• linkedin
  • Increase Font
  • Sharebar

    Anticoagulant dosing in obesity should be individualized and drug-specific

    Obesity is a growing problem in the United States. Currently, 68% of adult Americans are overweight (BMI >25 kg/m2).1Of those, 35% are obese (BMI >30 kg/m2) and 6% are morbidly obese (BMI >40 kg/m2).1-2 It is estimated that by 2030, 51% of the population will be obese and 11% will be morbidly obese.1 We are often confronted with dosing drugs in an obese patient. Unfortunately, many clinical trials exclude or have limited overweight patients enrolled; thus, optimal dosing for both safety and efficacy in this population is lacking. Pharmacokinetic studies in obese patients have shown that the volumes of distribution of lipophilic drugs and the clearance of hydrophilic drugs can be increased.3,4 For this reason, dosing in obesity should be patient- and drug-specific.

    Unfractionated heparin

    Obese patients are often initiated on anticoagulation for venous thromboembolism (VTE) prophylaxis, VTE treatment, or acute coronary syndrome (ACS) treatment. Concerns for bleeding in obese patients have raised the question of whether dose adjustments or dose capping is necessary. Unfractionated heparin (UFH) has a nonlinear pharmacokinetic profile and is not distributed into adipose tissue.4 Studies have shown that total body weight (TBW) is the most important predictor of anticoagulation requirements.5–7 However, physicians are often cautious of abnormally high doses of UFH. One retrospective study found that based on recommended dosing guidelines, only 10% of obese patients received the correct bolus dose and only 25% were initiated on the correct infusion dose. The gap between the recommended dose and prescribed dose amplified as body weight increased.8

    Since the adoption of TBW UFH protocols, numerous studies have been undertaken to determine optimal dosing in obese patients. Multiple studies have supported the use of TBW dosing protocols for obese patients.9,10 However, some studies found that using TBW, morbidly obese patients required smaller infusion rates or experienced greater aPTT values compared to their controls.11–14

    Low-molecular-weight heparins

    Low-molecular-weight heparins (LMWHs) are predominantly concentrated in the plasma with little distribution into adipose tissue.15 Guidelines offer little guidance except suggesting anti-Xa monitoring with subsequent dose adjustments in obese patients.16 Focusing on treatment dosing, some studies have compared anti-Xa levels based on weight in obese and non-obese patients and determined that dose adjustments may not be necessary.17 Bazinet et al found that when utilizing weight-based dosing of enoxaparin without dose capping there was no difference in subtherapeutic, therapeutic, or supratherapeutic levels among patients treated for atrial fibrillation (AF), ACS, or VTE.18

    Data from trials have not confirmed increased bleeding in obese patients. Al-Yaseen et al found rates of bleeding with dalteparin to be consistent with those previously reported, without significant alterations in anti-Xa levels.19 A retrospective review found no difference in the rate of major hemorrhage between obese and non-obese patients with ACS.20 The Computerized Registry of Patients with Venous Thromboembolism (RIETE) suggested no significant difference in recurrent VTE between obese (>100 kg) and non-obese patients treated with LMWH. Doses may have been capped; therefore, strong conclusions cannot be drawn.21 Pooled results suggest that to ensure adequate anticoagulation, treatment doses of UFH and LMWH should be based on TBW without capping. Due to conflicting results, special consideration and close monitoring should be taken into account when dosing morbidly obese patients with UFH. Anti-Xa monitoring may be appropriate for obese patients on LMWH therapy especially those weighing >190 kg as data are particularly lacking in these patients.22

    Concerns also exist with underdosing UFH and LMWH for VTE prophylaxis since obesity itself is a risk factor for the development of VTE in the hospitalized medical patient.23 Guidelines suggest that obese surgical patients or patients undergoing bariatric surgery may require higher prophylactic doses.24 Strategies such as increasing the fixed dose or administering a TBW-based dose have been studied. A study looking at morbidly obese patients found that heparin 7,500 units 3 times daily or enoxaparin 40 mg twice daily decreased VTE occurrence by 50% compared to standard prophylactic regimens.25 A subgroup analysis showed that compared to placebo, fixed-dose dalteparin was equally effective in non-obese and obese patients; however, no benefit was seen in patients with a BMI >40 kg/m2.26 Scholten et al compared higher than normal fixed-dosing strategies (enoxaparin 30 mg or 40 mg twice daily) in bariatric surgery patients. Results showed a decrease in VTE utilizing 40 mg twice daily without an increase in major bleeding.27 A retrospective analysis found that enoxaparin 0.5 mg/kg twice daily was effective at maintaining prophylactic anti-Xa levels without increasing major bleeds.28 Based on results of clinical trials, standard fixed doses of LMWH and UFH may not provide adequate VTE prophylaxis in obese patients. Trials have demonstrated that various dosing strategies providing higher doses of LMWH and UFH may be necessary.

    Warfarin

    Warfarin has been the only oral anticoagulant on the market in the United States for over 50 years. Numerous factors have been identified that affect warfarin dose requirements; however, the effects of obesity have not been established. One retrospective review found that when initiated in hospitalized patients, obese and morbidly obese patients with therapeutic INRs had higher average daily warfarin discharge doses than normal-weight patients; 6.7 mg, 6.7 mg, and 4.4 mg, respectively. Increased time to a therapeutic INR was also noted between normal-weight (6 days), obese (8 days), and morbidly obese patients (10 days). The obese and morbidly obese patients were significantly younger, which could affect the results as elderly patients frequently have lower warfarin requirements.29

    The recent addition of an oral direct thrombin inhibitor and two Xa-inhibitors expands our oral anticoagulation options. Unfortunately, studies focusing on dosing in obesity are lacking. Dabigatran is approved in the United States for prevention of stroke and systemic embolism in nonvalvular AF.30 The RE-LY trial noted a 20% decrease in trough concentrations in patients weighing >100 kg; however, dose adjustments have not been recommended.31 Although not approved for VTE prophylaxis in the United States, a post-hoc analysis compared dabigatran to enoxaparin 40 mg once daily for prevention of VTE in orthopedic surgery patients. No significant difference was noted in the composite end point of major VTE; however, the comparator dose of enoxaparin may be inappropriate for obese patients.32

    Rivaroxaban is approved for prevention of stroke and systemic embolism in nonvalvular AF, DVT and pulmonary embolism (PE) treatment and reduction of recurrence, and DVT prophylaxis after knee and hip surgery.33 A phase 2 study demonstrated that a TBW >120 kg was not associated with clinically significant changes in pharmacokinetic or pharmacodynamics parameters; thus, dose adjustments are not warranted.34 Studies with rivaroxaban have a small proportion of patients with a BMI of >28 kg/m2 or weights exceeding >100 kg; however, subgroup analyses have shown dose modifications are not needed.35–37

    Apixaban is the most recent agent to be approved for prevention of stroke and systemic embolism in nonvalvular AF.38  One study found that a 10-mg dose of apixaban yielded a 20% decrease in peak concentration in patients weighing >120 kg. The authors concluded that these alterations were not clinically significant and no dose alteration is needed.39 The ARISTOTLE trial reported weights as greater than or less than 60 kg, so efficacy in obesity cannot be assumed.40 Although the manufacturers of apixaban state dose adjustment for obese patients is not warranted, the subanalysis of ARISTOTLE has not been published.

    As the obesity epidemic continues to affect Americans, we struggle with ensuring adequate therapeutic drug concentrations of anticoagulants while balancing the increased risk of bleeding. Data on appropriate dosing of anticoagulants in obese patients is limited. Dosing of these medications should be based on patient- and drug-specific factors.

    References available online at www.drugtopics.com.

    Editor’s note: This article was published first in “Formulary” journal in June.

    Katie Buehler is assistant professor of pharmacy practice, department of pharmacy practice, St. Louis College of Pharmacy, St. Louis; and Abigail Yancey is associate professor of pharmacy practice, department of pharmacy practice, St. Louis College of Pharmacy, St. Louis. 

     

    **PUBLISH REFERENCES ONLINE ONLY**

    REFERENCES

    1. Go AS, Mozaffarian D, Roger VL, et al, on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;127:e6–e245.

    2. Sturm R, Hattori A. Morbid obesity rates continue to rise rapidly in the United States. Int J Obes (Lond). 2012 Sep 18; doi: 10.1038/ijo.2012.159 [Epub ahead of print].

    3. Hanley MJ, Abernethy DR, Greenblat DJ. Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet. 2010;49:71–87.

    4. Patel JP, Roberts LN, Arya R. Anticoagulating obese patients in the modern era. Br J Haematol. 2011;155:137–149.

    5. Cipolle RJ, Seifert RD, Neilan BA, Zaske DE, Haus E. Heparin kinetics: variables related to disposition and dosage. Clin Pharmacol Ther. 1981;29:387–393.

    6. Raschke RA, Reilly BM, Guidry JR, Fontana JR, Srinivas S. The weight-based heparin dosing nomogram compared with a “standard care“ nomogram: a  randomized controlled trial. Ann Intern Med. 1993;119:874–881.

    7. Linke LC, Katthagen BD. Weight-based heparin dosing is more effective in the treatment of postoperative deep vein thrombosis. Arch Orthop Trauma Surg. 1999;119:208–211.

    8. Hurewitz AN, Khan SU, Groth ML, Patrick PA, Brand DA. Dosing of unfractionated heparin in obese patients with venous thromboembolism. J Gen Intern Med. 2011;26:487–491. 

    9. Spruill WJ, Wade WE, Huckaby WG, Leslie RB. Achievement of anticoagulation by using a weight-based heparin dosing protocol for obese and nonobese patients. Am J Health Syst Pharm. 2001;58:2143–2146.

    10. Bauer SR, Ou NN, Dreesman BJ, et al. Effect of body mass index on bleeding frequency and activated partial thromboplastin time in weight-based dosing of unfractionated heparin: a retrospective cohort study. Mayo Clin Proc. 2009;84:1073–1078.

    11. Barletta JF, DeYoung JL, McAllen K, Baker R, Pendleton K. Limitations of a standardized weight-based nomogram for heparin dosing in patients with morbidobesity. Surg Obes Relat Dis. 2008;4:748–753.

    12. Riney JN, Hollands JM, Smith JR, Deal EN. Identifying optimal initial infusion rates for unfractionated heparin in morbidly obese patients. Ann Pharmacother. 2010;44:1141–1151.

    13. Lackie CL, Luzier AB, Donovan JA, Feras HI, Forrest A. Weight-based heparin dosing: clinical response and resource utilization. Clin Ther. 1998;20:699–710.

    14. Shalansky KF, FitzGerald JM, Sunderji R, et al. Comparison of a weight-based heparin nomogram with traditional heparin dosing to achieve therapeutic anticoagulation. Pharmacotherapy. 1996;16:1076–1084.

    15. Lim W. Using low molecular weight heparin in special patient populations. J Thromb Thrombolysis. 2010;29:233–240.

    16. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(Suppl):e24S–43S.

    17. Sanderink GJ, Le Liboux A, Jariwala N, et al. The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers. Clin Pharmacol Ther. 2002;72:308–318.

    18. Bazinet A, Almanric K, Brunet C, et al. Dosage of enoxaparin among obese and renal impairment patients. Thromb Res. 2005;116:41–50.

    19. 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;3:100–102.

    20. Spinler SA, Inverso SM, Cohen M, Goodman SG, Stringer KA, Antman EM for the ESSENCE and TIMI 11B studies. 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;146:33–41.

    21. Barba R, Marco J, Martín-Alvarez H, et al, for the RIETE Investigators. The influence of extreme body weight on clinical outcome of patients with venous thromboembolism: findings from a prospective registry (RIETE). J Thromb Haemost. 2005;3:856–862.

    22. Nutescu EA, Spinler SA, Wittkowsky A, Dager WE. Low-molecular-weight heparins in renal impairment and obesity: available evidence and clinical practice recommendations across medical and surgical settings. Ann Pharmacother. 2009;43:1064–1083.

    23. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(Suppl):e195S–226S.

    24. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(Suppl):e227S–277S.

    25. Wang TF, Milligan P, Wong CA, et al. Higher doses of prophylactic anticoagulation is more effective in preventing venous thromboembolism in morbidly obese inpatients (abstract). Presented at the American Society of Hematology Annual Meeting, December 12, 2012. Available at: https://ash.confex.com/ash/2012/webprogram/Paper50531.html. Accessed March 6, 2013.

    26. Kucher N, Leizorovicz A, Vaitkus PT, et al, for the PREVENT Medical Thromboprophylaxis Study Group. 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;165:341–345.

    27. 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;12:19–24.

    28. 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;45:1356–1362.

    29. Wallace JL, Reaves AB, Tolley EA, et al. Comparison of initial warfarin response in obese patients versus non-obese patients. J Thromb Thrombolysis. 2012 Sep 27; DOI 10.1007/s11239-012-0811-x [Epub ahead of print].

    30. Pradaxa dabigatran [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; December 2012.

    31. Boehringer Ingelheim Pharmaceuticals, Inc. Data on file. Body weight or BMI effects on Pradaxa. Westminster, PA; March 8, 2013. 

    32. 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;130:818–820.

    33. Xarelto rivaroxaban [package insert]. Titusville, NJ. Janssen Pharmaceuticals, Inc.; March 2013.

    34. 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;47:218–226.

    35. Turpie AG, Lassen MR, Eriksson BI, et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty—pooled analysis of four studies. Thromb Haemost. 2011;105:444–453.

    36. Patel MR, Mahaffey KW, Garg J, et al, and the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–891.

    37. Bauersachs S, Berkowitz SD, Brenner B, et al, for the EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499–2510.

    38. Eliquis apixaban [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; December 2012.

    39. Upreti VV, Wang J, Barrett Y, 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; doi: 10.1111/bcp.12114 [e-pub ahead of print]

    40. Granger CB, Alexander JH, McMurray JV, et al, for the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–992.

    0 Comments

    You must be signed in to leave a comment. Registering is fast and free!

    All comments must follow the ModernMedicine Network community rules and terms of use, and will be moderated. ModernMedicine reserves the right to use the comments we receive, in whole or in part,in any medium. See also the Terms of Use, Privacy Policy and Community FAQ.

    • No comments available
    Slideshows
    Small Doses: The Weekly News You Need to Know
    Small Doses: The Weekly News You ...

    Small doses is a weekly slideshow of the news you may have missed, made just for you and your busy lifestyle.

    25 Cities With The Lowest Pharmacist ...
    Strange, offbeat, and obscure ...