Results from the Trial of Ularitide’s Efficacy and Safety in Patients with Acute Heart Failure suggest that the standard model of AHF is incomplete. The trial found that vasodilation and the subsequent reduction of myocardial congestion improves heart failure outcomes during treatment but has no effect on long-term cardiovascular outcomes.

“The trial was not a test of a specific agent; it was a test of a hypothesis of the mechanism of heart failure,” said lead author Milton Packer, MD, from the Baylor Heart and Vascular Institute at Baylor University Medical Center in Dallas.

“We know that sodium retention and vasoconstriction lead to increased intravascular volume and acute ventricular distension that worsens heart failure events,” Packer said. “The question was whether this myocardial congestion induces myocardial micro-injuries that accelerate the rate of disease progression and increase long-term risk of cardiovascular death. Our data indicates that the answer is ‘no.’”

The results of TRUE-AHF were presented Nov. 13 as a late-breaking clinical trial during Scientific Sessions 2016.

It has long been recognized that sodium retention, vasoconstriction and transcapillary plasma shifts can lead to increased intravascular volume, acute ventricular distention and worsening heart failure events, Packer said. It is also known that myocardial micro-injuries, as evidenced by increasing levels of troponins, are associated with an accelerated rate of disease progression, increased rates of hospitalizations for heart failure and increased long-term risk of cardiovascular death.

The apparent association of cardiac wall stress, myocardial micro-injuries and increased heart failure events has led to growing attention on reduced time to treatment in heart failure trials. TRUE-AHF is not only the largest trial in AHF to date, it is the earliest to treatment, a mean of 6.1 hours after an unplanned hospitalization or emergency department visit for acutely decompensated heart failure.

Patients were randomized to a 48-hour infusion of ularitide, which is a synthetic natriuretic peptide, or placebo, with a mean of 15 months of follow-up. The co-primary endpoints included in-hospital cardiac events and a hierarchical clinical composite measure. Key secondary outcomes included rehospitalization and overall cardiovascular mortality.

A total of 2,157 patients were randomized, 1,088 to ularitide and 1,069 to placebo. Only one of the randomized patients was lost to follow-up.

Ularitide showed all of the expected treatment effects during the 48-hour infusion, Packer reported. Systolic blood pressure showed a significant drop compared to placebo and N-terminal proBNP levels fell 47 percent compared to placebo. The study drug also showed significant decreases in hemoglobin (p<0.001), serum creatinine (p=0.005) and hepatic transaminases (p<0.001), indicating intravascular decongestion. In-hospital heart failure events were significantly lower in the treatment arm (p=0.005) at 48 hours, requiring fewer interventions.

There was no difference between ularitide and placebo in myocardial injury as indicated by changes in high sensitivity cardiac troponin T levels at baseline and after 48 hours of treatment, and no improvement in long-term cardiovascular outcomes.

“We can decongest a heart and decongest the intravascular space to improve short-term outcomes,” Packer said. “However, this benefit does not reduce myocardial injury or change the natural history of these patients, including the long-term risk of cardiovascular death. This changes the way we think about acute heart failure.”