Comparable care, worse outcomes for women with stroke Louise D. McCullough and Judith H. Lichtman S e x d iffe re n c e s a re in c re a s in g ly re c o g n ize d in m a n y a re a s o f m e d ic in e , a n d s tro k e is no e x c e p tio n . W o m e n te n d to b e m o re a d v e rs e ly a ffe c te d by s tro k e th a n a re m e n a n d , a s a n e w s tu d y illu s tra te s , th is d is c re p a n c y c a n n o t b e a ttrib u te d s o le ly to s e x -re la te d d iffe re n c e s in a c u te s tro k e c a re . McCullough, L. D. & Lichtman, J. H. Nat. Rev. Neurol. 10, 3 6 7 -3 6 8 (2 014); published online 1 7 June 2 0 1 4 ; d o i:1 0 .1 0 3 8 /n rn e u ro l.2 0 1 4 .1 0 3

In the USA, stroke is the third leading cause of death in w omen—elderly women being at particularly high risk—but has dropped to fifth place am ong the leading causes of death in m en.1,2 Even more concerning is the growing incidence of stroke in women in low-income and middle-income countries, leading to an impending public health crisis for women worldwide. Studies have shown that compared with men, women are more likely to be institutionalized and have poor functional recovery after stroke.3-5 Early work suggested that the inferior outcomes in women could be attributed to a myriad of prehospital and hospital factors, such as delayed presentation, atypical symptoms, less efficient or tim ely work-up, delays in treatment with thrombolytics, and/or lower rates o f receipt o f recom m ended tre a t­ ments.5-7 Over the past few years, however, it has become apparent that the gaps in acute care experienced by women are narrowing. This narrow ing of the treatm ent gap is exemplified by new findings presented by Gattringer et al, who examined sex-related differences in acute stroke care in Austria.8 In this analysis of data collected from stroke units from 2005-2012, over 47,000 patients were identified. Although some differences in prehospital factors were observed between men and women, there were no marked dis­ parities in the care received once the patients were in the hospital. This is good news for women, as equal access to treatment, appro­ priate work-up and secondary prevention strategies enhances the chances of recovery. However, despite com parable care in the hospital and equal access to rehabilitation, women had poorer functional outcomes than men (modified Rankin Scale score 3-5: OR 1.26, 95% Cl 1.17-1.36) and required more


nursing care and assistance. The median age of women at the time of stroke was 7.6 years higher than that of men, but the differences in outcomes held after controlling for age. Several factors in the G attringer et al. study should be considered w hen trying to understand these sex differences. First, w omen had higher levels of pre-existing disability than did men. Second, women ten d ed to have m ore-severe strokes on adm ission, w ith higher N IH Stroke Scale (NIHSS) scores. Rates o f h y p erten sio n were equivalent between the sexes, but dia­ betes, hypercholesterolaemia, alcohol use, smoking, myocardial infarction and periph­ eral arterial disease were more prevalent in men. By contrast, atrial fibrillation was more frequent in women (32.3% prevalence, compared with 22.7% in men). Not surpris­ ingly, therefore, cardiac embolism was more

likely to be the identified aetiology of stroke in women, whereas macroangiopathy was more com mon in men. Embolic stroke led to a higher num ber of anterior circulation events in women, perhaps explaining the higher NIHSS scores. No differences in acute treatm ent were seen: 14.5% of m en and w om en received thrombolysis well within the 60 min golden h o u r’ (m edian 49 m in for w om en versus 48 min for men). Perhaps most importantly, no sex difference was observed in the use of oral anticoagulants, despite the higher prevalence of atrial fibrillation in women. This finding raises concerns, as it suggests that women are undertreated for the most im portant risk factor contributing to their strokes: cardiac embolism. One limitation of this study is that 3-month outcomes were available for less than 40%

Figure 1 1A ge-standardized s tro k e in cid e n ce per 1 0 0 ,0 0 0 person-years fo r 2 0 1 0 . R eprinted fro m The Lancet 3 8 3 , Feigin, V. L. e t al., Global and regional burden o f s tro k e d u rin g 1 9 9 0 - 2 0 1 0 : fin d in g s fro m th e Global B urden o f D isease S tudy 2 0 1 0 , 2 4 5 - 2 5 5 © (2 0 1 4 ), w ith p e rm issio n fro m Elsevier.

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NEW S & V IE W S o f p atien ts, although w om en and m en were equally represented (38.4% in women versus 39.5% in men), so this is unlikely to be a source of bias. Generalizability to other health-care systems (outside Austria) and non-stroke-unit settings might be limited, but emerging data from several US studies also suggest that sex disparities in acute stroke care are narrowing. W h at can be do n e to ad d ress th ese alarm ing statistics? Clearly, focusing on improving acute stroke care and access to rehabilitation for w omen may not be the answer, and we may be missing opportu­ nities for secondary prevention in at-risk patients. A ge-adjusted rates of transient ischaemic attack were higher for women than for men, highlighting the prospect of identifying and treating these patients to avoid more-serious stroke events. One strat­ egy would be to improve access to medica­ tions that have been shown to reduce the rates of large disabling strokes, most notably oral anticoagulants. This strategy m ight be effective in higher-incom e countries, but may be of m ore lim ited use in lowerincome countries, especially in rural areas where access to appropriate medications and monitoring is restricted. How does this new paper contribute to the bigger picture of stroke in women? If we con­ sider the demographic profile of ageing in the USA, elderly women will increasingly out­ num ber men in terms of stroke events and stroke-related deficits.3 From a more global perspective, as noted in a recent paper from The Lancet that included 119 studies from 21 regions of the world (Figure 1), despite the decrease in age-standardized m o rtality rates for stroke over the past two decades, the absolute num ber of strokes is increas­ ing annually, as are the numbers of strokerelated deaths and disability-adjusted life years lost, particularly in low-income and middle-income countries. A second new paper, by Wang and col­ leagues, highlights the em erging global epidemic of stroke in women, and should raise a red flag for clinicians.9 The study shows that rates of first-ever stroke have increased disproportionally in women in rural China. Among 14,920 residents par­ ticipating in the Tianjin Brain Study, the incidence of first-ever stroke grew by 8.0% annually in woman compared with 5.8% in men, narrowing the male:female incidence ratio from 2.6 to 1.4 over a 21-year period. D u rin g th is p e rio d , m any know n risk factors for stroke, including hypertension, obesity, alcohol consumption and diabetes

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mellitus, increased am ong w omen in this region.10 These findings have profound global implications for public health. More than half of the Chinese population lives in rural areas, and these data on secular trends over two decades signal a growing stroke epidemic for women in China as a whole. As the incidence of stroke increases in women, with the potential accompany­ ing sex-related differences in outcomes, the num ber of women needing assistance will continue to grow globally. The fact that sex-related disparities in stroke care are diminishing is encouraging, but it is unsettling that women with compa­ rable care still experience worse functional outcomes than do men. Attention to factors that disproportionally affect women, such as depression and social isolation, may lead to more appropriate and effective therapies, but additional research is needed to develop therapeutic targets based on psychosocial factors. Future research should address the factors that contribute to inferior post­ stroke outcomes in women, given that stroke is likely be a major global health burden for women in the coming years.

Com peting interests The authors declare no com peting interests.



American H eart A ssociation. Circulation 127, e 6 -e 2 4 5 (2 013). Leading causes o f death and num bers o f deaths, by sex, race, and Hispanic origin: United States, 1 9 8 0 and 2 0 1 0 . Centers for Disease Control and Prevention [online], h t t p : / / w w w .c d c .g o v /n c h s /d a ta /h u s /2 0 1 1 /0 2 6 .p d f (








Department of Neuroscience, University of Connecticut Health Centre, 263 Farmington Avenue, Farmington, CT 06032, USA (L.D.M.). Yaie School of Public Health, PO Box 208034, 60 College Street, New Haven, CT 06520-8034, USA (J.H.L.). Correspondence to: L.D.M. [email protected]

Go, A. S. et al. Heart disease and stroke s ta tis tic s — 2 0 1 3 update: a report from the


Bushnell, C. ef al. Guidelines fo r the prevention o f stroke in women: a s tatem en t fo r healthcare professionals from the American Heart A ssociation/A m erican Stroke Association. Stroke 4 5 ,1 5 4 5 - 1 5 8 8 (2014). Bushnell, C. D. etal. Sex differences in quality o f life a fte r ischem ic stroke. Neurology 82, 9 2 2 -9 3 1 (2014). Reeves, M. J. et al. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcom es. Lancet Neurol. 7, 9 1 5 -9 2 6 (2008). S m ith, M. A. e t al. Gender com parisons o f diagnostic evaluation fo r ischem ic stroke patients. Neurology 6 5 ,8 5 5 - 8 5 8 (2005). Reeves, M. J. et al. Quality o f care in women with ischem ic stroke in the GWTG program. Stroke 4 0 ,1 1 2 7 - 1 1 3 3 (2009). Gattringer, T. etal. Sex-related differences of acute stroke un it care: results from th e Austrian Stroke Unit Registry. Stroke h ttp ://d x .d o i.o rg / 1 0 .1161/STROKEAHA.1 1 4 .0 0 4 8 9 7 . Wang, J. e t al. Sex differences in tre nds of incidence and m o rtality o f first-ever stroke in rural Tianjin, China, from 1 9 9 2 to 2 0 1 2 .

Stroke h ttp ://d x .d o i.o rg /1 0 .1 1 6 1 / STROKEAH A.1 1 3 .0 0 3 8 9 9 . 10. Wang, J. e t al. Trends o f hypertension prevalence, awareness, tre a tm e n t and control in rural areas o f northern China during 1 9 9 1 -2 0 1 1 . J. Hum. Hypertens. 2 8 ,2 5 - 3 1 (2014).


D o e s a g g re s s iv e M S w a r r a n t a g g re s s iv e t r e a t m e n t ? Mark


Aggressive, refractory multiple sclerosis warrants unconventional therapy. A retrospective multicentre study assessed the effects of ablating the immune system, then reconstituting it using bone marrow derived stem cells. Though this particular regimen improved disability in some patients, others continued to relapse, perhaps indicating the treatment did not go far enough. Freedman, M. S. Nat. Rev. Neurol. 1 0 ,3 6 8 - 3 7 0 (2 014); published online 3 June 2 0 1 4 ; d o i:1 0 .1 0 3 8 /n rn e u ro l.2 0 1 4 .9 8

Despite the contention in some quarters that multiple sclerosis (MS) is som ething o th e r th a n an au to im m u n e disease, all effective, cu rre n tly approved m edications for treating the active phase of the disease (characterized by ongoing clinical

attacks and form ation of new MRI-visible lesions) aim to either modulate or suppress the im m une response. In some patients, however, MS cannot be adequately controlled with current treatments, warranting a more aggressive approach.

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