A systematic review of anticoagulants evaluating efficacy and safety in thromboembolic disease
DOI:
https://doi.org/10.18203/2394-6040.ijcmph20260154Keywords:
Venous thromboembolism, Anticoagulants, DOACAbstract
Venous thromboembolism (VTE) is a major global source of morbidity and mortality. Oral anticoagulants have become a safer and more effective alternative to conventional anticoagulants, such as heparin and warfarin, which have been the cornerstone of treatment. They have shown comparable efficacy with fewer significant bleeding episodes. This study investigated the efficacy and safety of oral anticoagulants in comparison with other conventional anticoagulant therapies in patients with venous thromboembolism. A systematic review was conducted where data were obtained from PubMed, Scopus, Google Scholar, and Clinicaltrials.gov, covering the period from January 2020 to July 2025. Study selection was conducted in accordance with PRISMA guidelines and illustrated using a PRISMA flowchart. Eligible studies included randomized clinical trials, cohort studies, and observational studies that compared direct oral anticoagulants (DOACs) with conventional or other anticoagulant therapies. Data extraction was performed independently by two reviewers (EA), who identified relevant studies and extracted information on study characteristics, outcomes, and efficacy from the included articles. It was found that VTE is effectively managed with prolonged anticoagulation therapy. Research indicates that a minimum duration of three to six months of oral anticoagulant use significantly reduces the risk of recurrent VTE and is associated with fewer major bleeding events. Among the available options, a 20 mg dose of rivaroxaban has been shown to offer the highest efficacy. In contrast, monotherapy with agents such as vitamin K antagonists, aspirin, or warfarin is generally less effective, whereas combination therapy with oral anticoagulants provides improved outcomes. It is concluded that for patients with venous thromboembolism, direct oral anticoagulants are a safer and more efficient therapeutic option than vitamin K antagonists and traditional anticoagulation treatments.
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References
Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al.; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808. DOI: https://doi.org/10.1056/NEJMoa1302507
Ho FK, Man KKC, Toshner M, Church C, Celis-Morales C, Wong ICK, et al. Thromboembolic risk in hospitalized and nonhospitalized COVID-19 patients: a self-controlled case series analysis of a nationwide cohort. Mayo Clin Proc. 2021;96(10):2587-97. DOI: https://doi.org/10.1016/j.mayocp.2021.07.002
Albers GW, Diener HC, Frison L, Grind M, Nevinson M, Partridge S, et al.; SPORTIF Executive Steering Committee for the SPORTIF V Investigators. Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA. 2005;293(6):690-8. DOI: https://doi.org/10.1001/jama.293.6.690
Lobastov K, Vorontsova A, Bargandzhiya A, Schastlivtsev I, Laberko L. Outpatient treatment for deep vein thrombosis with rivaroxaban: a single-center experience. Flebologiya. 2020;14(2):99. DOI: https://doi.org/10.17116/flebo20201402199
Zuily S, Cohen H, Isenberg D, Woller SC, Crowther M, Dufrost V, et al. Use of direct oral anticoagulants in patients with thrombotic antiphospholipid syndrome: guidance from the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2020;18(9):2126-37. DOI: https://doi.org/10.1111/jth.14935
Elshafei MN, Mohamed MFH, El-Bardissy A, Ahmed MB, Abdallah I, Elewa H, et al. Comparative effectiveness and safety of direct oral anticoagulants compared to warfarin in morbidly obese patients with acute venous thromboembolism: a systematic review and meta-analysis. J Thromb Thrombolysis. 2021;51(2):388-96. DOI: https://doi.org/10.1007/s11239-020-02179-4
Grosse SD, Nelson RE, Nyarko KA, Richardson LC, Raskob GE. The economic burden of incident venous thromboembolism in the United States: a review of estimated attributable healthcare costs. Thromb Res. 2016;137:3-10. DOI: https://doi.org/10.1016/j.thromres.2015.11.033
Matharu GS, Kunutsor SK, Judge A, Blom AW, Whitehouse MR. Clinical effectiveness and safety of aspirin for venous thromboembolism prophylaxis after total hip and knee replacement: a systematic review and meta-analysis of randomized clinical trials. JAMA Intern Med. 2020;180:376-84. DOI: https://doi.org/10.1001/jamainternmed.2019.6108
Branstetter JW. Anticoagulation therapy: current perspectives. Semin Thromb Hemost. 2024;50(8):643-53.
Giossi R, Menichelli D, D’Amico F, Idotta L, Cirino M, Scardoni L, et al. Efficacy and safety of direct oral anticoagulants in the pediatric population: a systematic review and meta-analysis. J Thromb Haemost. 2023;21(10):2784-96. DOI: https://doi.org/10.1016/j.jtha.2023.07.011
Hasan SS, Radford S, Kow CS, Zaidi STR. Venous thromboembolism in critically ill COVID-19 patients receiving prophylactic or therapeutic anticoagulation: a systematic review and meta-analysis. J Thromb Thrombolysis. 2020;50:814-21. DOI: https://doi.org/10.1007/s11239-020-02235-z
Alhousani M, Malik SU, Abu-Hashyeh A, Poznanski NJ, Al-Hasan S, Roth DF, et al. Using oral anticoagulants among chronic kidney disease patients to prevent recurrent venous thromboembolism: a systematic review and meta-analysis. Thromb Res. 2021;198:103-14. DOI: https://doi.org/10.1016/j.thromres.2020.11.036
Huang ZC, Li CQ, Liu XY, Cao ZC, Jia HY, Dong Y, et al. Efficacy and safety of direct oral anticoagulants in patients with atrial fibrillation and liver disease: a meta-analysis and systematic review. Cardiovasc Drugs Ther. 2021;35(6):1205-15. DOI: https://doi.org/10.1007/s10557-020-07065-y
Nakamura M, Tamaru S, Hirooka S, Hirayama A, Tsuji A, Hirata M. Efficacy and safety of warfarin for the treatment of venous thromboembolism: a multicenter prospective observational cohort study in Japan (AKAFUJI study). Circ J. 2024;88:359-68. DOI: https://doi.org/10.1253/circj.CJ-23-0158
Margaglione M, Antonucci E, D’Andrea G, Migliaccio L, Ageno W, Bucherini E, et al. Anticoagulation in Italian patients with venous thromboembolism and thrombophilic alterations: findings from the START2 register study. Blood Transfus. 2020;18(6):486-95.
Alosaimi HM, Alqahtani S, Balkhi B, Alqahtani M, Alzamil F, Alhossan A, et al. Real-world effectiveness and safety of rivaroxaban in patients with non-valvular atrial fibrillation and venous thromboembolism in Saudi Arabia. Peer J. 2022;10:e13974. DOI: https://doi.org/10.7717/peerj.13974
Bertoletti L, Gusto G, Khachatryan A, Quignot N, Chaves J, Moniot A, Mokgokong R. Effectiveness and safety of oral anticoagulants in the treatment of acute venous thromboembolism: a nationwide comparative cohort study in France. Thromb Haemost. 2022;122(8):1384-96. DOI: https://doi.org/10.1055/a-1731-3922
Ogino Y, Ishigami T, Minamimoto Y, Kimura Y, Akiyama E, Okada K, et al. Direct oral anticoagulant therapy for cancer-associated venous thromboembolism in routine clinical practice. Circ J. 2020;84(8):1330-8. DOI: https://doi.org/10.1253/circj.CJ-20-0084
Yamada N, Tamaru S, Umetsu M, Tsujita K, Nakamura M, Watanabe A, et al.; KUROSIO Study Investigators. Efficacy and safety of non–vitamin K antagonist oral anticoagulants for Japanese patients with venous thromboembolism: primary results from the KUROSIO study. Circ J. 2024;88(10):1672-8. DOI: https://doi.org/10.1253/circj.CJ-23-0954
Hess CN, Szarek M, Anand SS, Bauersachs RM, Patel MR, Debus ES, et al. Rivaroxaban and risk of venous thromboembolism in patients with symptomatic peripheral artery disease after lower extremity revascularization. JAMA Netw Open. 2022;5(6):e2215580. DOI: https://doi.org/10.1001/jamanetworkopen.2022.15580
Barrett CD, Moore HB, Moore EE, Chandler J, Sauaia A. Combination of aspirin and rosuvastatin for reduction of venous thromboembolism in severely injured patients: a randomized phase II clinical trial. Blood Coagul Fibrinolysis. 2023;34:499-507. DOI: https://doi.org/10.1097/MBC.0000000000001258
Costanzo L, Di Paola F, Pedi AM, Failla G, Mangiafico M. Long-term efficacy and safety of direct oral anticoagulants at reduced doses in the secondary prevention of venous thromboembolism and post-thrombotic syndrome. J Clin Med. 2024;13:2394. DOI: https://doi.org/10.3390/jcm13082394
Sun X, Zhang M, Sanagawa A, Mori C, Ito S, Iwaki S, et al. Circulating microRNA-126 in patients with coronary artery disease: correlation with LDL cholesterol. Thromb J. 2012;10:16. DOI: https://doi.org/10.1186/1477-9560-10-16
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al.; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-51. DOI: https://doi.org/10.1056/NEJMoa0905561
Su X, Yan B, Wang L, Cheng H, Chen Y. Comparative efficacy and safety of oral anticoagulants for the treatment of venous thromboembolism in patients with different renal functions: a systematic review and network meta-analysis. BMJ Open. 2022;12:e048619. DOI: https://doi.org/10.1136/bmjopen-2021-048619
Dentali F, Riva N, Crowther M, Turpie AG, Lip GY, Ageno W. Efficacy and safety of novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis. Circulation. 2012;126(20):2381-91. DOI: https://doi.org/10.1161/CIRCULATIONAHA.112.115410
Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, et al.; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-75. DOI: https://doi.org/10.1056/NEJMoa0800374
Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, et al.; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-92. DOI: https://doi.org/10.1056/NEJMoa1107039
Nanda K, McCrory DC, Myers ER, Bastian LA, Hasselblad V, Hickey JD, et al. Accuracy of the Papanicolaou test in screening for cervical cytologic abnormalities: a systematic review. Ann Intern Med. 2000;132(10):810-9. DOI: https://doi.org/10.7326/0003-4819-132-10-200005160-00009
Enríquez A, Baranchuk A, Corbalán R. Management of bleeding associated with direct oral anticoagulants: update on reversal strategies. Rev Med Chil. 2019;147:73-82. DOI: https://doi.org/10.4067/S0034-98872019000100073
Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic therapy for venous thromboembolism disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-52. DOI: https://doi.org/10.1016/j.chest.2015.11.026
Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med. 1997;336:1506-11. DOI: https://doi.org/10.1056/NEJM199705223362107
Holtz TH, Sternberg M, Kammerer S, Laserson KF, Riekstina V, Zarovska E, et al. Time to sputum culture conversion in multidrug-resistant tuberculosis: predictors and relationship to treatment outcome. Ann Intern Med. 2006;144(9):650-9. DOI: https://doi.org/10.7326/0003-4819-144-9-200605020-00008
Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, et al.; ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366(1):9-19. DOI: https://doi.org/10.1056/NEJMoa1112277
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al.; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-91. DOI: https://doi.org/10.1056/NEJMoa1009638
Prins MH, Lensing AWA, Bauersachs R, van Bellen B, Bounameaux H, Brighton TA, et al.; EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for symptomatic venous thromboembolism. Thromb J. 2013;11:21. DOI: https://doi.org/10.1186/1477-9560-11-21
Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in atrial fibrillation: a meta-analysis. Lancet. 2014;383(9921):955-62. DOI: https://doi.org/10.1016/S0140-6736(13)62343-0
Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al.; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-52. DOI: https://doi.org/10.1056/NEJMoa0906598
Singer DE, Albers GW, Dalen JE, Fang MC, Go AS, Halperin JL, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2008;133(6):546S-92S. DOI: https://doi.org/10.1378/chest.08-0678
Bai Y, Deng H, Shantsila A, Lip GYH. Rivaroxaban versus dabigatran or warfarin in real-world studies of stroke prevention in atrial fibrillation: a systematic review and meta-analysis. Stroke. 2017;48:970-6. DOI: https://doi.org/10.1161/STROKEAHA.116.016275
Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood. 2012;120:2954-62. DOI: https://doi.org/10.1182/blood-2012-06-415943
Brown PA, Shah B, Advani A, Aoun P, Boyer MW, Burke PW, et al. Acute lymphoblastic leukemia, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19(9):1079-109. DOI: https://doi.org/10.6004/jnccn.2021.0042
Harel Z, Jeyakumar N, Luo B, Silver SA, Akbari A, Molnar AO, et al. Safety of direct oral anticoagulants versus warfarin among older individuals with acute venous thromboembolism and chronic kidney disease. Kidney Med. 2022;4(9):100516. DOI: https://doi.org/10.1016/j.xkme.2022.100516
Chen J, Lv M, Wu S, Jiang S, Xu W, Qian J, et al. Severe bleeding risks of direct oral anticoagulants in venous thromboembolism: a network meta-analysis. Eur J Vasc Endovasc Surg. 2022;63(3):465-74. DOI: https://doi.org/10.1016/j.ejvs.2021.10.054
Sevilla-Cazes J, et al. Association between patient-reported medication adherence and anticoagulation control. Am J Med. 2017;130:1092-8. DOI: https://doi.org/10.1016/j.amjmed.2017.03.038
Van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism. Blood. 2014;124:1968-75. DOI: https://doi.org/10.1182/blood-2014-04-571232
Shih AW, Crowther MA. Reversal of direct oral anticoagulants: a practical approach. Hematology Am Soc Hematol Educ Program. 2016;612-9. DOI: https://doi.org/10.1182/asheducation-2016.1.612
Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy. Chest. 2012;141(2 Suppl):e691S-736S. DOI: https://doi.org/10.1378/chest.11-2300
Yasaka M, Minematsu K, Yamaguchi T. Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke. Intern Med. 2001;40:1183-8. DOI: https://doi.org/10.2169/internalmedicine.40.1183
Uygungül E, Ayrik C, Narci H, Erdoğan S, Toker I, Demir F, et al. Determining risk factors of bleeding in patients on warfarin treatment. Adv Hematol. 2014;2014:369084. DOI: https://doi.org/10.1155/2014/369084
Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants. Chest. 2012;141:e24S-43S. DOI: https://doi.org/10.1378/chest.11-2291
Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377:1319-30. DOI: https://doi.org/10.1056/NEJMoa1709118