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

Heart Failure:A Public Health Concern

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

Attained age (years)

Cumulativerisk (%)

20% Lifetime risk for HF after age 40

Framingham Heart Study

5050 60 70 80 900

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

40 5050 60 70 80 90

Hypertension is the No. 1 risk factor for HF

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

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

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

0 0.5 1 1.5 2 2.5 3 3.5

HERS study

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

CHD CHD + DM CHD + DM + BMI >36

CHD + DM + CrCl <42.8

AnnualHF

incidence(%)

Heart Failure Pathophysiology

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

• 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

• 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

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.

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

sympathoadrenal

system

Cardiac

fibrosis

Cardiomyocyte

Decreased myocardial

contractile strengthDiastolic

dysfunction

Systolic

dysfunction

Diabetes

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.

B1/B2 receptorAT1 receptor

Angiotensinogen

Angiotensin I

Angiotensin II

AT2 receptor

VasodilationGrowth inhibitionApoptosis

Degradation

Bradykinin/Kinins

Reactive oxygen speciesPro-inflammatory processVasoconstrictionCellular growth/proliferationApoptosisNeurohormonal activation

? Clinical significance

Primary targets of treatment in HF

Angiotensin receptor blockade in the CVD continuum

AtherosclerosisMyocardial

infarction

Endothelial

dysfunction

Coronary heart

disease

Plaque rupture

Risk factors

Dilation/

Remodeling

Heart failure

End-stage

heart failure

Hypertension

Hyperlipidemia

Diabetes

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

Clinical Trial Update

Survival studies of -blockade in HF

0.50.0 1.0

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

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

0.0001

0.00009

0.00013

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

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

–53%P = 0.0087

–44%P = 0.0039

–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.

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

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

Placebo

Events (n)

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

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

31223352647

98530063991

Relative risk (95% CI)

DiabetesNo diabetes

All 3 studies

0.0 1.0

CIBIS II

MERIT-HF

Total (n)randomized

33/27195/129228/156

61/50156/95

217/145

635/431

Deaths (n)Placebo/-blockade

58917002289

COPERNICUS

190/130

DiabetesNo diabetes

18867041

DiabetesNo diabetes

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

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 )

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

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

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

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

All-cause mortality

3 6 9 12 15 18

PlaceboP = 0.0008

Months

Risk reduction37%

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

Metoprololsuccinate CR/XL

%Patients

3 6 9 12 15 18

Placebo

P = 0.0005

Months

%Patients

3 6 9 12 15 18

Placebo

P = 0.0032

Months

Risk reduction43%

Sudden death

HF mortality

N = 1982 age ≥65 years

%Patients

Riskreduction

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

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

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

SENIORS: Primary and secondary outcomes

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

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 HFN = 551; 62% African American, 20% White, 15% HispanicNYHA class III/IV HF: No -blocker group 60%; -blocker group 45%

P < 0.001

No -blockers

-blockers

Months

Death at 1 year

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

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

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

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

Metoprolol succinate CR/XL 100 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)

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)

0 2 8 12 244

0 2 8 12 24

Time (hours)

Meanexerciseheart rate

Placebo

Atenolol 50 mg

Placebo

Atenolol 50 mg

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

Radial artery

systolic pressure(mm Hg)

0100 20010

Angiotensin I (ng/Kg)

ACEI + valsartan

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.

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.

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

2.0 3.00.0 1.0 3.5

P = 0.450

%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

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

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 candesartanLVEF ≤40%

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

0CV death/HF hospitalization All-cause mortality

1 year

2 years

%Reduction

P < 0.001

P = 0.001

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

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

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

0 6 12 18 24 30 36

6 12 18 24 30 36

Months Months

Probabilityof event

Death from any cause Combined CV endpoint*

CaptoprilValsartan/captoprilValsartan

*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

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

03 6 9 12

Previous DM

New DM

Previous DM

New DM

P = 0.43

P < 0.001

P < 0.005

P < 0.001

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

0.6 1.20.8

ARB+ACEI better

CHARM(HF)

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.

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.

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.

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

Odds ratio (95%

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

≥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)

4926 patients hospitalized with HF

Summary

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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