Current Therapies for the Management of Chronic and

Acute Heart Failure

John L. Tan, MD, PhDHeart Failure Program at the

North Texas Heart Center

Presbyterian Hospital of Dallas

Adapted from AHA Heart and Stroke Facts Statistical Update, 1999; Kannel and Belanger, 1991; Stevenson et al, 1993; O’Connell and Bristow, 1994AHA. 2001 Heart and Stroke Statistical Update.

Heart Failure: The Scope

Prevalence 4.6 million Americans

Incidence 550,000 new cases/year 10 per 1000 population after age 65

Morbidity 1,000,000 hospitalizations (2001) 5 to 10% of all admissions Most frequent cause of hosp in elderly

Mortality Contributes to 260,000 deaths/year Up to 70% of patients die suddenly Five year mortality rate ~50%

$38.1 billion in 1991

Rising to an estimated ~$54 billion in 1999

Accounting for approximately twice the cost for cancer or myocardial infarction

5.4% of total health care costs

Single largest expense for MedicareAdapted from AHA Heart and Stroke Facts Statistical Update, 1999; Kannel and Belanger, 1991; Stevenson et al, 1993; O’Connell and Bristow, 1994AHA. 2001 Heart and Stroke Statistical Update.

Cost of Heart Failure

Etiology of Heart Failure (SOLVD Registry)

Bourassa et al. J Am Coll Cardiol. 1993;22:14A-19A.

Ischemic heart disease68.6%

Hypertension7.2%

Other11.3%

Idiopathic cardiomyopathy

12.9% N=6063Valvular heart disease

Congenitalheart disease

ViralToxic

ThyroidPeripartum

The New Classification of Heart Failure

Stage Patient Description

A High risk for developing heart failure (HF)

• Hypertension• CAD • Diabetes mellitus• Family history of cardiomyopathy

B Asymptomatic HF • Previous MI• LV systolic dysfunction• Asymptomatic valvular disease

C Symptomatic HF • Known structural heart disease• Shortness of breath and fatigue• Reduced exercise tolerance

D Refractory end-stage HF

• Marked symptoms at rest despite maximal medical therapy (eg, those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions)

Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.

Heart failure is more than a symptomatic diseaseProduces symptoms, limits functional capacity, and impairsquality of life

Heart failure is a progressive diseaseWorsening symptoms and clinical deterioration, repeatedhospitalization, and death

Death occurs frequently even in the presence of minimalsymptoms or the absence of progressive symptoms

Symptoms do not always correspond with ejection fraction

Symptom Relief is Not Sufficient

Ventricular RemodelingVentricular Remodeling After Acute Infarction

Ventricular Remodeling in Diastolic and Systolic HF

Initial infarct

Expansion of infarct(hours to days)

Global remodeling(days to months)

Normal heart

Hypertrophied heart(diastolic HF)

Dilated heart(systolic HF)

Jessup M et al. N Engl J Med. 2003;348:2007

Myocardial InjuryMyocardial Injury Fall in LV performanceFall in LV performance

Activation of RAAS, SNS, ET,Activation of RAAS, SNS, ET,and othersand others

Myocardial toxicityMyocardial toxicity Peripheral vasoconstrictionPeripheral vasoconstrictionHemodynamic alterationsHemodynamic alterations

Remodeling andRemodeling andprogressiveprogressive

worsening ofworsening ofLV functionLV function Heart failureHeart failure

symptomssymptomsMorbidityMorbidity

and mortalityand mortality

ANPANPBNPBNP

-

-

Heart Failure PathophysiologyHeart Failure Pathophysiology

Neurohormonal Targets in Heart Failure

Angiotensinogen

Angiotensin I

AT II

AT1 Receptors

ACE Inhibitors

SNS Activation

EpinephrineNorepinephrine

Target Cells

~7000 patients evaluated in long-term placebo- controlled clinical trials

Improvement in cardiac function, symptoms, and clinical status; equivocal effects on exercise tolerance

Decrease in all-cause mortality by 20-25% (P<.001) and decrease in combined risk of death and hospitalization by 30-35% (P<.001)

Garg and Yusuf, 1995.

ACE Inhibitors in Heart Failure

1.0

0.8

0.6

0.5

0

0 21 3 4 5

Survival

Year

CONSENSUS

PROMISE

PRAISE

SOLVD-Prevention

SOLVD-Treatment

DIG

V-HeFT

ACE inhibitor arms of CONSENSUS, V-HeFT, and SOLVD trials.Placebo arms of PRAISE, PROMISE, and DIG trials (all receiving ACE inhibitors).

Mortality in Patients Receiving ACE Inhibitors

Neurohormonal Targets in Heart Failure

Angiotensinogen

Angiotensin I

AT II

AT1 Receptors

ACE Inhibitors

SNS Activation

EpinephrineNorepinephrine

Target Cells

-Blockers

-Blockers

Effect of -Blockade on All-Cause Mortality

0 0.25 0.5 0.75 1 1.25 1.5 1.75 2

Relative risk and 95% confidence intervals

CIBIS-I: 1.9 yearsplacebo 67/321 (20%); bisoprolol 53/320 (16%)P=.22

CIBIS-II: 1.3 yearsplacebo 228/1320 (17%); bisoprolol 156/1327 (12%)P=.0001

MERIT-HF: 12 monthsplacebo 217/2001 (11%); metoprolol 145/1990 (7%)P=.006

US Carvedilol Trials: 7.6 months placebo 31/398 (8%); carvedilol 22/696 (3%)

P=.001

All-cause mortality: 35% decreased risk

.

100

90

80

60

70

50

240 20161284 28

Placebo(n=1133)

Carvedilol(n=1156)

Months

% S

urv

ival

P=0.00014

COPERNICUS

The CHF Trials in Perspective: Patients Needed to Treat for One Year to

Save One Life

HF Stage Trial # of Patients

A HOPE 333 B SOLVD-Prevention 285 C SOLVD-Treatment 77 C CIBIS-II 23 C MERIT-HF 25 D COPERNICUS 14

Neurohormonal Targets in Heart Failure

Angiotensinogen

Angiotensin I

AT II

AT1 Receptors

ACE Inhibitors

SNS Activation

EpinephrineNorepinephrine

Target Cells

ARBs

12761272

11761136

10631013

948906

457422

Number at risk:CandesartanPlacebo

Time (years)

CHARM-Added: CHARM-Added: Primary EndpointPrimary Endpoint

HF, heart failure; HR, hazard ratio; CI, confidence interval.McMurray JJV et al. Lancet. 2003;362:767-771.

CV death or HF hospitalization (%)

0 1 2 30

10

20

30

40

50

Placebo

Candesartan

3.5

HR 0.85 (95% CI 0.75-0.96), P=0.011Adjusted HR 0.85, P=0.010

483 (37.9%)

538 (42.3%)

15% risk reduction

A-HEFT: Role of Hydralazine/NitratesA-HEFT: Role of Hydralazine/Nitrates

Taylor AL, et al. N Engl J Med. 2004;351:2049-57

Mortality 43%

Hospitalization 33%

A-HeFT: Hydralazine/Nitrates

African-Americans (n = 1050) LVEF < 35% or <45% with increased LVEDD NYHA Class III-IV ~70% on ACE-I, ~74% on -B Baseline SBP ~125 mm Hg Etiology of CMP

~40% Hypertension~23% CAD Taylor AL, et al. N Engl J Med. 2004;351:2049-57

Neurohormonal Targets in Heart Failure

Angiotensinogen

Angiotensin I

AT II

AT1 Receptors

ACE Inhibitors

SNS Activation

EpinephrineNorepinephrine

Target Cells

Aldosterone Receptor Blockers

RALES: Aldosterone Receptor BlockadeRALES: Aldosterone Receptor Blockade

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

Spironolactonen = 1663

NYHA III/IVLVEF < 40%

mortality 27%

hospitalization 36%(p<0.0002)

NYHA II NYHA III

HF12%

Other24%

Suddencardiacdeath64%

HF26%

Other15%

Suddencardiacdeath59%

Mode of Death in MERIT-HF

MERIT-HF Study Group. Lancet. 1999;353(9169):2001-2007.

Device Therapies in Heart Failure: Implantable

Cardioverter-Defibrillators

Patients with prior MI within 30 days and LVEF < 30% randomized in a 3:2 ratio 71 US centers and 5 European centers

Patients with prior MI within 30 days and LVEF < 30% randomized in a 3:2 ratio 71 US centers and 5 European centers

Conventional medical therapy

(n=490)

Conventional medical therapy

(n=490)

Implantable defibrillator

(n=742)

Implantable defibrillator

(n=742)

All Cause Mortality - Average follow-up of 20 monthsAll Cause Mortality - Average follow-up of 20 months

Stopped early by Data Safety Monitoring BoardStopped early by Data Safety Monitoring Board

MADIT II: Study Design

19.8%

14.2%

0%

5%

10%

15%

20%

25%

19.8%

14.2%

0%

5%

10%

15%

20%

25%

ConventionalTherapy

ConventionalTherapy

ICDICD

P=0.016P=0.016

DeathAvg. follow-up=20 months

DeathAvg. follow-up=20 months

MADIT II: All-Cause Mortality

Hazard Ratio =

0.65

Hazard Ratio =

0.65

R

SCD-HeFT: Enrollment SchemeDCM + CAD and CHF

EF < 35%

NYHA Class II or III

6 minute walk, Holter

Placebo Amiodarone ICDBardy G et al. NEJM 2005; 352:3

n=2521, 1:1:1

SCD-HeFT: Death from Any Cause

Bardy G et al. NEJM 2005; 352:3

23% RR Reduction in Death7.2% Absolute Reduction at 5 yrs

Bardy G et al. NEJM 2005; 352:3

SCD-HeFT: Death from Any Cause in Ischemic CHF

Bardy G et al. NEJM 2005; 352:3

SCD-HeFT: Death from Any Cause in Nonischemic CHF

SCD-HeFT: Primary Conclusions

In class II or III CHF patients with EF < 35% on good background drug therapy, the mortality rate for placebo-controlled patients is 7.2% per year over 5 years

Simple, single lead, shock-only ICDs decrease mortality by 23%

Amiodarone, when used as a primary preventative agent, does not improve survival

Bardy G et al. NEJM 2005; 352:3

Mortality Benefits of HF Therapies

1.3

3.8

1.9

0

0.5

1

1.5

2

2.5

3

3.5

4

SOLVD MERIT -HF SCD-HeFT

Absolute Annual Mortality Reduction During Trial

% A

bsol

ute

Red

ucti

on

Indications for ICDs in CHF

CHF for at least 3 months Ejection fraction less than or equal to 35% NYHA Class II or III symptoms Greater than 1 year life expectancy Ischemic or non-ischemic cardiomyopathy No QRS duration requirements

CMS Website

Device Therapies in Heart Failure: Cardiac

Resynchronization

Myocardial Dyssynchrony

Cardiac ResynchronizationCardiac Resynchronization in Heart Failure in Heart Failure

Indications: EF <35%

NYHA III-IV

QRS >130-150ms

Cha

nge

in 6

-min

ute

Wal

king

Dis

tanc

e (m

)

Months after Randomization

60

40

20

0

-20 0 1 3 6

P = 0.005

P = 0.003

P = 0.004

MIRACLE Trial, N Engl J Med 2002;346:1845-53

ControlResynchronized

Cardiac Resynchronizationin Heart Failure

Cha

nge

in Q

uali

ty-o

f-L

ife

Sco

re

Months after Randomization

0 1 3 6

0

-5

-10

-15

-20

-25

P < 0.001

P < 0.001P = 0.001

MIRACLE Trial, N Engl J Med 2002;346:1845-53

ControlResynchronized

Cardiac Resynchronizationin Heart Failure

The COMPANION Trial

1520 patients (1:2:2) NYHA Class III-IV EF </=35% QRS > 120 ms 11.9-16.5 month f/u Study withdrawal

26% Placebo 6% Bi-V Pacemaker 7% Bi-V-ICD

The COMPANION Trial

Bristow MR, et al. N Engl J Med. 2004;350:2140-50

The COMPANION TrialThe COMPANION Trial

Bristow MR, et al. N Engl J Med. 2004;350:2140-50

Optimal Therapy for Chronic Heart Failure

In Symptomatic Patients: Diuretics Digoxin

Optimal Therapy for Chronic Heart Failure

ACE Inhibitors (or ARBII Blockers) Beta-blockers ARBII Blockers or Hydralazine/Nitrates ICD Therapy (Class II or higher CHF)

Optimal Therapy for Chronic Heart Failure

In Persistent Class III-IV CHF: Spironalactone Bi-ventricular pacer (Prolonged QRS)

14.9%

19.9%

0%

5%

10%

15%

20%

14.9%

19.9%

0%

5%

10%

15%

20%

ConventionalTherapy

ConventionalTherapy

ICDICD

P=0.09P=0.09

New or Worsening Heart FailureNew or Worsening Heart Failure

MADIT II: CHF

Heart Failure Heart Failure Hospitalizations

0

100,000

200,000

300,000

400,000

500,000

600,000

Dis

char

ges

Women

Men

AHA, 1998 Heart and Statistical UpdateNCHS, National Center for Health Statistics

The number of heart failure hospitalizations is increasing in both men and women

CDC/NCHS: Hospital discharges include patients both living and dead.AHA Heart and Stroke Statistical Update 2001

Rising Hospital Admissions for Heart Failure

Inevitable progression of disease

Rising incidence of chronic heart failure (population aging, improved survival with AMI/revascularization)

Incomplete treatment during hospitalization

Poor application of chronic heart failure management guidelines

Noncompliance with diet and drugs

Emergency Department Visits for Congestive Heart Failure

Initial Episode * 21%

Repeat Visit 79%

Rates of Hospital Readmission2% within 2 days 20% within 1 month

50% within 6 months

Approximately 80% of the ED visits for CHF

result in hospitalizations

Cardiology Roundtable 1998

Utilization of HF Medications

50.8

12.8

57.4

80.8

41

01020304050

60708090

100

ACE-I ARBII-B Beta-Blocker Diuretics Digoxin

2300/7883 patients hospitalized with HF; prior known LV systolic dysfunction; outpatient medical regimen

ADHERE™ Registry Report Q1 2002 (4/01–3/02) of 180 US Hospitals. Presented at the HFSA Satellite Symposium, September 23, 2002

*Excludes patients with documented contraindications

Pat

ien

ts T

reat

ed (

%)

Causes of Hospital Readmissionfor Heart Failure

17%Other19%

Failure to Seek Care

16%Inappropriate Rx

Rx Noncompliance 24%

Diet Noncompliance24%

Vinson J Am Geriatr Soc 1990;38:1290-5

Heart Failure Costs

60.6%Hospitalizations$23.1 billion

38.6%Outpatient care$14.7 billion(3.4 visits/year/patient)

O’Connell and Bristow. J Heart Lung Transplant. 1994;13:S107-S112.

0.7%Transplants$270 million

Total = $38.1 billion(5.4% of total healthcare costs)

Congestion at Rest

Car

dia

c ou

tpu

t/P

erfu

sion

at R

est

Normal

No Yes

Low

Warm & Dry

(normal)

Warm & Wet

Cold & WetCold & Dry

Signs/symptoms

of congestion Orthopnea/PND JVD Ascites Edema Rales

Possible evidence of low perfusion Narrow pulse pressure Sleepy/obtunded Low serum sodium

Cool extremities Hypotension with ACE inhibitor Renal dysfunction (one cause)

Stevenson LW. Eur J Heart Fail. 1999;1:251

ADHF: Clinical Assessment

Risk Stratification of Patients with ADCHF

SYS BP 115 n=24,933

SYS BP 115 n=7,147

6.41% n=5,102

15.28% n=2,048

21.94% n=620

12.42% n=1,425

5.49% n=4,099

2.14% n=20,834

BUN 43 N=32,324

2.68% n=25,122

8.98% n=7,202

Cr 2.75 n=2,045

Fonarow et al. 2003Fonarow et al. 2003

%’s = mortality rates%’s = mortality rates

< >

<

< >

>

><

The ESCAPE Trial

Tested safety and efficacy of PA catheter use in ADCHF

433 patients with Class IV symptoms

Randomized to usual care versus PA catheter- guided therapy

No difference in mortality or length of stay

However, patients felt better with the PA catheter

Stevenson, LW. AHA 2004

Therapies for Acute Decompensated Heart Failure

Yes

R. Bourge, UAB Cardiology (adapted from L. Stevenson), Stevenson LW. Eur J Heart Failure 1999;1:251-257

No

Warm and DryPCW and CI

normal

Warm and WetPCW elevated

CI normal

Cold and WetPCW elevatedCI decreased

Cold and DryPCW low/normal

CI decreased

Vasodilators

Diuretics

Inotropes

Nl SVR High SVR

Congestion at Rest

LowPerfusion

at Rest

No

Yes

Parenteral Therapies for Decompensated Heart Failure

Treatment Limitations

Dobutamine Heart rate, arrhythmias,

Milrinone

Nitroglycerin Tolerance, side effects

Nitroprusside Difficult administration (titration), side effects

Heart rate, arrhythmias, hypotension

MVO2, ischemia, and tolerance

Intravenous Inotropic Agents for Decompensated Heart Failure

OPTIME. Gheorghiade et al. ACC Meeting 2000 Late Breaking Trials Session

Milrinonen=477

Controln=47260 Day Follow-up

Days until Discharge

48-hour infusion of milrinone (0.5mcg/kg/min) within 48 hours for worsening of CHF.

Adverse Events

Sustained Hypotension

Acute MI

Rehospitalized or Death

Death

5.7 + 13 5.9 + 13

12.6% 2.1%

10.7%

1.5%

3.2%

0.4%

35.3%

2.3%

35.0%

3.8%

*

*

* P<0.001

* P<0.05 pooled nesiritide compared to nitroglycerin

VMAC: PCWP Through 48 Hours

Young JB et al. AHA Meeting 2000 Late Breaking Trials Session

-11

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

Time

NTG Nesiritide

Mea

n C

han

ge (

mm

Hg)

3 h

6 h

9 h

12 h

24 h

36 h

48 h

Dobutamine (n=141)

Nes 0.015 g/kg/min (n=187)

Cum

ulat

ive

Mor

talit

y R

ate

(%)

Time from start of treatment (days)

Nes 0.030 g/kg/min (n=179)

Precedent: 6 Month Survival

05

10

15

20

25

30

35

0 30 60 90 120 150 180

Log - rank Test:Dobutamine vs nesiritide 0.015 g/kg/min p=0.041Dobutamine vs nesiritide 0.030 g/kg/min p=0.445Nes 0.015 g/kg/min vs nes 0.030 g/kg/min p=0.187

Elkayam U. et al, J. Cardiac Failure 2000;6 (Suppl 2):169

0 30 60 90 120 150 1800

10

20

30

40

50

60

70

80

90

100

Time Observed from the Start of Treatment (days)

NTG (n = 216)

Nesiritide 0.01 µg/kg/min (n = 211)

All Nesiritide (n = 273)

Stratified Log - rank Test:

NTG vs Nesiritide 0.01 µg/kg/min p=0.616

NTG vs All Nesiritide doses p=0.319

VMAC: Mortality RatesC

um

ula

tive

Mo

rtal

ity

Rat

e %

No increase in ischemic events in the acute coronary syndrome patients. (AMI Events 3 NTG, 1 nesiritide)

Young JB et al. AHA Meeting 2000 Late Breaking Trials Session

Scios. Natrecor label update. Revised April 25, 2005. Available at: http://www.natrecor.com/pdf/natrecor_pi.pdf.

Pooled mortality outcomes, extracted from revised nesiritide labeling*

End point, number of studies pooled

Nesiritide (%)

Control (%)

30-day mortality, 7 studies (n=1717)

5.3 4.3

180-day mortality, 4 studies (n=1167)

21.7 21.5

*Mortality hazard-ratio confidence intervals for nesiritide relative to control therapy include 1.00 for both pooled analyses as well as each individual study.

ADHF: Summary

There are currently NO long-term mortality data on ANY therapies currently in use

Risk stratification may be useful in guiding therapy

Best therapy may be to prevent decompensation Adherence to guidelines for the treatment of chronic HF

Patient support network to increase compliance

Adequate treatment of signs/symptoms of HF during hosp

Diuretics

Digoxin ACE-I

-Blocker ARB

AldoRB BNP

Bi-V Pacing ICD

LVAD/Transplant

. . .The Forest for the Trees