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Meta-Analysis of Multiple Primary Prevention Trials of
Cardiovascular Events Using Aspirin
Alfred A. Bartolucci, PhD,a,* Michal Tendera, MDb, and George Howard, DrPHa Several meta-analyses have focused on determination of the effectiveness of aspirin (ace-
tylsalicylic acid) in primary prevention of cardiovascular (CV) events. Despite these data,
the role of aspirin in primary prevention continues to be investigated. Nine randomized
trials have evaluated the benefits of aspirin for the primary prevention of CV events: the
British Doctors' Trial (BMD), the Physicians' Health Study (PHS), the Thrombosis Pre-
vention Trial (TPT), the Hypertension Optimal Treatment (HOT) study, the Primary
Prevention Project (PPP), the Women's Health Study (WHS), the Aspirin for Asymptom-
atic Atherosclerosis Trial (AAAT), the Prevention of Progression of Arterial Disease and
Diabetes (POPADAD) trial, and the Japanese Primary Prevention of Atherosclerosis With
Aspirin for Diabetes (JPAD) trial. The combined sample consists of about 90,000 subjects
divided approximately evenly between those taking aspirin and subjects not taking aspirin
or taking placebo. A meta-analysis of these 9 trials assessed 6 CV end points: total coronary
heart disease, nonfatal myocardial infarction (MI), total CV events, stroke, CV mortality,
and all-cause mortality. No covariate adjustment was performed, and appropriate tests for
treatment effect, heterogeneity, and study size bias were applied. The meta-analysis suggested
superiority of aspirin for total CV events and nonfatal MI, (p <0.05 for each), with nonsignif-
icant results for decreased risk for stroke, CV mortality, and all-cause mortality. There was no
evidence of a statistical bias (p >0.05). In conclusion, aspirin decreased the risk for CV events
and nonfatal MI in this large sample. Thus, primary prevention with aspirin decreased the risk
for total CV events and nonfatal MI, but there were no significant differences in the incidences
of stroke, CV mortality, all-cause mortality and total coronary heart disease.

2011 Elsevier
Inc. All rights reserved. (Am J Cardiol 2011;107:1796 –1801)
The aim of the present analysis was to examine the more Features of the studies included in the 9 trial recent trials that have been published since Bartolucci and meta-analysis are listed in and add data from those studies to enlarge the The United States Preventive Services Task de- sample and thus the power and precision. By adding these scribed the data collection and analysis from the first 5 primary studies, it may be increasingly possible to detect moderate, prevention trials—the British Doctors' Trial (BMD), the Phy- but potentially meaningful, differences that individual trials sicians' Health Study (PHS), the Thrombosis Prevention cannot detect. Added studies to our meta-analysis of the 6 Trial (TPT), the Hypertension Optimal Treatment (HOT) primary prevention studies include the Aspirin for Asymp- study, the Primary Prevention Project (PPP)—and the ad- tomatic Atherosclerosis Trial the Prevention of dition of the new data from the Women's Health Study Progression of Arterial Disease and Diabetes (WHS) was described by Bartolucci and The new trial, and the Japanese Primary Prevention of Atherosclero- sources of data are from the AAAT, POPADAD, and JPAD sis With Aspirin for Diabetes trial.
Because aspirin may have a differential effect on differ- ent aspects of cardiovascular (CV) disease, outcomes were In this report, we present a meta-analysis of 9 pri- classified as follows: (1) total coronary heart disease (CHD) mary prevention trials with aspirin, including the AAAT, as nonfatal and fatal myocardial infarction (MI) and death POPADAD, and JPAD trials, added to the 6 trials in- due to CHD; (2) nonfatal MI as confirmed MI that did not cluded in the previous meta-analyses (the Antithrombotic result in death; (3) total CV events as a composite of CV Trialists' Collaboration and Bartolucci and death, MI, or stroke; (4) stroke as ischemic or hemorrhagicstroke that may or may not have resulted in death; (5) CVmortality as death related to CHD or stroke; and (6) all- aDepartment of Biostatistics, School of Public Health, University of cause mortality as death related to any cause. Where appli- Alabama at Birmingham, Birmingham, Alabama; and b3rd Division of cable (data available), we performed a meta-analysis and Cardiology Medical University of Silesia, Katowice, Poland. Manuscript summary overview for each of these end points for the 9 received December 14, 2010; revised manuscript received and accepted study data sets. All 9 studies were screened for these out- February 12, 2011.
This study was supported by an unrestricted research grant from Bayer Data from the United States Preventive Services Task HealthCare AG (Leverkusen, Germany).
*Corresponding author: Tel: 205-934-4906; fax: 205-975-2540.
Force for each patient trial and data from the WHS, AAAT, E-mail address: (A.A. Bartolucci).
JPAD, and POPADAD were combined for analysis. For 0002-9149/11/$ – see front matter 2011 Elsevier Inc. All rights reserved.
Preventive Cardiology/Meta-Analysis of Aspirin in Primary Prevention Table 1Features of the trials included in the 9 study meta-analyses 6-Study* Meta-Analysis Aspirin dose (mg/dl) 75–300; 100–325 Healthy men/women, DBP Men/women, low brachial index Type 1 and 2 diabetes * Details of the 6 individual primary prevention trials (WHS, BMD, PHS, HOT, PPP, and TPT) are given in Bartolucci and DBP ⫽ diastolic blood pressure.
Statistical significance of cardiovascular end points in the primary Meta-analysis of predefined end points for the 9 study meta-analysis prevention trials All-cause mortality * Coronary and cerebrovascular death only.
neity across the studies, between-study variation, and X ⫽ statistically significant advantage of aspirin versus placebo within-study variation or patient selection. However, given (p ⬍0.05).
the summary data, within-study variation is not easily as-sessed. The standard procedure for the assessment of small each previously described end point, a meta-analysis was study effects (i.e., a trend for relatively smaller studies to performed for the comparison of aspirin with placebo or show larger treatment effects) has been the use of funnel control. A summary odds ratio with 95% confidence inter- plots using Egger's There has been considerable val was calculated. The odds ratio is the appropriate effect discussion regarding the properties of this The size statistic for our 5 risk ratio outcomes noted in the technique of Macaskill et was used to adjust for this previous paragraph. The odds ratio is the ratio of the odds of shortcoming (also see Harbord et an event occurring in 1 group to the odds of it occurring inanother group. The term is also used to refer to sample-based estimates of this ratio. Obviously, an odds ratio of 1 would indicate even odds or no difference between the 2 Among the 9 trials in the analysis, 50,868 subjects were groups of aspirin and control with respect to the odds of anevent such as MI. Calculation of the overall effect combin- treated with aspirin and 49,170 received placebo or control.
ing the 9 studies used the Mantel-Haenszel chi-square sta- lists each study and indicates if statistical signifi- tistic with 1 degree of freedom. This test does not assume cance of aspirin versus placebo was reached when using the that patients in 1 study can be directly compared with those odds ratio for any of the end points or groups of end points.
in another study, and it does not assume that any treatment The combined effects of aspirin on these end points are effects are similar in different studies. It does not assume listed in In subjects treated with aspirin, there was homogeneity but does take into account heterogeneity. Het- significantly decreased risk for nonfatal MI (p ⫽ 0.042) and erogeneity was calculated using the chi-square test with n ⫺ total CV events (p ⫽ 0.001). There was significant hetero- 1 degrees of freedom, where n represents the number of geneity (p ⱕ0.01) for several of the end points listed in studies contributing to the meta-analysis. Forest plots were (e.g., for total CHD events and nonfatal MI). The used to assess if there was significant heterogeneity (defined data for nonfatal MI and total CV events are shown in as p ⬍0.01) and allowed assessment by considering the and respectively.
direction of the results. A weighting factor was also used to present different outcomes in the studies that depended in part on the size of the study, which in turn included in the current meta-analysis. They show that most affected the inverse variance formula that the Mantel-Haen- studies have odds ratios ⬍1, with an overall advantage of szel procedure uses to calculate heterogeneity. The random- aspirin over placebo. We had the ability to reexamine our effects model also helps further account for the heteroge- results with respect to previous risk for CHD in studies that



The American Journal of Cardiology (www.ajconline.org) Figure 1. Forest plot of nonfatal CHD events. CI ⫽ confidence interval.
Figure 2. Forest plot of CV deaths, MI, and stroke. CI ⫽ confidence interval.
included TPT, PPP, AAAT, POPADAD, and JPAD, and we We included the 2 trials conducted in patients with diabetes found no change in our results. The remainder of the studies mellitus and no symptoms of CV disease (POPADAD and showed no previous risk for CHD. The results were consis- JPAD). Although patients with diabetes might represent a tent with those listed in all in favor of aspirin.
population different from those with high CV risk on the basisof the presence of classic risk factors alone, the studies clearly represent the primary prevention setting.
It is evident that aspirin is beneficial for patients who Systematic analysis of the outcomes from the 9 trials con- have previously been diagnosed with CHD and is probably firmed that aspirin decreases the incidence of nonfatal MI and beneficial to all patients at high risk for developing CHD, on CV events. However, aspirin had no statistically significant the basis of an appropriate assessment of known risk factors.
effect on CHD, stroke, CV mortality, and all-cause mortality, However, the 3 most recent studies on the use of aspirin in but was highly significant for overall CV events.
primary prevention for the most part were statistically in- In the ATTC antiplatelet therapy decreased the Although all these studies were underpow- combined outcome of any serious vascular event by about ered, there was a need to reassess the use of aspirin in this 25%, nonfatal MI by about 33%, nonfatal stroke by 25%, setting. We present a meta-analysis of all trials published to and vascular mortality by about 16%. Our results are for the date assessing the effect of aspirin in primary CV prevention.
most part consistent with the ATTC's results. The ATTC



Preventive Cardiology/Meta-Analysis of Aspirin in Primary Prevention Figure 3. Forest plot of all-cause mortality. CI ⫽ confidence interval.
Figure 4. Forest plot of CHD mortality. CI ⫽ confidence interval.
caution that in primary prevention aspirin is of uncertain net tained with the random-effects model, which accounts for value, because the reduction in occlusive events needs to be the randomness of the effects across studies.
weighed against any increase in major bleeds. Bleeds or The HOT and WHS are relatively larger than the other major bleeds were not our focus here, and we agree with the studies, accounting for approximately 59% of the sample.
ATTC that gastrointestinal bleeds, strokes, and heart attacks Thus, the meta-analysis accommodates for this difference by may not be equivalent, as we examine these end points assigning them greater weight (sample size) than the other separately. See for a summary of gastrointestinal studies. In addition, these 2 studies, when weighted accord- bleeds across studies.
ingly in the assessment of study size bias, did not contribute In our study, there was heterogeneity across studies for significantly to any bias, as presented in However, several outcomes. Possible sources of this heterogeneity weighting can also take into account other information in include patient selection and randomization, baseline dis- studies, such as length of follow-up, the detail of patient char- ease severity, management of intercurrent outcomes (such acteristics, information on entry, and eligibility criteria. This as bleeding, gastritis, and hypertension), and treatment strat- information may vary across studies and, if available, will be egies. However, the overall difference between aspirin and scored or weighted differently in each study.
placebo, as shown in this meta-analysis, is not affected by A limitation of our study is that it is a meta-analysis of significant heterogeneity, because similar results were ob- the results of published studies. Thus, we did not have the



The American Journal of Cardiology (www.ajconline.org) Figure 5. Forest plot of stroke events. CI ⫽ confidence interval.
Figure 6. Forest plot of total CHD. CI ⫽ confidence interval.
ability to do thorough cross-study checks that can be done Gastrointestinal bleeding for the 9 study meta-analysis using the raw data. Furthermore, the overall size of oursample and the differing cohorts within each study lend convincing evidence to the advantage of aspirin over pla- cebo or no aspirin for decreasing the risk for CV events in a range of patients. However, the benefits of primary pre- vention with aspirin must be considered in relation to the potential risks on a patient-by-patient basis.
1. Bartolucci AA, Howard G. Meta-analysis of data from the six primary prevention trials of cardiovascular events using aspirin. Am J Cardiol 2006;98:746 –750.
Preventive Cardiology/Meta-Analysis of Aspirin in Primary Prevention 2. Fowkes FGR, Price JF, Stewart MC, Butcher I, Leng GC, Pell AC, of individual participant data from randomized clinical trials. Lancet Sandercock PA, Fox KA, Lowe GD, Murray GD, for the Aspirin for Asymptomatic Atherosclerosis Trialists. Aspirin for prevention of car- 6. United States Preventive Services Task Force. Aspirin for the primary diovascular events in a population screened for a low ankle brachial prevention of cardiovascular events: recommendation and rationale.
index. JAMA 2010;303:841– 848.
Ann Intern Med 2002;136:157–160.
3. Belch J, MacCuish A, Campbell I, Cobbe S, Taylor R, Prescott RL, 7. Egger M, Smith D, Schneider M, Minder C. Bias in meta-analysis Bancroft J, MacEwan S, Shepard J, Macfarlane P, Morris A, Jung R, detected by a simple graphical test. BMJ 1997;315:629 – 634.
Kelly C, Connacher A, Peden N, Jamieson A, Matthews D, Leese G, 8. Egger M, Juni P, Bartlett C, Sterne J. How important are comprehen- McKnight J, O'Brien I, Semple C, Petrie J, Gordon D, Pringle S, sive literature searches and the assessment of trial quality in systematic MacWalter R; Prevention of Progression of Arterial Disease and Di- reviews? Empirical study. Health Technol Assess 2003;7:1– 4.
abetes Study Group; Diabetes Registry Group; Royal College of Phy- 9. Irwig L, Macaskill P, Berry G, Glasziou P. Bias in meta-analysis sicians Edinburgh. The Prevention of Progression of Arterial Disease detected by a simple graphical test. Graphical test is itself biased. BMJ and Diabetes (POPADAD) trial: factorial randomized placebo con- trolled trial of aspirin and antioxidants in patients with diabetes and 10. Sterne J, Egger M, Smith D. Investigating and dealing with publication asymptomatic peripheral arterial disease. BMJ 2008;337:a1840.
and other biases in meta-analysis. BMJ 2001;323:101–105.
4. Ogawa H, Nakayama M, Morimoto T, Uemura S, Kanauchi M, Doi N, 11. Macaskill P, Walter S, Irwig L. A comparison of methods to detect Jinnouchi H, Sugiyama S, Saito Y, for the Japanese Primary Preven- publication bias in meta-analysis. Stat Med 2001;20:641– 654.
tion of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Inves- 12. Schwarzer G, Antes G, Shumacher M. Inflation of type I error rate in tigators. Low-dose aspirin for primary prevention of atherosclerotic two statistical tests for the detection of publication bias in metaanalysis events in patients with type 2 diabetes: a randomized controlled trial.
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