vbwg improving outcomes in heart failure: new insights from vascular biology

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Improving Outcomes in Improving Outcomes in Heart Failure: New Insights Heart Failure: New Insights

From Vascular BiologyFrom Vascular Biology

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Heart Failure:A Public Health Concern

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Lloyd-Jones DM et al. Circulation. 2002;106:3068-72.

0

5

10

15

20

25

Attained age (years)

Cumulativerisk (%)

Men

40

20% Lifetime risk for HF after age 40

Women

Framingham Heart Study

5050 60 70 80 900

5

10

15

20

25

0

Lifetime risk for HF for given index ageis cumulative through age 94 years

40 5050 60 70 80 90

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Hypertension is the No. 1 risk factor for HF

20

40

60

0HTN

Population-attributable

risk (%)

MI Angina VHD LVH Diabetes

Hazard ratio M 2.1 6.3 1.4 2.5 2.2 1.8

W 3.3 6.0 1.7 2.1 2.8 3.7

Men Women

Levy D at al. JAMA. 1996;275:1557-62.VHD = valvular heart disease

Framingham Heart Study

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Diabetes: A frequent comorbidity with HF

Bell DSH. Diabetes Care. 2003;26:2433-41.Bertoni AG et al. Diabetes Care. 2004;27:699-703.

Adams KF et al. Am Heart J. 2005;149:209-16.

• Framingham data show HF in diabetic adults age 45 to 74 years

– 2x in men; 5x in women

• Medicare sample of diabetic adults age ≥65 years (1994–1999):

– HF prevalence in 1994: 22.4%

– Annual HF incidence: 7.9%

– Similar incidence by sex and race

– Significant ↑ with age and diabetes-related comorbidities

• National registry of >100,000 patients hospitalized with HF

(mean age 72.4 years)

– 44% had diabetes

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Diabetes is the No. 1 risk factor for HF in women with coronary disease

Bibbins-Domingo K Jr et al. Circulation.2004;110:1424-30.

Adjusted hazard ratio

Diabetes

Atrial fibrillation

Myocardial infarction >1 event

Creatinine clearance <40

Current smoking

BMI >35

Left bundle branch block

LV hypertrophy

Systolic BP ≥140

3.12.9

2.5

2.3

2.1

1.9

1.9

1.6

1.5

0 0.5 1 1.5 2 2.5 3 3.5

HERS study

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Increasing risk for HF in women with CHD: Impact of diabetes, renal insufficiency, obesity

Bibbons-Domingo K et al. Circulation.2004;110:1424-30.CrCl (ml/min) = creatinine clearance

HERS study; 2391 women with CHD and no HF at baseline

0

2

4

6

8

10

12

14

CHD CHD + DM CHD + DM + BMI >36

CHD + DM + CrCl <42.8

1.2

2.8

7.0

12.8

AnnualHF

incidence(%)

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Heart Failure Pathophysiology

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Important pathophysiologic mechanisms in HF (1)

Coronary arteries• Obstruction• Inflammation

Modified from Jessup M, Brozena S. N Engl J Med. 2003;348:2007-18.

Cardiac abnormalities

Myocardium or myocyte• Myocardial relaxation • Abnormal excitation- contraction coupling• -Adrenergic desensitization• Hypertrophy• Necrosis• Fibrosis• Apoptosis

FunctionalStructural

Left ventricular chamber• Remodeling

– Dilation– Increased sphericity– Aneurysmal dilatation

or wall thinning– Concentric hypertrophy

Mitral regurgitation

Intermittent ischemia or hibernating myocardium

Induced arterial and ventricular arrhythmias

Altered ventricular interaction

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• RAAS

• SNS (norepinephrine)

• Vasodilators (bradykinin, nitric oxide, prostaglandins)

• Natriuretic peptides

• Cytokines (endothelin, tumor necrosis factor, interleukins)

• Vasopressin

• Matrix metalloproteinases

Jessup M, Brozena S. N Engl J Med. 2003;348:2007-18.

Biologically active tissue

and circulating substances

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• Genetics, ethnicity, sex• Age• Use of alcohol, tobacco,

toxic drugs

Coexisting conditions• Hypertension• Diabetes• Renal disease• Coronary artery disease• Anemia• Obesity• Sleep apnea• Depression

Patient factors

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Neurohormonal model of HF

Ventricular remodeling

• Neurohormonal activation– RAAS, SNS

• Increased cytokine expression

• Immune and inflammatory changes

• Altered fibrinolysis

• Oxidative stress

• Apoptosis

• Altered gene expression

• Energy starvation

Injury to myocytes and extracellular matrix

Electrical, vascular, renal, pulmonary muscle, and other effects

Heart failure McMurray J, Pfeffer MA. Circulation. 2002;105:2099-106.

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Diabetes pathogenesis accelerates HF

Kirpichnikov D et al. J Card Fail. 2003;9:333-44.

Activation of

protein kinase C

Hyperglycemia

Heart failure

Decreased intracellular

calcium removal

Activated

RAAS

Activated

sympathoadrenal

system

Cardiac

fibrosis

Cardiomyocyte

death

Decreased myocardial

contractile strengthDiastolic

dysfunction

Systolic

dysfunction

Diabetes

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RAAS in CV continuum: Pivotal role of AT1 receptors in the failing heart

Adapted from Wassmann S, Nickenig G. Eur Heart J Suppl. 2004;6(suppl H):H3-9.

Renin

ACE

B1/B2 receptorAT1 receptor

Angiotensinogen

Angiotensin I

Angiotensin II

AT2 receptor

NO

VasodilationGrowth inhibitionApoptosis

Degradation

Bradykinin/Kinins

Reactive oxygen speciesPro-inflammatory processVasoconstrictionCellular growth/proliferationApoptosisNeurohormonal activation

? Clinical significance

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Primary targets of treatment in HF


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Angiotensin receptor blockade in the CVD continuum

AtherosclerosisMyocardial

infarction

Endothelial

dysfunction

ARB

Coronary heart

disease

Plaque rupture

ARB

Risk factors

Dilation/

Remodeling

Heart failure

End-stage

heart failure

ARB

Hypertension

Hyperlipidemia

Diabetes

ARB

Wassmann S, Nickenig G. Eur Heart J Suppl. 2004;6(suppl H):H3-9.

ARB

ARB

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Clinical Trial Update

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Survival studies of -blockade in HF

0.50.0 1.0

II-IV

III/IV*

III/IVCIBIS-II Bisoprolol

MERIT-HF Metoprolol succinate CR/XL

All pooled

Relative risk and 95% CI

Patients(N)

Favors-blocker

Total mortalityPlacebo/-blocker

NYHAclass

EFmean

COPERNICUS Carvedilol

2647

3991

2289

8927

28%

28%

20%

CIBIS-II Investigators. Lancet. 1999;353:9-13.MERIT-HF Study Group. Lancet. 1999;353:2001-7.

Packer M et al. N Engl J Med. 2001;344:1651-8.

228/156

217/145

190/130

635/431

P

0.0001

0.00009

0.00013

*not recorded in COPERNICUS, but placebo mortality indicates III/IV

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MERIT-HF: Metoprolol succinate CR/XL lowers risk of hospitalization with/without diabetes

Placebo(n = 490)

Metoprolol succinate CR/XL(n = 495)

Total # hospitaliz/patient-yrs

(%)

50

2625

15

–53%P = 0.0087

–44%P = 0.0039

25

910

30

50

70

–37%P = 0.0026

–35%P = 0.0002

All randomized NYHA III/IV, EF <25%

Diabetes No diabetes Diabetes No diabetes

Deedwania PC et al. Am Heart J. 2005;149:159-67.

16 13

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MERIT-HF: Benefit of -blockade with/without diabetes

145

50

14

95

31

200

72

20

128

40

Relative risk (95% CI)

All patients randomized

Diabetes

Diabetes, severe HF

No diabetes

No diabetes, severe HF

All patients randomized

Diabetes

Diabetes, severe HF

No diabetes

No diabetes, severe HF*

0.0 1.0

Favors metoprolol succinate CR/XL

Favorsplacebo

All-cause mortality

Hospitalization for CHF

Metoprolol succinate CR/XL


217

61

24

156

48

294

108

40

186

64

Placebo

Events (n)

*Severe HF = NYHA class III/IV, EF<0.25

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Pooled HF trials: Effect of -blockade on survival in diabetic patients

31223352647

98530063991

Relative risk (95% CI)

DiabetesNo diabetes

All

All 3 studies

0.0 1.0

CIBIS II

MERIT-HF

Total (n)randomized


1.8

33/27195/129228/156

61/50156/95

217/145

635/431

Deaths (n)Placebo/-blockade

58917002289

COPERNICUS

190/130

DiabetesNo diabetes

All

DiabetesNo diabetes

All

18867041

8927

DiabetesNo diabetes

All

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GEMINI: Design

Bakris GL et al. JAMA. 2004;292:2227-36.

Objective: Compare effects of -blockers with different pharmacologic properties on glycemic and metabolic control in patients with diabetes and hypertension receiving RAAS blockade

Participants: 1235 patients

Randomizedto treatment: Carvedilol 6.25 mg to 25 mg bid (n = 498) or

Metoprolol tartrate 50 mg to 200 mg bid (n = 737)

Follow-up: 35 weeks

Glycemic Effects in diabetes Mellitus: carvedilol-metoprolol comparison IN hypertensIves study

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Bakris GL et al. JAMA. 2004;292:2227-36.

Metoprolol tartrate

Carvedilol

% (SD) P % (SD) P

HbA1c 0.15 (0.04) <0.001 0.02 (0.04) 0.65

Insulin sensitivity –2.0 0.48 –9.1 0.004

GEMINI: Change in HbA1c and insulin sensitivity

Endpoint(mean )

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RESOLVD substudy: Effect of metoprolol succinate CR/XL on glucose and insulin

Demers C et al. Canadian Cardiovascular Congress; 2004. Calgary.

• 247 patients with heart failure

• Mean LVEF 28%

• 18% female

• 26% with diabetes

• At 17 weeks, patients taking enalapril candesartan were randomized to

– Metoprolol succinate CR/XL ≤200 mg/d* (n = 130) or – Placebo (n = 117)

• Blood samples analyzed at 17 weeks and after 43 weeks

*Phase 2 regimen

Randomized Evaluation of Strategies fOr Left Ventricular Dysfunction

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RESOLVD substudy: No effect on glucose and insulin with metoprolol succinate CR/XL

Glucose(mmol/L)

Insulin (mmol/L)

Glucose (mmol/L)

Insulin (mmol/L)

Metoprolol succinateCR/XL

8.26 107 8.31† 108†

Placebo 8.28 116 8.38 139

Demers C et al. Canadian Cardiovascular Congress; 2004. Calgary.

17 weeks* 43 weeks

*Phase 2: Start metoprolol succinate CR/XL†P = NS vs placebo

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Implications for -blockade in diabetes and HF

• HF is a frequent, often fatal complication of diabetes

• -Blockers are safe and well tolerated by patients with HF and diabetes

• -Blockade benefits diabetic patients by decreasing hospitalizations for HF and improving survival

• It is time to remove existing barriers for use of -blockers in patients with HF and diabetes


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MERIT-HF: Mortality benefit of -blockade in the elderly

All-cause mortality

0

5

10

20

15

3 6 9 12 15 18

PlaceboP = 0.0008

Months

Risk reduction37%

0

Deedwania PC et al. Eur Heart J. 2004;25:1300-9.

Metoprololsuccinate CR/XL

%Patients

2

4

6

3 6 9 12 15 18

Placebo


P = 0.0005

Months

0

0

%Patients

0

3

6

12

9

3 6 9 12 15 18

Placebo

P = 0.0032

Months

Risk reduction43%

0

Sudden death

HF mortality


N = 1982 age ≥65 years

%Patients

Riskreduction

61%

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Meta-analysis: -Blockade improves survival in elderly HF patients

Dulin BR et al. Am J Cardiol.2005;95:896-8.

COPERNICUS

Carvedilol (U.S.)

CIBIS-II

MERIT-HF

Overall

BEST

Placebo better

–1 1 10

-blocker better

Risk ratio (95% CI)

0.75 (0.58–0.98)

0.45 (0.24–0.86)

0.70 (0.49–0.99)

0.70 (0.52–0.95)

0.76 (0.64–0.90)

0.91 (0.78–1.05)

P = 0.002

Hazard ratio

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SENIORS: Design

• 2128 patients with HF or LVEF ≤35%

• ≥70 years of age (mean, 76 years)

• Randomly assigned to− Nebivolol titrated to 10 mg once daily over 16-week maximum (n = 1067)− Placebo (n = 1061)

• Primary outcome: Composite of all-cause mortality or CV hospital admission (time to first event)

• Follow-up: median 21 monthsFlather MD et al. Eur Heart J. 2005;26:215-25.

Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with heart failure

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SENIORS: Primary and secondary outcomes

100

90

80

70

60

50

100

90

80

70

60

500 6 12 18 24 30 0 6 12 18 24 30

HR 0.86 (0.74–0.99) P = 0.039

Time (months)

All-cause mortality or CV hospital admission

(primary outcome)

Nebivolol

Time (months)

All-cause mortality (main secondary outcome)

HR 0.88 (0.71–1.08) P = 0.214

Nebivolol 332 (31.1%)

Placebo 375 (35.3%)

Placebo

Event- free

survival (%)

169 (15.8%)

192 (18.1%)

Flather MD et al. Eur Heart J. 2005;26:215-25.

No. of events:

Nebivolol

Placebo

HR = hazard ratio

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SENIORS: Clinical relevance

• Confirms data indicating -blockade benefits elderly HF patients

• Extends evidence for benefit of -blockade to a broad range of elderly patients (age >70 years) with HF, including those with mild or preserved LV function

• As in previous large trials, both all-cause mortality and CV hospital admissions show a similar and consistent effect with -blockade

Flather MD et al. Eur Heart J. 2005;26:215-25.

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Benefit of -blockade on mortality in urban patients with HFN = 551; 62% African American, 20% White, 15% HispanicNYHA class III/IV HF: No -blocker group 60%; -blocker group 45%

0

10

20

P < 0.001

0 6

No -blockers

-blockers

Months

12

Death at 1 year

(%)

No -blocker 132 115 100

-blocker 239 229 212

Estep JD et al. Am Heart J. 2004;148:958-63.

17%

4%

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Not all -blockers are the same

Atenolol Tenormin 1 selective Yes Not FDA- approved for HF

Bisoprolol Zebeta 1 selective N/A Not FDA-approved for HF

Metoprolol tartrate

Lopressoror generic

1 selective Yes Not FDA-approved for HF

Metoprolol succinate

CR/XL

TOPROL-XL 1 selective No 200 mg qd

Carvedilol Coreg Non-selective (1, 1, 2)

No 25 mg bid†

Labetalol Normodyne Non-selective (1, 1, 2)

Yes Not FDA-approved for HF

Generic name

Brand name* Properties

AB-rated genericequiv available Dose for HF

* see prescribing information†COPERNICUS; other trials 50 mg bid for >75 kg

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Metoprolol tartrate vs metoprolol succinate CR/XL: Significant pharmacokinetic differences

Andersson B et al. J Card Fail. 2001;7:311-7.

Metoprolol tartrate 50 mg x 3

14 22 0808

300

200

100

0

Metoprolol succinate CR/XL 100 mg


Metoprolol tartrate 50 mg

Metoprolol tartrate 50 mg

Time (h)

Metoprolol succinate CR/XL 200 mg x 1

Metoprolol succinate CR/XL 100 mg x 1

Three-way crossover in patients with HF; N = 15

Plasmaconcentration

(mmol/L)

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Effect of metoprolol succinate CR/XL vs atenolol on exercise heart rate/SBP over 24 h

Blomqvist I et al. Eur J Clin Pharmacol. 1988;33(suppl):S19-24.

N = 10 healthy men

Systolic BP Exercise heart rate

Time (hours)

Meanexercise

SBP(mm Hg)

190

180

170

160

150

0

0 2 8 12 244

160

140

120

100

0

0 2 8 12 24

Time (hours)

4

Meanexerciseheart rate

(bpm)

Placebo

Atenolol 50 mg


Placebo

Atenolol 50 mg


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Recommended ACEI doses do not completely halt Ang II formation in HF42 HF patients on 40 mg long-acting ACEI (fosinopril, lisinopril, enalapril) or captopril 150 mg

Jorde UP et al. Circulation. 2000;101:844-6.*P < 0.05 vs after valsartan†P < 0.05 vs 10 ng/kg Ang I

20

0

Radial artery

systolic pressure(mm Hg)

25

15

10

5

0100 20010

†

†

Angiotensin I (ng/Kg)

ACEI + valsartan

ACEI

*

*

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CHARM Program: 3 Component trials comparing candesartan with placeboTarget dose, candesartan 32 mg

Overall trial: All-cause death

Primary outcome: CV death or CHF hospitalization

Median follow-up, 37 months

CHARM-Alternative

CHARM-Added

CHARM-Preserved

n = 2028

LVEF ≤40%ACE inhibitor

intolerant

n = 3023

LVEF >40%ACE inhibitor

treated/not treated

n = 2548

LVEF ≤40%ACE inhibitor

treated

Pfeffer MA et al. Lancet. 2003;362:759-66.Granger CB et al. Lancet. 2003;362:772-6.

McMurray JJV et al. Lancet. 2003;362:767-71.Yusuf S et al. Lancet. 2003;362:777-81.

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CHARM Program: Reduction in mortality and morbidity

Alternative(LVEF ≤40%; ACEI intolerant)

1.00.8 0.90.7 1.2 0.90.7 0.80.6 1.21.0 1.11.1

Added(LVEF ≤40%; ACEI treated)

Preserved(LVEF >40%; ACEI treated/

not treated)

Overall

CV death orHF hospitalizationAll-cause mortality

Adjusted hazard ratioP heterogeneity = 0.37

Adjusted hazard ratioP heterogeneity = 0.33

Pfeffer MA et al. Lancet. 2003;362:759-66.

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CHARM-Overall: CV death and non-CV death—Secondary endpoints

5

10

15

20

25

35

2.0 3.00.0 1.0 3.5

P = 0.450

Years

%Patients

13% Relative risk reduction(95% CI 4%–22%)

P = 0.006CV death

Non-CV death

Number at risk

Candesartan 3803 3563 3271 2215 761Placebo 3796 3464 3170 2157 743


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CHARM-Overall: Reduction in mortality and nonfatal MI with candesartan

Events (n)Placebo/candesartan

344/299Sudden death

HF death

CV death

Nonfatal MI

All deaths

260/209

769/691

148/116

945/886

Nonfatal MI/CV death 868/775

0.5 0.6 0.7 9.08.0 1.0 0.5

Riskreduction

15%

22%

12%

23%

9%

21%

P

0.036

0.008

0.012

0.032

0.055

0.004

Solomon SD et al. Circulation. 2004;110:2180-83.Demers C et al. Circulation. 2004;110(suppl):Abstract.

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CHARM—Low LVEF trials: Risk reductions at 1 and 2 years with candesartanLVEF ≤40%

Young JB et al. Circulation. 2004;110:2618-26.

3033

2320

50

40

30

20

10

0CV death/HF hospitalization All-cause mortality

1 year

2 years

%Reduction

P < 0.001

P < 0.001

P = 0.001

P = 0.001

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CHARM Program: Outcomes overview

Parameter

CHARM Added

CHARM Alternative

CHARM Preserved

CHARM Overall

Follow-up (months) 41 34 37 38

CV deaths (%) 23.7 vs 27.3* 21.6 vs 24.8 11.2 vs 11.3 18.2 vs 20.3*

HF hospitalization (%) 24.2 vs 28* 20.4 vs 28.2* 15.9* vs 18.3 19.9 vs 24.2*

Combined endpoint (%) 37.9 vs 42.3* 33 vs 40* 22 vs 24.3 30.2 vs 34.5*

NNT/year to prevent 1 CV death/HF hospitalization 85 40 132 73

Gleiter CH et al. Cardiovasc Drug Rev. 2004;22:263-84.*statistically significant

Candesartan vs placebo

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Candesartan n/N

Placebon/N

Hazard ratio(95% CI) P

163/2715 (6%) 202/2721 (7.4%) 0.78 (0.64–0.96) 0.02

CHARM-Overall: Reduction in new-onset diabetes

n = new-onset diabetesN = total patients

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VALIANT: Design

• 14,800 patients with acute MI + HF/LV dysfunction

• Receiving conventional therapy

• Randomly assigned (0.5 days to 10 days after acute MI) – Valsartan 160 mg bid (n = 4909) – Valsartan 80 mg bid + captopril 25 mg tid (n = 4885) – Captopril 50 mg tid (n = 4909)

• Primary outcome: death from any cause

• Follow-up: median 24.7 months

Pfeffer MA et al. N Engl J Med. 2003;349:1893-906.

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VALIANT: Treatments show similar effect on outcome

0.4

0.3

0.2

0.1

0.0

0 6 12 18 24 30 36

0.4

0.3

0.2

0.1

0.0

6 12 18 24 30 36

Months Months

Probabilityof event

Death from any cause Combined CV endpoint*

0

CaptoprilValsartan/captoprilValsartan

*CV death, reinfarction, or hospitalization for HF Pfeffer MA et al. N Engl J Med. 2003;349:1893-906.

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VALIANT: Poorer 1-year outcomes in patients with new-onset or previous diabetes

Months

Probabilityof event

All-cause mortality

Previous vs new diabetes diagnosis

Previous vs no diabetes

New vs no diabetes diagnosis

Aguilar D et al. Circulation. 2004;110:1572-8.

3 6 9 12

Months

Adverse CV events

0.4

0.3

0.2

0.1

0.0

03 6 9 12

0.4

0.3

0.2

0.1

0.0

0

Previous DM

No DM

No DM

New DM

Previous DM

New DM

P = 0.43

P < 0.001

P < 0.001

P < 0.005

P < 0.001

P < 0.001

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Clinical implications of CHARM and VALIANT

• In HF patients and in patients with acute MI and LV dysfunction,

evidence supports

– ARBs as alternative to ACEIs (in ACEI–intolerant patients)

– Benefit from addition of ARBs to ACEI-based regimens

• ARBs and ACEIs similarly reduce all-cause mortality and HF hospitalizations in patients with HF or high-risk MI

• Discharge prescription of ACEI or ARB meets new Medicare/Medicaid quality performance measures for HF/MI with LV dysfunction

Lee VC et al. Ann Intern Med. 2004;141:693-704.McClellen MB et al. Ann Intern Med. 2005;142:386-7.

ACC/AHA. www.acc.org

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Benefit of ARB + ACE inhibitor in HF

0.6 1.20.8

ARB+ACEI better

1.0

CHARM(HF)

1.4

ACEI alone better

VALIANT(post MI + HF/LV dysfunction)

Val-HeFT(HF)

1.20.8

HF hospitalization

1.0 1.40.6

All-cause mortality

ARB+ACEI better

ACEI alone better

Voors AA, van Veldhuisen DJ. Int J Cardiol. 2004;97:345-8.

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ARBs in LV dysfunction: Before/after CHARM and VALIANT

Before CHARM, VALIANT

After CHARM, VALIANT

ARBs superior to ACEI? No (ELITE II, OPTIMAAL) No

ARBs non-inferior to ACEI? ? (ELITE II, OPTIMAAL) Yes

ARBs additive on top of ACEI? ? (Val-HeFT)

Yes, HFNo, post-MI

Combination ARB, ACEI, and -blocker dangerous? ? (ELITE II, Val-HeFT) No

Voors AA, van Veldhuisen DJ. Int J Cardiol. 2004;97:345-8.

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Difference in target dosing among ARB trials

Trial Patients Study drug Outcome

CHARM Overall HFLVEF ≤40%LVEF >40%

Candesartan 32 mg qd vs Placebo

10% mortality13% CV death23% HF hosp

ELITE II HFLVEF ≤40%≥ 60 years

Losartan 50 mg qd vs Captopril 50 mg tid

Similar morbidity/mortality

OPTIMAAL Post-MI + HF Losartan 50 mg qd vs Captopril 50 mg tid

Mortality trend favors captoprilNo difference in morbidity

Val-HeFT HF Valsartan 160 mg bid vs Placebo + conventional HF Rx

No mortality 13.2% morbidity/mortality28% HF hosp

VALIANT Acute MI + HF/LV dysfunction

Valsartan 160 mg bid or Captopril 50 mg tid orValsartan 80 mg bid + captopril 50 mg tid

Similar mortality/morbidityNo added benefit with ACEI+ARB

Dickstein K et al. Lancet. 2002;360:752-60.Cohn JN et al. N Engl J Med. 2001;345:1667-75.

Pfeffer MA et al. N Engl J Med. 2003;349:1893-906.Pfeffer MA et al. Lancet. 2003;362:759-66.

Pitt B et al. Lancet. 2000;355:1582-7.

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Impact of RAAS modulation on mortality in HF patients with renal insufficiency Minnesota Heart Survey

Odds ratio (95%

CI)

0

1

2

3

4

5

6

7

P = 0.65P = 0.04

P = 0.002

P = 0.17

≥90 60–89 30–59 <30

Post-discharge mortality(mean follow-up 15 mo)

64 6863

48

0

20

40

60

80

≥90 60–89 30–59 <30

ACEI/ARB Rx at discharge

Berger AK et al. Circulation. 2004;110 (suppl III):III-749.

No ACEI/ARB at discharge ACEI and/or ARB at discharge

GFR (mL/min)

%

GFR (mL/min)

4926 patients hospitalized with HF

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Summary

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ACC/AHA stages of systolic HF and treatment options

Jessup M, Brozena S. N Engl J Med. 2003;348:2007-18.*In appropriate patients

vbwg improving outcomes in heart failure: new insights from vascular biology

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