The use of anticoagulation for the prevention of stroke in patients with symptomatic ICAS was reported in the literature as early as 1955 [5] and was considered the standard of care by many neurologists. A retrospective study in 1995 suggested that warfarin was superior to aspirin for secondary stroke prevention in patients with ICAS [6]. Following this retrospective analysis, a randomized clinical trial to compare antithrombotic medications for stroke prevention in patients with symptomatic ICAS was undertaken. The Warfarin–Aspirin Symptomatic Intracranial Disease (WASID) trial was a multicenter randomized double-blind, placebo-controlled trial comparing aspirin 1,300 mg/day to dose-adjusted warfarin (target INR 2–3) in patients with TIA or stroke within 4 months attributed to 50–99 % stenosis of a major intracranial artery [1]. Data from WASID showed that there was no significant benefit of warfarin over aspirin for prevention of stroke and vascular death in patients with symptomatic ICAS. In addition, WASID showed that aspirin was safer than warfarin, with a reduced rate of death and major hemorrhage. The WASID results lead to a change in the clinical management of patients with symptomatic ICAS, with significantly fewer neurologists prescribing warfarin for stroke prevention [7]. WASID subgroup analyses also confirmed that certain groups that were thought to be more responsive to anticoagulation, such as patients with vertebrobasilar stenosis [8], severe (70–99 %) stenosis, or previous stroke symptoms on antithrombotic therapy (medical failures) [9], had no significant benefit from warfarin over aspirin. Furthermore, WASID showed that patients with symptomatic ICAS remained at high risk for recurrent stroke whether taking aspirin or warfarin, with up to 18 % of patients having recurrent strokes in the territory of a 70–99 % stenosis after 1 year.

While aspirin was shown to be as effective in lowering stroke recurrence and even safer than warfarin for stroke prevention in patients with symptomatic ICAS in the WASID trial, newer antiplatelet regimens were being studied in patients with heterogenous causes of stroke, some of whom had ICAS. The Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke (MATCH) trial compared dual antiplatelet therapy with aspirin and clopidogrel versus clopidogrel alone for prevention of major vascular events in high-risk patients with recent ischemic stroke or transient ischemic attack (TIA) and at least one vascular risk factor [10]. This study included patients with non-cardioembolic causes of ischemic stroke, but only about 1/3 were determined to be strokes secondary to large artery atherosclerosis (i.e., ICAS and extracranial carotid disease). The results revealed that there was no significant benefit for stroke prevention in the dual antiplatelet therapy group over clopidogrel alone in this heterogeneous group. Additionally, there was an increased risk of major hemorrhage in the dual antiplatelet therapy arm beyond the third month of treatment [10]. Later, the Clopidogrel plus Aspirin for Infarction Reduction (CLAIR) [11] and the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) [12] studies suggested that the use of short-term dual antiplatelet therapy (aspirin and clopidogrel) may be effective at lowering the early risk of stroke recurrence in patients with stroke due to large artery atherosclerosis. In the CLAIR study, patients with recently symptomatic (≤7 days) ICAS or extracranial carotid stenosis who were treated with dual antiplatelet agents (clopidogrel and aspirin) had significantly lower rates of microembolic signals detected by transcranial Doppler (TCD) on days 2 and 7 after randomization compared with patients treated with aspirin monotherapy [11]. In a weighted analysis, the recurrent stroke events of CLAIR combined with the events from the CARESS study (limited to patients with recently symptomatic >50 % extracranial carotid stenosis), showed significantly more recurrent stroke events on aspirin alone compared with aspirin and clopidogrel combined [11, 12]. These studies provided a rationale for including short-term dual antiplatelet (aspirin plus clopidogrel) use in future studies of ICAS.

The use of short-term dual antiplatelet therapy (aspirin plus clopidogrel) for recently symptomatic ICAS is also supported by results from the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) Trial [4]. In SAMMPRIS, patients with 70–99 % ICAS of the major intracranial arteries who had had a stroke or TIA in the territory of the stenosis within the preceding 30 days were randomly assigned to either aggressive medical therapy plus percutaneous transluminal angioplasty and stenting (PTAS) or aggressive medical therapy alone [13]. Aggressive medical therapy included aspirin 325 mg/day during the entire follow-up period, clopidogrel 75 mg/day for 90 days after enrollment, and protocol-driven intensive medical management (described in detail later in the chapter). SAMMPRIS began recruitment in November 2008, but the National Institute of Neurological Disorders and Stroke (NINDS) stopped SAMMPRIS enrollment early due to the high rate of periprocedural stroke in the stenting arm [4]. The 30-day rate of stroke or death was 14.7 % in the PTAS group (nonfatal stroke, 12.5 %; fatal stroke, 2.2 %) and 5.8 % in the medical-management group (nonfatal stroke, 5.3 %; non-stroke-related death, 0.4 %) (p = 0.002). For comparison, patients in the WASID trial (with the same entry criteria as SAMMPRIS) who were given aspirin (1,300 mg/day) or warfarin (target INR 2-3) and usual blood pressure and LDL management had a 30-day rate of stroke or death of 10.7 %. The lower rate of stroke at 30 days in SAMMPRIS compared to WASID may be driven by the early use of dual antiplatelet treatment in SAMMPRIS, since the effects of aggressive risk factor and lifestyle modification on stroke recurrence at 30 days might not likely be apparent.

The Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) also provides support for the use of short term dual antiplatelet therapy in patients with ICAS. CHANCE was a randomized trial conducted in China that compared short-term dual antiplatelet therapy versus aspirin monotherapy for the prevention of subsequent stroke at 90 days in patients with non-cardioemoblic minor stroke or high-risk TIA [14]. The primary outcome was a new stroke event (ischemic or hemorrhagic) at 90 days. A total of 2,584 patients were randomly assigned to the clopidogrel-aspirin group and 2,586 to the aspirin group. Overall, CHANCE showed that the addition of clopidogrel to aspirin within 24 h after symptom onset reduced the risk of subsequent stroke by about 32 % as compared with aspirin alone [14]. However, a subgroup analysis reported that 55.83 % of patients in CHANCE had ICAS, suggesting some of the benefit of dual antiplatelet therapy may have been due to a benefit in ICAS patients. CHANCE patients with ICAS had a higher rate of recurrent stroke (12.47 % vs. 5.43 %, P < 0.0001) and poor outcome (mRS 0-2) (89.1 % vs. 97.02 %, P < 0.0001) at 90 days than the patients without ICAS. The primary end point rate was lower in ICAS patients treated with dual antiplatelets compared with aspirin only, but was not significant (11.26 % dual vs. 13.60 % aspirin; hazard ratio [HR] 0.79, 95 % CI 0.47–1.32). However, the authors concluded that the benefits of dual antiplatelet therapy tended to be more apparent in patients with ICAS than in patients without ICAS [15].

The current AHA/ASA guidelines for secondary stroke prevention [16] indicate that for patients with recent stroke due to 70–99 % intracranial stenosis, the addition of clopidogrel 75 mg/day to the use of aspirin for 90 days is reasonable, largely based on the results of the SAMMPRIS trial.

Other antiplatelet agents such as cilostazol (a phosphodiesterase inhibitor) have been studied in patients with ICAS. Kwon et al. randomized 135 patients with ICAS (MCA or basilar) to cilostazol (200 mg/day) plus aspirin (100 mg/day) or placebo plus aspirin (100 mg/day) and measured progression of ICAS by magnetic resonance angiography (MRA) and transcranial Doppler (TCD) at 6 months [17]. Progression of atherosclerosis was significantly lower in the cilostazol group than in the placebo group (p = 0.008) and there were no reported strokes or TIAs in either group. A subsequent trial [18] randomized 457 patients with symptomatic middle cerebral or basilar artery stenosis to cilostazol (100 mg twice daily) plus aspirin (75–100 mg/day) or clopidogrel (75 mg/day) plus aspirin (75–100 mg/day) to determine the number of new ischemic lesions on MRI at 7 months. There was no statistically significant difference in new ischemic lesions (18.7 % vs. 12.0 %, p = 0.078) or hemorrhagic events (0.9 % vs. 2.6 %; p = 0.163) between the cilostazol and clopidogrel groups [18].

Overall, there is no published data for the equivalence or superiority of other antiplatelet agent regimens such as monotherapy with extended release dipyridamole, clopidogrel, cilostazol or the combination of dipyridamole and aspirin for stroke prevention in patients with symptomatic ICAS.