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Figure 1.
Platelet activation follows atherosclerotic plaque disruption and consists of conformational changes, increased expression of glycoprotein (GP) IIb/IIIa receptors, and degranulation with release of prothrombotic substances such as thromboxane A2 (TXA2) and adenosine diphosphate (ADP). Aspirin, thienopyridines, and GP IIb/IIa receptor inhibitors block various pathways of thrombus formation. AA indicates acetylsalicylic acid; Cox, cyclooxygenase.

Platelet activation follows atherosclerotic plaque disruption and consists of conformational changes, increased expression of glycoprotein (GP) IIb/IIIa receptors, and degranulation with release of prothrombotic substances such as thromboxane A2 (TXA2) and adenosine diphosphate (ADP). Aspirin, thienopyridines, and GP IIb/IIa receptor inhibitors block various pathways of thrombus formation. AA indicates acetylsalicylic acid; Cox, cyclooxygenase.

Figure 2.
Aspirin irreversibly blocks cyclooxygenase and inhibits thromboxane A2 production throughout the 7 to 10 days lifetime of the anucleated platelet. Prostacyclin is synthesized in endothelial cells, which recover their cyclooxygenase function quickly, making aspirin effect on endothelial cells marginal compared with its antiplatelet effect. NSAID indicates nonsteroidal anti-inflammatory drug.

Aspirin irreversibly blocks cyclooxygenase and inhibits thromboxane A2 production throughout the 7 to 10 days lifetime of the anucleated platelet. Prostacyclin is synthesized in endothelial cells, which recover their cyclooxygenase function quickly, making aspirin effect on endothelial cells marginal compared with its antiplatelet effect. NSAID indicates nonsteroidal anti-inflammatory drug.

Figure 3.
While aspirin acts as an antiplatelet agent at low doses (<300 mg/d), it exerts antipyretic and analgesic effects at intermediate doses (300-2400 mg/d) and anti-inflammatory effects at higher doses (2400-4000 mg/d). Low-dose aspirin reaches appreciable plasma levels by 20 minutes and exerts antiplatelet effects within 60 minutes.

While aspirin acts as an antiplatelet agent at low doses (<300 mg/d), it exerts antipyretic and analgesic effects at intermediate doses (300-2400 mg/d) and anti-inflammatory effects at higher doses (2400-4000 mg/d). Low-dose aspirin reaches appreciable plasma levels by 20 minutes and exerts antiplatelet effects within 60 minutes.

Table 1. 
Aspirin Landmark Trials
Aspirin Landmark Trials
Table 2. 
Clopidogrel Landmark Trials
Clopidogrel Landmark Trials
1.
Yusuf  SZhao  FMehta  SRChrolavicius  STognoni  GFox  KK Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345494- 502Article
2.
Rauch  UOsende  JIFuster  VBadimon  JJFayad  ZChesebro  JH Thrombus formation on atherosclerotic plaques: pathogenesis and clinical consequences. Ann Intern Med. 2001;134224- 238Article
3.
Badimon  JJZaman  AHelft  GFayad  ZFuster  V Acute coronary syndromes: pathophysiology and preventive priorities. Thromb Haemost. 1999;82997- 1004
4.
Gum  PAKottke-Marchant  KPoggio  ED  et al.  Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol. 2001;88230- 235Article
5.
Fuster  VFayad  ZABadimon  JJ Acute coronary syndromes: biology. Lancet. 1999;353suppl 2SII5- 9Article
6.
Moreno  PRFalk  EPalacios  IFNewell  JBFuster  VFallon  JT Macrophage infiltration in acute coronary syndromes: implications for plaque rupture. Circulation. 1994;90775- 778Article
7.
Toschi  VGallo  RLettino  M  et al.  Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation. 1997;95594- 599Article
8.
Cannon  CPFuster  V Thrombogenesis, antithrombotic, and thrombolytic therapy. Fuster  VAlexander  RWO'Rourke  RAedsHurst's The Heart 10th ed. New York, NY McGraw-Hill Book Co2001;1373- 1436
9.
Falk  EShah  PKFuster  V Coronary plaque disruption. Circulation. 1995;92657- 671Article
10.
Davies  MJ Stability and instability: two faces of coronary atherosclerosis: the Paul Dudley White Lecture 1995. Circulation. 1996;942013- 2020Article
11.
De Reynal  BFrancon  F Aspirin still stands [in French]. J Belge Rhumatol Med Phys. 1965;20197- 204
12.
Flower  RJVane  JR Analgesic-antipyretics and anti-inflammatory agents: drugs employed in the treatment of gout. Gilman  AGGoodman  ISRall  TWMurad  FedsGoodman and Gilman's The Pharmacological Basis of Therapeutics 7th ed. New York, NY Macmillan1995;674- 675
13.
Craven  L Experiences with aspirin (acetylsalicyclic acid) in the nonspecific prophylaxis of coronary thrombosis. Miss Valley Med J. 1953;7538- 40
14.
Weiss  HJAledort  LM Impaired platelet-connective-tissue reaction in man after aspirin ingestion. Lancet. 1967;2495- 497Article
15.
Vane  JR Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231232- 235Article
16.
Ferreira  SHMoncada  SVane  JR Indomethacin and aspirin abolish prostaglandin release from the spleen. Nat New Biol. 1971;231237- 239Article
17.
Hamberg  MSvensson  JSamuelsson  B Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci U S A. 1975;722994- 2998Article
18.
Moncada  SGryglewski  RBunting  SVane  JR An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. 1976;263663- 665Article
19.
Mann  CC The Aspirin Wars: Money, Medicine and 100 Years of Rampant Competition.  New York, NY Alfred Knopf Inc1991;
20.
Roth  GJMajerus  PW The mechanism of the effect of aspirin on human platelets, I: acetylation of a particulate fraction protein. J Clin Invest. 1975;56624- 632Article
21.
Burch  JWStanford  NMajerus  PW Inhibition of platelet prostaglandin synthetase by oral aspirin. J Clin Invest. 1978;61314- 319Article
22.
Fuster  VDyken  MLVokonas  PSHennekens  Cfor the Special Writing Group, Aspirin as a therapeutic agent in cardiovascular disease. Circulation. 1993;87659- 675Article
23.
Hirsh  JDalen  JEFuster  VHarker  LBSalzman  EW Aspirin and other platelet-active drugs: the relationship between dose, effectiveness, and side effects. Chest. 1992;102suppl 4327S- 336SArticle
24.
Patrignani  PFilabozzi  PPatrono  C Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest. 1982;691366- 1372Article
25.
Reilly  IAFitzGerald  GA Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. Blood. 1987;69180- 186
26.
Ross  R Atherosclerosis: an inflammatory disease. N Engl J Med. 1999;340115- 126Article
27.
Ridker  PMCushman  MStampfer  MJTracy  RPHennekens  CH Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336973- 979Article
28.
Wu  RLamontagne  Dde Champlain  J Antioxidative properties of acetylsalicylic Acid on vascular tissues from normotensive and spontaneously hypertensive rats. Circulation. 2002;105387- 392Article
29.
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. BMJ. 1994;30881- 106Article
30.
Antithrombotic Trialists' Collaboration, Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;32471- 86Article
31.
Lewis  HD  JrDavis  JWArchibald  DG  et al.  Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina: results of a Veterans Administration Cooperative Study. N Engl J Med. 1983;309396- 403Article
32.
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;2349- 360
33.
Steering Committee of the Physicians' Health Study Research Group, Final Report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med. 1989;321129- 135Article
34.
The Medical Research Council's General Practice Research Framework, Thrombosis Prevention Trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet. 1998;351233- 241Article
35.
Hansson  LZanchetti  ACarruthers  SG  et al. for the HOT Study Group, Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet. 1998;3511755- 1762Article
36.
Hennekens  CHDyken  MLFuster  V Aspirin as a therapeutic agent in cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation. 1997;962751- 2753Article
37.
Sanmuganathan  PSGhahramani  PJackson  PRWallis  EJRamsay  LE Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials. Heart. 2001;85265- 271Article
38.
Peto  RGray  RCollins  RWheatley  K  et al.  Randomised trial of prophylactic daily aspirin in British male doctors. BMJ. 1988;296313- 316Article
39.
Jneid  HThacker  HL Coronary artery disease in women: different, often undertreated. Cleve Clin J Med. 2001;68441- 448Article
40.
Manson  JEStampfer  MJColditz  GA  et al.  A prospective study of aspirin use and primary prevention of cardiovascular disease in women. JAMA. 1991;266521- 527Article
41.
Gum  PAThamilarasan  MWatanabe  JBlackstone  EHLauer  MS Aspirin use and all-cause mortality among patients being evaluated for known or suspected coronary artery disease: a propensity analysis. JAMA. 2001;2861187- 1194Article
42.
Gorelick  PBBorn  GVD'Agostino  RBHanley  DF  JrMoye  LPepine  CJ Therapeutic benefit: aspirin revisited in light of the introduction of clopidogrel. Stroke. 1999;301716- 1721Article
43.
Savcic  MHauert  JBachmann  FWyld  PJGeudelin  BCariou  R Clopidogrel loading dose regimens: kinetic profile of pharmacodynamic response in healthy subjects. Semin Thromb Hemost. 1999;25suppl 215- 19
44.
Helft  GOsende  JIWorthley  SG  et al.  Acute antithrombotic effect of a front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin. Arterioscler Thromb Vasc Biol. 2000;202316- 2321Article
45.
Gent  MBlakely  JAEaston  JD  et al.  The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet. 1989;11215- 1220Article
46.
Balsano  FRizzon  PVioli  F  et al. for the Studio della Ticlopidina nell'Angina Instabile Group, Antiplatelet treatment with ticlopidine in unstable angina: a controlled multicenter clinical trial. Circulation. 1990;8217- 26Article
47.
CAPRIE Steering Committee, A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;3481329- 1339Article
48.
Creager  MA Results of the CAPRIE trial: efficacy and safety of clopidogrel: clopidogrel versus aspirin in patients at risk of ischaemic events. Vasc Med. 1998;3257- 260Article
49.
Caro  JJMigliaccio-Wallek  Not Availablefor the CAPRA (CAPRIE [clopidogrel versus aspirin in patients at risk of ischaemic events] Actual Practice Rates Analysis) Study Group, Generalizing the results of clinical trials to actual practice: the example of clopidogrel therapy for the prevention of vascular events. Am J Med. 1999;107568- 572Article
50.
Bhatt  DLChew  DPHirsch  ATRingleb  PAHacke  WTopol  EJ Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery. Circulation. 2001;103363- 368Article
51.
Moussa  IOetgen  MRoubin  G  et al.  Effectiveness of clopidogrel and aspirin versus ticlopidine and aspirin in preventing stent thrombosis after coronary stent implantation. Circulation. 1999;992364- 2366Article
52.
Berger  PBBell  MRRihal  CS  et al.  Clopidogrel versus ticlopidine after intracoronary stent placement. J Am Coll Cardiol. 1999;341891- 1894Article
53.
Muller  CButtner  HJPetersen  JRoskamm  H A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary-artery stents. Circulation. 2000;101590- 593Article
54.
Taniuchi  MKurz  HILasala  JM Randomized comparison of ticlopidine and clopidogrel after intracoronary stent implantation in a broad patient population. Circulation. 2001;104539- 543Article
55.
Bennett  CLConnors  JMCarwile  JM  et al.  Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med. 2000;3421773- 1777Article
56.
Steinhubl  SRBerger  PBMann III  JT  et al.  Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;2882411- 2420Article
57.
Bhatt  DLBertrand  MEBerger  PB  et al.  Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting. J Am Coll Cardiol. 2002;399- 14Article
58.
Herbert  JMDol  FBernat  AFalotico  RLale  ASavi  P The antiaggregating and antithrombotic activity of clopidogrel is potentiated by aspirin in several experimental models in the rabbit. Thromb Haemost. 1998;80512- 518
59.
Bossavy  JPThalamas  CSagnard  L  et al.  A double-blind randomized comparison of combined aspirin and ticlopidine therapy versus aspirin or ticlopidine alone on experimental arterial thrombogenesis in humans. Blood. 1998;921518- 1525
60.
Moshfegh  KRedondo  MJulmy  F  et al.  Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: enhanced inhibitory effects of combination therapy. J Am Coll Cardiol. 2000;36699- 705Article
61.
Mehta  SRYusuf  S The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme: rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease. Eur Heart J. 2000;212033- 2041Article
62.
Cannon  CPWeintraub  WSDemopoulos  LA  et al.  Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med. 2001;3441879- 1887Article
63.
Mehta  SRYusuf  SPeters  RJ  et al.  Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358527- 533Article
64.
Chew  DPBhatt  DLRobbins  MA  et al.  Effect of clopidogrel added to aspirin before percutaneous coronary intervention on the risk associated with C-reactive protein. Am J Cardiol. 2001;88672- 674Article
65.
Assali  ARSalloum  JSdringola  S  et al.  Effects of clopidogrel pretreatment before percutaneous coronary intervention in patients treated with glycoprotein IIb/IIIa inhibitors (abciximab or tirofiban). Am J Cardiol. 2001;88884- 886Article
66.
Topol  EJ The future of antiplatelet therapy: optimizing management in patients with acute coronary syndrome. Clin Cardiol. 2000;23Suppl 6VI-23- 28Article
67.
Kastrati  ASchomig  ASeyfarth  M  et al.  PlA polymorphism of platelet glycoprotein IIIa and risk of restenosis after coronary stent placement. Circulation. 1999;991005- 1010Article
68.
Nurden  AT Platelet glycoprotein IIIa polymorphism and coronary thrombosis. Lancet. 1997;3501189- 1191Article
69.
Walter  DHSchachinger  VElsner  MDimmeler  SZeiher  AM Platelet glycoprotein IIIa polymorphisms and risk of coronary stent thrombosis. Lancet. 1997;3501217- 1219Article
70.
Eikelboom  JWHirsh  JWeitz  JIJohnston  MYi  QYusuf  S Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation. 2002;1051650- 1655Article
71.
Not Available, Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;2852486Article
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Bhatt  DMarso  SHirsch  ARingleb  PTopol  E Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol. 2002;90625- 628Article
Review Article
May 26, 2003

Aspirin and Clopidogrel in Acute Coronary SyndromesTherapeutic Insights From the CURE Study

Author Affiliations

From the Division of Cardiology, University of Louisville, Louisville, Ky (Dr Jneid); Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio (Drs Bhatt and Francis); and the Cardiovascular Biology Research Laboratory (Drs Corti and Badimon) and the Zena and Michael A. Wiener Cardiovascular Institute (Dr Fuster), Mount Sinai Medical Center, New York, NY. Dr Bhatt has received honoraria for educational presentations from Sanofi-Synthelabo and Bristol-Myers-Squibb.

Arch Intern Med. 2003;163(10):1145-1153. doi:10.1001/archinte.163.10.1145
Abstract

Platelet adhesion, activation, and aggregation are central to thrombus formation, which follows atherosclerotic plaque disruption and causes acute coronary syndromes. Aspirin and clopidogrel exert their antiplatelet effects by inhibiting thromboxane A2 production and adenosine diphosphate–induced platelet aggregation pathways, respectively. Aspirin has proven benefits in primary and secondary prevention of coronary artery disease. Clopidogrel, an alternative antiplatelet agent used in patients with aspirin intolerance, is especially useful in combination with aspirin after coronary stent procedures. The CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) study demonstrates for the first time the benefit of adding clopidogrel to aspirin rather than using aspirin alone in patients having acute coronary syndromes without ST-segment elevation myocardial infarction. Patients who are resistant to aspirin (up to 10%) have higher rates of cardiovascular events and may derive special benefit from the combination therapy. Aspirin resistance can be assessed through platelet aggregometry testing, measurement of urinary thromboxane metabolites, and, possibly, genomic testing in the future.

The CURE1 (Clopidogrel in Unstable Angina to Prevent Recurrent Events) study provides evidence for the usefulness of clopidogrel in patients having acute coronary syndrome (ACS) without ST-segment elevation. The major finding of the study is that clopidogrel given in conjunction with aspirin improves the outcome of patients with ACS compared with aspirin treatment alone. Clopidogrel appears to add incremental value to conventional therapy. The purpose of this review is to critically analyze the findings of several antiplatelet trials with a focus on the CURE study, and to provide guidance in the use of aspirin and clopidogrel for patients with ACS.

PATHOPHYSIOLOGY OF ACS

Acute coronary syndrome is a spectrum of ischemic coronary events that share thesame pathophysiology and includes unstable angina, non–ST-segment elevation myocardial infarction (MI), ST-segment elevation MI, and sudden death. Acute thrombus formation on a disrupted atherosclerotic plaque seems to be the major mechanism responsible for the onset of ACS. The magnitude and stability of the thrombus formed is regulated by the nature of the exposed substrate (ie, the biochemical composition of the lesion and the degree of injury); the local rheological conditions; and the presence of certain systemic factors affecting blood thrombogenicity (eg, hyperlipidemia and diabetes).2,3 Conventional antiplatelet therapy with aspirin is designed to diminish platelet aggregation, but aspirin is a relatively weak antiplatelet drug. Moreover, up to 10% of patients do not respond to the antiplatelet effects of aspirin.4 Thus, aspirin effects, though important, are limited.

Plaque disruption depends on both passive and active phenomena.5 Among the different vascular lesions, those characterized by a thin fibrous cap, a large atheromatous core, macrophage infiltration, and a scarcity of smooth muscle cells are generally referred to as vulnerable plaques because of their high tendency to disruption.5 The highest macrophage density is encountered at the shoulders of the vulnerable plaque, where plaque rupture more frequently takes place. Macrophages produce proteolytic enzymes, especially matrix metalloproteinases, that actively dissolve the matrix of the fibrous cap, leading to plaque rupture and exposure of the underlying lipid core.6 The lipid core, a highly thrombogenic substance, is rich in tissue factor, a glycoprotein responsible for initiation of the extrinsic coagulation cascade.7 Once platelets are exposed to collagen and tissue factor, platelet adhesion occurs as the initial step, followed by platelet activation and release of various vasoactive substances. These released substances, especially thromboxane A2 and adenosine diphosphate (ADP), induce the binding of platelets to each other, causing platelet aggregation and formation of white thrombus. While platelets secure the primary hemostasis at the site of ruptured plaque, tissue factor induces thrombin formation by activating the extrinsic coagulation cascade. Thrombin then converts fibrinogen to fibrin and stabilizes the final clot or red thrombus (secondary hemostasis)8 that leads in some cases to ACS.

A meta-analysis of several postmortem studies involving patients who had died from cardiovascular causes showed the presence of thrombus on disrupted lesions in approximately two thirds of cases. These "culprit" lesions causing acute coronary events are usually eccentric and moderately stenosed (<50% of the artery's diameter).9 The remaining third of acute coronary events are secondary to eroded endothelium, which, in a highly thrombogenic blood milieu, leads to clot formation. Eroded lesions usually induce more severe stenosis and occur more commonly at a younger age, in women, and in diabetic and hyperlipidemic patients.10 Acute myocardial ischemia, caused by regional alteration in blood flow secondary to acute thrombus formation, can lead to ACS if the thrombus is not lysed by endogenous tissue plasminogen activator.

The key role of platelet activation and thrombosis in ACS is emphasized by the significant clinical benefits associated with the use of antiplatelet agents, such as aspirin (which blocks thromboxane A2 formation) and clopidogrel (which inhibits ADP-induced platelet aggregation) (Figure 1). However, platelet aggregation is a complex pathophysiologic process; multiple therapeutic agents may be required simultaneously to block its redundant pathways.

ASPIRIN
Historic Antecedents

Aspirin is known today to be an inexpensive, safe, and effective antiplatelet drug but its beginnings were less than easy. Piria isolated salicylic acid from the willow bark in 1838, but it was not until 1893 that Hoffman, a chemist at Bayer's laboratories, became interested in salicylic acid. At that time, Hoffman's rheumatic father had grown intolerant to the sodium salicylate available.11 Hoffman developed and purified acetylsalicylic acid, which was marketed in 1899 by the Bayer Company under the name of Aspirin (A for acetyl, and Spir for spiric acid, as salicylic acid was then known).11,12 It is ironic that the Bayer Company, which promoted the drug for its efficacy in relieving rheumatological conditions, issued a reassurance for the public that it did not have harmful effects on the heart. Though aspirin was first recognized in the 1950s to reduce the incidence of MI,13 mechanisms of its action remained unclear until 1967 when Weiss and Aledort14 published the first article to acknowledge the inhibitory effects of aspirin on platelets. Sir John R. Vane,15,16 who received the Nobel Prize for his work, found a dose-dependent inhibition of prostaglandin formation with aspirin, salicylate, and indomethacin, and provided further support for the therapeutic benefits of aspirin. His work and the work of others led also to the discovery of thromboxane A2 and prostacyclin (PGI2) in 1975 and 1976, respectively.17,18 Now, more than 100 years after its initial use, aspirin is still the most widely used drug in the world.19

How Does Aspirin Work?

Aspirin irreversibly inhibits cyclooxygenase, an enzyme responsible for the formation of eicosanoids, which include PGI2 and thromboxane A215,20,21 (Figure 2). Because thromboxane A2 promotes platelet aggregation, the acetylation of cyclooxygenase by aspirin decreases thromboxane generation in platelets, and therefore platelet aggregability, throughout the platelet's lifetime, which averages 7 to 10 days. Because only 10% of platelets are replaced daily, a single dose of aspirin inhibits aggregation in 50% of the platelets as late as 5 days after administration; however, only 20% of platelets, when not acetylated by aspirin, are enough to promote thrombus formation.22 Aspirin also inhibits PGI2 formation in endothelial cells. PGI2 is an eicosanoid that inhibits platelet aggregation and antagonizes the "blood-thinning" effects of aspirin; but endothelial cells, unlike the platelets, recover their cyclooxygenase function quickly, and this effect of aspirin appears to be short-lived and marginal compared with its antiplatelet effects.22 Aspirin reaches appreciable plasma levels by 20 minutes and exerts its platelet-inhibitory effect within 60 minutes.23 It is recommended that aspirin-naive patients having ACS chew a loading dose of at least 160 mg of aspirin to receive prompt antiplatelet effect.24,25

The benefits of aspirin emanate not only from its antiplatelet effects, but potentially also from its anti-inflammatory properties. Atherosclerosis is known to be a chronic inflammatory disease of the vessel wall,26 and it is not surprising that in a prospective study involving 543 apparently healthy men participating in the Physicians' Health Study, baseline C-reactive protein levels predicted future MI and stroke events.27 Incidentally, the benefits of aspirin in this prospective analysis are seen mainly among men whose C-reactive protein levels are in the highest quartile, with a small, nonsignificant reduction among those whose C-reactive protein levels are in the lowest quartile.27 This suggests that a major mechanism of action of aspirin occurs through its anti-inflammatory effects (Figure 3). The relative quantitative antiplatelet and anti-inflammatory benefits of aspirin in the treatment of coronary disease are not entirely clear. Recent evidence also points to potential antioxidative properties of aspirin. In one study,28 long-term administration of aspirin to both normotensive and hypertensive rats resulted in a decrease in nicotinamide adenine dinucleotide phosphate oxidase activity and, therefore, its generation of superoxide anion. However, the antioxidative properties of aspirin still need to be demonstrated in humans.

Antiplatelet Therapy Prevents Cardiovascular Events

The earliest comprehensive evidence for the efficacy of antiplatelet therapy in preventing cardiovascular events comes from the Antiplatelet Trialists' Collaboration study.29 This study, published in 1994, is a meta-analysis encompassing 145 randomized trials and including approximately 100 000 patients, of whom 70 000 were considered in the high-risk category because they had, or were at risk for, vascular disease. The meta-analysis found a 25% reduction in the combined end point of MI, stroke, and vascular death in users of antiplatelet therapy (P<.001). There was also a reduction of 34% in nonfatal MI rates, of 25% in nonfatal stroke rates, of 17% in vascular death rates, and of 16% in mortality rates from any cause. No evidence of increase in nonvascular death rates was noted with antiplatelet therapy. Direct comparisons of the different antiplatelet regimens were conducted in 10 000 patients, and no advantage of high-dose aspirin or any other antiplatelet drug over the medium dose of aspirin (75-325 mg) was found. Not unexpectedly, the beneficial effect of antiplatelet therapy was demonstrated across all patient subsets of the study, but the benefits were greater in the high-risk group.

The Antithrombotic Trialists' Collaboration group recently published an updated meta-analysis of all randomized antiplatelet trials in high-risk patients.30 Their systematic review included 287 studies (up to 1997) and involved patients with acute MI; acute ischemic stroke; previous MI; previous stroke or transient ischemic attack; coronary artery disease (CAD) from other categories; and peripheral arterial disease. It also included patients at risk of embolism and other conditions that placed them at high risk (diabetes, hemodialysis, carotid disease). The main outcome measured was serious vascular event defined as nonfatal MI, nonfatal stroke, or vascular death. The Antithrombotic Trialists' Collaboration group demonstrated a 22% overall odds reduction of serious vascular events in patients taking antiplatelet therapy compared with controls (10.7% vs 13.2%; P<.001) and approximately a one-sixth reduction in all-cause mortality (P<.001). The benefit was highest in patients with acute MI (30% odds reduction) and lowest in patients with acute stroke (11% odds reduction). The main outcome was mostly driven by a 34% reduction in nonfatal MI and a 25% reduction in nonfatal stroke, as vascular death was reduced by only 15% (P<.001). Most importantly, indirect comparisons of various aspirin regimens in the meta-analysis showed that a daily dose of aspirin in the range of 75 to 150 mg appears adequate. However, in clinical situations demanding immediate antithrombotic effect, such as ACS, a loading dose of 150 to 325 mg of aspirin is still considered the standard choice. While there was no benefit from adding dipyridamole to aspirin, addition of intravenous glycoprotein (GP) IIb/IIIa inhibitors to aspirin resulted in a 19% increase in the reduction of serious vascular events.

Several landmark trials established the efficacy of aspirin, particularly in primary and secondary prevention of CAD (Table 1).

Lewis and colleagues31 conducted one of the earliest placebo-controlled randomized trials of aspirin in patients with ACS. In a multicenter double-blind trial enrolling 1266 men with unstable angina, the combined primary end point of death and nonfatal MI at 12 weeks was reduced by 50% in patients receiving aspirin rather than placebo. Death and nonfatal MIs were also each reduced by 50% in the aspirin group. The Second International Study of Infarct Survival (ISIS-2)32 was a similar landmark trial of acute MI. The study showed that a daily 160-mg aspirin tablet, started within the first day of MI and continued for 5 weeks, conferred a significant 23% risk reduction in total vascular mortality, as well as a similar magnitude of risk reduction from all-cause mortality. Although the survival curves converged slightly over time, a significant survival benefit was still maintained after 15 months of median follow-up. There was an accompanying small absolute excess in minor bleeding events (0.6% vs 0.2%), but no significant increase in hemorrhagic strokes or bleeding events requiring transfusions. Aspirin therapy has now become conventional for all patients suspected of having an ACS.36

Aspirin's benefits in primary prevention of CAD are supported by many trials as well. The US Physicians' Health Study33 was the first and largest primary prevention study of aspirin in cardiovascular disease. A total of 22 701 healthy physicians received 325 mg of aspirin on alternating days. The aspirin arm of the study was terminated early (after an average follow-up of 60 months) when a 44% reduction in the risk of first MI was observed. This beneficial effect was seen primarily in patients older than 50 years. However, there was no beneficial effect of aspirin on cardiovascular mortality (the primary end point). Treated patients also showed a nonsignificant trend toward higher rates of strokes, mostly hemorrhagic, compared with patients taking placebo. The benefits of aspirin in primary prevention of cardiovascular disease in high-risk patients were later corroborated by other primary prevention studies. The Thrombosis Prevention Trial (TPT)34 demonstrated a 20% relative reduction in the combined end point of coronary death and nonfatal MI in 5085 high-risk male patients in the United Kingdom. The beneficial effect of the daily 75-mg dose of aspirin used in this study consisted almost entirely in the incidence reduction of nonfatal events. The Hypertension Optimal Treatment (HOT)35 trial randomized 18 790 hypertensive female and male patients, most of whom with no known CAD, to receive 75 mg of aspirin daily or placebo. A 15% reduction in vascular events and 36% reduction in MI were observed, but no significant impact on cardiovascular mortality. A meta-analysis in primary prevention conducted by Sanmuganathan et al37 included the 3 above trials, along with a study on British male physicians,38 and found significant 15% and 30% reductions in cardiovascular events and MI, respectively. They concluded that aspirin in primary prevention is safe and useful in patients with a 1-year coronary event risk greater than or equal to 1.5%. The benefits of aspirin in primary prevention of CAD apply to women as well.39 In an analysis from the Nurses' Health Study,40 women taking 1 to 6 tablets of aspirin weekly had a 25% (P = .04) relative risk reduction of first myocardial infarction in multivariate analysis. The relative risk reduction of first MI was even higher, reaching 32% (P = .02) in women older than 50 years.

A recent observational study showed a 33% survival benefit from aspirin in a multivariate analysis in stable patients with known or suspected CAD undergoing stress echocardiography.41 The greatest benefit from aspirin was observed in older patients, patients with known CAD, and patients with impaired exercise capacity.

CLOPIDOGREL
An Inhibitor of ADP-Induced Platelet Aggregation

Adenosine diphosphate is a substance released by activated platelets that amplifies platelet aggregability.42 The platelet ADP receptor is coupled to a G protein and subserves calcium release from internal cytosolic stores upon activation. This leads to conformational changes in and activation of the GP IIb/IIIa receptor, and to fibrinogen binding and platelet aggregation.36 Thienopyridine analogues (ticlopidine and clopidogrel) irreversibly inhibit the binding of ADP to its receptor. Clopidogrel has a quicker onset of action, and appears to be safer than ticlopidine, an earlier thienopyridine. Inhibition of ADP-induced platelet aggregation occurs 2 hours after a 300-mg loading dose of clopidogrel.43,44

Clopidogrel was approved in 1997 for use in secondary prevention of cardiovascular disease, and has been in widespread use since then (Table 2). It is most commonly used for the unlabeled indication of antiplatelet activity following percutaneous coronary intervention, where its efficacy is proven.

Thienopyridines Are Superior to Placebo in Preventing Vascular Events

Clopidogrel, the newer thienopyridine, has not been compared with placebo. Older trials, however, compared the therapeutic effects of ticlopidine and placebo and found a statistically significant superiority of ticlopidine. Men and women presenting with thromboembolic stroke and randomly assigned to ticlopidine had a 23% reduction in the combined end point of stroke, MI, and vascular death after a mean follow-up of 2 years.45 Another randomized controlled trial of ticlopidine in patients with unstable angina showed a 46% reduction in the primary combined end point of vascular death and MI compared with placebo.46

CAPRIE: The Rise of a Star

Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE)47 was a randomized head-to-head trial comparing the efficacy and safety of a daily 75-mg dose of clopidogrel with a daily 325-mg dose of aspirin in patients with cardiovascular disease. It included a total of 19 185 patients, distributed among 3 separately enrolled groups of patients with recent MI, stroke, or symptoms secondary to peripheral arterial disease. After an average of 1.9 years of follow-up, the data demonstrated a statistically significant 8.7% relative risk reduction in the combined end point of MI, ischemic stroke, and vascular death. Severe intracranial hemorrhage and gastrointestinal bleeding events occurred in 0.33% and 0.52% of patients, respectively, with clopidogrel. The rate of ever-reported gastrointestinal bleeding complication was significantly lower in the clopidogrel group than in the aspirin group (1.99% vs 2.66%; P<.002), and no difference in intracerebral hemorrhage, hemorrhagic death, thrombocytopenia, or neutropenia was noted between the 2 groups.48

Despite clopidogrel's apparent success, the difference between the 2 antiplatelet therapies was modest (equivalent to 5 events per 1000 patients). The cost to save 1 life in the CAPRIE study was $8181 for aspirin and $49 367 for clopidogrel, conferring a 7-fold cost advantage to aspirin.42 On the other hand, the absolute risk reduction reached with clopidogrel may be higher when the drug is used in actual clinical practice. Lower event rates might have occurred because of the "healthy patient" selection bias inherent in studies such as CAPRIE, and this may translate into a lower number of patients needing treatment and better cost-effectiveness for clopidogrel in clinical practice.49 Furthermore, the benefit of clopidogrel over aspirin appears to be amplified in high-risk patients. In a post hoc analysis from the CAPRIE study, Bhatt et al50 demonstrated the benefit of clopidogrel over aspirin in patients who had prior surgical revascularization.

Thienopyridine Use After Percutaneous Coronary Intervention

Clopidogrel has an efficacy similar to that of ticlopidine in preventing stent thrombosis.5154 Because of its better safety profile, however, clopidogrel has replaced ticlopidine as the favored thienopyridine following stent implantation. Neutropenia is associated with ticlopidine but not with clopidogrel; and although rare cases of thrombotic thrombocytopenic purpura have been described with clopidogrel (3-4 cases per million), causality has not been established.55

Clopidogrel is usually given for 1 month after stent implantation, but many physicians argue for a longer duration of therapy. How long one should use clopidogrel after percutaneous coronary intervention has recently been the subject of a clinical trial. Clopidogrel for the Reduction of Events During Observation (CREDO) was a multicenter, double-blind study of patients with stable and unstable angina who were undergoing percutaneous coronary intervention. The trial emonstrated the safety and efficacy of clopidogrel treatment before the procedure, and the beneficial effects of prolonged (1-year) vs short-term (1-month) dual antiplatelet therapy.56

Recently, Bhatt and colleagues57 performed a meta-analysis of the major randomized trials and registries comparing clopidogrel and ticlopidine use after coronary stent deployment. They demonstrated lower rates of major adverse cardiac events and in addition to the known adverse effects with clopidogrel and concluded that clopidogrel plus aspirin should be the standard antiplatelet regimen after stent deployment.

COMBINING CLOPIDOGREL AND ASPIRIN: DOES IT WORK?

Experimental studies have shown synergy between the thienopyridines and aspirin.5860 This is biologically plausible because they act through independent mechanisms. Their combination inhibits ADP-induced platelet activation and thromboxane A2 production, 2 different pathways that affect platelet aggregability.61 Clopidogrel in Unstable angina to prevent Recurrent Events (CURE),1 the largest randomized ACS trial to date, tested the efficacy of the combination of aspirin and clopidogrel compared with aspirin alone.

The CURE Trial

Study Design. The CURE study1 was a randomized, double-blind trial involving 482 centers from 28 countries (mostly European and South American, plus Canada and the United States). It investigated whether prolonged combined treatment with aspirin and clopidogrel would have incremental benefit over aspirin alone in vascular outcomes in patients having ACS without ST-segment elevation MI.

A total of 12 562 patients diagnosed as having ACS without ST-segment elevation were randomized within 24 hours of symptom onset to receive either a combination of aspirin and clopidogrel (6259 patients) or aspirin and placebo (6303 patients).

The clopidogrel group received an immediate loading dose of 300 mg of clopidogrel followed by 75 mg of clopidogrel daily, while aspirin was given to both groups at doses ranging from 75 mg to 325 mg daily at the treating physician's discretion. Treatment continued from 3 to 12 months (mean, 9 months), during which the patients had serial follow-up evaluations.

The mean age of patients was 64 years. Of this population of 12 562, 39% were women, 23% had diabetes, 59% had hypertension, and 59% were current or former smokers; only 13 were lost to follow-up.

Main Results. Using clopidogrel plus aspirin significantly reduced the risk of the first primary composite end point of nonfatal MI, stroke, and cardiovascular death (9.3% vs 11.4%, for a reduction of 20%) compared with aspirin alone.1 There was also a significant risk reduction rate of 14% in the second primary composite of cardiovascular death, stroke, nonfatal MI, and refractory ischemia (16.5% vs 18.8%). The superiority of the combined antiplatelet regimen was also observed across a number of important secondary end points: incidence rates were lowered by 26% for severe ischemia, by 9% for recurrent angina, by 8% for revascularization procedures, and by 18% for evidence of heart failure. It must be stressed, however, that the composite end points were driven mainly by the statistically significant decrease in the MI risk reduction rate (5.2% vs 6.7%, for a reduction of 23%), while other individual outcomes showed nonsignificant trends toward lower event rates: a 14% RR for stroke, a 7% RR for cardiovascular death, and a 7% RR for refractory ischemia.

Observations and Subgroup Analyses From CURE. The superiority of the combination of aspirin and clopidogrel appeared early in the course of treatment, with significant benefit occurring during the first 24 hours. This superiority was maintained through the 12-month study. At randomization, 25% of patients were taking lipid-lowering agents, 58% β-blockers, 36% angiotensin-converting enzyme inhibitors, and 72% were receiving unfractionated or low-molecular-weight heparin anticoagulant therapy. Nevertheless, subgroup analyses showed that the benefit of the combined regimen was maintained irrespective of the medications the patients were taking. There was also consistent benefit across different doses of aspirin and various risk groups, though the largest benefit (a 44% risk reduction) was observed in patients with prior revascularization. Dual antiplatelet therapy was superior whether or not patients were taking medications of proven survival benefit, such as β-blockers or statins, at randomization. Thus, the incremental benefit of clopidogrel could not be attributed to a higher risk profile of suboptimally treated patients.

Higher Bleeding Rates With Dual Antiplatelet Therapy. Patients assigned to the dual antiplatelet regimen had higher rates of major and minor bleeding, but no increase in life-threatening bleeding or intracranial hemorrhage.

Compared with aspirin use alone, a significant 1.38 relative risk of major bleeding episodes (P = .001)—mostly bleeding caused by PGI2 and bleeding at the puncture site—and a significant 2.12 relative risk of minor bleeding episodes (P<.001) were observed in the dual antiplatelet therapy group.

Although 6 of every 1000 patients required blood transfusions, the excess bleeding risk in the combined treatment was no higher than that seen in trials comparing the effects of aspirin and placebo, and lower than that seen in intravenous GP IIb/IIIa inhibitor trials, both of which being accepted treatments.

There was no significant difference in the rates of life-threatening bleeding events (nonsignificant 21% higher rates), hemorrhagic strokes, thrombocytopenia, and neutropenia between the 2 groups of the study. No cases of thrombotic thrombocytopenic purpura occurred in the CURE study.

Use of Dual Antiplatelet Therapy in Patients Awaiting Percutaneous Transluminal Coronary Artery Angioplasty and Coronary Artery

No significant excess in bleeding was seen when clopidogrel was stopped a median of at least 5 days before coronary artery bypass graft surgery; however, a 53% higher rate of major bleeding events was observed in the combination group, and the events were stopped less than 5 days before the procedure.

It is important to note that most patients were recruited from centers where early invasive procedures were not routinely performed (only 462 patients were from the United States compared with 2050 patients from Poland, for example). The Therapy with an Invasive or Conservative Strategy (TACTICS)–Thrombolysis in Myocardial Infarction (TIMI) 18 trial62 showed clear benefit of the early invasive strategy in ACS without ST-segment elevation, and many centers in the United States have adopted a similar aggressive strategy. Tirofiban was used upstream (ie, prior to coronary angiography) in TACTICS to passivate the coronary arteries before cardiac catheterization and potential percutaneous coronary intervention (PCI), which were performed within 4 to 48 hours of randomization. Adding clopidogrel in these circumstances may lead to excessive anticoagulating effects when one considers that aspirin, heparin, and GP IIb/IIIa inhibitors are also all being used. Data from 823 patients who received GP IIb/IIIa inhibitors in the CURE study (5.9% of the combination group and 7.2% of the aspirin alone group) were promising, with a significant 18% reduction in the use of GP IIb/IIIa inhibitors in those assigned to dual antiplatelet therapy rather than aspirin alone. However, bleeding rates in these subgroups of patients were not disclosed. Further studies are needed to define the respective roles and safety of clopidogrel and GP IIb/IIIa inhibitors in upstream therapy (ie, prior to undergoing coronary angiography and intervention). Moreover, the addition of clopidogrel to aspirin resulted in a significant 43% reduction in the use of thrombolytic agents compared with aspirin (1.1% in the combination group and 2% in aspirin alone group), but no data on bleeding rates were provided.

The PCI-CURE Study

PCI-CURE,63 a prospective, randomized, double-blind, placebo-controlled study including 2658 patients from the CURE population who underwent PCI, tested the hypothesis that pretreatment with clopidogrel followed by long-term treatment (mean, 8 months) was superior to no pretreatment and short-term treatment (4 weeks) after PCI. All patients were receiving aspirin, and the randomization was between clopidogrel and placebo. Patients received the study drug for a median of 10 days prior to procedure and had a significant risk reduction of 30% in the primary combined end point of cardiovascular death, MI, and urgent revascularization within 30 days of PCI (4.5% vs 6.4%; P = .03). When events from PCI to end of follow-up were accounted for, long-term therapy with clopidogrel and aspirin (mean, 8 months) showed a significant 17% risk reduction in the combined triple end point compared with the 1-month-only, open-label thienopyridine treatment (18.3% vs 21.7%; P = .03). The benefit conferred by pretreatment and long-term treatment with clopidogrel was seen across all subgroups and as early as 2 days after PCI. This benefit was secondary to lower rates of MI, mostly non–Q-wave MI, while no statistically significant impact on survival was observed. Of interest, benefit from dual antiplatelet therapy was evident prior to the PCI procedure, compared with the effects of aspirin alone. No data regarding the number of patients receiving GP IIb/IIIa inhibitors or the incremental value of clopidogrel in these patients were provided. The authors also mentioned that there were no higher rates of excess bleeding in patients receiving dual antiplatelet treatment along with GP IIb/IIIa inhibitors. Whether these observations from PCI-CURE apply to the highly aggressive therapeutic approach of the United States is not clear, but other studies have found an incremental benefit to pretreatment with clopidogrel, in addition to GP IIb/IIIa inhibitor use, with PCI.64,65

Aspirin Resistance: A Potential Target for Combination Therapy With Clopidogrel?

By using 1 of 2 methods of platelet aggregometry, Gum et al4 demonstrated that rates of aspirin resistance reached 5% to 10% in a prospective study involving 325 patients with stable cardiac disease who received 325 mg of aspirin daily (as the sole antiplatelet drug) for at least 7 days. The rate of aspirin semiresponders exceeded 20% in that study as well. Moreover, PIA2 polymorphism, attributed to a single nucleotide polymorphism in the gene encoding the GP IIIa portion of the GPIIb/IIIa receptor, was associated with increased risk in patients with ACS; with in-stent thrombosis; and with restenosis associated with coronary stenting.6669 This is believed to be secondary to decreased platelet inhibition by aspirin, and patients with this sort of aspirin resistance may derive the greatest benefit from dual antiplatelet therapy. It would be interesting to study the pattern of aspirin resistance in a population like that of CURE to test this hypothesis, in view of the potential emergence of genomic testing and platelet aggregometry testing as means to identify aspirin-resistant patients. Recently, Eikelboom et al70 used urinary levels of 11-dehydrothomboxane B2 as a surrogate for aspirin resistance in a case-controlled substudy from the HOPE trial. They showed that urinary levels of 11-dehydrothomboxane B2 predict future cardiovascular outcomes, with a risk of cardiovascular death 3.5 times higher in patients having urinary levels of 11-dehydrothomboxane B2 in the upper quartile than in those whose levels are in the lower quartile (P<.001).

CONCLUSIONS

The CURE1 trial showed a significant improvement in the combined outcome of cardiovascular death, nonfatal MI, and stroke with the use of dual oral antiplatelet therapy (aspirin and clopidogrel). This benefit was seen as early as 24 hours after randomization and through to 12 months of follow-up. The combined aspirin and clopidogrel regimen in ACS was also associated with a lower incidence of heart failure, recurrent angina, revascularization, and ischemia. However, these benefits occurred at the expense of increased major and minor bleeding complications. Of note, the perioperative bleeding rate in patients who had received clopidogrel and aspirin in the 5 previous days was increased, and this may complicate use of this combination in patients where early coronary artery bypass graft surgery is anticipated. Pretreatment with clopidogrel a few days before PCI and its prolonged use afterwards for several months (beyond the 1-month routine use of thienopyridines) have shown increased benefit in patients with ACSundergoing PCI. In the future, genomic and platelet aggregometry testing in clinical practice may help identify the aspirin-resistant patient, who will potentially benefit the most from addition of clopidogrel therapy.

The current evidence strongly supports the use of dual antiplatelet therapy (aspirin and clopidogrel) in the long-term treatment (for at least 12 months) of patients with ACS after PCI, after which aspirin should be continued indefinitely. Longer-term clopidogrel use should then be considered based on patient risk. Low-dose aspirin (81 mg) is adequate in secondary prevention because it has similar antithrombotic efficacy and fewer side effects (gastrointestinal hemorrhage, hemorrhagic stroke) than the 325-mg dose. However, a patient presenting in the acute phase of an unstable coronary syndrome should be treated with at least 162 mg of aspirin (corresponding to 2 "baby" tablets) and preferably a full 325-mg aspirin tablet. The most recent data support the use of low-dose aspirin (81-mg daily dose), for primary prevention of CAD in men older than 50 years who are at high and intermediate risk for CAD. The risk estimates for future CAD events can be calculated using validated scores such as the Framingham risk score71 and should be weighed against aspirin side effects. Clopidogrel should substitute aspirin in primary prevention of CAD only in patients who are intolerant or resistant to aspirin. The combination of aspirin plus clopidogrel vs aspirin alone is being studied in both secondary prevention and high-risk primary prevention in the ongoing CHARISMA (Clopidogrel for High Atherothrombic Risk and Ischemic Stabilization Management and Avoidance) trial.

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Article Information

Corresponding author and reprints: Gary S. Francis, MD, Department of Cardiology/F25, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195 (e-mail: francig@cesmtp.ccf.org).

Accepted for publication July 25, 2002.

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