Dyspnoea relief by serelaxin is similar in HFpEF and HFrEF patients
Serelaxin in acute heart failure patients with preserved left ventricular ejection fraction: results from the RELAX-AHF trial.
Filippatos G, Teerlink JR, Farmakis D, et al.
Eur Heart J. 2013 Dec 6. [Epub ahead of print]
BackgroundAcute heart failure (AHF) is characterised by high morbidity and mortality . Management of AHF patients is mostly based on drugs that improve acute symptoms, but have a neutral or negative effect on longer term outcome . Novel vasoactive agents have recently been evaluated, but did not show evidence for improvement of outcome [3-6].
Up to half of AHF patients have heart failure with preserved ejection fraction (HFpEF) . While medical therapy for patients with chronic heart failure with reduced left ventricular ejection fraction (HFrEF) has advanced, effective therapy for HFpEF is still missing.
Serelaxin is a recombinant form of human relaxin-2 that has been shown to improve symptoms and prevent organ damage with a reduction in 180 day mortality, in comparison with placebo [7,8]. Since a substantial number of patients in RELAX-AHF had a preserved left ventricular ejection fraction (LVEF), the authors analysed the efficacy and safety of serelaxin in patients with HFpEF, as compared to those with HFrEF. 1161 had been randomised to 48-h our intravenous infusion with serelaxin (n=581) or placebo (n=580) within 16 hours of presentation. 281 patients (26%) had HFpEF (>50% LVEF). Primary efficacy endpoint was dyspnoea improvement, defined as dyspnoea change from baseline in the visual analogue scale-area under the curve (VAS-AUC).
- Patients with HFpEF were older and more often female than patients with HFrEF, and less likely to have a history of ischaemic heart disease or of a prior AHF hospitalisation in the preceding year, and were more likely to have arterial hypertension and atrial fibrillation. Upon presentation, patients with HFpEF and HFrEF did not differ with regard to clinical signs and symptoms of congestion, although HFpEF patients had higher systolic blood pressure and lower NT-proBNP, troponin T and serum creatinine levels.
- Serelaxin induced dyspnoea relief to a similar extent in both HFpEF and HFrEF patients (mean AUC change: 461 vs. 397 mmxh, P(interaction)=0.8683).
- Serelaxin had a similar effect in HFpEF and HFrEF patients on CV death or hospitalisation for heart or renal failure (HF/RF) by day 60 (HR: 1.08 vs. 1.10, P(interaction)=0.97), days alive and out of hospital by day 60 (-1.28 vs. 0.86, P(interaction=0.19), CV death by day 180 (0.59 vs. 0.64, P(interaction)=0.87).
- The rate of hospitalisation for HF/RF was higher in the serelaxin than in the placebo group in both EF groups, but notably in patients with HFrEF (but note the smaller group size thus statistical power for HFpEF).
- There was no significant difference in the effect of serelaxin on all-cause death through day 180 in HFpEF and HFrEF patients (0.70, 0.63, P(interaction)=0.82), nor in the occurrence of confirmed blood pressure decrease, which may lead to dose reduction or discontinuation, nor in other safety endpoints.
- Serelaxin reduced plasma levels (measured from baseline to 48 h) of NT-proBNP, cardiac troponin T, cystatin-C, serum creatinine and BUN and transaminases as compared with placebo. No difference in these biomarkers indicative of organ damage appeared to exist based on ejection fraction status.
ConclusionThe RELAX-AHF study had shown that a 48-h infusion of serelaxin in AHF patients improved dyspnoea and other symptoms of congestion and decreased early AHF worsening and hospitalisation duration, as well as cardiovascular and all-cause mortality at 180 days. This analysis shows that these effects of serelaxin are similar in patients with HFrEF and HFpEF, both with regard to adverse events and benefits.
Find this article on Pubmed
1. Roger VL, Go AS, Lloyd-Jones DM, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation 2012;125:e2–220.
2. McMurray JJ, Adamopoulos S, Anker SD, et al; ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787–1847.
3. Gheorghiade M, Konstam MA, Burnett JC Jr, et al; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA 2007;297:1332–1343.
4. Mebazaa A, Nieminen MS, Packer M, et al; SURVIVE Investigators. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE randomized Trial. JAMA 2007;297:1883–1891.
5. Massie BM, O’Connor CM, Metra M, et al; PROTECT Investigators and Committees. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010;363:1419–1428.
6. O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:32–43.
7. Teerlink JR, Cotter G, Davison BA, et al.; RELAXin in Acute Heart Failure (RELAX-AHF) Investigators. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomized, placebo-controlled trial. Lancet 2013;381:29–39.
8. Metra M, Cotter G, Davison BA, et al; RELAX-AHF Investigators. Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: correlation with outcomes. J Am CollCardiol 2013;61:196–206.