DOAC use in patients with chronic kidney disease

Summary

Direct oral anticoagulants (DOACs) are increasingly prescribed substances in patients with indication for effective anticoagulation. Patients with chronic kidney disease (CKD) have a high burden of cardiovascular risk and are more likely to develop atrial fibrillation (AF) than patients without CKD. Patients with mild to moderate CKD benefit from DOACs, especially when having intolerance to vitamin K-antagonists (VKA). DOACs may in some cases be considered in patients with rare renal disease and hypercoagulabilic state. DOACs are to a large extent eliminated by renal excretion. Since prospective randomised data in CKD patients are sparse, the decision for anticoagulative therapy is challenging especially in patients with severe renal impairment. The direct factor Xa-inhibitors are approved for use even in patients with an estimated glomerular filtration rate (eGFR) between 15 and 30 ml/min. Careful monitoring of renal function on a regular basis is essential before initiation and after start of DOAC, especially for patients at risk for acute renal failure (elderly, diabetics, patients with preexisting kidney disease). None of the DOACs is approved in CKD patients with end-stage-renal-disease (ESRD) with or without dialysis. DOACs are not recommended for kidney transplant patients under immunosuppression with calcineurin inhibitors. In these patients conventional therapy with VKA is the only option, which has to be monitored closely since it has potential adverse effects.

Nachdruck aus und zu zitieren als: Hämostaseologie 2017; 37: 286–294 https://doi.org/10.5482/HAMO-17-01-1657857

 

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Zusammenfassung

Die direkten oralen Antikoagulantien (DOAK) werden zunehmend häufiger bei Patienten mit einer Indikation für eine effektive Antikoagulation verordnet. Im Vergleich zu Patienten ohne chronische Nierenerkrankung (CKD) haben Patienten mit CKD ein höheres kardiovaskuläres Risiko und eine höhere Wahrscheinlichkeit, Vorhofflimmern zu entwickeln. Die Behandlung mit DOAK ist bei Patienten mit milder bis mäßiger CKD von Vorteil, insbesondere wenn eine Unverträglichkeit gegen Vitamin-K-Antagonisten (VKA) besteht. DOAK können in Einzelfällen auch bei Patienten mit seltenen Nierenerkrankungen und Hyperkoagulabilität eingesetzt werden. Die DOAK werden zu einem großen Teil renal eliminiert. Da prospektive, randomisierte Daten zu CKDPatienten rar sind, ist die Entscheidung für eine Antikoagulation schwierig, insbesondere bei Patienten mit deutlich eingeschränkter Nierenfunktion. Die direkten Faktor-Xa-Hemmer sind auch bei Patienten mit einer geschätzten glomerulären Filtrationsrate (GFR) von 15 bis 30 ml/min zugelassen. Es ist jedoch notwendig, die Nierenfunktion vor und nach Beginn der DOAK sorgfältig und regelmäßig zu evaluieren, besonders bei Patienten mit einem höheren Risiko für ein akutes Nierenversagen (Ältere, Diabetiker, Patienten mit bekannter Nierenerkrankung). Kein DOAK ist bei CKD-Patienten mit terminaler Nierenerkrankung, ob mit oder ohne Dialysetherapie, zugelassen. DOAK sind nicht empfohlen bei nierentransplantierten Patienten, die unter Immunsuppression mit Calcineurin-Hemmern stehen. Bei diesen Patienten ist die konventionelle Therapie mit VKA die einzige Möglichkeit und muss aufgrund potenziell unerwünschter Nebenwirkungen engmaschig kontrolliert werden.

 

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Keywords

Atrial fibrillation - dialysis - anticoagulation - calcineurin-inhibitors

Schlüsselwörter

Vorhofflimmern - Dialyse - Antikoagulation - Calcineurin-Hemmer

 

 

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Conflict of interest

The authors declare that there are no conflicts of interest.

• References

• 1 Kucukkoylu S, Rump LC. [Renal insufficiency and cardiovascular diseases]. Internist 2012; 53: 791-801.
• 2 Saran R, Li Y, Robinson B. et al. US Renal Data System 2015 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kid Dis 2016; 67: S1-305.
• 3 Levey AS, de Jong PE, Coresh J. et al. The definition, classification, and prognosis of chronic kid-ney disease: a KDIGO Controversies Conference report. Kidney Int 2011; 80: 17-28.
• 4 Alonso A, Lopez FL, Matsushita K. et al. Chronic kidney disease is associated with the incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 2011; 123: 2946-2953.
• 5 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22: 983-988.
• 6 Kirchhof P, Benussi S, Kotecha D. et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace 2016; 18: 1609-1678.
• 7 Friberg L, Benson L, Lip GY. Balancing stroke and bleeding risks in patients with atrial fibrillation and renal failure: the Swedish Atrial Fibrillation Cohort study. Eur Heart J 2015; 36: 297-306.
• 8 Vazquez E, Sanchez-Perales C, Garcia-Garcia F. et al. Atrial fibrillation in incident dialysis patients. Kidney Int 2009; 76: 324-330.
• 9 Winkelmayer WC, Patrick AR, Liu J. et al. The increasing prevalence of atrial fibrillation among hemodialysis patients. JASN 2011; 22: 349-357.
• 10 Piccini JP, Stevens SR, Chang Y. et al. Committee RAS and Investigators. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts. Circulation 2013; 127: 224-232.
• 11 Wizemann V, Tong L, Satayathum S. et al. Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int 2010; 77: 1098-1106.
• 12 Mearns ES, White CM, Kohn CG. et al. Quality of vitamin K antagonist control and outcomes in atrial fibrillation patients: a meta-analysis and meta-regression. Thromb J 2014; 12: 14.
• 13 Ansell J, Hollowell J, Pengo V. et al. Descriptive analysis of the process and quality of oral anticoagulation management in real-life practice in patients with chronic non-valvular atrial fibrillation: the international study of anticoagulation management (ISAM). J Thromb Thrombol 2007; 23: 83-91.
• 14 Jun M, James MT, Manns BJ. et al. The association between kidney function and major bleeding in older adults with atrial fibrillation starting warfarin treatment: population based observational study. BMJ 2015; 350: h246.
• 15 Yang F, Chou D, Schweitzer P. et al. Warfarin in haemodialysis patients with atrial fibrillation: what benefit?. Europace 2010; 12: 1666-1672.
• 16 Chen JJ, Lin LY, Yang YH. et al. Anti-platelet or anti-coagulant agent for the prevention of ischemic stroke in patients with end-stage renal disease and atrial fibrillation - a nation-wide database analyses. Int J Cardiol 2014; 177: 1008-1011.
• 17 Shah M, Avgil-Tsadok M, Jackevicius CA. et al. Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation 2014; 129: 1196-1203.
• 18 Chan KE, Giugliano RP, Patel MR. et al. Nonvitamin K Anticoagulant Agents in Patients With Advanced Chronic Kidney Disease or on Dialysis With AF. J Am Coll Cardiol 2016; 67: 2888-2899.
• 19 Herzog CA, Asinger RW, Berger AK. et al. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2011; 80: 572-586.
• 20 January CT, Wann LS, Alpert JS. et al. 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 Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64: e1-76.
• 21 Bonde AN, Lip GY, Kamper AL. et al. Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study. J Am Coll Cardiol 2014; 64: 2471-2482.
• 22 Anderson Jr FA, Wheeler HB, Goldberg RJ. et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Int Med 1991; 151: 933-938.
• 23 Wattanakit K, Cushman M. Chronic kidney disease and venous thromboembolism: epidemiology and mechanisms. Curr Op Pulm Med 2009; 15: 408-412.
• 24 Ocak G, Vossen CY, Lijfering WM. et al. Role of hemostatic factors on the risk of venous thrombosis in people with impaired kidney function. Circulation 2014; 129: 683-691.
• 25 Mahmoodi BK, Gansevoort RT, Naess IA. et al. Association of mild to moderate chronic kidney disease with venous thromboembolism: pooled analysis of five prospective general population cohorts. Circulation 2012; 126: 1964-1971.
• 26 Cook D, Crowther M, Meade M. et al. Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors. Crit Care Med 2005; 33: 1565-1571.
• 27 Lindner G, Funk GC, Pfortmueller CA. et al. D-dimer to rule out pulmonary embolism in renal insufficiency. Am J Med 2014; 127: 343-347.
• 28 Tsai J, Abe K, Boulet SL. et al. Predictive accuracy of 29-comorbidity index for in-hospital deaths in US adult hospitalizations with a diagnosis of venous thromboembolism. PloS one 2013; 08: e70061.
• 29 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.
• 30 Rankin AJ, McQuarrie EP, Fox JG. et al. Venous Thromboembolism in Primary Nephrotic Syndrome - Is the Risk High Enough to Justify Prophylactic Anticoagulation?. Nephron 2017; 135: 39-45.
• 31 Sarasin FP, Schifferli JA. Prophylactic oral anticoagulation in nephrotic patients with idiopathic membranous nephropathy. Kidney Int 1994; 45: 578-585.
• 32 Radhakrishnan J, Cattran DC. The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines - application to the individual patient. Kidney Int 2012; 82: 840-856.
• 33 Lee T, Derebail VK, Kshirsagar AV. et al. Patients with primary membranous nephropathy are at high risk of cardiovascular events. Kidney Int 2016; 89: 1111-1118.
• 34 Negrini S, Pappalardo F, Murdaca G. et al. The antiphospholipid syndrome: from pathophysiology to treatment. Clin Exp Med. 2016 [Epub]..
• 35 Crowl A, Schullo-Feulner A, Moon JY. Warfarin monitoring in antiphospholipid syndrome and lupus anticoagulant. Ann Pharmacother 2014; 48: 1479-1483.
• 36 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41.
• 37 Levey AS, Stevens LA, Schmid CH. et al. A new equation to estimate glomerular filtration rate. Ann Int Med 2009; 150: 604-612.
• 38 Levey AS, Bosch JP, Lewis JB. et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Int Med 1999; 130: 461-470.
• 39 Fernandez-Prado R, Castillo-Rodriguez E, Velez-Arribas FJ. et al. Creatinine Clearance Is Not Equal to Glomerular Filtration Rate and Cockcroft-Gault Equation Is Not Equal to CKD-EPI Collaboration Equation. Am J Med 2016; 129: 1259-1263.
• 40 Schlieper G, Schwenger V, Remppis A. et al. [Anticoagulation in patients with chronic kidney disease : Recommendations from the working group “Heart-Kidney” of the German Cardiac Society and the German Society of Nephrology]. Internist 2017; 58: 512-521.
• 41 Maegdefessel L, Spin JM, Azuma J. et al. New options with dabigatran etexilate in anticoagulant therapy. Vascular health and risk management 2010; 06: 339-349.
• 42 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
• 43 Hijazi Z, Hohnloser SH, Oldgren J. et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation 2014; 129: 961-970.
• 44 Hariharan S, Madabushi R. Clinical pharmacology basis of deriving dosing recommendations for dabigatran in patients with severe renal impairment. J Clin Pharmacol 2012; 52: 119S-125S.
• 45 Lehr T, Haertter S, Liesenfeld KH. et al. Dabigatran etexilate in atrial fibrillation patients with severe renal impairment: dose identification using pharmacokinetic modeling and simulation. J Clin Pharmacol 2012; 52: 1373-1378.
• 46 Patel MR, Mahaffey KW, Garg J. et al. and Investigators RA. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.
• 47 Camm AJ, Lip GY, De Caterina R. et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012; 33: 2719-2747.
• 48 Fordyce CB, Hellkamp AS, Lokhnygina Y. et al. On-Treatment Outcomes in Patients With Worsening Renal Function With Rivaroxaban Compared With Warfarin: Insights From ROCKET AF. Circulation 2016; 134: 37-47.
• 49 Granger CB, Alexander JH, McMurray JJ. et al. Committees A and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
• 50 Goto S, Zhu J, Liu L. et al. Efficacy and safety of apixaban compared with warfarin for stroke prevention in patients with atrial fibrillation from East Asia: a subanalysis of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Am Heart J 2014; 168: 303-309.
• 51 Hohnloser SH, Hijazi Z, Thomas L. et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J 2012; 33: 2821-2830.
• 52 Pathak R, Pandit A, Karmacharya P. et al. Metaanalysis on risk of bleeding with apixaban in patients with renal impairment. Am J Cardiol 2015; 115: 323-327.
• 53 Giugliano RP, Ruff CT, Braunwald E. et al. and Investigators EA-T. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369: 2093-2104.
• 54 Bohula EA, Giugliano RP, Ruff CT. et al. Impact of Renal Function on Outcomes With Edoxaban in the ENGAGE AF-TIMI 48 Trial. Circulation 2016; 134: 24-36.
• 55 Heidbuchel H, Verhamme P, Alings M. et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015; 17: 1467-1507.
• 56 Chan KE, Edelman ER, Wenger JB. et al. Dabigatran and rivaroxaban use in atrial fibrillation patients on hemodialysis. Circulation 2015; 131: 972-979.
• 57 Khadzhynov D, Wagner F, Formella S. et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with endstage renal disease. Thromb Haemost 2013; 109: 596-605.
• 58 Wang X, Tirucherai G, Marbury TC. et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol 2016; 56: 628-636.
• 59 Kufel WD, Zayac AS, Lehmann DF. et al. Clinical Application and Pharmacodynamic Monitoring of Apixaban in a Patient with End-Stage Renal Disease Requiring Chronic Hemodialysis. Pharmacotherapy 2016; 36: e166-e171.
• 60 Cohen AT, Harrington RA, Goldhaber SZ. et al. and Investigators A. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med 2016; 375: 534-544.
• 61 Wannhoff A, Weiss KH, Schemmer P. et al. Increased levels of rivaroxaban in patients after liver transplantation treated with cyclosporine A. Transplantation 2014; 98: e12-13.
• 62 Vanhove T, Spriet I, Annaert P. et al. Effect of the direct oral anticoagulants rivaroxaban and apixaban on the disposition of calcineurin inhibitors in transplant recipients. Ther Drug Monit 2017; 39: 77-82.
• 63 Parasrampuria DA, Mendell J, Shi M. et al. Edoxaban drug-drug interactions with ketoconazole, erythromycin, and cyclosporine. Brit J Pharmacol 2016; 82: 1591-1600.
• 64 Dale BJ, Chan NC, Eikelboom JW. Laboratory measurement of the direct oral anticoagulants. Br J Haematol 2016; 172: 315-336.
• 65 Samuelson BT, Cuker A, Siegal DM. et al. Laboratory Assessment of the Anticoagulant Activity of Direct Oral Anticoagulants: A Systematic Review. Chest 2017; 151: 127-138.
• 66 AWMF-Leitlinie. 2015 http://www.awmf.org/ uploads/tx_szleitlinien/065-002l_S2k_VTE_2016-01.pdf.