1. Z.C Chen 奇美醫學中心 一般內科 心臟內科 陳志成醫師 The New Role of β-Blocker in Cardiovascular Disease

2. Z.C Chen The New Role of β-Blocker in Cardiovascular Disease 高血壓 冠狀動脈疾病 ( 冠心症 ) 心律不整 心臟衰竭 高血壓 冠狀動脈疾病 ( 冠心症 ) 心律不整 心臟衰竭

3. U.S. Department of Health and Human Services National Institutes of Health National Heart, Lung, and Blood Institute The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) National Heart, Lung, and Blood Institute National High Blood Pressure Education Program

4. 4  For persons over age 50, SBP is a more important than DBP as CVD risk factor.  Starting at 115/75 mmHg, CVD risk doubles with each increment of 20/10 mmHg throughout the BP range.  Persons who are normotensive at age 55 have a 90% lifetime risk for developing HTN.  Those with SBP 120–139 mmHg or DBP 80–89 mmHg should be considered prehypertensive who require health-promoting lifestyle modifications to prevent CVD. New Features and Key Messages

5. 5 New Features and Key Messages (Continued)  Thiazide-type diuretics should be initial drug therapy for most, either alone or combined with other drug classes.  Certain high-risk conditions are compelling indications for other drug classes.  Most patients will require two or more antihypertensive drugs to achieve goal BP.  If BP is >20/10 mmHg above goal, initiate therapy with two agents, one usually should be a thiazide-type diuretic.

6. 6 Blood Pressure Classification Normal<120and<80 Prehypertension120–139or80–89 Stage 1 Hypertension140–159or90–99 Stage 2 Hypertension>160or>100 BP ClassificationSBP mmHgDBP mmHg

7. 7 CVD Risk  HTN prevalence ~ 50 million people in the United States.  The BP relationship to risk of CVD is continuous, consistent, and independent of other risk factors.  Each increment of 20/10 mmHg doubles the risk of CVD across the entire BP range starting from 115/75 mmHg.  Prehypertension signals the need for increased education to reduce BP in order to prevent hypertension.

8. 8 BP Control Rates Trends in awareness, treatment, and control of high blood pressure in adults ages 18–74 National Health and Nutrition Examination Survey, Percent II 1976–80 II (Phase 1) 1988–91 II (Phase 2) 1991–941999–2000 Awareness 51736870 Treatment 31555459 Control 10292734 Sources: Unpublished data for 1999–2000 computed by M. Wolz, National Heart, Lung, and Blood Institute; JNC 6.

9. 9 Goals of Therapy  Reduce CVD and renal morbidity and mortality.  Treat to BP <140/90 mmHg or BP <130/80 mmHg in patients with diabetes or chronic kidney disease.  Achieve SBP goal especially in persons >50 years of age.

10. 10 Lifestyle Modification ModificationApproximate SBP reduction (range) Weight reduction5–20 mmHg/10 kg weight loss Adopt DASH eating plan8–14 mmHg Dietary sodium reduction2–8 mmHg Physical activity4–9 mmHg Moderation of alcohol consumption 2–4 mmHg

11. 11 Management of Hypertension in Adults in Primary Care NICE (National Institute for Health and Clinical Excellence) Guideline Updates June, 2006 NICE (National Institute for Health and Clinical Excellence) Guideline Updates June, 2006

12. 12 NOR-EM-060 ComparisonStudiesTotal n Effect size RR (95% CI) I 2 Mortality315,765 1.04 (0.91-1.20) 44.1 44.1 MI315,765 1.15 (0.82-1.60) 76.8 Stroke315,765 1.27 (0.73-2.23) 77.6 ResultsResults 0.50 0.75 1.001.25 Favours Thiazide Favours BB Beta-blockers vs thiazides

13. 13 NOR-EM-060 ComparisonStudiesTotal n Effect size RR (95% CI) I 2 Mortality323,625 1.04 (0.98-1.11) 0 MI323,619 0.94 (0.74-1.19) 69.3 Stroke323,619 1.15 (1.03-1.27) 5.2 Heart Failure323,619 0.85 (0.78-0.93) 0 Diabetes215,501 0.85 (0.76-0.94) 15.2 ResultsResults 0.50 0.75 1.001.25 Favours CCB Favours ACEi ACEi vs CCB

14. 14 NOR-EM-060 ComparisonStudiesTotal n Effect size RR (95% CI) I 2 Mortality19,103 0.89 (0.78-1.01) NA NA MI19,103 1.05 (0.86-1.28) NA NA Stroke19,103 0.75 (0.63-0.88) NA NA Heart Failure19,103 0.95 (0.76-1.18) NA NA Diabetes17,998 0.75 (0.64-0.88) NA NA ResultsResults 0.50 0.75 1.001.25 Favours BB Favours ARB ARB vs BB

15. 15 NOR-EM-060 ComparisonStudiesTotal n Effect size RR (95% CI) I 2 Mortality115,313 1.02 (0.93-1.12) NA NA MI115,313 1.17 (1.01-1.36) NA NA Stroke115,313 1.14 (0.97-1.33) NA NA Heart Failure115,313 0.88 (0.76-1.01) NA NA ResultsResults 0.50 0.75 1.001.25 Favours CCB Favours ARB ARB vs CCB

16. 16 NOR-EM-060 ComparisonStudiesTotal n Effect size RR (95% CI) I 2 Mortality229,697 1.00 (0.94-1.06) 0 MI330,204 0.87 (0.60-1.24) 66.5 66.5 Stroke330,204 1.13 (1.02-1.25) 0 Heart Failure229,697 1.07 (0.81-1.41) 67.1 67.1 ResultsResults 0.50 0.75 1.001.25 Favours Thiazide Favours ACEi ACEi vs thiazides

17. 17 NOR-EM-060 ComparisonStudiesTotal n Effect size RR (95% CI) I 2 Mortality344,075 0.94 (0.88-1.00) 5.7 5.7 MI (Inc. silent MI) 344,075 0.93 (0.83-1.03) 0 MI (ex. silent MI)344,075 0.91 (0.81-1.02) 0 Stroke221,499 0.77 (0.67-0.88) 0 Heart Failure241,833 0.96 (0.74-1.26) 67.4 Diabetes114,112 0.71 (0.64-0.78) NA ResultsResults 0.50 0.75 1.001.25 Favours BB Favours CCB CCB vs BB

18. 18 NOR-EM-060 ComparisonStudiesTotal n Effect size RR (95% CI) I 2 Mortality532,195 0.97 (0.93-1.02) 0 MI532,195 1.02 (0.96-1.08) 0 Stroke532,195 0.93 (0.84-1.04) 0 Heart Failure532,195 1.38 (1.25-1.53) 0.2 0.2 Diabetes320,885 0.82 (0.75-0.90) 43.8 43.8 ResultsResults 0.50 0.75 1.001.25 Favours thiazide Favours CCB CCB vs Thiazides

19. 19 NOR-EM-060 ComparisonStudiesTotal n Effect size RR (95% CI) I 2 Mortality39,745 0.88 (0.77-1.01) 0 MI39,745 0.75 (0.62-0.91) 0 Stroke39,745 0.64 (0.52-0.78) 0 ResultsResults 0.50 0.75 1.001.25 Favours Placebo Favours AHD AHD vs Placebo (ISH)

20. 20 RecommendationsRecommendations

21. 21 NOR-EM-060

22. 22 NOR-EM-060 RecommendationsRecommendations 55 歲以上之高血壓病人, 第一線用藥應為 CCB 或 thiazide 利尿劑. 55 歲以下之高血壓病人, 第一線用藥應為 ACEi. ( 若不能耐受, 則改為 ARB, 以下同 ) 若以 CCB 或 thiazide 利尿劑為第一線用藥, 加藥時應選擇 ACEi. 若以 ACEi 為第一線用藥, 加藥時應選擇 CCB 或 thiazide 利尿劑. 若需要第三線用藥, 則採用 CCB+ thiazide 利尿劑 +ACEi. 若三種藥物合併治療仍無法控制血壓時, 可加上第四線藥物且 / 或尋求專 家意見. 第四線藥物可為 :  較高劑量之 thiazide 利尿劑或其他類利尿劑 ( 需小心監測 )  Beta blocker  選擇性之 alpha blocker 55 歲以上之高血壓病人, 第一線用藥應為 CCB 或 thiazide 利尿劑. 55 歲以下之高血壓病人, 第一線用藥應為 ACEi. ( 若不能耐受, 則改為 ARB, 以下同 ) 若以 CCB 或 thiazide 利尿劑為第一線用藥, 加藥時應選擇 ACEi. 若以 ACEi 為第一線用藥, 加藥時應選擇 CCB 或 thiazide 利尿劑. 若需要第三線用藥, 則採用 CCB+ thiazide 利尿劑 +ACEi. 若三種藥物合併治療仍無法控制血壓時, 可加上第四線藥物且 / 或尋求專 家意見. 第四線藥物可為 :  較高劑量之 thiazide 利尿劑或其他類利尿劑 ( 需小心監測 )  Beta blocker  選擇性之 alpha blocker ACBBCC

23. 23 NOR-EM-060 Recommendations Recommendations 若四種藥物合併治療仍無法控制血壓時, 需尋求專家意見. Beta-blocker 非高血壓治療第一線建議用藥. 但在年輕的病人, 特別是 有以下情況者, 得以考慮第一線使用 :  對 ACEi / ARB 不能耐受, 或有禁忌症者  可能懷孕的婦女  證實有交感神經反應增強的病人  在上述情形下, 當第一線用藥為 beta-blocker 時, 建議使用 CCB 或 thiazide 類利尿劑當第二線用藥, 以減少新生糖尿病之風險. 若病人血壓控制不良, 不論用藥組合中是否包含 beta-blocker, 均應依前 述血壓治療規則用藥. 若病人血壓控制良好, 而用藥組合中包含 beta-blocker, 則需作長期評估, 但並不一定要將 beta-blocker 換為其他用藥. 若四種藥物合併治療仍無法控制血壓時, 需尋求專家意見. Beta-blocker 非高血壓治療第一線建議用藥. 但在年輕的病人, 特別是 有以下情況者, 得以考慮第一線使用 :  對 ACEi / ARB 不能耐受, 或有禁忌症者  可能懷孕的婦女  證實有交感神經反應增強的病人  在上述情形下, 當第一線用藥為 beta-blocker 時, 建議使用 CCB 或 thiazide 類利尿劑當第二線用藥, 以減少新生糖尿病之風險. 若病人血壓控制不良, 不論用藥組合中是否包含 beta-blocker, 均應依前 述血壓治療規則用藥. 若病人血壓控制良好, 而用藥組合中包含 beta-blocker, 則需作長期評估, 但並不一定要將 beta-blocker 換為其他用藥.CBCC

24. 2007 24 Hypertension as a Public Health Risk January, 2007

25. 2007 Canadian Hypertension Education Program Recommendations 25 Usual blood pressure threshold values for initiation of pharmacological treatment of hypertension ConditionInitiation SBP or DBP mmHg Systolic or Diastolic hypertension  140/90 Diabetes Chronic Kidney Disease  130/80 Indications for Pharmacotherapy

26. 2007 Canadian Hypertension Education Program Recommendations 26 Treatment Algorithm for Isolated Systolic Hypertension without Other Compelling Indications INITIAL TREATMENT AND MONOTHERAPY Thiazide diuretic Long-acting DHP CCB Lifestyle modification therapy ARB TARGET <140 mmHg

27. 2007 Canadian Hypertension Education Program Recommendations 27 Treatment of Hypertension in Patients with Ischemic Heart Disease Caution should be exercised when combining a non DHP-CCB and a beta-blocker If abnormal systolic left ventricular function: avoid non DHP-CCB (Verapamil or Diltiazem) 1. Beta-blocker 2. Long-acting CCB Stable angina ACE-I are recommended for most patients with established CAD* Short-acting nifedipine Those at low risk with well controlled risk factors may not benefit from ACEI therapy

28. 2007 Canadian Hypertension Education Program Recommendations 28 Treatment of Hypertension in Patients with Recent ST Segment Elevation-MI or non-ST Segment Elevation-MI Long-acting DHP CCB (Amlodipine, Felodipine) Beta-blocker and ACE-I Recent myocardial infarction Heart Failure ? NO YES Long-acting CCB If beta-blocker contraindicated or not effective An ARB can be used if the patient is intolerant to ACE-I

29. 2007 Canadian Hypertension Education Program Recommendations 29 The benefits of treating smokers with beta-blockers remain uncertain in the absence of a specific indications like angina or post-MI SmokingBeta-blocker Treatment of Hypertension for Patients Who Use Tobacco

31. The New Role of β-Blocker in Cardiovascular Disease 高血壓 冠狀動脈疾病 ( 冠心症 ) 心律不整 心臟衰竭 高血壓 冠狀動脈疾病 ( 冠心症 ) 心律不整 心臟衰竭

32. Z.C Chen 冠狀動脈心臟病的病理機轉冠狀動脈心臟病的病理機轉 氧氣供應 氧氣需求 冠狀動脈血流 冠狀動脈內徑 冠狀動脈血流灌流壓 血紅素含氧量 疾病時程 心跳速率 血壓 心肌收縮力量 左心室大小 收縮期時程

33. Z.C Chen Pharmacological Treatment in CAD

34. Z.C Chen ß-Blockers Mechanism of action  Blocks catecholamines from binding to ß-adrenergic receptors  Reduces HR, BP, myocardial contractility  Decreases AV nodal conduction  Decreases incidence of primary VF Mechanism of action  Blocks catecholamines from binding to ß-adrenergic receptors  Reduces HR, BP, myocardial contractility  Decreases AV nodal conduction  Decreases incidence of primary VF

35. Z.C Chen ß-Blockers Severe CHF/PE SBP <100 mm Hg Acute asthma (bronchospasm) 2nd- or 3rd-degree AV block Severe CHF/PE SBP <100 mm Hg Acute asthma (bronchospasm) 2nd- or 3rd-degree AV block Mild/moderate CHF HR <60 bpm History of asthma IDDM Severe peripheral vascular disease Absolute Contraindications Cautions

36. Z.C Chen The New Role of β-Blocker in Cardiovascular Disease 高血壓 冠狀動脈疾病 ( 冠心症 ) 心律不整 心臟衰竭 高血壓 冠狀動脈疾病 ( 冠心症 ) 心律不整 心臟衰竭

37. Z.C Chen 抗心律不整藥物抗心律不整藥物 1971 Vaughn Williams classification -Class I: 鈉離子通道阻斷劑 -Class II: β-blocker -Class III: 鉀離子通道阻斷劑 -Class IV: 鈣離子通道阻斷劑 1971 Vaughn Williams classification -Class I: 鈉離子通道阻斷劑 -Class II: β-blocker -Class III: 鉀離子通道阻斷劑 -Class IV: 鈣離子通道阻斷劑

38. Z.C Chen Indiction ofβ-blocker for Arrhythmia Inappropriate or unwanted sinus tachycardia Paroxymal atrial tachycardia provoked by emotion or exercise Exercise-induced ventricular arrhythmias Arrhythmia of pheochromocytoma ( with α-blocker) Hereditary prolonged QT syndrome Some heart failure Arrhythmia in mitral valve prolapse Inappropriate or unwanted sinus tachycardia Paroxymal atrial tachycardia provoked by emotion or exercise Exercise-induced ventricular arrhythmias Arrhythmia of pheochromocytoma ( with α-blocker) Hereditary prolonged QT syndrome Some heart failure Arrhythmia in mitral valve prolapse

39. The New Role of β-Blocker in Cardiovascular Disease 高血壓 冠狀動脈疾病 ( 冠心症 ) 心律不整 心臟衰竭 高血壓 冠狀動脈疾病 ( 冠心症 ) 心律不整 心臟衰竭

40. Population of CHF Prevalence 1-3% (general population) 10% (very elderly) Incidence 0.1-0.2% (general population) Double with each decade CHF population EU: 6.5 million USA: 5 million Japan: 2.4 million New CHF 1million/yr (worldwide)

41. Destinies of Heart Failure Pumping failureArrhythmogenicity Failing Heart Progressive HFSudden cardiac death

42. The Lancet 1999;353:2001-2007. MERIT-HF study group. NYHA II (5-15%) 12% 64%24% NYHA IV(30-70%) 56% 11% 33% CHF Other Sudden Death NYHA III (20-50%) 26% 15% 59% Death in Heart Failure Overall mortality 60%/5 years

43. Myocardial infarction EarlyLate Ventricular dysfunction Overt heart failure Time ANF Catecholamines Renin-angiotensin system (use of diuretics) Hormone Hormone Activation in Heart Failure Remodeling Hypertrophy & dilatation Apoptosis Regression to fetal phenotype Change of matrix

44. 11 receptors 22 myocyte hypertrophy + death, remodeling, ischemia + arrhythmias 11 receptors  Cardiac sympathetic activity  Sympathetic activity to kidneys & blood vessels vasoconstriction sodium retention  CNS sympathetic outflow Why Are ß-Blockers Useful in CHF? Packer AHA 2000

45. Mechanisms of Sudden Cardiac Death Ischaemia / infarction Myocardial damage Tachyarrhythmias Sudden Death Left ventricular remodelling  CHF Sympathetic activation  -receptor blockade

46.  ß-Blockers for Heart Failure Frog turns into Prince?

47. Carvedilol (n=696) Placebo (n=398) Survival Days 050100150200250300350400 1.0 0.9 0.8 0.7 0.6 0.5 Risk reduction = 65% p<0.001 Packer et al (1996) Lancet (1999) 0 200 400 600 800 1.0 0.8 0.6 0 Bisoprolol Placebo Time after inclusion (days) p<0.0001 Survival Risk reduction = 34% The MERIT-HF Study Group (1999) Months of follow-up Mortality % 036912151821 20 15 10 5 0 Placebo Metoprolol CR/XL p=0.0062 Risk reduction = 34% US Carvedilol Study  blockers in heart failure - all-cause mortality CIBIS-II MERIT-HF

48. 0 0.250.50.7511.251.51.752 Relative risk and 95% confidence intervals CIBIS-II: 1.3 years placebo 228/1320 (17%); bisoprolol 156/1327 (12%) P=.0001 MERIT-HF: 12 months placebo 217/2001 (11%); metoprolol 145/1990 (7%) P=.006 CIBIS-I: 1.9 years placebo 67/321 (20%); bisoprolol 53/320 (16%) P=.22 US Carvedilol Trials: 7.6 months* placebo 31/398 (8%); carvedilol 22/696 (3%) P=.001 * Not a planned endpoint. Effect of ß-Blocker on All-Cause Mortality

49. Class II Class III Class I Class IV US Carvedilol Programme (carvedilol) CIBIS II (bisoprolol) MERIT-HF (metoprolol) ?? Packer, AHA 2000

50. . 100 90 80 60 70 50 2402016128428 Placebo 18.5% Carvedilol 11.4% Months % Survival Nominal p=0.00014 35% risk reduction COPERNICUS - All-cause mortality 2002

51.  1 receptors  2 receptors Myocyte hypertrophy & death, dilatation, ischaemia & arrhythmia's  1 receptors Cardiac sympathetic activity Sympathetic activity to kidneys & blood vessels Vasoconstriction Sodium retention CNS sympathetic outflow Adrenergic activation Packer, AHA 2000

52. CAPRICORN(carvedilol) Class I Class IV US Carvedilol (carvedilol) CIBIS II (bisoprolol) MERIT-HF (metoprolol) COPERNICUS(carvedilol) Class II Class III Packer, AHA 2000

53. COMET - Primary Endpoint of Mortality Lancet 2003 Time (years) Mortality (%) 0 10 20 30 40 012345 Metoprolol Carvedilol hazard ratio 0.83, 95% CI 0.74-0.93, P = 0.0017 Number at risk Carvedilol151113671259 11551002383 Metoprolol151813591234 1105933352 17%

54. CAPRICORN(carvedilol) Class I Class IV COMET (carvedilol vs metoprolol) COPERNICUS(carvedilol) Class II Class III Packer, AHA 2000

55. Target doseMortality effect Metoprolol MDC100-150 mgNo  MERIT-HF200 mg  34% (sig) Bisoprolol CIBIS5 mg  20% (ns) CIBIS-II10 mg  34% (sig) What should be the target dose?

56. What should the target dose of carvedilol be?. 0 0.1 0.2 0.30.4Carvedilol 0 4 8 12 16 p<0.05 p=0.07 p=0.01 Mortality % Mean number per subject Mortality Cardiovascular hospitalisations Placebo 6.25 mg bid 12.5 mg bid 25 mg bid Placebo 6.25 mg bid 12.5 mg bid 25 mg bid Carvedilol p<0.001

57. Dosing for  blockers in heart failure DrugStarting doseTarget dose Bisoprolol1.25 mg qd10 mg qd Carvedilol3.125 mg bid6.25–25 mg bid Metoprolol12.5–25 mg qd200 mg qd (extended-release) The Medical Letter, June 26, 2000

58. CAPRICORN(carvedilol) Class I Class IV COMET (carvedilol vs metoprolol) COPERNICUS(carvedilol) Class II Class III Packer, AHA 2000

59. Trial NNT WOSCOPS (primary prevention)551 4S (secondary prevention)163 Enalapril in NYHA I/II100 MERIT-HF 27 CIBIS II 23 COPERNICUS 15 NNT ~ placebo mortality rate NNT to Prevent One Death in HF Trials

60. COPERNICUS Implications for public health Lives saved by treating 1000 patients for 1 year HOPE (ramipril)<1 SOLVD Prevention (enalapril) 7 SOLVD Treatment (enalapril) 17 MERIT-HF (metoprolol) 38 CIBIS-II (bisoprolol) 42 RALES (spironolactone) 52 COPERNICUS (carvedilol) 70 Packer, AHA 2000

61. CAPRICON (carvedilol postMI ) All patients treated with ACE inhibitors USCP (carvedilol) - 54% CIBIS II (bisoprolol) - 44% MERIT-HF (metoprolol) - 41% - 26% ß-Blockers Reduce SCD in HF

62. COPERNICUS (carvedilol) - 23% CIBIS II (bisoprolol) - 33% MERIT-HF (metoprolol) All patients treated with ACE inhibitors - 20% - 36% - 15% - 33% All-cause hospitalisation CHF hospitalisation ß-Blockers Prevent Hospitalisation

63.  1 receptors  1 receptors CARDIOTOXICITY  2 receptors Sympathetic activation BisoprololMetoprolol Propranolol Carvedilol Antiadrenergic therapy by  blockade Packer, AHA 2000

64. Metoprolol Cardiac norepinephrine Antioxidant effects Carvedilol  Cardiac norepinephrine Sympatheticantagonism  1 receptor blockade  1 and  2 receptor blockade  receptor upregulation  receptor suppression Packer, AHA 2000

65. Carvedilol provides comprehensive adrenergic blockade Adapted from M Packer  blockade Cardiac output Renal blood flow Renal blood flow Worsening heart failure Sodium retention

66. Carvedilol provides comprehensive adrenergic blockade Adapted from M Packer   blockade  blockade Cardiac output Renal blood flow Renal blood flow Worsening heart failure Sodium retention

67. Drug Treatments For CHF C H F ACE inhibitors  -blockers ARBs Vasodilators Aldosterone antagonists Digoxin ß-Agonists Inodilators (PDEI) PDEI with calcium sensitizer