Risk Factors of Ischemic Stroke
Numerous factors contribute to the risk of first stroke. The non-modifiable risk factors include increasing age, sex, race/ethnicity, family history, genetic factors, and low birth weight. While not modifiable, these risk factors may identify those who are at highest risk of stroke and who may benefit from aggressive treatment of any modifiable risk factors. Regarding age, each decade above 55 years of age leads to a doubling of stroke risk.⁴ Men carry an overall higher risk of stroke than women at younger ages, but women are at greater risk over the age of 85 years.⁵ This relatively greater risk in older women may reflect changing hormonal status and/or the use of hormone replacement therapy (HRT), as well as the fact that men with stroke risk factors may die earlier from cardiovascular disease.^6,7 Race and ethnic contributions to stroke risk are difficult to separate from other risk factors such as hypertension and diabetes, which are more prevalent in certain populations. Even taking into account these risk factors, however, stroke incidence rates remain higher among some racial ethnic groups (e.g. African- Americans).^8,9 Unidentified genetic risk factors may predispose these groups to stroke and may eventually help to explain the contribution of family history to stroke risk. Stroke is a manifestation of a variety of rare genetic disorders, but the association between most inherited coagulopathies e.g. protein C and S deficiency and arterial events is weak.^10,12 Finally, stroke incidence and stroke mortality are increased among individuals with low birth weight.^13,14

The long list of modifiable stroke risk factors is best separated into two groups:

" those that clearly contribute to risk and, if modified, reduce the risk of incident stroke; and " those that are associated with stroke, but have not been well studied or do not reduce the risk of stroke when treated.

Well documented risk factors that clearly benefit from specific management include hypertension, cigarette smoking, atrial fibrillation, dyslipidemia, diabetes mellitus, and asymptomatic carotid stenosis (see Table 1).^15-17 The discussion and treatment of these risk factors will be the focus of this article. Other well documented risk factors are cardiovascular and peripheral arterial disease, sickle cell disease, and obesity. Less well documented or potentially modifiable risk factors include metabolic syndrome, hyperhomocysteinemia, hypercoagulability, oral contraceptive use, inflammatory processes, migraine headache, and sleep apnea, among others.¹⁸

Hypertension
Blood pressure is a powerful determinant of stroke risk and, because hypertension is the most prevalent of the modifiable stroke risk factors throughout middle and older age, its treatment would produce the greatest impact on reducing the burden of stroke.¹⁹ Recent evidencebased guidelines on management of hypertension recommend antihypertensive agents and lifestyle modification to keep blood pressure <140/90, with even tighter control recommended for those with additional vascular risk factors such as diabetes and chronic kidney disease (see Table 2).²⁰ Overall, across multiple classes of antihypertensive therapy, blood pressure reduction is associated with approximately 30 40% reduction in the incidence of stroke, with more intensive lowering superior to less.^21,22 Placebo-controlled studies have demonstrated the efficacy of thiazide diuretics, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, and calcium-channel blockers in reducing stroke and cardiovascular outcomes.^21,22 In general, the choice of a particular class of agents is less important than the degree of blood pressure reduction achieved.