RELAXin in Acute Heart Failure - RELAX-AHF
Relaxin is a peptide hormone secreted during pregnancy that is associated with significant hemodynamic changes including increasing cardiac output and decreasing systemic vascular resistance. A similar pharmacological profile might have beneficial effects in patients with acute decompensated heart failure (ADHF). Serelaxin is a recombinant version of human relaxin-2. The current trial sought to compare the safety and efficacy of serelaxin in patients presenting with ADHF.
Serelaxin would be superior to placebo in improving symptoms of dyspnea in patients presenting with ADHF.
- Placebo Controlled
- Hospitalized for AHF
- Dyspnea at rest or with minimal exertion
- Pulmonary congestion on chest radiograph
- BNP ≥350 pg/ml or NT-pro-BNP ≥1400 pg/ml
- Received ≥40 mg intravenous (IV) furosemide (or equivalent) at any time between admission to emergency services (either ambulance or hospital, including the emergency department) and the start of screening for the study
- Systolic blood pressure >125 mm Hg
- Impaired renal function on admission (eGFR 30-75 ml/min/1.73 m2)
- Randomized within 16 hours from presentation
- Age ≥18 years
- Body weight <160 kg
Number of enrollees: 1,161
Duration of follow-up: 6 months
Mean patient age: 72 years
Percentage female: 37%
Ejection fraction: 38.7%
New York Heart Association class: 1 month prior to admission: III (45%), IV (16%)
- Current or planned treatment with any IV therapies (i.e., other vasodilators, [nesiritide], positive inotropic agents and vasopressors) or mechanical circulatory, renal, or ventilatory support, with the exception of IV furosemide (or equivalent), or of IV nitrates if patient has screening systolic blood pressure >150 mm Hg
- ADHF and/or dyspnea from arrhythmias or noncardiac causes, such as lung disease, anemia, or severe obesity
- Infection or sepsis requiring IV antibiotics
- Pregnant or breast-feeding
- Stroke within 60 days
- Acute coronary syndrome within 45 days
- Major surgery within 30 days
- Presence of acute myocarditis, significant valvular heart disease, hypertrophic/restrictive/constrictive cardiomyopathy
- Improvement in dyspnea between baseline an day 5, as measured by the VAS AUC
- Moderately or markedly improved patient-reported dyspnea relative to the start of study drug using the Likert scale at 6, 12, and 24 hours
- Worsening CHF
- Days alive and out of the hospital at day 60
- CV death/CHF or renal failure related hospitalization within 60 days
Patients were randomly assigned in a 1:1 ratio to receive either serelaxin 30 μg/kg/day or placebo.
Angiotensin-converting enzyme inhibitors (55%), angiotensin-receptor blockers (16%), beta-blockers (69%), intravenous loop diuretics (99.5%)
A total of 1,161 patients had been randomized, 581 to serelaxin and 580 to placebo. Baseline characteristics were fairly similar between the two arms. Median baseline ejection fraction was 38.7%, and about 52% had an ischemic cardiomyopathy. More than one third of these patients were hospitalized with CHF within the past year. An implantable cardioverter-defibrillator (ICD) was present in 14% and AF in 41%. The median estimated glomerular filtration rate (eGFR) at baseline was 53.5 ml/min/1.73 m2.
The primary endpoint of improvement in visual analog scale (VAS) area under the curve (AUC) between baseline and day 5 was significantly lower in the serelaxin arm as compared with the placebo arm (2436 vs. 2033 mm/hr, p = 0.007). This was true when compared with baseline at day 14 as well (8122 vs. 6855, p = 0.017). VAS score improvements were noted as early as 1 day (21.7 vs. 25.0 mm, p = 0.021) and increased steadily to day 5 (27.8 vs. 33.3 mm, p = 0.011). The coprimary endpoint of moderate to marked improvement in dyspnea as measured by the Likert scale was numerically lower but statistically not significant in the serelaxin arm at 6 hours (36% vs. 31%, p = 0.11), 12 hours (50% vs. 45%, p = 0.051), and 1 day (68% vs. 63%, p = 0.09). Favorable changes were noted in N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) (≥30% decrease at day 2: 69% vs. 58%, p = 0.0002) and creatinine (≥30% increase at day 2: 10.9% vs. 19.8%, p < 0.0001).
Clinical outcomes including cardiovascular (CV) death/CHF or renal failure related rehospitalization were similar between the two arms at 60 days (7.5% vs. 6.9%, hazard ratio 1.08, 95% confidence interval 0.70-1.66, p = 0.73). Similarly, 30-day mortality (2.1% vs. 3.3%, p = 0.20) and 30-day CV mortality (p = 0.24) were similar. However, all-cause (7.3% vs. 11.3%, p = 0.02) and CV death (6% vs. 9.5%, p = 0.028) were lower at 180 days in the serelaxin arm. Length of initial hospitalization was shorter in the serelaxin arm (9.1 vs. 9.6 days, p = 0.039). On subgroup analysis, mortality benefits were higher in patients ≥75 years, with no previous CHF hospitalization, not treated with beta-blockers at baseline, and GFR <50 ml/min.
Worsening CHF within the first 5 days of the index hospitalization (intensification of intravenous therapy for HF or mechanical ventilatory or circulatory support) was lower in the serelaxin arm (6.7% vs. 12.2%, p = 0.0016).
There were significantly greater decreases from baseline in systolic blood pressure during infusion (up to 48 hours) and after infusion (24 hours after discontinuation) in the serelaxin group compared with the placebo group (approximately 4-6 mm Hg difference). Adverse events related to renal impairment (6% vs. 9%, p = 0.03) and hypotension-related events at day 5 (5% vs. 4%, p = 0.78) were similar between the two arms.
The results of the RELAX-AHF trial indicate that a 48-hour infusion of serelaxin, a recombinant version of human relaxin (a peptide hormone secreted during pregnancy), is associated with improvements in dyspnea by day 5, lower rate of worsening HF during index hospitalization, reduced length of stay, but no difference in clinical outcomes at 60 days in patients presenting with ADHF. However, at 6-month follow-up, all-cause and CV mortality were both significantly reduced. There was no effect on rehospitalizations for CHF/renal failure. These results are very interesting, but further larger studies are needed to replicate these findings in this patient population. The subgroup analyses are also hypothesis-generating. Cost-effectiveness analyses are awaited.
Presented by Dr. John Teerlink at the European Society of Cardiology Congress, Barcelona, Spain, September 1, 2014.
Metra M, Ponikowski P, Cotter G, et al. Effects of serelaxin in subgroups of patients with acute heart failure: results from RELAX-AHF. Eur Heart J 2013;34:3128-36.
Metra M, Cotter G, Davison BA, et al. Effect of Serelaxin on Cardiac, Renal, and Hepatic Biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) Development Program: Correlation With Outcomes. J Am Coll Cardiol 2013;61:196-206.
Presented by Dr. Marco Metra at the European Society of Cardiology Congress, Amsterdam, Holland, September 2, 2013.
Teerlink JR, Cotter G, Davidson BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 2012;381:29-39.
Presented by Dr. John Teerlink at the American Heart Association Scientific Sessions, Los Angeles, CA, November 6, 2012.
Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Implantable Devices, SCD/Ventricular Arrhythmias, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: Follow-Up Studies, Area Under Curve, Body Weight, Hypotension, Cardiac Output, Blood Pressure, Creatinine, Dyspnea, Furosemide, Hemodynamics, Length of Stay, Renal Insufficiency, Cardiomyopathies, Visual Analog Scale, Heart Failure, Peptide Fragments, Glomerular Filtration Rate, Vascular Resistance, Confidence Intervals, Relaxin, Defibrillators, Implantable, Natriuretic Peptide, Brain, ESC Congress
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