阿司匹林和氯吡格雷在冠状动脉旁路移植术后抗血小板治疗的临床与基础研究
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摘要
目的：
1.通过分析体外循环与非体外循环冠状动脉旁路移植术(CCABG和OPCAB)围术期血小板的数量和功能的变化情况,掌握其一般规律,为进一步的研究奠定理论基础；
2.通过前瞻性随机研究,比较三种抗血小板治疗方案(阿司匹林、氯吡格雷及联合服用阿司匹林氯吡格雷)在OPCAB术后早期对患者的影响；以64层螺旋CT造影(multi-slice computed tomography Angiography, MSCTA)为评价手段,比较应用三种抗血小板治疗方案OPCAB术后近中期桥血管及吻合口的通畅情况；
3.建立兔自体静脉移植模型,比较阿司匹林、氯吡格雷、阿司匹林联合氯吡格雷三种抗血小板治疗方案对移植静脉内膜增生的影响。
材料与方法：
1.随机选取CCABG和OPCAB各30例病人,分别记录两组术前、术后当天、术后1天、5天和10天的血小板数量及二磷酸腺苷诱导的血小板聚集率(PAG)。术后当天的测量值需做红细胞压积校正以减小血液稀释导致的误差。描绘走行趋势图,分析术后血小板数量和聚集功能的变化规律；
2.从2008年8月～2009年6月期间,按纳入及排除标准选取在我院行OPCAB手术的180名患者。随机分为三组,每组60例,分别口服三种抗血小板药物：单服阿司匹林组(100mg,1次／日),单服氯吡格雷组(75mg,1次／日),联合服用阿司匹林(100mg,1次／日)氯吡格雷组(75mg,1次／日)。比较三组之间对术后凝血功能、引流量、血小板数量和功能、中性粒细胞数量及出血并发症等方面的变化。以64-MSCTA为主要评价手段,分析阿司匹林、氯吡格雷、阿司匹林联合氯吡格雷三种抗血小板治疗方案治疗下的中期桥血管及吻合口通畅情况。所有数据用SPSS 17.0软件进行统计学分析；
3.32只新西兰大白兔随机分为4组,每组8只,按抗血小板治疗方案分为对照组,阿司匹林组,氯吡格雷组,阿司匹林联合氯吡格雷组。用“套管技术(Cuff technique)”将兔自体颈外静脉移植入同侧颈动脉系统,6个月后采集标本,行电镜超微结构观察,切片染色并测量管腔面积、内弹力板围绕面积和外弹力板围绕面积,计算新生内膜及中膜面积,作定量分析；免疫组化观察Bax和Bcl-2表达,计算细胞阳性表达率。
结果：
1.在术后常规阿司匹林治疗的情况下,CCABG和OPCAB术后早期血小板数量先短暂下降,然后大幅上升,显著超过术前水平(P<0.01),CCABG组的变化更明显。术后血小板聚集率也有所升高(P<0.05),术后第10天OPCAB组基本恢复而CCABG组仍高于术前水平(P<0.05)；
2.三组之间在术后第10天的血浆凝血酶原时间、血浆活化部分凝血酶原时间、凝血酶时间、纤维蛋白原、血浆凝血酶原活动度、血浆凝血酶原活动度、国际标准化比值均无显著差异(P>0.05)；三组之间在引流量、术后第5天及10天的血小板数量、第5天的血小板聚集率、第10天的中性粒细胞百分比方面均无显著差异,术后第10天二药联用组的血小板聚集率显著低于其他两组’(P<0.05)。术后近中期(6月-1年)三组LIMA桥通畅率无显著性差异。用Fitzgibbon A+B级计算通畅率,三组之间LIMA和SVG桥血管通畅率无显著性差异,LIMA远端吻合口通畅率也无明显差异,但阿司匹林联合氯吡格雷组SVG的远端吻合口通畅率高于阿司匹林组。用Fitzgibbon A级计算通畅率,三组之间LIMA的桥血管通畅率无显著性差异,阿司匹林联合氯吡咯雷组SVG的桥血管通畅率高于单服阿司匹林组,三组之间LIMA吻合口通畅率对比无显著性差异,阿司匹林联合氯吡格雷组SVG吻合口通畅率均高于阿司匹林组和氯吡格雷组。阿司匹林组和氯吡格雷组之间均无显著性差异；
3.动物试验取移植静脉标本后,光镜下显示内膜增厚,弹性纤维及胶原纤维增多增粗,电镜下显示平滑肌细胞胞质内有大量肌丝及致密体,粗面内质网及高尔基器丰富,部分线粒体肿胀；四组之间中膜厚度和中膜面积均无显著性差异(P>0.05)。在新生内膜厚度及面积及其与中膜的厚度及面积比方面,氯吡格雷组和阿司匹林联合氯吡格雷组间、对照组和阿司匹林组间均无显著差异,但氯吡格雷组和阿司匹林联合氯吡格雷组均分别低于和阿司匹林组(P<0.05)。氯吡格雷组和阿司匹林联合氯吡格雷组的Bcl-2表达阳性率均分别低于对照组和阿司匹林组(P<0.05),氯吡格雷组和阿司匹林联合氯吡格雷组之间、和阿司匹林组之间均无显著差异(P>0.05)。而Bax蛋白表达在各组间则无统计学意义的差异。氯吡格雷组和阿司匹林联合氯吡格雷组的Bax／Bcl-2则明显升高。
结论：
1.无论是否应用体外循环,CABG术后均有血小板数量增加和功能提高,体外循环组的变化更明显,这可能是造成术后早期阿司匹林抵抗的原因之一；
2.三组对术后的凝血功能、出血等方面无显著差异,阿司匹林和氯吡格雷联用组在OPCAB术后10天对血小板聚集率的抑制作用显著强于一种药物单独应用；术后近中期(6月～1年),三组动脉桥血管通畅率无明显差异；阿司匹林联合氯吡格雷组的静脉桥及吻合口通畅率优于单服阿司匹林组和单服氯吡格雷组(P<0.05)。建议患者在术后可以耐受的情况下,联合服用阿司匹林(100mg／日)和氯吡格雷(75mg／日),以提高术后桥血管及吻合口的通畅率；
3.动物试验显示：氯吡格雷能抑制兔动脉移植静脉的内膜增生,机制可能与移植抑凋亡基因Bcl-2的表达有关,而阿司匹林则无任何抑制作用。
OBJECTIVES:
1. To observe the variation of platelet count and function after off-pump and on-pump coronary artery bypass.
2. To compare the impact of three strategies for the management of antiplatelet therapy (aspirin, clopidogrel, aspirin plus clopidogrel) on patients during the early period after coronary artery bypass grafting without CPB(OPCAB), the impact on grafts and their distal anastomoses'patency in 6 months-1 year follow-up by means of 64-MSCTA.
3. To compare the three strategies for the management of antiplatelet therapy on inhibition for neointimal hyperplasia in rabbit's autologous vein graft.
MATERIALS and METHODS:
1. From June 2009 to March 2010, sixty patients having received off-pump and on-pump coronary artery bypass grafting (OPCAB and CCABG) were retrospectively analyzed. Aspirin was managed (100mg 1/d) after operation. Platelet function was assessed by using adenyl diphosphoric acid-induced platelet aggregation (PAG). Blood samples were collected before the operation, immediately postoperatively, and on days 1,5, and 10. Platelet count was recorded collected before the operation, immediately postoperatively, and on days 1,3, and 10. The values on day of the operation were corrected according to hematocrit.
2. From August 2008 to June 2009,180 patients undergoing coronary artery bypass grafting without CPB were randomly assigned to three groups. Impact of three antiplatelet therapy on blood coagulation function, drainage volume, number of platelet and neutrophilic granulocyte, function of platelet were compared among three groups. The patency of LIMA grafts and SVGs and their distal anastomoses as well were analyzed by means of 64-MSCTA in 6 months～1 year follow-up after operation.
3. Thirty-two New Zealand rabbits were randomly assigned to four groups and the animal model was established by implanting right external jugular vein into the externaIcarotid of the same side with "cuff" technique. Three of the four groups were respectively given aspirin, clopidogrel, aspirin plus clopidogrel after operation. The vein grafts were removed after 6 months for observation under transmission electron microscope and scanning electron microscope. The thickness, area of newly born intima and media were measured. The expression of Bax and Bcl-2 was observed.
RESULTS:
1. In both groups, platelet count decreased transiently after operation and soon increased markedly (P<0.01). The change in CCABG group was more obvious. PAG also increased markedly in both groups (P<0.05). On day 10, PAG recovered in OPCAB group but was still higher in CCABG group (P<0.05).
2. Prothrombin time, activated partial thromboplastin time were tested and there were no significant differences among the three groups. Proserozym activity was higher in group of aspirin plus clopidogrel than group of aspirin (P<0.05) Drainage volume, number of platelet and neutrophilic granulocyte showed no significant differences among them. PAG was lower in aspirin plus clopidogrel group than another two groups (P<0.05). In postoperative 6 months～1 year's follow-up, with arithmetic method of Fitzgibbon A+B, there were no significant differences in patency of LIMA grafts and SVGs as well as distal anastomoses on LIMA grafts in the three groups (p>0.05). But the patency of distal anastomoses on SVGs in asprin plus clopidogrel group was higher than that in asprin group. With arithmetic method of Fitzgibbon A, there were no significant differences in patency of LIMA grafts among three groups. The patency of SVGs was higher in asprin plus clopidogrel group than in asprin group. There were no significant differences in LIMA distal anastomoses among three groups. The patency of SVGs distal anastomoses was higher in asprin plus clopidogrel group than in asprin group and in clopidogrel group respectively (p<0.05).
3. Transmission electron microscope showed the thickness of intima, elastic fiber and collagen fibers increased obviously. There were no significant differences in thickness, area of newly born intima, expression of Bax and Bcl-2 between clopidogrel group and aspirin plus clopidogrel group, but both were lower than that of controling group and aspirin group. There were no significant differences between controling group and aspirin group.
CONCLUSION:
1. Platelet count and function both increase after CABG regardless of CPB, but more markedly in those using CPB. This probably is one of the principal causes for aspirin resistance after CABG.
2. The three strategies of antiplatelet therapy are all safe during the early period of management after OPCAB. The management of aspirin plus clopidogrel can superiorly inhibite thrombocytic function than aspirin or clopidogrel alone. In postoperative 6 months～1 year's follow-up, there were no significant differences in patency of LIMA grafts and their distal anastomoses in three groups (p>0.05). The patency of SVGs and their distal anastomoses was higher in asprin plus clopidogrel group than in asprin group and clopidogrel group respectively (p<0.05). The safety of three strategies of antiplatelet therapy was proven within 1 year post operation. Asprin plus clopidogrel was advised to be managed for patients who have severe coronary artery disease.
3. Clopidogrel can efectively lessen the vein graft intima thickness and area, which was not enhanced by adding aspirin.
1.通过分析体外循环与非体外循环冠状动脉旁路移植术(CCABG和OPCAB)围术期血小板的数量和功能的变化情况,掌握其一般规律,为进一步的研究奠定理论基础；
2.通过前瞻性随机研究,比较三种抗血小板治疗方案(阿司匹林、氯吡格雷及联合服用阿司匹林氯吡格雷)在OPCAB术后早期对患者的影响；以64层螺旋CT造影(multi-slice computed tomography Angiography, MSCTA)为评价手段,比较应用三种抗血小板治疗方案OPCAB术后近中期桥血管及吻合口的通畅情况；
3.建立兔自体静脉移植模型,比较阿司匹林、氯吡格雷、阿司匹林联合氯吡格雷三种抗血小板治疗方案对移植静脉内膜增生的影响。
材料与方法：
1.随机选取CCABG和OPCAB各30例病人,分别记录两组术前、术后当天、术后1天、5天和10天的血小板数量及二磷酸腺苷诱导的血小板聚集率(PAG)。术后当天的测量值需做红细胞压积校正以减小血液稀释导致的误差。描绘走行趋势图,分析术后血小板数量和聚集功能的变化规律；
2.从2008年8月～2009年6月期间,按纳入及排除标准选取在我院行OPCAB手术的180名患者。随机分为三组,每组60例,分别口服三种抗血小板药物：单服阿司匹林组(100mg,1次／日),单服氯吡格雷组(75mg,1次／日),联合服用阿司匹林(100mg,1次／日)氯吡格雷组(75mg,1次／日)。比较三组之间对术后凝血功能、引流量、血小板数量和功能、中性粒细胞数量及出血并发症等方面的变化。以64-MSCTA为主要评价手段,分析阿司匹林、氯吡格雷、阿司匹林联合氯吡格雷三种抗血小板治疗方案治疗下的中期桥血管及吻合口通畅情况。所有数据用SPSS 17.0软件进行统计学分析；
3.32只新西兰大白兔随机分为4组,每组8只,按抗血小板治疗方案分为对照组,阿司匹林组,氯吡格雷组,阿司匹林联合氯吡格雷组。用“套管技术(Cuff technique)”将兔自体颈外静脉移植入同侧颈动脉系统,6个月后采集标本,行电镜超微结构观察,切片染色并测量管腔面积、内弹力板围绕面积和外弹力板围绕面积,计算新生内膜及中膜面积,作定量分析；免疫组化观察Bax和Bcl-2表达,计算细胞阳性表达率。
结果：
1.在术后常规阿司匹林治疗的情况下,CCABG和OPCAB术后早期血小板数量先短暂下降,然后大幅上升,显著超过术前水平(P<0.01),CCABG组的变化更明显。术后血小板聚集率也有所升高(P<0.05),术后第10天OPCAB组基本恢复而CCABG组仍高于术前水平(P<0.05)；
2.三组之间在术后第10天的血浆凝血酶原时间、血浆活化部分凝血酶原时间、凝血酶时间、纤维蛋白原、血浆凝血酶原活动度、血浆凝血酶原活动度、国际标准化比值均无显著差异(P>0.05)；三组之间在引流量、术后第5天及10天的血小板数量、第5天的血小板聚集率、第10天的中性粒细胞百分比方面均无显著差异,术后第10天二药联用组的血小板聚集率显著低于其他两组’(P<0.05)。术后近中期(6月-1年)三组LIMA桥通畅率无显著性差异。用Fitzgibbon A+B级计算通畅率,三组之间LIMA和SVG桥血管通畅率无显著性差异,LIMA远端吻合口通畅率也无明显差异,但阿司匹林联合氯吡格雷组SVG的远端吻合口通畅率高于阿司匹林组。用Fitzgibbon A级计算通畅率,三组之间LIMA的桥血管通畅率无显著性差异,阿司匹林联合氯吡咯雷组SVG的桥血管通畅率高于单服阿司匹林组,三组之间LIMA吻合口通畅率对比无显著性差异,阿司匹林联合氯吡格雷组SVG吻合口通畅率均高于阿司匹林组和氯吡格雷组。阿司匹林组和氯吡格雷组之间均无显著性差异；
3.动物试验取移植静脉标本后,光镜下显示内膜增厚,弹性纤维及胶原纤维增多增粗,电镜下显示平滑肌细胞胞质内有大量肌丝及致密体,粗面内质网及高尔基器丰富,部分线粒体肿胀；四组之间中膜厚度和中膜面积均无显著性差异(P>0.05)。在新生内膜厚度及面积及其与中膜的厚度及面积比方面,氯吡格雷组和阿司匹林联合氯吡格雷组间、对照组和阿司匹林组间均无显著差异,但氯吡格雷组和阿司匹林联合氯吡格雷组均分别低于和阿司匹林组(P<0.05)。氯吡格雷组和阿司匹林联合氯吡格雷组的Bcl-2表达阳性率均分别低于对照组和阿司匹林组(P<0.05),氯吡格雷组和阿司匹林联合氯吡格雷组之间、和阿司匹林组之间均无显著差异(P>0.05)。而Bax蛋白表达在各组间则无统计学意义的差异。氯吡格雷组和阿司匹林联合氯吡格雷组的Bax／Bcl-2则明显升高。
结论：
1.无论是否应用体外循环,CABG术后均有血小板数量增加和功能提高,体外循环组的变化更明显,这可能是造成术后早期阿司匹林抵抗的原因之一；
2.三组对术后的凝血功能、出血等方面无显著差异,阿司匹林和氯吡格雷联用组在OPCAB术后10天对血小板聚集率的抑制作用显著强于一种药物单独应用；术后近中期(6月～1年),三组动脉桥血管通畅率无明显差异；阿司匹林联合氯吡格雷组的静脉桥及吻合口通畅率优于单服阿司匹林组和单服氯吡格雷组(P<0.05)。建议患者在术后可以耐受的情况下,联合服用阿司匹林(100mg／日)和氯吡格雷(75mg／日),以提高术后桥血管及吻合口的通畅率；
3.动物试验显示：氯吡格雷能抑制兔动脉移植静脉的内膜增生,机制可能与移植抑凋亡基因Bcl-2的表达有关,而阿司匹林则无任何抑制作用。
OBJECTIVES:
1. To observe the variation of platelet count and function after off-pump and on-pump coronary artery bypass.
2. To compare the impact of three strategies for the management of antiplatelet therapy (aspirin, clopidogrel, aspirin plus clopidogrel) on patients during the early period after coronary artery bypass grafting without CPB(OPCAB), the impact on grafts and their distal anastomoses'patency in 6 months-1 year follow-up by means of 64-MSCTA.
3. To compare the three strategies for the management of antiplatelet therapy on inhibition for neointimal hyperplasia in rabbit's autologous vein graft.
MATERIALS and METHODS:
1. From June 2009 to March 2010, sixty patients having received off-pump and on-pump coronary artery bypass grafting (OPCAB and CCABG) were retrospectively analyzed. Aspirin was managed (100mg 1/d) after operation. Platelet function was assessed by using adenyl diphosphoric acid-induced platelet aggregation (PAG). Blood samples were collected before the operation, immediately postoperatively, and on days 1,5, and 10. Platelet count was recorded collected before the operation, immediately postoperatively, and on days 1,3, and 10. The values on day of the operation were corrected according to hematocrit.
2. From August 2008 to June 2009,180 patients undergoing coronary artery bypass grafting without CPB were randomly assigned to three groups. Impact of three antiplatelet therapy on blood coagulation function, drainage volume, number of platelet and neutrophilic granulocyte, function of platelet were compared among three groups. The patency of LIMA grafts and SVGs and their distal anastomoses as well were analyzed by means of 64-MSCTA in 6 months～1 year follow-up after operation.
3. Thirty-two New Zealand rabbits were randomly assigned to four groups and the animal model was established by implanting right external jugular vein into the externaIcarotid of the same side with "cuff" technique. Three of the four groups were respectively given aspirin, clopidogrel, aspirin plus clopidogrel after operation. The vein grafts were removed after 6 months for observation under transmission electron microscope and scanning electron microscope. The thickness, area of newly born intima and media were measured. The expression of Bax and Bcl-2 was observed.
RESULTS:
1. In both groups, platelet count decreased transiently after operation and soon increased markedly (P<0.01). The change in CCABG group was more obvious. PAG also increased markedly in both groups (P<0.05). On day 10, PAG recovered in OPCAB group but was still higher in CCABG group (P<0.05).
2. Prothrombin time, activated partial thromboplastin time were tested and there were no significant differences among the three groups. Proserozym activity was higher in group of aspirin plus clopidogrel than group of aspirin (P<0.05) Drainage volume, number of platelet and neutrophilic granulocyte showed no significant differences among them. PAG was lower in aspirin plus clopidogrel group than another two groups (P<0.05). In postoperative 6 months～1 year's follow-up, with arithmetic method of Fitzgibbon A+B, there were no significant differences in patency of LIMA grafts and SVGs as well as distal anastomoses on LIMA grafts in the three groups (p>0.05). But the patency of distal anastomoses on SVGs in asprin plus clopidogrel group was higher than that in asprin group. With arithmetic method of Fitzgibbon A, there were no significant differences in patency of LIMA grafts among three groups. The patency of SVGs was higher in asprin plus clopidogrel group than in asprin group. There were no significant differences in LIMA distal anastomoses among three groups. The patency of SVGs distal anastomoses was higher in asprin plus clopidogrel group than in asprin group and in clopidogrel group respectively (p<0.05).
3. Transmission electron microscope showed the thickness of intima, elastic fiber and collagen fibers increased obviously. There were no significant differences in thickness, area of newly born intima, expression of Bax and Bcl-2 between clopidogrel group and aspirin plus clopidogrel group, but both were lower than that of controling group and aspirin group. There were no significant differences between controling group and aspirin group.
CONCLUSION:
1. Platelet count and function both increase after CABG regardless of CPB, but more markedly in those using CPB. This probably is one of the principal causes for aspirin resistance after CABG.
2. The three strategies of antiplatelet therapy are all safe during the early period of management after OPCAB. The management of aspirin plus clopidogrel can superiorly inhibite thrombocytic function than aspirin or clopidogrel alone. In postoperative 6 months～1 year's follow-up, there were no significant differences in patency of LIMA grafts and their distal anastomoses in three groups (p>0.05). The patency of SVGs and their distal anastomoses was higher in asprin plus clopidogrel group than in asprin group and clopidogrel group respectively (p<0.05). The safety of three strategies of antiplatelet therapy was proven within 1 year post operation. Asprin plus clopidogrel was advised to be managed for patients who have severe coronary artery disease.
3. Clopidogrel can efectively lessen the vein graft intima thickness and area, which was not enhanced by adding aspirin.
引文
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6 Poston RS, Gu J, Brown JM, et al. Endothelial injury and acquired aspirin resistance as promoters of regional thrombin formation and early vein graft failure after coronary artery bypass grafting. J Thorac Cardiovasc Surg 2006,131:122-30.
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1.本研究样本量较小,随访时间较短,如能扩大样本量,延长随访时间,可能更有说服力。
2.如果将抗血小板治疗的出血并发症等因素纳入分析,对其安全性进行评估,结论将更有意义。
3.冠脉造影为评价桥血管及吻合口的金标准,如能使用造影进行评估(至少部分使用),则评估的结果将更准确。
4.影响桥通畅率的因素较多,除去抗血小板因素外,如吻合技术、桥血管的保护、靶血管的条件、序贯或单支吻合的选择、术后冠心病高危因素的控制,等等,如能将这些因素进一步统一并作数据分析,结果将更有意义。
5.动物试验选择的免疫组化基因较少,如能将增殖基因纳入,结果将更令人信服。
6.随着除阿司匹林之外的多种抗血小板治疗的临床使用,希望能有远期随访的研究将之进行比较,最终选出风险／受益比最小的方案。
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2 Zimmermann N, Kienzle P, Weber A-A, et al. Aspirin resistance after coronary artery bypass grafting. J Thorac Cardiovasc Surg 2001,121:982-4.
3 Ballotta A, Saleh HZ, El Baghdady HW, et al.Comparison of early platelet activation in patients undergoing onpump versus off-pump coronary artery bypass surgery. J Thorac Cardiovasc Surg 2007,134:132-8.
4 M(?)ller CH, Steinbru chel DA. Platelet function after coronary artery bypass grafting:is there a procoagulant activity after off-pump compared with on-pump surgery? Scand Cardiovasc J 2003,37:149-53.
5 Golan'ski J, Chlopicki S, Golan'ski R, et al.Resistance to aspirin in patients after coronary artery bypass grafting is transient:impact on the monitoring of aspirin antiplatelet therapy. TherDrug Monit 2005,27:484-90.
6 Poston RS, Gu J, Brown JM, et al. Endothelial injury and acquired aspirin resistance as promoters of regional thrombin formation and early vein graft failure after coronary artery bypass grafting. J Thorac Cardiovasc Surg 2006,131:122-30.
7 Raja SG, Berg GA. Impact of off-pump coronary artery bypass surgery on systemic inflammation:current best available evidence. J Card Surg 2007,22:445-55.
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11 Zimmermann N, Wenk A, Kim U, et al. Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation 2003,108:542-547.
12 Sanioglu S, Tetik S, Sokullu O. Aspirin resistance after CABG. Thorac Cardiovasc Surg 2009,57(5):281-5.
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21. Raja SG, Berg GA. Impact of off-pump coronary artery bypass surgery on systemic inflammation:current best available evidence. J Card Surg 2007,22:445-55.
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1.本研究样本量较小,随访时间较短,如能扩大样本量,延长随访时间,可能更有说服力。
2.如果将抗血小板治疗的出血并发症等因素纳入分析,对其安全性进行评估,结论将更有意义。
3.冠脉造影为评价桥血管及吻合口的金标准,如能使用造影进行评估(至少部分使用),则评估的结果将更准确。
4.影响桥通畅率的因素较多,除去抗血小板因素外,如吻合技术、桥血管的保护、靶血管的条件、序贯或单支吻合的选择、术后冠心病高危因素的控制,等等,如能将这些因素进一步统一并作数据分析,结果将更有意义。
5.动物试验选择的免疫组化基因较少,如能将增殖基因纳入,结果将更令人信服。
6.随着除阿司匹林之外的多种抗血小板治疗的临床使用,希望能有远期随访的研究将之进行比较,最终选出风险／受益比最小的方案。
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