ABSTRACT
A new generation of antithrombotic agents that target a single enzyme within the procoagulant
cascade is making its way into mainstream clinical practice. Borrowing selectively
from the properties of their parent anticoagulant, unfractionated heparin, as well
as from those of peptide anticoagulants from reptile or insect venoms, designers of
the new drugs have created targeted inhibitors of thrombin, factor Xa, or other specific
factors in the procoagulant pathways. These new agents promise efficacy and safety
profiles far more favorable than those of conventional anticoagulants for thromboprophylaxis
after major orthopedic surgery and require no laboratory monitoring of drug efficacy
in this setting. Ximelagatran, the oral “prodrug” of the direct thrombin inhibitor
melagatran, is in phase III of clinical development. Clinical trials using various
dosages of ximelagatran, sometimes preceded by subcutaneous melagatran, as thromboprophylaxis
after total hip or knee replacement surgery have suggested efficacy equal to or better
than that of warfarin and enoxaparin. The best dosing regimen and optimal timing of
first dose for melagatran and ximelagatran remain to be determined, as do the mechanism
and impact of drug disturbance of hepatic function. Fondaparinux, a selective, synthetic
inhibitor of factor Xa, has been shown in large clinical trials to be superior to
low-molecular-weight heparins and is approved as a fixed once-daily subcutaneous 2.5-mg
dose for thromboprophylaxis for hip or knee replacement surgery and after hip fracture
repair. Fixed-dose fondaparinux 2.5 mg initiated 6 to 8 hours after surgery achieved
superior efficacy and comparable safety in head-to-head comparisons with enoxaparin
for the prevention of venous thromboembolism after major orthopedic surgery. Fondaparinux
is the only agent approved for use in hip fracture patients in the United States at
this time and has recently gained approval for extended prophylaxis in this patient
population.
KEYWORDS
Thrombosis - thromboprophylaxis - orthopedic surgery - ximelagatran - fondaparinux
- low-molecular-weight heparin
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Wayne State University School of Medicine, Harper University Hospital, Karmanos Cancer
Institute
Detroit, MI 48201
eMail: andersen@karmanos.org
