Clinical Considerations with the Use of Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention

Despite the proven benefits of using antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI), a number of key questions remain to be answered. In recent years, clopidogrel dosing strategies among such patients have evolved considerably, with newer approaches involving loading doses prior to PCI and increases in the time interval and loading dosage in an effort to overcome variable responsiveness/hyporesponsiveness to platelet inhibition. Further, the role of glycoprotein (GP) IIb/IIIa antagonists in elective stenting continues to be defined, with recent evidence suggesting that most appropriate use of these agents is in high‐risk patients with elevated troponin levels. There appears to be a relationship between the use of GP IIb/IIIa antagonists with clopidogrel loading and attenuation of early inflammatory and cardiac marker release. Strategies to minimize the chance of late stent thrombosis in patients who receive drug‐eluting stents (DES) are also under intense investigation. Among some patients receiving sirolimus and paclitaxel DES, current standard long‐term antiplatelet strategies may be insufficient. Patient nonadherence to treatment and premature discontinuation and underutilization of antiplatelet therapies by physicians remain important clinical problems with potentially dire consequences. Copyright © 2008 Wiley Periodicals, Inc.     

A Review of Clinical Trials with Eptifibatide in Cardiology

Glycoprotein (GP) IIb/IIIa receptor antagonists inhibit the binding of ligands to activated platelet GP IIb/IIIa receptors and, therefore, prevent the formation of platelet thrombi. Additional antithrombin therapy should be given in connection with GP IIb/IIIa administration. Eptifibatide is a small heptapeptide, which is highly selective and rapidly dissociates from its receptor after cessation of therapy. In clinical trials (IMPACT‐II and ESPRIT) concomitant administration of eptifibatide to patients undergoing percutaneous coronary intervention (PCI) reduced thrombotic complications. In the PURSUIT trial, in patients with non‐ST‐elevation acute coronary syndromes, eptifibatide, compared to placebo, significantly reduced the primary endpoint of death and nonfatal myocardial infarction at 30 days. In patients with STEMI eptifibatide has been studied as an adjunct to fibrinolysis and primary PCI; it improved epicardial flow and tissue reperfusion. Current studies are evaluating eptifibatide as upstream therapy in high‐risk patients with NSTE‐ACS, in the EARLY‐ACS and in comparison with abciximab in patients with primary PCI in the EVA‐AMI trial.     

Antiplatelet therapy for elective coronary stenting: a moving target

The recognition of the major contribution of platelet-mediated mechanisms to the pathogenesis of thrombotic complications after coronary stenting has led to the development and evaluation of different antiplatelet regimens. The combination of aspirin and adenosine diphosphate antagonists such as ticlopidine and clopidogrel has solved the issue of acute stent thrombosis. The timing and dose of dual oral antiplatelet therapy have, however, changed over time with a shift from postintervention treatment to preintervention treatment with a high loading dose of clopidogrel. Pretreatment with aspirin and clopidogrel has been associated with a further 30% reduction in ischemic complications after coronary intervention. Recent data have even shown that in case of optimal pretreatment with such a dual oral antiplatelet therapy, glycoprotein IIb/IIIa antagonists are no longer mandatory for elective coronary stenting and should be reserved only for high-risk procedures or for acute coronary interventions.     

Efficacy and safety of bivalirudin in patients receiving clopidogrel therapy after diagnostic angiography for percutaneous coronary intervention in acute coronary syndromes

Objectives : This study sought to investigate if the efficacy of bivalirudin monotherapy is similar to heparin plus GP IIb/IIIa inhibition in patients with acute coronary syndromes (ACS) treated with clopidogrel following diagnostic angiography. Background : Prior trials have demonstrated that peri‐procedural bivalirudin therapy confers similar efficacy as heparin plus GP IIb/IIIa inhibitors, while lowering the risk of bleeding complications in ACS patients undergoing percutaneous coronary intervnetions (PCI). However, the incidence of adverse ischemic events post‐PCI appeared to be higher in patients receiving bivalirudin without adequate pretreatment with clopidogrel. Methods : Using the 2004/2005 Cornell Angioplasty Registry, we evaluated 980 consecutive patients undergoing urgent PCI for UA/NSTEMI who were treated with either bivalirudin or UFH plus GP IIb/IIIa inhibitor. We excluded patients who were on chronic clopidogrel therapy or received clopidogrel pretreatment prior to angiography. All patients received a clopidogrel load (≥300‐mg dose) immediately before or after the PCI. Long‐term all‐cause mortality was obtained for 100% of patients, with a mean follow‐up of 24.6 ± 7.7 months. Results : Of the 980 study patients, 461 (47.0%) were treated with bivalirudin and 519 (53.0%) patients received UFH plus GP IIb/IIIa inhibitor. DES were used in 88% of PCI; 45% of patients presented with NSTEMI. The incidence of in‐hospital death (0.4% vs. 0.2%, P = 0.604), post‐procedural MI (6.9% vs. 5.4%, P = 0.351), and MACE including death, stroke, emergent CABG/PCI, and MI (7.6% vs. 5.8%, P = 0.304) were similar in patients treated with bivalirudin versus UFH plus GP IIb/IIIa inhibitors, respectively. The incidence of in‐hospital stent thrombosis was similar (0.7% vs. 0%, P = 0.104), while major (0.9% vs. 2.9%, P = 0.034) and minor bleeding (10.4% vs. 18.9%, P < 0.001) was reduced in the bivalirudin‐treated group. By two‐years of follow‐up, after propensity‐score adjusted multivariate Cox regression analysis, there was no significant difference in long‐term mortality between the two groups (HR 1.18; 95%CI 0.64–2.19, P = 0.598). Conclusions : In patients presenting with ACS and receiving clopidogrel treatment after angiography (before or within 30 min of PCI), peri‐procedural bivalirudin monotherapy suppresses acute and long‐term adverse events to a similar extent as does UFH plus GP IIb/IIIa inhibitors, while significantly lowering the risk of bleeding complications. © 2010 Wiley‐Liss, Inc.     

Debate of adjunctive pharmacology for percutaneous coronary intervention: anticoagulation and clopidogrel are not (always) enough

Substantial controversy exists regarding the optimal pharmacologic cocktail for percutaneous coronary intervention (PCI). The most common approach typically includes aspirin, clopidogrel, unfractionated heparin (or enoxaparin), and (variably) a glycoprotein (GP) IIb/IIIa inhibitor. Some substitute bivalirudin with "bail-out" GP IIb/IIIa blockade for heparin and planned GP IIb/IIIa integrin blockade, an approach that necessarily includes aspirin and clopidogrel (for their antiplatelet effects). These shifts in adjunctive treatment paradigms should be examined in the context of available data from clinical studies. Several studies have demonstrated the phenomenon of clopidogrel resistance to be fairly prevalent; even in clopidogrel-responsive patients, steady state is achieved only 4-6 hours after a 600-mg loading dose. It would thus be anticipated that clopidogrel-resistant patients would benefit from GP IIb/IIIa blockade, particularly during the period immediately after intervention. Neither REPLACE-2 nor the recent ACUITY trial demonstrated an efficacy advantage for bivalirudin as a substitute for heparin plus GP IIb/IIIa blockade; instead, any advantage appears to be limited to reducing the propensity for bleeding. As bleeding is directly correlated with the degree of anticoagulation and is further augmented by GP IIb/IIIa blockade, an alternative to the bivalirudin strategy is to simply reduce the amount of heparin anticoagulation during PCI. Finally, the benefit-to-risk ratio of aggressive adjunctive antiplatelet/antithrombotic therapy might be further improved via risk stratification, with patients at higher risk for periprocedural events receiving intensive therapy and lower-risk patients being managed with less intensive regimens focused on minimizing the risk of bleeding.     

Complementary effects of thienopyridine pretreatment and platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention; results from the ESPRIT trial.

OBJECTIVES: This analysis sought to investigate the complementary effect of thienopyridine pretreatment and platelet glycoprotein (GP) IIb/IIIa integrin blockade in coronary stent intervention. BACKGROUND: Definitive evidence supporting combined antiplatelet therapy consisting of thienopyridine pretreatment and GP IIb/IIIa receptor blockade in patients undergoing percutaneous coronary intervention (PCI) with stent implantation is limited. METHODS: We retrospectively analyzed clinical outcomes by thienopyridine use in the 2,040 patients randomized to eptifibatide or placebo who underwent PCI in the ESPRIT trial. RESULTS: A total of 901 patients received a loading dose of thienopyridine before PCI (group 1), 123 received thienopyridine pretreatment without a loading dose (group 2), and 1,016 were not treated with thienopyridine before PCI (group 3). The composite incidence of death or myocardial infarction at 30 days was significantly lower in group 1 than in groups 2 and 3 combined (OR, 0.71 [95%CI, 0.52-0.99]; P = 0.0417). A similar trend was seen for the composite of death, myocardial infarction, or urgent target vessel revascularization (unadjusted OR, 0.77 [0.57-1.05]; P = 0.1025). After adjusting for baseline characteristics, these differences were no longer significant. No interactions were identified with eptifibatide assignment for any of the group comparisons. CONCLUSIONS: Pretreatment with a loading dose of thienopyridine lowers the rate of ischemic complications regardless of treatment with a GP IIb/IIIa inhibitor. Conversely, the efficacy of eptifibatide is maintained whether or not a loading dose of a thienopyridine is administered. Optimal outcomes are achieved in patients receiving thienopyridine pretreatment along with platelet GP IIb/IIIa inhibitor therapy.     

不同质子泵抑制剂对冠脉支架术后氯吡格雷抗血小板功能的影响

目的:观察埃索美拉唑、雷贝拉唑、雷尼替丁或法莫替丁对急性冠脉综合症（ACS）患者冠脉支架术后应用氯吡格雷抗血小板功能的影响。方法: 150例行经皮冠状动脉介入治疗（PCI）的ACS患者,入院后给予阿司匹林300 mg/d,氯吡格雷300 mg负荷剂量继以75 mg/d维持剂量抗血小板治疗,并随机分为质子泵抑制剂（PPI）A组（A1组:埃索美拉唑40 mg/d,n=30,A2组:雷贝拉唑20 mg/d,n=30）、H2受体拮抗剂(H2RA)B组（B1组:雷尼替丁300 mg/d,n=30,B2组:法莫替丁40 mg/d,n=30）和空白对照C组（C组:n=30）。采用ELISA法检测血浆CD62P、GPⅡb/Ⅲa含量及电阻抗法检测血小板聚集功能。结果: PPI或H2RA治疗前后,A组、B组与C组相比,上述指标的差值组间比较均无明显统计学差异,A1组、A2组、B1组、B2组与C组相比,治疗前后上述指标的差值组间比较均无统计学差异。结论: 埃索美拉唑、雷贝拉唑、雷尼替丁或法莫替丁对氯吡格雷的抗血小板活性无明显的影响。     

Poor responsiveness to antiplatelet drugs in acute coronary syndromes: clinical relevance and management

Cardiovascular diseases are the most common cause of mortality and morbidity in Western countries, accounting for more than 40% of total mortality. An optimal pharmacological management in these patients is of major importance and antiplatelet agents remain the cornerstone of acute coronary syndrome (ACS) therapy at hospital admission and during percutaneous coronary interventions (PCI). The recently described poor biological responses to aspirin and clopidogrel have been source of major concern, especially in era of drug eluting stent implantation. Indeed, insufficient platelet inhibition at the time of PCI has been consistently associated with an increased risk of complications and recurrence of ischemic events. Despite the lack of uniformly accepted definitions of aspirin and clopidogrel poor response, we sought to describe the current evidence and gaps in knowledge. While trials on the potential benefit of an increased antiplatelet maintenance dose after PCI have shown only marginal benefits, the strengthening of the initial antiplatelet regimens by additional loading doses of clopidogrel, by the administration of glycoprotein IIb/IIIa receptor inhibitors or phosphodiesterase inhibitors might further improve outcomes during ACS and PCI in patients with poor responsiveness to conventional dual antiplatelet therapy. Overall, tailoring the antiplatelet treatment on the basis of the individual biological response improves the short-term outcome after PCI. New and more potent antiplatelet drugs may overcome the clinical consequences of the poor response to antiplatelet agents.     

Comparative Pharmacology of GP IIb/IIIa Antagonists

GP IIb/IIIa antagonists are qualitatively different from classical antiplatelet agents, such as aspirin or clopidogrel. They do not inhibit platelet activation, i.e. intraplatelet signal generation or conduction but primarily act outside the platelet by competing with ligand (e.g. fibrinogen) binding that is essential for platelet bridging and aggregate formation. Three compounds are in clinical use: abciximab, an antibody fragment and two low-molecular weight compounds, tirofiban and eptifibatide. In comparison to the low-molecular weight compounds, abciximab has a substantially longer platelet half-life (4 h), i.e. slow off-rate and a short plasma half-life (20-30 min) without significant distribution into the extravascular space. The plasma half-life of tirofiban and eptifibatide is about 2 h and parallels the antiplatelet effect. The off-rate from the platelet GP IIb/IIIa receptor is much faster and there is a significant distribution into the extravascular space. These pharmacokinetic variables might influence the competition between the antagonists and fibrinogen for GP IIb/IIIa binding. Other pharmacological variables are a partial agonistic activity, facilitation of thrombolysis, modification of other integrin-related actions, including inflammatory responses, effects on vascular cells and apoptosis. Importantly, GP IIb/IIIa antagonists might also interfere with prothrombin binding to the platelet surface and, thus, might influence the coagulation pathway. There is no clear evidence that the biological activity of the agents is modified by gene polymorphism (HPA-1). All three compounds may cause thrombocytopenia, possibly related to drug-induced antibodies. There is no clear data suggesting that these pharmacological differences transfer into significant differences in clinical outcome, for example in patients with acute coronary syndromes (ACS) subjected to acute percutaneous coronary interventions (PCI). The only head-to-head comparison of all three clinically used parenteral compounds did not demonstrate differences in major adverse cardiac effects (MACE) at 30 days although those have been described in particular with long-term use of oral antagonists. The inherent problems with all GP IIb/IIIa antagonists are the narrow therapeutic range because the same mechanisms are involved in hemostasis and thrombosis and their inability to inhibit platelet activation.     

Platelet function in clopidogrel-treated patients with acute coronary syndrome.

Percutaneous coronary intervention (PCI) in patients presenting with acute coronary syndrome (ACS) is associated with increased risk of thrombotic complications. ACS enhances platelet activation; whether pretreatment with clopidogrel is sufficient to suppress platelet function in patients with ACS is not known. This study assessed platelet function in patients with and without ACS prior to PCI and after pretreatment with a single dose of 600 mg clopidogrel. Blood samples of 402 patients prior to PCI with (n = 119) or without (n = 283) ACS were collected at least 2 h after 600 mg clopidogrel administration. Maximal platelet aggregation in response to ADP (5 and 20 micromol/l), collagen (4 microg/ml) and TRAP (25 micromol/l) was measured with optical aggregometry. Surface expression of glycoprotein IIb/IIIa and P-selectin was assessed with flow cytometry at baseline and after stimulation with 5 and 20 micromol/l ADP. Agonist-induced platelet aggregation did not differ significantly between patients with and without ACS (P > or = 0.15). Parameters of platelet activation (glycoprotein IIb/IIIa and P-selectin surface expression) were significantly higher in ACS patients at baseline and after 5 and 20 micromol/l ADP stimulation (P < 0.0001). Patients with ACS continue to exhibit increased platelet activation after pretreatment with 600 mg clopidogrel. This finding supports the need for additional platelet function inhibition during PCI in patients with ACS.     

The Problem of Persistent Platelet Activation in Acute Coronary Syndromes and Following Percutaneous Coronary Intervention

Platelets play a central role in the atherosclerotic inflammatory response, thrombotic vascular occlusion, microembolization, vasoconstriction, and plaque progression. Persistent platelet activation poses a serious problem among patients with acute coronary syndromes (ACS) and those who have undergone percutaneous coronary intervention (PCI), placing them at risk for ischemic events and subacute stent thrombosis. Patients undergoing PCI are at risk for further ischemic events because of procedure‐related platelet activation as well as the inherent persistent platelet hyperreactivity and enhanced thrombin generation associated with ACS. Persistent platelet activation following an acute coronary event and/or PCI supports incorporating antiplatelet strategies into the standard medical management of such patients. In this clinical setting, antiplatelet therapies are capable of improving outcomes. Aspirin, thienopyridines, and glycoprotein IIb/IIIa inhibitors, the 3 major pharmacologic approaches to persistent platelet activation, target various levels of the hemostatic pathways and thrombus formation. Copyright © 2008 Wiley Periodicals, Inc.     

The pharmacodynamics of parenteral glycoprotein IIb/IIIa inhibitors

Glycoprotein (GP) IIb/IIIa antagonists are a unique class of antiplatelet agents introduced for the management of patients undergoing percutaneous coronary intervention (PCI) and those presenting with unstable angina or non-ST segment elevation (NSTE) myocardial infarction (MI), collectively recognized as acute coronary syndromes (ACS). Eptifibatide, abciximab, and tirofiban HCl are three GPIIb/IIIa antagonists approved for use by the Food and Drug Administration. Of the three agents, eptifibatide is approved for use in both PCI and NSTE ACS patient populations, whereas abciximab is indicated for patients undergoing PCI, and tirofiban is approved for patients with NSTE ACS. Dose selection for the initial trials using the three parenteral antagonists was based on in vitro and ex vivo pharmacodynamic assays conducted under different blood collection and platelet function assay conditions. Recent comparative pharmacodynamics studies, which used newly defined and standardized assay conditions, indicate that the platelet aggregation inhibition achieved with these dosing regimens is variable. Therefore, the differences in clinical efficacy as evidenced in the more recent clinical studies (e.g., Enhanced Suppression of the Platelet Receptor GPIIb/IIIa using Integrilin Therapy [ESPRIT], Global Use of Strategies to Open Occluded Coronary Arteries IV Acute Coronary Syndromes [GUSTO-IV ACS], and Do Tirofiban HCl and ReoPro Give Similar Efficacy Outcomes Trial [TARGET]) may be related to the variable antiplatelet effects of the approved dose regimens.     

Platelet Glycoprotein IIb/IIIa Integrin Blockade in Coronary Artery Disease: Current State of the Art

Platelets have been shown to play an important role in the pathogenesis of atherosclerosis, acute coronary syndromes, and ischemic complications after percutaneous coronary intervention. Fibrinogen binding via platelet surface glycoprotein (GP) IIb/IIIa receptors constitutes the "final pathway" in platelet aggregation leading to thrombus formation. The GP IIb/IIIa receptor inhibitors, a new class of antiplatelet agents that have emerged in recent years, show great promise in reducing complications of coronary angioplasty and acute coronary syndromes. This review will examine the biology of platelet GP IIb/IIIa receptors, the various classes of GP IIb/IIIa receptor antagonists, the results of the latest clinical trials, and their implications in current clinical practice.     

Therapeutic dissolution of an intracoronary thrombus by prolonged intravenous platelet glycoprotein IIb/IIIa antagonism

This case report describes the therapeutic dissolution of an intracoronary thrombus in a patient with ectatic coronary arteries post-myocardial infarction by prolonged intravenous glycoprotein (GP) IIb/IIIa antagonist administration. The report emphasizes the potential thrombotic complications in patients with ectatic coronary arteries and the beneficial use of GP IIb/IIIa receptor antagonists as direct thrombolytic agents even in partially organized thrombus formation. In addition to the well-documented effects of GP IIb/IIIa blockade in the scenario of percutaneous interventions, unstable angina, and non-Q wave infarction, the use of this new class of drugs in acute myocardial infarction seems to be promising and might also be considered in the setting of persistent thrombotic material within the coronary vasculature.     

What is the role for improved long-term antiplatelet therapy after percutaneous coronary intervention?

Background

Coronary stent placement has replaced balloon angioplasty as the percutaneous coronary intervention (PCI) method of choice, primarily because of its lower restenosis rate. Compared with aspirin (ASA) monotherapy or ASA plus warfarin, the ticlopidine and ASA combination is superior in reducing thrombotic events after stenting. Clopidogrel plus ASA appears to be at least as effective as ticlopidine and ASA. Intravenous glycoprotein IIb/IIIa inhibitors effectively prevent periprocedural thrombotic complications, but their short duration of action and parenteral dosing don’t allow for long-term protection. This review aimed to answer how long after PCI with a stent patients are at risk for recurrent thrombotic events and what the optimal way to prevent them is.

Results

Classically, ASA has been prescribed indefinitely, whereas adenosine diphosphate receptor antagonists have been discontinued after 2 to 4 weeks. However, the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial found that long-term dual antiplatelet therapy with clopidogrel and ASA was more effective than ASA alone in preventing major cardiovascular events in patients with acute coronary syndrome, including those treated with PCI.

Conclusion

Results from additional ongoing studies are needed to clarify the role of long-term dual oral antiplatelet therapy in preventing ischemic events in patients who have undergone PCI.     

Optimal management of platelet function after coronary stenting

Opinion statement Coronary stenting elicits vessel wall damage, and subsequent activation of platelets is implicated as a major component of complications such as acute, subacute, and late stent thrombosis. As such, dual antiplatelet therapy using aspirin and clopidogrel has become a routine adjunct to coronary stenting. Use of aspirin and clopidogrel with or without glycoprotein IIb/IIIa inhibitors after coronary stenting reduces the complication rate and improves long-term outcomes. Dual antiplatelet therapy using aspirin and clopidogrel is recommended for at least 4 weeks with bare metal stents, and for 3 to 6 months with drug-eluting stents for prevention of major adverse cardiac events. After coronary stenting, 1 year of dual antiplatelet therapy is recommended for prevention of future cardiac events. However, despite the use of antiplatelet agents, stent thrombosis occurs in approximately 1% of patients, with an increased likelihood of occurrence in high-risk patients or a lesion subset of patients. Although the incidence of stent thrombosis is low, stent thrombosis usually presents as acute coronary syndrome and the mortality rate is up to 45%. Thus, considering the widespread use of stents, a considerable number of people are inadequately protected from thrombotic events despite current standard antiplatelet therapy using aspirin and clopidogrel. A concern with clopidogrel is the loading time and loading dose required to achieve and maintain optimal inhibition of platelet aggregation. The current recommendation for ensuring maximum antiplatelet activity is administration of a 300-mg loading dose of clopidogrel initiated at least 6 hours prior to percutaneous coronary intervention (PCI), and ideally the day before. If this is not possible, a loading dose of 600 mg of clopidogrel should be administered at least 2 hours before PCI. Recently, new combinations of antiplatelet agents (ie, triple therapy using aspirin, clopidogrel, and cilostazol) and new drugs with potent antiplatelet effects (ie, Prasugrel [currently being developed by Sankyo Pharmaceuticals and Ube Pharmaceuticals in Japan and by Eli Lilly and Co. (Indianapolis, IN) in the United States], Cangrelor [currently being developed by AstraZeneca Pharmaceuticals, Wilmington, DE], and AZD6140) have been evaluated in clinical trials; such treatments may help reduce the number of cardiac events after coronary stenting.     

Platelet aggregation upon acetylsalicylic acid and clopidogrel treatment and glycoprotein IIb/IIIa content in patients with acute coronary syndrome

Interaction between aggregating activity of platelets and glycoprotein (GP) IIb/IIIa (fibrinogen receptor) content on their surface was investigated in patients with acute coronary syndrome (ACS). Eighty nine ACS patients were included into the study - 69 with and 20 without elevation of ST segment. Blood was collected within the first hour of admission to the clinic (1 day), and then at 3-5 and 8-12 days. All patients received standard antiaggregant therapy - acetylsalicylic acid - ASA (thromboxane A2 synthesis inhibitor) and clopidogrel (ADP receptor antagonist). Platelet aggregation was analyzed at the first time point when patients had already taken ASA but not clopidogrel, and then (3-5 and 8- 12 days) upon combined therapy with both preparations. Aggregation was induced by 5 and 20 uM ADP and measured by turbidimetric method. In comparison with the initial level (1 day, ASA) at days 3-5, i.e. after development of clopidogrel effect, platelet aggregation was decreased by 54 and 40% upon its stimulation with 5 and 20 uM ADP, and was not further changed at days 8-12. GP IIb/IIIa content on platelet surface was determined by binding of 125I-labelled monoclonal antibody CRC64. GP IIb/IIIa number varied from 31100 to 73000 per platelet with the mean level of 48500 +/- 8400 (mean +/- standard deviation). No differences were detected between mean GP IIb/IIIa number at 1, 3-5 and 8-12 days after ACS onset. Upon repeat GP IIb/IIIa measurement coefficient of variation was 6.1% demonstrating the stability of this parameter in each patient. Positive correlation between platelet aggregation and GP IIb/IIIa content was detected at the first day - correlation coefficients (r) 0.425 and 0.470 for 5 and 20 uM ADP (n=57, p<0.001). However positive association between these parameters was not revealed at 3-5 and 8-12 days, when patients received not only ASA but clopidogrel as well (r from -0.054 to -0.237, p>0.05). These results indicates that variations of GP IIb/IIIa content affect platelet aggregating activity within first hours of ACS upon ASA treatment. However after saturation with clopidogrel this factor has no significant influence on platelet aggregation, at least on aggregation induced by ADP which receptor is the target of this antiaggregant. Under such conditions aggregation parameters are presumably influenced first of all by individual characteristics of clopidogrel pharmacokinetics.     

Antithrombotic therapy in the cardiac catheterization laboratory: Focus on antiplatelet agents

Pharmacologic advances in the use of antithrombotic agents have paralleled the technologic innovations used in patients undergoing coronary interventions. The recognition of the central role of platelets in the development of complications related to coronary interventions led to the investigation and subsequent routine use of several antiplatelet agents as adjuvants to coronary intervention. Thus, the oral agents aspirin and either ticlopidine or clopidogrel are routinely administered after coronary stenting. Intravenous glycoprotein (GP) IIb/IIIa antagonists have been extensively studied and reduce adverse cardiac events in patients undergoing coronary interventions, especially those receiving intracoronary stents. Despite the growing use of GP IIb/IIIa antagonists, much information remains unknown as to the proper dosing and the effects these agents have on other elements of the hemostatic and vascular systems.     

Clopidogrel in interventional cardiology: questions answered and questions remaining

Clopidogrel is appropriate as a replacement for ticlopidine when used in combination with acetylsalicylic acid in the setting of percutaneous coronary intervention (PCI). Compared with ticlopidine, clopidogrel has comparable efficacy in reducing adverse cardiac events and a lower risk of hematological toxicity; both medications have been associated with rare cases of the very serious syndrome of thrombotic thrombocytopenic purpura. Clopidogrel should preferably be initiated with a loading dose of 300 mg before PCI, because most cases of thrombotic stent occlusion occur shortly after stent implantation, and attainment of target platelet inhibition is delayed for several days if a loading dose is not given. Bypass surgery in patients recently treated with clopidogrel appears to be associated with a significant increase in hemorrhagic complications. Long term therapy with clopidogrel after PCI may decrease late thrombotic stent occlusion and late vascular events; this hypothesis is currently being evaluated in randomized trials. By inhibiting platelet activation, clopidogrel may have a mechanism of benefit that is independent of the potent inhibition of platelet aggregation produced by the glycoprotein IIb/IIIa inhibitors.     

Antiplatelet Therapies: Recent Advances in the Development of Platelet Glycoprotein IIb/IIIa Antagonists

This article reviews recent advances in antiplatelet therapies, compares the antiplatelet/antithrombotic efficacy of various antiplatelet strategies to that of platelet glycoprotein (GP) IIb/IIIa receptor antagonists, and discusses issues in the development of long-term anti-GP IIb/IIIa therapy, and the potential adjunct strategies with GP IIb/IIIa antagonists.