- Email: [email protected]
Anticoagulation, atrial fibrillation, and chronic kidney disease—whose side are you on?
commentary
REFERENCES 1. Christensen EI, Birn H, Storm T, et al. Endocytic receptors in the renal proximal tubule. Physiology (Bethesda). 2012;27:223–236. 2. Lloyd SE, Pearce SH, Fisher SE, et al. A common molecular basis for three inherited kidney stone diseases. Nature. 1996;379:445–449. 3. Piwon N, Gunther W, Schwake M, Bosl MR, Jentsch TJ. ClC-5 Cl- -channel disruption impairs endocytosis in a mouse model for Dent’s disease. Nature. 2000;408:369–373. 4. Wang SS, Devuyst O, Courtoy PJ, et al. Mice lacking renal chloride channel, CLC-5, are a model for Dent’s disease, a nephrolithiasis disorder associated with defective receptormediated endocytosis. Hum Mol Genet. 2000;9:2937–2945. 5. Christensen EI, Devuyst O, Dom G, et al. Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin
6.
7.
8.
9.
in kidney proximal tubules. Proc Natl Acad Sci U S A. 2003;100:8472–8477. Gabriel SS, Belge H, Gassama A, et al. Bone marrow transplantation improves proximal tubule dysfunction in a mouse model of Dent disease. Kidney Int. 2017;91: 842–855. Syres K, Harrison F, Tadlock M, et al. Successful treatment of the murine model of cystinosis using bone marrow cell transplantation. Blood. 2009;114:2542–2552. Yeagy BA, Harrison F, Gubler MC, Koziol JA, Salomon DR, Cherqui S. Kidney preservation by bone marrow cell transplantation in hereditary nephropathy. Kidney Int. 2011;79: 1198–1206. Abounit S, Zurzolo C. Wiring through tunneling nanotubes–from electrical signals to organelle transfer. J Cell Sci. 2012;125: 1089–1098.
Anticoagulation, atrial fibrillation, and chronic kidney disease—whose side are you on? Gunnar Henrik Heine1 and Vincent Brandenburg2 Whether to initiate oral anticoagulant therapy in advanced chronic kidney disease patients with atrial fibrillation remains debatable. Although randomized trial data are lacking, observational studies yield controversial results. Keskar and colleagues analyzed data from a Canadian health care system and found that in elderly chronic kidney disease patients with atrial fibrillation, oral anticoagulant therapy did not prevent ischemic strokes, induced hemorrhages, but prolonged life. These paradoxical findings emphasize the dire need for an adequately powered randomized trial. Kidney International (2017) 91, 778–780; http://dx.doi.org/10.1016/j.kint.2016.11.028 Copyright ª 2017, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see clinical investigation on page 928
I
n the general population, prevention of thromboembolic events in patients with atrial fibrillation (AF) via oral anticoagulant therapy (OAT)
1 Saarland University Medical Center, Saarland University Faculty of Medicine, Internal Medicine IV–Nephrology and Hypertension, Homburg, Germany; and 2Department of Cardiology, University Hospital RWTH Aachen, Aachen, Germany
Correspondence: Gunnar Henrik Heine, Saarland University Medical Center and Saarland University Faculty of Medicine, Internal Medicine IV– Nephrology and Hypertension, D-66421 Homburg, Germany. E-mail: [email protected] 778
follows stringent guideline-based recommendations.1 Without a doubt, substantial evidence from large-scale randomized trials supports the notion that nearly all patients who have $1 risk factors for cerebral stroke or systemic embolization (defined as a CHA2DS2-VASc score of $1 in men and $2 in women) should receive OAT, as the benefit for stroke prevention clearly outweighs the bleeding risk in the general population. In contrast, prevention of stroke and systemic embolism is more challenging
and remarkably less evidence-based in advanced chronic kidney disease (CKD) patients, particularly once they reach end-stage renal disease. No adequately powered randomized, controlled trial analyzed the efficacy (i.e., prevention of thromboembolic events) and safety (i.e., no major bleeding events) of vitamin K antagonists (VKAs) or non– VKA oral anticoagulants (NOACs) in advanced CKD (e.g., in patients with a glomerular filtration rate [GFR] <30 ml/min per 1.73 m2 or on dialysis). With regard to less advanced CKD, retrospective subgroup analyses from 1 single randomized, controlled trial found much fewer strokes in CKD stage G3a/G3b patients on adjusted-dose warfarin than in those patients on low-dose warfarin plus aspirin.2 Such a paucity of evidence is noteworthy because AF is more likely to develop in patients with advanced CKD, and CKD patients with AF experience thromboembolic events more frequently than AF patients with intact kidney function.3 We acknowledge that it remains unclear whether this higher thromboembolic risk merely reflects a higher comorbidity burden in CKD patients or whether it indicates distinct pathophysiologic prothrombotic pathways caused by uremia. Remarkably, CKD per se is not included in the broadly established and popular CHA2DS2-VASc risk assessment score for prediction of thromboembolic events, whereas the alternative ATRIA (Anticoagulation and Risk Factor in Atrial Fibrillation) risk score integrates GFR and proteinuria. Thus, theoretically AF patients with CKD should benefit more overtly from OAT in terms of risk prevention than AF patients with intact renal function. Unfortunately, the risk of the side effects of anticoagulation therapy also increases in CKD patients, who are particularly at higher risk of experiencing bleeding events including intracerebral hemorrhage. The complexity of this matter even increases because traditional OAT with VKA has been thought to propagate and accelerate vascular calcification,4 a condition highly prevalent in CKD and Kidney International (2017) 91, 771–786
commentary
presumably related to adverse cardiovascular events and CKD progression.5 The absence of prospective, randomized, controlled trials stimulated several groups to conduct retrospective cohort analyses to assess the benefit (if any) of OAT in nondialysis CKD and end-stage renal disease patients. Focusing on administrative registry data, these analyses yielded conflicting findings: some early analyses suggested no benefits of OAT because the stroke risk was not reduced in the total cohort, and in elderly patients, the stroke incidence even increased with OAT. In contrast, others found a benefit of anticoagulation in terms of effective risk reduction for strokes.6 In the current issue of Kidney International, Keskar and colleagues7 place this degree of confusion and uncertainty at even higher levels. Analyzing data from a Canadian health care database, the authors claim that among elderly AF patients with an estimated GFR (eGFR) #45 ml/min per 1.73 m2, OAT (unexpectedly) did not substantially affect the ischemic stroke rate, but (expectedly) induced more hemorrhages. Despite these sober findings, total mortality was lower with OAT.7 In the absence of data on cause-specific death, we can only hypothesize potential explanations for this puzzling finding, which may comprise a lower rate of severe (lifelimiting) strokes with OAT, a lower rate of atherosclerotic events, or pure play of chance, driven by the relatively short follow-up period. Of note, cohort analyses cannot provide the same evidence level as randomized, controlled trials, and data from administrative registries are particularly imprecise and prone to bias. Their quality, which substantially depends on the correctness of data input by health care providers, falls behind that of specifically designed prospective cohort studies such as CRIC (Chronic Renal Insufficiency Cohort) study and GCKD (German Chronic Kidney Disease) study, let alone interventional trials. As 1 example, in administrative registries, comorbidities such as vascular disease, hypertension, and diabetes mellitus are not recorded Kidney International (2017) 91, 771–786
in a systematic and standardized way by treating physicians, which precludes a reliable calculation of thromboembolism (CHA2DS2-VASc) and bleeding risk scores. Thus, even with comprehensive and sophisticated adjustments, all these uncontrolled data are influenced by potentially neglected residual confounders and are unable to present more than an idea of the safety and efficacy of a particular treatment. Obviously, although these Canadian registry data further question the usefulness of OAT for stroke prevention in AF patients with a GFR <45 ml/min per 1.73 m2, the potential survival benefits with OAT fuels the discussion about the need for a randomized, controlled trial in this setting. With the currently limited evidence, clinical practices yield diverse standard operating procedures, dividing treating physicians into “believers” and “nonbelievers” regarding OAT for the primary prevention of embolism in AF patients with CKD. In our experience, nephrologists are more cautious and reluctant, whereas cardiologists tend to more willingly transfer guideline-based recommendations from the general
population to the CKD scenario. This discrepant approach is reflected by their society’s recommendations, which are more cautious in nephrology8 than in cardiology.1 As a second limitation, most published registry analyses of OAT among CKD patients with AF collected data in an era when few patients received NOACs.6,7 In the meantime, outside the field of nephrology, largescale clinical trials found NOACs to be at least as efficient as VKA for the prevention of thromboembolic events and at least as safe. In particular, the risk of intracerebral bleeding is much lower with NOACs than with VKAs. The benefit-to-risk ratio of NOACs reveals relevant interactions with renal function both in the upper and the lower GFR range.9 Fortunately, we now have subgroup analyses from all the large NOAC trials that prove noninferiority (partly even superiority) of all approved NOACs compared with warfarin in patients with mild to moderate CKD (down to patients with a creatinine clearance of 25 to 30 ml/min, roughly corresponding to CKD stages G3a and G3b).9
Indication for oral anticoagulation as stroke prevention in AF (if risk factor[s] present)
RCT(s) in the general population: Broad evidence that OAT reduces stroke risk
Cohort studies: Contradictory data and potentially more strokes in CKD stage G5 with OAT
Efficacy and safety of NOACs versus vitamin K antagonists (VKA)
RCT: NOACs noninferior (in some cases superior) to VKAs
RCT initiated Results not yet available in 2017 Mind potential risk of accumulation of NOAC
Association between stroke risk and renal function in AF
Risk of stroke and systemic embolism
Association between bleeding risk and renal function in AF
Bleeding risk
Prevalence of atrial fibrillation
NKD CKD G1 CKD G2
CKD G3a
CKD G3b
CKD G4
CKD G5
Figure 1 | Schematic summary of current evidence on oral anticoagulant therapy (OAT) for patients with atrial fibrillation (AF) across the spectrum of chronic kidney disease (CKD). NKD, no known kidney disease; NOACs, non–vitamin K antagonist oral anticoagulants; RCT(s), randomized controlled trial(s); VKA, vitamin K antagonists. 779
commentary
Several ongoing studies aim to compare NOACs and VKAs in patients with CKD stages G4 and G5. Even though these trials will be substantially smaller than trials from the general population, they will extend information on the safety and efficacy of NOACs to the most severe CKD GFR categories. Until these data are available, the lack of evidence precludes strong recommendations in favor of or against NOACs in CKD stage G4 and in dialysis patients, which is reflected in slightly different recommendations regarding NOAC use by European and US authorities. In particular, one first NOAC (apixaban) has been licensed for use among dialysis patients by the US Food and Drug Administration but not (yet) in Europe. Compared with other licensed NOACs, elimination of apixaban depends less on renal excretion; therefore, apixaban has a lower risk to accumulate in advanced CKD, but still requires, as do all NOACs available so far, adjustment for renal function. Perhaps novel NOACs that accumulate even less than apixaban in CKD may be available in the foreseeable future. On the other end of the GFR spectrum, the US Food and Drug Administration issued a black box warning cautioning against use of edoxaban if creatinine clearance exceeds 95 ml/min. Subgroup analyses from the ENGAGE TIMI-48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48) study suggest that edoxaban may become less effective than warfarin in patients with normal renal function, presumably because of (overly) effective renal elimination.9 Of note, pharmacokinetic studies (and subsequent recommendations of NOAC doses) still focus on creatinine clearance (estimated with the Cockcroft-Gault equation), whereas nephrologists are today accustomed to estimate the GFR with the CKDEPICrea equation. Substituting the latter
780
for the former may cause large dose errors, particularly when physicians will neglect that the CKD-EPICrea equation yields a GRF estimate that is standardized to a body surface area of 1.73 m2. However, for dosing adjustment in a given CKD patient, the actual rather than the BSAstandardized GFR is required. Thereby, GFR estimates from the CKD-EPI equation need correction for the actual BSA. As the Cockcroft-Gault equation integrates body weight and thus yields an estimator of the actual (nonstandardized) renal function, its results can directly be applied to a given CKD patient. Thus, although the CockcroftGault equation is much less precise than the CKD-EPI equation for definition and grading of chronic kidney disease, it will still be required for pharmacokinetic issues. In summary, cohort analyses of stroke prevention with OAT in CKD patients yield contradictory results, and, thus, they are of limited help for clinical practice. At best, these analyses may make nephrologists aware of the limited evidence of stroke prevention and of the higher bleeding risk in CKD patients with AF, but they are not convincing enough to keep CKD patients with their high risk of thromboembolism from receiving anticoagulation treatment. Facing the uncertainty and gaps in evidence of the risk/benefit ratio of OAT in advanced CKD (Figure 1), we suggest, as a potential cardiorenal consensus of CKD patients with AF and at least a moderate risk of thromboembolism (defined by a CHA2DS2-VASc score $2 for women and $1 for men), to offer preferably NOACs in CKD stage G3a/ 3b, to offer either NOACs or VKAs in CKD stage G4, taking into account patient characteristics and licensing regulation, and to choose between NOACs, VKAs, and no oral anticoagulation in CKD stage G5 patients on an individual basis. While writing this commentary in October 2016, the KDIGO (Kidney Disease: Improving Global Outcomes)
is convening a controversies conference on CKD and Arrhythmias in Berlin, Germany. It is hoped that the conference will offer a consensus recommendation on the use of VKAs and NOACs in advanced CKD patients with AF. DISCLOSURE
GHH received a speaker’s fee from Daiichi Sankyo. VB received research grants from Bayer, Pfizer, and Daiichi Sankyo in the last 3 years. REFERENCES 1. Kirchhof P, Benussi S, Kotecha D, et al., Task Force Members. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS: the Task Force for the 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 Endorsed by the European Stroke Organisation (ESO). Eur Heart J. 2016 Aug 27. http://dx.doi.org/10.1093/eurheartj/ ehw210. Accessed. 2. Hart RG, Pearce LA, Asinger RW, Herzog CA. Warfarin in atrial fibrillation patients with moderate chronic kidney disease. Clin J Am Soc Nephrol. 2011;6:2599–2604. 3. Providência R, Marijon E, Boveda S, et al. Meta-analysis of the influence of chronic kidney disease on the risk of thromboembolism among patients with nonvalvular atrial fibrillation. Am J Cardiol. 2014;114:646–653. 4. van Gorp RH, Schurgers LJ. New insights into the pros and cons of the clinical use of vitamin K antagonists (VKAs) versus direct oral anticoagulants (DOACs). Nutrients. 2015;7: 9538–9557. 5. Böhm M, Ezekowitz MD, Connolly SJ, et al. Changes in renal function in patients with atrial fibrillation: an analysis from the RE-LY trial. J Am Coll Cardiol. 2015;65: 2481–2493. 6. Tan J, Liu S, Segal JB, et al. Warfarin use and stroke, bleeding and mortality risk in patients with end stage renal disease and atrial fibrillation: a systematic review and metaanalysis. BMC Nephrol. 2016;17:157. 7. Keskar V, McArthur E, Wald R, et al. The association of anticoagulation, ischemic stroke, and hemorrhage in elderly adults with chronic kidney disease and atrial fibrillation. Kidney Int. 2017;91:928–936. 8. Herzog CA, Asinger RW, Berger AK, et al. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011;80:572–586. 9. Hijazi Z, Wallentin L. Renal function in atrial fibrillation: a multifaceted dilemma. Circulation. 2016;134:48–51.
Kidney International (2017) 91, 771–786
REFERENCES 1. Christensen EI, Birn H, Storm T, et al. Endocytic receptors in the renal proximal tubule. Physiology (Bethesda). 2012;27:223–236. 2. Lloyd SE, Pearce SH, Fisher SE, et al. A common molecular basis for three inherited kidney stone diseases. Nature. 1996;379:445–449. 3. Piwon N, Gunther W, Schwake M, Bosl MR, Jentsch TJ. ClC-5 Cl- -channel disruption impairs endocytosis in a mouse model for Dent’s disease. Nature. 2000;408:369–373. 4. Wang SS, Devuyst O, Courtoy PJ, et al. Mice lacking renal chloride channel, CLC-5, are a model for Dent’s disease, a nephrolithiasis disorder associated with defective receptormediated endocytosis. Hum Mol Genet. 2000;9:2937–2945. 5. Christensen EI, Devuyst O, Dom G, et al. Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin
6.
7.
8.
9.
in kidney proximal tubules. Proc Natl Acad Sci U S A. 2003;100:8472–8477. Gabriel SS, Belge H, Gassama A, et al. Bone marrow transplantation improves proximal tubule dysfunction in a mouse model of Dent disease. Kidney Int. 2017;91: 842–855. Syres K, Harrison F, Tadlock M, et al. Successful treatment of the murine model of cystinosis using bone marrow cell transplantation. Blood. 2009;114:2542–2552. Yeagy BA, Harrison F, Gubler MC, Koziol JA, Salomon DR, Cherqui S. Kidney preservation by bone marrow cell transplantation in hereditary nephropathy. Kidney Int. 2011;79: 1198–1206. Abounit S, Zurzolo C. Wiring through tunneling nanotubes–from electrical signals to organelle transfer. J Cell Sci. 2012;125: 1089–1098.
Anticoagulation, atrial fibrillation, and chronic kidney disease—whose side are you on? Gunnar Henrik Heine1 and Vincent Brandenburg2 Whether to initiate oral anticoagulant therapy in advanced chronic kidney disease patients with atrial fibrillation remains debatable. Although randomized trial data are lacking, observational studies yield controversial results. Keskar and colleagues analyzed data from a Canadian health care system and found that in elderly chronic kidney disease patients with atrial fibrillation, oral anticoagulant therapy did not prevent ischemic strokes, induced hemorrhages, but prolonged life. These paradoxical findings emphasize the dire need for an adequately powered randomized trial. Kidney International (2017) 91, 778–780; http://dx.doi.org/10.1016/j.kint.2016.11.028 Copyright ª 2017, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see clinical investigation on page 928
I
n the general population, prevention of thromboembolic events in patients with atrial fibrillation (AF) via oral anticoagulant therapy (OAT)
1 Saarland University Medical Center, Saarland University Faculty of Medicine, Internal Medicine IV–Nephrology and Hypertension, Homburg, Germany; and 2Department of Cardiology, University Hospital RWTH Aachen, Aachen, Germany
Correspondence: Gunnar Henrik Heine, Saarland University Medical Center and Saarland University Faculty of Medicine, Internal Medicine IV– Nephrology and Hypertension, D-66421 Homburg, Germany. E-mail: [email protected] 778
follows stringent guideline-based recommendations.1 Without a doubt, substantial evidence from large-scale randomized trials supports the notion that nearly all patients who have $1 risk factors for cerebral stroke or systemic embolization (defined as a CHA2DS2-VASc score of $1 in men and $2 in women) should receive OAT, as the benefit for stroke prevention clearly outweighs the bleeding risk in the general population. In contrast, prevention of stroke and systemic embolism is more challenging
and remarkably less evidence-based in advanced chronic kidney disease (CKD) patients, particularly once they reach end-stage renal disease. No adequately powered randomized, controlled trial analyzed the efficacy (i.e., prevention of thromboembolic events) and safety (i.e., no major bleeding events) of vitamin K antagonists (VKAs) or non– VKA oral anticoagulants (NOACs) in advanced CKD (e.g., in patients with a glomerular filtration rate [GFR] <30 ml/min per 1.73 m2 or on dialysis). With regard to less advanced CKD, retrospective subgroup analyses from 1 single randomized, controlled trial found much fewer strokes in CKD stage G3a/G3b patients on adjusted-dose warfarin than in those patients on low-dose warfarin plus aspirin.2 Such a paucity of evidence is noteworthy because AF is more likely to develop in patients with advanced CKD, and CKD patients with AF experience thromboembolic events more frequently than AF patients with intact kidney function.3 We acknowledge that it remains unclear whether this higher thromboembolic risk merely reflects a higher comorbidity burden in CKD patients or whether it indicates distinct pathophysiologic prothrombotic pathways caused by uremia. Remarkably, CKD per se is not included in the broadly established and popular CHA2DS2-VASc risk assessment score for prediction of thromboembolic events, whereas the alternative ATRIA (Anticoagulation and Risk Factor in Atrial Fibrillation) risk score integrates GFR and proteinuria. Thus, theoretically AF patients with CKD should benefit more overtly from OAT in terms of risk prevention than AF patients with intact renal function. Unfortunately, the risk of the side effects of anticoagulation therapy also increases in CKD patients, who are particularly at higher risk of experiencing bleeding events including intracerebral hemorrhage. The complexity of this matter even increases because traditional OAT with VKA has been thought to propagate and accelerate vascular calcification,4 a condition highly prevalent in CKD and Kidney International (2017) 91, 771–786
commentary
presumably related to adverse cardiovascular events and CKD progression.5 The absence of prospective, randomized, controlled trials stimulated several groups to conduct retrospective cohort analyses to assess the benefit (if any) of OAT in nondialysis CKD and end-stage renal disease patients. Focusing on administrative registry data, these analyses yielded conflicting findings: some early analyses suggested no benefits of OAT because the stroke risk was not reduced in the total cohort, and in elderly patients, the stroke incidence even increased with OAT. In contrast, others found a benefit of anticoagulation in terms of effective risk reduction for strokes.6 In the current issue of Kidney International, Keskar and colleagues7 place this degree of confusion and uncertainty at even higher levels. Analyzing data from a Canadian health care database, the authors claim that among elderly AF patients with an estimated GFR (eGFR) #45 ml/min per 1.73 m2, OAT (unexpectedly) did not substantially affect the ischemic stroke rate, but (expectedly) induced more hemorrhages. Despite these sober findings, total mortality was lower with OAT.7 In the absence of data on cause-specific death, we can only hypothesize potential explanations for this puzzling finding, which may comprise a lower rate of severe (lifelimiting) strokes with OAT, a lower rate of atherosclerotic events, or pure play of chance, driven by the relatively short follow-up period. Of note, cohort analyses cannot provide the same evidence level as randomized, controlled trials, and data from administrative registries are particularly imprecise and prone to bias. Their quality, which substantially depends on the correctness of data input by health care providers, falls behind that of specifically designed prospective cohort studies such as CRIC (Chronic Renal Insufficiency Cohort) study and GCKD (German Chronic Kidney Disease) study, let alone interventional trials. As 1 example, in administrative registries, comorbidities such as vascular disease, hypertension, and diabetes mellitus are not recorded Kidney International (2017) 91, 771–786
in a systematic and standardized way by treating physicians, which precludes a reliable calculation of thromboembolism (CHA2DS2-VASc) and bleeding risk scores. Thus, even with comprehensive and sophisticated adjustments, all these uncontrolled data are influenced by potentially neglected residual confounders and are unable to present more than an idea of the safety and efficacy of a particular treatment. Obviously, although these Canadian registry data further question the usefulness of OAT for stroke prevention in AF patients with a GFR <45 ml/min per 1.73 m2, the potential survival benefits with OAT fuels the discussion about the need for a randomized, controlled trial in this setting. With the currently limited evidence, clinical practices yield diverse standard operating procedures, dividing treating physicians into “believers” and “nonbelievers” regarding OAT for the primary prevention of embolism in AF patients with CKD. In our experience, nephrologists are more cautious and reluctant, whereas cardiologists tend to more willingly transfer guideline-based recommendations from the general
population to the CKD scenario. This discrepant approach is reflected by their society’s recommendations, which are more cautious in nephrology8 than in cardiology.1 As a second limitation, most published registry analyses of OAT among CKD patients with AF collected data in an era when few patients received NOACs.6,7 In the meantime, outside the field of nephrology, largescale clinical trials found NOACs to be at least as efficient as VKA for the prevention of thromboembolic events and at least as safe. In particular, the risk of intracerebral bleeding is much lower with NOACs than with VKAs. The benefit-to-risk ratio of NOACs reveals relevant interactions with renal function both in the upper and the lower GFR range.9 Fortunately, we now have subgroup analyses from all the large NOAC trials that prove noninferiority (partly even superiority) of all approved NOACs compared with warfarin in patients with mild to moderate CKD (down to patients with a creatinine clearance of 25 to 30 ml/min, roughly corresponding to CKD stages G3a and G3b).9
Indication for oral anticoagulation as stroke prevention in AF (if risk factor[s] present)
RCT(s) in the general population: Broad evidence that OAT reduces stroke risk
Cohort studies: Contradictory data and potentially more strokes in CKD stage G5 with OAT
Efficacy and safety of NOACs versus vitamin K antagonists (VKA)
RCT: NOACs noninferior (in some cases superior) to VKAs
RCT initiated Results not yet available in 2017 Mind potential risk of accumulation of NOAC
Association between stroke risk and renal function in AF
Risk of stroke and systemic embolism
Association between bleeding risk and renal function in AF
Bleeding risk
Prevalence of atrial fibrillation
NKD CKD G1 CKD G2
CKD G3a
CKD G3b
CKD G4
CKD G5
Figure 1 | Schematic summary of current evidence on oral anticoagulant therapy (OAT) for patients with atrial fibrillation (AF) across the spectrum of chronic kidney disease (CKD). NKD, no known kidney disease; NOACs, non–vitamin K antagonist oral anticoagulants; RCT(s), randomized controlled trial(s); VKA, vitamin K antagonists. 779
commentary
Several ongoing studies aim to compare NOACs and VKAs in patients with CKD stages G4 and G5. Even though these trials will be substantially smaller than trials from the general population, they will extend information on the safety and efficacy of NOACs to the most severe CKD GFR categories. Until these data are available, the lack of evidence precludes strong recommendations in favor of or against NOACs in CKD stage G4 and in dialysis patients, which is reflected in slightly different recommendations regarding NOAC use by European and US authorities. In particular, one first NOAC (apixaban) has been licensed for use among dialysis patients by the US Food and Drug Administration but not (yet) in Europe. Compared with other licensed NOACs, elimination of apixaban depends less on renal excretion; therefore, apixaban has a lower risk to accumulate in advanced CKD, but still requires, as do all NOACs available so far, adjustment for renal function. Perhaps novel NOACs that accumulate even less than apixaban in CKD may be available in the foreseeable future. On the other end of the GFR spectrum, the US Food and Drug Administration issued a black box warning cautioning against use of edoxaban if creatinine clearance exceeds 95 ml/min. Subgroup analyses from the ENGAGE TIMI-48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48) study suggest that edoxaban may become less effective than warfarin in patients with normal renal function, presumably because of (overly) effective renal elimination.9 Of note, pharmacokinetic studies (and subsequent recommendations of NOAC doses) still focus on creatinine clearance (estimated with the Cockcroft-Gault equation), whereas nephrologists are today accustomed to estimate the GFR with the CKDEPICrea equation. Substituting the latter
780
for the former may cause large dose errors, particularly when physicians will neglect that the CKD-EPICrea equation yields a GRF estimate that is standardized to a body surface area of 1.73 m2. However, for dosing adjustment in a given CKD patient, the actual rather than the BSAstandardized GFR is required. Thereby, GFR estimates from the CKD-EPI equation need correction for the actual BSA. As the Cockcroft-Gault equation integrates body weight and thus yields an estimator of the actual (nonstandardized) renal function, its results can directly be applied to a given CKD patient. Thus, although the CockcroftGault equation is much less precise than the CKD-EPI equation for definition and grading of chronic kidney disease, it will still be required for pharmacokinetic issues. In summary, cohort analyses of stroke prevention with OAT in CKD patients yield contradictory results, and, thus, they are of limited help for clinical practice. At best, these analyses may make nephrologists aware of the limited evidence of stroke prevention and of the higher bleeding risk in CKD patients with AF, but they are not convincing enough to keep CKD patients with their high risk of thromboembolism from receiving anticoagulation treatment. Facing the uncertainty and gaps in evidence of the risk/benefit ratio of OAT in advanced CKD (Figure 1), we suggest, as a potential cardiorenal consensus of CKD patients with AF and at least a moderate risk of thromboembolism (defined by a CHA2DS2-VASc score $2 for women and $1 for men), to offer preferably NOACs in CKD stage G3a/ 3b, to offer either NOACs or VKAs in CKD stage G4, taking into account patient characteristics and licensing regulation, and to choose between NOACs, VKAs, and no oral anticoagulation in CKD stage G5 patients on an individual basis. While writing this commentary in October 2016, the KDIGO (Kidney Disease: Improving Global Outcomes)
is convening a controversies conference on CKD and Arrhythmias in Berlin, Germany. It is hoped that the conference will offer a consensus recommendation on the use of VKAs and NOACs in advanced CKD patients with AF. DISCLOSURE
GHH received a speaker’s fee from Daiichi Sankyo. VB received research grants from Bayer, Pfizer, and Daiichi Sankyo in the last 3 years. REFERENCES 1. Kirchhof P, Benussi S, Kotecha D, et al., Task Force Members. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS: the Task Force for the 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 Endorsed by the European Stroke Organisation (ESO). Eur Heart J. 2016 Aug 27. http://dx.doi.org/10.1093/eurheartj/ ehw210. Accessed. 2. Hart RG, Pearce LA, Asinger RW, Herzog CA. Warfarin in atrial fibrillation patients with moderate chronic kidney disease. Clin J Am Soc Nephrol. 2011;6:2599–2604. 3. Providência R, Marijon E, Boveda S, et al. Meta-analysis of the influence of chronic kidney disease on the risk of thromboembolism among patients with nonvalvular atrial fibrillation. Am J Cardiol. 2014;114:646–653. 4. van Gorp RH, Schurgers LJ. New insights into the pros and cons of the clinical use of vitamin K antagonists (VKAs) versus direct oral anticoagulants (DOACs). Nutrients. 2015;7: 9538–9557. 5. Böhm M, Ezekowitz MD, Connolly SJ, et al. Changes in renal function in patients with atrial fibrillation: an analysis from the RE-LY trial. J Am Coll Cardiol. 2015;65: 2481–2493. 6. Tan J, Liu S, Segal JB, et al. Warfarin use and stroke, bleeding and mortality risk in patients with end stage renal disease and atrial fibrillation: a systematic review and metaanalysis. BMC Nephrol. 2016;17:157. 7. Keskar V, McArthur E, Wald R, et al. The association of anticoagulation, ischemic stroke, and hemorrhage in elderly adults with chronic kidney disease and atrial fibrillation. Kidney Int. 2017;91:928–936. 8. Herzog CA, Asinger RW, Berger AK, et al. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011;80:572–586. 9. Hijazi Z, Wallentin L. Renal function in atrial fibrillation: a multifaceted dilemma. Circulation. 2016;134:48–51.
Kidney International (2017) 91, 771–786