Use of Oral Anticoagulation in the Management of Atrial Fibrillation in Patients with ESRD: Con : Clinical Journal of the American Society of Nephrology

Journal Logo

Controversies in Nephrology

Use of Oral Anticoagulation in the Management of Atrial Fibrillation in Patients with ESRD: Con

Keskar, Vaibhav*; Sood, Manish M.

Author Information
Clinical Journal of the American Society of Nephrology 11(11):p 2085-2092, November 2016. | DOI: 10.2215/CJN.03200316
  • Free



Clinicians are faced with a difficult conundrum when deciding whether to prescribe anticoagulants for stroke prevention in kidney disease patients with atrial fibrillation. In the general population, the use of anticoagulants is well established by multiple, large randomized controlled trials. Furthermore, validated predictive scores exist that aid in identifying patients who will benefit the most (congestive heart failure, hypertension, anemia, diabetes mellitus and stroke [CHADS2], CHA2DS2-VASc) and who is at the highest risk of hemorrhagic complications (ORBI, HEMMORHAGE) (Table 1). This allows for informed decision-making regarding the risks and benefits of therapy. However, should the clinician extrapolate these data to patients with CKD/ESRD? Although reasonable, the nephrology literature contains numerous studies of therapies in the general population that did not work in CKD/ESRD (for example, renin angiotensin-aldosterone system blockade in dialysis patients to prevent cardiovascular outcomes). We argue that extrapolating the role of anticoagulation for stroke prevention in kidney disease patients with atrial fibrillation is currently not warranted. This review will discuss the following: (1) the unclear evidence for efficacy and significant limitations of the literature, (2) the large risk of complications related to therapy, (3) the inability to predict who should receive therapy, (4) the uncertainty of physicians, and (5) alternatives to warfarin. The discussion will be primarily focused on dialysis patients; however, summaries of studies in late stage CKD (stage 4/5) will be presented.

Table 1. - Atrial fibrillation stroke risk score and bleeding risk score acronyms
Stroke Risk Scores
  1. CHADS2

  2. • Congestive heart failure

  3. • Hypertension

  4. • Age ≥75 years

  5. • Diabetes mellitus

  6. Stroke or transient ischemic attack

  1. CHADS2-VASc

  2. • Congestive heart failure

  3. • Hypertension

  4. • Age ≥75 years

  5. • Diabetes mellitus

  6. Stroke or transient ischemic attack

  7. • Vascular disease

  8. • Age 65-74 years

  9. • Sex category

  1. R2CHADS2

  2. • Renal dysfunction

  3. • Congestive heart failure

  4. • Hypertension

  5. • Age ≥75 years

  6. • Diabetes mellitus

  7. Stroke or transient ischemic attack

Bleeding Risk Scores
  1. OBRI

  2. (Outpatient Bleeding Risk Index)

  3. • Age≥65

  4. • History of stroke

  5. • History of gastrointestinal bleeding

  6. • One or more of the following

  7.  • Recent myocardial infarction

  8.  • Hematocrit <30%

  9.  • Serum creatinine >1.5 mg/dL

  10.  • Diabetes mellitus


  2. • Hepatic or renal disease

  3. • Ethanol abuse

  4. • Malignancy

  5. • Older age (>75 years)

  6. • Reduced platelet count or function

  7. • Rebleeding risk (history of prior bleed)

  8. • Hypertension

  9. • Anemia

  10. • Genetic factors

  11. • Excessive fall risk

  12. Stroke


  2. • Hypertension

  3. • Abnormal renal and/or hepatic function

  4. Stroke

  5. • Bleeding tendency/predisposition

  6. • Labile INR on warfarin

  7. • Elderly (age >65 years)

  8. • Drugs (aspirin or NSAIDs) and/or alcohol

Is Warfarin Effective in Preventing Ischemic Strokes?

To date, randomized controlled trials assessing the efficacy and safety of warfarin in atrial fibrillation have systematically excluded patients with late stage CKD and those requiring RRT (1). As such, the entire evidence is based on observational studies; a few of which are small prospective studies and the majority retrospective administrative database studies. A selection of studies are summarized in Tables 2 and 3 (2–10).

Table 2. - Efficacy of warfarin in preventing ischemic strokes in CKD patients with atrial fibrillation
Study Country Design N Adjusted HR for Ischemic Stroke (95% CI) Comments
Banerjee et al., 2014 (9) France Retrospective 5912 (2982 with eGFR<60 ml/min per 1.73 m2 and 1550 on warfarin) 0.79 (0.44 to 1.42) a 1) Proteinuria data not available.
2) Small number of patients with eGFR≤30 ml/min per 1.73 m2.
Carrero et al., 2014 (8) Sweden Prospective 24317 (5292 on warfarin) eGFR>30–60 ml/min per 1.73 m2: 0.73 (0.66 to 0.80); 1) Postmyocardial infarct cohort so results may not be generalizable.
eGFR>15–30 ml/min per 1.73 m2: 0.84 (0.70 to 1.02); 2) GFR was determined by only one creatinine value. Potential for misclassification.
eGFR≤15 ml/min per 1.73 m2: 0.57 (0.37 to 0.86) 3) No INR data.
4) No data on duration of warfarin therapy or discontinuation rate.
5) Short follow-up 1 yr.
Lai et al., 2009 (10) United States Retrospective 399 (232 on warfarin) 0.71 (0.43 to 1.16) a 1) Unclear if incident atrial fibrillation population was studied.
2) Hemodialysis patients were grouped together with other CKD stages.
Olesen et al., 2012 (5) Denmark Retrospective 3587 (609 on warfarin) 0.84 (0.69 to 1.01) 1) CKD identified by ICD code.
2) GFR was determined by only one creatinine value. Potential for misclassification.
3) No INR data.
4) Unable to differentiate CKD stages.
HR, hazard ratio; 95% CI, 95 % confidence interval; INR, international normalized ratio; ICD, International Classification of Diseases.
aHazard ratio taken from reference Dahal et al. (12).

Table 3. - Efficacy of warfarin in preventing ischemic strokes in ESRD patients with atrial fibrillation
Study Country Design N Adjusted HR for Ischemic Stroke (95% CI) Comments
Shen et al., 2015 (2) United States Retrospective 12284 (1838 warfarin users) 0.73 (0.44 to 1.20) 1) Incident atrial fibrillation.
2) INR achieved was not reported.
3) 69.7% of users were off drug 1 yr after initiation.
Shah et al., 2014 (3) Canada Retrospective 1626 (756 warfarin users) 1.14 (0.78 to 1.67) 1) Unclear if nonvalvular AF was excluded.
2) Included patients >65 yr.
Genovesi et al., 2014 (4) Italy Prospective 290 (134 on warfarin) 0.12 (0.00 to 3.59) 1) INR variability included.
2) Small number of patients.
Olesen et al., 2012 (5) Denmark Retrospective 901 at baseline, 1378 during the study period (178 on warfarin) 0.44 (0.26 to 0.74) 1) Studied incident atrial fibrillation.
2) No INR data.
Winkelmayer et al., 2011 (6) United States Retrospective 2313 (warfarin in 249) 0.92 (0.61 to 1.37) 1) Studied incident atrial fibrillation in patients 66 yrs and older.
2) Warfarin users were less frail.
Chan et al., 2009 (7) United States Retrospective 1671 (508 on warfarin) 1.93 (1.29 to 2.90) 1) Studied incident hemodialysis patients with preexisting atrial fibrillation. Used propensity score matching and time-varying analysis.
HR, hazard ratio; 95% CI, 95 % confidence interval; INR, international normalized ratio; AF, atrial fibrillation.

Overall, the outcomes for dialysis patients on anticoagulants for stroke prophylaxis in atrial fibrillation seem conflicting. Chan et al. (7) retrospectively examined 1671 incident hemodialysis patients with atrial fibrillation, and found an increased risk of stroke (hazard ratio [HR], 1.93; 95% confidence interval [95% CI], 1.29 to 2.90) associated with warfarin use compared with nonuse. Similar results were reported by other investigators (3,4,6). In contrast to these negative studies, Olesen et al. (5) reported in patients taking warfarin the HR for stroke or systemic thromboembolism was 0.44 (95% CI, 0.26 to 0.74). The majority of studies to date have focused on hemodialysis patients, with a few including peritoneal dialysis patients (3,5,11). A recent systematic review and meta-analysis of observational studies of warfarin and atrial fibrillation in CKD/ESRD included 13 publications from 11 cohorts (six retrospective and five prospective) including >48,500 total patients with >11,600 warfarin users (12). In patients with atrial fibrillation and ESRD, warfarin did not decrease the risk of stroke (HR, 1.12; 95% CI, 0.69 to 1.82; P=0.65) or that of death (HR, 0.96; 95% CI, 0.81 to 1.13; P=0.60) but was associated with a higher risk of major bleeding (HR, 1.30; 95% CI, 1.08 to 1.56; P=0.01).

These findings seem to differ from those with late stage CKD where warfarin use appears to reduce stroke risk. In incident atrial fibrillation patients, Banerjee et al. (9) noted a 50% relative risk reduction for the composite of stroke/thromboembolism/all-cause mortality with vitamin K antagonist use across eGFR categories. Similar findings were reported by Carrero et al. (8) in CKD patients with atrial fibrillation postmyocardial infarction and by Olesen et al. (5). As the risk of stroke, hemorrhage, and atrial fibrillation differ substantially between CKD and dialysis patients, we must be cautious in extrapolating findings between the groups.

Several limitations of these studies render the interpretation of the results problematic. Administrative data has considerable issues related to data quality and accuracy (13). Studies that define CKD by International Classification of Diseases 9/10 codes are prone to misclassification as validation studies have reported positive predictive values consistently <50% (5,11,14). Further misclassification of AKI as CKD may occur in studies that used a single serum creatinine to define CKD (11,12,15). Issues regarding outcome ascertainment exist for ischemic stroke as International Classification of Diseases codes have a variable positive predictive value for ischemic strokes (range 46%–94%) (16). Furthermore, the timing of ischemic stroke events may be uncertain. A body of evidence is now emerging demonstrating up to 50% of dialysis patients experience silent cerebral infarcts with no clinical stroke history (17). Imaging may detect the presence of these silently accruing cerebral infarcts and they may erroneously be attributed to a lack of anticoagulation. Numerous studies are subject to an incident/prevalent bias (3,5,6,11). Many studies define the onset of atrial fibrillation during a hospital admission thereby missing the possible “true” onset and disease diagnosis that may have occurred as an outpatient. The timing matters as anticoagulants may have been prescribed and possible outcomes (transient ischemic attack/hemorrhage) already have taken place. No studies account for compliance with warfarin use and maintenance of therapeutic range international normalized ratio (INR). Other important confounders are often missing including the effect of proteinuria, vascular access, and receipt of heparin with hemodialysis. Lastly, warfarin therapy was not randomly allocated. Patients prescribed warfarin are selectively healthier than those with atrial fibrillation not treated with warfarin. For example, in the study by Carrero et al. mortality occurred in 17.5% (n=924) patients treated with warfarin compared with 23.3% (n=4434) not treated with warfarin (8). At first glance, this seems explainable by the prevention of ischemic strokes in the treatment group, thereby leading to a decrease in mortality. However, the mortality reduction is much larger than the number of strokes prevented, suggesting a selection bias in the treatment allocation where healthier patients receive warfarin. A similar observation is clear in the study by Banerjee et al. (9).

Taken together, the evidence for the efficacy of anticoagulation therapy is prone to considerable bias. Nonrandom allocation of warfarin, misclassification, nonvalidated data definitions, and lack of important confounders render the results difficult to interpret and not suitable for clinical decision and application.

What Are the Risks?

Risk of Bleeding

A growing body of evidence suggests the risk of bleeding is higher in CKD/ESRD (summarized in Tables 4 and 5). In a recent administrative data study of >500,000 adults with CKD, the risk of major hemorrhage increased in a graded fashion with declining eGFR and increasing albuminuria. The 3-year cumulative incidence of hemorrhage increased 20-fold across declining eGFR and increasing urine albumin to creatinine ratio groupings (18). In contrast, a few authors found no increased hemorrhage risk (11,12). Inconsistency in the CKD evidence is likely based on variable definitions of hemorrhage, short durations of follow-up, and intention-to-treat as opposed to as-treated analysis.

Table 4. - Major bleeding risk in atrial fibrillation patients with ESRD treated with warfarin
Study Country Design N Adjusted HR Major Bleeding (95% CI)
Shen et al., 2015 (2) United States Retrospective 12,284 (1838 warfarin users) GI bleeding: 1.36 (0.89 to 2.07)
Hemorrhagic stroke: 1.92 (0.82 to 4.48)
Shah et al., 2014 (3) Canada Retrospective 1626 (756 warfarin users) 1.44 (1.13 to 1.85)
Genovesi et al., 2014 (4) Italy Prospective 290 (134 on warfarin) 3.96 (1.15 to 13.68)
Olesen et al., 2012 (5) Denmark Retrospective 901 (178 on warfarin) 2.70 (2.38 to 3.07)
Winkelmayer et al., 2011 (6) United States Retrospective 2313 (warfarin in 249) GI bleeding: 0.90 (0.60 to 1.35)
Hemorrhagic stroke: 2.63 (1.01 to 6.88)
HR, hazard ratio; 95% CI, 95 % confidence interval; GI, gastrointestinal.

Table 5. - Major bleeding risk in atrial fibrillation in patients with CKD treated with warfarin
Study Country Design N Adjusted HR Major Bleeding (95% CI)
Banerjee et al., 2014 (9) France Retrospective 5912 (2982 with eGFR<60 ml/min per 1.73 m2 and 1550 on warfarin) 0.96 (0.55 to 1.67)
Carrero et al., 2014 (8) Sweden Prospective 24317 (5292 on warfarin) eGFR>30–60 ml/min per 1.73 m2: 1.08 (0.89 to 1.32)
eGFR>15–30 ml/min per 1.73 m2: 0.93 (0.60 to 1.44)
Olesen et al., 2012 (5) Denmark Retrospective 3587 (609 on warfarin) 2.24 (2.10 to 2.38)
HR, hazard ratio; 95% CI, 95 % confidence interval.

The risk of hemorrhage in ESRD is more clear and consistent. Overall, roughly one in seven incident hemodialysis patients has a major hemorrhagic event requiring hospitalization within the first 3 years of dialysis initiation (19). Among warfarin users with atrial fibrillation, Olesen et al. reported an HR of major hemorrhage on warfarin of 2.70 (95% CI, 2.38 to 3.07) (5) with similar findings by other investigators (2–4,6). Of particular concern is the increased risk of intracranial hemorrhage, which confers an especially poor prognosis. Both Winkelmayer et al. (6) and Shen et al. (2) report >2.5-fold increase in the risk of intracranial hemorrhage with warfarin usage (2,6).

The risk of major hemorrhage after warfarin initiation is heterogeneous with an increased risk in the initial few weeks after starting therapy (20). In a population-based study, the risk of major bleeding in the first 30 days after warfarin initiation had an adjusted incidence rate ratio of 10.3 (95% CI, 2.3 to 45.5) for eGFR<15 ml/min per 1.73 m2 compared with eGFR>90 ml/min per 1.73 m2 (20). The majority of studies define incident atrial fibrillation upon hospitalization, thereby possibly missing bleeding events for patients initiated on anticoagulants in the outpatient setting and significantly underestimating the risk.

An emerging cause of hemorrhage in the CKD/ESRD population is vitamin K deficiency and INR variability (4,21). Malnutrition, frequent antibiotic exposure, and chronic illness are proposed mechanisms of vitamin K deficiency in CKD/ESRD (21,22). This has led to poorer anticoagulation control as assessed by the proportion of out-of-range INRs (22,23). Limdi et al. examined patients with CKD stage 4/5 and found they required significantly lower warfarin dosages (P=0.001), spent less time with their INR within the target range (P=0.05), and were at a higher risk for overanticoagulation (INR>4; P=0.05), compared with patients with no, mild, or moderate CKD (22).

An interesting entity termed anticoagulant-related nephropathy has recently been described with warfarin use. Excessive anticoagulation coexists with AKI secondary to glomerular hemorrhage and tubular obstruction directly related to red blood cells. The presumed diagnosis of warfarin-related nephropathy is more common in CKD, is associated with higher mortality, and may accelerate ESRD (24,25).

Vascular Calcification and Calcific Uremic Arteriopathy

Calcific uremic arteriopathy, or calciphylaxis, is a rare disorder characterized by medial calcifications of arteries leading to painful, ulcerative skin lesions and is associated with warfarin therapy (26–30). The arrest of progression of lesions has been reported after switching from warfarin to heparin (26). Matrix GLA protein is an inhibitor of calcification in the arterial wall whose activity is inhibited by warfarin (31,32) This confers “biologic plausibility” for the hypothesis (33,34).

Can We Accurately Predict in CKD/ESRD Benefit and Harm from Warfarin Prophylaxis?

To date, numerous risk prediction scores for stroke and bleeding have been developed in the general population but few have been evaluated in CKD/ESRD (Table 6). The original CHADS2 score had excellent discrimination in predicting those who will go on to develop stroke from those who will not (c-statistic 0.82) (35). However, they are much less accurate in predicting stroke among those with CKD and ESRD, with c-statistics of 0.64 and 0.61–0.68, respectively (36–39). A modified risk formula, the R2CHADS2, which includes creatinine clearance, also is relatively poor at discrimination (c-statistic 0.63–0.67) (38,39). The problem lies in the factors included in the risk scores themselves. For example, applying the CHA2DS2-VASc score to a dialysis patient would require an accurate definition of congestive heart failure (How to distinguish from volume overload?), hypertension (Pre-, during or postdialysis? Forty-four-hour measure?), and anemia (optimal targets unknown). As these “risk factors” are ubiquitous but ill-defined in CKD/ESRD patients, almost all patients are categorized as high risk. In the study by Bonde et al. (9), over 90% and 80% of CKD and hemodialysis patients were deemed high risk (score of 2 or greater) with a recommendation to initiate anticoagulation. Figure 1 shows receiver operating characteristic curves of CHADS2 and CHA2DS2-VASc scores in predicting ischemic stroke in the ESRD population. Conversely, current bleeding risk scores seem to underestimate the risk of bleeding when applied to CKD/ESRD. The HAS-BLED score places only 28% of CKD and 20% of hemodialysis patients at high risk (3 or greater), compared with 18% of the general population (11).

Table 6. - Risk prediction scores for stroke in patients with CKD
Study Score Population Studied c-Statistic
Banerjee et al., (38) CHADS2 CKD 0.64 (0.61–0.67)
Banerjee et al., (38) CHA2DS2-VASc CKD 0.64 (0.62–0.67)
Chao et al., (39) CHADS2 ESRD undergoing RRT 0.608
Chao et al., (39) CHA2DS2-VASc ESRD undergoing RRT 0.682
Piccini et al., (36) R2CHADS2 CKD, creatinine clearance >30 ml/min 0.672 (0.651–0.692)
Bautista et al., (36) R2CHADS2 CKD, eGFR<30 ml/min per 1.73 m2 0.631
Values given are 95% confidence interval. C-statistic with 95% confidence interval, if available.
CHADS2, congestive heart failure, hypertension, anemia, diabetes mellitus and stroke.

Figure 1.:
Receiver operating characteristic curves of CHADS2 and CHA2DS2-VASc scores in predicting ischemic stroke in patients with ESRD. (Modified from Chao et al. reference 39, with permission). CHADS2, congestive heart failure, hypertension, anemia, diabetes mellitus and stroke.

Unclear What to Do? You Are Not Alone

The lack of clarity in the existing evidence has led to considerable uncertainty among physicians. A survey of Canadian nephrologists found >70% of respondents agree with clinical equipoise regarding warfarin use and a similar proportion would be willing to enroll patients in a clinical trial of warfarin versus placebo (40). Few nephrologists would prescribe warfarin when a patient presented with both a high stroke risk and a high bleeding risk (CHAD S2=5, CHA2DS2VASc=8) and a risk for falls (42). Also, that most respondents would discontinue warfarin use in this scenario highlighted the complexity of decision-making and uncertainty (40). The most recent guidelines from the Canadian Cardiovascular Society suggested patients with ESRD (eGFR<15 ml/min per 1.73 m2) not routinely receive anticoagulation or acetylsalicyclic acid for stroke prevention in atrial fibrillation (41). This is consistent with the KDIGO recommendation against the use of routine anticoagulation of dialysis patients with atrial fibrillation for primary prevention of stroke (42).

What Are the Alternatives to Warfarin?

The newer oral anticoagulants (NOACs) dabigatran, apixaban, rivaroxaban, and edoxaban are excreted renally to a variable extent. Randomized controlled trials that have examined their efficacy and safety in atrial fibrillation have excluded patients with advanced CKD. Analysis of data from the trials that included patients with CKD shows that the risk of stroke or systemic embolism in patients with creatinine clearance 30–49 ml/min is significantly lower with NOACs than conventional agents (3.9% versus 5.3%; odds ratio, 0.72; 95% CI, 0.57 to 0.92; absolute risk reduction, 1.4%; number needed to treat, 71) (43). In a recent meta-analysis of nine trials, Raccah et al. observed that NOACs were associated with a significantly decreased risk of major bleeding in patients with estimated creatinine clearance 50–80 ml/min (risk ratio, 0.84; 95% CI, 0.78 to 0.91), and a nonsignificant decrease in the risk of major bleeding in patients with estimated creatinine clearance <50 ml/min (risk ratio, 0.80; 95% CI, 0.63 to 1.01) when compared with use of warfarin (44). They have been used erroneously in the dialysis population with poor outcomes (45). In summary, although they may be a safer alternative to warfarin in patients with milder CKD, the safety and efficacy of NOACs in late stage CKD and dialysis patients remain unknown.


Stroke prevention in atrial fibrillation is going to be a more commonly encountered issue as the incidence of both atrial fibrillation and CKD are on the rise. The current evidence for CKD and ESRD is based on a few observational studies with methodologic limitations. The efficacy of anticoagulation for stroke prevention, despite the use of sophisticated analytic techniques and large cohorts, is currently inconclusive. Concurrently there are clear risks of harm with anticoagulation. Application of risk scores developed in the general population is inaccurate and inappropriate among those with CKD/ESRD. Lastly, the uncertainty regarding treatment decisions is widespread among fellow nephrologists and cardiologists.

At present, there is a pressing need for a randomized controlled trial(s) in this area. We feel that, with the considerable uncertainties and risk for harm, a trial of warfarin (or NOACs after an improved understanding of their actions with an eGFR<30 ml/min per 1.73 m2) versus placebo is warranted. Another promising therapy is left atrial appendage closure, which in early observational studies demonstrates a significant reduction in stroke and/or hemorrhage in CKD patients (46).

A conservative approach without the use of anticoagulants is warranted. The use of antiplatelet agents may represent a compromise (although untested) as they may partially mitigate the risk of stroke with a more reasonable hemorrhagic profile. If anticoagulation is to be initiated (for example on the basis of patient preferences or previous thromboembolic stroke), hemorrhagic reduction strategies such as discontinuation of antiplatelet agents, reduction in heparin use with dialysis, prophylactic proton pump inhibitor use, and the use of citrate locks for dialysis catheters should be considered. It is often in the caregivers psyche to treat or prescribe, as sitting idle is akin to doing nothing. However, in the scenario where treatment confers harm without clear benefit, often sitting idle is the most prudent therapeutic option.




M.M.S. is supported by the Jindal Research Chair for the Prevention of Kidney Disease.

Published online ahead of print. Publication date available at


1. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 84: 527–539, 1991
2. Shen JI, Montez-Rath ME, Lenihan CR, Turakhia MP, Chang TI, Winkelmayer WC: Outcomes after warfarin initiation in a cohort of hemodialysis patients with newly diagnosed atrial fibrillation. Am J Kidney Dis 66: 677–688, 2015
3. Shah M, Avgil Tsadok M, Jackevicius CA, Essebag V, Eisenberg MJ, Rahme E, Humphries KH, Tu JV, Behlouli H, Guo H, Pilote L: Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation 129: 1196–1203, 2014
4. Genovesi S, Rossi E, Gallieni M, Stella A, Badiali F, Conte F, Pasquali S, Bertoli S, Ondei P, Bonforte G, Pozzi C, Rebora P, Valsecchi MG, Santoro A: Warfarin use, mortality, bleeding and stroke in haemodialysis patients with atrial fibrillation. Nephrol Dial Transplant 30: 491–498, 2015
5. Olesen JB, Lip GY, Kamper AL, Hommel K, Køber L, Lane DA, Lindhardsen J, Gislason GH, Torp-Pedersen C: Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 367: 625–635, 2012
6. Winkelmayer WC, Liu J, Setoguchi S, Choudhry NK: Effectiveness and safety of warfarin initiation in older hemodialysis patients with incident atrial fibrillation. Clin J Am Soc Nephrol 6: 2662–2668, 2011
7. Chan KE, Lazarus JM, Thadhani R, Hakim RM: Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol 20: 2223–2233, 2009
8. Carrero JJ, Evans M, Szummer K, Spaak J, Lindhagen L, Edfors R, Stenvinkel P, Jacobson SH, Jernberg T: Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA 311: 919–928, 2014
9. Banerjee A, Fauchier L, Vourc’h P, Andres CR, Taillandier S, Halimi JM, Lip GY: A prospective study of estimated glomerular filtration rate and outcomes in patients with atrial fibrillation: the Loire Valley Atrial Fibrillation Project. Chest 145: 1370–1382, 2014
10. Lai HM, Aronow WS, Kalen P, Adapa S, Patel K, Goel A, Vinnakota R, Chugh S, Garrick R: Incidence of thromboembolic stroke and of major bleeding in patients with atrial fibrillation and chronic kidney disease treated with and without warfarin. Int J Nephrol Renovasc Dis 2: 33–37, 2009
11. Bonde AN, Lip GY, Kamper AL, Hansen PR, Lamberts M, Hommel K, Hansen ML, Gislason GH, Torp-Pedersen C, Olesen JB: Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study. J Am Coll Cardiol 64: 2471–2482, 2014
12. Dahal K, Kunwar S, Rijal J, Schulman P, Lee J: Stroke, Major Bleeding, and Mortality Outcomes in Warfarin Users With Atrial Fibrillation And Chronic Kidney Disease: A Meta-Analysis of Observational Studies. Chest 149: 951–959, 2016
13. Manuel DG, Rosella LC, Stukel TA: Importance of accurately identifying disease in studies using electronic health records. BMJ 341: c4226, 2010
14. Ronksley PE, Tonelli M, Quan H, Manns BJ, James MT, Clement FM, Samuel S, Quinn RR, Ravani P, Brar SS, Hemmelgarn BR; Alberta Kidney Disease Network: Validating a case definition for chronic kidney disease using administrative data. Nephrol Dial Transplant 27: 1826–1831, 2012
15. Siew ED, Matheny ME, Ikizler TA, Lewis JB, Miller RA, Waitman LR, Go AS, Parikh CR, Peterson JF: Commonly used surrogates for baseline renal function affect the classification and prognosis of acute kidney injury. Kidney Int 77: 536–542, 2010
16. McCormick N, Bhole V, Lacaille D, Avina-Zubieta JA: Validity of diagnostic codes for acute stroke in administrative databases: a systematic review. PLoS One 10: e0135834, 2015
17. Nakatani T, Naganuma T, Uchida J, Masuda C, Wada S, Sugimura T, Sugimura K: Silent cerebral infarction in hemodialysis patients. Am J Nephrol 23: 86–90, 2003
18. Molnar AO, Bota SE, Garg AX, Harel Z, Lam N, McArthur E, Nesrallah G, Perl J, Sood MM: The Risk of Major Hemorrhage with CKD [published online ahead of print January 28, 2016]. J Am Soc Nephrol doi:10.1681/ASN.2015050535
19. Sood MM, Bota SE, McArthur E, Kapral MK, Tangri N, Knoll G, Zimmerman D, Garg AX: The three-year incidence of major hemorrhage among older adults initiating chronic dialysis. Can J Kidn Heal Dis 1: 21, 2014
20. Jun M, James MT, Manns BJ, Quinn RR, Ravani P, Tonelli M, Perkovic V, Winkelmayer WC, Ma Z, Hemmelgarn BR; Alberta Kidney Disease Network: The association between kidney function and major bleeding in older adults with atrial fibrillation starting warfarin treatment: population based observational study. BMJ 350: h246, 2015
21. Phelan PJ, O’Kelly P, Holian J, Walshe JJ, Delany C, Slaby J, Winders S, O’Toole D, Magee C, Conlon PJ: Warfarin use in hemodialysis patients: what is the risk? Clin Nephrol 75: 204–211, 2011
22. Limdi NA, Beasley TM, Baird MF, Goldstein JA, McGwin G, Arnett DK, Acton RT, Allon M: Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol 20: 912–921, 2009
23. Kooiman J, van Rein N, Spaans B, van Beers KA, Bank JR, van de Peppel WR, del Sol AI, Cannegieter SC, Rabelink TJ, Lip GY, Klok FA, Huisman MV: Efficacy and safety of vitamin K-antagonists (VKA) for atrial fibrillation in non-dialysis dependent chronic kidney disease. PLoS One 9: e94420, 2014
24. Brodsky SV, Nadasdy T, Rovin BH, Satoskar AA, Nadasdy GM, Wu HM, Bhatt UY, Hebert LA: Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate. Kidney Int 80: 181–189, 2011
25. Brodsky SV, Collins M, Park E, Rovin BH, Satoskar AA, Nadasdy G, Wu H, Bhatt U, Nadasdy T, Hebert LA: Warfarin therapy that results in an International Normalization Ratio above the therapeutic range is associated with accelerated progression of chronic kidney disease. Nephron Clin Pract 115: c142–c146, 2010
26. Coates T, Kirkland GS, Dymock RB, Murphy BF, Brealey JK, Mathew TH, Disney AP: Cutaneous necrosis from calcific uremic arteriolopathy. Am J Kidney Dis 32: 384–391, 1998
27. Mazhar AR, Johnson RJ, Gillen D, Stivelman JC, Ryan MJ, Davis CL, Stehman-Breen CO: Risk factors and mortality associated with calciphylaxis in end-stage renal disease. Kidney Int 60: 324–332, 2001
28. Hayashi M, Takamatsu I, Kanno Y, Yoshida T, Abe T, Sato Y; Japanese Calciphylaxis Study Group: A case-control study of calciphylaxis in Japanese end-stage renal disease patients. Nephrol Dial Transplant 27: 1580–1584, 2012
29. Nigwekar SU, Bhan I, Turchin A, Skentzos SC, Hajhosseiny R, Steele D, Nazarian RM, Wenger J, Parikh S, Karumanchi A, Thadhani R: Statin use and calcific uremic arteriolopathy: a matched case-control study. Am J Nephrol 37: 325–332, 2013
30. Floege J, Kubo Y, Floege A, Chertow GM, Parfrey PS: The effect of cinacalcet on calcific uremic arteriolopathy events in patients receiving hemodialysis: The EVOLVE Trial. Clin J Am Soc Nephrol 10: 800–807, 2015
31. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G: Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 386: 78–81, 1997
32. Price PA, Williamson MK: Primary structure of bovine matrix Gla protein, a new vitamin K-dependent bone protein. J Biol Chem 260: 14971–14975, 1985
33. Holden RM, Clase CM: Use of warfarin in people with low glomerular filtration rate or on dialysis. Semin Dial 22: 503–511, 2009
34. Price PA, Faus SA, Williamson MK: Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol 18: 1400–1407, 1998
35. Piccini JP, Stevens SR, Chang Y, Singer DE, Lokhnygina Y, Go AS, Patel MR, Mahaffey KW, Halperin JL, Breithardt G, Hankey GJ, Hacke W, Becker RC, Nessel CC, Fox KA, Califf RM; ROCKET AF Steering Committee and Investigators: Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts. Circulation 127: 224–232, 2013
36. Bautista J, Bella A, Chaudhari A, Pekler G, Sapra KJ, Carbajal R, Baumstein D: Advanced chronic kidney disease in non-valvular atrial fibrillation: extending the utility of R2CHADS2 to patients with advanced renal failure. Clin Kidney J 8: 226–231, 2015
37. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ: Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 285: 2864–2870, 2001
38. Banerjee A, Fauchier L, Vourc’h P, Andres CR, Taillandier S, Halimi JM, Lip GY: Renal impairment and ischemic stroke risk assessment in patients with atrial fibrillation: the Loire Valley Atrial Fibrillation Project. J Am Coll Cardiol 61: 2079–2087, 2013
39. Chao TF, Liu CJ, Wang KL, Lin YJ, Chang SL, Lo LW, Hu YF, Tuan TC, Chung FP, Liao JN, Chen TJ, Lip GY, Chen SA: Incidence and prediction of ischemic stroke among atrial fibrillation patients with end-stage renal disease requiring dialysis. Heart Rhythm 11: 1752–1759, 2014
40. Juma S, Thomson BK, Lok CE, Clase CM, Blake PG, Moist L: Warfarin use in hemodialysis patients with atrial fibrillation: decisions based on uncertainty. BMC Nephrol 14: 174, 2013
41. Verma A, Cairns JA, Mitchell LB, Macel L, Stiell IG, Gladstone D, McMurtry MS, Connolly S, Cox JL, Dorial P, Ivers N, Leblanc K, Nattel S, Healey JS: 2014 Focused Update on the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation. Can J Cardio 30: 1114–1130, 2014
42. Herzog CA, Asinger RW, Berger AK, Charytan DM, Díez J, Hart RG, Eckardt KU, Kasiske BL, McCullough PA, Passman RS, DeLoach SS, Pun PH, Ritz E: Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 80: 572–586, 2011
43. Sardar P, Chatterjee S, Herzog E, Nairooz R, Mukherjee D, Halperin JL: Novel oral anticoagulants in patients with renal insufficiency: a meta-analysis of randomized trials. Can J Cardiol 30: 888–897, 2014
44. Raccah BH, Perlman A, Danenberg HD, Pollak A, Muszkat M, Matok I: Major Bleeding and Hemorrhagic Stroke with Direct Oral Anticoagulants in Patients with Renal Failure: Systematic Review and Meta-Analysis of Randomized Trials. Chest 149: 1516–1524, 2016
45. Chan KE, Edelman ER, Wenger JB, Thadhani RI, Maddux FW: Dabigatran and rivaroxaban use in atrial fibrillation patients on hemodialysis. Circulation 131: 972–979, 2015
46. Kefer J, Tzikas A, Freixa X, Shakir S, Gafoor S, Nielsen-Kudsk JE, Berti S, Santoro G, Aminian A, Landmesser U, Nietlispach F, Ibrahim R, Danna PL, Benit E, Budts W, Stammen F, De Potter T, Tichelbäcker T, Gloekler S, Kanagaratnam P, Costa M, Cruz-Gonzalez I, Sievert H, Schillinger W, Park JW, Meier B, Omran H: Impact of chronic kidney disease on left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation. Int J Cardiol 207: 335–340, 2016

Anticoagulation; chronic kidney disease; stroke; hemorrhage; atrial fibrillation; warfarin; Blood Coagulation; Humans; Incidence; Kidney Failure; Chronic; Renal Insufficiency; Chronic; Risk; Uncertainty

Copyright © 2016 by the American Society of Nephrology