Conference Coverage

TRUE-AHF: Urgent vasodilator therapy in acute HF provides no long-term benefit


– An investigational synthetic natriuretic peptide given early during hospitalization for acute decompensated heart failure didn’t produce any of the hoped-for intermediate- or long-term clinical benefits in the phase III TRUE-AHF study, Milton Packer, MD, reported at the American Heart Association scientific sessions.

The failure of this investigational vasodilator, ularitide, to influence downstream cardiovascular mortality or early readmission for heart failure closes the door on the once-promising hypothesis that myocardial microinjury occurring during ADHF is due to ventricular distension, observed Dr. Packer, the Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center, Dallas. “Ularitide did exactly what we expected it to do while we were giving it: we caused intravascular decompression, we reduced cardiac wall stress, but we did not affect cardiac microinjury, and we didn’t change long-term cardiovascular mortality or any of our secondary endpoints, including and in particular the 30-day risk of rehospitalization for heart failure,” he said.

Bruce Jancin/Frontline Medical News

Dr. Milton Packer

TRUE-AHF was a double-blind, randomized trial in which 2,157 patients hospitalized for acute decompensated heart failure (ADHF) at 156 centers in 23 countries were assigned to a 48-hour intravenous infusion of ularitide or placebo. Of note, treatment began early: a median of 6.1 hours from the time of initial clinical evaluation. That’s the soonest-ever intervention investigated in a clinical trial in ADHF.

During a median follow-up of 15 months there were 236 cardiovascular deaths in the ularitide group and 225 in the control group, a nonsignificant difference. Nor were there any differences between the two groups in secondary endpoints including length of stay in the ICU during the index hospitalization, rehospitalization for ADHF within 30 days of discharge, or the composite of all-cause mortality or cardiovascular hospitalization within 6 months, which occurred in 40.7% of the ularitide group and 37.2% of controls.

The explanation for this lack of long-term benefit lies in the finding that myocardial microinjury wasn’t prevented by the rapid reduction of cardiac distension produced by ularitide. This was evident in the therapy’s inability to dampen the rise in high-sensitivity cardiac troponin T which occurred in the initial 48 hours of the study.

“The trial demonstrated the effects and safety of ularitide. However, to gain long-term benefits on hospitalizations and death in patients following a hospital admission for heart failure, physicians must focus on the drugs that patients take as an outpatient rather than the drugs they receive as an inpatient,” Dr. Packer concluded.

Dr. Clyde Yancy

Dr. Clyde Yancy

Discussant Clyde Yancy, MD, called ADHF a persistent challenge.

“Readmission rates remain stubbornly at 20% within 30 days and near 50% at 6 months. Acute decompensation is an inflection point in the natural history of heart failure with subsequent 1-year mortality rates consistently approximating 25%. Clearly there is something about the hospitalization that is a herald event which speaks to much worse outcomes, compared with chronic ambulatory heart failure,” said Dr. Yancy, professor of medicine and chief of cardiology at Northwestern University in Chicago.

He agreed with Dr. Packer that in light of the TRUE-AHF results, what Dr. Yancy termed “the early injury hypothesis” isn’t worth further pursuit.

Ularitide thus joins a long list of failed therapies for ADHF. Treatments that have convincingly been shown to have no significant impact on mortality and at best only modest impact on morbidity include continuous IV infusion of loop diuretics in the DOSE trial; the arginine vasopressin antagonists, which failed to impress in EVEREST, SECRET, and TACTICS; nesiritide (Natrecor) in the ASCEND-HF trial; and levosimendan (Simdax), which proved disappointing in the SURVIVE and REVIVE II studies, according to Dr. Yancy.

The jury is still out on serelaxin, he added. The drug showed a favorable signal in the RELAX-AHF trial. The results of RELAX II are awaited with interest.

“Today we still don’t have an effective single intervention for acute decompensated heart failure other than process-of-care improvement,” the cardiologist noted.

What holds promise for improved long-term outcomes in ADHF at this point? Dr. Yancy said sacubitril/valsartan (Entresto) is intriguing based upon the results of the PARADIGM-HF trial (N Engl J Med. 2014;371:993-1004). But the drug needs to be studied prospectively in patients in the throes of ADHF before it can appropriately be recommended for the purpose of changing the natural history of this disorder, Dr. Yancy stressed.

Devices such as the implantable pulmonary catheter are under study as a promising means of altering the natural history of ADHF by identifying actionable signals of impending decompensation weeks beforehand, he added.

The TRUE-AHF trial was sponsored by Cardiorentis. Dr. Packer reported serving as a consultant to that company and more than a dozen other pharmaceutical and medical device companies.

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