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![[SYMPOSIUM]](../../../graphics/sym_logo.gif){kind=logo} SYMPOSIUM ON STROKEStroke preventionMATCHing therapy to the patient with TIA Nicolas U. Weir, MD, MSc, MRCP; Andrew M. Demchuk, MD, FRCPC; Alastair M. Buchan, MB, FRCPC; Michael D. Hill, MD, MSc, FRCPC VOL 117 / NO 1 / JANUARY 2005 / POSTGRADUATE MEDICINE
CME learning objectives
Dr Hill has received support from the Heart and Stroke Foundation of Alberta, Northwest Territories and Nunavet and the Canadian Institutes of Health Research. The authors disclose unlabeled use of aspirin and clopidogrel in combination for acute, short-term treatment (a few weeks) after minor stroke or TIA.
Preview: The short-term risk of stroke after transient ischemic attack (TIA) is about 10% to 20% in the first 3 months, with much of the risk front-loaded in the first week. Unfortunately, little is known about the best therapies for hyperacute stroke prevention after TIA. A recent trial referred to by the acronym MATCH (for Management of Atherothrombosis With Clopidogrel in High-risk Patients With Recent Transient Ischemic Attack or Ischemic Stroke) provides hypothesis-generating data to suggest that double antiplatelet therapy in the short term may be appropriate. Here, the authors discuss treatment considerations, outlining the current knowledge and stressing the need for formal randomized trials to definitively establish the effectiveness of preventive therapies after minor stroke or TIA.
Minor stroke and TIA are true medical emergencies, akin to unstable angina, that merit rapid diagnosis and intervention. Regrettably, however, in most parts of the world, health services have yet to catch up with this new understanding. They continue to manage minor stroke and TIA in a leisurely manner, offering "fast track" assessment within "only a few weeks" of the event. That said, beyond the knowledge that aspirin should be started within 48 hours of symptom onset, there is little data from randomized trials to guide management of minor stroke or TIA in the acute phase. Nearly all secondary prevention trials have recruited patients weeks to months after symptom onset and thus have missed the patients at highest risk--who by then have already had a stroke and hence are excluded from trial enrollment. Currently, physicians must rely on common sense in their selection of treatments, which essentially means starting established forms of secondary prevention as soon as possible. The importance of this approach has been demonstrated for carotid endarterectomy, in which maximum protection results from intervention within 2 weeks of an index event but no protection or even harm from intervention that is delayed beyond 3 months (1). Nonetheless, we continue to lack treatments specific to the acute phase of minor stroke and TIA, in which the high absolute risks may justify use of more powerful and riskier interventions than usually prescribed. These interventions might include, for example, various combinations of antiplatelet agents, novel antiplatelet agents, anticoagulants, acute blood pressure management, high-dose statin therapy, and ultra-early carotid revascularization. Lessons from the MATCH trialAlthough there have been no TIA trials of acute therapy to prevent early recurrence, two trials of double antiplatelet therapy have now been conducted. Results of the recent MATCH trial were much awaited. For this trial, investigators randomly assigned patients with stroke or TIA to receive aspirin or placebo over a baseline therapy of clopidogrel (75 mg daily) (2). Patients were at high atherosclerotic risk, determined by the presence of at least one of five risk factors: prior stroke, prior myocardial infarction (MI), angina pectoris, peripheral vascular disease, and diabetes. The primary outcome of the trial was a composite of stroke, MI, vascular death, and hospitalization for a vascular event. In total, 7,599 patients were enrolled and observed for 18 months. The main finding was that compared with clopidogrel alone, dual antiplatelet therapy led to both a nonsignificant reduction in the number of primary outcome events (absolute risk reduction, 1.0% [95% confidence interval (CI), -0.6% to 2.7%]; relative risk reduction, 6.4% [95% CI, -4.6% to 16.3%; P=.244]) and a significant increase in the number of life-threatening bleeding events (absolute risk increase, 1.3% [95% CI, 0.6% to 1.9%; P=.0001]). The increased risk of bleeding outweighed the benefits, and on balance, combination therapy was harmful when taken for 18 months (odds ratio for stroke, MI, vascular death, or major or life-threatening bleeding, 1.15 [95% CI, 1.01 to 1.30; P=.03]; absolute risk increase, 1.7%) (3). The MATCH data do not inform routine practice easily, however. In nearly all systems of healthcare, aspirin--not clopidogrel (Plavix)--is the antiplatelet agent of first choice. This is because (1) the evidence is more extensive and robust in support of aspirin than of clopidogrel (4); (2) for unselected patients with recent ischemic stroke, the benefit of clopidogrel over aspirin is not statistically significant (5); and (3) aspirin is cheap and thus highly cost-effective, while clopidogrel is more expensive. Nevertheless, there is evidence to support the superiority of thienopyridines over aspirin. A post hoc analysis of the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study (6) showed that in patients with preexisting symptomatic atherosclerotic disease, clopidogrel prevented a slightly greater number of serious ischemic events and vascular deaths than aspirin. In addition, a meta-analysis of randomized trials that compared aspirin with any thienopyridine (ie, clopidogrel or ticlopidine) (7) showed that thienopyridines afforded significantly, yet still marginally, better secondary prevention. It can be argued, therefore, that the MATCH trial investigated the benefits of combination therapy with aspirin and clopidogrel compared with the best antiplatelet agent (ie, clopidogrel) for a selected group of patients in an ideal world (where cost is not an issue). However, on a global basis, the question physicians really need answered is not whether aspirin adds to the benefit of clopidogrel but whether clopidogrel adds to the benefit of aspirin--and if any such improvement is sufficient to justify the cost of changing practice. Similarly, the MATCH data are not easy to generalize to all patients with minor stroke and TIA. First, many patients with minor stroke and TIA have none of the five risk factors stipulated in the study's inclusion criteria. Second, the study enrolled a disproportionately high number of patients with diabetes (68%) and hypertension (78%) and thus predominantly evaluated patients with small-vessel events (52%). Patients with lacunar events are more likely than those with large-artery or cardioembolic events to harbor evidence of past microhemorrhages on magnetic resonance imaging (8), and it is postulated that these patients are at increased risk of subsequent intracranial hemorrhage (8,9). Conceivably, the heightened risk of intracranial hemorrhage in patients taking aspirin and clopidogrel in the long term relates mainly to this subgroup. In contrast, only 34% of trial participants were thought to have had a minor stroke or TIA due to large-artery disease. Yet this is the very subgroup at highest risk for early recurrence of acute ischemic stroke (10,11). In this subgroup, the benefits of long-term use of aspirin and clopidogrel may outweigh the risks of bleeding, but these data were not reported. More encouraging, MATCH data provide helpful information about use of aspirin and clopidogrel soon after a minor stroke or TIA. Compared with clopidogrel alone, this combination therapy led to a 3.1% absolute reduction in the number of primary outcome events for patients enrolled within 7 days of their index event. On the other hand, the data show only a 1.4% absolute reduction for patients enrolled between 7 and 31 days and a 0.6% absolute increase for patients enrolled after 1 month. Although this trend was not statistically significant (P~.1), it was notable that the increased risk of intracranial bleeding associated with combination therapy became apparent only after 3 months and thereafter was evenly spread over time. Put simply, the MATCH data raise the possibility of short-term benefit, followed by longer-term harm, from combination therapy. Hence, a short course of aspirin and clopidogrel started immediately after a minor stroke or TIA may be an effective and safe way to provide ultra-early secondary prevention. Lessons from other recent trialsVarious trials in the fields of coronary artery disease treatment and cerebrovascular surgery support the suggestion that early use of aspirin and clopidogrel may be effective in certain high-risk settings. For example, the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) study (12) randomly assigned patients with unstable angina to clopidogrel or placebo (in addition to standard therapy) within 24 hours of symptom onset. The trial showed a clear benefit from clopidogrel, the advantage emerging within hours of randomization. A post hoc analysis of the Clopidogrel for the Reduction of Events During Observation (CREDO) trial (13) investigated use of clopidogrel in patients undergoing percutaneous coronary interventions. Its results showed greater protection from MI, stroke, and death in patients who received clopidogrel 6 to 24 hours before intervention than in those who received it 3 to 6 hours before the procedure. Additionally, a recent study on carotid endarterectomy (14) showed a reduction in microembolic signals postoperatively among patients who were treated with clopidogrel in addition to routine aspirin therapy. Interestingly, both the CURE and CREDO trials showed benefit from several months of treatment with combination therapy (12,13). Of course, as noted by Rothwell (3), it is important not to assume that what is true for coronary circulation is necessarily also true for cerebral circulation. Nonetheless, it seems likely that large-artery biology in carotid and vertebral arteries is at least similar to that in coronary arteries. In contrast, large-artery biology in coronary arteries seems unlikely to apply to small-artery lacunar disease or cardioembolic stroke. Alternative double-antiplatelet therapy with aspirin and extended-release dipyridamole has also been espoused on the basis of findings in the second European Stroke Prevention Study (ESPS-2) (15). Long-term therapy with this combination is safe, causes no increase in intracranial hemorrhage, and seems to provide greater protection from stroke than use of aspirin alone (15). However, little is known about the use of aspirin and dipyridamole in the acute phase after TIA or stroke, because ESPS-2 enrolled patients weeks after their event. The Calgary approachThe Calgary Stroke Program serves metropolitan Calgary and southern Alberta. Patients with TIA receive triage by telephone or in person in the emergency department according to clinical presentation. Those with vision or speech disturbance or weakness are considered to have a high-risk TIA and are immediately admitted to hospital to expedite their workup. By comparison, the condition of patients with isolated numbness, dysarthria, or dizziness is deemed more benign, and these patients are referred for outpatient clinical assessment, usually within a few days. The need to admit high-risk patients arose from our inability to routinely arrange investigations and manage their treatment as outpatient care within 48 hours. This necessity for speed has undoubtedly led to an increasing burden on our stroke services. Investigations at the Calgary Stroke Program focus on evaluation of the heart and cerebral vasculature. Among patients admitted to hospital, about 12% have symptomatic carotid stenosis suitable for revascularization by endarterectomy or stent placement. The procedure is usually carried out within a few days of presentation. All patients receive, as appropriate, antiplatelet therapy with aspirin, anticoagulation for atrial fibrillation, blood pressure management, statin therapy, and education about lifestyle, cigarette smoking, obesity, and exercise (16). If the mechanism of the event is thought to be large-artery disease but is not symptomatic carotid artery disease suitable for revascularization, we treat empirically with aspirin and clopidogrel for 3 months and then discontinue the clopidogrel. Whenever possible, however, we prefer to enter patients into a clinical trial. FASTER, an ongoing trialThe Fast Assessment of Stroke and TIA to Prevent Early Recurrence (FASTER) study is the first trial designed to provide information specifically related to hyperacute treatment of patients with minor ischemic stroke (National Institutes of Health Stroke Scale, <3) and TIA. Specifically, the trial will investigate the efficacy of a short course of double antiplatelet therapy and the impact of early use of simvastatin (17). It has a factorial design and is randomly assigning patients within 24 hours (ideally within 12 hours) of symptom onset to receive clopidogrel or placebo and simvastatin or placebo over baseline aspirin therapy. The primary outcome is stroke within 90 days. The pilot phase of FASTER started in 2002 and is well under way at 18 centers in Canada. The multinational phase of the trial, which aims to recruit 7,500 patients, is planned to start once the pilot phase is complete (18). ConclusionThe high risk of stroke after an initial minor stroke or TIA is now well understood. However, much remains to be learned about the best way to manage patients with these conditions. The MATCH data raise the intriguing possibility that a short course of aspirin and clopidogrel, started soon after an initial event, may be peculiarly effective at preventing stroke recurrence. Also, there is reason to suspect that combination therapy may be especially effective in patients with recent large-artery events. The FASTER trial represents a first step in trying to answer some of these questions and may serve as a model for acute stroke prevention trials in the future. Blood pressure management, use of a statin, reduction of blood glucose levels, and the timing of surgical or endovascular interventions in the acute setting of TIA and minor stroke also require assessment in the context of randomized clinical trials. References
Dr Weir is a stroke fellow, Dr Demchuk is associate professor and consultant stroke neurologist, and Dr Buchan is professor and consultant stroke neurologist, Calgary Stroke Program, department of clinical neurosciences, University of Calgary Faculty of Medicine, Foothills Medical Centre, Calgary, Alberta, Canada. Dr Hill is assistant professor and consultant stroke neurologist, Calgary Stroke Program, departments of clinical neurosciences, medicine, and community health, University of Calgary Faculty of Medicine, Foothills Medical Centre. Correspondence: Michael D. Hill, MD, Calgary Stroke Program, Department of Clinical Neurosciences, University of Calgary Faculty of Medicine, Foothills Medical Centre, Room 1242A, 1403 29th St NW, Calgary, Alberta T2N 2T9 Canada. E-mail: michael.hill@calgaryhealthregion.ca.
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