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TRUE-AHF: Ularitide improves congestion, does not reduce CV death in patients with acute HF
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NEW ORLEANS — Urgent administration of ularitide, an investigational natriuretic peptide, in patients with acute HF did not reduce risk for CV death despite providing decongestion and reducing wall stress, according to the results of the TRUE-AHF study.
“In many patients, over time there is an increase in intravascular volume resulting from a number of different pathophysiological processes,” Milton Packer, MD, distinguished scholar in cardiovascular science at Baylor University Medical Center, Dallas, said during a press conference at the American Heart Association Scientific Sessions.
“[This increase] causes acute ventricular distention, [which] .... causes an increase in wall stress ... and also causes a worsening in HF events. This is a reasonably worked out scientific pathway. There’s also another pathway that occurs with acute HF. People with acute HF appear to show evidence of cardiac microinjury [that] is not the result of coronary occlusion. We know that after a hospitalization for HF there is an accelerated risk for CV death. The question is, are these two processes causally related?”
Therefore, Packer colleagues investigated whether a drug known to reduce wall stress and intravascular volume administered as early as possible during an acute HF event would reduce long-term risk for CV death.
In previous studies, ularitide (Cardiorentis AG), a synthetic version of urodilatin, was associated with improvement in dyspnea and global clinical status and reduced risk for 30-day mortality compared with placebo, according to Packer.
The TRUE-AHF researchers randomly assigned 2,157 patients with acute HF from 156 centers in 23 countries (mean age, 68 years; 1,420 men) to receive ularitide or placebo. Mean time to administration was 6 hours.
The primary endpoints were CV mortality and a hierarchical clinical composite. In the composite, patients were characterized in one of five ways: moderate or marked symptom improvement without worsening of HF or death at 6, 24 and 48 hours; modest improvement or unchanged symptoms; worsening symptoms at 6, 24 or 48 hours; persistent or worsening HF requiring IV or mechanical interventions within 48 hours; and death within 48 hours. Secondary endpoints included length of stay, rehospitalization and biomarker metrics.
Compared with placebo, ularitide was associated with a drop in BP between infusion and 48 hours, and with a 47% decline in N-terminal pro-B natriuretic peptide (P < .001), a marker of wall stress, at 48 hours, Packer said here.
Ularitide was also associated with indicators of intravascular decongestion such as a rise in hemoglobin (P < .001), an increase in serum creatinine (P = .005) and a decline in hepatic transaminases (P < .001) at 48 hours, he said.
The drug was associated with fewer in-hospital worsening HF events at 48 hours than placebo (55 vs. 87; P = .005), he said.
At a median 15 months of follow-up, there was no difference between the groups in CV mortality (ularitide, 236 deaths; placebo, 225 deaths; HR = 1.03; 95% CI, 0.85-1.25) or in the distribution of the hierarchical clinical composite (P = .82) or cardiac microinjury (P = .7), Packer said.
Packer reported no significant differences in 30-day readmissions for HF (ularitide, 7.1%; placebo, 7%; P = 1), death from any cause or CV hospitalization at 6 months (ularitide, 40.7%; placebo, 37.2%; P = .1), or any other secondary outcome.
Patients assigned ularitide were more likely to have hypotension compared with those assigned placebo (22.4% vs. 10.1%), but rates of other adverse events were low and similar between the groups, he said.
“Our conclusions are a test of a scientific hypothesis: Does acute distention that occurs during acute HF the cause of myocardial injury and disease acceleration?” Packer said. “Our response to that is we can decongest the heart, we can decongest the intravascular space and, in doing that, we do not reduce microinjury or change the natural course of HF. That changes the way we look at acute HF and our scientific thinking about the disease.”
During a related discussion of the trial, Clyde W. Yancy, MD, MSc, professor of medicine and medical social science, chief of cardiology and associate director of the Bluhm Cardiovascular Institute at Northwestern Medicine, said researchers need to consider other therapeutic or device approaches that may help patients with acute decompensated HF, which “does not have a single effective intervention other than process improvement.” Yancy is also vice dean of diversity and inclusion at Northwestern University Feinberg School of Medicine.
Data from studies of sacubitril/valsartan (Entresto, Novartis) have suggested that the drug improves morbidity in patients with HF, “but it is not enlisted during the throes of an acute decompensated HF hospitalization. This must be tested prospectively, and it would be inappropriate to begin to deploy this available compound for the purposes of changing the natural outcomes of acute decompensated HF, but might this be [appropriate for] future investigation?” he asked.
On the device side, he said, an implantable pulmonary catheter “reflects a strategy, potentially, to demonstrate a reduction in morbidity, but not necessarily in the throes of acute compensated disease. ... It is a strategy to be explored.”
Given that TRUE-AHF disproved one hypothesis, it might be appropriate to further test a hypothesis that treating neurohormonal targets could improve outcomes in this population, Yancy said.
Ularitide is not yet approved for use in the United States; Cardiorentis AG received a fast-track designation for the agent in December 2015. – by Erik Swain
Reference:
Packer M, et al. LBCT.01 – Big Trials for Big Questions. Presented at: American Heart Association Scientific Sessions; Nov. 12-16, 2016; New Orleans.
Disclosure: The study was funded by Cardiorentis AG. Packer reports consulting for Admittance, Amgen, AstraZeneca, Bayer, BioControl, Boehringer Ingelheim, Boston Scientific, Celyad, Cardiorentis AG, Daiichi Sankyo, GlaxoSmithKline, Novartis, Novo Nordisk, Relypsa, Takeda and ZS Pharma. Yancy reports no relevant financial disclosures.
Perspective
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Marc A. Simon, MD, FACC
The authors are to be commended on conducting such a rigorous trial, but for treatment of acute decompensated HF as quickly as possible with ularitide, there were no long-term benefits. This speaks to the difficulty of this disease.
The study tested a hypothesis that we’ve had for quite some time. We see low levels of myocardial injury (low but positive troponin levels) in patients with acute decompensated HF that we assume are related to wall stress from ventricular dilation due to volume overload. This was a direct test of the hypothesis that acutely reversing volume overload and resultant wall stress will prevent long-term damage, but we didn’t see that. Despite seeing multiple markers of rapid volume unloading, such as a 47% decrease in N-terminal pro BNP at 48 hours, there was no change in CV mortality. This points to acute decompensated HF being much more complicated and heterogeneous, which makes studying this issue in such a broad context difficult. There is incredible variability in individual patients, ranging from the etiology of HF to the varying presence of underlying comorbidities such as ischemic coronary disease, diabetes, renal dysfunction and a large number of other factors. This is an area that is ripe for precision medicine. A question going forward is whether we can better define specific phenotypes in which a distinct benefit can be found for any given treatment.
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