Primary and Secondary Stroke Prevention in Women

Educational Objectives

The goal of this program is to improve management of primary and secondary stroke prevention in women. After hearing and assimilating this program, the clinician will be better able to:

1. Identify the risk factors for stroke in women.
2. Recommend guideline-based treatment strategies for stroke risk reduction in women.
3. Reduce cardiovascular risk in women with aspirin or surgical intervention.

Summary

Points of consideration: underrepresentation of women in stroke trials prevents full data extrapolation; women-specific risk factors, eg, pregnancy, oral contraceptives (OCs), menopause, hormone replacement therapy (HRT) must be considered; many data that compare women to men are post hoc subgroup analyses that need to be used with caution and should not be extrapolated

Risk Factors for Stroke in Women

Pregnancy: the incidence of stroke is ≈34 per 100,000 pregnant women (compared with ≈21 per 100,000 individuals in nonpregnant women); have the highest risk for stroke is highest during the third trimester and the postpartum period because of the hypercoagulable state created by an increased level of clotting factors (eg, fibrinogen); pregnancy-related hypertension is a leading cause of stroke in pregnancy; preeclampsia, gestational diabetes mellitus (GDM), and pregnancy-induced hypertension (PIH) increase the risk for future cardiovascular disease (CVD) and stroke beyond the childbearing years, although the reasons for this relationship are unclear

American Heart Association (AHA) guidelines for evaluation of stroke in women: all women 6 mo to 1 yr postpartum, as well as those past childbearing age, should be evaluated for a history of preeclampsia and eclampsia, and this should be documented as a risk factor; evaluate and treat these patients for CV risk factors; pre-pregnancy hypertension (PPH) may increase the risk for preeclampsia and stroke; antihypertensive medications for PPH should be selected based on the patient's future plans for pregnancy; aspirin therapy — to prevent preeclampsia, women with chronic primary or secondary hypertension or prior pregnancy-related hypertension should take low-dose aspirin (81 mg) starting at 12 wk of gestation until delivery (American Congress of Obstetricians and Gynecologists recommends aspirin during wk 12-28); calcium supplementation — a Cochrane review showed benefit for prevention of preeclampsia; oral calcium supplementation of 1 g per day may be considered for women with low dietary intake of calcium

Oral contraceptives (OCs): use of OCs increase overall risk for stroke by 2 to 2.7-fold; some systematic reviews found that progesterone-only OCs do not increase the risk for ischemic stroke (IS), whereas OCs that contain estrogen do increase risk; risk factors include older age, smoking, hypertension, history of migraines with aura, and prothrombotic mutations; progesterone-only options may be considered in patients with risk factors; testing for prothrombotic mutations before starting OCs is not generally recommended because they are uncommon; use of OC is a risk factor for cerebral venous sinus thrombosis (CVST)

Cerebral venous sinus thrombosis: has one of the most prominent differences in sex prevalence among patients 31 to 50 yr of age; women represent >70% of cases in CVST trials; inherited thrombophilia and any type of hypercoagulable state (eg, malignancy) are also risk factors but are not sex-dependent; anticoagulation should be initiated immediately independent of risk for hemorrhage or infarction; patients can present with a change in the type of headache or they might have a new-onset headache; magnetic resonance venography can help

Menopause and stroke: occurrence of menopause at <42 yr of age is associated with an increased risk for stroke; some studies suggest a difference in stroke risk following a hysterectomy vs hysterectomy and oophorectomy; some randomized controlled trials found no difference in primary and secondary prevention of stroke with HRT, although some studies suggested an increase in risk for stroke with HRT; recommendations from the American Society of Reproductive Medicine — HRT should be avoided in the absence of significant symptoms of menopause or if menopause symptoms are present and the patient has a contraindication to HRT, cardiac or stroke history, or an increased risk for stroke based on the Framingham stroke scale; in the absence of contraindications or history of stroke, use the Framingham Coronary Heart Disease risk score to estimate the overall risk, and calculate the years since the last menstrual period; guidelines on menopause and stroke should not be used for primary or secondary prevention of stroke in postmenopausal women; avoid use of selective estrogen receptor modulators, eg, raloxifene, tamoxifen, tibolone for primary prevention of stroke

Risk Factors for Stroke More Common in Women

Hypertension: one study showed that antihypertensive treatment in women >55 yr of age was associated with a risk reduction in fatal and nonfatal stroke events of 38%; evidence is insufficient to support a sex-specific approach to management of hypertension

Atrial fibrillation (AF): men and women <65 yr of age have equivalent risk for stroke, although some studies show that men may have a slightly increased stroke risk; among patients >65 yr of age, women are at higher risk; female sex is thought to be an independent predictor of stroke in patients with AF and is given 1 point on the CHA₂DS2-VASc score; on the CHA₂DS2-VASc, 2 points are given for patients age ≥75 yr; anticoagulation is recommended for a patient who is female and age ≥75 yr in the absence of other risk factors; studies for novel anticoagulants, eg, apixaban, dabigatran lack insufficient power to determine a sex difference; AHA recommendations — active screening, measurement of pulse, and electrocardiography are recommended; oral anticoagulation is not recommended for women <65 yr of age with AF and no other risk factors (CHADS₂ score of 0 or CHA₂DS2-VASc score of 1); antiplatelet therapy or aspirin are reasonable for select low-risk women

Migraine headache: migraines are more common in women than in men and are rarely associated with cryptogenic stroke (4 cases per 10,000 women annually); migraine with aura is thought to double the risk for IS seen with migraines; AHA recommendations — sufficient data are not available to recommend specific approaches for migraine treatment to lower the stroke risk, but triptans are contraindicated in patients with migraines and a history of stroke or coronary artery disease because of their vasoactive properties; treatments to reduce frequency of migraines are recommended; smoking cessation is strongly recommended for women with migraine headaches with aura

Interventions in Women

Use of aspirin: the Womens Health Study compared 100 mg of aspirin vs placebo for primary prevention; aspirin was associated with risk reduction of IS of 24%; a nonsignificant increase in hemorrhagic stroke was observed; gastrointestinal bleeding was more common in the aspirin group; women >65 yr of age had the most consistent benefit in reduction of stroke risk (≈30%); AHA recommendations — aspirin therapy (81 mg daily) can be useful in women >65 yr of age; unless contraindicated, aspirin therapy at a dose of 75 to 325 mg per day is reasonable for women with DM (although 81 mg is usually prescribed); prescribe clopidogrel (Plavix) for a high-risk woman with intolerance to aspirin; studies show comparable stroke risks for aspirin vs clopidogrel

Carotid stenosis (CS): stenosis of ≥70% is considered severe, and 50% to 60% is considered moderate; women have smaller caliber of the internal carotid arteries and shorter stenotic segments; ACAS and NASCET trials showed carotid endarterectomy (CEA) was more beneficial for patients with symptomatic severe CS than in those with moderate CS; in the NASCET trial, men comprised ≈69% of the study population; post hoc subgroup analysis showed that intervention may be less beneficial in women than in men, particularly in those with moderate CS; the analysis was not prespecified and may be biased due to small sample size and its post hoc nature, and the intervention is still offered to women; in a retrospective study of 299 patients with transient ischemic attack (TIA) and CS (47% of which were women), women were less likely to undergo CEA; the time to receipt of CEA was longer for women; interventions should be performed ≤2 wk of the stroke or TIA

AHA guidelines for CEA: CEA is recommended for women with TIA or IS ≤6 mo and ipsilateral severe CS if the perioperative morbidity and mortality risk is <6%; for women with moderate CS, CEA is recommended based on patient-specific factors (eg, age, comorbidities) and a perioperative risk of <6%; when indicated, CEA ≤2 wk of TIA or stroke is reasonable if no contraindications exist for early revascularization (eg, hemorrhagic conversion of stroke)

Readings

Bushnell C, McCullough LD, Awad IA, et al. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association [published correction appears in Stroke. 2014 Oct; 45(10); e214] [published correction appears in Stroke.2014 May; 45(5):e95]. Stroke. 2014; 45(5):1545-1588. doi:10.1161/01.str.0000442009.06663.48; Chaemsaithong P, Cuenca-Gomez D, Plana MN, et al. Does low-dose aspirin initiated before 11 weeks' gestation reduce the rate of preeclampsia? Am J Obstet Gynecol. 2020; 222(5):437-450. doi:10.1016/j.ajog.2019.08.047; Gallù M, Marrone G, Legramante JM, et al. Female sex as a thromboembolic risk factor in the era of nonvitamin K antagonist oral anticoagulants. Cardiovasc Ther. 2020;2020:1743927. doi:10.1155/2020/1743927; Madsen TE, Howard VJ, Jiménez M, et al. Impact of conventional stroke risk factors on stroke in women: an update. Stroke. 2018; 49(3):536-542. doi:10.1161/STROKEAHA.117.018418; Meeks JR, Bambhroliya AB, Alex KM, et al. Association of primary intracerebral hemorrhage with pregnancy and the postpartum period. JAMA Netw Open. 2020; 3(4):e202769. doi:10.1001/jamanetworkopen.2020.2769; Mirzaei H. Stroke in women: risk factors and clinical biomarkers. J Cell Biochem. 2017; 118(12):4191-4202. doi:10.1002/jcb.26130; Øie LR, Kurth T, Gulati S, et al. Migraine and risk of stroke. J Neurol Neurosurg Psychiatry. 2020; 91(6):593-604. doi:10.1136/jnnp-2018-318254; Orrapin S, Rerkasem K. Carotid endarterectomy for symptomatic carotid stenosis. Cochrane Database Syst Rev. 2017; 6(6):CD001081. doi:10.1002/14651858.CD001081.pub3; Ridker PM, Cook NR, Lee I, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005; 352:1293-1304. doi: 10.1056/NEJMoa050613; Rothwell PM, Eliasziw M, Gutnikov SA, et al. Carotid endarterectomy trialists collaboration. endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery. Lancet. 2004; 363(9413):915-924. doi:10.1016/S0140-6736(04)15785-1; Welten SJGC, Onland-Moret NC, et al. Age at menopause and risk of ischemic and hemorrhagic stroke. Stroke. 2021; 52(8):2583-2591. doi:10.1161/STROKEAHA.120.030558; Zhang Y, Parikh A, Qian S. Migraine and stroke. Stroke Vasc Neurol. 2017; 2(3):160-167. doi:10.1136/svn-2017-000077.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Murali was recorded at the 29th Annual Primary Health Care of Women Conference, held December 2-3, 2021, and presented by the University of Michigan Medical School, Department of Family Medicine. For information on upcoming CME activities from this presenter, please visit UMFamilyMedCME.com. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

OB690902

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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