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
Authors: Burkert Pieske, Rolf Wachter, Sanjiv J. Shah, Abigail Baldridge, Peter Szeczoedy, Ghionul Ibram, Victor Shi, Ziqiang Zhao, Martin R. Cowie, Aldo Carlos Prado, Liza Maria Marcela Wenetz, Daniela Garcia Brasca, Juan Pablo Albisu, Alberto Alfredo Fernandez, Alberto Liberman, Graciela Echeverria, Ines Bartolacci, Maria Ranz, Mercela Pedrotti, Daniela Tapia, Marina Robertson, Solana Exposito, Marcelo Barrionuevo, Jorge Hector Resk, Guillermo Mercau, Ricardo Leon de la Fuente, Horacio Avaca, Carlos Poy, Miguel Angel Hominal, Guillermo Cursack, Oscar Ariel Vogelmann, Marcelo Martin Casas, Marcelo Costantino, Josefina Chiriffe, Robert Zweiker, Lukas Jaroslaw Motloch, Johann Auer, Peter Siostrzonek, Wilhelm Grander, David Derthoo, Wilfried Mullens, Hans Vandekerckhove, Rachid Maamar, Marc Delforge, Tom Mulleners, Salvador Rassi, Adrian Paulo Morales Kormann, Aline Moraes, Euler Roberto Fernandes Manenti, Gilmar Reis, Lilia Nigro Maia, Marcus Vinicius Simoes, Ricardo Pereira Silva, Luiz Claudio Danzmann, Jose Francisco Kerr Saraiva, Maria Christiane Valeria Braga Braile Sternieri, Weimar sebba Barroso de Souza, Estevao Lanna Figueiredo, Maria Lubomirova Tzekova, Boryana Boeva, Dimo Vasilev, Snezhanka Tomova Tisheva Gospodinova, Maria Hristova Milanova, Valentina Mincheva Kabakchieva, Petkana Ivanova Valchanova, Bojidar Dimov, Plamen Petrovsky, Petyo Georgiev Georgiev, Natalia Spasova, Georgi Mazhdrakov, Mariana Konteva, Haralambi Obreshkov Benov, Stefan Vesselinov Denchev, Marie Parent, Catherine Demers, Danielle Dion, Ronald L Bourgeois, Michael Lawrence Heffernan, Gustavo Adolfo Moreno Silgado, Franklin Quiroz, Alberto Cadena, Jose Luis Accini Mendoza, Clara Saldarriaga, Camilo Arana, Libor Nechvatal, Katerina Linhartova, Zdenek Klimsa, Ladislav Busak, Dan Marek, Josef Slaby, Rostislav Polasek, Pavel Koleckar, Jiri Carda, Marta Kaislerova, Pavel Trestik, Petr Zajicek, Jiri Kuchar, Jiri Vondrak, Jiri Krupicka, Tomas Brychta, Pavel Lang, Hans Rickers, Jens Dahlgaard Hove, Ida Gustafsson, Olav Wendelboe Nielsen, Tiina Uuetoa, Silvia Noodla, Arvo Rosenthal, Riina Vettus, Laurent Fauchier, Victor Aboyans, Teodora Monica DUTOIU, Eric Decoulx, Guillaume De Geeter, Patrick Khanoyan, Erwan Donal, Yann Rosamel, Emmanuelle Berthelot, Marie-France Seronde, Bernhard Rudolf Winkelmann, Wilma Grosskopf, Johannes Haas, Bernhard Schmitt, Norbert Jahnke, Andreas Wilke, Gregor Simonis, Peter Bosiljanoff, Nikolaos Proskynitopoulos, Christoph Axthelm, Isabelle Schenkenberger, Felix Proepper, Norbert Frey, Frank Edelmann, Christian Fechtrup, Tobias Graf, Mirko Seidel, Wolfgang Fehske, Martin Prohaska, Bernhard Unsoeld, Christoph Birner, Wolfgang Jungmair, Andreas Hoelscher, Christoph Kadel, Kishor Lahiri, Heidrun Mehling, Andreas Hagenow, Ingomar F K Naudts, Jan Winkler, Peter Salbach, Ronald Naumann, Holger Killat, Dirk Bastian, Anselm Tobias Baeumer, Britta Goldmann, Alessandro Cuneo, Florian Hoepfner, Michel Noutsias, Jens Beermann, Werner Rieker, Dominik Buckert, Jochen Woehrle, Julian Westphal, Tarek Bekfani, Stefan Stoerk, Steffen Schnupp, Reinhard Stoehring, Till Neumann, Markus Knapp, Jana Bourgeois, Klaus Edel, Hans-Eckart Sarnighausen, Thorsten Nitschke, Michael Jeserich, Henning Ebelt, Axel Linke, Regina Gaub, Tim Sueselbeck, Matthias Stratmann, Nicole Toursarkissian, Inga Steinebach, Florian Krackhardt, Robert Schueler, Michael Brandt, Jens Placke, Verena Stangl, Christoph Schoebel, Diethelm Tschoepe, Ulrich Overhoff, Gunter Stenzel, Christoph Stellbrink, Markus Schwefer, Eduard Lorenz, Peter Uebel, Dirk Gluesing, Matthias Weissbrodt, Fiete John, Juan Luis Arango, Jose Miguel Castellanos, Clara Chang, Franklin Haase, Edgar Miguel Lopez, Alvaro Ovando, Veronica Paniagua, Maribel Vogel, Marco Antonio
Rodas Estrada, Iris Rodriguez, Vinicio Corona, Janos Takacs, Albert Varga, Noemi Nyolczas, Akos Kalina, Andras Csaba Nagy, Bela Merkely, Ashwani Mehta, Manojkumar
Bhavarilal Chopada, Nitin Kamalakar Ghaisas, Rishi Sethi, Dinesha Basavanna, Tom Devasia, Devendra Kumar Agarwal, Nirav Chandulal Bhalani, Urmil Girishbhai Shah, Bharat Bhushan Chanana, Sunil
Nilkanthrao Washimkar, Tamir Bental, Sorel Goland, Zaher Azzam, Jean Marc Weinstein, Eli Magen, Tuvia Ben Gal, Alessandro Fucili, Roberto Franco
Enrico Pedretti, Stefano De Servi, Barbara Baronio, Edoardo Gronda, Mario Barbagallo, Alberto Margonato, Franco Cosmi, Cristina Giannattasio, Daniela Pavan, Alberto Mazza, Emilio Ramazzina, Michele Senni, Corinna Antonia Inserra, Giuseppe Argiolas, Claudio Borghi, Iveta Sime, Irina Veze, Lija Mora, Natalja Pontaga, Jurgita Plisiene, Jelena Celutkiene, Leone Cepinskiene, Jose Luis
Arenas Leon, Salvador Leon, Francisco Padilla, Ricardo Campos Cerda, Gerard Linssen, Annemieke Jansen, Walter Hermans, Louise Bellersen, Peter Van der Meer, Dirk J.A. Lok, Marlon Olimulder, J.M.C. van Hal, Roel Troquay, Mihaly de Bie, Loek van Heerebeek, Roger Martin
Correa Flores, Dr. Luis Alberto Camacho, Aldo Rodriguez, Walter Alarco, Libia Isabel Lu, Juan Jorge
Alfredo Lema Osores, Walter Cabrera, Antonio Gaspar, Juliana Martins, Pedro Sarmento, Candida Fonseca, Dulce Brito, Irene Marques, Silvia Leao, Ana Nascimento, Aurora Andrade, Nicoleta Cindea Nica, Gabriela Valentina Ciobotaru, Simona Iuliana Coman, Iulian Copaci, Alina Dumitrascu, Laura Iosipescu, Ruxandra Jurcut, Constantin Militaru, Cristian Podoleanu, Gabriela Stanciulescu, Mirela Cleopatra Tomescu, Mariana Tudoran, Olga Cristina Voicu, Alina Giuca, Corina Delia Mercea, Iulia Teodorescu, Yury Grigorievich Shvarts, Ludmila Ivanovna Gapon, Nadezda Vladimirovna Izmozherova, Larisa Anatolievna Khaisheva, Vladimir Pavlovich Nosov, Maria Evgenievna Mozheiko, Elena Alekseevna Shutemova, Dmitry Valerievich Privalov, Andrey Baglikov, Alexander Alexianosovich Kastanayan, Zhanna Kobalava, Natalia Andreevna Koziolova, Dmitriy D Zotov, Aleksandr Lipchenko, Natalia Nikolaevna Burova, Natalia Polezhaeva, Iana Pavlova, Lyudmila Grigorievna Ermoshkina, Konstantin Nikolaevich Zrazhevsky, Svetlana Afanasievna Boldueva, Evgenia Vladimirovna Akatova, Sergey Yurievich Martsevich, Svetlana Apostolovic, Srdjan Boskovic, Goran Davidovic, Marina Deljanin-Ilic, Aleksandra Ilic, Andrej Dzupina, Peter Fulop, Tomas Jesensky, Jan Nociar, Anna Predmerska, Jaroslava Schichorova, Beata Sokolova, Jana Lukacova, Rudolf Smik, Dagmar Stofkova, Veronika Kolikova, Juraj Papincak, Ladislav Sabo, Lubica Urgeova, Vladimir Macek, Alexander Klabnik, Peter Letavay, Ladislav Prochazka, Daniela Vinanska, Ivan Majercak, Antonio Teyes Dominguez, Jose Manuel Garcia Pinilla, Manuel Geraldia Lama, Julio Nunez Villota, Luis Almenar Bonet, Jose Ramon Bover Freire, Gonzalo Pena Perez, Domingo Pascual Figal, Fernando Werner Diz, Antonio Garcia Quintana, Jose Diaz Fernandez, Jorge Gomez Cerezo, Julio Blazquez Encinar, Francisco Gomez Delgado, Pau Llacer Iborra, Francisco Javier Camacho Jurad, Julia Seller, Songsak Kiatchoosakun, Srisakul Chirakarnjanakorn, Nakarin Sansanayudh, Suphot Srimahachota, Tomon Thongsri, Weera Mahavanakul, Tayfun Sahin, Zerrin Yigit, Mehmet Melek, Mustafa Akin, Yuksel Cavusoglu, Mevlut Koc, Ismail Turkay Ozcan, Okan Onur Turgut, Mehmet Birhan Yilmaz, Hakan Altay, Haldun Muderrisoglu, Ozer Badak, Tarkan Tekten, Abdurrahman Oguzhan, Murathan Kucuk, Shahid Mahmood, Matthew J Dewhurst, N'Jaimeh Asamoah-Owusu, Piers Clifford, Amrit Takhar, Chris Hayes, Andrew Moriarty, Klaus Witte, Justin Cooke, Donald Haas, Edward Portnay, Scott Feitell, Christopher S Brown, Brack Hattler, Peter Fail, Tariq Haddad, Bhola Rama, Nikhil Kapoor, Shamaila Aslam, Michael Peters, Eulogio Sanchez, Sridhar Vijayasekaran, Steven D Lupovitch, Orvar Jonsson, Carsten Schmalfuss, Anuj Jain, Gina Mentzer, Norman Lepor, John Mignone, Waymon Drummond, Jonathan Soverow, Hanna Gaggin, Robert I Garver, Melvin Martinez-Castrillon, Naseem Jaffrani, Barry D Harris, Marc Bernstein, B Clay Sizemore, Terry Wells, Alan Charles Schwartz, Mohsin Alhaddad, Alexander White, Henry Dargie, Michel Komajda, Robert Foley, Gary Francis, Stuart Pocock, Allen P Kaplan, Nancy Brown, Bruce Zuraw, Paula J Busse
Journal: JAMA (2021)

<h3>Importance</h3> 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 &gt;40%). <h3>Objective</h3> 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%. <h3>Design, Setting, and Participants</h3> 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). <h3>Interventions</h3> 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. <h3>Main Outcomes and Measures</h3> 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. <h3>Results</h3> 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;<i>P</i> &lt; .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;<i>P</i> = .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%). <h3>Conclusions and Relevance</h3> 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. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT03066804