Platelet glycoprotein IIb/IIIa inhibitors in coronary artery disease

BACKGROUND: Inhibition of platelet activity at the injured coronary plaque is a target for novel therapeutic strategies. One of these mechanisms is the blockade of the platelet surface membrane glycoprotein (GP) IIb/IIIa receptor, which binds circulating fibrinogen or von Willebrand factor and crosslinks platelets as the final common pathway to platelet aggregation. Intravenous agents directed against this receptor include the chimeric monoclonal antibody fragment abciximab, the peptide inhibitor eptifibatide and nonpeptide mimetics tirofiban and lamifiban. RESULTS: During percutaneous coronary intervention, an absolute reduction of 1.5-6.5% in the 30-day risk of death, myocardial infarction or repeat urgent revascularization has been observed, with some variability in treatment effect among the agents tested. Treatment effect is achieved early with every modality of revascularization and maintained over the long-term up to 3 years. Increased bleeding risk may be minimized by reduction and weight adjustment of concomitant heparin dosing. In the acute coronary syndromes without ST segment elevation, absolute 1.5-3.2% reductions in 30-day rates of death or myocardial infarction have been achieved with 2- to 4-day courses of eptifibatide or tirofiban. Clinical benefit accrues during the period of drug infusion and is durable. Treatment effect may be enhanced among patients undergoing early coronary revascularization, with evidence of stabilization before intervention and suppression of postprocedural ischemic events. CONCLUSION: Thus, blockade of the platelet GP IIb/IIIa receptor reduces ischemic complications when used as an adjunct to percutaneous coronary intervention or the management of acute ischemic syndromes.     

Platelet glycoprotein IIb/IIIa receptor blockade and coronary resistance in unstable angina

OBJECTIVES: We designed a study to explore the effect of glycoprotein (GP) IIb/IIIa blockade on the atherosclerotic plaque and distal coronary vasculature. BACKGROUND: Platelet GP IIb/IIIa blockers have been proven to be beneficial in acute ischemic syndromes. This effect has also been attributed to the prevention of microvascular obstruction, although the underlying mechanisms have not been fully defined. METHODS: Eighteen patients with unstable refractory angina pectoris underwent cardiac catheterization and angioplasty. Trans-stenotic and microvascular resistances to flow were measured at baseline, during hyperventilation, and after intracoronary adenosine. Measurements were repeated early after abciximab administration and after successful percutaneous transluminal coronary angioplasty. RESULTS: Hyperventilation induced an ischemic attack in 12 of 18 patients and increased epicardial (12.8 +/- 16.9 vs. 6.1 +/- 6.1 mm Hg/ml per min, p < 0.05) and microvascular (9.9 +/- 7.5 vs. 6.8 +/- 5.8 mm Hg/ml per min, p < 0.05) coronary resistance. Abciximab had no significant effect on epicardial resistance, although it significantly reduced distal coronary resistance under all study conditions, including baseline (4.8 +/- 4.8 mm Hg/ml per min, p < 0.01), hyperventilation (5.1 +/- 5.4 mm Hg/ml per min, p < 0.01), and intracoronary adenosine (2.7 +/- 3.0 vs. 4.3 +/- 4.3 mm Hg/ml per min, p < 0.05). The hyperventilation test became negative in all patients after abciximab administration. CONCLUSIONS: These observations confirm the immediate beneficial effects of platelet GP IIb/IIIa blockade with abciximab in acute ischemic syndromes and suggest that improvement of microvascular function may play a central role in the mechanism of action of this drug.     

Platelet glycoprotein IIb/IIIa receptor blockade therapy for large coronary aneurysms and thrombi in Kawasaki disease

A 4-month-old girl with Kawasaki disease, large coronary artery aneurysms, and coronary thrombi was treated with standard therapy followed by abciximab, a platelet glycoprotein IIb/IIIa antagonist, in addition to standard heparin and warfarin sodium anticoagulation and low-dose aspirin. She did not develop evidence of ischemia, had no complications from the therapy, and showed resolution of the aneurysms and thrombi after 6 wk of therapy. Cathet. Cardiovasc. Diagn. 45:264–268, 1998. © 1998 Wiley-Liss, Inc.     

Oral glycoprotein IIb/IIIa antagonists in coronary artery disease

Despite the efficacy of intravenous glycoprotein IIb/IIIa inhibition in patients undergoing percutaneous coronary intervention and those presenting with acute coronary syndromes, the application of oral glycoprotein IIb/IIIa inhibition to the chronic management of coronary artery disease has not met with the same success. To explain these results, factors related to dosing, and inadequate inhibition or activation of platelet pro-coagulant activity have been recently suggested. However, although the disparity between intravenous and oral glycoprotein IIb/IIIa experience remains largely enigmatic, the discordant effect on ischemic endpoints observed within the phase III oral glycoprotein IIb/IIIa inhibitor trials potentially implicates a mechanism unrelated to platelet function.     

Platelet glycoprotein receptor site blockade in coronary artery disease

The advent of platelet glycoprotein IIb/IIIa receptor blockade has been one of the most significant advances in the treatment of coronary artery disease. This group of drugs has been widely tested both in patients with acute coronary syndromes who are being medically treated, as well as patients undergoing interventional procedures. Debate as to the optimal use if these agents remains spirited. This debate rests on several factors, including 1) economic issues, as these drugs are expensive, 2) controversy over the meaning of specific endpoints, eg, in an otherwise uncomplicated coronary intervention, the meaning of creatine phosphokinase elevation post-procedure, and 3) what is the risk benefit ratio given the costs involved and the potential risks? Several questions remain. Do all patients with acute coronary syndromes need this as a part of medical therapy? Do all patients undergoing percutaneous coronary interventions need this group of agents, or are there populations of patients who do not need them? Are there differences between the agents that are clinically important? Is there a specific device-drug interaction? Continued evaluation of these questions will facilitate improving the outcome of the diverse group of patients treated for coronary artery diseases.     

Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes

Antagonists of the platelet fibrinogen receptor glycoprotein IIb/IIIa are potent inhibitors of platelet function and provide marked protection from ischemic events in patients undergoing PCI. These agents are also of benefit in patients with unstable angina or non-ST segment elevation myocardial infarction (MI) and provide a 9% reduction in the combined endpoint of 30-day death or MI. This benefit is most marked in patients undergoing early PCI or those at increased risk due to history of diabetes or elevation of the cardiac marker troponin. Based on these findings, the combined American Heart Association and American College of Cardiology guidelines on the management of unstable angina and non-ST segment elevation MI recommend intravenous GPIIb/IIIa in patients in whom PCI is planned particularly those with elevated troponin or diabetes. The use of these agents is associated with a slight increase in major bleeding and in rare instances thrombocytopenia that usually resolves quickly after therapy is discontinued.     

Platelet glycoprotein IIb/IIIa inhibition in acute coronary syndromes

Acute coronary syndromes are a leading cause of hospitalization in industrialized countries. Current antithrombotic therapy focuses on relatively weak antiplatelet agents and heparin. The advent of inhibitors of the platelet glycoprotein IIb/IIIa receptor, the final common pathway for aggregation, provides a new therapeutic modality. Clinical trials with a total of more than 18,000 patients have clearly shown the benefits of intravenous IIb/IIIa blockade. Overall, at 30 days, 13 fewer deaths or myocardial infarctions occurred for every 1000 patients treated in these trials. This favorable outcome was extended to 6 months, resulting in 16 fewer such events per 1000 patients treated. Importantly, these benefits were not accompanied by an excessive occurrence in bleeding complications or thrombocytopenia. To further improve outcomes in this high-risk group of patients, strategies pertaining to prolonged periods of vessel passivation with oral formulations and early or delayed invasive approaches are being studied.     

Platelet glycoprotein IIb/IIIa inhibitors

Glycoprotein (GP) IIb/IIIa inhibitors including abciximab, eptifibatide and tirofiban have been studied extensively as short-term adjuncts to short-term heparin and indefinite aspirin in patients with acute coronary syndrome or undergoing percutaneous coronary interventions on native vessels. The drugs provide a small advantage in the composite endpoint of death, myocardial infarction, and need for revascularization at 30 days (1-2% of treated patients) at the expense of an increase in major and potentially fatal bleeding complications (1% of treated patients over heparin plus aspirin alone). Highest-risk patients appear to benefit the most; clopidogrel should also be considered in these patients. Patients undergoing percutaneous interventions on bypass grafts do not benefit. Whether one GP IIb/IIIa inhibitor is superior to another is incompletely clarified. Abciximab causes severe immune-mediated thrombocytopenia (<20,000/microl) in 0.7% of cases; this is more often than eptifibatide or tirofiban (0.2%). Pseudothrombocytopenia should be differentiated. Effective use of GP IIb/IIIa inhibitors for acute coronary syndrome and percutaneous coronary interventions requires discerning clinical judgment. The value of GP IIb/IIIa inhibitors is not established in other forms of vascular disease.     

Oral glycoprotein IIb/IIIa antagonism in patients with coronary artery disease

Dose-finding studies and trials of interaction of oral glycoprotein IIb/IIIa antagonists with other antiplatelet agents have been limited. We hypothesized that these detailed assessments could be first performed in patients with stable coronary artery disease (CAD) and then extrapolated to the target population. To this end, we performed 2 sequential studies. The first study examined the dose-related effects on indexes of platelet and vascular function induced by the oral inhibitor RPR 109891, when given alone and in combination with aspirin, in patients (n = 100) with stable CAD. The second study (the Antagonism of the FIbrinogen Receptor after Myocardial Events trial) assessed the pharmacodynamics and safety of derived regimens in patients (n = 320) with unstable coronary syndromes. In patients with stable CAD, platelet aggregation was dose dependently inhibited by RPR 109891, and the dose-response relation was shifted to the right by the concomitant administration of aspirin (p = 0.0001). The degree of platelet inhibition induced by 3 doses of RPR 109891 (plus aspirin) was lower in patients with unstable than stable CAD. No drug-related major bleeding occurred in either study. RPR 109891 treatment was associated with acute and delayed thrombocytopenia. In conclusion, chronic treatment with an oral glycoprotein IIb/IIIa antagonist (1) induces antiplatelet effects that are potentiated by concomitant administration of aspirin, (2) may require dose adjustment in syndromes of platelet activation, (3) is associated with a low rate of clinically significant bleeding when doses inducing incomplete inhibition of platelet aggregation are used, and (4) requires frequent monitoring of platelet count unless reliable predictors of delayed thrombocytopenia become available.     

Platelet glycoprotein IIb/IIIa receptor inhibitor preserves coronary flow reserve during progressive coronary arteriostenosis in swine

Thrombosis resulting from blood platelet aggregation via glycoprotein (GP) IIb/IIIa receptor activation triggers the local release of vasoactive substances. Therefore, inhibition of these receptors could affect coronary vasoactive function during thrombotic coronary arteriostenosis. Twenty pigs were instrumented with an aortic catheter and with hydraulic occluders and flow probes on both the left anterior descending (LAD) and the left circumflex (LCx) coronary arteries. One of these 2 coronary arteries was repeatedly injured by external clamping for 15-second periods at 30-minute intervals while the pigs were given either a GP IIb/IIIa receptor inhibitor (L-739,758) (n=5), heparin (n=5), aspirin (n=3), or saline (n=7). There were no baseline differences between the 4 groups in mean arterial pressure, resting coronary blood flow (CBF), or reactive hyperemic response (RHR), which was induced by brief coronary artery occlusion and expressed as flow debt repayment. After multiple injuries, resting CBF had decreased by 95+/-2% (ie, nearly complete coronary artery occlusion) at 15+/-4 minutes in the control group, whereas in the heparin-, aspirin-, and GP IIb/IIIa inhibitor-treated groups, resting CBF had decreased by only 21+/-7% at 18+/-3 minutes, 15+/-3% at 18+/-5 minutes, and 15+/-7% at 21+/-4 minutes, respectively, suggesting that heparin, aspirin, and the GP IIb/IIIa inhibitor each prevented injury-induced coronary artery occlusion. After the initial injury, the RHR was progressively reduced in the control and heparin- and aspirin-treated groups but not in the GP IIb/IIIa inhibitor-treated group. At a comparable level of resting CBF ( approximately 15% below baseline), the RHR was reduced more in the control (-56+/-9%), heparin-treated (-49+/-9%), and aspirin-treated (-61+/-12) groups (P:<0.05) than in the GP IIb/IIIa inhibitor-treated group (-26+/-6%). When the resting CBF had decreased by approximately 35%, the RHR still was reduced significantly more (P<0.01) in the heparin-treated group (-64+/-9%) than in the GP IIb/IIIa inhibitor-treated group (-21+/-6%). In a separate group of control pigs (n=4) subjected to 2 injuries, coronary perfusion pressure distal to the injury site was reduced by 14+/-1 mm Hg from the arterial pressure, and the RHR was 20+/-6%. When the distal coronary perfusion pressure was reduced similarly (-14+/-1 mm Hg) in a separate group of GP IIb/IIIa inhibitor-treated pigs (n=4) by 2 injuries and the use of a hydraulic occluder, the RHR was 130+/-16% (P<0.01 versus control). Our data demonstrate for the first time that a platelet GP IIb/IIIa receptor inhibitor can preserve the distal coronary vasodilatory response during progressive coronary arteriostenosis.     

The use of glycoprotein IIb/IIIa inhibitors in patients with coronary artery disease

Platelet membrane glycoprotein IIb/IIIa inhibitors, a new class of potent antiplatelet agents, have been used in the treatment of acute coronary syndromes as well as in the prevention of complications after percutaneous coronary interventions. Approximately 50,000 patients with coronary artery disease have been enrolled in randomized studies of glycoprotein IIb/IIIa inhibitors. The purpose of this article is to review the pharmacology of glycoprotein IIb/IIIa inhibitors, the results of the clinical trials using these agents, and their current use in percutaneous coronary interventions and the treatment of acute coronary syndromes.     

Use of glycoprotein IIb/IIIa inhibitors in patients with coronary artery disease.

GP IIb/IIIa inhibitors are one of the most exciting pharmacological advances in the treatment of coronary artery disease to be developed this decade. They have proven benefit in the treatment of patients undergoing high-risk percutaneous interventions and in patients with unstable angina or non-Q-wave myocardial infarction. In all of these patients, they should be used in conjunction with aspirin and heparin. Although bleeding complications are high in initial studies, they are much less common with increased clinical experience and careful attention to heparin dosing. Important questions that will be answered in the next several years include whether there are significant differences between the available agents and whether oral formulations will be safe and effective.     

Glycoprotein IIb/IIIa receptor blockade with coronary stent placement.

GP IIb/IIIa blockade for stenting offers almost complete inhibition of platelet aggregation and can bridge the delayed onset of action of ticlopidine. In the EPISTENT trial, GP IIb/IIIa blockade with abciximab reduced the 30-day cardiac event rate after stenting by more than 50% compared to placebo. Economic constraints may demand to restrict the use of GP IIb/IIIa blockade to subgroups that benefit most. Bail-out stenting constitutes one of these subgroups. Another group are patients with acute myocardial infarction. Moreover, the exquisitely high risk of residual dissection after stenting suggests to always employ GP IIb/IIIa blockade in this instance.