
. Diclofenac 96% and rofecoxib 66% increase
. Ibuprofen 34% and naproxen 27% increase
Schjerning A-M, PLoS One, 2013 Robert Baron MD, MS
Competing Risks
. Example: women with 10-year risk 10%
. Reduce risk by 30% with statins. Risk now 7%.
. Add NSAID. Increase risk by 50%
. Total risk now back to 10%.
Conclusions I
. Statins are effective and cost effective in selected groups of patients
. Screen most patients (shared decision-making) at age 21 (to identify those > LDL 190, other genetic lipid disorders) Robert Baron MD, MS
Conclusions II
. Use statins in women with ASCVD, LDL ≥190 and diabetes
. For those without ASCVD and diabetes, calculate 10 year risk (how best uncertain), and treat those with risk greater than 7.5% (maybe 10%). Use shared decision making.
. Use appropriate intensity statin (high and moderate)
Conclusions III . Monitor adherence, but do not treat to specific LDL goal
. Do not treat those over age 75 (unless ASCVD), on dialysis or moderate/severe CHF
. Do not treat with other lipid-modifying drugs in addition to statins (but may need if truly statin intolerant)
. Avoid other factors that raise risk as much as statins lower it (i.e. NSAIDS) Current and Emerging Strategies for Osteoporosis
Douglas C. Bauer, MD University of California, San Francisco
No Disclosures
What Would You Do? Mrs. C…
• Semi-retired 66 WF recently moved to California. No hx fracture. Sister had breast cancer, has 3 drinks/d, avoids diary. Healthy, no meds. Exam normal. • About 5’7” and weighs 130 • Hip BMD T-score -2.2 • No contraindication to treatment but little tolerance for mistakes…
Page 1 What Would You Do?
1) Start calcium 1000 mg + vitamin D 800 iu per day 2) Start alendronate 70 mg or risedronate 35 mg per week 3) Start raloxifene 60 mg/d 4) Both 1) and 2) 5) Both 1) and 3)
What’s New in Osteoporosis
• Risk stratification • Under recognition and poor compliance • New potential concerns about treatments • When to start and stop drug therapy
Page 2 What is Osteoporosis?
“A disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk.” WHO, 1993
Normal bone Osteoporosis
Traditional Risk Factors for Fracture
• The Big Three: older age, postmenopausal female, and Caucasian/Asian • Other important risk factors - Family history of fracture (hip) - Low body weight (<127 in women) - Smoker, >3 drinks/d - Certain drugs (steroids, AIs) and diseases (RA, sprue) - Previous fracture (especially hip or spine) • Measurement of bone mineral density (BMD) strongly predicts fracture
Page 3 Interpretation of Bone Density: The Basics
• Absolute mineral (calcium) content using x-rays • Relative to young adult reference population • T-score is the number of standard deviations above or below average 30 year old female – T greater than -1.0 = “normal” – T between -1.0 and -2.5 = “low bone mass” (previously “osteopenia”) – T less than -2.5 = “osteoporosis” • Z-score is number of SDs above or below others of the same age (use in those <50)
Hip BMD and Fracture Risk at Age 70
Hip fracture risk T-score 5 year Lifetime > -1 1% 4% -1 to -2 1% 8% -2 to -3 4% 16% < -3 9% 29%
Page 4 Hip BMD and Fracture Risk at Age 50
Hip fracture risk T-score 5 year Lifetime > -1 <1% 10% -1 to -2 1% 16% -2 to -3 1% 27% < -3 2% 41%
BMD and Risk Factors
30
25
20
15
10 Hip Fx Rate
5 (per 1000 woman-years) 0 >=5 Lowest Third Middle 3-4 Third Highest 0-2 Heel BMD Third # Risk Factors Cummings et al., NEJM 332(12):767-773, 1995
Page 5 Calculating Absolute Fracture Risk: FRAX http://www.shef.ac.uk/FRAX/tool.jsp
Who Should Be Tested and Treated*? • Preventive measures for everyone: adequate calcium/vitamin D, exercise, avoid bad habits • Hip BMD: women >65 (or >50 with risk factors), men>70, anyone >50 after fracture • Consider vertebral fracture assessment >70? • US pharmacologic treatment thresholds: – Anyone with hip or spine fracture – T-score (any site) < -2.5 – “Low bone mass” and FRAX 10 year hip fracture risk >3% or OP-related fracture risk >20%
*Revised 2013 NOF Guidelines
Page 6 Mrs. C
Repeat Screening: Risk at Age 65 of Developing Osteoporosis Over Next 15 Years
BMD Result 15 Yr Risk for Time to 10% Femoral Neck Osteoporosis BMD <–2.5
Normal > –1.0 0.8% 16.8 y
T = –1.01 to –1.49 4.6% 17.3 y
T = –1.50 to –1.99 20.9% 4.7 y
T = –2.00 to –2.49 62.3% 1.1 y
Gourlay, NEJM 2012
Page 7 Implications for Follow-up Testing • BMD results higher than –1.5 at age 65 can safely defer repeat screening until age 80 • BMD between –1.5 and –2 at age 65 merits repeat screening BMD at 5 years • BMD results –2 to –2.5 merits rescreening at 2 years • Caveat: applies to untreated white women >65 at average risk Gourlay, NEJM 2012
Under Recognition of Osteoporosis
• Among women with fracture or BMD<-2.5 about a third are evaluated and treated! • 12 months after hip fracture at the VA: 2% had DXA, 15% treated with appropriate drug • Ask about fracture history, note vertebral fractures, use chart reminders for DXA • Be aggressive about screening and, when indicated, appropriate treatment
Soloman, Mayo Clin Proc, 2005 Shibli-Rahhal, Osteo Internat, 2011
Page 8 Medical Work-up
• Very little data, lots of opinions • A reasonable start: – Vitamin D (25-OH, not 1,25-OH) – Serum calcium, Cr, TSH • Additional tests that may be helpful: – Sprue serology, SPEP, UEP • Unlikely to be helpful: – PTH, urine calcium Jamal et al, Osteo Inter, 2005
What Else Can Be Done To Prevent Osteoporosis?
Page 9 Non-pharmacologic Interventions
• Little new data • Smoking cessation, avoid alcohol abuse • Physical activity: modest transient effect on BMD; may reduce fracture risk • Conflicting data on hip protector pads (compliance is big issue)
Calcium and Vitamin D
• Chapuy, 1992 – Elderly women in long- term care – 30% decrease in hip fracture • Porthouse, 2005: – Women >70 with 1+ risk factor – No benefit on hip, nonspine (RR=1.01, CI: 0.71, 1.43) Chapuy, NEJM, 1992
• USPSTF meta-analysis: 11% fewer fractures (together not alone)
Page 10 Can Your Calcium Kill You?
• Meta-analysis of 15 calcium RCTs: CHD increased 30% – Not 1st endpoint, trials with vitamin D (WHI) excluded • Add calcium+D trials? Results similar after excluding those taking personal calcium supplements in WHI • Little supporting mechanistic data – No effect on surrogates (coronary calcium, IMT) – Dairy calcium not implicated • ASBMR Task Force: “the weight of the evidence is insufficient to conclude that calcium supplements cause adverse CV events…” Bolland, BMJ, 2011 Bockman,JCD, 2011
How Much Is Enough? The IOM Report
• Calcium –1200 mg/d for women >50, men >70 (maximum 2500 mg/d) –Dietary sources preferred (estimate intake using 300 mg plus 300-400 per diary serving) • Vitamin D (non-skeletal benefits not established) –600-800 IU/d (maximum 4,000/d) –Recommends serum levels 20-50 ng/ml
IOM Report, 2010
Page 11 What About the US Preventive Task Force? Widely Misquoted… • Insufficient evidence to assess risks/benefits for daily routine supplementation with calcium >1000 mg/d and vitamin D3 >400 IU • Recommends against routine supplements with calcium 1000 mg or less and vitamin D 400 IU or less to prevent fractures… –Not applicable if inadequate intake! • Vitamin D supplements effective for fall prevention ≥ 65 yr at high risk Moyer VA, USPTF, Ann Intern Med 2013; 691-6
Bisphosphonates
• Four approved agents: alendronate, risedronate, ibandronate, and zolendronic acid – No head-to-head fracture studies • What we know: fracture risk reduced 30-50% if – Existing vertebral fracture OR – Low hip BMD (T-score < -2.5) • What about those with low bone mass (“osteopenia”)? Multiple risk factors resulting in increased absolute risk?
Page 12 Effect of Alendronate on Non-spine Fracture Depends on Baseline BMD
Baseline hip BMD T -1.5 – -2.0 1.06 (0.77, 1.46)
T -2.0 – -2.5 0.97 (0.72, 1.29)
T < -2.5 0.69 (0.53, 0.88)
Overall 0.86 (0.73, 1.01) 0.1 1 10 Relative Hazard (± 95% CI) Cummings, Jama, 1998
Risedronate HIP Study: Two Groups
Group 1 • 5445 age <80; hip BMD T-score < -3.0 • 39% decreased hip fracture risk Group 2 • 3886 age >80; risk factors for hip fx • No significant effect on hip fracture risk
McClung, NEJM, 2001
Page 13 More Bad News: Compliance with Bisphosphonates is Poor • 50-60% persistence after one year – Multiple practice settings (similar to other preventive treatments) • Reasons for non-compliance – Burdensome oral administration (fasting, remain upright for 30 minutes) – Upset stomach and heartburn can occur – Asymptomatic until fracture • Trials show clinician interest (but not tests) can improve compliance Clowes, JCEM, 2004
RCT of Nurse Visits to Discuss Medication Compliance
Nurse visits q3 mo. improved adherence by 59%
Clowes, JCEM, 2004
Page 14 Does Dosing Interval Matter?
• Poor quality data: – Daily to weekly may improve compliance – Weekly to monthly may not • Yearly dosing available: zoledronic acid – Extremely potent IV bisphosphonate – Fracture reduction after 3 annual injections: hip 40%, spine 60%, non-spine 25% – Precautions: acute phase reaction, renal insufficiency • Don’t forget to discuss potential side effects… Black et al, NEJM, 2007
A New Side Effect of Potent Bisphosphonates?
Page 15 Osteonecrosis of the Jaw • Associated with potent bisphosphonate use: – 94% treated with IV bisphosphonates – 4% of cases have OP, most have cancer – 60% caused by tooth extraction. Other risk factors unknown. Infection? • Key points: extremely rare, early identification, conservative tx • Dental exam recommended before Rx, but no need to stop for dental procedures Woo et al; Ann Intern Med, 2006 ADA Guidelines, 2011
Other Things to Worry About
• Atrial fibrillation (zolendronate and alendronate RCTs) – No association in other trials – Likely spurious • Esophageal cancer – Case series (FDA author) and two conflicting cohorts, – Might be spurious • Subtrochantic fracture (with atypical features) – Likely real…
Page 16 Atypical Femoral Fractures (AFF)
• Hundreds of reports in long-term bisphosphonate users (and others) • Transverse not spiral, cortical thickening, minimal trauma • Often bilateral, prodromal pain, abn. imaging (x-ray, bone scan/MR) • ASBMR Task Force (JBMR, 2013): stress fractures from over- suppression. Other risk factors? (steroids, RA, DM, Asian…)
What Would You Do?
• Patient C. has now been on Ca/D and weekly alendronate for 5 years • Misses her dose about 8-10 times per year • No new fractures • Repeat hip BMD: T-score –2.4 (was -2.2) • How would you advise her?
Page 17 What Would You Do?
1) Urge better compliance and continue current oral bisphosphonate 2) Switch to IV bisphosphonate 3) Switch to raloxifene 60 mg/day 4) Stop bisphosphonate, continue Ca/D
How Long to Use Bisphosphonates?
• Long half-life also suggests that life- long treatment may not be necessary • Ongoing concerns about excessive suppression of bone resorption • FIT Long-term Extension (FLEX) study – 1099 ALN-treated FIT subjects – Randomized to ALN or PBO for 5 yr.
Black, Jama, 2006
Page 18 FLEX Change in Femoral Neck BMD: % Change from FIT Baseline
Start of FLEX 6
5
4 2% 3
2
1 Mean Percent Change Mean Percent 0 F 0 F 1 F 2 F 3 F 4 FL 0 FL 1 FL 2 FL 3 FL 4 FL 5 Year FIT FLEX
= Placebo P<0.001 ALN vs PBO = ALN (Pooled 5 mg and 10 mg groups)
Cumulative Incidence of Fractures During FLEX
PBO ALN (N = 437) (N = 662) RR (95% CI)
Non-spine
Non-vertebral 20% 19% 1.0 (0.8, 1.4) Hip 3% 3% 1.1 (0.5, 2.3) Vertebral Morphometric 11% 10% 0.9 (0.6, 1.2) Clinical 5% 2% 0.5 (0.2, 0.8)
Page 19 FDA View of Long-term Bisphosphonate Use (Sept. 2011) • Independent review of epidemiologic studies to date and all bisphosphonate trial data… • FDA conclusions about long-term efficacy – Confirmed FLEX and similar results from HORIZON (zoledronic acid for 3 yr. then 3 yr. off) – If no VF, no non-spine fracture benefit after 3-5 years • FDA conclusions about serious long-term harms – Causality uncertain and no agreement on effects of duration or cumulative dose • “Discuss with your provider.” And then what? Whitaker, NEJM, 2011
2014 Update: Who Should Be Treated and When to Stop? • NOF treatment thresholds: –Existing hip or vertebral fracture? Yes! –T-score < -2.5? Yes! –“Low bone mass” + FRAX score that exceeds absolute threshold? Probably not • Drug holiday after 5 yr of bisphosphonate? Maybe –No hip/vertebral fracture; no fracture on therapy –BMD T-score > -2.5 before stopping –How long? Monitor? Risk stratify after 3-5 yr
Page 20 Other Anti-resorptive Agents • Less effective than bisphosphonates –Calcitonin (poor quality studies) –Raloxifene (prevents vertebral fractures only; use for breast cancer?) • Hormone replacement • Denosumab (antibody to RANKL) –SQ q 6 months, not cleared by kidneys –Effective but expensive, less long-term data
Multiple Outcomes of Raloxifene Evaluation (MORE)
Design: 7705 women >55 with low BMD or fracture Raloxifene (60 or 120 mg) vs. placebo for 3 yr. Primary Endpoints: New spine fracture: RR = 0.65 (0.53, 0.79) Non-spine fracture: RR = 0.94 (0.79, 1.12) Other Endpoints: Breast cancer: RR = 0.24 (0.13, 0.44)
Page 21 Women’s Health Initiative
• RCT of ERT, PERT or PBO among women age 50- 79, 10,739 with hysterectomy. Primary prevention • PERT, ERT arms stopped after 5-7 years – Follow-up 93% complete • Endpoints: ERT vs. PBO – Hip RR = 0.61 (0.41, 0.91) – Non-spine RR = 0.70 (0.63, 0.79) – CVD RR = 1.12 (1.01, 1.24)
WHI Writing Group, Jama, 2004
Rank Ligand Inhibition: Denosumab
• Human monoclonal antibody against RANKL • Extremely potent inhibition of osteoclast activity • Preclinical studies: increased trabecular, cortical bone mass and increased strength • Rapid inhibition for months following a single injection, rapid resolution when stopped
Page 22 Denosumab Vs. Placebo: Fracture Risk (The FREEDOM Trial) –Multicenter study funded by Amgen –7808 postmenopausal women with OP –Denosumab, 60 mg SC every 6 months (n=3902) or placebo (n=3906) –3 years of follow-up (83% completed study) –Primary outcome: new vertebral fracture –Secondary outcomes: BMD, markers, non- spine fracture, hip fracture
Cummings et al, NEJM 2009
SQ Denosumab Vs. Placebo Every 6 Months for 3 Years (FREEDOM)
Dmab vs. PBO Fracture Outcome RR (95% CI) Vertebral 0.32 (0.26-0.41)
Hip 0.60 (0.37-0.97) Any Non-spine 0.80 (0.77-0.95)
Cummings et al, NEJM 2009
Page 23 The Future: Anabolic Agents
• Most treatments inhibit bone resorption (and formation) • Anabolic agents (anabolic steroids, fluoride, intermittent PTH) stimulate formation (and resorption) • Daily SQ PTH (1-34) for 18 mo. reduces vertebral and non-spine fracture. No hip fracture data • After teraparatide use bisphosphonate • Expensive, daily self-administered injections... – Use with severe OP, when other agents have failed?
Neer, NEJM, 2001
Daily SQ PTH (1-34) for 18 months
• Big effects on BMD – Spine increased 9-13% – Hip increased 3-6% – Wrist decreased 1-3% • Big effects on fracture – Vertebral decreased 65% – Non-spine decreased 54% • Well tolerated
Neer, NEJM, 2001
Page 24 Conclusions
• Absolute risk estimates help clinicians and patients • Aggressive screening and treatment = fewer fractures – Identify those who have already have the disease! • Bisphosphonates: treatment of choice – Use when spine/hip fracture or T<-2.5 – Adherence counseling. Intermittent dosing – Duration of therapy: 3-5 years then off for many • Denosumab and PTH effective, less clear when to use… • Stay tuned: statins, strontium, sclerostin Ab
But Be Skeptical of Wonder Drugs…
Page 25 Contraception in Medically Complicated Women Jody Steinauer, MD, MAS Dept. Ob/Gyn & Reproductive Sciences University of California, San Francisco
Disclosure Statement
July 8, 2014 I have nothing to disclose. Proportion of Women Using Contraceptive Method
Proportion of women with unmet need for family planning is as high as 50% by country www.unpopulation.org
Contraceptive Prevalence & Maternal Deaths
Ahmed et al. Lancet. 2012 Effect of Unmet Need for Contraception
Ahmed et al. Lancet. 2012
6.4 Million U.S. Pregnancies Annually
Unintended, despite method used 49% Intended
Unintended, no method used Objectives Inspire you to prioritize patient‐centered contraceptive counseling and provision in your practice Im plant Injectio n Condition Condition patch, ring ring patch, LNG--IUD Copper-IUD Copper-IUD Sub-co ndition C om bined pill, Progestin-only pill pill Progestin-only Anemias a) Thalassemia 1 1 1 1 1 2 b) S ickle cell disease‡ 2 1 1 1 1 2 Make you comfortable using CDC Medical c) Iron-deficiency anemia 1 1 1 1 1 2 Benign ovarian (including cysts) 1 1 1 1 1 1 tumors Breast disease a) Undiagnosed mass 2 2 2 2 2 1 b) Benign breast disease 1 1 1 1 1 1 c) Family history of cancer 1 1 1 1 1 1 i) current 4 4 4 4 4 1 ii) past and no evidence of 3 3 3 3 3 1 current disease for 5 years Cervical 1 1 1 1 1 1 ectropion Cervical 2 1 2 2 2 1 intraep ithelial neoplasia (CIN) Cirrhosis a) Mild (compensat ed) 1 1 1 1 1 1 b) Severe‡ (decompensated) 4 3 3 3 3 1 (DVT) i) higher risk for recurrent 4 2 2 2 2 1 /Pulmonary DVT/PE embolism (PE) ii) lower risk for recurrent 3 2 2 2 2 1 Eligibility Criteria (MEC) and the Selected DVT/PE b) Acute DVT/PE 4 2 2 2 2 2 i) higher risk for recurrent 4* 2 2 2 2 2 DVT/PE ii) lower risk for recurrent 3* 2 2 2 2 2 DVT/PE d) Family history (first-degree 2 1 1 1 1 1 re lat ives) (i) with prolonged 4 2 2 2 2 1 immobilization (ii) without prolonged 2 1 1 1 1 1 immobilization f) Minor surgery without 1 1 1 1 1 1 immobilization Practice Recommendations
Review challenging contraceptive cases 1: STI and IUD 2: Counseling 3: VTE 4: Obesity, DM 5: Implant VB
Are you familiar with the US Medical Eligibility Criteria for Contraception?
a. Yes b. No Are you familiar with the US Selected Practice Recommendations for Contraception?
a. Yes b. No
Can my patient use this method?
US Medical Eligibility Criteria (MEC) 1Can use the method No restrictions 2Can use the method Advantages generally outweigh theoretical or proven risks. 3 Should not use method Theoretical or proven risks unless no other generally outweigh method is appropriate advantages 4 Should not use method Unacceptable health risk Birth Control Methods
Medical Condition
MEC Category Where do you find the US MEC? For each method…
• When to start –“anytime if reasonably sure that she is not pregnant” • How long to use backup • Special considerations – explain recommendations by MEC • Missed or late doses
“Reasonably Sure Not Pregnant”
With exception of IUD – can start and do pregnancy test in 2-4 weeks ACOG Resource
Case #1
23 yo G0 is interested in using intrauterine contraception. When she was in college, she had Chlamydia. She has had 3 male partners in the past year. Every 3‐10 Years: Intrauterine Devices (IUD, IUC, IUD, IUS) Copper T 380A IUD 0.8% failure (1 yr) Levonorgestrel Intrauterine System (LNG‐IUS)
10 years • Levonorgestrel 20 mcg/day • 0.1% failure (1 yr) New LNG IUS –14 mcg/day 3‐5 years • 3 years
Lockhat Fertil Steril, 2005
Lower Dose LNG IUD • Lower dose of progestin (14 mcg v. 20 mcg) • Smaller size ‐ 28 mm x 30 mm ( v. 32mm x 32mm) – 3.8 mm diameter (1 mm less) • Equivalent efficacy, expulsion risk • Possibly more bleeding/spotting days • 6‐12% amenorrhea (v. 20‐50% higher dose) • May appeal to more women given its smaller size and shorter duration of use
Nelson, Obstet Gyneco, 2013 IUD Review • Current IUDs do NOT cause PID!!! – Transient increased risk at time of insertion –9.7/1000 w/in 20 days –1.4/1000 after 20 days – STI at time of insertion increases risk • Beyond time of insertion • Overall decreased risk with LNG IUS • No increased risk with Copper IUD • Okay to treat for PID with IUD in place Svensson L, et al. JAMA. 1984; Sivin I, et al. Contraception. 1991. Farley T, et al. Lancet. 1992; Hubacher, NEJM, 2003.
Routine GC/CT screening NOT necessary! • Retrospective cohort, n=57,728 IUDs • Evidence‐based STI screening, treat if + test
Overall PID risk = 0.54%
All women: Risk of PID Screened Women: Risk of PID Non-screening = Screening Same day = Pre-insertion OR= 1.05 (0.78, 1.43) OR=.997 (.64, 1.54)
Women appropriately selected Accurate screening time for non-screening Same day of insertion results < 26 yo Sufrin, Steinauer. Obstet Gynecol.2012. IUD: CDC Guidelines
Past PID
Current PID or cervicitis
C=continue I= Initiate High risk STI: caution
Selected Practice Recommendations
• Give anytime reasonable not pregnant –for IUD this is most important • Cu IUD –no backup • LNG IUD ‐ If within 7 days of period –no backup • If > 7days –backup x 7 days • Address bleeding tx • No need for string check • Evidence‐based STI and PID Case #1
23 yo G0 is interested in using intrauterine contraception. When she was in college, she had Chlamydia. She has had 3 male partners in the past year.
Case #2
A 32 yo G3P1T2 presents asking for birth control. She has used the pill before, liked it, and wants it again. She was using the pill the two times she became pregnant and had abortions. Contraceptive Counseling
• Preference‐sensitive decision • Patient‐centered care • Respect diverse priorities, concerns, experiences – Control – Safety concerns – Concern about or desire for side effects – Personal and friends’/family members’ experiences – Convenience – Efficacy
Contraceptive Counseling
• Develop awareness of your biases • Engage in shared decision‐making • Questions to pose patients – Which method did you come today wanting to use? – Are you interested in one of the most effective? Convenient? What does convenient mean to you? – When –if ever –do you want a (another) child? – What method(s) have you used in the past? – What are you doing to protect yourself from STIs? – What side effects are you willing to accept or desire? Contraceptive Method Use, U.S.* 10 million = 900,000 pregnancies each year 40 35 Most effective Effective 30 28% Least effective 25 20 15 10 6.6% 5 0
Method Mosher Vital Health Statistics, 2010 *Among the 38 million women currently Alan Guttmacher Institute, Facts In Brief, 2010. using birth control
How effective is the combined oral contraceptive for prevention of pregnancy?
9% failure rate in 1 year
How many pills, on average, do women forget to take each month (not including placebo)?
Typical use ≠ Perfect use Oral Contraceptives 2010: Missed Pills
6 Diary EMD 5 ← 5 pills 4
3
2 Mean Pills Missed Mean Pills 1 ← admit 1
0 123 Cycle Hou, Ob Gynecol, 2010
Contraception Methods
Least Effective Most Effective <88% 91% 94% >99%
Episodic Daily Weekly Monthly 3 mos 3‐5 yrs 3‐5 yrs 10 yrs Permanent
Barrier Progestin Patch Copper BTL NFP DMPA Implant OCPs Ring LNG‐IUD IUD Hysteroscopic EC (IM or SQ) Vasectomy
Combined Hormonal Progestin Only IUD Sterilization Natural Family Planning
Failure Rate Contraceptive Method Perfect Use Typical Use
No Method 85% 85% Withdrawal 4% 22% Periodic Abstinence Standard Days Method®*5% 12% Ovulation Method 3% 22% Symptothermal <1% 13‐20% Two‐Day Method® 4% 14% * Including Cycle Beads
Trussell J. Contraceptive Efficacy. In Contraceptive Technology.
Barrier Methods
Failure Rate Contraceptive Method Perfect Use Typical Use Condoms 2 % 18 % Cervical Cap (parous/nullip) 26%/9% 32%/16%
Sponge (parous/nulliparous) 20%/9% 24%/12%
Female Condoms 5 % 21 % Diaphragm 6 % 12 %
Trussell J. Contraceptive Efficacy. In Contraceptive Technology. Hormonal Methods
Failure Rate Contraceptive Method Perfect Use Typical Use Progestin Pills 0.3 % 9 % Combined Pill/Patch/Ring 0.3 % 9 % Combined 1‐month injection 0.3 % 9 % 3‐Month Injection 0.2 % 6 % Implants 0.05 % 0.05 % LNG IUD 0.2 % 0.2 % Copper IUD/LNG IUS 0.8 % <1 %
Trussell J. Contraceptive Efficacy. In Contraceptive Technology.
Patient Education Materials
MMany women ddo not understand efficacy and/or have other priorities. Daily: Combined Oral Contraceptives
• Estrogen + progestin • Traditional prescription flawed – Daily x 3 weeks / 1 week off • Extended cycle may ↑efficacy • Movement toward OTC
Baerwald, Contraception, 2004.
Extended Cycle: Shortened hormone‐free week
• 23, 24 or 26 days hormones + 2‐5 d placebo – Decreased ovarian activity at end of placebo – Shorter withdrawal bleeds – Similar breakthrough bleeding
24-day hormone pill - lower pregnancy rate 6.7% v. 4.7% over 3 years – HR 0.7 (CI 0.6-0.8) – 3 FDA‐approved products in US
Spona Contraception, 1996 ; Bachman Contraception, 2004; Endrikat Contraception, 2001; Dinger ObGyn, 2011. Extended Cycle: Fewer Hormone‐free Weeks • 12 weeks hormone/1 week off – 84 days LNG 150 µg/EE 30 µg; 7 days placebo – Decreased breakthrough bleeding over time
• Continuous for one year – Increased spotting in first six months – Median 1.5 days spotting in last trimester • FDA‐approved: ethinyl estradiol and levonorgestrel – 90 mcg levonorgestrel + 20 mcg EE
Anderson Contraception, 2003
Combined Hormonal Contraception • Give anytime reasonable not pregnant • If within 5 days of period –no backup • If > 5 days – backup x 7 days • Check blood pressure • Give up to 1‐year supply • If 2+ days missed – backup x 7 days • If in last week –omit HFI Case #2
A 32 yo G3P1T2 presents asking for birth control. She has only used the pill before and liked it. She became pregnant on the pill each time she became pregnant.
Case #3
19 yo G0, newly sexually active, wants to start the contraceptive vaginal ring. But she is concerned about what she has read in the news about the ring causing blood clots.
DVT Risk with the Contraceptive Vaginal Ring (CVR)
• Lidegaard O, et.al BMJ 2012. • 9, 429, 128 woman years of observation • Confirmed VTE events per 10 000 woman years – Non‐users of hormonal contraception 2.1 – Combined Oral Contraceptives 6.2 (RR 3.2) – Transdermal patches 9.7 (RR 7.9) – Vaginal ring 7.8 (RR 6.5)
Ring +1.6 additional cases / 10,000 women‐years. Adjusted Rate Ratio 1.9 (1.3‐2.7) v. COC
DVT Risk with the Contraceptive Vaginal Ring (CVR)
• Dinger, et al. Ob Gyn, 2013. • 66, 489 woman years of observation • Confirmed VTE events per 10 000 woman years – LNG COC 7.8 – All COC 9.2 – Vaginal ring 8.3 (HR 1.0, 0.3‐3.3)
Ring ‐ no increased risk compared with any pill. HR 0.8 (0.5‐1.5) DVT Risk with the Contraceptive Vaginal Ring (CVR)
• Sidney, et al., Contraception, 2013 • Retrospective cohort of 573, 680 women • Confirmed VTE events per 10 000 woman years – All COC –new users 8.2 (7‐9.6) – Vaginal ring 11.3 (4.26‐32)
Ring ‐ in adjusted analyses no increased risk compared with the pill. HR 1.1 (0.6‐2.2)
Case #3
19 yo G0, newly sexually active, wants to start the contraceptive vaginal ring. • Conflicting level 2 evidence –may cause slight increase risk relative to COC • Attributable risk very, very small • Level I evidence that women use it correctly compared with pill • May cause fewer unintended pregnancies and therefore fewer VTE overall VTE & Oral Progestin Type
• Desogestrel and drosperinone COCs may increase risk of VTE • BUT. . . Absolute risk remains low Non-pregnant, no COCs: 2-4 per 10,000 ♀-yrs Levonorgestrel COCs: 5.0 per 10,000 ♀-yrs Desogestrel COCs: 6.5 per 10,000 ♀-yrs Drosperinone COCs: 7.8 per 10,000 ♀-yrs
Lidegaard 2009 BMJ Heinemann 2007 Contraception
Choosing a COC
• Careful with very low‐dose estrogen – ↑ bleeding • Monophasic fine • Levonorgestrel may cause fewer VTE • No clear benefit of drospirenone – PMDD: fewer sxs 6 months – equivalent at 2 yr – Acne: Equivalent to other pills 30 or 35 mcg EE + levonorgestrel Shortened or erased placebo week if possible Monophasic
VanViet Cochrane 2006 LaGuardia Contraception, 2003 Freeman Womens Health 2001 van Vloten Cutis 2002 CDC MEC
All progestin-only methods are safe even if: 1)Current VTE 2)No anti-coagulation 3)Provoked or unprovoked VTE
Case #4
38 yo G2P1T1 woman is seeking contraception. She had pre‐eclampsia during her last pregnancy but otherwise reports she is healthy. Physical exam: Wt= 226 lbs, Ht= 5’5” (BMI=37.6) BP=138/89 Obesity and Contraception
Efficacy Adverse events • Pharmacokinetics • Risk of VTE • Oral vs. non‐oral • Risk of CV events • Risk of pregnancy • Metabolic effects – Weight gain? Lipid profiles?
1Institute of Medicine. Weight gain in pregnancy: Reexamining the guidelines
Obesity & Contraceptive Efficacy:
OCPs: no clear difference1,2 Longer time to steady state3 Patch: increased failure5 if >90kg ‐ BUT BMI more relevant measure 1,2 Ring: no difference1,2 ‐ No effect with BMI
IUC: no difference ETG implant: ‐lower serum level, DMPA: no difference1 but still inhibitory1,4 ‐may need longer needles
1 Lopez LM 2010 Cochrane 3 Edelman, Contraception, 2009; 4Westhoff 2005 2 McNicholas 2013 Obstet Gynecol Obstet Gynecol;5 Zieman 2002 Fertil Steril Obesity and Contraceptive Risks
• VTE risk – OCPs & obesity are independent RF for VTE • Obesity doubles risk of VTE – No data show synergistic, increased risk
– Risk is lower than pregnancy (29/10,000 ♀‐yrs)
Note: no safety information on women BMI>40
Contraception & Weight Gain • OCP, Patch, Ring: none or age‐expected change1,2,3,6 • LNG‐IUS: age‐expected wt gain4 • ETG implant: minimal if any effect5 • DMPA: •Ave 5‐6 kg over 3‐5yrs3,6 BMI>30 •Baseline BMI: •Nl and overwt had inc. risk7 BMI 25‐30 •No assoc for adolescents8 •Adolescents: BMI<25 •More pronounced wt gain5 •Early wt gain @ 6mo (>5%) predicts future wt gain8 Pantoja 2010
1. O’Connell 2001 Contraception 5. Darney 2009 Fertil Steril 2. Gallo 2004 Obstet Gynecol 6. Beksinka 2010 Contraception 3. Berenson 2009 AJOG 7. Pantoja 2010 Contraception 4. Ronnerdag 1999 Acta Obstet Gynecol Scand 8. Bonny 2010 Contraception Metabolic Syndrome
• Constellation of findings which increase risk of CHD, stroke, & type 2 DM Three or more: – Hypertension ≥130/85
– Insulin resistance FBS ≥100
– Central obesity Waist circumference ≥35”
– High triglycerides ≥150 mg/dL
– Low HDL ≤ 50mg/dL
Metabolic Syndrome & Contraception
Lipids CHC: TGL, HDL, LDL1 PCOS: improved LDL/HDL ratio2 DMPA: transient worsening of lipids post‐injection3 ETG Implant: Chol, LDL, HDL4,5 BP OCPs: 5% of OCP users develop reversible Htn (7mm Hg)6
Insulin Women without DM: Resistance OCP: No impact7 Ring: improved IR in PCOS8 DMPA: no effect9 vs. small increase in FBS (3mg/dL over2yrs)10 LNG IUD: no effect ETG Implant: no effect5 Obese women: DMPA increased IR v. non‐obese women Women with DM: DMPA: No RCTs. Increase in FBG 103‐112. OCP: No increase in insulin requirement or end organ damage.11 1. Winkler 2009 Contraception 2. Falsetti 1995 Acta Obstet Gyn Scand 6. Darney & Speroff 2005 Clin Guide for Contraception 3. WHO 1993 Contraception 7. Grimes 2009 Cochrane Database 4. Merki‐Feld 2008 Clin Endocrinol 8. Battaglia 2009 Fertil Steril 10. Berenson 2011 Obstet Gynecol 5. Inal 2008 Eur J Contracept Reprod Health Care 9. Fahmy 1991 Contraception 11. Skouby 1984 Fertil Steril CDC MEC
Bariatric Surgery & Contraception • Advisable to wait 1‐2 years after surgery before planning pregnancy1 • Fecundity & pregnancy rates often increase after surgery2,3 – Especially in adolescents(13% vs. 6%) • Recommend non‐oral methods for surgeries that impair GI absorption4 – Decreased absorption of OCPs
1. ACOG Practice Bulletin 105, 2009 2. Merhi 2007 Fertil Steril 3. Roeherig 2007 Obes Surg 4. Mehri 2007 Gynecol Obstet Invest CDC MEC
Oral absorption
Emergency Contraception
word Emergency Contraception: Oral LNG 120 mg x 1, up to 5 days
Ulipristal Acetate • Selective progesterone receptor modulator • Mechanism:1 – Delay follicular rupture • Will not harm existing pregnancy • Dosing: 30mg, FDA‐approved up to 5 days
1. Brache 2010 Hum Reprod
Emergency Contraception: Ulipristal Acetate Effectiveness:1,2 “Non‐inferior” to LNG: 1.4% vs. 2.2% Meta‐analysis of 3445 ♀ 120 hrs: OR = .55 (.32‐.93) 24 hrs: OR = .35 (.11‐.93) **More effective for obese women3 – Obese vs Normal/underweight: • LNG: OR 4.41 [2.05‐9.44], p=.0002 – No efficacy >80 kg • UA: OR: 2.62 [0.89‐7.00], NS
Side effects: Headache (20%), nausea (12%) 1. Glasier 2010 Lancet 2. Creinin 2006 Obstet Gynecol 3. Moreau, 2012 Contraception Alternatives to LNG EC & Ulipristal Acetate? • Copper IUD ‐ <0.1% failure – VERY effective as EC up to 5+ days – SPR can place beyond 5 days if not more than 5 days after ovulation – More effective than LNG EC
• Mifepristone (10, 25 or 50 mg) – More effective than LNG • Yuzpe regimen – More side effects and less effective
Cheng 2008 Cochrane Database
Case #4
38 yo G2P1T1 obese woman desires birth control. • Assess for other risk factors • If none all methods safer than pregnancy • If smoker or other RF –may avoid CHC • DMPA –concern for insulin resistance and weight gain • For EC – recommend UPA Case #5
28 yo G4P1 had a subdermal etonogestrel (ETG) implant placed 7 months ago. She has had bleeding every day for the last 6 weeks.
New ETG Subdermal Implant
• Replaced prior in November, 2011 • Identical but with radiopaque rod • Easier‐to‐use inserter • Must complete FDA‐approved training
word Women who Discontinue due to Bleeding Irregularities
CHC DMPA LNG-IUD Cu-IUD Implant 3% 1 7-12% 2,3 2.5% 4 5% 5 10% 6
1/3 of women who discontinue Implant do so for bleeding
1. Datey 1995 Contraception 2. Cropsey 2010 J Womens Health 3. Colli 1999 Contraception 4. Suhonen 2004 Contraception 5. Rivera 1999 Contraception 6. Blumenthal 2008 Eur J Contracept Reprod Health Care
ETG Implant & Bleeding
17 bleeding-spotting days/90d
Infrequent: 34% Amenorrhea 22% Prolonged bleeding 18% Frequent bleeding 6%
Darney 2009 Fertil Steril Mansour 2010 Contraception Mansour 2008 Eur J Contr Repro Health Care Implant & Bleeding: Counseling!!! • Pre‐insertion expectations – Bleeding usually light – “irregularly irregular” – Unpredictable for entire 3 years
• May improve dysmenorrhea – 77% with dysmenorrhea had resolution of sx
Mansour 2008 Eur J Contr Repro Health Care
Implant: Bleeding Treatment
Therapy Evidence?
1. COC x 21d/7d (3 mo) or Estrogen alone Minimal (0.5 mg estradiol x 21 d) (3 mo) 2. Cyclic progestin (MPA 10bid) x 21d/7d Anecdotal (3mo)
3. POP daily up to 3 mo Anecdotal
4. NSAIDs, COX‐2 inhibitors x 5‐10d Minimal Tranexamic acid 500 bid x 5d Anecdotal
CDC SPR: Rule out causes of bleeding. NSAIDS 5‐7 days
Estrogen or CHC 10‐20 days Adapted from Mansour et al 2010, and 2011 Contraception Case #5
28 yo G4P1 had a subdermal etonogestrel (ETG) implant placed 7 months ago. She has had bleeding every day for the last 6 weeks.
Summary
• Unintended pregnancy remains a common problem in the US. • Remember that in most circumstances unintended pregnancy poses greater risk than contraception. • CDC and ACOG provide useful resources for caring for patients with complex medical conditions. References • Many easily accessible resources exist to help solve contraception quandaries. . . .
UCSF Family Planning Consult Service (415) 443-6318
Thanks to Carolyn Sufrin, Mike Policar and Merrie Warden for sharing slides. Essentials of Women’s Health Hapuna Beach Prince Hotel, Hawaii July 6, 2014
New Developments in the Management of Sexually Transmitted Infections in Women
Michael S. Policar, MD, MPH Clinical Professor Ob, Gyn, and Repro Sciences, UCSF policarm @ obgyn.ucsf.edu
Categories of STI Screening and Testing
• Routine screening – Population based risk factors • Targeted screening – Personal behavioral risk factors • Contact testing – Suspected or known exposure to a person w/ STI Categories of STI Screening and Testing
• Co‐infection testing – If one STI, greater risk of being co‐infected • Diagnostic testing – Clinical symptoms or signs of a STI • Test‐of‐cure – Testing after treatment to detect treatment failure • Repeat screening – Screening after treatment to detect re‐infection
Routine Screening: Cervical Chlamydia
• CDC (2010) – Annually in sexually active women < 25 years old – Older women with risk factors – If practice‐site prevalence is >3% (CA STD Control Branch) • USPSTF (2007) – All sexually active non‐pregnant women <24 [A] – Older women who are at increased risk [A] – Recommend against routinely screening women > 25, whether pregnant or not, if not at increased risk [C] Why Routine Chlamydia Screening?
• Most prevalent in sexually active women < 26 years old – Larger ectropion bigger target for Ct infection – More likely to have multiple sexual partners – Less likely to use barrier contraceptives • Detection and treatment of asymptomatic Ct – Reduces PID rates by 56% – Reduces consequent infertility, chronic pelvic pain – Prevents horizontal transmission to sex partners
Are the Wrong Women Screened for Ct?
• 20‐50% of women in target age range are not screened • Yet, in many systems, screening rates for women over age 25 are equal to women 25 and younger So what?? • Ct rates in women over 25 are <1%; decline with age ‐ Chlamydia infects the columnar epithelium of the cervical ectropion; recedes with aging • As prevalence decreases, positive predictive value declines 2.8% 2.6% 35-39 yo: 0.15%
1.0%
CDC,2005
Ct Screening threshold Strategies for Improving Ct Screening Provider Level
• Screening procedures clear to all office staff • Unlink Chlamydia screening from pelvic exam – With NAAT, vaginal or urine samples are preferred • Practice “opportunistic prevention” – Screen at problem‐oriented visits if necessary • “Automate” office work flow – Kit on chart or exam room prep table in advance based on age or risk behaviors
Strategies for Improving Ct Screening System Level
• Make screening available from a variety of providers – Family & Internal Medicine, Pediatrics, Ob‐Gyn • Robust lab EHR…easy to check the need for screening • Consistent practice patterns across specialties – Clinical practice guidelines are clear and enforced – Champion(s) monitor impact, provide feedback • Practice performance is compared to peer group – Reward above average performance – Remediate below average performance Routine STI Screening: Gonorrhea
• CDC (2010) – Women under 25 years of age who are at increased risk for infection – Older women with risk factors – If PSP is >1% (CA STD Control Branch) • USPSTF (2005) – Screen all sexually active women, including pregnancy, if at increased risk for infection [B] – Do not screen men and women who are at low risk for infection [D recommendation]
USPSTF: Increased Risk for GC Infection
• Under 25 years of age • New or multiple sex partners • Previous GC or other STDs • Inconsistent condom use • Commercial sex work • Drug use Targeted Screening: Risk Factors
Ct screening in women >26 years old, or GC screening in women of any age, PSP <1% • History of GC, chlamydia, or PID in the past 2 years • More than 1 sexual partner in the past year • New sexual partner within 90 days • Reason to believe that a sex partner has had other partners in the past year Syphilis, HIV screening • Sexual history, partner behaviors, local prevalence
GC+Ct Screening Recommendations
• Nucleic acid amplification tests (NAAT) are preferred – Highly accurate: >98% sensitivity; >99% specificity – Men: first catch urine sample preferred – Women: vaginal swab preferred • Urine, cervical, LBC samples slightly less accurate • Sample endocervix only if speculum exam being done • In asymptomatic heterosexuals who engage in oral or anal sex, CDC does not recommend pharyngeal or anal samples Contact Testing for STI Exposure
• Test asymptomatic persons with high risk sexual exposure (new or multiple sexual partners) for – Gonorrhea – Chlamydia – Syphilis – HIV • Maybe: HSV‐2 serology • No contact testing for – HSV (culture), HPV (DNA) – HBV, HBC (strategy for HBV is vaccination)
CDC 2010: Screening for Hepatitis B
• Have you previously been vaccinated for Hepatitis B? – Yes…no further evaluation – No…consider being vaccinated if HB risk factors • If HB vaccine is offered, pre‐vaccination HB serology – Is not cost effective in low prevalence groups, – Is cost effective in high prevalence adult populations •IDU, MSM, sexual contacts of chronic carriers, persons from endemic countries – If screened, give 1st dose of vaccine at same time CDC 2010: Screening for Hepatitis C
• Sexual transmission is very uncommon • Candidates for targeted screening – Blood transfusion from a donor who later tested positive for hepatitis C – Injected illegal drugs, even if experimented a few times many years ago – Transfusion or organ transplant before 7/1992 – Recipient of clotting factor(s) made before 1987 – Ever been on long‐term kidney dialysis – Evidence of liver disease (e.g., abnormal LFTs)
Recommendations for Identification of Chronic Hep C Virus Infection, Persons Born 1945–1965 MMWR 2012;61(RR04);1‐18
• Adults born during 1945–1965 should receive one‐time testing for HCV without prior ascertainment of HCV risk, and • All persons identified with HCV infection should receive a brief alcohol screening and intervention, followed by referral to appropriate care services for HCV infection Testing for STI Co‐Infection
If positive for Test for • Chlamydia GC, syphilis, HIV • GC Chlamydia, syphilis, HIV • Syphilis Chlamydia, GC, HIV • Primary herpes Chlamydia, GC, syphilis, HIV • Recurrent herpes (?)… may be long standing • Trichomoniasis(?)… may be long standing • Ext genital warts (?)… may be long standing • BV, candida Not STIs, therefore don’t screen
Diagnostic Testing for GC and Ct
• Women . Men – Abnormal vaginal discharge – Dysuria – Urethral discharge – Abnormal vaginal bleeding – Testicular pain – Dyspareunia, chronic pelvic pain, PID – Mucopurulent cervicitis – Cervical friability – Unexplained infertility Indications for Treatment Gonorrhea (GC) + Chlamydia (Ct)
• Positive GC or Ct screening test • Sexual partner with known GC or Ct • Presumptive therapy of mucopurulent cervicitis or urethritis (treat both) • Pelvic inflammatory disease (treat both)
CDC 2010: Lower Genital Tract Chlamydia
• Preferred treatment – Azithromycin 1 gm orally, directly observed • First line treatment in pregnancy – Doxycycline 100 mg PO BID for 7 days • Avoid prolonged sun exposure (photosensitivity) • Alternative treatment – Ofloxacin 300 mg PO BID for 7 days – Levofloxacin 500 mg PO QD for 7 days – Erythromycin base or EES QID for 7 days • NOTE: Ciprofloxacin not effective! CDC 2010: Anogenital Gonorrhea
• Recommended regimens – Preferred: ceftriaxone 250 mg IM + dual therapy – If IM not an option: cefixime 400 mg PO + dual tx • Dual therapy drugs…either – Azithromycin 1 gram PO, or – Doxycycline 100 mg BID for 7 days • Purpose of dual therapy – Prevent (or delay) GC cephalosporin resistance – Co‐treat “for chlamydia”, even if NAAT is negative
CDC 2014: Anogenital Gonorrhea
• Recommended regimen – Ceftriaxone 250 mg IM x1 dose • plus Dual therapy – Azithromycin 1 gram PO – Doxycycline 100 mg BID for 7 days – Alternative therapy – If IM ceftriaxone not an option or EPT: Cefixime 400 mg PO + azithromycin 1 gram PO CDC 2010: Anogenital Gonorrhea
• Alternative oral cephalosporins – Cefpodoxime 400 mg PO, or – Cefuroxime axetil 1 gram PO • Alternative single IM dose – Ceftizoxime 500 mg – Cefotaxime 500 mg – Cefoxitin 2 gm • Alternative regimen if cephalosporin allergic – Azithromycin 2 grams PO x single dose – Perform test of cure
CDC 2010: Oropharyngeal Gonorrhea
• Recommended regimen – Ceftriaxone 250 mg IM + dual therapy – All other cephalosporins have lower cure rates • Dual therapy drugs…either – Azithromycin 1 gram PO, or – Doxycycline 100 mg BID for 7 days • Alternative regimen if cephalosporin allergic – Azithromycin 2 grams PO x single dose – Perform test of cure Test of Cure After Ct or GC Treatment
• Not after high efficacy, single dose treatment • Exceptions…perform test of cure – Pregnancy – Noncompliant with therapy – Persistent symptoms despite therapy – Suspect early reinfection after adequate therapy – Multi‐day antibiotics with high failure rate • e.g., Erythromycin TID for 7 days • Avoid non‐culture tests within 3 weeks of treatment, since dead organisms may be detected
Check List: Management of Ct and GC
Ensure timely and appropriate treatment – Within 14 days of specimen collection Test for other STDs – GC, syphilis, HIV Patient education and counseling Report case to the local health department Schedule follow‐up test in 3 months Ensure that sex partners are treated – All partners in the past 2 months Ct & GC Screening and Testing Post‐Treatment
• Re‐testing: women treated for chlamydia or GC should be re‐tested in 3 months – In young women, past infection is strong predictor of repeat infection •20% (14‐26%) rate of new infection(s) by an untreated partner or new partner within 12 months – Short time to repeat positive test – 4x risk of PID, 2x risk of ectopic pregnancy
Retesting for Ct & GC…Improving Clinic Practice
• Initial patient counseling – Stress importance of retest – Make retest appointment at the time of treatment • System to contact patient regarding retesting – Tickler system, with follow‐up if no return visit – Reminders by mail (self‐addressed letter or card) – Reminder phone calls, e‐mails, or text messages • Opportunistic re‐testing – Flag chart to ensure retesting opportunity not missed – Test at any subsequent visit (3‐12 months), but not earlier than 4 weeks from treatment Partner Management: WHO?
• Treat ALL sexual partners within 2 months of positive gonorrhea or chlamydia test – Ask how many people she has had sex with during the previous 2 months – Ask regardless of marital/relationship status – If last sexual contact was longer than 2 months ago, treat most recent partner
Partner Management: HOW?
• Traditional approaches – Patient notification of partner – Provider notification of partner – Health department referral • Preferred approach – Expedited Partner Therapy (EPT) •2010 CDC STD Treatment Guidelines •ACOG Committee Opinion #506, ObGyn, Sept 2011 Expedited Partner Treatment (EPT)
. Bring Your Own Partner (“BYOP”) – Bring her partner(s) at the time of her treatment so that both client and partner(s) can be counseled and treated . Patient‐delivered partner therapy (“PDPT”) 1. Provide patient with drugs intended for partners 2. Prescribe extra doses of medication in the index patients’ name 3. Write prescriptions in the partners’ names – Ideally with written instructions for the partner(s) . Legally permitted in CA: Ct (2001), GC (2007) − Other states: www.cdc.gov/std/ept for US map
Chlamydia and Gonorrhea Clinical Management in a Nutshell
“Screen, Treat, Treat, Screen” • Screen all appropriate patients for Ct and GC; • Treat all infected patients promptly; • Treat all of their recent partners; and • Screen all treated patients again three months after treatment (retest) Routine STI Screening: HIV Serology
• CDC (2010), USPSTF (2012) – Screen all individuals once between 13‐64 years old •Only if practice‐site prevalence (PSP) is at least 0.1% • Routine HIV screen in pregnancy, for insurance eligibility, entry into military, etc, all are acceptable – Repeat annually or more often if “known risk”
2014 CDC HIV Screening Algorithm Multi Spot Differentiation Positive Positive assay (DA) HIV‐1, 2 3rd or 4th or both generation HIV serology rd HIV‐1 RNA 3 : ab only Negative 4th: ab + ag Qualitative Negative
Note: Western Blot Negative Positive no longer used False pos screen False neg DA “Routine” STI Screening: Syphilis Serology
• CDC (2010) – All pregnant women; otherwise no recommendation • USPSTF (2004) – Recommends against routine screening of asymptomatic persons who are not at increased risk for syphilis infection [D recommendation] – Strongly recommends that clinicians screen persons at increased risk for syphilis infection [A]
Syphilis Screening
• Traditional protocol – Quantitative, non‐treponemal assay (RPR, VDRL) Confirmatory qualitative treponemal test (TPPA) • New protocol – New treponemal tests EIA/CLIA Non‐treponemal test (RPR, VDRL) – If discordant EIA+/RPR negative 2nd treponemal test (TPPA) HSV: Organism Tests
Sensit Specif Cost Comment PCR +4 +4 $$$$ Not in most labs HSV culture •ELVIS rapid +3 +4 $$$ 1 day; no typing •ELVIS std +3 +4 $$$ 5 days; typing* •Cytopathic +3 +3 $$$ Phasing out Herpes DFA +2 +3 $$ Scrape; plate Cytology +1 +3 $$ Scrape; plate
* HSV typing is helpful for counseling regarding recurrence risk, but not for clinical management decisions
HSV‐2 Serology: Diagnostic Testing
Used mainly to exclude genital herpes diagnosis • History suggestive of HSV but no lesions to test, OR • Culture negative recurrent lesion – Seronegative: not due to genital herpes – Seropositive: HSV lesion or prior infection • Suspected 1o herpes more than 6 weeks ago with initial testing negative; serology repeated – Seronegative: not due to genital herpes – Seropositive: HSV infection confirmed HSV‐2 Serology: Screening
Strategy Recommendation Screen general population Should not be offered Universal screening in Should not be offered pregnancy Screening in HIV‐positive Should generally be offered patients Screening in patients in Should generally be offered partnerships with HSV‐2 infected people Screening in patients at risk for Should be offered to select STD/HIV patients
Guidelines for the Use of HSV‐2 Type‐Specific Serologies, CA DHS 2003
CDC 2010: Treatment of Genital Herpes
Acyclovir Famciclovir Valacyclovir Primary •400 mg TID •250 mg TID •1 gram BID (7‐10 days) •200 mg 5 times/d Recurrent •800 mg TID x2d •1 gm BID x1d •500mg BID x3d •800 mg BID x5d •125mg BID x5d •1 gm QD x5d •400 mg TID x5d • 500 mg once, then 250 BID x2d Suppression •400 mg TID •250 mg BID •0.5‐1 gm QD Prophylaxis •400 mg BID** •250 mg BID •500 mg QD
** Drug class extrapolation, based upon suppressive regimen Limited data on famciclovir use in pregnancy Prevention of Genital Herpes
• partner HSV‐2 serostatus; susceptible if negative • Avoid intercourse/touch of lesions during outbreak • Condoms will provide some degree of protection • Patient treatment of during outbreak (or long term suppression) reduces shedding • Daily prophylactic treatment reduces shedding – Incident HSV infection reduced by 1.7% over 1 year • 96.4% don’t seroconvert in absence of treatment • 1.9% seroconvert with treatment – NNT: 59 people to prevent one case/ year
Reproductive Cancer Healthy Pregnancy Immunizations Chronic Health Behaviors related conditions STI and HIV Breast Cancer Alcohol S&C •Alcohol •TdaP, Td CV: HTN, counseling ; all •Mammography S&C booster, lipids sexually active F) •MMR, varicella Ct, GC, Syphilis •Genetic S&C Tobacco C&I •Tobacco Influenza T2DM screening C&I screen HIV screening •Preventive Diet •Folic acid •Hepatitis A, B Depression (adults at HR; all medication counseling if supplement •Meningococcal screen sexually active F) counseling CVD risk Contraception Cervix: Interpersonal •GDM •HPV Osteo- (women w/repro • Cytology and DV S&C screen (women 19‐26) porosis capacity • HPV + cytology •Rh screen screen •Anemia screen Colorectal: Well‐woman •STI screen •Pneumococcal Obesity •FOBT, visits •Bacteruria •Zoster screen; C&I •Colonoscopy, screen if obese •Sigmoid •Lactation Supports
S&C: screening and counseling C&I: counseling and interventions Take It To Your Practice • Use the 7 categories of STI screening and testing – Automate office to support routine Ct screening – Sexual history is essential for targeted screening – Screening without indication = more harm than good • Pelvic exam is unnecessary for GC and Ct screening • Treat partners (know your state law) • Optimize office procedures to support – Rescreening of patients treated within 3‐12 months – Expedited partner therapy (BYOP, PDPT)
• Reproductive Infectious Disease Pager (24/7) – (415) 443‐8726 • National Perinatal HIV Hotline (24/7) – (888) 448‐8765 • ReproIDHIV listserv – Clinical cases, patient referrals, sharing protocols/upcoming events, networking – Sponsored by UCSF National Clinicians’ Consultation Center, Infectious Disease Society of Obstetricians and Gynecologists (IDSOG), UCSF Fellowship in Reproductive Infectious Disease – Contact Shannon Weber at: [email protected] Amenorrhea and PCOS
Rebecca Jackson, MD University of California, San Francisco
No Financial disclosures The Plan
Amenorrhea—mostly secondary 1. Broad differential 2. Simple, stepwise, work-up Focus on PCOS 1. Clinical features 2. Diagnostic criteria 3. Treatment approach—short and long term sequelae Goal: Efficient (fewest visits) and cost- effective (targeted testing)
Case 1
A 26 yo P0 with previously 1. What term describes normal periods now reports no her symptoms? period for 5 months. She is 2. Physiologically, what normal weight and is not on causes this type of any medications. She denies bleeding pattern? hot flashes. 3. What is the differential? Q1: In addition to a urine pregnancy test and TSH, which of the following is the most appropriate test to obtain at this time? 1. Prolactin 2. FSH 3. Total testosterone and DHEAS 4. Transvaginal Ultrasound (TVUS) 5. All of the above 6. None of the above
Amenorrhea, Oligomenorrhea
. Amenorrhea – . Primary amenorrhea . No menarche by age 14 without secondary sexual characteristics . No menarche by age 16 with secondary sexual characteristics . Secondary amenorrhea – absence of menses in a previously menstruating woman . No menses for > 3 cycle lengths in previously cycling woman Or . No menses > 6 months in women with irregular cycles . Oligomenorrhea – <9 periods per year
Normal: Cycle= 28 days +- 7 d (21-35); Length=2-7 days; Heaviness=self-defined Primary Amenorrhea, approach
. Wide differential that includes anatomic, genetic and hormonal causes. . Includes physiologic delay, karotype abnormalities, congenital malformations as well as all of the causes of 2ndary amenorrhea.
Key questions include: 1. Secondary sexual characteristics present? 2. Level of gonadotropins (FSH/LH) 3. Uterus present? 4. Karyotype XX, Xo or XY 5. Patent outflow tract?
Reference: Primary Amenorrhea: workup
Constitutional Delay Exercise, Stress Anorexia Chronic illness Kallmann syndrome (lack of GnRH) CNS tumor
MASTER-HUNTER, Am Fam Physician. 2006 Apr Secondary amenorrhea: differential diagnosis In order of frequency: 1. Pregnancy (by far most common) 2. Polycystic ovarian syndrome (PCOS) & chronic anovulation due to obestiy (40% of non-pregnant) 3. Hypothalamic amenorrhea (weight loss / exercise) (35%) 4. Hyperprolactinemia (20%, not incl brst feeding) – Breastfeeding – Hypothyroid – Prolactinoma – Neuroleptic meds 5. Asherman's syndrome <5% 6. Premature ovarian failure <5%
Breakdown by Compartment Functional Hypothalamic: Hypothalamus (Exercise, thin, stress, illness
Pituitary Hyperprolactinemia: Pituitary adenoma, hypothyroid, Low estrogen neuroleptics, brst feeding
Premature Ovarian Failure Ovary Obesity/Insulin Resistance PCOS
Uterus Pregnant Normal estrogen Asherman’s Syndrome Progestin IUD, implant, DMPA Hypothalamic amenorrhea “Hypogonadotropic hypogonadism” Stress, low body weight/fat, low calorie intake, severe systemic illness alters the GnRH pulsatility of the hypothalamus (via increased CRH)
Low FSH, LH no ovulation, low estrogen state b/c low FSH Worry re: bone health Treat: underlying cause, replace estrogen (OCP) Short Hike: Pololu Valley
Pololu valley—end of the highway past Hawi 25 minutes down to black sand beach Can continue further to next valley
Hyperprolactinemia causes
Pituitary adenoma: Micro (<1cm) or Macro (>1cm). Secrete prolactin. Hypothyroid: Increased TRH stimulates prolactin secretion Neuroleptics: blocks dopamine which increases prolactin Breast feeding (and nipple stim) Hyperprolactinemia Similar presentation as Hypothalamic: “Hypogonadotropic hypogonadism” High prolactin alters the GnRH pulsatility of the hypothalamus
Low FSH, LH no ovulation, low estrogen state b/c low FSH Galactorrhea not a reliable sign—many do not have it. Worry re: bone health, macroadenoma causing visual impairment
Pituitary adenoma Level of prolactin generally proportional to size (<1cm=<200 ng/ml) Microadenomas: little risk of visual effects, can be treated conservatively or expectantly, Macroadenomas require treatment to prevent visual effects Get MRI if prolactin >100 or HA or visual field defects (some say MRI for all with no other known reason for elevation eg meds, nipple stim, hypothyroid) Treatment: dopamine ant agonist: decreases secretion and size of adenoma Pituitary adenoma treatment
Microadenoma: – Old way: Bromocriptine was the only dopamine antagonist available and poorly tolerated so gave OCP for menstrual regulation and to preserve bone. Reserved bromo for galactorrhea and pregnancy. – Now: Cabergoline--few side effectsfirst line treatment for symptomatic hyperprolactinemia and infertility. Give OCP if can’t tolerate (to protect bone). Macroadenoma-always treat w dopa agonists, possible surgery
Reference: hyperprolactinemia
Drugs that can cause hyperprolactinemia (partial list) – Antipsychotics (haloperidol, chlorpromazine, fluphenazine,many others); Antiemetic (Metoclopramide); Opioids (Methadone) Treatment prolactinoma: Cabergoline (dopa agonist) – Start low to minimize side effects: 0.25 mg twice a week or 0.5 mg once a week. – Increase slowly titrating to prolactin level up to 1.5 mg twice weekly. (Caution: Higher doses assoc with valvuloplasty) – Main side effect=nausea (can give intravag) – May be able to decrease or dc after 1-3 yrs but often can recur Premature ovarian failure/ primary ovarian insufficiency . Hypergonadotropic hypogonadism: . Diagnosis made if repeated FSH level >30, <40 years old
. Etiology: . Karyotype abnormality (X0, mosaic X0, fragile X) . Ovarian damage (chemo, xrt, surgery) . Auto-immune . Unknown in >50% . Worry: Low estrogen state OCP to prevent osteoporosis, treat hot flashes
. Infertility: egg donor, adoption
Case 2 A 28 yo woman reports very heavy periods about every 5 months since menarche. LMP 4 months ago -PMH significant for HTN, on no meds -Had one child at age 25, required clomiphene to become pregnant, pregnancy complicated by gestational diabetes -On further questioning, has had to wax her upper lip and chin for many years for “stubborn hair” and has acne For this patient, what additional testing is required to diagnose PCOS?
a. Ultrasound (28 yo heavy periods every 5 months since b. Total testosterone menarche, hirsutism, h/o infertility, h/o c. DHEA-S GDM) d. LH/FSH ratio e. All of the above f. None of the above
28 yo heavy periods every 5 Case 2 months since menarche, hirsutism, h/o infertility, h/o GDM
How would you classify her bleeding pattern? Physiologically, what causes this type of bleeding pattern? What is the differential? Pathophysiology: Anovulatory Bleeding Bricks & Mortar Estrogen=Bricks, build endometrium Progesterone (P) =Mortar, stabilize it, only have P if ovulate Normal menses: withdrawal of P causes wall to fall down, all at once (orderly bleed) Anovulation: No P so when wall grows too tall, it falls. Bleed is heavy because wall is tall. Bricks can also fall intermittently & incompletely ie irregularly irregular
PCOS
Affects 4-12% of women of reproductive age Associated with obesity (50%) and insulin resistance (45% with abn GTT) A common cause of infertility; once pregnant, higher risk of Sab, GDM Increased risk of: diabetes, endometrial cancer, cardiovascular disease, sleep apnea, lipid abnormalities, nonalcoholic steatohepatitis, metabolic syndrome, mood disorders, eating disorders. Clinical features Oligomenorrhea 30-50% Amenorrhea 20-50% Hirsutism 65-70% Polycystic ovary 80% Insulin resistance 30-70% Acne 27-35% Alopecia 3-5% Infertility 20-75% Overweight 40-85%
Pathophysiology Risk of Anovulation, Endometrial Subfertility amenorrhea hyperplasia/cancer
Estrogen Failed growth of without Dominant Follicle Progesterone Increased circulating LH Sex Hormone Free Genetics Binding Globuin Androgen Obesity Lifestyle Androgen Circulating production Insulin Hirsutism, Acne Acanthosis T2DM, nigracans CVD PCOS diagnosis 2 of the following 3: 1. Hyperandrogenism (clinical or biochemical) 2. Oligo- or anovulation 3. Polycystic ovaries (by ultrasound)
AND: Absence of pituitary or adrenal disease (eg nonclassic congenital adrenal hyperplasia, cushings, adrenal tumor)
Many can be diagnosed with history and PE alone (no labs, no sono)
Rotterdam criteria, confirmed by NIH consensus conference 2012
Rule out other diagnoses
1. Rule out other causes of amenorrhea/irregular Bleeding (we do routinely)
. Pregnancy pregnancy test . Hypothyroidism TSH . Hyperprolactinemia prolactin . (Premature Ovarian failure FSH (only if suspected eg has hot flushes and prolonged amenorrhea))
2. Rule out other causes of hyperandrogenism in select patients Rule out other diagnoses 1. Rule out other causes of amenorrhea/irregular Bleeding (we do routinely) 2. Rule out other causes of hyperandrogenism in select patients o Ashkenazi Jew, Hispanic + FH of infertility or hirsutism: non-classic congenital adrenal hyperplasia 17-hydroxyprogesterone o Signs of virulization (clitoromegaly, deep voice, rapid hirsutism, male balding): o Ovarian tumor total testosterone >200 g/dl o Adrenal tumor DHEA-S > 800 mcg/dl o Signs of Cushings syndrome (wide purplish striae, proximal muscle weakness) 24 hr urine cortisol
What’s in a Name?
NIH consensus panel 2012: “We believe the name “PCOS” is a distraction…. The name focuses on polycystic ovarian morphology which is neither necessary nor sufficient to diagnose the syndrome
It is time to expeditiously assign a name that reflects the complex metabolic, hypothalamic, pituitary, ovarian and adrenal interactions that characterize the syndrome—and their reproductive implications. Menstrual Dysfunction Oligo or amenorrhea – Typically begins in the peripubertal period – Periods typically very heavy with spotting between
Since no ovulation—no progesterone
Chronic unopposed estrogen stimulation of the endometrium leads to – Intermittent breakthrough bleeding – Heavy periods – Endometrial hyperplasia and/or cancer (3x increased risk) • low threshold to do EMB after ?5-8 years of untreated chronic anovulation, even in young women • Need to induce at least 4 periods per year to prevent
Hyperandrogenism
Most women have BOTH clinical and biochemical hyperandrogenism – Clinical: Hirsutism, acne – Chemical: Elevated total testosterone and/or DHEA-S. (Labs not necessary for diagnosis however many consultants will want them) Should not have virulization: rapid onset of hirsutism, increased muscle mass, deepening voice, clitoromegaly (search for underlying androgen producing neoplasm with DHEA-S and Total-T) Hirsutism: don’t just look, ask about shaving, plucking
Classic polycystic ovaries: >12 follicles in one ovary NOT SPECIFIC for PCOS. Can be seen in normally cycling women No need for u/s if has other 2 criteria Other TESTING?
LH/FSH ratio —No longer recommended, not sensitive or specific Tests of insulin resistance (not recommended, no reliable tests available, not sensitive or specific) Testosterone/DHEA-S—get if oligomenorrhea but no clinical signs of hyperandrogenism. Pelvic ultrasound: Get if has 1 of oligomenorrhea or hyperandrogenism (clinical or chemical)
Note: other tests (fasting glucose, oral GTT, lipids) are recommended to detect complications of PCOS but these are not necessary for diagnosis
For this patient, what additional testing is required to diagnose PCOS? a. Ultrasound (28 yo heavy periods every 5 months since b. Total testosterone menarche, hirsutism, c. DHEA-S h/o infertility, h/o d. LH/FSH ratio GDM) e. All of the above f. None of the above Meets diagnostic criteria with oligomenorrhea plus clinical hyperandrogenism Aims of managing PCOS Manage the presenting problem(s). Infertility Hirsutism Oligo/amenorrhoea Manage longterm risk DM CVD Endometrial hyperplasia and ca
Don’t forget contraception if not ready to conceive now! High risk pregnancies so want to plan them!
Get pregnant #1 WEIGHT LOSS Hirsutism/Acne Contraception (if ovulation Weight resumes) Loss Regulate Decrease risk for menses DM/ CVD
Prevent Endometrial Cancer #1 WEIGHT LOSS
Weight loss, Weight loss, Weight loss!
Even modest weight loss (5 to 10 percent reduction in body weight) may result in restoration of normal ovulatory cycles – If ovulatory: resolution of abnormal menses, infertility, hyperandrogenism and prevention of endometrial cancer Normalizes glucose metabolism and decreases risk of long term complications (DM, CVD)
#2 OCP Get pregnant Hirsutism/Acne Contraception
OCP (or pill/patch) Regulate Decrease risk for menses DM/ CVD
Prevent Endometrial Cancer #2 OCP
Combination OCP (patch or ring) first line treatment when fertility not desired – Regular, light, withdrawal bleeds – Prevention of endometrial hyperplasia – Decreases hirsutism via: • Decrease LH decrease androgen from ovary • Increase sex-hormone binding globulin decreases free testosterone – Caution DVT risk: BMI>30 + age>40
If OCP contraindicated progestin only method, will need separate treatment for hirsutism
Hirsutism (and acne)
Need 6 month OCP trial to determine if effective (see prescribing guide)
Decrease testosterone action: if OCP fail or not OCP candidate: spironolactone (caution—it’s a teratogen so need contraception)
Mechanical: hair removal
Decrease growth of hair: Vaniqa cream (eflornithine hydrochloride) (only works while taking it, not reliably covered by insurance)
What about metformin? Not effective for decreasing hirsutism Metformin? #4 (after wt loss, ocp, progestin only): – May reduce insulin levels, reduce ovarian androgens – Allows ovulation in ~50% with PCOS – Unknown if it protects endometrium (need to prove ovulation with D21 progesterone) – Despite lower androgen levels, no change in hirsutism – Lots of GI side effects
Metformin?
May be reasons to use it …. Improved weight loss, esp in obese women (~10% decrease BMI in 6 mos)
Prevent T2DM? ADA says consider in BMI>35, <60yo and impaired fasting and abnormal GTT. (Diet and exercise more effective) – Esp beneficial in women w prior GDM – Is it safe for many many years of use? No long term RCT’s looking at safety – Could consider short term use ie during reproductive years Reference: Prescribing Guide PCOS: OCP
OCP: 2nd line treatment (after wt loss). For higher risk VTE (bmi>30 or age>40), choose ocp with one of original progestins ie norethindrone If not higher risk VTE: choose OCP with minimal androgenicity: gestodene, norgestimate, drosperinone
Reference: Prescribing Guide Hirsutism Spironolactone : for hirsutism not responsive to OCP (or can’t take ocp): – 50 to 100 mg twice a day. – Caution hyperkalemia, dehydration, somnolence, teratogen (need reliable contraception). Eflornithine cream 13.9% (Vaniqa) – Inhibits hair growth (not a depilatory), must use indefinitely to prevent regrowth. – 32% had marked improvement – Results take 6-8 wk; if stop cream, regrowth in 8 wks Reference: Prescribing Guide PCOS: Progestins Progestin contraception: Can’t take OCP – Mirena IUD, Implant, DMPA (caution with DMPA: 1 yr to return to fertility) – “Mini-pill”: norethindrone daily – Achieve endometrial protection but not treatment of hirsutism:
Cyclic Progestin: Don’t want contraception but need endometrial protection – Induce withdrawal bleed every 2-3 months (4 bleeds per year to prevent cancer) – Provera 10 mg daily for 10 days
Reference: Prescribing Guide PCOS: Metformin Third line treatment: induces ovulation in ~50%, lots of side effects but does improve wt loss in obese women May not protect endometrium, may not improve hirsutism Dose goal is 500 mg tid or 850 bid with meals. Start 500 qd with meal and increase by 500mg every 1-2 wks. Up to 6 months for ovulation to occur Confirm ovulation with day 21 Infertility – Weight loss, weight loss, weight loss – Treatment of choice: Clomid. 80% ovulate, 33% pregnancy rate – Metformin? • Metformin alone no better than placebo for live birth rate. Clomid plus metformin no better than Clomid alone. • Often use if unable to induce ovulation with Clomid alone – Laparoscopic ovarian diathermy – Gonadotropin ovarian stimulation (high rate multiples, risk for ovarian hyperstimulation) –IVF
Laparoscopic ovarian diathermy?
Destroy ovarian cortex (theca cells decreased androgens increased FSH normal follicular developmentovulation Use in PCOS unresponsive to clomid and clomid+metformin (~30%) As effective and cheaper than gonadotropin therapy with fewer multiple gestations – ~50% ovulate; 37% live birth in 12 mos
Farquhar, Cochrane, 2012 Reduce T2DM & CV risks
10-20% will develop Type 2 DM by middle age – Risk greatest if obese, FH of DM + PCOS – PCOS alone (without obesity) independent risk factor for DM: 2-5 fold increase
Undiagnosed DM in up to 10% of those with PCOS important to diagnose pre-pregnancy to optimize pregnancy outcomes
Great opportunity for lifestyle change, especially if desiring pregnancy: – Weight Loss – Nutrition counselling –Exercise
Reduce T2DM & CV risks
Recommendations (ACOG, other orgs) – BP, BMI each visit; fasting lipids at diagnosis – 2 hour OGTT q 2 yrs • more sensitive for impaired glucose tolerance than fasting glucose • If abnormal: screen annually with FBG + HBA1C to detect T2DM – Consider Metformin if impaired glucose tolerance and obese, h/o GDM – Pregnancy planning: contraception until ready, prenatal vitamins, remove teratogens, optimize health Conclusions: PCOS
Diagnosis: 2 of 3 of oligoovulation, hyperandrogenism, polycystic ovaries
Rule out other causes amenorrhea: Upreg, TSH, PLN
Weight loss prevents and/or corrects all short and long term issues
Low androgenic OCP’s mainstay for women not desiring fertility
Long term issues: Screen for impaired glu tolerance, CV disease RFs, low threshold for EMB, induce bleed with OCP or progestins at least quarterly
Asherman’s Syndrome
• Excessive uterine scarring and loss of basalis of endometrium • Typically D&C PLUS infection or hysteroscopic surgery • D&C alone not typically associated (eg induced abortions)
• Only scenario in which you ovulate without menses therefore have molinimal sx (sx of ovulation) • Diagnose: failure to bleed after E plus P (can’t form endometrium); hysteroscopy to confirm. • Treatment: Hysteroscopic lysis of adhesions Back to the differential…
In order of frequency: 1. Pregnancy (by far most common) Upreg 2. Polycystic ovarian syndrome (PCOS) & chronic anovulation due to obestity (40% of non-pregnant) 3. Hypothalamic amenorrhea (weight loss / exercise) (35%) 4. Hyperprolactinemia (20%, not incl brst feeding) – Breastfeeding Prolactin – Hypothyroid TSH – Prolactinoma – Neuroleptic meds 5. Asherman's syndrome <5% 6. Premature ovarian failure <5% FSH
Step 1 Amenorrhea Work-up
Always: Urine pregnancy test. If Neg: TSH & PLN If hot flashes: FSH How can we distinguish between a 35 yo with … Hypothalamic amenorrhea (low estrogen state) PCOS in a normal weight woman who does not have hirsutism (normal estrogen) Premature ovarian failure but no hot flashes (low estrogen) FSH will be high Asherman’s Syndrome (normal estrogen)
Step 2: does she have estrogen (bricks)?
Challenge tests
Progestin challenge test (10 mg Provera x 10days) determines if endogenous estrogen is present (ie does she have bricks?) – Distinguishes hypothalamic amenorrhea (no bleeding or just spots) from PCOS and obesity induced anovulation (full withdrawal bleed) – serum estradiol level is not diagnostic Estrogen challenge test (Premarin 2.5 mg qd x 3 wks then Provera x 10 days) distinguishes hypothalamic amenorrhea (full withdrawal bleed) from Asherman’s (no bleeding or just spots) (ie can she make bricks, and is the outflow tract patent?) Stepwise Diagnosis Obtain HCG History of First Uterine Evaluate for negative Surgery Asherman’s Check Prolactin, TSH, +/-FSH TSH, FSH, FSH High Prolactin High TSH Prolactin Normal high Obese or clinical Rule out Abnormally thin hyperandrogenism Primary thyroid, hypothyroidism drugs, consider Selectively test for other causes (tumor, adrenal MRI Functional Ovarian hyperplasia, cushing) hypothalamic Failure amenorrhea Prolactinoma PCOS
2 visit amenorrhea workup
1. Visit 1: Good medication history, Upreg, TSH, PLN, FSH (unless you suspect PCOS by phenotype), and progestin challenge. 2. Visit 2: Get results and begin treatment. This will diagnose vast majority of cases 3. Visit 3-estrogen challenge--only necessary if progestin challenge negative and labs normal (leaving you with Asherman’s vs hypothalamic). Q1: In addition to a urine pregnancy test and TSH, which of the following is the most appropriate test to obtain at this time? A 26 yo P0 with 1. Prolactin previously normal periods now reports 2. FSH no period for 5 3. Total T + DHEAS months. She is normal weight and 4. Transvaginal Ultrasound is not on any 5. All of the above medications. She denies hot flashes. 6. None of the above
Recap: Amenorrhea Treatment 1. PCOS—Weight loss and protect the endometrium! (from hyperplasia due to unopposed E2) combined contraceptives, progestin. OCP also treat hirsutism. 2. Obesity induced anovulation same 3. Hyperprolactinemia due to microadenoma Cabergoline (OCP’s if can’t tolerate to protect bone) 4. Functional hypothalamic amenorrhea-- protect the bones! (from lack of E2) estrogen containing contraceptives 5. Premature ovarian failure same 6. Asherman’s syndrome Hysteroscopy if desires pregnancy Hike: White Road—Upper Hamakua Ditch Trail
Kapu?? Very muddy/wet 2 miles to cliff Extremely lush, lots of birds singing End of White Road—on left as you leave last Waimea subdivision Essentials of Women’s Health Hapuna Beach Prince Hotel, Hawaii July 8, 2014 Updated Guidelines for Managing Menopausal Symptoms
Michael S. Policar, MD, MPH Clinical Professor of Ob,Gyn, & RS UCSF School of Medicine [email protected]
• There are no relevant financial relationships with any commercial interests to disclose Key Points: NAMS 2007, 2008, 2010, 2012 Position Statement on Hormone Therapy
The 2012 Hormone Position Statement of The North American Menopause Society. Menopause 2012; 19 (3): 257‐271
Available at: menopause.org
NAMS Definitions
Acronym Full name ET Estrogen (E) therapy EPT Combined E+P therapy HT Hormone therapy (ET, EPT) MHT Menopausal hormone therapy Progestogen Progesterone or progestin (P) CC‐EPT Continuous‐combined E+P therapy CS‐EPT Continuous‐sequential E+P therapy
NAMS position statement. Menopause 2007. Abbreviations/Definitions
Abbreviation Definition EEstrogen
E2 Estradiol CEE Conjugated Equine Estrogen PProgesterone PProgestin P Progestogen (refers to either progesterone or progestin)
Act 1
Let’s Get This Out of the Way….
The WHI Re-analyzed Women’s Health Initiative (WHI)
• 1993‐2005: RCT with 17,000 women • Postmenopausal women 50‐79 years old – 33%: 50‐59 yrs old; 45%: 60‐69 yo; 22% 70‐79 yo – Average age: 64 years old • End points – Primary prevention of MI and stroke – Hip fracture, various cancers • Treatment arms – If uterus: CC‐EPT (CEE+MPA) vs. placebo – If no uterus: ET (CEE) vs. placebo
WHI: EPT Arm Study Results Released July 2002: Findings after 5.2 years
Event RR Attributable Attributable Number needed to Risk /10K/yr Benefit/ 10K/yr harm or benefit/ year Heart attack 1.29 7 1,100 Stroke 1.41 8 1,200 Breast CA 1.26 8 1,300 TE event 2.11 18 600 Colorectal 0.63 6 1,700 cancer Hip fractures 0.66 5 2,000 Discontinued early, as “risks greater than benefits” WHI : ET‐Only Study Arm Released 2004: Findings after 7 years
Outcome Change vs. Placebo Coronary heart disease No difference in risk Breast cancer No difference in risk Stroke Increased risk Hip fractures Decreased risk Dementia, cognitive change Trend toward increased (> 65 years old)
Should the WHI be used to evaluate the safety and efficacy of EPT in treating women with menopausal symptoms?
The Women’s Health Initiative – Was a drug study of the effect of hormones on CVD, cancer, fractures, and memory in older women (mainly in 60s, long post‐menopausal) – Was not a menopause study… •Only 3.5% subjects were “early menopause” •Excluded symptomatic menopausal women WHI: HT and Risk of CV Disease by Age and Years Since Menopause
Roussow JE. JAMA. 2007: Combined secondary analysis Death from Age at HT initiation Heart attack Stroke any cause 50–59 years ↓ 7% ↑ 13% ↓ 30% 60–69 years ↓ 2% ↑ 50% ↑ 5% 70–79 years ↑ 26% ↑ 21% ↑ 14%
“Women who initiated HT closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause, but this trend test did not meet our criterion* for statistical significance.” *Statistically significant defined as p<0.01.
WHI reanalysis 2008 HT and CVD: The Unified Hypothesis
Phillips LS, Langer RD, WHI Postmenopausal hormone 2004 therapy: critical reappraisal and a unified hypothesis. Fertility and Sterility 2005; 83:558‐66 HT & Breast Cancer
• EPT use >4‐5 years increased breast cancer risk – Increased absolute risk of EPT in WHI: “rare” – 4‐6 additional cases/10,000/yr of EPT for ≥ 5 yrs • Estrogen only regimens – WHI ET trial showed no increased risk after 7.1 yrs • 6 fewer cases/10,000 women/yr of ET use – Other studies showed that ET for < 5 yrs has little or no impact on breast cancer risk
NAMS position statement. Menopause 2008.
Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions USPSTF 2012
• The USPSTF recommends against the use of – EPT for prevention of chronic conditions in postmenopausal women •Grade: D Recommendation – ET for the prevention of chronic conditions in postmenopausal women who have had a hysterectomy •Grade: D Recommendation Act 2 Therapeutic Interventions • Lifestyle changes • Botanicals and PhytoSERMs • Non-hormonal Rx medications • Hormone Therapy (MHT)
Symptoms of Estrogen Deficiency
• Vasomotor symptoms (VMS) hot flashes, night sweats • Neuro‐behavioral changes short term memory loss • Bone loss increased hip, vertibral fracture risk • Vaginal atrophy vaginal dryness, dyspareunia, urge incontinence VMS Characteristics
• Experienced by 75% percent of menopausal women – May start during the peri‐menopause – On average last for 2 years, then wane – 25% have hot flushes > 5 years after menopause • Ethnic and racial differences – More common in African‐American women – Less common in Chinese, Japanese women • Smoking and obesity are risk factors
Avis NE. Qual Life Res. 2004.
Management of VMS: Lifestyle Changes
• Cool room temperature • Dress in layers – Remove outer layers if warm • Exercise routinely, at least 3‐4 days/week • Avoid triggers – Hot and spicy foods – Cigarettes – Alcohol
North American Menopause Society. Menopause. 2004. Kronenberg F. Ann Intern Med. 2002. Huntley AL. Menopause. 2003. Botanicals and PhytoSERMs
Probably better than placebo • Black cohosh No evidence of efficacy • Soy isoflavones Not better than pbo • Red clover isoflavones Not better than pbo • Evening primrose oil Not better than pbo • Dong quai Not better (as monotx) • Ginseng Not better than pbo • Vitamin ENot better than pbo • Chasteberry (Vitex) No studies
Botanicals: Black Cohosh
• 14 trials reported, including 4 randomized trials using placebo and/or estrogen treatment arm – 3 of 4 RCTs found black cohosh to be beneficial – 12 of 14 trials reported some benefit – Currently, longest trial is 6 months • NIH, large, randomized, prospective, 2‐year trial – Preliminary data fail to show binding to E receptors – Binding to serotonin receptor noted Botanicals and PhytoSERMs
• Positive effect of black cohosh vs placebo – Improvement is less than with estrogen • Some of the impact is due to placebo effect, which is none‐the‐less therapeutic • Relatively little risk of adverse effects • Reasonable first‐line choice for women – With mild menopausal symptoms – Who feel strongly about avoiding hormones – Who are willing to use medications that are not “proven” effective by EBM or regulated by FDA
Non‐Hormonal Hot Flash Therapies
% treated patients % placebo patients with >50% ↓HF with >50% ↓HF Venlafaxine 54‐70% 30% Paroxitine 50‐76% 35‐57% Sertraline 40‐56% 21‐41% Gabapentin 46‐84% 27‐47% Escitalopram 55% 36%
J Clinical Oncology June, 2009 VMS: Paroxetine 7.5 mg
• Most commonly used SSRI is paroxitine • Brisdelle™ is the only FDA‐approved nonhormonal therapy to treat VMS • Most common adverse reactions vs. placebo – Headache – Fatigue/malaise/lethargy – Nausea/vomiting
VMS and Gabapentin (GBP)
Author Dose % HF % HF↓ % HF↓ ↓ GBP Placebo Estrogen Butt DA 300 mg TID 51% 26% NA 2008 Guttuso TJ 900 2700 mg 54% 31% NA 2003 Pandya KG 300 mg TID 46% 18% NA 2005 Reddy SY Up to 2400 mg 71% 54% 72% 2006 (800 mg TID) Prescription HT Options: ET and EPT
Oral Transdermal Intravaginal ET • Micronized estradiol • Patches • Creams • Conjugated equine • Gels • Intravaginal estrogens (CEE) • Emulsion tablet • Synthetic conjugated • Spray • Rings estrogens • Esterified estrogens • Estropipate • Estradiol acetate EPT • CC‐EPT • E+P combination • CS‐EPT patches
Hormone Therapy Regimens Month 1 Month 2 Estrogen Therapy (ET) Estrogen
Continuous combined (CC) EPT Estrogen Progestin
Continuous-sequential (CS) EPT Estrogen Progestin 14d Off for 14 d Progestin 14d Off for 14 d
Continuous-pulsed (CP) EPT
3d 3d Choice of HT Regimen
• If no uterus: ET only • If uterus present – Goal is to avoid vaginal bleeding entirely, or, at least, to make it predictable • Endometrial activity predicts bleeding pattern – Recent spontaneous or induced bleeding •Continuous sequential – No bleeding for >2‐3 cycles •Continuous combined – Consider LNG IUC (Mirena. Skyla)…off label use
Continuous P Better Than Sequential
• Oral and transdermal similar risk • Type of progestin similar risk • Con nuous EP →76% in endometrial cancer risk compared to background population • Sequential EPT – 69% risk elevation if P was used monthly – 276% risk elevation if P was used q 3‐mos
Jaakkola S. Obstet Gynecol 2009. Hormone Therapy Dosages
• Lowest effective ET dose (+ a low P dose if a uterus) consistent with individual treatment goals, benefits, and risks • Lower doses better tolerated, may have more favorable benefit‐risk ratio than standard doses • Additional local ET may be needed for persistent vaginal symptoms
NAMS position statement. Menopause 2008
Hormone Therapy Starting Dosages
• Lower daily doses typically used with systemic ET • 0.3 mg oral CE • 0.5 mg oral micronized 17ß‐estradiol • 0.014‐0.025 mg transdermal 17ß‐estradiol patch • Typical lowest doses of progestogen • 2.5 mg oral MPA • 0.1 mg oral norethindrone acetate • 0.5 mg oral drospirenone • 50‐100 mg oral micronized progesterone
NAMS position statement. Menopause 2008 Choice of Estrogens
• Start low dose transdermal or oral ET • If suboptimal response, modify by – Change the estrogen dose (upward) – Change the estrogen preparation – Change delivery systems (oral transdermal) – Consider an estrogen‐androgen combination • Injectable estrogen not recommended – Dosage equivalencies are not known – Estrogen cannot be discontinued easily
HT Routes of Administration
• No clear benefit of one route of administration for systemic ET • Non‐oral routes may offer both advantages and disadvantages compared with oral route • Transdermal ET may be associated with lower DVT risk than oral (observational data, not RCTs) • Local ET preferred when solely vaginal symptoms
NAMS position statement. Menopause 2008. “First Line” Use: Transdermal Estrogen
• Underlying medical conditions – History of DVT or PTE – High triglyceride levels – Gall bladder disease • Need for “steady state” drug release – Daily mood swings (especially while on oral HT) – Migraine headaches • Inability to use oral tablets – Stomach upset due to oral estrogen intake – Problems with taking a daily pill
Off‐Label EPT Uses
• Insufficient endometrial safety evidence to recommend off‐label use of… – Long‐cycle progestogen (every 3‐6 mo. for 12‐14 days) – Vaginal administration of progesterone – Levonorgestrel intrauterine system (Mirena®, Skyla®) – Low‐dose estrogen without progestogen • Close endometrial surveillance recommended
NAMS position statement. Menopause OCs in Perimenopause
▪ Low estrogen OCs often prescribed because they relieve menopausal symptoms and prevent pregnancy ▪ Other hormonal methods (patch, ring) may be helpful ▪ Progestin IUD and DMPA will not address vasomotor symptoms
NAMS position statement. Menopause 2007
Estrogen plus Testosterone
• Moderate to severe VMS not improved by estrogen alone • Not FDA labelled for improvement of libido • Products – Esterified estrogens 1.25 mg + methyltestosterone (MeT) 2.5 mg (Covaryx®XT) – Esterified estrogens 0.625 mg + MeT 1.25 mg (Covaryx® H.S.) – Previously branded as Estratest Bazedoxifene 10mg with CE 0.45 mg
• FDA approved tissue selective estrogen receptor modulator (SERM) plus CE • Progestin‐free • Reduces VMS frequency and severity • Prevents loss of bone mass • Treats VVA • No increase in endometrial hyperplasia • Amenorrhea, breast tenderness adverse event rates and overall safety similar to placebo
Taylor HS. Menopause; 2012 (19);4:479‐485.
Compounded Hormone Therapy
• The marketing of compounded hormonal therapy – Only bioidentical hormones are used – Combination of 2 or 3 estrogens is more “natural” – Dosage is tailored to the individual – More “pure” than commercial products – Safer delivery systems (no dyes, etc) • The reality – The same hormones are used in commercial and
compounded 17b‐E2 and progesterone Compounded Hormone Therapy
Compounded hormones will work about as well as commercial HT products, but…
• Value of adding E1 + E3 has not been evaluated • Progesterone skin cream is not absorbed • Compounded hormone doses are not standardized • Salivary hormone levels are not useful • FDA‐approved HT products will offer – Bioidentical hormones – Choice of delivery systems – Formulary coverage/ lower out‐of‐pocket costs
Act 3
Practice Guidelines How can your patient use these treatments safely, effectively, and conveniently? Individualization of Therapy
• An individual risk profile is essential • Each woman must be informed of her known risks • Acceptance of HT risks varies with primary indication • Benefit‐risk ratio more acceptable for short‐term symptom relief in a younger population • Long‐term HT or use in older women less acceptable • Women with premature menopause have increased symptoms and risks if not treated
NAMS position statement. Menopause 2008.
Treatment of Hot Flashes
• If mild symptoms, try lifestyle, CAM therapy • Indications for hormone therapy – Moderate or severe symptoms – Non‐hormonal treatments have failed – No interest in non‐hormonal therapy • Titrate estrogen dosage upward if needed • When estrogen can’t be used, offer – SSRI or SNRI – Gabapentin, clonidine, a‐methyldopa – Progestins alone • Attempt discontinuation after 2 years Treatment of Sleep/ Irritability Symptoms
• If mild symptoms – Lifestyle change, CAM therapy • If severe symptoms or no response to above – Low dose HT, then titrate upward – If mood swings, transdermal E preferred • Depression component, or no response to HT – SSRI; sedating best is (paroxetine) – SNRI; venlafaxine
Treatment: Sleep Hygiene
• Environment – Minimize noise and light – Room temperature; keep room cool • Diet – Less food late in the day – Less fluid before bed • Exercise; more regular and earlier in the day • Less caffeine consumption, none past noon • Less alcohol consumption Menopausal Vaginal Thinning
• Dryness • Discharge/vaginitis – Yellow creamy – Bloody • Spotting or bleeding • Dyspareunia – Decreased lubrication – Less vaginal elasticity – Skin irritation
Kingsberg SA. J Sex Med 2013.
HT and Vaginal Thinning
• OTC vaginal lubricants often improve vaginal dryness and painful intercourse…first line therapy – “Intimate lubricant” (with silicon) for sex – Vaginal moisturizer, for times other than sex • When HT is considered solely for this indication, local (not systemic) vaginal ET is recommended • Progestogen generally not indicated with low‐dose, local vaginal ET NAMS position statement. Menopause 2007. Ospemiphene (Osphena) • Nonhormonal selective estrogen‐receptor modulator (SERM) – Estrogen agonist/antagonist – Tissue selective effects. – Only SERM approved in the United States to treat moderate to severe dyspareunia • 60mg oral dose
HT & Sexual Function
• Treatment of moderate to severe vaginal atrophy with systemic ET/EPT or local ET can relieve dyspareunia • One oral systemic ET product FDA is approved for dyspareunia • HT is not recommended as sole treatment of other sexual function problems (e.g., diminished libido)
NAMS position statement. Menopause 2008. HT and “Quality of Life”
• RCTs and retrospective studies show that HT has no effect on “quality of life” measures • Many woman who wean from HT state that they “feel worse”…even after 20 years after menopause! • Conventional wisdom – In women who “feel better on/ worse off” of HT, continue low dose HT if few or no risk factors – When (& how often) to re‐attempt wean uncertain – Don’t start HT for solely for improving QOL
Act 4
The Finale HT Discontinuance and Symptom Recurrence
• After 2 years of use, recommend drug vacation to determine whether HT is still needed • Vasomotor symptom recurrence similar whether tapered or abrupt discontinuance – 25‐50% chance of symptoms recurring when HT discontinued • Decision to resume HT must be individualized
NAMS position statement. Menopause 2008.
Fertility and Sterility Aug 2012; 98 (2):313‐14
Endorsed by 15 medical associations
• Systemic HT is an acceptable option for healthy women up to age 59 or <10 years of menopause and who are bothered by moderate to severe menopausal symptoms • Individualization is key in the decision to use HT • Consider quality‐of‐life priorities as well as her personal risk factors Global Consensus Statement on Menopausal Hormone Therapy T. J. de Villiers et al, Climacteric 2013;16:203–204
• MHT is the most effective treatment for vasomotor symptoms • Benefits more likely to outweigh risks for symptomatic women < 60 y.o. or < 10 years after menopause • MHT is effective for prevention of osteoporosis‐related fractures in at‐risk women < 60 y.o. or < 10 years after menopause
Global Consensus Statement on MHT
• In women with premature ovarian insufficiency, systemic MHT is recommended at least until the average age of the natural menopause • The use of custom‐compounded bioidentical hormone therapy is not recommended • Current safety data do not support the use of MHT in breast cancer survivors Appendix
Global Consensus Statement on MHT
• The risk of VTE and ischemic stroke increases with oral MHT but the absolute risk is rare below age 60 years – Lower risk with transdermal therapy • Use of MHT is an individual decision in terms of quality of life, as well as personal risk factors such as age, time since menopause and the risk of VTE , stroke, ischemic heart disease and breast cancer Estrogen Dose Equivalents
17‐β‐estradiol (E2) is the only formulation considered bioidentical*
Estrogen Standard Low Dose Ultra‐Low Dose Conjugated equine 0.625 0.3 estrogen (CEE)
Oral E2 1mg 0.5mg
Transdermal E2 0.05mg 0.025mg 0.014 mg Ethinyl estradiol 5mcg 0.025mg
*2007 Position Statement of the Endocrine Society.
ET Oral Tablets
Standard Product Brand Low dose dose Conjugated equine 0.3, 0.45 Premarin 0.625 mg estrogen mg Conjugated estrogen Cenestin 0.3, 0.45 0.625 mg (synth) Enjuvia mg Menest Esterified estrogen 0.625 mg 0.3 mg Estratab ET Oral Tablets (continued)
Standard Product Brand Low dose dose Ogen Estropipate Ortho‐est 0.625 mnone Generic Estrace Micronized E 1.0 mg 0.5 mg 2 Generic Estradiol acetate Femtrace 0.9 mg 0.45 mg
ET Transdermal: Patch* Brand name Mg/24 hr Use/ wk Alora 0.025, 0.05, 0.075, 0.1 2 Esclim 0.025, 0.0375, 0.05, 0.075, 0.1 2 Estraderm 0.05, 0.1 2 Vivelle 0.05, 0.1 2 Vivelle‐Dot 0.025, 0.0375, 0.05, 0.075, 0.1 2 Climara 0.025, 0.0375,0.05, 0.06, 0.075, 0.1 1 Menostar 0.014 ☼ 1
* All contain 17B- estradiol only ☼ Indicated only for prevention of osteoporosis ET Transdermal: Gels, Emulsions, Sprays*
Brand Type mg/24 hr Use name 0.25, 0.5, 1 mg/ Divigel Gel 1 packet daily packet Elestrin Gel 0.87 gm pump 1 pump daily EstroGel Gel 1.25 gm pump 1 pump daily Estrasorb Emulsion 1.74 gm/ pouch 2 pouches daily Evamist Spray 1.53 mg/ spray 1 spray daily
* All contain 17B‐ estradiol only
Progesterone/ Progestin Products
Oral Progestin Equiv dose Available doses MPA 5‐10 mg 1.2, 2.5, 5, 10 mg Micronized 200‐300 mg 100, 200 mg progesterone Drospirenone 0.5 mg/d 0.5 mg/d Norethindrone 1.0 mg/d 0.5, 1.0 mg/d acetate Norethindrone 0.7‐1.0 mg/d 0.35 mg Norgestimate 0.09 mg 0.09 mg Norgestrel 150 mcg/d 150 mcg/d EPT Oral Tablets
Brand Estrogen Progestin Dosing Activella 17‐E2 1 mg NETA 0.5 mg Once daily oral Angeliq 17‐E2 1 mg Drosperinone 0.5 mg Once daily oral EE 5 g NETA 1 mg FemHRT Once daily oral EE 2.5 g NETA 0.5 mg Prefest 17‐ E2 1mg NGM 0.09 mg E 3 days, E+P 3 days Premphase CEE 0.625 MPA 5 mg Once daily oral 14 active mg (CS‐EPT) 14 placebo Prempro CEE MPA Once daily oral 28 active 0.625 mg 5.0 mg; 2.5 mg (CC‐EPT) 0.45 mg 2.5 mg 0.3 mg 1.5 mg
EPT Transdermal Patches
Estrogen Progestin Dosing 17‐E2 NETA Twice weekly CombiPatch 0.05 mg 0.14 0.05 mg 0.25 mg 17‐E2 LNG Once weekly Climara Pro 0.045 mg 0.015 mg Vaginal Estrogen Therapies Product Brand Dosage Dose Conjugated Premarin Daily, then 1‐3 0.625 mg/ gram estrogen cream cream time/wk 0.01% Daily, then 1‐3 Estradiol cream Estrace (0.1 mg/ gm) time/wk Estradiol vaginal Daily for 2 wks, Vagifem 25 micrograms tablet BIW Estradiol ring Estring 7.5 mcg/ 24 hrs Every 90 days 0.05 mg/d Estradiol ring* Femring Every 3 months 0.1 mg/d *Intended to be used as systemic HT
Topical Vaginal Estrogen
Composition Brand Name Dose and sig Vaginal cream Estrace® Vaginal Initial: 2.0‐4.0g/d for 1‐2 wk 17β‐Estradiol Cream Maintenance: 1.0g/d (0.1 mg/g) Vaginal cream Premarin® Vaginal 0.5‐2.0 g/d or twice/wk conjugated Cream (0.625 mg/g) Use lowest estrogens effective dose Vaginal ring Estring® Ring contains 2 mg 17β‐estradiol releases 7.5 mcg/d for 90 d Vaginal ring Femring® Systemic dose ring for 90 d Estradiol acetate (Systemic dose and 12.4mg releases 50mcg/d indication) 24.8mg releases 100mcg/d Vaginal tablet Vagifem® 10mcg Initial: 1 tablet/d for 2 wk Estradiol (25mcg no longer Maintenance: 1 tab 2x /wk hemihydrate available) Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Management of Diabetes Mellitus: A Primary Care Perspective
Robert B. Baron MD MS Professor and Associate Dean UCSF School of Medicine
Declaration of full disclosure: No conflict of interest
Screening for Diabetes 2014
. BMI ≥25 plus other risk factors Inactivity Low HDL or high TG First degree relative PCOS High-risk ethnicity Acanthosis nigricans Gestational DM Hx CVD HTN . Age 45
ADA Diabetes Care, 2014
1 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Diagnosis of Diabetes 2014
. A1C ≥ 6.5% (New, 2010) . FPG ≥ 126 mg/dl (7.0 mmol/L) . 2-h plasma glucose ≥ 200 during OGTT . Symptoms and random plasma glucose ≥200 mg/dl (11.1 mmol/L) . Need two separate measurements
ADA Diabetes Care, 2014
Advantages of HbA1c as a Diagnostic Test
. Non fasting . Lower intra-individual variation . HbA1c: 2% . FPG: 6.5% . 2 hour plasma glucose: 16-17%
2 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Diagnosis of Pre-Diabetes 2014
. 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)
ADA Diabetes Care, 2014
Risk of Pre-Diabetes 2014
. 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, 2014
3 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Treatment of Pre-Diabetes 2014
. Weight loss 7%; physical activity 150 min/week
. Metformin (but only metformin) may be considered, especially for those with BMI >35, age <60, and women with history of gestational DM
ADA Diabetes Care, 2014
2014 Practice Guidelines: ASA
. ASA: only in those at increased CV risk (10 year risk >10%. (Typically men over 50, women over 60 with other risk factors)
2009: . ASA: over age 40 and for those with other CHD risk factors
ADA Diabetes Care, 2014
4 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
2014 Practice Guidelines: HTN and Lipids and Tobacco
. BP: Goal less than 130 and less than 80
. LDL: Goal less than 70 (with CVD); less than 100 (without CVD)
. Don’t forget tobacco ADA Diabetes Care, 2014
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
120 140 p • BP 119 133 • CV events plus death 1.87% 2.09% .20 • Mortality 1.28% 1.19% .55 • Stroke 0.32% 0.53% .01 • Adverse events 3.3% 1.3% .001
In type 2 DM: treating to 120 mm Hg did not reduce the rate of composite fatal and non-fatal CV events
ACCORD, NEJM 2010
5 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Case 1
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
Case 1 Her glycemic goal should be:
1. HbA1c <6.0%
2. HbA1c <6.5%
3. HbA1c <7.0%
4. HbA1c <7.5%
5. HbA1c <8.0%
6 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Glycemic Control Update . 3 important trials ADVANCE ACCORD VA Diabetes Trial
ACCORD Trial
NIH RCT in DM 2, 10,251 patients, known CVD or risk factors, mean A1c 8.1%
Intensive vs. standard BP (120 v. 140) Lipid control (statins v. statins + fibrates Normalization v. standard BS control (A1c 6 v. 7-7.9) Outcomes: CV events. Also microvascular events, quality of life, others
ACCORD, NEJM, 2008
7 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
ACCORD trial
Intensive Standard n=5,128 n=5,123 HR (95% CI)
A1c achieved: 6.5% 7.5% - 1° outcome: 352 371 0.90 (0.78-1.04) Total mortality 5.0% 3.1% 1.22 (1.01-1.46) CVD mortality 2.6% 1.8% 1.35 (1.04-1.76) Hypoglycemia 10.5% 3.5% - Wt. gain>10 kg 27.8% 14.1% -
ACCORD Trial
Standard Intensive
Deaths 203 257 11/1000/y 14/1000/y
Number Needed to Harm: 333
February 2008 (after 3.5 years): NIH stops this arm of study
8 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
ACCORD Trial 5-Year Outcomes Additional follow-up of 1.5 years
All subjects treated to HbA1c of 7-7.9% during this period
Results: Mortality still higher in intensive group (7.6% vs 6.4%; HR 1.19)
ACCORD, NEJM, 2011
Outcome of Intensive Glucose Lowering in Type 2 DM
Meta-analysis of 13 RCTs in DM 2; 34,533 pts
RR All cause mortality 1.04 (0.91 – 1.19 CV death 1.11 (0.86 – 1.43) Non-fatal MI 0.85 (0.74 – 0.96)* Microalbuminuria 0.90 (0.85 – 0.96)* Severe hypoglycemia 2.33 (21.62 -3.36)*
* P <0.001 Boussageon, BMJ 2011
9 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Outcome of Intensive Glucose Lowering in Type 2 DM
Over five year period: NNT to prevent one MI 117-150
NNT to prevent one microalbuminuria 32- 142
NNT to cause one episode of severe hypoglycemia 15-52
Boussageon, BMJ 2011
ORIGEN Trial
RCT, 12,537 subjects; impaired FBS, IGT, or new diabetes, and high CV risk
Mean FBS 131 mg/dl
Glargine to FBS <95 mg/dl; 6.2 years
Results: No difference in CV outcomes
ORIGEN, NEJM, 2012
10 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials Study Microvasc CVD Mortality UKPDS DCCT / EDIC* ACCORD ADVANCE VADT
Kendall DM, Bergenstal RM. © International Diabetes Center 2009 Initial Trial UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Long Term Follow‐up Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024) * in T1DM
Glycemic Control Summary
. No consistent evidence that tight glycemic control reduces risk of CVD in DM 2 . Possible subgroups with benefit: shorter diabetes duration, no CVD . Strong evidence to support decrease in microvascular disease outcomes with more intensive glucose control . More hypoglycemia and weight gain with more intensive regimens
11 Robert Baron, MD, MS
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2014 Practice Guidelines: Glucose Control
. Goal A1C ≤7 for most . Goal A1C <6.5 for some: short duration, long life expectancy, and no CVD . Goal less stringent (≤8) for history of hypoglycemia, limited life expectancy, mico or macrovascular complications, comorbid conditions, and those in whom the goal is difficult to attain ADA Diabetes Care, 2014
Critically Ill patients? Meta-analysis of 29 RCTs (n=8,432 patients)
Mortality Rates Tight Usual RR (95% CI) Overall 21.6% 23.3% 0.93 (0.85-1.03) Very tight, ≤110 mg/dl 23.0% 25.2% 0.90 (0.77-10.4) Moderate, <150 mg/dl 17.3% 18.0% 0.99 (0.83-1.18) Medical ICU 26.9% 29.7% 0.92 (0.82-1.04) Surgical ICU 8.8% 10.8% 0.88 (0.63-1.22) Med-Surg ICU 26.1% 27.0% 0.95 (0.80-1.13)
12 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Glycemic Control Summary
. No consistent evidence that tight glucose control improves mortality in hospitalized patients.
2014 Practice Guidelines: Glucose Control in Hospital
. Critically ill: Goal 140 - 180. . IV protocol
. Non-critically ill: premeal <140 if can be done safely; random < 180. Less stringent if severe comorbidities . Scheduled subcu insulin with basal, nutritional, and correction components ADA Diabetes Care, 2014
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MANAGEMENT OF DIABETES
Case 1 Her glycemic goal should be:
1. HbA1c <6.0%
2. HbA1c <6.5%
3. HbA1c <7.0%
4. HbA1c <7.5%
5. HbA1c <8.0%
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MANAGEMENT OF DIABETES
In my practice, I have initiated: 1. Exenatide (Byetta™) or Liraglutide (Victoza™)
2. Sitagliptin (Januvia™) or Saxagliptin (Onglyza™)
3. Both exenatide and sitagliptin
4. Pramlintide (Symlin™)
5. All three of the above
6. None of the above
Case 2: 48 yo woman with DM, BMI 33, on diet and exercise and max dose metformin. HbA1C is now 8.5. Your next best step is:
1.
2. Begin a sulfonylurea
3. Begin pioglitizone
4. Begin NPH insulin or long-acting insulin analogue
5. Begin exenatide (Byetta™), liraglutide (Victoza™), sitagliptin (Januvia™) or saxagliptin (Onglyza™)
15 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Generic Oral Hypoglycemic Slide
Change from Drug A to B, C, or D
Add Drug A to B, or B to A
HgA1c Add Drug C
Add Drug D
Time
Metformin
Lowers A1C 1.5-2% Weight loss (0-2 kg) Lowers triglyceride and LDL; increases HDL No hypoglycemia No self monitoring Inexpensive Disadvantages: GI side effects, decreased B12 absorption, risk of lactic acidosis
16 Robert Baron, MD, MS
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Metformin: The Safest Hypoglycaemic Agent in Chronic Kidney Disease?
“There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared with other oral hypoglycaemic treatments.”
Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes. Cochrane Database Syst Rev 2010;4: CD002967.
Rosiglitazone vs Pioglitazone
Observational study, FDA, 227,571 Medicare patients, over 3 years.
Rosi/Pio HR MI 1.06 Stroke 1.27 CHF 1.25 Death 1.14 Composite 1.18
Number Needed to Harm with Rosiglitazone = 60 per year Graham et al, JAMA 2010
17 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Thiazolidinediones (TZD)
Lowers A1C 0.4-1.5% No hypoglycemia when used alone Other risks: osteoporosis, bladder cancer with pioglitazone, weight gain edema FDA lifted restrictions on rosiglitazone in November 2013 No hypoglycemia No self monitoring Preference for pioglitazone
Oral Agent “Failure” Why does this occur?
Changing HbA1c goals Compliance, side effects Wrong diagnosis (LADA--latent autoimmune diabetes in adults 10%) Stress, diabetogenic medications Postprandial hyperglycemia Natural progression of the disease
18 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Relative Contributions of Fasting and Postprandial Plasma Glucose to Total Glycemic Excursions as a Function of A1C
80 Postprandial hyperglycemia Fasting hyperglycemia
60
40 Contribution (%) 20
0 1 2 3 4 5 (<7.3) (7.3–8.4) (8.5–9.2) (9.3–10.2) (>10.2) A1C (%) Quintiles
Monnier L et al. Diabetes Care. 2003;26:881-885.
Natural History of Type 2 Diabetes
Obesity IFG* Diabetes Uncontrolled hyperglycemia
350 300 Post-meal 250 Glucose Glucose 200 Fasting (mg/dL) 150 Glucose 100 50 250 200 Insulin Resistance Relative 150 Function 100 (%) Insulin Level` 50 Beta-cell failure 0 -10-50 5 1015202530
*IFG = impaired fasting glucose Years of Diabetes
19 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Natural History of Type 2 Diabetes Biguanide
Lifestyle SU Insulin
350 300 Post-meal Glucose 250 Glucose (mg/dL) 200 Fasting Glucose 150 100 50 250 Relative 200 Insulin Resistance Function 150 (%) 100 50 Insulin Level Beta-cell failure 0 -10-50 5 1015202530 Years of Diabetes
Insulin Plus Oral Agents Introduction of insulin – Bedtime – Intermediate/Long-acting insulins • NPH, glargine, levemir • 10 units – Self-monitoring of blood glucose (hypoglycemia education)
Insulin plus other oral agent combinations (maintain effect on insulin sensitivity)
20 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
When to go to > 1 shot per day
HgA1c >7 Glucose in AM at goal but glucose before dinner >140 Options Add premeal lispro/aspart Add bid premixed insulin – 70/30, 75/25
Questions Continue metformin ? Sulfonylurea, ? Thiazolidinedione (mostly not)
Function of Insulin in Regimens
Meal coverage (carbohydrates)
Basal insulin
Correction of high blood sugar
21 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
INCRETINS
Gut factors that promote insulin secretion in response to nutrients
Major incretins: GLP-1, CCK, GIP
Oral Glucose Promotes More Insulin Release than IV Glucose - Indicating a Role for Incretins
22 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Incretin Drugs
GLP Agonists DPP IV Inhibitors – Exenatide – Sitagliptin – Liraglutide – Saxagliptin – Exenatide Lar – Vildagliptin – Semaglutide – Alogliptin – Aliglutide – Linagliptin – Taspoglutide – Dutogliptin – Lixsenatide – Metogliptin
23 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
A1C (%) Effect (change from baseline)
Placebo BID 5 mcg exenatide BID 10 mcg exenatide BID MET 0.1 -0.4 -0.8
SFU 0.1 -0.5 -0.9
MET+SFU 0.2 -0.6 -0.8
Changes in A1C from baseline vs placebo statistically significant
Weight (change from baseline) & Hypoglycemia
Placebo 5 mcg exenatide BID 10 mcg exenatide BID BID
Weight (kg) -1.4 -3.1 -4.2
Hypoglycemia (%) MET 5.3 4.5 5.3 SFU 3.3 14.4 35.7 MET + SFU 1.26 19.2 27.8
Open-label extension study to 90 weeks: persistence in weight loss and A1C
24 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Side Effects
GI – Nausea (44% vs 18% with placebo); incidence lessens over time; 3% dropout rate due to nausea – Vomiting (13% vs 4%) – Diarrhea (13% vs 6%)
Headache (9% vs 6%) Hypoglycemia (see previous slide)
Improvements in HbA1C With Initial Co-administration of Sitagliptin and Metformin
Mean Baseline HbA1C = 8.8% N=1091
Placebo
-0.5 Sita 100 mg QD
Met 500 mg BID -1.0 -0.8 Met 1000 mg BID (%)* -1.0
1C -1.5 Sita 50 mg BID + -1.3 Met 500 mg BID
HbA Sita 50 mg BID + -2.0 -1.6 Met 1000 mg BID
-2.5 -2.1
* Placebo-subtracted LS mean change form baseline at Week 24. Sita=sitagliptin; Met=metformin. Aschner P, et al. Oral presentation at the EASD 42nd Annual Meeting; 14-17 September 2006; Copenhagen.
25 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Sitagliptin – adverse reactions
Number of patients (%)
Sitagliptin Placebo
Monotherapy n = 443 n = 363
Nasopharyngitis 23 (5.2) 12 (3.3)
+ pioglitazone n = 175 n = 178
Upper resp. 11 (6.3) 6 (3.4) infection
Small increase in WBC – neutrophil count higher by 200 on Sitagliptin
No nausea or vomiting
No weight loss
SGLT2 Inhibitors Sodium-glucose cotransporter 2 Inhibitors Inhibit glucose reabsorption in renal proximal tubule (Canagliflozin, Dapagilflozin) Potential advantages Weight loss (2.5-4kg), low risk of hypoglycemia, reduced BP, lowers A!C about 1% Potential disadvantages Polyuria, electrolyte disorders, UTI, fungal genital infections, syncope, increased Cr, expensive
26 Robert Baron, MD, MS
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Natural History of Type 2 Diabetes
Incretins/Others ? Thiazolidinedione ? - Biguanide
Lifestyle SU Insulin
350 300 Post-meal Glucose 250 Glucose (mg/dL) 200 Fasting Glucose 150 100 50 250 Relative 200 Insulin Resistance Function 150 (%) 100 50 Insulin Level Beta-cell failure 0 -10-50 5 1015202530 Years of Diabetes
Drug Cost Comparison
Drug and Dose Cost/month
Glucose strips (2 per day) $66 Sulfonylurea Generic $4-14 Brand $50 Rapaglinide 2 mg tid $193 Acarbose 100 mg tid $88 Metformin 1000 bid Generic $4-32 Brand $161 Rosiglitazone 8 mg qd $266 Pioglitazone 45 mg/d $245 Sitagliptin/Saxagliptin $207/190 Exenatide 10 mcg/Liraglutide 1.2mg $271/280 Glargine, 45 U/d $150
24 hour fitness Center $35 YMCA $65
27 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Case 2: 48 yo woman with DM, BMI 33, on diet and exercise and max dose metformin. HbA1C is now 8.5. Your next best step is:
1.
2. Begin a sulfonylurea
3. Begin pioglitizone
4. Begin NPH insulin or long-acting insulin analogue
5. Begin exenatide (Byetta™), liraglutide (Victoza™), sitagliptin (Januvia™) or saxagliptin (Onglyza™)
28 Robert Baron, MD, MS
MANAGEMENT OF DIABETES
Conclusions
. Tight glycemic control not effective in lowering total mortality or CV mortality (but is effective at preventing microvascular complications)
. Many newer diabetes agents available, all with some side effects and higher costs…few with hard outcome data.
. Glucose control may be more important early in diabetes
. Good BP, lipid control, smoking cessation, and aspirin use is important throughout the diabetes life course
Conclusions
The best way to treat DM in the long term…
Don’t develop it in the first place.
29 Part 1: 1. Cervical or endometrial polyp removal 2. IUD removal 3. Vulvar biopsy (and vulvar lesions) 4. Endometrial biopsy (and interpretation of EMB results) Part 2: 1. Pessary placement 2. IUD insertion— Copper T and Mirena Part 3: 1. Nexplanon insertion 2. Manual uterine aspiration with cervical dilation
If you aren’t currently doing this, you should! Can remove cervical polyps and small (<2cm) endometrial polyps Equipment: 1. Ring forceps. 2. Silver nitrate sticks. 3. Optional: allis clamp
Typically well tolerated without anesthesia. Occasionally, twisting is painful and procedure should be done with sedation Clean with betadine If polyp on a stalk, grasp as high as possible with ring forceps and begin to twist in one direction. When meet resistance in that direction, twist other way. Do not pull. Continue twisting process until polyp has been removed. Cauterize base with silver nitrate (helps kill remaining cells) If polyp not on a stalk: Unlikely that ring forceps will grasp it. Try allis clamp to “chomp it off”. Cauterize base with silver nitrate Send to pathology.
Return
If you aren’t currently doing this, you should.
No training necessary!
Most important: offer other form of reliable contraception, if desired.
Equipment: Ring forceps. Cytology brush. If strings visible, ask pt to cough and pull quickly on strings as she coughs (this helps with the visceral feeling pt will have you remove it). If strings not visible: try to tease them out by twisting cytology brush within the endocervix.
Complications: none that I know of. String can break off or if IUD embedded you won’t be able to remove it. Occasionally it hurts to remove (usually not). Return Supplies: 1. Punch biopsy (4 or 5 mm) 2. 1% lidocaine 3. Insulin syringe (not PPD syringe) 4. Suture removal kit (pick‐ups and scissors) 5. Gauze/silver nitrate for hemostasis
1. Clean with betadine or alcohol 2. 1% lidocaine in insulin syringe (PPD needles have barbs!). Have her cough as you stab. This hurts a lot! 3. Twist punch on skin as pushing. Push fairly hard. Check intermittently to see if through skin. Easy to go very deep once you penetrate skin. 4. Once circumferentially cut, use pick‐ups to lift plug of tissue and cut off with scissors 5. Use pressure to stop bleeding. Silver nitrate if necessary but burns. Potential biopsy site
Potential biopsy site Potential biopsy site Potential biopsy site
Potential biopsy site
Return Supplies: 1. Ibuprofen (Pre‐procedure) 2. EMB pipelle 3. 1% lidocaine for 12:00 cervix tenaculum site 4. Tenaculum 5. Fox swabs/ silver nitrate for hemostasis
1. BME to check size, position of uterus 2. Clean cervix with betadine 3. Attempt passing pipelle without using tenaculum. Place pipelle just inside os, she bears down while you push. If it “pops” through the internal os, get your sample as noted below. If it doesn’t pass, you’ll need tenaculum. 4. Always give lidocaine at tenaculum site. Good evidence that it decreases pain of the procedure. 2‐3 cc 1% lidocaine to 12:00 anterior cervix to get a 1 cm white bleb (I like 22 gauge, 4 in spinal needle). Have her “cough it in”. 5. Tenaculum: 1 cm wide bite, slowly close. 6. Pull firmly back on tenaculum as you push pipelle through os. Tenaculum should move about 2 cm. 7. Once pipelle passes or “pops” through the internal os, push it gently up to fundus and then back it away from fundus by about 1 cm. Do not push hard against the fundus. Do not repeatedly touch the fundus. Touching fundus=painful. 8. Obtain suction by pulling the stylette all the way back 9. Move the pipelle up and down within the uterus (below the fundus) while twisting. Count to 10 out loud. Remove pipelle at 10 seconds. 10. Carefully plunge specimen into specimen cup without touching the pipelle to the formalin or sides of cup. 11. Check specimen adequacy by shaking formalin and looking for tissue pieces. 12. If adequate and uterus gritty: done. If not gritty or inadequate: do another pass. Ibuprofen when hits the door. Help her with breathing. No breath holding. Count to 10? Gives her control and a time frame. Tell her you’ll count to 10 during the biopsy and will stop at 10 (and do so!). If need to do another pass, ask permission—I’ve never had anyone say no (they don’t want to go through this again if insuff sample!) If she can’t tolerate, STOP. Offer another visit with ativan, or procedure under sedation, or ultrasound if post‐ menopausal (no evidence that intrauterine lidocaine is helpful)
If trouble passing pipelle, use different vectors of traction on the tenaculum (up, down, right, left). If still can’t pass it and she can tolerate, paracervical block can relax os (~6‐8 cc 1% lido or chloroprocaine at 4:00 and 8:00 vag ‐ cervical junction). Can also try os finder, small dilators or ultrasound guidance. If known to be anxious or if attempt and fail, give ativan for next attempt (if pt willing). Works wonders. If known to be atrophic or if fail to place, try again (if patient willing) after giving misoprostol 400 mcg buccal or vaginal, 30‐60 min prior “Secretory endometrium”? Ovulation has occurred. Rules out anovulation. Likely anatomic lesion. “ Proliferative endometrium”? Unopposed estrogen effect. Either anovulatory bleeding or first half of cycle. If premenopause: treat as for anovulation (hormonal methods). If post‐menopause, give progestin to prevent endometrial hyperplasia. “Plasma cells”? Chronic endometritis: treat with Doxy or Clinda for 2 wks
“Proliferative with stromal breakdown and karyorrhexis” ‐‐‐> Classic for anovulation. Prolonged unopposed estrogen effect. Treat as above for proliferative. “Benign endocervical cells, no endometrium.” ‐‐> Non‐diagnostic. Could be atrophy but without endometrium, can’t r/o neoplasia. If post‐menopausal: Ultrasound to check endometrial thickness. If >=5 mm, needs repeat attempt at sampling (EMB vs D&C). If pre‐menopausal: Repeat EMB. Consider misoprostol pre‐ treatment (400mcg buccal or vaginal) “Benign superficial fragmented endometrium. No intact glands or stroma. No hyperplasia or carcinoma. Suboptimal for evaluation” Either atrophy or insufficient sample. If atrophy suspected clinically: do not re‐sample. Observe or add vaginal premarin if vaginal sx. If bleeding persists/recurs‐‐> Ultrasound (if post‐meno). D&C if continued blding If atrophy NOT suspected clinically: Post‐meno: U/S. Pre‐ meno: resample
“Simple hyperplasia” 1% chance of progression to carcinoma. Treat with progestin (Mirena is best). Rebiopsy 3‐6 months. Follow closely. “Simple hyperplasia with atypia” Atypia is most important risk indicator for cancer progression. 8% chance of progression to Ca. Progestin (prefer Mirena) or hysterectomy (esp if difficult to follow or biopsies difficult or not tolerated.) Biopsy q3‐6 mos until 2 normal. Complex, atypical hyperplasia 27% chance of progression to Ca. And, 30‐50% already have co‐existing carcinoma. Recommend hysterectomy. If refuse, do D&C to rule‐out coexisting carcinoma. High dose progestin (Megase) or Mirena IUD. Biopsy q3‐6 months until 3 normal. Failure to revert to normal by 9 mos is assoc with progression.
Return
Start with these 3 types. Get multiple sizes and keep in office. If these don’t work, refer
Ring with support
For prolapse plus incontinence: Incontinence dish with support
Incontinence Ring with knob Fold it like taco and slide it in vagina. When you feel it reach top of vagina, use your index finger to tilt it up behind the pubic symphysis
Test correct size: 1. Have her valsalva—shouldn’t come out 2. Walk around—shouldn’t feel it 3. Urinate—should be able to F/u in 2 wks and 4 wks for careful vaginal exam to ensure no vaginal ulcerations
Tilting it up behind the symphysis
If post‐menopausal: always start premarin cream twice weekly one month prior to placement and continue while uses pessary (to prevent ulceration) Placement is trial and error. Guess a size and try it Can be tough to remove: Hook finger under ring, change angle to dislodge it from under symphysis, then pull out
Teach self removal and insertion at subsequent visit. If unable to do, see her q 6‐8 wks for removal, wash,
Return reinsert
Both require tenaculum Sounding recommended before insertion I use plastic emb pipelle Levonorgestrel can be placed without sterile gloves Copper has to be loaded sterilely Ibuprofen pre‐procedure IUD Sterile gloves to load IUD
Speculum TCu 380A Betadine swabs 1% lidocaine for 12:00 tenaculum site EMB pipelle (to sound) Tenaculum Long, sharp scissors to cut strings
Get all supplies set up (don’t forget scissors, don’t open the IUD yet) Prepare the patient: BME to check uterine position and size Betadine to cervix 2‐3 cc 1% lidocaine to 12:00 anterior cervix to get a 1 cm white bleb (I like 22 gauge spinal needle). Have her “cough it in”. Tenaculum: 1 cm wide bite, slowly close. YES, you must use a tenaculum! Teneculum straightens out the endometrial canal. Without it, increased chance of perforation or of placing IUD below the fundus. I prefer EMB pipelle to metal sound (disposable, less likely to perforate with it) Why sound? 1. Measure depth of the uterus (use this to set the blue “depth gauge” on the device 2. Check its position (retro, mid, anteflexed) 3. Most important: to ensure that the IUD will pass through the cervix (so you don’t waste an IUD).
3. Load the Copper T 1. Fully peel back package so IUD is sitting on top. 2. Put on sterile gloves. 3. Place the white plunger rod in the clear insertion tube— use care not to plunge the IUD out the top of the tube!
4. Push ends of the arms of the T downward into the insertion tube. Hold the white plunger in place while you do this. Gently advance the loaded IUD into the uterine cavity. STOP when the blue depth‐gauge comes in contact with the cervix or when you reach fundus (light resistance is felt)
Hold the tenaculum and white plunger rod stationary, while partially withdrawing the insertion tube. This releases the Arms are down when inside inserter. arms of the Copper T. Withdrawing tube while holding inserter still allows arms to pop up and out. Unlike Mirena, this is done at fundus b/c arms swing lateral and up. Gently push the insertion tube up until you feel a slight resistance. Hold the white plunger rod stationary This step ensures placement high in the uterus
Gently and slowly withdraw the inserter tube and white insertion rod from the cervical canal until strings can be seen protruding from the cervical opening. Carefully trim strings to 3 cm using long scissors (short scissors can get caught on strings and pull out IUD)
Return Ibuprofen pre‐procedure IUD Sterile gloves to load IUD Speculum Betadine swabs 1% lidocaine for 12:00 tenaculum site EMB pipelle (to sound) Tenaculum Long, sharp scissors to cut strings Insertion tube IUD
Use EMB pipelle instead
sound
Position blue flange at the sounded length Alternatively: Push IUD up to fundus then withdraw 1.5 cm Arms are up while inside inserter. Pulling back blue tab releases the arms so they are initially straight up and then open laterally. Need space for this to occur which is why you need to be 1- 2 cm below the fundus.
The device has “memory” and if it has been inside the inserter too long, the arms tend to stay upright instead of bending laterally. Counting to 10 gives time for them to bend laterally and stay that way (prevents inadvertent removal of device as you withdraw inserter) Return Safe way of removing uterine contents Can be used for endometrial biopsy, early pregnancy loss, abortion, and management of septic abortion Highly effective Can be done in outpatient / ED setting There is generally no need to do sharp curettage after return Potential biopsy site
Potential biopsy site Interpretation of Clinical Research: Tricks of the Trade…
Douglas C. Bauer, MD University of California, San Francisco No disclosures
Tip #1: Always Ask “So What?”
• Surrogate endpoints vs. clinical endpoints • Statistically significant does not mean clinically significant – Examine effect size (relative risk, absolute risk, etc)
Page 1 Tip #2: When the Study is Positive…
• Five potential explanations – Cause-Effect (the goal, truth) – Bias (systematic error) – Chance (p-value) – Effect-cause (temporal relationship) – Confounding (third factor accounts for observed association) • Reporting the primary endpoint chosen before results known (trials.gov) • Between vs. within group comparisons
Tip #3: When the Study is Negative…
• Two potential explanations – There is no association (the goal, truth) – There is an association but the study did not detect it (underpowered, bad measurements) • Use confidence intervals to tell the difference – Example A: RR= 1.0 (CI: 0.2, 1.8) – Example B: RR= 1.0 (CI: 0.9, 1.1)
Page 2 Tip #4: Design Matters (1)
• Cross-sectional (single time point) –Cheap, easy –Reverse causation a concern • Case-control (subjects selected by knowing the outcome) –Reasonably cheap, easy –Selection of controls is key
#4 Design Matters (2) • Cohort (longitudinal) –More expensive, take time –Prospective (new data collected) or retrospective (previously collected) –Confounding always a concern • Trials (investigator decides who gets intervention) –Always expensive, challenging, ethical issues –Avoids confounding if randomized, blinded –Still susceptible to bias
Page 3 #4 Design Matters (3) • Meta-analysis (study level pooling) –Most useful when multiple conflicting studies. Poor quality a problem. –Observational studies vs. trials –Look for publication bias, heterogeneity • Meta-analysis (individual data pooling) –Horrendously difficult, but worth it –Allows uniform adjustment, subgroup analyses
Page 4 Diagnosis and Treatment of Common Thyroid Disorders
Douglas C. Bauer, MD UCSF Division of General Internal Medicine
No Disclosures
Page 1 Cases • 68 yr old female with new atrial fibrillation and no other findings except TSH=0.04, normal free T4 • 52 yr old female with 1 yr of fatigue and lassitude and no findings except TSH=9.0, nl free T4, anti-TPO positive • 45 yr old female, enlarged thyroid with dominant nodule since 1999, FNA benign. On T4 suppression ever since, TSH=0.1
Topics Covered • Rational use of thyroid tests • Subclinical thyroid disease • What can to wrong? –Too much –Too little –Too big • Screening for dysfunction and when to refer…
Page 2 Thyroid Tests: sTSH
• Very sensitive to circulating thyroid hormone levels • Excellent correlation with TRH stimulation (sTSH < 0.1) • Requires intact pituitary-hypothalamic axis; 4-6 weeks to equilibrate • Falsely low: severe illness, corticosteroids, dopamine • Normal range 0.5-4.4 mU/L (non-pregnant); $58
Page 3 Normal TSH in NHANEs • TSH values skewed upwards in elderly: Normal or disease? • NHANEs: >13,000 people 12 to 80+ years (Surks, JCEM 2007) – Exclude anyone with known thyroid disease or drugs that could effect TSH – Median TSH 1.39 mIU/L • 97.5th Percentile: < 60 around 4.0 mIU/L 60-69 up to 4.3 mIU/L 70-79 up to 5.9 mIU/L 80+ up to 7.5 mIU/L
Thyroid Tests: Free Thyroxine
• Measures unbound hormone • Replacing “index” assays • Gold standard: Equilibrium dialysis • Other immunoassays: Improving • Normal range, 9-24 pmol/L (non- pregnant); $64
Page 4 Are Both sTSH and Free T4 Necessary?
• American Thyroid Association says “Yes” • Others recommend sTSH first • Simultaneous ordering common in clinical practice • UCSF outpatient data (Bauer, Arch IM 2003) – Results when both tests ordered on the same specimen (N=3143) – Each test classified as low, normal or high
Diagnostic Redundancy of sTSH and Free T4
sTSH (mIU/L) < 0.5 0.5 – 5 > 5.5 < 9 4 16 49 Free T4 9 - 24 536 2024 309 (pmol/L) > 24 174 30 1
Page 5 Subclinical Thyroid Disease
• Subclinical hypothyroidism “Abnormally high sensitive TSH and normal thyroid hormone levels” • Subclinical hyperthyroidism “Abnormally low sensitive TSH and normal thyroid hormone levels”
Suggested Testing Strategy
• If sTSH is normal, STOP • If sTSH is low, measure T4, consider T3 • If sTSH is high, measure T4, consider TPO antibodies
Page 6 Thyroid Antibodies
• Anti-thyroperoxidase, TPO (titer<100, $78) –Similar to “anti-microsomal” –Most sensitive thyroid autoantibody –Specificity a problem • TSH receptor antibody (absent, $112) –Causes Grave’s disease –Rarely found in normal individuals
Thyroid Scans • Technetium 99 ($450) –Low radiation, quick –Useful for nodules in some circumstances –Useful to determine cause of hyperthyroidism • High uptake: Grave’s, toxic nodule • Low uptake: thyroiditis, thyroxine use
Page 7 Hyperthyroidism: Etiology
• Iatrogenic –Over replacement (30-50% given rx) –Suppression of CA, goiters, and nodules • Autoimmune (Grave’s disease) –Thyroid stimulating autoantibodies • Autonomous nodule(s) –Usually T4, occasionally T3 • TSH secreting tumors (rare)
Hyperthyroidism: Prevalence • Population based prevalence of suppressed TSH:
Author age men women Bagchi >55 1.8% 2.7% Falkenberg >60 1.9% Parle >60 5.5 6.3% Bauer >55 5.8%
Page 8 Crook’s Index*
Symptom/Sign Present Absent Palpitation +2 0 Cold prefer. +5 0 Hyperkinetic +4 -2 Weight loss +3 0 Lid lag +1 0
*hyperthyroid if 10 or more
Page 9 Hyperthyroidism in the Elderly
• Weight loss, palpitations, and nervousness less common • Tachycardia, exophthalmos, tremor less common • Atrial fibrillation more common • 8-10% are asymptomatic
Subclinical Hyperthyroidism: Cardiac Effects
• Shortened systolic time intervals –Clinical significance uncertain • Reduced exercise tolerance • Increased incidence of atrial fibrillation (Swain, Jama 1994) –Prospective cohort, N = 2000 –3-fold increase if sTSH < 0.1
Page 10 Subclinical Hyperthyroidism: Skeletal Effects
• Florid hyperthyroidism causes fractures • Effect on BMD, bone loss controversial • Increased fracture risk (Bauer, Ann IM 2001) - Prospective study, 9407 older women - TSH < 0.1 vs. normal - >3-fold increase in hip and vertebral fx. - Little effect on BMD • Mediated via accelerated bone turnover?
Subclinical Hyperthyroidism: Natural History
• Exogenous: Dose and GFR dependent • Endogenous: Few longitudinal data (Vadiveloo, JCEM 2011) –2024 untreated individuals, 7 yr F/U –1% developed overt hyperthyroidism –TSH normalized in 17% after 2 yr, 36% after 7 years (particularly if TSH between 0.1 and 0.4)
Page 11 Who Should Be Treated? • Exogenous (iatrogenic) –Dose reduction unless contraindicated • Endogenous-subclinical –Repeat and follow if uncomplicated –Consider treatment (as if overt) when TSH<0.1 in setting of atrial fibrillation or osteoporosis. No trials. • Endogenous-overt –Rule out thyroiditis. They get beta blocker –Everyone else gets beta blocker and...
Hyperthyroidism: Treatment • Anti-thyroid drugs (PTU and methimazole) –Remission: 30-50% after 12-18 mo –Side effects: rash, fever, arthritis, cytopenias (all rare). Use PTU in 1st trimester • Radioiodine –Best treatment for hot nodules –Remission: everyone –Side effects: transient thyroiditis (rare), hypothyroid (50%), worsening exophthalmous (steroids prevent), fetal hypothyroidism
Page 12 Radioiodine and Increased Mortality? • Franklyn, JCEM 1998 –7209 hyperthyroid pts, 15 yr follow-up –All cause mortality: 13% higher than age and sex matched populations –CV deaths increased, but not cancer –Mechanism unknown; clear dose- response • Ross, NEJM 2011 –CV risk increased in 1st year after tx –Likely due to transient hyperthyroidism
Hypothyroidism: Etiology
• Autoimmune (Hashimoto’s) • Iodine deficiency • Iatrogenic A. Radioiodine/ surgery B. Drugs (lithium, amiodarone) • Pituitary/ hypothalamic disease
Page 13 Hypothyroidism: Prevalence
• Population based prevalence of elevated TSH: Author Age Men Women Tunbridge >65 6.0% 10.9% Bagchi >55 1.8% 2.7% Parle >60 2.9% 11.6% Bauer >55 5.4%
Page 14 Billewicz Index*
Symptom/Sign Present Absent Bradykinesia +11 -3 Cold interance +4 -5 Coarse skin +7 -7 Pulse <75 +4 -4 Delayed AJ +15 -6 *hypothyroid if > 30
Overt Hypothyroidism in the Elderly
• “Classic” features often missing • Neuropsychiatric complaints common: depression, weakness, memory loss • Other clues: hypercholesterolemia, elevated CK, pleural effusion
Page 15 Subclinical Hypothyroidism: CV Outcomes • Observational studies: total cholesterol unchanged, but higher LDL and lower HDL • What about atherosclerosis? • Rotterdam population-based study (Hak, 2000) – Aortic atherosclerosis RR = 1.7 (1.1, 2.6) – CHD RR = 2.5 (0.7, 9.5) • Cardiovascular Health Study (Cappola, 2003) – CHD RR = 1.1 (0.9, 1.3) • Australian population-based study (Walsh, 2005) – CHD RR = 1.8 (1.2, 2.7)
Thyroid Studies Collaboration
HUNT Study
• Birmingham Study • Whickham Survey
• Cardiovascular Health Study - Leiden 85+ Study • Health, Aging and Body Composition Study Pisa cohort
Nagasaki Adult Health Study
Busselton Health Study
32
Page 16 Individual Level Meta-Analysis: Prospective Studies of Subclinical Hypothyroidism and CV Outcomes Rodondi, Jama 2010 41,685 individuals, 2,621 (6.3%) with subclinical hypothyroidism Number of outcomes: -2,791 CHD events, 1,715 CHD deaths and 14,449 total deaths Events / Multivariate* Participants HR (95% CI) I2 CHD events 2791 / 13355 1.23 (0.97, 1.56) 67%
CHD mortality 1715 / 41676 1.14 (0.96, 1.34) 0%
Total mortality 7770 / 41685 1.12 (0.95, 1.31) 67%
* Adjusted for gender, age, systolic blood pressure, current and former smoking, total cholesterol, and prevalent diabetes at baseline 33
Risk of CHD Events, CHD Mortality and Total Mortality by TSH Category
Subclinical hypothyroidism Euthyroidism Hazard Ratio (95% CI) * Events / Participants Events / Participants Panel A: TSH
CHD events † TSH 4.5-6.9 mU/L 202 / 854 2465 / 12063 1.07 (0.84, 1.35) TSH 7.0-9.9 mU/L 69 / 285 2465 / 12063 1.12 (0.88, 1.44) TSH 10-20 mU/L 55 / 153 2465 / 12063 2.00 (1.25, 3.20) Ptrend=0.004
CHD mortality ‡ TSH 4.5-6.9 mU/L 114 / 1873 1536 / 39056 1.11 (0.91, 1.34) TSH 7.0-9.9 mU/L 41 / 496 1536 / 39056 1.40 (0.96, 2.04) TSH 10-20 mU/L 24 / 251 1536 / 39056 1.64 (1.11, 2.42) Ptrend=0.007 Total mortality § TSH 4.5-6.9 mU/L 559 / 1873 6978 / 39064 1.06 (0.97, 1.17) TSH 7.0-9.9 mU/L 145 / 496 6978 / 39064 1.04 (0.82, 1.32) TSH 10-20 mU/L 88 / 252 6978 / 39064 1.13 (0.69, 1.86) Ptrend=0.65
HR adjusted for age and gender 34 Sizes of data markers are proportional to the inverse of the variance of the hazard ratios.
Page 17 Subclinical Hypothyroidism and CHF Events Among 2730 Adults Aged 70-79 in Health ABC
Rodondi, et al., Arch Intern Med 2005
Subclinical Hypothyroidism: Other Outcomes
• Observational studies of neuropsychiatric symptoms – Not reliably related to subclinical hypothyroidism • Four small double blinded trials, sTSH > 5-7 – Randomized to thyroxine or placebo – No significant change in weight, lipids, other laboratory values (too small for CV outcomes) – Psychometric testing: Inconsistent improvement in symptoms and memory scores
Page 18 Subclinical Hypothyroidism: Natural History and When to Treat • If persists >6 mo. spontaneous resolution rare • Antibodies predict overt hypothyroidism –5% per yr if TPO+, 2% per yr if TPO- • When to treat? Associated with worse CV outcomes, but no trials that Tx helps… –Treat if goiter or considering pregnancy –Many treat if TPO+, “symptomatic”, or TSH>10
Help is Coming! The TRUST Study
• Double blind RCT of 3,500 adults >65 from 4 EU countries – TSH between 5-20, normal T4 – Not currently treated • Randomized to placebo or levothyroxine, titrated to normal range • 3 years of follow-up for CV, neuropsychiatric and QOL outcomes. • Results expected in 2017 or so…
Page 19 Hypothyroidism: Treatment
• Replace with levothyroxine (T4) –T3 + T4 benefit unproven • Typical replacement dose 1.6 mcg/kg –Elderly or CAD: start low (0.025-0.05 mg/d), gradually increase dose • Maintain TSH within the normal range –Wait 6 weeks after dose change • Monitor yearly (noncompliance, reduced T4 clearance)
What About Treatment of Symptomatic but Euthyroid Patients? • Symptoms of hypothyroidism common –Real but not detected by usual tests? • Pollock, 2001 –Double blind RCT of 65 euthyroid adults –Half with typical hypo “symptoms” –3 mo. of T4 (0.1/d) or placebo, then cross-over –TSH fell with T4, but no difference in QOL, cognitive/psychological function
Page 20 Thyroid Nodules: Epidemiology and Evaluation • Nodules are common (and cancer is rare) –90% women over age 60 have one or more thyroid nodules at autopsy • Risk factors for cancer: neck irritation, FH • Evaluation: FNA first (with or without sono) –75% benign, 20% suspicious, 5% malignant –Best centers: false negative 2% false positive 1%
Thyroid Nodules: Treatment • Cancer - Histology is important (papillary best) - Surgery +/- 131I ablation - T4 suppression? If yes, TSH goal 0.1-0.4 • Benign nodules - Many shrink spontaneously - Meta analysis of T4 suppression Smaller: 26% vs. 12% (NNT=7) Larger: 8% vs. 17% (NNT=11) - T4 doesn’t prevent new nodules
Page 21 Screening Cost-effectiveness
• Danese and Sawin, 1995 – Cost-utility analysis, sTSH-based screening – Modeled progression, symptoms and CAD – Screening every 5 year from 35-65: $9,223 per QALY in women $22,595 per QALY in men – Sensitivity analysis: cost of TSH key ($25)
Screening for Subclinical Thyroid Disease • American Collage of Physicians, 1998 “…reasonable to screen women older than 50 years of age for unsuspected but symptomatic thyroid disease.” • American Thyroid Association, 2000 “…all adults starting at age 35 and repeated every 5 years.” • US Preventive Task Force, 2004 (and draft in 2013) “…evidence is insufficient to recommend for or against routine screening. Fair evidence exists that TSH can detect subclinical disease, but little evidence that treatment improves clinical outcomes”
Page 22 When to Refer to a Specialist? When Thyroid Tests are Confusing or… • Hypothyroidism – Pregnant women – Unstable CV disease – Likely central etiology • Hyperthyroidism – Overt disease (particularly thyroid storm) – Likely central etiology • Nodules/Goiter – Malignant or non-diagnostic FNA – Surgery required
Summary Take Home Points • sTSH is best test in most patients • Subclinical thyroid disease is common, associated with morbidity, and treatable • Low threshold to treat subclinical hypo until large trials available • Tx threshold for subclinical hyper unclear. Consider if a fib or fractures. • Screening with sTSH may be cost- effective but is not recommended
Page 23 Cases
• 68 yr old female with new atrial fibrillation and no other findings except TSH=0.04, normal free T4 • 52 yr old female with 1 yr of fatigue and lassitude and no findings except TSH=9.0, nl free T4, anti-TPO positive • 45 yr old women, enlarged thyroid with dominant nodule since 1999, FNA benign. On T4 suppression ever since, TSH=0.1
Page 24 Modern Management of Hypertension
Robert B. Baron MD Professor of Medicine Associate Dean for GME and CME
Declaration of full disclosure: No conflict of interest
Current Status of Hypertension
• Prevalence 29%; Blacks 33.5% • About 72.5% treated; 53.5% uncontrolled (>140/90) • Risk for poor control: Latinos, Blacks, age 18- 44 and ≥80, <300% poverty, < college degree • Better control: Any insurance, ≥2 visits, and a usual source of care
MMWR 2012;61: 703-709 Hypertension Control by Cardiovascular Disease and Risk: NHANES, 2003-04
Condition %HTN %Rx % Not Controlled
Average Risk 34 66 35 Diabetes 85 96 54 Chronic Kidney Disease 83 95 53 CHF 86 98 50 Cardiovascular Dis 85 95 51 Framingham Score ≥10 77 68 59
Bertoia ML, Hypertension 2011
In patients with elevated BP, my normal practice is:
1) Review the medical assistant’s recorded BP measurement
2) Retake the BP myself, using correct techniques, and record my value in the medical record Accurate BP Measurement
1) Seated for 5 minutes in chair 2) Arms bared and supported 3) No cigs, coffee; no talking 4) Correct fitting cuff for right arm (small cuff results in elevated BP: 3/2 mm Hg - 12/8 mm Hg) 5) First appearance of sound is SBP; disappearance is DBP 6) Two or more reading in 2 minutes averaged 7) Two visits to define HTN
Treatment Based on What Blood Pressure Measurement? • Office clinician measures are standard, used in trials
• Home BP measurement leads to less intensive drug Rx & BP control. Identifies “white-coat” HTN
• Ambulatory monitor measures higher correlation with CVD Clinic, Home and Ambulatory BP in Diagnosis of Hypertension • Systematic review comparing measures in initial diagnosis • 20 studies with 5683 patients, compared to ambulatory monitor daytime mean ≥135/85 Measure Definition Sensitivity Specificity
Home 135/85 85.7% 62.4% mean +LR = 2.28 –LR= 0.23 Clinic 140/90 74.6% 74.6% mean +LR = 2.94 +LR = 0.34
Hodgkinson J, et al. BMJ 2011: 342: d3621
Joint National Commission 8 (JNC 8) Three questions: 1)Does Rx at specific BP thresholds improve outcomes? 2) Does Rx to a specific BP goal improve outcomes? 3) Do various meds differ on outcomes? Nine recommendations 73 yo woman. BP=148/88. No DM. Creat 1.1. Otherwise well. On non-drug therapy. The next best step is:
1) Continue current therapy 2) Begin hydrochlorothiazide 3) Begin ace inhibitor 4) Begin calcium channel blocker 5) Begin beta blocker
Recommendations for Management of Hypertension
Recommendation 1 ≥60 years:
Lower BP at SBP ≥150 mm Hg or DBP ≥90 mm Hg
Treat to a goal SBP <150 mm Hg and goal DBP <90 mm Hg.
Strong Recommendation – Grade A (but not unanimous) JAMA.2014;311(5):507-520. Recommendation 1
• Evidence from 6 studies of patients over age 60, treated to goal ≤150/90: HYVET, Syst-Eur, SHEP, JATOS, VALISH, CARDIO-SIS
• Some evidence (lower quality) comparing ≤160 to ≤140 and ≤150 to ≤140 showing no additional benefit
Hypertension in the Very Elderly Trial (HYVET)
• 3845 patients ≥ 80 y, 2 years
• >160 mm Hg – goal of 150/80 mm Hg BP=173/91
• Indapamide SR 1.5 mg vs. placebo Added perindopril if needed
Beckett NS, NEJM 2008; 358: 1887-1898 HYVET Study Results
End Point Meds Placebo HR (95% CI)
Stroke 12.4 17.7 0.64 (0.46 -0.95)
CVA Death 6.5 10.7 0.55 (0.33 -0.93)
CHF 5.3 14.8 0.28 (0.17 -0.48)
CV Death 23.9 30.7 0.73 (0.55 -0.97)
Any Death 47.2 59.6 0.72 (0.59-0.88)
Beckett NS, NEJM 2008; 358: 1887-1898
HYVET Conclusions and Implications
• Benefits appear at 1 year of Rx • NNT = 20 to prevent one stroke • NNT = 10 to prevent one CHF • Never too old to treat SBP > 160 • Goal does not have to be < 140 73 yo woman. BP=148/88. No DM, Creatinine 1.1. Otherwise well. On non- drug therapy. The next best step is:
1) Continue current therapy 2) Begin hydrochlorothiazide 3) Begin ace inhibitor 4) Begin calcium channel blocker 5) Begin beta blocker
Recommendations for Management of Hypertension
Corollary Recommendation ≥60 years:
If treatment results in lower SBP (eg, <140 mm Hg) and is well tolerated treatment does not need to be adjusted.
Expert Opinion – Grade E
JAMA.2014;311(5):507-520. Recommendations for Management of Hypertension
Recommendation 2 <60 years:
Treat to lower BP at DBP ≥90 mm Hg
Treat to a goal DBP <90 mm Hg.
30-59 years, Strong Recommendation – Grade A 18-29 years, Expert Opinion – Grade E
JAMA.2014;311(5):507-520.
Recommendations for Management of Hypertension
Recommendation 3 <60 years:
Treat to lower BP at SBP ≥140 mm Hg
Treat to a goal SBP <140 mm Hg.
(Expert Opinion – Grade E)
JAMA.2014;311(5):507-520. Recommendations for Management of Hypertension
Recommendation 4 ≥18 years with chronic kidney disease (CKD) (GFR < 60 or proteinuria >30 mg alb/g creat):
Treat to lower SBP ≥140 mm Hg or DBP ≥90 mm Hg
Treat to goal SBP <140 mm Hg and goal DBP <90 mm Hg.
JAMA.2014;311(5):507-520. Expert Opinion – Grade E
Recommendations for Management of Hypertension
Recommendation 5
≥18 years with diabetes, treat to lower BP at SBP ≥140 mm Hg or DBP ≥90 mm Hg
Treat to a goal SBP <140 mm Hg and goal DBP <90 mm Hg.
Expert Opinion – Grade E JAMA.2014;311(5):507-520. 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
120 140 p • BP 119 133 • CV events plus death 1.87% 2.09% .20 • Mortality 1.28% 1.19% .55 • Stroke 0.32% 0.53% .01 • Adverse events 3.3% 1.3% .001 • In type 2 DM: treating to 120 mm Hg did not reduce the • rate of composite fatal and non-fatal CV events
ACCORD, NEJM 2010
Recommendations for Management of Hypertension
Recommendation 6 Nonblack population, including diabetes:
Initial treatment: Thiazide-type diuretic Calcium channel blocker (CCB) Angiotensin-converting enzyme inhibitor (ACEI) Angiotensin receptor blocker (ARB).
(Moderate Recommendation – Grade B JAMA.2014;311(5):507-520. 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
Efficacy of HCTZ Messerli FH, et al, JACC 2011; 57: 590-600
Medication Class Decrease in mm Hg HCTZ 6.5/4.5 12.5 -25 mg HCTZ 50 mg 12.0/5.4 ACE-I 12.9/7.7
ARB 13.3/7.8
CCB 11.0/8.1 Beta 11.2/8.5 Blockers Beta Blockers • Most effective as mono-therapy in younger persons and whites • Adverse effects: no clear depression or sexual dysfunction, but + fatigue • Glucose elevation with A1C increase by 0.2% • No lasting effect on lipids • Less efficacy in stroke prevention among those older than 60 years
Atenolol in hypertension: is it a wise choice?
No benefit to prevent MI or All-cause mortality
Bo Carlberg. LANCET 2004, Vol 364 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 (in non-blacks) • Don’t combine
Calcium Channel Blockers
• Effective in Blacks and elderly • Effective in preventing CV events • No increase risk of cancer • Short acting CCB may be harmful • Effective in systolic hypertension • Better outcomes in latest trials ACCOMPLISH Calcium Blockers Combined with ACE
• Comparison of combinations: ACE-I + HCTZ vs. ACE-I + amlodipine. 3 yrs
• 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
• Funded by Novartis: USA and 4 N Europe
Jamerson K, NEJM 2008; 359:2417-28
ACCOMPLISH Results
Primary Benazepril + Benazepril + Hazard Ratio Outcomes Amlodipine HCTZ (95% CI) N=5744 N=5762 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 334 (5.8%) 386 (6.7%) 0.86 (0.74-1.00) procedure 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
53 yo African-American man, BP=148/88. DM Type 2. Creatinine 1.1. Otherwise well. On non-drug therapy. The next best step is:
1) Continue current therapy 2) Begin hydrochlorothiazide 3) Begin ace inhibitor 4) Begin calcium channel blocker 5) Begin angiotensin receptor blocker Recommendations for Management of Hypertension
Recommendation 7 Black population, including diabetes:
Initial treatment: Thiazide-type diuretic Calcium Channel Blocker (CCB)
General black population: Moderate Rec – Grade B Black patients with diabetes: Weak Rec – Grade C
JAMA.2014;311(5):507-520.
53 yo African-American man, BP=148/88. + DM Type 2, Creatinine 1.1. Otherwise well. On non-drug therapy. The next best step is:
1) Continue current therapy 2) Begin hydrochlorothiazide 3) Begin ace inhibitor 4) Begin calcium channel blocker 5) Begin angiotensin receptor blocker Recommendations for Management of Hypertension
Recommendation 8 ≥18 years with CKD, initial (or add-on) treatment:
ACEI or ARB to improve kidney outcomes.
For all CKD patients with HTN regardless of race or diabetes
Moderate Recommendation – Grade B
JAMA.2014;311(5):507-520.
Recommendations for Management of Hypertension
Recommendation 9 If goal BP not reached within 1 month, increase the dose of the initial drug or add a second drug from one of the classes in recommendation 6 (thiazide-type diuretic, CCB, ACEI, or ARB).
Assess BP and adjust the treatment regimen until goal is reached.
If goal cannot be reached with 2 drugs, add and titrate a third drug from the list provided.
JAMA.2014;311(5):507-520. Recommendations for Management of Hypertension
Recommendation 9 Do not use and ACE and an ARB in the same patient.
If goal cannot be reached using the drugs in rec 6 drugs from other classes can be used.
Referral to a specialist may be indicated
Expert Opinion – Grade E
JAMA.2014;311(5):507-520.
Evidence-based Medications
ACE inhibitors Captopril Enalapril Lisinopril
Angiotensin receptor blockers Eprosartan Candesartan Losartan Valsartan Irbesartan Evidence-based Medications
Beta blockers Atenolol, Metoprolol Calcium channel blockers Amlodipine, Diltiazem ER Nitrendipine Thiazide-type diuretics Bendroflumethiazide, Chlorthalidone, Hydrocholorthiazide, Indapamide
Strategies to Dose BP Meds
1) One drug, titrate to max, add second
2) One drug, add second before max of initial
3) Two drugs at same time, separate or as combo What About Other Drugs?
• Spironolactone • Beta blockers • CNS sympatholytics: Clonidine • Methydopa: Little reason to use • 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
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 British Management of Hypertension
• If BP 140/90 in office, use ambulatory monitor to confirm • Estimate CV risk, evaluate for target organ effects (LVH, CKD, retinopathy) • Treat stage 1 with meds only if target organ damage, known CVD, diabetes, 10- year CV risk ≥ 20% • Offer meds to all at any age with stage 2 (>155/95) independent of other effects
Krause, BMJ 2011 Kaiser Northern California HTN Program • 80% control
Key elements • Patient registry • Sharing of performance metrics • Evidence-based guidelines • Medical assistant visits for BP • Single pill combination therapy
Jaffe, JAMA 2013
Key Points of JNC 8
1) ≥60 yo: goal ≤150 2) Others <140/<90 (including DM, CKD, race/ethnicity) 3) Non blacks: thiazide, CCB, ACEI, ARB 4) Blacks: thiazide, CCB 5) CKD: ACEI or ARB One Other Key Point
Take the BP accurately yourself, and record it in the medical record. Katherine Julian, MD Professor of Clinical Medicine, UCSF July 9, 2014 Vaccines Generally Available in the U.S. Tetanus Hepatitis B Diptheria Hepatitis A Pertussis Haemophilus influenzae Measles type B Mumps Rotovirus Rubella Inactivated polio Varicella Rabies Meningococcus Typhoid Pneumococcus Yellow fever Human Papillomavirus Japanese encephalitis Influenza
Vaccines Generally Available in the U.S. Tetanus Hepatitis B Diptheria Hepatitis A Pertussis Haemophilus influenzae Measles type B Mumps Rotovirus Rubella Inactivated polio Varicella Rabies Meningococcus Typhoid Pneumococcus Yellow fever Human Papillomavirus Japanese encephalitis Influenza Vaccines for Special Populations Plague Tularemia Smallpox Anthrax Botulism Tuberculosis –BCG Adenovirus
Key Website Centers for Disease Control and Prevention
http://www.cdc.gov/vaccines MMWR, Feb 7, 2014;63(05):110-112
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 Pertussis…Not Just for Kids
41,880 pertussis cases and 14 infant deaths in 2012 Classic Sx: post‐tussive emesis and inspiratory “whoop” 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…Not Just for Kids Highly contagious to home contacts Adults may act as reservoirs of the disease to vulnerable populations Majority of deaths in infants <2 months Immunity for pertussis wanes after childhood vaccination
Hewlett EL et al. NEJM, 2005;35:12 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 Adacel: age 11‐64 Boostrix: >10 years
Pertussis Vaccine –How Effective?
2781 subjects aged 15‐65 randomized to reduced dose of acellular pertussis vaccine or hepatitis A placebo Followed for 2.5 years Based on primary pertussis definition (cough and positive culture/PCR), vaccine 92% effective
Ward JL et al. NEJM, 2005;353(13) Tdap Recommendations
Adolescents: give Tdap instead of Td at routine 11‐12 year visit Adults >19 years: Tdap regardless of interval since last tetanus (if never had Tdap) Older Adults: recommended for all >65 yo Does not depend on contact with young children Both Adacel and Boostrix appear to be immunogenic If a choice, give Boostrix for now Health care workers with patient contact
Tdap Recommendations If pregnant woman Administer Tdap during EACH pregnancy, preferably during between 27‐36 weeks If not administered during pregnancy, Tdap should be administered immediately postpartum Adolescents and adults with close contact with an infant aged <12 months should receive a single dose of Tdap if they have not received Tdap previously JAMA 2014: 48 pregnant women—no adverse outcomes and babies with higher Ab rates when mother vaccinated in 3rd trimester
Munoz FM, et al. JAMA, 2014;311(17) Pneumococcus ‐ Background Gram + diplococcus, polysaccharide capsule Over 90 serotypes Colonizes the upper respiratory tract Causes 40,000 deaths annually in the U.S. Mainly transmitted by direct contact with respiratory secretions (ex: household)
Pneumococcus ‐ Background Risk factors for invasive disease Age >65 or <2 years People with chronic illness, immunocompromised Crowding, PPI’s Antecedent respiratory infection and recent Abx Smokers Pneumovax Polysaccharide Vaccine (PPSV23) 23 purified capsular polysaccharide antigens Represent at least 85‐90% of the serotypes that cause invasive pneumococcal infections Shorter Ab duration Decreases pneumococcal bacteremia Retrospective cohort 47K people >65 yrs; HR 0.56 Likely no effect on PNA
Jackson LA. NEJM, 2003;348:18.
Pneumovax Polysaccharide Vaccine PPSV23 ‐ Recommendations
Age >65 People >2 years old** with chronic illness Chronic cardiovascular disease Chronic pulmonary disease including ASTHMA Chronic liver disease, ETOH Diabetes Immunocompromising conditions Smokers People aged 2‐64 living in environments in which the risk for invasive pneumococcal disease is increased (no longer American Indians or Alaskan natives) 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 Max 3 doses
Pneumococcal 13‐Valent Conjugate Vaccine for Adults (PCV13) – Prevnar 13 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? Functional antibody responses higher than for polysaccharide vaccine Prevnar 13 approved by the FDA Dec 2011 (for adults >50 years) but not yet recommended by ACIP aside from immunocompromised CAPiTA Trial –85K subjects in Netherlands >65 yrs 46% fewer vaccine type pneumococcal CAP 75% fewer vaccine type invasive pneumococcal dz
March 2014 Press Release
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 Bonus Question to Case I What type of pneumovax should she have? 1) Polysaccharide vaccine (PPSV23)? 2) Conjugate vaccine –Prevnar13 (PCV13)?
Case 2 63 yo woman PMH: htn, DM Meds: HCTZ, metformin SH: Married, non‐smoker
What vaccine(s) does she need? 1) Hepatitis B 2) Varicella Zoster vaccine 3) Seasonal Influenza 4) #2 and #3 5) All of the above 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
Kimberlin DW, et al. NEJM, 2007;356(13).
Zoster 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 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 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 Licensed in March 2011 for adults >50 years 22K adults 50‐59 years followed 1 year Zostavax vs. placebo decreased risk of zoster by 69.8% ACIP: recommended for >60 years due to vaccine production shortages No need to determine if immune to chickenpox
Schmader et al, Clin Infect Dis 2012;54
Varicella Zoster Vaccine ‐ Contraindications
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 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 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
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? Olmstead County 1669 people with h/o zoster showing risk for recurrent zoster ~1/160
Yawn BP, et al. Mayo Clin Proc, 2011;86(2) Seasonal Influenza Vaccine Inactivated influenza vaccine (IIV) given by injection IIV3 (Trivalent) IIV4 (Quadrivalent – approved for 2013‐2014 season) RIV – Recombinant hemagglutinin influenza vaccine Available as trivalent formulation –RIV3 Live attenuated influenza vaccine (LAIV) Quadrivalent approved 2/12
Seasonal Influenza Vaccine Indications All people older than 6 months Unless there is a contraindication… Influenza Vaccine Strains for 2014‐2015 Flu Season
A/California/7/2009 (H1N1‐like)‐‐‐same A/Texas/50/2012 (H3N2‐like) B/Massachusetts/2/2012‐like—same as last year
For quadrivalent vaccine—2 A strains and 2 B strains B/Brisbane/60/2008—same as last year
Seasonal Influenza Vaccine Inactivated influenza vaccine (IIV3) Approved for all >6 months Live attenuated influenza vaccine (LAIV) 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 Seasonal Influenza Vaccine… The Evidence
In children, several studies suggest better efficacy of LAIV compared to IIV In adults, studies suggest better efficacy of IIV
Who Should NOT Get the Live Attenuated Influenza Vaccine? Outside recommended age ranges (<2yrs or >49yrs) Chronic medical conditions including asthma Pregnant women History of Guillain‐Barré Highly immunosuppressed Contact with highly immunosuppressed High Dose IIV3 Vaccine 12/09 FDA licensed Fluzone High‐Dose for >65 yrs Contains 60µg of hemagglutinin per strain virus vs. 15 µg in regular IIV 8/13: Press Release from Phase 3 Trial ‐ 24% more effective than regular dose in preventing influenza in adults > 65 yrs More local reactions
Intradermal Influenza Vaccine Fluzone intradermal vaccine approved by FDA in May 2011 Developed in hopes of conserving vaccine supply Needle 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 New Vaccines and Egg Allergies IIV and LAIV made with propagation of virus in embryonated eggs Recombinant Influenza Vaccine Trivalent (RIV3) –FluBok Egg free vaccine Approved ages 18‐49 Inactivated trivalent vaccine (ccIIV3) Flucelvax Canine kidney cell culture derived NOT egg free since initial seed virus passaged in eggs Approved >18 yrs ACIP recs: mild egg allergy can get RIV3 or IIV/ccIIV3 with additional safety precautions. Severe egg allergy: give RIV3 if 18‐49 yrs
Hepatitis B Vaccine 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) Unvaccinated adults >60 with DM may be vaccinated at discretion of treating clinician 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
Case 2 63 yo woman PMH: htn, DM Meds: HCTZ, metformin SH: Married, non‐smoker
What vaccine(s) does she need? 1) Hepatitis B 2) Varicella (zoster) 3) Seasonal Influenza 4) #2 and #3 5) All of the above 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?
1) No vaccines are needed at this time 2) HPV vaccine 3) Meningococcal vaccine 4) Both 2 and 3
Human Papillomavirus (HPV) Background 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% 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
Koutsky LA et al. NEJM, 2002;347(21)
HPV Vaccine Recommendations IM in a 3‐dose schedule (0, 1‐2, 6 months) Little effect on HPV infections present prior to vaccination Approved for girls as young as 9; focus on 11‐12 yo Catch‐up vaccination for 13‐26 yo if not previously vaccinated h/o HPV NOT a contraindication to vaccination SE: low‐grade fever, local reactions, fainting Contraindicated in anyone with hypersensitivity to yeast or to the vaccine HPV Vaccine in Boys/Men… HPV4 recommended for males 11‐12 yrs old; recommended 13‐21 years who have not been vaccinated Males 22‐26 may be vaccinated MSM recommended to be vaccinated through age 26 yrs
To Be Determined… Will non‐vaccine viral strains emerge? What is the durability of the immunity? 9‐valent HPV vaccine phase 3 trial Meningococcus Background Gram neg diplococcus Approximately 10% of adults carry N meningitidis in the nasopharynx 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 Vaccine Traditional vaccine (Menomune) ‐ tetravalent (A, C, Y, W‐135) polysaccharide vaccine (MPSV4) Antibody response is short‐lived (1‐5 yrs) Boosting may lead to immune hyporesponse with serogroups A, C Not effective in age < 2; FDA approved for ages 2‐10 and >55 Does NOT protect against serogroup B, which is the most prevalent in U.S. Meningococcal Conjugate Vaccine Newer vaccine (Menactra, Menveo) ‐ tetravalent polysaccharide conjugate vaccine (MCV4) Longer‐lasting Ab titers Contains antigens to serogroups A, C, Y, W‐135 (NOT B) Menactra now approved 9 months‐55 years Manveo approved ages 2‐55
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 Military recruits/travelers with increased risk Outbreak in NYC MSM, serogroup C Vaccine recommended fall 2012 based on HIV infection, neighborhood and behavioral risks Booster doses now routine for teenage vaccines 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 Also, 1st year college • No booster if primary students in dorms up to dose on/after age 16 age 21 Age 2‐55 yrs with HIV, 2 doses, 2 months apart Every 5 years complement deficiency or functional/anatomic asplenia Age 2‐55 yrs with 1 dose • Age 2‐6; after 3 years prolonged increased risk • Age >7 yrs, after 5 of exposure years
Coming Soon? Meningococcal serogroup B vaccine (4CMenB ‐ Bexsero) Approved in Europe, Canada Will apply for FDA approval Given to Princeton and UC Santa Barbara students following meningitis B outbreaks this spring (investigational drug) 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?
1) No vaccines are needed at this time 2) HPV vaccine 3) Meningococcal vaccine 4) Both 2 and 3
Measles Resurgence
2000: Considered eliminated in the US Jan 1‐June 6, 2014: 397 cases of measles in 18 States Most cases in unvaccinated people who were infected in other countries Most affected: England, France, Germany, India, and the Philippines
www.cdc.gov, accessed June 3, 2014 Measles Resurgence Morbillivirus, enveloped RNA virus with 1 serotype Sx: fever, 3 “C’s”: cough, coryza and conjunctivitis Pathognomonic enanthema: Koplik spots on the buccal mucosa Maculopapular rash
www.cdc.gov; accessed 6/3/14
Measles Recommendations ‐ MMR Children: 2 doses, 12‐15 mo and 4‐6 years Post high‐school students who are not immune: 2 doses at least 28 days apart Adults born after 1957 who are not immune need at least one dose International travelers who are not immune: 2 doses at least 28 days apart Infants 6‐11 months travelling internationally : 1 dose Haemophilus influenzae Type b (Hib) vaccine Hib: gram‐negative coccobacillus Causes PNA, bacteremia, meningitis Hib vaccine indicated in adults: Anatomic or functional asplenia – 1 dose Undergoing elective splenectomy –1 dose s/p stem cell transplant –3 doses 4 weeks apart 6‐12 months after transplant
Take Home Points… Don’t forget Tdap boosters ages 11+ Pneumococcus vaccine >65, people with asthma, chronic illness, and smokers Pneumococcus conjugate vaccine immunocompromised, asplenic, cochlear implants Zoster vaccine ages >60 (licensed for >50) Influenza vaccine everyone International travelers should be measles immune Hib for asplenic, stem cell transplant recipients http://www.cdc.gov/vaccines Caring for Challenging Patients in Women’s Health: Insights into Empathy and Professionalism Jody Steinauer, MD, MAS ______
Disclosures:
None
______
Notes:
Hot Topics In Clinical Nutrition
Robert Baron, MD MS Professor of Medicine Associate Dean for Graduate and Continuing Medical Education
Disclosure
No Relevant Financial Relationships I would describe my diet as: Balanced, healthy
Not as healthy as I want it to be
Vegetarian
Pesco-vegetarian
Mediterranean
Low carbohydrate
Low glycemic index
Gluten-free
Paleo
None of the above
Why Do We Care About What We Eat?
US Leading Causes of Death, CDC 1. Heart Disease 32.6% 2. Cancer 30.9% 3. Chronic lower respiratory disease 7.5% 4. Stroke 7.0%
5. Accidents 6.4% 6. Alzheimer’s disease 4.3% 7. Diabetes 3.7% 8. Influenza and pneumonia 2.9% 9. Nephritis, nephrotic syndrome & nephrosis 2.7%
10. Intentional self-harm (suicide) 2.0% Why Do We Care About What We Eat?
US Leading Causes of Death, CDC 1. Heart Disease 32.6% 2. Cancer 30.9% 3. Chronic lower respiratory disease 7.5% 4. Stroke 7.0%
5. Accidents 6.4% 6. Alzheimer’s disease 4.3% 7. Diabetes 3.7% 8. Influenza and pneumonia 2.9% 9. Nephritis, nephrotic syndrome & nephrosis 2.7%
10. Intentional self-harm (suicide) 2.0%
Lifestyle and Disease
1/3 of premature deaths in the U.S. are attributable to poor nutrition and physical inactivity.
Over 50% of American adults do not get the recommended amount of physical activity.
Only 10% of Americans eat a healthy diet consistent with federal nutrition recommendations. Too high in calories, saturated and trans fat, salt, and refined sugars. Too low in fruits, vegetables, whole grains, calcium, and fiber. Topics
Total calories and macronutrient balance
Dietary Fiber
US Dietary Guidelines
Sodium
Vegetarian Diets and Mediterranean Diets
Antioxidants and B vitamins
Fish oil
Recommendations
U.S. Calorie Intake
Calorie consumption in the U.S. has increased 30% over the past 4 decades.
Year Average calories consumed 1970 2,057 2008 2,674 Top calorie sources in U.S.
1. Grain-based desserts
2. Yeast breads
3. Chicken and chicken-mixed dishes
4. Soda, energy drinks, and sports drinks
5. Pizza
6. Alcoholic beverages
7. Pasta and pasta dishes
8. Mexican mixed dishes
9. Beef and beef dishes
10. Dairy desserts
Extra Calories From Eating Away From Home
Calories/meal Calories/meal at home at a restaurant Normal Weight 550 825 Overweight/Obese 625 900
Public Health Nutrition, 2013 Macronutrient Composition
Macronutrient composition: the relative proportions of fat, carbohydrate, and protein in the diet Bottom line: a wide range of macronutrient composition is consistent with a healthy diet in most clinical circumstances total calories “trumps” macronutrient composition achieving desired calorie intake will achieve most clinical goals
Dietary Fiber Plant matter Not digested by human digestive enzymes Some can be digested by gut bacteria Includes Cellulose, hemicellulose, pectins, gums, and mucilages, lignins Classified as soluble or insoluble IOM: Men 30-38 g/day. Women 21-25 g/day. Dietary Fiber: The Most Important Nutrient?
Heart: Lowers LDL, lowers triglycerides Diabetes: Reduces blood sugar Gut: Prevents constipation, hemorrhoids, diverticular disease Weight: Promotes satiety
Baron RB, BMJ 2013
Dietary Fiber: The Most Important Nutrient?
Meta-analysis of 22 cohort studies: Every 7 grams of fiber associated with a 9% decrease in CV events One portion of whole grains and one portion of legumes, or from two to four servings of fruits and vegetables.
Threapleton DE, BMJ, 2013 Quantifying Dietary Fiber (per serving)
Apple: 4.4 Shredded wheat 6.1 Blueberries: 3.6 Brown rice 1.5 White rice 0.3 Orange: 3.0 Peanuts 9.1 Grapes 0.8 Asparagus 1.4 Pear: 5.5 Kidney beans 6.8 Raspberries 8.0 Broccoli 1.1 White bread 0.7 Carrot 1.7 Wheat bread 1.9 Spinach 3.5 Wheat-bran cereal 7.4 Tomato 1.0 Cornflakes 0.9 Powdered psyllium 3.0 Oatmeal 4.8
Principles of a Healthy Diet
Wide variety of foods High food quality Moderation (right quantity) “Basic Four” Food Groups (1956)
Food Group Pyramid (1992) MyPlate (2010)
MyPlate Dietary Guidelines 2010 Enjoy food, but eat less
Make half your “plate” fruits and vegetables; consume beans, whole grains, nuts and seeds
Increase the intake of seafood & fat-free & low-fat milk and milk products
Drink water instead of sugary drinks
Compare sodium in foods and choose the lower v
Consume only moderate amounts of lean meats, poultry & eggs
Too Many Refined Grains
Federal guidelines recommend six 1 ounce servings per day for a 2000 calorie diet, and half should be whole grain.
The average person eats 8 servings of grains per day, and 7 of the 8 are refined. What is a serving of grain?
1/2 cup cooked rice or other cooked grain 1/2 cup cooked pasta 1/2 cup cooked hot cereal, such as oatmeal 1 six inch tortilla 1 slice of bread (1 oz.); ½ bun 1 very small (1 oz.) muffin ½-1 cup ready-to-eat cereal (½ cup = ½ a baseball)
Select whole grains Look for “whole” in the first ingredient on the label. Aim for total carbs/fiber = <10 for bread and <5 for cereals. Way Too Much Added Sugar
The average person consumes 30 teaspoons of sugar and sweeteners per day (over 15% of calories).
(Includes cane and beet sugar, high fructose corn syrup, corn syrup, dextrose, honey)
The AHA recommends < 6 teaspoons (24 grams) of added sugar per day for women, and < 9 (36 grams) for men .
A 20 oz. soda has twice that.
Nutrition Action Health Letter, CSPI, March, 2013
Salt and Public Policy
Coronary Heart Disease Policy Model to quantify benefits of modest salt reduction in U.S.
Benefit through a reduction in systolic blood pressure from 1-9 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 Sodium reduction and BP control in individual patients
Reduce sodium intake to ≤100 meq/d (2.4 g Na): 2-8 mm Hg in SBP DASH Diet: 6 mm alone; DASH diet plus sodium restriction: 14 mm Na
Dietary Guidelines 2010
Addressing Sodium: 2,300 mg per day for general population 1,500 mg for aged 51+, African Americans & hypertension, diabetes & kidney disease Sodium But:
1/2 of U.S. would qualify for 1,500 mg recommendation
Average current intake 3,400 mg per day (1.5 teaspoon salt)
Institute of Medicine: May 2013:
Limit everyone to 2,300 mg per day (1 teaspoon salt)
Evidence doesn’t support lower recommendations
Salt in the US Diet
80% in processed or pre‐ prepared foods
Sources: Mattes et al. Top sodium sources in U.S.
1. Yeast breads
2. Chicken and chicken-mixed dishes
3. Pizza
4. Soda, energy drinks, and sports drinks
5. Cold cuts
6. Condiments
7. Mexican mixed dishes
8. Sausage, franks, bacon and ribs
9. Regular chees
10. Grain-based desserts
Sources of sodium in US
35% from cereal and cereal products 26% from meat & meat products 8% from milk & milk products Mediterranean Diet: Healthy fats and good carbs with a big side of fruits and vegetables Primary Prevention of Cardiovascular Disease with a Mediterranean Diet NEJM, Feb. 25, 2013
7447 Men and women, type 2 diabetes or at least 3 CV risk factors. 4.8 years
Compared 1) Mediterranean diet supplemented with 4 Tbsp/day of olive oil or 2) with 1 ounce of nuts/day; vs. 3) a low fat diet (the control)
Results: 288 cardiovascular events occurred: 3.8% in the olive oil group, 3.4% in the nut group, and 4.4% in the control group. (P=0.015)
Eat about 1 ounce of nuts most days
1 ounce of nuts=1/4 cup or a small handful
But be aware of the calories… 1 ounce=160-200 calories Vegetarian Diets
Vegans Fruitarians Lacto-vegetarians Lacto-ovo vegetarians Pesco-vegetarians Pollo-vegetarians Flexitarians (Semi-vegetarians)
Vegetarian Diets: Observational Study Adventist Health Study 2 73,000 participants; 2570 deaths 5.8 years follow-up Compare: vegans, pesco-; lacto-ovo-; and semi-vegetarians to non- vegetariants Outcome: lowest mortality in pesco- vegetarians and vegans (15-20%).
Orlich, JAMA IM, 2013 Baron, JAMA IM, 2013 Antioxidants
Meta-analysis of 47 high-quality randomized trials of antioxidants 181,000 individuals 25,000 deaths
Bjelakovic, JAMA, 2007
Antioxidants: All-cause mortality Vitamin A 16% increase Beta-carotene 7% increase Vitamin E 4% increase Vitamin C 6% trend towards increase All p << 0.05 except vitamin C Bottom line: actively discourage anti-oxidant use
Bjelakovic, JAMA, 2007 Folate Supplements
Pooled meta-analysis of 8 large, high quality randomized trials 37,485 individuals 5,125 deaths 9,326 major vascular events 3,010 cancers
Clarke, Archives IM, 2010
Folate/Homocysteine RCTs
Homocysteine 25% decrease Death No effect: 1.02 (97-1.08) CVD events No effect: 1.01 (.97-1.05) Cancer No effect: 1.05 (.98-1.13) Folate does not prevent cancer or heart disease
Clarke, Archives IM, 2010 Folate And Neural Tube Defects (NTD)
70% reduction in 2nd occurrences 4 mg of folate 63% reduction in 1st occurrence 0.4 mg of folate Since flour fortification 46% reduction in NTD
Meta-analysis, Blencowe, IJE, 2010
Classification of Dietary Fat Omega 3 Fatty Acids: Meta-analysis
• 48 RCTs of 36,913 participants; 41 cohort trials • No significant effect of omega 3 fats on mortality, CV events, or cancer • Analysis of diet only trials: also no benefit • No reason to advise people to stop rich sources of omega 3 fats, but better trials needed
Cochrane Library, 2009
Since meta-analysis: Two additional RCTs
ORIGIN trial: NEJM June 2012 12,536 patients with DM or high sugar 1 g daily of omega-3 x 6.2 years NO reduction in death, CVD events
Risk and Prevention Trial: NEJM May 2013 12,513 patients at high risk for CVD 1 g daily of omega-3 x 5 years NO reduction in death, CVD events Calcium and Vitamin D: Summary
Calcium and Vitamin D Primary Prevention of Fractures: Insufficient (I) >400 D3 and >1000 Calcium: Insufficient (I) <400 D3 and >1000 Calcium: Discourage (D)
USPSTF 2013
Dietary Supplements: Summary
Beta-carotene Discourage - harmful Vitamin E Discourage - harmful Folate Prevent neural tube defects Omega-3s No benefit Vit D and Ca Use with bisphosphonates Correct deficiency, 20 ng/ml Michael Pollan’s Three Rules
Eat food Not too much Mostly plants
Baron’s Rules Eat unprocessed foods Eat the right amount to maintain your weight Eat something colorful at every meal (and every snack) Don’t drink calories If can’t make the “best” choice, make a better choice Be as fit as you can be: exercise daily Eat with your children The “Generic” Diet
Continued debate: macronutrient balance, amounts of meat/fish/fowl, other specific foods But almost all agree: Limit sugar, refined grains, large amounts of saturated and trans fat. Eat fruits and vegetables, healthy oils, whole grains, legumes and nuts Bottom line: Master a “generic” diet for primary care practice
Baron, RB JAMA Int Med, 2013
For More Information
USDA’s Food & Nutrition Information Center: http://fnic.nal.usda.gov/nal_display/index.php?info_cent er=4&tax_level=1
CDC Division of Nutrition, Physical Activity & Obesity: http://www.cdc.gov/nccdphp/dnpao/index.html
USDA National Agricultural Library: http://www.nutrition.gov/
Center for Science in the Public Interest (CSPI): http://www.cspinet.org/
ChooseMyPlate.gov: http://www.choosemyplate.gov/ For More Information
FDA: How to Understand and Use the Nutrition Facts Label: http://www.fda.gov/Food/ResourcesForYou/Consumers/ NFLPM/ucm274593.htm
FDA: Label Man – Make Your Calories Count: http://www.accessdata.fda.gov/videos/CFSAN/HWM/hw mintro.cfm
Nutrition.gov: Shopping, Cooking & Meal Planning: http://www.nutrition.gov/shopping-cooking-meal- planning
Healthy Eating Plate (Harvard): http://www.hsph.harvard.edu/nutritionsource/what- should-you-eat/pyramid/ Atrial Fibrillation: New Treatments and New Guidelines
Katherine Julian, MD July 10, 2014
No financial disclosures Epidemiology
Most common arrhythmia in clinical practice Projected prevalence of more than 10 million by the year 2050 Accounts for 1/3 of all hospitalizations for cardiac rhythm disturbances Increased prevalence with age: 8% in those older than 80 years
Why Is This Important?
AF associated with an increased risk of stroke Six-fold increase in rate of ischemic stroke Rate of ischemic stroke in non-valvular AF approx 5%/year AF accounts for 15% of all strokes Associated with increased CHF and all-cause mortality May be independently associated with MI
Singer DE, et al. Chest, 2004;126. Soliman EZ, et al. JAMA Intern Med. 2014 Atrial Fibrillation
Work-Up Rate vs. Rhythm Control Treatment Options Anti-coagulation Future Treatment Options
Case I
55 yo woman being seen for a new patient visit. Asymptomatic. PMH: HTN (untreated) PE: 150/80, HR 125 Irregularly irregular The EKG…
What Work-Up Does She Need?
Complete history and physical PIRATES Secondary Causes of AF
PIRATES – secondary causes Pericarditis Pulmonary disease/pulmonary embolism Ischemia Rheumatic heart disease Atrial myxoma Thyrotoxicosis Ethanol Sepsis
Secondary Causes of AF
Other Secondary Causes Obesity – likely due to LA dilatation ?Smoking Familial ?Inflammation Treat Underlying Etiology What Work-Up Does She Need?
Complete history and physical exam Pulmonary disease/pulmonary embolism Ischemia Ethanol Sepsis
January CT et al. AHA/ACC/HRS Practice Guidelines. J Am Coll Cardiol. 2014
What Work-Up Does She Need?
ECHO Rheumatic heart disease Atrial myxoma The real reason… LVH/LV size & function Occult valvular disease Occult pericardial disease
January CT et al. AHA/ACC/HRS Practice Guidelines. J Am Coll Cardiol. 2014 What Work-Up Does She Need?
Complete history and physical exam EKG TTE Associated labs TSH, renal and hepatic function Other tests based on history…ex: event monitor
January CT et al. AHA/ACC/HRS Practice Guidelines. J Am Coll Cardiol. 2014
Classification
Recurrent: 2 or more episodes Paroxysmal: arrhythmia terminates spontaneously or with treatment within 7 days of onset Persistent: sustained beyond 7 days and is not self- terminating Permanent: cardioversion has failed (or been foregone) Lone: patients <60 years without clinical/EKG evidence of cardiopulmonary disease (incl htn) Case I
55 yo woman being seen for a new patient visit. Asymptomatic. PMH: HTN (untreated) PE: 150/80, HR 125 Irregularly irregular
What is the Next Step for Our Case?
What should be our goal in treatment? 1) Convert her to sinus rhythm 2) Rate-control 3) Stroke prevention 4) #1 and #3 5) #2 and #3 Hemodynamic Consequences of AF Loss of atrial mechanical function - fibrosis Irregular ventricular response Elevated HR Results in: Reduction in diastolic filling, stoke volume, CO Risk of cardiomyopathy (chronic > 130 bpm) Asymptomatic afib 12X more common…
Rate or Rhythm?
AFFIRM Study Randomized 4070 patients with AF, F/U 3.5 years Rate-control = coumadin Rhythm-control = cardioversion/meds/coumadin No difference in survival, stroke or QOL Trend towards increased survival in rate-control (P = .08) Pts > 65 yrs and pts without h/o CHF had better outcomes with rate-control therapy More thrombotic events in rhythm arm
AFFIRM Investigators, NEJM, 2002;347 Rate or Rhythm?
AFFIRM Study…the Caveats… No symptomatic patients Average age of enrollees: 70 yrs Only 63% of patients in control arm in sinus rhythm
AFFIRM Investigators, NEJM, 2002;347
Rate or Rhythm for CHF Patients
1376 patients with h/o afib, EF<35%, sx of CHF RCT rate vs. rhythm Outcome: time to death from CV causes, followed 37 months Results 27% in rhythm-control group died from CV causes 25% in rate-control group died from CV causes HR 1.06 Other outcomes similar (CVA, worse CHF, all-cause mortality)
Roy, et al. NEJM, 2008;358. Rate Control
Previous goal HR: 60-80 bpm at rest; 90-115 bpm during exercise No evidence getting HR <80 vs. <110 any better for mortality Guidelines: <110 BPM Ok if no symptoms
Van Gelder IC et al. NEJM 2010;362 Groenveld HF, et al. J Am Coll Cardiol 2013
Rate Control
What do I use? First choice: beta-blockers or calcium-channel blockers Don’t give if Wolf-Parkinson-White or other accessory pathways OK to combine nodal-blocking agents Digoxin is second-line as it does not control HR during exercise
January CT et al. AHA/ACC/HRS Practice Guidelines. J Am Coll Cardiol. 2014 Rhythm vs. Rate…Bottom Line
Highly symptomatic or unstable: rhythm control If minimal symptoms: rate control is safe and appropriate (maintain goal HR <110) Anticoagulation therapy should be continued regardless of the strategy (rhythm vs. rate)
What About Cardioversion?
Electrical cardioversion preferred Best if within 7 days of AF onset Requires conscious sedation or anesthesia Most thrombi in atrial fibrillation arise from the LA appendage Cardioversion can reduce LA appendage function Peri-cardioversion period is particularly pro- thrombotic Regardless of mode of cardioversion Electrial Cardioversion
If AF < 48 hrs, AND low stroke risk, can safely undergo cardioversion without anticoagulant therapy Must be documented! If AF > 48 hrs (or unknown duration) OR high-risk for stroke (h/o stroke/TIA, mechanical heart valve), then 2 choices: Anti-coagulate X 3 weeks (therapeutic INR) before cardioversion TEE to r/o clot Anti-coagulate for at least 4 weeks afterward Anti-coagulate also for those who would not normally require coumadin
January CT et al. AHA/ACC/HRS Practice Guidelines. J Am Coll Cardiol. 2014
Cardioversion – Thrombus Risk
Other factors besides LA clot may affect stroke risk Age DM LA flow velocity HTN One study showed intra-atrial thrombus has been detected by TEE in 15% of patients with AF < 72 hours duration No difference in thrombus risk between electrical and pharmacologic cardioversion
January CT et al. AHA/ACC/HRS Practice Guidelines. J Am Coll Cardiol. 2014 Pharmacologic Cardioversion – Stable Patients
Pharmacologic cardioversion in AF Type 1C Flecainide Propafenone Type III Dofetilide (do not give out of the hospital) Ibutilide Alternative to above: amiodarone
January CT et al. AHA/ACC/HRS Practice Guidelines. J Am Coll Cardiol. 2014
The Next Step…
55 yo woman being seen for a new patient visit. Asymptomatic. PMH: HTN (untreated) PE: 150/80, HR 125 Irregularly irregular
Does she need anti-coagulation? 1) Yes, with coumadin 2) Yes, with ASA 3) Yes, with coumadin and ASA 4) Yes, with dabigatran (pradaxa) 5) No Key Point…
A rhythm control strategy does not negate the need for anticoagulation therapy Assuming anticoagulation is indicated
Risk/Benefits of Coumadin
Pooled analysis from five primary prevention trials in non-valvular AF Annual rate of stroke 4.3% in control group 1.4% risk of stroke in the warfarin group (NNT=32) Only 20% of subjects >75 yrs; excluded pts at risk for bleed Need to consider warfarin risks Symptomatic intracranial hemorrhage 0.4% with warfarin; 0.2% in control Major bleeding: 2.2% with warfarin; 0.9% in control
Bath PMW, et al. European Heart Journal, 2005 What About Aspirin?
Two randomized trials evaluated the use of ASA (75mg, 325mg) in primary stroke prevention Pooled data: Risk of stroke with ASA 4.2%; risk of stroke in controls 6.4% ASA may be better in preventing non- cardioembolic strokes and non-disabling strokes
Bath PMW, et al. European Heart Journal, 2005
Secondary Prevention of Stroke
Risk of stroke with warfarin 3.1%; placebo 10% Risk of stroke with ASA (300mg) 7.7%
EAFT Study Group, Lancet, 1993 Anti-Platelets vs. Coumadin?
ACTIVE-W trial 3335 patients with AF + 1 other stroke risk factor ASA + clopidogrel vs. coumadin Outcomes: stroke, non-CNS systemic embolus, MI or vascular death Stopped early because of superiority of warfarin in preventing vascular events (165 events vs. 234 events). Warfarin even better for those who entered the study already taking it.
Active Writing Group. Lancet, 2006;367(9526)
Anti-Coagulation
Bottom line…anticoagulation with warfarin superior to ASA and superior to ASA + clopidogrel. Effective in the prevention of primary and secondary stroke.
Active Writing Group. Lancet, 2006;367(9526) Who Needs Anti-Coagulation in AF?
CHADS2 previously used as accurate predictor of Risk Factor Score stroke CHF (or reduced systolic 1 function) 0 pts: no treatment Htn 1 1 pt: ASA vs. Age >75 yrs 1 anticoagulation* DM1 h/o Stroke/TIA 2 2 pts: anticoagulation Problem: doesn’t account for other stroke RF
Gage BF, et al. JAMA, 2001;285.
Who Needs Anti-Coagulation in AF?
For low-risk patients CHA2DS2-VASc outperformed CHADS2 . Now recommended
Risk Factor Score CHF/LV dysfunction 1 Htn 1 Age > 75 yrs 2 DM1 Stroke/TIA/Thromboembolism 2 Vascular Dz (h/o MI, PVD) 1 Age 65-74 yrs 1 Sex category (female) 1
Olesen JB et al. BMJ, 2011;342 January CT et al. AHA/ACC/HRS Practice Guidelines. J Am Coll Cardiol. 2014 Anticoagulation…Who Needs It?
CHA2DS2-VASc score Adjusted stroke rate based on cohort data (percent/year) 00% 11.3% 22.2% 33.2% 44.0% 56.7% 69.8% 79.6% 86.7% 9 15.2%
Lip GY et al. Stroke, 2010;41(12).
Anticoagulation…Who Needs It?
CHA2DS2-VASc No benefit of oral anticoagulation if patients low- risk (score=0) No treatment vs. ASA 81-325mg daily Neutral or positive benefit of anticoagulation for score >1 Score of 1: ASA or anticoagulation (anticoagulation preferred) Score >2: anticoagulation
January CT et al. AHA/ACC/HRS Practice Guidelines. J Am Coll Cardiol. 2014 Prediction for Major Bleeding Risk – HAS-BLED HAS-BLED risk scheme for AF Bleeding predisposition Hypertension Labile INR Abnormal renal/liver Elderly (age>65 yrs) function* Drugs*(NSAID or h/o Stroke/TIA steroids) or alcohol concomitantly
* = 2 different components
Lip GY, et al. J Am Coll Cardiol, 2011;57(2):173-180
HAS-BLED Risk Classification
HAS-BLED Bleeds/100 score patients Validated using trial data; 0 1.13 appears to be best prediction model 1 1.02 Max=9pts 2 1.88 Risk of major bleeding=intracranial, 3 3.74 transfusion, 4 8.70 hospitalization 5 12.50 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
CHADS2 score=1
CHA2DS2-VASc score = 2 points Offer anticoagulation
Anti-Coagulation Special Considerations
What about my 85 yo patient who falls? Predisposition to falling not considered a contraindication for warfarin What about my patient with a remote h/o GIB? Risk of recurrent bleeding 1.2% Resolved peptic ulcer disease bleeding (with H. Pylori testing/treatment) not a contraindication for warfarin
Man-Son-Hing M et al. Arch Intern Med, 2003;163. Anti-Coagulation Special Considerations
What are absolute contraindications to warfarin? Bleeding diathesis Thrombocytopenia (<50K) Untreated or poorly-controlled htn (> 160/90) Non-compliance with INR monitoring Relative contraindications Significant ETOH use, NSAID use without PPI, activities predisposing to trauma
Man-Son-Hing M et al. Arch Intern Med, 2003;163.
Anti-Coagulation Special Considerations What about stopping anti-coagulation for a procedure? Mechanical heart valve→heparin (UFH vs LMWH)…most of the time… Non-valvular AF High-risk (CHADS 5 or 6) →heparin Medium-risk (CHADS 3 or 4) →heparin full or low-dose Low-risk (CHADS 1 or 2) →ok to stop coumadin for <1 week Novel agent: hold 1 day prior to procedure. If complete hemostasis needed, hold for 48 hours
Kraai EP et al. J Thromb Thrombolysis, 2009;28 Non-Vitamin K Antagonist Oral
Anticoagulants (NOACs)_Oral Xa XII Inhibitors Rivaroxaban XI Apixaban (Edoxaban) IX VII
X Xa Direct Thrombin Inhibitor II IIa Dabigatran
Fibrin Fibrin Clot
NOACs – A Few Take Home Points Up Front All NOACs have a black box warning with 2 key points: Premature discontinuation (in afib trials) increases risk of thrombotic events Parental bridging if NOAC to warfarin Spinal/Epidural hematoma risk Decline in renal function leads to increased bleeding risk Do not use with mechanical heart valves NOACs
Dabigatran Rivaroxaban Apixaban Edoxaban (Pradaxa) (Xarelto) (Eliquis) 2010 2012 2012 Approval -Nonvalvular -Nonvalvular -Nonvalvular N/A Status Afib Afib Afib -DVT/PE -DVT -DVT Treatment* Prevention Prevention -DVT and PE treatment Mechanism DTI Anti-Xa Anti-Xa Anti-Xa
Renal 80% 30-60% 25% 35-39% Metabolism
NOACs Dabigatran Rivaroxaban Apixaban Edoxaban (Pradaxa) (Xarelto) (Eliquis)
T ½ Hours 12-17 5-9 8-15 9-10
CYP3A4 --- Yes Yes Yes
Substrate of Yes Yes --- Yes p-glycoprotein Antidote None None None None
Monitoring PTT Anti Xa Anti Xa Anti-XA
Plasma 35% 92-95% 87% 40-59% Protein Binding Dabigatran
AF Guidelines: “with prior stroke, TIA or
CHA2DS2-VASc > 2, oral anticoagulants recommended. Options include: warfarin, dabigatran, rivaroxaban, apixaban.”
January CT et al. AHA/ACC/HRS Practice Guidelines. J Am Coll Cardiol. 2014
Dabigatran
Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Study 18,113 patients with non-valvular 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
Primary outcome: stroke or embolism, F/U 2 years 1.69% warfarin 1.53% for 110mg dabigatran (non-inferior) 1.11% for 150mg dabigatran (superior) Rate of major bleeding 3.36% warfarin 2.71% dabigatran 110mg 3.11% dabigatran 150mg (p-value NS)
Connolly SJ. N Engl J Med, 2009;361.; Nagarakanti R, et al. Circulation, 2011;123
Dabigatran
Caveats… 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 As effective as coumadin post-cardioversion Dabigatran
Pros: No INR monitoring, fewer dietary/drug interactions Cons: BID, expensive, no antidote (somewhat dialyzable), renally cleared Dosing: 150mg BID if CrCl>30 (75mg BID if CrCl 15-30). Not for CrCl<15 Substrate of transporter p-glycoprotein P-gp inducers (St. John’s wart, rifampin) decrease levels P-gp inhibitors (ketoconazole) increase levels
Starting Dabigatran
Baseline labs: CBC, Cr, PTT (LFTs) Patient Education med guide Monitoring Follow-Up 2 weeks Adherence 1 month Adverse effects (GI) 3 months Bleeding/Stroke Continue monthly check-in 2014 Guidelines: “Re-evaluate renal function when clinically indicated and at least annually” Rising Concerns with Dabigatran…
12/7/11: FDA investigation into bleeding reports with pradaxa→260 fatal bleeding events 11/2/12: “bleeding rates associated with new use of Pradaxa do not appear to be higher than bleeding rates associated with new use of warfarin” Meta-analysis: more coronary events 30,514 patients OR 1.33 (CI 1.03-1.71) for MI or ACS May be class effect with direct thrombin inhibitors Uchino K and Hernandez AV. Arch of Intern Med, 2012
Factor Xa Inhibitors
Rivaroxaban, epixaban (edoxaban) 4/13 Cochrane Review on Xa Inhibitors vs. Warfarin: Decreased strokes (OR 0.78, CI 0.69-0.89) Decreased embolic events (OR 0.53, CI 0.32-0.87) Decreased intra-cranial hemorrhages (OR 0.56; CI 0.45-0.70) Decreased all-cause mortality (OR 0.88, CI 0.81- 0.97)
Bruins Slot KMH and Berge E. Cochrane Review, 2013 (8). Rivaroxaban (Xarelto)
Direct Xa inhibitor Once daily dosing 20mg qhs if CrCl >50 15mg if CrCl 15-50 Beware CYP3a4 inhibitors: diltiazem, amiodarone, verapamil will increase effect
Rivaroxaban - ROCKET AF Trial
14,264 non-valvular afib (mean CHADS2=3.5) Rivaroxaban 20mg/d vs. 15mg/d vs. warfarin Endpoint: stroke or systemic embolism Non-inferior to warfarin in AF patients 1.7% rivaroxaban vs. 2.2% warfarin Bleeding rates overall equal but statistically fewer intracranial and fatal bleeding with rivaroxaban (more GIB) Low rate of therapeutic INR (58%)
Patel MR, et al. N Engl J Med, 2011;365(10). Apixaban Factor Xa inhibitor ARISTOTLE Trial 18,201 afib patients with 1 additional risk factor
for stroke (mean CHADS2=2.1) Apixaban 5mg BID (2.5mg BID in select pts) vs. warfarin Outcomes: stroke, systemic embolism Apixaban superior to warfarin in primary outcome (1.27% vs. 1.6%) Lower mortality and less bleeding Approved Dec 2012
Granger CB, et al. N Engl J Med, 2011;365.
Apixaban
Dose 5mg vs. 2.5mg BID Use 2.5mg BID if 2 of the following: Cr >1.5 mg/dL, > 80 yrs, body weight <60 kg Not recommended if severe hepatic impairment New Medicines – Edoxaban ENGAGE Study
Design: Double-dummy RCT trial of 21,105 mod-high risk afib patients. Studied 2 edoxaban regimens (30mg and 60mg daily) End-pt: stroke or systemic embolism
Giugliano RP, et al. N Engl J Med, 2013;369.
New Medicines – Edoxaban ENGAGE Study Results: Edoxaban non-inferior to warfarin Primary end-point (stroke/systemic embolism) 1.5% warfarin 1.18% high-dose edoxaban (HR 0.79, CI 0.63-0.99) 1.61% low-dose edoxaban (HR 1.07, CI 0.87-1.31) Lower rates of major bleeding and mortality
Giugliano RP, et al. N Engl J Med, 2013;369. The Next Step…
55 yo woman being seen for a new patient visit. Asymptomatic. PMH: HTN (untreated) PE: 150/80, HR 125 Irregularly irregular
CHADS2 score=1; CHA2DS2-VASc score = 2 points; HAS-BLED 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 (or rivaroxaban or apixaban) 5) No
What’s “In” and What’s “Out”?
What’s “Out”---Dronedarone Approved July 2009 for low-to intermed-risk pts with AF Similar to amiodarone but non-iodinated, thus no thyroid/pulm toxicity 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.
Dronedarone in High-Risk Permanent Afib 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/vascular/CHF pts or pts with permanent afib
Connolly SJ et al. NEJM, 2011:365;24 What’s “In”--Ablation
Paroxysmal AF primarily emanates from the pulmonary veins Less effective than ablation for SVT, a-flutter Guidelines: ablation recommended (in experienced center) for pts with symptomatic, paroxysmal AF who have failed drug treatment
January CT et al. AHA/ACC/HRS Practice Guidelines. J Am Coll Cardiol. 2014
Future Directions
Obliteration of left atrial appendage Where 90% of thrombi form PROTECT AF Study 707 non-valvular AF patients + 1 stroke RF Watchman device vs. warfarin Percutaneous LA appendage closure filter device End-points: stroke, systemic embolism, CV death Mean follow-up 2.3 years Non-inferior to warfarin but more safety events
Circulation, 2013;127 Recap…Current Guidelines Paroxysmal Anticoagulate; treat if symptoms 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
Fuster et al. ACC/AHA/ESC Practice Guidelines. JACC, 2006;48(4).
Current Guidelines…To Maintain Sinus Rhythm No heart disease→flecainide, propafenone, dofetilide or sotolol (dronedarone) If no response→amiodarone or ablation If heart disease→dofetilide or sotolol (dronedarone) If no response→amiodarone or ablation If CHF→amiodarone or dofetilide If no response→ablation
January CT et al. AHA/ACC/HRS Practice Guidelines. J Am Coll Cardiol. 2014 Current Guidelines…To Maintain Sinus Rhythm Hypertension with LVH→amiodarone If no response→ablation Hypertension and NO LVH →flecainide, propafenone, sotolol (dronedarone) If no response→amiodaroneor dofetilide or ablation
January CT et al. AHA/ACC/HRS Practice Guidelines. J Am Coll Cardiol. 2014
Thank You!! Preconception Care: What Should a Reproductive Healthcare Provider Do?
Jody Steinauer, MD, MAS Dept. Ob/Gyn & Reproductive Sciences University of California, San Francisco
Disclosures
• I have no relevant financial disclosures.
Acknowledgements • Michael Policar and Beth Harleman Objectives
• Define preconception care • List medical conditions that increase adverse outcomes in pregnancy • Review the Reproductive Life Plan • Describe recommended preconception care practices Why Preconception Care?
• Since 1996, progress in the US to improve pregnancy outcomes has slowed, in part, because of inconsistent implementation of interventions before pregnancy to detect, treat, and help women modify behaviors, health conditions, and risk factors that contribute to adverse maternal and infant outcomes
CDC, MMWR 2006;55(No. RR‐6): 1‐23
Why Does Prenatal Care Have Limited Effect on Outcomes? • Most problems exist before onset of PNC • Small improvements are hard to detect • PNC limited effect on women who have not changed their behaviors due to pregnancy • PNC has limited impact on – Prematurity – Congenital anomalies: – Critical period of teratogenesis – Day 17 to Day 56 Infant Deaths by Cause; US 2002
9 % NN Deaths 6 % Inf. Deaths
National Center for Health Statistics, period linked birth/infant death data. www.marchofdimes.com/peristats.
Infant Deaths: Maternal Complications of Pregnancy
National Center for Health Statistics, period linked birth/infant death data. www.marchofdimes.com/peristats. Infant Deaths due to Maternal Complications of Pregnancy, U.S.
Cause of death for 1996‐1998 is based on the Ninth Revision, International Classification of Diseases (ICD‐9); cause of death for after 1998 is based on the Tenth Revision, International Classification of Diseases (ICD‐10). Data after 2001 are impacted by cause of death coding changes for maternal complications of pregnancy and not comparable to earlier years Source: National Center for Health Statistics, period linked birth/infant death data. Retrieved June 27, 2014, from www.marchofdimes.com/peristats.
Infant Deaths due to Prematurity Low Birthweight, US
National Center for Health Statistics, period linked birth/infant death data. www.marchofdimes.com/peristats. Infant Deaths due to Prematurity Low Birthweight, U.S.
Cause of death for 1996‐1998 is based on the Ninth Revision, International Classification of Diseases (ICD‐9); cause of death for after 1998 is based on the Tenth Revision, International Classification of Diseases (ICD‐10). Source: National Center for Health Statistics, period linked birth/infant death data. Retrieved June 27, 2014, from www.marchofdimes.com/peristats.
Many Maternal Health Conditions Cause Adverse Birth Outcomes • Diabetes, hypertension, obesity • Depression • Sexually transmitted infections • Alcohol, tobacco, prescription medications, illicit drugs US Birth Rates by Selected Age of Mother, 1990‐2011
Hypertension
• 8% of women ages 20‐44 have HTN, 28% have prehypertension • Rate of increase in women 2x that of men • African Americans have highest rates • Obesity associated with 4x increased risk • HTN in pregnancy: low‐birth weight, IUGR, abruption, PTD, perinatal mortality
NHANES 2011-2012 Figure 1. Prevalence of hypertension by body mass index (BMI)and for reproductive aged women, 20–44, United States, National Health and Nutrition Examination Survey, 1999–2008
Bateman BT, Shaw KM, Kuklina EV, Callaghan WM, et al. (2012) Hypertension in Women of Reproductive Age in the United States: NHANES 1999-2008. PLoS ONE 7(4): e36171. doi:10.1371/journal.pone.0036171 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036171
Age‐adjusted Percentage of U.S. Adults Who Were Obese or Who Had Diagnosed Diabetes
Centers for Disease Control and Prevention: National Diabetes Surveillance System http://www.cdc.gov/diabetes/statistics Diabetes Rates by Age of Mother
Preconception Care 101
• 2002: Systematic review of 21 trials – Need to promote readiness for pregnancy • 2005: First National Summit on Preconception Care and CDC select panel • 2006: CDC recommendations (in MMWR) for PCHC – 10 recommendations and key action steps • Preconception Health and Health Care Initiative – Clinical workgroup published report in 2008 – Assessment of evidence 2006: CDC recommendations for PCHHC Definition of Preconception Care • Preconception care is comprised of interventions that aim to identify and modify biomedical, behavioral, and social risks to a pregnancy outcome through prevention and management, emphasizing those that must be acted on before conception or early in pregnancy to have maximal impact • It is more than a single visit. It includes care before a first pregnancy or between pregnancies (interconception care.)
CDC, MMWR 2006;55(No. RR‐6): 1‐23 Effect of Short Inter‐pregnancy Intervals Obstetric Outcomes
3 2.54 2.5 2 1.73 1.72 1.5 1.33 1.3 1 0.5 0 3rd Tri VB PPROM PP Anemia Maternal Endometritis Death
Odds Ratio at pregnancy intervals of <6 months vs. 18‐23 months N=500,000 Conde‐Agudelo et al. BMJ 2000
Effect of Short Inter‐pregnancy Intervals Neonatal Outcomes 2.5 2.01 1.88 1.8 1.95 2 1.49 1.54 1.3 1.5
1
0.5
0 early fetal *low very low *PTD <37 PTD *SGA neonatal death brith wt birth wt wks <32wks (<10%) death (<2500g) (<1500g) Odds Ratio at pregnancy intervals of <6 months vs. 18‐23 months N=1.2 million Conde‐Agudelo et al. Ob/Gyne 2005 CDC 2006: Four Goals for Preconception Health • Improve knowledge, attitudes, and behaviors of men and women • Assure that all women of childbearing age receive preconception care services • Reduce risks indicated by a previous adverse pregnancy outcome through interventions during the interconception period; and • Reduce the disparities in adverse pregnancy outcomes.
Examples of Primary Prevention Opportunities: Congenital Anomalies
The Opportunity: The Potential Benefit:
Prevention of neural tube defects 50‐70% can be prevented if a woman has adequate levels of folic acid during earliest weeks of organogenesis—before she receives her prenatal vitamins
Birth Defects related to poor glycemic Can be reduced from ~10% to 2‐3% control of mother (including sacral through glycemic control of the agenesis, cardiac defects and neural woman before organogenesis tube defects)
The National Preconception Curriculum and Resources Guide for Clinicians Examples of Primary Prevention Opportunities: Congenital Anomalies
The Opportunity: The Potential Benefit:
Minimize a prospective mother’s Teratogenic substances interfere contact with teratogenic exposures with normal organ development such as prescribed medications, primarily during the period of environmental exposures and organogenesis alcohol
The National Preconception Curriculum and Resources Guide for Clinicians
What are Components of Preconception Care?
Assess Risk • Health, pregnancy intention, contraception Give Protection • Folic acid, immunizations Manage Conditions • Diabetes, Obesity, Hypothyroidism, STI
Avoid Harmful Exposures • Medications, alcohol, tobacco Reframe Clinical Visits as Preparation for Possible Pregnancy • Identify risk factors for herself and potential pregnancies • Counsel about strategies to reduce risk • Includes well‐woman visits, family planning encounters, chronic disease visits, postpartum
Assess Risk
Pregnancy Intendedness
• Recommendation: Screen women for their intentions to become or not become pregnant in the short‐ and long‐term and their risk of conceiving a pregnancy • Educate patients about how the reproductive life plan impacts contraceptive and decision‐making • Every woman should receive information and counseling about all forms of contraception and emergency contraception Assess Risk Screen for Risk of Pregnancy
Women who use less‐effective contraceptives • Relatively high risk of method failure • Many women with method failure will continue pregnancy to term • Study of 172 PCPs • Underestimated unintended pregnancy risk • Underestimated failure rate of pills, condoms • How do we promote effective contraception with a message to prepare for a healthy pregnancy? Assess Risk Paris, Contraception, 2012.
Reproductive Life Plan Questions
• Do you hope to have (any more) children? • How long do you plan to wait? • How much space between pregnancies? • What do you plan to do until you are ready to become pregnant? • What can I do today to help you achieve your plan?
A Assess Risk Assess Risk: History
• Reproductive history (PTB, CD, losses) • Environmental hazards and toxins • Medications that are known teratogens • Nutrition, folic acid intake, weight management • Genetic conditions and family history • Substance use, including tobacco and alcohol • Chronic medical conditions (DM, HTN) • Infectious diseases and vaccination • Family planning • Psychosocial concerns (depression or violence) Assess Risk
Assess Risk: Infectious Disease Screening • HIV Screening (A) – Once for all adults then based on risk • Chlamydia Screening (A) • HPV/cytology screening (A) • For high‐risk women – HCV (C), TB (B), GC (B), Syphilis (A) • Question –BV for h/o PTB (C) • Counseling (C) – CMV (high‐risk women), Listeria
A= good support; B = fair support; C= insufficient Assess Risk Give Protection: Take Folic Acid
• Folic acid supplementation reduces neural tube defects by two thirds • Recommendations – All women of childbearing age should take a folic acid‐containing multivitamin supplement – All women should ingest 0.4 mg (400 mcg) of folic acid daily – Start at least 3 months before conception A Give Protection
Give Protection: Vaccinations
• MMR (A) – screen first – contraindicated in preg • TdaP (B) –now recommended in pregnancy • Hepatitis B (A) • Varicella (B) screen first – contraindicated in preg • HPV (B) • Influenza – All pregnant women in flu season
Give Protection Manage Conditions: Hypertension
• Stop ACE inhibitors – Calcium channel blocker and/or diazide • Lifestyle modifications • Mild essential hypertension – Consider stopping meds (short time period) – Goal in pregnancy is <160/100 • Severe HTN, multiple medications, end‐organ – Control blood pressures – Early prenatal care –may be candidate for ASA end of first trimester A Manage Conditions
Manage Conditions: Diabetes
• All women with diabetes should be counseled about DM control before considering pregnancy – Maximize control with self‐glucose monitoring • *Insulin if necessary – Regular exercise program / weight control • Before pregnancy goal: HgA1C <6 (5.5 if possible) – Increased pregnancy loss at HgA1c>6 – Increased defects >8 • Poorly controlled DM –encourage effective birth control until control A Manage Conditions Manage Conditions: Healthy Weight
• Annual BMI calculation • BMI ≥ 25 kg/m2 should be counseled about risks to future pregnancies, including infertility – Offer specific strategies to decrease caloric intake and increase physical activity, such as structured weight loss programs – Exercise alone decreases risk • Low BMI (<20 kg/m2) – counsel about risk; screen for eating disorders A Manage Conditions
Manage Conditions: Thyroid Dz
• Hypothyroidism – Women must continue to take levothyroxine if they become pregnant – Dosages increase during early pregnancy • Should be seen immediately • If not possible take 2 additional doses per week until PNC • In pregnancy goal TSH <2.5 first trimester and <3 2nd and 3rd trimesters
A Manage Conditions Manage Conditions: Thyroid Dz
• Ensure 150‐200 mcg/day iodine in PNC • Hyperthyroidism –treated medically – Recommend PTU in first trimester and Methimazole in 2nd and 3rd trimesters – PTU – hepatotoxicity later in pregnancy – Methimazole – scalp deformities in 1st trimester
Manage Conditions
Manage Conditions: Seizure Disorders
• Counsel about risks of increased seizures during pregnancy and risks of medications – Trial off meds in those without a recent seizure • Contraception – Many enzyme‐inducing meds make hormonal contraception less effective* – CHC also decreases efficacy of seizure meds: lamotrigine monotherapy and valproate
*Carbamazepine, Felbamate, A Oxcarbazepine, Phenobarbatol, Manage Conditions Phenytoin, Topiramate Manage Conditions: Seizure Disorders
• The least toxic anticonvulsant medication should be initiated before pregnancy and adjusted for lowest effective range (avoid valproate, phenytoin) • For women taking antiepileptic drugs who are considering a pregnancy, folic acid supplementation 4 or 5 mg/day is recommended for 1 month prior to conception and until the end of the 1st trimester
A Manage Conditions
Avoid Exposures: Smoking
• Adverse perinatal outcomes can be prevented if women stop smoking before pregnancy • 11% prenatal smoking • IUGR, PTD, LBW, SIDS • Stopping smoking would deaths by 5% • Only 20% of women successfully stop during pregnancy – Surgeon general’s website A Avoid Harmful Exposures Avoid Exposures: Alcohol • 12% prenatal drinking and 3% binge • IUGR, birth defects, FAS • No established safe level of alcohol – Many organizations ‐ 1‐2 units of alcohol 2 x/ wk • Data on light drinking and obstetric outcomes – No convincing evidence of harm but overall evidence is weak so hard to conclude safety – Binge drinking is bad. • ACOG toolkit A Avoid Harmful Exposures Patra, BJOG, 2011; McCarthy, Ob Gyn, 2013
Avoid Exposures: Limits of the FDA Classification • Hard to remember • NOT a gradation of risk • May be misleading • 60% of category X drugs have no human data • No information on degree of risk • No information on timing of administration • A drug may end up in category X simply if it has no utility in pregnancy • Rarely updated Avoid Harmful Exposures Does the FDA Classification System Make Prescribing Safer? • 50% of pregnant women taking meds receive a category C, D or X drug • 1 in 6 reproductive age women receive a category D or X drug • Women who received a D or X drug are no more likely to have documentation of contraception than A or B drugs
Avoid Harmful Exposures Schwarz EB, Ann Int Med 2007, Sept 18; 147(6): 370-6
Drugs to Avoid in Pregnancy
• ACE‐I: fetal renal failure and hypotension • Tetracycline: abnormalities of bone and teeth • Fluoroquinolones: abnl cartilage development • Systemic retinoids: CNS, craniofacial, CV defects • Warfarin: skeletal and CNS defects • Anticonvulsants • Valproic acid: neural tube defects and Phenytoin: syndrome • Lamotrigine: (higher doses)? Carbamazepine? • NSAIDS: bleeding, premature closure of the ductus arteriosis • Live vaccines (MMR, oral polio, varicella, yellow fever): may cross placenta • Aspirin: First trimester A Avoid Harmful Exposures Medication Resources
• Drugs in Pregnancy and Lactation, 2011. • Medical Care of the Pregnant Patient, 2007, www.acponline.org • Reprotox (free for trainees) • Uptodate • NIH
What are Components of Preconception Care?
Assess Risk • Health, pregnancy intention, contraception Give Protection • Folic acid, immunizations Manage Conditions • Diabetes, Obesity, Hypothyroidism, STI
Avoid Harmful Exposures • Medications, alcohol, tobacco Assess Risk: History
• Reproductive history (PTB, CD, losses) • Environmental hazards and toxins • Medications that are known teratogens • Nutrition, folic acid intake, weight management • Genetic conditions and family history • Substance use, including tobacco and alcohol • Chronic medical conditions (DM, HTN) • Infectious diseases and vaccination • Family planning • Psychosocial concerns (depression or violence) Assess Risk
Georgia Preconception Toolkit
• Study of 300 low‐income women • 10‐minute targeted intervention • Improved knowledge at 3 & 6 months Dunlop, AJ Health Promotion, 2013 CDC Resources
ACOG, CME Summary • All clinical interactions with women of reproductive age should include assessment of pregnancy intention and risk. • Interventions before pregnancy can positively affect pregnancy outcomes. Acute Pelvic Pain
Rebecca Jackson, MD Professor, Obstetrics, Gynecology & Reproductive Sciences University of California, San Francisco
Preview
• Gynecologic causes of acute pelvic pain: emphasis on diagnosis and what’s new • Adnexal Torsion • Ruptured Ovarian Cyst •PID • Tubo-ovarian abscess (TOA) •Myomas • Endometriosis The Case of Ms. A
• Ms. A is a healthy, 41 year old Arabic-speaking woman, G3P3, who presented to the ER with LLQ pain.
• She was not pregnant. She also had a low grade fever and intermittent nausea and vomiting. The pain was sudden in onset and at times radiated down her left leg. It was worse when it first started and subsequently waxed and waned but was still 7 out of 10 when we saw her. It was worse with movement. She has never had pain like this before.
• She had one sexual partner (her husband), no history of STD's and used OCP's for irregular bleeding. She was on day 3 of her pill pack. Except for the N/V, she had no other GI symptoms. She also reported no vaginal discharge, no dysuria and ROS was negative.
Acute Pelvic Pain
Not pregnant- Not pregnant- GI/GU Pregnant Gyn • GU: stones, cystitis, • ECTOPIC • Ruptured ovarian cyst pyelonephritis ECTOPIC • Adnexal Torsion • GI: appendicitis, diverticultis, ECTOPIC • Endometriosis SBO, volvulus, IBD, • Abortion • PID, TOA gastroenteritis, constipation,, • Ruptured • CPP- exacerbation incarcerated hernia, bleeding Corpus • Dysmenorrhea peptic ulcer, ischemic bowel Luteum Cyst • Mittleschmerz • Musculoskeletal—muscle • Degenerating strain/injury, herniated disc, Fibroid • Degenerating or twisted myoma arthritis • Everything else on the • Ovarian • Other: abdominal non-pregnant hyperstimulation aneurysm; abdominal angina; list syndrome porphyria, sickle cell crisis, • Hematometra abdominal migraine Physical Exam
• T=38.3. Other VS Normal • Mod distress but stoic, difficulty changing positions in bed, pain worse when lying flat. • Abd: Soft, ND, +BS. Localized rebound in LLQ. Large firm mass in lower pelvis, tender. Negative bed shake. Positive left leg raise and left obturator sign. • Pelvic: Speculum-no mucopus, nl cervix etc. BME: Difficult b/c of pt discomfort but approx 16 wk mass-likely uterus, mod tender. Cervical motion tenderness in both directions. Left adnexal tenderness, unable to palpate adnexa b/c of pain. • Rectal: Confirms above.
Question #1 In a patient presenting with acute abdomino-pelvic pain, ultrasound will provide a definitive diagnosis for which of the following (mark all that apply):
1.PID 2.TOA (tubo-ovarian abscess) 3.Ruptured ovarian cyst 4.Endometriosis 5.Adnexal torsion 6.Degenerating myoma Could it be a fibroid? • Fibroids rarely cause acute or severe pain. • Acute pain only if degenerating, twisting on a pedicle or prolapsing through the cervix • Torsion of fibroid presentation identical to adnexal torsion but u/s shows solid mass • Prolapsing fibroid Waves of crampy abdominal pain accompanied by bleeding. Once prolapsed no pain. Easily diagnosed on speculum exam.
Pedunculated fibroids can twist • Presentation very similar to ovarian torsion: sudden onset severe pelvic pain, perhaps intermittent, assoc N/V, localized or generalized tenderness • Relatively rare Degenerating myoma •Rare • Occurs in very large myomas (>10cm) and more commonly in pregnancy • Onset gradual, not acute • Physical exam: localized tenderness over the myoma, tender uterus, possibly CMT. Typically no peritoneal signs. Can have low grade fever, sl incr WBC. •U/S—will show presence of large fibroid. Less reliable for diagnosis of degeneration but might see cystic changes suggestive of degeneration
Large degenerating fibroid
Transabdominal ultrasound of the uterus shows the very heterogeneous appearance of a degenerating fibroid (arrows), which contains irregular hypoechoic components.
Imaging of Acute Pelvic Pain. VANDERMEER, Clinical Obstetrics & Gynecology. 52(1):2‐20, March 2009.
© 2009 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2 Back to pt: Labs/Studies
• Labs: WBC initially 11.4 with 6.4 PMN's, later in day: 16.2 with 14 poly's. HCT init 37, down to 32.5. Plts 533. Lytes, LFT's, amylase all normal. ESR=18. Studies: • Abd Series: Negative • Ultrasound: Limited b/c of large fibroid uterus (17 x 10 x 11). Small amt of free fluid. Right ovary nl. Left ovary enlarged at 5.2 cm. Differential per radiology=torsion, TOA, ectopic. • Further work-up: Surgery consulted--felt not diverticulitis.
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A sexually active woman presents with gradual onset of worsening pelvic pain. In addition to pelvic organ tenderness on exam, which of the following findings must be present to make the diagnosis of PID prior to treating it? 1.Fever >38.0 2.CMT (cervical motion tenderness) 3.Cervical muco-pus 4.Increased white cell count 5.Ultrasound showing pyosalpinx 6.Absence of a competing diagnosis
Could it be PID?
• Onset/location: Subacute (1-2 days) onset of dull bilateral and central pelvic pain • Progression/Assoc sx: Pain gradually worsens and can be severe. Feel ill. "PID shuffle“. Possible fever, vag discharge, diarrhea, N/V. Worse with movement and lying flat. • Risk Factors: Age < 25 (rare after age 35-40). Multiple or new partners, unprotected sex, h/o STD. New IUD (<2 mos). Douching. • PROTECTIVE: OCP's, pregnancy, condoms, tubal ligation, possibly levonorgestrel IUD (Mirena) PID-etiology
• PID= ascending infection of upper genital tract: salpingitis, peritonitis, endometritis, TOA (tubo-ovarian abscess) • Etiology: polymicrobial (GC, CT, mycoplasma, gardnerella, prevotella, Ecoli, Hflu, peptostrepto, other anaerobic/aerobic vaginal flora). Similar to flora seen with BV. • 2/3 have concomitant BV
PID
• PE: abdominal tenderness, adnexal tenderness, CMT (or simply: pelvic organ tenderness). – Minimum criteria per CDC is lower abdominal or pelvic pain plus abdominal or pelvic organ tenderness on exam without competing diagnosis. – Additional evidence (improves specificity): Inc WBC, fever, Inc ESR, mucopus from cervix, EMB showing infection, positive cervical cultures. • DIAGNOSIS OF EXCLUSION! r/o appy, UTI etc Role of Mycoplasma Genitalium • Controversy: unclear if pathogen or bystander • Very difficult to culture, PCR shows MG in ~15% with PID • Most studies cross-sectional . Need more longitudinal studies to establish causality – 2 cohort studies show 8-13 fold increase PID in women with MG. Largest cohort study showed no association. • Unclear if assoc with long term sequelae. Implicated in tubal factor infertility in one study • Has been associated with treatment failure. Some strains resistant to tetracyclines (azithro ok)
PID Clinical Pearls • Range of severity from asymptomatic to sepsis. • Best to over-treat to avoid long-term sequelae of chronic pelvic pain, infertility, ectopic. – In PEACH trial, in treated women, infertility=17%, recurrent PID=14%, CPP=37% – Infertility increased with delay in treatment (>3days from sx), severity of illness, number episodes PID. • Repeat pelvic exam in 2-3 days(to ensure improving) • Negative GC and CT culture does not rule out PID—continue full course Abx • TREAT PARTNER, check for other STI’s 2010 PID treatment: CDC
• Outpatient: Cetriaxone 250mg IM + Doxy 100 mg/bid for 14 days +- Flagyl 500 mg bid for 14 days • Inpatient: Cefotetan (q12) or Cefoxetin (q6) 2g IV + Doxy 100 mg po bid for 14 days OR Gent + Clinda (900 mg q8) – 24 hours after improvement, can switch to Doxy only to complete 14 days unless TOA present, then use Clinda or Flagyl + Doxy
What’s new 2010 CDC for PID
• Quinolone resistant GC: quinolones no longer recommended, if cephalosporin not feasible: use levoflox +- flagyl if community prevalence low but get culture first to check susceptibility. • Greater emphasis on adding metronidazole to all regimens to cover anaerobes • Insuff evid to warrant removal of IUD ie treat through the PID • Possible association of PID with Mycoplasma Genitalium (azithro better than doxy for this) 2013: no cefixime for GC
Q2: A sexually active woman presents with gradual onset of worsening pelvic pain. In addition to pelvic organ tenderness on exam, which of the following findings must be present to make the diagnosis of PID prior to treating it? 1.Fever (increases specificity but not necessary for diagnosis) 2.CMT (CMT is a subset of pelvic organ tenderness) 3.Cervical muco-pus (increases specificity) 4.Increased white cell count (increases specificity) 5.Ultrasound showing pyosalpinx (u/s not necessary unless worry for TOA) 6.Absence of a competing diagnosis ***** Tubo-ovarian abcess
• No clear risk factors in those with PID • Diagnosis via ultrasound or CT. Suspect when not improving after 2 days of abx (80% of trtment failures due to TOA) • Tubo-ovarian complex (TOC): radiologic diagnosis. Ovary can still be seen separate from tubal mass. Unclear if should receive IV antibiotics (given lack of evidence, low threshold to admit)
. Tuboovarian abscess
Transvaginal image shows a dilated fallopian tube (arrows) with layering pus (arrowhead).
Imaging of Acute Pelvic Pain. VANDERMEER, Clinical Obstetrics & Gynecology. 52(1):2‐20, March 2009.
© 2009 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2 TOA: Treatment Evolving
• Historically, treated surgically. • In 90’s, trial of IV Abx. Surgery only if not improved within 3 days. Abx alone: 75% effective • Now, IR-guided (U/S or CT) aspiration or catheter placement has become accepted part of treatment (in conjunction with ABX).
TOA: Drainage
• Biggest questions are timing (antibiotic trial and drainage only if fails) and whether to do in all or a subset (eg only if >5cm). Insufficient evidence to answer these. • Largest study of aspiration (n=302): 1/3 needed more than one aspiration, 7% eventually needed surgery • A smaller study of transgluteal CT-guided catheter placement also with high success rate but more painful procedure TOA: Treatment • Admit: broad spectrum IV abx with anaerobic coverage • For small (<5cm) abscesses and for TOC, IV antibiotics without drainage often sufficient • Draining larger abscesses (>5cm) may speed recovery and decrease hospitalization • How long to continue IV Abx? Older studies7 days. CDC: at least 1 additional day after clinical improvement. • Oral antibiotics to complete 14 days: doxy plus flagyl or clinda (to ensure anaerobic coverage) • In older women, repeat U/S after resolution to r/o malignancy
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• Given unclear diagnosis, Ms A was admitted for observation. Not taken directly to OR b/c no further children desired. • Over the course of the evening/night, she became febrile and was started on antibiotics for presumed PID vs diverticulits. • Given difficulty imaging ovary on ultrasound, and unclear diagnosis, an MRI was obtained which confirmed large myomatous uterus and showed non-specific enlargement of left ovary, 9x5x6. No evidence of malignancy. No diverticulitis.
Could it be torsion?
• Onset and progression: Acute onset of severe pain. “Stabbing” in 70%. Can be preceded by exercise, sex, BM. Classically intermittent though not always. Often can elicit a history of similar though less severe pain prior to presentation. Can radiate to back, flank, groin (50%) • Assoc Sx: Very often assoc with N/V (70%) and sweating. Sometimes low grade fever. Torsion: Physical exam
• PE: Usually writhing in pain. (They look BAD). Exam often not that revealing. Usually have direct tenderness but do not typically have peritoneal signs (unless long standing necrosis). CMT usu unilateral. Tender adnexal mass on exam though exam often limited by pain. Minority will have fever • Labs: Mod inc WBC (in minority). WBC not associated with severity of torsion.
Pathophysiology
• Elongated utero-ovarian ligament (more common in kids) and/or increase in weight of ovary or tube due to cyst, mass or swelling* • Adnexa twists on its vascular pedicle • As venous flow is impeded, ovary swells, further impeding vascular flow • Result is ischemia and eventually necrosis
*Only 10% occur in normal sized ovaries (up to 50% in kids)—and these are at higher risk of recurrence Adnexal torsion: Risk Factors
• Most common cysts to twist: dermoid (mature teratoma)> serous cysts> hemorrhagic cysts • Size threshold: unknown—majority in cysts >=5 cm. Even very large cysts (20 cm) can twist • Location: Right (2/3) > >left • Age: Reproductive aged women>> post- menopausal
Adnexal torsion: Risk Factors (cont’d)
• More common in: – ovarian hyperstimulation syndrome (8% risk) – pregnancy • Less common in masses associated with (adhesions prevent twisting): – cancer – endometrioma – tubo-ovarian abscess • Tubal torsion (rare): increased risk after tubal ligation Role of Imaging
• Primary goal: determine if ovary is enlarged given torsion is rare with normal sized ovary • Ultrasound preferred but CT can reveal presence of mass • Doppler ultrasound can demonstrate presence or absence of blood flow. However, presence of flow does not rule out torsion and absence does not rule it in. • Torsion therefore remains a clinical diagnosis and surgery is only way to confirm
Ovarian torsion in a patient with acute pelvic pain 2 weeks postpartum. Sonography showed a markedly enlarged right ovary with no flow on color Doppler (not shown).
VANDERMEER, Clinical Obstetrics & Gynecology.
52(1):2‐20, March 2009. 2 Ultrasound to diagnose torsion • Studies small, most retrospective • Skill, experience required (ie sensitivity and specificity in practice less than in research studies) • Study of 199 women with acute pelvic pain: Finding Sensitivity Specificity Tissue edema 21% 100% Absent intra-ovarian vascularity 52% 91% Absent arterial flow 76% 99% Absent venous flow 100% 97% • Other studies report sensitivity 43%, specificity 92% for absent venous flow Nizar, J Clin US 2009
Torsion treatment
• Historically, oophorectomy universally recommended due to fear of embolism. This not borne out by literature • Remove cyst if present • If no cyst present, consider fixing ovary (oophoropexy) to prevent recurrence • Usually able to do via laparoscopy Oophorectomy or not?
• Typically, ovary untwisted at time of surgery and observed to determine if viable but visual determination is unreliable • Recent small cohort studies have found that ovarian function is preserved in 88-100% with simple untwisting even if ovary appears dusky (determined via u/s studies of follicles) • Case reports of subsequent necrosis, sepsis so only offer to women desiring future reproduction
How long before the ovary dies?
• Unknown • Depends on degree of ischemia • One study in children found median time from onset of pain of 14 hours in those with viable ovary vs 27 hrs with non-viable ovary Early diagnosis critical to save ovarian function. Call gyn early (even before ultrasound if high suspicion) Great Road Trip: Akaka Falls
On the way to Hilo. Incredibly lush. Quintessential Hawaii
Could it be a ruptured cyst? • Presentation varies from asymptomatic (usu for follicular cyst rupture) to extremely painful and/or hemodynamically unstable • Onset: Sudden, mod to severe pain. Often preceded by sex, exercise or BM. Typically starts on one side and becomes generalized lower pelvic pain. • Assoc Sx: Often N/V at onset which subsides. Possible low grade fever or dizziness. Worse with movement and lying flat. • Progression: Pain usually begins to recede within hours but can take as long as a day. Symptoms due to blood in abdomen (eg bloating, constipation), can take 2 weeks to subside. Ruptured ovarian cyst
• Common! • Corpus luteum cyst>follicular cyst >>>dermoid, endometrioma, TOA • Usually occurs in luteal phase. Period often late or accompanied by mid-cycle spotting. • Pain due to either blood from rupture site accumulating within ovary and stretching capsule or irritation of peritoneum by blood. • Much higher risk if anticoagulated or bleeding disorder (von-wd). Slightly decreased risk on OCP's
Diagnosis and treatment
• Diagnosis: DIAGNOSIS OF EXCLUSION. U/S often not helpful: cyst may or may not be present, free fluid may or may not be increased. Gold standard is laparoscopy (seldom used). • Treatment: – Usually outpatient. Ensure stable HCT. Pain meds. Close follow-up to ensure improving. – Admit for observation if pain severe or unsure of diagnosis – Laparoscopy: if hemodynamically unstable, worried about torsion or not improved within 24 hrs. FIGURE 16. Acute bleed from a left hemorrhagic cyst. There is a clot (arrows) posterior to the uterus (U) on transabdominal ultrasound. VANDERMEER, Clinical Obstetrics & 2 Gynecology. 52(1):2‐20, March 2009.
Prevention of recurrence?
• High dose (50mcg) pills known to suppress follicular cysts but risks do not justify use for this • Modern, lower dose pills: evidence is mixed and benefit is modest (25% decrease) at best. (About 30% of cycles are ovulatory on OCP) Prevention of recurrence?
• Implanon—higher rate of cysts than control (copper-T); Mirena levonorgestrel IUD higher rate of cysts than control (hysterectomy) • Depoprovera: unlike other methods, known to suppress ovulation reliably so will decrease hemorrhagic cysts. Lupron (GnRH agonist) also effective but more side effects
Women on anti-coagulation?
• In women being anti-coagulated, ovarian cyst rupture can be associated with life- threatening hemoperitoneum • Recommend depo-provera or Lupron to all anti-coagulated repro-aged women to prevent • Depo-provera can be given sub-q if concern for hematoma with intra-muscular injection Could it be endometriosis?
• May cause acute pelvic pain either at time of period (acute dysmenorrhea) or due to endometrioma cyst rupture. • History of prior dysmenorrhea, dyspareunea or pelvic pain • Rupture of endometrioma is uncommon but would present similarly to ovarian cyst rupture
Q1: In a patient presenting with acute abdomino- pelvic pain, ultrasound will provide a definitive diagnosis for …? (mark all that apply):
1.PID (can be useful to r/o competing diagnoses) 2.TOA (tubo-ovarian abscess) ***** 3.Ruptured ovarian cyst (even if it shows a cyst or increased free fluid, diagnosis is clinical) 4.Endometriosis (only useful if endometrioma present) 5.Adnexal torsion (use is to rule in an adnexal mass, presence/absence of flow not diagnostic) 6.Torsion of a pedunculated myoma (use is to rule in a myoma, twisting will not be visible) 7.Degeneration of a myoma (use is to rule in a myoma, may or may not show signs of degeneration) Case Summary
• Given lack of improvement on antibiotics and possibility of torsion, plan made to go to OR. Given symptomatic fibroids, patient desired hysterectomy at same time if possible.
• Op findings: large fibroid uterus, ruptured left ovarian cyst with large clot adherent to ovary but no active bleeding. Not twisted at time of surgery but path reported evidence of torsion. No evidence of degenerating myoma.
Conclusions: Acute Pelvic Pain • Ovarian torsion: Diagnosis of exclusion (U/S not diagnostic) and delay leads to ovarian death so refer to gyn or go to surgery earlier rather than later. Leaving ovary in-situ is becoming an acceptable option though studies are still small • Ovarian Cyst Rupture: Diagnosis of exclusion (U/S not diagnostic). Ensure hemodynamically stable. OCP’s not effective to prevent recurrence. Conclusions: Acute Pelvic Pain • PID: Diagnosis of exclusion. Overtreatment acceptable to prevent sequelae. Avoid floroquinolones due to resistant gonorrhea. Ok to keep IUD in place • TOA: Diagnosis via ultrasound. Admission and IV abx required +/- IR guided drainage
Questions? Essentials of Women’s Health Hapuna Beach Prince Hotel, Hawaii July 8, 2014 Vulvovaginal Disorders: Photo Quiz
Michael S. Policar, MD, MPH Clinical Professor of Ob,Gyn, & RS UCSF School of Medicine [email protected]
• There are no relevant financial relationships with any commercial interests to disclose - These painful lesions have been present for two weeks ‐ Which test would not be appropriate in the initial evaluation of the lesions: a. Herpes simplex culture of direct fluorescent antibody test b. Culture for Hemophilus ducreyi c. Serum VDRL d. Biopsy edge of the lesion e. All would be appropriate
Of the available options, optimal treatment of this condition is: a. Azithromycin 1 gram PO x1 b. Doxycycline 100 mg BID x7d c. Benzathine penicillin 2.4 million units IM given once d. Acyclovir 400 mg PO TID given for 10 days What is the diagnosis in this patient: a. Recurrent genital herpes simplex b. Candidal vulvitis c. Primary genital herpes simplex d. Can’t tell without more information
The test that should be used to confirm the diagnosis is a. No confirmatory test is necessary b. Cytology (Pap smear) of a lesional scraping c. Herpes simplex Type II serology d. Herpes simplex viral culture
Which statement regarding recurrent herpes is true a. Episodic use of antivirals will reduce further recurrent episodes b. Treatment during the ulcer phase will shorten the outbreak c. Famciclovir and valacyclovir are alternative treatments but are 10‐fold more expensive than ACV d. Acyclovir ointment applied 4 times a day is helpful Vulvar Ulcer: Differential Diagnosis
• Genital Herpes • Syphilis • Chancroid • “Tropical STD”: granuloma inguinale, LGV • Behcet’s Disease: mouth, eye, genital ulcers • Crohn’s Disease: – Knife‐cut ulcers, GI‐cutaneous fistulae • Lichen planus, lichen sclerosus
HSV: Epidemiology
• HSV serotypes – HSV‐1: 90% are oral lesions, 10% genital lesions – HSV‐2: 90% are genital lesions, 10% oral lesions • HSV serotypes in genital infections – Majority of genital infections caused by HSV‐2 – 15‐30% of genital infections caused by HSV‐1 – 30‐40 % new cases of genital HSV caused by HSV‐1 • Seroprevalence – HSV‐1: 60‐95% (80%) and HSV‐2: 20‐25% – 25‐30% repro age women infected with genital herpes Genital Herpes
• Natural history – Type specific antibodies 4‐8 weeks after infection – Viral shedding most in prodrome, lesion stages – Intermittant asymptomatic cervical shedding • Majority of HSV‐2 infections are asymptomatic – Only 20% of HSV‐2 seropositives have a clinical history of genital herpes • Progression of lesions – Prodrome: hyperesthesia, itching, neuralgia, malaise – Vesicles pustules ulcer crust pink skin – Lesions shed virus until pink skin present
Genital Herpes: Viral Shedding
• 80‐90% of infections unrecognized • 95% of people with genital HSV‐2 have intermittent subclinical shedding – Highest in 1st year after infection (25% of days), then declines; 4‐6% of days for many years – Similar frequency in persons with and without recognized symptoms – Accounts for most HSV‐2 transmission – Uncommon if genital herpes due to HSV‐1 Genital Herpes
• Primary Herpes – Bilateral, widespread lesions – Systemic symptoms: malaise, myalgia, fever – Urinary retention common – Lesions clear in 10‐14 days – HSV antibody negative – Likelihood of recurrent herpes outbreak • HSV‐2: 50% recurrence rate • HSV‐1: 10% recurrence rate
Genital Herpes
• Recurrent Herpes – Focal unilateral lesions, usually in same place – Few or no systemic symptoms – Lesions clear in 5‐7 days – HSV antibody positive Genital Herpes
• Non‐primary First Episode (NPFE) herpes – First clinical outbreak of genital herpes with characteristics of recurrent herpes…either • 1st recurrence after prior asypmtomatic case – Serology: HSV‐1 or ‐2 positive – Genital culture positive for same type • Prior infection with HSV‐1 (cross protection) – Serology: HSV‐1 positive, HSV‐2 negative – Genital culture or PCR HSV‐2 positive
HSV: Organism Tests
Sensit Specif Cost Comment PCR +4 +4 $$$$ Not in most labs HSV culture •ELVIS rapid +3 +4 $$$ 1 day; no typing •ELVIS std +3 +4 $$$ 5 days; typing* •Cytopathic +3 +3 $$$ Phasing out Herpes DFA +2 +3 $$ Scrape; plate Cytology +1 +3 $$ Scrape; plate
* HSV typing is helpful for counseling regarding recurrence risk, but not for clinical management decisions HSV‐2 Diagnostic Testing
Ulcerative lesion present • Herpes culture (ELVIS or cytopathic): early lesion • DFA: must unroof lesion and scrape • Cytology (Pap smear): late lesion Type‐specific serology • Culture negative recurrent lesion – If seronegative, not due to genital herpes • Suspect 1o herpes: initial testing negative and >6 wks prior – If seronegative, not due to genital herpes • History suggestive of HSV but no lesions to test – If seronegative, not due to genital herpes
Value of HSV‐2 Serology in Couples
Patient Patient POSITIVE NEGATIVE Partner • Recognize S/S • Recognize S/S POSITIVE • No prophylaxis • Prophylax partner • Condoms unnecessary Partner • Recognize S/S • No prophylaxis NEGATIVE • Prophylaxis of patient • Condoms unnecessary Prevention of Genital Herpes
• partner HSV‐2 serostatus; susceptible if negative • Avoid intercourse/touch of lesions during outbreak • Condoms will provide some degree of protection • Patient treatment of during outbreak (or long term suppression) reduces shedding • Daily prophylactic treatment reduces shedding – Incident HSV infection reduced by 1.7% over 1 year • 96.4% don’t seroconvert in absence of treatment • 1.9% seroconvert with treatment – NNT: 59 people to prevent one case/ year
HSV‐2 Serologic Screening
Should be generally offered • HIV positive patients [B] – If HIV+, HSV‐ , increasd risk of HSV acquisition – If HIV+, HSV+, increased risk of HIV transmission • Partnerships with HSV‐2 positive individual [B] – If patient is HSV‐2 negative; consider partner anti‐viral Rx or consistent condom use Should not be generally offered • Universal screening of asymptomatic individuals – In pregnancy [D] – In general population [D] HSV‐2 Serologic Screening
• At risk for STD/HIV (current STD or HR behavior), offer to select patients [C] if – Patient is motivated to reduce risky behavior – Patient is willing to use condoms or Rx consistently – Risk reduction counseling will be provided • Arguments against screening – Limited evidence that counseling or Rx works – Limited evidence that condoms will be used – Little value if risk reduction counseling not given
Genital Herpes and Antiviral Drugs • Primary Herpes – Shortens median duration of lesions by 3‐5 days • Therefore, initiate within 6 days of onset – May decrease systemic symptoms – No effect on subsequent risk, frequency, or severity of recurrences • Recurrent Herpes – Shortens the mean duration by 1 day – Initiate meds within 2 days of onset • Best to start with onset of prodromal symptoms • Patient should have supply of meds available CDC 2010: Treatment of Genital Herpes
Acyclovir Famciclovir Valacyclovir Primary •400 mg TID •250 mg TID •1 gram BID (7‐10 days) •200 mg 5 times/d Recurrent •800 mg TID x2d •1 gm BID x1d •500mg BID x3d •800 mg BID x5d •125mg BID x5d •1 gm QD x5d •400 mg TID x5d • 500 mg once, then 250 BID x2d Suppression •400 mg TID •250 mg BID •0.5‐1 gm QD Prophylaxis •400 mg BID** •250 mg BID •500 mg QD
** Drug class extrapolation, based upon suppressive regimen Limited data on famciclovir use in pregnancy
Primary Syphilis . Painless ulcer with “rolled edge” . Single ulcer at point of infection . Resolves in 4‐6 weeks
STD Atlas, 1997 Secondary syphilis
Multiple chancres
Syphilis: Atypical Chancres • 50% of genital chancres have atypical appearance • Extragenital chancres are larger • Locations – Lips, tongue, tonsils – Breast – Fingers Chancroid
Multiple painful chancres
May have inguinal adenopathy or buboes
Chancroid
• Due to Hemophilis ducreyi • 10% also have syphilis or herpes – Co‐factor for HIV infection • Symptoms/ signs – One or more painful genital ulcers – Regional adenopathy; may suppurate (buboe) • Lab: culture <80% sensitive; contact lab before sampling • Treatment – Azithromycin 1 gram PO – Ceftriaxone 250 mg IM • F/U in 7 days; treat partners within 10 days Morphology of Genital Ulcer Disease
Tender Firm Purulent Incubation Herpes Yes No No 5 days Syphilis No Yes No 21 days Chancroid Yes No Yes 5 days
• This lesion is tensely fluctulent and moderately tender • There is no redness or tissue induration • The patient is afebrile 1. The most likely diagnosis is: a. Vulvar abcess b. Vulvar hematoma c. Hydrocoele of the Canal of Nuck d. Hematocolpos 2. If vulvar hematoma, appropriate treatment is: a. Incise outside of the hymeneal ring and evacuate b. Incise inside of the hymeneal ring and evacuate c. Observe for enlargement and evacuate only if expansion d. Avoid evacuation because of the risk of hemorrhage
Management of Vulvar Hematoma
• Almost all are due to straddle injuries • Initial management – Pressure – Ice packs – Watchful waiting • Complex management – Use if extreme pain or failure of conservative mgt – Incise inside hymeneal ring, evacuate clots – Pack with strip gauze, sitzbaths This patient has a complaint of severe vulvar itching and pain to touch for one year
Which term is not a synonym for this condition a. Lichen sclerosus b. Squamous cell hypoplasia c. Atrophic dystrophy d. Kraurosis vulvae
Complaint of severe vulvar itching and pain to touch for one year
Which term is not a synonym for the diagnosis of this condition a. Chronic reactive intertrigo b. Squamous cell hyperplasia c. Hyperplastic dystrophy d. Neurodermatitis ISSVD 1987: Vulvar Dermatoses
Type ISSVD Term Old Terms Atrophic Lichen sclerosus • Lichen sclerosus et atrophicus • Kraurosis vulvae Hyper‐ Squamous cell • Hyperplastic dystrophy plastic hyperplasia • Neurodermatitis • Lichen simplex chronicus Systemic Other • Lichen planus dermatoses • Psoriasis Pre‐ VIN • Hyperplasic dystrophy/atypia malignant • Bowen’s disease • Bowenoid papulosis • Vulvar CIS ISSVD: International Society for the Study of Vulvar Disease
2006 ISSVD Classification of Vulvar Dermatoses
• No consensus agreement on a system based upon clinical morphology, path physiology, or etiology • Include only non‐Neoplastic, non‐infectious entities • Agreed upon a microscopic morphology based system • Rationale of ISSVD Committee – Clinical diagnosis no classification needed – Unclear clinical diagnosis seek biopsy diagnosis – Unclear biopsy diagnosis seek clinic pathologic correlation 2006 ISSVD Classification of Vulvar Dermatoses Path pattern Clinical Corrrelates Spongiotic Atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis Acanthotic Psoriasis, LSC (primary or superimposed), (VIN) Lichenoid Lichen sclerosus, lichen planus Dermal Lichen sclerosus homogenization Vesicolobullous Pemphigoid, linear IgA disease Acantholytic Hailey-Hailey disease, Darier disease, papular genitocrural acantholysis Granulomatous Crohn disease Vasculopathic Apthous ulcers, Behcet disease, plasma c. vulvitis
Lichen Sclerosus: Natural History
• Most common vulvar dermatosis • Bimodal ages: children, older women • Cause: probably autoimmune • Chronic, progressive, lifelong condition • Most common in Caucasian women • Can affect non‐vulvar areas • Squamous cell carcinoma of the vulva (SCCV) – 3‐5% lifetime risk – 30‐40% SCC of vulva develops with LS Lichen Sclerosus: Findings • Symptoms – Itching, burning, dyspareunia, dysuria • Signs – Thin white “parchment paper” epithelium – Fissures, ulcers, bruises, or hemorrhage – Submucosal hemorrhage – Depigmentation (white) or hyperpigmentation in “keyhole” distribution: vulva and anus – Introital stenosis and loss of vulvar architecture – Reduced skin elasticity
“Early” Lichen Sclerosus
Hyperpigmentation due to scarring
Loss of labia minora Lichen Sclerosus
Fissures
Thin white epithelium
“Late” Lichen Sclerosus Agglutination of clitoral hood Loss of labia minora Introital narrowing
Parchment paper epithelium 68 year old woman with urinary obstruction
Labial agglutination over urethral meatus
Lichen Sclerosus: Treatment
• Biopsy mandatory for diagnosis • Preferred treatment – Clobetasol 0.05% ointment QD x4 weeks, then QOD x4 weeks, then twice‐weekly for 4 weeks – Taper to med potency steroid (or clobetasol) 2‐4 times per month for life – Explain “titration” regimen to patient, including management of flares and recurrent symptoms – 30 gm tube of ultrapotent steroid lasts 3‐6 mo – Monitor every 3 months twice, then annually Lichen Sclerosus: Treatment
• Second line therapy – Pimecrolimus, tacrolimus – Retinoids, potassium para‐aminobenzoate • Testosterone (and estrogen or progesterone) ointment or cream no longer recommended • Explain chronicity and need for life‐long treatment • Adjunctive therapy: anti‐pruritic therapy – Antihistamines, especially at bedtime – Doxypin, at bedtime or topically – If not effective: amitriptyline, desipramine PO • Perineoplasty may help dyspareunia, fissuring
Lichen Simplex Chronicus
Thickened, raised, leathery epithelium Lichen Simplex Chronicus
• End‐stage outcome of acute inflammation: eczema, infections, LS • Occurs in women from 30 to 60 years of age • Accentuation of skin markings • Vulva is red or pink with overlying grey‐white keratin layer
Lichen Simplex Chronicus = Squamous Cell Hyperplasia
• Irritant initiates “scratch‐itch” cycle – Candida – Chemical irritant – Allergen – Lichen sclerosus • Presentation: always itching; sometimes pain, tenderness • Thickened leathery red (white if moisture) raised lesion • In absence of atypia, no malignant potential – If atypia present , classified as VIN L. Simplex Chronicus: Treatment
• Removal of irritants or allergens • Treatment – Triamcinolone acetonide (TAC) 0.1% ointment BID x4‐6 weeks, then QD – Other moderate strength steroid ointments – Intralesional TAC once every 3‐6 months • Anti‐pruritics – Hydroxyzine (Atarax) 25‐75 mg QHS – Doxepin 25‐75 mg PO QHS – Doxepin (Zonalon) 5% cream; start QD, work up
Lichen Sclerosus + LSC
• “Mixed dystrophy” deleted in 1987 ISSVD System • 15% all vulvar dystrophies • LS is irritant; scratching causes LSC • DDX: LS with plaque, candida, VIN • Treatment – Clobetasol x12 weeks, then steroid maintenance – Stop the itch!! General Vulvar Care Measures
• Wear loose fitting clothing • 100% cotton underwear – Rinse underwear twice – Low irritant soap; no use of fabric softeners • 100% cotton menstrual pads – www.gladrags.com • Mild bathing soaps: Cetaphil, Kiss‐My‐Face, Basis • Vulvar water rinse (or very soft toilet paper) • Use vaginal lubricants: Replens, KY, Olive Oil
Rules for Topical Steroid Use
• Topical steroids are not a cure – Use potency that will control condition quickly, then stop, use PRN, or maintain with low potency • Limit the amount prescribed to 15 grams • Ointments are stronger, last longer, less irritating • Show the patient exactly how to use it: thin film • L. minora are steroid resistant • L. majora, crural fold, thighs thin easily; get striae • At any suggestion of 2o candidal infection, use steroid along with topical antifungal drug Case Study
• 42 year old women with “dark bumps” on her vulva • Initially noticed by her partner; finding confirmed by family practice doctor • Bumps cause mild itching, but not severe • Smokes 1 pack of cigarettes per day for 20 years • Exam: multiple hyperpigmented papules
Genital Skin: Dark Lesions (% are in women only)
• 36% Lentigo, benign genital melanosis • 22% VIN • 21% Nevi (mole) • 10% Reactive hyperpigmentation (scarring) • 5% Seborrheic keratosis • 2% Malignant melanoma • 1% Basal cell or squamous cell carcinoma Vulvar Intraepithelial Neoplasia (VIN): Prior to 2004
• Due to infection with HPV 18 or LSC (no HPV) • Graded I‐III, based upon severity of atypia • Symptoms: itching, burning, ulceration • The mnemonic of the 4 P’s – Papule formation: raised lesion – Pruritic: itching is prominent – “Patriotic”: red, white, or blue (hyperpigmented) – Parakeratosis on microscopy
ISSVD 2004: Squamous VIN
• Since VIN 1 is not a cancer precursor; abandon the term – Instead, use “condyloma” or “flat wart” • Combine VIN‐2 and VIN‐3 into single “VIN” diagnosis • Two distinct variants of VIN – VIN, usual type • Warty type • Basaloid type • Mixed warty‐basaloid – VIN, differentiated (simplex) type Vulvar Intraepithelial Neoplasia
• Risk of invasion: greater if immunocompromised (steroids, HIV), >40 years old, previous lower genital tract neoplasia • Treatment – Wide local excision: highest cure rate, esp hair‐bearing
– CO2 laser ablation: best cosmetic result – Topical agents: imiquimod – Skinning or simple vulvectomy rarely used • Recurrence is common (48% at 15 years) – Monitor @ 6,12 months, then annually – Smoking cessation may reduce recurrence rate • Prevention: HPV‐4 vaccine
White VIN Hyperpigmented VIN
Vulvar Intraepithelial Neoplasia Lichen Sclerosus with Scarring
Junctional Nevus Vulvar Melanoma: ABCDE Rule
• A: Asymmetry • B: Border Irrigularities • C: Color black or multicolored • D: Diameter larger than 6 mm • E: Evolution – Any change in mole should arouse suspicion – Biopsy mandatory when melanoma is a possibility
Indications for Vulvar Biopsy
• Papular or exophtic lesions, except obvious condylomata • Thickened lesions (biopsy thickest region) to differentiate VIN vs. LSC • Hyperpigmented lesions (biopsy darkest area), unless obvious nevus or lentigo • Ulcerative lesions (biopsy at edge), unless obvious herpes, syphilis or chancroid • Lesions that do not respond or worsen during treatment • In summary: biopsy whenever diagnosis is uncertain Tips for Vulvar Biopsies
• Where to biopsy – Homogeneous : one biopsy in center of lesion – Heterogeneous: biopsy each different lesions • Skin local anesthesia – Most lesions will require ½ cc. lidocaine or less – Epinephrine will delay onset, but longer duration – Use smallest, sharpest needle: insulin syringe – Inject anesthetic s‐l‐o‐w‐l‐y • Alternative: 4% liposomal lidocaine (30 minutes) or EMLA (60 minutes) pre‐op
. Stretch skin; twist 3 or 4 mm Keyes punch back‐and‐ forth until it “gives” into fat layer Tips for Vulvar Biopsies
. Lift circle with forceps or needle; snip base . Hemostasis with AgNO3 stick or Monsels . Separate pathology container for each area biopsied
The most likely diagnosis is: a. Bartholin duct cellulitis b. Bartholin duct abcess c. Bartholin duct cyst d. Gartner’s duct cyst If this lesion is a Bartholins duct abcess, best initial treatment is: a. Oral antibiotic therapy b. Parenteral antibiotic therapy c. I&D with placement of a Word catheter or gauze packing d. Marsupialization
Bartholin Duct Conditions
• Bartholin duct and gland at 5, 7 o’clock cephalad (deep) to hymeneal ring • Makes serous secretion to “lubricate” introitus • If BG duct is transected or blocked, fluid accumulates – Non‐infected: BD cyst – Infected: BD abscess or cellulitis • Needle aspiration of fluid may aid in diagnosis • All treatments are designed to drain and create a new duct Bartholin Duct: Infectious Conditions
• Bartholin duct cellulitis – Most commonly due to skin streptococcus – Red induration of lateral perineum – No abcess cavity (fluctulence) palpated – Treat with PO cephalosporin, moist heat – Will either resolve or point as abcess – Treat immunecompromised women aggressively
Bartholin Duct: Infectious Conditions
• Bartholin duct abscess – Fluctulent abcess; pus with needle aspiration – Treatment •Incise and drain •Insert Word catheter x 6 weeks – Culture pus for gonorrhea – Cephalosporin if cellulitis; metronidazole if anaerobic Bartholin Duct: Non Infectious • Bartholin duct cyst – Nontender cystic mass – Treat only if symptomatic or recurrent – Tx: marsupialize or Word catheter x 6 weeks • Bartholin duct carcinoma – Most common in women over 40 – Can be adenoca, transitional cell, or squamous – Firm non‐tender mass at Bartholin gland – Suspect if BD cyst, abcess with mass after drainage
Bartholin Gland: Infectious Conditions
• Bartholin gland cellulitis – Painful red induration of lateral perineum at 5 or 7 o’clock, but no palpable abscess – Most commonly due to skin streptococcus – Treatment: oral cephalosporin, moist heat – Will either resolve or point as abcess – Admit immunecompromised women (especially diabetics) for IV antibiotics and close observation •May develop necrotizing fasciitis Bartholin Duct: Infectious Conditions
• Bartholin duct abscess – Usually due to Staph, but may contain anaerobes – Fluctulent painful abscess; if uncertain, needle aspiration will confirm pus – Treatment: I&D, then insert Word catheter for 6 weeks – Antibiotics usually not needed, unless •Cellulitis (cephalosporin) •Anaerobic smell with drainage (metronidazole)
BD Abscess: I&D . Retract abscess laterally to select incision site… inside the hymeneal ring if possible . Inject 3 cc. lidocaine . 1 cm incision with #15 blade perpendicular to abscess . Lyse loculations with clamp . Irrigate cavity with saline . Insert Word catheter; inflate until snug fit in abscess cavity . Tuck nipple into vagina Word Catheter: Correct Position Evaluation and Treatment of Common Musculoskeletal Complaints
Katherine Julian, MD July 2014
No conflicts of interest Outline of Session
Joint Anatomy (Knee and Shoulder) Exam Demonstration: HIT ME NOT1 History Inspect Touch Move Extra maneuvers Things to NOT miss Exam Practice Cases (knee and shoulder)
Neuman WR, Cato RK, Fosnocht KM, O’Rorke. SGIM, 2006
The Knee Knee: Top 3 Diagnoses in Primary Care Referrals to Ortho (at UCSF)
Osteoarthritis Meniscus tear Patellofemoral Pain
Courtesy of Carlin Senter, MD, UCSF
Knee Anatomy Quadriceps Tendon
Meniscus Patella Tendon
http://www.bigkneepain.com/knee_anatomy.html Quadriceps muscles extend the knee Hamstrings flex the knee
Flota.com http://www.rolfing.com.sg/Hamstring.html
Knee Ligaments – Provide Stability MCL: resists valgus Medial femoral condyle to medial tibia (crosses medial jointline) LDL: resists varus Lateral femoral condyle to fibular head (crosses lateral jointline) ACL: resists anterior
www.straightbackphysio.co.uk tibial translation PCL: resists posterior tibial translation Knee - History
Mechanism of injury? Effusion? Immediate or delayed Sounds? Unstable? Locking or catching
Knee - History
“Point to the Pain” Medial Knee Pain (most common) Osteoarthritis Anserine Bursitis Medial Meniscal Injury Lateral Knee Pain Lateral Meniscal Injury Osteoarthritis Iliotibial band tendonitis Knee - History
“Point to the Pain” Anterior Knee Pain (most common < 45 yrs) Patellofemoral syndrome Patellar tendonopathy Severe OA Prepatellar bursitis Posterior Knee Pain Baker’s Cyst Vascular Sciatica
Knee - Inspect
Symmetry (standing) Alignment (valgus/varus stresses) Atrophy of muscles Swelling vs. effusion Effusion=intra-articular joint pathology Swelling=soft tissue injury, www.bonesmart.org bursitis, tendonitis Redness Knee - Touch
Temperature By compartment Test for Effusion TAP the PAT Milk suprapatellar pouch with downward pressure Tap patella against femur (check for “bob”) Can also feel for effusion with hand wrapping around the tibia
Traumatic knee effusion Atraumatic knee effusion
ACL (or ligament) tear Meniscus tear Patellar OA dislocation/subluxation Crystal arthropathy (gout, Meniscus tear pseudogout) Patellar or quadriceps rupture Inflammatory arthritis Fracture Septic joint Bone contusion Benign or malignant tumor Cartilage injury OA exacerbation in OA pt Knee - Touch
Lying down with knee slightly flexed… Palpate and move the patella Tendons (two fingers) Quadriceps Patellar Tibia (two fingers) Tuberosity Medial: joint line, MCL, anserine bursa Lateral: joint line, LCL, fibular head, biceps femoris, iliotibial band
Knee - Move
Passive ROM Extend as far as possible (normal 0 degrees) Flex knee as far as possible (normal 135 degrees) Active ROM Resisted flexion and extension at 120 degrees “Lock” the Knee Can’t lock---suspicion for meniscal injury (bucket handle) Knee – Extra Maneuvers
Patellar assessment Patellar apprehension test Knee flexed 45⁰ Fingers at medial patella Try to move patella laterally
Knee – Extra Maneuvers
Anterior Cruciate Ligament Anterior Drawer Knee flexed 90⁰ Foot fixed slight external rotation Sens 22-41%, spec 97% Lachman Test Knee flexed 30⁰ Stabilize distal femur with one hand and grasp proximal tibia with the other Sens 75-100%, spec 95- 100% Compare both sides! Knee – Extra Maneuvers
Posterior Cruciate Ligaments Posterior sag sign Knee flexed 90 Look for posterior displacement of the tibia Posterior drawer test Knee flexed 90 Foot fixed in neutral position Thumbs at tibial tubercle Push posteriorly
Knee – Extra Maneuvers
Collateral ligaments MCL Leg slightly abducted Valgus Stress At full extension (0⁰ degrees). Repeat at 30⁰ flexion Why test at flexion and extension? Laxity only with flexion: isolated collateral ligament injury Laxity with both: collateral ligament injury + possible cruciate ligament injury Knee – Extra Maneuvers
Collateral ligaments LCL Leg slightly abducted Varus Stress At full extension (0⁰ degrees). At 30⁰ flexion Compare both sides
4 Tests to Assess for Meniscal Tear Isolated joint line tenderness McMurray Thessaly Squat Knee – Extra Maneuvers
Menisci McMurray Test Medial meniscus Feel medial joint line Tibia rotated externally Knee extended from maximal flexion to extension Add varus stress with extension Positive test = thud, click or pain
Knee – Extra Maneuvers
Menisci McMurray Test Lateral meniscus Feel lateral joint line Tibia rotated internally Knee extended from maximal flexion to extension Add valgus stress with extension Thessaly Test
Better sensitivity than McMurray Examine both knees Stand on normal first Flex 5⁰ then 20⁰ Positive test=pain at joint line with possible locking/catching sensation
Karachalios et al. JBJS, 87AL;955‐962.
Knee – Not To Miss
Effusion Joint Instability Ligament injury Red-flags Night pain Fever Weight Loss Limp Could indicate infection or tumor Practice!!
Knee Exam
History Extra Maneuvers Inspection Patellar apprehension Touch Anterior drawer/Lachman Effusion Posterior drawer Jointlines Valgus stress Tendons Varus stress McMurray Move Thessaly Passive ROM (extend, flex) (Squat) Active ROM at 120 degrees Lock the knee Common Knee Complaints
Case One 27 yo man with knee pain X 3 months. Started after injury in soccer game. Pain medial side of knee. Worse with twisting/squatting. Knee “gives out”. Swells intermittently. Dx? Meniscal tear
Meniscal Injuries
Menisci provide cushion between tibia and femur History: twisting injury to knee with foot in weight- bearing position. Popping or tearing sensation Pain medial or lateral Locking may occur Slow effusion; if no effusion, consider alternate dx Exam? Joint line tenderness Long-standing dz, may see quadriceps atrophy May see positive McMurray or Thessaly test Meniscal Injuries
Treatment RICE X 2-6 weeks Rest→crutches Ice Compression→bulky compression dsg from mid-thigh to mid- calf Elevation Exercise: quad strengthening with gentle ROM in 2-3 days Refer if no better 2-6 weeks May need surgery Concern for bucket-handle injury→referral
Common Knee Complaints
Case Two 18 yo woman with knee pain X 1 month Pain anterior knee. Hurts to walk and go up stairs. Knee “gives out” due to pain. Dx? Patellofemoral Pain Syndrome Patellofemoral Pain Syndrome
Cause unknown Pain over anterior aspect of knee in absence of other pathology Any injury/anatomic abnormality that predisposes to irregular movement of the patella can lead to PFS Symptoms Pain beneath/near patella Pain with squatting/prolonged sitting Pain with single leg knee dip
Patellofemoral Pain Syndrome
Treatment Reassurance No or limited bent-knee activities. Avoid stairs. Straight leg raises to prevent atrophy Quad stretching twice/day. One minute. NSAIDS, ice, heat May take 3 months to improve If not better, consider PT, re-examine (check Dx) Common Knee Complaints
Case Three 60 yo woman with six months of knee pain Pain medial aspect of knee. Relieved by rest with am stiffness. Dx? DJD
Knee DJD
Are symptoms from meniscus (catching/locking/localized) or arthritis (pain with weight-bearing, diffuse)? All patients with arthritis have meniscal tears X-ray Standing AP both knees, both laterals and merchant/sunrise view If normal X-ray→meniscal Common Knee Complaints
Case Four 37 yo woman with knee injury 2 years ago with knee instability Was playing tag football and was “clipped”. Knee swelled immediately, iced. Didn’t seek medical attention. Couldn’t bear weight immediately, but gradually improved. No pain now, knee unstable. Dx? Ligament tear (likely ACL)
Ligament Injuries
Mechanism: Forceful stress against knee when weight-bearing Valgus stress: MCL Varus stress: LCL Twisting injury (pop): ACL Ligament Injuries
Collateral (except complete LCL) RICE, early rehab Can use functional hinged braces Complete tear of LCL→surgery to prevent instability later Isolated cruciate injuries Attempt at non-surgical treatment unless high demands on joint
Ligament Injuries
Chronic instability Most often from ACL deficiency, deterioration Usually not painful (unless torn meniscus) Treatment depends on degree of instability and how much it bothers the patient PT Hamstring strengthening Common Knee Complaints
Case Five 45 yo man c/o pain in the posterior knee. Now swollen. On exam, posterior knee swollen with mass lateral to the medial hamstrings in the popliteal fossa Dx? Baker’s Cyst
Baker’s Cyst
Enlargement of popliteal cyst (semimembranous bursa present in medial aspect of popliteal space) Typically secondary to intra-articular pathology (for adults) Chronic effusion communicates from joint to cyst and fluid escapes into bursa Baker’s Cyst
Treat primary (underlying) abnormality Can aspirate and inject with steroids if needed…
Common Knee Complaints
Case Six 45 yo woman c/o anterior knee pain. Started gardening this spring. Knee is painful and red. Dx? Prepatellar bursitis Pre-Patellar Bursitis
Pre-patellar bursa lies between the skin and patella Acute Trauma→bloody Atraumatic (friction, kneeling) If red, aspirate it BUT NOT THE JOINT. If not red, leave it alone. Treatment: avoid friction, NSAIDS, time, immobilizer or ace-wrap PRN
The Shoulder Shoulder: Top 3 Diagnoses in Primary Care Referrals to Ortho (at UCSF) Rotator cuff disease Subacromial bursitis Tendinitis or tendinopathy Partial tear Full thickness tear Frozen shoulder (adhesive capsulitis) Glenohumeral joint osteoarthritis
Courtesy of Carlin Senter, MD, UCSF
The Shoulder - Anatomy
Three bones Scapula Clavicle Humerus 4 Articulations Glenohumeral Scapulothoracic Acromioclavicular Sternoclavicular Rotator Cuff Muscles (SITS)
Supraspinatus Abduction Infraspinatus External rotation Teres Minor External rotation (adduction) Subscapularis Internal rotation Adduction
Shoulder Impingement
Inflammation of the subacromial space Under the acromion and above the glenohumeral joint Structures=supraspinatus, subacromial bursa Sx: hurts with reaching, brushing hair Shoulder
Exam Demonstration: HIT ME NOT History Inspect Touch Move Extra maneuvers Things to NOT miss
Shoulder - History
Hand dominance Occupation/hobbies (Lifting? Overhead activities?) History of dislocation or recent injury? What hurts? Where does it hurt? Pain that radiates past elbow---consider cervical spine Don’t forget conditions that cause radiation of pain into shoulder ROM limitation? Shoulder - Inspect
Examine with both shoulders widely exposed Contour Symmetry Dislocation Fracture Atrophy (anterior AND posterior) Infraspinatous atrophy increases LR of rotator cuff disease Swelling Difficult to assess
Shoulder - Touch
Temperature 3 Places to Touch Acromioclavicular joint Subacromial space Biceps tendon Check both sides Some sites tender even if normal shoulder Shoulder - Move
Active ROM Forward Flexion Extension Abduction Internal Rotation (reach backwards behind shoulder blade) External Rotation (elbows at sides or hands behind head) Compare both sides!
Shoulder - Move
If full ROM actively, no need to test passive ROM If loss of both active and passive ROM?? 2 things to consider Adhesive capsulitis Severe OA of glenohumeral joint X-ray will help you differentiate Shoulder - Move
Supine Passive ROM Outward motion=external rotation Inward motion=internal rotation
Shoulder – Extra Maneuvers
Impingement tests Rotator cuff tests Biceps tests Labral tears AC joint: crossover maneuver Shoulder Impingement– Hawkin’s Test Forward flex arm to 90⁰ with elbow bent 90⁰ Arm then internally rotated Positive test = subacromial impingement
Shoulder Impingement – Neer’s Test “Near the ear” Thumb down Forward flexion of arm to 180 degrees Extra Maneuvers – Rotator Cuff Disease (RCD) RCD can include: Rotator cuff muscle tendinopathy (1 or more of the 4 rotator cuff muscles) Full tear Partial tear Subacromial bursitis Pain provocation tests Pain and strength tests
Extra Maneuvers Rotator Cuff - Painful Arc
If painful, positive LR 3.7 for RCD. If not painful, negative LR 0.36 for RCD
Hermans J, et al. The rational clinical examination: does this patient with shoulder pain have rotator cuff disease? JAMA, 2013;310(8). Extra Maneuvers Rotator Cuff - Drop Arm Test
Arm passively raised to 160⁰ Pt asked to slowly lower arm to the side Positive test = inability to control lowering and dropping of the arm Dx = large rotator cuff tear
Positive LR 3.3 for rotator cuff disease
Hermans J, et al. The rational clinical examination: does this patient with shoulder pain have rotator cuff disease? JAMA, 2013;310(8).
Extra Maneuvers Rotator Cuff – Empty Can Pain and strength test Tests supraspinatus (abduction) Arms abducted 90⁰ and forward flexed 30⁰ Thumbs downward Resist downward force Extra Maneuvers Rotator Cuff – External Rotation Pain and strength test Tests infraspinatus and teres minor Pts arms held at their sides with elbow flexed 90⁰ Patient pushes externally against resistance
Extra Maneuvers Rotator Cuff - Lift Off
Pain and strength test Tests subscapularis Arm internally rotated behind back Hand is lifted off back and pt must maintain position Alternate: bear hug to opposite shoulder Positive LR 5.6 for full thickness rotator cuff tear. Negative LR 0.04 Hermans J, et al. The rational clinical examination: does this patient with shoulder pain have rotator cuff disease? JAMA, 2013;310(8). Extra Maneuvers Rotator Cuff – External Rotation Lag Test
Strength test Tests supraspinatus and infraspinatus Examiner passively rotates the pt’s arm into full external rotation Positive=pt unable to maintain full external rotation Positive LR 7.2 for full thickness rotator cuff tear
Hermans J, et al. The rational clinical examination: does this patient with shoulder pain have rotator cuff disease? JAMA, 2013;310(8).
Extra Maneuvers Biceps - Speeds
Test for biceps pathology (tendinitis, tendinopathy, tear) Palms up, patient pushes up against resistance (elbows flexed) Positive = pain at proximal biceps tendon Sens 54% spec 81% Extra Maneuvers Biceps – Yergasons Test for biceps pathology (tendinitis, tendinopathy, tear) Pt supinates (twists out) against resistance “Turn a door knob” Positive = pain at proximal biceps tendon and strength Sens 41% spec 79%
Extra Maneuvers Labral Tear – O’Brien’s Test
Arm forward flexed to 90° Elbow fully extended Arm adducted 10° to 15° with thumb down Downward pressure Repeat with thumb up Suggestive of labral tear if more pain with thumb down Sens 59-94%; spec 28-92% Labral Tear
Young athletes from acute trauma, weight lifters Clicking or catching SLAP = superior labrum anterior-posterior is typical pattern MRI vs. MR arthrogram Tx conservative management (PT, injection, time); surgery if fails Pts > 50 yrs labrum degenerates, not a source of pain and is incidentally seen
Extra Maneuvers AC Joint - Crossover Maneuver Arm crosses over body Can be done passively by pt or physician Tests for AC joint OA or sprain Positive = pain at AC joint Shoulder – NOT to Miss
Referred pain! Cardiac Abdomen (subdiaphragmatic) Pulmonary (Pancoast tumor) Radicular Always examine the neck
NOT to Miss – Neck Exam
Inspection, palpation of C-spine, ROM Spurling’s Neck extended Head rotated towards affected shoulder Axial load placed Reproduction of shoulder/arm pain = possible nerve root compression More Practice…
Inspect Neck Exam Touch Spurling’s AC joint Extra maneuvers Subacromial space Hawkin’s Impingement Biceps tendon Neer’s Move Rotator cuff tests Drop arm Active (flexion, extension, abduction, internal/ext Empty can rotation) External rotation Painful arc? Lift off External rotation lag Passive if needed Crossover maneuver
Shoulder – Diagnostic Imaging
Who Needs an X-Ray? Chronic shoulder pain No improvement after treatment Odd hx or PE, history of trauma Standard plain radiographic series for the shoulder… Anteriorposterior Axillary (i.e. lateral) Scapular Y view Assesses shape of acromion Helps to determine humeral head dislocation Shoulder – Diagnostic Imaging
Why get X-rays? Can determine DJD of AC and glenohumeral joint Large rotator cuff tear = superior migration of humeral head Calcific tendinitis MRI Rotator cuff tears
Common Shoulder Complaints
Case One 65 yo woman with h/o overuse shoulder injury after painting. This was 4 months ago. Now with painful shoulder and limitation of motion On exam, limited active ROM and passive ROM DDx Adhesive capsulitis Glenohumeral joint OA What test to do next? X-ray Adhesive Capsulitis
Insidious onset of pain and restriction of motion in all planes Pain usually AFTER significant loss of motion Pain usually localized to rotator cuff; may radiate down deltoid and anterior aspect of arm Interferes with sleep More common in women and diabetics Cause unknown, but can be post-traumatic
Adhesive Capsulitis
Examination Deltoid and/or supraspinatus atrophy Tenderness around rotator cuff and biceps tendon Active and passive ROM restricted Best Dx test: no passive external rotation DDx: glenohumeral joint infection vs. DJD Treatment Prevention! Injection ROM exercises (hourly!) Shoulder Joint Infection
Red, angry-looking shoulder = septic arthritis of AC joint Aspirate, labs, X-Ray, refer Glenohumeral joint infection Rare Shoulder looks normal, just bigger SEVERE pain with any motion Often a fever More in diabetics, immunocompromised
Glenohumeral Arthritis
Rare Seen as secondary process RA, avascular necrosis, chronic rotator cuff disease Overuse of shoulder (ex: baseball pitchers) Age > 50 yrs Chronic pain, limited motion May see atrophy and crepitus Dx: X-ray Treatment: injection, NSAIDS, stretching Common Shoulder Complaints
Case Two 50 yo woman c/o pain in lateral aspect of arm. Started over last 6 weeks. No inciting trauma. Pain radiates down deltoid area. Pain worse at night. +painful arc, +Neers/Hawkins, +pain with empty can and 4/5 strength DDx?
Rotator Cuff Pathology
Risk factors for degeneration of the rotator cuff Age (tears rare <40) Impairment of cuff vascularity Repetitive microtrauma External abnormalities that narrow the subacromial space Osteophytes Shape of acromion With time, overlying bursa and tendons affected Rotator Cuff Pathology
Impingement Friction Overuse Bursitis→tendonitis→rotator cuff tear Bursitis = pain but not when testing cuff Tendonitis = hurts when cuff muscles are tested Rotator cuff tear = weakness (often without pain)
Rotator Cuff Pathology
Impingement/Bursitis History: pain with overhead activity Lateral shoulder (may radiate to deltoid) Often night pain Can’t lie on shoulder May have tenderness over supraspinatus insertion Rotator Cuff Tear - Treatment
If rotator cuff weakness present→order x-rays and MRI Full thickness tear→refer to ortho Better surgical outcomes if full thickness tears fixed earlier Less muscle atrophy and retraction
Rotator Cuff Tear
Treatment Partial/small tears Treat like tendonitis Some will require surgical treatment Based on pain, age, activity level, degree of tear Rotator Cuff Pathology
Impingement Treatment Activity modification No activity with elbow away from side Once daily, fully stretch overhead NSAID, ice Injection 3-6 weeks PRN PT AFTER pain subsides Regain ROM and strengthen rotator cuff
Common Shoulder Complaints
Case Three 40 yo man playing flag football over the last year (he’s the quarterback). Now with pain over anterior- lateral shoulder +TTP biceps tendon, +Speeds, +Yergason’s DDx? Biceps Tendonitis
Inflammation of biceps tendon and its sheath in the bicipital groove May be primary disorder or secondary to rotator cuff pathology Can be difficult to differentiate from rotator cuff disorders
Special Case: Rupture of Long Head of Biceps
Usually occurs without much trauma Result of advanced degeneration Sudden onset Sharp snap, pain, arm weakness (minimal, usually some supination lost) Usually, no treatment needed Modern Management of Sleep Disorders
Douglas C. Bauer, MD University of California, San Francisco
No Disclosures
“If Only I Could Sleep Like I Did Before…” Sleep Case
• 52 yr. old WF with >4 yr. of “poor sleep” • Difficulty with both initiation and maintenance of sleep. Few daytime symptoms • Bedtime 10PM, up between 7-10 depending upon her sleep that night. Naps intermittently. • Denies depression, anxiety, bad habits • Previous MD prescribed valium 5-10mg 3-5 times per week. • What else would want to know and what do you want to do?
Topics Covered
• Prevalence and potential consequences • Sleep physiology • Insomnia evaluation and treatment • Sleep disordered breathing and parasomnias Question: Which of the following statements is false?
1) Average duration of sleep in the US is 6.9 hours 2) The most common frequency of insomnia is almost every night 3) 95% of sleep disorders are never diagnosed and treated 4) The prevalence of sleep disorders increase with age
Sleep Disorders
• Sleep per night: 9 hr in 1910, 6.9 hr now • 40 million in US suffer from sleep disorders • 95% are undiagnosed and untreated • Sleep disorders 30% more common in women • Prevalence of sleep disorders increases with age • Frequent complaint in primary care… Percent Reporting Symptoms of Insomnia 35%
30%
25%
20%
15%
10%
5%
0% Almost Every Night Few times/week Few times/month Rarely/Never
2002 ‘Sleep in America’ poll, National Sleep Foundation
Definitions
• Insomnia (insufficient or poor quality sleep) – Latency (time to fall asleep) – Efficiency (proportion of time in bed asleep) • Hypersomnia (excessive daytime sleepiness) - Sleep disordered breathing/sleep apnea - Narcolepsy • Parasomnia (coordinated motor activity) -Restless leg syndrome Sleep Architecture
• REM (Rapid Eye Movement) - Characteristic eye movement - EEG resembles wakefulness • Non REM - 75% of sleep - Four stages: correlate with depth of sleep - Progressive cortical inactivity • Sleep architecture changes over age 65 - Reduced stage 3 and 4, phase advancement - total time, latency, efficiency
Special Populations: Insomnia in the Elderly
• High prevalence (> 50%) • Often secondary to a primary sleep disorder • Commonly associated with psychiatric disorders or depression Special Populations: Older Women Which of the Following is True?
1) Perimenopausal insomnia is primarily difficulty maintaining sleep 2) Insomnia is more common in peri- than postmenopausal women 3) Correlates with frequency of vasomotor symptoms 4) HRT fully relieves perimenopausal insomnia
Special Populations: Perimenopausal Women
• Prospective study of >3000 women 42-52 followed for 7 yr (SWAN) • Sleep complaints worse in both peri and postmenopausal women (40% vs. 22%) – Both initiation and maintenance of sleep impaired – Partly attributable to hot flushes – Improved but not fully reversed with HRT – Other neurocognitive effects?
Kravitz et al, Sleep, 2008 Presentation and Screening for Insomnia
• Typical presentation – Difficulty initiating or maintaining sleep – Wake after sleep onset – Early morning awakening – Awakening not rested • Recommended screening question: “Do you have trouble falling asleep or staying asleep?” • If positive, consider sleep questionnaire Medical Conditions That Cause Insomnia
• Hyperthyroidism • Heart failure • Arthritis • Neurological disorders • Chronic renal failure • Dementia/AD • Chronic lung disease • Parkinson’s disease
Drugs That Cause Insomnia
• Alcohol • Decongestants • CNS stimulants • Stimulating • Beta-blockers antidepressants • Bronchodilators • Thyroid hormones • Calcium channel • Nicotine blockers • Corticosteroids Evaluation of Insomnia: History, Exam and Labs
• General history and exam • Sleep pattern (patient and bedroom partner) - Insufficient sleep time - Delayed onset, frequent/early awakening - Associated nocturnal symptoms and daytime symptoms • Consider thyroid function, glucose, UA • Formal sleep study rarely indicated
Insomnia Therapies
• Which of following is superior to benzodiazepine receptor agonists for primary insomnia? 1) sleep hygiene 2) cognitive behavioral therapy 3) anti-histamines 4) anti-depressants (TCA, SSRI, and trazadone) Treatment of Insomnia: Non-Pharmacologic
• Treat underlying disorders • Begin with non-pharmacologic treatment* - Sleep education (changes with aging) - Sleep hygiene (diet, exercise, habits, environment) - Establish optimal sleep pattern
* “Relief from Insomnia” by Charles Morin
Non-Pharmacologic Therapy: Cognitive Behavioral Therapy • Cognitive therapy – Change maladaptive thought processes • Behavioral therapy (stimulus control, sleep restriction, relaxation, good sleep hygiene) • RCT of 46 adults with chronic insomnia – Superior short and long-term (6 mo) outcomes with CBT compared to zopiclone or placebo Sivertsen et al, Jama 2006 Buysse et al, Arch Intern Med, 2011 Suggested Approach to Insomnia In Primary Care
Insomnia Chronic Acute >4 wks <4 wks
Primary? Assess trigger Consider brief tx Secondary cause? Hypersomia or Sleep hygiene parasomnia? CBT Treat and Evaluate and treat Refer if persists reassess
Treatment of Insomnia: Pharmacologic
• Depression - TCA, trazadone, SSRI, combinations (suppress REM) - Not recommended if not depressed • Anxiety, panic - Benzodiazepines (suppress REM and non REM stage 3 and 4) - Not recommended if not anxious • Primary insomnia: what to use? Treatment of Insomnia: Pharmacologic
• Problems with anti-histamines: anti- cholinergic, sedation, cognitive dysfunction • Problems with benzodiazepines: habit forming, tachyphylaxis, suppression of REM sleep, cognitive dysfunction, falls • Short-term benzodiazepine use (<2 wk) may be helpful in some patients • Alternatives to benzodiazepines? Benzodiazepine Receptor Agonists
• Zolpidem (generic), zaleplon (Sonata), eszopiclone (Lunesta) - Activate 1 of 3 benzodiazepine receptors - No anxiolytic or muscle relaxing effects - No tolerance (studies up to one year) - Preserves REM, less withdrawal, little abuse - Rapid onset, half life 2-3 hours • Longer and shorter half-life versions available – CR zolpidem if awakens too early with generic – Sublingual zolpidem (Intermezzo) for middle of the night awakening. Note women 1.75 mg, men 3.5 mg
An unexpected side effect… Other Drugs
• Melatonin (OTC) - From pineal gland, receptors in hypothalamus - Low serum levels = poor sleep - Poor evidence for insomnia, maybe for jet lag or phase delay - Not regulated; long term safety? • Ramelteon (Rozerem) – Melatonin receptor agonist. FDA approved but no long-term safety data
AHRQ Evidence Report #108, 2011
What’s the Diagnosis? Hypersominas: Sleep Apnea
• Obstructive more common than central • Apnic episodes, loud snoring, choking, gasping during sleep • Key feature: insomnia not common but usually associated with daytime sleepiness • Risk factors include: • Older age • Male sex • Obesity • Craniofacial structure
Definition of Sleep Apnea
• Apnea = cessation of respiration • Hypopnea = partial decrease (>50%) of respiration • Duration 10 seconds Respiratory Disturbance Index (RDI): – # apneas + hypopneas / hour while asleep – Normal RDI < 5, severe apnea 15 Prevalence of Sleep Disordered Breathing
• Heavily dependent on definition used • 2-4% in younger adults (20-60 yrs) • > 10% in elderly
Consequences of Sleep Disordered Breathing
• Impaired QOL (as with insomnia) • Increased risk of accidents & injuries • Mild cognitive impairment/dementia – 85% increased risk if RDI>15 in older women • Increased risk of hypertension and cardiovascular events – Sleep Heart Study
Yaffe et al Jama, 2011 Sleep Heart Study: HTN by Quartiles of RDI
45% 40% P(trend)<.001 in 35% both men and 30% women 25% Men 20% Women 15% 10% 5% 0% <1.25 1.25-<4.0 4.0-<10.7 10.7+
Shahar, Am J Respir Crit Care Med. 2001 163(1):19-25
Sleep Heart Study: CVD by Quartiles of RDI* 1.60 1.40 1.20 1.00 P<.0003 0.80 0.60 0.40 0.20 0.00 Q1 (ref) Q2 Q3 Q4
*Both sexes, all ages Evaluation of Sleep Disorders: Sleep Studies • Polysomnography (oximetry, EEG, EKG, EMG, observation) • Home monitoring (oximetry + 1-2 others) if not medically complicated • Indications - Unexplained hypersomnia (esp. with snoring) - Unexplained sleep-related CV abn (pulm HTN) - Abnormal complex sleep behavior - Unremitting chronic insomnia that does not respond to therapy Flemons et al, Chest, 2003
Other Causes of Hypersomnia: Narcolepsy - Extreme daytime sleepiness, frequent brief naps, cataplexy - Rare, familial, presents in 20s and 30s - Requires sleep study and daytime Multiple Sleep Latency Test (MSLT) - Treatment: stimulants, anticholinergics Parasomnias: Restless Leg Syndrome • Intense dysesthesias, repetitive jerking - Worse at bedtime, frequently awakens patient - Often familial, progresses with age • Etiology unknown, associated with iron deficiency • Treatment - Sinemet 25/100 qhs (70% respond) - Clonazepam 0.5-2 mg qhs - Dopamine agonists (rotingotine, pergolide, etc) effective but intolerance common
Scholz et al, Cochrane Database, 2011
Conclusions • Sleep disorders are common • Associated with significant morbidity • Primary care providers can diagnose and treat most patients with insomnia • Drug treatments over utilized, non- pharmacologic treatment often successful • Specialty referral (sleep study) for selected patients with unexplained hypersomnia or severe insomnia Case
• 52 yr. old WF with >4 yr. of “poor sleep” • Difficulty with both initiation and maintenance of sleep. Few daytime symptoms • Bedtime 10PM, up between 7-10 depending upon her sleep that night. Naps intermittently. • Denies depression, anxiety, bad habits • Previous MD prescribed valium 5-10mg 3-5 times per week. • What else would want to know and what do you want to do? Update in the Diagnosis, Treatment and Prevention of Dementia*
Katherine Julian, M.D. Professor of Clinical Medicine University of California, San Francisco July 11, 2014
Conflicts of Interest
No Conflicts of Interest Case
EM is a 67 year-old woman with a h/o high blood pressure. Brought in by husband who is reporting that patient’s personality has changed over the last year. She is becoming more suspicious, and at times talks and “doesn’t make sense”.
Questions...
Does EM have dementia or Alzheimer’s Disease (AD)? How do I make the diagnosis? Outline
Clinical Presentation Diagnosis Updates in Treatment Updates in Prevention Resources
AD Prevalence
AD estimated prevalence 24.3 million world-wide in 2001 Predicted rise to 42.3 million in 2020 81.1 million by 2040 Lifetime risk of dementia after age 65 is 17-20% Costs $150 billion/yr
Ferri CP, et al. Lancet 2005; Simmons BB et al. AAFP 2011 Dementia Types
Alzheimer’s: most common, 70% Vascular: approx 17% Other types: 13% Parkinson-related Alcohol Dementia with Lewy Bodies
Pathophysiology of AD
Neuritic plaques Amyloid precursor protein cleaved Makes beta amyloid protein Accumulation initiates cell death Neurofibrillary tangles filaments of abnormally phosphorylated tau protein Loss of neurons Cholinergic, noradrenergic, serotonergic neurotransmitters Is it amyloid deposition that kills neurons OR are neurons being damaged by something else? Risk Factors for AD/Dementia
Age Down’s syndrome Head trauma Fewer years of formal education Female sex Family history Vascular risk factors (DM, htn, smoking)
Clinical Presentation of Dementia
Cognitive changes Personality changes Changes in day-to-day functioning IADLs that require calculation/planning first to be impaired Psychiatric symptoms Problem Behaviors Dementia under-diagnosed High index of suspicion Ask caregivers/surrounding family and friends Definitions of Dementia* by DSM5 Dementia No longer using the term “dementia” Neurocognitive disorder Due to… Alzheimer’s Disease Vascular Disease Lewy Body, etc
DSM5 Neurocognitive Disorders (NCD)
Minor neurocognitive disorder Modest cognitive decline from a previous baseline Can be in any domain (ex: memory, language, executive function, etc) Based on pt’s concerns AND knowledgeable informant (or clinician) AND Decline in neurocognitive performance (1-2 SD below normal) on formal testing or equivalent clinical evaluation Cognitive decline doesn’t interfere with independence but requires some compensation Can’t occur due to delirium Deficits can’t be from another mental disorder (ex: depression) Example: Mild cognitive impairment: impairment doesn’t affect function DSM5 Neurocognitive Disorders (NCD)
Major neurocognitive disorder Evidence of substantial cognitive decline in one or more domains Based on pt’s concerns AND knowledgeable informant (or clinician) AND Decline in neurocognitive performance (>2 SD below normal) on formal testing or equivalent clinical evaluation Cognitive decline is sufficient to interfere with independence (ex: requires assistance with IADLs or ADLs) Can’t occur due to delirium Deficits can’t be from another mental disorder
Rapid Screening for Cognitive Impairment
3/14 USPSTF insufficient evidence to recommend for or against screening (for dementia and MCI) Variety of office screening tests MMSE most studied: sens 88.3%; spec 86.2% (MOCA sens 90% in limited studies for MCI) Clock drawing sens range 67-97%; spec 69-94.2%
2014 USPSTF Consensus Statement Lin JS, et al. Ann Intern Med, 2013;159:601-612 Diagnostic Instruments Mini Mental Status Exam Maximum score 30 Score <24 suggests delirium or dementia Decline of 4 points over 1-4 years significant Scores correlated with education level; inversely correlated with age Not sensitive in people with higher levels of education
Diagnostic Instruments
MMSE Survey of 18,056 adults Scores relate to age Median score 29 in those 18-24 years Median score 25 in those >80 years Scores relate to educational level Median score 29 in those with >9 years schooling Median score 22 in those with 0-4 years schooling
Crum RM et al. JAMA, 1993;269(18) Work-Up of Cognitive Impairment
American Academy of Neurology recommendations: Vitamin B12, thyroid, depression screen Other tests as indicated: blood count, urine tests, liver tests, syphilis test, lumbar puncture Neuro imaging (CT or MRI) Do we need to do this?
“Reversible” Dementias…do they exist?
Meta-analysis in 2003 5620 subjects; potentially reversible causes in 9%; 0.6% actually resolved Causes of “dementia” in meta-analysis 56% AD 20% vascular 1% metabolic 0.9% depression 0.1% medications 15% Other (NPH, subdural hematoma, B12, tumor, Parkinson’s disease, HIV, frontal lobe)
Clarfield AM. Archives of Internal Medicine, 2003;163. “Reversible” Dementias…do they exist? Most reversible dementias were in patients who: Were relatively young Had mild or atypical symptoms Neuroimaging detected conditions in 2.2% 0.9% tumor, 1% NPH, 0.3% SDH Most did not change course of illness Reversible dementias less common Must weigh costs/benefits of neuro-imaging AGS recommends imaging: age <60, rapid decline (weeks/months), CA, HIV, anti-coagulation
Clarfield AM. Archives of Internal Medicine, 2003;163.
Neuro-Imaging – Updates
Semi-quantitative MRI Medial temporal lobe atrophy in AD New studies looking at hippocampal and cortical thickness Aß PET with florbetapir F-18 (Amyvid) highlights brain beta-amyloid Approved by FDA April 2012 Median sensitivity 92% (range 69-92%) and median specificity 95% (range 90-100%) Positive scan does not establish the dx—use as adjunct May overlap with other brain pathologies
Pearson SD, et al. JAMA, 2014;174(1). Example of 18F-FDG-PET
Alzheimer’s Disease Neuroimaging Initiative, Jan 2010
Diagnosis of AD – Updates
Abnormal CSF biomarkers Low beta-amyloid Increased tau/phosphotau concentrations No consensus on cutoff points for real practice Perfusion SPECT Resolution less but less expensive Diagnostic Instruments
Caution in interpreting MMSE score Consider appropriate age/education median scores MMSE scores for age/education available on the web Median LR for positive result 6.3 (CI 3.4-47) If positive initial screen, can consider further testing if appropriate
Holsinger T, et al. JAMA, 2007;297.
Diagnostic Instruments
Highly educated individuals Neuropsychological testing May be better in detecting early impairment
Holsinger T, et al. JAMA, 2007;297. Diagnostic Instruments…Take Home Points
Tests not quite ready for “prime time” but coming… PET scanning (although approved) MRI (atrophy of temporal lobe) CSF ß-amyloid CSF tau APOEε4 genotyping Not enough evidence for USPSTF to recommend screening for dementia in primary care
Case
78 year-old woman recently diagnosed with Alzheimer’s Disease. MMSE score is 19. What should you do next? 1) Start an acetylcholinesterase inhibitor (ex: donepezil or aricept) 2) Start memantine 3) Do not start any medications at this time 4) Discuss with the family/patient their wishes regarding treatment Treatment of AD Clarify goals Preserve function and independence Maintain quality of life Minimize excess disability and ensure safety Make long-term decisions early Treatment Options Symptomatic treatment of memory disturbance Symptomatic treatment of behavioral disturbance Disease-modifying treatment
Symptomatic Treatment of Memory Disturbance
Cholinesterase Inhibitors delay degradation of acetylcholine at the synaptic cleft. Indicated for mild- moderate Alzheimer’s Disease Donepezil (Aricept)--5-10mg/day Rivastigmine (Exelon)--6-12mg/day May cause weight loss Galantamine (Razadyne)--24-32mg/day or patch 4.6- 9.5mg May cause weight loss Cholinesterase Inhibitors
Donepezil and Galantamine Metabolized by cytochrome P450 system ChEIs Common side effects: nausea, vomiting, diarrhea Take with food Interruption of meds = start back at lowest dose If changing meds due to SE, washout period 7-14 days Vivid dreams: take in am Bradycardia, AV block
Cholinesterase Inhibitors…What’s the Data? Studies range 12 weeks to 3 years Pts on ChEIs compared to placebo ADAS-cog evaluates memory, attention, language, orientation (score 0-70) Average difference on ADAS-cog -4 Outcome Clinician Interview Based Assessment of Change Statistically significant differences, but most do not show clinically significant changes
Qaseem A, et al. Ann Intern Med, 2008;148. What’s Clinically Significant?
Long-term donepezil treatment evaluated 565 patients with mild-mod AD randomly assigned to donepezil 5mg or placebo for 12-week run-in Followed up to 3 years End points: Institutionalization or progression of disability (loss of ADLs)
AD2000 Collaborative Group, Lancet 2004;363.
Symptomatic Memory Treatment?
Long-term donepezil treatment No difference in rates of institutionalization or disability progression No difference in care costs, unpaid caregiver time, behavioral/psychological symptoms Costs of drug not offset by any positive outcomes
AD2000 Collaborative Group, Lancet 2004;363. Cholinesterase Inhibitors…Take Home Points
Likely no disease modifying effects – modest cognitive improvement Delay progression 6mo-1yr Guidelines: “Base the decision to initiate therapy on individualized assessment” Insufficient evidence regarding head-to-head comparisons; choose medication based on SE and dosing
Case
78 year-old woman recently diagnosed with Alzheimer’s Disease. MMSE score is 19. What should you do next? 1) Start an acetylcholinesterase inhibitor (ex: donepezil or aricept) 2) Do not start any medications at this time 3) Discuss with the family/patient their wishes regarding treatment Other Options in Memory Treatment?
80 year-old woman with progression of her Alzheimer’s Disease. She is currently being treated with Aricept at 10mg/day. Her recent MMSE=11. Are there other treatment options?
Other Options in Mod-Severe AD?
Memantine (Namenda) NMDA-receptor antagonist Glutamate stimulates NMDA receptor; overstimulation results in neuronal damage Pooled estimate from 3 trials (vs. placebo) Statistically significant improvements on ADAS-cog scale but modest clinical improvement Memantine combined with donepezil
Qaseem A, et al. Ann Intern Med, 2008;148 Tariot PN et al. JAMA, 2004;291(3). Other Options in Mod-Severe AD? New dose of donepezil 23mg daily approved 2010 for moderate-severe AD
Guidelines in Memory Treatment?
Take Home Points… First line therapy in mild-mod AD (if treatment decided) is cholinesterase inhibitors If treatment failure/not tolerated, can either: Change to another ChEI Add memantine Change to memantine (or increase donepezil) Consider memantine for moderate-to-severe dementia Guidelines in Memory Treatment?
When to stop treatment? If quality of life benefits no longer possible (as determined by family, provider) Pt dependent in all basic activities of daily living
Disease-Modifying Treatment of AD
Anti-oxidants? Vitamin E Anti-inflammatories? Statins? Ginkgo biloba? Treatment of AD: Vitamin E Free radicals and oxidative damage contributes to neuronal death Vitamin E traps free radicals Mixed results in studies 1997 study showing some benefit of vitamin E 2008 Cochrane review: no benefit of vitamin E 2014 JAMA: 2000 IU resulted in slower decline (approx. 6 mo) in mod-sev AD. Study underpowered
Sano et al. NEJM, 1997;336 Issac MD et al. Cochrane Database Syst Review, 2008 Dysken MW, JAMA, 2014;311(1)
Side Effects of Vitamin E?
Can increase risk of bleeding—particularly in pts on coumadin Meta-analysis of 19 RCT 135,967 patients on vitamin E (16.5-2000 IU/d) Dose >400 IU associated with increased mortality (Risk difference 39 per 10,000 people CI 3-74) Lower-dose vitamin E associated with decreased mortality IOM recommending dose <1000 IU/day
Miller ER, et al. Ann Intern Med, 2005;142:37-46. Treatment of AD
Negative trials Anti-inflammatories (ibuprofen, naproxen, celecoxib, indomethacin) Statins (simvastatin, atorvastatin) Dietary supplements (multi-vitamins, fatty acids) Mixed data on Gingko – Cochrane review inconsistent benefit High doses: GI SE, may increase bleeding in patients on ASA/coumadin
Birks J, et al. Cochrane Database of Systematic Reviews, 2007;2.
Disease-Modifying Treatments...Take Home Points
Mixed evidence for Vitamin E (Old) guidelines 1000 IU BID; IOM 1000 IU daily No evidence for other treatments What’s Next?
Amyloid precursor protein (APP) → amyloid-beta fragments
ß-secretase Ƴ-secretase
Inhibitor of Ƴ-secretase: Semagacestat Monoclonal Ab binds soluble amyloid beta fragments Solanezumab Bapineuzumab
What’s Next?
Question: Does semagacestat improve cognition in patients with probable Alzheimer’s disease? Study Design: Double-blind, PCT 1537 patients semagacestat (2 doses) vs. placebo Outcomes: Terminated early—worsened cognition scores, more weight loss, skin cancers, infections
Doody RS, et al. N Engl J Med, 2013;369(4). What’s Next?
Question: Do monoclonal antibodies Solanezumab and Bapineuzumab improve cognitive scores in mild-mod AD Study Design: 2 double-blind, RCT Outcomes: No improvement in cognitive testing. Safety finding: more brain edema
Doody RS, et al. N Engl J Med, 2014;370 Salloway S, et al. N Engl J Med, 2014;370
Prevention of AD Case
60 year-old woman with strong family history of Alzheimer’s Disease. She is concerned about her own risk for dementia. What is the best prevention treatment can you offer?
A) She should start ERT B) She should take a statin…forget about that package warning! C) She should start an NSAID D) She should exercise Updates in Prevention Estrogen Replacement Therapy
Women’s Health Initiative Memory Study 4532 healthy post-menopausal women (65-79) Randomized to estrogen/progestin or placebo Estrogen/progestin increased risk for probable dementia (HR 2.05) 2947 randomized to estrogen only or placebo Increased risk of development of probable dementia (HR 1.49; CI 0.83-2.66))
Shumaker SA, et al. JAMA, 2003;289(20). Shumaker SA, et al. JAMA, 2004;291(24).
More on Estrogen/Progesterone
Olmstead county cohort: all women 1950- 1987 who underwent oophorectomy prior to menopause for non-cancer indication 1,433 with unilateral; 1,824 with bilateral Each cohort member matched to control Oophorectomy before menopause: Increased risk of dementia compared to control (HR 1.46, CI 1.13-1.9)
Rocca WA, et al. Neurology, 2007;69. Estrogen/Progesterone
Findings supported by 2 other cohort studies showing earlier age with surgical menopause associated with cognitive decline
Is there a “window of opportunity” when hormones are actually beneficial?
Updates in AD Prevention Should Statins be in the Water?
RCT: Pravastatin vs. placebo in 5804 people aged 70-82 years No difference in cognitive function after 3.2 years RCT: Simvastatin vs. placebo in 20,536 people aged 40-80 No difference in incidence of dementia No evidence statins prevent vascular dementia
Shepard J, et al. Lancet, 2002;360. Heart Protection Study Collaborative Group. Lancet, 2002;360. Reports that statins may worsen cognition Case reports (described in 60 adults) Review of all statin studies: benefits outweigh risks 1 RCT simvastatin impaired some measures of cognition compared to placebo Preliminary data: hydrophilic statins (ie, pravastatin and rosuvastatin) may be less likely to contribute to cognitive impairment due to limited penetration across the blood-brain barrier
Rojas-Fernadez CH, et al. Ann Pharmacother, 2012.
Prevention of AD with Anti-Inflammatory Drugs
Meta-analysis of observational studies NSAIDS >2yrs reduced risk by 73% Confounding? RCT 2528 volunteers >70 yrs with FH AD Naproxen vs. Celebrex vs. Placebo Study stopped after 3 years: no evidence anti- inflammatories prevent AD
BMJ, 2003(327), Neurology 2007(68) Sleep and AD Sleep and AD = bidirectional relationship Brain regions involved in sleep and circadian control affected early in AD Patients with AD often have worse quality of sleep Sleep changes may precede onset of cognitive symptoms Amyloid deposition associated with worse sleep quality Chicken or the egg? Chronic disrupted sleep likely has some cognitive effect
Obesity and Risk of AD
Kaiser Permanente 6,583 members Sagittal abdominal diameter (SAD) measured 1964-1973 with medical records f/u 1994-2006 Marker for metabolic syndrome Higher SAD associated with increased dementia risk Highest quintile of SAD: HR for dementia 2.72 (CI 2.33-3.33) Thigh adiposity didn’t increase dementia risk
Whitmer RA, et al. Neurology, 2008 Exercise and Dementia Prevention
Meta-analysis 33,816 non-demented patients followed prospectively Subjects with high-level physical activity protected against cognitive decline (HR 0.62 CI 0.54-0.7) Low-moderate exercise also protective (HR 0.65; CI 0.57-0.75)
Sofi F et al. J Intern Med, 2011
Leisure Activities and Risk of AD
775 older adults followed for 5 years Current and past cognitive activities rated Higher rate of participation in cognitive activity was associated with reduced incidence of AD (HR 0.58)
Wilson RS, et al. Neurology, 2007;69 Prevention of AD – Cognitive Reserve
Evidence suggests that cognitive reserve is protective against AD Education Occupation Mental activities
β-Amyloid 42/40, Cognitive Reserve and Cognitive Decline
Yaffe K, et al. JAMA, 2011;305(3) Prevention of AD…Take Home Points
Estrogen replacement therapy is out for now… Statins good for hyperlipidemia but not to prevent dementia Get out there and exercise! Be a “pear” rather than an “apple” Chess never hurt anyone Stay in school
Prevention of AD Case
60 year-old woman with strong family history of Alzheimer’s Disease. She is concerned about her own risk for dementia. What is the best prevention treatment can you offer?
A) She should start ERT B) She should take a statin C) She should start an NSAID D) She should exercise Prevention of AD – Stay Positive!
Observational studies with increased dementia risk Mid-life htn Current Smoking Diabetes No evidence yet that treatment decreases dementia risk
Prevention of AD – Stay Positive! • To estimate impact of risk factor reduction on AD prevalence for 7 modifiable factors: . Diabetes ▪ Mid-life hypertension . Mid-life obesity ▪ Depression . Physical inactivity ▪ Low education . Smoking • Population attributable risks (PARs) • Tools to estimate proportion of disease attributable to given risk factor, accounting for prevalence & strength of association • Calculations • Risk factor prevalence worldwide, U.S. • Relative risk from most recent/comprehensive meta-analysis or systematic review Barnes, DE and Yaffe K. Lancet Neurol, 2011;10 Prevention of AD – Stay Positive
3,000,000 10% Reduction 25% Reduction 2,000,000
1,000,000
0 No. AD No. AD Cases Prevented, Worldwide
Barnes DE and Yaffe K. Lancet Neurol, 2011
Evaluation of Driving Risk in Dementia – Practice Parameter
Patient is at increased risk for unsafe driving if: Clinical Dementia Rating Scale > 0.5 (level A) Caregiver rates patient’s driving ability as marginal or unsafe (level B) Pt has a h/o crashes/traffic citations (level C) Pt has reduced driving mileage or self-reported situational avoidance (level C) MMSE < 24 (level C) Pt with aggressive/impulsive personality characteristics (level C)
Iverson DJ, et al. Neurology, 2010;74. Resources
Alzheimer’s Disease Education and Referral (ADEAR) Center 800-438-4380 http://www.nia.nih.gov/alzheimers Alzheimer’s Association 800-272-3900 www.alz.org Safe Return Program American Academy of Neurology http://www.aan.com/go/practice/guidelines Early Pregnancy Loss and Abortion: Patient-centered Counseling & Evidence-based Care Jody Steinauer, MD, MAS
Dept. of Obstetrics, Gynecology & Reproductive Sciences University of California, San Francisco
Disclosures
• I have no relevant financial disclosures. • I will discuss off-label use of misoprostol.
Acknowledgements • Robin Wallace & Carolyn Sufrin Julie is a 23 year-old G1P0 at 6+5 by LMP with spotting x 1 day, no pain, β-HCG = 2672.
MSD = 25mm, no fetal pole
Objectives
1. Review early pregnancy loss – Review diagnostic features – Compare management options • Discuss role of patient preferences • Expectant, medical, aspiration (office vs. OR) 2. Review first-trimester abortion – Pregnancy options counseling – aspiration and medication techniques Early Pregnancy Loss (EPL)
Clinical diagnosis: Ultrasound diagnosis: Spontaneous abortion Anembryonic gestation Vaginal bleeding + IUP, <20 wks Trophoblast development without threatened, inevitable, incomplete, development of an embryo complete
Embryonic demise Embryo with no cardiac activity • 15-20% of clinically-recognized pregnancies • 1 in 4 women experience EPL
Stages of SAB: VB, + IUP, <20 wks
STAGE: Os: Tissue & U/S:
No tissue passed Threatened Closed IUP on U/S
No tissue passed Inevitable Open IUP on U/S
Tissue passed Incomplete Open +/- IUP on U/S
Tissue passed Complete Closed No IUP on U/S Normal Implantation
Implantation: •5-7 days after fertilization •Takes ~72 hours •Invasion of trophoblast into decidua production of HCG
Embryonic disk: 1 wk after implantation
Diagnosis of EPL: β-HCG
• β-HCG detectable 6-12 days after ovulation • Median serum concentration: 4 weeks: 100 mIU/ml (5-450) 10 weeks: 60,000 (5,000 – 150,000) • Decline and plateau ~20,000 • No correlation b/t β-HCG and GA Diagnosis of EPL
Bleeding, pain, LMP, 1. Clinical presentation examination
2. β-HCG Isolated value, trend
3. Ultrasound Sac, pole, pseudosac
Ultrasound & Early Pregnancy: Key Findings
Gestational sac Double decidual sign Grows ~ 1mm/day Yolk Sac
Early circulatory system Embryonic Pole Grows ~ 1mm/day Cardiac Activity 100bpm140 bpm What is the beta-hcg level above which you should see at least a gestational sac if a pregnancy is normal and can call it abnormal if you don’t see it? a. 1500 b. 2000 c. 3000 d. 4000
Beta Curves, Redefined Letting go of the “double in 48 hours” rule • Rate of increase depends on gestational age1
• 49 normal intrauterine pregnancies • Doubling time varies by gestational age <5 wks: 1.5 d 5-6 wks: 2 d >7 wks: 3d
1. Pittaway 1985 Fertil Steril & Am J Ob Gyn Beta Curves, Redefined Letting go of the “double in 48 hours” rule • Early studies used 85% CI as lower limit1 – Retrospective study of 20 women – Mean doubling time 2 days – 66% increase in 48 hrs • Poor sensitivity and specificity in cohort: – Of 12 ectopics – 17% normal rise – Of 16 normal pregnancies - 18% abnormal rise • Newer data - different median and mean 2
1. Kadar 1981 Obstet Gynecol 2. Barnhart 2004 Obstet Gynecol
Beta Curves, Redefined Letting go of the “double in 48 hours” rule
• 287 women with pain or bleeding and +UPT – No IUP on U/S but eventually had normal IUP – Initial β-HCG < 5000 • Ave GA by LMP = 38 days (range, 0-107) • At least 2 β-HCG’s within 7 days
Barnhart 2004 Obstet Gynecol β HCG Trends in Normal IUP
99%Median of nl rise: IUPs 1 day1 day= rise 50%≥ 24% 2 2day day rise =124% ≥ 53%
Slowest expected increase for normal pregnancy = 53%
Barnhart 2004 Obstet Gynecol
Discriminatory &Threshold level
• Threshold = lowest at which you can see • 366 ♀ with VB/pain nl IUP 99% Predicted Probability of Detection Discriminatory Threshold Gestational sac 3510 2600 390 Yolk sac 17,716 1094 Fetal pole 47,685 1394
Old values: 1500= 80% & 2000= 91% prob. of seeing GS in viable IUP
Connolly 2013 Obstet Gynecol Society of Radiologists in Ultrasound: No Gestational Sac
• HCG > 2000 In women with desired – Non-viable pregnancy most likely, 2X ectopic pregnancy consider beta – Ectopic is 19 x more likelyhcg cut-offthan viable of >= 3000. pregnancy • HCG > 3000 – Ectopic 70 x more likely than Worryviable pregnancy about ectopic. • HCG 2000 – 3000 – Viable pregnancy: 2% chance – For each viable pregnancy: • 19 ectopics • 38 nonviable pregnancies
What is the mean sac diameter at which you should see a fetal pole if a pregnancy is normal and can call it abnormal if you don’t see it?
a. 18 mm b. 20 mm c. 21 mm d. 25 mm Ultrasound Diagnosis of EPL: Anembryonic Gestation
Mean sac diameter >=21mm (20 mm = 0.5% false positive) AND no fetal pole
Abdallah et al 2011 (Aug) Ultrasound Obstet Gynecol
Ultrasound Diagnosis of EPL:
This image cannot currently be displayed. Anembryonic Gestation MSD, no YS, no embryo
MSD (mm) Specificity False + Growth per day (wk) Specificity False + 8mm 64% 36% 0.2mm (1.4mm) 99% 1% 16mm 95.6% 4.4% 0.6mm (4.2mm) 90% 10% 20mm 99.5% 0.5% 1.0mm (7mm) 45% 55% 21mm 100% 0 1.2mm (8.4mm) 24% 76% GROWTH: MSD, + YS, no embryo 0 mm/d= 0 False+ MSD (mm) Specificity False + Growth per day (wk) Specificity False + 8mm 35.7% 64.3% 0.2mm 98.6 1.4 16mm 97.4% 2.6% 0.6mm 87.3 12.7 20mm 99.6% 0.4% 1.0mm 43.7 56.3 21mm 100% 0 1.2mm 25.2 74.8
Abdallah et al 2011 (Aug and Oct) Ultrasound Obstet Gynecol Ultrasound Diagnosis of EPL: Embryonic Demise
Fetal pole >= 5.3 mm AND no cardiac activity
Abdallah et al 2011 (Aug) Ultrasound Obstet Gynecol
Ultrasound Diagnosis of EPL: Embryonic Demise
CRL (mm) Specificity False + Growth per day (wk) Specificity False + 3mm 75% 25% 0.2mm (1.4mm) 100% 0% 4mm 91.7% 8.3% 0.6mm (4.2mm) 56.3% 63.7% 5mm 91.7% 8.3% 1.0mm (7mm) 0* 5.3mm 100% 0 1.2mm (8.4mm) 0% 0%
*16 FP, 0 TN. 37 TP, 1 TN
Abdallah et al 2011 (Aug & Oct) Ultrasound Obstet Gynecol Ultrasound Milestones
When should Abnormality you see it? Gestational Sac Discriminatory Level Ectopic v. abnl IUP β = 2000-3000+ Multiple gestation Complete SAB Yolk sac MSD>13-16mm (wait for fetal pole) Fetal pole MSD ≥ 21mm Anembryonic gestation
Cardiac activity Fetal pole ≥ 5.3mm Embryonic demise
Radiologists in Ultrasound: Account for Margin of Error
MSD 21 25 mm
Fetal pole 5.3 7 mm
Article problematic: Studies already account for error Recommend waiting 10-14 d Empty sac – risk of ectopic Summary: Diagnosis of EPL
• Be cautious of only one point of information • Determine whether pregnancy is desired • Clinical history varies • HCG rise in 48 hours: Minimum 53% • Ultrasound: – No growth of small sac (IUP not confirmed) – No cardiac motion of pole > 5.3 (7) mm – Anembryonic sac > 21 (25) mm MSD
Remember ectopic pregnancy
Julie is a 23 year-old G1P0 at 6+5 by LMP with spotting x 1 day, no pain. β-HCG = 2672
MSD = 25mm, no fetal pole
Anembryonic Gestation EPL Management
Expectant Medical aspiration
Depends on: 1. Hemodynamic stability 2. Patient preference and follow-up 3. Stage in miscarriage process 4. Local resources
Women’s Preferences
There is no “one best way.”
Expectant management is preferred over aspiration by 70% of women.
When uterine aspiration is indicated or preferred, the majority of women will choose an office-based procedure over one in the OR.
Smith 2006; Wieringa-de Waard 2002; Dalton 2006 Women’s Preferences • Surgery – Quick resolution – Want and value support from hospital staff1 • Expectant – Desire a natural solution1 – Fear of operation1 – More preferred with higher level information & support2 – 71% with success would opt for same in future3 • Misoprostol – Faster resolution – More natural solution without surgery
1. Ogden & Marker Brit J ObGyn 2004; 2. Molnar J Am Board of Fam Pract; 3. Wieringa-DeWaard et al. J of Clin Epi, 2004
Patient Priorities
Pain Time Complications
Safety Bleeding Privacy
Past Anesthesia Finality experience
Adapted from Wallace et al 2010 Patient Educ Couns ©Robin Wallace, 2011 Personal Priorities Physical Priorities o Treatment by your own provider o Least amount of pain possible o Recommendation of treatment from friend o Fewest days of bleeding after treatment or family member o Lowest risk of complications o Provider recommendation of treatment o Lowest risk of need for other steps o Experience symptoms of bleeding and o Avoid invasive procedure cramping in private o Avoid medications with side effects o Family responsibilities/needs o Avoid seeing blood o Avoid going to sleep in case of a aspiration procedure o Want to be asleep in case of a aspiration Emotional Priorities procedure o Most natural process o Avoid seeing the pregnancy tissue Time and Cost Priorities o Shortest time before miscarriage is complete Previous Miscarriage or Abortion o Shortest time in the clinic or hospital (if applicable) o Fastest return to fertility or normalcy o Different treatment from previous o Fewest number of clinic visits o Similar treatment to previous o Lowest cost of treatment to you
Adapted from Wallace et al 2010 Patient Educ Couns ©Robin Wallace, 2011
EPL Management Practices in the U.S.
50
45
40
35
30 Ob/Gyn CNM FP 25
20
15
10
5 Percent providers EPF of Percent 0 Expectant Misoprostol Office aspiration OR
n=976 ob-gyn, family medicine, CNMs
Adapted from Dalton AJOG 2010 Which management strategy for early pregnancy loss has the highest success at 1 week? a. Expectant management b. Medical management (misoprostol) c. Uterine aspiration
Overall Success Rates
Expectant Overall 60%-70% (14 days) Anembryonic 50% Embryonic Demise 35%-60% Incomplete 75% - 85%
Misoprostol 800 mcg PV 70% - 96% (7 days) Anembryonic 81% Embryonic Demise 88% Incomplete 93%
Aspiration 97% - 100% Expectant Management: Completion Rates
Day 7 Day 14 Day 46 (%) (%) (%) Incomplete Ab (n=221) 53 71*-84 91 Anembryonic gestation 25 53*/52 66 (n=92) Embryonic demise (n=138) 30 35*-59 76 Total (n=451) 40 61*-70 81
* n=203 - Casikar Luise 2002 BMJ *Casikar 2010 Ultrasound Obstet Gynecol
Expectant Management: Contraindications
• Uncertain diagnosis • Severe hemorrhage or pain • Infection • Suspected gestational trophoplastic disease • Indicated karyotyping
Same contraindications for medical management Expectant Limitations
•Size:Studies generally include gestations up to 9 weeks •Time:Safety established up to 6 weeks of observation • Maternal conditions: inappropriate for bleeding at home • Social: inability to obtain prompt emergency care, understand precautions
Misoprostol
• PGE1 analogue • Tabs 100 mcg unscored, 200 mcg scored • Inexpensive • Rapidly absorbed PO, PV, PR, SL, buccal • Common obstetrical uses: labor induction, medical abortion, PPH, cervical ripening Misoprostol: Off-label Use
• FDA approved for prevention/tx of gastric ulcers • Once licensed, FDA does not regulate how used1 • Commonly practiced, often standard of care1 • Not experimental if based on sound scientific evidence2
1. Friedman, FDA Deputy Commissioner speech to U.S. House of Representatives 1996 2. Rayburn, Obstet Gynecol 1993
Medical Management: Misoprostol for EPL • Small studies with wide range of doses, follow- up and definition of success – 800 mcg vaginally, repeated in 24h PRN1,2 – ↑ Side effects with PO, buccal, SL – 400-600 mcg buccal or sublingual3
• Success (avoid aspiration intervention) 70-96%4 – Incomplete: higher success • More acceptable than aspiration5,6 • 90% would choose again
1. .Zhang et al, NEJM, 2005 4. Sur et al. Best Pract ObG 2009 2. Weeks et al, Obstet Gynecol 2005 5. Wood et al, Ob Gyn 2002 3. Gemzell-Danielsson, Int J Obstet Gynecol 2007 6. Demetroulis et al, Hum Reprod 2001 Misoprostol vs. Aspiration: MEPF Study • 652 ♀ w/ EPL or incomplete Ab Miso or D&C • D1: Miso 800 mcg PV – D15: follow-up (all) • Success (no need for additional D&C) by D 8 – Miso: 84% (CI, 81-87) vs. D&C: 97% (CI, 94-100) – Lowest for anembryonic demise (81%) – 70% success after 1 dose; 60% after 2nd dose • Complications: No difference • Satisfaction: No difference (78% vs. 83%)
Zhang et al 2005 NEJM
Example of Misoprostol Algorithm
Miso 800 mcg PV
Cramping w/ clot/tissue No clinical passage in 24-48 hrs (Rhogam for Rh- women) in 24-48 hrs
7 Days Clinical f/u 2nd Dose Miso on D3 U/S if indicated
Sac present or Clinical signs No Sac & (Endometrium >30 mm) of passage (endometrium<=30mm) DONE! DONE!
If still sac (or endo>30mm) after 2 doses: Follow up precautions Recommend suction Bleeding should stop in 2-3 wks If wants expectant mgmt, f/u 2-4 wks Menses should resume in 6-8 weeks Suction if signs of infection or HD instability Adapted from Goldberg 2009 in Mgmt of unintended & abnl pregnancy Aspiration Management: Suction Curettage • Safe, high efficacy (>95%) • No need to do in Operating Room – Outpatient or ED setting – cost-effective – Manual Uterine Aspiration / Manual Vacuum Aspiration
Used with 5-12 mm cannulae Capacity 60 cc
Aspiration Management: MUA/MVA • Manual v. electric: no difference - complication (2.5% vs. 2.1%)1, pain, provider or pt. satisfaction2,3 • MUA in ER compared to EVA in OR:4
EVA in OR MUA in ER Wait time (↓52%) 7.14 hrs 3.45 hrs Procedure time 33 min 19 min Total cost (↓ 41%) $1404 $827
2012 study supports cost-effectiveness of outpatient MUA to OR-based UA5
1.Goldberg 2004 Ob Gyn; 2.Dean, Contraception 2003; 3. Edelman A. Ob Gyn 2001;184:1564; 4. Blumenthal 1992 IJOG; 5. Raush Fertil Steril 2012. Moving MUA out of OR
90% uterine aspirations are done in OR • Process described by U Michigan – Medical evidence review – Review of hospital policy for office procedures – Trained physicians, nurses, and MAs • Hands-on workshops – Institution of privileging program – Review experience of patients – Review cost – gyn reimbursement same, lower institutional cost - $1965 v. $968
Harris, AJOG, 2007.
Overall Success Rates
Expectant up to 70-85% in 2 wks
Misoprostol (800 mcg pv) up to 81-96% success in 1 week
Uterine Aspiration: 97%-100% The Patient – Provider Interaction
•Affects patient choice and satisfaction •One half of women would change their decision based on our recommendation
Support women in identifying their values in and priorities for management.
Be prepared to offer all options, including misoprostol and office-based uterine aspiration.
Molnar 2000
The Patient – Provider Interaction
• Threatened Abortion – Keep the patient informed • Provide reassurance, but avoid guarantees that “everything will be all right” • Provide support through process • What does the bleeding mean? – 50% ongoing pregnancy with closed os – 85% ongoing pregnancy with viable IUP on u/s
– Up to 30% of normal pregnancies have VB The Patient – Provider Interaction
• Remain silent after initial results or information • Follow-up with open-ended questions & active listening • Use neutral responses • Determine how the woman feels about the pregnancy • Normalize emotions • Validate feelings rather than trying to change them • Avoid opinions about what patient ‘‘should’’ do • Encourage seeking emotional support from others • Assure that you will be available to her through the process, and answer questions as they arise
Wallace, Patient Educ Couns, 2010.
Key Points: Management
• Offer all 3 management options if stable – Know success rates when counseling patients – Patient preference plays a major role – Minimal difference in risk • Need for aspiration intervention should be based on clinical judgment • Outpatient MUA is acceptable to women and cost-effective eplresources.org
Abortion
Case: Sara is a 24-year-old woman who had a baby 2 years ago who presents to you complaining of a missed period. Her pregnancy test is positive, and she is unsure about continuing the pregnancy. Pregnancies in the United States (6.6 Million) % of pregnancies 100
80
60 49 51
40
20
0 Intended Unintended Finer and Zolna, AJPH, 2014
Outcomes of Unintended Pregnancies (3.4 Million)
% of unintended pregnancies (excluding miscarriages – 20%) 100
80
60 60
40 40
20
0 Abortions Births 1.1 million in 2011 What proportion of abortions done in the US is done in the first trimester (12 weeks or less?)
a. 60% b. 70% c. 80% d. 90%
Abortions by Gestational Duration
% of abortions 100%
80% 63% 89% 60%
40% 17% 20% 9% 7% 3% 1% 0% <9 9–10 11–12 13–15 16–20 21+ Weeks
Source: Henshaw adjustments to Strauss et al., 2007 (2004 data) Pregnancy Test +: Counseling Points • What do you think/hope the results will be? • Validate and normalize • Seek understanding – Can you say more about what you are feeling? •Reframe – Use what you have learned from her – What I hear you saying is you are making this decision because you care about your children’s well-being • If needed find someone to help • www.faithaloud.org / www.yourbackline.org
Counseling Websites www.faithaloud.org www.yourbackline.org Obligations to Patient
• Study of1200 physicians: theoretical case • Would it be ethical to describe why the physician objects to the requested procedure? – 63% yes • Does the physician have obligation to present all options to patient, including information about the requested procedure? – 86% yes • Does the physician have an obligation to refer? – 71% yes
Curlin, NEJM, 2007.
Abortion Is Safe*
• Abortion is one of the safest procedures • Successful in 98-100% cases • Complications are rare (0.04% - 0.07%) • Abortion is even safer if earlier in pregnancy • Early abortion is very simple to perform
*When done by safe practitioner in safe conditions 20 Million Unsafe Abortions Occur Each Year
Annual abortions per 1,000 women 15–44
World
Developed countries
Developing countries
0 5 10 15 20 25 30 35
Safe abortions Unsafe abortions
Sedgh, 2007
Legal Status is Not Correlated with Incidence, only Safety
• The lowest abortion rates in the world - less than 10 - are in countries in Europe, where abortion is less restrictive. • In Africa and Latin America - where abortion laws are most restrictive - the rates are 29 and 31.
Sedgh et al., 2007 1st Trimester Abortion
• Vacuum Aspiration Abortion – Manual or electric – Less than 14 weeks gestation • Medical Abortion – Less than 9 weeks gestation
1st Trimester Aspiration Abortion
• Counseling – pregnancy options – procedural – contraception • Preoperative Assessment • Analgesia and Anesthesia • Cervical Dilation • Aspiration • Recovery Manual Vacuum Aspiration
• About 50% of U.S. abortion providers use MVAs1 • Usually without sharp curettage • Must empty syringe during procedure with gestation > 7 or 8 wks • Women appreciate less noise2,3,4
1. O’Connell, 2008, 2. Bird et al., 2001; 3. Edelman et al., 2001; 4. Dean et al 2003
Medical/Medication Abortion 1st Trimester Medical Abortion
• Take mifepristone in office • Go home with pain medications • Six hours to three days later: – Place misoprostol pills in vagina – Over next 4 to 24 hours+ bleeding • Return to clinic as early as 3 days later – Call earlier if unexpected symptoms
FDA-Approved vs. Evidenced-Based Regimens for Medical Abortion
FDA-Approved Evidenced-Based • 600 mg Mifeprex PO • 200 mg Mifeprex PO given in the clinic given in the clinic • Miso given orally •Miso vaginally/ buccally • 400 mcg misoprostol • 800 mcg misoprostol • Miso 2 days later •Miso 6 hrs-3 days* later • Miso given in the clinic • Pt takes at home • Follow-up day 14 • Follow-up day 3 to 14 • Gestational limit 7 wks • Gestational limit 9 wks
*3 days studied to 8 wks gestation Medical Abortion Efficacy
• FDA-approved regimen – 92-96% effective for gestation < 49 days – 50% complete abortion within 4 hours • Alternative regimen: – 96-99% effective for gestation < 63 days – 93% complete in less than 4 hours
Evidence-based Regimen
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Success Incomplete ab Continuing preg Medical Abortion Side Effects
• SIDE EFFECT % OF WOMEN • Bleeding longer than 30 days 9 • Bleeding before misoprostol (after mife) 21 – 47 • Passage of pregnancy before misoprostol 4 • Abdominal pain requiring narcotics 29 – 73 • Nausea 20 – 65 • Vomiting 10 – 44 • Diarrhea 3 – 29 • Chills or fever 7 – 44 • Headache 27 – 32 • Dizziness 12 – 38
An Abortion Is Safer the Earlier in Pregnancy It Is Performed
Deaths per 100,000 abortions 11.8 12
10 8.9 8
6 3.4 4 1.7 2 0.6 0.1 0.2 0.4 0 <9 9–10 11–12 13–15 16–20 21+ All abs. Births Abortions by gestation
Sources: All births and abortions: CDC.gov; Abortion by gestation: Bartlett et al., 2004 (1988–1997 data) Abortion Complications
• First-trimester – Infection 0.1% – Hemorrhage • Medication abortion – up to 1% • Aspiration abortion – 0.1% – Re-aspiration • Medication abortion – up to 5% • Aspiration abortion – 1%
Hakim-Elahi, Obstet Gynecol, 1990
Aspiration Abortion: Antibiotic Prophylaxis • Decreases post-aspiration infection – Recommend for all aspiration (EPF too) – Meta-analysis: RR 0.58 • My recommendations: – Doxy 100 mg po immediately before (or 400 mg night before) and 200 mg after – Azithro 1 gm before the procedure – Metronidazole 400mg before and 4 & 8 hrs after
Sawaya GF. Obstet Gynecol 1996 Cervical Block Decreases Pain
• 20 mL 1% buffered lidocaine • Slow, deep injection at tenac + 4 sites • Stratified by <8 weeks (early)/ 8-10 weeks (late)
Pain /100 BLOCK NO BLOCK
With block 49/58 24/35 p=.001
Dilation 34/51 75/83 p<.001
Aspiration 58/67 88/88 p<.001
Renner. Ob Gyn May 2012
Cervical Injections
Hybrid
Superficial vs. deep injection
Paracervical vs. intracervical
Ob/gyn shark Cervical Block for Uterine Aspiration
1. Deep injections better than superficial (but hurt) 2. Larger volume of injection better (20ml vs. less) 3. Slow injection helps with block pain 4. Buffering lidocaine - less pain than not or bupiv 5. Routinely waiting more than a couple minutes after administering block unlikely to be helpful 6. Adding vasopressin decreases bleeding and possibly re-aspiration 1 Wiebe et al. Am J Ob Gyn, 1992 and increases amount of 2. Stubblefielf. Int J Gynecol Obstet 1989 3. Wiebe et al Int J Gynecol Obstet 1995 block that can be used 4. Wiebe et al. Am J Ob Gyn, 1992 5. Phair et al Am J Ob Gyn, 2002 6. Wiebe et al, Contraception. 2003
Aspiration Abortion: Cervical Ripening to Decrease Risk of Cervical Laceration • SFP 2007 – Consider priming for all adolescents – All women over 12 to 14 weeks • WHO 2003 – Younger than 18 years old – Nulliparous over 9 weeks – All women over 12 weeks • RCOG 2004 – Younger than 18 years old – All women over 10 weeks Conclusions
• Abortion is common and usually early • Safe abortion decreases morbidity and mortality – Complications are rare • It is important to refer as soon as possible
Sawaya GF. Obstet Gynecol 1996 University of California San Francisco 6/30/2014 MDM15M01: Essentials of Women's Health
UCSF OCME Registrant List Page 1 of 4
Name City, State 1Afnan Jia Fremont, CA 2Afonicheva Lyudmila MD Torrance, CA 3Alpers Leila San Francisco, CA 4Avila-Kirwan Guadalupe MD Meadow Vista, CA 5Bansal Sumati DO Los Angeles, CA 6Baron Robert B. MD, MS San Francisco, CA 7Bauer Douglas C. MD San Francisco, CA 8Beach James L. DO Phoenix, AZ 9Beaulieu Richard MD Morin-Heights, PQ, Canada 10Belissary Nicole MD Modesto, CA 11Berman Sylvia A. CNM Fairfax, CA 12Bodle-Shingu Rebecca Marie MSN Olympia, WA 13Bonacich Jane MD Oakland, CA 14Brinker Todd M. MD Jacksonville, FL 15Broughton Vanessa St Joseph Du Lac, QC, Canada 16Bynum Daniel C. MD Mt. Vernon, WA 17Castro Mary Jane MD Beaumont, TX 18Chamberlain Peter M. MD La Canada Flintridge, CA 19Chenumalla Madhavi MD Foster City, CA 20Cremin Daniel J. MD Alameda, CA 21Cronbach Emily MD Oakland, CA 22Daley Timothy M. MD Scottsdale, AZ 23Davis Virginia (Ginny) K. PA-C Prunedale, CA 24Derbyshire Ella R. MD Bethel, AK 25Dureg Karen ADN Aiea, HI 26Elder Brenda FNP Fort Gibson, OK 27Ellman Megan MD Pismo Beach, CA 28Enloe Thomas S Hanford, CA 29Fedor George P. MD Montebello, CA 30Force Obrowski Sandra K force obrowski Rancho Cucamonga, CA 31Francis Rodney MD Lancaster, CA 32Francisco Lee-Lee MD Manteca, CA 33Garcia Rosa MD Tigard, OR 34George Michael J. MD Napa, CA 35Gilbert Darcel MD Lahaina, HI 36Gotmare Sonali MD Mountain View, CA 37Grammer Jacklin Soopikian Piedmont, CA 38Greenwood Margaret MS San Francisco, CA UCSF OCME Registrant List Page 2 of 4
Name City, State 39Hagloch Nancy MD Medford, OR 40Hansen Erica Diane Oakland, CA 41Hashemi Vahideh MD Cupertino, CA 42Helms Eric MD Hilo, HI 43Higgins Ilona L. MD Kamuela, HI 44Htein Sandy MD Torrance, CA 45Iniguez Maria G. MD Mill Valley, CA 46Jackson Rebecca A. MD Berkeley, CA 47Jacques Anne MD Orinda, CA 48Johnson Susan MD Martin, TN 49Joseph Mark Leland Grand Rapids, MI 50Julian Katherine A. MD San Francisco, CA 51Kelly-Hedrick Heather Marion MD Mercer Island, WA 52Khouri Issa MD Belmont, CA 53Kim Jeongwon MD Edgewater, NJ 54King Kristine MD Renton, WA 55Koh Yoojin MD Albany, CA 56Koonce William C. MD Santa Barbara, CA 57Lachance Deborah MD Kailua-Kona, HI 58Le Amy Broomfield, CO 59Leaphart Candance Wisconsin Rapids, WI 60Leung Jennifer MD San Diego, CA 61Lew Arthur MD Renton, WA 62Lewis Lisa K. DO Golden, CO 63Libao Elizabeth MD Elk Grove, CA 64Lim Lizbeth Los Angeles, CA 65Liu Melissa San Jose, CA 66Liu Sai-Ling DO Nome, AK 67Malik Geeta MD Sonoma, CA 68Mariwalla Kiran MD Solvang, CA 69Martinez David P Lakewood, CO 70Matlock Beth MD Orinda, CA 71Mays Raymond San Angelo, TX 72Micielli Renee MD Boulder, CO 73Moroye Marc M. MD Vancouver, WA 74Moschella Joan RNC, ANP San Jose, CA 75Nagarajan Suja MD Fremont, CA 76Nakelchik Masha MD San Jose, CA 77Nguyen Khanh MD Houston, TX 78Noack Tamara San Angelo, TX 79Oh Gigli Yue MD Seattle, WA 80Oh Shenton MD, MBA, CPE Seattle, WA UCSF OCME Registrant List Page 3 of 4
Name City, State 81Olabode Irene MD Abilene, TX 82Oseguera Maria MD Chula Vista, CA 83Patel Neeta MD Atherton, CA 84Payne Susan D. MD Lake Oswego, OR 85Pellegrino Kristen MD San Francisco, CA 86Pham David MD Huntington Beach, CA 87Pina Racquel Bakersfield, CA 88Pineda-Liu Christine MD Bellevue, WA 89Plotkin Mindy DO Lafayette, CA 90Policar Michael S. MD, MPH San Francisco, CA 91Posa Tania Rose Tacoma, WA 92Rangarajan Vai MD Palo Alto, CA 93Rivers Peggy J. Hillsboro, OR 94Russo Jennefer A. MD Long Beach, CA 95Rutledge Dale MD Salt Lake City, UT 96Saavedra Tino MD Denver, CO 97Salvekar Rama MD Oakland, CA 98Sangvai Manjeeri Atlanta, OH 99Sapugay Anna Maria MD Oakland, CA 100Sharp Terese Oalkland, CA 101Smith Christine MD Bathurst, NSW, Australia 102Smith Erica MD North Logan, UT 103Song Chin MD Hillsboro, OR 104Steinauer Jody E. MD, MAS San Francisco, CA 105Su Ted MD Sunnyvale, CA 106Swift Jean DO Kamuela, HI 107Taylor Deshawn MD Phoenix, AZ 108Tran Minhnga MD Albuquerque, NM 109Tsikata Setorme MD Edmonton, AB, Canada 110Tsuzaki Wray Y. MD Honolulu, HI 111Unger Richard R. MD Orinda, CA 112Veniegas Cheryl MD Las Vegas, NV 113Vyas Chirag MD Henderson, NV 114Washington A. Eugene MD Los Angeles, CA 115Weeks James A. MD Bend, OR 116Wright Ellen FNP Lihue, HI 117Yamamoto Irene MD Honolulu, HI 118Younan Centi S. MD Modesto, CA 119Zamvar Uma Sunnyvale, CA 120Zhang Ying MD Fremont, CA 121Zielinski Martha BSN Sunnyvale, CA UCSF OCME Registrant List Page 4 of 4
Name City, State
Total Number of Attendees for MDM15M01: 121