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Tolerability of Sacubitril/Valsartan in Advanced Heart Failure
Quick Takes
- This study reports that approximately one in six subjects developed intolerable side effects during the short run-in period with the lowest possible starting dose of sacubitril/valsartan.
- A multivariable analysis of the factors that predicted intolerance to sacubitril/valsartan showed that low MAP, low serum chloride, nonuse of ACEi or ARB, insulin use, presence of ICD or CRTD, and moderate or greater MR were predictive of run-in failure.
- These real-world data should help clinicians in identifying patients who may not tolerate renin-angiotensin antagonists and could benefit from advanced HF therapies including mechanical support.
Study Questions:
What is the tolerability of initiating sacubitril/valsartan in patients with chronic advanced heart failure (HF) with reduced ejection fraction?
Methods:
The investigators conducted the LIFE (LCZ696 In Hospitalized Advanced Heart FailurE) trial and enrolled 445 subjects with advanced HF for an unblinded run-in period of 3-7 days with sacubitril/valsartan 24/26 mg twice a day. The authors compared characteristics of subjects completing and failing run-in, performed multivariable analysis of clinical parameters associated with run-in failure, and developed a predictive model for short-term intolerance to sacubitril/valsartan. The individual candidate variables associated with run-in noncompletion with p < 0.25 were used as candidates in a multivariable logistic regression model using stepwise selection (p value to enter or stay in the model was the default of 0.05) to determine the set of factors that most strongly predicted run-in noncompletion.
Results:
Of 445 subjects entering run-in, 73 (18%) were intolerant of sacubitril/valsartan. Reasons for intolerance included systolic blood pressure <90 mm Hg (59%), symptoms of hypotension/dizziness with systolic blood pressure >90 mm Hg (19%), and renal dysfunction (creatinine >2.0 mg/dL) (12%). Multivariable predictors of intolerance included lower mean arterial pressure (MAP), lower serum chloride, presence of an implantable cardioverter-defibrillator (ICD) and/or cardiac resynchronization device (CRTD), moderate or greater mitral regurgitation (MR), nonuse of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) at the screening visit, and use of insulin at screening. Subjects with ≥4 predictors had a 48.9% probability of sacubitril/valsartan intolerance.
Conclusions:
The authors reported that intolerance to low doses of sacubitril/valsartan is common in patients with advanced chronic HF with reduced ejection fraction and may be predicted by the presence of certain risk factors.
Perspective:
This study reports that approximately one in six subjects developed intolerable side effects during the short run-in period with the lowest possible starting dose of sacubitril/valsartan. Furthermore, sacubitril/valsartan may be associated with dose-limiting side effects even in patients who are able to tolerate optimal doses of enalapril. A multivariable analysis of the factors that predicted intolerance to sacubitril/valsartan showed that low MAP, low serum chloride, nonuse of ACEi or ARB, insulin use, presence of ICD or CRTD, and moderate or greater MR were predictive of run-in failure. These real-world data should help clinicians in making evidence-based decisions when initiating therapies with renin-angiotensin antagonists in patients with severe advanced chronic HF and identify patients who may benefit from advanced therapies including mechanical support.
Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Prevention, Valvular Heart Disease, Implantable Devices, SCD/Ventricular Arrhythmias, Acute Heart Failure, Mitral Regurgitation
Keywords: Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Arterial Pressure, Blood Pressure, Chlorides, Cardiac Resynchronization Therapy, Creatinine, Defibrillators, Implantable, Enalapril, Heart Failure, Hypotension, Insulin, Kidney Diseases, Mitral Valve Insufficiency, Renin-Angiotensin System, Risk Factors, Secondary Prevention, Stroke Volume, Valsartan
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