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Description : Check out this medical PowerPoint presentation titled "Anticoagulation in Obesity - Exploring Enoxaparin and Direct Oral Anticoagulants" by Jordann Hoernemann, Pharm.D. and Sierra Kreft, Pharm.D.

This medical PowerPoint presentation talks about Anticoagulation in Obesity.

Obesity is associated with an increased risk of thromboembolic events, including deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke. Anticoagulation is the mainstay of treatment for these conditions, but the optimal dosing strategy for anticoagulants in obese patients can be challenging.

Tags : Anticoagulation in Obesity, Enoxaparin, Direct Oral Anticoagulants, thromboembolic events, deep vein thrombosis, pulmonary embolism, stroke, cardiology

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Anticoagulation in Obesity Exploring Enoxaparin and Direct Oral Anticoagulants Jordann Hoernemann, Pharm.D. & Sierra Kreft, Pharm.D. PGY-1 Acute Care Pharmacy ResidentsEssentia Health | Fargo, NDFriday, March 6th, 2020
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Disclosures The speakers of this presentation have no conflicts of interest to disclose. There will be off-label use discussion.
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Abbreviations BMI: Body mass index CI: Confidence interval CV: % coefficient of variation DOAC: Direct oral anticoagulant FD: Fixed dose HD: High dose ICD: International Classification of Diseases ISTH: International Society of Thrombosis and Haemostasis LD: Low dose LMWH: Low-molecular weight heparin OR: Odds ratio PAI-1: Plasminogen activator inhibitor-1 PE: Pulmonary embolism PTS: Post-thrombotic syndrome RYGB: Roux-en-Y gastric bypass tPA: Tissue plasminogen activator UFH: Unfractionated heparin VTE: Venous thromboembolism WC: Waist circumference WHR: Waist-to-hip ratio
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Objectives Address the association between obesity and venous thromboembolism development. Identify alternate VTE prophylactic dosing and monitoring strategies when using pharmacologic agents in obese, hospitalized patients. Evaluate the evidence regarding the role of enoxaparin and direct oral anticoagulants agents in the obese population.
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Poll Question #1 Do you regularly use weight-based dosing with all anticoagulants when initiating therapy in obese patients? No, all adult patients have the same amount of blood, therefore fixed dosing regimens are appropriate I have only adjusted warfarin doses for obese patients to achieve INR goals in a timely fashion I consider it but am not confident how to accurately dose available anticoagulants Always, I have found resources and guidance to confidently dose and anticoagulate my obese patients
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Epidemiology The prevalence of obesity was 39.8% and affected about 93.3 million of US adults in 2015~2016. Center for Disease Control and Prevention, October 2017.
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Venous Thromboembolism (VTE) Referring to blood clots in the veins including deep vein thrombosis (DVT) and pulmonary embolism (PE). Usually develop in the lower leg, thigh, and pelvis. Can also occur in the arm Underdiagnosed, yet a preventable medical condition. Center for Disease Control and Prevention, February 2020.
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VTE Risk Factors Serve as a tool for clinician use in patients >65 years of age for prescribing and dose adjustments Provide evidence-based recommendations created by an interdisciplinary panel of geriatric experts Analyze safety and risk-benefit ratio for at-risk people Center for Disease Control and Prevention, February 2020.
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Obese patients (BMI > 30 kg/m2) not only carry an increased risk of VTE, but also recurrent VTE and post-thrombotic syndrome. PTS is characterized by fibrotic injury due to thrombosis-induced inflammation. This results in thickened and nonfunctioning vein walls. VTE Prevalence in Obesity Miranda, Thrombosis Research, April 2017. Metz, Methodist Debakey Cardiovascular Journal, July 2018.
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VTE Prevalence in Obesity A meta-analysis found the likelihood of first spontaneous VTE among people who were obese was more than twice that of individuals with a normal BMI (OR= 2.33; 95% CI 1.68-3.24). A prospective, cohort study showed that the relative risk of unprovoked PE that was not associated with prior surgery, trauma, or cancer raised by 8% per 1 kg/m2 increase in BMI. Yang, Journal of Preventive Medicine & Public Health, November 2012.
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VTE Mechanism in Obesity Adipokines microRNAs Endothelial dysfunction Plaque rupture Platelet activation Delayed clot lysis Blokhin, Current Opinion in Hematology, September 2013.
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Impaired Fibrinolysis Plasmin: degrades fibrin t-PA: converts plasminogen to plasmin PAI-1: inhibits plasmin PAI-1 is released by vascular endothelium, liver, and adipose tissue Image: Gupta, Rare Bleeding Disorder, 2020. Blokhin, Current Opinion in Hematology, September 2013.
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Current Challenges Other than weight loss, no current published recommendations available to prevent/treat thrombosis in obese patients It is established that obese patients require significantly higher doses of warfarin to reach INR goals in a timely manner Uncertainty of weight-based and maximum doses of LMWH DOACs are approved with fixed doses and obese patients were excluded from the trials to support approval Using anti-Xa levels with these therapeutic options are not well established Blokhin, Current Opinion in Hematology, September 2013. Yang, Journal of Preventive Medicine & Public Health, November 2012.
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Non-Pharmacologic Treatment Regular physical activity can decrease PAI-1 activity Diets rich in vitamin E, vitamin B6, and fiber decrease risk of VTE Mechanical DVT prophylaxis is not recommended as monotherapy in hospitalized patients without pharmacologic prophylaxis, unless contraindicated. Guyatt, Chest, February 2012. Varraso, American Journal of Epidemiology, January 2012.
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Poll Question #2 Per the mechanism of increased risk of VTE in obese patients, which statement below is true? A. tPA is ineffective in those with a BMI > 30 kg/m2 B. Serum plasmin levels in obese patients are 2-fold greater C. Adipose tissues releases PAI-1, inhibiting plasmin from fibrinolysis D. Lack of conversion from prothrombin to thrombin
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Enoxaparin in Obesity Studies have shown distribution of low-molecular weight heparin (LMWH) is weight-based, compensating for absorption through adipose tissue. After subcutaneous administration, steady‐state exposure is achieved after the second dose in nonobese individuals vs. after the third dose in obese volunteers. Time to maximum anti‐Xa activity is estimated to be 1 hour longer in obese patients Anti-Xa activity, at steady state, is estimated to be 16% higher in obese patients vs. nonobese patients. Miranda, Thrombosis Research, April 2017. Sanderink, American Society for Clinical Pharmacology & Therapeutics. September 2002.
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Mechanism of action: Enoxaparin Enoxaparin binds to and potentiates antithrombin III This complex irreversibly inactivates clotting factor Xa Enoxaparin thereby inhibits cascade progression and the generation of thrombin Yang, Journal of Preventive Medicine & Public Health, November 2012.
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VTE Thromboembolic RecommendationsBariatric Surgery The American Society for Metabolic and Bariatric Surgery “… combination of mechanical prophylaxis and chemoprophylaxis should be considered…” “…LMWH offers better VTE prophylaxis than UFH without increasing the bleeding risk.” “Extended VTE prophylaxis should be considered…” Surgery for Obesity and Related Disease, March 2013.
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Enoxaparin Dosing Strategies Bariatric Surgery Borkgren- Okonek et al. 2008. Surgery for Obesity and Related Diseases Then, once daily x 10 days after discharge Upon discharge, once daily x 10 days Anti-factor Xa levels monitored serially and enoxaparin was dose adjusted to target a prophylactic range of 0.2 to 0.4 IU/mL +/- 10% Borkgren- Okonek et al. 2008. Surgery for Obesity and Related Diseases
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Borkgren- Okonek et al. 2008. Surgery for Obesity and Related Diseases Efficacy: Target prophylactic anti-factor Xa concentration was reached by 74% of patients after the third enoxaparin dose. No patients reached treatment anticoagulation concentrations Xa > 0.44 IU/mL Safety: One patient developed nonfatal VTE (0.45%) Four patients required blood transfusion (1.79%) Borkgren- Okonek et al. 2008. Surgery for Obesity and Related Diseases
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VTE Prophylaxis RecommendationsBariatric surgery Bariatric surgery, high VTE risk (off-label use) BMI ≤ 50 kg/m2: Subcutaneous enoxaparin 40 mg every 12 hours initiated at least 2 hours prior to surgery BMI > 50 kg/m2: Subcutaneous enoxaparin 60 mg every 12 hours initiated at least 2 hours prior to surgery *Dosing regimens are based on the best available evidence. *Optimal dosage and duration of prophylaxis is not established. Borkgren- Okonek et al. 2008. Surgery for Obesity and Related Diseases
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VTE Thromboembolic RecommendationsHospitalized Patients CHEST 2012 (9th edition) “For acutely-ill, hospitalized, medical patients at increased risk of thrombosis, we recommended anticoagulant thromboprophylaxis with low-molecular-weight heparin (LMWH), low-dose unfractionated heparin (LDUH) twice daily, LDUH three times daily, or fondaparinux.” Grade 1B Guyatt, Chest, February 2012.
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VTE Thromboembolic RecommendationsHospitalized Patients American Society of Hematology 2018 “In acutely ill hospitalized medical patients the ASH guideline panel recommends using LMWH over DOACs for VTE prophylaxis” Strong recommendation Schunnemann, Blood Advances, November 2018.
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Enoxaparin Dosing Strategies Obesity Freeman et al. 2012. American Journal of Hematology. Prospective, comparison of three enoxaparin dosing regimens Primary outcome: Achievement of goal peak anti-Factor Xa levels in medically-ill patients (n=31) with extreme obesity Defined as a peak anti-Factor Xa level between 0.2-0.5 IU/mL, measured 4-6 hours after enoxaparin administration Freeman, American Journal of Hematology, July 2012.
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Methods Freeman, American Journal of Hematology, July 2012.
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Characteristics of medically-ill patients with extreme obesity Expresses as mean ± SD Extreme obesity defined as (BMI ≥40kg/m2) Freeman, American Journal of Hematology, July 2012.
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Efficacy Target anti-Factor Xa levels were achieved significantly more often in the HD group vs FD and LD group Patients in the LD group achieved target anti- Factor Xa more often than in the FD group, but remained inferior to HD dosing. Freeman, American Journal of Hematology, July 2012.
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Safety No significant adverse effects were reported in any of the three groups. Patients were monitored for: Bleeding events Symptomatic deep vein thrombosis Symptomatic pulmonary embolism Heparin-induced thrombocytopenia Freeman, American Journal of Hematology, July 2012.
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Enoxaparin Dosing Strategies Obesity Wang et al, 2014 in the Journal of Thrombosis and Haemostasis. Retrospective cohort study Analyzed 9,241 inpatients with weight > 100 kg and BMI ≥ 40 kg/m2 Wang et al, January 2014, Journal of Thrombosis and Haemostasis.
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Wang et al, 2014, Journal of Thrombosis and Haemostasis. Primary efficacy outcome: Hospital-acquired VTE identified by ICD-9 diagnosis code Primary safety outcomes: Bleeding events identified by ICD-9 diagnosis code Wang et al, January 2014, Journal of Thrombosis and Haemostasis.
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Enoxaparin Dosing Strategies Obesity Scholten et al, 2002 in Obesity Surgery Evaluation of 481 patients post primary or revision bariatric surgery Scholten et al, February 2014, Obesity Surgery.
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Scholten et al, 2002, Obesity Surgery. In addition to enoxaparin, the DVT prophylaxis protocol included: early ambulation, compression stockings, and intermittent pneumatic compression. Scholten et al, February 2014, Obesity Surgery.
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Scholten et al, 2002, Obesity Surgery. Efficacy: Post-operative DVT complications Safety: Hemorrhage requiring treatment occurred to one patient in each group Scholten et al, February 2014, Obesity Surgery.
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VTE Prophylaxis RecommendationsObesity BMI ≥ 40 kg/m2, venous thromboembolic prophylaxis (off-label) Enoxaparin 40 mg twice daily is the most validated dose in the obese population based on clinical outcomes. Evidence from 3 separate trials have shown effectiveness and safety Scholten et al., Borkgren-Okonek et al., Wang et al. Two of the three studies resulted in significant lower rates of thrombosis when compared to standard enoxaparin dosing. Standard dosing: Enoxaparin 40 mg daily or 30 mg BID. Vandiver et al, May 2015, The Journal of Thrombosis and Thrombolysis.
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Summary of enoxaparin Distribution of LMWH is weight-based. Pharmacokinetic evidence has shown standard dosing of enoxaparin in obese patients results in plasma concentrations that are considered subtherapeutic. High-dose enoxaparin regimens have shown efficacy and safety in patients with a BMI ≥ 40 kg/m2 and/or undergoing bariatric surgery . Anti- Xa assays provide an indirect measurement of the effect of enoxaparin by measuring unbound factor Xa. The utility of measuring anti-Xa levels on prophylactic dosing is not universally established. Vandiver, Journal of Thrombus and Thrombolysis, May 2015.
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DOACs in Obesity DOACs are currently preferred over warfarin for VTE and stroke prevention in patients with atrial fibrillation The ISTH does not support using DOACs in patients with a BMI >40 kg/m2 or a weight >120 kg If DOACs are prescribed, obtain drug specific peak and trough levels to assess therapeutic efficacy Current results indicate DOACs provide similar safety and efficacy profiles compared to warfarin Zukkoor, American College of Cardiology, July 2019. January, American American College of Cardiology, January 2019. Martin, Journal of Thrombus and Thrombolysis, April 2016
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Direct Oral AnticoagulantsObesity Kido, Annals of Pharmacotherapy, August 2018. Kido and Ngorduraches: DOACs showed preference over warfarin in obese patients (> 120 kg or > 40 kg/m2)
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The Impacts of Body Weight on Rivaroxaban Pharmacokinetics Kubitza, Journal of Clinical Pharmacology, November 2008. Barsam, Research Practice in Thrombosis and Haemostasis, October 2017. Kubitza: Pharmacokinetics of rivaroxaban 10 mg after administration to different body weights, Geometric mean (CV) Another study, Barsam et al., evaluated rivaroxaban pharmacokinetics: Included 20 patients with a BMI ≧ 35 kg/m2 Dose adjustments are not likely required in obese patients Small population of morbidly obese
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ARISTOTLE Trial Sandhu, European Heart Journal, April 2016. Efficacy:
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ARISTOTLE Trial Sandhu, European Heart Journal, April 2016. Safety :
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‘Obesity Paradox’ in the ARISTOTLE trial Statistically, obese patients have a lower mortality rate due to PE compared to patients that are not obese with a PE Linked with elderly obese patients Failed to consider duration of life with obesity Underweight elderly patients have an increased risk of mortality, giving obese elderly a false fatality protection When assessed WC or WHR rather than BMI, obesity was positively associated with mortality. These statistics potentially provide a false illusion of mortality protection in obesity. Yang, Journal of Preventive Medicine & Public Health, November 2012.
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ARISTOTLE Trial Sandhu, European Heart Journal, April 2016. Efficacy:
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ARISTOTLE Trial Sandhu, European Heart Journal, April 2016. Safety:
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Edoxaban ENGAGE AF-TIMI 48 As BMI increased: There was a lower risk of VTE in men Significant increase with bleed risk in women Similar edoxaban plasma concentration troughs and anti-Factor Xa activity in obese patients compared to patients with a normal BMI Obesity may not alter the pharmacokinetic or pharmacodynamic activity of edoxaban Boriani, European Heart Journal, May 2019.
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Summary of DOACs Apixaban and rivaroxaban are preferred alternative anticoagulants to warfarin due to safety and efficacy profiles for patients with a weight > 120 kg or a BMI > 40 kg/m2 DOAC pharmacokinetic results show similar effects on patients with increased BMI compared to patients with normal BMI; no dose adjustments necessary Kido, Annals of Pharmacotherapy, August 2018. Kubitza, Journal of Clinical Pharmacology, November 2008. Barsam, Research Practice in Thrombosis and Haemostasis, October 2017. Sandhu, European Heart Journal, April 2016
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Poll Question #3 T.F., a 64-year-old, male patient that weights 207 kg (BMI 51 kg/m2) is admitted to Essentia Health- Fargo due to increased SOB, resulting in an asthma exacerbation. He is s/p bariatric surgery 7 days prior. DVT and PE ruled out and has no history of HIT. He is currently on continuous oxygen and is unable to ambulate with PT. The attending physician would like to initiate VTE prophylaxis. Which therapy option is most appropriate for T.F.? A. Enoxaparin 60 mg subcutaneous twice daily B. Apixaban 2.5 mg twice daily C. Warfarin dosed per pharmacy services D. Enoxaparin 60 mg subcutaneous daily, adjusted per Xa levels.
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Final Summary It is recommended that individual practices develop and adhere to a protocol for VTE prevention in obese and bariatric surgery patients. Enoxaparin 40 mg twice daily has been shown to be effective and safe in patients with a BMI ≥ 40 kg/m2. Weight-based enoxaparin dosing may also be considered. DOACs may be considered for VTE prophylaxis, and apixaban and rivaroxaban are the preferred agents. DOAC pharmacokinetics are similar in patients of all BMI categories and do not need weight-based dose adjustments.
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References Hales C., Carroll M., Fryar C., et al. Prevalence of Obesity Among Adults and Youth: United States, 2015-2016. Center for Disease Control and Prevention. https://www.cdc.gov/obesity/data/adult.html. Updated August 13, 2018. Accessed February 26, 2020. Venous thromboembolism (blood clots). Centers for Disease Control and Prevention. Updated February 7, 2020. Accessed February 26, 2020. 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. Thrombosis Research. 2017 April 12; 155: 1-5. Yang G, De Staerche C, Hooper WC. The effects of obesity on venous thromboembolism: A review. Journal of Preventive Medicine & Public Health. 2012 November; 2(4): 499-509. Blokhin IO, Lentz SR. Mechanisms of thrombosis in obesity. Current Opinion in Hematology. 2013 September; 20(5): 437-44. Image: Gupta S., Sealls W., Shapiro A. Plasminogen activator inhibitor type 1 deficiency disease overview. Rare Bleeding Disorders. http://www.rarecoagulationdisorders.org/diseases/plasminogen-activator-inhibitor-type-1-deficiency/disease-overview-2. Updated 2020. Accessed February 26, 2020. 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. European Heart Journal. 2016;37:2869-78. Guyatt GH, Akl EA, Crowther M, et al. American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Chest. 2012 Feb; 141(2 Suppl):7S-47S. Varraso R, Kabrhel C, Goldhaber SZ, et al. Prospective study of diet and venous thromboembolism in US men and women. American Journal of Epidemiology. 2012 Jan 15; 175(2):114-26. Sanderink G.J., Le Liboux A., Jariwala N., et al. The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers. American Society for Clinical Pharmacology & Therapeutics. 2002 September 11; 72(3): 308-318. Schunnemann H.J., Cushman M., Burnett A.E., et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Advances. 2018 November 27; 2(22): 3198-3225. Freeman A., Horner T., Pendleton R.C., et al. Prospective comparison of three enoxaparin dosing regimens to achieve target anti-factor Xa levels in hospitalized, medically ill patients with extreme obesity. American Journal of Hematology. 2012 July; 87(7): 740-743. Vandiver J.W., Ritz L.I., Lalama J.T. Chemical prophylaxis to prevent venous thromboembolism in morbid obesity: literature review and dosing recommendations. Journal of Thrombus and Thrombolysis. 2015 May 17; 41:475-481. Zukkoor, S. Antiarrhythmic and DOAC dosing in obesity. American College of Cardiology. https://www.acc.org/latest-in-cardiology/articles/2019/07/03/08/22/antiarrhythmic-and-doac-dosing-in-obesity. Updated July 3, 2019. Accessed February 26, 2020. 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. American College of Cardiology. 2019 January 21; 140: e125-e151. 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. Journal of Thrombosis and Haemostasis. 2016 April;14:1308-13. Kido K., Ngorsuraches S. Comparing the Efficacy and Safety of Direct Oral Anticoagulants With Warfarin in the Morbidly Obese Population With Atrial Fibrillation. Annals of Pharmacotherapy. 2018 August 22;53:165-70. 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. Journal of Clinical Pharmacology. 2008 November;47:218-26. Barsam S.J., Patel J.P., Roberts L.N., et al. The impact of body weight on rivaroxaban pharmacokinetics. Research Practice in Thrombosis and Haemostasis. 2017 October 9;1:180-187 Sandhu R.K., 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. European Heart Journal. 2016 April 12;37:2869-2878. Boriani G., Ruff C.T., Kuder J.F., 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. European Heart Journal. 2019 May 14;40:1541-50. Wang T.F., Milligan P.E, Wong C.A, et al. Efficacy and safety of high-dose thromboprophylaxis in morbidly obese inpatients. Journal of Thrombosis and Haemostasis. 2014 January; 111(1): 88-93 Scholten D.J., Hoedema R.M., Scholten S.E. A comparison of two different prophylactic dose regimens of low molecular weight heparin bariatric surgery. Obesity Surgery. 2002; 12: 19-24 Borkgren-Okonek M.J., Hart R.W., Pantano J.E., et al. Enoxaparin thromboprophylaxis in gastric bypass patients: extended duration, dose stratification, and antifactory Xa activity. Surgery for Obesity and Related Diseases. 2008; 4(5): 625-631. Metz A., Diaz J., Obi., et al. Venous Thrombosis and Post-Thrombotic Syndrome: From Novel Biomarkers to Biology. Methodist Debakey Cardiovascular Journal. 2018 July-Sept; 14(3): 173-181.