Ularitide Still a Bust After TRUE-AHF Peer Review

–As reported at AHA, novel vasodilator failed to improve outcomes in heart failure

Short-term treatment with the novel vasodilator ularitide did not lead to improved clinical outcomes in the long term. Results of the TRUE-AHF trial, first presented in preliminary form last November at the American Heart Association annual meeting, have now been published in the New England Journal of Medicine.

Heart failure specialists have long hoped that early stabilization and decongestion of newly hospitalized patients would lead to improved long-term outcome. TRUE-AHF is the most recent and the best demonstration that this hope appears to be futile.

In an accompanying editorial, Paul Hauptman (St. Louis University) writes that drugs like ularitide “have limited short-term effects that wane after the discontinuation of treatment.” The findings “should be no surprise … Exacerbations of chronic disease reflect the chronic disease, not the hospitalizations used to manage those exacerbations. The search for improved understanding of the pathophysiology of heart-failure decompensation continues, and so does the search for better treatments.”

In TRUE-AHF 2,157 patients with acute heart failure were randomized to placebo or ularitide for 48 hours. After a median followup of 15 months the rate of cardiovascular death was 21.7% in the ularitide group versus 21% in the placebo group (hazard ratio 1.03, CI 0.85-1.25, P=0.75).

The drug had previously been shown to produce short-term hemodynamic and clinical benefits. The study drug was administered within an average of 6 hours and performed as expected during the treatment period. Treatment with ularitide resulted in a significant reductions in blood pressure and N-terminal proBNP levels. During the ularitide infusion there was also a significant reduction in episodes of persistent or worsening heart failure.

No unexpected safety issues emerged in the trial, though there was an anticipated increase in hypotension during treatment with ularitide.

When TRUE-AHF was first presented last year, Milton Packer, the principal investigator of the trial, said that it effectively puts to rest the idea that short term IV therapy for heart failure would have long lasting benefits. “We have created a set of expectations for IV drugs which were entirely unrealistic,” he said.

Packer said the larger conceptual problem was thinking that IV vasodilators in heart failure would work like thrombolytic agents in acute coronary syndromes. The underlying reason for this difference with acute coronary syndromes is that acute heart failure is not an acute event, Packer explained. “Acute MI and stroke are acute events — there is a new clot, there is a loss of blood flow, there is tissue injury, and if you prevent that it is a good thing.” By contrast, said Packer, “acute heart failure is NOT an acute event.” In the weeks before patients are hospitalized for an “acute” event there is a gradual rise in intracardiac pressures, he explained.

Packer said that it “matters much less what you do in the hospital than in what you do for an outpatient,” because patients spend the vast majority of their time as outpatients and not in the hospital. “The drug clearly acts as a vasodilator during the time that it’s given,” he said. “This drug actually did what it is supposed to do, and maybe that shouldn’t be a surprise.

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