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(Circulation. 1998;98:1268-1278.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

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

Dean J. Kereiakes, MD; Neal S. Kleiman, MD; James J. Ferguson, MD; A. R. Zaki Masud, MD; Thomas M. Broderick, MD; Charles W. Abbottsmith, MD; John Paul Runyon, MD; Linda C. Anderson, RN, BSN; Robert J. Anders, PharmD; Roger J. Dreiling, MD; Gary L. Hantsbarger, MS; Brian Bryzinski, MD; Eric J. Topol, MD; ; for the Oral Glycoprotein IIb/IIIa Receptor Blockade to Inhibit Thrombosis (ORBIT) Trial Investigators

From the Carl and Edyth Lindner Center for Clinical Cardiovascular Research, Health Alliance of Greater Cincinnati (D.J.K, L.C.A.), Cincinnati, Ohio; Department of Cardiology and Internal Medicine (D.J.K., J.P.R.), University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Cardiology (N.S.K), Baylor University College of Medicine, Houston, Tex; St Luke's Episcopal Hospital (J.J.F), Texas Heart Institute, University of Texas Health Sciences Center, Dallas, Tex; Millard Fillmore Hospital (A.R.Z.M.), Buffalo, NY; Ohio Heart Health Center (D.J.K., T.M.B., C.W.A. J.P.R), Cincinnati, Ohio; G.D. Searle & Co (R.J.A., R.J.D., G.L.H., B.B.), Skokie, Ill; and Department of Cardiology, Cleveland Clinic Foundation (E.J.T), Cleveland, Ohio.

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. E-mail lindner{at}healthall.com

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
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 µmol/L ADP and 4 µg/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.

Key Words: glycoproteins • xemilofiban • receptors • platelets • thrombosis

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Parenteral platelet glycoprotein (GP) IIb/IIIa receptor antagonists have shown benefit in reducing ischemic complications after percutaneous coronary intervention and in the treatment of unstable angina pectoris.^{1 2 3 4 5} Except for abciximab, these agents have short duration of action. Thus, early clinical benefits observed after 24- to 72-hour intravenous infusions in hospital have not consistently been maintained in short-term (30-day) follow-up. This observation suggests the need for longer inhibition of platelet aggregation than can be achieved by parenteral therapy alone. In this context, less potent oral antiplatelet agents such as aspirin,⁶ ticlopidine,⁷ and clopidogrel⁸ are efficacious in long-term secondary suppression of vascular ischemic events.

The GP IIb/IIIa receptor is the final common pathway for platelet aggregation.⁹ Orally active antagonists to this receptor offer the potential for sustained platelet inhibition and enhanced long-term suppression of vascular ischemic events. Preliminary experience with oral GP IIb/IIIa blocking drugs has demonstrated dose-dependent inhibition of platelet aggregation.^{10 11 12} In prior studies, xemilofiban, a nonpeptide GP IIb/IIIa receptor antagonist, provided platelet inhibition for 8 to 10 hours after a single oral dose^{10 12} that was sustained during 2 weeks of oral therapy in patients after coronary stent deployment.¹⁰ The efficacy and clinical safety of this agent with more prolonged administration have not been reported. The Oral Glycoprotein IIb/IIIa Receptor Blockade to Inhibit Thrombosis (ORBIT) trial compared the pharmacodynamic response of 2 dose levels of xemilofiban with placebo on inhibition of platelet aggregation. Secondary objectives were to evaluate (1) the pharmacokinetic profile of xemilofiban after 2 and 4 weeks of therapy; (2) the safety profile of xemilofiban administered for 1 month after coronary intervention; and (3) the incidence of clinical cardiovascular events, including death, myocardial infarction, urgent coronary revascularization (surgery or angioplasty), and nonhemorrhagic stroke in follow-up at 3 months after randomization.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Study Population
From August 15, 1996, through December 26, 1996, 549 patients were enrolled at 31 clinical sites (see the "Appendix"). Inclusion criteria for the trial were age of 21 to 80 years, stable or unstable angina, recent myocardial infarction (>24 hours before enrollment), target lesion stenosis of 70% severity, and successful completion of percutaneous coronary revascularization with a Food and Drug Administration–approved device.

Patients were excluded from the trial for reasons identical to those previously delineated for the pilot trial.¹⁰ This study was approved by the institutional review board of each institution, and informed consent was obtained from each patient.

Study Protocol
Patients were randomized to 1 of 3 treatment groups: placebo, xemilofiban 15 mg, or xemilofiban 20 mg. Study medication was administered 3 times daily for 2 weeks and then 2 times daily for 2 weeks. All patients were followed clinically for 3 months.

A stratification procedure was used that was based on the type of revascularization procedure performed. Patients undergoing balloon angioplasty received double-blind study medication (Figure 1). Patients undergoing stent deployment had study medication administered in single-blind fashion to accommodate therapy with ticlopidine 250 mg orally twice daily for 4 weeks in individuals randomized to receive placebo (Figure 2). Concomitant administration of xemilofiban and ticlopidine was not permitted. All patients received oral aspirin 325 mg/d.

View larger version (21K): [in this window] [in a new window]   Figure 1. Study schematic for patients undergoing percutaneous coronary revascularization (PCR) without stent deployment without (A) or with (B) abciximab administration during the interventional procedure. ASA indicates acetylsalicylic acid.

View larger version (23K): [in this window] [in a new window]   Figure 2. Study schematic for patients undergoing percutaneous coronary revascularization (PCR) and stent deployment without (A) or with (B) abciximab during the interventional procedure. Patients randomized to placebo also received ticlopidine 250 mg orally BID for 1 month. ASA indicates acetylsalicylic acid.

On the basis of prior pilot studies,^{10 11} dosing with xemilofiban 3 times daily was anticipated to maintain 50% to 80% inhibition of ADP-induced platelet aggregation throughout 24 hours. We hypothesized that after 2 weeks of long-term therapy, twice-daily dosing may suffice in providing adequate platelet inhibition to prevent recurrent cardiac events.

Treatment arms were further stratified to accommodate abciximab administration at the discretion of the investigator during the interventional procedure. A blinded dosing strategy (Figures 1B and 2B) of xemilofiban was available to accommodate procedural abciximab administration with either xemilofiban or placebo therapy initiated at least 8 hours after discontinuation of abciximab. Abciximab-treated patients received a reduced dose of xemilofiban (10 mg TID) for 2 weeks because of the previously described potentiated dose response to xemilofiban when administered in close temporal sequence with abciximab therapy.¹³ After 2 weeks of a reduced xemilofiban dosing, these patients received either 15 or 20 mg xemilofiban administered twice daily for 2 more weeks as determined by the original randomization. In patients who did not receive abciximab during the interventional procedure (Figures 1A and 2A), study drug was initiated 30 minutes after completion of the procedure, provided that the activated clotting time was <175 seconds. Study drug was administered for 4 weeks, and all patients were followed for 3 months.

The prespecified end points used in analysis of clinical cardiac events included death, myocardial infarction, urgent revascularization (surgery or angioplasty), and nonhemorrhagic stroke. The diagnosis of myocardial infarction required chest pain attributable to myocardial ischemia 30 minutes in duration that was unresponsive to nitroglycerin and was associated with ST-segment elevation (0.1 mV) or new Q waves (0.04 second) in 2 contiguous ECG leads. The enzymatic criterion required before hospital discharge was either creatine kinase (CK)-MB or total CK 3 times the upper limit of normal; after hospital discharge, the criteria were any CK-MB elevated above normal and 3% of total CK or total CK 2 times the upper limit of normal if CK-MB was not available. Recurrent hospitalization for unstable angina pectoris or myocardial ischemia required a total CK <2 times normal and new ECG ST-T–wave abnormalities.

Bleeding events were independently adjudicated by the Data and Safety Monitoring Board and were classified as (1) severe or life threatening if intracranial hemorrhage or bleeding was associated with hemodynamic compromise, (2) moderate if they required transfusion but were without hemodynamic compromise, (3) mild if they did not require transfusion; and (4) insignificant if they did not require medical evaluation or treatment.

Blood transfusion was performed according to treatment guidelines of the American College of Physicians.¹⁴ Patients could be discontinued from the study for thrombocytopenia (<100 000 per 1 mm³), for development of a clinically significant adverse event requiring medical attention, or because of investigator judgment or patient decision. Early in the course of the trial, several patients were discontinued for profound (95%) inhibition of platelet aggregation in response to 20 µmol/ADP measured 8 hours after study drug administration even in the absence of clinical bleeding. A subsequent protocol amendment changed the criteria for study withdrawal to include both profound platelet inhibition (95% for 8 hours after dosing) and the presence of a mild, moderate, or severe bleeding event.

Interventional Procedure
Intravenous heparin was administered during the interventional procedure to achieve an activated clotting time 300 seconds for patients not receiving abciximab and 200 seconds in abciximab-treated patients. Vascular access sheaths were removed when the activated clotting time was 175 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 for stent procedures.

Platelet Studies
Platelet function studies were obtained in 230 patients enrolled at 12 participating centers. Ex vivo platelet aggregation response to both 20 µmol ADP and 4 µg/mL collagen was assessed immediately before; at 2, 4, 8, and 12 hours after the first dose of study drug; and again at 14 (before and 2 and 4 hours after dosing) and 28 (before and 2, 4, 8, and 12 hours after dosing) days of therapy. Platelet aggregation studies were performed as previously described.¹⁰

Statistical Analysis
Peak response (4 hours after dosing) inhibition of platelet aggregation was compared between treatment groups and between abciximab and nonabciximab patients at each visit by use of an ANOVA model with factors for xemilofiban dose group, previous abciximab use, and xemilofiban-by-abciximab interaction. The concentration response for platelet aggregation to xemilofiban was compared between abciximab and nonabciximab patients at each visit by use of regression analysis. Factors in the regression model were xemilofiban concentration, prior abciximab treatment (yes, no), and subject effects. In both models, platelet aggregation values were logit transformed to linearize dose response. Values <1% and >99% were set to 1% and 99% for analysis.

Cumulative rates of cardiovascular end-point events were calculated by the product-limit method. Treatments were compared within prospectively defined randomization strata with respect to event rates by use of the log rank test.

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Patient Population
Baseline characteristics of the 549 randomized patients are shown in Table 1. There were no differences in demographic characteristics between the 3 treatment groups. Abciximab was administered in 29% and stent deployment performed in 50% of the interventional procedures.

View this table: [in this window] [in a new window]   Table 1. Demographics and Procedural Data for All Randomized Patients

Pharmacokinetics
Plasma concentrations of SC-54701, the active form of xemilofiban, by dose are shown in Figure 3 after a single dose (visit 1) and after 4 weeks of therapy (visit 3). The time to peak plasma concentration was 4 hours after the first dose and 2 hours after steady-state dosing. A dose-related increase in peak plasma concentration and respective Cmax values of 13.96±9.4, 17.71±10.6, and 22.7±15.6 ng/mL (mean±SD) were observed after initial doses of 10, 15, and 20 mg. After 4 weeks of therapy, the peak plasma concentrations were 27.6±18.5 and 37.4±17.6 ng/mL for the 15- and 20-mg dose groups, respectively. Plasma concentrations were estimated to return to predose levels by 10 hours after dosing with a drug half-life approximating 4 hours. A correlation between the level of inhibition of ADP-induced platelet aggregation and plasma concentration was observed (Figure 4A, 4B, and 4C). Mean plasma concentrations of 10 and 18 ng/mL provided 50% and 80% inhibition of 20 µmol/L ADP-induced platelet aggregation after the first dose of xemilofiban. The plasma concentration of xemilofiban that provided 80% inhibition to 20 µmol/L ADP during steady-state dosing at 14 and 28 days was 24 mg/mL.

View larger version (19K): [in this window] [in a new window]   Figure 3. SC-54701 mean plasma concentration (ng/mL) by dose and time after initial dose of study drug (visit 1) and after 4 weeks of long-term oral therapy (visit 3) for all randomized patients. Data shown represent mean±SEM.

View larger version (21K): [in this window] [in a new window]   Figure 4. Relationship of platelet aggregation (%) induced by 20 mmol ADP and SC-54701 plasma concentration (ng/mL) for all randomized patients after first dose of study drug (A) and at 2 (B) and 4 (C) weeks of long-term oral therapy.

Pharmacodynamics
Dose-dependent inhibition of platelet aggregation in response to both ADP and collagen was observed after incremental doses of xemilofiban (Figures 5A and 6A). An effect of antecedent abciximab on xemilofiban-induced inhibition of both ADP- and collagen-induced platelet aggregation was observed (Figures 5B and 6B) as described previously and was no longer evident 2 weeks after abciximab therapy.¹³ Peak inhibition of platelet aggregation after a 10-mg dose of xemilofiban in abciximab-treated patients on day 1 exceeded the peak platelet inhibition after 15- or 20-mg doses of xemilofiban in patients who had not previously received abciximab (P<0.001). In patients not receiving abciximab during the interventional procedure, the peak response for each dose of xemilofiban and the concentration-response relationship were similar at 2 and 4 weeks of long-term oral therapy. Peak (4 hours after dosing) and trough (predose) levels of platelet aggregation and inhibition for both 20 µmol ADP and 4 µg/mL collagen on days 1, 14, and 28 are shown in Table 2.

View larger version (24K): [in this window] [in a new window]   Figure 5. Inhibition of platelet aggregation in response to 20 µmol/L ADP before (Pre) and 6 and 12 hours after the first dose of study drug (day 1) and at 14 and 28 days of long-term oral therapy for patients without (A) or with (B) antecedent abciximab therapy at the time of the interventional procedure. Data represent mean±SEM.

View larger version (24K): [in this window] [in a new window]   Figure 6. Platelet aggregation in response to 4 µg/mL collagen before (Pre) and 6 and 12 hours after the first dose of study drug (day 1) and after 14 and 28 days of long-term oral therapy for patients without (A) and with (B) antecedent abciximab therapy at the time of the interventional procedure.

View this table: [in this window] [in a new window]   Table 2. Peak and Trough Levels of Absolute Platelet Aggregation and Platelet Inhibition

Bleeding Events and Blood Transfusion
No intracranial hemorrhages occurred during the trial. One retroperitoneal (0.2%) hemorrhage was observed in a patient randomized to placebo who received abciximab during the interventional procedure. The occurrence of vascular access, gastrointestinal, and genitourinary bleeding was uncommon and was not related to dose of study drug or procedural abciximab therapy (Table 3). The most common site of bleeding, epistaxis, occurred more frequently in patients receiving 20 mg xemilofiban and was usually mild, not requiring discontinuation of study drug. Figure 7A and 7B shows the relationship between ADP- and collagen-induced platelet aggregation measured 4 hours after dosing (peak drug effect) on day 1 and the occurrence of bleeding events by treatment strategy. No statistically significant relationship between these parameters and the occurrence of moderate or severe bleeding was observed. A correlation between insignificant and mild bleeding and higher levels of xemilofiban-induced inhibition (P=0.02) was present. The relationship of bleeding events to plasma metabolite concentration is shown in Figure 7C.

View this table: [in this window] [in a new window]   Table 3. Bleeding Events and Blood Transfusion by Drug Treatment Allocation

View larger version (20K): [in this window] [in a new window]   Figure 7. Relationship between platelet aggregation measured 4 hours after study drug administration on day 1 in response to 20 µmol/L ADP (A) or 4 µg/mL collagen (B) and the occurrence and severity of bleeding events during the study by treatment strategy. Also shown is the relationship of corresponding plasma metabolite concentration (C) to bleeding events. Insig indicates insignificant; Mod, moderate, Sev, severe; and Conc, concentration.

The use of packed red blood cell transfusion was infrequent in either placebo- (1.7%) or xemilofiban- (1.8%) treated patients. A xemilofiban dose–related increase for insignificant and mild bleeding events, most of which occurred within 2 weeks of randomization, was observed (Table 4). The overall incidence of moderate (3.4% placebo; 1.3% xemilofiban) and severe (0% placebo; 1.1% xemilofiban) bleeding events was low.

View this table: [in this window] [in a new window]   Table 4. Incidence and Severity of Bleeding Events at 2 and 4 Weeks of Study Drug Therapy by Treatment Allocation

Thrombocytopenia (<100 000 per 1 mm³) was observed in 2 patients (0.5%) receiving xemilofiban on days 10 and 16 after randomization. These 2 patients had platelet counts of 62 000 and 8 000 per 1 mm³ and presented with a nonhemorrhagic stroke and epistaxis, respectively. The patient with epistaxis was also being treated with procainamide, and both patients had received abciximab during the interventional procedure. Platelet count returned to normal after discontinuation of xemilofiban therapy (486 000 per 1 mm³) in the patient with epistaxis, but the patient with a neurological deficit experienced a fatal pulmonary embolism shortly after hospital admission. Thrombocytopenia was not observed in any placebo-treated patient.

Study Withdrawal and Termination for Adverse Events
The incidence and reasons for withdrawal of patients terminating the study prematurely are shown in Table 5. Early in the trial, several patients were withdrawn on the basis of predefined platelet aggregation criteria for discontinuation in the absence of clinical bleeding. Discontinuation of study drug for bleeding events did not differ between xemilofiban- and placebo-treated patients. Protocol noncompliance occurred in 2% to 7% of patients by treatment regimen.

View this table: [in this window] [in a new window]   Table 5. Study Withdrawal by Pharmacological Treatment Regimen in All Randomized Patients

Cardiovascular Events
The incidence of death (all cause), myocardial infarction, nonhemorrhagic stroke, and urgent coronary revascularization (surgical or percutaneous) is shown for each treatment regimen in Table 6. After successful percutaneous intervention, the event rates in follow-up were low, particularly in patients randomized to receive xemilofiban 20 mg who did not receive abciximab during the interventional procedure. Composite cardiovascular event rates to 90 days by treatment regimen are shown in Figure 8. The distribution of cardiac events over time (Kaplan-Meier) by treatment allocation and abciximab therapy is shown in Figure 9A and 9B. In those patients who did not receive abciximab during intervention, more events were observed in placebo-treated patients after 60 days, resulting in a trend (P=0.04) favoring improved outcomes for the highest-dose (20 mg) xemilofiban therapy. This increased event rate was made up primarily of repeated coronary revascularization procedures. In patients who had received abciximab during intervention, an increase in cardiac events was observed in the group receiving xemilofiban 10 to 20 mg.

View this table: [in this window] [in a new window]   Table 6. Cardiovascular Event Rate at 90 Days by Pharmacological Treatment Strategy

View larger version (37K): [in this window] [in a new window]   Figure 8. Composite cardiovascular event rates to 90 days by treatment strategy. Patients were administered study drug for 28 days after randomization. Xemi indicates xemilofiban; Plac, placebo.

View larger version (29K): [in this window] [in a new window]   Figure 9. Distribution of cardiac events over time (to 90 days) by study drug treatment allocation for patients who did not receive procedural abciximab (A) and those who did receive abciximab during coronary intervention (B). *P=0.04 xemilofiban (Xemi) 20 mg vs placebo.

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
This randomized, placebo-controlled, blinded trial demonstrated that xemilofiban, in conjunction with aspirin, provides inhibition of platelet aggregation that is maintained over 4 weeks of therapy. Xemilofiban therapy initiated after percutaneous coronary intervention was well tolerated and did not increase serious bleeding events compared with placebo. Mild bleeding (particularly epistaxis) was observed more frequently in subjects receiving xemilofiban and correlated with the degree of platelet inhibition observed on day 1 (P=0.02). A trend toward reduction in cardiovascular events at 3 months was observed in patients who did not receive abciximab during coronary intervention and who were subsequently treated with xemilofiban compared with placebo.

This study provides data on therapy with an oral GP IIb/IIIa inhibitor superimposed on contemporary percutaneous revascularization techniques, including the concomitant administration of abciximab and aspirin. The importance of this fact lies not only in the proven benefit of aspirin for the treatment of atherosclerotic cardiovascular disease and for use after coronary intervention^{6 7} but also in the potential for enhanced platelet inhibition when aspirin and an orally active GP IIb/IIIa inhibitor are combined. Enhanced inhibition of both ADP- and collagen-induced platelet aggregation has been demonstrated for aspirin in combination with both xemilofiban (Searle study NG7-96-ST-045) and orbofiban,¹⁵ another longer-acting, orally active GP IIb/IIIa inhibitor. A more prolonged bleeding time was observed in patients who received this combination.^{15 16} Thus, the combination of an oral GP IIb/IIIa antagonist with aspirin may have implications for both the safety and efficacy of oral IIb/IIIa therapy. Prior studies have not provided data on concomitant therapy with aspirin.^{8 12} Similarly, an enhanced dose response for platelet inhibition to xemilofiban after abciximab therapy has been described.¹³ The greater efficacy of abciximab when given in conjunction with low-dose, weight-adjusted heparin¹ may increase the use of abciximab and thus the likelihood that an oral agent such as xemilofiban may be used chronically after procedural abciximab therapy. This study provides insight into both the safety and effectiveness of sequential dosing with an intravenous and an orally active agent.

Pharmacokinetics and Pharmacodynamics
A correlation was observed between plasma levels of xemilofiban and the degree of platelet inhibition. Although no correlation was demonstrated between either plasma levels or peak platelet inhibition and the occurrence of moderate or severe bleeding events in this study, a correlation (P=0.02) was observed between the subsequent occurrence of insignificant or mild bleeding and inhibition of platelet aggregation on day 1. This observation is concordant with the recent clinical experience with sibrafiban, another orally active peptidomimetic platelet GP IIb/IIIa antagonist.¹² The short half-life of xemilofiban (4 hours), coupled with a twice-daily dosing regimen used during the last 2 weeks of the protocol, allowed complete recovery in platelet function between doses. Although the peak level of platelet inhibition after xemilofiban was maintained during long-term therapy, intermittent recovery in platelet function may have conferred tolerability. Serious or major bleeding appears rare with either xemilofiban or sibrafiban.¹²

Clinical Events
Although this study was not powered to definitively evaluate differences in clinical outcomes between treatment groups, a trend with xemilofiban dose (20 mg) for a reduction of cardiovascular events at 3 months' follow-up in patients not receiving procedural abciximab was observed. The reduction in events occurred in subjects not treated with abciximab during the interventional procedure. In this respect, 2 points deserve mention. First, although the pharmacodynamic response to xemilofiban is altered immediately after abciximab therapy as noted previously, the late clinical response to xemilofiban in abciximab-treated patients was not studied in a randomized manner. The declining state of platelet receptor occupancy over weeks after abciximab therapy may have potential long-term ramifications for sequencing abciximab with orally active GP IIb/IIIa receptor inhibitors. Second, the potential for short-term (30 day) coronary vessel wall and platelet passivation with an oral GP IIb/IIIa inhibitor to confer late (3-month) clinical benefit after coronary intervention is suggested. This observation may parallel that of the recent PARAGON trial¹⁶ in which patients with unstable angina or non–Q-wave myocardial infarction received lamifiban or placebo intravenously for 72 hours and clinical outcomes were assessed at 1 and 6 months after treatment. Although no clinical benefit was observed at 30 days after lamifiban therapy,^{16 17} a significant reduction in late (6-month) cardiovascular events was observed in lamifiban-treated patients.¹⁷ Similarly, the timing of clinical events in the placebo group of the present study (occurring 60 days after randomization) resulted in a trend for clinical benefit after xemilofiban therapy that was evident only at 3 months' follow-up.

Questions Remaining for Oral Platelet GP IIb/IIIa Therapy
The present study provides new data on the safety, pharmacodynamic effects, and clinical efficacy of xemilofiban. The optimal level of platelet inhibition required to achieve clinical benefit still requires definition. Available data suggest that if inhibition of platelet aggregation by 50% to 80% (20 µmol ADP) is maintained for long periods of time, the occurrence of mild to moderate mucocutaneous hemorrhage may be frequent.^{11 12} The optimal duration (how many hours of the day) of platelet inhibition has not been determined. Can recovery in platelet function between doses of a shorter-acting agent enhance safety and tolerance yet still confer clinical benefit for suppression of vascular ischemic events? Can shorter-term (1- to 3-month) vascular passivation confer longer-term clinical benefit, or will lifetime therapy be required? What benefit will concomitant therapy with aspirin add to GP IIb/IIIa blockade?

Study Limitations
Although the dosing regimens for xemilofiban in the current trial were somewhat complex (Figures 1 and 2), every effort was made to accommodate current clinical practice and to evaluate safety and tolerability of xemilofiban in that context. Because a reduced dose of xemilofiban was administered for 2 weeks to abciximab-treated patients, the trends in clinical outcomes observed at 3 months could be explained in part by reduced xemilofiban dosing, antecedent abciximab therapy, or a "higher risk profile" in patients treated with abciximab.

Conclusions
Xemilofiban inhibited platelet aggregation when administered for 1 month after coronary intervention. Despite 50% to 80% inhibition of platelet aggregation (20 µmol ADP), xemilofiban therapy was well tolerated. Most bleeding events were insignificant or mild in severity and did not result in termination of study drug. Although this trial was not designed to provide conclusive data on clinical outcomes, a trend for reduction in cardiovascular events was observed in those patients not treated with abciximab at the time of coronary intervention who were randomized to receive xemilofiban (20 mg) compared with placebo. This observation awaits confirmation in the larger-scale phase III study of xemilofiban currently in progress.

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Participating Sites and Principal Investigators
The Lindner Center, Cincinnati, Ohio: Dean J. Kereiakes. UFHSCI/Division of Cardiology, Jacksonville, Fla: Theodore Bass. Watson Clinic LLP, Lakeland Fla: Kevin Browne. Jacksonville Cardiovascular Clinic, Jacksonville, Fla: Henry Chen. Northwestern Memorial Hospital, Chicago, Ill: Charles Davidson. Texas Heart Institute, Texas Medical Center, Houston, Tex: James Ferguson. Midwest Cardiovascular Research Foundation, Columbus, Ohio: Barry S. George. Midatlantic Cardiovascular Associates, Baltimore, Md: Sidney Gottlieb. St Joseph Mercy Oakland Research, Pontiac, Mich: James A. Heinsimer. University of Pennsylvania Medical Center, Philadelphia, Pa: Howard Herrmann. Dartmouth Hitchcock Medical Center, Lebanon, NH: Bruce Hettleman. McGuire VA Medical Center, Richmond, Va: Robert Jesse. University of Florida, Cardiology, Gainesville, Fla: Richard Kerensky. Methodist Hospital, Baylor College of Medicine, Houston, Tex: Neal Kleiman. Deaconess Medical Center, Spokane, Wash: Pierre Leimgruber. Buffalo Heart Group, Buffalo, NY: Zaki Masud. Harbourside Medical Tower, Tampa, Fla: Fadi Matar. Cooper Hospital UMC, Camden, NJ: William Matthai. Orange County Research Center, Orange, Calif: Joel Neutel. Duke University, Durham, NC: Robert Harrington. Mid Carolina Cardiology, Charlotte, NC: Bernard Reen. Heart Institute of St Petersburg, St Petersburg, Fla: Andrew Rosenthal. Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill: Gary Schaer. Heart & Vascular Institute of Texas, San Antonio, Tex: John Seaworth. New Mexico Heart Clinic, Albuquerque, NM: Neal Shadoff. Milwaukee Heart Institute, Milwaukee, Wis: Yoseph Shalev. The Cleveland Clinic Foundation, Cleveland, Ohio: Conrad Simpfendorfer. University of Arkansas for Medical Sciences, Little Rock, Ark: David Talley. Central Florida Cardiology Group, PA, Orlando, Fla: Andrew Taussig. Scripps Clinic, La Jolla, Calif: Paul Teirstein. Lancaster Heart Foundation, Lancaster, Pa: Seth Worley. Cardiac Laboratory Hartford Hospital, Hartford, Conn: Michael Azrin.

	Footnotes

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

Guest editor for this article was Eugene Braunwald, MD, Partners HealthCare Systems, Inc, Boston, Mass.

Received January 13, 1998; revision received May 11, 1998; accepted May 29, 1998.

	References

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
1. The EPILOG investigators. Platelet glycoprotein IIb/IIIa receptor blockade in low-dose heparin during percutaneous coronary revascularization. N Engl J Med. 1997;336:1689–1696.[Abstract/Free Full Text]

2. Tcheng JE, Harrington RA, Kottke-Marchant K, Kleiman NS, Ellis SG, Kereiakes DJ, Mick MJ, Navettafi FI, Smith JE, Worley SJ, Miller JA, Joseph DM, Sigmon KN, Kitt MM, du Mee CP, Califf RM, Topol EJ. Multicenter, randomized, double-blind placebo controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker integrilin in elective coronary intervention. Circulation. 1995;91:2151–2157.[Abstract/Free Full Text]

3. Schulman SP, Goldschmidt-Clermont PJ, Topol EJ, Califf RM, Navetta FI, Willerson JT, Chandra NC, Guerci AD, Ferguson JJ, Harrington RA, Lincoff AM, Yakubov SJ, Bray PF, Bahr RD, Wolfe CL, Yak PG, Anderson HV, Nygaard TW, Mason SJ, Effron MB, Fatterpacker A, Raskin S, Smith J, Brashears L, Gottdiener P, du Mee CP, Kitt MM, Gerstenblith G. Effects of integrilin, a platelet glycoprotein IIb/IIIa antagonist in unstable angina: a randomized multicenter trial. Circulation. 1996;94:2083–2089.[Abstract/Free Full Text]

4. The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing angioplasty. Circulation. 1997;96:1445–1453.[Abstract/Free Full Text]

5. White HD. Platelet Receptor Inhibition for Ischemic Syndrome Management (PRISM): results from late breaking clinical trials sessions at ACC '97. J Am Coll Cardiol. 1997;30:1–7.

6. Antiplatelet Trialist Collaboration. Collaborative overview of randomized trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:81–106.[Abstract/Free Full Text]

7. Gent M. A systematic overview of randomized trials of antiplatelet agents for the prevention of stroke, myocardial infarction and vascular death. In: Hass WK, Easton JD, eds. Ticlopidine, Platelets and Vascular Disease. New York, NY: Springer Verlag; 1993;99–116.

8. CAPRIE Steering Committee. A randomized, blinded, trial of Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE). Lancet. 1996;348:1329–1339.[Medline] [Order article via Infotrieve]

9. Phillips DR, Charro IF, Parise LV, Fitzgerald IA. The platelet membrane glycoprotein IIb/IIIa complex. Blood. 1988;71:831–843.[Free Full Text]

10. Kereiakes DJ, Kleiman N, Ferguson JJ, Runyon JP, Broderick TM, Higby NA, Martin LH, Hantsbarger G, McDonald S, Anders RJ. Sustained platelet glycoprotein IIb/IIIa blockade with oral xemilofiban in 170 patients following coronary stent deployment. Circulation. 1997;96:1117–1121.[Abstract/Free Full Text]

11. Simpfendorfer C, Kottke-Marchant K, Lowrie M, Anders RJ, Burns DM, Miller DP, Cove CS, DeFranco AC, Ellis SG, Moliterno DJ, Raymond RE, Sutton JM, Topol EJ. First chronic platelet glycoprotein IIb/IIIa integrin blockade: a randomized, placebo-controlled pilot study of xemilofiban in unstable angina with percutaneous coronary interventions. Circulation. 1997;96:76–81.[Abstract/Free Full Text]

12. Cannon CP, McCabe CH, Borzak S, Henry TD, Tischler MD, Mueller HS, Feldman R, Palmeri ST, Ault K, Hamilton SA, Rothman JM, Novotny WF, Braunwald E, for the TIMI 12 investigators. A randomized trial of an oral glycoprotein IIb/IIIa antagonist, sibrafiban, in patients post and acute coronary syndrome: results of the TIMI 12 trial. Circulation. 1998;97:340–349.[Abstract/Free Full Text]

13. Kereiakes DJ, Runyon JP, Kleiman NS, Higby NA, Anderson LC, Hantsbarger G, McDonald S, Anders RJ. Differential dose response to oral xemilofiban after antecedent intravenous abciximab administration for complex coronary intervention. Circulation. 1996;94:906–910.[Abstract/Free Full Text]

14. Practice strategies for elective red blood cell transfusion. Ann Intern Med. 1992;116:403–406.

15. Oliver S, Karim A, Burns DM, Anders RJ. Effect of aspirin on Orbofiban tolerability and pharmacodynamics. Abstracts; XIII World Congress of Cardiology, Rio de Janeiro, Brazil, April 26–30, 1998.

16. PARAGON Investigators. A randomized trial of potent platelet IIb/IIIa antagonism, heparin or both in patients with unstable angina: the PARAGON Study. Circulation. 1996;94(suppl I):I-553. Abstract.

17. Harrington RA, Moliterno DJ, van de Werf K, Keech A, Kleiman N, Bhapkar M. Rames A, Peek M, Topol EJ, Califf RM, Armstrong PW. Delaying and preventing ischemic events in patients with acute coronary syndromes using the platelet glycoprotein IIb/IIIa inhibitor lamifiban. J Am Coll Cardiol. 1997;29:409A. Abstract.

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