Guidelines that recommend the use of renin angiotensin system inhibitors (RASi)—angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibitors—in all patients with coronary artery disease (CAD) are not supported by the available evidence, according to a recent meta-analysis and systematic review.
Researchers identified 24 randomized trials of RASi versus placebo or active controls in 61,961 patients with stable CAD but without heart failure (defined as left ventricular ejection fraction ≥40% or without clinical heart failure). Patients were followed for an average of 3.2 years, for 198,275 total patient years of follow-up.
Five of the studies enrolled patients within three months of acute myocardial infarction (MI), 18 were placebo-controlled, and seven were active-controlled (four trials compared calcium antagonists, one compared thiazide diuretics, and two compared conventional treatment). Results were published online on Jan. 19 by The BMJ.
For all primary outcomes studied (all-cause mortality, cardiovascular mortality, MI, stroke, angina pectoris, and heart failure), RASi reduced risk when compared to placebo but not when compared to active controls. Upon further analysis, researchers found that the effect of RASi when compared with placebo on both all-cause and cardiovascular mortality was beneficial only in trials with high control event rates (>14.10 deaths and >7.65 cardiovascular deaths per 1,000 patient-years), not in those with low control event rates.
Secondary outcomes included revascularization, incident diabetes, and drug withdrawal due to adverse effects. RASi reduced the risk of revascularization when compared with placebo but not when compared with active controls, whereas RASi reduced the risk of incident diabetes when compared to both placebo and active controls. Compared with controls, angiotensin-converting enzyme inhibitors, but not angiotensin receptor blockers, significantly increased the risk of drug withdrawal due to adverse effects.
The study authors noted that earlier trials (e.g, the HOPE and EUROPA trials) showed positive results of RASi compared to placebo but that subsequent studies (e.g., the PEACE, QUIET, CAMELOT, and IMAGINE trials) failed to show similar benefits. “The lack of benefit in later trials could be due to lower event rate in these trials than those in the HOPE/EUROPA trials, owing to increased use of revascularization and lipid lowering treatment,” they wrote.
The authors noted limitations of the meta-analysis, such as that they were unable to control for between-trial differences, that not all trials reported each of the evaluated outcomes, and that not all trials provided ejection fraction data for all patients. They added that the active comparators were mainly calcium antagonists and that the results should not be extrapolated to drugs that were not tested in the included trials.