Renin-Angiotensin-Aldosterone System Modulators in Adults with Hypertension: A Network Meta-Analysis of Randomized Controlled Trials

Background Although a range of renin-angiotensin-aldosterone system (RAAS) modulators are available for blood pressure lowering, the optimal choice within this class remains unclear. We aimed to compare the efficacy and safety of RAAS modulators in the adult hypertensive population. Methods A systematic literature search was performed in PubMed, CENTRAL, and Embase. The primary efficacy outcome was all-cause mortality and the secondary efficacy outcome was cardiovascular mortality. Tolerability outcome was discontinuation due to adverse events. Safety outcomes included the occurrence of cough, dizziness, edema, hyperkalemia, and hypotension. Network meta-analyses were performed utilizing a random-effects model within a frequentist framework. Results We finally identified 51 articles from 49 randomized controlled trials. When compared to placebo, mineralocorticoid receptor antagonists (MRAs) significantly reduced the risk of all-cause mortality (odds ratio (OR) 0.83; 95% confidence interval (CI) 0.74-0.92) and cardiovascular mortality (OR 0.79; 95% CI 0.68-0.93), while none of other RAAS modulators significantly lowered the risk of all-cause or cardiovascular mortality. Individual comparisons indicated that MRAs were associated with a significantly lower risk of all-cause mortality than the other RAAS modulators (reduction: 16% compared with angiotensin-converting enzyme inhibitors (ACEIs), 14% compared with angiotensin receptor blockers (ARBs), and 22% compared with direct renin inhibitors (DRIs)). No difference in discontinuation due to adverse events was found in a comparison of RAAS modulators with placebo. With regard to safety outcomes, ACEIs have a higher risk of cough (OR 4.68; 95% CI 1.61-13.60), ARBs have a higher risk of dizziness (OR 1.42; 95% CI 1.06-1.91), hypotension (OR 2.10; 95% CI 1.02-4.34), and hyperkalemia (OR 1.99; 95% CI 1.17-3.41), and MRAs had a higher risk of hyperkalemia (OR 2.68; 95% CI 1.99-3.62) when compared to placebo. Conclusions MRAs were the only RAAS modulators with a survival benefit in adults with hypertension, although they carried a higher risk of hyperkalemia. Our data challenge current hypertension guidelines which recommend MRAs as fourth-line therapy, and suggest that MRAs should be prescribed earlier and more widely. Registration PROSPERO identifier number CRD42023405714.