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

BMJ 2013; 346 doi: (Published 28 January 2013) Cite this as: BMJ 2013;346:f360
  1. Harikrishna Makani, fellow in cardiovascular medicine1,
  2. Sripal Bangalore, director of cardiovascular outcomes group, assistant professor of medicine2,
  3. Kavit A Desouza, fellow in cardiovascular medicine1,
  4. Arpit Shah, resident in internal medicine1,
  5. Franz H Messerli, professor of clinical medicine1
  1. 1Division of Cardiology, St Luke’s Roosevelt Hospital, Columbia University College of Physicians and Surgeons, 1000 10th Avenue, New York, NY 10019, USA
  2. 2The Leon H Charney Division of Cardiology, New York University School of Medicine, New York, NY, USA
  1. Correspondence to: F H Messerli messerli.f{at}
  • Accepted 2 January 2013


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.


  • Contributors: HM supervised the study, had full access to all the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis. He is the guarantor. HM, SB, and FHM conceived and designed the study, acquired the data, drafted the manuscript, and critically revised the manuscript for important intellectual content. KAD and AS analysed and interpreted the data. All authors carried out the statistical analysis and had full access to all the data in the study.

  • Funding: This research received no specific grant from any funding agency in the public, commercial, or not for profit sectors. None of the authors received any compensation for their work on this manuscript.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: FHM is an ad hoc consultant and speaker for Novartis, Daiichi Sankyo, Pfizer, Takeda, Abbott, Medtronic, Servier, and Bayer; SB is on the advisory board of Daiichi Sankyo and Boehringer Ingelheim; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

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