Risks of dual blockade of the renin-angiotensin system compared with monotherapy: a systematic review and cumulative meta-analysis of randomized trials and observational studies

Abstract

Previous work has suggested that dual blockade using inhibitors of the renin-angiotensin system (RAS) would be associated with an increase in side effects compared to monotherapy. We reexamined the safety of dual RAS blockade, especially in patients at risk, and explored the stability of the evidence accumulated over the years. Systematic review with random-effects meta-analyses. We reviewed 15 previously published meta-analyses as the starting point. PubMed/Medline was searched for recent evidence from both observational and randomized controlled trials. Outcomes measures were: mortality (overall and cardiovascular), hyperkalemia, hypotension, renal failure, stroke, and treatment withdrawal due to adverse effects. We calculated relative risks (RR) and confidence intervals (95% CI) RESULTS: Dual RAS blockade was not associated with reduced relative risk (RR) overall mortality (RR:1.00, 0.96-1.05; 21 studies), cardiovascular mortality (RR:1.01, 0.94-1.09; 13 studies) or stroke (RR:1.02; 0.94-1.11; 11 studies) compared to monotherapy. Dual blockade was associated with an increased risk of hyperkalemia (RR:1.58, 1.37-1.81; 34 studies), hypotension (RR:1.66; 1.41-1.95; 25 studies), renal failure (RR:1.52;1.28-1.81; 29 studies) and treatment discontinuation due to adverse events (RR:1.26;1.22-1.30; 37 studies). These results were consistent in cohorts of patients with diabetes mellitus, kidney disease or heart failure. Dual RAS blockade increased (vs monotherapy) the risks of hyperkalemia, hypotension, renal failure and treatment discontinuation. Dual RAS blockade did not offer additional benefit in reducing overall mortality, cardiovascular mortality or stroke. These findings are consistent over time.