ARNI not superior to ARB for advanced HF

Sacubitril/Valsartan (LCZ696) In Patients With Advanced Heart Failure And Reduced Ejection Fraction: Results Of The LIFE Trial

Presented at ACC.21 by Prof. Douglas Mann, MD (St. Louis, MO, USA)

Introduction and methods

PARADIGM-HF showed that sacubitril/valsartan reduced morbidity and mortality in patients with chronic HFrEF compared to enalapril. However, less than 1% of patients in PARADIGM-HF had NYHA class IV HF. The LIFE trial investigated whether sacubitril/valsartan is superior to valsartan with respect to lowering NT-proBNP levels in patients with advanced HFrEF.

LIFE was a prospective, multicenter, double-blind, active-comparator trial in 335 patients with advanced HF. Key entry criteria included NYHA class IV symptoms in the previous 3 months, receiving GDMT for HF for ≥3 months or intolerant to GDMT, LVEF≤35%, BNP≥250 pg/mL or NT-proBNP≥800 pg/mL, SBP>90 mmHg and at least 1 additional objective finding of advanced HF. Patients were randomized 1:1 to receive either sacubitril/valsartan (n=167) or valsartan (n=168) during a 24-week double-blind treatment period. The primary endpoint was area under the curve (AUC) for the proportional change in NT-proBNP levels from baseline through 24 weeks. The secondary efficacy endpoint was days alive, out of hospital and free from HF events. Secondary tolerability endpoints included drug tolerability, hypotension, worsening renal function and hyperkalemia.

Main results

• The median NT-proBNP levels did not decrease either with sacubitril/valsartan nor with valsartan over 24 weeks. The primary endpoint of AUC for the proportional change in NT-proBNP levels from baseline through 24 weeks was not significantly different between the two treatment groups (P=0.45).
• There were no statistically significant differences between the two treatment groups in the secondary efficacy endpoint of days alive, out of hospital and free from HF events (P=0.45), nor in the secondary tolerability endpoints of hypotension (P=0.16) and worsening renal function (P=0.99). There was a small but statistically significant increase in the number patients with hyperkalemia in the sacubitril/valsartan arm compared to the valsartan arm (17 of 167 vs. 9 of 168 patients, P=0.035).
• The exploratory endpoint of CV death or HF hospitalization also showed no statistically significant difference between treatment groups (P=0.20).

Conclusion

Sacubitril/valsartan was not superior to valsartan with respect to changing NT-proBNP levels in patients with advanced HF. Sacubitril/valsartan did not improve the secondary endpoint of days alive, out of hospital and free from HF events and did not decrease CV death or HF hospitalization compared to valsartan. There was a higher number of patients experiencing non-life threatening hyperkalemia in sacubitril/valsartan arm compared to the valsartan arm.

Discussion

The discussant Gurusher Panjrath, MD (Washington, DC, USA) found the results surprising. He thinks that we need more insight about the phenotype of patients with advanced HF in this trial. A close look at the enrolment criteria is necessary to understand who had truly advanced HF vs. who had decompensated HF.

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