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

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. 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. Atrial fibrillation (AF) is one of the most common arrhythmias faced in clinical practice, and its incidence increases linearly with worsening kidney function and albuminuria [[1]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: 2946-2953Crossref PubMed Scopus (379) Google Scholar]. 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 [[2]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: 2707-2713Crossref PubMed Scopus (35) Google Scholar]. 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) [[3]Summary of Recommendation StatementsKidney Int Suppl. 2013; 3: 5-14Abstract Full Text Full Text PDF Scopus (196) Google Scholar]. 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 [[4]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: 659-663Crossref PubMed Scopus (1400) Google Scholar]. Some of this excess risk comes from atrial fibrillation, which is highly prevalent in CKD [[5]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: 1102-1107Crossref PubMed Scopus (343) Google Scholar]. 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 [[6]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: 625-635Crossref PubMed Scopus (736) Google Scholar].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 abnormalityStage 2 (mild)eGFR 60 to 89 mL/min/1.73m2, with albuminuria, haematuria, a pathological abnormality or structural abnormalityStage 3a (moderate)eGFR 45 to 59 mL/min/1.73m2Stage 3b (moderate)eGFR 30 to 44 mL/min/1.73m2Stage 4 (severe)eGFR 15 to 29 mL/min/1.73m2Stage 5 (ESKD)eGFR <15 mL/min/1.73m2, end stage kidney disease Open table in a new tab 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 [[7]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: 857-867Crossref PubMed Scopus (3864) Google Scholar]. 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 [8Connolly 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: 1139-1151Crossref PubMed Scopus (9162) Google Scholar, 9Patel 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: 883-891Crossref PubMed Scopus (7472) Google Scholar, 10Granger 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: 981-992Crossref PubMed Scopus (6986) Google Scholar]. This is of particular importance in kidney disease, where there is an increased baseline risk of bleeding [[2]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: 2707-2713Crossref PubMed Scopus (35) Google Scholar], and often both patients and physicians preferring no anticoagulation to warfarin, when that is the only available option [[11]Capodanno D. Angiolillo D.J. Antithrombotic therapy in patients with chronic kidney disease.Circulation. 2012; 125: 2649-2661Crossref PubMed Scopus (120) Google Scholar]. 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 [[12]Själander S. Själander A. Svensson P.J. Friberg L. Atrial fibrillation patients do not benefit from acetylsalicylic acid.Europace. 2014; 16: 631-638Crossref PubMed Scopus (67) Google Scholar,[13]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: 1903-1912Abstract Full Text Full Text PDF PubMed Scopus (1767) Google Scholar]. Antiplatelet agents should not be used for stroke prevention in AF [[14]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: 373-498Crossref Scopus (4312) Google Scholar,[15]Brieger D. Amerena J. Attia J. Bajorek B. Chan K.H. et al.NHFA CSANZ Atrial Fibrillation Guideline Working GroupNational 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: 1209-1266Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar].Table 2Mechanism of action and pharmacokinetics of warfarin and the NOACs.AnticoagulantMechanism of ActionHalf-LifeKidney ClearanceStandard AF DoseReduced DoseRecommended Dosing Relative to FoodWarfarin [[41]Mylan Health Pty Ltd. Australian Product Information - Coumadin (warfarin sodium) 2020. Available from.https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-02588-3Google Scholar]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 [[16]Boehringer Ingelheim Pty Limited. Australian Product Information - PRADAXA (dabigatran etexilate) capsule 2020. Available from.https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-01177-3&d=202007271016933Google Scholar]Factor II (thrombin) inhibitor≥50 mL/min ∼14 hr>30–≤50 mL/min ∼18 hr≤30 mL/min ∼28 hr85%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 [[42]Pfizer Australia Pty Limited. Australian PI - Eliquis (apixaban) 2020. Available from.https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-03072-3&d=202012021016933Google Scholar]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 foodRivaroxaban [[32]Bayer Australia Pty Ltd. Australian Product Information Xarelto - Rivaroxaban 2.5mg 10mg, 15mg and 20mg 2020. Available from.https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-01020-3Google Scholar]Factor Xa inhibitor5-9 hr (young);11-13 hr (elderly)35%20 mg ODFor CrCl≥50 mL/min15 mg ODFor CrCl15-49 mL/minTake 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. Open table in a new tab Abbreviations: INR, international normalised ratio; BD, twice daily; OD, once daily. NOACs are now firmly established as the preferred therapy for stroke prevention in AF [[14]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: 373-498Crossref Scopus (4312) Google Scholar,[15]Brieger D. Amerena J. Attia J. Bajorek B. Chan K.H. et al.NHFA CSANZ Atrial Fibrillation Guideline Working GroupNational 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: 1209-1266Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar]. 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 [[8]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: 1139-1151Crossref PubMed Scopus (9162) Google Scholar]. 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) [[16]Boehringer Ingelheim Pty Limited. Australian Product Information - PRADAXA (dabigatran etexilate) capsule 2020. Available from.https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-01177-3&d=202007271016933Google Scholar]. 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 [[10]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: 981-992Crossref PubMed Scopus (6986) Google Scholar]. 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 [[9]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: 883-891Crossref PubMed Scopus (7472) Google Scholar]. 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 [[9]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: 883-891Crossref PubMed Scopus (7472) Google Scholar]. 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 [[14]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: 373-498Crossref Scopus (4312) Google Scholar,[15]Brieger D. Amerena J. Attia J. Bajorek B. Chan K.H. et al.NHFA CSANZ Atrial Fibrillation Guideline Working GroupNational 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: 1209-1266Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar]. 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 [[15]Brieger D. Amerena J. Attia J. Bajorek B. Chan K.H. et al.NHFA CSANZ Atrial Fibrillation Guideline Working GroupNational 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: 1209-1266Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar]. 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 1Hypertension, 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 [[14]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: 373-498Crossref Scopus (4312) Google Scholar]. Patients with moderate kidney disease are at increased risk of both stroke/systemic embolism and bleeding compared to those with normal kidney function [[2]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: 2707-2713Crossref PubMed Scopus (35) Google Scholar]. 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 [[17]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: 818-826Crossref PubMed Scopus (74) Google Scholar]. Each of the landmark trials of NOAC versus warfarin [8Connolly 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: 1139-1151Crossref PubMed Scopus (9162) Google Scholar, 9Patel 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: 883-891Crossref PubMed Scopus (7472) Google Scholar, 10Granger 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: 981-992Crossref PubMed Scopus (6986) Google Scholar] 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 [[18]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: 181-189Crossref PubMed Scopus (87) Google Scholar]. 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) [[19]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: 1591-1597Crossref PubMed Scopus (26) Google Scholar]. Consequently, guidelines suggest caution with dabigatran in kidney disease and recommend the Factor Xa inhibitors (apixaban or rivaroxaban) as the preferred options [[20]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: 1330-1393Crossref PubMed Scopus (1413) Google Scholar]. 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) [[21]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: 637-645Crossref PubMed Scopus (134) Google Scholar,[22]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: 229-236Crossref PubMed Scopus (111) Google Scholar]. Apixaban has been shown to have superior efficacy and safety over warfarin for patients with moderate kidney disease [[23]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: 2821-2830Crossref PubMed Scopus (458) Google Scholar]. 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 [[23]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: 2821-2830Crossref PubMed Scopus (458) Google Scholar]. 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 [[24]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: 451-460Crossref PubMed Scopus (133) Google Scholar]. 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 [[25]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: 2779-2790Crossref PubMed Scopus (348) Google Scholar]. 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 [[26]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;