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陳榮明 Jimmy Chen 藥師 - 地區經理 嘉南 –藥學 各位醫師大家好 很感謝各位醫師抽空參加今天的藥品說明會 我叫做劉嘉湧

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Presentation on theme: "陳榮明 Jimmy Chen 藥師 - 地區經理 嘉南 –藥學 各位醫師大家好 很感謝各位醫師抽空參加今天的藥品說明會 我叫做劉嘉湧"— Presentation transcript:

1 陳榮明 Jimmy Chen 藥師 - 地區經理 嘉南 –藥學 各位醫師大家好 很感謝各位醫師抽空參加今天的藥品說明會 我叫做劉嘉湧
是目前負責Concor的產品經理 再接下來的時間,會跟各位報告兩個部分 第一個部分會先針對於beta-blocker目前在一些心血管疾病,例如糖尿病高血壓,心衰竭等 角色的轉變 第二個部分則是會針對各個beta-blocker的分類 來介紹Concor的特點 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 今天所介紹的藥品Concor他的學名是bisoprolol 是由德國默克藥廠研發,具有最高beta1選擇性的beta-blocker 在國內是由我們台田藥品代理 所通過的適應症包括的高血壓,狹心症以及心衰竭 在治療的劑量部分,針對高血壓以及狹心症的治療 每日劑量是5~10mg QD,也就是每日一到二錠即可穩定控制患者病情 至於說應用在心衰竭的治療的話,會在待會的CIBIS II試驗當中 作更詳盡的說明 比較起其他的beta-blocker,Concor由於具有最高的beta1選擇性 因此常見的副作用發生率非常的低 患者可以享有更好的生活品質 TANABE/MERCK KGaA TAIWAN TANABE

3 First Choice of Antihypertensive Agent
/0 ? ++ + +† - Diuretics -Blockers Calcium antagonists ACE inhibitors ARBs -Blockers‡ Central agents Peak Exercise* Plasma K+ Blood Lipids Insulin Resistance Renal Elderly CAD Stroke WHO/ISH First Choice JNC First Choice (Uncomplicated) Metabolic Outcome Studies VI 提起beta-blocker,一般會被認為是屬於老舊的一類產品, 特別是比較起目前其他的高血壓藥物 像是鈣離子阻斷劑 ACEI 以及最新研究的ARB等等 但是也因為beta-blocker研發的時間比較長久 反而有許多的大型臨床試驗證明 長期服用利尿劑以及beta-blocker能有效降低高血壓所併發心血管疾病的致病率以及致死率 此外這兩類的藥物也能 在MI方面能夠達到secondary prevention的效果 同時能降低中風及冠狀動脈疾病CAD的罹病率及死亡率 因此像是JNC VI 以及WHO 的 ISH guideline所一致推薦當作原發性高血壓的第一線選擇用藥 *capacity for maximum exercise. †Secondary protection well documented but primary protection less so. ‡Small  in stroke, angina, in ALLHAT, heart failure increased. JNC=Joint National Committee VI, 1997 WHO/ISH=World Health Organization-International Society of Hypertension, 1999. Taiwan Tanabe

4 Are the β-blockers all the same?
介紹完beta-blocker目前在相關心血管疾病的角色轉變之後 接下來要介紹的是各個beta-blocker的特點 到底,beta-blocker是否都是一樣的呢? 其實beta-blocker自從1968年代被應用至今 目前有許多種的beta-blocker被應用在臨床上面 他們之間其實具有很大的差異性

5 Classification of -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 在市面上這樣多的beta-blocker當中 可以根據是否具有beta1選擇性將藥物分成兩大類 在這其中又可以根據是否具有ISA的特性來分成四個subgroup 以Concor而言 Concor是具有beta1選擇性中不具有ISA的beta-blocker 而具有ISA的藥物則是以具有beta1選擇性的acebutolol以及不具beta選擇性的pindolol作為一個代表 ISA:Intrinsic Sympathomimetic Activity TAIWAN TANABE Adapted from: European Heart Journal (2004) 25,

6 Intrinsic Sympathomimetic Activity (ISA) or Partial Agonist Effect
The most obvious pharmacological aspect of Beta-blockers with ISA is that they produce less of a decrease in resting heart rate than agents without ISA TAIWAN TANABE

7 ISA Is Controversially Discussed
那麼是不是不具ISA的beta-blocker在臨床上會是較好的選擇呢 其實ISA的特性在臨床上並沒有一個絕對的好處以及壞處 必須依照病人的需要作相關的選擇 例如容易產生心搏過徐的病人 像是原本心跳就比較慢或是較年長的病人 由於ISA的藥物比較不會影響心跳 所以比較適合這一類的病人使用 另外他對於代謝,周邊循環以及肺功能的影響相對於沒有ISA的beta-blocker來的小 但是這是一個相對的比較 主要影響這些方面的因素還是得看藥物是否具有beta1的選擇性 相對的 具有ISA的藥物就比較不適合用於CAD的病人身上 因為它們會部分活化beta-receptor 所以在半夜交感神經活性比較低的時候 反而會增加心跳速率以及心臟細胞工作量 造成心肌耗氧量上升 對原先心肌細胞就已經受損的病人並不是一個適當的現象 此外ISA的藥物相對於不具ISA的藥物也會有比較多的睡眠障礙等副作用產生 TAIWAN TANABE

8 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 Cardiovascular Diseases. 27(5):335-71, 1985 Mar-Apr

9 β1 selectivity: Beta1選擇性可以說是beta-blocker相當重要的突破點之一

10 Physiological effect of adrenergic receptor
人體主要的beta接受體可分成beta1以及beta2 其中beta2主要分部在像是支氣管平滑肌以及血管平滑肌 另外對於血糖,血脂肪等代謝的調控 也是beta2接受體所調控的 因此傳統beta-blocker由於會同時阻斷beta1以及beta2接受體 容易發生平滑肌收縮所造成的支氣管收縮或者是因為末梢血液循環不良的副作用 對於糖尿病患者而言也容易產生代謝的不良影響 Adapted from:European Heart Journal. 21(5):354-64, 2000 Mar

11 Bisoprolol: ß1-selectivity of various ß-blockers
1:75 Atenolol Betaxolol 1:35 1:35 Metoprolol increasing ß -selectivity 1:20 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 TITLE: Bisoprolol: ß1-selectivity of various ß-blockers TEXT: Bisoprolol proved to be the compound with the highest ß1-selectivity in all in vitro and in vivo studies and in all animal species investigated. One measure of ß1-selectivity is the ratio of the constants of inhibition (ci) for the ß1- and ß2-receptor. The constants of inhibition of the ß-blockers bisoprolol, atenolol, betaxolol and propranolol were determined in ligand-binding studies using rat parotid gland (mainly occupied by ß1-receptors) and rat reticulocytes (mainly occupied by ß2-receptors) in human plasma: using a non-specific radiolabelled ligand, the ß1- and ß2-receptors of the rat parotid gland and reticulocytes were completely occupied. This cell suspension was then mixed with the plasma of volunteers pretreated with different ß-blockers. The non-specific radioligand was now displaced from the receptor by addition of this serum enriched with ß-blockers. Constants of inhibition of a characteristic magnitude for each ß-blocker and receptor type could be determined from these tests; the smaller the ci-value, the higher the affinity of the ß-blocker for the receptor type concerned. The ratio of c i/ß1 to c i/ß2 was 1:75 for bisoprolol, 1:35 for atenolol and betaxolol, 1: 20 for metoprolol, and 1.8 : 1 for propranolol. Bisoprolol therefore proved to be the ß-blocker with the highest ß1-selectivity in this model as well. REF: 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 Propranolol increasing ß -selectivity 2 300:1 ICI Ratio of constants of inhibition

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 b 2 1 h 3 6 12 4 8 24 TITLE: Bisoprolol: ß1-selectivity and lung function in coronary patients with chronic obstructive bronchitis TEXT: ß-adrenoceptor antagonists may induce bronchospasm in susceptible patients, presumably by unmasking parasympathetic and other bronchoconstrictor factors subsequent to the blockade of bronchial ß2-receptors. The dilatation of the bronchial muscles is mainly induced via ß2-receptors. Therefore ß1-selective ß-blockers are expected to have a lower risk for patients with chronic obstructive lung disease (COLD) compared to non-selective ß-blockers. In a randomized, placebo-controlled, double-blind, cross-over study in 12 patients with non-asthmatic chronic obstructive lung disease and co-existing stable angina pectoris, a single dose of atenolol 100 mg was compared to bisoprolol 20 mg. Effects on heart rate (HR) and airway resistance (AWR) were evaluated at various times up to 24 h after drug intake. Both ß-blockers decreased HR significantly compared to placebo, with no significant differences between the two test substances, although the reduction in HR was in some cases more pronounced with bisoprolol than with atenolol. There was an increase in AWR after atenolol, whereas the mean value remained unchanged after bisoprolol compared to placebo. The results reveal a benefit of a high ß1-selectivity: the risk of bronchoconstriction decreases with an increasing ß1-selectivity. Bisoprolol is a ß1-selective ß-blocker with no clinically relevant affinity to the ß2-receptors of the lung. REF: Dorow P. Eur J Clin Pharmacol 1986; 31:143–147 70 50 b 2 4 8 24 Placebo Bisoprolol(20mg) Atenolol(100mg)

13 Bisoprolol: ß1-selectivity and lung function in asthmatic hypertensives (2 h after administration)
AWR (cm H O s/l) 2 1.6 n = 12 x SEM 1.2 0.8 0.4 Chatterjee SS. J Cardiovasc Pharmacol 1986; 8 (Suppl. 11): 74–77 TITLE: Bisoprolol: ß1-selectivity and lung function in asthmatic hypertensives (2 h after administration) TEXT: ß-adrenoceptor antagonists may elevate airway resistance (AWR) in susceptible patients, presumably by unmasking parasympathetic and other bronchoconstrictor factors subsequent to the blockade of bronchial ß2-receptors. The dilatation of the bronchial muscles is mainly induced via ß2-receptors. Therefore ß1-selective ß-blockers are expected to have a lower risk for asthmatic patients compared to non-selective ß-blockers. In a randomized, four-way cross-over study in twelve asthmatic hypertensive patients the effects of bisoprolol 10 mg, bisoprolol 20 mg, atenolol 100 mg and placebo on lung function were compared. The difference of AWR between baseline and 2 h post dose are presented as mean ± SEM. Bisoprolol at both dosages had no relevant influence on AWR as compared with placebo, whereas there was a significant increase in AWR with atenolol, compared with placebo. Bisoprolol at both dose levels produced strong ß1-receptor blocking effects (decrease in HR), but had no influence on AWR, thus maintaining its ß1-selectivity even at a dosage of 20 mg. In contrast, atenolol showed a binding to ß2-receptor sites at equipotent therapeutic dose levels (100 mg atenolol is equipotent to 10 mg bisoprolol) and thus proved to be less ß1-selective. REF: Chatterjee SS. J Cardiovasc Pharmacol 1986; 8 (Suppl. 11): 74–77 – 0.4 – 0.8 10 mg 20 mg 100 mg Placebo Bisoprolol Atenolol

14 Bisoprolol: ß1-selectivity and lipid metabolism
in long-term therapy lipids (mmol/l) cholesterol (mmol/l) 5.0 7.0 total cholesterol LDL-cholesterol 4.0 6.0 3.0 5.0 triglycerides HDL-cholesterol Frithz G et al. J Cardiovasc Pharmacol 1986; 8 (Suppl. 11): 134–138 2.0 2.0 TITLE: Bisoprolol: ß1-selectivity and lipid metabolism in long-term therapy TEXT: The lipid metabolism is partly regulated by α - and ß-adrenergic mechanisms. ß-blockers – namely non-selective ones – are able to provoke a change in the plasma concentrations of lipids: total cholesterol as well as LDL-cholesterol (atherogenic risk factor) can be increased and HDL-cholesterol (atherogenic protective factor) can be decreased. 42 patients with essential hypertension were enrolled into an open long-term study. The 3 month dose-titration period was followed by a 10 month observation period. Laboratory values were evaluated seven times in total. Four parameters of lipid metabolism are presented versus time as mean ± SEM. There were no significant changes in total cholesterol or in the subgroups HDL-cholesterol and LDL-cholesterol during this long-term study. These findings are noteworthy, since results in the literature not only demonstrate an increase in LDL-cholesterol and a decrease in HDL-cholesterol for non-selective ß-blockers, but also for the ß1-selective drugs, e.g. metoprolol and atenolol. These results reflect the high ß1-selectivity of bisoprolol. Concerning triglycerides, an increase was observed during the initial titration phase as well as in the long-term study. Though not significant within each period, the overall increase from baseline to final value is statistically significant. It is still uncertain whether an increase in serum triglycerides is associated with an increase in an atherogenetic risk factor. REF: Frithz G et al. J Cardiovasc Pharmacol 1986; 8 (Suppl. 11): 134–138 1.0 1.0 3 5 7 9 11 13 months 3 5 7 9 11 13 months n=42 42 40 41 38* 40 41 n=42 42 40 39 35 40 41 (* n=36 for triglycerides) x ± SEM

15 Bisoprolol: ß1-selectivity and lipid metabolism
in long-term therapy ** * +10 Mepindolol 10 mg/day (n = 16) Bisoprolol 10 mg/day (n = 17) –10 Propranolol 160 mg/day (n = 15) Atenolol 100 mg/day (n = 22) % HDL-cholesterol 20 Fogari R et al. J Cardiovasc Pharmacol 1990; 16 (Suppl 5): S 76–80 30 TITLE: Bisoprolol: ß1-selectivity and lipid metabolism in long-term therapy TEXT: The aim of the study was to evaluate the effects of long-term monotherapy with four ß-blockers of different pharmacological properties on plasma lipids in hypertensives with normal cholesterol plasma levels. After a 1-month washout and a 1-month placebo period the patients were randomly allocated to either propranolol 160 mg/day, atenolol 100 mg/day, bisoprolol 10 mg/day, or mepindolol 10 mg/day as monotherapy. The patients were followed up for 3 years. Results for HDL-cholesterol are shown for each group versus time in changes relative to pre-treatment values. Bisoprolol and the ISA-blocker mepindolol did not significantly affect HDL-levels, which were substantially unchanged during all periods. On the contrary, both propranolol and atenolol significantly reduced HDL-concentrations. It appears that changes in the lipid profile are more or less related to ß2-blockade, being less obvious with ß1-selective drugs such as bisoprolol and compounds possessing ISA. REF: Fogari R et al. J Cardiovasc Pharmacol 1990; 16 (Suppl 5): S 76–80 Δ 40 6 12 18 24 30 36 months *p<0.05 vs. baseline **p<0.01

16 Bisoprolol: ß1-selectivity and glucose metabolism
Serum concentration after 0.1 I.U. insulin/kg body weight i.v., 3 hours after the oral administration of 3 different ß-blockers and placebo in healthy volunteers 5 4 3 2 1 30 45 60 90 120 min glucose (mmol/l) 1.7 1.5 1.3 1.1 0.9 0.7 lactate (mmol/l) Leopold G et al. Br J Clin Pharmacol 1986; 22:293–300 TITLE: Bisoprolol: ß1-selectivity and glucose metabolism TEXT: In treated diabetic patients (insulin or oral antidiabetics), adrenaline release is a key regulation mechanism to cope with hypoglycaemic conditions. Adrenaline stimulation via ß2-receptors in the liver increases the availability of glucose. Non-selective ß-blockers inhibit this counter-regulation. Furthermore, ß-blockers – especially non-selective ones – inhibit the adrenaline-mediated alarm symptoms of hypoglycaemia. The combination of these two items might result in a higher risk of hypoglycaemic shock. In this single-blind, cross-over study the ß1-selectivity of bisoprolol was investigated in comparison to metoprolol, propranolol and placebo in healthy volunteers using the model of insulin-induced hypoglycaemia. Immediately after the insulin infusion the glucose levels fell to a nadir of about 1 mmol/l in all treatment groups, producing a sympathetic stimulus through endogenous adrenaline release. The compensatory metabolic processes, mainly by glycogenolysis in muscles and liver and by hepatic gluconeogenesis, are preferentially mediated via ß2-adrenoceptors. Under the influence of a ß1-selective blockade the recovery of serum glucose is less impeded than following a non-selective ß-adrenoceptor blockade. The slope of the concentration curve under bisoprolol is not different from placebo, indicating that no ß2-receptor interaction can be seen. Under physiological conditions, hypoglycaemia leads to a rise in serum lactate concentrations, which is strongly reduced with propranolol (ß2-antagonistic action) but not with bisoprolol or metoprolol. Thus bisoprolol behaves as a ß1-selective adrenoceptor antagonist in the model of insulin-induced hypoglycaemia. Due to its high ß1-selectivity its effects are quite similar to placebo, with almost no influence on the duration of the hypoglycaemic phase. REF: Leopold G et al. Br J Clin Pharmacol 1986; 22:293–300 Bisoprolol 10 mg Propranolol 40 mg Metoprolol 50 mg Control

17 Hydrophilic Lipophilic Atenolol Nadolol Sotalol Propranolol Metoprolol
beta-blocker除了可以按照beta1選擇性或是ISA來分類之外 本身是屬於親水性或是親脂性也可能成為另外一種分類的依據 Beta-blocker本身可以另外分成親水性以及親脂性兩大類 第一大類親脂性的藥品 像是propranolol,metoprolol或是carvedilol 主要是經由肝臟作代謝 因此如果患者的肝臟功能不佳 可能需要作劑量調整,來減少藥品可能蓄積的危險性 接下來會分別針對於beta1選擇性, ISA, 脂溶性以及水溶性不同的差異性來分別介紹 而第二類屬於親水性的beta-blocker, 像是atenolol,nadolol等 主要是經由腎臟作排除 所以同樣的如果患者腎臟功能不良 服用這一類親水性的beta-blocker同樣得調整劑量 Propranolol Metoprolol Labetalol Carvedilol Timolol Pindolol Atenolol Nadolol Sotalol TAIWAN TANABE

18 Balance Clearance Bisoprolol 主要原因在於bisoprolol具有一個相當獨特的特點 他是半脂半水性的
因此一半經由肝臟作代謝 另一半則是經由腎臟作排除的作用 可以說是具有肝腎平衡的清除率 這樣的特點對於患者有怎樣的好處呢? 在相關的臨床試驗當中已經證明 針對輕度到中度肝臟,或是腎臟功能不好的患者 如果服用bisoprolol 5~10mg QD的劑量時候 是不需要作劑量的調整的 因此針對台灣目前有許多因為肝炎,糖尿病而導致 肝臟或是腎臟功能受損的患者而言 這樣的特點可以減少藥品蓄積所可能帶來的副作用 對於各位醫師的處方而言 更是相當的方便 因此bisoprolol可以說是一個相當特殊的beta-blocker TAIWAN TANABE

19 Bisoprolol: Comparison to ß1-selective ß-blockers
Criteria Bisoprolol Atenolol Metoprolol Acebutolol Celiprolol Plasma elimination half-life (h) 10 – 12 6 – 9 3 – 4 7 – 13 5 Absorption (%) > 90 50 > 95 70 First-pass effect + Bioavailability (%) 88 40 – 60 50* Protein binding (%) 30 3 12 11 – 25 25 Active metabolites Balanced clearance Borchard U. ß-Rezeptorenblocker, Klinik und Praxis, Aesopus Verlag 1996 TITLE: Bisoprolol: Comparison to ß1-selective ß-blockers TEXT: All relevant pharmacokinetic parameters for ß1-selective ß-blockers are displayed in this comparison. Plasma elimination half-life is highest for bisoprolol, thus providing the basis for single-daily dosage. Bioavailability, the result of a high absorption and a low first pass-effect and the basis for a small intra- and interindividual variability of pharmacokinetics, is thus very high for bisoprolol. Protein binding is low for all displayed drugs, representing the basis for kinetics being insensitive to drug-drug interactions and pathophysiological changes. Balanced clearance, the basis for kinetics being almost insensitive to renal or hepatic insufficiency, is demonstrated only for bisoprolol. REF: Borchard U. ß-Rezeptorenblocker, Klinik und Praxis, Aesopus Verlag 1996 *dose-dependent

20 Bisoprolol: Comparison to non-selective ß-blockers
Criteria Bisoprolol Pindolol Propranolol Carvedilol Plasma elimination half-life (h) 10 – 12 3 – 4 7 Absorption (%) > 90 90 85 First-pass effect + Bioavailability (%) 88 30 25 Protein binding (%) 60 93 98 Active metabolites Balanced clearance Borchard U. ß-Rezeptorenblocker, Klinik und Praxis, Aesopus Verlag 1996 TITLE: Bisoprolol: Comparison to non-selective ß-blockers TEXT: All relevant pharmacokinetic parameters for non-selective ß-blockers are displayed in comparison to bisoprolol. Plasma elimination half-life is highest for bisoprolol, thus providing the basis for single-daily dosage. Bioavailability, the result of a high absorption and a low first pass-effect and the basis for a small intra- and interindividual variability of pharmacokinetics, is thus very high for bisoprolol. Protein binding is low only for bisoprolol, representing the basis for kinetics being insensitive to drug-drug interactions and pathophysiological changes. Balanced clearance, the basis for kinetics being almost insensitive to renal or hepatic insufficiency, is demonstrated for bisoprolol. Pindolol, with a ratio of roughly 60% hepatic clearance and 40 % renal clearance, comes close. REF: Borchard U. ß-Rezeptorenblocker, Klinik und Praxis, Aesopus Verlag 1996

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

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

23 Bisoprolol: Dose-dependent blood pressure reduction in hypertensives
Δ SBP Bisoprolol Placebo Δ D BP Bisoprolol Placebo 28 56 84 91 days 28 56 84 91 days – 10 – 10 (mm Hg) – 20 (mm Hg) Kirsten R et al. J Cardiovasc Pharmacol 1986; 8 (Suppl. 11): 113–121 – 20 – 30 TITLE: Bisoprolol: Dose-dependent blood pressure reduction in hypertensives TEXT: In this study 45 male hypertensive patients were randomly allocated to either 5, 10, or 20 mg bisoprolol once daily for 12 weeks. Patients were followed up for hypertension rebound symptoms for one additional week after the end of active treatment. The decrease in blood pressure and heart rate during active treatment correlated well with increasing doses of bisoprolol at the different timepoints with e.g. a mean reduction of diastolic blood pressure with bisoprolol 5, 10 and 20 mg of 10 ± 4, 16 ± 6, and 20 ± 4 mmHg, respectively. After the end of active treatment, blood pressure and heart rate gradually returned to pre-treatment values within 1–2 weeks. Probably due to the long plasma elimination half-life, no rebound symptoms were observed. REF: Kirsten R et al. J Cardiovasc Pharmacol 1986; 8 (Suppl. 11): 113–121 – 40 – 30 Bisoprolol 5 mg n = 15/group Bisoprolol 10 mg x SEM Bisoprolol 20 mg

24 Davidov ME et al. Clin Cardiol 1994; 17: 263–268
Bisoprolol: Dose-dependent blood pressure reduction 3 and 24 hours after administration Bisoprolol dose Placebo 5 mg 10 mg 20 mg – 2 – 4 –3.0 –3.6 – 6 DBP sitting (mm Hg) – 8 –7.4 – 10 TITLE: Bisoprolol: Dose-dependent blood pressure reduction 3 and 24 hours after administration TEXT: In this study 240 patients with mild to moderate hypertension were randomly allocated to either 5, 10, or 20 mg bisoprolol once daily or placebo for 4 weeks. After three weeks of treatment a subgroup of 101 patients was selected and vital signs were recorded before drug intake (= 24 h post-dose) and 3 h post-dose. Compared to placebo 5, 10 and 20 mg bisoprolol caused a dose-dependent reduc-tion in diastolic blood pressure. The data demonstrate that most of the bisoprolol-induced decrease in diastolic blood pressure at 3 h post-dose was sustained at 24 h post-dose. Further, at 3 h post-dose bisoprolol was not associated with measurable or symptomatic orthostatic hypotension or bradycardia. This multicentre study demonstrates the 24 h antihypertensive efficacy of once-daily bisoprolol in patients with mild to moderate hypertension. REF: Davidov ME et al. Clin Cardiol 1994; 17: 263–268 – 12 –10.5 – 14 –12.7 –12.8 –13.4 – 16 –14.7 3 h p.a. 3 h p.a. n = 240 S ± SEM 24 h p.a. 24 h p.a.

25 Bisoprolol: Circadian rhythm
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) n = 8 Keim HJ. Therapiewoche 1988; 47:3507–3513 TITLE: Bisoprolol: Circadian rhythm TEXT: In 8 patients with mild to moderate hypertension 24-h blood pressure profiles were recorded by continuous ambulatory measurements after two weeks on placebo and after another four weeks on once daily bisoprolol 10 mg. Bisoprolol 10 mg once daily reduced casual as well as continuous systolic, diastolic and mean blood pressure and heart rate. The circadian blood pressure profile was maintained at a lower level. Blood pressure during active daylight periods was more reduced than night-time resting blood pressure. Excessive peak values were observed less frequently. Of special clinical relevance is the finding that the early morning rise in blood pressure is restrained under bisoprolol treatment. REF: Keim HJ. Therapiewoche 1988; 47:3507–3513

26 Bisoprolol: Treatment of hypertension in comparison to atenolol
Neutel JM et al. Am J Med 1993; 94:181–187 Bisoprolol: Treatment of hypertension in comparison to atenolol DBP Bisoprolol (n = 107) Atenolol (n = 96) night –5 ) mean change in diastolic blood pressure –10 (mm Hg TITLE: Bisoprolol: Treatment of hypertension in comparison to atenolol TEXT: The effect of the two agents over the entire 24-hour monitoring period in terms of mean change from baseline values is depicted graphically for diastolic blood pressure. Over the whole period of time bisoprolol was superior in effect compared to atenolol. Bisoprolol demonstrated a 33 % greater reduction in whole-day average diastolic blood pressure than atenolol (11.6 ± 0.7 mmHg vs 8.7 ± 0.8 mmHg, p < 0.01). REF: Neutel JM et al. Am J Med 1993; 94:181–187 –15 –20 10 a.m. 4 p.m. 10 p.m. 4 a.m. 10 a.m. time of day dose intake

27 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) TITLE: Bisoprolol: Long-term treatment of hypertension TEXT: The long-term efficacy and safety of bisoprolol were investigated in 102 patients with mild to moderate essential hypertension who had already been treated successfully (diastolic blood pressure ≤ 90 mmHg) with bisoprolol once daily for one year in preceding studies, continuing the dosage which had proved to be effective. Normotensive levels of diastolic blood pressure could be maintained during the second and third year of treatment. At the end of the 3-year follow-up period, 85 % of the patients had been adequately treated with bisoprolol 5 or 10 mg. Bisoprolol proved to be effective in long-term management of hypertension, without development of tolerance. REF: Giesecke HG et al. J Cardiovasc Pharmacol 1990; 16 (Suppl 5): 175 HR ( beats/min) 60 12 15 18 21 24 27 30 33 36 months n = 102 102 97 102 101 102 102 102 100 102 BisoDIAS Endgültig

28 Bisoprolol clinical study in Japan
Total patients=81 Period:12 weeks Dosage: Bisoprolol 5mg QD 發表期刊:日本老年醫學會雜誌 35卷 1號 (1998:1) P33~38 受試人數:81位(65歲以上的21位,未滿65歲的60位) 收錄患者型態: WHO分類1~2級高血壓 1:在四週內沒有接受過降壓藥品治療的患者 2:以beta-blocker以外的降壓藥品治療四周以上,但效果不明顯者(150/90 mmHg或平均血壓在110以上者),併用Bisoprolol 3:一天服用2~3次降壓藥品,服用四周以上時間,計算劑量後轉換成bisoprolol QD治療 平均年齡: 60位未滿65歲的患者:54.7± 6.8歲 21位65歲以上患者:70.1± 3.7歲 投與藥物與方式:bisoprolol 5mg QD 投與時間:12週 TAIWAN TANABE n=80 n=73 n=71 Adapted from:日本老年醫學會雜誌 35卷 1號 (1998:1) P33~38

29 Continue to surprise us Diabetic Hypertension
Beta-Blockers: Continue to surprise us Diabetic Hypertension 雖然許多的治療準則均建議針對於原發性高血壓患者 Beta-blocker可列於首選藥品 但是由於beta-blocker本身藥理特性 針對於一些患者而言,過去會被認為是比較不適合處方beta-blocker的 例如糖尿病高血壓,或者是心衰竭的患者 主要原因在於傳統beta-blocker對於糖尿病患者的代謝或者是心衰竭患者的心輸出量 會有不良的影響 然而近幾年來隨著一些大型臨床試驗的發表 反而發現適當的使用beta-blocker 對於剛剛所提及的患者,有相當的好處,能有效的減少心血管疾病的併發症 以及減少死亡率

30 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 • • • • • • • • • • • • 譬如說去年(2003)五月份所發表的JNC VII, 針對於高血壓患者合併有糖尿病或是有心衰竭的患者 Beta-blocker已經不再是相關的禁忌症了 主要也是因為相關大型臨床試驗的結果發表 使beta-blocker對相關心血管疾病治療的腳色有所改變 接下來就分別針對這兩種疾病的治療當中 分別介紹beta-blocker的腳色 • • • • • • • • • Adapted from: JAMA. 2003;289:

31 Beta-blockers: another choice for HT with DM therapy
首先是糖尿病高血壓治療的探討 對於糖尿病合併高血壓的患者而言 乙型阻斷劑在過去是被視為相對的禁忌症 主要是非選擇性的乙型阻斷劑會干擾血糖 而beta-blocker一般會被認為具有比較多的副作用發生 因此在臨床的應用當中,比較起其他類的心血管疾病藥品 應用上會有相當的限制 然而有關這樣的觀念已經逐漸有了轉變 最主要是UKPDS這一個針對於糖尿病治療方式 有著重大意義的臨床試驗的發表, 除了糖尿病高血壓的治療方式改變之外 Beta-blocker對於糖尿病高血壓的治療也成為必須考量的藥物之一

32 UK Prospective Diabetes Study
largest multi-centre randomised controlled trial of different therapies of Type 2 diabetes largest study ever conducted in the prevention of diabetic complications in type II diabetics: study duration: 23 clinical centres patient population: 5102 type 2 diabetic patients 53,000 patient years follow-up UKPDS的試驗主要是在英國執行的依大型臨床試驗 主要探討針對type2糖尿病患者,以不同治療方式,對於糖尿病可能併發的併發症的預防

33 UKPDS Blood Pressure Control Study tight 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 % (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) 首先是針對於血壓控制嚴謹與否 與相關心血管risk的分析 試驗的結果顯示 嚴格控制血壓的病患明顯的可以減少更多的心血管疾病的發生率 例如中風心衰竭腎病變等均可以減少相當高的比例 對於大血管的病變而言,控制糖尿病患者血壓似乎比控制糖尿病患者血糖 還能有效的降低相關的risk

34 Table 1—Indications for initial treatment and goals for adult hypertensive diabetic patients
Systolic Diastolic Goal (mmHg) 130 80 Behavioral therapy alone (maximum 3 months) then add pharmacologic treatment 130–139 80–89 Behavioral therapy pharmacologic treatment 140 90 也因此 目前針對於糖尿病高血壓患者的血壓標準 都設定的越來越嚴格 目前大多將目標數值控制在130/80以下 例如在2002年的ADA的糖尿病治療準則當中 建議糖尿病病患的血壓控制應該在130/80 以減少糖尿病病患本身心血管疾病的發生率 但是如果要將糖尿病高血壓患者的血壓 控制在130/80這一個比較嚴格的標準值之下 平均需要三點二個藥品 除了傳統ACEI以及利尿劑之外 可能需要合併其他的降壓藥品,來幫忙控制患者的血壓 Adapted from:DIABETES CARE, VOLUME 25, NUMBER 1, JANUARY 2002

35 UKPDS Study 剛剛有提到 UKPDS有針對乙型阻斷劑以及ACEI的個別療效作探討 試驗結果可以清楚看到 乙型阻斷劑以及ACEI均能有效的將血壓控制在目標值左右 Adapted from:BMJ, Volume 317(7160).September 12,

36 UKPDS Blood Pressure Control Study results favour ß-blocker:
但是在七個心血管相對風險因子的傾向而言 像是心肌梗塞,中風,整體死亡率等等 乙型阻斷劑對於糖尿病患者的好處,是與ACEI相當的 Adapted from:BMJ, Volume 317(7160).September 12,

37 UKPDS Study Intermittent claudication or cold feet 0 15 (4) <0.0001
Bronchospasm (6) <0.0001 雖然使用具有beta1選擇性的乙型阻斷劑對病患有好處 但是與ACEI相比較而言 乙型阻斷劑依然會有較多的副作用 而這些副作用剛剛有提到主要是beta2 receptor所調控 Adapted from:BMJ, Volume 317(7160).September 12,

38 UKPDS Blood Pressure Control Study implications
Before UKPDS After UKPDS management of blood pressure was not a high priority for type 2 diabetics first choice treatment ACE inhibitors management of blood pressure should have high priority in the treatment of type 2 diabetes first choice treatment ACE inhibitor or Beta-blocker 在UKPDS之前 有關血壓的控制並沒有受到重視 而主要的選擇藥品也是ACEI為主 而在UKPDS之後 對於糖尿病病患的血壓希望更嚴謹的控制 而選擇的藥品除了ACEI之外,乙型阻斷劑是另一個不錯的選擇

39 Treatment of Hypertension in 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. 例如2002年ADA的治療準則當中 對於糖尿病病患的起始治療藥品而言 就建議可以選用ACEI,ARB,利尿劑以及乙型阻斷劑 其中針對最近有發生過MI的病患 更是建議使用乙型阻斷劑以減少病患的死亡率 因此目前針對糖尿病高血壓患者而言, 合併Beta-blocker可將患者的血壓做更嚴謹的控制 降低更多心血管疾病的風險, 而具有beta1選擇性的beta-blocker, 更能有效減少相關的副作用以及對代謝的不良影響 使患者的接受程度更高 有關於beta-blocker之間beta1選擇性的比較 會在待會的第二部分跟各位醫師介紹 Adapted from:DIABETES CARE, VOLUME 25, NUMBER 1, JANUARY 2002

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

41 Randomised double-blind controlled study with two parallel groups
T I B B S Total 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 distribution of ischaemic episodes in patients with stable angina pectoris von Arnim Th et al. JACC 1995; 1: 231–230 TITLE: TIBBS - Total Ischaemic Burden Bisoprolol Study TEXT: The Total Ischaemic Burden Bisoprolol Study (TIBBS) enrolled 330 patients with stable angina pectoris, a positive exercise test and at least two transient ischaemic episodes during 48 h Holter monitoring from 30 centres in seven European countries. Study objectives were to evaluate the effects of bisoprolol once daily and nifedipine slow release (s.r.) twice daily on the occurrence and circadian distribution of ischaemic episodes in patients with stable angina pectoris. REF: von Arnim Th et al. JACC 1995; 1: 231–230

42 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 TITLE: TIBBS: Flow chart TEXT: TIBBS was a controlled study with two parallel groups. A placebo prephase of 10 days was followed by two treatment phases of 4 weeks each. Treatment during phase 1, i.e. the first 4 weeks, was initiated with either 10 mg bisoprolol once daily (with the additional administration of a placebo tablet in the evening) or 2 x 20 mg nifedipine s.r. Treatment during phase 2 was double the dose of phase 1 for each group, that is, 20 mg bisoprolol once daily or 2 x 40 mg nifedipine s.r. 48 h Holter monitoring was performed six to four days before randomization and after four and eight weeks of treatment. REF: von Arnim Th et al. JACC 1995; 1: 231–238 ETT episodes, Inclusion inclusion for for active prephase treatment 48 h Holter 48 h Holter 48 h Holter

43 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 TITLE: TIBBS: Number of ischaemic episodes at baseline, on low dose and on high dose TEXT: The number of ischaemic episodes was significantly reduced with both antianginal drugs in the low dosages (confidence intervals do not include zero). All reductions were significantly greater with bisoprolol than with nifedipine (p < ); the effects of bisoprolol were about twice those of nifedipine s.r. Doubling of the dosage in phase 2 had only marginal effects in both treatment groups. Therefore bisoprolol was superior to nifedipine s.r. in reducing the number of ischaemic episodes. REF: von Arnim Th et al. JACC 1995; 1: 231–238 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 BisoDIAS Endgültig

44 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 TITLE: TIBBS: Duration of ischaemic episodes at baseline, on low dose and on high dose TEXT: There was a significant reduction in the total duration of transient ischaemic episodes with bisoprolol and nifedipine s.r. The response was much more marked with bisoprolol. The difference between the two treatment groups in the low dosages was statistically significant (p < ). The additional effects of doubling the dose of either drug were small. REF: von Arnim Th et al. JACC 1995; 1: 231–238 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 BisoDIAS Endgültig

45 TIBBS: Total ischaemic burden at baseline, on low dose and on high dose
min. x mm 250 200 150 100 von Arnim Th et al. JACC 1995; 1: 231–238 TITLE: TIBBS: Total ischaemic burden at baseline, on low dose and on high dose TEXT: The total ischaemic burden was reduced in both treatment groups. Again the reduction with bisoprolol was significantly greater than with nifedipine s.r. with a p-value < at the lower dosages. Doubling the dose again had only small additive effects. Therefore bisoprolol was superior to nifedipine s.r. in reducing total ischaemic burden. REF: von Arnim Th et al. JACC 1995; 1: 231–238 50 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 BisoDIAS Endgültig

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

47 Continue to surprise us
Beta-Blockers: Continue to surprise us From Contraindication to Indication Heart Failure 除了糖尿病高血壓之外 Beta-blocker在心衰竭的治療所扮演的角色的轉變, 是近幾年來相當令人驚奇的一項轉變 由於beta-blocker本身具有negative inotropic的效果 因此對於cardiac output較低的心衰竭患者 會被認為具有不良的影響,在過去會被視為是絕對的禁忌症 但在近幾年來,同樣的由於相關大型試驗的發表 發現對於心衰竭的患者而言,如果適當,適量的合併beta-blocker治療 反而能有效減少心衰竭患者的死亡率以及降低相關心血管疾病的發生 接下來就針對於beta-blocker對於心衰竭患者的好處 以及bisoprolol所執行過的CIBIS II試驗跟各位醫師報告 對於心衰竭的龐大醫療成本支出,也能有效的減少

48 Compensatory mechanisms in CHF
The organism responds to the reduced cardiac output situation in CHF by a number of compensatory mechanisms to maintain cardiac output Frank-Starling mechanism (CO) Raised sympathetic-nervous activity Renin-angiotensin-aldosterone system Enhanced exploitation of blood oxygen in the peripheral 在CHF的初期 由於CO的下降 使的交感及RAA system的活性上升 CO的增加及體液的滯留的確可以滿足全身的血流不足 但在末期由於心跳速率加快使的每次LVEF下降且心肌的纖維化 代償機制再如何的強化仍舊無法回覆原先的血量 這時 惡性循環就開始了 血流不足 代償活化 仍舊不足 再繼續活化 反而會加速心臟衰竭的可能 如果這時介入一個beta blocker 阻斷掉惡性循環 雖然病人維持在一個偏低的血流量 卻不會繼續惡化下去 TAIWAN TANABE

49 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

50 -blockers 應用於治療CHF的理論基礎

51 -blockers 應用於治療CHF的理論基礎

52 CIBIS II -beneficial concomitant therapy in CHF
Publication:The Lancet 1999; 353:9-13 有關於beta-blocker對於心衰竭病人的好處已經有相關的臨床試驗證實 但是對於能否有效降低病人死亡率以及罹病率 並沒有相關的探討 針對這樣的觀念 Concor執行了 CIBIS 2 這一個大型的臨床試驗 CIBIS 2 於1999年發表在Lancet 是第一個以beta blocker對CHF患者的罹病率及死亡率的影響作為first endpoint的試驗 因試驗結果顯著而提前結束 接下來是針對這樣的觀念所執行的一個大型臨床試驗 TAIWAN TANABE

53 CIBIS II Cardiac 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) The Cardiac Insufficiency Bisoprolol Study II (CIBIS II)1 was the first double-blind placebo-controlled randomised trial in congestive heart failure (CHF) to show a significant beneficial effect of beta-blockade on total mortality. CIBIS II followed on logically from CIBIS,2 the first placebo-controlled study to evaluate the impact of the beta-1selective agent bisoprolol in patients with CHF. In CIBIS, there was a trend towards 20% lower mortality in the bisoprolol group after two years of treatment, but this did not reach statistical significance. However, CIBIS did show a significant reduction of 32% in hospital admissions for worsening heart failure, together with a significant improvement in functional status. In addition, meta-analyses of small or medium-sized randomized controlled trials also suggested that beta-blockade reduced all-cause mortality of about a third. CIBIS II followed logically from these encouraging results. On the basis of the annual mortality rate of 11.2% in the placebo group in CIBIS I, it was calculated that a sample size of about 2500 patients would be enough to demonstrate a clinically and statistically significant effect on mortality of about 25%. CIBIS II therefore included 2647 symptomatic ambulatory patients in NYHA class III or IV (ejection fraction <35%). Patients were recruited from 274 hospitals in 18 European countries. Importantly, all patients were required to be stable on standard treatment with ACE inhibitors and diuretics. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9-13. CIBIS Investigators and Committees. A randomized trial of ß-blockade in heart failure: the Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation 1994; 90: 1765 – 73. CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13

54 CIBIS II Objectives Primary objective All-cause mortality
Secondary objectives Cardiovascular mortality Hospital admissions Cardiovascular mortality or cardiovascular hospital admissions Permanent treatment withdrawal The primary endpoint of CIBIS II was effect on all-cause mortality. Secondary objectives included effects on cardiovascular mortality, hospital admissions, cardiovascular mortality or cardiovascular hospital admissions, and premature permanent treatment withdrawal. CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13

55 Main inclusion criteria
CIBIS II Main inclusion criteria Ambulatory patients with stable CHF of all aetiologies NYHA functional class III or IV Stable on ACE inhibitor and diuretic Aged 18 – 80 years Left ventricular ejection fraction - 35% To be included in CIBIS II, patients had be ambulatory, have symptomatic heart failure (NYHA Class III or IV), have a left ventricular ejection fraction of < 35%, and be aged years. They also had to be stable on existing heart failure treatment with ACE inhibitors and diuretics. CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13

56 CIBIS II Dose titration
Bisoprolol dose (mg) 10.00 7.50 5.00 The study drugs were up-titrated gradually according to tolerability. Patients were started on bisoprolol 1.25 mg (n= 1327) or placebo (n=1320) daily, the drug being increased successively to 2.50 mg, 3.75 mg, 5.00 mg, 7.50 mg, and mg, according to tolerance. Patients received the first three concentrations of each dose for 1 week, and the higher concentrations for 4 weeks. Investigators were asked to ensure that the highest tolerated dose was reached and maintained, if possible, for the duration of the trial. In contrast to earlier trials on carvedilol, there was no run-in period, and the assessment of clinical efficacy was not thereby confused by the exclusion of patients intolerant to the beta-blocker. The most common dose of bisoprolol during the maintenance phase was 10.0 mg (reached in 564 patients); 152 reached 7.5 mg and 176 reached 5.0 mg. CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13 3.75 2.50 1.25 W1 W2 W3 W4 W5 W6 W7 W8 W9 W10 W11 W12 W13 W14 W15 W16 Week No run-in period Dose increased according to tolerability

57 CIBIS II Characteristics (I)
Placebo Bisoprolol (n=1320) (n=1327) Demographic data Mean (range) age (years) 61 (22–80) 61 (26–80) Sex (M/F) 1062 (80%) 1070 (81%) 258 (20%) 257 (19%) NYHA class III 1096 (83%) 1106 (83%) IV (17%) (17%) Heart failure Documented ischaemic heart disease 654 (50%) 662 (50%) Primary dilated cardiomyopathy 157 (12%) 160 (12%) Others* 509 (40%) 505 (38%) Mean (SD) LV ejection fraction (5.5%) 27.5 (6.0%) *Coronary angiography unavailable or no history of myocardial infarction The baseline characteristics of the bisoprolol and placebo groups were similar. Most patients (approximately 80%) were male, with a mean age of 61 years. Most (83%) were in NYHA Class III at baseline, with 17% classified as stable NYHA Class IV (i.e. at the lower end of the NYHA Class IV range of severity). The commonest cause of CHF, accounting for half of all cases, was ischaemic heart disease. To classify for this aetiological group, a stenosis of 70% or more of at least one important coronary artery seen on angiography or a confirmed history of myocardial infarction (MI) was required. In 12% of cases CHF was due to primary dilated cardiomyopathy (normal coronary arteries on angiography). In the remaining cases the causes of CHF included valvular heart disease or hypertension, together with those with suspected but unproved ischaemic heart disease or cardiomyopathy (coronary angiography unavailable or no history of MI). The mean left ventricular ejection fraction at baseline was about 27.5%. CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13

58 CIBIS II Characteristics (II)
Placebo Bisoprolol (n=1320) (n=1327) Concomitant medication Diuretic 1310 (99%) 1305 (98%) ACE inhibitor 1274 (96%) 1273 (96%) Dihydropyridine-type calcium antagonist 23 (2%) 23 (2%) Use of concomitant medications was similar in the two treatment groups at baseline. Nearly all patients in CIBIS II were receiving a diuretic and an ACE inhibitor. Other commonly used medications were nitrates, digoxin, amiodarone, antiplatelet agents, and anticoagulants. Only 2% of patients were receiving dihydropyridine-type calcium antagonists. CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13 Nitrate 762 (58%) 773 (58%) Digoxin 670 (51%) 697 (53%) Amiodarone 206 (16%) 185 (14%) Anticoagulant 413 (31%) 399 (30%) Antiplatelet agent 558 (42%) 537 (40%)

59 CIBIS II Survival 34% reduction in all-cause mortality with bisoprolol
1.0 Bisoprolol: 156 deaths(11.8%) (n = 1327) Placebo: 228 deaths(17.3%) (n = 1320) log rank test, p < 0.8 Survival At the second interim analysis, the study was stopped on the advice of the Advisory and Safety Committee, because a significant difference in total mortality of p< had been observed. Patients were therefore followed up for a mean of 1.3 years. In the bisoprolol group, 156 (11.8%) patients died, compared with 228 (17.3%) in the placebo group (p<0.0001), amounting to a mortality reduction of 34%. The estimated annual mortality rate was 8.8% in the bisoprolol group and 13.2% in the placebo group. The magnitude of the mortality reduction seen in CIBIS II is consistent with meta-analyses of previous randomized placebo-controlled trials, and with the subsequent MERIT-HF study on metoprolol1 (34% reduction in mortality) and the COPERNICUS study on carvedilol2 (35% reduction in mortality). MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353: Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344(22): CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13 0.6 200 400 600 800 Time after inclusion (days) 34% reduction in all-cause mortality with bisoprolol

60 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 48 4% 49 4% There were significantly fewer cardiovascular deaths among patients on bisoprolol than among those on placebo (p=0.0049). Sudden death (within one hour of symptoms without previous worsening of heart failure symptoms) was reduced by 44% (p=0.0011), and there were non-significantly fewer deaths related to pump failure. The strikingly lower frequency of sudden deaths among patients receiving bisoprolol in CIBIS II suggests an important antiarrhythmic effect. Rates of deaths classified as due to MI, other cardiovascular causes or non-cardiovascular causes were not statistically significantly different between groups, although numbers were small. Strikingly, however, there was a significant reduction in deaths due to unknown causes (23 in the bisoprolol group compared with 49 in the placebo group, p=0.0012), and it has to be assumed that many of these deaths were in fact from cardiovascular causes. Due to the strict definitions in CIBIS II for sudden deaths or those associated with pump failure, many deaths had, therefore, to be classified as being of unknown cause. Unwitnessed or insufficiently documented deaths classified as unknown were probably sudden and some associated with pump failure. 47 4% CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13 40 p=0.58 36 3% 28 2% p=0.41 20 23 2% 23 2% p=0.75 18 1% 14 1% 7 1% 8 1% 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)

61 CIBIS II Main 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) To summarize, in CIBIS II, bisoprolol-treated patients showed a significant: 34% reduction in all-cause mortality (independent of aetiology) (p<0.0001) 44% reduction in sudden death (p<0.0011) 20% reduction in all-cause hospital admissions (p<0.0006) 36% reduction in hospital admissions due to worsening heart failure (p<0.0001). CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13

62 CIBIS II Conclusions CIBIS II successfully demonstrated that ß1-selective bisoprolol – given in addition to standard therapy – reduces significantly all-cause mortality and all-cause hospitalisation in CHF patients. Bisoprolol is the first ß-blocker which has proven its efficacy in a single large-scale CHF study with all-cause mortality as primary objective. Bisoprolol was as well tolerated as placebo with a premature permanent treatment withdrawal rate of 15% in both groups. In conclusion, when given in addition to standard therapy with diuretics and ACE inhibitors, beta-blockade with bisoprolol significantly reduces all-cause mortality and all-cause hospitalisation in patients with CHF. Bisoprolol is the first beta-blocker to have proven its efficacy in a single large-scale CHF study with all-cause mortality as the primary objective. Bisoprolol was as well tolerated as placebo with a permanent treatment withdrawal rate of 15% in both groups. As a result of CIBIS II and other large mortality studies on beta-blockade in CHF (MERIT-HF and COPERNICUS) the latest European guidelines1 clearly state that bisoprolol, metoprolol or carvedilol are now recommended for the treatment of all patients with stable, mild, moderate and severe heart failure and reduced left ventricular ejection fraction. Furthermore, they stipulate that, unless contra-indicated, all patients in NYHA classes II to IV should receive a beta-blocker as first-line therapy, in addition to standard treatment. 1. Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22(17): CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13

63 另外在後續針對CIBIS II當中,法國,德國以及英國參與試驗的患者
比較合併bisoprolol治療之後,患者整體的醫療花費 發現有合併bisoprolol治療的患者,即使每日的藥費有些微的增加 但是對於整體像是住院的醫療照護,併發症的醫療成本等等 反而能夠有效的降低5~10% 也就是說合併beta-blocker治療心衰竭,除了減少相關心血管事件以及死亡率之外 還可以減少整體的醫療成本, 因此目前針對beta-blocker應用在心衰竭而言, 依然是相當熱門的議題

64 ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult
Drug Initial Dose Maximum Dose β-receptor blockers Bisoprolol mg once daily mg once daily Carvedilol mg twice daily mg twice daily; 50mg twice daily for patients more than 85 kg Metoprolol tartrate mg twice daily mg twice daily Metoprolol succinate Extended release to 25 mg daily 目前針對心衰竭治療有發表大型臨床試驗 而且證明可減少患者死亡率的beta-blocker 除了bisoprolol之外,還有像是carvedilol以及metoprolol 如果要合併beta-blocker治療心衰竭的患者 必須患者的症狀穩定,而且已經接受像是ACEI或是Diuretic治療之後 再從低劑量的beta-blocker開始合併治療 起始劑量大概是一般治療劑量的1/4開始 例如bisoprolol對於高血壓以及狹心症的患者 治療劑量是5~10mg 應用在合併治療心衰竭而言,則是從1.25mg QD的低劑量開始 之後可參考CIBIS II當中劑量調整的流程 以及患者的情況做適當的調整 最大劑量是一天10mg QD

65 Major Trials of b-Blockade in Heart Failure
LVEF Target /Mean dose Mortality Sudden Death NYHA (mg/day) US Carvedilol < /45 mg 65% † 52% † mo II-IV carvedilol (P=.0001) (P<.05) CIBIS-II < /7.5 mg 34% 44% y III-IV bisoprolol (P<.0001) (P<.0011) MERIT-HF < /159 mg 34% 41% y II-IV metoprolol XL (P=.0062) (P=.002) BEST < /152 mg 10% 12% y III-IV bucindolol NS NS COPERNICUS < / 37 mg 35% NA mo IV carvedilol (P=.0014) †Not a planned endpoint.

66 Effect of b-Blockade on All-Cause Mortality
CIBIS-I: 1.9 years placebo 67/321 (20%); bisoprolol 53/320 (16%) P=.22 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 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 * Not a planned endpoint.

67 CIBIS III Cardiac Insufficiency Bisoprolol Study
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)

68 Chronic heart failure:
CIBIS III Background Chronic heart failure: still a major clinical and public health problem current pharmacological therapy: ACE-inhibitors Beta-blockers Diuretics Digitalis glycosides Aldosterone antagonists Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001; 22:

69 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: /CIRCULATIONAHA

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

71 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: /CIRCULATIONAHA

72 CIBIS III Primary objectives
First primary objective: Initiation of monotherapy with bisoprololol followed by the addition of enalapril (combination therapy) is comparable (non-inferior) to initiation with enalapril in CHF patients in preventing all-cause death and hospitalisation (combined endpoint) at end of study Second primary objective (if first primary objective is met): Initiation of monotherapy with bisoprolol is superior to initiation with enalapril in CHF patients (combined endpoint) at end of study

73 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 100 Bisoprolol-first 90 Enalapril-first 80 B/E vs E/B 163 vs 165 pts HR 0.97 (95% CI ) non-inferiority P=0.046 70 3% risk reduction 60 50 503 498 356 353 265 259 80 73 Numbers at risk months 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 ) non-inferiority P=0.019 70 60 50 Numbers at risk 505 389 388 291 277 87 76 DOI: /CIRCULATIONAHA months 6 12 18

74 All-cause hospitalization throughout study (ITT)
% without hospitalization Bisoprolol-first Enalapril-first 100 90 80 70 B/E vs E/B 151 vs 157 pts hospitalized HR 0.95 (95% CI ) P=0.66 (difference) 60 5% risk reduction 50 6 12 18 months Numbers at risk 505 386 289 85 505 387 277 76 DOI: /CIRCULATIONAHA

75 All cause mortality throughout study (ITT)
% survival Bisoprolol-first Enalapril-first 100 95 90 85 B/E vs E/B 65 vs 73 deaths HR 0.88 (95% CI ) P=0.44 (difference) 80 12% risk reduction 75 months 6 12 18 Numbers at risk 505 475 379 117 505 470 368 125 DOI: /CIRCULATIONAHA

76 Primary endpoint at end of monotherapy (ITT) (all cause mortality and all cause hospitalization)
% without endpoint Bisoprolol-first Enalapril-first 100 95 90 B/E vs E/B 109 vs 108 pts HR 1.02 (95% CI ) P=0.90 (difference) 85 2% risk increase 80 months 1 2 3 4 5 6 Numbers at risk 505 469 434 414 400 383 195 505 473 437 410 396 376 213 DOI: /CIRCULATIONAHA

77 Conclusions (1) In terms of combined mortality / hospitalization
Bisoprolol-first was non-inferior to enalapril-first in the ITT sample Bisoprolol-first was close to non-inferior to enalapril-first in the PP sample DOI: /CIRCULATIONAHA

78 Conclusions (2) There was no difference in safety between the two strategies, showing that a bisoprolol-first strategy does not cause concerns DOI: /CIRCULATIONAHA

79 Thoughts for the future
Bisoprolol-first might increase survival in the early phase of treatment, allowing a greater number of patients to subsequently benefit from combined β-blocker + ACEi. The bisoprolol-first strategy could be further improved with greater experience of up-titration of the β-blocker-first, leading to less worsening of CHF. This should be further examined. DOI: /CIRCULATIONAHA

80 Clinical implication The CIBIS III result supports a free choice
of initial treatment for CHF - enalapril or bisoprolol - based on the physician’s individual judgment in each patient DOI: /CIRCULATIONAHA

81 Put into clinical practice
CHF specific logo dosage easy to identify from all sides dose specific color code 有關於由於Concor 5mg心型錠劑 比較難以剝1/4錠來合併治療心衰竭的患者 台田藥品已經有申請Concor 1.25mg的上市 事實上在國外也是有針對於心衰竭此一適應症上市不同劑量的Concor 相信引進Concor 1.25mg之後 可以幫助國內心衰竭的患者減少相關的心血管併發症以及降低國內的醫療成本

82 Bisoprolol Hypertension Angina CHF β1:β2= 75:1 Non-ISA NHI price:
Concor 5 = NT 7.6 β1:β2= 75:1 Bisoprolol Balance Clearance Non-ISA CIBIS Ⅱ CIBISIII TIBBS DECREASE 除了剛剛所提及的特點 Concor具有更多的好處 這裡作一個整理來提供給各位參考當作是今天報告的結尾 Bisoprolol是目前具有最高beta1選擇性的beta-blocker 可以減少許多的副作用使患者的生活品質更高 而本身因為是屬於non-ISA的beta-blocker 針對缺血性心臟疾病,像是angina,MI等具有相當良好的療效 而目前也執行過許多大型臨床試驗 像是CIBIS2,TIBBS,DECREASE等等,均證實了concor對高血壓,狹心症甚至是心衰竭良好的療效以及安全性 而肝腎平衡清除率的效果 再針對輕度到中度,肝臟或是腎臟功能不良的患者 處方更方便也更加安全 在一項針對老年性高血壓的臨床試驗當中證實 Concor的T/P RATIO高達71%, QD的使用之下 具有更穩定的治療效果 目前每日健保價格也僅需要9元 可以說是相當具有藥品經濟性的藥品之一 以上的特點提供給各位醫師作參考 TAIWAN TANABE

83 Concor wins your heart!! Thanks for your coming! 最後很感謝各位來參加有關乙型阻斷劑的介紹
不知道各位對於今天所介紹的內容是否有疑問或是其他的command呢? Concor wins your heart!! TAIWAN TANABE


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