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

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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

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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

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STUDY PROTOCOL

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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

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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

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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%)

30-DAY ADVERSE EVENTS*

Introductio

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Methods

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Summary

MEAN PEAK CHANGE IN SCr*

Introductio

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*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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Baseline SCr ≤ 1.2mg/dl Baseline SCr > 1.2mg/dl

180-DAY SURVIVAL WAS IMPROVED WITH NESIRITIDE

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LENGTH OF STAY WAS SHORTER WITH NESIRITIDE

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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

Diuretic Resistance Predicts Mortality in Advanced HF

Neuberg GW et al. Am Heart J. 2002;144:31.

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

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.

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

DID WE LEARN ANYTHING FROM FUSION-II?

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

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