Optimizing Antiplatelet Therapy To Prevent Ischemic Stroke

Up to 30% of ischemic stroke survivors will have another stroke within five years, 18% of which will be fatal—and most of which are largely preventable, say the authors. The two neurologists report and discuss the latest findings on the relative merits of aspirin, ticlopidine, clopidogrel, and the combination of aspirin with dipyridamole in reducing ischemic stroke risk.

By Kelly D. Flemming, MD, and David O. Wiebers, MD

Stroke is a leading cause of disability in the United States, affecting over 700,000 people every year. Up to 30% of ischemic stroke survivors will have a subsequent stroke within five years, 18% of which will be fatal. Within that same time frame, mortality from myocardial infarction (MI) in stroke survivors can be as high as 39%, underscoring the importance of recognizing concomitant coronary disease in patients presenting with ischemic stroke or transient ischemic attack (TIA).

The use of antiplatelet therapy in combination with aggressive risk factor reduction can significantly decrease the risk of recurrent ischemic stroke, TIA, and vascular death. Relative risk reductions associated with risk factor management exceed those of the antiplatelet agents. Concomitant risk factor assessment and treatment, therefore, cannot be overemphasized as an integral component of stroke prevention. The focus of this article, however, will be the indications for and comparative efficacies of various antiplatelet agents in preventing ischemic stroke.

ASPIRIN USE: PRIMARY PREVENTION AND ACUTE INTERVENTION

While the efficacy of aspirin in the primary prevention of MI has been established, data on its role in the primary prevention of ischemic stroke and TIA are lacking. A recent meta-analysis combined five randomized trials, including the U.S. Physicians Health Study, to evaluate the safety and efficacy of aspirin versus placebo in the primary prevention of vascular disease. The results showed a 26% relative risk reduction in MI over an average of 4.6 years in 52,251 patients without clinically evident vascular disease. There was no significant reduction in stroke incidence, however, and an increased risk of intracranial hemorrhage was found in those patients treated with aspirin compared to placebo (relative risk, 1.35). This and other studies evaluating the efficacy of aspirin in the primary prevention of cerebral ischemic events, it should be pointed out, have been criticized because of low event rates and the fact that trial participants are often outside the age range of interest in ischemic stroke.

To date, no convincing evidence exists demonstrating the efficacy of aspirin in the primary prevention of stroke in patients without clinical evidence of vascular disease. However, those at higher risk because of a prior MI or angina, peripheral vascular disease, or hypertension may experience a modest benefit in the reduction of vascular events with daily use of aspirin.

As for acute intervention, little was known about the efficacy of early aspirin use in ischemic stroke until two recent large clinical trials, the Chinese Acute Stroke Trial (CAST) and the International Stroke Trial (IST). The CAST randomized over 20,000 patients who had had an acute ischemic stroke to 160 mg/day of aspirin or placebo. Over the four-week treatment period, there was a 14% relative risk reduction in mortality among the aspirin-treated patients (3.3% deaths vs. 3.9% in the placebo group). In addition, there were fewer recurrent ischemic strokes in the aspirin group. Similarly, the IST suggested a significant reduction in death and recurrent stroke with aspirin therapy. Taken together, the results of these two trials suggest that nine deaths or nonfatal strokes could be prevented per 1000 patients treated acutely with aspirin.

The value of hyperacute treatment with aspirin (within four to six hours of stroke onset) is not well known. Mean time to treatment in the CAST was 25 hours; in the IST, 19 hours.

Therefore, in the acute setting, aspirin 160 to 325 mg should be given at the onset of cerebral ischemic symptoms to prevent early death, recurrent infarction, and disability. No other antiplatelet agents have been studied in the acute setting. It is important to note, however, that aspirin should not be given within 24 hours of administering tissue plasminogen activator.

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SECONDARY PREVENTION WITH ASPIRIN

Various antiplatelet agents are currently available for secondary prevention of cerebral ischemic events and vascular death after a first ischemic stroke or TIA (see table below). These agents, which inhibit specific sequences in the clot formation process, include aspirin, ticlopidine, clopidogrel, and an aspirin-dipyridamole combination. Additional antiplatelet agents, such as the glycoprotein IIa/IIIb receptor antagonists, are currently in phase 2 studies. In the secondary prevention of ischemic stroke, attention must also be paid to primary prevention of MI and peripheral vascular disease since atherosclerosis (the primary underlying mechanism in 15% to 25% of patients with stroke) in one vascular bed is predictive of atherosclerosis in others.

Numerous studies have evaluated the safety and efficacy of aspirin in patients who have had an ischemic stroke or TIA. Several of these studies, however, were inconclusive because there were too few patients and event rates. The Antiplatelet Trialists' Collaboration (ATC), a meta-analysis of 145 randomized trials, evaluated the benefit of aspirin as well as other antiplatelet agents in various populations of patients at risk for vascular events. Overall, aspirin reduced the odds of nonfatal stroke by 31%, nonfatal MI by 35%, and the combined endpoint of stroke, MI, or vascular death by 25%. In those patients who had had an ischemic stroke or TIA, there was an odds reduction of 22% for nonfatal stroke, MI, or vascular death.

More recently, two meta-analyses have evaluated the effect of aspirin on ischemic stroke or TIA patients only. Algra and van Gijn performed a meta-analysis of 10 trials comparing aspirin to placebo in such patients. They concluded that aspirin doses above 30 mg/day reduce the relative risk of vascular events in patients with ischemic stroke or TIA by 13%. Similarly, a meta-analysis by Johnson concluded that aspirin reduced the relative risk of stroke by 15% in these patients. This was true whether a dose of 50 mg/day or 1600 mg/day was used.

Because of differences in primary outcome measurements and statistical analysis, the relative risk noted in these two meta-analyses is somewhat less than that suggested by the ATC. In the ATC, the primary outcome was stroke, MI, or vascular death; in the Johnson meta-analysis, the primary outcome was stroke alone. Furthermore, the ATC used odds ratios and odds reduction whereas the other two studies used relative risk reductions. This is important because odds ratios can exaggerate the risk.

What dose of aspirin to use in the secondary prevention of ischemic stroke or TIA had long been in question, with doses ranging from 30 mg/day to 1600 mg/day in various studies. The ATC and the meta-analyses by Johnson and by Algra and van Gijn, however, suggest no major difference in outcome with low, medium, and high doses of aspirin. In addition, the Second European Stroke Prevention Study (ESPS-2) also found that an aspirin dose as low as 50 mg/day was safe and efficacious.

However, these studies did find significant differences in bleeding rates with low, medium, and high doses, with higher rates associated with higher doses. Therefore, the Food and Drug Administration (FDA) and the American College of Chest Physicians currently recommend 50 to 325 mg/day of aspirin for secondary prevention of vascular disease and death in patients with recent ischemic stroke or TIA.

Aspirin is generally well tolerated. However, besides the risk of bleeding, it has also been associated with gastrointestinal upset. The risk of side effects increases with higher doses of aspirin.

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TICLOPIDINE AND CLOPIDOGREL

Ticlopidine was the first thienopyridine to be released. Two main studies looked at the safety and efficacy of ticlopidine in patients with ischemic stroke or TIA. The Canadian American Ticlopidine Study (CATS) trial randomized 1072 patients with recent thromboembolic stroke to either ticlopidine 250 mg twice daily or placebo and followed them for up to three years. The primary endpoint in this study was stroke, MI, or vascular death. In an intention-to-treat analysis, patients enrolled in the ticlopidine arm had a 23.3% relative risk reduction compared to placebo in preventing the primary outcome events.

The Ticlopidine Aspirin Stroke Study (TASS) compared ticlopidine 250 mg twice daily to aspirin 1300 mg daily in patients with recent ischemic stroke or TIA. The study found a 12% relative risk reduction in the primary endpoint of nonfatal stroke or death from any cause. Combining data from the CATS, TASS, and ATC trials, the relative risk reduction of ticlopidine over aspirin is approximately 10%.

Common side effects of ticlopidine include diarrhea and gastrointestinal upset. In some cases, diarrhea may be severe; other potentially severe side effects include skin rash, cholestatic jaundice, and neutropenia. In addition, 60 reported cases of thrombotic thrombocytopenic purpura (TTP) have been reported in association with ticlopidine. For these reasons, the manufacturer recommends monitoring liver function tests and obtaining a complete blood count with differential at baseline and every two weeks for three months thereafter if infection is suspected. Because other medications are equally efficacious and have less serious side effects, ticlopidine is not recommended as a first-line antiplatelet agent in the treatment of ischemic stroke.

Clopidogrel was the second thienopyridine to be introduced. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial is the only one that has assessed the safety and efficacy of clopidogrel. Unlike other studies, CAPRIE enrolled not only patients with ischemic stroke but also those with recent MI and peripheral vascular disease. More than 19,000 patients were randomized and stratified by vascular subtype to receive clopidogrel 75 mg/day or aspirin 325 mg/day in this double-blind, placebo-controlled intention-to-treat trial. The primary endpoints included ischemic stroke, MI, or vascular death. Additional endpoints included analyses of all vascular death and all-cause mortality.

Overall, there was an 8.7% relative risk reduction in primary outcome events in patients taking clopidogrel compared to those taking aspirin. In the ischemic stroke subgroup, however, there was no significant difference in primary endpoints between clopidogrel and aspirin (relative risk reduction, 7.15% vs. 7.71%, respectively; p=0.26). The most significant relative risk reduction (23.8%) was seen in the subgroup with peripheral vascular disease. The authors concluded that 24 major clinical events could be prevented if 1000 patients were treated with clopidogrel for one year.

Clopidogrel is well tolerated. Significant side effects may include dyspepsia, rash, diarrhea, and, rarely, intracerebral hemorrhage. In June 2000, a report revealed that 11 of the 3 million patients who had received clopidogrel had developed TTP. In those 11 cases, TTP occurred most often during the first two weeks of therapy. The manufacturer has since revised the labeling to warn of this potential complication.

ASPIRIN/DIPYRIDAMOLE COMBINATION

Several early trials evaluating the safety and efficacy of dipyridamole alone or in combination with aspirin versus aspirin alone showed no additional benefit in the combined endpoint of MI, stroke, and vascular death. The lack of efficacy, however, was attributed to sample size and low event rate.

The first European Stroke Prevention Study (ESPS-1) showed a 30% relative risk reduction in vascular events with the combination of aspirin and dipyridamole compared with placebo. Because this trial did not compare the aspirin/dipyridamole combination with aspirin alone, the ESPS-2 was conducted. This trial used a factorial design randomizing 6602 patients with recent ischemic stroke or TIA to one of four treatment regimens: placebo, aspirin 25 mg twice daily, extended-release dipyridamole 200 mg twice daily, or a combination of aspirin 25 mg twice daily and extended-release dipyridamole 200 mg twice daily. The primary endpoint was stroke, death from all causes, or stroke or death.

Several important observations came out of ESPS-2. First, aspirin alone was efficacious compared to placebo, even with a total daily dose of only 50 mg. Secondly, extended-release dipyridamole alone was also efficacious compared to placebo, with a relative risk reduction very similar to that seen with aspirin. Third, the combination of aspirin and extended-release dipyridamole was superior to either of the medications alone, suggesting a synergistic effect.

The 24-month stroke rate was 12.9% in the aspirin group, 13.2% in the dipyridamole group, 9.9% in the combination group, and 15.8% in the placebo group. In a factorial analysis, ischemic stroke risk was reduced by 21% with aspirin alone, 19.3% with dipyridamole alone, and 37% with combination therapy. This would suggest relative risk reductions for the combined endpoint of stroke or death of 12% for aspirin alone, 14.2% for dipyridamole alone, and 24.4% for combination therapy. The aspirin/dipyridamole combination yielded a significant stroke reduction of 23.1% over aspirin alone and a 24.7% reduction over dipyridamole alone. Combination therapy achieved 12.9% and 10.7% relative risk reductions over aspirin alone and dipyridamole alone, respectively, looking at the combination of stroke or death, which approaches statistical significance.

Potential side effects of aspirin/dipyridamole include headache, gastrointestinal problems (such as dyspepsia, nausea, and vomiting), and dizziness. In ESPS-2, the frequency of gastrointestinal bleeding with combination therapy was 4.1% compared to 2.1% in the placebo group. Headache is a common side effect, but it is usually transitory. In patients with a history of headaches, it is recommended that aspirin/dipyridamole therapy be started at a dose of one tablet daily for three days, then increased to twice daily.

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COMPARISON OF ANTIPLATELET AGENTS

All the available antiplatelet agents have been compared with aspirin but not with each other. It is therefore difficult to compare agents directly because the studies that have been done have varied widely in patient selection, aspirin doses, and primary endpoints (see table below).

Overall, it can be concluded that aspirin is safe and reduces the relative risk of stroke and vascular events by approximately 13% to 15%. Ticlopidine, clopidogrel, extended-release dipyridamole, and the combination of extended-release dipyridamole and aspirin are at least as effective as aspirin. Ticlopidine significantly reduces the relative risk of stroke but is limited by potential serious side effects. Clopidogrel significantly reduced the composite endpoint of ischemic stroke, MI, and vascular death in a group of patients with vascular disease, although the reduction was not significant in the ischemic stroke subgroup. The extended-release dipyridamole/aspirin combination is probably superior to clopidogrel in patients with ischemic stroke, reducing its incidence by 23.1% compared to aspirin and reducing the combined secondary endpoint of MI, stroke, or vascular death by 22% (see figure).

No clinical trials to date have addressed the selection of antiplatelet agents after a patient has recurrent cerebral ischemia while on aspirin or another antiplatelet agent. Many clinicians will select an alternative agent or add one to the aspirin therapy, but the safety and efficacy of combination therapy other than aspirin/dipyridamole is not known at this time.

Eventually, though, combination therapy will likely become the mainstay for the prevention of ischemic stroke and vascular events. It has the potential to affect several steps in the formation of platelet-derived clots. Interest has developed from the success of combination therapy in coronary and carotid stenting trials. In addition, the ESPS-2 trial suggests a synergistic response with the aspirin/dipyridamole combination. The Management of Atherothrombosis with Clopidogrel in High-risk Patients (MATCH) trial is under way to assess the safety and efficacy of clopidogrel and aspirin in patients with recent TIA or ischemic stroke.

Once a patient has suffered an ischemic stroke or TIA, secondary prevention must be based on the etiology of the ischemia. Appropriate antithrombotic therapy can thus be determined, interventions (such as endarterectomy or endovascular procedure) performed if necessary, and risk factors assessed and aggressively treated.

ISCHEMIC STROKE SUBTYPES

There are six ischemic stroke subtypes: cardioembolic, extracranial large-vessel disease, intracranial large-vessel disease, small-vessel disease, hypercoagulable states, and cryptogenic.

Cardioembolic. Most major sources of cardioembolic stroke such as atrial fibrillation, recent MI, dilated cardiomyopathy, and valvular heart disease are best treated with warfarin if no contraindications exist. For minor cardioembolic sources such as patent foramen ovale, atrial septal aneurysm, and mitral valve prolapse, the best treatment has yet to be established.

Extracranial large-vessel disease. Surgery plus aspirin is clearly more beneficial than aspirin alone in symptomatic carotid artery stenosis (more than 70% obstruction). In patients with moderate-grade stenosis (50% to 69% obstruction), surgery plus aspirin still has a modest benefit over aspirin alone. The recent Acetylsalicylic Acid and Carotid Endarterectomy (ACE) trial compared low-dose aspirin (81 or 325 mg/day) to high-dose aspirin (650 or 1300 mg/day) in 2804 patients undergoing carotid endarterectomy. Those patients who received the lower dose experienced fewer vascular events than those on the high dose.

Extensive aortic atherosclerotic disease is an established source of ischemic stroke. The most effective therapy, however, is in question.

Intracranial large-vessel disease. Optimal treatment of patients with symptomatic intracranial disease remains unresolved. However, ongoing prospective trials should help clarify some of the issues here.

Small-vessel disease. Lacunar infarctions are small infarctions resulting from thrombosis of a deep, penetrating end artery. Most commonly, these occur secondary to lipohyalinosis related to underlying hypertension. If a patient experiences a classic lacunar syndrome in the face of typical risk factors, antiplatelet agents are indicated, but the main focus should be on addressing the risk factors.

Hypercoagulable states. Patients who have abnormal coagulation studies are frequently treated with warfarin, despite the fact that no clear efficacy data exists. However, specific details regarding each coagulation abnormality as it relates to stroke is beyond the scope of this article.

Cryptogenic. A cryptogenic ischemic stroke is one for which no specific underlying etiology can be determined. After a thorough work-up, only 15% of patients will have this diagnosis. In such cases, an antiplatelet agent is generally indicated.

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LARGELY PREVENTABLE

Ischemic stroke is largely preventable through the identification and aggressive management of known risk factors. In conjunction with this, aspirin may be useful in the prevention of vascular events in patients with significant risk factors. It may also reduce mortality and disability from a first ischemic stroke.

Antiplatelet agents have been proven to reduce the risk of recurrent stroke as well as other vascular events. Selection of antiplatelet agents should be based on the relative safety, efficacy, cost, and the presence of other comorbidities.

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