Multicenter observational study on anticoagulation related bleeding events in emergency department patients

Abstract

We investigated bleeding complications in patients admitted to the emergency department (ED) who were taking oral anticoagulants and compared the rates of major and minor bleeding events between the direct oral anticoagulant (DOAC) and warfarin groups. We conducted a prospective, multicenter observational study of warfarinand DOAC-treated patients who presented to the EDs of tertiary-care hospitals between July 2020 and July 2021 with a bleeding event. Among 518 patients on anticoagulation therapy, 121 (23.4%) presented to EDs with bleeding events. A chart review revealed 73 (60.24%) patients with bleeding events who were taking a DOAC (i.e., apixaban, edoxaban, rivaroxaban, or dabigatran) and 48 who were taking warfarin. The rate of bleeding events was significantly higher among patients treated with warfarin than among those treated with DOACs (48/129 [37.2%] vs. 73/389 [18.8%], p<0,001). Subgroup analysis of the DOAC-treated patients revealed a significant difference in the frequency of bleeding events among the DOAC groups (p=0.016), with a significantly lower frequency in patients treated with rivaroxaban versus edoxaban (14.9% vs. 34.7%, p=0.002) and in those treated with apixaban versus edoxaban (18.8% vs. 34.7%, p=0.021). Our findings indicate that although the rates of overall bleeding events differed among DOAC-treated patients, the rates of bleeding events were lower than those in warfarin-treated patients. Additionally, major bleeding events occurred less frequently in patients treated with rivaroxaban or apixaban compared with edoxaban.

Keywords

• Oral anticoagulants
• bleeding events
• direct oral anticoagulant
• warfarin

References

1. [1] January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC Jr, Ellinor PT, Ezekowitz MD, Field ME, Furie KL, Heidenreich PA, Murray KT, Shea JB, Tracy CM, Yancy CW. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With
2. [2] Surgeons. Circulation. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, La Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Thomas GN, Valgimigli M, Van Gelder IC, Van
3. [3] Tastet L, Pibarot P, Shen M, Clisson M, Côté N, Salaun E, Arsenault M, Bédard É, Capoulade R, Puri R, Poirier P, Clavel MA. Oral Anticoagulation Therapy and Progression of Calcific Aortic Valve Stenosis. J Am Coll Cardiol. 2019;16;73(14):1869-1871. https://doi.org/10.1016/j.jacc.2019.01.043. oral anticoagulants:
4. [4] Dogan Y, Az A, Sogut O, Akdemir T, Kaplan O. Bleeding events in the emergency department with warfarin versus novel A five-year analysis. Niger J Clin Pract. 2022;25(8):1308-1317. https://doi.org/10.4103/njcp.njcp_125_22.
5. [5] Tran H, Joseph J, Young L, McRae S, Curnow J, Nandurkar H, Wood P, McLintock C. New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Australasian Society of Thrombosis and Haemostasis. Intern Med J. 2014;44(6):525-536. https://doi.org/10.1111/imj.12448.
6. [6] Sauter TC, Melis C, Hautz WE, Ricklin ME, Exadaktylos AK. Direct new oral anticoagulants: follow-up, guidelines and bleeding complications in general practice-a survey of Swiss general internal medicine practitioners. Springerplus. 2016;5(1):2030. https://doi.org/10.1186/s40064-016-3722-z.
7. [7] Carnicelli AP, Hong H, Connolly SJ, Eikelboom J, Giugliano RP, Morrow DA, Patel MR, Wallentin L, Alexander JH, Cecilia Bahit M, Benz AP, Bohula EA, Chao TF, Dyal L, Ezekowitz M, A A Fox K, Gencer B, Halperin JL, Hijazi Z, Hohnloser SH, Hua K, Hylek E, Toda Kato E, Kuder J, Lopes RD, Ma
8. [8] Lawal OD, Aronow HD, Shobayo F, Hume AL, Taveira TH, Matson KL, Zhang Y, Wen X. Comparative Effectiveness and Safety of Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and Chronic Liver Disease: A Nationwide Cohort Study. Circulation 2023;7;147(10):782-794. https://doi.org/10.1161/circulationaha.122.060687.

9. [9] Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151. https://doi.org/10.1056/NEJMoa0905561.
10. [10] Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin nonvalvular atrial fibrillation. N Engl J Med. 2011;8;365(10):883-891. https://doi.org/10.1056/NEJMoa1009638.
11. [11] Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, AlKhalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;15;365(11):981-992. https://doi.org/10.1056/NEJMoa1107039.
12. [12] Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AFTIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104. https://doi.org/10.1056/NEJMoa1310907.
13. [13] Khan F, Tritschler T, Kimpton M, Wells PS, Kearon C, Weitz JI, Büller HR, Raskob GE, Ageno W, Couturaud F, Prandoni P, Palareti G, Legnani C, Kyrle PA, Eichinger S, Eischer L, Becattini C, Agnelli G, Vedovati MC, Geersing GJ, Takada T, Cosmi B, Aujesky D, Marconi L, Palla A, Siragusa S, Bradbury CA, Parpia S, Mallick R, Lensing AWA, Gebel M, Grosso MA, Thavorn K, Hutton B, Le Gal G, Fergusson DA, Rodger MA; MAJESTIC Collaborators. Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Systematic Review and Meta-analysis. Ann Intern Med. 2021;174(10):1420-1429. https://doi.org/10.7326/M21-1094.
14. [14] Ferro JM, Coutinho JM, Dentali F, Kobayashi A, Alasheev A, Canhão P, Karpov D, Nagel S, Posthuma L, Roriz JM, Caria J, Frässdorf M, Huisman H, Reilly P, Diener HC; RE-SPECT CVT Study Group. Safety and Efficacy of Dabigatran Etexilate vs Dose-Adjusted Warfarin in Patients With Cerebral Venous Thrombosis: A Randomized Clinical Trial. JAMA Neurol. 2019;1;76(12):1457-1465. https://doi.org/10.1001/jamaneurol.2019.2764.
15. [15] Yaghi S, Shu L, Bakradze E, Salehi Omran S, Giles JA, Amar JY, Henninger N, Elnazeir M, Liberman AL, Moncrieffe K, Lu J, Sharma R, Cheng Y, Zubair AS, Simpkins AN, Li GT, Kung JC, Perez D, Heldner M, Scutelnic A, Seiffge D, Siepen B, Rothstein A, Khazaal O, Do D, Kasab SA, Rahman LA, [16] Woo HG, Chung I, Gwak DS, Kim BK, Kang JH, Kim BJ, Bae HJ, Han MK. Intracerebral hemorrhage associated with warfarin versus non-vitamin K antagonist oral anticoagulants in Asian patients. J Clin Neurosci. 2019;61:160 165. https://doi.org/10.1016/j.jocn.2018.10.102.
16. [17] Mitchell A, Watson MC, Welsh T, McGrogan A. Effectiveness and Safety of Direct Oral Anticoagulants versus Vitamin K Antagonists for People Aged 75 Years and over with Atrial Fibrillation: A Systematic Review and Meta Analyses of Observational Studies. J Clin Med. 2019;8(4):554. https://doi.org/10.3390/jcm8040554.
17. [18] Amin A, Keshishian A, Trocio J, Dina O, Le H, Rosenblatt L, Liu X, Mardekian J, Zhang Q, Baser O, Vo L. Risk of stroke/systemic embolism, major bleeding and associated costs in non-valvular atrial fibrillation patients who initiated apixaban, dabigatran or rivaroxaban compared with warfarin in the United States Medicare population. Curr Med Res Opin. 2017;33(9):1595-1604. https://doi.org/10.1080/03007995.2017.1345729.
18. [19] Jacobs V, May HT, Bair TL, Crandall BG, Cutler MJ, Day JD, Mallender C, Osborn JS, Stevens SM, Weiss JP, Woller SC, Bunch TJ. Long-Term Population-Based Cerebral Ischemic Event and Cognitive Outcomes of Direct Oral Anticoagulants Compared With Warfarin Among Long-term Anticoagulated Patients for Atrial Fibrillation. Am J Cardiol. 2016;118(2):210-214. https://doi.org/10.1016/j.amjcard.2016.04.039.
19. [20] Singer AJ, Quinn A, Dasgupta N, Thode HC Jr. Management and Outcomes of Bleeding Events in Patients in the Emergency Department Taking Warfarin or a Non-Vitamin K Antagonist Oral Anticoagulant. J Emerg Med. 2017;52(1):1-7. https://doi.org/10.1016/j.jemermed.2016.09.028.