New Drugs on the Horizon for VTE

The development of new antithrombotic agents for venous thromboembolism is changing the way we treat venous thrombosis and pulmonary embolism.

The incidence of deep venous thrombosis and pulmonary embolism has remained nearly constant since 1980, with yearly treatment costs in the billions of dollars. Frequent comorbid conditions include cancer, obesity, surgery within 3 months, immobility within 30 days, and hypertension. Acquired causes include old age, malignancy, surgery and trauma, immobilization, hormone replacement and oral contraceptives, pregnancy and the puerperium, and antiphospholipid antibodies. Genetic causes include deficiencies of natural coagulation inhibitors, Factor V Leiden, prothrombin 20210A, blood group non-O, hyperhomocysteinemia, high levels of clotting factors, and gene-gene/gene-environment interactions.

Treatment for venous thromboembolism (VTE) traditionally involves anticoagulation with standard unfractionated heparin followed by coumadin. Recently, heparin has been replaced by low-molecular-weight heparin (LMWH) as the preferred anticoagulant. Analysis suggests an improvement in recurrent thrombosis with LMWH, compared with standard heparin even in patients with proximal above-knee thrombi (those at greatest risk for embolization), as well as improvements in thrombotic complications, major hemorrhage, and mortality rates. Areas of ongoing interest include the use of LMWH for long-term therapy in certain cancer patients, demonstration of no differences in efficacy between once-a-day and twice-a-day LMWH dosing, and the fact that ambulation and the use of good strong surgical compression significantly decrease the incidence and severity of the post-thrombotic syndrome, without causing pulmonary embolism.

Two new classes of agents for venous thrombosis treatment have created excitement: direct thrombin inhibitors and specific factor Xa inhibitors. Ximelagatran, a direct thrombin inhibitor that is most like warfarin, is administered orally, with onset of action at 2 hours vs. 72–96 hours for warfarin. Ximelagatran has no food or drug interactions and has a wide therapeutic window. Thus, no coagulation monitoring has been found necessary. Unfortunately, there is no widely available antidote for its effects. Ximelagatran has been tested successfully for both the prophylaxis of orthopedic surgery and the extended prophylaxis after therapy for deep venous thrombosis (DVT) and pulmonary embolism (PE). However, ximelagatran causes an elevation in liver function tests in up to 6% of patients. Although ximelagatran has been approved in Germany for DVT prophylaxis in elective hip and knee replacement, it has not been recommended for approval by an FDA panel.

Fondaparinux and a relative, idraparinux, are most like LMWH. They target factor Xa without inhibiting thrombin. These drugs are given subcutaneously and demonstrate a half-life of 17 hours (fondaparinux) and 80–130 hours (indrapariux), vs. 4 hours for LMWH. They exhibit no endothelial or protein binding, and unfortunately, have no readily available antidote. Neither drug produces thrombocytopenia. Fondaparinux has been tested for the prophylaxis of major orthopedic surgery. In a metaanalysis of over 7,000 patients, there was greater than 50% risk reduction when fondaparinux was begun 6 hours after surgery, compared with LMWH begun 12–24 hours after surgery. Although major bleeding increased, critical bleeding did not.

Fondaparinux has also been effective in the prophylaxis in general medical patients, compared with placebo, and in abdominal surgery patients. The drug has also been effective for extended prophylaxis after hip fracture. Evaluation of the drug as a treatment for DVT and PE found that it was equal to LMWH for DVT and equal to standard heparin for PE. Fondaparinux has been approved as a once-daily, subcutaneous injection for the treatment of DVT and PE in acutely symptomatic patients. The dose given is based on body weight: 5 mg per body weight <50 kg; 7.5 mg per body weight 50–100 kg; and 10 mg per body weight >100 kg. Treatment for at least 5 days with concurrent administration of oral anticoagulation is recommended, until the INR is 2–3. Fondaparinux has also been approved for thrombosis prophylaxis in total hip, total knee, and hip fracture patients and in the extended prophylaxis of hip fracture patients.

Other antithrombotic agents being evaluated include oral heparins; other direct thrombin inhibitors like lepirudin, bivalirudin, and argatroban; defibrinating agents such as ancrod; anti-inflammatory agents such as P-selectin inhibitors; Factor VIIa inhibitors; tissue factor pathway inhibitor; and activated protein C. Lepirudin and argatroban have been approved for patients with heparin-associated thrombocytopenia. Use of P-selectin inhibitors or an inhibitor to P-selectin receptor is an area of ongoing research in our laboratory. Such an anti-inflammatory approach promises use of an antithrombotic agent that does not have direct anticoagulant activities, thus decreasing bleeding potential, and does not target a specific portion of the coagulation pathway. We anticipate that this approach will represent a significant improvement in patient safety.