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Thromb Haemost 2022; 122(05): 830-841
DOI: 10.1055/a-1588-9155
Stroke, Systemic or Venous Thromboembolism

Oral Anticoagulant Use in Patients with Morbid Obesity: A Systematic Review and Meta-Analysis

Tzu-Fei Wang
1   Department of Medicine, University of Ottawa at The Ottawa Hospital and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
,
Marc Carrier
1   Department of Medicine, University of Ottawa at The Ottawa Hospital and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
,
Karine Fournier
2   Library, University of Ottawa, Ottawa, Ontario, Canada
,
Deborah M. Siegal
1   Department of Medicine, University of Ottawa at The Ottawa Hospital and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
,
Grégoire Le Gal
1   Department of Medicine, University of Ottawa at The Ottawa Hospital and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
,
Aurélien Delluc 
1   Department of Medicine, University of Ottawa at The Ottawa Hospital and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
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Abstract

Objectives Obesity is associated with increased risks of atrial fibrillation (AF) and venous thromboembolism (VTE) for which anticoagulation is commonly used. However, data on the efficacy and safety of oral anticoagulants in patients with morbid obesity are limited.

Methods We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs) for AF or VTE in patients with morbid obesity.

Results We included three randomized controlled trials (5 studies) and 18 observational studies in adult patients with a body weight ≥120 kg, body mass index ≥40 kg/m2, or classified as morbid obesity who received DOACs or VKAs for AF or VTE (N = 77,687). The primary efficacy outcome was stroke/systemic embolism or recurrent VTE, and the primary safety outcome was major bleeding. DOACs were associated with a pooled incidence rate of stroke/systemic embolism of 1.16 per 100 person-years, compared to 1.18 with VKAs. The incidence of recurrent VTE on DOACs was 3.83 per 100 person-years, compared to 6.81 on VKAs. In both VTE and AF populations, DOACs were associated with lower risks of major bleeding compared to VKAs. However, all observational studies had moderate to serious risks of bias.

Conclusion Patients with morbid obesity on DOACs had similar risks of stroke/systemic embolism, lower rates of recurrent VTE, and major bleeding events compared to those on VKAs. However, the certainty of evidence was low given that studies were mostly observational with high risk of confounding.

Keywords

direct oral anticoagulants - vitamin K antagonists - atrial fibrillation - venous thromboembolism - morbid obesity

Supplementary Material



Publication History

Received: 23 June 2021

Accepted: 13 August 2021

Accepted Manuscript online:
16 August 2021

Article published online:
12 October 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 World Health Organization. Obesity and overweight. Accessed September 1, 2021 at: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight 2018
    PubMedGoogle Scholar
  • 2 Ward ZJ, Bleich SN, Cradock AL. et al. Projected U.S. state-level prevalence of adult obesity and severe obesity. N Engl J Med 2019; 381 (25) 2440-2450
    CrossrefPubMedGoogle Scholar
  • 3 Wanahita N, Messerli FH, Bangalore S, Gami AS, Somers VK, Steinberg JS. Atrial fibrillation and obesity–results of a meta-analysis. Am Heart J 2008; 155 (02) 310-315
    CrossrefPubMedGoogle Scholar
  • 4 Pomp ER, le Cessie S, Rosendaal FR, Doggen CJ. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br J Haematol 2007; 139 (02) 289-296
    CrossrefPubMedGoogle Scholar
  • 5 Delluc A, Mottier D, Le Gal G, Oger E, Lacut K. Underweight is associated with a reduced risk of venous thromboembolism. Results from the EDITH case-control study. J Thromb Haemost 2009; 7 (04) 728-729
    CrossrefPubMedGoogle Scholar
  • 6 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
    CrossrefPubMedGoogle Scholar
  • 7 Rodger MA, Le Gal G, Anderson DR. et al; REVERSE II Study Investigators. Validating the HERDOO2 rule to guide treatment duration for women with unprovoked venous thrombosis: multinational prospective cohort management study. BMJ 2017; 356: j1065
    CrossrefPubMedGoogle Scholar
  • 8 Martin KA, Lee CR, Farrell TM, Moll S. Oral anticoagulant use after bariatric surgery: a literature review and clinical guidance. Am J Med 2017; 130 (05) 517-524
    CrossrefPubMedGoogle Scholar
  • 9 Wallace JL, Reaves AB, Tolley EA. et al. Comparison of initial warfarin response in obese patients versus non-obese patients. J Thromb Thrombolysis 2013; 36 (01) 96-101
    CrossrefPubMedGoogle Scholar
  • 10 Tellor KB, Nguyen SN, Bultas AC, Armbruster AL, Greenwald NA, Yancey AM. Evaluation of the impact of body mass index on warfarin requirements in hospitalized patients. Ther Adv Cardiovasc Dis 2018; 12 (08) 207-216
    CrossrefPubMedGoogle Scholar
  • 11 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149 (02) 315-352
    CrossrefPubMedGoogle Scholar
  • 12 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 (06) 908-916
    CrossrefPubMedGoogle Scholar
  • 13 Di Nisio M, Vedovati MC, Riera-Mestre A. et al. Treatment of venous thromboembolism with rivaroxaban in relation to body weight. A sub-analysis of the EINSTEIN DVT/PE studies. Thromb Haemost 2016; 116 (04) 739-746
    PubMedGoogle Scholar
  • 14 Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14 (06) 1308-1313
    CrossrefPubMedGoogle Scholar
  • 15 Steffel J, Collins R, Antz M. et al; External reviewers. 2021 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Europace 2021; 2021: euab065
    PubMedGoogle Scholar
  • 16 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
    CrossrefPubMedGoogle Scholar
  • 17 Sterne JAC, Savović J, Page MJ. et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898
    Google Scholar
  • 18 Sterne JA, Hernán MA, Reeves BC. et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016; 355: i4919
    CrossrefPubMedGoogle Scholar
  • 19 Sandhu RK, Ezekowitz J, Andersson U. et al. The ‘obesity paradox’ in atrial fibrillation: observations from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Eur Heart J 2016; 37 (38) 2869-2878
    CrossrefPubMedGoogle Scholar
  • 20 Boriani G, Ruff CT, Kuder JF. et al. Relationship between body mass index and outcomes in patients with atrial fibrillation treated with edoxaban or warfarin in the ENGAGE AF-TIMI 48 trial. Eur Heart J 2019; 40 (19) 1541-1550
    CrossrefPubMedGoogle Scholar
  • 21 Hohnloser SH, Fudim M, Alexander JH. et al. Efficacy and safety of apixaban versus warfarin in patients with atrial fibrillation and extremes in body weight. Circulation 2019; 139 (20) 2292-2300
    CrossrefPubMedGoogle Scholar
  • 22 Boriani G, Ruff CT, Kuder JF. et al. Edoxaban versus warfarin in patients with atrial fibrillation at the extremes of body weight: an analysis from the ENGAGE AF-TIMI 48 trial. Thromb Haemost 2021; 121 (02) 140-149
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Arachchillage D, Reynolds R, Devey T, Maclean R, Kitchen S, van Veen JJ. Effect of extremes of body weight on drug level in patient treated with standard dose of rivaroxaban for venous thromboembolism; real life experience. Thromb Res 2016; 147: 32-35
    CrossrefPubMedGoogle Scholar
  • 24 Tittl L, Endig S, Marten S, Reitter A, Beyer-Westendorf I, Beyer-Westendorf J. Impact of BMI on clinical outcomes of NOAC therapy in daily care - results of the prospective Dresden NOAC Registry (NCT01588119). Int J Cardiol 2018; 262: 85-91
    CrossrefPubMedGoogle Scholar
  • 25 Aloi KG, Fierro JJ, Stein BJ. et al. Investigation of direct-acting oral anticoagulants and the incidence of venous thromboembolism in patients weighing ≥120 kg compared to patients weighing <120 kg. J Pharm Pract 2021; 34 (01) 64-69
    CrossrefPubMedGoogle Scholar
  • 26 Kalani C, Awudi E, Alexander T. et al. Evaluation of the efficacy of direct oral anticoagulants (DOACs) in comparison to warfarin in morbidly obese patients. Hosp Pract (1995) 2019; 47 (04) 181-185
    CrossrefPubMedGoogle Scholar
  • 27 Kido K, Ngorsuraches S. Comparing the efficacy and safety of direct oral anticoagulants with warfarin in the morbidly obese population with atrial fibrillation. Ann Pharmacother 2019; 53 (02) 165-170
    CrossrefPubMedGoogle Scholar
  • 28 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 (07) e359-e365
    CrossrefPubMedGoogle Scholar
  • 29 Netley J, Howard K, Wilson W. Effects of body mass index on the safety and effectiveness of direct oral anticoagulants: a retrospective review. J Thromb Thrombolysis 2019; 48 (03) 359-365
    CrossrefPubMedGoogle Scholar
  • 30 Peterson ED, Ashton V, Chen YW, Wu B, Spyropoulos AC. Comparative effectiveness, safety, and costs of rivaroxaban and warfarin among morbidly obese patients with atrial fibrillation. Am Heart J 2019; 212: 113-119
    CrossrefPubMedGoogle Scholar
  • 31 Spyropoulos AC, Ashton V, Chen YW, Wu B, Peterson ED. Rivaroxaban versus warfarin treatment among morbidly obese patients with venous thromboembolism: comparative effectiveness, safety, and costs. Thromb Res 2019; 182: 159-166
    CrossrefPubMedGoogle Scholar
  • 32 Costa OS, Beyer-Westendorf J, Ashton V. et al. Effectiveness and safety of rivaroxaban versus warfarin in obese nonvalvular atrial fibrillation patients: analysis of electronic health record data. Curr Med Res Opin 2020; 36 (07) 1081-1088
    CrossrefPubMedGoogle Scholar
  • 33 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 (02) 349-358
    CrossrefPubMedGoogle Scholar
  • 34 Deitelzweig S, Keshishian A, Kang A. et al. Effectiveness and safety of oral anticoagulants among NVAF patients with obesity: insights from the ARISTOPHANES study. J Clin Med 2020; 9 (06) E1633
    CrossrefPubMedGoogle Scholar
  • 35 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
    CrossrefPubMedGoogle Scholar
  • 36 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 (04) 344-350
    CrossrefPubMedGoogle Scholar
  • 37 Wysokinski WE, Froehling DA, Houghton DE. et al. Effectiveness and safety of apixaban and rivaroxaban for acute venous thromboembolism therapy in patients with extremes in bodyweight. Eur J Haematol 2020; 105 (04) 484-494
    CrossrefPubMedGoogle Scholar
  • 38 Quan S, Smith J, Wu C, Koshman SL, Nguyen B, Bungard TJ. Anticoagulant therapies and outcomes in obese patients with acute venous thromboembolism. Thromb Res 2020; 187: 56-62
    CrossrefPubMedGoogle Scholar
  • 39 Falk K, McComb MN, Shapiro NL, Uppuluri EM. Prescribing pattern of oral anticoagulants in patients with obesity. J Pharm Pract 2022; 35 (02) 248-255
    CrossrefPubMedGoogle Scholar
  • 40 Younis M, Elkaryoni A, Williams II GW. et al. The use of direct oral anticoagulants in the management of venous thromboembolism in patients with obesity. Cureus 2020; 12 (08) e10006
    PubMedGoogle Scholar
  • 41 Di Minno MN, Lupoli R, Di Minno A, Ambrosino P, Scalera A, Dentali F. 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 (01) 61-68
    CrossrefPubMedGoogle Scholar
  • 42 Boonyawat K, Caron F, Li A. et al. Association of body weight with efficacy and safety outcomes in phase III randomized controlled trials of direct oral anticoagulants: a systematic review and meta-analysis. J Thromb Haemost 2017; 15 (07) 1322-1333
    CrossrefPubMedGoogle Scholar
  • 43 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 (02) 388-396
    CrossrefPubMedGoogle Scholar
  • 44 Mai V, Marceau-Ferron E, Bertoletti L. et al. Direct oral anticoagulants in the treatment of acute venous thromboembolism in patients with obesity: a systematic review with meta-analysis. Pharmacol Res 2021; 163: 105317
    CrossrefPubMedGoogle Scholar
  • 45 Grymonprez M, De Backer TL, Steurbaut S, Boussery K, Lahousse L. Non-vitamin K antagonist oral anticoagulants (NOACs) versus warfarin in patients with atrial fibrillation and (morbid) obesity or low body weight: a systematic review and meta-analysis. Cardiovasc Drugs Ther 2021; DOI: 10.1007/s10557-020-07122-6.
    CrossrefPubMedGoogle Scholar
  • 46 Kido K, Shimizu M, Shiga T, Hashiguchi M. Meta-analysis comparing direct oral anticoagulants versus warfarin in morbidly obese patients with atrial fibrillation. Am J Cardiol 2020; 126: 23-28
    CrossrefPubMedGoogle Scholar
  • 47 Piran S, Traquair H, Chan N, Bhagirath V, Schulman S. Peak plasma concentration of direct oral anticoagulants in obese patients weighing over 120 kilograms: a retrospective study. Res Pract Thromb Haemost 2018; 2 (04) 684-688
    CrossrefPubMedGoogle Scholar
  • 48 Martin AC, Thomas W, Mahir Z. et al. Direct oral anticoagulant concentrations in obese and high body weight patients: a cohort study. Thromb Haemost 2021; 121 (02) 224-233
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Bhagirath VC, Eikelboom JW, Hirsh J. et al. Apixaban-calibrated anti-FXa activity in relation to outcome events and clinical characteristics in patients with atrial fibrillation: results from the AVERROES trial. TH Open 2017; 1 (02) e139-e145
    Article in Thieme ConnectPubMedGoogle Scholar
  • 50 Reilly PA, Lehr T, Haertter S. et al; RE-LY Investigators. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63 (04) 321-328
    CrossrefPubMedGoogle Scholar
  • 51 Martin KA, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. 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 (08) 1874-1882
    CrossrefPubMedGoogle Scholar