Effect of Serelaxin on Cardiac, Renal, and Hepatic Biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) Development Program: Correlation With Outcomes

Study Questions:

Does administration of serelaxin, a recombinant form of human relaxin-2 (a hormone that assists in adaptation to pregnancy-mediated physiologic cardiovascular changes), to patients with acute heart failure (HF) reduce myocardial and end-organ damage?

Methods:

This was a secondary analysis of the RELAX-AHF trial, which was a double-blind, randomized, placebo-controlled trial of intravenous serelaxin in patients presenting with acute HF and signs of congestion. Changes in high-sensitivity myocardial troponin T (hs-TnT, a correlate of myocardial damage), N-terminal pro–B-type natriuretic peptide (NT-proBNP), serum creatinine and cystatin-C (marker of renal dysfunction), and alanine aminotransferase (ALT, marker of liver injury) were assessed by treatment group.

Results:

Overall, higher hs-TnT levels and worsening renal and hepatic function were associated with increased 180-day all-cause mortality. There were 1,161 patients randomized (n = 581 to serelaxin). Mortality at 180 days was lower in patients treated with serelaxin (adjusted hazard ratio, 0.64; 95% confidence interval, 0.43-0.95). Baseline hs-TnT levels were similar between treatment groups, but were significantly lower at day 2 in patients treated with serelaxin (p = 0.013). Similarly, while serum creatinine, cystatin C, NT-proBNP, and ALT were similar between groups at baseline, patients treated with serelaxin had significant improvements in all measures after 2 days of therapy.

Conclusions:

The authors concluded that patients treated with serelaxin had improved outcome after therapy, with concomitantly less end-organ damage and congestion.

Perspective:

This study points out how critical timing is in defining a trial endpoint. The RELAX-AHF study, as originally published, did not yield significant differences in the combined primary outcome (death, readmission) at 60 days. However, in the present analysis, patients treated with the agent had significantly better survival at 180 days, with large separations in the Kaplan-Meier survival curve occurring after 60 days. The improvement in outcome, not surprisingly, mirrored improvements in end-organ function. Readmission rates are critical endpoints in the era of ‘accountable care,’ but the impetus for readmission is confounded and certainly not standardized. Given the improvement in survival at 180 days, further study of serelaxin and its impact on survival and rates of renal failure at 1 year is warranted.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Biological Markers, Heart Failure, Troponin T, Creatinine, Relaxin, Pregnancy, Cystatin C, Natriuretic Peptide, Brain


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