Published: January 2009
Stroke is the leading cause of morbidity and the third leading cause of death in the United States. The lifetime risk for stroke is greater than 1 in 6 for adults over age 55.1 Stroke survivors are at an increased risk of having a recurrent event, and recurrent stroke prevention, including the use of antithrombotic agents for ischemic stroke, is a critical piece of stroke management. Accumulating evidence suggests that for most patients with noncardioembolic stroke or transient ischemic attack (TIA), antiplatelet agents are preferable to oral anticoagulants for secondary stroke prevention. However, despite data supporting the use of antiplatelet agents, there continues to be considerable uncertainty regarding which antiplatelet agent to use.
Warfarin has been shown in multiple trials to be superior to aspirin for patients with atrial fibrillation, and is clearly indicated in patients with stroke caused by atrial fibrillation if they have no contraindications to therapy. Recent trials, however, have failed to show a significant benefit for warfarin over aspirin for other ischemic stroke subtypes.2 3 The Warfarin Aspirin Recurrent Stroke Study (WARSS) was a superiority trial that compared aspirin to warfarin for secondary stroke prevention in 2,206 patients with recent noncardioembolic stroke.2 The goal INR in this study was 1.4 to 1.8. Event rates (17.8% for warfarin vs 16.0% for aspirin) as well as major hemorrhage rates (3.4% for warfarin vs 2.7% for aspirin) were nonsignificantly higher in the warfarin arm. In subgroup analyses, no patient subgroup clearly benefited from warfarin compared with aspirin, including those with antiphospholipid antibodies,4 patent foramen ovale,5 6 and posterior circulation strokes. In addition, patients who were taking aspirin at the time of their initial stroke did not benefit from warfarin compared with aspirin.
The Warfarin vs Aspirin for Symptomatic Intracranial Disease study compared high-dose aspirin (1,300 mg) to warfarin (INR goal 2-3) in patients with symptomatic atherosclerotic intracranial stenosis.3 The study was stopped prematurely after enrollment of 569 of the planned 806 patients due to concerns about the safety of patients randomized to warfarin. Compared with aspirin, warfarin was associated with a higher rate of death (9.7% vs 4.3%, P = 0.02), major hemorrhage (8.3% vs 3.2%, P = 0.01), and myocardial infarction (MI) or sudden death (7.3% vs 2.9% P = 0.02).
The American College of Cardiology has recommended antiplatelet agents over oral anticoagulation for most patients with noncardioembolic stroke. For the subset of patients with noncardioembolic stroke with well-documented prothrombotic disorders, they suggest oral anticoagulation over antiplatelet agents.7
Aspirin is the single most common medication in the world. It has been shown to result in a 23% risk reduction for recurrent nonfatal stroke compared with placebo8 and has been the mainstay antiplatelet medication for stroke prevention. The drug works by inhibiting cyclooxygenase, which prevents prostaglandin and thromboxane A2 production from arachidonic acid. It has a rapid effect, with antiaggregate activity occurring within 1 hour of administration.9 The optimal aspirin dose for recurrent stroke prevention has been hotly debated over the years,10 11 but recent evidence supports lower doses of aspirin.10 12 Both the Food and Drug Administration and the American College of Cardiology now support aspirin doses between 50 and 325 mg, either alone or in combination with extended-release dipyridamole (ER-DP) for prevention of recurrent noncardioembolic TIA or stroke.7 13
Ticlopidine and clopidogrel are thought to decrease platelet aggregation by inhibiting the binding of adenosine 5´-diphosphate (ADP) receptor antagonists that inhibit ADP-induced fibrinogen binding to platelets.14 Significant inhibition is present after 2 to 3 days of therapy with ticlopidine 500 mg/d or clopidogrel 75 mg/d, with maximal inhibition occurring between 4 and 7 days. As with aspirin, the antiplatelet action lasts for the lifespan of the platelet, and therefore persists for 7 to 10 days after therapy is stopped.
Ticlopidine was initially approved for the secondary prevention of stroke and was subsequently found to be beneficial for other types of vascular events.15 16 It is typically administered twice daily with food. It is associated with a significant risk for severe neutropenia (approximately 1%), which occurs mainly in the first 2-3 months of treatment. There is also a lesser risk of thrombotic thrombocytopenic purpura. Because of these hemaotological adverse effects, complete blood counts are recommended every 2 weeks for the first 3 months that patients are on the drug.17 Diarrhea occurs in more than 20% of patients as well. These side effects have significantly limited its use.
Clopidogrel is structurally very similar to ticlopidine, differing only by the addition of a carboxymethyl side group. The 2- to 3-day lag from initiation of clopidogrel to platelet inhibition can be overcome by oral clopidogrel loading (300-600 mg), which can result in platelet inhibition in 2 to 3 hours. Much of the evidence for a benefit with this drug comes from the cardiac literature, where it has been shown to reduce recurrent events in patients with an acute MI and lower reocclusion rates in patients undergoing coronary angioplasty and stenting. Clopidogrel has a much better safety profile than ticlopidine does and carries a minimal risk for neutropenia. It has largely replaced ticlopidine in practice.
Dipyridamole. Dipyridamole inhibits platelet activation by increasing the levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate. Because of its short half-life, the regular form is taken every 8 hours and the extended-release form is taken twice per day. Currently, the most commonly used preparation combines the extended-release form of dipyridamole (200 mg) with aspirin (25 mg) into one pill. Headache, occurring in up to 38% of the patients, is a side effect of dipyridamole that could limit its use in some patients.
Ticlopidine has been evaluated in two large randomized controlled trials involving patients with TIA and stroke. It was compared with placebo in the Canadian American Ticlopidine Study, which included 1,072 patients with ischemic stroke.18 Patients in the ticlopidine group had a significant 23.3% reduction in the combined end point of stroke, MI, or vascular death compared with the placebo group (11.3% per year vs 14.8% per year; P = 0.02). A more clinically relevant question was how it compared with aspirin. This question was answered in the Ticlopidine Aspirin Stroke Study (TASS), which compared ticlopidine with high-dose aspirin (650 mg) in 3,069 patients with TIA or stroke.19 There was a 12% reduction in the primary end point of nonfatal stroke or death in patients receiving ticlopidine compared with those receiving aspirin (17% vs 19%; P = 0.048) Most of this benefit was attributable to the effect of ticlopidine on stroke (10% compared
with 13%; P = 0.024).
A TASS subgroup analysis showed a larger benefit for ticlopidine in African Americans prompting the African American Antiplatelet Stroke Prevention Study, in which ticlopidine was compared with aspirin for secondary stroke prevention in 1,800 African American stroke/TIA patients.20 The study found no benefit to ticlopidine over aspirin in African Americans. The negative results in this trial along with the hematologic side effects of ticlopidine and the availability of clopidogrel have significantly reduced the use of this drug for recurrent stroke prevention in patients with ischemic stroke.
The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial21 compared clopidogrel (75 mg) to aspirin (325 mg) in more than 19,000 patients with symptomatic vascular disease, defined by either recent ischemic stroke (within 1 week to 6 months), MI (within 35 days), or documented peripheral arterial disease. Among all patients, clopidogrel was associated with a significant 8.7% relative risk reduction (RRR) compared with aspirin for the primary end point of ischemic stroke, MI, or vascular death (5.32% compared with 5.83% per year; P = 0.043). The benefit of clopidogrel over aspirin was most pronounced for patients in the peripheral arterial disease subgroup (3.71% vs 4.86% per year; P = 0.0028). The benefit of clopidogrel was not statistically significant for the 6,431 patients in the stroke subgroup (7.15% vs 7.71% per year; P >0.2). Risks of hemorrhage were similar between the groups. Although the overall relative benefit of clopidogrel over aspirin in the CAPRIE trial was modest (absolute risk reduction of 0.5% per year) and there was no statistically significant benefit over aspirin for the stroke patients in this study, clopidogrel has become an important treatment option for patients with stroke.
Combination therapy with clopidogrel plus aspirin has been shown to be more effective than aspirin monotherapy in patients with acute MI, unstable angina, or coronary interventions.22 23 It is used commonly, especially for patients with coronary artery disease. The combination therapy for patients with stroke was first tested in the Management of Atherothrombosis with Clopidogrel in High-risk Patients (MATCH) trial, in which clopidogrel plus aspirin was compared with clopidogrel monotherapy.24 This specific comparison was new for a clinical trial and was based on the assumption that clopidogrel monotherapy is the gold standard for antiplatelet secondary prevention.25 There was no significant benefit to the combination of aspirin and clopidogrel for the primary end point of ischemic stroke, MI, or vascular death (15.7% vs 16.7%, P = 0.24), but the combination was associated with a twofold increase in the risk of both major (2% vs 1%, P = 0.001) and life-threatening (2.6% vs 1.3%; P = 0.001) bleeding.
The comparison made in the trial (aspirin added to clopidogrel therapy) does not mirror clinical practice. Rather, clopidogrel is typically added onto a background of aspirin therapy, and a trial with that design would therefore have allowed a more direct extrapolation to patient care. Nonetheless, the MATCH results do not support the use of combination therapy of clopidogrel plus aspirin for patients with stroke. Some have called for future trials to further evaluate the benefit and safety of the combination of aspirin and clopidogrel when administered immediately after TIA and ischemic stroke (ie, within 12 to 24 hours rather than 15 days) with a loading dose of clopidogrel (300 mg or 600 mg) and for a short period of 3 months, when the benefits are likely to be greatest and the cumulative risks of bleeding avoided.25
The combination of aspirin and dipyridamole has been compared with aspirin monotherapy for stroke prevention among patients with TIA or stroke in several clinical trials. A meta-analysis of these trials found a nonsignificant 6% reduction in the odds for the composite outcome of stroke, MI, or vascular death in patients on combination dipyridamole plus aspirin.26 This reduction was due entirely to its effect on stroke events, although that, too, was nonsignificant.
The European Stroke Prevention Study 2 (ESPS-2) evaluated the effect of extended-release dipyridamole (ER-DP) in recurrent stroke prevention.27 This trial involved a factorial design with four treatment groups: 25 mg aspirin, 200 mg ER-DP, 25 mg aspirin plus ER-DP, and placebo. The three active treatments significantly reduced the incidence of stroke compared with placebo: (aspirin vs placebo: 12.5% vs 15, RRR 18.1%, P = 0.01; ER-DP vs placebo: 12.7% vs 15%, RRR 16.3%,
P = 0.04; aspirin combined with ER-DP: 9.5% vs 15%, RRR 37.0%, P = 0.001).
The combination of aspirin and ER-DP was twice as effective for stroke prevention as either drug alone, indicating an additive benefit. Some view the positive results of this trial cautiously, since prior trials of dipyridamole have not demonstrated the same significant findings.
The incidence of major hemorrhage with aspirin monotherapy is approximately 1.5% per year. There is no relation between aspirin dose and risk for any-site bleeding.28 However, the incidence of gastrointestinal bleeding, the most common type of major bleed among patients receiving aspirin therapy, is positively correlated with dose.29 This is a main reason why low-dose aspirin is currently preferred to high-dose for secondary prevention of stroke.
Risks of hemorrhage of the other antiplatelet agents are generally similar to those of aspirin. Major hemorrhage with clopidogrel in the CAPRIE trial (1.4%) was similar to that in the aspirin arm (1.6%).21 Similarly, ER-DP plus aspirin resulted in rates of bleeding of any type similar to those of aspirin monotherapy (8.7% vs 8.2%).27 Ticlopidine was found to have a lower rate of major hemorrhage (0.5%) than aspirin (1.4%) (P < 0.05), and the rates of minor bleeding were similar between the two groups (9% vs 10%).19 clopidogrel in the CAPRIE trial (1.4%) was similar to that in the aspirin arm (1.6%).21
The last American Stroke Association guidelines for secondary stroke prevention, published in 1999, do not provide specific recommendations for choosing among antiplatelet agents. However, the 2004 Consensus statement published by the American College of Cardiology is more detailed.3 Based upon available evidence, the following main recommendations for the choice of antiplatelet agent for noncardioembolic stroke or TIA (eg, atherothrombotic, lacunar, or) were as follows:3
It should be noted that the strength of recommendations 2 and 3 are not backed by the highest strength evidence. The strength "grade2B" in recommendation 2 is used in situations where data comes from randomized trials that are seriously flawed or yield inconsistent results, and in which the benefits and risks of alternatives are closely balanced.30 The strength of grade 1C+ (recommendation 3) indicates that there is extremely compelling evidence of a treatment benefit but without a directly relevant randomized controlled trial.
As with any medication choices, individual patient characteristics play a role. Factors to keep in mind include medication costs and patient comorbidities.
The costs of prescription medications can be important in medication decisions. Clopidogrel and the combined ER-DP plus aspirin each costs approximately $115 per month. The potential benefits of these two alternatives to aspirin, which has a monthly cost of only a few dollars, must be carefully considered.
Stroke patients with unstable coronary artery disease or recent MI will generally benefit from the use of clopidogrel. Patients with gastric ulcers may best be served with low-dose aspirin or one of the other antiplatelet choices. For patients with headaches, the potential side effect of worsening headache with ER-DP should be discussed at the time treatment is started, or another antiplatelet agent could be chosen.
No clinical trials have directly addressed the issue of subsequent therapy for patients who experience recurrent episodes of brain ischemia while taking aspirin. The WARSS trial demonstrated that patients who had their baseline event while on aspirin had higher recurrent-event rates then the overall study population, regardless of treatment with warfarin or aspirin, suggesting that these patients constituted a population at higher risk. Some physicians select an alternative antiplatelet drug for patients who have an event while taking aspirin.7 Others suggest increasing the aspirin dose if it is low.11 Measuring platelet aggregation may be useful for identifying patients who have incomplete platelet inhibition on aspirin or clopidogrel. The effect of increasing antiplatelet dosages on subsequent stroke risk has not been studied.
A tremendous amount has been learned about antiplatelet agents and their use in the prevention of recurrent ischemic stroke, and much more information will become available in the next several years. Many ongoing clinical trials will provide future guidance for the optimal antithrombotic agent.
To further clarify the role of warfarin vs antiplatelet agents in specific stroke subgroups, warfarin will be compared with aspirin in the Warfarin versus Aspirin in patients with reduced left ventricular ejection fraction (WARCEF) trial, and warfarin will be compared with the combination of aspirin plus clopidogrel in patients with the aortic arch as a source of embolism (Aortic arch Related Cerebral Hazard [ARCH] trial). Trials are also under way to help clarify the choice in various stroke populations between combination antiplatelet treatment with clopidogrel plus aspirin vs aspirin monotherapy. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial will include patients with symptomatic vascular disease in either the peripheral, coronary, or cerebrovascular beds. The Secondary Prevention of Small Subcortical Strokes pilot study (SPS3) will be completed in patients with strokes due to small-vessel disease. In addition, there will be a direct comparison between clopidogrel and EP-DP as part of the Prevention Regimen for Effectively avoiding Second Strokes (PRoFESS) trial.