Sex-Based Differences in Response to Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke

Abstract

Background and Purpose-Women experience worse outcomes after stroke compared with men. Prior work has suggested sex-based differences in coagulation and fibrinolysis markers in subjects with acute stroke. We explored whether sex might modify the effect of recombinant tissue plasminogen activator (rtPA) on outcomes in patients with acute ischemic stroke. Methods-Using a combined database including subjects from the National Institute of Neurological Disorders and Stroke (NINDS), Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) A and B, and the Second European Cooperative Acute Stroke Study (ECASS II) trials, we examined 90-day outcomes in patients randomized to rtPA versus placebo by sex. We used logistic regression to control for potential confounders. Results-Among 988 women treated between 0 and 6 hours from symptom onset, patients receiving rtPA were significantly more likely than those receiving placebo to have a modified Rankin Score Յ1 (40.5% versus 30.3%, PϽ0.0008). Among 1190 men, the trend toward benefit in the overall group did not reach statistical significance (38.5% versus 36.7%, Pϭ0.52). An unadjusted analysis showed that women were significantly more likely to benefit from rtPA compared with men (Pϭ0.04). Controlling for age, baseline National Institutes of Health Stroke Scale, diabetes, symptom onset to treatment time, prior stroke, systolic blood pressure, extent of hypoattenuation on baseline computed tomography scan and several significant interaction terms (including onset to treatment time-by-treatment and systolic blood pressure-by treatment) did not substantially change the strength of the interaction between gender and rtPA treatment (Pϭ0.04). Conclusions-In this pooled analysis of rtPA in acute ischemic stroke, women benefited more than men, and the usual gender difference in outcome favoring men was not observed in the thrombolytic therapy group. For patients presenting at later time intervals, when the risks and benefits of rtPA are more finely balanced, sex may be an important variable to consider for patient selection.

Gender Differences in Acute Ischemic Stroke

“…This confirms earlier results of a pooled data analysis of 5 randomized clinical trials 11 with intravenous rtPA therapy, a posthoc analysis of a randomized clinical trial with intraarterial rtPA, and a posthoc analysis of gender effects in the Canadian Alteplase for Stroke Effectiveness Study (CASES, 1999(CASES, to 2001 21 but differs from the results of a posthoc analysis of the GAIN trial, which excluded patients with rapid clinical improvement within one hour after thrombolysis. 14 Comparison of thrombolysis-related and independent complications and mortality did not reveal significant differences between both groups.…”

“…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.…”

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…”

“…There are sex‐based differences in anatomy,1, 2, 3 vascular biology,4, 5 neuroprotective factors,6, 7 functional neuroanatomy,8 vascular risk factors and comorbidities,9, 10, 11, 12 and lifestyle factors and social roles13, 14 that may be important in stroke incidence and prognosis. The literature has shown sex differences in the risk of incident stroke,13, 15, 16 likelihood of favorable outcomes after a stroke,13 and responses to thrombolysis treatment 17, 18, 19. The importance of sex‐specific risk in clinical management of stroke was underscored in the first American Heart Association/American Stroke Association guideline dedicated to stroke prevention in women 20.…”

Factors that influence variation in clinical decision-making about thrombolysis in the treatment of acute ischaemic stroke: results of a discrete choice experiment

“…41 This is despite a pooled analysis of randomised controlled trials demonstrating that women are more likely than men to benefit from thrombolysis. 42,43 Research to assess and clarify the impact of sex on thrombolysis utilisation and outcomes using individual patient data collated from randomised trials is ongoing and should clarify this effect, if any. 15 Uncertainty exists regarding a number of patient factors, where there are 'grey' areas in the guidelines and/or research evidence.…”