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
FunctionPrepared for:
Agency for Healthcare Research and Quality (AHRQ)www.ahrq.gov
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
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 Diseasein 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.
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 Diseasein 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.
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.
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 forStable 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.
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.
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, orBoth 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.
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, orBoth 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.
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 H2O reabsorption
Vasoconstriction
Increased peripheral vascular resistance
Angiotensin II Type I Receptors
Vasodilation
Decreased peripheral
vascular resistance
Stimulatory signal
Reaction
Inhibitory pharmacologic effect
LEGEND
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
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.
High There are consistent results from good quality clinical trials. Further research is very unlikely to change the conclusions.
Moderate Findings are supported, but further research could change the conclusions.
Low There are very few clinical trials, or existing trials are flawed.
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.
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.
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
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
Clinical Trial Group Drug NFollowup
(Yrs)
PEACE ACEI Trandolapril 8,290 4.8
PART-2 ACEI Ramipril 617 4.7TRANSCEND ARB Telmisartan 5,926 4.7HOPE ACEI Ramipril 9,297 4.5
EUROPA ACEI Perindopril 12,218 4.2
SCAT ACEI Enalapril 460 4.0CAMELOT ACEI Enalapril 1,991 2.0
Kondo J, et al. ARB Candesartan 397 2.0
SMILE-ISCHEMIA ACEI Zofenopril 349 0.5Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.
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
Clinical Trial Group Drug
TrialTarget Dose
(mg/day)HOPE ACEI Ramipril 10PART-2 ACEI Ramipril 5–10SCAT ACEI Enalapril 20CAMELOT ACEI Enalapril 20EUROPA ACEI Perindopril 4–8PEACE ACEI Trandolapril 4SMILE-ISCHEMIA ACEI Zofenopril 60
TRANSCEND ARB Telmisartan 80Kondo J, et al. ARB Candesartan 4
Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.
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
Outcome
ACEI ARB
RiskLevel ofEvidence Risk
Level ofEvidence
Total Mortality Decreased High No effect ModerateCV Mortality Decreased Moderate No effect Moderate
Nonfatal MI Decreased High No evidence --
Stroke Decreased Moderate No effect ModerateCombined Risk of CV Mortality, Nonfatal MI, and Stroke
No effect Moderate Decreased Moderate
Atrial Fibrillation No effect High No effect HighTotal Hospitalizations No effect Moderate No effect ModerateAngina-Related Hospitalizations No effect High No effect High
HF-Related Hospitalizations Decreased High No effect Moderate
Revascularization Decreased High No effect ModerateColeman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.CV = cardiovascular; HF = heart failure; MI = myocardial infarction.
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
Outcomes
ACEI ARB
RiskLevel of Evidence Risk
Level of Evidence
Syncope Increased Low No evidence –
Cough Increased Low No evidence –
Angioedema No effect Low No evidence –
Hyperkalemia Increased Low Increased Low
Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.
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
Outcomes
Event Rate/100 Patients Over the Next 4 Years
Relative Risk
Reduction*
Number Needed to Treat
With ACEI to Prevent One Additional
Adverse Outcome†
WithoutACEI
WithACEI
Absolute Difference
In Event Rate
Totalmortality 8.5 7.4 1.3 13% 91
Nonfatal myocardial infarction
6.1 5.0 1.1 17% 91
Heart failure-related hospitalizations
2.6 2.0 0.6 22% 167
Need for revascularization 13.6‡ 12.3‡ 1.3‡ 10% 77
*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.
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*
Outcomes
Event Rate/100 Patients
Over the Next 5 Years
Relative Risk
Reduction†
Number Needed to Treat With an ARB to
Prevent One
Additional Adverse
Outcome ‡
Without
ARBWithARB
Absolute Differen
ce In Event
Rate
Combined risk of death from heart-related cause, suffering a nonfatal myocardial infarction, or having a stroke
14.8 13.0 1.8 12% 56* 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.
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.
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
Outcomes
ACEI Alone (N =
8,576)
ACEI/ARB Combinatio
n (N = 8,502)
ACEI/ARB CombinationVersus ACEI
Alonen n (P value)
Total number of discontinuations 2,099 2,495 < 0.001
Hypotension 149 406 < 0.001Syncope 15 29 0.03 Renal impairment 60 94 < 0.001Diarrhea 12 39 < 0.001
Modified from Yusuf S, et al. New Engl J Med 2008;358:1547-59.
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.
Trial Treatment Group DrugMARCATOR ACEI given the same day post-PTCA cilazapril
APRES ACEI given 5 to 7 days after CABG or 1 to 2 days after PTCA ramipril
Kondo J, et al. ACEI given after coronary stenting quinapril
PARIS ACEI given ≤48 hours after coronary stenting quinapril
QUIET ACEI given 12 to 72 hours after angioplasty quinapril
IMAGINE ACEI given ≤7 days after CABG quinapril
AACHEN ARB given 7 to 14 days before coronary stenting candesartan
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
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
Increased Risk of Harms Drug Level of Evidence
Hypotension ACEI Moderate
Need for subsequent revascularization ACEI or ARB High
Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.
Identifying Trade-offs for Your Patients:Summary of Results on Comparative Effectiveness of Adding ACEIs and/or ARBs to Standard Medical Therapy
Clinical Comparison Benefits* Harms*
Adding an ACEI to standard therapy versus standard therapy alone
Reduced total mortality, nonfatal myocardial infarction, heart failure-related hospitalizations, and the need for revascularization procedures
Possible increase in syncope, cough, and hyperkalemia
Adding an ARB to standard therapy versus standard therapy alone
Reduced incidence of one or more of the following: cardiovascular mortality, nonfatal myocardial infarction, and stroke
Possible increase in hyperkalemia
Adding an ACEI/ARB combination to standard therapy
No clinical benefit compared to adding just an ACEI to standard therapy
Increased risk of hypotension, syncope, and renal impairment
Adding an ACEI or an ARB close to a revascularization procedure versus standard therapy alone
No clinical benefit Increased risk for repeat revascularizations; Increased risk of hypotension
Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.
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.
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
1. Review the critical evidence to help your patients understand:
2. Explore each patient’s values by asking:
3. Encourage your patients to be involved in their care:
• Relevance of risk
reductions after adding an ACEI to their regimen.
• Risks for cough, syncope, and hyperkalemia after adding an ACEI and what they could mean.
• The option of using an ARB if intolerant to ACEIs.
• The harms of adding an ACEI or an ARB too close to a revascularization procedure.
• What worries you most about taking these types of medications?
• Do you have concerns about the cost of your medicines?
• Do you have any problems remembering to take your medicines?
• Discuss the benefits and risks of each choice.
• Talk about the impact their comorbidities will have on the decision to add an ACEI or ARB.
• Discuss other things they can do to help reduce their risk of heart attack and stroke.
