May 17, 2021—Sacubitril-valsartan offered no significant reduction in N-terminal-proB-type natriuretic peptide (NT-proBNP) or any improvement in multiple clinical outcomes, compared with valsartan alone, in patients with advanced heart failure, according to results of the LIFE trial presented at the virtual annual meeting of the American College of Cardiology, which took place from May 15 to 17. The findings were a surprise, given previous success with this combination.
“Sacubitril-valsartan is a first-in-class angiotensin receptor neprilysin inhibitor that was developed to increase natriuretic peptide levels by preventing their degradation as well as antagonize the renin-angiotensin-aldosterone system (RAAS) by blocking the type 1 angiotensin receptor,” said lead author Douglas L. Mann, MD, of Washington University School of Medicine in Saint Louis, during his presentation of the data.
Previously, the landmark PARADIGM-HF trial showed that the combination of sacubitril and valsartan improved morbidity and mortality, compared with enalapril, in patients with chronic heart failure with reduced ejection fraction, but less than 1% of those patients had New York Heart Association (NYHA) class IV heart failure. “The purpose of the LIFE trial was to test the hypothesis that sacubitril-valsartan is superior to valsartan with respect to lowering NT-proBNP levels in patients with advanced heart failure,” he said.
For the prospective, multicenter LIFE trial, 335 patients with NYHA class IV symptomatology in the previous 3 months were randomized 1:1 to either sacubitril-valsartan (n = 167) or valsartan alone (n = 168) for 24 weeks. The patients had received guideline-directed medical therapy for heart failure for at least 3 months or were intolerant to such therapy. All patients had a left ventricular ejection fraction (LVEF) of 35% or lower, BNP levels of at least 250 pg/mL or NT-proBNP levels of at least 800 pg/mL, systolic blood pressure of at least 90 mmHg, and at least one additional objective finding of advanced heart failure.
Before randomization, all patients were placed in a run-in with low doses (24-26 mg) of sacubitril-valsartan twice daily for 3 to 7 days. From baseline to 4 weeks, patients randomized to sacubitril-valsartan received either the same low dose or a high dose of 49-51 mg twice daily. From weeks 4 to 24, they received sacubitril-valsartan 97-103 mg twice daily or the maximum tolerated dose. For those randomized to valsartan alone, they received a dose of 40 mg or 80 mg twice daily from weeks 0 to 4 and 160 mg twice daily or the maximum tolerated dose from weeks 4 to 24.
The trial was stopped early, on March 23, 2020, because of the COVID-19 pandemic. This left the trial underpowered, as the initial accrual goal was 400 patients.
Baseline characteristics were well-matched between both groups in terms of age (58–60 years), sex (26%–28% female), and race (59 %–61% white). Baseline values for LVEF (20%–21%), systolic blood pressure (112–113 mm Hg), and NT-proBNP (1818–1931 pg/mL) were also similar for both groups. However, there were more patients with ischemic heart failure in the sacubitril-valsartan treatment arm (84% vs 72%).
No difference was observed between treatment arms with regard to the primary endpoint of area under the curve for the proportional change in NT-proBNP levels from baseline through 24 weeks (P = .45). There was a trend toward improvement in the primary endpoint in the sacubitril-valsartan arm in the subgroup of those 65 years or older (P = .08) and for patients without a defibrillator (P = .09). There was also a trend toward improvement in the primary endpoint in valsartan-treated patients with nonischemic heart failure (P = .09).
A nonsignificant difference between the sacubitril-valsartan and valsartan groups was observed for the secondary endpoint of days alive out of hospital or free from heart failure events (103 days vs 111 days, P = .45). No difference in tolerability endpoints was observed between both arms in terms of hypotension (17% vs 12%, P = .16) and worsening renal function (4% for each arm). Hyperkalemia was more common in patients taking sacubitril-valsartan (17% vs 9%, P = .35).
There was a nonsignificant 32% increase in relative risk of cardiovascular death or heart failure hospitalization (95% confidence interval 0.86–2.03, P = .20) and a nonsignificant 24% increase in the relative risk of heart failure hospitalizations (95% confidence interval 0.80–1.93, P = .33) in the sacubitril-valsartan arm, compared with the valsartan arm.
Only 1% of patients taking valsartan experienced serious adverse events, and none were reported with combination therapy. There was no difference between groups with respect to light-headedness, syncope, and near syncope. Premature discontinuation of study drug was similar in both treatment groups (29% for sacubitril-valsartan and 21% for valsartan).
Limitations of the LIFE trial included a small sample size and short study duration. The trial was not powered to detect changes in cardiovascular death/heart failure hospitalizations, heart failure hospitalizations, cardiovascular death, or all cause death.
“Sacubitril-valsartan was not superior to valsartan with respect to lowering NT-proBNP level,” concluded Dr. Mann. “The LIFE investigators were not only disappointed but surprised to see the results, which differed substantially from those of PARADIGM-HF.” They speculated that reasons for the negative findings could be that LIFE patients were far sicker than those in PARADIGM-HF (lower blood pressure, worse renal function, lower LVEF), that the run-in period in LIFE was shorter and used lower doses of sacubitril-valsartan than in PARADIGM-HF, and that the comparator in LIFE was valsartan, whereas enalapril was used in PARADIGM-HF.
“We believe that the results of the LIFE trial are consistent with prior observations that as heart failure advances, chronic excessive activation of RAAS blunts or overrides the effect of natriuretic peptides on the heart, vasculature, and kidneys,” concluded Dr. Mann.