Explicit Consideration of Baseline Factors to Assess Recombinant Tissue-Type Plasminogen Activator Response With Respect to Race and Sex

Abstract

Background and Purpose-Sex and race reportedly influence outcome after recombinant tissue-type plasminogen activator (rtPA). It is, however, unclear whether baseline imbalances (eg, stroke severity) or lack of response to thrombolysis is responsible. We applied balancing methods to test the hypothesis that race and sex influence outcome after rtPA independent of baseline conditions. Methods-We mapped group outcomes from the National Institute of Neurological Disorders and Stroke (NINDS) dataset based on race and sex onto a surrogate-control function to assess differences from expected outcomes at their respective National Institutes of Health Stroke Scale and age. Outcomes were also compared for subjects matched individually on key baseline factors using NINDS and 2 recent datasets from southeastern United States. Results-At similar National Institutes of Health Stroke Scale and age, 90-day good outcomes (modified Rankin Score, 0-2) in NINDS were similarly improved after rtPA for white men and women. There was a strong trend for improvement in black men. Conversely, black women treated with rtPA showed response rates no different from the controls. After baseline matching, there were nonsignificant trends in outcomes except for significantly fewer good outcomes in black versus matched white women (37% versus 63%; P=0.027). Pooling the 3 datasets showed a similar trend for poorer shortterm outcome for black women (P=0.054; modified Rankin Score, 0-1). Conclusions-Matching for key baseline factors indicated that race and sex influence outcome most strikingly in black women who demonstrated poorest outcomes after rtPA. This finding supports the hypothesis that poor response to rtPA, rather than differences in baseline conditions, contributes to the worse outcome. This finding requires prospective confirmation.

In-hospital outcomes of thrombolysis for acute ischemic stroke in patients with primary brain tumors

“…From an epidemiological perspective, the BTS cohort had more females and predominantly Caucasian patients, contrary to the existing knowledge about stroke demographics that AfricanAmerican patients and males bear a higher burden of stroke [25]. The lack of difference in vascular risk factors such as diabetes, hypertension, hyperlipidemia and atrial fibrillation in our study, suggests that other etiologies may play an important role in the causation of strokes in this population.…”

Blood transcriptome changes after stroke in an African American population

“…The identification of such candidate gene expression profiles may also open the opportunity of targeting drugs to such population differences. In addition to African American populations having a higher stroke risk,12 a recent retrospective analysis of rt‐PA studies suggested that African American women show no significant benefit from rt‐PA 13. Analysis of our transcriptome data show a clear transcriptome difference by sex following rt‐PA administration (unpubl.…”

“…Traditional risk factors for stroke, such as obesity, hypertension (uncontrolled), and lifestyle only partially account for the higher risk 11. Furthermore, race‐associated differences in response to rt‐PA have been recently described 12, 13. Gene expression studies of vascular disease reveal a difference in the transcriptome of African Americans versus Caucasians 14.…”

The Importance of Considering Sex Differences in Translational Stroke Research

“…Mandava et al reported that tPA-treated black women had significantly less likelihood of a good outcome (mRS 0-2) compared to white women 3 months following stroke [56]. It was suggested that this differential response to tPA might be due to a higher proportion of blacks presenting with a prothrombotic genotype of plasma inhibitor-1 (PAI-1), an inhibitor of tPA's enzymatic activity [57].…”

“…Previous analysis of the NINDS dataset did not show race as a predictor of functional outcome [58] but the study was not powered for subgroup analysis [59]. Therefore, explicit balancing methods were utilized in the study by Mandava et al to evaluate the influence on sex and race on tPA outcome independent on differences in baseline characteristics [56]. Taken together, sex differences in response to stroke treatment may be depend on the ethnicity of stroke patients and further studies that carefully consider baseline characteristics are warranted.…”