Arixtra approved to prevent deep vein thrombosis
The risk of venous thromboembolism (VTE)including deep vein thrombosis (DVT) and pulmonary embolism (PE)in patients recovering from orthopedic surgery remains high, despite prophylaxis with heparin, low molecular weight heparin (LMWH), or warfarin. But a new antithrombotic jointly developed by Organon and Sanofi-Synthelabo may offer advantages over current therapies. In December, after fast-track evaluation, Arixtra (fondaparinux sodium) gained Food & Drug Administration approval for DVT prophylaxis following hip fracture surgery and hip and knee replacement surgeries. It will become available during the first quarter of this year.
Fondaparinux, the first in the pentasaccharide class of synthetic antithrombotics, specifically inhibits activated factor X (factor Xa) at the junction of the intrinsic and extrinsic coagulation cascades. The drug binds to antithrombin, altering its configuration so it has greater affinity for factor Xa, said Alexander G. G. Turpie, M.D., professor of medicine at McMaster University in Hamilton, Ontario, and a lead researcher on the drug. Fondaparinux "has a profound effect on inhibiting the generation of thrombin," he said, and thus prevents clot formation.
The effectiveness of this mechanism was borne out in two studies published in November in the New England Journal of Medicine. The studies, which compared subcutaneous fondaparinux with LMWH Lovenox (enoxaparin, Aventis) in patients undergoing hip fracture surgery and major knee surgery, found that fondaparinux lowered the risk of VTE over 50% more than enoxaparin.
While safety outcomes were similar for the two drugs, fondaparinux demonstrated a slightly higher rate of minor bleeding in one study; in the other study, fondaparinux had a higher rate of nonspecific serious bleeding that caused a significant drop in hemoglobin or required blood transfusion. However, because the index used to assess nonspecific serious bleeding "hasn't been a validated tool," according to L. Midori Kondo, Pharm.D., clinical pharmacist at Kindred Hospital in Seattle, it is unclear whether fondaparinux carries a clinically relevant higher risk of bleeding.
Trials involving about 7,300 patients, half of whom got fondaparinux, showed that fondaparinux given six hours after surgery has the same safety profile as enoxaparin administered 12 hours postsurgery, Turpie emphasized. Further, he noted that many patients got fondaparinux earlier or later than delineated by the protocols, so the drug's edge over enoxaparin cannot be ascribed solely to timing of doses.
Instead, Turpie attributed fondaparinux's efficacy to its targeted inhibition of factor Xa and its pharmacokinetic profile, featuring a rapid onset of action, a stable dose-response relationship, and a half-life of 14 to 18 hours. Enoxaparin is "truly a once-a-day drug," he said, whose antithrombotic activity kicks in soon after the first dose and remains consistent throughout the 24-hour period.
Fondaparinux, which will be available in 2.5-mg prefilled syringes, has a fixed dosage and does not require weight-based adjustment, in contrast to LMWHs, Turpie said. However, because of an increased risk of bleeding, fondaparinux is contraindicated in patients weighing less than 50 kg.
Although the manufacturers say no monitoring is necessary for patients treated with fondaparinux, Kondo speculated that anti-Xa levels might be useful as a "rough marker" of anticoagulation in certain populations, including obese, underweight, and renally impaired patients.
In vitro studies have shown no cross-reactivity between fondaparinux and the antibodies that cause heparin-induced thrombocytopenia (HIT), Turpie said. But although HIT was not reported in clinical studies, Kondo advised caution in patients with known heparin allergy. If HIT does occur with fondaparinux, she said, the incidence is so low that "we will probably have to treat a lot of people" before seeing a single case.
Like LMWHs and heparinoids, fondaparinux's labeling carries a black box warning about the risk of epidural or spinal hematomas in anticoagulated patients who receive epidural/ spinal anesthesia or spinal puncture.
How the drug will be used in practice, Kondo predicted, will depend on pharmacoeconomic factors. In deciding whether to add fondaparinux to their formularies, she said, institutions will have to weigh "the cost of the [VTE] event versus the cost of the drug versus the cost of bleeding." She noted that many hospital formularies currently list enoxaparin because it is the only LMWH approved for both DVT prevention and treatment.
Fondaparinux's manufacturers plan to seek approval for additional indications, pending results of trials studying the drug for DVT prevention in abdominal surgery and treatment and for the treatment of unstable coronary disease.
Tzipora Lieder. New drug prevents clots after orthopedic surgery. Drug Topics 2002;2:20.