US Pharm. 2010;35(2):HS20-HS26.
The American Heart Association (AHA) has noted that 185,000 of 795,000 strokes reported yearly are recurrent and that a majority (87%) of reported strokes are ischemic.1 Furthermore, the economic burden of ischemic stroke was estimated at $68.9 billion in 2009, thus significantly impacting the cost of health care overall.1
The current American College of Chest Physicians (ACCP) guidelines for antithrombotic therapy for stroke recommend that patients who have experienced noncardioembolic stroke or transient ischemic attack (TIA) receive an antiplatelet drug—aspirin alone, clopidogrel alone, or combination extended-release (ER) dipyridamole and aspirin (Grade 1A recommendation).2 The ACCP’s recommendation grading system is given in TABLE 1.3
In 2002, the Antithrombotic Trialists’ Collaboration (ATC) published a meta-analysis evaluating the effects of antithrombotic agents in patients at high risk for vascular events.4 Twenty-one trials involving 18,270 patients with a previous history of stroke or TIA were included. Compared with placebo, antiplatelet agents overall had a 25% reduction in risk of the composite outcome of stroke, myocardial infarction (MI), and vascular death (P <.0001). In patients utilizing these agents for secondary prevention of stroke or TIA, the absolute risk reduction of new fatal and nonfatal strokes was 30% (95% CI 24%-35%).4
A major goal of therapy for patients who have experienced stroke is to prevent recurrent stroke and other outcomes, such as fatal and nonfatal cardiovascular (CV) events.5 This article will review antiplatelet therapies and the impact of recent literature on secondary stroke prevention in patients who have experienced noncardioembolic stroke.
Review of Current Agents
Aspirin: Aspirin’s antiplatelet activity is attributable to its irreversible inhibition of cyclo-oxygenase I, which suppresses the production of thromboxane A2 and subsequently prevents platelet aggregation. Based on findings from several studies, the ACCP guidelines advise the use of aspirin 50 mg to 100 mg per day for the prevention of ischemic stroke (Grade 1B).2,6-8 However, in 1998, the FDA approved the use of aspirin 50 mg to 325 mg for the prevention of ischemic stroke.9 The AHA and the American Stroke Association also recommend aspirin 50 mg to 325 mg for secondary stroke prevention.10 The appropriate dose of aspirin to be used for secondary prevention is still widely debated.
Higher doses of aspirin have been found to increase the risk of adverse effects (primarily increased bleeding) and have no added benefit for risk reduction. The Dutch TIA trial, conducted over 52 months, evaluated two doses of aspirin (273 mg vs. 30 mg).6 The 273-mg group comprised 1,576 patients and the 30-mg group included 1,555 patients. The two groups showed reductions of 15.2% and 14.7%, respectively, in outcome measures (stroke, MI, or vascular death). In addition, a bleeding rate of 2.6% occurred in patients taking 30 mg, versus 3.4% in those taking 273 mg.6
In the UK-TIA trial, 4.7% of patients taking aspirin 1,200 mg daily, 2.6% of patients taking 300 mg daily, and 1.6% of patients taking placebo experienced gastrointestinal (GI) bleeding.7 There was no difference in efficacy between the two aspirin-treatment groups.7
A 1996 mini–meta-analysis by Algra and van Gijn examined 10 studies that evaluated varying doses of aspirin versus placebo for secondary prevention of stroke or TIA in a total of 6,171 patients.8 Aspirin at low doses (<100 mg) led to a relative risk reduction (RRR) of 13%; respective RRRs for medium doses (300-325 mg) and high doses (>900 mg) were 9% and 14%. The authors concluded that doses greater than 30 mg did not confer any additional benefit.8
The ATC study found that high daily doses of aspirin (500-1,500 mg) had no advantage over medium doses (160-325 mg) or low doses (75-150 mg) (odds reduction 19%, 26%, and 32%, respectively) for long-term prevention of serious vascular events (nonfatal stroke, nonfatal MI, or vascular death).4 Regarding increased risk of extracranial bleeds for aspirin versus placebo, the odds ratio was 1.7 (95% CI 0.8-3.3) for doses less than 75 mg, 1.5 (95% CI 1.0-2.3) for doses 75 to 150 mg, and 1.4 (95% CI 1.0-2.0) for doses 160 mg to 325 mg.4 The ATC concluded that doses of 75 mg to 150 mg were appropriate for secondary stroke prevention.4
Algra and van Gijn’s conclusion that doses greater than 30 mg conferred no additional benefit for reduction of secondary stroke risk was based on their evaluation of a small number of studies.8 Unfortunately, there is a lack of information for doses less than 75 mg, so further studies are needed to fully determine the effect of lower doses on secondary stroke prevention.4 The ATC study demonstrated a greater odds reduction (32%) for doses of 75 mg to 150 mg compared with the other dose ranges, with similar reports of adverse events across all dose ranges. This helps support the ACCP’s recommendation of aspirin 50 to 100 mg daily for secondary stroke prevention.4
Clopidogrel: Clopidogrel blocks the activation of platelets by preventing adenosine diphosphate (ADP) activation of the glycoprotein GPIIb/IIIa complex. The ACCP guidelines endorse clopidogrel over aspirin (Grade 2B) for secondary stroke prevention.2
This recommendation is based on data from the CAPRIE trial.11 In this randomized, double-blind, international trial, 19,185 patients received either aspirin 325 mg or clopidogrel 75 mg daily. Patients had a recent (³1 wk but £6 mo before randomization) ischemic stroke, a recent (£35 days before randomization) MI, or symptomatic peripheral vascular disease. The primary outcome was first occurrence of an event (ischemic stroke, MI, or vascular death). Patients were followed for 1 to 3 years. Intent-to-treat analysis showed a 5.32% annual risk of the primary outcome in the clopidogrel group versus 5.83% in the aspirin group. This translates to an RRR of 8.7% (95% CI 0.3-16.5, P = .043) for clopidogrel. In patients with recent ischemic stroke (n = 6,431), the RRR for the primary outcome was 7.3% (95% CI –5.7-18.7, P = 0.26) and the RRR for stroke was 8% (95% CI –7.0-21.0, P = 0.28). There were no differences in terms of safety.11
Combination therapy with aspirin and clopidogrel is not recommended for secondary stroke prevention (Grade 1B).2 Only patients with recent acute coronary syndrome and/or a coronary stent should be treated with this combination (Grade 1A).2
The recommendation against combination therapy for secondary stroke prevention is based on data from two studies.12,13 The MATCH trial, a randomized, double-blind, placebo-controlled study, included data from 7,276 patients at high risk (defined as having ³1 of the following risk factors: previous ischemic stroke, previous MI, angina, diabetes, or symptomatic peripheral arterial disease [PAD] within the past 3 years).12 Patients were included if they were already receiving clopidogrel and had had a previous ischemic stroke or TIA in the last 3 months; patients who were older than 40 years, had severe comorbid conditions, had increased risk of bleeding, were scheduled for major or vascular surgery, or had contraindications to aspirin or clopidogrel were excluded. Patients received either aspirin 75 mg or placebo daily. The primary efficacy endpoint was first occurrence of an event (ischemic stroke, MI, or vascular death, including hemorrhagic death) or rehospitalization for an acute ischemic event (unstable angina, worsening PAD, or TIA). The duration of treatment and follow-up was 18 months. No significant differences in efficacy were detected between patients receiving clopidogrel 75 mg alone versus those receiving clopidogrel 75 mg plus aspirin 75 mg. There was, however, a significantly greater risk of life-threatening bleeds in combination patients (3%) versus patients receiving clopidogrel alone (1%) (95% CI 0.64-1.88, P <.0001).12
The CHARISMA trial, which included 15,603 patients, showed similar results.13 Patients were randomly assigned to receive clopidogrel 75 mg plus low-dose aspirin (75 mg-162 mg) or low-dose aspirin plus placebo. Patients had to be at least 45 years old and have multiple atherothrombotic risk factors, documented coronary artery disease, documented cerebrovascular disease, or documented symptomatic PAD. Patients were excluded if they had an indication for clopidogrel or if they were taking antithrombotics or nonsteroidal anti-inflammatory drugs. The primary efficacy endpoint was first occurrence of an event (stroke, MI, or death from CV causes). No significant differences in efficacy were found between patients receiving combination therapy and those receiving aspirin alone. Severe bleeding occurred in 1.7% of patients receiving combination therapy versus 1.3% of those receiving aspirin alone (95% CI 0.97-1.61, P = .09). Moderate bleeding occurred in 2.1% of patients receiving combination therapy versus 1.3% of those receiving aspirin alone (95% CI 1.27-20.8, P <.001).13
Dipyridamole: The ACCP guidelines recommend the combination of aspirin and ER dipyridamole (25 mg/200 mg twice daily) over aspirin alone (Grade 1A).2 This recommendation comes as a result of two published trials, ESPS-2 and ESPRIT.14,15
In the ESPS-2 trial, 6,602 patients with recent ischemic stroke or TIA were randomized to receive aspirin 25 mg twice daily, dipyridamole 200 mg twice daily, aspirin plus dipyridamole (25 mg/200 mg), or placebo.14 Exclusion criteria were age under 18 years, recent history of peptic ulcer disease or GI bleeding, bleeding disturbances, any condition requiring ongoing treatment with aspirin or anticoagulants, or life-threatening conditions. The study duration was 2 years. As expected, all treatments were superior to placebo, but the most notable finding was the superiority of the aspirin and dipyridamole combination to aspirin alone (RRR of stroke 23%). Bleeding was reported in 8.2% of the aspirin-only group compared with 8.7% of the combination group.14
The ESPRIT study compared aspirin (30-325 mg) alone versus aspirin plus dipyridamole in 2,739 patients.15 Participants were included if they had had a TIA or minor ischemic stroke in the previous 6 months. Exclusion criteria included cardioembolic stroke, cerebral ischemia associated with high-grade carotid stenosis with planned carotid endarterectomy or endovascular treatment, coagulation disorder, contraindications to aspirin or dipyridamole, or limited life expectancy. The primary outcome examined the composite of death from vascular causes, stroke, MI, or major bleeding (whichever happened first). Mean follow-up was 3.5 years. Primary outcome events occurred in 16% of patients receiving aspirin alone versus 13% of those receiving combination therapy (hazard ratio [HR] 0.8, 95% CI 0.66-0.98). Major bleeding occurred in 35 patients receiving combination therapy versus 53 patients receiving aspirin alone.15
Ticlopidine: Ticlopidine works in the same way as clopidogrel—by inhibiting ADP receptors. Although its efficacy in the prevention of ischemic stroke has been established in two large trials, ticlopidine’s use is limited by the risk of serious adverse effects, including severe neutropenia (about 1% incidence) and thrombotic thrombocytopenic purpura (>60 reported cases).16-19
Potential Future Agents
Triflusal: This agent has been reported to have similar efficacy to aspirin, but with fewer adverse effects.20 Although widely used in Europe and South America, triflusal is not available in the U.S., and therefore it will not be reviewed in this article.20
Cilostazol: This agent (indicated for treatment of PAD) currently is not recommended for secondary stroke prevention, owing to insufficient evidence.2 A recent pilot study of cilostazol and aspirin, however, showed positive results in reduction of recurrence of stroke and fewer bleeding events in the cilostazol group versus the aspirin group (7 vs. 1, P = .034).21
Terutroban: This agent, a thromboxane A2 receptor antagonist, is being evaluated in phase III trials for secondary stroke prevention. In addition to having an antithrombotic effect, terutroban may have activity against vasoconstriction and atherosclerosis. The PERFORM study is randomizing 18,000 patients to receive either aspirin or terutroban, and results are expected in 2011.22
Clopidogrel Versus Aspirin/ER Dipyridamole
As discussed earlier, the ACCP guidelines recommend clopidogrel or the combination of aspirin and ER dipyridamole (25 mg/200 mg twice daily) over aspirin alone.2 No guidelines exist to endorse one regimen over the other. The only guidance comes from a recent double-blind study (PRoFESS) comparing clopidogrel 75 mg with aspirin plus ER dipyridamole (25 mg/200 mg twice daily) in 20,332 patients.23 Patients had had a recent ischemic stroke (within 90 days of randomization), were at least 55 years old, had no contraindications to the study agents, and were deemed suitable for randomization. The primary efficacy outcome was recurrent stroke of any type, and mean follow-up was 2.5 years. No significant between-group difference in efficacy was found. Recurrent stroke occurred in 7.6% of the aspirin and dipyridamole group and 7.7% of the clopidogrel group (HR 1.07, 95% CI 0.97-1.18). More major hemorrhagic events occurred in the aspirin/dipyridamole group versus the clopidogrel group (4.1% vs. 3.6%; HR 1.15, 95% CI 1.00-1.32). Intracranial hemorrhage was counted as stroke in the primary outcome and also was higher in the aspirin plus dipyridamole group.23
The PRoFESS study was the first trial to compare clopidogrel and combination aspirin and dipyridamole. Although the study was unable to prove the superiority of one therapy over another, it presented interesting findings regarding side effects. Patients taking clopidogrel experienced fewer hemorrhagic events, while patients taking aspirin plus dipyridamole were more likely to discontinue therapy, owing primarily to headaches.23 It remains to be seen what effect this study will have on future updates to current guidelines for secondary stroke prevention.
All patients experiencing a noncardioembolic stroke or TIA should receive an antiplatelet drug for secondary stroke prevention.2 The optimal dose of aspirin is still being debated. Current guidelines favor clopidogrel or aspirin plus dipyridamole over aspirin alone.2 New evidence supports the benefit of clopidogrel alone versus the combination of aspirin and dipyridamole in secondary stroke prevention, owing to more hemorrhagic events seen with the combination.23 This and future studies may influence current recommendations. More studies are needed to support the recommendation of one agent over others. In addition, newer products are being researched that may increase the number of choices clinicians have for prevention of secondary stroke.
1. American Heart Association. Heart Disease and Stroke Statistics—2009 Update. Dallas, Texas: American Heart Association; 2009.
2. Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(suppl 6):630S–669S.
3. Guyatt GH, Cook DJ, Jaeschke R, et al. Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(suppl 6):123S-131S.
4. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86.
5. O’Donnell MJ, Hankey GJ, Eikelboom JW. Antiplatelet therapy for secondary prevention of noncardioembolic ischemic stroke: a critical review. Stroke. 2008;39:1638-1646.
6. A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. The Dutch TIA Trial Study Group. N Engl J Med. 1991;325:1261-1266.
7. Farrell B, Godwin J, Richards S, Warlow C. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry. 1991;54:1044-1054.
8. Algra A, van Gijn J. Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia. J Neurol Neurosurg Psychiatry. 1996;60:197-199.
9. Food and Drug Administration. Internal analgesic, antipyretic, and antirheumatic drug products for over-the-counter human use; Final Rule for professional labeling of aspirin, buffered aspirin, and aspirin in combination with antacid drug products. Fed Regist. 1998;63:56802-56819, 66015-66017.
10. Adams RJ, Albers G, Alberts MJ, et al. Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke. 2008;39:1647-1652.
11. CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329-1339.
12. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331-337.
13. Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:1706-1717.
14. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study: II. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143:1-13.
15. ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet. 2006;367:1665-1673.
16. Gent M, Blakely JA, Easton JD, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet. 1989;1:1215-1220.
17. Easton JD. The role of ticlopidine in prevention of ischemic stroke: a benefit-risk assessment. In: Hass WK, Easton JD, eds. Ticlopidine, Platelets and Vascular Disease. New York, NY: Springer-Verlag; 1993:141-155.
18. Bennett CL, Weinberg PD, Rozenberg-Ben-Dror K, et al. Thrombotic thrombocytopenic purpura associated with ticlopidine: a review of 60 cases. Ann Intern Med. 1998;128:541-544.
19. Chen DK, Kim JS, Sutton DM. Thrombotic thrombocytopenic purpura associated with ticlopidine use: a report of 3 cases and review of the literature. Arch Intern Med. 1999;159:311-314.
20. Costa J, Ferro JM, Matias-Guiu J, et al. Triflusal for preventing serious vascular events in people at high risk. Cochrane Database Syst Rev. 2005;(3):CD004296.
21. Huang Y, Cheng Y, Wu J, et al. Cilostazol as an alternative to aspirin after ischaemic stroke: a randomised, double-blind, pilot study. Lancet Neurol. 2008;7:494-499.
22. Bousser MG, Amarenco P, Chamorro A, et al. Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study. Cerebrovasc Dis. 2009;27:509-518.
23. Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008;359:1238-1251.
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