Unmet Need for a Factor Xa Inhibition Reversal Agent

JANUARY 24, 2017
This article was sponsored by Portola Pharmaceuticals, Inc.

Anticoagulants, which are commonly used in outpatient settings, are associated with a risk of bleeding. In certain situations, there is an urgent need to reverse the effects of an anticoagulant drug; for example, in cases of life-threatening bleeding.1 This article highlights available anticoagulant reversal agents, as well as unmet needs in anticoagulant reversal and late-stage clinical research in this area.
Pharmacologic therapies commonly used for anticoagulation in outpatient settings include warfarin and several non–vitamin K oral anticoagulants (NOACs).1-7 Available agents include the vitamin K antagonist warfarin2, the direct thrombin inhibitor dabigatran (Pradaxa)3, and the oral factor Xa (FXa) inhibitors rivaroxaban (Xarelto)4, apixaban (Eliquis)5, and edoxaban (Savaysa).6 Parenteral FXa inhibitors are also available, such as enoxaparin (Lovenox).8

In terms of stroke prevention among patients with nonvalvular atrial fibrillation (NVAF), data from clinical trials and meta-analyses suggest that NOACs are as effective as warfarin, and in some cases more effective than warfarin. NOACs are also safer than warfarin in terms of reduced major bleeding.9,10 In pivotal clinical trials evaluating NOACs in patients with NVAF, major bleeding occurred at an annual rate of 3.32% with dabigatran (at the US-approved dose for NVAF), 3.6% with rivaroxaban, 2.13% with apixaban, 2.75% with high-dose edoxaban (60 mg daily), and 1.61% with low-dose edoxaban (30 mg daily).3,6,11-15
As with all anticoagulants, a primary serious adverse event of concern with FXa inhibitors that affects uptake, use, and adherence is the risk of major uncontrolled bleeding and life-threatening bleeding events.9,16 In pivotal trials and real-world registries of patients receiving FXa inhibitors for NVAF, both major bleeding and intracranial hemorrhage (ICH) are associated with high rates of mortality. For example, among patients receiving rivaroxaban in the ROCKETAF trial, all-cause mortality at a median of 60 days (range: 8 to 246 days) was 48% in patients with an ICH and 20% in patients with any major bleed.16,17 Similarly, among patients receiving apixaban in the ARISTOTLE trial, the 30-day mortality rate was 45% in patients with an ICH and 11% in patients experiencing any major bleeding.18,19 Consistent with these findings, among patients receiving edoxaban in the ENGAGE-AF-TIMI trial, the 30-day mortality rate was 39% in patients with an ICH receiving high-dose edoxaban, 29% in patients with an ICH receiving low-dose edoxaban, and 7.7% to 8.3% in patients experiencing any major bleeding.20

Mortality related to FXa-associated bleeding is also seen in realworld registry data. Specifically, in the RASUNOA registry, overall ICH-related mortality was 28% (within 90 days of NOAC-associated ICH), and in the DRESDEN registry, the 90-day overall all-cause mortality rate was 10.2% in patients with rivaroxaban-associated major bleeding.21,22

Any major bleeding event may increase the risk of mortality.20 These events may include bleeding at a critical site (eg, surgical, intraocular, pericardial, intraspinal, intraarticular, and/or intramuscular site), major bleeding associated with hemodynamic instability, or bleeding related to major blunt or penetrating trauma.23-25 Notably, patients with major bleeding due to an ICH (eg, intracerebral, subdural, subarachnoid, extradural) are at especially high risk of mortality.16,21 The clinical burden of bleeding associated with the use of FXa inhibitors is substantial, and there remains an unmet need for a reversal agent for use in cases of life-threatening or uncontrolled bleeding. Furthermore, with the increasing use of FXa inhibitors, the number of patients who require reversal of the anticoagulant effects is anticipated to rise.26
Pharmacologic therapies for reversal of anticoagulation include vitamin K for patients receiving warfarin2 and idarucizumab (Praxbind) for patients experiencing bleeding associated with dabigatran27 (TABLE1,27-42). For FXa inhibitors, no agent for reversal of FXa activity is currently approved.26

Existing strategies for management of major bleeding associated with FXa inhibitors include use of prohemostatic agents (eg, 3-factor prothrombin complex concentrate [PCC], 4-factor PCC, activated PCC, recombinant factor VIIa), fresh frozen plasma, red blood cells, tranexamic acid, and desmopressin.1,4,5 None of these treatments are approved for use in patients treated with FXa inhibitors, and evidence for the use of these agents consists mostly of nonclinical data or preclinical data in healthy volunteers.4-6,33,34 Additionally, PCCs and recombinant factor VIIa carry boxed warnings for thrombotic and thromboembolic events.32,37,40

Given that in clinical trials of healthy volunteers PCCs do not affect anti-FXa activity, the off-label use of procoagulant agents, which is not supported by studies in bleeding patients, suggests the continued unmet clinical need for a specific FXa inhibitor reversal agent.34,35 A medicine to potentially address this unmet need is currently in late-stage development: andexanet alfa, a modified human FXa decoy protein for reversal of FXa inhibition.26,43-45 In September 2016, researchers published a preliminary descriptive analysis of interim data from the ongoing ANNEXA-4 study, which is evaluating andexanet alfa in bleeding patients who were receiving FXa inhibitors.45

The ANNEXA-4 preliminary analysis included 67 patients in the safety analysis, of whom 47 were eligible for inclusion in the efficacy analysis. All patients in this preliminary analysis had experienced acute major bleeding within 18 hours of receiving a dose of FXa inhibitor. These patients received a bolus dose of andexanet alfa followed by a 2-hour infusion.45 Investigators evaluated the anticoagulant effects of circulating FXa inhibitors through anti-FXa levels—a biomarker that directly measures anticoagulant activity and correlates with unbound anticoagulant plasma concentrations.46,47 Andexanet alfa promptly and significantly reversed anticoagulant activity by 89% (95% CI, 58%-94%) in patients receiving rivaroxaban and by 93% (95% CI, 87%-94%) in patients receiving apixaban.45 Reversal occurred at the first measurement after the end of the bolus.45

An independent adjudication committee rated hemostatic efficacy based on changes in hematoma volume in cases of ICH, changes in hemoglobin and hematocrit levels in cases of nonvisible bleeding, and hemostasis in cases of visible bleeding. For patients with musculoskeletal bleeding, improvements in pain relief and objective signs of bleeding without an increase in swelling defined hemostatic efficacy. Twelve hours after infusion, hemostatic efficacy was rated as “good” or “excellent” in 79% of patients in the efficacy population (95% CI, 64%-89%). Over 30 days of follow-up, overall mortality was 15%, ICH-related mortality was 21%, and 18% of patients experienced thrombotic events.45
Considering the substantial clinical burden of bleeding associated with use of FXa inhibitors, the lack of clinical data to support existing management strategies (eg, use of prothrombin complex concentrates, blood products, tranexamic acid, and desmopressin), and the fact that none of the currently used agents reverse anti-FXa activity, effective bleeding management for patients taking FXa inhibitors remains an unmet clinical need.1,4,5,26 An investigational drug designed to address this unmet need, andexanet alfa, is currently in late-stage development.26,43,44

The use of FXa inhibitors is growing, and there is no specific antidote available for these drugs. This article has reviewed the importance of anti-FXa activity and the limitations of currently available agents for the management of bleeding related to FXainhibitor use. The landscape is evolving, however, and pharmacists must maintain awareness of agents in development, such as andexanet alfa, a FXa inhibitor reversal agent that may be approved in 2017.

  1. Christos S, Naples R. Anticoagulation reversal and treatment strategies in major bleeding: update 2016. West J Emerg Med. 2016;17(3):264-270. doi: 10.5811/westjem.2016.3.29294.
  2. Coumadin (warfarin sodium) tablets for oral use, for injection, for intravenous use [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 1954.
  3. Pradaxa (dabigatran etexilate mesylate) capsules for oral use [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2010.
  4. Xarelto (rivaroxaban) tablets for oral use [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2011.
  5. Eliquis (apixaban) tablets for oral use [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 2012.
  6. Savaysa (edoxaban) tablets for oral use [prescribing information]. Parsippany, NJ: Daiichi Sankyo, Inc; 2015.
  7. Triplett DA. Coagulation and bleeding disorders: review and update. Clin Chem. 2000;46(8 pt 2):1260-1269.
  8. Lovenox (enoxaperin sodium) [package insert]. Bridgewater, NJ: Sanofi-Aventis,US, LLC; 2013.
  9. Hanley CM, Kowey PR. Are the novel anticoagulants better than warfarin for patients with atrial fibrillation? J Thorac Dis. 2015;7(2):165-171. doi: 10.3978/j.issn.2072-1439.2015.01.23.
  10. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955-962. doi: 10.1016/S0140-6736(13)62343-0.
  11. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151. doi: 10.1056/NEJMoa0905561.
  12. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L; Randomized Evaluation of Long-Term Anticoagulation Therapy Investigators. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363(19):1875-1876. doi: 10.1056/NEJMc1007378.
  13. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. doi: 10.1056/NEJMoa1009638.
  14. Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992. doi: 10.1056/NEJMoa1107039.
  15. Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104. doi: 10.1056/NEJMoa1310907.
  16. Hankey GJ, Stevens SR, Piccini JP, et al; ROCKET AF Steering Committee and Investigators. Intracranial hemorrhage among patients with atrial fibrillation anticoagulated with warfarin or rivaroxaban: the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation. Stroke. 2014;45(5):1304-1312. doi: 10.1161/STROKEAHA.113.004506.
  17. Piccini JP, Garg J, Patel MR, et al; ROCKET AF Investigators. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J. 2014;35(28):1873-1880. doi: 10.1093/eurheartj/ehu083.
  18. Held C, Hylek EM, Alexander JH, et al. Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J. 2015;36(20):1264-1272. doi: 10.1093/eurheartj/ehu463.
  19. Hylek EM, Held C, Alexander JH, et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): predictors, characteristics, and clinical outcomes. J Am Coll Cardiol. 2014;63(20):2141-2147. doi: 10.1016/j.jacc.2014.02.549.
  20. Giugliano RP, Ruff CT, Wiviott SD, et al. Mortality in patients with atrial fibrillation randomized to edoxaban or warfarin: insights from the ENGAGE AF-TIMI 48 trial. Am J Med. 2016;129(8):850-857.e2. doi: 10.1016/j.amjmed.2016.02.028.
  21. Purrucker JC, Haas K, Rizos T, et al. Early clinical and radiological course, management, and outcome of intracerebral hemorrhage related to new oral anticoagulants. JAMA Neurol. 2016;73(2):169-177. doi: 10.1001/jamaneurol.2015.3682.
  22. Beyer-Westendorf J, Förster K, Pannach S, et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood. 2014;124(6):955-962. doi: 10.1182/blood-2014-03-563577.
  23. Palmer C. Major trauma and the injury severity score—where should we set the bar? Annu Proc Assoc Adv Automot Med. 2007;51:13-29.
  24. Schulman S, Angeras U, Bergqvist D, et al; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost. 2010;8(1):202-204. doi: 10.1111/j.1538-7836.2009.03678.x.
  25. Desai J, Kolb JM, Weitz JI, Aisenberg J. Gastrointestinal bleeding with the new oral anticoagulants–defining the issues and the management strategies. Thromb Haemost. 2013;110(2):205-212. doi: 10.1160/TH13-02-0150.
  26. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413-2424. doi: 10.1056/NEJMoa1510991.
  27. Praxbind (idarucizumab) injection, for intravenous use [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2015.
  28. Mephyton (phytonadione tablet) [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals; 2012.
  29. Morotti A, Goldstein JN. New oral anticoagulants and their reversal agents. Curr Treat Options Neurol. 2016;18(11):47.
  30. DDAVP (desmopressin acetate) [package insert]. Bridgewater, NJ: Sanofi-Aventis US, LLC; 2007.
  31. Cyklokapron (tranexamic acid) [package insert]. New York, NY: Pfizer, Inc; 2016.
  32. FEIBA NF (anti-inhibitor coagulant complex) [package insert]. Deerfield, IL: Baxter Healthcare Corporation; 2010.
  33. Aronis KN, Hylek EM. Who, when, and how to reverse non-vitamin K oral anticoagulants. J Thromb Thrombolysis. 2016;41(2):253-272. doi: 10.1007/s11239-015-1297-0.
  34. Dzik WH. Reversal of oral factor Xa inhibitors by prothrombin complex concentrates: a re-appraisal. J Thromb Haemost. 2015;13(suppl 1):S187-S194. doi: 10.1111/jth.12949.
  35. 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(9):1428-1436. doi: 10.1111/jth.12599.
  36. Frontera JA, Lewin JJ rd, Rabinstein AA, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016;24(1):6-46. doi: 10.1007/s12028-015-0222-x.
  37. Kcentra (prothrombin complex concentrate [human]) [package insert]. Kankakee, IL: CSL Behring; 2014.
  38. Bebulin VH (factor IX complex), vapor heated [package insert]. Deerfield, IL: Baxter Healthcare Corporation; 2011.
  39. Profilnine (factor IX complex) [package insert]. Los Angeles, CA: Grifols USA, LLC; 2015.
  40. NovoSeven RT (coagulation factor VIIa [recombinant]) [package insert]. Plainsboro, NJ: Novo Nordisk A/S; 2015.
  41. Octaplas (pooled plasma [human] solvent/detergent treated) [package insert]. Hoboken, NJ: Octapharma USA, Inc; 2015.
  42. Lazo-Langner A, Lang ES, Douketis J. Clinical review: Clinical management of new oral anticoagulants: a structured review with emphasis on the reversal of bleeding complications. Crit Care. 2013;17(3):230. doi: 10.1186/cc12592.
  43. Portola Pharmaceuticals receives complete response letter from FDA for biologics license application for AndexXa (andexanet alfa) [news release]. South San Francisco, CA: Portola Pharmaceuticals; August 17, 2016. http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsArticle_pf&ID=2196085. Accessed October 25, 2016.
  44. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19(4):446-451. doi: 10.1038/nm.3102.
  45. Connolly SJ, Milling TJ Jr, Eikelboom JW, et al; ANNEXA-4 Investigators. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131-1141. doi: 10.1056/NEJMoa1607887.
  46. Kitchen S, Gray E, Mackie I, Baglin T, Makris M; BCSH committee. Measurement of non-coumarin anticoagulants and their effects on tests of Haemostasis: Guidance from the British Committee for Standards in Haematology. Br J Haematol. 2014;166(6):830-841. doi: 10.1111/bjh.12975.
  47. Samama MM, Contant G, Spiro TE, et al. Laboratory assessment of rivaroxaban: a review. Thromb J. 2013;11(1):11. doi: 10.1186/1477-9560-11-11.