Preliminary study of RELAXin in Acute Heart Failure - Pre-RELAX-AHF

Apr 27, 2009
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Corthera (USA)
Date Published:
01/01/2009
Date Updated:
04/27/2009
Original Posted Date:
04/27/2009
References

Description:

The goal of the trial was to evaluate treatment with relaxin, a natural human peptide, compared with placebo in patients with acute heart failure. This was a dose-finding phase IIb study.

Hypothesis:

Relaxin would be more effective in symptom relief.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patients Enrolled: 234
NYHA Class: I - 0%, II - 35%, III - 43%, IV - 13%
Mean Follow Up: 180 days
Mean Patient Age: 72 years
Female: 47%
Mean Ejection Fraction: 48% of patients with left ventricular ejection fraction <40%

Patient Populations:

  • Patients at least 18 years of age within 16 hours of presentation for acute heart failure; systolic blood pressure at least 125 mm Hg; and renal insufficiency, defined as a glomerular filtration rate 30-75 ml/min/1.73 m2
  • Acute heart failure was defined as dyspnea at rest or minimal exertion, pulmonary congestion on chest radiograph, and elevated BNP (≥350 pg/ml) or NT-proBNP (≥1400 pg/ml).

Exclusions:

  • Need for intravenous inotropic support
  • Fever
  • Severe pulmonary disease
  • Stenotic valvular heart disease
  • Acute coronary syndrome within the last 45 days
  • Troponin concentration more than 3 times the upper limit of normal

Primary Endpoints:

  • Relief of dyspnea as assessed by the Likert scale
  • In-hospital worsening of heart failure from baseline to day 5
  • Worsening of renal function
  • Length of hospital stay
  • Days alive out of the hospital up to day 60
  • Cardiovascular mortality or readmission for heart failure up to day 60
  • Cardiovascular mortality up to day 180

Drug/Procedures Used:

Patients admitted with acute heart failure were randomized to intravenous placebo (n = 62) or one of four doses of intravenous relaxin for 48 hours: 1) 10 µg/kg daily (n = 40), 2) 30 µg/kg daily (n = 43), 3) 100 µg/kg daily (n = 39), or 4) 250 µg/kg daily (n = 50).

Concomitant Medications:

At baseline, in the relaxin 10 µg/kg daily dose, the use of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker was 65%, nitrate was 25%, beta-blocker was 58%, calcium-channel blocker was 20%, aldosterone inhibitor was 33%, and digoxin was 30%.

Principal Findings:

Overall, 234 patients were randomized. There was no difference in baseline characteristics between the groups. For the relaxin 10 µg/kg group, which was representative of the other study groups, the mean age was 72 years, 47% were women, 63% had ischemic heart disease, 33% had diabetes, 70% had an N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) level >2000 ng/L, the mean systolic blood pressure was 145 mm Hg, and the mean pulse was 81 bpm.

The proportion of patients with moderately or markedly improved dyspnea was 28% with 10 µg relaxin (p = 0.54 compared with placebo), 40% with 30 µg (p = 0.044), 14% with 100 µg (p = 0.28), 22% with 250 µg (p = 0.86), and 23% with placebo.

Worsening heart failure through day 5 occurred in 20% of the 10 µg relaxin group (p = 0.75 compared with placebo), 12% of the 30 µg group (p = 0.29), 14% of the 100 µg group (p = 0.40), 10% of the 250 µg group (p = 0.15), and 21% with placebo. Cardiovascular death through 180 days occurred in 2.5% (p = 0.15 compared with placebo), 0% (p = 0.046), 2.9% (p = 0.17), 6.2% (p = 0.53), and 14.3%, respectively.

Patients with any serious adverse event through 30 days occurred in 18%, 17%, 8%, 16%, and 16%, respectively. More than 25% increase in serum creatinine through 5 days occurred in 10%, 21%, 29%, 24%, and 13%, respectively.

Interpretation:

Among patients admitted with decompensated heart failure, preserved blood pressure, and mild renal insufficiency, the use of relaxin appeared to be effective in improving heart failure symptoms. Among the four doses of relaxin, the 30 µg/kg daily dose appeared to produce the most benefit in dyspnea improvement relative to placebo. Worsening heart failure through 5 days was lowest in the 30 µg and 250 µg groups, although these differences were nonsignificant. Cardiovascular mortality through 180 days was significantly reduced in the 30 µg group. Serious adverse events were evenly distributed among the groups. Serum creatinine increase of more than 25%, ranged from 10% in the 10 µg group, to 13% with placebo, to 29% in the 100 µg group.

Relaxin is an endogenous human peptide that may produce beneficial clinical effects in heart failure patients through its vasodilatation properties. There were no important safety signals from this trial. This study provides support to the development of a larger phase III trial (RELAX-AHF-1) that would study relaxin (30 µg per kg daily) versus placebo on clinical outcomes.

References:

Teerlink JR, Metra M, Felker GM, et al. Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomized, placebo-controlled, parallel-group, dose-finding phase IIb study. Lancet 2009;373:1429-39.

Keywords: Myocardial Ischemia, Renal Insufficiency, Vasodilation, Heart Failure, Peptide Fragments, Blood Pressure, Glomerular Filtration Rate, Creatinine, Dyspnea, Relaxin, Diabetes Mellitus, Natriuretic Peptide, Brain


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