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Intolerance to ARNI is common in advanced chronic HFrEF
Literature - Vader JM, Givertz MM, Starling RC, et al. - JACC Heart Fail. 2022 Jul;10(7):449-456. doi: 10.1016/j.jchf.2022.04.013

Introduction and methods

Background and study aim

As patients with advanced HFrEF were underrepresented in the landmark PARADIGM-HF trial [1], the_LIFE_-LCZ696 In Hospitalized Advanced Heart FailurE- trial was designed to obtain additional information on safety, efficacy, and tolerability of sacubitril/valsartan versus valsartan in this patient group [2]. The LIFE trial did not require an initial run-in period in which patients had to be hemodynamically stable on an optimal dose of an ACEi before their first exposure to sacubitril/valsartan. This allowed for evaluation of the tolerability of sacubitril/valsartan in patients with advanced chronic HFrEF in a clinically applicable, real-world setting.


The LIFE trial was a prospective, multicenter, double-blind, phase 4 RCT in which 445 patients with advanced HFrEF and recent NYHA functional class IV symptomatology entered an unblinded run-in period of 3–7 days with administration of sacubitril/valsartan 24 mg/26 mg twice daily. In case of ACEI use, the medication was withheld for 36 hours before entry into the study’s run-in phase. Run-in success was defined prospectively as serum creatinine ≤2.0 mg/dL, systolic blood pressure ≥90 mmHg, and absence of symptoms of hypotension during the 7-day run-in period.

Clinical parameters associated with run-in failure and predictors of short-term intolerance to sacubitril/valsartan were assessed.

Main results

  • Of the 445 patients, 73 (18%) were intolerant of sacubitril/valsartan.
  • The reasons for intolerance included systolic arterial blood pressure <90 mmHg with or without symptoms (59%), followed by symptomatic postural hypotension with systolic arterial blood pressure >90 mmHg (19%), renal dysfunction (creatinine >2.0 mg/dL) (12%), and hyperkalemia (3%).
  • In a multivariable analysis, patients failing the run-in period had a lower mean arterial pressure (MAP), a lower serum chloride level, an implantable cardioverter-defibrillator (ICD) and/or cardiac resynchronization therapy-defibrillator (CRT-D), moderate or severe mitral regurgitation, nonuse of ACEI or ARB at the screening visit, and use of insulin at screening compared with patients who completed the run-in phase.
  • A predictive model using the individual candidate variables associated with run-in noncompletion showed that patients with ≤1 risk factors very rarely failed the run-in period (probability: 3.5%), whereas those with ≥4 risk factors had a 48.9% probability of being intolerant of sacubitril/valsartan.


This analysis of the LIFE trial showed that 18% of the patients with advanced chronic HFrEF were intolerant of the lowest possible starting dose of sacubitril/valsartan during a short run-in period. Hypotension was the most common intolerable side effect. Predictors of sacubitril/valsartan intolerance were low MAP, low serum chloride level (clinical surrogate of excessive RAAS activation), presence of an ICD and/or CRT-D, moderate or severe mitral regurgitation (sign of cardiac remodeling), nonuse of ACEI/ARB, and insulin use.


1. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;317:993–1004.

2. Mann DL, Givertz MM, Vader JM, et al. Effect of treatment with sacubitril/valsartan in patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA Cardiol. 2022;7:17–25.

Find this article online at JACC Heart Fail.

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Schedule17 May 2024