Keynote Presentation

Optimal Medical Management and Device Therapy for Chronic Heart Failure

Dallas, Texas

December 12, 2008 7:30 AM – 8:30 AM

Session 1: Keynote: Optimal Medical Management and Device Therapy for Chronic Heart Failure Learning Objectives

• Discuss clinical data and guideline recommendations for heart failure therapies that offer advantages in terms of morbidity and mortality for specific patient populations.

• Compare emerging therapies that target heart failure. Faculty Gregg C. Fonarow, MD Eliot Corday Professor of Cardiovascular Medicine and Science Director, Ahmanson-UCLA Cardiomyopathy Center Codirector, University of California at Los Angeles Preventative Cardiology Program Associate Chief, UCLA Division of Cardiology UCLA Medical Center Dr Fonarow serves as the director of the Ahmanson-UCLA Cardiomyopathy Center and is the director of the Cardiology Fellowship Program at the University of California at Los Angeles. His research interests center on heart failure management and implementing treatment algorithms to improve clinical outcome. Dr Fonarow has published a number of research studies and clinical trials in heart failure management. New therapies and management strategies for advanced heart failure and research into the pathophysiology of this disease are conducted at UCLA under his direction. He wrote the UCLA Clinical Practice Guidelines for heart failure, acute myocardial infarction, atherosclerosis prevention and treatment, and unstable angina. He has also developed and successfully implemented a comprehensive atherosclerosis treatment program at the UCLA Medical Center (Cardiac Hospitalization Atherosclerosis Management Program: CHAMP). Faculty Financial Disclosure Statement The presenting faculty report the following: Dr Fonarow is a member of the speakers bureau for GlaxoSmithKline; Pfizer Inc.; and Merck & Co., Inc. He is a consultant for Bristol-Myers Squibb/sanofi-aventis. He receives research grants from Guidant and Medtronic. Drug and Device Lists Generic Trade captopril Capoten carvedilol Coreg enalapril Vasotec eplerenone Inspra metoprolol Toprol-XL ramipril Altace spironolactone Aldactone

Devices DDDR dual-chamber rate-adaptive pacemaker VVI single-chamber ventricular demand pacer OptiVol Fluid Status Monitoring — automatic intrathoracic fluid status monitoring

Suggested Reading List Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346(24):1845-1853. Abraham WT, Young JB, Leon AR, et al. Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter-defibrillator, and mildly symptomatic chronic heart failure. Circulation. 2004;110(18):2864-2868. Bleeker GB, Schalij MJ, Holman ER, et al. Cardiac resynchronization therapy in patients with systolic left ventricular dysfunction and symptoms of mild heart failure secondary to ischemic or nonischemic cardiomyopathy. Am J Cardiol. 2006;98(2):230-235.

Session 1

Bradley DJ, Bradley EA, Baughman KL, et al. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials. JAMA. 2003;289(6):730-740. Bristow MR, Saxon LA, Boehmer J, et al. Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350(21):2140-2150. Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med. 2001;344(12):873-880. Cleland JG, Daubert JC, Erdmann E, et al; the Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352(15):1539-1549. Hunt SA, Abraham WT, Chin MH, et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112(12):e154-235. Spragg DD, Leclercq C, Loghmani M, et al. Regional alterations in protein expression in the dyssynchronous failing heart. Circulation. 2003;108(8):929-932.

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1

Optimal Medical Management and Device Therapy for Chronic Heart Failure

Gregg C. Fonarow, MD

Eliot Corday Professor of Cardiovascular Medicine and ScienceDirector, Ahmanson-UCLA Cardiomyopathy Center

Co-director, UCLA Preventative Cardiology ProgramAssociate Chief, UCLA Division of Cardiology

Presenter Disclosure Information

I will discuss off label use of medications or devices

DISCLOSURE INFORMATION:

“Heart Failure Care”

The following relationships exist related to this presentation:

Gregg C. Fonarow, MD, FACC – GlaxoSmithKline, Merck, AstraZeneca, Bristol Myers Squibb, Sanofi, Pfizer, Novartis, Scios, Medtronic, and Guidant: Research, Consultant, Speaker

Heart Failure Background

H t f il (HF) i j bli h lth bl lti i

Population Group Prevalence Incidence Mortality

Hospital Discharges Cost

Total population 5,200,000 550,000 50% at 5

years 1,100,000 $33.2 billion

1

Heart failure (HF) is a major public health problem resulting in substantial morbidity and mortality

Major cost-driver of HF is high incidence of hospitalizations1,2

Despite treatment advances large number of eligible patients are not receiving optimal care

11American Heart Association. American Heart Association. 2007 Heart and Stroke Statistical Update.2007 Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association; 2007. Dallas, Tex: American Heart Association; 2007. 22Hunt Hunt SA et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult. 2005. SA et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult. 2005.

Prognosis with Heart Failure Prognosis with Heart Failure

5060708090

100

rviv

al %

WomenMen

Overall5-year mortality 50%

Hospitalized Patients1-year mortality:

010203040

0 1 2 3 4 5 6 7 8 9 10

Sur

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

Survival after the onset of congestive heart failure in Framingham Heart Study subjectsHo Circulation 1993;88:107-115

Years

Mild to Moderate Symptoms 10-20%

Severe Symptoms40-60%

Outcomes During and After HF Hospitalization

In-hospital– Length of stay (mean) 6.2 days– Mortality rate 4.1%

Hospital readmissionsp– 20% at 30 days – 50% at 6 months

Longer-term mortality– 11.6% at 30 days – 33.1% at 12 months

Fonarow GC et al. J Card Failure. 2003;9:S79 Jong P et al. Arch Intern Med. 2002;162:1689

National Trends in Outcomes Among Patients Hospitalized with HFTrends in Crude and Adjusted Mortality Rates

Year N Crude Mortality (%) Adjusted Mortality (OR, 95% CI)30-day 1-year 30-day 1-year

1992 483,560 11.0 32.5 NA NA

1993 509,549 10.9 33.9 1.00 (referent) 1.00 (referent), ( ) ( )

1994 509,245 10.6 31.7 0.99 (0.98-1.00) 0.91 (0.90-0.92)

1995 510,529 10.5 31.5 1.00 (0.98-1.01) 0.91 (0.90-0.92)

1996 505,661 10.3 31.4 0.99 (0.97-1.00) 0.91 (0.90-0.92)

1997 507,986 10.2 31.7 0.98 (0.97-0.99) 0.92 (0.92-0.93)

1998 436,257 10.2 31.8 0.99 (0.97-1.00) 0.93 (0.92-0.93)

1999 494,733 10.3 31.7 1.01 (1.00-1.02) 0.93 (0.92-0.94)

National sample of 3,957,520 Medicare beneficiaries >65 who were hospitalized with HF between 1992 and 1999Kosiborod AJM 2006;119:e1-e7.

2

Natural History of Heart FailureNatural History of Heart Failure

viva

l

100%

Progression

Mechanism of DeathSudden Death 40%Worsened HF 40%Other 20%

Left Ventricular Dysfunction and Symptoms

Surv

Asymptomatic0%

Mild Moderate Severe

Annual Mortality

10% 10-20% 20 - 30 % 30 - 80%

Heart Failure PathophysiologyMyocardial injury Fall in LV performance

Activation of RAAS, SNS, ET,and others

Myocardial toxicityPeripheral vasoconstrictionHemodynamic alterations

Remodeling andprogressive

worsening ofLV function Heart failure symptomsMorbidity and mortality

ANPBNP

Fonarow GC. Rev Cardiovasc Med..2001;2:7–12.

Pathophysiologic Effects of Angiotensin IIPathophysiologic Effects of Angiotensin IIand Epinephrine/Norepinephrineand Epinephrine/Norepinephrine

C di M Fib bl P i h l A C ACardiac Myocyte Fibroblast Peripheral Artery Coronary ArteryHypertrophy

Apoptosis

Increased Wall Stress

Increased O2 Consumption

Cell Sliding

Impaired Relaxation

Collagen Synthesis

Hyperplasia

Decreased ComplianceFibrosis

Vasoconstriction

Hypertrophy

Endothelial Dysfunction

Vasoconstriction

Endothelial Dysfunction

Atherosclerosis

Thrombosis

Restenosis

ACC/AHA HF Guidelines:Management of Heart Failure (Stage C)Life Prolonging Therapy

ACE inhibitors (Class I, evidence A) all patients without contraindications or intolerance

β Blockers (Class I evidence A) all patients withoutβ-Blockers (Class I, evidence A) all patients without contraindications or intolerance

Aldosterone antagonists (Class I, evidence B) all patients with moderately severe or severe symptoms without contraindications or intolerance, when close monitoring can be assured

Hunt SA et al. J Am Coll Cardiol. 2005

Effect of ACE Inhibitors on MortalityEffect of ACE Inhibitors on Mortalityand Hospitalizations in Patients with HFand Hospitalizations in Patients with HF

0

10

-10

Mor

talit

y

-23

-35-31

Total Mortality Death or Hospitalization CHF Hospitalization

-20

-30

-40

-50

-60

% R

isk

of M

32 Trials of ACEI in Heart Failure ACEI (n = 3870) Placebo (n = 3235)Collaborative Group on ACE Inhibitor Trails JAMA 1995;273:1450-1456

OR 0.77 (0.67-0.88) p<0.001

Effect of ACE Inhibitors on MortalityEffect of ACE Inhibitors on Mortalityand Hospitalizations in Patients with HFand Hospitalizations in Patients with HF

Subgroup ACE Inhibitor Controls OR Male 22.9 33.2 0.63

Female 20.2 29.5 0.78< 60 22.2 31.1 0.71> 60 24.9 36.9 0.79

Class I 17.5 24.8 0.69Class II 19.5 28.4 0.68

32 Trials of ACEI in Heart Failure ACEI (n = 3870) Placebo (n = 3235)Collaborative Group on ACE Inhibitor Trails JAMA 1995;273:1450-1456

Class II 19.5 28.4 0.68Class III 22.1 43.2 0.58Class IV 46.2 59.2 0.69Ischemic 28.3 40.1 0.63

Nonischemic 23.2 29 0.72LVEF >25 23.6 29.6 0.85LVEF < 25 33.7 48 0.53

All Patients 22.4 32.6 0.65

Total Mortality or Hospitalization for Congestive Heart Failure

3

Survival Rates in Patients Receiving ACE Survival Rates in Patients Receiving ACE Inhibitors Across NYHA ClassesInhibitors Across NYHA Classes

1.0

0.8

Survival

SOLVD-Prevention

SOLVD T t t

0.6

0.5

00 21 3 4 5

Year

CONSENSUS

PROMISE

PRAISE

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).

ValHeFT: ARB added to Standard HF Care Including ACEI

Mortality

Placebo

Valsartan

viva

l (%

)

100

95

90

Months since Randomization

Prob

abili

ty o

f Sur

v

85

80

75

70

00 3 6 9 12 15 18 21 24 27

P=.80

Cohn J et al. N Engl J Med. 2001;345:1667–1675.

CHARM-Alternative

30

40

50

Placebo

Candesartan

406 (40.0%)

334 (33.0%)

With

CV

Dea

th

pita

lizat

ion

(%)

Primary outcome of CV death or CHF hospitalization

Granger CB, et al. Lancet. 2003;362:772-776.

Number at riskCandesartan 1,013 929 831 434 122Placebo 1,015 887 798 427 126

0 1 2 3Years

0

10

20

HR 0.77 (95% CI 0.67-0.89), P=.0004Adjusted HR 0.70, P<.0001

3.5

Prop

ortio

n W

or C

HF

Hos

p

Indicated for all patients with asymptomatic LV dysfunction and for Class I to IV heart failure. (Contraindications: hyperkalemia, angioedema, pregnancy)

Titrate to target doses (example enalapril 10 mg bid,

ACEI/ARB in Heart FailureACEI/ARB in Heart Failure

lisinopril 20 qd, ramipril 10 mg qd, benazepril 40 qd)

Monitor serum potassium and renal function. Advise checking chemistry panel 1-2 weeks after first dose.

If ACE inhibitor not tolerated or side effects, angiotensin receptor antagonist recommended.

Hunt SA, et al. ACC/AHA 2005 Practice Guidelines

Effects of AldosteroneEffects of Aldosterone

C di M Fib bl P i h l A KidCardiac Myocyte Fibroblast Peripheral Artery KidneyHypertrophy

Norepinephrine Release Collagen Synthesis

Hyperplasia

Decreased ComplianceFibrosis

Vasoconstriction

Hypertrophy

Endothelial DysfunctionPotassium LossSodium Retention

RALES: Aldosterone Antagonist Reduces All-Cause Mortality in Chronic HF

Spironolactone (25 mg) + standard care (n = 822)Placebo + standard care (n = 841)

of S

urvi

val (

%)

1.000.950.900.850.800.750.70

HR = 0.70 (95% CI, 0.60 to 0.82)

*Ejection fraction ≤35% Class III or IV symptoms at some point in prior 2 months.

Prob

abili

ty o 0.65

0.600.550.50

03 6 9 12 15 18 21 24 27

Months

0

0.45

30 33 36

P<.001

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

HR = hazard ratio; RR = risk reduction.

4

Standard post-AMI CareASA, BB, ACEI, statin, revascularization

Post AMI, LVEF < 40, Rales or S3

Eplerenone PostEplerenone Post--AMI Heart Failure AMI Heart Failure Efficacy and Survival Study (EPHESUS)Efficacy and Survival Study (EPHESUS)

Randomizationn=6644

Eplerenone Initiation25 qd, 50 mg at 4wks

Matching Placebo

Follow-up

Pitt NEJM 2003;348:1309-21

EPHESUS Co-Primary Endpoint:Total Mortality

Eplerenone + standard care (n = 3319)

Placebo + standard care (n = 3313)

Inci

denc

e (%

)

222018161412

(16.7%)

(14.4%)

Adapted from Pitt B et al. N Engl J Med. 2003;348:1309-1321.

Cum

ulat

ive

I

1086420

3 6 9 12 15 18 21 24 27

Months Since Randomization

HR = 0.85 (95% CI, 0.75 to 0.96)P = .008

0

HR = hazard ratio.

Early Benefits of Eplerenone When Added to Standard Post MI Patient Care

-10-505

10

(%)

All CauseMortality

CardiovascularMortality

Sudden CardiacDeath

Heart FailureHospitalization

30 Days

Pitt et al. N Engl J Med. 2003;348:1309-1321.

-31 -32-37

-18

-50-45-40-35-30-25-20-15

0

Rel

ativ

e R

isk

Indicated for patients with moderately severe or severe HF due to LVD (LVEF < 0.40). (Contraindications: hyperkalemia, Cr > 2.5 in men and > 2.0 in women)

Spironolactone 12.5 mg PO qd starting dose (or 6.25 mg in higher risk patients) or Eplerenone 25 mg qd. Decrease potassium supplementation and loop diuretic dose at time of initiation

Aldosterone Antagonists in Heart Failure

initiation.

Critical to very closely monitor serum potassium and renal function. Advise checking chemistry panel at 48 hours, 1 week, and 4 weeks.

Advance Spironolactone dose at 4 weeks to 25 mg PO qd or Eplerenone 50 mg which is the target dose. Avoid higher doses due to risk of hyperkalemia.

Hunt SA et al. J Am Coll Cardiol. 2005

Effect of Digoxin on Mortality in Heart FailureEffect of Digoxin on Mortality in Heart Failure: The Digitalis Investigation Group

Digoxin

Placebo

20

30

40

50

Relative Risk 0.9995% CI 0.91–1.07

P=.80

om A

ny C

ause

(%)

CV Mortality0%

HF Hospitalizations28%

DIG (Digitalis Investigation Group): 6,800 patients with LVEF <45% randomized to digoxin (n=3,403) or placebo (n=3,397) in addition to therapy with diuretics and ACEI followed for 37 months.The DIGITALIS Investigation Group. N Engl J Med. 1997;336:525–532.

00 4 8 12 16 20 24 28 32 36 40 44 48 52

10

20

All-cause mortality rates: Placebo 35.1%; Digoxin 34.8%

Mor

talit

y Fr

MonthsNumber of patients at risk:Placebo 3,403 3,239 3,105 2,976 2,868 2,758 2,652 2,551 2,205 1,881 1,506 1,168 734 339Digoxin 3,397 3,269 3,144 3,019 2,882 2,759 2,644 2,531 2,184 1,840 1,475 1,156 737 335

Total Hospitalizations6%

5

The Use of Beta Adrenergic Blocking Agents in Heart Failure

5

10

15

% c

hang

e

0 6 12 18 24

Time (weeks)

0

-5

-10

LVEF

Initial hemodynamic deterioration followed by reverse remodeling (decrease in EDV and ESV) with improved ventricular function over time (increased LVEF)

Effect of Carvedilol in Heart FailureEffect of Carvedilol in Heart FailureUS Heart Failure Trials Program

80

90

100Survival Proportion

CarvedilolP<0.001

65%

1094 Class II-IV CHF pts on triple therapy (ACEI, digoxin, diuretics)Carvedilol 6.25 bid test 2 weeks, then 12.5 bid, then 25 bid vs placeboPacker NEJM 1996;334:1349-55

0 50 100 150 200 250 300 350 400Follow-up (days)

50

60

70Placebo

Effect of Metoprolol CR/XL in Heart FailureEffect of Metoprolol CR/XL in Heart FailureMERIT-HF

90

95

100Survival Proportion

Metoprolol CR/XLPlacebo

RR 0.66 (0.53-0.81)P=0.0062

3991 pts with CHF Class II-IV, ave age 64 and LVEF 0.28 Randomized to Metoprolol CR/XL 12.5 mg or 25 mg PO qd, target dose 200 mg qdLancet 1999;353:2001-07

0 3 6 9 12 15 18 21Follow-up (months)

80

85

Placebo

Major Trials of Major Trials of ββ--BlockadeBlockadein Heart Failurein Heart Failure

Patients Follow-up NYHA LVEF Effects on(n) (yrs) Class (%) Outcomes

CIBIS 641 1.9 II-III < 35 All-cause mortality:↓ 22% NS

CIBIS-II 2647 1.3 II-III < 35 All-cause mortality:y↓ 34% (P<.0001)

MDC 383 1 II-III < 40 Death or need fortransplant: ↓ 30%, P<0.05

MERIT-HF 3991 1 II-III < 40 All-cause mortality:↓ 34% (P=.0062)

US Carvedilol 1094 7.5 II-III < 35 All-cause mortality*:Trials months ↓ 65% (P=.0001) COPERNICUS 2289 10.5 IV < 25

months

Effect of Carvedilol in Severe Heart FailureEffect of Carvedilol in Severe Heart FailureCOPERNICUS

85

90

95

100Survival Proportion

CarvedilolPl b

HR 0.65 (0.52-0.81)P=0.0001

n=1133

n=1156

2289 Class IV CHF pts, LVEF < 0.25, (not on inotropes x 4days) ave age 63, LVEF 0.20Carvedilol 3.125 bid, q 2 wks titration. 75% to target. withdrawl 16% placebo, 13% carvedilolPacker NEJM 2001;344:1651-8

0 2 4 6 8 10 12Follow-up (months)

70

75

80

85 Placebo

Allpatients

Annual placebo mortality rate (per patient-year)

19.7%

Effect of Carvedilol on Mortality

Effect of Carvedilol in Severe Heart FailureEffect of Carvedilol in Severe Heart Failure

Favors treatment Favors placebo

0.50.25 0.75 1.251.0

patients

Recent or recurrentdecompensation

28.5%

0

6

Safety of Initiating Carvedilol in Safety of Initiating Carvedilol in Patients with Severe Heart FailurePatients with Severe Heart Failure

Permanent Withdrawals40

30

Placebo

nent

ly

P = .02

10

20

00 3 6 9 12 15 18 21

Months

Carvedilol

% P

atie

nts P

erm

anW

ithdr

awn

Packer NEJM 2001;344:1651-8

Early Benefits and Early Safety of Carvedilol in Severe HF: COPERNICUS

15

11.4Placebo

Lower Risk for Worsening CHFEarly Mortality Reduction

3

2

ent (

%) Placebo

(n=1,133)

Risk Reduction ↓25%

(−35%–59%)

Packer M. N Engl J Med. 2001;344:1651–1658. Krum H. JAMA. 2003;289:712–718.

Highest-Risk Subgroup

10

All Patients

6.45.1

8.8Carvedilol

(n=1,133) (n=1,156) (n=316) (n=308)

5

0

1

00 2 4 6 8

Weeks After Randomization

Patie

nts

With

Eve

Carvedilol(n=1,156)

Event rates: Placebo 2.3%; Carvedilol 1.7%

Effects of SympatheticEffects of SympatheticActivation in Heart FailureActivation in Heart Failure

↑ Cardiac sympathetic activity ↑ Sympathetic activity to kidneys+ blood vessels

↑ CNS sympathetic outflow

β1-receptors

β2-receptors

α1-receptors

Activationof RAS

VasoconstrictionSodium retention

Myocyte deathIncreased arrhythmias

Disease progression

α 1- β1-

Bristow MR. Circulation. 2000;101:558-569.

Not All β-Blockers Reduce Mortality in HF

viva

l (%

)

Risk Reduction

↓ 10%(−2%, 22%)

60

80

100

rviv

al (%

)

P 214

80

100

90

70

BEST1 SENIORS2

Risk Reduction

↓ 12%(-8%, 29%)

Follow-Up (months)2,708 patients (CHF Class III–IV, average age 60, LVEF .23) randomized to placebo or bucindolol (3 mg titrated to 50 mg po BID).Number of events: bucindolol 411 (30%); placebo 449 (33%).

1BEST Investigators. N Engl J Med. 2001;344:1659-1667. 2Flather, M et al. Eur Heart J. 2005;26:215-225.

Surv P=.105

0 3 6 9 12 15 18 21 240

20

40 Sur P=.214

Placebo (n=1,061)Nebivolol (n=1,067)

60

0 6 12 18 24 3630

50

40

2,128 patients (CHF Class II–III, average age 76, average LVEF .36 with approximately 65% of patients with LVEF ≤.35) randomized to Placebo or nebivolol (1.25 mg titrated to 10 mg po QD). All-cause mortality was a secondary endpoint.Number of events: nebivolol 169 (15.8%); placebo 192 (18.1%).

Time (months)

Placebo (n=1,354)Bucindolol (n=1,354)

β-Blockers Differ in Their Long-Term Effects on Mortality in HF

Bisoprolol1

Bucindolol2

Carvedilol3-5

Metoprolol tartrate6

Beneficial No effectBeneficialNot well studiedMetoprolol tartrate

Metoprolol succinate7

Nebivolol8

Xamoterol9

Not well studiedBeneficialNo effectHarmful

1CIBIS II Investigators and Committees. Lancet. 1999;353:9-13. 2The BEST Investigators. N Engl J Med 2001; 344:1659-1667. 3Colucci WS, et al. Circulation 1996;94:2800-2806. 4Packer M, et al. N Engl J Med 2001;344:1651-1658. 5The CAPRICORN Investigators. Lancet. 2001;357:1385-1390. 6Waagstein F, et al. Lancet. 1993;342:1441-1446. 7MERIT-HF Study Group. Lancet. 1999;353:2001-2007. 8SENIORS Study Group. Eur Heart J. 2005; 26:215-225. 9The Xamoterol in Severe heart Failure Study Group. Lancet. 1990;336:1-6.

COMET: Effect Carvedilol vs Metoprolol Tartrate on Mortality in HF

ty (%

) Carvedilol

MetoprololTartrate

20

30

40 Risk Reduction↓ 17%

(7%, 26%)P=.0017

Extrapolation from the survival curves

Poole-Wilson PA, et al. Lancet. 2003;362:7-13.

Time (years)

Mor

talit

0

10

0 1 2 3 4 5

Metoprolol tartrate mean dose: 85 mg QD; Carvedilol mean dose: 42 mg QD. COMET did not evaluate metoprolol succinate, the agent used in the MERIT-HF Trial

psuggested that carvedilol extended median survival by 1.4 years as compared with metoprolol tartrate †

Mortality rates: metoprolol 40%; Carvedilol 34%.

7

Beta Blocker Therapy in Heart Failure

Indicated for all patients with asymptomatic LVD dysfunction and for Class I to IV Heart Failure with LVEF <0.40

Contraindications: cardiogenic shock, severe reactive airway disease, 2/3rd degree HB

U th 3 id b d b t bl k i HFUse one the 3 evidence-based beta blockers in HF: eg carvedilol, metroprolol succinate, bisoprolol

Start at very low HF doses and up-titrate to target doses at two week intervals, or highest dose short of target dose that is well tolerated

Monitor HR and BP

Hunt SA et al. J Am Coll Cardiol. 2005.

Neurohormonal Activation as the Therapeutic Target in Heart Failure

Therapies with Demonstrated Benefit in Clinical Trials

Sympathetic Nervous SystemBeta Adrenergic Blockers (carvedilol)

Renin Angiotensin Aldosterone SystemAngiotensin Converting Enzyme Inhibitors (Angiotensin II Receptor Antagonists)Aldosterone Antagonists

AHeFT: Trial SummaryAHeFT: Trial Summary

95

100

al (%

)

Fixed-dose HYD/ISDN

43% Decrease in Mortality

Days Since Baseline Visit Date0 100 200 300 400 500 600

85

90Surv

iva

P=.01

Placebo

Hazard ratio=0.57

1050 African Americans with Class III to IV HF, LVEF 24%, on ACEI, BB, AAAdapted from Taylor AL, et al. N Engl J Med. 2004;351:2052.

Device Therapy for Heart Failure

• Cardiac resynchronization therapy (CRT)• Implantable cardioverter-defibrillators (ICD)• Ventricular assist devices

B id t t l t• Bridge to transplant• Destination therapy

• Totally implanted artificial hearts• Cardiac reshaping devices• Ultrafiltration devices

Cardiac Resynchronization Therapy for Heart Failure

In patients with heart failure 27 to 53% of patients have IVCDs (RBBB, LBBB, IVCD)Abnormal conduction contributes to abnormal

t i l ti ti / t ti d b tventricular activation/contraction and subsequent dysynchrony between the RV and LV

– Reduced systolic performance– Mechanical inefficiency– Worsened prognosis

Aarronson Circulation 1997;96. Grines Circulation 1989;79 Xiao Int J Cardiol 1996;53

Cardiac Resynchronization Therapy: Weight of Evidence

>4,000 patients evaluated in randomized controlled trialsConsistent improvement in quality of life, functional status, and exercise capacityStrong evidence of reverse remodeling

↓ LV volumes and dimensions↑ LVEF↓ Mitral regurgitation

Reduction in HF and all-cause morbidity and mortality

Abraham WT. Circulation. 2003;108:2596-2603.

8

CRT Improves QoL and NYHA Functional Class

Average Change in QoL Score (MLWHF)

15-10

-50

NYHA: Proportion Improving 1 or More Class (%)

**

*

80

60

40

-20-15

MIR

ACLE

(1)

MUS

TIC

SR (2

)M

USTI

C AF

(3)

CONT

AK C

D...

MIR

ACLE

IC...

Control CRT

* * * *

* P<.05.

MIRACLE(1)

CONTAKCD (4)

MIRACLEICD (5)

Control CRT

1Abraham WT et al. N Engl J Med. 2002;346:1845-1853. 2Cazeau S. N Engl J Med. 2001;344:873-880.3Leclercq C et al. Eur Heart J. 2002;23:1780-1787. 4FDA Web site. Available at: http://www.fda.gov/cdrh/pdf/P010012b.pdf. Accessed August 2, 2002. 5Young JB et al. JAMA. 2003;289:2685-2694.

40

20

0

Effects of CRT on Ventricular Function in Heart Failure: MIRACLE Trial

7.25

7.50

eter

s

P<0.001

Left Ventricular Ejection Fraction (LVEF)

25

30

35

age

P<0.001

Left Ventricular End Diastolic Diameter (LVEDD)

6.50

6.75

7.00

ControlN=63

CRTN=61

Cen

time

Baseline 6 months

10

15

20

25

ControlN=81

CRTN=63

Perc

ent

Baseline 6 months

Abraham ACC 2001

CARE-HF: Effect of CRT Without an ICD on All-Cause Mortality

.50

.75

1.00

ee S

urvi

val

Medical

HR: 0.64 (95% CI: 0.48-0.85)

CRT

571192321365404Medical Rx889213351376409CRT plus meds

Number at risk0 500 1,000 1,500

.25

Even

t-Fre Medical

Therapy

P=.0019

Cleland JG, et al. N Engl J Med. 2005:352;1539-1549.

Days

0

CARE-HF: Clinical Outcomes

OMT (n=404)

CRT + OMT (n=409)

Hazard Ratio(95% CI) P Value

Death + CV Hospitalization 225 (55%) 159 (39%)

.63 ( 51 to 77)

<.001Hospitalization (.51 to .77)

CV Hospitalization 184 (46%) 125 (31%)

0.61 (.49 to .77)

<.001

All-Cause Death 120 (30%) 82 (20%)0.64

(.48 to .85)<.002

MR=mitral regurgitation; OMT=optimal medical therapy. Cleland JG et al. N Engl J Med. 2005;352:1539-1549.

CARE-HF: Effect of CRT on the Primary End Point in Predefined Subgroups

Cleland, J. G.F. et al. N Engl J Med 2005;352:1539-1549

CARE-HF: Hemodynamic, Echocardiographic, and Biochemical Assessments*

VariableDifference in Means at

3 Mo (95% CI) P ValueDifference in Means

at 18 Mo (95% CI) P Value

Heart rate, beats/min +1.1 (-1.2 to 3.4) .33 +1.0 (-1.5 to 3.6) .43

Systolic blood pressure, mm Hg +5.8 (3.5 to 8.2) <.001 +6.3 (3.6 to 8.9) <.001

Diastolic blood pressure, mm Hg +1.5 (0.1 to 2.9) .03 +1.3 (-1.8 to 4.4) .42

Interventricular mechanical delay ms -21 (-25 to -18) < 001 -21 (-25 to -17) < 001

* Differences were not adjusted for the higher mortality rate in the medical therapy group. A plus sign indicates a greater value, and a minus sign a smaller value, in the cardiac resynchronization group than in the medical therapy group.† The area was calculated as the area of the color-flow Doppler regurgitant jet divided by the area of the left atrium in systole, both in square centimeters.Cleland JGF, et al. N Engl J Med. 2005;352:1539-1549.

Interventricular mechanical delay, ms -21 (-25 to -18) <.001 -21 (-25 to -17) <.001

Left ventricular ejection fraction, % +3.7 (3.0 to 4.4) <.001 +6.9 (5.6 to 8.1) <.001

Left ventricular end-systolic volume index, mL/m2 -18.2 (-21.2 to -15.1) <.001 -26.0 (-31.5 to -20.4) <.001

Mitral regurgitation area† -0.051 (-0.073 to -0.028) <.001 -0.042 (-0.070 to

-0.014) .003

N-terminal pro-BNP, pg/mL -225 (-705 to 255) .36 -1122 (-1815 to -429) <.002

9

ICD

Subgroup Analyses Influencing Payment Approval

8

.9

1.0

Surv

ival

SexMale 1040Female 192

Age<60 yr 37060-69 yr 426≥70 yr 436

Variable No. of Patients Hazard Ratio

Improved Survival with Prophylactic ICD Therapy Patients with Prior MI and LVEF < 30: MADIT-II

HR 0.69 (0.51-0.93)

P = 0.016, NNT = 18

No ICD

0 1 2 3 40

.6

.7

.8

Year

Prob

abili

ty o

f

No. At RiskDefibrillator 742 503 (0.91) 274 (0.84) 110 (0.78) 9Conventional 490 329 (0.90) 170 (0.78) 65 (0.69) 3 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6

DefibrillatorBetter

ConventionalTherapy Better

All patients 1232

QRS interval<.12 sec 618.12-.15 sec 352>.15 sec 262

NYHA classI 461≥II 771

LVEF≤.25 831>.25 401

1232 Pts Stage B or Class II-III HF, Prior MI, LVEF < 0.30, on top of optimal med rx, f/u 20 months Moss AJ N Engl J Med 2002;346:877-1883

SCD-HeFT: Trial Design2521 Ischemic or Non-ischemic Chronic HF

on Standard HF Medications

EF ≤35%

NYHA Class II or III

Bardy GH, et al. N Engl J Med. 2005;352:225-237.

NYHA Class II or III

®Placebo Amiodarone ICD

mean age 60, 77% male, ischemic 52%, LVEF 0.24ACEI 85%, BB 69%, Ald Ant 19%, Statin 38%

SCD-HeFT Trial: SurvivalHR 97.5% Cl P

Amiodarone vs Placebo 1.06 0.86-1.30 0.53ICD vs Placebo 0.77 0.62-0.96 0.007

lity

.3

.4

Months of Follow-Up

Mor

ta

0 6 12 18 24 30 36 42 48 54 600

.1

.2

Amiodarone

ICD TherapyPlacebo

2521 patients with ischemic or non-ischemic NYHA class II-III heart failure and LVEF 35% or less

80

90

100

OPTCRT HR 0.76 (CI: 0.58−1.01)CRT-D HR 0.64 (CI: 0.48−0.86)

-Fre

e (%

)

CRT vs OPT: RR=24%, P=.060 (Critical boundary=.014)CRT-D vs OPT: RR=36%, P=.003 (Critical boundary=.022)

COMPANION: Secondary Endpoint of All-Cause Mortality

0 120 240 360 480 600 720 840 960 1,08050

60

70

80

Patie

nts

Even

t-

Days From Randomization

12-Month Event RatesOPT: 19%CRT: 15% (AR= 4%)CRT-D: 12% (AR= 7%)

Bristow M, et al. N Engl J Med. 2004;350:2140-2150.

19.8%

14.2%

19.0%

12.0%14.1%

7.9%

28.8%

22.0%

5 0%

10.0%

15.0%

20.0%

25.0%

30.0%

% M

orta

lity

Control Therapy

SCD-HeFT and Other ICD Device Trials in HF

P=0.007

P=0.065

P=0.004

P=0.016

0.0%

5.0%

MADIT II COMPANION DEFINITE SCD-HeFT

HF Etiology Ischemic: 100% Ischemic:59%Non-ischemic:41%

Non-ischemic: 100%

Ischemic: 52%Non-ischemic:48%

NYHA Class I/II/III(35%/35%/30%)

III/IV(87%/13%)

I/II/III(20%/60%/20%)

II/III(71%/29%)

LVEF < 30% < 35% < 35% < 35%

No. Pts 1232 1520 458 2521Follow-Up 20 months 12 months 24 months 45 monthsHazard Ratio 0.69 0.64 0.66 0.77

Important Comorbidities inHeart Failure

CardiovascularHypertensionCoronary artery diseasePeripheral vascular diseaseCerebral vascular disease

Non-CardiovascularObesityDiabetesAnemiaChronic kidney diseaseCerebral vascular disease

HyperlipidemiaAtrial fibrillation

Horwich and Fonarow, Chapter 40: Impact and Treatment of Comorbidities in Heart Failure

yThyroid diseaseCOPD / AsthmaSmokingSleep disordered breathingLiver diseaseArthritisCancer Depression

10

ACC/AHA Guidelines for HFComorbidites and Related Risks

Control of systolic and diastolic hypertension in accordance with recommended guidelines

Appropriate antihypertensive regimen frequently consists of several drugs used in combinationDrugs that are useful for the treatment of both hypertension and HF are preferred (eg, ACE inhibitors, β-blockers, aldosterone antagonists, diuretics)

• Treat lipid disorders• Encourage smoking cessation and regular exercise• Discourage alcohol intake/illicit drug use

Hunt SA et al. J Am Coll Cardiol. 2005

Patient Education is Essential in HFPatient Instructions

Monitor daily weightsSalt restricted diet (e.g. 2-3 gm sodium diet)Medications need for adherenceMedications, need for adherenceActivity Rx Smoking Cessation Advice/CounselingWhat to do if HF symptoms worsen Close follow-up and monitoring

Hunt SA et al. J Am Coll Cardiol. 2005

Heart Failure with Normal Systolic Function

Treatment of patients with predominantly diastolic dysfunction heart failure has not been well studied

Diuretics should be used cautiously, at low dose

Control hypertension

Diuretics should be used cautiously, at low dose initially, recognizing that the stiff heart is highly dependent on adequate preload

ACE inhibitors, calcium channel blockers, and beta blockers have favorable effects upon hemodynamics but their impact on longer term outcome is not known

Hunt SA et al. J Am Coll Cardiol. 2005

Rate control for atrial fibrillation

New Therapies for Heart Failure

Vasopeptidase inhibitors

Natriuretic peptides

Cytokine Antagonists

Phophodiesterase-5 inhibitors

Cardiac resynchronization therapy (class 1)

Ventricular constraint devicesCytokine Antagonists

Statins

Erythropoeitin

Immune modulation

Peripheral ultrafiltration

Ventricular constraint devices

Cell transplantation

Evidence-Based Treatment Across the Continuum of LVD and HF

Control VolumeReduce Mortality

Salt Restriction*Diuretics*β-BlockerACEI

or ARBAldosteroneAntagonist

Treat Residual

Digoxin*

Treat Residual SymptomsCRT ±

an ICD*Hyd/ISDN*

*For select indicated patients.

ICD*

Treat Comorbidities

Aspirin*Warfarin*

Statin*

Enhance Adherence

EducationDisease Management

Performance Improvement Systems

Long-Term Trends in Mortality With Heart Failure

WomenMenWomenMenWomenMenPeriod

5-Year Mortality,% (95% CI)

1-Year Mortality,% (95% CI)

30-Day Mortality,% (95% CI)

Temporal Trends in Age-Adjusted Mortality After the Onset of Heart Failure*

45 (33-55)59 (47-68)24 (14-33)28 (18-36)10 (3-15)11 (4-17)1990–1999

51 (39-60)65 (54-73)27 (17-35)33 (23-42)10 (4-16)12 (5-18)1980–1989

59 (45-69)75 (65-83)28 (17-38)41 (29-51)16 (6-24)15 (7-23)1970–1979

57 (43-67)70 (57-79)28 (16-39)30 (18-40)18 (7-27)12 (4-19)1950–1969

WomenMenWomenMen WomenMenPeriod

*All values were adjusted for age (<55, 55–64, 65–74, 75–84, and ≥ 85 years).Levy D et al. N Engl J Med. 2002;347:1397–1402.

11

Survival Trends in HF Patients With and Without Preserved EF

1.0

0.8

0.6

0 4

rviv

al

1987-19911992-19961997-2001

A. Patients With Reduced Ejection Fraction B. Patients With Preserved Ejection Fraction

1.0

0.8

0.6

0 4urvi

val

1987-19911992-19961997-2001

No. at Risk

1987-1991 819 525 424 336 274 220

1992-1996 857 594 481 395 331 273

1997-2001 748 520 447 319 210 114

0.4

0.2

0.00 1 2 3 4 5

Year

Su

P=.005

No. at Risk

1987-1991 510 377 313 263 216 117

1992-1996 771 537 447 375 314 262

1997-2001 885 629 513 365 230 138

0.4

0.2

0.00 1 2 3 4 5

Year

SuP=.36

Owan TE, et al. N Engl J Med. 2006;355:251-259.

60

5060708090

100

Utilization of Evidence-based HF Therapies IMPROVEMENT International Survey

of P

atie

nts

3420

12

01020304050

ACE Inhibitors Blockers ACEI + BB AldosteroneAntagonist

Perc

ent o

International survey: 15 countries, 1363 physicians, 11,062 patients: Year 2000.International survey: 15 countries, 1363 physicians, 11,062 patients: Year 2000.Outpatient regimen in patients with Stage C HF, documented systolic dysfunction. Outpatient regimen in patients with Stage C HF, documented systolic dysfunction. Cleland Lancet 2002360:1361Cleland Lancet 2002360:1361--39.39.

β-

5060708090

Risk-Treatment Mismatch in HF

ents

(%)

At Hospital Discharge 90 Day Follow-Up 1 Year Follow-Up

01020304050

Low Risk Average Risk High Risk

ACEI ACEI or ARB

β-Blocker

1 Year Mortality Rate

Patie

Use rates in absence of contraindications. For all drug classes, P<.001 for trend.Lee, D. JAMA. 2005;294:1240-1247.

ACEI ACEI or ARB

β-Blocker

ADHERE Quality of CareADHERE Quality of CareConformity to JCAHO HF Performance Indicators

ADHERE Quality of CareADHERE Quality of CareConformity to JCAHO HF Performance Indicators

AllPatients

(n = 54,639)

Patients atAcademic Hospitals

(n = 18,934)

Patients at Non-Academic Hospitals

(n = 35,705)P value †

HF-1 (%)Discharge Instruct 28.4 21.1 32.7 < 0.0001

HF-2 (%)LV Function 81.8 83.8 80.7 < 0.0001

HF-3 (%)Discharge ACE-I Rx 67.8 72.2 65.0 < 0.0001

JCAHO HF-4 (%)Smoking Cessation

Counseling34.4 28.7 38.0 < 0.0001

Fonarow GC et al. Arch Intern Med 2005;165:1469-1477.

ADHERE Quality of CareConformity to JCAHO HF Performance Indicators

72%

58%

70%

97%88% 85%

60%

80%

100%

Lagging Centers Leading Centers

zatio

n

6.1

8.0

10.0

Fonarow GC et al. Arch Intern Med 2005;165:1469-1477

1%8%

0%

20%

40%

81 142 admissions between 6/2002 – 12/2003 at 223 hospitalsGrouped by Leading (90th percentile) and Lagging (10th percentile) All P<0.0001

DischargeInstructions

LV FunctionMeasurement

ACEI use Smoking Cessation

% U

tiliz

5.0

3.1

1.4

0.0

2.0

4.0

6.0

Length of Stay(median)

Mortality

“Failure” of Usual Care in HFFailure to prescribe evidence-based medicationsFailure to discontinue medications that may exacerbate HFFailure to titrate medications to target dosesFailure to adhere to prescribed medicationsFailure to address co-morbidities adequately Failure to consider device therapiesFailure to provide adequate dietary counselingFailure to comply with dietary regimenFailure to seek early care with escalating symptomsFailure to provide adequate discharge planningFailure to provide adequate follow-upFailure to provide adequate monitoringFailure to identify patient social support systemsFailure to address patient and caregiver needs

12

Systems Clinical Practice

ACC/AHA/HFSA ACC/AHA/HFSA GuidelinesGuidelines

III IIIIIIa IIbIIbIIb IIIIIIIIIIII IIIIIIa IIbIIbIIb IIIIIIIIIIII IIIIIIa IIbIIbIIb IIIIIIIIIIIIIIIa IIbIIbIIb IIIIIIIII

Bridging the Gap Between Knowledge and Routine Clinical Practice

Adapted from the American Heart Association. Get With The Guidelines; 2001.

• Implement evidence-based care• Improve communications• Ensure compliance

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

• Improve quality of care • Improve outcomes

• Clinical trial evidence• National guidelines

Comprehensive Heart Failure Patient Management ProgramOptimization of heart failure medical regimenDetailed patient and family education Daily measuring and recording of weights Sodium restricted diet with detailed guidelines

Fonarow GC et al.Fonarow GC et al. J Am Coll Cardiol.J Am Coll Cardiol. 1997;30:7251997;30:725--732.732.

gTwo liter (64 oz) fluid restriction (if congestion)Patient self-monitored flexible-loop diuretic regimenAlcohol and smoking abstinenceProgressive walking exercise programVigilant follow-up by clinical nurse specialists and physicians

HF Disease Management Program:Impact on Hospitalizations

779295

Conventional HF Management System HF ManagementCE

Inhi

bito

r Use

Patie

nts

(%)

* **P=0.05 vs conventional management

Management 6 MonthsPre-comprehensive

g yat Discharge

g6 Months

Post-comprehensive

AC

214 Patients, 6 months conventional treatment pre- vs 6 months post-comprehensive management.Total medical costs: Pre ($18,808) vs Post ($9,555), P<0.0001. Fonarow GC. et al. J Am Coll Cardiol. 1997;30:725-732.

429

63Post-

comprehensiveRx

ConventionalCare

85% ReductionP=0.0001

Cumulative Hospitalizations (6

months)

Randomized Trials of Disease Management Programs for Heart Failure

Sensitivity analysis Mortality All-cause readmission HF-related readmission

OR CI OR CI OR CIOverall 0.80 0.69–0.93 • 0.76 0.69–0.94 • 0.58 0.50–0.67 •

High quality studies 0.70 0.53–0.91 • 0.75 0.63–0.80 • 0.58 0.45–0.75 •

Low quality studies 0 85 0 71 1 03 0 75 0 66 0 86 0 58 0 46 0 70

33 Randomized Trials, 5308 patients Roccaforte EJHF 2005;7:113-1144.

Low quality studies 0.85 0.71–1.03 0.75 0.66–0.86 0.58 0.46–0.70

Multidisciplinary 0.58 0.44–75 • 0.58 0.47–0.71 0.51 0.39–0.66 •

Nurse 0.93 0.77–1.11 0.82 0.74–0.91 • 0.61 0.51–0.73 •

Short intervention (0–3 m) 0.88 0.66–1.16 0.61 0.51–0.74 • 0.61 0.46–0.82 •

Medium intervention (3–6 m) 0.84 0.63–1.12 • 1.05 0.88–1.26 • 0.68 0.53–0.86 •

Long intervention (> 6 m) 0.73 0.59–0.91 0.71 0.62–0.82 0.47 0.37–0.61

• P <0.01

Why a Hospital-based System forHeart Failure Management?

PatientsPatient capture pointHave patients/family attention:

“teachable moment”Predictor of care in communityPredictor of care in community

Hospital structureStandardized

processes/protocols/orders/teamsJCAHO-ORYX Core Measures

Process improvement examples

Centers for Medicare and Medicaid Services—peer review organizations

HEDIS (post discharge)

Institutional Heart Failure Discharge Medication Program Reduces Readmissions and Mortality

100

tes

(%)

Pre-Intervention (n=11,038)Post-Intervention (n=8,045)

65

95*

HR 0.80p<0.0001

0

50

ACEI Rx Readmissions

Trea

tmen

t Rat

1 year Mortality

18*2338*

46

Intermountain Health Care: 10 Hospitals Pre 1/96-12/98 n=11,038 to 1/99-3/00 n=8,045Pearson Circulation 2001;104:II-838

HR 0.77p<0.0001

13

Outpatient Adherence to β-Blocker Therapy Post Acute MI

Discharged on β-blockers

ocke

r Use

rs

40

60

80

Not discharged on β-blockers

Days Since Discharge

0 30 90 180 270 365

% β

-Blo

0

20

40

Butler J et al. J Am Coll Cardiol. 2002;40:1589–1595.

OPTIMIZE-HFWhat are the components of OPTIMIZE-HF?

+

Web-based RegistryMeasure and benchmark

heart failure quality of care and meaningful outcomes

Process of Care Improvement Program

Customizable “Toolkit” to assist hospitals in improving care and regional meetings

to train hospital teams

OPTIMIZE-HF: Change in HF Performance Measures Over Time

60

7080

90100

ts (%

)

HF-1 Discharge Instructions P<0.0001

HF-2 LVF AssessmentP<0.0001

The OPTIMIZE-HF Registry [database]. Final Data Report. Duke Clinical Research Institute, July 2005.

01020

3040

50

Q12003

Q22003

Q32003

Q42003

Q12004

Q22004

Q32004

Q42004

Calendar Quarters

Patie

nt

x

HF-3 ACEI at DischargeP<0.1848

HF-4 Smoking Cessation CounselingP<0.0001

β-Blocker at DischargeP<0.0001

Impact of Evidence-Based HF Therapy Use at Hospital Discharge on Treatment Rates During F/U: OPTIMIZE-HF

95.2

73.4

60

80

100

ient

s Tr

eate

d

60 to 90 Day Post Discharge Follow-up

OR 42.4(95% CI 28.5-63.3)

P<0.0001OR 11 6

31.6

19.3

ACEI/ARBat Discharge

Yes

ACEI/ARB at Discharge

No

0

20

40

% o

f Elig

ible

Pat

Beta Blockerat Discharge

Yes

Beta Blockerat Discharge

No

OR 11.6(95% CI 8.35-16.1)

p<0.0001

34,057 HF patients hospitalized at 236 US hospitals participating in OPTMIZE-HF, f/u on 2500 with LVDFonarow HFSA 2004

Impact of Discharge Use of Beta Blocker on Early Clinical Outcomes in Heart Failure

l Pro

babi

lity

1.00

0.95

0.90

0 85

OPTIMIZE - HFKaplan-Meier Curves for Effect of Discharge Beta-Blocker Use on All-Cause Death*

(Patients with LVSD)

P=0.0003

*Only subset of patients with 60- to 90-day follow-up are included. Patients with beta-blocker contraindications are excluded.The OPTIMIZE-HF Registry [database]. Final Data Report. Duke Clinical Research Institute. July 2005. Accepted ACC 2006

Surv

ival 0.85

0.80

0.75

0.700 10 20 30 40 50 60 70 80 90 100 110 120 130

Patients at Risk

Beta-blocker 1,946 1,855 1,649 333 68

No Beta-blocker 362 337 304 60 7

Days After Hospital Discharge

Beta-Blocker No Beta-Blocker

Challenges to Implement a Heart Failure Performance Improvement System

This will not work in a community practice or hospitalThe cardiologists will not agree to thisWe cannot get a consensusThe managed care organization will not pay for itPatients do not want to be on a lot of medicationsThere is not enough timeIt ill t t hIt will cost too muchIt may not be safe to start ββ--blockerblocker medications in heart failure patientsThis will benefit the competitionThe administration will not pay for itWhat about the liability?It will take too much timeAll my patients are too complex for thisThe patients should all be followed by someone elseIt is too hard to get things through the practice committeeThe physicians at my office do not like cookbook medicineWe do not have anyone to do this

14

Key Elements to Quality Improvement: Why Do Some Programs Succeed?

Access to current and accurate data on treatment and outcomesHave stated goals

Bradley EH, et al. JAMA. 2001;285:2604-2611.

Administrative supportSupport among cliniciansUse of care maps and pathwaysUse of data to provide feedback

AHA GWTG-HF Web Based Patient Management Tool

Preliminary Results with GWTG-HF: Performance Measures

70

9183

87

7474

92

8187

8174

9283 86

8275

92

82 84 8179

9185

90 89

708090

100

Baseline Q1 Q2 Q3 Q4

p<0.0001p<0.0001P=0.046P=0.036

P=0.127

0102030405060

DC Instructions LVF Measurement ACEI/ARB Beta Blocker SmokingCessation

Data from 97 GWTG-HF hospitals and 18,516 HF patients were collected from 1/05-3/06Fonarow GC et al. HFSA 2006

Congestion Precedes Hospitalization

Pressure Change Hospitalization

(%)

20

30

40

Adamson PB et al. J Am Coll Cardiol. 2003; 41: 565

Days Relative to the Event

Baseline -7 -6 -5 -4 -3 -2 -1 Recovery

Chan

ge (

-10

0

10 RV Systolic Pressure

Estimated PA Diastolic Pressure

Heart Rate

Poor Sensitivity of Weight and BNP Changes Prior to Clinical Decompensation

Sensitivity Specificity

> 2 Kg Weight Gain over 48 72 hours 9% 97%over 48-72 hours

> 2% Weight Gain over 48-72 hours 17% 94%

> 100 pg/mL increase in BNP 47% 77%

Lewin J et al. Eur J Heart Fail 2005;7:953-7.

Implantable Hemodynamic Monitoring to Guide Heart Failure Care: COMPASS

from

HF-

rela

ted

italiz

atio

n

60%

80%

100%

ChronicleControl

21% trend for reduction in the relative risk of HF hospitalization. (p=0.27) 33% reduction in the proportion of patients with worsening HF. 22% reduction in HF events overall. 41% reduction in HF-related events among patients with NYHA class 3 HF. (p=0.03)

Bourge et al. Presented at ACC 2005

Free

dom

fho

sp

0 50 100 150 200

0%

20%

40%

RR = 0.79 (95%CI = 0.64 - 0.98)p=0.029

15

Impedance Prior to HF Admission

Flui

dLe

ss

70

80

90

danc

e (Ω

)

Impedance

Reference Baseline

Mor

e

F

-28 -21 -14 -7 0

60

Impe

d

Days Before Hospitalization

Reduction

Duration of Impedance Reduction

Yu CM et al. Circulation. 2005;112:841-8

Pulmonary Fluid Detection Monitoring

Flui

d In

dex

(Ωda

ys) Physician Programmable Threshold

OptiVol Fluid Index

20

60

100

Impe

danc

e (Ω

)

Daily Impedance

Reference Impedance

40 80 120 160 2000Days

0 40 80 120 160 200

70

80

90

Days

Devices as Patient Care Monitors

Auricchio and Abraham Circulation 2004; 109: 300-307

AF DiagnosticsYou want to know the following:

Number of AF episodes% of time spent in AFLongest duration of AFAverage ventricular rate during AF

Implantable Devices Offer Unique Means to Monitor HF Patients

Objectively track fluid accumulation and/or hemodynamics longitudinally over timeMultiple measurements per day are averaged to give a truer picture of that day’s trends Acute changes are compared to the patient’s own expected baselineIntrathoracic impedance is not affected by respiration or any complicating factors such as electrode placement that impact external systemsNo compliance issues as with patient weightsWealth of other valuable information

89

Relative-risk 2 yr MortalityNone - - 35%ACE Inhibitor 23% 27%Ald t A t 30% 19%

Cumulative Impact of Heart Failure TherapiesCumulative Impact of Heart Failure Therapies

Aldosterone Ant 30% 19%Beta Blocker 35% 12%CRT +/- ICD 36% 8%

Cumulative risk reduction if all four therapies are used: 77%Absolute risk reduction: 27%, NNT = 4

Adapted from Fonarow GC. Rev Cardiovasc Med. 2000;1:25-33

16

Advances in the Treatment of HFIncreased attention to prevention

ACEI / β-blocker / aldosterone antagonist combination established as the “cornerstone” of therapy

Evidence that β-blockers’ effects are not homogeneous

Downgrade in recommendation for use of digoxing g

Integration of CRT and ICD device therapy into the standard therapeutic regimen

Recognition that “special populations” of HF patients may benefit from or require different approaches

New strategies to improve utilization of evidence based therapies and monitor patients

Hunt SA, et al. ACC/AHA 2005 Practice Guidelines. Available at http://www.acc.org.

Key Aspects for Improving OutcomesOptimization of medical therapyOptimization of device therapyEducation for both inpatients and outpatients

Reasonable expectations being given to patientsp g g pConsistent information being given to patients

Increased outpatient access to healthcare professionalsLong term patient follow-upRoutine communication between HF and EP