Women suffer strokes more often and at an older age. Women have a worse outcome after stroke and suffer particularly from the impact on their independence in everyday life. In addition to specific risk factors such as pregnancy and use of oral contraceptives, other risk factors are of particular importance in women: arterial hypertension, atrial fibrillation, and migraine with aura. Women are underrepresented in clinical trials. Greater inclusion of women in stroke research is critical to improving future treatments.
More than 4.3 million women live in Switzerland. On average, women live about 4 years older than men. The nature and course of many diseases differ between the sexes. This is especially true for stroke. Unfortunately, women are underrepresented in clinical trials, which significantly limits the applicability of results to women. To address gender differences in stroke between men and women, the American Heart Association/American Stroke Association developed a joint position paper in 2014 [1]. The guidelines recommended therein for the prevention of ischemic stroke in women will be discussed in this summary.
Lower incidence in younger women
Ischemic stroke is far more common than hemorrhagic stroke, accounting for approximately 85%. Due to improved primary prevention options, the incidence of ischemic stroke has been reduced in many Western countries, with a particular decline in men. Mortality from ischemic stroke is approximately 74.3/100,000 for women compared with 78/100,000 for men. Mortality is lower in younger women than in men; however, as they age, it becomes similar to that of men, and later (around age 75) it even increases beyond that. In addition, women are older on average at the time of stroke. This is probably related to the neuroprotective effects of endogenous female steroid hormones such as estrogen and progesterone [2]. This is also the reason for the lower incidence of stroke in younger women. With the onset of menopause and a drop in hormone levels, the protective effect decreases. In summary, although the incidence of stroke in women is approximately 25% lower than that in men, more strokes occur in women than in men in absolute numbers because of the longer life expectancy of women [3].
Recovery from stroke and success of acute therapies.
Women also recover less well from stroke after accounting for their older average age. They are less likely to regain the skills to manage their daily lives independently. Women are more likely to be affected by depression after stroke, which also has a negative impact on quality of life [2]. The reasons for this disadvantage in recovery are not entirely clear; in addition to difficult-to-correct effects resulting from the (statistical) age difference between affected men and women, socioeconomic factors also seem to play a role.
For example, thrombolytic therapy with reversible tissue plasminogen activator (rtPA), although at least as effective in women as in men, is used less frequently in women [4,5]. This cannot be explained by the fact that women seek medical help later on symptoms of stroke or reach the hospital later. Studies have shown that women were less likely to receive advanced diagnostics such as echocardiography and cerebral imaging [6]. The causes of these differences in stroke diagnosis and treatment between the sexes have not yet been determined.
Risk factors
Arterial hypertension: In addition to gender-specific risk factors such as pregnancy and the use of hormone replacement therapy after menopause, other risk factors are also unequally distributed between the sexes (Table 1) . A significant role is played by arterial hypertension, which influences the risk of stroke to a particularly high degree. Although women are less likely to be diagnosed with arterial hypertension before menopause, the incidence after menopause exceeds that of men. Thus, women with stroke are more likely to have arterial hypertension than men. Just like men, they clearly benefit from treatment of hypertension; the risk of stroke can be reduced by approximately 38% with blood pressure control, although the type of treatment is less important than achieving normotensive blood pressure values [7]. Although women receive treatment for hypertension, and it is adjusted with similar frequency as in men, reaching the target blood pressure range appears to be more difficult in postmenopausal women than in men of the same age. Side effects of blood pressure medication are more common in women. In addition to possible compliance problems (poorer compliance in women taking blood pressure medication has never been shown), hormone-dependent and -independent sex-specific factors involved in systemic blood pressure regulation and local modulation of vascular resistance probably play a role here.
Thus, although there are differences in blood pressure regulation and response to therapy, current recommendations for the treatment of arterial hypertension in the primary prevention of stroke are the same for women and men and should be implemented consistently in both sexes.
Obesity, metabolic syndrome, and lifestyle factors: Obesity is an independent risk factor for stroke. In particular, the abdominal form (hip circumference >88 cm in women) is associated with increased risk of stroke and is more common in women than in men. There is a linear relationship between body mass index (BMI) and stroke risk, independent of gender. Whether obesity affects stroke outcomes differently in women and men is unclear. The metabolic syndrome, which combines several cardiovascular factors (abdominal type of obesity, insulin resistance, arterial hypertension, dyslipidemia), seems to be associated with a higher risk of stroke in women, and to cause more strokes in women. Pro-inflammatory and pro-thrombotic factors are thought to be causative. A healthy lifestyle with plenty of exercise, a diet rich in fruits and vegetables and low in saturated fatty acids (“Mediterranean”), without smoking and with only moderate alcohol consumption has a positive influence on the risk of stroke in women and men [8]. Measures to support a healthy lifestyle are recommended for both women and men in prevention.
Atrial fibrillation: Atrial fibrillation (Vhfli) increases in frequency with age and is thus a particularly relevant risk factor for stroke in the elderly (causing approximately 25% of ischemic strokes in >80-year-olds). As women reach older ages, Vhfli is more common in women with stroke. Furthermore, the risk of stroke in women with Vhfli >75 years is higher than that of men of the same age. This is reflected in the newer scores that are intended to be used to estimate embolic risk and make anticoagulation decisions in patients with AF, such as the CHA2DS2-VASc score. According to current AHA recommendations, anticoagulation should be initiated in all women >75 years of age, even if no other risk factors are present. The good efficacy of the new anticoagulants (direct and indirect thrombin inhibitors) compared with Marcoumar was comparable in the pivotal trials for women and men.
Depression and psychosocial stress: Depression is not only a known consequence of stroke, but also increases the risk of stroke. The significance is considerable (approximately 35% increased risk of stroke with self-reported feelings of sadness or depression for more than 2 weeks in the past 12 months) [9] and approximately equal for both sexes. The influence of therapies or the way depression was surveyed in the studies has not yet been clarified. Since depression and psychosocial stress occur more frequently in women than in men, it can be assumed that these risk factors are particularly important in women.
Migraine with aura: Many people suffer from migraine-typical headaches, women about four times as often as men. Only migraine with aura (prevalence 4-5%) has been shown to be associated with increased risk of stroke. Aura symptoms may vary in nature (transient visual phenomena, unilateral tingling paresthesias, paralysis, or speech disturbances) and usually precede migraine headaches. The risk of stroke is increased by about a factor of 2 in people with this type of migraine. If there are other risk factors, such as smoking and taking estrogen-containing contraceptives, the risk increases significantly. Migrainous strokes are less severe than others and usually do not result in relevant functional limitations. Nevertheless, in view of the increased risk, especially in women with migraine, it is important to support the nicotine stop. Reducing the frequency of migraine attacks with basic prophylaxis can be considered, although this has not been shown to reduce the risk of stroke.
Women-specific risk factors: Strokes rarely occur during pregnancy (34/100,000 pregnancies). However, the risk is increased compared to non-pregnant women of the same age, especially in the 3rd trimester and postpartum. Complications during pregnancy such as gestational diabetes, elevated blood pressure, and pre-eclampsia are associated with an increased risk of stroke later in life. The guidelines recommend prophylaxis with low-dose aspirin from 12 weeks of age. Pregnancy week in women with chronic primary or secondary arterial hypertension or previous pregnancy-associated hypertension. Calcium supplementation may be considered to prevent preeclampsia in women with low calcium intake. Treatment of arterial hypertension should be done with the attending obstetricians and with consideration of the side effect profile of the antihypertensives.
Use of estrogen-containing oral contraceptives, as opposed to progestin pills, is associated with a slightly increased risk of ischemic stroke. The increase in risk is less than that due to pregnancy. Women with additional risk factors (smoking, arterial hypertension, older age, prothrombotic factors) have an additional increased risk with estrogen-containing oral contraceptives, which is why these preparations should be avoided here. Postmenopausal hormone replacement therapy is not recommended for primary or secondary stroke prophylaxis because of the increased risk here as well.
Other stroke prevention strategies
Although stroke affects women more often than men, the underrepresentation of women in clinical therapy trials is striking. This asymmetry also affects other clinical trials outside neurology. In studies of drug therapy with antiplatelet agents, the proportion of women ranged from 30-53%, and in carotid intervention studies, the proportion was as low as 25-34%. This implies that study results can only be applied to women to a limited extent. The current AHA guideline clearly expresses the urgent need for better representation of women in therapy trials to draw conclusions about gender differences. In the current situation, the same therapeutic principles should apply to women as to men regarding:
- Medium-high grade symptomatic stenosis of the internal carotid artery (carotid stenosis): Endarterectomy recommended, preferably within two weeks of event; stenting may be an alternative.
- Aspirin therapy in secondary prevention; should be started early.
For primary prevention, consider low-dose aspirin in women at increased risk of stroke due to diabetes or with a high vascular risk profile, in the absence of contraindications. The benefit in terms of prevention of stroke in primary prevention seems to be slightly higher in women than in men. Recommendations for primary preventive interventional treatment of asymptomatic carotid stenosis were not given in the current statement, because the overall data situation is controversial here anyway due to the longer-standing clinical studies on the subject and the now significantly improved conservative therapy. Detection of high-grade, asymptomatic carotid stenosis should be followed by search for and adjustment of risk factors and initiation of aspirin therapy.
Better examination of gender-specific factors.
Women are more likely than men to experience stroke, have poorer outcomes, and do not receive the same access to therapies. One factor here could be older age at the time of the stroke. Biological and socioeconomic differences are certainly contributory factors. Risk factors are present in different degrees in women and men and have different effects on stroke risk. The response to preventive treatments is also not the same.
Women can thus be considered particularly vulnerable. It is important for the practice to reveal differences in prevention and to create optimal treatment for women as well. Better study of gender-specific factors in the development of stroke and in the effectiveness of therapeutic interventions may help develop therapies that better protect women from stroke.
Literature:
- Bushnell C, et al: Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014; 45(5): 1545-88.
- Girijala RL, Sohrabji F, Bush RL: Sex differences in stroke: review of current knowledge and evidence. Vasc Med. 2016.
- Ovbiagele B.: National sex-specific trends in hospital-based stroke rates. J Stroke Cerebrovasc Dis. 2011; 20(6): 537-40.
- Meseguer, et al: Outcomes of intravenous recombinant tissue plasminogen activator therapy according to gender: a clinical registry study and systematic review. Stroke. 2009; 40(6): 2104-10.
- Asdaghi N, et al: Sex Disparities in Ischemic Stroke Care: FL-PR CReSD Study (Florida-Puerto Rico Collaboration to Reduce Stroke Disparities). Stroke. 2016; 47(10): 2618-26.
- Reeves MJ, et al: Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol. 2008; 7(10): 915-26.
- Turnbull F et al: Do men and women respond differently to blood pressure-lowering treatment? Results of prospectively designed overviews of randomized trials. Eur Heart J. 2008; 29(21): 2669-80.
- O’Donnell MJ, et al: Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study. Lancet. 2016; 388(10046): 761-75.
- O’Donnell MJ, et al: Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet. 2010; 376(9735): 112-23.
InFo NEUROLOGY & PSYCHIATRY 2017; 15(1): 19-23.
