Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials

• Published in: BMJ (Online) Vol. 346; no. 7896; p. 13
• Main Authors: Makani, Harikrishna, Bangalore, Sripal, Desouza, Kavit A, Shah, Arpit, Messerli, Franz H
• Format: Journal Article
• Language: English
• Published: England British Medical Journal Publishing Group 28.01.2013; BMJ Publishing Group; BMJ Publishing Group LTD; BMJ Publishing Group Ltd
• Subjects: ACE inhibitors; Angiotensin; Angiotensin Receptor Antagonists - adverse effects; Angiotensin Receptor Antagonists - therapeutic use; Angiotensin-Converting Enzyme Inhibitors - adverse effects; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; Bias; Blood pressure; Cardiology; Cardiovascular diseases; Clinical trials; Collaboration; Data processing; Diabetes; Diuretics; Drug Therapy, Combination; Enzymes; Evidence-based medicine; Experimentation; Female; Health outcomes; Heart; Heart diseases; Heart failure; Heart Failure - therapy; Hospital admissions; Hospitalization; Humans; Hyperkalemia; Hyperkalemia - therapy; Hypertension; Hypotension; Hypotension - therapy; Kidney diseases; Kidney failure; Kidneys; Male; Meta-analysis; Middle Aged; Mortality; Patients; Randomized Controlled Trials as Topic; Renal failure; Renal Insufficiency - therapy; Renin; Renin angiotensin system; Renin-Angiotensin System - drug effects; Sensitivity analysis; Statistical analysis; Treatment Outcome
• ISSN: 0959-8138; 1756-1833; 1756-1833
• DOI: 10.1136/bmj.f360

Objective To compare the long term efficacy and adverse events of dual blockade of the renin-angiotensin system with monotherapy.Design Systematic review and meta-analysis.Data sources PubMed, Embase, and the Cochrane central register of controlled trials, January 1990 to August 2012.Study selection Randomised 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. Analysis was stratified by trials with patients with heart failure versus patients without heart failure.Results 33 randomised 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 0.97, 95% confidence interval 0.89 to 1.06) and cardiovascular mortality (0.96, 0.88 to 1.05) compared with monotherapy. Compared with monotherapy, dual therapy was associated with an 18% reduction in admissions to hospital for heart failure (0.82, 0.74 to 0.92). However, compared with monotherapy, dual therapy was associated with a 55% increase in the risk of hyperkalaemia (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 v P=0.15), and renal failure was significantly higher in the cohort with heart failure (P<0.001 v P=0.79).Conclusion Although dual blockade of the renin-angiotensin system may have seemingly beneficial effects on certain surrogate endpoints, it failed to reduce mortality and was associated with an excessive risk of adverse events such as hyperkalaemia, hypotension, and renal failure compared with monotherapy. The risk to benefit ratio argues against the use of dual therapy.