Restenosis after Carotid Interventions and Its Relationship with Recurrent Ipsilateral Stroke: A Systematic Review and Meta-analysis.

OBJECTIVE: Do asymptomatic restenoses > 70% after carotid endarterectomy (CEA) and carotid stenting (CAS) increase the risk of late ipsilateral stroke? METHODS: Systematic review identified 11 randomised controlled trials (RCTs) reporting rates of restenosis > 70% (and/or occlusion) in patients who had undergone CEA/CAS for the treatment of primary atherosclerotic disease, and nine RCTs reported late ipsilateral stroke rates. Proportional meta-analyses and odds ratios (OR) at end of follow-up were performed. RESULTS: The weighted incidence of restenosis > 70% was 5.8% after "any" CEA, median 47 months (11 RCTs; 4249 patients); 4.1% after patched CEA, median 32 months (5 RCTs; 1078 patients), and 10% after CAS, median 62 months (5 RCTs; 2716 patients). In four RCTs (1964 patients), one of 125 (0.8%) with restenosis > 70% (or occlusion) after CAS suffered late ipsilateral stroke over a median 50 months, compared with 37 of 1839 (2.0%) in CAS patients with no significant restenosis (OR 0.87; 95% CI 0.24-3.21; p = .8339). In seven RCTs (2810 patients), 13 out of 141 (9.2%) with restenosis > 70% (or occlusion) after CEA suffered late ipsilateral stroke over a median 37 months, compared with 33 out of 2669 (1.2%) in patients with no significant restenoses (OR 9.02; 95% CI 4.70-17.28; p < .0001). Following data correction to exclude patients whose surveillance scan showed no evidence of restenosis > 70% before stroke onset, the prevalence of stroke ipsilateral to an untreated asymptomatic > 70% restenosis was seven out of 135 (5.2%) versus 40 out of 2704 (1.5%) in CEA patients with no significant restenosis (OR 4.77; 95% CI 2.29-9.92). CONCLUSIONS: CAS patients with untreated asymptomatic > 70% restenosis had an extremely low rate of late ipsilateral stroke (0.8% over 50 months). CEA patients with untreated, asymptomatic > 70% restenosis had a significantly higher risk of late ipsilateral stroke (compared with patients with no restenosis), but this was only 5% at 37 months. Overall, 97% of all late ipsilateral strokes after CAS and 85% after CEA occurred in patients without evidence of significant restenosis or occlusion.

Post-Carotid Endarterectomy Hypertension. Part 1: Association with Pre-operative Clinical, Imaging, and Physiological Parameters.

OBJECTIVE/BACKGROUND: Post-endarterectomy hypertension (PEH) is a well recognised, but poorly understood, phenomenon after carotid endarterectomy (CEA) that is associated with post-operative intracranial haemorrhage, hyperperfusion syndrome, and cardiac complications. The aim of the current study was to identify pre-operative clinical, imaging, and physiological parameters associated with PEH. METHODS: In total, 106 CEA patients undergoing CEA under general anaesthesia underwent pre-operative evaluation of 24 hour ambulatory arterial blood pressure (BP), baroreceptor sensitivity, cerebral autoregulation, and transcranial Doppler measurement of cerebral blood flow velocity (CBFv) and pulsatility index. Patients who met pre-existing criteria for treating PEH after CEA (systolic BP [SBP] > 170 mmHg without symptoms or SBP > 160 mmHg with headache/seizure/neurological deficit) were treated according to a previously established protocol. RESULTS: In total, 40/106 patients (38%) required treatment for PEH at some stage following CEA (26 in theatre recovery [25%], 27 while on the vascular surgical ward [25%]), while seven (7%) had SBP surges > 200 mmHg back on the ward. Patients requiring treatment for PEH had a significantly higher pre-operative SBP (144 ± 11 mmHg vs. 135 ± 13 mmHg; p < .001) and evidence of pre-existing impairment of baroreceptor sensitivity (3.4 ± 1.7 ms/mmHg vs. 5.3 ± 2.8 ms/mmHg; p = .02). However, PEH was not associated with any other pre-operative clinical features, CBFv, or impaired cerebral haemodynamics. Paradoxically, autoregulation was better preserved in patients with PEH. All four cases of hyperperfusion associated symptoms were preceded by PEH. Length of hospital stay was significantly increased in patients with PEH (p < .001). CONCLUSION: In this study, where all patients underwent CEA under general anaesthesia, PEH was associated with poorly controlled pre-operative BP and impaired baroreceptor sensitivity, but not with other peripheral or central haemodynamic parameters, including impaired cerebral autoregulation.

Carotid Stenting Prior to Coronary Bypass Surgery: An Updated Systematic Review and Meta-Analysis.

OBJECTIVES: The aim was to determine 30-day outcomes in patients with concurrent carotid and cardiac disease who underwent carotid artery stenting (CAS) followed by coronary artery bypass grafting (CABG). METHODS: This was a systematic review with searches of PubMed/Medline, Embase, and Cochrane databases. "Same-day" procedures involved CAS + CABG being performed on the same day, and "staged" interventions involved at least 1 day's delay between undergoing CAS and then CABG. RESULTS: There were 31 eligible studies (2727 patients), with 80% being neurologically asymptomatic with unilateral stenoses. Overall, the 30-day death/stroke rate was 7.9% (95% confidence interval [CI] 6.9-9.2), while death/stroke/MI was 8.8% (95% CI 7.3-10.5). Staged CAS + CABG was associated with 30-day death/stroke rate of 8.5% (95% CI 7.3-9.7) compared with 5.9% (95% CI 4.0-8.5) after "same-day" procedures. Outcomes following CAS + CABG in neurologically symptomatic patients were poorer, with procedural stroke rates of 15%. There were five antiplatelet (APRx) strategies: (a) no APRx (death/stroke/MI, 4.2%; no data on bleeding complications); (b) single APRx before CAS and CABG, then dual APRx after CABG (death/stroke/MI, 6.7%; 7.3% bleeding complications); (c) dual APRx pre-CAS down to one APRx pre-CABG (death/stroke/MI, 10.1%; 2.8% bleeding complications); (d) dual APRx pre-CAS, both stopped pre-CABG (death/stroke/MI, 14.4%); (e) dual APRx pre-CAS and continued through CABG (death/stroke/MI, 16%). There were insufficient data on bleeding complication in the last two strategies. CONCLUSIONS: In a cohort of predominantly asymptomatic patients with unilateral carotid stenoses, the 30-day rate of death/stroke was about 8%. Notwithstanding the effect of potential biases, this meta-analysis did not find evidence that outcomes after same-day CAS + CABG were higher than after staged interventions. However, outcomes were poorer in neurologically symptomatic patients. More data are required to establish the optimal antiplatelet strategy in patients undergoing same-day or staged CAS + CABG.

Gene and Protein Expression of Chemokine (C-C-Motif) Ligand 19 is Upregulated in Unstable Carotid Atherosclerotic Plaques.

OBJECTIVE/BACKGROUND: The aim was to investigate the expression of genes associated with carotid plaque instability and their protein products at a local and systemic level. METHODS: Carotid plaques from 24 patients undergoing carotid endarterectomy (CEA) were classified as stable or unstable using clinical, histological, ultrasound, and transcranial Doppler criteria, and compared using whole genome microarray chips. Initial results of differentially expressed genes were validated by quantitative reverse transcriptase polymerase chain reaction in an independent group of 96 patients undergoing CEA. The protein product of genes significantly differentially expressed between patients with stable and unstable plaques were analysed by plaque immunohistochemistry and serum protein quantification by enzyme-linked immunosorbent assay on a further independent cohort. RESULTS: Expression of chemokine (c-c-motif) ligand 19 (CCL19) was significantly upregulated in plaques from patients with clinically unstable disease (p < .001). Cathepsin G expression was upregulated in histologically unstable plaques (p = .04). Serum concentration of CCL19 was significantly higher in patients with clinically unstable plaques (p = .02). Immunohistochemical staining for CCL19 demonstrated positive staining in histologically and clinically unstable plaques (p = .03). CCL19 also co-localised with CD3+ T-cell lymphocytes in the core region, around where CCL19 was expressed. CONCLUSIONS: CCL19 is significantly overexpressed in patients with unstable carotid atherosclerotic plaques and may be a possible novel biomarker for identifying high-risk patients in whom more urgent intervention may be indicated.

Late Survival in Nonoperated Patients with Infrarenal Abdominal Aortic Aneurysm.

OBJECTIVE/BACKGROUND: Historical studies report high rupture rates in patients with nonoperated abdominal aortic aneurysms (AAAs) of > 5.5 cm diameter, although a recent audit has questioned this. METHODS: This was a retrospective review of 138/764 (18%) patients with AAAs evaluated in a preassessment anaesthetic clinic (PAC) between 2006 and 2012, who either did not undergo elective AAA repair or who underwent deferred repair. The remaining 626 underwent repair. Patients with severe comorbidities (dementia, advanced malignancy, life-expectancy < 1 year) and not referred to PAC were excluded. RESULTS: At a median of 27 months, 71 (52%) died, 36 (51%) following rupture. Cumulative survival, free from rupture or surgery for acute symptoms, was 96% at 1 year, 84% at 3 years, and 64% at 5 years, where baseline AAA diameters were 5.5-6.9 cm. For diameters ≥ 7 cm, survival, free from rupture, was 65% at 1 year, 29% at 3 years, and 0% at 5 years. Median interval to rupture was 47 months (AAA diameter 5.5-6.9 cm) and 21 months where baseline diameters were ≥ 7 cm. Rupture accounted for 32% of late deaths in patients with AAAs of 5.5-5.9 cm diameter, 46% in those with AAAs measuring 6.0-6.9 cm in diameter, and 71% in patients with AAA measuring ≥ 7 cm in diameter. CONCLUSION: Approximately half of all late deaths in this nonoperated cohort were not AAA related, suggesting that even had repair been undertaken, it would not have prolonged patient survival. The incidence of rupture in "high-risk" patients with an AAA < 7 cm diameter was < 5% at 1 year, thereby giving ample time to optimise risk factors and improve pre-existing medical conditions prior to undertaking a deferred intervention. Even if these patients did not undergo surgical repair, the risk of late rupture was relatively low. By contrast, nonoperated patients with AAAs ≥ 7 cm in diameter face a very high risk of rupture and will probably benefit from elective surgery, with the caveat that a higher procedural risk might have to be incurred.

Editor's Choice - Delays to Surgery and Procedural Risks Following Carotid Endarterectomy in the UK National Vascular Registry.

OBJECTIVE: Guidelines recommend that patients suffering an ischaemic transient ischaemic attack (TIA) or stroke caused by carotid artery stenosis should undergo carotid endarterectomy (CEA) within 14 days. METHOD: The degree to which UK vascular units met this standard was examined and whether rapid interventions were associated with procedural risks. The study analysed patients undergoing CEA between January 2009 and December 2014 from 100 UK NHS hospitals. Data were collected on patient characteristics, intervals of time from symptoms to surgery, and 30-day postoperative outcomes. The relationship between outcomes and time from symptom to surgery was evaluated using multilevel multivariable logistic regression. RESULTS: In 23,235 patients, the median time from TIA/stroke to CEA decreased over time, from 22 days (IQR 10-56) in 2009 to 12 days (IQR 7-26) in 2014. The proportion of patients treated within 14 days increased from 37% to 58%. This improvement was produced by shorter times across the care pathway: symptoms to referral, from medical review to being seen by a vascular surgeon, and then to surgery. The spread of the median time from symptom to surgery among NHS hospitals shrank between 2009 and 2013 but then grew slightly. Low-, medium-, and high-volume NHS hospitals all improved their performance similarly. Performing CEA within 48 h of symptom onset was associated with a small increase in the 30-day stroke and death rate: 3.1% (0-2 days) compared with 2.0% (3-7 days); adjusted odds ratio 1.64 (95% CI 1.04-2.59) but not with longer delays. CONCLUSIONS: The delay from symptom to CEA in symptomatic patients with ipsilateral 50-99% carotid stenoses has reduced substantially, although 42% of patients underwent CEA after the recommended 14 days. The risk of stroke after CEA was low, but there may be a small increase in risk during the first 48 h after symptoms.

Fate of Distal False Aneurysms Complicating Internal Carotid Artery Dissection: A Systematic Review.

BACKGROUND: False aneurysm formation occurs in 13-49% of internal carotid artery dissections (ICADs). In light of the uncertainty regarding the clinical course, expansion rates and optimal treatment of post-ICAD false aneurysms, a systematic review of the literature was undertaken to establish the fate of the nonoperated distal ICA false aneurysm after ICAD. METHODS: PubMed/MEDLINE, Embase, and Cochrane databases were systematically searched up to 13 August 2015 for studies reporting clinical outcomes and imaging surveillance in patients who were found to have developed a false aneurysm associated with ICAD, with specific emphasis on the fate of the nonoperated false aneurysm. RESULTS: Eight studies reported on the course/clinical outcome of ICAD-associated false aneurysms in 166 patients. Of these, five of 166 false aneurysms (3%) increased in size; 86 of 166 (52%) remained unchanged in diameter; 35 of 166 (21%) diminished in size; 32 of 166 (19%) resolved completely; three of 166 (2%) thrombosed; and five 166 (3%) were repaired surgically. Another four of 166 (2%) underwent late surgery (0.5-5.0 years later). During the course of surveillance, none of the nonoperated false aneurysms associated with spontaneous ICAD gave rise to any new neurological or compressive symptoms. CONCLUSIONS: In this systematic review, >95% of nonoperated false aneurysms affecting the distal internal carotid artery that developed after an ICAD did not increase in size and were not associated with any delayed neurological symptoms suggesting that conservative management and serial surveillance is the optimal mode of treatment. As nearly all studies suffered from serious bias, reporting standards for diagnosis and follow-up are needed in order to better define their natural history.

Randomized controlled trials: still the backbone of vascular surgery?

Prior to the introduction of evidence-based medicine, decision-making was largely based upon 'intuitive reasoning', whereby senior clinicians dictated practice based upon personal dogma, personal experience and (often) biased observational studies. This era began to end (in vascular surgery) following completion of the landmark randomized trials in carotid disease, which recruited patients throughout the 1980s. Despite scepticism amongst some surgeons of the time these particular randomized trials have stood the test of time and remain the cornerstone of virtually every guideline of practice to this day. The carotid randomized trials became a beacon for using 'evidence' rather than 'intuitive reasoning' and randomized trials have now been used to determine optimal practice in a plethora of carotid surgery and stenting trials, lower limb revascularization and numerous aortic aneurysm based studies. The literature abounds with situations where practice (previously based on observational study data) was changed overnight following publication of a well-designed randomized trial. However, while observational studies are prone to selection bias, randomized trials bring their own unique limitations including problems with external validity, they take too long to complete, they are very expensive, they are notorious for problems with recruitment and they can frequently become obsolete. This has led to a (not unreasonable) call for more observational studies to be used in the development of practice guidelines. Unfortunately, the principle guideline bodies around the world, e.g. National Institute for Health and Care Excellence (NICE) and the American Heart Association (AHA), prioritize randomized trial evidence above all else. Until that changes, guideline makers will find it very difficult to deviate from using historical randomized trial evidence, even when high quality observational data suggest that 'real world' practice bears little comparison to that reported in the randomized trials. Nowhere is that more evident than in developing contemporary guidelines for the management of asymptomatic carotid disease.

Stroke/Death Rates Following Carotid Artery Stenting and Carotid Endarterectomy in Contemporary Administrative Dataset Registries: A Systematic Review.

BACKGROUND: Randomised trials have reported higher stroke/death rates after carotid artery stenting (CAS) versus carotid endarterectomy (CEA). Despite this, the 2011 American Heart Association (AHA) guidelines expanded CAS indications, partly because of the Carotid Revascularization Endarterectomy versus Stenting Trial, but also because of improving outcomes in industry sponsored CAS Registries. The aim of this systematic review was: (i) to compare stroke/death rates after CAS/CEA in contemporary dataset registries, (ii) to examine whether published stroke/death rates after CAS fall within AHA thresholds, and, (iii) to see if there had been a decline (over time) in procedural risk after CAS/CEA. METHODS: PubMed/Medline, Embase, and Cochrane databases were systematically searched according to the recommendations of the PRISMA statement from January 1, 2008 until February 23, 2015 for administrative dataset registries reporting outcomes after both CEA and CAS. RESULTS: Twenty-one registries reported outcomes involving more than 1,500,000 procedures. Stroke/death after CAS was significantly higher than after CEA in 11/21 registries (52%) involving "average risk for CEA" asymptomatic patients and in 11/18 registries (61%) involving "average risk for CEA" symptomatic patients. In another five registries, CAS was associated with higher stroke/death rates than CEA for both symptomatic and asymptomatic patients, but formal statistical comparison was not reported. CAS was associated with stroke/death rates that exceeded risk thresholds recommended by the AHA in 9/21 registries (43%) involving "average risk for CEA" asymptomatic patients and in 13/18 registries (72%) involving "average risk for CEA" symptomatic patients. In 5/18 registries (28%), the procedural risk after CAS in "average risk" symptomatic patients exceeded 10%. CONCLUSIONS: Data from contemporary administrative dataset registries suggest that stroke/death rates following CAS remain significantly higher than after CEA and often exceed accepted AHA thresholds. There was no evidence of a sustained decline in procedural risk after CAS.

Dual Antiplatelet Therapy Prior to Expedited Carotid Surgery Reduces Recurrent Events Prior to Surgery without Significantly Increasing Peri-operative Bleeding Complications.

OBJECTIVE: A daily Rapid-Access TIA Clinic was introduced in 2008, where symptomatic patients were started on 75 mg aspirin + 40 mg simvastatin by the referring doctor, before attending the clinic. Following clinic assessment, patients with 50-99% stenoses were transferred to the vascular unit for carotid endarterectomy (CEA). In two audits (n = 212 patients), the median delay from transfer to the vascular unit to undergoing CEA was 3 days, during which time 28 patients (13%) suffered recurrent neurological events. It was hypothesized that early introduction of dual antiplatelet therapy (by adding clopidogrel 75 mg once parenchymal haemorrhage was excluded in the TIA clinic) might significantly reduce recurrent events between transfer to the surgical unit and undergoing CEA. METHODS: Prospective audit in 100 consecutive, recently symptomatic patients receiving dual antiplatelet therapy. Endpoints were: prevalence of recurrent events between transfer from the TIA clinic and undergoing CEA; rates of spontaneous embolization prior to undergoing CEA; and prevalence of haemorrhagic complications RESULTS: The median delay from symptom to CEA was 8 days (IQR 5-15). The median delay between transfer from the TIA clinic to CEA was 3 days (IQR 2-5), during which time three patients (3%) suffered recurrent TIAs. This represents a fivefold reduction compared with previous audit data (OR 4.9, 95% CI 1.5-16.6, p = .01) and was matched by a fourfold reduction in the prevalence of spontaneous embolization from 39/189 (21%) previously to 5/83 (5%) in the current audit (OR 4.1, 95% CI 1.5-10.7, p = .0047). The 30-day death/stroke rate was 1%. There were three haemorrhagic complications: stroke caused by haemorrhagic transformation of an infarct; exploration for neck haematoma; and debridement and skin grafting for spontaneous shin haematoma. CONCLUSION: Early introduction of dual antiplatelet therapy was associated with a significant reduction in recurrent neurological events and spontaneous embolization prior to CEA, without incurring a significant increase in major peri-operative bleeding complications.

Long-term Mortality in Patients with Asymptomatic Carotid Stenosis: Implications for Statin Therapy.

OBJECTIVE: Recent studies with asymptomatic carotid patients on best medical management have shown that the annual risk of stroke has decreased to approximately 1%. There is no evidence that a similar decrease in mortality has occurred. In addition, the intensity of statin therapy for these patients has not yet been determined. The aims of this review were to determine (a) the reported long-term all-cause and cardiac-related mortality in patients with asymptomatic carotid stenosis (ACS) > 50%, (b) whether there has been a decrease in mortality in recent years, (c) the available methods of mortality risk stratification, and (d) whether the latest ACC/AHA guidelines on the treatment of serum lipids can be applied to this group of patients. METHODS: Systematic review of PubMed, EuroPubMed, and Cochrane Library and meta-analysis using random effects for pooled proportions were performed regarding long-term all-cause and cardiac-related mortality and the associated risk factors in ACS patients. The last day for literature search was October 30, 2014. RESULTS: Seventeen studies were retrieved reporting 5-year all-cause mortality in 11,391 patients with ACS >50%. The 5-year cumulative all-cause mortality across all 17 studies was 23.6% (95% CI 20.50-26.80). Twelve additional studies, reporting both all-cause and cardiac mortality with a minimum of 2 year follow-up and involving 4,072 patients were identified. Of the 930 deaths reported, 589 (62.9%; 95% CI 58.81-66.89) were cardiac-related. This translates into an average cardiac-related mortality of 2.9% per year. CONCLUSIONS: All-cause and cardiac mortality in ACS patients are very high. Although risk stratification is possible, most patients are classified as high risk. In view of this high risk, aggressive statin therapy is indicated if the new ACC/AHA guidelines on serum lipids are to be adhered to.