Thomas M. Broderick

Time course, magnitude, and consistency of platelet inhibition by abciximab, tirofiban, or eptifibatide in patients with unstable angina pectoris undergoing percutaneous coronary intervention

Adjunctive platelet glycoprotein IIb/IIIa blockade during percutaneous coronary intervention (PCI) reduces platelet-mediated adverse ischemic outcomes. Although abciximab, eptifibatide, and tirofiban have received U.S. Food and Drug Administration approval for use, these agents differ in their pharmacodynamic profiles. Each of these agents has been compared in randomized trials with placebo for patients undergoing PCI, but no randomized comparative studies of these agents have been performed. We compared ex vivo platelet function by both standard light transmission aggregometry and rapid platelet function assay during and after administration of abciximab, eptifibatide, or tirofiban in approved dose regimens on a randomized basis at the time of PCI in patients with unstable angina pectoris. A reduced intensity of platelet inhibition by light transmission aggregometry was observed for tirofiban compared with either eptifibatide or abciximab. In addition, the 30-minute bolus strategy used for tirofiban was associated with delayed onset of maximal platelet inhibition relative to the initiation of bolus infusion. Whether the trends in platelet function observed in this study will be translated into differences in clinical outcomes awaits definition by larger scale randomized clinical trials comparing these platelet glycoprotein IIb/IIIa inhibitors.

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

BACKGROUNDnParenteral 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.nnnMETHODS AND RESULTSnAfter 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.nnnCONCLUSIONSnXemilofiban 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.

Usefulness of Stent Length in Predicting In-Stent Restenosis (The MULTI-LINK Stent Trials)

The cumulative experience of 4 clinical trials using the MULTI-LINK coronary stent design was analyzed. Multivariable logistic regression identified postprocedure in-stent minimum lumen diameter (p = 0.0001), stent length (p = 0.0038), smoking (p = 0.0105). and diabetes (p = 0.0803) as the most important predictors of in-stent restenosis at late (6- to 9-month) angiographic follow-up.

Sustained Platelet Glycoprotein IIb/IIIa Blockade With Oral Xemilofiban in 170 Patients After Coronary Stent Deployment

BACKGROUNDnInhibition of platelet aggregation with parenteral glycoprotein (GP) IIb/IIIa receptor blockers can reduce the ischemic complications of angioplasty. Sustained efficacy and safety of protracted GP IIb/IIIa blockade with an orally administered agent have not previously been determined. This study is the first randomized, dose-ranging, single-blind, placebo-controlled trial of xemilofiban, an oral platelet GP IIb/IIIa receptor antagonist, administered to patients after intracoronary stent deployment. The pharmacodynamic efficacy of xemilofiban-induced platelet inhibition and clinical safety of this agent was evaluated during chronic therapy.nnnMETHODS AND RESULTSnAfter elective intracoronary stent deployment, patients were randomized to receive placebo (250 mg ticlopidine P.O. BID) or xemilofiban in doses of 5, 10, 15, or 20 mg P.O. BID. All patients received 325 mg aspirin P.O. QD. Inhibition of 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 1 and 2 weeks of chronic therapy. Study drug was discontinued after 2 weeks, and all patients were followed clinically for > or = 30 days. Oral xemilofiban resulted in a dose-dependent inhibition of platelet aggregation in response to both agonists that was sustained through 2 weeks of chronic therapy. Doses of xemilofiban required to achieve > or = 50% inhibition of platelet aggregation were > or = 10 mg, and the duration of inhibition was 8 to 10 hours. No significant hemorrhagic episodes or blood transfusions were observed in this trial.nnnCONCLUSIONSnOral xemilofiban in doses of > or = 10 mg produced > or = 50% inhibition of platelet aggregation in response to ADP and collagen for 8 to 10 hours after dosing. Platelet inhibition was sustained through 2 weeks of chronic therapy. The optimal duration of oral GP IIb/IIIa blockade to effectively suppress recurrent ischemic events after coronary intervention remains to be determined.

Efficacy of abciximab induced platelet blockade using a rapid point of care assay.

Anciximab provides potent, but variable degrees of platelet inhibition both during the duration of intravenous administration and at 12 hours following therapy. Platelet function was assessed using the PC-RPFA system in 78 patients scheduled for percutaneous coronary revascularization who were administered the standard abciximab weight-adjusted bolus and 12-hour infusion. The PC-RPFA system is a cartridge-based, semiautomated point-of-care whole-blood assay that incorporates fibrinogen-coated polystyrene beads, buffers, and a modified thrombin receptor activating peptide (Isotrap) in lyophilized form. The instrument detects the agglutination rate between the stimulated platelets and the fibrinogen-coated beads, and provides a quantitative digital display in less than 2 minutes. No differences in the level of platelet inhibition were observed in these abciximab-treated patients by diabetic status, gender, smoking, diagnosis (unstable angina, chronic stable angina, recent myocardial infarction), or abciximab treatment status (first time vs. retreatment). Nocorrelation of the PC-RPFA rate of platelet aggregation with clinical demographic factors was observed, with the exception of baseline hematocrit (r2 = 0.4556). The relationship between the PC-RPFA rate of aggregation and hematocrit reflects light absorbance by erythrocytes and is specific to the PC-RPFA system. The absolute rate of platelet aggregation (slope) reported by the PC-RPFA is correlated with percent aggregation, thus making it potentially possible to predict the level of aggregation without reference to a baseline (pretreatment) measure of platelet function. This correlation was closest for patients having <40% baseline aggregation (r2 = 0.55). Thus, PC-RPFA provides a rapid point-of-care assessment of platelet function that could allow for adjustment of abciximab dosing to achieve targeted levels of platelet inhibition. The utility of this device to optimize therapy with platelet glycoprotein IIb/IIIa inhibitors is currently being evaluated.

IIb’s are not IIb’s

Platelet glycoprotein (GP) IIb/IIIa receptor blockade improves clinical outcomes after percutaneous coronary intervention (PCI) and for patients who present with non-ST-segment elevation acute coronary syndromes. Although this class of therapeutic agents has been defined by a common affinity for the platelet GP IIb/IIIa receptor, the 3 currently available agents differ markedly in pharmacodynamic and pharmacokinetic profile as well as receptor affinity. Differential (separate) binding sites on the GP IIb/IIIa receptor explain the observation that abciximab binding to platelets is not influenced by either tirofiban or eptifibatide. Abciximab (ReoPro, chimeric 7E3 Fab) is a low K(d) (high affinity) agent with a very short plasma t(1/2) and a prolonged duration of action at the platelet target receptor. Eptifibatide and tirofiban are high K(d) (low affinity) agents with a relatively long plasma t(1/2) and short duration of action at the platelet target receptor. These pharmacodynamic differences underlie the phenomena of gradual redistribution in abciximab binding and smooth tapering of abciximab antiplatelet effect after discontinuation of therapy. Furthermore, abciximab demonstrates affinity for both the CD11b/18 (alpha(m)beta(2) or MAC 1) and alpha(V)beta(3) (vitronectin) receptors. Although a survival advantage in favor of abciximab has been observed after PCI in both randomized controlled trials and high-volume clinical practice, no survival benefit has been observed to date after eptifibatide or tirofiban therapy for PCI. The mechanism of survival advantage after abciximab therapy has not been defined but may be distinct from the degree of platelet GP IIb/IIIa receptor inhibition during the duration of intravenous treatment. Although this important new class of therapeutic agent was simplistically defined by a common affinity for the GP IIb/IIIa receptor, this solitary unifying attribute may not define agent-specific benefit.

Procedural and late outcomes following MULTI-LINK DUET coronary stent deployment

The MULTI-LINK DUET is the next generation MULTI-LINK stent with modified strut geometry. Safety and efficacy of the MULTI-LINK DUET were evaluated in a prospective multicenter registry and were compared with prior MULTI-LINK stent experience from the ASCENT randomized trial. A total of 270 patients received 302 MULTI-LINK DUET stents and were evaluated using a composite primary end point of major cardiac events (death, Q-wave and non-Q-wave myocardial infarction, and requirement for coronary revascularization) attributable to the target stenosis cumulative to 30 days following enrollment. Quantitative coronary angiography was performed at a mean follow-up of 6 +/- 2 (+/-SD) months. No difference in primary end point or in angiographic restenosis to 6 months was observed between MULTI-LINK DUET and MULTI-LINK experiences. The MULTI-LINK DUET demonstrated improved device and procedural success, less postprocedural in-stent stenosis, larger postprocedural minimal lumen diameter, and fewer postprocedural marginal dissections compared with the MULTI-LINK stent. Multivariate regression modeling identified stent length, diabetes mellitus, poststent minimal lumen diameter, lesion eccentricity, and current smoking as independent predictors of in-stent restenosis. Thus, the MULTI-LINK DUET Registry demonstrates enhanced procedural performance with clinical and angiographic outcomes similar to those previously observed for the MULTI-LINK stent in the ASCENT randomized trial.

Partial reversal of heparin anticoagulation by intravenous protamine in abciximab-treated patients undergoing percutaneous intervention.

Serious hemorrhage and vascular complications after abciximab therapy are associated with elevated activated clotting time values. Our preliminary experience suggests that low-dose intravenous protamine administration is both safe and effective in reducing elevated in-laboratory activated clotting time values and the potential for serious hemorrhage in abciximab-treated patients.

High Platelet Count in Platelet-Rich Plasma Reduces Measured Platelet Inhibition by Abciximab but not Tirofiban nor Eptifibatide Glycoprotein IIb/IIIa Receptor Antagonists

We evaluated the differential effect of platelet count in platelet-rich plasma (PRP) on the level of ex vivo inhibition of platelet aggregation provided by abciximab, eptifibatide, and tirofiban as part of a randomized, comparative trial of these agents on platelet function in patients with unstable angina pectoris undergoing percutaneous coronary intervention. Platelet count <350 K/µL in PRP reduced measured platelet inhibition by abciximab, but not eptifibatide nor tirofiban. This observation suggests the need for standardized, uniform platelet counts in PRP during future comparisons of the degree of platelet inhibition by these agents.