Cardiovascular Clinical Trialists (CVCT) Forum – Paris 2012 - Workshop 1 : Dosing Issues, Questions

MODIGLIANI Workshop 1 - Friday November 30, 2012 :THE THROMBOSIS TRIALISTS WORKSHOPDOSE AND TARGET PATIENT POPULATIONS ISSUESChairpersons: Peter CLEMMENSEN, Copenhagen, DEN - George-Andrei DAN, Bucharest, ROMWebcast: Johanne SILVAIN, Paris, FRAThe development of new antithrombotic agents is a challenging area of cardiovascular medicine.These agents generally have a narrow therapeutic margin, and it is often difficult to find the optimal balance between efficacy (reduction of ischemic events) and safety (no excess of bleeding events).➢ Phase II trials are designed to generate signals of safety and efficacy and to select the dose or doses for phase III pivotal trials. However, phase II data are limited by small numbers of events and short follow-up. Some recent phase III trials have produced results that were unanticipated from the phase II findings.➢ Adaptive designs to explore safety (bleeding) risks have been proposed to overcome the current limitations of dose selection for phase III. Several concerns with these designs remain unresolved, such as appropriate methods to control Type I error for both safety and efficacy. Also, adaptive designs will only be useful if they are accepted by the regulatory agencies. The agencies have not announced a final position yet. Implementation of adaptive designs requires early and in-depth interaction between the agencies and study sponsors.➢ With the newer anti-thrombotic agents progressively potentially replacing warfarin, we are moving from a target INR guided dosing to an indication/risk guided dosing. Different doses are being developed for different indications. There is an intense discussion on whether doses of anticoagulants should be similar or different for preventing DVT after orthopedic surgery, for treating DVT and pulmonary embolism, for AFib, for prevention after ACS and for prevention in artificial valves. Dose - effect relationships are difficult to establish. A balance should be found between the dose relationship with clinical benefit and the dose relationship with the risk of bleeding. An intense discussion is also ongoing on whether a range of doses rather than one single dose should be made available for the same disease.➢ Exploring new indications for the newer anti-thrombotic agents might be one target of interest in patients with heart failure. In patients with coronary artery disease and HF, a majority of deaths (including sudden death) appear to be related to ischemia and worsening of heart failure. The presence of pulmonary embolism as a cause of worsening HF is underestimated and certain underlying pathophysiological mechanisms are common to both arterial and venous thrombi. It has been recognized since long that HF is associated with hypercoagulable state, and, at the cellular level, it has been reported that thrombin exerts multiple actions on cardiomyocytes which can favor the genesis of arrhythmias and myocyte injury. Antithrombotic strategies to reduce the risk of death, myocardial infarction (MI), or stroke have been tested in several randomized trials. These studies were underpowered and the recently published WARCEF trial is inconclusive. With the newestant-thrombotic agents being probably safer, heart failure might be one of the next diseases where to expand the indications of new antithrombotics. Designing an anti-thrombotic trial in HF might also yield meaningful data regarding the potential role of thrombosis in patients with heart failure.The aim of this session is to explore novel, scientifically rigorous methodologies through an open, cooperative dialogue among investigators, regulators, and sponsors.Session program:Dosing issues• How to secure the optimal dose(s) for phase III? Can adaptive design help?Speaker: Nancy GELLER, NHLBI, USADiscussant: Michael GIBSON, Boston, USA• Different doses, different indications? DVT and pulmonary embolism, Atrial fibrillation, ACS, artificial valvesSpeaker: Freek VERHEUGT, Amsterdam, NEDDiscussant ACS: Maarten SIMOONS, Rotterdam, NEDIndustry viewpoint: Scott BERKOWITZ, Bayer, USA - Christophe GAUDIN, Sanofi, FRA - Lloyd HASKEL, J&J, USA - Yasser KHDER, Boehringer Ingelheim, FRA - Joerg KOGLIN, Merck, USA - John LAWRENCE, BMS, USARegulatory viewpoint: Angeles ALONSO, EMEA, ESP - Pieter DE GRAEF, EMEA, NED - Kaori SHINAGAWA, PMDA, JAPNew indications: Is heart failure a viable new potential indication for anti-thrombosis therapySpeaker: Faiez ZANNAD, Nancy, FRADiscussants: Efthymios DELIARGYRIS, MedCo, USA - Lloyd HASKEL, J&J, USARegulatory viewpoint: Krishna PRASAD, MHRA, GBR