RCT (drug) - Johns Hopkins Medicine

Report
Presenters for Journal Club:
James Cooper
Eugenie Shieh
Aaron Schueneman
Tim Niessen
Introduction
• Nesitiride developed as a novel IV vasodilator
in decompensated heart failure
• Recombinant brain natriuretic peptide
• Alternative to inotropic therapy
• 1st randomized double blind trial of Nesitiride
in decompensated heart failure
Study Outline
• Hypothesis: Niseritide improves dyspnea and PCWP (vs IV
NG or placebo)
• Study Design: Randomized Controlled Trial
• Setting: 55 community and academic hospitals in U.S.
• Participants: 489 pt w/ dyspnea at rest from
decompensated HF
• Data Collection: dyspnea scale, followed by measurement
of PCWP at 3 hours
• Primary Outcomes:
– Change in PCWP
– dyspnea at 3 hrs
• Secondary Outcomes:
– Safety
– 30-day re-hospitalization rate, 7-day and 6-month mortality
Methods
Inclusion Criteria
Exclusion Criteria
•
•
•
•
Dyspnea at rest due to dCHF
(class IV) severe enough to
require hospitalization and IV tx
Cardiac etiology of dyspnea =
PCWP ≥ 20 + 2 of the following
– JVD
– PND or 2-pillow orthopnea
– Abdominal discomfort due to
mesenteric ischemia
– CXR c/w dCHF
•
•
Acute decompensation of
chronic HF, gradual worsening of
chronic HF, new acutely dCHF
Allowed prior and current use of
dobutamine and dopamine
•
•
•
•
•
SBP < 90 mmHg
Cardiogenic shock or volume
depletion
Contraindication to IV vasodilator
Acutely unstable clinical status
that would not permit a 3 hr
placebo period
Use of IV NTG that could not be
withheld
Mechanical ventilation
Anticipated survival <30-35 days
Methods
Investigator’s
clinical decision
No RHC
RHC
Randomization
3hr NTG
nesiritide
placebo
Crossover to double
blind treatment
3-48 hr
same
same
NTG
nesiritide
Same as left
Results: Patient Characteristics
•
•
•
•
•
•
•
84% had class III/IV HF prior to presentation
Vast majority had evidence of fluid overload
ACS accounted for 12% of presentations
85% had EF < 40%; mean EF 27%
21% had creatinine > 2.0 mg/dl
47% had diabetes mellitus
Mean SBP 121mmHg; 18% < 100mmHg; 22% >
140mmHg
• Mean PCWP 28mmHg;
• Mean cardiac index 2.2 L/min/m2
• Groups well matched
Primary Endpoint #1: Change in PCWP
Primary Outcome #2: Change in Dyspnea
Primary Outcome #2: Change in Dyspnea
Results: Secondary Endpoints
• More headache in NTG group (20% vs. 8%)
• No difference in number of ischemic events,
hypotensive episodes or arrhythmias in first 24h
• Duration of hypotension > in nesiritide (2.2 vs. 0.7
hours)
• 30-day re-admit rate nesiritide vs. NTG:
– 23% vs. 20% for all causes
– 7% vs. 13% for CHF specifically
• 7-day mortality: 0.5% NTG vs. 1.5% nesiritide
• 6-month all cause mortality:
– NTG 20.8% (95% CI 15.5% - 26.5%)
– Nesiritide 25.1% (95% CI 20.0% – 30.5%)
Author Conclusions
• Nesiritide rapidly improves hemodynamics as
measured by RHC better than placebo and
better than nitroglycerin.
• Nesiritide subjectively improves dyspnea,
compared to placebo and is no different when
compared to nitroglycerin.
Strengths
• Large, multicenter, with heterogeneous
patient population
• Randomized.
• Placebo then crossover to active controls
• Double-dummy blinded.
FDA Approval
JAMA 2006;296:1877
Dissent
“Nesiritide was approved on the basis of a single
trial in which surrogate end points were
assessed three hours after administration… In
my view nesiritide has not yet met the minimal
criteria for safety and efficacy”
Topol, NEJM 2005 353:114
Lies, Damned Lies, and Statistics
• Endpoint selection:
– Surrogate outcome measures.
– “hard” vs subjective outcomes / blinding
– Clinical vs statistical significance
• Placebo vs head-to-head comparisons &
“standard therapy”:
NEJM 2011;365:32-43

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