Effect of Sacubitril/Valsartan vs Standard Medical Therapies on Plasma NT-proBNP Concentration and Submaximal Exercise Capacity in Patients With Heart Failure and Preserved Ejection Fraction
Burkert Pieske, Rolf Wachter, Sanjiv J. Shah, Abigail S. Baldridge, Peter Szeczoedy, Ghionul Ibram, Victor Shi, Ziqiang Zhao, Martín Cowie, Aldo Carlos Prado, Liza Maria Marcela Wenetz, Daniela García Brasca, Juan Pablo Albisu, Alberto Alfredo Fernandez, Alberto Liberman, Graciela Echeverria, Ines Bartolacci, Maria Ranz, Mercela Pedrotti, Daniela Tapía, Marina Robertson, Solana Exposito, Marcelo Barrionuevo, Jorge Hector Resk, Guillermo Mercau, Ricardo León de la Fuente, Horacio Avaca, Carlos Poy, Miguel Hominal, Guillermo Cursack, Oscar Ariel Vogelmann, Marcelo Martín Casas, Marcelo Costantino, Josefina Chiriffe, Robert Zweiker, Lukas J. Motloch, Johann Auer, Peter Siostrzonek, Wilhelm Grander, David Derthoo, Wilfried Müllens, Hans Vandekerckhove, Rachid Maamar, Marc Delforge, Tom Mulleners, Salvador Rassi, Adrian Kormann, Aline Moraes, Euler Roberto Fernandes Manenti, Gilmar Reis, Lília Nigro Maia, Marcus Vinı́cius Simões, Ricardo Pereira Silva, Luiz Cláudio Danzmann, José Francisco Kerr Saraiva, Maria Christiane Valéria Braga Braile-Sternieri, Weimar sebba Barroso de Souza, Estêvão Lanna Figueiredo, M. Tzekova, Boryana Boeva, Dimo Vasilev, Snezhanka Tomova Tisheva Gospodinova, Maria Milanova, Valentina Mincheva Kabakchieva, Petkana Ivanova Valchanova, Bojidar I Dimov, Plamen Dimitrov Petrovsky, P Georgiev, Natalia Spasova, Georgi Mazhdrakov, Mariana Konteva, Haralambi O Benov, Stefan Vesselinov Denchev, Marie Parent, Catherine Demers, Danielle Dion, Ronald Bourgeois, M Heffernan, GUSTAVO ADOLFO MORENO SILGADO, Franklin Quiroz, Alberto Cadena, J.L. Mendoza, Clara Saldarriaga, Camilo Arana, Libor Nechvátal, Kateřina Linhartová, Zdeněk Klimsa, Ladislav Busak, Dan Marek, Josef Slaby, Rostislav Polášek, Pavel Koleckar, Jiri Carda, Marta Kaislerova, Pavel Trestik, Petr Zajíček, Jiří Kuchař, Jiří Vondrák, J Krupicka, Tomáš Brychta
Abstract
Importance: There is limited evidence on the benefits of sacubitril/valsartan vs broader renin angiotensin system inhibitor background therapy on surrogate outcome markers, 6-minute walk distance, and quality of life in patients with heart failure and mildly reduced or preserved left ventricular ejection fraction (LVEF >40%). Objective: To evaluate the effect of sacubitril/valsartan on N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, 6-minute walk distance, and quality of life vs background medication-based individualized comparators in patients with chronic heart failure and LVEF of more than 40%. Design, Setting, and Participants: A 24-week, randomized, double-blind, parallel group clinical trial (August 2017-October 2019). Of 4632 patients screened at 396 centers in 32 countries, 2572 patients with heart failure, LVEF of more than 40%, elevated NT-proBNP levels, structural heart disease, and reduced quality of life were enrolled (last follow-up, October 28, 2019). Interventions: Patients were randomized 1:1 either to sacubitril/valsartan (n = 1286) or to background medication-based individualized comparator (n = 1286), ie, enalapril, valsartan, or placebo stratified by prior use of a renin angiotensin system inhibitor. Main Outcomes and Measures: Primary end points were change from baseline in plasma NT-proBNP level at week 12 and in the 6-minute walk distance at week 24. Secondary end points were change from baseline in quality of life measures and New York Heart Association (NYHA) class at 24 weeks. Results: Among 2572 randomized patients (mean age, 72.6 years [SD, 8.5 years]; 1301 women [50.7%]), 2240 (87.1%) completed the trial. At baseline, the median NT-proBNP levels were 786 pg/mL in the sacubitril/valsartan group and 760 pg/mL in the comparator group. After 12 weeks, patients in the sacubitril/valsartan group (adjusted geometric mean ratio to baseline, 0.82 pg/mL) had a significantly greater reduction in NT-proBNP levels than did those in the comparator group (adjusted geometric mean ratio to baseline, 0.98 pg/mL) with an adjusted geometric mean ratio of 0.84 (95% CI, 0.80 to 0.88; P < .001). At week 24, there was no significant between-group difference in median change from baseline in the 6-minute walk distance with an increase of 9.7 m vs 12.2 m (adjusted mean difference, -2.5 m; 95% CI, -8.5 to 3.5; P = .42). There was no significant between-group difference in the mean change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (12.3 vs 11.8; mean difference, 0.52; 95% CI, -0.93 to 1.97) or improvement in NYHA class (23.6% vs 24.0% of patients; adjusted odds ratio, 0.98; 95% CI, 0.81 to 1.18). The most frequent adverse events in the sacubitril/valsartan group vs the comparator group were hypotension (14.1% vs 5.5%), albuminuria (12.3% vs 7.6%), and hyperkalemia (11.6% vs 10.9%). Conclusions and Relevance: Among patients with heart failure and left ventricular ejection factor of higher than 40%, sacubitril/valsartan treatment compared with standard renin angiotensin system inhibitor treatment or placebo resulted in a significantly greater decrease in plasma N-terminal pro-brain natriuretic peptide levels at 12 weeks but did not significantly improve 6-minute walk distance at 24 weeks. Further research is warranted to evaluate potential clinical benefits of sacubitril/valsartan in these patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03066804.