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Efficacy and Safety of Dual Blockade of the Renin-Angiotensin System: Meta-Analysis of Randomised Trials
Study Questions:
What are the long term-efficacy and adverse events of dual blockade of the renin-angiotensin system compared with monotherapy?
Methods:
This was a systematic review and meta-analysis. Randomized controlled trials comparing dual blockers of the renin-angiotensin system with monotherapy, reporting data on either long-term efficacy (≥1 year) or safety events (≥4 weeks), and with a sample size of at least 50 were included. Analysis was stratified by trials with patients with heart failure versus patients without heart failure.
Results:
A total of 33 randomized controlled trials with 68,405 patients (mean age 61 years, 71% men) and mean duration of 52 weeks were included. Dual blockade of the renin-angiotensin system was not associated with any significant benefit for all-cause mortality (relative risk [RR], 0.97; 95% confidence interval [CI], 0.89-1.06) and cardiovascular mortality (RR, 0.96; 95% CI, 0.88-1.05) compared with monotherapy. Compared with monotherapy, dual therapy was associated with an 18% reduction in admissions to the hospital for heart failure (RR, 0.82; 95% CI, 0.74-0.92). However, compared with monotherapy, dual therapy was associated with a 55% increase in the risk of hyperkalemia (p < 0.001), a 66% increase in the risk of hypotension (p < 0.001), a 41% increase in the risk of renal failure (p = 0.01), and a 27% increase in the risk of withdrawal owing to adverse events (p < 0.001). Efficacy and safety results were consistent in cohorts with and without heart failure when dual therapy was compared with monotherapy except for all-cause mortality, which was higher in the cohort without heart failure (p = 0.04 vs. p = 0.15), and renal failure was significantly higher in the cohort with heart failure (p < 0.001 vs. p = 0.79).
Conclusions:
The authors concluded that the risk to benefit ratio argues against the use of dual blockade of the renin-angiotensin system.
Perspective:
The current study failed to show any benefit for all-cause mortality and cardiovascular mortality with dual therapy (any two of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, or aliskiren) compared with monotherapy. Although compared with monotherapy dual therapy was associated with a reduction in admissions to the hospital for heart failure mainly in the cohort with heart failure, the risks of hyperkalemia, hypotension, renal failure, and withdrawal owing to drug-related adverse events were significantly increased. Based on available data and overall risk-benefit analysis, use of dual blockade of the renin-angiotensin system should be avoided.
Keywords: Angiotensin Receptor Antagonists, Risk, Hypotension, Renin-Angiotensin System, Hyperkalemia, Heart Diseases, Renal Insufficiency, Fumarates, Angiotensin II Type 1 Receptor Blockers, Cardiology, Heart Failure
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