Serelaxin, A Novel Treatment for Acute Heart Failure- The RELAX-AHF Trial Prof. John R. Teerlink, MD, FAHA University of California, San Francisco and San Francisco VA Medical Center Prof. Marco Metra, MD University of Brescia, Brescia, Italy on behalf of the RELAX-AHF Executive and Steering Committees, Investigators & Patients Embargoed for 4:51pm PT, Tuesday, Nov. 6 LBCT-06 - J. Teerlink - RELAX-AHF
Pregnancy & the Heart PARAMETER PREGNANCY Cardiac Output (L/min) 20% Increase Systemic Vascular 30% Decrease Resistance (dyn.s.cm 2 ) Global Arterial Compliance 30% Increase (mL/mm Hg) Renal Blood Flow (mL/min/ 50-85% Increase 1.73m 2 ) Creatinine Clearance (mL/ 40-65% Increase min/1.73m 2 ) • Relaxin has been shown to mediate these changes, as well as to have anti-ischemic, anti-inflammatory, anti-fibrotic effects. • Relaxin is elevated through 9 months of pregnancy and mediates physiologic hemodynamic adjustments to growing baby • Pharmacologic use of serelaxin may produce these beneficial effects in acute heart failure Baylis, C. Am J Kid Dis 1999; Schrier, RW, et al. Am J Kid Dis 1987; Jeyebalan, A, et al. Adv Exp Med Biol 2007; Teichman SL et al. Curr Heart Fail Rep 2010;7:75–82. Helal I, et al. Nature Reviews 2012;293-300.
Pre-RELAX-AHF Teerlink JR, et al. Lancet 2009;373:1429-39. CV Death (KM) • 234 patient, dose finding Phase II Events n (KM%) study 16 HR 0.25 7 (14%) • Optimal dose across multiple clinical (0.08-0.79) Placebo 14 outcome domains was 30mcg/kg/d (n=42) P=0.019 • Serelaxin had trends to: 12 - Improved dyspnea relief 10 - Decreased congestion - Reduced diuretic use 8 - Less worsening of heart failure - Shorter length of stay 6 Serelaxin - Reduced days alive out of hospital (n=172) - Improved cardiovascular and all- 4 5 (3%) cause survival 2 • No significant adverse events • No hypotension SAEs; 0 Days 0 120 180 60 Hypotension AEs similar to placebo 62 52 29 16 Placebo 172 149 91 32 Serelaxin
Objectives and Hypothesis • Based upon the hypothesis-generating results of Pre-RELAX-AHF, the RELAX-AHF trial was designed to test the efficacy and safety of serelaxin in patients with acute heart failure (AHF). • We hypothesized that serelaxin (30 mcg/kg/d iv) would improve dyspnea to a greater extent than placebo by one or both measures at 24 hours (Likert) and/or 5 days (VAS AUC), and improve other clinical outcomes.
Inclusion and Exclusion Criteria Key Inclusion Criteria Key Exclusion Criteria • Hospitalized for AHF • Current or planned treatment with any IV therapies [i.e. other vasodilators, – Dyspnea at rest or with minimal exertion (nesiritide), positive inotropic agents and – Pulmonary congestion on chest radiograph vasopressors] or mechanical circulatory, – BNP ≥ 350 pg/mL or NT-pro-BNP ≥ 1400 pg/mL renal, or ventilatory support, with the • Received ≥40 mg IV furosemide (or exception of IV furosemide (or equivalent), equivalent) at any time between admission or of IV nitrates if patient has screening to emergency services (either ambulance or SBP >150 mmHg hospital, including the ED) and the start of • AHF and/or dyspnea from arrhythmias or screening for the study non-cardiac causes, such as lung disease, • Systolic blood pressure > 125 mmHg anemia, or severe obesity • Impaired renal function on admission • Infection or sepsis requiring IV antibiotics (sMDRD eGFR 30-75 mL/min/1·73 m 2 ) • Pregnant or breast-feeding • Randomised within 16 hours from • Stroke within 60d; ACS within 45d; major presentation surgery within 30d • Age ≥ 18 years of age • Presence of acute myocarditis, significant • Body weight < 160 kg valvular heart disease, hypertrophic/ restrictive/ constrictive cardiomyopathy
Key Efficacy Measures Timeline: D0 D1 D2 D5 D14/Index D60 D180 Treatment Serelaxin/Placebo Primary 6, 12, 24 h Likert p<0.025 for either 1° Dyspnea EP EP or p<0.05 for both 1° Dyspnea EPs VAS AUC 0-100 mm; 0, 6, 12, 24h, D2-D5 Biomarkers WHF LoS (index/ICU) Secondary Days Alive Out of Hospital EP CV death+ HF/RF Re-hospitalization CV death In-hospital benefits Out-patient benefits
Patient population (1) Placebo Serelaxin Parameter (N=580) � (N=581) � Age (years) Mean 72.5 71.6 Systolic BP at baseline (mmHg) Mean 142.1 142.2 Heart Rate at Baseline (bpm) Mean 80.4 78.9 Respiratory Rate at baseline (breaths/ min) Mean 22.0 21.8 % 37.2 * HF Hospitalization (in the past year) 31.2 Most Recent Ejection Fraction Mean 38.7 38.6 < 40% % 54.9 54.7 NYHA (1 month prior to admission) % 46.7 43.7 III % 17.0 14.4 IV % Medical History 87.9 85.4 Hypertension % Hyperlipidemia % 54.0 52.3 Stroke or Other Cerebrovascular event % 14.5 12.6 Atrial fibrillation/ atrial flutter at presentation % 42.4 40.1 Diabetes Mellitus % 46.9 48.0
Patient population (2) Placebo Serelaxin Parameter (n’ placebo/n’ serelaxin) (N=580) � (N=581) � Concomitant Heart Failure Meds at Baseline ACE inhibitors % 55.2 53.9 ARB % 16.7 15.1 Beta-blocker % 70.2 66.6 Aldosterone antagonist % 29.8 33.2 Digoxin % 18.6 20.7 Time from present. to random. (hr) Mean 7.9 7.8 Duration of study drug administration (hr) Mean 43.8 41.2 7.2 6.7 IV nitrates at randomisation % NT-proBNP (mg/L)** Geometric Mean 5003 5125 Troponin T (pg/ml)** 0.036 0.034 Geometric Mean eGFR (MDRD; mL/kg/1.73m 2 ) Mean 53.3 53.7 ** Core lab values
1° Endpoint: Dyspnea Relief (VAS AUC) Placebo 35 19.4% increase in AUC with serelaxin Serelaxin from baseline through day 5 Change from baseline (mm) 30 (Mean difference of 448 mm-hr) 25 20 AUC with placebo, 2308 ± 3082 15 AUC with serelaxin, 2756 ± 2588 *P=0.0075 10 5 0 0 12 hrs 1 2 3 4 5 6 Days
1° Endpoint: Dyspnea Relief (Likert) Proportion of subjects with moderately or markedly better dyspnea by Likert by time point 80 Placebo p=0.086 70 Serelaxin 60 p=0.051 50 p=0.113 40 p=0.702 30 20 10 n=180 n=205 n=256 n=288 n=362 n=389 n=150 n=156 0 6 hr 12 hr 24 hr 6, 12, and 24 hr p value by Chi-square test
2° Endpoint: CV Death or HF/RF Re-hospitalization through Day 60 K-M estimate for Composite event components (%) time to first event (%) HR=0.7 HR=1.2 14 Serelaxin p=0.236 p=0.300 6 12 HR 1.03 ( 0.75, 1.42) 12 p=0.862 5 10 10 Placebo 4 8 8 3 6 6 2 4 4 1 2 2 n=27 n=19 n=50 n=60 0 0 0 0 14 30 45 60 Placebo Serelaxin Placebo Serelaxin 580 559 539 522 501 581 563 531 514 498 CV death: HF/RF re-hospitalization: Time in trial (days) % subjects % subjects * p value by log rank test **HR estimate by Cox model
2° Endpoint: Days Alive and Out of Hospital through Day 60 Data from Chris Bush *p=0.35 Serelaxin 8.9 48.3 2.6 1.2 N=(581) Average days of Average days alive Average days alive Average days Average index hospitalization and out of hospital and out of hospital re-hospitalized days dead Placebo 1.9 9.5 47.7 1.8 N=(580) Days Alive Out of Hospital = total follow-up time (D60) - days in hospital or dead *p value by 2-sided Wilcoxon rank sum test
CV Death through Day 180 K-M estimate CV death (ITT) (%) 14 Number of 12 Events, n HR 0.63 (0.41, 0.96); p=0.028 (%)* Placebo (N=580) 10 55 (9.5%) NNT = 29 8 6 35 (6.0%) Serelaxin (N=581) 4 2 0 0 14 30 60 90 120 150 180 Days 580 567 559 547 535 523 514 444 Placebo 581 573 563 555 546 542 536 463 Serelaxin
Signs and Symptoms of Congestion Signs and Symptoms of Congestion at Day 2 DOE Orthopnea Edema Rales JVP p=0.02 p=0.002 p=0.01 p=0.008 p=0.06 100 None 80 None None None <6 cm Patients % Mild 60 1 pillow 40 1+ Moderate <1/3 6-10 cm 20 2 pillows 2+ 1/3-2/3 Severe 3+ >30 >10 cm >2/3 0 p value by 2-sided Wilcoxon rank sum test of change from baseline
Worsening of Heart Failure Kaplan-Meier estimate D14 Cumulative proportion of worsening heart failure for time to WHF (%) to Day 5 (%) 18 18 Placebo (N=573) *p<0.001 through Day 5 **HR 0.7 (0.51, 0.96); p=0.024 16 16 Serelaxin (N=570) 14 14 12 12 10 10 8 8 6 6 4 4 2 2 n= 11 3 16 4 31 10 44 17 57 25 64 36 69 37 573 570 573 570 0 0 6 hr 12 hr Day 1 Day 2 Day 3 Day 4 Day 5 Day 5 Day 14 (Numbers of subjects with WHF shown for each time point) Worsening Heart Failure (WHF) was defined as worsening signs and/or symptoms of HF that required an intensification of IV therapy for heart failure or mechanical ventilatory or circulatory support. *p value by Wilcoxon test **p value by log rank test for Serelaxin vs. Placebo; HR estimate by Cox model, HR<1.0 favors Serelaxin
Intravenous Diuretic Use IV diuretics use (cumulative Total daily dose IV diuretics (mg) total dose from day 1-5 (mg)) 70 250 *p=0.0057 Placebo 60 Serelaxin 200 50 *p=0.0078 150 40 *p=0.0003 30 100 *p=0.0103 20 50 10 N= 573 574 573 572 573 572 573 571 572 570 N=573 N=572 0 0 Day 1 Day 2 Day 3 Day 4 Day 5 *p value by t test
Index Hospitalization LOS Index Hospitalization Length of Length of ICU/CCU Stay (Days) Stay (Days) Placebo Serelaxin 12 4.5 *p=0.029 *p=0.039 4 10 n=580 n=578 3.5 n=581 n=574 8 3 2.5 6 2 4 1.5 1 2 0.5 0 0 Patients still in the hospital at Day 60 are censored *p value by 2-sided Wilcoxon rank sum test at Day 60. Patients who died in-hospital are imputed as the maximum +1 day.
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