ABSTRACT
Therapy for venous thromboembolism (VTE) currently involves a minimum of 3 months
of anticoagulation. After cessation of therapy, however, recurrent venous thrombosis
occurs at rates of 6 to 9% per year. Clinical trials have demonstrated the benefits
of extending anticoagulation beyond 3 months for the prevention of recurrent VTE events.
Despite this, many eligible patients do not receive the required thromboprophylaxis
and the incidence of recurrent VTE remains too high for a preventable condition. A
reason for failure to use prophylaxis is the fear of bleeding complications with current
oral anticoagulants such as warfarin. Warfarin has an unpredictable pharmacokinetic
profile and a variable dose-response relationship that requires frequent coagulation
monitoring and dose adjustments to maintain a target intensity that is both safe and
effective. Alternative strategies for long-term prophylaxis, which may potentially
provide more consistent anticoagulant responses and reduce coagulation monitoring
requirements, include the use of low-molecular-weight heparin (LMWH), treatment with
warfarin at a lower intensity, and the introduction of novel anticoagulants. The long-term
use of LMWH has been found to be a particularly favorable treatment option for cancer
patients in whom it is difficult to control the intensity of anticoagulation. In clinical
trials, LMWH significantly reduced the risk of recurrent VTE without increasing bleeding
risk. The parenteral administration of the LMWHs, however, is a drawback for long-term
use in the outpatient setting. A clinical trial assessing the efficacy and safety
of long-term low-intensity warfarin treatment found this therapy to be better than
placebo, but another study showed that conventional intensity warfarin was significantly
more efficacious than low-intensity warfarin. New therapies in development that may
offer improved safety-efficacy profiles are the synthetic pentasaccharides fondaparinux
and idraparinux and the oral direct thrombin inhibitor ximelagatran. Parenterally
administered fondaparinux has been shown to be as effective as LMWH for the acute
treatment (5 to 7 days) of symptomatic deep vein thrombosis. Idraparinux, with once-weekly
parenteral dosing, is currently being assessed in phase III clinical trials for the
long-term secondary prevention of VTE. Ximelagatran is the first oral agent in the
new class direct thrombin inhibitors. With a fast onset of action and oral administration,
ximelagatran is a candidate for both acute and chronic therapy. The Thrombin Inhibitor
in Venous Thromboembolism (THRIVE) clinical trial program has demonstrated that this
agent has a favorable benefit-risk profile compared with standard therapy for the
initial treatment (6 months) and secondary prevention (up to 18 months) of VTE. However,
in a substantial proportion (6 to 13%) of patients given extended ximelagatran therapy,
elevated serum transaminase enzymes developed, typically in the first 2 to 4 months
of treatment. Even though these elevations usually abated without clinical sequelae
whether or not treatment was continued, their clinical relevance remains unclear.
In addition, locally reported coronary events occurred more frequently in ximelagatran-treated
patients during the initial 6 months of treatment, the reason for which is yet unclear.
The consistent anticoagulant response and fixed oral dosing without coagulation monitoring
allows ximelagatran to overcome many of the limitations inherent to current treatment
options for VTE treatment and secondary prevention, provided the problem of liver
enzyme elevation and coronary events is resolved.
KEYWORDS
Venous thromboembolism treatment and secondary prevention - oral anticoagulation -
low-molecular-weight heparin - synthetic pentasaccharides - ximelagatran - THRIVE
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Menno V HuismanM.D.
Department of General Internal Medicine, Leiden University Medical Center
P.O. Box 9600, 2300RC Leiden 1211
The Netherlands
