LIFE clinical trial review

LIFE clinical trial review

LIFE trial (LCZ696 in Advanced Heart Failure) compared sacubitril/valsartan with valsartan in patients with advanced heart failure and a reduced left ventricular ejection fraction and recent New York Heart Association class IV symptoms. As of now, the use of sacubitril/valsartan is not endorsed by practice guidelines in NYHA class IV heart failure with reduced LVEF because of limited clinical data in that group of patients. LIFE trial showed that sacubitril/valsartan did not reduce NT-proBNP or clinical outcomes among patients with advanced HFrEF and comorbidities. It was a double blind randomized clinical trial on 335 patients with advanced heart failure. The trial was stopped early in March 2020 owing to COVID-19 risk [1].

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial had less than 1% patients with NYHA class IV symptoms [2]. That was the rationale behind starting the LIFE trial. LIFE was a 24 week prospective multicenter, double blind, double dummy active comparator trial. It checked safety, efficacy and tolerability of sacubitril/valsartan with valsartan in patients with advanced HFrEF. Plan was to randomize 400 patients, though it had to be stopped early because of COVID-19 concerns. Elevated BNP or NT-proBNP and one or more objective finding of advanced heart failure were needed for enrollment in addition to NYHA class IV symptoms and LVEF ≤35% [3].

72 eligible patients were not able to tolerate sacubitril/valsartan, 100 mg/d, during the short run-in period and 49 patients discontinued sacubitril/valsartan during the 24 weeks of the trial. Sacubitril/valsartan did not improve the clinical composite of number of days alive, outside the hospital, and free from heart failure events. There was a statistically significant increase in non-life-threatening hyperkalemia in the sacubitril/valsartan arm. No other safety concerns were observed in the LIFE trial. Thus the LIFE trial did not show a statistically significant difference between sacubitril/valsartan and valsartan alone, in patients with chronic advanced HFrEF. The primary outcome evaluated in the trial was area under the curve for the proportional change in the ratio of NT-proBNP to baseline. This was also statistically not significant with a P=0.45  [1].

References

1. Mann DL, Givertz MM, Vader JM, Starling RC, Shah P, McNulty SE, Anstrom KJ, Margulies KB, Kiernan MS, Mahr C, Gupta D, Redfield MM, Lala A, Lewis GD, DeVore AD, Desvigne-Nickens P, Hernandez AF, Braunwald E; LIFE Investigators. Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA Cardiol. 2022 Jan 1;7(1):17-25. doi: 10.1001/jamacardio.2021.4567. PMID: 34730769; PMCID: PMC8567189.
2. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30. PMID: 25176015.
3. Mann DL, Greene SJ, Givertz MM, Vader JM, Starling RC, Ambrosy AP, Shah P, McNulty SE, Mahr C, Gupta D, Redfield MM, Lala A, Lewis GD, Mohammed SF, Gilotra NA, DeVore AD, Gorodeski EZ, Desvigne-Nickens P, Hernandez AF, Braunwald E; LIFE Investigators. Sacubitril/Valsartan in Advanced Heart Failure With Reduced Ejection Fraction: Rationale and Design of the LIFE Trial. JACC Heart Fail. 2020 Oct;8(10):789-799. doi: 10.1016/j.jchf.2020.05.005. Epub 2020 Jun 10. Erratum in: JACC Heart Fail. 2020 Dec;8(12):1059. PMID: 32641226; PMCID: PMC7286640.