Undergoing Elective Angioplasty in Patients with Stable Coronary Artery

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Pharmacodynamics and safety of lefradafiban, an oral platelet glycoprotein IIb/IIIa receptor antagonist, in patients with stable coronary artery disease undergoing elective angioplasty

K M Akkerhuis, M J B M van den Brand, C van der Zwaan, H O J Peels, H Suryapranata, L R van der Wieken, J Stibbe, J Hoffmann, T Baardman, J W Deckers and M L Simoons

Heart 2001;85;444-450 doi:10.1136/heart.85.4.444

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444 Heart 2001;85:444–450 Pharmacodynamics and safety of lefradaﬁban, an oral platelet glycoprotein IIb/IIIa receptor antagonist, in patients with stable coronary artery disease undergoing elective angioplasty

K M Akkerhuis, MJBMvandenBrand, C van der Zwaan, HOJPeels, H Suryapranata, L R van der Wieken, J Stibbe, J HoVmann, T Baardman, J W Deckers, M L Simoons

Abstract Objective—Lefradafiban is the orally active prodrug of fradafiban, a glycoprotein IIb/IIIa receptor antagonist. The present phase II study aimed to determine the dose of lefradafiban that provides 80% blockade of the glycoprotein IIb/IIIa receptors by fradafiban, and to study the pharmacodynamics and safety of diVerent doses in patients with stable angina undergoing angioplasty. Design—A double blind, placebo controlled, dose finding study. Setting—Four academic and community hospitals in the Netherlands. Patients—64 patients with stable coronary artery disease undergoing elective percutaneous Thoraxcenter, transluminal coronary angioplasty. Erasmus University and University Interventions—30 mg, 45 mg, and 60 mg of lefradafiban three times daily or placebo was given Hospital Rotterdam, for 48 hours. Netherlands Main outcome measures—The primary safety end point was the occurrence of bleeding, clas- K M Akkerhuis sified as major, minor, or insignificant according to the thrombolysis in myocardial infarction MJBMvandenBrand (TIMI) criteria. EYcacy indices included per cent fibrinogen receptor occupancy (FRO), ex vivo C van der Zwaan platelet aggregation, and plasma concentrations of fradafiban. M L Simoons Results—Administration of lefradafiban 30, 45, and 60 mg three times daily resulted in a dose Department of dependent increase in median FRO levels of 71%, 85%, and 88%, respectively. Inhibition of Cardiology, University platelet aggregation was closely related to FRO. There were no major bleeding events. The 60 mg Hospital Groningen, lefradafiban group had a high (71%) incidence of minor and insignificant bleeding. The Netherlands incidence of bleeding was 44% in the 30 mg and 45 mg groups, compared with 9% in placebo HOJPeels patients. Puncture site bleeding was the most common event. The odds of bleeding increased by Department of 3% for every 1% increase in FRO. Cardiology, Hospital Conclusions—Lefradafiban is an eVective oral glycoprotein IIb/IIIa receptor blocker. The clini- De Weezenlanden, cal eVectiveness of doses up to 45 mg three times daily should be investigated. Zwolle, Netherlands (Heart 2001;85:444–450) H Suryapranata Keywords: platelet aggregation inhibitors; glycoprotein IIb/IIIa blockers; lefradafiban; angioplasty Department of Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, Platelet adhesion, activation, and aggregation ischaemia in patients with unstable angina or Netherlands are pivotal events in the process leading to cor- non-ST-segment elevation myocardial L R van der Wieken onary thrombosis in patients with unstable infarction.11–13 coronary artery disease.1 This process is also The clinical use of monoclonal antibodies Department of activated during percutaneous transluminal Haematology, and small molecules as GP IIb/IIIa receptor University Hospital coronary angioplasty (PTCA) by local vascular blockers is limited to the treatment of acute Rotterdam, injury, which exposes circulating platelets to episodes of unstable angina, or treatment dur- Netherlands various prothrombotic stimuli within the sub- ing coronary procedures, as oral administration 23 J Stibbe endothelium. The final common pathway to is not feasible. Lefradafiban (Boehringer Ingel- coronary thrombus formation involves aggre- Boehringer Ingelheim, heim, Germany) is an orally active prodrug Germany gation of platelets through cross linkage of their which is metabolised in two steps to fradafiban, JHoVmann glycoprotein (GP) IIb/IIIa receptors by the an intravenously active, non-peptide GP IIb/ primary binding ligand fibrinogen.4 T Baardman IIIa receptor inhibitor.14 In studies with healthy Several inhibitors of the GP IIb/IIIa receptor volunteers, both fradafiban and lefradafiban Cardialysis BV, have been developed. The monoclonal anti- led to a reversible and dose dependent Clinical Research body c7E3 (abciximab) has been shown to Management and Core 14 reduce the incidence of death and myocardial inhibition of platelet aggregation. Laboratories, Our aim in this first phase II study was to Rotterdam infarction in patients undergoing PTCA, with J W Deckers or without stent deployment.5–8 Small mol- determine the dose regimen of lefradafiban ecules (eptifibatide, tirofiban) given intrave- that provides 80% blockade of the platelet GP Correspondence to: nously also reduce complications associated IIb/IIIa receptors by fradafiban, as well as to Dr Akkerhuis, Cardialysis BV, PO Box 2125, 3000 CC with PTCA, although their eVects were of bor- study the pharmacodynamics and safety of dif- Rotterdam, The Netherlands derline significance.910 These intravenous GP ferent doses in patients with stable coronary [email protected] IIb/IIIa receptor blockers have also recently artery disease undergoing elective PTCA, in Accepted 12 September been shown to reduce the incidence of death, order to select the appropriate range of dose 2000 recurrent myocardial infarction, and recurrent regimens for subsequent larger studies.

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Oral platelet glycoprotein IIb/IIIa receptor antagonist 445

Methods CONCOMITANT TREATMENT STUDY POPULATION Before the start of the PTCA, all patients Patients aged between 18 and 80 years with received an intravenous bolus of heparin of stable coronary artery disease were eligible for 5000 IU, as well as an intravenous bolus of enrolment if they were scheduled for elective 250 mg aspirin. During the procedure, heparin PTCA. Patients were excluded if they suVered was repeated in boluses of 5000 IU after 30, 60 from unstable angina or if there was a total and, if necessary, 120 minutes. Aspirin was occlusion of the vessel to be treated. Other cri- continued in a dose of 100 mg daily. The use of teria for exclusion included myocardial infarc- ticlopidine together with lefradaﬁban was tion within the preceding 14 days; planned excluded by the protocol because no interac- stent implantation; major surgery or trauma tion data were available at that time. Therefore, within the preceding six weeks; any history of if stenting was performed, the study drug was discontinued and ticlopidine (250 mg once or cerebrovascular haemorrhage or haemorrhagic twice a day) was initiated. Other drugs were diathesis, cardiopulmonary resuscitation, or continued as before randomisation and ad- complicated puncture of a major vein or artery justed as required by the clinical status of the within the preceding six weeks; retinopathy patient. grade 3 or greater; gastrointestinal or genito-

urinary bleeding within the preceding six CLINICAL AND LABORATORY MONITORING weeks; peptic ulcer disease; platelet count A coronary angiogram was performed immedi- 9 < 100 × 10 /l; uncontrolled hypertension ately before and after PTCA. Coronary flow (systolic blood pressure > 200 mm Hg and/or was classified according to the thrombolysis in diastolic blood pressure > 100 mm Hg); cur- myocardial infarction (TIMI) study classifi- rent treatment with oral anticoagulants or any cation by a central angiographic core labora- antiplatelet agent other than acetylsalicylic tory (Cardialysis BV).15 Sheaths were removed acid, including any non-steroidal anti- 4–6 hours after discontinuation of the heparin inflammatory agent; pregnant or nursing infusion and as close as possible to the next women or women not using medically ap- intake of study drug, assuming that the platelet proved means of contraception; known hepatic inhibitory activity of fradafiban would be at its or renal insuYciency; or any other concomitant nadir. Patients underwent daily clinical assess- serious illness which would limit life expect- ment for the occurrence of bleeding complica- ancy or interfere with the study end points. tions and other adverse events as well as exten- The study protocol was reviewed and sive laboratory evaluation for haematology, approved by each hospital’s institutional review coagulation, and biochemistry. They returned board, and informed consent was obtained for a follow up visit two weeks after hospital from each patient before participation in the discharge, which was not to take place within trial. 48 hours from first study drug administration. Samples for determination of FRO and plasma concentrations of fradafiban were STUDY DESIGN AND DOSE SELECTION obtained at baseline and at 2, 4, 12, 24, 36, and The initial protocol envisaged a dose escala- 48 hours after the first dose of the study drug. tion, starting with lefradafiban 60 mg three Blood for determination of FRO was stored in times daily or placebo, and increasing to 75 mg a Monovette prefilled with ACD (trisodium and 90 mg three times daily. Based on phase I citrate, citric acid, dextrose). Platelet rich data in healthy volunteers, the latter dose was plasma was prepared by centrifugation and expected to achieve fibrinogen receptor occu- mixed with labelled fradafiban. After incuba- pancy (FRO) levels of more than 80%.14 How- tion and centrifugation, the supernatant as well ever, after studies on the first group of 21 as the platelet pellet were counted for free patients treated with lefradafiban 60 mg three ligand in a 4 ml scintillation cocktail. Non- times daily had been completed, it became specific binding was determined in the pres- apparent that this dose was associated with a ence of unlabelled fradafiban. The specific high incidence of bleeding and with FRO levels binding was calculated using corrections for of more than 80% (see Results). Therefore, the spillover, extracellular space, and non-specific binding. The percentage of FRO was then cal- dose for the next group was reduced to 30 mg culated from the specific binding data, using three times daily. After the safety of this corrections for receptor aYnity and dilution of regimen had been established, a third group ACD. was investigated receiving lefradafiban 45 mg Blood for determination of plasma frad- three times daily or placebo. afiban concentrations was drawn into tubes Within each dose level, patients were ran- with EDTA. Plasma was separated immedi- domised in a 4:1 ratio to receive lefradafiban or ately by centrifugation and stored at −20°C placebo in a double blind manner. The study until analysis. Plasma concentrations of drug was given as an oral solution three times a fradafiban were measured using a validated day for two days. It was not to be taken within high performance liquid chromatographic two hours after or one hour before a meal. The method with fluorescence detection.14 The first dose was given two hours before the start lower limit of quantification was 1 ng/ml. of the PTCA. An additional loading dose was Ex vivo platelet aggregation was assessed in a given 3.5 hours after the first dose, while subgroup of 32 patients at baseline and at 2, 4, subsequent doses were given at eight hour 24, and 48 hours after study drug initiation. intervals. Platelet aggregation was measured in citrated

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446 Akkerhuis, van den Brand, van der Zwaan, et al

platelet rich plasma and recorded by a aggregation and plasma concentrations of Chrono-log aggregometer during a 6–8 minute fradafiban. interval after induction by two agonists: 1 mmol/l ADP and 2 mg/ml collagen, respec- STATISTICAL ANALYSIS tively. Results are expressed as maximum per Descriptive analyses of angiographic, aggrega- cent aggregation achieved in platelet rich tion, and safety data are presented. The associ- plasma, using platelet poor plasma as reference ation of % FRO, expressed as area under the of 100%. curve (AUC), with the first bleeding event was Ivy bleeding times determined with standard assessed using logistic regression analysis, the techniques were obtained at baseline and at the null hypothesis being that the risk of bleeding end of the 48 hour treatment period. Measure- was not aVected by FRO levels. The AUC was ment of bleeding times was discontinued at 15 calculated until the first bleeding, as well as minutes. over the whole treatment interval. The relation between bleeding and heparin administration as well as with the activated partial thrombo- SAFETY AND EFFICACY INDICES plastin time (aPTT) AUC was investigated The primary safety end point in this trial was with logistic regression analysis in a similar the occurrence of bleeding complications, clas- way. sified as major, minor, or insignificant according to the criteria of the TIMI study group.16 Results Major bleeding was defined as intracranial or Sixty four patients were enrolled: 16 received bleeding associated with a decrease in haemo- lefradafiban at a dose of 30 mg three times globin of more than 3.1 mmol/l (5 g/dl) or a fall daily, 16 received 45 mg three times daily, 21 in haematocrit of more than 15%. Minor received 60 mg three times daily, and 11 bleeding was defined as observed blood loss received placebo. The majority (73%) of the with a decrease in haemoglobin of 1.9– patients were male (table 1). Their mean age 3.1 mmol/l (3.1–5.0 g/dl) or a fall in haemat- was 61 years (range 39–79 years). A previous ocrit of 10–15%. Spontaneous gross haema- myocardial infarct was present in 15 patients turia or haematemesis, as well as a decrease in (23%), while three (5%) had undergone haemoglobin of 2.5–3.1 mmol/l or a fall in coronary artery bypass surgery, and seven haematocrit of 12–15% without an identifiable (11%) had had PTCA. All patients received the bleeding site, were also considered to indicate study drug and underwent PTCA as sched- minor bleeding. Blood loss insuYcient to meet uled. The treated segments were in the right criteria for minor bleeding was classified as coronary artery in 14 patients (22%), in the insignificant. Haemoglobin values were ad- circumflex coronary artery in 19 (30%), and in justed if patients received packed red blood the left anterior descending coronary artery in cells or whole blood within 48 hours of the 31 (48%). Coronary flow was normal (TIMI measurement.17 grade III) in 54 patients (84%). Following The primary eYcacy variable was the FRO PTCA, TIMI grade III flow was achieved in all level in percentages, expressed as area under patients, except two in the placebo group the curve normalised per hour. Secondary eY- (TIMI 0), both caused by dissection. A stent cacy variables included the ex vivo platelet was placed in nine patients. In these patients, the study drug was discontinued and ticlopi- Table 1 Clinical and angiographic characteristics at baseline dine (250 mg once or twice a day) was begun.

Lefradafiban dose (× 3 daily) PHARMACODYNAMICS AND INHIBITION OF Placebo 30 mg 45 mg 60 mg PLATELET AGGREGATION (n=11) (n=16) (n=16) (n=21) Plasma concentrations of fradafiban increased Patient demographics in a dose dependent manner in patients treated Age (years) (mean (SD)) 58 (7) 65 (8) 62 (13) 60 (12) with lefradafiban. Geometric means of the Male sex (n) 8 14 11 14 maximum plasma concentration of fradafiban Diabetes (n) – 3 1 2 Hypertension (n) 2 2 6 5 at steady state were 158, 314, and 394 ng/ml Previous MI (n) 1 5 5 4 during treatment with lefradafiban 30, 45, and Previous PTCA or CABG (n) 1 3 3 3 60 mg three times daily, respectively (table 2). Angiographic variables The pharmacokinetic profile of lefradafiban Segments to be treated (n) was predictable and no significant deviations RCA 3 2 3 6 from dose proportionality were observed. LAD 6 9 8 8 LCX 2 5 5 7 There was a close correlation between the Perfusion grade, TIMI flow (n) plasma concentrations of fradafiban and FRO Grade 0 1 – 1 – Grade 1 1 – – 1 (fig 1). FRO increased in a dose dependent Grade 2 1 2 1 2 manner in patients treated with lefradafiban. Grade3 8 141418 Median FRO was 0% in the placebo group, Lesion type by AHA/ACC (n) A1–2171% in the lefradafiban 30 mg group, 85% in B1 5 354 the lefradafiban 45 mg group, and 88% in the B2 5 10 6 9 lefradafiban 60 mg group (table 2). Minimum, C – 335 Missing – – – 2 mean, and maximum FRO values were also dose dependent. Plasma fradafiban concentra- AHA/ACC, American Heart Association/American College of Cardiology; CABG, coronary tions of 170 ng/ml were required to achieve artery bypass grafting; LAD, left anterior descending artery; LCX, left circumflex artery; MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty; RCA, right 80% FRO (fig 1). There was little variation in coronary artery; TIMI, thrombolysis in myocardial infarction. FRO within each patient (fig 2), while the

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Oral platelet glycoprotein IIb/IIIa receptor antagonist 447

Table 2 EYcacy and safety end points A. 30 mg three times daily 100 Lefradaﬁban dose (× 3 daily)

Placebo 30 mg 45 mg 60 mg (n=11) (n=16) (n=16) (n=21) 50 EYcacy indices Plasma concentration of fradaﬁban (ng/ml)* 0 158 (27) 314 (24) 394 (22) FRO (%)—minimum 0 54 74 78 FRO (%)—median 0 71 85 88 FRO (%)—maximum 0 80 89 95 FRO (%)—mean† 0 69 (12) 83 (6) 87 (5) 0 Bleeding time B. 45 mg three times daily At baseline (min) 3.3 4.0 4.1 5.3 100 After 48 hours (min) 4.4 7.8 19.2 25.0

Bleeding complications Patients with bleeding, n (%) 1 (9) 7 (44) 7 (44) 15 (71) Number of bleeding events (n) 1 8 9 29 Location of bleeding (n) 50 Vascular puncture site 1 6 6 15 Gingival – 1 2 10 FRO (%) FRO (%) Skin – 1 1 2 Haematuria – – – 2

Severity of bleeding by TIMI (n) 0 Major – – – – Minor – – 1 2 C. 60 mg three times daily Insigniﬁcant 1 8 8 27 100

*Mean maximum fradaﬁban plasma concentration at steady state (Cmax,ss) with the relative coef- ﬁcient of variation (%) in parentheses. †Relative coeYcient of variation (%) in parentheses. All FRO values are expressed as area under the curve normalised per hour. Relative coeYcient of 50 variation = 100 × (standard deviation/mean).

100 FRO (%)

0 024 12 24 36 48

50 Time (hours)

FRO (%) Figure 2 Degree of fibrinogen receptor occupancy (FRO) during oral administration of lefradafiban (A) 30 mg, (B) 45 mg, and (C) 60 mg three times daily. Each line represents data from an individual patient in one of the 0 three lefradafiban groups during 48 hours of oral treatment. 0 200 400 600 800 Each line is based on FRO data obtained at one of the Plasma concentration (ng/ml) prespecified sample time points (baseline and 2, 4, 12, 24, 36, and 48 hours after the study drug was started). Figure 1 Relation between the plasma concentration of the active drug fradafiban and the degree of fibrinogen receptor 100 occupancy (FRO). 80 interpatient variability was greater among patients receiving the lower dose than among 60 those treated with the higher doses (fig 2 and 40 table 2), reflecting the plasma concentration– 20

FRO relation (fig 1). Aggregation (%) Ex vivo platelet aggregation was measured in 32 patients and decreased with higher FRO 0 02040 60 80 100 levels (fig 3). In placebo patients, platelet FRO (%) aggregation was approximately 60% of normal. Figure 3 Relation between the degree of fibrinogen Inhibition of platelet aggregation to values receptor occupancy (FRO) and inhibition of ex vivo below 20%, or greater than 80% inhibition, platelet aggregation induced by 1 mmol/l ADP in platelet was observed in all patients with FRO values rich plasma. Each point represents data from a subject at a single time point during the 48 hours of oral treatment with above 80%. lefradafiban 30, 45, or 60 mg three times daily. Bleeding times measured at 48 hours were in the normal range for all patients with FRO values below 70%, while prolonged bleeding and insignificant bleeding complications were times were observed in the majority of patients frequent in the highest dose group (60 mg with higher FRO values (fig 4). three times a day), in which 15 of 21 patients (71%) experienced such events (table 2). ADVERSE EVENTS There was one haematoma in the placebo Adverse events resulting in discontinuation of group, while bleeding was reported in seven study drug treatment occurred in four patients: (44%) of 16 patients receiving lefradafiban angina with cardiogenic shock in one (30 mg), 30 mg three times daily, as well as in seven leucopenia in one (30 mg), and bleeding in two (44%) of 16 patients receiving lefradafiban other patients, both in the 45 mg group. No 45 mg three times daily (table 2). Arterial and major bleeding events were reported. Minor venous puncture site bleeding was most

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448 Akkerhuis, van den Brand, van der Zwaan, et al

patient (fig 2). The level of inhibition achieved >15 in patients who also received aspirin and heparin was greater than observed in volun- 10 teers receiving lefradafiban without additional drug treatment. In the placebo group, platelet 5 aggregation was already decreased to 60%. In the phase I studies, inhibition of platelet aggregation of more than 80% was achieved with 0 14 Bleeding time (minutes) 02040 60 80 100 lefradafiban doses of 90 mg three times daily. FRO (%) In the present study, this was achieved with Figure 4 Relation between the degree of fibrinogen 45 mg three times daily. This suggests an inter- receptor occupancy (FRO) and ivy bleeding times at 48 action between the GP IIb/IIIa receptor hours after first study drug administration. Each point blocker and aspirin. represents data from a subject in the lefradafiban 30, 45, or 60 mg group. As in other studies with GP IIb/IIIa receptor blockers, bleeding occurred frequently at these common. All bleeding events occurred more levels of platelet inhibition and was dose than two hours after administration of the first dependent. The incidence of bleeding compli- dose. cations in the lefradafiban 30 and 45 mg By logistic regression analysis, higher values groups was similar to the rates observed in of FRO were found to be significantly related studies with other oral GP IIb/IIIa blockers at to an increased incidence of bleeding. The similar levels of platelet inhibition,18 19 while odds of bleeding increased by a factor of 1.03 even more bleeding occurred in the highest for every 1% increase in FRO (p < 0.01). The dose group (71%). In studies with sibrafiban relation between bleeding and heparin admin- and xemilofiban, a gradual increase in bleeding istration, as well as with the aPTT AUC, was was observed for higher dose levels with a explored in a similar way. When heparin greater degree of platelet inhibition.18 19 The administration and aPTT AUC were restricted results of the logistic regression analysis in the to observations before the bleeding event, the present study support these observations, with relation with bleeding was significant for an increase in the risk of bleeding by 3% for heparin (p = 0.04) but failed to reach conven- every 1% increase in FRO. It should be appre- tional significance for aPTT (p = 0.08). ciated that in the majority of cases the bleeding A clinically relevant fall in blood leucocyte was insignificant, with a low incidence of minor count (< 3.0 × 109/l) was observed in three bleeding complications (TIMI classification) patients, two of whom were treated with and no major bleeding (table 2). Furthermore, lefradafiban 60 mg three times daily, and one all patients received aspirin and heparin and with lefradafiban 30 mg three times daily. The underwent invasive coronary procedures. Inter- lowest values were 0.9 × 109/l (from 5.9 × 109/l actions between the GP IIb/IIIa receptor at baseline), 1.9 × 109/l (from 4.7 × 109/l), and blocker abciximab and heparin have been 2.3 × 109/l (from 7.4 × 109/l), observed at 4, 24, reported in previous studies.56 As demon- and 48 hours after first study drug dose, strated in the EPILOG (evaluation of PTCA to respectively. After discontinuation of study improve long term outcome by c7E3 GP drug, the leucocyte count in these patients IIb/IIIa recptor blockade) and EPISTENT returned to normal levels without additional (evaluation of platelet GP IIb/IIIa inhibitor for measures within 2–5 days. stenting) studies, it is likely that a further Median values for haematological variables reduction in the heparin dose in a weight at baseline were within normal limits in all adjusted manner might reduce bleeding com- treatment groups. There was a small decrease plications in patients receiving lefradafiban in haemoglobin and thrombocyte concentra- without decreasing the clinical eYcacy.78Spe- tions during the trial, which was comparable cial care should be given to the access site of among all treatment groups. Median leucocyte vascular sheaths. Sheaths should be removed count did not change. Serum concentrations of early (4–6 hours) following the procedure, after thromboplastin, thrombin, and fibrinogen were the heparin has been stopped and the activated not aVected. Median concentrations of bio- clotting time is 175 seconds or less.7 Given the chemical variables at baseline were within the interpatient variability in the degree of platelet normal range in all treatment groups and inhibition observed with oral GP IIb/IIIa remained within these limits at 24 and 48 receptor antagonists, another potential strategy hours. for reducing bleeding complications during longer term treatment could be to monitor the Discussion degree of platelet inhibition achieved in Administration of lefradafiban, an oral prodrug individual patients by using a platelet function of the GP IIb/IIIa receptor blocker fradafiban, bedside assay and to titrate the dose to a target resulted in rapid and eVective inhibition of level of inhibition.20 21 platelet aggregation in patients with stable cor- While a gradual dose dependent increase in onary artery disease undergoing elective bleeding was observed, as in studies with PTCA. Doses of lefradafiban of 30, 45, and 60 sibrafiban and xemilofiban,18 19 the relation mg three times daily caused a dose dependent between bleeding time and per cent FRO in the increase in fradafiban plasma concentrations, present study suggests a threshold eVect. The an increase in FRO, and inhibition of platelet bleeding time was not increased at FRO values aggregation. With the three times daily dosing of less than 70%, while a pronounced increase regimen, a stable FRO was achieved in each was observed at higher levels. It should be

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Oral platelet glycoprotein IIb/IIIa receptor antagonist 449

appreciated, however, that measurement of acute coronary syndromes (orbofiban in pa- bleeding time does not reflect a tendency to tients with unstable coronary syndromes trial spontaneous bleeding in clinical practice. (OPUS-TIMI-16), and sibrafiban versus aspi- In three patients receiving lefradafiban, a rin to yield maximum protection from ischemic clinically significant fall in blood leucocyte heart events post-acute coronary syndromes count was observed, although the mean leuco- trial (SYMPHONY)).24–26 None of the trials cyte count did not change in the overall popu- showed a clear treatment benefit of long term lation. Leucopenia from bone marrow depres- GP IIb/IIIa inhibition, while all three trials sion has been reported for another antiplatelet showed a trend towards an increased mortality agent (ticlopidine).22 This, however, occurs in the GP IIb/IIIa inhibitor group.24–26 In this mostly after 2–4 weeks of treatment. In the respect, several points deserve consideration. present study, leucopenia occurred immedi- First, the patient populations included in these ately after the first dose or within two days. In trials were at relative low risk of recurrent all three patients, leucocytes returned rapidly thrombotic events.24–26 Furthermore, the phar- in the peripheral blood after discontinuation of macokinetic and pharmacodynamic profile of study drug. Leucopenia had not been observed these agents is characterised by a steep in previous studies with lefradafiban in healthy dose–response relation and by a short half life volunteers and therefore was an unexpected relative to the dosing interval.18 19 25 This may finding in the present study. Following the have caused widely fluctuating inhibition of observation of the leucopenia in the three platelet aggregation and allowed complete patients, an amendment was made which recovery of platelet function between doses in increased the frequency of the haematological some patients, with exposure of activated GP evaluations to monitor the safety of the patients IIb/IIIa receptors on the platelet’s surface.27 and investigate the potential underlying patho- Additionally, recent studies have raised the physiological mechanisms. However, no addi- possibility that platelet receptor antagonists tional patients experienced this adverse event. may, at low concentrations, alter the steric con- A recently presented second phase II study formation of the GP IIb/IIIa receptor sites and, with lefradafiban in patients with acute coron- paradoxically, enhance the thrombogenicity of ary syndromes has confirmed the increased these sites.27 28 Compared with the other oral incidence of leucopenia, or rather neutropenia, agents, the three times daily lefradafiban associated with lefradafiban, and has provided dosing regimen may result in higher average some insight into the pathophysiological fradafiban concentrations with less peak– mechanisms involved.23 In accordance with the trough fluctuation and more stable levels of present study, the decrease in neutrophils was inhibition of platelet aggregation. characterised by early onset (immediately after It is a challenge to exploit the potential ben- first does of the study drug or within the next eficial antithrombotic eVect of oral GP IIb/IIIa two days) and a rapid recovery after discon- inhibitors in balance with the associated risk of tinuation of lefradafiban. Based on analysis of haemorrhage. Dose titration to a target degree blood and bone marrow samples obtained in of platelet inhibition, measured with a rapid patients with neutropenia in that study, it was platelet function assay, may improve the overall concluded that the observed neutropenia did safety and eYcacy profile.20 21 To increase the not result from bone marrow depression but treatment benefit of (oral) GP IIb/IIIa block- rather from a reversible redistribution of ers, one may choose to treat only patients who neutrophils by margination or clustering. More are at high risk of recurrent thrombotic investigations are needed to clarify the precise complications, such as those who present with mechanisms involved, as well as to determine raised troponin concentrations and continue the optimum duration of surveillance and the on medical treatment. These patients may gain possible clinical associations. particular benefit from a more aggressive long The clinical benefit of treatment with GP term therapeutic approach.29 30 IIb/IIIa receptor blockers in patients undergo- Lefradafiban in doses up to 45 mg three ing percutaneous intervention has been estab- times daily achieved stable FRO values of more lished by several studies using diVerent than 80% in patients with stable coronary inhibitors.5–10 In the present limited series, all artery disease undergoing elective PTCA, with patients receiving lefradafiban had a successful acceptable safety during short term treatment. PTCA without apparent thrombotic complica- These doses may therefore be tested in further tions, while acute closure was observed during studies to assess whether long term treatment PTCA in one patient in the placebo group. is indeed beneficial in patients with acute cor- Oral compounds such as lefradafiban oVer an onary syndromes at high risk of thrombotic opportunity for long term treatment with an complications, without an excess of bleeding eVective platelet aggregation inhibitor, which complications. may enhance the early benefit of an intravenous agent and prevent subsequent thrombotic We acknowledge the significant contribution of the following: events in patients at risk. Dr Rolf Brickl, Department of Pharmacokinetics and Drug Three recently presented large clinical trials Metabolism; Dr Brian Guth, Department of Pharmacology; Dr Gerhard Nehmiz and Suzanne Stolz, Department of Medical have evaluated this concept of long term oral Data Services—Boehringer Ingelheim Pharma KG; Carlie GP IIb/IIIa inhibition with xemilofiban in Dille-Amo, Judith Rozendaal, Rene Stadhouders, Clemens Disco and Dr Gerrit-Anne van Es—Cardialysis BV, Clinical patients after percutaneous coronary interven- Research Management and Core Laboratories; Thea Muskee, tion (evaluation of oral xemilofiban in control- Department of Haematology, University Hospital Rotterdam. We also wish to thank the local hospital personnel and the ling thrombotic events trial (EXCITE)) and patients who agreed to participate. The study was supported by with orbofiban and sibrafiban in patients after Boehringer Ingelheim.

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450 Akkerhuis, van den Brand, van der Zwaan, et al

1 Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of system in patients treated with recombinant tissue coronary artery disease and the acute coronary syndromes. plasminogen activator and streptokinase. J Am Coll Cardiol N Engl J Med 1992;326:242–50,310–18. 1988;11:1–11. 2 Haerker LA. Role of platelets and thrombosis in mecha- 17 Landefeld CS, McGuire E, Rosenblatt MW. A bleeding risk nisms of acute occlusion and restenosis after angioplasty. index for estimating the probability of major bleeding in Am J Cardiol 1987;60:20–8B. hospitalized patients starting anticoagulant therapy. Am J 3 Tenaglia AN, Fortin DF, CaliV RM, et al. Predicting the risk Med 1990;89:569–78. of abrupt vessel closure after angioplasty in an individual 18 Kereiakes DJ, Kleiman NS, Ferguson JJ, et al, for the patient. J Am Coll Cardiol 1994;24:1004–11. ORBIT Trial Investigators. Pharmacodynamic eYcacy, 4 Lefkovits J, Plow EF, Topol EJ. 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The following electronic only articles are published in con- junction with this issue of Heart (see also p 443).

Behçet’s disease with a large intracardiac Serious adverse events experienced by patients with thrombus: a case report chronic heart failure taking spironolactone M Baykan, Sq Çelik, C Erdöl, E C Baykan,~ I Durmus¸, CBerry,JJVMcMurray S Bahadir, H Erdöl, C Örem, H Çakirbay In patients with chronic heart failure, spironolactone Behçet’s disease is recognised as a chronic multisystem added to conventional treatment may lead to serious disorder with vasculitis as its underlying pathological proc- and, occasionally, fatal hyperkalaemia. In some cases ess. Cardiac involvement is rare and often associated with this seems to happen because spironolactone causes poor prognosis. A case of a 33 year old man with Behçet’s diarrhoea. Four cases involving men with New York disease, presenting with a large right ventricle and right Heart Association functional class III heart failure atrial thrombus, is reported. Two dimensional (cross are presented. As these cases revealed, close sectional), colour Doppler, and transoesophageal echo- monitoring of blood chemistry is mandatory after cardiography, angiography, computed tomography, and starting spironolactone, and patients should be advised magnetic resonance imaging were used to diagnose the to stop spironolactone immediately if diarrhoea disease. With cyclophosphamide and dexamethasone develops. treatment, the cardiac lesions progressively resolved. (Heart 2001;85:e8) www.heartjnl.com/cgi/content/full/85/ (Heart 2001;85:e7) www.heartjnl.com/cgi/content/full/85/ 4/e8 4/e7