Treatment of chronic heart failure (HF) is underpinned by a firm evidence base. The same cannot be said for most acute HF but this may be set to change, as discussed at the British Society for Heart Failure (BSH) Annual Day for Training and Revalidation. Held on February 7th 2013, at the Wellcome Collection Conference Centre, London, this meeting included a number of excellent presentations and interactive case-based discussions focussing on particularly challenging and controversial issues. Dr Michael Pope reports on some of the highlights.
A new treatment for acute heart failure?
The recently published RELAX-AHF (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure) study was a prospective, randomised, double-blind, placebo-controlled trial carried out in a targeted population of patients with acute HF.1 Relaxin is a physiological hormone that regulates maternal adaptations to pregnancy, increasing cardiac output, renal blood flow, and arterial compliance, alongside decreased peripheral vascular resistance.2,3 Serelaxin is a recombinant human relaxin-2 shown to have beneficial effects on symptoms and outcomes in early studies.4
The primary end points in this study were measures of patient reported dyspnoea at six, 12, and 24 hours. According to the visual analogue scale area under the curve (AUC), serelaxin significantly improved symptoms. Most intriguing was the unexpected finding that serelaxin was associated with significantly reduced cardiovascular and all-cause mortality at 180 days. Furthermore, serelaxin was associated with decreased use of intravenous loop diuretics, decreased length of initial hospital stay, and of intensive care or cardiac care days.
Many aspects of these results, however, preclude us from declaring serelaxin the new ‘wonder drug’. Professor Theresa McDonagh (King’s College London) pointed out that this HF patient population, by nature of the exclusion of patients with a systolic blood pressure ≤125 mmHg creates a fairly low risk population making it difficult to extrapolate the findings to other patients.
Equally, it’s difficult to translate statistical significance into actual clinical significance. In particular, a “448 mm x h” increase in AUC seems an obscure measurement of genuine improvement in dyspnoea. Nonetheless, the finding is supported by the decreased use of diuretics, and fewer patients experiencing worsening heart failure in the serelaxin-treated group. The data regarding 180-day mortality also needs to be interpreted cautiously.
Professor John McMurray (University of Glasgow) highlighted the delicacy of the statistical significance when the number of events is small, the trial not powered for this analysis, and this was not a pre-specified primary end point. Furthermore, this result is not supported by the hospitalisation statistics, which show no significant difference in death or readmission at either 30 or 60 days.
Professor McMurray also contrasted these results with that of the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial of the novel drug nesiritide, a recombinant B-type natriuretic peptide.5 This demonstrated no significant difference in dyspnoea or 30 day outcomes between nesiritide and placebo, in combination with standard therapies. Nesiritide however was associated with increased rates of hypotension.
The measurement used for dyspnoea here was the Likert scale, which although showing a trend towards improved dyspnoea, did not reach statistical significance. This was also found with serelaxin, which only reached statistical significance when measured using the AUC on the visual analogue scale.
Nevertheless, the findings are potentially exciting, demonstrate the clinical safety of serelaxin, and suggest interesting potential for this new therapy. Further studies are awaited with considerable interest.
The next Heart Failure Day for Training and Revalidation will take place on 20th March 2014, in Glasgow.
The BSH also gratefully acknowledges the support provided by the Friends of BSH: Alere, Edwards Lifesciences, HeartWare, Medtronic, Novartis, Pfizer, Servier, St. Jude Medical and Thoratec.
Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Cosham, Portsmouth PO6 3LY
1. Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 2013;381:5–11. http://dx.doi.org/10.1016/S0140-6736(12)61855-8
2. Conrad KP. Maternal vasodilation in pregnancy: the emerging role of relaxin. Am J Physiol Regul Integr Comp Physiol 2011;301:R267–R275. http://dx.doi.org/10.1152/ajpregu.00156.2011
3. Teichman SL, Unemori E, Teerlink JR, Cotter G, Metra M. Relaxin: review of biology and potential role in treating heart failure. Curr Heart Fail Rep 2010;7:75–82. http://dx.doi.org/10.1007/s11897-010-0010-z
4. Teerlink JR, Metra M, Felker GM et al. Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study. Lancet 2009;373:1429–39. http://dx.doi.org/10.1016/S0140-6736(09)60622-X
5. 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. http://dx.doi.org/10.1056/NEJMoa1100171