Skip Navigation
Department of Health and Human Services www.hhs.gov
 
Slide Tray
0 slides

Return to Slide Library

Slides

Add Presentation to Slide Tray Presentation:

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

Slides: 13–24 of 29
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), 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. The benefit endpoints include total mortality, cardiovascular (CV) death, nonfatal myocardial infarction (MI), stroke, composite endpoint (CV death, nonfatal MI, stroke), revascularization, and quality-of-life measures. The harms endpoints include hyperkalemia, cough, angioedema, hypotension, rash, blood dyscrasias, syncope, and withdrawal from a trial.

Comparative Effectiveness Review: Outcomes of Interest

This 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.

Clinical Questions Addressed by the CER for Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function

This 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 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; Yiu 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 Zannad 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.

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

This 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 a recent myocardial infarction or who had a revascularization procedure within 3 to 6 months of trial enrollment, depending on the trial. 
The PEACE trial studied the addition of an ACEI, trandolapril, or usual care in N = 8,290 patients at an average followup time of 4.8 years. The PART-2 trial studied the addition of an ACEI, ramipril, or usual care in 617 randomized patients at an average followup time of 4.7 years. The TRANSCEND trial studied the addition of an ARB, telmisartan, or usual care in 5,926 patients at an average followup time of 4.7 years. The HOPE trial studied the addition of an ACEI, ramipril, or usual care in 9,297 patients at an average followup time of 4.5 years. The EUROPA trial studied the addition of an ACEI, perindopril, or usual care in 12,218 patients at an average followup time of 4.2 years. The SCAT trial studied the addition of an ACEI, enalapril, or usual care in 460 patients at an average followup time of 4.0 years.  The CAMELOT trial studied the addition of an ACEI, enalapril, or usual care in 1,991 patients at an average followup time of 2.0 years.  The trial published by J Kondo, et al. studied the addition of an ARB, candesartan, or usual care in 397 patients at an average followup time of 2.0 years. The SMILE-ISCHEMIA trial studied the addition of an ACEI, zofenopril, or usual care in 349 patients at an average followup time of 0.5 years. 
Of the 9 trials that were evaluated, 7 had investigated ACEIs and two 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/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=335).

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 Function

This 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 ARB. Available evidence is insufficient to determine if different doses of ACEIs or ARBs impact outcomes in this patient population. The HOPE trial studied the addition of an ACEI, ramipril, or usual care and had a trial target dose of 10 mg/day. The PART-2 trial studied the addition of an ACEI, ramipril, or usual care and had a trial target dose of 5 to 10 mg/day. The SCAT trial studied the addition of an ACEI, enalapril, or usual care and had a trial target dose of 20 mg/day.  The CAMELOT trial studied the addition of an ACEI, enalapril, or usual care and had a trial target dose of 20 mg/day.  The EUROPA trial studied the addition of an ACEI, perindopril, or usual care and had a trial target dose of 4-8 mg/day. The PEACE trial studied the addition of an ACEI, trandolapril, or usual care and had a trial target dose of 4 mg/day. The SMILE-ISCHEMIA trial studied the addition of an ACEI, zofenopril, or usual care and had a trial target dose of 60 mg/day. The TRANSCEND trial studied the addition of an ARB, telmisartan, or usual care and had a trial target dose of 80 mg/day. The trial published by J Kondo, et al. studied the addition of an ARB, candesartan, or usual care and had a trial target dose of 4 mg/day. 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/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=335).

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

This 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.

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

This 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 level of evidence associated with each outcome is low or insufficient, 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.

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

On 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.

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 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.

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*

ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) was the only large, multicenter, randomized, double-blinded, active-controlled clinical trial available for the review of the comparative effectiveness of combining ramipril, an angiotensin-converting enzyme inhibitor (ACEI) with telmisartan, an angiotensin II receptor blocker (ARB) and then adding the combination (ramipril + telmisartan) to standard medical therapy, as opposed to adding only an ACEI (ramipril) to standard medical therapy in patients with stable vascular disease and a normal left ventricular systolic function (LVSF). There were no statistically significant benefits that resulted from adding the ACEI/ARB combination, but there was evidence of an increased risk for adverse events among patients who received this combination.

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

This 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. 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.

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

This 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, 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 discuss these data in greater detail.

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

Pages: Previous 1 [2] 3 Next