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Aspirin for the prevention of cardiovascular events in patients without clinical cardiovascular disease: A meta-analysis of randomized trials
Aspirin for the prevention of cardiovascular events in patients without clinical cardiovascular disease: A meta-analysis of randomized trials Jeffrey S. Berger, MD, MS, FACC, a,b,c Anuradha Lala, MD, a Mori J. Krantz, MD, d,e Gizelle S. Baker, PhD, f and William R. Hiatt, MD d,e New York, NY; and Denver, Colorado
Background The benefit of aspirin to prevent cardiovascular events in subjects without clinical cardiovascular disease relative to the increased risk of bleeding is uncertain. Methods A meta-analysis of randomized trials of aspirin versus placebo/control to assess the effect of aspirin on major cardiovascular events (MCEs) (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), individual components of the MCE, stroke subtype, all-cause mortality, and major bleeding. Nine trials involving 102,621 patients were included: 52,145 allocated to aspirin and 50,476 to placebo/control. Results Over a mean follow-up of 6.9 years, aspirin was associated with a reduction in MCE (risk ratio [RR] 0.90, 95% CI 0.85-0.96, P b .001). There was no significant reduction for myocardial infarction, stroke, ischemic stroke, or all-cause mortality. Aspirin was associated with hemorrhagic stroke (RR 1.35, 95% CI 1.01-1.81, P = .04) and major bleeding (RR 1.62, 95% CI 1.31-2.00, P b .001). In meta-regression, the benefits and bleeding risks of aspirin were independent of baseline cardiovascular risk, background therapy, age, sex, and aspirin dose. The number needed to treat to prevent 1 MCE over a mean follow-up of 6.9 years was 253 (95% CI 163-568), which was offset by the number needed to harm to cause 1 major bleed of 261 (95% CI 182-476). Conclusions The current totality of evidence provides only modest support for a benefit of aspirin in patients without clinical cardiovascular disease, which is offset by its risk. For every 1,000 subjects treated with aspirin over a 5-year period, aspirin would prevent 2.9 MCE and cause 2.8 major bleeds. (Am Heart J 2011;162:115-124.e2.)
Aspirin is effective in decreasing cardiovascular morbidity and mortality in patients with clinical evidence of cardiovascular disease (CVD).1,2 Specifically, benefits of aspirin are well defined for secondary prevention of acute myocardial infarction (MI) and stroke, forming the basis for current clinical practice guidelines.3-6 These respon-
From the aDepartment of Medicine, Division of Cardiology, New York University School of Medicine, New York, NY, bDivision of Hematology, New York University School of Medicine, New York, NY, cDivision of Vascular Surgery, Department of Surgery, New York University School of Medicine, New York, NY, dDivision of Cardiology, Department of Medicine, University of Colorado Denver School of Medicine, Denver, Colorado, eSection of Vascular Medicine, Colorado Prevention Center, Denver, Colorado, and fDepartment of Biostatistics and Informatics, Colorado School of Public Health, Denver, Colorado. Roger S. Blumenthal, MD served as guest editor for this article. Dr Berger was partially funded by an American Heart Association Fellow to Faculty Award (0775074N). Dr Krantz was partially funded by grant U01 HL079160 from the National Heart, Lung, and Blood Institute. Submitted March 3, 2011; accepted April 6, 2011. Reprint requests: Jeffrey S. Berger, MD, MS, FACC, The Leon H Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016. E-mail: [email protected] 0002-8703/$ - see front matter © 2011, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2011.04.006
sive populations include patients who have experienced plaque rupture or vessel occlusion sufficient to induce a symptomatic state (eg, stable angina7 or transient ischemic attack),8,9 acute coronary syndrome,10-12 or ischemic stroke.13 The data demonstrating benefit of aspirin in patients without clinical CVD are less certain.14,15 This includes populations at risk based on age, risk factors such as diabetes or hypertension, or evidence of subclinical atherosclerosis.16 Clinical decision making is further complicated by several meta-analyses of the older trials that found a significant decrease in the composite of major cardiovascular events (MCEs) by approximately 12%,17,18 but newer trials of aspirin in patients at high risk but without clinical CVD have failed to achieve their primary end points.19-21 Thus, the benefit-to-risk relationship needs further definition in light of the newer evidence. The most recent meta-analysis reviewed 6 primary prevention trials and concluded that current evidence did not clearly support a net benefit of aspirin relative to the excess bleeding risk in primary prevention.17 This analysis did not identify any potential subgroups as response modifiers including age, gender, diabetes or
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Table I. Design of trials included in the meta-analysis PHS Year of 1989 publication No. of 22071 participants Healthy Patient population male doctors
Country Mean year follow-up Aspirin dose
Primary end point
BDT
TPT
HOT
PPP
WHS
POPADAD
JPAD
AAA
1988
1998
1998
2001
2005
2008
2008
2010
5139
5085
18790
4495
39876
1276
2539
3350
Healthy male doctors
Men at high risk for CVD
USA
UK
UK
5
5.6
6.7⁎
325 mg every other day CV death
500 mg daily or 300 mg† CV death, nonfatal MI, stroke, TIA
75 mg daily (controlled release) All ischemic heart disease (coronary death and fatal and nonfatal MI)
Healthy Men and Men and females women with women N1 hypertension cardiovascular risk factor
UK, USA, Asia 3.8
Italy
USA
UK
Japan
3.7
10
6.7
4.4⁎
75 mg daily 100 mg daily CV death, nonfatal MI, stroke
Men and Men and women with women with diabetes and diabetes ABI ≤0.99
CV death, MI, stroke
100 mg 100 mg every daily other day CV death, CV death, nonfatal MI, nonfatal MI, stroke stroke, critical limb ischemia
Men and women in general population with ABI ≤0.95 UK 8.2
81 mg or 100 mg daily 100 mg daily (enteric coated) CV death, All ischemic heart disease, MI, stroke, revascularization stroke, and peripheral artery disease
CV, Cardiovascular; TIA, transient ischemic attack. ⁎ Median year follow-up. † If requested.
other risk factors, or predicted 5-year risk of CVD. However, the publication of 3 new trials in at-risk populations allows for further evaluation of these potential risk modifiers. Thus, the current meta-analysis includes new data and tests the null hypothesis on the available data that there is no net benefit relative to risk for aspirin when used in patients without clinical CVD.
Methods Search strategy From 1966 to 2005, a computerized search was performed that identified 6 published randomized trials of aspirin in patients without clinical CVD. In the previous meta-analysis of these trials, aspirin therapy significantly reduced the risk of an MCE (nonfatal MI, nonfatal stroke, or cardiovascular death) by 12% in women and 14% in men.18 From 2005 to the present, a subsequent review of the literature (MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE) identified 3 additional primary prevention studies of aspirin for a total of 9 trials for analysis.19-21
Study selection Primary prevention trials that involved a randomized comparison of aspirin versus placebo or control in patients without clinical CVD (eg, established or symptomatic) were included in this analysis. The criteria for inclusion of trials were as follows: (1) aspirin alone was used for the primary prevention of CVD; (2) comparisons of outcomes were made between aspirin and placebo or open control groups; and (3) data were available on MI, stroke, and cardiovascular deaths. Our search included only those studies published in English.
Outcome measures The primary outcome was the risk ratio (RR) of aspirin therapy compared with placebo or control on the composite MCE end point, which includes nonfatal MI, nonfatal stroke, or cardiovascular death. Secondary outcomes included all MI, all stroke, allcause mortality, and cardiovascular mortality. The primary safety outcome was the occurrence of major bleeding as defined by each study. Because the definition of major bleeding differed by trial, gastrointestinal hemorrhage and cerebral hemorrhage were reported separately. In addition, stroke subtypes (ischemic or hemorrhagic) were examined from data available in the 8 studies that reported strokes by subtype. The adjudication process to subtype stroke was not provided for all the trials. The HOT trial22 did not include data by stroke subtypes.
Statistical analysis The composite end point was analyzed using the data as they were reported in the included publications. A random-effects model was the primary analysis because of the differences across the studies in patient characteristics (including underlying disease population) and aspirin dosing. To determine the appropriateness of pooled RR estimates, heterogeneity among the trials was examined using the Q statistic for each of the end points analyzed. It was determined that pooled estimates from the random-effects model of the RR were reasonable because the Q statistic did not indicate statistically significant heterogeneity and the I2 statistic was b37% for all end points other than fatal and nonfatal MI. For the MI end point, there was moderate heterogeneity (63% of variation because of heterogeneity) that was statistically significant. A sensitivity analysis of the primary analysis was performed to examine the robustness of the results. This was done by examining the impact of systematically removing 1 study from
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Table II. Patient characteristics included in the meta-analysis
Age (mean) Female (%) Mean SBP (mm Hg)
Diabetes (%) Total cholesterol (mg/dL) Smokers (%) BMI (kg/m2) Annual risk of cardiovascular events (%)
PHS
BDT
TPT
HOT
PPP
WHS
POPADAD
JPAD
AAA
53 (9) 0 126
50-78 0 136
58 0 139
62 47 170
64 (8) 58 145
60 56 145
65 45 135
62 72 148
2.4 212 11 24.9 (3) 0.67
2 NA 13 NA 1.54
NA 247 41 27.4 1.53
8 236 16 28.4 1.19
17 236 15 27.6(5) 0.76
55 (7) 100 b120/75, 32%; 120-9/75-84, 32%; 130-9/85-89, 19%; N140/90, 16% 2.6 NA 13 26 (5) 0.26
100 213 31 24 (4) 2.53
100 201 21 29 0.82
3 240 65 NA 0.99
SBP, Systolic blood pressure; BMI, body mass index.
the analysis and recalculating the results. In addition, specific subsets of the studies were analyzed to evaluate the consistency of the effects of aspirin when studies that were restricted to persons with diabetes were excluded,19,21 studies enrolling patients with subclinical atherosclerosis (by a low anklebrachial index [ABI]) were excluded,19,20 and studies that included extended or controlled release aspirin were removed.20,23,24 In addition, the data were analyzed using a fixed-effect model, and the results were compared with the random-effects model. Linear meta-regression analyses on the log-transformed RR with the study as the unit of analysis were performed to evaluate potential effect modifiers (year of study publication, baseline cardiovascular risk as assessed by incidence of events on placebo, mean age of the trial participant, sex, and dose of aspirin). Studies were weighed by the precision of the effect estimate. The potential publication bias was examined by constructing a funnel plot in which sample size was plotted against log RRs for the primary end point available from all studies. Statistical analyses were performed using Review Manager 5.0.23 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark, 2008). P b .05 was judged as statistically significant.
Results Nine prospective randomized trials involving 102,621 participants were identified for inclusion. A total of 710,053 person-years of exposure were recorded: 359,709 in the aspirin group and 350,344 in the placebo or control group. All trials included patients without clinical CVD, which was defined as the absence of a cardiovascular event, or clinical symptoms of CVD including angina or transient ischemic attack. Among the 3 new trials,19-21 2 included only diabetic patients,19,21 and 2 required a low ABI measurement as a marker of subclinical atherosclerosis for inclusion.19,20 Of the 9 trials, 3 included only men,23-25 and 1 included only women.26 Details of the included studies appear in Table I, and characteristics of participants are summarized in Table II.
Dosage of aspirin ranged from 100 mg every other day to 500 mg daily. Two trials used enteric-coated aspirin,20,24 and 1 trial used a longer preparation tablet.23 Follow-up ranged from 4.4 to 10.1 years and was N95% complete in all trials. The weighted mean follow-up time was 6.9 years.
Major cardiovascular events A total of 2,029 MCEs occurred among 52,145 (3.86%) patients allocated to aspirin compared with 2,099 MCEs among 50,476 (4.16%) patients assigned to placebo or control (Figure 1). Pooled results using a random-effects model demonstrated a significant 10% reduction in the risk of MCE (RR 0.90, 95% CI 0.85-0.96, P b .001). In aggregate, the absolute risk reduction was 0.39% (95% CI 0.18%-0.61%) over a mean follow-up of 6.9 years, which corresponds to a number needed to treat of 253 (95% CI 163-568) to prevent a single MCE. Myocardial infarction A total of 993 fatal and nonfatal MI events occurred among 52,145 (1.90%) patients allocated to aspirin compared with 1,075 MI events among 50,476 (2.13%) patients assigned to placebo or control (Figure 2). Pooled results demonstrated a 14% risk reduction in both fatal and nonfatal MI, which failed to reach statistical significance (RR 0.86, 95% CI 0.74-1.00, P = .06). For the end point of nonfatal MI, there was a 16% reduction in events with aspirin versus placebo or control; however, the results did not reach statistical significance (RR 0.84, 95% CI 0.70-1.01, P = .06). Stroke A total of 741 fatal and nonfatal strokes occurred among 52,145 (1.42%) patients allocated to aspirin compared with 746 strokes among 50,476 (1.48%) patients assigned to placebo or control (Figure 3). Pooled results demonstrated a nonsignificant 6% reduction in the risk of stroke (RR 0.94, 95% CI 0.84-1.06, P = .31). Eight of the studies
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Figure 1
Effect of aspirin on the prevention of MCE. Major cardiovascular events defined as the composite of nonfatal MI, nonfatal stroke, or cardiovascular death.
Figure 2
Effect of aspirin on the prevention of MI (fatal and nonfatal).
provided data on type of stroke. For the end point of nonfatal stroke, there was a nonsignificant 8% reduction in events with aspirin versus placebo or control (RR 0.92, 95% CI 0.80-1.06, P = .26). To further understand the benefit versus risk, the relationship of aspirin on ischemic and hemorrhagic stroke was explored independently (Figure 3). For the end point of ischemic stroke, there was a nonsignificant 13% reduction in events with aspirin versus placebo or control (RR 0.87, 95% CI 0.73-1.02, P = .09). For the end point of hemorrhagic stroke, there was a significant 35% increase in events with aspirin versus placebo or control (RR 1.35, 95% CI 1.01-1.81, P = .04). The absolute risk increase was 0.06% (95% CI 0.003-0.126) over a mean follow-up of 6.9 years, corresponding to a number needed to harm of 1,560 (95% CI 794-33,333) to cause 1 hemorrhagic stroke.
Death A total of 1,962 deaths occurred among 52,145 (3.76%) patients allocated to aspirin compared with
1,933 among 50,476 (3.83%) patients assigned to placebo or control (Figure 4). Pooled results demonstrated a nonsignificant reduction of 6% in the risk of death (RR 0.94, 95% CI 0.89-1.00, P = .07). For the end point of cardiovascular death, there was no reduction in events with aspirin versus placebo or control (RR 0.99, 95% CI 0.85-1.14, P = .86).
Major bleeding A total of 458 major bleeding events occurred among 52,145 (0.88%) patients allocated to aspirin compared with 278 major bleeding events among 50,421 (0.55%) patients assigned to placebo or control (Figure 5). Pooled results demonstrated a significant 62% increase in the risk of major bleeding (RR 1.62, 95% CI 1.31-2.00, P b .001). In aggregate, the absolute risk was 0.38% (95% CI 0.21%-0.55%) over a mean follow-up of 6.9 years, which corresponds to a number needed to harm of 261 (95% CI 182-476) to cause a single major bleeding event over 6.9 years. For the end point of gastrointestinal hemorrhage, there was a significant 29% increase
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Figure 3
A
B
C
Effect of aspirin on the prevention of stroke (fatal and nonfatal), ischemic stroke, and hemorrhagic stroke.
in events with aspirin versus placebo or control (RR 1.29, 95% CI 1.24-1.47, P b .001).
aspirin on MCE or major bleeding (see Supplemental Figures 6 and 7 in the online Appendix).
Meta-regression Linear meta-regression models were used to assess the impact of study-level covariates on the risk of MCE and major bleeding. There was no relationship between any of the covariates examined (year of study publication as a surrogate for any changes in background cardiovascular preventive therapies, baseline cardiovascular risk as assessed by incidence of events on placebo, mean age of the trial participant, sex of the trial participant, and dose of aspirin) and the effect of
Aspirin dose and formulation Although aspirin dose ranged from 100 mg every other day to 500 mg/d, 7 of the 9 trials used a dose between 75 and 162.5 mg/d. There did not appear to be any relationship between aspirin dose and the effect of aspirin on MCE or major bleeding (Supplemental Figures 6E and 7E in the online Appendix). Three trials used a different aspirin formulation than regular aspirin. The BDT and AAA trials used an enteric-coated aspirin formulation, whereas the TPT trial used a controlled
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Figure 4
A
B
Effect of aspirin on the prevention of all-cause death and cardiovascular death.
release formulation. When analyses were repeated after excluding these trials, the association between aspirin and the primary outcome of MCE yielded an effect size (RR 0.89, 95% CI 0.83-0.95) similar in magnitude and direction to the overall results.
Sensitivity analysis There was no difference in results between the fixedeffect (RR 0.90) or the random-effect model (RR 0.90) for the primary outcome of MCE. The RR varied between 0.891 and 0.893 when each study was systematically removed from the model. The POPADAD19 and JPAD21 trials exclusively enrolled patients with diabetes, and both demonstrated no significant effect on the composite of cardiovascular events. Because aspirin may not be beneficial in patients with diabetes,27 the primary analysis was repeated after excluding these 2 trials. The association between aspirin and the primary outcome of MCE yielded an effect size (1,868 events among 50,245 patients taking aspirin [3.7%] vs 1,924 events among 48,561 control patients [4.0%]; RR 0.90, 95% CI 0.84-0.96) identical to the overall results. The AAA20 and POPADAD19 trials exclusively enrolled patients with subclinical atherosclerosis determined by a
low ABI. Because aspirin may not be beneficial in patients with PAD,28 the primary analysis was repeated after excluding these 2 trials. A similar effect of aspirin was observed (RR 0.89, 95% CI 0.83-0.95) relative to the overall result.
Discussion The current meta-analysis included 9 prevention trials in N100,000 subjects without clinical evidence of CVD treated with aspirin versus placebo or control for the prevention of ischemic cardiovascular events. The pooled results found a statistically significant 10% relative reduction in the primary end point of MCE and a statistically significant 62% relative increase in major bleeding events. The absolute benefit versus risk demonstrated that, in 1,000 patients treated for 5 years, there were approximately 3 ischemic events avoided that was associated with an excess of 3 major bleeds resulting in no net benefit to risk for aspirin in this population. These results were consistent across a number of subgroups suggesting that a more targeted approach to maximize benefit and minimize risk could not be identified. The year of publication of the trials ranged from 1988 to 2010 and spanned over a decade during which there
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Figure 5
Effect of aspirin on major bleeding.
were major improvements in the medical prevention and treatment of CVD,29,30 yet publication year did not have either a positive or negative impact on the overall estimate of the benefit or risk of aspirin (Supplemental Figures 6A and 7A in the online Appendix). The risk of CVD events in the placebo/control groups was also quite broad, ranging from 0.25% per year in the Women's Health Study to 2.7% in the POPADAD trial (expressed over a decade per the Framingham coronary heart disease risk score this baseline risk ranges from 2.5% to 27%). Yet, using this baseline risk assessment or components of that risk including populations enriched with diabetes did not impact the estimate of benefit or risk of aspirin (Supplemental Figures 6B and 7B in the online Appendix). Cardiovascular risk estimates can also be significantly influenced by measures of subclinical atherosclerosis such as the ABI or carotid intima-media thickness.31-33 However, in the most recent AAA trial20 where a low ABI was used as an inclusion criterion or in the POPADAD trial19 where a reduced ABI and diabetes were inclusion criteria, the trials were not just statistically negative, but the point estimates of benefit in both were near 1.00. Finally, although the dose of aspirin ranged from 100 mg every other day (50 mg/d)26 to 500 mg/d,24 the dose of aspirin did not impact the results (Supplemental Figures 6E and 7E in the online Appendix). Taken together, aspirin retains a modest yet statistically significant benefit on decreasing nonfatal cardiovascular events. These benefits are offset by a consistent signal of major bleeding risk including hemorrhagic stroke. These new results need to be considered by clinicians making difficult decisions about the value of primary preventive pharmacotherapies (relative to drugs with unequivocal benefit such as statins and blood pressure medications). The goal of the current study was to perform a comprehensive meta-analysis of all randomized trials with aspirin as preventive therapy in patients without established or symptomatic CVD. Previous meta-ana-
lyses17,18,34 have been restricted to older trials with lower risk populations and did not include all contemporary randomized trials. Twenty years ago, 2 landmark trials24,25 evaluated the effect of aspirin in primary prevention. Neither the BDT24 nor the PHS25 demonstrated a benefit for aspirin in the reduction of their primary end point (Table III). However, the PHS25 was able to demonstrate a decrease in the secondary end point of fatal and nonfatal MI by 44%, leading to the widespread recommendations and use of aspirin in primary prevention. Since then, there have been 4 randomized trials22,23,26,35 of aspirin in primary prevention and 3 more recent randomized trials19-21 in patients with diabetes and/or subclinical atherosclerosis (defined by reduced ABI). None of these 7 trials demonstrated a beneficial effect of aspirin on their prespecified primary end point (Table III).16 If one were to evaluate the traditional composite end point of nonfatal MI, nonfatal stroke, or cardiovascular death, only 1 of the 9 trials was associated with a statistically significant reduction. Thus, the benefit observed in our meta-analysis with aspirin is only seen after combining all the data in aggregate. Bleeding risk is consistently increased with aspirin therapy across the trials. Despite different definitions of major bleeding among the trials, there was a strong signal of increased risk. Of the 9 trials, 4 found a statistically significant increase in major bleeding, and in pooled analysis, the risk was increased by 62%. Hemorrhagic stroke is a less common but clinically important end point because of its significant morbidity. Incidence of hemorrhagic stroke increased by approximately 0.1% (1 per 1,000 patients treated); however, in the pooled analysis, aspirin was associated with a significant 36% increase in the risk of hemorrhagic stroke. Because aspirin was associated with a significant reduction in cardiovascular events but a proportional increase in bleeding complications, it is essential to understand the absolute benefit versus risk. Three MCEs were prevented for every 1,000 patients treated with
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Table III. Primary efficacy end point for each trial Study, year PHS, 1989 BDT, 1988 TPT, 1998
HOT, 1998 PPP, 2001 WHS, 2005 POPAD, 2008 JPAD, 2008 AAA, 2010
Primary efficacy end point Cardiovascular mortality CV death, nonfatal MI and stroke or TIA All ischemic heart disease (coronary death and fatal and nonfatal MI) CV death, nonfatal MI, stroke CV death, MI, stroke CV death, nonfatal MI, stroke CV death, nonfatal MI or stroke, or amputation for critical limb ischemia CV death, nonfatal MI, stroke, UA, PVD, new angina CV death, MI, stroke, revascularization
HR (95% CI)
P
RR 0.96 (0.60-1.54)
.87 NS
20% (1-35) reduction
.04⁎
RR 0∙91 (0∙79-1∙04) 0∙71 (0∙48-1∙04) 0.91 (0.80-1.03) 0.98 (0.76-1.26)
.17†
0.80 (0.58-1.10)
.16
1.03 (0.84-1.27)
NS
NS .13 .86
NS, Not significant. ⁎ After including silent MI, the reduction was no longer significant (P = .07). † After excluding silent MI, the reduction became statistically significant (P = .03).
aspirin over a period of 5 years, at the cost of inducing 3 major bleeding events. Intracranial hemorrhage was statistically significantly higher in the aspirin group, but the number needed to harm was 1,560 (b1 in 1,000 patients treated). There are several potential explanations for the lowerthan-expected proportional benefit observed with aspirin in this trial data set. Trials included in this analysis spanned several decades, and during this period, there has been considerable improvement of outcomes with the adoption of statins and angiotensin-converting enzyme inhibitors.29,36 Although no significant heterogeneity was observed between proportional reduction in MCE and time of publication, 4 of 5 trials published before 2002 had a proportional reduction of N10%, whereas only 1 of 4 trials published after 2003 had such a benefit. Moreover, the larger proportional benefit (N15%) observed in trials of aspirin in patients with clinical CVD occurred in trials N15 years ago. Consistent with this hypothesis, the CHARISMA trial (published in 2006) tested clopidogrel plus aspirin versus aspirin alone in patients with and without clinical CVD and demonstrated a nonsignificant increased risk of MCE with combination antiplatelet therapy in the primary prevention subgroup of the trial.37 Thus, if aspirin alone is of uncertain benefit in these subjects, dual antiplatelet therapy may be even more suspect. An additional explanation on the lack of a net benefit over risk may be that concomitant therapies have minor antiplatelet affects that may attenuate any potential benefit of aspirin. In fact, statins,38,39 fish oil,40 angiotensin-converting enzyme inhibitors,41,42
fibrates,39,43 phosphodiesterase inhibitors such as cilostazol,44 and selective serotonin reuptake inhibitors45 have all been shown to reduce platelet activity. Unfortunately, few of the aspirin trials reported concomitant medications and what, if any, modifying effect these medications may have on the effect of aspirin. Although some have suggested an attenuated effect of aspirin in certain high-risk groups, such as persons with diabetes 27 and peripheral artery disease,28 there was no difference in the results when trials that exclusively enrolled those populations were excluded. Finally, dose and aspirin formulation differed across the trials, which may have contributed to the lower proportional benefit. However, there was no difference in the effect of aspirin when adjusting for aspirin dose or after excluding trials that used a longer acting or enteric-coated formulation.
Limitations There are several limitations to this study. Some imprecision exists in the frequency of events because the protocols for data collection and definitions of efficacy and safety events varied among the studies. However, all of the trials allowed for the assessment of a common MCE outcome that served as a primary end point for analysis. For the safety end point, definitions of major bleeding varied across the trials, and these variations made it difficult to determine accurate measure of bleeding and approximate risk. Therefore, both gastrointestinal hemorrhage and hemorrhagic stroke were used as complementary end points to help evaluate risk. The current meta-analysis was not performed on individual patient data because complete individual data were not available, and therefore, comprehensive assessment within different higher-risk groups was not able to be performed. Nonetheless, the analyses were able to adjust for the incidence of adverse events in the placebo group (a surrogate for baseline risk) in each individual trial, which had no effect on the overall results. A proportion of patients included in this metaanalysis had documented subclinical atherosclerosis, as detected by a lower ABI. Although some would consider this a limitation because of the higher-risk cohort included, no change in the effect of aspirin was observed after exclusion of these patients, and the results were nearly identical.
Conclusions This meta-analysis of N100,000 randomized patients (N700,000 person-year follow-up) comparing aspirin versus placebo or control demonstrated that aspirin decreased MCE by approximately 10% among patients without clinical CVD. Major bleeding, however, occurred more frequently with aspirin therapy. The decision to use
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aspirin for the prevention of a first MI or stroke remains a complex issue. Weighing the overall benefit and risk requires careful consideration by the physician and patient before initiating aspirin for preventive therapy in patients without clinical CVD.
Acknowledgements We thank Dr Sanjay Kaul for his insightful comments and editorial assistance.
Disclosures Dr Jeffrey Berger reports receiving research support from Astra Zaneca and has received honoraria for advisory board participation from Astra Zaneca. Dr William Hiatt reports receiving research support from Astra Zaneca. Conflicts of interest: none. Drs Berger and Hiatt had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
References 1. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ (Clin Res ed) 2002;324:71-86. 2. Berger JS, Brown DL, Becker RC. Low-dose aspirin in patients with stable cardiovascular disease: a meta-analysis. Am J Med 2008;121: 43-9. 3. Patrono C, Baigent C, Hirsh J, et al. Antiplatelet drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008;133:199S-233S. 4. Smith Jr SC, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006;113:2363-72. 5. Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 writing group to review new evidence and update the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction, writing on behalf of the 2004 writing committee. Circulation 2008;117:296-329. 6. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 2002 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007;116:e148-304.
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7. Juul-Moller S, Edvardsson N, Jahnmatz B, et al. Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. The Swedish Angina Pectoris Aspirin Trial (SAPAT) group. Lancet 1992;340:1421-5. 8. The SALT Collaborative Group. Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991;338:1345-9. 9. Farrell B, Godwin J, Richards S, et al. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991;54:1044-54. 10. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349-60. 11. Lewis Jr HD, Davis JW, Archibald DG, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med 1983;309:396-403. 12. Wallentin LC. Aspirin (75 mg/day) after an episode of unstable coronary artery disease: long-term effects on the risk for myocardial infarction, occurrence of severe angina and the need for revascularization. Research Group on Instability in Coronary Artery Disease in Southeast Sweden. J Am Coll Cardiol 1991;18:1587-93. 13. Chen ZM, Sandercock P, Pan HC, et al. Indications for early aspirin use in acute ischemic stroke : a combined analysis of 40 000 randomized patients from the Chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke 2000;31:1240-9. 14. Krantz MJ, Berger JS, Hiatt WR. An aspirin a day: are we barking up the wrong willow tree? Pharmacotherapy 2010;30:115-8. 15. Berger JS. Aspirin as preventive therapy in patients with asymptomatic vascular disease. JAMA 2010;303:880-2. 16. Cardiovascular and Renal Drugs Advisory Committee. Available at: http://www.fda.gov/ohrms/DOCKETS/ac/03/questions/4012Q1_Final.pdf. Last accessed on March 13, 2010. 17. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative metaanalysis of individual participant data from randomised trials. Lancet 2009;373:1849-60. 18. Berger JS, Roncaglioni MC, Avanzini F, et al. Aspirin for the primary prevention of cardiovascular events in women and men: a sexspecific meta-analysis of randomized controlled trials. JAMA 2006; 295:306-13. 19. Belch J, MacCuish A, Campbell I, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ (Clin Res ed) 2008;337:a1840. 20. Fowkes FG, Price JF, Stewart MCW, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index. JAMA 2010;303:841-8. 21. Ogawa H, Nakayama M, Morimoto T, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 2008;300:2134-41. 22. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998;351: 1755-62. 23. The Medical Research Council's General Practice Research Framework. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the
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24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998;351:233-41. Peto R, Gray R, Collins R, et al. Randomised trial of prophylactic daily aspirin in British male doctors. Br Med J (Clin Res ed) 1988;296: 313-6. Final report on the aspirin component of the ongoing Physicians' Health Study. Steering Committee of the Physicians' Health Study Research Group. N Engl J Med 1989;321:129-35. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352:1293-304. De Berardis G, Sacco M, Strippoli GF, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: metaanalysis of randomised controlled trials. BMJ (Clin Res ed 2009;339: b4531. Berger JS, Krantz MJ, Kittelson JM, et al. Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials. JAMA 2009;301:1909-19. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N Engl J Med 2007;356: 2388-98. Hunink MG, Goldman L, Tosteson AN, et al. The recent decline in mortality from coronary heart disease, 1980-1990. The effect of secular trends in risk factors and treatment. JAMA 1997;277: 535-42. Berger JS, Jordan CO, Lloyd-Jones D, et al. Screening for cardiovascular risk in asymptomatic patients. J Am Coll Cardiol 2010;55:1169-77. Fowkes FG, Murray GD, Butcher I, et al. Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis. JAMA 2008;300:197-208. O'Leary DH, Polak JF, Kronmal RA, et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999;340:14-22. Eidelman RS, Hebert PR, Weisman SM, et al. An update on aspirin in the primary prevention of cardiovascular disease. Arch Intern Med 2003;163:2006-10. de Gaetano G. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collab-
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
orative Group of the Primary Prevention Project. Lancet 2001;357: 89-95. Cooper R, Cutler J, Desvigne-Nickens P, et al. Trends and disparities in coronary heart disease, stroke, and other cardiovascular diseases in the United States: findings of the national conference on cardiovascular disease prevention. Circulation 2000; 102:3137-47. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-17. Haramaki N, Ikeda H, Takenaka K, et al. Fluvastatin alters platelet aggregability in patients with hypercholesterolemia: possible improvement of intraplatelet redox imbalance via HMG-CoA reductase. Arterioscler Thromb Vasc Biol 2007;27:1471-7. Damas JK, Puccetti L, Aukrust P. Early anti-thrombotic and antiinflammatory actions of statins and fibrates—time for adjuvant therapy in acute coronary syndromes? Thromb Haemost 2005;94: 1-3. Lee JH, O'Keefe JH, Lavie CJ, et al. Omega-3 fatty acids: cardiovascular benefits, sources and sustainability. Nat Rev Cardiol 2009;6:753-8. Okrucka A, Pechan J, Kratochvilova H. Effects of the angiotensin-converting enzyme (ACE) inhibitor perindopril on endothelial and platelet functions in essential hypertension. Platelets 1998;9: 63-7. Moser L, Callahan KS, Cheung AK, et al. ACE inhibitor effects on platelet function in stages I-II hypertension. J Cardiovasc Pharmacol 1997;30:461-7. Barter PJ, Rye KA. Cardioprotective properties of fibrates: which fibrate, which patients, what mechanism? Circulation 2006;113: 1553-5. Goto S. Cilostazol: potential mechanism of action for antithrombotic effects accompanied by a low rate of bleeding. Atheroscler Suppl 2005;6:3-11. Serebruany VL, Glassman AH, Malinin AI, et al. Platelet/ endothelial biomarkers in depressed patients treated with the selective serotonin reuptake inhibitor sertraline after acute coronary events: the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART) Platelet Substudy. Circulation 2003;108:939-44.
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Appendix. Supplementary data Supplemental Figure 6
Association between the RR of aspirin versus placebo or control on the prevention of MCE and year of study publication (a surrogate for changes in background cardiovascular preventive therapies) (A), baseline cardiovascular risk (as assessed by the annual risk of MCE on placebo) (B), mean age of trial participant (C), percent female of trial enrollment (D), and dose of aspirin used (E). Major cardiovascular events defined as the composite of nonfatal MI, nonfatal stroke, or cardiovascular death. CV, Cardiovascular.
124.e2 Berger et al
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Supplemental Figure 7
Association between the RR of aspirin versus placebo or control on the risk of major bleeding and year of study publication (a surrogate for changes in background cardiovascular preventive therapies) (A), baseline cardiovascular risk (as assessed by the annual risk of MCE on placebo) (B), mean age of trial participant (C), percent female of trial enrollment (D), and dose of aspirin used (E). Major cardiovascular events defined as the composite of nonfatal MI, nonfatal stroke, or cardiovascular death. CV, Cardiovascular.
Background The benefit of aspirin to prevent cardiovascular events in subjects without clinical cardiovascular disease relative to the increased risk of bleeding is uncertain. Methods A meta-analysis of randomized trials of aspirin versus placebo/control to assess the effect of aspirin on major cardiovascular events (MCEs) (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), individual components of the MCE, stroke subtype, all-cause mortality, and major bleeding. Nine trials involving 102,621 patients were included: 52,145 allocated to aspirin and 50,476 to placebo/control. Results Over a mean follow-up of 6.9 years, aspirin was associated with a reduction in MCE (risk ratio [RR] 0.90, 95% CI 0.85-0.96, P b .001). There was no significant reduction for myocardial infarction, stroke, ischemic stroke, or all-cause mortality. Aspirin was associated with hemorrhagic stroke (RR 1.35, 95% CI 1.01-1.81, P = .04) and major bleeding (RR 1.62, 95% CI 1.31-2.00, P b .001). In meta-regression, the benefits and bleeding risks of aspirin were independent of baseline cardiovascular risk, background therapy, age, sex, and aspirin dose. The number needed to treat to prevent 1 MCE over a mean follow-up of 6.9 years was 253 (95% CI 163-568), which was offset by the number needed to harm to cause 1 major bleed of 261 (95% CI 182-476). Conclusions The current totality of evidence provides only modest support for a benefit of aspirin in patients without clinical cardiovascular disease, which is offset by its risk. For every 1,000 subjects treated with aspirin over a 5-year period, aspirin would prevent 2.9 MCE and cause 2.8 major bleeds. (Am Heart J 2011;162:115-124.e2.)
Aspirin is effective in decreasing cardiovascular morbidity and mortality in patients with clinical evidence of cardiovascular disease (CVD).1,2 Specifically, benefits of aspirin are well defined for secondary prevention of acute myocardial infarction (MI) and stroke, forming the basis for current clinical practice guidelines.3-6 These respon-
From the aDepartment of Medicine, Division of Cardiology, New York University School of Medicine, New York, NY, bDivision of Hematology, New York University School of Medicine, New York, NY, cDivision of Vascular Surgery, Department of Surgery, New York University School of Medicine, New York, NY, dDivision of Cardiology, Department of Medicine, University of Colorado Denver School of Medicine, Denver, Colorado, eSection of Vascular Medicine, Colorado Prevention Center, Denver, Colorado, and fDepartment of Biostatistics and Informatics, Colorado School of Public Health, Denver, Colorado. Roger S. Blumenthal, MD served as guest editor for this article. Dr Berger was partially funded by an American Heart Association Fellow to Faculty Award (0775074N). Dr Krantz was partially funded by grant U01 HL079160 from the National Heart, Lung, and Blood Institute. Submitted March 3, 2011; accepted April 6, 2011. Reprint requests: Jeffrey S. Berger, MD, MS, FACC, The Leon H Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016. E-mail: [email protected] 0002-8703/$ - see front matter © 2011, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2011.04.006
sive populations include patients who have experienced plaque rupture or vessel occlusion sufficient to induce a symptomatic state (eg, stable angina7 or transient ischemic attack),8,9 acute coronary syndrome,10-12 or ischemic stroke.13 The data demonstrating benefit of aspirin in patients without clinical CVD are less certain.14,15 This includes populations at risk based on age, risk factors such as diabetes or hypertension, or evidence of subclinical atherosclerosis.16 Clinical decision making is further complicated by several meta-analyses of the older trials that found a significant decrease in the composite of major cardiovascular events (MCEs) by approximately 12%,17,18 but newer trials of aspirin in patients at high risk but without clinical CVD have failed to achieve their primary end points.19-21 Thus, the benefit-to-risk relationship needs further definition in light of the newer evidence. The most recent meta-analysis reviewed 6 primary prevention trials and concluded that current evidence did not clearly support a net benefit of aspirin relative to the excess bleeding risk in primary prevention.17 This analysis did not identify any potential subgroups as response modifiers including age, gender, diabetes or
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Table I. Design of trials included in the meta-analysis PHS Year of 1989 publication No. of 22071 participants Healthy Patient population male doctors
Country Mean year follow-up Aspirin dose
Primary end point
BDT
TPT
HOT
PPP
WHS
POPADAD
JPAD
AAA
1988
1998
1998
2001
2005
2008
2008
2010
5139
5085
18790
4495
39876
1276
2539
3350
Healthy male doctors
Men at high risk for CVD
USA
UK
UK
5
5.6
6.7⁎
325 mg every other day CV death
500 mg daily or 300 mg† CV death, nonfatal MI, stroke, TIA
75 mg daily (controlled release) All ischemic heart disease (coronary death and fatal and nonfatal MI)
Healthy Men and Men and females women with women N1 hypertension cardiovascular risk factor
UK, USA, Asia 3.8
Italy
USA
UK
Japan
3.7
10
6.7
4.4⁎
75 mg daily 100 mg daily CV death, nonfatal MI, stroke
Men and Men and women with women with diabetes and diabetes ABI ≤0.99
CV death, MI, stroke
100 mg 100 mg every daily other day CV death, CV death, nonfatal MI, nonfatal MI, stroke stroke, critical limb ischemia
Men and women in general population with ABI ≤0.95 UK 8.2
81 mg or 100 mg daily 100 mg daily (enteric coated) CV death, All ischemic heart disease, MI, stroke, revascularization stroke, and peripheral artery disease
CV, Cardiovascular; TIA, transient ischemic attack. ⁎ Median year follow-up. † If requested.
other risk factors, or predicted 5-year risk of CVD. However, the publication of 3 new trials in at-risk populations allows for further evaluation of these potential risk modifiers. Thus, the current meta-analysis includes new data and tests the null hypothesis on the available data that there is no net benefit relative to risk for aspirin when used in patients without clinical CVD.
Methods Search strategy From 1966 to 2005, a computerized search was performed that identified 6 published randomized trials of aspirin in patients without clinical CVD. In the previous meta-analysis of these trials, aspirin therapy significantly reduced the risk of an MCE (nonfatal MI, nonfatal stroke, or cardiovascular death) by 12% in women and 14% in men.18 From 2005 to the present, a subsequent review of the literature (MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE) identified 3 additional primary prevention studies of aspirin for a total of 9 trials for analysis.19-21
Study selection Primary prevention trials that involved a randomized comparison of aspirin versus placebo or control in patients without clinical CVD (eg, established or symptomatic) were included in this analysis. The criteria for inclusion of trials were as follows: (1) aspirin alone was used for the primary prevention of CVD; (2) comparisons of outcomes were made between aspirin and placebo or open control groups; and (3) data were available on MI, stroke, and cardiovascular deaths. Our search included only those studies published in English.
Outcome measures The primary outcome was the risk ratio (RR) of aspirin therapy compared with placebo or control on the composite MCE end point, which includes nonfatal MI, nonfatal stroke, or cardiovascular death. Secondary outcomes included all MI, all stroke, allcause mortality, and cardiovascular mortality. The primary safety outcome was the occurrence of major bleeding as defined by each study. Because the definition of major bleeding differed by trial, gastrointestinal hemorrhage and cerebral hemorrhage were reported separately. In addition, stroke subtypes (ischemic or hemorrhagic) were examined from data available in the 8 studies that reported strokes by subtype. The adjudication process to subtype stroke was not provided for all the trials. The HOT trial22 did not include data by stroke subtypes.
Statistical analysis The composite end point was analyzed using the data as they were reported in the included publications. A random-effects model was the primary analysis because of the differences across the studies in patient characteristics (including underlying disease population) and aspirin dosing. To determine the appropriateness of pooled RR estimates, heterogeneity among the trials was examined using the Q statistic for each of the end points analyzed. It was determined that pooled estimates from the random-effects model of the RR were reasonable because the Q statistic did not indicate statistically significant heterogeneity and the I2 statistic was b37% for all end points other than fatal and nonfatal MI. For the MI end point, there was moderate heterogeneity (63% of variation because of heterogeneity) that was statistically significant. A sensitivity analysis of the primary analysis was performed to examine the robustness of the results. This was done by examining the impact of systematically removing 1 study from
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Table II. Patient characteristics included in the meta-analysis
Age (mean) Female (%) Mean SBP (mm Hg)
Diabetes (%) Total cholesterol (mg/dL) Smokers (%) BMI (kg/m2) Annual risk of cardiovascular events (%)
PHS
BDT
TPT
HOT
PPP
WHS
POPADAD
JPAD
AAA
53 (9) 0 126
50-78 0 136
58 0 139
62 47 170
64 (8) 58 145
60 56 145
65 45 135
62 72 148
2.4 212 11 24.9 (3) 0.67
2 NA 13 NA 1.54
NA 247 41 27.4 1.53
8 236 16 28.4 1.19
17 236 15 27.6(5) 0.76
55 (7) 100 b120/75, 32%; 120-9/75-84, 32%; 130-9/85-89, 19%; N140/90, 16% 2.6 NA 13 26 (5) 0.26
100 213 31 24 (4) 2.53
100 201 21 29 0.82
3 240 65 NA 0.99
SBP, Systolic blood pressure; BMI, body mass index.
the analysis and recalculating the results. In addition, specific subsets of the studies were analyzed to evaluate the consistency of the effects of aspirin when studies that were restricted to persons with diabetes were excluded,19,21 studies enrolling patients with subclinical atherosclerosis (by a low anklebrachial index [ABI]) were excluded,19,20 and studies that included extended or controlled release aspirin were removed.20,23,24 In addition, the data were analyzed using a fixed-effect model, and the results were compared with the random-effects model. Linear meta-regression analyses on the log-transformed RR with the study as the unit of analysis were performed to evaluate potential effect modifiers (year of study publication, baseline cardiovascular risk as assessed by incidence of events on placebo, mean age of the trial participant, sex, and dose of aspirin). Studies were weighed by the precision of the effect estimate. The potential publication bias was examined by constructing a funnel plot in which sample size was plotted against log RRs for the primary end point available from all studies. Statistical analyses were performed using Review Manager 5.0.23 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark, 2008). P b .05 was judged as statistically significant.
Results Nine prospective randomized trials involving 102,621 participants were identified for inclusion. A total of 710,053 person-years of exposure were recorded: 359,709 in the aspirin group and 350,344 in the placebo or control group. All trials included patients without clinical CVD, which was defined as the absence of a cardiovascular event, or clinical symptoms of CVD including angina or transient ischemic attack. Among the 3 new trials,19-21 2 included only diabetic patients,19,21 and 2 required a low ABI measurement as a marker of subclinical atherosclerosis for inclusion.19,20 Of the 9 trials, 3 included only men,23-25 and 1 included only women.26 Details of the included studies appear in Table I, and characteristics of participants are summarized in Table II.
Dosage of aspirin ranged from 100 mg every other day to 500 mg daily. Two trials used enteric-coated aspirin,20,24 and 1 trial used a longer preparation tablet.23 Follow-up ranged from 4.4 to 10.1 years and was N95% complete in all trials. The weighted mean follow-up time was 6.9 years.
Major cardiovascular events A total of 2,029 MCEs occurred among 52,145 (3.86%) patients allocated to aspirin compared with 2,099 MCEs among 50,476 (4.16%) patients assigned to placebo or control (Figure 1). Pooled results using a random-effects model demonstrated a significant 10% reduction in the risk of MCE (RR 0.90, 95% CI 0.85-0.96, P b .001). In aggregate, the absolute risk reduction was 0.39% (95% CI 0.18%-0.61%) over a mean follow-up of 6.9 years, which corresponds to a number needed to treat of 253 (95% CI 163-568) to prevent a single MCE. Myocardial infarction A total of 993 fatal and nonfatal MI events occurred among 52,145 (1.90%) patients allocated to aspirin compared with 1,075 MI events among 50,476 (2.13%) patients assigned to placebo or control (Figure 2). Pooled results demonstrated a 14% risk reduction in both fatal and nonfatal MI, which failed to reach statistical significance (RR 0.86, 95% CI 0.74-1.00, P = .06). For the end point of nonfatal MI, there was a 16% reduction in events with aspirin versus placebo or control; however, the results did not reach statistical significance (RR 0.84, 95% CI 0.70-1.01, P = .06). Stroke A total of 741 fatal and nonfatal strokes occurred among 52,145 (1.42%) patients allocated to aspirin compared with 746 strokes among 50,476 (1.48%) patients assigned to placebo or control (Figure 3). Pooled results demonstrated a nonsignificant 6% reduction in the risk of stroke (RR 0.94, 95% CI 0.84-1.06, P = .31). Eight of the studies
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Figure 1
Effect of aspirin on the prevention of MCE. Major cardiovascular events defined as the composite of nonfatal MI, nonfatal stroke, or cardiovascular death.
Figure 2
Effect of aspirin on the prevention of MI (fatal and nonfatal).
provided data on type of stroke. For the end point of nonfatal stroke, there was a nonsignificant 8% reduction in events with aspirin versus placebo or control (RR 0.92, 95% CI 0.80-1.06, P = .26). To further understand the benefit versus risk, the relationship of aspirin on ischemic and hemorrhagic stroke was explored independently (Figure 3). For the end point of ischemic stroke, there was a nonsignificant 13% reduction in events with aspirin versus placebo or control (RR 0.87, 95% CI 0.73-1.02, P = .09). For the end point of hemorrhagic stroke, there was a significant 35% increase in events with aspirin versus placebo or control (RR 1.35, 95% CI 1.01-1.81, P = .04). The absolute risk increase was 0.06% (95% CI 0.003-0.126) over a mean follow-up of 6.9 years, corresponding to a number needed to harm of 1,560 (95% CI 794-33,333) to cause 1 hemorrhagic stroke.
Death A total of 1,962 deaths occurred among 52,145 (3.76%) patients allocated to aspirin compared with
1,933 among 50,476 (3.83%) patients assigned to placebo or control (Figure 4). Pooled results demonstrated a nonsignificant reduction of 6% in the risk of death (RR 0.94, 95% CI 0.89-1.00, P = .07). For the end point of cardiovascular death, there was no reduction in events with aspirin versus placebo or control (RR 0.99, 95% CI 0.85-1.14, P = .86).
Major bleeding A total of 458 major bleeding events occurred among 52,145 (0.88%) patients allocated to aspirin compared with 278 major bleeding events among 50,421 (0.55%) patients assigned to placebo or control (Figure 5). Pooled results demonstrated a significant 62% increase in the risk of major bleeding (RR 1.62, 95% CI 1.31-2.00, P b .001). In aggregate, the absolute risk was 0.38% (95% CI 0.21%-0.55%) over a mean follow-up of 6.9 years, which corresponds to a number needed to harm of 261 (95% CI 182-476) to cause a single major bleeding event over 6.9 years. For the end point of gastrointestinal hemorrhage, there was a significant 29% increase
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Figure 3
A
B
C
Effect of aspirin on the prevention of stroke (fatal and nonfatal), ischemic stroke, and hemorrhagic stroke.
in events with aspirin versus placebo or control (RR 1.29, 95% CI 1.24-1.47, P b .001).
aspirin on MCE or major bleeding (see Supplemental Figures 6 and 7 in the online Appendix).
Meta-regression Linear meta-regression models were used to assess the impact of study-level covariates on the risk of MCE and major bleeding. There was no relationship between any of the covariates examined (year of study publication as a surrogate for any changes in background cardiovascular preventive therapies, baseline cardiovascular risk as assessed by incidence of events on placebo, mean age of the trial participant, sex of the trial participant, and dose of aspirin) and the effect of
Aspirin dose and formulation Although aspirin dose ranged from 100 mg every other day to 500 mg/d, 7 of the 9 trials used a dose between 75 and 162.5 mg/d. There did not appear to be any relationship between aspirin dose and the effect of aspirin on MCE or major bleeding (Supplemental Figures 6E and 7E in the online Appendix). Three trials used a different aspirin formulation than regular aspirin. The BDT and AAA trials used an enteric-coated aspirin formulation, whereas the TPT trial used a controlled
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Figure 4
A
B
Effect of aspirin on the prevention of all-cause death and cardiovascular death.
release formulation. When analyses were repeated after excluding these trials, the association between aspirin and the primary outcome of MCE yielded an effect size (RR 0.89, 95% CI 0.83-0.95) similar in magnitude and direction to the overall results.
Sensitivity analysis There was no difference in results between the fixedeffect (RR 0.90) or the random-effect model (RR 0.90) for the primary outcome of MCE. The RR varied between 0.891 and 0.893 when each study was systematically removed from the model. The POPADAD19 and JPAD21 trials exclusively enrolled patients with diabetes, and both demonstrated no significant effect on the composite of cardiovascular events. Because aspirin may not be beneficial in patients with diabetes,27 the primary analysis was repeated after excluding these 2 trials. The association between aspirin and the primary outcome of MCE yielded an effect size (1,868 events among 50,245 patients taking aspirin [3.7%] vs 1,924 events among 48,561 control patients [4.0%]; RR 0.90, 95% CI 0.84-0.96) identical to the overall results. The AAA20 and POPADAD19 trials exclusively enrolled patients with subclinical atherosclerosis determined by a
low ABI. Because aspirin may not be beneficial in patients with PAD,28 the primary analysis was repeated after excluding these 2 trials. A similar effect of aspirin was observed (RR 0.89, 95% CI 0.83-0.95) relative to the overall result.
Discussion The current meta-analysis included 9 prevention trials in N100,000 subjects without clinical evidence of CVD treated with aspirin versus placebo or control for the prevention of ischemic cardiovascular events. The pooled results found a statistically significant 10% relative reduction in the primary end point of MCE and a statistically significant 62% relative increase in major bleeding events. The absolute benefit versus risk demonstrated that, in 1,000 patients treated for 5 years, there were approximately 3 ischemic events avoided that was associated with an excess of 3 major bleeds resulting in no net benefit to risk for aspirin in this population. These results were consistent across a number of subgroups suggesting that a more targeted approach to maximize benefit and minimize risk could not be identified. The year of publication of the trials ranged from 1988 to 2010 and spanned over a decade during which there
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Figure 5
Effect of aspirin on major bleeding.
were major improvements in the medical prevention and treatment of CVD,29,30 yet publication year did not have either a positive or negative impact on the overall estimate of the benefit or risk of aspirin (Supplemental Figures 6A and 7A in the online Appendix). The risk of CVD events in the placebo/control groups was also quite broad, ranging from 0.25% per year in the Women's Health Study to 2.7% in the POPADAD trial (expressed over a decade per the Framingham coronary heart disease risk score this baseline risk ranges from 2.5% to 27%). Yet, using this baseline risk assessment or components of that risk including populations enriched with diabetes did not impact the estimate of benefit or risk of aspirin (Supplemental Figures 6B and 7B in the online Appendix). Cardiovascular risk estimates can also be significantly influenced by measures of subclinical atherosclerosis such as the ABI or carotid intima-media thickness.31-33 However, in the most recent AAA trial20 where a low ABI was used as an inclusion criterion or in the POPADAD trial19 where a reduced ABI and diabetes were inclusion criteria, the trials were not just statistically negative, but the point estimates of benefit in both were near 1.00. Finally, although the dose of aspirin ranged from 100 mg every other day (50 mg/d)26 to 500 mg/d,24 the dose of aspirin did not impact the results (Supplemental Figures 6E and 7E in the online Appendix). Taken together, aspirin retains a modest yet statistically significant benefit on decreasing nonfatal cardiovascular events. These benefits are offset by a consistent signal of major bleeding risk including hemorrhagic stroke. These new results need to be considered by clinicians making difficult decisions about the value of primary preventive pharmacotherapies (relative to drugs with unequivocal benefit such as statins and blood pressure medications). The goal of the current study was to perform a comprehensive meta-analysis of all randomized trials with aspirin as preventive therapy in patients without established or symptomatic CVD. Previous meta-ana-
lyses17,18,34 have been restricted to older trials with lower risk populations and did not include all contemporary randomized trials. Twenty years ago, 2 landmark trials24,25 evaluated the effect of aspirin in primary prevention. Neither the BDT24 nor the PHS25 demonstrated a benefit for aspirin in the reduction of their primary end point (Table III). However, the PHS25 was able to demonstrate a decrease in the secondary end point of fatal and nonfatal MI by 44%, leading to the widespread recommendations and use of aspirin in primary prevention. Since then, there have been 4 randomized trials22,23,26,35 of aspirin in primary prevention and 3 more recent randomized trials19-21 in patients with diabetes and/or subclinical atherosclerosis (defined by reduced ABI). None of these 7 trials demonstrated a beneficial effect of aspirin on their prespecified primary end point (Table III).16 If one were to evaluate the traditional composite end point of nonfatal MI, nonfatal stroke, or cardiovascular death, only 1 of the 9 trials was associated with a statistically significant reduction. Thus, the benefit observed in our meta-analysis with aspirin is only seen after combining all the data in aggregate. Bleeding risk is consistently increased with aspirin therapy across the trials. Despite different definitions of major bleeding among the trials, there was a strong signal of increased risk. Of the 9 trials, 4 found a statistically significant increase in major bleeding, and in pooled analysis, the risk was increased by 62%. Hemorrhagic stroke is a less common but clinically important end point because of its significant morbidity. Incidence of hemorrhagic stroke increased by approximately 0.1% (1 per 1,000 patients treated); however, in the pooled analysis, aspirin was associated with a significant 36% increase in the risk of hemorrhagic stroke. Because aspirin was associated with a significant reduction in cardiovascular events but a proportional increase in bleeding complications, it is essential to understand the absolute benefit versus risk. Three MCEs were prevented for every 1,000 patients treated with
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Table III. Primary efficacy end point for each trial Study, year PHS, 1989 BDT, 1988 TPT, 1998
HOT, 1998 PPP, 2001 WHS, 2005 POPAD, 2008 JPAD, 2008 AAA, 2010
Primary efficacy end point Cardiovascular mortality CV death, nonfatal MI and stroke or TIA All ischemic heart disease (coronary death and fatal and nonfatal MI) CV death, nonfatal MI, stroke CV death, MI, stroke CV death, nonfatal MI, stroke CV death, nonfatal MI or stroke, or amputation for critical limb ischemia CV death, nonfatal MI, stroke, UA, PVD, new angina CV death, MI, stroke, revascularization
HR (95% CI)
P
RR 0.96 (0.60-1.54)
.87 NS
20% (1-35) reduction
.04⁎
RR 0∙91 (0∙79-1∙04) 0∙71 (0∙48-1∙04) 0.91 (0.80-1.03) 0.98 (0.76-1.26)
.17†
0.80 (0.58-1.10)
.16
1.03 (0.84-1.27)
NS
NS .13 .86
NS, Not significant. ⁎ After including silent MI, the reduction was no longer significant (P = .07). † After excluding silent MI, the reduction became statistically significant (P = .03).
aspirin over a period of 5 years, at the cost of inducing 3 major bleeding events. Intracranial hemorrhage was statistically significantly higher in the aspirin group, but the number needed to harm was 1,560 (b1 in 1,000 patients treated). There are several potential explanations for the lowerthan-expected proportional benefit observed with aspirin in this trial data set. Trials included in this analysis spanned several decades, and during this period, there has been considerable improvement of outcomes with the adoption of statins and angiotensin-converting enzyme inhibitors.29,36 Although no significant heterogeneity was observed between proportional reduction in MCE and time of publication, 4 of 5 trials published before 2002 had a proportional reduction of N10%, whereas only 1 of 4 trials published after 2003 had such a benefit. Moreover, the larger proportional benefit (N15%) observed in trials of aspirin in patients with clinical CVD occurred in trials N15 years ago. Consistent with this hypothesis, the CHARISMA trial (published in 2006) tested clopidogrel plus aspirin versus aspirin alone in patients with and without clinical CVD and demonstrated a nonsignificant increased risk of MCE with combination antiplatelet therapy in the primary prevention subgroup of the trial.37 Thus, if aspirin alone is of uncertain benefit in these subjects, dual antiplatelet therapy may be even more suspect. An additional explanation on the lack of a net benefit over risk may be that concomitant therapies have minor antiplatelet affects that may attenuate any potential benefit of aspirin. In fact, statins,38,39 fish oil,40 angiotensin-converting enzyme inhibitors,41,42
fibrates,39,43 phosphodiesterase inhibitors such as cilostazol,44 and selective serotonin reuptake inhibitors45 have all been shown to reduce platelet activity. Unfortunately, few of the aspirin trials reported concomitant medications and what, if any, modifying effect these medications may have on the effect of aspirin. Although some have suggested an attenuated effect of aspirin in certain high-risk groups, such as persons with diabetes 27 and peripheral artery disease,28 there was no difference in the results when trials that exclusively enrolled those populations were excluded. Finally, dose and aspirin formulation differed across the trials, which may have contributed to the lower proportional benefit. However, there was no difference in the effect of aspirin when adjusting for aspirin dose or after excluding trials that used a longer acting or enteric-coated formulation.
Limitations There are several limitations to this study. Some imprecision exists in the frequency of events because the protocols for data collection and definitions of efficacy and safety events varied among the studies. However, all of the trials allowed for the assessment of a common MCE outcome that served as a primary end point for analysis. For the safety end point, definitions of major bleeding varied across the trials, and these variations made it difficult to determine accurate measure of bleeding and approximate risk. Therefore, both gastrointestinal hemorrhage and hemorrhagic stroke were used as complementary end points to help evaluate risk. The current meta-analysis was not performed on individual patient data because complete individual data were not available, and therefore, comprehensive assessment within different higher-risk groups was not able to be performed. Nonetheless, the analyses were able to adjust for the incidence of adverse events in the placebo group (a surrogate for baseline risk) in each individual trial, which had no effect on the overall results. A proportion of patients included in this metaanalysis had documented subclinical atherosclerosis, as detected by a lower ABI. Although some would consider this a limitation because of the higher-risk cohort included, no change in the effect of aspirin was observed after exclusion of these patients, and the results were nearly identical.
Conclusions This meta-analysis of N100,000 randomized patients (N700,000 person-year follow-up) comparing aspirin versus placebo or control demonstrated that aspirin decreased MCE by approximately 10% among patients without clinical CVD. Major bleeding, however, occurred more frequently with aspirin therapy. The decision to use
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aspirin for the prevention of a first MI or stroke remains a complex issue. Weighing the overall benefit and risk requires careful consideration by the physician and patient before initiating aspirin for preventive therapy in patients without clinical CVD.
Acknowledgements We thank Dr Sanjay Kaul for his insightful comments and editorial assistance.
Disclosures Dr Jeffrey Berger reports receiving research support from Astra Zaneca and has received honoraria for advisory board participation from Astra Zaneca. Dr William Hiatt reports receiving research support from Astra Zaneca. Conflicts of interest: none. Drs Berger and Hiatt had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
References 1. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ (Clin Res ed) 2002;324:71-86. 2. Berger JS, Brown DL, Becker RC. Low-dose aspirin in patients with stable cardiovascular disease: a meta-analysis. Am J Med 2008;121: 43-9. 3. Patrono C, Baigent C, Hirsh J, et al. Antiplatelet drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008;133:199S-233S. 4. Smith Jr SC, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006;113:2363-72. 5. Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 writing group to review new evidence and update the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction, writing on behalf of the 2004 writing committee. Circulation 2008;117:296-329. 6. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 2002 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007;116:e148-304.
Berger et al 123
7. Juul-Moller S, Edvardsson N, Jahnmatz B, et al. Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. The Swedish Angina Pectoris Aspirin Trial (SAPAT) group. Lancet 1992;340:1421-5. 8. The SALT Collaborative Group. Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991;338:1345-9. 9. Farrell B, Godwin J, Richards S, et al. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991;54:1044-54. 10. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349-60. 11. Lewis Jr HD, Davis JW, Archibald DG, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med 1983;309:396-403. 12. Wallentin LC. Aspirin (75 mg/day) after an episode of unstable coronary artery disease: long-term effects on the risk for myocardial infarction, occurrence of severe angina and the need for revascularization. Research Group on Instability in Coronary Artery Disease in Southeast Sweden. J Am Coll Cardiol 1991;18:1587-93. 13. Chen ZM, Sandercock P, Pan HC, et al. Indications for early aspirin use in acute ischemic stroke : a combined analysis of 40 000 randomized patients from the Chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke 2000;31:1240-9. 14. Krantz MJ, Berger JS, Hiatt WR. An aspirin a day: are we barking up the wrong willow tree? Pharmacotherapy 2010;30:115-8. 15. Berger JS. Aspirin as preventive therapy in patients with asymptomatic vascular disease. JAMA 2010;303:880-2. 16. Cardiovascular and Renal Drugs Advisory Committee. Available at: http://www.fda.gov/ohrms/DOCKETS/ac/03/questions/4012Q1_Final.pdf. Last accessed on March 13, 2010. 17. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative metaanalysis of individual participant data from randomised trials. Lancet 2009;373:1849-60. 18. Berger JS, Roncaglioni MC, Avanzini F, et al. Aspirin for the primary prevention of cardiovascular events in women and men: a sexspecific meta-analysis of randomized controlled trials. JAMA 2006; 295:306-13. 19. Belch J, MacCuish A, Campbell I, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ (Clin Res ed) 2008;337:a1840. 20. Fowkes FG, Price JF, Stewart MCW, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index. JAMA 2010;303:841-8. 21. Ogawa H, Nakayama M, Morimoto T, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 2008;300:2134-41. 22. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998;351: 1755-62. 23. The Medical Research Council's General Practice Research Framework. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the
American Heart Journal July 2011
124 Berger et al
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998;351:233-41. Peto R, Gray R, Collins R, et al. Randomised trial of prophylactic daily aspirin in British male doctors. Br Med J (Clin Res ed) 1988;296: 313-6. Final report on the aspirin component of the ongoing Physicians' Health Study. Steering Committee of the Physicians' Health Study Research Group. N Engl J Med 1989;321:129-35. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352:1293-304. De Berardis G, Sacco M, Strippoli GF, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: metaanalysis of randomised controlled trials. BMJ (Clin Res ed 2009;339: b4531. Berger JS, Krantz MJ, Kittelson JM, et al. Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials. JAMA 2009;301:1909-19. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N Engl J Med 2007;356: 2388-98. Hunink MG, Goldman L, Tosteson AN, et al. The recent decline in mortality from coronary heart disease, 1980-1990. The effect of secular trends in risk factors and treatment. JAMA 1997;277: 535-42. Berger JS, Jordan CO, Lloyd-Jones D, et al. Screening for cardiovascular risk in asymptomatic patients. J Am Coll Cardiol 2010;55:1169-77. Fowkes FG, Murray GD, Butcher I, et al. Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis. JAMA 2008;300:197-208. O'Leary DH, Polak JF, Kronmal RA, et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999;340:14-22. Eidelman RS, Hebert PR, Weisman SM, et al. An update on aspirin in the primary prevention of cardiovascular disease. Arch Intern Med 2003;163:2006-10. de Gaetano G. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collab-
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
orative Group of the Primary Prevention Project. Lancet 2001;357: 89-95. Cooper R, Cutler J, Desvigne-Nickens P, et al. Trends and disparities in coronary heart disease, stroke, and other cardiovascular diseases in the United States: findings of the national conference on cardiovascular disease prevention. Circulation 2000; 102:3137-47. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-17. Haramaki N, Ikeda H, Takenaka K, et al. Fluvastatin alters platelet aggregability in patients with hypercholesterolemia: possible improvement of intraplatelet redox imbalance via HMG-CoA reductase. Arterioscler Thromb Vasc Biol 2007;27:1471-7. Damas JK, Puccetti L, Aukrust P. Early anti-thrombotic and antiinflammatory actions of statins and fibrates—time for adjuvant therapy in acute coronary syndromes? Thromb Haemost 2005;94: 1-3. Lee JH, O'Keefe JH, Lavie CJ, et al. Omega-3 fatty acids: cardiovascular benefits, sources and sustainability. Nat Rev Cardiol 2009;6:753-8. Okrucka A, Pechan J, Kratochvilova H. Effects of the angiotensin-converting enzyme (ACE) inhibitor perindopril on endothelial and platelet functions in essential hypertension. Platelets 1998;9: 63-7. Moser L, Callahan KS, Cheung AK, et al. ACE inhibitor effects on platelet function in stages I-II hypertension. J Cardiovasc Pharmacol 1997;30:461-7. Barter PJ, Rye KA. Cardioprotective properties of fibrates: which fibrate, which patients, what mechanism? Circulation 2006;113: 1553-5. Goto S. Cilostazol: potential mechanism of action for antithrombotic effects accompanied by a low rate of bleeding. Atheroscler Suppl 2005;6:3-11. Serebruany VL, Glassman AH, Malinin AI, et al. Platelet/ endothelial biomarkers in depressed patients treated with the selective serotonin reuptake inhibitor sertraline after acute coronary events: the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART) Platelet Substudy. Circulation 2003;108:939-44.
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Appendix. Supplementary data Supplemental Figure 6
Association between the RR of aspirin versus placebo or control on the prevention of MCE and year of study publication (a surrogate for changes in background cardiovascular preventive therapies) (A), baseline cardiovascular risk (as assessed by the annual risk of MCE on placebo) (B), mean age of trial participant (C), percent female of trial enrollment (D), and dose of aspirin used (E). Major cardiovascular events defined as the composite of nonfatal MI, nonfatal stroke, or cardiovascular death. CV, Cardiovascular.
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Supplemental Figure 7
Association between the RR of aspirin versus placebo or control on the risk of major bleeding and year of study publication (a surrogate for changes in background cardiovascular preventive therapies) (A), baseline cardiovascular risk (as assessed by the annual risk of MCE on placebo) (B), mean age of trial participant (C), percent female of trial enrollment (D), and dose of aspirin used (E). Major cardiovascular events defined as the composite of nonfatal MI, nonfatal stroke, or cardiovascular death. CV, Cardiovascular.