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Update on b -Blockers In the Management of Heart Failure

Update on b -Blockers In the Management of Heart Failure. “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.”. -Heart Failure Society of America (1999).

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Update on b -Blockers In the Management of Heart Failure

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

  2. “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.” -Heart Failure Society of America (1999) Heart Failure Society of America (HFSA) Practice Guidelines. J Cardiac Fail. 1999;5:357-382.

  3. “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 Braunwald E. Harrison’s Principles of Internal Medicine. 14th ed. 1998:1287-1297. Cohn JN. Circulation. 1988;78:1099-1107. Definitions of Heart Failure

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

  5. Prognosis in Heart Failure • 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 American Heart Association. 2001 Heart and Stroke Statistical Update. Dallas, TX.: American Heart Association, 2000; Ho KKL et al. JACC. 1993;22:6A-13A.

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

  7. 100 PNE > 900 pg/mL 80 60 PNE > 600 and < 900 pg/mL PNE < 600 pg/mL Cumulative Mortality (%) 40 20 2 Year P < .0001 Overall P < .0001 0 0 6 12 18 24 30 36 42 48 54 60 Months Francis G et al. Circulation. 1993;87(suppl VI):VI-40 - VI-48. Mortality by Baseline Plasma Norepinephrine Level (PNE)

  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 b and a1 receptors Am J Hypertens 1998; 11: 23S-37S

  9. PROPERTIES OF -BLOCKERS

  10. b-Blocker Effects On Ejection Fraction in Heart Failure b-Blocker Discontinued Pharmacologic Effect LVEF Biologic Effect b-Blocker Initiated 0 1 3 6 8 Time (months) Eichhorn EJ, JCF. 2000;6(suppl 1):40-46.

  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 Placebo Carvedilol % Risk (n=208) (n=207) Reduction All-cause 26 20 24%mortality (12.5%) (10%) Risk of hospitalization for 84 64 28%cardiovascular reasons (40%) (31%) Combined risk of 97 74 29%mortality & hospitalization (47%) (36%) Lancet 1997; 349: 375-380.

  13. Effect of carvedilol on progressionof 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 hospitalisation 24% for any reason Death and hospitalisation 27% for CV reasons Death and hospitalisation 31% for heart failure • Circulation 2002; 106: 2194-9

  16. Primary EndpointAll-cause mortality DesignRandomized, placebo-controlled, double-blind trial in 2708 NYHA Class III or Class IV patients Follow-up24 months mean follow-up DosingBucindolol titrated from3 mg to maximum 100 mg BID as tolerated by patient ResultsNonsignificant relative risk reduction in all-cause mortality (10% , P = .10) The Beta-Blocker Evaluation of Survival Trial Investigators. N Engl J Med. 2001;344:1659-1667. BEST Study(Beta-Blocker Evaluation of Survival Trial)

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

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

  23. CAPRICORN: Effect on combined risk of mortality and cardiovascular hospitalizations 8% 15% 16 14 12% 12 10 All-cause mortality or CV hospitalization (%) 8 6 4 2 0 Placebo Carvedilol 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 12.5 mg bd 6.25 mg bd 20% 13% other 3.125 mg bd 3% 4% 50 mg bd 4% 25 mg bd 57% Heart 2000; 84:615-619

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

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

  28. Per cent of patients able to tolerate carvedilol treatment, grouped according to traditional contraindications and precautions in prescribing a b-blocker 100 88 86 85 84 80 60 40 16 15 Per cent 14 12 20 0 (n=127) Diabetes PVD (n=58) (n=795) All patients COPD/asthma (n=89) Tolerated Not Tolerated 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 b 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 b blockers early in treatment may prevent the need for treatment delays during later stages of therapy

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

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