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the Efficacy, Safety, and Tolerability of Additional Serelaxin Administration to Standard Therapy in Asian Patients with Acute Heart Failure: The RELAX-AHF-ASIA trial
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Journal of Cardiac Failure Vol. 24 No. 11 November 2018
The Efficacy, Safety, and Tolerability of Additional Serelaxin Administration to Standard Therapy in Asian Patients with Acute Heart Failure: The RELAXAHF-ASIA trial D1XNAOKI X SATO, MD, D2X X PhD*,1, CAROLYN D3X X S.P. LAM, MBBS, D4X X PhDy, JOHN D5X X R. TEERLINK, MD D6X X z, BARRY D7X X H. GREENBERG, MD D8X X x, HIROYUKI D9X X TSUTSUI, MD, D10X X PhDk, { yy D1XBYUNG-HEE X OH, MD, D12X X PhD , JIAN D13X X ZHANG, MD, D14X X PhD , TSUSHUNG D15X X A. HUA, D16XPhD X zz, XING D17X X LI WANG, MD, D18X X PhDzz, JUNBO D19X X GE, MD D20X X {{,1 ON BEHALF OF RELAX-AHF-ASIA INVESTIGATORS; *Cardiology and Intensive Care Unit, Nippon Medical School, Musashi-Kosugi Hospital, Kawasaki, Japan; yNational Heart Centre Singapore and Duke-NUS, Singapore; zUniversity of California, San Francisco and San Francisco Veterans Affairs Medical Center, California, USA; xDivision of Cardiology, University of California, San Diego, La Jolla California, USA; k Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; {Department of Internal Medicine, Seoul National University, College of Medicine, Seoul, Republic of Korea; yyFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; zzNovartis Pharmaceuticals Corp., East Hanover, New Jersey, USA; {{Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China Background: Acute heart failure (AHF) is associated with a high risk of post-discharge rehospitalisation and mortality. Existing evidence suggested potential therapeutic benefits of serelaxin in patients with AHF, although corresponding data in Asian patients remained scarce. RELAX-AHF-ASIA, a multinational, randomised, double-blind, placebo-controlled, Phase III trial, evaluated the effects of serelaxin on symptom relief and clinical outcomes in Asian AHF patients. Methods: Patients diagnosed with AHF based on clinical criteria regardless of ejection fraction, with a systolic blood pressure 125 mmHg and mild-to-moderate renal dysfunction were randomised within 16 hours of presentation to receive 48-hour intravenous infusion of 30 mg/kg/day serelaxin or placebo in addition to standard therapy. The patients were followed-up for up to 180 days. A novel trichotomous primary endpoint was used in the RELAX-AHF-ASIA trial. It included: (1) treatment success (moderate/
Funding acknowledgements: a Novartis affiliate company. Trial registration number: ClinicalTrials.gov Identifier: NCT02007720 1 Principal investigator.
marked improvement in patient-reported dyspnoea and physician-assessed signs of congestion on Day 2); (2) treatment failure (in-hospital worsening of signs and/or symptoms of heart failure [HF] requiring intensification of intravenous HF therapy or mechanical ventilation, renal/circulatory support, rehospitalisation due to HF/renal failure or death through Day 5) and (3) unchanged status. Secondary endpoints included time to in-hospital worsening HF through Day 5 and all-cause and cardiovascular deaths through Day 180. Results: Although the trial aimed to randomise 1520 AHF patients, it was prematurely terminated following the neutral read-out of the large phase III RELAX-AHF-2 trial. A total of 876 patients were randomised in the RELAX-AHF-ASIA trial and the final analysis was performed with 870 patients (serelaxin, 437; placebo, 433). The trial was conducted at 127 centres in 11 countries: (China, 15; India, 7; Japan, 50; Republic of Korea, 14; Malaysia, 7; Philippines, 9; Singapore, 2; Jordan, 3; Lebanon, 4; Taiwan, 10; Thailand, 6). The mean age was 70 years and 64% of patients were men. The demographics and baseline characteristics were well balanced between treatment groups. Due to premature termination of this trial, only exploratory analysis for primary and secondary endpoints was performed. The proportion of patients with treatment failure was less in the serelaxin group (4.1%) than in the placebo group (8.3%), but the primary endpoint failed to achieve statistical significance. Serelaxin significantly reduced in-hospital worsening HF through Day 5 with a hazard ratio of 0.41 (95% confidence interval: 0.20, 0.84; P=0.0119), using a Cox-regression model. There was no difference in time to cardiovascular mortality and all-cause mortality through Day 180. No new or unexpected safety findings were reported in this trial. The frequency of serious adverse events was similar between groups, and serelaxin infusion was well tolerated. Conclusion: The RELAX-AHF-ASIA as the first randomised clinical trial specifically in Asian AHF patients represents a landmark trial in Asia. Although the trial was prematurely terminated, it demonstrated that serelaxin was well tolerated and that it improved a novel trichotomous primary endpoint, albeit not statistically, compared with placebo. Exploratory analysis revealed that worsening HF significantly improved with serelaxin treatment. Although RELAX-AHF-ASIA could not confirm the primary endpoint, it demonstrated that future clinical trials of AHF could be successfully conducted in Asian countries.
Journal of Cardiac Failure Vol. 24 No. 11 November 2018
The Efficacy, Safety, and Tolerability of Additional Serelaxin Administration to Standard Therapy in Asian Patients with Acute Heart Failure: The RELAXAHF-ASIA trial D1XNAOKI X SATO, MD, D2X X PhD*,1, CAROLYN D3X X S.P. LAM, MBBS, D4X X PhDy, JOHN D5X X R. TEERLINK, MD D6X X z, BARRY D7X X H. GREENBERG, MD D8X X x, HIROYUKI D9X X TSUTSUI, MD, D10X X PhDk, { yy D1XBYUNG-HEE X OH, MD, D12X X PhD , JIAN D13X X ZHANG, MD, D14X X PhD , TSUSHUNG D15X X A. HUA, D16XPhD X zz, XING D17X X LI WANG, MD, D18X X PhDzz, JUNBO D19X X GE, MD D20X X {{,1 ON BEHALF OF RELAX-AHF-ASIA INVESTIGATORS; *Cardiology and Intensive Care Unit, Nippon Medical School, Musashi-Kosugi Hospital, Kawasaki, Japan; yNational Heart Centre Singapore and Duke-NUS, Singapore; zUniversity of California, San Francisco and San Francisco Veterans Affairs Medical Center, California, USA; xDivision of Cardiology, University of California, San Diego, La Jolla California, USA; k Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; {Department of Internal Medicine, Seoul National University, College of Medicine, Seoul, Republic of Korea; yyFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; zzNovartis Pharmaceuticals Corp., East Hanover, New Jersey, USA; {{Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China Background: Acute heart failure (AHF) is associated with a high risk of post-discharge rehospitalisation and mortality. Existing evidence suggested potential therapeutic benefits of serelaxin in patients with AHF, although corresponding data in Asian patients remained scarce. RELAX-AHF-ASIA, a multinational, randomised, double-blind, placebo-controlled, Phase III trial, evaluated the effects of serelaxin on symptom relief and clinical outcomes in Asian AHF patients. Methods: Patients diagnosed with AHF based on clinical criteria regardless of ejection fraction, with a systolic blood pressure 125 mmHg and mild-to-moderate renal dysfunction were randomised within 16 hours of presentation to receive 48-hour intravenous infusion of 30 mg/kg/day serelaxin or placebo in addition to standard therapy. The patients were followed-up for up to 180 days. A novel trichotomous primary endpoint was used in the RELAX-AHF-ASIA trial. It included: (1) treatment success (moderate/
Funding acknowledgements: a Novartis affiliate company. Trial registration number: ClinicalTrials.gov Identifier: NCT02007720 1 Principal investigator.
marked improvement in patient-reported dyspnoea and physician-assessed signs of congestion on Day 2); (2) treatment failure (in-hospital worsening of signs and/or symptoms of heart failure [HF] requiring intensification of intravenous HF therapy or mechanical ventilation, renal/circulatory support, rehospitalisation due to HF/renal failure or death through Day 5) and (3) unchanged status. Secondary endpoints included time to in-hospital worsening HF through Day 5 and all-cause and cardiovascular deaths through Day 180. Results: Although the trial aimed to randomise 1520 AHF patients, it was prematurely terminated following the neutral read-out of the large phase III RELAX-AHF-2 trial. A total of 876 patients were randomised in the RELAX-AHF-ASIA trial and the final analysis was performed with 870 patients (serelaxin, 437; placebo, 433). The trial was conducted at 127 centres in 11 countries: (China, 15; India, 7; Japan, 50; Republic of Korea, 14; Malaysia, 7; Philippines, 9; Singapore, 2; Jordan, 3; Lebanon, 4; Taiwan, 10; Thailand, 6). The mean age was 70 years and 64% of patients were men. The demographics and baseline characteristics were well balanced between treatment groups. Due to premature termination of this trial, only exploratory analysis for primary and secondary endpoints was performed. The proportion of patients with treatment failure was less in the serelaxin group (4.1%) than in the placebo group (8.3%), but the primary endpoint failed to achieve statistical significance. Serelaxin significantly reduced in-hospital worsening HF through Day 5 with a hazard ratio of 0.41 (95% confidence interval: 0.20, 0.84; P=0.0119), using a Cox-regression model. There was no difference in time to cardiovascular mortality and all-cause mortality through Day 180. No new or unexpected safety findings were reported in this trial. The frequency of serious adverse events was similar between groups, and serelaxin infusion was well tolerated. Conclusion: The RELAX-AHF-ASIA as the first randomised clinical trial specifically in Asian AHF patients represents a landmark trial in Asia. Although the trial was prematurely terminated, it demonstrated that serelaxin was well tolerated and that it improved a novel trichotomous primary endpoint, albeit not statistically, compared with placebo. Exploratory analysis revealed that worsening HF significantly improved with serelaxin treatment. Although RELAX-AHF-ASIA could not confirm the primary endpoint, it demonstrated that future clinical trials of AHF could be successfully conducted in Asian countries.