TY - JOUR
T1 - Effect of Treatment with Sacubitril/Valsartan in Patients with Advanced Heart Failure and Reduced Ejection Fraction
T2 - A Randomized Clinical Trial
AU - Mann, Douglas L.
AU - Givertz, Michael M.
AU - Vader, Justin M.
AU - Starling, Randall C.
AU - Shah, Palak
AU - McNulty, Steven E.
AU - Anstrom, Kevin J.
AU - Margulies, Kenneth B.
AU - Kiernan, Michael S.
AU - Mahr, Claudius
AU - Gupta, Divya
AU - Redfield, Margaret M.
AU - Lala, Anuradha
AU - Lewis, Gregory D.
AU - Devore, Adam D.
AU - Desvigne-Nickens, Patrice
AU - Hernandez, Adrian F.
AU - Braunwald, Eugene
N1 - Funding Information:
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
Funding Information:
on the steering committee for the PARADISE-MI trial for Novartis (unpaid) and is a member of the scientific advisory board for MyoKardia, for which he receives compensation. Dr Starling received honoraria for serving on the steering committee for the PARAGLIDE trial sponsored by Novartis. Dr Shah reports receiving research grant support from Merck, Bayer, Abbott, and Medtronic. Dr Anstrom reports receiving research support from the National Institutes of Health (NIH), Merck, Bayer, and Patient-Centered Outcomes Research Institute (PCORI). Dr Mahr is a consultant for Abbott, Medtronic, and Abiomed. Dr Lewis has been a consultant for and received research support from Cytokinetics and Applied Therapeutics and received research support from Amgen and AstraZeneca. Dr DeVore has received research support through his institution from the American Heart Association, Amgen, AstraZeneca, Bayer, Intra-Cellular Therapies, American Regent, the National Heart, Lung, and Blood Institute (NHLBI), Novartis, and PCORI; and is a consultant for Novartis. Dr Desvigne-Nickens is an employee of the NHLBI and is a consultant for Novartis. Dr Hernandez has received research grants and served as a consultant for 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, NovoNordisk, and Verve. No other disclosures were reported.
Publisher Copyright:
© 2021 American Medical Association. All rights reserved.
PY - 2022/1
Y1 - 2022/1
N2 - Importance: The use of sacubitril/valsartan is not endorsed by practice guidelines for use in patients with New York Heart Association class IV heart failure with a reduced ejection fraction because of limited clinical experience in this population. Objective: To compare treatment with sacubitril/valsartan treatment with valsartan in patients with advanced heart failure and a reduced ejection fraction and recent New York Heart Association class IV symptoms. Design, Setting, and Participants: A double-blind randomized clinical trial was conducted; a total of 335 patients with advanced heart failure were included. The trial began on March 2, 2017, and was stopped early on March 23, 2020, owing to COVID-19 risk. Intervention: Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily) in addition to recommended therapy. Main Outcomes and Measures: The area under the curve (AUC) for the ratio of N-terminal pro-brain natriuretic peptide (NT-proBNP) compared with baseline measured through 24 weeks of therapy. Results: Of the 335 patients included in the analysis, 245 were men (73%); mean (SD) age was 59.4 (13.5) years. Seventy-two eligible patients (18%) were not able to tolerate sacubitril/valsartan, 100 mg/d, during the short run-in period, and 49 patients (29%) discontinued sacubitril/valsartan during the 24 weeks of the trial. The median NT-proBNP AUC for the valsartan treatment arm (n = 168) was 1.19 (IQR, 0.91-1.64), whereas the AUC for the sacubitril/valsartan treatment arm (n = 167) was 1.08 (IQR, 0.75-1.60). The estimated ratio of change in the NT-proBNP AUC was 0.95 (95% CI 0.84-1.08; P =.45). Compared with valsartan, treatment with sacubitril/valsartan did not improve the clinical composite of number of days alive, out of hospital, and free from heart failure events. Aside from a statistically significant increase in non-life-threatening hyperkalemia in the sacubitril/valsartan arm (28 [17%] vs 15 [9%]; P =.04), there were no observed safety concerns. Conclusions and Relevance: The findings of this trial showed that, in patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels. Trial Registration: ClinicalTrials.gov Identifier: NCT02816736.
AB - Importance: The use of sacubitril/valsartan is not endorsed by practice guidelines for use in patients with New York Heart Association class IV heart failure with a reduced ejection fraction because of limited clinical experience in this population. Objective: To compare treatment with sacubitril/valsartan treatment with valsartan in patients with advanced heart failure and a reduced ejection fraction and recent New York Heart Association class IV symptoms. Design, Setting, and Participants: A double-blind randomized clinical trial was conducted; a total of 335 patients with advanced heart failure were included. The trial began on March 2, 2017, and was stopped early on March 23, 2020, owing to COVID-19 risk. Intervention: Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily) in addition to recommended therapy. Main Outcomes and Measures: The area under the curve (AUC) for the ratio of N-terminal pro-brain natriuretic peptide (NT-proBNP) compared with baseline measured through 24 weeks of therapy. Results: Of the 335 patients included in the analysis, 245 were men (73%); mean (SD) age was 59.4 (13.5) years. Seventy-two eligible patients (18%) were not able to tolerate sacubitril/valsartan, 100 mg/d, during the short run-in period, and 49 patients (29%) discontinued sacubitril/valsartan during the 24 weeks of the trial. The median NT-proBNP AUC for the valsartan treatment arm (n = 168) was 1.19 (IQR, 0.91-1.64), whereas the AUC for the sacubitril/valsartan treatment arm (n = 167) was 1.08 (IQR, 0.75-1.60). The estimated ratio of change in the NT-proBNP AUC was 0.95 (95% CI 0.84-1.08; P =.45). Compared with valsartan, treatment with sacubitril/valsartan did not improve the clinical composite of number of days alive, out of hospital, and free from heart failure events. Aside from a statistically significant increase in non-life-threatening hyperkalemia in the sacubitril/valsartan arm (28 [17%] vs 15 [9%]; P =.04), there were no observed safety concerns. Conclusions and Relevance: The findings of this trial showed that, in patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels. Trial Registration: ClinicalTrials.gov Identifier: NCT02816736.
UR - http://www.scopus.com/inward/record.url?scp=85118979071&partnerID=8YFLogxK
U2 - 10.1001/jamacardio.2021.4567
DO - 10.1001/jamacardio.2021.4567
M3 - Article
C2 - 34730769
AN - SCOPUS:85118979071
SN - 2380-6583
VL - 7
SP - 17
EP - 25
JO - JAMA Cardiology
JF - JAMA Cardiology
IS - 1
ER -