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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

John W. Eikelboom, FRACP, FRCPA; Graeme J. Hankey, MD, FRACP, FRCP; Jim Thom, MSc; Deepak L. Bhatt, MD; P. Gabriel Steg, MD; Gilles Montalescot, MD, PhD; S. Claiborne Johnston, MD, PhD; Steven R. Steinhubl, MD; Koon-Hou Mak, MD, FRCP; J. Donald Easton, MD; Christian Hamm, MD; Tingfei Hu, MS; Keith A.A. Fox, MB, ChB, FRCP, FESC; Eric J. Topol, MD, on behalf of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) Investigators

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.

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.

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