AHRQ’s Effective Health Care Program: Applying Existing Evidence to Guide Prescription Medication Use Monday, November 22, 2010 CALL-IN TELEPHONE NUMBER: (888) ACCESS CODE: # #

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Agenda Brief Overview of AHRQ’s Effective Health Care Program- Amanda Brodt, facilitator Brief Overview of AHRQ’s Effective Health Care Program- Amanda Brodt, facilitator Comparative Effectiveness of ACE Inhibitors and/or ARBs Added to Standard Medical Therapy for Treating Patients With Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function- C. Michael White, Pharm.D., FCP, FCCP Comparative Effectiveness of ACE Inhibitors and/or ARBs Added to Standard Medical Therapy for Treating Patients With Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function- C. Michael White, Pharm.D., FCP, FCCP Q&A from Audience Q&A from Audience

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Patient-Centered Outcomes Research and AHRQ’s Effective Health Care Program Amanda Brodt, M.P.H. AHRQ’s Office of Communications and Knowledge Transfer

Patient-Centered Outcomes Research Benefits Harms Also known as comparative effectiveness research Also known as comparative effectiveness research Unbiased and practical, evidence-based information Unbiased and practical, evidence-based information Compares drugs, devices, tests and surgeries, and approaches to health care Compares drugs, devices, tests and surgeries, and approaches to health care – benefits and harms – what is known and what isn’t Descriptive, not prescriptive Descriptive, not prescriptive

HorizonScanning Evidence Need Need Identification Identification EvidenceSynthesis Evidence Generation GenerationStrategiesInterventionsConditionsPopulations DisseminationTranslation Improvements in in Health Care Health Care Research Platform Infrastructure – Methods Development – Training A Framework for Patient-Centered Outcomes Research

Research Focus: 14 Priority Conditions Arthritis and nontraumatic joint disorders Arthritis and nontraumatic joint disorders Cancer Cancer Cardiovascular disease, including stroke and hypertension Cardiovascular disease, including stroke and hypertension Dementia, including Alzheimer’s disease Dementia, including Alzheimer’s disease Depression and other mental health disorders Depression and other mental health disorders Developmental delays, ADHD and autism Developmental delays, ADHD and autism Diabetes mellitus Diabetes mellitus Functional limitations and disability Functional limitations and disability Infectious diseases, including HIV/AIDS Infectious diseases, including HIV/AIDS Obesity Obesity Peptic ulcer disease and dyspepsia Peptic ulcer disease and dyspepsia Pregnancy including preterm birth Pregnancy including preterm birth Pulmonary disease/asthma Pulmonary disease/asthma Substance abuse Substance abuse 8

Effective Health Care Program Translation Products 9 Executive Summary Web Site Clinician Guide Consumer Guide Policymaker Summary Interactive Case Study CE Modules Faculty Slides Patient Decision Aid (available soon) Systematic Review Report

Medication Resources 10

Public Involvement Topic Generation Topic Development Topic Refinement Research Review Research Needs Development Report Translation & Dissemination During the Research Process Web links Newsletter blurbs Articles or commentaries Web conferences Continuing Education Disseminating the Findings Nominate topics using the online Nominate topics using the online form form Participate in key question Participate in key question refinement refinement Comment via the web on draft key Comment via the web on draft key questions and reports questions and reports 11

Comparative Effectiveness of ACE Inhibitors and/or ARBs Added to Standard Medical Therapy for Treating Patients With Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function C. Michael White, Pharm.D., FCP, FCCP Professor of Pharmacy, University of Connecticut Director, UCONN/HH Evidence-based Practice Center, Hartford, CT 12

 Background  Questions addressed  Results for each question Outline of Material 13

 An estimated 80 million American adults (1 in 3) have one or more forms of cardiovascular disease.  38.1 million are estimated to be age 60 or older.  16.8 million adults have ischemic heart disease, also known as coronary heart disease. Health Impact of Cardiovascular Disease in the United States Miniño AM, et al. Natl Vital Stat Rep 2006;54(19):1-49; Lloyd-Jones D, et al. Circulation 2009;119:e

 Standard therapy that can reduce cardiovascular events:  Antiplatelet therapy  Statins  β-blockers  Aggressive modification of risk factors  ACEIs and ARBs have established benefit in patients with heart failure and myocardial infarctions with left ventricular (LV) dysfunction. Standard Therapy for Stable Ischemic Heart Disease Gibbons RJ, et al. J Am Coll Cardiol 2002;41:159-68; Fraker TD, Fihn SD. J Am Coll Cardiol 2007;50:

 Despite standard medical therapy, these patients continue to experience considerable morbidity and mortality.  ACEIs and ARBs have established benefit in patients with heart failure and left ventricular dysfunction.  The evidence for prophylactic use of ACEIs and ARBs in patients without heart failure and with preserved left ventricular systolic function is less clear. Rationale for Additional Therapies for Patients With Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II-receptor blocker. 16

RAAS System Angiotensinogen Angiotensin I Angiotensin II Kininogen Bradykinin Inactive Ceconi C, et al. Cardiovasc Res 2007;73:237-46; Faxon DP, et al. Circulation 2004;109: ; Schmidt-Ott KM, et al. Regul Pept 2000; 93:65-77; Song JC, White CM. Pharmacotherapy 2000;20:130-9; Song JC, White CM. Clin Pharmacokinet 2002;41:207-24; Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October Angiotensin-converting enzyme Renin Kallikrein Kininase II Angiotensin- converting enzyme inhibitor Angiotensin II- receptor blocker Aldosterone secretion Increased Na + and H 2 O reabsorption Vasoconstriction Increased peripheral vascular resistance Angiotensin II Type I Receptors Vasodilation Decreased peripheral vascular resistance Stimulatory signal Reaction Inhibitory pharmacologic effect LEGEND 17

 The topic was nominated in a public process.  A specialized Technical Expert Panel guided selection of the clinical questions that the research would address.  The research was based on a well-defined systematic literature review process.  The methods used followed the Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews.  The draft underwent public comment and peer review.  The final report is available online at The Development Process 18

 The GRADE system of the Cochrane Collaboration was used to rate the strength of evidence resulting from the research but with a slight modification.  The modified system uses four domains — risk of bias, consistency, directness, and precision — for assessment.  For the purposes of the review, the strength of evidence pertaining to each key question was classified into three broad categories or grades: Rating the Strength of Evidence: Modified GRADE AHRQ. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0; Brozek J, et al. GRADEpro Version 3.2 for Windows. Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October

 The comparative effectiveness of different combination treatments:  ACEI or ARB + Standard Therapy Versus Standard Therapy Alone  ACEI + ARB + Standard Therapy Versus ACEI + Standard Therapy  ACEI or ARB + Standard Therapy Versus Standard Therapy Alone Close to a Revascularization Procedure  The benefits and harms associated with each treatment modality.  The differences in the benefits or harms between various subpopulations of patients. Clinical Questions Addressed Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October

Outcomes of Interest  End Points: Benefits  Total mortality  Cardiovascular (CV) death  Nonfatal myocardial infarction (MI)  Stroke  Composite endpoint (CV death, nonfatal MI, stroke)  Revascularization  Quality-of-life measures  End Points: Harms  Hyperkalemia  Cough  Angioedema  Hypotension  Rash  Blood dyscrasias  Syncope  Withdrawal from trial Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October

Trials Evaluating the Addition of an ACEI or ARB to Standard Medical Therapy for Stable IHD and Preserved LV Function Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October

Drugs and Target Doses Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October

Benefits With HIGH Levels of Evidence From Adding an ACEI to Standard Medical Therapy for Stable IHD With Preserved LV Function *The difference between the two event rates, divided by the event rate for patients not treated with an ACEI. †The difference between the event rate in patients treated without an ACEI and with an ACEI × 100. ‡ Event rate over 3.7 years. Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October

Benefits With HIGH Levels of Evidence From Adding an ACEI to Standard Medical Therapy for Stable IHD With Preserved LV Function* * Only the data from the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease ( TRANSCEND) trial were used in the analysis. † The difference between the two event rates, divided by the event rate for patients not treated with an ARB. ‡ The difference between the event rate in patients treated without an ARB and with an ARB × 100. Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October

Evidence-Based Harms of Adding an ACEI or an ARB to Standard Medical Therapy for Stable IHD With Preserved LV Function Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October The balance of benefits to harms is favorable. 26

 Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) was the only trial that investigated the addition of an ACEI/ARB combination to standard medical therapy versus standard medical therapy plus an ACEI alone.  There was no evidence of any greater clinical benefit with the addition of the ACEI/ARB combination as opposed to an ACEI alone.  In third arm, ARB therapy provided similar benefits to ACE inhibitor. ACEI/ARB Combination vs. ACEI Alone for Stable IHD With Preserved LV Function Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October

 Balance of benefits to harms not favorable.  No benefits, risks elevated (Moderate Level of Evidence). Harms of ACEI/ARB Combination vs. ACEI Alone for Stable IHD With Preserved LV Systolic Function Modified from Yusuf S, et al. New Engl J Med 2008;358:

CABG = coronary artery bypass grafting surgery; PTCA = percutaneous transluminal coronary angioplasty. Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October The Addition of ACEI or ARB to Standard Medical Therapy (SMT) Versus SMT Alone Close to a Revascularization Procedure in IHD with Preserved LV Function Seven trials conducted. 29

 The balance of benefits to harms was not favorable  There were no clinical benefits from adding ACEIs or ARBs close to a revascularization procedure.  There was an increased risk for these harms: ACEI or an ARB to Standard Medical Therapy (SMT) Versus SMT Alone Close to a Revascularization Procedure in Stable IHD and Preserved LV Function Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October

Final Summary of Results Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October

Informed Decisionmaking Process Using These Project Results 32

 Additional data needed to address the benefits and harms in the following patient subpopulations:  Patients who are receiving antiplatelet therapy  Patients of different ethnicities (especially African Americans and Latinos)  Patients who have genetic polymorphisms of the angiotensin-converting enzyme gene or the angiotensin II type I receptor gene Gaps in Knowledge Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October

Questions To submit a question: – Press the “Ask Question” button located at the bottom of the screen. – When you click on the button, a box will appear at the bottom of your screen requesting that you enter your question. – Once completed, press the “Submit” button. 34

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