Rolofylline, an Adenosine A<sub>1</sub>−Receptor Antagonist, in Acute Heart Failure

Massie, Barry M.; O’Connor, Christopher M.; Metra, Marco; Ponikowski, Piotr; Teerlink, John R.; Cotter, Gad; Weatherley, Beth Davison; Cleland, John G.F.; Givertz, Michael M.; Voors, Adriaan A.; DeLucca, Paul; Mansoor, George A.; Salerno, Christina M.; Bloomfield, Daniel M.; Dittrich, Howard C.

doi:10.1056/nejmoa0912613

Cited by 475 publications

(312 citation statements)

References 28 publications

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“…This is consistent with previous trials testing drugs acting on peripheral vessels and/or renal function in patients with AHF 29, 30. The prognosis of the patients with AHF was not found to be related to left ventricular ejection fraction31 and a similar benefit of serelaxin on clinical outcomes was observed in both patients with preserved and reduced ejection fraction 32.…”

Section: Discussionsupporting

confidence: 90%

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Teerlink

Voors

Ponikowski

et al. 2017

European J of Heart Fail

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105

103

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Patients admitted for acute heart failure (AHF) experience high rates of in‐hospital and post‐discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin‐2, a hormone with vasodilatory and end‐organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX‐AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all‐cause and cardiovascular mortality by 37% through day 180. RELAX‐AHF‐2 ( ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX‐AHF‐2 is a multicentre, randomized, double‐blind, placebo‐controlled, event‐driven, phase 3 trial enrolling ∼6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild‐to‐moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all‐cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in‐hospital length of stay during index AHF. The results from RELAX‐AHF‐2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF.

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Section: Discussionsupporting

confidence: 90%

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Teerlink

Voors

Ponikowski

et al. 2017

European J of Heart Fail

Self Cite

105

103

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“…First, a cardiorenal mechanistic cohort was used to investigate the association between pro-ENK and renal function including hemodynamic parameters which were measured by radioactive tracers in patients with stable chronic heart failure 8,9 . Second, the PROTECT (Placebo-controlled Randomized study of the selective A1 adenosine receptor antagonist rolofylline for the patients hospitalized with acute heart failure and volume Overload to assess Treatment Effect on Congestion and renal functTion) study cohort (acute heart failure cohort) was used to study the association between pro-ENK and prognosis in patients with acute heart failure 10 . Measurement of pro-ENK was performed using a sandwich immunoassay with antibodies against the proenkephalin A 119-159 peptide by Sphingotec inc. 5,7 .…”

Section: Methodsmentioning

confidence: 99%

“…The details of the design, results, and conclusions of this study have already been published 10,12,13 . In brief, 2,033 patients with acute heart failure with renal function impairment (estimated creatinine clearance between 20 to 80 mL/min with Cockcroft-Gault formula) were included and randomized to rolofylline or placebo.…”

Section: Acute Heart Failure Cohortmentioning

confidence: 99%

Clinical Correlates and Prognostic Value of Proenkephalin in Acute and Chronic Heart Failure

Matsue

Maaten

Struck³

et al. 2017

Journal of Cardiac Failure

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“…A1R antagonists have been recommended for the treatment of cardiorenal syndrome [469]. Therefore, A1R antagonists are not recommended as a treatment for acute heart failure with renal dysfunction [470,471], although rolofylline, a selective A1R antagonist, had some beneficial effects for high risk acute decompensated heart failure [472].…”

Section: Pathophysiology and Therapeutic Potentialmentioning

confidence: 99%

Cardiac purinergic signalling in health and disease

Burnstock

Pelleg

2014

Purinergic Signalling

119

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This review is a historical account about purinergic signalling in the heart, for readers to see how ideas and understanding have changed as new experimental results were published. Initially, the focus is on the nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory nerves, as well as in intracardiac neurons. Control of the heart by centers in the brain and vagal cardiovascular reflexes involving purines are also discussed. The actions of adenine nucleotides and nucleosides on cardiomyocytes, atrioventricular and sinoatrial nodes, cardiac fibroblasts, and coronary blood vessels are described. Cardiac release and degradation of ATP are also described. Finally, the involvement of purinergic signalling and its therapeutic potential in cardiac pathophysiology is reviewed, including acute and chronic heart failure, ischemia, infarction, arrhythmias, cardiomyopathy, syncope, hypertrophy, coronary artery disease, angina, diabetic cardiomyopathy, as well as heart transplantation and coronary bypass grafts.

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Rolofylline, an Adenosine A₁−Receptor Antagonist, in Acute Heart Failure

Cited by 475 publications

References 28 publications

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Clinical Correlates and Prognostic Value of Proenkephalin in Acute and Chronic Heart Failure

Cardiac purinergic signalling in health and disease

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Rolofylline, an Adenosine A1−Receptor Antagonist, in Acute Heart Failure

Cited by 475 publications

References 28 publications

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Clinical Correlates and Prognostic Value of Proenkephalin in Acute and Chronic Heart Failure

Cardiac purinergic signalling in health and disease

Contact Info

Product

Resources

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Rolofylline, an Adenosine A₁−Receptor Antagonist, in Acute Heart Failure