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(Circulation. 1997;96:1117-1121.)
© 1997 American Heart Association, Inc.

Articles

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

Dean J. Kereiakes, MD; Neal Kleiman, MD; James J. Ferguson, MD; John Paul Runyon, MD; Thomas M. Broderick, MD; Nancy A. Higby, RN; Linda H. Martin, RN; Gary Hantsbarger, MS; Shawn McDonald, MS; ; Robert J. Anders, PharmD¹

From the Department of Cardiology and Internal Medicine (D.J.K., J.P.R.), University of Cincinnati College of Medicine (Ohio); Division of Cardiology (N.K.), Baylor University College of Medicine; St Luke's Episcopal Hospital (J.J.F.), Texas Heart Institute, Baylor College of Medicine at the University of Texas Health Sciences Center; The Ohio Heart Health Center (T.M.B.); The Carl and Edyth Lindner Center for Clinical Cardiovascular Research at The Health Alliance of Greater Cincinnati (N.A.H., L.H.M.) (Ohio); and G.D. Searle & Co (G.H., S.M., R.J.A.), Skokie, Ill.

Correspondence to Dean J. Kereiakes, MD, FACC, The Carl and Edyth Lindner Center for Clinical Cardiovascular Research, 2123 Auburn Ave, Suite 424, Cincinnati, OH 45219.

	Abstract

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Background Inhibition 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.

Methods and Results After elective intracoronary stent deployment, patients were randomized to receive placebo (250 mg ticlopidine PO BID) or xemilofiban in doses of 5, 10, 15, or 20 mg PO BID. All patients received 325 mg aspirin PO QD. Inhibition of ex vivo platelet aggregation in response to 20 µmol/L ADP and 4 µg/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 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 50% inhibition of platelet aggregation were 10 mg, and the duration of inhibition was 8 to 10 hours. No significant hemorrhagic episodes or blood transfusions were observed in this trial.

Conclusions Oral xemilofiban in doses of 10 mg produced 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.

Key Words: stents • thrombosis • myocardial infarction • antagonists, receptor

	Introduction

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Placebo-controlled, randomized trials of parenteral platelet glycoprotein (GP) IIb/IIIa receptor antagonists have demonstrated efficacy of these agents in reducing ischemic complications of percutaneous coronary intervention.^{1 2} The GP IIb/IIIa receptor may also be important in the pathogenesis of subacute stent thrombosis.³ Parenteral GP IIb/IIIa blockade has been shown to reduce the incidence of periprocedural myocardial infarction in patients with unplanned or emergency intracoronary stent deployment (Reference 4⁴ and EPILOG, unpublished data). Recent studies have correlated platelet GP IIb/IIIa receptor density with subsequent subacute stent thrombosis.³ Indeed, fewer thrombotic events were observed after coronary stent deployment in patients receiving combined platelet inhibition with aspirin and ticlopidine when compared during a randomized trial with patients treated with coumadin and aspirin.⁵ In addition, GP IIb/IIIa blockade has been shown to inhibit platelet aggregation and thrombus formation in animal stent models.^{6 7} Orally active GP IIb/IIIa receptor blockers are under development to allow more sustained receptor antagonism than can be provided by parenteral agents, thus offering the potential for enhanced long-term benefit and secondary prevention of recurrent ischemic events.^{8 9} However, the efficacy and clinical safety of protracted GP IIb/IIIa blockade with an oral agent are unknown. This report describes our experience with xemilofiban, a new orally active nonpeptide GP IIb/IIIa receptor antagonist, in patients after intracoronary stent placement.

	Methods

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Subjects
From October 1, 1995, through May 1, 1996, 170 patients were enrolled into a single-blind, placebo-controlled, dose-ranging, pharmacokinetic/pharmacodynamic study of xemilofiban (GD Searle), an orally active antagonist of the RGD recognition site on the platelet GP IIb/IIIa receptor, after intracoronary stent deployment. The objectives of this study were to evaluate the safety profiles of 5-, 10-, 15-, and 20-mg doses of xemilofiban compared with placebo administered for a period of <14 days after stent placement and to evaluate the pharmacodynamic response (ex vivo inhibition of platelet aggregation) and pharmacokinetic profile after 1 and 2 weeks of therapy. Clinical events, including death, myocardial infarction, coronary artery bypass graft surgery, repeat percutaneous coronary revascularization, or admission for ischemic cardiac chest pain, as well as bleeding events, were tracked for 30 days after stent deployment. Bleeding events were classified as severe or life threatening (eg, intracranial, retroperitoneal), moderate (eg, requiring transfusion), or minor (eg, not requiring transfusion or causing hemodynamic compromise). Participating centers are listed in the "Appendix." This study was approved by the institutional review board of each institution, and informed consent was obtained from each patient. All patients received aspirin (325 mg PO QD) beginning 2 hours before the procedure and throughout the study period. Oral xemilofiban was initiated on the morning after the interventional procedure on a randomized basis in doses of 5, 10, 15, or 20 mg BID. Patients randomized to receive xemilofiban placebo administered twice daily also received 250 mg ticlopidine PO BID begun immediately after the procedure in accordance with standard therapy after stent placement.¹⁰ When indicated, abciximab (Centocor) was administered as a weight-adjusted bolus (0.25 mg/kg) and 12-hour intravenous infusion (0.6 mg/h) based on clinical criteria at the discretion of the investigator to 30 patients during the stent procedure. In these patients, xemilofiban was begun 8 to 18 hours after the discontinuation of abciximab.¹¹ Patient demographics are shown in Table 1. Patients were discharged from the hospital the day after intervention and reevaluated after 1 and 2 weeks of oral therapy for platelet pharmacodynamic studies. Study drug was discontinued after 2 weeks of treatment, and all patients were followed clinically for 30 days.

View this table: [in this window] [in a new window]   Table 1. Patient Demographics

Interventional Procedure
Intravenous heparin was administered during the interventional procedure to achieve an in-laboratory activated clotting time (ACT) of 300 seconds for patients not receiving abciximab and 200 seconds in abciximab-treated patients. Vascular access sheaths were removed early when the ACT was <170 seconds, and heparin was not routinely administered after the procedure. Stent deployment was followed by high pressure (16 atm) balloon dilatation, and intravascular ultrasound evaluation was not routinely used. The Palmaz-Schatz coronary stent was deployed in 165 patients, and a Gianturco-Roubin flex stent was used in 5 patients.

Platelet Studies
Ex vivo platelet aggregation in response to both 20 µmol/L ADP and 4 µg/mL collagen was assessed at 2, 4, 6, 8, and 12 hours after the first dose of study drug and again at 7 and 14 days of continuous oral therapy. Blood was collected in 3.8% sodium citrate tubes, and platelet aggregation was measured in platelet-rich plasma by the turbidimetric method with single-lot 20 µmol/L ADP/L (Biodata) and single-lot 4 µg/mL horse collagen (Chronolog). Platelet aggregation was quantified as the maximal change in light transmission occurring within 5 minutes of addition of agonist. No correction for platelet count was made.^{12 13}

Statistical Methods
To determine whether the dose response to xemilofiban differed among visits, an analysis was performed on the platelet aggregation values obtained 4 hours after administration of study drug at each visit (V1, first dose; V2, day 7; V3, day 14). Aggregation values were submitted to a mixed-effects ANCOVA. Main factors in the ANCOVA model were baseline aggregation value, dose of xemilofiban, ticlopidine use (yes or no), antecedent abciximab use (yes or no), and visit (visit 1, 2, or 3). Interaction effects included in the model were visitxabciximab, dosexabciximab, dosexvisit, and dosexvisitxabciximab. Effects of primary interest in this analysis were the main effect of visit and the dosexvisit interaction effect.

The effects of abciximab and the interaction effect involving abciximab were included in the model because prior analysis¹¹ indicated that patients receiving antecedent treatment with abciximab had significantly lower platelet aggregation values than did non–abciximab-treated patients for the same dose of xemilofiban. This pharmacodynamic interaction was observed after the initial dose of xemilofiban and resolved by 1 week of chronic oral therapy.¹¹

Effects for ticlopidine and the interaction effect involving ticlopidine are included in the model because preliminary examination of plotted aggregation data indicated that the ticlopidine-treated group had lower ADP-induced aggregation than would be predicted on the basis of a linear dose-response to xemilofiban, particularly at days 7 and 14.

The within-subject variance structure of observations was modeled as an unstructured variance/covariance matrix. This analysis was done using the PROC MIXED procedure in SAS version 6.09 (SAS Institute Inc).

In principle, platelet aggregation values are bounded by 0% and 100%. (In practice, values slightly over 100% are sometimes reported.) The bounded nature of platelet aggregation values violates an assumption of ANCOVA, so for purposes of model fitting and hypothesis testing, logits of the platelet aggregation values were used. For the logit transformation, values of 100% were set to 99%, and values of 0% were set to 1%.

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
One-hundred seventy patients were enrolled into this study. Of these, 163 patients had complete platelet aggregation data, both at baseline and at 4 hours after dosing for at least one visit.

ADP-Induced Platelet Aggregation
With respect to ADP-induced platelet aggregation, there was a statistically significant (P<.001) dose response with lower levels of aggregation seen at higher xemilofiban doses (Table 2). Platelet studies from patients who did not receive antecedent abciximab are depicted in Fig 1. Baseline aggregation, an assessment of resting platelet responsiveness, correlated significantly with ADP-induced platelet aggregation. ADP-induced aggregation values were similar between visits (P=.46). The slope of the dose response did not differ among visits (P=.35) and was similar for patients with and without antecedent abciximab (P=.153). The analysis of dose responsexabciximabxvisit assessed xemilofiban dose response across visits in the context of gradually diminishing GPIIb/IIIa receptor occupancy by abciximab. Ticlopidine inhibition of ADP-induced platelet aggregation increased over time, with lower levels of aggregation (P=.041) at days 7 and 14.

View this table: [in this window] [in a new window]   Table 2. Results of Analysis of ADP-Induced Platelet Aggregation (Measured 4 Hours After Dosing)

View larger version (33K): [in this window] [in a new window]   Figure 1. Inhibition of platelet aggregation response to 20 µmol/L ADP stimulation by ticlopidine (placebo) and incremental (5, 10, 15, and 20 mg) doses of xemilofiban (A) after the initial dose of study drug (visit 1) and 1 week (visit 2) and (B) after 2 weeks of chronic oral therapy (visit 3). Patients depicted are those with complete data (136) of the 140 patients who did not receive antecedent abciximab therapy. Error bars indicate ±SEM.

Collagen-Induced Platelet Aggregation
With respect to collagen-induced platelet aggregation, there was a statistically significant (P=.014) dose response, with lower levels of aggregation seen at higher xemilofiban doses (Table 3). Platelet studies from patients who did not receive antecedent abciximab are depicted (Fig 2). Although collagen-induced aggregation values were lower at visit 1 than at other visits (P=.028), this effect was seen entirely among patients with antecedent abciximab treatment (P<.001). The steepness of the dose response did not vary between visits (P=.49) and was similar for patients with and without antecedent abciximab treatment (P=.12).

View this table: [in this window] [in a new window]   Table 3. Results of Analysis of Collagen-Induced Platelet Aggregation (Measured 4 Hours After Dosing)

View larger version (33K): [in this window] [in a new window]   Figure 2. Inhibition of platelet aggregation response to 4 µg/L collagen stimulation by ticlopidine (placebo) and incremental (5, 10, 15, and 20 mg) doses of xemilofiban (A) after the initial dose of study drug (visit 1) and at 1 week of chronic oral therapy (visit 2) and (B) after 2 weeks of chronic oral therapy (visit 3). Patients depicted are those with complete data (136) of the 140 patients who did not receive antecedent abciximab therapy. Error bars indicate ±SEM.

Clinical Outcomes
There were no episodes of severe life-threatening or moderate (requiring transfusion) hemorrhage, even in those patients who received sequential abciximab- xemilofiban GP IIb/IIIa receptor blockade. Three minor bleeding events prompting study drug discontinuation were observed, including 1 patient receiving xemilofiban placebo and ticlopidine who developed a groin hematoma, 1 patient receiving 10 mg xemilofiban (no antecedent abciximab) with epistaxis, and 1 patient receiving 15 mg xemilofiban (antecedent abciximab) with mild hemoptysis. There were no recurrent myocardial ischemic events in the 30 sequentially (abciximab-xemilofiban) treated patients. Subacute stent thrombosis occurred in 2 of the 140 patients (1.4%) not treated with abciximab. Stent thrombosis occurred 4 and 7 days after stent deployment. Both patients had unstable angina pectoris and were receiving 10 and 15 mg xemilofiban BID, respectively. One of these patients had inadvertently discontinued aspirin therapy at the time of hospital discharge. Three other patients had cardiac events prompting study drug discontinuation, which included a pulmonary embolus (placebo), cardiac failure (10 mg xemilofiban), and a small nonhemorrhagic stroke (10 mg xemilofiban). Four patients with protocol noncompliance and 2 patients with other adverse events were also discontinued, leaving 156 (92%) to complete the study.

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Xemilofiban, a new orally active platelet IIb/IIIa antagonist, was associated with a stepwise dose-response inhibition of ex vivo platelet aggregation in response to 20 µmol/L ADP and 4 µg/mL collagen when administered to patients after stent deployment. The dose-response platelet inhibitory effects of xemilofiban were maintained after 2 weeks of continuous oral therapy. Xemilofiban therapy was well tolerated, and no episodes of severe life-threatening or transfusion requiring hemorrhage were observed in this trial. Subacute stent thrombosis occurred in 2 of the 140 patients who did not receive abciximab at the time of stent deployment. This incidence appears similar to the incidence of ischemic events observed in recent series of patients receiving aspirin alone (2.8%)¹⁵ or ticlopidine and aspirin combined (1.6%)¹⁶ after "optimal" stent deployment. Several important points regarding this observation must be made. First, the present study was designed as a dose-ranging study, and significant (>50%) inhibition of platelet aggregation was observed only at the higher doses tested (10 to 20 mg). Second, the dosing interval used in the present study (BID) appears to be suboptimal to achieve sustained (>50%) platelet inhibition and allowed for recovery in platelet function to near-baseline levels between doses. Third, knowledge of platelet pharmacodynamics was available only in retrospect and was not used to guide therapy. This third consideration is of particular importance in light of recent data suggesting dynamic fluctuation in platelet surface expression of GP IIb/IIIa as a function of disease state activity.¹⁷ Platelet surface expression of GP IIb/IIIa receptors and the ability to inhibit platelet aggregation may be influenced by an internal "pool" of receptors.^{18 19}

These observations raise important issues relative to GP IIb/IIIa blockade by oral competitive antagonists. Because of interpatient and intrapatient variability in drug absorption and bioavailability, differences in steady state GP IIb/IIIa receptor expression, and dynamic fluctuation in receptor expression, "optimal" dosing of xemilofiban may require concurrent "on-line" pharmacodynamic testing.²⁰

Indeed, the optimal target for long-term therapy in terms of inhibition of platelet aggregation has yet to be determined and will reflect a balance between clinical efficacy in suppression of ischemic events and consequent risk of hemorrhage. The Antiplatelet Trialists Collaboration has provided compelling evidence that prolonged use of antiplatelet drugs results in a relative risk reduction for the occurrence of ischemic stroke, myocardial infarction, or vascular death.²¹ A significant reduction in these vascular ischemic events was observed after long-term administration of clopidogrel, a novel thienopyridine derivative chemically related to ticlopidine, compared with aspirin therapy alone in patients with vascular disease.²² Because clopidogrel affects ADP-dependent activation of the platelet GP IIb/IIIa complex, producing inhibition of ADP-induced platelet aggregation of similar magnitude with ticlopidine,^{23 24} the potential clearly exists for clinical benefit to accompany more generalized and pronounced GP IIb/IIIa inhibition as observed after xemilofiban therapy. In the present study, xemilofiban therapy in combination with aspirin was associated with much greater inhibition of platelet aggregation in response to agonists than ticlopodine in combination with aspirin (Figs 1 and 2).

In conclusion, this study provides data on the dose response and duration of platelet inhibition, from which dose regimens can be derived to target levels of platelet inhibition (<50%, 50% to 80%) for future longer-term trials. Although the duration of platelet inhibition after xemilofiban is between 8 and 10 hours, and thus suggests utility for every 8-hour dosing, pharmacodynamic data for such a regimen are not provided by this study. The clinical efficacy and safety of longer-term platelet inhibition by xemilofiban will require further study in a larger-scale randomized trial.

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Participating Sites
Christ Hospital/University of Cincinnati Medical Center (Ohio): Dean J. Kereiakes, MD/John Paul Runyon, MD, Principal Investigators; Nancy Higby, RN, Coordinator.

New England Deaconess Hospital, Boston, Mass: Michael T. Johnstone, MD, Principal Investigator; Carol McKenna, RN, Peggy McGowan-Gump, RN, Coordinators.

University of Florida/J.H. Miller Health Center (Gainesville): Richard A. Kerensky, MD, Principal Investigator; Elizabeth A. Franco, RN, Coordinator.

Baylor College of Medicine/Methodist Hospital, Houston, Tex: Neal S. Kleiman, MD, Principal Investigator; Dale Rose, RN, Kelly Maresh, RN, Coordinators.

University of South Florida Health Science Center (Tampa): Fadi A. Matar, MD, Principal Investigator; Paula D'Ambra, RN, Coordinator.

Scripps Clinic and Research Foundation, La Jolla, Calif: Paul S. Teirstein, MD, Principal Investigator; Francesca Markel, RN, Coordinator.

St Luke's Episcopal Hospital, Houston, Tex: James J. Ferguson, MD, Principal Investigator; Mary Harlan, RN, Coordinator.

Millard Fillmore Hospital, Buffalo, NY: A.R. Zaki Masud, MD, Principal Investigator; Theresa Giambra, RN, Coordinator.

Sinai Samaritan Medical Center, Milwaukee Heart Institute (Wisc): Yoseph Shalev, MD, Principal Investigator; Ann Wendorf, RN, Coordinator.

Duke University Medical Center, Durham, NC: James P. Zidar, MD, Principal Investigator; Michelle Rund, RN, Coordinator.

	Footnotes

 
Guest editor is Barry S. Coller, MD, Mount Sinai Medical Center, New York, NY.

¹ Contributing centers and investigators are listed in "Appendix."

Received December 9, 1996; revision received March 10, 1997; accepted March 23, 1997.

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