Current Therapies for the Management of Chronic and Acute Heart Failure

John L. Tan, MD, PhD Heart Failure Program at the North Texas Heart Center Presbyterian Hospital of Dallas

Heart Failure: The Scope Prevalence Incidence 4.6 million Americans 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% Adapted from AHA Heart and Stroke Facts Statistical Update, 1999; Kannel and Belanger, 1991; Stevenson et al, 1993; O’Connell and Bristow, 1994 AHA. 2001 Heart and Stroke Statistical Update.

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

Etiology of Heart Failure (SOLVD Registry) Valvular heart disease Congenital heart disease Viral Toxic Other 11.3% Thyroid Peripartum Idiopathic cardiomyopathy 12.9% Hypertension 7.2% N=6063 Ischemic heart disease 68.6% Bourassa et al. J Am Coll Cardiol. 1993;22:14A-19A.

The New Classification of Heart Failure A B C D

Stage

High risk for developing heart failure (HF) Asymptomatic HF Symptomatic HF Refractory end-stage HF Hunt SA et al.

J Am Coll Cardiol.

2001;38:2101 –2113.

Patient Description

• Hypertension • CAD • Diabetes mellitus • Family history of cardiomyopathy • Previous MI • LV systolic dysfunction • Asymptomatic valvular disease • Known structural heart disease • Shortness of breath and fatigue • Reduced exercise tolerance • 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)

Symptom Relief is Not Sufficient Heart failure is more than a symptomatic disease Produces symptoms, limits functional capacity, and impairs quality of life Heart failure is a progressive disease Worsening symptoms and clinical deterioration, repeated hospitalization, and death Death occurs frequently even in the presence of minimal symptoms or the absence of progressive symptoms Symptoms do not always correspond with ejection fraction

Ventricular Remodeling

Ventricular Remodeling After Acute Infarction

Initial infarct Global remodeling (days to months) Expansion of infarct (hours to days)

Ventricular Remodeling in Diastolic and Systolic HF

Normal heart Hypertrophied heart (diastolic HF) Jessup M et al.

N Engl J Med.

2003;348:2007 Dilated heart (systolic HF)

Heart Failure Pathophysiology

Myocardial Injury Fall in LV performance Activation of RAAS, SNS, ET, and others

-

ANP BNP Myocardial toxicity Morbidity and mortality Peripheral vasoconstriction Hemodynamic alterations

-

Remodeling and progressive worsening of LV function Heart failure symptoms

Neurohormonal Targets in Heart Failure Angiotensinogen

ACE Inhibitors

Angiotensin I AT II SNS Activation AT 1 Receptors Epinephrine Norepinephrine Target Cells

ACE Inhibitors in Heart Failure  ~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.

1.0

Mortality in Patients Receiving ACE Inhibitors

Survival 0.8

PROMISE

0.6

0.5

0 0

CONSENSUS PRAISE

1 2 Year 3

ACE inhibitor arms of CONSENSUS, V-HeFT, and SOLVD trials.

Placebo arms of PRAISE, PROMISE, and DIG trials (all receiving ACE inhibitors).

SOLVD-Prevention SOLVD-Treatment DIG V-HeFT

4 5

Neurohormonal Targets in Heart Failure Angiotensinogen Angiotensin I

ACE Inhibitors

b

-Blockers

AT II SNS Activation AT 1 Receptors Epinephrine Norepinephrine b

-Blockers

Target Cells

Effect of b -Blockade on All-Cause Mortality

P

=.22

P

=.0001

P

=.006

P

=.001

CIBIS-I: 1.9 years placebo 67/321 (20%); bisoprolol 53/320 (16%) CIBIS-II: 1.3 years placebo 228/1320 (17%); bisoprolol 156/1327 (12%) MERIT-HF: 12 months placebo 217/2001 (11%); metoprolol 145/1990 (7%) US Carvedilol Trials: 7.6 months placebo 31/398 (8%); carvedilol 22/696 (3%)

0 0.25

0.5

0.75

1 1.25

1.5

Relative risk and 95% confidence intervals 1.75

2

COPERNICUS

All-cause mortality: 35% decreased risk 100 90 80 Carvedilol (n=1156) 70 Placebo (n=1133) 60 50 0 P=0.00014

4 8 12 16 Months 20 .

24 28

The CHF Trials in Perspective: Patients Needed to Treat for One Year to Save One Life HF Stage Trial # of Patients A B C C C D HOPE SOLVD-Prevention SOLVD-Treatment CIBIS-II MERIT-HF COPERNICUS 333 285 77 23 25 14

Neurohormonal Targets in Heart Failure

Angiotensinogen

ACE Inhibitors

Angiotensin I AT 1 Receptors

ARBs

AT II SNS Activation Epinephrine Norepinephrine Target Cells

CHARM-Added:

Primary Endpoint

50 40 Placebo 538 (42.3%) 483 (37.9%) 15% risk reduction CV death or HF hospitalization (%) 30 20 Candesartan HR 0.85 (95% CI 0.75-0.96),

P

=0.011

Adjusted HR 0.85,

P

=0.010

10 0 0 1 Number at risk: Candesartan Placebo 1276 1272 1176 1136 HF, heart failure; HR, hazard ratio; CI, confidence interval.

McMurray JJV et al.

Lancet.

2003;362:767-771.

2 Time (years) 1063 1013 3 3.5

948 906 457 422

A-HEFT: Role of Hydralazine/Nitrates Mortality 43% Hospitalization 33% Taylor AL, et al. N Engl J Med. 2004;351:2049-57

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 -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

ACE Inhibitors

Angiotensin I AT II SNS Activation AT 1 Receptors Epinephrine Norepinephrine

Aldosterone Receptor Blockers

Target Cells

RALES: Aldosterone Receptor Blockade Spironolactone n = 1663 NYHA III/IV LVEF < 40% mortality 27% hospitalization 36% (p<0.0002) Pitt B, et al. N Engl J Med. 1999;341:709-717

Mode of Death in MERIT-HF

NYHA II NYHA III HF 12% Other 24% Sudden cardiac death 64% Other 15% HF 26% Sudden cardiac death 59% MERIT-HF Study Group. Lancet. 1999;353(9169):2001-2007.

Device Therapies in Heart Failure: Implantable Cardioverter-Defibrillators

MADIT II: Study Design

Patients with prior MI within 30 days and LVEF < 30% randomized in a 3:2 ratio 71 US centers and 5 European centers Implantable defibrillator (n=742) Conventional medical therapy (n=490)

All Cause Mortality - Average follow-up of 20 months Stopped early by Data Safety Monitoring Board

25% 20% 15%

MADIT II: All-Cause Mortality

19.8% Death Avg. follow-up=20 months P=0.016

Hazard Ratio = 0.65

14.2% 10% 5% 0% Conventional Therapy ICD

SCD-HeFT: Enrollment Scheme

DCM + CAD and CHF EF < 35% NYHA Class II or III 6 minute walk, Holter

R

n=2521, 1:1:1 Placebo Amiodarone ICD Bardy G et al. NEJM 2005; 352:3

SCD-HeFT: Death from Any Cause 23% RR Reduction in Death 7.2% 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 Bardy G et al. NEJM 2005; 352:3

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

Absolute Annual Mortality Reduction During Trial

3.8

4 3.5

3 2.5

2 1.5

1 0.5

0 1.3

1.9

SOLVD MERIT -HF SCD-HeFT

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 Resynchronization in Heart Failure Indications:  EF <35%  NYHA III-IV  QRS >130-150ms

Cardiac Resynchronization in Heart Failure

60

P = 0.004

P = 0.003

Control Resynchronized

40

P = 0.005

20 0

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

-20 0 1 3

Months after Randomization

6

Cardiac Resynchronization in Heart Failure

0

P < 0.001

P = 0.001

-5

P < 0.001

Control Resynchronized

-10 -15 -20

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

-25 0 1 3 6

Months after Randomization

The COMPANION Trial

      1520 patients (1:2:2) NYHA Class III-IV EF 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 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)

20% 15% 10% 5% 0%

MADIT II: CHF

New or Worsening Heart Failure P=0.09

19.9% 14.9% Conventional Therapy ICD

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

600,000 500,000 400,000 300,000 200,000 100,000 0 '7 9 '8 1 '8 3 Women Men '8 5 '8 7 '8 9 '9 1 '9 3 '9 5 '9 7

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%

Approximately 80% of the ED visits for CHF result in hospitalizations

Repeat Visit 79%

Rates of Hospital Readmission 2% within 2 days 20% within 1 month 50% within 6 months

Cardiology Roundtable 1998

Utilization of HF Medications

100 90 80 70 60 50 40 30 20 10 0 50.8

12.8

57.4

80.8

41 ACE-I ARBII-B Beta-Blocker Diuretics Digoxin

*Excludes patients with documented contraindications

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

Causes of Hospital Readmission for Heart Failure Diet Noncompliance 24% Rx Noncompliance 24% 16% Inappropriate Rx 19% Failure to Seek Care Vinson J Am Geriatr Soc 1990;38:1290-5 17% Other

60.6% Hospitalizations $23.1 billion Heart Failure Costs 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)

ADHF: Clinical Assessment

Congestion at Rest No Yes Normal Low Warm & Dry (normal) Cold & Dry Warm & Wet Cold & Wet

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

Risk Stratification of Patients with ADCHF

< BUN 43

N=32,324

>

2.68% n=25,122 8.98% n=7,202

<

5.49%

SYS BP 115

n=24,933 n=4,099 2.14%

>

n=20,834

%’s = mortality rates Fonarow et al. 2003 SYS BP 115

n=7,147

<

15.28% n=2,048 6.41%

>

n=5,102

< Cr 2.75

n=2,045

>

12.42% n=1,425 21.94% n=620

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

Congestion at Rest No Yes Low Perfusion at Rest No Warm and Dry PCW and CI normal Yes Cold and Dry PCW low/normal CI decreased Warm and Wet PCW elevated CI normal Cold and Wet PCW elevated CI decreased

Nl SVR High SVR

Vasodilators Diuretics Inotropes

R. Bourge, UAB Cardiology (adapted from L. Stevenson), Stevenson LW.

Eur J Heart Failure

1999;1:251-257

Parenteral Therapies for Decompensated Heart Failure

Treatment Limitations

Dobutamine Milrinone Nitroglycerin Nitroprusside Heart rate, arrhythmias, MVO 2, ischemia, and tolerance Heart rate, arrhythmias, hypotension Tolerance, side effects Difficult administration (titration), side effects

Intravenous Inotropic Agents for Decompensated Heart Failure

60 Day Follow-up Days until Discharge Milrinone n=477 5.7 + 13 Control n=472 5.9 + 13 Adverse Events 12.6%

*

2.1% Sustained Hypotension 10.7%

*

3.2% Acute MI 1.5% 0.4% Rehospitalized or Death 35.0% 35.3% Death

* P<0.001

3.8% 2.3%

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

OPTIME. Gheorghiade et al.

ACC Meeting 2000 Late Breaking Trials Session

VMAC:

PCWP Through 48 Hours

-7 -8 -9 -10 -11 0 -1 -2 -3 -4 -5 -6

* * * * *

NTG Nesiritide

* P<0.05 pooled nesiritide compared to nitroglycerin *

Time

Young JB et al.

AHA Meeting 2000 Late Breaking Trials Session

Precedent:

6 Month Survival

Log - rank Test: Dobutamine vs nesiritide 0.015



g/kg/min p=0.041

Dobutamine vs nesiritide 0.030



g/kg/min p=0.445

Nes 0.015



g/kg/min vs nes 0.030



g/kg/min p=0.187

35 30 25 20 15 10 5 0 0 30 60 90 120 Dobutamine (n=141) Nes 0.030  g/kg/min (n=179) Nes 0.015  g/kg/min (n=187) 150 Time from start of treatment (days) 180 Elkayam U. et al,

J. Cardiac Failure

2000;6 (Suppl 2):169

VMAC: Mortality Rates

100 90 80 70 60 50 40 30 20 Stratified Log - rank Test: NTG vs Nesiritide 0.01 µg/kg/min p=0.616

NTG vs All Nesiritide doses p=0.319

NTG (n = 216) Nesiritide 0.01 µg/kg/min (n = 211) All Nesiritide (n = 273) 10 0 0 30 60 90 120 150 Time Observed from the Start of Treatment (days) 180

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

Pooled mortality outcomes, extracted from revised nesiritide labeling*

End point, number of studies pooled 30-day mortality, 7 studies (n=1717) 180-day mortality, 4 studies (n=1167) Nesiritide (%) 5.3

21.7

Control (%) 4.3

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.

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

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

. . .The Forest for the Trees

Digoxin ACE-I b -Blocker AldoRB Bi-V Pacing Diuretics ICD ARB BNP LVAD/Transplant