Efficacy of Renin Angiotensin Aldosterone System Inhibitors on Cardiovascular Outcomes in Hypertensive Population: A Network Meta-analysis of Randomized Controlled Trials.

BACKGROUND

Renin-angiotensin-aldosterone system (RAAS) inhibitors are widely used for lowering blood pressure, but the optimal choice of RAAS inhibitors in reducing cardiovascular events remains unclear.

OBJECTIVES

We aimed to compare the efficacy of RAAS inhibitors on cardiovascular outcomes in hypertensive population.

METHODS

A systematic literature search was performed in PubMed and the Central Cochrane Library. The primary efficacy outcome was major adverse cardiovascular events (MACE). Individual components of MACE including cardiovascular mortality, myocardial infarction, stroke, and heart failure were also analyzed. Network meta-analyses were conducted via a random-effects model within frequentist framework.

RESULTS

We analyzed 43 randomized controlled trials. Mineralocorticoid receptor antagonists (MRAs) significantly reduced the risk of MACE compared with placebo [risk ratio (RR) 0.82; 95% confidence interval (CI) 0.75-0.90] and were superior to angiotensin receptor blockers (ARBs; RR 0.87; 95% CI 0.78-0.99) and direct renin inhibitors (DRIs; RR 0.83; 95% CI 0.70-0.99). MRAs showed a nonsignificant trend toward benefit compared with angiotensin-converting enzyme inhibitors (ACEIs; RR 0.91; 95% CI 0.78-1.05). After excluding trials that specifically enrolled patients with heart failure, protective effect of MRAs was not significant, but suggested a trend toward benefit (RR 0.89; 95% CI 0.78-1.01). Subgroup analyses for diabetes and chronic kidney disease consistently showed significant MACE reduction with MRAs, regardless of whether patients had these comorbidities at baseline or not, while other RAAS inhibitors showed inconsistent results in the subgroup analysis. For individual events, MRAs showed higher efficacy in reducing cardiovascular mortality (RR 0.80; 95% CI 0.72-0.88) and heart failure (RR 0.83; 95% CI 0.70-0.98) compared with placebo, while ACEIs were more effective in reducing myocardial infarction (RR 0.65; 95% CI 0.51-0.82) and ARBs showed higher efficacy in reducing stroke (RR 0.88; 95% CI 0.80-0.98) compared with placebo.

CONCLUSIONS

MRAs outperformed ARBs and DRIs in reducing MACE in patients with hypertension, with a nonsignificant trend toward benefit compared with ACEIs. This benefit was most pronounced in populations with heart failure and MRAs provided consistent cardiovascular protection across subgroups with diabetes or renal comorbidities. Given the current positioning of the guidelines, MRAs may merit earlier consideration in hypertension management, pending confirmatory outcome-driven randomized trials.

REGISTRATION: PROSPERO identifier number CRD42023473004, registered on 28 October 2023.