Factor Xa Inhibitors

1. Mechanism of action: Fondaparinux (subcutaneous or IV) is a synthetic pentasaccharide that binds only to antithrombin; apixaban (oral), edoxaban (oral), and rivaroxaban (oral) cause factor Xa inhibition that is not mediated by antithrombin.

2. Monitoring of the anticoagulant effect is not necessary. However, within 2 to 4 hours of the administration of rivaroxaban, a prolonged prothrombin time (international normalized ratio [INR]) typically occurs (the effect is less pronounced after the administration of apixaban). Rivaroxaban, apixaban, and edoxaban have little or no effect on the activated partial thromboplastin time (aPTT) and thrombin time. In patients planned for urgent invasive procedures associated with a high risk of bleeding, the prothrombin time (PT) and aPTT are not reliable tests to measure the anticoagulant effect of apixaban, edoxaban, and rivaroxaban. More reliable measures of the anticoagulant effects of rivaroxaban, apixaban, and edoxaban require the use of anti–factor Xa assays specific to these agents.

3. Contraindications are the same as with heparins and additionally include pregnancy and breastfeeding; do not use these agents in patients with creatinine clearance <15 mL/min, patients with severe liver failure, or in combination with other anticoagulants, dual antiplatelet therapy, thrombolytic agents, and drugs that can potentiate or impede the anticoagulant effect (eg, azole antifungal agents, and HIV protease inhibitors). Blood levels of rivaroxaban increase in patients receiving concomitant clarithromycin, erythromycin, cyclosporine (INN ciclosporin), tacrolimus, or fluconazole. Rifampin (INN rifampicin), phenobarbital, carbamazepine, phenytoin, and hypericum (St John’s wort) reduce the efficacy of rivaroxaban and apixaban.

4. Discontinuation of treatment before surgical procedures: see Perioperative Direct Oral Anticoagulant (DOAC) Management.

5. Complications: Mainly bleeding (in contrast to heparins, factor Xa inhibitors are not known to cause heparin-induced thrombocytopenia), allergic reactions. Andexanet alfa is a reversal agent to neutralize the anticoagulant effect of oral factor Xa inhibitors and may have a therapeutic role in selected patients with intracranial hemorrhage. Andexanet alfa is only available in some countries and is expensive ($10,000-12,000 USD). The anticoagulant effect of oral factor Xa inhibitors may also be neutralized by a 4-factor prothrombin complex concentrate (PCC) 30 IU/kg. PCC is more widely available but is also expensive ($4000-5000 USD). The role of other prohemostatic agents, which include tranexamic acid, cryoprecipitate, and recombinant factor VII, in bleeding management is uncertain but can be considered in bleeding that is refractory to administration of reversal agents. In addition, there is uncertainty about the potential prothrombotic effects of all prohemostatic agents in this clinical setting.