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REVIEW TOPIC OF THE WEEK

Nonvitamin K Anticoagulant Agentsin Patients With Advanced ChronicKidney Disease or on Dialysis With AF

Kevin E. Chan, MD, MSCI,a,b Robert P. Giugliano, MD, SM,c Manesh R. Patel, MD,d Stuart Abramson, MD,e

Meg Jardine, MBBS, PHD,f Sophia Zhao, MD, PHD,a Vlado Perkovic, MBBS, PHD,f Franklin W. Maddux, MD,b

Jonathan P. Piccini, MD, MHSCd

ABSTRACT

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Nonvitamin K-dependent oral anticoagulant agents (NOACs) are currently recommended for patients with atrial fibril-

lation at risk for stroke. As a group, NOACs significantly reduce stroke, intracranial hemorrhage, and mortality, with lower

to similar major bleeding rates compared with warfarin. All NOACs are dependent on the kidney for elimination, such that

patients with creatinine clearance <25 ml/min were excluded from all the pivotal phase 3 NOAC trials. It therefore

remains unclear how or if NOACs should be prescribed to patients with advanced chronic kidney disease and those on

dialysis. The authors review the current pharmacokinetic, observational, and prospective data on NOACs in patients with

advanced chronic kidney disease (creatinine clearance <30 ml/min) and those on dialysis. The authors frame the evidence

in terms of risk versus benefit to bring greater clarity to NOAC-related major bleeding and efficacy at preventing

stroke specifically in patients with creatinine clearance <30 ml/min. (J Am Coll Cardiol 2016;67:2888–99)

© 2016 by the American College of Cardiology Foundation.

P atients with atrial fibrillation (AF) are in-creasingly being treated with nonvitaminK-dependent oral anticoagulant agents

(NOACs) because these drugs are at least as effectiveas warfarin, are safer, do not require routine moni-toring, and are simpler to use (1–5). In 2013, NOACsaccounted for 62% of new prescriptions of anticoagu-lant agents in the United States, and their adoption isincreasing (1).

Although NOACs hold great promise, they alsohave drawbacks, such as limited availability of and

m the aFresenius Medical Care North America, Waltham, Massachuset

spital, Boston, Massachusetts; cCardiovascular Division, Brigham andWom

search Institute, Duke University Medical Center, Durham, North Carolina

dicine, Portland, Maine; and the fGeorge Institute for Global Health, Un

ering committee member of the RENAL-AF trial, which is funded by Bri

dical Care. Dr. Piccini receives grants for clinical research from ARCA B

ality, Gilead, Johnson & Johnson, and St. Jude Medical; and serves as a con

dtronic. Dr. Giugliano was the principal investigator of the ENGAGE AF–TI

m Daiichi-Sankyo to the Brigham and Women’s Hospital, where he is em

ntinuing medical education activities from Boehringer Ingelheim, Bristol-M

llege of Cardiology, Pfizer, and Portola. Dr. Maddux is an employee of F

dine is supported by a Career Development Fellowship from the National H

little experience with reversal agents, as well ashigher costs. Currently, all NOACs depend to someextent on renal function for clearance. Consequently,NOACs may potentially accumulate in patients withrenal dysfunction, leading to an increased risk forbleeding. Additionally, patients with advancedchronic kidney disease (CKD) (creatinine clearance[CrCl] <30 ml/min) are already at increased risk forbleeding from uremia-induced platelet dysfunction(6,7). Patients on hemodialysis have added bleedingrisks from repeated vascular access cannulation,

ts; bDivision of Nephrology, Massachusetts General

en’s Hospital, Boston, Massachusetts; dDuke Clinical

; eMaine Medical Center, Tufts University School of

iversity of Sydney, Sydney, Australia. Dr. Chan is a

stol-Myers Squibb; and is an employee of Fresenius

iopharma, the Agency for Healthcare Research and

sultant to Janssen Pharmaceuticals, Pfizer-BMS, and

MI 48 trial, which was supported by a research grant

ployed; and has received honoraria for consulting or

yers Squibb, Daiichi-Sankyo, Janssen, The American

resenius Medical Care and has stock ownership. Dr.

ealth and Medical Research Council of Australia and

AB BR E V I A T I O N S

AND ACRONYM S

ACC = American College of

Cardiology

AF = atrial fibrillation

AHA = American Heart

Association

CI = confidence interval

CKD = chronic kidney disease

CrCl = creatinine clearance

ESRD = end-stage renal

disease

FDA = U.S. Food and Drug

Administration

HR = hazard ratio

HRS = Heart Rhythm Society

NOAC = nonvitamin K-

dependent anticoagulant agent

PK = pharmacokinetic

J A C C V O L . 6 7 , N O . 2 4 , 2 0 1 6 Chan et al.J U N E 2 1 , 2 0 1 6 : 2 8 8 8 – 9 9 NOACs in Advanced CKD and Dialysis

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dialysis membrane interactions, higher than averageblood pressures, and considerable heparin adminis-tration during treatment. Because patients withadvanced CKD and end-stage renal disease (ESRD)were excluded from all of the pivotal phase 3 NOACtrials, no randomized controlled trial data guideNOAC use when the CrCl is <25 ml/min, althoughthe U.S. Food and Drug Administration (FDA)label supports NOAC dosing for patients withCrCl #15 ml/min.

The most recent 2014 American Heart Association(AHA), American College of Cardiology (ACC), andHeart Rhythm Society (HRS) guideline for the man-agement of patients with AF recommends warfarin asthe anticoagulant agent of choice in patients withadvanced CKD or ESRD (8). Despite these recommen-dations and the lack of prospective trials to validate theefficacy and safety of NOACs in this patient population,the prescription of these drugs is becoming moreprevalent, as we showed in our previous publication(9). Our updated analysis, as of October 2015 (unpub-lished data from Fresenius Medical Care), indicatesthat 23.5% of patients with advanced CKD and 11.6% ofthose on dialysis with AF who are anticoagulated wereprescribed NOACs (Central Illustration). Among theNOAC-treated patients with CKD (n ¼ 102,504), themost commonly used drug was apixaban (10.4%), fol-lowed by rivaroxaban (9.5%), dabigatran (3.5%), andedoxaban (0.1%). Among the NOAC-treated dialysispatients (n ¼ 140,918), the most commonly used drugwas apixaban (10.5%), followed by rivaroxaban (0.8%),dabigatran (0.3%), and edoxaban (0.01%).

This review summarizes the available evidenceregarding the efficacy (prevention of stroke) andsafety (major bleeding) of the 4 currently availableNOACs (apixaban, rivaroxaban, dabigatran, andedoxaban), with particular emphasis on the outcomesin subgroups of patients with AF with CKD. Pharma-cokinetic (PK) data for patients with advanced CKDand those on dialysis will be discussed, as well as thedata on reversal agents. Finally, we outline the stepsrequired to determine if NOACs are appropriatetreatment options in patients with AF with advancedCKD or on dialysis.

the National Heart Foundation; has received speaking fees from Amgen an

Boehringer Ingelheim; has received unrestricted research funding from Gamb

served on a steering committee for a trial funded by Janssen; all honoraria a

Dr. Patel is supported by research grants from AstraZeneca, Bayer, Procyrio

Institute; and is a consultant advisory board member to AstraZeneca, Jansen

steering committee of a trial of an unrelated compound funded by Janssen; h

area; and has a policy of honoraria going to his institution. All other authors h

to the contents of this paper to disclose.

Manuscript received January 20, 2016; revised manuscript received Februar

RENAL PHARMACOKINETICS OF

ANTICOAGULANT AGENTS

Uremia affects every organ system in thebody and influences the pharmacokinetics ofmany drugs. Uremia can impair plasma pro-tein binding, which may lead to increasedfree drug levels in the blood, and in turn,renal failure can also impair nonrenal drugmetabolism by reduction and hydrolysis re-actions (10,11).

Renal elimination of drugs occurs predom-inantly through glomerular filtration and oc-casionally through tubular secretion andreabsorption. When the glomerular filtrationrate and tubular function are impaired byrenal disease, the clearance of drugs elimi-nated by these mechanisms will be decreased,and the plasma half-lives of the drugs will beprolonged. This can result in increased total

drug exposure, as quantified by the area under thecurve (Figure 1).Without appropriate dose adjustment,repeated dosing of a drug that is inadequately clearedcould lead to bioaccumulation over time and toxicityfrom supratherapeutic levels of the drug (Figure 2). Tocounteract decreased renal drug elimination, medi-cations can be given at a lower dose or frequency toprevent unintended drug accumulation (11).

Anticoagulant drug dosing in patients with renalimpairment is based on glomerular filtration rate,which is impractical to measure directly in an officesetting. Instead, the glomerular filtration rate canbe estimated by measuring the 24-h urine CrCl,because almost all creatinine is eliminated throughthe glomerulus. Because collecting urine for 24 h isa tedious process, CrCl is typically estimated byan equation, using a single serum creatininemeasurement.

For NOAC dosing, CrCl should be calculated usingthe Cockcroft-Gault formula, because the pivotalphase 3 NOAC trials have reported outcomes by CrClusing that formula (12). This is despite the fact thatthe Cockcroft-Gault formula can overestimate trueCrCl by 10% to 40%, and newer estimating equations,

d Roche; has received advisory board funding from

ro, Baxter, CSL, Amgen, Eli Lilly and Merck; and has

re contributed directly to clinical research programs.

n, Jansen, and the National Heart, Lung, and Blood

, Bayer, Genzyme, and Merck. Dr. Perkovic chairs the

as consulted for Bristol-Myers Squibb in an unrelated

ave reported that they have no relationships relevant

y 16, 2016, accepted February 23, 2016.

CENTRAL ILLUSTRATION Use of Nonvitamin K-Dependent Oral Anticoagulant Agents in Patients WithAdvanced Chronic Kidney Disease and on Dialysis: Substantial and Growing

Chan, K.E. et al. J Am Coll Cardiol. 2016;67(24):2888–99.

Prevalence of nonvitamin K-dependent oral anticoagulant agent (NOAC) use is rising among patients with advanced chronic kidney disease (CKD) and those on dialysis

anticoagulated for atrial fibrillation, despite the most recent American Heart Association, American College of Cardiology, and European Heart Rhythm Society guideline,

which discourages the use of NOACs when creatinine clearance (CrCl) is<30 ml/min. There are few randomized trial data on NOACs in this population. All NOACs depend

on the kidney for elimination, and it is unclear if severe renal impairment leads to drug bioaccumulation to precipitate inadvertent bleeding.

FIGURE 1 Pharmacokinetic Curves for Renally Cleared Drugs in Patients With Normal and Impaired Kidney Function

100

80

60

40

20

00 6 12 18 24

Time (Hours)

Drug

Con

cent

ratio

n (n

g/m

L)

0 6 12 18 24Time (Hours)

100

80

60

40

20

0

A B

Pharmacokinetic (PK) curves illustrating the peak, trough, and total drug exposure for a renally cleared drug in a patient with normal kidney

function (A) and in a patient with impaired kidney function (B). Decreased drug clearance resulted in increased peak level, trough level, and

total drug exposure. Total drug exposure is quantified by the area under the PK curve, in blue.

Chan et al. J A C C V O L . 6 7 , N O . 2 4 , 2 0 1 6

NOACs in Advanced CKD and Dialysis J U N E 2 1 , 2 0 1 6 : 2 8 8 8 – 9 9

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FIGURE 2 Pharmacokinetic Curve Illustrating the Effect of Drug Multidosing in a

Patient With Impaired Renal Function, Resulting in Bioaccumulation of the

Drug Level

100

80

60

40

20

00 12 24 36 48 60 72

Time (Hours)

Drug

Con

cent

ratio

n (n

g/m

L)A mismatch between drug dose and drug clearance results in the carryover of excess drug

level to the next dosing interval, which occurs every 24 h.

FIGURE 3 Pharmacokinetics of Warfarin

warfarin

parent drug(99% bound)

CYP2C9metabolized

Inactivemetabolite

renal elimination

Warfarin does not depend on the kidney for elimination.

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such as the MDRD (Modification of Diet in RenalDisease) and CKD-EPI (Chronic Kidney DiseaseEpidemiology Collaboration) equations, have beenshown to be more accurate (13–15). The Cockcroft-Gault equation is as follows:

CrCl ðml=minÞ ¼ ð140� ageÞ �weight ðkgÞ � sex72� serum creatinine ðmg=dlÞ

where sex ¼ 1 in men and 0.85 in women. It is alsoimportant to note that CrCl estimations derived fromthese equations are valid only when a patient’screatinine level is in a steady state. It is a mistake toextrapolate CrCl calculations using creatinine valuesfrom acutely ill patients with acute kidney injury.Drug dosing in patients with acute kidney injuryshould be individualized until the creatinine levelstabilizes, which may take weeks or longer (11).

Drug removal through hemodialysis is determinedprimarily by molecular size. Small molecules (<1,500Da) are amenable to removal through high-flux dial-ysis membranes. Protein-bound drugs are not clearedby dialysis, whereas unbound drugs in the intravas-cular space may be cleared. A drug with a high vol-ume of distribution, arbitrarily defined at >0.7 l/kg,indicates a highly tissue-bound drug, where a signif-icant amount of drug is distributed in the extravas-cular space that is not directly accessible to theextracorporeal circulation for removal by dialysis.Measured drug levels are expected to reboundafter hemodialysis is completed and are the result ofdrug concentrations in the intra- and extravascularcompartment reequilibrating after dialysis (11).

WARFARIN

Warfarin, originally used as a rodenticide in 1948, waslater found to be effective and relatively safe forpreventing thrombosis and was approved for use asan anticoagulant agent in 1954 (16). Warfarin is notdialyzable, because 99% is bound to plasma proteins,and elimination of the drug is almost entirely byhepatic metabolism into an inactive metabolite(Figure 3). Very little of the parent compound isexcreted in the urine (11,17,18). Studies also suggestthat patients with advanced CKD and on dialysisrequire reduced doses of warfarin. This may be in partdue to alterations of hepatic metabolism of warfarinsecondary to renal failure (19). Animal studies in CKDhave shown a significant down-regulation (40% to85%) of hepatic cytochrome P-450 metabolism, whichcorroborates with clinical data (17,19–21).

Warfarin is minimally dependent on the kidney forelimination, such that progression of CKD or acutechanges in creatinine can minimally influence

anticoagulation levels from the drug. Warfarin has theadvantages of clinical familiarity, low cost, and wide-spread availability of reversal agents. Reversal ofwarfarin’s anticoagulant effect can be accomplishedwith vitamin K or fresh-frozen plasma for non-emergent situations, with 4-factor prothrombin com-plexes recommended for life-threatening bleeding(22). Warfarin significantly increases the risk forbleeding as CrCl decreases. This is likely secondary tosuperimposed platelet dysfunction from worseninguremia. A patient on warfarin with CrCl <30 ml/minhas a 4.9-fold (95% confidence interval [CI]: 2.6 to 9.1)increased relative risk for bleeding compared

TABLE 1 Estimated Major Bleeding Rates for Patients on

Warfarin by Creatinine Clearance

Kidney FunctionMajor Bleeding

(Events per 100 Patient-Years)

CrCl $60 ml/min 6.2 (4.1–8.9)

CrCl 30–59 ml/min 8.3 (5.1–12.8)

CrCl <30 ml/min 30.5 (17.0–50.3)

Dialysis 54–100

Data from Limdi et al. (17) and Elliott et al. (64).

CrCl ¼ creatinine clearance.

Chan et al. J A C C V O L . 6 7 , N O . 2 4 , 2 0 1 6

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with patients on warfarin without renal disease(Table 1) (17).

NOACs

Currently, there are 4 FDA-approved NOACs forstroke prevention in patients with AF: apixaban,rivaroxaban, dabigatran, and edoxaban. Table 2summarizes the renal clearance, effect of dialysis,and reversal agents for these medications; in addi-tion, it outlines the hazard ratios (HRs) for stroke andbleeding from the pivotal phase 3 trials among sub-jects with CrCl <50 ml/min (referent to warfarin).

APIXABAN. Apixaban is a direct factor Xa inhibitorwith 27% renal elimination (Figure 4A). In theAVERROES (Apixaban Versus Acetylsalicylic Acid toPrevent Stroke in Atrial Fibrillation Patients WhoHave Failed or Are Unsuitable for Vitamin K Antago-nist Treatment) trial (n ¼ 5,599 subjects withcreatinine <2.5 mg/dl), subjects with AF who wereunable to take warfarin were randomized to apixaban5 mg twice per day or aspirin. A reduced dose ofapixaban 2.5 mg twice per day was given to patientswho met at least 2 of the following criteria: serumcreatinine between 1.5 and 2.5 mg/dl, age $80 years,and body weight #60 kg. The study showed thatapixaban was superior to aspirin in preventing strokeor systemic embolization (HR: 0.32; 95% CI: 0.19 to0.56), and the trial was stopped prematurely by theData and Safety Monitoring Board because of over-whelming efficacy (23). No significant difference inthe rate of major bleeding between the groups wasobserved (HR: 1.06; 95% CI: 0.58 to 1.93). The supe-riority of apixaban over aspirin in stroke preventionand a similar incidence of major bleeding were pre-served among patients with CrCl of 25 to 50 ml/min inthe study.

In the ARISTOTLE (Apixaban for Reduction inStroke and Other Thromboembolic Events in AtrialFibrillation) trial (n ¼ 18,201 subjects withcreatinine <2.5 mg/dl), patients were randomized toapixaban 5 mg twice per day or warfarin. Because

they met the same criteria used in the AVERROES trialfor dose reduction, 4.7% of apixaban patientsreceived a lower dose of 2.5 mg twice per day. Overall,apixaban significantly decreased the risk for strokeand systemic embolism (HR: 0.79; 95% CI: 0.66 to0.95) and major bleeding (HR: 0.69; 95% CI: 0.60 to0.80) compared with warfarin (2). These trends per-sisted in post hoc analyses among patients with CrClof 25 to 50 ml/min, in whom apixaban demonstrated anonsignificantly decreased risk for stroke (HR: 0.79;95% CI: 0.55 to 1.14) and a significantly decreased riskfor bleeding (HR: 0.50; 95% CI: 0.38 to 0.66) referentto warfarin (24,25). Because of multiple criteria fordose reduction, it is uncertain how many patientswith CrCl of 25 to 50 ml/min received the 2.5-mgversus the 5-mg apixaban dose and whether doseaffects these HR estimates.

Apixaban was FDA approved in December 2012 forthe prevention of stroke and systemic embolism inpatients with nonvalvular AF at a dose of 5 mg twiceper day and with a 2.5-mg twice-daily dose in patientswith 2 of the following: serum creatinine between1.5 and 2.5 mg/dl, age $80 years, and body weight#60 kg. In the original labeling, the drug was notrecommended for patients with CrCl <25 ml/min.

The drug label was amended in January 2014 forpatients with renal impairment, including those withESRD maintained on hemodialysis. For these pa-tients, no dose reduction (5 mg twice daily) wassuggested unless patients were also $80 years of ageor had body weight #60 kg, in which case the reduceddose of 2.5 mg twice per day could be used. Patientswith creatinine >2.5 mg/dl, with CrCl <25 ml/min, oron long-term dialysis were excluded from theARISTOTLE trial; therefore, these dosing suggestionswere based partially on a single-dose (not multidose)PK study in 8 hemodialysis subjects matched to8 subjects with normal renal function (26). In thisstudy, the post-hemodialysis administration of 5 mgapixaban resulted in 36% higher drug exposurecompared with healthy subjects with normal renalfunction. In another 10-mg single-dose PK study of 24subjects with mild and moderate CKD compared with8 subjects with normal kidney function, total apix-aban exposure was estimated via regression modelsto be 44% greater in subjects with CrCl of 15 ml/minthan in subjects with normal kidney function (27).Thus, under current dosing suggestions on the apix-aban label, patients with advanced and end-stagekidney disease could be exposed to 40% more drug.Further studies are needed to establish the optimalapixaban dose in this population.

In terms of dialysis clearance, only 6.7% of apix-aban is cleared by a 4-h hemodialysis session

TABLE 2 Characteristics of Warfarin and Nonvitamin K-Dependent Oral Anticoagulant Agents

Warfarin Apixaban Rivaroxaban Dabigatran Edoxaban

Renal clearance of parent drug <1% 27% 36% 80% 50%

Removal with 4 h of hemodialysis <1% 7% <1% 50%–60% 9%

Volume of distribution, l (66) 8 21 50 50–10 107

Reversal agent Vitamin K, FFP,4F-PCC

4F-PCC 4F-PCC Idarucizumab 4F-PCC

Lowest CrCl drug can be prescribedper FDA label, ml/min

Can be usedon dialysis

<15* 15 15 15

HR (95% CI) of stroke referentto warfarin, CrCl <50 ml/min

Reference 0.79 (0.55–1.14) 0.88 (0.65–1.19) 0.56 (0.37–0.85) 0.87 (0.65–1.18)†

HR (95% CI) of major bleedingreferent to warfarin, CrCl <50 ml/min

Reference 0.50 (0.38–0.66) 0.98 (0.84–1.14) 1.01 (0.79–1.30) 0.76 (0.58–0.98)†

*A 5-mg twice-daily dose of apixaban is suggested for patients with CrCl <15 ml/min. This dosing suggestion was based on a small single-dose pharmacokinetic and phar-macodynamic (anti-Xa activity) study. Clinical efficacy and long-term safety studies have not been done in this population; therefore, use apixaban with caution in patients withadvanced or end-stage chronic kidney disease. †30–50 ml/min for the comparison of edoxaban versus warfarin (37).

CI ¼ confidence interval; CrCl ¼ creatinine clearance; FDA ¼ U.S. Food and Drug Administration; FFP ¼ fresh-frozen plasma; 4F-PCC ¼ 4-factor prothrombin complexconcentrate; HR ¼ hazard ratio.

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(Optiflux F180NR dialyzer, dialysate flow rate 500ml/min, blood flow rate 350 to 500 ml/min, no hepa-rin) (26); therefore, in patients who have overdosed orare having life-threatening bleeding, dialysis wouldnot be an effective means to remove apixaban fromthe circulation.

FIGURE 4 Pharmacokinetics of Nonvitamin K-Dependent Oral Antic

A apixaban

parent drug(87% bound)

CYP3A4/5 and6% clearedwith dialysis

P-glycoprotein

27% renal elimination

inactive metabolite

~50% in feces

Cdabigatran etexilate

dabigatran active

(35% bound)

50-60% clearedwith dialysis

80% renal elimination

(A) Apixaban, (B) rivaroxaban, (C) dabigatran, and (D) edoxaban.

RIVAROXABAN. Rivaroxaban is also a direct factorXa inhibitor, and the kidneys eliminate 36% of theparent drug and the remainder is hepatically metab-olized into an inactive form (Figure 4B) (28). InROCKET-AF (Rivaroxaban Once Daily Oral DirectFactor Xa Inhibition Compared With Vitamin K

oagulant Agents

B rivaroxaban

parent drug(95% bound)

CYP3A4/5 and CYP2J2metabolized

36% renal elimination

51% inactive metabolite

7% feces

Dedoxaban

10% metabolite

parent drugCYP3A4

(55% bound)

9% clearedwith dialysis

40% bile50% renal eliminationelimination

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Antagonism for Prevention of Stroke and EmbolismTrial in Atrial Fibrillation), a randomized controlledtrial of 14,264 patients with AF at moderate to high riskfor stroke (mean CHADS2 score 3.5 � 0.9), all of whomhad CrCl >30 ml/min, rivaroxaban was noninferior towarfarin at preventing stroke and systemic embolism(3). Additionally, the occurrence of nonmajor clini-cally relevant or major bleeding was not significantlydifferent between the 2 groups. Patients with CrCl>50 ml/min received 20 mg rivaroxaban once daily,whereas subjects with CrCl of 30 to 49ml/min received15 mg once daily. There was no evidence of heteroge-neity in outcomes in patients treated with the 15- or20-mg dose compared with warfarin (29); further-more, the effect estimates for stroke prevention weresimilar for rivaroxaban subjects with CrCl of 50 to80 ml/min (HR: 0.85; 95% CI: 0.67 to 1.08) and 30 to50 ml/min (HR: 0.88; 95% CI: 0.65 to 1.19) relative towarfarin. For major bleeding, there was no differencein bleeding risk in the CKD population betweenrivaroxaban and warfarin overall.

The FDA approved a 20-mg once-daily rivarox-aban dose in November 2011. The label included arecommended 15-mg once-daily dose for patientswith CrCl between 15 and 50 ml/min. Of note, Kubitzaet al. (28) reported a 52% increase in drug exposure anda 26% increase in peak concentration after a single10-mg dose among 8 patients with a mean CrCl of43 ml/min. These data suggest that the dose of rivar-oxaban in patients with moderate CKD needed tomatch the exposure of patients with no renal impair-ment may have to be lower than 15 mg; however, thesePK findings were not validated by outcomes from theROCKET-AF subgroup analysis of patients with CKD.No increased bleeding was seen in patients withmoderate CKD on 15 mg of rivaroxaban (HR: 0.98; 95%CI: 0.84 to 1.14) referent to warfarin, which was thesame as the main conclusion of the full study. Rivar-oxaban is not recommended for use in patients withCrCl <15 ml/min or those on dialysis. An inconse-quential amount of rivaroxaban is cleared by dialysis(30). A 7-day trial of rivaroxaban 10 mg daily among 18maintenance hemodialysis patients (FX60, 4 h, bloodflow rate 400 ml/min, dialysate flow rate 500 ml/min,citrate anticoagulation) resulted in drug exposurelevels similar to healthy volunteers given 20 mg;however, the coefficient of variationwas twice as high,suggesting moderate interpatient variability in theclearance or metabolism of the drug.

DABIGATRAN. Dabigatran is a direct thrombin inhib-itor and was the first FDA-approved NOAC, at a dose of150 mg twice per day for CrCl >30 ml/min. The drughas a renal clearance of at least 80% and is thus highly

dependent on the kidney for removal from the body(Figure 4C). In the RE-LY (Randomized Evaluation ofLong-Term Anticoagulation Therapy) trial, dabigatran150 mg twice daily was superior to warfarin for theprevention of stroke and systemic embolism(HR: 0.66; 95% CI: 0.53 to 0.82) in patients with AFand 1 or more additional risk factors for stroke;furthermore, no increase in major bleeding was seenwith the drug (HR: 0.93; 95% CI: 0.81 to 1.07) (4). In aseparate analysis in relation to renal function, cubicsplines were used to model the rate of major bleedingby CrCl for warfarin and 150 mg of dabigatran. Here,there was no statistical difference in bleeding betweenthe 2 drugs; however, the rate of major hemorrhageamong dabigatran-treated patients accelerated andsurpassed warfarin when the CrCl fell below 50ml/min(31). Thus, multiple dosing guidelines advise cautionwith dabigatran when CrCl is between 30 and50 ml/min (32). Accordingly, the U.S. label prohibitsdabigatran coadministration with drugs that inhibitP-glycoprotein. Dabigatran is also the only dialyzableNOAC. A 4-h hemodialysis session will remove 50% to60% of plasma dabigatran, with a 10% rebound indabigatran levels post-dialysis (33).

The FDA approved a low dose of dabigatran (75 mgtwice daily) for patients with CrCl between 15 and30 ml/min in 2010. The approval of a 75-mg dose inpatients with stage 4 CKD was on the basis of a phase IPK study of 29 subjects, 11 of whom had CrCl<30 ml/min. Model simulations showed that dabiga-tran 75 mg daily in patients with advanced CKD had a32% lower steady-state peak and 42% lower troughlevel compared with patients with moderate CKD on150 mg of dabigatran twice per day (34,35). This isin contrast to another study that found a 6-fold in-crease in dabigatran exposure in patients withCrCl <30 ml/min compared with healthy subjects (33).

EDOXABAN. Edoxaban is the most recent factor Xainhibitor approved for use in the United States. Thekidneys clear approximately 50% of the unmetabo-lized drug (Figure 4D). Total drug exposure was foundto increase by 32%, 74%, and 72% in patients withmild, moderate, and severe renal impairment,respectively (36).

In the ENGAGE AF–TIMI 48 (Effective Anti-coagulation With Factor Xa Next Generation in AtrialFibrillation–Thrombolysis In Myocardial Infarction48) trial of 21,105 patients with AF with CrCl>30 ml/min, subjects received 60 mg of edoxaban, or30 mg if their CrCl was between 30 and 50 ml/min,body weight was <60 kg, or a strong P-glycoproteininhibitor was coadministered. Edoxaban was non-inferior at preventing stroke and systemic embolism

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and superior at preventing major bleeding (HR: 0.80;95% CI: 0.71 to 0.91) compared with warfarin. Insubgroup analyses among patients with CrCl between30 and 50 ml/min, edoxaban remained noninferiorfor stroke prevention compared with warfarin.Bleeding was also significantly decreased (HR: 0.76;95% CI: 0.58 to 0.98) with edoxaban (37).

A post hoc analysis of the ENGAGE AF–TIMI 48 trialfor patients on edoxaban (vs. warfarin) whose CrClfell below 30 ml/min after baseline (n ¼ 1,202) showedthat stroke (2.36 vs. 1.89 events per 100 patient-years)and major bleeding (6.83 vs. 6.49 events per 100patient-years) rates were similar (38). Another pro-spective safety study of 93 patients found similar3-month bleeding rates in patients with stage 4 CKDon 15 mg of edoxaban versus 30 or 60 mg of edoxabanwith mean CrCl of 70 ml/min (39). Both of the studiesmentioned in the preceding text were underpowered,and these results should be regarded as hypothesisgenerating, given how few events occurred in thesestudies.

Edoxaban is poorly cleared by dialysis: 4 h of he-modialysis decreased total drug exposure by only 9%(F180NR, blood flow rate 350 ml/min, dialysate flowrate 500 ml/min) (40).

SHOULD WE ANTICOAGULATE PATIENTS

WITH AF WITH ADVANCED OR END-STAGE

KIDNEY DISEASE TO PREVENT STROKE?

Patients with AF with advanced CKD or on dialysis areat high risk for adverse events and are complicated tomanage. Most of these patients will have CHA2DS2-VASc scores >2, and studies indicate that the rates ofAF, stroke, and bleeding all increase as kidney func-tion worsens (25). There are no prospective ran-domized studies on the efficacy and safety ofanticoagulation to prevent stroke in this population.Thus, we do not know the magnitude of stroke pre-vention conferred by anticoagulation in patients withadvanced CKD or on dialysis, nor whether the strokeprevention benefit of warfarin or NOACs outweighs theincreased risk for bleeding. The risk for anticoagulant-related bleeding remains a serious clinical concern.Dialysis patients are more likely to die of bleedingevents than from embolic stroke. An unpublishedanalysis from the Fresenius Medical Care Researchdatabase showed that 2.7% of all deaths were second-ary to hemorrhage, and 1% were from embolic stroke.

Multiple observational studies in CKD and dialysishave identified an association between warfarin useand increased risk for embolic stroke and bleeding(41–44), whereas other studies suggest that warfarinis protective against stroke in this population (45).

Interpretation of these findings is challenging, as theresults may be confounded by indication and theinclination to treat sicker patients.

Overall, it remains uncertain whether anti-coagulation provides more benefit than harm whenused to prevent stroke in patients with AF withadvanced CKD or on dialysis. The 2014 AHA, ACC, andHRS guideline for the management of patients with AFstates that it is reasonable to prescribe warfarin(international normalized ratio 2.0 to 3.0) to patientswith nonvalvular AF with CHA2DS2-VASc scores of 2 orgreater who have CrCl <15 ml/min or are on hemodi-alysis (8). In contrast, the KDIGO (Kidney Disease:Improving Global Outcomes) guidelines state thatroutine anticoagulation of dialysis patients with AF forthe primary prevention of stroke is not indicated (46).

Taken together, the aggregated data suggest thatanticoagulation increases the risk for bleeding by atleast 20% in patients with advanced CKD or on dial-ysis, but what remains unclear is the degree to whichwarfarin and NOACs reduce the risk for stroke inpatients with advanced CKD or ESRD (41,42,45).Randomized clinical trials in the general populationhave suggested that warfarin reduces the risk forstroke by 64% in patients with AF compared withplacebo (47). There is some evidence that anti-coagulation does not lead to similar risk reduction inthe advanced CKD and ESRD populations (48).Although patients with advanced CKD and ESRD areat higher risk for stroke, this risk for stroke may notbe significantly modifiable by anticoagulation in pa-tients with advanced renal disease. There are severalreasons to explain why vitamin K antagonism may beassociated with a lower margin of benefit in patientswith advanced CKD or dialysis. First, uremia-inducedplatelet dysfunction may protect against thrombosis.Second, competing comorbid risks may attenuate theopportunity for benefit. More specifically, patientswith CKD have numerous competing comorbiditiesthat shorten their life expectancies and the follow-uptime for stroke events. The average life expectancy ofa dialysis patient is 5 years; moreover, 24% of CKDstage 4 and 45% of CKD stage 5 patients will diewithin 5 years (49,50). Until well-done, prospective,randomized studies are available, physicians mustindividually balance the risk for stroke in each patientagainst the perceived magnitude of stroke preventionanticoagulant agents may provide.

NOAC USE IN PATIENTS WITH LATE-

OR END-STAGE KIDNEY DISEASE

If oral anticoagulation is indicated and the perceivedbenefits outweigh the risks for therapy, the 2014

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AHA, ACC, and HRS guidelines endorse warfarinas the first-line therapy in patients with CKDstage 4 (CrCl 15 to 30 ml/min) or CKD stage 5(CrCl <15 ml/min) or on dialysis, because all NOACspartially rely on the kidney for elimination (8).Similarly, the 2015 updated European Heart RhythmAssociation practical guide on the use of nonvitaminK antagonist anticoagulant agents in patients withnonvalvular AF recommends refraining from NOACuse in dialysis patients and patients with CKD withCrCl <30 ml/min, given that there are few random-ized trial data in this population (32). Although theU.S. label for NOACs supports their use when CrCl isas low as 15 ml/min, extreme caution should be used,as these recommendations were based mostly on PKdata, and limited efficacy data support this practice.PK studies are only moderately reliable for quanti-fying the relationship between NOAC dose with totaldrug exposure and anticoagulation level (e.g., factorXa activity), which are used as surrogates of efficacyand safety in PK studies (51). Renal disease progres-sion, hemodynamically related fluctuations in creat-inine, and acute kidney injury commonly occur inpatients with poor kidney function. This can lead tounexpected decreases in CrCl and create a mismatchbetween NOAC dose and renal function to increasethe risk for bleeding. Ultimately, randomized, pro-spective studies are needed to establish the efficacyand safety of NOACs in the advanced CKD and dial-ysis population.

Despite the paucity of evidence and guidelinesthat clearly recommend against the use of NOACs inESRD, observational data have shown NOAC useamong dialysis patients to be substantial andincreasing; furthermore, 1 study found that manypatients were prescribed higher doses of rivaroxabanand dabigatran that were not properly reduced toaccount for any renal impairment (9). There wasevidence of higher bleeding risk associated withdabigatran (relative risk: 1.48; 95% CI: 1.21 to 1.81)and rivaroxaban (relative risk: 1.38; 95% CI: 1.03 to1.83) compared with warfarin, yet there was inade-quate power to compare stroke outcomes betweenthe groups.

NOACs may be considered first-line therapy in pa-tients who need anticoagulation with concurrentcalcific uremic arteriolopathy, a rare but devastatingcalcific disease of the small vessels, where warfarinhas been strongly associated with disease progression(52). Patients who are intolerant of warfarin and havehistories of warfarin skin necrosis or protein C/Sdeficiency might benefit from off-label NOAC ther-apy; however, this is highly speculative. If NOACs areused in patients with advanced CKD, close

monitoring of renal function is advised, perhapsevery 2 to 4 months and during acute illness. In theserare instances in which NOACs are prescribed, a sug-gested dose of apixaban 2.5 to 5 mg twice daily can begiven to patients on dialysis, but rivaroxaban oredoxaban at a reduced dose could also be effective.Dabigatran is less favorable because the risk forbleeding substantially increases when CrCl dropsbelow 50 ml/min. In dialysis patients, drug levelswould substantially fluctuate with dialysis treatment,given that dialysis clears 50% to 60% of the drug.Drug bioaccumulation would occur when patientsmiss their dialysis treatment, which could lead toserious bleeding. Finally, patients who are intolerantof warfarin may consider nonpharmacological ther-apy for stroke prevention with percutaneous leftatrial appendage closure (53). Occlusion of the leftatrial appendage may be particularly attractive inpatients with ESRD, given the observed large reduc-tion in bleeding (54).

Last, reducing the intradialytic heparin dose meritsconsideration in patients initiated on warfarin or aNOAC to potentially decrease the risk for peritreat-ment bleeding. There is little evidence to guide suchpractices, but stopping or reducing the heparin doseby at least 50% appears reasonable. Patients can berechallenged on heparin if they experience clottingduring treatment.

MAJOR HEMORRHAGE IN THE SETTING OF

NOACs: ISSUES SPECIFIC TO ADVANCED

CKD AND DIALYSIS PATIENTS

Dabigatran is the only NOAC that is very dependenton the kidney for elimination and is also highlydialyzable, with 50% to 60% of plasma dabigatranremoved with a 4-h hemodialysis session (55).Hemodialysis for dabigatran removal should beconsidered when the severity of bleeding necessitatesfaster drug clearance, and it would be unsafe to waitfor the drug to be completely eliminated by the nativekidneys. A patient with CrCl of 55 ml/min could clear88% of total body dabigatran in 45 h (3 half-lives;Table 3) through intrinsic kidney function or with 3serial 4-h hemodialysis sessions (1 half-life per ses-sion). It may be reasonable to wait 45 h if bleeding iscontrolled, but active bleeding that does not respondto conventional measures merits consideration formore aggressive measures.

In patients with life-threatening bleeding whoneed immediate dabigatran reversal, physicians mayconsider idarucizumab, which was shown toneutralize the anticoagulant effect of dabigatranwithin 30 min in a study of 90 patients with median

TABLE 3 Dabigatran Half-Lives by Renal Function

Creatinine Clearance, ml/min Half-Life (h)

$80 13

50–80 15

30–49 18

<30 28

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CrCl of 58 ml/min (56). Idarucizumab is partiallydependent on the kidney for elimination (32% withinthe first 6 h) but is approved for patients with kidneydisease.

The anticoagulant effects of warfarin, apixaban,rivaroxaban, and edoxaban can be reversed by4-factor prothrombin complex concentrate (57–59),which can replete coagulation factors much fasterthan fresh-frozen plasma, with less volume overload,which is favorable to patients with advanced CKD andon dialysis who are prone to volume overload (60).

Last, patients with advanced CKD or on dialysis areprone to uremic platelet dysfunction. Activelybleeding patients can be given desmopressin. Dialysiscan also partially correct the bleeding time and otherin vitro tests of platelet function in approximatelytwo-thirds of uremic patients (61–63).

SUMMARY AND FUTURE DIRECTIONS

NOAC use in patients with advanced CKD and ondialysis is substantial and increasing, despite AHA,ACC, and HRS and European Heart Rhythm Associa-tion guidelines that endorse warfarin as the antico-agulant of choice when CrCl is <30 ml/min. There arefew randomized trial data on NOACs among patientswith advanced CKD or on dialysis.

Phase 3 AF trials in the general population haveshown that NOACs decrease both stroke and bleedingin comparison with warfarin, whereas patients withadvanced CKD and ESRD have a baseline increasedrisk for both stroke and bleeding (64,65). Because oftheir high risk, patients with advanced CKD and ESRDcould potentially derive great benefit from NOACs ifthe benefits for stroke and cardiovascular eventsprove to be similar to or greater than those shown inthe general population with warfarin and NOACs,with a bleeding risk that remains acceptable.Furthermore, it is encouraging that these favorable

effects carried over to subgroup analyses amongpatients with CrCl between 25 and 50 ml/min whowere enrolled in the phase III AF trials and that theeffects are similar in other high-risk groups, such asthose with advanced age or low body weight.

All NOACs are dependent on the kidney forelimination. Thus, the most critical developmentissue for NOAC use in the advanced CKD anddialysis population is to determine the appropriatedose reduction that optimizes the prevention ofstroke yet minimizes the risk of bleeding. Well-donemultidose PK studies are necessary to estimate theappropriate NOAC dose, recognizing that PK modelshave limited accuracy in predicting populationpharmacokinetics.

Randomized controlled trials are ultimatelyneeded to validate PK-driven hypotheses by demon-strating clinical efficacy (stroke prevention) andsafety (bleeding) of NOACs versus placebo in patientswith AF with advanced CKD and on dialysis. Pre-vention of stroke with NOACs in patients with AFwould become the standard of care if such a trialindicated superiority at stroke prevention, withacceptable bleeding risks referent to placebo.Comparative efficacy trials between NOACs and otheranticoagulant agents would be less informative. Thisis because warfarin and aspirin have not been provedto be effective and safe for preventing stroke inpatients with AF with severe renal impairment, as nophase III efficacy trials have been conducted inpatients with CrCl <25 ml/min; furthermore, someobservational studies suggest that warfarin maycause harm in this population.

In conclusion, the improved safety profile ofNOACs compared with warfarin for the general pop-ulation raises the prospect of an improved anti-coagulation strategy for patients with advanced renalimpairment and an indication for anticoagulation.High-quality randomized trials should be conductedin these populations, given their altered drug meta-bolism profile and high rates of both clotting andbleeding events.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Kevin E. Chan, Fresenius Kidney Care, 920 WinterStreet, Waltham, Massachusetts 02451. E-mail: kevin.chan@fmc-na.com.

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KEY WORDS apixaban, dabigatran,edoxaban, renal dialysis, rivaroxaban, stroke