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The Journal of Emergency Medicine, Vol. 35, No. 1, pp. 87–90, 2008Copyright © 2008 Elsevier Inc.

Printed in the USA. All rights reserved0736-4679/08 $–see front matter

Editorial

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ANTIPLATELET THERAPY IN ACUTEORONARY SYNDROME: NOT ASONFUSING AS YOU THINK

he approach to the patient with an acute coronaryyndrome (ACS) has undergone many remarkable ad-ances in the past 30 years. These improvements includeoth diagnostic methods and therapeutic interventions.iagnostically, the 12-lead electrocardiogram and re-

ated imaging, serum markers, echocardiography, anduclear scanning, used in appropriate systems of care,ave all increased the emergency physician’s ability tovaluate patients suspected of ACS. Therapeutically, fi-rinolytic therapy and interventional, catheter-based tech-iques have revolutionized the treatment of patients withT-segment elevation myocardial infarction (STEMI); ad-

unctive therapies with antiplatelet, antithrombotic, and ad-energic blocking agents continue to improve the outcomef selected patients with all forms of ACS—STEMI, non-T-segment elevation myocardial infarction (NSTEMI),nd unstable angina (USA).

Antiplatelet therapy represents one such significantdvancement in ACS care. The review in this edition ofhe Journal of Emergency Medicine by Pollack and Hol-ander investigates the current literature base—often be-ildering in scope, content, and depth—concerning an-

iplatelet therapy in the ACS patient (USA, NSTEMI,nd STEMI), making recommendations regarding theirse (1). The agents reviewed by the authors includespirin (ASA), IIb/IIIa glycoprotein inhibitors (GPI), andlopidogrel. Certainly, ASA and GPI have more or lessound their niches in the emergency department (ED)CS patient. Clopidogrel, in many ways, has yet to find

ts specific niche in the ED.In the ACS patient, dramatic reductions in morbidity

nd mortality have been seen with the administration ofhese agents. Aspirin, the original antiplatelet agent, rep-esents the most cost-effective treatment available inCS management; mortality reductions in myocardial

nfarction are very impressive, ranging from 25% to0%, particularly when used with reperfusion therapy.he ISIS-2 trial provides the strongest evidence thatspirin independently reduces the mortality of patientsith acute myocardial infarction (AMI) without fibrino-

ytic therapy (overall 23% reduction) and is synergistic e

87

hen used with fibrinolytic therapy (42% reduction inortality) (2). The most appropriate dose for the emer-

ency physician is 162–325 mg given once in the EDoon after arrival (3). Essentially, the only contrain-ications to ASA therapy in the ED chest pain patientuspected of ACS are serious aspirin allergy and ac-ive, clinically significant hemorrhage. The emergencyhysician should strongly consider ASA use in theatient suspected of ACS early in the evaluation. Thisecommendation is straightforward with significantbjective support. In fact, the American College ofardiology/American Heart Association (ACC/AHA),

n the 2007 Guidelines, recommends the use of ASAarly in the evaluation of the USA, NSTEMI, orTEMI patient (Class I recommendation with level Avidence) (4,5).

The GPIs are a potent class of antiplatelet agent withemarkable success in reducing morbidity and mortalityn the acute coronary syndrome patient; these agents,owever, have demonstrated significant clinical utility innly a subset of ACS patients—those undergoing percu-aneous coronary intervention. Numerous trials haveemonstrated their effectiveness in ACS patients man-ged with a catheter-based management strategy, includ-ng the EPIC trial, the EPILOG trial, and the IMPACT-IIrial (6–8). In these trials, significant reductions in re-urrent ACS, urgent revascularization, and death wereoted. Furthermore, a meta-analysis noted that ACS pa-ients who underwent percutaneous coronary interven-ion (PCI) benefited markedly from glycoprotein inhibi-or use (9). Conversely, in ACS patients who areanaged medically without mechanical revasculariza-

ion, consistent benefit with GPI therapy is not found.or instance, the GUSTO IV trial, the PRISM trial, theRISM-PLUS trial, and the IMPACT-AMI failed toemonstrate consistent benefit in the ACS patient man-ged medically, that is, without PCI (10–12).

These trial results were further supported by a meta-nalysis that found that GPI use did not improve theutcome of the ACS patient managed in a conservativeashion (9).

The ACC/AHA guidelines have suggested the follow-ng with respect to GPI use in the ACS patient: initiallylanned, early PCI (Class I recommendation with level A

vidence), and initial conservative therapy with recurrent

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88 Editorial

r recalcitrant symptoms and subsequent planned PCIClass IIa recommendation with level B/C evidence)4,5).

Clopidogrel, a thienpyridine antiplatelet agent, is aery potent platelet inhibitor; clopidogrel inhibits theransformation of the glycoprotein IIb-IIIa receptor intots high-affinity binding state, thus preventing plateletggregation for the duration of the life of the platelet.

When considering clopidogrel administration to a pa-ient with ACS in the ED, issues for the emergencyhysician to consider include ability to tolerate ASA,nitial management (medical vs. PCI), time-to-PCI per-ormance in catheter-based strategies, and the potentialeed for coronary artery bypass grafting (CABG). Per-aps the most “black-and-white” indication for clopi-ogrel in the ED is the high-risk ACS patient who isntolerant to ASA. This high-risk presentation would beharacterized by objective abnormality; either meaning-ul positive serum marker value or a clinically signifi-ant, abnormal 12-lead electrocardiogram. In this in-tance, of course, medical intolerance indicates trueedical intolerance of ASA in the form of significant,

otentially life-threatening allergic event—not gastroin-estinal upset. The ACC/AHA Guidelines 2007, in fact,ist this as an acceptable indication (4).

The particular management strategy selected for aatient is a significant consideration in the decision todminister clopidogrel early in the management course.learly, ACS patients managed medically, or with a

trategy of deferred cardiac catheterization, are potentialandidates for clopidogrel (13–16). In fact, ACS patientsanaged with medical therapy, or deferred PCI � 6 h

rom clopidogrel administration, are the most appropriateandidates for this agent, either in the ED or soon afterdmission to the hospital. The ACS scenarios describedn these statements include medical management of un-table angina, NSTEMI, and STEMI—in all such in-tances, these high-risk ACS patients may be treated witharly clopidogrel therapy in conjunction with other treat-ents such as nitrates, morphine, ASA, heparin, and

eta-blockade. In the patient with unstable angina, ben-fit has been demonstrated in the outcomes of USAatients when treated with clopidogrel when a conserva-ive therapy is planned (13). If the patient undergoes aatheter-based management strategy, the combination oflopidogrel and GPI did not show significant improve-ent in outcome in patients who did not receive the drug

t least 6 h before PCI (14). As with USA, the NSTEMIatient demonstrates improved outcome with clopidogrelherapy when a conservative care plan is used (15). Theajority of these patients will receive PCI at some point

n their hospital course, but the vast majority will not bemergent—therefore, they would likely benefit from re-

eiving clopidogrel early in the course of therapy (13). In a

he last initially non-invasive therapy group, the STEMIatient treated with fibrinolytic agent, there is goodvidence for clopidogrel therapy in conjunction withbrinolytic therapy followed by deferred cardiac cath-terization (at least 2 days post-AMI). Decreased car-iovascular death, recurrent AMI, and recurrent isch-mia requiring urgent revascularization have beeneen in this group without a concomitant increase inemorrhage or need for transfusion (16). In fact, these of clopidogrel does not seem to show benefit if therug is given � 6 h before PCI performance, regard-ess of the clinical setting (14).

On the contrary, ACS patients with PCI performedoon after arrival (i.e., less than the 6-h interval fromlopidogrel dosing) are less likely to benefit from sucharly therapy. Benefit for early administration of clopi-ogrel is not found in patients with USA or NSTEMIanaged with PCI in a scenario that does not allow at

east a 6-h window of administration opportunity forlopidogrel. In the invasive strategy ACS group managedith early PCI, clopidogrel has not demonstrated con-

lusive benefit. If a GPI is used in the USA/NSTEMIatient, benefit derived from clopidogrel therapy doesot reach clinical significance in improving outcome14). Likewise, the STEMI patient managed with emer-ent PCI is not a candidate for early ED clopidogrel use.n the STEMI PCI group, there is benefit to clopidogreldministration before PCI, but only if given an extendederiod of time before PCI (i.e., 6 h if 300-mg load is usedr as early as 3–4 h if 600-mg loading dose is employed)14). This strategy, of course, is not beneficial in STEMIatients undergoing emergent PCI because they will noteceive the benefit of periprocedural protection. Further-ore, this patient subpopulation may have a higher like-

ihood of emergent CABG (� 5%) (17). Therefore, it iseasonable to propose that STEMI patients in a primaryCI setting do not receive clopidogrel before PCI—at

east in the ED.The last significant issue to review regarding early

lopidogrel therapy involves the ACS patient who willequire urgent CABG. In their review of USA/NSTEMIanagement, Fitchett and colleagues noted a significant

isk associated with early clopidogrel therapy involvingerioperative bleeding if CABG occurred within 5 days;ecall that there is no good criteria that have been proveno predict which ACS patients will not require CABG18). These authors remind us that clopidogrel tends toork best in patients who are truly high risk, yet these

ame patients are also most likely to require urgentABG (18). The American College of Emergency Phy-

icians Clinical Policy group states that there is insuffi-ient evidence to make any recommendations with re-ard to the exact location or timing of clopidogrel

dministration (i.e., ED vs. catheterization laboratory)

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The Journal of Emergency Medicine 89

19). The ACC/AHA suggest—in the form of a Class Iecommendation—that clopidogrel should be withheldor at least 5 days before CABG. They further state that,f CABG is performed within 5 days of clopidogrel use,atients have an increased incidence of operative andost-operative hemorrhage, increased need for transfu-ions, increased need for re-operation for hemostasis,nd increased post-operative mortality. So here is wherehe major problem is encountered—the emergency phy-ician should administer clopidogrel to those patientsho have high-risk ACS and who will probably not

equire CABG within 5 days (4,5). Thus, with regard toarly clopidogrel therapy, a major point of considerationnvolves the ability to predict which patients will requirergent CABG.

A recent study has attempted to answer just thisuestion. In an attempt to determine which patientsan safely receive clopidogrel before PCI, Hoekstrand colleagues and Mehta and colleagues evaluatedpproximately 60,000 patients from the CRUSADEegistry (20,21). Of these patients, 14% underwentABG during their hospitalization—a rather high ratef CABG in that most centers report a 2–5% incidencef coronary surgery. Using multivariate analysis, noingle or combination of features reliably identifiedhich patients would not require CABG (21).Thus, it seems impossible to reliably predict which

atients will require CABG and which patients will notequire CABG in urgent fashion. This problem repre-ents the true dilemma for the emergency physician withespect to clopidogrel in that the vast majority of ACSatients do not require urgent CABG, and a large portionf the ACS population would then potentially benefitrom clopidogrel. The answer to this particular clopi-ogrel question is best provided by local discussionmong the emergency physicians, cardiologists, and car-iac surgeons such that local practice patterns can beptimized throughout the spectrum of ACS care—fromhe street to the coronary care unit.

The array of antiplatelet and anticoagulant therapiesvailable to the emergency physician is both impressivend bewildering; the literature discussing these variousgents is quite heterogeneous, with somewhat confusingndications. Clearly, aspirin is indicated in the vast ma-ority of ACS patients early in their ED course. Glyco-rotein inhibitors, another useful antiplatelet agent, areost appropriately administered in the ACS patient un-

ergoing PCI. Lastly, clopidogrel, yet another antiplate-et agent, is likely best administered to the ACS patientho is either medically managed or undergoes deferredCI; its application � 6 h before PCI is unlikely to

enefit the patient.

1

Jarred Thomas, MD

Department of Emergency MedicineUniversity of Alabama Birmingham

Birmingham, AL

William J. Brady, MD

Department of Emergency MedicineUniversity of Virginia

Charlottesville, VA

doi:10.1016/j.jemermed.2007.09.033

REFERENCES

1. Pollack CV, Hollander JE. Antiplatelet therapy in acute coronarysyndromes: the emergency physician’s perspective. J Emerg Med2008;35:5–13.

2. ISIS-2 (Second International Study of Infarct Survival) Collabo-rative Group. Randomized trial of intravenous streptokinase, oralaspirin, both, or neither amount 17,187 cases of suspected acutemyocardial infarction: ISIS-2. Lancet 1988;2:349.

3. Brady WJ, Harrigan RA, Chan TC. Acute coronary syndromes. In:Marx J, Hockberger R, Walls R, eds. Rosen’s emergency medicine—concepts and clinical practice, 6th edn. St. Louis, MO: Mosby, Inc.;2005:1154–98.

4. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the AmericanCollege of Cardiology/American Heart Association Task Force onPractice Guidelines (Writing Committee to Revise the 2002 Guide-lines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaborationwith the American College of Emergency Physicians, the Societyfor Cardiovascular Angiography and Interventions, and the Societyof Thoracic Surgeons endorsed by the American Association ofCardiovascular and Pulmonary Rehabilitation and the Society forAcademic Emergency Medicine. J Am Coll Cardiol 2007;50:e1–157.

5. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guide-lines for the management of patients with ST-elevation myocardialinfarction; a report of the American College of Cardiology/Amer-ican Heart Association Task Force on Practice Guidelines (Com-mittee to Revise the 1999 Guidelines for the Management ofPatients with Acute Myocardial Infarction). J Am Coll Cardiol2004;44:E1–211.

6. The EPIC Investigators. Use of a monoclonal antibody directedagainst the platelet glycoprotein IIb/IIIa receptor in high-risk cor-onary angioplasty. N Engl J Med 1994;330:956–61.

7. The Epilog Investigators. Platelet glycoprotein IIb/IIIa receptorblockade and low-dose heparin during percutaneous coronary re-vascularization. N Engl J Med 1997;336:1689–96.

8. The IMPACT-II Investigators. Randomised placebo-controlled trialof effect of eptifibatide on complications of percutaneous coronaryintervention: IMPACT II. Integrilin to Minimise Platelet Aggregationand Coronary Thrombosis-II. Lancet 1997;349:1422–8.

9. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycop-rotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet 2002;359:189–98.

0. Simoons ML; GUSTO IV-ACS Investigators. Effect of glycopro-tein IIb/IIIa receptor blocker abciximab on outcome in patientswith acute coronary syndromes without early coronary revascu-larisation: the GUSTO IV-ACS randomised trial. Lancet 2001;357:1915–24.

1. Zhao XQ, Théroux P, Snapinn M, Sax FL. Intracoronary thrombusand platelet glycoprotein IIb/IIIa receptor blockade with tirofiban in

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unstable angina or non-Q-wave myocardial infarction. Angiographicresults from the PRISM-PLUS trial (Platelet receptor inhibition forischemic syndrome management in patients limited by unstable signsand symptoms). PRISM-PLUS Investigators. Circulation 1999;100:1609–15.

2. Ohman EM, Kleiman NS, Gacioch G, et al. Combined acceleratedtissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrinreceptor blockade with Integrilin in acute myocardial infarction.Results of a randomized, placebo-controlled, dose-ranging trial.IMPACT-AMI Investigators. Circulation 1997;95:846–54.

3. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK;Clopidogrel in Unstable Angina to Prevent Recurrent Events TrialInvestigators. Effects of clopidogrel in addition to aspirin in pa-tients with acute coronary syndromes without ST-segment eleva-tion. N Engl J Med 2001;345:494–502.

4. Steinhubl SR, Ellis SG, Wolski K, et al. Ticlopidine pretreatmentbefore coronary stenting is associated with sustained decrease inadverse cardiac events. Circulation 2001;103:1403–9.

5. Fox KAA, Mehta SR, Peters R, et al. Benefits and risks of thecombination of clopidogrel and aspirin in patients undergoingsurgical revascularization for non–ST-elevation acute coronarysyndrome: the Clopidogrel in Unstable angina to prevent Recurrent

ischemic Events (CURE) trial. Circulation 2004;110:1202–8.

6. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clo-pidogrel to aspirin and fibrinolytic therapy for myocardial in-farction with ST-segment elevation. N Engl J Med 2005;352:1179 – 89.

7. Stone GW, Brodie BR, Griffin JJ, et al. Role of cardiac surgery inthe hospital phase management of patients treated with primaryangioplasty for acute myocardial infarction. Am J Cardiol 2000;85:1292–6.

8. Fitchett DH, Borgundvaag B, Cantor W, et al. Non-ST segmentelevation acute coronary syndromes: a simplified risk-orientedalgorithm. Can J Cardiol 2006;22:663–77.

9. Fesmire FM, Decker WW, Biercks DB, et al. Clinical policy:critical issues in the evaluation and management of adult patientswith non-ST-segment elevation acute coronary syndromes. AnnEmerg Med 2006;48:270–301.

0. Hoekstra JW, Pollack CV, Roe MT, et al. Improving the care ofpatients with non-ST-elevation acute coronary syndromes in theemergency department: the CRUSADE initiative. Acad EmergMed 2002;9:1146–55.

1. Mehta RH, Chen AY, Pollack CV, et al. Challenges in predictingthe need for coronary artery bypass grafting at presentation inpatients with non-ST-segment elevation acute coronary syn-

dromes. Am J Cardiol 2006;98:624–7.