Five Years of Sacubitril/Valsartan-a Safety Analysis of Randomized Clinical Trials and Real-World Pharmacovigilance

Cardiovasc Drugs Ther. 2022 Oct;36(5):915-924. doi: 10.1007/s10557-021-07210-1. Epub 2021 Jun 14.


Purpose: In PARADIGM-HF, sacubitril/valsartan showed a significant reduction in mortality and hospitalization for patients with heart failure with reduced ejection fraction. Despite proven efficacy, sacubitril/valsartan has moderate uptake in clinical practice. This study explores the safety profile of sacubitril/valsartan by comparing adverse events in RCT and real-world use.

Methods: We studied hypotension, renal dysfunction, hyperkalemia, and angioedema associated with sacubitril/valsartan in RCTs and pharmacovigilance databases. A random-effects meta-analysis was performed with six RCTs investigating sacubitril/valsartan vs. control/comparators in heart failure patients. WHO's VigiBase, FAERS, and EMA's EudraVigilance were mined to obtain spontaneously reported real-world adverse events. Disproportionality analysis was performed with the FDA's OpenVigil 2.0.

Results: Six RCTs enrolled 15,538 patients with heart failure with reduced and preserved ejection fractions. There was no statistical difference for the composite of hypotension, renal dysfunction, hyperkalemia, and angioedema between sacubitril/valsartan and its comparators viz. ACEi or ARBs (OR 1.23, CI 0.98-1.56; p = 0.08). A total of 103,038 adverse events were registered in the spontaneous reporting systems. Hypotension was the most reported adverse event. Proportions of composite adverse events were 20% in VigiBase, 17% in FAERS, and 39% with EudraVigilance. Disproportionality analysis showed a lower risk of adverse events with sacubitril/valsartan than other guideline-directed heart failure medications used in clinical practice.

Conclusion: With increased uptake of sacubitril/valsartan, risks of hypotension, renal dysfunction, hyperkalemia, and angioedema appear low and acceptable in RCTs and global clinical practice.

Keywords: Disproportionality analysis; 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* / drug therapy
  • Angiotensin Receptor Antagonists / adverse effects
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Biphenyl Compounds
  • Drug Combinations
  • Heart Failure* / diagnosis
  • Heart Failure* / drug therapy
  • Humans
  • Hyperkalemia* / chemically induced
  • Hyperkalemia* / diagnosis
  • Hyperkalemia* / drug therapy
  • Hypotension* / chemically induced
  • Hypotension* / diagnosis
  • Hypotension* / drug therapy
  • Kidney Diseases*
  • Pharmacovigilance
  • Randomized Controlled Trials as Topic
  • Stroke Volume
  • Tetrazoles / adverse effects
  • Treatment Outcome
  • Valsartan / adverse effects


  • Aminobutyrates
  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • Biphenyl Compounds
  • Drug Combinations
  • Tetrazoles
  • sacubitril
  • Valsartan