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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
• 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
Introductio
n
Methods
Results
Summary
BACKGROUND
• 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
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OBJECTIVES
To explore the effects of perioperative administration of nesiritide on clinical outcomes and safety in heart failure patients undergoing cardiac surgery.
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NAPA TRIAL DESIGN• Multi-center (54 centers)
• Randomized
• Double-blind
• Placebo-controlled
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NAPA TRIAL DESIGN• LV dysfunction (EF≤40%)
• NYHA Class II - IV
• undergoing CABG ± MVS
• using cardiopulmonary bypass
Introductio
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Summary
EXCLUSION CRITERIA• Planned AVR/r
• Off-pump
• Ongoing or chronic dialysis
• Hemodynamic criteria– Mean PAP < 15 mm Hg– CVP < 6 mm Hg– SBP < 90 mm Hg
Introductio
n
Methods
Results
Summary
OUTCOME MEASURES• 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
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STUDY POPULATION
Introductio
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Methods
Results
Summary
Nesiritide (n=141)
Placebo (n=138)
Male Sex (%) 79% 78%
Age (yrs) 63.6 ± 10.5 64.1 ± 11.3
Ejection Fraction (%) 29.7 ± 7.5 30.1 ± 7.3
Serum Creatinine (mg/dL) 1.07 ± 0.4 1.11 ± 0.4GFR (mL/min/1.73 m2) 82.0 ± 30.3 77.6 ± 28.1Baseline BNP (pg/mL) 431 ± 615 406 ± 511SBP (mm Hg) 122 ± 21 120 ± 21Mean PAP (mm Hg) 25.4 ± 8.8 25.6 ± 8.7
STUDY POPULATION
Introductio
n
Methods
Results
Summary
Medical History n (%)Nesiritide
(n=141)
Placebo
(n=138)
Non–insulin-dependent diabetes mellitus 43 (31%) 45 (32%)
Insulin-dependent diabetes mellitus 26 (19%) 23 (16%)
Chronic obstructive pulmonary disease 25 (18%) 25 (18%)
Other pulmonary disease 17 (12%) 21 (15%)
Peripheral vascular disease 30 (22%) 29 (21%)
Diabetic nephropathy 8 (6%) 6 (4%)
Other chronic renal disease 33 (25%) 28 (21%)
MEAN PEAK CHANGE IN SCr*
Introductio
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Methods
Results
Summary
*Through hospital discharge or study Day 14, whichever came first
RENAL BENEFIT WAS GREATER IN PATIENTS WITH RENAL DYSFUNCTION AT BASELINE
Introductio
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Methods
Results
Summary
Baseline SCr ≤ 1.2mg/dl Baseline SCr > 1.2mg/dl
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
Results
Summary
• Improved Survival at 180 days
• Improved Postop Renal Function– Greater improvement in patients with renal
dysfunction at baseline
• 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 InformationClyde 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
Jong P et al. Arch Intern Med. 2002;162:1689
0
25
50
75
100
20%
50%
30days
6mo
Hospital Readmissions
0
25
50
75
100
12%
50%
30days
12mo
Mortality
33%
5yr
Median hospital LOS: 6 days
Annual mortality rate-NYHA class III HF-12% [COPERNICUS DATA]NYHA class II HF-7% [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
Goldberg RJ et al. Arch Intern Med 2007; 167:490-496.
OR (95% CI) of characteristics as predictors of short-term and long-term all-cause mortality
after hospitalization with acute HF Characteristic 3 mo 5 yAge •55-64 0.30 (0.13–0.70) 1.27 (0.80–2.01)•>85 1.55 (0.88–2.74) 6.27 (3.94–10.00)BMI >30 0.55 (0.40–0.77) 0.62 (0.47–0.82)Edema 1.20 (0.92–1.56) 1.38 (1.07–1.77)Serum urea nitrogen (per mg/dL rise)
1.02 (1.01–1.03) 1.02 (1.01–1.03)
COPD 1.19 (0.94–1.52) 1.97 (1.53–2.54)Hypertension 0.77 (0.61–0.99) 1.00 (0.79–1.28)Stroke 1.40 (1.04–1.90) 1.49 (1.04–2.13)Heart failure 1.04 (0.77–1.40) 2.20 (1.72–2.83)Peripheral vascular disease
0.76 (0.55–1.06) 1.42 (1.02–1.97)
Treatment Options for Acute HF-TODAY- are these agents safe and
effective?Diuretics, Aquaretics
& Ultrafiltration
Fluid
volume
Vasodilators
Preloadand/or
Afterload
Inotropes
Contrac
-tility
Natriuretic Peptides
Fluid volume
PreloadAfterload
Neuro-hormones
Increaselusitropy
Increased morbidityand mortality Diuretic therapy
Impaired renalfunction
Decreased renal perfusion
Diuretic resistance
Diminishedblood flow
Neurohormonalactivation
Potential Deleterious Effects of Diuretics and Cardiorenal Syndrome of HF
Neurohormonalactivation
VasoconstrictionCongestion
Pathologicremodeling
Treatment Options for Acute HF-TODAY- are these agents safe and
effective?Diuretics, Aquaretics
& Ultrafiltration
Fluid
volume
Vasodilators
Preloadand/or
afterload
Inotropes
Contrac
-tility
Natriuretic Peptides
Fluid volume
PreloadAfterload
Neuro-hormones
Increaselusitropy
• Reduces preload• Relieves ischemia• Improves symptomatic HF
Nitroglycerin
Nitroprusside
Vasodilators
• Reduces afterload• Reduces blood pressure• Increases cardiac output
Nesiritide• Reduces preload & afterload• Increases cardiac output• Decreases neurohormonal
activation• Relieves dyspnea
None of the above have been shown to improve mortalityfor ADHF in randomized controlled clinical trials
Hemodynamic Effects of Nesiritide vs Placebo vs IV NTG
*†*
†*
†
††
†
†*
Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531
During 3-hr placebo periodPlacebo n = 62 IV NTG n = 60Nesiritide n = 124
After 3-hr periodIV NTG n = 92Nesiritide n = 154
*P0.05 vs placebo†P0.05 vs IV NTG
PCWP – Placebo
PCWP – IV NTG
PCWP – Nesiritide
End of Placebo-Controlled Period
Time on Study Drug (hr)
0 0.25 0.5 1 2 3 6 9 12 24 36 48
–9
–8
–7
–6
–5
–4
–3
–2
–1
0
†*
*
Ch
ang
e F
rom
Bas
elin
e in
P
CW
P (
mm
Hg
)
VMAC: Dyspnea Improvement
*Added to standard carePublication Committee for the VMAC Investigators. JAMA. 2002;287:1531
Dyspnea at 3 hrP
rop
ort
ion
of
Su
bje
cts
(%)
Nitroglycerin* (n = 143)
Nesiritide*
(n = 204)Placebo* (n = 142)
40
30
20
10
0
10
20
30
40
50
60
70
80
90
100P=0.191
P=0.034 Markedly better
Moderately better
Minimally better
No change
Minimallymarkedly worse
Risk of Worsening Renal Failure:Nesiritide Relative to Control Therapies
Sackner-Bernstein JD et al. Circulation 2005;111:1487-1491.
P ≤ 0.003
P ≤ 0.012
P ≤ 0.002
≤ 0.03 mcg/kg/min
≤ 0.015 mcg/kg/min
≤ 0.06 mcg/kg/min
Nesiritide BetterNesiritide Better
0.01 mcg/kg/min
0.015 mcg/kg/min
0.03 mcg/kg/min
Odds Ratio (and 95% confidence intervals)
P=0.17
P=0.02
P=0.001
0 1 2
Nesiritide WorseNesiritide Worse
3 4 5
Odds Ratios Of Worsening Serum Creatinine (>0.5 mg/dL) By Nesiritide Dose Group
Abraham WT. Serum Creatinine Elevations in Patients Receiving Nesiritide are Related to Starting Dose HFSA 2005
FUSION II: Primary Composite Endpoint Through Week 12
Placebo Placebo CombinedCombined
N=306N=306
Nesiritide Nesiritide CombinedCombined
N=605N=605 *P*P-value-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*
39%
5%
15%
32%
4%
16%
>0.5 mg/dL >100% >=50% to at least 2 mg/dL
Serum Creatinine Increase from Baseline
Nesiritide Combined
Placebo Combined
*Outpatient Clinic Visit Values Only
Pe r
cen
t o
f p
atie
nts
wi t
h S
Cr
i ncr
ease
s
P=0.046P=0.046
P=0.458P=0.458
P=0.931P=0.931
Treatment Options for Acute HF-TODAY- are these agents safe and
effective?Diuretics, Aquaretics
& Ultrafiltration
Fluid
volume
Vasodilators
Preloadand/or
afterload
Inotropes
Contra-ctility
Natriuretic Peptides
Fluid volume
PreloadAfterload
Neuro-hormones
Increaselusitropy
Mathew and Katz, Drugs Aging, 1998
Haikala and Linden, J Cardiovasc Pharmacol, 1995
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)
Intracellular calcium concentration
0
5
10
15
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7
% c
ell
sh
ort
en
ing
Ca2+ sensitizers
Desensitizingagents
Relationship between i[Ca2+] and Cell Shortening
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 (0.34-0.95)
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
0
10
20
30
40
50
60
70
clinical status
Improvedno changeWorsened
75% of patients treated with Levosimendan were either unchanged or worsened
Approximate Time-dependent Rates of “Moderate or Marked" Improvement in
Patient Global Assessment
IntervalLevosimendan, n=299 (%)
Placebo, n=301 (%) p
24 h* 60 46 0.026
48 h 63 58 0.053
5 d 76 65 0.001
*infusions halted at 24 hours
Packer M et al. American Heart Association Scientific Sessions 2005; November 13–16, 2005; Dallas, TX.
Adverse Events in REVIVE-2
Selected adverse eventsLevosimendan(%)
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.
Mebazaa A. 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, n=664 (%)
Dobutamine, n=663 (%)
HR(95% CI)
180 d Primary end point
26 28 0.91(0.74-1.13)
31 d Secondary end point
12 14 0.85(0.63-1.15)
5 d Post hoc 4 6.0 0.72(0.44-1.16)
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