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RELAX-AHF: Administration of serelaxin to patients with acute heart failure: are the any differences across RELAX- AHF subgoups?

Heart Failure (HF)

Presenter abstract
Discussant report
All the Scientific resources on ESC Congress 365


By Marco Metra
John R Teerlink, San Francisco, CA, US; Gad Cotter, Durham, NC, US; Beth Davison, Durham, NC, US; G. Michael Felker, Durham, NC, US; Gerasimos Filippatos, Athens, Greece; Barry H Greenberg, San Diego, CA, US; Tsushung Hua, Hannover, NJ, US; Piotr Ponikowski, Wroclaw, Poland; Elaine Unemori, San Carlos, CA, US; Adriaan A. Voors, Groningen, Netherlands; Thomas M Severin, Basel, Switzerland; On Behalf of the RELAX-AHF Investigators.

In RELAX-AHF, serelaxin improved the Visual Analogue Scale (VAS) Area Under the Curve dyspnoea primary endpoint, reduced cardiovascular (CV) and all-cause death at 180 days and had no effect on the change in dyspnoea by the 7-level Likert scale (other primary endpoint) and on the secondary endpoints of CV death or heart failure (HF)/ renal failure rehospitalization and days alive and out of the hospital before day 60.

We assessed the effects of serelaxin versus placebo in multiple pre-specified and other subgroups of interest with respect of the two primary endpoints of dyspnoea relief, the secondary endpoint of outcomes at day 60, and CV death and all-cause death at day 180.
Results. The improvement by serelaxin in the VAS dyspnoea endpoint as well as its neutral effect on the Likert scale and on the 60 days outcomes endpoint were similar across all of the subgroups. Similar results, with no difference between subgroups, were also found with respect to most of the subgroups for 180 day CV and all-cause mortality. However, results suggest that serelaxin effects may be larger in patients aged >75 years, patients with no prior HF hospitalization, patients with atrial fibrillation, patients with lymphocytes ≤ 12%, and patients not receiving ACE inhibitors or aldosterone antagonists just prior to baseline.

The effects of serelaxin versus placebo were homogenous across multiple subgroups with respect to the primary dyspnoea relief endpoints, 60-day composite outcomes, and 180-day mortality. Larger benefits were seen in elderly patients, patients with no previous HF hospitalization, atrial fibrillation, and not previously treated with antagonists of the renin-angiotensin-aldosterone system, and those with inflammation. However, the present study is underpowered for the subgroup analyses and many analyses were performed. Thus, these results must be considered as hypothesis-generating. 

Discussant Report

Roland Schmieder
In the last years new treatment strategies for acute heart failure have either failed to demonstrate clinical benefits in randomized controlled clinical trials or safety issues have emerged that limited their clinical use (e.g. tolvaptan, rolofylline, nesiritide, levosimendan) [1].
In the RELAX-AHF trial serelaxin was associated with dyspnea relief, (primary objective), but no effect on readmission to hospital for heart or renal failure or on cardiovascular death through day 60 was observed. However, at day 180 a significant decline in cardiovascular and all cause death rates was noted [2] [3].

The authors now present an extensive subgroup analysis confirming the major finding of the already published RELAX-AHF study, namely that the effects of serelaxin vs. placebo were homogenous and consistent across multiple subgroups with respect to dyspnea relief and the two secondary efficacy endpoints. However, nominally significant treatment-by-subgroup interactions were observed with the better mortality rate at day 180 in patients older than 75 years, in those with HF hospitalization in the previous year, with lack of betablocker treatment at baseline, and estimated glomerular filtration rate < 50 ml/min/1.73 m².

From a statistical perspective the results may be criticized due to the large number of subgroups (n=23) in face of the population size (n=1161) and event rates (n=90 for cardiovascular and n=107 for all cause death during the first 180 days) [4]. Unfortunately, the definition of the subgroups did not follow a strict guidance but were triggered by regulatory requirements and academic purposes, and not all were pre-specified.

From a clinical perspective the now presented information is relevant, the effects of serelaxin are not restricted to certain subgroups, and new hypothesis have been generated that could be tested in the upcoming RELAX-AHF-2 trial comprising more than 6,000 patients and having mortality as primary endpoint.

Interestingly, estimated glomerular filtration rate < 50 ml/min/1.73m² was linked to lower mortality at day 180 which nicely corresponds to the strong vasodilatory effect of serelaxin on the renal vasculature [2]. Whether indeed serelaxin may have particular benefits in patients with reduced renal function (which has been repeatedly shown to indicate worse outcome in heart failure patients) needs yet to be proven, hopefully in the RELAX-AHF-2 trial [5] [6].

In conclusion, the authors should be congratulated for the thorough, extensive and somewhat exhausting subgroup analysis confirming consistent efficacy data among various subgroups, and interesting hypothesis have been generated from the treatment-by-subgroup-interaction with respect to mortality.

Potential question:
No treatment by subgroup interaction with respect to the decline in systolic blood pressure to serelaxin infusion was analyzed (in the pre-RELAX-AHF with a greater early drop in systolic blood pressure was found to be an independent predictor of worsening renal function in AHF).

1 - McMurray, JJ, Adamopoulos, S, Anker, SD, Auricchio, A, Bohm, M, Dickstein, K, Falk, V, Filippatos, G, Fonseca, C, Gomez-Sanchez, MA, Jaarsma, T, Kober, L, Lip, GY, Maggioni, AP, Parkhomenko, A, Pieske, BM, Popescu, BA, Ronnevik, PK, Rutten, FH, Schwitter, J, Seferovic, P, Stepinska, J, Trindade, PT, Voors, AA, Zannad, F, Zeiher, A. 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.
2 - Teichman, SL, Unemori, E, Dschietzig, T, Conrad, K, Voors, AA, Teerlink, JR, Felker, GM, Metra, M, Cotter, G. Relaxin, a pleiotropic vasodilator for the treatment of heart failure. Heart Fail Rev. 2009;14:321-329.
3 - Teerlink, JR, Cotter, G, Davison, BA, Felker, GM, Filippatos, G, Greenberg, BH, Ponikowski, P, Unemori, E, Voors, AA, Adams, KF, Jr., Dorobantu, MI, Grinfeld, LR, Jondeau, G, Marmor, A, Masip, J, Pang, PS, Werdan, K, Teichman, SL, Trapani, A, Bush, CA, Saini, R, Schumacher, C, Severin, TM, Metra, M. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet. 2013;381:29-39.
4 - Assmann, SF, Pocock, SJ, Enos, LE, Kasten, LE. Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet. 2000;355:1064-1069.
5 - Logeart, D, Tabet, JY, Hittinger, L, Thabut, G, Jourdain, P, Maison, P, Tartiere, JM, Solal, AC. Transient worsening of renal function during hospitalization for acute heart failure alters outcome. Int J Cardiol. 2008;127:228-232.
6 - Metra, M, Cotter, G, Gheorghiade, M, Dei Cas, L, Voors, AA. The role of the kidney in heart failure. Eur Heart J. 2012;33:2135-2142.




RELAX-AHF: Administration of serelaxin to patients with acute heart failure: are the any differences across RELAX- AHF subgoups?

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.