New and Alternative Anticoagulants

Jordan Knepper and Thomas W. Wakefield

There are many pharmacologic options in current use to treat and prevent venous thromboembolism (VTE). These medications include unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), factor Xa inhibitors (anti-Xa drugs), direct thrombin inhibitors (anti-IIa drugs), and vitamin K antagonists. UFH and direct thrombin inhibitors (such as argatroban and bivalirudin) are used intravenously, requiring invasive administration and monitoring of dose effect. The LMWHs such as enoxaparin and the pentasaccharide fondaparinux require subcutaneous administration but do not require monitoring. In the setting of long-term treatment or prevention of VTE, Vitamin K antagonists (such as warfarin) are often used. However, vitamin K antagonists require frequent monitoring and have a myriad of interactions with medications and foods. Some of these anticoagulants (UFH, LMWH, and vitamin K antagonists) have known compounds capable of reversing their anticoagulant effects. Novel oral anticoagulants are becoming available that are administered orally and require no monitoring. The following deserve note.

Fondaparinux

Fondaparinux is a pentasaccharide that is in current use for the prevention and treatment of VTE with a subcutaneous delivery. Similar to LMWHs, fondaparinux is derived from UFH. It is based on the pentasaccharide moiety on the heparin molecule that selectively inhibits factor Xa by way of anti-thrombin. Because this is a synthetic compound and this group does not have the full molecular compound of the active heparin molecule, fondaparinux lacks direct thrombin inhibition. Current dosing for fondaparinux is fixed, though in some initial trials the dosing was weight based. For VTE prophylaxis the dose is 2.5 mg subcutaneously daily, and the therapeutic anticoagulation dose is 7.5 mg subcutaneously daily. Fondaparinux exhibits no endothelial or protein binding and does not produce thrombocytopenia. However, no antidote is readily available.

Fondaparinux has been approved for DVT prophylaxis in patients with total hip or total knee replacement and patients with hip fracture, in extended prophylaxis for hip-fracture patients, in abdominal surgery prophylaxis, and for the treatment of DVT and pulmonary embolism (PE). For the treatment of VTE, fondaparinux has been found equal to LMWH for DVT. It has been found equal to standard heparin in treating PE.

Even though fondaparinux is not approved for the treatment of heparin-induced thrombocytopenia and thrombosis, several reports of successful treatment with fondaparinux have been published. Though some data indicated lower allergenic potential with fondaparinux, there are case reports of heparin-induced thrombocytopenia with this compound.

Apixaban

Apixaban is a direct factor Xa inhibitor introduced by Bristol-Myers Squibb and is currently approved in the US for the prevention of stroke in patients with atrial fibrillation. This compound is an oral anticoagulant with twice-daily dosing. The ADVANCE-1^∗ trial compared apixaban 2.5 mg orally twice daily with enoxaparin 30 mg subcutaneous injection twice daily in total knee replacement patients to prevent VTE. The trial reported a rate of VTE of 9% in the trial group and 8.8% in the control group. The bleeding rates were significantly lower in the apixaban group, but major bleeding rates were similar between compounds. This study did not reach the noninferiority goal set out by its investigators.

Therefore, the ADVANCE-2 trial compared the 2.5 mg twice daily of apixaban with 40 mg daily of enoxaparin in the same population for VTE prophylaxis. VTE was reported in 15.1% of the apixaban patients and 24.4% of the enoxaparin patients, significantly favoring apixaban. The authors concluded that apixaban was noninferior to the 40 mg daily regimen of enoxaparin, without an increase in bleeding outcome. The ADVANCE-3 trial showed results of 2.5 mg twice daily of apixaban compared to 40 mg daily of enoxaparin in hip replacement patients as VTE prophylaxis. The primary outcome of VTE occurred in 1.4% of the apixaban group compared with 3.9% of the enoxaparin group. The results favoring apixaban were statistically significant and showed noninferiority, but the bleeding events were not significantly different.

In addition to the apixaban trials in VTE, this compound shows promise in the area of atrial fibrillation prophylaxis. The AVERROES^∗ trial showed that apixaban significantly decreased the stroke and systemic thromboembolization rate compared with 81 mg of aspirin in patients unfit for vitamin K antagonist treatment, without significant increase in bleeding. Furthermore, The AMPLIFY trail showed that 10 mg twice daily apixaban for a week, then 5 mg twice daily apixaban for six months was non-inferior to standard LMWH/ Warfarin in the treatment of acute VTE. Lastly, the AMPLIFY-EXT investigators reported that in extended prophylaxis (12 months) with apixaban after a standard treatment course with anticoagulant for VTE, there was a marked decrease in recurrences with minimal increase in bleeding.

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