James Cooper Eugenie Shieh Aaron Schueneman Tim Niessen Introduction Nesitiride developed as a novel IV vasodilator in decompensated heart failure Recombinant brain natriuretic peptide ID: 714815
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Slide1
Presenters for Journal Club:
James CooperEugenie ShiehAaron SchuenemanTim NiessenSlide2
Introduction
Nesitiride developed as a novel IV vasodilator in decompensated heart failureRecombinant brain natriuretic peptideAlternative to
inotropic
therapy
1
st
randomized double blind trial of
Nesitiride
in
decompensated
heart failure
Slide3
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 mortalitySlide4
Methods
Inclusion CriteriaDyspnea at rest due to dCHF (class IV) severe enough to require hospitalization and IV txCardiac 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 dCHFAllowed prior and current use of dobutamine and dopamine
Exclusion Criteria
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 daysSlide5
Methods
RHC
No RHC
NTG
nesiritide
placebo
3hr
NTG
nesiritide
3-48
hr
Crossover to double blind treatment
same
same
Same as left
Investigator’s clinical decision
RandomizationSlide6
Results: Patient Characteristics
84% had class III/IV HF prior to presentationVast majority had evidence of fluid overloadACS accounted for 12% of presentations85% 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 Slide7
Results: Between Group Differences
More men in the nesiritide vs. NTG group (73% vs. 60%)More in the nesiritde group vs. NTG group:Were on class III anti-arrhythmics
at baseline (19% vs. 12%)
Were given a
vasoactive
IV drug within 24 hours prior to the study (29% vs. 25%)
Had a study drug added to ongoing therapy with either dopamine or
dobutamine
(18% vs. 10%)Slide8
Primary Endpoint #1: Change in PCWPSlide9
Primary Outcome #2: Change in
DyspneaSlide10
Primary Outcome #2: Change in DyspneaSlide11
Results: Secondary Endpoints
More headache in NTG group (20% vs. 8%)No difference in number of ischemic events, hypotensive episodes or arrhythmias in first 24hDuration 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%
nesiritide6-month all cause mortality:NTG 20.8% (95% CI 15.5% - 26.5%)Nesiritide 25.1% (95% CI 20.0% – 30.5%)Slide12
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.Slide13
Strengths
Large, multicenter, with heterogeneous patient populationRandomized.Placebo then crossover to active controls Double-dummy blinded. Slide14
FDA Approval
JAMA 2006;296:1877Slide15
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 353:114Slide16
Lies, Damned Lies, and Statistics
Endpoint selection:Surrogate outcome measures.“hard” vs subjective outcomes / blindingClinical vs statistical significance
Placebo
vs
head-to-head comparisons & “standard therapy”: Slide17
NEJM 2011;365:32-43