Sex-Based Differences in the Effect of Intra-Arterial Treatment of Stroke

Abstract

on behalf of the PROACT-2 InvestigatorsBackground and Purpose-Sex influences outcome after intravenous thrombolysis. In a combined analysis of the tissue plasminogen activator clinical trials, a sex-by-treatment interaction was observed. We sought to confirm that observation in an independent data set. Methods-Data were from the Pro-Urokinase for Acute Cerebral Thromboembolism-2 (PROACT-2) trial. Baseline factors were compared by sex. The primary outcome was an assessment of a sex-by-treatment interaction term within a logistic regression model, using a modified Rankin Scale score Յ2 at 90 days as the binary outcome. We also assessed whether there were differences in CT-scan appearance and recanalization at 2 hours post-treatment. Results-In the PROACT-2 study of intra-arterial stroke thrombolysis, in both women and men, prourokinase resulted in better outcomes than control. A sex by prourokinase treatment interaction was observed, with women showing a larger treatment effect (20% absolute benefit) compared with men (10% absolute benefit). The reason for this interaction is that thrombolytic treatment nullifies the worse outcome for untreated women compared with men. The reasons for effect modification do not include improved recanalization at 2 hours among women. Conclusions-Women with middle cerebral artery ischemic stroke benefit more from intra-arterial therapy. Further study of how sex affects stroke outcome is needed. Key Words: gender Ⅲ stroke Ⅲ thrombolysis S everal studies have reported that treatment and outcomes differ between women and men for general stroke care. 1-4 Reasons for this result may include social factors, age or perhaps true differences in biology. [5][6][7] Analysis of pooled results of the intravenous tissue plasminogen activator (tPA) trials in acute ischemic stroke revealed surprising evidence that women may benefit more than men from intravenous thrombolysis. 8 This analysis was consistent with previously cited studies in that nonthrombolysed women fared worse than nonthrombolysed men. Among tPA-treated patients, the sex-effect was absent, and this resulted in female sex being a significant modifier of treatment-effect. However, this analysis was a post-hoc assessment and the association could have been the result of chance. We sought to confirm this result in an independent data set. MethodsThe Pro-Urokinase for Acute Cerebral Thromboembolism-2 (PROACT-2) study has been previously reported. 9 In brief, the study was a randomized, controlled, open-label clinical trial with blinded outcome evaluation, enrolling 180 patients with angiographically proven middle cerebral artery occlusion, randomized in a 2:1 ratio to intra-arterial prourokinase or heparin control. The study demonstrated a 15% absolute benefit in functional independence at 90-days (modified Rankin Score 0 to 2) accruing to patients receiving treatment with prourokinase. In this analysis we used data from the study to evaluate the hypothesis that sex influences outcome after treatment with prourokinase with a greater tre...

Outcome Predictors in Acute Basilar Artery Occlusion

“…18,19 the presence of arterial hypertension was identified as a predictor of clinical outcome based only on univariate analysis, but not multivariate logistic regression analysis in the present study and the study conducted by Jung et al 9 , who reported the influence on not only three month survival, but also long-term survival. in contrast, the presence of diabetes mellitus was identified as a significant independent negative predictor of good outcome in both studies.…”

Field Synopsis of the Role of Sex in Stroke Prediction Models

“…Similarly, all 3 models for stroke incidence among patients with arrhythmias indicated that women were at higher risk, concordant with the literature 65, 66, 67. Conversely, our finding that all 4 models estimate lower risk of death after ischemic stroke for women than otherwise similar men was surprising given the inconsistency of the literature, which has frequently reported worse prognoses in women (particularly in populations untreated with thrombolysis) 17, 68, 69, 70. Finally, it is notable that about half of the models predicting stroke in a population sample were sex stratified (thereby allowing the effects of risk factors to vary among men and women), in keeping with evidence that sex modifies the effect of some risk factors on stroke risk 20, 71…”

Gender Differences in Acute Ischemic Stroke

“…These findings confirm the results of an earlier smaller study showing a higher recanalization rate in women. 13 Given the fact that women with AIS not treated with rtPA have less likely favorable clinical outcomes, [3][4][5]12 these findings underscore the probable higher efficiency of rtPA treatment in women and lead to the question for what reason thrombolysis might be more effective. An appealing explanation might be the better recanalization of a fibrin-rich embolic occlusion associated with cardioembolism compared to a platelet-rich occlusion associated with thromboembolism and preexisting atherosclerosis.…”

“…22,23 Another explanation might be differences in the endogenous fibrinolytic activity in women compared to men. 12 Further investigation is required exploring the underlying biochemical interactions. …”

“…10 With regard to treatment of stroke with recombinant tissue plasminogen activator (rtPA), it is still under debate whether women benefit more from acute therapy as pooled data analysis of randomized clinical trials indicated. 11,12 Women and men treated with rtPA had similar outcomes, whereas women in the placebo group had less favorable clinical outcomes. In this context the results of another study reporting on a higher recanalization rate in women compared to men with acute ischemic stroke (AIS) treated with rtPA 13 underline the question of a possible higher efficacy of acute treatment in women.…”