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Carotid endarterectomy after systemic thrombolysis in a stroke population
From the Canadian Society for Vascular Surgery
Carotid endarterectomy after systemic thrombolysis in a stroke population William Fortin, MD,a,b,c Miguel Chaput, MD, MSc,b Stephane Elkouri, MD, MSc,a Nathalie Beaudoin, MD,a and Jean-François Blair, MD,a Montreal, Quebec, Canada
ABSTRACT Objective: Vascular specialists are increasingly being requested to perform carotid endarterectomy (CEA) after intravenous thrombolysis (IVT) for stroke patients, raising concerns about hemorrhagic complications. Few case series and registry reports have assessed the question, and even fewer studies have included a control group. The aim of this study was to evaluate the overall outcome of patients undergoing CEA after IVT and to compare them with contemporary patients with CEA after simple stroke (non-IVT group). It also aimed to evaluate the differences in outcomes of stroke patients requiring CEA between nonvascular and vascular centers. Methods: The data of 169 consecutive patients who have undergone CEA after stroke in a single center was analyzed from January 2011 to December 2016, 27 of them (16%) having undergone previous IVT. A comparative analysis between the non-IVT and the IVT groups was performed. The time between stroke diagnosis and referral to a vascular specialist was also studied. Results: Age, sex, and cardiovascular comorbidities were similar in both groups. Median time between stroke and CEA was 13 days (Q1-Q3, 8-23 days), with 16 of the 27 patients (59%) in the IVT group undergoing CEA less than 14 days after the initial event. There were three intracranial hemorrhages (2.1%) in the non-IVT group versus one (3.7%) in the IVT group (P ¼ NS). The overall 30-day combined stroke and death rate was 7.1% (6.3% in the non-IVT group vs 11.1% in the IVT group; P ¼ .70). The incidence of postoperative cervical hematoma requiring reoperation was similar in both groups (2.1% vs 3.7%; P ¼ NS). The median time between diagnosis of stroke and referral to a vascular specialist was higher for patients in nonvascular centers compared with vascular centers (3.5 days vs 1.0 day; P < .001), which translated to fewer patients referred from nonvascular centers undergoing surgery in the 14-day window period (38% vs 67%; P < .001). Conclusions: In this retrospective analysis, CEA after IVT showed similar outcomes when compared with the overall CEA after stroke population. Stroke patients diagnosed in nonvascular centers were referred later than those in vascular centers and, although postoperative outcomes were similar, that was correlated with fewer patients undergoing surgery in a timely fashion. (J Vasc Surg 2019;-:1-6.) Keywords: Endarterectomy; Carotid; Intravenous thrombolysis; Thrombolytic therapy; Acute ischemic stroke; Stroke
Stroke represents the third leading cause of disability worldwide and its societal burden is expected to rise in the coming decades.1-3 One of the most important causes of stroke is carotid atherosclerotic disease, accounting for approximately 15% of all events.4 CEA has been performed for decades and has shown consistent risk reduction of ipsilateral stroke occurrence for symptomatic patients with significant carotid From the Division of Vascular Surgery, Centre Hospitalier de l’Université de Montréal (CHUM)a; the Division of Vascular Surgery, Hôpital MaisonneuveRosemontb; and the Faculty of Medicine, Université de Montréal.c Author conflict of interest: none. Presented at the Fortieth Annual Meeting of the Canadian Society for Vascular Surgery, Montreal, Quebec, Canada, September 28-29, 2018. Correspondence: Jean-François Blair, MD, Centre Hospitalier de l’Université de Montréal (CHUM), Division of Vascular Surgery, Montreal, QC, Canada H2W 1T8 (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214 Copyright Ó 2019 by the Society for Vascular Surgery. Published by Elsevier Inc. https://doi.org/10.1016/j.jvs.2019.05.061
atherosclerosis, regardless of the initial presenting symptom (amaurosis fugax, transient ischemic attack [TIA], or stroke).5-7 However, it has also been increasingly recognized that all symptomatic carotid disease does not present the same risk of ipsilateral stroke after CEA, with amaurosis fugax having the lowest risk, and stroke or crescendo TIA the highest.8 Historically, many surgeons would tend to delay CEA after significant neurologic symptoms (ie, stroke), although in the past decades an increasing body of literature has been suggesting that performing CEA in the first 14 days after initial symptoms might provide the best risk reduction of stroke occurrence in this particularly vulnerable population. Therefore, most expert medical societies recommend that CEA should be performed in this time period for all symptomatic patients.9,10 Intravenous thrombolysis (IVT) has shown considerable benefits in terms of mortality and morbidity in patients suffering from ischemic stroke when given in a timely manner.11 Although the half-life of alteplase is only 3 to 5 minutes, it has previously been demonstrated that patients undergoing thrombolytic therapy may show 1
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hematologic abnormalities lasting for several days.12 This observation has led to increasing concerns about the safety of carotid endarterectomy (CEA) after IVT.13 The current literature on the subject suggests that CEA after IVT is safe compared with CEA in overall symptomatic patients. However, with data showing significant differences between presenting symptoms and outcomes after CEA, comparing patients undergoing CEA after stroke with patients undergoing CEA after IVT and stroke could represent a more valid analysis. The goal of this study was to provide additional evidence about perioperative complications related to CEA performed after IVT in a comparable CEA poststroke population and to analyze if stroke patients with significant carotid disease had different outcomes whether the diagnosis was made in an academic hospital or its referring centers.
METHODS Stroke patients management. Patients presenting with symptoms of acute stroke were promptly evaluated by a neurologist and underwent confirmatory imagery and consequent treatment. Once acute ischemic stroke was confirmed, patients presenting with symptoms onset of less than 4.5 hours were considered for IVT, and a standardized protocol of Holter monitoring, cardiac echocardiography, and carotid duplex ultrasound examination in the first 48 hours after admission was initiated. CEA. CEA was performed by three different surgeons. Conventional eversion endarterectomy was performed in the vast majority of patients (168/169). The technique consists of a traditional longitudinal approach and careful dissection from the common carotid to the internal carotid distal to stenosis. After systemic anticoagulation is achieved, the internal carotid artery is then transected via an oblique incision at the bifurcation, and eversion endarterectomy is performed. Endarterectomy of the common and external carotid arteries is performed and the internal carotid artery is reattached to the bifurcation with a 6-0 Prolene running suture. Shunt use was rare in this series (4.1%), and the decision whether to use a shunt or not was left to the surgeon’s discretion on overall clinical and radiologic findings for each patient. Heparin reversal was performed routinely at the end of surgery. Data collection and patient selection. This study is a retrospective review of consecutive patients that underwent CEA after stroke in a single institution over a 5-year period, from January 2011 to December 2016. Patients from 2017 and 2018 were not included because protocol approval by local ethics committees and data collection was initiated earlier. All patients 18 years of age or older that underwent CEA after acute ischemic stroke diagnosed by a neurologist were included. All patients underwent CEA at the Centre Hospitalier de l’Université de Montréal (CHUM, Quebec, Canada), by 3 different
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ARTICLE HIGHLIGHTS d
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Type of Research: Single-center, retrospective cohort study Key Findings: Carotid endarterectomy (CEA) after intravenous thrombolysis was performed in 27 patients, and 30-day stroke and death rates were comparable with a similar cohort of 142 patients who underwent CEA after stroke. Time of referral for stroke patients from nonvascular hospitals to a vascular specialist were significantly longer than for patients diagnosed in vascular hospitals, which translated to less patients undergoing CEA in the 14-day window period. Take Home Message: CEA performed in patients who underwent prior intravenous thrombolysis for stroke shows similar results compared with patients undergoing CEA after stroke.
surgeons. Data regarding demographic factors, diagnostic modalities, percent stenosis, time to initial symptoms, IVT, and National Institute of Health Stroke Scale (NIHSS) scores (IVT patients), CEA, and referral to a vascular service, as well as perioperative and 30-day outcomes were collected. The study protocol was preapproved by the main local ethics committee (project no. 17.241). Primary and secondary end points. Primary end points consisted of the occurrence of postoperative intracranial hemorrhage (ICH), cervical hematoma requiring reoperation, and stroke and death rates. Secondary end points were combined stroke and death by center of referral, the time between initial stroke diagnosis and referral to a vascular specialist, and the time between initial stroke symptoms and surgery. Comparative analysis. A comparative analysis was performed between patients who received prior IVT and those who did not. A secondary comparative analysis was done between patients referred from an academic vascular center and patients referred from a peripheral hospital or a hospital without an in-house vascular service. Statistical analyses. Primary end points were expressed in rates, and compared using c2 tests with continuity correction when absolute event rates were lower than five. Time between stroke diagnosis and referral to a vascular specialist was compared using a median test because of skewed populations, and a multivariate logistical regression was used for the time between stroke diagnosis and CEA comparison. Pre- and post-IVT NIHSS scores were compared using paired t-tests. Post hoc analysis of cervical hematomas related to antiplatelet regimens was done using c2 tests.
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Table I. Baseline characteristics of study population (N ¼ 170): Stroke patients undergoing carotid endarterectomy (CEA) Characteristics
Non-IVT (n ¼ 142)
Table III. Postoperative neck hematomas and reoperation by perioperative antiplatelet regimen
IVT (n ¼ 27)
Male sex
90 (63)
18 (67)
Neck hematoma
Age, years
69 (41-94)
68 (37-85)
Neck hematoma þ reoperation
Active smoking Hypertension
72 (51)
11 (41)
102 (72)
17 (63)
Hyperlipidemia
97 (68)
14 (52)
Coronary disease
34 (24)
10 (37)
Atrial fibrillation
16 (11)
2 (7)
Previous stroke/TIA
19 (13)
4 (15)
Diabetes
40 (28)
7 (26)
None or ASA (n ¼ 114)
Clopidogrel or DAPT (n ¼ 44)
P value
14 (12.3)
6 (13.6)
.80
3 (2.6)
1 (2.3)
NS
ASA, Acetylsalicylic acid; DAPT, dual antiplatelet therapy. Values are presented as number (%).
Table IV. Management and timing of carotid endarterectomy (CEA) in stroke patients with significant carotid disease by type of medical institution
Degree of ipsilateral stenosis 50%-69%
28 (20)
5 (19)
70%-99%
112 (79)
22 (81)
2 (1)
1 (4)
Median time between stroke diagnosis and referral in days (Q1-Q3)
93 (66)
19 (70)
Stroke-to-CEA < 14 days
Antiplatelet therapya None ASA Clopidogrel
13 (9)
1 (4)
DAPT
25 (18)
5 (19)
ASA, Acetylsalicylic acid; DAPT, dual antiplatelet therapy; IVT, intravenous thrombolysis; TIA, transient ischemic attack. Values are presented as number (%) or mean (range). a At the time of surgery (nine missing values).
Table II. Perioperative (30-day) outcomes Overall (N ¼ 169)
Non-IVT (n ¼ 142)
IVT (n ¼ 27)
New stroke (all)
11 (6.5)
8 (4.7)
3 (11.1)
.53
ICH
4 (2.4)
3 (2.1)
1 (3.7)
NS
12 (7.1)
9 (6.3)
3 (11.1)
.70
4 (2.4)
3 (2.1)
1 (3.7)
NS
Combined stroke/death Neck hematoma þ reoperation
3
-
P value
ICH, Intracranial hemorrhage; IVT, intravenous thrombolysis. Values are presented as number (%).
RESULTS In the study period, of the 455 consecutive patients who underwent CEA at the institution for symptomatic disease, 169 (37%) had stroke as an initial diagnosis. Of this subpopulation, 27 (16%) received IVT before CEA. Demographic and preoperative data were similar between the non-IVT and the IVT groups (Table I). Most patients had severe (>70%) ipsilateral carotid stenosis and, although most patients were on acetylsalicylic acid alone at the time of surgery, around 20% were on dual antiplatelet therapy in both groups. Regarding the thrombolysis group, the mean time between stroke and IVT was 2.8 hours (range, 1.5-4.5 hours), and 16 (59%) had CEA in the 14-day window period. The median time between IVT and CEA was 8 days (Q1-Q3, 5-18 days). The mean
Vascular centers (n ¼ 85)
Nonvascular centers (n ¼ 71)
1.0 (0-3)
3.5 (2-7)
<.001
57 (67%)
29 (38%)
<.001a
P value
ASA, Acetylsalicylic acid; DAPT, dual antiplatelet therapy. Values are presented as number (%). a Adjusted for age, gender, and intravenous thrombolysis (IVT).
NIHSS score before and after IVT decreased from 12 to 5 (P < .001). The overall 30-day postoperative stroke and death rate was 7.1% in the study population, and was similar in both the non-IVT and IVT groups (Table II). Three patients (2.1%) suffered ICH in the non-IVT group, and one (3.7%) in the IVT group, which was not statistically significant. Of those, the three patients who underwent CEA alone had 4, 8, and 47 days, respectively, between the index event and surgery. ICH was diagnosed 24 to 120 hours postoperatively, with one patient presenting in a peripheral hospital without readmission to the main institution. The patient who suffered postoperative ICH in the IVT group had a massive hemispheric stroke at presentation, with minimal response to thrombolysis. After significant clinical improvement and several multidisciplinary discussions with the neurologic team, it was decided to proceed to CEA 15 days after the initial event. The patient developed ICH 2 days after surgery and subsequently died. Both the non-IVT and the IVT groups showed a similar rate of reintervention for cervical hematoma (2.1 vs 3.7%; P ¼ NS). A post hoc analysis was done, comparing patients on either no antiplatelet regimen at the time or surgery or only aspirin with patients on either clopidogrel or dual antiplatelet therapy (Table III). No significant differences were seen in terms of rates of neck hematomas or rates of reoperation secondary to a neck hematoma. Regarding the management of the stroke population with a significant ipsilateral carotid disease, the median time between stroke and endarterectomy was 13 days
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Table V. Current literature on carotid endarterectomy (CEA) after intravenous thrombolysis (IVT) Author
Year
No.
Endo et al18
1998
1
N/A
19
Median IVT-CEA, days
30-day stroke, No. (%) 0 (0)
ICH, No. (%) 0 (0)
Eckstein et al
1999
3
6
0 (0)
0 (0)
McPherson et al20
2001
5
2
0 (0)
0 (0)
Bartoli et al21
2009
12
8
Crozier et al22
2011
10
8
0 (0)
0 (0)
Shalhoub37
2011
6
N/A
0 (0)
0 (0)
23
1 (8.3)
1 (8.3)
Leseche et al
2012
7
6
0 (0)
0 (0)
Rathenborg et al24
2013
22
11
0 (0)
0 (0)
Barroso et al25
2013
4
N/A
0 (0)
0 (0)
Yong et al26
2013
7
7
1 (14)
1 (14) 0 (0)
27
Koraen-Smith et al
2014
71
10
2 (2.8)
Rathenborg et al28
2014
202
12
7 (3.5)
N/A
Vellimana et al29
2014
11
N/A
2 (18)
2 (18)
Bazan et al30
2015
25
9.5
0 (0)
0 (0)
31
Yamamoto et al
2016
1
0.5
0 (0)
0 (0)
Azzini et al17
2016
34
N/A
0 (0)
0 (0)
Ahmed et al16
2017
25
7.5
1 (4)
Gunka et al15
2017
13
2
1 (7.7)
N/A 0 (0)
ICH, Intracranial hemorrhage; N/A, not available. The median IVT-CEA is the median time between IVT and carotid endarterectomy; 30-days stroke is the ipsilateral stroke reoccurrence rate at 30-days after endarterectomy.
(Q1-Q3, 8-23 days), and 52% of the patients were operated in the 14-day window period. In this population, the vascular service received referrals from 10 different hospitals for CEA, 2 being academic vascular centers and 8 being nonvascular hospitals. The median time between stroke diagnosis and referral to a vascular specialist was 1.0 day in vascular and 3.5 days in nonvascular hospitals, and this difference in time to referral was associated with almost twice as many patients from academic centers undergoing CEA in the 14-day window compared with nonvascular centers (67 vs 38%; P < .001), even after adjustment for measurable confounding factors (Table IV). The 30-day stroke and death rate was not statistically different between patients referred from vascular and nonvascular centers (9.8% vs 5.5%; P ¼ .49).
DISCUSSION CEA after systemic thrombolysis has been a topic of interest for almost two decades. Currently, IVT is recommended for patients presenting with ischemic stroke with an initial symptom onset of less than 4.5 hours, but with the recent advent of mechanical thrombectomy (MT) for the management of acute ischemic stroke, the future role of IVT has been questioned.14,15 However, MT remains a tertiary care center treatment requiring specialized neuro-interventional teams and, therefore, many patients presenting with acute ischemic stroke would probably remain best treated with early thrombolytic therapy rather than later MT. Also, recent evidence
suggests that IVT and MT may fare better as a combination of treatments rather than either of the two entities being used alone, which reinforces the assumption that IVT is not about to disappear from the treatment algorithm of acute ischemic stroke management, and hence vascular specialists will keep being asked to proceed to CEA or carotid artery stenting for symptomatic carotid stenosis in patients who were previously treated with thrombolytic therapy.15-17 To the authors’ knowledge, 20 different groups have studied the combination of IVT and CEA in acute stroke patients, and most authors suggest that thrombolytic therapy seems to have little or no impact on postoperative complications after CEA (Table V).18-36 However, a recent registry database review by Vellimana et al29 including 551 patients undergoing CEA after IVT showed a higher rate of postoperative ICH in patients undergoing surgery less than 7 days after thrombolysis, compared with overall patients undergoing CEA or CAS, regardless of initial symptomatology. This finding suggests that patients receiving IVT before surgery fare worse than those who undergo CEA or CAS alone, and that it may be safer to wait 1 week before the two treatments. Yet, as noted by the authors in their article, their registry analysis did not account for patients’ presenting symptoms, hence leading to the possibility for their control group to include patients with atrial fibrillation or TIA. Indeed, most series had either no comparative group, or compared post-IVT patients that inevitably suffered
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from stroke to samples consisting mainly of patients experiencing amaurosis fugax or TIA.21,24,25,27,29,31,36 This study was designed to provide a more adequate comparative group of stroke patients undergoing CEA in the same center by the same surgeons. The results suggest that CEA after IVT in this context seems to be safe, with comparable postoperative stroke and death rates and similar hemorrhagic complication rates. Regarding the only patient who suffered ICH in the IVT group, he presented initially with a hemispheric stroke and underwent surgery more than 2 weeks after IVT. Whether thrombolysis was contributive or not to the bleeding in this context is rather questionable. In the light of the actual literature and the present study, the authors would tend to proceed to CEA in the 7- to 14-day window after IVT, excluding patients presenting with severe or hemispheric stroke. The overall stroke and death rate in this series is considerable (7.1%), but this could be better explained by the decision to select only stroke patients rather than by the institution itself. Indeed, Halm et al8 demonstrated, in a review of more than 9000 patients who underwent CEA, that patients presenting initially with stroke had postoperative stroke and death rate of 7.89%. Also, this study provides an analysis of the outcomes of stroke patients undergoing CEA, comparing vascular with nonvascular centers. It provides further evidence that patients diagnosed in peripheral nonvascular centers were referred later to a vascular specialist, which translated to fewer patients undergoing CEA in the optimal 14-day window. Multiple confounding factors could contribute to this finding, including the possible delay of treatment related to vascular specialist access, deferred transfers for patients coming from peripheral hospitals, and surgeons’ opinion on the safety of an early CEA for a given patient, but the correlation remains surprisingly strong. Although this research demonstrated that there was no difference in postoperative outcomes between the two groups, this observation remains concerning, because patients suffering from a stroke in peripheral centers remain at risk of reoccurrence for a longer period before undergoing definitive surgical treatment. Unfortunately, information about stroke reoccurrence in the time period between initial diagnosis and CEA was not reliable due to the study design, so the direct effect of delayed referrals on repeated stroke could not be measured. However, this sheds light on the importance of education of the different medical teams intervening in the management of stroke patients about the crucial role of timely CEA’s benefits on stroke reoccurrence. Another interesting observation is that academic vascular centers had “stroke protocols”, composed of the combination of Holter monitoring, transthoracic ultrasonography and carotid duplex ultrasound in the first 48 hours after the admission of all stroke patients. The implementation of these protocols
in all hospitals managing stroke patients might represent a simple way to standardize the diagnosis of ipsilateral carotid stenosis in these vulnerable patients, and could have the potential to reduce the time of referral to a vascular specialist. The limitations of this study include the absence of systematic coagulation assessments post-IVT, which restrains the understanding of potential hematologic abnormalities at the time of surgery. Also, by study design, only patients that underwent CEA at the main institution were included in the analysis, thus stroke patients that were evaluated for CEA but subsequently treated medically because they were considered too sick were not included, creating a potential selection bias. Another limitation of this research is its retrospective nature, making it prone to selection bias and the relatively small number of outcomes limiting its power. Nonetheless, this analysis is among the largest to include a contemporary control group.
CONCLUSIONS CEA after IVT seems to be safe and to provide comparable results compared with stroke patients undergoing CEA alone. Stroke patients with significant ipsilateral stenosis managed in nonvascular centers had delayed referral to a vascular specialist compared with those managed in vascular centers, which was correlated to less patients undergoing surgery in the 14-day window period, but showed similar postoperative outcomes.
AUTHOR CONTRIBUTIONS Conception and design: WF, JB Analysis and interpretation: WF, MC, SE, NB, JB Data collection: WF Writing the article: WF, MC Critical revision of the article: WF, MC, SE, NB, JB Final approval of the article: WF, MC, SE, NB, JB Statistical analysis: WF Obtained funding: Not applicable Overall responsibility: JB
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22. Barroso B, Laurens B, Demasles S, Faik M, Ledoyer G. Early carotid artery endarterectomy after intravenous thrombolysis therapy. Int J Stroke 2013;8:E28. 23. Yong YP, Saunders J, Abisi S, Sprigg N, Varadhan K, MacSweeney S, et al. Safety of carotid endarterectomy following thrombolysis for acute ischemic stroke. J Vasc Surg 2013;58:1671-7. 24. Koraen-Smith L, Troëng T, Björck M, Kragsterman B, Wahlgren CM. Urgent carotid surgery and stenting may be safe after systemic thrombolysis for stroke. Stroke 2014;45:776-80. 25. Rathenborg LK, Venermo M, Troëng T, Jensen LP, Vikatmaa P, Wahlgren C, et al. Editor’s choice-Safety of carotid endarterectomy after intravenous thrombolysis for acute ischaemic stroke: a case-controlled multicentre registry study. Eur J Vasc Endovasc Surg 2014;48:620-5. 26. Vellimana AK, Yarbrough CK, Blackburn S, Strom RG, Pilgram TK, Lee JM, et al. Intravenous tPA therapy is an independent risk factor for symptomatic intracerebral hemorrhage following carotid endarterectomy. Neurosurgery 2014;74:254. 27. Bazan HA, Zea N, Jennings B, Smith TA, Vidal G, Sternbergh WC III. Urgent carotid intervention is safe after thrombolysis for minor to moderate acute ischemic stroke. J Vasc Surg 2015;62:1529-38. 28. Yamamoto Y, Okazaki T, Yoda K, Tada Y, Nagahiro S. Successful emergency carotid endarterectomy after thrombolysis with intravenous recombinant tissue-type plasminogen activator. J Med Investig 2016;63:300-4. 29. Vellimana AK, Washington CW, Yarbrough CK, Pilgram TK, Hoh BL, Derdeyn CP, et al. Thrombolysis is an independent risk factor for poor outcome after carotid revascularization. Neurosurgery 2018;83:922-30. 30. Ahmed N, Kelleher D, Madan M, Sochart S, Antoniou GA. Carotid endarterectomy following thrombolysis for acute ischaemic stroke. VASA. Zeitschrift fur Gefasskrankheiten 2017;46:116-20. 31. Gunka I, Krajickova D, Lesko M, Renc O, Raupach J, Jiska S, et al. Safety of early carotid endarterectomy after intravenous thrombolysis in acute ischemic stroke. Ann Vasc Surg 2017;44:353-60. 32. Azzini C, Gentile M, De Vito A, Traina L, Sette E, Fainardi E, et al. Very early carotid endarterectomy after intravenous thrombolysis. Eur J Vasc Endovasc Surg 2016;51:482-6. 33. McPherson C, Woo D, Cohen PL, Pancioli A, Kissela B, Carrozzella J, et al. Early carotid endarterectomy for critical carotid artery stenosis after thrombolysis therapy in acute ischemic stroke in the middle cerebral artery. Stroke 2001;32: 2075-80. 34. Eckstein HH, Schumacher H, Dörfler A, Forsting M, Jansen O, Ringleb P, et al. Carotid endarterectomy and intracranial thrombolysis: simultaneous and staged procedures in ischemic stroke. J Vasc Surg 1999;29:459-71. 35. Endo S, Kuwayama N, Hirashima Y, Akai T, Nishijima M, Takaku A. Results of urgent thrombolysis in patients with major stroke and atherothrombotic occlusion of the cervical internal carotid artery. Am J Neuroradiol 1998;19:1169-75. 36. Ijäs P, Aro E, Eriksson H, Vikatmaa P, Soinne L, Venermo M. Prior intravenous stroke thrombolysis does not increase complications of carotid endarterectomy. Stroke 2018;49:1843-9. 37. Shalhoub J, Thapar A, Franklin I, Jenkins H, Davies A. Acute carotid endarterectomy after stroke thrombolysis appears safe but registry data is required. Conference proceedings, Association of Surgeons of Great Britain and Ireland (ASGBI). Br J Surg 2011;98:213. Submitted Feb 9, 2019; accepted May 25, 2019.
Carotid endarterectomy after systemic thrombolysis in a stroke population William Fortin, MD,a,b,c Miguel Chaput, MD, MSc,b Stephane Elkouri, MD, MSc,a Nathalie Beaudoin, MD,a and Jean-François Blair, MD,a Montreal, Quebec, Canada
ABSTRACT Objective: Vascular specialists are increasingly being requested to perform carotid endarterectomy (CEA) after intravenous thrombolysis (IVT) for stroke patients, raising concerns about hemorrhagic complications. Few case series and registry reports have assessed the question, and even fewer studies have included a control group. The aim of this study was to evaluate the overall outcome of patients undergoing CEA after IVT and to compare them with contemporary patients with CEA after simple stroke (non-IVT group). It also aimed to evaluate the differences in outcomes of stroke patients requiring CEA between nonvascular and vascular centers. Methods: The data of 169 consecutive patients who have undergone CEA after stroke in a single center was analyzed from January 2011 to December 2016, 27 of them (16%) having undergone previous IVT. A comparative analysis between the non-IVT and the IVT groups was performed. The time between stroke diagnosis and referral to a vascular specialist was also studied. Results: Age, sex, and cardiovascular comorbidities were similar in both groups. Median time between stroke and CEA was 13 days (Q1-Q3, 8-23 days), with 16 of the 27 patients (59%) in the IVT group undergoing CEA less than 14 days after the initial event. There were three intracranial hemorrhages (2.1%) in the non-IVT group versus one (3.7%) in the IVT group (P ¼ NS). The overall 30-day combined stroke and death rate was 7.1% (6.3% in the non-IVT group vs 11.1% in the IVT group; P ¼ .70). The incidence of postoperative cervical hematoma requiring reoperation was similar in both groups (2.1% vs 3.7%; P ¼ NS). The median time between diagnosis of stroke and referral to a vascular specialist was higher for patients in nonvascular centers compared with vascular centers (3.5 days vs 1.0 day; P < .001), which translated to fewer patients referred from nonvascular centers undergoing surgery in the 14-day window period (38% vs 67%; P < .001). Conclusions: In this retrospective analysis, CEA after IVT showed similar outcomes when compared with the overall CEA after stroke population. Stroke patients diagnosed in nonvascular centers were referred later than those in vascular centers and, although postoperative outcomes were similar, that was correlated with fewer patients undergoing surgery in a timely fashion. (J Vasc Surg 2019;-:1-6.) Keywords: Endarterectomy; Carotid; Intravenous thrombolysis; Thrombolytic therapy; Acute ischemic stroke; Stroke
Stroke represents the third leading cause of disability worldwide and its societal burden is expected to rise in the coming decades.1-3 One of the most important causes of stroke is carotid atherosclerotic disease, accounting for approximately 15% of all events.4 CEA has been performed for decades and has shown consistent risk reduction of ipsilateral stroke occurrence for symptomatic patients with significant carotid From the Division of Vascular Surgery, Centre Hospitalier de l’Université de Montréal (CHUM)a; the Division of Vascular Surgery, Hôpital MaisonneuveRosemontb; and the Faculty of Medicine, Université de Montréal.c Author conflict of interest: none. Presented at the Fortieth Annual Meeting of the Canadian Society for Vascular Surgery, Montreal, Quebec, Canada, September 28-29, 2018. Correspondence: Jean-François Blair, MD, Centre Hospitalier de l’Université de Montréal (CHUM), Division of Vascular Surgery, Montreal, QC, Canada H2W 1T8 (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214 Copyright Ó 2019 by the Society for Vascular Surgery. Published by Elsevier Inc. https://doi.org/10.1016/j.jvs.2019.05.061
atherosclerosis, regardless of the initial presenting symptom (amaurosis fugax, transient ischemic attack [TIA], or stroke).5-7 However, it has also been increasingly recognized that all symptomatic carotid disease does not present the same risk of ipsilateral stroke after CEA, with amaurosis fugax having the lowest risk, and stroke or crescendo TIA the highest.8 Historically, many surgeons would tend to delay CEA after significant neurologic symptoms (ie, stroke), although in the past decades an increasing body of literature has been suggesting that performing CEA in the first 14 days after initial symptoms might provide the best risk reduction of stroke occurrence in this particularly vulnerable population. Therefore, most expert medical societies recommend that CEA should be performed in this time period for all symptomatic patients.9,10 Intravenous thrombolysis (IVT) has shown considerable benefits in terms of mortality and morbidity in patients suffering from ischemic stroke when given in a timely manner.11 Although the half-life of alteplase is only 3 to 5 minutes, it has previously been demonstrated that patients undergoing thrombolytic therapy may show 1
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hematologic abnormalities lasting for several days.12 This observation has led to increasing concerns about the safety of carotid endarterectomy (CEA) after IVT.13 The current literature on the subject suggests that CEA after IVT is safe compared with CEA in overall symptomatic patients. However, with data showing significant differences between presenting symptoms and outcomes after CEA, comparing patients undergoing CEA after stroke with patients undergoing CEA after IVT and stroke could represent a more valid analysis. The goal of this study was to provide additional evidence about perioperative complications related to CEA performed after IVT in a comparable CEA poststroke population and to analyze if stroke patients with significant carotid disease had different outcomes whether the diagnosis was made in an academic hospital or its referring centers.
METHODS Stroke patients management. Patients presenting with symptoms of acute stroke were promptly evaluated by a neurologist and underwent confirmatory imagery and consequent treatment. Once acute ischemic stroke was confirmed, patients presenting with symptoms onset of less than 4.5 hours were considered for IVT, and a standardized protocol of Holter monitoring, cardiac echocardiography, and carotid duplex ultrasound examination in the first 48 hours after admission was initiated. CEA. CEA was performed by three different surgeons. Conventional eversion endarterectomy was performed in the vast majority of patients (168/169). The technique consists of a traditional longitudinal approach and careful dissection from the common carotid to the internal carotid distal to stenosis. After systemic anticoagulation is achieved, the internal carotid artery is then transected via an oblique incision at the bifurcation, and eversion endarterectomy is performed. Endarterectomy of the common and external carotid arteries is performed and the internal carotid artery is reattached to the bifurcation with a 6-0 Prolene running suture. Shunt use was rare in this series (4.1%), and the decision whether to use a shunt or not was left to the surgeon’s discretion on overall clinical and radiologic findings for each patient. Heparin reversal was performed routinely at the end of surgery. Data collection and patient selection. This study is a retrospective review of consecutive patients that underwent CEA after stroke in a single institution over a 5-year period, from January 2011 to December 2016. Patients from 2017 and 2018 were not included because protocol approval by local ethics committees and data collection was initiated earlier. All patients 18 years of age or older that underwent CEA after acute ischemic stroke diagnosed by a neurologist were included. All patients underwent CEA at the Centre Hospitalier de l’Université de Montréal (CHUM, Quebec, Canada), by 3 different
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ARTICLE HIGHLIGHTS d
d
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Type of Research: Single-center, retrospective cohort study Key Findings: Carotid endarterectomy (CEA) after intravenous thrombolysis was performed in 27 patients, and 30-day stroke and death rates were comparable with a similar cohort of 142 patients who underwent CEA after stroke. Time of referral for stroke patients from nonvascular hospitals to a vascular specialist were significantly longer than for patients diagnosed in vascular hospitals, which translated to less patients undergoing CEA in the 14-day window period. Take Home Message: CEA performed in patients who underwent prior intravenous thrombolysis for stroke shows similar results compared with patients undergoing CEA after stroke.
surgeons. Data regarding demographic factors, diagnostic modalities, percent stenosis, time to initial symptoms, IVT, and National Institute of Health Stroke Scale (NIHSS) scores (IVT patients), CEA, and referral to a vascular service, as well as perioperative and 30-day outcomes were collected. The study protocol was preapproved by the main local ethics committee (project no. 17.241). Primary and secondary end points. Primary end points consisted of the occurrence of postoperative intracranial hemorrhage (ICH), cervical hematoma requiring reoperation, and stroke and death rates. Secondary end points were combined stroke and death by center of referral, the time between initial stroke diagnosis and referral to a vascular specialist, and the time between initial stroke symptoms and surgery. Comparative analysis. A comparative analysis was performed between patients who received prior IVT and those who did not. A secondary comparative analysis was done between patients referred from an academic vascular center and patients referred from a peripheral hospital or a hospital without an in-house vascular service. Statistical analyses. Primary end points were expressed in rates, and compared using c2 tests with continuity correction when absolute event rates were lower than five. Time between stroke diagnosis and referral to a vascular specialist was compared using a median test because of skewed populations, and a multivariate logistical regression was used for the time between stroke diagnosis and CEA comparison. Pre- and post-IVT NIHSS scores were compared using paired t-tests. Post hoc analysis of cervical hematomas related to antiplatelet regimens was done using c2 tests.
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Table I. Baseline characteristics of study population (N ¼ 170): Stroke patients undergoing carotid endarterectomy (CEA) Characteristics
Non-IVT (n ¼ 142)
Table III. Postoperative neck hematomas and reoperation by perioperative antiplatelet regimen
IVT (n ¼ 27)
Male sex
90 (63)
18 (67)
Neck hematoma
Age, years
69 (41-94)
68 (37-85)
Neck hematoma þ reoperation
Active smoking Hypertension
72 (51)
11 (41)
102 (72)
17 (63)
Hyperlipidemia
97 (68)
14 (52)
Coronary disease
34 (24)
10 (37)
Atrial fibrillation
16 (11)
2 (7)
Previous stroke/TIA
19 (13)
4 (15)
Diabetes
40 (28)
7 (26)
None or ASA (n ¼ 114)
Clopidogrel or DAPT (n ¼ 44)
P value
14 (12.3)
6 (13.6)
.80
3 (2.6)
1 (2.3)
NS
ASA, Acetylsalicylic acid; DAPT, dual antiplatelet therapy. Values are presented as number (%).
Table IV. Management and timing of carotid endarterectomy (CEA) in stroke patients with significant carotid disease by type of medical institution
Degree of ipsilateral stenosis 50%-69%
28 (20)
5 (19)
70%-99%
112 (79)
22 (81)
2 (1)
1 (4)
Median time between stroke diagnosis and referral in days (Q1-Q3)
93 (66)
19 (70)
Stroke-to-CEA < 14 days
Antiplatelet therapya None ASA Clopidogrel
13 (9)
1 (4)
DAPT
25 (18)
5 (19)
ASA, Acetylsalicylic acid; DAPT, dual antiplatelet therapy; IVT, intravenous thrombolysis; TIA, transient ischemic attack. Values are presented as number (%) or mean (range). a At the time of surgery (nine missing values).
Table II. Perioperative (30-day) outcomes Overall (N ¼ 169)
Non-IVT (n ¼ 142)
IVT (n ¼ 27)
New stroke (all)
11 (6.5)
8 (4.7)
3 (11.1)
.53
ICH
4 (2.4)
3 (2.1)
1 (3.7)
NS
12 (7.1)
9 (6.3)
3 (11.1)
.70
4 (2.4)
3 (2.1)
1 (3.7)
NS
Combined stroke/death Neck hematoma þ reoperation
3
-
P value
ICH, Intracranial hemorrhage; IVT, intravenous thrombolysis. Values are presented as number (%).
RESULTS In the study period, of the 455 consecutive patients who underwent CEA at the institution for symptomatic disease, 169 (37%) had stroke as an initial diagnosis. Of this subpopulation, 27 (16%) received IVT before CEA. Demographic and preoperative data were similar between the non-IVT and the IVT groups (Table I). Most patients had severe (>70%) ipsilateral carotid stenosis and, although most patients were on acetylsalicylic acid alone at the time of surgery, around 20% were on dual antiplatelet therapy in both groups. Regarding the thrombolysis group, the mean time between stroke and IVT was 2.8 hours (range, 1.5-4.5 hours), and 16 (59%) had CEA in the 14-day window period. The median time between IVT and CEA was 8 days (Q1-Q3, 5-18 days). The mean
Vascular centers (n ¼ 85)
Nonvascular centers (n ¼ 71)
1.0 (0-3)
3.5 (2-7)
<.001
57 (67%)
29 (38%)
<.001a
P value
ASA, Acetylsalicylic acid; DAPT, dual antiplatelet therapy. Values are presented as number (%). a Adjusted for age, gender, and intravenous thrombolysis (IVT).
NIHSS score before and after IVT decreased from 12 to 5 (P < .001). The overall 30-day postoperative stroke and death rate was 7.1% in the study population, and was similar in both the non-IVT and IVT groups (Table II). Three patients (2.1%) suffered ICH in the non-IVT group, and one (3.7%) in the IVT group, which was not statistically significant. Of those, the three patients who underwent CEA alone had 4, 8, and 47 days, respectively, between the index event and surgery. ICH was diagnosed 24 to 120 hours postoperatively, with one patient presenting in a peripheral hospital without readmission to the main institution. The patient who suffered postoperative ICH in the IVT group had a massive hemispheric stroke at presentation, with minimal response to thrombolysis. After significant clinical improvement and several multidisciplinary discussions with the neurologic team, it was decided to proceed to CEA 15 days after the initial event. The patient developed ICH 2 days after surgery and subsequently died. Both the non-IVT and the IVT groups showed a similar rate of reintervention for cervical hematoma (2.1 vs 3.7%; P ¼ NS). A post hoc analysis was done, comparing patients on either no antiplatelet regimen at the time or surgery or only aspirin with patients on either clopidogrel or dual antiplatelet therapy (Table III). No significant differences were seen in terms of rates of neck hematomas or rates of reoperation secondary to a neck hematoma. Regarding the management of the stroke population with a significant ipsilateral carotid disease, the median time between stroke and endarterectomy was 13 days
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Table V. Current literature on carotid endarterectomy (CEA) after intravenous thrombolysis (IVT) Author
Year
No.
Endo et al18
1998
1
N/A
19
Median IVT-CEA, days
30-day stroke, No. (%) 0 (0)
ICH, No. (%) 0 (0)
Eckstein et al
1999
3
6
0 (0)
0 (0)
McPherson et al20
2001
5
2
0 (0)
0 (0)
Bartoli et al21
2009
12
8
Crozier et al22
2011
10
8
0 (0)
0 (0)
Shalhoub37
2011
6
N/A
0 (0)
0 (0)
23
1 (8.3)
1 (8.3)
Leseche et al
2012
7
6
0 (0)
0 (0)
Rathenborg et al24
2013
22
11
0 (0)
0 (0)
Barroso et al25
2013
4
N/A
0 (0)
0 (0)
Yong et al26
2013
7
7
1 (14)
1 (14) 0 (0)
27
Koraen-Smith et al
2014
71
10
2 (2.8)
Rathenborg et al28
2014
202
12
7 (3.5)
N/A
Vellimana et al29
2014
11
N/A
2 (18)
2 (18)
Bazan et al30
2015
25
9.5
0 (0)
0 (0)
31
Yamamoto et al
2016
1
0.5
0 (0)
0 (0)
Azzini et al17
2016
34
N/A
0 (0)
0 (0)
Ahmed et al16
2017
25
7.5
1 (4)
Gunka et al15
2017
13
2
1 (7.7)
N/A 0 (0)
ICH, Intracranial hemorrhage; N/A, not available. The median IVT-CEA is the median time between IVT and carotid endarterectomy; 30-days stroke is the ipsilateral stroke reoccurrence rate at 30-days after endarterectomy.
(Q1-Q3, 8-23 days), and 52% of the patients were operated in the 14-day window period. In this population, the vascular service received referrals from 10 different hospitals for CEA, 2 being academic vascular centers and 8 being nonvascular hospitals. The median time between stroke diagnosis and referral to a vascular specialist was 1.0 day in vascular and 3.5 days in nonvascular hospitals, and this difference in time to referral was associated with almost twice as many patients from academic centers undergoing CEA in the 14-day window compared with nonvascular centers (67 vs 38%; P < .001), even after adjustment for measurable confounding factors (Table IV). The 30-day stroke and death rate was not statistically different between patients referred from vascular and nonvascular centers (9.8% vs 5.5%; P ¼ .49).
DISCUSSION CEA after systemic thrombolysis has been a topic of interest for almost two decades. Currently, IVT is recommended for patients presenting with ischemic stroke with an initial symptom onset of less than 4.5 hours, but with the recent advent of mechanical thrombectomy (MT) for the management of acute ischemic stroke, the future role of IVT has been questioned.14,15 However, MT remains a tertiary care center treatment requiring specialized neuro-interventional teams and, therefore, many patients presenting with acute ischemic stroke would probably remain best treated with early thrombolytic therapy rather than later MT. Also, recent evidence
suggests that IVT and MT may fare better as a combination of treatments rather than either of the two entities being used alone, which reinforces the assumption that IVT is not about to disappear from the treatment algorithm of acute ischemic stroke management, and hence vascular specialists will keep being asked to proceed to CEA or carotid artery stenting for symptomatic carotid stenosis in patients who were previously treated with thrombolytic therapy.15-17 To the authors’ knowledge, 20 different groups have studied the combination of IVT and CEA in acute stroke patients, and most authors suggest that thrombolytic therapy seems to have little or no impact on postoperative complications after CEA (Table V).18-36 However, a recent registry database review by Vellimana et al29 including 551 patients undergoing CEA after IVT showed a higher rate of postoperative ICH in patients undergoing surgery less than 7 days after thrombolysis, compared with overall patients undergoing CEA or CAS, regardless of initial symptomatology. This finding suggests that patients receiving IVT before surgery fare worse than those who undergo CEA or CAS alone, and that it may be safer to wait 1 week before the two treatments. Yet, as noted by the authors in their article, their registry analysis did not account for patients’ presenting symptoms, hence leading to the possibility for their control group to include patients with atrial fibrillation or TIA. Indeed, most series had either no comparative group, or compared post-IVT patients that inevitably suffered
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from stroke to samples consisting mainly of patients experiencing amaurosis fugax or TIA.21,24,25,27,29,31,36 This study was designed to provide a more adequate comparative group of stroke patients undergoing CEA in the same center by the same surgeons. The results suggest that CEA after IVT in this context seems to be safe, with comparable postoperative stroke and death rates and similar hemorrhagic complication rates. Regarding the only patient who suffered ICH in the IVT group, he presented initially with a hemispheric stroke and underwent surgery more than 2 weeks after IVT. Whether thrombolysis was contributive or not to the bleeding in this context is rather questionable. In the light of the actual literature and the present study, the authors would tend to proceed to CEA in the 7- to 14-day window after IVT, excluding patients presenting with severe or hemispheric stroke. The overall stroke and death rate in this series is considerable (7.1%), but this could be better explained by the decision to select only stroke patients rather than by the institution itself. Indeed, Halm et al8 demonstrated, in a review of more than 9000 patients who underwent CEA, that patients presenting initially with stroke had postoperative stroke and death rate of 7.89%. Also, this study provides an analysis of the outcomes of stroke patients undergoing CEA, comparing vascular with nonvascular centers. It provides further evidence that patients diagnosed in peripheral nonvascular centers were referred later to a vascular specialist, which translated to fewer patients undergoing CEA in the optimal 14-day window. Multiple confounding factors could contribute to this finding, including the possible delay of treatment related to vascular specialist access, deferred transfers for patients coming from peripheral hospitals, and surgeons’ opinion on the safety of an early CEA for a given patient, but the correlation remains surprisingly strong. Although this research demonstrated that there was no difference in postoperative outcomes between the two groups, this observation remains concerning, because patients suffering from a stroke in peripheral centers remain at risk of reoccurrence for a longer period before undergoing definitive surgical treatment. Unfortunately, information about stroke reoccurrence in the time period between initial diagnosis and CEA was not reliable due to the study design, so the direct effect of delayed referrals on repeated stroke could not be measured. However, this sheds light on the importance of education of the different medical teams intervening in the management of stroke patients about the crucial role of timely CEA’s benefits on stroke reoccurrence. Another interesting observation is that academic vascular centers had “stroke protocols”, composed of the combination of Holter monitoring, transthoracic ultrasonography and carotid duplex ultrasound in the first 48 hours after the admission of all stroke patients. The implementation of these protocols
in all hospitals managing stroke patients might represent a simple way to standardize the diagnosis of ipsilateral carotid stenosis in these vulnerable patients, and could have the potential to reduce the time of referral to a vascular specialist. The limitations of this study include the absence of systematic coagulation assessments post-IVT, which restrains the understanding of potential hematologic abnormalities at the time of surgery. Also, by study design, only patients that underwent CEA at the main institution were included in the analysis, thus stroke patients that were evaluated for CEA but subsequently treated medically because they were considered too sick were not included, creating a potential selection bias. Another limitation of this research is its retrospective nature, making it prone to selection bias and the relatively small number of outcomes limiting its power. Nonetheless, this analysis is among the largest to include a contemporary control group.
CONCLUSIONS CEA after IVT seems to be safe and to provide comparable results compared with stroke patients undergoing CEA alone. Stroke patients with significant ipsilateral stenosis managed in nonvascular centers had delayed referral to a vascular specialist compared with those managed in vascular centers, which was correlated to less patients undergoing surgery in the 14-day window period, but showed similar postoperative outcomes.
AUTHOR CONTRIBUTIONS Conception and design: WF, JB Analysis and interpretation: WF, MC, SE, NB, JB Data collection: WF Writing the article: WF, MC Critical revision of the article: WF, MC, SE, NB, JB Final approval of the article: WF, MC, SE, NB, JB Statistical analysis: WF Obtained funding: Not applicable Overall responsibility: JB
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