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Clinical Review | Clinician's Corner

Aspirin for the Prevention of Cardiovascular Events in Patients With Peripheral Artery Disease:  A Meta-analysis of Randomized Trials FREE

Jeffrey S. Berger, MD, MS; Mori J. Krantz, MD; John M. Kittelson, PhD; William R. Hiatt, MD
[+] Author Affiliations

Author Affiliations: Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania, Philadelphia (Dr Berger); Duke Clinical Research Institute, Durham, North Carolina (Dr Berger); Department of Medicine, Section of Vascular Medicine, Divisions of Geriatrics (Dr Hiatt) and Cardiology (Drs Krantz and Hiatt), University of Colorado Denver School of Medicine, Denver; Department of Biostatistics and Informatics, Colorado School of Public Health (Dr Kittelson); and Colorado Prevention Center (Drs Krantz and Hiatt), Denver.


JAMA. 2009;301(18):1909-1919. doi:10.1001/jama.2009.623.
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Published online

Context Randomized trials have shown that aspirin decreases the risk of cardiovascular events in patients with symptomatic coronary and cerebrovascular disease. Despite guideline recommendations for secondary prevention in peripheral artery disease (PAD), the effect of aspirin in this population is not well established.

Objective To investigate the effect of aspirin on cardiovascular event rates in patients with PAD.

Data Sources and Study Selection MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, Science Citation Index (1966 to December 2008), and unpublished studies from the supplemental index of the Antithrombotic Trialists' Collaboration. Eligible studies were prospective, randomized controlled trials of aspirin therapy, with or without dipyridamole that reported cardiovascular event rates. Eighteen trials involving 5269 individuals were identified.

Data Extraction Studies were reviewed to determine the number of participants, mean follow-up, and the primary end point of cardiovascular events (nonfatal myocardial infarction [MI], nonfatal stroke, and cardiovascular death). Data on the secondary end points of all-cause mortality, major bleeding, and the individual components of the primary outcome measure were also abstracted. For the primary end point, the analysis had 88% power to detect a 25% reduction and 70% power to detect a 20% reduction in cardiovascular events in the aspirin group compared with the control group.

Data Synthesis Among 5269 participants, cardiovascular events were experienced by 251 (8.9%) of 2823 patients taking aspirin (alone or with dipyridamole) and by 269 (11.0%) of 2446 in the control group (pooled relative risk [RR], 0.88; 95% confidence interval [CI], 0.76-1.04). Aspirin therapy was associated with a reduction in the secondary outcome of nonfatal stroke (52 of 2823 vs 76 of 2446; RR, 0.66; 95% CI, 0.47-0.94) but was not associated with significant reductions in all-cause or cardiovascular mortality, MI, or major bleeding. In the subset of 3019 participants taking aspirin alone vs control, aspirin was associated with a nonsignificant reduction in cardiovascular events (125 of 1516 vs 144 of 1503; RR, 0.75; 95% CI, 0.48-1.18), a significant reduction in nonfatal stroke (32 of 1516 vs 51 of 1503; RR, 0.64; 95% CI, 0.42-0.99), but no statistically significant reductions in all-cause or cardiovascular mortality, MI, or major bleeding.

Conclusions In patients with PAD, treatment with aspirin alone or with dipyridamole resulted in a statistically nonsignificant decrease in the primary end point of cardiovascular events and a significant reduction in nonfatal stroke. Results for the primary end point may reflect limited statistical power. Additional randomized controlled trials of aspirin therapy are needed to establish the net benefit and bleeding risks in PAD.

Figures in this Article

Quiz Ref IDAlthough aspirin is effective in the prevention of cardiovascular events in patients with symptomatic coronary heart disease and cerebrovascular disease,13 its effect in patients with peripheral artery disease (PAD) is uncertain.4,5 In the largest investigation to date, the Antithrombotic Trialists' Collaboration (ATC) meta-analysis of 135 000 high-risk patients from 287 clinical trials demonstrated a reduction in myocardial infarction (MI), stroke, and death with antiplatelet therapy in all patients with symptomatic cardiovascular disease.6,7 In the subset of 42 PAD trials, which included 9214 patients and studied multiple antiplatelet agents compared with placebo, antiplatelet therapy was associated with a significant 23% reduction in cardiovascular events.7 However, nearly two-thirds of the PAD trials evaluated antiplatelet agents other than aspirin. It is possible that the overall benefit of antiplatelet therapy in PAD may have been driven by therapeutic regimens other than aspirin. The uncertainty about the benefit of aspirin in PAD was further raised by a meta-analysis of aspirin in PAD limited to studies in the ATC8 meta-analysis and by a recent large randomized controlled trial of aspirin therapy involving patients with diabetes and asymptomatic PAD that demonstrated no benefit of aspirin for reducing cardiovascular events.9

Despite the paucity of data supporting aspirin therapy for patients with PAD, major US and international guidelines cite the ATC meta-analysis as evidence to prescribe aspirin as first-line therapy to patients with PAD.10,11 However, the US Food and Drug Administration concluded that there was insufficient evidence to support a labeling indication for aspirin to treat PAD.12 In addition, the recent Transatlantic InterSociety Consensus (TASC) II international guidelines for PAD gave aspirin a level C recommendation for patients with isolated PAD (without clinical evidence of coronary or cerebrovascular disease).13 To assess the benefit of aspirin in treating PAD, the current meta-analysis evaluated all available evidence from prospective, randomized controlled trials of aspirin alone or in combination with other antiplatelet drugs. This meta-analysis tested the null hypothesis that aspirin was not different from placebo or control in reducing the risk of the combined primary end point of nonfatal MI, nonfatal stroke, and cardiovascular death.

Literature Search

A comprehensive search was performed to identify randomized controlled trials in MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Science Citation Index (SCI), Web of Science, and Social Science Citation Index (SSCI) in any language between 1966 and December 31, 2008, using the search terms aspirin, peripheral artery disease, peripheral arterial occlusive diseases, claudication, and randomized controlled trials, as well as combinations of these terms. Experts were questioned, bibliographies of retrieved articles were searched for other relevant studies, and major scientific meetings were monitored for the results of trials still under way at the time of the MEDLINE search. Data concerning study design, baseline patient characteristics, treatment, follow-up, and results were extracted from these reports. Additional data, when necessary, were derived from prior reports. In several studies, the primary outcome data were not part of the original publications, and therefore these data were obtained from the supplemental index of the Antithrombotic Trialists' Collaboration meta-analysis.14

Study Selection

Two investigators ( J.S.B., M.J.K.) independently evaluated studies for inclusion. Inclusion criteria were (1) prospective, randomized, controlled, studies either open-label or blinded; (2) assignment of PAD participants to aspirin treatment or a placebo or control group; and (3) available data on all-cause mortality, cardiovascular death, MI, stroke, and major bleeding. Trials with no events in any of the study groups were excluded. Any disagreements were resolved by discussion and consensus. The search was also cross-referenced to include aspirin trials involving patients with PAD noted in the most recent Antithrombotic Trialists' Collaboration meta-analysis.7 A total of 165 potentially eligible studies were identified and 107 were excluded because they were not randomized controlled trials (eg, review articles, editorials, letters to the editor, case reports, case-control studies, and meta-analyses). Of the randomized trials, 26 evaluated the effect of antiplatelet drugs other than aspirin and 14 were excluded because the population was not composed entirely of participants with PAD or there was no placebo or control group (Figure 1). Study quality was assessed for each trial using the Jadad score, a 5-point study quality assessment instrument.15

Place holder to copy figure label and caption
Figure 1. Flow Diagram of the Literature Search and Trial Selection Process
Graphic Jump Location

PAD indicates peripheral artery disease.

Outcome Measures

The primary outcome was the relative risk (RR) reduction of aspirin therapy on the composite end point of nonfatal MI, nonfatal stroke, and cardiovascular death in the population of patients who received any aspirin therapy (with or without dipyridamole). Secondary outcomes were all-cause mortality and each component of the primary end point. The primary safety outcome was the occurrence of major bleeding as defined by each study.

Statistical Analysis

Data were analyzed using the intention-to-treat results from the included studies. Patient characteristics, aspirin dosages, and length of follow-up differed across studies, so the RR for each study was assumed to have a random offset from the population mean RR (ie, a random-effects model).16 Given the limited number of studies, trials were included even if 1 of the treatment groups did not have any cardiovascular events. In these cases a fixed value (0.5) was added to the patient groups with and without events to allow calculation of an RR. This adjustment tends to bias results toward the null.17 Secondary sensitivity analyses showed that results remained the same even if these studies were excluded.

The Cochran Q statistic and I2 statistic were calculated to assess the degree of heterogeneity among the trials.18 The Q statistic did not indicate statistically significant heterogeneity for any end point. The I2 statistic showed mild heterogeneity (<30%) for all end points except nonfatal MI compared between aspirin monotherapy and placebo or control, which showed moderate heterogeneity (I2 = 46.2%). Therefore, although the studies had different characteristics, pooled estimates of the RR were judged reasonable. The primary result was presented as the Mantel-Haenszel pooled RR and 95% confidence interval (CI), calculated from the random effects model.

Subgroup analyses were performed to evaluate the effect of aspirin monotherapy vs placebo or control, aspirin therapy at currently recommended doses (75-325 mg/d); trials with a follow-up of more than a year; trials designed to assess cardiovascular events; trials that exclusively enrolled patients with both diabetes and PAD; and quality of the randomized trial (Jadad score ≥4). Statistical tests of the differences between the risk reductions in 2 subgroups were based on the standard error of the estimated pooled RRs calculated on each subgroup separately. Sensitivity analyses were conducted to further explore the robustness of the results. This was done to identify any study that may have exerted a disproportionate influence on the summary treatment effect by deleting 1 study at a time and repeating the analyses. Results obtained with a fixed-effects model were also compared with those obtained with a random-effects model. Funnel plots of the effect size vs the standard error of the log-transformed effect were generated for each end point to assess for publication bias.19

With 5000 patients, this meta-analysis had approximately 88% power to detect a 25% difference (from 10% to 7.5%) and 70% power to detect a 20% difference (from 10% to 8%) in the RR of cardiovascular death, MI, or stroke in the aspirin group vs placebo or control groups. The type 1 error rate was set at α = .05, and all tests were 2-sided.

All statistical analyses were performed using Review Manager version 5.0.17 (Nordic Cochrane Centre, Copenhagen, Denmark). Statistical tests were judged statistically significant if the 2-sided P value was less than .05.

Eighteen prospective randomized trials involving 5269 participants were identified for inclusion.9,2035 Seven trials tested aspirin monotherapy vs placebo or control, 7 trials examined combined aspirin and dipyridamole vs placebo or control, and 4 trials had multiple arms (aspirin monotherapy, aspirin plus dipyridamole, and placebo). Of the 5269 participants, 2823 were randomized to aspirin therapy (of whom 1516 received aspirin monotherapy) and 2446 were randomized to placebo or control.

Details of the included studies are summarized in the Table. Duration of follow-up ranged from 10 days to 6.7 years. Aspirin doses ranged from 100 mg/d to 1500 mg/d for aspirin monotherapy and from 25 mg of aspirin and 75 mg of dipyridamole to 325 mg of aspirin and 75 mg of dipyridamole 3 times a day for each combination. Participants with PAD included patients with claudication, those undergoing percutaneous intervention or bypass surgery, and asymptomatic patients with an ankle brachial index of 0.99 or less. Two trials exclusively enrolled patients with both diabetes and PAD.9,22

Table Graphic Jump LocationTable. Design of Trials Included in the Meta-analysis

Figure 2 shows the effect of any aspirin vs placebo or control on the primary end point of combined cardiovascular events. A total of 251 (8.9%) cardiovascular events occurred among 2823 patients receiving any aspirin therapy compared with 269 (11.0%) events among 2446 control patients. The pooled RR showed a 12% reduction in cardiovascular event rates, which was not statistically significant (RR, 0.88; 95% CI, 0.76-1.04). Results for associations of aspirin therapy with the individual components of the primary end points revealed that the risk of nonfatal stroke was significantly lower in the aspirin group than in the placebo (52 events among 2823 patients [1.8%]) or in the control group (76 events among 2446 patients [3.1%]; RR, 0.66, 95% CI, 0.47-0.94; Figure 3). No significant differences were noted for any other secondary end point (Figure 4). Bleeding risk was not significantly increased (51 events among 2823 patients [1.8%] vs 44 events among 2446 patients [1.8%]; RR, 0.99; 95% CI, 0.66-1.50; Figure 4). However, bleeding was not formally adjudicated or reported in most studies, which limits the ability to establish the association of aspirin with major bleeding among participants with PAD.

Place holder to copy figure label and caption
Figure 2. Effect of Any Aspirin on the Prevention of Composite Cardiovascular End Points
Graphic Jump Location

Major cardiovascular events are defined as the composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Zero weight denotes a study in which there were no occurrences of the indicated event. A blank row denotes a study in which the indicated event was not measured. aPooled relative risks (RRs) are from a random-effects model. CI indicates confidence interval.

Place holder to copy figure label and caption
Figure 3. Effect of Any Aspirin on the Prevention of Nonfatal Myocardial Infarction, Nonfatal Stroke, and Cardiovascular Death
Graphic Jump Location

Zero weight denotes a study in which there were no occurrences of the indicated event. A blank row denotes a study in which the indicated event was not measured. aPooled relative risks (RRs) are from a random-effects model. CI indicates confidence interval.

Place holder to copy figure label and caption
Figure 4. Effect of Any Aspirin on the Prevention of Any Death and Major Bleed
Graphic Jump Location

Zero weight denotes a study in which there were no occurrences of the indicated event. A blank row denotes a study in which the indicated event was not measured. aPooled relative risks (RRs) are from a random-effects model. CI indicates confidence interval.

Aspirin Monotherapy

The “Composite cardiovascular end points” panel in Figure 5 shows the effect of aspirin monotherapy on the primary end point. A total of 125 cardiovascular events occurred among 1516 patients (8.2%) receiving aspirin monotherapy compared with 144 events among 1503 patients (9.6%) in the placebo or control groups (RR, 0.75; 95% CI, 0.48-1.18). Aspirin monotherapy was associated with a significant reduction in the risk of nonfatal stroke (32 events among 1516 patients [2.1%] vs 51 events among 1503 patients [3.4%]; RR, 0.64; 95% CI, 0.42-0.99). No significant differences were identified for associations of aspirin monotherapy with other secondary outcomes (Figure 5).

Place holder to copy figure label and caption
Figure 5. Effect of Aspirin Monotherapy on the Prevention of Adverse Outcomes
Graphic Jump Location

Major cardiovascular events defined as the composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Zero weight denotes a study in which there were no occurrences of the indicated event. A blank row denotes a study in which the indicated event was not measured. aPooled relative risks (RRs) are from a random-effects model. CI indicates confidence interval.

Variation by Aspirin Dose

Two of the trials comparing aspirin monotherapy with placebo used low-dose aspirin (100 mg/d),9,21 These trials reported 112 cardiovascular events among 823 participants taking low-dose aspirin and 127 events among 819 patients assigned to the placebo group (13.6% vs 15.5%; RR, 0.64; 95% CI, 0.25-1.68). Although this benefit of low-dose aspirin was not statistically significant, the population studied was quite small and the 95% CI was wide, potentially limiting detection of important cardioprotective effects.

Sensitivity Analyses

The Prevention of Progression of Arterial Disease and Diabetes (POPADAD)9 and VA-Cooperative22 trials exclusively enrolled patients with diabetes and PAD, and both demonstrated RRs on composite cardiovascular end points very close to 1.00 (Figure 2). Although the difference in risk reduction between these studies and the others was not statistically significant, a potential for differential effects in populations with or without diabetes cannot be ruled out. Importantly, these 2 studies contribute about 60% of the data for the analysis of the primary outcome measure; thus, the results should be interpreted in the context of an overall population with a high prevalence of diabetes. The POPADAD trial9 had the largest sample size and longest duration of follow-up. When analyses were repeated after excluding the POPADAD trial, the association between aspirin and the primary outcome of cardiovascular events yielded an effect size (146 events among 2185 patients taking aspirin [6.7%] vs 161 events among 1808 control patients [8.9%]; RR, 0.83; 95% CI, 0.67-1.02) similar in magnitude and direction to the overall results.

The primary findings of this meta-analysis did not differ in trials with follow-up periods of greater than 1 year9,21,22,30,3235 (221 events among 1727 patients [12.8%] vs 241 events among 1533 patients [15.7%]; RR, 0.89; 95% CI, 0.76-1.05) or in trials specifically designed to assess cardiovascular events9,21,22 (148 events among 933 patients [15.9%] vs 167 events among 940 [17.8%]; RR, 0.92; 95% CI, 0.76-1.13). Similarly the primary results were unchanged if the trials with no events in 1 arm were excluded2428 (243 events among 2222 patients [10.9%] vs 260 events among 2018 patients [12.9%]; RR, 0.88; 95% CI, 0.75-1.04) or if a fixed-effects inverse-variance analysis was used (RR, 0.88; 95% CI, 0.76-1.04). In the 6 trials that had a Jadad score of 4 or higher,9,20,21,25,28,30 the primary results were similar (124 events among 1245 patients [10.0%] vs 138 events among 1112 patients [12.4%]; RR, 0.78; 95% CI, 0.53-1.14).

Funnel plots of the effect size vs the standard error of the log-transformed results were performed by plotting study precision (1 per standard error) against the prevention of cardiovascular events (primary end point). No skewed distribution was observed, suggesting no substantial evidence of publication bias (data not shown).

Quiz Ref IDResults of this meta-analysis demonstrated that for patients with PAD, aspirin therapy alone or in combination with dipyridamole did not significantly decrease the primary end point of cardiovascular events, results that may reflect limited statistical power. Based on the lower limit of the 95% CI, the current data rule out a 25% risk reduction in cardiovascular events with aspirin, but smaller levels of benefit, such as a 20% reduction, cannot be excluded with the available evidence. Quiz Ref IDAspirin therapy was associated with a significant reduction in the secondary end point of nonfatal stroke. No significant benefit was noted for all other secondary end points, including nonfatal MI, cardiovascular mortality, or all-cause mortality.

These findings contrast with literature that supports a more definitive role of aspirin in the treatment of symptomatic coronary heart disease and cerebrovascular disease.2 There are several potential explanations for these findings. Compared with the abundance of randomized trials evaluating aspirin and other antiplatelet agents in the primary and secondary prevention of coronary heart disease and cerebrovascular disease, patients with PAD have been underrepresented in randomized trials. This is highlighted by examining the largest randomized trials of aspirin vs placebo in populations other than PAD including primary prevention of cardiovascular events in women (n = 39 878),36 secondary prevention of coronary heart disease (n = 17 187),37 and secondary prevention of cerebrovascular disease (n = 20 000).38 In contrast, the single largest study of aspirin involving patients with PAD included only 1276 participants.9

Differences between combinations of aspirin with dipyridamole and aspirin doses across studies may have influenced the efficacy of aspirin. Experience with antiplatelet agents in other clinical settings supports varying efficacy of different antiplatelet medications in distinct patient populations. For example, although some studies demonstrate that a combination of aspirin and dipyridamole reduced risk of ischemic stroke in cerebrovascular disease,39 this antiplatelet regimen is not more effective than aspirin alone for patients with coronary heart disease.3 Similarly, although warfarin in combination with aspirin prevents cardiovascular events among patients with coronary heart disease,40 warfarin combined with aspirin is not efficacious for patients with PAD.41Quiz Ref IDRegarding aspirin dose, a lower dose of aspirin is at least as effective as higher aspirin doses in patients with symptomatic coronary heart disease and is associated with less harm, resulting in recommendations for a lower dose of aspirin for secondary prevention of cardiovascular disease.42 Current, US PAD guidelines support the use of low-dose aspirin despite the fact that the only 2 studies that evaluated a low aspirin dose for PAD were reported after publication of the guidelines.10 Of these 2 trials, the POPADAD study included PAD patients with diabetes who were otherwise asymptomatic for cardiovascular disease and reported no benefit for aspirin therapy with a hazard ratio of 0.98.9 The second trial (the Critical Leg Ischaemia Prevention Study [CLIPS]), was conducted in a population that included asymptomatic PAD patients (approximately 25%) and a high proportion of PAD patients with diabetes (approximately 75%).21 The CLIPS trial demonstrated a significant benefit for aspirin, with a 64% risk reduction in cardiovascular events in the aspirin-treated group. However the CLIPS trial planned a sample size of 2000 patients followed up for a mean of 2 years but terminated early due to difficulty recruiting patients and nontrial use of aspirin after only 366 participants were randomized.

Variation in patient phenotype may also influence the results of this meta-analysis, which combined patients with symptomatic and asymptomatic PAD; with or without diabetes, claudicants, and need for peripheral revascularization; and with mild, moderate, and severe PAD. Patients with PAD are at heightened cardiovascular risk because of increased atherothrombosis burden,43,44 endothelial dysfunction,45 platelet activation,46,47 insulin resistance, and diabetes.48 Thus, a number of mechanisms may explain the increased risk of cardiovascular events in patients with PAD. Whether this increased risk is similar in all types of PAD remains uncertain. Unfortunately, outcomes stratified by phenotype at enrollment were unavailable in many of the studies.

Quiz Ref IDPeripheral artery disease may represent a diffuse form of atherosclerosis with a high inflammatory burden4951 and platelet activation52 that may be less responsive to aspirin than other cardiovascular diseases. Despite its irreversible platelet inhibition, aspirin is a weaker antiplatelet drug than other agents. In a prospective randomized trial, picotamide significantly reduced mortality in patients with diabetes and PAD compared with aspirin.53 This may reflect picotamide's greater potency given a dual mechanism of action through inhibition of platelet thromboxane-A2 synthase and antagonism of thromboxane-A2 receptors.

Several studies suggest that aspirin delays the rate of PAD progression, reduces the need for lower extremity revascularization, and reduces graft failure in patients who have undergone lower extremity revascularization procedures.26,30,54 Furthermore, because aspirin reduces cardiovascular morbidity and mortality in other high-risk populations and because it is inexpensive, many physicians and national and international guidelines recommend aspirin as first-line therapy for those with PAD.10,11 However, based on the current findings, there is a critical need for future comparative studies of aspirin and newer, more potent antiplatelet agents to test in PAD patients that are designed to assess long-term risks and outcomes. Only appropriately powered trials with adjudication of cardiovascular and bleeding events can provide definitive conclusions regarding the appropriate antiplatelet regimen for patients with PAD. A randomized, double-blind, placebo-controlled trial involving 3350 patients with PAD, the Aspirin in Asymptomatic Atherosclerosis (AAA) study (Trial registration number: ISRCTN 66587262), is currently under way and is likely to provide important information.

Limitations

The major limitations of this meta-analysis reflect the limitations of published literature on aspirin for treating PAD. Many of these trials were small and of short duration, resulting in few major cardiovascular events. Although no significant benefit of any aspirin therapy was shown for the primary cardiovascular end point, the overall meta-analysis was underpowered to detect risk reductions less than 25%. Similarly, the meta-analysis was underpowered to determine the impact of aspirin on individual components of the primary composite end point. Despite combining multiple studies, the total number of events in this analysis was relatively small. Moreover, the pooled results include trials that were not originally intended to explore cardiovascular outcomes and did not centrally adjudicate cardiovascular events. Similarly, definitions of major bleeding varied across the trials. These variations in major bleeding definitions make it difficult to determine accurate measure of bleeding and approximate risk. Because many studies were performed more than 10 years ago, changes in the diagnosis and treatment of PAD over time may limit the applicability of these results to current patients. Furthermore, a description of patient-level data was not available making it difficult to ascertain whether specific subgroups of PAD patients may benefit from aspirin therapy.

This meta-analysis was conducted using a detailed protocol developed prior to study initiation and used a rigorous search for published and unpublished studies, along with explicit methods for study selection, data extraction, and data analysis. Nevertheless, the generalizability of all meta-analyses is limited by protocol heterogeneity and differences among study populations. A random-effects analysis was used to account for potential differential effects across studies. The results generalize to the treatment of PAD insofar as the included studies ultimately reflect the patients and therapeutic approaches representative of current clinical practice.55,56

This meta-analysis did not demonstrate a significant benefit of aspirin on cardiovascular events when compared with placebo or control. However the current evidence was insufficient to rule out small yet important benefits of aspirin (as suggested by the point estimate of a 12% risk reduction). Aspirin did, however, significantly reduce the risk of nonfatal stroke. In most trials included in this meta-analysis, major bleeding events were not formally assessed and therefore a full risk-benefit analysis was not performed. Larger prospective studies of aspirin and other antiplatelet agents are warranted among patients with PAD in order to draw firm conclusions about clinical benefit and risks.

Corresponding Author: William R. Hiatt, MD, Department of Medicine, University of Colorado Denver, School of Medicine, C/O The Colorado Prevention Center, 789 Sherman St, Ste 200, Denver, CO 80203 (will.hiatt@UCDenver.edu).

Author Contributions: Dr Hiatt had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Berger, Hiatt.

Acquisition of data: Berger, Krantz, Hiatt.

Analysis and interpretation of data: Berger, Krantz, Kittelson, Hiatt.

Drafting of the manuscript: Berger, Krantz, Kittelson, Hiatt.

Critical revision of the manuscript for important intellectual content: Krantz, Kittelson, Hiatt.

Statistical analysis: Berger, Krantz, Kittelson, Hiatt.

Administrative, technical, or material support: Berger, Krantz.

Study supervision: Hiatt.

Financial Disclosures: Drs Hiatt and Krantz report that they have served on the US Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee in the review of antithrombotic therapies and Dr Hiatt previously reviewed the use of aspirin for primary prevention and for treatment of PAD. Drs Krantz and Hiatt report that they have received grant support for projects related to the use of clopidogrel and previously served on the speaker's bureau of the BMS-Sanofi-Aventis Partnership (speaker bureau activities ended in 2008). Dr Berger reports receiving research support from AstraZeneca and has received honoraria for advisory board participation from The Medicines Group. Dr Kittelson reports no conflicts related to this article.

Funding/Support: Dr Berger was partially funded by grants 5K12HL83772-2, a Research Career Development Award from the National Heart, Lung, and Blood Institute and 0775074N an American Heart Association Fellow to Faculty Award. Dr Krantz was partially funded by grant U01 HL079160 from National Heart, Lung, and Blood Institute.

Role of the Sponsor: There was no financial support for this manuscript.

Additional Contributions: We thank Andrew Starrett, PhD, Denver, Colorado, for his contributions to the statistical analysis, and we thank Phillippe Lechat, MD, Pharmacology Department, Pitie-Salpetriere Hospital, Paris, France, and Pascal Priollet, MD, Department of Vascular Medicine, St Joseph Hospital, Paris, France, for their suggestions on the initial conceptualization of this article. None received compensation for their contributions.

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PubMed   |  Link to Article
Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? use and avoidance of continuity corrections in meta-analysis of sparse data [published correction appears in Stat Med. 2006;25(15):2700].  Stat Med. 2004;23(9):1351-1375
PubMed   |  Link to Article
Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews.  Ann Intern Med. 1997;127(9):820-826
PubMed   |  Link to Article
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test.  BMJ. 1997;315(7109):629-634
PubMed   |  Link to Article
Study group on pharmacological treatment after PTA.  Platelet inhibition with ASA/dipyridamole after percutaneous balloon angioplasty in patients with symptomatic lower limb arterial disease: a prospective double-blind trial.  Eur J Vasc Surg. 1994;8(1):83-88
PubMed   |  Link to Article
Catalano M, Born G, Peto R.Critical Leg Ischaemia Prevention Study (CLIPS) Group.  Prevention of serious vascular events by aspirin amongst patients with peripheral arterial disease: randomized, double-blind trial.  J Intern Med. 2007;261(3):276-284
PubMed   |  Link to Article
Colwell JA, Bingham SF, Abraira C,  et al.  VA Cooperative Study of antiplatelet agents in diabetic patients after amputation for gangrene: unobserved, sudden, and unexpected deaths.  J Diabet Complications. 1989;3(4):191-197
PubMed   |  Link to Article
Donaldson D, Salter M, Kester R,  et al.   The influence of platelet inhibition on the patency of femoro-popliteal Dacron bypass grafts.  Vasc Surg. 1985;19:224-230
Link to Article
Ehresmann U, Alemany J, Loew D. Use of acetylsalicylic acid in the prevention of re-occlusion following revascularization interventions: results of a double-blind long term study [in German].  Med Welt. 1977;28(26):1157-1162
PubMed
Goldman M, McCollum C. A prospective randomised study to examine the effect of aspirin plus dipyridamole on the patency of prosthetic femoro-popliteal grafts.  Vasc Surg. 1984;18:217-221
Link to Article
Green RM, Roedersheimer LR, DeWeese JA. Effects of aspirin and dipyridamole on expanded polytetrafluoroethylene graft patency.  Surgery. 1982;92(6):1016-1026
PubMed
Harajola PT, Muerala H, Frick MH. Prevention of early reocclusion by dipyridamole and ASA in arterial reconstructive surgery  J Cardiovasc Surg (Torino). 1981;22(2):141-144
PubMed
Heiss HW, Just H, Middleton D, Deichsel G. Reocclusion prophylaxis with dipyridamole combined with acetylsalicylic acid following PTA.  Angiology. 1990;41(4):263-269
PubMed   |  Link to Article
Hess H, Keil-Kuri E. Theoretische grundlagen der prophylaxe obliterierender arteriopathien mit aggregationshemmern und ergebnisse einer langzeitstudie mit ASS (Colfarit). In: Marx R, Breddin HK, eds. Proceedings of Colfarit Symposium III. Köln, Germany: Bayer; 1975:80-87
Hess H, Mietaschk A, Deichsel G. Drug-induced inhibition of platelet function delays progression of peripheral occlusive arterial disease: a prospective double-blind arteriographically controlled trial.  Lancet. 1985;1(8426):415-419
PubMed   |  Link to Article
Kohler TR, Kaufman JL, Kacoyanis G,  et al.  Effect of aspirin and dipyridamole on the patency of lower extremity bypass grafts.  Surgery. 1984;96(3):462-466
PubMed
McCollum C, Alexander C, Kenchington G, Franks PJ, Greenhalgh R. Antiplatelet drugs in femoropopliteal vein bypasses: a multicenter trial.  J Vasc Surg. 1991;13(1):150-161
PubMed   |  Link to Article
Schoop W. Late results of conservative therapy of arterial occlusive diseases [in German].  Internist (Berl). 1984;25(7):429-433
PubMed
Schoop W, Levy H. Prevention of peripheral arterial occlusive disease with antiaggregants [abstract].  Thromb Haemost. 1983;50:137
Zekert F. Klinische anwendung von aggregationshemmern bei arterieller verschlußkrankheit. In: Zekert F, ed. Thrombosen, Embolien und Aggregationshemmer in der Chirurgie. Stuttgart, Germany: Schattauer; 1975:68-72
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(13):1293-1304
PubMed   |  Link to Article
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(8607):349-360
PubMed
CAST (Chinese Acute Stroke Trial) Collaborative Group.  Randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke.  Lancet. 1997;349(9066):1641-1649
PubMed   |  Link to Article
O'Donnell MJ, Hankey GJ, Eikelboom JW. Antiplatelet therapy for secondary prevention of noncardioembolic ischemic stroke: a critical review.  Stroke. 2008;39(5):1638-1646
PubMed   |  Link to Article
Andreotti F, Testa L, Biondi-Zoccai GG, Crea F. Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients.  Eur Heart J. 2006;27(5):519-526
PubMed   |  Link to Article
Anand S, Yusuf S, Xie C,  et al; Warfarin Antiplatelet Vascular Evaluation Trial Investigators.  Oral anticoagulant and antiplatelet therapy and peripheral arterial disease.  N Engl J Med. 2007;357(3):217-227
PubMed   |  Link to Article
Campbell CL, Smyth S, Montalescot G, Steinhubl SR. Aspirin dose for the prevention of cardiovascular disease: a systematic review.  JAMA. 2007;297(18):2018-2024
PubMed   |  Link to Article
Golomb BA, Dang TT, Criqui MH. Peripheral arterial disease: morbidity and mortality implications.  Circulation. 2006;114(7):688-699
PubMed   |  Link to Article
Steg PG, Bhatt DL, Wilson PW,  et al; REACH Registry Investigators.  One-year cardiovascular event rates in outpatients with atherothrombosis.  JAMA. 2007;297(11):1197-1206
PubMed   |  Link to Article
Brevetti G, Schiano V, Chiariello M. Endothelial dysfunction: a key to the pathophysiology and natural history of peripheral arterial disease?  Atherosclerosis. 2008;197(1):1-11
PubMed   |  Link to Article
Lee WJ, Sheu WH, Chen YT,  et al.  Circulating CD40 ligand is elevated only in patients with more advanced symptomatic peripheral arterial diseases.  Thromb Res. 2006;118(5):619-626
PubMed   |  Link to Article
Cassar K, Bachoo P, Ford I, Greaves M, Brittenden J. Platelet activation is increased in peripheral arterial disease.  J Vasc Surg. 2003;38(1):99-103
PubMed   |  Link to Article
Pande RL, Perlstein TS, Beckman JA, Creager MA. Association of insulin resistance and inflammation with peripheral arterial disease: the National Health and Nutrition Examination Survey, 1999 to 2004.  Circulation. 2008;118(1):33-41
PubMed   |  Link to Article
Iwashima Y, Horio T, Suzuki Y,  et al.  Adiponectin and inflammatory markers in peripheral arterial occlusive disease.  Atherosclerosis. 2006;188(2):384-390
PubMed   |  Link to Article
McDermott MM, Greenland P, Green D,  et al.  D-dimer, inflammatory markers, and lower extremity functioning in patients with and without peripheral arterial disease.  Circulation. 2003;107(25):3191-3198
PubMed   |  Link to Article
Lowe GD, Yarnell JW, Rumley A, Bainton D, Sweetnam PM. C-reactive protein, fibrin D-dimer, and incident ischemic heart disease in the Speedwell study: are inflammation and fibrin turnover linked in pathogenesis?  Arterioscler Thromb Vasc Biol. 2001;21(4):603-610
PubMed   |  Link to Article
Kudoh T, Sakamoto T, Miyamoto S,  et al.  Relation between platelet microaggregates and ankle brachial index in patients with peripheral arterial disease.  Thromb Res. 2006;117(3):263-269
PubMed   |  Link to Article
Neri Serneri GG, Coccheri S, Marubini E, Violi F.Drug Evaluation in Atherosclerotic Vascular Disease in Diabetics (DAVID) Study Group.  Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study.  Eur Heart J. 2004;25(20):1845-1852
PubMed   |  Link to Article
Goldhaber SZ, Manson JE, Stampfer MJ,  et al.  Low-dose aspirin and subsequent peripheral arterial surgery in the Physicians' Health Study.  Lancet. 1992;340(8812):143-145
PubMed   |  Link to Article
Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses.  Ann Intern Med. 2001;135(11):982-989
PubMed   |  Link to Article
Poole C, Greenland S. Random-effects meta-analyses are not always conservative.  Am J Epidemiol. 1999;150(5):469-475
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Flow Diagram of the Literature Search and Trial Selection Process
Graphic Jump Location

PAD indicates peripheral artery disease.

Place holder to copy figure label and caption
Figure 2. Effect of Any Aspirin on the Prevention of Composite Cardiovascular End Points
Graphic Jump Location

Major cardiovascular events are defined as the composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Zero weight denotes a study in which there were no occurrences of the indicated event. A blank row denotes a study in which the indicated event was not measured. aPooled relative risks (RRs) are from a random-effects model. CI indicates confidence interval.

Place holder to copy figure label and caption
Figure 3. Effect of Any Aspirin on the Prevention of Nonfatal Myocardial Infarction, Nonfatal Stroke, and Cardiovascular Death
Graphic Jump Location

Zero weight denotes a study in which there were no occurrences of the indicated event. A blank row denotes a study in which the indicated event was not measured. aPooled relative risks (RRs) are from a random-effects model. CI indicates confidence interval.

Place holder to copy figure label and caption
Figure 4. Effect of Any Aspirin on the Prevention of Any Death and Major Bleed
Graphic Jump Location

Zero weight denotes a study in which there were no occurrences of the indicated event. A blank row denotes a study in which the indicated event was not measured. aPooled relative risks (RRs) are from a random-effects model. CI indicates confidence interval.

Place holder to copy figure label and caption
Figure 5. Effect of Aspirin Monotherapy on the Prevention of Adverse Outcomes
Graphic Jump Location

Major cardiovascular events defined as the composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Zero weight denotes a study in which there were no occurrences of the indicated event. A blank row denotes a study in which the indicated event was not measured. aPooled relative risks (RRs) are from a random-effects model. CI indicates confidence interval.

Tables

Table Graphic Jump LocationTable. Design of Trials Included in the Meta-analysis

References

Awtry EH, Loscalzo J. Aspirin.  Circulation. 2000;101(10):1206-1218
PubMed   |  Link to Article
Berger JS, Brown DL, Becker RC. Low-dose aspirin in patients with stable cardiovascular disease: a meta-analysis.  Am J Med. 2008;121(1):43-49
PubMed   |  Link to Article
Tran H, Anand SS. Oral antiplatelet therapy in cerebrovascular disease, coronary artery disease, and peripheral arterial disease.  JAMA. 2004;292(15):1867-1874
PubMed   |  Link to Article
Hiatt WR, Krantz MJ. The efficacy of aspirin in peripheral arterial disease: an unresolved question.  J Mal Vasc. 2007;32(2):71-72
PubMed   |  Link to Article
Hankey GJ, Norman PE, Eikelboom JW. Medical treatment of peripheral arterial disease.  JAMA. 2006;295(5):547-553
PubMed   |  Link to Article
Antiplatelet Trialists' Collaboration.  Collaborative overview of randomised trials of antiplatelet therapy–I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients [published correction appears in BMJ. 1994;308(6943):1540].  BMJ. 1994;308(6921):81-106
PubMed   |  Link to Article
Antithrombotic Trialists' Collaboration.  Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.  BMJ. 2002;324(7329):71-86
PubMed   |  Link to Article
Lechat P, Priollet P. Prevention of major ischemic events in lower limb arterial disease: does aspirin play a role? [in French].  J Mal Vasc. 2006;31(3):129-134
PubMed   |  Link to Article
Belch J, MacCuish A, Campbell I,  et al; Prevention of Progression of Arterial Disease and Diabetes Study Group; Diabetes Registry Group; Royal College of Physicians Edinburgh.  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. 2008;337:a1840Link to Article
Link to Article
Hirsch AT, Haskal ZJ, Hertzer NR,  et al; American Association for Vascular Surgery; Society for Vascular Surgery; Society for Cardiovascular Angiography and Interventions; Society for Vascular Medicine and Biology; Society of Interventional Radiology; ACC/AHA Task Force on Practice Guidelines Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease; American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; Vascular Disease Foundation.  ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic).  Circulation. 2006;113(11):e463-e654
PubMed   |  Link to Article
Sobel M, Verhaeghe R.American College of Chest Physicians; American College of Chest Physicians.  Antithrombotic therapy for peripheral artery occlusive disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest. 2008;133(6):(suppl)  815S-843S
PubMed   |  Link to Article
Food and Drug Administration.  Internal analgesic, antipyretic, and antirheumatic drug products for over-the-counter human use; final rule for professional labeling of aspirin, buffered aspirin, and aspirin in combination with antacid drug products.  Fed Regist. 1999;64(177):49652-49655
PubMed
Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).  J Vasc Surg. 2007;45:(suppl S)  S5-S67
PubMed   |  Link to Article
Antithrombotic Trialists' Collaboration.  Individual results of unconfounded trials of one antiplatelet regimen versus control [Table A].  BMJ. 2002;324(7329):71http://www.bmj.com/cgi/content/full/324/7329/71/DC1/3. doi:10.1136/bmj.324.7329.71. Accessed April 13, 2009
Link to Article
Jadad AR, Moore RA, Carroll D,  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary?  Control Clin Trials. 1996;17(1):1-12
PubMed   |  Link to Article
DerSimonian R, Laird N. Meta-analysis in clinical trials.  Control Clin Trials. 1986;7(3):177-188
PubMed   |  Link to Article
Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? use and avoidance of continuity corrections in meta-analysis of sparse data [published correction appears in Stat Med. 2006;25(15):2700].  Stat Med. 2004;23(9):1351-1375
PubMed   |  Link to Article
Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews.  Ann Intern Med. 1997;127(9):820-826
PubMed   |  Link to Article
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test.  BMJ. 1997;315(7109):629-634
PubMed   |  Link to Article
Study group on pharmacological treatment after PTA.  Platelet inhibition with ASA/dipyridamole after percutaneous balloon angioplasty in patients with symptomatic lower limb arterial disease: a prospective double-blind trial.  Eur J Vasc Surg. 1994;8(1):83-88
PubMed   |  Link to Article
Catalano M, Born G, Peto R.Critical Leg Ischaemia Prevention Study (CLIPS) Group.  Prevention of serious vascular events by aspirin amongst patients with peripheral arterial disease: randomized, double-blind trial.  J Intern Med. 2007;261(3):276-284
PubMed   |  Link to Article
Colwell JA, Bingham SF, Abraira C,  et al.  VA Cooperative Study of antiplatelet agents in diabetic patients after amputation for gangrene: unobserved, sudden, and unexpected deaths.  J Diabet Complications. 1989;3(4):191-197
PubMed   |  Link to Article
Donaldson D, Salter M, Kester R,  et al.   The influence of platelet inhibition on the patency of femoro-popliteal Dacron bypass grafts.  Vasc Surg. 1985;19:224-230
Link to Article
Ehresmann U, Alemany J, Loew D. Use of acetylsalicylic acid in the prevention of re-occlusion following revascularization interventions: results of a double-blind long term study [in German].  Med Welt. 1977;28(26):1157-1162
PubMed
Goldman M, McCollum C. A prospective randomised study to examine the effect of aspirin plus dipyridamole on the patency of prosthetic femoro-popliteal grafts.  Vasc Surg. 1984;18:217-221
Link to Article
Green RM, Roedersheimer LR, DeWeese JA. Effects of aspirin and dipyridamole on expanded polytetrafluoroethylene graft patency.  Surgery. 1982;92(6):1016-1026
PubMed
Harajola PT, Muerala H, Frick MH. Prevention of early reocclusion by dipyridamole and ASA in arterial reconstructive surgery  J Cardiovasc Surg (Torino). 1981;22(2):141-144
PubMed
Heiss HW, Just H, Middleton D, Deichsel G. Reocclusion prophylaxis with dipyridamole combined with acetylsalicylic acid following PTA.  Angiology. 1990;41(4):263-269
PubMed   |  Link to Article
Hess H, Keil-Kuri E. Theoretische grundlagen der prophylaxe obliterierender arteriopathien mit aggregationshemmern und ergebnisse einer langzeitstudie mit ASS (Colfarit). In: Marx R, Breddin HK, eds. Proceedings of Colfarit Symposium III. Köln, Germany: Bayer; 1975:80-87
Hess H, Mietaschk A, Deichsel G. Drug-induced inhibition of platelet function delays progression of peripheral occlusive arterial disease: a prospective double-blind arteriographically controlled trial.  Lancet. 1985;1(8426):415-419
PubMed   |  Link to Article
Kohler TR, Kaufman JL, Kacoyanis G,  et al.  Effect of aspirin and dipyridamole on the patency of lower extremity bypass grafts.  Surgery. 1984;96(3):462-466
PubMed
McCollum C, Alexander C, Kenchington G, Franks PJ, Greenhalgh R. Antiplatelet drugs in femoropopliteal vein bypasses: a multicenter trial.  J Vasc Surg. 1991;13(1):150-161
PubMed   |  Link to Article
Schoop W. Late results of conservative therapy of arterial occlusive diseases [in German].  Internist (Berl). 1984;25(7):429-433
PubMed
Schoop W, Levy H. Prevention of peripheral arterial occlusive disease with antiaggregants [abstract].  Thromb Haemost. 1983;50:137
Zekert F. Klinische anwendung von aggregationshemmern bei arterieller verschlußkrankheit. In: Zekert F, ed. Thrombosen, Embolien und Aggregationshemmer in der Chirurgie. Stuttgart, Germany: Schattauer; 1975:68-72
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(13):1293-1304
PubMed   |  Link to Article
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(8607):349-360
PubMed
CAST (Chinese Acute Stroke Trial) Collaborative Group.  Randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke.  Lancet. 1997;349(9066):1641-1649
PubMed   |  Link to Article
O'Donnell MJ, Hankey GJ, Eikelboom JW. Antiplatelet therapy for secondary prevention of noncardioembolic ischemic stroke: a critical review.  Stroke. 2008;39(5):1638-1646
PubMed   |  Link to Article
Andreotti F, Testa L, Biondi-Zoccai GG, Crea F. Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients.  Eur Heart J. 2006;27(5):519-526
PubMed   |  Link to Article
Anand S, Yusuf S, Xie C,  et al; Warfarin Antiplatelet Vascular Evaluation Trial Investigators.  Oral anticoagulant and antiplatelet therapy and peripheral arterial disease.  N Engl J Med. 2007;357(3):217-227
PubMed   |  Link to Article
Campbell CL, Smyth S, Montalescot G, Steinhubl SR. Aspirin dose for the prevention of cardiovascular disease: a systematic review.  JAMA. 2007;297(18):2018-2024
PubMed   |  Link to Article
Golomb BA, Dang TT, Criqui MH. Peripheral arterial disease: morbidity and mortality implications.  Circulation. 2006;114(7):688-699
PubMed   |  Link to Article
Steg PG, Bhatt DL, Wilson PW,  et al; REACH Registry Investigators.  One-year cardiovascular event rates in outpatients with atherothrombosis.  JAMA. 2007;297(11):1197-1206
PubMed   |  Link to Article
Brevetti G, Schiano V, Chiariello M. Endothelial dysfunction: a key to the pathophysiology and natural history of peripheral arterial disease?  Atherosclerosis. 2008;197(1):1-11
PubMed   |  Link to Article
Lee WJ, Sheu WH, Chen YT,  et al.  Circulating CD40 ligand is elevated only in patients with more advanced symptomatic peripheral arterial diseases.  Thromb Res. 2006;118(5):619-626
PubMed   |  Link to Article
Cassar K, Bachoo P, Ford I, Greaves M, Brittenden J. Platelet activation is increased in peripheral arterial disease.  J Vasc Surg. 2003;38(1):99-103
PubMed   |  Link to Article
Pande RL, Perlstein TS, Beckman JA, Creager MA. Association of insulin resistance and inflammation with peripheral arterial disease: the National Health and Nutrition Examination Survey, 1999 to 2004.  Circulation. 2008;118(1):33-41
PubMed   |  Link to Article
Iwashima Y, Horio T, Suzuki Y,  et al.  Adiponectin and inflammatory markers in peripheral arterial occlusive disease.  Atherosclerosis. 2006;188(2):384-390
PubMed   |  Link to Article
McDermott MM, Greenland P, Green D,  et al.  D-dimer, inflammatory markers, and lower extremity functioning in patients with and without peripheral arterial disease.  Circulation. 2003;107(25):3191-3198
PubMed   |  Link to Article
Lowe GD, Yarnell JW, Rumley A, Bainton D, Sweetnam PM. C-reactive protein, fibrin D-dimer, and incident ischemic heart disease in the Speedwell study: are inflammation and fibrin turnover linked in pathogenesis?  Arterioscler Thromb Vasc Biol. 2001;21(4):603-610
PubMed   |  Link to Article
Kudoh T, Sakamoto T, Miyamoto S,  et al.  Relation between platelet microaggregates and ankle brachial index in patients with peripheral arterial disease.  Thromb Res. 2006;117(3):263-269
PubMed   |  Link to Article
Neri Serneri GG, Coccheri S, Marubini E, Violi F.Drug Evaluation in Atherosclerotic Vascular Disease in Diabetics (DAVID) Study Group.  Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study.  Eur Heart J. 2004;25(20):1845-1852
PubMed   |  Link to Article
Goldhaber SZ, Manson JE, Stampfer MJ,  et al.  Low-dose aspirin and subsequent peripheral arterial surgery in the Physicians' Health Study.  Lancet. 1992;340(8812):143-145
PubMed   |  Link to Article
Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses.  Ann Intern Med. 2001;135(11):982-989
PubMed   |  Link to Article
Poole C, Greenland S. Random-effects meta-analyses are not always conservative.  Am J Epidemiol. 1999;150(5):469-475
PubMed   |  Link to Article
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