Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials
Why the study?
Does dual blockade of the renin-angiotensin system reduce mortality or heart failure hospitalizations compared to monotherapy in patients with and without heart failure?
Population
33 RCTs pooling 68,405 patients (mean age 61 years, 71% men) with and without heart failure
Comparison
Dual blockade of the renin-angiotensin system vs Monotherapy
Design
Meta-analysis
Follow-up
mean 52 weeks
Authors
Discussion
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Implication
Dual blockade should be avoided due to excess harms without mortality benefit; challenges prior rationale for combination RAS inhibition in guidelines.
Key Points
- To compare the long-term efficacy and adverse event profiles of dual renin-angiotensin system blockade versus monotherapy in patients with and without heart failure.
- Systematic review and meta-analysis of 33 randomised controlled trials (N=68,405; mean age 61 years, 71% men; mean duration 52 weeks) identified via PubMed, Embase, and Cochrane databases from 1990 to 2012.
- Included trials with sample sizes ≥50 comparing dual renin-angiotensin system inhibitors with monotherapy reporting long-term efficacy (≥1 year) or safety outcomes (≥4 weeks), stratified by heart failure status.
- Dual blockade was not associated with significant reductions in all-cause mortality (RR 0.97, 95% CI 0.89 to 1.06) or cardiovascular mortality (RR 0.96, 95% CI 0.88 to 1.05), despite reducing heart failure hospital admissions by 18% (RR 0.82, 95% CI 0.74 to 0.92).
- Compared with monotherapy, dual blockade significantly increased the risks of hyperkalaemia by 55% (P<0.001), hypotension by 66% (P<0.001), renal failure by 41% (P=0.01), and treatment withdrawal due to adverse events by 27% (P<0.001).
- Adverse effects were consistent across subgroups, though renal failure was significantly higher in heart failure patients (P<0.001 vs P=0.79 in non-heart failure) and all-cause mortality differed between cohorts (P=0.04 in non-heart failure vs P=0.15 in heart failure).
Structured PICO
Does dual blockade of the renin-angiotensin system reduce mortality or heart failure hospitalizations compared to monotherapy in patients with and without heart failure?
P
Population
33 RCTs pooling 68,405 patients (mean age 61 years, 71% men) with and without heart failure
I
Intervention
Dual blockade of the renin-angiotensin system
C
Comparator
Monotherapy (single blockade of the renin-angiotensin system)
O
Outcome
All-cause mortality, cardiovascular mortality, admissions to hospital for heart failure, and safety events (hyperkalaemia, hypotension, renal failure, withdrawal owing to adverse events)hard clinical
Dual blockade of the renin-angiotensin system does not reduce mortality but significantly increases the risk of hyperkalemia, hypotension, and renal failure compared to monotherapy, arguing against its clinical use.
Cite This Study
Makani et al. (2013) studied this question.