Connolly SJ, Crowther M, Eikelboom JW, et al; ANNEXA-4 Investigators. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2019 Apr 4;380(14):1326-1335. doi: 10.1056/NEJMoa1814051. Epub 2019 Feb 7. PubMed PMID: 30730782; PubMed Central PMCID: PMC6699827.
Piran S, Khatib R, Schulman S, et al. Management of direct factor Xa inhibitor-related major bleeding with prothrombin complex concentrate: a meta-analysis. Blood Adv. 2019 Jan 22;3(2):158-167. doi: 10.1182/bloodadvances.2018024133. Review. PubMed PMID: 30658963; PubMed Central PMCID: PMC6341194.
Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018 Nov 27;2(22):3257-3291. doi: 10.1182/bloodadvances.2018024893. PubMed PMID: 30482765; PubMed Central PMCID: PMC6258922.
Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest. 2018 Nov;154(5):1121-1201. doi: 10.1016/j.chest.2018.07.040. Epub 2018 Aug 22. PubMed PMID: 30144419.
Steffel J, Verhamme P, Potpara TS, et al; ESC Scientific Document Group. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018 Apr 21;39(16):1330-1393. doi: 10.1093/eurheartj/ehy136. PubMed PMID: 29562325.
Farge D, Bounameaux H, Brenner B, et al. International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol. 2016 Oct;17(10):e452-e466. doi: 10.1016/S1470-2045(16)30369-2. Review. PubMed PMID: 27733271.
Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb;149(2):315-352. doi: 10.1016/j.chest.2015.11.026. Epub 2016 Jan 7. Erratum in: Chest. 2016 Oct;150(4):988. PubMed PMID: 26867832.
Baglin T, Hillarp A, Tripodi A, Elalamy I, Buller H, Ageno W. Measuring Oral Direct Inhibitors (ODIs) of thrombin and factor Xa: A recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2013 Jan 24. doi: 10.1111/jth.12149. [Epub ahead of print] PubMed PMID: 23347120.
Debourdeau P, Farge D, Beckers M, et al. International clinical practice guidelines for the treatment and prophylaxis of thrombosis associated with central venous catheters in patients with cancer. J Thromb Haemost. 2013 Jan;11(1):71-80. doi: 10.1111/jth.12071. Review. PubMed PMID: 23217208.
1. Mechanism of action: Fondaparinux (subcutaneous or IV) is a synthetic pentasaccharide that binds only to antithrombin; rivaroxaban (oral), apixaban (oral), edoxaban (oral), and betrixaban (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 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, 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-alpha is available is some jurisdictions to neutralize the anticoagulant effect but is expensive and not widely available. The anticoagulant effect of oral factor Xa inhibitors may be neutralized by a 4-factor prothrombin complex concentrate (PCC) 25 IU/kg (the dose may be repeated twice). 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 cases of 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.