Prof John R Teerlink MD a , Gad Cotter MD b, Beth A Davison PhD b, G Michael Felker MD c, Prof Gerasimos Filippatos MD d,Prof Barry H Greenberg MD e, Prof Piotr Ponikowski MD f, Elaine Unemori PhD g, Prof Adriaan A Voors MD h, Kirkwood F Adams MDi, Prof Maria I Dorobantu MD j, Liliana R Grinfeld MD k, Prof Guillaume Jondeau MD l, Prof Alon Marmor MD m, Prof Josep MasipMD n, Peter S Pang MD o, Prof Karl Werdan MD p, Sam L Teichman MD g, Angelo Trapani PhD q, Christopher A Bush PhD q, Rajnish Saini MD q, Christoph Schumacher PhD r, Thomas M Severin MD r, Prof Marco Metra MD s, for the RELAXin in Acute Heart Failure (RELAX-AHF) Investigators
Presenter DisclosureInformationJohn R. Teerlink, M.D., F.A.C.C., F.A.H.A., F.E.S.C. Professor of Clinical Medicine, University of California, San Francisco Director of Heart Failure, San Francisco Veterans Affairs Medical CenterThe following relationships exist related to thispresentation:Consulting Fees and Grants Corthera, Inc. Significant Level
BackgroundSerelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo.
RelaxinPeptide hormoneSimilar in size and shape to insulin (MW 5963)Found in men and womenNormal hormone of pregnancyWomen “exposed” for 9 months to increased plasma concentrations:0.8-1.6 ng/ml pregnancy*Benign safety profile*Szlachter et al, Obstet & Gynecol 1982;59:167-70; Stewart et al, J Clin Endocrinol Metab 1990;70:1771-3.Relaxin
Relaxin Mechanisms of ActionVasodilation NO, cGMP effectors Induction of NOS II/III Upregulation of endothelialendothelin type B receptor,which mediates vasodilationPreferential dilation ofconstricted vessels Relaxin-upregulated ETBreceptors act as vasodilating ET-1sinkAnti-inflammatory Down-modulation ofinflammatory cytokines linked tooutcome in HF (TNF-α, TGF-β)Other: Anti-ischemic, Anti-apoptotic, Anti-fibroticRelaxin Receptor LGR7Teichman, SL, et al. Heart Fail Rev 2009; Dschietzig, T, et al. Pharmacol Therap 2006
Acute Heart Failure SyndromesHospitalizations over 1.1 million annually in U.S.and have tripled in last 3 decadesPost-discharge mortality (10-20%) andrehospitalization (20-30%) within 3-6 monthsApproximately 75-90% of patients have normal orelevated blood pressure on presentationApproximately 90% present with dyspneaCentral role of vasoconstriction(arterial, venous; systemic, pulmonary and renal)Neurohormonal activation/ InflammationMyocardial (subendocardial) ischemiaGheorghiade M, Pang P. J Am Coll Cardiol 2009;53:557–73.
RELAX-AHF was an international, double-blind,placebo-controlled trial, enrolling patients admittedto hospital for acute heart failure who were randomlyassigned (1:1) via a central randomisation schemeblocked by study centre to standard care plus 48-hintravenous infusions of placebo or serelaxin (30μg/kg per day) within 16 h from presentation.
All patients had dyspnoea, congestion on chestradiograph, increased brain natriuretic peptide (BNP)or N-terminal prohormone of BNP, mild-to-moderaterenal insufficiency, and systolic blood pressure greaterthan 125 mm Hg. Patients, personnel administeringstudy drug, and those undertaking study-relatedassessments were masked to treatment assignment.
The primary endpoints evaluating dyspnoeaimprovement were change from baseline in the visualanalogue scale area under the curve (VAS AUC) today 5 and the proportion of patients with moderate ormarked dyspnoea improvement measured by Likertscale during the first 24 h, both analysed by intentionto treat.
Enrollment:1161Study Start Date:October 2007Study Completion Date:September 2012Primary Completion Date:September 2012 (Final datacollection date for primary outcome measure)
Inclusion CriteriaHospitalized for acute heart failureDyspnea at rest or with minimal exertionPulmonary congestionAble to provide informed consentSystolic blood pressure > 125 mmHgImpaired renal function defined as an eGFR of 30-75mL/min/1.73m2
Exclusion Criteria:Use of other IV therapies for acute heart failureFever or sepsisRecent major neurologic eventRecent major surgeryRecent acute coronary syndromeOther recent investigational drug use
1161 patients were randomly assigned to serelaxin(n=581) or placebo (n=580). Serelaxin improved theVAS AUC primary dyspnoea endpoint (448 mm × h,95% CI 120—775; p=0·007) compared with placebo,but had no significant effect on the other primaryendpoint (Likert scale; placebo, 150 patients [26%];serelaxin, 156 [27%]; p=0·70
No significant effects were recorded for thesecondary endpoints of cardiovascular death orreadmission to hospital for heart failure or renalfailure (placebo, 75 events [60-day Kaplan-Meierestimate, 13·0%]; serelaxin, 76 events [13·2%]; hazardratio [HR] 1·02 [0·74—1·41], p=0·89] or days alive outof the hospital up to day 60 (placebo, 47·7 [SD 12·1]days; serelaxin, 48·3 [11·6]; p=0·37).
Serelaxin treatment was associated with significantreductions of other prespecified additional endpoints,including fewer deaths at day 180 (placebo, 65 deaths;serelaxin, 42; HR 0·63, 95% CI 0·42—0·93; p=0·019).
Cardiovascular Deaths to Day 1800 .80 .8 50 .90 .9 510 3 0 6 0 9 0 1 2 0 1 5 0 1 8 0DaysP la ce boR e la xin 1 0 m cg/kg/dR e la xin 1 0 0 m cg/kg/dR e la xin 2 5 0 m cg/kg/dR e la xin 3 0 m cg/kg/d(p< 0 .0 5 )
The FDA has granted "breakthrough therapy"designation to serelaxin (Novartis Pharmaceuticals),the novel recombinant form of human relaxin 2 thathas demonstrated promising clinical findings in acuteheart failure (AHF).