Stroke Prevention in Women: Guidelines and Beyond Cheryl Bushnell, MD, MHS Associate Professor of Neurology Director, Wake Forest Baptist Stroke

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1 Stroke Prevention in Women: Guidelines and Beyond Cheryl Bushnell, MD, MHS Associate Professor of Neurology Director, Wake Forest Baptist Stroke Center

2 Objectives To discuss the evidence for sex differences in: Stroke epidemiology in NC Unique risk factors for women Traditional risk factors Stroke Prevention in Women Guideline recommendations for each risk factor

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4 Why discuss sex differences in stroke? Men have a higher stroke incidence than women But, women have a 20% lifetime prevalence of stroke vs. 17% in men 1 In 2006, there was an excess of ~30,000 stroke deaths in women 2 By the year 2050: An excess of 68,000 stroke deaths in women 3 198,000 stroke events in white women vs. 129,000 in men 3 1) Seshadri, et al. Stroke 2006;37: ) Lloyd-Jones D, Adams R, Carnethon M, et al. Circulation 2009:119e-e181 3) Reeves, et al. Lancet Neurology 2008;7:915-26

5 Stroke Mortality (per 100,000) US Stroke Mortality Rates for Women, Non-Hisp White Black Am Indian Asian / PI Hispanic

6 Female-Male US Stroke Mortality Ratio, Non-Hisp White Black Am Indian Asian / PI Hispanic

7 N.C. Stroke Death Rates by Age and Gender, 2004 Death Rate per 100,000 1,800 1,600 1,400 1,200 1, Females Males Overall < Females ,568.2 Males ,367.0 Overall ,511.2 Age Group ICD-10 codes I60-I69. Rates per 100,000 population. Data Source: Compressed Mortality File, CDC Wonder. The Burden of CVD in N.C. January, 2008 N.C. Justus-Warren Heart Disease & Stroke Prevention Task Force

8 Figure 2.5. Stroke Death Rates by Gender, N.C., Age-adjusted Death Rate per 100, '79 '81 '83 '85 '87 '89 '91 '93 '95 '97 '99 '01 '03 Year Males Females : ICD-10 codes I60-I69; : ICD-9 codes , multiplied by comparability ratio of Rates per 100,000 population, age-adjusted to the 2000 U.S. standard population. Data Source: Compressed Mortality File, CDC Wonder. The Burden of CVD in N.C. January, 2008 N.C. Justus-Warren Heart Disease & Stroke Prevention Task Force

9 Sex-Specific Risk Factors Risk Factor Sex-specific Risk Stronger prevalence in women Similar prevalence in men and women Pregnancy Pre-eclampsia Gestational diabetes Oral contraceptive use Postmenopausal hormone use Changes in hormonal status Migraine with aura Atrial fibrillation Diabetes X X X X X X X X X Bushnell, et al. Stroke 2014; Feb 6

10 Sex-Specific Risk Factors- continued Risk Factor Sex-specific Risk Stronger prevalence in women Similar prevalence in men and women Hypertension Physical inactivity Age Prior cardiovascular disease Obesity Diet Smoking Metabolic syndrome Depression Psychosocial stress X X X X X X X X X X Bushnell, et al. Stroke 2014; Feb 6

11 The first ever guidelines on stroke prevention in women

12 Pregnancy, Preeclampsia and Stroke

13 Pregnancy and Stroke Increased risk during pregnancy and postpartum period (6-12 weeks after delivery) -occurs in about 34 per 100,000 pregnancies -21 per 100,000 non-pregnant women James, et al Obstet Gynecol

14 Young stroke survivor Sarah was 24 yo and healthy Delivered a healthy baby boy in 2011 by Cesarean section 12 days after delivery, she developed high blood pressure, blurred vision and right leg weakness, then had a seizure MRI brain showed 2 separate hemorrhages, evidence of severe hypertension She had ongoing partial seizures, now treated

15 Risk factors and treatment issues What kind of oral contraceptives are safe? What is the risk of preeclampsia with subsequent pregnancies? What is the risk of developing other risk factors, such as hypertension? What is her risk of stroke later in life?

16 Stroke Risk, Preeclampsia, and Hypertension

17 Steegers, et al Lancet 2010

18 Short and Long-Term Inflammation in Women with Preeclampsia 106 women with preeclampsia (cases) 212 women with normal pregnancies (controls) IL-6 (pro-inflammatory) increases from 1 st to 3 rd trimester IL-6/IL-10 ratio (pro- to anti-inflammatory), sicam, and svcam-1 (endothelial and inflammatory) increased in cases vs controls 20 years after pregnancy Freeman, et al. Hypertension 2004;43:708

19 Preeclampsia-eclampsia increases risk of stroke for the first year postpartum Tang, et al. Stroke 2009;40:1162-8

20 Preeclampsia-eclampsia increases risk of stroke Tang, et al. Stroke 2009;40:1162-8

21 Preeclampsia and risk of future stroke Bellamy, et al. BMJ 2007; doi: /bmj

22 Evidence that preeclampsia increases risk for cerebrovascular disease later Systematic review of preeclampsia/eclampsia (5 case-control and 10 cohort studies) McDonald, et al. Am Heart J 2008;156:918-30

23 Preeclampsia may be first sign of vascular risk in women Bushnell and Chireau. Stroke Res Treat 2011;2011:858134

24 Provider awareness of the risk of vascular disease Anonymous survey sent to internists and Ob/Gyns Internists were unsure or did not know preeclampsia was associated with heart disease (56%), stroke (48%), and decreased life expectancy (79%) Ob/Gyns: heart disease (23%), stroke (38%), and decreased life expectancy (77%) Only 9% of internists and 38% of Ob/Gyns provide cardiovascular risk-reduction counseling to their patients with preeclampsia Young, et al. Hypertens Pregnancy 2012:31:50-8

25 Gaps in knowledge for preeclampsia and future stroke risk How do we identify women at the greatest risk for stroke months and years after pregnancy? Subclinical vascular markers? Serum biomarkers? Risk factor development?

26 What can we do now to prevent stroke? Risk factors for stroke are recognizable Preeclampsia is a risk factor (not risk marker) Healthy lifestyle interventions reduce risk of stroke Likely effective in women with history of preeclampsia Berks, et al Brit J Obstet Gynecol 2013

27 Recommendations: Treatment of HTN in Pregnancy and Postpartum Class III Recommendations Atenolol, ARB's and direct renin inhabitors are contraindicated in pregnancy and should not be used Class, (LOE) Class III, LOE C Prevention of Stroke in Women with a History of Preeclampsia Class IIa Recommendations Because of the increased risk of future hypertension and stroke one to 30 years after delivery in women with a history of preeclampsia (Level of Evidence B) it is reasonable to (1) consider evaluating all women starting 6 months to the one year postpartum, as well as those who are past childbearing age, for a history of preeclampsia/eclampsia, and document their history of preeclampsia/eclampsia as a risk factor, and (2) evaluate and treat for cardiovascular risk factors including hypertension, obesity, smoking and dyslipidemia. Class, (LOE) Class IIa, LOE C Bushnell, et al. Stroke 2014;Feb 6

28 Oral contraceptives

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30 Oral contraceptive use: the landscape How many women use OCs? 10.7 million women aged15-44 years What is the incidence of stroke in this age group? (Lidegaard NEJM 2012) Ages 15-19: 3.4/100,000 Ages 45-49: 64.4/100,000

31 Oral contraceptives and ischemic stroke risk Meta-analyses of stroke risk with OC use: OR 2.12 to 2.75 (Gillum 2000; Chan 2004; Baillargeon 2005) No risk with progestogen only pills (Chakhtoura 2009) Population-based analysis (Lidegaard, NEJM 2012) RR 1.40 (95% CI ) to 2.20 ( ), with doses of ethinyl estradiol of 30 to 40 micrograms RR 2.49 ( ) with vaginal ring RR 3.15 ( ) with transdermal patch

32 OCs and hemorrhagic stroke World Health Organization studies (Lancet 1996) Combined OC formulations Risk depends on geographic region (developing >> developed countries)

33 OCs and stroke: RATIO study Kemmeren, et al. Stroke 2002;33:1202

34 OC use and genetic or acquired prothrombotic factors First author, year Slooter, 2005 Biomarker (genetic or acquired) FVL MTHFR 677TT Adjusted OR: non-oc users 0.4 ( ) 1.1 ( ) Adjusted OR: OC users 11.2 ( ) 5.4 ( ) Pruissen, 2008 FXIII Tyr204Phe 8.8 (4.3-18) 20 (9-46) Andersson, 2012 vwf > 90 th percentile ADAMTS13 < 10 th percentile Urbanus, 2009 Lupus anticoagulant (Ratio s/c > 1.15) 1.6 ( ) 1.8 ( ) 11.4 ( ) 5.1 ( ) 33.6 ( ) ( )

35 Class I Recommendations: Oral Contraceptives Class I Recommendations Measurement of blood pressure prior to initiation of hormonal contraception is recommended. Class, (LOE) Class I, LOE B Bushnell, et al. Stroke 2014;Feb 6

36 Class III Recommendations: Oral Contraceptives Class III Recommendations OCs may be harmful in women with additional risk factors (e.g. cigarette smoking, prior thromboembolic events). Class, (LOE) Class III, LOE B Routine screening for prothrombotic mutations prior to initiation of hormonal contraception is not useful Class III, LOE A Bushnell, et al. Stroke 2014;Feb 6

37 Class IIb Recommendations: Oral Contraceptives Class IIb Recommendations Class, (LOE) Among OC users, aggressive therapy for stroke risk factors may be reasonable. Class I, LOE C Bushnell, et al. Stroke 2014;Feb 6 37

38 Migraines with aura

39 Migraines with aura and stroke Kurth, Chabriat, and Bousser Lancet Neurology 2012

40 Migraines with visual aura Risk increased with OC use and smoking MacClellan, et al. Stroke 2007

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42 Migraines with aura and stroke risk Absolute risk: 4 additional ischemic stroke cases per 10,000 women per year when migraine w/aura was the assumed underlying cause of stroke Kurth and Diener. Stroke 2012

43 Recommendations: Migraine with Aura Class IIb Recommendations Because there is an association between higher migraine frequency and stroke risk, treatments to reduce migraine frequency might be reasonable, through evidence is lacking that this treatment reduces the risk of first stroke. Class IIa Recommendations Due to the increased stroke risk seen in women with migraine headaches with aura and smoking, it is reasonable to strongly recommend smoking cessation in women with migraine headaches and aura. Class, (LOE) Class IIb LOE C Class, (LOE) Class IIa LOE B Bushnell, et al. Stroke 2014;Feb 6 43

44 Menopause and Hormone Replacement

45 Early Menopause and Stroke Risk HR 2.03, 95% CI Lisabeth L, et al. Stroke. 2009; 40:

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47 Age at menopause and stroke risk No consistent findings Complex relationships between reproductive age, surgical menopause, lifetime estrogen exposure, pregnancies, breast-feeding, contraceptive use Cigarette smoking, malnutrition, lower socioeconomic status, and heredity are associated with earlier age at menopause Lisabeth and Bushnell. Lancet Neurology 2011;11:82-91

48 Risk factors and menopause Study of Women Across the Nation (SWAN) 3302 women in menopausal transition 1054 women with non-surgical final menstrual period without HT use Only total cholesterol, LDL-C, and apolipoprotein B were substantially increased the 1 year before and after FMP Other risk factors were associated with aging Matthews, et al. JACC 2009;54:

49 Hormonal replacement Commonly studied formulations: conjugated equine estrogens, medroxyprogesterone Less commonly studied: Estradiol No role in stroke secondary prevention (HERS, WEST) Increased risk in primary prevention trials (WHI) No benefit in risk with SERMS and a possible increased risk of fatal stroke with raloxifene.

50 Outcomes in Women Estrogen Stroke Trial Viscoli et al. NEJM 345 (17): 1243, 2001

51 Ischemic stroke risk by WHI hormone trial Hendrix, S. L. et al. Circulation 2006;113:

52 Mendelsohn and Karas. Science 2005

53 What if HRT is started earlier? Timing hypothesis: Kronos Early Estrogen Protection Study of women ages within 36 months of final menstrual period Outcomes: coronary artery calcium scores and carotid intimal media thickness (IMT) Initial results presented at North American Menopause Society meeting Oct 2012, no significant change in subclinical vascular disease with estrogen

54 Recommendations: Menopause and Postmenopausal Hormone Therapy Class III Recommendations Hormone therapy (conjugated equine estrogen) with or without medroxyprogesterone) should not be used for primary or secondary prevention of stroke in postmenopausal women. Selective estrogen receptor modulators, such as raloxifene, tamoxifen, or tibolone, should not be used for primary prevention of stroke. Class, (LOE) Class III LOE A Class III LOE A Bushnell, et al. Stroke 2014;Feb 6

55 Guideline Summary Now what?

56 Women in Stroke Clinical Trials Women account for < ½ of subjects enrolled in NIH stroke prevention clinical drug trials Low participation of women in stroke prevention clinical trials limits the generalization of results Bushnell, et al. Stroke 2014;Feb 6

57 Representation of Women in Clinical Trials Representation of Women in Carotid Intervention Trials TRIAL Total patients enrolled (% of women) NASCET 663 (32) NASCET moderate 2303 (29) ECST 3035 (28) ACAS 1662 (34) ACST 3165 (34) EVA-3s 520 (25) SPACE 1207 (28) CREST 2491 (35) Representation of Women in Antiplatelet Trials TRIAL Total patients enrolled (% of women) ACE 2806 (30) ESPC (42) CAPRIE (30) MATCH 7624 (37) AAASPS 1824 (53) ESPRIT 2714 (35) ProFESS (37) SPS (37) Bushnell, et al. Stroke 2014;Feb 6

58 Framingham Stroke Risk Profile in Women: Probability of Stroke Within 10 Years Points Age,y Untreated SBP, mmhg Treated SBP, mmhg Diabetes No Yes Cigs No Yes CVD No Yes AF No Yes LVH No Yes Yes

59 Framingham Stroke Risk Score: What does this mean for women? Points 10-Year Probability, % Points 10-Year Probability, % Points 10-Year Probability, % For a score of 10 points, men have 10% and women have 6% 10-year risk of stroke.

60 Recommendations on treatment for traditional risk factors See AHA/ASA Primary and Secondary Prevention guidelines

61 Major gaps in evidence for sexspecific recommendations BP lowering approaches in women vs men Prospective data on the pathophysiology of long-term stroke risk after preeclampsia, as well as intervention trials to reduce risk Risk of hemorrhagic stroke with OC use Stroke risk related to early onset and type of menopause, and lifetime estrogen exposure Formulations of natural or transdermal estrogen for menopausal therapy initiated early

62 Major gaps in evidence for sexspecific recommendations (cont) Strategies to reduce the frequency of migraine with aura Appropriate doses of newer oral anticoagulants to prevent stroke in older, low body weight women with atrial fibrillation Mechanisms underlying the relationship between depression, psychosocial stress, and stroke risk Does carotid endarterectomy reduce stroke risk better than medical therapy in women?

63 Most important gap in evidence for sex-specific recommendations: The lack of a stroke risk score that includes risk factors unique to women

64 Sex Differences in Stroke Risk Summary and Future Directions Stroke risk differs in men and women Women s unique risk factors differ by age and menopausal status Current stroke risk scores do not account for ages below 55, or sex-specific risk factors More research is needed to understand the biology of sex differences in stroke risk

65 Questions?