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Update on Antiplatelet Therapy for Stroke Prevention
Ralph L. Sacco, MD;
Mitchell S. Elkind, MD
Arch Intern Med. 2000;160:1579-1582.
INTRODUCTION
The high rates of mortality and long-term disability associated with ischemic stroke, coupled with its prevalence, necessitate good, long-term preventive strategies. Risk-factor management is effective for individuals with preclinical and clinical cerebrovascular disease. Patients suffering from a transient ischemic attack or stroke are particularly vulnerable to subsequent stroke. Most of these individuals are candidates for antiplatelet treatment to prevent a recurrence. Available antiplatelet therapies include aspirin, ticlopidine, and clopidogrel. The combination of low-dose aspirin plus extended-release dipyridamole has been shown to offer safe, effective antiplatelet therapy for appropriate patients. In the second European Stroke Prevention Study,1 the combination was found to be significantly more effective than either drug alone, at the cost of relatively few treatment-related adverse effects. This combination is currently recommended as one of the first-line treatments for stroke prevention after first transient ischemic attack or stroke.
Stroke has a tremendous impact on public health. It is the third leading cause of death and the leading cause of substantial disability in the United States.2 Recent epidemiologic studies estimate that more than 700,000 strokes occur each year.3 Despite recent advances in immediate stroke treatment, prevention is still by far the best method for reducing stroke morbidity. Many risk factors for stroke have been identified, and many of these can be modified to reduce risk. Even individuals who have experienced a transient ischemic attack (TIA) or ischemic stroke, and are thus at high risk of subsequent stroke, may reduce their risk with appropriate management.
Antiplatelet agents, which interfere with thrombus formation by platelets in diseased or damaged blood vessels, are indicated for most patients after a first TIA or stroke to reduce the risk of subsequent stroke.4 Aspirin, ticlopidine, clopidogrel, and dipyridamole are antiplatelet therapies that are effective after TIA or stroke. Until recently, the appropriate dose of aspirin and the value of added dipyridamole were controversial. Based on recent evidence, the Food and Drug Administration and the American College of Chest Physicians (ACCP) now support the use of low-dose aspirin (50 to 325 mg daily) alone and in combination with extended-release dipyridamole for secondary stroke prevention.4-5 The clinical evidence behind these guidelines is reviewed.
RISK OF STROKE AFTER A FIRST TIA OR STROKE
Stroke risk is low among healthy persons but increases as an individual ages and/or develops risk factors for stroke. After a TIA or stroke, the risk of stroke is high, particularly within the first 30 days, and remains elevated over time. Estimates indicate that as many as 40% of those who survive a first TIA or stroke will have a subsequent stroke within 5 years.6
Risk-factor modification is an effective way to reduce stroke risk, regardless of the stage of cerebrovascular disease. Numerous risk factors for first stroke have been identified, and all but a few are modifiable (Table 1).7 Among the modifiable risk factors, hypertension is probably the most important. Nearly 60% of the US population has hypertension, and estimates suggest that almost half of all strokes could be prevented with adequate blood pressure control.8 Reduction in blood cholesterol levels and control of blood glucose may also reduce the risk of first stroke.9 Atrial fibrillation greatly increases stroke risk; this condition is relatively rare among young persons but becomes increasingly prevalent with age. Anticoagulant treatment with warfarin significantly reduces the stroke risk associated with atrial fibrillation.10 Treatment with hepatic hydroxymethyl glutaryl coenzyme A–reductase inhibitors also reduces stroke risk by about 30% in patients with elevated cholesterol levels and/or symptomatic atherosclerosis and after myocardial infarction (MI).11 According to recent clinical trials, persons with asymptomatic carotid stenosis of at least 60% may benefit from surgical removal of atherosclerotic plaque, provided the surgical risk is low (<3%).12 Stroke risk due to cigarette smoking and heavy alcohol use (more than 5 drinks daily) may be modifiable without medical intervention.
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Table 1. Risk Factors for First Ischemic Stroke
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A patient with a previous TIA or stroke has an increased risk of subsequent stroke, although other risk factors for stroke among these individuals are less clear.7 The risk of stroke associated with a prior TIA or stroke can be reduced with appropriate treatment. Individuals who suffer a cardioembolic TIA or stroke are generally treated with oral anticoagulants (warfarin) to prevent a recurrence.4 Patients whose first TIA or stroke is due to another cause are candidates for antiplatelet therapy.4 For patients with symptomatic carotid stenosis greater than 50%, carotid endarterectomy may be indicated in addition to antiplatelet therapy.13 Options for stroke prevention before or after a first TIA or stroke include drug therapy, surgery, and lifestyle changes. The drugs used are (1) antiplatelet agents (aspirin, ticlopidine, clopidogrel, dipyridamole, and aspirin plus extended-release dipyridamole), (2) oral anticoagulants (warfarin), (3) cholesterol-lowering drugs (hepatic hydroxymethyl glutaryl coenzyme A–reductase inhibitors ["statin" drugs]), and (4) antihypertensive agents (diuretics, angiotensin-converting enzyme inhibitors,  -blockers, calcium channel blockers, and  -blockers). The surgical treatment is carotid endarterectomy; and lifestyle changes include smoking cessation, moderation in alcohol consumption, appropriate physical activity, and weight reduction. This list is continually expanding as our understanding of the underlying causes of stroke increases.
EFFICACY OF ANTIPLATELET AGENTS IN CLINICAL TRIALS
Numerous trials have examined the efficacy of antiplatelet treatment, primarily with aspirin, for prevention of vascular events. Many of these trials were small and inconclusive on their own. However, the Antiplatelet Trialists' Collaboration (APTC) involved a meta-analysis to determine the effect of antiplatelet therapy (with any agent) in various populations at risk for vascular events.14 Based on 17 trials, the findings of the APTC were that antiplatelet treatment reduced the odds of nonfatal stroke, nonfatal MI, or vascular death by 22% in persons with a history of TIA or stroke.14 Overall, the benefits of antiplatelet therapy were evident in both men and women, young and old, those with hypertension and those without, and those with diabetes and those without.
Another meta-analysis by Algra and van Gijn,15 which was restricted to aspirin therapy in patients with cerebrovascular disease, found that aspirin reduced the odds of stroke, MI, or vascular death by 16%. A similar 15% overall relative risk reduction for stroke was found by Johnson et al16 in an additional meta-analysis of aspirin trials in patients with cerebrovascular disease. In the absence of a definitive single trial establishing the optimal aspirin dose for preventing stroke and other vascular events among persons with prior TIA or stroke, each of these 2 meta-analyses also evaluated the benefits of different aspirin doses. Algra and van Gijn15 concluded that aspirin reduces the risk of stroke, MI, or vascular death by about 13% at any dose between 50 and 1500 mg daily. Johnson et al16 also found no dose relationship for the effects of aspirin within this dose range. Two trials that directly compared high and low doses found no significant difference in efficacy; however, gastrointestinal adverse effects were less prevalent with low-dose aspirin.17-18 Most recently, the ASA (acetylsalicylic acid) and Carotid Endarterectomy (ACE) trial in North America directly compared low (81 or 325 mg daily) and high (650 or 1300 mg daily) aspirin doses in 2804 patients who underwent carotid endarterectomy because of symptomatic or asymptomatic carotid stenosis.19 During the study, patients who received low-dose aspirin experienced fewer vascular events than did those who received high-dose aspirin; these differences were statistically significant for stroke, MI, or death at 3 months after carotid endarterectomy. The ACE study results support the idea that low-dose aspirin may be preferable to high doses.
Ticlopidine is another antiplatelet agent that has been evaluated in 2 large, randomized, controlled trials involving patients with cerebrovascular disease. Compared with placebo, ticlopidine (500 mg daily) significantly reduced the risk of stroke, MI, or vascular death by 23% (P=.02) after 2 years (N=1072).20 Compared with aspirin (1300 mg daily), ticlopidine provided a 12% reduction (P=.05) in the risk of stroke or death, and a 21% reduction (P=.02) in the risk of fatal or nonfatal stroke at 3 years among 3069 patients with TIA or minor stroke.21 The frequency of adverse effects (primarily diarrhea and rash) and the risk of neutropenia, thrombocytopenia, and thrombocytopenic thrombotic purpura have limited the use of this drug.21-22
Clopidogrel, a relative of ticlopidine, was compared with aspirin (75 mg daily and 325 mg daily) in a single trial, which enrolled 19,185 patients with atherosclerotic vascular disease manifested in 1 of 3 ways: prior MI, prior stroke, or peripheral vascular disease.23 After an average of 1.91 years of follow-up, the annual incidence of stroke, MI, or vascular death was 5.83% in the aspirin group and 5.32% in the clopidogrel group, providing a statistically significant 8.7% (P=.05) relative risk reduction with clopidogrel. Among patients with prior stroke, there was a nonsignificant reduction in the incidence of these vascular outcomes from 7.71% with aspirin to 7.15% with clopidogrel. Clopidogrel demonstrated a safety profile comparable with that of aspirin.
The combination of aspirin plus dipyridamole has been compared with aspirin alone for stroke prevention in patients with cerebrovascular disease in several clinical trials.1, 24-26 Nonetheless, the second European Stroke Prevention Study (ESPS-2) can be considered as distinct from the earlier trials for 2 reasons. First, studies comparing the aspirin/dipyridamole combination with aspirin alone before ESPS-2 were small (the largest included 890 patients divided into 3 groups), limiting the statistical power of those studies to detect treatment differences. An additional larger trial, the European Stroke Prevention Study (ESPS-1; N=2500 divided into 2 groups), lacked an aspirin-only treatment arm, preventing any determination of the contributions of each drug to the observed benefit.27
The second factor distinguishing ESPS-2 from early trials is drug dose. Prior studies using high-dose aspirin found no additional benefit of the combination over aspirin alone. However, evidence from preclinical studies suggests that high doses of aspirin may actually interfere with the action of dipyridamole. Results of experiments using a hamster model of thrombosis show that dipyridamole combined with aspirin in ratios of about 10:1 or higher effectively inhibit thrombus formation, whereas a ratio of 1:1 has little effect.28-29 In contrast to earlier studies, ESPS-2 evaluated a relatively high dose of extended-release dipyridamole combined with low-dose aspirin in a final dose ratio of 8:1. This specific dose combination produced an additive inhibitory effect on platelet aggregation compared with placebo and either drug alone in a randomized, double-blind human ex vivo study involving 4 groups of 24 healthy volunteers.30 The study evaluated inhibition of platelet aggregation in whole blood under flow conditions on a cultured subendothelial matrix after 4 days of treatment, compared with baseline values. The platelet inhibitory effects of the aspirin/extended-release dipyridamole combination were significantly greater than those of aspirin alone, both for total aggregation and for the formation of large aggregates in particular.30
EVIDENCE FOR EFFICACY OF LOW-DOSE ASPIRIN AND EXTENDED-RELEASE DIPYRIDAMOLE: THE ESPS-2 TRIAL
The ESPS-2 trial is the largest to evaluate antiplatelet agents for stroke prevention in patients with prior TIA or stroke.1 The study randomized 6602 patients into 1 of 4 treatment groups: low-dose aspirin (25 mg twice daily) alone, extended-release dipyridamole (200 mg twice daily) alone, aspirin and extended-release dipyridamole combined (same doses), or placebo. Patients were observed for 2 years to determine the effects of these drugs on the incidence of stroke and death from any cause.
At the end of the study, each of the active treatments significantly reduced the risk of stroke (Table 2).1 The 18% risk reduction observed with low-dose aspirin alone was comparable with the benefit observed in earlier studies of low-dose aspirin in stroke patients31 However, ESPS-2 was the first study to show an independent statistically significant reduction in stroke risk with extended-release dipyridamole alone, which is an important finding for patients who are intolerant of low-dose aspirin. The combination of aspirin and extended-release dipyridamole was twice as effective for stroke prevention as either drug alone, indicating an additive benefit. Because of its size and factorial design, this study was able to show a statistically significant benefit of this particular combination of low-dose aspirin and extended-release dipyridamole over aspirin alone.
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Table 2. Results of ESPS-2: Efficacy*
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A good safety assessment is essential with medications for stroke prevention, as they must be administered for extended periods—potentially many years. Low-dose aspirin and extended-release dipyridamole were each well tolerated in ESPS-2. Long clinical experience with both aspirin and dipyridamole had already revealed certain adverse effects to be expected with these drugs (Table 3); the ESPS-2 investigators monitored extensively for these and for any additional events. The quality of the safety assessment was evident from the overall incidence of adverse effects among patients treated with placebo, which was comparable with that among patients in the other treatment groups (Table 3).1 As expected, aspirin was associated with an increased risk of bleeding events and dipyridamole with a higher incidence of headaches and gastrointestinal events (primarily diarrhea). Most of these were mild.
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Table 3. Percentage of Patients Reporting at Least 1 Adverse Effect in ESPS-2*
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NEW PRESCRIBING HABITS ARE RECOMMENDED
In response to the preponderance of evidence favoring low-dose aspirin for stroke prevention, the Food and Drug Administration has issued new professional labeling for aspirin indicating that the appropriate dose for stroke prevention after TIA or stroke is 50 to 325 mg daily.5 Similarly, the ACCP has issued new guidelines recommending low-dose aspirin (50 to 325 mg daily) as a first-line preventive treatment after noncardioembolic TIA or stroke.4 Aspirin has been the mainstay of antiplatelet therapy, but recent years have seen an increase in the number of available options. The growing armamentarium includes aspirin, ticlopidine, clopidogrel, and dipyridamole. The ACCP evaluated the other antiplatelet agents and, based on the results of the ESPS-2 trial, also recommends the combination of low-dose aspirin plus extended-release dipyridamole as a potential first-line therapy for secondary stroke prevention. According to the ACCP,
Aspirin, clopidogrel, ticlopidine, and the combination of aspirin and dipyridamole are all acceptable options for initial therapy. . . . Clopidogrel is recommended in favor of ticlopidine because it has a lower incidence of significant adverse effects. The combination of dipyridamole and aspirin bid may be more effective than clopidogrel and has a similarly favorable adverse effect profile.4
AUTHOR INFORMATION
Accepted for publication November 17, 1999.
The authors acknowledge the assistance of Marsha Scott, PhD, in preparation of the manuscript.
Reprints: Ralph L. Sacco, MD, Neurological Institute; 710 W 168th St, Room 547, Box 6, New York, NY 1003 2 (e-mail: rls1{at}columbia.edu).
From the Department of Neurology and Public Health (Epidemiology), the Sergievsky Center, and the Neurological Institute, College of Physicians and Surgeons of Columbia University, and the New York Presbyterian Hospital, New York, NY.
REFERENCES
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1. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143:1-13.
FULL TEXT
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ISI
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2. American Heart Association. 1999 Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association; 1998.
3. Broderick J, Brott T, Kothari R, et al. The Greater Cincinnati/Northern Kentucky Stroke Study: preliminary first-ever and total incidence rates of stroke among blacks. Stroke. 1998;29:415-421.
FREE FULL TEXT
4. Albers GW, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest. 1998;114(suppl):683S-698S.
5. Food and Drug Administration Department of Health and Human Services. 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. Federal Register. 1998;63:56802-56819.
6. Sacco RL. Risk factors, outcomes, and stroke subtypes for ischemic stroke. Neurology. 1997;49(suppl 4):S39-S44.
7. Sacco RL. Identifying patient populations at high risk for stroke. Neurology. 1998;51(suppl 3):S27-S30.
8. Gorelick PB. Stroke prevention: an opportunity for efficient utilization of health care resources during the coming decade. Stroke. 1994;25:220-224.
ABSTRACT
9. Elkind MS, Sacco RL. Stroke risk factors and stroke prevention. Semin Neurol. 1998;18:429-440.
ISI
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10. Laupacis A, Albers G, Dalen J, Dunn MI, Jacobson AK, Singer DE. Antithrombotic therapy in atrial fibrillation. Chest. 1998;114(suppl):579S-589S.
11. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials. JAMA. 1997;278:313-321.
FREE FULL TEXT
12. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA. 1995;273:1421-1428.
FREE FULL TEXT
13. Barnett HJM, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med. 1998;339:1415-1425.
FREE FULL TEXT
14. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:81-106.
FREE FULL TEXT
15. 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.
FREE FULL TEXT
16. Johnson ES, Lanes SF, Wentworth CE, Satterfield MH, Abebe BL, Dicker LW. A metaregression analysis of the dose-response effect of aspirin on stroke. Arch Intern Med. 1999;159:1248-1253.
FREE FULL TEXT
17. The Dutch TIA Trial Study Group. 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. N Engl J Med. 1991;325:1261-1266.
ABSTRACT
18. UK-TIA Study Group. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry. 1991;54:1044-1054.
FREE FULL TEXT
19. Taylor DW, Thorpe KE for the ACE Trial Study Group. Randomised trial of acetylsalicylic acid for the prevention of perioperative stroke and death after carotid endarterectomy. Presented at: The Challenge of Stroke: The Lancet Conference; October 15-16, 1998; Montreal, Quebec.
20. Gent M, Blakely JA, Easton JD, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet. 1989;1:1215-1220.
ISI
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21. Hass WK, Easton JD, Adams HPJ, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med. 1989;321:501-507.
ABSTRACT
22. Bennett CL, Weinberg PD, Brozenberg-Ben-Dror K, Yarnold PR, Kwaan HC, Green D. Thrombotic thrombocytopenic purpura associated with ticlopidine: a review of 60 cases. Ann Intern Med. 1998;128:541-544.
FREE FULL TEXT
23. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329-1339.
FULL TEXT
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ISI
| PUBMED
24. American-Canadian Co-Operative Study Group. Persantine aspirin trial in cerebral ischemia, II: endpoint results. Stroke. 1985;16:406-415.
FREE FULL TEXT
25. Bousser MG, Eschwege E, Haguenau M, et al. "AICLA" controlled trial of aspirin and dipyridamole in the secondary prevention of athero-thrombotic cerebral ischemia. Stroke. 1983;14:5-14.
FREE FULL TEXT
26. Guiraud-Chaumeil B, Rascol A, David J, Boneu B, Clanet M, Bierme R. Prévention des récidives des accidents vasculaires cérébraux ischémiques par les anti-agrégants plaquettaires: résultats d'un essai thérapeutique contrôlé de 3 ans. Rev Neurol (Paris). 1982;138:367-385.
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27. ESPS Group. European Stroke Prevention Study. Stroke. 1990;21:1122-1130.
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28. Eisert WG, Muller TH. Dipyridamole and aspirin show more than additive effect in acute thrombosis model in vivo [abstract]. Blood. 1987;70(suppl 370a):1336.
29. Eisert WG, Gerster U, Muller TH. Synergy of dipyridamole (DIP) and acetylsalicylic acid (ASA) in recurrent arterial thrombosis in vivo [abstract]. Arteriosclerosis. 1988;8:675a.
30. Müller TH, Su CAPF, Weisenberger H, Brickl R, Nehmiz G, Eisert WG. Dipyridamole alone or combined with low-dose acetylsalicylic acid inhibits platelet aggregation in human whole blood ex vivo. Br J Clin Pharmacol. 1990;30:179-186.
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31. The SALT Collaborative Group. Swedish Aspirin Low-dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet. 1991;338:1345-1349.
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