By: Danielle Marut, PharmD (left), Jessica Traeger, PharmD, BCCCP (right)
The use of oral factor Xa inhibitors, including rivaroxaban and apixaban, has increased over the last several years. Historically, strategies for the treatment of bleeding patients taking these agents included supportive care (due to the drugs’ short half-lives) or prothrombin complex concentrates (PCC), which are not FDA-approved for the reversal of factor Xa inhibitors. Drug-specific anti-Xa levels for rivaroxaban and apixaban are not FDA-approved or widely available, leading to difficulty in measuring and monitoring their anticoagulation effect.1,2,3 The 2016 Neurocritical Care Society guideline for reversal of antithrombotics in intracranial hemorrhage (ICH) suggest to administer 4-factor or activated PCC at a dose of 50 units/kg for patients with ICH taking factor Xa inhibitors (low quality evidence).4 A targeted reversal agent, coagulation factor Xa (recombinant), inactivated-zhzo (AndexXa®), formerly known as andexanet alfa, was recently approved by the FDA.5 Due to limited comparative data and high cost, there is controversy over what the optimal reversal agent should be for patients who present with life-threatening bleeding, including ICH.
The evidence for PCCs for factor Xa inhibitor reversal in pharmacokinetic studies in healthy volunteers is conflicting. Eerenberg et al. compared the administration of 50 units/kg PCC to placebo for reversal of rivaroxaban. Both prothrombin time (PT) and endogenous thrombin potential (ETP) improved.6 ETP is the amount of thrombin that can be generated after coagulation is activated, and is a tool to assess hyper- or hypo-coagulability. However, Levi et al. compared 50 units/kg of PCC to placebo for reversal of rivaroxaban and found no difference in anti-Xa activity, a transient improvement in PT, but improved ETP.7 In real world patients, a single-center, prospective pilot study evaluated reversing rivaroxaban with 4-factor PCC.8 Thirteen patients who presented with a life-threatening bleed (77% ICH or SDH) were included. Patients received 25 units/kg of PCC, and were monitored for changes in ETP and peak thrombin potential (Cmax). The ETP and Cmax improved by 68% (p=0.001) and 54% (p=0.001) respectively. Three patients had signs of re-bleeding or progression of ICH after PCC administration. No thromboses were documented within seven days of treatment.
Three recent, larger observational studies evaluated hemostatic efficacy, mortality and thromboembolic complications in patients with major bleeding who received 4-factor PCC. Majeed et al. evaluated 84 patients who were receiving rivaroxaban (54%) or apixaban and were treated with PCC for management of major bleeding (70% ICH).9 Patients received median (IQR) 26.7 (21.4-29.9) units/kg of PCC. Hemostatic efficacy, defined by the ISTH criteria, was achieved in 69% of patients, mortality was 32% and three patients experienced a thromboembolic event. Similarly, Allison et al. evaluated 33 patients that were treated with 4-factor PCC for the management of rivaroxaban (82%) or apixaban-induced major bleeding (91% intracranial bleed).10 The mean dose of PCC administered was 32.5 ± 4.4 units/kg. The majority of patients achieved hemostasis (84%) defined as a stable radiographic image, mortality was 15% and no patients experienced a thromboembolic event. A study by Schulman et al. analyzed the efficacy of PCC (mean dose 26.4 ± 7.7 units/kg) for reversal of rivaroxaban (56%) or apixaban in the setting of acute major bleeding in 66 patients (55% intracranial bleed).11 In a post-hoc analysis, this study found PCCs resulted in excellent or good hemostasis in 76% of patients with intracranial bleeds using the same criteria by Sarode et al.12, which had led to the FDA approval of 4-factor PCC for warfarin reversal. The overall 30-day mortality was 14%, and 8% experienced thromboembolic events. While these studies included a large proportion of patients with intracranial bleeds and the results are largely consistent, the observational designs and differing definitions of hemostatic efficacy used limit generalizability
In May 2018 andexanet was approved by the FDA for the reversal of rivaroxaban or apixaban in patients with major bleeding. Andexanet binds to factor Xa inhibitors with high affinity, neutralizing their effect and allowing native factor Xa to initiate clotting.5
The phase II ANNEXA-A and ANNEXA-R studies evaluated the change in anti-factor Xa activity when andexanet was administered as a bolus compared to a bolus plus 2-hour infusion.13 The bolus plus infusion significantly reduced anti-factor Xa activity by 92% and 97% for apixaban and rivaroxaban respectively. The inhibition of anti-factor Xa activity persisted for one to two hours after the end of the infusion, followed by a return to placebo levels. This led to the dosing of a bolus dose plus a two-hour infusion to effectively reverse factor Xa inhibitors.
ANNEXA-4 was a multicenter, prospective, open-label, single-arm trial that assessed andexanet’s safety and efficacy.14 Patients who presented with acute major bleeding and had received apixaban, rivaroxaban, edoxaban or enoxaparin within the prior 18 hours were included. The full study included 352 patients; 91% had been taking either apixaban or rivaroxaban.14 The majority of patients had intracranial (64%) or gastrointestinal (26%) bleeding. The mean initial decrease in anti-factor Xa activity was 92% for both apixaban and rivaroxaban after the completion of the andexanet bolus. There was excellent or good hemostasis, as used by Sarode et al. in 82% (204 of 249 patients who could be evaluated). Mortality after 30 days was 14%, and thrombotic events were observed in 10% of patients, leading to a boxed warning in the product’s labeling.
The data for andexanet is promising but currently limited to only one non-comparative clinical trial, while the evidence for PCCs is observational and variable. There have yet to be any published studies directly comparing the efficacy and safety of PCCs to andexanet that could help clarify the issue. It is challenging to recommend an optimal dose for PCCs for factor Xa inhibitor reversal due to inconsistencies in the published literature and available guidelines, while andexanet has rigorous pharmacokinetic studies documenting effective reversal based on the agent/dose to be reversed and time from last administration. There are concerns about the risk of increased thromboembolic events in patients who are treated with PCCs. However, despite methodological limitations and variable dosing, an increased risk does not appear present in the published data on the use of PCCs for factor Xa inhibitor reversal. The risk of thromboembolic events with andexanet seen in ANNEXA-4 is difficult to interpret with the single-arm design of the trial. A risk-benefit analysis is advised to prevent additional harm. Because of the lack of robust evidence to reverse factor Xa inhibitors, clinicians should consider the patient’s overall clinical situation, timing from last dose administered and product availability when deciding between PCCs, andexanet or supportive care.
- Cuker A, Siegal DM, Crowther MA, et al. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol. 2014; 64(11):1128–39.
- Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals Inc; January 2019.
- Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; June 2018.
- Frontera JA, Lewin III JJ, Rabinstein AA, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage. Neurocrit Care. 2016;24:6-46.
- Andexxa (andexanet alfa) [prescribing information]. South San Francisco, CA: Portola Pharmaceuticals, Inc; December 2018.
- Eerenberg ES, Kamphuiden PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573-9.
- Levi M, Moore KT, Castillejos CF, et al. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost. 2014;12:1428–36.
- Schenk B, Goerke S, Beer R, et al. Four-factor prothrombin complex concentrate improves thrombin generation and prothrombin time in patients with bleeding complications related to rivaroxaban: a single-center pilot trial. Thromb J. 2018;16:1.
- Majeed A, Agren A, Holmstrom M, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood. 2017; 130(15):1706-12.
- Allison TA, Lin PJ, Gass JA, et al. Evaluation of the use of low-dose 4-factor prothrombin complex concentrate in the reversal of direct oral anticoagulants in bleeding patients. J Intensive Care Med. Epub Sept 2018.
- Schulman S, Gross PL, Ritchie B, et al. Prothrombin complex concentrate for major bleeding on factor Xa inhibitors: a prospective cohort study. Thromb Haemost. 2018;118(5):842-51.
- Sarode R, Milling TJ, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128(11):1234-43.
- Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373:2413-24.
- Connolly SJ, Crowther M, Eikelboom JW, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. [Epub ahead of print].