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(Circulation. 1997;96:76-81.)
© 1997 American Heart Association, Inc.

Articles

First Chronic Platelet Glycoprotein IIb/IIIa Integrin Blockade

A Randomized, Placebo-Controlled Pilot Study of Xemilofiban in Unstable Angina With Percutaneous Coronary Interventions

Conrad Simpfendorfer, MD; Kandice Kottke-Marchant, MD, PhD; Marsha Lowrie, RN; Robert J. Anders, Pharm D; Daniel M. Burns; Dave P. Miller, MS; Christopher S. Cove, MD; Anthony C. DeFranco, MD; Stephen G. Ellis, MD; David J. Moliterno, MD; Russell E. Raymond, DO; Joseph M. Sutton, MD; ; Eric J. Topol, MD

From The Department of Cardiology, Cell Biology (K.K.-M.), and Biostatistics and Epidemiology (D.P.M.), The Cleveland Clinic Foundation, Cleveland, Ohio, and GD Searle & Co (R.J.A., D.M.B.), Skokie, Ill.

Correspondence to Conrad Simpfendorfer, MD, Department of Cardiology, Desk F25, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195.

	Abstract

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Background Clinical studies have demonstrated the efficacy of intravenous administration of agents that block platelet glycoprotein IIb/IIIa receptors in the setting of percutaneous coronary revascularization. Although the optimal duration of treatment has not been determined, more prolonged receptor blockade has been associated with increased efficacy. Orally active glycoprotein IIb/IIIa receptor antagonists may be advantageous and required for chronic therapy.

Methods and Results Thirty patients with unstable angina who were undergoing percutaneous coronary interventions were randomized to placebo or Xemilofiban 35 mg orally before and 20 to 25 mg TID for 30 days after angioplasty. Bleeding events, platelet aggregation, and pharmacokinetic and hematologic parameters were assessed during hospitalization and at 2 and 4 weeks after drug initiation. Xemilofiban produced a rapid, sustained, marked inhibition of platelet aggregation. ADP-induced platelet aggregation at 2 hours after the initial dose at 2 and 4 weeks was 15%, 8%, and 11% in the Xemilofiban group compared with 80%, 68%, and 69% in the placebo group. Among 20 patients randomized to Xemilofiban there was 1 death after emergency coronary bypass surgery complicated by severe bleeding diathesis, and 3 patients had major bleeding events. Patients on Xemilofiban for 30 days reported episodes of mild mucocutaneous bleeding.

Conclusions Xemilofiban, an orally active glycoprotein IIb/IIIa receptor inhibitor, produced rapid, sustained, extensive inhibition of platelet aggregation for a period of up to 30 days. At the dose initially tested, however, acute major bleeding and mucocutaneous bleeding during chronic administration were encountered.

Key Words: glycoproteins • platelets • angina • revascularization • drugs • platelet aggregation inhibitors

	Introduction

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The currently accepted approach to prevent coronary arterial thrombosis during percutaneous coronary intervention is oral aspirin. While such therapy has been proven to prevent procedural ischemic complications,¹ it is known that aspirin is a relatively weak antiplatelet drug, inhibiting only thromboxane A₂–mediated platelet aggregation. More recently, the platelet glycoprotein IIb/IIIa receptor has been identified as the pivotal mediator of platelet aggregation, making it a logical target for control of the platelet response to vascular injury.^{2 3}

In the first large-scale trial, Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC), bolus administration of abciximab (c7E3) followed by a 12-hour infusion reduced the occurrence of acute ischemic events by 35% and by 6 months reduced the need for repeat target vessel revascularization by 26%. The group receiving the intravenous bolus without infusion had only a 10% reduction in early events and no reduction in target vessel revascularization.^{4 5} These observations and other clinical syndromes for which long-term antiplatelet therapy would be desirable have prompted the search for oral glycoprotein IIb/IIIa inhibitors.^{6 7}

This study was designed to assess the safety and pharmacokinetic and pharmacodynamic responses of long-term administration of Xemilofiban (Searle), an oral glycoprotein IIb/IIIa receptor antagonist, to patients with unstable angina undergoing percutaneous coronary interventions.

	Methods

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Patient Population
This was a randomized, single-center, single-blind, placebo-controlled pilot study. A total of 30 patients with unstable angina undergoing percutaneous coronary revascularization were entered into the study. Entry criteria included age 18 to 80 years and lesions categorized as ACC/AHA type B or C. Exclusion criteria included a known history of bleeding disorder, recent gastrointestinal bleeding, stroke within 2 years, major surgery within 6 weeks, severe hypertension, bleeding time >30 minutes, platelet count <150 000/µL, serum creatinine >2 mg/dL, and patients taking vitamin E or fish oil supplements. The protocol was approved by the Cleveland Clinic Foundation Institutional Review Board, and all patients provided informed consent.

Drug Therapy
Patients were randomized to receive 20 or 25 mg TID Xemilofiban or placebo for 30 days. One to 3 hours before the revascularization procedure, all patients received a loading dose of 35 mg of Xemilofiban or placebo. After the procedure, patients received study drug 4 to 6 hours after the loading dose and every 8 hours thereafter.

Aspirin was given to all patients before the coronary intervention and was continued at a dose of 160 mg daily. After vascular access was established, heparin was administered by Hemochron monitor as an initial bolus of 80 to 100 U/kg to achieve an initial activated clotting time (ACT) of 350 to 400 seconds. Sheaths were removed at the middose time period, provided the heparin infusion had been discontinued.

Platelet Function Studies
Blood samples were obtained before revascularization, 2 and 4 hours after the initial study drug loading dose, and 2 hours after the postrevascularization dose for platelet counts, platelet aggregation studies, and pharmacokinetics. At 2- and 4-week visits, blood samples were procured before the morning dose for platelet counts, platelet aggregation, and pharmacokinetic studies and 2 hours after a dose for platelet aggregation and pharmacokinetics.

Platelet Aggregation Tests
Blood was collected into tubes containing ethylene diamine tetra-acetic acid (EDTA) for platelet counts and into polypropylene tubes (Monovette, Sarstedt) containing 1 mL 3.8% sodium citrate for platelet aggregation studies. Platelet aggregation in platelet-rich-plasma (200 000 to 250 000/µL) was assessed in a Bio/Data PAP-4 optical aggregometer in response to 20 µmol/L ADP, 4 µg/mL collagen (Chronolog), and 20 µmol/L thrombin receptor–activating peptide (TRAP-14, Sigma), and 1.2 mg/mL ristocetin. Results are expressed as maximum percent aggregation, with the patient's own platelet-poor plasma as a reference of 100% aggregation.

Pharmacokinetic Measurements
A 7-mL blood sample was collected into a chilled vacutainer containing sodium heparin. Within 25 minutes, samples were centrifuged and the plasma was frozen at -70°C. Samples were used for measurement of Xemilofiban active molecule (SC-54701) concentrations in plasma by high-performance liquid chromatography, with a limit of detection of 1 ng/mL.

Safety and Efficacy End Points
The primary objective of the study was to evaluate the safety and tolerability of Xemilofiban 20 to 25 mg TID compared with placebo for a period of up to 1 month. The secondary objective was to evaluate the pharmacodynamic response (inhibition of platelet aggregation) and pharmacokinetics after 1 month of therapy.

Patients were seen for follow-up at 2 and 4 weeks for physical examination, careful recording of unusual or excessive bleeding, standard clinical laboratory determinations, and platelet aggregation studies. The severity of bleeding events was classified according to the Thrombolysis in Myocardial Infarction (TIMI) study group criteria.⁸ Major bleeding is defined as any intracranial hemorrhage or a drop in hemoglobin of >5 g/dL or hematocrit of >15%. Minor bleeding was defined as a drop in hemoglobin of 3 to 5 g/dL or hematocrit of 10% to 15% from the study entry until the time of lowest hemoglobin or hematocrit. In addition, any gross hematuria or hematemesis was categorized as minor bleeding. The study was discontinued for any major bleeding, the insertion of a coronary endovascular stent (because of required treatment with warfarin), or patient withdrawal from the protocol.

Statistical Analysis
The placebo and Xemilofiban groups were compared with the use of two-sample t tests. In instances in which the variance differed greatly between the two groups, the unequal variance formula was used. The variables analyzed did not differ greatly from the gaussian distribution; however, the general results were confirmed by use of the nonparametric Wilcoxon test, while the probability values reflect the t tests.

	Results

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Between December 1994 and May 1995, 30 patients were enrolled in the study. Initially, 25 patients were randomized to Xemilofiban 25 mg or placebo. Fifteen additional patients were to be randomized to Xemilofiban 20 mg. This last group was discontinued early by the sponsor as a result of the occurrence of severe bleeding events. Thus, 20 patients received Xemilofiban (16 patients received 25 mg TID and 4 received 20 mg TID) and 10 patients received placebo. Baseline patient characteristics and procedural variables are listed in Table 1.

View this table: [in this window] [in a new window]   Table 1. Clinical and Angiographic Characteristics

In-Hospital Events
Of the 20 patients randomized to Xemilofiban, 13 had no complications and were discharged on long-term drug therapy. Seven patients were withdrawn early from study because of bleeding complications (4), stent placement (2), and canceled procedure (1). Five subjects in the placebo group were withdrawn because of patient request (3), stent placement (1), and placement of intra-aortic balloon (1). There were 4 bleeding complications in the Xemilofiban group. Two patients developed puncture site bleeding that required transfusion. Both patients were receiving postprocedure heparin infusions.

It is important to note that 2 patients had severe bleeding complications. A 69-year-old man entered the study 10 days after a myocardial infarction. The patient had been receiving continuous intravenous heparin. Successful rotational atherectomy of the circumflex coronary artery was performed after a 35-mg dose of Xemilofiban 1 hour before the procedure. A second dose of Xemilofiban (25 mg) was administered 4 hours later. Ten hours after the initial dose, the patient developed severe hematemesis. Emergency endoscopy revealed active bleeding from gastric erosions and ulcerations. During a period of 43 hours, the patient was given 22 units of packed red blood cells, 11 units of fresh frozen plasma, and 5 units of pooled donor platelets. The nadir hematocrit was 21.3%, and the platelet count transiently decreased to 72 000/µL. The patient eventually recovered fully. Fig 1 depicts this patient's SC-54701 plasma concentrations and platelet aggregation values over time.

View larger version (22K): [in this window] [in a new window]   Figure 1. Plasma concentration of active compound (SC-54701) and ex vivo platelet aggregation to ADP, collagen, and thrombin receptor activating peptide (TRAP) after the administration of Xemilofiban 35 mg at time 0 followed by 25 mg 4 hours later.

A 59-year-old woman, an insulin-dependent diabetic, received a 35-mg loading dose of Xemilofiban before balloon angioplasty of the circumflex coronary artery. A second dose (20 mg) was administered 4 hours after the loading dose. The angioplasty procedure was complicated by a spiral dissection in the target vessel that could not be stabilized by intracoronary stenting. The procedure was further complicated by significant periaccess site bleeding and hypotension. After emergency bypass surgery, she continued to bleed profusely, requiring 54 units of packed red blood cells over a period of 5 days. Plasma drug levels collected throughout the hospitalization demonstrated sustained presence of the active drug with profound inhibition of platelet aggregation for up to 80 hours despite extensive transfusion of blood products (fresh frozen plasma, 13 U; platelets, 35 U; cryoprecipitate, 18 U). Platelet aggregation returned to normal coincident with the return of plasma concentration to subtherapeutic levels (Fig 2). The patient developed acute renal failure and was dialyzed on three occasions. Eventually she developed multiorgan failure and died 6 days after the initial procedure.

View larger version (21K): [in this window] [in a new window]   Figure 2. Plasma concentration of active compound (SC-54701) and ex vivo platelet aggregation to ADP and collagen after the administration of Xemilofiban 35 mg at time 0 followed by 20 mg 4 hours later in a patient with severe hemorrhagic complications.

Follow-up
Eighteen patients (13 Xemilofiban, 5 placebo) were followed to 30 days, and there were no coronary events. In the group of patients assigned to Xemilofiban, 1 patient refused to continue 8 days after intervention because of hemorrhoidal bleeding, and 1 patient with a history of colitis was withdrawn on day 21 because of bloody diarrhea. Nine of the 10 patients on Xemilofiban who completed 30-day follow-up described minor bleeding events such as epistaxis, gingival bleeding with tooth brushing, easy bruisability, and prolonged bleeding at the site of shaving or abrasions. Among these patients there were no episodes of major bleeding or blood transfusions.

Pharmacodynamic Studies
Compared with aspirin alone, Xemilofiban produced a significantly more profound inhibition of platelet aggregation to ADP (Fig 3), collagen, and TRAP (Table 2). The effect on ristocetin-induced aggregation with Xemilofiban and placebo was 56% versus 80% at 2 hours, 59% versus 78% at 4 hours, and 61% versus 71% at 6 hours, respectively (P=.265).

View larger version (19K): [in this window] [in a new window]   Figure 3. ADP 20 µmol/L induced ex vivo platelet aggregation in patients receiving Xemilofiban or placebo. Data are presented as mean±SD.

View this table: [in this window] [in a new window]   Table 2. Platelet Aggregation (%)

Although there was interpatient variability in the degree of inhibition of platelet aggregation, Xemilofiban provided 80% inhibition to ADP in 83% of patients at 2 hours, 85% at 4 hours, and 100% at 6 hours. During follow-up only 36% of patients had this level of inhibition before their morning dose (12 to 14 hours after evening dose) but recovered to 83% of patients 2 hours after the morning dose. Table 3 demonstrates the correlation between plasma concentrations of Xemilofiban and platelet aggregation. At any given time, patients with the highest plasma levels tended to have the least platelet aggregation.

View this table: [in this window] [in a new window]   Table 3. Correlation Between Plasma Concentrations of SC-54701 and Platelet Aggregation

Pharmacokinetic Studies
Plasma concentrations of the active moiety of Xemilofiban (SC-54701) are shown in Fig 4. The mean plasma concentration 2 hours after the initial dose was 67±45 ng/mL and peaked at 92±44 ng/mL 6 hours after the dose. At the predose sampling during the 2- and 4-week follow-up visits, 59% of patients may have had less than effective plasma concentrations (20 ng/mL).

View larger version (16K): [in this window] [in a new window]   Figure 4. Plasma concentration of Xemilofiban active moiety (SC-54701). Data are presented as mean±SD.

Hematological Parameters
Table 4 outlines changes in hemoglobin, hematocrit, and platelet counts in the two groups. The median decrease in hematocrit was 5.9% in the Xemilofiban group and 4% in the placebo group. Transient thrombocytopenia occurred only in the 2 patients with serious complications described previously (72 000/µL and 125 000/µL, respectively). No patient had thrombocytopenia during late follow-up.

View this table: [in this window] [in a new window]   Table 4. Hematologic Parameters

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Randomized, controlled trials have demonstrated that intravenous administration of agents that competitively inhibit the platelet glycoprotein IIb/IIIa receptors reduce the incidence of both early ischemic complications and clinical restenosis after percutaneous coronary revascularization.^{4 5 9} However, the optimal duration of drug administration to obtain blood vessel passivation, defined as the process that converts a platelet-reactive surface into a nonreactive surface, has not been determined.¹⁰ While intravenous glycoprotein IIb/IIIa antagonists might be effective in short-term situations, long-term receptor blockade can be practically achieved only with orally active agents.

Xemilofiban (SC-54684A), a prodrug of a nonpeptide mimetic of the tetra peptide RGDF, has been shown to be readily absorbed and metabolized to the active moiety SC-54701, a potent, specific inhibitor of the platelet glycoprotein IIb/IIIa. In previous studies in animals and healthy volunteers, this agent produced dose-dependent inhibition of platelet aggregation.^{11 12 13} This effect is enhanced when Xemilofiban is used in combination with aspirin or heparin.¹⁴

In the present study, Xemilofiban produced rapid, profound inhibition of platelet aggregation that correlated with plasma concentrations of the drug. This effect was maintained during a period of 4 weeks. At the dose tested in this pilot study, 2 patients had severe bleeding complications associated with delayed plasma clearance of the compound and prolonged inhibition of platelet aggregation. During the follow-up period of 4 weeks, there were no serious bleeding events or thrombocytopenia, but patients reported frequent episodes of mucocutaneous bleeding.

Challenges and Limitations
This was the first clinical pilot study evaluating an oral glycoprotein IIb/IIIa antagonist in patients undergoing invasive coronary interventions. This study was designed with doses selected to define the upper dose range in patients undergoing coronary angioplasty. It was anticipated that during the acute phase, near complete (>80%) inhibition of ADP-induced platelet aggregation was required. The dose of 20 to 25 mg TID was initially selected on the basis of the results of phase I studies, indicating that 30 mg TID was the maximally tolerated dose in volunteers. Thirty-five milligrams was chosen for a loading dose to ensure that adequate plasma concentrations were present at the time of procedure, followed 4 to 6 hours later by a 25-mg dose to maintain a high plasma concentration.

The risk of this strategy is emphasized by the 2 patients who experienced serious bleeding events. Although the reported bioavailability of Xemilofiban compares favorably with other oral agents being investigated,^{14 15 16 17 18} it appears that 30% of the active compound is absorbed and the absolute bioavailablity is 13%. Preclinical studies have also shown that after oral administration, nearly all of the drug's primary pathway of elimination is renal (personal communication, A.A. Karim). The most severe complication occurred in a diabetic patient with mild underlying renal impairment (BUN, 32 mg/dL; creatinine, 1.6 mg/dL). Severe hemodynamic compromise during percutaneous transluminal coronary angioplasty and subsequent emergency bypass surgery resulted in acute renal failure. This was associated with persistently high plasma levels of SC-54701 and profound inhibition of platelet aggregation refractory to usual reversal strategies. This case underscores the need for carefully screening patients with clinical or subclinical renal impairment. EPIC demonstrated a marked propensity to major bleeding events among diabetic patients receiving abciximab.¹⁹

Another factor that may have contributed to bleeding complications in this pilot study is the use of full heparinization with target ACT values of 350 to 400 seconds. PROLOG and EPILOG have since shown that lower doses of heparin and early sheath removal significantly reduce bleeding events.²⁰

During the 4-week posthospital phase, Xemilofiban provided substantial levels of inhibition of platelet aggregation that correlated with plasma concentration levels of the active drug. The variability observed during this period could have been due to patient compliance or with the three-times-daily schedule.

Several orally active inhibitors of platelet glycoprotein IIb/IIIa receptors are currently under investigation.^{15 16 17 18} Future developments of these drugs should examine the appropriate minimum levels of inhibition of platelet aggregation for effective and safe chronic therapy. The role of administering a high dose level in the acute setting before coronary intervention may need to be reevaluated for oral compounds. Intravenous agents that lead to rapid, intense, but readily reversible platelet inhibition are best suited for patients undergoing percutaneous coronary interventions.^{21 22 23}

Conclusions
Xemilofiban, a potent, orally active platelet glycoprotein IIb/IIIa receptor antagonist, produced marked, sustained inhibition of platelet aggregation for a period of 1 month. Because the administration of an oral agent such as Xemilofiban before percutaneous procedures may make it more difficult to manage severe bleeding events, future developments of oral agents should evaluate their use for long-term therapy after percutaneous interventions.

	Acknowledgments

 
This work was sponsored by GD Searle & Company, Skokie, Ill. The authors wish to recognize and thank Betty Wazowicz, MHSA, Michael E. Saunders, MD, and John Alexander, MD, for their expertise, efforts, and contributions.

Received September 3, 1996; revision received February 3, 1997; accepted February 7, 1997.

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