Heart Failure Care in 2004: A Therapeutic Update Khanh L. Hoang, MD Heart Failure Program at the North Texas Heart Center Presbyterian Hospital of Dallas

Epidemiology and Economics of Heart Failure

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. JACC 2002 AHA heart disease and stroke statistics.

The Heart Failure Epidemic

Prevalence 5 million Americans

Incidence 550,000 new cases/year

Morbidity 1,000,000 hospitalizations (2001)

8 to 10% of all admissions Most frequent cause of hosp in

elderly

Mortality Contributes to >260,000 deaths/year Five year mortality rate ~50%

Prevalence of HF Increases With Age

US, 1988–1994AHA. Heart Disease and Stroke Statistics—2004 Update

0

2

4

6

8

10

20–24 25–34 35–44 45–54 55–64 65–74 75+

Age (yr)

Pop

ulat

ion

(%)

Males

Females

$28 billion projected cost in 2004

Approximately twice the cost of treating all cancers, or all other CV diseases

7% of total heath 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, 1994AHA. 2001 Heart and Stroke Statistical Update.

Cost of Heart Failure

Estimated Costs of HF in US

8%

8% 10%

7%

14%

53%

Hospitalization$14.6

Lost Productivity/Mortality*

$2.1Home Healthcare

$2.1

Drugs/Other Medical Durables

$2.7

Physicians/Other Professionals

$1.8

Nursing Home$3.5

*Lost future earnings of persons who will die in 2004, discounted by 3%AHA. Heart Disease and Stroke Statistics—2004 Update

Total CostTotal Cost$27.8 billion$27.8 billionTotal CostTotal Cost$27.8 billion$27.8 billion

Heart Failure HospitalizationsHeart 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

Emergency Department Visits for Emergency Department Visits for Congestive Heart FailureCongestive 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

Hospitalization Due to HF Continues to Rise

• Progression of disease inevitable• Incidence of HF rising

– aging US population

– improved survival for CHD

• Patient noncompliance with meds and diet • HF management guidelines not followed• HF not treated appropriately during hospitalization

AdHeRE: Utilization of Chronic HF Therapies

2300/7883 patients hospitalized with HF; prior known dx of systolic dysfunction HF; outpatient medical regimenADHERE™ 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

50.8

12.8

57.4

80.8

41

0102030405060708090

100

Outpatient HF Medication

Pat

ien

ts T

reat

ed (

%) ACE Inhibitor ARB -Blocker Diuretic Digoxin

Adhere Registry for Acute Decompensated HF

Asymptomatic 51%

No mention 10%

Improved but still symptomatic 39%

The Adhere Registry 3rd Qtr National Benchmark Report

Many patientsare discharged while still symptomatic

Adhere Registry for Acute Decompensated HF

0

5

10

15

20

25

30

35

40

>20 20-15 15-10 10-5 5-0 0-5 5-10 > 10

20% of patients have no weight loss or a net weight gain during their hospital stay

Change in Weight (lbs)

Per

cent

age

of p

atie

nts

Net loss Net gain

The Adhere Registry 3rd Qtr National Benchmark Report

Pathophysiology 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

Peripartum CMEtOH

Thyroid DzInfectious Dz

Myocardial InjuryMyocardial Injury LV systolic dysfunctionLV systolic dysfunction

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

Myocardial toxicityMyocardial toxicity Peripheral vasoconstrictionPeripheral vasoconstrictionNaNa++ and H and H220 retention0 retention

Remodeling (dilation)Remodeling (dilation) and progressiveand progressive

worsening ofworsening ofLV functionLV function Heart failureHeart failure

symptomssymptomsMorbidityMorbidity

and mortalityand mortality

Heart Failure PathophysiologyHeart Failure Pathophysiology

Neurohormonal Targets in Heart Failure

Angiotensinogen

Angiotensin I

AT II

AT1 Receptors

SNS Activation

EpinephrineNorepinephrine

Target Cells

ACE-I

AldosteroneReceptor inhib

ARB

B-Blockers

B-Blockers

SYMPATHETIC NERVOUS SYSTEM

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM

Chronic HF therapy:lessons from the clinical trials


Angiotensinogen

Angiotensin I

AT II

AT1 Receptors

ACE Inhibitors

SNS Activation


Target Cells

ACE Inhibition in Clinical Trials: Reduction of Total Mortality in CHF Patients

No. of PatientsAgent # of trials ACE-I Placebo Odds Ratio (CI)Benazepril 2 143 90 0.36 (0.07-1.90)Captopril 6 352 345 0.79(0.54-1.14)Cilazapril 1 11 10 0.12 (0-6.20)Enalapril 7 1690 1691 0.78(0.67-0.91)Lisinopril 4 351 195 0.62(0.23-1.67)Perindopril 1 61 64 0.14 (0-7.16)Quinapril 5 548 327 0.79 (0.22-2.85)Ramipril 6 714 513 0.67 (0.36-1.24)TOTAL 32 3,870 3,235 0.77 (0.67-0.88)

Average Mortality Reduction ~24%

Modified from Garg R, et al. JAMA, 1995; 273:1450-1456

Mortality benefit in ACE Inhibitor Trials: Meta-analysis

N=12,763 patients

P < 0.0001

Flather, Yusuf et al. Lancet 2000;355:1575.

10

10

0

40

30

20

5432

Time since randomization (years)

Cum

ulat

i ve

mor

t ali

ty (

%)

ACE inhibitor

Placebo

ACE-I mortality 25%

Recommended target doses of commonly used ACE-I

• Enalapril (Vasotec) 10 mg bid

• Captopril (Capoten) 50 mg tid

• Lisinopril (Prinivil, Zestril) 40 mg qd

• Ramipril (Altace) 20 mg qd

The ATLAS TrialThe ATLAS Trial

Low vs high-dose Lisinopril (5 mg/d vs. 32 mg/d)

•Class II-IV HF•EF < 30%

•Tolerability same in both groups

•High dose group :

24% hospitalizations 12% risk of death/hosp No mortality difference

Packer M, et al.Circulation. 1999;100:2312-18


Angiotensinogen

Angiotensin I

AT II

AT1 Receptors

SNS Activation


Target Cells

ARBs

ACE-I

Hazard RatioHazard Ratio

AgeAge

GenderGender

NYHA Class.NYHA Class.

% EF% EF

Beta BlockersBeta Blockers

OverallOverall

7070 7070

MaleMaleFemaleFemale

III/IVIII/IVIIII

< 25< 25>> 25 25

WithWithWithoutWithout

1.051.051.331.33

1.121.121.141.14

1.191.191.371.37

1.001.001.191.19

1.771.771.051.05

1.131.13

HazardHazardRatioRatio

3.03.01.01.00.80.80.60.6 2.02.0

Hazard Ratio of DeathHazard Ratio of Deathwith 95% C.I.with 95% C.I.Subgroups at BaselineSubgroups at Baseline

Favors LosartanFavors Losartan Favors CaptoprilFavors Captopril

ELITE IIELITE II Mortality by SubgroupMortality by Subgroup

Lancet Lancet 2000;355:1582-872000;355:1582-87

913913661661

10831083491491

798798776776

29029012841284

32532512491249

15741574

NNCaptoprilCaptopril

901901677677

11021102476476

801801777777

26726713111311

35435412241224

15781578

NNLosartanLosartan

Val-HeFT: adding an ARB to an ACE-I improves morbidity, but not mortality

Maggioni AP et al. J Am Coll Cardiol. 2002;40:1414

P=0.017

ValsartanPlacebo

80

Time Since Randomization (mo)

90

100

70

60

50

0 6 12 18 24 30

Pro

bab

ilit

y o

fE

ven

t-F

ree

Su

rviv

al

N=5010 patientsNYHA II-IV

VALIANT Trial

19.9% 19.3% 19.5%

0%

10%

20%

30%

Valsartan Combo Captopril

19.9% 19.3% 19.5%

0%

10%

20%

30%


All-cause Mortality Valsartan vs captopril

HR 1.00, 97.5% CI 0.90-1.11, p=0.98Combo vs captopril

HR 0.98, 97.5% CI 0.89-1.09, p=0.73

CV Death, re-MI,or hospitalization for HF Valsartan vs captopril HR 0.95, p=0.20Combo vs captopril HR 0.97, p=0.37

N Engl J Med 2003;349:1893-906N Engl J Med 2003;349:1893-906

31.1% 31.9% 31.1%

0%

10%

20%

30%

40%


31.1% 31.9% 31.1%

0%

10%

20%

30%

40%


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

Summary: use of ACE-I and ARBs in the treatment of chronic HF

ACE-I have a long-standing, proven mortality benefit. ARBs and ACEI have similar efficacy as single agents, though

trends favor ACE-I. ACC/AHA guidelines recommend ACEI as first-line Rx for HF.

ARBs are appropriate for ACE-intolerant* patients. Adding ARB to ACEI leads to reduced hospitalizations, but not

improved survival. If patient remains hypertensive after appropriate dose of ACE-I and

beta-blockers, and spironolactone (in class III-IV), consider adding an ARB.

* The incidence of hyperkalemia, renal insufficiency and hypotension are equivalent in ACE and ARBs.


Angiotensinogen

Angiotensin I

AT II

AT1 Receptors

SNS Activation


Target Cells

-Blockers

-Blockers

ACE-I

ARB

Effects of -Blockade on Hospitalizations in Heart Failure

Heart Failure

Hos

pita

liza

tion

s/10

0 pt

s

P=.001 P<.05 P<.05 P<.05 P=not reported0

60

10

20

30

40

50

P=.003

Cardiovascular

All-cause

Placebo(n=2001)

Met CR/XL(n=1990)

Placebo(n=398)

Carvedilol(n=696)

MERIT-HF US Carvedilol Trials

30%

53%

16%

30%

11%

25%

MERIT-HF: Analysis of number of hospitalizations (from: Goldstein S. European Society of Cardiology presentation. 1999.) Mean follow-up = 1 yr.

US Carvedilol: Analysis of hospitalizations/patient (Adapted from: Fowler, et al. J Am Coll Cardiol. 1996 [Abstract]). Mean follow-up = 6.5 months.

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

Mortality reduction compared to placebo

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

All-Cause Mortality: COMET

Carvedilol 1511 1366 1259 1155 1002 383Metoprolol 1518 1359 1234 1105 933 352

No. of Patients at Risk

40

30

20

10

0

1 2 3 4 5Time (yr)

Mo

rta

lity

(%) Carvedilol

Metoprolol

0

P=0.0017

Cumulative Mortality in Patients With Severe HF: COPERNICUS

Packer M et al. N Engl J Med. 2001;344:1651

Placebo 1133 937 703 580 446 286 183 114Carvedilol 1156 947 733 620 479 321 208 142


Carvedilol(n = 1156)

Placebo(n = 1133)

0

60

80

90

100

0

Months

Su

rviv

al (

% o

f P

ati

ents

)

3 6 9 12 15 18 21

70

P=0.0014 (adjusted)P=0.00013 (unadjusted)

NYHA IV


Angiotensinogen

Angiotensin I

AT II

AT1 Receptors

SNS Activation


Target Cells

-Blockers

-Blockers

ACE-I

ARB

Aldosterone Receptor Blockers

The RALES TrialThe RALES Trial

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)

14.4%

16.7%

0%

5%

10%

15%

20%

14.4%

16.7%

0%

5%

10%

15%

20%

All-cause Mortality

RR 0.85

p=0.008

All-cause Mortality

RR 0.85

p=0.008

EPHESUS Trial: Primary Endpoints

26.7%

30.0%

0%

10%

20%

30%

40%

26.7%

30.0%

0%

10%

20%

30%

40%

CV Death or Hospitalization

RR 0.83

p=0.005

CV Death or Hospitalization

RR 0.83

p=0.005

EplerenoneEplerenone PlaceboPlacebo



Diuretics in HF treatment

No long-term studies of diuretic therapy for treatment of HF; effects on morbidity and mortality not known1

Patients may become unresponsive to high doses of diuretic drugs if they

Consume large amounts of dietary sodium2

Take agents that can block effects of diuretics (eg, NSAIDs, COX-2 inhibitors)1

Have significant impairment of renal function or perfusion1

Diuretic resistance can generally be overcome by

IV administration of diuretics2 Using 2 or more diuretics in combination2

1Ravnan SL et al. Congest Heart Fail. 2002;8:802Brater DC. Drugs. 1985;30:427

All-Cause Mortality: Digoxin

DIG Investigation Group. N Engl J Med 1997;336:525

P=0.80

Placebo

Digoxin

0

10

20

30

40

50

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Mo

rtal

ity

(%)

Months

Placebo 3403 3239 3105 2976 2868 2758 2652 2551 2205 1881 1506 1168 734 339Digoxin 3397 3269 3144 3019 2882 2759 2644 2531 2184 1840 1475 1156 737 335


Chronic HF Medications According to NYHA Class

Diuretics

Digoxin

ACE inhibitors

Beta blockers

Spironolactone

ARBs* (ACE-I intolerant patients)

Hydralazine/nitrates* (ACE-I / ARB intolerant, Black patients (A-Heft)

Drug Class I Class II Class III Class IV

Almeda FQ, Hollenberg SM. Postgrad Med. 2003;113:41*Mortality benefit compared to placebo, but second-line agents after ACE-I

Therapies for Acute Decompensated

Heart Failure

Factors contributing to acute decompensated HF (ADHF)

• CV factors– Superimposed ischemia or

infarction

– Uncontrolled HTN

– Primary valvular disease

– Uncontrolled afib

– Excessive tachycardia

• Systemic factors– Infection, uncontrolled DM

– Anemia, pregnancy

– Thyroid dz

– Electrolyte disorders

• Patient factors– Rx noncompliance

– Dietary indiscretion

– EtOH

– Substance abuse

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 (rare in HF)

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: Hemodynamic Profile Assessment

Yes


No

Warm & DryPCWP normal

CI normal (compensated)

Cold & WetPCWP elevatedCI decreased

Cold & DryPCWP low/normal

CI decreased

VasodilatorsNitroprussideNitroglycerinNesiritide

Inotropic DrugsDobutamine

Milrinone

Normal SVR

High SVR

Congestion at Rest

Car

dia

c ou

tpu

t/P

erfu

sion

at R

est Normal

Low

Warm & WetPCWP elevated

CI normal

Acute HF: hemodynamics guide therapy

Diuretics and

Parenteral Therapies for Parenteral Therapies for Acute Decompensated Heart FailureAcute Decompensated Heart Failure

Treatment Limitations

Dobutamine Heart rate, arrhythmias,

Milrinone

Nitroglycerin Tolerance, hypotension, headache

Nitroprusside Hypotension, tolerance, toxicity

Heart rate, arrhythmias, hypotension

ischemia, and tolerance

Nesiritide Hypotension

Natriuretic Peptides

Physiology of Natriuretic PeptidesPhysiology of Natriuretic Peptides

BNP

Adapted from Wilkins MR. Redondo J. Brown LA. Lancet 1997;349:1307-1310

Promotesvasodilation

Inhibits cell proliferation

Inhibits reninPromotes natriuresis

Sympathetic Nervous System

Inhibits SNS

Acute DecompensatedHeart Failure

Physiologic Effects of Neurohormones

Renin-Angiotensin- Aldo-System (RAAS)

-Vasoconstriction

-Sodium retention -Aldosterone release

-Increased sympathetic activity -Smooth muscle cell

proliferation

-Vasodilation -Sodium excretion -Aldosterone blockade-Decreased sympathetic activity -Antiproliferation of vascular smooth muscle cells

Burnett JC Jr. J Hypertens. 1999;17(suppl 1):S37

Natriuretic Peptide System (BNP)

Shah M et al. Rev Cardiovasc Med. 2001;2(suppl 2):S2

Neurohormonal Imbalance in Decompensated HF

ANPBNPNO

Endothelin

Aldosterone

Angiotensin IINorepinephrine

Epinephrine

Vasoconstriction Vasodilation

Bradykinin

Hemodynamic Effects of NesiritideHemodynamic Effects of Nesiritide

-60

-40

-20

0

20

40

60

HR CVP PCWP SVR CI SVI

Placebo

Nesiritide

Cha

nge

from

bas

elin

e (%

)

**

+

+

* p <0.01 vs placebo+ p<0.05 vs placebo

16 patients received a 4-hour continuous infusion of hBNP (0.025 and 0.05 g/kg/min) or placebo.Abraham WT et al. J Cardiac Failure 1998;4:37-44

Clinical Trials with

Nesiritide (Natrecor)

Natrecor® (nesiritide) Efficacy: VMAC Trial

Vasodilation in the Management of Acute

Congestive Heart Failure Trial

• 489 patients with Acute Decompensated HF

• Randomized to Nesiritide vs IV nitroglycerin vs placebo

• Primary end points: reduction in PCWP and dyspnea at 3 hr

• Background standard of care could include:– IV / oral diuretics, Dobutamine, Dopamine, chronic cardiac and

noncardiac therapies

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

Added to standard therapy; N = 242

*P<0.05 vs placebo plus standard carePublication Committee for the VMAC Investigators. JAMA. 2002;287:1531

VMAC Trial: Hemodynamic Improvement

Nesiritide reduced mean PCWP within 15 min

Symptoms improved Results persisted >24 hr No evidence of decreased

effect over time (tachyphylaxis) No significant increase in

heart rate

Nesiritide reduced mean PCWP within 15 min

Symptoms improved Results persisted >24 hr No evidence of decreased

effect over time (tachyphylaxis) No significant increase in

heart rate

Placebo

Mea

n C

han

ge

in P

CW

P (

mm

Hg

)

Nitroglycerin Nesiritide

–6

–5

–4

–3

–2

–1

0.25

1 2 3BL

0 PCWP

Hours

0.5

**

*

* **

Burger AJ et al. Am Heart J. 2002;144:1102

PRECEDENT : Clinical Effects and

Proarrhythmic Potential of Nesiritide • Randomized, controlled

• Parallel arms – Dobutamine 5 mcg/kg/min

– Nesiritide 0.015 mcg/kg/min

– Nesiritide 0.030 mcg/kg/min

• N = 255

• ADHF – NYHA class III or IV

• 24-hr baseline Holter

• 24-hr Holter during treatment

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: Precedent: 6 Month Survival6 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

Precedent Study:Nesiritide is Not Proarrhythmic

Nesiritide decreased or had a neutral effect on ventricular ectopy and heart rate

Change in heart rate and ectopy compared to baseline

-14

-12

-10

-8

-6

-4

-2

0

2

4

Mea

n C

han

ge

fro

m B

asel

ine

in

Eve

nts

/ho

ur

or

Ave

rag

e H

R (

BP

M)

Heart Rate PVB Repetitive Beats

Nesiritide 0.015mcg/kg/min (n = 84)

Nesiritide 0.030mcg/kg/min (n = 79)

Burger AJ, et al. Am Heart J. 2002;144:1102-1108.

Yes


No

Warm & DryPCWP normal

CI normal (compensated)

Cold & WetPCWP elevatedCI decreased

Cold & DryPCWP low/normal

CI decreased

VasodilatorsNitroprussideNitroglycerin and Diuretics

Inotropic DrugsDobutamine

Milrinone

Normal SVR

High SVR

Congestion at Rest

LowPerfusion

at Rest

No

Yes

Warm & WetPCWP elevated

CI normal

Natriuretic PeptideNesiritide or

Acute HF: hemodynamics guide therapy

Hemodynamic Monitoring

IV Inotropic Agent(s)

Nesiritide

Refractory Therapy

Initial Therapy

OxygenIV Diuretics

Volume Overloaded, Dyspnea, SBP >90 mm Hg

MechanicalAssist

CompensationOptimize Oral HF Drug Regimen

Optimize Patient EducationDischarge Home

Inadequate Response

Increase Nesiritide Dose

(to max of 0.03 mcg/kg/min)

Abraham WT et al. Rev Cardiovasc Med. 2001;2:235

Treatment Algorithm for ADHF

BNP as a diagnostic tool

Endogenous BNP

• 32–amino acid peptide secreted primarily from ventricles of heart

• Released in response to stretch and increased volume in ventricles

• Plasma BNP levels correlate with– LV end diastolic (PCWP) pressure– NYHA classification

• Plasma BNP may be used as marker to diagnose acute heart failure.

Dao Q et al. J Am Coll Cardiol. 2001;37:379

BN

P C

on

cen

tra

tio

n

(pg

/mL

)

186 ± 22

791 ± 165

2013 ± 266

HF Severity

Mild Moderate Severe0

500

1000

1500

2000

2500

BNP Concentration and Degree of HF Severity

Dao Q et al. J Am Coll Cardiol. 2001;37:379

HF very unlikely (2%)

BNP <100 pg/mL

PossibleExacerbationof HF (25%)

Yes

HF likely(75%)

No

Baseline LV dysfunction,underlying cor pulmonale?

BNP 100–400 pg/mL

HF very likely (95%)

BNP >400 pg/mL

Physical examination, chest x-ray, ECG, BNP level

Patient presents with dyspnea

Maisel A. Rev Cardiovasc Med. 2002;3(suppl 4):S10

Clinically Validated Algorithm for using

BNP in diagnosis of acute HF

BNP Concentration Predicts Clinical Events After Hospital

Discharge

Harrison A et al. Ann Emerg Med. 2002;39:131

Cu

mu

lati

ve P

rob

abili

ty o

f

HF

Vis

it, A

dm

issi

on

, or

Dea

th (

%)

Time (days)

0 20 40 60 80 100 120 140 160 180

BNP < 230 pg/mL

BNP 230–480 pg/mL

BNP > 480 pg/mL

0

5

10

15

20

25

30

35

40

45

50

55

Factors which may lower the specificity of BNP assay

Falsely high BNP• Age, female gender• Renal insufficiency

(GFR<60)• Pulmonary HTN (cor

pulmonale, PE’s)• Pure RV dysfunction

Falsely low BNP• “Flash” pulmonary

edema• Acute mitral

regurgitation

Device Therapies for Advanced Heart Failure

Cardiac Resynchronization Therapy Cardiac Resynchronization Therapy (CRT) in Heart Failure(CRT) in Heart Failure

Indications: EF <35%

NYHA III-IV

QRS >130 ms

Cha

nge

in 6

-min

ute

Wal

king

Dis

tanc

e (

)

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

Control

Resynchronized

MIRACLE: Cardiac Resynchronizationin Heart Failure

Impr

ovin

g Q

uali

ty o

f L

ife

Sco

re (

)

Cardiac Resynchronization: Clinical Events

CONTROL CARDIAC- HAZARD RATIO pEVENT GROUP RESYNCH (95% CI) Value

(N=225) GROUP (N=228)

no. of patients

Death from any cause 16 12 0.73 (0.34 - 1.54) 0.40

Death or worsening HFrequiring hosp 44 28 0.60 (0.37 – 0.96) 0.03

Hosp for worsening HF 34 18 0.50 (0.28 – 0.88) 0.02

Worsening HF leading to use of IV med for HF 35 16 0.43 (0.24 – 0.77) 0.0040


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

COMPANION

• 1520 patients NYHA III-IV

• LVEF < 35%

• QRS > 120 ms

• Randomized to Medical Rx vs CRT vs CRT + ICD

• Results: – CRT risk of death/hospitalization by 34% (p < 0.002) and

all-cause mortality by 24% (p = 0.06)

– CRT + ICD risk of death/hospitalization by 40% (p < 0.001) and

all-cause mortality by 36% (p = 0.003).

N Engl J Med 2004;350:2140-

Heart Failure Update 2004

• ACE-I* and B-blockers as firstline therapy for patients with LVEF<40%, regardless of symptoms.

• ARBs in patients who are ACE-I intolerant.• The addition of ARBs to ACE-I yields equivocal

benefit over ACE-I monotherapy.• *Hydralazine/Nitrates in black patients (A-HeFT).• Spironolactone in class III-IV patients.

Heart Failure Update 2004

• In acute HF: BNP provides both a diagnostic and first-line therapeutic tool (Nesiritide/Natrecor).

• Inotropic drugs are indicated primarily in the setting of acute HF associated with cardiogenic shock.

• CRT improve symptoms in patients with advanced CHF and wide QRS, who are refractory to maximal HF medical therapy.

• ICD improves survival in post-MI patients with advanced HF and LVEF < 30%.

ACE-I and ASA

• ACE-I inhibit kinin degradation• Increased kinin mediates release of vasodilator prostaglandins• ASA is a prostaglandin synthesis inhibitor• In SOLVD, pts on ASA and enalapril had no increased

survival benefit over ASA alone. • However, most of the evidence does not support a significant

inhibitory effect of ASA on the benefit of ACE-I• Alternative options to using ASA w/ACE-I:

– Ticlid does not interfere with kinin synthesis. – ASA 81mg may not interfere as much with ACE-I.

– Use ARB, which does not affect kinin metabolism.

ACEI utilization rates

• Many pts are not treated, or underdosed.

• Cardiologists, and academic centers are more likely to use ACEI than community physicians

• Lack of use generally due to perceived intolerance due to age, renal dysfunction.

ACEI in Blacks

• Blacks respond less well to ACE-I than to most other antihypertensive drugs.

• In SOLVD, there was no reduction in hospitalization rates in drug arm.

• In V-Heft, blacks had mortality benefit with hydralazine/isordil, but not whites.

• A-Heft

The A-HEFT TrialThe A-HEFT Trial

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

n = 1050NYHA III/IV

LVEF < 35% or < 45%

(LVEDD increased)

mortality 43%

hospitalization 33%

Uptodate ValHeft graph showing increased mortality in pts on

ACEI+ARB+BB

NEJM 2001;345:1667

Current Treatments for ADHF

Diuretics

ReduceReduceFluidFluid

VolumeVolume

Vasodilators

DecreaseDecreasePreloadPreload

andandAfterloadAfterload

(SVR)(SVR)

Inotropes

AugmentAugmentContract-Contract-

IlityIlity(Cardiac (Cardiac Output)Output)

Natriuretic Peptide


andandAfterload; Afterload; Reduce Reduce

Fluid Fluid VolumeVolume


andandAfterload; Afterload; Reduce Reduce

Fluid Fluid VolumeVolume

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


CRTControl

MIRACLE: Cardiac Resynchronization (CRT) improves symptoms in HF

Advanced HF: Therapeutic Options?

• ACE inhibitors: decrease in mortality in class IV HF (CONSENSUS)

• Beta blockers: decrease in mortality in advanced HF (COPERNICUS)

• Aldosterone receptor antagonists: decrease in mortality in class III–IV HF (RALES)

• Digoxin: reduction in combined morbidity/mortality (DIG) • Mechanical support: improved outcomes in class IV HF

(REMATCH)• Nesiritide for ADHF • Hospice• Heart transplantation

The COMPANION TrialThe 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

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

OPTIMEOPTIME

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

Endogenous BNP LevelsEndogenous BNP Levels and Pulmonary Wedge Pressures and Pulmonary Wedge Pressures

PC

W (

mm

Hg)

Hours

BN

P (p

g/ml)

15

17

19

21

23

25

27

29

31

33

baseline 4 8 12 16 20 24600

700

800

900

1000

1100

1200

1300

PAWBNP

15 heart failure patients responding to vasodilators and diureticsMaisel Cardiovascular Symposium Highlights 2001

Breathing Not Properly trial showing ppv and npv of bnp

N Engl J Med. 2002;347(3):161-167.

PRECEDENT Study DesignPRECEDENT Study Design

Baseline HolterMonitoring

Nesiritide 0.015 µg/kg/min

Nesiritide 0.030 µg/kg/min

Dobutamine 5 µg/kg/min

-24 0 24Hours

Holter Baseline and at 24-hours Blood Pressure, Heart Rate At baseline, 15 & 30 minutes, 3, 8, 16 and 24 hrsGlobal clinical status At baseline, 3 and 24 hrs

Burger AJ. et al. J Cardiac Failure 1999;5 (Suppl 1):178

Fusion I mortality data

• CHF graph page 25 fig 28 nesiritide v standard of care

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

VMACVMAC Mortality Rates Over 6 MonthsMortality Rates Over 6 Months

Cu

mu

lati

ve M

ort

alit

y R

ate

%

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

Vasodilation in the Management of Vasodilation in the Management of Acute Congestive Heart Failure (VMACAcute Congestive Heart Failure (VMAC))

• Phase III randomized, double-blind, placebo-controlled

• Multi-center (55) in the U.S.

• Randomization strategy based upon right heart catheter

• 498 patients enrolled from Oct. 1999 to July 2000

• Acutely decompensated heart failure with dyspnea

• Nesiritide vs. intravenous nitroglycerin vs. placebo

Young JB et al. J Cardiac Failure 2000;6 (suppl 2):182

Hemodynamic(balanced vasodilation) Veins Arteries Coronary arteries

Neurohormonal aldosterone endothelin norepinephrine

Renal sodium and water excretion

Cardiac Lusitropic Antifibrotic Antiremodeling

Abraham WT et al. J Card Fail. 1998;4:37Clemens LE et al. J Pharmacol Exp Ther. 1998;287:67Marcus LS et al. Circulation. 1996;94:3184Tamura N et al. Proc Natl Acad Sci U S A. 2000;97:4239 Zellner C et al. Am J Physiol. 1999;276(3 pt 2):H1049

Physiologic Actions of Endogenous BNP

FUSION I: Minimum Number of Days Alive & Out of Hospital

0

5

10

15

20

25

30

35

All Patients Low Risk patients High Risk Patients

Num

ber

of D

ays

Standard Care Low Dose Natrecor High Dose Natrecor

* P<0.05 pooled nesiritide compared to nitroglycerin

VMAC: VMAC: PCWPPCWP Through 48 HoursThrough 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

• Change from baseline in PCWP at 3 hours in catheterized subjects

• Change in dyspnea at 3 hours in all subjects

Young JB. et al. J Cardiac Failure 2000;6 (suppl 2):182

VMAC: VMAC: Primary EndpointsPrimary Endpoints

FUSION I Study Design

n = 69

n = 72

n = 69 Nesiritide 0.01 µg/kg/min, following bolus – Inotropes not permitted

Nesiritide 0.005 µg/kg/min, following bolus – Inotropes not permitted

Standard Care – Inotropes permitted

-30 to -5 days post hospital discharge

Weekly Outpatient Visits

n = 210

4 Weeks

Screening

12 Weeks

Follow-up

FUSION I: Inclusion Criteria

• Adults who are NYHA Functional Classification III/IV

• At least 2 hospital admissions (or unscheduled visit requiring IV vasoactive treatment) for acutely decompensated CHF within the last 12 months, with at least one of these admissions in the past 30 days

• On optimal treatment with long term oral CHF medications

• 6–minute walk test is < 400 meters

5.5%

3.9%

0%

2%

4%

6%

8%

5.5%

3.9%

0%

2%

4%

6%

8%

Serious hyperkalemia

p=0.002

Serious hyperkalemia

p=0.002

EPHESUS Trial: Serious Adverse Events

0.5%0.6%

0.0%

0.5%

1.0%

1.5%

0.5%0.6%

0.0%

0.5%

1.0%

1.5%

Gynecomastia

p=0.70

Gynecomastia

p=0.70




Heart Failure Care Update

• Scope of the Problem ($$$)• Basic pathophysiology of CHF• Drugs for Chronic HF : lessons from the clinical trials • Acute HF: IV inotropes and IV vasodilators (Natrecor)• BNP as a diagnostic tool• Device therapies (Biventricular pacemakers, ICDs)

Survival benefit in both symptomatic and asymptomatic LV dysfunction (LVEF<40%), both idiopathic and post-MI

Improvement in symptoms and functional status, lower rate of readmission

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

Uptodate graph: ACEI + BB’s more beneficial than either one

alone (diamond graph)

Cleland et al, BMJ 1999;318:824.

Outcomes in Patients Hospitalized With HF

N = 38,702Aghababian RV. Rev Cardiovasc Med. 2002;3(suppl 4):S3Jong P et al. Arch Intern Med. 2002;162:1689

0

25

50

75

100

20%

50%

30Days

6Months

Hospital ReadmissionsHospital Readmissions

0

25

50

75

100

12%

50%

30Days

12Months

MortalityMortality

33%

5Years

Median LOS: 6 days

Heart Failure Costs

68.6%Hospitalizations$23.1 billion

30.7%Outpatient care$14.7 billion(3.4 visits/year/patient)

O’Connell and Bristow. J Heart Lung Transplant. 1999;13:S107-S112.

0.7%Transplants$270 million

Total = $56.1 billion(5.4% of total healthcare costs)

Clinical Assessment ofClinical Assessment of Hemodynamic StatusHemodynamic Status

Congestion at Rest

LowPerfusion

at RestC

NO

NO YES

YES L

A BWarm &

DryWarm &

Wet

Cold & WetCold & Dry

(Complex)(Low Profile)

BNP Concentration for the BNP Concentration for the Prediction of Clinical EventsPrediction of Clinical Events

Maisel A, et al. Annals of Emergency Medicine 2002

0 20 40 60 80 100 120 140 160 1800%

5%

10%

15%

20%

25%

30%

35%

40%

45%

BNP < 230 pg/ml

BNP 230-480 pg/ml

BNP > 480 pg/ml

Death or Heart Failure Hospitalization

Days

Causes of Hospital ReadmissionCauses of Hospital Readmissionfor Heart Failurefor 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 PathophysiologyHeart Failure Pathophysiology

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

-

-

Cumulative Mortality in Patients With Severe HF: RALES

P<0.001

(n = 822)Spironolactone

(n = 841)PlaceboP

rob

abili

ty o

f S

urv

iva

l

0.00

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

0 3 6 9 12 15 18 21 24 27 30 33 36

Months

Placebo 841 775 723 678 628 592 565 483 379 280 179 92 36

Spironolactone 822 766 79 698 669 639 608 526 419 316 193 122 43


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

Physiologic Effects of thePhysiologic Effects of the RAAS and NPS RAAS and NPS

Adapted from Burnett JC, J Hypertens 1999;17(Suppl 1):S37-S43

RAAS (Renin-Angiotensin Aldosterone System)

Activation of AT1 receptorsby angiotensin II

VasoconstrictionSodium retentionIncreased aldosterone releaseIncreased cellular growthIncreased sympathetic nervous activity

NPS (Natriuretic Peptide System) ANP, BNP Vasodilation

Sodium excretionDecreased aldosterone levelsInhibition of RAASInhibition of sympathetic nervous activity

CNP VasodilationDecreased vascular smooth muscle growthDecreased aldosterone levels

Final measurement in 1156 advanced HF patients after tailored vasodilator therapyFonarow HFSA 2001

0

0.2

0.4

0.6

0.8

1

0 1 2 3 4 5 6 7 8 9 10 11 12

PCW <12 PCW 12-14.9 PCW 15-17.9 PCW >18

P = 0.00001

Months

Su

rviv

al %

PCW Quartiles

PCWP Predicts Subsequent Mortality PCWP Predicts Subsequent Mortality in Heart Failurein Heart Failure

Elevated BNP Levels in Elevated BNP Levels in Decompensated Heart FailureDecompensated Heart Failure

Mea

n B

NP

C

once

ntr

atio

n (

pg/

ml)

AsymptomaticLV Dysfunction

(n=14)

38 ± 4141 ± 31

1076 ± 138

No CHF(n=139)

CHF(n=97)

0

200

400

600

800

1000

1200

1400

Maisel A. et al. J Am Coll Cardiol 2001;37(2):379-85

P < 0.001

ADHERE CART Analysis

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., Accepted HFSA 2003Fonarow et al., Accepted HFSA 2003

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

< >

<

< >

>

><

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

73.9% 76.4%

0%

20%

40%

60%

80%

100%

73.9% 76.4%

0%

20%

40%

60%

80%

100%

CarvedilolCarvedilol MetoprololMetoprolol

P=0.1222P=0.1222

COMET: All-Cause Mortality and Hospitalizations

Hazard Ratio = 0.93

95% CI 0.86-1.02

Hazard Ratio = 0.93

95% CI 0.86-1.02

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

0 6 12 18 24Months

0

10

20

30

40

50

60

Total Mortality Risk%

199

257

PCW > 16 mmHg

PCW < 16 mmHg

P=0.001

0 6 12 18 24Months

0

10

20

30

40

50

60

Total Mortality Risk%

236

220

Cardiac Index > 2.6 L/min-M2

Cardiac Index < 2.6 L/min/M2

PCWP but not CI Predicts PCWP but not CI Predicts Subsequent Mortality in Heart FailureSubsequent Mortality in Heart Failure

Final measurement in 456 advanced HF patients after tailored vasodilator therapy Fonarow Circulation 1994;90:I-488

P=NS

Diuretics

Digoxin ACE-I

-Blocker ARB

AldoRB BNP

Bi-V Pacing ICD

LVAD

. . .The Forest for the Trees

Urinary Excretion Data for hBNPUrinary Excretion Data for hBNPU

rina

ry s

odiu

m e

xcre

tion

(mE

q/hr

)U

rina

ry v

olum

e(m

L/h

r)

Uri

nary

pot

assi

um e

xcre

tion

(mE

q/hr

)C

reat

inin

e cl

eara

nce

(mL

/min

)

0

25

50

75

100

125

0

25

50

75

100

0

1

2

3

4

Placebo BNP

Placebo BNP Placebo BNP

Placebo BNP

P<0.05

P<0.01

A

B

C

D

0

1

2

3

4

Marcus LS et al. Circulation. 1996;94:3184-3189

BNP ConcentrationBNP Concentration and Heart Failure Severity and Heart Failure Severity

BN

P C

once

ntr

atio

n (

pg/

ml)

186 ± 22

791 ± 165

2013 ± 266

Mild(n=27)

Moderate(n=34)

Severe(n=36)

0

500

1000

1500

2000

2500

Maisel A. et al. J Am Coll Cardiol 2001;37(2):379-85

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

All-Cause Mortality in PROMISE

Packer M et al. N Engl J Med. 1991;325:1468

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21

Su

rviv

al P

rob

ab

ility

Placebo 224 159 116 78 59 35 12Milrinone 233 155 109 69 49 30 6

Month of Study

Placebo

Milrinone

P=0.038

Use of Dobutamine in FIRST: Increased Mortality

O’Connor CM et al. Am Heart J. 1999;138:78

Follow-up (years)

No Dobutamine

Dobutamine

P=0.0001

Fra

ctio

n S

urv

ived

0 0.25 0.75 1.25 1.50

0

0.25

0.50

0.75

1.0

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

Documents

Heart Failure Care in 2004: A Therapeutic Update Khanh L. Hoang, MD Heart Failure Program at the North Texas Heart Center Presbyterian Hospital of Dallas