Direct Oral Anticoagulant Use in Chronic Kidney Disease and Dialysis Patients With Venous Thromboembolism: A Systematic Review of Thrombosis and Bleeding Outcomes
Restricted accessResearch articleFirst published online June, 2021
Direct Oral Anticoagulant Use in Chronic Kidney Disease and Dialysis Patients With Venous Thromboembolism: A Systematic Review of Thrombosis and Bleeding Outcomes
To evaluate how treatment with DOACs for VTE affects thrombosis and bleeding outcomes compared to warfarin in CKD and dialysis patients.
Data Sources:
A literature search was conducted for studies evaluating VTE and bleeding outcomes with DOAC use in CKD and dialysis patients. Searches conducted through EMBASE, MEDLINE/PubMed, Scopus, and Cochrane Central Register of Controlled Trials, from inception to September 22, 2020.
Study Selection and Data Extraction:
Randomized controlled trials, cohort studies, and case series with ≥10 patients included.
Data Synthesis:
From 7286 studies, nine studies met inclusion criteria. There was no significant difference between DOACs (dabigatran, rivaroxaban, apixaban) and warfarin for reducing recurrent VTE and bleeding events in moderate CKD patients. The risk of overall major bleeding increased when the degree of kidney impairment increased. There was no significant difference between apixaban and warfarin for VTE outcomes in dialysis patients.
Relevance to Patient Care and Clinical Practice:
There continues to be a controversial debate whether it may be more beneficial to use DOACs versus warfarin in CKD/dialysis patients with venous thromboembolism (VTE). The risk vs benefit of using DOACs in the CKD/ESKD population should continue to be evaluated for each individual patient.
Conclusion:
Apixaban may be used cautiously as an alternative in acute VTE treatment in severe CKD patients. Insufficient evidence is available to suggest the use of dabigatran and rivaroxaban in this patient population. The benefit of using DOACs in this population for VTE treatment should be weighed against the potential bleeding risk in patients with CKD.
OcakGVerduijnMVossenCY, et al. Chronic kidney disease stages 1-3 increase the risk of venous thrombosis. J Thromb Haemost. 2010;8:2428-2435. doi:10.1111/j.1538-7836.2010.04048.x
2.
WattanakitKCushmanMStehman-BreenCHeckbertSRFolsomAR.Chronic kidney disease increases risk for venous thromboembolism. J Am Soc Nephrol. 2008;19:135-140. doi:10.1681/ASN.2007030308
3.
InkerLAAstorBCFoxCH, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis. 2014;63:713-735. doi:10.1053/j.ajkd.2014.01.416
4.
MahmoodiBK.Microalbuminuria and risk of venous thromboembolism. JAMA. 2009;301:1790-1797. doi:10.1001/jama.2009.565
5.
RibicCCrowtherM.Thrombosis and anticoagulation in the setting of renal or liver disease. Hematology Am Soc Hematol Educ Program. 2016;2016:188-195. doi:10.1182/asheducation-2016.1.188
6.
AmbühlPMWüthrichRPKorteWSchmidLKrapfR.Plasma hypercoagulability in haemodialysis patient: impact of dialysis and anticoagulation. Nephrol Dial Transplant. 1997;12:2355-2364. doi:10.1093/ndt/12.11.2355
7.
SoodMMKomendaPSoodARRigattoCBuetiJ.The intersection of risk and benefit: is warfarin anticoagulation suitable for atrial fibrillation in patients on hemodialysis?Chest. 2009;136:1128-1133. doi:10.1378/chest.09-0730
8.
DecoususHTapsonVFBergmannJF, et al. Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest. 2011;139:69-79. doi:10.1378/chest.09-3081
9.
Venous thromboembolism in renally impaired patients and direct oral anticoagulants (VERDICT). ClinicalTrials.gov identifier: NCT02664155. Updated August 20, 2020. Accessed October 6, 2020. https://clinicaltrials.gov/ct2/show/NCT02664155
10.
Safety and efficacy of apixaban in severe renal impairment. ClinicalTrials.gov identifier: NCT03399305. Updated July 9, 2019. Accessed October 6, 2020. https://clinicaltrials.gov/ct2/show/NCT03399305
11.
WangXTirucheraiGMarburyTC, et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol. 2016;56:628-636. doi:10.1002/jcph.628
12.
DiasCMooreKTMurphyJ, et al. Pharmacokinetics, pharmacodynamics, and safety of single-dose rivaroxaban in chronic hemodialysis. Am J Nephrol. 2016;43:229-236. doi:10.1159/000445328
13.
HigginsJPTAltmanDGGøtzschePC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. doi:10.1136/bmj.d5928
BauersachsRMLensingAWPrinsMH, et al. Rivaroxaban versus enoxaparin/vitamin K antagonist therapy in patients with venous thromboembolism and renal impairment. Thromb J. 2014;12:25. doi:10.1186/1477-9560-12-25
16.
GoldhaberSSchulmanSErikssonH, et al. Dabigatran versus warfarin for acute venous thromboembolism in elderly or impaired renal function patients: pooled analysis of RE-COVER and RE-COVER II. Thromb Haemost. 2017;117:2045-2052. doi:10.1160/TH17-03-0176
17.
GaertnerSCordeanuEMNouriS, et al. Rivaroxaban versus standard anticoagulation for symptomatic venous thromboembolism (REMOTEV observational study): analysis of 6-month outcomes. Int J Cardiol. 2017;226:103-109. doi:10.1016/j.ijcard.2016.10.045
18.
ReedDPalkimasSHockmanRAbrahamSLeTMaitlandH.Safety and effectiveness of apixaban compared to warfarin in dialysis patients. Res Pract Thromb Haemost. 2018;26:291-298. doi:10.1002/rth2.12083
19.
SarrattSCNesbitRMoyeR.Safety outcomes of apixaban compared with warfarin in patients with end-stage renal disease. Ann Pharmacother. 2017;51:445-450. doi:10.1177/1060028017694654
20.
SchaferJHCaseyALDupreKAStaubesBA.Safety and efficacy of apixaban versus warfarin in patients with advanced chronic kidney disease. Ann Pharmacother. 2018;52:1078-1084. doi:10.1177/1060028018781853
21.
StantonBEBaraschNSTellorKB.Comparison of the safety and effectiveness of apixaban versus warfarin in patients with severe renal impairment. Pharmacotherapy. 2017;37:412-419. doi:10.1002/phar.1905
22.
HanniCPetrovitchEAliM, et al. Outcomes associated with apixaban vs warfarin in patients with renal dysfunction. Blood Adv. 2020;4:2366-2371. doi:10.1182/bloodadvances.2019000972
23.
HerndonKGuidryTJWassellKElliottW.Characterizing the safety profile of apixaban versus warfarin in moderate to severe chronic kidney disease at a Veterans Affairs hospital. Ann Pharmacother. 2020;54:554-560. doi:10.1177/1060028019897053
24.
EINSTEIN Investigators; BauersachsRBerkowitzSD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510. doi:10.1056/NEJMoa1007903
25.
EINSTEIN–PE Investigators; BüllerHRPrinsMH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-1297. doi:10.1056/NEJMoa1113572
26.
SchulmanSKearonCKakkarAK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342-2352. doi:10.1056/NEJMoa0906598
27.
SchulmanSKakkarAKGoldhaberSZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129:764-772. doi:10.1161/CIRCULATIONAHA.113.004450
28.
SchulmanSKearonC; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692-694. doi:10.1111/j.1538-7836.2005.01204.x
29.
MehranRRaoSVBhattDL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123:2736-2747. doi:10.1161/CIRCULATIONAHA.110.009449
30.
GeldhofVVandenbrieleCVerhammePVanasscheT.Venous thromboembolism in the elderly: efficacy and safety of non-VKA oral anticoagulants. Thrombosis J. 2014;12:21. doi:10.1186/1477-9560-12-21
31.
WillettKCMorrillAM.Use of direct oral anticoagulants for the prevention and treatment of thromboembolic disease in patients with reduced renal function: a short review of the clinical evidence. Ther Clin Risk Manag. 2017;13:447-454. doi:10.2147/TCRM.S88911
32.
ParkerKThachilJ.The use of direct oral anticoagulants in chronic kidney disease. Br J Haematol. 2018;183:170-184. doi:10.1111/bjh.15564
33.
van EsNCoppensMSchulmanSMiddeldorpSBüllerHR.Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014;124:1968-1975. doi:10.1182/blood-2014-04-571232
34.
FeuringMSchulmanSErikssonH, et al. Net clinical benefit of dabigatran vs warfarin in venous thromboembolism: analyses from RE-COVER®, RE-COVER™ II, and RE-MEDY™. J Thromb Thrombolysis. 2017;43:484-489. doi:10.1007/s11239-017-1479-z
35.
KnaufFChaknosCMBernsJSPerazellaMA.Dabigatran and kidney disease: a bad combination. Clin J Am Soc Nephrol. 2013;8:1591-1597. doi:10.2215/CJN.01260213
36.
BowieMValenciaVPerez-AlvarezITranMH.Safety analysis of apixaban versus warfarin in patients with advanced kidney disease. J Thromb Thrombolysis. 2018;46:246-252. doi:10.1007/s11239-018-1683-5
37.
JunMLixLMDurandM, et al. Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study. BMJ. 2017;359:j4323. doi:10.1136/bmj.j4323
KooimanJvan der HulleTMaasH, et al. Pharmacokinetics and pharmacodynamics of dabigatran 75 mg b.i.d. in patients with severe chronic kidney disease. J Am Coll Cardiol. 2016;67:2442-2444. doi:10.1016/j.jacc.2016.03.516
De VrieseASCaluwéRBailleulE, et al. Dose-finding study of rivaroxaban in hemodialysis patients. Am J Kidney Dis. 2015;66:91-98. doi:10.1053/j.ajkd.2015.01.022
42.
FeldbergJPatelPFarrellA, et al. A systematic review of direct oral anticoagulant use in chronic kidney disease and dialysis patients with atrial fibrillation. Nephrol Dial Transplant. 2019;34:265-277. doi:10.1093/ndt/gfy031
43.
ByonWGaronzikSBoydRAFrostCE.Apixaban: a clinical pharmacokinetic and pharmacodynamic review. Clin Pharmacokinet. 2019;58:1265-1279. doi:10.1007/s40262-019-00775-z
44.
MavrakanasTASamerCFNessimSJFrischGLipmanML.Apixaban pharmacokinetics at steady state in hemodialysis patients. J Am Soc Nephrol. 2017;28:2241-2248. doi:10.1681/ASN.2016090980
45.
HuttenBAPrinsMHGentMGinsbergJTijssenJGBüllerHR.Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol. 2000;18:3078-3083. doi:10.1200/JCO.2000.18.17.3078
46.
KeyNSKhoranaAAKudererNM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2020;38:496-520. doi:10.1200/JCO.19.01461
47.
RaskobGEvan EsNVerhammeP, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378:615-624. doi:10.1056/NEJMoa1711948
48.
YoungAMMarshallAThirlwallJ, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018;36:2017-2023. doi:10.1200/JCO.2018.78.8034
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
