ASCEND-HF - Nesiritide for acute decompensated heart failure

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

Bottom line: In patients hospitalized with acute decompensated HF, nesiritide does not provide any clinically meaningful benefit when added to standard care, & increases the risk of symptomatic hypotension (NNH 32).


  • Nesiritide, a recombinant form of B-type natriuretic peptide (BNP) & the first therapeutic natriuretic peptide, was approved for use in 2001 based on surrogate benefit (reduction in pulmonary capillary wedge pressure [PCWP]) & reduction in dyspnea at 3 hours compared to placebo or nitroglycerin.
  • Meta-analyses of small nesiritide trials found a possible increased risk of AKI & death vs placebo.

Patients (n=7007 analyzed)

  • Included:
    • Hospitalized for HF (regardless of EF)
    • Within 24h of initiation of in-hospital IV treatment of HF <24h of enrolment
    • Dyspnea at rest or with minimal activity (ie leading to NYHA functional class 3-4)
    • Plus at least 1 of: RR 20+, pulmonary congestion/edema with rales 1/3 of the way up or more of the lung fields
    • Plus at least 1 objective measure of HF (congestion/edema on CXR, BNP >400 pg/mL or NTproBNP >1000 npg/mL, PCWP >20 mm hg, LVEF <40% in the previous 12 months)
  • Excluded:
    • SBP <100 mm Hg, or <110 mm Hg if using IV nitroglycerin
    • Dobutamine (at rate of 5+ ug/kg of body wt/min)
    • Milrinone, levosimendan within 30 days
    • Persistent uncontrolled HTN; ACS; severe pulmonary disease; ESRD with renal replacement therapy; clinically-significant anemia
    • "Other contraindications for vasodilators"
  • Baseline characteristics
    • Age 67 y
    • Female 34%
    • PMHx: Ischemic heart disease 60%, HTN 73%, AF 37%
    • Median ~16h from hospitalization to study drug initiation
    • SBP 124, HR 82
    • EF <40% (80%), 40% or more (20%)
    • BNP ~990 pg/mL, NTproBNP ~4500 ph/mL
    • Na 139, SCr ~106 umol/L 
    • Meds: Loop diuretic 95%, ACEI/ARB 60%, BB 58%, MRA 28%, digoxin 27%
  • Generalizability: Good; trial population is representative of patients hospitalized for ADHF, excluding those at high risk of hypotension & those on inotropes


  • I: Nesiritide
    • Optional loading dose: 2 ug/kg IV bolus
    • Maintenance dose: 0.010 ug/kg/min continuous infusion for >24h, max 7 days
    • Median infusion duration 41h (IQR 24-48h)
  • C: Matching placebo infusion
  • Co-interventions for all: Diuretics, morphine, other vasoactive medications guided by use of a standard-of-care manual


  • Co-primary outcome 1: Self-reported dyspnea on 7-point Likert scale (range markedly better to markedly worse)
    • Moderately/markedly better @ 6h: Nesiritide 44.5%, placebo 42.1% (p=0.03)
    • Moderately/markedly better @ 24h: Nesiritide 68.2%, placebo 66.1% (p=0.007)
    • Although these differences were statistically significant, they are not clinically important
  • Co-primary outcome 2: All-cause mortality or re-hospitalization for HF @ 30 days:
    • Nesiritide 9.4%, placebo 10.1% (hazard ratio [HR] 0.93, 95% confidence interval 0.9-1.08)
    • Death: 3.6% vs 4.0% (p>0.05)
  • Secondary outcomes
    • Persistent/worsening HF or death prior to discharge: Nesiritide 4.2%, placebo 4.8% (p=0.30)
  • Adverse effects
    • Symptomatic hypotension: Nesiritide 7.2%, placebo 4.0%, number needed to harm (NNH) 32 (p<0.001)
    • Asymptomatic hypotension: Nesiritide 21.4%, placebo 12.4%, NNH 12
    • eGFR decreased by >25% from baseline: Nesiritide 31.4%, placebo 26.2% (p=0.11)

Internal validity

  • Unclear risk of allocation bias (randomization & allocation concealment procedures not adequately reported)
  • Low risk of performance & detection bias (double-blind with matching placebo)
  • Low risk of attrition bias
    • Modified ITT analysis of all patients who received study drug (98% of randomized)
    • <3% loss-to-follow-up for evaluation of symptoms at 6-24h 

Other studies of nesiritide

  • 2000 NEJM study:
    • In the first part of the trial, 127 ADHF patients were randomized to double-blind treatment with nesiritide 0.015 ug/kg/min, nesiritide 0.03/ug/kg/min or placebo. At 6h, nesiritide reduced dyspnea, improved global clinical status & reduced PCWP more than placebo.
    • In the second part of this trial, 305 ADHF patients were randomized to open-label nesiritide 0.015 ug/kg/min, nesiritide 0.03/ug/kg/min or another vasoactive agent (inotrope, nitroglycerin or nitroprusside at attending physician's discretion). There was no difference in any efficacy measure between groups.
  • VMAC: This was a double-blind RCT of 489 ADHF patients comparing nesiritide to nitroglycerin IV & placebo x3h, followed by a comparison of nesiritide vs nitroglycerin x24h.
    • By 3h, nesiritide decreased PCWP (-5 mm Hg) & right atrial pressure (-3 mm Hg) more than nitroglycerin (-3 & -2) & placebo (-2 & 0). Nesiritide also reduced dyspnea @ 3h more than placebo, but not nitroglycerin.
    • There were no differences in dyspnea or global clinical status @ 24h. The rate of adverse effects was higher in the nitroglycerin group, largely due to more headaches vs nesiritide. Rates of hypotension were similar between these 2 groups.
  • ROSE: In this double-blind trial of 360 ADHF patients with renal dysfunction, there was no difference between nesiritide, dopamine or placebo in cumulative urine output or renal function after 72h of study treatment.