Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial - ASCEND-HF

Description:

Nesiritide is a recombinant intravenous (IV) formulation of human B-type natriuretic peptide (BNP). Earlier studies seemed to indicate that it was associated with increased renal failure and mortality; thus, its use was abandoned for the most part, especially in the United States. ASCEND-HF sought to compare outcomes after IV nesiritide versus placebo infusion in patients with acutely decompensated heart failure (ADHF).

Hypothesis:

Nesiritide would be superior to placebo in improving acute dyspnea at 6 or 24 hours, and all-cause mortality and chronic heart failure (CHF) readmission at 30 days in patients with ADHF.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized

Patient Populations:

  • Hospitalization for ADHF <24 hours from IV treatment
  • Dyspnea at rest or with minimal activity
  • Presence of one clinical sign: respiratory rate ≥20 breaths/minute or rales >1/3 base
  • Presence of one objective measure: chest x-ray with pulmonary edema, BNP ≥400 pg/ml or NT-proBNP ≥1000 pg/ml, prior EF <40% within 12 months, or pulmonary capillary wedge pressure >20 mm Hg

    Number of enrollees: 7,007
    Duration of follow-up: 30 days
    Mean patient age: 67 years
    Percentage female: 34%

Exclusions:

  • Hypotension at baseline
  • Significant lung disease
  • Acute coronary syndrome
  • Severe anemia or active bleeding
  • Treatment with levosimendan or milrinone within 30 days before randomization
  • Unstable doses of other IV vasoactive medication within 3 hours
  • Dobutamine ≥5 μg/kg/min at time of randomization

Primary Endpoints:

  • Improvement in self-assessed dyspnea, as compared with baseline at 6 and 24 hours, using a 7-point Likert scale
  • All-cause mortality or CHF hospitalization at 30 days

Secondary Endpoints:

  • Overall well-being, as assessed by Likert scale at 6 and 24 hours
  • Persistent or worsening HF and all-cause mortality from randomization through discharge
  • Number of days alive and outside of the hospital from randomization through 30 days
  • Cardiovascular rehospitalization and cardiovascular mortality from randomization through 30 days
  • All-cause mortality
  • Worsening renal function
  • Investigator-reported hypotension

Drug/Procedures Used:

Patients presenting with ADHF and requiring IV treatment were randomized within 24 hours of hospitalization to receive IV infusion of nesiritide or matching placebo, in addition to standard therapy, which included diuretics and morphine. Bolus nesiritide was at the investigator’s discretion (2 μg/kg if used) followed by a continuous IV infusion of 0.01 μg/kg/min for up to 7 days.

Concomitant Medications:

Loop diuretics (95.0%), inotropes (4.4%), and vasodilators (14.8%), angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (61%), and beta-blockers (58%)

Principal Findings:

A total of 7,007 patients were enrolled, 3,496 to nesiritide and 3,511 to placebo. Baseline characteristics were fairly similar between the two arms. About 42% had diabetes mellitus, and 60% had ischemic cardiomyopathy. About 80% of the patients had a left ventricular ejection fraction (LVEF) <40%. Mean systolic blood pressure was 124 mm Hg, and mean heart rate was 82 bpm. Treatment began within 24 hours of hospitalization, and was continued for 1-7 days. Baseline BNP was 990 pg/ml, N-terminal (NT)-proBNP was about 4500 pg/ml, and mean baseline creatinine was 1.2 mg/dl.

At 6 hours, moderate or marked improvement in shortness of breath was slightly better with nesiritide, as compared with placebo (44.5% vs. 42.1%, p = 0.03 [not statistically significant based on predefined significant p value of ≤0.005]). Similar results were noted at 24 hours (68.2% vs. 66.1%, p = 0.007 [not statistically significant based on predefined significant p value of ≤0.005]). At 30 days, the incidence of death or CHF hospitalization was similar between the two arms (9.4% vs. 10.1%, p = 0.31). Similarly, death (3.6% vs. 4.0%, p > 0.05) and CHF rehospitalization (6.0% vs. 6.1%, p > 0.05) were similar. Other secondary endpoints including cardiovascular death or cardiovascular rehospitalization through 30 days (10.9% vs. 11.8%, p = 0.24), and patient well-being at 6 hours (41.4% vs. 40.3%, p = 0.32) and at 24 hours (65.7% vs. 63.7%, p = 0.02) were similar between the two arms.

The incidence of worsening renal failure (31.4% vs. 29.5%, p = 0.11) was similar between the two arms, whereas any hypotension (26.6% vs. 15.3%, p < 0.001) and symptomatic hypotension (7.1% vs. 4.0%, p < 0.001) were higher in the nesiritide arm. Changes in both serum creatinine and blood urea nitrogen (BUN) were similar in nesiritide-treated and placebo-treated patients (p = 0.20 and p = 0.41) from baseline to discharge. Worsening renal failure was associated with increased mortality and readmissions.

Interpretation:

The results of the ASCEND-HF trial indicate that nesiritide is associated with mild improvements in dyspnea and renal function, and no difference in the composite endpoint of death or CHF hospitalization at 30 days in patients hospitalized with ADHF. While there was no increase in 30-day mortality or renal failure with nesiritide, the incidence of hypotension, including symptomatic hypotension, was higher with nesiritide.

When nesiritide was initially introduced, it was adopted with great enthusiasm for acute improvements in dypsnea 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 current trial indicates that although there is no increase in adverse clinical outcomes with nesiritide, there is also no significant improvement in dyspnea or short-term clinical outcomes. The clinical utility of nesiritide is thus likely to be minimal.

References:

van Deursen VM, Hernandez AF, Stebbins A, et al. Nesiritide, Renal Function, and Associated Outcomes During Hospitalization for Acute Decompensated Heart Failure: Results From ASCEND-HF. Circulation 2014;Jul 29:[Epub ahead of print].

O'Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:32-43.

Presented by Dr. Adrian Hernandez at the American Heart Association Scientific Sessions, Chicago, IL, November 14, 2010.

Clinical Topics: Anticoagulation Management, Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Pulmonary Edema, Pulmonary Wedge Pressure, Diuretics, Hypotension, Blood Urea Nitrogen, Blood Pressure, Creatinine, Dyspnea, Heart Rate, Morphine, Renal Insufficiency, Research Personnel, Cardiomyopathies, Heart Failure, Peptide Fragments, Stroke Volume, Respiratory Sounds, Hospitalization, United States, Diabetes Mellitus, Natriuretic Peptide, Brain


< Back to Listings