Gender Differences in Stroke Among Older Adults
Stroke is a common disease in the older population. Many gender differences are seen in the epidemiology, outcomes, and treatment of geriatric stroke. Although these differences are not fully understood, recognition of gender differences may help with appropriate treatment and improve outcomes.

Stroke is the leading cause of disability and the third leading cause of death in the United States. Age is the principal nonmodifiable risk factor for this disease. The incidence of stroke increases significantly with age in both men and women, with half of all strokes occurring in people over age 75, and one-third in the population over age 85. Although the entire older population is at risk for stroke, there are gender differences in the incidence by age subgroups. The incidence of stroke is higher in men up to age 75, similar in the 75-84 age group, and higher in women in the age group greater than 85.

Despite the higher risk in men, the lifetime risk of stroke is higher in women. The Framingham study calculated lifetime risk of stroke among middle age men and women and found that the lifetime risk in women age 55 was 21% and in men age 55, 17%. This may be attributed to the longer life span in women. Some of these incidence and risk differences may also be biological. However, there are many other gender differences in stroke such as outcomes, risk factors, treatment, and mortality that have more complicated and unexplained underlying etiologies.

An easily obtainable outcome measure is stroke mortality. Using United States death certificate data in the 1995-1998 period, Ayala et al. found over 600,000 stroke deaths. Of these, 61% were women. However, after adjusting for age, they found stroke death rates were lower in women than in men for ischemic stroke overall. When examined by race, white women had higher stroke death risk than white men. Pooled data from multiple studies also showed that in individuals over age 70, the 1-year mortality was 24% in white men and 27% in white women, but 25% in black men and 22% in black women. Mean age of stroke death was 79.6 years, but men had a younger age at stroke death than women.

Although mortality may not be higher in women, functional outcome may be. Di Carlo et al. found in a large registry that 3-month disability and handicap were higher in women after adjusting for age. In this group, women were significantly older when presenting with first stroke (74 years as compared to 69). They were also more likely to be living alone or living in an institution prior to stroke. Another study found similar results; at 3 months, women were more dependent and living in an institution after stroke than men. They postulate depression as playing a role since women are more likely to be depressed after stroke than men.

However, another explanation could be that strokes that are more disabling occur more frequently in women. One way to evaluate if this is true is by looking at stroke subtypes. Ischemic strokes may be classified into different categories, outlined in Table 1 . In a population-based study of first ischemic stroke, individuals with lacunar strokes had milder deficits compared with other subtypes. Rates of recurrent stroke were higher in large vessel atherosclerosis and cardiac emboli. Stroke subtype distribution changes when comparing patients of different ages, with older patients having more embolic strokes than younger ones. No significant gender differences are observed in subtypes within this specific group of patients. On the other hand, the Warfarin-Aspirin Symptomatic Intracranial Disease Study (WASID) found women with intracranial atherosclerosis had a 2-year rate of stroke or vascular death of 28.4% compared with 16.6% in men.

However, in a large hospital-based registry, unknown subtype was significantly higher among women, and was found to be associated with less workup in women patients with a lower proportion of brain imaging performed in women. Similarly, in another study, women were found to be less likely to have echocardiography or any carotid investigation when hospitalized for stroke after controlling for other confounding variables such as age and initial stroke severity. It is possible that women are not evaluated as aggressively as men and possibly not treated appropriately.

The only acute treatment available for ischemic stroke is intravenous tissue plasminogen activator (tPA). In acute stroke, differences have been reported after tPA use. Although there did not appear to be gender differences in response to IV tPA, an anlaysis of data from the Glycine Antagonist in Neuroprotection (GAIN) trial showed men demonstrated better functional recovery than women after tPA. They found men had better likelihood of BI >95 and mRS<1 compared with women. However, there was no difference in mortality. They speculate that higher levels of procoagulant factors in women may contribute to this finding. However, a pooled analysis of tPA trials showed the opposite; women may respond better to IV tPA than men. This study pooled data from tPA trials up to 6 hours and therefore was a different treatment window. It still remains to be determined whether there is true gender difference in response to IV tPA.

The proportion of individuals with ischemic stroke who receive IV tPA is small and cannot therefore explain all differences in outcome. Other possibilities include differences in secondary stroke prevention.

American Heart Association guidelines for secondary stroke prevention recommend blood pressure control using diuretics and angiotensin converting enzyme (ACE) inhibitors, lipid control, smoking cessation, carotid endarterectomy in patients with symptomatic stenosis 70-99%, warfarin in patients with atrial fibrillation, and antiplatelet therapy in patients with atherothrombotic disease. They also do not recommend postmenopausal hormone replacement with estrogen with or without progestin. These guidelines are based on a large body of clinical trial data.

Despite these established practices, some studies have found gender differences in medical treatment for stroke prevention. In an older adult cohort (mean age 80) after stroke, women were less likely to have adequate blood pressure control. A Swedish registry also found in an older population, mean age 75, women with first stroke were less likely to be treated with antithrombotic drugs and less likely to receive anticoagulation when found to have atrial fibrillation.

Atrial fibrillation (AF) is the most frequent persistent cardiac arrhythmia among older adults. Over 30% of all strokes in persons aged 80-89 are associated with AF. Older women have higher annual rates of thromboembolism off warfarin than older men (3.5% vs 1.8%, unadjusted relative risk of 1.9), with similar rates of efficacy and major hemorrhagic events. In spite of compelling evidence in all age groups in favour of warfarin for AF treatment, physicians are still reluctant to prescribe anticoagulation to older adults, especially to women and those over 80 years of age. The populations most likely to benefit from anticoagulation may be less likely to receive it. Why these disparities in medical therapy exist is not clear.

Differences in surgical therapy are also apparent. This is evident from the results of clinical trials in carotid endarterectomy. Carotid stenosis is a risk factor for stroke. In the North American Symptomatic Carotid Endarterectomy Trial (NASCET) study, individuals with symptomatic carotid stenosis had a 26% risk of recurrent stroke with medical treatment after a transient ischemic attack (TIA) or minor stroke and an ipsilateral carotid stenosis of 70% or more. Men benefited from the procedure, but to a lesser degree, with 50-69% stenosis. Women, however, have a less clear-cut benefit in this range of stenosis because of increased perioperative risk and may be better treated medically.

In the Asymptomatic Carotid Artery Stenosis study (ACAS), a large randomized trial of endarterectomy in asymptomatic carotid stenosis, the study was stopped early because a significant benefit of surgery was found. The rate of ipsilateral stroke, any perioperative stroke or death in surgically-treated patients was 5% over 5 years while in medically treated patients the rate was 11% (55% risk reduction, p=0.004). The benefit was most notable among men compared to women.

Another large randomized trial showed that among persons less than 75 years of age with severe carotid stenosis, the risk of stroke in the medically treated patients was 11% and the immediate surgery group had a risk of 3.8% at 5 years. The immediate 30-day risk of stroke or death after endarterectomy was 3.1%. In contrast to ACAS, the surgical benefits were similar in men and women. A meta-analysis of both the ACAS and the Asymptomatic Carotid Surgery Trial (ACST) did not suggest significant benefit for women in this setting, and therefore endarterectomy will need to be approached cautiously in women.

One of the obvious biological differences between genders is hormonal. The relationship between hormonal status in women and risk of vascular disease has been the focus of many studies. Premenopausal women seem to be protected from vascular disease. Both basic science research and observational data have suggested a possible beneficial effect of hormone replacement therapy (HRT) on cardiovascular disease. Three major clinical trials have assessed HRT and stroke risk in postmenopausal women.

The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized trial of estrogen and progestin in postmenopausal women with known coronary heart disease (CHD). Overall, there was no difference between the HRT and placebo groups in myocardial infarction (MI) or CHD death. There was a significant time effect in which there were more events in the HRT group in the first year with fewer events in subsequent years. The HERS II study had a longer term follow up and did not find persistent lower risk at a mean of 6.8 years of follow up. In the HERS cohort, examining only stroke outcomes, no difference was found in stroke risk between the hormone and placebo arms.

Another randomized trial evaluated hormone use in patients with stroke. In the Women-s Estrogen for Stroke Trial (WEST), postmenopausal women who had recent stroke or TIA were randomized to estrogen versus placebo. Outcomes of stroke or death were assessed. They found no difference between the estrogen and placebo group in death or stroke but women assigned to estrogen appeared to have a higher risk of fatal stroke.

The Women-s Health Initiative (WHI) trial addressed the role of HRT on primary prevention. Over 16,000 women without cardiac disease were followed for a mean of 5.6 years. Subjects were randomized to estrogen versus placebo; 1.8% of the estrogen/progestin group had a stroke compared with 1.3% in the placebo group. The hazard ratio of women on hormones versus placebo was 1.31 for either ischemic or hemorrhagic stroke. Ischemic stroke risk was increased by 44%.

The gender differences in stroke are complicated. Although some biological differences such as hormonal state and longer lifespan may explain some differences, there is still much that is not understood. Gender is likely a marker for multiple medical, genetic, and socioeconomic factors that will require further study to elucidate.