No Late Clinical Gain With Early IV Therapy: TRUE-AHF Published

April 14, 2017

Boston, MA — Long-term events such as cardiovascular mortality and heart-failure hospitalization were not affected by a 48-hour infusion of the vasodilator ularitide (Cardiorentis) in patients hospitalized with acute heart failure in a large randomized trial said to challenge the traditional expectation that early intravenous (IV) therapy might improve late CV outcomes in the disorder[1].

The Trial of Ularitide Efficacy and Safety in Acute Heart Failure (TRUE-AHF) was published April 12. 2017 in the New England Journal of Medicine, with lead author Dr Milton Packer (Baylor Heart and Vascular Institute, Baylor University, Dallas, TX). Packer had presented TRUE-AHF at the November American Heart Association 2016 Scientific Sessions, as covered extensively at the time by heartwire from Medscape.

Although the early 48-hour ularitide infusions seemed to significantly improve natriuretic peptide levels, a marker of cardiac wall stress, there was no reduction in myocardial injury as measured by troponins, nor improvement in a novel short-term clinical composite end point, write the investigators.

"There is a hypothesis that somehow if you intervene early in patients with heart failure using something magical for 48 hours, that somehow just giving a drug for 48 hours changes the course of the disease for months and years afterward," Packer had said to heartwire after his presentation of the study at the AHA 2016 meeting. "That's true of acute coronary syndromes, but it's not true of acute heart failure."

According to the study, it appears that ularitide "has limited short-term effects that wane after the discontinuation of treatment," writes Dr Paul J Hauptman (Saint Louis University School of Medicine, Missouri) in an editorial accompanying the TRUE-AHF publication[2].

"It also appears that we do not have a mandate to establish rapid-response teams for patients who present with acute decompensated heart failure. At this point, we should remind ourselves that the primary immediate objective of treatment is the patient-centric goal of symptom relief."

TRUE-AHF randomly assigned 2157 patients with acute heart failure to a continuous 48-hour IV dose of ularitide at 15 ng/kg per minute or placebo on top of standard therapy; treatment started a median of 6 hours after their initial clinical evaluation, according to the group.

The hazard ratio (HR) for cardiovascular death for active therapy during a median of 15 months was 1.03 (95% CI 0.85–1.25; P=0.75). The lack of effect was seen across nearly all prespecified patient subgroups, including those defined by baseline troponin and natriuretic peptide levels.

Co–Primary Outcomes in TRUE-AHF, Ularitide vs Placebo

Co–primary end points Ularitide, n=1088 (%) Placebo, n=1069 (%) P
CV death 21.7 21.0 0.75
"Hierarchical clinical composite outcome" in first 48 hours*     0.82
Improved 48.6 47.5  
Unchanged 44.8 44.2  
Worse 6.6 8.3  
*Primarily involving heart failure symptoms and clinical status and patient global assessment; see publication for full definition.

Ularitide is a synthetic analog of the endogenous vasodilating natriuretic-peptide urodilatin and is often compared with nesiritide (Natrecor, Scios/Johnson & Johnson), a bioengineered form of human B-type natriuretic peptide that has its own colorful history as a possible treatment for acute heart failure.

TRUE-AHF was supported by Cardiorentis. Packer reports personal fees from Cardiorentis during the conduct of the study, and personal fees from Admittance, Amgen, CardioKinetix, Cardiorentis, Daiichi-Sankyo, GlaxoSmithKline, Novartis, Relypsa, Boehringer Ingelheim, Bayer,
Sanofi, Takeda, and ZS Pharma outside the submitted work. Disclosures for the coauthors are available on the journal website. Hauptman reports personal fees from St. Jude Medical, personal fees from Sensible Medical, personal fees from Corvia, personal fees from Relypsa, personal fees from Amgen, personal fees from Otsuka, grants from Alnylam, and grants from the National Heart, Lung, and Blood Institute, outside the submitted work.

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