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OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Prof. John R. Teerlink
Prof. David Newby,
By John R Teerlink, FESC (San Francisco, United States of America)View Discussant report
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List of Authors: John R. Teerlink 1, Marco Metra 2, Adriaan A. Voors 3, Piotr Ponikowski 4, Barry H. Greenberg 5, Gerasimos Filippatos 6, G. Michael Felker 7, Beth Davison 8, Gad Cotter 8, Tsushung A. Hua 9, and Thomas M. Severin 10, on behalf of the RELAX-AHF investigators.
1-University of California San Francisco & San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA; 2-University of Brescia, Brescia, Italy; 3-University Medical Center Groningen, Groningen, The Netherlands; 4-Medical University, Military Hospital, Wroclaw, Poland; 5-University of California at San Diego, San Diego, CA, USA; 6-Athens University Hospital, Attikon, Athens, Greece; 7-Duke University School of Medicine, Durham, NC, USA; 8-Momentum Research Inc., Durham, NC, USA; 9-Novartis Pharmaceuticals Corp., East Hanover, NJ, USA; 10-Novartis Pharma AG, Basel, Switzerland
What is new compared to the prior presentation(s) of the trial?The prior report presented the two primary endpoints of the RELAX-AHF trial, while the current report focuses on the reduction of worsening heart failure (WHF; a component of the VAS AUC 1° endpoint; a very topical, emerging endpoint in AHF). These new analyses will give details on the extent of the risk reduction, the subtypes of WHF that were affected (including recurrent events and types of therapies administered for the events), and the impact of WHF on other outcomes in the RELAX-AHF trial.Purpose/ BackgroundWorsening heart failure (WHF) has been shown to be related to poor clinical outcomes and has emerged as an important, novel endpoint in clinical trials. In RELAX-AHF, serelaxin significantly improved the 1° endpoint of dyspnea relief (area under the curve of the change from baseline in dyspnea measured by visual analogue scale through day 5; VAS AUC; p=0.0075). Additional analyses have demonstrated that this improvement was driven by marked reductions in WHF.MethodsPatients admitted to hospital for acute heart failure with dyspnea at rest or with minimal exertion who had objective evidence of heart failure (elevated natriuretic peptides, congestion on chest radiograph), mild to moderate renal insufficiency, and systolic blood pressure >125 mm Hg were enrolled within 16 hours of presentation and randomized to a 48-hour infusion of serelaxin (Ser; 30 mcg/kg/d) or placebo (Pla). Worsening heart failure (WHF) was defined as worsening signs and/or symptoms of HF requiring intensification of HF intravenous therapy or new mechanical, ventilatory or circulatory support. ResultsOf 1161 patients in RELAX-AHF, 110 died or had WHF by day 5; 96% of WHF were documented as adverse events. WHF was only modestly predicted by baseline variables. Patients who had WHF were slower to discontinue intravenous loop diuretic therapies (p<0.00001), had prolonged index hospital (+8.0 days, p<0.00001) and ICU/CCU (+4.9 d, p<0.00001) length of stay, higher NT-proBNP (p=0.005), cystatin-C (p=0.0061) and hs-cTroponin-T (p<0.001) at day 2, and two-fold increased risk of 180-day all-cause mortality (HR: 1.98, 95%CI 1.14-3.43, p=0.0148). Serelaxin treatment markedly reduced WHF events. Within 5d, fewer serelaxin-treated patients died or experienced WHF (KM est: Pla 12.2%, Ser 6.7%; HR: 0.53, 95%CI 0.36-0.79, p=0.0016) compared to the placebo group. Recurrent WHF or death with prior WHF within 5 days occurred in 15 (2.6%) placebo and 4 (0.7%) serelaxin patients, resulting in a total of 87 WHF or death events in the placebo compared to 43 events in the serelaxin group (rate ratio of 0.48; 95%CI 0.32-0.73, p=0.0005). WHF events were reduced by serelaxin in all subtypes of WHF regardless of rescue intervention. In patients who died or experienced WHF within 5 days, only 24 (4.1%) serelaxin-treated patients, compared to 49 (8.4%) placebo-treated patients (p=0.003) were treated with IV positive inotropic drug or mechanical intervention, new IV nitrates or IV nitroprusside, or re-initiation/ doubling of daily dose of IV diuretic. As noted previously, these reductions in WHF in the serelaxin-treated patients were associated with reduced biomarkers of end organ dysfunction/ damage, reduced length of index hospital (–0.9 days; p=0.039) and ICU/CCU (–0.3 days, p=0.029) length of stay, as well as a 37% reduction in 180-day mortality (placebo, 65 deaths; serelaxin, 42; HR 0.63, 95% CI 0.43–0.93; p=0.020). ConclusionsIn the RELAX-AHF trial, WHF was a frequent and clinically meaningful event, occurring in 12% of placebo-treated patients within 5 days, and was associated with longer duration of intravenous therapies, increased markers of end-organ damage and dysfunction, prolonged index hospital and ICU/CCU length of stay, and increased 180-day mortality. Serelaxin treatment reduced WHF events within 5 days by almost 50%, and in all subtypes of WHF regardless of the rescue therapy. Serelaxin treatment significantly reduced clinically relevant WHF events, which were associated with improvements in longer-term outcomes. Reduction in WHF is an important target of acute HF treatment and a potential mechanism to improve outcomes.
By David Newby, FESC (Edinburgh, United Kingdom)See Presenter abstract
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