Gender Differences in Prevention of Stroke

Gender differences in the primary prevention of stroke with aspirin
Eric E Adelman1, Lynda Lisabeth1,2 & Devin L Brown†1

ABSTRACT   
Aspirin is used to prevent ischemic stroke and other types of cardiovascular disease. Seven trials of aspirin focusing on the effectiveness of primary prevention of stroke and other cardiovascular events have been performed, but three of these did not include women. Data from these trials, and one meta-analysis, suggest that aspirin prevents myocardial infarction in men and stroke in women, although the findings in women were driven by the results of a single large study, and a subsequent meta-analysis did not find a gender difference. The reasons for the possible gender differences in aspirin’s effectiveness are not entirely clear.

Medscape: Continuing Medical Education Online
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Future Medicine Ltd. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.   Release date: 23 May 2011; Expiration date: 23 May 2012

Learning Objectives
Upon completion of this activity, participants should be able to:

• Describe gender-specific findings from trials of aspirin focusing on the effectiveness of primary prevention of stroke and other cardiovascular events
• Describe professional society guidelines regarding use of aspirin for primary prevention of stroke and other cardiovascular events in women
• Describe risks of aspirin used for primary prevention of stroke and other cardiovascular events in women

Authors and Disclosures
Eric E Adelman, MD, Stroke Program, Department of Neurology, University of Michigan, Cardiovascular Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.  Disclosure: Eric E Adelman has disclosed no relevant financial relationships.

Lynda Lisabeth, PhD, Stroke Program, Department of Neurology, University of Michigan, Cardiovascular Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA; and Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.  Disclosure: Lynda Lisabeth has disclosed no relevant financial relationships.

Devin L Brown, MD, Stroke Program, Department of Neurology, University of Michigan, Cardiovascular Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.   Disclosure: Devin L Brown has disclosed no relevant financial relationships.

Editor
Elisa Manzotti, Editorial Director, Future Science Group, London, UK. Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

In the USA, stroke is the third leading cause of death and the leading cause of disability [1].While treatments for acute stroke and options for secondary stroke prevention have proliferated in recent years, the greatest potential to reduce the impact of stroke lies in primary prevention.

Every year in the USA there are close to 800,000 strokes [1]. While approximately 185,000 are recurrent strokes, approximately three-quarters are new events and greater than half occur in women [1]. Risk factors for stroke such as hypertension, smoking, diabetes, physical inactivity and obesity are becoming more prevalent in an aging US population. Lost earnings and caregiving costs due to stroke put a tremendous burden on society and underscore the need for effective preventive strategies [2]. Given disparities in stroke burden by gender, these strategies should be assessed in both men and women.

The ancient Greeks knew that willow bark had analgesic properties but it was centuries before chemists working in Bayer’s laboratories synthesized aspirin [3]. Although it was recognized that aspirin contributed to bleeding, it was not until the 1960s that the anti-thrombotic effects of aspirin were described [4]. At present, aspirin has a well-defined role in the treatment of acute ischemic stroke [5]. In secondary prevention, where patients are at high risk of future cardiovascular events, aspirin is effective in preventing stroke in men and women [6]. Aspirin’s effectiveness in primary stroke prevention is less clear, and may differ by gender.

Aspirin’s mechanism of action & hypothesized role in stroke prevention    

In platelets, COX-1 is an enzyme that metabolizes arachadonic acid into prostaglandins, including thromboxane A2, which induces platelet aggregation [7]. Aspirin inhibits platelet aggregation by irreversibly inhibiting COX-1, preventing the production of thromboxane A2. The inhibition lasts for the life of the platelet, which is approximately 8 days [8]. In addition to platelet inhibition, aspirin may also improve reactivity in atherosclerotic blood vessels [9].

The majority of strokes are due to cerebral ischemia, but a substantial minority are hemorrhagic [1]. While antiplatelet therapy is thought to reduce the risk of ischemic stroke, it may increase the risk of hemorrhagic strokes, including intraparenchymal and subarachnoid hemorrhages. The purported benefit of aspirin in the primary prevention of stroke lies in its ability to prevent ischemic stroke without increasing the risk of hemorrhagic stroke.

Gender & stroke    
Men have a higher age-adjusted incidence of stroke than women [10,11]. However, older women, aged over 75 years, appear to have a higher risk of stroke than men [12,13]. Compared with men, on average women are older when they experience their first ischemic stroke [14]. Since women live longer than men, and have a higher incidence than men at older ages, the cumulative lifetime risk of stroke in women exceeds that of men [15].

After a stroke, women are more likely than men to have worse functional outcomes and poorer quality of life [16]. The source of these disparities is not fully understood; although it has been suggested that women are less likely than men to be treated with thrombolytic medication, which can reduce the risk of disability [17]. However, so few stroke patients are treated with thrombolytics that this probably does not account for poorer stroke outcomes among women. The increased burden of stroke in women highlights the need to examine gender differences in stroke prevention.

Objective    
Over the past 25 years there have been seven large randomized trials that have attempted to determine whether aspirin is effective for the primary prevention of stroke and other cardiovascular events. Three of these trials did not enroll women; a small number of the events occurred in women in the nongender-specific trials, and one trial enrolled exclusively women. This article aims to examine gender difference observed in the primary prevention of stroke with aspirin.

Method   
We performed a MEDLINE search of primary prevention trials that studied aspirin with stroke as an outcome. Guidelines from US, British and European organizations were reviewed. We also reviewed the citations from the articles to find additional references.

The seven primary prevention trials of aspirin in cardiovascular disease (CVD) are summarized in Table 1 and described later. In the trials, the primary end point was generally a combination of myocardial infarction (MI), stroke or vascular death. Stroke was typically specified as a secondary end point.

This article first summarizes each of the seven primary prevention trials. Trials that included only men are briefly summarized while the trials that included both genders and only women will be discussed in more detail. Next, the two meta-analyses of the first six primary prevention trials are discussed and we explore reasons for the gender differences. Finally, because recommendations based on trial interpretation are conflicting, we conclude with a summary of the various guidelines dictating the use of aspirin for primary prevention.

Primary prevention trials    
Trials that included only men
Three early trials of aspirin in primary prevention enrolled only men: the British Doctors Trial (BDT), Physicians’ Health Study (PHS) and Thrombosis Prevention Trial (TPT) and all assessed stroke as a secondary outcome [18–20]. In the BDT there was no significant difference in the stroke rate between the aspirin and control groups (32.4/10,000 patient-years in the aspirin group versus 28.5/10,000 patient-years in the control group); in addition, the 95% CI was wide and included the null. In the PHS, there were more strokes in the aspirin group when compared with the placebo group (119 vs 98), but the increase in relative risk (RR) was not statistically significant (RR: 1.22; 95% CI: 0.93–1.60; p = 0.15). The TPT found no difference in the risk of ischemic and hemorrhagic stroke between the aspirin and placebo groups (2.9 per 1000 person-years vs 3.0 per 1000 person-years, respectively).

Hypertension Optimal Treatment trial
The Hypertension Optimal Treatment (HOT) trial examined aspirin and blood pressure control for prevention of cardiovascular events [21]. This was the first randomized controlled trial of aspirin in primary prevention of CVD to include women – 47% of the 18,790 subjects. Men and women aged 50–80 years with hypertension (i.e., diastolic blood pressure ≥100 and ≤115 mmHg) were recruited for the study [22]. The participants were randomly assigned to aspirin 75 mg daily or placebo. They were also randomized into three diastolic goal blood pressure groups: ≤90, ≤85 or ≤80 mmHg. The primary antihypertensive agent used was felodipine, although angiotensin-converting enzyme inhibitors, β-blockers and diuretics were also used at various stages. The randomization was stratified by various cardiovascular risk factors, including gender. The average follow-up was 3.8 years and 491 patients (2.6%) were lost to follow-up. No primary outcome measure was defined in the published report, but the investigators examined stroke, MI and cardiovascular death. Gender differences in effectiveness were not explicitly reported.

There was no difference in the risk of hemorrhagic and ischemic strokes between the aspirin and placebo groups (RR: 0.98; 95% CI: 0.78–1.24; p = 0.88). While there were five fatal hemorrhagic strokes in the aspirin group compared with three in the placebo group, there was no difference in the frequency of nonfatal hemorrhagic strokes between the two groups. Aspirin significantly reduced the risk of clinical MI (RR: 0.64; 95% CI: 0.49–0.85; p = 0.002), but not the combination of clinical and silent MI (RR: 0.85; 95% CI: 0.69–1.05; p = 0.13) or cardiovascular mortality (RR: 0.95; 95% CI: 0.75–1.20; p = 0.65). There was no difference in fatal hemorrhages, but major and minor bleeding was more common in the aspirin group.

Primary Prevention Project
The Primary Prevention Project (PPP) examined the effect of aspirin and vitamin E in the primary prevention of cardiovascular events in patients aged ≥65 years with at least one cardiovascular risk factor [23]. Subjects were randomized, open-label, to aspirin 100 mg daily or no aspirin, along with vitamin E 300 mg daily or no vitamin E in a 2 × 2 factorial design. The study was stopped prematurely after the results of the TPT and HOT studies became available. A total of 4495 subjects participated and 58% were women. The median follow-up was 4 years and 92.3% of subjects had complete follow-up.

The primary outcome was a combined end point that included nonfatal stroke, nonfatal MI and cardiovascular death. Aspirin provided a nonsignificant 29% reduction in the primary outcome (RR: 0.71; 95% CI: 0.48–1.04), but no effect on the risk of all stroke types (RR: 0.67; 95% CI: 0.36–1.27). There were two intracranial hemorrhages in the aspirin group and none in the placebo group. Aspirin was associated with a significant decrease in cardiovascular death (RR: 0.56; 95% CI: 0.31–0.99; p = 0.049). While overall bleeding episodes were more common in the aspirin group, fatal bleeding was more common in the placebo group (one vs three deaths). The primary end point, cardiovascular deaths, total deaths and combined cardiovascular events were similar between men and women.

Women’s Health Study
The Women’s Health Study (WHS) evaluated aspirin 100 mg every other day and vitamin E 600 IU every other day in a double-blind, placebo controlled, 2 × 2 factorial design for the primary prevention of CVD and cancer in women [24]. Female health professionals aged 45 years and older were recruited to participate. No men were enrolled in the trial. The study enrolled 39,876 women and the primary end point was a combination of cardiovascular death, stroke and MI. Secondary end points included stroke and MI. The average follow-up time was 10.1 years and 2.8% of patients were lost to follow-up.

Aspirin provided a nonsignificant reduction in the risk of the primary combined end point (RR: 0.91; 95% CI: 0.80–1.03; p = 0.13). There was a 17% reduction in the risk of stroke (RR: 0.83; 95% CI: 0.69–0.99; p = 0.04). When stroke was subdivided into ischemic and hemorrhagic types, aspirin conferred a 24% risk reduction in ischemic stroke (RR: 0.76; 95% CI: 0.63–0.93; p = 0.0009) and a nonsignificant increase in the risk of hemorrhagic stroke (RR: 1.24; 95% CI: 0.82–1.87; p = 0.31). There was no difference in the risk of MI between the aspirin and placebo groups (RR: 1.02; 95% CI: 0.84–1.25; p = 0.83) and aspirin did not reduce the risk of cardiovascular death (RR: 0.95; 95% CI: 0.74–1.22; p = 0.68). Subgroup analysis showed that older women (>65 years) tended to have more benefit from aspirin than younger women, although a formal test for effect measure modification was not reported. Vitamin E did not significantly impact the effect of aspirin. Bleeding requiring a transfusion was more common in the aspirin group (RR: 1.40; 95% CI: 1.07–1.83; p = 0.02), but there was no excess of fatal bleeding.

Aspirin for Asymptomatic Atherosclerosis
The Aspirin for Asymptomatic Atherosclerosis (AAA) study was a double-blind, placebo controlled, randomized trial that enrolled 3350 subjects aged 50–75 years with asymptomatic peripheral vascular disease to enteric coated aspirin 100 mg daily or placebo [25]. In total, 72% of the study population were women and the subjects were followed for an average of 8.2 years and 0.3% of patients were lost to follow-up. The trial was stopped early owing to futility.

The primary end point was a composite of fatal and nonfatal stroke, coronary event or revascularization. There was no difference in the primary outcome between the aspirin and placebo groups (hazard ratio [HR]: 1.03; 95% CI: 0.84–1.27). In a subgroup analysis, there was a suggestion that aspirin was harmful for men (HR: 1.15; 95% CI: 0.86–1.54) and beneficial for women (HR: 0.92; 95% CI: 0.68–1.23) with respect to the primary outcome, but neither result was statistically significant. A test for effect measure modification by gender was not reported. There was no difference in the risk of stroke between the aspirin (fatal: 0.4%; 95% CI: 0.2–0.9; nonfatal: 2.2%; 95% CI: 1.6–3.0) and placebo groups (fatal: 0.7%; 95% CI: 0.4–1.2; nonfatal: 2.3; 95% CI: 1.7–3.1). The risk of death was not reduced by aspirin (HR: 0.95; 95% CI: 0.77–1.16). There were more major hemorrhages in the aspirin group (HR: 1.71; 95% CI: 0.99–2.97), including 11 intracranial bleeds, compared with seven intracranial bleeds in the placebo group.

Summary of primary prevention trial results
In the seven trials described previously, aspirin reduced the risk of stroke, a secondary end point, only in the WHS, a study that exclusively enrolled women and had the largest sample size of all of the studies. Gender differences were not reported in the HOT trial. In the PPP, aspirin did not reduce the risk of stroke overall, or in women in subgroup analysis. The lack of efficacy for aspirin may be due to a low number of strokes in these trials and low power [26]. Combining trial data in a meta-analysis has the potential to reduce the probability of type II error, thus it is an attractive tool when examining the trials of aspirin in the primary prevention of stroke.

Meta-analyses    
The primary prevention trials used differing doses and formulations of aspirin, which challenges the appropriateness of combining data across trials. However, the variation in doses in the trials was small and is unlikely to be clinically significant. Nevertheless, in healthy women, aspirin 100 mg every other day, the dose used in the WHS, produced less platelet inhibition than 81 mg daily [27], although it is unclear if differences in a platelet function assay are clinically meaningful. It is also noteworthy that a single trial, the WHS, which enrolled exclusively women, contributed approximately 40% of the total subjects, and approximately 78% of the female subjects to the meta-analyses.

A gender-specific meta-analysis of the first six aspirin primary prevention trials (all except the AAA) by Berger et al., was published in 2006 [28]. When the trials were pooled, there were a total of 1285 cardiovascular events in the 51,342 female participants and 2047 cardiovascular events in the 44,114 male participants. There was no significant heterogeneity across trials for the end points analyzed.

Strokes were experienced in 625 women and 597 men. In women, there was a 17% reduction in the odds of stroke (95% CI: 0.70–0.97; p = 0.02); however, aspirin did not have an effect on stroke in men (odds ratio [OR]: 1.13; 95% CI: 0.96–1.33; p = 0.14). In women, aspirin decreased the odds of an ischemic stroke (OR: 0.76; 95% CI: 0.63–0.93; p = 0.008) without increasing the risk of hemorrhagic stroke (OR: 1.07; 95% CI: 0.42–2.69; p = 0.89). In men, there was no effect on ischemic stroke (OR: 1.00; 95% CI: 0.72–1.41; p = 0.98), but aspirin increased the odds of a hemorrhagic stroke by 69% (95% CI: 1.04–2.73; p = 0.03). These results are summarized in Figure 1.

Aspirin reduced the odds of MI in men by 32% (95% CI: 0.54–0.86; p = 0.001), but it had no statistically significant effect in women (OR: 1.01; 95% CI: 0.84–1.21; p = 0.95). When all-cause and cardiovascular mortality was examined, aspirin did not have a significant effect in men or women.

The Antithrombotic Trialists’ Collaboration (ATTC) reported results from a combined analysis, from the same six primary prevention trials (BDT, PHS, TPT, HOT, PPP and WHS) [29]. They found a small, but significant reduction in the risk of vascular events for patients taking aspirin compared with the control group (absolute difference 0.06% per year; RR: 0.88; 95% CI: 0.82–0.94; p = 0.0001). There was no significant heterogeneity across the subgroups including gender. There was also no difference in stroke outcome between the aspirin and control groups (RR: 0.95; 95% CI: 0.85–1.06). When stroke types were examined, aspirin reduced the risk of ischemic stroke by 14% (RR: 0.86; 95% CI: 0.74–1.00; p = 0.05), but increased the risk of hemorrhagic stroke by 32% (RR: 1.32; 95% CI: 1.00–1.75; p = 0.05). When the effect of aspirin on ischemic stroke was examined by gender, there was a benefit for women (RR: 0.77; 95% CI: 0.59–0.99) but not men (RR: 1.01; 95% CI: 0.74–1.39). This conclusion was supported by a borderline significant test for heterogeneity across genders (χ2 1 = 3.1; p = 0.08). However, the authors note that when this was adjusted for multiple comparisons (an adjustment not undertaken in the Berger et al. meta-analysis [28]), it was no longer significant (p = 0.88).

There was no difference in vascular death between the aspirin and control groups (rate ratio: 0.97; 95% CI: 0.87–1.09). Aspirin was associated with an 18% reduction in major coronary events (95% CI: 0.75–0.90; p < 0.0001), but the absolute difference between the groups was small (0.06% per year) and this was driven by nonfatal events. Aspirin seemed to reduce the risk of major coronary events in men but was not significant in women, but this difference was no longer significant after correcting for multiple comparisons.

Summary of meta-analyses results
The Berger meta-analysis supported gender differences in aspirin’s effectiveness in primary stroke prevention. Aspirin reduced the risk of ischemic stroke for women without an increase in hemorrhagic stroke. While in men, aspirin had no effect on the risk of ischemic stroke, but increased the risk of hemorrhagic stroke. The ATTC study found similar gender differences for ischemic stroke, but with adjustment for multiple comparisons, the test for effect measure modification by gender was no longer significant.

Aspirin & the risk of hemorrhage: results of meta-analyses    
The most feared bleeding complication of aspirin is hemorrhagic stroke. In the Berger et al. meta-analysis, aspirin was associated with a 69% (OR: 1.69; 95% CI: 1.04–2.73) increase in the risk of hemorrhagic stroke in men, but no increased risk in women (OR: 1.07; 95% CI: 0.42–2.69) [28]. In the ATTC analysis, aspirin increased the risk of hemorrhagic stroke by 32% (95% CI: 1.00–1.75) [29]. The risk of hemorrhagic stroke due to aspirin was studied specifically in a meta-analysis that examined studies that randomized subjects to aspirin for both primary and secondary prevention of cardiovascular events, and used hemorrhagic stroke as an outcome [30]. This analysis found that aspirin was associated with an 84% increase in the risk of hemorrhagic stroke (RR: 1.84; 95% CI: 1.24–2.74; p < 0.001) [30]. They found no association between subject age group (<64 vs ≥64 years) or aspirin dose (<413 vs ≥413 mg per day) and risk of hemorrhagic stroke, but women were not specifically analyzed and the study was published before the WHS was completed. A review article on aspirin and hemorrhagic stroke estimated the risk of intracranial hemorrhage while taking aspirin as 0.2 events per 1000 patient-years [31].

Aspirin also increases the risk of gastrointestinal (GI) bleeding (RR: 1.54; 95% CI: 1.30–1.82 in the ATTC meta-analysis) [29]. In the Berger et al. meta-analysis, ‘major bleeding’, which was predominantly GI bleeding, was more common in the aspirin group for both women (OR: 1.68; 95% CI: 1.13–2.52; p = 0.01) and men (OR: 1.72; 95% CI: 1.35–2.20; p < 0.001) [28].

Additional considerations may inform the risk–benefit ratio of aspirin use, such as is the relative consequences of GI bleeding compared with stroke. Patients may be willing to take the risk of GI bleeding to prevent an ischemic stroke because stroke is likely to have more pronounced negative impact on their quality of life [32]. The risk benefit calculation may be different in women compared with men because they have poorer quality of life after stroke [33].

Reason for the gender difference    
The etiology of aspirin’s gender-specific effects is not entirely clear. Many drugs are metabolized differently and have different pharmacodynamic properties in women compared with men [34]. However, this does not account for differing aspirin effects by gender in primary but not in secondary stroke prevention studies [6,29].

Becker et al. compared the effects of low dose (81 mg per day) aspirin on platelets in close to 1300 healthy generally middle-aged men and women with a family history of premature coronary artery disease [35]. Prior to aspirin treatment, women had more reactive platelets than men. While aspirin decreased platelet reactivity by a relatively similar amount in men and women, platelet reactivity was still higher in women because they had more reactive platelets at baseline. Higher dose aspirin (325 mg) did not seem to overcome this effect, but even higher doses were not tested [36]. In addition, resistance to aspirin therapy appears to be more common in women than men [37]. It is unclear how gender differences in platelet inhibition and aspirin resistance contribute to aspirin’s beneficial effect for stroke in women, but not men. This is particularly puzzling in light of the lack of gender-specific effects in secondary prevention of stroke and CVD [6,29].

Summary of guidelines    
The recommendations from relevant guidelines are summarized in Table 2. Many guidelines do not separate recommendations regarding aspirin use in primary prevention of stroke from primary prevention of all types of CVD.

The American Heart Association (AHA) recommends aspirin for primary prevention of cardiovascular events, including stroke, for men and women who are at high risk (6–10% 10-year risk) when the benefits outweigh the risks of treatment [38]. Aspirin is recommended for stroke prevention for women when the risk of stroke is high enough that the benefits of aspirin outweigh the risks [38]. The AHA notes that aspirin is not useful in preventing stroke in patients at low risk [38].

The US Preventative Services Task Force (USPSTF) recommends aspirin for men aged 45–79 years and women aged 55–79 years, when the potential protective benefits in CVD (stroke in women, MI in men) outweigh the risk of GI bleeding [39]. They note that there is not enough evidence to make a recommendation for patients aged 80 years and over and recommend against the use of aspirin in women younger than 55 years and in men younger than 45 years for prevention of stroke and MI, respectively [39].

The European Stroke Organization (ESO) recommends aspirin for ischemic stroke prevention in women aged over 45 years who have ‘good GI tolerance’ and are at low risk of intracerebral hemorrhage, but comment that the magnitude of benefit is small. For men, aspirin can be considered to prevent MI, but the authors of the ESO guidelines note it does not reduce the risk of stroke [101]. The European Society of Cardiology (ESC) guidelines recommend aspirin for primary prevention of CVD only if patients are at high cardiovascular risk and their blood pressure is controlled, and notes that aspirin reduces the risk of stroke, but not MI in women [40]. The Joint British Societies’ (JBS) 2 Guidelines recommend aspirin for women aged 65 years or older, who have a 10-year risk of CVD ≥20% who have a blood pressure of less than 150/90 [41]. There were no specific recommendations for men, but the guidelines provide a general recommendation to use aspirin in patients aged 50 years or older, who have a 10-year risk of CVD ≥20% and a blood pressure of less than 150/90 [41].

Owing to the lack of clear evidence of benefit for aspirin in patients with diabetes, the various guideline statements are more heterogeneous [42]. For patients with diabetes, the AHA states that aspirin is not useful in stroke prevention [38]. The American Diabetes Association (ADA) indicates that aspirin (75–162 mg daily) can be considered for the primary prevention of CVD, including stroke, for patients at high risk (10-year risk >10%) [43]. For lower risk patients (men aged <50 years or women aged <60 years without major risk factors) the ADA notes that there is not sufficient evidence to recommend aspirin for the primary prevention of CVD [43]. European guidelines that address patients with diabetes recommend using aspirin (75–250 mg daily) to prevent stroke [44]. British guidelines recommend aspirin for people with diabetes who have had the disease for more than 10 years or are aged 50 years or older whose hypertension is being treated [41]. Aspirin is recommended by US, British and European agencies to prevent stroke in patients with atrial fibrillation who are at low risk of embolism or unable to take anticoagulation medication [38,41,101].

Future perspective    
There is some concern that despite the many primary prevention trials that have enrolled tens of thousands of patients, aspirin still has uncertain benefits in the primary prevention of stroke. The negative trials may have been underpowered to detect an effect of aspirin because of the low number of strokes [26]. In total, the data suggest that aspirin prevents MI in men and stroke in women. The mortality benefit for aspirin is small, if present. Aspirin also puts patients at increased risk for bleeding complications, including hemorrhagic stroke. It could be argued that a GI bleed is not as debilitating as an ischemic stroke or MI; therefore, patients may be willing to accept the bleeding risks of aspirin to prevent ischemic disease. The lack of a clear signal of efficacy from the trials suggests that if aspirin has a clinically meaningful benefit, it is modest.

The Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) study, scheduled for completion in 2014, is examining aspirin use in patients at higher risk of CVD and includes men and women [102]. The expected higher rate of events in this trial will increase the power needed to show a benefit for aspirin, if it is truly present. Until more data are available, it seems reasonable to offer, but not strongly recommend, aspirin for the primary prevention of stroke in women who are at low risk of bleeding complications. The data suggest that aspirin does not reduce the risk of stroke in men, but that its benefit in reducing the risk of MI may justify its use in this population.

Table 1. Primary prevention trials of aspirin in preventing cardiovascular disease.
Table 2. Guideline statements regarding aspirin for the primary prevention of stroke†.
Executive summary
The burden of stroke & aspirin’s utility
• Stroke is a common cause of death and a leading cause of disability.

• Stroke has a tremendous economic impact on society.

• Aspirin has a well-defined role in treatment of acute ischemic stroke and secondary ischemic stroke prevention. No gender differences are observed in these settings.

Aspirin’s mechanism of action

• Aspirin inhibits platelet aggregation by blocking thromboxane A2.
• Aspirin’s mechanism in decreasing the risk of ischemic stroke is unclear.
• Aspirin may increase the risk of hemorrhagic stroke.

Gender & stroke

• Men have a higher age-adjusted incidence of stroke than women; however, amongst the elderly (those aged over 75 years), women have a higher incidence of stroke than men.
• Since women live longer than men, their cumulative lifetime risk of stroke exceeds that of men.
• There are gender disparities in the acute treatment of stroke and in stroke outcomes.

Primary prevention trial

• No primary prevention trial has had stroke as a primary end point
• The British Doctors Trial (BDT), Physicians’ Health Study (PHS) and Thrombosis Prevention Trial (TPT) enrolled only men and found no difference in the risk of stroke between the aspirin and no aspirin groups or placebo groups.
• The Hypertension Optimal Treatment trial enrolled men and women and found no difference in the risk of stroke between aspirin and placebo.
• The Primary Prevention Project (PPP) enrolled men and women and found no difference in the risk of stroke between aspirin and placebo; however, aspirin was found to decrease the risk of cardiac death.
• The Women’s Health Study (WHS), which enrolled only women and was the largest of the trials, found a 17% reduction in the risk of stroke (relative risk: 0.83; 95% CI: 0.69–0.99).
• The Aspirin for Asymptomatic Atherosclerosis (AAA) study enrolled men and women and found no difference in the risk of stroke between aspirin and placebo.

  Meta-analyses

• When combining the trials, the WHS contributed close to 80% of the female subjects to the analyses.
• An early meta-analysis of the first six primary prevention trials found that aspirin reduced the odds of stroke in women by 17% but did not reduce the odds of stroke in men.
• A subsequent meta-analysis found the same gender differences in aspirin’s effectiveness but with additional statistical adjustments the differences were not significant.
• Neither meta-analysis found that aspirin reduced the risk of mortality.

Aspirin & the risk of hemorrhage

• Aspirin probably increases the risk of hemorrhagic stroke. Men may be at higher risk of hemorrhagic stroke while taking aspirin compared with women.
• Aspirin increases the risk of gastrointestinal (GI) bleeding.
• Owing to the poorer quality of life associated with a stroke compared with a GI bleed, patients may be willing to tolerate the risk of GI bleeding to reduce the risk of stroke.

Reasons for the gender differences

• Many drugs are metabolized differently and have different pharmacodynamic properties in men and women.
• Women may have more reactive platelets than men, leading to less inhibition by aspirin. Aspirin resistance may also be more common in women.
• How these differences in platelet reactivity and aspirin resistance contribute, if at all, to gender differences in aspirin’s effectiveness in preventing stroke is unclear.

Summary of guidelines

• The American Heart Association (AHA) recommends aspirin for patients at high risk of cardiovascular disease (CVD) when the benefits outweigh the risks. Aspirin is recommended specifically for stroke prevention in women when the risk of stroke is high enough that the benefits outweigh the risks.
• The US Preventative Services Task Force (USPSTF) recommends aspirin for men aged 45–79 years and women aged 55–79 years when the potential benefits (stroke in women, myocardial infarction in men) outweigh the risks of GI bleeding.
• The European Stroke Organization (ESO) recommends aspirin to reduce the risk of ischemic stroke in women over the age of 45 years who have ‘good GI tolerance’ and are at low risk of intracerebral hemorrhage.
• The European Society of Cardiology (ESC) recommends aspirin for primary prevention of CVD only if patients are at high cardiovascular risk and their blood pressure is controlled, and notes that aspirin reduces the risk of stroke, but not myocardial infarction in women.
• The Joint British Societies’ (JBS) 2 Guidelines recommend aspirin for women aged 65 years or older, who have a 10-year risk of CVD ≥20% and a blood pressure of less than 150/90. There were no specific recommendations for men, but the guidelines provide a general recommendation to use aspirin in patients aged 50 years or older, who have a 10-year risk of CVD ≥20% and a blood pressure of less than 150/90.
• The American Diabetes Association (ADA) indicates that aspirin can be considered for the primary prevention of stroke and CVD for patients at high risk.

Future perspective

• The lack of benefit observed in most trials of aspirin in the primary prevention of stroke may be related to underpowered trials.
• The trials do suggest that aspirin reduces the risk of stroke in women but not men.
• More research is necessary in order to determine if aspirin reduces the risk of stroke in men and has a mortality benefit when used in primary prevention.
• It is reasonable to offer, but not strongly recommend, aspirin for the primary prevention of stroke in women who are at low risk of bleeding. The data suggest that aspirin does not reduce the risk of stroke in men, but its benefit in reducing the risk of myocardial infarction may justify its use in this population.

Full Text:  Future Medicine

Bibliography   
Papers of special note have been highlighted as: • of interest •• of considerable interest

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Websites
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Affiliations

About the faculty:  Eric E Adelman 1Stroke Program, Department of Neurology, University of Michigan, Cardiovascular Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
Lynda Lisabeth 1Stroke Program, Department of Neurology, University of Michigan, Cardiovascular Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA

Cardiology, Gastrointestinal, Medications, Pharmacology, stroke