流行病学和复发高危因素
ICAS causes about 5–10% of strokes in white people, 15–29% of transient ischaemic attacks or strokes in black people, and up to 30–50% of strokes in Asian people. Potential explanations for racial and ethnic differences in the prevalence of ICAS include genetic susceptibility of some racial and ethnic groups, and differences in lifestyle and risk factor profiles between races.
Traditional risk factors associated with ICAS include hypertension, smoking, diabetes mellitus, and hyperlipidaemia. In the Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial, the most important modifiable risk factors for an increased risk of recurrent stroke and vascular events associated with ICAS were raised blood pressure and cholesterol concentrations. In the trial, which enrolled 569 patients with 50–99% symptomatic ICAS, the risk factors most strongly associated with recurrent ischaemic stroke and other major vascular events were mean systolic blood pressure greater than 140 mm Hg and mean cholesterol concentration greater than 5∙20 mmol/L (200 mg/dl) during follow-up.
Some imaging characteristics, such as degree of stenosis and collateral circulation, affect risk of recurrent events and outcome in patients with ICAS. In the WASID trial, patients with at least 70% stenosis of a major intracranial artery had an increased risk of recurrent stroke in the territory of the stenosis compared with patients with 50–69% stenosis. However, the presence of robust collaterals in patients with greater than or equal to 70% stenosis mitigated the risk of recurrent stroke.
ICAS相关卒中的发病机制
There are three main hypothesised mechanisms of stroke related to ICAS: hypoperfusion, artery-to-artery embolism, and plaque extension over small penetrating artery ostia (also known as branch atheromatous disease). Combinations of these ischaemic mechanisms can also occur—eg, when hypoperfusion prevents clearing of a distal embolus.
The underlying mechanism of stroke is typically inferred by characteristics on neuroimaging. For example, ischaemic infarcts in a watershed distribution on brain imaging suggest hypoperfusion through a highly stenotic artery, whereas a distal wedge-shaped territorial infarct might indicate artery–artery embolism. High-resolution MRI, an emerging imaging method, can be used to identify plaque extension over small penetrating artery ostia, which can result in lacunar infarctions. Importantly, the initial stroke mechanism in ICAS might be a predictor of the mechanism of subsequent stroke or the risk of recurrent stroke.
影像诊断
Diagnostic methods used to identify ICAS include transcranial Doppler (TCD) ultrasound, MRA, CT angiography (CTA), conventional cerebral angiography, and high-resolution MRI. TCD, MRA, CTA, and highresolution MRI are non-invasive methods that provide safer and less expensive ways to assess the intracranial arteries than conventional cerebral angiography; however, the accuracy of these methods is less clearly established. The Stroke Outcomes and Neuroimaging of Intracranial Atheroclerosis (SONIA) trial assessed the accuracy of TCD and MRA compared with catheter cerebral angiography 35 and showed that TCD and MRA had high negative predictive values (86–91%) but low positive predictive values (36–59%). These data suggest that TCD and MRA are useful screening tests for exclusion of intracranial arterial stenosis, but are unreliable to establish diagnosis of ICAS and estimate the severity of stenosis . Other studies in which catheter angiography was used as the standard reference suggest that CTA is more accurate than MRA for the diagnosis of ICAS and that CTA has a high sensitivity and specificity for detection of 50% or higher ICAS.
However, neither CTA nor any of the other non-invasive diagnostic tests accurately measure the degree (or percentage) of intracranial stenosis. Conventional cerebral angiography is therefore the gold standard for diagnosis and quantification of luminal stenosis of the intracranial circulation, which is a key prognostic indicator.
治疗
抗栓治疗
Anticoagulation was first reported as a treatment for symptomatic ICAS in 1955. Subsequently, data from a retrospective study suggested that warfarin was more effective than aspirin for stroke prevention in patients with symptomatic ICAS. However, data from WASID (a double-blinded, randomised trial comparing aspirin [1300 mg per day] with warfarin [target international normalised ratio (INR) 2–3]) showed no benefit of warfarin over aspirin for prevention of stroke and vascular death in patients with ICAS. Aspirin was also shown to be safer than warfarin, with a lower rate of death and major haemorrhage than warfarin. Some subgroups of patients with symptomatic ICAS, such as those with severe (70–99%) stenosis, vertebrobasilar stenosis, or previous stroke symptoms on antithrombotic therapy (so-called medical failures), were previously thought to benefit from anticoagulation therapy; however, findings from the WASID study showed that none of these subgroups has a significant benefit from warfarin.
The use of short-term dual antiplatelet therapy (aspirin and clopidogrel) could be particularly effective at lowering the early risk of stroke recurrence in patients with ICAS. In the CLopidogrel plus Aspirin for Infarction Reduction (CLAIR) study, 43 patients with recently (≤7 days) symptomatic ICAS who were given clopidogrel (300 mg for the first day, then 75 mg per day) plus aspirin (75–160 mg per day) had significantly lower rates of microembolic signals detected by use of TCD on day 2 and day 7 after randomisation than did those given aspirin (75–160 mg per day) alone. Additionally, when the recurrent stroke events in the CLAIR study were combined in a weighted analysis with the events from the similarly designed Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial (limited to patients with recently [within 3 months] symptomatic >50% extracranial carotid stenosis), patients given aspirin alone had significantly more recurrent stroke events than did those given aspirin and clopidogrel combined.
The use of short-term combination aspirin and clopidogrel followed by aspirin alone is also supported by the early results of the NIH-funded multicentre randomised Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial. In SAMMPRIS, patients with 70–99% ICAS who had had a stroke or transient ischaemic attack within the preceding 30 days were randomly assigned to aggressive medical management plus angioplasty and stenting (PTAS) or aggressive medical management alone for stroke prevention. Aggressive medical management included protocol-driven intensive management of blood pressure and LDL concentration, with target levels of less than 140 mm Hg (<130 mm Hg in patients with diabetes) for systolic blood pressure and LDL lower than 1∙81 mmol/L, use of a lifestyle modification programme, and the combination of aspirin (325 mg per day) and clopidogrel (75 mg per day) for 90 days followed by aspirin (325 mg per day) alone for the remainder of the trial. Enrolment in SAMMPRIS was halted early in 2011 because of the high rate of periprocedural stroke in the stenting arm, although follow-up of enrolled patients will end in 2013. Patients in the aggressive medical management alone group had a 30-day rate of stroke or death of 5∙8%, which is substantially lower than the 10∙7% rate at 30 days in patients in the WASID trial (with the same entry criteria as SAMMPRIS) who were given aspirin (1300 mg per day) or warfarin (target INR 2–3) and usual blood pressure and LDL management. Because the effect of intensive risk factor management and a lifestyle modification programme on stroke recurrence within the first 30 days would be expected to be modest, the lower rate of stroke at 30 days in SAMMPRIS than in WASID might be largely driven by early use of dual antiplatelet treatment in SAMMPRIS.
The antiplatelet agent cilostazol, a phosphodiesterase inhibitor, might decrease progression of atherosclerosis in patients with symptomatic middle cerebral and basilar artery stenosis. Kwon and colleagues randomly assigned 135 individuals to either daily cilostazol (200 mg per day) plus aspirin (100 mg per day) or placebo plus aspirin (100 mg per day). Disease progression of symptomatic ICAS, as measured by MRA and TCD at 6 months, was significantly lower in the cilostazol group than in the placebo group. No individuals in either group had strokes or transient ischaemic attacks. In a follow-up trial, 457 patients with symptomatic middle cerebral or basilar artery stenosis were randomly assigned to cilostazol (100 mg twice daily) plus aspirin (75–150 mg per day) or clopidigrel (75 mg per day) plus aspirin (75–150 mg per day) to establish the number of new ischaemic lesions on MRI at 7 months. New ischaemic lesions (18∙7% vs 12∙0%; p=0∙078) or haemorrhagic events (0∙9% vs 2∙6%; p=0∙163) did not differ significantly between the cilostazol and clopidogrel groups. No data have been published for the superiority or equivalence of other antiplatelet regimens such as monotherapy with clopidigrel, cilostazol, or extended release dipyridamole, or the combination of dipyridamole and aspirin for stroke prevention in patients with symptomatic ICAS.
危险因素管理
Results of secondary stroke prevention trials focusing on lowering of LDL concentrations or blood pressure showed significant reductions in recurrent stroke risk with a statin and angiotensin-converting-enzyme (ACE) inhibitor. However, these trials were undertaken in patients with heterogeneous causes of stroke. Data for the specific effect of risk factor control on risk of recurrent stroke in patients with ICAS are based on post-hoc analyses of the WASID and SAMMPRIS trials. The results of WASID suggested that patients with poorly controlled systolic blood pressure (>140 mm Hg) and cholesterol (>5∙20 mmol/L) during follow-up had the highest rates of major vascular events, including recurrent stroke. By contrast with the common practice of maintenance of slightly raised blood pressure in patients with ICAS to reduce the risk of stroke from distal hypoperfusion, increased mean systolic blood pressures during follow-up in WASID did not lower the risk of stroke in the territory of the stenotic artery, and actually increased the risk of recurrent stroke overall.
Additional supporting evidence for the role of risk factor control in stroke prevention in patients with ICAS comes from the SAMMPRIS trial. Patients in the aggressive medical management alone group of the SAMMPRIS trial had a much lower rate of stroke than expected (5∙8% at 30 days and 12∙2% at 1 year) compared with patients in the WASID trial who met the SAMMPRIS entry criteria and received aspirin or warfarin and usual management of vascular risk factors (10∙7% at 30 days and 25% at 1 year). The lower risk in patients in the SAMMPRIS trial from 90 days after enrolment (when clopidogrel was stopped) to 1 year compared with risk in patients in the WASID trial suggests that intensive risk factor management in SAMMPRIS had an important role, but this effect will only become clearer at the end of the trial when analyses correlating risk factor control with outcomes will be done.
外科治疗
Extracranial to intracranial bypass surgery was the most commonly used and most thoroughly studied surgical technique for stroke prevention in patients with symptomatic ICAS. The extracranial to intracranial bypass trial, undertaken in the 1980s, was a prospective, international, multicentre, randomised trial comparing extracranial to intracranial bypass (superficial temporal artery to the middle cerebral artery) and medical therapy in 1377 patients with extracranial carotid occlusion or intracranial carotid or middle cerebral artery stenosis. The procedure did not lower the rate of stroke compared with aspirin in the group as a whole, and was associated with a worse outcome than was aspirin alone in patients with middle cerebral artery stenosis. On the basis of these findings, extracranial to intracranial bypass has been abandoned as a treatment for the prevention of stroke in patients with symptomatic anterior circulation ICAS. Bypass has been done for vertebrobasilar insufficiency, but available data from case series suggest a high complication rate.
血管内治疗
Endovascular treatment emerged as a potential option for stroke prevention for ICAS in the 1980s. Angioplasty alone was typically used to treat severe ICAS in patients with recurrent ischaemic events on medical therapy. The outcome data with angioplasty have largely been limited to single-centre, observational, retrospective reports that show periprocedural stroke rates of 4–50%. Some of the variability in the outcome data is attributable to the heterogeneity of the patients treated. Generally, lower complication rates were reported in less acute cases whereas higher rates of stroke and mortality were recorded in patients with unstable symptoms. Device development and improvements in the technical aspects of the procedure, such as the application of undersized angioplasty balloons and a slow balloon inflation technique, have shown more promising results. Nevertheless, there are no prospective, multicenter, externally adjudicated studies on angioplasty alone to treat ICAS and no data comparing patients treated with angioplasty alone versus concurrent medically treated controls. Angioplasty alone is often associated with immediate elastic recoil of treated arteries, residual post-procedure stenosis in as many as 50% of treated patients, restenosis, and dissection.
Because of these limitations of angioplasty and the success of stenting in the coronary circulation, stenting became the preferred endovascular treatment for ICAS for most interventionists. Initial experience with percutaneous angioplasty and stenting (PTAS) with coronary balloon expandable stents showed improved post-treatment luminal diameters compared with angioplasty alone; however, difficulty in navigation of the intracranial vessels, and trauma during balloon inflation and deployment of the stents, resulted in high morbidity and mortality rates. Drug-eluting stents are commonly used to prevent restenosis after stenting in the coronary circulation and have been used for this purpose for intracranial stenosis in a few small, single center studies, which show conflicting results for the incidence of restenosis. Moreover, the US Food and Drug Administration (FDA) did not approve an investigational device exemption to use these stents in a pilot study of patients with intracranial stenosis because the safety of drug elution in the cerebral circulation has not been established.
In 2005, the FDA approved the self-expanding Wingspan stent (Stryker Neurovascular, Freemont, CA, USA) for use under the humanitarian device exception in medically refractory patients with transient ischaemic attack or stroke secondary to 50–99% stenosis of a major intracranial artery. This approval was based on findings from a European and Asian study of 45 patients. Subsequently, the results of two multicentre registry studies in the USA (the National Institutes of Health [NIH]-sponsored Wingspan registry and the US Winspan registry) suggested that intracranial PTAS with the Wingspan stent could be done with high technical success rates and with 30-day stroke rates of 6–9%.
As noted earlier, the SAMMPRIS trial, which began enrolment in 2008, assessed high-risk patients with 70–99% ICAS who had had a stroke or transient ischaemic attack within the preceding 30 days to establish whether aggressive medical management plus angioplasty and stenting with the Wingspan system was superior to aggressive medical management alone for stroke prevention. SAMMPRIS had enrolled 451 patients before enrolment was stopped in April, 2011, because of the high risk of periprocedural stroke and death in the PTAS group. The 30-day rate of stroke or death was 14∙7% in the PTAS group and 5∙8% in the medical group. The 1-year primary endpoint (30-day rate of stroke and death and ischaemic stroke after 30 days) rates were 20∙0% in the PTAS group and 12∙2% in the medical group. Contrary to the investigators’ hypothesis, findings from SAMMPRIS showed that aggressive medical management was superior to PTAS in the treatment of patients with high-risk symptomatic ICAS.
In an attempt to better understand the mechanism of periprocedural complications associated with PTAS in the SAMMPRIS trial, investigators undertook a detailed review of the PTAS patients who had had intracerebral haemorrhage, subarachnoid haemorrhage, ischaemic stroke, or cerebral infarct with temporary signs within 30 days of treatment. The results of these analyses showed that three patients had ischaemic stroke during the diagnostic angiogram (although two were deemed to be unconnected with the procedure); 21 patients had either an ischaemic stroke (n=19) or cerebral infarct with temporary signs (n=2) within 30 days of PTAS (15 of the ischaemic strokes occurred in the perforator territories of the stenotic arteries after successful angioplasty and stenting, and many of these occurred in the basilar artery [n=8]); six patients had subarachnoid haemorrhage (three from wire perforation), and seven patients had a delayed intraparenchymal haemorrhage. Risk factors that were significantly associated with periprocedural ischaemic events were non-smoking (possibly because smoking increases the conversion of clopidogrel to its active metabolite), basilar artery stenosis, diabetes, and older age, whereas risk factors associated with periprocedural intracranial haemorrhages included high percentage of stenosis and clopidogrel load associated with an activated clotting time above the target range.
Although these periprocedural complication rates in SAMMPRIS were higher than previously reported in the Wingspan humanitarian device exception study and Wingspan registries, the increased periprocedural risk was not due to operator inexperience. Possible explanations for the higher periprocedural events in SAMMPRIS than in the previous registries include the higher severity of stenosis needed for enrolment in SAMMPRIS and the earlier treatment in SAMMPRIS (within 30 days of the qualifying event), which might have increased the risk of PTAS. Additionally, SAMMPRIS had a more rigorous adjudication process, with local evaluation by study neurologists (not required in the registries) followed by external blinded adjudication by a committee of expert neurologists. Researchers in other studies have subsequently reported higher rates of periprocedural events with the Wingspan Stenting System than in the Humanitarian Device Exception Study and registries. Periprocedural complications might not be limited to the Wingspan stent—enrolment in an industry-sponsored randomised trial of intracranial stenting with the balloon expandable Pharos Vitesse Neurovascular Stent System (Codman Neurovascular, Raynham, MA, USA versus medical management was also prematurely terminated in January, 2012. The final results of this trial are expected in October, 2013.
治疗推荐
On the basis of current data from randomised trials, we recommend the following treatment for patients with symptomatic ICAS.
Patients with moderate stenosis (<70%) or patients whose transient ischaemic attack or stroke occurred more than 30 days ago (even if they have >70% stenosis) should be treated with aspirin (325 mg/day) and intensive risk factor management, primarily to achieve systolic blood pressure of less than 140 mm Hg and LDL concentration greater than 1∙81 mmol/L . In WASID, such patients made up 75% of the study cohort and had a stroke rate of 3–9% with usual risk factor management, which suggests that their stroke rate would be even lower with intensive risk factor management.
For patients with 70–99% stenosis and events within the past 30 days, a combination of clopidogrel (75 mg per day) with aspirin (325 mg per day) for 90 days seems warranted, on the basis of the results of SAMMPRIS 46 and CLAIR, followed by aspirin (325 mg per day) alone plus intensive risk factor management (figure 3). We do not recommend the use of clopidogrel in addition to aspirin for more than 90 days after initiation of treatment because of the risk of major haemorrhage from more prolonged use of dual antiplatelet therapy that was established in the MATCH and CHARISMA trials. However, the benefit of prolonged use of dual antiplatelet therapy for high-risk patients with intracranial stenosis might outweigh the risk of major haemorrhage, but this effect will need to be proven in future trials before the treatment can be recommended.
Patients in the SAMMPRIS study who were managed with dual antiplatelet therapy for 90 days followed by aspirin alone plus intensive risk factor management had a primary endpoint rate of 12∙2% at 1 year (as of April, 2011, data analysis), which implies that a subgroup of these patients still had a risk of stroke at 1 year that exceeds 12∙2%.
Lancet Neurol 2013; 12: 1106–14
