Aspirin and Clopidogrel in Acute Coronary Syndromes Therapeutic Insights from the CURE Study

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 production 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 especially 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 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. 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 aspirin 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 effects, 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-

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is not lysed by endogenous tissue – plasminogen activator. Thienopyridines ADP The key role of platelet activation 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 aggregation) (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-

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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 for the ease are not entirely clear. Recent evi- formation of eicosanoids, which in- dence also points to potential Endoperoxides 15,20,21 clude PGI2 and thromboxane A2 antioxidative properties of aspirin. In 28 (Figure 2). Because thromboxane A2 one study, long-term administra- Prostacyclin Prostaglandins Thromboxane promotes platelet aggregation, the tion of aspirin to both normotensive (PGE, PGF) acetylation of cyclooxygenase by as- and hypertensive rats resulted in a de- Figure 2. Aspirin irreversibly blocks pirin decreases thromboxane genera- crease in nicotinamide adenine di- cyclooxygenase and inhibits thromboxane A2 tion in platelets, and therefore plate- nucleotide phosphate oxidase activ- production throughout the 7 to 10 days lifetime of the anucleated platelet. Prostacyclin is let aggregability, throughout the ity and, therefore, its generation of synthesized in endothelial cells, which recover platelet’s lifetime, which averages 7 to superoxide anion. However, the an- their cyclooxygenase function quickly, making 10 days. Because only 10% of plate- tioxidative properties of aspirin still aspirin effect on endothelial cells marginal compared with its antiplatelet effect. NSAID lets are replaced daily, a single dose need to be demonstrated in humans. indicates nonsteroidal anti-inflammatory drug. of aspirin inhibits aggregation in 50% of the platelets as late as 5 days after Antiplatelet Therapy Prevents administration; however, only 20% of Cardiovascular Events platelets, when not acetylated by as- Antiplatelet pirin, are enough to promote throm- The earliest comprehensive evi- 22 bus formation. Aspirin also inhib- dence for the efficacy of antiplate- Aspirin its PGI2 formation in endothelial cells. let therapy in preventing cardiovas- Analgesic PGI2 is an eicosanoid that inhibits cular events comes from the Antipyretic Anti-inflammatory platelet aggregation and antagonizes Antiplatelet Trialists’ Collabora- the “blood-thinning” effects of as- tion study.29 This study, published Figure 3. While aspirin acts as an antiplatelet pirin; but endothelial cells, unlike in 1994, is a meta-analysis encom- agent at low doses (Ͻ300 mg/d), it exerts the platelets, recover their cyclooxy- passing 145 randomized trials and antipyretic and analgesic effects at intermediate genase function quickly, and this including approximately 100000 pa- doses (300-2400 mg/d) and anti-inflammatory effect of aspirin appears to be short- tients, of whom 70000 were con- effects at higher doses (2400-4000 mg/d). Low-dose aspirin reaches appreciable plasma lived and marginal compared with sidered in the high-risk category be- levels by 20 minutes and exerts antiplatelet its antiplatelet effects.22 Aspirin cause they had, or were at risk for, effects within 60 minutes. reaches appreciable plasma levels by vascular disease. The meta-analysis 20 minutes and exerts its platelet- found a 25% reduction in the com- risk patients.30 Their systematic re- inhibitory effect within 60 min- bined end point of MI, stroke, and view included 287 studies (up to utes.23 It is recommended that aspi- vascular death in users of antiplate- 1997) and involved patients with rin-naive patients having ACS chew let therapy (PϽ.001). There was also acute MI; acute ischemic stroke; pre- a loading dose of at least 160 mg of a reduction of 34% in nonfatal MI vious MI; previous stroke or tran- aspirin to receive prompt antiplate- rates, of 25% in nonfatal stroke rates, sient ischemic attack; coronary ar- let effect.24,25 of 17% in vascular death rates, and tery disease (CAD) from other The benefits of aspirin emanate of 16% in mortality rates from any categories; and peripheral arterial dis- not only from its antiplatelet effects, cause. No evidence of increase in ease. It also included patients at risk but potentially also from its anti- nonvascular death rates was noted of embolism and other conditions inflammatory properties. Atheroscle- with antiplatelet therapy. Direct that placed them at high risk (diabe- rosis is known to be a chronic in- comparisons of the different anti- tes, hemodialysis, carotid disease). flammatory disease of the vessel platelet regimens were conducted The main outcome measured was se- wall,26 and it is not surprising that in in 10000 patients, and no advan- rious vascular event defined as non- a prospective study involving 543 ap- tage of high-dose aspirin or any fatal MI, nonfatal stroke, or vascular parently healthy men participating in other antiplatelet drug over the death. The Antithrombotic Trialists’ the Physicians’ Health Study, base- medium dose of aspirin (75-325 Collaboration group demonstrated a line C-reactive protein levels pre- mg) was found. Not unexpectedly, 22% overall odds reduction of seri- dicted future MI and stroke events.27 the beneficial effect of antiplatelet ous vascular events in patients tak- Incidentally, the benefits of aspirin in therapy was demonstrated across ing antiplatelet therapy compared this prospective analysis are seen all patient subsets of the study, but with controls (10.7% vs 13.2%; mainly among men whose C- the benefits were greater in the PϽ.001) and approximately a one- reactive protein levels are in the high- high-risk group. sixth reduction in all-cause mortal- est quartile, with a small, nonsignifi- The Antithrombotic Trialists’ ity (PϽ.001). The benefit was high- cant reduction among those whose Collaboration group recently pub- est in patients with acute MI (30% C-reactive protein levels are in the lished an updated meta-analysis of all odds reduction) and lowest in pa- lowest quartile.27 This suggests that randomized antiplatelet trials in high- tients with acute stroke (11% odds

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Trial Patients Antiplatelet Regimen Major Findings Remarks Lewis et al,31 1983 1266 Men with unstable 324 mg of buffered aspirin A 50% reduction in the A significant 51% angina solution daily vs combined primary end reduction was placebo for 12 wk point of death/nonfatal observed in each of MI after 12 wk of the individual follow-up outcomes of death and nonfatal MI ISIS-2 (Second 17 187 Patients with 160 mg of aspirin daily vs A 23% reduction in total The significant benefit was International Study of suspected MI placebo for 5 wk vascular mortality persistent at 15 mo of Infarct Survival),32 median follow-up 1988 US Physician’s Health 22 701 Healthy physicians 325 mg of aspirin on A 44% decrease in first Nonsignificant trend Study,33 1989 alternating days vs MI; benefits mostly toward higher stroke placebo those older than 50 y rates; mostly hemorrhagic Thrombosis Prevention 5085 High-risk male 75 mg of aspirin daily vs A 20% relative reduction in Benefits mostly derived Trial (TPT),34 1998 patients from the placebo composite of coronary from reduction in United Kingdom death and nonfatal MI nonfatal MI events Hypertension Optimal 18 790 Female and male 75 mg of aspirin daily vs A 15% relative reduction in No significant impact on Treatment (HOT) hypertensive patients placebo vascular events; 36% CV mortality trial,35 1998 (Ͼ92% of patients reduction in MI have no known CAD)

Abbreviations: CAD, coronary artery disease; CV, cardiovascular; MI, myocardial infarction.

reduction). The main outcome was group. The Second International marily in patients older than 50 mostly driven by a 34% reduction in Study of Infarct Survival (ISIS-2)32 years. However, there was no ben- nonfatal MI and a 25% reduction in was a similar landmark trial of acute eficial effect of aspirin on cardiovas- nonfatal stroke, as vascular death was MI. The study showed that a daily cular mortality (the primary end reduced by only 15% (PϽ.001). Most 160-mg aspirin tablet, started within point). Treated patients also showed importantly, indirect comparisons of the first day of MI and continued for a nonsignificant trend toward higher various aspirin regimens in the meta- 5 weeks, conferred a significant 23% rates of strokes, mostly hemor- analysis showed that a daily dose of risk reduction in total vascular mor- rhagic, compared with patients tak- aspirin in the range of 75 to 150 mg tality, as well as a similar magnitude ing placebo. The benefits of aspirin appears adequate. However, in clini- of risk reduction from all-cause mor- in primary prevention of cardiovas- cal situations demanding immedi- tality. Although the survival curves cular disease in high-risk patients ate antithrombotic effect, such as converged slightly over time, a sig- were later corroborated by other pri- ACS, a loading dose of 150 to 325 mg nificant survival benefit was still mary prevention studies. The of aspirin is still considered the stan- maintained after 15 months of me- Thrombosis Prevention Trial (TPT)34 dard choice. While there was no ben- dian follow-up. There was an accom- demonstrated a 20% relative reduc- efit from adding dipyridamole to as- panying small absolute excess in mi- tion in the combined end point of pirin, addition of intravenous nor bleeding events (0.6% vs 0.2%), coronary death and nonfatal MI in glycoprotein (GP) IIb/IIIa inhibi- but no significant increase in hem- 5085 high-risk male patients in the tors to aspirin resulted in a 19% in- orrhagic strokes or bleeding events United Kingdom. The beneficial crease in the reduction of serious vas- requiring transfusions. Aspirin effect of the daily 75-mg dose of as- cular events. therapy has now become conven- pirin used in this study consisted al- Several landmark trials estab- tional for all patients suspected of most entirely in the incidence re- lished the efficacy of aspirin, par- having an ACS.36 duction of nonfatal events. The ticularly in primary and secondary Aspirin’s benefits in primary Hypertension Optimal Treatment prevention of CAD (Table 1). prevention of CAD are supported by (HOT)35 trial randomized 18790 hy- Lewis and colleagues31 con- many trials as well. The US Physi- pertensive female and male pa- ducted one of the earliest placebo- cians’ Health Study33 was the first tients, most of whom with no known controlled randomized trials of aspi- and largest primary prevention study CAD, to receive 75 mg of aspirin rin in patients with ACS. In a of aspirin in cardiovascular dis- daily or placebo. A 15% reduction multicenter double-blind trial enroll- ease. A total of 22701 healthy phy- in vascular events and 36% reduc- ing 1266 men with unstable angina, sicians received 325 mg of aspirin on tion in MI were observed, but no sig- the combined primary end point of alternating days. The aspirin arm of nificant impact on cardiovascular death and nonfatal MI at 12 weeks the study was terminated early (af- mortality. A meta-analysis in pri- was reduced by 50% in patients re- ter an average follow-up of 60 mary prevention conducted by San- ceiving aspirin rather than placebo. months) when a 44% reduction in muganathan et al37 included the 3 Death and nonfatal MIs were also the risk of first MI was observed. above trials, along with a study on each reduced by 50% in the aspirin This beneficial effect was seen pri- British male physicians,38 and found

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 significant 15% and 30% reduc- tions in cardiovascular events and Table 2. Clopidogrel Landmark Trials MI, respectively. They concluded that aspirin in primary prevention is Trial Patients Antiplatelet Regimen Major Finding safe and useful in patients with a Clopidogrel in 12 562 Patients with Aspirin, 325 mg + A 20% reduction in 1-year coronary event risk greater Unstable angina acute clopidogrel, composite of to prevent non−ST-segment 75 mg vs aspirin, nonfatal MI, than or equal to 1.5%. The benefits Recurrent Events elevation 325 mg + placebo stroke, and CV of aspirin in primary prevention of (CURE),1 2001 death after a CAD apply to women as well.39 In mean follow-up of an analysis from the Nurses’ Health 9mo Study,40 women taking 1 to 6 tab- Clopidogrel versus 19 185 Patients with Clopidogrel, 75 mg/d An 8.7% relative Aspirin in Patients recent MI, stroke, vs aspirin, 325 reduction in the lets of aspirin weekly had a 25% at Risk of or PAD symptoms mg/d composite of MI, (P=.04) relative risk reduction of Ischemic Events ischemic stroke, first myocardial infarction in mul- (CAPRIE),47 1996 and vascular tivariate analysis. The relative risk death after an average follow-up reduction of first MI was even of 1.9 y higher, reaching 32% (P=.02) in Clopidogrel for the 2116 Patients Aspirin, 325 mg + A 26.9% reduction in women older than 50 years. Reduction of undergoing clopidogrel, the composite of A recent observational study Events during elective PCI or at 75 mg vs aspirin, death, MI, or showed a 33% survival benefit from Observation high likelihood to 325 mg + placebo stroke after 1 y (CREDO),56 2002 undergo PCI (both arms of follow-up aspirin in a multivariate analysis in received stable patients with known or sus- combination pected CAD undergoing stress ech- therapy in the first ocardiography.41 The greatest ben- 30 d) efit from aspirin was observed in Abbreviations: CV, cardiovascular; MI, myocardial infarction; PAD, peripheral artery disease; older patients, patients with known PCI, percutaneous coronery intervention. CAD, and patients with impaired ex- ercise capacity. neous coronary intervention, where in patients with cardiovascular dis- CLOPIDOGREL its efficacy is proven. ease. It included a total of 19185 patients, distributed among 3 sepa- An Inhibitor of ADP-Induced Thienopyridines Are Superior rately enrolled groups of patients Platelet Aggregation to Placebo in Preventing with recent MI, stroke, or symp- Vascular Events toms secondary to peripheral arte- Adenosine diphosphate is a sub- rial disease. After an average of 1.9 stance released by activated plate- Clopidogrel, the newer thienopyri- years of follow-up, the data demon- lets that amplifies platelet aggrega- dine, has not been compared with strated a statistically significant 8.7% bility.42 The platelet ADP receptor is placebo. Older trials, however, com- relative risk reduction in the com- coupled to a G protein and sub- pared the therapeutic effects of ticlo- bined end point of MI, ischemic serves calcium release from inter- pidine and placebo and found a sta- stroke, and vascular death. Severe in- nal cytosolic stores upon activa- tistically significant superiority of tracranial hemorrhage and gastro- tion. This leads to conformational ticlopidine. Men and women pre- intestinal bleeding events occurred changes in and activation of the GP senting with thromboembolic stroke in 0.33% and 0.52% of patients, re- IIb/IIIa receptor, and to fibrinogen and randomly assigned to ticlopi- spectively, with clopidogrel. The rate binding and platelet aggregation.36 dine had a 23% reduction in the com- of ever-reported gastrointestinal Thienopyridine analogues (ticlopi- bined end point of stroke, MI, and bleeding complication was signifi- dine and clopidogrel) irreversibly in- vascular death after a mean fol- cantly lower in the clopidogrel group hibit the binding of ADP to its re- low-up of 2 years.45 Another random- than in the aspirin group (1.99% vs ceptor. Clopidogrel has a quicker ized controlled trial of ticlopidine in 2.66%; PϽ.002), and no difference onset of action, and appears to be patients with unstable angina showed in intracerebral hemorrhage, hem- safer than ticlopidine, an earlier a 46% reduction in the primary com- orrhagic death, thrombocytopenia, thienopyridine. Inhibition of ADP- bined end point of vascular death and or neutropenia was noted between induced platelet aggregation oc- MI compared with placebo.46 the 2 groups.48 curs 2 hours after a 300-mg load- Despite clopidogrel’s apparent ing dose of clopidogrel.43,44 CAPRIE: The Rise of a Star success, the difference between the Clopidogrel was approved in 2 antiplatelet therapies was modest 1997 for use in secondary preven- Clopidogrel vs Aspirin in Patients at (equivalent to 5 events per 1000 tion of cardiovascular disease, and has Risk of Ischemic Events (CAPRIE)47 patients). The cost to save 1 life in the been in widespread use since then was a randomized head-to-head trial CAPRIE study was $8181 for aspi- (Table 2). It is most commonly used comparing the efficacy and safety of rin and $49367 for clopidogrel, con- for the unlabeled indication of anti- a daily 75-mg dose of clopidogrel ferring a 7-fold cost advantage to as- platelet activity following percuta- with a daily 325-mg dose of aspirin pirin.42 On the other hand, the

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 absolute risk reduction reached with demonstrated lower rates of major 12562, 39% were women, 23% had clopidogrel may be higher when the adverse cardiac events and in addi- diabetes, 59% had hypertension, and drug is used in actual clinical prac- tion to the known adverse effects 59% were current or former smok- tice. Lower event rates might have oc- with clopidogrel and concluded that ers; only 13 were lost to follow-up. curred because of the “healthy pa- clopidogrel plus aspirin should be tient” selection bias inherent in the standard antiplatelet regimen af- Main Results. Using clopidogrel plus studies such as CAPRIE, and this may ter stent deployment. aspirin significantly reduced the risk translate into a lower number of pa- of the first primary composite end tients needing treatment and better COMBINING CLOPIDOGREL point of nonfatal MI, stroke, and car- cost-effectiveness for clopidogrel in AND ASPIRIN: DOES IT WORK? diovascular death (9.3% vs 11.4%, for clinical practice.49 Furthermore, the a reduction of 20%) compared with benefit of clopidogrel over aspirin ap- Experimental studies have shown aspirin alone.1 There was also a sig- pears to be amplified in high-risk pa- synergy between the thienopyri- nificant risk reduction rate of 14% in tients. In a post hoc analysis from the dines and aspirin.58-60 This is biologi- the second primary composite of car- CAPRIE study, Bhatt et al50 demon- cally plausible because they act diovascular death, stroke, nonfatal strated the benefit of clopidogrel over through independent mechanisms. MI, and refractory ischemia (16.5% aspirin in patients who had prior sur- Their combination inhibits ADP- vs 18.8%). The superiority of the gical revascularization. induced platelet activation and throm- combined antiplatelet regimen was boxane A2 production, 2 different also observed across a number of im- Thienopyridine Use After pathways that affect platelet aggrega- portant secondary end points: inci- Percutaneous Coronary bility.61 Clopidogrel in Unstable an- dence rates were lowered by 26% for Intervention gina to prevent Recurrent Events severe ischemia, by 9% for recur- (CURE),1 the largest randomized ACS rent angina, by 8% for revasculariza- Clopidogrel has an efficacy similar trial to date, tested the efficacy of the tion procedures, and by 18% for evi- to that of ticlopidine in preventing combination of aspirin and clopido- dence of heart failure. It must be stent thrombosis.51-54 Because of its grel compared with aspirin alone. stressed, however, that the compos- better safety profile, however, clo- ite end points were driven mainly by pidogrel has replaced ticlopidine as The CURE Trial the statistically significant decrease in the favored thienopyridine follow- the MI risk reduction rate (5.2% vs ing stent implantation. Neutrope- Study Design. The CURE study1 was 6.7%, for a reduction of 23%), while nia is associated with ticlopidine but a randomized, double-blind trial in- other individual outcomes showed not with clopidogrel; and although volving 482 centers from 28 coun- nonsignificant trends toward lower rare cases of thrombotic thrombo- tries (mostly European and South event rates: a 14% RR for stroke, a 7% cytopenic purpura have been de- American, plus Canada and the RR for cardiovascular death, and a 7% scribed with clopidogrel (3-4 cases United States). It investigated RR for refractory ischemia. per million), causality has not been whether prolonged combined treat- established.55 ment with aspirin and clopidogrel Observations and Subgroup Analy- Clopidogrel is usually given for would have incremental benefit over ses From CURE. The superiority of 1 month after stent implantation, but aspirin alone in vascular outcomes the combination of aspirin and clo- many physicians argue for a longer in patients having ACS without ST- pidogrel appeared early in the course duration of therapy. How long one segment elevation MI. of treatment, with significant ben- should use clopidogrel after percu- A total of 12562 patients diag- efit occurring during the first 24 taneous coronary intervention has nosed as having ACS without ST- hours. This superiority was main- recently been the subject of a clini- segment elevation were random- tained through the 12-month study. cal trial. Clopidogrel for the Reduc- ized within 24 hours of symptom At randomization, 25% of patients tion of Events During Observation onset to receive either a combina- were taking lipid-lowering agents, (CREDO) was a multicenter, double- tion of aspirin and clopidogrel (6259 58% ␤-blockers, 36% angiotensin- blind study of patients with stable patients) or aspirin and placebo converting enzyme inhibitors, and and unstable angina who were un- (6303 patients). 72% were receiving unfractionated or dergoing percutaneous coronary in- The clopidogrel group re- low-molecular-weight heparin anti- tervention. The trial emonstrated the ceived an immediate loading dose of coagulant therapy. Nevertheless, sub- safety and efficacy of clopidogrel 300 mg of clopidogrel followed by group analyses showed that the ben- treatment before the procedure, and 75 mg of clopidogrel daily, while as- efit of the combined regimen was the beneficial effects of prolonged (1- pirin was given to both groups at maintained irrespective of the medi- year) vs short-term (1-month) dual doses ranging from 75 mg to 325 mg cations the patients were taking. antiplatelet therapy.56 daily at the treating physician’s dis- There was also consistent benefit Recently, Bhatt and col- cretion. Treatment continued from across different doses of aspirin and leagues57 performed a meta- 3 to 12 months (mean, 9 months), various risk groups, though the larg- analysis of the major randomized during which the patients had se- est benefit (a 44% risk reduction) was trials and registries comparing clo- rial follow-up evaluations. observed in patients with prior re- pidogrel and ticlopidine use after The mean age of patients was vascularization. Dual antiplatelet coronary stent deployment. They 64 years. Of this population of therapy was superior whether or not

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 patients were taking medications of compared with 2050 patients from prior to procedure and had a signifi- proven survival benefit, such as Poland, for example). The Therapy cant risk reduction of 30% in the pri- ␤-blockers or statins, at randomiza- with an Invasive or Conservative mary combined end point of cardio- tion. Thus, the incremental benefit of Strategy (TACTICS)–Thrombolysis vascular death, MI, and urgent clopidogrel could not be attributed in Myocardial Infarction (TIMI) 18 revascularization within 30 days of to a higher risk profile of subopti- trial62 showed clear benefit of the early PCI (4.5% vs 6.4%; P=.03). When mally treated patients. invasive strategy in ACS without ST- events from PCI to end of follow-up segment elevation, and many centers were accounted for, long-term therapy Higher Bleeding Rates With Dual in the United States have adopted a with clopidogrel and aspirin (mean, Antiplatelet Therapy. Patients as- similar aggressive strategy. Tirofiban 8 months) showed a significant 17% signed to the dual antiplatelet regi- was used upstream (ie, prior to coro- risk reduction in the combined triple men had higher rates of major and nary angiography) in TACTICS to end point compared with the minor bleeding, but no increase in passivate the coronary arteries before 1-month-only, open-label thienopy- life-threatening bleeding or intra- cardiac catheterization and potential ridine treatment (18.3% vs 21.7%; cranial hemorrhage. percutaneous coronary intervention P=.03). The benefit conferred by pre- Compared with aspirin use (PCI), which were performed within treatment and long-term treatment alone, a significant 1.38 relative risk of 4 to 48 hours of randomization. Add- with clopidogrel was seen across all major bleeding episodes (P=.001)— ingclopidogrelinthesecircumstances subgroups and as early as 2 days af- mostly bleeding caused by PGI2 and may lead to excessive anticoagulat- ter PCI. This benefit was secondary bleeding at the puncture site—and a ing effects when one considers that to lower rates of MI, mostly non–Q- significant 2.12 relative risk of mi- aspirin, heparin, and GP IIb/IIIa in- wave MI, while no statistically sig- nor bleeding episodes (PϽ.001) were hibitors are also all being used. Data nificant impact on survival was ob- observed in the dual antiplatelet from 823 patients who received GP served. Of interest, benefit from dual therapy group. IIb/IIIa inhibitors in the CURE study antiplatelet therapy was evident prior Although 6 of every 1000 pa- (5.9% of the combination group and to the PCI procedure, compared with tients required blood transfusions, 7.2% of the aspirin alone group) were the effects of aspirin alone. No data the excess bleeding risk in the com- promising, with a significant 18% re- regarding the number of patients re- bined treatment was no higher than duction in the use of GP IIb/IIIa in- ceiving GP IIb/IIIa inhibitors or the that seen in trials comparing the ef- hibitors in those assigned to dual an- incremental value of clopidogrel in fects of aspirin and placebo, and tiplatelet therapy rather than aspirin these patients were provided. The au- lower than that seen in intravenous alone. However, bleeding rates in thors also mentioned that there were GP IIb/IIIa inhibitor trials, both of these subgroups of patients were not no higher rates of excess bleeding in which being accepted treatments. disclosed. Further studies are needed patients receiving dual antiplatelet There was no significant differ- to define the respective roles and treatment along with GP IIb/IIIa in- ence in the rates of life-threatening safety of clopidogrel and GP IIb/IIIa hibitors. Whether these observa- bleeding events (nonsignificant 21% inhibitors in upstream therapy (ie, tions from PCI-CURE apply to the higher rates), hemorrhagic strokes, prior to undergoing coronary angi- highly aggressive therapeutic thrombocytopenia, and neutrope- ographyandintervention).Moreover, approach of the United States is nia between the 2 groups of the study. the addition of clopidogrel to aspirin not clear, but other studies have No cases of thrombotic thrombocy- resulted in a significant 43% reduc- found an incremental benefit to topenic purpura occurred in the tion in the use of thrombolytic agents pretreatment with clopidogrel, in CURE study. compared with aspirin (1.1% in the addition to GP IIb/IIIa inhibitor combination group and 2% in aspi- use, with PCI.64,65 Use of Dual Antiplatelet Therapy rinalonegroup),butnodataonbleed- in Patients Awaiting Percutaneous ing rates were provided. Aspirin Resistance: Transluminal Coronary Artery A Potential Target for Angioplasty and Coronary Artery The PCI-CURE Study Combination Therapy With Clopidogrel? No significant excess in bleeding was PCI-CURE,63 a prospective, random- seen when clopidogrel was stopped ized, double-blind, placebo- By using 1 of 2 methods of platelet ag- a median of at least 5 days before controlled study including 2658 pa- gregometry, Gum et al4 demonstrated coronary artery bypass graft sur- tients from the CURE population who that rates of aspirin resistance reached gery; however, a 53% higher rate of underwent PCI, tested the hypoth- 5% to 10% in a prospective study in- major bleeding events was ob- esis that pretreatment with clopido- volving 325 patients with stable car- served in the combination group, grel followed by long-term treat- diac disease who received 325 mg of and the events were stopped less ment (mean, 8 months) was superior aspirin daily (as the sole antiplatelet than 5 days before the procedure. to no pretreatment and short-term drug) for at least 7 days. The rate of It is important to note that most treatment (4 weeks) after PCI. All pa- aspirinsemirespondersexceeded20% patients were recruited from centers tients were receiving aspirin, and the in that study as well. Moreover, PIA2 where early invasive procedures were randomization was between clopido- polymorphism, attributed to a single notroutinelyperformed(only462pa- grel and placebo. Patients received the nucleotide polymorphism in the gene tients were from the United States study drug for a median of 10 days encoding the GP IIIa portion of the

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 GPIIb/IIIa receptor, was associated nomic and platelet aggregometry test- 2. Rauch U, Osende JI, Fuster V, Badimon JJ, Fayad with increased risk in patients with ing in clinical practice may help iden- Z, Chesebro JH. Thrombus formation on atherosclerotic plaques: pathogenesis and clinical con- ACS; with in-stent thrombosis; and tify the aspirin-resistant patient, who sequences. Ann Intern Med. 2001;134:224-238. with restenosis associated with coro- will potentially benefit the most from 3. Badimon JJ, Zaman A, Helft G, Fayad Z, Fuster V. nary stenting.66-69 This is believed to addition of clopidogrel therapy. Acute coronary syndromes: pathophysiology and be secondary to decreased platelet in- The current evidence strongly preventive priorities. Thromb Haemost. 1999;82: supports the use of dual antiplatelet 997-1004. hibition by aspirin, and patients with 4. Gum PA, Kottke-Marchant K, Poggio ED, et al. Pro- this sort of aspirin resistance may de- therapy (aspirin and clopidogrel) in file and prevalence of aspirin resistance in pa- rive the greatest benefit from dual an- the long-term treatment (for at least tients with cardiovascular disease. Am J Cardiol. tiplatelet therapy. It would be inter- 12 months) of patients with ACS af- 2001;88:230-235. esting to study the pattern of aspirin ter PCI, after which aspirin should be 5. Fuster V, Fayad ZA, Badimon JJ. Acute coronary syndromes: biology. Lancet. 1999;353(suppl 2): resistance in a population like that continued indefinitely. Longer-term SII5-9. of CURE to test this hypothesis, in clopidogrel use should then be con- 6. Moreno PR, Falk E, Palacios IF, Newell JB, Fus- view of the potential emergence of ge- sidered based on patient risk. Low- ter V, Fallon JT. Macrophage infiltration in acute nomic testing and platelet aggregom- dose aspirin (81 mg) is adequate in coronary syndromes: implications for plaque rup- etry testing as means to identify secondary prevention because it has ture. Circulation. 1994;90:775-778. 7. Toschi V, Gallo R, Lettino M, et al. Tissue factor aspirin-resistant patients. Recently, similar antithrombotic efficacy and modulates the thrombogenicity of human athero- 70 Eikelboom et al used urinary levels fewer side effects (gastrointestinal sclerotic plaques. Circulation. 1997;95:594-599. of 11-dehydrothomboxane B2 as a sur- hemorrhage, hemorrhagic stroke) 8. Cannon CP, Fuster V. Thrombogenesis, antithrom- rogate for aspirin resistance in a case- than the 325-mg dose. However, a pa- botic, and thrombolytic therapy. In: Fuster V, Al- controlled substudy from the HOPE tient presenting in the acute phase of exander RW, O’Rourke RA, eds. Hurst’s The Heart. 10th ed. New York, NY: McGraw-Hill Book Co; trial. 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Analgesic-antipyretics and CONCLUSIONS ate risk for CAD. The risk estimates anti-inflammatory agents: drugs employed in the treatment of gout. In: Gilman AG, Goodman IS, for future CAD events can be calcu- Rall TW, Murad F, eds. Goodman and Gilman’s 1 The CURE trial showed a signifi- latedusingvalidatedscoressuchasthe The Pharmacological Basis of Therapeutics.7th cant improvement in the combined Framingham risk score71 and should ed. New York, NY: Macmillan; 1995:674-675. outcome of cardiovascular death, be weighed against aspirin side effects. 13. Craven L. Experiences with aspirin (acetylsalicyclic nonfatal MI, and stroke with the use Clopidogrel should substitute aspirin acid) in the nonspecific prophylaxis of coronary thrombosis. Miss Valley Med J. 1953;75:38-40. of dual oral antiplatelet therapy (as- in primary prevention of CAD only in 14. Weiss HJ, Aledort LM. Impaired platelet- pirin and clopidogrel). This benefit patients who are intolerant or resis- connective-tissue reaction in man after aspirin in- was seen as early as 24 hours after ran- tant to aspirin. The combination of as- gestion. Lancet. 1967;2:495-497. domization and through to 12 months pirin plus clopidogrel vs aspirin alone 15. Vane JR. Inhibition of prostaglandin synthesis as isbeingstudiedinbothsecondarypre- a mechanism of action for aspirin-like drugs. Nat of follow-up. The combined aspirin New Biol. 1971;231:232-235. and clopidogrel regimen in ACS was ventionandhigh-riskprimarypreven- 16. Ferreira SH, Moncada S, Vane JR. Indomethacin also associated with a lower inci- tion in the ongoing CHARISMA (Clo- and aspirin abolish prostaglandin release from the dence of heart failure, recurrent an- pidogrelforHighAtherothrombicRisk spleen. Nat New Biol. 1971;231:237-239. gina, revascularization, and ische- and Ischemic Stabilization Manage- 17. Hamberg M, Svensson J, Samuelsson B. Throm- ment and Avoidance) trial. boxanes: a new group of biologically active mia. However, these benefits occurred compounds derived from prostaglandin endoper- at the expense of increased major and oxides. Proc Natl Acad Sci U S A. 1975;72:2994- minor bleeding complications. Of Accepted for publication July 25, 2002. 2998. note, the perioperative bleeding rate Corresponding author and re- 18. Moncada S, Gryglewski R, Bunting S, Vane JR. in patients who had received clopi- An enzyme isolated from arteries transforms pros- prints: Gary S. Francis, MD, Depart- taglandin endoperoxides to an unstable sub- dogrel and aspirin in the 5 previous ment of Cardiology/F25, Cleveland stance that inhibits platelet aggregation. Nature. days was increased, and this may Clinic Foundation, 9500 Euclid Ave, 1976;263:663-665. complicate use of this combination in Cleveland, OH 44195 (e-mail: francig 19. Mann CC. 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