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NEW ORLEANS -- Short term vasodilator treatment for acute heart failure in the hospital did not lead to long term clinical benefits in the largest and most rigorous trial in the field yet performed, researchers said.
In the TRUE-AHF trial 2,157 patients with acute heart failure were randomized to placebo or ularitide, an investigational natriuretic peptide from Cardiorentis which had previously been shown to produce short term hemodynamic and clinical benefits. Milton Packer, MD, of Baylor University, presented the results of TRUE-AHF on Sunday at a late-breaking clinical trial session at the American Heart Association in New Orleans.
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 significantly greater reduction 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.
However, the short term biomarker effects of ularitide did not translate into clinical benefit. After a median followup of 15 months, there was no significant difference in either of the co-primary endpoints, cardiovascular mortality or a clinical composite endpoint. Further, there were no changes in clinically relevant secondary endpoints, including the rate of rehospitalization at 6 months.
In general ularitide was well tolerated, with no indication of renal dysfunction, though there was an expected increase in hypotension during the treatment infusions.
In an interview, Packer said the trial 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. These expectations were raised in an earlier trial, RELAX-AHF with serelaxin (Novartis), but had not been rigorously tested until now.
In TRUE-HF, said Packer, "we've done a trial where we've gone in as early as you can go and we have shown that the drug works while it's given and it stops working after we stop it."
"When the drug was given it exerted the effects that we expected it to do -- lower BP, BNP, acute events -- but there was no effect after the infusion on mortality, troponin, or hospitalizations."
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.
One implication is 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."
Packer said whether this short term effect has clinical value, despite the absence of a long term effect, is "a very interesting regulatory question." Packer said he is not aware of Cardiorentis's future plans for the drug.
Packer said there is another clinical trial, a followup to the RELAX-AHF trial with serelaxin, that is examining the long term effect of this intravenous IV drug for heart failure. "There is every reason to think the result will be the same," said Packer.
Clyde Yancy, MD, of Northwestern University and the discussant at the AHA presentations, largely agreed with Packer. He said that after the long list of trials that have failed to show any long term benefit for early acute treatment, future efforts should focus on devices or new drugs to improve outcomes. He specifically pointed to Entresto (sacubitril and valsartan) and the CardioMEMS device as better possible alternatives to obtain that goal. He said that earlier administration of Entresto might be beneficial but would need to be tested, since earlier testing was not looked at in PARADIGM.