ESC Congress 2016 - 34

sElEcTEd uPdATEs New Drugs in Acute Heart Failure Written by Phil Vinall Official Peer-Reviewed Highlights From 34 October 2016 Milton Packer, MD, Baylor University Medical Center, Dallas, Texas, USA, reviewed the background leading up to the TRUE-AHF Ularitide trial [NCT01661634], which was designed to examine the association between cardiac troponin release, worsening heart failure (HF), and increased cardiovascular (CV) mortality. In recent years, new drug investigations have shifted to measuring in-hospital worsening of HF and all-cause or CV mortality endpoints. About 10% to 20% of patients develop worsening of their HF during the first 7 days after admission to the hospital [Torre-Amione G et al. J Card Fail. 2009; Weatherley DB et al. Fundam Clin Pharmacol. 2009]; this implies a failure of the patient's prior treatment and signifies instability in their clinical status that may adversely influence their in-hospital and long-term clinical course. One hypothesis for this worsening is a possible link between release of cardiac troponin, in-hospital worsening of HF, and increased cardiovascular mortality (Figure 1). The TRUE-AHF Ularitide trial is examining this hypothesis. Ularitide is a synthetic analogue of urodilatin, which causes systemic and renal vasodilation, diuresis and natriuresis, and inhibition of the renin-angiotensin system. Two small studies, SIRIUS I and II, showed ularatide to be associated with hemodynamic and symptomatic benefits in acute HF. TRUE-AHF aims to characterize the benefits and risks of ularitide in a single trial. There are 2 co-primary endpoints: clinical improvement and prevention of in-hospital worsening of HF (short-term) and CV mortality (long-term). Time from admission to start of study drug is only 6 hours. The trial has completed enrollment with 2157 patients randomized to either ularitide (15 ng/kg/min) or placebo. Data will be presented at the American Heart Association Scientific Sessions in November 2016. During a symposium on new drugs for acute HF, Marco Metra, MD, University of Brescia, Brescia, Italy, reported that serelaxin can improve long-term survival in HF patients. Serelaxin is the recombinant form of human relaxin-2, a naturally occurring hormone involved in mediating hemodynamic changes during pregnancy. Preclinical and clinical studies suggest that serelaxin acts via multiple pathways to improve hemodynamics at the vascular, cardiac, and renal level, and that it provides effective congestion relief. Thus, it may be an effective agent for the treatment of patients with HF. In addition, this novel agent may protect the heart, kidneys, and liver from damage by inhibiting inflammation, oxidative stress, cell death, and tissue fibrosis, while stimulating angiogenesis [Diez J, Ruilope LM. Eur Heart J Cardiovasc Pharmacother. 2016]. In the RELAX-AHF trial, treatment of acute HF with serelaxin was associated with relief of dyspnea and improvement in other clinical outcomes, but not a reduction in hospital readmissions [Teerlink JR et al. Lancet. 2013]. HF worsening was significantly reduced with serelaxin compared with placebo (6.7% vs 12.2%; HR, 0.53; 95% CI, 0.36 to 0.79; P = .0016), as were CV mortality (6.1% vs 9.6%; HR, 0.63; 95% CI, 0.41 to 0.96; P =. 028) and all-cause mortality (7.3% vs 11.3%; HR, 0.63; 95% CI, 0.42 to 0.93; P = .02) through Day 180 [Teerlink JR. AHA 2012]. Also in RELAX-AHF, changes in markers of cardiac (high-sensitivity cardiac troponin T), renal (creatinine and cystatin-C), hepatic (aspartate transaminase and alanine transaminase) damage and decongestion (N-terminal pro-brain natriuretic peptide) at Day 2 and worsening HF during admission were associated with 180-day mortality. Serelaxin improved these markers consistent with the prevention of organ damage and faster decongestion [Metra M et al. J Am Col Cardiol. 2013]. RELAXAHF 2 [NCT01870778] a study of the efficacy, safety, and tolerability of serelaxin added to standard therapy in AHF has completed enrollment and is ongoing. CXL-1427 is a second generation agent that delivers nitroxyl (HNO), an unstable gas that was first shown to affect cardiac contractility in 2003. Javed Butler, MD, MPH, MBA, Heart Institute, Stony Brook University, Stony Brook, New York, USA, presented data showing that HNO delivered through the nitroxyl prodrug CXL-1427 enhances myocardial contractility and vasodilation, and increases cardiac output. www.escardio.org/ESCcongressinreview http://www.escardio.org/ESCcongressinreview

Table of Contents for the Digital Edition of ESC Congress 2016