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INTRODUCTION — Antiplatelet therapy is used for both the management of acute ischemic stroke and for the prevention of stroke. Antiplatelet therapy reduces the incidence of stroke in patients at high risk for atherosclerosis and in those with known symptomatic cerebrovascular disease.
Antiplatelet therapy for secondary stroke prevention will be reviewed here. Antiplatelet therapy for acute ischemic stroke and for primary stroke prevention is discussed separately. (See "Antithrombotic treatment of acute ischemic stroke and transient ischemic attack" and "Overview of primary prevention of coronary heart disease and stroke".)
Prevention of recurrent stroke with antithrombotic therapy in patients with atrial fibrillation is reviewed elsewhere. (See "Antithrombotic therapy to prevent embolization in atrial fibrillation".)
ASPIRIN — Aspirin, the most commonly used antiplatelet agent, inhibits the enzyme cyclooxygenase, reducing production of thromboxane A2, a stimulator of platelet aggregation. This interferes with the formation of thrombi, thereby reducing the risk of stroke. (See "Benefits and risks of aspirin in secondary and primary prevention of cardiovascular disease".)
The effectiveness of aspirin for preventing ischemic stroke and cardiovascular events is supported by a meta-analysis from the Antithrombotic Trialists Collaboration (ATC) published in 2002 . The ATC analyzed 195 randomized controlled trials comparing antiplatelet therapy, primarily aspirin, with placebo in the prevention of stroke, myocardial infarction (MI), and vascular death among high-risk patients with some vascular disease or other condition implying an increased risk of occlusive vascular disease. Patients treated with an antiplatelet agent (primarily aspirin) had a 25 percent relative risk reduction in nonfatal stroke compared with placebo.
Among the subset of patients in the 2002 ATC with prior cerebrovascular disease (TIA or stroke), antiplatelet therapy reduced the risk of secondary stroke, MI, or vascular death by 22 percent; the absolute benefit was 36 events prevented per 1000 patients treated for 29 months . The benefit of antiplatelet therapy was independent of sex, age (greater or less than 65), diabetes, or hypertension. Similar results were reported in a 2009 ATC meta-analysis of 16 placebo-controlled secondary prevention trials; aspirin reduced the risk of any serious vascular event by 19 percent and reduced the risk of ischemic stroke by 22 percent .
Stopping antiplatelet therapy in high-risk patients may itself increase the risk of stroke. One study found that 13 of 289 patients hospitalized with cerebral infarction had recently stopped antiplatelet therapy; most had been taking aspirin . In all 13, the antiplatelet agent had been discontinued within 6 to 10 days of stroke onset, a time course consistent with the known lifespan (about 10 days) of inhibited platelets. Additionally, a case-control study comparing 309 patients with stroke to 309 matched controls found that discontinuation of aspirin was associated with a significantly increased risk of TIA or ischemic stroke (odds ratio 3.4, 95% CI 1.08-10.63) .
In addition to its benefit for secondary stroke prevention, treatment with aspirin decreases the risk of other cardiovascular events in a wide range of patients with established disease. Furthermore, there is considerable evidence that long-term aspirin use reduces the risk of death from certain cancers. (See "Benefits and risks of aspirin in secondary and primary prevention of cardiovascular disease" and "Cancer prevention", section on 'Aspirin and other anti-inflammatory drugs'.)
Dose of aspirin — The dose of aspirin in secondary stroke prevention studies ranged between 20 to 1300 mg. Most studies have found that 50 to 325 mg/day of aspirin is as effective as higher doses [1,5-10]. Furthermore, lower doses within this range appear to provide the same benefit as higher doses [1,6,10].
As an example, a review of 195 trials of secondary prevention by the ATC showed that doses of 75 to 150 mg/day produced the same risk reduction, compared with placebo, as doses of 150 to 325 mg/day . In the ATC analysis of trials directly comparing aspirin <75 mg/day to aspirin ≥75 mg/day, there was no significant difference in effectiveness between the two regimens. However, the ATC noted that aspirin doses of <75 mg/day have been less widely assessed than doses of 75 to 150 mg/day, so uncertainty remains regarding the effectiveness of doses <75 mg/day compared with higher aspirin doses.
Even lower doses may be effective, as demonstrated in the Dutch TIA Trial . This study found similar efficacy for stroke prevention with 30 mg compared with 283 mg of aspirin per day in patients who had had a TIA or minor ischemic stroke. In the European Stroke Prevention Study-2 (ESPS-2), 50 mg of aspirin daily reduced stroke risk by 18 percent compared with placebo (29 strokes prevented per 1000 treated), an effect of comparable magnitude to the other trials cited above . This benefit seen with very low-dose aspirin is consistent with laboratory observations that 30 mg of aspirin per day results in complete suppression of thromboxane A2 production .
Given the apparent equivalent benefit of different doses of aspirin for ischemic stroke prevention, and the increased risk of bleeding complications with higher dose aspirin discussed below, we recommend a dose of 50 to 100 mg/day when using aspirin for the secondary prevention of ischemic stroke. This recommendation is similar to the dose of 75 to 100 mg/day recommended by current guidelines from the American College of Chest Physicians .
Toxicity and risk of bleeding — Lower doses of aspirin appear to be associated with less gastrointestinal toxicity [5,11,14]. In the UK TIA trial, for example, gastrointestinal hemorrhage occurred in 1.6 percent of patients on placebo, 2.6 percent on 300 mg aspirin, and 4.7 percent on 1200 mg aspirin . A similar dose relationship was seen for milder gastrointestinal symptoms.
In an analysis of data from 31 randomized, controlled trials, aspirin doses ≤200 mg/day were associated with a significantly lower rate of major bleeding events compared with higher doses . However, there was no difference in major bleeding when aspirin <100 mg/day was compared with 100 to 200 mg/day. When the overall rate of bleeding complications (including major, minor and insignificant events) was considered, aspirin <100 mg/day was associated with a lower risk compared with the 100 to 200 mg/day and >200 mg/day groups
A later meta-analysis of 22 randomized trials of low-dose aspirin (75 to 325 mg/day) versus placebo for cardiovascular prophylaxis reached similar conclusions within the low-dose range . Compared with placebo, aspirin increased the relative risk of any major bleeding, major gastrointestinal bleeding, and intracranial bleeding by 1.7- to 2.1-fold. However, the absolute annual increase in risk for any major bleeding episode (mostly gastrointestinal) and for intracranial bleeding was 0.13 and 0.03 percent, respectively. Furthermore, there was no evidence of an increased risk of bleeding with "high" low-dose aspirin (>162 to 325 mg/day) compared with "low" low-dose aspirin (75 to 162 mg/day).
CLOPIDOGREL — Clopidogrel is a thienopyridine that inhibits ADP-dependent platelet aggregation.
The CAPRIE trial randomly assigned 19,185 patients with recent stroke, MI, or symptomatic peripheral artery disease (divided roughly equally between these three enrolling diseases) to treatment with aspirin (325 mg) or clopidogrel (75 mg) . The primary end point, a composite outcome of stroke, MI, or vascular death, was significantly reduced with clopidogrel treatment compared with aspirin treatment (5.3 versus 5.8 percent annually, relative risk reduction 8.7 percent, 95% CI 0.3-16.5 percent).
The benefit of clopidogrel over aspirin in the CAPRIE trial varied based on enrolling disease . Most of the benefit was observed in patients with peripheral artery disease, and the difference in composite outcome between clopidogrel and aspirin treatment in patients with recent stroke and myocardial infarction was not significant. However, the strength of these observations is limited, since they are based on subgroup analyses.
Polymorphisms in the hepatic enzymes involved in the metabolism of clopidogrel (eg, CYP1A2, CYP3A4, CYP2C19) or within the platelet P2Y12 receptor may affect the ability of clopidogrel to inhibit platelet aggregation. However, there are no convincing prospective data to support routine testing for clopidogrel resistance with in vitro tests of platelet function or genotyping in patients with cardiovascular disease, particularly for those with a history of stroke or TIA. A 2010 clinical alert from the American College of Cardiology Foundation and the American Heart Association noted that adherence to existing guidelines for the use of antiplatelet therapy should remain the basis for therapy, and further that there is insufficient evidence to recommend routine platelet function testing or genetic testing for clopidogrel .
The issue of resistance/nonresponse to clopidogrel in cardiovascular disease is discussed in greater detail separately. (See "Clopidogrel resistance and clopidogrel treatment failure".)
Side effects of clopidogrel — The side effect profile of clopidogrel is favorable compared with aspirin, with a slightly higher frequency of rash and diarrhea, but a slightly lower frequency of gastric upset or gastrointestinal bleeding . Unlike its close relative ticlopidine (see 'Ticlopidine' below), severe neutropenia is not seen more frequently with clopidogrel than with aspirin .
Aspirin plus clopidogrel — For most patients with ischemic stroke, the combined long-term use of aspirin and clopidogrel does not offer greater benefit for stroke prevention than either agent alone but does substantially increase the risk of bleeding complications [19-22].
This conclusion is supported by results from the MATCH trial . This study enrolled 7599 patients with stroke or TIA who also had some additional "high-risk" feature, defined as prior MI, prior stroke (in addition to the index event), diabetes, angina, or symptomatic peripheral artery disease (PAD). The primary end point was a composite of ischemic stroke, MI, vascular death, or rehospitalization for acute ischemia. Patients were randomly assigned to the combination of clopidogrel (75 mg daily) plus aspirin (75 mg daily) versus clopidogrel (75 mg daily) alone. Follow-up was 18 months. The following observations were reported :
Several authors have noted limitations of MATCH. For instance, 54 percent of MATCH subjects qualified for trial entry because of a lacunar stroke, a stroke subtype that has the lowest recurrence risk . Furthermore, data regarding interaction between treatment and stroke mechanism were not reported, raising the question of whether combination therapy might still play a role in particular stroke subtypes. (See 'Stroke subtypes' below.)
The combination of aspirin and clopidogrel has been shown to have benefit over aspirin alone in patients with acute coronary syndromes. However, there are important differences between patients with coronary and cerebrovascular disease , and between short-term therapy initiated in the acute setting, and longer term preventative therapy. The results of the MATCH trial serve to emphasize these differences. (See "Antiplatelet agents in acute non-ST elevation acute coronary syndromes", section on 'Clopidogrel'.)
In contrast to the MATCH trial , which evaluated aspirin plus clopidogrel versus clopidogrel alone in patients with stroke or TIA, the CHARISMA trial evaluated aspirin plus clopidogrel versus aspirin alone in 15,603 patients with either documented cardiovascular disease (coronary, ischemic cerebrovascular, or peripheral arterial) or, in 21 percent of patients, multiple atherothrombotic risk factors (eg, diabetes, hypertension, primary hypercholesterolemia, current smoking, asymptomatic carotid stenosis ≥70 percent) . Patients were randomly assigned to low-dose aspirin (75 to 162 mg/day) plus either clopidogrel (75 mg/day) or placebo. The following observations were reported at a median of 28 months :
Stroke subtypes — The use of dual antiplatelet therapy with aspirin plus clopidogrel has been studied in different subtypes of ischemic stroke, including small vessel disease and large artery atherosclerosis.
In a randomized trial (SPS3) evaluating over 3000 patients with subcortical (ie, lacunar) stroke confirmed by MRI, the arm testing the combination of aspirin plus clopidogrel versus aspirin alone was terminated before completion because of a higher frequency of bleeding events (mostly systemic) and a higher mortality rate in patients assigned to dual antiplatelet therapy compared with those assigned to aspirin only . In the final analysis, subjects treated with aspirin plus clopidogrel compared with aspirin alone had a significantly increased annual rate of both major hemorrhage (2.1 versus 1.1 percent, hazard ratio [HR] 1.97, 95% CI 1.41-2.71) and all-cause mortality (2.1 versus 1.4 percent, HR 1.52, 95% CI 1.14-2.04) . These results, particularly when interpreted together with those of the MATCH trial (see 'Aspirin plus clopidogrel' above), suggest that dual antiplatelet therapy with aspirin and clopidogrel is harmful for long-term use in patients with lacunar stroke. Furthermore, treatment with aspirin and clopidogrel compared with aspirin alone in the SPS3 trial did not reduce the risk of recurrent stroke .
Two small trials (CARESS and CLAIR) of patients with recently symptomatic large artery stenosis found that, compared with aspirin alone, early treatment with aspirin plus clopidogrel reduced the number of microembolic signals detected on transcranial Doppler ultrasound [27,28]. However, whether this surrogate measure would translate into clinical benefit for patients with symptomatic large artery stenosis remains uncertain.
In the SAMMPRIS trial, which evaluated angioplasty and stenting plus intensive medical management versus intensive medical management alone for patients with recently symptomatic intracranial large artery stenosis, all subjects received combined aspirin and clopidogrel for the first 90 days after enrollment . The results were notable for a reduced rate of recurrent stroke and death in the medical management arm compared with historical controls, suggesting that short-term dual antiplatelet therapy is beneficial in this scenario. Therefore, we suggest dual antiplatelet therapy with aspirin plus clopidogrel for 90 days, followed by antiplatelet monotherapy, for patients with recently symptomatic intracranial large artery disease. (See "Intracranial large artery atherosclerosis", section on 'SAMMPRIS trial'.)
The use of antiplatelets in the acute phase (the first 48 hours) of ischemic stroke is discussed separately. (See "Antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Antiplatelet agents'.)
The use of aspirin plus clopidogrel to prevent recurrent stroke in patients with atrial fibrillation is reviewed elsewhere. (See "Antithrombotic therapy to prevent embolization in atrial fibrillation", section on 'Aspirin plus clopidogrel'.)
DIPYRIDAMOLE — Dipyridamole impairs platelet function by inhibiting the activity of adenosine deaminase and phosphodiesterase, which causes an accumulation of adenosine, adenine nucleotides, and cyclic AMP. Dipyridamole may also cause vasodilation.
Dipyridamole is currently available in two forms:
The effectiveness of dipyridamole monotherapy for secondary stroke prevention was established by the following studies:
Side effects of dipyridamole — Headache is a well known side effect of dipyridamole , and was the most frequent adverse event associated with extended-release dipyridamole in two large clinical trials, ESPS-2 and ESPRIT [6,31]. In a study of subjects aged 55 or older treated with the combination of aspirin-extended-release dipyridamole, headache developed in 39.7 percent after a single dose, and women were significantly more likely to develop headache than men (49.6 and 28.6 percent, respectively) . The headaches associated with aspirin-extended-release dipyridamole treatment were mostly self-limited, and treatment with acetaminophen was not significantly better than with placebo, as measured by response at two hours (75.5 and 69.4 percent). The overall incidence of headache declined markedly over seven days to less than 20 percent. Gastric upset and/or diarrhea requiring drug cessation was also more common with dipyridamole compared with aspirin or placebo in ESPS-2.
Notably, aspirin use was associated with significantly greater overall bleeding and gastrointestinal bleeding compared with dipyridamole or placebo in ESPS-2 and a subsequent meta-analysis [6,30]. In fact, in ESPS-2, the frequency of bleeding complications with dipyridamole was comparable to placebo.
Cardiac effects — Concern that dipyridamole use might lead to increased rates of myocardial ischemia has been largely laid to rest by data from two large clinical trials (ESPS-2 and ESPRIT) and a meta-analysis [30,31,33]. This concern is related to the potential for dipyridamole to cause vasodilation of coronary vessels , and it first arose with the use of intravenous dipyridamole in cardiac stress testing . Because of this issue, the 2002 American College of Cardiology/American Heart Association guideline for the management of patients with chronic stable angina recommend avoidance of dipyridamole in patients with stable angina .
However, the following observations suggest that extended-release dipyridamole use for stroke prevention is NOT associated with an increased risk of myocardial ischemia or infarction:
Aspirin plus dipyridamole — The beneficial effects of aspirin and dipyridamole for secondary stroke prevention appear to be additive such that the combination of aspirin-extended-release dipyridamole is significantly more effective than aspirin alone for stroke prevention. The data supporting this conclusion come from the following randomized trials:
ESPRIT included patients using aspirin doses ranging from 30 to 325 mg daily, allaying concerns that the very low aspirin dose (25 mg twice daily) used in ESPS-2 was in part responsible for the benefit of combined aspirin-extended-release dipyridamole over aspirin alone.
The specific dipyridamole preparation may be important. In the meta-analysis cited above, the combination of aspirin and immediate-release dipyridamole was nonsignificantly better than aspirin alone for secondary prevention of stroke (RR 0.83, 95% CI 0.59-1.15) . In contrast, extended release dipyridamole was used in all or the vast majority of patients in the much larger ESPS-2 and ESPRIT trials [6,31], and aspirin-extended-release dipyridamole was associated with a significant reduction in stroke risk compared with aspirin alone (RR 0.76, 95% CI 0.65-0.89) .
There has been concern that dipyridamole might induce coronary ischemia by a coronary steal phenomenon caused by vasodilation. Although the combination of aspirin-extended-release dipyridamole does not provide additional benefit over aspirin alone for reducing MI, neither ESPS-2 nor ESPRIT found an increase in risk [6,31]. (See 'Cardiac effects' above.)
Aspirin plus extended-release dipyridamole versus clopidogrel — The PRoFESS trial showed that clopidogrel monotherapy and aspirin-extended-release dipyridamole have similar risks and benefits for secondary stroke prevention . The trial enrolled 20,332 patients with noncardioembolic ischemic stroke and randomly assigned them to treatment with either aspirin-extended-release dipyridamole (25/200 mg twice daily) or clopidogrel (75 mg once daily). PRoFESS had a 2x2 factorial design in which the patients were also randomly assigned to telmisartan or placebo, the results of which are discussed elsewhere. (See "Antihypertensive therapy to prevent recurrent stroke or transient ischemic attack", section on 'PRoFESS trial'.)
At an average follow-up of 2.5 years, the following observations were noted with antiplatelet therapy:
Despite the evidence of benefit in the CATS and TASS trials, ticlopidine is generally not considered a first-line antiplatelet agent for stroke prevention because of side effects and relatively high cost. (See 'Choosing initial therapy' below.)
Side effects of ticlopidine — The most serious complication of ticlopidine therapy is severe neutropenia, which occurs in approximately 1 percent of patients. Thus, for the first three months of treatment, patients must undergo biweekly complete blood counts. This side effect limits the utility of ticlopidine. Other common side effects, which occur more frequently with ticlopidine than aspirin, are rash and diarrhea.
Cilostazol — The antiplatelet agent cilostazol is a phosphodiesterase 3 inhibitor that is used mainly for intermittent claudication in patients with peripheral artery disease. Several controlled trials have found that cilostazol is effective for preventing cerebral infarction.
These data support the safety and efficacy of cilostazol for secondary stroke prevention in Asian populations. However, there are as yet no high-quality data regarding the use of cilostazol for secondary stroke prevention in non-Asian ethnic groups. Also, the lower tolerability and higher cost of cilostazol compared with aspirin may limit its more widespread use for stroke prevention.
Triflusal — Triflusal is an antiplatelet agent that is structurally related to aspirin. It is available as a licensed pharmaceutical in some European and Latin American countries, but is considered investigational in the United States.
In a randomized trial with 2113 patients, the effectiveness of triflusal was similar to aspirin (325 mg/day) at preventing vascular events after stroke, but it did have a lower rate of hemorrhagic complications . Similar findings were noted in a smaller randomized trial and a meta-analysis of four trials [46,47]. It is not clear whether triflusal would have had a lower rate of hemorrhagic complications than lower-dose aspirin .
CHOOSING INITIAL THERAPY — Aspirin is effective for secondary stroke prevention in patients with noncardioembolic TIA and ischemic stroke. However, clopidogrel treatment was better than aspirin as measured by a composite outcome of stroke, MI, or vascular death in the CAPRIE study , and the combination of aspirin-extended-release dipyridamole had greater benefit for secondary stroke risk reduction than aspirin alone in two clinical trials (ESPS-2 and ESPRIT) [6,31].
Current guidelines from the American Heart Association/American Stroke Association (AHA/ASA) and the American College of Chest Physicians (ACCP) recommend that patients with a noncardioembolic (ie, atherothrombotic, lacunar, or cryptogenic) stroke or TIA and no contraindication receive an antiplatelet agent to reduce the risk of recurrent stroke [13,49]. These guidelines note that aspirin, clopidogrel, and the combination of aspirin-extended-release dipyridamole are all acceptable options for preventing recurrent noncardioembolic ischemic stroke or TIA. The 2012 ACCP guidelines include cilostazol in this group of recommended antiplatelet agents, and further suggest the use of the combination of aspirin-extended-release dipyridamole or clopidogrel over aspirin or cilostazol .
Given the available data, we suggest treatment with either clopidogrel 75 mg daily as monotherapy, or aspirin-extended-release dipyridamole 25 mg/200 mg twice a day, rather than aspirin alone. Some experts still prefer aspirin as the first-line agent, noting that the alternative antiplatelet regimens (clopidogrel or aspirin-extended-release dipyridamole) have an apparent modest advantage in benefit that is potentially offset by a disadvantage in cost.
Immediate-release dipyridamole cannot be routinely recommended for secondary prevention of ischemic stroke, given the limited evidence supporting its effectiveness and the significant pharmacokinetic differences between it and extended-release dipyridamole. Ticlopidine is rarely used because of its side-effect profile and lack of clear superiority over the other available agents. Aspirin and clopidogrel should not be used in combination for stroke prevention, given the lack of greater efficacy compared with either agent alone, and given the substantially increased risk of bleeding complications.
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