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Mr Harvey White,
Presenter | see Discussant report
Marc Sabatine, (United States of America)
List of Authors: Marc S. Sabatine, MD, MPH on behalf of the SEPIA-ACS1 TIMI 42 Investigators
Background: For many years, unfractionated heparin (UFH) has been the cornerstone of anticoagulant therapy for patients presenting with a non-ST-elevation acute coronary syndromes (NSTE ACS). However, UFH has numerous limitations, including being an indirect, non-selective inhibitor of coagulation factors with unpredictable pharmacodynamic activity. In contrast, otamixaban is a novel, synthetic, intravenous, direct, selective inhibitor of Factor Xa with an initial half life of 30 minutes and predictable pharmacodynamic activity.
Methods: We randomized 3241 patients within 24 hours of presentation of a NSTE ACS (with either an elevated biomarker of necrosis or ST segment deviation and in whom an invasive strategy was planned) to receive double-blinded treatment with one of 5 doses of otamixaban (0.08 mg/kg bolus followed by infusions ranging from 0.035 to 0.175 mg/kg/hr) or UFH + the glycoprotein IIb/IIIa inhibitor (GPI) eptifibatide (ClinicalTrials.gov unique identifier: NCT00317395). The primary efficacy endpoint was the composite of all-cause death, new myocardial infarction, severe recurrent ischemia requiring urgent revascularization, or bailout use of a GPI through day 7. The primary safety endpoint was TIMI major or minor bleeding unrelated to CABG. Dose arm 1 (lowest dose) was stopped early at the recommendation of the Data Safety Monitoring Committee due to inadequate anticoagulation; the remaining dose arms enrolled to scheduled completion.
Results: The mean age of subjects was 61 years and 31% were female. A total of 99% underwent angiography, 63% underwent PCI, and 4% underwent CABG; 98% were treated with aspirin and 98% with clopidogrel. The rate of the primary efficacy and safety endpoints are shown in the Figure. There was no statistically significant difference in the rate of the primary efficacy endpoint across the otamixaban arms. However, in all of the otamixaban arms except dose arm 1, the point estimate for the primary efficacy endpoint favored otamixaban over UFH + GPI. Specifically, at intermediate doses (dose arm 3, 0.105 mg/kg/hr and dose arm 4, 0.140 mg/kg/hr) treatment with otamixaban resulted in approximately 40% reductions in the primary efficacy endpoint (RR 0.61, 95% CI 0.36-1.02 and RR 0.58, 95% CI 0.34-0.996, respectively) and approximately 45% reductions in death or MI (RR 0.52, 95% CI 0.28-0.98 and RR 0.56, 95% CI 0.30-1.03, respectively) as compared with UFH + GPI. There was a significant dose response in terms of the primary safety endpoint among the 5 otamixaban arms (P=0.0003), but the rate in otamixaban dose arms 3 & 4 (3.1-3.4%) were not significantly higher than the rate with UFH + GPI (2.7%).
Otamixaban is a novel, synthetic, direct, selective inhibitor of Factor Xa that, at intermediate doses in patients presenting with NSTE ACS, may be associated with as much as a 40% lower risk of ischemic events and a comparable risk of bleeding compared with UFH + GPI. These data are encouraging for additional studies of otamixaban in patients with NSTE ACS.
Discussant | see Presenter abstract
Harvey White, FESC (New Zealand)Presentation webcastPresentation slides
The SEPIA-ACS1 TIMI 42 (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-Acute Coronary Syndromes-Thrombolysis In Myocardial Infarction) trial is a well performed trial. It tested otamixaban which is a short acting intravenous direct factor Xa inhibitor with a half life of about 3 hours compared to unfractionated heparin (UFH) plus eptifibatide in patients with non-ST elevation acute coronary syndrome (NSTEACS). The trial identified a signal for reduction in ischaemic events with otamixaban but also a signal associated with increased bleeding. This is an important study with a high rate of angiography (98%) and guideline recommended medications. The trial was a large dose ranging trial in 3241 patients with NSTEACS following a dose ranging trial in 947 patients undergoing urgent PCI (SEPIA PCI trial). This is to be compared to a previous era when small numbers of patients were investigated in order to select a dose for a phase III trial e.g. in GUSTO 1 <100 patients were tested with the streptokinase/TPA combination and in GUSTO IIa <50 patients were tested with the hirudin dose that was evaluated in GUSTO IIa. The patients enrolled in SEPIA-ACS1 were at high risk for ischaemia (ST deviation ≥0.1mv in the UFH plus eptifibatide group 57%, elevated biomarker in the UFH plus eptifibatide group 79%) and underwent a planned early invasive strategy. The primary endpoint was a composite of death, MI, urgent revascularization and bailout IIb/IIIa antagonists for an ischaemic or thrombotic endpoint. Five doses of otamixaban were tested (0.08mg/kg bolus followed by infusions of 0.035, 0.070, 0.105, 0.140, or 0.175mg/kg/hr) or a control of UFH plus eptifibatide with a single bolus of eptifibatide rather than 2 boluses: 180ug/kg and infusion for 18-24 hours with renal adjustment. This is different to the double bolus 180ug/kg 10 minutes apart used in the ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) and EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndrome) trials and would not be expected to achieve blockade of greater than 90% of available glycoprotein IIb/IIIa receptors in more than 90% of patients. The primary safety endpoint was TIMI major or minor bleeding not related to CABG. This raises the question to what definition of bleeding should be used? There are many different definitions for bleeding. Also different bleeds have different meaning e.g.: intracranial haemorrhage has quite a different clinical meaning than a fall in haemoglobin. Over what time period should we capture the information about bleeding? Perhaps it should be 96 hours with PCI with a landmark analysis out to 30 days or 120 hours with medical treatment with a landmark analysis out to 30 days. Also is there an acceptable ceiling for major bleeding? In the EARLY ACS trial, TIMI major bleeding with upstream eptifibatide was 2.6% at 120 hours vs 1.8% for patients who received eptifibatide in the catheterisation laboratory. Clearly we need a common template to be available so that trials can be compared. There is also a need to have reversible agents so that once present, bleeding can be stopped.Bleeding is associated with increased morbidity and mortality (OASIS 5) and it would seem reasonable to test a dose with decreased bleeding than control. Clearly there is much to be gained in capturing minor bleeding, but for selection of a drug dose to move into phase 3 trials, perhaps we should be more focused on what is a ceiling for unacceptable bleeding. This ceiling may be gleaned from major bleeding data and may be around the level of 2.6% with upstream eptifibatide as in EARLY ACS.The primary endpoint in SEPIA- ACS1 included adjudicated thrombotic and non-thrombotic procedural complications during the index PCI (including abrupt or threatened closure, new intracoronary thrombus, side branch closure, distal embolization, no-reflow, thrombus in catheter or adherent to guidewire, coronary dissection with decreased flow, difficulty in reaching or crossing lesion, unplanned stent use, suboptimal results, coronary perforation (tamponade)). The 0.035mg/kg/hr does was stopped because of clinical evidence of inadequate anticoagulation. The primary endpoint was reduced from 6.2% in the combined UFH plus eptifibatide arm 4.6%, 3.8%, 3.6% and 4.3% (P trend=0.34). For death and MI there was a similar approximately 57% reduction for the 4 doses of otamixaban (2.8%, 2.6%, 2.7%, 2.8%) compared with UFH plus eptifibatide. Rates of the primary safety endpoint of TIMI major and minor bleeding across the 5 otamixaban dose were 1.6%, 1.6%, 3.1%, 3.4% and 5.4% (P trend=0.0001); the rate in the control arm was 2.7%. Patients treated with 0.070mg/kg/hr tended to have higher rates of bailout glycoprotein IIb/IIIa inhibitor vs; 1.99, (95% CI 0.73-5.44), whereas higher doses of otamixaban had similar use to that observed with UFH plus eptifibatide In SEPIA-PCI there were 8 catheter thromboses. Perhaps supplemental UFH should be considered to prevent contact thrombosis with otamixaban as with the indirect factor X inhibitor fondaparinux (OASIS 5, OASIS 6). It would be interesting to know how many cases of new intracoronary, catheter or guidewire thrombus occurred in the current trial. In addition, further information could be provided in respect of different loading doses of clopidogrel for both efficacy and bleeding and for the etiology of strokes; were some of these intracranial haemorrhages; 3 strokes occurred in the 0.105mg/kg/hr dose and 1 in the 0.07mg/kg/hr dose. Myocardial infarction was part of the composite endpoint and used the universal definition for MI and PCI but not for CABG where only 5x elevation of biomarkers or new Q waves was required and not both or evidence of new graft or native coronary artery occlusion. The universal redefinition of MI recommended that a universal definition template be available with different definitions and cutpoints for biomarkers and hopefully that will be available on line, so we can make comparisons with other trials. The investigators of the SEPIA-ACS1 trial suggested that “Otamixaban 0.105-0.140mg/kg/hr appears to be best range for further study as a replacement for UFH plus glycoprotein IIb/IIIa”. However the lower dose of Otamixaban (0.07mg/kg/hr) had similar efficacy for the primary endpoint, and for death and MI. In addition it had the lowest bleeding compared with the next two doses (52%, 47% lower for major and minor bleeding) and 59% lower than control; 1.6% vs 2.7%. Importantly TIMI major bleeding was also similar in the 0.07mg/kg/hr group to control (1.8%) and 53%, 69% lower than the next two higher doses but there were increased thrombotic complications and 2.2% (1.1% control) use of IIb/IIIa antagonists compared with bivalirudin in the ACUITY trial where 7% of bailout IIb/IIIa antagonists were used. However this should be evaluated from the point of view as to whether hard clinical adverse events ensued. There continues to be an unmet need for patients with acute coronary syndromes for both ischaemia and the new paradigm for bleeding. SEPIA-ACS1 provides new information which will enable appropriate dose selection for a phase III trial.
Clinical Efficacy and Safety of Otamixaban, an Intravenous, Selective Factor Xa Inhibitor for the Treatment of Non-ST-Elevation Acute Coronary Syndromes: Results of SEPIA-ACS1 TIMI 42
This congress report accompanies a presentation given at the ESC Congress 2009. Written by the author himself/herself, this report does not necessarily reflect the opinion of the European Society of Cardiology.