TAIWAN TANABE

1. 陳榮明 Jimmy Chen 藥師 - 地區經理 嘉南 –藥學 TAIWAN TANABE

2. FOR CARDIOVASCULAR DISEASES The Highest ß1-selectivity. The Best Quality of Life CONCORTM 5mg/1.25mg Bisoprolol hemifumarate Indications: Hypertension,Angina,CHF Dosage:5 ~ 10mg QD ,1.25-QD TANABE/MERCK KGaA TAIWAN TANABE

3. Are the β-blockers all the same?

4. Classification of -Blockers -Blockers 1-Selective Non-1-Selective Without ISA Bisoprolol Atenolol Betaxolol Metoprolol With ISA Acebutolol Without ISA Nadolol Propranolol Sotaolol Timolol Carvedilol With ISA Carteolol Pindolol Labetalol ISA:Intrinsic Sympathomimetic Activity TAIWAN TANABE Adapted from: European Heart Journal (2004) 25, 1341-1362

5. Secondary prevention of myocardial infarction with different types of β -blockers Reduction of mortality β1-selective without ISA % Non-selective without ISA -30 β1-selective with ISA Non-selective with ISA -20 -10 β-blockers without ISA β-blockers with ISA TAIWAN TANABE Adapted form:Progress in CardiovascularDiseases. 27(5):335-71, 1985 Mar-Apr

6. β1 selectivity:

7. Physiological effect of adrenergic receptor Adapted from:European Heart Journal. 21(5):354-64, 2000 Mar

8. Bisoprolol: ß1-selectivity of various ß-blockers Bisoprolol 1:75 Betaxolol Atenolol 1:35 1:35 Metoprolol increasing 1:20 ß -selectivity 1 Wellstein A et al. J Cardiovasc Pharmacol 1986; 8 (Suppl. 11): 36-40 Wellstein A et al. Eur Heart J 1987; 8 (Suppl. M): 3–8 no selectivity 1.8:1 Propranolol increasing ß -selectivity 2 300:1 ICI 118.551 Ratio of constants of inhibition

9. b 2 4 8 24 b 2 4 8 24 h 1 3 6 12 1 3 6 12 1 3 6 12 Bisoprolol: ß1-selectivity and lung function in coronary patients with chronic obstructive bronchitis AWR (cm H O/I/s) 2 9 8 b = before 7 n = 12 x ± SEM HR (beats/min) Dorow P. Eur J Clin Pharmacol 1986; 31:143–147 90 70 50 b 2 4 8 24 Placebo Bisoprolol(20mg) Atenolol(100mg)

10. Hydrophilic Lipophilic Propranolol Metoprolol Labetalol Carvedilol Timolol Pindolol Atenolol Nadolol Sotalol TAIWAN TANABE

11. Balance Clearance Bisoprolol TAIWAN TANABE

12. Criteria Bisoprolol Atenolol Metoprolol Acebutolol Celiprolol Plasma elimination 10 – 12 6 – 9 3 – 4 7 – 13 5 half-life (h) Absorption (%) > 90 50 > 95 70 50 First-pass effect – – + + – Bioavailability (%) 88 50 50 40 – 60 50* Protein binding (%) 30 3 12 11 – 25 25 Active metabolites – – – + – Balanced clearance + – – – – Bisoprolol: Comparison to ß1-selective ß-blockers Borchard U. ß-Rezeptorenblocker, Klinik und Praxis, Aesopus Verlag 1996 *dose-dependent

13. Three indications of Bisoprolol • Essential Hypertension • Angina • Stable Chronic Heart Failure (Moderate~Severe)

14. Three Indications of Bisoprolol • Essential Hypertension • Angina • Stable Chronic Heart Failure (Moderate~Severe)

15. Bisoprolol: Dose-dependent blood pressure reductionin hypertensives Δ Δ SBP D BP Placebo Bisoprolol Placebo Bisoprolol 28 56 84 91 days 28 56 84 91 days 0 0 – 10 – 10 (mm Hg) (mm Hg) – 20 Kirsten R et al. J Cardiovasc Pharmacol 1986; 8 (Suppl. 11): 113–121 – 20 – 30 – 40 – 30 Bisoprolol 5 mg n = 15/group Bisoprolol 10 mg x SEM ± Bisoprolol 20 mg

16. Bisoprolol: Dose-dependent blood pressure reduction3 and 24 hours after administration Bisoprolol dose Placebo 5 mg 10 mg 20 mg • Davidov ME et al. Clin Cardiol 1994; 17:263–268 0 – 2 – 4 –3.0 –3.6 – 6 DBP sitting (mm Hg) – 8 –7.4 – 10 – 12 –10.5 – 14 –12.7 –12.8 –13.4 – 16 –14.7 3 h p.a. 3 h p.a. n = 240 ± SEM S 24 h p.a. 24 h p.a.

17. 180 160 Bisoprolol: Circadian rhythm 140 SBP 120 100 (mm Hg) 80 DBP 60 1 3 5 7 9 11 13 15 17 19 21 23 h last day of placebo after 4 weeks of bisoprolol(10mg) Keim HJ. Therapiewoche 1988; 47:3507–3513 n = 8

18. Bisoprolol: Treatment of hypertensionin comparison to atenolol DBP 0 • Neutel JM et al. Am J Med 1993; 94:181–187 Bisoprolol (n = 107) Atenolol (n = 96) night –5 ) –10 mean change in diastolic blood pressure (mm Hg –15 –20 10 a.m. 4 p.m. 10 p.m. 4 a.m. 10 a.m. time of day dose intake

19. Bisoprolol: Long-term treatment of hypertension 180 140 SBP (m m Hg) 100 Giesecke HG et al. J Cardiovasc Pharmacol 1990; 16 (Suppl 5): 175 DBP (m m Hg) HR beats/min) ( 60 0 12 15 18 21 24 27 30 33 36 months 102 102 97 102 101 102 102 102 100 102 n = Endgültig

20. Beta-Blockers: Continue to surprise us Diabetic Hypertension

21. JNC Ⅶ Clinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes Recommended Drugs Diuretic Beta-Blocker ACE Inhibitor ARB CCB Aldosterone Antagonist High-Risk Conditions With Compelling Indication* Heart Failure Post-myocardial infarction High coronary disease risk Diabetes Chronic kidney disease Recurrent stroke prevention Clinical Trial Basis ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHERT, RALES ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS ALLHAT, HOPE, ANBP2, LIFE, CONVINCE NKF-ADA Guidelin, UKPKS, ALLHAT NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK PROGRESS • • • • • • • • • • • • • • • • • • • • • Adapted from: JAMA. 2003；289：2560-2572

22. UK Prospective Diabetes Study • largest multi-centre randomised controlled trial of different therapies of Type 2 diabeteslargest study ever conducted in the prevention of diabetic complications in type II diabetics: • study duration: 1977 - 1997 • 23 clinical centres • patient population: 5102 type 2 diabetic patients • 53,000 patient years follow-up

23. UKPDS Blood Pressure Control Studytight vs. less tight: results Tight blood pressure control significantly reduces risks for • any diabetes-related endpoint 24% (p=0.0046) • diabetes-related deaths 32% (p=0.019) • stroke 44% (p=0.013) • microvascular disease 37% (p=0.0092) • heart failure 56% (p=0.0043) • retinopathy progression 34% (p=0.0038) • deterioration of vision 47% (p=0.0036)

24. UKPDS Study Adapted from:BMJ, Volume 317(7160).September 12, 1998.713-720

25. UKPDS Blood Pressure Control Study results favour ß-blocker: Adapted from:BMJ, Volume 317(7160).September 12, 1998.713-720

26. management of blood pressure was not a high priority for type 2 diabetics first choice treatment ACE inhibitors UKPDS Blood Pressure Control Studyimplications Before UKPDS After UKPDS • management of blood pressure should have high priority in the treatment of type 2 diabetes • first choice treatment • ACE inhibitor or Beta-blocker

27. Treatment of Hypertensionin Adults With Diabetes A-level evidence: • Initial drug therapy may be with ACE inhibitors, ARBs, β-blockers, or diuretics. Additional drugs may be chosen from these classes or another drug class. • In patients with a recent myocardial infarction, β-blockers, in addition,should be considered to reduce mortality. • Adapted from:DIABETES CARE, VOLUME 25, NUMBER 1, JANUARY 2002

28. Three Indications of Bisoprolol • Essential Hypertension • Angina • Stable Chronic Heart Failure (Moderate~Severe)

29. T I B B STotal Ischaemic Burden Bisoprolol Study Randomised double-blind controlled study with two parallel groups Objectives: To evaluate the effects of Bisoprolol o.d.and Nifedipine slow release b.i.d.on the occurrence and circadian distributionof ischaemic episodes in patientswith stable angina pectoris von Arnim Th et al. JACC 1995; 1: 231–230

30. TIBBS: Flow chart 20 mg o.d. Bisoprolol Placebo 10 mg o.d. Bisoprolol 20 mg b.i.d. Nifedipine s.r. 40 mg b.i.d. Nifedipine s.r. 10 days 4 weeks 4 weeks von Arnim Th et al. JACC 1995; 1: 231–238 > History If 2 ischaemic ETT episodes, Inclusion inclusion for for active prephase treatment 48 h Holter 48 h Holter 48 h Holter

31. TIBBS: Number of ischaemic episodes at baseline,on low dose and on high dose No./48 h 10 8 6 4 von Arnim Th et al. JACC 1995; 1: 231–238 2 0 Baseline 10 mg 20 mg Baseline 20 mg 40 mg Bisoprolol o.d. (n = 111) Nifedipine s.r. b.i.d. (n = 112) x SEM ± Endgültig

32. TIBBS: Duration of ischaemic episodes at baseline,on low dose and on high dose minutes 120 90 60 von Arnim Th et al. JACC 1995; 1: 231–238 30 0 Baseline 10 mg 20 mg Baseline 20 mg 40 mg Bisoprolol o.d. (n = 111) Nifedipine s.r. b.i.d. (n = 112) x SEM ± Endgültig

33. TIBBS: Total ischaemic burden at baseline,on low dose and on high dose min. x mm 250 200 150 von Arnim Th et al. JACC 1995; 1: 231–238 100 50 0 Baseline 10 mg 20 mg Baseline 20 mg 40 mg Bisoprolol o.d. (n = 111) Nifedipine s.r. b.i.d. (n = 112) x SEM ± Endgültig

34. Three Indications of Bisoprolol • Essential Hypertension • Angina • Stable Chronic Heart Failure (Moderate~Severe)

35. Beta-Blockers: Continue to surprise us From Contraindication to Indication Heart Failure

36. Chronically raised sympathetic tonus is accompanied by a number of unfavourable cadiovascular effects • Rise in oxygen consumption • Arrhythmogenicity • Diminished diastolic filling • Systolic function impairment • Cardiotoxic effect of endogenous catecholamines • Down-regulation of the -receptors • Metabolic disorders TAIWAN TANABE

37. -blockers 應用於治療CHF的理論基礎

38. -blockers 應用於治療CHF的理論基礎

39. CIBIS II -beneficial concomitant therapy in CHF Publication:The Lancet 1999; 353:9-13 TAIWAN TANABE

40. CIBIS IICardiac Insufficiency Bisoprolol Study • Double-blind, placebo-controlled, randomised trial • 2,647 patients included (NYHA III + IV) • Bisoprolol administered on top of standard therapy(diuretic + ACE inhibitor) CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13

41. CIBIS II Objectives • Primary objective • All-cause mortality • Secondary objectives • Cardiovascular mortality • Hospital admissions • Cardiovascular mortality orcardiovascular hospital admissions • Permanent treatment withdrawal CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13

42. CIBIS IIDose titration Bisoprolol dose (mg) 10.00 7.50 5.00 CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13 3.75 2.50 1.25 W2 W3 W4 W8 W12 W1 W5 W6 W7 W9 W10 W11 W13 W14 W15 W16 Week • No run-in period • Dose increased according to tolerability

43. CIBIS II Survival 1.0 Bisoprolol: 156 deaths(11.8%) (n = 1327) Placebo: 228 deaths(17.3%) (n = 1320) log rank test, p < 0.0001 0.8 Survival CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13 0.6 0 0 200 400 600 800 Time after inclusion (days) • 34% reduction in all-cause mortality with bisoprolol

44. CIBIS II Causes of deaths Patients 100 p=0.0011 80 83 6% Bisoprolol (n = 1327) 60 Placebo (n = 1320) p=0.0012 p=0.17 49 4% 48 4% 47 4% CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13 40 p=0.58 36 3% p=0.41 28 2% 23 2% 23 2% 20 p=0.75 18 1% 14 1% 8 1% 7 1% 0 Sudden Pump Myocardial Other cardio- Non-cardio- Unknown cause death failure infarction vascular deaths vascular deaths of death Hazard ratio: (95% CI) 0.56 0.74 0.85 1.17 0.75 0.45 (0.39 – 0.80) (0.48 – 1.14) (0.31 – 2.34) (0.67 – 2.03) (0.37 – 1.50) (0.27 – 0.74)

45. CIBIS IIMain results at a glance • In the bisoprolol-treated group of patients there was a reduction in • All-cause mortality (independent of aetiology) by 34% (p<0.0001) • Sudden death by 44% (p<0.0011) • All-cause hospital admissions by 20% (p<0.0006) CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13

46. CIBIS IIICardiac Insufficiency Bisoprolol Study CIBIS III Comparison of the efficacy and safety of initiation of treatment with bisoprolol or enalapril as monotherapy followed by their combination in patients with chronic heart failure (CHF)

47. Hypothesis Initiation of treatment in patients with CHF with the β1-selective β-blocker bisoprolol (to which enalapril is subsequently added) is as effective and safe as a regimen beginning with the ACEi enalapril (to which bisoprolol is subsequently added). DOI: 10.1161/CIRCULATIONAHA.105.582320

48. 6 months 24 months week week week week week week week week week week week week 0 2 4 6 8 10 12 ... 28 30 32 34 36 ... 20 10 5 enalapril (mg/d) 10 7.5 5 3.75 2.5 bisoprolol (mg/d) 1.25 10 7.5 5 3 .75 2.5 Randomisation 1.25 bisoprolol (mg/d) 20 10 5 enalapril (mg/d) Combination therapy Monotherapy 6 months 6 to 18 months CIBIS IIIDose titration

49. Primary objective To show that initial mono-therapy with bisoprolol followed by combination therapy with enalapril is comparable (non-inferior) to the reverse order in preventing death and hospitalization for all causes (combined endpoint). DOI: 10.1161/CIRCULATIONAHA.105.582320

50. Combined primary endpoint % without endpoint Per-protocol (PP) population Bisoprolol-first significantly non-inferior to enalapril-first if upper limit of 95% CI below hazard ratio (HR) 1.17, P<0.025. (=RR 1.125, AR +5%) In the PP population, bisoprolol- first was not significantly non-inferior to enalapril-first In the ITT population, bisoprolol- first was significantly non-inferior to enalapril-first 100 Bisoprolol-first 90 Enalapril-first 80 B/E vs E/B 163 vs 165 pts HR 0.97 (95% CI 0.78-1.21) non-inferiority P=0.046 3% risk reduction 70 60 50 503 498 356 353 265 259 80 73 Numbers at risk months 0 6 12 18 % without endpoint Intention-to-treat (ITT) population 100 90 6% risk reduction 80 B/E vs E/B 178 vs 186 pts HR 0.94 (95% CI 0.77-1.16) non-inferiority P=0.019 70 60 50 505 505 389 388 291 277 87 76 Numbers at risk DOI: 10.1161/CIRCULATIONAHA.105.582320 months 0 6 12 18