Dosage of Anticoagulants in Obesity: Recommendations Based on a Systematic Review

Abstract

Anticoagulants are frequently used as thromboprophylaxis and in patients with atrial fibrillation (AF) or venous thromboembolism (VTE). While obesity rates are reaching epidemic proportions worldwide, the optimal dosage for obese patients has not been established for most anticoagulants, including low-molecular-weight heparin (LMWH), non–vitamin K antagonist oral anticoagulants (NOAC), and pentasaccharides (fondaparinux). The aim of the present systematic review was to summarize the current knowledge and provide recommendations on dosage of LMWH, NOAC, and fondaparinux in obese patients (body mass index [BMI] ≥ 30 kg/m² or body weight ≥ 100 kg). Based on a systematic search in PubMed and Embase, a total of 72 studies were identified. For thromboprophylaxis with LMWH in bariatric surgery (n = 20 studies), enoxaparin 40 mg twice daily, dalteparin 5,000 IE twice daily, or tinzaparin 75 IU/kg once daily should be considered for patients with BMI ≥ 40 kg/m². For thromboprophylaxis with LMWH in nonbariatric surgery and in medical inpatients (n = 8 studies), enoxaparin 0.5 mg/kg once or twice daily or tinzaparin 75 IU/kg once daily may be considered in obese patients. For treatment with LMWH (n = 18 studies), a reduced weight-based dose of enoxaparin 0.8 mg/kg twice daily should be considered in patients with BMI ≥ 40 kg/m², and no dose capping of dalteparin and tinzaparin should be applied for body weight < 140 kg. As regards NOAC, rivaroxaban, apixaban, or dabigatran may be used as thromboprophylaxis in patients with BMI < 40 kg/m² (n = 4 studies), whereas rivaroxaban and apixaban may be administered to obese patients with VTE or AF, including BMI > 40 kg/m², at standard fixed-dose (n = 20 studies). The limited available evidence on fondaparinux (n = 3 studies) indicated that the treatment dose should be increased to 10 mg once daily in patients weighing > 100 kg.

Keywords

Anticoagulants - thromboprophylaxis - obesity

Publication History

Article published online:
23 December 2020

• References

• 1 Obesity and overweight (fact sheet). World Health Organization. . Accessed February 23, 2020 at: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
• 2 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
• 3 Frost L, Hune LJ, Vestergaard P. Overweight and obesity as risk factors for atrial fibrillation or flutter: the Danish Diet, Cancer, and Health Study. Am J Med 2005; 118 (05) 489-495
• 4 Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet 2010; 49 (02) 71-87
• 5 Klexane (summary of product characteristics). Accessed December 20, 2019 at: https://www.medicines.org.uk
• 6 Innohep (summary of product characteristics). Accessed December 20, 2019 at: https://www.medicines.org.uk
• 7 Fragmin (summary of product characteristics). Accessed December 20, 2019 at: https://www.medicines.org.uk
• 8 Steib A, Degirmenci SE, Junke E. et al. Once versus twice daily injection of enoxaparin for thromboprophylaxis in bariatric surgery: effects on antifactor Xa activity and procoagulant microparticles. A randomized controlled study. Surg Obes Relat Dis 2016; 12 (03) 613-621
• 9 Celik F, Huitema AD, Hooijberg JH, van de Laar AW, Brandjes DP, Gerdes VE. Fixed-dose enoxaparin after bariatric surgery: the influence of body weight on peak anti-Xa levels. Obes Surg 2015; 25 (04) 628-634
• 10 Gelikas S, Eldar SM, Lahat G. Anti-factor Xa levels in patients undergoing laparoscopic sleeve gastrectomy: 2 different dosing regimens of enoxaparin. Surg Obes Relat Dis 2017; 13 (10) 1753-1759
• 11 Khoursheed M, Al-Bader I, Al-Asfar F. et al. Therapeutic effect of low-molecular weight heparin and incidence of lower limb deep venous thrombosis and pulmonary embolism after laparoscopic bariatric surgery. Surg Laparosc Endosc Percutan Tech 2013; 23 (06) 491-493
• 12 Brunetti L, Wassef A, Sadek R. et al. Anticoagulant activity of enoxaparin and unfractionated heparin for venous thromboembolism prophylaxis in obese patients undergoing sleeve gastrectomy. Surg Obes Relat Dis 2019; 15 (03) 363-373
• 13 Borkgren-Okonek MJ, Hart RW, Pantano JE. et al. Enoxaparin thromboprophylaxis in gastric bypass patients: extended duration, dose stratification, and antifactor Xa activity. Surg Obes Relat Dis 2008; 4 (05) 625-631
• 14 Rottenstreich A, Elazary R, Kalish Y. Abdominal thrombotic complications following bariatric surgery. Surg Obes Relat Dis 2017; 13 (01) 78-84
• 15 Raftopoulos I, Martindale C, Cronin A, Steinberg J. The effect of extended post-discharge chemical thromboprophylaxis on venous thromboembolism rates after bariatric surgery: a prospective comparison trial. Surg Endosc 2008; 22 (11) 2384-2391
• 16 Escalante-Tattersfield T, Tucker O, Fajnwaks P, Szomstein S, Rosenthal RJ. Incidence of deep vein thrombosis in morbidly obese patients undergoing laparoscopic Roux-en-Y gastric bypass. Surg Obes Relat Dis 2008; 4 (02) 126-130
• 17 Scholten DJ, Hoedema RM, Scholten SE. A comparison of two different prophylactic dose regimens of low molecular weight heparin in bariatric surgery. Obes Surg 2002; 12 (01) 19-24
• 18 Singh K, Podolsky ER, Um S. et al. Evaluating the safety and efficacy of BMI-based preoperative administration of low-molecular-weight heparin in morbidly obese patients undergoing Roux-en-Y gastric bypass surgery. Obes Surg 2012; 22 (01) 47-51
• 19 Rowan BO, Kuhl DA, Lee MD, Tichansky DS, Madan AK. Anti-Xa levels in bariatric surgery patients receiving prophylactic enoxaparin. Obes Surg 2008; 18 (02) 162-166
• 20 Simone EP, Madan AK, Tichansky DS, Kuhl DA, Lee MD. Comparison of two low-molecular-weight heparin dosing regimens for patients undergoing laparoscopic bariatric surgery. Surg Endosc 2008; 22 (11) 2392-2395
• 21 Ojo P, Asiyanbola B, Valin E, Reinhold R. Post discharge prophylactic anticoagulation in gastric bypass patient-how safe?. Obes Surg 2008; 18 (07) 791-796
• 22 Paige JT, Gouda BP, Gaitor-Stampley V. et al. No correlation between anti-factor Xa levels, low-molecular-weight heparin, and bleeding after gastric bypass. Surg Obes Relat Dis 2007; 3 (04) 469-475
• 23 Leeman M, Biter LU, Apers JA. et al. A single-center comparison of extended and restricted thromboprophylaxis with LMWH after metabolic surgery. Obes Surg 2020; 30 (02) 553-559
• 24 Magee CJ, Barry J, Javed S, Macadam R, Kerrigan D. Extended thromboprophylaxis reduces incidence of postoperative venous thromboembolism in laparoscopic bariatric surgery. Surg Obes Relat Dis 2010; 6 (03) 322-325
• 25 Simoneau MD, Vachon A, Picard F. Effect of prophylactic dalteparin on anti-factor Xa levels in morbidly obese patients after bariatric surgery. Obes Surg 2010; 20 (04) 487-491
• 26 Gaborit B, Moulin PA, Bege T. et al. Lean body weight is the best scale for venous thromboprophylaxis algorithm in severely obese patients undergoing bariatric surgery. Pharmacol Res 2018; 131: 211-217
• 27 Tseng EK, Kolesar E, Handa P. et al. Weight-adjusted tinzaparin for the prevention of venous thromboembolism after bariatric surgery. J Thromb Haemost 2018; 16 (10) 2008-2015
• 28 Venclauskas L, Maleckas A, Arcelus JI. ESA VTE Guidelines Task Force. European guidelines on perioperative venous thromboembolism prophylaxis: Surgery in the obese patient. Eur J Anaesthesiol 2018; 35 (02) 147-153
• 29 Al Otaib N, Bootah Z, Al Ammari MA. et al. Assessment of anti-factor Xa activity of enoxaparin for venous thromboembolism prophylaxis in morbidly obese surgical patients. Ann Thorac Med 2017; 12 (03) 199-203
• 30 Ludwig KP, Simons HJ, Mone M, Barton RG, Kimball EJ. Implementation of an enoxaparin protocol for venous thromboembolism prophylaxis in obese surgical intensive care unit patients. Ann Pharmacother 2011; 45 (11) 1356-1362
• 31 Miranda S, Le Cam-Duchez V, Benichou J. et al. Adjusted value of thromboprophylaxis in hospitalized obese patients: A comparative study of two regimens of enoxaparin: The ITOHENOX study. Thromb Res 2017; 155: 1-5
• 32 Rostas JW, Brevard SB, Ahmed N. et al. Standard dosing of enoxaparin for venous thromboembolism prophylaxis is not sufficient for most patients within a trauma intensive care unit. Am Surg 2015; 81 (09) 889-892
• 33 Bickford A, Majercik S, Bledsoe J. et al. Weight-based enoxaparin dosing for venous thromboembolism prophylaxis in the obese trauma patient. Am J Surg 2013; 206 (06) 847-851 , discussion 851–852
• 34 Freeman A, Horner T, Pendleton RC, Rondina MT. Prospective comparison of three enoxaparin dosing regimens to achieve target anti-factor Xa levels in hospitalized, medically ill patients with extreme obesity. Am J Hematol 2012; 87 (07) 740-743
• 35 Rondina MT, Wheeler M, Rodgers GM, Draper L, Pendleton RC. Weight-based dosing of enoxaparin for VTE prophylaxis in morbidly obese, medically-Ill patients. Thromb Res 2010; 125 (03) 220-223
• 36 Hainer JW, Barrett JS, Assaid CA. et al. Dosing in heavy-weight/obese patients with the LMWH, tinzaparin: a pharmacodynamic study. Thromb Haemost 2002; 87 (05) 817-823
• 37 Kucher N, Leizorovicz A, Vaitkus PT. et al. Efficacy and safety of fixed low-dose dalteparin in preventing venous thromboembolism among obese or elderly hospitalized patients: a subgroup analysis of the PREVENT trial. Arch Intern Med 2005; 165 (03) 341-345
• 38 Spinler SA, Inverso SM, Cohen M, Goodman SG, Stringer KA, Antman EM. ESSENCE and TIMI 11B Investigators. Safety and efficacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: analysis from the ESSENCE and TIMI 11B studies. Am Heart J 2003; 146 (01) 33-41
• 39 Curry MA, LaFollette JA, Alexander BR, Evans KS, Tran RH, Kempton CL. Evaluation of treatment-dose enoxaparin in acutely ill morbidly obese patients at an academic medical center: a randomized clinical trial. Ann Pharmacother 2019; 53 (06) 567-573
• 40 Barras MA, Duffull SB, Atherton JJ, Green B. Individualized dosing of enoxaparin for subjects with renal impairment is superior to conventional dosing at achieving therapeutic concentrations. Ther Drug Monit 2010; 32 (04) 482-488
• 41 Thompson-Moore NR, Wanat MA, Putney DR, Liebl PH, Chandler WL, Muntz JE. Evaluation and pharmacokinetics of treatment dose enoxaparin in hospitalized patients with morbid obesity. Clin Appl Thromb Hemost 2015; 21 (06) 513-520
• 42 Bazinet A, Almanric K, Brunet C. et al. Dosage of enoxaparin among obese and renal impairment patients. Thromb Res 2005; 116 (01) 41-50
• 43 Czupryn MJ, Exline C. Dosing of enoxaparin in morbidly obese patients: a retrospective cohort. Hosp Pharm 2018; 53 (05) 331-337
• 44 Spinler SA, Ou FS, Roe MT. et al. Weight-based dosing of enoxaparin in obese patients with non-ST-segment elevation acute coronary syndromes: results from the CRUSADE initiative. Pharmacotherapy 2009; 29 (06) 631-638
• 45 Hagopian JC, Riney JN, Hollands JM, Deal EN. Assessment of bleeding events associated with short-duration therapeutic enoxaparin use in the morbidly obese. Ann Pharmacother 2013; 47 (12) 1641-1648
• 46 Deal EN, Hollands JM, Riney JN, Skrupky LP, Smith JR, Reichley RM. Evaluation of therapeutic anticoagulation with enoxaparin and associated anti-Xa monitoring in patients with morbid obesity: a case series. J Thromb Thrombolysis 2011; 32 (02) 188-194
• 47 Lalama JT, Feeney ME, Vandiver JW, Beavers KD, Walter LN, McClintic JR. Assessing an enoxaparin dosing protocol in morbidly obese patients. J Thromb Thrombolysis 2015; 39 (04) 516-521
• 48 Lee YR, Palmere PJ, Burton CE, Benavides TM. Stratifying therapeutic enoxaparin dose in morbidly obese patients by BMI class: a retrospective cohort study. Clin Drug Investig 2019; 40 (01) 33-40
• 49 Lee YR, Vega JA, Duong HN, Ballew A. Monitoring enoxaparin with antifactor Xa levels in obese patients. Pharmacotherapy 2015; 35 (11) 1007-1015
• 50 van Oosterom N, Winckel K, Barras M. Evaluation of weight based enoxaparin dosing on anti-Xa concentrations in patients with obesity. J Thromb Thrombolysis 2019; 48 (03) 387-393
• 51 Maclachlan KH, Stevens HP, Tran HA, Chunilal SD. Weight-based enoxaparin for venous thromboembolism in obesity gives similar anti-Xa levels to patients <100 kg, with no increase in major bleeding. Semin Thromb Hemost 2019; 45 (01) 94-99
• 52 Sanderink GJ, Le Liboux A, Jariwala N. et al. The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers. Clin Pharmacol Ther 2002; 72 (03) 308-318
• 53 Al-Yaseen E, Wells PS, Anderson J, Martin J, Kovacs MJ. The safety of dosing dalteparin based on actual body weight for the treatment of acute venous thromboembolism in obese patients. J Thromb Haemost 2005; 3 (01) 100-102
• 54 Barrett JS, Gibiansky E, Hull RD. et al. Population pharmacodynamics in patients receiving tinzaparin for the prevention and treatment of deep vein thrombosis. Int J Clin Pharmacol Ther 2001; 39 (10) 431-446
• 55 McCaughan GJB, Favaloro EJ, Pasalic L, Curnow J. Anticoagulation at the extremes of body weight: choices and dosing. Expert Rev Hematol 2018; 11 (10) 817-828
• 56 Eriksson BI, Dahl OE, Feuring M. et al. Dabigatran is effective with a favourable safety profile in normal and overweight patients undergoing major orthopaedic surgery: a pooled analysis. Thromb Res 2012; 130 (05) 818-820
• 57 Pineo GF, Gallus AS, Raskob GE. et al. Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups. J Thromb Haemost 2013; 11 (03) 444-451
• 58 Krauss ES, Cronin M, Dengler N. et al. The effect of BMI and gender on bleeding events when rivaroxaban is administered for thromboprophylaxis following total hip and total knee arthroplasty. Semin Thromb Hemost 2019; 45 (02) 180-186
• 59 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
• 60 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
• 61 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
• 62 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
• 63 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
• 64 Lip GYH, Merino JL, Banach M. et al. Impact of body mass index on outcomes in the edoxaban versus warfarin therapy groups in patients underwent cardioversion of atrial fibrillation (from ENSURE-AF). Am J Cardiol 2019; 123 (04) 592-597
• 65 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
• 66 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
• 67 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
• 68 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
• 69 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
• 70 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
• 71 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
• 72 Kalani C, Awudi E, Alexander T, Udeani G, Surani S. Evaluation of the efficacy of direct oral anticoagulants (DOACs) in comparison to warfarin in morbidly obese patients. Hosp Pract 1995; 2019: 1-5
• 73 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
• 74 Perales IJ, San Agustin K, DeAngelo J, Campbell AM. Rivaroxaban versus warfarin for stroke prevention and venous thromboembolism treatment in extreme obesity and high body weight. Ann Pharmacother 2019; (e-pub ahead of print) DOI: 10.1177/1060028019886092.
• 75 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 2019; (e-pub ahead of print) DOI: 10.1177/897190019854578.
• 76 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
• 77 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
• 78 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
• 79 Wasan SM, Feland N, Grant R, Aston CE. Validation of apixaban anti-factor Xa assay and impact of body weight. Thromb Res 2019; 182: 51-55
• 80 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
• 81 Zhou Y, Ma J, Zhu W. Efficacy and safety of direct oral anticoagulants versus warfarin in patients with atrial fibrillation across BMI categories: a systematic review and meta-analysis. Am J Cardiovasc Drugs 2020; 20 (01) 51-60
• 82 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
• 83 Steele KE, Canner J, Prokopowicz G. et al. The EFFORT trial: Preoperative enoxaparin versus postoperative fondaparinux for thromboprophylaxis in bariatric surgical patients: a randomized double-blind pilot trial. Surg Obes Relat Dis 2015; 11 (03) 672-683
• 84 Martinez L, Burnett A, Borrego M, Streeter JC, Townsend K, Garcia D. Effect of fondaparinux prophylaxis on anti-factor Xa concentrations in patients with morbid obesity. Am J Health Syst Pharm 2011; 68 (18) 1716-1722
• 85 Davidson BL, Büller HR, Decousus H. et al; Matisse Investigators. Effect of obesity on outcomes after fondaparinux, enoxaparin, or heparin treatment for acute venous thromboembolism in the Matisse trials. J Thromb Haemost 2007; 5 (06) 1191-1194
• 86 Wei MY, Ward SM. The anti-factor Xa range for low molecular weight heparin thromboprophylaxis. Hematol Rep 2015; 7 (04) 5844
• 87 Egan G, Ensom MH. Measuring anti-factor xa activity to monitor low-molecular-weight heparin in obesity: a critical review. Can J Hosp Pharm 2015; 68 (01) 33-47
• 88 Laposata M, Green D, Van Cott EM, Barrowcliffe TW, Goodnight SH, Sosolik RC. College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: the clinical use and laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and related compounds, and argatroban. Arch Pathol Lab Med 1998; 122 (09) 799-807
• 89 Kovacs MJ, Keeney M, MacKinnon K, Boyle E. Three different chromogenic methods do not give equivalent anti-Xa levels for patients on therapeutic low molecular weight heparin (dalteparin) or unfractionated heparin. Clin Lab Haematol 1999; 21 (01) 55-60
• 90 Kitchen S, Iampietro R, Woolley AM, Preston FE. Anti Xa monitoring during treatment with low molecular weight heparin or danaparoid: inter-assay variability. Thromb Haemost 1999; 82 (04) 1289-1293