Anticoagulants in atrial fibrillation patients with chronic kidney disease

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1 Anticoagulants in atrial fibrillation patients with chronic kidney disease Robert G. Hart, John W. Eikelboom, Alistair J. Ingram and Charles A. Herzog Abstract Atrial fibrillation is an important cause of preventable, disabling stroke and is particularly frequent in patients with chronic kidney disease (CKD). Stage 3 CKD is an independent risk factor for stroke in patients with atrial fibrillation. Warfarin anticoagulation is efficacious for stroke prevention in atrial fibrillation patients with stage 3 CKD, but recent observational studies have challenged its value for patients with end-stage renal disease and atrial fibrillation. Novel oral anticoagulants such as dabigatran, apixaban and rivaroxaban are at least as efficacious as warfarin with reduced risks of intracranial haemorrhage. However, all these agents undergo renal clearance to varying degrees, and hence dosing, efficacy, and safety require special consideration in patients with CKD. Overall, the novel oral anticoagulants have performed well in randomized trials of patients with stage 3 CKD, with similar efficacy and safety profiles as for patients without CKD, albeit requiring dosing modifications. The required period of discontinuation of novel oral anticoagulants before elective surgery is longer for patients with CKD owing to their reduced renal clearance. Although much remains to be learned about the optimal use of these new agents in patients with CKD, they are attractive anticoagulation options that are likely to replace warfarin in coming years. Hart, R. G. et al. Nat. Rev. Nephrol. 8, (2012); published online 24 July 2012; doi: /nrneph REVIEWS Introduction Atrial fibrillation is a frequent cause of disabling ischaemic stroke owing to embolism of stasis-precipitated thrombi forming in the left atrial appendage in patients with this common cardiac dysrhythmia. Atrial fibrillation and chronic kidney disease (CKD) frequently coexist: about one-third of outpatients with atrial fibrillation have CKD, 1 and 15% of patients with CKD have atrial fibrillation based on ascertainment by electrocardiography or patient self-report. 2,3 Atrial fibrillation is nearly three times as frequent in patients with stage 3 CKD as in age-matched and sex-matched patients without CKD. 3 Multiple randomized trials have established warfarin anticoagulation to be highly efficacious for stroke prevention with acceptably low bleeding rates for most patients with atrial fibrillation. Warfarin is currently recommended by most guidelines for patients with atrial fibrillation who have a substantial absolute risk of stroke. Patients with advanced renal disease have been excluded from participation in recent randomized trials of antithrombotic therapies in patients with atrial fibrillation because of their increased risk of bleeding and, for some agents, renal clearance of the drugs being tested. Competing interests R. G. Hart and J. W. Eikelboom declare associations with the following companies: Bayer Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb. C. A. Herzog declares an association with the following company: Johnson and Johnson. See the article online for full details of the relationships. A. J. Ingram declares no competing interests. Consequently, the efficacy for stroke prevention and the safety of anticoagulants have been poorly defined for CKD patients with atrial fibrillation. Because of the practical challenges associated with warfarin use that include ongoing adjustment of warfarin dose to maintain anticoagulation intensity in a relatively narrow therapeutic range, novel oral anticoagulants have recently been introduced that are more selective in their anticoagulant mechanisms, and are easier to dose without the need for regular laboratory monitoring of anticoagulant effect. 4 The relative roles of warfarin versus the novel oral anticoagulants are areas of ongoing research and controversy, 5,6 as much remains to be learned about the optimal use of the novel oral anticoagulants outside of clinical trials and in specific patient subgroups, particularly in patients with CKD. Nevertheless, it is likely that the current generation of novel oral anticoagulants will eventually replace warfarin as the preferred anticoagulant for many, and probably most, patients with atrial fibrillation. Here we review available data relevant to anticoagulation of CKD patients with atrial fibrillation, considering patients with stages 3 and 4 CKD and end-stage renal disease (ESRD) separately. Although dual antiplatelet therapy with clopidogrel and aspirin also reduces the incidence of stroke in patients with atrial fibrillation, it is less efficacious than warfarin and insufficient data are available concerning the safety of long-term dual antiplatelet therapy in patients with CKD; therefore, dual antiplatelet therapy is not considered here. 7,8 Division of Neurology (R. G. Hart), Division of Hematology and Thromboembolism (J. W. Eikelboom), Division of Nephrology (A. J. Ingram), Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada. Division of Cardiology, Department of Medicine, Hennepin County Medical Center, 701 Park Avenue, Minneapolis, MN 55415, USA (C. A. Herzog). Correspondence to: R. G. Hart NATURE REVIEWS NEPHROLOGY VOLUME 8 OCTOBER

2 Key points Atrial fibrillation is particularly frequent in patients with chronic kidney disease (CKD) Stage 3 CKD is an independent risk factor for stroke in patients with atrial fibrillation Recent observational studies have challenged the value of warfarin anticoagulation for patients with end-stage renal disease and atrial fibrillation Novel oral anticoagulants such as dabigatran, apixaban and rivaroxaban are noninferior or superior to warfarin, with reduced risks of intracranial haemorrhage In randomized trials to date, the novel oral anticoagulants have performed well in patients with stage 3 CKD, with similar efficacy and safety profiles as for patients without CKD, although dosing modifications are required The required period of discontinuation of novel oral anticoagulants before elective surgery is longer for patients with CKD than for patients without renal dysfunction Novel oral anticoagulants In the past decade, four novel oral anticoagulants (two direct thrombin inhibitors ximelagatran and dabigatran, and two factor Xa inhibitors apixaban and rivaroxaban) have been tested in large phase III randomized trials for prevention of stroke in patients with atrial fibrillation Phase III trial results regarding a fifth agent (the factor Xa inhibitor edoxaban) are anticipated in late 2012 (Table 1). 15 All trials have excluded participants with severe renal impairment. Ximelagatran was withdrawn from the market in 2006 due to rare, but serious, hepatotoxicity. Additional novel oral anti coagulants, some with reduced renal clearance, are under development, but are not anticipated to be available for clinical use in the near future. The novel anticoagulants mentioned above share the advantage of not requiring regular anticoagulation monitoring and frequent dose adjustments. On the downside, no antidote to rapidly reverse anticoagulant effect has been established to date for any of the novel anticoagulants in the event of acute serious bleeding (other than acute haemo dialysis for those agents that are not highly protein-bound such as dabigatran). 16 All currently available novel oral anticoagulants have substantial renal clearance, with half-lives prolonged in patients with CKD (Table 1). Four recent large randomized trials have assessed the efficacy and safety of the three novel oral anti coagulants (dabigatran, apixaban, and rivaroxaban) that are currently approved for clinical use (Table 2) These three agents were shown to be noninferior or superior to adjusted-dose warfarin for stroke prevention. Serious bleeding with the new agents in clinical trials has been comparable to, or less than that with high-quality warfarin anticoagulation. The reduced risk of intracranial haemorrhage with the new oral anticoagulants compared with warfarin was unexpected, but consistent and important as intra cranial haemorrhage is the most devastating complication of warfarin anticoagulation. 17 Compared with warfarin, dabigatran was associated with significantly reduced cardiovascular mortality, apixaban was associated with significantly reduced total mortality, and rivaroxaban was associated with a trend toward reduced mortality (P = 0.15). Of note, concern has been raised about bleeding risks in frail, elderly patients with renal impairment who are given dabigatran, the novel oral anticoagulant most widely used to date outside of clinical trials. 18,19 Warfarin in patients with CKD The efficacy of warfarin for stroke prevention in patients with atrial fibrillation is proportional to the quality of anticoagulation (that is, by sustaining the optimal intensity of warfarin anticoagulation over time). Observational studies suggest that increased time-in-therapeutic range (TTR) with an international normalized ratio (INR) of 2 3 predicts improved clinical outcomes, including reduction in stroke and bleeding However, a higher achieved average TTR in these studies might reflect healthier patients (for example, fewer concomitant medications, less liver disease and less frequent heart failure with hepatic congestion), and better outcomes could be a result of better concomitant care for which INR control is a marker. Hence, the link Table 1 Key pharmacological characteristics of novel oral anticoagulants Feature Dabigatran etexilate Drug Apixaban Rivaroxaban Edoxaban Coagulation target Thrombin Factor Xa Factor Xa Factor Xa Prodrug Yes No No No Bioavailability (%) Not known Protein binding (%) Dosing frequency* Twice daily Twice daily Once daily Once daily Half-life (h) Renal clearance (%) Routine monitoring No No No No Drug interactions P-glycoprotein CYP3A4 and P glycoprotein CYP3A4 and P glycoprotein CYP3A4 and P glycoprotein Approved for ESRD No No No No *For patients with atrial fibrillation. Abbreviation: ESRD, end-stage renal disease. Adapted with permission from Wolters Kluwer Health Eikelboom, J. W. & Weitz, J. I. New anticoagulants. Circulation 121 (13), (2010). 570 OCTOBER 2012 VOLUME 8

3 Table 2 Overview of phase III randomized trials of new oral anticoagulants* Study (n) Agents Design features RE-LY 9 (18,113) AVERROES 10 (5,599) ROCKET AF 11 (14,264) ARISTOTLE 12 (18,201) Dabigatran 150 mg or 110 mg twice daily vs warfarin Apixaban 5 mg twice daily vs aspirin Rivaroxaban 20 mg per day vs warfarin Apixaban 5 mg twice daily vs warfarin Warfarin given open-label Double-blind; restricted to those deemed unsuitable for warfarin Double-blind; restricted to those at high risk of stroke Double-blind Exclusion criteria related to CKD ecrcl <30 ml/min Serum creatinine >221 μmol/l or ecrcl <25 ml/min ecrcl <30 ml/min Serum creatinine >221 μmol/l or ecrcl <25 ml/min Dose adjustment related to CKD None 2.5 mg twice daily if serum creatinine 133 μmol/l plus age 80 years or weight 60 kg 15 mg per day if CrCl <50 ml/min 2.5 mg twice daily if serum creatinine 133 μmol/l plus age 80 years or weight 60 kg Stage 3 CKD (%) 19% ecrcl ml/ min 30% ecrcl ml/ min 21% ecrcl ml/ min 15% ecrcl ml/ min Mean time in therapeutic range (INR 2 3) Main results 64% Stroke, non-cns embolism and cardiovascular mortality reduced by dabigatran 150 mg vs warfarin; major haemorrhage reduced by dabigatran 110 mg vs warfarin; intracranial bleeding reduced by both doses of dabigatran vs warfarin; no significant difference in total mortality NA Stroke and non-cns embolism reduced by apixaban vs aspirin; major haemorrhage and intracranial bleeding comparable with both agents; no significant difference in cardiovascular or total mortality 55% Rivaroxaban noninferior to warfarin for stroke and non-cns embolism; major haemorrhage comparable with both agents; intracranial bleeding reduced by rivaroxaban vs warfarin; no significant difference in cardiovascular or total mortality 62% Stroke, non-cns embolism, major haemorrhage, intracranial bleeding and total mortality reduced by apixaban vs warfarin; no significant difference in cardiovascular mortality *Publication of the phase III ENGAGE AF TIMI 48 trial testing the factor Xa inhibitor edoxaban is anticipated in late Among all participants; for results in subgroups of patients with stage 3 CKD, see Table 3. Abbreviations: CKD, chronic kidney disease; CNS, central nervous system; ecrcl, estimated creatinine clearance; INR, international normalized ratio; NA, not available. between higher TTR and improved clinical outcomes may be causal or reflect an association, or likely both. For patients with atrial fibrillation receiving warfarin in clinical practice, TTRs average 55%, 23,24 and in recent randomized trials, the mean TTRs ranged from 55% to 64% (Table 2). 9,11,12 Among patients with atrial fibrillation assigned to warfarin in the ROCKET AF trial, 1,476 participants with estimated creatinine clearance (ecrcl) of ml/min had a median TTR of 58%, identical to that of other participants. 25 A general impression exists that anticoagulation control is particularly difficult in patients with ESRD and atrial fibrillation who are given warfarin, but data are limited and inconsistent. Studies have typically reported the average of all recorded INRs or the fraction of all INRs that fall within the therapeutic range, but these metrics generally underestimate the TTR. In a small retrospective study of 11 patients with ESRD given warfarin (five for atrial fibrillation and six for venous thromboembolism), the TTR for the conventional target INR range of 2 3 was 50%. 26 In a prospective study from an anticoagulation clinic, patients with severe renal disease (47 of 53 undergoing dialysis) followed for approximately 1 year, 40% of all INRs were in the therapeutic range (the TTR was not provided), and the average maintenance warfarin dosage was significantly lower than for patients without renal failure (3.9 mg per day versus 4.8 mg per day, respectively). 27 A trial of low-intensity warfarin (target INR ) in 56 patients on haemodialysis reported 47% of INRs to be in the target range. 28 Stage 3 CKD patients with atrial fibrillation Stroke risk and warfarin efficacy Atrial fibrillation is not uncommon (18% in one large study 2 ) among patients with predialysis CKD. Conversely, one-third of outpatients with atrial fibrillation have CKD. 1 Among atrial fibrillation participants in recent randomized trials of anticoagulant therapy with exclusion criteria based on renal function and whose patients were younger than population-based atrial fibrillation cohorts, 15 21% had an ecrcl of ml/min. 9,10,12,25 Stage 3 CKD is an independent predictor of stroke in patients with atrial fibrillation (hazard ratio [HR] ~1.5), after adjustment for other risk factors. 1,29 31 The mechanisms underlying the increased risk of stroke conferred by stage 3 CKD status in patients with atrial fibrillation are unclear and probably multiple. 1 Stage 3 CKD may be a marker for end-organ damage from hypertension and diabetes mellitus, adding predictive information that is not captured by considering just the prevalence (but not the severity, duration, or treatment) of vascular factors. The magnitude conferred by stage 3 CKD status on stroke risk is similar to other predictors in the widely used CHADS 2 scheme. 32,33 Among 89 participants in the Stroke Prevention in Atrial Fibrillation (SPAF) III trials with stage 3 CKD and a CHADS 2 score of 0, the observed stroke risk without anticoagulation was 2.3% per year (that is, moderate risk), albeit based on only three events. 30 In our view, all atrial fibrillation patients with stage 3 CKD should be considered to NATURE REVIEWS NEPHROLOGY VOLUME 8 OCTOBER

4 Table 3 Phase III trials of antithrombotic therapies in atrial fibrillation patients with moderate CKD Study Agent n CKD severity Interventions Outcomes in CKD participants SPAF III 30 Warfarin 516 egfr ml/min* Mean 50 ml/min Warfarin INR 2 3 vs low, ineffective-dose warfarin plus aspirin RE-LY 9 Dabigatran 3, ml/min Warfarin INR 2 3 vs dabigatran 150 mg or 110 mg twice daily AVERROES 10,29 Apixaban 1,697 egfr ml/min* Apixaban 5 mg twice daily vs aspirin ARISTOTLE 12 Apixaban 3, ml/min Apixaban 5 mg twice daily vs warfarin ROCKET AF 25 Rivaroxaban 2, ml/min Median 42 ml/min Warfarin INR 2 3 vs rivaroxaban 15 mg daily Ischaemic stroke/systemic embolism reduced by 76% (95% CI 42 90), by warfarin (P <0.001) Stroke/non-CNS embolism rate 2.8% per year with warfarin, 2.2% per year with dabigatran 110 mg twice daily (NS), and 1.5% per year with dabigatran 150 mg twice daily (P <0.01); similar rates of major haemorrhage in all three treatment arms Stroke/non-CNS embolism rate 5.6% per year with aspirin vs 1.8% per year with apixaban (P <0.001); major bleeding 2.2% per year on aspirin vs 2.5% per year with apixaban (NS) Stroke/non-CNS embolism rate 2.7% per year with warfarin, 2.1% per year with apixaban (NS); major bleeding reduced by half with apixaban vs warfarin (P <0.01) Stroke/non-CNS embolism rate 3.4% per year with warfarin, 3.0% per year with rivaroxaban (NS); major bleeding rates nearly equal *Based on the CKD EPI equation. 71 ecrcl using the Cockcroft Gault formula. 39 Restricted to patients with atrial fibrillation deemed unsuitable for adjusteddose warfarin. 10 Dosage reduced to 2.5 mg twice daily for participants with two of the following criteria: age 80 years, body weight 60 kg, or serum creatinine concentration 133 μmol/l. Abbreviations: CKD, chronic kidney disease; CNS, central nervous system; ecrcl, estimated creatinine clearance; egfr, estimated glomerular filtration rate; INR, international normalized ratio; NS, not significant. have at least moderate stroke risk, independent of other predictive factors. Among those with stage 3 CKD, the CHADS 2 score seems to additionally stratify stroke risk based on two studies. 29,30 Of note, these correlations are based on ecrcl or estimated glomerular filtration rate (egfr) calculated from a single measurement of serum creatinine and sensitive to variations and error in laboratory measurement. Warfarin anticoagulation markedly reduces the incidence of stroke in stage 3 CKD patients with atrial fibrillation. In a subgroup analysis of 516 atrial fibrillation participants with stage 3 CKD in the randomized SPAF III trial, ischaemic stroke or systemic embolism was reduced by 76% (95% CI 42 90, P <0.001) by adjusted-dose warfarin compared with aspirin plus low, ineffective doses of warfarin (Table 3). 30 Bleeding during warfarin anticoagulation In recent randomized trials, participants with stage 3 CKD had consistently higher rates of major haemorrhage during warfarin anticoagulation than did other participants, but whether this outcome would persist if adjusted for age and underlying cause of CKD is unclear. In the ROCKET AF trial, major haemorrhage with warfarin occurred at a rate of 3.2% per year in those with an ecrcl of >50 ml/min (mean age 71 years) versus 4.7% per year in those with an ecrcl of ml/min (mean age 79 years). 25 In the ARISTOTLE trial, major haemorrhage was more than twice as frequent among participants with an ecrcl of ml/min given warfarin compared with other participants (6.4% per year versus 2.5% per year, respectively). 12 Warfarin-assigned participants with an ecrcl of ml/min in the RE LY study had a substantial rate of major haemorrhage (5.4% per year), which was higher than that of other participants (3.2% per year). 9 However, these higher rates are not adjusted for differences in age. A longitudinal cohort analysis found stage 3 CKD not to be an independent predictor of major or minor haemorrhage during warfarin anticoagulation. 27 In short, it is clear that atrial fibrillation patients with stage 3 CKD have about twice the rate (averaging about 5% per year in recent clinical trials) of major bleeding during warfarin anticoagulation compared with those with better renal function, but it is uncertain whether this outcome is accounted for by differences in age and other associated comorbidities. Four schemes to stratify risk of bleeding during warfarin anticoagulation have been published to date, and three have included abnormal renal function as a risk factor. 34,36,37 In the derivation dataset of the ATRIA scheme, an ecrcl of <30 ml/min was an independent predictor of major haemorrhage. 36 None of these schemes has yet been sufficiently validated for general clinical use. 38 Novel oral anticoagulants All recent phase III randomized trials evaluating the novel oral anticoagulants in patients with atrial fibrillation have included participants with stage 3 CKD (Table 2). In most trials, results were reported for subgroups with an ecrcl (assessed using the Cockcroft Gault formula) 39 between 30 ml/min and 49 ml/min (that is, the lower two-thirds of the conventional stage 3 CKD range). 572 OCTOBER 2012 VOLUME 8

5 In the RE LY randomized trial, which compared two doses of dabigatran with warfarin, patients were excluded if their ecrcl was <30 ml/min. 9 Dabigatran trough levels correlate with efficacy for stroke prevention and are altered in patients with CKD because about 80% of dabigatran is excreted unchanged by the kidney. 40 The efficacy of dabigatran compared with warfarin in a subgroup of 3,505 participants with an ecrcl of ml/min has been reported. 9 The rate of stroke or non-central-nervous-system embolism was 2.8% per year among those assigned to warfarin, 1.5% per year (P <0.01) in those given dabigatran 150 mg twice daily, and 2.2% per year in those given dabigatran 110 mg twice daily (Table 3, Figure 1). 9 Although significantly fewer major haemorrhages occurred in those assigned to dabigatran 110 mg twice daily versus warfarin among all RE LY participants, major haemorrhage rates were about equal with warfarin and dabigatran among those with an ecrcl of ml/min. 41 However, there was no statistical heterogeneity of effect according to renal function, so cautious interpretation requires that the reduced rate of major haemorrhages observed with the dabigatran 110 mg dose in the total cohort be applied to participants with stage 3 CKD. In summary, those with an ecrcl ml/min in the RE LY trial had a significantly reduced rate of stroke with the 150 mg twice daily dose compared with warfarin, and with a similar rate of major haemorrhage. 9,41 For the dabigatran 110 mg twice daily dose compared with warfarin, there was no significant differences in stroke or major haemorrhage among participants with an ecrcl of ml/min. The AVERROES trial compared apixaban with aspirin in patients with atrial fibrillation deemed unsuitable for warfarin, mostly owing to a perceived risk of bleeding or patient preference (40% had previously received a vitamin K antagonist). 10 Participants were assigned to apixaban 5 mg twice daily, reduced to 2.5 mg twice daily in participants with a serum creatinine concentration 1.5 mg/dl ( 133 μmol/l) and either age 80 years or body weight 60 kg. In the subgroup of patients with stage 3 CKD (n = 1,697, 30% of the cohort, mean egfr 49 ml/min), apixaban significantly reduced the rate of stroke compared with aspirin (1.8% per year versus 5.6% per year, respectively; HR 0.32, 95% CI , P <0.001). 29 No significant difference was found in major haemorrhage in patients with stage 3 CKD by treatment: 2.2% per year with aspirin versus 2.5% per year with apixaban (HR 1.2, 95% CI ). The ARISTOTLE randomized trial assessed apixaban 5 mg twice daily in 18,201 patients with atrial fibrillation and reported superiority to warfarin in preventing stroke or systemic embolism (HR 0.79, 95% CI ), with less bleeding and lower mortality. 12 The dose of apixaban was reduced to 2.5 mg twice daily for participants who had a serum creatinine concentration 1.5 mg/dl ( 133 μmol/l) and either age 80 years or a body weight 60 kg. Among 3,017 participants with an ecrcl of ml/min (89% between ml/min), stroke rates were higher than in other participants, but the efficacy of apixaban relative to warfarin in this subgroup (HR 0.78) Relative risk reduction Dabigatran 150 mg Stroke or systemic embolism Major haemorrhage Dabigatran 110 mg Anticoagulant Apixaban Rivaroxaban Figure 1 Relative risk reductions in stroke or systemic embolism and major haemorrhage by novel oral anticoagulants versus warfarin in patients with moderate CKD. 9,12,25 Patients with CKD had estimated creatinine clearances of ml/min, except for those treated with apixaban (25 50 ml/min). Risk reductions were statistically significant for dabigatran 150 mg on stroke and for apixaban on major haemorrhage. Abbreviation: CKD, chronic kidney disease. was not statistically different from that of other participants. 12 There was a significant interaction between the effect of apixaban (given in the reduced dose to many patients with reduced ecrcl per protocol) versus warfarin on major haemorrhage according to renal impairment (P = 0.03); those with an ecrcl of ml/min had half the rate of major haemorrhage with apixaban (3.3%) versus warfarin (6.7%). Based on the available results of the ARISTOTLE trial, apixaban administered according to the renal dose-adjusted scheme resulted in a trend toward superior efficacy and significantly less bleeding than warfarin for those with reduced ecrcl (Figure 1). The ROCKET AF randomized trial excluded participants with an ecrcl <30 ml/min and reduced the dose of rivaroxaban to 15 mg per day for those with an ecrcl of ml/min. 11,25 Among these 2,950 participants (21% of the total trial cohort), the median TTR was 58% and was not different from the TTR in those with a higher ecrcl. 25 By intention-to-treat analysis, the rate of stroke or non-central-nervous-system embolism was 3.4% per year with warfarin and 3.0% per year with rivaroxaban (HR 0.86, 95% CI ) with no heterogeneity of treatment effect compared with other participants. In participants with CKD, the rates of the composite of major haemorrhage or clinically relevant nonmajor bleeding were similar among those given rivaroxaban and warfarin (HR 0.98, 95% CI ). 25 A reduction in intracranial haemorrhage with rivaroxaban compared with warfarin was evident in those with reduced ecrcl given rivaroxaban 15 mg daily, albeit not statistically significant (HR 0.81, 95% CI ), but commensurate with the effect in the entire trial. In short, there was no evidence of heterogeneity for any outcome comparing the treatment effects of rivaroxaban versus warfarin between those with versus those without reduced ecrcl. 25 NATURE REVIEWS NEPHROLOGY VOLUME 8 OCTOBER

6 Warfarin INR ( ) Apixaban 2.5/5.0 mg twice daily 0.32 ( ) HR (95% CI) Anticoagulant better Aspirin better Figure 2 Hazard ratios for subgroups of patients with stage 3 CKD from two randomized trials comparing anticoagulation with aspirin. 29,30 For warfarin comparison from the SPAF III study, the outcome was ischaemic stroke and systemic embolism and the aspirin group additionally received low, ineffective doses of warfarin. 30 For apixaban the outcome was stroke and systemic embolism. 29 Abbreviations: CKD, chronic kidney disease; HR, hazard ratio; INR, international normalized ratio. Dabigatran 110 mg twice daily 0.77 ( ) Dabigatran 150 mg twice daily 0.55 ( ) Rivaroxaban 15 mg once daily 0.86 ( ) Apixaban 2.5/5.0 mg twice daily 0.79 ( ) HR (95% CI) New oral anticoagulant better Warfarin better Figure 3 Hazard ratios for subgroups of patients with stage 3 CKD (estimated creatinine clearances ml/min or ml/min for apixaban) from randomized trials comparing novel oral anticoagulants with warfarin for the primary outcome of stroke and systemic embolism. 9,12,25 The width of the 95% CI are estimated from published figures for dabigatran and apixaban. 9,12 Abbreviations: CKD, chronic kidney disease; HR, hazard ratio. Based on this absence of hetero geneity, the overall trial results are assumed to apply to best characterize the effect in the subgroup with ecrcl of ml/min treated with rivaroxaban 15 mg per day: rivaroxaban is noninferior to warfarin for prevention of stroke with similar risks of major bleeding and reduced risks of intracranial and fatal bleeding. 11 Randomized trials and regulatory agency approvals Five randomized trials that included 11,685 patients with stage 3 CKD (with some with stage 4 CKD) and atrial fibrillation have tested four anticoagulants (Table 3). The two trials (SPAF III 30 and AVERROES 29 ) that compared oral anticoagulation with aspirin in 2,213 patients with CKD confirm that the large reduction in stroke conferred by warfarin and apixaban in patients with atrial fibrillation overall extends to those with stage 3 CKD (Figure 2). Given the substantial rates of major haemorrhage during warfarin anticoagulation in patients with stage 3 CKD described above, does the absolute reduction in stroke outweigh the absolute increase in major haemorrhage? Too few major bleeding events were observed in the SPAF III trial for meaningful analysis. 30 Among participants with stage 3 CKD in the AVERROES trial, there was an absolute reduction in stroke of 3.8% per year and a 0.3% per year increase in major haemorrhage with apixaban versus aspirin. 29 Based on these limited data from randomized trials, the benefit seems to substantially exceed the risk, and most patients with stage 3 CKD and atrial fibrillation are likely to importantly benefit from anticoagulation. That participants in clinical trials are selected as healthier and less prone to bleeding complications than the average patient seen in clinical practice is an important caveat, however. 18 Randomized comparisons of three novel oral anticoagulants with warfarin involving 9,472 participants with CKD indicate superiority or noninferiority to warfarin for stroke prevention (Figure 3) with comparable or reduced bleeding risks (Figure 1). Consequently, the novel oral anticoagulants seem to be reasonable alternatives to warfarin for stroke prevention in stage 3 CKD patients with atrial fibrillation. The FDA, 42,43 Health Canada, 44,45 and European Medicines Agency 46,47 have approved dabigatran and rivaroxaban for use in atrial fibrillation patients with stage 3 CKD; apixaban is currently undergoing evaluation by these regulatory agencies (Table 4). In our view, it cannot be determined with confidence which of the novel oral anticoagulants is preferred in stage 3 CKD patients with atrial fibrillation. Single trials, wide confidence intervals surrounding the estimated effects in subgroups of patients with CKD, absence of significant interactions of CKD subgroups with overall effects, differences in trial populations, differing dosing regimens, and lack of head-to-head comparisons combine to prevent reliable comparisons. Stage 4 CKD patients with atrial fibrillation Small numbers of participants with stage 4 CKD (egfr ml/min) were included in the ARISTOTLE randomized trial comparing apixaban with warfarin (n = 270) 12 and in the AVERROES randomized trial comparing apixaban with aspirin (n = 70), 29 but no results for these subgroups have been published. The FDA has approved a reduced dose of dabigatran (75 mg twice daily) for patients with stage 4 CKD, 42 based on pharmaco kinetic and pharmacodynamic studies. 48 Other regulatory agencies have not approved the use of dabigatran in patients with stage 4 CKD (Table 4). Rivaroxaban 15 mg per day has been approved by some major regulatory agencies for stage 4 CKD, 43,47 although such patients were excluded from participation in the ROCKET AF trial (Table 4). We are unaware of clinical end point data supporting efficacy or safety of either dabigatran or rivaroxaban in patients with stage 4 CKD. Similarly, no data exist to support the efficacy and safety of warfarin for stage 4 CKD patients with atrial fibrillation, although advocated by some guidelines. 49 Stage 4 CKD emerged as an independent predictor of major haemorrhage during warfarin anticoagulation from multivariate analysis of one large outpatient cohort study of patients with atrial fibrillation. 36 Interrupting anticoagulation for surgery Because the half-life of the novel oral anticoagulants is prolonged in patients with CKD, longer interruption 574 OCTOBER 2012 VOLUME 8

7 Table 4 Major regulatory agency recommendations for novel oral anticoagulants in patients with CKD* Agency FDA 42,43 European Medicines Agency 46,47 Health Canada 44,45 Drug Dabigatran Apixaban Rivaroxaban Stage 3 CKD: 150 mg twice daily NR 15 mg daily for CrCl ml/min Stage 4 CKD: 75 mg twice daily Stage 3 CKD: 110 mg twice daily if aged >80 years or at high risk of bleeding Stage 4 CKD: not approved CrCl ml/min: either 110 mg or 150 mg twice daily except 110 mg twice daily for those aged >75 years and CrCl <50 ml/min Stage 4 CKD: not approved NR NR 15 mg daily for CrCl ml/min 15 mg daily for CrCl ml/min Stage 4 CKD: not approved *Edoxaban has not been considered by these agencies. Reduce the dose to 75 mg twice daily in stage 3 CKD when given with systemic ketoconazole or dronedarone; avoid use of dabigatran in stage 4 CKD with P glycoprotein inhibitors. Abbreviations: CKD, chronic kidney disease; CrCl, creatinine clearance; NR, no recommendations to date. of treatment for these patients is required before elective surgery. 50 For patients with an ecrcl of ml/ min, the half-life of dabigatran is estimated to be 18 h. Withdrawing dabigatran for 2 4 days (and at least 5 days for patients with stage 4 CKD) and a normal activated partial thromboplastin time before surgery is recommended. 51 For rivaroxaban, with less renal clearance than dabigatran, withholding treatment for 2 days in patients with stage 3 CKD and 3 days in patients with stage 4 CKD is recommended. In the event of massive haemorrhage, haemodialysis can be used in patients receiving dabigatran, but not for the more highly protein-bound rivaroxaban and apixaban (Table 1). Although factor VIIa and four-factor prothrombin complex concentrates have been used in these situations, their value in reversing the clinical anticoagulant effects and controlling clinical haemorrhage is uncertain. 16 Humanized Fab fragment for dabigatran, and recombinant, active-site-blocked G1a-domainless factor Xa to neutralize rivaroxaban and apixaban, are under development. ESRD patients with atrial fibrillation Among patients on haemodialysis, the overall prevalence of atrial fibrillation is variously estimated at 7 20%, at least double that of age-matched patients without ESRD The frequency is most strongly related to age; in the study by Genovesi et al., the cross-sectional prevalence of atrial fibrillation was 17% in patients on haemodialysis aged years, increasing to 37% for those aged years. 53 In an analysis of USRDS/Medicaid data, there was a graded increase from approximately 2% to 17% over the age range <55 years to >85 years. 54 Atrial fibrillation was an independent risk factor for ischaemic stroke in patients with ESRD in the study by Vázquez et al. (odds ratio 2.3, 95% CI ) 55 and in the DOPPS I and II analysis (HR 1.3, 95% CI ). 56 By contrast, the prospective study by Genovesi et al. found no increase in stroke in patients on haemodialysis with atrial fibrillation. 57 From available studies that are limited by small patient numbers, concurrent antithrombotic treatment, different methods of stroke detection and uncertain reliability of identification of atrial fibrillation, it is not possible to accurately estimate the rate of stroke in ESRD patients with atrial fibrillation who are not receiving antithrombotic therapy. For example, in one large dialysis clinic-based study, strokes were identified only at the time of hospitalization (that is, probable underdetection), patients with transient ischaemic attack were included, and nearly half had received warfarin. 52 A stroke rate of about 7% per year for all strokes (including intracerebral haemorrhage) is a reasonable estimate based on available data. 52,56 58 These imperfect data are, however, consistent with the notion that although the rates of stroke in ESRD patients with atrial fibrillation are higher than for ESRD patients without atrial fibrillation, the relative increase does not seem to be as large as that for patients without ESRD, in part because of the higher background stroke rate in patients with ESRD. Limited data exist regarding stratification of stroke risk in ESRD patients with atrial fibrillation. A large retrospective study of patients on haemodialysis with atrial fibrillation reported that increasing age, heart failure, and systolic blood pressure correlated with stroke risk among haemodialysis patients with atrial fibrillation, but whether these predictors resulted from multi variate analy sis was not clear. 52 Multivariate analysis of another study reported prior stroke, diabetes mellitus, and advancing age to be independently predictive of hospitalization for stroke, but hypertension and heart failure were not. 56 Both of these studies plus a third study 59 reported that the CHADS 2 scheme successfully stratified stroke risk in ESRD patients with atrial fibrillation, but the contribution of individual components of the CHADS 2 score seemed to differ. It is therefore uncertain how reliably the CHADS 2 scheme and other stroke risk stratification schemes apply to ESRD patients with atrial fibrillation. ESRD seems to be an independent risk factor for major haemorrhage during warfarin therapy. 27,60 In studies of US dialysis patients with atrial fibrillation between 1996 and 2004, 26 44% were treated with warfarin. 52,56 Despite the frequent use of warfarin in patients on haemo dialysis, data on bleeding rates are meagre. A systematic review of bleeding rates during warfarin anticoagulation in patients on haemodialysis published in 2007 identified only three studies and no randomized trials evaluating NATURE REVIEWS NEPHROLOGY VOLUME 8 OCTOBER

8 Table 5 Anticoagulation options for CKD patients with atrial fibrillation* CKD stage Anticoagulant options Stage 3 (egfr ml/min) Warfarin (target INR 2 3) Dabigatran 110 mg or 150 mg twice daily Apixaban 5 mg twice daily Rivaroxaban 15 mg daily for egfr ml/ min; 20 mg daily for egfr ml/min Stage 4 (egfr ml/min) Warfarin (target INR 2 3) Dabigatran 75 mg twice daily Rivaroxaban 15 mg daily ESRD (egfr <15 ml/min or dialysis) Primary prevention: no anticoagulation Secondary prevention: warfarin (target INR 2 3) *Recommendations based on results of large randomized trials for stage 3 CKD but not for stage 4 CKD or ESRD. Regulatory approvals are inconsistent (see Table 4). Relatively recent recommendation. Abbreviations: CKD, chronic kidney disease; egfr, estimated glomerular filtration rate; ESRD, end-stage renal disease; INR, international normalized ratio. conventional intensity warfarin. 61 In these three studies, the annualized bleeding rates for full- intensity warfarin anticoagulation were very high (10 54%). 61 Subsequently, 255 patients on haemodialysis were retrospectively analyzed according to time-dependent use of antithrombotic therapy and it was found that patients with ESRD on warfarin had a fourfold increase in major haemorrhage, with an absolute rate of 3.1% per year. 62 Patients on dialysis seem to spend less time within the therapeutic INR range, with a tendency to supratherapeutic INR values. 27 In addition to warfarin-associated haemorrhage, there is concern about accentuation of vascular calcification and calciphylaxis by chronic warfarin use in patients with ESRD. 63 Extrapolating the striking efficacy of warfarin anticoagulation shown in randomized clinical trials 64 to atrial fibrillation patients on haemodialysis, the 2005 K/DOQI guidelines state: Anticoagulation in nonvalvular atrial fibrillation: Dialysis patients are at increased risk for bleeding and careful monitoring should accompany intervention. 65 Recent retrospective analyses of large dialysis databases have raised concern regarding the efficacy of warfarin anticoagulation in haemodialysis patients with atrial fibrillation. 52,56,58,66 Studies from a national dialysis network of incident dialysis patients identified the use of warfarin with an increased risk of stroke and overall mortality. 52,66 The increased risk of stroke with warfarin demonstrated a dose effect with higher INRs associated with increased, not decreased, risk of stroke. 67 A study from the DOPPS database reported increased hazard ratio for stroke for those receiving warfarin. 56 This study also found that warfarin use in patients aged >75 years was associated with an increased risk of stroke (perhaps as a result of haemorrhagic stroke, although this effect could not be determined). An unacceptably high rate of haemorrhagic stroke (2.6% per year) has been reported in patients on haemodialysis given warfarin for atrial fibrillation with no apparent reduction in ischaemic stroke in a retrospective cohort study. 58 These observational data have prompted doubts about the value of warfarin anticoagulation in ESRD patients with atrial fibrillation Of note, an international survey of dialysis providers reported that 54% of responders recently changed opinion regarding the risk/benefit of warfarin for atrial fibrillation patients on dialysis and 71% believed that guidelines for warfarin anti coagulation established for the general population should not be extrapolated to patients on dialysis. 70 In our view and concordant with newly revised guidelines, 69 there are at present insufficient data to recommend routine anticoagulation with warfarin for ESRD patients with atrial fibrillation for the primary prevention of stroke. Previous nonlacunar cardioembolic stroke or transient ischemic attack, however, are such potent risk factors for subsequent disabling stroke that warfarin anticoagulation seems reasonable (but not mandatory) for secondary prevention of stroke in ESRD patients with atrial fibrillation. These recommendations are based on such low-quality evidence that it is reasonable not to discontinue warfarin in ESRD patients with atrial fibrillation who have had good INR control and without bleeding. At present, the novel oral anticoagulants discussed above have not been approved for use in patients with ESRD. There is an urgent need for randomized clinical trials of anticoagulant (warfarin and/or other novel anti coagulants with minimal renal clearance) for stroke prevention in ESRD patients with atrial fibrillation. Using egfr and ecrcl to tailor therapy Anticoagulation options for CKD patients with atrial fibrillation depend on the degree of renal impairment (Table 5). The clinical studies of patients with CKD and atrial fibrillation cited above used ecrcl or egfr using equations based on measurements of serum creatinine levels. Extrapolating the results of these studies to measure ment of creatinine clearance (CrCl) using timed urine collection would be tenuous, and we do not favour direct measurement of CrCl in routine clinical practice. In addition, for the same value of the serum creatinine concentration, the ecrcl will most often exceed the egfr, with the latter used to define the stage of CKD due to the difference in commonly used estimating equations. 39,71 73 Many clinical laboratories automatically provide an egfr that accompanies measurement of serum creatinine levels. 73 Consequently, it is challenging to apply these data to everyday clinical management, particularly the results of routine laboratory values for the egfr when clinical studies were based on ecrcl. 39,73 Given the uncertainties and pending additional information, we favour management based on egfr calculated by the CKD EPI equation 71 or the MDRD equation. 74 The egfr should be obtained before initiating anti coagulation and at least annually thereafter (and at least every 6 months in those with an egfr <45 ml/min). Before changing the dose of a novel oral anti coagulant or discontinuing anticoagulation for declining renal function, the serum creatinine measurement should be repeated after 1 month, and egfr reassessed due to instability related to laboratory measurement variation. 29,75 Conclusions CKD and atrial fibrillation frequently coexist. The presence of CKD is an important factor to consider 576 OCTOBER 2012 VOLUME 8

9 when anticoagulating patients with atrial fibrillation to prevent stroke, particularly when using the novel oral anti coagulants discussed in this Review. We speculate that future studies will result in further refinement of the optimal dosing of the novel oral anticoagulants in patients with CKD, but even at the current state of knowledge, they are attractive options that are likely to eventually replace warfarin for most stage 3 and 4 CKD patients with atrial fibrillation. Recent studies have challenged the value of warfarin anticoagulation for ESRD patients with atrial fibrillation except for those with prior embolic brain ischaemia. Oral anticoagulants suitable for use in ESRD patients with atrial fibrillation that are safer and easier to administer than adjusted-dose warfarin are urgently needed. Review criteria This Review was based on a combination of the working knowledge and expert opinion of the authors. The authors views were supported by citing the key relevant publications in the field. 1. Go, A. S. et al. for the ATRIA Study Investigators. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation. The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. Circulation 119, (2009). 2. Soliman, E. Z. et al. Chronic kidney disease and prevalent atrial fibrillation: the Chronic Renal Insufficiency Cohort (CRIC). Am. Heart J. 159, (2010). 3. Baber, U. et al. Association of chronic kidney disease with atrial fibrillation among adults in the United States: Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Circ. Arrhythm. Electrophysiol. 4, (2011). 4. Eikelboom, J. W. & Weitz, J. I. New anticoagulants. Circulation 121, (2010). 5. Ansell, J. New oral anticoagulants should not be used as first-line agents to prevent thromboembolism in patients with atrial fibrillation. Circulation 125, (2012). 6. Granger, C. B. & Armaganijan, L. V. Newer oral anticoagulants should be used as first-line agents to prevent thromboembolism in patients with atrial fibrillation and risk factors for stroke or thromboembolism. Circulation 125, (2012). 7. The ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N. Engl. J. Med. 360, (2009). 8. Connolly, 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 367, (2006). 9. Connolly, S. J. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 361, (2009). 10. Connolly, S. J. et al. for the AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N. Engl. J. Med. 364, (2011). 11. Patel, M. R. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 365, (2011). 12. Granger, C. B. et al. for the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 365, (2011). 13. Executive Steering Committee on behalf of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with nonvalvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 362, (2003). 14. SPORTIF Executive Steering Committee for the SPORTIF V Investigators. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA 293, (2005). 15. Ruff, C. T. et al. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective anticoagulation with factor xa next GEneration in Atrial Fibrillation- Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF TIMI 48). Am. Heart J. 160, (2010). 16. Kaatz, S. et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am. J. Hematol. 87 (Suppl. 1), S141 S145 (2012). 17. Hart, R. G. et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE LY trial. Stroke 43, (2012). 18. Harper, P., Young, L. & Merriman, E. Bleeding risk with dabigatran in the frail elderly. N. Engl. J. Med. 366, (2012). 19. U. S. Food and Drug Administration. Pradaxa (dabigatran etexilate mesylate): drug safety communication safety review of post-market reports of serious bleeding events [online], safetyinformation/ safetyalertsforhumanmedicalproducts/ ucm htm (2011). 20. Connolly, S. J. et al. on behalf of the ACTIVE W Investigators. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 118, (2008). 21. White, H. D. et al. Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control: results from SPORTIF III and V. Arch. Intern. Med. 167, (2007). 22. Jones, M. et al. Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvular atrial fibrillation: a record linkage study in a large British population. Heart 91, (2005). 23. Baker, W. L., Cios, D. A., Sander, S. D. & Coleman, C. I. Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J. Manag. Care Pharm. 15, (2009). 24. Rose, A. J., Ozonoff, A., Henault, L. E. & Hylek, E. M. Warfarin for atrial fibrillation in community-based practise. J. Thromb. Haemost. 6, (2008). 25. Fox, K. A. 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. 32, (2011). 26. To, A. C., Yehia, M. & Collins, J. F. Atrial fibrillation in haemodialysis patients: do guidelines for anticoagulation apply? Nephrology (Carlton) 12, (2007). 27. Limdi, N. A. et al. Kidney function influences warfarin responsiveness and hemorrhagic complications. J. Am. Soc. Nephrol. 20, (2009). 28. Crowther, M. A. et al. Low-intensity warfarin is ineffective for the prevention of PTFE graft failure in patients on hemodialysis: a randomized controlled trial. J. Am. Soc. Nephrol. 13, (2002). 29. Eikelboom, J. W. et al. Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease. J. Stroke Cerebrovasc. Dis. (in press). 30. Hart, R. G., Pearce, L. A., Asinger, R. W. & Herzog, C. A. Warfarin in atrial fibrillation patients with moderate chronic kidney disease. Clin. J. Am. Soc. Nephrol. 6, (2011). 31. Nakagawa, K. et al. Chronic kidney disease and CHADS 2 score independently predict cardiovascular events and mortality in patients with nonvalvular atrial fibrillation. Am. J. Cardiol. 107, (2011). 32. Gage, B. F. et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 285, (2001). 33. Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology 69, (2007). 34. Lip, G. Y., Frison, L., Halperin, J. L. & Lane, D. A. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. J. Am. Coll. Cardiol. 57, (2011). 35. Shireman, T. I. et al. Development of a contemporary bleeding risk model for elderly warfarin recipients. Chest 130, (2006). 36. Fang, M. C. et al. A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J. Am. Coll. Cardiol. 58, (2011). 37. Gage, B. F. et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am. Heart J. 151, (2006). 38. Loewen, P. & Dahri, K. Risk of bleeding with oral anticoagulants: an updated systematic review and performance analysis of clinical prediction rules. Ann. Hematol. 90, (2011). NATURE REVIEWS NEPHROLOGY VOLUME 8 OCTOBER

10 39. Cockcroft, D. W. & Gault, M. H. Prediction of creatinine clearance from serum creatinine. Nephron 16, (1976). 40. U. S. Food and Drug Administration. Dabigatran Briefing Document [online], downloads/advisorycommittees/ committeesmeetingmaterials/drugs/ cardiovascularandrenaldrugsadvisorycommittee/ ucm pdf (2010). 41. Eikelboom, J. W. et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial. Circulation 123, (2011). 42. U. S. Food and Drug Administration. FDA approved drug products: label information for PRADAXA [online], label/2012/022512s009lbl.pdf (2010). 43. U. S. Food and Drug Administration. FDA approved drug products: Xarelto [online], drugsatfda/index.cfm?fuseaction=search. Overview&DrugName=XARELTO (2011). 44. Health Canada. Drugs and Health Products: Pradax [online], noc-ac/info.do?lang=eng&no=11817 (2010). 45. Health Canada. Drugs and Health Products: Xarelto [online], noc-ac/info.do?lang=eng&no=12966 (2012). 46. European Medicines Agency. Product information: Pradaxa [online], europa.eu/docs/en_gb/document_library/ EPAR_-_Product_Information/human/000829/ WC pdf (2012). 47. European Medicines Agency. Product information: Xarelto [online], europa.eu/docs/en_gb/document_library/ EPAR_-_Product_Information/human/000944/ WC pdf (2012). 48. Stangier, J., Rathgen, K., Stähle, H. & Mazur, D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallelgroup, single-centre study. Clin. Pharmacokinet. 49, (2010). 49. Skanes, A. C. et al. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can. J. Cardiol. 28, (2012). 50. Warkentin, T. E. et al. Recombinant factor VIIa (rfviia) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood 119, (2012). 51. van Ryn, J. et al. Dabigatran etexilate a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb. Haemost. 103, (2010). 52. Chan, K. E., Lazarus, J. M., Thadhani, R. & Hakim, R. M. Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J. Am. Soc. Nephrol. 20, (2009). 53. Genovesi, S. et al. Prevalence of atrial fibrillation and associated factors in a population of longterm hemodialysis patients. Am. J. Kidney Dis. 46, (2005). 54. Wetmore, J. B. et al. The prevalence of and factors associated with chronic atrial fibrillation in Medicare/Medicaid-eligible dialysis patients. Kidney Int. 81, (2012). 55. Vázquez, E. et al. Comparison of prognostic value of atrial fibrillation versus sinus rhythm in patients on long-term hemodialysis. Am. J. Cardiol. 92, (2003). 56. Wizemann, V. et al. Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int. 77, (2010). 57. Genovesi, S. et al. Atrial fibrillation and morbidity and mortality in a cohort of long-term hemodialysis patients. Am. J. Kidney Dis. 51, (2008). 58. Winkelmayer, W. C., Liu, J., Setoguchi, S. & Choudry, N. K. Effectiveness and safety of warfarin initiation in older hemodialysis patients with atrial fibrillation. Clin. J. Am. Soc. Nephrol. 6, (2011). 59. Chou, C. Y. et al. Outcome of atrial fibrillation among patients with end-stage renal disease. Nephrol. Dial. Transplant. 25, (2010). 60. McMahon, D. A., Smith, D. M., Carey, M. A. & Zhou, X. H. Risk of major hemorrhage for outpatients treated with warfarin. J. Gen. Intern. Med. 13, (1998). 61. Elliott, M. J., Zimmerman, D. & Holden, R. M. Warfarin anticoagulation in hemodialysis patients: a systematic review of bleeding rates. Am. J. Kidney Dis. 50, (2007). 62. Holden, R., Harman, G. J., Wang, M., Holland, D. & Day, A. G. Major bleeding in hemodialysis patients. Clin. J. Am. Soc. Nephrol. 3, (2008). 63. Holden, R. M. & Booth, S. L. Vascular calcification in chronic kidney disease: the role of vitamin K. Nat. Clin. Pract. Nephrol. 3, (2007). 64. Hart, R. G., Pearce, L. A. & Aguilar, M. I. Metaanalysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann. Intern. Med. 146, (2007). 65. K/DOQI Workgroup. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am. J. Kidney Dis. 45, S1 S153 (2005). 66. Chan, K. E., Lazarus, J. M., Thadhani, R. & Hakim, R. M. Anticoagulant and antiplatelet usage associates with mortality among hemodialysis patients. J. Am. Soc. Nephrol. 20, (2009). 67. Yang, F., Chou, D., Schweitzer, P. & Hanon, S. Warfarin in haemodialysis patients with atrial fibrillation: what benefit? Europace 12, (2010). 68. Marinigh, R., Lane, D. A. & Lip, G. Y. Severe renal impairment and stroke prevention in atrial fibrillation: implications for thromboprophylaxis and bleeding risk. J. Am. Coll. Cardiol. 57, (2011). 69. Herzog, C. A. et al. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 80, (2011). 70. Barany, P. Warfarin treatment in ESRD: Survey Results [online], org/warfarin_treatment_in_esrd.htm (2012). 71. Levey, A. S. et al. for the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann. Intern. Med. 150, (2009). 72. Levey, A. S. & Coresh, J. Chronic kidney disease. Lancet 379, (2012). 73. Stevens, L. A., Coresh, J., Greene, T. & Levey, A. S. Assessing kidney function measured and estimated glomerular filtration rate. N. Engl. J. Med. 354, (2006). 74. Levey, A. S. et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann. Intern. Med. 130, (1999). 75. Coresh, J. et al. Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am. J. Kidney Dis. 39, (2002). Author contributions All authors contributed equally to discussion of content for the article, researching data to include in the manuscript, and reviewing and editing of the manuscript before submission. R. G. Hart and J. W. Eikelboom wrote the manuscript. 578 OCTOBER 2012 VOLUME 8

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