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CLINICAL RESEARCH STUDY

Effect of Aspirin on Mortality in the Primary Prevention

of Cardiovascular DiseaseNina Raju, MD, MsC,a Magdalena Sobieraj-Teague, MBBS,b Jack Hirsh, MD,c Martin ODonnell, MD, PhD,c

John Eikelboom, MD, MsCc

aHaematology Unit, Queensland Pathology and Department of Internal Medicine, Prince Charles Hospital, Brisbane, Australia; bSA

Pathology, Flinders Medical Centre, Adelaide, Australia; cThrombosis Medicine, McMaster University, Hamilton, Canada.

ABSTRACT

OBJECTIVE: The lack of a mortality benefit of aspirin in prior meta-analyses of primary prevention

trials of cardiovascular disease has contributed to uncertainty about the balance of benefits and risks

of aspirin in primary prevention. We performed an updated meta-analysis of randomized controlledtrials of aspirin to obtain best estimates of the effect of aspirin on mortality in primary prevention.

METHODS: Eligible articles were identified by searches of electronic databases and reference lists.

Outcomes of interest were all-cause mortality, cardiovascular mortality, myocardial infarction, stroke,

and bleeding. Data were pooled from individual trials using the DerSimonian-Laird random-effects

model, and results are presented as relative risk (RR) and 95% confidence intervals (CIs).

RESULTS: Nine randomized controlled trials enrolling 100,076 participants were included. Aspirin

reduced all-cause mortality (RR 0.94; 95% CI, 0.88-1.00), myocardial infarction (RR 0.83; 95% CI,

0.69-1.00), ischemic stroke (RR 0.86; 95% CI, 0.75-0.98), and the composite of myocardial infarction,

stroke, or cardiovascular death (RR 0.88; 95% CI, 0.83-0.94), but did not reduce cardiovascular

mortality (RR 0.96; 95% CI, 0.84-1.09). Aspirin increased the risk of hemorrhagic stroke (RR 1.36;

95% CI, 1.01-1.82), major bleeding (RR 1.66; 95% CI, 1.41-1.95), and gastrointestinal bleeding (RR

1.37; 95% CI, 1.15-1.62). A lack of availability of patient-level data precluded exploration of benefits

and risks of aspirin in key subgroups.CONCLUSION: Aspirin prevents deaths, myocardial infarction, and ischemic stroke, and increases

hemorrhagic stroke and major bleeding when used in the primary prevention of cardiovascular

disease.

2011 Elsevier Inc. All rights reserved. The American Journal of Medicine (2011) 124, 621-629

KEYWORDS: Aspirin; Meta-analysis; Primary prevention

Aspirin reduces nonfatal and fatal cardiovascular events in

patients with a history of symptomatic cardiovascular dis-

ease, and it is widely accepted that the benefits of aspirin

outweigh the increased risk of bleeding in this setting.1,2 In

patients without a history of cardiovascular disease, aspirinhas not been shown to reduce mortality,3-10 and it is uncer-

tain whether the reduction in myocardial infarction and

ischemic stroke outweighs the increased risk of bleeding.

Uncertainty about the balance between the risks and the

benefits of aspirin in the primary prevention of cardiovas-

cular disease is reflected in conflicting recommendations byguideline panels.11-15 The 2002 and 2007 American Heart

Association guidelines and the 2008 American College of

Chest Physicians guidelines recommend aspirin for pri-

mary prevention of cardiovascular disease in patients with a

10-year risk of coronary heart disease of 10%,11,12,14 the

2005 Joint British Societies guidelines recommend aspirin

for patients with a 10-year risk of cardiovascular events

of20%,16 and the 2007 European Society of Cardiology

guidelines recommend aspirin for patients with a markedly

increased 10-year risk of cardiovascular disease mortality.13

Funding: None.

Conflict of Interest: None of the authors have any conflicts of interest

associated with the work presented in this manuscript.

Authorship: All authors had access to the data and played a role in

writing this manuscript.

Requests for reprints should be addressed to Magdalena Sobieraj-

Teague, MBBS, Flinders Medical Centre, Flinders Drive, Bedford Park,

SA 5042, Australia.

E-mail address: [email protected]

0002-9343/$ -see front matter 2011 Elsevier Inc. All rights reserved.

doi:10.1016/j.amjmed.2011.01.018
mailto:[email protected]:[email protected]

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The 2009 US Preventive Services Taskforce guideline panel

makes separate recommendations for aspirin according to

patient age and sex, and provides thresholds of 10-year

coronary heart disease risk (men) and stroke risk (women)

at which the number of nonfatal cardiovascular events and

serious bleeds is closely bal-

anced.15 The 2009 Antithrombotic

Trialists Collaboration overviewinterprets the primary prevention

data differently. By contrasting

the lack of a significant mortality

benefit of aspirin in primary pre-

vention trials with the 10% reduc-

tion in mortality in the secondary

prevention trials, the Antithrom-

botic Trialists Collaboration writ-

ing group concluded that aspirin is

of uncertain net value in patients

without documented cardiovascu-

lar disease because the reductionin ischemic events is closely

matched by the increase in major

bleeding, irrespective of an indi-

viduals baseline risk of cardio-

vascular disease.10

Since the publication of the aforementioned guide-

lines,10-16 the results of 3 additional randomized controlled

trials of aspirin for the primary prevention of cardiovascular

disease involving more than 7000 subjects have been pub-

lished.17-19 Subjects in these trials did not have a history of

symptomatic cardiovascular disease but were at increased

risk of cardiovascular events because of diabetes or a re-duced ankle-brachial index.

We performed a meta-analysis of all randomized con-

trolled trials of aspirin for the primary prevention of car-

diovascular disease to obtain best estimates of aspirin com-

pared with placebo or no aspirin on all-cause and

cardiovascular mortality and on other major cardiovascular

outcomes, including myocardial infarction, stroke, and

bleeding.

MATERIALS AND METHODS

We adopted the Preferred Reporting Items for Systematicreviews and Meta-Analyses guidelines for the reporting of

this meta-analysis.20,21 A protocol was prospectively devel-

oped detailing the study objectives, primary and secondary

outcomes, criteria for study selection, approach to assessing

study quality, data synthesis, and statistical analyses.

Data Sources and SearchesWe identified relevant published randomized controlled tri-

als comparing aspirin with placebo or no aspirin treatment

in individuals without a history of symptomatic cardiovas-

cular disease. Two investigators (MST, NR) independently

searched MEDLINE (1966 to May 2010), EMBASE (1980to May 2010), CINAHL (1982 to May 2010), and the

Cochrane library (to May 2010) using the terms aspirin,

acetylsalicylic acid, cardiovascular disease, myocardial in-

farction, stroke, cerebrovascular disease, mortality, death,

survival, randomized trial, controlled trial, random, pre-

vent, and primary prevention. Bibliographies of journal ar-

ticles were hand-searched, and a

related article PubMed search

was performed to identify addi-tional relevant articles. We also

searched the National Institutes of

Health Clinical Trials Registry

(www.clinicaltrials.gov) and con-

tacted experts to identify unpub-

lished studies.

Study SelectionTwo investigators (MST, NR)

independently evaluated studies

for inclusion using predefined

criteria. Relevance was assessedusing a hierarchic approach

based on title, abstract, and full

text publication. Disagreement

on study eligibility was resolved

by discussion and involvement

of a third reviewer (JWE).

To be eligible for inclusion, studies had to meet the

following criteria: (a) randomized controlled trial; (b) in-

clude adults without a history of symptomatic cardiovascu-

lar disease (95% of enrolled participants); (c) compare

aspirin (any dose) with placebo or no aspirin treatment

for the prevention of cardiovascular disease; and (d)

report at least one of the following outcomes: all-cause

mortality, cardiovascular mortality, myocardial infarc-

tion, stroke, and bleeding. Randomized controlled trials

in which aspirin was combined with a second antithrom-

botic agent were not included, unless there were separate

placebo and aspirin-only treatment groups, in which case

only the data from these groups were included.

Data Extraction and Quality AssessmentTwo investigators (MST, NR) independently extracted

data on study design, participant characteristics, eligibil-ity criteria, intervention and comparator, quality, and the

following outcomes: all-cause mortality, cardiovascular

mortality, major cardiovascular events, myocardial in-

farction, all-cause stroke, ischemic stroke, hemorrhagic

stroke, major bleeding, and gastrointestinal bleeding. We

accepted investigators definitions of outcomes and did

not retrospectively reclassify events. Authors were con-

tacted in cases in which study methodology or study data

required clarification.

Risk of bias was assessed using criteria adapted from the

Cochrane Methods Group Guidelines on Systematic Re-

views of Interventions.22 These criteria include proper gen-eration of the treatment allocation sequence; proper con-

CLINICAL SIGNIFICANCE

In patients without a history of cardio-vascular disease, long-term treatmentwith aspirin reduces all-cause mortality,myocardial infarction, and ischemicstroke, and increases hemorrhagic strokeand major bleeding.

The reduction in all-cause mortalityshould be taken into account by clini-cians and guideline panels when makingrecommendations about the use of as-pirin for primary prevention of cardio-vascular disease.

622 The American Journal of Medicine, Vol 124, No 7, July 2011
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cealment of the allocation sequence; blinding of

participants, investigators, and outcome assessors; com-

pleteness of follow-up; intention to treat analysis; and treat-

ment compliance.

Data Synthesis and AnalysisInterobserver agreement for full text study selection was

measured using Cohens unweighted kappa statistic. Re-sults are presented using relative risk, and all effect

estimates are presented with 95% confidence intervals

(CIs). Relative risks for the prespecified primary and

secondary outcomes were calculated by pooling individ-

ual trial data with the DerSimonian-Laird random-effects

model using Cochrane Collaboration Review Manager

software, version 5.0 (The Nordic Cochrane Centre, Co-

penhagen, The Cochrane Collaboration, 2008). Results

obtained with a random-effects model were compared

with those obtained using a fixed-effects model. A

2-sided P value of .05 was considered statistically sig-

nificant. Heterogeneity was assessed using the I2 statisticand chi-square test, and potential sources of statistical

heterogeneity were explored by examining differences in

trial populations, the dose of aspirin, co-interventions,

outcome definitions, and trial quality.

Sensitivity analyses were performed by exclusion of

studies deemed to be of lower quality (open-label studies,

incomplete follow-up), studies using a higher dose of aspi-

rin (150 mg/d), and studies completed before 2000 to

assess the robustness of our results.

RESULTS

Study SelectionThe process of study selection is outlined in Figure 1.

Reviewer agreement at the level of study selection from full

text articles as assessed by Cohens unweighted kappa was

0.86 (standard error 0.14).

Study CharacteristicsNine studies involving 100,076 participants were included.

Study and participant characteristics are summarized in Ta-ble 1. Three of the nine studies, the British Doctors Trial

Figure 1 Process of study selection.

623Raju et al Effect of Aspirin on Mortality

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(BDT),23 Physicians Health Study (PHS),24 and Thrombo-

sis Prevention Trial (TPT),25 did not include women,

whereas the Womens Health Study (WHS)26 exclusively

enrolled women. The Prevention of Progression of Arterial

Disease and Diabetes (POPADAD) trial17 and Japanese

Primary Prevention of Atherosclerosis with Aspirin for Di-

abetes (JPAD)18 recruited only patients with diabetes mel-

litus. The Aspirin for Asymptomatic Atherosclerosis

(AAA)19 study enrolled men and women without a history

of symptomatic cardiovascular disease but with an ankle-

brachial index0.95. Two studies, BDT23 and the Hyper-

tension Optimal Trial (HOT),27 included a small proportion

of participants (5%) with a history of ischemic heart

disease, stroke, or transient ischemic attack.

Risk of BiasWith the exception of the BDT, PHS, and WHS,23,24,26

which did not specify the method of allocation conceal-

ment, all studies reported the process of sequence gen-eration and concealment of allocation. The PHS, TPT,

WHS, POPADAD, AAA, and HOT17,19,24-27 were double-

blinded studies, and the remaining 3 trials, the BDT, JPAD,

and Primary Prevention Project (PPP),18,23,28 were open-

label. Although the open-label design is unlikely to have

biased the main outcome of mortality, it may have influ-

enced ascertainment of nonfatal cardiovascular outcomes,

in particular when outcomes were self-reported. In all trials,

outcome adjudicators were blinded to treatment allocation.

All studies reported completeness of follow-up. Vital

status was determined for all participants in the BDT, PHS,

and TPT.23-25 Loss to follow-up was highest (7.6%) in theJPAD study,18 followed by the HOT (2.6%),27 and was less

than 1% in the other studies. The numbers lost to follow-up

exceeded the total number of primary events in the HOT,

WHS, and JPAD.18,26,27 Treatment adherence was not re-

ported for the WHS26 and ranged from 50% to 93% for the

other studies with the lowest adherence in the POPADAD

trial.17

All studies were analyzed according to an intention-to-

treat principle. Three studies were terminated prematurely,

the PHS and PPP24,28 because of the apparent therapeutic

advantage of aspirin, and the AAA

19

because of the improb-ability of finding a difference in the primary end point and

an increased risk of bleeding with aspirin.

OutcomesAll-Cause Mortality. Aspirin therapy was associated with

a 6% reduction in all-cause mortality (3.65% vs 3.74%, RR

0.94; 95% CI, 0.88-1.0) (Figure 2, Table 2). With the

exception of TPT,25 the point estimate in each study sug-

gested a reduction in mortality, although none of the studies

were powered to detect a mortality benefit of aspirin. There

was no statistical evidence of heterogeneity among the stud-

ies for the outcome of all-cause mortality (I2 0%, 2 1.70, P .99).T

abl

e

1

StudyandParticipantCharacteristics

StudyName

(Public

ationYear)

Patients

(n)

AspirinDose

Design

AdditionalTherapies

Male(%)

MeanFollow-Up(y)

CurrentSmokers(%)

DM

(%)

HT(%)

MeanAge(y)

Elderly

BDT23

(1988)

5139

300-5

00mg/d

Openlabel

None

100

6

31

2

10

N/A

14%

70y

PHS24(

1989)

22,0

71

325mgalternateday

Doubleblinded

Betacarotene

100

5

11

2

9

N/A

7%

70y

HOT27

(1998)

18,7

90

75mg/d

Doubleblinded

Felodipine

otheragentstoachievetargetBP

53

3.8

16

8

100

61.5

32%

65y

TPT25

(1998)

2540

75mg/d

Doubleblinded

Warfarin

100

6.4

41

2

26

57.3

N/A

PPP28

(2001)

4495

100mg/d

Openlabel

VitaminE

42

3.6

15

17

68

64.4

50%

65y

WHS26

(2005)

39,8

76

100mgalternateday

Doubleblinded

VitaminEandbetacarotene

0

10.1

13

3

26

54.6

10%

65y

JPAD18

(2008)

2539

81mgor100mg/d

Openlabel

None

55

4.4

(median)

21

100

58

64.5

54%

65y

POPADAD17

(2008)

1276

100mg/d

Doubleblinded

Antioxidant

44

6.7

(median)

31

100

N/A

60.3

52%

60y

AAA19

2010

3350

100mg/d

Doubleblinded

None

28

8.2

33

3

N/A

62.0

N/A

BDT,

BritishDoctorsTrial;PHS,

PhysiciansHealthStudy;TPT,

ThrombosisPreventionTrial;HOT,

HypertensionOptimalTreatmentstud

y;PPP,

PrimaryPreventionProjecttrial;WHS,

WomensHealthStudy;

JPAD,

JapanesePrimaryPreventionofAtherosclerosiswithAspirinforDiabetestrial;POPADAD,

PreventionOfProgressionOfArterialDiseaseAndDiabetestrial;AAA,

AspirinforAsym

ptomaticAtherosclerosis

trial;

DM,

diabetesmellitus;HT,hypertension;N/

A,

notavailable.


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Cardiovascular Mortality. There was no reduction in the

risk of cardiovascular mortality in participants assigned to

aspirin (Figure 2, Table 2). Only the JPAD18 showed a

reduction in cardiovascular death with aspirin, but this was

based on only 11 events.

Major Cardiovascular Events (Composite of Cardiovas-

cular Mortality, Nonfatal Myocardial Infarction, andNonfatal Stroke). Aspirin use was associated with a 12%

reduction in major cardiovascular events (3.66% vs 3.98%,

RR 0.88; 95% CI, 0.83-0.94) with no statistical evidence of

heterogeneity (I2 0%, 2 7.56, P .48) (Figure 3,

Table 2). The reduction in major cardiovascular events was

primarily attributable to a reduction in myocardial

infarction.

Myocardial Infarction (Composite of Fatal and Nonfatal

Myocardial Infarction). The largest measured benefit of

aspirin was in the prevention of myocardial infarction with

a relative risk reduction of 17% (1.68% vs 1.91%, RR 0.83;95% CI, 0.69-1.00) (Figure 3, Table 2). Heterogeneity in

myocardial infarction results (I2 71%, 2 27.51,

P .0006) was not explained by differences in trial popu-

lations, aspirin dose, or methodological quality of the stud-

ies (data not shown), but statistical heterogeneity was no

longer evident after removing the PHS from the analyses.24

The PHS was stopped early because of benefit, which can

result in an inflated estimate of treatment effect.29

Stroke (Composite of Fatal and Nonfatal Stroke). Aspi-

rin reduced the risk of ischemic stroke (0.97% vs 1.10%,

RR 0.86; 95% CI, 0.75-0.98, P for heterogeneity 0.48),

but this was offset by a concomitant increase in hemor-

rhagic stroke (0.27% vs 0.19%, RR 1.36; 95% CI, 1.01-

1.82, P for heterogeneity 0.63). Thus, there was no

reduction in all-cause stroke (Figures 3 and 4, Table 2).

Bleeding. Aspirin increased the risk of major bleeding

(RR 1.66; 95% CI, 1.41-1.95) with no statistical evidence

of heterogeneity (I2 0%, 2 6.01, P .42) (Figure

4). Aspirin also increased the risk of gastrointestinalbleeding. Statistical heterogeneity for the outcome of

Study or Subgroup

1.1.1 All-cause mortality

BDT

PHS

HOT

TPT

PPPWHS

POPADAD

JPAD

AAASubtotal (95% CI)

Total events

Heterogeneity: Tau = 0.00; Chi = 1.70, df = 8 (P = 0.99); I = 0%

Test for overall effect: Z = 2.00 (P = 0.05)

1.1.2 Cardiovascular mortality

BDT

PHS

HOT

TPTPPP

WHS

JPAD

POPADAD


Total events



Events

270

217

284

113

62609

94

34

176

1859

148

81

133

4917

120

1

43

35

627

Total

3429

11037

9399

1268

222619934

638

1262

167550868

3429

11037

9399

12682226

19934

1262

638

167550868

Events

151

227

305

110

78642

101

38

186

1838

79

83

140

4931

126

10

35

30

583

Total

1710

11034

9391

1272

226919942

638

1277

167549208

1710

11034

9391

12722269

19942

1277

638

167549208

M-H, Random, 95% CI

0.89 [0.74, 1.08]

0.96 [0.79, 1.15]

0.93 [0.79, 1.09]

1.03 [0.80, 1.32]

0.81 [0.58, 1.13]0.95 [0.85, 1.06]

0.93 [0.72, 1.21]

0.91 [0.57, 1.43]

0.95 [0.78, 1.15]0.94 [0.88, 1.00]

0.93 [0.72, 1.22]

0.98 [0.72, 1.32]

0.95 [0.75, 1.20]

1.00 [0.68, 1.48]0.56 [0.31, 1.01]

0.95 [0.74, 1.22]

0.10 [0.01, 0.79]

1.23 [0.80, 1.89]

1.17 [0.72, 1.89]0.96 [0.84, 1.09]

Year

1988

1989

1998

1998

20012005

2008

2008

2010

1988

1989

1998

19982001

2005

2008

2008

2010

oitaRksiRoitaRksiRtnemtaertoN/obecalPniripsA

M-H, Random, 95% CI

0.5 0.7 1 1.5 2Favours Aspirin Favours control

Figure 2 Relative risk of all-cause mortality and cardiovascular mortality in participants treated with and without

aspirin.


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gastrointestinal bleeding was not explained by differ-

ences in study populations, aspirin dose, or study quality

(data not shown).

Sensitivity Analyses. Sensitivity analysis performed by

excluding studies considered to be at higher risk of bias

(open label: BDT, JPAD, and PPP;18,23,28 high loss to

follow-up (5%): JPAD;18 early termination of study:

PHS, PPP, AAA19,24,28) demonstrated a consistent treat-

ment effect of aspirin on all-cause mortality (data not

shown). Similarly, consistent results were seen when

studies using aspirin at a dosage of 150 mg/d (BDT,

PHS)23,24 were excluded (RR 0.94; 95% CI, 0.88-1.01)

and when studies published before 2000 were excluded

(BDT, PHS, HOT, TPT)23-25,27 (data not shown).

Assessment of Publication Bias. Beggs adjusted-rank

correlation test30 provided no evidence of publication

bias for any of the outcomes that we examined (data not

shown).

DISCUSSIONOur meta-analysis of 9 aspirin primary prevention trials

involving 100,076 patients demonstrates that long-term

aspirin compared with placebo or no aspirin reduces

all-cause mortality, myocardial infarction, and ischemic

stroke; does not reduce cardiovascular mortality; andincreases hemorrhagic stroke, major bleeding, and gas-

trointestinal bleeding.

In the absence of a mortality benefit of aspirin, treat-

ment guidelines for the use of aspirin for primary pre-

vention of cardiovascular disease have based their rec-

ommendations on the trade-off between the reduction of

nonfatal myocardial infarction and the increase in bleed-

ing. Applying this trade-off in clinical practice can be

challenging because the balance between a reduction in

nonfatal ischemic events and an increase in bleeding is

strongly influenced by individual patient values and pref-

erences. The authors of the 2009 Antithrombotic Trial-ists Collaboration overview suggested that the benefits

and harms of aspirin were so finely balanced that aspirin

was of uncertain value in patients without previous car-

diovascular disease, irrespective of their baseline cardio-

vascular risk.10 Our results demonstrating that aspirin

reduces all-cause mortality in individuals without a his-

tory of symptomatic cardiovascular disease tilts the bal-

ance in favor of the use of aspirin for primary prevention

and should be taken into account by clinicians and future

treatment guidelines.

The most likely reason why our meta-analysis reported

a reduction in mortality when aspirin is used for the

primary prevention of cardiovascular disease whereas

previous meta-analyses did not is that our meta-analysis

included more patients and more outcome events, thereby

improving the precision of the estimates of treatmenteffect. The 3 recently published trials (POPADAD,

JPAD, AAA) included in this meta-analysis involved

patients with diabetes or asymptomatic atherosclerosis

who were underrepresented in previous trials. Further

information regarding the efficacy and safety of aspirin

for primary prevention of cardiovascular disease and in

specific populations will be provided by the results of

ongoing randomized controlled trials of aspirin in the

elderly (Aspirin in Reducing Events in the Elderly

trial),31 patients with diabetes (Aspirin and Simvastatin

Combination for Cardiovascular Events Prevention Trial

in Diabetes; A Study of Cardiovascular Events in Diabe-tes),32,33 and in different ethnic groups (eg, Japanese

Primary Prevention Project).34

We propose 2 possible explanations for why aspirin

reduces all-cause mortality but not cardiovascular mor-

tality. The first possible explanation is that aspirin re-

duces both cardiovascular and noncardiovascular deaths

so that when the data for these 2 outcomes are combined,

a significant reduction in all-cause mortality becomes

evident. Aspirin has been reported to reduce mortality in

patients with cancer,35,36 and the Antithrombotic Trial-

ists Collaboration meta-analysis also reported fewer

noncardiovascular deaths in patients receiving aspirincompared with placebo for the secondary prevention of

Table 2 Pooled Estimates of the Benefits and Risks of Aspirin in Primary Prevention of Cardiovascular Disease

Outcome

Total Events in

Aspirin Arm (%)

Total Events in Non-

Aspirin Arm (%)

Pooled Relative Risk

(95% CI)

Relative Risk Reduction

(95% CI)

All-cause mortality 1859 (3.65) 1838 (3.74) 0.94 (0.88-1.00) 6% (0-12)

Cardiovascular mortality 627 (1.23) 583 (1.18) 0.96 (0.84-1.09) 4% (9 to 16)

Major cardiovascular events 1861 (3.66) 1957 (3.98) 0.88 (0.83-0.94) 12% (6-17)

Myocardial infarction 854 (1.68) 942 (1.91) 0.83 (0.69-1.00) 17% (0-31)All-cause stroke 720 (1.42) 733 (1.49) 0.93 (0.82-1.05) 7% (5 to 18)

Ischemic stroke 403 (0.97) 439 (1.10) 0.86 (0.75-0.98) 14% (2-25)

Hemorrhagic stroke 112 (0.27) 76 (0.19) 1.36 (1.01-1.82) 36% (1 to 82)

Gastrointestinal bleed 1947 (4.10) 1560 (3.28) 1.37 (1.15-1.62) 37% (15 to 62)

Major bleed 406 (0.83) 234 (0.50) 1.66 (1.41-1.95) 66% (41 to 95)

CI Confidence interval.


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cardiovascular disease.10 The second possible explana-

tion is that cardiovascular deaths may have been misat-

tributed to noncardiovascular causes.

A potential limitation of our meta-analysis is that the in-cluded studies were conducted over a 30-year period during

which there have been major advances in cardiovascular pre-

vention and an increase in the concomitant use of other effec-

tive primary prevention strategies, such as blood pressure con-

trol and lipid-lowering therapy. Despite an increase in the useof other cardiovascular prevention therapies, the event rates in

Study or Subgroup

1.2.1 Cardiovascular events

BDT

PHS

HOT

TPT

PPP

WHS

POPADAD

JPAD


Total events


Test for overall effect: Z = 3.96 (P < 0.0001)

1.2.2 Myocardial infarction

BDT

PHS

HOT

TPT

PPP

WHS

JPAD

POPADAD


Total events



1.2.3 Stroke

BDT

PHS

HOT

TPT

PPP

WHS

JPAD

POPADAD


Total events



1.2.4 Ischemic stroke

BDT

PHS

TPT

PPP

WHS

POPADAD

JPAD


Total events



Events

289

320

315

112

47

477

127

40

134

1861

169

139

82

69

19

198

12

76

90

854

91

119

146

18

16

221

28

37

44

720

61

91

10

16

170

3

22

30

403

Total

3429

11037

9399

1268

2226

19934

638

1262

167550868

3429

11037

9399

1268

2226

19934

1262

638

167550868

3429

11037

9399

1268

2226

19934

1262

638

167550868

3429

11037

1268

2226

19934

638

1262

167541469

Events

147

388

368

147

71

522

132

46

136

1957

88

239

127

98

28

193

14

69

86

942

39

98

148

26

24

266

32

50

50

733

29

82

18

22

221

5

25

37

439

Total

1710

11034

9391

1272

2269

19942

638

1277

167549208

1710

11034

9391

1272

2269

19942

1277

638

167549208

1710

11034

9391

1272

2269

19942

1277

638

167549208

1710

11034

1272

2269

19942

638

1277

167539817

M-H, Random, 95% CI

0.98 [0.81, 1.19]

0.82 [0.71, 0.95]

0.86 [0.74, 0.99]

0.76 [0.61, 0.97]

0.67 [0.47, 0.97]

0.91 [0.81, 1.03]

0.96 [0.77, 1.20]

0.88 [0.58, 1.33]

0.99 [0.78, 1.24]0.88 [0.83, 0.94]

0.96 [0.75, 1.23]

0.58 [0.47, 0.72]

0.65 [0.49, 0.85]

0.71 [0.52, 0.95]

0.69 [0.39, 1.23]

1.03 [0.84, 1.25]

0.87 [0.40, 1.87]

1.10 [0.81, 1.50]

1.05 [0.78, 1.40]0.83 [0.69, 1.00]

1.16 [0.80, 1.69]

1.21 [0.93, 1.58]

0.99 [0.79, 1.24]

0.69 [0.38, 1.26]

0.68 [0.36, 1.28]

0.83 [0.70, 0.99]

0.89 [0.54, 1.46]

0.74 [0.49, 1.12]

0.88 [0.59, 1.31]0.93 [0.82, 1.05]

1.05 [0.68, 1.63]

1.11 [0.82, 1.49]

0.56 [0.26, 1.20]

0.74 [0.39, 1.41]

0.77 [0.63, 0.94]

0.60 [0.14, 2.50]

0.89 [0.50, 1.57]

0.81 [0.50, 1.31]0.86 [0.75, 0.98]

Year

1988

1989

1998

1998

2001

2005

2008

2008

2010

1988

1989

1998

1998

2001

2005

2008

2008

2010

1988

1989

1998

1998

2001

2005

2008

2008

2010

1988

1989

1998

2001

2005

2008

2008

2010


M-H, Random, 95% CI

0.5 0.7 1 1.5 2Favours aspirin Favours control

Figure 3 Ischemic cardiovascular events in participants treated with and without aspirin.


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8/9

placebo-treated patients and the relative benefits of aspirin

compared with placebo or no aspirin were fairly consistent

over time.

CONCLUSIONS

Our results demonstrate a consistent pattern of reduced mortalityin all of the aspirin primary prevention trials and a significant,

albeit modest, reduction in all-cause mortality when the data are

pooled. This reduction in all-cause mortality tilts the balance

between the benefits and risks of treatment in favor of the use of

aspirin. The results of our meta-analysis are in agreement with

those of the 2009 Antithrombotic Trialists Collaboration meta-

analysis in secondary prevention and demonstrate that aspirin alsois beneficial in the primary prevention population.

Study or Subgroup

1.3.1 Hemorrhagic stroke

BDT

PHS

TPT

PPP

WHSJPAD

POPADAD


Total events



1.3.2 Major bleeding

BDT

PHS

HOT

TPT

PPPWHS


Total events


Test for overall effect: Z = 6.14 (P < 0.00001)

1.3.3 Gastrointestinal bleeding

PHS

TPT

HOT

PPP

WHS

POPADAD

JPAD


Total events



Events

13

23

2

10

516

2

5

112

29

48

136

8

24127

34

406

842

22

107

17

910

28

12

9

1947

Total

3429

11037

1268

2226

199341262

638

167541469

3429

11037

9399

1268

222619934

167548968

11037

1268

9399

2226

19934

638

1262

167547439

Events

6

12

0

3

417

3

4

76

7

28

78

4

691

20

234

696

10

55

5

751

31

4

8

1560

Total

1710

11034

1272

2269

199421277

638

167539817

1710

10979

9391

1278

226919942

167547244

11034

1272

9391

2269

19942

638

1277

167547498

M-H, Random, 95% CI

1.08 [0.41, 2.84]

1.92 [0.95, 3.85]

5.02 [0.24, 104.37]

3.40 [0.94, 12.33]

1.24 [0.83, 1.88]0.87 [0.29, 2.57]

0.67 [0.11, 3.98]

1.25 [0.34, 4.65]1.36 [1.01, 1.82]

2.07 [0.91, 4.71]

1.71 [1.07, 2.72]

1.74 [1.32, 2.30]

2.02 [0.61, 6.68]

4.08 [1.67, 9.96]1.40 [1.07, 1.83]

1.70 [0.98, 2.94]1.66 [1.41, 1.95]

1.21 [1.10, 1.33]

2.21 [1.05, 4.64]

1.94 [1.41, 2.69]

3.47 [1.28, 9.38]

1.21 [1.10, 1.33]

0.90 [0.55, 1.49]

3.04 [0.98, 9.39]

1.13 [0.44, 2.91]1.37 [1.15, 1.62]

Year

1988

1989

1998

2001

20052008

2008

2010

1988

1989

1998

1998

20012005

2010

1989

1998

1998

2001

2005

2008

2008

2010


M-H, Random, 95% CI

0.1 0.2 0.5 1 2 5 10Favours aspirin Favours control

The HOT study did not report hemorrhagic stroke. The JPAD and POPADAD studies

did not report major bleeding and BDT did not report gastrointestinal bleeding.

Figure 4 Relative risk of hemorrhagic stroke, major bleeding, and gastrointestinal bleeding in participants

treated with and without aspirin.


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