Safety and tolerability of sacubitril-valsartan: a systematic review and meta-analysis

Expert Opin Drug Saf. 2021 May;20(5):577-588. doi: 10.1080/14740338.2021.1877658. Epub 2021 Jan 27.


Introduction: Sacubitril-valsartan is a recently approved drug. However, there are few data regarding safety issues. We aimed to summarize the available evidence regarding sacubitril-valsartan's safety and tolerability.Methods: We conducted a systematic review with meta-analysis of randomized controlled trials (RCTs) enrolling patients receiving sacubitril-valsartan for any condition, compared with standard therapy or placebo. Database search was performed in October 2019. Outcomes were adverse events (AEs), serious AEs (SAEs), discontinuation due to AEs, and five AEs of special interest. Data were reported using risk ratio (RR) and 95% confidence interval (95%CI).Results: We included 20 RCTs (22510 participants). When compared with active controls, there were no differences in SAEs (RR=0.93, 95%CI 0.86-1.01) and AEs (RR=1.00, 95%CI 0.97-1.03). However, sacubitril-valsartan resulted in an 8% risk reduction in discontinuation due to AEs (95%CI 0.85-0.99) and an increased risk of hypotension (RR=1.45, 95%CI 1.27-1.67). The risk of angioedema was higher with follow-ups greater than 12 months (RR=2.36, 95%CI 1.29-4.33). There were no further significant differences in the remaining AEs' risk.Conclusions: Sacubitril-valsartan was at least as safe and tolerable as active control, with a similar need of administration cautiousness, except for a higher risk of hypotension. However, one should consider the study's limitations.

Keywords: adverse effects; angiotensin-converting enzyme inhibitor; angiotensin-receptor blocker; calcium channel blocker; meta-analysis; sacubitril; sacubitril-valsartan; safety.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Aminobutyrates / administration & dosage
  • Aminobutyrates / adverse effects*
  • Angioedema / chemically induced
  • Angioedema / epidemiology
  • Angiotensin Receptor Antagonists / administration & dosage
  • Angiotensin Receptor Antagonists / adverse effects*
  • Biphenyl Compounds
  • Drug Combinations
  • Humans
  • Hypotension / chemically induced
  • Hypotension / epidemiology
  • Randomized Controlled Trials as Topic
  • Risk
  • Tetrazoles / administration & dosage
  • Tetrazoles / adverse effects*
  • Valsartan


  • Aminobutyrates
  • Angiotensin Receptor Antagonists
  • Biphenyl Compounds
  • Drug Combinations
  • Tetrazoles
  • Valsartan
  • sacubitril and valsartan sodium hydrate drug combination