c Me Article Cvd

7/31/2019 c Me Article Cvd

1/19

Gender Differences in the Primary Prevention

of Stroke With Aspirin

Faculty: Eric E. Adelman, MD; Lynda Lisabeth, PhD; Devin L. Brown, MD

This article is a CME certified activity. To earn credit for this activity visit:

http://www.medscape.org/viewarticle/742845

CME Information

CME Released: 05/25/2011; Valid for credit through 05/25/2012

Target Audience

This activity is intended for primary care clinicians, internists, geriatricians, neurologists, and other

healthcare professionals involved in primary prevention of stroke.

Goal

The goal of this activity is to describe gender differences observed in the primary prevention of

stroke with aspirin.

Learning Objectives

Upon completion of this activity, participants will be able to:

1. Describe gender-specific findings from trials of aspirin focusing on the effectiveness of

primary prevention of stroke and other cardiovascular events2. Describe professional society guidelines regarding use of aspirin for primary prevention of

stroke and other cardiovascular events in women3. Describe risks of aspirin used for primary prevention of stroke and other cardiovascular

events in women

Credits Available

Physicians - maximum of 1.00AMA PRA Category 1 Credit(s)

All other health care professionals completing continuing education credit for this activity will be

issued a certificate of participation.

Physicians should claim only the credit commensurate with the extent of their participation in the

activity.

Accreditation Statements

For Physicians
http://www.medscape.org/viewarticle/742845http://www.medscape.org/viewarticle/742845


2/19

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 jointsponsorship of Medscape, LLC and Future Medicine Ltd. Medscape, LLC is accredited by the

ACCME to provide continuing medical education for physicians.

Medscape, LLC designates this Journal-based CME activity for a maximum of 1.00AMA PRACategory 1 Credit(s). Physicians should claim only the credit commensurate with the extent oftheir participation in the activity. Medscape, LLC staff have disclosed that they have no relevant

financial relationships.

Contact This Provider

For questions regarding the content of this activity, contact the accredited provider for thisCME/CE activity noted above. For technical assistance, [email protected]

Instructions for Participation and Credit

There are no fees for participating in or receiving credit for this online educational activity. For

information on applicability and acceptance of continuing education credit for this activity, please

consult your professional licensing board.

This activity is designed to be completed within the time designated on the title page; physicians

should claim only those credits that reflect the time actually spent in the activity. To successfully

earn credit, participants must complete the activity online during the valid credit period that isnoted on the title page.

Follow these steps to earn CME/CE credit*:

1. Read the target audience, learning objectives, and author disclosures.2. Study the educational content online or printed out.

3. Online, choose the best answer to each test question. To receive a certificate, you must

receive a passing score as designated at the top of the test. MedscapeCME encourages youto complete the Activity Evaluation to provide feedback for future programming.

You may now view or print the certificate from your CME/CE Tracker. You may print the

certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for

6 years; at any point within this time period you can print out the tally as well as the certificates byaccessing "Edit Your Profile" at the top of your Medscape homepage.

*The credit that you receive is based on your user profile.

Hardware/Software Requirements

To access Medscape Education users will need

A computer with an Internet connection.

Internet Explorer 6.x or higher, Firefox 2.x or higher, Safari 2.x or higher, or any otherW3C standards compliant browser.
mailto:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]


3/19

Adobe Flash Playerand/or an HTML5 capable browser may be required for video or audio

playback.

Occasionally other additional software may be required such asPowerPointorAdobe

Acrobat Reader.

Authors and Disclosures

As an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in aposition to control the content of an education activity to disclose all relevant financial

relationships with any commercial interest. The ACCME defines "relevant financial relationships"

as financial relationships in any amount, occurring within the past 12 months, including financial

relationships of a spouse or life partner, that could create a conflict of interest.

Medscape, LLC, encourages Authors to identify investigational products or off-label uses of

products regulated by the US Food and Drug Administration, at first mention and whereappropriate in the content.

Author(s)

Eric E. Adelman, MD

Stroke Program, Department of Neurology, University of Michigan, Cardiovascular Center, Ann

Arbor, Michigan. Disclosure: Eric E. Adelman, MD, has disclosed no relevant financial

relationships.

Lynda Lisabeth, PhD

Stroke Program, Department of Neurology, University of Michigan, Cardiovascular Center;Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor,

Michigan Disclosure: Lynda Lisabeth, PhD, has disclosed no relevant financial relationships.

Devin L. Brown, MD

Stroke Program, Department of Neurology, University of Michigan, Cardiovascular Center, Ann

Arbor, Michigan. Disclosure: Devin L. Brown, MD, has disclosed no relevant financialrelationships.

Editor(s)

Elisa Manzotti

Editorial Director, Future Science Group, London, United Kingdom. Disclosure: Elisa Manzotti

has disclosed no relevant financial relationships.
http://get.adobe.com/flashplayer/http://office.microsoft.com/en-us/powerpoint/http://office.microsoft.com/en-us/powerpoint/http://office.microsoft.com/en-us/powerpoint/http://get.adobe.com/reader/http://get.adobe.com/reader/http://get.adobe.com/flashplayer/http://office.microsoft.com/en-us/powerpoint/http://get.adobe.com/reader/http://get.adobe.com/reader/


4/19

CME Author(s)

Laurie Barclay, MD

Freelance writer and reviewer, Medscape, LLC. Disclosure: Laurie Barclay, MD, has disclosed no

relevant financial relationships.

CME Reviewer(s)

Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC. Disclosure: Nafeez Zawahir, MD, has disclosed norelevant financial relationships.

Sarah Fleischman

CME Program Manager, Medscape, LLC. Disclosure: Sarah Fleischman has disclosed no relevant

financial relationships.

FromWomen's Health

Gender Differences in the Primary Prevention of

Stroke With Aspirin CME

Eric E. Adelman, MD; Lynda Lisabeth, PhD; Devin L. Brown, MD

Posted: 01/01/1970; Women's Health. 2011;7(3):341-353. 2011 Future Medicine Ltd.

CME Released: 05/25/2011; Valid for credit through 05/25/2012

Abstract and Introduction

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, andone 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 genderdifferences in aspirins effectiveness are not entirely clear.

Introduction
http://www.medscape.org/viewpublication/30079http://www.medscape.org/viewpublication/30079


5/19

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 recentyears, 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 andobesity 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 effectivepreventive strategies.[2] Given disparities in stroke burden by gender, these strategies should beassessed in both men and women.

The ancient Greeks knew that willow bark had analgesic properties but it was centuries before

chemists working in Bayers 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 aspirinwere 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] Aspirins effectiveness in primarystroke prevention is less clear, and may differ by gender.

Aspirins 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 lastsfor 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 purportedbenefit 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, onaverage 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 poorerquality 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 thrombolyticsthat 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


6/19

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 cardiovascularevents. 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 asan 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 ofmyocardial infarction (MI), stroke or vascular death. Stroke was typically specified as a secondary

end point.

Table 1. Primary Prevention Trials of Aspirin in Preventing Cardiovascular Disease.

This article first summarizes each of the seven primary prevention trials. Trials that included onlymen 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 guidelinesdictating the use of aspirin for primary prevention.

Primary Prevention Trials

Trials That Included Only Men


7/19

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 assessedstroke as a secondary outcome.[1820] 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 thenull. 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: 0.931.60; 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 per1000 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 inprimary prevention of CVD to include women 47% of the 18,790 subjects. Men and women aged

5080 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. Theywere also randomized into three diastolic goal blood pressure groups: 90, 85 or 80 mmHg. The

primary antihypertensive agent used was felodipine, although angiotensin-converting enzymeinhibitors, -blockers and diuretics were also used at various stages. The randomization wasstratified 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: 0.781.24; 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 inthe frequency of nonfatal hemorrhagic strokes between the two groups. Aspirin significantly

reduced the risk of clinical MI (RR: 0.64; 95% CI: 0.490.85; p = 0.002), but not the combinationof clinical and silent MI (RR: 0.85; 95% CI: 0.691.05; p = 0.13) or cardiovascular mortality (RR:

0.95; 95% CI: 0.751.20; p = 0.65). There was no difference in fatal hemorrhages, but major andminor 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 riskfactor.[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 4495subjects 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: 0.481.04), but no effect on the risk of all stroke types (RR: 0.67; 95% CI:

0.361.27). 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: 0.310.99; p = 0.049). While overall bleeding episodes were more common in the aspiringroup, fatal bleeding was more common in the placebo group (one vs three deaths). The primary


8/19

end point, cardiovascular deaths, total deaths and combined cardiovascular events were similar

between men and women.

Womens Health Study

The Womens 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 womenand 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% ofpatients were lost to follow-up.

Aspirin provided a nonsignificant reduction in the risk of the primary combined end point (RR:

0.91; 95% CI: 0.801.03; p = 0.13). There was a 17% reduction in the risk of stroke (RR: 0.83;

95% CI: 0.690.99; 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: 0.630.93; 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: 0.841.25; p = 0.83) and aspirin did not reduce the risk of cardiovascular death(RR: 0.95; 95% CI: 0.741.22; 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 ofaspirin. Bleeding requiring a transfusion was more common in the aspirin group (RR: 1.40; 95%

CI: 1.071.83; 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, placebocontrolled, randomized trial that enrolled 3350 subjects aged 5075 years with asymptomatic

peripheral vascular disease to enteric coated aspirin 100 mg daily or placebo.[25] In total, 72% of thestudy 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: 0.841.27). In a subgroup analysis, there was asuggestion that aspirin was harmful for men (HR: 1.15; 95% CI: 0.861.54) and beneficial for

women (HR: 0.92; 95% CI: 0.681.23) 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: 0.20.9; nonfatal:

2.2%; 95% CI: 1.63.0) and placebo groups (fatal: 0.7%; 95% CI: 0.41.2; nonfatal: 2.3; 95% CI:1.73.1). The risk of death was not reduced by aspirin (HR: 0.95; 95% CI: 0.771.16). There were

more major hemorrhages in the aspirin group (HR: 1.71; 95% CI: 0.992.97), including 11intracranial 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 ofthe 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


9/19

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 toolwhen 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 100mg 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, contributedapproximately 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 Bergeret al., was published in 2006.[28] When the trials were pooled, there were a total of1285 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 inthe odds of stroke (95% CI: 0.700.97; p = 0.02); however, aspirin did not have an effect on stroke

in men (odds ratio [OR]: 1.13; 95% CI: 0.961.33; p = 0.14). In women, aspirin decreased the odds

of an ischemic stroke (OR: 0.76; 95% CI: 0.630.93; p = 0.008) without increasing the risk ofhemorrhagic stroke (OR: 1.07; 95% CI: 0.422.69; p = 0.89). In men, there was no effect on

ischemic stroke (OR: 1.00; 95% CI: 0.721.41; p = 0.98), but aspirin increased the odds of a

hemorrhagic stroke by 69% (95% CI: 1.042.73; p = 0.03). These results are summarized in Figure

1.


10/19

Figure 1. Effect of Aspirin on the Primary Prevention of Stroke.

Reproduced with permission from [28] American Medical Association (2006).BDT: British Doctors Trial; HOT: Hypertension Optimal Treatment; PHS: Physicians Health

Study; PPP: Primary Prevention Project; TPT: Thrombosis Prevention Trial; WHS: WomensHealth Study.

Aspirin reduced the odds of MI in men by 32% (95% CI: 0.540.86; p = 0.001), but it had no

statistically significant effect in women (OR: 1.01; 95% CI: 0.841.21; 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


11/19

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: 0.820.94; 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: 0.851.06). When stroke types were examined, aspirin reduced the risk of ischemic strokeby 14% (RR: 0.86; 95% CI: 0.741.00; p = 0.05), but increased the risk of hemorrhagic stroke by

32% (RR: 1.32; 95% CI: 1.001.75; 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: 0.590.99) but not men

(RR: 1.01; 95% CI: 0.741.39). This conclusion was supported by a borderline significant test forheterogeneity across genders (21 = 3.1; p = 0.08). However, the authors note that when this was

adjusted for multiple comparisons (an adjustment not undertaken in the Bergeret 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: 0.871.09). Aspirin was associated with an 18% reduction in major coronary events (95%

CI: 0.750.90; p < 0.0001), but the absolute difference between the groups was small (0.06% peryear) 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 aspirins effectiveness in primary strokeprevention. 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 forischemic 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 Bergeret al. meta-

analysis, aspirin was associated with a 69% (OR: 1.69; 95% CI: 1.042.73) increase in the risk ofhemorrhagic stroke in men, but no increased risk in women (OR: 1.07; 95% CI: 0.422.69). [28] In

the ATTC analysis, aspirin increased the risk of hemorrhagic stroke by 32% (95% CI: 1.001.75).[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 ofcardiovascular 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:

1.242.74; p < 0.001).[30] They found no association between subject age group (


12/19

Additional considerations may inform the riskbenefit 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 GIbleeding 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 aspirins gender-specific effects is not entirely clear. Many drugs are metabolizeddifferently 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]

Beckeret al. compared the effects of low dose (81 mg per day) aspirin on platelets in close to 1300healthy 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 reactivitywas 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 isunclear how gender differences in platelet inhibition and aspirin resistance contribute to aspirins

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.

Table 2. Guideline Statements Regarding Aspirin for the Primary Prevention of Stroke.


13/19

The American Heart Association (AHA) recommends aspirin for primary prevention ofcardiovascular events, including stroke, for men and women who are at high risk (610% 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 outweighthe 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 4579

years and women aged 5579 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 enoughevidence 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 inwomen 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 ofstroke.[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 JointBritish 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 bloodpressure 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


14/19

that aspirin (75162 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


15/19

There are gender disparities in the acute treatment of stroke and in stroke outcomes.

Primary Prevention Trials

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 nodifference in the risk of stroke between aspirin and placebo.

The Primary Prevention Project (PPP) enrolled men and women and found no difference inthe risk of stroke between aspirin and placebo; however, aspirin was found to decrease the

risk of cardiac death.

The Womens 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: 0.690.99).

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 theanalyses.

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 aspirins 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 ofhemorrhagic 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 aspirins 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 highenough that the benefits outweigh the risks.


16/19

The US Preventative Services Task Force (USPSTF) recommends aspirin for men aged

4579 years and women aged 5579 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 atlow 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 ageneral 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 theprimary 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 strokemay 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 ofstroke 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.

This article is a CME certified activity. To earn credit for this activity visit:

http://www.medscape.org/viewarticle/742845

References

1. Lloyd-Jones D, Adams RJ, Brown TM et al.: Heart disease and stroke statistics 2010

update: a report from the American Heart Association. Circulation 121, e46e215 (2010).2. Brown DL, Boden-Albala B, Langa KM et al.: Projected costs of ischemic stroke in the

United States.Neurology 67, 13901395 (2006).

3. Hennekens CH: Update on aspirin in the treatment and prevention of cardiovasculardisease.Am. Heart J. 137, S9S13 (1999).

4. Weiss HJ, Aledort LM: Impaired platelet-connective-tissue reaction in man after aspirin

ingestion.Lancet2, 495497 (1967).5. Chen ZM, Sandercock P, Pan HC et al.: Indications for early aspirin use in acute ischemic

stroke: a combined analysis of 40,000 randomized patients from the Chinese Acute Stroke

trial and the International Stroke Trial. On behalf of the CAST and IST collaborative

groups. Stroke 31, 12401249 (2000).6. Antiplatelet Trialists' Collaboration: Collaborative overview of randomised trials of

antiplatelet therapy I: Prevention of death, myocardial infarction, and stroke by

prolonged antiplatelet therapy in various categories of patients.BMJ308, 81106 (1994). Summary of antiplatelet trials in primary and secondary prevention.

7. Awtry EH, Loscalzo J: Aspirin. Circulation 101, 12061218 (2000).

Summary of aspirin's mechanism and clinical use.
http://www.medscape.org/viewarticle/742845http://www.medscape.org/viewarticle/742845


17/19

8. Burch JW, Stanford N, Majerus PW: Inhibition of platelet prostaglandin synthetase by oral

aspirin.J. Clin. Invest. 61, 314319 (1978).9. Husain S, Andrews NP, Mulcahy D, Panza JA, Quyyumi AA: Aspirin improves endothelial

dysfunction in atherosclerosis. Circulation 97, 716720 (1998).

10. Sudlow CL, Warlow CP: Comparable studies of the incidence of stroke and its pathologicaltypes: results from an international collaboration. Stroke 28, 491499 (1997).

11. Carandang R, Seshadri S, Beiser A et al.: Trends in incidence, lifetime risk, severity, and

30-day mortality of stroke over the past 50 years.JAMA 296, 29392946 (2006).

12. Lofmark U, Hammarstrom A: Evidence for age-dependent education-related differences inmen and women with first-ever stroke. Results from a community-based incidence study in

northern Sweden.Neuroepidemiology 28, 135141 (2007).

13. Rothwell PM, Coull AJ, Silver LE et al.: Population-based study of event-rate, incidence,case fatality, and mortality for all acute vascular events in all arterial territories (Oxford

Vascular Study).Lancet366, 17731783 (2005).

14. Petrea RE, Beiser AS, Seshadri S, Kelly-Hayes M, Kase CS, Wolf PA: Gender differencesin stroke incidence and poststroke disability in the Framingham Heart Study. Stroke 40,

10321037 (2009).

15. Bousser MG: Stroke in women: the 1997 Paul Dudley White international lecture.Circulation 99, 463467 (1999).

Review of epidemiology, risk factors and preventative strategies regarding stroke inwomen.

16. Reeves MJ, Bushnell CD, Howard G et al.: Sex differences in stroke: epidemiology,clinical presentation, medical care, and outcomes.Lancet Neurol. 7, 915926 (2008).

Comprehensive review of gender differences in stroke.

17. Schumacher HC, Bateman BT, Boden-Albala B et al.: Use of thrombolysis in acuteischemic stroke: analysis of the nationwide inpatient sample 1999 to 2004. Ann. Emerg.

Med. 50, 99107 (2007).

18. Peto R, Gray R, Collins Ret al.: Randomised trial of prophylactic daily aspirin in Britishmale doctors.BMJ296, 313316 (1988).

19. Steering Committee of the Physicians' Health Study Research Group: final report on the

aspirin component of the ongoing Physicians' Health Study.N. Engl. J. Med. 321, 129135 (1989).

20. Medical Research Council: Thrombosis Prevention Trial: randomised trial of low-intensity

oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of

ischaemic heart disease in men at increased risk.Lancet351, 233241 (1998).21. Hansson L, Zanchetti A, Carruthers SG et al.: Effects of intensive blood-pressure lowering

and low-dose aspirin in patients with hypertension: principal results of the Hypertension

Optimal Treatment (HOT) randomised trial.Lancet351, 17551762 (1998).22. Hansson L, Zanchetti A: The Hypertension Optimal Treatment (HOT) study patient

characteristics: randomization, risk profiles, and early blood pressure results.Blood Press.

3, 322327 (1994).

23. Collaborative Group of the Primary Prevention Project: Low-dose aspirin and vitamin E inpeople at cardiovascular risk: a randomised trial in general practice.Lancet357, 8995

(2001).

24. Ridker PM, Cook NR, Lee IM et al.: A randomized trial of low-dose aspirin in the primaryprevention of cardiovascular disease in women.N. Engl. J. Med. 352, 12931304 (2005).

25. Fowkes FG, Price JF, Stewart MC et al.: Aspirin for prevention of cardiovascular events in

a general population screened for a low ankle brachial index: a randomized controlled trial.JAMA 303, 841848 (2010).

26. Gorelick PB: Challenges of designing trials for the primary prevention of stroke. Stroke 40,

S82S84 (2009).


18/19

Discusses issues of sample size and cardiovascular event rates that make primary

prevention trials for stroke difficult to conduct.27. Swaim L, Hillman RS: Aspirin administered to women at 100 mg every other day produces

less platelet inhibition than aspirin administered at 81 mg per day: implications for

interpreting the Women's Health Study.J. Thromb. Thrombolysis 28, 94100 (2009).28. Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL: Aspirin for

the primary prevention of cardiovascular events in women and men: a sex-specific meta-

analysis of randomized controlled trials.JAMA 295, 306313 (2006).

Meta-analysis that suggested gender differences in aspirin's effectiveness in preventingstroke.

29. Antithrombotic Trialists' Collaboration: Aspirin in the primary and secondary prevention of

vascular disease: collaborative meta-analysis of individual participant data fromrandomised trials.Lancet373, 18491860 (2009).

Combined analysis of primary prevention trials that included individual patient data. The

authors found gender differences in aspirin's effectiveness in preventing ischemic stroke,but after adjustments for multiple comparisons the differences were no longer significant.

30. He J, Whelton PK, Vu B, Klag MJ: Aspirin and risk of hemorrhagic stroke: a meta-ana-

lysis of randomized controlled trials.JAMA 280, 19301935 (1998). A meta-analysis that describes the risk of hemorrhagic stroke with aspirin.

31. Gorelick PB, Weisman SM: Risk of hemorrhagic stroke with aspirin use: an update. Stroke36, 18011807 (2005).

32. Pignone M, Earnshaw S, Tice JA, Pletcher MJ: Aspirin, statins, or both drugs for theprimary prevention of coronary heart disease events in men: a cost-utility analysis.Ann.

Intern. Med. 144, 326336 (2006).

33. Gray LJ, Sprigg N, Bath PM et al.: Sex differences in quality of life in stroke survivors:data from the Tinzaparin in Acute Ischaemic Stroke Trial (TAIST). Stroke 38, 2960-2964

(2007).

34. Anderson GD: Sex and racial differences in pharmacological response: where is theevidence? Pharmacogenetics, pharmacokinetics, and pharmacodynamics.J. Womens

Health (Larchmt) 14, 19-29 (2005).

35. Becker DM, Segal J, Vaidya D et al.: Sex differences in platelet reactivity and response tolow-dose aspirin therapy.JAMA 295, 1420-1427 (2006).

36. Qayyum R, Becker DM, Yanek LRet al.: Platelet inhibition by aspirin 81 and 325 mg/day

in men versus women without clinically apparent cardiovascular disease.Am. J. Cardiol.

101, 1359-1363 (2008).37. Gum PA, Kottke-Marchant K, Poggio ED et al.: Profile and prevalence of aspirin

resistance in patients with cardiovascular disease.Am. J. Cardiol. 88, 230-235 (2001).

38. Goldstein LB, Bushnell CD, Adams RJ et al.: Guidelines for the primary prevention ofstroke: a guideline for healthcare professionals from the American Heart Association/

American Stroke Association. Stroke 42(2), 517-584 (2011).

39. U.S. Preventative Services Task Force: Aspirin for the prevention of cardiovascular

disease: U.S. Preventive Services Task Force recommendation statement.Ann. Intern.Med. 150, 396-404 (2009).

40. Graham I, Atar D, Borch-Johnsen Ket al.: European guidelines on cardiovascular disease

prevention in clinical practice: executive summary: fourth joint task force of the Europeansociety of cardiology and other societies on cardiovascular disease prevention in clinical

practice (constituted by representatives of nine societies and by invited experts).Eur.

Heart J. 28, 2375-2414 (2007).41. British Cardiac Society, British Hypertension Society, Diabetes UK, Heart UK, Primary

Care Cardiovascular Society, and Stroke Association: JBS 2: Joint British societies'

guidelines on prevention of cardiovascular disease in clinical practice.Heart91, v1-v52(2005).


19/19

c Me Article Cvd

Documents

Transcript of c Me Article Cvd