Orlando, Florida – October 7-9, 2011

Medical Management of Acutely Decompensated Heart Failure

William T. Abraham, MDDirector, Division of Cardiovascular Medicine

Goals of Acute Heart Failure Therapy

Alleviate symptoms

Reduce extracellular fluid volume excess (“congestion”)

Improve hemodynamics• Decrease left and right ventricular filling pressures• Increase cardiac output (?)

Maintain perfusion to vital organs

How Do We Accomplish These Goals?

With hemodynamic interventions• Diuretics• Nitrovasodilators• Natriuretic peptides• Positive inotropic agents

Sympathomimetic agentsPhosphodiesterase inhibitorsCalcium channel sensitizers

• Mechanical interventions that improve hemodynamics

Pharmacological Approach To Acute Heart Failure Therapy

Diuretics to reduce ECF volume• IV loop diuretics ± metolazone/thiazide

Intravenous vasodilators to reduce ventricular filling pressures• Nesiritide, nitroglycerin, nitroprusside

Intravenous inotropic agents to improve cardiac output• Sympathomimetic agents• Phosphodiesterase inhibitors

Importance of Diuretic Therapy in Acutely Decompensated Heart Failure

Beneficial effects of diuretic therapy:• ↓ End-diastolic volume (preload)• ↓ Systemic vascular resistance

(acutely, may ↑ SVR)• ↑ Cardiac output / stroke volume• ↓ Congestive symptoms• ↑ Exercise capacity

Key to successful initiation and titration of ACE inhibitors, β-blockers, vasodilators

6

LoopLoopofof

HenleHenle

CollectingCollectingDuctDuct

CortexCortex

OuterOuterMedullaMedulla

InnerInnerMedullaMedulla

AldosteroneAldosterone--sensitivesensitiveGlomerulusGlomerulus

Acetazolamide

ProximalProximalConvolutedConvolutedTubuleTubule Furosemide

Ethacrynic AcidBumetanideTorsemide

ThiazidesMetolazone

SpironolactoneTriamterene

Amiloride

Tubular Sites of Action of Commonly-used Diuretics

Abraham and Schrier, 1994

Limitations Of Diuretic Therapy

Electrolyte abnormalities• Hypokalemia• Hypomagnesemia• Hyponatremia

Volume depletionPre-renal azotemiaHyperuricemiaDiuretic resistance

8

Loop Diuretics Diminish GFR In Patients with Heart Failure

Gottlieb et al., 2000

63.4

81.5

40

50

60

70

80

90

Placebo Furosemide

Glo

mer

ular

Filt

ratio

n R

ate

(ml/m

in)

p < 0.001

n = 12

9

Increased MorbidityIncreased MorbidityAnd MortalityAnd Mortality

Diuretic TherapyDiuretic Therapy

Impaired RenalImpaired RenalFunctionFunction

Decreased RenalDecreased RenalPerfusionPerfusion

DevelopmentDevelopmentOf DiureticOf DiureticResistanceResistance

DiminishedDiminishedBlood FlowBlood Flow

NeurohormonalNeurohormonalActivationActivation

The “Iatrogenic” Cardio-Renal Syndrome of Heart Failure

Abraham WT, 2004

10

Ultrafiltration Fluid Removal System

FDA approvedUses peripheral venous access (can also use central access)Total extracorporeal blood volume 33 mLDesigned to remove up to 500 ml of fluid per hour with adjustable flow rates of 10-40 mL/minHighly automated, computer controlled operation with simple operator interface

Ultrafiltration versus IV Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure: A Prospective Randomized Clinical Trial

The UNLOAD Trial

Costanzo MR, et al., JACC 2007

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Primary End Point: Weight Loss at 48 Hr

Effects on Worsening Heart Failure Over 90 days

0.0220.022330330123123Days ReDays Re--hospitalizedhospitalized

P ValueP ValueSCSCUFUF

0.0090.00944442121(Unscheduled office + ED visits) %(Unscheduled office + ED visits) %

0.0220.0223.83.81.41.4Number of ReNumber of Re--hospitalization hospitalization days/patientdays/patient

0.0370.0370.460.460.220.22ReRe--hospitalizations/patienthospitalizations/patient

0.0220.02232321818Patients RePatients Re--hospitalized %hospitalized %

0.0220.022330330123123Days ReDays Re--hospitalizedhospitalized

P ValueP ValueSCSCUFUF

0.0090.00944442121(Unscheduled office + ED visits) %(Unscheduled office + ED visits) %

0.0220.0223.83.81.41.4Number of ReNumber of Re--hospitalization hospitalization days/patientdays/patient

0.0370.0370.460.460.220.22ReRe--hospitalizations/patienthospitalizations/patient

0.0220.02232321818Patients RePatients Re--hospitalized %hospitalized %

Intravenous Positive Inotropic Agents

Phosphodiesterase inhibitors• milrinone• enoximone

Sympathomimetics• dopamine• dobutamine• isoproterenol• epinephrine• norepinephrine

Calcium channel sensitizers• levosimendan

15

Selection of an Inotropic Agent

Mehra M. Heart/Lung 1997; 26:280-288.

Dobutamine Milrinone

SBP<80 1st choice Usually incombination withpressor

Pulmonary Not a good 1st choiceHTN pulmonary lowers PVR

vasodilator

Myocardial ↑ myocardial 1st choiceischemia O2 demand ↓↔ myocardial O2

demand

Limitations Of Positive Inotropic Therapy

Tolerance/TachyphylaxisHypotensionTachycardiaOther arrhythmias• Ventricular tachycardia• Atrial fibrillation/flutter

Increased mortality?

IV Milrinone During Hospitalization for Decompensated Heart Failure

Cuffe MS et al. JAMA 2002; 287:1541–1547.

Eve

nt R

ate

( %)

Treatment Failure From Adverse Event (48 h)

Sustained Hypotension

Acute MI Mortality

MilrinoneMilrinonePlaceboPlacebo

Afib

P < 0.001 P < 0.001

P = 0.18

P = 0.004 P = 0.19

12.6

2.1

10.7

3.21.5

0.4

4.6

1.5

3.82.3

0

5

10

15

20OPTIME-CHF: In-hospital Adverse Events

18

Hemodynamic Effects of Vasodilators

CO = cardiac output; HR = heart rate; LVFP = left ventricular filling pressure;SVR = systemic vascular resistance.

Nitroglycerin

Nitroprusside

Synthetic hBNP

HR CO LVFP SVR

Limitations Of Nitrovasodilators

Tolerance/TachyphylaxisHypotensionToxicity• Thiocyanate• Cyanide

Vasoconstrictor activationFluid retention

Natriuretic Peptides

Produce selective renal afferent arteriolar vasodilation

Inhibit sodium reabsorption in the collecting duct

Improve/maintain glomerular filtration

Inhibit renin and aldosterone (and possibly vasopressin and adrenergic activity)

Improve systemic hemodynamics

The Natriuretic Peptide Family

Naturally Occurring• ANP - Atrial or A-Type Natriuretic Peptide• BNP - Brain or B-Type Natriuretic Peptide• CNP - C-Type Natriuretic Peptide• DNP - Dendroaspis or D-Type Natriuretic Peptide• Urodilatin - Extended form of ANP

Designer

22

Added to standard therapy; N = 242*P<0.05 for nesiritide or placebo vs placebo† P<0.05 for nesiritide vs. nitroplycerin

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

VMAC Trial: PCWP Through 3 Hours

Placebo

Mea

nC

hang

e in

PC

WP

(mm

Hg)

Nitroglycerin Nesiritide

–6

–5

–4

–3

–2

–1

1 2 3BL

0

Hours

* †*

* †* † * * †

ASCEND‐HF Trial

Landmark trial presented at AHA LBCT Session November 2010

Largest RCT in ADHF (7,141 subjects)

Results clearly demonstrate the safety of natriuretic peptides in the treatment of ADHF

Unambiguously answers the critical questions raised by meta‐analyses published in 2005

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ASCEND-HF Trial: Primary Endpoint

Investigational Strategies in ADHF

Second-Generation Natriuretic Peptides• Urodilatin• CD-NP

Relaxin

Nitroxyl Donors

Vasopressin Antagonists

Others

Approach to Acute Therapy in Volume Overloaded Heart Failure Patients

IV Diuretics

Adequate Perfusion

IV Diureticsplus

IV Vasodilators

Reduced Perfusion

IV Diureticsplus

IV Inotropes

Cardiogenic Shock

Clinical Congestion