*Factor Xa Inhibitors (Fondaparinux, Rivaroxaban, Apixaban, Edoxaban)

Chapter: Factor Xa Inhibitors (Fondaparinux, Rivaroxaban, Apixaban, Edoxaban)
McMaster Section Editor(s): James Douketis
Section Editor(s) in Interna Szczeklika: Krystyna Zawilska, Anetta Undas, Wiktoria Leśniak
McMaster Author(s): James Douketis
Author(s) in Interna Szczeklika: Anetta Undas, Krystyna Zawilska
Additional Information

1. Mechanism of action: Fondaparinux (subcutaneous or intravenous) is a synthetic pentasaccharide that binds only to antithrombin; rivaroxaban (oral), apixaban (oral), and edoxaban (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 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 and thrombin time. In patients planned for urgent invasive procedures associated with a high risk of bleeding, the prothrombin time may be used to provide a crude estimate of the anticoagulant effect of rivaroxaban, edoxaban, and, to a lesser extent, apixaban. 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, double antiplatelet therapy, thrombolytic agents, azole antifungal agents, and human immunodeficiency virus 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 (Table 1): Rivaroxaban, apixaban, and edoxaban can be managed relatively easily in patients requiring an elective surgical or other invasive procedure because of the short half-life of these drugs (8-10 hours) and the resultant rapid offset and onset of action. In general, patients having a minor surgery (associated with a low risk of bleeding) can receive the last drug dose two days before the surgery or procedure (none on the day of surgery) and can resume the drug the day afterwards. Patients having a major surgery and/or spinal anesthesia (associated with a high bleeding risk) can receive the last drug dose 3 days before the surgery or procedure (none on the day of surgery) and can resume the drug 1 to 2 days afterwards when hemostasis is secured. In patients having major surgery, the time interval between the last dose of rivaroxaban, apixaban, or edoxaban and surgery is at least 5 drug half-lives (ie, ~60 hours). Research is ongoing to inform best practices regarding the perioperative management of rivaroxaban, apixaban, and edoxaban.

5. Complications: Mainly bleeding (in contrast to heparins, factor Xa inhibitors are not known to cause heparin-induced thrombocytopenia), allergic reactions. No antidote is available to neutralize the anticoagulant effect; however, it can be partially neutralized by a 4-factor prothrombin complex concentrate (PCC) 25 U/kg (the dose may be repeated twice) or activated PCC 50 U/kg (maximum, 200 U/kg/d). The role of other prohemostatic agents, which include tranexamic acid, cryoprecipitate, and recombinant factor VII, in bleeding management is uncertain. In addition, there is uncertainty about the potential prothrombotic effects of all prohemostatic agents in this clinical setting.

TablesTop

Table 1. Discontinuation of new oral anticoagulants before planned surgical interventions

Creatinine clearance (mL/min)

Rivaroxaban

Apixaban

Dabigatran

Risk of bleeding

Low

High

Low

High

Low

High

≥80

≥24 h

≥48 h

≥24 h

≥48 h

≥24 h

≥48 h

50-80

≥24 h

≥48 h

≥24 h

≥48 h

≥36 h

≥72 h

30-50b

≥24 h

≥48 h

≥24 h

≥48 h

≥48 h

≥96 h

15-30b

≥36 h

≥48 h

≥36 h

≥48 h

Do not use

Do not use

<15

No approved indication for use

a Time of the last intake of the drug before surgery.

b The majority of these patients may receive a lower dose of dabigatran (110 mg bid) or apixaban (2.5 mg bid), or have to receive the lower dose of rivaroxaban (15 mg once daily).

Adapted from: Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J. 2013 Jul;34(27):2094-106. doi: 10.1093/eurheartj/eht134. Epub 2013 Apr 26.

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