Clinical-based evidence demonstrates that long-term oral
anticoagulant therapy with the
vitamin K antagonists is highly effective for the
secondary prevention of
venous thromboembolism (VTE). However, owing to fear of
bleeding complications and the inconvenience of coagulation monitoring, many patients do not receive the required
duration of treatment. This can lead to a high incidence of recurrent VTE events and has prompted the evaluation of alternative treatment strategies and the development of new
anticoagulants for VTE management. For patient groups in which it is particularly difficult to maintain the target intensity of anticoagulation,
low-molecular-weight heparin (
LMWH) has been found to significantly reduce the risk of recurrent VTE without increasing
bleeding risk. The parenteral administration of
LMWH, however, is a drawback for long-term use in the outpatient setting. Long-term
warfarin use at a lower intensity (international normalized ratio [INR] 1.5-2.0) has also been assessed as a possible strategy to reduce
bleeding complications and the need for monitoring, but results were disappointing when compared with conventional-intensity
warfarin (INR 2.0-3.0). New
therapies in development that may potentially offer a more favourable benefit-risk profile and greater consistency and predictability of response include the synthetic pentasaccharides,
fondaparinux and
idraparinux. These par enterally administered indirect
factor Xa inhibitors have a predictable pharmacokinetic profile, allowing use without coagulation monitoring.
Fondaparinux to date has only been evaluated in the initial treatment (5-7 days) of symptomatic
deep vein thrombosis. In contrast,
idraparinux, with its longer half-life (80 h) allowing once-weekly parenteral dosing, has the potential for long-term treatment and is currently being assessed in phase III trials for the
secondary prevention of VTE. Currently, the most promising new therapeutic option is the first of the oral
direct thrombin inhibitors,
ximelagatran. The
THRombin Inhibitor in
VEnous thromboembolism (THRIVE) clinical trial programme has demonstrated that this agent is as effective as standard
therapy for the acute treatment (THRIVE Treatment) and
secondary prevention (THRIVE lll) of VTE events and is well tolerated when used for 6 months or over extended periods up to 1.5 years. Furthermore, with
oral administration, fixed dosing and no requirement for anticoagulation monitoring,
ximelagatran has the potential to facilitate optimal use and duration of VTE treatment by overcoming the limitations of current agents.