Advertisement

Effect of Chronic Antiplatelet and Anticoagulant Medication in Neck Haematoma and Perioperative Outomes After Carotid Endarterectomy

  • Joana Cruz Silva
    Correspondence
    Corresponding author: Joana da Cruz Silva, Angiology and Vascular Surgery Department, Centro Hospitalar e Universitário de Coimbra, Portugal, Praceta Rua Prof. Mota Pinto, 3004-561 Coimbra, Portugal, (00351)961491699
    Affiliations
    Angiology and Vascular Surgery Department, Centro Hospitalar e Universitário de Coimbra, Praceta Rua Prof. Mota Pinto, 3004-561 Coimbra, Portugal
    Search for articles by this author
  • Vânia Constâncio
    Affiliations
    Angiology and Vascular Surgery Department, Centro Hospitalar e Universitário de Coimbra, Praceta Rua Prof. Mota Pinto, 3004-561 Coimbra, Portugal
    Search for articles by this author
  • Pedro Lima
    Affiliations
    Angiology and Vascular Surgery Department, Centro Hospitalar e Universitário de Coimbra, Praceta Rua Prof. Mota Pinto, 3004-561 Coimbra, Portugal
    Search for articles by this author
  • Gabriel Anacleto
    Affiliations
    Angiology and Vascular Surgery Department, Centro Hospitalar e Universitário de Coimbra, Praceta Rua Prof. Mota Pinto, 3004-561 Coimbra, Portugal
    Search for articles by this author
  • Manuel Fonseca
    Affiliations
    Angiology and Vascular Surgery Department, Centro Hospitalar e Universitário de Coimbra, Praceta Rua Prof. Mota Pinto, 3004-561 Coimbra, Portugal
    Search for articles by this author
Open AccessPublished:September 14, 2022DOI:https://doi.org/10.1016/j.avsg.2022.08.018

      Abstract

      Objectives

      A retrospective analysis of neck haematoma, stroke and mortality after symptomatic and asymptomatic carotid endarterectomy (CEA) was conducted, in order to determine the most appropriate perioperative medication for these patients. Thirty-day outcomes of moderate and severe neck bleeding were also investigated.

      Methods

      Patients undergoing CEA in a Vascular Surgery department were analysed (2015-2019). Pre-procedure antithrombotic medication (from the 5-days prior to surgery) was identified. End point predictors were identified by univariate and multivariable analyses and adjusted for confounders.

      Results

      A total of 304 CEA were included. Almost half of the included patients (49.67%) were under low-dose aspirin, 17.55% other single antiplatelet agent, 12.59% dual antiplatelet therapy, 8.61% anticoagulation and 10.92% no antithrombotic therapy. There was 8.22% rate of important haematoma, including 4.93% severe (requiring surgical exploration) hematomas and a 30-day all-stroke incidence of 2.94% in symptomatic and 1.79% asymptomatic patients (p=.51). When compared to aspirin, severe haematoma was more prevalent with single clopidogrel or triflusal (RR 4.25, p=.11), dual antiplatelet group (RR 11.84, p=.002) and anticoagulation (RR 8.604, p=.02). Dual antiaggregation and anticoagulation did not confer post-operative stroke protection compared to single aspirin in either symptomatic or asymptomatic patients. Non-significant higher intra-hospital mortality was noted in no medication, dual antiplatelet and anticoagulation groups in contrast to aspirin. Severe neck bleeding was associated with increased congestive heart failure (9.26-fold, p=.03) and longer hospital stay (11.20±24.69 days versus 3.18±4.79 with no bleeding, p<.001), with a tendency for higher hospital readmission at 30-days (4.66-fold, p=.13). Mortality and stroke rates were similar.

      Conclusions

      Double antiaggregation and anticoagulation did not confer better perioperative outcomes after elective CEA in our study. These regimens were associated with increased risk of neck haematoma, especially severe bleeding, with similar rates of neurologic events in both symptomatic and asymptomatic patients and no mortality benefit. Monotherapy with aspirin appears to be the safest perioperative antithrombotic regimen for elective CEA.

      Keywords

      Introduction

      Carotid endarterectomy (CEA) is considered the standard treatment for >50% symptomatic carotid stenosis and for selective cases of >70% asymptomatic carotid stenosis
      • Naylor
      • et al.
      Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
      . Although postoperative stroke and death represent the most devastating complications following carotid endarterectomy, the most frequent complication is neck haematoma, with a described incidence up to 15.8%
      • Welling R.E.
      • Ramadas H.S.
      • Gansmuller K.J.
      • et al.
      Cervical wound hematoma after carotid endarterectomy.
      • Gisbert S.M.
      • Almonacil V.A.
      • Garcia J.M.
      • et al.
      Predictors of cervical bleeding after carotid endarterectomy.
      • Oldag A.
      • Schreiber S.
      • Schreiber S.
      • et al.
      Risk of wound hematoma at carotid endarterectomy under dual antiplatelet therapy.
      • Payne D.A.
      • Twigg M.W.
      • Hayes P.D.
      • Naylor A.R.
      Antiplatelet Agents and risk factors for bleeding postcarotid endarterectomy.
      • Barnett H.J.
      • Taylor D.W.
      • Haynes R.B.
      • et al.
      Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
      . Beyond patient concern and the possibility of hospitalization prolongation with inherent associated financial costs, emergent surgical exploration may be needed in severe neck haematoma. In most serious cases it may compromise airways and invasive ventilation or even tracheostomy might be needed.
      It is recommended that patients undergoing CEA should receive antiplatelet medication in the perioperative and in the long-term period as a secondary prevention of arteriosclerotic arterial disease
      • Naylor
      • et al.
      Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
      ,
      • Kretschmer G.
      • Pratschner T.
      • Prager M.
      • et al.
      Antiplatelet treatment prolongs survival after carotid bifurcation endarterectomy analysis of the clinical series followed by a controlled trial.
      . Research as shown that antiplatelet therapy reduces any stroke after carotid endarterectomy, but may increase haemorrhagic complications
      • Engelter S.
      • Lyrer P.
      Antiplatelet therapy for preventing stroke and other vascular events after carotid endarterectomy.
      . It is also mentioned that early introduction of double antiplatelet therapy with aspirin and clopidogrel after minor stroke may be considered for early secondary stroke prevention
      • Naylor
      • et al.
      Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
      ,

      Powers WJ et al. 2018 Guidelines for early management of patients with acute ischemic stroke. AHA/ASA Guideline. Stroke 2018;49:e46-99.

      . This suggestion is based on a study in which double antiaggregation during 21 days initiated early (<24 hours) after minor stroke or transient ischaemic attack (TIA) significantly reduced new strokes or TIAs
      • Wang Y.
      • Wang Y.
      • Zhao X.
      • et al.
      Clopidogrel with aspirin in acute minor stroke or transient ischemic attack.
      . Other investigations in mostly symptomatic carotid stenosis, revealed a reduction in micro-embolisation after 2-7 days of double antiaggregation
      • Lau A.Y.
      • Zhao Y.
      • Chen C.
      • et al.
      Dual antiplatelets reduce microemboli signals in patients with transient ischemic attack and minor stroke: subgroup analysis of CLAIR study.
      • Batcheider A.
      • Hunter J.
      • Cairns V.
      • et al.
      Dual antiplatelet therapy prior to expedited carotid surgery reduces recurrent events prior to surgery without significantly increasing peri-operative bleeding complications.
      • Markus H.S.
      • Droste D.W.
      • Kaps M.
      • et al.
      Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using Doppler embolic signal detection: The Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial.
      . Another study failed to show statistically significant stroke reduction with aspirin plus clopidogrel during 90 days versus single antiplatelet therapy when introduced within 24 hours of symptom onset
      • Kennedy J.
      • Hill M.D.
      • Ryckborst K.J.
      • et al.
      Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomized controlled pilot trial.
      . Even in asymptomatic patients with indication for CEA, there is a considerable possibility of chronic antithrombotic medication with antiplatelet agents for secondary prevention of peripheral or coronary artery disease or anticoagulants for cardiac arrhythmia, mechanical cardiac prosthetic valves or previous thromboembolism, among others.
      There is currently no consensus regarding optimal antithrombotic medication in the pre-operative period of CEA. There are noteworthy variations in the pre-operative medication prescription among vascular surgeons in both symptomatic and asymptomatic carotid stenosis
      • Hamish M.
      • Gohel M.S.
      • Sheperd A.
      • et al.
      Variations in the pharmacological management of patients treated with carotid endarterectomy: a survey of European vascular surgeons.
      . Therefore, doubt persists regarding potential benefits of maintaining double antiplatelet therapy or anticoagulation in the days preceding surgery considering the potential bleeding risk.
      We conducted a retrospective study analysing perioperative outcomes after symptomatic and asymptomatic patients submitted to carotid endarterectomy under several regimens of chronic pre-operative single antiplatelet therapy, dual antiplatelet therapy and anticoagulation, in order to determine the most appropriate perioperative medication for these patients. Main assessed complications were moderate neck haematoma and neck bleeding requiring surgical exploration, all cause stroke, intra-hospital death and stroke plus mortality. Other addressed results were 30-day mortality, myocardial infarction (MI) and congestive heart failure, pneumonia, duration of surgery, duration of hospitalisation and all-cause 30-day hospital readmission. As secondary goals we evaluated the above mentioned outcomes in patients with moderate and severe neck haematoma and appraised other potential risk factors for neck bleeding.

      Materials and Methods

      Subjects and Database

      We retrospectively identified all patients submitted to carotid endarterectomy in the department of Angiology and Vascular Surgery in our institution (Centro Hospitalar e Universitário de Coimbra, a central referral hospital for vascular surgery in Portugal) from a 5-year period, 2015-2019. The investigation was approved by local institutional medical ethical committee. Only patients ≥18 years-old and submitted to elective surgery where included. Patients operated under singular conditions, such as restenosis, carotid dissection, carotid aneurysm and simultaneous cardiac surgery were excluded.

      Variable Definitions and Outcomes

      Multiple demographic, clinical and surgical variables were collected (Table 1). Of the 310 carotid endarterectomies with the inclusion criteria, information was available from 304 surgeries.
      Table 1Characteristics of study participants, perioperative medication and surgical data.
      Characteristics(n=304)Frequency % (n)
      Age (years; average±SD, range)70.63±8.05 (47-88)
      Male gender83.55% (254)
      Comorbidities
       Previous stroke/ TIA/ amaurosis fugax71.05% (216)
      Stroke/ TIA/ amaurosis fugax <6 months (n=216)62.96% (136)
      Stroke/ TIA/ amaurosis fugax <1 month (n=216)28.70% (62)
      Stroke/ TIA/ amaurosis fugax <15 days (n=216)9.26% (20)
       Hypertension92.43% (281)
       Diabetes39.80% (121)
       Obesity12.83% (39)
       Smoking13.49% (41)
       CKD9.21% (28)
       COPD9.54% (29)
       Coronary disease22.37% (68)
       Congestive heart failure13.16% (40)
       Neoplasia5.59% (17)
      Contralateral carotid stenosis29.28% (89)
       Contralateral occlusion (n=89)14.61% (13)
       Contralateral stenosis >70% (n=89)15.73% (14)
       Contralateral stenosis 50-70% (n=89)69.66% (62)
      Perioperative antiplatelet/ anticoagulant therapy (n=302)
       Single antiplatelet therapy67.22% (203)
      ASA 100-150mg49.67% (150)
      Clopidogrel 75mg7.95% (24)
      Triflusal 300mg BID8.28% (25)
      Other
      ticlopidine 250mg twice a day or pentoxifylline 400mg three times a day.
      1.32% (4)
       Dual antiplatelet therapy12.59% (38)
      ASA 100-150mg + clopidogrel 75mg8.61% (26)
      ASA 100-150mg + triflusal 300mg BID1.32% (4)
      ASA 100-150mg + pentoxifylline 400mg TID1.99% (6)
      ASA 100-150mg + ticagrelor 90mg BID0.66% (2)
       Anticoagulation
      Therapeutic LMWH
      tinzaparin 175IU/Kg daily or enoxaparin 1mg/Kg 12/12h or enoxaparin 1mg/Kg daily if CrCl<30ml/min.
      8.61% (26)
       Anticoagulation + antiplatelet therapy
      ASA 100-150mg + therapeutic LMWH
      tinzaparin 175IU/Kg daily or enoxaparin 1mg/Kg 12/12h or enoxaparin 1mg/Kg daily if CrCl<30ml/min.
      0.66% (2)
       No medication10.92% (33)
      Surgical procedure
       Eversion/ partial eversion97.37% (296)
       Patch2.63% (8)
       General anaesthesia97.70% (297)
       Duration of surgery (minutes; average±SD)55.21±18.48
       Protamine use (mg; average±SD) (n=284)16.45% (50), 13.22±4.77
       UFH use (IU; average±SD) (n=284)100.00% (284), 2886±940
       Sustained post-operative hypertension
      considered if systolic blood pressure ≥160mmHg for ≥15 minutes during the first 6 hours in post-anesthesia care unit.
      (systolic pressure in mmHg; average±SD) (n=303)
      48.84% (148), 157.38±22.41
       Discharge after surgery (days; average±SD, range)3.59±7.28 (2-100)
      SD, standard deviation; TIA, transient ischaemic attack; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; ASA, acetylsalicylic acid; BID, twice a day; TID, three times a day; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin.
      ∗a ticlopidine 250mg twice a day or pentoxifylline 400mg three times a day.
      ∗b tinzaparin 175IU/Kg daily or enoxaparin 1mg/Kg 12/12h or enoxaparin 1mg/Kg daily if CrCl<30ml/min.
      ∗c considered if systolic blood pressure ≥160mmHg for ≥15 minutes during the first 6 hours in post-anesthesia care unit.
      Symptomatic carotid stenosis was considered in the presence of a neurologic event in the last 180 days related to a carotid stenosis >50%. Degree of carotid stenosis was defined according to the North Symptomatic Carotid Endarterectomy Trial (NASCET) criteria
      • Barnett H.J.
      • Taylor D.W.
      • Eliasziw M.
      • et al.
      Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Colaborators.
      . General or locoregional anesthesia was dependent on anesthetist and surgeon preference. CEA was performed under continuous electroencephalography monitoring. There was a preference in the department for not using carotid shunt and for eversion or partial eversion technique using a longitudinal incision over carotid bulb with plaque eversion. Patching was used only if extensive plaque through internal carotid artery. Intra-operative UFH was used in all surgeries before arterial clamping, UFH doses (40-100UI/Kg) and protamine use was according to surgeon preference. Activated clotting time was not calculated routinely. Drain was used in the totality of surgeries. All patients stayed in the post-anesthesia care unit for at least 6-hours and were posteriorly transferred to a surgical ward.
      Pre-procedure antiplatelet and anticoagulant regimens were assessed individually and also categorized into five groups to facilitate comparability: no antiplatelet therapy, monotherapy with aspirin or acetylsalicylic acid (ASA), monotherapy with another antiplatelet agent other than ASA, dual antiplatelet therapy and anticoagulation (with or without single antiaggregant). Antiplatelet and anticoagulant medication was considered during the five days previous to surgery. Chronic medication not taken in that period was considered as “no medication”. Only antiplatelet therapy taken for more than five consecutive days or with loading dose during that pre-operative period was considered. Pre-operative antiaggregants were omitted in the day of surgery and resumed the following day. Hospitalised anticoagulated patients were medicated with enoxaparin 1mg/Kg 12 hours before surgery and in the evening after the procedure.
      Moderate and severe neck haematoma, all stroke, intra-hospital mortality, and composite outcome 30-day all stroke/mortality/MI/neck haematoma were defined as primary outcomes. Evaluated secondary outcomes were MI, congestive heart failure, pneumonia, duration of surgery, prolongation of hospitalisation and hospital readmission at 30-days.
      It was defined as moderate neck haematoma any post-operative neck bleeding with need for prolongation of hospitalisation time for vigilance and severe neck haematoma any haematoma with surgical exploration and drainage due to rapid expansion, dysphagia or airways compression. Minor stroke was defined as 0-2 modified Rankin scale points and a major stroke as 3-5 points (disabling stroke). MI was defined by troponin level.

      Statistical Analysis

      Variables were compared between the different groups of antiplatelet and anticoagulant therapy using t-test for continuous variables and chi-squared or Fisher’s exact test for categorical variables. Outcomes were also compared using chi-squared test and adjusted for potential confounders. ASA was used as control group for the antiplatelet and anticoagulant regimens and absence of important (moderate and severe) neck haematoma as reference for the outcomes related to this complication. Logistic regression was used to identify predictors of neck haematoma and to adjust for confounder variables. Multiple regression was used to predict value of variables if p-value <.2.
      Significant value was set at p-value <.05. Statistical analyses was performed using SPSS version 25.0 statistical software package®.

      Results

      Antithrombotic Medication and Surgical Data

      A total of 304 carotid endarterectomies were included in the study, corresponding to 298 patients. Of those surgeries, 62.96% were considered symptomatic carotid stenosis. Characteristics of study participants, surgical information and pre-operative antithrombotic medication are detailed in Table 1. The most used regimen was low-dose ASA in almost half of the included patients (49.67%). A total of 10.92% of the patients stopped antithrombotic chronic therapy in the five days before surgery, in according to surgeon preference. This conduct was more frequent in the first years of the enrollment. ASA was started the day following surgery in this group. LMWH was used as a switch from chronic therapeutic oral anticoagulation: warfarin in seven patients and novel oral anticoagulants (NOACs) in the remaining 72.08% (19 cases). All patients under warfarin had International Normalised Ratio (INR) <1.5 in pre-operative analysis. Reasons for chronic double antiaggregation or anticoagulation in our study are described in Table 2. Merely 18.42% of the patients were under dual antiplatelet therapy due to coronary artery disease and 30.00% for neurologic event in the past 1-month.
      Table 2Causes for perioperative dual antiplatelet medication and anticoagulation in study participants.
      Causes for perioperative medicationFrequency % (n)
      Dual antiplatelet therapy (n=38)
       Coronary disease18.42% (7)
       Previous stroke/ TIA78.95% (30)
      Stroke/ TIA <6 months (n=30)63.33% (19)
      Stroke/ TIA <1 month (n=30)30.00% (9)
      Stroke/ TIA <15 days (n=30)10.00% (3)
       Unknown2.63% (1)
      Anticoagulation (n=28)
       Atrial fibrillation71.43% (20)
       Cardiac valve surgery7.14% (2)
       Deep vein thrombosis3.57% (1)
       Central retinal artery occlusion7.14% (2)
       Unknown10.71% (3)
      TIA, transient ischaemic attack.
      Eversion or partial eversion technique was used in the majority of the cases (97.37%). Average clamping time was 13.57±6.06 minutes (minimum 4.50, maximum 41.00 minutes). Therapeutic dose of UFH was used in 15.14% (43 endarterectomies) and subtherapeutic (40 to 80UI/Kg) in the other 84.86%. Heparin reversal with protamine was used in only 16.45% of the surgeries. Demographic data, comorbidities and surgical variables detailed in Table 1 were similar between the five different previously defined antithrombotic groups, except for coronary artery disease (higher rates in patients under dual antiplatelet therapy, p<.001) and congestive heart failure (higher rates in patients under anticoagulation, p=.002). There was no association between antithrombotic perioperative regimen and UFH intra-operative dose (p=.46) or use of protamine (p=.75).

      Neck Haematoma

      There was 8.22% moderate/severe haematoma (25 cases), including 4.93% of severe (requiring surgical exploration) hematomas (15 cases) in our study population. Arterial bleeding was present in 3 cases and capillary oozing in 12 cases.
      Predictors of moderate and severe neck haematoma are described in Table 3. After multiple regression for factors with p-value<.20, only perioperative dual antiplatelet therapy (odds ratio (OR) 5.22, CI 1.95-11.86, p<.001) and sustained post-operative hypertension during post-anesthesia care unit (OR 1.52, CI 0.65-3.51, p=.058) retained significant statistical value. Although there was a higher value of important neck haematoma without intra-operative protamine use, this value did not reach statistical significate in our investigation (1.80% and 6.12% haematoma rate with and without protamine use, respectively, p=.49). Use of protamine was not associated with post-operative neurologic events or myocardial infarction (p=.85).
      Table 3Predictors of neck haematoma – logistic regression.
      CharacteristicsORCI 95%P-value
      Non-modifiable factors
       Age--.88
       Male gender2.390.55-10.48.40
       Comorbidities
      Stroke/ TIA/ amaurosis fugax <6 months1.150.51-2.62.73
      Hypertension2.050.27-15.92.71
      Diabetes1.210.53-2.76.65
      Obesity1.330.43-4.10.54
      Smoking0.240.03-1.89.22
      CKD0.390.05-2.99.49
      COPD0.370.05-2.87.49
      Coronary disease2.541.08-5.95.03
      Congestive heart failure1.290.42-3.96.66
      Neoplasia1.530.33-7.11.64
      Modifiable factors
       Use of patch0.630.04-11.171.00
       General anaesthesia1.460.19-11.491.00
       Perioperative dual antiplatelet therapy4.811.95-11.86<.001
       Perioperative anticoagulation0.970.21-4.37.33
       No protamine1.420.50-4.04.49
       Use of subtherapeutic UFH dose1.690.38-7.53.69
       Sustained post-operative hypertension
      Considered if systolic blood pressure ≥160mmHg for ≥15 minutes during the first 6 hours in post-anesthesia care unit.
      1.520.66-3.51.10
      OR, odds ratio; CI, confidence interval; TIA, transient ischaemic attack; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; UFH, unfractionated heparin. A p-value <.05 was considered statistically significant.
      ∗a Considered if systolic blood pressure ≥160mmHg for ≥15 minutes during the first 6 hours in post-anesthesia care unit.
      Primary and secondary outcomes after carotid endarterectomy are detailed in Figure 1 (by group of antithrombotic therapy in) and in Table 4 (by individual regimen), respectively. There was a higher percentage of important neck haematoma in patients under dual antiaggregation, especially aspirin plus clopidogrel (relative-risk (RR) 4.94 times, p=.001) and aspirin plus ticagrelor (RR 21.41, p<.001), and anticoagulation (2.47 times, p=.16) compared to only aspirin. This difference was more accentuated when comparing severe reoperated haematoma rates (RR 14.46, p<.001 in aspirin plus clopidogrel, RR 37.59, p<.001 in aspirin plus ticagrelor, RR 8.68, p=.004 LMWH). Single clopidogrel and triflusal perioperative use also had highest tendency for neck haematoma when compared to aspirin group (RR 3.14, p=.32 and RR 6.02, p=.004, for severe haematoma in clopidogrel and triflusal group, respectively).
      Figure thumbnail gr1
      Figure 1Multivariable regression analysis evaluating the impact of antiplatelet and anticoagulant therapy (grouped) on the risk of the following primary outcomes: any stroke in symptomatic and asymptomatic population (30-days), all-cause intra-hospital death, any stroke or death (30-days), severe neck hematoma with reoperation and total major complication including any stroke, death, MI and moderate/severe neck haematoma (30-days). CEA, carotid endarterectomy; RR, relative risk; CI, confidence interval; ASA, acetylsalicylic acid; MI, myocardial infarction. A p-value <.05 was considered statistically significant.
      Table 4Outcomes according to perioperative antiplatelet and anticoagulant therapy.
      30-days outcomesAntiplatelet/ anticoagulant therapy (n=302)

      Frequency % (n)
      ASAClop.(n=24)Triflusal(n=25)Other single antiplatelet(n=4)Global single antiplateletNo medication (n=33)ASA+ clop. (n=26)ASA+ triflusal (n=4)ASA+ pentox. (n=6)ASA + ticagrelor (n=2)Global dual antiplateletLMWH (n=26)ASA+ LMWH (n=2)Global anticoag.
      Control(n=150)P-valueP-valueP-valueP-value
      Intra-hospital mortality1.33%(2)0.00%0.00%0.00%p=.403.03%(1), p=.493.85%(1)0.00%0.00%0.00%p=.57; p∗a=.393.85%(1)0.00%p=.40 ; p∗a=.78
      All-cause mortality2.67%(4)0.00%0.00%0.00%p=.233.03%(1), p=.917.69%(2)0.00%0.00%0.00%p=.42; p∗a=.573.85%(1)0.00%p=.79 ; p∗a=.98
      Major stroke1.33%(2)0.00%0.00%0.00%p=.400.00%, p=.513.85%(1)0.00%0.00%0.00%p=.570.00%0.00%p=.54
      Any stroke2.67%(4)4.17%(1)0.00%0.00%p=.753.03%(1), p=.913.85%(1)0.00%0.00%0.00%p=.990.00%0.00%p=.38
      Intra-hospital mortality + any stroke2.67%(4)4.17%(1)0.00%0.00%p=.756.06%(2), p=.323.85%(1)0.00%0.00%0.00%p=.993.85%(1)0.00%p=.79
      Important neck haematoma4.67%(7)8.33%(2)8.00%(2)0.00%p=.793.03%(1), p=.6823.08%(6)9.09%(1)0.00%100.00%(2)p<.00111.54%(3)0.00%p=.20
      Reoperated haematoma1.33%(2)4.17%(1)8.00%(2)0.00%p=.083.03%(1), p=.4919.23%(5)0.00%0.00%50.00%(1)p<.00111.54%(3)0.00%p=.006
      Myocardial infarction0.67%(1)4.17%(1)0.00%0.00%p=.440.00%, p=.640.00%0.00%0.00%0.00%p=.610.00%0.00%p=.66
      Congestive heart failure0.67%(1)0.00%0.00%0.00%p=.550.00%, p=.640.00%0.00%0.00%0.00%p=.617.69%(2)0.00%p=.02 ; p∗a=.61
      Pneumonia2.00%(3)0.00%0.00%0.00%p=.303.03%(1), p=.710.00%0.00%16.67%(1)0.00%p=.81 ; p∗a=.873.85%(1)0.00%p=.61 ; p∗a=.30
      All-cause hospital readmission4.00%(6)0.00%4.00%(1)0.00%p=.473.03%(1), p=.790.00%0.00%16.67%(1)0.00%p=.693.85%(1)0.00%p=.91
      Post-operative discharge (days; average±SD)3.40±5.00---2.62±1.233.48±5.52----5.50±15.87--4.04±7.69
      p=.26p=.94p=.17p=.57
      Duration of surgery(minutes; average±SD)55.13±17.11---59.11±20.06 p=.1755.09±20.16----53.71±19.37--51.67±17.97
      p=.99p=.66p=.33
      ASA, acetylsalicylic acid; SD, standard deviation. A p-value <.05 was considered statistically significant. ∗a P-value adjusted to subpopulation disparities.
      Outcomes in patients with moderate/severe neck bleeding are described in Figure 2. Three of the fifteen patients with reoperated heck haematoma were admitted in intensive care unit due to impaired ventilation and two patients developed neck wound infection. Despite there is a trend for worse 30-day outcomes and higher hospital readmission rates, haematoma was not statistically significantly associated with worse primary outcomes mortality (6.67% versus 1.43%, p=.13, intra-hospital death in patients with reoperated and no neck haematoma, respectively) and stroke in our study (no stroke in patients with neck bleeding versus 1.08% major stroke and 2.51% all stroke, p=.54, in no haematoma). Cardiac complications (6.67% versus 0.72%, p=.03, post-operative congestive heart failure) and duration of hospitalisation (11.20±24.69 days versus 3.18±4.79 days, p<.001) where significantly greater in patients with severe haematoma compared to no haematoma.
      Figure thumbnail gr2
      Figure 2Evaluated 30-days outcomes of patients submitted to carotid endarterectomy with important neck haematoma (moderate haematoma and reoperated patients due to neck haematoma, n=25) and with reoperated neck haematoma (n=15) comparing to patients without important neck haematoma (n=279). Dichotomous variables are presented with percentage. Continuous variables are presented with average and 95% confidence interval. A p-value <.05 was considered statistically significant.

      Perioperative Stroke

      There was a 0.99% major 30-day stroke rate (3 cases) and 1.31% minor 30-day stroke rate (4 cases) in our study. Of the described events, two were haemorrhagic strokes (1 major event in a patient under double antiaggregation a few hours after surgery and 1 minor event in a patient under aspirin five days after hospital discharge due to a hypertensive crisis).
      More post-operative strokes were identified in symptomatic patients (2.94% versus 1.79% in symptomatic and asymptomatic patients, respectively, p=.51; 3.23% versus 2.07% in patients with and without stroke in the previous 1-month, respectively, p=.59). Figure 1 shows stroke rates in both symptomatic and asymptomatic patients according to group of antithrombotic therapy. Although it did not reach statistical relevance, there was a leaning to stroke protection in asymptomatic patients (but not symptomatic ones) under single or dual antiplatelet therapy or anticoagulation compared to no pre-operative antithrombotic therapy.

      Other Outcomes

      Intra-hospital, all cause 30-day mortality and secondary outcomes in cohorts with different antiplatelet and anticoagulation therapies are detailed in Table 4. Higher mortality was noted in patients with no medication, dual antiaggregation with aspirin plus clopidogrel and therapeutic LMWH compared to aspirin (RR for intra-hospital mortality 2.27 and p=.49 with no medication, RR 2.89 and p=.36 under aspirin plus clopidogrel and also under LMWH). These rates retained no statistical value after adjustment for subpopulation disparities. Effect of LMWH in post-operative congestive heart failure vanished after adjustment for subgroup differences.
      No relevant difference was noted in duration of surgery, duration of hospitalisation or post-surgery acute myocardial infarction and pneumonia proportions among different antithrombotic schemes.

      Discussion

      We retrospectively analysed perioperative outcomes after carotid endarterectomy under several regimens of antithrombotic therapy. We had 8.22% of important cervical haematomas and 4.93% of severe haematomas in our study requiring surgical exploration. Despite absence of defined criteria for neck haematoma which can challenge comparison between studies, these values are in line with published data of 5.5-15.8% cervical haematoma and 2.3-5.6% cervical bleeding with reoperation
      • Gisbert S.M.
      • Almonacil V.A.
      • Garcia J.M.
      • et al.
      Predictors of cervical bleeding after carotid endarterectomy.
      ,
      • Oldag A.
      • Schreiber S.
      • Schreiber S.
      • et al.
      Risk of wound hematoma at carotid endarterectomy under dual antiplatelet therapy.
      ,
      • Barnett H.J.
      • Taylor D.W.
      • Haynes R.B.
      • et al.
      Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
      . The relatively elevated reoperation values in our cohort represent a defensive attitude.
      Perioperative dual antiplatelet therapy was the most relevant predictor of neck haematoma in our study (OR 5.22, p<.001). When compared to aspirin, both dual therapy (particularly aspirin plus clopidogrel and aspirin plus ticagrelor) and anticoagulation had much higher bleeding rates, especially severe haematomas (RR 5.07, p<.001 and RR 2.29, p=.20 for moderate/severe haematoma and RR 11.84, p=.002 and RR 8.04, p=.02 for severe haematoma under double antiplatelet and anticoagulant medication, respectively). Other single antiplatelet therapies, namely clopidogrel and triflusal, had higher severe haematoma rates when compared to aspirin (group RR 4.25, p=.11). A proportion of 1.7-9.4 times more cervical haematomas under aspirin plus clopidogrel
      • Rosenbaum A.
      • Rizvi A.Z.
      • Alden P.B.
      • et al.
      Outcomes related to antiplatelet or anticoagulation use in patients undergoing carotid endarterectomy.
      • Jones D.W.
      • Goodnery P.P.
      • Conrad M.F.
      • et al.
      Dual antiplatelet therapy reduces stroke but increases bleeding at the time of carotid endarterectomy.
      • Hale B.
      • Pan W.
      • Misselbeck T.S.
      • et al.
      Combined clopidogrel and aspirin therapy in patients undergoing carotid endarterectomy is associated with an increased risk of postoperative bleeding.
      and 2.0-3.0 times under anticoagulation
      • Gisbert S.M.
      • Almonacil V.A.
      • Garcia J.M.
      • et al.
      Predictors of cervical bleeding after carotid endarterectomy.
      ,
      • Jones D.W.
      • Goodnery P.P.
      • Conrad M.F.
      • et al.
      Dual antiplatelet therapy reduces stroke but increases bleeding at the time of carotid endarterectomy.
      has been described in the literature. Still, anticoagulation scheme is not detailed in these publications. In similarity with our findings, Oldag et al
      • Oldag A.
      • Schreiber S.
      • Schreiber S.
      • et al.
      Risk of wound hematoma at carotid endarterectomy under dual antiplatelet therapy.
      described 4.3% haematoma requiring surgical evacuation in patients under simple clopidogrel versus 1.2% under aspirin.
      An additional independent risk factor for neck haematoma in our investigation was post-operative hypertension during post-anesthesia care unit (OR 1.52, p=.058). A few articles establish relation between postoperative hypertension and neck haematoma
      • Welling R.E.
      • Ramadas H.S.
      • Gansmuller K.J.
      • et al.
      Cervical wound hematoma after carotid endarterectomy.
      ,
      • Gisbert S.M.
      • Almonacil V.A.
      • Garcia J.M.
      • et al.
      Predictors of cervical bleeding after carotid endarterectomy.
      ,
      • Payne D.A.
      • Twigg M.W.
      • Hayes P.D.
      • Naylor A.R.
      Antiplatelet Agents and risk factors for bleeding postcarotid endarterectomy.
      . Newman et al
      • Newman J.E.
      • Bown M.J.
      • Sayers R.D.
      • et al.
      Post-carotid endarterectomy hypertension. Part 1: association with pre-operative clinical, imaging, and physiological parameters.
      showed that patients with relevant post-endarterectomy hypertension had significantly higher pre-operative systolic blood pressure and pre-existing impaired baroreceptor sensitivity. Illuminati et al
      • Illuminati G.
      • Schneider F.
      • Pizzardi G.
      • et al.
      Dual antiplatelet therapy does not increase the risk of bleeding after carotid endarterectomy: results of a prospective study.
      published their experience with 188 carotid endarterectomies under aspirin plus clopidogrel for recent coronary artery stenting, with no postoperative cervical haematoma requiring reexploration, proving that severe cervical bleeding might be avoided under meticulous care and strict post-operative blood pressure control. They described a prolonged operation time (average 130 minutes in comparison with 55 minutes in our population), greater blood volume in suction drains and longer postoperative hospitalization in aspirin plus clopidogrel group. Moreover, in our experience, moderate/severe cervical haematomas were 3.40 times more when no intra-operative protamine was used (p=.49). Protamine was administrated in only 16.45% of the surgeries, which might have underestimated its effect. Several previous publications proved its benefit with no increased risk for stroke and myocardial infarction
      • Kakisis J.D.
      • Antonopoulos C.N.
      • Moulakakis K.G.
      • et al.
      Protamine reduces bleeding complications without increasing the risk of stroke after carotid endarterectomy: a meta-analysis.
      • Stone D.H.
      • Giles K.A.
      • Kubilis P.
      • et al.
      Protamine reduces serious bleeding complications associated with carotid endarterectomy in asymptomatic patients without increasing the risk of stroke, myocardial infarction, or death in a large national analysis.
      • Stone D.H.
      • Nolan B.W.
      • Schanzer A.
      • et al.
      Protamine reduces bleeding complications associated with carotid endarterectomy without increasing the risk of stroke.
      . Saghir et al
      • Saghir R.
      • Humm G.
      • Rix T.
      Haematomas after carotid endarterectomy can be reduced by direct pressure to the neck postoperatively.
      also reported lower bleeding when applying direct pressure to the cervical incision immediately after surgery.
      In our analysis, reoperation group had increased congestive heart failure (9.26-fold, p=.03) and longer hospital stay (11.20±24.69 days versus 3.18±4.79, p<.001), with a tendency for higher hospital readmission at 30-days (4.66-fold, p=.13), therefore accounting for higher morbidity and financial costs. Mortality and stroke rates were comparable to controls. Other series specify catastrophic consequences after reoperation, with 13-30 fold increase in death, 7-9 fold increase in stroke and 4-8 fold increase in MI
      • Jones D.W.
      • Goodnery P.P.
      • Conrad M.F.
      • et al.
      Dual antiplatelet therapy reduces stroke but increases bleeding at the time of carotid endarterectomy.
      ,
      • Stone D.H.
      • Giles K.A.
      • Kubilis P.
      • et al.
      Protamine reduces serious bleeding complications associated with carotid endarterectomy in asymptomatic patients without increasing the risk of stroke, myocardial infarction, or death in a large national analysis.
      ,
      • Stone D.H.
      • Nolan B.W.
      • Schanzer A.
      • et al.
      Protamine reduces bleeding complications associated with carotid endarterectomy without increasing the risk of stroke.
      . Hemorrhage or haematoma has been independently associated with 30-day hospital readmission after CEA in Braet et al
      • Braet D.J.
      • Smith J.B.
      • Bath J.
      • et al.
      Risk factors associated with 30-day hospital readmission after carotid endarterectomy.
      publication.
      In our group we had a combined 30-day all-stroke rate of 2.30% (0.33% haemorrhagic stroke) and a combined all-stroke and death rate of 2.96%. Previous studies relate up to 5.5% post-endarterectomy stroke incidence
      • Barnett H.J.
      • Taylor D.W.
      • Haynes R.B.
      • et al.
      Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
      with intracranial haemorrhage up to 0.8%
      • McDonald R.J.
      • Cloft H.J.
      • Kallmes D.R.
      Intracranial hemorrhage is much more common after carotid stenting than after endarterectomy: evidence from the National Inpatient Sample.
      and 1.8-7.0% combined stroke and death
      • Barnett H.J.
      • Taylor D.W.
      • Haynes R.B.
      • et al.
      Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
      ,
      • Zimmermann A.
      • Knappicj C.
      • Tsantilas P.
      • et al.
      Different perioperative antiplatelet therapies for patients treated with carotid endarterectomy in routine practice.
      ,
      European carotid surgery trialists’ collaborative group randomized trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST).
      . Though published papers report diminished microembolisation in symptomatic patients under double antiaggregation
      • Lau A.Y.
      • Zhao Y.
      • Chen C.
      • et al.
      Dual antiplatelets reduce microemboli signals in patients with transient ischemic attack and minor stroke: subgroup analysis of CLAIR study.
      ,
      • Batcheider A.
      • Hunter J.
      • Cairns V.
      • et al.
      Dual antiplatelet therapy prior to expedited carotid surgery reduces recurrent events prior to surgery without significantly increasing peri-operative bleeding complications.
      , no specific antithrombotic group conferred significant protection against post-operative stroke and death in both symptomatic and asymptomatic patients in our investigation. All antithrombotic regimens seemed to confer some degree of protection against stroke in asymptomatic patients but not in symptomatic ones. This disparity might be explained by higher risk of neurologic complications in symptomatic patients in the post-operative period, which cannot be reduced by perioperative dual antiplatelet therapy or anticoagulation. Barkat et al
      • Barkat M.
      • Hajibandeh S.
      • Hajibandeh S.
      • et al.
      Systematic review and meta-analysis of dual versus single antiplatelet therapy in carotid interventions.
      meta-analysis corroborates absence of variation in stroke/death between single and dual antiplatelet therapy in CEA. Zimmermann et al
      • Zimmermann A.
      • Knappicj C.
      • Tsantilas P.
      • et al.
      Different perioperative antiplatelet therapies for patients treated with carotid endarterectomy in routine practice.
      had worse combined stroke and death outcomes in patients with no perioperative antiplatelet therapy in their nationwide database.
      Furthermore, a slight increase in mortality was noted in dual antiplatelet and anticoagulant therapy groups, which can be attributed to elevated cardiac disease in these clusters. Our outcomes are supported by CHARISMA trial
      • Bhatt D.L.
      • Fox K.A.
      • Hacke W.
      • et al.
      Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.
      , in which asymptomatic patients under dual antiplatelet therapy had increased bleeding and all-cause mortality.
      Ultimately, it is essential to determine the most appropriate perioperative medication when CEA. As a take-home message, double antiaggregation and anticoagulation did not confer better perioperative outcomes after elective CEA in our study. Instead neck bleeding was considerable increased in these groups (in particular aspirin plus clopidogrel and aspirin plus ticagrelor). Severe haematoma resulted in increased morbidity.
      Since most risk of recurrent stroke in carotid-stenosis caused events are in the first days after symptoms, with prevalence up to 20.9% at 72 hours, 6.7-16.6% at 7 days and 3.7-25.0% at 14 days
      • Dis A.
      • Cuadrado-Godia E.
      • Rodriguez-Campello A.
      • et al.
      High risk of early neurological recurrence in symptomatic carotid stenosis.
      ,
      • Marname M.
      • Prendeville S.
      • McDonnell C.
      • et al.
      Plaque inflammation and unstable morphology are associated with early stroke recurrence in symptomatic carotid stenosis.
      , there is an increase awareness to perform early CEA if indicated. However, several units have concerns completing pre-operative studies and delayed transfer to surgical centres. Increased awareness to the importance of early carotid stenosis examination in patients admitted to stroke units and the presence of detailed referral protocols to vascular surgery centres could help to accomplish timely CEA when indicated. As recommended by international practice guidelines, precocious introduction of aspirin and clopidogrel may be considered after stroke
      • Naylor
      • et al.
      Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
      ,

      Powers WJ et al. 2018 Guidelines for early management of patients with acute ischemic stroke. AHA/ASA Guideline. Stroke 2018;49:e46-99.

      and continued for up to 21 days
      • Wang Y.
      • Wang Y.
      • Zhao X.
      • et al.
      Clopidogrel with aspirin in acute minor stroke or transient ischemic attack.
      . If surgery is scheduled in that time or if recent coronary artery stent, we suggest surgery under dual antiplatelet therapy with meticulous hemostasis care, intra-operative protamine use and strict blood pressure control in a dedicated unit
      • Illuminati G.
      • Schneider F.
      • Pizzardi G.
      • et al.
      Dual antiplatelet therapy does not increase the risk of bleeding after carotid endarterectomy: results of a prospective study.
      . Anti-hypertensive medication should be considered in the morning of the surgery in hypertensive patients for better control
      • Newman J.E.
      • Bown M.J.
      • Sayers R.D.
      • et al.
      Post-carotid endarterectomy hypertension. Part 1: association with pre-operative clinical, imaging, and physiological parameters.
      . After that period, we advise withholding the second antiplatelet agent pre-operatively and maintain aspirin monotherapy since it appears to be the safest antithrombotic option for elective CEA. Risk-benefit of prophylactic LMWH should be weighed in chronic anticoagulated patients.
      Our study has several limitations. First, it is a single centre retrospective study, which narrows the number of included patients and can limit statistical value of some variables, especially in subgroups under antithrombotic regimens with fewer patients. Second, the effect of none antithrombotic therapy could have been masked by the fact that most patients were under chronic single antiaggregation (which was stopped days before hospitalisation) and due to early introduction of aspirin after surgery in our investigation. Third, although its effect would have been minimal, antiplatelet therapy resistance was not accounted. Finally, only elective surgeries were included and these conclusions cannot be applied to emergent cases.
      Despite these limitations, the fact that antithrombotic regimens are clearly specified and surgical technique/ perioperative care are standardized in our study may be considered a strength. Also, antithrombotic therapies were grouped in five regimens (no antiplatelet therapy, monotherapy with aspirin, monotherapy with another antiplatelet agent, dual antiplatelet therapy and anticoagulation) in order to improve comparability with other published material and increase statistical power. Main results are significant and are in line with previous research. However, further prospective multicenter investigations are needed to compare specific individual antithrombotic regimens safety and eventual benefits.

      Conflict of Interest Statement

      This research did not receive any specific grant from funding agencies in the public, commercial, or non-profit sectors.

      References

        • Naylor
        • et al.
        Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
        Eur J Vasc Endovasc Surg. 2018; 55: 3-81
        • Welling R.E.
        • Ramadas H.S.
        • Gansmuller K.J.
        • et al.
        Cervical wound hematoma after carotid endarterectomy.
        Ann Vasc Surg. 1989; 3: 229-231
        • Gisbert S.M.
        • Almonacil V.A.
        • Garcia J.M.
        • et al.
        Predictors of cervical bleeding after carotid endarterectomy.
        Ann Vasc Surg. 2014; 28: 366-374
        • Oldag A.
        • Schreiber S.
        • Schreiber S.
        • et al.
        Risk of wound hematoma at carotid endarterectomy under dual antiplatelet therapy.
        Langenbecks Arch Surg. 2012; 397: 1275-1782
        • Payne D.A.
        • Twigg M.W.
        • Hayes P.D.
        • Naylor A.R.
        Antiplatelet Agents and risk factors for bleeding postcarotid endarterectomy.
        Ann Vasc Surg. 2010; 24: 900-907
        • Barnett H.J.
        • Taylor D.W.
        • Haynes R.B.
        • et al.
        Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
        N Eng J Med. 1991; 325: 445-453
        • Kretschmer G.
        • Pratschner T.
        • Prager M.
        • et al.
        Antiplatelet treatment prolongs survival after carotid bifurcation endarterectomy analysis of the clinical series followed by a controlled trial.
        Ann Surg. 1990; 211: 317e22
        • Engelter S.
        • Lyrer P.
        Antiplatelet therapy for preventing stroke and other vascular events after carotid endarterectomy.
        Cochrane Database Syst Rev. 2003; 3CD001458
      1. Powers WJ et al. 2018 Guidelines for early management of patients with acute ischemic stroke. AHA/ASA Guideline. Stroke 2018;49:e46-99.

        • Wang Y.
        • Wang Y.
        • Zhao X.
        • et al.
        Clopidogrel with aspirin in acute minor stroke or transient ischemic attack.
        N Engl J Med. 2013; 369: 11e9
        • Lau A.Y.
        • Zhao Y.
        • Chen C.
        • et al.
        Dual antiplatelets reduce microemboli signals in patients with transient ischemic attack and minor stroke: subgroup analysis of CLAIR study.
        Int J Stroke. 2014; 9: 127-132
        • Batcheider A.
        • Hunter J.
        • Cairns V.
        • et al.
        Dual antiplatelet therapy prior to expedited carotid surgery reduces recurrent events prior to surgery without significantly increasing peri-operative bleeding complications.
        Eur J Vasc Endovasc Surg. 2015; 50: 412-419
        • Markus H.S.
        • Droste D.W.
        • Kaps M.
        • et al.
        Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using Doppler embolic signal detection: The Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial.
        Circulation. 2005; 111: 2233e40
        • Kennedy J.
        • Hill M.D.
        • Ryckborst K.J.
        • et al.
        Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomized controlled pilot trial.
        Lancet Neurol. 2007; 6: 961-969
        • Hamish M.
        • Gohel M.S.
        • Sheperd A.
        • et al.
        Variations in the pharmacological management of patients treated with carotid endarterectomy: a survey of European vascular surgeons.
        Eur J Vasc Endovasc Surg. 2009; 38: 402-407
        • Barnett H.J.
        • Taylor D.W.
        • Eliasziw M.
        • et al.
        Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Colaborators.
        N Eng J Med. 1998; 339: 1415-1425
        • Rosenbaum A.
        • Rizvi A.Z.
        • Alden P.B.
        • et al.
        Outcomes related to antiplatelet or anticoagulation use in patients undergoing carotid endarterectomy.
        Ann Vasc Surg. 2010; 25: 25-31
        • Jones D.W.
        • Goodnery P.P.
        • Conrad M.F.
        • et al.
        Dual antiplatelet therapy reduces stroke but increases bleeding at the time of carotid endarterectomy.
        J Vasc Surg. 2016; 63: 1262-1270
        • Hale B.
        • Pan W.
        • Misselbeck T.S.
        • et al.
        Combined clopidogrel and aspirin therapy in patients undergoing carotid endarterectomy is associated with an increased risk of postoperative bleeding.
        Vascular. 2013; 21: 194-204
        • Newman J.E.
        • Bown M.J.
        • Sayers R.D.
        • et al.
        Post-carotid endarterectomy hypertension. Part 1: association with pre-operative clinical, imaging, and physiological parameters.
        Eur J Vasc Endovasc Surg. 2017; 54: 551-563
        • Illuminati G.
        • Schneider F.
        • Pizzardi G.
        • et al.
        Dual antiplatelet therapy does not increase the risk of bleeding after carotid endarterectomy: results of a prospective study.
        Ann Vasc Surg. 2016; 40: 39-43
        • Kakisis J.D.
        • Antonopoulos C.N.
        • Moulakakis K.G.
        • et al.
        Protamine reduces bleeding complications without increasing the risk of stroke after carotid endarterectomy: a meta-analysis.
        Eur J Vasc Endovasc Surg. 2016; 52: 296-307
        • Stone D.H.
        • Giles K.A.
        • Kubilis P.
        • et al.
        Protamine reduces serious bleeding complications associated with carotid endarterectomy in asymptomatic patients without increasing the risk of stroke, myocardial infarction, or death in a large national analysis.
        Eur J Vasc Endovasc Surg. 2020; 60: 800-807
        • Stone D.H.
        • Nolan B.W.
        • Schanzer A.
        • et al.
        Protamine reduces bleeding complications associated with carotid endarterectomy without increasing the risk of stroke.
        J Vasc Surg. 2010; 51: 559-564
        • Saghir R.
        • Humm G.
        • Rix T.
        Haematomas after carotid endarterectomy can be reduced by direct pressure to the neck postoperatively.
        Ann Roll Surg Engl. 2018; 00: 1-4
        • Braet D.J.
        • Smith J.B.
        • Bath J.
        • et al.
        Risk factors associated with 30-day hospital readmission after carotid endarterectomy.
        Vascular. 2021; 29: 61-68
        • McDonald R.J.
        • Cloft H.J.
        • Kallmes D.R.
        Intracranial hemorrhage is much more common after carotid stenting than after endarterectomy: evidence from the National Inpatient Sample.
        Stroke. 2011; 42: 2782-2787
        • Zimmermann A.
        • Knappicj C.
        • Tsantilas P.
        • et al.
        Different perioperative antiplatelet therapies for patients treated with carotid endarterectomy in routine practice.
        J Vasc Surg. 2018; 68: 1753-1763
      2. European carotid surgery trialists’ collaborative group randomized trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST).
        Lancet. 1998; 351: 1379-1387
        • Barkat M.
        • Hajibandeh S.
        • Hajibandeh S.
        • et al.
        Systematic review and meta-analysis of dual versus single antiplatelet therapy in carotid interventions.
        Eur J Vasc Endovasc Surg. 2017; 53: 53-67
        • Bhatt D.L.
        • Fox K.A.
        • Hacke W.
        • et al.
        Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.
        N Engl J Med. 2006; 354: 1706-1717
        • Dis A.
        • Cuadrado-Godia E.
        • Rodriguez-Campello A.
        • et al.
        High risk of early neurological recurrence in symptomatic carotid stenosis.
        Stroke. 2009; 40: 2727-2731
        • Marname M.
        • Prendeville S.
        • McDonnell C.
        • et al.
        Plaque inflammation and unstable morphology are associated with early stroke recurrence in symptomatic carotid stenosis.
        Stroke. 2014; 45: 801-806