- Novel anticoagulant are used in the prevention and treatment of thromboembolism. Inspite of their safety and efficacy, the lack of specific antidote to reverse its anticoagulation effects is an important limitation.
- Idarucizumab and adexanet are new reversal agents approved by FDA for reversal of NOAC.
Idarucizumab
It is highly selective and specific monoclonal antibody fragment (fab) which binds dabigatran with high affinity.
- Dose: 5gm infusion
- Availability : 2.5g/ vial
- Stability : 2-8 C
- Headache
- Constipation
- Nausea
Evidence
RE-VERSE AD Trial( Pollack et al. NEJM. 2015) prospective cohort study was done to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding or required an urgent procedure. Study found that Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes.
Further RE-VERSE AD Trial group published ( Pollack et al. NEJM. 2017) in his multicentric, prospective open label study done to determine whether 5gm of IV idarucizumab would be able to reverse anticoagulation effect patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B).The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B,the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals.
Andexanet
Andexanet alfa is a modified recombinant inactive form of human factor Xa, which binds and sequesters factor Xa inhibitor molecules, rapidly reducing anti–factor Xa activity and restoring thrombin generation.
- Andexanet Alfa is approved by FDA from may 2018 to reverse apixaban and rivaraxaban in patients with life threatening or uncontrolled bleeding.
- Dose :
- Low dose: 400mg @ 30mg/min followed by an infusion of 4mg/min for upto 2 hours.
- High dose: 800mg @ 30mg /min followed by 8 mg/min for upto 2 hours.
- Regimen is choosen based on time and size of the dose.
- If the last dose of rivaroxaban was 10 mg apixaban less than 5mg or less and drug administration was less than 8 hours ago or unknown, give the low dose.
- If the last dose of rivaroxaban was more than 10 mg, apixaban more than 5mg or of an unknown amount and drug administration was less than 8 hours ago or unknown, give the high dose.
- Route : IV
- Availability: 100mg lyophilised powder
- Stability: 2-8 C
- Dilution: 100mg in 10ml sterile water
- Deep vein thrombosis,
- Arterial thrombosis,
- Pulmonary embolism,
- Ischemic stroke,
- Acute myocardial infarction, and death
- ANNEXA-I Connolly et (NEJM.2023) published a study on Andexanet for factor Xa inhibitor associated Acute ICH taken within 15h.Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P=0.003).Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P=0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke.
ANNEXA-4 Connolly et al (NEJM.2019) published a multicentric, prospective, open label study report (n=352)of andexanet alfa for bleeding associated with factor Xa inhibitors (Apixaban, Rivoraxaban). They evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2-hour infusion. In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti–factor Xa activity 92%(baseline value 149.7 ng/ml was reduced to 11.1 ng/ml after adexanet bolus), and 82% (204 out of 249) of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria.
ANNEXA-4 Miling et al (Circulation.2023) published a extended study(n=479) on Andexanet Alfa for major bleeding within 18 hours factor Xa inhibitors administration. Study found that in patients with major bleeding associated with the use of FXa inhibitors, treatment with andexanet alfa reduced anti-FXa activity and was associated with good or excellent hemostatic efficacy in 80% of patients.
ANNEXA A & ANNEXA R (Siegal at al. NEJM.2015) published a two part randomised, double blinded, placebo controlled study to assess the safety in older volunteers. Part 1: IV bolus alone. Part 2: IV bolus followed by continuous 120 minute infusion. ANNEX-A received apixaban 5mg BD for 3.5 days whereas ANNEXA-R received rivaroxaban 20mg OD for 4 days.On day 4 ANNEXA-A received Part 1 : 400mg bolus; Part 2: 400mg bolus followed by 4mg/min infusion for 120 minutes. ANNEXA-R recieved Part 1 : 800mg bolus; Part 2: 800mg bolus followed by 8mg/min infusion for 120 minutes. Among apixiban treated patients(n=24), anti-factor Xa activity was reduced by 94% those who received an adexanet bolus and thrombin generation was 100% restored .Among rivoraxaban treated patients(n=27), anti-factor Xa activity was reduced by 92% those who received an adexanet bolus and thrombin generation was 96% restored. These effects were sustained in bolus plus infusion. No serious adverse or thrombotic events were reported.
Arapazine/Ciraparantag/PER977 (Universal Anticoagulant)
It is small water soluble molecule that binds to the drug inactivating it. It was originally developed as a reversal agent for heparin and fondaparinux but also seems to have activity against oral anti-Xa agents and dabigatran.
Current phase II studies have employed a single IV bolus, with laboratory evidence of reversal observed by 30 minutes. No FDA approval yet.
Conclusion
- Two main reversal agents Idarucizumab for dabigatran and Andexanet for Factor Xa Inhibitors is FDA approved and will change how anticoagulants are used and potential bleeding complications are treated. Ongoing development and probable fast track approval of Arapazine a universal anticoagulant may be game changer.
- Reed M, Tadi P, Nicolas D. Andexanet Alfa. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519499/
- Milling TJ Jr, Kaatz S. Preclinical and Clinical Data for Factor Xa and "Universal" Reversal Agents. Am J Med. 2016 Nov;129(11S):S80-S88. doi: 10.1016/j.amjmed.2016.06.009. Epub 2016 Aug 27. PMID: 27575436; PMCID: PMC5568764.
- Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371:2141–2142. doi: 10.1056/NEJMc141180
- Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kam CW, Kamphuisen PW, Kreuzer J, Levy JH, Royle G, Sellke FW, Stangier J, Steiner T, Verhamme P, Wang B, Young L, Weitz JI. Idarucizumab for Dabigatran Reversal - Full Cohort Analysis. N Engl J Med. 2017 Aug 3;377(5):431-441. doi: 10.1056/NEJMoa1707278. Epub 2017 Jul 11. PMID: 28693366.
- Hu TY, Vaidya VR, Asirvatham SJ. Reversing anticoagulant effects of novel oral anticoagulants: role of ciraparantag, andexanet alfa, and idarucizumab. Vasc Health Risk Manag. 2016 Feb 17;12:35-44. doi: 10.2147/VHRM.S89130. PMID: 26937198; PMCID: PMC4762436.
