Published online before print October 6, 2008, doi: 10.1161/CIRCULATIONAHA.108.768283
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(Circulation. 2008;118:1705-1712.)
© 2008 American Heart Association, Inc.
Coronary Heart Disease |
Incomplete Inhibition of Thromboxane Biosynthesis by Acetylsalicylic Acid
Determinants and Effect on Cardiovascular Risk
From McMaster University (J.W.E.), Hamilton, Ontario, Canada; Neurology Department (G.J.H.), Royal Perth Hospital, Perth, Australia; Haematology Department (J.T.), Royal Perth Hospital, Perth, Australia; VA Boston Healthcare System and Brigham and Women’s Hospital (D.L.B.), Boston, Mass; Cleveland Clinic (T.H.), Cleveland, Ohio; INSERM U-698 (P.G.S.), Université Paris VII, AP-HP, Paris, France; Institut de Cardiologie (APHP) and Unit 856 (INSERM), Pitié-Salpêtrière Hospital (G.M.), Paris, France; UCSF Neurology (S.C.J.), San Francisco, Calif; Geisinger Clinic (S.R.S.), Danville, Pa; Gleneagles Medical Centre (K.-H.M.), Singapore; Brown University (J.D.E.), Providence, RI; Kerckhoff Heart Center (C.H.), Bad-Nauheim, Germany; University and Royal Infirmary of Edinburgh (K.A.A.F.), Edinburgh, United Kingdom; and The Scripps Research Institute and Scripps Clinic (E.J.T.), La Jolla, Calif.
Correspondence to Professor Graeme J. Hankey, MD, FRACP, FRCP, Consultant Neurologist and Head of Stroke Unit, Department of Neurology, Royal Perth Hospital, 197 Wellington St, Perth, Australia 6000. E-mail gjhankey{at}cyllene.uwa.edu.au
Received January 31, 2008; accepted July 29, 2008.
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Abstract |
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Background— Incomplete inhibition of platelet thromboxane generation, as measured by elevated urinary 11-dehydro thromboxane B2 concentrations, has been associated with an increased risk of cardiovascular events. We aimed to determine the external validity of this association in aspirin-treated patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial and to determine whether there are any modifiable factors or interventions that lower urinary 11-dehydro thromboxane B2 concentrations that could thereby reduce cardiovascular risk.
Methods and Results— Urinary 11-dehydro thromboxane B2 concentrations were measured in 3261 aspirin-treated patients at least 1 month after they had been randomly assigned to placebo or clopidogrel. Baseline urinary 11-dehydro thromboxane B2 concentrations in the highest quartile were associated with an increased risk of stroke, myocardial infarction, or cardiovascular death compared with the lowest quartile (adjusted hazard ratio 1.66, 95% CI 1.06 to 2.61, P=0.03). Increasing age, female sex, history of peripheral artery disease, current smoking, and oral hypoglycemic or angiotensin-converting enzyme inhibitor therapy were independently associated with higher urinary concentrations of 11-dehydro thromboxane B2, whereas aspirin dose 
150 mg/d, history of treatment with nonsteroidal antiinflammatory drugs, history of hypercholesterolemia, and statin treatment were associated with lower concentrations. Randomization to clopidogrel (versus placebo) did not reduce the hazard of cardiovascular events in patients in the highest quartile of urinary 11-dehydro thromboxane B2 levels.
Conclusions— In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B2 are an externally valid and potentially modifiable determinant of stroke, myocardial infarction, or cardiovascular death in patients at risk for atherothrombotic events.
Key Words: aspirin • aspirin resistance • atherosclerosis
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Introduction |
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Acetylsalicylic acid (ASA) reduces the risk of serious cardiovascular events by
20% in a broad range of high-risk patients.1 The primary effect of ASA on hemostasis is to acetylate platelet cyclooxygenase (COX)-1 and thereby inhibit the synthesis of thromboxane A2, a powerful platelet agonist.2,3 Acetylation of platelet COX-1 by ASA is rapid, irreversible, and permanent (for the life of the platelet), because platelets lack the biosynthetic machinery necessary to synthesize new protein, and it is believed to be saturable at low doses.4–8 Acetylation of platelet COX-1 does not attain functional relevance until the maximal capacity to generate thromboxane A2 is reduced by at least 95%.2,9 However, very small amounts of residual COX-1 activity can generate sufficient amounts of thromboxane to support thromboxane-dependent platelet function. Thus, as much as 99% inhibition of serum thromboxane may be necessary to optimally inhibit platelets.10
Clinical Perspective p 1712
Some patients treated with ASA continue to generate thromboxane A2 and thereby activate platelets.11,12 Possible mechanisms of continued thromboxane generation despite ASA treatment include poor compliance with ASA treatment, inadequate ASA dose, concomitant use of other COX inhibitors that interfere with the antiplatelet effects of ASA, increased rate of platelet turnover, transcellular metabolism of prostaglandin precursors, and true "resistance" of COX-1 to the inhibitory effects of ASA (eg, due to a genetic polymorphism of the COX-1 gene).11–15
Continued thromboxane production despite ASA therapy, as manifested by elevated concentrations of 11-dehydro thromboxane B2 (a stable metabolite of thromboxane A2) in the urine, has been associated with an increased risk of serious cardiovascular events in 1 study of high-vascular-risk patients.16 However, this finding has not been validated externally in an independent data set. If it were externally validated, knowledge of the determinants of elevated concentrations of 11-dehydro thromboxane B2 could generate new interventions to lower concentrations of 11-dehydro thromboxane B2 and thereby reduce cardiovascular risk.
In this prespecified substudy of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial, we aimed to prospectively verify the hypothesis that incomplete suppression of thromboxane generation with usual doses of ASA, as measured by elevated concentrations of 11-dehydro thromboxane B2 in the urine, is associated with an increased risk of subsequent serious vascular events. We also aimed to identify the independent and significant determinants of urinary 11-dehydro thromboxane B2 concentrations, as well as whether the addition of an ADP receptor antagonist, clopidogrel, to ASA would reduce ASA-insensitive thromboxane biosynthesis and thereby improve survival free of cardiovascular events.
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Methods |
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The methods of the CHARISMA trial have been described in detail elsewhere.17,18 Briefly, CHARISMA was a multinational, multicenter, randomized, parallel-group, double-blind trial of clopidogrel versus placebo in high-risk patients at risk of atherothrombotic events. The institutional review committee at each participating center approved the study, and all subjects gave informed consent. A total of 15 603 patients with either clinically established cardiovascular disease or multiple risk factors were randomly assigned to receive clopidogrel (75 mg/d) or placebo. All patients received ASA (75 to 162 mg/d). Patients were followed up for a median of 28 months. The primary efficacy outcome for the CHARISMA trial was a composite of stroke, myocardial infarction (MI), and cardiovascular death.
Patients
A total of 3261 patients from 224 sites in 12 countries complied with a request to provide a first-morning-urine specimen at least 1 month after randomization. A minimum 1-month interval between randomization and urine collection ensured steady state suppression of thromboxane generation and reduced the likelihood of recruiting a patient soon after an acute atherothrombotic event, which might be a cause of platelet activation.
Urine Sample Transport and Storage
Urine samples were stored at –20°C or below (noncyclical defrost freezer) until transported on dry ice to the central laboratory in Perth, Australia, where they were stored at –80°C until analysis.
Follow-Up and Ascertainment of Clinical Outcomes
Patients were followed up prospectively at 1, 3, and 6 months after randomization and every 6 months thereafter until the trial was completed. At each follow-up, we recorded use of medications, including ASA dose, and clinical outcomes. The primary outcome was the composite of stroke, MI, and cardiovascular death.
Analysis of Urine Samples
The urine samples were thawed and assayed for 11-dehydro thromboxane B2 with a commercially available enzyme immunoassay (Cayman Chemical, Ann Arbor, Mich). This assay has interassay and intra-assay coefficients of variation of 12.1% and 10%, respectively. Control urine samples with assigned values for 11-dehydro thromboxane B2 were run with each batch (kindly supplied by AspirinWorks, Broomfield, Colo). Laboratory staff performing the assays were blinded to treatment allocation and to whether the patient had experienced a primary outcome event.
Statistical Analysis
Means or proportions for baseline demographics, cardiovascular risk factors, history of previous vascular events, randomized study treatments, and cointerventions before urine collection were calculated for patients who experienced the primary outcome (stroke, MI, or cardiovascular death) and those who did not experience this outcome. The significance of any difference between those who experienced the primary outcome and those who did not was tested with a Student’s t test for means and a 
2 test for proportions. Because 11-dehydro thromboxane B2 values were skewed, geometric means were calculated after log transformation of the raw data. Median concentrations were also calculated. The significance of any differences in median 11-dehydro thromboxane B2 concentrations between patients who experienced stroke, MI, or cardiovascular death and those who did not experience this outcome and between different treatment groups (ASA dose, clopidogrel, nonsteroidal antiinflammatory drug use, statins) was tested with a Wilcoxon rank sum test. The association between increasing urinary 11-dehydro thromboxane B2 concentrations and risk of stroke, MI, or cardiovascular death was examined after the samples were divided into quartiles according to the distribution of 11-dehydro thromboxane B2 concentrations in the entire study cohort.
Adjusted estimates of the association between increasing urinary 11-dehydro thromboxane B2 concentrations and risk of stroke, MI, or cardiovascular death were obtained by means of Cox regression modeling that controlled for prespecified demographic variables, cardiovascular risk factors, history of previous vascular events, randomized study treatment, and cointerventions. The main model considered the time of randomization as time zero, on the basis of the assumption that urinary 11-dehydro thromboxane B2 concentrations at the time of urine collection were representative of levels at randomization. Urinary 11-dehydro thromboxane B2 concentration was fitted in the model by quartiles as an ordinal variable.
Because some patients may have experienced an outcome event after randomization but before urine collection, we performed separate analyses (1) by using the time of urine collection as time zero and then (2) after excluding patients who experienced an outcome event in the 3 months before urine collection. Our aim in performing these additional analyses was to explore the consistency of the association between 11-dehydro thromboxane B2 concentration and risk of stroke, MI, or cardiovascular death in these patients.
The association between urinary 11-dehydro thromboxane B2 concentrations and outcome was examined separately for individual components of the primary composite outcome. Multiple logistic regression modeling was used to examine the association between baseline patient characteristics, randomized treatment allocation and cointerventions, and quartiles of urinary 11-deydro thromboxane B2 concentrations.
Statistical analyses were performed with SAS version 8.0.2. (SAS Institute Inc, Cary, NC). All probability values are 2-sided; CIs were calculated at the 95% level.
The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.
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Baseline Characteristics and Treatments
Baseline characteristics are shown in Table 1, and treatment data, including randomized study drug use and cointerventions before urine collection, are shown in Table 2. The characteristics of patients included in the present study are similar to the characteristics of patients in the CHARISMA trial not included in the present study (data not presented).
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Patients who experienced the primary outcome (stroke, MI, or cardiovascular death) were followed up for a mean of 662 days, and those who did not experience this outcome were followed up for a mean of 831 days (P<0.001). Patients who experienced the primary outcome were older, more likely to have a history of stroke or carotid endarterectomy, and more often treated with any clopidogrel (randomized or open label), a β-blocker, diuretics, and insulin than those who did not experience the primary outcome.
Urinary Thromboxane Collection
Urine was collected a median of 12.9 months after randomization among patients who experienced the primary outcome and a median of 14.9 months after randomization among those who did not (P=0.70). Among the 144 patients with primary outcome events, 9 experienced the primary outcome in the 3 months before urine collection.
Effect of Clopidogrel and Other Treatments on 11-Dehydro Thromboxane B2 Levels
Table 3 shows the effects of clopidogrel, nonsteroidal antiinflammatory drugs (NSAIDs), and statins on urinary 11-dehydro thromboxane B2 concentrations. Randomized treatment with clopidogrel or any use of clopidogrel before urine collection did not significantly impact 11-dehydro thromboxane B2 concentrations; however, patients receiving NSAIDs and patients treated with statins had significantly lower 11-dehydro thromboxane B2 concentrations than patients not receiving those treatments.
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Table 4 shows the effect of ASA dose on urinary 11-dehydro thromboxane B2 concentrations. Patients receiving ASA 150 mg/d had lower 11-dehydro thromboxane B2 concentrations than those receiving <100 mg/d or 100 to 149 mg/d, but there were no significant differences between the 2 groups with a lower ASA dose in urinary 11-dehydro thromboxane B2 concentrations.
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Association Between 11-Dehydro Thromboxane B2 Concentrations and Primary Outcome
Table 5 shows that urinary concentrations of 11-dehydro thromboxane B2 were significantly higher among patients who developed the primary composite outcome of stroke, MI, or cardiovascular death than among those who remained free of these events. Figure 1 shows Kaplan-Meier survival curves for stroke, MI, or cardiovascular death according to quartiles of urinary 11-dehydro thromboxane B2 concentrations (log-rank trend test P=0.02). Table 6 shows that the adjusted hazard for stroke, MI, or cardiovascular death was greater among patients with the highest quartile of urinary 11-dehydro thromboxane B2 concentration than among those in the lowest quartile (adjusted hazard ratio [HR] 1.66, 95% CI 1.06 to 2.61). A similar pattern of association remained evident when the time of urine collection was used as time zero (adjusted hazard for stroke, MI, death=1.57, 95% CI 0.87 to 2.84; adjusted HR for cardiovascular death=2.16, 95% CI 0.97 to 4.83) and after the exclusion of patients who experienced an outcome event in the 3 months before urine collection (adjusted HR 1.51, 95% CI 0.95 to 2.40).
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There was an independent association between urinary 11-dehydro thromboxane B2 concentration and both stroke (adjusted HR 2.36, 95% CI 1.19 to 4.68) and cardiovascular death (adjusted HR 2.59, 95% CI 0.91 to 7.42) but not MI (adjusted HR 0.89, 95% CI 0.45 to 1.75). Clopidogrel compared with placebo did not influence the hazard of stroke, MI, or cardiovascular death in patients in the highest quartile of urinary 11-dehydro thromboxane B2 concentration (HR 0.91, 95% CI 0.54 to 1.53, P=0.71).
Association Between 11-Dehydro Thromboxane B2 Concentrations and Bleeding
There was a nonsignificant trend toward increasing frequency of moderate or severe GUSTO [Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries) bleeding in patients with increasing quartiles of urinary 11-dehydro thromboxane B2 concentrations: 2.0% in the lowest quartile, 2.0% in the second quartile, 2.2% in the third quartile, and 3.2% in the highest quartile (P for trend=0.16).
Determinants of 11-Dehydro Thromboxane B2 Concentrations
Table 7 shows that the variables that were independently and significantly associated with quartiles of urinary 11-dehydro thromboxane B2 concentrations were increasing age, female sex, current cigarette smoking, hypercholesterolemia, history of peripheral artery angioplasty or bypass surgery, mean ASA dose, and concomitant use of NSAIDS, statins, angiotensin-converting enzyme inhibitors, or oral hypoglycemic drugs. The c-statistic for the model was 0.62.
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Discussion |
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The principal findings were as follows: (1) values of urinary 11-dehydro thromboxane B2 concentration in the upper quartile in a broad population of high-risk patients treated with usual doses of ASA (75 to 162 mg/d) were independently associated with an increased risk of serious cardiovascular events; (2) increasing age, female sex, history of peripheral artery disease, current smoking, and oral hypoglycemic or angiotensin-converting enzyme inhibitor therapy were independently associated with higher concentrations of 11-dehydro thromboxane B2 in the urine, whereas ASA dose
150 mg/d, history of treatment with NSAIDs, history of hypercholesterolemia, and statin treatment were associated with lower concentrations; and (3) randomization to clopidogrel (versus placebo) did not reduce urinary 11-dehydro thromboxane B2 levels or reduce the hazard of cardiovascular events in patients in the highest quartile of urinary 11-dehydro thromboxane B2 levels. The strengths of the present study are that we based our hypothesis on earlier observations in an unrelated patient population. We collected, stored, and shipped samples in a standardized fashion and kept the samples frozen until analyzed. We adjusted our analyses for variables that potentially confound the association between urinary thromboxane and outcome.
The potential limitations are several. First, there were baseline differences between those who experienced stroke, MI, or cardiovascular death and those who remained free of these events (Table 1), which could confound the association between urinary thromboxane concentration and outcome. There were also differences between patients who were and those who were not treated with statins or higher doses of ASA that could confound the association between these treatments and urinary thromboxane concentrations. However, after adjustment for these differences, a clear association remained between urinary 11-dehydro thromboxane B2 concentrations and risk of stroke, MI, or cardiovascular death and between statins or higher doses of ASA and urinary 11-dehydro thromboxane B2 concentrations. Second, urinary concentrations of 11-dehydro thromboxane B2 measured months after randomization may not be representative of levels at baseline (randomization); however, a consistent association with stroke, MI, or cardiovascular death remained when the time of urine collection was set as zero in the regression analyses. Third, urinary 11-dehydro thromboxane B2 concentrations may have increased after recent thrombotic events; however, the association between urinary 11-dehydro thromboxane B2 concentrations and the primary outcome remained after patients who experienced stroke or MI within 3 months of urine collection were excluded and in analyses restricted to fatal outcomes. Fourth, noncompliance with aspirin therapy could account for variability in urinary 11-dehydro thromboxane B2 concentrations, but the present data show that factors not related to compliance with aspirin therapy, including age and sex, as well as use of several concomitant therapies, independently determine urinary 11-dehydro thromboxane B2 concentrations. Fifth, we did not randomly select patients for inclusion in the present study and restricted eligibility to 12 countries participating in the CHARISMA trials; however, the baseline characteristics of the >3000 control subjects included in the present study are similar to the baseline characteristics of the CHARISMA study population, which suggests that our results are likely to be representative of subjects included in the overall trial. Finally, urinary 11-dehydro thromboxane B2 concentration is not a specific measure of the antiplatelet effects of ASA.
Despite these potential limitations, our first finding confirms the results and external validity of the Heart Outcomes Prevention Evaluation (HOPE) Study, which found a 1.8-fold increase in risk of stroke, MI, or cardiovascular death among patients in the highest quartile of 11-dehydro thromboxane B2 levels compared with those in the lowest quartile.16 Unlike our earlier analyses from the HOPE study, we did not find a significant association between urinary 11-dehydro thromboxane B2 levels in the third or second quartiles compared with the first quartile; however, the present study was underpowered for these analyses, because the number of outcome events in the first 3 quartiles was low.
Our second finding that NSAIDs and higher doses of ASA (150 mg/d) are associated with reduced 11-dehydro thromboxane B2 concentrations is biologically plausible and may be clinically relevant. Nucleated cells such as monocytes and vascular endothelial cells potentially can provide prostaglandin H2 to platelets, thereby bypassing platelet COX-1, or can use prostaglandin H2 to synthesize their own thromboxane A2, because they are contain substantial amounts of thromboxane synthase.14 Arachidonic acid conversion to prostaglandin H2 is catalyzed by COX-1 or -2. Low-dose ASA blocks COX-1 in platelets, but nucleated cells can regenerate COX-1. Consequently, nucleated cells can provide a source of prostaglandin H2 even during low-dose ASA treatment. Nucleated cells can also produce prostaglandin H2 via COX-2.14 Whereas COX-1 is blocked at least 95% by low-dose ASA, inhibition of COX-2 requires higher doses of ASA or treatment with an NSAID that has COX-2–inhibitory activity. However, it cannot be assumed that lowering thromboxane levels with higher doses of ASA will translate into reduced risk of cardiovascular events. Inhibition of COX-2 also reduces endothelial cell synthesis of prostacyclin and has adverse effects on blood pressure and renal function, which may explain why both traditional (non-COX-selective) and COX-2–selective NSAIDs increase cardiovascular events.19–22 Furthermore, even if greater inhibition of urinary 11-dehydro thromboxane B2 concentrations can be achieved with higher doses of ASA, any resulting benefit in reducing ischemic cardiovascular events might be offset by increased bleeding, and there is no evidence that higher doses of ASA are more effective than lower doses.23
The mechanism of lower 11-dehydro thromboxane B2 levels in patients treated with statins is uncertain but may be an indirect effect on vascular endothelium. Patients with elevated low-density lipoprotein cholesterol levels have enhanced platelet reactivity and elevated 11-dehydro thromboxane B2 concentrations in the urine.24 Statins inhibit platelet hyperreactivity and reduce urinary 11-dehydro thromboxane B2 concentrations in patients with type IIa hypercholesterolemia,24,25 and they improve endothelial function in patients with coronary artery disease.26,27 Reduced tissue factor expression and release from dysfunctional endothelium during statin therapy may reduce generation of thrombin, a powerful platelet agonist, and thereby reduce platelet activation and aggregation.28
The present finding that female sex was an independent determinant of elevated 11-dehydro thromboxane B2 concentrations in the urine, which in part reflects enhanced in vivo platelet activation, is consistent with recent reports demonstrating greater platelet reactivity among ASA-treated women than men29 and quantitative differences between females and males in their clinical response to ASA.30
We failed to confirm the hypothesis that adding clopidogrel to ASA would reduce urinary 11-dehydro thromboxane B2 concentrations and exert a greater effect in reducing cardiovascular risk among patients with the highest quartile of 11-dehydro thromboxane B2 concentrations. The rationale for this hypothesis was that if ASA does not inhibit COX-1 by at least 95%, ADP could still promote thromboxane A2 formation by activating platelets,31 and treatment with an ADP receptor antagonist could augment suppression of thromboxane generation by ASA. Although the addition of clopidogrel to aspirin has been shown to improve clinical outcomes in large clinical trials,32–35 the present study failed to demonstrate a significant effect of the addition of clopidogrel to aspirin in patients with higher thromboxane levels.
In conclusion, the present results confirm those of an earlier study16 that incomplete suppression of thromboxane generation, as measured by an elevated urinary concentration of 11-dehydro thromboxane B2, is an independent and potentially modifiable determinant of clinical outcome in patients at risk of atherothrombotic events treated with ASA. Moreover, we found that the independently significant factors associated with higher urinary concentrations of 11-dehydro thromboxane B2 were increasing age, female sex, history of peripheral artery disease, current smoking, and oral hypoglycemic or angiotensin-converting enzyme inhibitor therapy, whereas lower concentrations were associated with ASA dose 150 mg/d, history of treatment with NSAIDs, history of hypercholesterolemia, and statin treatment. The effectiveness and safety of high-dose ASA (300 to 325 mg/d) compared with lower doses (75 to 100 mg/d) is currently undergoing evaluation in a prospective trial. The potential for statins to mediate some of their favorable effect on vascular events by lowering urinary concentrations of 11-dehydro thromboxane B2 (as well as blood low-density lipoprotein cholesterol concentrations) is intriguing and worthy of further study.
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Acknowledgments |
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Anne Claxton, research nurse, Stroke Unit, Royal Perth Hospital, coordinated the collection of the urine samples from all centers.
Disclosures
Dr Eikelboom has received consulting fees from sanofi-aventis, Bristol-Myers Squibb, Astra Zeneca, GSK, McNeil, Thrombovision, Portola, and Boehringer Ingelheim and grants from sanofi-aventis, Bristol-Myers Squibb, Bayer, and GSK. He is named on a patent for a method for measuring aspirin resistance (patent number: 7081347); any royalties that might accrue from this source are being donated to McMaster University. Dr Hankey has received consulting fees and lecture fees from sanofi-aventis, Bristol-Myers Squibb, Bayer, and Boehringer Ingelheim. Dr Bhatt has received research grants from Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi Aventis, and The Medicines Company and served as a consultant to Arena, Astellas, Astra Zeneca, Bristol-Myers Squibb, Cardax, Centocor, Cogentus, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, McNeil, Medtronic, Millennium, Molecular Insights, Otsuka, Paringenix, PDL, Philips, Portola, Sanofi Aventis, Schering Plough, Scios, Takeda, The Medicines Company, tns Healthcare, and Vertex. Dr Steg has received research grants from sanofi-aventis; served on the speakers’ bureaus of Boehringer-Ingelheim, BMS, GSK, Nycomed, sanofi-aventis, Servier, and The Medicines Company; and served on the consulting/advisory boards of Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Endotis, GSK, Medtronic, MSD, Nycomed, Sanofi-aventis, Servier, and The Medicines Company. Dr Montalescot has received consulting and lecture fees from sanofi-aventis and Bristol-Myers Squibb. Dr Johnston has received research support from sanofi-aventis. Dr Steinhubl has received consulting fees from sanofi-aventis, AstraZeneca, Eli Lilly, and the Medicines Company. Dr Mak has received research support from sanofi-aventis and Bristol-Myers Squibb. Dr Easton has received consulting fees from sanofi-aventis and Bristol-Myers Squibb. Dr Hamm has received consultant and speaker honorarium from sanofi-aventis. Dr Fox has received consulting fees from sanofi-aventis; lecture fees from sanofi-aventis and Bristol-Myers Squibb; and grant support from sanofi-aventis. Dr Topol has received a research grant and serves as a consultant to sanofi-aventis and received a research grant from Accumetrics. The remaining authors report no conflicts.
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Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00050817.
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