Selective Factor Xa Inhibition Improves Efficacy of Venous Thromboembolism Prophylaxis in Orthopedic Surgery

Philip C. Comp, M.D., Ph.D.

Disclosures

Pharmacotherapy. 2003;23(6) 

In This Article

Alternative Strategies in Antithrombotic Drug Development

Although targeted factor Xa inhibition appears to hold great promise as a strategy for the development of improved antithrombotic agents for venous thromboembolism prophylaxis in major orthopedic surgery, other classes of drugs under clinical development demonstrate a similar potential. Notable among these are the direct thrombin-specific inhibitor ximelagatran (AstraZeneca, London, England) and the oral heparin formulation sodium N-[8-(2-hydroxy-benzoyl)amino]caprylate (SNAC) heparin (Emisphere Technologies, Inc., Tarrytown, NY).

Ximelagatran is a prodrug that is administered orally and then rapidly metabolizes to its active form, melagatran. The drug exerts its antithrombotic effect by directly binding to circulating and bound thrombin, thereby inhibiting catalytic activity by an antithrombin III-independent mechanism. Oral ximelagatran dosing represents a distinct advantage over the subcutaneous and intravenous formulations typical of approved agents for thromboprophylaxis. The drug appears to offer ease of clinical administration in that, like fondaparinux and to a lesser extent LMWH, there is no need to monitor the drug's anticoagulant effect routinely.

A number of phase II and III trials have compared ximelagatran (alone or in combination with melagatran) with warfarin or LMWHs for thromboprophylaxis in major hip and knee surgery.[141,142,143,144,145,146,147,148] Among the phase III studies, oral ximelagatran 24 mg twice/day administered postoperatively was found to be well tolerated and at least as effective as warfarin for preventing total thromboembolism in patients who underwent knee replacement surgery.[146] These findings recently were supported by the demonstration that oral ximelagatran 36 mg twice/day safely provides superior benefit, relative to warfarin, for the composite end point of distal and/or proximal DVT and/or objectively confirmed symptomatic venous thromboembolism and/or all-cause mortality in this same surgical population.[147]

Postoperative administration of subcutaneous melagatran followed by oral ximelagatran was not found to be superior to preoperatively administered enoxaparin in patients undergoing total hip or knee replacement.[144] Also, in another phase III trial comparing postoperative ximelagatran with postoperative enoxaparin in patients undergoing total hip replacement, enoxaparin-treated patients had significantly fewer venous thromboembolism events than did ximelagatran-treated patients, whereas bleeding rates were low and comparable between the groups.[145] Although these trials, disappointingly, demonstrated no added benefit in prevention of venous thromboembolism with ximelagatran relative to enoxaparin, more recent phase III findings in hip and knee replacement populations are encouraging. A regimen of subcutaneous melagatran, administered immediately before surgery and again on the evening after surgery, plus oral ximelagatran 24 mg twice/day starting on the morning after surgery, produced a significant reduction in the rate of proximal DVT with pulmonary embolism, relative to preoperative enoxaparin. Although no differences were noted in clinically important bleeding complications between the two groups, bleeding events in this trial were more frequent with ximelagatran.[148] Based on these collective findings, although the direct thrombin-specific inhibitor ximelagatran has not yet been approved for the prevention of venous thromboembolism in major orthopedic surgery, it would appear to represent a potentially valuable addition to the anticoagulants currently available for this indication.

Oral SNAC heparin reflects a different approach to the development of antithrombotic agents, one based on adapting long-standing existing therapies (i.e., heparin and LMWH) for oral dosing, a clinically more attractive route of administration.[149,150,151] The carrier molecule SNAC, an amino acid derivative, serves as a vehicle for transporting heparin across the wall of the gut and into the bloodstream. The feasibility of oral delivery of anticoagulant doses of heparin with SNAC has been established,[149] and studies in animal models suggest efficacy in DVT treatment.[151] However, in a recent phase III trial comparing oral SNAC heparin with enoxaparin for prevention of venous thromboembolism in hip replacement surgery, SNAC heparin failed to reach its primary end point,[152] and the true clinical potential of SNAC heparin remains unclear.

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