达比加群临床用药建议参考幻灯片.ppt

1、达比加群酯用于非瓣膜病心房颤动患者 卒中预防的临床应用建议,1,RE-LY研究,达比加群酯概述,达比加群酯的临床应用,特殊人群的临床应用,常见问题的处理,小结,2,3,抗凝血药作用机制,利伐沙班 Rivaroxaban,抗凝血酶,华法林通过抑制维生素K依赖性凝血因子、的活化达到抗凝的目的。,达比加群Dabigatran,华法林,3,4,达比加群：全新的直接凝血酶抑制剂,达比加群为全新的直接凝血酶抑制剂（DTI）,以浓度依赖的方式特异性阻断凝血酶(游离型或血栓结合型)活性而发挥强效抗血栓作用. 这是继华法林之后50年来上市的首个新型口服抗凝血药物，具有里程碑意义,4,5,5,与给药剂量呈正比增高

2、的Cmax 和AUC提示： 在较宽的剂量范围内保持线性药代动力学特征,Stangier J. Clin Pharmacokinet 2008:47:28595,AUC = 药时曲线下面积; CrCl = 肌酐清除率 Cmax = 最高浓度; ss = 稳态 pVTE = 原发性静脉血栓栓塞,达比加群：药代动力学可预测,5,6,Stangier J. Clin Pharmacokinet 2008;47:28595,迅速吸收(2小时内达到Cmax ) 食物可使 Cmax 延后2 小时 手术可使 Cmax 延后4小时,Cmax = 最高浓度,在12名健康男性中给予单剂150mg,达比加群酯正处于临

3、床研发过程中，其在房颤患者卒中预防的临床应用尚未获得注册批准,达比加群：口服迅速吸收,6,达比加群在患者体内迅速起效,7,活化部分凝血激酶时间（aPTT）的时间曲线与达比加群血浆药时曲线平行，提示在迅速起效,Stangier J. Clin Pharmacokinet 2008;47:28595,达比加群酯正处于临床研发过程中，其在房颤患者卒中预防的临床应用尚未获得注册批准,7,8,Stangier J et al. Br J Clin Pharmacol 2007;64:292303,aPPT = 活化部分凝血激酶时间; ECT = 蝰蛇毒凝血时间; INR = 国际标准化比率; PD =

4、药效学; PK = 药代动力学; TT = 凝血酶凝血时间,达比加群血浆浓度 (ng/mL),活化部分凝血激酶时间（aPPT） 随着达比加群的药物浓度增加而延长,达比加群：药物浓度与药效密切相关,8,9,国际标准化比率(INR)、活化部分组织凝血活酶时间 (aPTT)、凝血酶凝血时间(TT)和蝰蛇毒凝血时间(ECT) (比率)的时间曲线与达比加群血浆浓度时间曲线保持平行,Stangier J et al. Br J Clin Pharmacol 2007;64:292303,几何均数 (n=6) 200 mg 达比加群酯,达比加群药效评估： 血浆浓度与凝血指标平行,9,达比加群PK/PD特点总

5、结,线性药代动力学（PK）特征，药效可预测 口服给药起效迅速，不依赖P450细胞色素酶 药物浓度和临床抗凝效果具有密切联系 药物间相互作用小，且无具有临床意义的药物食物相互作用 均衡的疗效与安全性，无需进行抗凝监测 在原发性VTE预防方面，有效性和安全性等同于依诺肝素 药物过量/严重出血有抗凝逆转策略,10,PD = 药效学; PK = 药代动力学; VTE =静脉血栓栓塞,10,RE-LY研究,达比加群酯概述,达比加群酯的临床应用,特殊人群的临床应用,常见问题的处理,小结,11,*存在严重心瓣膜疾病，筛查前14天内曾发生卒中或6个月内发生严重卒中，出血风险升高的疾病，肌酐清除率30 mL/m

6、in, 活动性肝病和妊娠； BID = 一天2次; INR = 国际标准化比率 Ezekowitz MD et al. Am Heart J 2009;157:80510; Connolly SJ et al. N Engl J Med 2009;361:11395,RE-LY试验: 研究设计,主要目标: 明确达比加群的疗效不劣于华法林 中位随访2年：最短1年，最长3年,伴1个危险因子的房颤患者 不存在禁忌症*,达比加群酯 110 mg BID,华法林 1 mg, 3 mg, 5 mg (INR 2.03.0),达比加群酯 150 mg BID,确诊的房颤伴至少一项： 1.既往卒中TIA或全身

7、栓塞 2. LVEF40%以下 3.症状性心衰NYHA2级 4.年龄75岁以上 5.75岁以下且以下至少一项糖尿病、高血压、冠心病,12,卒中或全身性栓塞的发生率,BID =一日两次; NI =非劣; RR =相对风险; RRR =相对风险的降低; Sup = 优势 Connolly SJ et al. N Engl J Med 2010;363:18756,13,RR 0.65 (95% CI: 0.520.81),1.54,1.11,1.71,P2 or Owren PT INR1.5, over-dosing or accumulation of dabigatran should be

8、 considered. These results are indicative of a concentration of dabigatran 600 g/L, based on data from the PETRO trial less than1% of the patients on 150 mg bid would have Cmax 600 g/L,50,RELY Asian subgroup analysis,Dabigatran Versus Warfarin Effects on Ischemic and Hemorrhagic Strokes and Bleeding

9、 in Asians and Non-Asians With Atrial Fibrillation,Masatsugu Hori. Stroke. 2013;44:1891-1896.,51,Baseline Demographic Characteristics of Asian and Non-Asian Patients,52,The effects of dabigatran against stroke and SE are similar in Asian and non-Asian patients for both doses of dabigatran compared w

10、ith warfarin. Although Asian patients on warfarin had considerably more time below therapeutic range and were younger, there was a trend for more bleeding in Asian than in non-Asian patients. Dabigatran reduced the risk of bleeding outcomes more in Asians than in non-Asians.,stroke,Bleeding,53,Pharm

11、acokinetics and pharmacodynamics in Japanese and Caucasian subjects after oral administration of dabigatran etexilate,Hartter et al. Thromb Haemost 2012; 107: 260269,54,Dabigatran 150 mg twice-daily has been approved in the US, Canada, Europe and Japan for prevention of stroke in patients with AF A

12、dose of 220 mg once-daily is approved for the prevention of VTE after hip or knee arthroplasty in more than 75 countries. There is no need for any dose adjustment in different ethnic groups,55,The effect of dabigatran on the activated partial thromboplastin time and thrombin time as determined by th

13、e HTI assay in patient plasma samples,Hapgood et al. Thromb Haemost 2013; 110: 308315,56,The modest correlation between the aPTT and dabigatran levels that is lost at higher levels (i.e. 300 ng/ml) The TT was too sensitive to quantify dabigatran levels. Excessive TT while plasma dabigatran levels are b