For patients with symptomatic intracranial atherosclerosis (ICAS), antithrombotic agents are the mainstay of therapy. Anticoagulation (warfarin) is not widely used since it is not more effective than aspirin and carries a high risk of bleeding. New oral anticoagulants are showing promise, but their use has not been investigated in appropriate clinical trials. Since the recurrent stroke risk is high with aspirin monotherapy, dual antiplatelets are considered in the early stage of symptomatic ICAS. Based on the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) and Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) results, aspirin plus clopidogrel has been recommended. However, this combination was not superior to aspirin monotherapy in patients with ICAS in the CHANCE substudy. Progression of ICAS is common, and it is associated with recurrent strokes. In the Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis (TOSS) study, aspirin plus cilostazol was more effective than aspirin monotherapy in preventing progression. The TOSS II trial showed that the overall change in stenosis was better with aspirin plus cilostazol than with aspirin plus clopidogrel. Aside from antithrombotic therapy, risk factor management is critical for secondary prevention, and high blood pressure is clearly linked to recurrent stroke. However, blood pressure may have to be cautiously managed in the early stage of stroke. Considering that ICAS is the major cause of stroke worldwide, further investigations are needed to establish optimal management strategies for patients with ICAS.
Intracranial atherosclerotic disease (ICAS) is more prevalent in Asians and Blacks than in Caucasians [
Although there have been a few general reviews on ICAS [
There is much contention as to the role of anticoagulation in the management of patients with ICAS. Anticoagulation with warfarin has been empirically used for patients with severe occlusive disease in the vertebrobasilar artery and recurrent ischemic stroke despite antiplatelet treatment according to the favorable results of clinical trials performed in 1960s [
However, the failure of warfarin therapy was mainly derived from the high incidence of bleeding rather than the lack of efficacy. Since the new oral anticoagulants (NOACs) have comparable efficacy and are associated with significantly fewer bleeding complications than warfarin, NOACs may be used in patients with ICAS. Indeed, the WASID study showed that in patients whose international normalized ratio (INR) was maintained within the ideal therapeutic window (2.0–3.0), the risk of stroke reduced to 5.1% per year (95% CI 2.7–8.7%) from 24.9% per year (95% CI 15.8–37.3%) among those whose INR was <2.0, and the risk of major hemorrhage was 3.5% per year (95% CI 1.6–6.6%) compared with 15.2% (95% CI 6.6–30.0%) for those whose INR ranged from 3.1 to 4.4 [
Aspirin is the most widely used antiplatelet in the world. However, when aspirin alone is used in symptomatic patients with ICAS, patients were reported to develop recurrent stroke at an annual rate of 4–19% [
The combined use of aspirin and clopidogrel seems to have benefits over aspirin monotherapy for the management of acute coronary syndrome, as demonstrated by 2 large clinical trials: the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial [
Subsequently, treatment with the combined use of aspirin and clopidogrel was examined in patients at high risk of secondary ischemic events. Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events (CHANCE) investigators randomly assigned 5,170 patients to combination therapy (clopidogrel and aspirin) or aspirin monotherapy treatment groups within 24 hours after the onset of minor ischemic stroke or high-risk TIA [
Aspirin plus clopidogrel may also improve the outcome of ICAS patients. In the Stenting and Aggressive Medical Therapy for Intracranial Stenosis (SAMMPRIS) trial [
In the more recent CHANCE substudy on 481 patients with ICAS [
An important issue for clopidogrel is that it is an inactive pro-drug that requires conversion to the active metabolite via CYP2C19. It has been suggested that clopidogrel resistance is more prevalent in Asians than in whites. In another CHANCE substudy [
Cilostazol has vasodilating, anti-inflammatory, and anti-atherogenic effects in addition to its antiplatelet effect, and it has been shown to be effective in the symptomatic improvement of intermittent claudication [
Therefore, trial of cilostazol in symptomatic intracranial stenosis (TOSS) investigators attempted to examine the efficacy of cilostazol in the management of ICAS. The TOSS I study [
Therefore, cilostazol appears to be effective in the prevention of stenosis progression in patients with symptomatic ICAS. However, both the TOSS I and TOSS II trials have limitations in that the numbers of patients were small, all patients were Korean, and, most importantly, the main endpoint was the progression of ICAS and not clinical outcome. Despite those limitations, cilostazol is currently widely used in some parts of the world (mostly Asia). It has been previously shown that the stenosis of intracranial arteries frequently progresses [
As discussed above, the presence of loss of function alleles may exert an effect during treatment with clopidogrel. One drug that has the potential to resolve this resistance issue is ticagrelor, an antiplatelet agent that acts by the same mechanism as clopidogrel (inhibition of the platelet ADP receptor P2Y12). Since ticagrelor is an active agent, the resistance issue can be avoided [
However, ticagrelor may be effective in certain groups of stroke patients, especially those with atherosclerotic stroke. In a substudy of SOCRATES, investigators examined the efficacy of ticagrelor in patients with ipsilateral atherothromobotic stroke [
Vorapaxar, a selective antagonist of protease activator receptor-1 (PAR-1), is a new class of antiplatelet agent [
Hypertension, diabetes, dyslipidemia, and cigarette smoking are risk factors associated with cerebral artery atherosclerosis including ICAS. The differences in risk factors between ICAS and extracranial atherosclerosis (ECAS) have been subject to debate; dyslipidemia seems to be more closely associated with ECAS, while advanced hypertension, metabolic syndrome, or diabetes may be more closely associated with ICAS [
Previously, risk factor management has not been seriously considered in the clinical research on ICAS. However, in the recent SAMMPRIS trial, investigators attempted to use a multimodal aggressive risk factor approach for stroke prevention: targeting systolic blood pressure (SBP) ≤140 mm Hg (≤130 mm Hg if diabetic) and low-density lipoprotein (LDL) cholesterol <70 mg/dL. The study neurologists and coordinators at each site implemented risk factor management for both primary (SBP and LDL cholesterol) and secondary (non-high density lipoprotein cholesterol, hemoglobin A1c (HbA1c), smoking, weight management, physical activity) targets and were assisted by an evidence-based, educational, lifestyle modification program (INTERxVENT) that was administered at regularly scheduled times to all patients throughout the study.
Compared to similar patients treated with usual management approach in the WASID trial, patients enrolled in SAMMPRIS had substantially better risk factor control: within the first 30 days, mean SBP decreased by >5 mm Hg and mean LDL cholesterol decreased by >20 mg/dL. Among WASID patients who met the SAMMPRIS entry criteria, the stroke and death rate was 10.7% at 30 days and the primary endpoint was 25% at 1 year. These rates were much higher than those of the SAMMPRIS patients who were assigned to the medication-only group whose 30-day rate of stroke or death was 5.8% and whose 1-year rate of primary endpoint occurrence was 12.2%. Since the antithrombotics that were used differed between the 2 studies (aspirin plus clopidogrel in SAMMPRIS vs. aspirin or warfarin in WASID), the 2 groups cannot be directly compared, but it is likely that the improved risk factor control contributed to better outcomes in the medical management arm of SAMMPRIS.
In a recent prospective observational study involving 50 acute stroke patients with symptomatic ICAS (≥70%), intensive medical therapy for 12 months with the therapeutic targets of LDL cholesterol <70 mg/dL, HbA1c <6.5%, and SBP <140 mm Hg resulted in relatively good outcomes in terms of ICAS progression: regression occurred in 49% of patients, quiescence in 43%, and progression in 8% [
However, the intensity of the control of blood pressure and cholesterol levels remains subject to debate. In the following section, we present a detailed discussion of the management of those 2 important risk factors, i.e., blood pressure and cholesterol, for secondary prevention in patients with ICAS.
Hypertension is an important risk factor for ICAS, and may be a factor more closely associated with ICAS than ECAS [
Using 567 patients from the WASID trial, investigators analyzed the frequency of ischemic stroke according to the mean SBP and mean diastolic blood pressure (DBP) during the study period [
More recently, using the data set of 402 patients with symptomatic ICAS who were enrolled in the TOSS II study, investigators attempted to examine the relationship between mean SBP and the progression of ICAS, which was defined as a worsening by 1 grade or more at the 7-month follow-up MRA [
Thus, both the WASID and TOSS II substudies indicate that very high mean SBP (≥160 mm Hg) is closely associated with a high risk of recurrent stroke and ICAS progression. However, the findings regarding the low-normal blood pressure appear contradictory. This discrepancy may be attributable to the fact that the patients in the TOSS II trial were enrolled sooner following their stroke events than those in the WASID trial. In other words, the hazard of excessive blood pressure reduction, if it exists, may be more apparent in the early stage of stroke. Moreover, the 2 data sets are not comparable because the primary endpoints were different (recurrent stroke in WASID vs. ICAS progression in TOSS II). It remains unclear why the progression rate tended to be higher in the low-normal (<120 mm Hg) SBP group in the TOSS II substudy.
The potential danger of excessive blood pressure reduction in patients with ICAS can be attributed primarily to early neurological progression (END), which could not be captured in studies where outcomes were defined as recurrent stroke or mortality. In a recent multicenter study [
The occurrence of END in patients with ICAS is likely to be caused by a perfusion defect in the territory of the stenosed artery. According to a study that enrolled 95 patients with ICAS [
This observation suggests that an increase rather than a decrease in blood pressure may be beneficial in patients with END, which is presumably due to unstable cerebral perfusion in the early stage of stroke. Although the benefit of so-called ‘induced hypertension’ has not been fully documented, some small studies have demonstrated improved outcomes in cerebral perfusion [
Finally, long-term treatment with ACE inhibitors was reported to prevent the progression of atherosclerotic processes detected by carotid duplex scan [
Current guidelines emphasize lipid-lowering (statin) therapy to reduce the risk of atherosclerotic strokes [
Nevertheless, there is some evidence that statin therapy is important in the secondary prevention of stroke in ICAS patients. In one study [
Currently, the Treat-Stroke-To-Target (TST) trial is ongoing (clinicalTrials.gov identifier, NCT01252875). In this study, patients with ischemic stroke (within 3 months) or TIA (within 15 days) and evidence of atherosclerotic vascular diseases were randomized to maintain an LDL cholesterol level of either 100±10 mg/dL or <70 mg/dL. The number of target patients was 3,760, and they will be followed up for at least 12 months. The primary endpoint was the composite of nonfatal ischemic stroke, nonfatal myocardial infarction, and any vascular death. Partly because both Caucasian (French) and Asian (Koreans) patients are enrolled, and partly because the location of atherosclerosis is mandatorily documented in the protocol, it is expected that the study result may provide an answer as to whether the therapeutic target of LDL cholesterol should vary according to different ethnicities (whites vs. Asians) and different locations of atherosclerosis (ICAS vs. ECAS).
Finally, it has been suggested that the statin therapy strategy may have be modified according to the pathologic nature of ICAS. With recent advances in high-resolution MRI techniques, intracranial arterial plaque can be visualized. It has been shown that ICAS has heterogeneous features in terms of plaque instability and vascular remodeling [
Despite the high prevalence of ICAS throughout the world, clinical trials focusing on ICAS have been rare, and further active clinical studies are needed. As previously discussed, NOACs should be examined for their efficacy in secondary stroke prevention in ICAS patients since they offer effective anticoagulation with decreased occurrence of bleeding complications compared to warfarin. Although cilostazol has been found to be efficacious in preventing the progression of ICAS, its effect on clinical outcomes still needs to be tested through larger studies. The efficacy of clopidogrel should also be re-examined, possibly with concomitant tests on genetic polymorphisms such as the loss of function gene. Ticagrelor is one of the promising drugs that should be tested in symptomatic patients with ICAS. Testing various combinations of antiplatelets with different basic mechanisms (e.g., cilostazol plus clopidogrel) may provide valuable information as well. Finally, studies on the duration of dual antiplatelets should be performed given that the benefit of long-term dual antiplatelet therapy may be counteracted by the potentially increased incidence of bleeding complications.
Imaging techniques such as MRA, CTA, and catheter angiography can examine luminal stenosis, but not vascular wall pathology. Therefore, non-atherosclerotic etiologies such as moyamoya disease (MMD), dissection, and vasculitis may be erroneously categorized as ICAS. One diagnostic tool that can be used to examine the vessel wall is high-resolution vessel wall MRI [
In addition, ICAS leads to stroke or TIA via diverse mechanisms including artery-to-artery embolism, in-situ thrombotic occlusion, branch occlusion, and hemodynamic impairment [
The authors have no financial conflicts of interest.
This study was supported by a grant from the Ministry for Health, Welfare, and Family Affairs, Republic of Korea (HI14C1985).