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(Stroke. 2005;36:1447.)
© 2005 American Heart Association, Inc.

Original Contributions

Arterial Occlusive Lesions Recanalize More Frequently in Women Than in Men After Intravenous Tissue Plasminogen Activator Administration for Acute Stroke

Sean I. Savitz, MD; Gottfried Schlaug, MD, PhD; Louis Caplan, MD Magdy Selim, MD, PhD

From the Division of Cerebrovascular Disease, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass.

Correspondence to Magdy Selim, MD, PhD, Department of Neurology, Division of Cerebrovascular Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Palmer 127, Boston, MA 02215. E-mail mselim{at}bidmc.harvard.edu

	Abstract

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Background and Purpose— Previous reports suggest that women achieve better outcome than men after intravenous thrombolysis for ischemic stroke. Coagulation and fibrinolysis differ between sexes. These findings prompted us to investigate possible gender differences in arterial recanalization after intravenous tissue plasminogen activator (IV tPA).

Methods— We identified 100 consecutive patients who presented with acute ischemic stroke and received IV tPA within 6 hours of onset. Only patients with large artery anterior circulation strokes, as determined by MRI/MRA or CT/CTA before treatment, who had follow-up vascular study within 72 hour after treatment were included. We compared demographics, clinical features, admission medications, symptom-to-needle and treatment-to-repeat vascular imaging times, baseline National Institutes of Health Stroke Severity score, radiological and laboratory data, stroke mechanism, and outcome between the sexes.

Results— 39 patients met all inclusion/exclusion criteria (22 men and 17 women). The recanalization rate was significantly higher in women (94% versus 59%; P=0.02). This difference remained statistically significant after excluding patients whose strokes were attributed to internal carotid artery occlusive lesions, and when the analysis was limited to those treated within 3 hours of stroke onset. All other confounding variables did not differ significantly between the sexes.

Conclusions— In our cohort, vascular occlusive lesions were more likely to recanalize in women than men in response to IV tPA. These preliminary findings need to be validated in larger prospective studies.

Key Words: gender • outcome • stroke • thrombolysis

	Introduction

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A pooled analysis of 2178 patients who participated in the National Institute of Neurological Disorders and Stroke (NINDS) study,¹ the Second European Cooperative Acute Stroke Study (ECASS II),² and Alteplase Thrombolysis for Acute Non-interventional Therapy in Acute Ischemic Stroke (ATLANTIS) trial³ showed that women, treated with intravenous (IV) tissue-plasminogen activator (tPA) within 6 hours of stroke onset had better functional outcome after 90 days compared with men.⁴ Age, conventional risk factors, stroke severity, symptom-to-needle time, blood pressure, and extent of hypoattenuation on baseline computed tomography did not account for this gender-dependent differential functional outcome.⁴

Early recanalization after thrombolysis is associated with better clinical outcome by salvaging penumbral brain tissue.^5–6 Gender differences in coagulation and fibrinolysis have been reported in acute ischemic stroke and other vascular disorders.^7–8 Such differences could theoretically influence arterial recanalization resulting from treatment with tPA and affect functional outcome after ischemic stroke. The cerebral vasculature was not routinely evaluated after tPA administration to assess for successful recanalization in any of these trials. Therefore, we aimed to investigate if treatment with IV tPA within 6 hours of ischemic stroke onset results in a higher frequency of arterial recanalization in women than in men.

	Materials and Methods

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Study Design and Patient Selection
We reviewed our prospectively collected stroke database and identified 100 consecutive patients treated with thrombolysis within 6 hours of ischemic stroke symptom onset. Patients treated between 3 to 6 hours after stroke onset (n=13) were part of 2 experimental trials using typical IV tPA dosing in the extended time window; no preselection was applied. We included only patients who received standard IV tPA for a stroke within the vascular distribution of an imaging-documented occlusion of the internal carotid artery (ICA), middle cerebral artery (MCA), or both (ICA/MCA), and who had a repeat vascular study within 72 hours after tPA. Each patient received 0.9 mg/kg of IV tPA (maximum 90 mg) according to the NINDS guidelines.¹ Patients were excluded if they had a small vessel or posterior circulation stroke (n=6) or arterial dissection (n=3), if they received intra-arterial (IA) tPA (n=15) or other experimental thrombolytic or neuroprotective therapies (n=5), if they did not have a vascular imaging study before treatment (n=5) or a vascular occlusion of a major cerebral vessel on imaging (n=5), or if they did not have a follow-up vascular study (n=22).

Data Collection and Clinical Evaluation
We retrieved the following data for each patient: (1) demographics; (2) risk factors for stroke (hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease [CAD], atrial fibrillation, and smoking); (3) admission blood pressure (BP) and temperature; (4) blood glucose, basic coagulation parameters, and hematocrit levels at admission; (5) medications on admission, with particular attention to antiplatelets, anticoagulants, lipid-lowering agents, and estrogen replacement therapy (HRT); (6) the National Institute of Health Stroke Scale (NIHSS) score¹ at baseline and within 72 hours of tPA administration, as recorded by stroke-trained neurologists certified in its application; (7) stroke-onset-to-treatment time; (8) treatment-to-repeat vascular imaging time; (9) radiological data; (10) length of hospitalization (LOH); (11) discharge status; and (12) functional status at discharge and 30 to 45 days, as assessed by modified Rankin scale (mRS).

Imaging
Either brain MRI or CT scans were used to determine the presence of an anterior circulation stroke or to exclude hemorrhage before administering tPA. The presence of large artery occlusion was assessed by MRA or CTA. All patients who were treated between 3 and 6 hours after stroke onset (n=13) had MRI/MRA with diffusion-weighted and perfusion-weighted imaging (DWI/PWI). An experienced researcher, blinded to patient’s identity, measured the volumes of DWI lesions. Specific sequence details of MRI/MRA and CT/CTA and volumetric measurements have been previously described.^9,10

We used a thrombolysis in myocardial infarction (TIMI) flow grades-derived scale^11,12 to assess the presence and degree of arterial recanalization on post-treatment MRAs/CTAs. One neuroradiologist, blinded to clinical history, interpreted the images. A vessel was considered not recanalized if no flow signal was detected (TIMI0); partially recanalized if a minimal flow signal was seen beyond the area of arterial occlusion, but not in most of the vascular bed distal to it (TIMI1) or if a more robust, but incomplete, flow signal was seen beyond the occlusion site and the distal vascular bed (TIMI2); and completely recanalized if a flow signal of normal intensity was detected on MRA/CTA (TIMI3).¹¹ Five patients had transcranial Doppler (TCD) studies within 72 hours after tPA. Insonation of the intracranial vessels was obtained as described by Aaslid et al.¹³ An experienced ultrasonographer used the parameters described by Demchuk et al¹⁴ for the grading of a normal, narrowed, or occluded vessel.

Assessment of Degree of Functional and Neurological Recovery
We determined neurological improvement, defined as a decrease of 4 points in the NIHSS within 72 hours after tPA compared with the baseline NIHSS. We allocated patients on discharge to 1 of 4 categories: patients returned home with or without services, transferred to an acute rehabilitation facility, transferred to a chronic care facility, or died in-house. In addition, mRS scores were collected on discharge and at 30 to 45 days.

Statistical Analysis
Patients were divided into 2 groups based on their sex. Data are summarized as mean±SD or percentages, as appropriate. Statistical significance for intergroup differences was assessed by Student t test for continuous variables and Fisher exact test for categorical comparisons. P<0.05 was regarded significant.

	Results

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Patient Characteristics (Demographic and Clinical Features)
Thirty-nine patients met all inclusion/exclusion criteria: 17 women (44%) and 22 men (56%) were treated with IV tPA within 6 hours of a stroke secondary to a documented stenosis or occlusion of the ICA plus MCA or the MCA alone. Table 1 lists demographics and clinical features. There were no significant differences between men and women in any of these variables. The majority of our patients were whites and had a higher median age (73 years) compared with NINDS, ATLANTIS, and ECASS II trials’ cohorts. Only 1 woman was using HRT before stroke onset. A lower percentage of women were using antiplatelets and statins, compared with men, at the time of stroke onset. These differences were not significant. All patients who were using warfarin at stroke onset had a subtherapeutic international normalization ratio (INR). Two women (12%) and 3 men (14%) were started on intravenous heparin before their repeat vascular imaging.

View this table: [in this window] [in a new window]   TABLE 1. Demographics and Baseline Clinical Features

Table 2 summarizes imaging findings, stroke mechanism, NIHSS, and symptom-to-needle time. There were no significant differences in any of these variables. Thirty-seven patients (16 women and 21 men) had MRI/MRA and 2 patients (1 man and 1 woman) had CT/CTA at baseline. Five patients (2 women, 3 men) had TCD after treatment with tPA. The mean time from tPA administration-to-repeat vascular study was 36±20 hours in women and 27±18 hours in men (P=0.14, t-test).

View this table: [in this window] [in a new window]   TABLE 2. Radiological Data, Stroke Mechanisms, and Time Parameters

Outcomes
The recanalization rate for MCA and ICA/MCA occlusive lesions was 94% (59% complete; 35% partial) in women versus 59% (36% complete; 23% partial) in men (P=0.02, Fisher exact test). This gender difference in recanalization remained statistically significant even after excluding patients whose strokes were attributed to ICA/MCA occlusive lesions (5 women and 9 men). The recanalization rate in women with isolated MCA occlusive lesions was 100% (67% complete; 33% partial) versus 61% (54% complete; 7% partial) in men (P=0.02). Table 3 lists the degrees of recanalization according to TIMI grades.

View this table: [in this window] [in a new window]   TABLE 3. Recanalization Status According to TIMI Grades

Results were similar when the analysis was limited to the subgroup of patients who received tPA within 3 hours from stroke onset (11 women and 15 men). The overall recanalization rate was 100% in women (TIMI3=64%; TIMI2=27%; TIMI1=9%) versus 60% in men (TIMI3=40%; TIMI2=20%; P=0.02). Again, the difference in recanalization remained statistically significant after excluding patients whose strokes were attributed to ICA/MCA occlusive lesions (2 women and 6 men), in which 100% of women recanalized versus 55% of men (P=0.03).

Twelve women (71%) and 17 men (77%) had their vascular imaging repeated within 24 hours of tPA administration. In this subgroup, the recanalization rate for MCA and ICA/MCA occlusive lesions was also 100% in women (TIMI3=60%; TIMI2=20%; TIMI1=20%) versus 55% in men (TIMI3=33%; TIMI2=22%; TIMI0=45%; P=0.01).

As Table 2 indicates, there were no significant differences in mean baseline DWI lesion volumes between women and men. Women had smaller lesion volumes on scans after tPA, but this difference was not statistically significant.

Seventy percent of women (12/17) showed neurological improvement, defined as a decrease of 4 points on NIHSS within 72 hours of treatment with tPA, compared with 36% (8/22) of men (P=0.04). The mean LOH for women was 7±3 days (range 3 to 17) versus 7±4 days (range 3 to 21) for men (P=0.9, t-test). Forty-one percent of women versus 27% of men were discharged home (P=0.5), whereas more men died in hospital (27% versus12%; P=0.4). With regard to patients’ functional outcome, 65% of women and 36% of men had a mRS 2 (P=0.05) on discharge. Seven patients (3 women and 4 men) were lost to follow-up after discharge. Among the remaining subjects, 67% of women versus 43% of men (P=0.3) had a comparable mRS at 30 to 45 days.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
In this cohort of stroke patients, arterial recanalization after IV tPA for anterior circulation strokes was more frequent among women than men despite comparable age, blood pressure, symptom-to-needle time, and stroke mechanism. In addition, neurological improvement within 72 hours of treatment occurred significantly more frequently in women.

Several anatomical, pathophysiological, and biochemical factors could potentially account for the observed difference in response to tPA between sexes. The site and mechanism of vascular occlusion may influence the response to thrombolytic therapy. Fibrin-rich embolic occlusions, often seen with cardioembolism, are thought to recanalize more often than platelet-rich thromboses on pre-existing atherosclerotic lesions.^15–16 An approximately equal percentage of women and men in the present study had cardioembolic strokes according to TOAST classification.¹⁷

We have previously shown that stroke patients with isolated MCA occlusions have a higher rate of recanalization after IV tPA compared with patients who had ICA/MCA occlusions.¹⁰ Although a higher percentage of men than women had ICA/MCA occlusions in the present study, the gender-based differential response to tPA remained statistically significant even after excluding patients whose strokes were attributed to ICA occlusive lesions.

Variations in blood pressure and viscosity can cause physiological and hemodynamic changes, which might impact clot formation and/or recanalization. High BP may facilitate the passage of clots and reperfusion. In contrast, hyperglycemia and hyperchromia might increase blood viscosity, facilitating clot formation and impeding recanalization. We found no difference in admission blood pressure, glucose, or basic coagulation parameters between sexes, suggesting that the observed difference in recanalization was not related to these variables. There was a nonsignificant trend toward a lower hematocrit level in women. This could have facilitated the effects of thrombolysis. There was an equal incidence of tobacco use in both genders. This is noteworthy because smoking increases fibrinogen levels and platelets aggregation, resulting in a relatively hypercoagulable state.¹⁸

Positive interactions between medications could have augmented the thrombolytic effects of tPA in some of our patients. Cardiac studies have shown that concomitant use of antithrombotics with IV tPA leads to higher coronary patency rates.^19,20 We found no significant differences in the percentage of patients using various antihypertensives including angiotensin-converting enzyme inhibitors, statins, antiplatelets, or anticoagulants at the time of tPA administration. We also excluded patients who had endovascular interventions including intra-arterial tPA or received other experimental stroke therapies from our study. This indicates that the observed gender difference in recanalization after tPA is unlikely to be related to other concomitant treatments.

Estrogen status can alter the balance between coagulation and fibrinolysis. Gebara et al²¹ found that premenopausal women with high estrogen status and postmenopausal women using HRT had lower levels of plasminogen activator inhibitor (PAI-1) antigen and thus greater fibrinolytic potential, compared with patients with low estrogen status such as men and postmenopausal women not using HRT. Similarly, the Atherosclerosis Risk in Communities study showed that the levels of PAI-1 antigen were lower in current users of HRT than in nonusers.²² Eighty-two percent of women in our study were postmenopausal, and only one was using HRT. Therefore, the potential influence of estrogen on the fibrinolytic status of our patients was limited.

The gender-based differential response to tPA could be attributed to enhanced endogenous fibrinolytic activity in women compared with men. Differences between sexes in biomarkers of coagulation and fibrinolysis have been reported in patients with acute stroke and cardiovascular disorders. Regulation of endogenous fibrinolysis involves multiple complex interactions.^23–25 Some evidence suggests that the effectiveness of IV tPA for acute stroke is enhanced in patients who have the apolipoprotein (apo) E2 phenotype.²⁶ There is a gender difference in the effects of apoE2 polymorphism on plasma levels of lipoprotein A, which are higher in women with apoE2 than in men.²⁷ Future studies are required to elucidate the biochemical mechanisms underlying higher recanalization rates after tPA in women.

Our study has limitations imposed by its small sample size and retrospective nature. Earlier angiographic studies reported a recanalization rate of 25% to 66% within 24 hours of IV tPA treatment for carotid artery territory stroke.^28,29 More recent studies using MRA¹¹ and TCD⁵ reported that recanalization occurred within 48 hours in 70% to 92% of patients treated with IV tPA. Although the overall recanalization rate in our study (74%) is more or less in line with these studies, we acknowledge that our small sample size may have led us to overestimate the rate of recanalization. Similarly, the assessment of recanalization up to 72 hours may have led us to overestimate the true rate of thrombolysis-induced recanalization. Spontaneous arterial recanalization has been reported in 32% of patients during the first 24 hours after onset of anterior circulation stroke, increasing up to 50% by the fourth day.³⁰ The impact of spontaneous recanalization as a confounding variable is likely minimal because 29 of our 39 patients were re-evaluated for recanalization within the first 24 hours after tPA administration, and the observed gender-based differential response to tPA remained statistically significant when the analysis was limited to these patients. There are technical differences between MRA, CTA, and TCD, which could potentially influence assessment of recanalization and its degree. The impact of these various modalities on our results is unclear.

Neurological improvement within 72 hours of treatment was significantly more frequent in women compared with men, and more women had a favorable outcome on discharge. However, we did not find a significant difference in functional outcome at 30 to 45 days. One explanation is that most women recovered significantly before discharge as opposed to men who recovered more slowly. Although LOH did not differ between men and women, LOH depends on several factors unrelated to clinical conditions such as insurance and family preference. Overall, there was less DWI lesion growth in women than men and a nonsignificant trend toward smaller infarct volumes after treatment in women, despite approximately equal initial infarct volumes between the sexes. The lack of consistent results regarding clinical outcome measures is possibly a result of our small sample size.

In conclusion, we found that arterial occlusive lesions were more likely to recanalize in women than in men after IV tPA for acute stroke in this small cohort of patients. The role of gender on the effects of IV tPA may have important therapeutic implications. Gender may be an important variable in the decision to pursue more aggressive thrombolytic approaches such as combining IV with IA tPA or mechanical clot retrieval in men. Our findings are preliminary and need to be validated in larger-scale, prospective, controlled studies.

	Acknowledgments

 
S.S. is supported by a grant from the AHA Fellow to Faculty Transition award. G.S. is supported by grants from the NIH/NINDS (R01NS045049) and the Doris Duke Charitable Foundation. M.S. is supported by grants from the Harvard Center for Neurodegeneration and Repair, and Cierra Foundation. The authors thank Elena Makovetskaya for assisting with MRI volumetric measurements.

Received April 7, 2005; accepted April 29, 2005.

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This Article Abstract Full Text (PDF) All Versions of this Article: 36/7/1447    most recent 01.STR.0000170647.42126.a8v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Savitz, S. I. Articles by Selim, M. Search for Related Content PubMed PubMed Citation Articles by Savitz, S. I. Articles by Selim, M. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Stroke Related Collections CT and MRI Acute Cerebral Infarction Emergency treatment of Stroke Computerized tomography and Magnetic Resonance Imaging Doppler ultrasound, Transcranial Doppler etc. Thrombolysis Coagulation and fibronolysis