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Improving Outcomes in Heart Failure: New Insights From Vascular Biology. Heart Failure: A Public Health Concern. 20% Lifetime risk for HF after age 40. Framingham Heart Study. Men. Women. 25. 25. 20. 20. 15. 15. Cumulative risk (%). 10. 10. 5. 5. 0. 0. 0. 40. 50. 50. 60.

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Slide1 l.jpg

Improving Outcomes in Heart Failure: New Insights From Vascular Biology


Slide2 l.jpg

Heart Failure:

A Public Health Concern


20 lifetime risk for hf after age 40 l.jpg
20% Lifetime risk for HF after age 40

Framingham Heart Study

Men

Women

25

25

20

20

15

15

Cumulative

risk (%)

10

10

5

5

0

0

0

40

50

50

60

70

80

90

40

50

50

60

70

80

90

Attained age (years)

Lifetime risk for HF for given index age

is cumulative through age 94 years

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


Hypertension is the no 1 risk factor for hf l.jpg
Hypertension is the No. 1 risk factor for HF

Framingham Heart Study

60

40

Population-attributable

risk (%)

20

0

HTN

MI

Angina

VHD

LVH

Diabetes

Men

Women

VHD = valvular heart disease

Levy D at al. JAMA. 1996;275:1557-62.


Diabetes a frequent comorbidity with hf l.jpg
Diabetes: A frequent comorbidity with HF

  • 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

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.


Diabetes is the no 1 risk factor for hf in women with coronary disease l.jpg
Diabetes is the No. 1 risk factor for HF in women with coronary disease

HERS study

Diabetes

3.1

Atrial fibrillation

2.9

Myocardial infarction >1 event

2.5

Creatinine clearance <40

2.3

Systolic BP ≥140

2.1

Current smoking

1.9

BMI >35

1.9

Left bundle branch block

1.6

LV hypertrophy

1.5

0

0.5

1

1.5

2

2.5

3

3.5

Adjusted hazard ratio

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


Increasing risk for hf in women with chd impact of diabetes renal insufficiency obesity l.jpg
Increasing risk for HF in women with CHD: Impact of diabetes, renal insufficiency, obesity

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

14

12.8

12

10

Annual

HF

incidence

(%)

8

7.0

6

4

2.8

2

1.2

0

CHD

CHD + DM

CHD + DM + BMI >36

CHD + DM + CrCl <42.8

CrCl (ml/min) = creatinine clearance

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


Slide8 l.jpg

Heart Failure diabetes, renal insufficiency, obesityPathophysiology


Important pathophysiologic mechanisms in hf 1 l.jpg
Important pathophysiologic mechanisms in HF (1) diabetes, renal insufficiency, obesity

Cardiac abnormalities

Structural

Functional

Coronary arteries

  • Obstruction

  • Inflammation

  • 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

  • Myocardium or myocyte

  • Myocardial relaxation

  • Abnormal excitation- contraction coupling

  • -Adrenergic desensitization

  • Hypertrophy

  • Necrosis

  • Fibrosis

  • Apoptosis

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


Important pathophysiologic mechanisms in hf 2 l.jpg
Important pathophysiologic mechanisms in HF (2) diabetes, renal insufficiency, obesity

Biologically active tissue

and circulating substances

  • 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.


Important pathophysiologic mechanisms in hf 3 l.jpg
Important pathophysiologic mechanisms in HF (3) diabetes, renal insufficiency, obesity

Patient factors

Coexisting conditions

  • Hypertension

  • Diabetes

  • Renal disease

  • Coronary artery disease

  • Anemia

  • Obesity

  • Sleep apnea

  • Depression

  • Genetics, ethnicity, sex

  • Age

  • Use of alcohol, tobacco, toxic drugs

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


Neurohormonal model of hf l.jpg
Neurohormonal model of HF diabetes, renal insufficiency, obesity

Injury to myocytes and extracellular matrix

  • Neurohormonal activation

    – RAAS, SNS

  • Increased cytokine expression

  • Immune and inflammatory changes

  • Altered fibrinolysis

  • Oxidative stress

  • Apoptosis

  • Altered gene expression

  • Energy starvation

Ventricular remodeling

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

Heart failure

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


Diabetes pathogenesis accelerates hf l.jpg
Diabetes pathogenesis accelerates HF diabetes, renal insufficiency, obesity

Diabetes

Activated

RAAS

Activated

sympathoadrenal

system

Hyperglycemia

Activation of

protein kinase C

Cardiomyocyte

death

Cardiac

fibrosis

Decreased intracellular

calcium removal

Decreased myocardial

contractile strength

Diastolic dysfunction

Systolic

dysfunction

Heart failure

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


Raas in cv continuum pivotal role of at 1 receptors in the failing heart l.jpg
RAAS in CV continuum: Pivotal role diabetes, renal insufficiency, obesityof AT1 receptors in the failing heart

Angiotensinogen

Bradykinin/Kinins

Renin

Angiotensin I

Degradation

ACE

Angiotensin II

AT2 receptor

AT1 receptor

B1/B2 receptor

NO

? Clinical significance

Reactive oxygen species

Pro-inflammatory process

Vasoconstriction

Cellular growth/proliferation

Apoptosis

Neurohormonal activation

Vasodilation

Growth inhibition

Apoptosis

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


Primary targets of treatment in hf l.jpg
Primary targets of treatment in HF diabetes, renal insufficiency, obesity

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


Angiotensin receptor blockade in the cvd continuum l.jpg
Angiotensin receptor blockade diabetes, renal insufficiency, obesityin the CVD continuum

Coronary heart

disease

ARB

Plaque rupture

ARB

ARB

Atherosclerosis

Myocardial

infarction

Dilation/

Remodeling

Endothelial

dysfunction

ARB

ARB

Heart failure

ARB

End-stage

heart failure

Risk factors

Hypertension

Hyperlipidemia

Diabetes

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


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Clinical Trial Update diabetes, renal insufficiency, obesity


Survival studies of blockade in hf l.jpg
Survival studies of diabetes, renal insufficiency, obesity-blockade in HF

Total mortality

Placebo/-blocker

Patients

(N)

Favors

-blocker

EF

mean

NYHA

class

P

CIBIS-II Bisoprolol

2647

228/156

III/IV

28%

0.0001

MERIT-HF

Metoprolol succinate CR/XL

3991

217/145

II-IV

28%

0.00009

COPERNICUS Carvedilol

2289

190/130

III/IV*

20%

0.00013

8927

635/431

All pooled

0.0

0.5

1.0

Relative risk and 95% CI

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.

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


Merit hf metoprolol succinate cr xl lowers risk of hospitalization with without diabetes l.jpg
MERIT-HF: Metoprolol succinate CR/XL diabetes, renal insufficiency, obesitylowers risk of hospitalization with/without diabetes

NYHA III/IV, EF <25%

All randomized

Diabetes

No diabetes

Diabetes

No diabetes

70

50

50

Total # hospitaliz/patient-yrs

(%)

26

30

25

25

16

15

13

9

10

–37%

P = 0.0026

–35%

P = 0.0002

–53%

P = 0.0087

–44%

P = 0.0039

Metoprolol succinate CR/XL

(n = 495)

Placebo

(n = 490)

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


Merit hf benefit of blockade with without diabetes l.jpg
MERIT-HF: Benefit of diabetes, renal insufficiency, obesity-blockade with/without diabetes

Events (n)

Favors metoprolol succinate CR/XL

Favorsplacebo

Metoprolol succinate CR/XL

All-cause mortality

Placebo

217

145

All patients randomized

61

50

Diabetes

24

14

Diabetes, severe HF

No diabetes

156

95

No diabetes, severe HF

48

31

Hospitalization for CHF

All patients randomized

200

294

Diabetes

108

72

Diabetes, severe HF

40

20

No diabetes

128

186

No diabetes, severe HF*

40

64

0.0

1.0

Relative risk (95% CI)

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

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


Pooled hf trials effect of blockade on survival in diabetic patients l.jpg
Pooled HF trials: Effect of -blockade diabetes, renal insufficiency, obesityon survival in diabetic patients

Total (n)

randomized

Deaths (n)

Placebo/-blockade

CIBIS II

Diabetes

312

33/27

No diabetes

2335

195/129

2647

All

228/156

MERIT-HF

985

Diabetes

61/50

3006

No diabetes

156/95

3991

217/145

All

COPERNICUS

Diabetes

589

No diabetes

1700

190/130

2289

All

All 3 studies

Diabetes

1886

No diabetes

7041

All

635/431

8927

0.0

1.0

1.8

Relative risk (95% CI)

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


Gemini design l.jpg
GEMINI: Design diabetes, renal insufficiency, obesity

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

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

Randomized

to 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

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


Gemini change in hba 1c and insulin sensitivity l.jpg
GEMINI: Change in HbA diabetes, renal insufficiency, obesity1cand insulin sensitivity

Endpoint

(mean )

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


Resolvd substudy effect of metoprolol succinate cr xl on glucose and insulin l.jpg
RESOLVD substudy: Effect of metoprolol succinate CR/XL on glucose and insulin

Randomized Evaluation of Strategies fOr Left Ventricular Dysfunction

  • 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

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

*Phase 2 regimen


Resolvd substudy no effect on glucose and insulin with metoprolol succinate cr xl l.jpg
RESOLVD substudy: No effect on glucose glucose and insulinand insulin with metoprolol succinate CR/XL

17 weeks*

43 weeks

*Phase 2: Start metoprolol succinate CR/XL

†P = NS vs placebo

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


Implications for blockade in diabetes and hf l.jpg
Implications for glucose and insulin-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

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


Merit hf mortality benefit of blockade in the elderly l.jpg
MERIT-HF: Mortality benefit glucose and insulinof -blockade in the elderly

Sudden death

All-cause mortality

20

12

Risk reduction

37%

Risk reduction

43%

Placebo

Placebo

P = 0.0008

9

15

P = 0.0032

Metoprolol

succinate CR/XL

Metoprolol succinate CR/XL

%

Patients

%

Patients

6

10

3

5

HF mortality

0

0

6

Risk

reduction

61%

Placebo

3

6

9

12

15

18

0

3

6

9

12

15

18

0

Months

Months

P = 0.0005

4

%

Patients

Metoprolol succinate CR/XL

2

0

0

3

6

9

12

15

18

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

Months

N = 1982 age ≥65 years


Meta analysis blockade improves survival in elderly hf patients l.jpg
Meta-analysis: glucose and insulin-Blockade improves survival in elderly HF patients

Hazard ratio

Placebo better

-blocker better

0.75 (0.58–0.98)

COPERNICUS

0.45 (0.24–0.86)

Carvedilol (U.S.)

0.70 (0.49–0.99)

CIBIS-II

0.70 (0.52–0.95)

MERIT-HF

BEST

0.91 (0.78–1.05)

0.76 (0.64–0.90)

Overall

P = 0.002

–1

1

10

Risk ratio (95% CI)

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


Seniors design l.jpg
SENIORS: Design glucose and insulin

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

  • 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 months

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


    Seniors primary and secondary outcomes l.jpg
    SENIORS: Primary and secondary outcomes glucose and insulin

    All-cause mortality or CV hospital admission (primary outcome)

    All-cause mortality (main secondary outcome)

    100

    100

    HR 0.88 (0.71–1.08) P = 0.214

    90

    90

    HR 0.86 (0.74–0.99)

    P = 0.039

    Nebivolol

    Event- free survival (%)

    80

    80

    Placebo

    Nebivolol

    70

    70

    60

    60

    Placebo

    50

    50

    0

    6

    12

    18

    24

    30

    0

    6

    12

    18

    24

    30

    Time (months)

    Time (months)

    No. of events:

    169 (15.8%) 192 (18.1%)

    Nebivolol 332 (31.1%) Placebo 375 (35.3%)

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

    HR = hazard ratio


    Seniors clinical relevance l.jpg
    SENIORS: Clinical relevance glucose and insulin

    • 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.


    Benefit of blockade on mortality in urban patients with hf l.jpg
    Benefit of glucose and insulin-blockade on mortality in urban patients with HF

    N = 551; 62% African American, 20% White, 15% Hispanic

    NYHA class III/IV HF: No -blocker group 60%; -blocker group 45%

    20

    17%

    No -blockers

    Death at 1 year

    (%)

    10

    P < 0.001

    4%

    -blockers

    0

    0

    6

    12

    Months

    No -blocker 132 115 100

    -blocker 239 229 212

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


    Not all blockers are the same l.jpg
    Not all glucose and insulin-blockers are the same

    Generic name

    Brand name*

    AB-rated generic

    equiv available

    Properties

    Dose for HF

    * see prescribing information

    †COPERNICUS; other trials 50 mg bid for >75 kg


    Metoprolol tartrate vs metoprolol succinate cr xl significant pharmacokinetic differences l.jpg
    Metoprolol tartrate vs metoprolol succinate CR/XL: Significant pharmacokinetic differences

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

    300

    Metoprolol succinate CR/XL 200 mg x 1

    200

    Plasmaconcentration

    (mmol/L)

    Metoprolol tartrate 50 mg x 3

    100

    Metoprolol succinate CR/XL 100 mg x 1

    0

    08

    14

    22

    08

    Time (h)

    Metoprolol succinate CR/XL 100 mg

    Metoprolol succinate CR/XL 200 mg

    Metoprolol tartrate 50 mg

    Metoprolol tartrate 50 mg

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


    Effect of metoprolol succinate cr xl vs atenolol on exercise heart rate sbp over 24 h l.jpg
    Effect of metoprolol succinate CR/XL vs atenolol on exercise heart rate/SBP over 24 h

    N = 10 healthy men

    Systolic BP

    Exercise heart rate

    160

    190

    Placebo

    Placebo

    180

    140

    Meanexercise

    SBP

    (mm Hg)

    Meanexercise

    heart rate

    (bpm)

    170

    Atenolol 50 mg

    120

    Atenolol 50 mg

    160

    Metoprolol succinate CR/XL 100 mg

    Metoprolol succinate CR/XL 100 mg

    100

    150

    0

    0

    0

    2

    4

    8

    12

    24

    0

    2

    4

    8

    12

    24

    Time (hours)

    Time (hours)

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


    Recommended acei doses do not completely halt ang ii formation in hf l.jpg
    Recommended ACEI doses do not heart rate/SBP over 24 h completely halt Ang II formation in HF

    42 HF patients on 40 mg long-acting ACEI (fosinopril, lisinopril, enalapril) or captopril 150 mg

    25

    *

    20

    ACEI

    Radial artery systolic pressure

    (mm Hg)

    *

    15

    10

    ACEI +

    valsartan

    5

    0

    100

    0

    10

    200

    Angiotensin I (ng/Kg)

    *P < 0.05 vs after valsartan

    †P < 0.05 vs 10 ng/kg Ang I

    Jorde UP et al. Circulation. 2000;101:844-6.


    Charm program 3 component trials comparing candesartan with placebo l.jpg
    CHARM Program: 3 Component trials comparing candesartan with placebo

    Target dose, candesartan 32 mg

    Primary outcome: CV death or CHF hospitalization

    Overall trial: All-cause death

    CHARM-

    Alternative

    CHARM-

    Added

    CHARM-

    Preserved

    n = 2028

    LVEF ≤40%

    ACE inhibitor

    intolerant

    n = 2548

    LVEF ≤40%

    ACE inhibitor

    treated

    n = 3023

    LVEF >40%

    ACE inhibitor

    treated/not treated

    Median follow-up, 37 months

    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.


    Charm program reduction in mortality and morbidity l.jpg
    CHARM Program: Reduction placeboin mortality and morbidity

    CV death or

    HF hospitalization

    All-cause mortality

    Alternative

    (LVEF ≤40%; ACEI intolerant)

    Added

    (LVEF ≤40%; ACEI treated)

    Preserved

    (LVEF >40%; ACEI treated/not treated)

    Overall

    0.6

    0.7

    0.8

    0.9

    1.0

    1.1

    1.2

    1.1

    0.7

    0.8

    0.9

    1.0

    1.2

    Adjusted hazard ratio

    P heterogeneity = 0.37

    Adjusted hazard ratio

    P heterogeneity = 0.33

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


    Charm overall cv death and non cv death secondary endpoints l.jpg
    CHARM-Overall: CV death and placebonon-CV death—Secondary endpoints

    35

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

    P = 0.006

    25

    CV death

    20

    %

    Patients

    15

    10

    Non-CV death

    5

    P = 0.45

    0

    Years

    0.0

    1.0

    2.0

    3.0

    3.5

    Number at risk

    Candesartan 3803 3563 3271 2215 761

    Placebo 3796 3464 3170 2157 743

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


    Charm overall reduction in mortality and nonfatal mi with candesartan l.jpg
    CHARM-Overall: Reduction in mortality placeboand nonfatal MI with candesartan

    Events (n)

    Placebo/candesartan

    Risk

    reduction

    P

    Sudden death

    344/299

    15%

    0.036

    HF death

    260/209

    22%

    0.008

    CV death

    769/691

    12%

    0.012

    Nonfatal MI

    148/116

    23%

    0.032

    Nonfatal MI/CV death

    868/775

    21%

    0.004

    All deaths

    945/886

    9%

    0.055

    0.5

    0.6

    0.7

    8.0

    9.0

    1.0

    0.5

    Solomon SD et al. Circulation. 2004;110:2180-83.

    Demers C et al. Circulation. 2004;110(suppl):Abstract.


    Charm low lvef trials risk reductions at 1 and 2 years with candesartan l.jpg
    CHARM—Low LVEF trials: Risk reductions placeboat 1 and 2 years with candesartan

    LVEF ≤40%

    CV death/HF hospitalization

    All-cause mortality

    0

    10

    20

    20

    %

    Reduction

    23

    P = 0.001

    P < 0.001

    30

    30

    33

    P < 0.001

    1 year

    P = 0.001

    40

    2 years

    50

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


    Charm program outcomes overview l.jpg
    CHARM Program: Outcomes overview placebo

    Candesartan vs placebo

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

    *statistically significant


    Charm overall reduction in new onset diabetes l.jpg
    CHARM-Overall: Reduction in new-onset diabetes placebo

    n = new-onset diabetes

    N = total patients

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


    Valiant design l.jpg
    VALIANT: Design placebo

    • 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.


    Valiant treatments show similar effect on outcome l.jpg
    VALIANT: Treatments show similar effect placeboon outcome

    Death from any cause

    Combined CV endpoint*

    0.4

    0.4

    0.3

    0.3

    Probability

    of event

    0.2

    0.2

    0.1

    0.1

    0.0

    0.0

    0

    6

    12

    18

    24

    30

    36

    0

    6

    12

    18

    24

    30

    36

    Months

    Months

    Valsartan

    Valsartan/captopril

    Captopril

    *CV death, reinfarction, or hospitalization for HF

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


    Valiant poorer 1 year outcomes in patients with new onset or previous diabetes l.jpg
    VALIANT: Poorer 1-year outcomes in patients with new-onset or previous diabetes

    All-cause mortality

    Adverse CV events

    0.4

    0.4

    Previous DM

    0.3

    0.3

    New DM

    0.2

    0.2

    Probability

    of event

    Previous DM

    No DM

    New DM

    0.1

    0.1

    No DM

    0.0

    0.0

    0

    3

    6

    9

    12

    3

    6

    9

    12

    0

    Months

    Months

    Previous vs new diabetes diagnosis

    Previous vs no diabetes

    New vs no diabetes diagnosis

    P = 0.43

    P < 0.001

    P < 0.001

    P < 0.005

    P < 0.001

    P < 0.001

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


    Clinical implications of charm and valiant l.jpg
    Clinical implications of CHARM or previous diabetesand 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


    Benefit of arb ace inhibitor in hf l.jpg
    Benefit of ARB + ACE inhibitor in HF or previous diabetes

    HF hospitalization

    All-cause mortality

    ARB+ACEI better

    ACEI alone better

    ARB+ACEI better

    ACEI alone better

    CHARM

    (HF)

    VALIANT

    (post MI + HF/LV dysfunction)

    Val-HeFT

    (HF)

    0.6

    0.8

    1.0

    1.2

    1.4

    0.6

    0.8

    1.0

    1.2

    1.4

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


    Arbs in lv dysfunction before after charm and valiant l.jpg
    ARBs in LV dysfunction: Before/after or previous diabetesCHARM and VALIANT

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


    Difference in target dosing among arb trials l.jpg
    Difference in target dosing among ARB trials or previous diabetes

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

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

    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.


    Impact of raas modulation on mortality in hf patients with renal insufficiency l.jpg
    Impact of RAAS modulation on mortality or previous diabetesin HF patients with renal insufficiency

    Minnesota Heart Survey

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

    ACEI/ARB Rx at discharge

    7

    P = 0.17

    6

    80

    68

    64

    63

    5

    60

    Odds

    ratio

    (95% CI)

    48

    4

    P = 0.002

    %

    40

    P = 0.04

    3

    P = 0.65

    20

    2

    1

    0

    ≥90

    60–89

    30–59

    <30

    0

    ≥90

    60–89

    30–59

    <30

    GFR (mL/min)

    GFR (mL/min)

    No ACEI/ARB at discharge

    ACEI and/or ARB at discharge

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

    4926 patients hospitalized with HF


    Slide52 l.jpg

    Summary or previous diabetes


    Acc aha stages of systolic hf and treatment options l.jpg
    ACC/AHA stages of systolic HF or previous diabetesand treatment options

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

    *In appropriate patients


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