Is there an acceptable ceiling for bleeding for an antithrombotic drug dose to be tested in a phase 3 trial?

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 i.v. direct factor Xa inhibitor with a half-life of 30 min, compared with 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 non urgent percutaneous coronary intervention (PCI; SEPIA PCI trial). This is to be compared with 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 ,100 patients were tested with the streptokinase–tissue plasminogen activator (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 0.1 mV 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, myocardial infarction (MI), urgent revascularization, and bail-out IIb/IIIa antagonists for an ischaemic or thrombotic endpoint. Five doses of otamixaban were tested (0.08 mg/kg bolus followed by infusions of 0.035, 0.070, 0.105, 0.140, or 0.175 mg/kg/h) or a control of UFH plus eptifibatide with a single bolus of eptifibatide rather than two boluses: 180 mg/kg and infusion for 18–24 h with renal adjustment. This is different from the double bolus 180 mg/kg 10 min apart used in the ESPIRT (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 .90% of available glycoprotein IIb/IIIa receptors in .90% of patients. The primary safety endpoint was TIMI major or minor bleeding not related to coronary artery bypass graft (CABG). This raises the question of what definition of bleeding should be used. There are many different definitions of bleeding. Also, different bleeds have different meanings, 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 h with PCI with a landmark analysis out to 30 days or 120 h with medical treatment with a landmark analysis out to 30 days. Also is there an acceptable ceiling for major bleeding? The Table 1 shows rates of TIMI major bleeding in recent trials. In the EARLY ACS trial TIMI major bleeding with upstream eptifibatide was 2.6% at 120 h vs. 1.8% for patients who received eptifibatide in the catheterization laboratory. Clearly we need a common template to be available so 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 compared with control. Clearly there is much to be gained in capturing minor bleeding, but for selection of a drug dose to move into phase III trials, perhaps we should be more focused on what is a ceiling for unacceptable bleeding. This ceiling may be gleaned from major bleeding data