No improved outcomes with serelaxin in acute HF
Effects of Serelaxin in Patients with Acute Heart Failure
Introduction and methods
Of patients hospitalized with acute heart failure (HF), 10-15% have worsening HF [1-3] and 10-15% die within 60-90 days after discharge . Risk of death in hospitalized patients is 5-10 fold higher compared to patients who have not been hospitalized, even months after the episode, suggesting that congestion and end-organ damage accelerate disease progression and increase risk of mortality [5,6].
Relaxin is a hormone that plays a role in changes in CV and renal function during pregnancy [7,8]. It has vasodilatory, antifibrotic and anti-inflammatory effects  and protective effects on end organs. Serelaxin, a recombinant form of human relaxin-2, reduced incidence of worsening HF during hospitalization and in an exploratory analysis lowered CV mortality at 180 days compared to placebo in the Relaxin in Acute Heart Failure (RELAX-AHF) trial . However, the RELAX-AHF trial was not powered to test the effect of seralaxin on CV mortality. Therefore, a second trial, the RELAX-AHF-2, was designed to test the effect of serelaxin on the primary outcomes CV mortality at 180 days and incidence of worsening HF in the first 5 days.
RELAX-AHF-2 was a multicenter, randomized, double-blind, placebo-controlled, event-driven trial examining the effect of serelaxin compared to placebo in patients with acute HF. Patients were eligible when they were hospitalized for acute HF with dyspnea, congestion, elevated plasma levels of natriuretic peptides, SBP ≥125 mmHg, mild-to-moderate renal impairment. From October 2013 to February 2017, 6600 patients were enrolled and randomized within 16 hours after presentation at the hospital to receive a 48-hr IV infusion of serelaxin or placebo, in addition to standard care. Co-primary endpoints were death from CV causes at 180 days and worsening HF at 5 days. Endpoint of worsening HF also included death from any cause and rehospitalization for HF.
Infusions were discontinued in 21.9% in the serelaxin group and 15.7% in the placebo group, mainly due to a too large decrease in SBP (18.5% and 12.5%, respectively).
- Mean blood pressure was lower in the serelaxin group compared to the placebo group after 30 min of infusion and remained lower for 3 days.
- At day 180, there was no difference in incidence of death due to CV causes between the two groups (8.7% in the serelaxin group and 8.9% in the placebo group, HR:0.98, 95%CI:0.83-1.15, P=0.77).
- No difference in HF worsening at day 5 was observed between the groups (6.9% in the serelaxin group vs. 7.7% in the placebo group, HR:0.89, 95%CI: 0.75-1.07, P=0.19).
- Secondary endpoints of incidence of death from any cause at 180 days, death from CV causes or rehospitalization for HF or renal failure and median length of stay were similar in the 2 groups.
- Percentage of patients that experienced at least one adverse event was similar in the groups (53.1% in the serelaxin group and 52.1% in the placebo group).
Infusion with serelaxin for 48 hours in patients who were hospitalized for acute HF did not reduce CV death at day 180, nor HF worsening after 5 days compared to placebo in the RELAX-AHF-2 trial.
Milton Packer started his editorial comment  by saying that for a long time physicians believed that all patients with HF had acute HF and that HF was resolved after diuresis. The chronicity of HF was for a long time not recognized.
In the 1980s research on therapies for HF started and found that combination therapy with neurohormonal antagonists reverses ventricular remodeling and improves outcomes. Use of these drugs in primary care has been suboptimal (one of the reason may be the clinically silent progression of the disease) and physicians have focused on treating worsening HF episodes. In the 1980s, episodes of worsening HF were often dramatic and life-threating, and response after therapy was fast and lifesaving.
Nowadays, most hospitalized patients with worsening HF do not have a new acute disorder, but rather decompensation of chronic underlying ventricular dysfunction. This is a result of a gradual progressive increase in cardiac filling pressure during the previous weeks, which is often not immediately life-threatening.
Packer continued by mentioning that although most patients recover within days after intensification of medical therapy, early release of troponin is observed, indicative of myocardial injury. He then asked: ‘Could emergency interventions to reduce volume overload salvage a few cardiomyocytes, which might (in turn) have benefits for long-term prognosis?’ And ‘is decompensated heart failure similar to an acute coronary syndrome, for which it is critical to perform an emergency intervention to minimize irreversible cardiac injury?’
He concludes that decompensation is not an acute disease or an indicator that requires immediate intervention. It is important to stabilized patients, but even more important is to treat patients between hospitalizations to improve outcomes. ‘A focus on intensive outpatient care (rather than an obsession with inpatient therapy) is needed to reduce the burden of HF’.