Incomplete Inhibition of Thromboxane Biosynthesis by Acetylsalicylic Acid : Determinants and Effect on Cardiovascular Risk
Identifieur interne : 008C60 ( Main/Exploration ); précédent : 008C59; suivant : 008C61Incomplete Inhibition of Thromboxane Biosynthesis by Acetylsalicylic Acid : Determinants and Effect on Cardiovascular Risk
Auteurs : John W. Eikelboom [Canada] ; Graeme J. Hankey [Australie] ; Jim Thorn [Australie] ; Deepak L. Bhatt [États-Unis] ; P. Gabriel Steg [France] ; Gilles Montalescot [France] ; S. Claiborne Johnston [États-Unis] ; Steven R. Steinhubl [États-Unis] ; Koon-Hou Mak [Singapour] ; J. Donald Easton [États-Unis] ; Christian Hamm [Allemagne] ; TINGFEI HU [États-Unis] ; Keith A. A. Fox [Royaume-Uni] ; Eric J. Topol [États-Unis]Source :
- Circulation : (New York, N.Y.) [ 0009-7322 ] ; 2008.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
Abstract
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.
Affiliations:
- Allemagne, Australie, Canada, France, Royaume-Uni, Singapour, États-Unis
- Ohio, Ontario, Rhode Island, Écosse, Île-de-France
- Hamilton (Ontario), Paris, Providence (Rhode Island), Édimbourg
- Université Brown, Université McMaster
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Claiborne Johnston</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>UCSF Neurology</s1><s2>San Francisco, Calif</s2><s3>USA</s3><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>UCSF Neurology</wicri:noRegion></affiliation></author><author><name sortKey="Steinhubl, Steven R" sort="Steinhubl, Steven R" uniqKey="Steinhubl S" first="Steven R." last="Steinhubl">Steven R. Steinhubl</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Geisinger Clinic</s1><s2>Danville, Pa</s2><s3>USA</s3><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Geisinger Clinic</wicri:noRegion></affiliation></author><author><name sortKey="Mak, Koon Hou" sort="Mak, Koon Hou" uniqKey="Mak K" first="Koon-Hou" last="Mak">Koon-Hou Mak</name><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>Gleneagles Medical Centre</s1><s3>SGP</s3><sZ>9 aut.</sZ></inist:fA14><country>Singapour</country><wicri:noRegion>Gleneagles Medical Centre</wicri:noRegion></affiliation></author><author><name sortKey="Easton, J Donald" sort="Easton, J Donald" uniqKey="Easton J" first="J. Donald" last="Easton">J. Donald Easton</name><affiliation wicri:level="4"><inist:fA14 i1="10"><s1>Brown University</s1><s2>Providence, RI</s2><s3>USA</s3><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Providence (Rhode Island)</settlement><region type="state">Rhode Island</region></placeName><orgName type="university">Université Brown</orgName></affiliation></author><author><name sortKey="Hamm, Christian" sort="Hamm, Christian" uniqKey="Hamm C" first="Christian" last="Hamm">Christian Hamm</name><affiliation wicri:level="1"><inist:fA14 i1="11"><s1>Kerckhoff Heart Center</s1><s2>Bad-Nauheim</s2><s3>DEU</s3><sZ>11 aut.</sZ></inist:fA14><country>Allemagne</country><wicri:noRegion>Bad-Nauheim</wicri:noRegion><wicri:noRegion>Kerckhoff Heart Center</wicri:noRegion><wicri:noRegion>Kerckhoff Heart Center</wicri:noRegion></affiliation></author><author><name sortKey="Tingfei Hu" sort="Tingfei Hu" uniqKey="Tingfei Hu" last="Tingfei Hu">TINGFEI HU</name><affiliation wicri:level="2"><inist:fA14 i1="12"><s1>Cleveland Clinic</s1><s2>Cleveland, Ohio</s2><s3>USA</s3><sZ>12 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Fox, Keith A A" sort="Fox, Keith A A" uniqKey="Fox K" first="Keith A. A." last="Fox">Keith A. A. Fox</name><affiliation wicri:level="3"><inist:fA14 i1="13"><s1>University and Royal Infirmary of Edinburgh</s1><s2>Edinburgh</s2><s3>GBR</s3><sZ>13 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Édimbourg</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Topol, Eric J" sort="Topol, Eric J" uniqKey="Topol E" first="Eric J." last="Topol">Eric J. Topol</name><affiliation wicri:level="1"><inist:fA14 i1="14"><s1>The Scripps Research Institute and Scripps Clinic</s1><s2>La Jolla, Calif</s2><s3>USA</s3><sZ>14 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>The Scripps Research Institute and Scripps Clinic</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">08-0517990</idno><date when="2008">2008</date><idno type="stanalyst">PASCAL 08-0517990 INIST</idno><idno type="RBID">Pascal:08-0517990</idno><idno type="wicri:Area/PascalFrancis/Corpus">003213</idno><idno type="wicri:Area/PascalFrancis/Curation">002E40</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">003151</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">003151</idno><idno type="wicri:doubleKey">0009-7322:2008:Eikelboom J:incomplete:inhibition:of</idno><idno type="wicri:Area/Main/Merge">009565</idno><idno type="wicri:Area/Main/Curation">008C60</idno><idno type="wicri:Area/Main/Exploration">008C60</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Incomplete Inhibition of Thromboxane Biosynthesis by Acetylsalicylic Acid : Determinants and Effect on Cardiovascular Risk</title><author><name sortKey="Eikelboom, John W" sort="Eikelboom, John W" uniqKey="Eikelboom J" first="John W." last="Eikelboom">John W. Eikelboom</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>McMaster University</s1><s2>Hamilton, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Hamilton (Ontario)</settlement><region type="state">Ontario</region></placeName><orgName type="university">Université McMaster</orgName></affiliation></author><author><name sortKey="Hankey, Graeme J" sort="Hankey, Graeme J" uniqKey="Hankey G" first="Graeme J." last="Hankey">Graeme J. Hankey</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Neurology DepartmentRoyal Perth Hospital</s1><s2>Perth</s2><s3>AUS</s3><sZ>2 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Neurology DepartmentRoyal Perth Hospital</wicri:noRegion></affiliation></author><author><name sortKey="Thorn, Jim" sort="Thorn, Jim" uniqKey="Thorn J" first="Jim" last="Thorn">Jim Thorn</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Haematology Department Royal Perth Hospital</s1><s2>Perth</s2><s3>AUS</s3><sZ>3 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Haematology Department Royal Perth Hospital</wicri:noRegion></affiliation></author><author><name sortKey="Bhatt, Deepak L" sort="Bhatt, Deepak L" uniqKey="Bhatt D" first="Deepak L." last="Bhatt">Deepak L. Bhatt</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>VA Boston Healthcare System and Brigham and Women's Hospital</s1><s2>Boston, Mass</s2><s3>USA</s3><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>VA Boston Healthcare System and Brigham and Women's Hospital</wicri:noRegion></affiliation></author><author><name sortKey="Steg, P Gabriel" sort="Steg, P Gabriel" uniqKey="Steg P" first="P. Gabriel" last="Steg">P. Gabriel Steg</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>INSERM U-698 Université Paris VII, AP-HP</s1><s2>Paris</s2><s3>FRA</s3><sZ>5 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Montalescot, Gilles" sort="Montalescot, Gilles" uniqKey="Montalescot G" first="Gilles" last="Montalescot">Gilles Montalescot</name><affiliation wicri:level="3"><inist:fA14 i1="06"><s1>Institut de Cardiologie (APHP) and Unit 856 (INSERM), Pitié-Salpêtrière Hospital</s1><s2>Paris</s2><s3>FRA</s3><sZ>6 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Claiborne Johnston, S" sort="Claiborne Johnston, S" uniqKey="Claiborne Johnston S" first="S." last="Claiborne Johnston">S. Claiborne Johnston</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>UCSF Neurology</s1><s2>San Francisco, Calif</s2><s3>USA</s3><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>UCSF Neurology</wicri:noRegion></affiliation></author><author><name sortKey="Steinhubl, Steven R" sort="Steinhubl, Steven R" uniqKey="Steinhubl S" first="Steven R." last="Steinhubl">Steven R. Steinhubl</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Geisinger Clinic</s1><s2>Danville, Pa</s2><s3>USA</s3><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Geisinger Clinic</wicri:noRegion></affiliation></author><author><name sortKey="Mak, Koon Hou" sort="Mak, Koon Hou" uniqKey="Mak K" first="Koon-Hou" last="Mak">Koon-Hou Mak</name><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>Gleneagles Medical Centre</s1><s3>SGP</s3><sZ>9 aut.</sZ></inist:fA14><country>Singapour</country><wicri:noRegion>Gleneagles Medical Centre</wicri:noRegion></affiliation></author><author><name sortKey="Easton, J Donald" sort="Easton, J Donald" uniqKey="Easton J" first="J. Donald" last="Easton">J. Donald Easton</name><affiliation wicri:level="4"><inist:fA14 i1="10"><s1>Brown University</s1><s2>Providence, RI</s2><s3>USA</s3><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Providence (Rhode Island)</settlement><region type="state">Rhode Island</region></placeName><orgName type="university">Université Brown</orgName></affiliation></author><author><name sortKey="Hamm, Christian" sort="Hamm, Christian" uniqKey="Hamm C" first="Christian" last="Hamm">Christian Hamm</name><affiliation wicri:level="1"><inist:fA14 i1="11"><s1>Kerckhoff Heart Center</s1><s2>Bad-Nauheim</s2><s3>DEU</s3><sZ>11 aut.</sZ></inist:fA14><country>Allemagne</country><wicri:noRegion>Bad-Nauheim</wicri:noRegion><wicri:noRegion>Kerckhoff Heart Center</wicri:noRegion><wicri:noRegion>Kerckhoff Heart Center</wicri:noRegion></affiliation></author><author><name sortKey="Tingfei Hu" sort="Tingfei Hu" uniqKey="Tingfei Hu" last="Tingfei Hu">TINGFEI HU</name><affiliation wicri:level="2"><inist:fA14 i1="12"><s1>Cleveland Clinic</s1><s2>Cleveland, Ohio</s2><s3>USA</s3><sZ>12 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Fox, Keith A A" sort="Fox, Keith A A" uniqKey="Fox K" first="Keith A. A." last="Fox">Keith A. A. Fox</name><affiliation wicri:level="3"><inist:fA14 i1="13"><s1>University and Royal Infirmary of Edinburgh</s1><s2>Edinburgh</s2><s3>GBR</s3><sZ>13 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Édimbourg</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Topol, Eric J" sort="Topol, Eric J" uniqKey="Topol E" first="Eric J." last="Topol">Eric J. Topol</name><affiliation wicri:level="1"><inist:fA14 i1="14"><s1>The Scripps Research Institute and Scripps Clinic</s1><s2>La Jolla, Calif</s2><s3>USA</s3><sZ>14 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>The Scripps Research Institute and Scripps Clinic</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Circulation : (New York, N.Y.)</title><title level="j" type="abbreviated">Circulation : (N. Y. N.Y.)</title><idno type="ISSN">0009-7322</idno><imprint><date when="2008">2008</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Circulation : (New York, N.Y.)</title><title level="j" type="abbreviated">Circulation : (N. Y. N.Y.)</title><idno type="ISSN">0009-7322</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acetylsalicylic acid</term><term>Analgesic</term><term>Antiplatelet agent</term><term>Antipyretic</term><term>Atherosclerosis</term><term>Biosynthesis</term><term>Cardiovascular disease</term><term>Non steroidal antiinflammatory agent</term><term>Thromboxane</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Pathologie de l'appareil circulatoire</term><term>Athérosclérose</term><term>Thromboxane</term><term>Biosynthèse</term><term>Acide acétylsalicylique</term><term>Antipyrétique</term><term>Analgésique</term><term>Antiinflammatoire non stéroïde</term><term>Inhibiteur thromboagrégation</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Background-Incomplete inhibition of platelet thromboxane generation, as measured by elevated urinary 11-dehydro thromboxane B<sub>2</sub> 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 B<sub>2</sub> concentrations that could thereby reduce cardiovascular risk. Methods and Results-Urinary 11-dehydro thromboxane B<sub>2</sub> 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 B<sub>2</sub> 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 B<sub>2</sub>, 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 B<sub>2</sub> levels. Conclusions-In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B<sub>2</sub> are an externally valid and potentially modifiable determinant of stroke, myocardial infarction, or cardiovascular death in patients at risk for atherothrombotic events.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>Canada</li><li>France</li><li>Royaume-Uni</li><li>Singapour</li><li>États-Unis</li></country><region><li>Ohio</li><li>Ontario</li><li>Rhode Island</li><li>Écosse</li><li>Île-de-France</li></region><settlement><li>Hamilton (Ontario)</li><li>Paris</li><li>Providence (Rhode Island)</li><li>Édimbourg</li></settlement><orgName><li>Université Brown</li><li>Université McMaster</li></orgName></list><tree><country name="Canada"><region name="Ontario"><name sortKey="Eikelboom, John W" sort="Eikelboom, John W" uniqKey="Eikelboom J" first="John W." last="Eikelboom">John W. Eikelboom</name></region></country><country name="Australie"><noRegion><name sortKey="Hankey, Graeme J" sort="Hankey, Graeme J" uniqKey="Hankey G" first="Graeme J." last="Hankey">Graeme J. Hankey</name></noRegion><name sortKey="Thorn, Jim" sort="Thorn, Jim" uniqKey="Thorn J" first="Jim" last="Thorn">Jim Thorn</name></country><country name="États-Unis"><noRegion><name sortKey="Bhatt, Deepak L" sort="Bhatt, Deepak L" uniqKey="Bhatt D" first="Deepak L." last="Bhatt">Deepak L. Bhatt</name></noRegion><name sortKey="Claiborne Johnston, S" sort="Claiborne Johnston, S" uniqKey="Claiborne Johnston S" first="S." last="Claiborne Johnston">S. Claiborne Johnston</name><name sortKey="Easton, J Donald" sort="Easton, J Donald" uniqKey="Easton J" first="J. Donald" last="Easton">J. Donald Easton</name><name sortKey="Steinhubl, Steven R" sort="Steinhubl, Steven R" uniqKey="Steinhubl S" first="Steven R." last="Steinhubl">Steven R. Steinhubl</name><name sortKey="Tingfei Hu" sort="Tingfei Hu" uniqKey="Tingfei Hu" last="Tingfei Hu">TINGFEI HU</name><name sortKey="Topol, Eric J" sort="Topol, Eric J" uniqKey="Topol E" first="Eric J." last="Topol">Eric J. Topol</name></country><country name="France"><region name="Île-de-France"><name sortKey="Steg, P Gabriel" sort="Steg, P Gabriel" uniqKey="Steg P" first="P. Gabriel" last="Steg">P. Gabriel Steg</name></region><name sortKey="Montalescot, Gilles" sort="Montalescot, Gilles" uniqKey="Montalescot G" first="Gilles" last="Montalescot">Gilles Montalescot</name></country><country name="Singapour"><noRegion><name sortKey="Mak, Koon Hou" sort="Mak, Koon Hou" uniqKey="Mak K" first="Koon-Hou" last="Mak">Koon-Hou Mak</name></noRegion></country><country name="Allemagne"><noRegion><name sortKey="Hamm, Christian" sort="Hamm, Christian" uniqKey="Hamm C" first="Christian" last="Hamm">Christian Hamm</name></noRegion></country><country name="Royaume-Uni"><region name="Écosse"><name sortKey="Fox, Keith A A" sort="Fox, Keith A A" uniqKey="Fox K" first="Keith A. A." last="Fox">Keith A. A. Fox</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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