Rivaroxaban: Oral direct factor Xa inhibition for the prevention and treatment of venous and arterial thrombosis

Misselwitz, Frank , Perzborn, Elisabeth , Kubitza, Dagmar , Laux, Volker. Bayer Schering Pharma AG, Aprather Weg 18a, 42096 Wuppertal, Germany.

Anticoagulants are used for the prevention and treatment of venous and arterial thromboembolic disorders. Unfractionated heparin (UFH) remains the intravenous anticoagulant of choice for acute thrombotic conditions. Low molecular weight heparins (LMWHs) have proven efficacy and a good safety profile, but their use is limited due to subcutaneous administration. Warfarin, which until recently was the only available oral anticoagulant – and is still the most frequently prescribed anticoagulant. LMWHs and warfarin still remain the cornerstone of antithrombotic prophylaxis and treatment. Over the past decades many approaches to developing antithrombotic drugs that interfere with enzymes in the coagulation cascade have been explored.

In the search for new anticoagulants, the activated serine protease Factor Xa (FXa) appears to be a particularly promising target and has attracted great interest in recent years. Once it was established that FXa inhibitors could potentially have the haemostatic properties of a safe anticoagulant, new compounds were first developed and tested in the late 1980s. These were originally naturally occurring FXa inhibitors and recombinant forms of these compounds, before research started focussing on selective, small-molecule, oral, direct inhibitors of FXa. Rivaroxaban is the first such compound which has been approved for clinical use. This review will present the development of rivaroxaban, from the structure-activity relationship studies that led to its discovery to the main preclinical and clinical studies performed to date on this promising drug, and will give a brief overview of other oral, direct FXa inhibitors which are in advanced clinical development.

Following the discovery of FXa as a valuable target for anticoagulants, preliminary studies seemed to indicate that FXa inhibitors could constitute an improved alternative to the currently available standard therapies. To date, of all the oral, direct FXa inhibitors in clinical development, rivaroxaban has demonstrated the greatest potential in the prevention of venous thromboembolism after major orthopedic surgery, e.g. total hip or knee arthroplasty, due to its superiority to the LMWH enoxaparin and its balanced safety profile. Thus, rivaroxaban may offer a more effective alternative to LMWH in this indication, with added benefits of once-daily, oral, fixed dosing.