Editor's Choice - Timing of Carotid Intervention in Symptomatic Carotid Artery Stenosis: A Systematic Review and Meta-Analysis.

OBJECTIVE: This review aimed to analyse the timing of carotid endarterectomy (CEA) and carotid artery stenting (CAS) after the index event as well as 30 day outcomes at varying time periods within 14 days of symptom onset. METHODS: A systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-analysis statement, comprising an online search of the Medline and Cochrane databases. Methodical quality assessment of the included studies was performed. Endpoints included procedural stroke and/or death stratified by delay from the index event and surgical technique (CEA/CAS). RESULTS: Seventy-one studies with 232 952 symptomatic patients were included. Overall, 34 retrospective analyses of prospective databases, nine prospective, three RCT, three case control, and 22 retrospective studies were included. Compared with CEA, CAS was associated with higher 30 day stroke (OR 0.70; 95% CI 0.58 - 0.85) and mortality rates (OR 0.41; 95% CI 0.31 - 0.53) when performed ≤ 2 days of symptom onset. Patients undergoing CEA/CAS were analysed in different time frames (≤ 2 vs. 3 - 14 and ≤ 7 vs. 8 - 14 days). Expedited CEA (vs. 3 - 14 days) presented a sampled 30 day stroke rate of 1.4%; 95% CI 0.9 - 1.8 vs. 1.8%; 95% CI 1.8 - 2.0, with no statistically significant difference. Expedited CAS (vs. 3 - 14 days) was associated with no difference in stroke rate but statistically significantly higher mortality rate (OR 2.76; 95% CI 1.39 - 5.50). CONCLUSION: At present, CEA is safer than transfemoral CAS within 2/7 days of symptom onset. Also, considering absolute rates, expedited CEA complies with the accepted thresholds in international guidelines. The ideal timing for performing CAS (when indicated against CEA) is not yet defined. Additional granular data and standard reporting of timing of intervention will facilitate future monitoring.

Platelet Biomarkers in Patients with Atherosclerotic Extracranial Carotid Artery Stenosis: A Systematic Review.

OBJECTIVE: The aim was to enhance understanding of the role of platelet biomarkers in the pathogenesis of vascular events and risk stratifying patients with asymptomatic or symptomatic atherosclerotic carotid stenosis. DATA SOURCES: Systematic review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. REVIEW METHODS: A systematic review collated data from 1975 to 2020 on ex vivo platelet activation and platelet function/reactivity in patients with atherosclerotic carotid stenosis. RESULTS: Forty-three studies met the inclusion criteria; the majority included patients on antiplatelet therapy. Five studies showed increased platelet biomarkers in patients with ≥ 30% asymptomatic carotid stenosis (ACS) vs. controls, with one neutral study. Preliminary data from one study suggested that quantification of "coated platelets" in combination with stenosis severity may aid risk stratification in patients with ≥ 50% - 99% ACS. Platelets were excessively activated in patients with ≥ 30% symptomatic carotid stenosis (SCS) vs. controls (≥ 11 positive studies and one neutral study). Antiplatelet-High on Treatment Platelet Reactivity (HTPR), previously called "antiplatelet resistance", was observed in 23% - 57% of patients on aspirin, with clopidogrel-HTPR in 25% - 100% of patients with ≥ 50% - 99% ACS. Aspirin-HTPR was noted in 9.5% - 64% and clopidogrel-HTPR in 0 - 83% of patients with ≥ 50% SCS. However, the data do not currently support the use of ex vivo platelet function/reactivity testing to tailor antiplatelet therapy outside of a research setting. Platelets are excessively activated (n = 5), with increased platelet counts (n = 3) in recently symptomatic vs. asymptomatic patients, including those without micro-emboli on transcranial Doppler (TCD) monitoring (n = 2). Most available studies (n = 7) showed that platelets become more reactive or activated following carotid endarterectomy or stenting, either as an acute phase response to intervention or peri-procedural treatment. CONCLUSION: Platelets are excessively activated in patients with carotid stenosis vs. controls, in recently symptomatic vs. asymptomatic patients, and may become activated/hyper-reactive following carotid interventions despite commonly prescribed antiplatelet regimens. Further prospective multicentre studies are required to determine whether models combining clinical, neurovascular imaging, and platelet biomarker data can facilitate optimised antiplatelet therapy in individual patients with carotid stenosis.

Editor's Choice - Effect of Carotid Interventions on Cognitive Function in Patients With Asymptomatic Carotid Stenosis: A Systematic Review.

OBJECTIVE: To determine the effect of carotid endarterectomy (CEA) and carotid artery stenting (CAS) on early (baseline vs. maximum three months) and late (baseline vs. at least five months) cognitive function in patients with exclusively asymptomatic carotid stenoses (ACS). METHOD: Searches were conducted in PubMed/Medline, Embase, Scopus, and the Cochrane library. This systematic review includes 31 non-randomised studies. RESULTS: Early post-operative period: In 24 CEA/CAS/CEA+CAS cohorts (n = 2 059), two cohorts (representing 91/2 059, 4.4% of the overall study population) reported significant improvement in cognitive function, while one (28/2 059, 1%) reported significant decline. Three cohorts (250/2 059, 12.5% reported "mixed findings" where some cognitive scores significantly improved, and a similar proportion declined. The majority (nine cohorts; 1 086/2 059, 53%) reported no change. Seven cohorts (250/2 059, 12.1%) were mostly unchanged but one to two individual test scores improved, while two cohorts (347/2 059, 16.8%) were mostly unchanged with one to two individual test scores worse. Late post-operative period: In 21 cohorts (n = 1 554), one (28/1 554, 1.8%) reported significantly worse cognitive function, one reported significant improvement (24/1 554, 1.5%), while a third (19/1 554, 1.2%) reported "mixed findings". The majority were unchanged (six cohorts; 1 073/1 554, 69%) or mostly unchanged, but with one to two cognitive tests showing significant improvement (11 cohorts; 386/1 554, 24.8%). Overall, there was a similar distribution of findings in small, medium, and large studies, in studies with controls vs. no controls, in studies comparing CEA vs. CAS, and in studies with shorter/longer late follow up. CONCLUSION: Notwithstanding accepted limitations regarding heterogeneity within non-randomised studies, CEA/CAS rarely improved overall late cognitive function in ACS patients (< 2%) and the risk of significant cognitive decline was equally low (< 2%). In the long term, the majority were either unchanged (69%) or mostly unchanged with one to two test scores improved (24.8%). Until new research identifies vulnerable ACS subgroups (e.g., impaired cerebral vascular reserve) or provides evidence that silent embolisation from ACS causes cognitive impairment, evidence supporting intervention in ACS patients to prevent/reverse cognitive decline is lacking.

Editor's Choice - Asymptomatic Carotid Stenosis and Cognitive Impairment: A Systematic Review.

OBJECTIVE: The aim was to evaluate the relationship between asymptomatic carotid stenosis (ACS) of any severity and cognitive impairment and to determine whether there is evidence supporting an aetiological role for ACS in the pathophysiology of cognitive impairment. DATA SOURCES: PubMed/Medline, Embase, Scopus, and the Cochrane library. REVIEW METHODS: This was a systematic review (35 cross sectional or longitudinal studies) RESULTS: Study heterogeneity confounded data interpretation, largely because of no standardisation regarding cognitive testing. In the 30 cross sectional and six longitudinal studies (one included both), 33/35 (94%) reported an association between any degree of ACS and one or more tests of impaired cognitive function (20 reported one to three tests with poorer cognition; 11 reported four to six tests with poorer cognition, while three studies reported seven or more tests with poorer cognition). There was no evidence that ACS caused cognitive impairment via silent cortical infarction, or via involvement in the pathophysiology of lacunar infarction or white matter hyperintensities. However, nine of 10 studies evaluating cerebral vascular reserve (CVR) reported that ACS patients with impaired CVR were significantly more likely to have cognitive impairment and that impaired CVR was associated with worsening cognition over time. Patients with severe ACS but normal CVR had cognitive scores similar to controls. CONCLUSION: Notwithstanding significant heterogeneity within the constituent studies, which compromised overall interpretation, 94% of studies reported an association between ACS and one or more tests of cognitive impairment. However, "significant association" does not automatically imply an aetiological relationship. At present, there is no clear evidence that ACS causes cognitive impairment via silent cortical infarction (but very few studies have addressed this question) and no evidence of ACS involvement in the pathophysiology of white matter hyperintensities or lacunar infarction. There is, however, better evidence that patients with severe ACS and impaired CVR are more likely to have cognitive impairment and to suffer further cognitive decline with time.

Carotid Endarterectomy Following Intravenous Thrombolysis in the UK.

OBJECTIVE: The aim of this study was to evaluate the effect of pre-operative intravenous thrombolytic therapy (ivTT) on short term outcomes after carotid endarterectomy (CEA) among patients who presented with ischaemic stroke. METHODS: A retrospective study using a large population based dataset from the National Vascular Registry in the United Kingdom (UK-NVR). The cohort included adult patients who underwent CEA for ischaemic stroke between 1 January 2014 and 31 December 2019. NVR records provided information on patient demographics, Rankin score, medication, time from onset of symptoms to surgery and whether the patient received ivTT prior to surgery. Logistic regression was used to evaluate the relationship between ivTT and rates of any stroke at 30 days after CEA and in hospital complication rates for neck haematoma. Secondary outcomes included in hospital cardiac and respiratory complications, and cranial nerve injury. RESULTS: Between 2014 and 2019, 9 030 patients presented with a stroke and underwent CEA, of whom 1 055 (11.7%) had received pre-operative ivTT. Those receiving ivTT were younger (mean 70.6 vs. 72.0 years, p < .001). The median (IQR) time from symptom to CEA was 10 days (6 - 17) for ivTT patients and 11 days (7 - 20) for CEA patients not receiving ivTT. Post-operative rates of 30 day stroke were similar between the no ivTT (2.1%) and ivTT (1.8%) cohorts (p = .48). In hospital neck haematomas were statistically significantly more common in CEA patients receiving ivTT (3.7%) vs. no ivTT (2.3%) (p = .006). There was no statistically significant association between 30 day stroke and neck haematoma complications when stratified for delays from symptom onset to CEA, but the overall cohort contained few adverse events for analysis during the very early time period. CONCLUSION: The use of ivTT before CEA in stroke patients was not associated with an increased risk of 30 day stroke, but there was an increase in the risk of neck haematoma.

A Systematic Review of Procedural Outcomes in Patients With Proximal Common Carotid or Innominate Artery Disease With or Without Tandem Ipsilateral Internal Carotid Artery Disease.

OBJECTIVE: To establish 30 day and mid term outcomes in patients treated for significant stenoses affecting the proximal common carotid artery (CCA) or innominate artery (IA) with/without tandem disease of the ipsilateral internal carotid artery (ICA). METHODS: Systematic review of early and mid term outcomes in 1 969 patients from 77 studies (1960-2017) who underwent: (i) hybrid open retrograde angioplasty/stenting of the IA/proximal CCA plus carotid endarterectomy (CEA) in patients with tandem disease of the ipsilateral proximal ICA (n = 700); (ii) isolated open surgery to the IA or proximal CCA (no CEA) (n = 686); or (iii) an isolated endovascular approach to IA or proximal CCA stenoses (no CEA) (n = 583). RESULTS: In the hybrid group with tandem disease (66% involving proximal CCA), the 30 day death/stroke was 3.3%, with a late ipsilateral stroke rate of 3.3% at a median six years follow up. Late re-stenosis was 10.5% for proximal CCA/IA and 4.1% for the ICA. In the isolated open surgery group (78% involving the IA), the 30 day death/stroke was 7%, with a late ipsilateral stroke rate of 1% at a median 12 years follow up. Late re-stenosis within aortic bypasses was 2.6%. In the isolated endovascular group (52% IA, 47% proximal CCA), the majority of procedures were done percutaneously (84%), with a 30 day death/stroke rate of 1.5%. Late ipsilateral stroke was 1% at a median four years follow up, with a re-stenosis rate of 9%. CONCLUSION: Procedural risks were higher following isolated open surgical interventions involving the proximal CCA/IA, compared with proximal lesions treated by isolated angioplasty/stenting, or in tandem with CEA. This higher morbidity/mortality may, however, reflect a greater proportion of innominate (vs. proximal CCA) lesions in open surgical series, changes in patient selection, time dependent evolution of medical interventions, and publication bias. The available data were limited and related to very different patient groups and management strategies spanning 57 years. Caution is raised, particularly for open surgery IA and CCA surgery, and for any procedures in asymptomatic patients. In symptomatic patients, the data cautiously support an "endovascular first" strategy for isolated proximal CCA/IA lesions and a hybrid approach for tandem proximal CCA/IA and ICA stenoses.

Changing Patterns of Carotid Endarterectomy Between 2011 and 2017 in England.

Background and Purpose- Carotid endarterectomy (CEA) reduces the risk of stroke in recently symptomatic patients and less so in asymptomatic patients. Recent evidence suggests that the number of CEAs may be declining. The aim of this study was to investigate annual patterns of CEA in asymptomatic and symptomatic patients in England from 2011 to 2017. Methods- Data from the National Vascular Registry were used to describe (1) the number of CEA procedures in England and its 9 geographic regions from 2011 to 2017, (2) the characteristics of patients undergoing CEA, and (3) whether rates of CEA correlated with the number of vascular arterial units within each region. Annual stroke incidence for each region was derived from official population figures and the number of index stroke admissions per year. Results- The overall number of CEAs performed in England fell from 4992 in 2011 to 3482 in 2017, a 30% decline. Among symptomatic patients, there was a 25% decline, the number of CEAs falling from 4270 to 3217. In asymptomatic patients, there were 722 CEAs performed in 2011 and 265 in 2017, a 63% decline. CEAs per 100 000 adults within all regions declined over time but the size of change varied across the regions (range, 1.7-5.5 per 100 000). The regional numbers of CEAs per year were associated with changes in the regional stroke incidence, the proportion of CEAs performed in asymptomatic patients, and the number of hospitals performing CEA. Conclusions- This population-based study revealed a 63% decline in CEAs among asymptomatic patients between 2011 and 2017, possibly because of changing attitudes in the role of CEA. Reasons for the 25% decline in CEAs among symptomatic patients are unclear as UK guidelines on CEA have not changed for these patients. Whether the proportion of symptomatic patients with 50% to 99% ipsilateral stenosis has changed requires investigation.

Optimal Antiplatelet Therapy in Moderate to Severe Asymptomatic and Symptomatic Carotid Stenosis: A Comprehensive Review of the Literature.

OBJECTIVES: Carotid stenosis patients are at risk of vascular events despite antiplatelet therapy. Data on prescribed antiplatelet regimens have not been comprehensively collated from trials to guide optimal therapy in this population. METHODS: This review was conducted in line with the current Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Medline, Ovid, Embase, Web of Science, and Google Scholar from 1988 to 2018 were searched using the search terms "carotid stenosis", "asymptomatic", "symptomatic", "antiplatelet", and "anti-platelet" to identify randomised trials in patients with asymptomatic or symptomatic extracranial moderate-severe carotid stenosis on any form of antiplatelet therapy in which vascular events and pre specified composite outcome events were reported. RESULTS: Twenty-five studies were judged eligible for inclusion. Data from one randomised controlled trial showed no significant difference in benefit with aspirin versus placebo in asymptomatic carotid stenosis, but it is still reasonable to recommend aspirin (81-325 mg daily) for prevention of vascular events in these patients. Low to medium dose aspirin (81-325 mg daily) is superior to higher doses (>650 mg daily) at preventing recurrent vascular events in patients undergoing endarterectomy. Data from endovascular treatment (EVT) trials support peri-procedural treatment of asymptomatic and symptomatic patients with 81-325 mg of aspirin daily. The use of peri-procedural aspirin-clopidogrel in patients undergoing EVT is based on one pilot trial, but appears safe. Short-term aspirin-dipyridamole or aspirin-clopidogrel treatments are equally effective at reducing micro-embolic signals on transcranial Doppler ultrasound in patients with ≥50% symptomatic carotid stenosis. There is insufficient evidence to recommend routine aspirin-clopidogrel combination therapy to reduce the risk of recurrent clinical ischaemic events in patients with symptomatic moderate-severe carotid stenosis. CONCLUSIONS: This comprehensive review outlines an evidence based approach to antiplatelet therapy in carotid stenosis patients. Future trials should randomise such patients to receive different antiplatelet regimens to assess their efficacy and safety and to optimise peri-procedural and long-term preventive treatment in this patient cohort.

Editor's Choice - An Updated Systematic Review and Meta-analysis of Outcomes Following Eversion vs. Conventional Carotid Endarterectomy in Randomised Controlled Trials and Observational Studies.

INTRODUCTION: A 2011 meta-analysis comparing eversion (eCEA) with conventional (cCEA) carotid endarterectomy in 16,251 patients concluded that eCEA was associated with lower rates of peri-operative stroke and late occlusion compared with cCEA. However, randomised controlled trials (RCTs) showed no difference in outcomes. Since then, the literature contains outcome data on 49,500 patients undergoing eCEA or cCEA. An updated meta-analysis was performed to establish whether eCEA confers significant benefit over cCEA. METHODS: This was a systematic review of PubMed/Medline, Embase, and Cochrane databases for RCTs and observational studies (OSs) comparing eCEA with cCEA. A sensitivity analysis was also performed using data from OSs with a Newcastle-Ottawa score >5. RESULTS: There were 25 eligible studies (5 RCTs, 20 OSs) involving 49,500 CEAs (16,249 eCEAs; 33,251 cCEAs). RCT data: Compared with cCEA, eCEA did not confer significant reductions in 30 day stroke, death, death/stroke, death/stroke/MI, or neck haematoma. However, eCEA was associated with reduced late restenosis (OR 0.40; p = .001). OS data: eCEA was associated with significant reductions in 30 day death (OR 0.46; p < .0001), stroke (OR 0.58; p < .0001), death/stroke (OR 0.52; p < .0001), death/stroke/MI (OR 0.50; p < .0001), and late restenosis (OR 0.49; p = .032) compared with cCEA. RCT and OS data combined: eCEA was associated with significant reductions in 30 day death (OR 0.55; p < .0001), stroke (OR 0.63; p = .004), death/stroke (OR 0.58; p < .0001), and late restenosis (OR 0.45; p = .004) compared with cCEA. eCEA vs. patched cCEA (RCT and OS data): There were no differences between the two procedures except for neck haematoma, where eCEA was better than patched cCEA. CONCLUSIONS: Using combined RCT and OS data, eCEA was superior to cCEA regarding peri-operative outcomes (stroke, death, death/stroke) and late restenosis, but was similar to patched CEA in both early and late outcomes. This updated meta-analysis suggests that early and late outcomes following cCEA are similar to eCEA, provided the arteriotomy is patched.

Which patients with asymptomatic carotid stenosis benefit from revascularization?

PURPOSE OF REVIEW: To summarize why there are polarized opinions regarding the management of patients with asymptomatic carotid disease and whether it is possible to identify patients who might benefit from carotid interventions. RECENT FINDINGS: Carotid Revascularization Endarterectomy Versus Stenting Trial and Asymptomatic Carotid Trial 1 (ACT-1) recently concluded that outcomes after carotid endarterectomy and carotid stenting were not significantly different in asymptomatic patients and that procedural risks were below the accepted 3% threshold. However, systematic reviews suggest that Carotid Revascularization Endarterectomy Versus Stenting Trial/ACT-1 results may not be generalizable into routine practice. In parallel, meta-analyses suggest that stroke rates on medical therapy may be declining, suggesting that Asymptomatic Carotid Atherosclerosis Study/Asymptomatic Carotid Surgery Trial data, which have underpinned every practice guideline since 1995, are too historical for use in 2017. A recent review has, however, identified a number of clinical/imaging features that may be associated with higher rates of stroke on medical therapy. SUMMARY: The majority of surgeons/interventionists are unlikely to accept radical changes in practice until new randomized trials confirm that the risk of stroke on modern medical therapy is significantly lower than that previously accepted. In the interim, it would be preferable to target interventions into a smaller cohort who present with clinical/imaging features that might render them 'higher risk for stroke' on medical therapy.

Post-carotid Endarterectomy Hypertension. Part 2: Association with Peri-operative Clinical, Anaesthetic, and Transcranial Doppler Derived Parameters.

OBJECTIVE/BACKGROUND: The first paper in this series observed that pre-operative baroreceptor dysfunction and poorly controlled hypertension were independently predictive for identifying patients who went on to require treatment for post-endarterectomy hypertension (PEH). The second paper examines the influence of intra-operative patient, transcranial Doppler (TCD) ultrasound, and anaesthetic variables on the incidence of PEH. METHODS: In total, 106 patients underwent carotid endarterectomy (CEA) under general anaesthesia. Systolic blood pressure (SBP) changes, anaesthetic and vasoactive agents, analgesia, and post-operative pain scores, as well as TCD derived changes in middle cerebral artery (MCA) velocity during surgery were recorded. Patients who met pre-existing unit criteria for treating PEH after CEA (SBP > 170 mmHg without symptoms or SBP > 160 mmHg with headache/seizure/neurological deficit) were treated according to an established and validated protocol. RESULTS: In total, 40/106 patients (38%) required treatment for PEH following CEA (26 in theatre recovery [25%], 27 back on the vascular surgery ward [25%]), whereas seven (7%) had SBP surges > 200 mmHg on the ward. Patients requiring treatment for PEH had significantly higher pre-induction SBP (174 ± 21 mmHg vs. 153 ± 21 mmHg; p < .001), the greatest decreases in SBP after induction of anaesthesia (median decrease 100 ± 32 mmHg vs. 83 ± 24 mmHg; p = .01) and were significantly more likely to experience moderate/severe pain scores post-operatively (p = .003). Logistic regression analysis of the pre- and intra-operative data revealed that higher pre-induction mean SBP and lower pre-operative (impaired) BRS were the only independent predictors of PEH. CONCLUSION: This analysis of intra-operative variables has demonstrated that patients with poorly controlled and/or labile hypertension at induction of general anaesthesia were those at greatest risk of requiring treatment for PEH in the post-operative period after CEA. No other variables, including use of vasopressors, treatment of hypotension, anaesthetic agents, or changes in MCA velocity after clamp release and restoration of flow were able to predict who might go on to require treatment for PEH. Identification of at-risk individuals and aggressive blood pressure control in the post-operative period remains the mainstay of treatment.

Debate: Whether carotid endarterectomy is safer than stenting in the hyperacute period after onset of symptoms.

The carotid artery has been a regular battleground for debates regarding many issues, including appropriate management of symptomatic and asymptomatic lesions, the conduct, timing, and safety of such interventions, and now, whether endarterectomy or stenting is safer in the hyperacute period. Our discussants agree that, as a prophylactic procedure, a carotid intervention should occur early after index symptoms to prevent as many strokes as possible. However, which intervention is best?