Anticoagulant dosing in renal impairment

Summary

Anticoagulants are widely used for prophylaxis and treatment of venous thromboembolism in the elderly, who commonly have renal impairment and other comorbidities. Renal impairment is a risk factor for bleeding and thrombosis during anticoagulant therapy and can influence the balance between the safety and efficacy of such agents. Some anticoagulants, such as fondaparinux and the direct acting oral thrombin inhibitor dabigatran etexilate are contraindicated for use in patients with severe renal impairment (eGFR <30 ml/min). However, also the direct acting oral FXa-inhibitors rivaroxaban, edoxaban and apixaban need caution regarding dosing advice or contraindications when used in patients with renal impairment.

Zusammenfassung

Antikoagulanzien werden häufig bei älteren Patienten eingesetzt, die eine mehr oder minder stark eingeschränkte Nierenfunktion haben. Gleichzeitig ist die eingeschränkte Nierenfunktion ein Risikofaktor für das Auftreten von Blutungen unter Antikoagulanziengabe. Um so wichtiger ist das Wissen um die korrekte Dosierung, wie sie z.B. in der Fachinformation festgelegt ist. Einige primär über die Niere ausgeschiedene Antikoagulanzien wie z.B. Fondaparinux oder der orale, direkte Thrombinhemmer Dabigatran sind so bei Patienten mit schwerer Nierenfunktionseinschränkung (eGFR <30 ml/min) kontraindiziert, für die Therapie mit Enoxaparin werden Dosisanpassungen und anti-FXa-Kontrollen empfohlen. Aber auch für die oralen, direkten FXa-Hemmer (Rivaroxaban, Edoxaban und Apixaban) gibt es beachtenswürdige Dosisempfehlungen und Warnhinweise bei eingeschränkter Nierenfunktion.

Keywords

Anticoagulation - renal impairment - direct oral anticoagulants - DOAC

Schlüsselwörter

Antikoagulation - Nierenfunktionseinschränkung - Direkte Orale Antikoagulanzien - DOAK

• References

• 1 Stein PD. et al. Venous thromboembolism according to age: the impact of an aging population. Arch Intern Med 2004; 164: 2260-2265.
• 2 Jokhadar M, Wenger NK. Review of the treatment of acute coronary syndrome in elderly patients. Clin Interv Aging 2009; 4: 435-444.
• 3 Robert-Ebadi H, Le Gal G, Righini M. Use of anticoagulants in elderly patients: practical recommendations. Clin Invest Med 2009; 4: 165-177.
• 4 Zhang QL, Rothenbacher D. Prevalence of chronic kidney disease in population-based studies: systematic review. BMC Public Health 2008; 8: 117.
• 5 Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev 2009; 41: 67-76.
• 6 Verbeeck RK, Musuamba FT. Pharmacokinetics and dosage adjustment in patients with renal dysfunction. Eur J Clin Pharmacol 2009; 65: 757-773.
• 7 Grand’Maison A, Charest AF, Geerts WH. Anticoagulant use in patients with chronic renal impairment. Am J Cardiovasc Drugs 2005; 5: 291-305.
• 8 Wannamethee SG, Shaper AG, Lowe GD, Lennon L, Rumley A, Whincup PH. Renal function and cardiovascular mortality in elderly men: the role of inflammatory, procoagulant, and endothelial biomarkers. Eur Heart J 2006; 27: 2975-2981.
• 9 Committee for Medicinal Products for Human Use.. Note for guidance on the evaluation of the pharmacokinetics of medicinal products in patients with impaired renal function. London: EMEA; 2004. Available at: http://www.ema.europa.eu/pdfs/human/ewp/022502en.pdf Accessed October 6, 2015.
• 10 Limdi NA, Limdi MA, Cavallari L. et al. Warfarin dosing in patients with impaired kidney function. Am J Kidney Dis 2010; 56: 823-831.
• 11 Dahal K. et al. Stroke, Major Bleeding and Mortality Outcomes in Warfarin Users with Atrial Fibrillation and Chronic Kidney Disease: A Meta-analysis of Observational Studies. Chest. 2015 Sep 17 [epub ahead]
• 12 Hirsh J, Bauer KA, Donati MB. et al. Parenteral anticoagulants: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008; 133: 141S-159S.
• 13 Dager WE, Kiser TH. Systemic anticoagulation considerations in chronic kidney disease. Adv Chronic Kidney Dis 2010; 17: 420-427.
• 14 Becker RC, Spencer FA, Gibson M. et al. Influence of patient characteristics and renal function on factor Xa inhibition pharmacokinetics and pharmacodynamics after enoxaparin administration in non-ST-segment elevation acute coronary syndromes. Am Heart J 2002; 143: 753-759.
• 15 Sanderink GJ. et al. Pharmacokinetics and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment. Thromb Res 2002; 105: 225-231.
• 16 Lim W, Dentali F, Eikelboom JW, Crowther MA. Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med 2006; 144: 673-684.
• 17 Hoffmann P, Keller F. Increased major bleeding risk in patients with kidney dysfunction receiving enoxaparin: a meta-analysis. Eur J Clin Pharmacol 2012; 68: 757-765.
• 18 Lobo BL. Use of newer anticoagulants in patients with chronic kidney disease. Am J Health Syst Pharm 2007; 64: 2017-2026.
• 19 Fox KA, Bassand JP, Mehta SR. Influence of renal function on the efficacy and safety of fondaparinux relative to enoxaparin in non ST-segment elevation acute coronary syndromes. Ann Intern Med 2007; 147: 304-310.
• 20 Turpie AG. et al. Pharmacokinetic and clinical data supporting the use of fondaparinux 1.5 mg once daily in the prevention of venous thromboembolism in renally impaired patients. Blood Coagul Fibrinolysis 2009; 20: 114-121.
• 21 Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008; 36: 386-399.
• 22 Meyer dos Santos S, Harder S. Benefit-Risk Assessment of Dabigatran in the treatment of stroke prevention in non-valvular Atrial Fibrillation. Drug Saf 2014; 37: 295-307.
• 23 Fellows SE, Rosini JM. et al. Hemorrhagic gastritis with dabigatran in a patient with renal insufficiency. J Emerg Med 2013; 44: e221-e225.
• 24 Wychowski MK, Kouides PA. Dabigatran-induced gastrointestinal bleeding in an elderly patient with moderate renal impairment. Ann Pharmacother 2012; 46: e10.
• 25 Lee MJ. et al. The Need for a Coagulation Assay after Initiation of New Oral Anticoagulants in Patients with Renal Dysfunction: A Case Report. J Clin Neurol 2015; 11: 395-397.
• 26 Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D. Metabolism and excretion of rivaroxaban, an oral, direct Factor Xa inhibitor, in rats, dogs and humans. Drug Metab Dispos 2009; 37: 1056-1064.
• 27 Kubitza D, Becka M, Mueck W. et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban – an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol 2010; 70: 703-712.
• 28 Raghavan N. et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 2009; 37: 74-81.
• 29 Chang M, Yu Z, Shenker A. et al. Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban. J Clin Pharmacol. 2015 Sep 11. Epub ahead of print]
• 30 Ogata K, Mendell-Harary J, Tachibana M. et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel Factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 2010; 50: 743-753.
• 31 Jönsson S, Simonsson US, Miller R, Karlsson MO. Population pharmacokinetics of edoxaban and its main metabolite in a dedicated renal impairment study. J Clin Pharmacol 2015; 55: 1268-1279.
• 32 Long CL, Raebel MA, Price DW, Magid DJ. Compliance with dosing guidelines in patients with chronic kidney disease. Ann Pharmacother 2004; 38: 853-858.
• 33 Baum S, Harder S. Appropriate dosing in patients with impaired renal function on medical wards before and after an educational intervention. Int J Clin Pharmacol Ther 2010; 48: 29-35.
• 34 van Dijk EA. et al. Drug dosage adjustments according to renal function at hospital discharge. Ann Pharmacother 2006; 40: 1254-1260.
• 35 Nielsen PB. et al. Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on safety and efficacy outcomes in atrial fibrillation patients: a systemic review and meta-regression analysis. Clin Res Cardiol 2015; 104: 418-429.