In the International Stroke Trial (IST), patients received aspirin 300 mg within 48 h of ischemic stroke, which was associated with significant reductions in the 2-week recurrence of ischemic stroke and combined outcome of nonfatal stroke or death [1]. In the Chinese Acute Stroke Trial (CAST), patients who received aspirin 160 mg daily, as compared to placebo, within 48 h of ischemic stroke had a 14% reduction in mortality at 4 weeks [2].

The ticagrelor was not superior to aspirin in reducing stroke, myocardial infarction, and death at 90 days in the SOCRATES trial enrolling ischemic stroke or TIA patients within 24 h of onset [3].

The CHANCE trial randomly assigned Chinese patients within 24 h of onset of minor ischemic stroke or high-risk TIA to dual antiplatelet therapy with clopidogrel plus aspirin vs. aspirin [4]. There was a reduction in the risk of any stroke for the clopidogrel plus aspirin, as compared to aspirin. The rate of hemorrhagic stroke was not different between the two groups at 90 days. A meta-analysis of early dual antiplatelet therapy vs. monotherapy for noncardioembolic ischemic stroke or TIA patients showed significant reduction of recurrent stroke [5]. Ongoing trials, such as POINT [6] and TARDIS [7], are likely to provide more insights into the role and type of early antiplatelet treatment for acute ischemic stroke and TIA.

Among ischemic stroke patients with prior use of antiplatelet agent, low-dose intravenous tPA (0.6 mg/kg), as compared to standard-dose intravenous tPA (0.9 mg/kg), showed a trend toward lower rates of death or disability [8].

Aspirin, the most commonly used antiplatelet agent, prevents recurrent stroke in patients with a history of recent stroke or TIA [9, 10]. A meta-analysis of 16 secondary prevention trials suggested that aspirin reduced the risk of recurrent ischemic stroke by 22% and any vascular event by 19% [11]. Several studies reported that Aspirin showed the strongest benefit effect for secondary stroke prevention in the early weeks after ischemic stroke or TIA patients [12]. Aspirin reduced the relative risk of recurrent ischemic stroke within the first 6 weeks by 58% [12]. The aspirin treatment benefit for secondary prevention was similar regardless of doses range (from 30 to 1300 mg) [9, 10], although the data for doses <75 mg were limited.

The gastrointestinal bleeding is a major complication of aspirin, and especially higher doses of aspirin are associated with greater risk [9, 10]. For patients who use lower doses of aspirin (≤325 mg), the annual risk of serious gastrointestinal bleeding is about 0.4%, which can lead to 2.5-fold increase in the risk compared with nonusers [9, 10, 13]. Aspirin doses ≤200 mg daily were associated with a lower rate of major bleeding events compared with higher doses in a pooled analysis of 31 randomized controlled trials [14]. Despite aspirin therapy which is related to an increased risk of hemorrhagic stroke, the overall benefit of aspirin use on myocardial infarction and ischemic stroke may outweigh its adverse effects on the risk of hemorrhagic stroke in patients with vascular risks.

The CAPRIE trial randomly assigned patients with recent stroke, myocardial infarction, or peripheral artery disease to treatment with clopidogrel (75 mg/day) and aspirin (325 mg/day) [13]. The ischemic stroke, myocardial infarction, or vascular death occurred 5.3% patients per year in the clopidogrel group and 5.8% patients per year in the aspirin group (relative risk reduction 8.7%; 95% CI, 0.3% to 16.5%). Most of the benefit was observed in patients with peripheral artery disease, and the composite outcome was not different in patients with recent stroke. However, CAPRIE was not specifically designed to determine whether clopidogrel was superior to aspirin among stroke patients.

Two RCTs have investigated the effect of dipyridamole combined with aspirin vs. aspirin in patients with history of TIA or stroke [15, 16]. In ESPS-2 trial, combination therapy (aspirin 25 mg twice daily and dipyridamole 200 mg twice daily), as compared with aspirin alone (aspirin 25 mg twice daily), reduced the risk of stroke by 23% (P = 0.006). There was no significant bleeding event in the combination therapy group, but headache and gastrointestinal symptoms were more frequent in the combination group [16]. However, there are some concerns when interpreting the study results because the quality of reported data and a relatively low-dose (50 mg daily) aspirin treatment. The ESPRIT trial was a prospective, randomized, open-label, blinded auditing of outcome events; this was designed to compare aspirin (30–325 mg daily) plus dipyridamole (200 mg twice daily) with aspirin alone (30–325 mg daily) for the prevention of stroke, myocardial infarction, vascular death, or major bleeding among patients with a TIA or ischemic stroke within 6 months [16]. In the combination therapy groups, 83% of patients took the extended-release dipyridamole, and 17% of patients took the immediate-release dipyridamole. The primary outcome events were occurred in 13% of the combination therapy patients, and in 16% of the aspirin therapy patients for 3.5 years (HR, 0.80; 95% CI, 0.66–0.98). However, a limitation of this study was that the investigators did not report post-randomization risk factor management.

Among >20,000 patients with noncardioembolic ischemic stroke, stroke recurrence was 9.0% in the aspirin/dipyridamole group and 8.8% in the clopidogrel group over 2.5 years (HR, 1.01; 95% CI, 0.92–1.11) [17]. There were more major hemorrhagic events among aspirin plus extended-release dipyridamole recipients than among clopidogrel recipients (HR, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (HR, 1.42; 95% CI, 1.11 to 1.83) [17].

In the substudy of the CHARISMA trial, there was no significant benefit for cardiovascular events; however, the bleeding risk was higher in the combination therapy group compared with aspirin-alone group after a stroke or TIA event [18]. In the SPS3 trial, patients with lacunar stroke within 180 days were randomized to clopidogrel 75 mg combined with aspirin 325 mg daily versus aspirin 325 mg daily [19]. The recurrent ischemic stroke and intracranial hemorrhage rate were not significantly different between dual antiplatelet and aspirin monotherapy. The risk of major hemorrhage, primarily driven by an increased risk for gastrointestinal hemorrhage, and all-cause mortality were significantly higher in the combination therapy group [19].

The MATCH trial analyzed the effectiveness of the combination therapy of clopidogrel with aspirin compared with clopidogrel monotherapy for the prevention of vascular events among patients with a recent ischemic stroke or TIA [20]. During the 3.5-year follow-up period, there was no significant benefit of combination therapy for preventing cardiovascular events or death, readmission, and peripheral ischemic event compared to clopidogrel monotherapy. Life-threatening bleedings were higher in the group receiving aspirin and clopidogrel versus clopidogrel monotherapy [20].

A meta-analysis of completed clinical trials indicates that dual antiplatelet therapy, as compared to aspirin monotherapy, had a neutral effect on the prevention of recurrent stroke and intracranial hemorrhagic events [21]. Long-term dual antiplatelet therapy vs. clopidogrel monotherapy appeared to raise the risk of intracranial hemorrhage in people with a prior ischemic stroke or TIA and did not prevent recurrent ischemic events [21].

The effectiveness of cilostazol compared with aspirin for secondary stroke prevention was examined by two major randomized controlled trials conducted in East Asia [22, 23]. One trial showed that cilostazol was associated with a nonsignificant reduction in any recurrent stroke during 12–18-month follow-up (HR, 0.62; 95% CI, 0.30–1.26) [22]. In a cilostazol for prevention of secondary stroke (CSPS 2), non-inferiority trial, the prevalence of recurrent ischemic stroke or hemorrhagic stroke was 2.76% in the cilostazol group and 3.71% in the aspirin group (HR, 0.74; 95% CI, 0.64–0.98) at 29-month follow-up [23]. Ischemic stroke was not reduced significantly by cilostazol compared to aspirin (2.43% per year versus 2.75% per year; HR, 0.89; 95% CI, 0.65–1.20). However, the cilostazol group was related to fewer intracranial and systemic hemorrhage compared with the aspirin group (0.77% versus 1.78% per year; HR, 0.46; 95% CI, 0.30–0.71). The cilostazol clinical studies were conducted in Asia, so it is uncertain whether this effect is applicable to other races. An ongoing trial, CSPS.​com, is investigating the safety and efficacy of dual antiplatelet treatment involving cilostazol for secondary ischemic stroke prevention, in comparison with that of antiplatelet monotherapy.