Pharmacodynamic efficacy, clinical safety, and outcomes after prolonged platelet Glycoprotein IIb/IIIa receptor blockade with oral xemilofiban: results of a multicenter, placebo-controlled, randomized trial.

BACKGROUND: Parenteral administration of platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor blockers can reduce ischemic complications of coronary angioplasty. Orally active GP IIb/IIIa blockers may allow more sustained receptor antagonism with the potential for long-term secondary prevention. The pharmacodynamic efficacy, clinical safety, and outcomes after prolonged receptor blockade with an orally active GP IIb/IIIa antagonist are not known. The Oral Glycoprotein IIb/IIIa Receptor Blockade to Inhibit Thrombosis (ORBIT) Trial is a multicenter, placebo-controlled, randomized trial of xemilofiban, an oral platelet GP IIb/IIIa blocking agent, administered to patients after percutaneous coronary intervention. METHODS AND RESULTS: After successful elective percutaneous coronary intervention, 549 patients were randomized to receive either placebo or xemilofiban in a dose of 15 or 20 mg. Stented patients randomized to placebo also received ticlopidine 250 mg orally BID for 4 weeks. Patients who received abciximab during the coronary intervention and who were randomized to receive xemilofiban were administered a reduced dosage (10 mg TID for 2 weeks) followed by the randomized maintenance dose of 15 or 20 mg BID for 2 more weeks. All patients received 325 mg aspirin PO QD. Ex vivo platelet aggregation in response to 20 micromol/L ADP and 4 microg/mL collagen was measured over time after the initial dose of study drug and at days 14 and 28 of long-term therapy in 230 patients. All patients were followed clinically for 90 days. Xemilofiban inhibited platelet aggregation to both ADP and collagen with peak levels of inhibition that were similar at 14 and 28 days of long-term oral therapy. Plasma levels of xemilofiban correlated with the degree of platelet inhibition. Peak platelet inhibition on day 1 correlated with the subsequent occurrence of insignificant or mild bleeding events. Although this study was not powered to evaluate differences in clinical outcomes, a trend (P=0.04) was observed for reduction of cardiovascular events at 3 months in patients not treated with abciximab who received the highest dose (20 mg) of xemilofiban studied. CONCLUSIONS: 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.

Directional coronary atherectomy in acute myocardial infarction.

To date, application of directional coronary atherectomy (DCA) in acute myocardial infarction (AMI) has had limited reports. In eleven patients with AMI, DCA was applied. In three of these patients, DCA was used as a stand-alone procedure without use of thrombolytic agents. In each case a guidewire was placed across the stenosis, and in eight patients balloon angioplasty was utilized as a predilating modality prior to DCA. The thrombolytic agent urokinase was utilized in five of these eight patients, either before, during, or after angioplasty and/or DCA. DCA success (defined as ability to cross the lesion, reduction of less than or equal to 20% in stenosis and thrombolysis--when a thrombus is present) was achieved in 10 of 11 patients. One patient had persistent abrupt reclosure of an LAD lesion, accompanied by hemodynamic compromise, necessitating intra-aortic balloon pump insertion and subsequent emergent coronary artery bypass graft surgery. Final angiograms revealed residual stenoses less than or equal to 20%, and adequate thrombolysis. Significant cardiac events were limited to one emergent CABG, Q wave MI in four patients, and non-Q wave MI in two patients. Clinically all eleven patients improved, survived the AMI/CABG, and were discharged. This clinical experience demonstrates the feasibility and safety of DCA application in selected patients who experience acute myocardial infarction.