ABSTRACT & COMMENTARY
Renin-angiotensin System Antagonists in Stable CAD
By Michael H. Crawford, MD, Editor
Sorbets E, et al. Renin-angiotensin system antagonists and clinical outcomes in stable coronary artery disease without heart failure. Eur Heart J 2014;35:1760-1768.
Renin-angiotensin system antagonists
(RASAs) such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been shown to have beneficial effects in patients with heart failure, reduced left ventricular (LV) systolic function, acute myocardial infarction, hypertension, diabetes, and chronic kidney disease. However, clinical trial results do not consistently show a benefit in stable coronary artery disease (CAD) patients without heart failure or reduced LV function. Part of this trial inconsistency is due to advances in medical care and the fact that trials enter highly selected patient populations that may not reflect the predominant patients seen in practice. Large observational database studies can be of value for shedding light on clinical dilemmas. Thus, this analysis of the Reduction of Atherothrombosis for Continued Health (REACH) cohort was done to try to clarify the role of RASAs in the management of stable CAD patients without heart failure. The primary combined outcome of REACH was cardiovascular (CV) death, myocardial infarction (MI), or stroke over a 4-year follow-up period. Secondary outcomes included CV hospitalizations for an atherothrombotic event, and tertiary outcomes included all-cause mortality and heart failure. A propensity score adjustment was applied to a multivariate logistic regression model with ACEI/ARB use as the dependent variable. As an internal validity check, the effect of statins on the outcomes was performed in the same manner.
Almost 21,000 patients met the entry requirements, of which about 13,000 were on RASAs and 7500 were not. During a median follow-up of 44 months, 1527 experienced a primary outcome event (12%). The rate of these events was not different between RASA users and non-users (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.91-1.16; P = 0.66). There were no differences in the secondary or tertiary outcomes. On the other hand, statin use was associated with a lower incidence of the primary outcome (HR 0.74; 95% CI, 0.65-0.83; P < 0.001). The authors concluded that the use of RASAs was not associated with beneficial outcomes in stable CAD patients without heart failure.
COMMENTARY
Older randomized trials such as HOPE and EUROPA showed benefits from ACEIs in stable CAD patients without heart failure. However, more recent trials such as PEACE and IMAGINE did not. This progression of results suggests that modern evidence-based secondary prevention strategies in CAD patients trumps any potential beneficial effect of RASAs purely for prophylaxis.
There are several strengths to this study. It is very large (almost 21,000 patients) and even without propensity matching, the benefits of RASAs are unimpressive. Also, it is a contemporary international population of patients and the results are consistent over all subsets of the patients. In addition, the analysis of the results of statin therapy performed in the same manner shows a robust benefit in these patients.
There are limitations to this study. Confounding by unmeasured variables is always an issue in observational studies. One prominent issue in this regard is that there was no systemic assessment of LV function. However, if there were patients with unrecognized LV systolic dysfunction, their response to RASAs did not seem to influence the results. The lack of information about the doses of ACEI/ARBs is a problem since trials have shown that their benefit is seen predominantly at higher doses, which may not have been used in this observational study of routine clinical practice. Regardless of these limitations, after seeing the results of PEACE, IMAGINE, and this observational study, I am no longer using RASAs in stable CAD patients without heart failure or LV systolic dysfunction unless another clean cut indication for their use, such as hypertension, is present.
