Atrial Fibrillation in CKD: Balancing the Risks and Benefits of Anticoagulation

In Practice Atrial Fibrillation in CKD: Balancing the Risks and Benefits of Anticoagulation Khai P. Ng, MRCP,1 Nicola C. Edwards, PhD,2 Gregory Y.H. Lip, MD,3 Jonathan N. Townend, MD,2 and Charles J. Ferro, MD1 Chronic kidney disease (CKD) and atrial fibrillation are common conditions that often coexist and are associated with increased risk of stroke. Despite the wealth of evidence for optimal management of atrial fibrillation in the general population, the role of anticoagulation with warfarin in individuals with CKD with atrial fibrillation is far less well defined. Current recommendations for anticoagulation in patients treated with dialysis and those with an earlier stage of CKD are based on clinical trials in the general atrial fibrillation population that have largely excluded individuals with CKD. Observational studies of anticoagulation in dialysis patients have produced conflicting results, mainly because of increased risk of bleeding. This, together with warfarin’s potential adverse effects on ectopic/vascular calcification and progression of CKD, may result in negating the benefits associated with anticoagulation in the general population. With the recent emergence of novel oral anticoagulants, there is an urgent need for a better understanding of the complex inter-relationship among CKD, atrial fibrillation, stroke, and bleeding risk. This knowledge is paramount to optimize the potential benefits of treatment and minimize the potential harms in this very high-risk and growing population. Am J Kidney Dis. xx(x):xxx. © 2013 by the National Kidney Foundation, Inc. INDEX WORDS: Chronic kidney disease; atrial fibrillation; anticoagulation; warfarin; dabigatran; stroke; bleeding.

CASE PRESENTATION A 77-year-old black man with long-standing stage 3 chronic kidney disease (CKD; serum creatinine of 2.38 mg/dL, corresponding to estimated glomerular filtration rate [GFR] of 32 mL/min/ 1.73 m2 using the 4-variable MDRD [Modification of Diet in Renal Disease] Study equation)1 and diabetes mellitus is found to have atrial fibrillation (AF) during a routine clinical examination, with a ventricular rate of 60-70 beats/min. His medical history includes an ischemic stroke 9 months earlier without major sequelae and a significant gastrointestinal bleed, requiring a blood transfusion, from a duodenal ulcer that occurred 3 months after initiating aspirin therapy. He is staunchly independent and lives many miles from the nearest medical facility, with which he has minimal contact.

PREVALENCE AND INCIDENCE OF AF IN CKD There are more than 1.5 million patients with end-stage renal disease (ESRD) receiving dialysis treatment across the globe.2,3 Despite the huge medical cost associated with renal replacement therapy, the health-economic impact of the much more prevalent earlier stages of CKD, which are associated with significant premature morbidity and mortality, is even greater.4,5 There has been growing global awareness and recognition of early CKD as a public health problem since the introduction of a clearer multilayered definition of the condition based on GFR proposed by the NKF-KDOQI (National Kidney Foundation–Kidney Disease Outcome Quality Initiative) in 2002.6,7 CKD is associated strongly with increased cardiovascular morbidity and mortality.8-10 The phenotype of cardiovascular disease associated with CKD is multifactoAm J Kidney Dis. 2013;xx(x):xxx

rial, with arterial stiffening causing heart failure, stroke, and arrhythmic sudden death and premature atherosclerosis causing vascular occlusive events.11 There also is increasing recognition that the prevalence of AF is high9,10,12,13 and that it is associated with significant cardiovascular morbidity and mortality.14,15 There are clear and evidence-based guidelines for the use of anticoagulation in the prevention of thromboembolic stroke in the general population with AF.16,17 However, despite the wealth of evidence regarding optimal management of AF in the general population, the role of anticoagulants in the CKD population with AF is far less well defined. The distinctive nature of a simultaneous increase in both thromboembolic and bleeding risk in CKD poses a difficult challenge.18-31 A review of the management of AF focusing on patients with late-stage CKD by Aronow32 favored the use of warfarin in treating on an individual basis. With the recent emergence of From the Departments of 1Nephrology and 2Cardiology, Queen Elizabeth Hospital Birmingham and University of Birmingham; and 3University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom. Received September 28, 2012. Accepted in revised form February 21, 2013. Address correspondence to Charles J. Ferro, MD, Department of Nephrology, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2WB, United Kingdom. E-mail: [email protected] © 2013 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2013.02.381 1

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novel anticoagulants,33 better understanding of the complex inter-relationship among different stages of CKD, AF, and stroke will be paramount in optimizing the effect of treatment and minimizing the harm. In this overview, we examined the available evidence for the increased thrombotic and bleeding risks in CKD, as well as the potential benefits and risks of the use of anticoagulants in this population.

RISK OF AF IN CKD The prevalence of AF in the general population is ⬃1% and increases markedly with age.15,34 Patients with ESRD on dialysis therapy are known to have a higher prevalence of AF compared with the general population, ranging from 7%-27%.35-38 Similarly, the prevalence of AF in the non–dialysis-dependent CKD population appears to be similar to that of the dialysis population, at 18%-21%.31,39,40 Recent large population-based studies have demonstrated an independent inverse relationship between AF and GFR.10,12,39,40 In the Atherosclerosis Risk in Communities (ARIC) Study, patients with GFR of 60-89, 30-59, and 15-29 mL/min/1.73 m2 had hazard ratios (HRs) of 1.3, 1.6, and 3.2, respectively, of developing new-onset AF during a follow-up of 10 years compared with those with GFR ⱖ90 mL/min/ 1.73 m2.12 Similarly, in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study, age-, race-, and sex-adjusted odds ratios for prevalent AF were significantly higher in patients with CKD compared with those without.10 Interestingly, the ARIC Study also reported 2- and 3.2-fold increased risks of AF in patients with microalbuminuria and macroalbuminuria, respectively, compared with those with a urine albumin-creatinine ratio ⬍30 mg/g.12 Diabetes mellitus, elevated body mass index, hypertension, and heart failure are well-established risk factors for AF in the general population,41 many of which often coexist with CKD. Nonetheless, data from the Chronic Renal Insufficiency Cohort (CRIC) Study suggested that the risk factors predisposing patients with CKD to AF were not entirely the same as those in the general population.40 While old age and the presence of heart failure or other cardiovascular disease correlated independently with the occurrence of AF, hypertension, diabetes, alcohol intake, and body mass index did not.40 Additionally, upregulation of the renin-angiotensin-aldosterone system (RAAS),42 heightened systemic inflammation,43,44 vascular calcification,11,45 calcium-phosphate metabolism dysregulation,45 abnormal endothelial function,46 and a high prevalence of left ventricular hypertrophy47,48 also 2

may contribute to the increased risk of developing AF in patients with CKD. Most, but not all,49 studies show that AF confers an increased risk of ischemic stroke and death in dialysis patients.38,50-52 Interestingly, this attributable risk might not be as high as for the general population.53 Roldan et al54 reported an increased HR of thrombotic/ vascular events or bleeding with each 30-mL/min/ 1.73 m2 decrease in GFR. Intriguingly, a cohort study reported a bidirectional relationship between AF and CKD, whereby the incidence of AF increased with decreased GFR and the risk of developing CKD and proteinuria increased in the presence of AF during the 6-year follow-up period.13

OTHER RISKS OF THROMBOEMBOLISM IN CKD: PATHOPHYSIOLOGIC MECHANISMS Virchow’s triad enlists 3 key factors that predispose to thrombus formation: endothelial injury, abnormal blood flow (stasis/turbulence), and hypercoagulability. Left atrial appendage stasis, endothelial injury secondary to progressive atrial dilation leading to endocardial denudation, and increased activation of platelets and coagulation factors in AF fulfills the triad and results in substantial risk of thromboembolism.55-57 All 3 of these factors, left atrial stasis,58 endothelial injury/dysfunction,59,60 and enhanced coagulation/platelet activation,61-66 appear to be enhanced in patients with CKD (Fig 1). A summary of key studies is presented in Table 1. The drivers of many of the observed prothrombotic effects in CKD remain unclear. Strong suspicion rests on both chronic inflammation and upregulation of the RAAS. Both ESRD and earlier stages of CKD are associated with elevated levels of inflammatory markers.62,65,66 Activation of the RAAS is already known to be associated with a prothrombotic tendency in hypertensive patients.69 Modulation of the RAAS has been the single most important advance in improving cardiovascular70 and kidney71,72 outcomes in patients with CKD over and above the expected benefits from blood pressure reduction. It is intriguing to speculate whether RAAS inhibition improves outcomes, at least in part, by improving the prothrombotic state.

THROMBOEMBOLISM IN CKD: CLINICAL OBSERVATIONS Stroke is undoubtedly one of the most devastating consequences of thromboembolism. Table 2 summarizes key studies of the epidemiology of thromboembolism in CKD. Numerous studies have confirmed CKD as an independent risk factor for stroke after adjustments for conventional risk factors.2,18,21-23 Patients with CKD are over-represented in cohorts of Am J Kidney Dis. 2013;xx(x):xxx

Atrial Fibrillation in CKD

High prevalence of atrial fibrillation

Stasis or turbulent blood flow

Chronic Inflammation Endothelial stress injury

Endothelial dysfunction

Endothelial Injury

CKD stage 3-5ND

Platelet dysfunction & increased reactivity Enhanced coagulation: (Raised TAT, Factor VII, Factor VIII, Fibrinogen and impaired tissue factor induced activated protein C response)

Impaired platelet-vessel wall interaction

THROMBUS FORMATION

Hypercoagulability

Fibrinolysis activity: (Disproportionate increased in coagulation activity compared to fibrinolysis activity) Altered fibrin clot: (More rigid, less permeable and less susceptible to fibrinolysis)

Figure 1. Potential mechanisms of increased thromboembolic risk in patients with chronic kidney disease stages 3-5 nondialysis (CKD 3-5ND). Factors known to be associated with CKD, including the increased prevalence of atrial fibrillation, chronic inflammation, endothelial injury, platelet dysfunction, and abnormalities in coagulation and fibrinolysis, lead to abnormalities in all 3 factors of Virchow’s triad, enhancing the risk of thrombus formation. Abbreviation: TAT, thrombin-antithrombin complex.

patients with acute stroke.76-78 The adverse effect of CKD on risk of stroke and mortality was shown to be especially crucial for female patients with AF.87 More recently, the AVERROES (Apixaban Versus Acetylsalicylic Acid to Prevent Strokes in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment), ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation), and 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) studies also observed a consistent trend toward increased stroke risk in patients with creatinine clearance (CCr) ⬍50 mL/min/ 1.73 m2 (GFR ⬍60 mL/min/1.73 m2 in AVERROES) compared with those with higher CCr or GFR regardless of the allocated anticoagulant treatments.88-91 In addition to AF, several pathophysiologic mechanisms potentially contribute to the increased risk of stroke in patients with CKD, including carotid plaque structure, composition, and morphology79; Am J Kidney Dis. 2013;xx(x):xxx

heightened inflammation43,44; vascular calcification and arterial stiffness11,80; hypertension92; and anemia.81 There also is strong and consistent evidence of an adverse interaction between CKD and outcomes after stroke.15,76,78,83-86

BLEEDING RISK IN CKD Paradoxically, as well as being associated with increased risk of thromboembolism, ESRD is known to be associated with increased bleeding risk, including intracerebral hemorrhage93 and gastrointestinal bleeding.94 Nonetheless, it is less clear precisely how this risk extends to earlier stages of CKD or if there is a GFR threshold below which bleeding risk increases. Recent observational and interventional studies have provided some useful information on this front. Serum creatinine concentrations ⬎1.5 mg/dL have been identified as an independent predictor of major bleeding events.95 In a prospective cohort study of 12,222 Japanese patients, Shimizu et al93 reported significant heightened risk of hemorrhagic stroke in those with GFR ⬍60 mL/min/1.73 m2. An in3

Ng et al Table 1. Pathophysiologic Observations of Thromboembolism in CKD Study

Study Type

N

Population

Findings

Left Atrial Blood Stasis Yagishita et al58 (2010)

Observational

321

Pts with persistent AF

GFR an independent predictor of reduced left atrial appendage emptying velocity and presence of left atrium spontaneous echo contract

Hrafnkelsdottir et al59 (2004) Heintz et al60 (1994)

Comparative

18

Comparative

40

Thijs et al61 (2008)

Cross-sectional

93

Landray et al62 (2004)

Comparative

522

334 CKD pts, 92 CAD pts, and 96 apparently healthy individuals with no history of CV or kidney disease (age- and sex-matched)

Mercier et al63 (2001)

Cross-sectional

150

3 age- and sex-matched groups of individuals: maintenance HD pts, NDD-CKD, healthy controls

Tanaka et al64 (2009) Shlipak et al65 (2003)

Observational

190

Cross-sectional

5,888

Pts with AF not receiving anticoagulant Population-based cohort of age ⱖ65 y

Tomura et al66 (1991)

Cross-sectional

18

CKD pts on conservative treatment

Sjoland et al67 (2007)

Comparative

46

22 ESRD pts and 24 healthy controls

Undas et al68 (2008)

Comparative

66

33 pts on maintenance hemodialysis and 33 age- and sex-matched healthy controls

Endothelial Injury/Dysfunction Nondiabetic nonsmoking CKD pts (GFR, 11-28) and age-matched healthy controls 20 healthy donors and 20 CKD pts

Maximal release rate of active tPA and capacity for acute tPA release markedly impaired in kidney pts vs controls CKD pts had higher endogenous levels of ET-1, plasma cAMP, and enhanced ET-1–stimulated ADP-induced platelet aggregation than healthy volunteers

Platelet and Coagulation Dysfunction Nondiabetic pts with MDRD Study–estimated CCr 13-63

Expression of P-selectin, glycoprotein 53, and activated fibrinogen receptor statistically significantly inversely related to eGFR CKD associated with higher fibrinogen, plasma vWF, and soluble P-selectin, but not with higher CRP level

Decreased kidney function associated with enhanced tissue factor coagulation pathway and reduced tissue factor–induced response to activated protein C Decreased GFR significant predictor for elevation of TAT and D-dimer in pts with nonvalvular AF After adjustment for baseline differences, CRP, fibrinogen, IL-6, factor VIIc, factor VIIIc, plasminantiplasmin complex, and D-dimer levels significantly higher in CKD pts Coagulation activity significantly increased in CKD pts, fibrinolysis secondary to coagulation is only slightly enhanced

Altered Fibrin Clot Fibrin clots made from plasma of ESRD pts less permeable (P ⬍ 0.001), less compactable (P ⬍ 0.001), and less susceptible to fibrinolysis (P ⬍ 0.001) than clots from controls Hemodialysis pts produced fibrin clots that had less porous structure, were less susceptible to fibrinolysis, began fibrin protofibril formation more quickly and showed increased overall fibre thickness compared with controls. Clot permeability and lysis time correlated with F2isoprostanes, lipoprotein A and fibrinogen

Note: GFR and CCr given in mL/min/1.73 m2. Abbreviations: ADP, adenosine diphosphate; AF, atrial fibrillation; CAD, coronary artery disease; cAMP, cyclic adenosine monophosphate; CCr, creatinine clearance; CKD, chronic kidney disease; CV, cardiovascular; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; ET-1, endothelin 1; GFR, glomerular filtration rate; HD, hemodialysis; IL-6, interleukin 6; MDRD, Modification of Diet in Renal Disease; NDD, non– dialysis-dependent; pt, patient; TAT, thrombin-antithrombin complex; tPa, tissue plasminogen activator; vWF, von Willebrand factor.

creased risk of bleeding events in patients with CCr ⬍50 mL/min/1.73 m2 (GFR ⬍60 mL/min/1.73 m2 in the AVERROES Study) also were noted in sub4

group analyses of the AVERROES, ARISTOTLE, and ROCKET-AF studies regardless of treatment assignments compared with those without CKD.89-91 Am J Kidney Dis. 2013;xx(x):xxx

Study

Study Type

N

Population

Findings

Risk of Stroke in CKD Koren-Morag et al22 (2006) Holzmann et al73 (2012)

Cross-sectional Longitudinal, 12 y f/u

539,287

Chou et al74 (2011)

Community-based prospective cohort

1,312

Muntner et al75 (2012)

Prospective, median f/u of 2.1 y

Yahalom et al76 (2009) Xu et al77 (2011)

Longitudinal

821

Prospective

1,014

Longitudinal

3,778

6,685

20,386

Pts with chronic CHD Swedish adults with no previous stroke or MI; 12 y of f/u

Taiwan adult population

Adults ⱖ45 y without previous CBVD history

For pts with GFR ⱕ60, HR of 1.54 (1.13-2.09) for incident ischemic stroke For ischemic stroke, HRs of 1.09 (1.04-1.14), 1.24 (1.101.39), and 2.27 (1.63-3.17); for hemorrhagic stroke, HRs of 1.04 (0.93-1.15), 1.26 (0.96-1.64), and 2.31 (1.10-4.87) for CKD stages 2, 3, and 4, respectively Adults with CKD stage 3b, vs those with eGFR ⱖ90, at significantly higher risk of prevalent silent brain infarct (prevalence of 37.5% vs 2.6%) Reduced eGFR and higher albuminuria levels associated with increased risk of incident stroke symptoms

Prevalence of CKD in Stroke

Kumai et al78 (2012)

821 pts with acute ischemic or hemorrhagic stroke Chinese pts with radiologic evidence of stroke

CKD present in 36% (by MDRD Study equation) and 18% (by Mayo Clinic equation) High prevalence of CKD (47.7%) in Chinese pts with incident stroke

Pts with first-ever ischemic stroke from the Fukuoka Stroke Registry

CKD, defined as proteinuria or low eGFR (⬍60), diagnosed in 35%

Mechanisms of Increased Risk of Stroke in CKD 79

Pelisek et al (2011)

Cross-sectional

114

Pts who underwent carotid endarterectomy

Ohishi et al80 (2011) Abramson et al81 (2003)

Prospective

531

Pts with essential hypertension

Prospective

13,716

Oguri et al82 (2009)

Comparative

1,041

Participants in ARIC Study

Japanese individuals with CKD (Continued)

Vs pts without CKD, CKD pts had significantly more vascular calcification, unstable and ruptured plaque lesions, and a significantly lower amount of collagenous fibers; CKD pts also had significantly increased serum fibrinogen, hs-CRP, PTH, fetuin A, and MMP-7 levels Increased arterial stiffness (high PWV) and CKD were independent predictors for stroke Combination of CKD and anemia associated with a substantial increase in stroke risk, independent of other known stroke risk factors BCHE genotype a significant independent determinant of ischemic stroke in CKD pts

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Table 2. Clinical Observations of Thromboembolism in CKD

5

6 Table 2 (Cont’d). Clinical Observations of Thromboembolism in CKD Study

Study Type

N

Population

Findings

Impact of CKD on Stroke Outcome Pts hospitalized with acute stroke Pts with acute ischemic or hemorrhagic stroke

Calculated CCr ⱖ51.27 significantly predicted better longterm survival, even after adjustment for confounders 1 y after stroke, proportion of pts with Barthel Index ⬍75a or death were 40.5%, 72.6%, and 83% for those with MDRD Study eGFR ⬎60, 45-60, and 15-44, respectively (P ⬍ 0.001)a

1,350

Pts admitted with first-ever stroke

Retrospective

1,758

Pts with acute stroke

Ovbiagele86 (2011)

Retrospective

1,127,842

HRs for all-cause mortality of 1.21 (1.01-1.46) and 1.76 (1.14-2.73) for pts with baseline eGFR of 30-60 and ⬍30, respectively, vs those with eGFR ⬎60; probability of CV event during f/u was 45.2 (38.7-51.7), 67.4 (56.2-78.6), and 77.6 (53.5-100) for pts with eGFR ⬎60, 30-60, and ⬍30, respectively (log-rank test 21.1, P ⫽ 0.001) Reduced eGFR independent predictor of death/disability at the end of mo 12 in pts with hemorrhagic stroke (OR, 2.353 [1.063-5.209]), but not ischemic stroke (OR, 1.625 [0.881-2.999]) CKD associated with increased overall mortality (OR, 1.63 [1.52-1.75]) regardless of stroke type: ischemic stroke (OR, 1.70 [1.55-1.86]), subarachnoid hemorrhage (OR, 1.93 [1.45-2.58]), intracerebral hemorrhage (OR, 1.28 [1.10-1.49]); association was greater especially in female and younger pts

Kumai et al78 (2012)

Longitudinal

83

MacWalter et al (2007) Yahalom et al76 (2009)

Longitudinal, 7-y f/u

Tsagalis et al84 (2009)

Prospective, f/u 1-120 mo or until death

Hao et al85 (2010)

Longitudinal

2,042 821

3,778

Pts discharged from hospital with diagnosis of stroke

CKD independently associated with significantly higher risks of neurologic deterioration, in-hospital mortality, and poor functional outcome after ischemic stroke

Note: CCr given in mL/min; GFR given in mL/min/1.73 m2. The 95% confidence intervals are given in parentheses for HRs and ORs. Abbreviations: ARIC, Atherosclerosis Risk in Communities; BCHE, butyrylcholinesterase; CBVD, cerebrovascular disease; CCr, creatinine clearance; CHD, coronary heart disease; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; f/u, follow-up; GFR, glomerular filtration rate; HR, hazard ratio; hs-CRP, high-sensitivity C-reactive protein; MDRD, Modification of Diet in Renal Disease; MI, myocardial infarction; MMP-7, matrix-metalloproteinase 7; OR, odds ratio; PWV, pulse wave velocity; pts, patients; PTH, parathyroid hormone. a Lower Barthel Index score signifies greater disability.

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Am J Kidney Dis. 2013;xx(x):xxx

Pts with first-ever ischemic stroke from the Fukuoka Stroke Registry

Atrial Fibrillation in CKD

↑ Vascular prostaglandin I2 Altered von Willebrand Factor

Abnormal platelet-vessel wall interaction

↑ Parathyroid Hormone

↑ Inflammatory markers

↑ Nitric oxide

CKD stage 5D

↓ GpIIb/IIIa receptor binding to fibrinogen

Abnormal Platelet Adhesion & Aggregation

Less scavenger of nitric oxide

Anemia

Bleeding diathesis ↓ADP and Thromboxane A2

Uremic toxin & ↑Guanidinosuccinic acid

Interact

Plalelet abnormalities: -

Subnormal dense granule content Impaired release of α granule protein and β thromboglobulin ↓ Intracellular ADP and serotonin ↑ Intracellular cAMP Abnormal mobilization of platelet calcium Abnormal platelet arachidonic acid metabolism Reduced thromboxane A2 Deficient in cytoskeletal proteins

Abnormal Platelet Release Reaction & Amplification

Figure 2. Potential mechanisms of increased bleeding events in patients with chronic kidney disease stage 5 on dialysis (CKD stage 5D). A number of factors known to be associated with CKD, including increased vascular prostaglandin I2, decreased von Willebrand factor, hyperparathyroidism, chronic inflammation, increased nitric oxide bioavailability, anemia, accumulation of uremic toxins, and platelet abnormalities, lead to abnormal platelet adhesion and aggregation, as well as abnormal platelet release reactions and amplifications. All these combine, leading to a greater risk of bleeding in patients with CKD. Abbreviations: ADP, adenosine diphosphate; cAMP, cyclic adenosine monophosphate; GpIIb/IIIa, glycoprotein IIb/IIIa.

Larger hematoma volumes,96 increased risk of hemorrhagic transformation after ischemic stroke,97 and poorer survival outcome after intracerebral hemorrhage98 appear to be associated with reduced GFR. Impaired platelet adhesion, enhanced nitric oxide synthesis, decreased storage and secretion of plateletactivating mediators, altered intraplatelet calcium mobilization, disturbances in platelet aggregation, increased formation of vascular prostaglandin I2, impaired platelet glycoprotein IIb-IIIa receptor activation and its binding to fibrinogen and von Willebrand factor, anemia, and the presence of uremic toxins have all been postulated in contributing to increased bleeding risks in dialysis patients (Fig 2).20,99-102 Initiation of dialysis therapy has been shown to reduce bleeding risk.103 Interestingly, treatment with erythropoietin also appears to reduce bleeding risk, possibly by improving platelet function.104 To date, studies of bleeding tendency in predialysis CKD cohorts are scarce and often of small scale, which have produced Am J Kidney Dis. 2013;xx(x):xxx

divergent findings.105-108 It appears plausible that the severity of the hemostatic abnormality may have a graded relationship with the severity of CKD, but the exact mechanisms of uremic bleeding remain controversial and the hemostatic abnormalities in the CKD population not receiving dialysis remain underresearched.

ANTICOAGULANTS IN CKD The reported use of warfarin is highly variable in this challenging population, ranging from 2%-37%.27 Systematic reviews of multiple randomized controlled trials (RCTs) have demonstrated that the benefit of dose-adjusted warfarin outweighs the risk of stroke prevention in AF in the general population when international normalized ratio (INR) is maintained at 2-3.16,109 However, current recommendations for dealing with patients with CKD are based mainly on extrapolation from clinical trials in the general population that have largely excluded patients 7

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with CKD.110 Observational studies of anticoagulation in dialysis patients have produced conflicting results, with both better111 and worse38,112-115 outcomes being associated with the use of warfarin. A historical cohort of 3,374 hemodialysis patients showed improved survival with warfarin use in patients later hospitalized for AF.111 Chan et al115 reported increased risk of stroke with the use of warfarin in 1,671 hemodialysis patients with pre-existing AF in a retrospective cohort. Similarly, a study of 2,313 hemodialysis patients with new-onset AF demonstrated that warfarin use did not reduce the incidence of ischemic stroke, but doubled the risk of hemorrhagic stroke.112 The international Dialysis Outcomes and Practice Patterns Study (DOPPS) also reported a greater risk of stroke in warfarin users, especially the elderly.38 However, the apparent association between warfarin use and increased stroke risk in hemodialysis patients with AF does not necessarily imply causality given the observational nature of these studies. In contrast to the conflicting information for the dialysis population, the limited data seem to favor the use of dose-adjusted warfarin for stroke prevention in the non–dialysis-dependent CKD population with AF.116,117 A retrospective study of 399 patients demonstrated that warfarin use significantly reduced the incidence of thromboembolic stroke in patients with CKD across all stages without increasing major bleeding.116 In addition, subgroup analysis of the SPAF3 (Stroke Prevention in Atrial Fibrillation 3) study also reported an impressive 76% reduction in ischemic stroke/systemic embolism when comparing doseadjusted warfarin to treatment with aspirin plus a low fixed-dose warfarin regimen.117 However, the incidence of major bleeding was too small in the subgroup for meaningful comparisons to be made between treatment arms.117 A recent retrospective analysis of Danish national registries also reported a favorable effect of warfarin in reducing stroke in patients with CKD and AF, although increased bleeding risk was associated with treatment compared to the general population.31 A large prospective cohort study of patients receiving warfarin noted an inverse correlation between GFR and major bleeding events, but not between GFR and thromboembolic events.118 Recent studies of novel oral anticoagulant agents in the form of the direct thrombin inhibitor (dabigatran) and the factor Xa inhibitors (apixaban and rivaroxaban) have all demonstrated encouraging results and provide new prospects for stroke prevention for patients with AF in both the general population (Table 3) and (from subgroup analyses) patients with non– dialysis-dependent CKD (Table 4).91,119-121 For those who were deemed unsuitable to receive warfarin, apixaban has been shown to reduce stroke and sys8

temic embolism by 68% (HR, 0.32; 95% confidence interval, 0.18-0.55) compared to aspirin for patients with GFR of 30-60 mL/min in the subgroup analysis of the AVERROES Study.90 In the RELY (Randomized Evaluation of Long-term Anticoagulation Therapy) Study, high-dose dabigatran (150 mg twice daily) was superior to lower dose dabigatran (110 mg twice daily) and was equivalent to dose-adjusted warfarin in reducing stroke risk or systemic embolization with similar safety profiles.119 Two further trials, ARISTOTLE and ROCKET-AF, compared apixaban and rivaroxaban, respectively, to warfarin.91,121 Apixaban was found to be more effective than warfarin, whereas rivaroxaban was shown to be noninferior to warfarin in preventing stroke or systemic embolism in the overall study population. Both studies demonstrated no evidence of heterogeneity of the treatment effects across different categories of kidney function.91 In brief, these 4 studies and their CKD subanalyses suggested that patients with CCr of 30-49 mL/min could achieve at least similar, if not greater, risk reductions in stroke and systemic embolic events as those with CCr ⱖ50 mL/min when comparing dabigatran, apixaban, or rivaroxaban with warfarin or aspirin, without increased risk of bleeding.88-91,119-121 Subgroup analysis of the ARISTOTLE Study reported a greater reduction in major bleeding events for those who received apixaban compared with those who received warfarin in patients with moderately or severely decreased kidney function (CCr ⱕ50 mL/min). Nonetheless, it is important to highlight that patients with more advanced CKD (CCr ⬍30 mL/min for RELY and ROCKET-AF; CCr ⬍25 mL/min or creatinine ⬎2.5 mg/dL for AVERROES and ARISTOTLE) were excluded from these trials. Furthermore, patients with CKD represented only ⬃20% of the total study populations. It also is important to note that the doses of both apixaban and rivaroxaban were reduced according to CCr or serum creatinine level.91,120,121 A recent audit of bleeding events in patients receiving dabigatran drew attention to the significant inherent differences between RCT participants and patients encountered in clinical practice, who often are much older and frailer and with a greater prevalence of decreased kidney function. This audit highlighted the potential underestimation of bleeding risks in these patients and expressed concern about the lack of effective reversal agents for the novel anticoagulants.122 Although several small studies reported a potential reversal effect of nonspecific agents (ie, prothrombin complex concentrate or recombinant factor VIIa) on healthy volunteers and case studies described the use of hemodialysis for dabigatran removal,123,124 prospective validation to fully establish respective antidotes for dabigatran and rivaroxaban Am J Kidney Dis. 2013;xx(x):xxx

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Table 3. Randomized Controlled Trials of Novel Anticoagulant Agents in AF

Study

N

Population

Connolly et al119 (2009) (RELY)

18,113 Pts with AF who were at increased risk of stroke

Connolly et al120 (2011) (AVERROES)

5,999 Pts with AF who were at increased risk of stroke and unsuitable for warfarin 18,201 Pts with AF and ⱖ1 additional risk factor for stroke 14,264 Pts with AF who were at increased risk of stroke

Granger et al91 (2011) (ARISTOTLE) Patel et al121 (2011) (ROCKET)

F/U (mo)

Anticoagulant Therapy

24

6,076 on dabigatran 150 mg 2⫻/d vs 6,015 on dabigatran 110 mg 2⫻/d vs 6,022 on dose-adjusted warfarin 13.2 2,808 on apixaban 5 mg 2⫻/d vs 2,791 on aspirin 81-324 mg 1⫻/d

21.6 9,120 on apixaban 5 mg or 2.5 mg 2⫻/d vs 9,081 on dose-adjusted warfarin 23.5 7,131 on rivaroxaban 20 mg or 15 mg 1⫻/d vs 7,133 on dose-adjusted warfarin

Hemorrhagic Stroke (%/y)

Thromboembolic Events (%/y)

Mortality (%/y)

3.11 vs 2.71 vs 3.36; P ⫽ 0.003 for 2.71 vs 3.36

0.10 vs 0.12 vs 0.38; P ⬍ 0.001

1.11 vs 1.53 vs 1.69; P ⬍ 0.001

3.64 vs 3.75 vs 4.13; P ⫽ NS

1.4 vs 1.2; P ⬍ 0.57

0.2 vs 0.3; P ⫽ 0.45

1.6 vs 3.7; P ⬍ 0.001

3.5 vs 4.4; P ⫽ 0.07

2.13 vs 3.09; P ⬍ 0.001

0.24 vs 0.47; P ⬍ 0.001

1.27 vs 1.60; P ⫽ 0.01

3.52 vs 3.94; P ⫽ 0.047

14.9 vs 14.5; P ⫽ 0.44

0.5 vs 0.7; P ⫽ 0.02

2.1 vs 2.4; P ⬍ 0.001 for noninferiority

0.2 vs 0.5a; P ⫽ 0.003

Bleeding Events (%/y)

Abbreviations: AF, atrial fibrillation; ARISTOTLE, Apixaban for Reduction in Stroke and other Thromboembolic Events in Atrial Fibrillation; AVERROES, Apixaban Versus Acetylsalicylic Acid to Prevent Strokes in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment; F/U, follow-up; NS, not significant; pts, patients; RELY, Randomized Evaluation of Long Term Anticoagulant Therapy With Dabigatran Etexilate; ROCKET, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial. a Fatal bleeding.

9

10 Table 4. Studies of Aspirin, Warfarin, and Novel Anticoagulant Agents in AF in Patients With CKD

N

Study Type

Lai et al116 (2009)

Observational retrospective

399

CKD with AF (23% receiving HD)

None

Hart et al117 (2011)

Post hoc analysis of SPAF III (RCT)

516

Pts with AF, CKD stage 3, high risk of stroke

None

Connolly et al119 Subgroup analysis 3,505 CCr ⬍50 (2009) of RELY (RCT)

CKD Population

Exclusion Based on Kidney Function

Study

Pts with AF who were at CCr ⬍30 increased risk of stroke (CCr ⫽ 30-49)

F/U (mo)

23-31 23% on HD; 33% GFR ⬍15

24

24

Subgroup analysis 1,697 CKD of AVERROESa stage 3 (RCT)

Pts with AF who were at CCr ⬍25 or Cr increased risk of ⬎2.5 mg/dL stroke and unsuitable for warfarin

13.2

Granger et al91 (2011)

Subgroup analysis 3,005 CCr ⱕ30 of ARISTOTLEb (RCT)

Pts with AF and ⱖ1 additional risk factor for stroke

21.6

(Continued)

Stroke/Thromboembolic Events (%/y)a

Dose-adjusted warfarin (INR target, 2-3): 3.48; not on warfarin: 13.57; P ⬍ 0.001 49% with GFR 30-59 Dose-adjusted warfarin (INR target, 2-3): 1.45; fixed low-dose warfarin ⫹ aspirin (INR ⫽ 1.3 ⫾ 0.8): 7.05; P ⬍ 0.01 3,505 with CCr 30-50; Dabigatran 150 mg 8,766 with CCr 50-79; 2⫻/d: 2.15, 1.7, and 5,826 with CCr ⱖ80 0.94, respectively; dabigatran 110 mg 2⫻/d: 1.52, 1.20, and 0.75, respectively; dose-adjusted warfarin: 2.78, 1.76, and 0.98, respectively; P(int) ⫽ 0.54 1,697 with GFR 30-59; Apixaban: 1.8; aspirin 3,828 with GFR ⱖ60 81-324 mg 1⫻/d: 5.6 for GFR 30-59 (P ⬍ 0.001); apixaban: 1.7; aspirin 81-324 mg 1⫻/d: 2.8 for GFR ⱖ60 (P ⫽ 0.009) 7,496 with CCr ⬎80; Apixaban: 1.0, 1.2, and 7,565 with CCr 51-80; 2.1, respectively; 3,005 with CCr 25-50 dose-adjusted warfarin: 1.1, 1.7, and 2.7, respectively; P(int) ⫽ 0.72

Major Bleeding Events (%/y)a

Dose-adjusted warfarin (INR target, 2-3), 5.42; not on warfarin, 4.70; P ⫽ NS Dose-adjusted warfarin (INR target, 2-3), 1.25; fixed low-dose warfarin ⫹ aspirin (INR ⫽ 1.3 ⫾ 0.8), 1.8; P ⫽ 0.65 NA

Apixaban: 2.5; aspirin 81-324 mg 1⫻/d: 2.2 for GFR 30-59 (P ⫽ 0.58); apixaban: 0.9; aspirin 81-324 mg 1⫻/d: 2.2 for GFR ⱖ60 (P ⫽ 0.85) Apixaban: 1.5, 2.5, and 3.2, respectively; dose-adjusted warfarin: 1.8, 3.2, and 6.4, respectively; P(int) ⫽ 0.03

Ng et al

Am J Kidney Dis. 2013;xx(x):xxx

Eikelboom et al90 (2012)

CCr ⬍25 or Cr ⬎2.5 mg/dL

CKD Severity

Study

Study Type

N

CKD Population

Exclusion Based on Kidney Function

F/U (mo)

CKD Severity

Fox et al89 (2011)

Subgroup analysis 2,950 CCr 30-49 of ROCKET-AFc (RCT)

Pts with AF who were at CCr ⬍30 increased risk of stroke

23.6

2,950 with CCr 30-49; 11,277 with CCr ⱖ50

Olesen et al31 (2012)

Subgroup analysis 3,587 non–endof retrospective stage CKD observational study of Danish National Registries

Pts discharged from hospital with diagnosis of nonvalvular AF

NA

132,372 with no kidney disease; 3,587 with non–end-stage CKD; 901 with ESRD on RRT

NA

Stroke/Thromboembolic Events (%/y)a

Major Bleeding Events (%/y)a

Rivaroxaban: 2.32, 1.57; dose-adjusted warfarin: 2.77, 2.00; P(int) ⫽ 0.76 No kidney disease on warfarin: HR of 0.59 (0.56-0.61); on aspirin: 1.11 (1.061.14); on warfarin and aspirin: 0.70 (0.64-0.74); non–end-stage CKD on warfarin: 0.84 (0.69-1.01); on aspirin: 1.25 (1.071.47); on warfarin and aspirin: 0.76 (0.56-1.03); ESRD on RRT on warfarin: 0.44 (0.260.74); on aspirin: 0.88 (0.59-1.32); on warfarin and aspirin: 0.82 (0.37-1.80)b

Rivaroxaban: 4.49, 3.39; dose-adjusted warfarin: 4.70, 3.17; P(int) ⫽ 0.48 No kidney disease on warfarin: HR of 1.28 (1.23-1.33); on aspirin: 1.21 (1.161.26); on warfarin and aspirin: 2.18 (2.07-2.30); non–end-stage CKD on warfarin: 1.36 (1.17-1.59); on aspirin: 1.12 (0.961.30); on warfarin and aspirin: 1.63 (1.32-2.02); ESRD on RRT on warfarin: 1.27 (0.911.77); on aspirin: 1.63 (1.18-2.26); on warfarin and aspirin: 1.71 (0.98-2.99)d

Note: CCr given in mL/min. eGFR given in mL/min/1.73 m2 except as indicated. Values in parentheses are 95% confidence intervals. Conversion factor for units: creatinine in mg/dL to ␮mol/L, ⫻88.4; GFR in mL/min/1.73 m2 to mL/s/1.73 m2, ⫻0.01667. Abbreviations: AF, atrial fibrillation; AVERROES, Apixaban Versus Acetylsalicylic Acid to Prevent Strokes in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment; ARISTOTLE, Apixaban for Reduction in Stroke and other Thromboembolic Events in Atrial Fibrillation; BMI, body mass index; CKD, chronic kidney disease; CCr, creatinine clearance; Cr, creatinine; ESRD, end-stage renal disease; F/U, follow-up; GFR, glomerular filtration rate; HD, hemodialysis; HR, hazard ratio; INR, international normalized ratio; NA, not available/applicable; NS, not significant; P(int), P value interaction; Pts, patients; RCT, randomized controlled trial; RELY, Randomized Evaluation of Long Term Anticoagulant Therapy; 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; RRT, renal replacement therapy; SPAF III, Stroke Prevention in Atrial Fibrillation 3. a Units as shown unless otherwise specified. b Apixaban dose reduction from 5 mg twice daily to 2.5 mg twice daily for patients with 2 or more of the following criteria: age ⱖ80 years, BMI ⱕ60 kg, and creatinine level ⱖ133 ␮mol/L. c Rivaroxaban dose reduction from 20 mg once daily to 15 mg once daily if CCr is 30-49 mL/min. d For each disease group (no kidney disease, non– end-stage CKD, and ESRD on RRT), receiving no medication was the reference category.

Atrial Fibrillation in CKD

Am J Kidney Dis. 2013;xx(x):xxx

Table 4 (Cont’d). Studies of Aspirin, Warfarin, and Novel Anticoagulant Agents in AF in Patients With CKD

11

Ng et al

are still outstanding.125,126 Additionally, drug interactions also need to be taken into account. Dabigatran, apixaban, and rivaroxaban are dependent on Pglycoprotein and CYP3A4 for their clearance.127 Patients with CKD also often are using multiple medications, and care should be taken when these agents are prescribed concomitantly with drugs such as verapamil, amiodarone, or droneradone because they potentially can significantly increase the bleeding risk.127,128

RISK STRATIFICATION FOR STROKE AND BLEEDING IN AF AND CKD In the wake of important predictors of stroke being identified, various stroke risk schemes have been published. The simplest and most widely used is the CHADS2 score (Box S1, provided as online supplementary material).129 Without antithrombotic treatment, each 1-point increment in CHADS2 score corresponds to a factor of 1.5 increase in stroke rate per 100 patient-years.130 However, most scores used, including the CHADS2 score, have a low predictive value for stroke.17 The latest European Society of Cardiology AF Guidelines17 de-emphasize the use of risk categories and recognizes that risk is a continuum. They encourage the use of a multiple risk factor– based approach for more detailed stroke assessment. The CHA2DS2-VASc (Box 1) scoring system is such an approach. It is superior to the CHADS2 score in identifying truly low-risk individuals who are unlikely to benefit from anticoagulation and is as good as and possibly better than the CHADS2 score in terms of predictive ability of thromboembolic risk.131-133 Use of the CHA2DS2-VASc score is recommended, especially for those with CHADS2 score less than 2. According to the European Society of Cardiology guidelines,17 no antithrombotic therapy is advised if the score is 0. Oral anticoagulation or aspirin potentially could be recommended for those with a score of 1, with the preference for oral anticoagulant therapy in the general population. Box 1. The CHA2DS2-VASc Score for Stroke Risk Stratification in Patients With Atrial Fibrillation Congestive heart failure: 1 point Hypertension: 1 point Age ⱖ75 y: 2 points Diabetes mellitus: 1 point History of stroke or transient ischemic attack or thromboembolism: 2 points Vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque): 1 point Age 65-74 y: 1 pt Sex category (female sex): 1 point Reproduced from Lip et al131 with permission from the American College of Chest Physicians. 12

Box 2. The HAS-BLED Score to Assess 1-Year Risk of Major Bleeding in Patient With AF Hypertensiona: 1 point Abnormal renalb or liver functionc: 1 point each Stroke: 1 point Bleeding history or predisposition: 1 point Labile INRsd: 1 point Elderlye: 1 point Drugsf or alcohol concomitantly: 1 point each Abbreviation: INR: international normalized ratio. Uncontrolled hypertension with systolic blood pressure ⬎160 mm Hg. b Presence of long-term dialysis, kidney transplantation, or serum creatinine level ⱖ2.26 mg/dL. c Chronic hepatic disease (ie, cirrhosis) or biochemical evidence of significant hepatic derangement (ie, bilirubin ⬎2 times the upper limit of normal in association with aspartate or alanine aminotransferase or alkaline phosphatase level greater than 3 times the upper limit of normal). d Time in therapeutic range ⬍60%. e Age older than 65 years or frail condition. f Antiplatelet agents or nonsteroidal anti-inflammatory drugs. Reproduced from Pisters et al135 with permission from the American College of Chest Physicians. a

It has been suggested recently that using the final letter “c” in the CHA2DS2-VASc acronym for “chronic severe renal impairment” might lead to further improved discrimination of the score, but this remains to be validated.134 Using DOPPS data, Wizemann et al38 demonstrated increasing stroke event rates with increasing CHADS2 score in hemodialysis patients. However, whereas old age, diabetes mellitus, and history of stroke correlated significantly with increased risk of stroke, congestive heart failure and hypertension did not.38 To date, both CHADS2 and CHA2DS2-VASc scores have not been specifically validated in the non–dialysis-dependent CKD population. The recently described bleeding risk score HASBLED (Box 2) has clearly acknowledged CKD as a crucial bleeding risk factor.135 This scoring system defined decreased kidney function as the presence of long-term dialysis therapy, kidney transplantation, or serum creatinine level ⱖ2.26 mg/dL. This level of creatinine denotes severely decreased kidney function and thus ignores lesser but potentially significant levels of decreased kidney function.135 More work is needed to determine how the presence of CKD should be included in bleeding risk scores.15

BALANCING THE RISKS AND BENEFITS OF ANTICOAGULATION The incidence of overanticoagulation and minor and major hemorrhagic complications increases with worsening kidney function.136 Several mechanisms by which CKD is associated with increased bleeding risk from warfarin anticoagulation have been postuAm J Kidney Dis. 2013;xx(x):xxx

Atrial Fibrillation in CKD

lated. Warfarin half-life is shorter and there is greater unbound warfarin fraction in patients with decreased kidney function.137,138 Vitamin K deficiency139 also may contribute to INR instability in CKD.140 Warfarin use also might have other unwanted actions on patients with CKD. Overanticoagulation (INR ⬎3.0) is associated with faster progression of CKD by unknown mechanisms.141 Importantly, warfarin has adverse effects on ectopic/vascular calcification, impairing the carboxylation of vitamin K–dependent proteins, bone Gla protein, and matrix Gla protein, which play crucial roles in regulating bone mineralization and inhibiting vascular calcification, respectively.142 matrix Gla protein-deficient mice develop severe extensive arterial calcification, osteoporosis, and pathologic fractures in early life.143 Similar rapid arterial calcification also was observed in rats receiving high-dose warfarin.144 Lower circulating matrix Gla protein levels are associated with increased aortic valve and coronary artery calcification.145,146 Patients on long-term warfarin treatment were found to have lower bone density and a 2-fold increase in aortic valve calcification.147,148 Hemodialysis patients on warfarin therapy have a greater prevalence of vertebral fracture, severe aortic calcification, and increased mortality in those who received long-term warfarin treatment.149 In addition, warfarin use is a risk factor for developing calciphylaxis.150,151 The lack of RCTs examining the safety, efficacy, and benefit to risk ratio of the use of warfarin in different stages of CKD contributes to the difficulty achieving consensus on anticoagulation treatment in CKD. The relevance and validity of risk scoring systems in guiding the prescription of oral anticoagulants for stroke prevention in patients with CKD with AF remains unclear given that the thromboembolism and bleeding susceptibility in patients with CKD differ from those in the general population. Furthermore, the potentially deleterious cardiovascular effects of warfarin are crucial and need to be taken into consideration. Encouragingly, the emergence of novel anticoagulants that do not affect vitamin K–dependent proteins may provide an exciting prospect.91,119-121 However, most of these agents are in part renally excreted; dabigatran in particular is 80% renally cleared.119 Awareness of their prolonged half-life and optimal dosing to reduce bleeding complications therefore are crucial when considering their use in patients with CKD. To date, dabigatran and rivaroxaban have obtained approval from the US Food and Drug Administration, European Medicine Agency, and Health Canada for use in patients with non–dialysis-dependent CKD. However, their recommendations for use are heterogeneous regarding dose reduction and GFR thresholds.19 The knowledge gaps in regard to risks Am J Kidney Dis. 2013;xx(x):xxx

and benefits of anticoagulation with warfarin for stroke prevention and the efficacy and safety of dabigatran in patients with CKD were highlighted in a recent KDIGO (Kidney Disease: Improving Global Outcome) publication that emphasized the urgent need for RCTs to examine anticoagulants for stroke prevention in patients with CKD, particularly in patients with significantly reduced GFR (⬍30 mL/min/1.73 m2).152 The newer oral factor Xa inhibitor betrixaban has minimal renal excretion and therefore may be especially worthy of study in patients with CKD.153

CONCLUSIONS CKD and AF are 2 commonly coexisting prothrombotic conditions with an apparent bidirectional relationship, which urgently warrants further investigation. Decreased kidney function also appears to be associated with an increased risk of hemorrhagic complications. Even using the most conservative estimates of AF prevalence, it affects at least 7% of all dialysis patients. When considering the millions of patients with less severe forms of CKD worldwide with AF, the paucity of data for treatment is astounding. There is more than enough justification for mechanistic studies and well-designed clinical trials to truly understand and treat AF in patients with CKD. Novel anticoagulants for stroke prevention in AF to date have shown noninferiority compared with warfarin, with trends toward superiority. However, the studies to date have not enrolled sufficient numbers of patients with more advanced CKD on or off dialysis therapy to fully establish their efficacy or safety in these populations. Moreover, because most of these novel anticoagulants are partially cleared by the kidneys, pharmacokinetic and dynamic data are essential to design dose regimens for patients with all forms of CKD, and further outcome trials are needed in patients with CKD before widespread use is considered in this difficult patient group. However, there is no doubt that the potential exists for a therapeutic benefit of these novel anticoagulants in those with CKD on and off dialysis therapy. CASE REVIEW The index case presented a common scenario encountered in routine clinical practice. The patient has asymptomatic AF found on a routine clinical examination, not requiring ventricular rate-controlling therapy. The patient has a CHADS2 score of 4, giving a stroke risk of 8.5% per year. He also has a CHA2DS2-VASc score of 5, indicating that he is at high risk of stroke. Both risk scores support the need for anticoagulation, although they have not yet been validated in CKD populations. However, this man also has an HASBLED score of 4, suggesting he has an 8.7% annual 13

Ng et al

risk of a major bleed. Thus, the decision to perform anticoagulation may not be as straightforward as would first appear. This complex dilemma was discussed extensively between the patient, cardiologist, and nephrologist. The patient expressed a desire to receive anticoagulation therapy because he was concerned about the disabling neurologic sequelae of a stroke and was prepared to accept the significant risk of major bleeding. He initially was attracted to the idea of the newer non–vitamin K–based anticoagulants because of no requirement for regular invasive monitoring and the reported lower incidence of bleeding. However, he subsequently changed his mind due to a lack of long-term efficacy and safety data for their use in patients with significantly decreased kidney function. Furthermore, he expressed concern about the paucity of available pharmacologic agents capable of acutely reversing the anticoagulant effects of the newer agents in the event of major bleeding, other than case reports of intermittent hemodialysis in the case of dabigatran. The patient was started on warfarin treatment with the aim of keeping his INR within a range of 2.0-3.0. He agreed to attend regular appointments at his nearest anticoagulant clinic and was considering the option of home testing and self-management of his INR.154

ACKNOWLEDGEMENTS Support: Dr Ng is funded by Birmingham & Black Country Comprehensive Local Research Network; Dr Ferro is funded by a National Institute for Health Research Fellowship. Financial Disclosure: Dr Lip has served as a consultant for Bayer, Astellas, Merck, Sanofi, BMS/Pfizer, Daiichi-Sankyo, Biotronik, Portola, and Boehringer Ingelheim and has been on the speakers’ bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim, and Sanofi Aventis. Dr Ferro has received lecture fees and advisory board fees from Genzyme Corp. The other authors declare that they have no relevant financial interests.

SUPPLEMENTARY MATERIAL Box S1: The CHADS2 score for assessment of stroke risk in patients with atrial fibrillation. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2013.02.381) is available at www.ajkd.org.

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