Recanalization and Outcome After Intra-Arterial Thrombolysis in Middle Cerebral Artery and Internal Carotid Artery Occlusion
Does Sex Matter?
Background and Purpose— Recent studies have reported sex differences in recanalization and outcome after intravenous thrombolysis (IVT) in acute ischemic stroke.
Methods— We analyzed sex differences in outcome in consecutive patients with middle cerebral artery (MCA) M1 or M2 and internal carotid artery (ICA) occlusion treated with intra-arterial thrombolysis (IAT). Recanalization immediately after thrombolysis and outcome after 3 months were assessed.
Results— Two hundred five patients (111 men) with MCA and 43 (22 men) with ICA occlusion were identified. Baseline variables did not differ between the sexes except for a higher prevalence of smokers among men in the MCA group (31% vs 12%; P=0.001). Partial or complete recanalization (TIMI flow 2 or 3) of the MCA was observed in 71 (75%) women and 80 (72%) men (P=0.488). In the ICA group, 14 (67%) women and 11 men (50%) showed TIMI 2 or 3 recanalization (P=0.425). Favorable outcome (modified Rankin Scale score 0 to 2) was seen in 57 women (61%) and 63 men (57%) with MCA occlusion (P=0.512) and in 6 women (28%) and 4 men (18%) with ICA occlusion (P=0.656). After multiple-regression analyses, there was still no association between sex and outcome (P=0.763 for MCA and P=0.813 for ICA occlusion) or recanalization (P=0.488 for MCA and P=0.104 for ICA occlusion).
Conclusions— There was no association between sex and recanalization or outcome after IAT. These findings are in contrast to previous studies reporting better recanalization and outcome after IVT in women and might have implications in the selection of patients for IAT or IVT.
Stroke is a major health issue in women and men. The prevalence of stroke and institutionalization and death rates are higher in women despite a lower incidence but because of their longer life expectancy.1–3 In recent studies, sex-based differences have been observed with respect to clinical presentation, management, and clinical outcomes of stroke of all subtypes.4–6 Sex-based differences in coagulation and fibrinolysis in acute ischemic stroke have been described.7,8
In a pooled analysis of intravenous thrombolysis (IVT) with recombinant tissue-type plasminogen activator (rt-PA) in acute ischemic stroke, women derived a greater benefit than men, independently of other variables.9 Another study reported sex differences in recanalization rates after IVT in acute stroke patients with middle cerebral artery occlusion (MCAO).10 A recent study reported no sex-specific differences in angiographic recanalization and clinical outcome after intra-arterial thrombolysis (IAT) with urokinase or rt-PA in anterior and posterior circulation ischemic stroke.11 However, the lack of sex differences in that study might be explained by the modest sample size. Therefore, we aimed to determine sex differences in a large, homogeneous series of patients with MCA main stem (M1) or main branch (M2) or internal carotid artery (ICA) occlusion who were treated with IAT.
Patients and Methods
This study was based on the Bernese Stroke Data Bank, which is a systematic, prospective registry of consecutive patients with ischemic stroke admitted to a university hospital–based tertiary stroke center. We reviewed our patients with angiographically documented M1 or M2 MCAO, ICAO, or internal carotid T occlusion (ICAT) who underwent IAT within 6 hours of ischemic stroke symptom onset. An ICAT occlusion was diagnosed when the intracranial ICA, the ipsilateral MCA, or the ipsilateral A1 segment of the anterior cerebral artery was occluded. After exclusion of intracranial hemorrhage as the cause of stroke or other nonischemic causes for the neurologic deficits by computed tomography (CT) or magnetic resonance imaging scans, diagnostic cerebral 4-vessel digital subtraction arteriography was performed. When arteriography revealed an arterial occlusion corresponding to the clinical symptoms, patients underwent IAT with 500 000 to 1 250 000 IU urokinase (urokinase HS Medac) over 60 to 90 minutes.
Clinical and radiologic data for some of these patients, inclusion and exclusion criteria, and the technique used for IAT have been published previously.12,13 In brief, IAT was performed when (1) a diagnosis of ischemic stroke was established; (2) the baseline National Institutes of Health Stroke Scale (NIHSS) score was ≥4 points or isolated hemianopia or aphasia was present; (3) the time of symptom onset was clearly defined; (4) treatment could be initiated within 6 hours of symptom onset; and (5) the patient or his/her family consented to arteriography and potential thrombolysis.
The following stroke risk factors were assessed: sex, hypertension (defined by preadmission history and medical records), diabetes mellitus (defined by a venous plasma glucose concentration of ≥7.0 mmol/L after an overnight fast on at least 2 separate occasions and/or ≥11.1 mmol/L 2 hours after oral ingestion of 75 g glucose and on 1 other occasion during the 2-hour test or a history of treated diabetes mellitus), current cigarette smoking, and hypercholesterolemia (defined as total venous plasma cholesterol concentration ≥5 mmol/L or a history of treated hypercholesterolemia).
All patients were evaluated by a neurologist immediately after admission, and stroke severity was determined according to the NIHSS score.14 The degree of vessel recanalization was determined by control arteriography immediately after IAT and was classified by a neuroradiologist according to Thrombolysis in Myocardial Infarction (TIMI) grades: TIMI 0=no recanalization, TIMI 1=minimal recanalization, TIMI 2=partial recanalization, and TIMI 3=complete recanalization.15 In 1 woman, recanalization could not be classified because of insufficient image quality. The TOAST classification was used to determine the etiology of stroke.16 Clinical follow-up information was obtained through neurologic examination (n=207) or a structured telephone interview (n=40) by a neurologist 3 months after the onset of stroke symptoms. The modified Rankin Scale score (mRS) was recorded.17 One female patient was lost to follow-up.
Statistical analysis was performed with SPSS 10.0 for MacIntosh statistical software (SPSS Inc). For sex differences in categorical variables, χ2 tests were performed. For comparisons of mean age between men and women, Student’s t test was used. Other continuous variables were compared with the Mann-Whitney U test. The following variables were analyzed separately for MCAO (M1 and M2) and ICA occlusion (ICAO and ICAT occlusion): hypertension, diabetes, hyperlipidemia, smoking, NIHSS on admission, stroke etiology, time from symptom onset to thrombolysis, early ischemic signs on CT scan, dense-artery sign on CT scan, intracerebral hemorrhage, vessel recanalization, and clinical outcome at 3 months. For comparison of recanalization, we divided patients into 2 groups. Patients with TIMI grades 2 and 3 were classified as those with “sufficient recanalization,” and patients with TIMI grades 0 and 1 were classified as those with “insufficient recanalization.” For analyses of clinical functional outcome, we divided patients into 2 groups of favorable (mRS score 0 to 2) and unfavorable outcome or death (mRS score 3 to 6). Then, multiple-regression analysis with a forward-stepwise method was performed.
Presenting Characteristics, Risk Factors, and Clinical Findings
A total of 205 consecutive patients with M1 or M2 occlusions of the MCA (111 men, 54%) and 43 patients with ICAO (22 men, 51%) were treated with IAT. Their mean±SD age was 61±13 years in the MCA group and 60±12 years in the ICA group.
Demographic and clinical data and vascular risk factors of both sexes are shown in Tables 1 and 2⇓. Age, initial stroke severity (NIHSS score), time from symptom onset to treatment, stroke etiology, early CT signs of ischemia, type of MCA or ICA occlusion, and hemorrhagic complications did not differ significantly between women and men. The prevalence of vascular risk factors was similar in both groups except for tobacco use in the MCA group, which was more common among men (P=0.001).
Vessel Recanalization, Bleeding Complications, and Clinical Functional Outcome
Vessel recanalization rates determined by arteriography immediately after IAT did not differ significantly between women and men: Partial or complete recanalization (TIMI 2 or 3) was achieved in 71 of 93 (76%) women and 80 of 111 (72%) men (P=0.488) with MCA occlusion. In the ICA group, 14 of 21 (67%) women and 11 of 22 men (50%) showed TIMI 2 or 3 recanalization (P=0.425). Complete recanalization (TIMI 3) occurred in 19 (20%) women and 20 (18%) men with MCAO (P=0.663) and in 1 woman (5%) and none of the men with ICAO (P=0.981). Table 3 shows vessel recanalization status according to the location of vessel occlusion. Symptomatic intracranial hemorrhage occurred in 5 (5%) women and 7 (6%) men with MCAO (P=0.764) and in 2 men (9%) and 2 women (9%) with ICAO (0=0.961).
mRS scores at 3 months for men and women are shown in Figures 1 and 2⇓. Favorable outcome (mRS 0 to 2) after 3 months was seen in 57 of 93 (61%) women and 63 of 111 (57%) men with MCAO (P=0.512) and in 6 women (28%) and 4 men (18%) with ICAO (P=0.656). Mortality at 3 months in the MCA group was 16% (18 of 111 men) in male patients and 9% (8 of 93 women) in female patients (P=0.104). In the ICA group, 10 men (45%) and 6 women (27%) had died after 3 months (P=0.252). After multiple-regression analyses, there was still no association between gender and outcome (P=0.763 for MCAO and 0.813 for ICAO) or recanalization (P=0.488 for MCAO and 0.104 for ICAO).
In this study of 248 patients with acute ischemic anterior circulation stroke after M1 or M2 MCAO or ICAO, there was no sex difference in the angiographic recanalization rate and clinical outcome after IAT. These results are in line with the data of a previous smaller study, which found no differences in recanalization rates in 40 women and 41 men with anterior or posterior circulation ischemic strokes treated with intra-arterial urokinase or rt-PA.11
In our study, demographic and clinical variables were similar in both sexes except for more smokers among men in the MCA group. In addition, we included only patients with MCA M1 or M2 or ICAO in this study and performed separate analyses for each vessel to have a homogeneous patient populations. Data were collected prospectively, the sample size is large, and analysis of recanalization and clinical follow-up examinations were performed by neurologists and neuroradiologists who were not aware of the aim of the study. Nevertheless, as with every observational study, we cannot exclude with certainty potentially unknown confounders, which might have influenced our result of no sex differences. The recently published sex differences on the effect of IAT in the Prolyse in Acute Cerebral Thromboembolism (PROACT)-2 trial do not contradict our results. In PROACT-2, there were no differences in complete or partial vessel recanalization immediately after thrombolysis, as in our study. The sex-by-treatment interaction in PROACT-2 with women showing a larger treatment effect was mainly caused by the fact that IAT nullifies the worse outcome for untreated women compared with men.18
Our data indicating no sex-specific effect of IAT are in contrast with previous studies of intravenous rt-PA, which showed differences of outcome in women and men. In a pooled analysis of the National Institute of Neurological Disorders and Stroke (NINDS) trial, the Second European Cooperative Acute Stroke Study (ECASS II), and Alteplase Thrombolysis for Acute Non-interventional Therapy in Acute Ischemic Stroke (ATLANTIS) trial, IVT was more effective in women than men, independently of other variables.9 However, that analysis did not include data on the localization of stroke and the type of vessel occlusion. This may be 1 of the reasons for the discrepancy with the results of the present study. Another study reported higher complete or partial recanalization rates (94% vs 59%, P=0.02) as determined by magnetic resonance angiography or CT angiography after IVT in women with acute large-artery, anterior-circulation strokes.10
Potential sex-dependent differences of the response to IVT and IAT are difficult to explain. First, a smaller diameter of the intracranial arteries in women may result in smaller clot volumes and explain the higher likelihood of recanalization in women after IVT, despite lower local concentrations of the fibrinolytic agent.19,20 Second, sex-based differences in coagulation and fibrinolysis among patients with acute ischemic stroke have been described and might have a different impact in IVT compared with IAT. Third, estrogens have been shown to have a neuroprotective effect in animal models.21,22 Finally, a recent report has shown a trend that women are less likely than men to receive IVT, suggesting that selection bias may be a potential confounder.23
In conclusion, our results do not indicate any association of sex, vessel recanalization, and clinical outcome after IAT. These findings are in disagreement with previous studies reporting higher recanalization rates and better outcomes after IVT in women and might have implications for the selection of patients for IAT or IVT. Future research on thrombolysis should include sex-specific analyses.
- Received August 31, 2006.
- Revision received October 27, 2006.
- Accepted November 6, 2006.
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