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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Antiplatelet therapy in percutaneous coronary intervention

Christoph Bode1,* and Kurt Huber2

1 Department of Internal Medicine III (Cardiology), University of Freiburg, Hugstetter Str. 55 Freiburg, Germany 79106
2 Wilhelminenspital der Stadt Wien, Montleartstrasse 37, Vienna, Austria A-1160

* Corresponding author. Tel: + 49 761 270 3441; fax: + 49 761 270 3200. E-mail address: christoph.bode{at}uniklinik-freiburg.de


   Abstract
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 Abstract
Introduction
 Antiplatelet therapy in...
 Antiplatelet therapy in...
 Effects of bleeding on...
 Conclusion
 Funding
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The goal of antiplatelet therapy for patients with acute coronary syndromes undergoing percutaneous coronary intervention (PCI) is to reduce the risk of ischaemic events without increasing the risk of bleeding. Aspirin, the most widely used antiplatelet agent, is effective, safe, and inexpensive and is recommended for all patients undergoing PCI. Clopidogrel, the thienopyridine agent, has been shown to reduce the rates of adverse cardiac events and mortality when given in a loading dose before PCI and in a maintenance dose thereafter. It has been extensively studied in patients with non–ST-elevation myocardial infarction (NSTEMI), but less so in patients with ST-elevation myocardial infarction (STEMI). Questions remain as to the optimal loading and maintenance doses of clopidogrel, timing of administration before PCI, and duration of therapy after placement of bare-metal or drug-eluting stents. New, more potent thienopyridines with faster onset of action are in development. Used with PCI, glycoprotein (GP) IIb/IIIa inhibitors reduce the rates of death, myocardial infarction, and urgent target-vessel revascularization in patients with STEMI and NSTEMI. Although GP IIb/IIIa inhibitors are most often used at the time of PCI, early administration in the emergency department or ambulance may improve clinical outcomes. All antiplatelet agents carry a risk of bleeding, which may significantly affect clinical outcomes.

Key Words: Antiplatelet agents • Percutaneous coronary intervention • Acute coronary syndromes • Aspirin • Thienopyridines • Glycoprotein IIb/IIIa inhibitors


   Introduction
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 Abstract
 Introduction
Antiplatelet therapy in...
 Antiplatelet therapy in...
 Effects of bleeding on...
 Conclusion
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Percutaneous coronary intervention (PCI), usually with stenting, has become the standard treatment for acute coronary syndromes (ACS). During this procedure, trauma commonly occurs to the arterial endothelium that, among other effects, causes the activation and aggregation of platelets. Because platelet aggregation may lead to coronary thrombosis in a patient already vulnerable to it, antiplatelet agents are essential adjunctive therapies in patients with ACS undergoing PCI. The goal of antiplatelet therapy is to provide maximal protection against thrombosis without increasing the risk of bleeding. Both PCI and antiplatelet therapy are evolving fields, and numerous questions remain regarding which agents, in which combinations, at what dosages, and for what durations will best achieve that goal. Aspirin, thienopyridines, and glycoprotein (GP) IIb/IIIa inhibitors are the mainstays of antiplatelet therapy in patients undergoing PCI.

Aspirin irreversibly inhibits cyclo-oxygenase-1, preventing the conversion of arachidonate to thromboxane (Tx) A2, a potent platelet agonist.1 A single aspirin dose of 160 mg or chronic dosing of 75 mg/day completely inhibits platelet TxA2 production.1,2 The Antithrombotic Trialists’ Collaboration meta-analysis of 287 studies of antiplatelet therapy in high-risk patients with vascular disease established that antiplatelet therapy, primarily with aspirin, reduces the incidence of death, myocardial infarction (MI), or stroke by 25%.3 Therefore, aspirin is given routinely to all patients with ST-elevation MI (STEMI), non–ST-elevation MI (NSTEMI), and unstable angina (UA), and is assumed to benefit equally those undergoing and those not undergoing PCI. Because the role of aspirin in ACS is well defined and undisputed, the balance of this article will focus primarily on the clinical use of thienopyridines and GP IIb/IIIa inhibitors, about which questions remain.

Thienopyridines irreversibly block the adenosine diphosphate (ADP) receptor P2Y12 on the platelet cell surface, inhibiting the ADP coagulation pathway.1 Clopidogrel and ticlopidine are prodrugs, requiring metabolism in the liver by the cytochrome P450 1A pathway to active metabolites.4 With its equivalent efficacy, faster onset of action, and better safety profile, clopidogrel has largely replaced ticlopidine in clinical practice.5–7 Clopidogrel has been shown to be as effective as aspirin in the prevention of ischaemic events in patients at risk.8 Because clopidogrel and aspirin affect distinct pathways in the coagulation cascade, they are most often used in combination, which has been shown to decrease the incidence of ischaemic events by 20% in patients with NSTEMI or UA compared with aspirin alone.9

The final common pathway of the various mechanisms of platelet aggregation is the binding of fibrinogen to adjacent platelets by means of GP IIb/IIIa integrin on the platelet surface.10 Abciximab, tirofiban, and eptifibatide are potent GP IIb/IIIa inhibitors for intravenous administration that reduce the incidence of death and recurrent MI in high-risk patients undergoing PCI.11–14


   Antiplatelet therapy in percutaneous coronary intervention for ST-elevation myocardial infarction
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Primary percutaneous coronary intervention
Percutaneous coronary intervention, usually with stenting, performed within 90 min of first medical contact, is the treatment of choice for most patients presenting with STEMI.15 Antiplatelet therapy is used before, during, and after PCI to reduce the risk of peri-procedural and post-procedural ischaemic events.10

Thienopyridines
Early trials established that aspirin with ticlopidine was superior to aspirin alone or anticoagulation plus aspirin for the prevention of ischaemic events in patients undergoing PCI.16,17 Randomized, controlled trials of clopidogrel vs. placebo in primary PCI for patients with STEMI have not been conducted, and its efficacy in that setting has been assumed based on the results of studies of patients with ACS undergoing elective PCI and patients with STEMI treated with fibrinolysis before PCI. Recently, a trial has been initiated that will randomize patients with STEMI to one of the two groups: the first will receive 600 mg of clopidogrel in the ambulance and the second will not receive clopidogrel before intervention.18 In the subgroup of patients enrolled in the CURE trial who underwent PCI, treatment with clopidogrel and aspirin for a median of 10 days before PCI resulted in a 30% reduction in the 30-day risk of cardiovascular death, MI, or urgent target-vessel revascularization.19 The CLARITY study included 1863 patients with STEMI who underwent PCI after fibrinolysis.20 Upon presentation, patients were randomized to receive a 300 mg loading dose of clopidogrel, followed by 75 mg/day, or placebo. In the clopidogrel group, there was a 46% reduction in the 30-day rate of cardiovascular death, recurrent MI, or stroke compared with the placebo group (P = 0.008). Clopidogrel treatment improved outcomes consistently whether PCI was performed on an urgent or elective basis and regardless of the time from drug initiation until the procedure. Since most patients received open-label clopidogrel after the procedure, the observed benefit can be attributed to pre-treatment with clopidogrel.

Because platelet aggregation is inhibited ~2 h after a 600 mg loading dose of clopidogrel, PCI started before that time is performed without the benefit of full platelet inhibition.21 Prasugrel, a new thienopyridine, has a faster onset of action and may provide better protection when PCI is performed urgently.22 The TRITON-TIMI 38 trial compared prasugrel and clopidogrel in 13 608 moderate- to high-risk patients with ACS scheduled to undergo PCI.23 Among the 3534 patients with STEMI, the composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke occurred in 10.0% of prasugrel-treated patients and 12.4% of clopidogrel-treated patients (P = 0.02). Also, the incidence of stent thrombosis was significantly reduced. However, these benefits come at a price. In the overall study cohort, patients randomized to prasugrel had higher rates of major bleeding (2.4 vs. 1.8%, P = 0.03), life-threatening bleeding (1.4 vs. 0.9%, P = 0.01), and fatal bleeding (0.4 vs. 0.1%, P = 0.002).

The ideal duration of clopidogrel treatment after PCI for STEMI is unknown, but is influenced by the type of stent placed and the patient’s risk for bleeding.24 Although the patients in PCI–CURE did not have STEMI, the 25% reduction in cardiovascular death or MI resulting from a mean of 9 months of clopidogrel treatment suggests that at least that duration of therapy is appropriate.19

Blockade of the P2Y12 receptor with clopidogrel is irreversible, and some concern has been raised regarding the administration of this agent before coronary angiography, during which it might be discovered that the patient requires coronary artery grafting. Thus, the patient would undergo surgery with an increased bleeding risk or be forced to wait for platelet function to be sufficiently restored. This situation is rare and the risk is relatively low, such that withholding clopidogrel before PCI would not be justified.

GP IIb/IIIa inhibitors
Of the three available GP IIb/IIIa inhibitors, only abciximab has been extensively studied in patients with STEMI undergoing primary PCI. A meta-analysis examined six trials including 3755 patients who were randomized to abciximab or placebo and followed for 6 months (five trials) or 1 month (one trial).25 Overall, the treatment with abciximab reduced the rates of death (3.4 vs. 4.9%, P = 0.03), target-vessel revascularization (11.8 vs. 14.4%, P = 0.02), and major adverse cardiac events (MACEs) (17.0 vs. 21.1%, P = 0.001). Reinfarction rates were unaffected by abciximab treatment. The beneficial effects of abciximab were confined to patients who received stents, and did not appear in those treated with balloon angioplasty. Major bleeding occurred more often in abciximab-treated patients, but the difference was significant only in patients who received a dose of 100 U/kg heparin, not in those who received a dose of 70 U/kg, underlining the importance of studying drug combinations. A more recent meta-analysis of three trials of abciximab in patients with STEMI undergoing PCI found that, over 3 years of follow-up, abciximab reduced the rate of death or reinfarction to 12.9 vs. 19.0% with placebo (relative risk [RR], 0.633; 95% confidence interval [CI], 0.452–0.887; P = 0.008).26

In a study of 4010 patients with ACS undergoing revascularization, eptifibatide treatment failed to demonstrate a significant improvement over placebo in the composite endpoint of death, MI, or urgent revascularization at 30 days.27 In a similar but even larger trial, a higher dose of eptifibatide resulted in a significant reduction in the 30-day occurrence of the composite of death or MI (14.2 vs. 15.7%, P = 0.04), a benefit that was observed 96 h after randomization and maintained throughout the trial.28 Thus, eptifibatide is an effective agent for the treatment of ACS in the PCI setting.

Guideline recommendations for antiplatelet therapy for percutaneous coronary intervention in ST-elevation myocardial infarction
Current clinical guidelines call for the administration of aspirin to all patients with STEMI as soon as possible after the diagnosis is made.24 Patients already on daily aspirin therapy should be given 75–325 mg of aspirin before PCI; those not taking aspirin should be given 500 mg at least 3 h before the procedure or 300 mg intravenously immediately before the procedure.24 After PCI, aspirin should be continued at 75–160 mg/day indefinitely.15

Clopidogrel should be administered in a loading dose of 300 mg at least 6 h before PCI or, if this is not possible, in a dose of 600 mg at least 2 h before.24 After implantation of a bare-metal stent (BMS), clopidogrel should be continued at 75 mg/day for 4–6 weeks, and after implantation of a drug-eluting stent (DES), for 12 months.24,29

Administration of abciximab before the diagnostic angiogram (‘upstream’) or just before PCI is acceptable.30–32 Eptifibatide and tirofiban are not as well studied in STEMI, but may be considered for use in that setting.24,32

Facilitated percutaneous coronary intervention
Facilitated PCI is a strategy intended to increase the success rate of PCI. This may take the form of treating the patient first with a thrombolytic agent alone, with reduced-dose fibrinolysis plus a GP IIb/IIIa inhibitor, or treating with a GP IIb/IIIa inhibitor alone soon after initial medical contact, rather than waiting until the patient reaches the cardiac catheterization laboratory.

Thrombolytic agents
As a planned strategy, fibrinolysis before PCI shows no benefit over primary PCI alone, and may even be harmful. A meta-analysis of 17 trials found that facilitated PCI with thrombolysis resulted in higher rates of death, re-infarction, and urgent target-vessel revascularization.33 The ASSENT-4 PCI trial demonstrated that administration of full-dose tenecteplase before delayed PCI results in increased rates of ischaemic cardiac complications, in-hospital stroke, and the combined endpoint of death, congestive heart failure, and shock.34 However, facilitated PCI may be carried out when a patient presents to a hospital without a cardiac catheterization laboratory, where fibrinolysis is performed before transport to a PCI-equipped facility. This should be considered only if transport time precludes the performance of PCI within 90 min. Several clinical trials, discussed below, have addressed the use of antiplatelet agents in patients treated with facilitated PCI.

Thienopyridines
In the CLARITY trial, 3491 patients with STEMI were randomized to receive a 300 mg loading dose of clopidogrel followed by 75 mg/day or placebo at the time of fibrinolysis; all patients also received aspirin.35 The 1863 patients who then underwent PCI were analysed separately.20 Most patients who received stents were given open-label clopidogrel. The median time from drug initiation to PCI was 3 days. After 30 days, patients who had been randomized to clopidogrel had a 46% reduction in the rate of the composite of cardiovascular death, recurrent MI, or stroke (3.6 vs. 6.2%; adjusted odds ratio [OR], 0.54; 95% CI, 0.35–0.85; P = 0.008). Among each of the components of the endpoint, there was a trend favouring clopidogrel treatment. The benefit of clopidogrel treatment was seen regardless of the fibrinolytic agent used, whether a GP IIb/IIIa inhibitor was given, and whether the PCI was urgent or elective.

GP IIb/IIIa inhibitors with or without thrombolytic agents
Facilitated PCI using half-dose reteplase with abciximab or abciximab alone was investigated in 253 patients with STEMI, most of whom presented to a hospital without a cardiac catheterization laboratory.36 In the admitting hospital, patients were randomized to receive reteplase in two boluses of 5 U, 30 min apart, plus abciximab as a bolus of 0.25 mg/kg followed by a 0.125 µg/kg per minute infusion, or abciximab alone. After transportation to an interventional centre, patients underwent PCI at the physician’s discretion. During initial angiography, TIMI grade-3 flow was observed more often in patients who received combination therapy, but final infarct size did not differ between the two groups. Six months after randomization, there was no significant difference between groups in the rate of the cumulative incidence of death, recurrent MI, or stroke. The authors concluded that the strategy of administering half-dose reteplase with abciximab before PCI had no advantages over abciximab alone.

A meta-analysis of four trials comparing a reduced-dose thrombolytic agent plus a GP IIb/IIIa inhibitor with a GP IIb/IIIa inhibitor alone given during PCI in patients with STEMI also failed to discern any long-term advantage to combination treatment, but did find that it was associated with an increased risk for bleeding.37

A meta-analysis of six trials found a significant increase in open infarct arteries and a trend towards reduced mortality when a GP IIb/IIIa inhibitor alone was given in the ambulance or emergency department rather than in the cardiac catheterization laboratory.30 Similarly, administration of eptifibatide in the emergency department rather than the catheterization laboratory was found to improve epicardial flow and myocardial perfusion.38

Rescue percutaneous coronary intervention
In patients with STEMI, failed fibrinolysis may be followed by PCI, an approach termed ‘rescue PCI’. A few studies suggest that the use of abciximab in this setting may improve in-hospital, 30-day, and 6-month outcomes, but the limited size of these studies and the retrospective design of one preclude drawing conclusions from them.39,40 Abciximab may increase the frequency of major and minor bleeding episodes in these patients.41

Percutaneous coronary intervention scheduled after successful thrombolysis
Percutaneous coronary intervention is frequently used after successful thrombolysis to maintain patency of the artery. An observational study of 473 STEMI patients treated with fibrinolysis found that the 154 patients who also received PCI had a significantly lower 1 year mortality rate than those who did not receive PCI (7 vs. 21%, P < 0.001).42 Two-thirds of the PCI-treated patients were given clopidogrel. Although there is insufficient evidence to state that PCI after successful thrombolysis is a preferred strategy, nor whether PCI should be performed immediately after thrombolysis or later,43 if this strategy is used, there is no evidence that the standard antiplatelet regimen should be changed.


   Antiplatelet therapy in percutaneous coronary intervention for non–ST-elevation myocardial infarction
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Thienopyridines
The role of clopidogrel in PCI for NSTEMI patients was confirmed by the analysis of the subgroup of 2658 patients undergoing PCI in the PCI–CURE trial.19 All patients received aspirin and were randomized to treatment with a 300 mg loading dose of clopidogrel followed by maintenance therapy or placebo. PCI was performed for a median of 10 days after randomization. Following PCI, patients who received stents received 2–4 weeks of open-label treatment with either clopidogrel or ticlopidine, after which they resumed the treatment to which they had been randomized for 3–12 months. Significantly fewer patients taking clopidogrel than taking placebo had an MI or refractory ischaemia before PCI. At 30 days, cardiovascular death, MI, or urgent revascularization had occurred in 4.5% of clopidogrel patients and 6.4% of placebo patients (RR, 0.70; 95% CI, 0.50–0.97; P = 0.03). After a mean of 8 months of follow-up after PCI, cardiovascular death or MI occurred in 6.0% of clopidogrel patients and 8.0% of placebo patients (RR, 0.75; 95% CI, 0.56–1.00, P = 0.047) (Figure 1).19 The benefit of clopidogrel was present in all demographic and clinical subgroups and regardless of the timing of PCI. There were more minor bleeding episodes in the clopidogrel group, but no significant differences between groups in the rates of major bleeding.


Figure 1
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  		Figure 1 Kaplan–Meier cumulative hazard rates for cardiovascular death or MI from randomization to end of follow-up in PCI-CURE. A = median time from randomization to PCI. B = 30 days after median time of PCI. Reprinted from Mehta et al.19 Copyright 2001, with permission from Elsevier.

 
The CREDO trial randomized 2116 patients with ACS to a 300 mg loading dose of clopidogrel or placebo 3–24 h before PCI; all patients received aspirin.44 After PCI, all patients received 28 days of clopidogrel treatment in a dose of 75 mg/day. Patients then resumed the treatment to which they had been randomized. At 1 year, the composite of death, MI, or stroke was reduced by 26.9% in the clopidogrel group (P = 0.02). In contrast, there was no significant difference at 28 days in the rate of death, MI, or target-vessel revascularization between the two groups. However, in patients who received the loading dose of clopidogrel ≥6 h before PCI, there was an almost-significant 38.6% reduction in the composite endpoint at 28 days (P = 0.051).44 When the duration of pre-treatment in CREDO was examined as a continuous variable, it was found that a significant benefit in outcomes was obtained only if clopidogrel was given at least 12 h before PCI, and that the ideal duration of treatment approached 24 h.45

Many clinicians have attempted to enhance the results obtained with clopidogrel by increasing the loading dose. This approach received support from the ALBION trial, which randomized 103 patients with NSTEMI to clopidogrel loading doses of 300, 600, or 900 mg, followed by maintenance doses of 75 mg/day plus aspirin.21 Platelet function testing showed that higher clopidogrel doses were associated with faster onset of platelet inhibition and greater reduction in platelet activation. There were fewer MACEs in patients who received 600 or 900 mg loading doses, although the differences were not significant. No excess of bleeding was associated with higher doses.

The suppression of platelet aggregation found with a 600 mg clopidogrel loading dose in ALBION has been confirmed in other studies, but there is some question as to whether further benefit is obtained with a 900 mg loading dose.46,47 Among the 10 074 patients with UA/NSTEMI included in TRITON-TIMI 38, the composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke occurred in 9.9% of patients randomized to prasugrel and 12.1% of patients randomized to clopidogrel (P = 0.002).23

GP IIb/IIIa inhibitors
A meta-analysis of eight trials that randomized a total of 9290 patients with ACS to conventional therapy plus an abciximab bolus within 1 h before PCI followed by a 12 h infusion or to conventional therapy plus placebo found that abciximab treatment resulted in an absolute reduction in mortality of 0.74% at 6 months (P = 0.040) and 0.94% at 1 year (P = 0.031) (Figure 2).11 Mortality was lower in abciximab-treated patients before 6 months, but the differences were not statistically significant.


Figure 2
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  		Figure 2 Six-month mortality from the combined results of eight trials of patients undergoing PCI randomized to placebo or abciximab bolus within 1 h before PCI followed by 12 h infusion. Reprinted from Anderson et al.11 Copyright 2001, with permission from Elsevier.

 
The ISAR-REACT 2 study examined the effects of abciximab in 2022 high-risk patients with non–ST-elevation (NSTE)–ACS undergoing PCI.48 All patients received a 600 mg loading dose of clopidogrel ≥2 h before PCI; they also received aspirin. Patients were randomized in the catheterization laboratory to receive heparin plus either abciximab, in a bolus of 0.25 mg/kg followed by an infusion of 0.125 µg/kg per minute for 12 h, or placebo. At 30 days, the combined endpoint of death, MI, or target-vessel revascularization occurred in 8.9% of abciximab patients and 11.9% of placebo patients (RR, 0.75; 95% CI, 0.58–0.97; P = 0.03). Most of the risk reduction resulted from a decreased incidence of death and MI. Further analysis showed that abciximab treatment benefited only those patients who had an elevated troponin level.

In the treatment of patients with ACS undergoing PCI, abciximab given as a bolus of 0.25 mg/kg followed by an infusion of 0.125 µg/kg per minute for 12 h has been shown to be superior at 30 days to tirofiban given as a bolus of 10 µg/kg followed by an infusion of 0.15 µg/kg per minute for 18–24 h, although survival rates at 1 year were similar.13,49 When a higher dose of tirofiban—a bolus of 25 µg/kg followed by an infusion of 0.15 µg/kg/minute for 24–48 h—was compared with placebo in high-risk patients with ACS undergoing PCI, tirofiban was found to reduce the incidence of death, MI, urgent target-vessel revascularization, or thrombotic bailout with GP IIb/IIIa inhibitor therapy at 185 days by 42% (hazard ratio [HR], 0.51, 95% CI, 0.29–0.88, P = 0.01).50

In the ESPRIT trial, eptifibatide given to ACS patients undergoing PCI as two 180 µg/kg boluses 10 min apart and a continuous infusion of 2.0 µg/kg per minute for 18–24 h or until hospital discharge was shown to reduce the incidence of death, MI, urgent target-vessel revascularization, or crossover bailout therapy from 10.5 to 6.6% at 48 h (P = 0.0015). At 30 days, eptifibatide reduced the incidence of death, MI, and urgent target-vessel revascularization from 10.5 to 6.8% (P = 0.0034).51 One year follow-up found that eptifibatide-treated patients continued to have lower rates of death or MI (8.0 vs. 12.4%; HR, 0.63; 95% CI, 0.48–0.83; P = 0.001).14 The ongoing EARLY ACS trial will evaluate the early use of eptifibatide—at least 1 day before PCI—in patients with NSTEMI.52

Three approaches to reperfusion of coronary arteries in patients with ACS were investigated in the EPISTENT trial.12 A total of 2399 patients were randomized to undergo stenting with adjunctive therapy with abciximab, stenting without abciximab, or balloon angioplasty with abciximab. Abciximab therapy was begun up to 60 min before intervention. At 1 year follow-up, stenting plus abciximab resulted in a 57% reduction in mortality compared with stenting alone; mortality rates were similar between the balloon angioplasty plus abciximab group and the stenting alone group.

Guideline recommendations for antiplatelet therapy for percutaneous coronary intervention in non–ST-elevation myocardial infarction
Guidelines recently released by the European Society of Cardiology (ESC)29 recommend aspirin for all patients with NSTE–ACS without contraindications in a loading dose of 160–325 mg (non-enteric) and in a long-term maintenance dose of 75–100 mg/day. All patients undergoing PCI should receive a 600 mg loading dose of clopidogrel, followed by 75 mg/day for 12 months. In patients treated with clopidogrel in whom coronary artery bypass grafting is planned, the procedure should be delayed for 5 days, if possible, to reduce the risk of bleeding.

Patients scheduled for PCI who are at intermediate to high risk, particularly patients with elevated troponins, ST depression, or diabetes, should receive eptifibatide or tirofiban and should be continued on the same drug during and after PCI. High-risk patients not pre-treated with a GP IIb/IIIa inhibitor should receive abciximab immediately following angiography. GP IIb/IIIa inhibitors should be used concomitantly with an anticoagulant agent.29

Drug-eluting stents may carry a higher risk for late-stent thrombosis than BMS, particularly when used in complex situations, which has led the ESC to recommend 1 year of dual antiplatelet therapy after implantation of either a sirolimus- or paclitaxel-eluting stent.29,53


   Effects of bleeding on long-term outcomes
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The most serious adverse effect of antiplatelet agents is bleeding. Recent evidence suggests that, in addition to being an acute clinical problem, bleeding may affect long-term outcomes. An analysis of pooled data from four clinical trials studying the effects of anticoagulants and GP IIb/IIIa inhibitors in patients with NSTEMI found that mortality increased with the severity of bleeding and that mortality rates at 30 days were 10 times higher in patients with severe bleeding than in patients with no bleeding.54 At 6 months, compared with patients without bleeding, the HRs for death were 1.4 (95% CI, 1.2–1.6) for patients with mild bleeding, 2.1 (95% CI, 1.8–2.4) for patients with moderate bleeding, and 7.5 (95% CI, 6.1–9.3) for patients with severe bleeding. Of particular concern is the increased mortality rate among patients with minor bleeding, which is usually not considered a serious clinical event. Therefore, as new antiplatelet agents are developed and evaluated, their safety will be of greatest concern.


   Conclusion
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Clinical trials conducted over the past decade have established that antiplatelet therapy is an essential component of the care of patients with ACS undergoing PCI because it reduces the incidence of MACEs. Future research will be directed at determining the optimal dose and timing of clopidogrel before, during, and after PCI; the appropriate duration of clopidogrel therapy after implantation of BMS and DES; the role of more potent thienopyridines with faster onset of action; and the degree of benefit obtained from the use of GP IIb/IIIa inhibitors in patients with STEMI.


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Sponsored by an educational grant from Daiichi Sankyo Europe GmbH and Eli Lilly and Company.


   Acknowledgments
 
Conflict of interest: Dr Bode declares that he has received consultancy fees and speaker honoraria from AstraZeneca, sanofi-aventis, and GlaxoSmithKline. Dr Huber has received honoraria for oral presentations and participation in steering committees of international trials from the following companies: AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Hoffmann-La Roche, The Medicines Company, Merck, Merck Sharp & Dohme, Nycomed, Pfizer, and sanofi-aventis.


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  1. Cattaneo M. Aspirin and clopidogrel: efficacy, safety, and the issue of drug resistance. Arterioscler Thromb Vasc Biol (2004) 24:1980–1987.[Abstract/Free Full Text]
  2. Patrono C. Aspirin as an antiplatelet drug. N Engl J Med (1994) 330:1287–1294.[Free Full Text]
  3. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ (2002) 324:71–86.[Abstract/Free Full Text]
  4. Cattaneo M. Platelet P2 receptors: old and new targets for antithrombotic drugs. Expert Rev Cardiovasc Ther (2007) 5:45–55.[CrossRef][Medline]
  5. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH, for the CLASSICS Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation (2000) 102:624–629.[Abstract/Free Full Text]
  6. Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest (2004) 126(Suppl.):234–264.[CrossRef]
  7. Bhatt DL, Bertrand ME, Berger PB, L’Allier PL, Moussa I, Moses JW, Dangas G, Taniuchi M, Lasala JM, Holmes DR, Ellis SG, Topol EJ. Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting. J Am Coll Cardiol (2002) 39:9–14.[Abstract/Free Full Text]
  8. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet (1996) 348:1329–1339.[CrossRef][Web of Science][Medline]
  9. The 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.[Abstract/Free Full Text]
  10. Montalescot G, Andersen HR, Antoniucci D, Betriu A, de Boer MJ, Grip L, Neumann FJ, Rothman MT. Recommendations on percutaneous coronary intervention for the reperfusion of acute ST elevation myocardial infarction. Heart (2004) 90:e37–e49.[Abstract/Free Full Text]
  11. Anderson KM, Califf RM, Stone GW, Neumann FJ, Montalescot G, Miller DP, Ferguson JJ 3rd, Willerson JT, Weisman HF, Topol EJ. Long-term mortality benefit with abciximab in patients undergoing percutaneous coronary intervention. J Am Coll Cardiol (2001) 37:2059–2065.[Abstract/Free Full Text]
  12. Topol EJ, Mark DB, Lincoff AM, Cohen E, Burton J, Kleiman N, Talley D, Sapp S, Booth J, Cabot CF, Anderson KM, Califf RM, for the EPISTENT Investigators. Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: results from a multicentre randomised trial. Lancet (1999) 354:2019–2024.[CrossRef][Web of Science][Medline]
  13. Mukherjee D, Topol EJ, Bertrand ME, Kristensen SD, Herrmann HC, Neumann FJ, Yakubov SJ, Bassand JP, McClure RR, Stone GW, Ardissino D, Moliterno DJ, for the TARGET Investigators. Mortality at 1 year for the direct comparison of tirofiban and abciximab during percutaneous coronary revascularization: do tirofiban and ReoPro give similar efficacy outcomes at trial 1-year follow-up? Eur Heart J (2005) 26:2524–2528.[Abstract/Free Full Text]
  14. O’Shea JC, Buller CE, Cantor WJ, Chandler AB, Cohen EA, Cohen DJ, Gilchrist IC, Kleiman NS, Labinaz M, Madan M, Hafley GE, Califf RM, Kitt MM, Strony J, Tcheng JE, for the ESPRIT Investigators. Long-term efficacy of platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention. JAMA (2002) 287:618–621.[Abstract/Free Full Text]
  15. Van de Werf F, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KAA, Julian D, Lengyel M, Neumann FJ, Ruzyllo W, Thygesen C, Underwood SR, Vahanian A, Verheugt FWA, Wijns W. Management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J (2003) 24:28–66.[Free Full Text]
  16. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KKL, Giambartolomei A, Diver DJ, Lasorda DM, Williams DO, Pocock SJ, Kuntz RE, for the Stent Anticoagulation Restenosis Study Investigators. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. N Engl J Med (1998) 339:1665–1671.[Abstract/Free Full Text]
  17. Schomig A, Neumann FJ, Kastrati A, Schuhlen H, Blasini R, Hadamitzky M, Walter H, Zitzmann-Roth EM, Richardt G, Alt E, Schmitt C, Ulm K. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med (1996) 334:1084–1089.[Abstract/Free Full Text]
  18. Zeymer U, Arntz HR, Darius H, Huber K, Senges J. Efficacy and safety of clopidogrel 600 mg administered pre-hospitally to improve primary percutaneous coronary intervention in patients with acute myocardial infarction (CIPAMI): study rationale and design. Cardiology (2007) 108:265–272.[CrossRef][Web of Science][Medline]
  19. Mehta SR, Yusuf S, Peters RJG, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht HJ, Zhao F, Chrolavicius S, Copland I, Fox KAA, for the Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI–CURE study. Lancet (2001) 358:527–533.[CrossRef][Web of Science][Medline]
  20. Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, Lewis BS, Murphy SA, McCabe CH, Braunwald E, for the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)–Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA (2005) 294:1224–1232.[Abstract/Free Full Text]
  21. Montalescot G, Sideris G, Meuleman C, Bal-dit-Sollier C, Lellouche N, Steg PG, Slama M, Milleron O, Collet JP, Henry P, Beygui F, Drouet L, for the ALBION Trial Investigators. A randomized comparison of high clopidogrel loading doses in patients with non–ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol (2006) 48:931–938.[Abstract/Free Full Text]
  22. Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS, Jakubowski JA, Naganuma H, Winters KJ. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J (2007) 153:66.e9–66.e16.
  23. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann F-J, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM, for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med (2007) 357:2001–2015.[Abstract/Free Full Text]
  24. Silber S, Albertsson P, Aviles FF, Camici PG, Colombo A, Hamm C, Jorgensen E, Marco J, Nordrehaug JE, Ruzyllo W, Urban P, Stone GW, Wijns W. Guidelines for percutaneous coronary interventions. Eur Heart J (2005) 26:804–847.[Free Full Text]
  25. de Queiroz Fernandes Araujo JO, Veloso HH, Braga De Paiva JM, Filho MW, Vincenzo De Paola AA. Efficacy and safety of abciximab on acute myocardial infarction treated with percutaneous coronary interventions: a meta-analysis of randomized, controlled trials. Am Heart J (2004) 148:937–943.[CrossRef][Web of Science][Medline]
  26. Montalescot G, Antoniucci D, Kastrati A, Neumann FJ, Borentain M, Migliorini A, Boutron C, Collet JP, Vicaut E. Abciximab in primary coronary stenting of ST-elevation myocardial infarction: a European meta-analysis on individual patients’ data with long-term follow-up. Eur Heart J (2007) 28:443–449.[Abstract/Free Full Text]
  27. The IMPACT-II Investigators. Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Lancet (1997) 349:1422–1428.[CrossRef][Web of Science][Medline]
  28. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med (1998) 339:436–443.[Abstract/Free Full Text]
  29. Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A, Fernandez-Aviles F, Fox KAA, Hasdai D, Ohman EM, Wallentin L, Wijns W. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J (2007) 28:2–63.
  30. Montalescot G, Borentain M, Payot L, Collet JP, Thomas D. Early vs late administration of glycoprotein IIb/IIIa inhibitors in primary percutaneous coronary intervention of acute ST-segment elevation myocardial infarction: a meta-analysis. JAMA (2004) 292:362–366.[Abstract/Free Full Text]
  31. Godicke J, Flather M, Noc M, Gyongyosi M, Arntz HR, Grip L, Gabriel HM, Huber K, Nugara F, Schroder J, Svensson L, Wang D, Zorman S, Montalescot G. Early versus periprocedural administration of abciximab for primary angioplasty: a pooled analysis of 6 studies. Am Heart J (2005) 150:1015.e11–1015.e17.
  32. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, Jacobs AK, Kern MJ, King SB 3rd, Morrison DA, O’Neill WW, Schaff HV, Whitlow PL, Williams DO. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol (2006) 47:216–235.[Free Full Text]
  33. Keeley EC, Boura JA, Grines CL. Comparison of primary and facilitated percutaneous coronary interventions for ST-elevation myocardial infarction: quantitative review of randomised trials. Lancet (2006) 367:579–588.[CrossRef][Web of Science][Medline]
  34. Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT-4 PCI) Investigators. Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): randomised trial. Lancet (2006) 367:569–578.[CrossRef][Web of Science][Medline]
  35. Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH, Braunwald E, for the CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med (2005) 352:1179–1189.[Abstract/Free Full Text]
  36. Kastrati A, Mehilli J, Schlotterbeck K, Dotzer F, Dirschinger J, Schmitt C, Nekolla SG, Seyfarth M, Martinoff S, Markwardt C, Clermont G, Gerbig HW, Leiss J, Schwaiger M, Schomig A, for the Bavarian Reperfusion Alternatives Evaluation (BRAVE) Study Investigators. Early administration of reteplase plus abciximab vs abciximab alone in patients with acute myocardial infarction referred for percutaneous coronary intervention: a randomized controlled trial. JAMA (2004) 291:947–954.[Abstract/Free Full Text]
  37. Sinno MCN, Khanal S, Al-Mallah MH, Arida M, Weaver WD. The efficacy and safety of combination glycoprotein IIbIIIa inhibitors and reduced-dose thrombolytic therapy–facilitated percutaneous coronary intervention for ST-elevation myocardial infarction: a meta-analysis of randomized clinical trials. Am Heart J (2007) 153:579–586.[CrossRef][Web of Science][Medline]
  38. Gibson CM, Kirtane AJ, Murphy SA, Rohrbeck S, Menon V, Lins J, Kazziha S, Rokos I, Shammas NW, Palabrica TM, Fish P, McCabe CH, Braunwald E, for the TIMI Study Group. Early initiation of eptifibatide in the emergency department before primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: results of the Time to Integrilin Therapy in Acute Myocardial Infarction (TITAN)-TIMI 34 trial. Am Heart J (2006) 152:668–675.[CrossRef][Web of Science][Medline]
  39. Gruberg L, Suleiman M, Kapeliovich M, Hammerman H, Grenadier E, Boulus M, Amikam S, Markiewicz W, Beyar R. Glycoprotein IIb/IIIa inhibitors during rescue percutaneous coronary intervention in acute myocardial infarction. J Invasive Cardiol (2006) 18:59–62.[Medline]
  40. Petronio AS, Musumeci G, Limbruno U, De Carlo M, Baglini R, Paterni G, Donne MGD, Caravelli P, Nardi C, Mariani M. Abciximab improves 6-month clinical outcome after rescue coronary angioplasty. Am Heart J (2002) 143:334–341.[CrossRef][Web of Science][Medline]
  41. Miller JM, Smalling R, Ohman EM, Bode C, Betriu A, Kleiman NS, Schildcrout JS, Bastos E, Topol EJ, Califf RM, for the GUSTO-III Investigators. Effectiveness of early coronary angioplasty and abciximab for failed thrombolysis (reteplase or alteplase) during acute myocardial infarction (results from the GUSTO-III trial). Am J Cardiol (1999) 84:779–784.[CrossRef][Web of Science][Medline]
  42. McClelland AJJ, Owens CG, Walsh SJ, McCarty D, Mathew T, Stevenson M, Gracey H, Khan MM, Adgey AAJ. Percutaneous coronary intervention and 1 year survival in patients treated with fibrinolytic therapy for acute ST-elevation myocardial infarction. Eur Heart J (2005) 26:544–548.[Abstract/Free Full Text]
  43. Cantor WJ, Brunet F, Ziegler CP, Kiss A, Morrison LJ. Immediate angioplasty after thrombolysis: a systematic review. CMAJ (2005) 173:1473–1481.[Abstract/Free Full Text]
  44. Steinhubl SR, Berger PB, Mann JT III, Fry ETA, DeLago A, Wilmer C, Topol EJ, for the CREDO Investigators. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA (2002) 288:2411–2420.[Abstract/Free Full Text]
  45. Steinhubl SR, Berger PB, Brennan DM, Topol EJ, for the CREDO Investigators. Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention. J Am Coll Cardiol (2006) 47:939–943.[Abstract/Free Full Text]
  46. Kastrati A, von Beckerath N, Joost A, Pogatsa-Murray G, Gorchakova O, Schomig A. Loading with 600 mg clopidogrel in patients with coronary artery disease with and without chronic clopidogrel therapy. Circulation (2004) 110:1916–1919.[Abstract/Free Full Text]
  47. von Beckerath N, Taubert D, Pogatsa-Murray G, Schomig E, Kastrati A, Schomig A. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) trial. Circulation (2005) 112:2946–2950.[Abstract/Free Full Text]
  48. Kastrati A, Mehilli J, Neumann FJ, Dotzer F, ten Berg J, Bollwein H, Graf I, Ibrahim M, Pache J, Seyfarth M, Schuhlen H, Dirschinger J, Berger PB, Schomig A, for the Intracoronary Stenting Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) Trial Investigators. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA (2006) 295:1531–1538.[Abstract/Free Full Text]
  49. Topol EJ, Moliterno DJ, Herrmann HC, Powers ER, Grines CL, Cohen DJ, Cohen EA, Bertrand M, Neumann FJ, Stone GW, DiBattiste PM, Demopoulos L, for the TARGET Investigators. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med (2001) 344:1888–1894.[Abstract/Free Full Text]
  50. Valgimigli M, Percoco G, Barbieri D, Ferrari F, Guardigli G, Parrinello G, Soukhomovskaia O, Ferrari R. The additive value of tirofiban administered with the high-dose bolus in the prevention of ischemic complications during high-risk coronary angioplasty: the ADVANCE trial. J Am Coll Cardiol (2004) 44:14–19.[Abstract/Free Full Text]
  51. The ESPRIT Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. Lancet (2000) 356:2037–2044.[CrossRef][Web of Science][Medline]
  52. Giugliano RP, Newby LK, Harrington RA, Gibson CM, Van de Werf F, Armstrong P, Montalescot G, Gilbert J, Strony JT, Califf RM, Braunwald E, on behalf of the EARLY ACS Steering Committee. The early glycoprotein IIb/IIIa inhibition in non-ST-segment elevation acute coronary syndrome (EARLY ACS) trial: a randomized placebo-controlled trial evaluating the clinical benefits of early front-loaded eptifibatide in the treatment of patients with non–ST-segment elevation acute coronary syndrome—study design and rationale. Am Heart J (2005) 149:994–1002.[CrossRef][Web of Science][Medline]
  53. Bavry AA, Kumbhani DJ, Helton TJ, Borek PP, Mood GR, Bhatt DL. Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials. Am J Med (2006) 119:1056–1061.[CrossRef][Web of Science][Medline]
  54. Rao SV, O’Grady K, Pieper KS, Granger CB, Newby LK, Van de Werf F, Mahaffey KW, Califf RM, Harrington RA. Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Am J Cardiol (2005) 96:1200–1206.[CrossRef][Web of Science][Medline]

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