TY - JOUR
T1 - Tolerability of Sacubitril/Valsartan in Patients With Advanced Heart Failure
T2 - Analysis of the LIFE Trial Run-In
AU - LIFE Investigators
AU - Vader, Justin M.
AU - Givertz, Michael M.
AU - Starling, Randall C.
AU - McNulty, Steven E.
AU - Anstrom, Kevin J.
AU - Desvigne-Nickens, Patrice
AU - Hernandez, Adrian F.
AU - Braunwald, Eugene
AU - Mann, Douglas L.
N1 - Funding Information:
Research reported in this publication was supported by the NHLBI of the NIH under award number U10 HL084904 (for the Coordinating Center) and award numbers U10 HL110297, U10 HL110342, U10 HL110309, U10 HL110262, U10 HL110338, U10 HL110312, U10 HL110302, U10 HL110336, and U10 HL110337 (for the Regional Clinical Centers). The NHLBI contributed to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication. Novartis Pharmaceutical Corporation provided study drug and partial funding through its investigator-initiated trial program CLCZ696BUS04T, but did not contribute to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication. Neither the NHLBI nor Novartis Pharmaceutical Corporation were involved in manuscript submission. Dr Mann serves on the steering committee for the PARADISE-MI trial for Novartis; and is a member of the Scientific Advisory Board for MyoKardia. Dr Anstrom has received research support from the National Institutes of Health (NIH), Merck, Bayer, and PCORI. Dr Starling serves on the steering committee for the PARAGLIDE trial sponsored by Novartis. Dr Desvigne-Nickens is an employee of the NHLBI; and is a consultant for Novartis. Dr Hernandez has received research grants and consulting fees from AstraZeneca, Amgen, Bayer, Merck, and Novartis. Dr Braunwald has received research support through his institution from AstraZeneca, Daiichi-Sankyo, Merck, and Novartis; and is a consultant for Amgen, Boehringer Ingelheim/Lilly, Cardurion, MyoKardia, Novo-Nordisk, and Verve. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Publisher Copyright:
© 2022 American College of Cardiology Foundation
PY - 2022/7
Y1 - 2022/7
N2 - Background: The LIFE (LCZ696 In Hospitalized Advanced Heart FailurE) trial, which evaluated sacubitril/valsartan in patients with advanced heart failure (HF) with reduced ejection fraction and recent New York Heart Association functional class IV symptomatology, did not require tolerance to a renin angiotensin system antagonist before initiating sacubitril/valsartan, thus affording an opportunity to study the tolerability of sacubitril/valsartan in advanced HF with reduced ejection fraction. Objectives: The goal of this analysis of the LIFE trial is to characterize the tolerability of initiating sacubitril/valsartan in patients with chronic advanced HF with reduced ejection fraction. Methods: In the LIFE trial, 445 subjects with advanced HF entered an unblinded run-in period of 3-7 days with sacubitril/valsartan 24/26 mg twice a day. The authors compared characteristics of subjects completing and failing run-in, performed multivariable analysis of clinical parameters associated with run-in failure, and developed a predictive model for short-term intolerance to sacubitril/valsartan. Results: Of 445 subjects entering run-in, 73 (18%) were intolerant of sacubitril/valsartan. Reasons for intolerance included systolic blood pressure <90 mm Hg (59%), symptoms of hypotension/dizziness with systolic blood pressure >90 mm Hg (19%), and renal dysfunction (creatinine >2.0 mg/dL) (12%). Multivariable predictors of intolerance included lower mean arterial pressure, lower serum chloride, presence of an implantable cardioverter-defibrillator and/or cardiac resynchronization device, moderate or greater mitral regurgitation, nonuse of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker at the screening visit, and use of insulin at screening. Subjects with 4 or more predictors had a 48.9% probability of sacubitril/valsartan intolerance. Conclusions: Intolerance to low doses of sacubitril/valsartan is common in patients with advanced chronic HF with reduced ejection fraction and may be predicted by the presence of certain risk factors.
AB - Background: The LIFE (LCZ696 In Hospitalized Advanced Heart FailurE) trial, which evaluated sacubitril/valsartan in patients with advanced heart failure (HF) with reduced ejection fraction and recent New York Heart Association functional class IV symptomatology, did not require tolerance to a renin angiotensin system antagonist before initiating sacubitril/valsartan, thus affording an opportunity to study the tolerability of sacubitril/valsartan in advanced HF with reduced ejection fraction. Objectives: The goal of this analysis of the LIFE trial is to characterize the tolerability of initiating sacubitril/valsartan in patients with chronic advanced HF with reduced ejection fraction. Methods: In the LIFE trial, 445 subjects with advanced HF entered an unblinded run-in period of 3-7 days with sacubitril/valsartan 24/26 mg twice a day. The authors compared characteristics of subjects completing and failing run-in, performed multivariable analysis of clinical parameters associated with run-in failure, and developed a predictive model for short-term intolerance to sacubitril/valsartan. Results: Of 445 subjects entering run-in, 73 (18%) were intolerant of sacubitril/valsartan. Reasons for intolerance included systolic blood pressure <90 mm Hg (59%), symptoms of hypotension/dizziness with systolic blood pressure >90 mm Hg (19%), and renal dysfunction (creatinine >2.0 mg/dL) (12%). Multivariable predictors of intolerance included lower mean arterial pressure, lower serum chloride, presence of an implantable cardioverter-defibrillator and/or cardiac resynchronization device, moderate or greater mitral regurgitation, nonuse of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker at the screening visit, and use of insulin at screening. Subjects with 4 or more predictors had a 48.9% probability of sacubitril/valsartan intolerance. Conclusions: Intolerance to low doses of sacubitril/valsartan is common in patients with advanced chronic HF with reduced ejection fraction and may be predicted by the presence of certain risk factors.
KW - New York Heart Association class IV
KW - advanced heart failure
KW - guideline-directed medical therapy
KW - sacubitril/valsartan
KW - tolerability
UR - http://www.scopus.com/inward/record.url?scp=85132700147&partnerID=8YFLogxK
U2 - 10.1016/j.jchf.2022.04.013
DO - 10.1016/j.jchf.2022.04.013
M3 - Article
C2 - 35772853
AN - SCOPUS:85132700147
SN - 2213-1779
VL - 10
SP - 449
EP - 456
JO - JACC: Heart Failure
JF - JACC: Heart Failure
IS - 7
ER -