Pharmacodynamic Efficacy, Clinical Safety, and Outcomes After Prolonged Platelet Glycoprotein IIb/IIIa Receptor Blockade With Oral Xemilofiban

Kereiakes, Dean J.; Kleiman, Neal S.; Ferguson, James J.; Masud, Arif; Broderick, Thomas M.; Abbottsmith, Charles W.; Runyon, John Paul; Anderson, Laura; Anders, Robert J.; Dreiling, Roger J.; Hantsbarger, G; Bryzinski, Brian; Topol, Eric J.

doi:10.1161/01.cir.98.13.1268

Cited by 87 publications

(40 citation statements)

References 15 publications

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“…11 With oral administration, peaks and troughs (corresponding to the drug's half-life) exist in the level of platelet inhibition; these are not present with intravenously administered IIb/IIIa inhibitors. In addition, substantial variability between patients in the level of inhibition has been observed with all oral agents 12,13 ; this is related in part to differences in bioavailability. As such, with a fixed dose, some orbofibantreated patients have as high as 100% inhibition at peak and others as low as 0% to 20% inhibition at trough.…”

Section: Potential Explanations For Lack Of Benefitmentioning

confidence: 99%

Oral Glycoprotein IIb/IIIa Inhibition With Orbofiban in Patients With Unstable Coronary Syndromes (OPUS-TIMI 16) Trial

et al. 2000

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Background —Although intravenous glycoprotein IIb/IIIa inhibitors are beneficial in patients with acute coronary syndromes, prolonged oral IIb/IIIa inhibition might provide an additional reduction in recurrent events. Methods and Results —Investigators at 888 hospitals in 29 countries enrolled 10 288 patients with acute coronary syndromes, which was defined as ischemic pain at rest within 72 hours of randomization, associated with positive cardiac markers, electrocardiographic changes, or prior cardiovascular disease. Patients received aspirin and were randomized to receive, for the duration of the trial, (1) 50 mg of orbofiban twice daily (50/50 group), (2) 50 mg of orbofiban twice daily for 30 days followed by 30 mg of orbofiban twice daily (50/30 group), or (3) a placebo. The primary composite end point was death, myocardial infarction, recurrent ischemia requiring rehospitalization, urgent revascularization, or stroke. The trial was terminated prematurely because of an unexpected increase in 30-day mortality in the 50/30 orbofiban group. Mortality through 10 months was 3.7% for the placebo group versus 5.1% in the 50/30 group ( P =0.008) and 4.5% in the 50/50 group ( P =0.11). There were no differences in the primary end point (22.9%, 23.1%, and 22.8%, for the placebo, 50/30, and 50/50 groups, respectively). Major or severe bleeding (but not intracranial hemorrhage) was higher with orbofiban; it occurred in 2.0%, 3.7% ( P =0.0004), and 4.5% ( P <0.0001) of patients, respectively. Exploratory subgroup analyses found that patients who underwent percutaneous coronary intervention had a lower mortality and a significant reduction in the composite end point ( P =0.001) with orbofiban. Conclusions —Fixed-dose orbofiban failed to reduce major cardiovascular events and was associated with increased mortality in this broad population of patients with acute coronary syndromes; however, a benefit was observed among patients who underwent percutaneous coronary intervention.

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Section: Potential Explanations For Lack Of Benefitmentioning

confidence: 99%

Oral Glycoprotein IIb/IIIa Inhibition With Orbofiban in Patients With Unstable Coronary Syndromes (OPUS-TIMI 16) Trial

et al. 2000

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“…The Oral Glycoprotein IIb/IIIa Receptor Blockade to Inhibit Thrombosis (ORBIT) trial was a randomized dose-ranging trial of xemilofiban in patients undergoing percutaneous intervention. 34 Peak inhibition of platelet aggregation was similar following the same dose of xemilofiban administered on Days 14 and 28 of the trial. The time to peak blood level following the same dose of xemilofiban was reduced from 4 h following the first dose of drug to 2 h with steady-state dosing during chronic therapy.…”

Section: Xemilofibanmentioning

confidence: 84%

“…The time to peak blood level following the same dose of xemilofiban was reduced from 4 h following the first dose of drug to 2 h with steady-state dosing during chronic therapy. 34 Most bleeding events were observed during the first 2 weeks of therapy on a three-times daily dosing regimen. 34 …”

Section: Xemilofibanmentioning

confidence: 99%

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Oral platelet glycoprotein IIb/IIIa receptor inhibitors—part I

Cannon

2003

Clinical Cardiology

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Summary:With the central importance of antiplatelet therapy in patients with coronary artery disease and the numerous positive trials with glycoprotein (GP) IIb/IIIa inhibitors given intravenously, it was hoped that one could extend the benefit of IIb/IIIa inhibition to long-term treatment. Although the hypothesis that prolonged oral IIb/IIIa inhibition was appealing, many issues have been identified in the initial Phase II trials that would limit the usefulness of these compounds. Variability of the level of platelet inhibition was one major culprit that distinguished the oral compounds from intravenous ones. The problems that arose were that increased bleeding has been seen when levels of platelet inhibition are high (e.g., > 90%) and that, conversely, efficacy would likely be limited when levels of platelet inhibition were low. If further development of this class of drugs is undertaken, formal dosing studies would have to establish an oral dosing strategy that achieves appropriately high (80-95% inhibition) and steady levels of inhibition.

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“…Unfortunately, large phase III trials of these oral agents have shown no therapeutic benefit and development of most of these agents has been abandoned. A major problem with GPIIb/IIIa antagonists is a relatively narrow safety/efficacy window, since high doses cause an unacceptable compromise to haemostasis, accompanied by wide pharmacokinetic and pharmacodynamic variations between individuals [Kereiakes et al, 1996[Kereiakes et al, , 1998Kleiman et al, 1995;Lehne et al, 1998;Simoons et al, 1994;Simpfendorfer et al, 1997;Storey et al, 1999;Tcheng et al, 1995]. On this background, it may be hypothesised that P 2T receptor antagonism offers an alternative strategy to GPIIb/IIIa antagonists.…”

Section: P 2t Receptor Antagonists Vs Gpiib/iiia Antagonistsmentioning

confidence: 99%

Clinical experience with antithrombotic drugs acting on purine receptor pathways

Storey¹

2001

Drug Development Research

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Rupture of atherosclerotic plaques and subsequent thrombus formation in coronary arteries are key events in the progression of coronary artery disease and the pathogenesis of acute coronary syndromes. Platelets play a crucial role in this thrombus formation and the success of aspirin in reducing cardiovascular morbidity and mortality has spurred on the search for antiplatelet agents that have an alternative mechanism of action and may, therefore, add to the therapeutic effects of aspirin. The thienopyridines, ticlopidine and clopidogrel, act via metabolites on the platelet ADP receptor subtype designated P 2T , and these agents have proven clinical efficacy, either as alternatives to aspirin or, in prevention of coronary stent thrombosis, in combination with aspirin. Potent P 2T receptor antagonists have been developed that act directly on the receptor and have a rapid onset of action. One such antagonist, AR-C69931MX, is being developed for clinical use. AR-C69931MX is a potent antagonist of ADP-induced platelet activation, aggregation, and secretion and also antagonises platelet responses to all other agonists in view of the central role of the P 2T receptor in amplifying platelet responses. Phase II studies of intravenous AR-C69931MX in patients with acute coronary syndromes show that this agent has a rapid onset of action, rapidly achieving steady-state inhibition of platelet aggregation, with a half-life of only a few minutes. AR-C69931MX appears to be safe and well tolerated as adjunctive therapy in these patients, and more effective inhibition of platelet function is achieved than with the thienopyridine clopidogrel. Orally active antagonists are also being developed that may be more effective than the thienopyridines. Drug Dev. Res. 52:202-212, 2001.

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Pharmacodynamic Efficacy, Clinical Safety, and Outcomes After Prolonged Platelet Glycoprotein IIb/IIIa Receptor Blockade With Oral Xemilofiban

Abstract: Xemilofiban inhibited platelet aggregation and was well tolerated during 28 days of long-term oral therapy. The observed trend in reduction of cardiovascular events in follow-up awaits confirmation in the larger-scale phase III study (EXCITE trial) currently in progress.

Cited by 87 publications

References 15 publications

Oral Glycoprotein IIb/IIIa Inhibition With Orbofiban in Patients With Unstable Coronary Syndromes (OPUS-TIMI 16) Trial

Oral Glycoprotein IIb/IIIa Inhibition With Orbofiban in Patients With Unstable Coronary Syndromes (OPUS-TIMI 16) Trial

Oral platelet glycoprotein IIb/IIIa receptor inhibitors—part I

Clinical experience with antithrombotic drugs acting on purine receptor pathways

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