The management of Acute Decompensated Heart...

KUHKUHCardiovascular Cardiovascular

CenterCenter

The Management of The Management of Acute Decompensated Heart FailureAcute Decompensated Heart Failure

KyuKyu HyungHyung RyuRyu MD, FACCMD, FACCCardiovascular Center, Cardiovascular Center,

KonkukKonkuk University Hospital, Seoul, KoreaUniversity Hospital, Seoul, Korea


CenterCenter

Acute Decompensated Heart Failure Acute Decompensated Heart Failure (ADHF)(ADHF)

DefinitionDefinition: Rapid onset of symptom and signs secondary to : Rapid onset of symptom and signs secondary to abnormal cardiac functionabnormal cardiac functionCardiac dysfunction Cardiac dysfunction : systolic or diastolic dysfunction: systolic or diastolic dysfunction: arrhythmia: arrhythmia: preload and : preload and afterloadafterload mismatchmismatchIncrease in the number of hospitalization and high Increase in the number of hospitalization and high mortalitymortalityOften life threatening and require urgent treatment Often life threatening and require urgent treatment


CenterCenterSignificant Clinical and Economic Burden of HFSignificant Clinical and Economic Burden of HF

Persons with HF in USPersons with HF in US :: 5.0 million5.0 million

Overall prevalence Overall prevalence :: 2.2%2.2%

IncidenceIncidence :: 550,000/yr550,000/yr

Mortality in 2001Mortality in 2001 :: 52,82852,828

Cost Cost :: $25.8 billion$25.8 billionAHA. Heart Disease and Stroke Statistics—2004 Update


CenterCenterPrevalence of HF Increases with AgePrevalence of HF Increases with Age

0

2

4

6

8

10

20–24 25–34 35–44 45–54 55–64 65–74 75+

Pop

ulat

ion

(%) Males

Females

US, 1988–1994AHA. Heart Disease and Stroke Statistics—2004 Update

Age (yr)


CenterCenterUnderlying Heart Disease In KHFS

Ischemic heart disease

701 (38.3%)

Cardiomyopathy397 (21.7%)

Hypertensive heart disease

338 (18.5%)

Valvular heart disease302 (16.5%)

Unknown orothers 91 (5%)


CenterCenterOutcomes in Patients Hospitalized With HFOutcomes in Patients Hospitalized With HF

20%

50%

Hospital Readmissions

12%

50%

33%

Mortality100100

7575

50 50

25 25

0 030

Days6

Months30

Days12

Months5

YearsN = 38,702Aghababian RV. Rev Cardiovasc Med. 2002;3(suppl 4):S3Jong P et al. Arch Intern Med. 2002;162:1689

Median LOS: 6 days


CenterCenter

Cumulative Survival Rate By Underlying Heart Disease In KHFS

0

.2

.4

.6

.8

1

Ischemic heart diseaseHypertensive heart diseaseCardiomyopathyValvular heart disease

Cum

. Sur

viva

l

0.8300.8300.8340.8340.8740.8740.9260.926VHDVHD

0.6120.6120.7890.7890.8030.803

2yr2yr

0.7000.7000.8250.8250.9080.908HHDHHD0.6070.6070.7020.7020.7940.794IHDIHD

0.7180.7180.8450.8450.9150.915CMPCMP

3yr3yr1yr1yr6mo6mo

0 10 20 30 40 50 60 70

Months after admission


CenterCenterDistribution of LV Dysfunction In KHFSDistribution of LV Dysfunction In KHFS

A(LVE + EF<40%)382(40%)

C(LVE + EF≥45%)110(11%) B(LVnl + EF<40%)

131(13.4%)

D(LVnl + EF≥45%)235(25%)

E(EF40-45%)99(10%)

A+B(LVEF <40%) : 513 (54%)C+D(LVEF ≥45%) : 345 (36%)


CenterCenterClinical status of ADHFClinical status of ADHF

I : Acute decompensated heart failure with symptom

II : Hypertensive AHF hypertension/hypertensive crisis and preserved LV function

III: Acute heart failure with pulmonary edemasevere respiratory distress (O2 saturation<90%)


CenterCenterClinical status of ADHFClinical status of ADHF

IV : Cardiogenic shockSBP<90mmHg, drop of mean BP > 30mmHg,low urine output (<0.5ml/kg/h),pulse rate > 60BPM

V : High output failurehigh heart rate, warm peripheral, pulmonary congestion

VI : Right sided acute heart failure low output syndrome, ↑JVP, congestion, hypotension


CenterCenterClinical status and Precipitating factorsClinical status and Precipitating factors

I : Acute decompensated heart failure with mild symptom- pre-existing HF (cardiomyopathy)- acute severe myocarditis- postpartum cardiomyopathy

II : Hypertensive AHF - Hypertensive crisis

III : Acute heart failure with pulmonary edema - Valvular regurgitation- Severe AS


CenterCenterClinical status and Precipitating factorsClinical status and Precipitating factors

IV : Cardiogenic shockIV : Cardiogenic shock-- acute coronary syndromeacute coronary syndrome

V : High output V : High output -- septicemiasepticemia-- thyrotoxicosisthyrotoxicosis-- anemiaanemia

VI : Right sided acute heart failure VI : Right sided acute heart failure -- asthmaasthma-- RV infarctionRV infarction


CenterCenterMechanism of Reversibility in ADHFMechanism of Reversibility in ADHF

Normalized LV function after the optimal Normalized LV function after the optimal management of ADHFmanagement of ADHF

Reversible LV dysfunctionReversible LV dysfunction-- respond to treatmentrespond to treatment-- especially, ischemia, stunning, hibernation especially, ischemia, stunning, hibernation


CenterCenterReversibility of ADHFReversibility of ADHF

Control hypertensionControl hypertension

Coronary revascularization (PCI, CABG)Coronary revascularization (PCI, CABG)

ValvuloplastyValvuloplasty, replacement, replacement

Mechanical assist device (VAD)Mechanical assist device (VAD)

Control the precipitating factor of ADHF Control the precipitating factor of ADHF -- anemia, anemia, thyrotoxicosisthyrotoxicosis, sepsis, sepsis


CenterCenterPathophysiology of ADHFPathophysiology of ADHFPathophysiology of ADHF

ESC guideline of acute heart failure, European heart journal 2005;26:384-416

KUHKUHCardiovascular CenterCardiovascular Center


CenterCenterDiagnostic tools of ADHFDiagnostic tools of ADHF

Clinical evaluationClinical evaluation

-- assess peripheral circulation, temperatureassess peripheral circulation, temperature

-- JVPJVP

-- chest auscultationchest auscultation

-- cardiac palpation, auscultationcardiac palpation, auscultation

-- abdominal and carotid bruitabdominal and carotid bruit


CenterCenterDiagnostic tools of ADHFDiagnostic tools of ADHF

EKGEKG

Chest XChest X--ray and imaging techniquesray and imaging techniques

EchocardiographyEchocardiography

Laboratory testLaboratory test


CenterCenterLaboratory testLaboratory test

Always

Urea and Electrolytes (Na+, K+, Urea, Creatinine)

AlwaysBlood glucose

AlwaysCKMB, cardiac TnI/TnT

Always (may be falsely positive if CRP elevated or patient has been hospitalized for prolonged period)

D-dimer

AlwaysCRP

AlwaysPlatelet count

AlwaysBlood count


CenterCenterLaboratory testLaboratory test

If patient anticoagulated or in severe heart failureINR

In severe heart failure, or in diabetic patientsArterial blood gases

To be consideredTransaminases

To be consideredUrinanalysis

To be consideredPlasma BNP or NTproBNP


CenterCenterPlasma BPlasma B--type type natriureticnatriuretic peptide (BNP)peptide (BNP)

Reflect the LV wall stretch and volume overloadReflect the LV wall stretch and volume overload

Exclude and/or identify CHF for dyspneaExclude and/or identify CHF for dyspnea

Good negative predictive value to exclude HFGood negative predictive value to exclude HF


CenterCenterPlasma BPlasma B--type type natriureticnatriuretic peptide (BNP)peptide (BNP)

Decision cut point Decision cut point -- 300 pg/ml (NT300 pg/ml (NT--proBNPproBNP))-- 100 pg/ml (BNP)100 pg/ml (BNP)

Influenced by various condition (renal failure, sepsis)Influenced by various condition (renal failure, sepsis)

Important prognostic information in ADHFImportant prognostic information in ADHF


CenterCenterDiagnosis of ADHFDiagnosis of ADHFDiagnosis of ADHF




CenterCenterAssessment of LV function Assessment of LV function Assessment of LV function




CenterCenterTreatment GoalsTreatment Goals

Clinical

↓ symptoms (dyspnea and/or fatigue)

↓ clinical signs

↓ body weight

↑ diuresis

↑ oxygenation



Laboratory

Serum electrolyte normalization

↓ BUN and/or creatinine

↓ S-bilirubin

↓ plasma BNP

Blood glucose normalization



Hemodynamic

PCWP < 18 mmHg

↑ cardiac output and/or stroke volume

Right atrial pressure ≤ 8mmHg

SVR : 1000-1200 dynes sec cm-5



Outcome↓ length of stay in the intensive care unit↓ duration of hospitalization↑ time to hospital re-admission↓ mortality

TolerabilityLow rate of therapeutic withdrawal Low incidence of adverse effects


CenterCenterTreatment of ADHFTreatment of ADHFImmediate goal of treatment




CenterCenterEvidence of congestion and low perfusionEvidence of congestion and low perfusion

Evidence for Congestion

Orthopnea

JVD

Edema

Ascites

Rales

Abd-jugular reflex

Evidence for low perfusion

Narrow pulse pressure

Cool extremities

May be sleepy, obtunded

Worsening renal function


CenterCenterAssessment of Assessment of HemodynamicHemodynamic ProfileProfile

Congestion?

Warm/Dry

Cold/Dry

Warm/Wet

Cold/Wet

NO YES

NO

Low Perfusion?

YES

Adapted from LW Stevenson


CenterCenterPatient Selection and TreatmentPatient Selection and Treatment

Congestion at RestCongestion at Rest

Yes

Cold & WetPCWP elevatedCI decreased

MOST PATIENTSNormal SVRI High SVRI

Warm & WetPCWP elevated

CI normal FAIRLY COMMON

No

Fonarow GC. Rev Cardiovasc Med. 2001;2(suppl 2):S7–S12.

LowLowPerfusionPerfusion

at Restat Rest

Warm & DryPCWP normal

CI normal (compensated)

RARE

Cold & DryPCWP low/normal

CI decreasedRARE

VasodilatorsNitroprussideNitroglycerin

or

NatriureticPeptidesNesiritide

No

Yes

Inotropic DrugsDobutamine

Milrinone


CenterCenterTreatment Options based on Treatment Options based on HemodynamicHemodynamic ProfileProfile

Warm/Dry

Cold/Dry

Warm/Wet

Cold/Wet


NO YES

NO

YES

Low Perfusion?

Congestion?

DRY OUTDiuresisNesiritideNitroprusside



Congestion?

Warm/Dry

Cold/Dry

Warm/Wet

Cold/Wet

NO YES

NOMaintain BP and DRY OUTLow

Perfusion?

YES

If BP >90NesiritideNitroprussideDiuresis+/- Inotropes

If BP <90InotropesNesiritideNitroprussideDiuresis



Congestion?

Warm/Dry

Cold/Dry

Warm/Wet

Cold/Wet

NO YESInotropesDON’T DIURESE

NO

If BP low:Vasodilators may not beindicated

Low Perfusion?

YES

Right heart catheterization is very helpful for accurate assessment and appropriate Rx especially vasodilators



CenterCenter

Pharmacological and Pharmacological and NonNon--pharmacological managements of ADHFpharmacological managements of ADHF


CenterCenterNon Non phamacologicalphamacological managementmanagement

Bed rest & salt restrictionBed rest & salt restriction

IABPIABP

Coronary intervention, CABGCoronary intervention, CABG

PericardiocentesisPericardiocentesis


CenterCenterNon Non phamacologicalphamacological managementmanagement

Valvular replacement or Valvular replacement or plastyplasty

Cardiac resynchronization therapyCardiac resynchronization therapy

VADVAD

Cardiac transplantationCardiac transplantation


CenterCenterPharmacological managementPharmacological management

MorphineMorphine

DiureticsDiuretics

VasodilatorVasodilator

InotropicsInotropics

othersothers


CenterCenterMorphine and its analogueMorphine and its analogue

Early stage of severe ADHFEarly stage of severe ADHF

Restless and dyspneaRestless and dyspnea

Induce Induce venodilationvenodilation and mild arterial dilationand mild arterial dilation

Reduce heart rate Reduce heart rate

Bolus 3mg at a time and repeat, if requiredBolus 3mg at a time and repeat, if required


CenterCenterDiuretics in ADHFDiuretics in ADHF

Usually, loop diuretics Usually, loop diuretics

Higher dose than that of optimal volume statusHigher dose than that of optimal volume status

Doses should be doubled if increased effect is desiredDoses should be doubled if increased effect is desired


CenterCenterDiuretics in ADHFDiuretics in ADHF

Addition of Addition of metolazonemetolazone and IV and IV thiazidethiazide in diuretic in diuretic resistance resistance

Adequacy of oral diuretic dosing should be Adequacy of oral diuretic dosing should be demonstrated prior to dischargedemonstrated prior to discharge

Consider Consider cardiorenalcardiorenal syndrome syndrome ::↓↓ renal perfusion, renal perfusion, ↑↑adrenergic system, adrenergic system, ↑↑RAS RAS


CenterCenterInotropicsInotropics in ADHFin ADHF

DobutamineDobutamine-- increased cardiac outputincreased cardiac output-- decrease SVR, pulmonary vascular resistancedecrease SVR, pulmonary vascular resistance-- diuretic effectdiuretic effect

DopamineDopamine-- 33μμg/kg/min : increase renal blood flow g/kg/min : increase renal blood flow -- vasoconstriction in higher dosevasoconstriction in higher dose


CenterCenterInotropicsInotropics in ADHFin ADHF

MilrinoneMilrinone-- phosphodiesterasephosphodiesterase inhibitor inhibitor -- increase sensitivity of beta stimulation increase sensitivity of beta stimulation

ProarrhythmicProarrhythmic effect effect


CenterCenterRationale for inotropic drugs in ADHF




CenterCenterVasodilator in ADHFVasodilator in ADHF

NitroprussideNitroprusside

-- dramatically, decrease systemic vascular resistances dramatically, decrease systemic vascular resistances

((afterloadafterload) )

-- usually, require invasive monitoringusually, require invasive monitoring

-- titrate carefully, because of hypotensiontitrate carefully, because of hypotension

-- consider coronary steal, pulmonary shunt consider coronary steal, pulmonary shunt


CenterCenterVasodilator in ADHFVasodilator in ADHF

NitroglycerinNitroglycerin-- commonly used in acute ischemic syndromecommonly used in acute ischemic syndrome-- decreased preload and decreased preload and afterloadafterload-- consider reflex sympathetic consider reflex sympathetic overactivityoveractivity

NesiritideNesiritide


CenterCenterNesiritideNesiritide ((hBNPhBNP) Is Identical to ) Is Identical to the Endogenous Hormonethe Endogenous Hormone

• Identical amino acid sequence• Identical pharmacologic profile

DR I

MKR

G

SS

SSGL

GF

CCS S

GSGQVM

K V LR

RH

KPS

Clemens LE et al. J Pharmacol Exp Ther. 1998;287:67–71.


CenterCenter


CenterCenterPharmacologic Actions of Pharmacologic Actions of hBNPhBNP

Hemodynamic1,2

(balanced vasodilation)veinsarteriescoronary arteries

Neurohumoral2aldosterone4

endothelin2

norepinephrine4

Renal1,5,6

diuresisnatriuresisGFR

DR I

MKRG

S SSSGLG

FC CS SG

SGQVMK V L RR

H

KPS

Cardiac 3

lusitropicantifibroticanti-remodeling

1. Marcus LS et al. Circulation. 1996;94:3184–3189.2. Zellner C et al. Am J Physiol. 1999;276(3 pt 2):H1049–H1057.3. Tamura N et al. Proc Natl Acad Sci U S A. 2000;97:4239–4244.4. Abraham WT et al. J Card Fail. 1998;4:37–44.5. Clemens LE et al. J Pharmacol Exp Ther. 1998;287:67–71.6. Rayburn BK, Bourge RC. Rev Cardiovasc Med. 2001;2(suppl 2):S25–S31


CenterCenterHemodynamicHemodynamic Effects of Effects of NesiritideNesiritidein Heart Failure Patientsin Heart Failure Patients

Abraham WT et al. J Cardiac Failure 1998;4:37-44

PCWP* #

-60

-40

-20

0

HR

Cha

nge

from

bas

elin

e (%

)

* +

+

20

40

60A Randomized, DoubleA Randomized, Double--Blind, PlaceboBlind, Placebo--Controlled TrialControlled Trial

Placebo (n = 4)Nesiritide (n = 10)

* p <0.01 vs baseline+ p<0.05 vs baseline# p < 0.05 vs placebo

RAP SVR CI SVI


CenterCenterEffects of Effects of NatriureticNatriuretic Peptides on the KidneyPeptides on the Kidney

Dilatation of afferent and constriction of efferent Dilatation of afferent and constriction of efferent renal arterioles, leading to pressure augmentation renal arterioles, leading to pressure augmentation within the glomerular capillaries and, thus, to within the glomerular capillaries and, thus, to increased GFRincreased GFR11

Relaxation of mesangial cells, which enhances Relaxation of mesangial cells, which enhances effective surface area for filtrationeffective surface area for filtration22

1. Rayburn BK, Bourge RC. Rev Cardiovasc Med. 2001;2(suppl 2):S25–S31.2. Appel RG. Am J Physiol. 1990;251:F1036–F1042.


CenterCenterEffects of Effects of NatriureticNatriuretic Peptides on the KidneyPeptides on the Kidney

Inhibition of Inhibition of angiotensinangiotensin IIII––stimulated sodium and stimulated sodium and water water reabsorptionreabsorption in proximal convoluted tubulesin proximal convoluted tubules11

Inhibition of tubular water transport by antagonizing Inhibition of tubular water transport by antagonizing effect of vasopressineffect of vasopressin11

Decrease in plasma Decrease in plasma reninrenin and aldosteroneand aldosterone22

1. Appel RG. Am J Physiol. 1990;251:F1036–F1042.2. Holmes SJ et al. J Clin Endocrinol Metab. 1993;76:91–96.


CenterCenterNesiritideNesiritide Efficacy Trial: Effects of Efficacy Trial: Effects of NesiritideNesiritideon Urine Outputon Urine Output11 and Diuretic Useand Diuretic Use22

P < 0.001

P = 0.004

560659

0

100

200

300

400

500

600

700

Placebo (n = 42) Nesiritide, 0.015 µg/kg/min (n = 43)

Nesiritide, 0.030 µg/kg/min (n = 43)

% Receiving Diuretics % Receiving Diuretics (24 h) (24 h) 2.2.

90%90% 72%72% 50%50%

6-H

our M

ean

Urin

e O

utpu

t (m

L)

380

1. Colucci WS et al. N Engl J Med. 2000;343:246–253.2. Data on file. Scios Inc.


CenterCenterThe Effects of The Effects of NesiritideNesiritideon on NeurohormonesNeurohormones in CHFin CHF

Norepinephrine(pg/mL)1

Aldosterone(pmol/L)1

Endothelin-1(pg/dL)2

0

100

200

300

400

500

600

700

800

900

Before NesiritideDuring Nesiritide

P < 0.001

P < 0.05

P = 0.06

670

383

860

690

595

496

1. Abraham WT et al. J Card Fail. 1998;4:37–44.2. Aronson D et al. J Am Coll Cardiol. 2001;37(2 suppl A):148A.


CenterCenterComparative TrialComparative Trial

MulticenterMulticenter, randomized, active, randomized, active--controlledcontrolled305 subjects with 305 subjects with decompensateddecompensated CHF requiring IV CHF requiring IV vasoactivevasoactive therapytherapyUp to 7 days of RxUp to 7 days of RxCentral Central hemodynamichemodynamic monitoring NOT requiredmonitoring NOT required

Standard Care IV agent

(investigator determined)*

Natrecor® 0.015 µg/kg/min

Natrecor® 0.030 µg/kg/min

N = 305

*i.e. dobutamine, dopamine, milrinone, nitroglycerin, nitroprusside

Colucci WS, et al. N Engl J Med 2000;343:246-53


CenterCenter

Comparative Trial: Comparative Trial: Duration of TreatmentDuration of Treatment

Mea

n D

urat

ion

(hr)

p < 0.05p < 0.05 p < 0.05

p < 0.05

Silver MA. et al. J Am Coll Cardiol 2002; 39 (5): 798-803

0

20

40

60

80

100

Initial Study Drug All IV Vasoactive Drugs

Dobutamine (n=58)Nesiritide 0.015 (n=103)Nesiritide 0.030 (n=100)


CenterCenter

Readmission Rates and MortalityReadmission Rates and MortalityNesiritideNesiritide Versus Versus DobutamineDobutamine

**

*

† †

20%13%

31%

8%4%

18% 11%

4%

24%

0%

10%

20%

30%

40%

All readmissionsat 21 days

CHF readmissionsat 21 days

6-Month mortality

Per

cent

of p

atie

nts

(%) Dobutamine (n=58)

Nesiritide 0.015 (n=103)Nesiritide 0.030 (n=100)

p < 0.05 vs. dobutamine

† p < 0.06 vs. dobutamineSilver MA. et al. J Am Coll Cardiol 2002; 39 (5): 798-803


CenterCenterVasodilationVasodilation in the Management of Acute in the Management of Acute Congestive Heart Failure (VMAC) TrialCongestive Heart Failure (VMAC) Trial

VMAC Investigators. JAMA. 2002;187:1531–1540.

DesignDesignPhase III randomized, doublePhase III randomized, double--blind, placeboblind, placebo--controlled controlled Multicenter (55) in the United StatesMulticenter (55) in the United StatesRandomization strategy based on Randomization strategy based on rightright--sided heart sided heart catheterizationcatheterization489 patients enrolled from October 1999 to July 2000489 patients enrolled from October 1999 to July 2000Acutely decompensated heart failure with dyspnea on Acutely decompensated heart failure with dyspnea on admissionadmissionNesiritide vs IV nitroglycerin vs placebo Nesiritide vs IV nitroglycerin vs placebo when added to when added to standard therapystandard therapy

fixedfixed--dose IV nesiritidedose IV nesiritidevariablevariable--dose IV nesiritidedose IV nesiritideIV nitroglycerinIV nitroglycerinplaceboplacebo


CenterCenterVMAC: Study DesignVMAC: Study Design

Treatment Duration (h)0

Months6

Eligible Patients(N = 489)

Catheterized(n = 246)

Noncatheterized(n = 243)

Stratified Randomized

Nitroglycerin (n = 60)

Placebo (n = 62)

NES fixed dose (n = 62)

NES adjustable dose (n = 62)



NES adjustable dose (n = 62)

3-Hour Placebo-Controlled Period

Active-Controlled Period

1 2 3


Placebo (n = 80)




End of Study Drug

Added to standard therapy

Scios Inc. NDA 20-920 Cardiovascular and Renal Drugs Advisory Committee Briefing Document: Natrecor (nesiritide) for Injection. Sunnyvale, CA: Scios Inc; May 25, 2001.


CenterCenterVMAC: PCWP Through 3 HoursVMAC: PCWP Through 3 Hours

Mean PCWP (mm Hg) Mean Change in PCWP (mm Hg)

–4

–1

††

* * **

* *†

†

30

P = NS

28

26

24

22 –7

20

–1018

2 h

3 h

1 m

in

15 m

in

30 m

inBL

3 h

2 h

15 m

in30

minBL

1 h

TimeTime

*P < 0.05 vs placebo.†P < 0.05 vs nitroglycerin.

Placebo Nitroglycerin Nesiritide



CenterCenterVMAC: PCWP Through 48 HoursVMAC: PCWP Through 48 HoursM

ean

Cha

nge

in P

CW

P (m

m H

g)

Time

Nesiritide

36 h

24 h

12 h9 h

6 h

30 m

in 1 h

2 h

3 h

-11

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

**

*

*

* **

*

Nitroglycerin

48 h

*P < 0.05 pooled nesiritide vs nitroglycerin. VMAC Investigators. JAMA. 2002;187:1531–1540.


CenterCenterNesiritideNesiritide: Greater Pulmonary : Greater Pulmonary VasodilationVasodilationThan NitroglycerinThan Nitroglycerin

PAP = pulmonary artery pressure; PVR = pulmonary vascular resistance.VMAC Investigators. JAMA. 2002;187:1531–1540

*P < 0.05 vs placebo; †P < 0.05 vs nitroglycerin.

Nitroglycerin

Nesiritide

Placebo

BL 1 2 3–8–7–6–5–4–3–2–1012

*† *† *† *†*†M

ean

Cha

nge

Syst

olic

PA

P (m

m H

g)

Mea

n C

hang

e PA

P (m

m H

g)

BL 1 3–6

–5

–4

–3

–2

–1

0

*†*†

*†*†

*†

Time (h) Time (h)

Mea

n C

hang

e PV

R (d

ynes

-s-c

m-5

)

BL 1 3–40

–30

–20

–10

0

10

20

30

*

Time (h)

*

*

Mea

n C

hang

e D

iast

olic

PA

P (m

m H

g)

BL 15 30 1 2 3–6–5–4–3–2–101234

†

† †

Time (h)

*†*†

*†

2

2


CenterCenter

NesiritideNesiritide Efficacy: Efficacy: Dyspnea Improvement in VMAC TrialDyspnea Improvement in VMAC Trial

Dyspnea at 3 hrP values are based on van Elteren test with 7-point ordinal scale

*Added to standard therapy

Prop

ortio

n of

Sub

ject

s (%

)

Nitroglycerin* (n = 143)

Nesiritide*(n = 204)

Placebo* (n = 142)

-40-30-20-10

0102030405060708090

100P=0.191

P=0.034

Markedly better

Moderately better

Minimally better

No change

Minimally or Markedly worse

Dyspnea at 3 hr

Publication Committee for the VMAC Investigators. JAMA.2002;287:1531


CenterCenter

VMAC: KaplanVMAC: Kaplan--Meier Estimate of Meier Estimate of Mortality Rate by Treatment GroupMortality Rate by Treatment Group

Cum

ulat

ive

Mor

talit

y R

ate

(%)

100

0

90

80

70

60

50

40

30

20

10


Nesiritide, 0.01 µg/kg/min (n = 211)

All Nesiritide (n = 273)

Time Observed From the Start of Treatment (d)0 30 60 90 120 150 180

Stratified log-rank test:Nitroglycerin vs nesiritide, 0.01 µg/kg/min, p = 0.616Nitroglycerin vs all nesiritide, p = 0.319

Scios Inc. NDA 20–920 Cardiovascular and Renal Drugs Advisory Committee Briefing Document: Natrecor (nesiritide) for Injection. Sunnyvale, CA: Scios Inc; May 25, 2001.


CenterCenter

VMAC: Relationship Between Decrease in VMAC: Relationship Between Decrease in PCWP and Decrease in SBP With PCWP and Decrease in SBP With VasodilationVasodilation

Stevenson LW on behalf of the VMAC Study Group. Presented at: HFSA 5th Annual Scientific Meeting 2001; September 9–12, 2001; Washington, DC.

Decrease PCWP

Fall in SBP

NTG

–12

–10

–8

–6

–4

–2

0

2

4

6

1 h NTG 31–60

µg/kg/min

3 h NTG 31–60

µg/kg/min

1 h BNP 3 h BNP

Fall in SBP

Decrease PCWP

BNP

Decrease in PCWP

Fall in SBP

NTG: BNP:


CenterCenter

VMAC: VMAC: NesiritideNesiritide Safety versus IV Safety versus IV NTG adverse Events (First 24 Hours)NTG adverse Events (First 24 Hours)

Nitroglycerin(n=216)

Natrecor(n=273) 1p-value

Any Adverse Event 146 (68%) 140 (51%) <0.001

Headache 44 (20%) 21 (8%) <0.001

Abdominal Pain 11 (5%) 4 (1%) 0.032

Symptomatic Hypotension 10 (5%) 12 (4%) 1.000

Ventricular Tachycardia 11 (5%) 9 (3%) 0.362

Angina Pectoris 5 (2%) 5 (2%) 0.756

Nausea 13 (6%) 10 (4%) 0.283

Dizziness 4 (2%) 7 (3%) 0.7621 Fisher's Test

Publication Committee for the VMAC Investigators. JAMA 2002; 287(12): 1531 -40


CenterCenter

Lack of Ischemic Cardiovascular Lack of Ischemic Cardiovascular Adverse Events in VMACAdverse Events in VMAC

Adverse Events 24 Hours After Start of Study DrugNitroglycerin Nitroglycerin All NesiritideAll Nesiritide

(n = 216) (n = 216) (n = 273) (n = 273)

Symptomatic hypotensionSymptomatic hypotension 10 (5%)10 (5%) 12 (4%)12 (4%)

Ventricular tachycardiaVentricular tachycardia 11 (5%) 11 (5%) 9 (3%) 9 (3%)

Myocardial infarctionMyocardial infarction 3 (1.4%) 3 (1.4%) 2 (0.7%) 2 (0.7%)

AnginaAngina 5 (2%) 5 (2%) 5 (2%) 5 (2%)

p = not significant.



CenterCenterVMAC: Clinical ImplicationsVMAC: Clinical Implications

• Nesiritide rapidly reduced PCWP and relieved symptoms in patients with acute heart failure more effectively than standard care alone and standard care plus IV nitroglycerin

• Nesiritide was as safe as and better tolerated than IV nitroglycerin



CenterCenter

NesiritideNesiritide vsvs DobutamineDobutamine: : Clinical Effects and Clinical Effects and ProarrhythmicProarrhythmic Potential Potential

PRECEDENT Trial

Burger AJ et al. Am Heart J. 2002;144:1102–1108.

Randomized, controlledRandomized, controlledParallel arm Parallel arm

Dobutamine Dobutamine >> 5 5 µµg/kg/ming/kg/minNesiritide, 0.015 Nesiritide, 0.015 µµg/kg/ming/kg/minNesiritide, 0.030 Nesiritide, 0.030 µµg/kg/ming/kg/min

N = 255 N = 255 Acutely decompensated CHFAcutely decompensated CHF

NYHA class III or IVNYHA class III or IV2424--h baseline Holterh baseline Holter2424--h Holter during treatmenth Holter during treatment


CenterCenter

Effect of ShortEffect of Short--Term Term NesiritideNesiritide vsvsDobutamineDobutamine on 6on 6--Month SurvivalMonth Survival

Cum

ulat

ive

Mor

talit

y R

ate

(%)

Treatment Duration (d)

Log-rank test:Dobutamine vs nesiritide, 0.015 µg/kg/min: P = 0.040Dobutamine vs nesiritide, 0.030 µg/kg/min: P = 0.366

Dobutamine (n = 58)

Nesiritide, 0.030 µg/kg/min(n = 103)Nesiritide, 0.015 µg/kg/min(n = 100)

0

5

10

15

20

25

30

35

0 30 60 90 120 150 180

Silver MA et al. J Am Coll Cardiol. 2002;39:798–803.


CenterCenterArrhytmiaArrhytmia between between NesiritideNesiritide and and DobutamineDobutamine

-60

-40

-20

0

20

40

60

80

Dobutamine Nesiritide 0.015 Nesiritide 0.03

VT/24 hr

Couplet/24 hr

Triplet/24 hr

VPBs/hr

* *

*

*

* †

†

†

† : p<0.05 (vs dobutamine)* : p<0.001 (vs dobutamine)


CenterCenterPRECEDENT : Clinical ImplicationsPRECEDENT : Clinical Implications

Nesiritide had no proarrhythmic effects, whereas Nesiritide had no proarrhythmic effects, whereas dobutamine was associated with an increased risk dobutamine was associated with an increased risk of SVT and cardiac arrestof SVT and cardiac arrest

Nesiritide use resulted in shorter duration of IV Nesiritide use resulted in shorter duration of IV medications and lower rate of remedications and lower rate of re--hospitalizationhospitalization



CenterCenterPRECEDENT : Clinical ImplicationsPRECEDENT : Clinical Implications

NesiritideNesiritide, 0.015 , 0.015 µµg/kg/min, was associated with g/kg/min, was associated with improved 6improved 6--month survival compared with inmonth survival compared with in--hospital use of hospital use of dobutaminedobutamine



CenterCenterFUSION Study DesignFUSION Study Design

n = 69

n = 72

n = 69 Nesiritide 0.01 µg/kg/min, following bolus– Inotropes not permitted

Nesiritide 0.005 µg/kg/min, following bolus– Inotropes not permitted

Standard Care – Inotropes permitted

-30 to -5 days post hospital discharge

Follow-upWeekly Outpatient VisitsScreening

n = 210

4 Weeks12 Weeks

Yancy CW et al. Am J Cardiol. 2004;94(5):595-601


CenterCenterReasons for Study Drug TerminationReasons for Study Drug Termination

11 (1%)11 (1%)7 (1%)7 (1%)4 (<1%)4 (<1%)Adverse EventAdverse Event

Patients with Termination Due Patients with Termination Due to:to:

9 (6%)9 (6%)5 (7%)5 (7%)4 (6%)4 (6%)Adverse EventAdverse Event

1628 (99%)1628 (99%)814 (99%)814 (99%)814 (99%)814 (99%)Normal TerminationNormal Termination

Infusions with Termination Due Infusions with Termination Due to:to:

All All NesiritideNesiritide(n = 141)(n = 141)

NesiritideNesiritide0.01 0.01

(n = 69)(n = 69)

NesiritideNesiritide0.005 0.005

(n = 72)(n = 72)

Yancy CW et al. Am J Cardiol. 2004; 94: 595-601


CenterCenterSelected AESelected AE’’s s –– All PatientsAll Patients

0

5

10

15

20

25

30

35

40

45

50

Heart Failure SymptomaticHypotension

AsymptomaticHypotension

Renal AEs*

% o

f Pat

ient

s

Standard Care Nesiritide 0.005 Nesiritide 0.01

*Renal AEs include:

BUN increased, abnormal kidney function, acute kidney failure, increased creatinine, and oliguria


CenterCenter

Clinical Outcomes Through Week 12 Clinical Outcomes Through Week 12 –– All PatientsAll Patients

StandardCare

(n = 69)

Nesiritide0.005Dose(n = 72)

Nesiritide0.01Dose

(n = 69)

All NesiritidePatients(n = 141)

Patients alive and never hospitalized

Days alive and out of hospitalMean ± SD25thpercentile

74 ±1873.8

76 ± 1574.2

79 ± 1179.0

78 ± 1377.6

Clinical Outcome

29 (42%) 39 (54%) 35 (51%) 74 (52%)

Deaths 7 (10%) 6 (8%) 3 (4%) 9 (6%)

All cause hospitalization 37 (54%) 32 (44%) 33 (48%) 65 (46%)

Yancy CW et al. Am J Cardiol. 2004; 94: 595-601


CenterCenterImprovement in Left Ventricular Systolic FunctionImprovement in Left Ventricular Systolic Function

0.090.090.030.030.440.44N/AN/APP value*value*

4.6 +/4.6 +/-- 4.24.25.3 +/5.3 +/-- 5.05.04.0 +/4.0 +/-- 3.33.33.2 +/3.2 +/-- 3.83.8Change at 12 Change at 12 weeksweeks

28.25 +/28.25 +/-- 14.814.827.7 +/27.7 +/-- 13.813.828.8 +/28.8 +/-- 15.815.829.6 +/29.6 +/-- 18.618.6EF at BaselineEF at Baseline

All Patients All Patients (n=77)(n=77)

Nesiritide Nesiritide 0.01 Dose0.01 Dose

(n=37)(n=37)


(n=40)(n=40)

Standard Standard CareCare

(n=38)(n=38)

0.090.090.030.030.440.44N/AN/APP value*value*

4.6 +/4.6 +/-- 4.24.25.3 +/5.3 +/-- 5.05.04.0 +/4.0 +/-- 3.33.33.2 +/3.2 +/-- 3.83.8Change at 12 Change at 12 weeksweeks

28.25 +/28.25 +/-- 14.814.827.7 +/27.7 +/-- 13.813.828.8 +/28.8 +/-- 15.815.829.6 +/29.6 +/-- 18.618.6EF at BaselineEF at Baseline

All Patients All Patients (n=77)(n=77)


(n=37)(n=37)


(n=40)(n=40)

Standard Standard CareCare

(n=38)(n=38)

*Compared to standard care.


CenterCenterNesiritideNesiritide: Overall Clinical Profile: Overall Clinical Profile

Vasodilation (venous > arterial)Vasodilation (venous > arterial)11

Rapidly improves symptoms of congestionRapidly improves symptoms of congestion11

Does not increase heart rate Does not increase heart rate (decreases myocardial oxygen demand)(decreases myocardial oxygen demand)11

Is not proarrhythmicIs not proarrhythmic11

1. Fonarow GC. Rev Cardiovasc Med. 2001;2(suppl 2):S32–S35.


CenterCenterNesiritideNesiritide: Overall Clinical Profile: Overall Clinical Profile

Neurohormonal suppression Neurohormonal suppression (decreases (decreases aldosteronealdosterone, NE), NE)11

Mild Mild diuresisdiuresis / natriuresis/ natriuresis22

No evidence of tachyphylaxisNo evidence of tachyphylaxis33

Symptomatic hypotension as low as 4% in VMACSymptomatic hypotension as low as 4% in VMAC11

Dosing convenience Dosing convenience (bolus + standard(bolus + standard--dose IV infusion)dose IV infusion)33

1. Fonarow GC. Rev Cardiovasc Med. 2001;2(suppl 2):S32–S35.2. Rayburn BK, Bourge RC. Rev Cardiovasc Med. 2001;2(suppl 2):S25–S31.3. Natrecor (nesiritide) [package insert]. Sunnyvale, CA: Scios Inc; 2001.


CenterCenterRole of Role of NesiritideNesiritide : Summary: Summary

First, used in addition to diuretics and before First, used in addition to diuretics and before conventional vasodilators and conventional vasodilators and inotropesinotropes

Excellent benefit / risk profile; Excellent benefit / risk profile; hypotension is the major side effecthypotension is the major side effect

Avoid in patients with cardiogenic shock, systolic Avoid in patients with cardiogenic shock, systolic blood pressure <90 mm Hg, or in patients with low blood pressure <90 mm Hg, or in patients with low cardiac filling pressurescardiac filling pressures


CenterCenterRole of Role of NesiritideNesiritide : Summary: Summary

Can be used in patients with renal disease, acute Can be used in patients with renal disease, acute coronary syndromes, diastolic dysfunction, and with coronary syndromes, diastolic dysfunction, and with serious arrhythmiasserious arrhythmias

Initial bolus dose (2 mcg/kg) followed by a fixedInitial bolus dose (2 mcg/kg) followed by a fixed--dose infusion (0.01 mcg/kg/min) dose infusion (0.01 mcg/kg/min)

may increase infusion rate of may increase infusion rate of nesiritidenesiritide up to a up to a maximum of 0.03 maximum of 0.03 µµg/kg/ming/kg/min


CenterCenter

Expanding the Therapeutic Applications of Expanding the Therapeutic Applications of NatriureticNatriuretic Peptides Peptides

Efficacy Trial, VMAC, PROACTION, PRECEDENT, FUSION I

Dyspnea & PCWP in ADHFOver 1,400 patients

Ongoing or Pending Investigations

FUSION II

Serial Outpatient Infusion

NAPAPeri-Post CT

Surgery Administration

TMACContinuous

Infusion Prior to heart

Transplantation

EMACContinuous Outpatient

Infusion End-Stage HF

PMACEarly ED

Administration in aHF w/

Pulmonary

REMACEarly

Administration aHF worsening Renal function

CMACEarly ED + Cath Administration

in ACS

Future Possibilities

CKD PAH Surgery PEDS Diastolic HF

The management of Acute Decompensated Heart...

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