Angioedema with sacubitril/valsartan: Trial-level meta-analysis of over 14,000 patients and real-world evidence to date

Int J Cardiol. 2021 Jan 15:323:188-191. doi: 10.1016/j.ijcard.2020.08.067. Epub 2020 Aug 22.


Background: Sacubitril/valsartan reduces the risk of hospitalizations and death among patients with heart failure (HF) with reduced ejection fraction; its use is poised to increase worldwide. As bradykinin is a substrate of neprilysin, angioedema was a theoretical concern potentiated by neprilysin inhibition.

Methods: We explored angioedema in clinical trials and real-world pharmacovigilance data. We conducted a trial-level random-effects meta-analysis of 5 RCTs studying the effects of sacubitril/valsartan in heart failure. FDA Adverse Event Reporting System (FAERS) provided real-world pharmacovigilance data in the US.

Results: The 5 trials enrolled 14,841 patients with follow-up ranging from 2 to 27 months. The collective rate of angioedema in RCTs was 0.5% in sacubitril/valsartan arms vs. 0.3% in control arms (pooled odds ratio of 1.35; 95% confidence interval - 0.45 to 4.1; P = .59) with moderate heterogeneity (I2 55.2.%). These relative effects were driven by the larger PARADIGM-HF and PARAGON-HF experiences. FAERS pharmacovigilance data identified 426 angioedema cases over the last 5 years out of 40,559 adverse events reported related to sacubitril/valsartan.

Conclusions: Rates of angioedema with sacubitril/valsartan are reported to be low in RCTs and real-world clinical practice.

Keywords: Angioedema; FDA Adverse Event Reporting System; Real-world pharmacovigilance; Sacubitril/valsartan.

Publication types

  • Meta-Analysis

MeSH terms

  • Aminobutyrates / adverse effects
  • Angioedema* / chemically induced
  • Angioedema* / diagnosis
  • Angioedema* / epidemiology
  • Angiotensin Receptor Antagonists / adverse effects
  • Biphenyl Compounds
  • Drug Combinations
  • Heart Failure* / diagnosis
  • Heart Failure* / drug therapy
  • Heart Failure* / epidemiology
  • Humans
  • Stroke Volume
  • Tetrazoles / adverse effects
  • Valsartan


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