1. Stroke John C. Stevenson Editor: Martin Birkhäuser

2. Stroke Ischemic (thrombotic/embolic) –86% Hemorrhagic –Intracerebral10% –Subarachnoid4%

3. Female stroke prevalence USA females, 2004 www.americanheart.org

4. Copyright ©2006 American Heart Association Ischemic stroke by race Hendrix SL. et al. Circulation 2006;113:2425–34 0.04 0.03 0.02 0.01 0.00 0.04 0.03 0.02 0.01 0.00 Cumulative hazard Time (years) 0 1 2 3 4 5 6 7 8 CEE CEE Placebo CEE CEE Placebo WhitesBlacks Number at risk CEE Placebo4075 40193963389838353767340122011111 CEE4007 39403898384337863725334821251037 835821812801784773687472242 782766754738725717648421192

5. Female stroke mortality UK females, 2004 www.heartstats.org

6. Female stroke mortality (USA) Third leading cause of death in USA Rates strongly age-related: –50–59 years:0.6–0.8/1000 women/year –60–64 years:~2/1000 women/year –65–74 years:4.2/1000 women/year –75–87 years:11.3/1000 women/year Bushnell CD. Stroke 2006;37:2387–99 Rothwell PM. Lancet 2004;363:1925–33

7. Increased stroke risk Age History/family history –Prior stroke, TIA, MI –Atrial fibrillation Gender –Incidence greater in males –Mortality greater in females Hypertension Smoking Diabetes mellitus Arterial disease –Carotid, peripheral, coronary Lifestyle –diet, exercise

8. HRT and stroke: current users 01 2 Rosenberg Pedersen Pettiti Paganini-Hill Grodstein Relative risk Paganini-Hill A. Maturitas 2001;38:243–61

9. HRT and stroke Nurses Health Study Ischemic strokeRR 1.13 (CI 0.90–1.41) –(total 142) RR 1.26 (CI 1.00–1.61) adjusted Hemorrhagic strokeRR 0.89 (CI 0.62–1.27) –(total 50)RR 0.93 (CI 0.64–1.34) adjusted Dose effect – significant increase with CEE ≥ 0.625 mg No duration effect over > 10 years Grodstein, et al. Ann Intern Med 2000;133:933–41

10. HRT and stroke Randomized clinical trials HERSRR 1.1 (CI 0.9–1.5) WESTRR 1.1 (CI 0.8–1.4) WHI (ischemic)RR 1.4 (CI 1.1–1.9) WHI (hemorrhagic)RR 0.8 (CI 0.4–1.6) WHI (E alone)RR 1.4 (CI 1.1–1.8) Hulley, et al. J Am Med Assoc 1998;280:605–13; Viscoli, et al. N Eng J Med 2001;345:1243–49 Wassertheil-Smoller, et al. J Am Med Assoc 2003;289:2673–84 Women’s Health Initiative Steering Committee. J Am Med Assoc 2004;291:1701–12

11. Risk of stroke with HRT in the WHI No significant increase in risk of cerebral vascular accidents in WHI studies in the 50–59-year cohort E + P HR 1.46 (0.43–1.56) 1 E alone HR 1.09 (0.59–2.21) 2 1 Wassertheil-Smoller, et al. J Am Med Assoc 2003; 2 Hendrix, et al. Circulation 2006

12. General population of women ages 50–59 years First-year CHD and vascular events with HT use in 2 trials of younger postmenopausal women and expected annual rates in women in the USA and Europe Lobo R, Arch Intern Med 2004;164:482–4

13. SERMs and stroke Randomized clinical trials Tamoxifen RR 1.82 (CI 1.41–2.36) (meta-analysis) Raloxifene RR 1.15 (CI 0.93–1.41) (RUTH) Bushnell & Goldstein. Neurology 2004;63:1230–33 Barrett-Connor, et al. N Engl J Med 2006;355:125–37

14. Stroke prevention Low-dose aspirin Blood pressure control Lipid lowering –Diet ± statins, fibrates, etc. Lifestyle measures –Low saturated fat/low salt diet –Physical activity –Smoking cessation Avoid high-dose HRT –? Use low-dose non-oral HRT if necessary

15. HRT and stroke: Misperceptions The risk of both venous and arterial thromboembolism is increased during HRT Stroke risk is substantially increased in women receiving HRT IMS Global Summit 2008. Climacteric 2008;11:267–72

16. HRT and stroke: Evidence It is unclear at present whether there is a statistical increase in ischemic stroke with standard HRT in healthy women aged 50–59 The WHI data showed no statistically significant increase in risk; nevertheless, even if statistically increased, as found in the Nurses’ Health Study, the low prevalence of this occurrence in this age group makes the attributable risk extremely small IMS Global Summit 2008. Climacteric 2008;11:267–72

17. Safety data from studies of low-dose and ultra-low-dose regimens of estrogen and progestogen are encouraging Climacteric 2007;10:181–96 HRT: cerebrovascular events