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The better target: IIa or Xa?
HemOnc Today asked Jeffrey Weitz, MD, and Howard A. Liebman, MD, whether Factor IIa (thrombin) or Factor Xa appears to be a better target for oral anticoagulant therapies.
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Factor IIa (thrombin)
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First of all, I want to be clear that we are speculating based on nothing, and the results of the clinical trials will tell us the answer. And even with the clinical trial results, if you dive in more closely, they don’t necessarily tell you that one target is better because it is not all about targets; it is also about the pharmacologic properties of the drug.
That being said, if you really want to clamp down on clotting, the best target you could ever take is thrombin. The whole idea with Factor Xa is that it really does only one thing in clotting, and that’s convert prothrombin to thrombin, whereas thrombin has all these other effects. If you inhibit Factor Xa, you inhibit thrombin; that’s how it works. What does it matter if you inhibit upstream or you inhibit downstream? You’re still blocking thrombin generation.
The ximelagatran results taught us that you can inhibit thrombin over the long term at least as well as with warfarin. You don’t have to monitor it and you can give it in fixed doses. It didn’t stay on the market because of the liver toxicity, but there was absolutely no problem with long-term safety from a bleeding perspective. What data do we have that Factor Xa is effective long term for treatment of patients with established thrombosis? We really don’t have a huge amount of data. The MATISSE DVT and PE trials demonstrated that fondaparinux is as effective and safe as heparin or low–molecular-weight (LMW) heparin for initial treatment of pulmonary embolism or deep vein thrombosis, respectively. When idraparinux, the long-acting pentasaccharide, was compared with heparin or LMW heparin followed by a vitamin K antagonist for long-term therapy, idraparinux was non-inferior to conventional treatment in patients with deep vein thrombosis. In patients with pulmonary embolism, however, the risk of recurrent venous thrombosis was higher with idraparinux. This may just be a matter of dose, but the same dose of idraparinux caused excessive bleeding, including fatal bleeding, in older patients with atrial fibrillation. These findings raise a note of caution about the benefit-to-risk profile of Factor Xa inhibitors for extended treatment. In pure speculation, I would guess that Factor Xa might be a good target for prophylaxis but perhaps not for treatment, and that thrombin would perhaps be not so great a target for prophylaxis but would be a great target for treatment.
Jeffrey Weitz, MD, is a Professor of Medicine and Biochemistry at McMaster University and Director of Henderson Research Centre, Hamilton, Ontario.
Factor Xa
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I have to agree with Professor Weitz that any discussion regarding the superiority of direct Factor Xa inhibition vs. direct thrombin inhibition for the treatment and/or prophylaxis of venous thrombosis is purely speculative. Results from well designed clinical trials will provide the answer.
However, it must be remembered that Factor Xa is the first enzyme in the common pathway of coagulation. Inhibition of one Factor Xa molecule prevents the generation of 50 thrombin molecules. While some thrombin generation can persist with incomplete inhibition of Factor Xa, some intrinsic thrombin generation is necessary to initiate important feed-back pathways of coagulation inhibition by activation of Protein C and activation of fibrinolysis by the release of tissue plasminogen activators.
Can selective inhibition of Factor Xa be effective for both venous thrombosis prophylaxis and treatment? The answer is clearly yes! Fondaparinux, an indirect inhibitor of Factor Xa, has demonstrated efficacy in primary VTE prophylaxis in medical and surgical patients and is as effective as LMW heparin in the initial treatment of venous thrombosis. Fondaparinux was also shown to be as effective as unfractionated (UF) heparin in the initial therapy of uncomplicated pulmonary embolism. It is notable that in the same Matisse PE study, fondaparinux appeared to be even more effective than UF heparin in the treatment of cancer patients with PE; a patient population known to be at a significantly higher risk of recurrent thrombosis. Professor Weitz mentions the ximelagatran experience for the initial treatment and secondary prophylaxis of established thrombosis. While the THRIVE Treatment Study demonstrated equivalent recurrence rates at 6 months for patient treated with ximelagatran vs. LMW heparin and warfarin, it should be noted that the rate of recurrence during the first month of treatment was greater in the ximelagatran cohort compared to the patients treated with LMW heparin followed by warfarin. This would suggest superiority of the LMW heparin, with its predominant indirect Factor Xa inhibition, in the initial treatment of established thrombosis, while ximelagatran was more effective than warfarin in preventing recurrent VTE in the subsequent five months of therapy. I would predict that the direct oral Factor Xa inhibitors will prove to be both effective and safe in the treatment and long-term secondary prophylaxis of venous thromboembolism.
Howard A. Liebman, MD, is Chief of Hematology, Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases at Norris Cancer Hospital and Professor of Medicine and Pathology at the University of Southern California-Keck School of Medicine, Los Angeles.