TRUE-AHF results raise questions around ADHF disease process

Heart failure

By Sunalie Silva

17 Nov 2016

Results from a trial of an intravenous infusion of a potent vasodilatory agent in patients with acute decompensated heart failure fundamentally changes scientific thinking about the disease and treatment strategies, an expert has said.

Dr Milton Parker from Baylor University Medical Centre in Dallas, Texas presented the findings from TRUE-AHF at the American Heart Association’s 2016 Scientific Sessions held in New Orleans earlier this week.

The study is the first randomised, double-blind, placebo-controlled trial to assess the efficacy and safety of the addition of an early infusion of the natriuretic peptide ularitide in addition to conventional therapy in 2,157 patients with acute decompensated heart failure.

It found that a 48-hour intravenous infusion of the potent vasodilatory agent reduced cardiac wall stress, induced cardiac decongestion, and lowered the risk of in-hospital heart failure events in patients with the condition. However, the beneficial vasodilatory effects wore off as soon as the treatment stopped.

The drug also increased haemoglobin and serum creatinine and decreased hepatic transaminases – biomarkers used to measure intravascular decongestion.

In-hospital heart failure events and the need for treatment of persistent or worsening events were also reduced during the infusion.

But those effects did not prevent cardiac microinjury, as indicated by troponin measurements.

The intervention also had no effect on cardiovascular mortality and there was no difference between arms for a hierarchical clinical composite endpoint at 48 hours.

During a median follow-up of 15 months, there were 236 cardiovascular deaths in the ularitide arm and 225 in the placebo arm (HR 1.03; 95% CI 0.85-1.25).

The major side effect of ularitide was hypotension, which occurred more frequently than in the placebo arm (22.4% vs 10.1%) but the drug was otherwise well tolerated.

While ularitide did not improve outcomes over placebo long-term the findings from the trial will fundamentally “change the way we look at acute HF and our scientific thinking about our disease,” Dr Parker said.

“We tested ularitide because it gave us an opportunity to test a cardiac decompression-intravascular decongestion hypothesis … [and] we could not show that a drug that had the desired vasodilator properties, and didn’t have any other side effects that we could see, caused any affect on cardiac micro injury or long-term disease progression.

“If there is a drug out there given for only 48 hours that would affect long-term outcomes, I would tell you it’s not because that drug is a vasodilator, it’s not because it reduces wall stress its because it must have an additional mechanism of action.”

He also stressed that the study should not be seen as a drug trial but rather one designed to test a medical hypothesis about the disease process – and one that had increasingly been gaining acceptance among experts in the field.

For many patients, Dr Parker said, an increase in intravascular volume over time would cause acute ventricular distension, wall stress and a worsening of heart failure events.

For others, there is evidence of myocardial microinjury – as if patients were having ‘tiny infarcts’ – leading to an acceleration of the disease process, a worsening of heart failure events and cardiovascular death.

The question tested in TRUE-AHF, Dr Parker said, is whether the two processes are causally related – does acute distension that occurs during acute HF cause myocardial injury and disease acceleration; and can intervening at this point, and intervening early, reduce microinjury and change the natural course of the disease?

Is it still worthwhile pursuing the early injury hypothesis?

Past AHA president Dr Clyde Yancy who commented on the study at the press conference said that certain trials, regardless of whether their outcomes are positive or negative, are important.

Detailing a ‘litany’ of failed drug therapies for HF – continuous infusion of loop diuretics, ultrafiltration, inotropes, AVP antagonists and now the natriuretic peptide ularitide – Dr Yancy argued that in these failures, “we’ve been informed of what we need to do differently for this condition.”

Before seeking out new drugs, he argued that better phenotyping, identifying better targets and perhaps even a return to neurohormanal targets, which are known to be dysregulated in HF and for which effective interventions already exist, should all be considered before going forward.

“It is really most important for us to think back about the science that we know, understand how we’ve been informed by TRUE-AHF and then evaluate what really makes sense as we go forward.”

Asking whether it was still worthwhile to pursue the early injury hypothesis as TRUE-AHF did, Dr Yancy thought not.

“I think a compelling statement can be made that the result of TRUE AHF really negate the importance of this particular component and our treatment strategy.”

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