ASCEND-HF - Nesiritide for acute decompensated heart failure
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).
Context
- 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
Interventions
- 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
Results
- 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.