Relaxin receptor agonist did not meet primary endpoints in phase 3 study in acute heart failureNews - Apr. 29, 2017
Paris, France | RELAX-AHF-2: Serelaxin in acute heart failure
Presented at ESC Heart Failure 2017 by: John R TEERLINK (San Francisco, United States of America) and Marco METRA (Brescia, Italy)
- CV mortality through day 180 was similar for patients receiving serelaxin (285 in 3274, 8.7%) or placebo (290 in 3271, 8.9%, HR: 0.98, 95%CI: 0.83-1.15, P-value: 0.3857).
- WHF through day 5 was nominally lower with serelaxin but this did not reach significance (serelaxin: 6.9%, placebo: 7.7%, HR: 0.89, 95%CI: 0.75-1.07, P=0.0968).
- All-cause mortality through day 180 did not differ significantly between treatment groups (11.2% with serelaxin vs. 11.9% with placebo, HR: 0.94, 95%CI: 0.81-1.08, P=0.3890).
- The Kaplan-Meier curves of CV death or rehospitalisation due to heart/renal failure through day 180 for both treatment largely overlapped (24.3% vs. 24.9%, HR: 0.97, 95%CI: 0.88-1.07, P=0.2744).
- Length of hospital stay did not significantly differ between treatments (median duration on serelaxin: 6.824 days, vs placebo: 6.857, mean difference: -0.183, 95%CI: -0.645 to 0.280).
- Safety analyses confirmed the safe use of serelaxin.
All primary and key secondary efficacy results of the RELAX-AHF-2 study were neutral, and no new safety concerns were observed. These results do not confirm a benefit of serelaxin for the treatment of AHF patients.
Dr. Teerlink more specifically discussed the results. He showed that no pre-specified subgroups were identified that preferentially benefit from treatment with serelaxin, with regard to adjudicated CV death, nor to WHF through day 5.
In search of explanations for the differences seen in the results of RELAX-AHF-1 and -2, he compared the observed systolic blood pressure (SBP) during study drug infusion in both treatment groups. In both studies, the SBPs for both treatment arms overlapped well. Thus, it was concluded that the pharmacological effect was the same in both studies, in terms of the vasodilatory effect.
When comparing key selected variables, only NT-proBNP differed between the populations of both studies, which was a difference by design. Patients in RELAX-AHF-2 had higher values, and were sicker.
Comparing outcome rates in the placebo groups of both studies, revealed that fewer patients on placebo in RELAX-AHF-2 showed WHF through day 5 as compared to the earlier, smaller RELAX-AHF-1 study (7.7% vs. 12.0%). All-cause death was a little higher in RELAX-AHF-2 (11.9% vs. 11.3% in AHF-1), with CV death accounting for 9.0% and 9.6% respectively in study 2 and 1, and non-CV death for 3.0% and 1.7%. During the discussion, dr. Alexandre Mebazaa (Paris, France) noted that clearly the placebo group is doing better every year. This is, however, not seen in daily practice. It was suggested that studies should select patients in worse conditions, to approach daily clinic more, and to find more benefit of the drug, as biological and clinical data do suggest that it works.
A biomarker substudy in about 1000 patients indeed confirm effects of serelaxin on cardiac and renal biomarkers (lower hs-TnT, lower NT-proBNP and lower Cystatin C). A posthoc analysis in this substudy showed a nominal improvement in WHF through day 5 (4.7% vs. 7.7%, HR: 0.60, 95%CI: 0.36-0.98, P=0.0286).
Dr. Frank Ruschitzka (Zurich, Switzerland) concluded that the field has been misled by the analogy to ACS. He stated that we do not know the enemy, and do not have a treatment. Treatment with serelaxin may remain a good rationale, as there are ‘glimpses of hope in the clinical data’. But heart failure is not one disease, but rather hundreds. So he thinks that we need to go more selective and identify patients better who might benefit from a specific treatment. This view was also expressed by others in this discussion. Dr. John Cleland (London, Great Britain) and Milton Packer (Dallas, USA) agreed that novel studies should take a different approach
In addition, the option to treat earlier was considered, possibly by identifying patients while still at home, rather than only starting treatment at presentation. Decompensation often starts in the weeks, not hours, before admission. Repeated admission might be worth exploring as well.
Our coverage of ESC HF 2017 is based on the information provided during the congress.