Thursday, September 04, 2014

Alert - UpdatesPlus-Heart Failure: RELAX-AHF data reported at ESC describing the impact of worsening HF and the preventative effect of serelaxin

This alert comes from our UpdatesPlus - Heart Failure servicea regular analysis providing depth information on all key recent events in the area.  To receive further information or instruction on how to access the service please contact

  • Novartis has developed human recombinant Relaxin-2 as serelaxin for the potential treatment of AHF
  • Teerlink et al previously reported co-primary endpoints from Phase 2/3 RELAX-AHF study
  • Only one co-primary endpoint (AUC dyspnea over 5d, a composite of patient’s reported dyspnea on a visual analog scale and the events of worsening heart failure or death) was met with the second (moderate/marked dyspnea over 24hr) not met in the overall study cohort.  The study was however prospectively designed and powered to allow the trial to be considered positive if it met only one of the primary endpoints with a p less than 0.025  (OR both primary endpoints with a p less than 0.05)

  • The p value of 0.0075 on the AUC dyspnea over 5d measure was enough to consider the trial positive, but was insufficient for product approval by the FDA which demands a p less than 0.00125 to be considered sufficiently positive for approval on the basis of a single trial. 

  • RELAX-AHF specified worsening in-hospital HF as part of the primary endpoint to be recorded in the study and these data were presented for the first time by John Teerlink at ESC
  • Worsening heart failure was defined as worsening HF signs and symptoms requiring intensified IV therapies or device support
  • RELAX-AHF reported prolonged IV therapies with worsening HF
  • The study reported important findings regarding the impact of worsening HF, including increases in various biomarkers (NT-proBNP, hs-cTroponin T and Cystatin-C);  hospital stay (+4.9d in ICU; +8d total hospital stay) and mortality 
  • Given the impact of worsening HF and the fact that the AUC dyspnea relief through 5d primary endpoint appeared to be driven by worsening heart failure, the ESC presentation delivered data on the impact of serelaxin on worsening heart failure. 
  • RELAX-AHF reported a significant, approximately 50% reduction in death or worsening HF in patients treated with serelaxin vs placebo over 5d
  • Of interest, approximately 12% of patients with worsening HF suffered recurrent worsening over 5d and serelaxin significantly reduced both first and recurrent events from a total of 85 events in the placebo- to 41 events in the serelaxin-treated group

Comments:  Despite the serious consequences of worsening HF and the fact that serelaxin appears to reverse this, the FDA review did not accept these data for supporting approval.  This was because RELAX-AHF was a single trial for this new therapeutic agent in an area with multiple failed trials. In addition, while the primary endpoint was significantly improved, the appropriateness of assignment of the worst score to the patients with worsening heart failure was debated. Although the importance of the worsening heart failure events was acknowledged, it was not the primary endpoint, neither were they adjudicated or, according to the reviewer, rigorously measured.  RELAX-AHF also revealed the exciting observation that all-cause and CV mortality were reduced, a finding previously suggested in the Phase 2 Pre-RELAX-AHF study. This possibly mortality benefit prompted the start of Phase 3 RELAX-AHF-2 with CV mortality selected as a primary endpoint.  A second study, the open-label RELAX-AHF-EU study is evaluating worsening HF or mortality at 5d, while RELAX-AHF-Asia is evaluating the effects of serelaxin on a clinical composite within the first 5 days including worsening of heart failure.  If these studies can confirm a reduction in worsening HF or mortality, serelaxin may offer a significant advance.  This would not only be in terms of potential cost savings (as a very rough estimate we suggest the cost of increased ICU and total hospital stay alone could be as high as $30-40,000/patient) but also in terms of mortality.  RELAX-AHF suggests that for every 100 pts treated, 6 may avoid worsening HF, saving a considerable amount in healthcare resources


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