奇美醫學中心 一般內科 心臟內科 陳志成醫師

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

2. 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

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

4. New Features and Key Messages • 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.

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. Blood Pressure Classification

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. BP Control Rates Trends in awareness, treatment, and control of high blood pressure in adults ages 18–74 Sources: Unpublished data for 1999–2000 computed by M. Wolz, National Heart, Lung, and Blood Institute; JNC 6.

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. Lifestyle Modification

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

12. Results Beta-blockers vs thiazides Favours BB Favours Thiazide 0.50 0.75 1.00 1.25

13. Results ACEi vs CCB Favours ACEi Favours CCB 0.50 0.75 1.00 1.25

14. Results ARB vs BB Favours ARB Favours BB 0.50 0.75 1.00 1.25

15. Results ARB vs CCB Favours ARB Favours CCB 0.50 0.75 1.00 1.25

16. Results ACEi vs thiazides Favours ACEi Favours Thiazide 0.50 0.75 1.00 1.25

17. Results CCB vs BB Favours CCB Favours BB 0.50 0.75 1.00 1.25

18. Results CCB vs Thiazides Favours CCB Favours thiazide 0.50 0.75 1.00 1.25

19. Results AHD vs Placebo (ISH) Favours AHD Favours Placebo 0.50 0.75 1.00 1.25

20. Recommendations

22. Recommendations A C B B C C • 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

23. Recommendations C B C C • 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.

24. Hypertensionas a PublicHealth Risk January, 2007

25. Usual blood pressure threshold values for initiation of pharmacological treatment of hypertension Indications for Pharmacotherapy

26. Treatment Algorithm for Isolated Systolic Hypertension without Other CompellingIndications TARGET <140 mmHg INITIAL TREATMENT AND MONOTHERAPY Lifestyle modification therapy Thiazide diuretic ARB Long-acting DHP CCB

27. 1. Beta-blocker 2. Long-acting CCB Stable angina ACE-I are recommended for most patients with established CAD* Short-acting nifedipine 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) Those at low risk with well controlled risk factors may not benefit from ACEI therapy

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

29. Smoking Beta-blocker The benefits of treating smokers with beta-blockers remain uncertain in the absence of a specific indications like angina or post-MI 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

32. 冠狀動脈心臟病的病理機轉 氧氣供應 氧氣需求 心跳速率 血壓 心肌收縮力量 左心室大小 收縮期時程 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

33. Pharmacological Treatment in CAD

34. 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

35. 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 AbsoluteContraindications Cautions ß-Blockers

36. 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

37. 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

38. 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

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

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

41. Failing Heart Pumping failure Arrhythmogenicity Progressive HF Sudden cardiac death Destinies of Heart Failure

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

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

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

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

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

47. US Carvedilol Study Survival 1.0 0.9 0.8 0.7 0.6 0.5 Carvedilol (n=696)  blockers in heart failure - all-cause mortality Placebo (n=398) Risk reduction = 65% p<0.001 0 50 100 150 200 250 300 350 400 Days Packer et al (1996) Survival Mortality % CIBIS-II 1.00.80.6 0 20 MERIT-HF Placebo Bisoprolol 15 Metoprolol CR/XL 10 Placebo Risk reduction = 34% Risk reduction = 34% 5 p=0.0062 p<0.0001 0 0 200 400 600 800 0 3 6 9 12 15 18 21 Months of follow-up Lancet (1999) Time after inclusion (days) The MERIT-HF Study Group (1999)

48. CIBIS-I: 1.9 yearsplacebo 67/321 (20%); bisoprolol 53/320 (16%) P=.22 CIBIS-II: 1.3 yearsplacebo 228/1320 (17%); bisoprolol 156/1327 (12%) P=.0001 MERIT-HF: 12 monthsplacebo 217/2001 (11%); metoprolol 145/1990 (7%) P=.006 US Carvedilol Trials: 7.6 months*placebo 31/398 (8%); carvedilol 22/696 (3%) P=.001 0.25 0.5 0.75 1 1.25 1.5 1.75 2 Relative risk and 95% confidence intervals Effect of ß-Blocker onAll-Cause Mortality 0 * Not a planned endpoint.

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

50. % Survival 100 90 Carvedilol 11.4% 80 Placebo 18.5% 70 Nominal p=0.00014 35% risk reduction 60 50 Months 0 4 8 12 16 20 24 28 COPERNICUS - All-cause mortality 2002 .