Correction of the effect of direct oral and parenteral anticoagulants in hemorrhagic stroke

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BACKGROUND

Hemorrhagic stroke is associated with high risk of adverse outcome and follows intake of anticoagulants and antiplatelet agents in 25% of cases. The latest clinical guidelines of the Neurocritical Care Society for correction (reversal) of the effect of anticoagulants and antiplatelet agents in hemorrhagic stroke were published in 2016.

MATERIAL AND METHODS

In accordance with PRISMA recommendations, we reviewed the PubMed, eLibrary and UpToDate databases to a depth of 5 years and selected 48 articles.

RESULTS AND DISCUSSION

Direct oral anticoagulants are currently common. To reverse their effect, one can use specific antidotes (idarucizumab is recommended for dabigatran, andexanet alfa (not yet registered In Russia) for factor Xa inhibitors (rivaroxaban, apixaban)) and combination of prothrombin complex concentrate and tranexamic acid. Protamine sulfate is antidote for unfractionated and low molecular weight heparins. Protamine sulfate completely inactivates unfractionated heparin, but it is less effective against low molecular weight heparin. It is characterized by high probability of anaphylactic reactions, especially after repeated administrations. The effectiveness of andexanet alpha and activated factor VII for reversing the effect of low molecular weight heparin is being studied. Fondaparinux sodium is used for heparin-induced thrombocytopenia. Protamine sulfate is ineffective for reversing the effect of fondaparinux. One can use prothrombin complex concentrate and andexanet alpha, but their effectiveness is unclear. Ciraparantag is being studied in clinical trials. Apparently, ciraparantag is highly effective as an antidote for various anticoagulants.

CONCLUSION

Early hemostatic therapy and reversal of anticoagulant effects in patients with hemorrhagic stroke significantly reduce the risk of adverse outcomes. This problem is being studied. Regular literature review with creation of updated clinical guidelines is needed.

Keywords:

hemorrhagic stroke

anticoagulants

DOAC

heparin

antidotes

Authors:

Baranich A.I.

Burdenko Neurosurgical Center;
Plekhanov Russian University of Economics

RSCI AuthorID: 1006875
Scopus AuthorID: 57202735861
ORCID: 0000-0002-1167-0742

Sychev A.A.

Burdenko Neurosurgical Center

SPIN RSCI: 1171-7690
Scopus AuthorID: 36997601100
ORCID: 0000-0002-0038-1005

Savin I.A.

Burdenko Neurosurgical Center

SPIN RSCI: 1342-7065
Scopus AuthorID: 35974373500
ORCID: 0000-0003-3874-4147

Kudrina V.G.

Plekhanov Russian University of Economics;
Russian Medical Academy of Continuous Professional Education

ORCID: 0000-0002-4329-1165

Kozlov A.V.

Burdenko Neurosurgical Center;
Andijan State Medical Institute

ORCID: 0000-0002-3181-6470

Received:

18.07.2024

Accepted:

21.11.2024

List of references:

Concha M, Cohen AT. Recommendations for Research Assessing Outcomes for Patients With Anticoagulant-Related Intracerebral Bleeds. Stroke. 2021;52(4):1520-1526. https://doi.org/10.1161/STROKEAHA.120.031730
Maragkos GA, Nelton EB, Richter S, Stippler M. Low Risk of Traumatic Intracranial Hematoma Expansion with Factor Xa Inhibitors without Andexanet Reversal. World Neurosurgery. 2020;142:e95-e100. https://doi.org/10.1016/j.wneu.2020.06.069
Frontera JA, Lewin JJ 3rd, Rabinstein AA, Aisiku IP, Alexandrov AW, Cook AM, del Zoppo GJ, Kumar MA, Peerschke EI, Stiefel MF, Teitelbaum JS, Wartenberg KE, Zerfoss CL. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocritical Care. 2016;24(1):6-46. https://doi.org/10.1007/s12028-015-0222-x
Baranich AI, Sychev AA, Savin IA, Kudrimna VG, Vozlov AV. Correction of the effect of vitamin K antagonists and antiplatelet agents in hemorrhagic stroke. Burdenko’s Journal of Neurosurgery. 2024;88(6):103-109. (In Russ.). https://doi.org/10.17116/neiro202488061103
Ballestri S, Romagnoli E, Arioli D, Coluccio V, Marrazzo A, Athanasiou A, Di Girolamo M, Cappi C, Marietta M, Capitelli M. Risk and Management of Bleeding Complications with Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Venous Thromboembolism: a Narrative Review. Advances in Therapy. 2023;40(1):41-66. https://doi.org/10.1007/s12325-022-02333-9
Shin SS, Marsh EB, Ali H, Nyquist PA, Hanley DF, Ziai WC. Comparison of Traumatic Intracranial Hemorrhage Expansion and Outcomes Among Patients on Direct Oral Anticoagulants Versus Vitamin k Antagonists. Neurocritical Care. 2020;32(2):407-418. https://doi.org/10.1007/s12028-019-00898-y
Miller MM, Lowe J, Khan M, Azeem MU, Muehlschlegel S, Jun-O’Connell AH, Goddeau RP Jr, Moonis M, Gritters D, Silver B, Henninger N. Clinical and Radiological Characteristics of Vitamin K Versus Non-Vitamin K Antagonist Oral Anticoagulation-Related Intracerebral Hemorrhage. Neurocritical Care. 2019;31(1):56-65. https://doi.org/10.1007/s12028-019-00671-1
Marcolini E, Stretz C, DeWitt KM. Intracranial Hemorrhage and Intracranial Hypertension. Emergency Medicine Clinics of North America. 2019;37(3):529-544. https://doi.org/10.1016/j.emc.2019.04.001
Hutcheson B, Spetz S, Davenport J, Shuler E. Time to oral anticoagulant reversal in intracranial hemorrhage with an emergency medicine pharmacist presence. The American Journal of Emergency Medicine. 2024;80:114-118. https://doi.org/10.1016/j.ajem.2024.03.014
Sheth KN, Solomon N, Alhanti B, Messe SR, Xian Y, Bhatt DL, Hemphill JC, Frontera JA, Chang RC, Danelich IM, Huang J, Schwamm L, Smith EE, Goldstein JN, Mac Grory B, Fonarow GC, Saver JL. Time to Anticoagulation Reversal and Outcomes After Intracerebral Hemorrhage. JAMA Neurology. 2024;81(4):363-372. https://doi.org/10.1001/jamaneurol.2024.0221
Chen A, Stecker E, A Warden B. Direct Oral Anticoagulant Use: A Practical Guide to Common Clinical Challenges. Journal of the American Heart Association. 2020;9(13):e017559. https://doi.org/10.1161/JAHA.120.017559
Clinical Excellence Commission, 2023, Direct Oral Anticoagulant (DOAC) Guidelines. https://www.cec.health.nsw.gov.au/keep-patients-safe/medication-safety/high-risk-medicines/anticoagulants
Christensen H, Cordonnier C, Kõrv J, Lal A, Ovesen C, Purrucker JC, Toni D, Steiner T. European Stroke Organisation Guideline on Reversal of Oral Anticoagulants in Acute Intracerebral Haemorrhage. European Stroke Journal. 2019;4(4):294-306. https://doi.org/10.1177/2396987319849763
Makhoul T, Kelly G, Kersten B, Nadler M, Zammit CG, Jones CMC, Scott R, Acquisto NM. Incidence of thromboembolic events following administration of four-factor prothrombin complex concentrate (4F-PCC) for oral anticoagulation reversal. Thrombosis Research. 2020;194:158-164. https://doi.org/10.1016/j.thromres.2020.06.028
Ballestri S, Romagnoli E, Arioli D, Coluccio V, Marrazzo A, Athanasiou A, Di Girolamo M, Cappi C, Marietta M, Capitelli M. Risk and Management of Bleeding Complications with Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Venous Thromboembolism: a Narrative Review. Advances in Therapy. 2023;40(1):41-66. https://doi.org/10.1007/s12325-022-02333-9
Nestor MA, Boling B. Reversing Direct Oral Anticoagulants in Acute Intracranial Hemorrhage. Critical Care Nurse. 2019;39(3):e1-e8. https://doi.org/10.4037/ccn2019160
Galstyan GM. Label and off-label applications of prothrombin complex concentrates. New perspectives of old drugs. Russian journal of hematology and transfusiology. 2018;63(1):78-91. (In Russ.). https://doi.org/10.25837/HAT.2018.30..1..008
Ghadimi K, Levy JH, Welsby IJ. Prothrombin Complex Concentrates for Bleeding in the Perioperative Setting. Anesthesia & Analgesia. 2016;122(5):1287-1300. https://doi.org/10.1213/ANE.0000000000001188
Ostroumova OD, Listratov AI, Ostroumova TM, Kochetkov AI, Sychev DA. Drug-induced non-traumatic intracranial hemorrhage associated with the use of anticoagulants and antiplatelet agents. Nevrologiya, neiropsikhiatriya, psikhosomatika. 2022;14(6):80-88. (In Russ.). https://doi.org/10.14412/2074-2711-2022-3-94-100
Nestor MA, Boling B. Reversing Direct Oral Anticoagulants in Acute Intracranial Hemorrhage. Critical Care Nurse. 2019;39(3):e1-e8. https://doi.org/10.4037/ccn2019160
Ammar AA, Elsamadicy AA, Ammar MA, Reeves BC, Koo AB, Falcone GJ, Hwang DY, Petersen N, Kim JA, Beekman R, Prust M, Magid-Bernstein J, Acosta JN, Herbert R, Sheth KN, Matouk CC, Gilmore EJ. Emergent external ventricular drain placement in patients with factor Xa inhibitor-associated intracerebral hemorrhage after reversal with andexanet alfa. Clinical Neurology and Neurosurgery. 2023;226:107621. https://doi.org/10.1016/j.clineuro.2023.107621
Ghenbot Y, Arena JD, Howard S, Wathen C, Kumar MA, Schuster JM. Anticoagulation Holiday: Resumption of Direct Oral Anticoagulants for Atrial Fibrillation in Patients with Index Traumatic Intracranial Hemorrhage. World Neurosurgery X. 2022;17:100148. https://doi.org/10.1016/j.wnsx.2022.100148
Lu VM, Phan K, Rao PJ, Sharma SV, Kasper EM. Dabigatran reversal by idarucizumab in the setting of intracranial hemorrhage: A systematic review of the literature. Clinical Neurology and Neurosurgery. 2019;181:76-81. https://doi.org/10.1016/j.clineuro.2019.04.013
Chuck CC, Kim D, Kalagara R, Rex N, Madsen TE, Mahmoud L, Thompson BB, Jones RN, Furie KL, Reznik ME. Modeling the Clinical Implications of Andexanet Alfa in Factor Xa Inhibitor-Associated Intracerebral Hemorrhage. Neurology. 2021;97(21):e2054-e2064. https://doi.org/10.1212/WNL.0000000000012856
Toyoda K, Arakawa S, Ezura M, Kobayashi R, Tanaka Y, Hasegawa S, Yamashiro S, Komatsu Y, Terasawa Y, Masuno T, Kobayashi H, Oikawa S, Yasaka M. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity: Prespecified Subgroup Analysis of the ANNEXA-4 Study in Japan. Journal of Atherosclerosis and Thrombosis. 2024;31(3):201-213. https://doi.org/10.5551/jat.64223
Peacock WF, Grotta JC, Steiner T. Idarucizumab for Reversal of Dabigatran in Early/Emergency Surgeries: A Case Series. Journal of Emergency Medicine. 2019;57(6):e167-e173. https://doi.org/10.1016/j.jemermed.2019.09.038
Giovino A, Shomo E, Busey KV, Case D, Brockhurst A, Concha M. An 18-month single-center observational study of real-world use of andexanet alfa in patients with factor Xa inhibitor associated intracranial hemorrhage. Clinical Neurology and Neurosurgery. 2020;195:106070. https://doi.org/10.1016/j.clineuro.2020.106070
Küpper C, Feil K, Klein M, Feuerecker R, Lücking M, Thanbichler F, Dietrich D, Zerkaulen I, Jandl M, Marziniak M, Poppert H, Wunderlich S, Topka H, Dieterich M, Kellert L. Idarucizumab administration in emergency situations: the Munich Registry of Reversal of Pradaxa® in clinical routine (MR REPAIR). Journal of Neurology. 2019;266(11):2807-2811. https://doi.org/10.1007/s00415-019-09492-w
Kermer P, Eschenfelder CC, Diener HC, Grond M, Abdalla Y, Abraham A, Althaus K, Becks G, Berrouschot J, Berthel J, Bode FJ, Burghaus L, Cangür H, Daffertshofer M, Edelbusch S, Eggers J, Gerlach R, Gröschel K, Große-Dresselhaus F, Günther A, Haase CG, Haensch CA, Harloff A, Heckmann JG, Held V, Hieber M, Kauert A, Kern R, Kerz T, Köhrmann M, Kraft P, Kühnlein P, Latta J, Leinisch E, Lenz A, Leithner C, Neumann-Haefelin T, Mäurer M, Müllges W, Nolte CH, Obermann M, Partowi S, Patzschke P, Poli S, Pulkowski U, Purrucker J, Rehfeldt T, Ringleb PA, Röther J, Rossi R, El-Sabassy H, Sauer O, Schackert G, Schäfer N, Schellinger PD, Schneider A, Schuppner R, Schwab S, Schwarte O, Seitz RJ, Senger S, Shah YP, Sindern E, Sparenberg P, Steiner T, Szabo K, Urbanek C, Sarnowksi BV, Weissenborn K, Wienecke P, Witt K, Wruck R, Wunderlich S. Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany-Updated series of 120 cases. International Journal of Stroke. 2020;15(6):609-618. https://doi.org/10.1177/1747493019895654
Costa OS, Connolly SJ, Sharma M, Beyer-Westendorf J, Christoph MJ, Lovelace B, Coleman CI. Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhage: a propensity score-overlap weighted analysis. Critical Care. 2022;26(1):180. https://doi.org/10.1186/s13054-022-04043-8
Ammar AA, Ammar MA, Owusu KA, Brown SC, Kaddouh F, Elsamadicy AA, Acosta JN, Falcone GJ. Andexanet Alfa Versus 4-Factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage. Neurocritical Care. 2021;35(1):255-261. https://doi.org/10.1007/s12028-020-01161-5
Troyer C, Nguyen W, Xie A, Wimer D. Retrospective review of Andexanet Alfa versus 4-Factor Prothrombin Complex Concentrate for reversal of DOAC-Associated Intracranial Hemorrhage. Journal of Thrombosis and Thrombolysis. 2023;55(1):149-155. https://doi.org/10.1007/s11239-022-02715-4
Korobey MJ, Sadaka F, Javed M, Moynihan M, Alsaei A. Efficacy of 4-Factor Prothrombin Complex Concentrates in Factor Xa Inhibitor-Associated Intracranial Bleeding. Neurocritical Care. 2021;34(1):112-120. https://doi.org/10.1007/s12028-020-00968-6
Lipski M, Pasciolla S, Wojcik K, Jankowitz B, Igneri LA. Comparison of 4-factor prothrombin complex concentrate and andexanet alfa for reversal of apixaban and rivaroxaban in the setting of intracranial hemorrhage. Journal of Thrombosis and Thrombolysis. 2023;55(3):519-526. https://doi.org/10.1007/s11239-022-02752-z
Dobesh PP, Fermann GJ, Christoph MJ, Koch B, Lesén E, Chen H, Lovelace B, Dettling T, Danese M, Ulloa J, Danese S, Coleman CI. Lower mortality with andexanet alfa vs 4-factor prothrombin complex concentrate for factor Xa inhibitor-related major bleeding in a U.S. hospital-based observational study. Research and Practice in Thrombosis and Haemostasis. 2023;7(6):102192. https://doi.org/10.1016/j.rpth.2023.102192
Barra ME, Das AS, Hayes BD, Rosenthal ES, Rosovsky RP, Fuh L, Patel AB, Goldstein JN, Roberts RJ. Evaluation of andexanet alfa and four-factor prothrombin complex concentrate (4F-PCC) for reversal of rivaroxaban- and apixaban-associated intracranial hemorrhages. Journal of Thrombosis and Haemostasis. 2020;18(7):1637-1647. https://doi.org/10.1111/jth.14838
Bradshaw PG, Keegan S, Foertsch M, Yang GL, Ngwenya LB, Srinivasan V. Andexanet alfa after 4-factor PCC administration for intracranial hemorrhage: a case series. Journal of Thrombosis and Thrombolysis. 2022;54(2):295-300. https://doi.org/10.1007/s11239-022-02658-w
Siepen BM, Forfang E, Branca M, Drop B, Mueller M, Goeldlin MB, Katan M, Michel P, Cereda C, Medlin F, Peters N, Renaud S, Niederhauser J, Carrera E, Kahles T, Kägi G, Bolognese M, Salmen S, Mono ML, Polymeris AA, Wegener S, Z’Graggen W, Kaesmacher J, Schaerer M, Rodic B, Kristoffersen ES, Larsen KT, Wyller TB, Volbers B, Meinel TR, Arnold M, Engelter ST, Bonati LH, Fischer U, Rønning OM, Seiffge DJ. Intracerebral haemorrhage in patients taking different types of oral anticoagulants: a pooled individual patient data analysis from two national stroke registries. Stroke and Vascular Neurology. 2024:svn-2023-002813. https://doi.org/10.1136/svn-2023-002813.
Hostettler IC, Seiffge DJ, Werring DJ. Intracerebral hemorrhage: an update on diagnosis and treatment. Expert Review of Neurotherapeutics. 2019;19(7):679-694. https://doi.org/10.1080/14737175.2019.1623671
Chaudhary R, Singh A, Chaudhary R, Bashline M, Houghton DE, Rabinstein A, Adamski J, Arndt R, Ou NN, Rudis MI, Brown CS, Wieruszewski ED, Wanek M, Brinkman NJ, Linderbaum JA, Sorenson MA, Atkinson JL, Thompson KM, Aiyer AN, McBane RD 2nd. Evaluation of Direct Oral Anticoagulant Reversal Agents in Intracranial Hemorrhage: A Systematic Review and Meta-analysis. JAMA Network. 2022;5(11):e2240145. https://doi.org/10.1001/jamanetworkopen.2022.40145
Sheikh-Taha M, Crawley RM. Reversal of Apixaban and Rivaroxaban Using Activated Prothrombin Complex Concentrates in Patients with Major Bleeding. American Journal of Cardiovascular Drugs. 2020;20(3):295-299. https://doi.org/10.1007/s40256-019-00383-z
Zabolotskikh IB, Sinkov SV, Bulanov AY, Vorobyova NA, Eremenko AA, Kuzovlev AN, Kulikov AV, Lebedinskii KM, Popov AS, Roitman EV. Perioperative management of patients with hemostatic system disorders. Methodological recommendations of the All-Russian public organization “Federation of Anesthesiologists and Reanimatologists” and the National Association of Specialists in Thrombosis, Clinical Hemostasiology and Hemorheology. Annals of Critical Care. 2024;(1):7-46. (In Russ.). https://doi.org/10.21320/1818-474X-2024-1-7-46
Garcia DA, Burnett AE. Heparin and LMW heparin: Dosing and adverse effects. UpToDate. 2024 [online] [Accessed June 3, 2024]. Available at: https://www.uptodate.com/contents/heparin-and-lmw-heparin-dosing-and-adverse-effects?search=heparine&source=search_result&selectedTitle=3%7E150&usage_type=default&display_rank=2
Fareed J, Hoppensteadt D, Walenga J, Iqbal O, Ma Q, Jeske W, Sheikh T. Pharmacodynamic and pharmacokinetic properties of enoxaparin: implications for clinical practice. Clinical Pharmacokinet. 2003;42(12):1043-1057. https://doi.org/10.2165/00003088-200342120-00003
Freeman WD, Weitz JI. Reversal of anticoagulation in intracranial hemorrhage. UpToDate. 2024 [online] [Accessed June 3, 2024]. Available at: https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage?search=warfarin&topicRef=1334&source=see_link
Levy JH, Ghadimi K, Kizhakkedathu JN, Iba T. What’s fishy about protamine? Clinical use, adverse reactions, and potential alternatives. Journal of Thrombosis and Haemostasis. 2023;21(7):1714-1723. https://doi.org/10.1016/j.jtha.2023.04.005
Sweidan AJ, Singh NK, Conovaloff JL, Bower M, Groysman LI, Shafie M, Yu W. Coagulopathy reversal in intracerebral haemorrhage. Stroke and Vascular Neurology. 2020;5(1):29-33. https://doi.org/10.1136/svn-2019-000274
Leentjens J, Middeldorp S, Jung C. A short review of ciraparantag in perspective of the currently available anticoagulant reversal agents. Drug Discovery Today. 2022;27(10):103332. https://doi.org/10.1016/j.drudis.2022.07.017
Ansell J, Bakhru S, Laulicht BE, Tracey G, Villano S, Freedman D. Ciraparantag reverses the anticoagulant activity of apixaban and rivaroxaban in healthy elderly subjects. European Heart Journal. 2022;43(10):985-992. https://doi.org/10.1093/eurheartj/ehab637

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