Published online before print May 14, 2007, doi: 10.1161/CIRCULATIONAHA.106.653428
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(Circulation. 2007;115:2642-2651.)
© 2007 American Heart Association, Inc.
Interventional Cardiology |
Randomized, Double-Blind, Dose-Ranging Study of Otamixaban, a Novel, Parenteral, Short-Acting Direct Factor Xa Inhibitor, in Percutaneous Coronary Intervention
The SEPIA-PCI Trial
From the Division of Cardiology (M.C.), Newark Beth Israel Medical Center, Newark, NJ; Cleveland Clinic (D.L.B.), Cleveland, Ohio; Duke University Medical Center (J.H.A.), Durham, NC; Hopital La Pitié Salpétrière (G.M.), Paris, France; University of Freiburg Medical Center (C.B.), Freiburg, Germany; Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital (T.H.), Minneapolis, Minn; sanofi-aventis (J.-F.T.), Bridgewater, NJ; Kuols River Private Hospital (J.S.), Capetown, South Africa; General University Hospital (S.S.), Prague, Czech Republic; and Medical Center (J.D.S.), Alkmaar, the Netherlands.
Correspondence to Marc Cohen, MD, FACC, Cardiac Catheterization Lab Administration, Newark Beth Israel Medical Center, 201 Lyons Ave, Newark, NJ 07112. E-mail marcohen{at}sbhcs.com
Received July 24, 2006; accepted March 9, 2007.
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Abstract |
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Background— The optimal anticoagulant regimen for percutaneous coronary intervention (PCI) remains to be determined. Otamixaban, a selective and direct inhibitor of factor Xa, was investigated in patients undergoing nonurgent percutaneous coronary intervention.
Methods and Results— In this double-blind, double-dummy, parallel-group, dose-ranging trial, 947 patients were randomly assigned to either 1 of 5 weight-adjusted otamixaban regimens or weight-adjusted unfractionated heparin (UFH) before percutaneous coronary intervention. The primary end points were change in prothrombin fragments 1+2 (F1+2), and anti-factor Xa activity. The main secondary end points were Thrombolysis In Myocardial Infarction (TIMI) bleeding at day 3 or hospital discharge (whichever came first) and 30-day ischemic events. The median change in F1+2 from baseline to the end of infusion was greater with the highest otamixaban dose compared with UFH (–0.3 versus –0.2 ng/mL, P=0.008). Anti-factor Xa levels were 65, 155, 393, 571, and 691 ng/mL with otamixaban doses 1 to 5, respectively. Significant TIMI bleeding (major or minor) occurred in 2.0%, 1.9%, 3.8%, 3.9%, and 2.6% of patients receiving otamixaban doses 1 to 5, respectively, and in 3.8% of patients receiving UFH. Four TIMI major bleeds were observed. Ischemic events occurred in 5.8%, 7.1%, 3.8%, 2.5%, and 5.1% of patients receiving otamixaban doses 1 to 5, respectively, and in 5.6% of patients receiving UFH.
Conclusions— Otamixaban reduced F1+2 significantly more than UFH at the highest dose regimen, whereas no significant difference in the incidence of TIMI bleeding was observed between the otamixaban and UFH groups. These results set the stage for adequately powered clinical outcome trials of selective direct factor Xa inhibition in patients with acute coronary syndromes.
Key Words: angioplasty • anticoagulants • coronary disease • factor Xa • revascularization
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Introduction |
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Bursts of thrombin production are frequently encountered in patients with acute coronary syndromes (ACS).1 In these patients, a decrease in markers of thrombin generation during anticoagulant therapy is related to improved clinical outcomes.2 Factor Xa plays a pivotal role in the generation of thrombin and is a logical target for treatment of arterial thrombosis. Unfractionated heparin (UFH) inhibits thrombin and factor Xa (after binding to antithrombin) but has several important limitations.3 Therefore, newer agents with a more predictable anticoagulant effect and with greater anti-factor Xa activity have been developed.4–12 One such drug is otamixaban {2-(R)-(3-carbamimidoylbenzyl)-3-(R)-[-4-(1-oxypyridin-4-yl) benzoylamin]-butyric acid methyl ester, hydrochloride salt}, a parenteral, synthetic small molecule that selectively inhibits factor Xa.8–10 This novel drug potently (Ki=0.5 nmol/L) and directly inhibits free and proteinase-bound factor Xa, independent of platelet function or anti-thrombin III. Percutaneous coronary intervention (PCI) patients routinely experience arterial injury and sudden intense thrombotic stimuli during balloon angioplasty and stent deployment.13 In the present trial, otamixaban was investigated in patients undergoing nonurgent PCI.
Clinical Perspective p 2651
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Methods |
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The SEPIA-PCI Trial (Study to Evaluate the Pharmacodynamics, the Safety and Tolerability, and the Pharmacokinetics of Several Intravenous Regimens of the Factor Xa Inhibitor Otamixaban (XRP0673), in Comparison to Intravenous Unfractionated Heparin in Subjects Undergoing Non-Urgent Percutaneous Coronary Intervention) was a multinational, double-blind, double-dummy, exploratory, parallel-group, dose-ranging phase II study that randomized 947 patients undergoing nonurgent PCI between September 2004 and July 2005 from 76 sites in 10 countries (United States, Canada, France, Germany, Spain, the Netherlands, Belgium, Czech Republic, Slovakia, and South Africa). All patients gave written informed consent. The ethics review board at each participating institution approved the study. An independent data and safety monitoring board periodically reviewed the data. All primary clinical outcomes were adjudicated by a blinded clinical events committee.
Inclusion and Exclusion Criteria
Patients were eligible if they were 
18 years of age and were due to undergo nonurgent PCI of a native coronary vessel(s) with a femoral approach, and if they gave informed consent. Exclusion criteria included pregnancy, treatment with other investigational drugs or devices within 30 days before enrollment or planned use of investigational drugs or devices during the study, recent ACS (within 48 hours), New York Heart Association class III or IV congestive heart failure, hemodynamic instability, significant valvular disease, active or recent (<3 months) significant bleeding, bleeding disorder, ischemic stroke <12 months or history of hemorrhagic stroke, international normalized ratio >1.2, and creatinine clearance 
30 mL/min (Cockroft-Gault).
Study Protocol
Eligible patients were randomized before the PCI (1:1:1:1:1:1) to 1 of 5 otamixaban regimens and UFH placebo or UFH and otamixaban placebo. Otamixaban (or placebo) was given as a weight-adjusted intravenous bolus followed by a 3-hour infusion (dose 1=0.025 mg/kg followed by 0.035 mg · kg–1 · h–1; dose 2=0.045 mg/kg followed by 0.065 mg · kg–1 · h–1; dose 3=0.080 mg/kg followed by 0.120 mg · kg–1 · h–1; dose 4=0.120 mg/kg followed by 0.160 mg · kg–1 · h–1; and dose 5=0.140 mg/kg followed by 0.200 mg · kg–1 · h–1). UFH (or placebo) was also given as a weight-adjusted intravenous bolus (50 to 70 U/kg) just before PCI to achieve an activated clotting time of 200 to 300 seconds with glycoprotein (GP) IIb/IIIa inhibitors and 300 to 350 seconds without the planned use of GP IIb/IIIa inhibitors. Blinded activated clotting times were monitored with an encrypted Hemochron Jr. Signature (ITC, Edison, NJ). It was strongly recommended that patients receive aspirin (160 to 500 mg, if not already using chronic aspirin therapy) and a loading dose of clopidogrel 300 to 600 mg before the wire crossing the lesion. GP IIb/IIIa inhibitor use was at the treating physician’s discretion. Randomization was stratified by planned use of GP IIb/IIIa inhibitors and country. Study medication was administered after sheath insertion and within 
20 minutes before PCI. During PCI, the protocol recommended that patients receive catheter-flushing solution preferably without UFH, or if UFH was necessary, with a UFH concentration <5000 IU/L. If a closure device was used, the sheath was removed at the end of PCI. If no closure device was used, sheaths were removed 1 hour after completion of study drug or when the blinded activated clotting time was <180 seconds. Patients remained hospitalized for at least 18 hours after the end of drug or placebo infusions.
Study Objectives
The primary objectives were to (1) compare the effects of several regimens of otamixaban and UFH on change in prothrombin fragments 1+2 (F1+2; a marker of thrombin generation) from baseline to the end of infusion and (2) determine the effect of several regimens of otamixaban on anti-factor Xa activity at the end of infusion. Secondary objectives included activated partial thromboplastin time as a marker of coagulation, assessment of bleeding, and clinical ischemic events. Bleeding was assessed according to the Thrombolysis In Myocardial Infarction (TIMI) criteria14 as major, minor, or minimal bleeding through day 3 or hospital discharge (whichever came first) and the composite of major, minor, and minimal bleeding. TIMI major bleeding was defined as intracranial or as clinically significant overt signs of bleeding associated with a decrease in hemoglobin concentration of >5 g/dL. Minor bleeding was defined as any clinically significant overt sign of bleeding (including imaging) associated with a fall in hemoglobin of 3 to 5 g/dL. Minimal bleeding was any clinically significant overt sign of bleeding (including imaging) that was associated with a fall in hemoglobin of <3 g/dL. A transfusion of 1 U of blood was assumed to result in an increase of 1 g/dL in hemoglobin or of 3% in hematocrit. All adverse events and laboratory safety data were collected through day 14 (day of last visit), and all serious adverse events were collected through day 30 (day of last contact).
Clinical ischemic events included the composite of death, myocardial infarction (MI), or target-vessel revascularization through 30 days. MI was defined as creatine kinase (CK)–myocardial band isoenzyme (CK-MB; or as total CK if CK-MB was not available) >2 times the upper limit of normal and 1 or more of the following supportive criteria: ischemic symptoms when at rest, ST/T-wave changes suggestive of ischemia, or new significant Q waves (>0.04 seconds) in 2 or more contiguous leads. Within 24 hours of PCI, MI was defined as CK-MB (or total CK if CK-MB was not available) elevation 3 times the upper limit of normal and, if CK-MB was elevated before the procedure, an increase of 50% from that level, or new significant Q waves (>0.04 seconds) in 2 or more contiguous leads. Within 24 hours of CABG, MI was defined as CK-MB (or total CK, if CK-MB was not available) >5 times the upper limit of normal with new significant Q waves (>0.04 seconds) in 2 or more contiguous leads or CK-MB (or total CK if CK-MB was not available) 10 times the upper limit of normal. Target-vessel revascularization included PCI or CABG that involved at least 1 target vessel treated during the index procedure. Urgent revascularization was defined as PCI or CABG that occurred within 24 hours of an ischemic event that included pain, dynamic ST/T-wave changes, acute pulmonary edema, ventricular arrhythmias, or hemodynamic instability. The prespecified mixed efficacy/safety composite was defined as the composite of death, MI, target-vessel revascularization, or TIMI major or minor bleeding.
Data and Blood Collection
Blood samples were collected at randomization (before trial-drug dosing and before PCI), at the end of the 3-hour trial-drug infusion, and 24 hours after the end of the trial-drug infusion. In patients receiving otamixaban, anti-factor Xa activity was measured with a chromogenic assay that used otamixaban as the reference standard, with results expressed in nanograms of otamixaban per milliliter. F1+2 were measured by an ELISA based on the sandwich principle.
Statistical Methods
Analysis Populations
There were 3 main populations for analysis (Figure). The primary population for analyses of F1+2 and anti-factor Xa activity (named "treated with coprimary end point(s)" population) consisted of all randomized patients who were treated with the study drug and had adequate data for at least 1 primary end point. This includes for F1+2 all patients treated with otamixaban or UFH who had 2 adequate samples (1 at baseline and 1 at the end of the infusion) and for anti-factor Xa activity, all patients treated with otamixaban who had 1 adequate sample at the end of the infusion. The safety analysis population consisted of all patients randomized and treated with the study drug. The population for clinical efficacy analysis consisted of all patients randomized with clinical outcome data at day 30 (and no earlier than day 3 in case of early study withdrawal). The randomized patients were analyzed according to the study drug received (if drug was received) or assigned (if no drug was received).
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Statistical Analyses
Unless otherwise stated, all hypotheses were tested at a 2-sided significance level of 5%. Statistical analyses were performed by the Statistics Department of sanofi-aventis using the SAS software package version 8.2 (SAS Institute, Cary, NC). Continuous data were summarized with the number of observations, mean, SD, minimum, median, interquartile range, and maximum by treatment group. The primary analysis for F1+2 was defined as the comparison of each otamixaban dosage group with UFH with regard to the change in F1+2 from baseline to the end of infusion using (after rank transformation) an ANCOVA model that included factors for GP IIb/IIIa inhibitor use, treatment group, and ranked baseline F1+2 value. The primary analysis for anti-factor Xa activity was the comparison of each of the 4 higher otamixaban dosage groups with the lowest otamixaban dosage group with regard to anti-factor Xa activity at the end of infusion, which used (after a rank transformation of the variable) an ANOVA model that included factors for GP IIb/IIIa inhibitor use and treatment group. The 2 primary hypotheses were each tested at a 2-sided significance level of 2.5%. The following closed testing procedure was followed. The first comparison was between the highest otamixaban dosage group and the reference group (UFH group for F1+2 and the lowest otamixaban dosage group for anti-factor Xa activity). The next highest otamixaban dosage group was compared with the reference group only if the previous comparison was significant (
<2.5%).
The secondary analyses were conducted in the safety analysis population and defined as the comparison of dosages of otamixaban to UFH to identify a safe range of otamixaban doses. There were no adjustments for multiplicity. The incidence at day 3 or hospital discharge (whichever came first) of the composite of TIMI major, minor, or minimal bleeding was compared between UFH and each otamixaban dosage, after controlling for the use of GP IIb/IIIa inhibitors, with a Cochran-Mantel-Haenszel test. Probability values were generated for exploratory purposes only. The incidence at day 30 of the composite of all-cause death, MI, or target-vessel revascularization was compared in the clinical efficacy analysis population, between UFH and each otamixaban dosage, after controlling for the use of GP IIb/IIIa inhibitors, with a Cochran-Mantel-Haenszel test.
Sample Size Justification
Because the primary study objective was based on 2 coprimary end points, the -level was adjusted to 0.025 for multiple-comparisons risk control. A sample size of 154 in each group would have 80% power to detect a treatment difference of 0.2 nmol/L in change from baseline in F1+2, assuming that the common SD is 0.55 nmol/L, using a Wilcoxon (Mann-Whitney) rank sum test with a 0.025 2-sided significance level. The sample size calculation was based on the assumptions described herein. In a previous small study of patients with stable coronary artery disease (10 to 12 patients per group), a decrease in F1+2 ranging from 0.3 to 0.5 nmol/L was observed with otamixaban compared with no change in F1+2 with placebo. Therefore, we sought to demonstrate a decrease in F1+2 of 0.2 nmol/L compared with an active control, UFH. The empirical SD of F1+2 was 0.5 nmol/L in patients with stable angina. We assumed that the SD in a PCI study would increase by 10%. With regard to anti-factor Xa activity, a sample size of 154 in each group would lead to a power >80% to differentiate otamixaban doses.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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A total of 947 patients were randomized to receive either 1 of 5 otamixaban dose regimens (787 patients) or UFH (160 patients). Randomization was stratified by the planned use of GP IIb/IIIa inhibitors: 729 in the "no GP IIb/IIIa inhibitors" stratum and 218 in the "planned GP IIb/IIIa inhibitors" stratum. Among all randomized patients (Figure), 17 (1.8%) were not treated with the study drug. Another 80 patients were not evaluable for the 2 primary end points owing to inadequate F1+2 and anti-factor Xa samples, which left 850 patients (89.7% of all randomized) evaluable for at least 1 primary end point. This included 765 patients analyzed for F1+2 (80.8% of all randomized) and 699 analyzed for anti-factor Xa activity (88.8% of the randomized otamixaban population). The study drug was discontinued prematurely in 3.0% of patients in the pooled otamixaban groups and in 3.8% of those in the UFH group, mainly owing to adverse events. One patient in the otamixaban dose 4 group was lost to follow-up at day 15, and 1 patient in the UFH group withdrew consent at day 20.
Demographics and Baseline Characteristics (Safety Population)
The treatment groups were similar with regard to demographic characteristics, vital signs, risk factors, and indications for percutaneous intervention. Patients were predominantly white (95.6%), and male (77%). The median age was 63 years (interquartile range 56 to 70 years), with 13.5% of patients aged 75 years (maximum age was 86 years). A small proportion (2.9%) of the population had a body weight >120 kg. Of the patients, 12% had a creatinine clearance between 30 and 60 mL/min (no patient had a creatinine clearance <30 mL/min). Among patients randomized to 1 of the otamixaban groups, 102 (13.2%) had a recent ACS (ie, within 7 days before randomization) versus 17 (10.8%) in the UFH group (Table 1).
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Among patients scheduled to receive GP IIb/IIIa inhibitors, 33 (15.6%) received abciximab, 149 (70.6%) received eptifibatide, 18 (8.5%) received tirofiban, and 11 (5.2%) did not receive GP IIb/IIIa inhibitors. Thirty (4.2%) patients received GP IIb/IIIa inhibitors even though this was not planned at randomization. A total of 921 treated patients (99.0%) had an index PCI, and among them, 869 (94.4%) had at least 1 stent (bare-metal or drug-eluting stent) implanted. A closure device was used in 45% of the randomized, treated patients, which was balanced between the treatment groups.
Prior chronic treatment with aspirin and clopidogrel was received in 86% and 47% of patients, respectively (defined as treatment administered for >2 days before randomization). In patients not receiving prior chronic clopidogrel treatment, a loading dose of clopidogrel (300 mg) was administered before PCI in 77.1% of patients, of whom 60% received the loading dose of clopidogrel >2 hours before the start of PCI. Per protocol, it was recommended that treatment with both aspirin and clopidogrel be administered from day 1 through at least the end of the study (day 31). Compliance of >80% with aspirin and clopidogrel was observed in 910 (97.8%) and 901 (96.9%) patients, respectively.
Primary Efficacy Analyses (Based on the Population of Treated Patients With Coprimary End Point)
One patient (in the otamixaban dose 1 group) did not receive the initial bolus of otamixaban as specified in the protocol. All treated patients began the 3-hour intravenous infusion of otamixaban (or placebo) and received the bolus of UFH or placebo. The primary analysis for the first primary end point variable (F1+2) revealed that the first comparison between the highest dose of otamixaban and UFH was statistically significant at the 2.5% level of significance (P=0.008; Table 2). At the second step of the step-down procedure, the comparison between otamixaban dose 4 and UFH was not significant (P=0.1191); therefore, as prespecified, no other comparisons were performed. The anti-factor Xa activity at the end of infusion (Table 3) increased significantly with increasing otamixaban dose regimens (P<0.0001, trend test). The anti-factor Xa activity observed with otamixaban dose 1 (median 65 ng/mL) was significantly lower than that observed with each of the 4 other higher doses of otamixaban (medians of 155, 393, 571, and 691 ng/mL with otamixaban doses 2 to 5, respectively; P<0.0001 for all).
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Clinical Safety Analysis (Safety Population)
In both GP IIb/IIIa inhibitor strata, a significant dose-effect relationship was observed across the otamixaban dose groups for the composite end point of TIMI major, minor, or minimal bleeding through day 3/hospital discharge (range=24.8% to 55.1%; P<0.0001, Cochran-Armitage trend test; Table 4). Bleeding was more common in patients randomized in the "planned use of GP IIb/IIIa inhibitor" than in the other stratum. There were significantly fewer TIMI major, minor, or minimal bleeds observed in the otamixaban dose 1 group than in the UFH group (24.8% versus 37.3%, P=0.018), but significantly more bleeds occurred in the otamixaban dose 4 and 5 groups (49.7%, P=0.030, and 55.1%, P=0.002, respectively, Cochran-Mantel-Haenszel tests adjusted for planned GP IIb/IIIa inhibitor use) than in the UFH group. Almost all bleeding events were TIMI minimal bleeds. The overall incidence of significant TIMI bleeding (major or minor) was 3.0% (2.8% with otamixaban pooled, 3.8% with UFH), with no dose effect observed in the otamixaban groups and no significant difference observed between any otamixaban group and the UFH group. There were only 4 TIMI major bleeding events (1 in otamixaban dose 4 group, 1 in otamixaban dose 5 group, and 2 in the UFH group).
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The majority of bleeding through day 3/hospital discharge was procedure related (in 37% of patients); 7.4% of patients had spontaneous bleeding. In total, 35.2% experienced a vascular access site hemorrhage, with a dose effect seen within the otamixaban regimens. The majority of bleeding events were also vascular access site–related (2.4% otamixaban pooled, 2.5% UFH; Table 5). No intracranial hemorrhage was observed between day 3 and hospital discharge.
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The same dose-effect trend in bleeding was observed through day 14, with bleeding occurring in 27.5% of patients receiving otamixaban dose 1 and in up to 57.7% of those given otamixaban dose 5 versus 38.0% in the UFH group. Between day 3/hospital discharge and day 14, 3 additional patients experienced a significant TIMI major or minor bleed, which was not related to the study drug.
No dose effect was observed for nonhemorrhagic adverse events, which were reported at a comparable rate with otamixaban (40.3%, pooled otamixaban) and UFH (39.2%). Overall, discontinuation of blinded study medication due to an adverse event was not common (1.5%).
Clinical Efficacy Analysis
In total, 746 (97%) patients in the otamixaban groups and 144 (92%) patients in the UFH group had successful PCIs, as determined by the investigators. Thrombus was observed during PCI (in a coronary artery or catheter, or adherent to the guidewire) in 8 patients randomized to the otamixaban groups (1.0%) and in 2 patients randomized to the UFH group (1.3%). Two of these cases (catheter/guidewire-related thromboses) were considered serious (both received otamixaban dose 1). No thrombus was seen in patients receiving otamixaban and a GP IIb/IIIa inhibitor.
There was no clear dose-response relationship in the incidence of ischemic events through day 30 across the otamixaban treatment groups (5.8%, 7.1%, 3.8%, 2.5%, and 5.1% with doses 1 to 5, respectively; P=0.268, Cochran-Armitage trend test; Table 6), nor was there any significant difference in the rate of ischemic events between the UFH group (5.6%) and each of the 5 otamixaban groups. In the 77% of the patients randomized to the "no planned use of GP IIb/IIIa inhibitor" stratum, the incidence of the triple composite end point was 7.4%, 5.9%, 1.6%, 0.8%, and 5.9% in the groups receiving otamixaban doses 1 to 5, respectively, compared with 4.8% in the UFH group. No patients died up to day 30. Three deaths were reported after day 30: 1 patient given the otamixaban dose 1 regimen (a 65-year-old man who was randomized but not treated and who experienced an MI on day 12, followed by cardiac failure, and death on day 34 due to ventricular arrhythmia) and 2 patients given the otamixaban dose 5 regimen (a 55-year-old man who received treatment as per protocol, underwent an uncomplicated procedure, was well on day 31, and experienced sudden death on day 78, and a 79-year-old woman with multiple coronary risk factors, including diabetes mellitus, who was randomized 7 days after an inferior MI, had a staged successful procedure with multiple stent implantation, and on day 9 experienced an MI with stent occlusion, went into cardiac failure, and died on day 33). For MI, a maximum CK-MB value 5 times the upper limit of normal was observed in 2.6% of otamixaban patients (range 1.3% to 4.5%) compared with 3.8% of UFH patients. Among patients randomized in the otamixaban groups in the "no planned use of GP IIb/IIIa inhibitor stratum," 10 (1.3%) received a bail-out GP IIb/IIIa inhibitor during PCI.
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Effects on the Coagulation Marker Activated Partial Thromboplastin Time
A dose-related effect within the otamixaban groups was observed on activated partial thromboplastin time at the end of the 3-hour infusion (Table 7). Minimal change in activated partial thromboplastin time was observed with otamixaban dose 1. At other otamixaban doses, activated partial thromboplastin time returned to baseline (<50 seconds in >75% of patients) within 30 minutes and 1, 2, and 4 hours at doses 2, 3, 4, and 5, respectively.
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Discussion |
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Prevention of coronary artery thrombosis in patients with unstable angina or non–ST-segment elevation MI,15 as well as in patients experiencing arterial injury during PCI, is the key goal of antithrombotic therapy.13,16 Despite its shortcomings, UFH remains the most commonly used anticoagulant during PCI. Newer drugs such as bivalirudin17 and intravenous enoxaparin18 have been investigated in elective PCI. Factor X occupies a pivotal role in the coagulation cascade, and its activation leads to the generation of thrombin. Selective inhibition of factor Xa is therefore an attractive target for new anticoagulant drugs and might provide an increased benefit:risk ratio over standard anticoagulants such as UFH and enoxaparin, which target both factor X and factor II.
Otamixaban: Pharmacology and Previous Clinical Experience
Otamixaban is a selective and direct inhibitor of factor Xa8 and, unlike other anticoagulants such as UFH, enoxaparin, or fondaparinux, does not require antithrombin as a cofactor. Both in vitro and ex vivo studies indicate that otamixaban reduces thrombin generation by inhibition of fluid-phase and clot-bound factor Xa without effects on platelet aggregation.8 The effective half-life of otamixaban in humans is short (1.5 to 2 hours9,10,19), and when administered intravenously, it presents a rapid on/off of anticoagulant activity related to short initial elimination of the drug on cessation of the dose.
Current and Previous Studies With Anti-Factor Xa Inhibitors
On the basis of results of the present SEPIA-PCI trial, nonurgent PCI was found to be both safe and feasible with otamixaban as the sole anticoagulant, with or without GP IIb/IIIa inhibitors. There was a clear otamixaban dose response on bleeding: Lower doses appeared "safer" than UFH, whereas the highest otamixaban dose regimen significantly increased the composite bleeding end point compared with UFH. However, the rate of TIMI major bleeds, even at the higher doses of otamixaban, was exceedingly low. This compares favorably to the dramatic reduction in major bleeding with intravenous enoxaparin versus UFH observed in the recently presented STEEPLE trial (Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention Patients).18
No dose response was seen on F1+2, but marked variability in the range of values for F1+2 may make it a poor surrogate. No dose response on ischemic events was seen, but the present study with 947 patients was not powered for these outcomes. In the recently published ASPIRE study (Arixtra Study in Percutaneous Coronary Intervention: a Randomized Evaluation),7 a significant decrease in the release of F1+2 was seen with fondaparinux versus UFH 6 and 12 hours after PCI; however, no data were presented regarding the periprocedural levels of F1+2. In the present study, no significant difference was observed with regard to clinical events during PCI across otamixaban doses. All otamixaban doses tested with or without planned GP IIb/IIIa inhibitors appeared to be associated with reasonably low rates of clinical events; however, serious catheter/guidewire thrombus was observed in 2 patients treated with the lowest otamixaban dose without GP IIb/IIIa inhibitors. Catheter thrombosis was also seen in the recently published OASIS (Organization to Assess Strategies for Ischemic Syndromes)-6 trial,20 in which 22 patients receiving 2.5 mg of fondaparinux had guiding-catheter thrombosis compared with 0 patients in the control group, which indicates that a 2.5-mg dose of fondaparinux may be insufficient to protect against guiding-catheter thrombosis.
Alexander et al6,21 completed 2 small clinical trials of another selective direct factor Xa inhibitor, DX-9065a, based on the initial observations of Dyke et al.5 These dose-ranging PCI and ACS pilot trials demonstrated a clinical effect roughly similar to that for intravenous UFH.22 Some early preclinical work has been done on a promising oral, selective, direct anti-factor Xa inhibitor, BAY 59-7939; however, no clinical experience has been reported yet in coronary interventions.12,23
Clinical Utility of Prothrombin F1+2 and Anti-Factor Xa Activity
To the best of our knowledge, SEPIA-PCI provides 1 of the largest clinical data sets (>900 patients with serial measurements) regarding the behavior of anti-factor Xa activity and that of the thrombotic markers F1+2 in clinical practice. There is significant variability in the latter, which to some extent limits its usefulness as a surrogate marker. Median anti-factor Xa activity values increased across the 5 groups with increasing otamixaban dose, which indicates that weight-adjusted dosing of otamixaban was adequate and did not necessitate monitoring of anticoagulation for dose adjustment during therapy. On the basis of the results of our trial, a relationship could be hypothesized between increasing anti-factor Xa activity and bleeding (mostly minimal) but not between increased suppression of F1+2 release and improved clinical outcomes.
Study Limitations
This was a phase II clinical trial and therefore was not adequately powered to determine the efficacy and safety of otamixaban. Further testing is required to confirm the efficacy and safety of otamixaban. The relatively low rate of clinical ischemic events did not allow for the detection of a dose response with otamixaban.
Conclusions
SEPIA-PCI met its 2 coprimary objectives to evaluate F1+2 (relative to UFH) and anti-factor Xa activity (with different otamixaban doses). F1+2 was reduced significantly more with higher doses of otamixaban than with UFH, and there was a significant dose response across otamixaban dose regimens in anti-factor Xa activity. There was no dose effect and no significant difference in the incidence of TIMI major or minor bleeding between the otamixaban and UFH groups. There was a clear dose response with regard to the incidence of the composite of TIMI major, minor, and minimal bleeding at day 3 or hospital discharge, with the majority of hemorrhages characterized as minimal and observed at the vascular access site. These results set the stage for more definitive trials with otamixaban in non–ST-segment elevation ACS.
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Acknowledgments |
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We would like to acknowledge the invaluable help of Maria Brynildsen, Anne Paccaly, and Florence Joulain.
Source of Funding
Sanofi-aventis sponsored the SEPIA-PCI trial. Members of the steering committee designed the trial with input from the sponsor. The content of the manuscript, in its entirety, is the responsibility of the listed authors.
Disclosures
All authors received research support from sanofi-aventis for their participation in the SEPIA-PCI trial. In addition, Dr Cohen received research support from sanofi-aventis and served on the speaker’s bureau for sanofi-aventis. Dr Bhatt served on the speaker’s bureau for Bristol Myers Squibb, sanofi-aventis and The Medicines Company and received honoraria from and served as a consultant for AstraZeneca, Bristol-Myers Squib, Centocor, Eisal, Eli Lilly, GlaxoSmithKline, Milennium, ParinGenix, PDL BioPharma, sanofi-aventis, Schering-Plough, and the Medicines Company. Prof Montalescot received research support from sanofi-aventis, Eli Lilly and Bristol-Myers Squibb and served as a consultant for sanofi-aventis, Eli Lilly, Bristol-Myers Squibb, Merck Sharpe & Dohme, GlaxoSmithKline, Proctor & Gamble, Schering-Plough, Alcomed, and AstraZeneca. Dr Henry received research support from sanofi-aventis and served on the speaker’s bureau for sanofi-aventis. Dr Tamby is an employee of sanofi-aventis and owns sanofi-aventis company stock.
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CLINICAL PERSPECTIVE
Percutaneous coronary intervention patients routinely experience arterial injury and sudden intense thrombotic stimuli during balloon angioplasty and stent deployment. In the present dose-ranging study, otamixaban was investigated in patients undergoing nonurgent percutaneous coronary intervention. In this trial, 947 patients were assigned to receive either 1 of 5 doses of otamixaban or weight-adjusted unfractionated heparin. The safety of the different doses was assessed, as was the level of prothrombin fragments (F1+2) and anti-factor Xa activity. The results of this study showed that nonurgent percutaneous coronary intervention was both safe and feasible with otamixaban as the sole anticoagulant with or without glycoprotein IIb/IIIa inhibitors. Prothrombin fragments were reduced significantly more with higher doses of otamixaban than with unfractionated heparin, and there was a significant dose response across otamixaban dose regimens in anti-factor Xa activity. There was no dose effect and no significant difference in the incidence of Thrombolysis In Myocardial Infarction major or minor bleeding between the otamixaban and unfractionated heparin groups. This preliminary study suggests otamixaban may prove to be a suitable alternative to currently available anticoagulants in percutaneous coronary intervention patients, and it sets the stage for adequately powered clinical outcome trials of selective direct factor Xa inhibition in patients with non–ST-segment–elevation acute coronary syndromes.
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Footnotes |
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The online-only Data Supplement, consisting of a list of trial participants, clinical centers, and principal investigators, is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.106.653428/DC1.
Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00133731.
Guest Editor for this article was Paul S. Teirstein, MD.
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