Carotid Intervention

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 (number needed to treat).  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.

• 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.

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.

It has been well established that carotid endarterectomy is beneficial for stroke prevention in appropriate patients. There are three large trials of endarterectomy for symptomatic stenosis: the North American Symptomatic Carotid Endarterectomy Trial (NASCET),¹⁷⁷the European Carotid Surgery Trial (ECST)¹⁷⁸ and the Veterans Affairs 309 Trial.¹⁷⁹ According to a pooled analysis of these trials, endarterectomy is highly beneficial in symptomatic patients with severe (70–99 percent) angiographic stenosis (NNT = six to prevent one stroke over five years), moderately beneficial for symptomatic patients with moderate (50–69%) stenosis (NNT = 22 to prevent one stroke over five years) and not beneficial for mild (< 50%) stenosis.¹⁸⁰ Guidelines on carotid endarterectomy from the American Heart Association⁴⁵ and the Canadian Neurosurgical Society⁴⁶ recommend surgery for symptomatic high-grade stenosis (70–99%), but have not been updated to include the most recent evidence regarding symptomatic patients with moderate stenosis or patients with asymptomatic stenosis.

The risks of carotid endarterectomy in relation to the timing of surgery was investigated in a systematic review of the literature on the complications of carotid endarterectomy.¹⁸¹ The operative risk of stroke and death was not increased in neurologically stable patients when surgery was performed early (< 3 to 6 weeks) rather than late (> 3 to 6 weeks). However, in unstable patients who underwent “urgent” endarterectomy for “stroke-in-evolution” or “crescendo transient ischemic attacks,” there was an increased perioperative risk (20%) that was significantly higher than the risk in stable patients.

A recent study by Gladstone, using data from the Registry of the Canadian Stroke Network (RCSN), examined factors associated with the timing of carotid endarterectomy surgery.¹⁸²A cohort of 1011 patients were found to have symptomatic carotid stenosis, and among those, 105 patients with severe (80 percent of cohort) or moderate (29 percent of cohort) stenosis underwent carotid endarterectomy within six months and were included in the analysis. The median time from index event to surgery was 30 days (interquartile range, 10 to 81). Overall, approximately one third (38 of 105) underwent surgery within two weeks, half (53 of 105) received surgery within 1 month, and one fourth (26 of 105) had surgery >3 months after the presenting event. In the multivariable analysis, early surgery (within two weeks) was significantly more likely to occur if the index event was a TIA rather than a completed stroke (OR, 2.6; 95% CI, 1.1 to 6.1). Age, sex, and degree of stenosis were not found to be significant predictors of early surgery. Over the study timeframe, there was an improvement in the median time to endarterectomy, decreasing from 74 days in 2003 to 21 days in 2006 (P_0.022 for median regression analysis). The proportion of patients undergoing early carotid endarterectomy (within 2 weeks) improved significantly over time: 18.2 percent in 2003, 25.0 percent in 2004, 45.5 percent in 2005, and 44.8 percent in 2006 (P_0.036; Cochran-Armitage trend test). Patients who did not undergo surgery were significantly older with more severe strokes and more comorbidities. The six-month mortality rate was 3.4 percent in the surgical group and 12.9 percent in the non-surgical group (p=0.0003).

Endarterectomy for symptomatic patients should be performed with a maximum combined perioperative stroke and death rate of six percent, according to the American Academy of Neurology guidelines¹⁸³ and the Canadian Neurosurgical Society guidelines; ⁴⁶ the American Heart Association guidelines⁴⁵ recommend a five percent rate for patients with transient ischemic attack and seven percent for patients with stroke. Women appear to have a higher perioperative risk and do not appear to benefit from carotid endarterectomy for symptomatic moderate (50–69%) stenosis, ¹⁸⁴ or when performed after greater than 2 weeks for symptomatic, high-grade (70–99%) stenosis.¹⁸⁵All of these guidelines recommend that endarterectomy for asymptomatic patients be performed with a maximum combined perioperative stroke and death rate of less than three percent.

For the Carotid Endarterectomy Trialists’ Collaboration, Rothwell and associates analyzed pooled data

(5893 patients with 33 000 patient-years of follow-up) from the European Carotid Surgery Trial and North American Symptomatic Carotid Endarterectomy Trial.¹⁸⁵ The findings indicated that the benefit from endarterectomy depends not only on the degree of carotid stenosis but also on several other clinical characteristics, including the timing of surgery after the presenting event. In patients with severe stenosis (70–99 percent), surgery was most effective when performed within two weeks of the index transient ischemic attack or stroke (NNT = three to prevent one stroke in five years), and this benefit declined quickly over time (NNT = 125 for patients who undergo surgery more than 12 weeks after the symptomatic event). This time-dependent decline in benefit was even more pronounced in patients with moderate stenosis (50%–69%); endarterectomy performed within the first two weeks of the ischemic event was beneficial, but the benefit was lost (and there was net harm) when surgery was delayed more than three months. Therefore, the Carotid Endarterectomy Trialists’ Collaboration recommended that carotid endarterectomy should be done within two weeks of the patient’s last symptoms.

Carotid endarterectomy for asymptomatic carotid artery disease has been controversial. The Asymptomatic Carotid Atherosclerosis Study (ACAS) Group randomized 1662 asymptomatic patients with carotid artery stenosis of 60 percent or greater reduction in diameter to receive carotid endarterectomy, with daily ASA administration and medical risk factor management for all patients.¹⁸⁶ After a median follow-up of 2.7 years, the absolute risk reduction for ipsilateral stroke was 3.0 percent for surgical patients compared with patients treated medically. The MRC [Medical Research Council] Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group randomized 3120 asymptomatic patients with substantial carotid narrowing equally between earlier carotid endarterectomy (half received carotid endarterectomy by one month, 88 percent by one year) and indefinite deferral of any carotid endarterectomy (only four percent per year received carotid endarterectomy) over a 10-year period.¹⁸⁷ Patients were followed for up to five years (mean 3.4 years). The absolute risk reduction for ipsilateral stroke was 3.1 percent. Subgroup analyses found no significant heterogeneity in the perioperative hazards or (apart from the importance of cholesterol) in the long-term postoperative benefits. These benefits were separately significant for males and females, for those with about 70 , 80 and 90 percent carotid artery narrowing on ultrasound and for those younger than 65 and 65–74 years of age (though not for older patients, half of whom died within five years from unrelated causes).

Asymptomatic carotid artery stenosis (unlike symptomatic carotid artery stenosis) is a relatively low-risk condition, and these studies confirm its natural history, although there is evidence that patients with higher degrees of asymptomatic stenosis are at a higher risk over time.¹⁸⁸ Overall, the absolute risk reduction with carotid endarterectomy is small (3.0 percent), translating into a number needed to treat of about 33. Gladstone and Sahlas recommended that carotid endarterectomy should be considered only for carefully selected patients with carotid artery stenosis of at least 60 percent who are less than 75 years old, have a good life expectancy and are at low surgical risk.¹⁸⁹A similar recommendation has been issued by the American Academy of Neurology.¹⁸³ They recommended in asymptomatic patients that “it is reasonable to consider carotid endarterectomy for patients between the ages of 40 and 75 years and with asymptomatic stenosis of 60 to 99 percent if the patient has an expected 5-year life expectancy and if the surgical stroke or death frequency can be reliably documented to be < 3 percent (Level A).” The American Stroke Association included a recommendation that “patients with asymptomatic carotid artery stenosis be screened for other treatable causes of stroke and that intensive therapy of all identified stroke risk factors be pursued (Level of Evidence C).”⁷

Practice gaps in carotid disease management have been identified. According to a recent Canadian study, the appropriate patients who are most likely to benefit from endarterectomy are not always being referred, and many procedures are performed inappropriately on patients at low risk of stroke.¹⁹⁰ In an Oxfordshire, United Kingdom, population-based study of transient ischemic attack and stroke patients referred for endarterectomy for > 50 percent stenosis, only six percent had surgery within two weeks of their ischemic event and only 43 percent within three months; 32 percent of patients had a recurrent stroke while awaiting endarterectomy.¹⁹¹ Stroke prevention clinics have been found to have an important role in promoting adherence to guidelines and ensuring appropriate patient selection and timely referral for this procedure. Delays from presenting event to initial assessment, carotid imaging and endarterectomy are new key indicators that should be monitored as part of stroke quality assurance programs.

Studies that compared carotid endarterectomy to carotid stenting have recently emerged in the research literature. A Cochrane systematic review of 10 trials which included 3178 patients with carotid stenosis

comparison of any stroke or death within 30 days of treatment favoured surgery(fixed-effects OR 1.35), but the difference was not statistically significant using the random effects model. Endovascular treatment was significantly better than surgery in avoiding cranial neuropathy (OR 0.15) and myocardial infarction (OR 0.34). There was no significant difference between endovascular treatment and surgery in the following comparisons: 30-day stroke, MI, or death (OR1.12); 30-day disabling stroke or death (OR 1.19); 30-day death OR 0.99); 24-month death or stroke (OR 1.26); and 30-day death or stroke in endovascular patients treated with or without protection devices (OR 0.75).  The authors concluded that results do not support a change in clinical practice away from recommending carotid endarterectomy as the treatment of choice for suitable carotid artery stenosis but support continued recruitment in the large ongoing trials.

A more recent meta-analysis in the British Medical Journal in 2010, which included the results from the International Carotid Stenting Study (ICSS), evaluated the relative short term safety and intermediate term efficacy of carotid endarterectomy versus carotid artery stenting.¹⁹³ The analysis included randomized controlled trials which compared carotid endarterectomy with carotid artery stenting in patients with carotid artery stenosis with or without symptoms. The primary end point was a composite of mortality or stroke. Secondary end points were death, stroke, myocardial infarction, or facial neuropathy (as individual end points), and mortality or disabling stroke (as a composite end point). Eleven trials were included (4796 patients)in the analysis, with 10 that reported on short-term outcomes (n=4709) and nine on intermediate term outcomes (1-4 years). The peri-procedural risk of mortality or stroke was lower for carotid endarterectomy (odds ratio 0.67, 95% confidence interval 0.47 to 0.95; P=0.025) than for carotid stenting, mainly because of a decreased risk of stroke (0.65, 0.43 to 1.00; P=0.049), whereas the risk of death (1.14, 0.56 to 2.31; P=0.727) and the composite end point mortality or disabling stroke (0.74, 0.53 to 1.05; P=0.088) did not differ significantly. The odds of periprocedural myocardial infarction (2.69, 1.06 to 6.79; P=0.036) or cranial nerve injury (10.2, 4.0 to 26.1; P<0.001) was higher in the carotid endarterectomy group than in the carotid stenting group. In the intermediate term, the two treatments did not differ significantly for stroke or death (hazard ratio 0.90, 95% confidence interval 0.74 to 1.1; P=0.314). The authors concluded that carotid endarterectomy was found to be superior to carotid artery stenting for short-term outcomes but the difference was not significant for intermediate term outcomes; this difference was mainly driven by nondisabling stroke. Significantly fewer cranial nerve injuries and myocardial infarctions occurred with carotid artery stenting.

Two randomized trials that directly compared the safety of carotid stenting to carotid endarterectomy in symptomatic patients have been release this past year: the International Carotid Stenting Study¹⁹⁴ and the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).¹⁷⁶ In the ICSS study, patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy.¹⁹⁴ The primary outcome measure of the trial was the three-year rate of fatal or disabling stroke in any territory, which has not been analyzed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Between randomization and 120 days, there were 34 (Kaplan-Meier estimate 4·0%) events of disabling stroke or death in the stenting group compared with 27 (3·2%) events in the endarterectomy group (hazard ratio [HR] 1·28, 95% CI 0·77—2·11). The incidence of stroke, death, or procedural myocardial infarction was 8·5 percent in the stenting group compared with 5·2 percent in the endarterectomy group (72 vs. 44 events; HR 1·69, 1·16—2·45, p=0·006). Risks of any stroke (65 vs. 35 events; HR 1·92, 1·27—2·89) and all-cause death (19 vs. seven events; HR 2·76, 1·16—6·56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs. 50 events; p=0·0197). The investigators concluded that at present, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery. The primary outcome analysis of the efficacy of carotid artery stenting compared with endarterectomy is not yet available.¹⁹⁴

The CREST trial is the largest ongoing trial examining the relative effectiveness of carotid artery stenting (CAS) versus carotid endarterectomy (CEA) in preventing stroke, myocardial infarction, and death.¹⁷⁶ The trial included 2502 patients with a median follow-up period of 2.5 years. 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. The study results showed no significant difference in the estimated four-year rates of the primary end point between the stenting group and the endarterectomy group (7.2 percent and 6.8 percent, respectively; hazard ratio with stenting, 1.11; 95% confidence interval, 0.81 to 1.51; P=0.51). There was no differential treatment effect with regard to the primary end point according to symptomatic status (P = 0.84) or sex (P = 0.34). The four-year rate of stroke or death was 6.4 percent with stenting and 4.7 percent with endarterectomy (hazard ratio, 1.50; P=0.03); the rates among symptomatic patients were 8.0 percent and 6.4 percent (hazard ratio, 1.37; P=0.14), and the rates among asymptomatic patients were 4.5 percent and 2.7 percent (hazard ratio, 1.86; P = 0.07), respectively. Peri-procedural rates of individual components of the end points differed between the stenting group and the endarterectomy group: for death (0.7% vs. 0.3%, P=0.18), for stroke (4.1% vs. 2.3%, P = 0.01), and for myocardial infarction (1.1% vs. 2.3%, P = 0.03). After this period, the incidences of ipsilateral stroke with stenting and with endarterectomy were similarly low (2.0% and 2.4%, respectively; P=0.85). The investigators concluded that among patients with symptomatic or asymptomatic carotid stenosis, the risk of the composite primary outcome of stroke, myocardial infarction, or death did not differ significantly in the group undergoing carotid-artery stenting and the group undergoing carotid endarterectomy. During the peri-procedural period, there was a higher risk of stroke with stenting and a higher risk of myocardial infarction with endarterectomy.

The clinical trials and subgroup analysis reports for stenting versus endarterectomy have indicated that patient age greater than 70 years has a significant impact on primary outcomes.^194a A preplanned meta-analysis was recently reported by the Carotid Stenting Trialists Collaboration that included patient-level data for 3433 patients with symptomatic carotid stenosis who were randomly assigned and analyzed in the Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial, the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) trial, and the International Carotid Stenting Study (ICSS).  The data was pooled and analyzed with fixed-effect binomial regression models adjusted for source trial. The primary outcome event was any stroke or death. In the first 120 days after randomization (ITT analysis), any stroke or death occurred significantly more often in the carotid stenting group (153 [8·9%] of 1725) than in the carotid endarterectomy group (99 [5·8%] of 1708, risk ratio [RR] 1·53, [95% CI 1·20—1·95], p=0·0006; absolute risk difference 3·2 [1·4—4·9]). Of all subgroup variables assessed, only age significantly modified the treatment effect: in patients younger than 70 years (median age), the estimated 120-day risk of stroke or death was 50 (5·8%) of 869 patients in the carotid stenting group and 48 (5·7%) of 843 in the carotid endarterectomy group (RR 1·00 [0·68—1·47]); in patients 70 years or older, the estimated risk with carotid stenting was twice that with carotid endarterectomy (103 [12·0%] of 856 vs. 51 [5·9%] of 865, 2·04 [1·48—2·82], interaction p=0·0053, p=0·0014 for trend). In the PP analysis, risk estimates of stroke or death within 30 days of treatment among patients younger than 70 years were 43 (5·1%) of 851 patients in the stenting group and 37 (4·5%) of 821 in the endarterectomy group (1·11 [0·73—1·71]); in patients 70 years or older, the estimates were 87 (10·5%) of 828 patients and 36 (4·4%) of 824, respectively (2·41 [1·65—3·51]; categorical interaction p=0·0078, trend interaction p=0·0013].  The conclusions stated by the Trialist Collaboration were that stenting for symptomatic carotid stenosis should be avoided in older patients (age ≥70 years), but might be as safe as endarterectomy in younger patients.