Safety and Efficacy of Direct Oral Anticoagulants Compared to Warfarin in Patients with Venous Thromboembolism and Morbid Obesity
,
Abstract
Introduction: Several guidelines recommend using direct oral anticoagulants (DOACs) over warfarin for the prevention of venous thromboembolism (VTE), except in cases of morbid obesity. The use of DAOCs in patients with morbid obesity has not been thoroughly evaluated due to the lack of representation in large clinical trials. To address this knowledge gap, we conducted a systematic review and meta-analysis of existing literature to determine the efficacy and safety of DOACs in patients with morbid obesity.
Materials and Methods: A systematic review of studies comparing DOACs with warfarin in patients with morbid obesity and diagnosed with acute VTE was conducted using electronic literature searches up to December 2021. Efficacy and safety were defined as the rate of recurrent VTE and major bleeding, respectively.
Results: A total of 30822 patients were included across 13 studies. Recurrent VTE events were observed in 713 of 12945 patients treated with DOACs, compared to 966 of 17877 patients treated with warfarin (OR, 0.70; 95% CI, 0.50-0.99; P=0.04; I2=69%). Major bleeding events occurred in 195 of 12675 patients on DOACs and in 386 of 17572 patients on warfarin (OR, 0.69; 95% CI, 0.58-0.82; P<0.0001; I2=0%). Similar findings were noted for two specific DOACS, apixaban and rivaroxaban, when evaluated individually against warfarin.
Conclusion: Our meta-analysis indicated that DOACs are both safe and effective in preventing VTE in patients with morbid obesity. DAOCs resulted in comparable outcomes to those observed with warfarin use. This analysis consolidates extensive observational data from a large patient cohort, thereby enhancing the evidence base for the use of DOACs in patients with morbid obesity.
1. Burnett AE, Mahan CE, Vazquez SR, et al. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis. 2016;41(1):206-232.
2. Stevens SM, Woller SC, Baumann Kreuziger L, et al. Executive Summary: Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest. 2021;160(6):2247-2259.
3. Hotoleanu C. Association between obesity and venous thromboembolism. Med Pharm Rep. 2020;93(2):162-168.
4. Eichinger S, Hron G, Bialonczyk C, et al. Overweight, Obesity, and the Risk of Recurrent Venous Thromboembolism. Arch Intern Med. 2008;168(15):1678-1683.
5. Russo V, Cattaneo D, Giannetti L, et al. Pharmacokinetics of Direct Oral Anticoagulants in Patients With Atrial Fibrillation and Extreme Obesity. Clin Ther. 2021;43(9):e255-e263.
6. Martin KA, Beyer-Westendorf J, Davidson BL, et al. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: Updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J Thromb Haemost. 2021;19(8):1874-1882.
7. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. PLoS Med. 2021;18(3):e1003583.
8. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692-694.
9. Cunningham A, Stein CM, Chung CP, et al. An automated database case definition for serious bleeding related to oral anticoagulant use. Pharmacoepidemiol Drug Saf. 2011;20(6):560-566.
10. Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses. Oxford; 2000.
11. Choi Y, Kushnir M, Billett HH. Apixaban Is Safe and Effective in Morbidly Obese Patients: A Retrospective Analysis of 390 Patients with BMI ≥40. Blood. 2017;130(Supplement 1):1105-1105.
12. Patil T, Lebrecht M. A single center retrospective cohort study evaluating use of direct oral anticoagulants (DOACs) in morbidly obese veteran population. Thromb Res. 2020;192:124-130.
13. Falk K, McComb MN, Shapiro NL, et al. Prescribing Pattern of Oral Anticoagulants in Patients with Obesity. J Pharm Pract. 2022;35(2):248-255.
14. Kushnir M, Choi Y, Eisenberg R, et al. Efficacy and safety of direct oral factor Xa inhibitors compared with warfarin in patients with morbid obesity: a single-centre, retrospective analysis of chart data. Lancet Haematol. 2019;6(7):e359-e365.
15. Perales IJ, San Agustin K, DeAngelo J, et al. Rivaroxaban Versus Warfarin for Stroke Prevention and Venous Thromboembolism Treatment in Extreme Obesity and High Body Weight. Ann Pharmacother. 2020;54(4):344-350.
16. Costa OS, Beyer-Westendorf J, Ashton V, et al. Effectiveness and safety of rivaroxaban versus warfarin in obese patients with acute venous thromboembolism: analysis of electronic health record data. J Thromb Thrombolysis. 2021;51(2):349-358.
17. Sa RA, Al-Ani F, Lazo-Langner A, et al. Efficacy and Safety of Direct Oral Anticoagulants in Obese Patients with Venous Thromboembolism. Blood. 2019;134(Supplement_1):3675-3675.
18. Cohen A, Sah J, Lee T, et al. Effectiveness and Safety of Apixaban vs. Warfarin in Venous Thromboembolism Patients with Obesity and Morbid Obesity. J Clin Med. 2021;10(2):200.
19. Lachant DJ, Bach C, Fe A, et al. Direct oral anticoagulant therapy in patients with morbid obesity after intermediate- or high-risk pulmonary emboli. ERJ Open Res. 2021;7(1):00554-02020.
20. Samaranayake CB, Keir G, Slader SAA, et al. Use of direct oral anticoagulants for acute pulmonary embolisms in obesity: a propensity-matched, multicentre case-control study. ERJ Open Res. 2021;7(3):00379-02021.
21. Crouch A, Ng TH, Kelley D, et al. Multi-center retrospective study evaluating the efficacy and safety of apixaban versus warfarin for treatment of venous thromboembolism in patients with severe obesity. Pharmacotherapy. 2022;42(2):119-133.
22. Quan S, Smith J, Wu C, et al. Anticoagulant therapies and outcomes in obese patients with acute venous thromboembolism. Thromb Res. 2020;187:56-62.
23. Cook J, Wiczer T, Gerlach A, et al. Comparison of Direct Oral Factor Xa Inhibitors versus Warfarin for the Treatment of Venous Thromboembolism in Obese or Overweight Patients: A Retrospective Analysis.J Hematol Oncol Pharm.2021; 11(2): 77-83.
24. Spyropoulos AC, Ashton V, Chen YW, et al. Rivaroxaban versus warfarin treatment among morbidly obese patients with venous thromboembolism: Comparative effectiveness, safety, and costs. Thromb Res. 2019;182:159-166.
25. Elshafei MN, Mohamed MFH, El-Bardissy A, et al. Comparative effectiveness and safety of direct oral anticoagulants compared to warfarin in morbidly obese patients with acute venous thromboembolism: systematic review and a meta-analysis. J Thromb Thrombolysis. 2021;51(2):388-396.
26. Katel A, Aryal M, Neupane A, et al. Efficacy and Safety of Direct Oral Anticoagulants in Venous Thromboembolism Compared to Traditional Anticoagulants in Morbidly Obese Patients: A Systematic Review and Meta-Analysis. Cureus. 2021;13(4): e14572.
27. Mhanna M, Beran A, Al-Abdouh A, et al. Direct Oral Anticoagulants Versus Warfarin in Morbidly Obese Patients With Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-analysis. Am J Ther. 2021;28(5):e531.
28. Di Minno MND, Lupoli R, Di Minno A, et al. Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: A meta-analysis of randomized controlled trials. Ann Med. 2015;47(1):61-8.
29. Upreti VV, Wang J, Barrett YC, et al. Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects. Br J Clin Pharmacol. 2013;76(6):908-916.
30. Kubitza D, Becka M, Zuehlsdorf M, et al. Body Weight Has Limited Influence on the Safety, Tolerability, Pharmacokinetics, or Pharmacodynamics of Rivaroxaban (BAY 59-7939) in Healthy Subjects. J Clin Pharmacol. 2007;47(2):218-226.
31. Agnelli G, Buller HR, Cohen A, et al. Oral Apixaban for the Treatment of Acute Venous Thromboembolism. N Engl J Med. 2013;369(9):799-808.
32. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. N Engl J Med. 2010;363(26):2499-2510.
33. Buck MM, Haddon AM, Paneccasio A, et al. Safety and Efficacy of Rivaroxaban and Apixaban in Patients with Increased Body Mass: a Systematic Review. Clin Drug Investig. 2021;41(4):353-369.
34. Berger JS, Laliberté F, Kharat A, et al. Real-world effectiveness and safety of rivaroxaban versus warfarin among non-valvular atrial fibrillation patients with obesity in a US population. Curr Med Res Opin. 2021;37(6):881-890.
2. Stevens SM, Woller SC, Baumann Kreuziger L, et al. Executive Summary: Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest. 2021;160(6):2247-2259.
3. Hotoleanu C. Association between obesity and venous thromboembolism. Med Pharm Rep. 2020;93(2):162-168.
4. Eichinger S, Hron G, Bialonczyk C, et al. Overweight, Obesity, and the Risk of Recurrent Venous Thromboembolism. Arch Intern Med. 2008;168(15):1678-1683.
5. Russo V, Cattaneo D, Giannetti L, et al. Pharmacokinetics of Direct Oral Anticoagulants in Patients With Atrial Fibrillation and Extreme Obesity. Clin Ther. 2021;43(9):e255-e263.
6. Martin KA, Beyer-Westendorf J, Davidson BL, et al. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: Updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J Thromb Haemost. 2021;19(8):1874-1882.
7. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. PLoS Med. 2021;18(3):e1003583.
8. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692-694.
9. Cunningham A, Stein CM, Chung CP, et al. An automated database case definition for serious bleeding related to oral anticoagulant use. Pharmacoepidemiol Drug Saf. 2011;20(6):560-566.
10. Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses. Oxford; 2000.
11. Choi Y, Kushnir M, Billett HH. Apixaban Is Safe and Effective in Morbidly Obese Patients: A Retrospective Analysis of 390 Patients with BMI ≥40. Blood. 2017;130(Supplement 1):1105-1105.
12. Patil T, Lebrecht M. A single center retrospective cohort study evaluating use of direct oral anticoagulants (DOACs) in morbidly obese veteran population. Thromb Res. 2020;192:124-130.
13. Falk K, McComb MN, Shapiro NL, et al. Prescribing Pattern of Oral Anticoagulants in Patients with Obesity. J Pharm Pract. 2022;35(2):248-255.
14. Kushnir M, Choi Y, Eisenberg R, et al. Efficacy and safety of direct oral factor Xa inhibitors compared with warfarin in patients with morbid obesity: a single-centre, retrospective analysis of chart data. Lancet Haematol. 2019;6(7):e359-e365.
15. Perales IJ, San Agustin K, DeAngelo J, et al. Rivaroxaban Versus Warfarin for Stroke Prevention and Venous Thromboembolism Treatment in Extreme Obesity and High Body Weight. Ann Pharmacother. 2020;54(4):344-350.
16. Costa OS, Beyer-Westendorf J, Ashton V, et al. Effectiveness and safety of rivaroxaban versus warfarin in obese patients with acute venous thromboembolism: analysis of electronic health record data. J Thromb Thrombolysis. 2021;51(2):349-358.
17. Sa RA, Al-Ani F, Lazo-Langner A, et al. Efficacy and Safety of Direct Oral Anticoagulants in Obese Patients with Venous Thromboembolism. Blood. 2019;134(Supplement_1):3675-3675.
18. Cohen A, Sah J, Lee T, et al. Effectiveness and Safety of Apixaban vs. Warfarin in Venous Thromboembolism Patients with Obesity and Morbid Obesity. J Clin Med. 2021;10(2):200.
19. Lachant DJ, Bach C, Fe A, et al. Direct oral anticoagulant therapy in patients with morbid obesity after intermediate- or high-risk pulmonary emboli. ERJ Open Res. 2021;7(1):00554-02020.
20. Samaranayake CB, Keir G, Slader SAA, et al. Use of direct oral anticoagulants for acute pulmonary embolisms in obesity: a propensity-matched, multicentre case-control study. ERJ Open Res. 2021;7(3):00379-02021.
21. Crouch A, Ng TH, Kelley D, et al. Multi-center retrospective study evaluating the efficacy and safety of apixaban versus warfarin for treatment of venous thromboembolism in patients with severe obesity. Pharmacotherapy. 2022;42(2):119-133.
22. Quan S, Smith J, Wu C, et al. Anticoagulant therapies and outcomes in obese patients with acute venous thromboembolism. Thromb Res. 2020;187:56-62.
23. Cook J, Wiczer T, Gerlach A, et al. Comparison of Direct Oral Factor Xa Inhibitors versus Warfarin for the Treatment of Venous Thromboembolism in Obese or Overweight Patients: A Retrospective Analysis.J Hematol Oncol Pharm.2021; 11(2): 77-83.
24. Spyropoulos AC, Ashton V, Chen YW, et al. Rivaroxaban versus warfarin treatment among morbidly obese patients with venous thromboembolism: Comparative effectiveness, safety, and costs. Thromb Res. 2019;182:159-166.
25. Elshafei MN, Mohamed MFH, El-Bardissy A, et al. Comparative effectiveness and safety of direct oral anticoagulants compared to warfarin in morbidly obese patients with acute venous thromboembolism: systematic review and a meta-analysis. J Thromb Thrombolysis. 2021;51(2):388-396.
26. Katel A, Aryal M, Neupane A, et al. Efficacy and Safety of Direct Oral Anticoagulants in Venous Thromboembolism Compared to Traditional Anticoagulants in Morbidly Obese Patients: A Systematic Review and Meta-Analysis. Cureus. 2021;13(4): e14572.
27. Mhanna M, Beran A, Al-Abdouh A, et al. Direct Oral Anticoagulants Versus Warfarin in Morbidly Obese Patients With Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-analysis. Am J Ther. 2021;28(5):e531.
28. Di Minno MND, Lupoli R, Di Minno A, et al. Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: A meta-analysis of randomized controlled trials. Ann Med. 2015;47(1):61-8.
29. Upreti VV, Wang J, Barrett YC, et al. Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects. Br J Clin Pharmacol. 2013;76(6):908-916.
30. Kubitza D, Becka M, Zuehlsdorf M, et al. Body Weight Has Limited Influence on the Safety, Tolerability, Pharmacokinetics, or Pharmacodynamics of Rivaroxaban (BAY 59-7939) in Healthy Subjects. J Clin Pharmacol. 2007;47(2):218-226.
31. Agnelli G, Buller HR, Cohen A, et al. Oral Apixaban for the Treatment of Acute Venous Thromboembolism. N Engl J Med. 2013;369(9):799-808.
32. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. N Engl J Med. 2010;363(26):2499-2510.
33. Buck MM, Haddon AM, Paneccasio A, et al. Safety and Efficacy of Rivaroxaban and Apixaban in Patients with Increased Body Mass: a Systematic Review. Clin Drug Investig. 2021;41(4):353-369.
34. Berger JS, Laliberté F, Kharat A, et al. Real-world effectiveness and safety of rivaroxaban versus warfarin among non-valvular atrial fibrillation patients with obesity in a US population. Curr Med Res Opin. 2021;37(6):881-890.
| Files | ||
| Issue | Vol 19 No 4 (2025) | |
| Section | Original Article(s) | |
| Keywords | ||
| Direct oral anticoagulants (DOACs); Warfarin; Morbid obesity; Venous thromboembolism (VTE) | ||
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How to Cite
1.
Katel A, Niraula S, Aryal M, Neupane N, Neupane A, Bhatt V. Safety and Efficacy of Direct Oral Anticoagulants Compared to Warfarin in Patients with Venous Thromboembolism and Morbid Obesity. Int J Hematol Oncol Stem Cell Res. 2025;19(4):320-331.
