Neurology

Antiplatelet Agents for Secondary Prevention of Ischemic Stroke Arshad Majid, Norman Delanty, and Jonathan Kantor

OBJECTIVE:

To review and summarize the efficacy, mechanisms of action, and cost of the options available when choosing antiplatelet agents for secondary stroke prevention.

DATA SOURCES:

This article is based on a review of the literature found with MEDLINE, CINAHL, and Cochrane Reviews (1980– June 2000) and abstracts from relevant international scientific meetings. We searched for the terms aspirin, ticlopidine, dipyridamole, antiplatelet, and clopidogrel.

STUDY SELECTION: English-language articles, both reviews and original studies, were evaluated, and all information considered relevant was included in this review. In addition, guidelines from the American Heart Association are included. DATA SYNTHESIS:

Aspirin is a relatively inexpensive and effective agent for secondary stroke prevention, and lower doses of aspirin appear as effective as higher doses. Ticlopidine has been used alone or in combination with aspirin, but serious adverse effects have limited its use. Clopidogrel has emerged as a safe and effective alternative to ticlopidine and lacks some of the serious adverse effects associated with ticlopidine, but is not superior to aspirin in secondary stroke prevention. Unlike previous studies, one recent trial showed that dipyridamole in combination with aspirin is superior to aspirin alone.

CONCLUSIONS: Antiplatelet therapy is a key component of secondary prevention strategies in ischemic stroke. While aspirin has been the cornerstone in the management of stroke, other classes of antiplatelet drugs present new opportunities to optimize antiplatelet therapy. KEY WORDS: antiplatelets, aspirin, clopidogrel, dipyridamole, stroke, ticlopidine.

Ann Pharmacother 2001;35:1241-7.

schemic stroke is one of the most common causes of Iannually death and disability, affecting an estimated 700 000 people in the US. Disabling strokes are often preceded 1

by transient ischemic attacks (TIAs) or other minor strokes, and the risk of recurrent strokes resulting in long-term disability is substantial.2-5 The long-term recurrence rate can be as high as 40% over five years, the highest rate of recurrence being in the first 30 days.4 Secondary prevention strategies rely largely on risk factor reduction, carotid endarterectomy, anticoagulation for cardioembolic strokes, and antiplatelet agents for atherothrombotic strokes.6,7 Despite a plethora of recent research on antiplatelet therapy, recommendations regarding optimal treatment for patients at risk of atherothrombotic stroke remain controversial and ill-de-

Author information provided at the end of the text.

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fined. Aspirin remains the best-studied and most commonly used antiplatelet medication, and it is widely considered the front-line medication for the prevention of ischemic stroke. Several other medications, including dipyridamole, clopidogrel, and ticlopidine, have also been studied and provide alternative and possibly additive choices for antiplatelet therapy. Each agent is discussed separately here in light of existing scientific evidence. Aspirin Aspirin, the prototypical antiplatelet agent, has been studied extensively, and numerous randomized, controlled trials have suggested that it provides a risk reduction of between 13% and 31% in patients with multiple risk factors for stroke.8,9 Aspirin’s mechanism of action is irreversible inhibition of cyclooxygenase, resulting in reduction of

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thromboxane biosynthesis and attenuation of platelet aggregation (Figure 1).10 Two studies, CAST (Chinese Acute Stroke Trial)11 and IST (International Stroke Trial),12 suggest that the benefits of aspirin are apparent early after stroke and treatment should begin as soon as possible. In IST, the randomization occurred within 48 hours of symptoms, and treatment began immediately. In the group treated with aspirin, there were significant decreases (2p < 0.001) in the incidence of ischemic stroke and death at two weeks (2.8% vs. 3.9%; 2p < 0.001). At six months, the aspirintreated group had a significantly reduced rate of death or dependency (11.3% vs. 12.4%; 2p < 0.02). In CAST, similar reductions in the recurrence of ischemic stroke and death were observed, further supporting the early use of aspirin after stroke and TIA. Aspirin’s adverse effect profile includes diarrhea, gastrointestinal irritation, ulceration, and bleeding.13-15 Despite the large number of published studies on aspirin as an antiplatelet agent in the prevention of ischemic stroke, the issue regarding optimal dosing is still contentious. Two studies have directly compared different doses of aspirin in patients with prior history of stroke and TIA. The UK-TIA (United Kingdom — Transient Ischemic Attack) trial14 compared aspirin 300 mg/d with 1200 mg/d and placebo. The incidence of vascular events was comparable for the two doses of aspirin (21.6% with 1200 mg/d vs. 22.1% with 300 mg/d). The Dutch TIA trial15 compared 30 mg/d of aspirin with 283 mg/d in patients with a previous history of TIA. The incidence of vascular events was 14.7% in the 30-mg/d group and 15.2% in the 283mg/d group. Both studies suggest that low doses of aspirin are as effective as higher doses. Importantly, the groups receiving the lower doses of aspirin had a lower incidence of adverse effects including lower bleeding rates and gas-

trointestinal symptoms. Interestingly, a recent meta-analysis16 on aspirin trials showed that lower doses of aspirin (and modified-release preparations) do not appear to reduce the risk of gastrointestinal hemorrhage, but other gastrointestinal symptoms such as dyspepsia or other aspirinrelated adverse effects were not assessed. Although the data are very convincing that lower doses of aspirin are as effective as higher doses, it is plausible that low doses of aspirin may not be sufficient for all patients. Some patients appear to be resistant to the effects of aspirin. Screening tests including bleeding time and in vitro platelet aggregation tests have been proposed to identify patients resistant to aspirin, but these tests are not in routine clinical use.17,18 In addition, the clinical relevance of these screening tests is unknown, and the link between bleeding time or platelet aggregation and subsequent stroke while patients take aspirin has not been established. The American Heart Association (AHA)19 recommends a dosage range of 50–325 mg/d of aspirin for most TIA patients. There is currently no evidence that patients who have strokes while on aspirin, so-called “aspirin failures,” benefit from a change in antiplatelet agent or increase in aspirin dose. Finally, aspirin is relatively inexpensive, especially when compared with newer antiplatelet medications. ASPIRIN AND ATRIAL FIBRILLATION

Aspirin has also been shown to be efficacious in the secondary prevention of stroke in patients with atrial fibrillation. However, these patients are best treated with warfarin unless there are specific contraindications to this medication.7 The EAFT (European Atrial Fibrillation Trial)20 enrolled patients within three months of their TIA or minor stroke. Subjects were randomized to receive adjusted-dose warfarin (international normalized ratio 2.5– 4), aspirin 300 mg/d, or placebo. Strokes occurred at 12% per year in the placebo group, at 10% per year in the aspirin group, and only 4% per year in the warfarin group. The AHA also recommends aspirin (50 –325 mg/d) for patients who do not tolerate warfarin. Dipyridamole

Figure 1. Simplified flow diagram of thrombus formation. Aspirin inhibits thromboxane A2 synthesis. Ticlopidine and clopidogrel block adenosine diphosphate (ADP) receptors on platelets. Glycoprotein (GP) IIb/IIIa antagonists block the binding of platelet GP IIb/IIIa receptors to exposed fibrin. Dipyridamole inhibits platelet aggregation by inhibiting phosphodiesterase (PDE) and by increasing cyclic-3,5-adenosine monophosphate and cyclic-3,5guanosine monophosphate within platelets (not shown).

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The beneficial effect of aspirin on the prevention of ischemic stroke may be accentuated when it is combined with dipyridamole. Dipyridamole is a pyrimido-pyrimidine derivative that exerts vasodilatory effects on coronary resistance vessels and has antithrombotic effects. The mechanism of action of dipyridamole is still not fully understood, but it is thought to inhibit platelet aggregation by elevating concentrations of cyclic-3,5-adenosine monophosphate by inhibiting phosphodiesterase, by activating the enzyme adenylate cyclase, and inhibiting uptake of adenosine from vascular endothelium and erythrocytes.10,21,22 Dipyridamole may also www.theannals.com

Antiplatelet Agents for Secondary Prevention of Stroke

increase cyclic-3,5-guanosine monophosphate, which inhibits platelet activation and aggregation.21 A number of studies have investigated the efficacy of dipyridamole in stroke prevention. However, the design of the earlier trials provided limited information on which to base future treatment strategies. The French Toulouse study23 enrolled 440 patients into groups receiving aspirin, aspirin/dihydroergotamine, aspirin/dihydroergotamine/dipyridamole, or dihydroergotamine alone. There were no statistically significant differences between the groups. The Accidents Ischemiques Cerebraux Lies a L’Atherosclerosis24 and The American–Canadian Co-operative study25 compared aspirin and aspirin/dipyridamole with placebo. Aspirin and dipyridamole combination treatments did not confer extra benefit compared with aspirin alone. A much larger study enrolling 2500 patients, ESPS-1 (European Stroke Prevention Trial 1)26 compared aspirin/dipyridamole with placebo. Although there was an overall reduction of 38% in stroke compared with placebo, the lack of an aspirin-only arm in this study did not permit comparison with aspirin alone. While early studies with dipyridamole failed to show a significant additional effect on stroke prevention, ESPS 227 suggested that sustained-release dipyridamole 400 mg alone and in combination with low-dose aspirin 50 mg/d is effective in stroke prevention. This study, which enrolled 6602 patients, found that dipyridamole or aspirin given alone resulted in risk reductions of 16.3% and 18.1%, respectively, over placebo. When given in combination, there is a risk reduction of 37% over placebo. However, aspirin/dipyridamole combination treatment did not have a statistically significant effect on mortality. Some authors have voiced concern over methodologic elements of the ESPS 2 study, including their choice of aspirin dosage and the use of placebo as a control. Indeed, because aspirin is widely considered the first-line antiplatelet agent, the efficacy of alternative antiplatelet agents would be better assessed by comparing them with aspirin rather than placebo. It is unfortunate that the dose of aspirin that was chosen for ESPS 2 has not been evaluated in clinical trials prior to this study. In addition, the dose of aspirin 25 mg twice daily falls short of the 75–325 mg recommended by the American College of Cardiology/AHA task force on practice guidelines for patients with angina.28 The lower dose of aspirin may therefore be inadequate for patients at risk of myocardial infarction. Moreover, dipyridamole can enhance exercise-induced myocardial ischemia and needs to be used with caution in patients with ischemic heart disease. Dipyridamole is well tolerated by most patients, with a low reported incidence of gastrointestinal irritation and rash.27 Patients taking dipyridamole alone or in combination with aspirin did, however, have a higher incidence of headache when compared with the aspirin or placebo groups.27,29 Approximately 8% of patients withdrew from treatment in ESPS 2 because of headaches compared with only 2.1% in the placebo or aspirin group. However, the majority of patients seem to rapidly develop tolerance to headaches over a www.theannals.com

period of a few days. In one study,30 67% of volunteers had headache on day 1 compared with only 3% on days 4–5. It is therefore important to counsel patients about this adverse effect and the likelihood that it will resolve over a few days. Ticlopidine Ticlopidine is a thienopyridine derivative that inhibits platelet aggregation by the inhibition of adenosine diphosphate–mediated platelet activation.31 It also reduces blood viscosity due to reduction in plasma fibrinogen and an increase in red blood cell deformability.25 There have been two major studies examining the effect of ticlopidine on reducing the risk of ischemic stroke. TASS (Ticlopidine Aspirin Stroke Study)32 compared the use of ticlopidine 500 mg versus aspirin 1300 mg/d in preventing stroke in patients with a history of TIA or stroke. The results of this study showed that the risk of stroke or stroke death over a three-year period was 21% lower in patients taking ticlopidine compared with patients in the aspirin arm of the trial. The second major study to assess the use of ticlopidine in preventing stroke, CATS (Canadian American Ticlopidine Study),33 compared the use of ticlopidine versus placebo in preventing ischemic stroke. It found a 23.3% lower risk of fatal stroke in patients randomized to ticlopidine rather than placebo, based on intention-to-treat analysis. This trial did not, however, compare the use of ticlopidine with aspirin. Important adverse effects of ticlopidine include neutropenia and thrombocytopenia, which occur in approximately 2.4% of patients, generally within the first three months of therapy.32-34 The risk of neutropenia and the resultant need for frequent blood monitoring has limited the use of ticlopidine in clinical practice. Other adverse effects include diarrhea, rash, and gastrointestinal upset.32,33 There has been renewed interest in ticlopidine following a subgroup analysis of TASS data. Although not statistically significant due to the small number of patients in the subgroups, the relative benefits of ticlopidine appear to be more pronounced in African-Americans and other “nonwhites.”35,36 Furthermore, there were no reports of ticlopidine-induced severe neutropenia in African-Americans. In light of these data, the National Institutes of Health has sponsored a study evaluating ticlopidine in African-Americans. The AAASPS (African American Antiplatelet Stroke Prevention Study)35 will evaluate ticlopidine 500 mg/d versus aspirin 650 mg/d in 1800 patients for the prevention of recurrent stroke, vascular death, and myocardial infarction. Clopidogrel Clopidogrel, closely related to ticlopidine in both molecular structure and activity, was developed as an alternative to ticlopidine that lacks its neutropenic adverse effects.10 Clopidogrel 75 mg once daily produces the equivalent inhibition of adenosine diphosphate induced in vitro platelet aggregation to that of ticlopidine 250 mg twice daily. The CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) study37 enrolled more than 19 000 at-risk

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patients in a randomized, double-blind trial of clopidogrel 75 mg/d versus aspirin 325 mg/d in the prevention of vascular events, including ischemic stroke. This study found that patients taking clopidogrel had an annual incidence of ischemic stroke, myocardial infarction, or vascular death of 5.32% versus a 5.83% annual incidence in patients treated with aspirin. This difference is statistically significant (p = 0.043), representing an 8.7% risk reduction between the two treatments. However, there was no significant difference in the incidence of stroke or myocardial infarction between the aspirin and clopidogrel groups. Indeed, the combined 8.7% risk reduction with clopidogrel largely reflects a 23.8% reduction in peripheral arterial events. Unlike ticlopidine, clopidogrel presents a very low risk of neutropenia, but recent reports38 of thrombotic thrombocytopenic purpura (TTP) in 11 patients taking clopidogrel have highlighted the possible risk of this potentially serious adverse effect. However, it is not entirely clear whether all the reported cases of TTP associated with clopidogrel can actually be attributed to this medication.39 Nevertheless, it is important to remain vigilant about the possibility of this adverse effect, although routine platelet counts for patients on clopidogrel are not warranted at this time. Clopidogrel has a similar adverse effect profile as aspirin.40 The lower incidence of gastrointestinal hemorrhage with clopidogrel, which led to permanent discontinuation of treatment (0.52% vs. 0.93%), is offset by the lower incidence of rash with aspirin (0.41% vs. 0.9%).37 The efficacy of smaller or larger doses of clopidogrel and combination treatments with other antiplatelet agents is unknown. Glycoprotein IIb/IIIa Inhibitors A new class of agents, the glycoprotein (GP) IIb/IIIa receptor antagonists, has shown some efficacy in the treatment of coronary artery disease.41 GP IIb/IIIa receptors promote platelet adhesion to exposed fibrin, which is present at sites of atheroma. Abciximab, a GP IIb/IIIa receptor antagonist, is a parenterally administered antiplatelet agent.

A recent double-blind, multicenter, randomized dose-escalation trial evaluated the safety of abciximab in acute ischemic stroke.42 The results of this pilot study suggest that abciximab appears to be safe in acute stroke. In addition, there was a trend toward an improved functional outcome at three months compared with placebo. The results of ongoing larger studies using acute treatment in ischemic stroke are awaited. Chronic dosing trials, however, have shown less promise. The BRAVO (Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion) trial 43,44 was the first chronic dosing study to include secondary stroke prevention as an end point. The target enrollment of BRAVO was 9200 patients to evaluate the efficacy of lotrafiban, an oral GP IIb/IIIa inhibitor, versus other antiplatelet agents in the prevention of a composite clinical end point of death from any cause, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, or urgent ischemia-driven revascularization. However, the BRAVO trial was stopped early due to increased mortality and adverse effects in the lotrafiban group.45 Moreover, BRAVO was the fifth trial of an oral GP IIb/IIIa inhibitor to show an adverse outcome. Presently, it appears unlikely that oral GP IIb/IIIa inhibitors will have any role in the chronic treatment strategies for secondary stroke prevention in the near future.46 Future Directions Clinicians faced with new antiplatelet agents are often uncertain regarding optimal treatment strategies for their patients. While aspirin remains the treatment of choice in many circles, some clinicians have begun to adopt drugs such as clopidogrel as front-line agents for stroke prevention. Although newer antiplatelet agents such as ticlopidine and clopidogrel appear to be as effective as aspirin in stroke prevention, they are also substantially more costly (Tables 113-15,27-30,32-34,37,38 and 223). The number of strokes avoided per 1000 patients treated and the number of patients that must be treated to prevent

Table 1. Antiplatelet Medications Used in the Treatment of Ischemic Stroke Drug Aspirin 81 mg (EC)

Mechanism irreversible inhibition of cyclooxygenase

Aspirin 325 mg (EC)

Costa ($/mo) 0.90

Main Adverse Effects gastrointestinal irritation and ulceration13-15

1.80 91.20

headache, gastrointestinal irritation27-30

inhibits ADP-mediated platelet activation

101.40

gastrointestinal irritation, rash,37 TTP38

inhibits ADP-mediated platelet activation

111.60

neutropenia, TTP, rash, diarrhea32-34

Aspirin/dipyridamole (25/200 mg)

inhibits phosphodiesterase, elevates cAMP and cGMP

Clopidogrel 75 mg Ticlopidine 500 mg

ADP = adenosine diphosphate; cAMP = cyclic-3,5-adenosine monophosphate; cGMP = cyclic-3,5-guanosine monophosphate; EC = enteric coated; TTP = thrombotic thrombocytopenic purpura. a Prices are Hospital of the University of Pennsylvania average wholesale prices.

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one stroke are meaningful figures to clinicians (Table 3).27,32,37 We derived these figures from existing studies, using aspirin as the baseline treatment. Notably, clopidogrel appears to provide relatively little benefit over aspirin in preventing stroke and no benefit at all in preventing fatal stroke. Only ticlopidine and combination aspirin/dipyridamole seem to provide benefit over aspirin in the secondary prevention of stroke. Approximately 34 additional patients need to be treated over two years with dipyridamole/aspirin compared with aspirin alone to prevent one stroke. For ticlopidine, 40 additional patients need to be treated over three years compared with aspirin alone to prevent one stroke (the number needed to treat may be lower for African-American patients). It also appears that dipyridamole/aspirin treatment may be cost-effective in secondary stroke prevention when compared with aspirin and clopidogrel alone.47-49 A conservative estimate of the healthcare cost of one stroke is $50 000.47,50 The cost per stroke averted with dipyridamole/aspirin versus aspirin alone is estimated to be $28 472.47 Since the potential benefits of aspirin/dipyridamole against myocardial infarction and peripheral vascular disease have not been established, a complete cost-effectiveness analysis cannot be undertaken. One of the most dramatic and important gaps in the medical literature is that no large studies, with the exception of ESPS 2, have examined whether aspirin used in combination with the newer antiplatelet agents would provide an additive or synergistic effect in the prevention of

ischemic stroke. A frequent clinical conundrum is the management of patients who have suffered a stroke while taking aspirin. Future trials will ideally include cohorts treated with combination therapy. Based on the mechanism of action of these newer antiplatelet agents, it seems plausible that they would have a synergistic effect when used with aspirin (Figure 1). However, concerns about increased adverse effects would also need to be addressed. A particular concern regarding all stroke prevention studies relates to the lumping together of all strokes regardless of etiology. Antiplatelet agents will likely have different efficacies depending on whether the stroke is cardioembolic, large artery, or lacunar. Cardioembolic strokes, TIAs, and patients with atrial fibrillation are best treated with warfarin if tolerated.16 If there are specific contraindications for warfarin therapy, the patient should be treated with aspirin 30 –325 mg/d.7 It would be highly desirable and feasible for future trials to tier patients according to the etiology of stroke or TIA. It appears that aspirin should remain the mainstay of antiplatelet therapy for the secondary prevention of ischemic stroke. Dipyridamole, when used with low-dose aspirin, appears to further reduce the risk of ischemic stroke, but questions remain about the lack of benefit with the addition of dipyridamole in previous studies. In addition, the dose of aspirin used in the ESPS26,27 is lower than the dose recommended by the AHA for patients with angina. High-risk patients or patients who have strokes or TIAs while on aspirin may be suitable candidates for aspirin/dipyridamole

Table 2. Percentage of Patients Experiencing Adverse Events in ESPS 223 Type of Event

Placebo

Aspirin

Dipyridamole

Aspirin/Dipyridamole

All adverse events

56.6

60

62.5

64

All gastrointestinal eventsa

28.2

30.4

30.5

32.5 12.1

Diarrhea

9.3

6.6

15.4

Bleeding (total)b

4.5

8.2

4.7

8.7

Mild

3.2

5.0

3.2

5.1

Moderate–severe Headache

1.3

3.2

4.3

3.6

32.4

33.1

37.2

38.2

ESPS 2 = European Stroke Prevention Trial 2. Includes nausea, vomiting, dyspepsia, gastric pain, and diarrhea. b Includes epistaxis, proctorrhagia, melena, hematuria, and hematemesis. a

Table 3. Benefit of Various Antiplatelet Medications over Aspirin in the Prevention of Ischemic Stroke Period of Benefit (y)

Medication

RR Reduction Over Aspirin (%)

No. Strokes Avoided (over Aspirin)/1000 People

No. Patients That Must Be Treated to Prevent 1 Strokeb

Dipyridamole27

2

NSa

NS

NS

Dipyridamole/aspirin27

2

19

29.7

33.7

Ticlopidine32

3

21

25.2

39.7

Clopidogrel37

1 person-year

NS

NS

NS

RR = relative risk. a No statistically significant benefit over aspirin. b Versus aspirin alone.

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combination therapy.7 Sustained-release dipyridamole monotherapy may be suitable for patients who do not tolerate aspirin due to gastrointestinal symptoms, but it is not currently available in the US. Clopidogrel appears to be as effective as aspirin in the prevention of stroke, but the CAPRIE study37 did not evaluate the concomitant use of aspirin and clopidogrel. Clopidogrel may be suitable for the very small group of patients who do not tolerate aspirin or dipyridamole or for patients who have peripheral vascular disease. Although there are no supporting clinical data, some physicians also advocate changing to clopidogrel for patients who have strokes while on aspirin. Although it does appear to provide some benefit over aspirin, ticlopidine use has decreased in many circles due to its adverse effect profile. However, there is renewed interest in ticlopidine for African-American patients following subgroup analysis of the TASS32 data, which suggests that the beneficial effects of ticlopidine are more pronounced in African-American patients. These promising preliminary results await confirmation in the ongoing AAASPS trial.35 Summary While dipyridamole, ticlopidine, and clopidogrel appear to have a role in the prevention of ischemic stroke, further cost-effectiveness studies and clinical trials are needed to determine whether and in what combination these medications should be used in patients at risk of ischemic stroke. Finally, despite the availability of new agents, recent studies51-53 show that up to 30% of patients who could benefit from antiplatelet agents are actually not on these medications. Arshad Majid MD, Resident, Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA Norman Delanty MD, Consultant Neurologist, Department of Neurology, Royal College of Surgeons, Beaumont Hospital, Dublin, Ireland Jonathan Kantor MD MPH, Fellow, Department of Epidemiology and Biostatistics, University of Pennsylvania School of Medicine Reprints: Arshad Majid MD, Department of Transitional Medicine, Presbyterian Hospital, 266, Wright Saunders, Philadelphia, PA 191042699. FAX 215/243-4649; E-mail [email protected]

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7. Wolf PA, Clagett GP, Easton JD, Goldstein LB, Gorelick PB, KellyHayes M, et al. Preventing ischemic stroke in patients with prior stroke and transient ischemic attack: a statement for healthcare professionals from the Stroke Council of the American Heart Association. Stroke 1999;30:1991-4. 8. 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. 9. Antiplatelet Trialists’ Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. BMJ 1988;296:320-1. 10. Schafer AI. Antiplatelet therapy. Am J Med 1996;101:199-209. 11. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet 1997;349:1641-9. 12. International Stroke Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both or neither, among 19435 patients with acute ischaemic stroke. Lancet 1997; 349:1569-81. 13. SALT Collaborative Group. Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular events. Lancet 1991;33:1345-9. 14. Farrel B, Godwin J, Richards S, Warlow C. The United Kingdom Transient Ischemic Attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991;54:1044-54. 15. The Dutch TIA Trial Study Group. A comparison of two doses of aspirin (30 mg vs 283 mg a day) in patients after transient ischemic attack or minor stroke. N Engl J Med 1991;325:1261-6. 16. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000;321:1183-7. 17. Kawasaki T, Ozeki Y, Igawa T, Kambayashi J. Increased platelet sensitivity to collagen in individuals resistant to low-dose aspirin. Stroke 2000;31:591-5. 18. Grotemeyer KH, Scharafinski HW, Husstedt IW. Two-year follow-up of aspirin responder and aspirin non-responder. A pilot-study including 180 post-stroke patients. Thromb Res 1993;71:397- 403. 19. Albers GW, Hart RG, Lutsep HL, Newell DW, Sacco RL. Supplement to the guidelines for the management of transient ischemic attacks: a statement from the Ad Hoc Committee on Guidelines for the Management of Transient Ischemic Attacks. Stroke Council, American Heart Association. Stroke 1999;30:2502-25. 20. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention of vascular events in patients with non-rheumatic atrial fibrillation and recent ischaemic attack or minor stroke. Lancet 1993;342: 1255-62. 21. Gresele P, Arnout J, Deckmyn H, Vermylen J. Mechanism of the antiplatelet action of dipyridamole in whole blood: modulation of adenosine concentration and activity. Thromb Haemost 1986;55:12-8. 22. Tsuya T, Okada M, Horie H, Ishikawa K. Effect of dipyridamole at the usual oral dose on exercise-induced myocardial ischemia in stable angina pectoris. Am J Cardiol 1990;66:275-8. 23. Giraud-Chaumeil B, Rascol A, David J, Boneu B, Clanet M, Bierme R. Prevention des recidives des accidents vascullaires cerebraux ischemiques par les anti-aggregants plaquettaires: resuls d’un essai therapeutique controle de 3 ans. Rev Neurol (Paris) 1992;138:367-85. 24. Bousser MG, Eschwege E, Haguenau M, Lefaucconier JM, Thibult N, Touboul PJ. AICLA controlled trial of aspirin and dipyridamole in the secondary prevention of atherothrombotic cerebral ischemia. Stroke 1983;14:4-14. 25. The American–Canadian Co-operative Study Group. Persantine trial in cerebral ischemia, II: end point results. Stroke 1985;16:406-15. 26. The ESPS Group. The European Stroke Prevention Study (ESPS): principal end-points. Lancet 1987;2:1351-4. 27. 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. 28. Gibbons RJ, Chatterjee K, Daley J, Douglas JS, Fihn SD, Gardin JM, et al. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 1999;33:2092-197. 29. Theis JG, Deichsel G, Marshall S. Rapid development of tolerance to dipyridamole-associated headaches. Br J Clin Pharmacol 1999;48:750-5. 30. European Stroke Prevention Study 2. Efficacy and safety data. J Neurol Sci 1997;151(suppl):S1-77.

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Antiplatelet Agents for Secondary Prevention of Stroke 31. de Maat MP, Arnold AE, van Buuren S, Wilson JH, Kluft C. Modulation of plasma fibrinogen levels by ticlopidine in healthy volunteers and patients with stable angina pectoris. Thromb Haemost 1996;76:166-70. 32. Hass WK, Easton JD, Adams HP Jr, Pryse-Phillips W, Molony BA, Anderson S, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high risk patients. N Engl J Med 1989;321:501-7. 33. Gent M, Blakely JA, Easton JD, Ellis DJ, Hachinski VC, Harbison JW, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989;1:1215-20. 34. 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;159:311-4. 35. Albers GW, Hart RG, Lutsep HL, Newell DW, Sacco RL. Addendum to the supplement to the guidelines for the management of transient ischemic attacks. Stroke 2000;31:1001. 36. Weisberg LA. The efficacy and safety of ticlopidine and aspirin in nonwhites: analysis of a patient subgroup from the Ticlopidine Aspirin Stroke Study. Neurology 1993;43:27-31. 37. CAPRIE Steering Committee. A randomised, blinded trial of Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE). Lancet 1996;348:1329-39. 38. Bennett CL, Connors JM, Carwile JM, Moake JL, Bell WR, Tarantolo SR, et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000;342:1773-7. 39. Hankey GJ. Clopidogrel and thrombotic thrombocytopenic purpura. Lancet 2000;356:269-70. 40. Hankey GJ, Sudlow CL, Dunbabin DW. Thienopyridine derivatives (ticlopidine, clopidogrel) versus aspirin in preventing stroke and other serious vascular events in high vascular risk patients. Cochrane Database Syst Rev 2000;2:CD001246. 41. The EPIC investigators. Use of monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor. N Engl J Med 1994;330:956-61. 42. The Abciximab in Ischemic Stroke Investigators. Abciximab in acute ischemic stroke: a randomized double-blind placebo-controlled, dose-escalation study. Stroke 2000;31:601-9. 43. Topol EJ, Easton JD, Amarenco P, Califf R, Harrington R, Graffagnino C, et al. Design of the Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial. Am Heart J 2000;139:927-33. 44. Carroll RC, Craft RM, Morris SA, Liu F. Lotrafiban: an oral platelet glycoprotein IIb/IIIa blocker. Expert Opin Investig Drugs 2000;9:2673-87. 45. BRAVO trial stopped: lotrafiban increases mortality, Heart wire news, www.theheart.org; Dec 12, 2000. 46. Heeschen C, Hamm CW. Difficulties with oral platelet glycoprotein IIb/IIIa receptor antagonists. Lancet 2000;33:330-1. 47. Shah H, Gondek K. Aspirin plus extended-release dipyridamole or clopidogrel compared with aspirin monotherapy for the prevention of recurrent ischemic stroke: a cost-effectiveness analysis. Clin Ther 2000;22: 362-70. 48. Chambers M, Hutton J, Gladman J. Cost-effectiveness analysis of antiplatelet therapy in the prevention of recurrent stroke in the UK. Aspirin, dipyridamole and aspirin– dipyridamole. Pharmacoeconomics 1999;16: 577-93. 49. Sarasin FP, Gaspoz JM, Bounameaux H. Cost-effectiveness of new antiplatelet regimens used as secondary prevention of stroke or transient ischemic attack. Arch Intern Med 2000;160:2773-8. 50. Matchar DB. The value of stroke prevention and treatment. Neurology 1998;51(suppl):S31-5. 51. Stafford RS. Aspirin use is low among United States outpatients with coronary artery disease. Circulation 2000;101:1097-111. 52. Irving RJ, Oram SH, Boyd J, Rutledge P, McRae F, Bloomfield P. Ten year audit of secondary prevention in coronary bypass patients. BMJ 2000;321:22-3. 53. Kalra L, Perez I, Melbourn A. Stroke risk management. Stroke 1998;29: 53-7.

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EXTRACTO OBJETIVO: Repasar y resumir la eficacia, mecanismo de acción y el costo asociado al uso de agentes antiplaquetarios para la prevención del reinfarto cerebral. FUENTE DE INFORMACIÓN: MEDLINE, CINAHL y Cochrane Reviews (1980–2000). También, extractos provenientes de reuniones científicas internacionales. Los términos claves utilizados fueron: aspirina, ticlopidina, dipiridamol, antiplaquetario y clopidogrel. SELECCIÓN DE FUENTES DE INFORMACIÓN: Artículos originales o de repaso general del tópico en cuestión publicados en inglés. También, las guías de la American Heart Association. SÍNTESIS: La aspirina es un agente relativamente barato y eficaz usado en la prevención del reinfarto cerebral. Dosis bajas de este medicamento parecen ser tan efectivas como dosis altas. La ticolopidina ha sido empleada sola y en combinación con la aspirina, pero sus efectos adversos han limitado su uso. El clopidogrel ha surgido como una terapia alternativa eficaz y segura comparada con la ticlopidina, y carece de algunos de los efectos adversos serios asociados al uso de la ticlopidina. Sin embargo, ha demostrado ser inferior a la aspirina en la prevención del reinfarto cerebral. A diferencia de estudios previos, un estudio reciente ha demostrado que el dipiridamol combinado con la aspirina es superior a la aspirina administrada sola. CONCLUSIONES: La terapia antiplaquetaria es un componente esencial de la prevención secundaria de infartos cerebrales isquémicos. Aunque la aspirina ha sido la piedra angular en el manejo del infarto cerebral, otras clases de agentes antiplaquetarios presentan nuevas alternativas para optimizar la terapia antiplaquetaria.

Encarnación C Suárez RÉSUMÉ

Revoir la littérature concernant l’efficacité, les mécanismes d’action et les coûts des différents antiplaquettaires utilisés dans la prévention secondaire d’un accident vasculaire cérébral. SOURCES DES DONNÉES: Revue des bases de données sur MEDLINE, CINAHL, et Cochrane de 1980 à 2000 ainsi que les résumés des réunions scientifiques internationales. Les mots-clés suivants ont été utilisés: aspirine, ticlopidine, dipyridamole, clopidogrel et antiplaquettaire. Les articles en langue anglaise ont été évalués. De plus, les lignes directrices de l’Association Américaine du Cœur ont été intégrées dans cette évaluation. ANALYSE DES DONNÉES: L’aspirine s’avère un médicament efficace et peu dispendieux pour la prévention secondaire d’un AVC. De plus, les faibles doses d’aspirine semblent aussi efficaces que les doses élevées. La ticlopidine a été utilisée seule et en association avec l’aspirine mais des effets indésirables importants limitent son utilisation. Le clopidogrel est une alternative efficace à la ticlopidine sans toutefois posséder les effets indésirables sévères associés à la ticlopidine. Le clopidogrel n’est cependant pas supérieur à l’aspirine dans la prévention secondaire de l’AVC. Une étude récente a mis en évidence que le dipyridamole en association avec l’aspirine est supérieure à l’aspirine utilisée seule. CONCLUSIONS: Les antiplaquettaires représentent des traitements de première ligne dans la prévention secondaire d’AVC. Même si l’aspirine demeure le présentement le médicament de premier choix, de nouveaux antiplaquettaires représentent des options intéressantes pour optimiser la prévention secondaire. OBJECTIF:

The Annals of Pharmacotherapy

Louise Mallet

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