Angiotensin-converting enzyme inhibitors in coronary artery disease and preserved left ventricular systolic function

The benefits of angiotensin-converting enzyme (ACE) inhibitors have been shown in patients with diabetes, hypertension,^1,2 and recent myocardial infarction (MI),^3,4 as well as after revascularization and in those with left ventricular dysfunction.^5,6 Recent evidence has suggested that ACE inhibitors may have antiatherosclerotic effects in these patient subgroups,^7,8 as shown in subgroup analyses in the Survival and Ventricular Enlargement (SAVE) and Studies of Left Ventricular Dysfunction (SOLVD) trials.

There has been controversy, however, regarding the use of ACE inhibitors in patients with preserved left ventricular systolic function and coronary artery disease (CAD). A reduction in nonfatal MI and mortality from cardiovascular events was shown with ACE inhibitor use in 2 large studies.^9,10 Several other studies, however, did not show these advantages.^2,11-13 To evaluate whether ACE inhibitors have a beneficial influence on all-cause mortality, death from cardiovascular events, nonfatal MI, and the rate of revascularization among patients with preserved left ventricular function and CAD, we conducted a comprehensive literature review and meta-analysis.¹⁴

Subjects and methods

We performed an extensive literature search to identify randomized, placebo-controlled studies that evaluated subjects with CAD and normal left ventricular function who were treated with ACE inhibitors. Studies that included subjects with a left ventricular ejection fraction < 40%, those without a placebo arm, and those that had a follow-up period of < 2 years were excluded. We also excluded studies that did not provide rates of death, nonfatal MI, or revascularization. The pooled relative risks (RRs) and 95% confidence intervals (CIs) were computed for all-cause mortality, cardiovascular mortality, nonfatal MI, and revascularization using the random-effects model. Employing the inverse of the pooled absolute risk reduction, we calculated the pooled number needed to treat to prevent 1 event.

We used the formula I² = [(Q — df)/Q] x 100%, where Q is the chi-square statistic and df is its degrees of freedom, to estimate between-study heterogeneity. An I² value > 50% indicates significant heterogeneity. A funnel plot was used to graphically assess publication bias. We performed subgroup analysis and used the statistical test of interaction to evaluate heterogenity between groups,¹⁵ which included outcome measures (a follow-up duration ≤ 2 years vs > 2 years and a drop in systolic blood pressure < 5 mm Hg vs ≥ 5 mm Hg) and the study population (proportion of diabetes mellitus < 20% vs ≥ 20%).

Results

Six of 894 studies met the inclusion criteria, resulting in a total of 16,728 subjects in the placebo arm and 16,772 in the treatment arm. Each subject was followed up for at least 2 years, with a mean follow-up period of 4.4 years.

The characteristics of the trials included in our analysis are shown in the

. Subjects in the Heart Outcomes Prevention Evaluation (HOPE) study received evidence-based therapies less often, were older, had diabetes more often, and were more often women. Although subjects in the Angiotensin-Converting Enzyme Inhibition in Stable Coronary Artery Disease (PEACE) study had a lower risk profile, they were more often receiving antiplatelet agents, beta blockers, and lipid-lowering therapies.

Table

The

P

P

P

P

shows the cumulative effect of ACE inhibitor use in this subject population. Subjects taking ACE inhibitors had a reduction in coronary revascularization rates (RR = 0.93; 95% CI, 0.87-1.00; = .04), all-cause death (RR = 0.87; 95% CI, 0.81-0.94; = .001), nonfatal MI (RR = 0.84; 95% CI, 0.75-0.94; = .003), and death from cardiovascular events (RR = 0.83; 95% CI, 0.72-0.96; = .01).

Figure

To prevent any of the unfavorable end points (1 cardiovascular or noncardiovascular death, nonfatal MI, or the need for revascularization), 100 patients need to be treated with ACE inhibitors. Based on the I² analyses, there was no heterogeneity among all these studies in all outcomes. In addition, we could not detect a marked association among the various subgroups (follow-up duration ≤ 2 years vs > 2 years, a drop in systolic blood pressure < 5 mm Hg vs ≥ 5 mm Hg, and proportion of diabetes mellitus < 20% vs ≥ 20%) and the various end points.

Discussion

This meta-analysis provides evidence showing that among patients with CAD and normal left ventricular function, ACE inhibitor therapy added to standard treatment is valuable. Compared with other therapies, the advantage of ACE inhibitors in this population is modest, as 100 patients need to be treated to prevent an event (cardiac or noncardiac death, nonfatal MI, or the need for coronary revascularization). This is supported by basic science and animal model data, which suggest that several pathways for the cardioprotective effects of ACE inhibitors are possible. These agents have been shown to increase endothelial function, reduce vascular inflammation, and decrease the advancement of atherosclerosis.^16,17

Despite this, the results of the randomized controlled trials did not uniformly support the bench data. This could be attributed to many factors in the design of each trial, the ACE inhibitor used, and the patient population studied. The lack of statistical power is evident in most of these negative trials. A meta-analysis, pooling data from more than 33,000 patients, can eliminate this drawback and identify smaller alterations in end points. In addition, the outcomes of each individual trial were affected by variations in the baseline treatments and risk profiles.

Although the HOPE trial included subjects with the highest risk profile, they were less often receiving other proven therapies. The opposite was noted in the PEACE trial. Because HMG-CoA reductase inhibitors (statins) improve endothelial function (possibly by the same mechanism as ACE inhibitors), a lower rate of statin use in the HOPE trial could unmask the beneficial effects of ACE inhibitors. On the other hand, the fact that most of these trials used tissue-specific ACE inhibitors excludes the possibility that the differences between the included trials are secondary to the pharmacokinetic and pharmacodynamic characteristics of different ACE inhibitors.

It is still debatable whether the benefit of ACE inhibitors is secondary to the lowering of blood pressure. The emerging awareness that ACE inhibitors can prevent endothelial impairment and restore endothelial function more than what would be anticipated solely from decreasing blood pressure has been supported by several clinical trials and experimental studies. Despite the fact that the effect of ACE inhibitors on the primary end point was not the same in the PEACE and HOPE studies, the magnitude of blood pressure reduction was similar. Therefore, the difference in the degree of blood pressure reduction does not appear to be the only reason for the inconsistency between these 2 studies.

One of the strengths of our analysis is that it helps to clarify the benefits of ACE inhibitor treatment among patients with preserved left ventricular function and CAD who received varying treatment regimens in different studies. Many clinical study results may be applicable only to those patients with attributes similar to those who participated in the study. But if the findings are the same in different studies with different subject groups and different treatment regimens, then the treatments under review can be considered to be applicable to the general population. Additionally, when there were inconsistencies among the original studies, we were able to provide a more impartial assessment of the literature by resolving discrepancies through the incorporation of the actual evidence.

Our analysis had some limitations. We had to use the information provided in the published reports of the trials, rather than the original patient data. A possible bias is disease misclassification. Broad definitions were used for CAD and preserved left ventricular function in some studies.^9,10 Publication bias is another potential limitation. However, the system we used to isolate the trials in the literature was thorough and was likely to obtain all pertinent studies on the subject; we reviewed unpublished studies, as well. Furthermore, the funnel plot did not reveal any indication of publication bias.

The results of our meta-analysis substantiate the favorable effects of ACE inhibitors. This corroborates the findings of other meta-analyses that demonstrated the ability of ACE inhibitors to prevent new-onset diabetes and atrial fibrillation,^18,19 although studies that evaluated angiotensin receptor blockers were also included in these analyses. For patients with CAD, congestive heart failure, impaired fasting glucose, hypertension, and prediabetic conditions, treatment with ACE inhibitors should be considered, as existing data substantiate their use.

Conclusions

Our systematic literature review and meta-analysis of randomized clinical trials that evaluated the use of ACE inhibitors among subjects with CAD and preserved left ventricular function showed that treatment with ACE inhibitors is beneficial. Angiotensin-converting enzyme inhibitors resulted in a modest decrease in revascularization procedures, nonfatal MI, cardiovascular mortality, and all-cause mortality when used in conjunction with traditional therapy.