房颤新型抗凝药物临床应用和评价专家讲座

房颤新型抗凝药品临床

应用与评价吴书林广东省心血管病研究所广东省人民医院房颤新型抗凝药物临床应用和评价第1页ESC指南主要更新

关于非瓣膜病房颤血栓栓塞危险分层继续沿用了CHADS2评分提出了新CHA2DS2-VASc评分提出了主要危险原因和临床相关非主要危险原因概念CHA2DS2-VASc评分主要用于补充CHADS2评分中1分（中危)分层房颤新型抗凝药物临床应用和评价第2页危险原因评分充血性心衰/左室功效不全1高血压1年纪≥75岁2糖尿病1卒中/TIA/血栓栓塞2血管疾病1年纪65－74岁1性别（女性）1总分9ESC指南主要更新

血栓风险评分更新——CHA2DS2-VASc评分新增原CHADS2

评分标准为1分总分从CHADS2

中6分增加到9分房颤新型抗凝药物临床应用和评价第3页CHA2DS2VASC积分与中风相关性%/yearCHA2DS2-VASc0-1634234083536544378525666118574518-9125NoofpatientsStrokeandsystemicembolism0123456SingerDE,etal.:AnnInternMed.151,297-305,房颤新型抗凝药物临床应用和评价第4页CHA2DS2-VASc积分与出血发生率Major(includingintracranial)bleedingCHA2DS2-VASc0-1634234083536544378525666118574518-9125Noofpatients012345678%/yearMajorIntracranialSingerDE,etal.:AnnInternMed.151,297-305,房颤新型抗凝药物临床应用和评价第5页一项主要危险原因或多于两项非主要危险原因口服抗凝药(华法林)评分≥2评分=1一项非主要危险原因口服抗凝药或阿司匹林.推荐:口服抗凝药.评分=0没有危险原因阿司匹林或不抗凝.推荐:不抗凝IBIAIBIAIIaBIIaBESC指南主要更新

确定了基于CHA2DS2-VASc评分系统抗凝策略房颤新型抗凝药物临床应用和评价第6页当前主要抗凝药品及作用路径房颤新型抗凝药物临床应用和评价第7页华法林有效预防血栓栓塞并发症02468AFASAK58%

7–

81SPAF67%

27–

85BAATAF86%

51–

96CAFA42%

-

68–

80SPINAF79%

52–

90TOTAL68%

50–79StrokeIncidence(%)p<0.03p<0.01p<0.02p>0.2p<0.002p<0.001ControlsWarfarin房颤新型抗凝药物临床应用和评价第8页华法林应用不足服药后起效和停药后消失速度都很慢个体药品剂量反应差异大易与各种食物和药品发生相互作用治疗窗窄有出血危险性（1-3%/每年)因为INR监测“不方便”，服用率低（50-60%－－国外)房颤新型抗凝药物临床应用和评价第9页INR统计卡:提醒INR波动大房颤新型抗凝药物临床应用和评价第10页理想抗凝药品?有效预防血栓栓塞事件出血风险低固定剂量口服生物利用度好不需常规监测可逆性快速起效与食物和药品相互作用少药品过量时有反抗药品房颤新型抗凝药物临床应用和评价第11页当前主要抗凝药品及作用路径房颤新型抗凝药物临床应用和评价第12页当前主要新型抗凝药品及相关Ⅲ期临床试验药品作用路径Ⅲ期临床试验对照组研究设计研究例数研究进展Dabiga-tran凝血酶抑制剂RELYWarfarinNon-inferiority18500完成Apixa-banXa因子拮抗剂AVERROESARISTOTLEAspirinWarfarinSuperiorityNon-inferiority560018000完成Rivaro-xabanXa因子拮抗剂ROCKE-AFWarfarinNon-inferiority14269完成Edoxa-banXa因子拮抗剂ENGAGEWarfarinNon-inferiority16500进行中房颤新型抗凝药物临床应用和评价第13页达比加群（Dabigatran)前体药品（达比加群酯)，在体内转化为含有直接抗凝血活性达比加群生物利用率为6.5%，半衰期为12-17小时，经肾脏排泄率为80%临床应用中不需要严密剂量监控即使活化部分凝血酶原时间不宜用于准确量化达比加群血浆浓度，但在紧急情况可用于判断是否抗凝过分房颤新型抗凝药物临床应用和评价第14页RE-LY:ANon-inferiorityTrialAtrialfibrillation≥1RiskFactorAbsenceofcontra-indications951centersin44countriesRWarfarinadjusted(INR2.0-3.0)N=6000DabigatranEtexilate110mgBIDN=6000DabigatranEtexilate150mgBIDN=6000BlindedEventAdjudication.OpenBlinded房颤新型抗凝药物临床应用和评价第15页BaselineCharacteristicsCharacteristicDabigatran110mgDabigatran150mgWarfarinRandomized601560766022Meanage(years)71.471.571.6Male(%)64.363.263.3CHADS2score(mean)0-1(%)2(%)3+(%)2.132.634.732.72.232.235.232.62.130.937.032.1Priorstroke/TIA(%)19.920.319.8PriorMI(%)16.816.916.1CHF(%)32.231.831.9BaselineASA(%)40.038.740.6WarfarinNaïve(%)49.949.851.4房颤新型抗凝药物临床应用和评价第16页StrokeorSystemicEmbolismWarfarinbetterDabigatranbetter房颤新型抗凝药物临床应用和评价第17页Ischemic/UnspecifiedStrokeD110mgvs.WarfarinD150mgvs.WarfarinRR=1.1195%CI=0.89-1.40P=0.35RR=0.7695%CI=0.60-0.98P=0.03YearsofFollow-upCumulativeHazardRates0.00.020.040.060.0800.51.01.52.02.5Dabigatran110Dabigatran150Warfarin房颤新型抗凝药物临床应用和评价第18页HemorrhagicStrokeD110mgvs.WarfarinD150mgvs.WarfarinRR=0.3195%CI=0.17-0.56P<0.001RR=0.2695%CI=0.14-0.49P<0.001YearsofFollow-upCumulativeHazardRates0.00.010.020.030.0400.51.01.52.02.5Dabigatran110Dabigatran150Warfarin房颤新型抗凝药物临床应用和评价第19页MI,DeathandNetclinicalBenefitD110mgD150mgwarfarinD110mgvs.WarfarinD150mgvs.WarfarinAnnualrateAnnualrateAnnualrateRR95%CIpRR95%CIpMI0.7%0.7%0.5%1.350.98-1.870.071.381.00-1.910.048Death3.8%3.6%4.1%0.910.80-1.030.130.880.77-1.000.05NetClinicalBenefit7.1%6.9%7.6%0.920.84-1.020.100.910.82-1.000.04NetClinicalBenefitincludesvascularevents,deathandmajorbleed房颤新型抗凝药物临床应用和评价第20页Dabigatran150mgvs.110mgDabigatran110mgDabigatran150mgD150mgvs.D110mgNumberrate/yrNumberrate/yrRelativeRisk95%CIpStrokeandsystemicembolism1.5%1.1%0.730.58-0.910.005Hemorrhagicstroke0.1%0.1%0.850.39-1.830.67MajorHemorrhage2.7%3.1%1.161.00-1.340.05NetClinicalBenefit7.1%6.9%0.980.89-1.080.66*NetClinicalBenefitincludesvascularevents,deathandmajorbleed房颤新型抗凝药物临床应用和评价第21页Adverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupAdverseeventsoccurringin>5%ofanygroupCommonAdverseEvents*Occurredmorecommonlyondabigatranp<0.001房颤新型抗凝药物临床应用和评价第22页指南对达比加群推荐ACCF指南提议含有卒中或系统性栓塞危险原因房颤患者，且未植入人工心脏瓣膜或无影响血流动力学瓣膜病，无严重肾功效不全（肌酐去除率<15mL/min)或严重肝脏疾病（影响基线状态凝血功效)，达比加群能够做为华法林替换治疗预防卒中和系统性栓塞（I，B)。服用华法林INR控制良好患者换用达比加群受益有限达比加群组发生心力衰竭百分比高于华法林组(0.7%vs0.5%，P=0.048),有统计学意义，而比较低剂量组（P=0.07)则无统计学意义。所以，在心力衰竭病人应慎用房颤新型抗凝药物临床应用和评价第23页ESC指南达比加群两种剂型被同意用于房颤患者脑卒中预防，需考虑卒中和出血危险分层假如需应用口服抗凝药，达比加群可考虑做为华法林替换治疗（1)假如患者出血危险低，鉴于达比加群150mg日两次预防卒中和系统性栓塞有效性高，可考虑应用（2)假如患者出血风险高，鉴于达比加群110mg日两次预防血栓栓塞事件一样有效而颅内出血和严重出血发生率较低对于只有一项临床相关非主要卒中危险原因，可考虑应用达比加群110mg日两次房颤新型抗凝药物临床应用和评价第24页利伐沙班（Rivaroxaban)利伐沙班生物利用度为80%血浆半衰期7-11小时2/3经肝脏代谢，1/3经肾脏排泄房颤新型抗凝药物临床应用和评价第25页房颤新型抗凝药物临床应用和评价第26页主要疗效终点:脑卒中或非中枢神经性全身栓塞主要安全性终点:大出血或临床相关非大出血事件房颤患者随机双盲/双模拟(n~14,000)依据标准治疗指南，每个月进行监测利伐沙班20mg一日一次肌酐去除率30-49ml/min者15mg华法林INR目标值-2.5(2.0-3.0)ROCKETAF

-研究设计*所入选病人中,只有2种风险原因而且既往无脑卒中、TIA或全身栓塞病史患者占总体10％危险原因

CHF

高血压年纪75

糖尿病或脑卒中,TIA或

系统性栓塞最少需要2或3项*房颤新型抗凝药物临床应用和评价第27页28of26主要疗效终点

-脑卒中及非CNS栓塞事件发生率为每100患者-年基于‘治疗人群中符合方案治疗病例’存在风险患者数:利伐沙班组

69586211578654684406340724721496634华法林组

70046327591155424461347825391538655华法林组HR(95%CI):0.79(0.66,0.96)P-值非劣效性:<0.001随机分组后天数累积事件发生率(%)利伐沙班组利伐沙班组华法林组事件发生率1.712.16房颤新型抗凝药物临床应用和评价第28页关键次要疗效终点利伐沙班组华法林组事件发生率事件发生率HR(95%CI)P-value血管性死亡,

脑卒中,栓塞3.113.630.86(0.74,0.99)0.034脑卒中类型

出血性

缺血性

未知

0.26

1.34

0.06

0.44

1.42

0.10

0.59(0.37,0.93)

0.94(0.75,1.17)

0.65(0.25,1.67)

0.024

0.581

0.366非CNS栓塞0.040.190.23(0.09,0.61)0.003心梗0.911.120.81(0.63,1.06)0.121全因死亡

血管相关

非血管相关

未知原因1.87

1.53

0.19

0.152.21

1.71

0.30

0.200.85(0.70,1.02)

0.89(0.73,1.10)

0.63(0.36,1.08)

0.75(0.40,1.41)0.073

0.289

0.094

0.370房颤新型抗凝药物临床应用和评价第29页主要安全性终点利伐沙班组华法林组事件发生率事件发生率HR

(95%CI)P-值大出血及临床相关非大出血事件14.9114.521.03(0.96,1.11)0.442大出血事件3.603.451.04(0.90,1.20)0.576临床相关非大出血事件11.8011.371.04(0.96,1.13)0.345房颤新型抗凝药物临床应用和评价第30页不良事件及肝酶监测数据利伐沙班组(%)N=7111华法林组(%)N=7125全部不良事件全部严重不良事件造成研究药品中止不良事件82.437.315.782.238.215.2鼻衄外周水肿眩晕鼻咽炎心衰支气管炎呼吸困难腹泻10.16.16.15.95.65.65.35.38.66.26.36.45.95.95.55.6ALT升高

>3xULN>5xULN>3xULN及TBili>2xULN2.91.00.42.91.00.5房颤新型抗凝药物临床应用和评价第31页ROCKET-AF小结疗效:在预防脑卒中及非CNS栓塞方面,利伐沙班疗效不劣于华法林凡是服用研究药品患者中,利伐沙班疗效都优于华法林在ITT人群中,结果趋势相同,但未到达优效性安全性:出血和不良事件发生率相近利伐沙班组ICH、主要器官出血及致死性出血更少结论:利伐沙班耐受性良好,一日一次,治疗期间疗效更加好,且出血情况有所改进,已被证实可作为华法林替换药品房颤新型抗凝药物临床应用和评价第32页ROCKET-AF入选人群，包含了亚洲人群13%，亚太地域入选人群占15%所入选病人中，按照CHADS2