Advertisement
Heart, Lung and Circulation

Oral Anticoagulant Use in Patients With Atrial Fibrillation and Chronic Kidney Disease: A Review of the Evidence With Recommendations for Australian Clinical Practice

Open AccessPublished:November 03, 2022DOI:https://doi.org/10.1016/j.hlc.2022.09.003
      Chronic kidney disease is common in patients with atrial fibrillation (AF) and is associated with heightened risks of stroke/systemic embolisation and bleeding. In this review we outline the evidence for AF stroke prevention in kidney disease, identify current knowledge gaps, and give recommendations for anticoagulation at various stages of chronic kidney disease.
      Overall, anticoagulation is underused. Warfarin use becomes increasingly difficult with advancing kidney disease, with difficulty maintaining international normalised ratio (INR) in therapeutic range, increased risk of intracranial and fatal bleeding compared to non-vitamin K oral anticoagulants (NOACs), and high rates of discontinuation. Similarly, the direct thrombin inhibitor dabigatran is not recommended as it is predominantly renally excreted with consequent increased plasma levels and bleeding risk with advanced kidney disease. The Factor Xa inhibitors apixaban and rivaroxaban have less renal excretion (25–35%), modest increases in plasma levels with advancing kidney disease, and are the preferred first line choice for anticoagulation in moderate kidney disease based on strong evidence from randomised clinical trials (RCTs). In severe kidney disease there is a paucity of RCT data, but extrapolation of the pharmacokinetic and RCT data for moderate kidney disease, and observational studies, support the considered use of dose-adjusted Factor Xa inhibitors unless the bleeding risk is prohibitive. In Australia, apixaban is approved for creatinine clearance down to 25 mL/min, and rivaroxaban down to 15 mL/min. For end-stage kidney disease warfarin is the only agent approved, but we recommend against anticoagulation (except in selected cases) due to high bleeding risk, multiple co-morbidities, and questionable benefit.

      Keywords

      Overview of Atrial Fibrillation and Anticoagulation

      Atrial fibrillation (AF) is one of the most common arrythmias faced in clinical practice, and its incidence increases linearly with worsening kidney function and albuminuria [
      • Alonso A.
      • Lopez F.L.
      • Matsushita K.
      • Loehr L.R.
      • Agarwal S.K.
      • Chen L.Y.
      • et al.
      Chronic kidney disease is associated with the incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study.
      ]. The most feared complication of AF is ischaemic stroke, caused by thromboembolism of clot from the left atrium to the brain. Many of the factors that drive stroke risk (such as congestive heart failure, hypertension, diabetes, vascular disease and increasing age) are highly prevalent in patients with chronic kidney disease (CKD). It is therefore not surprising that patients with CKD and AF are at increased risk of thromboembolic stroke and should be strongly considered for anticoagulant therapy [
      • Bonde A.N.
      • Lip G.Y.
      • Kamper A.-L.
      • Fosbøl E.L.
      • Staerk L.
      • Carlson N.
      • et al.
      Renal function and the risk of stroke and bleeding in patients with atrial fibrillation: an observational cohort study.
      ].
      Chronic kidney disease is defined as the presence of abnormal kidney function or structure for more than 3 months. It is classified according to the categories of estimated glomerular filtration rate (eGFR), which ranges from CKD stage 1 (normal eGFR ≥90 mL/min/1.73 m2, but the presence of albuminuria, haematuria, a pathological abnormality or a structural abnormality) to CKD stage 5 (end stage kidney disease, eGFR <15 mL/min/1.73 m2 and/or patient on dialysis) (Table 1) [
      Summary of Recommendation Statements
      ]. Cardiovascular morbidity and mortality increase progressively as kidney function declines. As a result, patients with CKD are 20 times more likely to die from cardiovascular events than survive to reach dialysis [
      • Keith D.S.
      • Nichols G.A.
      • Gullion C.M.
      • Brown J.B.
      • Smith D.H.
      Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization.
      ]. Some of this excess risk comes from atrial fibrillation, which is highly prevalent in CKD [
      • Soliman E.Z.
      • Prineas R.J.
      • Go A.S.
      • Xie D.
      • Lash J.P.
      • Rahman M.
      • et al.
      Chronic kidney disease and prevalent atrial fibrillation: the Chronic Renal Insufficiency Cohort (CRIC).
      ]. Patients with CKD and AF have particularly high rates of mortality and disability, particularly from ischaemic stroke and systemic thromboembolism. This risk can be significantly reduced with the use of anticoagulation, but the use of such therapies needs to be balanced against the concomitant increased bleeding risk in patients with CKD [
      • Olesen J.B.
      • Lip G.Y.
      • Kamper A.L.
      • Hommel K.
      • Køber L.
      • Lane D.A.
      • et al.
      Stroke and bleeding in atrial fibrillation with chronic kidney disease.
      ].
      Table 1Stages of chronic kidney disease (Kidney Health Australia).
      Stage 1normal eGFR ≥90 mL/min/1.73m2, with albuminuria, haematuria, a pathological abnormality or structural abnormality
      Stage 2 (mild)eGFR 60 to 89 mL/min/1.73m2, with albuminuria, haematuria, a pathological abnormality or structural abnormality
      Stage 3a (moderate)eGFR 45 to 59 mL/min/1.73m2
      Stage 3b (moderate)eGFR 30 to 44 mL/min/1.73m2
      Stage 4 (severe)eGFR 15 to 29 mL/min/1.73m2
      Stage 5 (ESKD)eGFR <15 mL/min/1.73m2, end stage kidney disease
      At first glance, warfarin may seem a good anticoagulant choice for patients with chronic kidney disease. Warfarin is not renally excreted, and is dose adjusted to achieve an INR of 2.0 to 3.0; this target INR applies to patients across all levels of kidney function (Table 2). In a meta-analysis of randomised controlled trials, warfarin has been shown to reduce stroke risk in AF by ∼60% versus either placebo or aspirin [
      • Hart R.G.
      • Pearce L.A.
      • Aguilar M.I.
      Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.
      ]. However, the biggest drawback of warfarin is bleeding risk, with up to 30% increase in major bleeding and 30–70% increase in intracranial haemorrhage compared to non-vitamin K oral anticoagulants (NOACs) in randomised trials [
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • Eikelboom J.
      • Oldgren J.
      • Parekh A.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      ,
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • Pan G.
      • Singer D.E.
      • Hacke W.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      ,
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • Lopes R.D.
      • Hylek E.M.
      • Hanna M.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      ]. This is of particular importance in kidney disease, where there is an increased baseline risk of bleeding [
      • Bonde A.N.
      • Lip G.Y.
      • Kamper A.-L.
      • Fosbøl E.L.
      • Staerk L.
      • Carlson N.
      • et al.
      Renal function and the risk of stroke and bleeding in patients with atrial fibrillation: an observational cohort study.
      ], and often both patients and physicians preferring no anticoagulation to warfarin, when that is the only available option [
      • Capodanno D.
      • Angiolillo D.J.
      Antithrombotic therapy in patients with chronic kidney disease.
      ]. Some of these patients are prescribed antiplatelet therapy as an alternative. However, neither aspirin monotherapy nor dual antiplatelet therapy are adequate substitutes for warfarin or other oral anticoagulant therapy; they are significantly less effective than warfarin for stroke prevention, with similar overall bleeding risk [
      • Själander S.
      • Själander A.
      • Svensson P.J.
      • Friberg L.
      Atrial fibrillation patients do not benefit from acetylsalicylic acid.
      ,
      • Connolly S.
      • Pogue J.
      • Hart R.
      • Pfeffer M.
      • Hohnloser S.
      • Chrolavicius S.
      • et al.
      Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial.
      ]. Antiplatelet agents should not be used for stroke prevention in AF [
      • Hindricks G.
      • Potpara T.
      • Dagres N.
      • Arbelo E.
      • Bax J.J.
      • Blomström-Lundqvist C.
      • et al.
      2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS) The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC.
      ,
      • Brieger D.
      • Amerena J.
      • Attia J.
      • Bajorek B.
      • Chan K.H.
      • et al.
      NHFA CSANZ Atrial Fibrillation Guideline Working Group
      National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand: Australian Clinical Guidelines for the Diagnosis and Management of Atrial Fibrillation 2018.
      ].
      Table 2Mechanism of action and pharmacokinetics of warfarin and the NOACs.
      AnticoagulantMechanism of ActionHalf-LifeKidney ClearanceStandard AF DoseReduced DoseRecommended Dosing Relative to Food
      Warfarin [
      Mylan Health Pty Ltd. Australian Product Information - Coumadin (warfarin sodium) 2020. Available from.
      ]
      Vitamin K antagonist (Factors II, VII, IX and X)40 hr0Blood monitoring; Dose adjustment to INR 2 to 3-Take with or without food (multiple foods can affect INR levels; consistent diet recommended)
      Dabigatran [
      Boehringer Ingelheim Pty Limited. Australian Product Information - PRADAXA (dabigatran etexilate) capsule 2020. Available from.
      ]
      Factor II (thrombin) inhibitor≥50 mL/min ∼14 hr

      >30–≤50 mL/min ∼18 hr

      ≤30 mL/min ∼28 hr
      85%150 mg BD110 mg BD (moderate renal impairment; age ≥75 years; other factors with increased bleeding risk)Take with or without food (with food preferred to reduce dyspepsia)
      Apixaban [
      Pfizer Australia Pty Limited. Australian PI - Eliquis (apixaban) 2020. Available from.
      ]
      Factor Xa inhibitor12 hr27%5 mg BD2.5 mg BD
      If ≥2 of the following features: age ≥80 years, weight ≤60 kg, serum creatinine ≥133 μmol/L.
      Take with or without food
      Rivaroxaban [
      Bayer Australia Pty Ltd. Australian Product Information Xarelto - Rivaroxaban 2.5mg 10mg, 15mg and 20mg 2020. Available from.
      ]
      Factor Xa inhibitor5-9 hr (young);

      11-13 hr (elderly)
      35%20 mg OD

      For CrCl

      ≥50 mL/min
      15 mg OD

      For CrCl

      15-49 mL/min
      Take with food (leads to near complete absorption)
      Abbreviations: INR, international normalised ratio; BD, twice daily; OD, once daily.
      If ≥2 of the following features: age ≥80 years, weight ≤60 kg, serum creatinine ≥133 μmol/L.
      NOACs are now firmly established as the preferred therapy for stroke prevention in AF [
      • Hindricks G.
      • Potpara T.
      • Dagres N.
      • Arbelo E.
      • Bax J.J.
      • Blomström-Lundqvist C.
      • et al.
      2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS) The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC.
      ,
      • Brieger D.
      • Amerena J.
      • Attia J.
      • Bajorek B.
      • Chan K.H.
      • et al.
      NHFA CSANZ Atrial Fibrillation Guideline Working Group
      National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand: Australian Clinical Guidelines for the Diagnosis and Management of Atrial Fibrillation 2018.
      ]. Three (3) NOACs are available in Australia; the direct thrombin inhibitor dabigatran, and the factor Xa inhibitors apixaban and rivaroxaban.
      The efficacy of dabigatran was established in the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial, involving 18,113 patients with AF at risk of stroke. Two (2) different doses of dabigatran (150 mg twice daily and 110 mg twice daily) were studied against warfarin in a 1:1:1 randomisation [
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • Eikelboom J.
      • Oldgren J.
      • Parekh A.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      ]. The 150 mg dose had better efficacy than warfarin, with similar rates of major bleeding (35% greater reduction in stroke or systemic embolism with dabigatran vs warfarin). The 110 mg dose had similar efficacy to warfarin, but significantly lower bleeding (20% lower risk of major bleeding and 70% lower risk of intracranial bleeding). Dabigatran is the only NOAC with a direct reversal agent available in the Australian market, but against this advantage is the fact it is predominantly renally excreted (80% renal elimination), resulting in two-to-three-fold higher plasma levels in patients with moderate renal impairment compared to those with normal renal function (Figure 1) [
      Boehringer Ingelheim Pty Limited. Australian Product Information - PRADAXA (dabigatran etexilate) capsule 2020. Available from.
      ].
      Figure thumbnail gr1
      Figure 1Effect of kidney function on drug exposure (AUC) for dabigatran and Factor Xa inhibitors [
      Boehringer Ingelheim Pty Limited. Australian Product Information - PRADAXA (dabigatran etexilate) capsule 2020. Available from.
      ,
      Bayer Australia Pty Ltd. Australian Product Information Xarelto - Rivaroxaban 2.5mg 10mg, 15mg and 20mg 2020. Available from.
      ,
      Pfizer Australia Pty Limited. Australian PI - Eliquis (apixaban) 2020. Available from.
      ]
      Refer to PI before prescribing. No cross-study comparison intended.
      Abbreviations: PI, prescriber information; AUC, area under curve.
      Apixaban was studied in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, in which 18,201 AF patients were randomised to apixaban or warfarin [
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • Lopes R.D.
      • Hylek E.M.
      • Hanna M.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      ]. The primary dose of apixaban was 5 mg twice daily, with a half dose of 2.5 mg twice daily given to patients with ≥2 of the following three criteria: age ≥80 years, weight ≤60 kg, serum creatinine ≥133 μmol/l. Only 428 of the 9,120 patients randomised to apixaban fulfilled these criteria and received the 2.5 mg dose. The primary endpoint (stroke or systemic embolism) was significantly lower with apixaban than warfarin (RRR 21%, p=0.01 for superiority), although this was driven largely by a reduction in haemorrhagic stroke on apixaban. Rates of ischaemic stroke and systemic embolism were similar for both drugs. Other types of bleeding were also significantly lower on apixaban and overall, there was a 31% relative risk reduction (RRR) in International Committee on Thrombosis and Haemostasis major bleeding compared to warfarin. Although only a relatively small number qualified for the 2.5 mg twice daily dose, the results in those patients who did qualify for dose reduction were consistent with the overall trial result.
      The ROCKET AF trial, comparing rivaroxaban to warfarin, studied a higher risk group than either RE-LY or ARISTOTLE. To qualify for the trial, patients with AF required either a prior history of stroke or systemic embolism, or at least two of the following risk factors for stroke: ejection fraction ≤35%, hypertension, diabetes mellitus, age ≥75 years [
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • Pan G.
      • Singer D.E.
      • Hacke W.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      ]. Consequently, these patients were at greater risk of stroke (and bleeding), with a mean CHADS2 score of 3.5, compared to baseline CHADS2 score of 2.1 in both RE-LY and ARISTOTLE. 14,264 patients were randomised to rivaroxaban or warfarin, with the rivaroxaban dose determined by renal function. The standard dose was 20 mg once daily, with dose reduction to 15 mg once daily for patients with moderate renal impairment (CKD 3, CrCl 30–49 ml per min). In this high-risk population, rivaroxaban had similar efficacy (prevention of stroke or systemic embolism) and overall bleeding rates as warfarin, but with significantly lower rates of critical bleeding, fatal bleeding, and intracranial haemorrhage [
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • Pan G.
      • Singer D.E.
      • Hacke W.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      ].
      Given the impressive efficacy and safety profile demonstrated in these landmark trials, NOACs are recommended as the preferred anticoagulant choice for stroke prevention in AF in Australian and worldwide guidelines [
      • Hindricks G.
      • Potpara T.
      • Dagres N.
      • Arbelo E.
      • Bax J.J.
      • Blomström-Lundqvist C.
      • et al.
      2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS) The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC.
      ,
      • Brieger D.
      • Amerena J.
      • Attia J.
      • Bajorek B.
      • Chan K.H.
      • et al.
      NHFA CSANZ Atrial Fibrillation Guideline Working Group
      National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand: Australian Clinical Guidelines for the Diagnosis and Management of Atrial Fibrillation 2018.
      ]. The decision to anticoagulate is predominantly based on the assessment of stroke risk, with anticoagulation considered for patients with CHA2DS2-VA of 1 and recommended for a CHA2DS2-VA of 2 or more, unless the bleeding risk is felt to be too high [
      • Brieger D.
      • Amerena J.
      • Attia J.
      • Bajorek B.
      • Chan K.H.
      • et al.
      NHFA CSANZ Atrial Fibrillation Guideline Working Group
      National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand: Australian Clinical Guidelines for the Diagnosis and Management of Atrial Fibrillation 2018.
      ]. Because many features prevalent in patients with AF (such as increased age, hypertension, and kidney disease) contribute to both stroke risk and bleeding risk, this decision is not always straightforward, but even in high-risk subgroups, the net clinical benefit is generally in favour of anticoagulation. Bleeding risk assessment scores such as the HAS-BLED
      Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile INR, Elderly, Drugs or alcohol.
      score provide opportunities to reduce bleeding risk through identification and adjustment of modifiable risk factors such as concomitant medication, hypertension, and alcohol intake. Bleeding risk scores should generally not be used as a reason to avoid treatment with oral anticoagulants [
      • Hindricks G.
      • Potpara T.
      • Dagres N.
      • Arbelo E.
      • Bax J.J.
      • Blomström-Lundqvist C.
      • et al.
      2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS) The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC.
      ].

      Patients With Moderate Kidney Disease (CrCl 30–49 mL/min)

      Patients with moderate kidney disease are at increased risk of both stroke/systemic embolism and bleeding compared to those with normal kidney function [
      • Bonde A.N.
      • Lip G.Y.
      • Kamper A.-L.
      • Fosbøl E.L.
      • Staerk L.
      • Carlson N.
      • et al.
      Renal function and the risk of stroke and bleeding in patients with atrial fibrillation: an observational cohort study.
      ]. Warfarin is of proven benefit in moderate kidney disease but has specific limitations including increased difficulty keeping patients in therapeutic range (partly driven by co-morbidities and interaction with concomitant medications), and higher risk of intracranial haemorrhage and fatal bleeding [
      • Yang F.
      • Hellyer J.A.
      • Than C.
      • Ullal A.J.
      • Kaiser D.W.
      • Heidenreich P.A.
      • et al.
      Warfarin utilisation and anticoagulation control in patients with atrial fibrillation and chronic kidney disease.
      ].
      Each of the landmark trials of NOAC versus warfarin [
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • Eikelboom J.
      • Oldgren J.
      • Parekh A.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      ,
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • Pan G.
      • Singer D.E.
      • Hacke W.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      ,
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • Lopes R.D.
      • Hylek E.M.
      • Hanna M.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      ] included a substantial proportion of patients with moderate kidney disease, and therefore there is a large body of evidence to support NOAC use in this patient population. A meta-analysis of these trials showed a reduction in both stroke/systemic embolism and bleeding risk with NOACs compared to warfarin [
      • Ha J.T.
      • Neuen B.L.
      • Cheng L.P.
      • Jun M.
      • Toyama T.
      • Gallagher M.P.
      • et al.
      Benefits and harms of oral anticoagulant therapy in chronic kidney disease: a systematic review and meta-analysis.
      ]. NOACs are safer and more effective than warfarin in this high-risk group and are recommended as the preferred choice in Australian and international guidelines. There are, however, important differences between individual NOACs.
      Dabigatran is predominantly renally excreted and therefore drug levels and anticoagulant effect are heavily influenced by kidney function (with at least three-fold increase for CrCl 30–49 mL/min compared to normal kidney function) (Figure 1) [
      • Knauf F.
      • Chaknos C.M.
      • Berns J.S.
      • Perazella M.A.
      Dabigatran and kidney disease: a bad combination.
      ]. Consequently, guidelines suggest caution with dabigatran in kidney disease and recommend the Factor Xa inhibitors (apixaban or rivaroxaban) as the preferred options [
      • Steffel J.
      • Verhamme P.
      • Potpara T.S.
      • Albaladejo P.
      • Antz M.
      • Desteghe L.
      • et al.
      The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
      ]. Apixaban and rivaroxaban are predominantly metabolised by the liver and have relatively low renal excretion (25–35%) and only a small increase in drug levels across worsening levels of kidney function (Figure 1) [
      • Chang M.
      • Yu Z.
      • Shenker A.
      • Wang J.
      • Pursley J.
      • Byon W.
      • et al.
      Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban.
      ,
      • Dias C.
      • Moore K.T.
      • Murphy J.
      • Ariyawansa J.
      • Smith W.
      • Mills R.M.
      • et al.
      Pharmacokinetics, pharmacodynamics, and safety of single-dose rivaroxaban in chronic hemodialysis.
      ].
      Apixaban has been shown to have superior efficacy and safety over warfarin for patients with moderate kidney disease [
      • Hohnloser S.H.
      • Hijazi Z.
      • Thomas L.
      • Alexander J.H.
      • Amerena J.
      • Hanna M.
      • et al.
      Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial.
      ]. The ARISTOTLE trial included nearly 3,000 patients with eGFR ≤50 mL/min/1.73m2. Apixaban remained more effective than warfarin in reducing stroke or systemic embolism in these patients and caused less major bleeding [
      • Hohnloser S.H.
      • Hijazi Z.
      • Thomas L.
      • Alexander J.H.
      • Amerena J.
      • Hanna M.
      • et al.
      Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial.
      ]. In fact, the relative reduction in major bleeding was greater and the absolute benefits of apixaban more pronounced in patients with CKD, due to the higher baseline risks. This was also true of patients with rapidly deteriorating renal function (a patient group in which the variable dosing of warfarin could be a theoretical advantage). In ARISTOTLE, patients with an annual decrease in GFR of 20% or more were significantly better off on apixaban than on warfarin [
      • Hijazi Z.
      • Hohnloser S.H.
      • Andersson U.
      • Alexander J.H.
      • Hanna M.
      • Keltai M.
      • et al.
      Efficacy and Safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
      ]. However, it is important to ensure patients are on the correct dose. Nearly all these patients were treated with 5 mg twice daily apixaban, and only one in 10 (149 patients) met the dose reduction criteria to receive 2.5 mg twice daily dose. Subsequent registry studies suggest there may be inadequate protection if the 2.5 mg dose is used without appropriate criteria for dose adjustment [
      • Yao X.
      • Shah N.D.
      • Sangaralingham L.R.
      • Gersh B.J.
      • Noseworthy P.A.
      Non-vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction.
      ]. Dose reduction should only occur according to the product label; that is, when two or more of the following three criteria are present: age ≥80 years, weight ≤60 kg, serum creatinine ≥133 μmol/L.
      Rivaroxaban has the advantage of a specific dose adjustment for patients with kidney disease, with a standard 20 mg once daily dose for those with normal or mildly decreased kidney function (CrCl ≥50 mL/min), and a 15 mg once daily dose for patients with CrCl 15–49 mL/min. Pharmacokinetic data shows that this 25% reduction in dose (from 20 mg daily to 15 mg daily) adequately adjusts for the modest increase in drug levels that would otherwise be seen in kidney disease [
      • Mueck W.
      • Lensing A.W.
      • Agnelli G.
      • Decousus H.
      • Prandoni P.
      • Misselwitz F.
      Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention.
      ]. Of all the NOAC trials, ROCKET AF included the largest proportion of patients with moderate kidney disease (2,950; 21% of trial population) [
      • Fox K.A.
      • Piccini J.P.
      • Wojdyla D.
      • Becker R.C.
      • Halperin J.L.
      • Nessel C.C.
      • et al.
      Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment.
      ]. Nearly 1,500 AF patients with CrCl 30–50 mL/min received 15 mg rivaroxaban once daily. These patients, who by way of trial design and inclusion criteria were at high stroke risk (mean CHADS2 score 3.7), had similar stroke protection on 15 mg rivaroxaban compared to dose adjusted warfarin (HR 0.84; CI 0.57–1.23) [
      • Fox K.A.
      • Piccini J.P.
      • Wojdyla D.
      • Becker R.C.
      • Halperin J.L.
      • Nessel C.C.
      • et al.
      Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment.
      ]. Major bleeding rates were also similar, with a trend towards more gastrointestinal bleeding offset by a reduction in fatal bleeding with rivaroxaban. In those with worsening kidney function (>20% decrease in CrCl during study), rivaroxaban maintained at least as good an efficacy and safety profile as warfarin [
      • Fordyce C.B.
      • Hellkamp A.S.
      • Lokhnygina Y.
      • Lindner S.M.
      • Piccini J.P.
      • Becker R.C.
      • et al.
      On-treatment outcomes in patients with worsening renal function with rivaroxaban compared with warfarin.
      ].

      Severe Kidney Disease (CrCl 15–29 mL/min)

      Until recently, only warfarin was available in Australia for patients with severe kidney disease. This led to difficult treatment decisions, especially for patients with moderate kidney disease (CKD stage 3) on NOAC therapy whose kidney function declined into severe kidney disease (CKD stage 4). There is general reluctance of both patients and physicians to transition over to warfarin, and aspirin is ineffective, hence patients with severe kidney disease all too often receive no anticoagulation (despite having a higher risk of stroke than patients with more modest degrees of kidney disease) [
      • Capodanno D.
      • Angiolillo D.J.
      Antithrombotic therapy in patients with chronic kidney disease.
      ]. Because of the exclusion criteria of the original NOAC trials, there is very little randomised data on NOAC use in severe kidney disease. However, extrapolation of trial data from patients with moderate kidney disease, pharmacokinetic data, and analyses of retrospective non-randomised datasets all support the considered use of apixaban and rivaroxaban.
      Dabigatran is 80% renally excreted, and patients with CrCl <30 mL/min have six-fold higher plasma levels than those with normal kidney function (Figure 1) [
      • Stangier J.
      • Rathgen K.
      • Stähle H.
      • Mazur D.
      Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study.
      ]. Dabigatran is contraindicated in patients with CrCl <30 mL/min in Australia [
      Boehringer Ingelheim Pty Limited. Australian Product Information - PRADAXA (dabigatran etexilate) capsule 2020. Available from.
      ].
      In contrast, apixaban and rivaroxaban are predominantly metabolised by the liver and levels are only modestly affected by kidney disease. Apixaban is licenced for use down to a CrCl of 25 mL/min, based on the inclusion criteria of the ARISTOTLE trial. Only 270 patients with CrCl between 25 and 29 mL/min were enrolled, but a recently published sub-analysis of these patients shows significantly less bleeding with apixaban compared to warfarin [
      • Stanifer J.W.
      • Pokorney S.D.
      • Chertow G.M.
      • Hohnloser S.H.
      • Wojdyla D.M.
      • Garonzik S.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation and advanced chronic kidney disease.
      ].
      There are no randomised controlled trials of rivaroxaban in AF patients with severe kidney disease. The ROCKET AF trial did show favourable results for rivaroxaban compared to warfarin in patients with CrCl 30–49 mL/min [
      • Fox K.A.
      • Piccini J.P.
      • Wojdyla D.
      • Becker R.C.
      • Halperin J.L.
      • Nessel C.C.
      • et al.
      Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment.
      ], and a non-randomised propensity matched study of AF patients with CrCl <30 mL/min (81% with CrCl 15-29 mL/min) showed that rivaroxaban had at least equivalent efficacy and safety to warfarin [
      • Weir M.R.
      • Ashton V.
      • Moore K.T.
      • Shrivastava S.
      • Peterson E.D.
      • Ammann E.M.
      Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and stage IV-V chronic kidney disease.
      ]. Accordingly, the Australian Therapeutic Goods Administration has recently approved an update to the product information for rivaroxaban allowing use in advanced kidney disease (down to a CrCl of 15 mL/min) [
      Bayer Australia Pty Ltd. Australian Product Information Xarelto - Rivaroxaban 2.5mg 10mg, 15mg and 20mg 2020. Available from.
      ]. This is a welcome development that extends treatment options for these high-risk patients.
      As should always be the case when initiating anticoagulant therapy, the relative risks and benefits of treatment must be considered beforehand, and caution should be applied when there is an unmodifiable high bleeding risk or where there is concomitant medication that may increase the anticoagulation effect. Ultimately, decisions regarding initiating or continuing NOAC therapy in patients with non-valvular AF and severe kidney disease should involve specialist physician consultation, ideally including specialist nephrologist involvement with ongoing risk assessment and management.

      End-Stage Kidney Disease (CKD Stage 5, CrCl <15 mL/min)

      Whether to continue (or initiate) anticoagulation for AF patients with end stage kidney disease on haemodialysis is a more complex decision. These patients have a higher risk of bleeding, significant co-morbidities and competing risks that make the risk of stroke a less pressing issue for the majority [
      • Randhawa M.S.
      • Vishwanath R.
      • Rai M.P.
      • Wang L.
      • Randhawa A.K.
      • Abela G.
      • et al.
      Association between use of warfarin for atrial fibrillation and outcomes among patients with end-stage renal disease: a systematic review and meta-analysis.
      ]. There are no adequately powered randomised trials, and meta-analyses of observational trials of warfarin suggest a significant increase in bleeding (including haemorrhagic stroke) without a clear reduction in either ischaemic stroke or mortality in this cohort [
      • Randhawa M.S.
      • Vishwanath R.
      • Rai M.P.
      • Wang L.
      • Randhawa A.K.
      • Abela G.
      • et al.
      Association between use of warfarin for atrial fibrillation and outcomes among patients with end-stage renal disease: a systematic review and meta-analysis.
      ]. Other concerns with warfarin in this population include an increased rate of vascular calcification [
      • Peeters F.
      • Dudink E.
      • Kimenai D.M.
      • Weijs B.
      • Altintas S.
      • Heckman L.I.B.
      • et al.
      Vitamin K antagonists, non-vitamin k antagonist oral anticoagulants, and vascular calcification in patients with atrial fibrillation.
      ], and the potentially fatal complication of calciphylaxis. Perhaps as a consequence of these concerns, up to 70% of end-stage kidney disease (ESKD) patients initiated on warfarin discontinue it within the first year [
      • Shen J.I.
      • Montez-Rath M.E.
      • Lenihan C.R.
      • Turakhia M.P.
      • Chang T.I.
      • Winkelmayer W.C.
      Outcomes after warfarin initiation in a cohort of hemodialysis patients with newly diagnosed atrial fibrillation.
      ], and only 25% of AF patients undergoing dialysis in Australia are anticoagulated [
      • Wizemann V.
      • Tong L.
      • Satayathum S.
      • Disney A.
      • Akiba T.
      • Fissell R.B.
      • et al.
      Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy.
      ].
      The limited data available for NOACs in CKD stage 5 suggest they cause less bleeding than warfarin, but whether they are more effective in stroke reduction and whether this outweighs the bleeding risk compared to no anticoagulation remains unclear. Only two small, randomised trials have been reported to date. The Valkyrie study, primarily designed to assess the effect of vitamin K2 on vascular calcification in ESKD, randomised 132 haemodialysis patients to warfarin, rivaroxaban 10 mg once daily, or rivaroxaban and vitamin K2 2,000 μg thrice weekly [
      • De Vriese A.S.
      • Caluwe R.
      • Van Der Meersch H.
      • De Boeck K.
      • De Bacquer D.
      Safety and efficacy of vitamin k antagonists versus rivaroxaban in hemodialysis patients with atrial fibrillation: a multicenter randomized controlled trial.
      ]. It showed significantly less bleeding, and no difference in stroke, for rivaroxaban compared to warfarin. A pharmacokinetic and pharmacodynamics study showed that a 10 mg dose of rivaroxaban in haemodialysis patients without residual kidney function resulted in drug exposure similar to a 20 mg dose in healthy volunteers [
      • De Vriese A.S.
      • Caluwe R.
      • Bailleul E.
      • De Bacquer D.
      • Borrey D.
      • Van Vlem B.
      • et al.
      Dose-finding study of rivaroxaban in hemodialysis patients.
      ]. The second reported randomised trial, the RENal hemodialysis patients ALlocated apixaban versus warfarin in Atrial Fibrillation (RENAL-AF) trial, was presented at the American Heart Association annual scientific meeting in 2019 but has not yet been published in a peer reviewed journal. This trial showed no difference in bleeding, intracranial haemorrhage, stroke or cardiovascular death for patients randomised to apixaban (predominantly 5 mg twice daily) or warfarin [
      • De Vriese A.S.
      • Caluwe R.
      • Van Der Meersch H.
      • De Boeck K.
      • De Bacquer D.
      Safety and efficacy of vitamin k antagonists versus rivaroxaban in hemodialysis patients with atrial fibrillation: a multicenter randomized controlled trial.
      ]. However, the trial was ceased early due to loss of funding with only 154 patients randomised, and so was likely underpowered to detect meaningful differences in events. Both trials lacked the statistical power to assess differences in thromboembolic events, and the lack of a placebo arm means the important question of whether no anticoagulation is the safest option cannot be answered.
      Non-randomised retrospective cohort analyses of NOACs in ESKD have shown conflicting results. An analysis from the US Renal Data System reported apixaban had a similar rate of stroke and systemic embolism as warfarin, but a lower risk of major bleeding [
      • Siontis K.C.
      • Zhang X.
      • Eckard A.
      • Bhave N.
      • Schaubel D.E.
      • He K.
      • et al.
      Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States.
      ]. However, a separate analysis from the same dataset, this time comparing apixaban with no anticoagulation, reported apixaban increased fatal and intracranial bleeding without any reduction in stroke, transient ischaemic attack or systemic embolisation [
      • Mavrakanas T.A.
      • Garlo K.
      • Charytan D.M.
      Apixaban versus no anticoagulation in patients undergoing long-term dialysis with incident atrial fibrillation.
      ].
      Further randomised trials are underway, including AXADIA (apixaban 2.5 mg twice daily vs. warfarin) (NCT02933697)
      Compare Apixaban and Vitamin-K Antagonists in Patients With Atrial Fibrillation (AF) and End-Stage Kidney Disease (ESKD).
      , Strategies for the Management of Atrial Fibrillation in patiEnts Receiving Dialysis (SAFE-D) (apixaban vs. warfarin vs. no anticoagulation) (NCT03987711), and Oral Anticoagulation in Haemodialysis Patients (AVKDIAL) (vitamin K antagonists vs. no anticoagulation) (NCT02886962), and these will give further information on whether anticoagulation with vitamin K antagonists or NOACs have a role in ESKD.
      In the meantime, international guidelines emphasise the lack of evidence and recommend caution in considering anticoagulation in these patients. In Australia, NOACs are not approved for patients with CKD stage 5. Based on limited observational and trial-data in patients with atrial fibrillation and CKD stage 5, including those on dialysis, anticoagulation therapy should be individualised. The default strategy should be no anticoagulation, and clinicians and patients should make a shared decision after discussion of the benefits and harms of treatment options, taking into consideration patients’ competing risks, values, and preferences.

      Conclusions

      Anticoagulation is strongly recommended for all AF patients with moderate kidney disease (CrCl 30–49 mL/min) and a CHA2DS2-VA risk ≥2, unless there is an unacceptably high bleeding risk without reversible cause. Anti-platelet therapy is ineffective for stroke prevention in AF, and NOACs are first line therapy (over warfarin). Apixaban and rivaroxaban are preferred over dabigatran (levels of which increase substantially with kidney disease). Care should be taken to choose the correct apixaban dose to avoid either excessive or inadequate anticoagulation: the full dose (5 mg twice daily) should be used in moderate kidney disease unless the patient meets at least two criteria (age ≥80 yrs, weight ≤60 kg, serum creatinine ≥133 μmol/L) for dose reduction to 2.5 mg twice daily. Rivaroxaban has a specific dose for patients with chronic kidney disease, with 15 mg once daily proven safe and effective for patients with moderate kidney disease.
      Patients with severe kidney disease (CrCl 15–29 mL/min) are often at high risk of both stroke and bleeding. The decision to anticoagulate should take into account these competing risks. If the decision is made to anticoagulate, the limited data available suggests NOACs (apixaban or rivaroxaban) are preferable to warfarin, which is often poorly tolerated, with difficulty maintaining adequate time in therapeutic range and high rates of discontinuation. In Australia, apixaban is licenced for use down to CrCl of 25 mL/min, and rivaroxaban is licenced for use down to a CrCl of 15 mL/min.
      Tabled 1
      Recommendations:
      • 1.
        Anticoagulation is strongly recommended for all AF patients with moderate kidney disease (CrCl 30–49 mL/min). The preferred agents are the NOACs apixaban and rivaroxaban, levels of which are only modestly affected by kidney disease. Both medications have proven efficacy and safety against warfarin in moderate kidney disease.
      • 2.
        Patients with severe kidney disease (CrCl 15–29 mL/min) should be considered for anticoagulation unless there is an unacceptably high unmodifiable bleeding risk. Apixaban (down to CrCl of 25 mL/min) and rivaroxaban (down to a CrCl of 15 mL/min) are the preferred agents.
      • 3.
        Anticoagulation should not be used in patients with CKD stage 5 (including those receiving dialysis), other than in selected cases where there is likely to be substantial benefit without excess bleeding risk. In Australia, only warfarin is approved for use in CKD stage 5.

      Disclosures

      The authors received honoraria from Bayer to attend an advisory board meeting on anticoagulation for AF and kidney disease, at the end of which this manuscript was initially proposed by the lead author and a draft concept discussed. The manuscript was drafted by the lead author (and edited with input from all co-authors, with editorial support from Sophie Gibb), with no influence or editorial input from Bayer or other commercial entities.
      CH has received research support, honoraria, or is a member of advisory boards for: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, CSL Behring, Eli Lilly, Janssen, The Medicines Company, Medtronic, Merck Sharp and Dohme, Novartis and Pfizer/BMS.
      SB’s institution has received fees from Bayer, AstraZeneca and Vifor for advisory board membership, and speaker’s honoraria from Bayer, Pfizer, AstraZeneca and Vifor. SB has received research grants from NHMRC and in-kind research support from Bayer .
      PK has no further disclosures.
      HT has no further disclosures.
      BD has received educational honoraria/speaker’s fees from Bayer.
      SL has received honoraria from Bayer for advisory board membership and speaker’s honoraria from Bayer, Boehringer Ingelheim, AstraZeneca and Pfizer.
      AW has received speaker’s fees and conference travel support in the last three years from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Gore Medical, Lilly, Medtronic and Pfizer.
      JJ has received speaker’s fees from Aspen, Bayer, Novo Nordisk and Roche.
      JD has no further disclosures.
      VP has received honoraria from Retrophin, Janssen, Merck, Servier, AbbVie, Astellas, AstraZeneca, Bayer, Baxter, BMS, Boehringer Ingelheim, Dimerix, DURECT, Eli Lilly, Gilead, GSK, Mitsubishi Tanabe, Novartis, Novo Nordisk, Pfizer, PharmaLink, Relypsa, Sanofi, Vifor Pharma and Tricida.

      Acknowledgements

      The authors thank Sophie Gibb, PhD CMPP, of WriteSource Medical Pty Ltd, Australia for providing editorial support funded by Bayer Australia Ltd in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

      References

        • Alonso A.
        • Lopez F.L.
        • Matsushita K.
        • Loehr L.R.
        • Agarwal S.K.
        • Chen L.Y.
        • 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
        • Bonde A.N.
        • Lip G.Y.
        • Kamper A.-L.
        • Fosbøl E.L.
        • Staerk L.
        • Carlson N.
        • et al.
        Renal function and the risk of stroke and bleeding in patients with atrial fibrillation: an observational cohort study.
        Stroke. 2016; 47: 2707-2713
        • Summary of Recommendation Statements
        Kidney Int Suppl. 2013; 3: 5-14
        • Keith D.S.
        • Nichols G.A.
        • Gullion C.M.
        • Brown J.B.
        • Smith D.H.
        Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization.
        Arch Intern Med. 2004; 164: 659-663
        • Soliman E.Z.
        • Prineas R.J.
        • Go A.S.
        • Xie D.
        • Lash J.P.
        • Rahman M.
        • et al.
        Chronic kidney disease and prevalent atrial fibrillation: the Chronic Renal Insufficiency Cohort (CRIC).
        Am Heart J. 2010; 159: 1102-1107
        • Olesen J.B.
        • Lip G.Y.
        • Kamper A.L.
        • Hommel K.
        • Køber L.
        • Lane D.A.
        • et al.
        Stroke and bleeding in atrial fibrillation with chronic kidney disease.
        N Engl J Med. 2012; 367: 625-635
        • Hart R.G.
        • Pearce L.A.
        • Aguilar M.I.
        Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.
        Ann Intern Med. 2007; 146: 857-867
        • Connolly S.J.
        • Ezekowitz M.D.
        • Yusuf S.
        • Eikelboom J.
        • Oldgren J.
        • Parekh A.
        • et al.
        Dabigatran versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2009; 361: 1139-1151
        • Patel M.R.
        • Mahaffey K.W.
        • Garg J.
        • Pan G.
        • Singer D.E.
        • Hacke W.
        • et al.
        Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
        N Engl J Med. 2011; 365: 883-891
        • Granger C.B.
        • Alexander J.H.
        • McMurray J.J.
        • Lopes R.D.
        • Hylek E.M.
        • Hanna M.
        • et al.
        Apixaban versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2011; 365: 981-992
        • Capodanno D.
        • Angiolillo D.J.
        Antithrombotic therapy in patients with chronic kidney disease.
        Circulation. 2012; 125: 2649-2661
        • Själander S.
        • Själander A.
        • Svensson P.J.
        • Friberg L.
        Atrial fibrillation patients do not benefit from acetylsalicylic acid.
        Europace. 2014; 16: 631-638
        • Connolly S.
        • Pogue J.
        • Hart R.
        • Pfeffer M.
        • Hohnloser S.
        • Chrolavicius S.
        • et al.
        Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial.
        Lancet. 2006; 367: 1903-1912
        • Hindricks G.
        • Potpara T.
        • Dagres N.
        • Arbelo E.
        • Bax J.J.
        • Blomström-Lundqvist C.
        • et al.
        2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS) The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC.
        Eur Heart J. 2020; 42: 373-498
        • Brieger D.
        • Amerena J.
        • Attia J.
        • Bajorek B.
        • Chan K.H.
        • et al.
        • NHFA CSANZ Atrial Fibrillation Guideline Working Group
        National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand: Australian Clinical Guidelines for the Diagnosis and Management of Atrial Fibrillation 2018.
        Heart Lung Circ. 2018; 27: 1209-1266
      1. Boehringer Ingelheim Pty Limited. Australian Product Information - PRADAXA (dabigatran etexilate) capsule 2020. Available from.
        • Yang F.
        • Hellyer J.A.
        • Than C.
        • Ullal A.J.
        • Kaiser D.W.
        • Heidenreich P.A.
        • et al.
        Warfarin utilisation and anticoagulation control in patients with atrial fibrillation and chronic kidney disease.
        Heart. 2017; 103: 818-826
        • Ha J.T.
        • Neuen B.L.
        • Cheng L.P.
        • Jun M.
        • Toyama T.
        • Gallagher M.P.
        • et al.
        Benefits and harms of oral anticoagulant therapy in chronic kidney disease: a systematic review and meta-analysis.
        Ann Intern Med. 2019; 171: 181-189
        • Knauf F.
        • Chaknos C.M.
        • Berns J.S.
        • Perazella M.A.
        Dabigatran and kidney disease: a bad combination.
        Clin J Am Soc Nephrol. 2013; 8: 1591-1597
        • Steffel J.
        • Verhamme P.
        • Potpara T.S.
        • Albaladejo P.
        • Antz M.
        • Desteghe L.
        • et al.
        The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
        Eur Heart J. 2018; 39: 1330-1393
        • Chang M.
        • Yu Z.
        • Shenker A.
        • Wang J.
        • Pursley J.
        • Byon W.
        • et al.
        Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban.
        J Clin Pharmacol. 2016; 56: 637-645
        • Dias C.
        • Moore K.T.
        • Murphy J.
        • Ariyawansa J.
        • Smith W.
        • Mills R.M.
        • et al.
        Pharmacokinetics, pharmacodynamics, and safety of single-dose rivaroxaban in chronic hemodialysis.
        Am J Nephrol. 2016; 43: 229-236
        • Hohnloser S.H.
        • Hijazi Z.
        • Thomas L.
        • Alexander J.H.
        • Amerena J.
        • Hanna M.
        • 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
        • Hijazi Z.
        • Hohnloser S.H.
        • Andersson U.
        • Alexander J.H.
        • Hanna M.
        • Keltai M.
        • et al.
        Efficacy and Safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
        JAMA Cardiol. 2016; 1: 451-460
        • Yao X.
        • Shah N.D.
        • Sangaralingham L.R.
        • Gersh B.J.
        • Noseworthy P.A.
        Non-vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction.
        J Am Coll Cardiol. 2017; 69: 2779-2790
        • Mueck W.
        • Lensing A.W.
        • Agnelli G.
        • Decousus H.
        • Prandoni P.
        • Misselwitz F.
        Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention.
        Clin Pharmacokinet. 2011; 50: 675-686
        • Fox K.A.
        • Piccini J.P.
        • Wojdyla D.
        • Becker R.C.
        • Halperin J.L.
        • Nessel C.C.
        • et al.
        Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment.
        Eur Heart J. 2011; 32: 2387-2394
        • Fordyce C.B.
        • Hellkamp A.S.
        • Lokhnygina Y.
        • Lindner S.M.
        • Piccini J.P.
        • Becker R.C.
        • et al.
        On-treatment outcomes in patients with worsening renal function with rivaroxaban compared with warfarin.
        Circulation. 2016; 134: 37-47
        • Stangier J.
        • Rathgen K.
        • Stähle H.
        • Mazur D.
        Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study.
        Clin Pharmacokinet. 2010; 49: 259-268
        • Stanifer J.W.
        • Pokorney S.D.
        • Chertow G.M.
        • Hohnloser S.H.
        • Wojdyla D.M.
        • Garonzik S.
        • et al.
        Apixaban versus warfarin in patients with atrial fibrillation and advanced chronic kidney disease.
        Circulation. 2020; 141: 1384-1392
        • Weir M.R.
        • Ashton V.
        • Moore K.T.
        • Shrivastava S.
        • Peterson E.D.
        • Ammann E.M.
        Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and stage IV-V chronic kidney disease.
        Am Heart J. 2020; 223: 3-11
      2. Bayer Australia Pty Ltd. Australian Product Information Xarelto - Rivaroxaban 2.5mg 10mg, 15mg and 20mg 2020. Available from.
        • Randhawa M.S.
        • Vishwanath R.
        • Rai M.P.
        • Wang L.
        • Randhawa A.K.
        • Abela G.
        • et al.
        Association between use of warfarin for atrial fibrillation and outcomes among patients with end-stage renal disease: a systematic review and meta-analysis.
        JAMA Netw Open. 2020; 3: e202175-e
        • Peeters F.
        • Dudink E.
        • Kimenai D.M.
        • Weijs B.
        • Altintas S.
        • Heckman L.I.B.
        • et al.
        Vitamin K antagonists, non-vitamin k antagonist oral anticoagulants, and vascular calcification in patients with atrial fibrillation.
        TH Open. 2018; 2: e391-e398
        • Shen J.I.
        • Montez-Rath M.E.
        • Lenihan C.R.
        • Turakhia M.P.
        • Chang T.I.
        • Winkelmayer W.C.
        Outcomes after warfarin initiation in a cohort of hemodialysis patients with newly diagnosed atrial fibrillation.
        Am J Kidney Dis. 2015; 66: 677-688
        • Wizemann V.
        • Tong L.
        • Satayathum S.
        • Disney A.
        • Akiba T.
        • Fissell R.B.
        • et al.
        Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy.
        Kidney Int. 2010; 77: 1098-1106
        • De Vriese A.S.
        • Caluwe R.
        • Van Der Meersch H.
        • De Boeck K.
        • De Bacquer D.
        Safety and efficacy of vitamin k antagonists versus rivaroxaban in hemodialysis patients with atrial fibrillation: a multicenter randomized controlled trial.
        J Am Soc Nephrol. 2021; 32: 1474-1483
        • De Vriese A.S.
        • Caluwe R.
        • Bailleul E.
        • De Bacquer D.
        • Borrey D.
        • Van Vlem B.
        • et al.
        Dose-finding study of rivaroxaban in hemodialysis patients.
        Am J Kidney Dis. 2015; 66: 91-98
        • Siontis K.C.
        • Zhang X.
        • Eckard A.
        • Bhave N.
        • Schaubel D.E.
        • He K.
        • et al.
        Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States.
        Circulation. 2018; 138: 1519-1529
        • Mavrakanas T.A.
        • Garlo K.
        • Charytan D.M.
        Apixaban versus no anticoagulation in patients undergoing long-term dialysis with incident atrial fibrillation.
        Clin J Am Soc Nephrol. 2020; 15: 1146-1154
      3. Mylan Health Pty Ltd. Australian Product Information - Coumadin (warfarin sodium) 2020. Available from.
      4. Pfizer Australia Pty Limited. Australian PI - Eliquis (apixaban) 2020. Available from.