Aspirin and Clopidogrel in Acute Coronary Syndromes Therapeutic Insights from the CURE Study
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REVIEW ARTICLE Aspirin and Clopidogrel in Acute Coronary Syndromes Therapeutic Insights From the CURE Study Hani Jneid, MD; Deepak L. Bhatt, MD; Roberto Corti, MD; Juan J. Badimon, PhD; Valentin Fuster, MD, PhD; Gary S. Francis, MD latelet adhesion, activation, and aggregation are central to thrombus formation, which follows atherosclerotic plaque disruption and causes acute coronary syndromes. Aspi- rin and clopidogrel exert their antiplatelet effects by inhibiting thromboxane A2 pro- duction and adenosine diphosphate–induced platelet aggregation pathways, respec- Ptively. 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 espe- cially useful in combination with aspirin after coronary stent procedures. The CURE (Clopido- grel 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 spe- cial 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. Arch Intern Med. 2003;163:1145-1153 The CURE1 (Clopidogrel in Unstable An- same pathophysiology and includes un- gina to Prevent Recurrent Events) study pro- stable angina, non–ST-segment elevation vides evidence for the usefulness of clopi- myocardial infarction (MI), ST-segment el- dogrel in patients having acute coronary evation MI, and sudden death. Acute syndrome (ACS) without ST-segment el- thrombus formation on a disrupted ath- evation. The major finding of the study is erosclerotic plaque seems to be the major that clopidogrel given in conjunction with mechanism responsible for the onset of aspirin improves the outcome of patients ACS. The magnitude and stability of the with ACS compared with aspirin treat- thrombus formed is regulated by the na- ment alone. Clopidogrel appears to add in- ture of the exposed substrate (ie, the bio- cremental value to conventional therapy. chemical composition of the lesion and the The purpose of this review is to critically degree of injury); the local rheological con- analyze the findings of several antiplatelet ditions; and the presence of certain sys- trials with a focus on the CURE study, and temic factors affecting blood thromboge- to provide guidance in the use of aspirin and nicity (eg, hyperlipidemia and diabetes).2,3 clopidogrel for patients with ACS. Conventional antiplatelet therapy with as- pirin is designed to diminish platelet ag- PATHOPHYSIOLOGY OF ACS gregation, but aspirin is a relatively weak antiplatelet drug. Moreover, up to 10% of Acute coronary syndrome is a spectrum patients do not respond to the antiplate- of ischemic coronary events that share the let effects of aspirin.4 Thus, aspirin ef- fects, though important, are limited. Plaque disruption depends on both From the Division of Cardiology, University of Louisville, Louisville, Ky (Dr Jneid); 5 Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio (Drs Bhatt passive and active phenomena. Among the and Francis); and the Cardiovascular Biology Research Laboratory (Drs Corti and different vascular lesions, those character- Badimon) and the Zena and Michael A. Wiener Cardiovascular Institute (Dr Fuster), ized by a thin fibrous cap, a large athero- Mount Sinai Medical Center, New York, NY. Dr Bhatt has received honoraria for matous core, macrophage infiltration, and educational presentations from Sanofi-Synthelabo and Bristol-Myers-Squibb. a scarcity of smooth muscle cells are gen- (REPRINTED) ARCH INTERN MED/ VOL 163, MAY 26, 2003 WWW.ARCHINTERNMED.COM 1145 ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 is not lysed by endogenous tissue – plasminogen activator. Thienopyridines ADP The key role of platelet activa- tion and thrombosis in ACS is em- phasized by the significant clinical ADP Platelet benefits associated with the use of antiplatelet agents, such as aspirin (which blocks thromboxane A2 formation) and clopidogrel (which TXA2 inhibits ADP-induced platelet ag- gregation) (Figure 1). However, ADP ADP platelet aggregation is a complex – ADP GP llb/llla ADP pathophysiologic process; multiple Inhibitors ADP therapeutic agents may be required ADP simultaneously to block its redun- dant pathways. Cox AA TXA2 ADP ASPIRIN TXA2 TXA2 TXA Historic Antecedents Fibrinogen – 2 TXA2 GP llb/llla Receptor TXA2 Aspirin is known today to be an in- Aspirin expensive, safe, and effective anti- Inactive GP llb/llla platelet 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, 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 a chemist at Bayer’s laboratories, be- prothrombotic substances such as thromboxane A2 (TXA2) and adenosine diphosphate (ADP). Aspirin, came interested in salicylic acid. At thienopyridines, and GP IIb/IIa receptor inhibitors block various pathways of thrombus formation. that time, Hoffman’s rheumatic fa- AA indicates acetylsalicylic acid; Cox, cyclooxygenase. ther had grown intolerant to the so- dium salicylate available.11 Hoffman erally referred to as vulnerable plaques thrombin formation by activating developed and purified acetylsali- because of their high tendency to dis- the extrinsic coagulation cascade. cylic acid, which was marketed in ruption.5 The highest macrophage Thrombin then converts fibrinogen 1899 by the Bayer Company under density is encountered at the shoul- to fibrin and stabilizes the final clot the name of Aspirin (A for acetyl, and ders of the vulnerable plaque, where or red thrombus (secondary hemo- Spir for spiric acid, as salicylic acid was plaque rupture more frequently takes stasis)8 that leads in some cases to then known).11,12 It is ironic that the place. Macrophages produce proteo- ACS. Bayer Company, which promoted the lytic enzymes, especially matrix me- A meta-analysis of several post- drug for its efficacy in relieving rheu- talloproteinases, that actively dis- mortem studies involving patients matological conditions, issued a re- solve the matrix of the fibrous cap, who had died from cardiovascular assurance for the public that it did not leading to plaque rupture and expo- causes showed the presence of have harmful effects on the heart. sure of the underlying lipid core.6 The thrombus on disrupted lesions in ap- Though aspirin was first recognized lipid core, a highly thrombogenic proximately two thirds of cases. in the 1950s to reduce the incidence substance, is rich in tissue factor, a These “culprit” lesions causing acute of MI,13 mechanisms of its action re- glycoprotein responsible for initia- coronary events are usually eccen- mained unclear until 1967 when tion of the extrinsic coagulation cas- tric and moderately stenosed (Ͻ50% Weiss and Aledort14 published the cade.7 Once platelets are exposed to of the artery’s diameter).9 The re- first article to acknowledge the in- collagen and tissue factor, platelet ad- maining third of acute coronary hibitory effects of aspirin on plate- hesion occurs as the initial step, fol- events are secondary to eroded en- lets. Sir John R. Vane,15,16 who re- lowed by platelet activation and re- dothelium, which, in a highly throm- ceived the Nobel Prize for his work, lease of various vasoactive substances. bogenic blood milieu, leads to clot found a dose-dependent inhibition of These released substances, espe- formation. Eroded lesions usually in- prostaglandin formation with aspi- cially thromboxane A2 and adeno- duce more severe stenosis and oc- rin, salicylate, and indomethacin, and sine diphosphate (ADP), induce the cur more commonly at a younger provided further support for the binding of platelets to each other, age, in women, and in diabetic and therapeutic benefits of aspirin. His causing platelet aggregation and hyperlipidemic patients.10 Acute work and the work of others led also formation of white thrombus. myocardial ischemia, caused by re- to the discovery of thromboxane A2 While platelets secure the primary gional alteration in blood flow sec- and prostacyclin (PGI2) in 1975 and hemostasis at the site of ruptured ondary to acute thrombus forma- 1976, respectively.17,18 Now, more plaque, tissue factor induces tion, can lead to ACS if the thrombus than 100 years after its initial use, as- (REPRINTED) ARCH INTERN MED/ VOL 163, MAY 26, 2003 WWW.ARCHINTERNMED.COM 1146 ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 pirin is still the most widely used drug a major mechanism of action of as- 19 Membrane Lipid in the world. pirin occurs through its anti-inflam- (Phosphatidylcholine) matory effects (Figure 3). The rela- How Does Aspirin Work? tive quantitative antiplatelet and Phospholipase A2 – Corticosteroids anti-inflammatory benefits of aspi- Arachidonic Acid Aspirin irreversibly inhibits cyclooxy- rin in the treatment of coronary dis- Cyclooxygenase – Aspirin, NSAID genase, an enzyme responsible