Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial

Teerlink, John R.; Cotter, Gad; Davison, Beth A.; Felker, G. Michael; Filippatos, Gerasimos; Greenberg, Barry; Ponikowski, Piotr; Unemori, Elaine; Voors, Adriaan A.; Adams, Kirkwood F.; Dorobanțu, Maria; Grinfeld, Liliana; Jondeau, Guillaume; Marmor, Alon; Masip, Josep; Pang, Peter S.; Werdan, Karl; Teichman, Sam L.; Trapani, Angelo J.; Bush, Christopher; Saini, Rajnish; Schumacher, Christoph; Severin, Thomas; Metra, Marco

doi:10.1016/s0140-6736(12)61855-8

Cited by 825 publications

(787 citation statements)

References 41 publications

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“…These findings support a sustained benefit of serelaxin beyond the initial 48 h of administration. Better relief of congestion and protection from damage to the myocardium, kidneys, and liver seem the most likely mechanisms for these long‐term beneficial effects 19, 20. These results were also consistent with a reduction in WHF episodes in serelaxin‐treated patients.…”

Section: Introductionsupporting

confidence: 68%

“…However, in one study, only two‐thirds of the enrolled patients with a suspected diagnosis of AHF within 1 h of presentation were confirmed to have AHF at 6 h after presentation, suggesting that too rapid enrolment might result in patients without AHF being included in the trial 28. In both Pre‐RELAX‐AHF21 and RELAX‐AHF19 patients were randomized within 16 h of presentation at a median of 8–9 h; this time frame is the goal for RELAX‐AHF‐2 as well.…”

Section: Discussionmentioning

confidence: 99%

“…Assuming the 180 day CV death rate is 9.0% in the placebo group, which is ∼80% of 11.3% of all‐cause death observed in the placebo group in RELAX‐AHF,19 ∼6800 patients will need to be enrolled. The observed overall rate of the primary CV mortality endpoint will be assessed on a blinded basis, and adjustments to patient enrolment made in order to achieve the required number of events.…”

Section: Study Design and Methodsmentioning

confidence: 99%

“…Nitric oxide, endothelial endothelin type B receptor, vascular endothelial growth factor, and cAMP act as mediators for the vasodilatory as well as anti‐fibrotic and anti‐inflammatory effects of serelaxin 16. With these pleiotropic effects ( Figure 2), serelaxin may benefit AHF patients18 not only through its favourable haemodynamic effects, but also via its protective effects on the heart, kidney, and other organs, leading to potential mortality benefits19 as suggested by the data from RELAX‐AHF 20…”

Section: Introductionmentioning

confidence: 99%

“…infusion for up to 48 h in AHF patients have been evaluated in two multicentre, randomized, double‐blind, placebo‐controlled trials: (i) the dose‐finding phase 2 study Pre‐RELAX‐AHF,21 and (ii) the phase 2 registration study RELAX‐AHF 19. In both of these trials, patients were admitted for acute heart failure with persistent dyspnoea despite i.v.…”

Section: Introductionmentioning

confidence: 99%

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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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109

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: Introductionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Study Design and Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

109

103

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Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Renal Dysfunction

Chen

Anstrom

Givertz

et al. 2013

JAMA

441

242

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Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested.OBJECTIVE To test the 2 independent hypotheses that, compared with placebo, addition of low-dose dopamine (2 μg/kg/min) or low-dose nesiritide (0.005 μg/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, placebo-controlled clinical trial (Renal Optimization Strategies Evaluation [ROSE]) of 360 hospitalized patients with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15-60 mL/min/1.73 m 2 ), randomized within 24 hours of admission. Enrollment occurred from September 2010 to March 2013 across 26 sites in North America. INTERVENTIONS Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategy. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n = 122) and nesiritide (n = 119) groups were independently compared with the pooled placebo group (n = 119). MAIN OUTCOMES AND MEASURES Coprimary end points included 72-hour cumulative urine volume (decongestion end point) and the change in serum cystatin C from enrollment to 72 hours (renal function end point).RESULTS Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (dopamine, 8524 mL; 95% CI, 7917-9131 vs placebo, 8296 mL; 95% CI, 7762-8830 ; difference, 229 mL; 95% CI, −714 to 1171 mL; P = .59) or on the change in cystatin C level (dopamine, 0.12 mg/L; 95% CI, 0.06-0.18 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, 0.01; 95% CI, −0.08 to 0.10; P = .72). Similarly, low-dose nesiritide had no significant effect on 72-hour cumulative urine volume (nesiritide, 8574 mL; 95% CI, 8014-9134 vs placebo, 8296mL; 95% CI, 7762-8830; difference, 279 mL; 95% CI, −618 to 1176 mL; P = .49) or on the change in cystatin C level (nesiritide, 0.07 mg/L; 95% CI, 0.01-0.13 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, −0.04; 95% CI, −0.13 to 0.05; P = .36). Compared with placebo, there was no effect of low-dose dopamine or nesiritide on secondary end points reflective of decongestion, renal function, or clinical outcomes. CONCLUSION AND RELEVANCEIn participants with acute heart failure and renal dysfunction, neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy.

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Outpatient Worsening Heart Failure as a Target for Therapy

2018

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As the public health and economic burdens of heart failure continue to grow, recognizing the entity of outpatient WHF is critical. Efforts to reduce heart failure hospitalization should include developing effective therapies and care strategies for outpatient WHF. The outpatient WHF population represents a major opportunity for therapeutic advancements that could fundamentally change heart failure care delivery.

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Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial

Cited by 825 publications

References 41 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

Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Renal Dysfunction

Outpatient Worsening Heart Failure as a Target for Therapy

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