抗血小板药物在心血管介入治疗应用的进展
作者：钱杰
单位：100037 北京市，中国医学科学院 中国协和医科大学 心血管病研究所 阜外心血管病医院 冠心病研究室
关键词：
高润霖审校 高润霖审校
急性冠状动脉闭塞目前仍然是经皮冠状动脉腔内成形术(PTCA)面临的一个重要问题，其发生率在2%～11%[1]。由此导致的并发症包括：心肌梗塞(MI)最高发生率达40%，急诊冠状动脉旁路移植术最高6%，同没有发生闭塞的患者相比，其死亡率增加5倍。在导致冠状动脉闭塞的发生原因中，主要包括夹层、血栓形成和血管痉挛。由于支架的广泛应用已基本解决了夹层的防治问题，而硝酸酯类药物也可以预防血管痉挛的发生，其余的三分之一则主要由于血栓形成所致。
PTCA的治疗作用主要是通过挤碎斑块和扩大血管外径来增加血管内径，此外，冠状动脉内超声显示大多数扩张动脉段均有一些内膜夹层[2]。因此，当动脉壁深层组织受到损伤时，就会导致外源性组织凝血通路激活，血栓形成。Steele等检查了猪颈动脉扩张后的病理切片，发现所有受到中膜损伤的血管均有附壁血栓形成，并有明显的血小板沉积，主要是内膜下胶原暴露所致。此外，内皮和内皮下组织的损伤也会导致抗凝血作用的前列环素合成减少。Neuman等[3]证明在扩张部位有中性粒细胞和血小板激活，从而导致斑块撕裂的同时发生血栓形成过程。
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目前，介入性冠状动脉疾病治疗中常用于防治急性血栓形成的抗血小板药物主要包括以下几种。
阿司匹林(aspirin)
既往有3个随机、安慰剂对照临床试验对阿司匹林用于PTCA患者的作用进行了研究(但均同时加用了潘生丁)。在Schwartz等[4]进行的研究中，治疗组患者在PTCA术前开始服用阿司匹林加潘生丁(分别为330 mg，75 mg)每日3次，持续4～6个月，结果治疗组Q波MI发生仅3例，而对照组为13例(P=0.011 3)。另外两个研究结果与此类似。因此，PTCA患者可服用阿司匹林防治急性血栓形成。但阿司匹林在使用过程中存在一些欠缺：不能防止血小板最初的粘附；小剂量或缓释阿司匹林仍然有胃肠道刺激作用，并可以导致出血；可抑制前列环素的合成；但不能抑制血小板激活的许多其它通路如：二磷酸腺苷(ADP)或肾上腺素通路；不能对和纤维蛋白原结合的血小板发生作用；此外，还有15%～45%的人对它没有反应。
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噻氯匹定(ticlopidine)
2个随机、安慰剂对照临床试验报告了噻氯匹定用于不使用阿司匹林的PTCA患者的临床效果，结果可明显减少急性血管闭塞发生率。但其同阿司匹林合用的抗血小板作用没有进行临床试验。两个回顾性研究对此进行了分析[5，6]。结果显示二者合用没有减少急性闭塞、再狭窄和总临床事件发生率。因此，需要新的前瞻性临床试验来验证是否二者合用优于单用一种药物。
最近，许多临床试验检查了噻氯匹定同阿司匹林合用与单独使用阿司匹林对冠状动脉支架置入术患者的作用。在Leon等[7]进行的研究中，557例患者接受单独阿司匹林治疗，550例患者接受阿司匹林加华法林治疗，546例患者接受阿司匹林加噻氯匹定治疗。结果显示：3组的终点事件发生率依次为3.6%、2.4%和0.6%(P<0.001)，阿司匹林加噻氯匹定组患者支架内血栓发生率最低，尽管这组患者出血发生率比单独用阿司匹林组患者高。在MATTIS研究中[8]，阿司匹林加噻氯匹定组患者出血和并发症发生率均低于阿司匹林加口服抗凝剂组。其它研究也得到近似或较为一致的结果。因此，冠状动脉支架置入术后建议合用两种药物。然而，由于噻氯匹定可导致致命的中性粒细胞减少症和血小板减少性紫癜(TTP)，而且起效慢，因此，在应用中应于注意。
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Clopidogrel
Clopidogrel在化学结构上和功能上同噻氯匹定相似，但副作用较少。一项随机、对照比较噻氯匹定和Clopidogrel用于支架置入术患者的临床试验刚刚在欧洲完成。在研究中，1 020例患者分别接受如下治疗：服用300 mg Clopidogrel后每天服用75 mg，持续28天；Clopidogrel每天服用75 mg，持续28天；服用250 mg噻氯匹定后每天2次，每次服用250 mg，持续28天。结果显示：无论Clopidogrel是否加用负荷剂量，其耐受性均好于噻氯匹定，但二者的急性临床事件发生率没有明显差异。因此，如果肯定Clopidogrel的作用至少和噻氯匹定相当，而其副作用明显少于噻氯匹定，则可取代噻氯匹定。事实上，目前已经使用Clopidogrel的50多万例患者中尚没有发现TTP患者。此外，Clopidogrel比噻氯匹定便宜30%，还不需要经常监测患者的血常规。但目前还需要更多的临床试验来回答一些有关Clopidogrel的问题：作用效果是否同噻氯匹定相当？最佳剂量用法如何？同阿司匹林合用于支架置入术患者的效果如何？
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血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂
血小板激活后一个最重要的反应是激活纤维蛋白原受体。这个受体位于未激活的血小板表面，是一种糖蛋白Ⅱb/Ⅲa受体，平时处于无功能状态，当血小板被激活时，受体发生变形，成为有功能型。同这个受体结合的分子有一个特异的识别序列，由精氨酸—甘氨酸—天门冬氨酸组成，简称为RGD序列。含有此序列的药物，也可以和这种受体结合，从而起到抗血小板、抗血栓形成作用。
目前已有超过15 000例冠状动脉介入治疗患者使用了此类药物，已经完成的主要研究包括：使用ReoPro(abciximab或c7E3Fab)的EPIC、EPILOG和CAPTURE研究；使用Tirofiban(Aggrastat)的RESTORE研究和使用Integrelin(intrifiban)的IMPACT Ⅱ研究等。
EPIC研究[9]目的是确定高危PTCA患者使用ReoPro是否可以明显减少急性闭塞的发生率。终点包括30天时死亡，MI或需要再次血管再通手术发生率。结果表明：注射加静脉滴注ReoPro可减少终点事件35%(12.8%比8.3%;P=0.008)，这种有益作用持续到第3年(P＝0.009)，但轻微出血明显增加[10]。人们认为EPIC研究中过多出血是因为肝素剂量造成的，于是进行了ReoPro加小剂量肝素的试验，并用于随后的EPILOG研究[11]，其6个月时临床效果同EPIC研究类似，虽然治疗组有出血减少的趋势，但没有达到统计学差异。CAPTURE研究[12]入选的是对阿司匹林、肝素、硝酸盐类等标准抗心绞痛治疗反应不佳的患者。30天结果也同上述研究类似。但在6个月时，两组间没有差异。
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上述结果明确了ReoPro在PTCA手术中的地位，但除了增加出血的问题外，和它安全性有关的另一个问题是它的免疫原性。由于它是一个人—鼠结合抗体，因此，它用于一个有免疫应答的患者可能会导致严重后果。此外，还有0.4%～1.0%的患者可能发生血小板减少症。
Tirofiban是非肽类的糖蛋白Ⅱb/Ⅲa受体拮抗剂，其分子中含有可以被受体识别的类似RGD序列的结构。同ReoPro不同，它没有免疫原性。经过静脉使用，起效非常快，半衰期短，和出血时间呈剂量依赖的关系。RESTORE研究把tirofiban用于PTCA术后再闭塞的高危患者[13]。此药明显减少了终点事件的发生率，差异在2天(减少38%，P<0.005)和7天(减少27%,P=0.027)时都可以观察到。但30天时两组间没有达到统计学差异。
Integrelin是从蛇毒提取的含有RGD序列的肽段。IMPACT研究目的是确定它是否可以提高普通患者进行PTCA或旋磨治疗的临床效果[14]。150例患者分为3组：Integrelin注射加滴注4小时；Integrelin注射加滴注12小时；或安慰剂组。研究终点为术后30天时死亡、MI和血管再通手术发生率。尽管终点事件有下降的趋势，特别是在12小时组，但没有达到统计学差异，这可能和实验规模太小有关。IMPACT-Ⅱ研究在进行PTCA的患者中比较了两个剂量Integrelin的作用[15]。3 778例患者分为3组：小剂量组、大剂量组或安慰剂组，主要终点同IMPACT研究相同。结果两组剂量的Integrelin都降低了24小时终点事件发生风险(小剂量组是27%，P＝0.017；大剂量组是25%，P＝0.026)，但30天时，Integrelin和安慰剂间没有明显差异。
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目前，此类药物除了用于PTCA患者，还在进行其它适应证的研究。ReoPro用于急性MI直接PTCA治疗的RAPPORT研究已经完成[16]。483例患者分为安慰剂或ReoPro加阿司匹林及肝素组。终点为术后6个月时死亡、MI和血管再通手术发生率。结果两组间没有明显差异。但30天时治疗组明显减少终点事件发生风险(P=0.038)。
血小板糖蛋白Ⅱb/ⅡIa受体拮抗剂同广泛使用冠状动脉支架治疗基本同时进入临床领域。几乎所有早期的临床试验均以PTCA患者为对象。EPISTENT试验[17]对ReoPro用于支架置入术患者的效果进行了研究。2 399例患者随机分为支架加安慰剂，PTCA加ReoPro，支架加ReoPro 3组。由死亡、MI和血管再通手术发生率构成的终点事件发生率依次为10.8%、6.9%(减少风险36%，P=0.007)和5.3%(减少风险51%，P<0.001)。没有发现出血事件增加的现象。
综上所述，血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂代表了目前介入性心脏病学最大进展之一。大规模、随机、对照临床试验已无可争议地确认了其在心脏病介入治疗中的地位，它可大约减少患者围手术期缺血并发症50%～60%，而且，当肝素使用剂量合适时可不明显增加出血事件发生率。但此类药物非常昂贵，目前在我国还难以广泛使用。
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阿司匹林在几年前还是PTCA患者唯一的抗血小板药物，随后噻氯匹定同阿司匹林合用于冠状动脉支架置入术患者，由于Clopidogrel出现后，其作用和噻氯匹定相当，且副作用明显减少，因此有可能取而代之。血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂的出现使抗血小板治疗取得突破性进展，但还需要更多的临床试验验证其同其它抗血小板、抗凝药物合用的临床效果及最佳用法。除了上述的抗血小板药物外，还有其它一些药物正在研制中，如vWF因子抗体和凝血烷A2合酶抑制剂等。希望在不久的将来，随着新药的发展，可以得到疗效更好、副作用更少、价格更低的抗血小板药物，以便为患者提供更好的治疗。
参考文献
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7 Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic drug regimens after coronary artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med, 1998,339:1665—1671.
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12 CAPTURE investigators. Randomized placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet, 1997,349:1429—1435.
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15 Aguirre FV, Topol EJ, Ferguson JJ, et al. Effect of platelet glycoprotein(GP) Ⅱb/Ⅲa antagonism with integrelin on activated clotting times during coronary interventions: results from the IMPACT-Ⅱ trial. Circulation, 1996,94(suppl I):I-197-I-198.
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17 The EPISTENT Investigators. Randomized placebo-controlled and balloon angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-Ⅱb/Ⅲa blockade. Lancet, 1998,352:87—92.
Antiplatelet Therapy in Interventional Cardiology
Division of Coronary Heart Disease, Cardiovascular Institute and Fu Wai Hospital, CAMS and PUMC, Beijing (100037)
Qian Jie, Gao Runlin.
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Introduction
Acute coronary occlusion remains a problem in the setting of percutaneous transluminal coronary angioplasty (PTCA). Historically, the frequency of abrupt vessel closure has ranged from 2% to 11%. In -hospital complications include a myocardial infarction rate of up to 40%, a 6% rate of coronary artery bypass grafting and a fivefold increase in mortality, compared with patients without abrupt closure.
In order of frequency, the most common causes of abrupt closure are coronary artery dissection, thrombus formation, and vasospasm. Among the mechanical escape strategies for treating abrupt closure are redilatalion, prolonged balloon inflation, perfusion balloons, directional coronary atherectomy, and intracoronary stenting. The management of flow-limiting dissection has been revolutionized by the use of intracoronary stenting, and spasm can be managed with nitroglycerin. Intracoronary thrombus accounts for the majority of remaining cases in 19-33% of all acute occlusions. However, this is based on angiographic data and most likely represents an underestimation of its true incidence.
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Pathophysiology of intracoronary thrombus formation after percutaneous transluminal coronary angioplasty
The therapeutic increase in internal luminal diameter following PTCA is largely due to plaque fracture as well an increase in external diameter. In addition, most dilated arterial segments also show evidence of at least some intimal dissection when viewed via intra-coronary (IC) ultrasound. When deeper arterial injury occurs, activation of the tissue pathway of thrombus formation often results. Using a heparinized pig model, Steele et al. examined dilated carotid artery segments histologically. All nine pigs with medial tears had mural thrombi. All showed marked platelet deposition, presumably from the exposure of blood to fibrillar collagen, predominately found in the medial and adventitial layers. In addition, the destruction of endothelial and subendothelial layers may lead to a decrease in antithrombotic prostaglandin (prostacyslin) production. In humans, Neuman et al. have demonstrated neutrophil and platelet activation at the site of the balloon-injured coronary artery plaque. The result is an unchecked activation of the coagulation cascade. In patients with acute coronary syndromes (unstable angina, acute MI), plaque rupture may have already occurred spontaneously, resulting in activation of thrombus formation.
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Prevention of Intracoronary Thrombus
There are some routine measures that should be undertaken prior to mechanical intervention to assist in the prevention of acute closure due to thrombus. Most important of these is the use of antiplatelet therapy. The medicine that used in antiplatelet therapy will be discussed here.
Aspirin
Three placebo-controlled randomized trials have evaluated the use of aspirin in patients undergoing balloon angioplasty (although dipyridamole was used in conjunction with aspirin in three studies, dipyridamole and aspirin appear to be no more effective than aspirin alone). In one study, the active-drug group took oral aspirin-dipyridamole combination (330 mg, 75 mg) three times daily, beginning 24 hours before PTCA, and continued four to seven months. Result showed: there were 13 periprocedural Q-wave myocardial infarctions in the placebo group and 3 in the treatment group (p=0.011 3). And other two studies also revealed a significant reduction in adverse events (Q-wave MI and abrupt closure). Thus, the short-term use of antiplatelet agents in relation to PTCA can be recommended. However, aspirin is a suboptimal antiplatelet agent, it has relative weak antiplatelet activity. Furthermore, between 15-45% of patients are resistant to its antiplatelet effects, and many patients do not tolerate it due to gastrointestinal discomfort and bleeding.
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Ticlopidine
Two prospective placebo-controlled randomized trial reported a significant reduction in acute vessel closure with ticlopidine among patients, not on aspirin, who underwent balloon angioplasty. Little is known about whether the efficacy of antiplatelet therapy is increased by combining aspirin with ticlopidine in patients undergoing balloon angioplasty. Two retrospective analyses examining this issue have been performed. The analysis found no benefit from the combination of aspirin and ticlopidine in terms of reducing the frequency of reocclusion, restenosis, or the number of clinical events. A similar analysis of patients undergoing direct angioplasty in the STENT-PAMI trial came to a similar conclusion. So, we need new randomized trials to answer the question if ticlopidine and aspirin are superior to aspirin alone.
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Recently, many randomized trials have examined the combined use of aspirin and ticlopidine in patients undergoing coronary stent placement. For example, in one study 1 965 patients included. There were 557 patients received aspirin alone, 550 patients received aspirin and warfarin, others received aspirin and ticlopidine. The result showed: as compared with aspirin alone and a combination of aspirin and warfarin, treatment with aspirin and ticlopidine resulted in a lower rate of stent thrombosis, although there were more hemorrhagic complication than with aspirin alone. In MATTIS study, 350 high-risk patients included. Result showed that aspirin and ticlopidine treatment group had less bleeding and vascular complication than aspirin and oral anticoagulation treatment group and there is a marked trend suggesting a decrease in cardiac events in ticlopidine group. Other studies also had same result: aspirin and ticlopidine were more effective at reducing stent thrombosis and other major adverse events than aspirin alone and aspirin combined with coumadin. Bleeding was less frequent with aspirin and ticlopidine than aspirin and coumadin. So, after coronary stenting, aspirin and ticlopidine should be considered for the prevention of serious complication of stent thrombosis. However, the main problem of the medicine is neutropenia and thrombocytopenic purpura (TTP) which is life threatening. Furthermore, hematological studies have confirmed the slow onset of action of ticlopidine in patients undergoing stent placement without pretreatment with ticlopidine.
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Clopidogrel
Clopidogrel is a thienopyridine closely related to ticlopidine in chemical structure and function. It has similar efficacy and a better side-effect profile. A randomized trial comparing ticlopidine and clopidogrel among stent patients- the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS) was recently completely in Europe. In this trial, 1 020 stent patients were randomly assigned to receive the following: clopidogrel with a 300 mg loading does followed by 75 mg/day for 28 days; clopidogrel 75 mg without a loading does followed by 75 mg/day for 28 days; or ticlopidine 250 mg followed by 250mg twice daily for 28 days. The results of the trial indicated that clopidogrel, with and without a loading does, was better tolerated than ticlopidine. However, the study was not sized to detect a difference in the frequency of stent thrombosis and other major adverse events. Other study of clopidogrel is undergoing now. If clopidogrel is confirmed to be equivalent (and not superior) to ticlopidine in preventing stent thrombosis and procedural infarction, it nonetheless be preferred because side effects including nausea, vomiting, diarrhea, neutropenia, and TTP are far fewer than with ticlopidine. In fact, with over 500 000 patients treated, TTP has not been reported with clopidogrel. Clopidogrel is approximately 30% less expensive than ticlopidine; the cost of therapy is further reduced by the absence of a need to monitor blood counts in patients treated with clopidogrel. The main problems unanswered about clopidogrel include: Is clopidgrel as effective as ticlopidine, or more effective? What is the optimal loading does of clopidogrel? There are few data indicating an optimal loading does with clopidogrel; a loading does greater than 300 mg may be safe and achieve platelet inhibition even more rapidly. And it remains unclear whether the clopidogrel or ticlopidine are efficacious when combined with aspirin in patients undergoing balloon angioplasty and other interventions, as they clearly are in patients undergoing stent placement.
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GP Ⅱb/Ⅲa blockers
Selective inhibition of the platelet glycoprotein (GP) Ⅱb/Ⅲa surface blocker is a potent mechanism to inhibit platelet aggregation and thrombus formation. Over 15000 patients have been enrolled in pivotal trials of GP Ⅱb/Ⅲa receptor blockade with the parenteral inhibitors abciximab, eptifibatide, and tirofiban during coronary intervention, unequivocally establishing the clinical efficacy of this class of therapy in this setting. Reductions of up to 50-60% in the risk of important clinical endpoints have been achieved with these agents, a treatment effect that extends to all components of the composite clinical endpoints (death, myocardial infarction, and emergency revascularization). The main completed studies include: EPIC, EPILOG, and CAPTURE of abciximab; IMPACT Ⅱ of eptifibatide; RESTORE of tirofiban.
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The role of abciximab therapy among patients undergoing direct or primary angioplasty for acute myocardial infarction was evaluated in the ReoPro in Acute MI Primary PTCA Organization and Randomization Trial (RAPPORT). A total of 483 patients undergoing angioplasty within 12 hours of onset of symptoms were randomized to receive placebo or abciximab in addition to aspirin and heparin. The primary endpoint of death, recurrent MI, or any (elective or urgent) repeat target vessel revascularization by 6 months was not different in the 2 treatment groups, owing to absence of an effect of abciximab therapy on long-term revascularization procedures. The composite endpoint of death, reinfarction, or urgent repeat target vessel revascularization was significantly decreased by abciximab from 11.2% to 5.8% at 30 days. Hemorrhagic complication were increased by abciximab in RAPPORT, likely as a result of the relatively high heparin doses and long vascular access sheath dwell times (median, 19 hours).
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The introduction of GP Ⅱb/Ⅲa receptor blockade into clinical interventional practice was paralleled by the widespread acceptance of elective coronary stenting as a safe and effective means of decreasing revascularization rates after percutaneous interventions. All of the initial pivotal studies of GP Ⅱb/Ⅲa blockade had excluded enrollment of patients undergoing elective stent implantation, reserving the use of stent for bailout indications. The Evaluation of Platelet Inhibition in STENTing (EPISTENT) trial was designed to evaluate the clinical benefit of abciximab therapy in decreasing ischemic complications among patients undergoing elective stent implantation, as well as to assess the clinical efficacy of abciximab (with balloon angioplasty) relative to stenting. A total of 2 399 patients were enrolled, treated with aspirin, and randomized to receive stent plus placebo, balloon angioplasty plus abciximab, or stent plus abciximab. The primary efficacy composite endpoint of death, MI, or urgent repeat revascularization occurred in 10.8% of patients in the stent plus placebo arm, 6.9% of patients in the balloon plus abciximab arm (36% relative risk reduction, p=0.007), and 5.3% of patients in the stent plus abciximab arm (51% relative risk reduction, p<0.001). Compared with stenting decreased the rates of death, MI, and repeat revascularization. Compared with stenting alone, abciximab with balloon angioplasty was associated with equivalent rates of death and revascularization but greater safety with regard to lower rates of MI. Treatment effect of abciximab was present in all patient subgroups. No increase in hemorrhagic complications was observed in patients receiving abciximab relative to placebo.
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The main problem with this, as well as other classes of agents directed against platelet function or coagulation, is bleeding. Thrombocytopenic occurs in frequently after GP Ⅱb/Ⅲa inhibition but may be profound (platelet count <20 000/mm3); the excess risk of profound thrombocytopenic associated with abciximab (0.4-1%) appears to be higher than with eptifibatide or tirofiban. The development of a human antichimeric antibody response in approximately 5-6% of patients receiving abciximab raises the question of safety of readministration of this agent. No antibodies have been observed to develop in response to treatment with eptifibatide or tirofiban. The cost/benefit ratio of this medicine still need further study.
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Summary
As interventional cardiology has grown, the number of devices available to the operator has expanded greatly. Similarly, our therapeutic armamentarium of anticoagulant and antiplatelet drugs has also grown dramatically. We have just begun the process of technology transfer, moving agents from the structured world of controlled clinical trials to the real world of clinical practice. However, we will have a lot more to learn as our therapeutic options continue to expand in the near future. The task of carrying out relevant clinical trials with these new agents has become much more difficult as the standards of care rapidly evolve. The importance of adequate anticoagulant and antiplatelet therapy for interventional procedures is undisputed. The challenge for clinicians in the years to come will be how to safely, effectively, and appropriately incorporate our expanding therapeutic armamentarium into real-world clinical practice., 百拇医药
单位：100037 北京市，中国医学科学院 中国协和医科大学 心血管病研究所 阜外心血管病医院 冠心病研究室
关键词：
高润霖审校 高润霖审校
急性冠状动脉闭塞目前仍然是经皮冠状动脉腔内成形术(PTCA)面临的一个重要问题，其发生率在2%～11%[1]。由此导致的并发症包括：心肌梗塞(MI)最高发生率达40%，急诊冠状动脉旁路移植术最高6%，同没有发生闭塞的患者相比，其死亡率增加5倍。在导致冠状动脉闭塞的发生原因中，主要包括夹层、血栓形成和血管痉挛。由于支架的广泛应用已基本解决了夹层的防治问题，而硝酸酯类药物也可以预防血管痉挛的发生，其余的三分之一则主要由于血栓形成所致。
PTCA的治疗作用主要是通过挤碎斑块和扩大血管外径来增加血管内径，此外，冠状动脉内超声显示大多数扩张动脉段均有一些内膜夹层[2]。因此，当动脉壁深层组织受到损伤时，就会导致外源性组织凝血通路激活，血栓形成。Steele等检查了猪颈动脉扩张后的病理切片，发现所有受到中膜损伤的血管均有附壁血栓形成，并有明显的血小板沉积，主要是内膜下胶原暴露所致。此外，内皮和内皮下组织的损伤也会导致抗凝血作用的前列环素合成减少。Neuman等[3]证明在扩张部位有中性粒细胞和血小板激活，从而导致斑块撕裂的同时发生血栓形成过程。
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目前，介入性冠状动脉疾病治疗中常用于防治急性血栓形成的抗血小板药物主要包括以下几种。
阿司匹林(aspirin)
既往有3个随机、安慰剂对照临床试验对阿司匹林用于PTCA患者的作用进行了研究(但均同时加用了潘生丁)。在Schwartz等[4]进行的研究中，治疗组患者在PTCA术前开始服用阿司匹林加潘生丁(分别为330 mg，75 mg)每日3次，持续4～6个月，结果治疗组Q波MI发生仅3例，而对照组为13例(P=0.011 3)。另外两个研究结果与此类似。因此，PTCA患者可服用阿司匹林防治急性血栓形成。但阿司匹林在使用过程中存在一些欠缺：不能防止血小板最初的粘附；小剂量或缓释阿司匹林仍然有胃肠道刺激作用，并可以导致出血；可抑制前列环素的合成；但不能抑制血小板激活的许多其它通路如：二磷酸腺苷(ADP)或肾上腺素通路；不能对和纤维蛋白原结合的血小板发生作用；此外，还有15%～45%的人对它没有反应。
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噻氯匹定(ticlopidine)
2个随机、安慰剂对照临床试验报告了噻氯匹定用于不使用阿司匹林的PTCA患者的临床效果，结果可明显减少急性血管闭塞发生率。但其同阿司匹林合用的抗血小板作用没有进行临床试验。两个回顾性研究对此进行了分析[5，6]。结果显示二者合用没有减少急性闭塞、再狭窄和总临床事件发生率。因此，需要新的前瞻性临床试验来验证是否二者合用优于单用一种药物。
最近，许多临床试验检查了噻氯匹定同阿司匹林合用与单独使用阿司匹林对冠状动脉支架置入术患者的作用。在Leon等[7]进行的研究中，557例患者接受单独阿司匹林治疗，550例患者接受阿司匹林加华法林治疗，546例患者接受阿司匹林加噻氯匹定治疗。结果显示：3组的终点事件发生率依次为3.6%、2.4%和0.6%(P<0.001)，阿司匹林加噻氯匹定组患者支架内血栓发生率最低，尽管这组患者出血发生率比单独用阿司匹林组患者高。在MATTIS研究中[8]，阿司匹林加噻氯匹定组患者出血和并发症发生率均低于阿司匹林加口服抗凝剂组。其它研究也得到近似或较为一致的结果。因此，冠状动脉支架置入术后建议合用两种药物。然而，由于噻氯匹定可导致致命的中性粒细胞减少症和血小板减少性紫癜(TTP)，而且起效慢，因此，在应用中应于注意。
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Clopidogrel
Clopidogrel在化学结构上和功能上同噻氯匹定相似，但副作用较少。一项随机、对照比较噻氯匹定和Clopidogrel用于支架置入术患者的临床试验刚刚在欧洲完成。在研究中，1 020例患者分别接受如下治疗：服用300 mg Clopidogrel后每天服用75 mg，持续28天；Clopidogrel每天服用75 mg，持续28天；服用250 mg噻氯匹定后每天2次，每次服用250 mg，持续28天。结果显示：无论Clopidogrel是否加用负荷剂量，其耐受性均好于噻氯匹定，但二者的急性临床事件发生率没有明显差异。因此，如果肯定Clopidogrel的作用至少和噻氯匹定相当，而其副作用明显少于噻氯匹定，则可取代噻氯匹定。事实上，目前已经使用Clopidogrel的50多万例患者中尚没有发现TTP患者。此外，Clopidogrel比噻氯匹定便宜30%，还不需要经常监测患者的血常规。但目前还需要更多的临床试验来回答一些有关Clopidogrel的问题：作用效果是否同噻氯匹定相当？最佳剂量用法如何？同阿司匹林合用于支架置入术患者的效果如何？
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血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂
血小板激活后一个最重要的反应是激活纤维蛋白原受体。这个受体位于未激活的血小板表面，是一种糖蛋白Ⅱb/Ⅲa受体，平时处于无功能状态，当血小板被激活时，受体发生变形，成为有功能型。同这个受体结合的分子有一个特异的识别序列，由精氨酸—甘氨酸—天门冬氨酸组成，简称为RGD序列。含有此序列的药物，也可以和这种受体结合，从而起到抗血小板、抗血栓形成作用。
目前已有超过15 000例冠状动脉介入治疗患者使用了此类药物，已经完成的主要研究包括：使用ReoPro(abciximab或c7E3Fab)的EPIC、EPILOG和CAPTURE研究；使用Tirofiban(Aggrastat)的RESTORE研究和使用Integrelin(intrifiban)的IMPACT Ⅱ研究等。
EPIC研究[9]目的是确定高危PTCA患者使用ReoPro是否可以明显减少急性闭塞的发生率。终点包括30天时死亡，MI或需要再次血管再通手术发生率。结果表明：注射加静脉滴注ReoPro可减少终点事件35%(12.8%比8.3%;P=0.008)，这种有益作用持续到第3年(P＝0.009)，但轻微出血明显增加[10]。人们认为EPIC研究中过多出血是因为肝素剂量造成的，于是进行了ReoPro加小剂量肝素的试验，并用于随后的EPILOG研究[11]，其6个月时临床效果同EPIC研究类似，虽然治疗组有出血减少的趋势，但没有达到统计学差异。CAPTURE研究[12]入选的是对阿司匹林、肝素、硝酸盐类等标准抗心绞痛治疗反应不佳的患者。30天结果也同上述研究类似。但在6个月时，两组间没有差异。
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上述结果明确了ReoPro在PTCA手术中的地位，但除了增加出血的问题外，和它安全性有关的另一个问题是它的免疫原性。由于它是一个人—鼠结合抗体，因此，它用于一个有免疫应答的患者可能会导致严重后果。此外，还有0.4%～1.0%的患者可能发生血小板减少症。
Tirofiban是非肽类的糖蛋白Ⅱb/Ⅲa受体拮抗剂，其分子中含有可以被受体识别的类似RGD序列的结构。同ReoPro不同，它没有免疫原性。经过静脉使用，起效非常快，半衰期短，和出血时间呈剂量依赖的关系。RESTORE研究把tirofiban用于PTCA术后再闭塞的高危患者[13]。此药明显减少了终点事件的发生率，差异在2天(减少38%，P<0.005)和7天(减少27%,P=0.027)时都可以观察到。但30天时两组间没有达到统计学差异。
Integrelin是从蛇毒提取的含有RGD序列的肽段。IMPACT研究目的是确定它是否可以提高普通患者进行PTCA或旋磨治疗的临床效果[14]。150例患者分为3组：Integrelin注射加滴注4小时；Integrelin注射加滴注12小时；或安慰剂组。研究终点为术后30天时死亡、MI和血管再通手术发生率。尽管终点事件有下降的趋势，特别是在12小时组，但没有达到统计学差异，这可能和实验规模太小有关。IMPACT-Ⅱ研究在进行PTCA的患者中比较了两个剂量Integrelin的作用[15]。3 778例患者分为3组：小剂量组、大剂量组或安慰剂组，主要终点同IMPACT研究相同。结果两组剂量的Integrelin都降低了24小时终点事件发生风险(小剂量组是27%，P＝0.017；大剂量组是25%，P＝0.026)，但30天时，Integrelin和安慰剂间没有明显差异。
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目前，此类药物除了用于PTCA患者，还在进行其它适应证的研究。ReoPro用于急性MI直接PTCA治疗的RAPPORT研究已经完成[16]。483例患者分为安慰剂或ReoPro加阿司匹林及肝素组。终点为术后6个月时死亡、MI和血管再通手术发生率。结果两组间没有明显差异。但30天时治疗组明显减少终点事件发生风险(P=0.038)。
血小板糖蛋白Ⅱb/ⅡIa受体拮抗剂同广泛使用冠状动脉支架治疗基本同时进入临床领域。几乎所有早期的临床试验均以PTCA患者为对象。EPISTENT试验[17]对ReoPro用于支架置入术患者的效果进行了研究。2 399例患者随机分为支架加安慰剂，PTCA加ReoPro，支架加ReoPro 3组。由死亡、MI和血管再通手术发生率构成的终点事件发生率依次为10.8%、6.9%(减少风险36%，P=0.007)和5.3%(减少风险51%，P<0.001)。没有发现出血事件增加的现象。
综上所述，血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂代表了目前介入性心脏病学最大进展之一。大规模、随机、对照临床试验已无可争议地确认了其在心脏病介入治疗中的地位，它可大约减少患者围手术期缺血并发症50%～60%，而且，当肝素使用剂量合适时可不明显增加出血事件发生率。但此类药物非常昂贵，目前在我国还难以广泛使用。
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阿司匹林在几年前还是PTCA患者唯一的抗血小板药物，随后噻氯匹定同阿司匹林合用于冠状动脉支架置入术患者，由于Clopidogrel出现后，其作用和噻氯匹定相当，且副作用明显减少，因此有可能取而代之。血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂的出现使抗血小板治疗取得突破性进展，但还需要更多的临床试验验证其同其它抗血小板、抗凝药物合用的临床效果及最佳用法。除了上述的抗血小板药物外，还有其它一些药物正在研制中，如vWF因子抗体和凝血烷A2合酶抑制剂等。希望在不久的将来，随着新药的发展，可以得到疗效更好、副作用更少、价格更低的抗血小板药物，以便为患者提供更好的治疗。
参考文献
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7 Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic drug regimens after coronary artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med, 1998,339:1665—1671.
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9 The EPIC investigators. Use of a monoclonal antibody directed against the platelet glycoprotein Ⅱb/Ⅲa receptors in high-risk coronary angioplasty. N Engl J Med, 1994，330:956—961.
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12 CAPTURE investigators. Randomized placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet, 1997,349:1429—1435.
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15 Aguirre FV, Topol EJ, Ferguson JJ, et al. Effect of platelet glycoprotein(GP) Ⅱb/Ⅲa antagonism with integrelin on activated clotting times during coronary interventions: results from the IMPACT-Ⅱ trial. Circulation, 1996,94(suppl I):I-197-I-198.
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17 The EPISTENT Investigators. Randomized placebo-controlled and balloon angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-Ⅱb/Ⅲa blockade. Lancet, 1998,352:87—92.
Antiplatelet Therapy in Interventional Cardiology
Division of Coronary Heart Disease, Cardiovascular Institute and Fu Wai Hospital, CAMS and PUMC, Beijing (100037)
Qian Jie, Gao Runlin.
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Introduction
Acute coronary occlusion remains a problem in the setting of percutaneous transluminal coronary angioplasty (PTCA). Historically, the frequency of abrupt vessel closure has ranged from 2% to 11%. In -hospital complications include a myocardial infarction rate of up to 40%, a 6% rate of coronary artery bypass grafting and a fivefold increase in mortality, compared with patients without abrupt closure.
In order of frequency, the most common causes of abrupt closure are coronary artery dissection, thrombus formation, and vasospasm. Among the mechanical escape strategies for treating abrupt closure are redilatalion, prolonged balloon inflation, perfusion balloons, directional coronary atherectomy, and intracoronary stenting. The management of flow-limiting dissection has been revolutionized by the use of intracoronary stenting, and spasm can be managed with nitroglycerin. Intracoronary thrombus accounts for the majority of remaining cases in 19-33% of all acute occlusions. However, this is based on angiographic data and most likely represents an underestimation of its true incidence.
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Pathophysiology of intracoronary thrombus formation after percutaneous transluminal coronary angioplasty
The therapeutic increase in internal luminal diameter following PTCA is largely due to plaque fracture as well an increase in external diameter. In addition, most dilated arterial segments also show evidence of at least some intimal dissection when viewed via intra-coronary (IC) ultrasound. When deeper arterial injury occurs, activation of the tissue pathway of thrombus formation often results. Using a heparinized pig model, Steele et al. examined dilated carotid artery segments histologically. All nine pigs with medial tears had mural thrombi. All showed marked platelet deposition, presumably from the exposure of blood to fibrillar collagen, predominately found in the medial and adventitial layers. In addition, the destruction of endothelial and subendothelial layers may lead to a decrease in antithrombotic prostaglandin (prostacyslin) production. In humans, Neuman et al. have demonstrated neutrophil and platelet activation at the site of the balloon-injured coronary artery plaque. The result is an unchecked activation of the coagulation cascade. In patients with acute coronary syndromes (unstable angina, acute MI), plaque rupture may have already occurred spontaneously, resulting in activation of thrombus formation.
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Prevention of Intracoronary Thrombus
There are some routine measures that should be undertaken prior to mechanical intervention to assist in the prevention of acute closure due to thrombus. Most important of these is the use of antiplatelet therapy. The medicine that used in antiplatelet therapy will be discussed here.
Aspirin
Three placebo-controlled randomized trials have evaluated the use of aspirin in patients undergoing balloon angioplasty (although dipyridamole was used in conjunction with aspirin in three studies, dipyridamole and aspirin appear to be no more effective than aspirin alone). In one study, the active-drug group took oral aspirin-dipyridamole combination (330 mg, 75 mg) three times daily, beginning 24 hours before PTCA, and continued four to seven months. Result showed: there were 13 periprocedural Q-wave myocardial infarctions in the placebo group and 3 in the treatment group (p=0.011 3). And other two studies also revealed a significant reduction in adverse events (Q-wave MI and abrupt closure). Thus, the short-term use of antiplatelet agents in relation to PTCA can be recommended. However, aspirin is a suboptimal antiplatelet agent, it has relative weak antiplatelet activity. Furthermore, between 15-45% of patients are resistant to its antiplatelet effects, and many patients do not tolerate it due to gastrointestinal discomfort and bleeding.
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Ticlopidine
Two prospective placebo-controlled randomized trial reported a significant reduction in acute vessel closure with ticlopidine among patients, not on aspirin, who underwent balloon angioplasty. Little is known about whether the efficacy of antiplatelet therapy is increased by combining aspirin with ticlopidine in patients undergoing balloon angioplasty. Two retrospective analyses examining this issue have been performed. The analysis found no benefit from the combination of aspirin and ticlopidine in terms of reducing the frequency of reocclusion, restenosis, or the number of clinical events. A similar analysis of patients undergoing direct angioplasty in the STENT-PAMI trial came to a similar conclusion. So, we need new randomized trials to answer the question if ticlopidine and aspirin are superior to aspirin alone.
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Recently, many randomized trials have examined the combined use of aspirin and ticlopidine in patients undergoing coronary stent placement. For example, in one study 1 965 patients included. There were 557 patients received aspirin alone, 550 patients received aspirin and warfarin, others received aspirin and ticlopidine. The result showed: as compared with aspirin alone and a combination of aspirin and warfarin, treatment with aspirin and ticlopidine resulted in a lower rate of stent thrombosis, although there were more hemorrhagic complication than with aspirin alone. In MATTIS study, 350 high-risk patients included. Result showed that aspirin and ticlopidine treatment group had less bleeding and vascular complication than aspirin and oral anticoagulation treatment group and there is a marked trend suggesting a decrease in cardiac events in ticlopidine group. Other studies also had same result: aspirin and ticlopidine were more effective at reducing stent thrombosis and other major adverse events than aspirin alone and aspirin combined with coumadin. Bleeding was less frequent with aspirin and ticlopidine than aspirin and coumadin. So, after coronary stenting, aspirin and ticlopidine should be considered for the prevention of serious complication of stent thrombosis. However, the main problem of the medicine is neutropenia and thrombocytopenic purpura (TTP) which is life threatening. Furthermore, hematological studies have confirmed the slow onset of action of ticlopidine in patients undergoing stent placement without pretreatment with ticlopidine.
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Clopidogrel
Clopidogrel is a thienopyridine closely related to ticlopidine in chemical structure and function. It has similar efficacy and a better side-effect profile. A randomized trial comparing ticlopidine and clopidogrel among stent patients- the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS) was recently completely in Europe. In this trial, 1 020 stent patients were randomly assigned to receive the following: clopidogrel with a 300 mg loading does followed by 75 mg/day for 28 days; clopidogrel 75 mg without a loading does followed by 75 mg/day for 28 days; or ticlopidine 250 mg followed by 250mg twice daily for 28 days. The results of the trial indicated that clopidogrel, with and without a loading does, was better tolerated than ticlopidine. However, the study was not sized to detect a difference in the frequency of stent thrombosis and other major adverse events. Other study of clopidogrel is undergoing now. If clopidogrel is confirmed to be equivalent (and not superior) to ticlopidine in preventing stent thrombosis and procedural infarction, it nonetheless be preferred because side effects including nausea, vomiting, diarrhea, neutropenia, and TTP are far fewer than with ticlopidine. In fact, with over 500 000 patients treated, TTP has not been reported with clopidogrel. Clopidogrel is approximately 30% less expensive than ticlopidine; the cost of therapy is further reduced by the absence of a need to monitor blood counts in patients treated with clopidogrel. The main problems unanswered about clopidogrel include: Is clopidgrel as effective as ticlopidine, or more effective? What is the optimal loading does of clopidogrel? There are few data indicating an optimal loading does with clopidogrel; a loading does greater than 300 mg may be safe and achieve platelet inhibition even more rapidly. And it remains unclear whether the clopidogrel or ticlopidine are efficacious when combined with aspirin in patients undergoing balloon angioplasty and other interventions, as they clearly are in patients undergoing stent placement.
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GP Ⅱb/Ⅲa blockers
Selective inhibition of the platelet glycoprotein (GP) Ⅱb/Ⅲa surface blocker is a potent mechanism to inhibit platelet aggregation and thrombus formation. Over 15000 patients have been enrolled in pivotal trials of GP Ⅱb/Ⅲa receptor blockade with the parenteral inhibitors abciximab, eptifibatide, and tirofiban during coronary intervention, unequivocally establishing the clinical efficacy of this class of therapy in this setting. Reductions of up to 50-60% in the risk of important clinical endpoints have been achieved with these agents, a treatment effect that extends to all components of the composite clinical endpoints (death, myocardial infarction, and emergency revascularization). The main completed studies include: EPIC, EPILOG, and CAPTURE of abciximab; IMPACT Ⅱ of eptifibatide; RESTORE of tirofiban.
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The role of abciximab therapy among patients undergoing direct or primary angioplasty for acute myocardial infarction was evaluated in the ReoPro in Acute MI Primary PTCA Organization and Randomization Trial (RAPPORT). A total of 483 patients undergoing angioplasty within 12 hours of onset of symptoms were randomized to receive placebo or abciximab in addition to aspirin and heparin. The primary endpoint of death, recurrent MI, or any (elective or urgent) repeat target vessel revascularization by 6 months was not different in the 2 treatment groups, owing to absence of an effect of abciximab therapy on long-term revascularization procedures. The composite endpoint of death, reinfarction, or urgent repeat target vessel revascularization was significantly decreased by abciximab from 11.2% to 5.8% at 30 days. Hemorrhagic complication were increased by abciximab in RAPPORT, likely as a result of the relatively high heparin doses and long vascular access sheath dwell times (median, 19 hours).
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The introduction of GP Ⅱb/Ⅲa receptor blockade into clinical interventional practice was paralleled by the widespread acceptance of elective coronary stenting as a safe and effective means of decreasing revascularization rates after percutaneous interventions. All of the initial pivotal studies of GP Ⅱb/Ⅲa blockade had excluded enrollment of patients undergoing elective stent implantation, reserving the use of stent for bailout indications. The Evaluation of Platelet Inhibition in STENTing (EPISTENT) trial was designed to evaluate the clinical benefit of abciximab therapy in decreasing ischemic complications among patients undergoing elective stent implantation, as well as to assess the clinical efficacy of abciximab (with balloon angioplasty) relative to stenting. A total of 2 399 patients were enrolled, treated with aspirin, and randomized to receive stent plus placebo, balloon angioplasty plus abciximab, or stent plus abciximab. The primary efficacy composite endpoint of death, MI, or urgent repeat revascularization occurred in 10.8% of patients in the stent plus placebo arm, 6.9% of patients in the balloon plus abciximab arm (36% relative risk reduction, p=0.007), and 5.3% of patients in the stent plus abciximab arm (51% relative risk reduction, p<0.001). Compared with stenting decreased the rates of death, MI, and repeat revascularization. Compared with stenting alone, abciximab with balloon angioplasty was associated with equivalent rates of death and revascularization but greater safety with regard to lower rates of MI. Treatment effect of abciximab was present in all patient subgroups. No increase in hemorrhagic complications was observed in patients receiving abciximab relative to placebo.
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The main problem with this, as well as other classes of agents directed against platelet function or coagulation, is bleeding. Thrombocytopenic occurs in frequently after GP Ⅱb/Ⅲa inhibition but may be profound (platelet count <20 000/mm3); the excess risk of profound thrombocytopenic associated with abciximab (0.4-1%) appears to be higher than with eptifibatide or tirofiban. The development of a human antichimeric antibody response in approximately 5-6% of patients receiving abciximab raises the question of safety of readministration of this agent. No antibodies have been observed to develop in response to treatment with eptifibatide or tirofiban. The cost/benefit ratio of this medicine still need further study.
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Summary
As interventional cardiology has grown, the number of devices available to the operator has expanded greatly. Similarly, our therapeutic armamentarium of anticoagulant and antiplatelet drugs has also grown dramatically. We have just begun the process of technology transfer, moving agents from the structured world of controlled clinical trials to the real world of clinical practice. However, we will have a lot more to learn as our therapeutic options continue to expand in the near future. The task of carrying out relevant clinical trials with these new agents has become much more difficult as the standards of care rapidly evolve. The importance of adequate anticoagulant and antiplatelet therapy for interventional procedures is undisputed. The challenge for clinicians in the years to come will be how to safely, effectively, and appropriately incorporate our expanding therapeutic armamentarium into real-world clinical practice., 百拇医药