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Secondary Prevention Of Stroke

9. Management of Extracranial Carotid Disease and Intracranial Atherosclerosis

7th Edition – 2020 UPDATED


Definitions

Carotid stenosis is termed symptomatic if associated with a Symptomatic Event: ipsilateral carotid-territory cerebral or retinal ischemic event (ischemic stroke, transient ischemic attack, transient monocular blindness, or retinal artery occlusion) within the preceding 6 months. 

Carotid endarterectomy (CEA): surgical removal of atherosclerotic plaques within an extracranial carotid artery, usually the common carotid and proximal internal carotid artery, to prevent thromboembolic stroke.

Carotid Artery Stenting (CAS):  a minimally invasive endovascular procedure in which a stent (a slender, metal-mesh tube) is inserted into the area of narrowing to prevent thromboembolic stroke events by keeping the artery open and compressing plaque against the artery walls, this also includes potentially both pre- and post-balloon catheter dilatation (angioplasty).

 
Recommendations

Note: These recommendations are applicable to ischemic stroke and transient ischemic attack.

9.1 Symptomatic Carotid Stenosis

9.1.1 Imaging

  1. If revascularization is being considered for carotid stenosis based only on carotid ultrasound, then CTA or contrast enhanced MRA is recommended to confirm the degree of stenosis and guide surgical decision-making, as well as to assess for tandem disease [Evidence Level C]. 
    1. Conversely, carotid ultrasound may be required after initial diagnosis of carotid stenosis using CTA or contrast-enhanced MRA if heavily calcified plaque or other features make quantification of stenosis less reliable [Evidence Level C]. Please refer to section on Acute Stroke Management, section 4.2 Neurovascular (Brain and Vascular) Imaging for details regarding vascular and brain parenchymal imaging for patients with suspected stroke or transient ischemic attack.

9.1.2 Indications for carotid revascularization 

  1. Patients with a symptomatic event attributed to an ipsilateral 50 to 99 percent carotid artery stenosis should be evaluated without delay for potential carotid revascularization by a health professional with stroke expertise [Evidence Level B].  
    1. In men with 50 to 99 percent and women with 70 to 99 percent symptomatic carotid artery stenosis, carotid endarterectomy (CEA) is recommended and should be performed as soon as possible following the qualifying event [Evidence Level A].
    2. In women with 50 to 69 percent symptomatic carotid stenosis, CEA may be considered in those at highest risk of stroke recurrence and upon consideration of other patient factors [Evidence Level B].

9.1.3 Procedures

  1. Carotid revascularization (CEA or Carotid artery stenting (CAS)) should be performed by a proceduralist/centre that routinely audits their performance results, especially perioperative stroke, and death rates [Evidence Level B].  
    1. For CEA, the randomized trials upon which these recommendations are based (benefits accrued for patients undergoing surgery within 6 months of symptoms) involved combined perioperative stroke and death rates of 6 - 7 % [Evidence Level A]. 
    2. For CAS, the randomized trial upon which these recommendations are based involved combined periprocedural stroke and death rates of 5% [Evidence Level B]. 
  2. Carotid endarterectomy is generally more appropriate than CAS for patients over age 70 years who are otherwise fit for surgery as current evidence indicates stenting carries a higher peri-procedural risk of stroke and death in older patients. [Evidence Level A]. 
  3. Carotid stenting may be considered for patients who are not operative candidates for technical, anatomic, or medical reasons [Evidence Level A]. 

9.1.4 Timing

  1. In clinically stable patients (men and women), CEA should be performed as early as possible following a qualifying event [Evidence Level B] and ideally within 14 days [Evidence Level A].   
  2. In men with 50-69 percent stenosis the benefit of CEA is greatest when performed within 14 days of the qualifying event [Evidence Level A] and is attenuated when performed beyond 14 days of the qualifying event (Refer to Table 9 below for summary of recurrent stroke risk at various time points). 
Section 9.1 Clinical Considerations
  1. Most data regarding optimal timing of carotid revascularization for symptomatic carotid stenosis are derived from studies of CEA and not CAS. However, it may be reasonable to consider that similar recommendations regarding timing also apply to CAS

  2. In exceptional situations, if local system barriers preclude timely access to CEA while CAS is more rapidly accessible, this latter revascularization procedure may be considered in patients otherwise considered eligible for CAS. However, every effort must be made to enable local systems of care to ensure timely access to CEA.

  3. It may be reasonable to consider delaying CEA beyond 48 hours of the qualifying event as surgery before this time may be associated with a higher risk of perioperative complications, particularly when the qualifying event was a stroke and not a transient ischemic attack.

  4. For patients with moderate or severe stroke due to symptomatic carotid stenosis, the benefit of carotid revascularization is uncertain and should be considered on an individual basis, as such patients were excluded from trials of CEA and CAS.

  5. In acute stroke patients with tandem lesions (cervical carotid stenosis or occlusion and ipsilateral intracranial large vessel occlusion) who have undergone EVT but in whom no acute CAS has been performed during the EVT procedure, subsequent carotid revascularization by CAS and CEA should be considered if the patient otherwise remains a candidate for either procedure (as determined by residual degree of carotid stenosis, stroke severity, patient recovery, infarct size, reperfusion and bleeding risk and other factors).

9.2 Asymptomatic and Remotely Symptomatic Carotid Artery Stenosis
  1. Individuals with asymptomatic carotid artery stenosis should receive aggressive medical management of risk factors as defined throughout the Secondary Prevention of Stroke Module (for example, blood pressure, diabetes, cholesterol, antiplatelet therapy, smoking cessation, and lifestyle changes) [Evidence Level B].
  2. Carotid endarterectomy may be considered for highly selected patients with 60 to 99 percent carotid stenosis who are asymptomatic or were remotely symptomatic (i.e., greater than six months prior to presentation) [Evidence Level A]. 
    1. The benefit of carotid endarterectomy for women with 60-99 percent asymptomatic carotid artery stenosis is not clear and should only be considered in highly selected patients [Evidence Level B] in consultation with a health professional with stroke expertise.
    2. Patients should be evaluated to determine eligibility for carotid endarterectomy, such as a life expectancy of more than five years, and an acceptable risk of surgical complications [Evidence Level A].
    3. In carefully selected patients, carotid endarterectomy should be performed by a surgeon who routinely audits their performance results and demonstrates a less than 3 percent risk of peri-operative morbidity and mortality [Evidence Level B].
    4. Important improvements in best medical therapy (control of blood pressure, lipids, diabetes, and smoking) since the major trials of endarterectomy for asymptomatic stenosis possibly make their results less applicable to contemporary management practise (Evidence Level C)
  3. Carotid stenting may be considered in patients with 60 to 99 percent asymptomatic carotid stenosis who are not operative candidates for technical, anatomic or medical reasons provided there is a less than 3 percent risk of peri-procedural morbidity and mortality [Evidence Level A].
Section 9.2 Clinical Considerations:
  1. Although their impact on clinical decision-making regarding revascularization of asymptomatic patients is uncertain, several factors may confer a higher risk of stroke in patients with asymptomatic stenosis, including:           

    1. Progression of stenosis over time

    2. Ipsilateral covert brain infarcts on imaging

    3. Ipsilateral intracranial embolization detected on transcranial Doppler

    4. Plaque morphology on non-invasive imaging (ex. volume, echolucency, intraplaque hemorrhage) 

9.3 Symptomatic Vertebral Artery Stenosis
  1. (NEW FOR 2020):  For patients with symptomatic vertebral artery stenosis (extracranial or intracranial), medical therapy is recommended over stenting for secondary stroke prevention [Evidence Level B]. 
9.4 Symptomatic Intracranial Artery Stenosis
  1. For patients with a recent ischemic stroke or transient ischemic attack due to symptomatic intracranial artery stenosis of 70-99 percent, medical therapy is recommended over stenting for secondary stroke prevention [Evidence Level B].
    Note: The SAMMPRIS protocol consisted of 3 months of dual antiplatelet therapy with acetylsalicylic acid and clopidogrel (excluding high bleeding risk patients), and is typically followed by antiplatelet monotherapy thereafter, plus intensive lipid-lowering therapy with high-dose statin, blood pressure treatment, and structured lifestyle modification addressing smoking cessation, exercise and diet
     
  2. In patients who have been managed with maximal medical therapy in the presence of intracranial stenosis and experience a recurrent stroke, there is lack of evidence to guide management decisions; intracranial angioplasty (with or without stenting) may be reasonable in carefully selected patients [Evidence Level C].
9.5 Cervicocephalic Artery Dissection
  1. (NEW FOR 2020): For patients with ischemic stroke or transient ischemic attack that is preceded by head/neck trauma, cervical spine mechanical trigger event, or prominent head/neck pain, a diagnosis of carotid or vertebral artery dissection should be suspected [Evidence Level C].

  2. For patients with ischemic stroke or transient ischemic attack in whom a carotid or vertebral artery dissection is suspected, CTA or MRA of the head and neck (or catheter angiogram) is recommended as the diagnostic neurovascular imaging test rather than ultrasound [Evidence Level C].  
    Note: CTA or MRA are the preferred non-invasive diagnostic imaging tests for patients with a suspected cervicocephalic artery dissection, as neck ultrasound does not fully visualize the vertebral arteries and can miss distal carotid artery dissections originating above the angle of the jaw. 

  3. Antithrombotic therapy for stroke prevention is recommended for individuals with a diagnosis of an acute or recent extracranial carotid or vertebral artery dissection [Evidence Level B].  

    1. (New for 2020): There is uncertainty about the comparative efficacy of antiplatelet therapy vs. anticoagulation with heparin or warfarin; either treatment is considered reasonable based on current evidence [Evidence Level B]; decisions should be based on individual risk/benefit analysis taking into consideration the imaging features of the dissection (presence and degree of stenosis, intraluminal thrombus, vessel occlusion, pseudoaneurysm), brain imaging, patient characteristics, and estimated bleeding risk [Evidence Level C].  

    2. The optimal duration of antithrombotic therapy post-dissection is uncertain; decisions may be based on individual clinical factors and imaging appearances on follow-up vascular imaging [Evidence Level C]. 

  4. There is a lack of evidence regarding the safety and efficacy of anticoagulation for intracranial arterial dissections and treatment decisions should be individualized [Evidence Level C].  

Section 9.5 Clinical Considerations
  1. There is insufficient evidence at this time to make a recommendation regarding the use of DOACs in patients with arterial dissections [Evidence Level C].

Refer to Section One for recommendations on urgent vascular imaging in patients with acute transient ischemic attack and non-disabling stroke.

Refer to Section 2 on aggressive prevention management, and Section 6 on antiplatelet therapy.

Rationale +-

Carotid endarterectomy is a surgical procedure that removes atherosclerotic plaque from the proximal internal carotid artery. Successful carotid endarterectomy substantially reduces the risk of recurrent stroke in patients who present with a hemispheric transient ischemic attack or minor stroke and an ipsilateral high-grade carotid stenosis. One death or severe stroke is prevented for every six patients with symptomatic severe (70 to 99 percent) carotid stenosis treated with carotid endarterectomy, and one for every 22 patients treated with stenosis less than 70 percent (Rothwell 2004; Orrapin, et al, 2017).  For selected patients with asymptomatic carotid stenosis, carotid endarterectomy reduces the risk of stroke from about two percent per year to about one percent per year.   Aggressive medical management was superior to intracranial stenting for patients with 70 to 99% stenosis of a major intracranial artery.

People who have experienced stroke and their families have reported that they received minimal education on carotid stenosis, and they wanted to learn more as this is an area not often included in general information on stroke.

System Implications +-
  1. Protocols to ensure timely access to diagnostic services for evaluating carotid arteries.
  2. Development of agreements and processes for rapid access to surgical consults, including a mechanism for expedited referrals as required for carotid interventions.
  3. Ensure navigation of system is supported increasing patient compliance. Mechanims to increase compliance should be explored and assessed.
Performance Measures +-
  1. Proportion of stroke or TIA patients with moderate to severe (50 percent to 99 percent) symptomatic carotid artery stenosis who undergo a carotid revascularization procedure following an index stroke/TIA event. (KQI)
  2. Proportion of stroke/TIA patients with moderate to severe (50 percent to 99 percent) carotid artery stenosis who undergo a carotid revascularization procedure following an index event within 2 weeks of first hospital or SPC assessment. (KQI)
  3. Median time from onset of index ischemic stroke or TIA symptoms to carotid revascularization (days, hours). (KQI)
  4. Proportion of stroke patients requiring carotid intervention who undergo the procedure within two weeks of the index stroke event.
  5. Proportion of stroke patients with moderate carotid stenosis (50 percent to 69 percent) who undergo carotid intervention procedure following the incident stroke event.
  6. Proportion of stroke patients with mild carotid stenosis (less than 50 percent) who undergo carotid intervention procedure following the incident stroke event.
  7. Proportion of carotid endarterectomy patients who experience perioperative in-hospital stroke, acute myocardial infarction or death.
  8. The 30-day in-hospital mortality rate after carotid endarterectomy and stroke rate by carotid occlusion severity.
  9. Proportion of patients who undergo carotid endarterectomy within two weeks, between two and four weeks, between four weeks and three months, and between three and six months of stroke onset.
  10. Proportion of patients who wait more than three months for carotid endarterectomy or whose surgery is cancelled because of long wait times. Proportion of patients who experience a subsequent stroke event or death while waiting for carotid endarterectomy.

Measurement Notes

  • Time interval measurements should be taken from the time the patient or family reports as the time of stroke symptom onset to the actual date of surgery.
  • The stroke onset time will depend on patient report or that of a reliable observer at the time of the event.
  • Analysis should be stratified between those patients undergoing carotid stenting and those patients undergoing carotid endarterectomy, by severity of stenosis and by whether the patient had symptomatic or asymptomatic carotid artery disease.
  • Data source for surgical date should be surgical note, nurses’ notes and discharge summary.
  • In some cases, it may be more appropriate or relevant to record the time interval from the first time the patient has contact with medical care until the time of carotid surgery. This has occurred in cases where the patient was out of the country at the time of the stroke event and chose to return to Canada before seeking definitive medical intervention. It is important to note the nature of the start time when calculating turnaround times or intervention times.
Summary of the Evidence +-

Management of Extracranial Carotid Artery Disease and Intracranial Atherosclerosis Evidence Table and Reference List

Table 9:  Risk of recurrent stroke among patients with carotid stenosis ≥50% and recent stroke awaiting carotid endarterectomy or carotid stenting.

Carotid Endarterectomy

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, advanced age or severe coronary artery disease. The percutaneous approach also avoids the risks of general anesthesia and the local complications of neck hematoma, 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). In the final results (Derdeyn et al. 2014), after a median duration of follow-up period of 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). More recently, the SPACE-2 trail (Reiff et al. 2019), reported there were no deaths or myocardial infarctions (MI) in any of the study groups (best medical management, CEA and CAS) within 30 days, or in ipsilateral stroke at one year.

Carotid Artery Stenting vs. Carotid Endarterectomy

The risk of periprocedural death and stroke have been shown to be higher following CAS procedures compared with CEA. Zhang et al. (2015) included the results from 35 studies comparing CEA and CAS. Overall, the risk of the primary outcome (stroke or death within 30 days) was significantly higher with CAS (RR=1.51, 95% CI 1.32-1.74, p<0.001). The risk of any stroke or death did not differ significantly between groups at 2 or 3-year follow-up; however, the risk was significantly increased at 4- and 10-years’ follow-up for CAS-treated patients (RR=1.24, 95% CI 1.04-1.46, p=0.01 and RR=2.27, 95% CI 1.39-3.71, p=0.001, respectively). Brott et al. (2019) included the results from 4 RCTs (EVA-3S, SPACE, ICSS and CREST), and reported the risk of stroke or death was increased significantly during the periprocedural and post-procedural periods in the CAS group (11.4% vs. 8.3%; HR=1·45, 95% CI 1·20 to 1·75). The risk difference in the outcome of stroke or death between CEA and CAS favoured the CEA group at 1 year (3.1%), 3 years (2.8%), 5 years (3.0%), 7 years (3.7%) and 9 years (4.1%) after randomization. A recent Cochrane review (Müller et al. 2020) included the results of 22 trials of patients with symptomatic stenosis, who had experienced a minor stroke, those with asymptomatic stenosis or both asymptomatic and symptomatic carotid stenosis. The treatment contrasts included any CEA procedure vs. any endovascular technique (primarily stenting +/- protection devices). Among patients with symptomatic stenosis, stenting was associated with a higher risk of death or any stroke within 30 days of treatment (OR=1.70, 95% CI 1.31- 2.19). In pre-planned subgroup analysis, using data from 6 trials, the risk of periprocedural death or stroke did not differ significantly between stenting and CEA in patients <70 years (OR=1.11, 95% CI 0.74 to 1.64), but was significantly higher in patients ≥70 years treated with stenting (OR=2.23, 95% CI 1.61 to 3.08). The risk of death or any stroke between randomization and 30 days after treatment or ipsilateral stroke until the end of follow-up was also higher in the stenting group.  Among patients with asymptomatic stenosis, the risk of death or any stroke within 30 days of treatment was also significantly higher in those who received a stenting procedure compared with CEA (RR=1.72 95% CI 1.00 to 2.97), while there was no significant difference between groups for the other primary or secondary outcomes. The authors suggested that for patients with symptomatic stenosis, the combined procedural safety and long-term efficacy profile favours CEA, while in patients with asymptomatic carotid stenosis, there may be a small increase in the risk of stroke or death within 30 days of treatment associated with stenting, but further trials are necessary to provide additional data.

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).

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).

Timing of Revascularization Procedures

When indicated, revascularization procedures should be performed as soon as possible following minor stroke or TIA; ideally, within 14 days. Without these procedures, the risk of recurrent events is high. Johansson et al. (2013) reported the overall frequency of ipsilateral ischemic stroke recurrence before CEA was 18.6% in the ANSYSCAP study. The frequency of ipsilateral ischemic stroke recurrence was 5.2% within two-days, 7.9% within 7days, and 11.2% within 14 days of the presenting event. Johansson et al. (2016) included 377 patients with symptomatic carotid stenosis (50-99%), who were eligible for CEA or CAS. Of these, 51 patients had an ipsilateral ischemic stroke or retinal artery occlusion within 90 days. The percentage of patients who experienced recurrent events increased with time of delay from event to procedure (1 day, 2.7%; 3 days, 6.6%; 14 days, 11.5%; 30 days, 13.7% and 90 days: 18.8%). The pattern of results was similar for the outcome of disabling or fatal stroke.

Hospital and Operator Volumes

Increasing experience of an operator or hospital has been shown to reduce the number of adverse events. Poorthuis et al. (2019) included the results of 87 studies examining the association between operator or hospital volumes and outcomes after carotid revascularization procedures. The risk of the primary outcome (procedural death or stroke within 90 days) was significantly lower among high-volume operators following both CEA and CAS procedures (CEA: unadjusted RR=0.59, 95% CI 0.42–0.83; 9 cohorts and CAS: unadjusted RR=0.50, 95% CI 0.32–0.79; 1 cohort), although there was wide variability in the descriptions of low and high-volume operators.

Cervical Artery Dissection

While the incidence of cervical artery dissections (CeAD) is relatively low, estimated to be between 2.6 to 2.9 per 100,000, CeAD is over-represented among persons less than 45 years (Weimar et al. 2010). Given the increased risk of recurrent stroke associated with CeAD, 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 (Markus et al. 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. At one year (Markus et al. 2019), the risks of ipsilateral stroke, ipsilateral stroke or TIA, any stroke or TIA, or any stroke or death were similar between groups in both the intention-to-treat and per-protocol analyses. Among 181 patients who had MRI or CTA imaging performed at baseline and repeated at 3 months, there was no difference in the presence of residual narrowing or occlusion between those receiving antiplatelet therapy (n = 56 of 92) vs those receiving anticoagulant therapy (n = 53 of 89) (p = .97).

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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