终-新型口服抗凝药的研究进展
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）术后需服用抗血小板药物
• 比较了华法林联合氯吡格雷（二联治疗）与华法林联合氯
吡格雷、阿司匹林（三联治疗）的安全性；
• 主要终点为PCI术后1年内任何出血事件（分别按TIMI标准
、GUSTO标准和BARC标准评定），次要终点为死亡、心肌梗 死、靶血管血运重建、卒中、支架血栓。
Lancet, 2013, 381:1107-1115
Oldgren J.. Eur Heart J. 2011, 32: 2781-2789.
APPRAISE-R2iskTFarcitoarsl • Age ≥65 years
• Diabetes mellitus
Recent (≤7days) Acute Coronary Syndrome • Prior MI within 5 years (STEMI or NS•TEC-eAreCbSro) vascular disease At Least 2 Additiona• lPReirsipkh-Feraacltvoarsscular disease
Slide by C. Michael Gibson, M.S., M.D.
N Engl J Med 2011; 365:699-708
Slide by C. Michael Gibson, M.S., M.D.
N Engl J Med 2011; 365:699-708
APPRAISE 2: Primary Outcome
CV Death, MI, Ischemic Stroke
Apixaban
279 (7.5%)
Placebo
15
10
HR 0.80 P=0.0003
5
HR 0.77 P=0.0001
Clopidogrel
12.1 (781)
9.9 (643)
Prasugrel
HR 0.81 (0.73-0.90) P=0.0004 NNT= 46
0 0 30 60 90
Slide by C. Michael Gibson, M.S., M.D.
Thrombin Generation in ACS
• Maximum thrombin levels are higher in samples from patients with ACS, initiation phase of
thrombin generation shorter
300
Acute Coronary
WOEST研究
• What is the Optimal antiplatElet and anticoagu-
lant therapy in patients with oral anticoagulation and coronary StenTing (WOEST)
• 服用抗凝药物的冠心病患者行经皮冠状动脉介入治疗（PCI
p-value 0.001 <0.001 <0.001 <0.001 0.001 0.030
Fatal bleeding: Apixaban = 5 vs. Placebo = 0
ISTH major bleeding = bleeding leading to death, occurring in a critical location, or associated with a ≥2 g/dL drop in hemoglobin or transfusion of 2 or more units of PRBC.
征或置入药物洗脱支架患者服用氯吡格雷至少1年。
• 结果显示，二联组出血事件54例（19.4%），明显低于三联组
的126例（44.4%，HR 0.36，95% CI 0.26-0.50，P＜0.001 ）。多发性出血事件二联组仅有6例（2.2%），而三联组为34 例（12.0%）；二联组需接受输血治疗11例（3.9%），而三联 组为27例（9.5%，P =0.011）。两组的次要终点校正后分析 结果相似（11.1% vs17.6%，P ＞0.05）。二联组支架血栓4 例（1.4%），三联为9例（3.2%），差异无统计学意义（ P =0.165）。
ITT= 13,608
LTFU = 14 (0.1%)
180
270
360
450
Days Wiviott SD et al. NEJM 2007;357:2001-2015
Positive Feedback Loop: Thrombin Begets Platelet Activation Which Begets Thrombin
• 93% power to detect a 20% risk reduction at a one-sided α of 0.025 Analysis: time PtorifmirasrtyeOveunttco(smtrea:tiCfiVedD: esainthg,leMvI,sI.sdcuhaelmainctSiptlraotkeelet therapy) Key subgroups: single / dSuaafleatny:tiTpIlMatIeMleat jtohreBralepey,drinevgascularized / not revascularized
N=10,800
• Aspirin • Other antiplatelet therapy
Randomiz•eC1l:i1nical heart failure or LV EF <40% Double b•linRdenal dysfunction (CrCl <60 mL/min)
• No revascularization for ACS event
Persistent Elevation of Thrombin Generation in Post-ACS Patients
F 1.2 nmol/L
Slide by C. Michael Gibson, M.S., M.D.
Merlini et al. Circ 1994;90:61-68
Meta Analysis of Warfarin in ACS: Efficacy
250
Syndromes n=28
Thrombin (nM)
200
Coronwk.baidu.comry
Artery
150
Disease
n=25
100
Control
50
0
0
200
400
600
800
1000
1200
Time (seconds)
Slide by C. Michael Gibson, M.S., M.D.
Adapted from Brummel-Ziedins K, et al. J Thromb Haem 2008;6: 104–110
WOEST研究
Lancet, 2013, 381:1107-1115
WOEST研究
• 入选573例患者随机分入二联组（n =284）和三联组（n =289
），最后进入分析的患者有563例（二联组 n =279，三联 组 n =284），约65%的患者置入药物洗脱支架。
• 置入裸金属支架后服用氯吡格雷至少1个月，而急性冠脉综合
Lancet, 2013, 381:1107-1115
问题
• 既往口服抗凝剂的患者抗凝的策略？ • ACS抗凝的策略？ • 房颤＋PCI患者抗凝的策略？ • DVT、PE抗凝的策略？
Residual Risk of CV Death, MI, Stroke
Primary Endpoint (%)
Thrombin Generation
“Amplification” “Burst”
“Activation”
Slide by C. Michael Gibson, M.S., M.D.
Platelet Activation
ACS: Platelet Resistance to Clopidogrel Declines Over Time
一般情况
口服抗凝药
维生素K拮抗剂
新型口服抗凝药
华法林
达比加群 利伐沙班 阿哌沙班
ACS
房颤＋PCI
房颤
ATLAS
PIONEER
ROCKET-AF
DVT/PE EINSTEIN
RE-DEEM II
• RE-DEEM II期临床试验入选1861例ACS患者，在双联抗
血小板治疗的基础上，随机加用达比加群酯（剂量 50mg-150mg不等）或安慰剂治疗，随访6个月。结果显 示，达比加群酯组D-二聚体水平（反映凝血负荷）较 安慰剂组有明显下降，但心血管死亡、心梗及脑卒中 的复合终点无明显下降，相反达比加群酯组主要或非 主要的临床相关出血事件，呈剂量依赖性升高，分别 为安慰剂组的1.8倍（50mg）和4.3倍（150mg）。
293 (7.9%)
HR 0.95; 95% CI 0.80-1.11; p=0.509
Slide by C. Michael Gibson, M.S., M.D.
N Engl J Med 2011; 365:699-708
APPRAISE 2: Bleeding
TIMI major
TIMI major or minor
= 15%
14 Resistance
0
<= -30 (-20,-10] (0,10] (20,30] (40,50] >60 (-30,-20] (-10,0] (10,20] (30,40] (50,60]
Aggregation (%)
Gurbel et al. Circulation. 2003;107: 2908-2913
口服抗凝药物的临床应用
——当AF遇上STENT 蒋萍
一般情况
口服抗凝药
维生素K拮抗剂
新型口服抗凝药
华法林
达比加群 利伐沙班 阿哌沙班
ACS
房颤＋PCI
房颤
ATLAS
PIONEER
ROCKET-AF
DVT/PE EINSTEIN
问题
• 既往口服抗凝剂的患者抗凝的策略？ • ACS抗凝的策略？ • 房颤＋PCI患者抗凝的策略？ • DVT、PE抗凝的策略？
ISTH major ISTH major or clinically relevant non-major GUSTO severe Intracranial
Apixaban N=3705
1.3 2.2 2.7
3.2
1.0 0.3
Placebo N=3687
0.5 0.8
1.1
1.2
0.3 0.1
2 Hours
Resistance 24
Resistance = 63%
12
0
<= -30 (-20,-10] (0,10] (20,30] (40,50] >60 (-30,-20] (-10,0] (10,20] (30,40] (50,60]
Aggregation (%)
5 Days
Resistance
Projected evAepnitxraabtea:n8%5 m/ ygeaBr,IDmedian f/u 1.25 years Event driveCnrC: l9<3480 pmal/tmieinnt2s.5wmitghBthIDe primary outcomePlacebo
• 80% power to detect a 20% risk reduction at a one-sided α of 0.005
20 Resistance
Resistance = 31%
10
0
<= -30 (-20,-10] (0,10] (20,30] (40,50]
>60
(-30,-20] (-10,0] (10,20] (30,40] (50,60]
Aggregation (%)
30 Days
28
Resistance
22
Resistance = 31%
11
% of Patients
0
<= -10
(0,10]
(20,30]
(40,50]
>60
(-10,0]
(10,20]
(30,40]
(50,60]
Aggregation (%)
Slide by C. Michael Gibson, M.S., M.D.
24 Hours
Recurrent MI
Slide by C. Michael Gibson, M.S., M.D.
Rothberg et al., Ann Int Med 2005;143:241-250
思考
• ACS的抗凝治疗是有效的。 • 停用了静脉抗凝药物后，还需要加用口服抗凝药吗？ • 选用那种口服抗凝药？
• 比较了华法林联合氯吡格雷（二联治疗）与华法林联合氯
吡格雷、阿司匹林（三联治疗）的安全性；
• 主要终点为PCI术后1年内任何出血事件（分别按TIMI标准
、GUSTO标准和BARC标准评定），次要终点为死亡、心肌梗 死、靶血管血运重建、卒中、支架血栓。
Lancet, 2013, 381:1107-1115
Oldgren J.. Eur Heart J. 2011, 32: 2781-2789.
APPRAISE-R2iskTFarcitoarsl • Age ≥65 years
• Diabetes mellitus
Recent (≤7days) Acute Coronary Syndrome • Prior MI within 5 years (STEMI or NS•TEC-eAreCbSro) vascular disease At Least 2 Additiona• lPReirsipkh-Feraacltvoarsscular disease
Slide by C. Michael Gibson, M.S., M.D.
N Engl J Med 2011; 365:699-708
Slide by C. Michael Gibson, M.S., M.D.
N Engl J Med 2011; 365:699-708
APPRAISE 2: Primary Outcome
CV Death, MI, Ischemic Stroke
Apixaban
279 (7.5%)
Placebo
15
10
HR 0.80 P=0.0003
5
HR 0.77 P=0.0001
Clopidogrel
12.1 (781)
9.9 (643)
Prasugrel
HR 0.81 (0.73-0.90) P=0.0004 NNT= 46
0 0 30 60 90
Slide by C. Michael Gibson, M.S., M.D.
Thrombin Generation in ACS
• Maximum thrombin levels are higher in samples from patients with ACS, initiation phase of
thrombin generation shorter
300
Acute Coronary
WOEST研究
• What is the Optimal antiplatElet and anticoagu-
lant therapy in patients with oral anticoagulation and coronary StenTing (WOEST)
• 服用抗凝药物的冠心病患者行经皮冠状动脉介入治疗（PCI
p-value 0.001 <0.001 <0.001 <0.001 0.001 0.030
Fatal bleeding: Apixaban = 5 vs. Placebo = 0
ISTH major bleeding = bleeding leading to death, occurring in a critical location, or associated with a ≥2 g/dL drop in hemoglobin or transfusion of 2 or more units of PRBC.
征或置入药物洗脱支架患者服用氯吡格雷至少1年。
• 结果显示，二联组出血事件54例（19.4%），明显低于三联组
的126例（44.4%，HR 0.36，95% CI 0.26-0.50，P＜0.001 ）。多发性出血事件二联组仅有6例（2.2%），而三联组为34 例（12.0%）；二联组需接受输血治疗11例（3.9%），而三联 组为27例（9.5%，P =0.011）。两组的次要终点校正后分析 结果相似（11.1% vs17.6%，P ＞0.05）。二联组支架血栓4 例（1.4%），三联为9例（3.2%），差异无统计学意义（ P =0.165）。
ITT= 13,608
LTFU = 14 (0.1%)
180
270
360
450
Days Wiviott SD et al. NEJM 2007;357:2001-2015
Positive Feedback Loop: Thrombin Begets Platelet Activation Which Begets Thrombin
• 93% power to detect a 20% risk reduction at a one-sided α of 0.025 Analysis: time PtorifmirasrtyeOveunttco(smtrea:tiCfiVedD: esainthg,leMvI,sI.sdcuhaelmainctSiptlraotkeelet therapy) Key subgroups: single / dSuaafleatny:tiTpIlMatIeMleat jtohreBralepey,drinevgascularized / not revascularized
N=10,800
• Aspirin • Other antiplatelet therapy
Randomiz•eC1l:i1nical heart failure or LV EF <40% Double b•linRdenal dysfunction (CrCl <60 mL/min)
• No revascularization for ACS event
Persistent Elevation of Thrombin Generation in Post-ACS Patients
F 1.2 nmol/L
Slide by C. Michael Gibson, M.S., M.D.
Merlini et al. Circ 1994;90:61-68
Meta Analysis of Warfarin in ACS: Efficacy
250
Syndromes n=28
Thrombin (nM)
200
Coronwk.baidu.comry
Artery
150
Disease
n=25
100
Control
50
0
0
200
400
600
800
1000
1200
Time (seconds)
Slide by C. Michael Gibson, M.S., M.D.
Adapted from Brummel-Ziedins K, et al. J Thromb Haem 2008;6: 104–110
WOEST研究
Lancet, 2013, 381:1107-1115
WOEST研究
• 入选573例患者随机分入二联组（n =284）和三联组（n =289
），最后进入分析的患者有563例（二联组 n =279，三联 组 n =284），约65%的患者置入药物洗脱支架。
• 置入裸金属支架后服用氯吡格雷至少1个月，而急性冠脉综合
Lancet, 2013, 381:1107-1115
问题
• 既往口服抗凝剂的患者抗凝的策略？ • ACS抗凝的策略？ • 房颤＋PCI患者抗凝的策略？ • DVT、PE抗凝的策略？
Residual Risk of CV Death, MI, Stroke
Primary Endpoint (%)
Thrombin Generation
“Amplification” “Burst”
“Activation”
Slide by C. Michael Gibson, M.S., M.D.
Platelet Activation
ACS: Platelet Resistance to Clopidogrel Declines Over Time
一般情况
口服抗凝药
维生素K拮抗剂
新型口服抗凝药
华法林
达比加群 利伐沙班 阿哌沙班
ACS
房颤＋PCI
房颤
ATLAS
PIONEER
ROCKET-AF
DVT/PE EINSTEIN
RE-DEEM II
• RE-DEEM II期临床试验入选1861例ACS患者，在双联抗
血小板治疗的基础上，随机加用达比加群酯（剂量 50mg-150mg不等）或安慰剂治疗，随访6个月。结果显 示，达比加群酯组D-二聚体水平（反映凝血负荷）较 安慰剂组有明显下降，但心血管死亡、心梗及脑卒中 的复合终点无明显下降，相反达比加群酯组主要或非 主要的临床相关出血事件，呈剂量依赖性升高，分别 为安慰剂组的1.8倍（50mg）和4.3倍（150mg）。
293 (7.9%)
HR 0.95; 95% CI 0.80-1.11; p=0.509
Slide by C. Michael Gibson, M.S., M.D.
N Engl J Med 2011; 365:699-708
APPRAISE 2: Bleeding
TIMI major
TIMI major or minor
= 15%
14 Resistance
0
<= -30 (-20,-10] (0,10] (20,30] (40,50] >60 (-30,-20] (-10,0] (10,20] (30,40] (50,60]
Aggregation (%)
Gurbel et al. Circulation. 2003;107: 2908-2913
口服抗凝药物的临床应用
——当AF遇上STENT 蒋萍
一般情况
口服抗凝药
维生素K拮抗剂
新型口服抗凝药
华法林
达比加群 利伐沙班 阿哌沙班
ACS
房颤＋PCI
房颤
ATLAS
PIONEER
ROCKET-AF
DVT/PE EINSTEIN
问题
• 既往口服抗凝剂的患者抗凝的策略？ • ACS抗凝的策略？ • 房颤＋PCI患者抗凝的策略？ • DVT、PE抗凝的策略？
ISTH major ISTH major or clinically relevant non-major GUSTO severe Intracranial
Apixaban N=3705
1.3 2.2 2.7
3.2
1.0 0.3
Placebo N=3687
0.5 0.8
1.1
1.2
0.3 0.1
2 Hours
Resistance 24
Resistance = 63%
12
0
<= -30 (-20,-10] (0,10] (20,30] (40,50] >60 (-30,-20] (-10,0] (10,20] (30,40] (50,60]
Aggregation (%)
5 Days
Resistance
Projected evAepnitxraabtea:n8%5 m/ ygeaBr,IDmedian f/u 1.25 years Event driveCnrC: l9<3480 pmal/tmieinnt2s.5wmitghBthIDe primary outcomePlacebo
• 80% power to detect a 20% risk reduction at a one-sided α of 0.005
20 Resistance
Resistance = 31%
10
0
<= -30 (-20,-10] (0,10] (20,30] (40,50]
>60
(-30,-20] (-10,0] (10,20] (30,40] (50,60]
Aggregation (%)
30 Days
28
Resistance
22
Resistance = 31%
11
% of Patients
0
<= -10
(0,10]
(20,30]
(40,50]
>60
(-10,0]
(10,20]
(30,40]
(50,60]
Aggregation (%)
Slide by C. Michael Gibson, M.S., M.D.
24 Hours
Recurrent MI
Slide by C. Michael Gibson, M.S., M.D.
Rothberg et al., Ann Int Med 2005;143:241-250
思考
• ACS的抗凝治疗是有效的。 • 停用了静脉抗凝药物后，还需要加用口服抗凝药吗？ • 选用那种口服抗凝药？