The Antiplatelet Saga Continues
--------------------------------------------------------------------------------STROKE 杂志:
CHARISMA
The Antiplatelet Saga Continues
John W. Norris, MD; Henry J. Barnett, MD, CC
Ever since the Antithrombotic Trialists reported a clear benefit from aspirin in the secondary prevention of vascular disease in patients with a variety of cardiovascular events,1 there has been a search for more effective antithrombotic agents. The first relatively nontoxic drug to undergo randomized clinical trial was clopidogrel in the CAPRIE study2 (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) where 3 groups of patients (myocardial ischemia (MI), ischemic stroke or peripheral arterial disease) were given either aspirin or the drug. The compound end point of MI, ischemic stroke and vascular death was significantly reduced by clopidogrel compared with patients taking aspirin. However, the substantial benefit on vascular outcome evident in the peripheral vascular group was not shared by either the stroke patients or those with MI.
Because aspirin and clopidogrel have different biochemical pathways inhibiting platelet adhesiveness, a combination of the 2 drugs might be even more effective in secondary prevention of vascular events. In CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) the dual antiplatelet therapy was found even more beneficial than clopidogrel alone in reducing combined cardiac and cerebral ischemic end points,but a group with aspirin alone was not included.3 This was followed by CREDO (Clopidogrel for the Reduction of Events During Observation), and once again clopidogrel was found more effective than placebo in reducing the compound end points of death and myocardial and cerebral infarction in patients undergoing percutaneous coronary intervention.
However, all these studies failed to show any significant prophylactic effect on the outcome of patients with cerebral ischemia. In the MATCH study (Management of Atherothrombosis with Clopidogrel in High risk patients) a combination of clopidogrel and aspirin was compared with clopidogrel alone specifically in patients with ischemic stroke or transient ischemic attacks (TIAs).5 The addition of aspirin made no significant difference to reducing subsequent major vascular events but did increase the risk of bleeding.
The CHARISMA trial (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance) was designed to specifically address patients at particularly high vascular risk.6 Over 15 000 patients with either cardiac, cerebral or peripheral ischemia, or asymptomatic patients (with multiple vascular risk factors) were followed for a mean of 28 months. The results were disappointing. The combination of clopidogrel and aspirin was no more effective than aspirin alone in reducing the rate of subsequent myocardial infarction, stroke or vascular death. Also, as in the MATCH trial, the dual antiplatelet combination caused more frequent and more serious
bleeding.
Are these results so surprising? Examining the CAPRIE data, there is no doubt that the compound end points were significantly fewer in the clopidogrel group compared with the aspirin group. However, when the 3 individual outcomes (myocardial ischemia, stroke and peripheral vascular disease) were evaluated separately, only the relative risk reduction (RRR) for peripheral vascular disease (PVD) was effectively reduced: (stroke 7.3%, MI _3.7% and PVD 23.8%) The trialists attributed the discrepancy in the stroke group to the heterogeneity of the disorder, a correct but frequently overlooked observation. Similarly, in the CURE study, when the 3 components of the compound end point are analyzed separately, there is a significantly beneficial effect on MI, but
only a nonsignificant beneficial trend in ischemic stroke. In fact, the MI patients had unstable angina, a high risk condition already established by pathological studies to be
specifically induced by intramyocardial platelet emboli. Because the MATCH trial showed that the clopidogrel and aspirin combination was no more effective in secondary prevention than clopidogrel alone, and because the risk of serious bleeding complications with dual antiplatelet therapy was 3.0%, use of this combination in patients with stroke or TIA cannot be recommended.
CHARISMA was a well conducted study, with prespecified end points, clearly defined entry criteria, and although sponsored by Industry, there was considerable autonomy in the conduct of the trial by the investigators. However, the lack of any major therapeutic effect is not so surprising, considering that in CAPRIE the overall RRR of clopidogrel compared with aspirin was only 8.7%, with an absolute risk reduction of only 0.5%, mostly from the effect on PVD. In MATCH, the closest analogous trial, results were similar, with a 5.9% RRR and a mere 0.72% absolute risk reduction.
What have we learned so far from over 20 years of antiplatelet trials? Accumulating evidence indicates that clopidogrel is only marginally more effective than aspirin in
secondary prevention of vascular end points, and this effect is predominantly on peripheral vascular disease and those with unstable angina. There is no convincing evidence that clopidogrel (either alone or combined with aspirin) improves the outcome in patients presenting with TIA or stroke, and the cost is 80 times that of aspirin alone. Further antiplatelet studies are currently in progress. However, in spite of over a decade of
expensive and time consuming antiplatelet drug wars, the simple fact remains that aspirin is still the first choice of antiplatelet agents in the secondary prevention of stroke.
Also, unlike heart attacks, brain attacks are a misnomer, and include patients with a great variety of different etiologies, all with differing responses to antiplatelet agents. It is time to discard compound end points and conduct trials restricted to clearly defined types of ischemic stroke, even though this may require larger numbers of subjects. Otherwise, history will just keep repeating itself. 非凡的领导力
――抗血小板传奇继续
John W. Norris, MD; Henry J. Barnett, MD, CC
自从抗栓实验报道阿司匹林对各种心血管事件患者的血管病二级预防有明确益处以来，人们一直在探索更有效的抗栓剂。首先经受随机对照临床试验的是相对无毒药物氯吡格雷，在CAPRIE研究（缺血事件高危患者氯吡格雷与阿司匹林的比较）中，三类患者（心肌缺血，缺血性卒中患者或周围动脉病）给予阿司匹林或氯吡格雷治疗。与阿司匹林组相比，氯吡格雷组显著减少由心肌缺血、缺血性卒中和血管性死亡组成的联合终点事件。然而，卒中和心肌缺血患者并不像周围血管病患者那样在血管结局方面获得明显的实质利益。
因为阿司匹林和氯吡格雷在抑制血小板黏附方面有不同的生化机制，两药的联合应用可能对血管事件的二级预防更有效。在CURE（氯吡格雷预防不稳定心绞痛患者的复发事件）研究中发现，在降低心脑缺血联合终点事件方面，双重抗血小板治疗比单独应用氯吡格雷更有益，但并不优于单独应用阿司匹林组。随后的CREDO（氯吡格雷减少观察期内事件）研究中再次发现，在经皮冠脉介入术后患者中，氯吡格雷较安慰剂组更能有效减少由死亡、心肌及脑梗塞组成的联合终点事件。
然而，所有这些研究对脑缺血患者结局未见显著预防效果。MATCH研究（在高危患者中应用氯吡格雷处理动脉粥样硬化性血栓形成）中，针对缺血性卒中或短暂性脑缺血发作（TIAs）患者联用氯吡格雷和阿司匹林与单用氯吡格雷对照。加用阿司匹林在减少以后主要的血管事件方面并没有显著不同但确实增加了出血风险。
CHARISMA试验（氯吡格雷对高度的动脉粥样硬化性血栓形成风险和缺血稳定的处理和预防）专门针对有特别高血管事件风险患者而设计。这个试验随访超过15000名有心、脑或周围血管缺血患者平均28个月，结果令人失望。联用氯吡格雷和阿司匹林较单用阿司匹林在减少后来的心肌梗塞、卒中或血管性死亡事件比率方面效果相当。而且在MATCH试验中双重抗血小板治疗导致更多、更严重的出血。
这些结果令人惊讶么？分析CAPRIE研究数据，毫无疑问氯吡格雷组较阿司匹林组减少了联合终点事件。然而，当我们分别对这三类患者结局（心肌缺血，卒中和周围血管病）单独分析时发现，仅周围血管病患者的相对危险降低率减少有显著意义（卒中组7.3％，心肌缺血组-3.7％，周围血管病组23.8％）。这个试验将卒中类患者的偏差归结为一种正确但常易忽略的观测所致的混杂偏倚。同样在CURE研究中，当把联合终点事件的三个成分拿出来单独分析时，发现对心肌缺血患者效果有显著差异，但对缺血性卒中患者差异无显著性。事实上，心肌缺血患者有不稳定心绞痛，病理学研究已证实这种高危状态可由心肌内血小板栓子诱发。因为MATCH试验显示氯吡格雷和阿司匹林联合治疗在二级预防中并不比单用氯吡格雷组更有益，且双重抗血小板治疗所致严重出血并发症风险为3％，因此不推荐在卒中或TIA患者中联合应用氯吡格雷和阿司匹林。
CHARISMA研究管理规范，有预先限定的终点事件及明确的入围标准，尽管由企业赞助，但研究者对试验的管理有很大的自主性。然而考虑到在CAPRIE研究中氯吡格雷组较阿司匹林组整体的相对危险降低率仅为8.7％，绝对危险降低率仅为0.5％，且主要来自对周围血管疾病的影响，则CHARISMA研究主要疗效的缺乏并不那么令人惊讶。在与之最类似的MATCH试验中，结果差不多，相对危险降低率为5.9％，绝对危险降低率仅为0.72％。
到目前为止我们从20多年的抗血小板实验中学到了什么？累积的证据表明氯吡格雷在血管性终点事件的二级预防方面较阿司匹林部分有效，主要是指对周围血管疾病及不稳定心绞痛患者。目前没有令人信服的证据表明氯吡格雷（单用或与阿司匹林联用）较单用阿司匹林可以改善TIA或卒中患者的结局，且费用为后者的80倍。当前更多的抗血小板研究还在进行当中，然而，经过十几年既花钱又费时的抗血小板药物斗争，简单的事实仍是：阿司匹林在卒中的二级预防中仍是一线抗血小板药。
另外，不像心脏病发作，脑发作是一个误称，包含各种各样对抗血小板药反应均不同的不同病因的患者。即使需要更多的受试者，也该是抛弃联合终点事件并实施限于明确的缺血性卒中类型的试验的时候了。否则，历史将只是重复它自己。
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