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Bringing RAAS modulation to acute heart failure patients

Heart Failure 2016 Congress News

Michael Felker (Duke University School of Medicine, Durham, North Carolina, USA)

Late Breaking Trials I: Focus on acute heart failure; 21 May, 14:15–15:45; London

The results of a trial presented this afternoon will answer the question of whether a novel biased angiotensin receptor ligand improve outcomes in acute heart failure patients via modulation of the renin-angiotensin-aldosterone-system (RAAS).

Michael Felker (Duke University School of Medicine, Durham, North Carolina, USA) explained that, although RAAS modulation in acute heart failure has previously not been effective, there is renewed interest as it is a “fundamental building block of successful therapy” in chronic heart failure.

The current agent, TRV207, is a b­-arrestin biased ligand of the angiotensin­-2 type 1 receptor (AT1R). Dr Felker told Heart Failure Congress News that, unlike traditional angiotensin receptor blockers (ARBs), it does not simply turn on or off the receptor but blocks some adverse pathways while activating favourable pathways.

He said: “Basically, it blocks vasoconstriction and sodium retention, which are what we think of as adverse effects of angiotensin signalling, but at the same time it promotes improvements in contractility, which are blocked by traditional ARBs.”

Dr Felker and colleagues conducted an international, multi-centre, placebo-controlled, parallel dose-finding trial, in which AHF patients are randomised to one of three parallel TRV027 doses or matching placebo as a continuous intravenous infusion for between 48 hours and 96 hours, alongside usual care.

Unusually, the primary endpoint is a composite of five clinical endpoints: time to death or heart failure rehospitalisation to day 30; time to worsening heart failure to day 5; change in dyspnea visual analogue scale score to day 5; and length of initial hospital stay. A statistical framework is then used to combined and weight the five components to create a single value.

“One of the challenges of early phase trials in heart failure generally, and in acute heart failure in particular, is that we don’t have good surrogate endpoints for efficacy, so that we can do a small trial and say we believe, based on this surrogate endpoint, that we’re going to have effects on clinical outcomes in a bigger study,” Dr Felker said.

“What often happens is we look at a bunch of things and we try to make a decision about whether the overall picture looks favourable or not, but often we arbitrarily pick one endpoint and say: ‘This was the primary endpoint of the study.’”

Another innovative aspect of the study was the use of an adaptive design. Once the first 300 patients were randomised, the doses were re-weighted so that more patients were given the most favourable-looking dose and the sample size increased accordingly.

Dr Felker noted that, while this design is “very common in oncology”, it has not typically been used in cardiovascular disease.

View the session programme and access the resources on SP&P