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  • Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Patients With Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic FunctionThis slide set is based on a comparative effectiveness review (CER) titled, Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors (ACEIs) or Angiotensin II-Receptor Blockers (ARBs) Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease (IHD), that was developed by the University of Connecticut/Hartford Hospital Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ) and is available online at effectivehealthcare.ahrq.gov (Contract No. 290-2007-10067-I). CERs represent comprehensive systematic reviews of the literature usually comparing two or more types of treatment, such as different drugs, for the same disease. Primary clinical trials were identified from searches of MEDLINE (1966 to February 2009), Embase (1974 to February 2009), and the Cochrane Central Register of Controlled Trials (1966 to February 2009). The methods used to develop this CER followed version 1.0 of the Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews published by AHRQ (draft available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf). References:Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18 (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I). Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.
  • Outline of MaterialThis slide set is based on a comparative effectiveness review (CER) titled, Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors (ACEIs) or Angiotensin II-Receptor Blockers (ARBs) Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease (IHD), that was developed by the University of Connecticut/Hartford Hospital Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ) and is available online at effectivehealthcare.ahrq.gov (Contract No. 290-2007-10067-I). CERs represent comprehensive systematic reviews of the literature usually comparing two or more types of treatment, such as different drugs, for the same disease. Primary clinical trials were identified from searches of MEDLINE (1966 to February 2009), Embase (1974 to February 2009), and the Cochrane Central Register of Controlled Trials (1966 to February 2009). The methods used to develop this CER followed version 1.0 of the Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews published by AHRQ (draft available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf). The talk will cover the current evidence on the burden of cardiovascular disease in the U.S. followed by the available statistics and characteristics of the target population, patients with stable ischemic heart disease (IHD) and preserved left ventricular systolic function (LVSF). We will briefly discuss the comparative effectiveness review process, including the specific questions addressed in this CER and the results from this research. Finally, the benefits and harms of each treatment modality are presented in such a way as to promote doctor-patient communication in order to facilitate an informed decisionmaking process.References:Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18 (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I). Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.
  • Health Impact of Cardiovascular Disease in the United StatesAn estimated 80 million American adults (1 in 3) have one or more forms of cardiovascular disease. Among these adults, 38,100,000 are estimated to be age 60 or older, and about 16.8 million adults have ischemic heart disease, also known as coronary heart disease. Cardiovascular disease has been the leading cause of death in the United States in every year since 1900, except in 1918, accounting for more deaths than any other single cause or group of causes of death. Cardiovascular disease claims more lives each year than cancer, chronic lower respiratory diseases, accidents, and diabetes mellitus combined. According to current data, nearly 2,400 Americans die of cardiovascular disease each day, an average of 1 death every 37 seconds. References:Miniño AM, Heron MP, Smith BL. Deaths: preliminary data for 2004. Natl Vital Stat Rep 2006;54(19):1-49.Lloyd-Jones D, Adams R, Carnethon M, et al, for the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009;119:e21-181.
  • Characteristics of Stable Ischemic Heart DiseasePeople with stable ischemic heart disease can have advanced atherosclerosis, which reduces the maximal ability of the coronary arteries to supply blood to the myocardium (Gibbons et al., 2002). Symptoms of stable ischemic heart disease range from asymptomatic ischemic episodes to severely debilitating symptoms and from large vessel disease to diffuse microvascular disease (Gibbons et al., 2002). People with stable ischemic heart disease may or may not have had an acute coronary syndrome in the past but are at increased risk of such an event in the future (Gibbons et al., 2002). References:Gibbons RJ, Abrams J, Chatterjee K, et al, for the American College of Cardiology and the American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol. 2003;41:159-618.Fraker TD Jr, Fihn SD, for the 2002 Chronic Stable Angina Writing Committee. 2007 chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 guidelines for the management of patients with chronic stable angina. J Am Coll Cardiol . 2007;50:2264-74.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.
  • Standard Therapy for Stable Ischemic Heart DiseaseIn patients with stable ischemic heart disease, antiplatelet therapy with a single agent (aspirin or clopidogrel) and statin therapy (if the concentrations of low-density lipoprotein and non–high-density lipoprotein are above 100 mg/dL and 130 mg/dL, respectively) can reduce the risk of cardiovascular events (Gibbons et al., 2002; Fraker and Fihn, 2007). Other drugs — such as fast-acting nitrates (nitroglycerin tablets or spray), negative chronotropic agents (β-blockers; nondihydropyridine calcium channel blockers), and vasodilators (calcium channel blockers; long-acting nitrates) — can be used in patients with stable ischemic heart disease to relieve symptoms but do not impact the risk of cardiovascular events (Gibbons et al., 2002; Fraker and Fihn, 2007). For this reason, it is important to evaluate new therapeutic modalities that may impact cardiovascular events in patients with stable ischemic heart disease in addition to standard medical therapy.References:Gibbons RJ, Abrams J, Chatterjee K, et al, for the American College of Cardiology and the American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol. 2003;41:159-618.Fraker TD Jr, Fihn SD, for the 2002 Chronic Stable Angina Writing Committee. 2007 chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 guidelines for the management of patients with chronic stable angina. J Am Coll Cardiol . 2007;50:2264-74.
  • Rationale for Additional Therapies for Patients With Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic FunctionDespite standard medical therapy, patients with stable ischemic heart disease and preserved left ventricular systolic function continue to experience considerable morbidity and mortality. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have established benefit in patients with heart failure and left ventricular dysfunction. The available evidence for prophylactic use of ACEIs and ARBs in patients without heart failure and with preserved left ventricular systolic function is less clear. References:Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18 (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I). Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.
  • Guidelines for the Use of ACEIs, ARBs, or Both to Treat Patients With Cardiac DiseaseA closer look at the current American College of Cardiology and American Heart Association guidelines reveals that angiotensin-converting enzyme inhibitors (ACEIs) are indicated for patients who have chronic heart failure or myocardial infarction and left ventricular dysfunction, which is defined as a left ventricular ejection fraction ≤40%. Angiotensin II receptor blockers (ARBs) are reserved for patients who cannot tolerate ACEIs. In patients with heart failure, combining an ACEI with an ARB has been shown to provide additional benefits over an ACEI alone. However, it is unclear if ACEIs or ARBs impact the risk of future cardiovascular events in patients without left ventricular systolic dysfunction (LVSD).To determine if the same benefits seen with ACEIs and ARBs will extend to patients without heart failure or LVSD, trials have been conducted to evaluate the use of ACEIs and ARBs — alone or in combination — in patients who have stable ischemic heart disease and preserved LVSD. Previous systematic reviews have not included recent ACEI trials conducted in this population. Additionally, no systematic review has evaluated ARB therapy or ACEI and ARB combination therapy in this population. From this body of evidence, the benefits and harms associated with the use of these therapies in this population of patients may be discerned.References:Baker WL, Coleman CI, Kluger J, et al. Effectiveness of therapies for stable ischemic heart disease. Systematic Review: Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II–Receptor Blockers for Ischemic Heart Disease. Ann Intern Med 2009 Oct 19. [Epub ahead of print]. Available at: http://www.annals.org/cgi/content/full/0000605-200912150-00162v1. Hunt SA, Abraham WT, Chin MH, et al, for the American College of Cardiology, the American Heart Association Task Force on Practice Guidelines, the American College of Chest Physicians, the International Society for Heart and Lung Transplantation, and the Heart Rhythm Society. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005;112:e154-e235.Matchar DB, McCrory DC, Orlando LA, et al. Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers for treating essential hypertension. Ann Intern Med 2008;148:16-29.Pfeffer MA, McMurray JJ, Velazquez EJ, for the Valsartan in Acute Myocardial infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;149:1893-1906.Smith SC, Allen J, Blair SN, et al, for the American Heart Association, the American College of Cardiology, and the National Heart, Lung, and Blood Institute. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006;113:2363-72.
  • Pharmacologic Effects of Agonists on the Renin-Angiotensin-Aldosterone SystemDespite standard therapy, patients with stable ischemic heart disease and preserved left ventricular systolic function continue to be at risk for future cardiovascular events. The Renin-Angiotensin-Aldosterone System (RAAS) is critical for regulating blood pressure, electrolyte balance, and fluid volume homeostasis and plays a pivotal role in the pathogenesis of hypertension, congestive heart failure, and diabetic nephropathy. Pharmacological agonists of this system include angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs). These drugs block adverse effects of the RAAS by blocking the activity of angiotensin II. Through the stimulation of angiotensin II type-1 receptors, angiotensin II may have several potentially harmful activities including: Induction of aldosterone production, which can cause sodium retention and increased fluid retention that, in turn, leads to an increase in blood pressure.Increased aldosterone production, which can possibly lead to promotion of pathogenic remodeling (i.e., atherosclerosis and fibrosis).Constriction of blood vessels, which can lead to increased blood pressure. Potential reduction in the availability of nitric oxide through the production of free radicals and the induction of endothelial dysfunction that may impact endothelial wall integrity.ACEIs act on the RAAS by blocking the conversion of angiotensin I into angiotensin II and inhibiting the breakdown of bradykinin, which is a potent vasodilator. ARBs block the angiotensin II type-1 receptor and reduce the pharmacologic effects of angiotensin II, regardless of whether angiotensin II is created by the angiotensin-converting enzyme or by pathways that do not include this enzyme.ACEIs and ARBs may potentially provide several pharmacological effects over and above that of blood pressure reduction alone, which may impact cardiovascular events.References:Ceconi C, Fox KM, Remme WJ, et al, for the EUROPA Investigators and the PERTINENT Investigators and the Statistical Committee. ACE inhibition with perindopril and endothelial function. Results of a substudy of the EUROPA study: PERTINENT. Cardiovasc Res 2007;73:237-46.Faxon DP, Fuster V, Libby P, et al, for the American Heart Association. Atherosclerotic Vascular Disease Conference: Writing Group III: pathophysiology. Circulation 2004;109:2617-25.Schmidt-Ott KM, Kagiyama S, Philips I. The multiple actions of angiotensin II in atherosclerosis. Regul Pept 2000;93:65-77.Song JC, White CM. Pharmacologic, pharmacokinetic, and therapeutic differences among angiotensin II receptor blockers. Pharmacotherapy 2000;20:130-9.Song JC, White CM. Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin-converting enzyme inhibitors: an update. Clin Pharmacokinet. 2002;41:207-24.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.
  • The CER Development ProcessThe comparative effectiveness review topic, Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease, was nominated in a public process. Sufficient research into the current literature determined that there was a need for the available evidence on the addition of ACEIs and ARBs to standard medical therapy for patients with stable ischemic heart disease and preserved left ventricular systolic function (LVSF) and that there was an adequate number of clinical trials to be included in a comparative effectiveness review (CER). Based on this research, the Agency for Healthcare Research and Quality (AHRQ) commissioned the University of Connecticut/Hartford Hospital Evidence-Based Practice Center to prepare the CER with input from a Technical Expert Panel. This advisory panel was comprised of experts in different specialties, including cardiologists, a cardiovascular pharmacist/pharmacologist, and a health policy pharmacist. The panel identified important issues, reviewed proposed methods, defined parameters for the review of evidence, and helped to refine the key clinical questions that the research would subsequently address. Once formulated, the key clinical questions were published online and were made available for public commentary in order to refine the scope and focus of the research questions. A comprehensive systematic review of the literature was then conducted using several well-known databases, including MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. All methods used in the review followed version 1.0 of AHRQ’s Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews (available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf) and the trial end points were determined a priori. Based on the findings of the review, a draft CER was prepared and published online for public comment, and the draft underwent rigorous peer review to improve the final product. After the CER was finalized, the complete report was published on the Internet (available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf) and a condensed version was published in the Annals of Internal Medicine (available at: http://www.annals.org/content/early/2009/10/19/0003-4819-151-12-200912150-00162.full).References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0 [Draft posted Oct. 2007]. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Baker WL, Coleman CI, Kluger J, et al. Effectiveness of therapies for stable ischemic heart disease. Systematic Review: Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II–Receptor Blockers for Ischemic Heart Disease. Ann Intern Med 2009 Oct 19. [Epub ahead of print]. Available at: http://www.annals.org/cgi/content/full/0000605-200912150-00162v1. Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.
  • Rating the Strength of Evidence From the CER: A Modification of the GRADE MethodologyTo determine the strength of the evidence resulting from the systematic review, researchers used the methodology of the University of Connecticut/Hartford Hospital Evidence-Based Practice Center for grading, which is based on the GRADE (Grading of Recommendations, Assessment, DEvelopment) system of the Cochrane Collaboration. This system uses four required domains — risk of bias, consistency, directness, and precision — for assessments. All assessments were made by two investigators who resolved disagreements through discussion. The strength of evidence pertaining to each key question was classified into three broad categories or grades: high, moderate, or low. References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0 [Draft posted Oct. 2007]. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Brozek J, Oxman A, Schünemann H. GRADEpro Version 3.2 for Windows. 2008. Available at: http://www.cc-ims.net/gradepro.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.
  • Comparative Effectiveness Review: Outcomes of InterestA comparative effectiveness review (CER) titled, Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors (ACEIs) or Angiotensin II-Receptor Blockers (ARBs) Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease (IHD), was developed by the University of Connecticut/Hartford Hospital Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ) and published online (available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=334). This CER was based on a comprehensive systematic review of the literature. The methods for developing this CER followed the Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0, published by AHRQ (available at http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf). The clinical outcomes and harms of interest are outlined in this slide and were determined a priori. References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0 [Draft posted Oct. 2007]. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.
  • Clinical Questions Addressed by the CER for Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic FunctionThis CER focused on a population of patients with stable ischemic heart disease (IHD) and preserved left ventricular systolic function (LVSF). The clinical trials evaluated in this CER included ischemic heart disease patients without left ventricular systolic dysfunction, which was defined as having a left ventricular ejection fractions greater than 40%. The key questions centered around the comparative effectiveness of 1) adding an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) to standard medical therapy versus standard medical therapy alone, 2) combining an ACEI with an ARB and adding them to standard medical therapy versus adding an ACEI alone to standard medical therapy, or 3) adding an ACEI or an ARB to standard medical therapy versus standard medical therapy alone in patients with stable IHD and preserved LVSF who are in close proximity to a revascularization procedure. The comparative effectiveness of ACEIs versus ARBs was not a focus of the CER.This CER focused on a population of patients with stable IHD who also have preserved LVSF. The key questions centered around the comparative effectiveness of ACEIs or ARBs added to standard medical therapy versus standard medical therapy alone; or centered around the combined use of ACEIs and ARBs added to standard medical therapy versus an ACEI added to standard medical therapy. Among the clinical trials included in this general category, some were conducted where recent coronary revascularization procedures were a prerequisite for enrollment. These clinical trials were evaluated separately from those in which this was not a prerequisite. References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0 [Draft posted Oct. 2007]. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.
  • 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 FunctionThis slide summarizes the most pertinent results from the Comparative Effectiveness Review (CER) on the benefits and harms of adding an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) to standard medical therapy for stable ischemic heart disease with preserved left ventricular systolic function as compared to standard medical therapy alone or with a placebo. The next several slides (14–19) will discuss these data in greater detail. When considered together, the benefits and harms of adding an ACEI or an ARB to standard medical therapy indicate that there may be a clinical benefit from such therapy for some patients with stable ischemic heart disease and preserved left ventricular systolic function (LVSF). However, the potential risks of cough, syncope, or hyperkalemia should be considered for each individual patient before adding an ACEI or an ARB to his or her treatment regimen. Very few of the trials evaluated for the CER compared the addition of an ACEI or an ARB or both to an active control. Only two trials compared the addition of an ACEI or a calcium channel blocker to standard medical therapy (Nissen et al., 2004; You et al., 2004).In both trials, the clinical benefits were similar between the two treatment arms, and there was some limited evidence that ACEIs may increase the risk for hypotension and cough. Additional trials are required to make any definitive clinical recommendations with regard to the addition of calcium channel blockers over ACEIs to standard medical therapy.Cardiovascular events are the leading cause of death in patients treated with hemodialysis for chronic kidney disease. Among these patients, left ventricular hypertrophy is considered to be an ischemic heart disease equivalent, as defined by the National Kidney Foundation. In a clinical trial conducted by Zonnad et al. (2006), however, there was no impact on cardiovascular mortality after fosinopril, an ACEI, was added to standard therapy for patients with end-stage renal disease and left ventricular hypertrophy.References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0 [Draft posted Oct. 2007]. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.National Kidney Foundation Task Force on Cardiovascular Disease. K/DOQI Clinical practice guidelines for managing dyslipidemias in chronic kidney disease. Available at: http://www.kidney.org/professionals/Kdoqi/guidelines_lipids/i.htm.Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure. The CAMELOT study: a randomized controlled trial. JAMA 2004;292(18):2217-26. You U, Sumiyoshi T, Kokama K, et al. Comparison of nifedipine retard with angiogenesis converting enzyme inhibitors in Japanese hypertensive patients with coronary artery disease: the Japan Multicenter Investigation for Cardiovascular diseases-B (JMIC-B) randomized trial. Hypertens Res 2004;27:181-91.Zonnad F, Kessler M, Lehert P, et al, for the FOSIDIAL Investigators. Prevention of cardiovascular events in end-stage renal disease: results of a randomized trial of Fosinopril and implications for future studies. Kidney Int 2006;70:1318-24.
  • Summary of Evaluated Trials That Investigated the Addition of an ACEI or an ARB to Standard Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic FunctionThis table is a brief overview summary of the randomized, placebo-controlled trials that met the inclusion criteria for the comparative effectiveness review (CER). The patients enrolled in these trials had stable ischemic heart disease and preserved left ventricular systolic function and were randomized to receive standard medical therapy alone or standard medical therapy combined with an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB). The enrollment criteria for all of the trials excluded patients who had had a recent myocardial infarction or who had had a revascularization procedure within 3 to 6 months of trial enrollment, depending on the trial. Of the 9 trials that were evaluated, 7 had investigated ACEIs and 2 had investigated ARBs. The median follow-up for the trials was 3.5 years (range, 0.5–4.8).For further details on the trials that were evaluated, please refer to the original CER on which this slide is based (available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf). References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0 [Draft posted Oct. 2007]. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Borghi C, Ambrosioni E, on behalf of the Survival of Myocardial Infarction Long-term Evaluation (SMILE) Study Group. Effects of zofenopril on myocardial ischemia in postmyocardial infarction patients with preserved left ventricular function: the Survival of Myocardial Infarction Long-term Evaluation (SMILE)-ISCHEMIA study. Am Heart J 2007;153:e7-14.Kondo J, Sone T, Tsuboi H, et al. Effects of low-dose angiotensin II receptor blocker candesartan on cardiovascular events in patients with coronary artery disease. Am Heart J 2003;146:e20.Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 2004;292:2217-26.Braunwald E, Domanski MF, Fower SE, et al, for the PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351:2058-68. Teo KK, Burton JR, Buller CE, et al. Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: the Simvastatin/enalapril Coronary Atherosclerosis Trial (SCAT). Circulation 2000;102:1748-54.Fox KM, for the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomized, double-blind, placebocontrolled, multicentre trial (the EUROPA study). Lancet 2003;362:782-8.Yusuf S, Sleight P, Pogue J, et al, for the Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-53. MacMahon S, Sharpe N, Gamble G, et al, for the PART-2 Collaborative Research Group. Randomized, placebo-controlled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease: Prevention of Atherosclerosis with Ramipril. J Am Coll Cardiol 2000;36:438-43. Yusuf S, Teo K, Anderson C, et al, for the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) Investigators. Effects of angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomized controlled trial. Lancet 2008; 372:1174-83.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.
  • 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 FunctionThis table summarizes the daily target dose of the angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) used in the randomized placebo-controlled clinical trials that met the inclusion criteria for the comparative effectiveness review (CER). The patients enrolled in these trials had stable ischemic heart disease and preserved left ventricular systolic function and were randomized to receive standard medical therapy alone or standard medical therapy combined with an ACEI or an angiotensin II receptor blocker ARB. Available evidence is insufficient to determine if different doses of ACEIs or ARBs impact outcomes in this patient population. For further details on the dosing regiments that were used in the trials reviewed in this CER, please refer to the original comparative effectiveness review on which this slide is based (available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf). References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0 [Draft posted Oct. 2007]. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Borghi C, Ambrosioni E, on behalf of the Survival of Myocardial Infarction Long-term Evaluation (SMILE) Study Group. Effects of zofenopril on myocardial ischemia in postmyocardial infarction patients with preserved left ventricular function: the Survival of Myocardial Infarction Long-term Evaluation (SMILE)-ISCHEMIA study. Am Heart J 2007;153:e7-14.Kondo J, Sone T, Tsuboi H, et al. Effects of low-dose angiotensin II receptor blocker candesartan on cardiovascular events in patients with coronary artery disease. Am Heart J 2003;146:e20.Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 2004;292:2217-26.Braunwald E, Domanski MF, Fower SE, et al, for the PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351:2058-68. Teo KK, Burton JR, Buller CE, et al. Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: the Simvastatin/enalapril Coronary Atherosclerosis Trial (SCAT). Circulation 2000;102:1748-54.Fox KM, for the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomized, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003;362:782-8.Yusuf S, Sleight P, Pogue J, et al, for the Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-53. MacMahon S, Sharpe N, Gamble G, et al, for the PART-2 Collaborative Research Group. Randomized, placebo-controlled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease: Prevention of Atherosclerosis with Ramipril. J Am CollCardiol 2000;36:438-43. Yusuf S, Teo K, Anderson C, et al, for the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) Investigators. Effects of angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomized controlled trial. Lancet 2008; 372:1174-83.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.
  • 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 FunctionThis slide provides an overall summary of the evidence-based benefits of adding an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) to standard medical therapy for patients with stable ischemic heart disease and preserved left ventricular systolic function, as compared to standard medical therapy alone or with a placebo. The strength or level of evidence associated with each outcome, as assessed in the Comparative Effectiveness Review, is also indicated. Subsequent slides will detail the outcomes with high levels of evidence.References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0 [Draft posted Oct. 2007]. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.
  • 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 FunctionThis slide provides an overall summary of the evidence-based harms of adding an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) to standard medical therapy for patients with stable ischemic heart disease and preserved left ventricular systolic function, as compared to standard medical therapy alone or with a placebo. The strength or level of evidence associated with each outcome, as assessed in the Comparative Effectiveness Review, is also indicated.Although many of the trials included in the CER analyses reported harms data, the reporting of adverse events was not consistent across the trials. Additionally, several trials included a prerandomization run-in period, during which subjects who could not tolerate the trial drug were excluded. Such exclusion may limit the applicability of the harms data for the overall population with stable ischemic heart disease. References:Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.
  • 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 FunctionOn average, 91 patients with stable ischemic heart disease (IHD) and preserved left ventricular systolic function (LVSF) will need to be treated with an angiotensin-converting enzyme inhibitor (ACEI) over 4 years to prevent 1 additional death. In other words, on average, 8.5 in 100 patients with stable IHD will die in the next 4 years. If an ACEI were to be added to the treatment regimens of 100 patients, then 7.4 patients — or 1 less patient — will die. The absolute difference in event rates between the groups of patients who were treated or were not treated with an ACEI is 1.1, with a relative risk reduction in total mortality of 13%. The benefits with respect to nonfatal myocardial infarction (MI) are similar. On average, 91 patients with stable IHD and preserved LVSF will need to be treated with an ACEI over 4 years to prevent 1 additional nonfatal MI. So, on average, 6.1 in 100 patients with stable IHD will have a nonfatal MI in the next 4 years. If an ACEI were to be added to the treatment regimens of 100 patients, then 5 patients — or 1 less patient — will have a nonfatal MI. The absolute difference in event rates between the two treatment groups is also 1.1, with a relative risk reduction in nonfatal MIs of 17%.With regard to hospitalization for heart failure, on average, 167 patients with stable IHD and preserved LVSF will need to be treated with an ACEI over 4 years to prevent 1 additional hospitalization. On average, 2.6 in 100 patients with stable IHD will be hospitalized for heart failure-related reasons in the next 4 years. If an ACEI were to be added to the treatment regimens of 100 patients, then 2 patients — or nearly 1 less — would be hospitalized for heart failure-related reasons. The absolute difference in event rates between the two treatment groups is less than 1, with a relative risk reduction of 22% for heart failure-related hospitalizations. Finally, on average, 77 patients with stable IHD and preserved LVSF will need to be treated with an ACEI over 3.7 years to prevent 1 additional revascularization surgery. Stated another way, on average, 13.6 in 100 patients with stable IHD will need revascularization surgery in the next 4 years. If an ACEI were to be added to the treatment regimens of 100 patients, then 12.3 patients — or about 1 less patient — would need this surgery. The absolute difference in event rates between the two treatment groups is 1.3, with a relative risk reduction of 10% for revascularization surgery.Overall, the absolute difference in event rates between the patients treated with an ACEI and those who received standard treatment alone is 1.3 or less. Moreover, the addition of an ACEI did not significantly reduce atrial fibrillation or angina-related hospitalizations. All of these data were determined to be at a high level of evidence, meaning that future trials are unlikely to change the estimated differences between these treatment groups.References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0 [Draft posted Oct. 2007]. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.
  • 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 FunctionThe Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) trial (Yusuf et al., 2008) was the only trial that met the inclusion criteria for the addition of an angiotensin II receptor blocker (ARB) to standard medical therapy for patients with stable ischemic heart disease (IHD) and preserved left ventricular function (LVSF) as compared to standard medical therapy alone or with a placebo. Patients who could not tolerate angiotensin-converting enzyme inhibitors (ACEIs) were enrolled in the study and were treated with telmisartan. The results of this trial showed that the difference in event rates between the two treatment groups to be less than 2. On average, 56 patients who have stable IHD and preserved LVSF and cannot tolerate ACEIs will need to be treated with an ARB over 5 years to prevent one or more of the following events: cardiovascular death, nonfatal myocardial infarction, or stroke. In other words, on average, 14.8 of every 100 patients will experience one or more of these cardiovascular events in the next 5 years. If an ARB were to be added to the treatment regimens of 100 patients, 13 of them would have a risk of suffering one or more of these cardiovascular events. The relative risk reduction in the combined risk for cardiovascular death, nonfatal myocardial infarction, or stroke is 12%. All of these data were determined to be at a high level of evidence, meaning that future trials are unlikely to change the estimated differences between these treatment groups.References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0 [Draft posted Oct. 2007]. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.Yusuf S, Teo K, Anderson C, et al, for the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) Investigators. Effects of angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomized controlled trial. Lancet 2008; 372:1174-83.
  • 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 FunctionThis slide summarizes the detailed evidence from the Comparative Effectiveness Review (CER) with regard to combination therapy with an angiotensin-converting enzyme inhibitor (ACEI) and an angiotensin II receptor blocker (ARB). In the only trial available for analysis, the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET; Yusuf et al., 2008), an ACEI/ARB combination (ramipril + telmisartan) was added to standard medical therapy for patients with stable ischemic heart disease (IHD) and a preserved left ventricular systolic function (LVSF) and compared to the addition of only an ACEI (ramipril). ONTARGET also compared ramipril to telmisartan (ARB); this, however, was not part of the analysis of this CER and will not be discussed in this slide.Based on the analysis of this single trial, the CER found no evidence that adding an ACEI/ARB combination to standard therapy provides any additional clinical benefit to patients with stable IHD and preserved LVSF when compared to adding an ACEI alone with regard to total mortality, cardiovascular mortality, fatal + nonfatal myocardial infarction, fatal + nonfatal stroke, the composite risk of the previous three outcomes, new atrial fibrillation, worsening or new angina, hospitalizations for angina, heart failure-related hospitalizations, or revascularizations. The level of evidence for these findings was deemed to be moderate (see slide 10). However, there also is a moderate level of evidence that there is an increased risk for the adverse events listed in this slide when ACEIs and ARBs are combined. The incidences of cough and angioedema did not reach statistical significance between the two treatment groups. The incidences of rash and blood dyscrasias were not reported in the original trial report.References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0 [Draft posted Oct. 2007]. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=334.Yusuf S, Teo KK, Pogue J, et al, for the ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. New Engl J Med 2008;358:1547-59.
  • Results of Trials Evaluating the Addition of an ACEI or an ARB to Standard Medical Therapy (SMT) Versus SMT Alone Close to a Revascularization ProcedureThis slide summarizes the most pertinent results from the Comparative Effectiveness Review (CER) on the benefits and harms of adding an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) to standard medical therapy, as opposed to standard medical therapy alone, in patients with stable ischemic heart disease (IHD) and preserved left ventricular systolic function (LVSF) who have recently undergone, or are about to undergo, a revascularization procedure. Although ACEIs or ARBs may be beneficial to patients with stable IHD and preserved LVSF (see slide 16), no significant clinical benefits were identified in the CER analysis among such patients who were in close proximity to a revascularization procedure. Moreover, there was an increased risk of adverse events when an ACEI or an ARB was administered within 2 weeks before or after such a procedure. In four large clinical trials (i.e., HOPE, EUROPA, PEACE, and TRANSCEND), patients with stable IHD and preserved LVSF who had a revascularization procedure within 3 to 6 months of trial enrollment were excluded. Given these results, it is likely that this subpopulation of patients with stable IHD and preserved LVSF who are in close proximity to a revascularization procedure are characteristically different from patients who underwent revascularization at least 3 to 6 months ago. The following slides (23 and 24) discuss these data in greater detail. References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0 [Draft posted Oct. 2007]. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=334.
  • Characteristics of Trials Evaluating the Addition of an ACEI or an ARB to Standard Medical Therapy (SMT) Versus SMT Alone Close to a Revascularization ProcedureThis slide summarizes the seven trials that were evaluated in the Comparative Effectiveness Review (CER) to assess the benefits and harms of adding an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) to standard medical therapy, as opposed to standard medical therapy alone, in patients with stable ischemic heart disease who are in close proximity to a revascularization procedure. The patient population in these trials ranged from small (n = 91) to moderate (n = 2,553) in size. Typically, ACEIs were administered within a week after a revascularization procedure (as listed in the slide); in one trial, an ARB was given within 7 to 14 days before coronary stenting. In many of these trials, these treatment modalities were chosen to assess their impact on restenosis after these revascularization procedures. For detailed information on these trials, refer to the original comparative effectiveness review available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0 [Draft posted Oct. 2007]. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Faxon DP, for the Multicenter American Research Trial With Cilazapril After Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MARCATOR) Study Group. Effect of high dose angiotensin-converting enzyme inhibition on restenosis: final results of the MARCATOR study, a multicenter, double-blind, placebo-controlled trial of cilazapril. J Am Coll Cardiol 1995;25:362-9.Kjøller-Hansen L, Steffensen R, Grande P. The Angiotensin-converting Enzyme Inhibition Post Revascularization Study (APRES). J Am Coll Cardiol 2000;35:881-8.Kondo J, Sone T, Tsuboi H, et al. Effect of quinapril on intimal hyperplasia after coronary stenting as assessed by intravascular ultrasound. Am J Cardiol 2001;87:443- 5.Meurice T, Bauters C, Hermant X, et al. Effect of ACE inhibitors on angiographic restenosis after coronary stenting (PARIS): a randomized, double-blind, placebo-controlled trial. Lancet 2001;357:1321-4.Pitt B, O’Neill B, Feldman R, et al. The Quinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol 2001;87:1058-63. Radke PW, Figulla HR, Drexler H, et al, for the AACHEN Trial Investigators. A double-blind, randomized, placebo-controlled multicenter clinical trial to evaluate the effects of the angiotensin II receptor blocker candesartan cilexetil on intimal hyperplasia after coronary stent implantation. Am Heart J 2006;152:e1-6.Rouleau JL, Warnica WJ, Baillot R, et al, for the IMAGINE (Ischemia Management With Accupril Post-Bypass Graft via Inhibition of the Converting Enzyme) Investigators. Effects of angiotensin-converting enzyme inhibition in low-risk patients early after coronary artery bypass surgery. Circulation 2008;117:24-31.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=334.
  • 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 ProcedureOverall, there was no significant clinical benefit to the addition of an ACEI or an ARB to standard medical therapy close to a revascularization procedure with regard to total mortality, cardiovascular mortality, nonfatal myocardial infarction, stroke, the composite of the previous three outcomes, atrial fibrillation, angina-related hospitalizations, or heart failure-related hospitalizations. The strength of this evidence was rated “low-moderate” in the comparative effectiveness review. Additionally, there was evidence of an increase in adverse events. The seven clinical trials assessed in this analysis revealed: Hypotension increased 5.5% in the control group and 12% in those taking ACEIs.Additional revascularization procedures were needed in 11% of the patients who started an ACEI or an ARB close to a revascularization procedure and in 6% of those who initiated only standard medical therapy.References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0 [Draft posted Oct. 2007]. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.
  • Identifying Trade-offs for Your Patients: Summary of Results on Comparative Effectiveness of Adding ACEIs and/or ARBs to Standard Medical TherapyThe decision to add an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) to the standard treatment regimen for patients with stable ischemic heart disease (IHD) and preserved left ventricular systolic function should be considered on a case-by-case basis by both the attending physician and the patient. This chart summarizes the benefits and harms associated with therapies that include ACEIs, ARBs, or both. For a detailed analysis of the benefits of adding an ACEI or ARB to standard medical therapy, see the complete comparative effectiveness review available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=334. *In reviewing the benefits and harms listed in the table:An important point to consider is that while many of the trials included in these analyses reported harms data, adverse event reporting was not consistent across the trials. Additionally, several trials included a prerandomization run-in period, during which candidates who could not tolerate the trial drug were excluded. This may limit the applicability of the harms data to the entire IHD population. For specific details on trials that were evaluated, please refer to the original comparative effectiveness review, on which this slide talk is based (available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=334). Note: Angioedema, a rare but potentially serious reaction, has been reported in several trials. Patients who are or may become pregnant while taking an ACEI or an ARB should be made aware of the risk of birth defects caused by these drugs.This information is taken from the 2007 report, Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin II Receptor Antagonists (ARBS) for Treating Essential Hypertension, written by the Duke Evidence-Based Practice Center and funded by AHRQ. The report can be viewed at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=45&returnpage=References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0 [Draft posted Oct. 2007]. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.
  • Gaps in Knowledge About ACEIs and ARBs as Treatment for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic FunctionIn the trials that this Comparative Effectiveness Review (CER) was based on, only a few had detailed subanalyses of disease or patient characteristics that correlated with the improved patient outcomes derived from adding an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) to the treatment regimen of patients with stable ischemic heart disease (IHD) and preserved left ventricular systolic function (LVSF). In addition, harms data were not available for many of the subpopulation analyses. Therefore, this evidence should be used mainly to generate hypotheses. From the subpopulation analyses, it is clear that more evidence is needed to determine whether there are patient characteristics or clinical factors that can determine whether patients with stable IHD and preserved LVSF will benefit more or less from the addition of an ACEI or an ARB to their standard therapies. Gender, diabetic status, the presence or absence of hypertension, the presence or absence of specific concomitant therapies, or a patient’s history of revascularization are all potential factors that may play a role in responsiveness to ACEIs or ARBs. Additional meta-analyses and clinical trials are needed to determine the benefits and harms of ACEIs and ARBs to these different subpopulations of patients. References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0 [Draft posted Oct. 2007]. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.
  • 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 FunctionDeciding to add an angiotensin-converting enzyme inhibitor (ACEI) or and angiotensin II receptor blocker (ARB) to your patient’s treatment regimen is a small but important part of the relationship between you and your patient who has stable ischemic heart disease with preserved left ventricular systolic function. References:Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0 [Draft posted Oct. 2007]. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf.Coleman CI, Baker WL, Kluger J, et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II-Receptor Blockers Added to Standard Medical Therapy for Treating Stable Ischemic Heart Disease. Comparative Effectiveness Review No. 18. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) Rockville, MD: Agency for Healthcare Research and Quality; October 2009. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.

Transcript

  • 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. Outline of Material
    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
  • 3. Health Impact of Cardiovascular Diseasein the United States
    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.
    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.
    Miniño AM, et al. Natl Vital Stat Rep 2006;54(19):1-49; Lloyd-Jones D, et al. Circulation 2009;119:e21-181.
  • 4. Characteristics of Stable Ischemic Heart Disease
    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.
    Gibbons RJ, et al. J Am CollCardiol2003;41:159-68; Fraker TD, Fihn SD. J Am CollCardiol2007;50:2264-74; Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.
  • 5. Standard Therapy forStable Ischemic Heart Disease
    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)
    Gibbons RJ, et al. J Am CollCardiol2002;41:159-68; Fraker TD, Fihn SD. J Am CollCardiol2007;50:2264-74.
  • 6. Rationale for Additional Therapies for Patients With Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function
    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.
    ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker.
  • 7. Guidelines for the Use of ACEIs, ARBs, orBoth to Treat Patients With Cardiac Disease
    American College of Cardiology and American Heart Association guidelines say 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.
    For these reasons, 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 (e.g., patients with an LVEF >40%).
    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.
  • 8. Pharmacologic Effects of Agonists on the Renin-Angiotensin-Aldosterone System
    Angiotensinogen
    Kininogen
    Kallikrein
    Renin
    Vasodilation
    Angiotensin I
    Bradykinin
    Angiotensin-converting enzyme inhibitor
    Angiotensin-converting enzyme
    Kininase II
    Angiotensin II
    Inactive
    Decreased peripheralvascular resistance
    Angiotensin II-receptor blocker
    Angiotensin II Type I Receptors
    LEGEND
    Stimulatory signal
    Reaction
    Aldosterone secretion
    Vasoconstriction
    Inhibitory pharmacologic effect
    Ceconi C, et al. Cardiovasc Res 2007;73:237-46; Faxon DP, et al. Circulation 2004;109:2617-2625; Schmidt-Ott KM, et al. RegulPept 2000; 93:65-77; Song JC, White CM. Pharmacotherapy 2000;20:130-9; Song JC, White CM. ClinPharmacokinet2002;41:207-24; Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.
    Increased Na+ and H2O reabsorption
    Increased peripheral vascular resistance
  • 9. The CER Development Process
    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.
    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.
  • 10. Rating the Strength of Evidence From the CER:A Modification of the GRADE Methodology
    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:
    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.
  • 11. 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.
  • 12. Clinical Questions Addressed by the Comparative Effectiveness Review for Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function
    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.
    Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.
  • 13. 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
    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.
    Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009
  • 14. 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.
  • 15. 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.
  • 16. 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
    CV = cardiovascular; HF = heart failure; MI = myocardial infarction.
    Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.
  • 17. 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.
  • 18. 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.
  • 19. 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.
  • 20. 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
    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.
    Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.
  • 21. Overall Summary of the Evidence-Based Benefits and Harms of Adding anACEI/ARB Combination Versus an ACEI Alone to Standard Medical Therapy forStable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function
    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).
    Modified from Yusuf S, et al. New Engl J Med 2008;358:1547-59.
  • 22. 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
    • Seven trials met the inclusion criteria for this analysis.
    • 23. There was no clinical benefit from adding an ACEI or an ARB to standard medical therapy in close proximity to a revascularization procedure.
    • 24. There was an increased risk of adverse events.
    Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.
  • 25. 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
    CABG = coronary artery bypass grafting surgery; PTCA = percutaneous transluminal coronary angioplasty.
    Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.
  • 26. 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
    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:
    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. Gaps in Knowledge About ACEIs and ARBs as Treatment for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function
    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 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.
    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