Advances in long-term stroke prevention with antiplatelet therapy

Advances in Long-term Stroke Prevention With Antiplatelet Therapy Lawrence M. Brass,

MD

Stroke is a leading cause of mortality and major disability. There is considerable evidence from randomized trials that antiplatelet therapy is effective in the secondary prevention of ischemic strokes. Aspirin, the most widely evaluated agent, has consistently been found to be effective. However, higher doses are no more effective than lower doses and are associated with a higher incidence of adverse events. Clopidogrel has been shown to be more effective than aspirin in preventing recurrent ischemic events in patients with atherosclerosis manifested by ischemic stroke, myocardial infarction, or peripheral arterial disease. Ticlopidine has also been shown to be more effective than aspirin in the reduction of recurrent strokes and in the composite end point of stroke and death. Dipyridamole, in the sustained release formulation, in combination with aspirin, has been shown to be more effective than aspirin alone, particularly in the reduction of nonfatal strokes. Data from recent clinical trials has shown that there are new and effective treatment options available with antiplatelet therapy for the secondary prevention of ischemic stroke. Key Words: Ischemic stroke—Therapy—Prevention—Antiplatelet agents. Copyright © 2001 by National Stroke Association

Stroke is a major public health problem. Each year in the United States, an estimated 730,000 patients suffer a new or recurrent stroke.1 Stroke is a leading cause of serious long-term disability and is the third leading cause of death, accounting for 1 of every 14.5 deaths.2 The efficacy of antiplatelet therapy in the reduction of ischemic strokes and other major ischemic events in patients with a previous transient ischemic attack (TIA) or stroke has been convincingly shown in the meta-analysis Antiplatelet Trialists’ Collaboration (ATC) and in randomized trials, such as Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE), Ticlopidine Aspirin Stroke Study (TASS), and Second European Stroke Prevention Study (ESPS-2).3-6 Oral antiplatelet agents used in stroke patients include aspirin, dipyrid-

amole in combination with aspirin, and the adenosine diphosphate (ADP) receptor antagonists clopidogrel and ticlopidine. Physicians prescribing these medications need an understanding of the effective dosing, safety profile of individual agents, patient compliance issues, and actual versus anticipated or theoretical benefits of these agents in lowering the risk for stroke and other ischemic events such as myocardial infarction (MI) and vascular death. This article reviews recent major randomized clinical trials that have defined the role of antiplatelet therapy in secondary stroke prevention.

From the Division of Neurology, Yale University School of Medicine, and Veterans Affairs Medical Center, New Haven, CT. Address correspondence to Lawrence M. Brass, MD, Department of Neurology, PO Box 208018, Yale University School of Medicine, 15 York St, New Haven, CT 06520-8018. Copyright © 2001 by National Stroke Association 1052-3057/01/1002-0101$35.00/0 doi:10.1053/jscd.2001.24789

Aspirin reduces thromboxane A2–mediated platelet aggregation by selectively and irreversibly inhibiting the enzyme cyclooxygenase, but it only minimally inhibits platelet aggregation induced by ADP, collagen, and thrombin.7 The role of antiplatelet therapy in the prevention of vascular events was addressed in a meta-analysis of 145

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Antiplatelet Agents in Stroke Prevention Aspirin

Journal of Stroke and Cerebrovascular Diseases, Vol. 10, No. 2, Suppl 1 (March), 2001: pp 18-23

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Figure 1. Effects of antiplatelet therapy on nonfatal stroke in 4 main high-risk categories and in low-risk patients. (Reprinted from Antiplatelet Trialists’ Collaboration3 with permission from the BMJ Publishing Group.)

randomized trials published through 1990 and involving more than 70,000 high-risk patients.3 These trials included patients with acute or previous MI and previous stroke or TIA, as well as other patients considered to be at high risk of adverse vascular events. The most widely evaluated antiplatelet regimen was medium-dose (75 to 325 mg/day) aspirin. Among patients treated with an antiplatelet regimen containing aspirin, there was a significant reduction of 25% in vascular events, including nonfatal MI, nonfatal stroke, and vascular death. Risk reductions for specific events in patients compared with the controls (2 P⬍ .00001) were 34% for nonfatal MI, 31% for nonfatal stroke, and 17% for vascular death. Among more than 10,000 patients with a previous stroke or TIA, the risk of another vascular event or nonfatal stroke was significantly reduced (2 P⬍ .00001) (Fig 1). These results reinforce the fact that antiplatelet therapy reduces mortality because of ischemic events in patients with a previous stroke or TIA independent of age, sex, and history of diabetes or hypertension.8-11 Despite these compelling data, there is considerable evidence to suggest that antiplatelet therapy is underused in patients with stroke.12 The question of whether higher doses of aspirin (⬎325 mg) provide greater protection against stroke in high-risk patients was answered in the United Kingdom-Transient Ischemic Attack (UK-TIA) aspirin trial that evaluated high (600 mg twice daily) and low (150 mg twice daily) doses of aspirin in patients with a previous TIA or minor ischemic stroke.9 Results showed no differences in efficacy, but there was an increased incidence of adverse effects associated with the high doses. However, post hoc analysis of data from the North American Symptomatic

Carotid Endarterectomy Trial suggested that, after carotid endarterectomy, higher doses of aspirin (ⱖ650 mg/d) were associated with greater long-term benefits of surgery than lower doses (⬍325 mg/d).13 This dosage issue was addressed in the Aspirin and Carotid Endarterectomy (ACE) Trial.14 A total of 2,849 patients undergoing carotid endarterectomy were randomly assigned to receive either low-dose (81 mg or 325 mg/d) or high-dose aspirin (650 mg or 1,300 mg/d) for 3 months. Within 30 days and 3 months of the procedure, the risk of stroke, MI, and death was lower in the 2 low-dose groups than in the 2 high-dose groups (Table 1).14 These results were just the opposite of what was expected and lent support to the use of lower doses of aspirin in patients undergoing carotid endarterectomy. Results of a meta-analysis of 11 randomized trials showed that aspirin in doses of 50 mg per day to 1,500 mg per day reduced the risk of stroke in 5,228 poststroke/TIA patients by approximately 15%. The lack of a dose-response relationship in this analysis supports the use of low doses of aspirin, which are effective in reducing the risk of stroke and may minimize the risk of gastrointestinal adverse effects.15 Thienopyridine Derivatives Clopidogrel and ticlopidine are prodrugs and require biotransformation in the liver to active forms to exhibit antithrombotic activity.16 Both of these agents are noncompetitive but selective antagonists of ADP-induced platelet aggregation specific for the ADP pathway. Clopidogrel and ticlopidine are both thienopyridines but have different active metabolites.17

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Table 1. Results of the ACE Trial EVENT RATE

Event-Defining failure All patients 30 days No. of patients Any stroke, MI, or death Any stroke or death Ipsilateral stroke or death 3 months No. of patients Any stroke, MI, or death Any stroke or death Ipsilateral stroke or death Efficacy Analysis 30 days No. of patients Any stroke, MI, or death Any stroke or death Ipsilateral stroke or death 3 Months No. of patients Any stroke, MI, or death Any stroke or death Ipsilateral stroke or death

Low-dose ASA (%)

High-dose ASA (%)

Relative risk high/low dose (95% CI)

Absolute P difference (% SE)

NNT

1,395 75 (5.4) 66 (4.7) 58 (4.2)

1,409 99 (7.0) 86 (6.1) 81 (5.7)

1.31 (0.98-1.75) 1.29 (0.94-1.76) 1.38 (1.0-1.92)

1.6 (0.9) 0.07 1.4 (0.9) 0.109 1.6 (0.8) 0.052

61 72 62

1,395 87 (6.2) 79 (5.7) 68 (4.9)

1,409 118 (8.4) 100 (7.1) 91 (6.5)

1.34 (1.03-1.75) 1.25 (0.94-1.67) 1.32 (0.98-1.80)

2.1 (1.0) 0.03 1.4 (0.9) 0.12 1.6 (0.9) 0.07

46 69 63

566 21 (3.7) 19 (3.4) 17 (3.0)

550 45 (8.2) 38 (6.9) 36 (6.5)

2.21 (1.33-3.65) 2.06 (1.20-3.53) 2.18 (1.24-3.83)

4.5 (1.4) 0.002 3.6 (1.3) 0.007 3.5 (1.3) 0.005

22 28 28

566 24 (4.2) 22 (3.9) 20 (3.5)

550 55 (10.0) 45 (8.2) 41 (7.5)

2.36 (1.48-3.75) 2.10 (1.28-3.46) 2.11 (1.25-3.55)

5.8 (1.5) 0.0002 4.3 (1.4) 0.003 3.9 (1.4) 0.004

17 23 25

Abbreviations: ASA, acetylsalicylic acid; NNT, number needed to treat with low-dose acetylsalicylic acid to prevent 1 event; MI, myocardial infarction; CI, confidence interval; SE, standard error. (Reprinted from Taylor DW, et al.14 with permission by The Lancet Ltd.)

Clopidogrel. Clopidogrel is an ADP receptor antagonist with greater molar potency and activity in animal models of thrombosis than ticlopidine.16,18 Data from plateletaggregation studies in atherosclerotic patients showed that clopidogrel 75 mg once daily inhibited ADP-induced platelet aggregation equally as well as 250 mg twice daily of ticlopidine.16,19 The CAPRIE4 trial was designed to compare the efficacy of clopidogrel (75 mg/d) to aspirin (325 mg/d) in reducing the risk of ischemic stroke, MI, or vascular death in 19,185 patients with recent ischemic stroke, recent MI, or established peripheral arterial disease. Results of the study showed a statistically significant relative risk reduction of 8.7% for clopidogrel over aspirin (P ⫽ .043) (Fig 2).4 Clopidogrel showed a highly significant effect over aspirin in reductions of MI outcomes, with a relative risk reduction of 19.2% (P ⫽ .008).20 Clopidogrel was well tolerated. Patients receiving aspirin reported more frequent gastrointestinal hemorrhage (P ⫽ .05) and severe upper gastrointestinal discomfort (P ⫽ .096) than patients who took clopidogrel.4 Ticlopidine. The effectiveness of ticlopidine in stroke prevention was evaluated in 2 large trials conducted over a decade ago. The Canadian American Ticlopidine Study21 assessed the effect of ticlopidine (500 mg/d) versus pla-

cebo in reducing the risk of subsequent stroke, MI, or vascular death in 1,072 patients who had a recent thromboembolic stroke. The event rate per year for the com-

Figure 2. Cumulative risk of ischemic stroke, MI, or vascular death for patients with recent ischemic stroke, MI, or symptomatic peripheral vascular disease treated with 75 mg/d clopidogrel (CLOP; n ⫽ 9,599) or 325 mg/d aspirin (ASA; n ⫽ 9,586). Numbers in parentheses indicate the number of patients still receiving treatment. The average risk rate per year for the combined end point was 5.32% for CLOP and 5.83% for ASA (P ⫽ .043). (Reprinted from CAPRIE Steering Committee4 with permission by The Lancet Ltd.)

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Image Unavailable. Please See Print Journal.

Figure 3. Occurrence of stroke, MI, or vascular death for patients with recent thromboembolic stroke treated with 500 mg/day ticlopidine (TIC; n ⫽ 525) or placebo (PLA; n ⫽ 528). Numbers in parentheses indicate the number of patients still receiving treatment. The average event rates per year were 10.8% for TIC and 15.3% for PLA (P ⫽ .006). (Reprinted with permission.21)

bined end point of stroke, MI, or vascular death was 10.8% with ticlopidine and 15.3% in the placebo group, which showed a 30.2% risk reduction with ticlopidine (P ⫽ .006) (Fig 3). Diarrhea and skin rash were the most frequently reported side effects with ticlopidine. Severe neutropenia was noted in about 1% of patients receiving ticlopidine. The TASS6 compared ticlopidine (500 mg/d) and aspirin (1,300 mg/d) in 3,069 patients with recent TIA, stroke, or mild persistent focal cerebral or retinal ischemia. The 3-year event rate for the primary end point of nonfatal stroke or death from all causes was 17% for ticlopidine and 19% for aspirin, showing a 12% risk reduction with ticlopidine (P ⫽ .048). Adverse effects reported with

Figure 4. Odds ratios for active treatment compared with placebo. CI, confidence interval; TIA, transient ischemic attack; ASA, aspirin; DP, sustained release dipyridamole. (Reprinted from Diener HC, et al.5 with permission from Elsevier Science.)

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ticlopidine included diarrhea (20%), skin rash (14%), and severe but reversible neutropenia (⬍1%). Dipyridamole. Dipyridamole is a phosphodiesterase inhibitor that has vasodilator and antiplatelet properties. The mechanism of action of dipyridamole as an antiplatelet agent involves inhibition of phosphodiesterase resulting in an intraplatelet accumulation of cyclic adenosine monophosphate, blockade of adenosine uptake, and uptake of prostaglandin (PG12) synthesis.22 The effectiveness of dipyridamole in combination with aspirin for the prevention of ischemic events has been evaluated in a number of trials. In the ATC,3 a metaanalysis of 14 trials comparing aspirin alone to the combination of aspirin plus immediate-release dipyridamole showed no statistically significant differences in the combined outcome of MI, stroke, or vascular death between the 2 regimens. More recently, the ESPS-25 evaluated the safety and efficacy of low-dose aspirin (50 mg/d) compared with extended-release dipyridamole (400 mg/d), the 2 agents in combination, or placebo for secondary prevention of ischemic stroke in 6,602 patients with a previous stroke or TIA. Primary end points were stroke, death, and stroke or death together. Patients were followed-up for 2 years. Results of the study showed that stroke risk was reduced by 18% with aspirin alone (P ⫽ .013), 16% with dipyridamole alone (P ⫽ .039), and 37% with combination therapy (P ⬍ .001) compared with the placebo. The risk of stroke or death was reduced by 13% with aspirin alone (P ⫽ .016), 15% with dipyridamole alone (P ⫽ .015), and 24% with the combination (P ⬍ .001) compared to the placebo. There was no significant effect on death alone (Fig 4),5 and the combination did not reduce the inci-

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dence of MI. When compared with each agent alone, stroke risk was reduced with the combination by 23% compared with aspirin alone (P ⫽ .006) and by 25% compared with dipyridamole alone (P ⫽ .002). Thus, the combination of aspirin and dipyridamole may be more effective than either agent alone for the endpoint of stroke alone. Headache was the most frequent occurring adverse event in the dipyridamole alone and aspirindipyridamole groups, whereas bleeding from any site was more commonly seen in patients who received aspirin and the combination. Headache and gastrointestinal events were the most common reasons for early study discontinuation in approximately 30% of patients receiving dipyridamole and the combination.

with or without abciximab was not associated with stent thrombosis and did not increase the risk of intracranial hemorrhage. The results of these studies show that there are new options with antiplatelet therapy in the long-term management of stroke prevention. Additional data will be available from the Management of Atherothrombosis with Clopidogrel in High Risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) trial, which has been initiated to show the effectiveness of the clopidogrel plus aspirin combination in patients with a recent TIA or ischemic stroke and an additional risk factor, i.e., diabetes or PAD.

Conclusions The Case for Long-term Combination Therapy Acting at different sites in the pathway of platelet activation, antiplatelet agents used in combination may show superiority to monotherapy in reducing thrombotic events. The antiaggregating effects of clopidogrel (75 mg once daily) in combination with aspirin (325 mg once daily) were evaluated in 18 healthy male volunteers for 10 days.23 Results of the study using an ex vivo model of human thrombogenesis showed that the aspirin and clopidogrel combination provided an approximate 70% reduction in platelet thrombus formation (P ⬍ .001) compared with aspirin alone. The effectiveness of the aspirinticlopidine combination after coronary stenting has been shown in a number of clinical trials.24-26 However, the safety and tolerability profile of ticlopidine may result in early discontinuation of treatment. The Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS) was designed to evaluate the safety and tolerability of clopidogrel (with and without a loading dose) plus aspirin in comparison with the ticlopidine plus aspirin combination.27 The primary study end point, which consisted of major peripheral or bleeding complications, neutropenia, thrombocytopenia, or early discontinuation because of noncardiac adverse events, occurred in 9.1% of ticlopidine-treated patients and in 4.6% of clopidogrel-treated patients (P ⫽ .005) at 28 days. These data showed that the safety/tolerability of clopidogrel in combination with aspirin is superior to that of the ticlopidine plus aspirin combination. In another pilot trial (not an efficacy trial) the aspirin-clopidogrel combination was evaluated to assess the degree of platelet inhibition.28 Results of the study showed complete inhibition of platelet aggregation in 50 of 55 patients (91%). In addition, there were no major or fatal bleeding events reported. The safety and efficacy of clopidogrel were also evaluated as adjunctive therapy to aspirin with or without abciximab in 89 patients who underwent carotid artery stenting in a noncomparative study.29 Clopidogrel in addition to aspirin

Antiplatelet therapy is effective in the secondary prevention of atherothrombotic stroke. Ongoing research offers the prospects of newer antiplatelet agents with improved efficacy and better safety profiles; combination antiplatelet therapies are also being investigated for use in the long-term prevention of stroke. Clopidogrel has been shown to be safe and effective as monotherapy. Preliminary studies have shown the short-term efficacy and safety of the combination of clopidogrel plus aspirin. Studies are under way to evaluate the safety and efficacy of clopidogrel in combination with aspirin for the longterm prevention of ischemic events in patients with atherosclerosis.

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