Predicting the Tolerability of Sacubitril/Valsartan in Advanced Heart Failure
By Michael H. Crawford, MD, Editor
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 select 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, 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 sacubitril/valsartan, 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. Thus, it is not surprising these were the two most common reasons for failure to tolerate sacubitril/valsartan among advanced, chronic HF patients. The 18% non-tolerance observed in the LIFE run-in phase was similar to other experience with sacubitril/valsartan and other neurohormonal antagonists. In PARADIGM-HF, 25% to 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.
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.