Efficacy and Safety of Ularitide for the Treatment of Acute Decompensated Heart Failure - TRUE-AHF

May 18, 2017
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Presenter/Author:
Milton Packer, MD, FACC
Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Cardiorentis
Date Presented:
11/13/2016
Date Published:
04/12/2017
Date Updated:
05/18/2017
Original Posted Date:
11/13/2016
References

Contribution To Literature:

The TRUE-AHF trial showed that early administration of ularitide is not superior to placebo in improving CV outcomes among patients with ADHF despite a more pronounced effect on acute intravascular decongestion.

Description:

The goal of the trial was to assess the efficacy of ularitide, a novel natriuretic peptide, in improving cardiovascular (CV) outcomes among patients with acute decompensated heart failure (ADHF).

Study Design

Patients were randomized in a 1:1 fashion to either ularitide infusion (n = 1,069) or placebo (n = 1,088). Treatment was initiated a median of 6 hours after the initial clinical evaluation.

  • Total number of enrollees: 2,157
  • Duration of follow-up: Median 15 months
  • Mean patient age: 68.5 years
  • Percentage female: 34%

Inclusion criteria:

  • Men or women, aged 18-85 years
  • Unplanned hospitalization or emergency department visit for ADHF
  • Dyspnea at rest, worsened within the past week
  • Evidence of HF on chest X-ray
  • B-type natriuretic peptide (BNP) >500 pg/ml or N-terminal pro-BNP >2000 pg/ml
  • Persistence of dyspnea at rest despite ≥40 mg of intravenous furosemide (or equivalent)
  • Systolic blood pressure ≥116 mm Hg and ≤180 mm Hg
  • Start of study drug infusion within 12 hours after initial clinical assessment

Exclusion criteria:

  • Known active myocarditis, obstructive hypertrophic cardiomyopathy, congenital heart disease, restrictive cardiomyopathy, constrictive pericarditis, uncorrected clinically significant primary valvular disease
  • Treatment with dobutamine at a dose >5 μg/kg/min or use of drugs for support of blood pressure at the time of randomization
  • Treatment with levosimendan, milrinone, or any other phosphodiesterase inhibitor within 7 days before randomization
  • Treatment with nesiritide within 30 days before randomization
  • Creatinine clearance <25 ml/min/1.73 m²
  • Planned coronary revascularization procedure (percutaneous coronary intervention or coronary artery bypass grafting) within 5 days of randomization
  • Clinical diagnosis of acute coronary syndrome
  • Anemia

Other salient features/characteristics:

  • Left ventricular ejection fraction <40%: 65%
  • Time to treatment ≤6 hours: 49%
  • Prior CHF: 76%
  • Systolic blood pressure: 135 mm Hg; heart rate: 85 bpm
  • NT-proBNP: 7139 pg/ml; cardiac troponin T: 33 pg/ml

Principal Findings:

The primary efficacy outcome, cardiovascular mortality for ularitide vs. placebo, was 21.7% vs. 21.0%, p = 0.75

Co-primary: Hierarchical clinical composite outcome ≤48 hours of randomization: improved: 48.6% vs. 47.5%, p > 0.05

Secondary outcomes for ularitide vs. placebo:

Overall, ularitide led to significant increases in hemoglobin (p < 0.001) and serum creatinine (p = 0.005) and decreases in NT-proBNP (p < 0.001) and hepatic transaminases (p < 0.001), compared with placebo.

  • Hypotension: 22.4% vs. 10.1%, p < 0.001
  • Length of stay in hospital during the first 30 days: 160.8 vs. 148.2 hours, p = 0.16
  • Rehospitalization for HF within 30 days of hospital discharge: 7.1% vs. 7.0%, p = 1.0
  • All-cause mortality or CV hospitalization within 6 months: 40.7% vs. 37.2%, p = 0.1

Interpretation:

The results of this trial indicate that early administration of ularitide, a synthetic analogue of urodilatin that results in systemic and renal vasodilation, diuresis and natriuresis, and inhibition of the renin-angiotensin system, is not superior to placebo in reducing CV outcomes despite a more pronounced effect on acute intravascular decongestion. Systemic hypotension was more common with ularitide.

When another similar agent, nesiritide, was introduced a decade or so ago, it was adopted with great enthusiasm for acute improvements in dyspnea in patients with ADHF. When reports suggested that it was associated with higher mortality and renal failure, its use was largely abandoned in the United States. The ASCEND-HF trial from 2010 found no increase in adverse clinical outcomes with nesiritide, but also no significant improvements in dyspnea or short-term clinical outcomes. Taken together, the current trial suggests that this strategy may have limited utility in improving CV outcomes among patients with ADHF.

References:

Packer M, O’Connor C, McMurray JJ, et al., on behalf of the TRUE-AHF Investigators. Effect of Ularitide on Cardiovascular Mortality in Acute Heart Failure. N Engl J Med 2017;376:1956-64.

Editorial: Hauptman PJ. Disease Modification in Acute Decompensated Heart Failure. N Engl J Med 2017;376:1987-8.

Presented by Dr. Milton Packer at the American Heart Association Annual Scientific Sessions (AHA 2016), New Orleans, LA, November 13, 2016.

Keywords: AHA Annual Scientific Sessions, Atrial Natriuretic Factor, Blood Pressure, Dyspnea, Heart Failure, Hypotension, Natriuretic Peptide, Brain, Peptide Fragments, Renal Insufficiency, Stroke Volume


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