Toward the Simplification of Antithrombotic Treatment of Venous Thromboembolism

For almost half a century, physicians have treated noncritical patients who have acute venous thromboembolism with adjusted doses of unfractionated heparin or, more recently, fixed doses of low-molecular-weight heparin (LMWH), followed by oral warfarin for variable periods. Although both forms of heparin are safe and effective therapies to prevent recurrent venous thromboembolism (1), physicians are increasingly using LMWHs because of their longer half-life, more predictable pharmacologic effects, and convenience. The subcutaneous administration of fixed doses, adjusted only to body weight, is straightforward even outside the hospital. Despite convincing evidence that LMWH is a safe and effective treatment of venous thromboembolism on an at-home basis (2, 3), this strategy is far from being routine practice for 2 main reasons. First, physicians fear the consequences of undertreating venous thromboembolism because pulmonary embolism can be fatal. This is particularly true for patients with primary pulmonary embolism. Indeed, LMWHs have not been as extensively investigated in patients with primary symptomatic pulmonary embolism as in patients with deep venous thrombosis (DVT). Second, physicians are concerned about convenience for the patient because of the need for careful laboratory monitoring of anticoagulation status during the first days of treatment, indispensable to guarantee the correct overlap between heparins and oral anticoagulants. With the introduction of fondaparinux, the first synthetic pentasaccharide, we now have a new class of antithrombotic agents that specifically inhibit factor Xa and lack activity against thrombin. Fondaparinux has a linear pharmacokinetic profile and a longer half-life, allowing once-daily administration. Its effects are unusually consistent because it is not metabolized, is completely bioavailable, and does not bind to plasma proteins. In particular, it does not bind to platelet factor 4, which makes the development of immune thrombocytopenia extremely unlikely. Indeed, to my knowledge, no case of this potentially life-threatening complication has been reported. Although this compound does not possess a specific antidote, antidotes are rarely required for bleeding complications during management of venous thromboembolism (4). After publication of a large series of studies in patients undergoing hip or knee total arthroplasty (5), fondaparinux was approved for prophylaxis of venous thromboembolism after both elective and emergency major orthopedic surgery. In this setting, once-daily administration of 2.5 mg of fondaparinux reduced venous thromboembolism risk by more than 50% in comparison with enoxaparin but did not increase the risk for major bleeding (5). The Matisse Investigators' DVT study, which appears in this issue (6), is part of a comprehensive evaluation of fondaparinux involving the treatment of almost 4500 patients with clinically symptomatic DVT or pulmonary embolism. In a recently published pulmonary embolism study from the same investigators (7), fondaparinux, 7.5 mg once daily, was as effective and safe as adjusted-dose intravenous unfractionated heparin in patients with acute pulmonary embolism. The rate of recurrent venous thromboembolism was 3.8% (42 of 1103) in patients treated with fondaparinux compared with 5.0% (56 of 1110) in patients treated with unfractionated heparin. In the clinical trial in patients with DVT (6), 3.9% (43 of 1098) of patients with DVT treated with a fixed dose of fondaparinux, 7.5 mg subcutaneously once daily, developed a symptomatic thromboembolic event compared with 4.1% (45 of 1107 patients) of patients treated twice daily with a body weightadjusted dose of enoxaparin. The data from these trials suggest that fondaparinux could be a simplified and practical treatment that is as effective as unfractionated heparin or enoxaparin for either DVT or pulmonary embolism. The results of the Matisse Investigators' studies have some important implications as well as one limitation. These findings may further stimulate physicians to try home treatment of patients with venous thromboembolism. In addition, they challenge the view that drugs that selectively inhibit factor Xa would not treat established thrombosis as successfully as do compounds that possess antithrombin activity (8). However, neither study reports the follow-up of patients after anticoagulation. This approach is a proper way to assess the effectiveness of initial antithrombotic treatment. It has provided helpful information in comparative studies carried out until the mid-1990s (3, 9, 10) but has been virtually abandoned in recent times; I do not know why. Is there room for further improvement and simplification of the antithrombotic treatment of patients with venous thromboembolism? Yes, there is. Simultaneous administration of fondaparinux and oral anticoagulants still requires careful laboratory monitoring during the first days of therapy. Even now, most physicians view laboratory monitoring as a serious obstacle to providing ambulatory treatment to their patients. One new development points to effective and safe treatment of venous thromboembolism with selective antithrombin drugs (such as ximelagatran) in fixed doses from the first dose without the need for laboratory monitoring (11). Another development heralds freedom from daily injections and laboratory monitoring: a long-acting formulation of pentasaccharide, idraparinux, which can be administered in fixed doses once weekly (12). After almost 50 years without any substantial progress, antithrombotic treatment of patients with venous thromboembolism has finally evolved. We can expect major improvements in antithrombotic therapy as the use of factor Xa or thrombin inhibitors becomes more widespread. They will probably allow for an antithrombotic treatment that is not only effective and safe but also simple enough for all physicians to use for most of their patients outside of the hospital.