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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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slide2

Heart Failure:

A Public Health Concern

20 lifetime risk for hf after age 40
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
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
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
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
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.

important pathophysiologic mechanisms in hf 1
Important pathophysiologic mechanisms in HF (1)

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
Important pathophysiologic mechanisms in HF (2)

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
Important pathophysiologic mechanisms in HF (3)

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
Neurohormonal model of HF

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
Diabetes pathogenesis accelerates HF

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
RAAS in CV continuum: Pivotal role of 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
Primary targets of treatment in HF

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

angiotensin receptor blockade in the cvd continuum
Angiotensin receptor blockade in 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.

survival studies of blockade in hf
Survival studies of -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
MERIT-HF: Metoprolol succinate CR/XL lowers 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
MERIT-HF: Benefit of -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
Pooled HF trials: Effect of -blockade on 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
GEMINI: Design

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
GEMINI: Change in HbA1cand 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
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
RESOLVD substudy: No effect on glucose and 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
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

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

merit hf mortality benefit of blockade in the elderly
MERIT-HF: Mortality benefit of -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
Meta-analysis: -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
SENIORS: Design

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
SENIORS: Primary and secondary outcomes

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
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.

benefit of blockade on mortality in urban patients with hf
Benefit of -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
Not all -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
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
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
Recommended ACEI doses do not 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
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
CHARM Program: Reduction in 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
CHARM-Overall: CV death and non-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
CHARM-Overall: Reduction in mortality and 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
CHARM—Low LVEF trials: Risk reductions at 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
CHARM Program: Outcomes overview

Candesartan vs placebo

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

*statistically significant

charm overall reduction in new onset diabetes
CHARM-Overall: Reduction in new-onset diabetes

n = new-onset diabetes

N = total patients

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

valiant design
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.

valiant treatments show similar effect on outcome
VALIANT: Treatments show similar effect on 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
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
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

benefit of arb ace inhibitor in hf
Benefit of ARB + ACE inhibitor in HF

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
ARBs in LV dysfunction: Before/after CHARM and VALIANT

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

difference in target dosing among arb trials
Difference in target dosing among ARB trials

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
Impact of RAAS modulation on mortality in 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

acc aha stages of systolic hf and treatment options
ACC/AHA stages of systolic HF and treatment options

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

*In appropriate patients