非瓣膜性房颤患者脑卒中危险因素分析及血栓前状态干预研究
|
摘要
目的:本研究通过联合反映血栓前状态(PTS)的凝血分子标志物、临床及超声指标进行多因素分析,评估非瓣膜性房颤(NVAF)患者血栓栓塞风险的危险因素。并比较抗凝和联合抗血小板(阿司匹林+氯吡格雷)治疗对血栓前状态的干预。
对象和方法:将符合入选标准的,且未服用华法林及抗血小板药物或至少停服2周以上的66例NVAF患者分为两组:脑卒中组(26例)和非脑卒中组(40例);另选20例无房颤的器质性心脏病患者为对照组。ELISA法测定所有患者血浆可溶性P-选择素(GMP-140)、血管性血友病因子(vWF)、D-dimer (D-D)含量,并行生化全套、心超检查,对结果进行多因素分析。66例NVAF患者中的40例,分为两组分别予以抗凝和联合抗血小板干预。
结果:(1)房颤卒中组、非卒中组和对照组在性别构成、房颤病程、基本病因(高血压、冠心病、扩心病、肺心病)上无明显差别,卒中组年龄、糖尿病患病率(74.5±9.7岁;19.2%)高于非卒中组(68.3±8.8岁;12.5%,P<0.05)。(2)卒中组左房内径大于非卒中组和对照组(51.36±6.54mm VS 46.15±6.23mm VS 36.92±8.98mm,P<0.05)。卒中组总胆固醇、LDL-C、收缩压高于非卒中组。凝血状态血浆标志物GMP-140、vWF、D-D水平在卒中组均高于非卒中组和对照组(GMP-140:20.94±5.81ng/ml VS 15.67±4.08ng/ml VS 9.28±5.37 ng/ml;vWF:226.65±44.96% VS 193.67±45.35% VS 150.70±23.23%;D-D 1.81±3.46 mg/l VS 0.72±0.73 mg/l VS 0.22±0.27 mg/l,P<0.05)。(3)NVAF患者血栓栓塞的独立危险因素为:年龄(P=0.033),左房内径增大(P=0.025),GMP-140(P=0.030),D-D(P=0.004)浓度增高。其中D-D浓度增高的相对危险度(OR=4.296 95%CI 0.697～6.465)大于年龄(OR=1.003 95%CI 0.923～1.090)、左房内径增大(OR=1.019 95%CI 0.861～1.204)和GMP-140(OR=1.208 95%CI 0.939～1.552)。根据这四个独立危险因素建立的回归模型对本实验NVAF患者脑卒中的发生有一定预测准确率(83.3%)。(4)ROC曲线显示,D-D曲线下面积(AUC) 0.856(95%CI 0.742-0.971),GMP-140 AUC 0.800(95%CI 0.666-0.934),均>0.7,P<0.01,对脑卒中有较高预测价值;年龄和左房内径AUC分别为0.685(95%CI 0.410-0.076)和0.647(95%CI 0.482-0.812),有一定预测价值。(5)NVAF患者抗凝干预组(调整剂量华法林组)及联合抗血小板干预组(阿司匹林+氯吡格雷组)治疗前GMP-140、vWF、D-D分别为16.83±5.64ng/ml、190.78±45.35%、0.71±0.86mg/l及15.95±3.81ng/ml、193.71±38.74%、0.75±0.71mg/l,两组间无明显差异,治疗后浓度分别下降为10.78±2.16 ng/ml、147.11±72.59%、0.24±0.23mg/l及10.28±2.75 ng/ml、137.05±47.64%、0.25±0.21mg/l,与治疗前相比均有明显改善(P<0.05)。
结论:1.单因素分析显示年龄、糖尿病、收缩压增高、总胆固醇和LDL-C升高,左房内径增大、GMP-140、vWF及D-D浓度增高是持续性非瓣膜性房颤脑卒中危险因素;2.多因素分析显示脑卒中的独立危险因素是:高龄、左房内径增大、GMP-140及D-D浓度增高。且D-D浓度增高的评估价值优于其他因素;3.基于独立危险因素的回归方程对本试验NVAF患者卒中风险有一定预测准确率4.联合抗血小板治疗和抗凝治疗都能改善非瓣膜性房颤患者血栓前状态,但长期疗效有待进一步观察。
Objective: This study is to make a multivariate analysis for risk of thromboembolism in nonvaluvlar atrial fibrillation(NVAF) patients , by combining several sensentive thrombus molecular markers,clinical and echocardiographic factors,then compare anticoagulation therapy with double-antiplatelet therapy for intervention of prethrombotic state.
Methods:66 NVAF patients that never received anticoagulation or antiplatelet therapy or have stopped in recent two weeks,were divided into two groups:ischemic stroke group(n=26) and non-ischemic stroke group(n=40). 20 patients with heart disease but in sinus rhythm were selected as control. The plasma GMP-140,vWF,D-D levels were determined by ELISA to all subjects,and so were chemical check and echocardiography.In the end, the multivariate anlysis was made for the results.Then 40 patients from 66 NVAF cases were divided into two randomised groups to give anticoagulation therapy and double antiplatelet therapy respectively. The plasma GMP-140,vWF,D-D levels were determined before and after therapy.
Results: (1) There was no significant difference in gender,AF duration and associated diseases(hypertention,coronary heart disease,dilated cardiomyopathy and pulmonary heart disease)among three groups;The age and ratio of diabete disease of stroke group(74.5±9.7,19.2%) were higher than non-ischemic group(68.3±8.8,12.5%,P<0.05). (2) The left atrial dimension(LAD) of stroke group(51.36±6.5mm)was greatly larger than the latter groups(46.15±6.23mm,36.92±8.98mm,P<0.05).Total cholesterol(TC),low density lipoprotein cholesterol(LDL-C),systolic blood pressure(SBP) of stroke group were higher than non-ischemic group.In the thrombus molecular markers,the plasma levels of GMP-140,vWF,D-D in stroke group were higher than the latter groups(GMP-140:20.94±5.81ng/ml VS 15.67±4.08ng/ml VS 9.28±5.37 ng/ml;vWF:226.65±44.96% VS 193.67±45.35% VS 150.70±23.23%;D-D 1.81±3.46 mg/l VS 0.72±0.73 mg/l VS 0.22±0.27 mg/l , P<0.05). (3) The age(P=0.033) , increase of LAD(P=0.025) ,GMP-140(P=0.030) and D-D(P=0.004) were independently assosicated with thromboembolism;the related risk degree of increase of D-D(OR=4.296 95%CI 0.697～6.465) was greater than age(OR=1.003 95%CI 0.923～1.090), LAD(OR=1.019 95%CI 0.861～1.204) and GMP-140(OR=1.208 95%CI 0.939～1.552).The regression modle based on these four independent factors predicted the occurrence of stroke in NVAF patients to some degrees,with predicted accurate ratio being 83.3%. (4) ROC Curve showed that Area Under the Curve(AUC) of D-D was 0.856(95%CI 0.742-0.971),and GMP-140 was 0.800(95%CI 0.666-0.934),all larger than 0.7,P<0.01,so D-D and GMP-140 had higher predicted value.The AUC of age and LAD were 0.685(95%CI 0.410-0.076),0.647(95%CI 0.482-0.812),so these index had pedicted value to some extent. (5) In dose-adjusted warfarin anticoagulation group and dual antiplatelet group, the levels of GMP-140, vWF and D-D (16.83±5.64ng/ml, 190.78±45.35%,0.71±0.86mg/l VS 15.95±3.81ng/ml,193.71±38.745,0.75±0.71mg/l respectively,P<0.05), significantly descended to 10.78±2.16 ng/ml,147.11±72.59%,0.24±0.23mg/l VS 10.28±2.75 ng/ml,137.05±47.64%,0.25±0.21mg/l after therapy.
Conclusions: 1. The single risk factor analysis in NVAF patients shows that: age, diabetes,increase of SBP,TC,LDL-C,LAD,GMP-140,vWF and D-D are risk factors.2. Increase of age,LAD,GMP-140 and D-D are independent risk factors for stroke. Moreover,the assessment value of increase of D-D is higher than others.The regression modle can predict the occurrence of stroke to some extent.3. The anticoagulation therapy and dual antiplatelet therapy all can improve PTS in NVAF patients,but the long term effect should be observed.
对象和方法:将符合入选标准的,且未服用华法林及抗血小板药物或至少停服2周以上的66例NVAF患者分为两组:脑卒中组(26例)和非脑卒中组(40例);另选20例无房颤的器质性心脏病患者为对照组。ELISA法测定所有患者血浆可溶性P-选择素(GMP-140)、血管性血友病因子(vWF)、D-dimer (D-D)含量,并行生化全套、心超检查,对结果进行多因素分析。66例NVAF患者中的40例,分为两组分别予以抗凝和联合抗血小板干预。
结果:(1)房颤卒中组、非卒中组和对照组在性别构成、房颤病程、基本病因(高血压、冠心病、扩心病、肺心病)上无明显差别,卒中组年龄、糖尿病患病率(74.5±9.7岁;19.2%)高于非卒中组(68.3±8.8岁;12.5%,P<0.05)。(2)卒中组左房内径大于非卒中组和对照组(51.36±6.54mm VS 46.15±6.23mm VS 36.92±8.98mm,P<0.05)。卒中组总胆固醇、LDL-C、收缩压高于非卒中组。凝血状态血浆标志物GMP-140、vWF、D-D水平在卒中组均高于非卒中组和对照组(GMP-140:20.94±5.81ng/ml VS 15.67±4.08ng/ml VS 9.28±5.37 ng/ml;vWF:226.65±44.96% VS 193.67±45.35% VS 150.70±23.23%;D-D 1.81±3.46 mg/l VS 0.72±0.73 mg/l VS 0.22±0.27 mg/l,P<0.05)。(3)NVAF患者血栓栓塞的独立危险因素为:年龄(P=0.033),左房内径增大(P=0.025),GMP-140(P=0.030),D-D(P=0.004)浓度增高。其中D-D浓度增高的相对危险度(OR=4.296 95%CI 0.697～6.465)大于年龄(OR=1.003 95%CI 0.923～1.090)、左房内径增大(OR=1.019 95%CI 0.861～1.204)和GMP-140(OR=1.208 95%CI 0.939～1.552)。根据这四个独立危险因素建立的回归模型对本实验NVAF患者脑卒中的发生有一定预测准确率(83.3%)。(4)ROC曲线显示,D-D曲线下面积(AUC) 0.856(95%CI 0.742-0.971),GMP-140 AUC 0.800(95%CI 0.666-0.934),均>0.7,P<0.01,对脑卒中有较高预测价值;年龄和左房内径AUC分别为0.685(95%CI 0.410-0.076)和0.647(95%CI 0.482-0.812),有一定预测价值。(5)NVAF患者抗凝干预组(调整剂量华法林组)及联合抗血小板干预组(阿司匹林+氯吡格雷组)治疗前GMP-140、vWF、D-D分别为16.83±5.64ng/ml、190.78±45.35%、0.71±0.86mg/l及15.95±3.81ng/ml、193.71±38.74%、0.75±0.71mg/l,两组间无明显差异,治疗后浓度分别下降为10.78±2.16 ng/ml、147.11±72.59%、0.24±0.23mg/l及10.28±2.75 ng/ml、137.05±47.64%、0.25±0.21mg/l,与治疗前相比均有明显改善(P<0.05)。
结论:1.单因素分析显示年龄、糖尿病、收缩压增高、总胆固醇和LDL-C升高,左房内径增大、GMP-140、vWF及D-D浓度增高是持续性非瓣膜性房颤脑卒中危险因素;2.多因素分析显示脑卒中的独立危险因素是:高龄、左房内径增大、GMP-140及D-D浓度增高。且D-D浓度增高的评估价值优于其他因素;3.基于独立危险因素的回归方程对本试验NVAF患者卒中风险有一定预测准确率4.联合抗血小板治疗和抗凝治疗都能改善非瓣膜性房颤患者血栓前状态,但长期疗效有待进一步观察。
Objective: This study is to make a multivariate analysis for risk of thromboembolism in nonvaluvlar atrial fibrillation(NVAF) patients , by combining several sensentive thrombus molecular markers,clinical and echocardiographic factors,then compare anticoagulation therapy with double-antiplatelet therapy for intervention of prethrombotic state.
Methods:66 NVAF patients that never received anticoagulation or antiplatelet therapy or have stopped in recent two weeks,were divided into two groups:ischemic stroke group(n=26) and non-ischemic stroke group(n=40). 20 patients with heart disease but in sinus rhythm were selected as control. The plasma GMP-140,vWF,D-D levels were determined by ELISA to all subjects,and so were chemical check and echocardiography.In the end, the multivariate anlysis was made for the results.Then 40 patients from 66 NVAF cases were divided into two randomised groups to give anticoagulation therapy and double antiplatelet therapy respectively. The plasma GMP-140,vWF,D-D levels were determined before and after therapy.
Results: (1) There was no significant difference in gender,AF duration and associated diseases(hypertention,coronary heart disease,dilated cardiomyopathy and pulmonary heart disease)among three groups;The age and ratio of diabete disease of stroke group(74.5±9.7,19.2%) were higher than non-ischemic group(68.3±8.8,12.5%,P<0.05). (2) The left atrial dimension(LAD) of stroke group(51.36±6.5mm)was greatly larger than the latter groups(46.15±6.23mm,36.92±8.98mm,P<0.05).Total cholesterol(TC),low density lipoprotein cholesterol(LDL-C),systolic blood pressure(SBP) of stroke group were higher than non-ischemic group.In the thrombus molecular markers,the plasma levels of GMP-140,vWF,D-D in stroke group were higher than the latter groups(GMP-140:20.94±5.81ng/ml VS 15.67±4.08ng/ml VS 9.28±5.37 ng/ml;vWF:226.65±44.96% VS 193.67±45.35% VS 150.70±23.23%;D-D 1.81±3.46 mg/l VS 0.72±0.73 mg/l VS 0.22±0.27 mg/l , P<0.05). (3) The age(P=0.033) , increase of LAD(P=0.025) ,GMP-140(P=0.030) and D-D(P=0.004) were independently assosicated with thromboembolism;the related risk degree of increase of D-D(OR=4.296 95%CI 0.697～6.465) was greater than age(OR=1.003 95%CI 0.923～1.090), LAD(OR=1.019 95%CI 0.861～1.204) and GMP-140(OR=1.208 95%CI 0.939～1.552).The regression modle based on these four independent factors predicted the occurrence of stroke in NVAF patients to some degrees,with predicted accurate ratio being 83.3%. (4) ROC Curve showed that Area Under the Curve(AUC) of D-D was 0.856(95%CI 0.742-0.971),and GMP-140 was 0.800(95%CI 0.666-0.934),all larger than 0.7,P<0.01,so D-D and GMP-140 had higher predicted value.The AUC of age and LAD were 0.685(95%CI 0.410-0.076),0.647(95%CI 0.482-0.812),so these index had pedicted value to some extent. (5) In dose-adjusted warfarin anticoagulation group and dual antiplatelet group, the levels of GMP-140, vWF and D-D (16.83±5.64ng/ml, 190.78±45.35%,0.71±0.86mg/l VS 15.95±3.81ng/ml,193.71±38.745,0.75±0.71mg/l respectively,P<0.05), significantly descended to 10.78±2.16 ng/ml,147.11±72.59%,0.24±0.23mg/l VS 10.28±2.75 ng/ml,137.05±47.64%,0.25±0.21mg/l after therapy.
Conclusions: 1. The single risk factor analysis in NVAF patients shows that: age, diabetes,increase of SBP,TC,LDL-C,LAD,GMP-140,vWF and D-D are risk factors.2. Increase of age,LAD,GMP-140 and D-D are independent risk factors for stroke. Moreover,the assessment value of increase of D-D is higher than others.The regression modle can predict the occurrence of stroke to some extent.3. The anticoagulation therapy and dual antiplatelet therapy all can improve PTS in NVAF patients,but the long term effect should be observed.
引文
1. Schellinger PD, Juttler E, Meyding-Lamade UK,et al. The vavle of platelet inhibitors in the secondary prophylaxis of stroke——a review. Fortschr Neurol Psychiatr,2004;72(5):270-281.
2. Hankey GJ, Sudlow CL, Dunbabin DW. Thienopyridines or aspirin to prevent stroke and other serious vascular events in patients at high risk of vascular disease? A systematic review of the evidence form randomized trials.Strok,2000;31(7):177 9-1784.
3. Markus HS, Droste DW, Kaps M, et al.Dual antiplatelet threapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogerl and Aspirin for Reduction of Emboli in Symptomatic Cartoid Stenosis(CARESS) trial. Circulation, 2005;111(17):2233-40
4. Diener HC,Bogousslavsky J,Brass LM,et al. Aspirin and clopidogrel compared with clopidogreal alone after recent ischaemic attack in high-risk patients (MATCH): ranomised, double-blind, placebo-controlled trial. Lancet 2004; 364 (9431):331- 337.
5. Jeong JH. Prevalence of and risk factors for atrial fibrillation in Korean adults older than 40 years.J Korean Med Sci,2005; 20(1):26-30.
6. Asinger RW,Koehler J,Pearce LA,et al. Pathophysiologic correlates of thromboem -bolism in nonvalvularatrial fibrillation: Dense spontaneous echocardiographic contrast(The Stroke Prevention in Atrial fibrillation(SPAF2III) study).J Am Soc Echocardigor,1999; 12:1082-1096.
7. Wolf PA,Abbott RD,Kannel WB,et al. Atrial fibrillation as an independent risk factor for stroke:Framingham Study.Stroke,1991; 22:983-988.
8. Schmieder RE,Martus P,Klingbeil A,et al. Reversal of left ventricular hypertrop- hy in essential hypertension: a meta-analysis of randomized double-blind studies JAMA 1996; 275:1057-13.
9. Mondillo S,Sabatini L,Agricola E,et al. Correlation between left atrial size, prothrobombotic state and markers of endothelial dysfunction in patients with lone chronic nonrheumatic atrial fibrillation.Int J Cardiol,2000; 75(2-3):227-232.
10. Bauer KA,Rosenberg RD. The pathophysiology of the prethrombotic state in humas-in sights gained from studies using markers of hemosteatic system activation.Blood,1987; 70(2):343
11. 王振义.血栓前状态研究现状.中华血液学杂志,1991; 12(9):477-478.
12. Lip GY,Rumley A,Dunn FG,et al. Plasma fibrinogen and fibrin D-dimer in patients with atrial fibrillation: effects of cardioversion to sinus rhythm.Int J Cardiol 1995; 51:245-251.
13. Li-Saw-Hee FL,Blann AD,Gurney D,et a1.Plasma von willebrand factor,fibrinog- en and soluble P-selectin levels in paroxysmal,persistent and permanent atrial fibrillation. European Heart Journal,2001; 22:1741-1747.
14. Chen MC,Chang HW,Juang ss,et al. Increased plasma levels of soulble P-selection in rheumatic mitral stenosis.Chest,2004; 126(1):54-58.
15. Blann AD,Nadar SK,Lip GY. The adhesion molecule P-selection and cardiovascu- lar disease.Eur Heart J,2003; 24(24):2166-2179.
16. Pongratz G,Bradt-Pohlman M,henneke KH,et al. Platelet activation in embolic and preembolic ststus of patients with nonrheumatic atrial fibrillation.Circulation 2003; 134(3):622-625.
17. 高明东,孙根义.Von Willebrand 因子与血栓相关性疾病.天津医药,2002;30 (8):510-512.
18. Li-Saw-Hee FL, Blann AD, Lip GY. A cross-sectional and diumal study of thrombogenesis among patients with chronic atrial fibrillation. J Am Coll Cardiol, 2000; 35:1926-1931.
19. Lip GYH,Lowe GDO,Rumley A,et al. Increased markers of thrombogenesis in chronic atrial fibrillation:Effects of Warfrin treatemt.Br Heart J,1995; 73:527-523.
20. Mahe I,Drout L,Chassany O,et al. D-dimer:a characteristic of the coagulation state of each patient with chronic atrial fibrillation.Thromb Res,2002; 107(1-2):1-6.
21. Jafri SM, Msmmen E F, Masura S J, et al. Effects of warfarin on markers ofhypercoagulability in patients with heart faliure.Am Heart J,1997; 134(1):27-36.
22. Miklos Somloi,MD,Janos Tomcasanyi,MD,phD,Erzsebet N agy,MD,et al.D-dimer determination as a screening tool to exclude atrial thrombi in atrial fibrillation.The American Journal of Cardiology,2003; 92:85-87.
23. Nozawa T,Inoue H,Hirai T,et al.D-dimer level influences thromboembolic events in patients with atrial fibrillation.Int J Cardiol,2006; 109(1):59-61.
24. Enta K,Iwade K,Aosaki M,et al. Predictive value of coagulative molecular marker for thromboembolism in patients with nonvalvular atrial fibrillation:prosective five year follow-up study.J Cardiol,2004; 44(6):223-232.
25. Daniel WG. Should transesophageal echocardiography be used to guide cardiversion. N Engl J Med,1993; 328(11):803-804.
26. Eckman MH,Rosand J,Kundsen MA,et al. Can patients be anticoagulated after intracerebral hemorrhage? A decision analysis.Stroke,2003; 34(7):1710-1716.
27. 孙振球,徐勇勇.医学统计学.人民卫生出版社,北京 2003:258.
28. 洪楠,林爱军,侯军.统计产品和服务解决方案教程.清华大学出版社,北京, 1999:64-68.
29. Stefan HH,Stuart JC. Combined antiplatelet therapy in atrial fibrillation: Review of the leiterature and future research avenues. Cardiovasc Electrophysiol 2003; 14(Supp1): S60.
30. The bault JJ,Kiefer G,Lowe GD,et a1.Repeated dose pharma Codynamics of clopidogrelin healthy subjects.Semin Thromb Hemost,1999; 25(Suppl2):s9.
31. Denninger MH,Necciari J,Serre Lacroix E,et a1.Clopidogrel antiplatelet activity is independent of age and presence of atherosclerosis.Semin Thromb Hemost,1999; 25(Supp12):S41.
32. Dol F,Gaich C,Bemat A,et a1. Effect of clopidogrel on thrombin generation in the rat.Thromb Res,1992; 65(Suppl1): S160.
33. Diener HC, Lowenthal A . Antiplatelet therapy to prevent stroke: Risk brain hemorrhage and efficacy of aspirin.J Neurol Sci,1997; 153:112.
34. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial.Lancet2006; 367:1903-12.
35. Lorenzoni R,Lazzerini G,Cocci F,et al. Short-term prevention of thromboemblic: complications in patiens with atrial fibrillation with aspirin plus clopidogerl: the Clopidogrel-Aspirin Atrial Fibrillation(CLAAF) pilot study.Am Heart J,2004; 148 (1):e6.
1. Kannel WB,Wolf PA,Benjamin EJ,et al. Prevalence,incidence,prognosis, and predisposing conditions for atrial fibrillation:population-based estimates[J].Am J Cardiol,1998; 82:2NN.
2. Kannel WB,Abbott RD,Savage DD,et al. Epidemiologic features of chronic atrial fibrillation:The Framingham Study[J]. N Engl J atrial Med,1982; 306:1018.
3. Wolf PA ,Abbott RD ,Kannel WB ,et al. Atrial fibrillation as an independent risk factor for stroke : Framingham Study[J ]. Stroke ,1991; 22 :983-988.
4. 马长生,周玉杰,马煜,等. 中国人非瓣膜性心房颤动患者脑卒中发生率及影响因素的回顾性前瞻研究(摘要)[J]. 中国循环杂志,1999; 14(增刊):110.
5. Petersen P. Thromboembolic complications in atrial fibrillation [J].Stroke,1999; 21: 4-13.
6. Braunwald E. ed. Heart disease: a textbook of cardiovascular medicine [M]. 5thed. Beijing:science press,1999; 655.
7. Orsinelli DA. Current recommendations for the anticoagulation of patients with atrial fibrillation[J].Prog Cardiovasc Dis,1996; 39:1-20.
8. Jaber WA,Prior DL,Thamilarasan M,et al. Efficacy of anticoagulation in resolving left atrial and left atrial appendage thrombi:A transesophageal echocardiographic study[J].Am Heart J,2000; 140:150.
9. Igarashi Y,Kasai H,Yamashita F,et al. Lipoprotein(a),left atrial appendage fuction and thromboembolic risk in patients with chronic nonvalvular atrial fibrillation[J]. Jpn Circ J,2000; 64:93.
10. Shinohara H,Fukuda N,Soeki T,et al. Relationship between flow dynamics in the left atrium and hemostatic abnormalities in patients with nonvalvular atrial fibrillation [J].Jpn Heart J,1998; 39:721-730.
11. Blake IW. Spontaneous echo contrast: where there’s smoke there’s fire[J]. Echocardiography,2000; 17:373.
12. Igrarashi Y,Kasai H,Yamashita F,et al. Lipoprotein(a),left atrial appendage function and thromboembolic risk in patients with chronic nonvalvular atrial fibrillation[J].Jpn Circ J,2000; 64:93..
13. Minamino T,Kitakaze M,Asanuma H,et al. Plasma adenosine levels and plateletactivation in patients with atrial fibrillation [J].Am J Cardiol,1999; 83:194-198.
14. Pongratz G,Pohlmann BM,Henneke KH,et al. Platelet activation in embolic and preembolic status of patients with nonrheumatic atrial fibrillation[J].Chest,1997; 111:929-933.
15. Minamino T,Kitakaze M,Sanada S,et al. Increased expression of P-selection on platelets is a risk factor for silent cerebral infarction in patient with atrial fibrillation[J].Circulation,1998; 98:1721-1727.
16. Palabrica T,Lobb R,Furie BC,et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selection on adherent platelets[J].Nature,1992; 359:848-851.
17. Yamamoto K,Ikeda U,Fukazawa H,et al. Effects of asprin on status of thrombin generation in atrial fibrillation[J ].Am J Cardiol,1996; 77:528- 530.
18. Kaha SR,Solymoss S,Flegel KM. Nonvalvular atrial fibrillation:evidence for a prothrombotic state[J].Can Med Assoc J,1997; 157:673-681.
19. Lip GY,Lowe GD,Rumley A,et al. Increased markers of thrombogensis in chronic atrial fibrillation :effects of warfarin treatment [J].Br Heart J ,1995; 73:527-533.
20. Dietrich WD,Miller LP,Prado R,et al. Acadesine reduces indiumlabeled platelet deposition after photothrombosis of the common artery in rats [J].Stroke,1995;26: 111-116.
21. Stroke Prevention in Atrial Fibrillation Investigators. Risk factor for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data form five randomized controlled trials[J].Arch Intern Med,1994; 154:1449.
22. Morley J,Marinchak R,Rials SJ,et al. Atrial fibrillation,anticogulation, and stroke [J].Am J Cardiol,1996; 77:38A-44A.
23. Gregorg W,James E,Laupacis A. Antithrombotic therapy in atrial fibrillation[J]. Chest,2001; 119:194S-206S.
24. Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation : stroke prevention in atrial fibrillation II study[J].Lancet ,1994; 343:687.
25. Gallus AS,Baker RI,Chong BH,et al. Consensus guidelines for warfarin therapy. Recommendations form the Australasian society of thrombosis and haemostasis[J]. MJA,2000; 172:600.
26. Hylek EM,Skates SJ,Sheehan MA,et al.An analysis of the lowest effective intensi-ty of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation [J].N Engl J Med ,1996; 335:540.
27. Hellemons BS,LangenbergM,Lodder J,et al. Primary prevention of arterial throm- boemolism in non-rheumatic aterial fibrillation in primarcy:randomized controlled trial comparing two intrnsities of coumarin with aspirin [J].BMJ,1999; 319:958.
28. SPAF investigaters. Adjusted-dose warfarin versus low-intensity,fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke prevention in atrial fibrillation III randomised clinical trial [J].Lancet,1996; 348:633.
29. Koudstaal PJ . Antiplatelet therapy for preventing stroke in patients with nonrheunmatic atrial fibrillation and a history of stroke or transient ischemic attacks[J]. Cochrane Database Syst Rev,2000; (2):CD000186.
30. Dol F,Gaich C,Bemat A,et a1.Effect of clopidogrel on thrombin generation in the rat[J].Thromb Res ,1992; 65(Suppl 1):S160.
31. Schellinger PD,Juttle E,Meyding-Lamade UK,et al.The value of pletelet inhibitors in the secondary prophylaxis of stroke-review[J]. Fortschr Neurol Psychiatr,2004; 72(5):270-281.
32. Stefan HH,Stuart JC. Combined antiplatelet therapy in atrial fibrillation: Review of the leiterature and future research avenues. Cardiovasc Electrophysiol 2003; 14(Supp1): S60.
33. Diener HC , Lowenthal A. Antiplatelet therapy to prevent stroke: Risk brain hemorrhage and efficacy of aspirin.J Neurol Sci,1997; 153:112.
34. Lorenzoni R,Lazzerini G,Cocci F,et al. Short-term prevention of thromboemblic: complications in patiens with atrial fibrillation with aspirin plus clopidogerl: the Clopidogrel-Aspirin Atrial Fibrillation (CLAAF) pilot study.Am Heart J,2004; 14 8(1):e6.
35. Hart RG,Sherman DG,Easton JD,et al. Prevention of stroke in patients with non- valvular atrial fibrillation[J].Neurology,1998; 51:674-681.
36. Cox JL,Ad N,Palazzo T. Impact of the maze procedure on the stroke rate in patients with atrial fibrillation[J]. Thorac Cardiovasc Surg,1999; 118:833.
37. Falk RH,Podrid PJ. Atrial fibrillation mechanisms and management[M].2 nd ed.Maple Press ,1997; 277.
38. Hirsh J,Dalen JE ,Anderson D ,et al. Oral anticoagulants.Machanism of action,clinical effectiveness and optimal therapeutic range[J].Chest,1998;114 (Suppl):445s.
2. Hankey GJ, Sudlow CL, Dunbabin DW. Thienopyridines or aspirin to prevent stroke and other serious vascular events in patients at high risk of vascular disease? A systematic review of the evidence form randomized trials.Strok,2000;31(7):177 9-1784.
3. Markus HS, Droste DW, Kaps M, et al.Dual antiplatelet threapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogerl and Aspirin for Reduction of Emboli in Symptomatic Cartoid Stenosis(CARESS) trial. Circulation, 2005;111(17):2233-40
4. Diener HC,Bogousslavsky J,Brass LM,et al. Aspirin and clopidogrel compared with clopidogreal alone after recent ischaemic attack in high-risk patients (MATCH): ranomised, double-blind, placebo-controlled trial. Lancet 2004; 364 (9431):331- 337.
5. Jeong JH. Prevalence of and risk factors for atrial fibrillation in Korean adults older than 40 years.J Korean Med Sci,2005; 20(1):26-30.
6. Asinger RW,Koehler J,Pearce LA,et al. Pathophysiologic correlates of thromboem -bolism in nonvalvularatrial fibrillation: Dense spontaneous echocardiographic contrast(The Stroke Prevention in Atrial fibrillation(SPAF2III) study).J Am Soc Echocardigor,1999; 12:1082-1096.
7. Wolf PA,Abbott RD,Kannel WB,et al. Atrial fibrillation as an independent risk factor for stroke:Framingham Study.Stroke,1991; 22:983-988.
8. Schmieder RE,Martus P,Klingbeil A,et al. Reversal of left ventricular hypertrop- hy in essential hypertension: a meta-analysis of randomized double-blind studies JAMA 1996; 275:1057-13.
9. Mondillo S,Sabatini L,Agricola E,et al. Correlation between left atrial size, prothrobombotic state and markers of endothelial dysfunction in patients with lone chronic nonrheumatic atrial fibrillation.Int J Cardiol,2000; 75(2-3):227-232.
10. Bauer KA,Rosenberg RD. The pathophysiology of the prethrombotic state in humas-in sights gained from studies using markers of hemosteatic system activation.Blood,1987; 70(2):343
11. 王振义.血栓前状态研究现状.中华血液学杂志,1991; 12(9):477-478.
12. Lip GY,Rumley A,Dunn FG,et al. Plasma fibrinogen and fibrin D-dimer in patients with atrial fibrillation: effects of cardioversion to sinus rhythm.Int J Cardiol 1995; 51:245-251.
13. Li-Saw-Hee FL,Blann AD,Gurney D,et a1.Plasma von willebrand factor,fibrinog- en and soluble P-selectin levels in paroxysmal,persistent and permanent atrial fibrillation. European Heart Journal,2001; 22:1741-1747.
14. Chen MC,Chang HW,Juang ss,et al. Increased plasma levels of soulble P-selection in rheumatic mitral stenosis.Chest,2004; 126(1):54-58.
15. Blann AD,Nadar SK,Lip GY. The adhesion molecule P-selection and cardiovascu- lar disease.Eur Heart J,2003; 24(24):2166-2179.
16. Pongratz G,Bradt-Pohlman M,henneke KH,et al. Platelet activation in embolic and preembolic ststus of patients with nonrheumatic atrial fibrillation.Circulation 2003; 134(3):622-625.
17. 高明东,孙根义.Von Willebrand 因子与血栓相关性疾病.天津医药,2002;30 (8):510-512.
18. Li-Saw-Hee FL, Blann AD, Lip GY. A cross-sectional and diumal study of thrombogenesis among patients with chronic atrial fibrillation. J Am Coll Cardiol, 2000; 35:1926-1931.
19. Lip GYH,Lowe GDO,Rumley A,et al. Increased markers of thrombogenesis in chronic atrial fibrillation:Effects of Warfrin treatemt.Br Heart J,1995; 73:527-523.
20. Mahe I,Drout L,Chassany O,et al. D-dimer:a characteristic of the coagulation state of each patient with chronic atrial fibrillation.Thromb Res,2002; 107(1-2):1-6.
21. Jafri SM, Msmmen E F, Masura S J, et al. Effects of warfarin on markers ofhypercoagulability in patients with heart faliure.Am Heart J,1997; 134(1):27-36.
22. Miklos Somloi,MD,Janos Tomcasanyi,MD,phD,Erzsebet N agy,MD,et al.D-dimer determination as a screening tool to exclude atrial thrombi in atrial fibrillation.The American Journal of Cardiology,2003; 92:85-87.
23. Nozawa T,Inoue H,Hirai T,et al.D-dimer level influences thromboembolic events in patients with atrial fibrillation.Int J Cardiol,2006; 109(1):59-61.
24. Enta K,Iwade K,Aosaki M,et al. Predictive value of coagulative molecular marker for thromboembolism in patients with nonvalvular atrial fibrillation:prosective five year follow-up study.J Cardiol,2004; 44(6):223-232.
25. Daniel WG. Should transesophageal echocardiography be used to guide cardiversion. N Engl J Med,1993; 328(11):803-804.
26. Eckman MH,Rosand J,Kundsen MA,et al. Can patients be anticoagulated after intracerebral hemorrhage? A decision analysis.Stroke,2003; 34(7):1710-1716.
27. 孙振球,徐勇勇.医学统计学.人民卫生出版社,北京 2003:258.
28. 洪楠,林爱军,侯军.统计产品和服务解决方案教程.清华大学出版社,北京, 1999:64-68.
29. Stefan HH,Stuart JC. Combined antiplatelet therapy in atrial fibrillation: Review of the leiterature and future research avenues. Cardiovasc Electrophysiol 2003; 14(Supp1): S60.
30. The bault JJ,Kiefer G,Lowe GD,et a1.Repeated dose pharma Codynamics of clopidogrelin healthy subjects.Semin Thromb Hemost,1999; 25(Suppl2):s9.
31. Denninger MH,Necciari J,Serre Lacroix E,et a1.Clopidogrel antiplatelet activity is independent of age and presence of atherosclerosis.Semin Thromb Hemost,1999; 25(Supp12):S41.
32. Dol F,Gaich C,Bemat A,et a1. Effect of clopidogrel on thrombin generation in the rat.Thromb Res,1992; 65(Suppl1): S160.
33. Diener HC, Lowenthal A . Antiplatelet therapy to prevent stroke: Risk brain hemorrhage and efficacy of aspirin.J Neurol Sci,1997; 153:112.
34. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial.Lancet2006; 367:1903-12.
35. Lorenzoni R,Lazzerini G,Cocci F,et al. Short-term prevention of thromboemblic: complications in patiens with atrial fibrillation with aspirin plus clopidogerl: the Clopidogrel-Aspirin Atrial Fibrillation(CLAAF) pilot study.Am Heart J,2004; 148 (1):e6.
1. Kannel WB,Wolf PA,Benjamin EJ,et al. Prevalence,incidence,prognosis, and predisposing conditions for atrial fibrillation:population-based estimates[J].Am J Cardiol,1998; 82:2NN.
2. Kannel WB,Abbott RD,Savage DD,et al. Epidemiologic features of chronic atrial fibrillation:The Framingham Study[J]. N Engl J atrial Med,1982; 306:1018.
3. Wolf PA ,Abbott RD ,Kannel WB ,et al. Atrial fibrillation as an independent risk factor for stroke : Framingham Study[J ]. Stroke ,1991; 22 :983-988.
4. 马长生,周玉杰,马煜,等. 中国人非瓣膜性心房颤动患者脑卒中发生率及影响因素的回顾性前瞻研究(摘要)[J]. 中国循环杂志,1999; 14(增刊):110.
5. Petersen P. Thromboembolic complications in atrial fibrillation [J].Stroke,1999; 21: 4-13.
6. Braunwald E. ed. Heart disease: a textbook of cardiovascular medicine [M]. 5thed. Beijing:science press,1999; 655.
7. Orsinelli DA. Current recommendations for the anticoagulation of patients with atrial fibrillation[J].Prog Cardiovasc Dis,1996; 39:1-20.
8. Jaber WA,Prior DL,Thamilarasan M,et al. Efficacy of anticoagulation in resolving left atrial and left atrial appendage thrombi:A transesophageal echocardiographic study[J].Am Heart J,2000; 140:150.
9. Igarashi Y,Kasai H,Yamashita F,et al. Lipoprotein(a),left atrial appendage fuction and thromboembolic risk in patients with chronic nonvalvular atrial fibrillation[J]. Jpn Circ J,2000; 64:93.
10. Shinohara H,Fukuda N,Soeki T,et al. Relationship between flow dynamics in the left atrium and hemostatic abnormalities in patients with nonvalvular atrial fibrillation [J].Jpn Heart J,1998; 39:721-730.
11. Blake IW. Spontaneous echo contrast: where there’s smoke there’s fire[J]. Echocardiography,2000; 17:373.
12. Igrarashi Y,Kasai H,Yamashita F,et al. Lipoprotein(a),left atrial appendage function and thromboembolic risk in patients with chronic nonvalvular atrial fibrillation[J].Jpn Circ J,2000; 64:93..
13. Minamino T,Kitakaze M,Asanuma H,et al. Plasma adenosine levels and plateletactivation in patients with atrial fibrillation [J].Am J Cardiol,1999; 83:194-198.
14. Pongratz G,Pohlmann BM,Henneke KH,et al. Platelet activation in embolic and preembolic status of patients with nonrheumatic atrial fibrillation[J].Chest,1997; 111:929-933.
15. Minamino T,Kitakaze M,Sanada S,et al. Increased expression of P-selection on platelets is a risk factor for silent cerebral infarction in patient with atrial fibrillation[J].Circulation,1998; 98:1721-1727.
16. Palabrica T,Lobb R,Furie BC,et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selection on adherent platelets[J].Nature,1992; 359:848-851.
17. Yamamoto K,Ikeda U,Fukazawa H,et al. Effects of asprin on status of thrombin generation in atrial fibrillation[J ].Am J Cardiol,1996; 77:528- 530.
18. Kaha SR,Solymoss S,Flegel KM. Nonvalvular atrial fibrillation:evidence for a prothrombotic state[J].Can Med Assoc J,1997; 157:673-681.
19. Lip GY,Lowe GD,Rumley A,et al. Increased markers of thrombogensis in chronic atrial fibrillation :effects of warfarin treatment [J].Br Heart J ,1995; 73:527-533.
20. Dietrich WD,Miller LP,Prado R,et al. Acadesine reduces indiumlabeled platelet deposition after photothrombosis of the common artery in rats [J].Stroke,1995;26: 111-116.
21. Stroke Prevention in Atrial Fibrillation Investigators. Risk factor for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data form five randomized controlled trials[J].Arch Intern Med,1994; 154:1449.
22. Morley J,Marinchak R,Rials SJ,et al. Atrial fibrillation,anticogulation, and stroke [J].Am J Cardiol,1996; 77:38A-44A.
23. Gregorg W,James E,Laupacis A. Antithrombotic therapy in atrial fibrillation[J]. Chest,2001; 119:194S-206S.
24. Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation : stroke prevention in atrial fibrillation II study[J].Lancet ,1994; 343:687.
25. Gallus AS,Baker RI,Chong BH,et al. Consensus guidelines for warfarin therapy. Recommendations form the Australasian society of thrombosis and haemostasis[J]. MJA,2000; 172:600.
26. Hylek EM,Skates SJ,Sheehan MA,et al.An analysis of the lowest effective intensi-ty of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation [J].N Engl J Med ,1996; 335:540.
27. Hellemons BS,LangenbergM,Lodder J,et al. Primary prevention of arterial throm- boemolism in non-rheumatic aterial fibrillation in primarcy:randomized controlled trial comparing two intrnsities of coumarin with aspirin [J].BMJ,1999; 319:958.
28. SPAF investigaters. Adjusted-dose warfarin versus low-intensity,fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke prevention in atrial fibrillation III randomised clinical trial [J].Lancet,1996; 348:633.
29. Koudstaal PJ . Antiplatelet therapy for preventing stroke in patients with nonrheunmatic atrial fibrillation and a history of stroke or transient ischemic attacks[J]. Cochrane Database Syst Rev,2000; (2):CD000186.
30. Dol F,Gaich C,Bemat A,et a1.Effect of clopidogrel on thrombin generation in the rat[J].Thromb Res ,1992; 65(Suppl 1):S160.
31. Schellinger PD,Juttle E,Meyding-Lamade UK,et al.The value of pletelet inhibitors in the secondary prophylaxis of stroke-review[J]. Fortschr Neurol Psychiatr,2004; 72(5):270-281.
32. Stefan HH,Stuart JC. Combined antiplatelet therapy in atrial fibrillation: Review of the leiterature and future research avenues. Cardiovasc Electrophysiol 2003; 14(Supp1): S60.
33. Diener HC , Lowenthal A. Antiplatelet therapy to prevent stroke: Risk brain hemorrhage and efficacy of aspirin.J Neurol Sci,1997; 153:112.
34. Lorenzoni R,Lazzerini G,Cocci F,et al. Short-term prevention of thromboemblic: complications in patiens with atrial fibrillation with aspirin plus clopidogerl: the Clopidogrel-Aspirin Atrial Fibrillation (CLAAF) pilot study.Am Heart J,2004; 14 8(1):e6.
35. Hart RG,Sherman DG,Easton JD,et al. Prevention of stroke in patients with non- valvular atrial fibrillation[J].Neurology,1998; 51:674-681.
36. Cox JL,Ad N,Palazzo T. Impact of the maze procedure on the stroke rate in patients with atrial fibrillation[J]. Thorac Cardiovasc Surg,1999; 118:833.
37. Falk RH,Podrid PJ. Atrial fibrillation mechanisms and management[M].2 nd ed.Maple Press ,1997; 277.
38. Hirsh J,Dalen JE ,Anderson D ,et al. Oral anticoagulants.Machanism of action,clinical effectiveness and optimal therapeutic range[J].Chest,1998;114 (Suppl):445s.