By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: An analysis of the sacubitril/valsartan run-in period for chronic, advanced heart failure patients showed 18% could not tolerate the lowest dose, usually because of hypotension or renal dysfunction. Investigators identified six predictors of non-tolerance, which may help clinicians choose the best candidates.
SOURCE: Vader JM, Givertz MM, Starling RC, et al. Tolerability of sacubitril/valsartan in patients with advanced heart failure: Analysis of the LIFE trial run-in. JACC Heart Fail 2022;10:449-456.
The Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial showed sacubitril/valsartan treatment lowered the risk of cardiovascular (CV) mortality and heart failure (HF) hospitalizations by 20% vs. enalapril treatment. Researchers used a two-period run-in to ensure patients could tolerate enalapril and combination sacubitril/valsartan. Drug trial run-in periods include patients who tolerate the target doses of the study drugs for randomization. This practice carries implications for real-life clinical applications of the studied drugs.
The LCZ696 In Hospitalized Advanced Heart FailurE (LIFE) trial was a Phase IV randomized, controlled trial of hospitalized advanced HF patients, a group that was underrepresented in PARADIGM-HF. LIFE showed no differences between sacubitril/valsartan vs. valsartan alone in lowering NT-proBNP levels, which was the primary endpoint. Although it was underpowered for clinical outcomes, the numerical data did not favor sacubitril/valsartan. LIFE did not include a run-in period for valsartan in this chronic, advanced HF population, which provides an opportunity to study the tolerability of sacubitril/valsartan.
LIFE was conducted in 38 U.S. centers that enrolled patients with reduced ejection fraction (EF), recent New York Heart Association class IV symptoms, a systolic blood pressure > 90 mmHg, and an estimated glomerular filtration rate of > 20 mL/min/1.73 m2. There was an unblinded run-in period for sacubitril/valsartan for three to seven days, within seven days of the screening visit, which began with the 50-mg dose (24 mg sacubitril and 26 mg valsartan) twice daily. Run-in success was defined as a serum creatinine level < 2.0 mg/dL, systolic blood pressure > 90 mmHg, and no symptoms of hypotension. Because of the COVID-19 pandemic, the trial ended early after 445 patients entered the run-in period.
Among these 445 patients, 18% did not tolerate the sacubitril/valsartan combination, with 59% recording systolic blood pressure < 90 mmHg. The second most common reason was renal dysfunction (12%). The authors examined clinical variables to determine multivariable predictors of run-in failure. They chose six with the highest C-statistic: lower mean arterial pressure (MAP; cut point 78 mmHg), lower serum chloride (cut point 98 mmol/L), absent angiotensin-converting enzyme or angiotensin receptor blocker (ACE/ARB) use at screening, presence of an implantable cardioverter-defibrillator/cardiac resynchronization therapy defibrillator (ICD/CRT-D), moderate-to-severe mitral regurgitation, and use of insulin at screening. The predictive model produced a C-statistic of 0.784 and showed patients with one factor rarely failed run-in. Patients with four or more carried a 50% risk of intolerance. The authors concluded among patients hospitalized with advanced, chronic HF with reduced EF, intolerance to sacubitril/valsartan was common and was predictable by considering certain clinical characteristics.
COMMENTARY
Hypotension and renal dysfunction are seen commonly in the up-titration of neurohormonal antagonists for the treatment of HF and are predictors of higher near-term mortality rates. It is unsurprising these were the two most common reasons for failure to tolerate the combination of sacubitril/valsartan among advanced, chronic HF patients. The 18% non-tolerance observed in the LIFE run-in phase was similar to other experiences with sacubitril/valsartan and other neurohormonal antagonists. In PARADIGM-HF, 25%-30% of patients in the initial run-in with enalapril could not tolerate it. In the second run-in phase, among those who tolerated enalapril, about 30% could not tolerate sacubitril/valsartan.
The predictive clinical factors also are not surprising. Hypotension and renal dysfunction are common side effects of vasodilator drugs. Electrolyte abnormalities reflect the activation of the renin-angiotensin system. The cardiac remodeling seen in advanced heart failure would explain the predictive value of ICD/CRT-D use and moderate-to-severe mitral regurgitation. Finally, the absence of ACE/ARB use would suggest intolerance to these drugs already, and sacubitril/valsartan includes an ARB. The explanation for insulin use as a predictor is unclear. It could identify a particular patient type or be an effect of the drug itself, which is known to exacerbate sodium and water retention. Also, insulin-induced hypoglycemia may further trigger the neurohormonal responses to HF.
There were limitations to this study. Although the absolute number of run-in patients who dropped out was small, the study design did not permit an analysis of the patients who dropped out after the run-in period. Also, there were no NT-proBNP data from the run-in period. Still, this information should help clinicians select the appropriate chronic, advanced HF patients for this expensive new therapy.
An analysis of the sacubitril/valsartan run-in period for chronic, advanced heart failure patients showed 18% could not tolerate the lowest dose, usually because of hypotension or renal dysfunction. Investigators identified six predictors of non-tolerance, which may help clinicians choose the best candidates.
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