HEART FAILURE Guidelines for the Treatment Facts … · Guidelines for the Treatment of HEART FAILURE ... Stopped due to increase mortality in moxonidine arm? ... Therapies in Heart

1

Guidelines for the Treatment of

HEART FAILURE

Leslie W. Miller

University of Minnesota

HEART FAILUREFacts

• 5 million patients with CHF in U.S.

• 550,000 new cases/year

• 300,000 deaths/year

• 4 fold increase in risk mortality

• >10% people over 65 yo will develop HF

End-Stage Congestive Heart FailureScope of Problem

• 1 million hospitalizations/year as #1 Diagnosis,

• 2.5 million as # 2 or 3 Discharge Diagnosis

• Average LOS=5.7 days

• Highest DRG Volume Dx (days X # pts)

• Highest readmission rate

• Number 1 discharge Diagnosis in pts >63 y.o.

• Increasing age of population will double in 15 yrs

HEART FAILUREEstimated Prevalence by Age & Gender

0.3 0.21.3

4.7

8.2

10.1

4.9

0.50.72.1

0.10

2

4

6

8

10

12

20-29 30-39 40-49 50-59 60-69 70-79 >80

Age (Years)

Males Females

10.6

Total = 5 million

% of Population

9

Demographic TrendsElderly U.S. population will double with graying of “baby boomer”generation

0

25

50

75

1990 2000 2010 2020 2030

Projected Elderly

Population Age 65+

(millions)12.6% total US population

31.5 million

65.6 million

21.8% total US population

ACC/AHA Guidelines on Heart FailureDefinition

HF is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.No longer “Congestive” HF, because not all patients have volume overload, but low output

2

Symptomatic HEART FAILUREDiastolic Dysfunction

Ejection Fraction

103

9

3

8

35

3 19

10

0%

20%

40%

60%

80%

100%

Men Women

>.60.50-.59.41-.49.31-.40<.30

(n=40) (n=33)

Vasan et al, JACC ‘99;33(7):1948-55

E.F.

Primary Diastolic Dysfunction

Hypertension is the leading cause

Prevalence Increases in advancing Age

Effects Women > men

ECHO is the best way to make diagnosis

Treatment: control HR and BP

No mortality benefits in Diastolic HF

Rx: Beta Blockers, ARB,ACEI, CCB

Treatment of Heart Failure Changing Goals for Therapy

ERA TARGET THERAPY

60’s Symptoms Diuretic/Digoxin

70’s Hemodynamics Inotropes/Vasodil.

80’s Survival ACEI/β-Blockers

90’s Remodeling ACEI/β-Blockers

2000 Prevention Earlier Dx/Rx

Pathophysiology of CHF

CHF SyndromeRemodeling

Altered Gene Expression

NP’s SNS Cytokines VP

↓ contractility↑ wall stress

ADM ET-1

Ischemia Valve Infection Inflam. Genetic ToxinsHTN

RAAS

ACC/AHA Guidelines on Heart FailureDrug Treatment

Beta Blocker

Digoxin

Diuretic

ACEIHydral/Nitr

ARB

3

Treatment of Heart Failure

Neurohormonal Antagonism

What is the Renin-Angiotensin System (RAS)?Angiotensinogen

Angiotensin I

Angiotensin II

Angiotensin IIReceptors

(Subtype AT 1)

Vasoconstriction

Blood Pressure

Renin

nonACE ACE

Aldosteronesecretion

Sympatheticactivation

Inactive fragments

ChymaseCAGECathepsin G

BradykininSubstance PEnkephalins

Renin

Bradykinin,Substance P

ACE Inhibitor

Angio-tensinogen

Angiotensin IAngiotensin II

Chymase, Cage etc.

ACE Inhibitors – Mechanism of Action

ACE

VasoconstrictionAldosteroneVasopressinSympathetic

tPAProstaglandinsVasodilation

Kininase II

Treatment of Heart FailureHOPE - Secondary Endpoint Results

7.4

16

3.8

9.4

18.4

5.5

0

5

10

15

20

25

% w

ith a

n ev

ent

RamiprilPlacebo

All Heart Failure Any RevascularizationProcedure

New Onset of Diabetes Mellitus

22% Risk Reductionp=0.0005

15% Risk Reductionp=0.0013

31% Risk Reductionp<0.01

4

• Consistent Survival BenefitRelative Risk Reduction 15-20%Absolute Risk 3-4%

• 7-10% intolerance

• No significant change in cardiac ejection fract.

• May not be as effective in Afr.-Americans

• Genotype may influence response

• May be a dose maximum – alternative pathway

Limitations of Medical Rx of HFACE Inhibitors

Pathophysiology of CHF Renin Angiotensin SystemAlternate Pathway – ARB’s

Angiotensin II

Angiotensin I

ATIConstrictionGrowth

ATIIVasodilationAntiprolit.

Renin

ACE(I)

Angiotensinogen

CaspaceCathepsin

Receptor

XARB

X

Val-HeFTStudy Design

HF patients ≥18 yr; EF<40%; NYHA II–IV

Valsartan40 mg bid titrated

to160 mg bid

906 deaths (events reported)

Randomized to

Receiving Standard TherapyACEI, diuretics, digoxin , β-blockers (stratified)

Placebo

J. N. Cohn et. al, J. Card. Fail. 1999; 5: 155-160

0

20

40

60

80

100

0 0.5 1 1.5 2 2.5 3 3.5

CHARM: ADDED TrialCumulative Event Outcome

Candesartann=1272

Placebon=1276

Pro

porti

on w

ith C

ardi

ovas

cula

r Dea

th o

rH

ospi

tal A

dmis

sion

for C

HF

(%)

Years

Lancet 2003;362:767-771

P=0.011

• No significant benefit over ACEI (or difference)

• Addition to ACEI decreases hospitalizations, and

may improve survival

Better tolerated than ACEI’s

• Use of High dose ACEI(>20 mg/d) may lead to

conversion of ANG I-II via alternative pathway

LimitationsARB’s

Sympathetic Activation and Increased Heart Failure Mortality

1.0

0.8

0.6

0.4

0.2

00 10 20 30 40 50 60

Time (Months)

Prob

abili

ty o

f Sur

viva

l

PNE < 400 pg/mL

PNE 400-800 pg/mLPNE > 800 pg/mL

Cohn, JN et al. N Engl J Med 1984; 311:819-824.PNE = Plasma norepinephrine

5

Spill

over

of N

orep

inep

hrin

eto

Pla

sma

(% o

f nor

mal

)

500

300

100

0

1104%

Total Heart Gut &Liver

Lungs Kidney

Norepinephrine Spillover in Heart Failure

Esler et al. Hypertension 1988

1000

Rec

epto

r Den

sity

(fm

ol/m

g)

Non-failing

Failing (IDC)

* P < 0.05 vs. non-failingIDC = Idiopathic Dilated Cardiomyopathy Bristow MR et al. Clin Drug Ther 1989

Adrenergic Receptor Densities in Human LV Myocardium

70

60

50

40

30

20

10

0β1 β2 α1

*

*

Sympathetic activation

Remodelling Effects

Metoprolol

Propranolol

Carvedilol

Antiadrenergic Therapy-βeta Blockade

β2receptors

β1receptors

α1receptors

6

0

5

10

15

20

%

diuretic

digoxin

diuretic

digoxin

ACE-I

diuretic

digoxin

ACE-I

diuretic

digoxin

ACE-I

β blocker

diuretic

digoxin

ACE-I

β blocker

diuretic

digoxin

ACE-I

β blocker

ARB

SOLVD-T (1991)

RRR 21%

MERIT(1999)

RRR 33%

CHARM-Added (2003) (β blocker subgroup)

RRR 30%

Improving survival in CHF1-year mortality

Beta Blockers in CHFRole of Norepinephrine

Moxonidine (Moxcon) Study

Moxonidine: Central acting agent (Clonipin) causes a decrease in norepinephrin

Study: 1,950 patients enrolled (4,500 goal) All on ACE, Dig, Diuretic + Moxonidine vs Placebo

Stopped due to increase mortality in moxonidine arm

? Too rapid a reduction NE

Sympathetic Nervous Blockade Failed MOXCON Trial

0123456789

10111213141516

Death Worse HF MI

% P

atie

nts

CardiovascSAE

Combination

Placebo (n=875)Moxonidine (n=918)

Eur J Heart Fail. 2003 Oct;5(5):659-67 Floras JN. Circulation. 2002;105:1753.

Relationship Between LV Remodeling and CV Events Post-MI

0

1

2

3

4

5

6

7

End Diastole End Systole

∆in

LV

Area

at 1

Yea

r (cm

2 )

No Events n=309

CV Events n=111p<0.001

St. John Sutton M et al. Circulation. 1994;89:68–75.

2-D echocardiography obtained at a mean of 11.1 ± 3.2 days after acute MI and 1 year later

p<0.001

0

20

40

60

>4 cm/m2 <4 cm/m2LVEDD

2-Ye

ar M

orta

lity

(%)

P = 0.004

Lee TH et al. Am J Cardiol 1993

Ventricular Remodeling in HF Relationship Between LV Size

and Outcome in CHF

7

∆LV

ESVI

(bip

lane

) [m

l/m2 ]

P values for ∆ BL to M6, M12, M18

Remodeling: CARMEN TrialEffect of ACEI vs BB on LVEDV

Carvedilol & EnalaprilCarvedilolEnalapril

-7

Month 6 Month 12 Month 18Baseline

NS P < 0.002

-6

-5

-4

-3

-2

-1

0

P < 0.05

• Fairly Consistent Survival BenefitRelative Risk Reduction 25-65%Absolute Risk Reduction 7-9%(on top of ACE, Dig, Diuretic)

• Significant increase E.F.• Primarily Class II-III HF, but also Class IV• May be less effective in Afr.-Americans• Class effect, but also unique individual agents

Limitations of Medical Rx of HFBeta Blockers

Use of Evidence-Based Therapies in Heart Failure

LVEF Documented at < 0.40

44.3

10.0

40.9

68.0

31.9

Outpatient HF Medication

Patie

nts

Rec

eivi

ng T

hera

py (%

)

ARB

ß-Blocker

Diuretic

Digoxin

ACE Inhibitor

0

10

20

30

40

50

60

70

80

90

100

Excludes patients with documented contraindications. The ADHERE database. Data from 2300/7883 patients hospitalized with heart failure; prior known diagnosis of systolic dysfunction heart failure; outpatient medical regimen. Collected between July 2001 and July 2002 (unpublished data). 180 US Hospitals.

Saluresis and Diuresis

Complications of Diuretic Therapy for Heart Failure

↑ Distal Ca++Reabsorption

↓ Plasma Volume

↓ Uric AcidClearance

Diuretic Therapy

↓ Cardiac Output ↓ Renal Blood Flow

Hyponatremia

↑ PRA

↓ GFR

↑ ProximalReabsorption

↑ Aldosterone

Kaliuresis

Hypokalemia

Glucose IntoleranceHypocalcemiaHyperuricemia

↓ CalciumClearance

Pre-renalAzotemia

PosturalHypotension

↓ Renal Reabsorption of Na (and Mg) Hypomagnesemia

SLIDE NOT FINISHED

8

The RALES Trial: Effect ofSpironolactone on Survival in CHF

Months

Prob

abili

ty o

f Sur

viva

l

Number at riskPlacebo 841 775 723 678 628 592 565 483 379 280 179 92 36Spironolactone 822 766 739 698 669 639 608 526 419 316 193 122 43

Total mortality↓ 30% (p < 0.001)

Pitt B, et al. N Engl J Med 1999; 341:709-717

Spironolactone

Placebo

1.00

0.95

0.90

0.85

0.80

0.75

0.70

0.65

0.60

0.55

0.50

0.45

0.000 3 6 9 12 15 18 21 24 27 30 33 36

DIG Study

Sudden death

Pump failure

Cardiovascular

All cause mortality

Cause of Death

1.12

0.86

1.03

1.00

Risk Ratios

0.13(0.96-1.31)

(0.76-0.99)

(0.95-1.12)

0.92(0.93-1.09)

P valueConfidence Intervals

NP’s

BNP(ventricle)

DNP(kidney)

Pathophysiology of CHFNatriuretic Peptides

ANP(atria)

CNP(endothelium)

rhBNPD

R I

MKRG

S SS

SGLG

FC CS SG

SGQVMK V L R

RH

KPS

Effects of NesiritideVASODILATION

CARDIACINDEX

PreloadAfterloadPCWPDyspnea

HEMODYNAMIC

CARDIACNo increase in HRNot proarrhythmic

AldosteroneEndothelinNorepinephrine

SYMPATHETIC AND NEUROHORMONAL SYSTEMS

RENAL

NATRIURESISDIURESIS

Fluid volumePreloadDiuretic usage

[Hb]<11.8g/dL (n=102)

[Hb] 11.8-13.2g/dL (n=107)

[Hb] 13.3-14.4g/dL (n=114)

[Hb] >14.4g/dL (n=113)

6004002000

1.0

.9

.8

.7

.6

.5

.4

Time (days)

Dea

th o

r Urg

ent T

rans

plan

t

Data courtesy Dr. G. Fonarow (UCLA) adjusted for age, sex, BMI, LVEF, LVEDD, SCr, etiology, DM

The Effect of Anemia on Survival in CHF Patients Outside the Clinical Trial Setting

Hb quartiles

9

Effect of Anemia Treatment on Regression of LVH*

*Portoles et al. Am J Kidney Dis. 1997;29:541-548. 2. Casale et al. Ann Intern Med. 1986;10:173-178.

130

150

170

190

Baseline 6 mo

LVM

I (g/

m2 )

*

P < .05N = 11

LVMI

20

25

30

35

40

Hct

(%)

Hct

P < .001N = 11

*Note: Normal LVMI2 = 125 g/m2

Pathophysiology of CHFMediators of Vascular Tone

VasodilatorsOld

Beta Adrenergic Recept.

NewNatriuretic Peptides Nitric OxideAdrenomedullinBradykinin

VasoconstrictorsOldAlpha Adrenergic Recept.

NewEndothelinAngiotensin II

↔

• Age -ELITE , HOPE• Race –ACEI, Beta Blockers, Hydral/Nit• Gender –DIG Trial• Etiology-PRAISE (CCB) • Dose- ATLAS• Genomics-BETA 2AR, iNOS, ACE I/D• Pharmacogenomics-Metoprolol

Limitations of Drug Therapy for HFFactors Affecting Outcome

• Many issues that effect the response to a given oral HF drug

• ACEI’s, ARB’s, and BB’s remain the most consistent drugs to favorably alter survival

• Most promising new drugs have not been shown to have a survival benefit

• Device therapies will likely play a significant role in HF therapy in the future

Limitations of Oral HF TherapySummary

Stem Cell Therapy in AMI:TOPCARE Study

Assmus et al, Circulation 2002;106:3009-17

Intracoronary Infusion

20 pts3-6 days post MI

9 pts: Bone marrowaspiration

11 pts: 250 cc peripheral blood drawn

Mononuclear cellsisolated

Ex vivo EPC expansionin cell culture (3 days)

10

TOPCARE-AMI

4 Month Follow-up:• Improved EF• Improved wall motion• Reduced end-systolic

diameter

No change in matched reference group

No difference b/w BM or PB groups

No Placebo group

Assmus et al, Circulation 2002;106:3009-17

Baseline 4-months

University of Frankfurt