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N Engl J Med. 2010 Oct 7;363(15):1419-28. doi: 10.1056/NEJMoa0912613.

Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure.

Collaborators (226)

O'Connor CM, Massie BM, Bloomfield D, Cotter G, Dittrich HC, Metra M, Ponikowski P, Teerlink J, Weatherley B, Borer J, Blantz R, Fleming T, Gorelick P, Komajda M, McMurray J, Rothrock J, Swedberg K, Teerlink JR, Carson P, Hauptman P, Iragui V, Lovett D, Miller A, Mohr JP, Pina I, Thomson S, Varosy P, Zile M, O'Connor CM, Cleland J, Givertz M, Ponikowski P, Voors A, Adams K, Böhm M, Cleland J, Fillipatos G, Givertz M, Gottlieb S, Grinfeld L, Gupta D, Jondeau G, Lotan C, Mareev V, Parker J, Ruda M, Špinar J, Tang W, Torre-Amione G, Jorde U, Voors A, Werdan K, Allall O, Amuchastegui M, Caccavo A, Colque R, Diez M, Ferrari G, Goicoechea R, Guzman L, Masuelli MG, Perna E, Ramos MS, Quiroga A, Convens C, El Allaf D, Goethals M, Nellessen E, Van Mieghem W, Ducharme A, Ezekowitz J, Haddad H, Klinke P, Lepage S, Parker J, Rajda M, Sussex B, Belohlavek J, Herold M, Hutyra M, Janek B, Jansky P, Solar M, Spinar J, Spinarova L, Cohen-Solal A, Funck F, Galinier M, Jondeau G, Habib G, Isnard R, Trochu JN, Böhm M, Felix S, Hengstenberg C, Olbrich HG, Mirtovic V, Stangl K, Weil J, Werdan K, Zotz R, Forster T, Keltai M, Kovács Z, Lupkovics G, Tomcsányi J, Tóth K, Aronson D, Butnaru A, Fink G, Hershkoviz R, Katz A, Lewis B, Lotan C, Marmor A, Omary M, Reisin L, Weiss T, Zahger D, Zeltser D, Zimlichman R, Balbi M, Gronda E, Metra M, Bellersen L, Cornel JH, Götte M, Herrman JP, Heymans S, Lenderink T, Schroeder-Tanka J, Voors A, Withagen A, Dluzniewski M, Grzybowski J, Kawecka-Jaszcz K, Kopaczewski J, Korzeniowska J, Krzeminska-Pakula M, Kuc K, Ponikowski P, Prokopczuk J, Stepinska J, Szelemej R, Tracz W, Trusz-Gluza M, Wysokinski A, Arutyunov G, Boldueva S, Gratsiansky N, Lusov V, Mareev V, Moiseev V, Novikova N, Petrov A, Ruda M, Shlyakhto E, Simanenkov V, Tereschenko S, Tyurina T, Vasilieva E, Yakusevich V, Zadionchenko V, Zateyshchikov D, Amosova K, Faynyk A, Sirenko Y, Dorobantu M, Georgescu CA, Ionescu DD, Macarie CE, Salajan AM, Stamate CS, Stefanescu M, Vinereanu D, Billberg EB, Dahlström U, Fu M, Banerjee P, Cleland J, Memon A, Senior R, Adams K, Ambrosia A, Bart B, Bensimhon D, Bilsker M, Bourge R, Bozkurt B, Cabuay B, Chandrasekaran S, Chiong J, Chung E, Colvin-Adams M, Czerska B, Dunlap M, Farr MJ, Fowler M, Givertz M, Greenberg B, Greenspan M, Gupta D, Hauptman P, Karia D, Klapholz M, Martinez-Arraras J, Mather P, McGrew F, Meymandi S, Miller A, Murali S, Murray D, Naz T, Oren R, Ouyang P, Rubinstein D, Saleh N, Shah M, Smull D, Van Bakel A, Vossler M, Walsh M, Wencker D, Winchester M, Zakhary B, Zolty R.

Author information

1
University of California at San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121, USA. barry.massie@va.gov

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.).

PMID:
20925544
DOI:
10.1056/NEJMoa0912613
[Indexed for MEDLINE]
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