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Management of Extracranial Carotid Disease and Intracranial Atherosclerosis

5th Edition
2014 UPDATE
December 2014

The Canadian Stroke Best Practice Recommendations for the Secondary Prevention of Stroke, 5th Edition 2014 module is published in the International Journal of Stroke (IJS) (Online Open‑Access available December 2014; Printed Journal scheduled for April 2015).

To access the specific recommendations for Management of Extracranial Carotid Disease and Intracranial Atherosclerosis and all other sections of the Secondary Prevention of Stroke module, please click on this URL which will take you to the recommendations online in the IJS:  http://onlinelibrary.wiley.com/doi/10.1111/ijs.12439/full. For the French version of these recommendations, open the appendix at this link : http://onlinelibrary.wiley.com/store/10.1111/ijs.12439/asset/supinfo/ijs12439-sup-0001-si.pdf?v=1&s=b0ed4fff1d7fc435cf4e2a83ccbcbffbdad767de.

All other supporting information, including performance measures, implementation resources, evidence summaries and references, remain available through www.strokebestpractices.ca, and not through the IJS.  Please click on the appropriate sections below for this additional content.

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 nine patients with symptomatic severe (70 to 99 percent) carotid stenosis treated with carotid endarterectomy). 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.

System Implications
  • Protocols to ensure timely access to diagnostic services for evaluating carotid arteries.
  • Development of agreements and processes for rapid access to surgical consults, including a mechanism for expedited referrals as required for carotid interventions.
Performance Measures
  1. Proportion of stroke patients with moderate to severe (50 percent to 99 percent) carotid artery stenosis who undergo a carotid intervention procedure following an index stroke event.
  2. Median time from stroke symptom onset to carotid endarterectomy surgery (core).
  3. Proportion of stroke patients requiring carotid intervention who undergo the procedure within two weeks of the index stroke event.
  4. Proportion of stroke patients with moderate carotid stenosis (50 percent to 69 percent) who undergo carotid intervention procedure following the incident stroke event.
  5. Proportion of stroke patients with mild carotid stenosis (less than 50 percent) who undergo carotid intervention procedure following the incident stroke event.
  6. Proportion of carotid endarterectomy patients who experience perioperative in-hospital stroke, acute myocardial infarction or death.
  7. The 30-day in-hospital mortality rate after carotid endarterectomy and stroke rate by carotid occlusion severity.
  8. 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.
  9. Proportion of patients who wait more than three months for carotid endarterectomy or whose surgery is cancelled because of long wait times.
  10. 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, Evidence Tables and References

Extracranial Carotid Disease and Intracranial Atherosclerosis Evidence Tables and Reference List

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), the European Carotid Surgery Trial (ECST) and the Veterans Affairs Trial. 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 randomized 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. 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 two-year follow-up period (King et al. 2013).

There are three large trials that have evaluated the risks and benefits of CEA in this 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 angioplasty with stenting emerged (CEA) 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, require a shorter recovery period. Several large trials assessing the safety and effectiveness of CEA (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 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).

The Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) included 504 patients with symptomatic or asymptomatic carotid artery stenosis of ≥30%, considered to require revascularization 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).

Two randomized trials that directly compared the safety of CEA with CAS (with protection) have been published recently. The International Carotid Stenting Study (ICSS) and Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST).   The 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 MI, (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). The 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).