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Erschienen in: Drug Safety 3/2012

01.03.2012 | Original Research Articles

The Safety of an Adenosine A1-Receptor Antagonist, Rolofylline, in Patients with Acute Heart Failure and Renal Impairment

Findings from PROTECT

verfasst von: Professor John R. Teerlink, Vicente J. Iragui, Jay P. Mohr, Peter E. Carson, Paul J. Hauptman, David H. Lovett, Alan B. Miller, Ileana L. Piña, Scott Thomson, Paul D. Varosy, Michael R. Zile, John G. F. Cleland, Michael M. Givertz, Marco Metra, Piotr Ponikowski, Adriaan A. Voors, Beth A. Davison, Gad Cotter, Denise Wolko, Paul DeLucca, Christina M. Salerno, George A. Mansoor, Howard Dittrich, Christopher M. O’Connor, Barry M. Massie

Erschienen in: Drug Safety | Ausgabe 3/2012

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Abstract

Background: Adenosine exerts actions in multiple organ systems, and adenosine receptors are a therapeutic target in many development programmes.
Objective: The aim of this analysis was to evaluate the safety of rolofylline, an adenosine A1-receptor antagonist, in patients with acute heart failure.
Methods: The effect of rolofylline was investigated in patients hospitalized for acute heart failure with impaired renal function. Intravenous rolofylline 30 mg or placebo was infused over 4 hours daily for up to 3 days. Adverse events (AEs) and serious AEs (SAEs) were recorded from baseline through 7 and 14 days, respectively, and clinical events were adjudicated through 60 days.
Results: Of 2033 patients enrolled, 2002 received study drug randomized 2 : 1 to rolofylline or placebo. Rolofylline and placebo were associated with a similar risk of pre-specified groups of AEs or SAEs, other than selected neurological events. Investigator-reported seizures occurred in 11 (0.8%) rolofylline-treated patients and zero patients receiving placebo (p = 0.02). Stroke occurred in 21 (1.6%) patients assigned to rolofylline compared with 3 (0.5%) placebo-treated patients through 60 days with a greater risk for stroke in the rolofylline group (hazard ratio 3.49; 95% CI 1.04, 11.71; p = 0.043). There was no temporal relation to rolofylline administration and no specific stroke subtype or clinical characteristics that predicted stroke in the rolofylline group.
Conclusions: Rolofylline treatment was associated with an increased seizure rate, an anticipated complication of A1-receptor antagonists. An unanticipated, disproportionate increase in strokes in the rolofylline-treated patients emerged, although no clear temporal relation, aetiology, stroke subtype or interacting factor suggestive of a causal mechanism was identified. Further research into stroke as a potential complication of adenosine-modulating therapies is required. Additionally, this study underscores the value of longer follow-up durations for AEs, even for agents with short treatment periods, such as in acute heart failure.
Trial Registration: ClinicalTrials.gov identifiers NCT00328692 and NCT00354458.
Literatur
1.
Zurück zum Zitat Kiesman WF, Elzein E, Zablocki J. A1 adenosine receptor antagonists, agonists, and allosteric enhancers. Handb Exp Pharmacol 2009; 193: 25–58PubMedCrossRef Kiesman WF, Elzein E, Zablocki J. A1 adenosine receptor antagonists, agonists, and allosteric enhancers. Handb Exp Pharmacol 2009; 193: 25–58PubMedCrossRef
2.
Zurück zum Zitat Boison D. Adenosine and epilepsy: from therapeutic rationale to new therapeutic strategies. Neuroscientist 2005 Feb; 11 (1): 25–36PubMedCrossRef Boison D. Adenosine and epilepsy: from therapeutic rationale to new therapeutic strategies. Neuroscientist 2005 Feb; 11 (1): 25–36PubMedCrossRef
3.
Zurück zum Zitat Cotter G, Dittrich HC, Weatherley BD, et al. The PROTECT pilot study: a randomized, placebo-controlled, dosefinding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment. J Card Fail 2008 Oct; 14 (8): 631–40PubMedCrossRef Cotter G, Dittrich HC, Weatherley BD, et al. The PROTECT pilot study: a randomized, placebo-controlled, dosefinding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment. J Card Fail 2008 Oct; 14 (8): 631–40PubMedCrossRef
4.
Zurück zum Zitat Weatherley BD, Cotter G, Dittrich HC, et al. Design and rationale of the PROTECT study: a placebo-controlled randomized study of the selective A1 adenosine receptor antagonist rolofylline for patients hospitalized with acute decompensated heart failure and volume overload to assess treatment effect on congestion and renal function. J Card Fail 2010 Jan; 16 (1): 25–35PubMedCrossRef Weatherley BD, Cotter G, Dittrich HC, et al. Design and rationale of the PROTECT study: a placebo-controlled randomized study of the selective A1 adenosine receptor antagonist rolofylline for patients hospitalized with acute decompensated heart failure and volume overload to assess treatment effect on congestion and renal function. J Card Fail 2010 Jan; 16 (1): 25–35PubMedCrossRef
5.
Zurück zum Zitat Massie BM, O’Connor CM, Metra M, et al. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010; 363 (15): 1419–28PubMedCrossRef Massie BM, O’Connor CM, Metra M, et al. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010; 363 (15): 1419–28PubMedCrossRef
6.
Zurück zum Zitat Kunitz SC, Gross CR, Heyman A, et al. The pilot Stroke Data Bank: definition, design, and data. Stroke 1984 Jul-Aug; 15 (4): 740–6 Kunitz SC, Gross CR, Heyman A, et al. The pilot Stroke Data Bank: definition, design, and data. Stroke 1984 Jul-Aug; 15 (4): 740–6
7.
Zurück zum Zitat Adams Jr HP, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. TOAST: Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993 Jan; 24 (1): 35–41PubMedCrossRef Adams Jr HP, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. TOAST: Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993 Jan; 24 (1): 35–41PubMedCrossRef
8.
Zurück zum Zitat Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 1985 Apr-Jun; 4 (2): 213–26 Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 1985 Apr-Jun; 4 (2): 213–26
9.
Zurück zum Zitat Cleland JG, Freemantle N, Coletta AP, et al. Clinical trials update from the American Heart Association: REPAIRAMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE. Eur J Heart Fail 2006 Jan; 8 (1): 105–10PubMedCrossRef Cleland JG, Freemantle N, Coletta AP, et al. Clinical trials update from the American Heart Association: REPAIRAMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE. Eur J Heart Fail 2006 Jan; 8 (1): 105–10PubMedCrossRef
10.
Zurück zum Zitat Felker GM, Benza RL, Chandler AB, et al. Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study. J Am Coll Cardiol 2003 Mar 19; 41 (6): 997–1003PubMedCrossRef Felker GM, Benza RL, Chandler AB, et al. Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study. J Am Coll Cardiol 2003 Mar 19; 41 (6): 997–1003PubMedCrossRef
11.
Zurück zum Zitat VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA2002Mar 27; 287 (12): 1531–40 VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA2002Mar 27; 287 (12): 1531–40
12.
Zurück zum Zitat Fredholm BB, Chen JF, Masino SA, et al. Actions of adenosine at its receptors in the CNS: insights from knockouts and drugs. Annu Rev Pharmacol Toxicol 2005; 45: 385–412PubMedCrossRef Fredholm BB, Chen JF, Masino SA, et al. Actions of adenosine at its receptors in the CNS: insights from knockouts and drugs. Annu Rev Pharmacol Toxicol 2005; 45: 385–412PubMedCrossRef
13.
Zurück zum Zitat Boison D. The adenosine kinase hypothesis of epileptogenesis. Prog Neurobiol 2008 Mar; 84 (3): 249–62CrossRef Boison D. The adenosine kinase hypothesis of epileptogenesis. Prog Neurobiol 2008 Mar; 84 (3): 249–62CrossRef
14.
Zurück zum Zitat Ribeiro JA. What can adenosine neuromodulation do for neuroprotection? Curr Drug Targets CNS Neurol Disord 2005 Aug; 4 (4): 325-9PubMedCrossRef Ribeiro JA. What can adenosine neuromodulation do for neuroprotection? Curr Drug Targets CNS Neurol Disord 2005 Aug; 4 (4): 325-9PubMedCrossRef
15.
Zurück zum Zitat Givertz MM, Massie BM, Fields TK, et al. The effects of KW-3902, an adenosine A1-receptor antagonist,on diuresis and renal function in patients with acute decompensated heart failure and renal impairment or diuretic resistance. J Am Coll Cardiol 2007 Oct 16; 50 (16): 1551–60PubMedCrossRef Givertz MM, Massie BM, Fields TK, et al. The effects of KW-3902, an adenosine A1-receptor antagonist,on diuresis and renal function in patients with acute decompensated heart failure and renal impairment or diuretic resistance. J Am Coll Cardiol 2007 Oct 16; 50 (16): 1551–60PubMedCrossRef
16.
Zurück zum Zitat Dittrich HC, Gupta DK, Hack TC, et al. The effect of KW-3902, an adenosine A1 receptor antagonist, on renal function and renal plasma flow in ambulatory patients with heart failure and renal impairment. J Card Fail 2007 Oct; 13 (8): 609–17PubMedCrossRef Dittrich HC, Gupta DK, Hack TC, et al. The effect of KW-3902, an adenosine A1 receptor antagonist, on renal function and renal plasma flow in ambulatory patients with heart failure and renal impairment. J Card Fail 2007 Oct; 13 (8): 609–17PubMedCrossRef
17.
Zurück zum Zitat The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. JAMA 1998 Apr 22–29; 279 (16): 1265–72 The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. JAMA 1998 Apr 22–29; 279 (16): 1265–72
18.
Zurück zum Zitat Sherman DG, Dyken Jr ML, Gent M, et al. Antithrombotic therapy for cerebrovascular disorders: an update. Chest 1995 Oct; 108 (4 Suppl.): 444–56SCrossRef Sherman DG, Dyken Jr ML, Gent M, et al. Antithrombotic therapy for cerebrovascular disorders: an update. Chest 1995 Oct; 108 (4 Suppl.): 444–56SCrossRef
19.
Zurück zum Zitat Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl JMed 2001 Nov 15; 345 (20): 1444–51CrossRef Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl JMed 2001 Nov 15; 345 (20): 1444–51CrossRef
20.
Zurück zum Zitat McMurray JJ, Teerlink JR, Cotter G, et al. Effects of tezosentan on symptoms and clinical outcomes in patients with acute heart failure: the VERITAS randomized controlled trials. JAMA 2007 Nov 7; 298 (17): 2009–19PubMedCrossRef McMurray JJ, Teerlink JR, Cotter G, et al. Effects of tezosentan on symptoms and clinical outcomes in patients with acute heart failure: the VERITAS randomized controlled trials. JAMA 2007 Nov 7; 298 (17): 2009–19PubMedCrossRef
21.
Zurück zum Zitat Greenberg B, Thomas I, Banish D, et al. Effects of multiple oral doses of an A1 adenosine antagonist, BG9928, in patients with heart failure: results of a placebo-controlled, dose-escalation study. J Am Coll Cardiol 2007 Aug 14; 50 (7): 600–6PubMedCrossRef Greenberg B, Thomas I, Banish D, et al. Effects of multiple oral doses of an A1 adenosine antagonist, BG9928, in patients with heart failure: results of a placebo-controlled, dose-escalation study. J Am Coll Cardiol 2007 Aug 14; 50 (7): 600–6PubMedCrossRef
221.
Zurück zum Zitat Suzuki T, Hirata K, Elkind MS, et al. Metabolic syndrome, endothelial dysfunction, and risk of cardiovascular events: the Northern Manhattan Study (NOMAS). Am Heart J 2008 Aug; 156 (2): 405–10PubMedCrossRef Suzuki T, Hirata K, Elkind MS, et al. Metabolic syndrome, endothelial dysfunction, and risk of cardiovascular events: the Northern Manhattan Study (NOMAS). Am Heart J 2008 Aug; 156 (2): 405–10PubMedCrossRef
23.
Zurück zum Zitat Kitagawa H, Mori A, Shimada J, et al. Intracerebral adenosine infusion improves neurological outcome after transient focal ischemia in rats. Neurol Res 2002 Apr; 24 (3): 317–23PubMedCrossRef Kitagawa H, Mori A, Shimada J, et al. Intracerebral adenosine infusion improves neurological outcome after transient focal ischemia in rats. Neurol Res 2002 Apr; 24 (3): 317–23PubMedCrossRef
24.
Zurück zum Zitat Fantidis P. The role of intracellular 3’5’-cyclic adenosine monophosphate (cAMP) in atherosclerosis. Curr Vasc Pharmacol 2010 Jul; 8 (4): 464–72PubMedCrossRef Fantidis P. The role of intracellular 3’5’-cyclic adenosine monophosphate (cAMP) in atherosclerosis. Curr Vasc Pharmacol 2010 Jul; 8 (4): 464–72PubMedCrossRef
25.
Zurück zum Zitat Sebastiao AM, Ribeiro JA. Adenosine receptors and the central nervous system. Handb Exp Pharmacol 2009; 193: 471–534PubMedCrossRef Sebastiao AM, Ribeiro JA. Adenosine receptors and the central nervous system. Handb Exp Pharmacol 2009; 193: 471–534PubMedCrossRef
26.
Zurück zum Zitat Stone TW, Ceruti S, Abbracchio MP. Adenosine receptors and neurological disease: neuroprotection and neurodegeneration. Handb Exp Pharmacol 2009; 193: 535–87PubMedCrossRef Stone TW, Ceruti S, Abbracchio MP. Adenosine receptors and neurological disease: neuroprotection and neurodegeneration. Handb Exp Pharmacol 2009; 193: 535–87PubMedCrossRef
Metadaten
Titel
The Safety of an Adenosine A1-Receptor Antagonist, Rolofylline, in Patients with Acute Heart Failure and Renal Impairment
Findings from PROTECT
verfasst von
Professor John R. Teerlink
Vicente J. Iragui
Jay P. Mohr
Peter E. Carson
Paul J. Hauptman
David H. Lovett
Alan B. Miller
Ileana L. Piña
Scott Thomson
Paul D. Varosy
Michael R. Zile
John G. F. Cleland
Michael M. Givertz
Marco Metra
Piotr Ponikowski
Adriaan A. Voors
Beth A. Davison
Gad Cotter
Denise Wolko
Paul DeLucca
Christina M. Salerno
George A. Mansoor
Howard Dittrich
Christopher M. O’Connor
Barry M. Massie
Publikationsdatum
01.03.2012
Verlag
Springer International Publishing
Erschienen in
Drug Safety / Ausgabe 3/2012
Print ISSN: 0114-5916
Elektronische ISSN: 1179-1942
DOI
https://doi.org/10.2165/11594680-000000000-00000

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