Utility of platelet adp receptor antagonism in the emergency department: a review☆

Introduction 

Atherothrombosis is a pathophysiologic process that culminates in ischemic events across a wide variety of vascular beds. Stroke, acute ST-segment-elevation myocardial infarction (AMI), unstable angina (UA) and non-ST-segment-elevation MI (NSTEMI), acute and subacute stent thrombosis after coronary interventions, and acute peripheral arterial occlusive disease all result from platelet activation and aggregation leading to vascular occlusion. Due to the acute and precipitous nature of the initial presentation, people experiencing these events often present to the Emergency Department (ED). The role of anticoagulation (with unfractionated or low-molecular-weight heparin and warfarin) and thrombolytic therapy in the management of acute ischemic events has been thoroughly evaluated 1, 2, 3.

Annually, approximately 1.8 million people in the United States experience acute coronary syndrome (ACS) (4). Of these, 450,000 patients are admitted to the hospital through the ED with AMI. Despite increasingly sophisticated medical treatment, the incidence of cardiovascular death and MI continues to be in the 6–8% range both during the index hospitalization for non-ST-elevation acute coronary syndromes and for each year thereafter over at least the next 2 years (5). The burden of atherothrombotic disease is also manifest by another 434,000 patients who are admitted each year with stroke (6). In addition, approximately 300,000 transient ischemic attacks (TIAs) occur annually in the United States and many of these patients present to EDs for evaluation. A recent study found that 10.5% of 180 TIA patients returned to the ED within 90 days with a stroke; half of those occurred in the first 2 days post-TIA (6). Other adverse cardiovascular events, including congestive heart failure (CHF), MI, ventricular dysrhythmias, and UA were also common during follow-up among these patients whose initial ED presentation was prompted by neurologic signs and symptoms.

New therapies are therefore sought to improve these outcomes. ADP receptor antagonists inhibit platelet aggregation and may be efficacious in the secondary prevention of stroke, MI, and vascular death. This article will review the pathophysiology of atherothrombosis and discuss the role of ADP receptor antagonists in reducing morbidity and mortality associated with events that result from this process. The potential utility of this therapeutic approach in the ED setting will be specifically evaluated.

Pathophysiology 

Atherothrombosis is an important physiologic factor in the development of acute events. Atherothrombosis can be defined as superimposed thrombus formation in the setting of pre-existing atherosclerotic plaque (7). Platelets are activated when vessel wall endothelium is damaged. Activated platelets bind to collagen within the newly exposed arterial subendothelial matrix at the base of the plaque, inducing a conformational change in the cell as well as degranulation of a variety of platelet granules. This leads to release of chemoattractant agents that recruit more platelets to the area, resulting in further aggregation (8). A variety of mediators induce the activated state in platelets; these include collagen, thromboxane A2, thrombin, and adenosine diphosphate (ADP). ADP further binds to surface receptors on neighboring platelets, amplifying the cyclical process of platelet activation, degranulation and aggregation (9).

The ultimate result of platelet activation is elaboration of glycoprotein IIb/IIIa receptors on the platelet surface. Once activated, these receptors bind fibrinogen and von Willebrand factor, which promote platelet cross-linking and subsequent thrombus formation (10). Activation of cyclooxygenase in platelets results in the elaboration of thromboxane A2, which further activates neighboring platelets and helps generate a relatively more fibrinolytic-resistant aggregate. Products of the coagulation pathway, also stimulated by tissue factor from within the ruptured plaque, act to convert prothrombin to thrombin, which in turn converts fibrinogen to fibrin and further stabilizes the platelet aggregate into a luminal clot (11). The clot may trigger an acute vascular event in situ if it is of sufficient size with respect to the vessel lumen, or it may be the source of platelet-aggregate emboli that can cause downstream ischemia or infarction (12). Interrupting the process of platelet activation is an important potential intervention in attenuating the clinical effects of acute atherothrombosis.

Antiplatelet agents 

Therapeutic interference with this complex process may be attempted at multiple points (Figure 1). The approved therapeutic agents useful in this approach are discussed below.

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Figure 1. Platelet activation and aggregation. Platelet interactions with agonists and antagonists of platelet aggregation, the vessel wall, other platelets, and adhesive macromolecules. Agents in italics prevent the formation, or inhibit the function, of the adjacent agonists of platelet aggregation. Adapted from Almony GT, Lefkovits J, Topol EJ. Antiplatelet and anticoagulant use after myocardial infarction. Clin Cardiol 1996;19:357–65.

Aspirin 

Aspirin irreversibly inhibits cyclooxygenase and reduces thromboxane A2 and prostaglandin synthesis, resulting in less effective platelet aggregation (13). It is recommended for immediate use in AMI, UA and NSTEMI, and indefinitely thereafter 1, 2, 14. Aspirin reduces the frequency of ischemic complications after percutaneous coronary intervention (PCI). An empiric dose of aspirin 80 to 325 mg at least 2 h before the procedure is generally recommended by the American College of Cardiology/American Heart Association (ACC/AHA) Guidelines 2, 15. Antiplatelet therapy is specifically recommended in acute ischemic stroke and for stroke prevention in patients who have had a noncardioembolic (atherothrombotic, lacunar or cryptogenic) stroke or TIA (16). Acceptable options include aspirin 50 to 325 mg/day, aspirin 25 mg and extended-release dipyridamole 200 mg twice daily, or clopidogrel 75 mg/day (16). Additionally, aspirin should be considered for patients with nonvalvular atrial fibrillation based on an assessment of the risk of embolism and bleeding (17).

Therapy with aspirin has its complications. The majority of adverse events associated with aspirin therapy are related to gastrointestinal (GI) toxicity, including an increased risk of GI bleeding. Several studies have observed an increase in the risk of hemorrhagic stroke in patients treated with aspirin in the setting of AMI or acute ischemic stroke; this may be dose related (13).

Not all patients treated with aspirin derive sufficient benefit in terms of preventing atherothrombotic sequelae (18). This may be due to an inadequate dose, a paradoxical thrombogenic effect of aspirin (via, most likely, an increase in 12-hydroxyeicosatetraenoic acid [12-HETE] synthesis resulting in increased platelet adhesion), or some poorly defined aspirin resistance 13, 18, 19, 20, 21. Furthermore, the antiplatelet effect of a fixed dose of aspirin is not constant over time in all patients (20). In these patients, antiplatelet therapy with an ADP receptor antagonist may be indicated.

Glycoprotein IIb/IIIa receptor antagonists 

Glycoprotein (GP) IIb/IIIa receptor antagonists exert a beneficial effect in ACS by inhibiting fibrinogen cross-linking of activated platelets. They occupy the platelet surface integrin GP IIb/IIIa receptors, preventing the binding of fibrinogen to platelets, platelet-to-platelet linkages, and platelet aggregation (22). These agents are currently available in intravenous formulations (abciximab, eptifibatide and tirofiban) in the United States. These agents have clinical utility in the management of patients with UA or NSTEMI who have continuing ischemia or other high-risk features, and in all those patients going to PCI 1, 14, 15. Current stroke guidelines do not specifically address these agents 16, 17.

The major adverse effect seen with intravenous administration of the GP IIb/IIIa receptor antagonists is an increased risk of bleeding (1). Major bleeding rates for intravenous GP IIb/IIIa receptor antagonists were as much as two to three times greater than for placebo in early trials, although substantial responsibility for that extent of bleeding is likely attributable to higher heparin doses than are currently utilized in conjunction with IIb/IIIa agents (1).

ADP receptor antagonists: ticlopidine and clopidogrel 

Inhibition of platelet ADP receptors results in reductions in both platelet activation and platelet aggregation, via prevention of ADP-induced fibrinogen binding to the glycoprotein IIb/IIIa receptors 23, 24. It may also manifest a secondary inhibitory effect by preventing degranulation of activated platelets (8).

There are two ADP receptor antagonists approved for clinical use and the agents are chemically similar. The first to be developed was ticlopidine. This was followed by the development of clopidogrel, which differs from ticlopidine by the addition of a carboxymethyl side group (25). This structural change may account for clopidogrel’s milder side effect profile and more rapid induction of antiplatelet activity (see below) (26). Both agents have been studied in clinical trials of patients with atherothrombosis. Both agents are recommended in PCI guidelines (Class I), for AMI patients allergic or unresponsive to aspirin therapy (Class IIb), and for patients with UA or NSTEMI who are unable to take aspirin due to hypersensitivity or major GI intolerance (Class IB) 1, 2. Clopidogrel carries a grade IA recommendation for use in the secondary prevention of stroke (16).

ADP receptor antagonists may be indicated in the ED, but the potential utility of ticlopidine for the emergency physician is limited by at least four important issues:

The most common adverse effects associated with clopidogrel are rash and GI upset; clopidogrel has been only very rarely associated with TTP and no specific laboratory monitoring is required during its use. A single 300 mg loading dose of clopidogrel provides significantly greater inhibition of ADP-induced platelet aggregation on the first day of treatment than either ticlopidine 500 mg/day or clopidogrel 75 mg/day (36). Use of either ADP receptor antagonist is contraindicated in patients with active bleeding and both should be used with caution in patients with a significant risk of bleeding complications.

Combination antiplatelet therapy 

The synergistic effect of combination antiplatelet therapy using aspirin and an ADP receptor antagonist has recently received attention in the management of acute coronary syndromes. Early animal and human studies showed that more complete antiplatelet inhibition could be achieved by simultaneously targeting multiple sites of platelet activation 29, 37, 38, 39. Cadroy and colleagues assessed the antithrombotic effects of the combination of aspirin and clopidogrel, with or without a 300 mg loading dose, vs. aspirin alone in a model of arterial thrombosis. An antithrombotic effect was found 6 h after administration of the aspirin and clopidogrel combination without a loading dose, and it was significantly superior to the effect of aspirin alone (p ≤ 0.03). The antithrombotic effects when a loading dose of clopidogrel was used were evident within 90 min and achieved a level at 6 h similar to that on day 10. The clopidogrel and aspirin combination at day 10 was significantly more potent than aspirin alone (p < 0.001) (29). These findings are consistent with those seen in ACS patients in the CURE Trial (40).

The combination of ticlopidine and aspirin was established early as the regimen of choice in coronary artery stenting 41, 42, 43, 44, 45. Generally, aspirin therapy is given indefinitely, while the duration of therapy with ticlopidine is usually 2 to 4 weeks. Clopidogrel has recently replaced ticlopidine in this setting because of its similar efficacy, more rapid onset of activity, and more acceptable safety profile (46). Further investigation into expanded use of combination antiplatelet therapy with aspirin and ADP receptor antagonists is currently under- way in the management of both cardiovascular and cerebrovascular disease. There are relatively few data on combination therapy with ADP receptor antagonists and glycoprotein IIb/IIIa receptor antagonists for patients with ACS in which the ADP agent is administered first; in fact, patients given IIb/IIIa blockers within 3 days before randomization were excluded from enrollment in the CURE Trial (40). As-yet unpublished results from the TARGET study, however, indicate that a loading dose of clopidogrel prior to PCI with adjunctive abciximab or tirofiban given after the clopidogrel is associated with improved outcomes at 30 days 47, 48.

Use of ADP receptor antagonists in reduction of coronary events 

Clinical trials have demonstrated that ADP receptor antagonists are effective in the secondary prevention of atherosclerotic disease. A meta-analysis of three large studies of ticlopidine vs. placebo or control in 2392 patients with atherosclerotic disease (recent stroke, unstable angina or intermittent claudication) showed a 29% reduction in relative risk of further vascular events (p = 0.0006) (49). The potential impact of clopidogrel on the prevention of vascular events was studied in the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) protocol (50). In this trial, 19,185 patients with a recent acute arterial thrombotic episode (ischemic stroke within 1 week to 6 months; MI ≤ 35 days old; or atherosclerotic peripheral arterial disease) were randomized in double-blinded fashion to either aspirin 325 mg/day or clopidogrel 75 mg/day. The mean follow-up interval was nearly 2 years. Clopidogrel was associated with a relative risk reduction of 8.7% in the composite endpoint of ischemic stroke, MI or vascular death (p = 0.043). It was concluded that in a patient population similar to that in CAPRIE, clopidogrel would be expected to prevent 24 major clinical events/1000 patients treated for 1 year compared to 19 major events prevented with aspirin (50). Additional analysis of all patients enrolled in CAPRIE showed a 19.2% risk reduction (p = 0.008) for MI compared to aspirin (51). The occurrence of adverse events between clopidogrel and aspirin was similar, although rash and diarrhea were more common with the former and gastrointestinal upset and liver dysfunction were more common with the latter (50). Results of selected trials using ADP receptor antagonists for the prevention of coronary atherothrombosis are summarized in Table 1.

Table 1. Trials of ADP Receptor Antagonists in Preventing Coronary Atherothrombosis

	Author (Reference)	Trial (N)	Antiplatelet Agents	Selected Outcome	Results
	Hall, 1996 (54)	Post-stent study (N = 326)	Ticlopidine 250 mg b.i.d. × 1 month + ASA 325 mg × 5 days vs. ASA 325 mg; after 1 month, ASA 325 mg indefinitely	Stent thrombosis at 1 month; MACE	0.8% vs. 2.9% (p = 0.20); 0.8% vs. 3.9% (p = 0.10)
	Albiero, 1997 (55)	Post-stent study (N = 801)	Ticlopidine 250 mg b.i.d. × 1 month + ASA 325 mg long-term vs. ASA 325 mg long-term	Stent thrombosis at 1 month; MACE	1.9% vs. 1.9% (p = 1); 2.0% vs. 1.9% (p = 1)
	Balsano, 1990 (52)	UA trial (N = 652)	Ticlopidine 250 mg b.i.d. + conventional therapy (BB, CCB, nitrates) vs. conventional therapy	Vascular death, nonfatal MI	7.3% vs. 13.6%; RRR = 46.3% with ticlopidine (p = 0.009)
	CAPRIE Steering Committee, 1996 (50)	CAPRIE (N = 19,185)	Clopidogrel 75 mg vs. ASA 325 mg	Ischemic stroke, MI, or vascular death	RRR = 8.7% (p = 0.043)
	Bertrand, 2000 (42)	CLASSICS (N = 1020)	1) Clopidogrel 300 mg loading dose + ASA 325 mg on day 1 then clopidogrel 75 mg + ASA 325 mg; 2) Clopidogrel 75 mg + ASA 325 mg; 3) Ticlopidine 250 mg bid + ASA 325 mg	Major peripheral or bleeding, neutropenia, thrombocytopenia, or early drug discontinuation due to noncardiac AE	RRR = 50% with clopidogrel + ASA (p = 0.005)
	Moore, 2000 (46)	CREDO (N = 2000)	Clopidogrel 300 mg + ASA 325 mg 3–24 h pre-PCI vs. placebo + ASA 325 mg pre-PCI; all patients on clopidogrel 75 mg + ASA 325 mg post-PCI	All-cause death, MI, or urgent target vessel revascularization	On-going
	CURE Study Investigators, 2001 (40)	CURE (N = 12,563)	ASA 325 mg + clopidogrel 75 mg vs. placebo for 3 months to 1 year	CV death, MI, stroke; CV death, MI, stroke, refractory ischemia	RRR = 20% (p = 0.00005); RRR = 14% (p = 0.0004)

CAPRIE = Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events; CLASSICS = Clopidogrel Aspirin Stent International Cooperative Study; CREDO = Clopidogrel for the Reduction of Events During Observation; CURE = Clopidogrel in Unstable Angina to Prevent Recurrent Events; ASA = aspirin; CCB = calcium channel blockers; BB = beta-blockers; MACE = major adverse cardiac events; RRR = relative risk reduction; AE = adverse events; b.i.d. = twice daily; MI = myocardial infarction; UA = unstable angina; mg = milligrams; PCI = percutaneous coronary intervention; CV = cardiovascular.

Presently, the safety and efficacy of ticlopidine and clopidogrel continue to be evaluated in patients with ACS and in patients undergoing PCI. The risk of MI during a 6-month follow-up was significantly reduced vs. placebo (4.8 vs. 8.9%, respectively, p = 0.039) when ticlopidine was given in 652 patients with UA receiving conventional therapy (beta-adrenergic blockers, calcium-channel antagonists and nitrates) (52). The double end-point of MI and cardiovascular death was also reduced by the addition of ticlopidine, although this difference was not significant. However, a similar reduction in the combination of fatal and nonfatal MI (5.1 vs. 10.9%, respectively, p = 0.006) was shown (52).

The largest and most definitive study of the effects of an ADP receptor antagonist in ACS is the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial. CURE was a multicenter, randomized study to evaluate the combination of clopidogrel and aspirin vs. aspirin alone in patients with UA and non-ST-elevation ACS. CURE was designed to determine whether acute and long-term treatment with clopidogrel and aspirin is superior to aspirin alone, with a reasonable safety margin, in the management of patients with ACS. Patients were eligible for inclusion if they presented within 24 h of experiencing chest pain and had either diagnostic electrocardiographic (EKG) changes or positive cardiac markers. The study included 12,562 patients. Baseline characteristics showed 75% had UA, 25% had an elevated enzyme or troponin level; 94% had EKG abnormalities; and 50% had ST-segment deviation. Clopidogrel 300 mg or placebo was administered as a loading dose as soon as treatment was allocated. This was followed by clopidogrel 75 mg/day (or placebo) and aspirin 75–325 mg/day. In addition, most patients received “best medical” therapy including heparin or low molecular weight heparin (LMWH), beta-blockers, calcium channel blockers, ACE inhibitors and lipid-lowering agents; only a small minority of patients, however, received IIb/IIIa receptor blockers. Treatment continued for a minimum of 3 months and varying periods up to 1 year (40). The primary study endpoint was a composite of death, reinfarction or stroke. At 12-month follow-up, 11.4% of patients randomized to placebo vs. 9.3% of patients on clopidogrel reached the primary endpoint. This represents a 20% risk reduction (p < 0.001), with benefits seen within a few hours after the initiation of therapy (p = 0.002) and sustained over time. Major bleeding (defined as disabling or symptomatic intracranial or intraocular bleeding; or transfusion > 2 units) but not life-threatening bleeding (defined as hemoglobin level decline of > 5 g/dl; hypotension requiring inotropes; bleeding requiring surgery or > 4 units of blood; intracranial bleeding) was modestly increased (3.7% vs. 2.7% in placebo; p = 0.001) (40). Emergency physicians will be particularly interested in subgroup analysis from the CURE data, yet to be published, that delineates more specifically the time-to-treatment effect for clopidogrel, and the potential impact on bleeding complications of irreversible ADP receptor blockade on patients who were taken to emergency coronary artery by-pass grafting (CABG) after coronary angiography.

Aggressive treatment and intervention for UA and NSTEMI in the ED remains a relatively new phenomenon, unlike the ED management of patients with ST-segment elevation events. The issue of short-term morbidity and mortality from ACS is critical to the emergency physician’s approach to the syndrome, and is addressed by antiplatelet therapy with agents such as aspirin, ADP receptor blockers and GP IIb/IIIa receptor antagonists. That the full and irreversible therapeutic benefit of clopidogrel administered in a loading dose (300 mg bolus) is evident within 2 hours makes use of this drug consistent with an early treatment approach 28, 29, 30. A potential concern pertinent to administering clopidogrel for ACS in the ED is that at least 10–15% of these patients typically go to coronary artery by-pass grafting during the index hospitalization, and irreversibly inhibited platelets may create problems for, or cause delays in, surgical management 53, 54. This is highlighted in the 2002 update to the 2000 ACC/AHA non-ST-segment elevation (NSTE) ACS guidelines, in which the following recommendations relative to platelet ADP receptor inhibition are promulgated (1):

How are these recommendations to be implemented in the ED? Patients suspected of having ACS should be given aspirin (162–325 mg) as soon as possible—at home, in the EMS setting or in the ED. Patients with true aspirin allergy should receive clopidogrel, presumably at a loading dose (300 mg, although this is not specified in the Guidelines), instead of aspirin. In addition, clopidogrel should be administered in the ED (per the Guidelines, “as soon as possible on admission”) to patients who will not undergo catheterization or interventional management over the ensuing 24–36 h, and to those who are not eligible for CABG. Patients going to the catheterization laboratory within that interval should receive clopidogrel during their course, but consideration should be given to withholding clopidogrel in the ED, as the coronary anatomy is not yet known. Only after determining the nature of the culprit coronary lesion(s) is it clear whether or not patients with NSTE ACS will require urgent or emergent CABG, and the risk of bleeding with a loading dose of clopidogrel on board prior to CABG may well outweigh the benefit of this additional level of antiplatelet therapy (40). It is not currently feasible to predict reliably in the ED which ACS patients will be found to require urgent or emergent CABG.

Emergency physicians who wish to administer clopidogrel in ACS patients can remedy their concerns by contributing to the development of a multidisciplinary ACS pathway, by which they know that patients going to interventions will receive the drug once the coronary anatomy is defined and the need for CABG has been excluded. Patients who are not candidates for catheterization or for CABG should receive clopidogrel in the ED.

Although the addition of a platelet GP IIb/IIIa inhibitor in patients receiving aspirin, clopidogrel and heparin in CURE was well tolerated, fewer than 10% of patients received this combination. Therefore, additional information on the safety of the addition of heparin (LMWH or unfractionated heparin) and a glycoprotein IIb/IIIa inhibitor in patients already receiving aspirin and clopidogrel should be obtained. Also, it is not yet clear whether clopidogrel improved the outcome in patients who received GP IIb/IIIa antagonists after randomization. The 2002 Guidelines give a positive Class IIa, Level B recommendation to the addition of a GP IIb/IIIa agent to heparin, aspirin and clopidogrel in patients in whom an interventional approach is planned.

The CURE study provides strong evidence for the addition of clopidogrel to aspirin in the ED as part of overall management of patients with UA/NSTEMI, in whom CABG is contraindicated or in whom a noninterventional approach is intended—an especially useful approach in hospitals that do not have a routine capacity for early invasive procedures (40). One reasonable approach for hospitals in which patients with UA/NSTEMI undergo diagnostic catheterization within 24 to 36 h of admission, is to withhold clopidogrel until it is clear that CABG will not be scheduled within the next several days; that is, it should not be initiated in the ED. A loading dose of clopidogrel can be given to a patient on the catheterization table if a PCI is to be carried out immediately. If PCI is not performed, clopidogrel can be administered after the catheterization.

Late vascular occlusive sequelae post-PCI are other examples of platelet-mediated events that can result in acute thrombotic events. Ticlopidine has been widely used in the last decade in combination with aspirin for the prevention of atherothrombosis after deployment of coronary stents (3). There have been no consistent data showing superiority of this combination over aspirin alone, and the applicability of this indication to ED practice is questionable 55, 56.

The Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS) showed that the combination of clopidogrel and aspirin is superior in safety to the combination of ticlopidine and aspirin in 1020 post-coronary stent patients started on one of three 28-day antiplatelet regimens: a 300 mg loading dose of clopidogrel followed by the combination of aspirin and clopidogrel; aspirin and clopidogrel without a loading dose; or ticlopidine and aspirin. The primary combined endpoint of major peripheral or bleeding complications, neutropenia, thrombocytopenia or early discontinuation of therapy was reached in 9.1% of the ticlopidine-treated patients and 4.6% in the combined clopidogrel-treated patients (p = 0.005). The use of a 300-mg loading dose of clopidogrel was not associated with an increased risk of bleeding and was well tolerated (42). The ongoing CREDO (Clopidogrel for the Reduction of Events During Observation) trial will evaluate the efficacy and safety of clopidogrel with or without a loading dose and short- and long-term (28 day–1 year) combination therapy with aspirin given before and continued after PTCA (46).

Use of ADP receptor antagonists in reducing cerebrovascular events 

In the cerebrovascular circulation, ADP receptor antagonists have demonstrated efficacy in the prevention of recurrent stroke in patients with a history of prior stroke or transient ischemic attack (TIA) 50, 57, 58. Ticlopidine was significantly more effective than aspirin in reducing the incidence of stroke after previous ischemic stroke or TIA, and was more effective than placebo in reducing the incidence of stroke, MI or vascular death after thromboembolic stroke in two clinical studies 57, 58.

Additional analyses of the CAPRIE data have shown that patients who present with stroke or TIA experience a significant number of subsequent ischemic events in all categories (MI, stroke, peripheral arterial occlusion) (59). Reduction in hospitalization for these events was statistically significant (p = 0.011) in those patients receiving clopidogrel (50). There was also a significant reduction in the total number of rehospitalizations for ischemic events or bleeding with clopidogrel use compared to aspirin (1502 vs. 1673, respectively; p = 0.01) over an average 1.6-year treatment period. This reduction in rehospitalization was consistent across individual outcomes of angina, TIA, limb ischemia and bleeding. The data showed a 7.9% relative risk reduction in the combined endpoint of vascular death, stroke, MI or re-hospitalization for ischemic events or bleeding (15.1% to 13.7%, respectively, at 1 year; p = 0.11) (59). Certain high-risk subgroups (patients with diabetes, dyslipidemia, prior revascularization [coronary, carotid or peripheral], and aspirin-resistant patients) appeared to receive amplified benefit from clopidogrel 60, 61, 62. Results of selected trials using ADP receptor antagonists for the prevention of cerebrovascular atherothrombosis are summarized in Table 2.

Table 2. ADP Receptor Antagonists in Preventing Cerebrovascular Atherothrombosis

	Author (Reference)	Trial (N)	Antiplatelet Agents	Selected Outcome	Results
	Hass, 1989 (56)	TASS (N = 3069)	Ticlopidine 250 mg b.i.d. vs. ASA 650 mg b.i.d.	Nonfatal stroke or death	RRR = 12% (p = 0.048)
	Gent, 1989 (57)	CATS (N = 1072)	Ticlopidine 250 mg b.i.d. vs. placebo	Stroke, MI, vascular death	RRR = 30% (p = 0.006)
	CAPRIE Steering Committee, 1996 (50)	CAPRIE (N = 19,185)	Clopidogrel 75 mg vs. ASA 325 mg	Ischemic stroke, MI, or vascular death	RRR = 8.7% (p = 0.043)
	Moore, 2000 (46)	MATCH (N = 7600)	Clopidogrel 75 mg + ASA 75 mg vs. clopidogrel 75 mg	Vascular death, nonfatal stroke/MI, & rehospitalization for acute ischemic events	Ongoing

TASS = Ticlopidine Aspirin Stroke Study; CATS = Canadian American Ticlopidine Study; MATCH = Management of Atherothrombosis with Clopidogrel in High-risk Patients with recent transient ischemic attack or stroke Trial; MI = myocardial infarction; ASA = aspirin; mg = milligrams; b.i.d. = twice daily; RRR = relative risk reduction.

The currently ongoing Management of Atherothrombosis with Clopidogrel in High-risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) Trial is evaluating the efficacy of a clopidogrel-aspirin combination compared to clopidogrel alone in preventing recurrent cerebrovascular and cardiovascular ischemic events in high-risk patients with cerebrovascular ischemia in the preceding 3 months. No clopidogrel-loading dose is included in this protocol. The total expected enrollment is 7600 patients. If MATCH is positive and the combination is shown to be effective and safe, such a protocol may be appropriate for the ED in patients whose acute central nervous system findings are determined to be ischemic in origin (63).

In one institution in which the author has worked, a protocol for TIA patients was developed in which clopidogrel was started empirically (with a loading dose) after a negative brain computed tomography (CT) scan (Figure 2). Patients are discharged on clopidogrel and managed as outpatients if results of carotid Doppler studies and echocardiography—also obtained in the ED—do not mandate inpatient therapy. Patients are also discharged on aspirin. This approach has not been prospectively validated, but is consistent with that supported by the latest meta-analysis from the Antithrombotic Trialists’ Collaboration (ATC), which showed an independent benefit accruing to clopidogrel (64).

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Figure 2. Proposed flowchart for evaluation and management of patients with TIA (Pollack, unpublished). NIHSS, National Institutes of Health Stroke Score; ED Obs, Emergency Department Observation Unit; AF, atrial fibrillation; ASA, aspirin.

Conclusion 

Acute atherothrombosis may present in a variety of ways depending upon the location of the occlusion. The underlying pathophysiology of the disease process, however, is the result of platelet activation and aggregation. ADP receptor antagonists can successfully reduce platelet activation and aggregation. Clinical trials have demonstrated their utility in preventing recurrent ischemic events. The latest iteration of the ACC/AHA guidelines for the management of NSTE acute coronary syndrome call for evidence-based clopidogrel therapy. There is suggestive evidence that the early initiation of these agents in the ED may improve clinical outcomes, and critical pathways for the evaluation and therapy of patients with chest pain and acute neurologic deficits should include the appropriate use of both aspirin and clopidogrel.