Sex differences in the management and outcomes of stroke

`Background:` Women appear to experience worse outcomes after stroke than men but the causes of these differences have not been conclusively determined. There is also some evidence that women receive evidence-based stroke care less often than men but how this influences outcomes after stroke is unclear. There is a need for high-quality studies to explore these sex differences to inform interventions to address these differences. `Aims:` My aims were to 1) quantify the sex differences in management and outcomes of stroke; and 2) to identify factors that contribute to the worse outcomes in women. `Methods:` Two different data sources were used in the thesis. The first was individual participant data (IPD) on long-term outcomes after stroke from 13 population-based stroke incidence studies conducted in Europe, Australasia, South America, and the Caribbean between 1987 and 2014, forming the INternational STroke oUtCome sTtudy (INSTRUCT). Data on sociodemographics, stroke-related factors, pre-stroke health, stroke management, and post-stroke factors were obtained. Study outcomes were: (1) severity of acute stroke, (2) long-term all-cause mortality, (3) functional outcomes and participation restriction, and (4) HRQoL up to 5 years after stroke. I performed IPD meta-analyses of the sex differences in these outcomes (at 1 and 5 years after stroke) and contributing factors, forming the first four studies of the thesis. The second dataset included first-ever strokes admitted to 39 hospitals between 2010 and 2014 in the Australian Stroke Clinical Registry (AuSCR) - a national stroke registry. The AuSCR incorporates standardised methods of data collection for important processes of stroke care in Australia and patient outcomes. Study factors included sociodemographics, stroke-related factors, evidence-based processes received in hospital (i.e. stroke unit care, thrombolysis, secondary prevention medications), and self-reported 3-month indicators (e.g. living arrangements). Study outcomes were (1) all-cause mortality, (2) causes of death (COD) up to 1 year after stroke, and (3) HRQoL at 3-6 months follow-up. The causes of the sex differences in stroke care and outcomes were investigated using the AuSCR, forming the other three studies as part of the thesis. \\(Results:\\) In the meta-analyses of 16,957 strokes included in the INSTRUCT, women were about 35% more likely to be deceased and 32% more likely to have a poor functional outcome by 1 year after stroke compared to men. Women also had greater participation restriction and poorer HRQoL than men. The sex differences in stroke outcomes were mostly explained by women's greater age, greater pre-stroke functional limitations and more severe strokes than men. The presence of atrial fibrillation (AF) also accounted for the greater mortality in women and post-stroke depression contributed to the sex differences in HRQoL. There was limited evidence that stroke management, socioeconomic status, cardiovascular risk factors, or other comorbidities were responsible for the worse outcomes in women compared to men. Similar results were observed in 5-year analyses. Further examination of stroke severity at the acute stage showed that pre-stroke factors only partly explained why women presented with more severe strokes compared to men. In the analyses of the AuSCR on 14,118 strokes, women had a 40% greater all-cause mortality at 1 year following stroke. The COD differed between sexes with women having more deaths attributed to stroke or other cardiovascular diseases (CVD; e.g. AF and heart failure) than men. Women's lower aspirin administration within 48 hours of admission, advanced age and stroke severity explained the greater all- and specific-cause mortality. About 60% of the participants (n=6852) had HRQoL assessments at 3-6 months. Women had worse HRQoL than men, with the difference mostly explained by age, stroke severity, and 3-month place of residence (aged care). However, older women had poorer HRQoL than older men, independent of the measured covariates including evidence-based care and other factors. \\(Conclusions:\\) Women faced poorer outcomes after stroke than men. Worse outcomes in women were mostly because of pre-stroke factors including age but also stroke severity, pre-stroke functional limitations and, to a lesser extent, AF. Of all aspects of management examined, only lower aspirin administration in women contributed to their greater mortality. The findings highlight the importance of better management of vascular risk factors and comorbidity in the elderly, with more women prevalent in that age group than men. The findings suggest opportunities for interventions to reduce sex differences in stroke outcome may include better access to evidence-based care for cardiovascular and general health, and opportunities for post-stroke rehabilitation, especially targeting those with less capacity to recover (i.e. pre-stroke functional limitation, more severe strokes and mood disorders). Further research on the potential biological origin of sex differences in stroke severity may also be warranted.