Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure
Barry M Massie, Christopher M O'Connor, Marco Metra, Piotr Ponikowski, John R Teerlink, Gad Cotter, Beth Davison Weatherley, John G F Cleland, Michael M Givertz, Adriaan Voors, Paul DeLucca, George A Mansoor, Christina M Salerno, Daniel M Bloomfield, Howard C Dittrich, PROTECT Investigators and Committees, Christopher M O'Connor, Barry M Massie, Daniel Bloomfield, Gad Cotter, Howard C Dittrich, Marco Metra, Piotr Ponikowski, John Teerlink, Beth Weatherley, Jeffrey Borer, Roland Blantz, Thomas Fleming, Philip Gorelick, Michel Komajda, John McMurray, John Rothrock, Karl Swedberg, John R Teerlink, Peter Carson, Paul Hauptman, Vicente Iragui, David Lovett, Alan Miller, Jay P Mohr, Ileana Pina, Scott Thomson, Paul Varosy, Michael Zile, Christopher M O'Connor, John Cleland, Michael Givertz, Piotr Ponikowski, Adriaan Voors, Kirkwood Adams, Michael Böhm, John Cleland, Gerasimos Fillipatos, Michael Givertz, Stephen Gottlieb, Liliana Grinfeld, Dinesh Gupta, Guillaume Jondeau, Chaim Lotan, Vyacheslav Mareev, John Parker, Mikhail Ruda, Jindrich Špinar, Wilson Tang, Guillermo Torre-Amione, Ulrich Jorde, Adriaan Voors, Karl Werdan, Oscar Allall, Marcos Amuchastegui, Alberto Caccavo, Roberto Colque, Mirta Diez, Gustavo Maria Ferrari, Ramon Francisco Goicoechea, Luis Guzman, Marcelo Gustavo Masuelli, Eduardo Perna, María Silvina Ramos, Ariel Quiroga, Carl Convens, Dia El Allaf, Marc Goethals, Eric Nellessen, Walter Van Mieghem, Anique Ducharme, Justin Ezekowitz, Haissam Haddad, Peter Klinke, Serge Lepage, John Parker, Miroslaw Rajda, Bruce Sussex, Jan Belohlavek, Martin Herold, Martin Hutyra, Bronislav Janek, Petr Jansky, Miroslav Solar, Jindrich Spinar, Lenka Spinarova, Alain Cohen-Solal, François Funck, Michel Galinier, Guillaume Jondeau, Gilbert Habib, Richard Isnard, Jean-Noël Trochu, Michael Böhm, Stephan Felix, Christian Hengstenberg, Hans-Georg Olbrich, Veselin Mirtovic, Karl Stangl, Joachim Weil, Karl Werdan, Rainer Zotz, Tamas Forster, Matyas Keltai, Zsolt Kovács, Géza Lupkovics, János Tomcsányi, Kalman Tóth, Doron Aronson, Adi Butnaru, Gershon Fink, Rami Hershkoviz, Amos Katz, Basil Lewis, Chaim Lotan, Alon Marmor, Muhamad Omary, Leonardo Reisin, Teddy Weiss, Doron Zahger, David Zeltser, Reuven Zimlichman, Manrico Balbi, Edoardo Gronda, Marco Metra, Louise Bellersen, Jan Hein Cornel, Marco Götte, Jean-Paul Herrman, Stephane Heymans, Timo Lenderink, Jutta Schroeder-Tanka, Adriaan Voors, Adrie Withagen, Miroslaw Dluzniewski, Jacek Grzybowski, Kalina Kawecka-Jaszcz, Jerzy Kopaczewski, Jolanta Korzeniowska, Maria Krzeminska-Pakula, Krzysztof Kuc, Piotr Ponikowski, Janusz Prokopczuk, Janina Stepinska, Roman Szelemej, Wieslawa Tracz, Maria Trusz-Gluza, Andrzej Wysokinski, Grigory Arutyunov, Svetlana Boldueva, Nikolai Gratsiansky, Victor Lusov, Vyacheslav Mareev, Valentin Moiseev, Nina Novikova, Alexander Petrov, Mikhail Ruda, Evgeny Shlyakhto, Vladimir Simanenkov, Sergey Tereschenko, Tatiana Tyurina, Elena Vasilieva, Vladimir Yakusevich, Vladimir Zadionchenko, Dmitry Zateyshchikov, Kateryna Amosova, Andriy Faynyk, Yuri Sirenko, Maria Dorobantu, Catalina Arsenescu Georgescu, Dan Dominic Ionescu, Cezar Eugen Macarie, Adriana Marta Salajan, Costel Sorin Stamate, Mihai Stefanescu, Dragos Vinereanu, Eva Britt Billberg, Ulf Dahlström, Michael Fu, Prithwish Banerjee, John Cleland, Anwar Memon, Roxy Senior, Kirkwood Adams, Alphonse Ambrosia, Bradley Bart, Daniel Bensimhon, Martin Bilsker, Robert Bourge, Biykem Bozkurt, Barry Cabuay, Suresh Chandrasekaran, Jun Chiong, Eugene Chung, Monica Colvin-Adams, Barbara Czerska, Mark Dunlap, Mary Jane Farr, Michael Fowler, Michael Givertz, Barry Greenberg, Mitchell Greenspan, Dinesh Gupta, Paul Hauptman, Dershek Karia, Marc Klapholz, Joaquin Martinez-Arraras, Paul Mather, Frank McGrew, Sheba Meymandi, Alan Miller, Srinivas Murali, David Murray, Tehmina Naz, Ron Oren, Pamela Ouyang, David Rubinstein, Nizar Saleh, Monica Shah, David Smull, Adrian Van Bakel, Mark Vossler, Mary Walsh, Detlef Wencker, Mark Winchester, Boshra Zakhary, Ronald Zolty, Barry M Massie, Christopher M O'Connor, Marco Metra, Piotr Ponikowski, John R Teerlink, Gad Cotter, Beth Davison Weatherley, John G F Cleland, Michael M Givertz, Adriaan Voors, Paul DeLucca, George A Mansoor, Christina M Salerno, Daniel M Bloomfield, Howard C Dittrich, PROTECT Investigators and Committees, Christopher M O'Connor, Barry M Massie, Daniel Bloomfield, Gad Cotter, Howard C Dittrich, Marco Metra, Piotr Ponikowski, John Teerlink, Beth Weatherley, Jeffrey Borer, Roland Blantz, Thomas Fleming, Philip Gorelick, Michel Komajda, John McMurray, John Rothrock, Karl Swedberg, John R Teerlink, Peter Carson, Paul Hauptman, Vicente Iragui, David Lovett, Alan Miller, Jay P Mohr, Ileana Pina, Scott Thomson, Paul Varosy, Michael Zile, Christopher M O'Connor, John Cleland, Michael Givertz, Piotr Ponikowski, Adriaan Voors, Kirkwood Adams, Michael Böhm, John Cleland, Gerasimos Fillipatos, Michael Givertz, Stephen Gottlieb, Liliana Grinfeld, Dinesh Gupta, Guillaume Jondeau, Chaim Lotan, Vyacheslav Mareev, John Parker, Mikhail Ruda, Jindrich Špinar, Wilson Tang, Guillermo Torre-Amione, Ulrich Jorde, Adriaan Voors, Karl Werdan, Oscar Allall, Marcos Amuchastegui, Alberto Caccavo, Roberto Colque, Mirta Diez, Gustavo Maria Ferrari, Ramon Francisco Goicoechea, Luis Guzman, Marcelo Gustavo Masuelli, Eduardo Perna, María Silvina Ramos, Ariel Quiroga, Carl Convens, Dia El Allaf, Marc Goethals, Eric Nellessen, Walter Van Mieghem, Anique Ducharme, Justin Ezekowitz, Haissam Haddad, Peter Klinke, Serge Lepage, John Parker, Miroslaw Rajda, Bruce Sussex, Jan Belohlavek, Martin Herold, Martin Hutyra, Bronislav Janek, Petr Jansky, Miroslav Solar, Jindrich Spinar, Lenka Spinarova, Alain Cohen-Solal, François Funck, Michel Galinier, Guillaume Jondeau, Gilbert Habib, Richard Isnard, Jean-Noël Trochu, Michael Böhm, Stephan Felix, Christian Hengstenberg, Hans-Georg Olbrich, Veselin Mirtovic, Karl Stangl, Joachim Weil, Karl Werdan, Rainer Zotz, Tamas Forster, Matyas Keltai, Zsolt Kovács, Géza Lupkovics, János Tomcsányi, Kalman Tóth, Doron Aronson, Adi Butnaru, Gershon Fink, Rami Hershkoviz, Amos Katz, Basil Lewis, Chaim Lotan, Alon Marmor, Muhamad Omary, Leonardo Reisin, Teddy Weiss, Doron Zahger, David Zeltser, Reuven Zimlichman, Manrico Balbi, Edoardo Gronda, Marco Metra, Louise Bellersen, Jan Hein Cornel, Marco Götte, Jean-Paul Herrman, Stephane Heymans, Timo Lenderink, Jutta Schroeder-Tanka, Adriaan Voors, Adrie Withagen, Miroslaw Dluzniewski, Jacek Grzybowski, Kalina Kawecka-Jaszcz, Jerzy Kopaczewski, Jolanta Korzeniowska, Maria Krzeminska-Pakula, Krzysztof Kuc, Piotr Ponikowski, Janusz Prokopczuk, Janina Stepinska, Roman Szelemej, Wieslawa Tracz, Maria Trusz-Gluza, Andrzej Wysokinski, Grigory Arutyunov, Svetlana Boldueva, Nikolai Gratsiansky, Victor Lusov, Vyacheslav Mareev, Valentin Moiseev, Nina Novikova, Alexander Petrov, Mikhail Ruda, Evgeny Shlyakhto, Vladimir Simanenkov, Sergey Tereschenko, Tatiana Tyurina, Elena Vasilieva, Vladimir Yakusevich, Vladimir Zadionchenko, Dmitry Zateyshchikov, Kateryna Amosova, Andriy Faynyk, Yuri Sirenko, Maria Dorobantu, Catalina Arsenescu Georgescu, Dan Dominic Ionescu, Cezar Eugen Macarie, Adriana Marta Salajan, Costel Sorin Stamate, Mihai Stefanescu, Dragos Vinereanu, Eva Britt Billberg, Ulf Dahlström, Michael Fu, Prithwish Banerjee, John Cleland, Anwar Memon, Roxy Senior, Kirkwood Adams, Alphonse Ambrosia, Bradley Bart, Daniel Bensimhon, Martin Bilsker, Robert Bourge, Biykem Bozkurt, Barry Cabuay, Suresh Chandrasekaran, Jun Chiong, Eugene Chung, Monica Colvin-Adams, Barbara Czerska, Mark Dunlap, Mary Jane Farr, Michael Fowler, Michael Givertz, Barry Greenberg, Mitchell Greenspan, Dinesh Gupta, Paul Hauptman, Dershek Karia, Marc Klapholz, Joaquin Martinez-Arraras, Paul Mather, Frank McGrew, Sheba Meymandi, Alan Miller, Srinivas Murali, David Murray, Tehmina Naz, Ron Oren, Pamela Ouyang, David Rubinstein, Nizar Saleh, Monica Shah, David Smull, Adrian Van Bakel, Mark Vossler, Mary Walsh, Detlef Wencker, Mark Winchester, Boshra Zakhary, Ronald Zolty
Abstract
Background: Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses mediated by adenosine may be involved. We tested the hypothesis that the use of rolofylline, an adenosine A1-receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure.
Methods: We conducted a multicenter, double-blind, placebo-controlled trial involving patients hospitalized for acute heart failure with impaired renal function. Within 24 hours after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive daily intravenous rolofylline (30 mg) or placebo for up to 3 days. The primary end point was treatment success, treatment failure, or no change in the patient's clinical condition; this end point was defined according to survival, heart-failure status, and changes in renal function. Secondary end points were the post-treatment development of persistent renal impairment and the 60-day rate of death or readmission for cardiovascular or renal causes.
Results: Rolofylline, as compared with placebo, did not provide a benefit with respect to the primary end point (odds ratio, 0.92; 95% confidence interval, 0.78 to 1.09; P=0.35). Persistent renal impairment developed in 15.0% of patients in the rolofylline group and in 13.7% of patients in the placebo group (P=0.44). By 60 days, death or readmission for cardiovascular or renal causes had occurred in similar proportions of patients assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P=0.86). Adverse-event rates were similar overall; however, only patients in the rolofylline group had seizures, a known potential adverse effect of A1-receptor antagonists.
Conclusions: Rolofylline did not have a favorable effect with respect to the primary clinical composite end point, nor did it improve renal function or 60-day outcomes. It does not show promise in the treatment of acute heart failure with renal dysfunction. (Funded by NovaCardia, a subsidiary of Merck; ClinicalTrials.gov numbers, NCT00328692 and NCT00354458.).
Source: PubMed