RSS-Feed abonnieren
![](/products/assets/desktop/img/oa-logo.png)
DOI: 10.1055/s-0043-1776989
Direct-Acting Oral Anticoagulants in patients at extremes of body weight: a review of pharmacological considerations and clinical implications
![](https://www.thieme-connect.de/media/10.1055-s-00033990/202401/lookinside/thumbnails/10-1055-s-0043-1776989_23070032-1.jpg)
Abstract
Patients at extremes of body weight are underrepresented in randomized controlled trials of direct-acting oral anticoagulants (DOACs). Therefore, their optimal anticoagulant treatment remains a topic of debate.
The aim of this narrative review is to summarize the evidence on the pharmacokinetic and pharmacodynamic profile of DOACs for treating patients at extremes of body weight in venous thromboembolism (VTE) and in the prevention of cardioembolic stroke in nonvalvular atrial fibrillation (NVAF). A literature search was conducted in the main bibliographic databases, and the most relevant reviews and original articles on the topic were selected.
Although data in these patient groups are limited, apixaban and rivaroxaban show a favorable pharmacokinetic and pharmacodynamic profile in obese VTE treatment and NVAF patients and, in the case of apixaban, also in underweight patients. In particular, these drugs demonstrated comparable efficacy and safety to standard therapy. Very few data were available for dabigatran and edoxaban; the latter drug was safer at a lower dose, mainly in underweight patients.
Our findings are in line with the last International Society of Haemostasis and Thrombosis position paper and European Heart Rhythm Association 2021 practical guide, suggesting the use of apixaban and rivaroxaban in morbidly obese patients (>120 kg or body mass index ≥40 kg/m2) and the reduced dosage of edoxaban in low-weight patients. Future studies should focus on large populations of patients at extremes of body weights to acquire more clinical and pharmacokinetic evidence on all available DOACs, especially those currently less investigated.
Keywords
direct-acting oral anticoagulants - obese - underweight - extremes of body weight - pharmacokineticsPublikationsverlauf
Eingereicht: 28. Juli 2023
Angenommen: 16. Oktober 2023
Artikel online veröffentlicht:
08. Januar 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Stevens SM, Woller SC, Kreuziger LB. et al. Antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report. Chest 2021; 160 (06) e545-e608
- 2 Ortel TL, Neumann I, Ageno W. et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020; 4 (19) 4693-4738
- 3 Konstantinides SV, Meyer G, Becattini C. et al; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41 (04) 543-603
- 4 Hindricks G, Potpara T, Dagres N. et al; ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42 (05) 373-498
- 5 January CT, Wann LS, Calkins H. et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74 (01) 104-132
- 6 van der Hulle T, Kooiman J, den Exter PL, Dekkers OM, Klok FA, Huisman MV. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2014; 12 (03) 320-328
- 7 Douxfils J, Ageno W, Samama CM. et al. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost 2018; 16 (02) 209-219
- 8 Eikelboom JW, Quinlan DJ, Hirsh J, Connolly SJ, Weitz JI. Laboratory monitoring of non-vitamin K antagonist oral anticoagulant use in patients with atrial fibrillation: a review. JAMA Cardiol 2017; 2 (05) 566-574
- 9 Malik AH, Yandrapalli S, Shetty S. et al; MAGIC (Meta-analysis And oriGinal Investigations in Cardiology) Investigators. Impact of weight on the efficacy and safety of direct-acting oral anticoagulants in patients with non-valvular atrial fibrillation: a meta-analysis. Europace 2020; 22 (03) 361-367
- 10 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
- 11 Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen PW. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation 2008; 117 (01) 93-102
- 12 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
- 13 Pomp ER, le Cessie S, Rosendaal FR, Doggen CJM. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br J Haematol 2007; 139 (02) 289-296
- 14 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 (Mar): j1065
- 15 Fryar CD, Carroll MD, Afful J. Prevalence of underweight among adults aged 20 and over: United States, 1960–1962 through 2017–2018. . NCHS Health EStats. 2020
- 16 Chen A, Stecker E. , A Warden B Direct oral anticoagulant use: a practical guide to common clinical challenges. J Am Heart Assoc 2020; 9 (13) e017559
- 17 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; 23 (10) 1612-1676
- 18 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
- 19 Wang T-F, Carrier M, Fournier K, Siegal DM, Le Gal G, Delluc A. Oral anticoagulant use in patients with morbid obesity: a systematic review and meta-analysis. Thromb Haemost 2022; 122 (05) 830-841
- 20 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 2022; 36 (04) 749-761
- 21 Covert K, Branam DL. Direct-acting oral anticoagulant use at extremes of body weight: literature review and recommendations. Am J Health Syst Pharm 2020; 77 (11) 865-876
- 22 Di Minno MND, 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
- 23 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
- 24 Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13 (11) 2119-2126
- 25 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
- 26 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
- 27 Bauersachs R, Berkowitz SD, Brenner B. et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
- 28 Büller HR, Prins MH, Lensin AW. et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366 (14) 1287-1297
- 29 Eerenberg ES, Middeldorp S, Levi M, Lensing AW, Büller HR. Clinical impact and course of major bleeding with rivaroxaban and vitamin K antagonists. J Thromb Haemost 2015; 13 (09) 1590-1596
- 30 Ballerie A, Nguyen Van R, Lacut K. et al. Apixaban and rivaroxaban in obese patients treated for venous thromboembolism: drug levels and clinical outcomes. Thromb Res 2021; 208: 39-44
- 31 Speed V, Patel JP, Roberts LN, Patel RK, Arya R. FIRST Registry Investigators. UK real-world experience of prescribing rivaroxaban for acute venous thromboembolism in obesity: results from the FIRST registry. Thromb Res 2021; 197: 16-19
- 32 Weitz JI, Lensing AWA, Prins MH. et al; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 2017; 376 (13) 1211-1222
- 33 Kubitza D, Becka M, Zuehlsdorf M, Mueck W. 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 (02) 218-226
- 34 Agnelli G, Buller HR, Cohen A. et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369 (09) 799-808
- 35 Cohen AT, Pan S, Byon W, Ilyas BS, Taylor T, Lee TC. Efficacy, safety, and exposure of apixaban in patients with high body weight or obesity and venous thromboembolism: insights from AMPLIFY. Adv Ther 2021; 38 (06) 3003-3018
- 36 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 (02) 200
- 37 Harkness W, Pipitone O, Joss J. , et al Observed Apixaban Anti-Xa Levels in obese patients. Annals of Pharmacotherapy 2022; 56 (11) 1215-1221
- 38 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
- 39 Agnelli G, Buller HR, Cohen A. et al; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368 (08) 699-708
- 40 Büller HR, Décousus H, Grosso MA. et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
- 41 Schulman S, Kearon C, Kakkar AK. et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 (24) 2342-2352
- 42 Schulman S, Kakkar AK, Goldhaber SZ. et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129 (07) 764-772
- 43 Schulman S, Kearon C, Kakkar AK. et al; RE-MEDY Trial Investigators, RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368 (08) 709-718
- 44 Aloi KG, Fierro JJ, Stein BJ, Lynch SM, Shapiro RJ. 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
- 45 Klok FA, Hösel V, Clemens A. et al. Prediction of bleeding events in patients with venous thromboembolism on stable anticoagulation treatment. Eur Respir J 2016; 48 (05) 1369-1376
- 46 Klok FA, Barco S, Konstantinides SV. External validation of the VTE-BLEED score for predicting major bleeding in stable anticoagulated patients with venous thromboembolism. Thromb Haemost 2017; 117 (06) 1164-1170
- 47 Verhamme P, Wells PS, Segers A. et al. Dose reduction of edoxaban preserves efficacy and safety for the treatment of venous thromboembolism. An analysis of the randomised, double-blind HOKUSAI VTE trial. Thromb Haemost 2016; 116 (04) 747-753
- 48 Balla SR, Cyr DD, Lokhnygina Y. et al. Relation of risk of stroke in patients with atrial fibrillation to body mass index (from patients treated with rivaroxaban and warfarin in the rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation trial). Am J Cardiol 2017; 119 (12) 1989-1996
- 49 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
- 50 O'Kane CP, Avalon JCO, Lacoste JL. et al. Apixaban and rivaroxaban use for atrial fibrillation in patients with obesity and BMI ≥50 kg/m2 . Pharmacotherapy 2022; 42 (02) 112-118
- 51 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
- 52 Connolly SJ, Ezekowitz MD, Yusuf S. et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
- 53 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
- 54 Giugliano RP, Ruff CT, Braunwald E. et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
- 55 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
- 56 Boriani G, De Caterina R, Manu MC, Souza J, Pecen L, Kirchhof P. Impact of weight on clinical outcomes of edoxaban therapy in atrial fibrillation patients included in the ETNA-AF-Europe registry. J Clin Med 2021; 10 (13) 2879
- 57 Patel MR, Mahaffey KW, Garg J. et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
- 58 Lee S-R, Choi EK, Park CS. et al. Direct oral anticoagulants in patients with nonvalvular atrial fibrillation and low body weight. J Am Coll Cardiol 2019; 73 (08) 919-931
- 59 Lee C-H, Lin TY, Chang SH. et al. Body mass index is an independent predictor of major bleeding in non-valvular atrial fibrillation patients taking dabigatran. Int J Cardiol 2017; 228: 771-778
- 60 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