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

Abstract

This editorial refers to ‘Otamixaban for the treatment of patients with non-ST-elevation acute coronary syndromes (SEPIA-ACS1 TIMI 42): a randomised, double-blind, active-controlled, phase 2 trial’†, by M. Sabatine, published in the Lancet , 2009;374:787–795. 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).1 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 GUSTO2 <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.3 The patients enrolled in SEPIA-ACS14 were at …