Antiplatelets versus Anticoagulants in the Treatment of Extracranial Carotid and Vertebral Artery Dissection
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.266290
Source of Support: None, Conflict of Interest: None
Keywords: Anticoagulation, antiplatelets, extracranial dissection, outcome
Cervicocephalic arterial dissections account for 2% of all ischemic strokes and the proportion is considerably higher in stroke among the young reaching up to 20%.,,
Earlier studies concerning the risk of recurrent events after dissection have shown conflicting results: a few have suggested significantly increased risk of up to 15–20%.,, This recurrence is mostly due to thromboembolism from the dissection site, and hence, antithrombotic agents are the treatment of choice. However, the choice of antithrombotic agent is a matter of debate when one considers the differences in the safety and efficacy of antiplatelets and anticoagulants. Though efficacious, treatment with anticoagulants is associated with increased bleeding risk requiring regular monitoring and strict patient compliance compared to treatment with antiplatelets. Anticoagulants might prevent embolism from a fresh thrombus but can result in extension of the intramural hemorrhage, which occurs in one-third of the patients according to magnetic resonance imaging (MRI). Hence, the use of anticoagulants can be justified only if the efficacy significantly outweighs that of antiplatelets.
Very few studies including a single randomized controlled trial have compared the safety and efficacy of antiplatelets and anticoagulants in extracranial carotid and vertebral artery dissection, but they were done among European population.,, Studies have shown that patients of Asian ethnicity are at a greater risk of hemorrhage while receiving vitamin K antagonist therapy., Hence, the safety of antiplatelets versus anticoagulants in the western population may not be applicable in the Indian population. In addition, there is currently no role of anticoagulation in acute ischemic stroke of noncardioembolic etiology., Our study was undertaken to compare the safety and efficacy of antiplatelets and anticoagulants in the treatment of extracranial carotid and vertebral artery dissection and to investigate the predictors of outcome.
Prospectively collected data of radiologically proven cases of extracranial carotid and vertebral artery dissection admitted in the Stroke Unit, Comprehensive Stroke Care Program, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology from January 2005 to October 2015 were retrospectively analyzed. Inclusion criteria were age ≥18 years, a radiologically defined dissection, and treatment initiated within 48 hours of symptom onset. Patients with isolated intracranial dissection, subarachnoid hemorrhage, and baseline modified Rankin score (mRS) ≥3 were excluded from the study.
Records of 246 consecutive patients of extracranial dissection were reviewed, of which 46 were excluded if they did not meet the strict radiological criteria for dissection (n = 27) or were lost to follow-up at three months (n = 19). All patients underwent vessel imaging with either digital subtraction angiography (DSA)/computed tomographic angiography (CTA) or magnetic resonance angiography (MRA). Radiological features for the diagnosis of dissection were the flame-shaped tapering of the vessel, uniform narrowing of the vessel or the string sign, double barrel sign, pseudoaneurysm, or the presence of an intimal flap. According to the site of the dissection, the groups defined were carotid versus vertebral, unilateral vs bilateral, and those with dissection confined to the extracranial segments/extracranial dissection extending to intracranial compartment. Imaging studies performed at three-month/six-month follow-up were used to assess recanalization. When the imaging findings were normal, it was considered as complete recanalization; partial recanalization was considered if there was a residual stenosis. Demographic data, risk factors, and neurological evaluation including National Institutes of Health Stroke Scale (NIHSS) and modified Rankin scale (mRS) were documented. The type of initial presenting event [stroke, transient ischemic attack (TIA), or local symptoms] and the severity of the initial event assessed by NIHSS at admission were noted. All 200 patients were initially managed with either antiplatelets or anticoagulants at the discretion of the treating neurologist. At the three-month follow-up, all patients on single antiplatelet were continued on the same and those on dual antiplatelets or anticoagulants were changed to single antiplatelet except in 7 patients. Oral anticoagulants were continued in 2 patients who had metallic heart valve in situ, and 5 patients with ischemic heart disease were continued on dual antiplatelets. Follow-up was done after three and six months by neurological examination, including mRS score assessment by a neurologist. Excellent outcome was defined as mRS ≤ 2. Patients who developed recurrent ischemic or hemorrhagic events within the same time frame were also assessed in detail both clinically and using imaging studies. Primary outcome measures were recurrent ischemic events in the form of stroke or TIA and symptomatic intracranial hemorrhage. Secondary outcomes were major extracranial hemorrhage or death. TIA was defined as an acute onset transient neurological deficit attributed to focal ischemia of the brain or retina lasting for less than 24 hours. Stroke was defined as an acute onset focal neurological deficit confirming to a vascular territory lasting more than 24 hours. SICH was defined as radiological evidence of appropriately located intracranial bleed with neurologic deterioration of ≥ 4 points in NIHSS. Major extracranial bleeding was defined as clinical bleeding with a drop in hemoglobin by at least 2 g/dl or necessitating transfusion of two or more units of red cells.
All statistical analysis was performed using SPSS version 17 software. Continuous variables were expressed as mean ± SD. Categorical variables were reported as proportions. Baseline characteristics were compared between the antiplatelet and anticoagulant group. Differences in continuous variables were assessed by one-way analysis of variance, and differences between proportions were assessed by the Chi-square test. The incidence of ischemic and hemorrhagic complications in dissection patients in the two treatment groups was studied. The predictors of outcome were assessed using univariate and multivariate analysis. Chi-square test was used to compare the efficacy and safety of antiplatelets vs anticoagulants in the treatment of dissection. Significance was declared at P ≤ 0.05.
Two hundred patients with spontaneous extracranial carotid and vertebral artery dissection were retrospectively studied. The mean age of the patients was 43.48 ± 13.08 years, and 76.5% of the patients were males. The presenting symptom was stroke in 74.5%, TIA in 18.5%, and local symptoms in 7% of the patients. One hundred and thirty-two patients (66%) had carotid artery dissection, and 68 patients (34%) had vertebral artery dissection. Fourteen patients (7%) had bilateral dissection. One hundred and forty-seven patients (73.5%) had dissection confined to extracranial carotid or vertebral arteries while 53 patients (26.5%) had dissection in the extracranial arteries extending to the intracranial compartment. Sixty-four patients (32%) were treated with anticoagulation alone and 136 patients (68%) with antiplatelets alone. The demographic and clinical details are shown in [Table 1].
At the three-month follow-up, 106 (53%) patients had an excellent outcome (mRS, 0–2) and mortality at three months was 1% (2 patients). Thirty-nine (60.9%) patients in the anticoagulant group and 67 (49.3%) patients in the antiplatelet group had an excellent three-month outcome (P = 0.123). Multivariate analysis of the predictors of outcome revealed that the only significant predictors of three-month outcome were the initial presenting event and the severity of the initial event, as assessed by the NIHSS at admission [Table 2].
At the three-month follow-up, ischemic events occurred in 7 (3.5%) patients, 3 (1.5%) with stroke and 4 (2%) with TIA. Six (4.41%) patients in the antiplatelet group and 1 patient (1.56%) in the anticoagulant group had recurrent ischemic events (P = 0.434). Symptomatic intracranial hemorrhage occurred in 11 (5.5%) patients of whom 6 were on anticoagulants and 5 on antiplatelets (P = 0.185). Symptomatic hemorrhagic transformation of the infarct occurred within 2 weeks of the initial symptom in 9 of the 11 patients, and in 2 patients, 6 weeks after the initial event. Two patients died during the three-month follow-up. One patient had a malignant left MCA stroke secondary to left ICA dissection and developed symptomatic hemorrhagic transformation while on single antiplatelet resulting in death on day 10. Another patient had a left MCA stroke following left ICA dissection and succumbed 57 days later following anticoagulant-induced right parietooccipital bleed with intraventricular extension. [Table 3] shows the comparison of the recurrent events in the two treatment groups.
During the three–six-month follow-up of the 198 patients, 119 (60.1%) had excellent outcome. The most important predictor of six-month outcome was the initial presenting event. Seven (3.53%) patients had recurrence of ischemic events, of whom 6 (3.03%) patients had stroke and one (0.51%) had TIA. All recurrent ischemic events occurred in the territory supplied by the artery initially involved by dissection.
In our study of 200 patients with extracranial carotid and vertebral artery dissection, 53% had excellent outcome and mortality was 1% during the three-month follow-up. Recurrent ischemic events occurred in 7 (3.5%) patients. This was comparable with the results of the CADISS trial, in which 4 (2%) of 250 patients had stroke recurrence, the study involving 298 patients of cervical carotid artery dissection by Georgiadis et al. where 0.3% had ischemic stroke and 3.4% had TIA, and the study involving 99 patients of vertebral artery dissection where only a single patient (1%) had recurrent ischemic event. Symptomatic intracranial hemorrhage occurred in 11 (5.5%) patients in our study, which was significantly more than that compared to a single patient (0.4%) in the CADISS trial, 2 patients (0.7%) in the study by Georgiadis et al., and none in the study on vertebral artery dissection by Arauz et al.
There was no significant difference in the safety and efficacy of antiplatelets versus anticoagulants in our study. Six patients in the antiplatelet group and in one patient in the anticoagulant group had recurrent ischemic events (P = 0.434). This was comparable to the CADISS trial where stroke occurred in 2% of the patients on antiplatelets versus 1% on anticoagulants (P = 0.63), as well as the study by Georgiadis et al. in which 5.9% of the patients on anticoagulants and 2.1% on aspirin developed ischemic events (P = 0.1). However, though not statistically significant, our study observed that bleeding risk was more in patients on anticoagulants. In our study, 6 patients (9.4%) on anticoagulants versus 5 (3.7%) on antiplatelets had symptomatic intracranial hemorrhage (P = 0.185). This lack of statistical significance may be due to the overall lower number of bleeds in our study population. In the CADISS trial and in the study on carotid artery dissection by Georgiadis et al., it was 1% in the anticoagulant group versus 0 in the antiplatelet group. This increase in bleeding risk with anticoagulants may be attributed to the fact that patients of Asian ethnicity are at a greater risk of hemorrhage while receiving vitamin K antagonist therapy., This demonstrates a need for caution when regarding anticoagulation in patients with dissection, especially those with more severe strokes who are at a higher risk of bleeding. However, the presence of intramural thrombus or a free-floating thrombus would warrant the use of anticoagulants to prevent embolization that may occur during recanalization of the thrombus. But in early cases with minimal vessel wall injury, antiplatelets may be used to prevent platelet aggregation and thrombus formation. A recent study by Li et al. concluded that antiplatelet therapy is an effective treatment for vertebral artery dissection. The selection of treatment regimens should depend on the clinical manifestations and imaging findings in patients.
Multivariate analysis in our study revealed that stroke as the initial presenting event and the severity of stroke as assessed by NIHSS at admission were the only significant predictors of the three-month outcome. These findings were consistent with the data from the only randomized trial  as well as observational studies,, suggesting that these groups are at the highest risk of recurrent events. Hence, dissections presenting with local symptoms alone have a benign course and those presenting initially with stroke have a higher risk of recurrent events a worse outcome.
Our study has shown that the frequency of recurrent ischemic events and that of treatment-related adverse effects did not differ significantly based on the antithrombotic medication used and that there was no significant difference in the safety or efficacy of these two treatments, thus favoring the use of antiplatelets as they are cheaper and their use less cumbersome for patients or providers? Hence, as proposed in the meta-analysis on antiplatelets versus anticoagulants in cervical artery dissection, anticoagulants are better avoided in severe strokes, (i.e. with NIHSS score ≥15), accompanying intracranial dissection, local syndromes alone without stroke/TIA, concomitant diseases with increased bleeding risk, and insufficient intracranial collaterals.
The strengths of our study are that it included only clinicoradiologically definite cases of dissection. The study population included 200 patients, three- and six-month follow up along with meticulously recorded outcomes. Hence, the chance of missing a recurrent ischemic event such as TIA/stroke was very remote. Furthermore, our study is relevant to the treatment and prognosis of extracranial carotid and vertebral artery dissection in the Asian population whereas all previous studies have been conducted in the western population.
Our study has obvious limitations. First, our treatment allocation was in a nonrandomized pattern. Second, the choice between antiplatelet and anticoagulant drugs was at the discretion of the clinician and allocation to treatment changed over time, with patients in the early years of the study being treated with anticoagulation and recent patients with antiplatelets. Third, the disease heterogeneity in the form of the variable presenting event and vessel involved might have caused different groups to respond differently to treatments. We also excluded patients who did not have a three-month outcome, which might have led to exclusion of patients with severe disability and patients with good outcome who did not come for review.
The risk of recurrent events in carotid and vertebral artery dissection is low. Antiplatelets and anticoagulants are equally effective in preventing recurrent ischemic events in patients with extracranial carotid and vertebral artery dissection. Though not statistically significant, SICH was significantly higher in the anticoagulant group. Stroke as the initial presenting event and severity of stroke are the only significant predictors of a poor three-month outcome.
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[Table 1], [Table 2], [Table 3]