Angioedema in heart failure patients treated with sacubitril/valsartan (LCZ696) or enalapril in the PARADIGM-HF study

Int J Cardiol. 2018 Aug 1:264:118-123. doi: 10.1016/j.ijcard.2018.03.121.


Background: PARADIGM-HF demonstrated significant clinical benefits for sacubitril/valsartan (LCZ696, an angiotensin receptor neprilysin inhibitor) versus the angiotensin-converting enzyme inhibitor (ACEI) enalapril in patients with heart failure with reduced ejection fraction. As inhibition of ACE, and co-inhibition of ACE and neprilysin, may increase the risk of angioedema, this was an adverse event of special interest.

Methods: Following sequential enalapril and sacubitril/valsartan run-ins, patients were randomized to twice-daily sacubitril/valsartan 200 mg or enalapril 10 mg. The study design incorporated two wash-out periods (~36 h each) to minimize any potential risk of angioedema due to overlapping ACE and neprilysin inhibition. Suspected cases of angioedema were reported to, and blindly adjudicated by, an independent angioedema adjudication committee (AAC).

Results: Of the 10,513 patients entering the enalapril run-in, 9419 entered the sacubitril/valsartan run-in and 8432 received double-blind treatment. Overall, 148 suspected angioedema events occurring in 144 patients were reported to AAC, with one event reported during screening period. Of the remaining 147 events, 54 were confirmed as angioedema by AAC. A confirmed event was experienced by 15 (0.14%) and 10 (0.11%) patients, during the enalapril and sacubitril/valsartan run-ins, respectively, and by 10 (0.24%) and 19 (0.45%) patients in the corresponding randomized arms during the double-blind phase. The frequency of confirmed angioedema was higher in black patients. Most events were mild. Only five patients required hospitalization and none required mechanical airway support.

Conclusion: The number of confirmed angioedema events in PARADIGM-HF was low and there was no-marked excess risk of angioedema with sacubitril/valsartan versus enalapril.

Keywords: Angioedema; Enalapril; HFrEF; Heart failure; Sacubitril/valsartan; Safety.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aminobutyrates* / administration & dosage
  • Aminobutyrates* / adverse effects
  • Angioedema* / chemically induced
  • Angioedema* / diagnosis
  • Angioedema* / therapy
  • Angiotensin Receptor Antagonists / administration & dosage
  • Angiotensin Receptor Antagonists / adverse effects
  • Angiotensin-Converting Enzyme Inhibitors / administration & dosage
  • Angiotensin-Converting Enzyme Inhibitors / adverse effects
  • Anti-Allergic Agents / administration & dosage*
  • Biphenyl Compounds
  • Double-Blind Method
  • Drug Combinations
  • Enalapril* / administration & dosage
  • Enalapril* / adverse effects
  • Female
  • Heart Failure / drug therapy*
  • Heart Failure / physiopathology
  • Hospitalization / statistics & numerical data
  • Humans
  • Male
  • Middle Aged
  • Risk Assessment
  • Stroke Volume / drug effects
  • Tetrazoles* / administration & dosage
  • Tetrazoles* / adverse effects
  • Treatment Outcome
  • Valsartan


  • Aminobutyrates
  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • Anti-Allergic Agents
  • Biphenyl Compounds
  • Drug Combinations
  • Tetrazoles
  • Enalapril
  • Valsartan
  • sacubitril and valsartan sodium hydrate drug combination