Clinical Context

Despite advances in therapy, ischemic heart disease (IHD) remains the most common cause of morbidity and mortality in the United States. The prevalence of IHD is estimated at 16.8 million adults, and the death rate is 278.9 per 100,000 people, with IHD responsible for over 35 percent or all deaths nationwide.¹

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor blockers/antagonists (ARBs) have been shown to improve clinical outcomes for some patients, including those with heart failure and those with myocardial infarction (MI) and ventricular dysfunction.^2–9 However, the comparative effectiveness of ACE inhibitors and ARBs alone or in combination for patients with IHD remains uncertain. Their potential role in the management of the broader population of patients with known IHD or at high risk for IHD is also unclear.

To address this area of uncertainty, a comparative effectiveness review (CER) project sponsored by the Agency for Healthcare Research and Quality (AHRQ) was awarded to the University of Connecticut Evidence-based Practice Center (EPC). The subsequent CER reviewed data available through July of 2009 comparing the benefits and harms of adding ACE inhibitors, ARBs, or both to standard medical therapy in adults with stable IHD or IHD risk equivalents.^10–11 The report specifically addressed the following seven key questions:

• Key Question 1. In patients with stable IHD or IHD risk equivalents who have preserved left ventricular (LV) systolic function, what is the comparative effectiveness of ACE inhibitors or ARBs added to standard medical therapy when compared to standard medical therapy alone in terms of total mortality, cardiovascular mortality, nonfatal MI, stroke, the composite endpoint of the latter three items, and atrial fibrillation? What is the evidence of benefit on other outcomes such as symptom reporting, hospitalization, revascularization, and quality-of-life measures?
• Key Question 2. In patients with stable IHD or IHD risk equivalents who have preserved LV systolic function and are receiving standard medical therapy, what is the comparative effectiveness of combining ACE inhibitors and ARBs vs. either an ACE inhibitor or ARB alone in terms of total mortality, cardiovascular mortality, nonfatal MI, stroke, the composite endpoint of the latter three items, and atrial fibrillation? What is the evidence of benefit on other outcomes such as symptom reporting, hospitalization, revascularization, and quality-of-life measures?
• Key Question 3. In patients with IHD and preserved LV function who had to have recently undergone, or are set to undergo, a coronary revascularization procedure, what is the comparative effectiveness of ACE inhibitors or ARBs added to standard medical therapy when compared to standard medical therapy alone in terms of total mortality, cardiovascular mortality, nonfatal MI, stroke, the composite endpoint of the latter three items, and atrial fibrillation? What is the evidence of benefit on other outcomes such as symptom reporting, hospitalization, revascularization, and quality of life measures?
• Key Question 4. In patients with stable IHD or IHD risk equivalents who have preserved LV systolic function, what are the comparative harms of adding ACE inhibitors or ARBs to standard medical therapy when compared to standard medical therapy alone?
• Key Question 5. In patients with stable IHD who have preserved LV systolic function and are receiving standard medical therapy, what is the evidence of comparative harms of combination ACE inhibitor and ARB therapy vs. use with either an ACE inhibitor or ARB alone?
• Key Question 6. In patients with IHD and preserved LV systolic function who had to have recently undergone, or are set to undergo, a coronary revascularization procedure, what are the comparative harms of ACE inhibitors or ARBs added to standard medical therapy when compared to standard medical therapy alone?
• Key Question 7. What is the evidence that benefits or harms differ by subpopulations, including: demographics [sex, age, ethnicity, left ventricular ejection fraction (LVEF)], clinical course (previous treatment with a stent or coronary artery bypass surgery, degree and location of lesion, presence and pattern of symptoms), dose of the ACE inhibitor or ARB used, comorbidities (diabetes, renal dysfunction, hypertension), and other medications (vitamins, lipid-lowering drugs, beta-blockers, antiplatelet agents)?

These seven key questions are graphically displayed in Figure 1 through an analytic framework.

Figure 1

Analytic framework.

The CER found strong evidence that ACE inhibitors reduced total mortality and nonfatal MI in comparison to placebo among adults with stable IHD and preserved ventricular function, but increased the risk for syncope and cough. There was low to moderate evidence that ARBs reduced a composite of cardiovascular endpoints compared to placebo and were well-tolerated. The one available study directly comparing the impact of ACE inhibitors and ARBs on cardiovascular outcomes in patients with IHD revealed no significant difference between the classes in the rate of cardiovascular outcomes, but demonstrated higher rates of cough and angioedema among patients treated with ACE inhibitors, and higher rates of hypotensive symptoms among patients treated with ARBs.¹² The same study compared combination therapy with ACE inhibitors and ARBs to monotherapy with each class of agents and found no difference in vascular outcomes, but a higher discontinuation rate in the combination therapy group due to medication side effects.

Research Gaps

Although 41 studies including over 64,000 randomized patients were evaluated in this CER, the authors identified multiple areas where insufficient evidence existed to answer the key questions regarding the comparative effectiveness of ACE inhibitors and ARBs. While there was a high strength of evidence for ACE inhibitors compared to placebo for total mortality, the evidence was insufficient, low, or moderate for the impact of ACE inhibitors or ARBs on several cardiovascular outcomes, including cardiovascular mortality, nonfatal myocardial infarction, or stroke, suggesting that future research on the impact of ACE inhibitors or ARBs on cardiovascular outcomes may influence their conclusions. In addition, the report highlighted the potential utility of an individual patient data meta-analysis of major ACE inhibitor or ARB trials or future trials to provide insight into the impact of ACE inhibitors and ARBs on the following areas:

• Comparative benefits and harms in minority groups, including Asians, African Americans and Latinos.
• Comparative benefits and harms in patients with single- vs. multi-vessel disease and specifically with left anterior descending artery disease.
• Comparative benefits and harms in patients with a baseline ejection fraction (EF) between 40 percent and 70 percent.
• Comparative benefits and harms in patients taking adenosine diphosphate drugs vs. those taking no antiplatelet therapy.
• Comparative benefits and harms in patients with a history of revascularization.
• Comparative benefits and harms associated with adding ACE inhibitors or ARBs to standard medical therapy in patients with stable IHD and preserved left ventricular function vs. adding other cardiovascular drugs such as calcium channel blockers.
• Comparative benefits and harms associated with adding ACE inhibitors or ARBs to standard medical therapy in patients without proven stable IHD but with IHD risk equivalents.
• Comparative benefits and harms relating to dosing intensity of ACE inhibitors or ARBs.
• Comparative benefits and harms in patients with genetic polymorphisms within the ACE gene or the angiotensin II type 1 receptor.

The above evidence gaps represented areas where the EPC thought there was an underlying pharmacological rationale for suspecting potential differences; given the large number of clinical trials that have already been conducted, the University of Connecticut team thought that meta-analysis of individual patient data was the most efficient method to begin to address these gaps.

In addition to the priorities identified in the IHD CER, there are other evidence gaps which need to be addressed by future research in order to inform decisionmaking and resource allocation with respect to use of ACE inhibitors and ARBs. These include differences in treatment- and outcome-associated costs; the incidence of rare but serious side effects such as angioedema; differential impact on quality of life; and variation in observed population outcomes due to differences in patient selection, treatment adherence, or the uptake of evidence-based recommendations. Based on discussions with the University of Connecticut EPC, review of a recent draft update of a related CER of ACE inhibitors and ARBs in hypertension,^13–14 and discussions with our stakeholder group, we expanded the list of categories for future research. This expanded list included five research areas that were outside the scope of the original CER report, but for which the University of Connecticut EPC investigators, the Duke EPC team, and the stakeholder group felt that additional research was needed.

The decision to expand the list of research gaps beyond those identified in the original CER was based on two different rationales. The first was based on clinical overlap between our target condition, IHD, and other conditions for which ACE inhibitors and ARBs have an indication and a strong evidence base, such as hypertension, congestive heart failure, and chronic kidney disease. These conditions are interrelated and share several risk factors and clinical outcomes, yet are typically separated in comparative effectiveness trials and systematic reviews of the literature. We expanded our list of potential research gaps based on this literature to include outcomes of interest not included in the initial review (e.g. renal insufficiency, new diagnosis of heart failure) and research questions that have been raised in systematic reviews of these conditions (such as medication class effect, dose response, and alternative comparisons) that may span across these clinical conditions. The second rationale was reflected in the comments of several stakeholders who believed the clinical efficacy of ACE-inhibitors and ARBs was sufficiently well known and the most pressing challenge was improving the implementation of this evidence base for patients likely to benefit. Based on this input, medication adherence and enhanced evidence based use were added as important research gaps for consideration.

This initial list of future research priorities is summarized below in Table 1 according to the PICO (population, interventions, comparators of interest, and outcomes) format. The identified research gaps are also identified on our analytic framework in Figure 2 with letter coding. Those research gaps that were outside the scope of the original CER are shaded in gray in Table 1 and throughout the report.

Table 1

Research gaps organized by PICO format.

Figure 2

Analytic framework depicting research gaps.

A list of research gaps is a common component of CERs and is an important step in outlining a future research agenda; however, such lists do not always clearly suggest how future research should be prioritized, or what research projects are in fact feasible. In this pilot project, we sought to expand on the work done by the University of Connecticut EPC in the original CER to identify and prioritize gaps in the evidence supporting the comparative effectiveness of ACE inhibitor and ARB therapy in patients with IHD. This prioritization process combined a review of recently published and ongoing studies, engagement of nine stakeholders, and participation of these stakeholders in both qualitative and quantitative exercises of research needs prioritization.