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Antiplatelet Therapy in Acute Coronary Syndrome: Not as Confusing as You Think
The Journal of Emergency Medicine, Vol. 35, No. 1, pp. 87–90, 2008 Copyright © 2008 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/08 $–see front matter
Editorial e ANTIPLATELET THERAPY IN ACUTE CORONARY SYNDROME: NOT AS CONFUSING AS YOU THINK
when used with fibrinolytic therapy (42% reduction in mortality) (2). The most appropriate dose for the emergency physician is 162–325 mg given once in the ED soon after arrival (3). Essentially, the only contraindications to ASA therapy in the ED chest pain patient suspected of ACS are serious aspirin allergy and active, clinically significant hemorrhage. The emergency physician should strongly consider ASA use in the patient suspected of ACS early in the evaluation. This recommendation is straightforward with significant objective support. In fact, the American College of Cardiology/American Heart Association (ACC/AHA), in the 2007 Guidelines, recommends the use of ASA early in the evaluation of the USA, NSTEMI, or STEMI patient (Class I recommendation with level A evidence) (4,5). The GPIs are a potent class of antiplatelet agent with remarkable success in reducing morbidity and mortality in the acute coronary syndrome patient; these agents, however, have demonstrated significant clinical utility in only a subset of ACS patients—those undergoing percutaneous coronary intervention. Numerous trials have demonstrated their effectiveness in ACS patients managed with a catheter-based management strategy, including the EPIC trial, the EPILOG trial, and the IMPACT-II trial (6 – 8). In these trials, significant reductions in recurrent ACS, urgent revascularization, and death were noted. Furthermore, a meta-analysis noted that ACS patients who underwent percutaneous coronary intervention (PCI) benefited markedly from glycoprotein inhibitor use (9). Conversely, in ACS patients who are managed medically without mechanical revascularization, consistent benefit with GPI therapy is not found. For instance, the GUSTO IV trial, the PRISM trial, the PRISM-PLUS trial, and the IMPACT-AMI failed to demonstrate consistent benefit in the ACS patient managed medically, that is, without PCI (10 –12). These trial results were further supported by a metaanalysis that found that GPI use did not improve the outcome of the ACS patient managed in a conservative fashion (9). The ACC/AHA guidelines have suggested the following with respect to GPI use in the ACS patient: initially planned, early PCI (Class I recommendation with level A evidence), and initial conservative therapy with recurrent
The approach to the patient with an acute coronary syndrome (ACS) has undergone many remarkable advances in the past 30 years. These improvements include both diagnostic methods and therapeutic interventions. Diagnostically, the 12-lead electrocardiogram and related imaging, serum markers, echocardiography, and nuclear scanning, used in appropriate systems of care, have all increased the emergency physician’s ability to evaluate patients suspected of ACS. Therapeutically, fibrinolytic therapy and interventional, catheter-based techniques have revolutionized the treatment of patients with ST-segment elevation myocardial infarction (STEMI); adjunctive therapies with antiplatelet, antithrombotic, and adrenergic blocking agents continue to improve the outcome of selected patients with all forms of ACS—STEMI, nonST-segment elevation myocardial infarction (NSTEMI), and unstable angina (USA). Antiplatelet therapy represents one such significant advancement in ACS care. The review in this edition of the Journal of Emergency Medicine by Pollack and Hollander investigates the current literature base— often bewildering in scope, content, and depth— concerning antiplatelet therapy in the ACS patient (USA, NSTEMI, and STEMI), making recommendations regarding their use (1). The agents reviewed by the authors include aspirin (ASA), IIb/IIIa glycoprotein inhibitors (GPI), and clopidogrel. Certainly, ASA and GPI have more or less found their niches in the emergency department (ED) ACS patient. Clopidogrel, in many ways, has yet to find its specific niche in the ED. In the ACS patient, dramatic reductions in morbidity and mortality have been seen with the administration of these agents. Aspirin, the original antiplatelet agent, represents the most cost-effective treatment available in ACS management; mortality reductions in myocardial infarction are very impressive, ranging from 25% to 40%, particularly when used with reperfusion therapy. The ISIS-2 trial provides the strongest evidence that aspirin independently reduces the mortality of patients with acute myocardial infarction (AMI) without fibrinolytic therapy (overall 23% reduction) and is synergistic 87
88
or recalcitrant symptoms and subsequent planned PCI (Class IIa recommendation with level B/C evidence) (4,5). Clopidogrel, a thienpyridine antiplatelet agent, is a very potent platelet inhibitor; clopidogrel inhibits the transformation of the glycoprotein IIb-IIIa receptor into its high-affinity binding state, thus preventing platelet aggregation for the duration of the life of the platelet. When considering clopidogrel administration to a patient with ACS in the ED, issues for the emergency physician to consider include ability to tolerate ASA, initial management (medical vs. PCI), time-to-PCI performance in catheter-based strategies, and the potential need for coronary artery bypass grafting (CABG). Perhaps the most “black-and-white” indication for clopidogrel in the ED is the high-risk ACS patient who is intolerant to ASA. This high-risk presentation would be characterized by objective abnormality; either meaningful positive serum marker value or a clinically significant, abnormal 12-lead electrocardiogram. In this instance, of course, medical intolerance indicates true medical intolerance of ASA in the form of significant, potentially life-threatening allergic event—not gastrointestinal upset. The ACC/AHA Guidelines 2007, in fact, list this as an acceptable indication (4). The particular management strategy selected for a patient is a significant consideration in the decision to administer clopidogrel early in the management course. Clearly, ACS patients managed medically, or with a strategy of deferred cardiac catheterization, are potential candidates for clopidogrel (13–16). In fact, ACS patients managed with medical therapy, or deferred PCI ⬎ 6 h from clopidogrel administration, are the most appropriate candidates for this agent, either in the ED or soon after admission to the hospital. The ACS scenarios described in these statements include medical management of unstable angina, NSTEMI, and STEMI—in all such instances, these high-risk ACS patients may be treated with early clopidogrel therapy in conjunction with other treatments such as nitrates, morphine, ASA, heparin, and beta-blockade. In the patient with unstable angina, benefit has been demonstrated in the outcomes of USA patients when treated with clopidogrel when a conservative therapy is planned (13). If the patient undergoes a catheter-based management strategy, the combination of clopidogrel and GPI did not show significant improvement in outcome in patients who did not receive the drug at least 6 h before PCI (14). As with USA, the NSTEMI patient demonstrates improved outcome with clopidogrel therapy when a conservative care plan is used (15). The majority of these patients will receive PCI at some point in their hospital course, but the vast majority will not be emergent—therefore, they would likely benefit from receiving clopidogrel early in the course of therapy (13). In
Editorial
the last initially non-invasive therapy group, the STEMI patient treated with fibrinolytic agent, there is good evidence for clopidogrel therapy in conjunction with fibrinolytic therapy followed by deferred cardiac catheterization (at least 2 days post-AMI). Decreased cardiovascular death, recurrent AMI, and recurrent ischemia requiring urgent revascularization have been seen in this group without a concomitant increase in hemorrhage or need for transfusion (16). In fact, the use of clopidogrel does not seem to show benefit if the drug is given ⬍ 6 h before PCI performance, regardless of the clinical setting (14). On the contrary, ACS patients with PCI performed soon after arrival (i.e., less than the 6-h interval from clopidogrel dosing) are less likely to benefit from such early therapy. Benefit for early administration of clopidogrel is not found in patients with USA or NSTEMI managed with PCI in a scenario that does not allow at least a 6-h window of administration opportunity for clopidogrel. In the invasive strategy ACS group managed with early PCI, clopidogrel has not demonstrated conclusive benefit. If a GPI is used in the USA/NSTEMI patient, benefit derived from clopidogrel therapy does not reach clinical significance in improving outcome (14). Likewise, the STEMI patient managed with emergent PCI is not a candidate for early ED clopidogrel use. In the STEMI PCI group, there is benefit to clopidogrel administration before PCI, but only if given an extended period of time before PCI (i.e., 6 h if 300-mg load is used or as early as 3– 4 h if 600-mg loading dose is employed) (14). This strategy, of course, is not beneficial in STEMI patients undergoing emergent PCI because they will not receive the benefit of periprocedural protection. Furthermore, this patient subpopulation may have a higher likelihood of emergent CABG (⬎ 5%) (17). Therefore, it is reasonable to propose that STEMI patients in a primary PCI setting do not receive clopidogrel before PCI—at least in the ED. The last significant issue to review regarding early clopidogrel therapy involves the ACS patient who will require urgent CABG. In their review of USA/NSTEMI management, Fitchett and colleagues noted a significant risk associated with early clopidogrel therapy involving perioperative bleeding if CABG occurred within 5 days; recall that there is no good criteria that have been proven to predict which ACS patients will not require CABG (18). These authors remind us that clopidogrel tends to work best in patients who are truly high risk, yet these same patients are also most likely to require urgent CABG (18). The American College of Emergency Physicians Clinical Policy group states that there is insufficient evidence to make any recommendations with regard to the exact location or timing of clopidogrel administration (i.e., ED vs. catheterization laboratory)
The Journal of Emergency Medicine
(19). The ACC/AHA suggest—in the form of a Class I recommendation—that clopidogrel should be withheld for at least 5 days before CABG. They further state that, if CABG is performed within 5 days of clopidogrel use, patients have an increased incidence of operative and post-operative hemorrhage, increased need for transfusions, increased need for re-operation for hemostasis, and increased post-operative mortality. So here is where the major problem is encountered—the emergency physician should administer clopidogrel to those patients who have high-risk ACS and who will probably not require CABG within 5 days (4,5). Thus, with regard to early clopidogrel therapy, a major point of consideration involves the ability to predict which patients will require urgent CABG. A recent study has attempted to answer just this question. In an attempt to determine which patients can safely receive clopidogrel before PCI, Hoekstra and colleagues and Mehta and colleagues evaluated approximately 60,000 patients from the CRUSADE registry (20,21). Of these patients, 14% underwent CABG during their hospitalization—a rather high rate of CABG in that most centers report a 2–5% incidence of coronary surgery. Using multivariate analysis, no single or combination of features reliably identified which patients would not require CABG (21). Thus, it seems impossible to reliably predict which patients will require CABG and which patients will not require CABG in urgent fashion. This problem represents the true dilemma for the emergency physician with respect to clopidogrel in that the vast majority of ACS patients do not require urgent CABG, and a large portion of the ACS population would then potentially benefit from clopidogrel. The answer to this particular clopidogrel question is best provided by local discussion among the emergency physicians, cardiologists, and cardiac surgeons such that local practice patterns can be optimized throughout the spectrum of ACS care—from the street to the coronary care unit. The array of antiplatelet and anticoagulant therapies available to the emergency physician is both impressive and bewildering; the literature discussing these various agents is quite heterogeneous, with somewhat confusing indications. Clearly, aspirin is indicated in the vast majority of ACS patients early in their ED course. Glycoprotein inhibitors, another useful antiplatelet agent, are most appropriately administered in the ACS patient undergoing PCI. Lastly, clopidogrel, yet another antiplatelet agent, is likely best administered to the ACS patient who is either medically managed or undergoes deferred PCI; its application ⬍ 6 h before PCI is unlikely to benefit the patient.
89
Jarred Thomas, MD Department of Emergency Medicine University of Alabama Birmingham Birmingham, AL William J. Brady, MD Department of Emergency Medicine University of Virginia Charlottesville, VA doi:10.1016/j.jemermed.2007.09.033
REFERENCES 1. Pollack CV, Hollander JE. Antiplatelet therapy in acute coronary syndromes: the emergency physician’s perspective. J Emerg Med 2008;35:5–13. 2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither amount 17,187 cases of suspected acute myocardial 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 2007 guidelines for the management of patients with unstable angina/ non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/NonST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007;50:e1– 157. 5. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). J Am Coll Cardiol 2004;44:E1–211. 6. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994;330:956 – 61. 7. The Epilog Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689 –96. 8. The IMPACT-II Investigators. Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT II. Integrilin to Minimise Platelet Aggregation and Coronary Thrombosis-II. Lancet 1997;349:1422– 8. 9. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a metaanalysis of all major randomised clinical trials. Lancet 2002;359: 189 –98. 10. Simoons ML; GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial. Lancet 2001;357: 1915–24. 11. Zhao XQ, Théroux P, Snapinn M, Sax FL. Intracoronary thrombus and platelet glycoprotein IIb/IIIa receptor blockade with tirofiban in
90
12.
13.
14. 15.
Editorial unstable angina or non-Q-wave myocardial infarction. Angiographic results from the PRISM-PLUS trial (Platelet receptor inhibition for ischemic syndrome management in patients limited by unstable signs and symptoms). PRISM-PLUS Investigators. Circulation 1999;100: 1609 –15. Ohman EM, Kleiman NS, Gacioch G, et al. Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarction. Results of a randomized, placebo-controlled, dose-ranging trial. IMPACT-AMI Investigators. Circulation 1997;95:846 –54. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494 –502. Steinhubl SR, Ellis SG, Wolski K, et al. Ticlopidine pretreatment before coronary stenting is associated with sustained decrease in adverse cardiac events. Circulation 2001;103:1403–9. Fox KAA, Mehta SR, Peters R, et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non–ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial. Circulation 2004;110:1202– 8.
16. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352: 1179 – 89. 17. Stone GW, Brodie BR, Griffin JJ, et al. Role of cardiac surgery in the hospital phase management of patients treated with primary angioplasty for acute myocardial infarction. Am J Cardiol 2000; 85:1292– 6. 18. Fitchett DH, Borgundvaag B, Cantor W, et al. Non-ST segment elevation acute coronary syndromes: a simplified risk-oriented algorithm. Can J Cardiol 2006;22:663–77. 19. Fesmire FM, Decker WW, Biercks DB, et al. Clinical policy: critical issues in the evaluation and management of adult patients with non-ST-segment elevation acute coronary syndromes. Ann Emerg Med 2006;48:270 –301. 20. Hoekstra JW, Pollack CV, Roe MT, et al. Improving the care of patients with non-ST-elevation acute coronary syndromes in the emergency department: the CRUSADE initiative. Acad Emerg Med 2002;9:1146 –55. 21. Mehta RH, Chen AY, Pollack CV, et al. Challenges in predicting the need for coronary artery bypass grafting at presentation in patients with non-ST-segment elevation acute coronary syndromes. Am J Cardiol 2006;98:624 –7.
Editorial e ANTIPLATELET THERAPY IN ACUTE CORONARY SYNDROME: NOT AS CONFUSING AS YOU THINK
when used with fibrinolytic therapy (42% reduction in mortality) (2). The most appropriate dose for the emergency physician is 162–325 mg given once in the ED soon after arrival (3). Essentially, the only contraindications to ASA therapy in the ED chest pain patient suspected of ACS are serious aspirin allergy and active, clinically significant hemorrhage. The emergency physician should strongly consider ASA use in the patient suspected of ACS early in the evaluation. This recommendation is straightforward with significant objective support. In fact, the American College of Cardiology/American Heart Association (ACC/AHA), in the 2007 Guidelines, recommends the use of ASA early in the evaluation of the USA, NSTEMI, or STEMI patient (Class I recommendation with level A evidence) (4,5). The GPIs are a potent class of antiplatelet agent with remarkable success in reducing morbidity and mortality in the acute coronary syndrome patient; these agents, however, have demonstrated significant clinical utility in only a subset of ACS patients—those undergoing percutaneous coronary intervention. Numerous trials have demonstrated their effectiveness in ACS patients managed with a catheter-based management strategy, including the EPIC trial, the EPILOG trial, and the IMPACT-II trial (6 – 8). In these trials, significant reductions in recurrent ACS, urgent revascularization, and death were noted. Furthermore, a meta-analysis noted that ACS patients who underwent percutaneous coronary intervention (PCI) benefited markedly from glycoprotein inhibitor use (9). Conversely, in ACS patients who are managed medically without mechanical revascularization, consistent benefit with GPI therapy is not found. For instance, the GUSTO IV trial, the PRISM trial, the PRISM-PLUS trial, and the IMPACT-AMI failed to demonstrate consistent benefit in the ACS patient managed medically, that is, without PCI (10 –12). These trial results were further supported by a metaanalysis that found that GPI use did not improve the outcome of the ACS patient managed in a conservative fashion (9). The ACC/AHA guidelines have suggested the following with respect to GPI use in the ACS patient: initially planned, early PCI (Class I recommendation with level A evidence), and initial conservative therapy with recurrent
The approach to the patient with an acute coronary syndrome (ACS) has undergone many remarkable advances in the past 30 years. These improvements include both diagnostic methods and therapeutic interventions. Diagnostically, the 12-lead electrocardiogram and related imaging, serum markers, echocardiography, and nuclear scanning, used in appropriate systems of care, have all increased the emergency physician’s ability to evaluate patients suspected of ACS. Therapeutically, fibrinolytic therapy and interventional, catheter-based techniques have revolutionized the treatment of patients with ST-segment elevation myocardial infarction (STEMI); adjunctive therapies with antiplatelet, antithrombotic, and adrenergic blocking agents continue to improve the outcome of selected patients with all forms of ACS—STEMI, nonST-segment elevation myocardial infarction (NSTEMI), and unstable angina (USA). Antiplatelet therapy represents one such significant advancement in ACS care. The review in this edition of the Journal of Emergency Medicine by Pollack and Hollander investigates the current literature base— often bewildering in scope, content, and depth— concerning antiplatelet therapy in the ACS patient (USA, NSTEMI, and STEMI), making recommendations regarding their use (1). The agents reviewed by the authors include aspirin (ASA), IIb/IIIa glycoprotein inhibitors (GPI), and clopidogrel. Certainly, ASA and GPI have more or less found their niches in the emergency department (ED) ACS patient. Clopidogrel, in many ways, has yet to find its specific niche in the ED. In the ACS patient, dramatic reductions in morbidity and mortality have been seen with the administration of these agents. Aspirin, the original antiplatelet agent, represents the most cost-effective treatment available in ACS management; mortality reductions in myocardial infarction are very impressive, ranging from 25% to 40%, particularly when used with reperfusion therapy. The ISIS-2 trial provides the strongest evidence that aspirin independently reduces the mortality of patients with acute myocardial infarction (AMI) without fibrinolytic therapy (overall 23% reduction) and is synergistic 87
88
or recalcitrant symptoms and subsequent planned PCI (Class IIa recommendation with level B/C evidence) (4,5). Clopidogrel, a thienpyridine antiplatelet agent, is a very potent platelet inhibitor; clopidogrel inhibits the transformation of the glycoprotein IIb-IIIa receptor into its high-affinity binding state, thus preventing platelet aggregation for the duration of the life of the platelet. When considering clopidogrel administration to a patient with ACS in the ED, issues for the emergency physician to consider include ability to tolerate ASA, initial management (medical vs. PCI), time-to-PCI performance in catheter-based strategies, and the potential need for coronary artery bypass grafting (CABG). Perhaps the most “black-and-white” indication for clopidogrel in the ED is the high-risk ACS patient who is intolerant to ASA. This high-risk presentation would be characterized by objective abnormality; either meaningful positive serum marker value or a clinically significant, abnormal 12-lead electrocardiogram. In this instance, of course, medical intolerance indicates true medical intolerance of ASA in the form of significant, potentially life-threatening allergic event—not gastrointestinal upset. The ACC/AHA Guidelines 2007, in fact, list this as an acceptable indication (4). The particular management strategy selected for a patient is a significant consideration in the decision to administer clopidogrel early in the management course. Clearly, ACS patients managed medically, or with a strategy of deferred cardiac catheterization, are potential candidates for clopidogrel (13–16). In fact, ACS patients managed with medical therapy, or deferred PCI ⬎ 6 h from clopidogrel administration, are the most appropriate candidates for this agent, either in the ED or soon after admission to the hospital. The ACS scenarios described in these statements include medical management of unstable angina, NSTEMI, and STEMI—in all such instances, these high-risk ACS patients may be treated with early clopidogrel therapy in conjunction with other treatments such as nitrates, morphine, ASA, heparin, and beta-blockade. In the patient with unstable angina, benefit has been demonstrated in the outcomes of USA patients when treated with clopidogrel when a conservative therapy is planned (13). If the patient undergoes a catheter-based management strategy, the combination of clopidogrel and GPI did not show significant improvement in outcome in patients who did not receive the drug at least 6 h before PCI (14). As with USA, the NSTEMI patient demonstrates improved outcome with clopidogrel therapy when a conservative care plan is used (15). The majority of these patients will receive PCI at some point in their hospital course, but the vast majority will not be emergent—therefore, they would likely benefit from receiving clopidogrel early in the course of therapy (13). In
Editorial
the last initially non-invasive therapy group, the STEMI patient treated with fibrinolytic agent, there is good evidence for clopidogrel therapy in conjunction with fibrinolytic therapy followed by deferred cardiac catheterization (at least 2 days post-AMI). Decreased cardiovascular death, recurrent AMI, and recurrent ischemia requiring urgent revascularization have been seen in this group without a concomitant increase in hemorrhage or need for transfusion (16). In fact, the use of clopidogrel does not seem to show benefit if the drug is given ⬍ 6 h before PCI performance, regardless of the clinical setting (14). On the contrary, ACS patients with PCI performed soon after arrival (i.e., less than the 6-h interval from clopidogrel dosing) are less likely to benefit from such early therapy. Benefit for early administration of clopidogrel is not found in patients with USA or NSTEMI managed with PCI in a scenario that does not allow at least a 6-h window of administration opportunity for clopidogrel. In the invasive strategy ACS group managed with early PCI, clopidogrel has not demonstrated conclusive benefit. If a GPI is used in the USA/NSTEMI patient, benefit derived from clopidogrel therapy does not reach clinical significance in improving outcome (14). Likewise, the STEMI patient managed with emergent PCI is not a candidate for early ED clopidogrel use. In the STEMI PCI group, there is benefit to clopidogrel administration before PCI, but only if given an extended period of time before PCI (i.e., 6 h if 300-mg load is used or as early as 3– 4 h if 600-mg loading dose is employed) (14). This strategy, of course, is not beneficial in STEMI patients undergoing emergent PCI because they will not receive the benefit of periprocedural protection. Furthermore, this patient subpopulation may have a higher likelihood of emergent CABG (⬎ 5%) (17). Therefore, it is reasonable to propose that STEMI patients in a primary PCI setting do not receive clopidogrel before PCI—at least in the ED. The last significant issue to review regarding early clopidogrel therapy involves the ACS patient who will require urgent CABG. In their review of USA/NSTEMI management, Fitchett and colleagues noted a significant risk associated with early clopidogrel therapy involving perioperative bleeding if CABG occurred within 5 days; recall that there is no good criteria that have been proven to predict which ACS patients will not require CABG (18). These authors remind us that clopidogrel tends to work best in patients who are truly high risk, yet these same patients are also most likely to require urgent CABG (18). The American College of Emergency Physicians Clinical Policy group states that there is insufficient evidence to make any recommendations with regard to the exact location or timing of clopidogrel administration (i.e., ED vs. catheterization laboratory)
The Journal of Emergency Medicine
(19). The ACC/AHA suggest—in the form of a Class I recommendation—that clopidogrel should be withheld for at least 5 days before CABG. They further state that, if CABG is performed within 5 days of clopidogrel use, patients have an increased incidence of operative and post-operative hemorrhage, increased need for transfusions, increased need for re-operation for hemostasis, and increased post-operative mortality. So here is where the major problem is encountered—the emergency physician should administer clopidogrel to those patients who have high-risk ACS and who will probably not require CABG within 5 days (4,5). Thus, with regard to early clopidogrel therapy, a major point of consideration involves the ability to predict which patients will require urgent CABG. A recent study has attempted to answer just this question. In an attempt to determine which patients can safely receive clopidogrel before PCI, Hoekstra and colleagues and Mehta and colleagues evaluated approximately 60,000 patients from the CRUSADE registry (20,21). Of these patients, 14% underwent CABG during their hospitalization—a rather high rate of CABG in that most centers report a 2–5% incidence of coronary surgery. Using multivariate analysis, no single or combination of features reliably identified which patients would not require CABG (21). Thus, it seems impossible to reliably predict which patients will require CABG and which patients will not require CABG in urgent fashion. This problem represents the true dilemma for the emergency physician with respect to clopidogrel in that the vast majority of ACS patients do not require urgent CABG, and a large portion of the ACS population would then potentially benefit from clopidogrel. The answer to this particular clopidogrel question is best provided by local discussion among the emergency physicians, cardiologists, and cardiac surgeons such that local practice patterns can be optimized throughout the spectrum of ACS care—from the street to the coronary care unit. The array of antiplatelet and anticoagulant therapies available to the emergency physician is both impressive and bewildering; the literature discussing these various agents is quite heterogeneous, with somewhat confusing indications. Clearly, aspirin is indicated in the vast majority of ACS patients early in their ED course. Glycoprotein inhibitors, another useful antiplatelet agent, are most appropriately administered in the ACS patient undergoing PCI. Lastly, clopidogrel, yet another antiplatelet agent, is likely best administered to the ACS patient who is either medically managed or undergoes deferred PCI; its application ⬍ 6 h before PCI is unlikely to benefit the patient.
89
Jarred Thomas, MD Department of Emergency Medicine University of Alabama Birmingham Birmingham, AL William J. Brady, MD Department of Emergency Medicine University of Virginia Charlottesville, VA doi:10.1016/j.jemermed.2007.09.033
REFERENCES 1. Pollack CV, Hollander JE. Antiplatelet therapy in acute coronary syndromes: the emergency physician’s perspective. J Emerg Med 2008;35:5–13. 2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither amount 17,187 cases of suspected acute myocardial 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 2007 guidelines for the management of patients with unstable angina/ non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/NonST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007;50:e1– 157. 5. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). J Am Coll Cardiol 2004;44:E1–211. 6. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994;330:956 – 61. 7. The Epilog Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689 –96. 8. The IMPACT-II Investigators. Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT II. Integrilin to Minimise Platelet Aggregation and Coronary Thrombosis-II. Lancet 1997;349:1422– 8. 9. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a metaanalysis of all major randomised clinical trials. Lancet 2002;359: 189 –98. 10. Simoons ML; GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial. Lancet 2001;357: 1915–24. 11. Zhao XQ, Théroux P, Snapinn M, Sax FL. Intracoronary thrombus and platelet glycoprotein IIb/IIIa receptor blockade with tirofiban in
90
12.
13.
14. 15.
Editorial unstable angina or non-Q-wave myocardial infarction. Angiographic results from the PRISM-PLUS trial (Platelet receptor inhibition for ischemic syndrome management in patients limited by unstable signs and symptoms). PRISM-PLUS Investigators. Circulation 1999;100: 1609 –15. Ohman EM, Kleiman NS, Gacioch G, et al. Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarction. Results of a randomized, placebo-controlled, dose-ranging trial. IMPACT-AMI Investigators. Circulation 1997;95:846 –54. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494 –502. Steinhubl SR, Ellis SG, Wolski K, et al. Ticlopidine pretreatment before coronary stenting is associated with sustained decrease in adverse cardiac events. Circulation 2001;103:1403–9. Fox KAA, Mehta SR, Peters R, et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non–ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial. Circulation 2004;110:1202– 8.
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