1. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors and/or Angiotensin II Receptor Blockers Added to Standard Medical Therapy for Treating Patients With Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov

2.  Background  Process for developing the Comparative Effectiveness Review (CER)  Questions addressed in the CER  Results for each question in the CER  Informed decisionmaking for physicians and patients Outline of Material

3.  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 (1) Miniño AM, et al. Natl Vital Stat Rep 2006;54(19):1-49; Lloyd-Jones D, et al. Circulation 2009;119:e21-181.

4.  Every year, cardiovascular disease has accounted for more deaths than any other single cause or group of causes of death in the United States since 1900 (excluding 1918).  Nearly 2,400 Americans die of cardiovascular disease each day, an average of one death every 37 seconds. Health Impact of Cardiovascular Disease in the United States (2) Miniño AM, et al. Natl Vital Stat Rep 2006;54(19):1-49; Lloyd-Jones D, et al. Circulation 2009;119:e21-181.

5.  Atherosclerosis reduces the supply of blood and oxygen to the myocardium.  Symptoms range from asymptomatic ischemic episodes to severely debilitating symptoms.  Disease can manifest in large vessels or as diffuse microvascular disease.  There is an increased risk of acute coronary syndrome. Characteristics of Stable Ischemic Heart Disease Gibbons RJ, et al. J Am Coll Cardiol 2003;41:159-68; Fraker TD, Fihn SD. J Am Coll Cardiol 2007;50:2264-74; Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

6.  Standard therapy that can reduce cardiovascular events:  Single or dual antiplatelet therapy  Statins  β-blockers  Aggressive modification of risk factors  Standard therapy that can help with symptoms:  Fast-acting nitrates  Negative chronotropic agents (β-blockers; nondihydropyridine calcium channel blockers)  Vasodilators (calcium channel blockers; long-acting nitrates) 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;50:2264-74.

7.  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.

8.  American College of Cardiology and American Heart Association guidelines state that ACEIs can be used in addition to standard therapy in patients who have:  Chronic heart failure.  Myocardial infarction and left ventricular dysfunction (defined as a left ventricular ejection fraction (LVEF) ≤40%).  ARBs are reserved for patients who cannot tolerate ACEIs.  In patients with heart failure, combining an ACEI with an ARB may provide additional benefit over an ACEI alone. Guidelines for the Use of ACEIs, ARBs, or Both to Treat Patients With Cardiac Disease (1) Baker WL, et al. Ann Intern Med 2009 Oct 19. [Epub ahead of print]; Hunt SA, et al. Circulation 2005;112:e154-235; Pfeffer MA, et al. N Engl J Med 2003;149:1893-906; Smith SC, et al. Circulation 2006;113:2363-72.

9.  Clinical trials have been conducted to evaluate the use of ACEIs, ARBs, or both in patients with stable ischemic heart disease but without heart failure or left ventricular systolic dysfunction (patients with an LVEF >40%). Guidelines for the Use of ACEIs, ARBs, or Both to Treat Patients With Cardiac Disease (2) Baker WL, et al. Ann Intern Med 2009 Oct 19. [Epub ahead of print]; Hunt SA, et al. Circulation 2005;112:e154-235; Pfeffer MA, et al. N Engl J Med 2003;149:1893-906; Smith SC, et al. Circulation 2006;113:2363-72.

10. Pharmacologic Effects of Antagonists on the Renin-Angiotensin-Aldosterone 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;109:2617-2625; 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 2009. 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

11.  The topic was nominated in a public process.  A specialized Technical Expert Panel guided selection of the clinical questions that the CER would address.  The research for the CER was based on a well-defined systematic literature review process.  The methods used for data collection and meta-analysis followed the Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews.  The draft CER was made available for public comment and underwent a rigorous peer-review process to improve the final product.  The complete final report is available online at http://effectivehealthcare.ahrq.gov/ehc/products/57/335/ bodyfinal.pdf. The CER Development Process

12.  The GRADE system of the Cochrane Collaboration was used to rate the strength of evidence resulting from the CER 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 CER, the strength of evidence pertaining to each key question was classified into three broad categories or grades: Rating the Strength of Evidence From the CER: A Modification of the GRADE Methodology 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 2009.

13. Comparative Effectiveness Review: 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 2009.

14.  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 by the Comparative Effectiveness Review for Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

15.  Adding an ACEI or an ARB can provide additional clinical benefits for some patients.  Adding an ACEI may increase the risk of cough, syncope, or hyperkalemia.  Adding an ARB may increase the risk of hyperkalemia.  Adding an ACEI does not impact cardiovascular mortality in patients with end-stage renal disease and left ventricular hypertrophy. Results of Trials Evaluating the Addition of an ACEI or an ARB to Standard Therapy for Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009

16. Summary of Evaluated Trials That Investigated the Addition of an ACEI or an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

17. Target Doses for ACEIs and ARBs in Trials Investigating the Addition of an ACEI or an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

18. Overall Summary of the Evidence-Based Benefits of Adding an ACEI or an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009. CV = cardiovascular; HF = heart failure; MI = myocardial infarction.

19. Overall Summary of the Evidence-Based Harms of Adding an ACEI or an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

20. Benefits With HIGH Levels of Evidence That Result From Adding an ACEI to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic 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 2009.

21. Benefits With HIGH Levels of Evidence That Result From Adding an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic 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 2009.

22.  The 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.  There was evidence that patients who received the ACEI/ARB combination were at increased risk for adverse events. Results of Trials That Evaluated the Addition of an ACEI/ARB Combination Versus an ACEI Alone to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

23.  There were no clinical benefits for the ACEI/ARB (ramipril + telmisartan) combination (Moderate Level of Evidence).  The risk of harms was higher in the ACEI/ARB combination treatment group (Moderate Level of Evidence). Overall Summary of the Evidence-Based Benefits and Harms of Adding an ACEI/ARB Combination Versus an ACEI Alone to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function Modified from Yusuf S, et al. New Engl J Med 2008;358:1547-59.

24.  Seven trials met the inclusion criteria for this analysis.  There was no clinical benefit from adding an ACEI or an ARB to standard medical therapy in close proximity to a revascularization procedure.  There was an increased risk of adverse events. Results of Trials Evaluating the Addition of an ACEI or an ARB to Standard Medical Therapy (SMT) Versus SMT Alone Close to a Revascularization Procedure Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

25. CABG = coronary artery bypass grafting surgery; PTCA = percutaneous transluminal coronary angioplasty. Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009. Characteristics of Trials Evaluating the Addition of an ACEI or an ARB to Standard Medical Therapy (SMT) Versus SMT Alone Close to a Revascularization Procedure

26.  Overall, there were no clinical benefits to adding ACEIs or ARBs to standard medical therapy close to a revascularization procedure.  There was an increased risk for these harms: Analysis of Trials That Tested the Addition of an ACEI or an ARB to Standard Medical Therapy (SMT) Versus SMT Alone Close to a Revascularization Procedure Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

27. Identifying Trade-offs for Your Patients: Summary of Results on Comparative Effectiveness of Adding ACEIs and/or ARBs to Standard Medical Therapy Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

28.  Meta-analyses or future clinical trials that evaluate the use of ACEIs or ARBs to treat patients who have stable ischemic heart disease and preserved left ventricular systolic function are needed to address the benefits and harms in the following patient subpopulations:  Patients who are receiving antiplatelet therapy or who have a history of revascularization.  Patients of different ethnicities (especially African Americans and Latinos).  Patients with stenosis in the left anterior descending artery, as compared to other coronary arteries.  Patients with single-vessel versus multi-vessel disease.  Patients who have genetic polymorphisms of the angiotensin-converting enzyme gene or the angiotensin II type I receptor gene.  Patients on different dosing intensities of ACE inhibitors or ARBs. Gaps in Knowledge About ACEIs and ARBs as Treatment for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

29. Steps in the Informed Decisionmaking Process for Adding an ACEI or an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function