Angiotensin-converting enzyme (ACE) inhibitors have been shown to be beneficial in the management of multiple cardiovascular disease states.
Angiotensin-converting enzyme (ACE) inhibitors have been shown to be beneficial in the management of multiple cardiovascular disease states. The primary effects of this class of drugs are mediated via the renin-angiotensin-aldosterone system. Thus, ACE inhibitors act by decreasing the production of angiotensin II and preventing the breakdown of kinins. The end result is decreased vasoconstriction, aldosterone and vasopressin release, sodium and water retention, and sympathetic activation. Other pleitropic effects of ACE inhibitors include improved endothelial function, reductions in myocardial remodeling, and favorable effects on the coagulation cascade. This spectrum of salutary physiologic actions of ACE inhibition has led to multiple well-accepted studies investigating whether ACE inhibitors can prevent the progression of cardiovascular disease.
Several large trials have demonstrated clear mortality benefit using ACE inhibitors in patients with coronary artery disease (CAD) and left ventricular dysfunction.1 However, the role of ACE inhibitors in patients with stable CAD and preserved left ventricular systolic function remains controversial, with some trials suggesting reduced cardiovascular events2 while others have found no benefit.3 These discrepant results may be explained by inherent differences in the study designs, including the ACE inhibitor used (lipophilic vs non-lipophilic), distribution of cardiac risk factors (diabetes), patient selection criteria, disease classification (determination of systolic function and CAD), and background cardioprotective drug use (proportion on statins).4 In addition, several of the smaller trials had relatively low event rates and, therefore, may have lacked the statistical power necessary to detect significant differences between groups.
When individual trials fail to adequately answer a research question, a meta-analysis is often warranted. In this issue of , Dr Al-Mallah presents a meta-analysis of 6 of the largest and most robust of the trials investigating ACE inhibitors in patients with stable CAD and preserved left ventricular systolic function. The pooled analyses suggest ACE inhibitor therapy was associated with a decrease in cardiovascular mortality, nonfatal myocardial infarction, revascularization, and all-cause mortality.5 Although these results are compelling and suggest that ACE inhibitors lower cardiovascular events in patients with stable CAD and preserved systolic function, a few limitations of this study should be mentioned. First, visual inspection of the individual risk estimates reveals wide confidence intervals with marked overlap, particularly for the smaller negative trials, raising concern for chance as a plausible explanation for the differences in point estimates. However, the authors performed a test for study heterogeneity (to look for inconsistency among the trials) and found none. Second, the meta-analysis relied on published study data with no access to individual level data. Because, as previously mentioned, the trials differed in their definition of exposure status (CAD and left ventricular function), the results (despite the author’s good-faith efforts) could be biased due to misclassification and the study comparisons may not be valid. And, finally, a meta-analysis relies on pooling data that is published, and publication bias is always a concern. However, the authors performed an extensive literature search and reviewed relevant unpublished data, making this less likely.
Thus, we are left with the well-established facts that ACE inhibitors are effective in reducing mortality and morbidity from cardiovascular events among patients with left ventricular systolic dysfunction, in those with acute myocardial infarction, in high-risk patients with diabetes, and in those with renal dysfunction. The current study supports the notion that the use of this class of drugs could legitimately be extended even more broadly. As Dr Al-Mallah suggests, ACE inhibitors added to conventional therapy may be modestly beneficial in patients with preserved left ventricular systolic function and CAD. However, before embracing this view (which is not without economic and patient safety implications), further longitudinal prospective studies using a real-world cohort of patients with stable coronary disease and preserved ventricular function should probably be done. Regardless, this careful meta-analysis underscores the fact that we already have a very useful pharmacopeia that influences the natural history of complex cardiovascular diseases. We just have to figure out the proper strategies and contexts for its use.