Transcript Trial Overview - Clinical Trial Results

THE NAPA TRIAL:
Nesiritide Administered Peri-Anesthesia
in Patients Undergoing Cardiac Surgery
Mark J. Russo, MD, MS
Division of Cardiothoracic Surgery &
International Center for Health Outcomes and Innovation Research
College of Physicians and Surgeons, Columbia University, New York, NY
BACKGROUND
• Nesiritide is recombinant human B-type
natriuretic peptide
Introduction
Methods
Results
Summary
• When administered to patients with heart
failure, it:
– decreases preload and afterload
– decreases pulmonary vascular resistance
– increases cardiac output
• In some studies:
– increased urine output
– reduced diuretic requirements
– suppression of aldosterone, endothelin, norepinephrine
BACKGROUND
Introduction
Methods
Results
Summary
• Nesiritide is approved for treatment of
patients with acutely decompensated
congestive heart failure who have
dyspnea at rest or with minimal activity
• Several small, retrospective studies
suggested beneficial effects in patients
undergoing cardiac surgery
OBJECTIVES
Introduction
Methods
Results
Summary
To explore the effects of perioperative
administration of nesiritide on clinical
outcomes and safety in heart failure
patients undergoing cardiac surgery.
NAPA TRIAL DESIGN
Introduction
Methods
Results
Summary
•
Multi-center (54 centers)
•
Randomized
•
Double-blind
•
Placebo-controlled
NAPA TRIAL DESIGN
Introduction
Methods
Results
Summary
•
LV dysfunction (EF≤40%)
•
NYHA Class II - IV
•
undergoing CABG ± MVS
•
using cardiopulmonary bypass
EXCLUSION CRITERIA
Introduction
Methods
Results
Summary
•
Planned AVR/r
•
Off-pump
•
Ongoing or chronic dialysis
•
Hemodynamic criteria
– Mean PAP < 15 mm Hg
– CVP < 6 mm Hg
– SBP < 90 mm Hg
STUDY PROTOCOL
Introduction
Methods
Results
Summary
OUTCOME MEASURES
Introduction
Methods
Results
Summary
•
Mean peak change in serum Cr and GFR
through hospital discharge or POD #14
•
Cardiac, renal, and pulmonary adverse events
•
Mortality (30-day and 180-day)
•
Mean ICU LOS & total hospital LOS
STUDY POPULATION
Male Sex (%)
Introduction
Methods
Results
Summary
Age (yrs)
Ejection Fraction (%)
Serum Creatinine (mg/dL)
GFR (mL/min/1.73 m2)
Baseline BNP (pg/mL)
SBP (mm Hg)
Mean PAP (mm Hg)
Nesiritide
(n=141)
Placebo
(n=138)
79%
78%
63.6 ± 10.5
64.1 ± 11.3
29.7 ± 7.5
30.1 ± 7.3
1.07 ± 0.4
82.0 ± 30.3
431 ± 615
122 ± 21
25.4 ± 8.8
1.11 ± 0.4
77.6 ± 28.1
406 ± 511
120 ± 21
25.6 ± 8.7
STUDY POPULATION
Medic al His t ory n (% )
Nes irit ide P lac ebo
(n= 141)
(n= 138)
Non– ins ulin-dependent diabet es mellit us
43 (31%)
45 (32%)
Introduction
Methods
Ins ulin-dependent diabet es mellit us
26 (19%)
23 (16%)
Chronic obs t ruc t iv e pulmonary dis eas e
25 (18%)
25 (18%)
Results
Summary
Ot her pulmonary dis eas e
17 (12%)
21 (15%)
P eripheral v as c ular dis eas e
30 (22%)
29 (21%)
8 (6%)
6 (4%)
33 (25%)
28 (21%)
Diabet ic nephropat hy
Ot her c hronic renal dis eas e
30-DAY ADVERSE EVENTS*
Introduction
Methods
Results
Summary
MEAN PEAK CHANGE IN SCr*
Introduction
Methods
Results
Summary
*Through hospital discharge or study Day 14, whichever came first
RENAL BENEFIT WAS GREATER IN PATIENTS
WITH RENAL DYSFUNCTION AT BASELINE
Baseline SCr ≤ 1.2mg/dl
Introduction
Methods
Results
Summary
Baseline SCr > 1.2mg/dl
180-DAY SURVIVAL WAS
IMPROVED WITH NESIRITIDE
Introduction
Methods
Results
Summary
LENGTH OF STAY WAS
SHORTER WITH NESIRITIDE
Introduction
Methods
Results
Summary
LIMITATIONS
Introduction
Methods
Results
Summary
•
Usual-care medications and other
treatment interventions were not
specified in the protocol.
•
Patients enrolled in this study represent
only a subset of patients undergoing
CABG
•
The 180-day mortality end point was
added late in the study as an additional
safety end point
NAPA FINDINGS
Introduction
Methods
•
Improved Survival at 180 days
•
Improved Postop Renal Function
– Greater improvement in patients with renal
dysfunction at baseline
Results
Summary
•
Decreased LOS
Safety and Efficacy of Therapies for
Acute Decompensated Heart Failure
Clyde W. Yancy, MD
Medical Director
Baylor Heart and Vascular Institute
Baylor University Medical Center
Dallas, TX
Disclosure Information
Clyde W. Yancy, MD
• Grants/Research Support:
GlaxoSmithKline; Medtronic, Inc.;
NitroMed, Inc.; Scios Inc.
• Support/Consultant: AstraZeneca
Pharmaceuticals LP; GlaxoSmithKline;
Medtronic, Inc.; NitroMed, Inc.; Scios Inc.
• Speaker’s Bureau: GlaxoSmithKline;
Novartis Pharmaceuticals Corporation
Outcomes in Patients
Hospitalized With HF
100
Hospital Readmissions
100
Mortality
75
75
50%
50
50%
50
33%
20%
25
25
0
0
30
days
6
mo
Median hospital LOS: 6 days
Jong P et al. Arch Intern Med. 2002;162:1689
12%
30
days
12
mo
5
yr
Annual mortality rateNYHA class III HF12% [COPERNICUS DATA]
NYHA class II HF7% [SCD-HeFT DATA]
Explanations for Increased Mortality Risk
in ADHF
• Absence of understanding
- What is the relevant pathophysiology of
ADHF?
• Acts of commission
- Administration of agents that cause harm
• Acts of omission
- Failure to administer therapies known to be
effective
• Failure of follow-up
OR (95% CI) of characteristics as predictors of
short-term and long-term all-cause mortality
after hospitalization with acute HF
Characteristic
Age
•55-64
•>85
BMI >30
Edema
Serum urea nitrogen
(per mg/dL rise)
COPD
Hypertension
Stroke
Heart failure
Peripheral vascular
disease
3 mo
5y
0.30 (0.13–0.70)
1.55 (0.88–2.74)
0.55 (0.40–0.77)
1.20 (0.92–1.56)
1.02 (1.01–1.03)
1.27 (0.80–2.01)
6.27 (3.94–10.00)
0.62 (0.47–0.82)
1.38 (1.07–1.77)
1.02 (1.01–1.03)
1.19 (0.94–1.52)
0.77 (0.61–0.99)
1.40 (1.04–1.90)
1.04 (0.77–1.40)
0.76 (0.55–1.06)
1.97 (1.53–2.54)
1.00 (0.79–1.28)
1.49 (1.04–2.13)
2.20 (1.72–2.83)
1.42 (1.02–1.97)
Goldberg RJ et al. Arch Intern Med 2007; 167:490496.
Treatment Options for Acute HFTODAY- are these agents safe and
Diuretics,
effective?
Aquaretics
&
Ultrafiltration

Fluid
volume
Vasodilators

Preload
and/or
Afterload
Inotropes
Natriuretic
Peptides


Contrac
-tility
Fluid volume
Preload
Afterload
Neurohormones

Increase
lusitropy
Potential Deleterious Effects of Diuretics
and Cardiorenal Syndrome of HF
Increased morbidity
and mortality
Pathologic
remodeling
Congestion
Neurohormonal
activation
Diuretic
resistance
Impaired renal
function
Diuretic therapy
Neurohormonal
activation
Vasoconstriction
Diminished
blood flow
Decreased renal
perfusion
Diuretic Resistance Predicts Mortality in
Advanced HF
Neuberg GW et al. Am Heart J. 2002;144:31.
Treatment Options for Acute HFTODAY- are these agents safe and
Diuretics,
effective?
Aquaretics
&
Ultrafiltration

Fluid
volume
Vasodilators

Preload
and/or
afterload
Inotropes
Natriuretic
Peptides


Contrac
-tility
Fluid volume
Preload
Afterload
Neurohormones

Increase
lusitropy
Vasodilators
Nitroglycerin
Nitroprusside
Nesiritide
• Reduces preload
• Relieves ischemia
• Improves symptomatic HF
• Reduces afterload
• Reduces blood pressure
• Increases cardiac output
• Reduces preload & afterload
• Increases cardiac output
• Decreases neurohormonal
activation
• Relieves dyspnea
None of the above have been shown to improve mortality
for ADHF in randomized controlled clinical trials
Hemodynamic Effects of Nesiritide
vs Placebo vs IV NTG
Time on Study Drug (hr)
Change From Baseline in
PCWP (mm Hg)
0 0.25 0.5 1
2
3
6
9 12 24 36 48
0
PCWP – Placebo
–1
PCWP – IV NTG
–2
PCWP – Nesiritide
–3
–4
–5
–6
During 3-hr placebo period
Placebo
n = 62
IV NTG
n = 60
Nesiritide
n = 124
*
†
*
†
*
–7
–8
†
*
*
†
*
†
†
–9
†
†
After 3-hr period
IV NTG
n = 92
Nesiritide
n = 154
End of Placebo-Controlled Period
*P0.05 vs placebo
†P0.05 vs IV NTG
Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531
ns
5 Mins
*Added
VMAC: Dyspnea Improvement
Proportion of Subjects (%)
Dyspnea at 3 hr
100
90
80
70
60
50
40
30
20
10
0
10
20
30
40
#
P=0.034
P=0.191
Nitroglycerin*
(n = 143)
1 Hour
to standard care1 Hour
® or nitroglycerin
® or nitroglycerin
orMins
compared
to placebo
Natrecor
compared
to for
placebo
5
1 Hour
Publication
Committee
the VMAC
red
to
nitroglycerin
ompared
to
nitroglycerin
5 Mins®
1 Hour
#
#
#
#
Nesiritide* Placebo*
(n = 204) (n = 142)
33Hours
Hours
Hours
Investigators. JAMA.3 2002;287:1531
3 Hours
Markedly
Better
Markedly
Better
Markedly
Markedly
Moderately
Better
Better
Better
Moderately
Markedly
Markedly
better
Better
Moderately
Moderately
Better
Minimally
Moderately
better
Better
Minimally
Better
Moderately
Better
Minimally
Minimally
better
Minimally
Better
MinimallyBetter
MinimallyMinimally
Markedly
No Change
Markedly
No change
Change
Better
No
Worse
MinimallyWorse
MinimallyMarkedly
No Change
MinimallyMarkedly
No
Change
MinimallyWorse
Minimally
MinimallyMarkedly
No
Change
Worse
Markedly
No
Markedly
No Change
Change
markedly
worse
Worse
MinimallyWorse
Worse
MinimallyMarkedly
No Change
Markedly
Worse
No Change
MinimallyWorse
Markedly
No Change
Worse
What are the risks of nesiritide therapy?
Risk of Worsening Renal Failure:
Nesiritide Relative to Control Therapies
Sackner-Bernstein JD et al. Circulation 2005;111:1487-1491.
≤ 0.03 mcg/kg/min
≤ 0.015 mcg/kg/min
≤ 0.06 mcg/kg/min
P ≤ 0.003
P ≤ 0.012
P ≤ 0.002
Odds Ratios Of Worsening Serum Creatinine
(>0.5 mg/dL) By Nesiritide Dose Group
Nesiritide Worse
Nesiritide Better
0.01 mcg/kg/min
P=0.17
0.015 mcg/kg/min
P=0.02
0.03 mcg/kg/min
P=0.001
0
1
2
3
4
Odds Ratio (and 95% confidence intervals)
Abraham WT. Serum Creatinine Elevations in Patients Receiving Nesiritide are Related to Starting Dose HFSA 2005
5
DID WE LEARN ANYTHING
FROM FUSION-II?
FUSION II: Primary Composite
Endpoint Through Week 12
Placebo Nesiritide
Combined Combined
N=306
N=605
*P-value
All cause mortality and
CV/renal
hospitalization†
36.8%
36.7%
0.79
All Cause Mortality
9.6%
9.5%
0.98
CV/renal
hospitalization
33.9%
32.9%
0.95
*P value: NES vs. placebo stratified by dose group
†Modified ITT: all treated ITT patients
SAFETY
Protocol Specified Changes
in Serum Creatinine*
P=0.046
Nesiritide Combined
39%
Placebo Combined
32%
P=0.931
16%
P=0.458
4%
>0.5 mg/dL
5%
>100%
>=50% to at least 2 mg/dL
Serum Creatinine Increase from Baseline
*Outpatient Clinic Visit Values Only
15%
Treatment Options for Acute HFTODAY- are these agents safe and
Diuretics,
effective?
Aquaretics
&
Ultrafiltration

Fluid
volume
Vasodilators

Preload
and/or
afterload
Inotropes
Natriuretic
Peptides


Contractility
Fluid volume
Preload
Afterload
Neurohormones

Increase
lusitropy
Calcium Sensitizing Agents: Overview
• Increase cardiac contractility by increasing
sensitivity of myofilaments to Ca2+
• Do not increase intracellular Ca2+ levels
• Generate increased contractile force for a
given level of intracellular Ca2+
• May provide a “more economical” increase
in inotropic effect (i.e. without a significant
increase in myocardial O2 consumption)
Mathew and Katz, Drugs Aging, 1998
Haikala and Linden, J Cardiovasc Pharmacol, 1995
Relationship between i[Ca2+]
and Cell Shortening
% cell shortening
15
Ca2+ sensitizers
Desensitizing
agents
10
5
0
0.0 0.1
0.2 0.3
0.4
0.5
0.6
0.7
Intracellular calcium concentration
Hemodynamic Effects and Mortality
Rates of Levosimedan vs. Dobutamine-LIDO
End point
Levosimedan
Dobutamine
HR
(95% CI)
p
value
Hemodynamic
improvement
28%
15%
1.9 (1.1-3.3)
0.022
Mortality at 180
days
26%
38%
0.57 (0.340.95)
0.029
Follath et al. Lancet 2002;360:196
REVIVE-2
• 600 pts c ADHF
• Randomized to
placebo vs.
levosimendan
• Composite endpoint- Improvement in 6 hrs
- Requirement for
vasoactive Rx
- Death
70
60
50
40
Improved
no change
Worsened
30
20
10
0
clinical status
75% of patients treated with Levosimendan were
either unchanged or worsened
Approximate Time-dependent Rates of
“Moderate or Marked" Improvement in
Patient Global Assessment
Levosimendan,
Interval
n=299 (%)
24 h*
60
48 h
63
5d
76
*infusions halted at 24 hours
Placebo,
n=301 (%)
46
58
65
Packer M et al. American Heart Association Scientific
Sessions 2005; November 13–16, 2005; Dallas, TX.
p
0.026
0.053
0.001
Adverse Events in REVIVE-2
Selected adverse events
Levosimendan
(%)
Placebo
(%)
Hypotension
49.2
35.5
Headache
29.4
14.6
Ventricular tachycardia
24.1
16.9
Cardiac failure
22.4
26.6
Atrial fibrillation
8.4
0.2
Ventricular extrasystoles
7.4
0.2
Packer M et al. American Heart Association Scientific
Sessions 2005; November 13–16, 2005; Dallas, TX.
All-cause Mortality by Time since the
First Infusion in the SURVIVE-W Trial
Interval
Analysis
Levosimendan, Dobutamine, HR
n=664 (%)
n=663 (%)
(95% CI)
180 d
Primary
end point
26
28
0.91
(0.74-1.13)
31 d
Secondary 12
end point
14
0.85
(0.63-1.15)
5d
Post hoc
6.0
0.72
(0.44-1.16)
4
Mebazaa A. American Heart Association Scientific Sessions 2005; November 13–16,
2005; Dallas, TX.
Evaluation and Management of Patients
With ADHF: Recommendations
• Patients admitted with ADHF and evidence of fluid overload
be treated initially with loop diuretics
• When congestion fails to improve in response to diuretic
therapy, the following options should be considered
- Sodium and fluid restriction
- Increased doses of loop diuretics
- Continuous infusion of a loop diuretic
- Addition of a second type of diuretic
- Ultrafiltration
• In the absence of symptomatic hypotension, IV NTG, NTP,
or nesiritide may be considered as an addition to diuretic
therapy for rapid improvement of congestive symptoms in
patients with ADHF
Adams KF et al. J Card Fail. 2006;12:10
Section 12: Evaluation and Management
of Patients with ADHF
• 12.15- “In the absence of hypotension, IV NTG,
sodium nitroprusside or nesiritide may be
considered as an addition to diuretic therapy for
rapid improvement of congestive symptoms in
patients admitted with ADHF”. [Strength of
evidence B]
• 12.17- “Intravenous vasodilators, (nitroprusside,
nitroglycerin or nesiritide) may be considered in
patients with ADHF and advanced HF who have
persistent severe HF despite aggressive
treatment with diuretics and standard oral
therapies” [Strength of evidence C]
J Cardiac Failure. 2006;12:10–38
Evaluation and Management of Patients With
ADHF: Recommendations
• 12.16 IV vasodilators (IV NTG or NTP) and diuretics
are recommended for rapid relief in patients with acute
pulmonary edema or severe hypertension
• IV inotropes (milrinone or dobutamine) may be
considered to relieve symptoms and improve end-organ
function in patients with advanced HF
J Cardiac Failure. 2006;12:10–38
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