Renin-Angiotensin System Inhibitors in Coronary Artery Disease Without Heart Failure

Renin-angiotensin system (RAS) inhibitors are not superior to other agents in reducing cardiovascular events in patients with stable coronary artery disease (CAD) without heart failure (HF), according to a new systematic review and meta-analysis published in the British Medical Journal.¹

Sripal Bangalore, MD, of New York University School of Medicine in New York City, and colleagues set out to assess the efficacy of RAS inhibitors compared with active controls or placebo in patients with stable CAD without HF (defined as left ventricular ejection fraction [LVEF] ≥40% or without symptomatic clinical HF). Trials were included only if a minimum of 100 patients were enrolled and had follow-up of at least 1 year.

Primary outcomes were all-cause mortality, cardiovascular death, myocardial infarction (MI), angina pectoris, stroke, and HF. Secondary outcomes were revascularization, incident diabetes, and drug withdrawal due to adverse effects.

The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines on stable ischemic heart disease² recommend using RAS inhibitors in patients who also have hypertension, diabetes, LVEF ≤40%, or chronic kidney disease unless contraindicated and in patients with other vascular disease. However, several previous studies found that RAS inhibitors did not confer benefit compared with placebo or active controls.

Since RAS inhibitors were compared separately with placebo or active controls, a test for interaction was used to compare the quantitative (magnitude) and qualitative direction of the effect size for the placebo and the active control trials, with P _interaction <.05 considered statistically significant.

Of 24 trials consisting of 198,285 patient-years of follow-up, 18 were placebo controlled and 7 used active controls (calcium antagonists, thiazide diuretic, and conventional treatment).

The researchers found that RAS inhibitors reduced the risk of all-cause mortality (rate ratio [RR], 0.84; 95% CI, 0.72-0.98), cardiovascular mortality (RR, 0.74; 95% CI, 0.59-0.94), MI (RR, 0.82; 95% CI, 0.76-0.88), stroke (RR, 0.79; 95% CI, 0.70-0.89), angina (RR, 0.94; 95% CI, 0.89-0.99), and HF (RR, 0.78; 95% CI, 0.71-0.86) when compared with placebo.

However, this benefit was not found when RAS inhibitors were compared with active controls (all-cause mortality [RR, 1.05; 95% CI, 0.94-1.17; P_interaction =.006]; cardiovascular mortality [RR, 1.08; 95% CI, 0.93-1.25; P_interaction <.001]; MI [RR, 0.99; 95% CI, 0.87-1.12; P_interaction =.01]; stroke [RR, 1.10; 95% CI, 0.93-1.31; P_interaction =.002], and angina [RR, 1.07; 95% CI, 0.85-1.35; P_interaction =.03).

Bayesian meta-regression analysis demonstrated that the effect of RAS inhibitors on all-cause mortality and cardiovascular mortality when compared with placebo was dependent on the control event rate — ie, RAS inhibitors were beneficial only in trials with high control event rates (>14.10 deaths and >7.65 cardiovascular deaths per 1000 patient-years).

The researchers noted certain limitations in their study, including between-trial differences and the absence of ejection fraction threshold data in some trials. Moreover, not all trials reported each of the outcomes tested. Additionally, the active comparators were mainly calcium antagonists, so “the results should not be extrapolated to other drugs not tested in the included trials,” they cautioned.

Nevertheless, the researchers pointed to an important clinical implication of their study: the “blanket recommendation” to use RAS inhibitors in all patients with CAD is “not supported by evidence.”

Disclosures

Dr Bangalore reports receiving honoraria from Daiichi-Sankyo, Pfizer, Abbott, Merck, Boehringer Ingelheim, Gilead, and Abbott Vascular. Dr Wandel is employed by and holds shares of Novartis Pharma AG. Dr Messerli reports receiving honoraria from Daiichi-Sankyo, Pfizer, Abbott, Servier, Ipca Laboratories, Menarini, and Relypsa.

References

1. Bangalore S, Fakheri R, Wandel S, Toklu B, Wandel J, Messerli FH. Renin angiotensin system inhibitors for patients with stable coronary artery disease without heart failure: systematic review and meta-analysis of randomized trials [published online January 19, 2017]. BMJ.  doi:10.1136/bmj.j4
2. Fihn SD, Gardin JM, Abrams J, et al; for the American College of Cardiology Foundation, American Heart Association Task Force on Practice Guidelines, American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons. 2012 ACCF/AHA/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College  of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60(24):e44-e164. doi:10.1016/j.jacc.2012.07.013