Peri-operative Stroke or Death

In the three trials of endarterectomy for symptomatic carotid stenosis, where postoperative complications were systematically reviewed, the overall pooled operative mortality was 1.1% (95% CI: 0.8–1.5), and the operative risk of stroke and death within 30 days of surgery was 7.1% (95% CI: 6.3–8.1) (Rothwell et al., 2003b).

A systematic review of 57 surgical case series, involving a total of 13,285 CEAs, indicated that the reported peri-operative risk of stroke and death varied widely from <1% to more than 30%, but was usually about 3–8%, and was on average 5.1% (95% CI: 4.6–5.6%) (Rothwell et al., 1996a,b; Goldstein et al., 1997). The risk was higher in surgical case series in which patients were assessed postoperatively by a neurologist (7.7% [95% CI: 5.0–10.2%], odds ratio [OR]: 1.62 [95% CI: 1.45–1.81]) (Rothwell, 1996a).

Based on the results from the trials, about one in 14 patients undergoing CEA for symptomatic carotid stenosis experiences a peri-operative stroke or dies in the peri-operative period. However, this risk cannot be generalized to one’s own institution, surgeons, or patients. In particular, personal experience, and recent case series, suggest that operative rates of CEA for symptomatic patients have declined considerably since NASCET and ECST were published (Matsen et al., 2006). A recent local prospective audit of a large number of patients undergoing CEA by each surgeon and centre is therefore required, and referring doctors (and patients) should have access to the peri-operative stroke and death rate of their prospective surgeon(s) and centres, derived from such an independent and rigorous audit (Goldstein et al., 1997). However, interpretation of unusually high or low operative risks must take into account the effects of chance and case mix. Otherwise, over-simplistic interpretation of crude results may lead to unjustified criticism of individual surgeons, and not to improvements in patient care.

There are several other important prognostic factors for stroke, and peri-operative stroke and death associated with CEA which may influence the decision to operate.

Prognostic Factors for Peri-operative Stroke or Death

Patient factors The risk of peri-operative stroke is greater in patients with symptomatic carotid stenosis than asymptomatic carotid stenosis. However, patients with symptoms of minor stroke lasting less than 7 days have a lower risk than those with stroke lasting longer, while patients with ocular ischaemia due to carotid stenosis (e.g. amaurosis fugax) have the lowest risk of peri-operative stroke or death (Rothwell et al., 1996b).

Other patient factors which have been associated with an increased risk of peri-operative stroke and death in trials of CEA for symptomatic carotid stenosis (Table 20.3) are as follows:

1. 
   

   1. Female gender (perhaps because of smaller carotid arteries, perhaps more difficult to operate on).

   
   
2. 
   

   2. Systolic blood pressure (SBP) >180 mm Hg (perhaps increased risk of reperfusion injury and cerebral haemorrhage).

   
   
3. 
   

   3. Peripheral arterial disease (a marker of atherosclerotic plaque burden).

   
   
4. 
   

   4. Occlusion of the contralateral ICA (indicates poor collateral cerebral circulation).

   
   
5. 
   

   5. Stenosis of the ipsilateral external carotid artery (poor collateral circulation) (Rothwell et al., 1997). The risk of peri-operative stroke or death associated with CEA does not appear to be related to the degree of ipsilateral internal carotid stenosis (Table 20.4).

Importantly, the operative risk of stroke and death is unrelated to the risk of stroke with best medical treatment alone (Rothwell et al., 2003b, 2005) (see Tables 20.2, 20.3, 20.4).

Surgical factors The surgical factors which may be associated with an increased risk of peri-operative stroke or death are: (a) inexperience due to low surgeon and hospital case volumes (Feasby et al., 2002); and (b) undertaking CEA in the very acute phase of stroke in evolution and crescendo TIAs, and during coronary artery surgery for patients with angina whose carotid stenosis was discovered during preparation for coronary artery surgery (Bond et al., 2003). For neurologically stable patients, such as those enrolled into the trials, there was no evidence of any increase in operative risk in patients operated on within 2 weeks of their last event (Rothwell et al., 2004). Moreover, in a systematic review of surgical case series, early surgery in neurologically stable patients was not associated with an increased operative risk (Bond et al., 2003). These data have led to pressure on surgeons to operate very soon after the onset of symptoms. However, operating on patients with unstable plaque might be hazardous and recent registry data have suggested that the risk is significantly increased in patients operated on within 2 days of symptoms (Strömberg et al., 2012). Thus, the optimal time to operate is probably on the third day after minor symptoms, which allows time for antiplatelet therapy to become active.

Local Adverse Effects of CEA

Other specific adverse effects of CEA, besides those inherent in any operation, include:

1. 
   

   1. lower cranial nerve palsy (about 5–9% of patients),

   
   
2. 
   

   2. peripheral nerve palsy (about 1% of patients),

   
   
3. 
   

   3. major neck haematoma requiring surgery or extended hospital stay (about 5–7% of patients), and

   
   
4. 
   

   4. wound infection (3%).

Prognostic Factors for Peri-operative Cranial Nerve Palsy

Patients undergoing CEA for recurrent carotid stenosis have an increased risk of cranial nerve injury and wound haematoma (Bond et al., 2003).

The risk of functionally disabling bilateral vagal and hypoglossal nerve palsies is also increased in patients who have already had an endarterectomy on one side or are undergoing bilateral CEAs.

Evidence from the Cochrane Library

The most recent systematic review for the Cochrane Library was published in 2017 and included data from the 6343 patients enrolled in the NASCET, ECST, and VA trials. No new completed studies were identified. The authors performed a pooled analysis of 6092 participants in whom individual data were available using a re-analysis of all the baseline angiograms for stenosis severity using the NASCET method and a uniform definition of outcome events (Orrapin and Rerkasem, 2017).

Mild carotid stenosis (NASCET <50%) For patients with very mild stenosis measuring <30%, surgery increased the 5-year risk of any stroke or operative death with a risk ratio (RR) of 1.25 (95% CI: 0.99–2.01). For patients with mild stenosis measuring 30–49%, there was no evidence of benefit or harm, with a risk ratio of 0.97 (95% CI: 0.79–1.19). The assumed event rates for this degree of stenosis were 21% with best medical treatment alone and 20% with additional carotid surgery (Figure 20.3).

Moderate carotid stenosis (NASCET: 50–69%) For patients with moderate stenosis, surgery significantly reduced the risk of any stroke or operative death by 23% (RR 0.77, 95% CI: 0.63–0.94). This corresponded to a reduction from an assumed 5-year risk of 23% to 18% with surgery and a number needed to treat (NNT) of around 20 to prevent one event (Figure 20.3).

Figure 20.3 Forest plots showing the effects of CEA plus best medical therapy (surgery) vs best medical therapy alone (no surgery) in patients with recently symptomatic carotid stenosis in subgroups of severity of carotid stenosis (1, near occlusion; 2, 70–99%; 3, 50–69%; and 4, 30–49%).

Reproduced from Orrapin and Rerkasem (2017) with permission.

Severe carotid stenosis (NASCET 70–99%) For patients with severe stenosis, excluding those with near-occlusion, surgery reduced the risk of any stroke or operative death by 47% (RR 0.53, 95% CI: 0.42–0.67%). This corresponds to a reduction from an assumed 5-year risk of 29% to 15% with surgery and a NNT of around 7 to prevent one event (Figure 20.3).

Near-occlusion In patients with near occlusion (defined as very severe stenosis associated with distal luminal collapse of the ICA), there was no evidence of overall benefit or harm from surgery (RR 0.95, 95% CI: 0.59–1.53).

Other outcome measures The Cochrane review also analysed several other outcomes, including ipsilateral carotid territory stroke or operative stroke or death, and disabling or fatal ipsilateral ischaemic stroke or operative stroke or death. The conclusions in relation to the benefit of surgery at different degrees of stenosis were very similar to those discussed above in relation to any stroke or operative death.

Sex

Women had a lower risk of ipsilateral ischaemic stroke on medical treatment and a higher operative risk in comparison to men. For recently symptomatic carotid stenosis, surgery is very clearly beneficial in women with ≥70% stenosis, but not in women with 50–69% stenosis (Figure 20.5). In contrast, surgery reduced the 5-year absolute risk of stroke by 8.0% (3.4–12.5) in men with 50–69% stenosis. This sex difference was statistically significant even when the analysis of the interaction was confined to the 50–69% stenosis group.

Figure 20.5 Absolute risk reduction (ARR) in 5-year cumulative risk of ipsilateral carotid territory ischaemic stroke or any stroke or death within 30 days after surgery plotted separately for patients with 70–99% stenosis (excluding near-occlusion) and those with 50–69% stenosis stratified by the time from last symptomatic event to randomization. Numbers above bars indicate actual absolute risk reduction. Vertical bars are 95% CIs.

Reproduced from Rothwell et al. (2004), with permission.

Age

Benefit from CEA increased with age in patients with recently symptomatic stenosis, particularly in patients aged over 75 years because of their high risk of stroke on medical treatment without a substantially increased risk of peri-operative stroke (Figure 20.4). These findings are consistent with a systematic review of all published surgical case series which reported no increase in the operative risk of stroke and death in older age groups (Rothwell, 2005).

There is therefore no justification for withholding CEA in patients aged over 75 years who are deemed to be medically fit to undergo surgery.

Timing of CEA

Given the high early risk of stroke on medical treatment alone after a TIA or minor stroke in patients with carotid disease (Lovett et al., 2003, 2004; Coull et al., 2004) and the lack of an increased operative risk in neurologically stable patients (see above), early surgery is likely to be most effective. The pooled analysis of data from the trials shows that the benefit from endarterectomy is greatest in patients randomized within 2 weeks of their last event (Figures 20.4 and 20.5). This was particularly important in patients with 50–69% stenosis, where the reduction in the 5-year risk of stroke with surgery was considerable in those who were randomized within 2 weeks of their last event (14.8%, 95% CI: 6.2–23.4), but minimal in patients randomized later (Figure 20.5). It should be borne in mind that surgery was often delayed by up to a week or two after patients were randomized in the RCTs and therefore the benefit of surgery might extend for a week or two longer between symptoms and the date of surgery.

Other Prognostic Factors

Benefit from surgery is probably also greatest in patients presenting with stroke, intermediate in those with cerebral TIA, and lowest in those with retinal events (see Figure 20.4). There was also a trend in the trials towards greater benefit in patients with irregular plaque than a smooth plaque.

The outcome within the ECST of individuals with different characteristics that influence future risk of stroke have been incorporated into a model that predicts the 5-year ipsilateral risk of stroke on medical treatment alone in patients with recently symptomatic carotid stenosis. Although this model was derived from the ECST, it was validated externally using data from NASCET after the ECST angiograms and outcome event definitions were re-analysed to match NASCET (Rothwell and Warlow, 1999; Rothwell et al., 2005). The ECST model showed an excellent fit with the NASCET data (Figure 20.6).

Figure 20.6 Reliability of the ECST risk model in predicting the 5-year rate of ipsilateral ischaemic stroke on medical treatment alone in patients with 50–99% stenosis included in NASCET (filled squares). The 30-day risk of operative stroke in patients randomized to surgery in NASCET stratified by predicted risk on medical treatment is shown to demonstrate that patients at high risk when treated medically did not have a high risk from surgery.

Reproduced from Rothwell et al. (2005) with permission.

Rothwell and colleagues (2005) provided colour-coded tables to allow clinicians to quickly assess an individual patient’s 5-year risk of ipsilateral stroke treated medically from five clinically important variables (Figure 20.7). It should be noted that because the data used to calculate the risk of stroke plotted in Figures 20.6 and 20.7 was derived from ECST, the results are likely to overestimate the current risks of stroke on modern medical therapy in patients being considered for surgery in the current era. Various stands of evidence suggest that current rates of stroke in patients with carotid stenosis treated optimally are now at least half those recorded in ECST and NASCCET (Cheng and Brown, 2017).

Figure 20.7 Tables showing predicted absolute risk of ipsilateral ischaemic stroke at 5 years in patients with recently symptomatic carotid stenosis treated with medical therapy alone according to five clinically important patient characteristics in (A) men and (B) women. This table was derived from ECST data using a Cox regression model. The terms Stroke, TIA, and Ocular in the tables refer to the most severe symptomatic ipsilateral ischaemic event in the past 6 months.

Reproduced from Rothwell et al. (2005) with permission.

Interpretation of the Evidence

There is insufficient evidence from randomized trials to reliably determine the RRs and benefits of eversion and conventional CEA. It is possible that carotid eversion is associated with a lower risk of long-term carotid occlusion and restenosis, but it is still unclear whether this is associated with a lower rate of subsequent neurological events. The recent meta-analysis of case series suggests that eversion CEA is safer and more durable than conventional CEA with primary closure, but eversion CEA has similar outcomes to conventional patched CEA. Patching is discussed in more detail below.

Implications for Practice

Until more reliable evidence is available, the choice of the surgical technique for CEA should depend on the experience and preference of the operating surgeon.

Implications for Research

Further randomized trials are needed to more precisely define the relative and absolute benefits and risks of eversion and conventional CEA, and establish the clinically relevance (or not) of restenosis of the carotid artery (that was previously operated on) as a cause of subsequent stroke. Studies analysing the costs of eversion and conventional CEA are also needed.

Implications for Practice

There is insufficient evidence from RCTs to support or refute the use of routine or selective shunting during CEA and there is little evidence to support the use of one form of monitoring over another in selecting patients requiring a shunt. The use of EEG monitoring combined with carotid pressure assessment may reduce the number of shunts required without increasing the stroke rate, but more data are required to prove this.

Implications for Research

A large, multicentre randomized trial is required to assess whether shunting reduces the risk of peri-operative and long-term death and stroke. Even a modest 25% reduction in the RR of peri-operative stroke or death would result in approximately 15 fewer strokes and deaths per 1000 patients undergoing endarterectomy. However, to detect this reliably (80% power, 5% significance level) would require between 3000 and 5000 patients.

Two policies could be considered: routine shunting for all patients undergoing CEA or selective shunting in those at high risk of intra-operative cerebral ischaemia. The trial needs to be truly randomized, have long-term follow-up (several years), and have blinded outcome assessment, preferably by neurologists. Patients should be stratified by age, sex, degree of ipsilateral and contralateral internal carotid stenosis, the experience of the surgeon, the use of patching, and, in selective shunting, the method of monitoring of cerebral ischaemia.

As regards the method of monitoring in selective shunting, until the efficacy of shunting has been demonstrated, further trials of the method of monitoring are probably not merited. However, a systematic review of the sensitivity and specificity of the various methods of monitoring for cerebral ischaemia would be worthwhile to identify the best method of monitoring to be used in any trial of selective shunting.

Interpretation of the Evidence

Limited evidence suggests that carotid patch angioplasty might reduce the risk of peri-operative arterial occlusion and restenosis, and longer-term stroke or death.

Implications for Practice

Although some vascular surgeons do not routinely use patching in patients undergoing CEA, the present data from RCTs (albeit based on small numbers) appear to support a recommendation in favour of routine patching.

The use of selective patching (e.g. for very narrow arteries) has not been studied in RCTs, so no evidence-based recommendations can be made.

Implications for Research

The potential benefit of routine patching could be clinically important (up to 40 strokes prevented per 1000 patients treated) but in order to have reliable evidence on the risks and benefits of patching compared to primary closure, a large multicentre RCT will be required.

This trial should concentrate on clinical outcomes (deaths, all strokes, particularly fatal or disabling strokes, and ipsilateral strokes) as opposed to restenosis and have long-term follow-up (perhaps 5 years).

Assuming a 30-day risk of stroke or death of 5%, the trial would need to recruit about 3000 patients to have an 90% chance of detecting a reduction in the absolute risk of death or stroke to 2.5% (this number would also give a >90% chance of detecting a reduction in the risk of stroke or death at 5 years from 25% to 20%). Such a trial should use a secure method of randomization and be performed on a truly intention-to-treat basis with complete follow-up of all patients. Patients rather than arteries should be randomized so that the number of deaths and strokes is reported on a patient basis rather than an artery basis. Clinical follow-up should be blinded with independent assessment of strokes, preferably by neurologists. The results should be analysed according to the degree of narrowing of the artery and whether the patient had had a previous stroke or TIA or not. It would be possible to use a factorial design for such a trial so that some other procedure could be tested simultaneously, such as routine shunting. Until the benefit of carotid patching in terms of clinical outcomes for the patient is established, any future trials should include a control group of primary closure.

Interpretation of the Evidence

It is likely that the differences between different types of patch material are very small. Consequently, more data than are currently available will be required to establish whether any differences do exist.

Some evidence exists that PTFE patches may be superior to collagen impregnated Dacron grafts in terms of peri-operative stroke rates and restenosis. However, the evidence is limited and more studies that compare different types of synthetic graft are required to make firm conclusions.

Pseudo-aneurysm formation might be more common after use of a vein patch compared with a synthetic patch.

Implications for Practice

There is no evidence to support the use of vein over synthetic patch material in CEA. The decision of which type of patch to use, if any, remains a matter of individual preference. However, if synthetic material is used, the currently available (limited) evidence from a single trial appears to show benefits from PTFE as opposed to Dacron material.

Implications for Research

Further trials comparing one type of patch with another are required, but they will need large numbers of patients. Further, more trials are required which compare different types of synthetic graft material.

Antiplatelet vs Control

A systematic review of RCTs evaluating whether antiplatelet agents are safe and beneficial after CEA (Engelter and Lyrer, 2003, 2004) identified six trials of antiplatelet therapy administered for at least 30 days after CEA in a total of 907 patients who were followed up for at least 3 months. Most trials used high dose aspirin alone or in combination with other antiplatelet drugs.

Antiplatelet therapy was associated with a significant reduction in the odds of stroke of any type during follow-up (OR 0.58, 95% CI: 0.34–0.98; p = 0.04) but not death (OR 0.77, 95% CI: 0.48–1.24), intracranial haemorrhage (OR 1.71, 95% CI: 0.73–4.03), or other serious vascular events.

Aspirin Plus Clopidogrel vs Aspirin

Given the high risk of recurrence in patients with recent symptoms despite aspirin therapy, it is logical to try to improve medical therapy in patients waiting for CEA. One such approach is to use combined antiplatelet therapy. In one study, 100 patients were assigned aspirin 150 mg per day for 4 weeks prior to CEA and then, on the night before CEA, they were randomized to placebo plus long-term aspirin 150 mg per day (n = 54) or clopidogrel 75 mg per day plus long-term aspirin 150 mg per day (n = 46) (Payne et al., 2004). Compared with placebo plus aspirin, assignment to clopidogrel plus aspirin was associated with a small (8.8%) but significant reduction in platelet response to adenosine diphosphate (ADP) (p = 0.05), a 10-fold reduction in the RR of patients having >20 emboli detected by TCD within 3 hours of CEA (OR 10.23, 95% CI: 1.3–83.3; P = 0.01), and a significantly increased time from flow restoration to skin closure (an indirect marker of haemostasis) (P = 0.04). Surgeons often report increased bleeding in patients taking combined aspirin and clopidogrel, but in this study there was no increase in bleeding complications or blood transfusions.

These results are supported by the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic carotid Stenosis (CARESS) trial, which has shown that among patients with symptomatic carotid stenosis (before, not after, CEA), that the addition of clopidogrel to aspirin reduces the incidence of cerebral microemboli before (not after) CEA. The CARESS study was a randomized, double-blind, controlled trial comparing clopidogrel plus aspirin versus aspirin in 107 patients with recently (past 3 months) symptomatic carotid artery stenosis >50% and at least one characteristic microembolic signal (MES) detected during a 1-hour TCD recording of the ipsilateral middle cerebral artery (MCA) before randomization. At randomization, patients were assigned either a 300 mg loading dose of clopidogrel (four tablets), followed by 75 mg clopidogrel once daily from day 2 to day 7 ± 1, or a matching placebo loading dose, and once daily placebo from day 2 to day 7 ± 1. Patients in both arms also received 75 mg aspirin (ASA) once daily from day 1 to day 7 ± 1 (on top of clopidogrel or placebo). All study drugs were administered orally. The primary efficacy endpoint was the occurrence of ≥ 1 MES versus none (MES positive or negative patient), detected by off-line analysis (by central reading centre) of the 1-hour recording carried out on day 7 ± 1. Intention-to-treat analysis revealed a significant reduction in the primary endpoint: 43.8% of dual-therapy patients were MES positive on day 7, as compared with 72.7% of monotherapy patients (relative risk reduction 39.8%, 95% CI: 13.8–58.0; p = 0.0046) (Markus et al., 2005).

Interpretation of the Evidence

Antiplatelet drugs reduce the odds of stroke after CEA, but not other major outcomes. However, a statistically significant hazardous effect of antiplatelet therapy may have been missed because of the relatively small sample size.

There is some evidence that the combination of clopidogrel and aspirin might be more effective than aspirin alone in reducing post-operative thromboemboli, as detected by TCD (Payne et al., 2004). Data from several studies suggest that the presence of asymptomatic embolization, as measured by TCD evidence of MESs, might predict future strokes or TIAs in patients with symptomatic stenosis; the risk is reported to be 8- to 31-fold higher in patients who are MES positive (or who have ≥1 MES per TCD recording) than patients who have MES negative ICA stenosis (Valton et al., 1998; Molloy and Markus, 1999).

Implications for Practice

Antiplatelet therapy should be prescribed for all patients after CEA. Aspirin should probably be the first-line agent. Other antiplatelet agents such as clopidogrel and extended-release dipyridamole plus aspirin have also been shown to be effective in patients with TIA and ischaemic stroke not undergoing CEA (Chapter 9), and are likely (based on reasoning [Chapter 2], but not evidence) to also be effective after CEA. Many physicians and surgeons routinely prescribe the combination of aspirin and clopidogrel after TIA or stroke up to the time of CEA and then continue single therapy after surgery.

Implications for Research

Further research should focus on the effectiveness and safety of combinations of aspirin with other antiplatelet drugs.

There is preliminary evidence to suggest that a short period of treatment with aspirin and clopidogrel, for perhaps 1 month, might be more effective than aspirin during the acute phase of the event when patients with symptomatic carotid stenosis are at high risk of recurrent ischaemic events (Payne et al., 2004; Markus et al., 2005). This requires confirming in an adequately powered, dedicated study in a large number of patients with the occurrence of recurrent stroke, other serious vascular events, and bleeding complications as the primary outcome measure.

Implications for Practice

As the effect of warfarin in patients with symptomatic carotid stenosis undergoing CEA is likely to be qualitatively similar to that seen in other patients with TIA and ischaemic stroke due to arterial disease (based on reasoning [Chapter 18], not evidence), there is no indication to use oral anticoagulation after CEA. However, an exception can be patients with TIA or ischaemic stroke who have both an apparently symptomatic carotid stenosis and atrial fibrillation.

Warfarin is effective and indicated in patients with TIA or ischaemic stroke who are in atrial fibrillation (Chapter 18). The decision to recommend anticoagulation and/or endarterectomy in these patients depends to some extent on whether the recent TIA or stroke is thought to be cardioembolic or due to carotid thromboembolism. This is can be difficult, if not impossible, to determine sometimes. But if the computed tomography (CT) or magnetic resonance imaging (MRI) (diffusion-weighted imaging, DWI) brain scan shows multiple recent infarcts in multiple vascular territories, or echocardiography reveals apical thrombus or atrial enlargement, the source is likely to be the heart and anticoagulation is probably indicated. Alternatively, if echocardiography is normal and perhaps if any ischaemic lesions on brain imaging are confined to the ipsilateral carotid territory, it may be more appropriate to recommend endarterectomy and antiplatelet therapy.