Abstract & Commentary
Source: Buller HR, et al for the Matisse Investigators. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis. Ann Intern Med 2004;140:867-873.
Fondaparinux, a synthetic polysaccharide, represents a new class of anti-thrombotic agents that specifically inhibit factor Xa of the clotting cascade and lack activity against thrombin. Advantages of fondaparinux include its predictable and sustained anticoagulant effect, complete bioavailability, and lack of binding to plasma proteins. In addition, because it does not bind platelet proteins and lacks cross-reactivity with heparin-induced antibodies, immune thrombocytopenia is extremely unlikely.
While previous studies have demonstrated its effectiveness for deep vein thrombosis (DVT) prophylaxis, no large study has compared fondaparinux with the low-molecular weight heparins (LMWH) for the initial treatment of patients with DVT. In this multi-centered international study, the investigators compared fondaparinux with enoxaparin for the initial treatment of DVT. More than 2,000 patients initially diagnosed with lower extremity DVT were randomized to receive either fondaparinux 7.5 mg SQ daily (5.0 mg for patients weighing less than 50 kg, 10.0 mg for patients weighing more than 100 kg) (1,098 patients) or enoxaparin 1 mg/kg SQ twice daily (1,107 patients) for at least five days until vitamin K antagonists induced an international normalized ratio (INR) of 2.0. Patients could be treated at home or in the hospital based upon physician discretion.
During the three-month study period, patients were followed and assessed for the primary outcome of recurrent deep venous thromboembolism, pulmonary embolism, or death in which pulmonary embolism was a contributing cause. The primary safety outcomes were episodes of major bleeding and mortality during the three-month study period. The study was powered with a non-inferiority margin of 3.5% in absolute difference in recurrence rates.
The investigators found no significant difference in rates of recurrent venous thromboembolism between the fondaparinux and enoxaparin groups (3.9% vs 4.1%, respectively). There also was no significant difference in major bleeding rates, occurring in 12 (1.1%) fondaparinux patients and 13 (1.2%) enoxaparin patients. Overall mortality rates at the end of the three-month study period were similar for the two groups as well (3.8% vs 3.0%, respectively). In addition, on subgroup analysis, the investigators found that both treatments had similar efficacy and safety independent of body weight, but that decreased renal function increased the risk of bleeding complications in both treatment groups. Based on their findings, the authors conclude that fondaparinux, a specific inhibitor of activated factor X, is as effective, safe, and more convenient than enoxaparin, an LMWH agent, for the treatment of DVT.
Commentary by Theodore C. Chan, MD, FACEP
This industry-sponsored study is an impressively large, randomized trial conducted at 157 centers located on four different continents. Fondaparinux represents a new selective inhibitor of factor Xa, which, unlike the heparins, exerts no effect on antithrombin and thrombin in the clotting cascade. While this study demonstrated equal efficacy and safety with this new agent, a few points need to be highlighted. First, a large number of DVT patients (2,416) were excluded from the study, including patients who had symptomatic pulmonary embolism. Second, while the authors highlight the utility of single daily dosing, fewer than 10% of patients in either the fondaparinux or enoxaparin arm were treated as outpatients. Thus, more study is required to assess the true utility of this agent in the outpatient setting. Third, while decreased risk of heparin-induced thrombocytopenia is a purported advantage of this new class of agents, thrombocytopenia actually occurred in equal numbers of patients (0.6%) in both groups, and none had antiplatelet antibodies induced. Fourth, it is important to remember that unlike protamine for heparin, there is no specific antidote for these new selective factor Xa inhibitors. Despite these limitations, selective factor Xa inhibitors, such as fondaparinux (as well as even newer, longer-acting agents that allow weekly dosing, such as idraparinux), likely will begin to play a greater role in the treatment of venous thromboembolic disease in the future.
Dr. Chan, Associate Clinical Professor of Medicine, Emergency Medicine, University of California, San Diego, is on the Editorial Board of Emergency Medicine Alert.