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The influence of gender on the effects of aspirin in preventing myocardial infarction Yerman, Todd; Gan, Wen Q; Sin, Don D Oct 18, 2007

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ralssBioMed CentBMC MedicineOpen AcceResearch articleThe influence of gender on the effects of aspirin in preventing myocardial infarctionTodd Yerman, Wen Q Gan and Don D Sin*Address: Department of Medicine (Respiratory Division), University of British Columbia, and The James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, St. Paul's Hospital, Vancouver, British Columbia, CanadaEmail: Todd Yerman - todd.yerman@utoronto.ca; Wen Q Gan - wenqi@interchange.ubc.ca; Don D Sin* - dsin@mrl.ubc.ca* Corresponding author    AbstractBackground: There is considerable variation in the effect of aspirin therapy reducing the risk ofmyocardial infarction (MI). Gender could be a potential explanatory factor for the variability. Weconducted a systematic review and meta-analysis to determine whether gender mix might play arole in explaining the large variation of aspirin efficacy across primary and secondary MI preventiontrials.Methods: Randomized placebo-controlled clinical trials that examined the efficacy of aspirintherapy on MI were identified by using the PUBMED database (1966 to October 2006). Weightedlinear regression technique was used to determine the relationship between log-transformedrelative risk (RR) of MI and the percentage of male participants in each trial. The reciprocal of thestandard error of the RR in each trial (1/SE) was used as the weight.Results: A total of 23 trials (n = 113 494 participants) were identified. Overall, compared withplacebo, aspirin reduced the risk of non-fatal MI (RR = 0.72, 95% confidence interval (CI) 0.64–0.81,p < 0.001) but not of fatal MI (RR = 0.88, 95% CI 0.75–1.03, p = 0.120). A total of 27% of thevariation in the non-fatal MI results could be accounted for by considering the gender mix of thetrials (p = 0.017). Trials that recruited predominantly men demonstrated the largest risk reductionin non-fatal MI (RR = 0.62, 95% CI 0.54–0.71), while trials that contained predominately womenfailed to demonstrate a significant risk reduction in non-fatal MI (RR = 0.87, 95% CI 0.71–1.06).Conclusion: Gender accounts for a substantial proportion of the variability in the efficacy ofaspirin in reducing MI rates across these trials, and supports the notion that women might be lessresponsive to aspirin than men.BackgroundAlthough it is widely accepted that aspirin reduces the riskof myocardial infarction (MI) on average by 25%, there isconsiderable variation in the effect sizes reported acrossnot been well studied. One potential explanatory variableis gender. There is emerging evidence to indicate thatwomen have an increase risk of aspirin resistance com-pared to men, potentially making aspirin less effective inPublished: 18 October 2007BMC Medicine 2007, 5:29 doi:10.1186/1741-7015-5-29Received: 1 May 2007Accepted: 18 October 2007This article is available from: http://www.biomedcentral.com/1741-7015/5/29© 2007 Yerman et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 7(page number not for citation purposes)the trials ranging from zero to 50% relative to placebo [1].To date, factors responsible for this heterogeneity havewomen [2]. Moreover, women who develop atherosclero-sis tend to be older, have more co-morbid conditions andBMC Medicine 2007, 5:29 http://www.biomedcentral.com/1741-7015/5/29more extensive disease at the time of diagnosis, whichmight also interfere with the actions of aspirin [2]. Thus,the gender mix of published trials could be an importantdeterminant of the variability in the reported findings.The primary purpose of this study was to determine theinfluence of gender mix on the reported efficacy of aspirinon fatal and non-fatal MI in published clinical trials.MethodsSearch for relevant studiesWe conducted a comprehensive literature search by usingthe PUBMED electronic database (1966 to October 2006)to identify randomized placebo-controlled clinical trialsthat examined the efficacy of aspirin therapy on myocar-dial infarction (MI). We limited the search to randomizedcontrolled trials conducted in human subjects and pub-lished in English language, using aspirin and MI-specificsearch terms. We supplemented the electronic search byprobing the reference lists of retrieved articles and previ-ous reviews on this topic, and by a search of the Anti-thrombotic Trialists' Collaboration website [3] andEMBASE. We also contacted primary authors where neces-sary for clarification of data.Study selection and data abstractionThe primary objective of this study was to determine theimpact of gender mix on the reported efficacy of aspirinon MI rates. We excluded trials that: (1) had a follow-upperiod of less than 3 months; (2) co-administered aspirinwith another agent; (3) prescribed aspirin for clinical indi-cations other than for primary or secondary cardiovascu-lar prevention (e.g. pain, headache, or arthriticsymptoms); (4) did not have a placebo arm; (5) had apaucity of MI events (fewer than 10) during follow-up; or(6) had unacceptable methodological quality score (Jadadscore of less than 3) [4]. From each retrieved article, twoindependent investigators abstracted the following infor-mation: project name, characteristics of participants, sam-ple size, average age of the sample at baseline,proportionality of current smokers and male participants,duration of follow up, and dosage of aspirin (Table 1),and calculated the relative risks (RR) and 95% confidenceintervals (CI) for fatal and non-fatal MI separately as wellas combined [5-27]. Any questions or discrepanciesregarding these data were resolved through iteration andconsensus.Statistical analysisWe used both unweighted and weighted linear regressiontechniques to determine the relationship between log-transformed RR of MI and gender mix of the trial partici-pants (i.e. the percentage of male or female subjects ineach trial). In the weighted analysis, we used the recipro-duced similar results, we report on the weighted analysisonly unless otherwise indicated. All tests were two-tailedin nature and were performed using SAS statistical soft-ware (version 9.1, SAS Institute, Carey, NC, USA).In a separate analysis, we divided the original trials intotertile groups based on the percentage of male participantsincluded in each trial. We used a random effects model tocombine the results of the trials to take into account bothwithin as well as between trial variances [28]. Data analy-ses were conducted using STATA statistical software(STATA release 9, STATA Corporation, College Station,Texas, USA) and Review Manager V. 4.2 (Revman TheCochrane Collaboration, Oxford, UK).ResultsThe original search in PUBMED yielded 637 citations.EMBASE did not contribute any additional citations. Theabstracts of these articles were selected and reviewed. Ofthese, 61 articles were retrieved for detailed examination.From these, 23 trials were selected as they met the inclu-sion and exclusion criteria of the study: 21 of these trialsreported on non-fatal MI, 15 trials reported on fatal MI,and 17 reported on both fatal and non-fatal MI. The selec-tion process is depicted in Figure 1. The baseline charac-teristics of participants in the selected trials aresummarized in Table 1[5-27]. Overall, there were 113 494participants in the 23 included trials; 49.3% were men.The baseline mean age of the trial participants rangedbetween 52 and 73 years; the prevalence of current smok-ers varied from 11% to 60%. The duration of follow-upwas from 1–10 years and the dosage of aspirin varied from75–1500 mg per day.The main findings of the study are summarized in Table2. Overall, aspirin significantly reduced the risk of non-fatal MI compared with placebo (RR = 0.72, 95% CI 0.64–0.81, p < 0.001) (Figure 2). There was a trend towardslower fatal MI rates with aspirin (RR = 0.88, 95% CI 0.75–1.03, p = 0.120) (Table 2). Aspirin therapy significantlyreduced the combined endpoint of fatal and non-fatal MI(RR = 0.79, 95% CI 0.72–0.87, p < 0.001) (Table 2).In a meta-regression analysis, we observed a significantrelationship between gender mix (i.e. proportionality ofmale or female participants in each trial) and the effective-ness of aspirin in reducing non-fatal MI rates in these trials(R2 = 0.27, p = 0.017) (Figure 3). However, we failed toobserve a significant impact of gender mix on the effectsizes for fatal MI (R2 = 0.03, p = 0.514). The relationshipbetween gender mix and the effectiveness of aspirin inreducing the combined end point of fatal and non-fatalMI was only marginally significant (R2 = 0.21, p = 0.065).Page 2 of 7(page number not for citation purposes)cal of the standard error of the RR in each trial (1/SE) asthe weight. As the weighted and unweighted analysis pro-The inclusion of average age and smoking status of thetrial participants made very little impact to the overallBMC Medicine 2007, 5:29http://www.biomedcentral.com/1741-7015/5/29Page 3 of 7(page number not for citation purposes)Table 1: Characteristics of selected trialsAuthor (year) Trial name Participants SamplesizeMean age at baseline (year)Current smoker (%)Male (%) Follow-up (year)Aspirin dose (mg/day)Ridker et al [26] (2005) Women's Health Study (WHS) Healthy women ≥ 45 years in USA 39 876 55 13 0 10.0 100†de Gaetano [19] (2001) Primary Prevention Project (PPP) Patients with at least one of the major recognized cardiovascular risk factors in Italy4 495 64 15 42 3.6 100Cote et al [18] (1995) Asymptomatic Cervical Bruit Study (ACBS)Patients with asymptomatic carotid stenosis in Canada372 67 37 45 2.3 325ETDRS Study Group [13] (1992) Early Treatment Diabetic Retinopathy Study report (ETDRS)Patients with a clinical diagnosis of diabetes mellitus3 711 18–70 44# 52 5.0 650Juul-Moller et al [24] (1992) Swedish Angina Pectoris Aspirin Trial (SAPAT)Patients with chronic stable angina 2 035 67 16 52 4.2 75Hansson et al [23] (1998) Hypertension Optimal Treatment Study (HOT)Patients with hypertension and diastolic blood pressure between 100 mmHg and 115 mmHg from countries in Europe, America, and Asia18 790 62 16 53 3.8 75Swedish cooperative [8] (1987) Swedish Cooperative Study (Swedish Coop)Patients with cerebral infarction, minor or major stroke505 68 52 62 2.0 1 500EAFT Study Group [14] (1993) European Atrial Fibrillation Trial (EAFT)Patients with non-rheumatic atrial fibrillation 782* 73 19 63 2.3 300SALT Collaborative Group [11] (1991)Swedish Aspirin Low-Dose Trial (SALT)Patients after transient ischaemic attack (TIA) or minor stroke1 360 67 25 66 2.7 75Cairns et al [17] (1985) Canadian multicenter trial (Canadian) Patients with unstable angina who were hospitalized in coronary care units in Canada278* 57 35 70 1.5 1 300Stroke Prevention in Atrial Fibrillation Study group [12] (1991)Stroke Prevention in Atrial Fibrillation Study (SPAF)Patients with constant or intermittent atrial fibrillation1 120* 67 16 71 1.3 325Sorensen et al [27] (1983) A Danish cooperative study (Danish Coop)Patients experienced at least one reversible cerebral ischemic attack203 59 24¶ 73 2.0 1 000Farrell et al [22] (1991) United Kingdom transient ischaemic attack aspirin trial (UK-TIA)Patients with a transient ischaemic attack or minor ischaemic stroke2 435 60 53 73 4.0 300/1 200Persantine-Aspirin Reinfarction Study Research Group [5] (1980)Persantine-aspirin Reinfarction Study (PARIS)Patients recovered from myocardial infarction 1 216* 56 27 77 3.4 972Breddin et al [16] (1980) German-Austrian aspirin trial (GAAT) Patients who had survived a myocardial infarction for 30–42 days626 45–70 58 78 2.0 1 500Elwood and Sweetnam [21] (1979) Aspirin and secondary mortality after myocardial infarction (Cardiff-II)Patients with confirmed myocardial infarction 1 725‡ 56 60 85 1.0 900AMIS Study Group [6] (1980) Aspirin myocardial infarction study (AMIS)Patients experienced at least one myocardial infarction in USA4 524 55 27 89 3.0 1 000Elwood et al [20] (1974) Secondary prevention of mortality from myocardial infarction (Cardiff-I)Patients with recent myocardial infarction 1 239‡ 55 NA 100 1.1 300Coronary Drug Project Research Group [7] (1980)Coronary Drug Project Aspirin Study (CDPA)Patients with a history of myocardial infarction 1 529‡ NA NA 100 1.8 324Lewis et al [25] (1983) Veterans Administration Cooperative Study (VACS)Patients with unstable angina in USA 1 266 56 50 100 1.0 324Steering Committee of the Physicians' Health Study Research Group [9] (1989)Physicians' Health Study (PHS) Healthy male physicians in USA 22 071 52 11 100 5.0 325†The RISC Group [10] (1990) Research Group on Instability in Coronary Artery Disease (RISC)Men with unstable coronary artery disease in Southeast Sweden796* 58 38 100 1.0 75Medical Research Council's General Practice Research Framework Group [15] (1998)Thrombosis prevention Trial (TPT) Patients at high risk of cardiovascular disease in UK2 540 58 41 100 4.0 75NA: not available.*Only the participants in placebo group and aspirin group were included.† Every other day.‡ Data are from [4].¶ > 15 cigarettes/day.# ≥ 6 cigarettes/day.BMC Medicine 2007, 5:29 http://www.biomedcentral.com/1741-7015/5/29findings. For the end point of non-fatal MI, the R2 valuewas 0.32 (p = 0.038). For fatal MI, it was 0.09 (p = 0.465)and for the combined end point of fatal and non-fatal MI,it was 0.28 (p = 0.072).When the original trials were divided into tertile groupsbased on the gender mix (0–66%, 70–89%, 100% maleparticipants in each trial), the beneficial effect of aspirin inreducing non-fatal MI was found to be the greatest in thetertile group containing the largest percentage of maleparticipants (RR = 0.62, 95% CI 0.54–0.71), test for heter-ogeneity, p = 0.48). In contrast, the tertile group with thesmallest percentage of male participants failed to demon-strate any benefits of aspirin in reducing non-fatal MI (RR= 0.87, 95% CI 0.71–1.06), test for heterogeneity, p =0.26) (Table 3). Similar findings were observed in theanalysis that combined non-fatal and fatal MI together(Table 3).DiscussionThe findings of the present study indicate that aspirin iseffective in reducing the risk for non-fatal MI. There washowever considerable variation in the reported efficacy ofaspirin across the trials. We found that approximately27% of the total variation could be accounted for by con-sidering the differences in the gender mix of the trials. Ingeneral, the trials that contained predominantly male sub-Table 2: Relative risks and 95% confidence intervals of myocardial infarction in each trialSource Male (%) Non–fatal MI Fatal MI Fatal and non-fatal MIWHS [26] (2005) 0 1.02 (0.83–1.25) 1.17 (0.54–2.52) 1.03 (0.84–1.25)PPP [19] (2001) 42 0.69 (0.36–1.34) 0.68 (0.19–2.40) 0.69 (0.39–1.23)ACBS [18] (1995) 45 1.71 (0.51–5.75) NA NAETDRS [13] (1992) 52 NA NA 0.85(0.73–1.00)SAPAT [24] (1992) 52 0.61 (0.43–0.87) 1.02 (0.50–2.07) 0.68 (0.50–0.92)HOT [23] (1998) 53 NA NA 0.85 (0.69–1.05)Swedish cooperative [8] (1987) 62 0.88 (0.45–1.72) 1.00 (0.33– 3.05) 0.91 (0.52, 1.60)EAFT [14] (1993) 63 0.94 (0.35–2.47) 0.90 (0.52–1.56) 0.91 (0.56–1.46)SALT [11] (1991) 66 0.91 (0.59–1.41) 0.65 (0.36–1.16) 0.80 (0.57–1.13)Canadian group study [17] (1985) 70 1.29 (0.49–3.36) 0.54 (0.22–1.31) 0.80 (0.43–1.48)SPAF [12] (1991) 71 0.57 (0.19–1.70) NA NADanish cooperative [27] (1983) 73 0.25 (0.05–1.16) 0.67 (0.20–2.31) 0.43 (0.17–1.08)UK–TIA [22] (1991) 73 0.86 (0.68–1.11) 1.01 (0.74–1.39) 0.92 (0.77–1.11)PARIS [5] (1980) 77 0.68 (0.47–1.01) 0.79 (0.55–1.15) 0.74 (0.57–0.95)GAAT [16] (1980) 78 0.63 (0.39–1.03) 0.58 (0.30–1.12) 0.61 (0.42–0.89)Cardiff–II [21] (1979) 85 0.49 (0.33–0.75) NA NAAMIS [6] (1980) 89 0.78 (0.63–0.96) 1.08 (0.89–1.31) 0.93 (0.81–1.07)Cardiff–I [20] (1974) 100 0.68 (0.31–1.49) NA NACDPA [7] (1980) 100 0.86 (0.52–1.42) NA NAVACS [25] (1983) 100 0.49 (0.29–0.81) 0.17 (0.02–1.42) 0.45 (0.28–0.74)PHS [9] (1989) 100 0.61 (0.49–0.75) 0.38 (0.19–0.80) 0.58 (0.47–0.72)RISC [10] (1990) 100 0.49 (0.33–0.73) NA NATPT [15] (1998) 100 0.68 (0.53–0.89) 1.13 (0.78–1.63) 0.81 (0.66–0.99)Total 49 0.72 (0.64–0.81) 0.88 (0.75–1.03) 0.79 (0.72–0.87)Flow diagram of study selectionigure 1Flow diagram of study selection. MI, myocardial infarc-tion.Same cohort reports: n=21Total MI events less than 10: n=8No placebo control: n=4Duration less than 3 month: n=3No sufficient data: n=2Did not meet criteria or duplicate articles: n=612Studies retrieved: n=61Studies identified: N=23Non-fatal MI: n=21Fatal MI: n=15Non-fatal and fatal MI: n=17Search results: N=673PUBMED: n=673Page 4 of 7(page number not for citation purposes)MI, myocardial infarction; NA, not available.BMC Medicine 2007, 5:29 http://www.biomedcentral.com/1741-7015/5/29jects demonstrated large benefits of aspirin in reducingnon-fatal MI rates. In contrast, trials that contained mostlyfemale subjects failed to show any beneficial effect of aspi-rin on this end point. These data are consistent with thenotion that aspirin therapy might be less effective inreducing non-fatal MI in women than in men.Why aspirin would be less effective in reducing MI risk inwomen is largely a mystery. However, recent data indicatethat women are more likely to demonstrate aspirin resist-ance compared to men. In a study by Chen and col-leagues, women compared to men were 2.3 times morelikely to be aspirin-resistant [29] and in the study by Gumand colleagues, women were 2.5 times more likely todemonstrate aspirin resistance [2]. The mechanismsunderlying these observations are uncertain.There are also emerging data demonstrating major struc-tural and physiological differences in coronary vascula-ture between men and women [30]. For instance, womenhave smaller coronary vessels, which are generally stifferthan those in men owing to increased deposition offibrotic tissue and remodeling of the vessel walls. Womenare also more likely to demonstrate impaired vasodilatoryresponses to acetylcholine [31]. Moreover, when womendevelop atherosclerosis, their lesions are usually more dif-fuse and extensive than those observed in men [32].Although in both men and women, the leading cause ofmorbidity and mortality is ischemic heart disease [33],women, especially in the younger age groups (less than 50years of age), have short-term mortality rates that are twicethose observed in men following MIs [34]. Our findingsin the context of the emerging literature regarding possi-ble aspirin resistance in women suggest that cliniciansshould be cautious in prescribing aspirin in women espe-cially for primary prevention. Whether or not other anti-platelet agents would be more effective for women isunclear. Future clinical studies specifically powered toThe impact of gender mix on the reported efficacy of aspirin in reducing non-fatal myocardial infarction riskFigure 3The impact of gender mix on the reported efficacy of aspirin in reducing non-fatal myocardial infarction risk. The regression line is weighted by the reciprocal of the standard error (1/SE) of the relative risk of each trial. The diameter of each circle is proportional to 1/SE of each trial.-1.50-1.00-0.500.000.500 10 20 30 40 50 60 70 80 90 100Percentage of Male ParticipantsLog-transformed Relative Riskof Nonfatal Myocardial InfarctionWHS2005ACBS1995PPP2001SAPAT1992Swedish1987EAFT1993 SALT1991Canadian1985SPAF1991UK-TIA1991Danish1983PARIS1980GAAT1980Cardiff1979AMIS1980 CDPA1980TPT1998RISC1990VACS1985Cardiff1974PHS1989R2 = 0.27, P = 0.017Log-transformed Relative Riskof Nonfatal Myocardial InfarctionTable 3: Relative risks and 95% confidence intervals of myocardial infarction stratified by percentage of male participantsMale (%) Non-fatal MI p* Fatal MI p* Both fatal and non-fatal MI p*0–66 0.87 (0.71–1.06) 0.26 0.87 (0.65–1.17) 0.86 0.86 (0.79–0.95) 0.5270–89 0.72 (0.61–0.86) 0.23 0.91 (0.75–1.11) 0.24 0.82 (0.71–0.95) 0.13100 0.62 (0.54–0.71) 0.48 0.55 (0.20–1.53) 0.01 0.63 (0.46–0.85) 0.02Total 0.72 (0.64–0.81) 0.03 0.88 (0.75–1.03) 0.19 0.79 (0.72–0.87) < 0.05The effect of aspirin on the risk for non-fatal myocardial inf-arction (MI) compared with placeboFigure 2The effect of aspirin on the risk for non-fatal myocardial inf-arction (MI) compared with placebo..1 .2 .5 1 2 50.72 (0.64,0.81)WHS2005PPP2001ACBS1995SAPAT1992Swedish1987EAFT1993SALT1991Cairns1985SPAFS1991Danish1983UK-TIA1991PARIS1980GAAT1980Cardiff-II1979AMIS1980Cardiff-I1974CDPA1980PHS1989RISC1990TPT1998VACS1985Overall (95% CI)Relative Risk for Non-Fatal MI Page 5 of 7(page number not for citation purposes)MI, myocardial infarction.*Test for heterogeneity, p value is from χ2 test. Ransom effects model was used in all combinations.BMC Medicine 2007, 5:29 http://www.biomedcentral.com/1741-7015/5/29evaluate sex-specific end points will be needed to deter-mine whether other anti-platelet agents might be moreeffective in women compared with aspirin.There were limitations to the present study. Firstly, we didnot have access to the primary data. As such, we could notdetermine the influence of other risk factors such as co-morbidities that have also been associated with aspirin-resistance [35]. These factors could further explain thelarge variation in results reported across the trials. Sec-ondly, as with most systematic reviews, there was a possi-bility of publication or selection bias. To mitigate thispossibility, we conducted an extensive search andincluded all trials that met the inclusion and exclusion cri-teria of the present study. Thirdly, we could not determinethe mechanism by which gender modifies the efficacy ofaspirin for MIs.ConclusionThe present study found that the gender mix of trialsaccounted for a substantial proportion of the variability inthe reported efficacy of aspirin in reducing MI rates. Trialsthat recruited predominantly men demonstrated the larg-est benefits; while trials that recruited mostly womenfailed to demonstrate any benefits. These data are consist-ent with the notion that aspirin is less efficacious inwomen (for the reduction of MIs) and raise the possibilitythat women are more susceptible to aspirin resistance.Competing interestsThis project is supported by ICEBERGS (InterdisciplinaryCapacity Enhancement: Bridging Excellence in Respira-tory Disease and Gender Studies), which is funded by theCanadian Institutes of Health Research (IGH/ICRH), theCanadian Lung Association, and the Heart and StrokeFoundation of Canada.DDS is a Canada Research Chair in COPD and a seniorscholar with the Michael Smith Foundation for HealthResearch.Authors' contributionsAll of the authors made substantial contributions to themanuscript and had full access to the data. All authorsread and approved the final version of the manuscript.References1. Hayden M, Pignone M, Phillips C, Mulrow C: Aspirin for the pri-mary prevention of cardiovascular events: a summary of theevidence for the U.S. Preventive Services Task Force.  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