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new englandjournal of medicineTheestablished in 1812march 31, 2005vol.352no.13 A Randomized Trial of Low-Dose Aspirin

in the Primary Prevention of Cardiovascular Disease in Women

Paul M Ridker, M.D., Nancy R. Cook, Sc.D., I-Min Lee, M.B., B.S., David Gordon, M.A.,

J. Michael Gaziano, M.D., JoAnn E. Manson, M.D., Charles H. Hennekens, M.D., and Julie E. Buring, Sc.D.abstractbackground

Randomized trials have shown that low-dose aspirin decreases the risk of a first myo-cardial infarction in men, with little effect on the risk of ischemic stroke. There are fewsimilar data in women.

methods

We randomly assigned 39,876 initially healthy women 45 years of age or older to re-ceive 100 mg of aspirin on alternate days or placebo and then monitored them for 10years for a first major cardiovascular event (i.e., nonfatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes).

results

During follow-up, 477 major cardiovascular events were confirmed in the aspirin group,as compared with 522 in the placebo group, for a nonsignificant reduction in risk withaspirin of 9 percent (relative risk, 0.91; 95 percent confidence interval, 0.80 to 1.03;P=0.13). With regard to individual end points, there was a 17 percent reduction in therisk of stroke in the aspirin group, as compared with the placebo group (relative risk,0.83; 95 percent confidence interval, 0.69 to 0.99; P=0.04), owing to a 24 percent re-duction in the risk of ischemic stroke (relative risk, 0.76; 95 percent confidence inter-val, 0.63 to 0.93; P=0.009) and a nonsignificant increase in the risk of hemorrhagicstroke (relative risk, 1.24; 95 percent confidence interval, 0.82 to 1.87; P=0.31). Ascompared with placebo, aspirin had no significant effect on the risk of fatal or nonfatalmyocardial infarction (relative risk, 1.02; 95 percent confidence interval, 0.84 to 1.25;P=0.83) or death from cardiovascular causes (relative risk, 0.95; 95 percent confidenceinterval, 0.74 to 1.22; P=0.68). Gastrointestinal bleeding requiring transfusion wasmore frequent in the aspirin group than in the placebo group (relative risk, 1.40; 95percent confidence interval, 1.07 to 1.83; P=0.02). Subgroup analyses showed that as-pirin significantly reduced the risk of major cardiovascular events, ischemic stroke,and myocardial infarction among women 65 years of age or older.

conclusions

From the Divisions of Preventive Medicine(P.MR., N.R.C., I-M.L., D.G., J.M.G., J.E.M.,J.E.B.), Cardiovascular Medicine (P.MR.,J.M.G.), and Aging (J.M.G., J.E.B.), Depart-ment of Medicine, Brigham and Women'sHospital, Harvard Medical School; the De-partment of Epidemiology, Harvard Schoolof Public Health (P.MR., N.R.C., I-M.L.,J.E.M., J.E.B.); Veterans Affairs BostonHealthcare System (J.M.G.); and the De-partment of Ambulatory Care and Preven-tion, Harvard Medical School (J.E.B.) — allin Boston; and the Departments of Medi-cine and Epidemiology and Public Health,University of Miami School of Medicine,and the Department of Biomedical Sci-ence, Center of Excellence, Florida Atlan-tic University, Miami (C.H.H.). Addressreprint requests to Dr. Buring at theDivision of Preventive Medicine, Brighamand Women’s Hospital, 900 Common-wealth Ave. East, Boston, MA 02215, or atjburing@rics.bwh.harvard.edu.

This article was published at www.nejm.orgon March 7, 2005.

N Engl J Med 2005;352:1293-304.

In this large, primary-prevention trial among women, aspirin lowered the risk of strokewithout affecting the risk of myocardial infarction or death from cardiovascular causes,leading to a nonsignificant finding with respect to the primary end point.

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lthough aspirin is effective inthe treatment of acute myocardial infarc-tion and in the secondary prevention of

cardiovascular disease among both men and wom-en,1 its use in primary prevention remains contro-versial. To date, five randomized trials involving55,580 participants have evaluated aspirin in theprimary prevention of cardiovascular disease.2-6 Inaggregate, these trials indicate that, as comparedwith placebo, aspirin therapy was associated with asignificant, 32 percent reduction in the risk of my-ocardial infarction, but the data on the risk of strokeand death from cardiovascular disease remain in-conclusive.7 Moreover, three of these trials evaluat-ed men exclusively, and fewer than 180 of the 2402vascular events occurred in women. Thus, at thistime, the current recommendations for the use ofaspirin in primary prevention in women are basedon limited direct data from women.8-10

Direct evidence regarding the effects of aspirinin women is necessary because cardiovascular dis-ease is the leading cause of death among both wom-en and men. Direct evidence is also relevant be-cause of the potential for sex-based differences insalicylate metabolism11 and continuing uncertain-ty regarding the cardiovascular effects of hormone-replacement therapy.12 Moreover, in addition to apaucity of data on women, the prophylactic use ofaspirin in both sexes has prompted concern owingto the potentially increased risk of hemorrhagicstroke.13 This issue is particularly complex, sincethe relative proportion of stroke to myocardial in-farction differs between women and men.

We addressed these questions in the Women’sHealth Study, a large randomized, double-blind, pla-cebo-controlled trial of low-dose aspirin in the pri-mary prevention of cardiovascular disease among39,876 apparently healthy women followed for amean of 10 years for the major cardiovascular eventsof myocardial infarction, stroke, and death from car-diovascular causes.a

The new england journal of medicine

methodsstudy designThe Women’s Health Study is a two-by-two facto-rial trial evaluating the balance of risks and bene-fits of low-dose aspirin (100 mg every other day;Bayer HealthCare) and vitamin E (600 IU everyother day; Natural Source Vitamin E Association),in the primary prevention of cardiovascular diseaseand cancer. The trial was designed to evaluate thelowest dose of aspirin that would have a cardiopro-1294

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tective effect, while minimizing gastrointestinalside effects through the use of a low dose and al-ternate-day administration. The design of the studyhas previously been described in detail.14,15 In brief,between September 1992 and May 1995, letters ofinvitation were mailed to more than 1.7 million fe-male health professionals. A total of 453,787 com-pleted the questionnaires, with 65,169 initially will-ing and eligible to enroll. Women were eligible ifthey were 45 years of age or older; had no historyof coronary heart disease, cerebrovascular disease,cancer (except nonmelanoma skin cancer), or othermajor chronic illness; had no history of side effectsto any of the study medications; were not taking as-pirin or nonsteroidal antiinflammatory medications(NSAIDs) more than once a week (or were willingto forego their use during the trial); were not takinganticoagulants or corticosteroids; and were not tak-ing individual supplements of vitamin A, E, or betacarotene more than once a week. For the purposesof this study, inhibitors of cyclooxygenase, wheth-er selective or nonselective, were considered to beNSAIDs.

Eligible women were enrolled in a three-monthrun-in period of placebo administration to identifya group likely to be compliant with long-term treat-ment. A total of 39,876 women were willing, eligi-ble, and compliant during the run-in period and un-derwent randomization: 19,934 were assigned toreceive aspirin and 19,942 to receive placebo. Writ-ten informed consent was obtained from all partic-ipants. The trial was approved by the institutionalreview board of Brigham and Women’s Hospital,Boston, and was monitored by an external data andsafety monitoring board.

Every 12 months, the women were sent a year’ssupply of monthly calendar packs containing ac-tive agents or placebo as well as questionnaires oncompliance, side effects, the occurrence of relevantclinical end points, and risk factors. Study medica-tions and end-point ascertainment were continuedin a blinded fashion through the scheduled end ofthe trial (March 31, 2004). Follow-up and validationof reported end points were completed in February2005. Rates of follow-up with respect to morbidityand mortality were 97.2 percent complete and 99.4percent complete, respectively.

All the women were followed for myocardial in-farction, stroke, or death from cardiovascular caus-es. Medical records were obtained for all women inwhom a cardiovascular end point was reported tooccur and were reviewed in a blinded fashion byan end-points committee of physicians. Myocardial

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low-dose aspirin and cardiovascular disease in women

infarction was confirmed if symptoms met Worldand other randomized treatment assignments (vi-Health Organization criteria and if the event was as-tamin E and beta carotene, which was a componentsociated with abnormal levels of cardiac enzymes orof the trial for a median of 2.1 years17). Prespecifieddiagnostic electrocardiograms. A confirmed strokesubgroup analyses were performed according towas defined as a new neurologic deficit of suddenthe presence or absence of major cardiovascularonset that persisted for at least 24 hours. Clinical in-risk factors. Modification of the effect of aspirinformation, computed tomographic scans, and mag-by the risk factors was assessed with the use of in-netic resonance images were used to distinguishteraction terms between subgroup indicators andhemorrhagic from ischemic events.16 Death wasaspirin assignment, with tests for trend performedconfirmed to be from cardiovascular causes on thewhen subgroup categories were ordinal. To exam-basis of an examination of autopsy reports, deathine effects among women who were compliant,certificates, medical records, and information ob-we performed a sensitivity analysis in which fol-tained from the next of kin or other family mem-low-up data were censored at the time a woman re-bers. The use of coronary revascularization (bypassported having taken less than two thirds of thesurgery or percutaneous coronary angioplasty) wasstudy medication during the previous year. In ad-confirmed by a review of the medical records. A con-ditional analyses, data were censored on womenfirmed transient ischemic attack was defined as aif and when they started taking NSAIDs more thanneurologic deficit of sudden onset that lasted forthree times a month.less than 24 hours. Death from any cause was con-firmed by the end-points committee or on the basisresultsof a death certificate. Only confirmed end pointswere included in this analysis. For women with aprimary analysesreported myocardial infarction, the most commonAs shown in Table 1, the aspirin and placebo groupsdiagnoses among those in whom the diagnosis waswere similar with respect to baseline characteris-not confirmed were stable or unstable angina ortics. The average duration of follow-up from ran-chest pain without evidence of infarction. For wom-domization to the end of the trial was 10.1 yearsen with a reported stroke, the most common alter-(range, 8.2 to 10.9). At the completion of the trial,native diagnosis was transient cerebral ischemia.

999 women had had a first major cardiovascularevent (Table 2), for an absolute event rate of 253 perstatistical analysis

100,000 person-years. Of these women, 477 wereAll primary analyses were performed on an inten-in the aspirin group and 522 were in the placebotion-to-treat basis. The primary end point was agroup, indicating that there was a nonsignificantcombination of major cardiovascular events, in-reduction in risk of 9 percent (relative risk, 0.91; 95cluding nonfatal myocardial infarction, nonfatalpercent confidence interval, 0.80 to 1.03; P=0.13).stroke, and death from cardiovascular causes, andRegarding individual end points, women in thethe trial was initially designed to have a statisticalaspirin group had a 17 percent reduction in the riskpower of 86 percent to detect a 25 percent reduc-of stroke (relative risk, 0.83; 95 percent confidencetion in this end point. Secondary end points includ-interval, 0.69 to 0.99; P=0.04), as compared withed the individual end points of fatal or nonfatal myo-women in the placebo group; a 24 percent reductioncardial infarction, fatal or nonfatal stroke, ischemicin the risk of ischemic stroke (relative risk, 0.76; 95stroke, hemorrhagic stroke, and death from cardio-percent confidence interval, 0.63 to 0.93; P=0.009);vascular causes. Additional analyses included theand a nonsignificant increase in the risk of hem-incidence of death from any cause, transient ische-orrhagic stroke (relative risk, 1.24; 95 percent con-mic attack, and the need for coronary revascular-fidence interval, 0.82 to 1.87; P=0.31) (Table 2).ization. If more than one end point occurred in aThere was no significant difference between thegiven woman, only the first event within each cate-groups in the risk of fatal stroke (relative risk in thegory was counted; for the primary combined endaspirin group, 1.04; 95 percent confidence interval,point, the first event in each woman was counted.0.58 to 1.86; P=0.90), but the aspirin group had aCox proportional-hazards models were used todecreased risk of nonfatal strokes (relative risk,calculate relative risks and 95 percent confidence0.81; 95 percent confidence interval, 0.67 to 0.97;intervals for the comparison of event rates in the as-P=0.02), as compared with the placebo group.pirin and placebo groups after adjustment for age

There was no evidence that, as compared with

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Table 1. Baseline Characteristics of the Women.Characteristic AgeMean ±SD (yr) 45–54 yr (%) 55–64 yr (%) ≥65 yr (%)Smoking status (%) Current Past or neverBody-mass index*Mean ±SD <25.0 (%) 25.0 to 29.9 (%) ≥30.0 (%)Menopausal status and use of HRT(%)†PremenopausalUncertainPostmenopausal and current HRTPostmenopausal and no HRTHypertension (%)‡ Yes NoBlood pressure (%) <120/<75 mm Hg 120–129/75–84 mm Hg 130–139/85–89 mm Hg ≥140/≥90 mm Hg32.232.219.516.132.931.819.315.932.632.019.416.026.074.025.774.325.974.127.517.730.424.427.618.229.724.427.618.030.024.426.1±5.150.830.918.326.0±5.050.831.018.226.0±5.150.830.918.213.087.013.386.713.186.954.6±7.060.229.510.354.6±7.060.229.510.354.6±7.060.229.510.3Aspirin (N=19,934)Placebo (N=19,942)Total (N=39,876)placebo, aspirin reduced the overall risk of myocar-dial infarction (relative risk, 1.02; 95 percent con-fidence interval, 0.84 to 1.25; P=0.83), fatal myo-cardial infarction (relative risk, 1.16; 95 percentconfidence interval, 0.54 to 2.51; P=0.70), nonfa-tal myocardial infarction (relative risk, 1.01; 95 per-cent confidence interval, 0.83 to 1.24; P=0.90), ordeath from cardiovascular causes (relative risk,0.95; 95 percent confidence interval, 0.74 to 1.22;P=0.68). However, aspirin therapy was associatedwith a 22 percent reduction in the risk of transientischemic attack (relative risk, 0.78; 95 percent con-fidence interval, 0.64 to 0.94; P=0.01), with no sig-nificant effects on the risk of coronary revascular-ization (relative risk, 1.04; 95 percent confidenceinterval, 0.90 to 1.20; P=0.61) or death from anycause (relative risk, 0.95; 95 percent confidence in-terval, 0.85 to 1.06; P=0.32).

Figures 1 and 2 present the cumulative inci-dence rates of major cardiovascular events, stroke,

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myocardial infarction, ischemic stroke, and hem-orrhagic stroke according to the year of follow-up.Because it has been suggested that the ability of as-pirin to inhibit platelet function diminishes overtime,18 we also evaluated incidence rates accordingto the length of follow-up. A beneficial effect of as-pirin on stroke was observed early in the trial andpersisted throughout the trial, with no apparent ben-efit of aspirin on myocardial infarction at any pointduring follow-up.

Neither treatment with vitamin E nor treatmentwith beta carotene significantly modified the effectof aspirin on the primary or secondary end points.

subgroup analyses

There was no evidence that any of the cardiovas-cular risk factors considered, except smoking sta-tus and age, modified the effect of aspirin on theprimary end point of major cardiovascular events(Table 3). We observed a greater benefit of aspirin

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low-dose aspirin and cardiovascular disease in women

Table 1. (Continued.)CharacteristicAspirin (N=19,934)Placebo (N=19,942)Total (N=39,876)Hyperlipidemia (%)§ Yes29.929.129.5 No70.170.970.5Diabetes (%) Yes2.72.52.6 No97.397.597.4Parental history of myocardial infarction before 60 yr of age (%) Yes13.012.912.9 No87.087.187.110-yr risk of coronary heart disease (%)¶ <5.0%84.484.684.5 5.0 to 9.9%11.811.311.5 ≥10.0%3.94.14.0No. of risk factors (%)¿ 041.842.442.1 134.134.134.1 218.017.217.6 ≥36.26.36.2*The body-mass index is the weight in kilograms divided by the square of the height in meters.†HRT denotes hormone-replacement therapy.

‡Hypertension was defined as a systolic blood pressure of at least 140 mm Hg, a diastolic blood pressure of at least 90 mm Hg, or self-reported physician-diagnosed hypertension.

§Hyperlipidemia was defined as a total cholesterol level of at least 240 mg per deciliter (6.2 mmol per liter) or self-report-ed physician-diagnosed high cholesterol levels.

¶This variable was calculated with the Framingham risk score for those with blood specimens.¿Risk factors were smoking, hypertension, hyperlipidemia, diabetes, and obesity.

Table 2. Incidence and Relative Risk of Confirmed Cardiovascular End Points.Aspirin PlaceboRelative Risk End Point(N=19,934)(N=19,942)(95% CI)*P Valueno. of eventsMajor cardiovascular event†4775220.91 (0.80–1.03)0.13Stroke2212660.83 (0.69–0.99)0.04Ischemic1702210.76 (0.63–0.93)0.009Hemorrhagic51411.24 (0.82–1.87)0.31Fatal23221.04 (0.58–1.86)0.90Nonfatal1982440.81 (0.67–0.97)0.02Myocardial infarction1981931.02 (0.84–1.25)0.83Fatal14121.16 (0.54–2.51)0.70Nonfatal1841811.01 (0.83–1.24)0.90Death from cardiovascular causes1201260.95 (0.74–1.22)0.68Transient ischemic attack1862380.78 (0.64–0.94)0.01Coronary revascularization3893741.04 (0.90–1.20)0.61Death from any cause6096420.95 (0.85–1.06)0.32* CI denotes confidence interval.

†A major cardiovascular event was defined as a nonfatal myocardial infarction, a nonfatal stroke, or death from cardiovas-cular causes.

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0.03Placebo0.02Aspirin0.01P=0.130.000246810Years of Follow-upsis in which follow-up data were censored at thetime a woman reported having taken less than twothirds of the study medication during the preced-ing year. In this analysis, aspirin, as compared withplacebo, reduced the risk of major cardiovascularevents by 13 percent, reduced the risk of stroke by26 percent, reduced the risk of ischemic stroke by33 percent, and had no significant effect on the riskof myocardial infarction (relative risk, 1.03; 95 per-cent confidence interval, 0.81 to 1.32; P=0.79).Some women started taking NSAIDs during thetrial — a potentially important issue with respect tothe risk of thrombotic events, since certain NSAIDscan compete with aspirin for receptors on plate-lets.19 According to our data, however, the lack ofan effect of aspirin therapy on the risk of myocar-dial infarction was not explained by concomitantuse of NSAIDs.20

side effects

Figure 1. Cumulative Incidence Rates of the Primary End Point of Major Car-diovascular Events.A major cardiovascular event was defined as a nonfatal myocardial infarction, a nonfatal stroke, or death from cardiovascular causes.Cumulative Incidence of Major Cardiovascular Eventson the risk of major cardiovascular events amongformer smokers and those who had never smoked,with an apparent increased risk among currentsmokers (P for interaction <0.001), although it isimportant to interpret this information in the con-text of multiple comparisons. In addition, age sig-nificantly modified the effect of aspirin on the riskof both major cardiovascular events and myocar-dial infarction (P for interaction=0.05 and 0.03, re-spectively). The most consistent benefit of aspirinwas observed among the subgroup of women 65years of age or older at study entry; in this sub-group, the risk of major cardiovascular events wasreduced by 26 percent among those who took aspi-rin as compared with those who took placebo (rel-ative risk, 0.74; 95 percent confidence interval, 0.59to 0.92; P=0.008), and the risk of ischemic strokewas reduced by 30 percent (relative risk, 0.70; 95percent confidence interval, 0.49 to 1.00; P=0.05).This was also the only subgroup in which aspirin,as compared with placebo, significantly reducedthe risk of myocardial infarction (relative risk,0.66; 95 percent confidence interval, 0.44 to 0.97;P=0.04).

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Reports of gastrointestinal bleeding and pepticulcer were confirmed by means of follow-up ques-tionnaires. These side effects were significantlymore common among women in the aspirin groupthan among women in the placebo group (Table 4).There were 127 episodes of gastrointestinal bleed-ing requiring transfusion in the aspirin group, ascompared with 91 in the placebo group (relative risk,1.40; 95 percent confidence interval, 1.07 to 1.83;P=0.02). Self-reported hematuria, easy bruising,and epistaxis were frequent among women in bothgroups, with small but significant excesses amongthose in the aspirin group. The percentage of wom-en reporting any symptoms suggestive of gastric up-set was virtually identical in the two groups. Therewere five fatal gastrointestinal hemorrhages, two inthe aspirin group and three in the placebo group.discussionIn this large, placebo-controlled, primary-preven-tion trial involving 39,876 initially healthy wom-en, prophylactic aspirin at a dose of 100 mg everyother day was associated with a nonsignificant re-duction in the risk of major cardiovascular events,a reduced risk of total stroke and of ischemic stroke,a nonsignificant increase in the risk of hemorrhagicstroke, and no significant effect on the risk of my-ocardial infarction or death from cardiovascularcauses. With respect to the primary end point ofmajor cardiovascular events as well as the individ-ual end points of fatal or nonfatal stroke and my-

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low-dose aspirin and cardiovascular disease in women

0.020.02eenccoinnteecrdicenkPlacebodaifcnnIII oertv0.01Aspirinl eaiviSidt 0.01AspirintrafaaloPlaceboluucmmoyuuMCC fP=0.04oP=0.830.000.0002468100246810Years of Follow-upYears of Follow-up0.020.02eeececknknoeerotdrdSiti cSccnni IcIg iem0.01Placebo eavvhr0.01iteAspirinitrahaolclusumP=0.31mI mefuouH CCfP=0.009oAspirin0.000.00Placebo02468100246810Years of Follow-upYears of Follow-upFigure 2. Cumulative Incidence Rates of Stroke, Myocardial Infarction, Ischemic Stroke, and Hemorrhagic Stroke.ocardial infarction, consistent benefits of aspirin(relative risk, 0.76; 95 percent confidence inter-were observed among the subgroup of womenval, 0.62 to 0.95; P=0.01) but had no significantwho were 65 years of age or older. We found no ev-effect on the risk of stroke (relative risk, 0.97; 95idence that menopausal status, the use or nonusepercent confidence interval, 0.83 to 1.13; P=0.69).of hormone-replacement therapy after menopause,In analyses stratified according to sex (Fig. 3), com-or global cardiovascular-risk status modified thebined data on women from the Women’s Healtheffect of aspirin. As expected, the frequency of sideStudy, the Hypertension Optimal Treatment (HOT)effects related to bleeding and ulcers was increasedstudy,5,21 and the Primary Prevention Project6 (andamong women who received aspirin.

Roncaglioni MC: personal communication) indi-Our findings must be interpreted in the contextcate that aspirin therapy was associated with a sig-of those of other completed, randomized trials ofnificant, 19 percent reduction in the risk of strokeaspirin in the primary and secondary prevention of(relative risk, 0.81; 95 percent confidence interval,cardiovascular disease. In secondary prevention, the0.69 to 0.96; P=0.01), with no reduction in the riskAntithrombotic Trialists’ Collaboration showed thatof myocardial infarction (relative risk, 0.99; 95aspirin clearly reduced the risk of cardiovascularpercent confidence interval, 0.83 to 1.19; P=0.95).events, myocardial infarction, and ischemic strokeBy contrast, the aggregate data on men from thein both men and women.1 To address the effectsPhysicians’ Health Study,2 the British Doctors’of aspirin in primary prevention, we performed aTrial,3 the Thrombosis Prevention Trial,4 the HOTrandom-effects meta-analysis that included currentstudy,5,21 and the Primary Prevention Project6 indi-data from the Women’s Health Study, as well ascate that aspirin therapy was associated with a sig-data from five prior trials involving 55,580 partici-nificant, 32 percent reduction in the risk of myo-pants with no history of heart disease.2-6,21 Over-cardial infarction (relative risk, 0.68; 95 percentall, as compared with placebo, aspirin therapy sig-confidence interval, 0.54 to 0.86; P=0.001) and anificantly reduced the risk of myocardial infarctionnonsignificant increase in the risk of stroke (rela-n engl j med 352;13

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Total No. Aspno.24,02511,7544,0975,23534,60519,84912,0817,12610,9737,14911,9489,7042012340.86 (0.71–1.03)0.11861130.76 (0.57–1.00)0.051501490.98 (0.78–1.23)0.8579780.98 (0.72–1.34)0.92606967750.91 (0.66–1.27)0.5924430.57 (0.35–0.94)0.031655630.88 (0.61–1.26)0.4730310.97 (0.59–1.60)0.91231161111.05 (0.81–1.36)0.7250530.96 (0.65–1.41)0.81411581750.89 (0.72–1.11)0.3170840.83 (0.60–1.13)0.24571842230.82 (0.68–1.00)0.05951260.75 (0.58–0.98)0.0467970.69 (0.50–0.94)720.78 (0.55–1.11)490.85 (0.56–1.29)231.01 (0.56–1.79)350.47 (0.26–0.85)650.9 (0.63–1.27)970.71 (0.52–0.96)3193920.80 (0.69–0.93)0.0031572070.75 (0.61–0.92)0.0061191740.67 (0.53–0.85)0.0010.020.160.440.980.010.540.031571271.30 (1.03–1.64)0.0363581.14 (0.80–1.63)0.4850461.14 (0.76–1.70)0.52761311750.74 (0.59–0.92)0.00868860.78 (0.57–1.08)0.1353750.70 (0.49–1.00)0.05411831860.98 (0.80–1.20)0.8476900.84 (0.62–1.14)0.2660750.80 (0.57–1.12)0.19881631611.01 (0.81–1.26)0.9277900.85 (0.63–1.16)0.3157710.80 (0.57–1.14)0.2169no.no.no.561.23 (0.87–1.75)0.25751.17 (0.86–1.59)0.32620.66 (0.44–0.97)0.04531.50 (1.06–2.13)0.021221390.87 (0.68–1.10)0.2567764518385881730.92 (0.66–1.28)0.63681.11 (0.80–1.54)0.52460.98 (0.65–1.47)0.9126 0.69 (0.38–1.26)0.23261.49 (0.91–2.46)0.11511.12 (0.77–1.63)0.57900.9 (0.67–1.21)0.49PlaRR (95% CI)AspPlaAspPlaAspPlaP ValueRR (95% CI)P ValueRR (95% CI)P ValueRR (95% CI)P ValueMajor CV EventStrokeIschemic StrokeMyocardial Infarction10,31729,55012,79912,5817,6426,2951581900.81 (0.65–1.00)0.051311380.94 (0.74–1.20)0.621071130.94 (0.72–1.22)0.63514772701.04 (0.75–1.45)0.81402412520.96 (0.81–11.15)0.692352700.84 (0.71–1.00)0.051091380.76 (0.59–0.98)0.041111280.88 (0.68–1.13)0.31430.94 (0.61–1.45)0.79570.89 (0.61–1.30)0.54620.75 (0.51–1.09)0.13761010.73 (0.54–0.98)0.04911200.73 (0.56–0.96)781010.78 (0.58–1.05)27373665350.78 (0.47–1.29)450.82 (0.53–1.26)480.74 (0.48–1.15)900.7 (0.51–0.96)0.020.100.340.360.180.03981010.95 (0.72–1.25)0.6910024436664921.10 (0.83–1.46)0.52191.28 (0.70–2.34)0.42421.02 (0.66–1.56)0.94591.11 (0.78–1.58)0.55680.92 (0.66–1.30)0.65Table 3. Incidence and Relative Risk of Cardiovascular Events, According to Baseline Characteristics.*GroupAge45–54 yr55–64 yr≥65 yrSmoking status Current Past or neverBody-mass index†<25.025.0 to 29.9≥30.0Menopause and HRTn engl j med 352;13

PremenopausalUncertainPostmenopausal, current HRT The new england journal of medicine

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130–139/85–89 mm Hg ≥140/≥90 mm Hg

low-dose aspirin and cardiovascular disease in women

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The new england journal of medicine

Table 4. Incidence and Relative Risk of Side Effects.*Side EffectGastrointestinal bleeding Any Requiring transfusionPeptic ulcerHematuriaEasy bruisingEpistaxisAny report of gastric upset910 (4.6)127 (0.6)542 (2.7)3,039 (15.2)10,561 (53.0)3,801 (19.1)11,856 (59.5)751 (3.8)91 (0.5)413 (2.1)2,879 (14.4)8,494 (42.6)3,321 (16.7)11,915 (59.7)1.22 (1.10–1.34)1.40 (1.07–1.83)1.32 (1.16–1.50)1.06 (1.01–1.12)1.40 (1.37–1.45)1.16 (1.11–1.22)0.99 (0.97–1.02)<0.001 0.02<0.0010.02<0.001<0.0010.59Aspirin (N=19,934)Placebo (N=19,942)Relative Risk (95% CI)P Valueno. of events (%)*The presence of gastrointestinal bleeding or peptic ulcer was confirmed by a specific follow-up questionnaire. CI denotes confidence interval.

tive risk, 1.13; 95 percent confidence interval, 0.96to 1.33; P=0.15). The differences between menand women were significant at the P=0.01 level formyocardial infarction and at the P=0.005 level forstroke.

The reasons for any sex-based differences in theefficacy of aspirin for primary prevention are un-clear and require further exploration. Although theobserved reductions in the risk of stroke could bedue to chance, the reduced risk of transient ische-mic attack associated with aspirin therapy addssupport to the possibility of a causal interpretation.We cannot rule out the possibility that our null find-ing for the risk of myocardial infarction in womenwas due to an insufficient dose of aspirin or to thealternate-day regimen. However, we believe theseexplanations to be unlikely for three reasons.

First, we have previously shown that the doseof 100 mg every other day used in the Women’sHealth Study reduces thromboxane levels by 93 per-cent and prostacyclin levels by 85 percent and thatthese effects are similar in men and women.22 Sec-ond, in the HOT study, a 75-mg daily dose of aspi-rin significantly lowered the risk of myocardial in-farction overall, with a 42 percent reduction in therisk among men but a far smaller and nonsignifi-cant reduction among women.21 Third, since thedose and alternate-day regimen of aspirin used inour study were adequate to lower the risk of stroke,it is unlikely that any hypothesized sex-based dif-ferences in the resistance to aspirin were at playoverall. However, resistance to aspirin may be moreprevalent among smokers,23 and this resistancemay have played some role in the increased riskwith aspirin observed among current smokers. We

1302

also believe it unlikely that a reduction in the effica-cy of aspirin over time is a viable explanation, sincethe cumulative incidence data presented in Figures1 and 2 offer no support for this hypothesis. Fur-thermore, suboptimal compliance is an unlikely ex-planation, since aspirin did not decrease the riskof myocardial infarction among women with highrates of compliance — an observation again in con-trast to data on stroke among the same women.With regard to daily clinical practice, our datademonstrate that aspirin therapy was associatedwith a net reduction in the risk of stroke amongwomen, with a reduction in the risk of the far morecommon ischemic stroke and an increase in the riskof hemorrhagic stroke. This observation is partic-ularly relevant, since as compared with men, wom-en have a relatively greater proportion of strokesthan of myocardial infarctions. Among women inthe placebo group, there were more strokes thanmyocardial infarctions (266 vs. 193), and thus, theratio of incident strokes to incident myocardial in-farctions was 1.4:1, as compared with the ratio of0.4:1 among men in the Physicians’ Health Study.2From a policy perspective, our findings clearly dem-onstrate the importance of studying women as wellas men in major cardiovascular clinical trials.

An interesting finding in our subgroup analyseswas that the most consistent benefit of aspirin wasobserved among women 65 years of age or older.This group of 4097 women composed 10 percentof the study population yet had almost one thirdof the cardiovascular events. In this group, aspirinuse, as compared with placebo use, led to 44 few-er myocardial infarctions, strokes, or deaths fromcardiovascular causes (P=0.008) but to 16 more

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low-dose aspirin and cardiovascular disease in women

TrialRelative Risk of Myocardial Infarction TrialRelative Risk of Stroke among Menamong MenBDT, 1988BDT, 1988PHS, 1989PHS, 1989TPT, 1998TPT, 1998HOT, 1998HOT, 1998PPP, 2001PPP, 2001RR=0.68 (0.54–0.86)RR=1.13 (0.96–1.33)P=0.001P=0.15CombinedCombined0.20.51.02.05.00.20.51.02.05.0Aspirin BetterPlacebo BetterAspirin BetterPlacebo BetterTrialRelative Risk of Myocardial InfarctionTrialRelative Risk of Stroke among Women among WomenHOT, 1998HOT, 1998PPP, 2001PPP, 2001WHS, 2005WHS, 2005RR=0.99 (0.83–1.19)RR=0.81 (0.69–0.96)P=0.95P=0.01CombinedCombined0.20.51.02.05.00.20.51.02.05.0Aspirin BetterPlacebo BetterAspirin BetterPlacebo BetterFigure 3. Aspirin in the Primary Prevention of Myocardial Infarction and Stroke among Men and Women.The results of a sex-specific random-effects meta-analysis of data from six trials are shown: the British Doctors’ Trial (BDT), the Physicians’ Health Study (PHS), the Thrombosis Prevention Trial (TPT), the Hypertension Optimal Treatment (HOT) study, the Primary Prevention Project (PPP), and the current Women’s Health Study (WHS). The relative risk (RR) and 95 percent confidence interval (in parentheses) are shown for each trial (indicated by the box and horizontal line through each box, respectively), and the relative risk is shown for the combined results (indicated by the diamond and the dashed line in each graph). For the relative risk of myocardial infarction among women, the dashed line is coincident with the solid line at 1.00. The size of the box is proportional to the amount of information in the corresponding trial.gastrointestinal hemorrhages requiring transfu-woman consults her physician or health care pro-sion (P=0.05), emphasizing, as with any agent, thevider, so that the net absolute benefits and risks forimportance of balancing benefits and risks. Thisthe individual patient can be ascertained.

age-based difference deserves further investigation.

Supported by grants (HL-43851 and CA-47988) from the Nation-With respect to guidelines in primary preven-al Heart, Lung, and Blood Institute and the National Cancer Insti-tion, in 2002, the Preventive Services Task Force24tute, Bethesda, Md. Aspirin and aspirin placebo were provided by

Bayer HealthCare. Vitamin E and vitamin E placebo were providedand the American Heart Association9 recommend-by the Natural Source Vitamin E Association.

ed aspirin for adults whose 10-year risks of a first

Dr. Ridker reports having received grant support from Bayer. Dr.coronary-heart-disease event were at least 6 percentCook reports having served as a consultant to Bayer. Dr. Gaziano re-and 10 percent, respectively. However, this may beports having served as a consultant to, and receiving grant supportfrom, Bayer and McNeil. Dr. Hennekens reports having served as acomplex for women, since in our study overall, as-consultant to Bayer and McNeil and receiving grant support from

pirin lowered the risk of stroke without affectingBayer.

the risk of myocardial infarction or death from car-We are indebted to the 39,876 participants in the Women’s HealthStudy for their dedicated and conscientious collaboration; to the en-diovascular causes. Thus, as with men, any decisiontire staff of the Women’s Health Study, under the leadership of Da-about the use of aspirin in primary preventionvid Gordon, Maria Andrade, Susan Burt, Mary Breen, Marilyn Chown,

among women must ultimately be made after aLisa Fields-Johnson, Georgina Friedenberg, Inge Judge, Jean Mac-Fadyen, Geneva McNair, Laura Pestana, David Potter, Philomena

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low-dose aspirin and cardiovascular disease in women

Quinn, Claire Ridge, Fred Schwerin, and Harriet Samuelson; toChristine Albert, Michelle Albert, Gavin Blake, Claudia Chae, WendyChen, Richard Doll, Carlos Kase, Tobias Kurth, Richard Peto, Aruna

Pradhan, Kathryn Rexrode, Bernard Rosner, and H. Jacqueline Sukfor their assistance in the design and conduct of the trial; and espe-cially to James Taylor for chairing the end-points committee.

appendixMembers of the data and safety monitoring board included L. Cohen, R. Collins, T. Colton, D. DeMets, I.C. Henderson, A. La Croix, R. Pren-tice, and N. Wenger (chair) and M.F. Cotch, F. Ferris, L. Friedman, P. Greenwald, N. Kurinij, M. Perloff, E. Schron, and A. Zonderman (ex of-ficio members).references1.Antithrombotic Trialists’ Collaboration.

Collaborative meta-analysis of randomisedtrials of antiplatelet therapy for preventionof death, myocardial infarction, and strokein high risk patients. BMJ 2002;324:71-86.[Erratum, BMJ 2002;324:141.]

2.Steering Committee of the Physicians’Health Study Research Group. Final reporton the aspirin component of the ongoingPhysicians’ Health Study. N Engl J Med 1989;321:129-35.

3.Peto R, Gray R, Collins R, et al. Ran-domised trial of prophylactic daily aspirin inBritish male doctors. Br Med J (Clin Res Ed)1988;296:313-6.

4.The Medical Research Council’s Gener-al Practice Research Framework. Thrombo-sis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarinand low-dose aspirin in the primary preven-tion of ischaemic heart disease in men at in-creased risk. Lancet 1998;351:233-41.

5.Hansson L, Zanchetti A, Carruthers SG,et al. Effects of intensive blood-pressure low-ering and low-dose aspirin in patients withhypertension: principal results of the Hyper-tension Optimal Treatment (HOT) random-ised trial. Lancet 1998;351:1755-62.

6.Collaborative Group of the Primary Pre-vention Project. Low-dose aspirin and vita-min E in people at cardiovascular risk:a randomised trial in general practice. Lan-cet 2001;357:89-95. [Erratum, Lancet 2001;357:1134.]

7.Eidelman RS, Hebert PR, Weisman SE,Hennekens CH. An update on aspirin in theprimary prevention of cardiovascular dis-ease. Arch Intern Med 2003;163:2006-10.8.Hayden M, Pignone M, Phillips C, Mul-row C. Aspirin for the primary prevention of

cardiovascular events: a summary of the evi-dence for the U.S. Preventive Services TaskForce. Ann Intern Med 2002;136:161-72.9.Pearson TA, Blair SN, Daniels SR, et al.AHA guidelines for primary prevention ofcardiovascular disease and stroke: 2002 up-date: consensus panel guide to comprehen-sive risk reduction for adult patients withoutcoronary or other atherosclerotic vasculardiseases. Circulation 2002;106:388-91.10.Mosca L, Appel LJ, Benjamin EJ, et al.Evidence-based guidelines for cardiovascu-lar disease prevention in women. Circulation2004;109:672-93.

11.Montgomery PR, Berger LG, MitenkoPA, Sitar DS. Salicylate metabolism: effectsof age and sex in adults. Clin Pharmacol Ther1986;39:571-6.

12.Manson JE, Hsia J, Johnson KC, et al. Es-trogen plus progestin and the risk of coro-nary heart disease. N Engl J Med 2003;349:523-34.

13.Rodondi N, Bauer DC. Assessing the risk/benefit profile before recommending aspi-rin for the primary prevention of cardiovas-cular events. Am J Med 2004;117:528-30.14.Buring JE, Hennekens CH. The Wom-en’s Health Study: summary of the study de-sign. J Myocardial Ischemia 1992;4:27-9.15.Rexrode KM, Lee IM, Cook NR, Henne-kens CH, Buring JE. Baseline characteristicsof participants in the Women’s Health Study.J Womens Health Gend Based Med 2000;9:19-27.

16.Atiya M, Kurth T, Berger K, Buring JE,Kase CS. Interobserver agreement in the clas-sification of stroke in the Women’s HealthStudy. Stroke 2003;34:565-7.

17.Lee I-M, Cook NR, Manson JE, BuringJE, Hennekens CH. b-Carotene supplemen-

tation and incidence of cancer and cardio-vascular disease: the Women’s Health Study.J Natl Cancer Inst 1999;91:2102-6.

18.Pulcinelli FM, Pignatelli P, Celestini A,Riondino S, Gazzaniga PP, Violi F. Inhibi-tion of platelet aggregation by aspirin pro-gressively decreases in long-term treated pa-tients. J Am Coll Cardiol 2004;43:979-84.19.Catella-Lawson F, Reilly MP, Kapoor SC,et al. Cyclooxygenase inhibitors and the an-tiplatelet effects of aspirin. N Engl J Med2001;345:1809-17.

20.Kurth T, Glynn RJ, Walker AM, et al. In-hibition of clinical benefits of aspirin onfirst myocardial infarction by nonsteroidalantiinflammatory drugs. Circulation 2003;108:1191-5.

21.Kjeldsen SE, Kolloch RE, Leonetti G, etal. Influence of gender and age on prevent-ing cardiovascular disease by antihyperten-sive treatment and acetylsalicylic acid: theHOT study. J Hypertens 2000;18:629-42.22.Ridker PM, Hennekens CH, Tofler GH,Lipinska I, Buring JE. Anti-platelet effects of100 mg alternate day oral aspirin: a random-ized, double-blind, placebo-controlled trialof regular and enteric coated formulationsin men and women. J Cardiovasc Risk 1996;3:209-12.

23.Sanderson S, Emery J, Baglin T, Kin-month A-L. Narrative review: aspirin resis-tance and its clinical implications. Ann In-tern Med 2005;142:370-80.

24.Preventive Services Task Force. Aspirinfor the primary prevention of cardiovascularevents: recommendation and rationale. AnnIntern Med 2002;136:157-60.

clinical problem-solving seriesThe Journal welcomes submissions of manuscripts for the Clinical Problem-Solving series. This regular feature considers the step-by-step process of clinical decision making. For more information, please see http://authors.nejm.org.1304n engl j med 352;13

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