Introduction

Platelet adhesion to the subendothelial matrix exposed at sites of endothelial erosion and plaque rupture during acute coronary syndromes (ACS) and induced by percutaneous coronary intervention (PCI) results in platelet activation and the release of important secondary agonists. Prostaglandins are derived from platelet membrane phospholipids after platelet activation. These prostaglandins are converted to thromboxane A₂ by cycloxoygenase-1 and subsequent thromboxane synthase activity. Adenosine diphosphate is released from dense granules. These two agonists exhibit complementary effects by their autocrine and paracrine functions. It has been shown that sustained activation of the glycoprotein (GP) IIb/IIIa receptor is critically dependent on continuous downstream signaling from the P2Y₁₂ receptor, an important adenosine diphosphate receptor. The binding of activated GPIIb/IIIa receptors to dimeric fibrinogen on adjacent platelets results in initial thrombus formation. Therefore, inhibition of COX-1 by aspirin and the P2Y₁₂ receptor by a P2Y₁₂ inhibitor with oral loading doses is a first line treatment strategy in patients with ACS and in patients undergoing PCI.¹ However, there are limitations associated with oral P2Y₁₂ receptor inhibitors that include requirement for in vivo conversion (thienopyridines), delayed onset of action, suboptimal platelet inhibition, irreversible inhibition (thienopyridines) and delayed offset. Even the more potent oral P2Y₁₂ inhibitors, prasugrel and ticagrelor, are associated with delayed inhibition particularly in patients with ACS.² In the acute setting, therapy with potent platelet inhibitors that have fast onset and offset is desirable to attenuate thrombotic complications. Parenterally administered GPIIb/IIIa inhibitors provide immediate and potent platelet inhibition and have been used for the past two decades. However, elevated bleeding risk has been associated with these agents and remains a major concern.^3-5 Routine use of GPIIb/IIIa inhibitors in high-risk patients has recently decreased, and their use is often reserved for bail-out situations in many centers. In the current era, short-course GPIIb/IIIa inhibitor therapy and therapy with the intravenous P2Y₁₂ receptor blocker cangrelor has gained interest.^3,6

Cangrelor

Cangrelor is an adenosine triphosphate analog that selectively and specifically blocks P2Y₁₂ receptor-mediated platelet activation. It is the only intravenous P2Y₁₂ inhibitor available for clinical use. Blockade is direct, reversible, and competitive.⁷ Cangrelor has a linear dose-dependent pharmacokinetic profile that leads to stable antiplatelet effects. Platelet inhibition is rapid and potent, occurring within minutes. Cangrelor has a 3-6-minute plasma half-life with rapid platelet function recovery within 30-60 minutes after discontinuation of infusion. Inactivation occurs through dephosphorylation.⁸ Additionally, cangrelor is not renally cleared and does not require dose adjustment in patients presenting renal failure. Cangrelor was approved for clinical use by the US Food and Drug Administration as an adjunct to PCI to reduce the risk of myocardial infarction (MI), repeat coronary revascularization, and stent thrombosis in patients who have not been treated with a P2Y₁₂ platelet inhibitor and are not being given a GPIIb/IIIa inhibitor.⁹

CHAMPION PCI (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition – PCI) and CHAMPION PLATFORM (Clopidogrel Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition – PLATFORM) were two randomized clinical trials that evaluated the efficacy and safety of cangrelor in patients undergoing PCI.^10,11 CHAMPION PCI randomly assigned 8,716 patients to receive either a bolus and infusion of cangrelor followed by 600 mg clopidogrel or only a clopidogrel 600 mg loading dose within 30 minutes of the start of PCI. Patients were eligible for enrollment in the study if they had stable angina, unstable angina, or non-ST-segment elevation MI with obstructive coronary artery disease (CAD) and were scheduled to undergo PCI. An additional 1,000 patients with ST-segment elevation MI (STEMI) for whom primary PCI was planned were also eligible. The infusion began within 30 minutes before PCI and continued for at least 2 hours or until the conclusion of the index procedure, whichever was longer. At the treating physician's discretion, the infusion could be continued for 4 hours. Patients could not have received fibrinolytic agents or GPIIb/IIIa inhibitors within the previous 12 hours or clopidogrel at a dose of more than 75 mg per day in the previous 5 days.¹⁰

CHAMPION PLATFORM randomly assigned 5,362 patients who had not received any thienopyridine in the previous 7 days or fibrinolytic agents or GPIIb/IIIa inhibitors within the previous 12 hours to receive a bolus and infusion of cangrelor followed by a 600 mg of clopidogrel at the end of the infusion or to receive a clopidogrel 600 mg loading dose immediately after the procedure.¹¹ In CHAMPION PLATFORM, patients had non-ST-segment elevation ACS. A small percentage of patients (~5%) with stable angina were initially eligible at the beginning of the trial before a protocol amendment. Therefore, the two trials differed somewhat by the patient types included and the timing of clopidogrel administration in the control group. Cangrelor was not superior to clopidogrel in either of the two trials with respect to the primary endpoint of death from any cause, MI, or ischemia-driven revascularization at 48 hours, and both trials were terminated prematurely by the Data and Safety Monitoring Board for futility during interim analysis.¹¹ However, a post hoc analysis of the pooled CHAMPION PCI and CHAMPION PLATFORM trial data demonstrated a significant reduction in the primary endpoint of death, MI, and ischemia-driven revascularization with cangrelor when the universal definition of MI (similar to the definition in CHAMPION PHOENIX) was used (odds ratio [OR] 0.82, 95% confidence interval [CI], 0.68-0.99; p = 0.03), rather than the per-protocol definition. The per-protocol definition of MI was the appearance of new Q waves (duration >0.03 seconds) in 2 contiguous electrocardiographic leads or cardiac biomarkers ≥3 times the local upper limit of normal, as well as a rise >50% above the baseline when biomarkers were initially elevated.¹² The short times from randomization to PCI in the CHAMPION PCI and CHAMPION PLATFORM trials represents a diagnostic challenge to identify a PCI-related MI in patients with elevated biomarkers at presentation because in these cases, increased biomarker levels after the procedure may reflect the initial thrombotic event rather than a result of the procedure. Therefore, the universal definition of MI, like that used in the subsequent CHAMPION PHOENIX (Cangrelor vs. Standard Therapy to Achieve Optimal Management of Platelet Inhibition – PHOENIX) (see below), may enhance discrimination in detecting PCI-related MI and may allow a more rigorous assessment of the therapeutic benefit of adjunctive pharmacologic interventions.¹³

CHAMPION PHOENIX evaluated the safety and efficacy in reducing acute ischemic events with addition of cangrelor to dual antiplatelet therapy (aspirin plus clopidogrel) in P2Y₁₂ inhibitor-naïve patients undergoing PCI for the spectrum of CAD manifestations (STEMI, non-ST-segment elevation ACS, or stable angina). In this trial, 11,145 patients were randomized in a double-blind, double-dummy, placebo-controlled fashion. Patients were excluded if they had received any P2Y₁₂ inhibitor or abciximab within 7 days or fibrinolytic or GPIIb/IIIa inhibitors in the last 12 hours. Patients in the cangrelor group received an initial bolus followed by an infusion (30 mg/kg bolus followed by an infusion of 4 mg/kg/min for at least 2 hours or the duration of the PCI procedure, whichever was longer) and placebo capsules. At the end of the infusion, patients received a clopidogrel 600-mg loading dose. Patients randomly assigned to clopidogrel received either 600 mg (74%) or 300 mg of clopidogrel (26%) based on clinician preference as well as a placebo bolus and infusion followed by placebo capsules. The primary endpoint was a composite of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours. The definition of periprocedural MI was based on the universal definition of MI and involved an assessment of baseline biomarker status. In patients with normal biomarkers at baseline, an MI was considered to have occurred if there was post-PCI elevation in creatine kinase-MB three times or more than the upper limit of normal. If baseline biomarkers were abnormal, additional clinical evidence of ischemia was required. Stent thrombosis included definite stent thrombosis according to the Academic Research Consortium definition or intraprocedural stent thrombosis, which was assessed by a blinded angiographic core laboratory. The primary safety endpoint was severe bleeding not related to coronary artery bypass graft surgery (CABG) at 48 hours, according to the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) criteria. Cangrelor significantly reduced the composite of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours compared with the clopidogrel group (4.7 vs. 5.9%; p = 0.005), predominantly driven by reductions in the rate of MI and stent thrombosis. The treatment effect of cangrelor was consistent across subgroups regardless of the indication for PCI (stable angina or ACS) and whether the patient received a clopidogrel 300 mg or 600 mg loading dose. The reduction in periprocedural MI with cangrelor was consistent regardless of the definition used. According to the per-protocol definition, cangrelor significantly reduced the rate of MI (3.8 vs. 4.7%; p = 0.02). Additionally, there was a significant association between the occurrence of MI and mortality at 30 days. The reduction in stent thrombosis was also consistent across patients presenting with stable angina and ACS. Patients treated with cangrelor were less likely to need bailout GPIIb/IIIa inhibitors (2.3 vs. 3.5%; p < 0.001) and had fewer procedural complications (3.4 vs. 4.5%; p = 0.002). Cangrelor significantly reduced the rate of intraprocedural stent thrombosis compared with clopidogrel (0.6 vs. 1.0%; p = 0.04). The primary safety endpoint, GUSTO severe bleeding, was infrequent, and the rates were not significantly different between groups (0.16 vs. 0.11%; p = 0.44), although ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) major bleeding (a more sensitive definition) was more frequent with cangrelor (4.3 vs. 2.5%; p < 0.001), mainly owing to higher incidence of hematoma at the site of vascular access. There was no effect of cangrelor on bleeding based on access site used, although the absolute rates of bleeding were much lower with the radial approach (ACUITY major bleeding for femoral cohort, 5.2% with cangrelor vs. 3.1% with clopidogrel [p < 0.0001]; radial cohort, 1.5% with cangrelor vs. 0.7% with clopidogrel [p = 0.04]). Overall, the net benefit in reduction of adverse clinical events (ischemic plus bleeding events) was significantly reduced in the cangrelor group.⁸

The clinical benefit of adjunctive cangrelor therapy was consistent at 30 days. Interestingly, in the subgroup analysis of patients who received bivalirudin (n = 2,059), cangrelor significantly reduced ischemic events and stent thrombosis of a similar magnitude as CHAMPION PHOENIX.¹⁴ However, these results should be carefully interpreted because several analyses from multiple ACS trials have shown no association of periprocedural MI with long-term mortality. In addition, a position paper suggested a higher threshold of biomarker elevation be considered than was used in the CHAMPION PHOENIX analysis.^15-17 Moreover, it has been suggested that post-PCI early bleeding may be a much stronger predictor of long-term mortality than periprocedural MI, second only to spontaneous MI.¹⁶

Subsequently, a patient-level, pooled meta-analysis of all 3 phase III trials, involving a total of 24,910 patients, demonstrated that cangrelor significantly reduced the rate of the composite outcome of death, MI according to the universal definition, ischemia-driven revascularization, or stent thrombosis at 48 hours compared with clopidogrel (3.8 vs. 4.7%; OR 0.81, 95% CI, 0.71-0.91; p < 0.001).¹⁸ Cangrelor also reduced the rate of the individual endpoint of stent thrombosis (0.5 vs. 0.8%; OR 0.59, 95% CI, 0.43-0.80; p < 0.001). Cangrelor did not increase the risk of GUSTO severe bleeding, GUSTO moderate bleeding, or the need for blood transfusion but did increase ACUITY major bleeding (4.2 vs. 2.8%; p < 0.001). However, when excluding hematomas greater than 5 cm in diameter, the absolute difference in ACUITY major bleeds was small but still statistically significant (1.3 vs. 1.0%; p = 0.007).¹⁸

Outside of the CHAMPION program, cangrelor has also been studied in the phase II clinical trial BRIDGE (Maintenance of Platelet Inhibition With Cangrelor After Discontinuation of Thienopyridines in Patients Undergoing Surgery).¹⁹ This double-blinded study evaluated the use of cangrelor with placebo in 210 patients with ACS or patients treated with a coronary stent who had received a thienopyridine and were awaiting CABG (within 48 hours to 7 days of randomization). Patients were randomized to receive a cangrelor "bridge" intravenous infusion or placebo infusion. The primary outcome of the BRIDGE trial was levels of platelet reactivity measured by the VerifyNow P2Y₁₂ test (Accriva, San Diego, CA); specifically, the percentage of patients who maintained platelet reactivity of <240 platelet reactivity units for all blood samples analyzed during study drug infusion before CABG. The main safety endpoint was excessive CABG-related bleeding. For the primary endpoint, a greater proportion of patients treated with cangrelor had low levels of platelet reactivity throughout the treatment period (98.8 vs. 19.0%; p < 0.001). Excessive CABG-related bleeding was not significantly different between the cangrelor and placebo groups.¹⁹ Although this study was small and underpowered for hard outcomes such as death, MI, or stent thrombosis, the results support consideration of cangrelor for bridging patients who require discontinuation of an oral thienopyridine before surgery. However, cangrelor is not currently approved for this indication.

Transition to an Oral P2Y₁₂ Inhibitor

Ultimately, the vast majority of patients receiving cangrelor will be switched to an oral P2Y₁₂ inhibitor. The oral P2Y₁₂ inhibitor should be given at the recommended loading dose (600 mg clopidogrel, 180 mg ticagrelor, or 60 mg prasugrel). Clopidogrel and prasugrel should be given immediately after discontinuation of cangrelor to reduce pharmacodynamic interactions. Due to the competitive binding with the same adenosine diphosphate-binding site for the P2Y₁₂ receptor, cangrelor can attenuate the efficacy of these drugs.^20,21 However, ticagrelor binds to the P2Y₁₂ receptor at a different binding site in a non-competitive manner.²³ In theory, administration of ticagrelor before cangrelor discontinuation would result in the most consistent suppression of platelet aggregation because there would be no gap between the dissipation of cangrelor's effect and the onset of effect of the oral P2Y₁₂ inhibitor. Currently, ticagrelor can be administered before, during, or after cangrelor infusion. No drug interaction has been described when transitioning from any oral P2Y₁₂-receptor inhibitor to cangrelor, which can therefore be started at any time.²²

Place in Therapy: Cangrelor

An estimated 5-6% of patients with STEMI experience resuscitated cardiac arrest, and 64% of those patients will be unconscious during initial evaluation, with many proceeding to primary PCI.²³ These patients and any patient who cannot take oral medications (for example, the patient is vomiting or sedated) would be potential candidates for intravenous antiplatelet therapy. In addition, an early reduced pharmacodynamic effect of prasugrel and ticagrelor has been reported in these patients.²⁴ Use of cangrelor in the patient with stable CAD who is being considered for ad hoc PCI after coronary angiography is a major consideration to reduce post-PCI thrombotic events.²⁵ Bridging therapy in patients treated with antiplatelet agents to reduce the risk of thrombotic events in the phase between drug cessation and surgery may also be a role for cangrelor in the future, even though it is not currently a labeled as an indication. In preparation for surgery, P2Y₁₂ inhibitors are commonly discontinued 5-7 days before surgery to minimize bleeding risk during the procedure.^4,5 The latter practice can be especially problematic in patients who have undergone recent drug-eluting stenting and who are at risk for thrombosis if antiplatelet therapy is interrupted.²⁶ GPIIb/IIIa inhibitors have been used as an antiplatelet bridge to surgery, although the safety and efficacy of this approach has also not been clearly established.^27,28 Cangrelor is currently indicated for patients who have not been treated with a P2Y₁₂ inhibitor. It should be noted that cangrelor has not been adequately studied in head-to-head comparisons with ticagrelor and prasugrel. Whether cangrelor adds clinical benefit to patients treated with these agents is entirely unknown.

An international expert consensus on switching platelet P2Y₁₂ receptor-inhibiting therapies suggested that it is reasonable to wait to start cangrelor bridging (0.75 mcg/kg/min infusion without a bolus) for up to 3-4 days after prasugrel discontinuation and 2-3 days of clopidogrel and ticagrelor discontinuation to minimize the duration of infusion. Platelet function testing might also help to time the initiation of cangrelor bridging in an efficient fashion. With respect to transition from cangrelor to thienopyridines, it was suggested to administer the thienopyridine immediately after discontinuation of cangrelor with a loading dose (clopidogrel 600 mg or prasugrel 60 mg) to avoid a potential drug-drug interaction. Ticagrelor should be administered immediately after discontinuation of cangrelor infusion or up to 30 minutes before the end of the infusion as a 180 mg loading dose.²²

GPIIb/IIIa Inhibitors

In the era of balloon angioplasty, the addition of GPIIb/IIIa inhibitors to the armamentarium of antiplatelet agents represented a significant therapeutic advance compared with therapy with aspirin plus unfractionated heparin. GPIIb/IIIa inhibitors inhibit the final pathway of platelet aggregation by competing with von Willebrand factor and fibrinogen for GPIIb/IIIa receptor binding. GPIIb/IIIa inhibitors provide fast and potent antiplatelet effects. Compared with cangrelor, these agents inhibit the platelet response to all agonists and are therefore more potent antiplatelet agents than cangrelor. GPIIb/IIIa inhibitors provide rapid and nearly complete platelet aggregation inhibition, overcoming the delayed and poor platelet inhibition induced by a clopidogrel loading dose.²⁹ The benefits of pretreatment with GPIIb/IIIa inhibitors were noted in high-risk patients in early clinical trials that showed a significant reduction in MI and urgent revascularization before and after angioplasty.^30,31 However, the clinical benefits of GPIIb/IIIa inhibitors were mainly shown in the era before the routine use of dual antiplatelet therapy, the advent of new stent technologies, radial artery interventions, thrombus aspiration, potent oral P2Y₁₂ inhibitors, and direct thrombin inhibitors. Currently, GPIIb/IIIa inhibitors are used in up to one-third of patients during PCI for ACS in the United States,³² and their use varies by geographic region,³³ provider preference, indication for PCI, and associated comorbidities.

GPIIb/IIIa inhibitor therapy has been associated with a reduction in adverse cardiovascular events, including MI, at the expense of increased bleeding and thrombocytopenia.^32,34,35 More recent trials and systematic reviews, specifically in patients pre-treated with thienopyridines, have shown contradicting evidence in the benefit of routine use of GPIIb/IIIa inhibitors.^32,34-36 In a meta-analysis of 10,123 patients undergoing primary PCI, nonfatal MI at 30 days was reduced from 8.3 to 5.1% (p < 0.001) with use of GPIIb/IIIa inhibitors at the expense of a significant increase in the risk of minor bleeding (3 vs. 1.7%; p < 0.001) and thrombocytopenia (0.8 vs. 0.04%; p = 0.004).³⁶ The increase in major bleeding events was not significant (1.2 vs. 0.9%; p = 0.22). The reduction in nonfatal MI was irrespective of thienopyridine pre-treatment, and upon meta-regression, the benefits of GPIIb/IIIa inhibitors were consistent in earlier versus more recent clinical trials. There were no differences in 30-day or 1-year mortality rates. With the introduction of more potent adenosine diphosphate-receptor blockers, the incremental value of GPIIb/IIIa inhibitors in reducing periprocedural MI remains to be determined. Currently, the administration of GPIIb/IIIa inhibitors is an accepted treatment option for patients undergoing primary PCI and patients with visible thrombus burden.

Another approach in administering GPIIb/IIIa inhibitors is through the intracoronary route of delivery. This approach can lead to a higher local concentration of antiplatelet agent aiding in a higher receptor occupancy with disruption of platelet crosslinking and augmenting thrombus resolution to a greater extent.^37-39 Intracoronary GPIIb/IIIa inhibitor therapy may also limit the risk of myocardial damage from thromboembolism in the microvasculature. Intracoronary administration of GPIIb/IIIa inhibitor has been tested in several small studies and shown to be safe and associated with some benefits when compared with intravenous administration, but these results have not been confirmed in large-scale clinical trials.^40-44

Strategies employing shorter GPIIb/IIIa inhibitor infusions and use of a radial approach may provide greater degrees of net benefit. Earlier trials of GPIIb/IIIa inhibitors employed 18-24 hour infusions, and these durations of therapy were associated with greater bleeding than their comparator arms that included use of bivalirudin.^45-47 GPIIb/IIIa inhibitors have the greatest role in the treatment of high-risk patients and those with high-risk PCI angiographic features (visible thrombus and high-risk anatomy) who have low risk of bleeding.⁴⁸ Currently, the American College of Cardiology and American Heart Association guidelines provide a Class IIa recommendation for GPIIb/IIIa inhibitors at the time of primary PCI (abciximab, double-bolus eptifibatide, or high-bolus-dose tirofiban) in selected patients with STEMI receiving unfractionated heparin (with or without stenting or clopidogrel pretreatment), and a Class IIb indication for intracoronary Abciximab.^3,5 With the evolution of PCI complexity, GPIIb/IIIa inhibitors may still play a significant role in challenging clinical settings, such as settings of complex elective anatomy and cardiogenic shock where there are inadequate antiplatelet effects present. These patient subgroups were largely excluded in previous studies.

Place in Therapy: GPIIb/IIIa Inhibitors

The ideal parenteral antiplatelet agent would provide immediate and robust periprocedural ischemic benefit without attendant excess bleeding risk.³ GPIIb/IIIa inhibitors have been associated with reduced thrombotic events after PCI compared with heparin and bivalirudin therapy alone,^3-5,35,49 but their routine use, notably with prolonged infusion durations, has been associated with increased severe bleeding complications⁵⁰ and potentially increased PCI-related costs. Provisional use of GPIIb/IIIa inhibitors, shortened GPIIb/IIIa inhibitor infusion duration, novel delivery systems, and augmented use of radial access will likely improve the net clinical benefit of GPIIb/IIIa inhibitors. Moreover, the effect of inhibition of all agonist-induced pathways of platelet aggregation by GPIIb/IIIa inhibitors compared with cangrelor may provide greater protection from ischemic events. Furthermore, recent advances in the overall quality in periprocedural care that have led to stepwise improvements in PCI outcomes will potentially influence the risk-benefit profile of GPIIb/IIIa inhibitors. At present, there are no randomized clinical trials comparing the utility of cangrelor and GPIIb/IIIa inhibitors. GPIIb/IIIa inhibitor use is expected to continue in bailout/rescue scenarios, but the introduction and uptake of cangrelor may also limit their use in clinical practice.

In conclusion, with the increasing complexity of PCI in the high-risk patient, parenteral antiplatelet agents continue to have an important therapeutic role. Limitations in the pharmacodynamic effects of all oral P2Y₁₂ inhibitors are well described. Insufficient platelet inhibition has been associated with periprocedural thrombotic events in numerous studies. Parenteral agents obviate these limitations but are associated with greater bleeding. Whether to use cangrelor or GPIIb/IIIa inhibitors is an unresolved issue that has yet to be adequately addressed in a clinical trial. Moreover, whether GPIIb/IIIa inhibitors or cangrelor add significant clinical antithrombotic effects in the patient with strong P2Y₁₂ inhibition is similarly unknown. The major potential benefit of GPIIb/IIIa inhibitors over cangrelor is inhibition of aggregation induced by all agonists. The downside is a slower offset of pharmacodynamic effect and, as a downstream inhibitor, less effect on platelet activation. Short-term GPIIb/IIIa inhibitor therapy with agents that have a faster offset (low molecular weight GPIIb/IIIa inhibitors) coupled with radial artery intervention may significantly improve the safety profile of GPIIb/IIIa inhibitors and restore interest in their use in the complex, high-risk patient.

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Keywords: Acute Coronary Syndrome, Adenosine, Adenosine Triphosphatases, Adenosine Monophosphate, Adenosine Diphosphate, Administration, Intravenous, Angina, Stable, Angina, Unstable, Angioplasty, Angioplasty, Balloon, Antibodies, Monoclonal, Antithrombins, Aspirin, Biomarkers, Blood Platelets, Clinical Trials Data Monitoring Committees, Comorbidity, Confidence Intervals, Consensus, Control Groups, Coronary Angiography, Coronary Artery Disease, Drug Interactions, Fibrinogen, Fibrinolytic Agents, Half-Life, Heart Arrest, Heparin, Hirudins, Immunoglobulin Fab Fragments, Medical Futility, Microvessels, Molecular Weight, Odds Ratio, Peptide Fragments, Peptides, Percutaneous Coronary Intervention, Phospholipids, Platelet Activation, Platelet Aggregation, Platelet Aggregation Inhibitors, Platelet Glycoprotein GPIIb-IIIa Complex, Platelet Membrane Glycoprotein IIb, Pyridines, Prostaglandins, Radial Artery, Random Allocation, Recovery of Function, Renal Insufficiency, Shock, Cardiogenic, Myocardial Infarction, Stents, Thienopyridines, Thienopyridines, Thrombocytopenia, Thromboembolism, Thrombosis, Thromboxane A2, Purinergic P2Y Receptor Antagonists, Ticlopidine, Tyrosine, Vomiting, von Willebrand Factor

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