Extracranial Carotid Disease and Intracranial Atherosclerosis Evidence Tables and Reference List
Risk of recurrent stroke among patients with carotid stenosis and awaiting carotid endarterectomy or carotid stenting
Carotid endarterectomy (CEA) has been shown to be beneficial for preventing stroke recurrence in patients who have sustained a minor stroke or TIA with ipsilateral high-grade carotid stenosis. There are three large trials comparing endarterectomy for symptomatic stenosis with best medical treatment in such patients: The North American Symptomatic Carotid Endarterectomy Trial (NASCET, 1991), the European Carotid Surgery Trial (ECST, 1998) and the Veterans Affairs Trial (Mayberg et al. 1991). The results of these three trials were pooled in a Cochrane review (Rerkasem & Rothwell 2011). The risk of any stroke or operative death at 5-years in patients with severe stenosis (70–99%) was significantly reduced in patients in the CEA group (RR=0.53, 0.42-0.67, p<0.0001, NNT=6) with an associated absolute risk reduction of 16.0%. For patients with moderate stenosis (50-69%) the risk was also reduced (RR=0.77, 0.63- 0.94, p=0.001, NNT=22). For patients with mild stenosis, there was no benefit of treatment. Perioperative death or stroke incidence was 7.0% (95% CI 6.2 to 8.0). The greatest benefit of treatment was found in men, patients aged 75 years or over, and patients randomised within two weeks after their last ischaemic event.
The use of CEA for asymptomatic carotid artery disease is more controversial, given that it is a lower-risk condition. Significant improvements have been made in the medical management of stroke risk factors during the previous 20 years, including the use of statins, antihypertensive agents, and antiplatelets or anticoagulants. Using data from the Asymptomatic Carotid Emboli Study (ACES), which included 477 patients with at least 70% carotid stenosis and no symptoms in the carotid artery territory for at least the previous 2 years, the use of antiplatelet and antihypertensive agents were both significant independent predictors of lower stroke risk or TIA at the end of the follow-up period (King et al. 2013). There are three large trials that have evaluated the risks and benefits of CEA in the asymptomatic group. The Asymptomatic Carotid Atherosclerosis Study (ACAS) Group, the MRC [Medical Research Council] Asymptomatic Carotid Surgery Trial (ACST) Collaborative Trial and the Veterans Affairs Trial. The results of these trials were pooled in a Cochrane review (Chambers & Donnan 2008). Median duration of follow-up ranged from 2.7-4.0 years. Although the risk of perioperative stroke death was higher in the CEA group (3.0% vs. 0.46%, RR= 6.49, 95% CI 2.53-16.61, p<0.0001), CEA was associated with significant reductions in the risk of perioperative stroke or death or subsequent ipsilateral stroke, (RR=0.71, 95% CI 0.55-0.90, p= 0.0051) as well as stroke or death or any subsequent stroke (RR= 0.69, 95% CI 0.57- 0.83, p<0.0001). The greatest benefits were evident in men and younger patients. There were insufficient data to determine whether increasing degree of stenosis was associated with increasing beneﬁt from surgery. In 10-year follow-up of ACST (Halliday et al. 2010) in which patients were randomized to receive immediate treatment vs. delayed, immediate CEA was associated with a reduced occurrence of stroke at both 5 and 10 years (6.4% vs. 11.8%, p<0.0001 and 10.8% vs. 16.9%, p<0.0001, respectively). The authors concluded that despite a 3% perioperative stroke or death rate, CEA for asymptomatic carotid stenosis reduced the risk of ipsilateral stroke, and any stroke, by approximately 30% over three years, while acknowledging that the absolute risk reduction with carotid endarterectomy is small (1%/year).
Carotid Artery Stenting vs. Best Medical Management
Carotid-artery angioplasty with stenting emerged (CAS) has emerged as an alternative to carotid endarterectomy in patients at high risk for complications for endarterectomy such as contralateral occlusion or severe coronary artery disease. The percutaneous approach also avoids the risks of general anaesthesia and the local complications of neck haematoma, infection, cervical strain and cranial nerve damage associated with endarterectomy and, requires a shorter recovery period. Several large trials assessing the safety and effectiveness of CAS (without the use of embolic protection devices) have been conducted.
The Stenting and Aggressive Medical Management for Preventing Stroke in Intracranial Stenosis (SAMMPRIS) trial, was the first large open-label clinical trial that randomly assigned patients who had a recent transient ischemic attack or stroke attributed to severe stenosis to receive aggressive medical management alone or aggressive medical management plus percutaneous transluminal angioplasty with stenting (PTAS), using the Wingspan stent system (Chimowitz et al. 2011). The primary end point was stroke or death within 30 days after enrollment or after a revascularization procedure for the qualifying lesion during the follow-up period or stroke in the territory of the qualifying artery beyond 30 days. Enrollment was stopped after 451 patients were enrolled because there was a significant increase in the number of patients in the PTAS group had a primary outcome event (20.5% vs. 11.5%, p=0.009). There was also an increased number of patients in the PTAS group who experienced any stroke during the study period (22.3% vs. 14.1%, p=0.03). The final results of this trial have been published recently (Derdeyn et al. 2014). The median follow-up period was 32.4 months. Fewer patients in the medical group had a primary endpoint event (15% vs. 23%) and the cumulative probability of the primary endpoints was significantly smaller in the medical group (p=0.0252). A similar trial, Vitesse Stent Ischemic Therapy (VISSIT) was halted after the recruitment of 112 patients, when the negative results from the SAMMPRIS trial became available (Zaidat et al. 2015). Among patients who had been randomized up to that point, the 1-year primary outcome occurred significantly more frequently in patients in the stenting group (36.2% vs. 15.1%, mean difference=21.1%, 95% CI 5.4-36.8%, p=0.02). The risk of stroke recurrence (but not TIA) within one year was also significantly higher in the stenting group (34.5 vs. 9.4%, mean difference 25.1%, 95% CI 10.5-39.6%, p=0.003).
Carotid Artery Stenting (without embolic protection) vs. Carotid Endarterectomy
The Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) included 504 patients with symptomatic or asymptomatic carotid artery stenosis of ≥30%, considered to require revascularisation and suitable for surgery or endovascular treatment (Brown et al. 2001). Patients were randomized to endovascular treatment with balloon angioplasty with or without stent insertion or CEA. Stents were used in 55 patients. At the time the trial was conducted, no protection devices were available. The median delay from randomization to surgery was 20 days (endovascular treatment) and 27 days (CEA). Mean length of follow-up was 2 years. There were no differences between groups (endovascular treatment vs. CEA) including death (3% vs. 2%), disabling stroke (4% vs. 4%), non-disabling stroke (4% vs. 4%), death or disabling stroke (6% vs. 6%) or death or any stroke (10% vs. 10%) within 30 days. At one year following treatment, severe carotid stenosis (70%-99%) was more common in patients who had received endovascular treatment (14% vs. 4%; p<0.001). In a long-term follow-up study (Ederle et al. 2009), the 8-year cumulative incidence of disabling stroke or death was non-significantly higher in the endovascular treatment group (45.2% vs. 50.4%, HR=1.02, 95% CI 0.79-1.32) as was the combined outcome of non-perioperative stroke or TIA (HR=1.37, 95% CI 0.95-1.97).
The Stent-Supported Percutaneous Angioplasty of the Carotid Artery versus Endarterectomy (SPACE) Trial included 1,200 patients, with symptomatic carotid artery stenosis, who had experienced TIA or moderate stroke within 180 days and with severe carotid artery stenosis (≥ 50% according to NASCET) (Ringleb et al. 2006). Patients were randomized to receive CAS (27% used embolic protection devices) or CEA after a median delay of 4-5 days. The trial was stopped prematurely due to concerns regarding funding and futility. There were no differences between groups on either any of the primary outcomes of 30-day ipsilateral stroke or death, or any of the secondary outcomes (disabling stroke or death from any cause within 30 days, disabling stroke, or procedural failures).
Carotid Artery Stenting (with embolic protection) vs. Carotid Endarterectomy
Several randomized trials that directly compared the safety of CEA with CAS (with protection) among patients who were symptomatic and/or asymptomatic have been published. The results from most of them suggest that during long-term follow-up, stenting is as effective as CEA.
The Asymptomatic Carotid Trial (ACT 1) (Rosenfield et al. 2016), a noninferiority trial was stopped early due to slow enrolment. While the protocol aimed to recruit 1,658 patients, data from only 328 patients were available for follow-up assessment at 5 years. At one year, the occurrence of the primary outcome (composite of death, stroke, or myocardial infarction within 30 days of the procedure or ipsilateral stroke within 1 year of the procedure) was 3.8% for stenting group compared with 3.4% for CEA group. The threshold of a 3%-point difference for inferiority was not exceeded (upper 95% CI for difference was 2.27%), suggesting that CAS was not inferior to endarterectomy. Survival from 30 days to 5 years was not significantly different between groups (87.1% stenting group vs. 89.4% CEA group, p=0.21).
The International Carotid Stenting Study (ICSS) trial enrolled 1,713 patients >40 years, with symptomatic carotid artery stenosis ≥50% using the NASCET criteria (Ederle et al. 2010). Between randomization and 120 days, stenting was associated with an increased risk of stroke, death or procedural myocardial infarction, (8.5% vs. 5.2%, HR=1.69, 95% CI 1.16-2.45, p=0.006) any stroke (7.7% vs. 4.1%, HR=1.92, 95% CI 1.27-2.89, p=0.002), any stroke or death (8.5% vs. 4.7%, HR=1.86, 95% CI 1.26-2.74, p=0.001) and all-cause mortality (2.3% vs. 0.8%, HR=2.76, 95% CI 1.16-6.56, p=0.017). In the long-term study analysis Bonati et al. (2015) reported that after a median duration of 4.2 years the risk of any stroke was significantly increased in the stenting group (HR=1.71, 95% CI 1.28 -2.3, p=0.0003), while stenting was not associated with an increased risk of fatal or disabling stroke (HR=1.06, 95% CI 0.72-1.57, p=0.77). There was also a significantly increased risk of the outcome of periprocedural stroke/procedural death or ipsilateral stroke during follow-up (HR=1.72, 95% CI 1.24-2.39, p=0.001).). In both the per protocol and intention-to-treat analyses, the cumulative 5-year stroke risk was significantly higher in the stenting group (HR=1.53, 95% CI 1.02-2.31 and HR=1.71, 95% CI 1.28-2.30, respectively), while the 5-year risk of fatal or disabling stroke was not increased. The distribution of modified Rankin Scores was similar between groups.
The Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) trial included 2,502 patients with asymptomatic or symptomatic carotid artery stenosis who had experienced a minor stroke or TIA within the previous 180 days (Brott et al. 2010). The primary end point was the composite of any stroke, myocardial infarction, or death during the peri-procedural period or ipsilateral stroke within four years after randomization. There was no significant difference in the estimated four-year rates of the primary end point between groups (7.2% vs. 6.8%); however, the 4-year rate of stroke or death was higher in the stenting group (6.4% vs. 4.7%, HR=1.50, 95% CI 1.05-2.15, p=0.03). During the periprocedural period, there was a significantly increased risk of stroke or death associated with stenting, but no difference in risk for stroke, death or MI between treatment conditions from 31 days to end of follow-up. After the 30-day, periprocedural period, incidence of ipsilateral stroke was similarly low in both groups (2.0 vs. 2.4%, p=0.85). At 10 years, there was no significant difference between groups in the risk of the primary outcome, which included stroke, death or MI (HR=1.10, 95% CI 0.83-1.44, p=0.51), or in the risk of stroke between groups (HR=0.99, 95% CI 0.64-1.52) (Brott et al. 2016).
A Cochrane review (Bonati et al. 2012) included 16 trials of patients with symptomatic stenosis, who had experienced a minor stroke, asymptomatic stenosis or both asymptomatic and symptomatic carotid stenosis. The treatment contrasts included any CEA procedure vs. any endovascular technique. Endovascular therapy was associated with a higher risk of death or any stroke within 30 days of treatment (OR=1.72, 95% CI 1.29- 2.31, p<0.0003), and death or any stroke between randomization and 30 days after treatment or ipsilateral stroke until the end of follow-up. The risk was highest in the group of studies with follow-up of 2.4 years, or longer. There was no difference between treatment groups for the outcomes of death or major or disabling stroke between randomization and 30 days after treatment (OR=1.28, 95% CI 0.93-1.77, p=0.13) or any stroke between randomization and 30 days after treatment (OR=1.21, 95% CI 0.36- 4.04, 9=0.76), although the risk was increased among the subgroup of patients at standard surgical risk, who received endovascular treatment. Endovascular therapy was associated with a reduced risk of cranial nerve palsy within 30 days of surgery and access site hematoma (OR=0.37, 95% CI 0.18- 0.77, p= 0.0082). The authors suggested that while endovascular treatment was associated with an increased risk of peri-procedural stroke or death compared with endarterectomy, the excess risk may be limited to older patients. The results from another meta-analysis, examining the same treatment contrasts, and using the results from 13 RCTs reported that compared with CEA, stenting was associated with an increase of 19 strokes and 10 fewer MIs for every 1000 patients treated (Murad et al. 2011).
Cervical Artery Dissection
While the incidence of cervical artery dissections (CAD) is relatively low, estimated to be between 2.6 to 2.9 per 100,000, CAD is over-represented among persons less than 45 years (Weimar et al. 2010). Given the increased risk of recurrent stroke associated with CAD, treatment with either antiplatelets or anticoagulants for at least 3 months is recommended. Based on the results of the Cervical Artery Dissection in Stroke (CADISS) Study (2015), treatment with either agent appears to be equally effective for the prevention of recurrent stroke. In this trial, 250 patients with extracranial carotid or vertebral artery dissection were randomized, within 7 days of the event, to receive antiplatelet agents (dipyridamole, aspirin or clopidogrel, alone or in combination) or anticoagulant therapy (UFH, LMWH, followed by warfarin, with a target INR of 2-3), for the study duration. At the end of 3 months, the frequency of the primary outcome (stroke or death), was similar between groups. There were 4 recurrent strokes (3 antiplatelet vs. 1 anticoagulant) and no deaths in either group. There was a single case of major bleeding in the anticoagulant group. Similar findings were reported in a meta-analysis including the results of 34 non-randomized studies examining the same treatment contrast (Menon et al. 2008). There were 13/185 (7.0%) in the antiplatelet group and 17/447 (3.8%) in the anticoagulant group who suffered a TIA or stroke. The risk difference between groups was not significant (5%, 95% CI -1% to 11%, p = 0.11). The use of novel oral anticoagulants (NOAC) for the prevention of recurrent stroke following CAD has not been well studied. There are no RCTs to date. In a retrospective study (Caprio et al. 2014) including 149 patients with CAD, who were prescribed antithrombotic medication at hospital discharge, there were 2 recurrent strokes during a median of 7.5 months follow-up in the NOAC group compared with one each in the anticoagulant (AC) and antiplatelet (AP) groups. There were significantly fewer major hemorrhagic events in the NOAC group (0 vs. 8 [AC] and 1 (AP], p=0.034).
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Johansson EP, Arnerlöv C, Wester P. Risk of recurrent stroke before carotid endarterectomy: the ANSYSCAP study. International Journal of Stroke. 2013;8(4):220-7.
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