In patients with advanced heart failure with reduced ejection fraction (HFrEF), the combination of sacubitril/valsartan was not superior to valsartan for lowering NT-proBNP and did not improve other clinical outcomes, according to results from the LIFE trial presented May 17 during ACC.21.

The multicenter study randomized 335 HFrEF patients to sacubitril/valsartan (n=167) or valsartan (n=168) for a 24-week follow-up. At baseline, the EF was ≤20%, systolic blood pressure was about 113 mm Hg, estimated glomerular filtration rate was 63.6 mL/min/1.73m2 in the combination arm and 65.7 mL/min/1.73m2 in the valsartan arm, and NT-proBNP was 1,931 pg/ml and 1,818 pg/ml in the respective arms. Most of the patients were white (60%), 60 years old, and about a third were women.

The trial was stopped early, in March 2020, because of the high risk for adverse outcomes in this vulnerable population during the COVID-19 pandemic. The original protocol and statistical plan specified an analysis of 400 patients and the revised statistical plan specified 335 patients so none of the collected clinical endpoints would be impacted by COVID-19. The statistical power was nominally reduced from 88% to 79% for the primary endpoint of area under the curve for the proportional change in NT-proBNP from baseline through 24 weeks.

Results showed that neither treatment regimen reduced the median NT-proBNP below the baseline level. Similarly, there was no difference between sacubitril/valsartan and valsartan for the secondary efficacy endpoint of days alive, out of hospital or free from HF events (103.2 vs. 111.2, respectively; p=0.45).

In terms of tolerability endpoints, the average daily dose of sacubitril/valsartan was 195.3 mg and valsartan was 154.4 mg (both reached only 48% of the target dose). Hypotension occurred in 17% and 12% of the sacubitril/valsartan and valsartan groups, respectively (p=0.16), and hyperkalemia occurred in 17% and 9% (p=0.035). Worsening renal function was seen in 4% of both groups. 

For key tertiary clinical outcomes, no improvement was seen with sacubitril/valsartan compared with valsartan: cardiovascular death or HF hospitalization (hazard ratio [HR], 1.32; p=0.20); HF hospitalization (HR, 1.24; p=0.33), and cardiovascular death or all-cause death.

"We make the assumption that all heart failure patients are the same and therefore will respond the same to all therapies," says Douglas L. Mann, MD, FACC, the study's lead author. "However, the patient population with advanced heart failure is different from patients with less advanced heart failure because of the end organ changes that occur in the heart and kidneys. These end organ changes limit the ability of the failing heart to respond to conventional therapies to the same extent as occurs in patients with milder forms of heart failure. This is one of the lessons we learned from the LIFE trial."

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: ACC Annual Scientific Session, ACC21, Heart Failure, Stroke Volume, Drug Combinations

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