1. Update on  -Blockers In the Management of Heart Failure

2. Heart Failure Society of America (HFSA) Practice Guidelines. J Cardiac Fail. 1999;5:357-382. -Heart Failure Society of America (1999) “The single most significant addition to the pharmacological management of heart failure since the publication of previous guidelines [ACC/AHA] involves the use of beta-receptor antagonists.”

3. Definitions of Heart Failure Braunwald E. Harrison’s Principles of Internal Medicine. 14 th ed. 1998:1287-1297. Cohn JN. Circulation. 1988;78:1099-1107. “Heart failure may be considered to be the condition in which an abnormality of cardiac function is responsible for the inability of the heart to pump blood at a rate commensurate with the requirements of the metabolizing tissues…” E. Braunwald “Heart failure represents a syndrome in which cardiac dysfunction is associated with reduced exercise tolerance, a high incidence of ventricular arrhythmias, and shortened life expectancy.” J.N. Cohn

4. NYHA Functional Capacity Classification 1994 Revisions to the classification of functional capacity and objective assessment of patients with disease of the heart. Circulation. 1994; 90:644-645. Class IV: Class III: Class II: Class I: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or angina. Unable to carry on any physical activity without discomfort. Symptoms present at rest. With any physical activity, symptoms increase. Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in fatigue, palpitation, dyspnea, or angina. Slight limitation of physical activity. Ordinary physical activity results in fatigue, palpitation, dyspnea, or angina.

5. American Heart Association. 2001 Heart and Stroke Statistical Update. Dallas, TX.: American Heart Association, 2000; Ho KKL et al. JACC. 1993;22:6A-13A. In people diagnosed with heart failure, sudden death occurs at 6 to 9 times the rate of the general population 5-year mortality rate is 50% Median survival following onset is 1.7 years for men and 3.2 years for women Prognosis in Heart Failure

6. Pathogenesis and Sequelae of Heart Failure Adapted from Cohn J. N Engl J Med. 1996;335:490-498. Coronary artery disease Hypertension Cardiomyopathy Valvular disease Left ventricular dysfunction Non- cardiac factors Remodeling Low ejection fraction Arrhythmia Death Pump failure Symptoms: Dyspnea Fatigue Edema Chronic heart failure Neurohormonal stimulation Endothelial dysfunction Vasoconstriction Renal sodium retention

7. Mortality by Baseline Plasma Norepinephrine Level (PNE) Francis G et al. Circulation. 1993;87(suppl VI):VI-40 - VI-48. 100 80 60 40 20 06121824303642485460 Months Cumulative Mortality (%) PNE > 900 pg/mL PNE > 600 and < 900 pg/mL PNE < 600 pg/mL 2 Year P <.0001 Overall P <.0001 0

8. Effects of SNS Activation in Heart Failure  Dysfunction/death of cardiac myocytes  Provokes myocardial ischemia  Provokes arrhythmias  Impairs cardiac performance These effects are mediated via stimulation of  and  1 receptors Am J Hypertens 1998; 11: 23S-37S

9. PROPERTIES OF  -BLOCKERS Name  -1 Selective  -blockade LipophilicIncreases ISA Other ancillary properties AtenololYesNo AcebutololDisputedNo DisputedNo BisoprololYesNoWeakNo BucindololNo YesDisputedVasodilator action CarvedilolNoYes No Antioxidant, effects on endothelial function CeliprololYesNo  -2 only No MetoprololYesNoYesNo NebivololYesNo? Vasodilation through nitric oxide PropranololNo YesNo Membrane stabilizing Effect TimololNo WeakNoAnti-platelet effects XamoterolYesNo MarkedNo

10. Eichhorn EJ, JCF. 2000;6(suppl 1):40-46. LVEF Time (months) Biologic Effect Pharmacologic Effect  -Blocker Initiated  -Blocker Discontinued 01368  -Blocker Effects On Ejection Fraction in Heart Failure

11. Landmark studies reported so far US CARVEDILOL HEART FAILURE STUDY Mild to moderate HF; LVEF < 35% N = 1094, t = 15.1 mnths Carvedilol (25-50 mg bid) vs placebo NEJM 1996; 334 : 1349 - 55

12. ANZ Multicentre Heart Failure Trial PlaceboCarvedilol% Risk (n=208)(n=207)Reduction All-cause262024% mortality(12.5%)(10%) Risk of hospitalization for846428% cardiovascular reasons(40%)(31%) Combined risk of977429% mortality & hospitalization(47%)(36%) Lancet 1997; 349: 375-380.

13. Effect of carvedilol on progression of congestive heart failure All randomized patients Endpoint Placebo Carvedilol (n=134) (n=232) Primary endpoint 28 (21%) 25 (11%)* Death due to CHF 4 (3%) 0 (0%) Hospitalization due to worsening CHF 8 (6%) 9 (4%) Increase in CHF medication 16 (12%) 16 (7%) * Placebo vs. carvedilol, p = 0.008 Drugs of Today 1998; 34 (Suppl B): 1-23.

14. COPERNICUS (CarvedilOl ProspEctive RaNdomIsed CUmulative Survival Study): Effect on Mortality 35% Mortality (%) NEJM 2001; 344: 1651-8

15. COPERNICUS: Effect on combined risk of death and hospitalisations Parameter % risk reduction with carvedilol Death or hospitalisation24% for any reason Death and hospitalisation27% for CV reasons Death and hospitalisation31% for heart failure Circulation 2002; 106: 2194-9

16. BEST Study (Beta-Blocker Evaluation of Survival Trial) The Beta-Blocker Evaluation of Survival Trial Investigators. N Engl J Med. 2001;344:1659-1667. Primary Endpoint All-cause mortality Design Randomized, placebo-controlled, double-blind trial in 2708 NYHA Class III or Class IV patients Follow-up 24 months mean follow-up Dosing Bucindolol titrated from 3 mg to maximum 100 mg BID as tolerated by patient Results Nonsignificant relative risk reduction in all-cause mortality (10%, P =.10)

17. CARDIAC INSUFFICIENCY BISOPROLOL STUDY-II (CIBIS II) Moderate to severe HF, LVEF < 35% N=2647, t = 1.3 years Bisoprolol (10 mg od) vs placebo Lancet 1999; 353 : 9 –13

18. MEtoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) Mild to moderate HF; LVEF < 40% N = 3991 t = 1 year Metoprolol CR/XL (200 mg od) vs placebo Lancet 1999; 353: 2001-2007

19. Carvedilol Or Metoprolol European Trial COMET 17% Lancet 2003; 362: 7-13

20.  Cardiovascular mortality was reduced by 20% in carvedilol group as compared to metoprolol group. 20% Lancet 2003; 362: 7-13

21. Reduces total mortality by 54.3% 8.1 3.7 0 1 2 3 4 5 6 7 8 9 No. of deaths (%) ACE Inhibitor + diuretic + digitalis ACE inhibitor + diuretic + digitalis + Metoprolol extended release Circulation 2000; 101: 378-384 Randomized Evaluation of Strategies for left ventricular Dysfunction Pilot Study (RESOLVD)

22. CAPRICORN: Effect on total mortality 15% 12% 0 2 4 6 8 10 12 14 16 PlaceboCarvedilol % mortality 23% Lancet 2001; 357: 1385-90

23. CAPRICORN: Effect on combined risk of mortality and cardiovascular hospitalizations 15% 12% 0 2 4 6 8 10 12 14 16 PlaceboCarvedilol All-cause mortality or CV hospitalization (%) 8% Lancet 2001; 357: 1385-90

24.  Target dose was achieved by more than 70% of patients in both the treatment groups. Lancet 2003; 362: 7-13

25. First stable dose of carvedilol achieved in study patients 3.125 mg bd 4% 6.25 mg bd 13% 12.5 mg bd 20% other 3% 50 mg bd 4% 25 mg bd 57% Heart 2000; 84:615-619

26. Low withdrawal rates 15.3 13.9 0 5 10 15 20 Patient withdrawals (%) Lancet 1999; 353: 2001-2007 ACE Inhibitor + diuretic + digitalis ACE inhibitor + diuretic + digitalis + Metoprolol extended release Well tolerated when added to standard therapy

27. Per cent of patients unable to tolerate carvedilol treatment, grouped according to New York Heart Association (NYHA) functional class 3 9 13 22 0 5 10 15 20 25 I (n=59)II (n=201)III (n=254)IV (n=118) Per cent not tolerated N=808 Heart 2000; 84:615-619 NYHA Class

28. Per cent of patients able to tolerate carvedilol treatment, grouped according to traditional contraindications and precautions in prescribing a  -blocker 88 85 86 84 12 15 14 16 0 20 40 60 80 100 All patients (n=795) COPD/asthma (n=89) Diabetes (n=127) PVD (n=58) ToleratedNot Tolerated Per cent Heart 2000; 84:615-619

29. WHEN TO START TREATMENT?  If no contraindication  Early use of  blockers risk of adverse reactions Which to use?  Carvedilol  Metoprolol extended-release  Bisoprolol How to initiate and titrate  blockers doses?  Start low, go slow  Titration interval = 2-4 weeks  2-3 hours observation period

30. Titration of  blockers in HF Careful initial unpward dose adjustment ensures favourable minimizes adverse clinical management events  Eligible candidates: Non hospitalized patients with HF (NYHA class II or III), stable with standard HF therapy

31. Dose Initiation  In patients with clinically stable HF for 2-weeks with standard therapy (ACEI + diuretics)  At very low doses Dose Titration Patients who tolerate slow upward Maximally tolerated initial doses dose adjustment target doses Titration interval: > 2 weeks  Upward titration is delayed until any adverse effects observed with lower doses have resolved  Careful  blockers early in treatment may prevent the need for treatment delays during later stages of therapy

33. Slow upward titration Improves drug gives time for doctor to tolerability respond to changes in patient status by altering concomitant HF therapies