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REVIEW

C URRENT OPINION
C
URRENT
OPINION

Novel oral anticoagulants in chronic kidney disease: ready for prime time?

Justin Ashley a,b and Manish M. Sood a,b

Purpose of review Patients with chronic kidney disease (CKD) are at increased risk of atrial fibrillation, stroke, and bleeding posing unique clinical challenges. Novel oral anticoagulants (NOACs) including dabigatran, rivaroxaban, and apixaban have become recognized as alternative therapy to Vitamin K Antagonists (VKA) regarding the prevention of venous thromboembolism (VTE) and reduce the risk of stroke in atrial fibrillation. However, the understanding of NOACs in CKD is still underdeveloped. This review summarizes recent literature on the efficacy and safety of NOACs in patients with CKD.

Recent findings Studies focusing on patients with moderate kidney disease were drawn from post hoc analyses from three major NOAC trials, meta-analyses, and postmarketing surveillance studies. Cumulatively, these studies continue to demonstrate NOACs as equivalent if not superior therapies to VKAs in regards to both efficacy and safety. These studies are limited by small sample sizes as well as a lack of direct comparison between NOACs.

Summary The role of NOACs in managing VTE and atrial fibrillation is increasing. Current research suggests that NOACs are at least as efficacious and well tolerated as VKAs. More research is required to elucidate which NOAC is preferable in the clinical setting.

Keywords apixaban, atrial fibrillation, chronic kidney disease, dabigatran, novel oral anticoagulants, rivaroxaban

INTRODUCTION

Chronic kidney disease (CKD) and cardiovascular morbidity and mortality are intricately linked [1–4] posing unique challenges in the clinical setting [5]. Atrial fibrillation is the most common arrhythmia in the CKD and dialysis populations and affects 15– 20% of patients [1,4,6,7]. Declining estimated glo- merular filtration rate (eGFR) and proteinuria are independently associated with the risk of develop- ing atrial fibrillation [8–10]. The combination of atrial fibrillation and CKD can lead to a four-fold to five-fold higher risk of stroke [2–4,6,7,9,11]. CKD is also highly associated with venous thromboembolism (VTE) including deep vein thrombosis (DVT), and pulmonary embo- lism [12–14]. The reported relative risk for VTE was higher in patients with CKD, increasing with CKD severity, compared with patients with normal kid- ney function [mild CKD – relative risk (RR) 1.28, 95% CI 1.02–1.59; CKD stage 3/4 – RR 2.09, 95% CI 1.47–2.96] [15]. Vitamin K antagonists (VKA) such as warfarin are the mainstay for stroke prevention in atrial

fibrillation and VTE [5]. However, multiple drug and dietary interactions with warfarin compounded by vitamin K deficiency in the CKD population [16] limits the time in therapeutic range (TTR). This significantly affects warfarin’s safety and efficacy [17,18]. There is little evidence of the effectiveness of VKAs in stroke reduction in patients with advanced CKD or on dialysis. In fact, there may be an increased bleeding risk [19–21]. Nonvitamin K oral anticoagulants (novel oral anticoagulants; NOAC) are a group of anticoagu- lants that directly antagonize either factor II or Xa in the coagulation cascade [22]. Dabigatran, a direct thrombin inhibitor, inhibits the protease enzyme that is responsible for the conversion of fibrinogen

a The Ottawa Hospital, University of Ottawa and b The Ottawa Hospital Research Institute, Ottawa, Canada

Correspondence to Manish M. Sood, MSc, MD, The Ottawa Hospital, University of Ottawa, Ottawa, ON K1H 8L6, Canada. E-mail: msood@toh.ca

Curr Opin Nephrol Hypertens 2018, 27:000–000

DOI:10.1097/MNH.0000000000000410

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Epidemiology and prevention

KEY POINTS

NOACs are changing the landscape in regards to the management of atrial fibrillation and VTE.

Lack of RCT data regarding NOACs in patients with CKD and on dialysis.

Recent post hoc analyses, meta analyses, and real- world studies continue to identify NOACs as well tolerated and efficacious alternatives to warfarin, particularly apixaban.

Future studies need to directly compare NOACs against each other to identify which NOAC is most appropriate in the CKD and dialysis population.

to fibrin – the final step in the coagulation cascade [22,23]. Rivaroxaban, apixaban, and edoxaban work by inhibiting factor Xa, the rate-limiting step in the coagulation cascade [23].

Multiple randomized controlled trials [24–27] and real-world studies [28–32] have identified NOACs as safer (i.e. lower risk of bleeding and all- cause mortality) and more efficacious (i.e. lower risk of ischemic stroke and embolic events) medications in the general population whenever compared with warfarin [24,25,27]. A recent meta-analysis found that major bleeding was reduced by 19% in patients with atrial fibrillation on NOACs compared with warfarin [23,33]. With a shorter half-life and less dietary and medication interactions, NOACs have a more predictable pharmacological profile than VKAs [5]. This reduces the need for frequent blood testing and improves patient adherence. NOACs still have clinical challenges. Unlike warfarin, NOACs do not have a standardized test to monitor drug levels [23]. Secondly, all NOACs are renally excreted to various degrees (Table 1). Accord- ingly, as patient’s eGFR decline the effects of NOACs become less predictable [34 & ] consequently increas- ing bleeding risk. To address this, NOACs often have

Table 1. Renal clearance and dosing of novel oral anticoagulants in patients with chronic kidney disease

Renal dosing

NOAC

Renal clearance Health Canada

USA FDA

Dabigatran

80%

Atrial fibrillation CrCl ¼ 30–50 ml/min: 150 mg oral twice daily CrCl < 30ml/min: contraindicated Treatment and prevention of VTE CrCl 30–50 ml/min has not been studied – cannot recommend

Atrial fibrillation and VTE CrCl >30 ml/min: 150 mg oral twice daily CrCl ¼ 15–30 ml/min: 75 mg oral twice daily CrCl <15 ml/min: contraindicated

Rivaroxaban 30%

Atrial fibrillation CrCl ¼ 30–49: 15 mg p.o. once daily CrCl <30 ml/min: not recommended VTE CrCl ¼ 50–80 ml/min: 15 mg p.o. b.i.d. 21 days then 20 mg p.o. daily CrCl ¼ 30–49 ml/min: 15 mg p.o. b.i.d. 21 days then 20 mg p.o. daily CrCl <30 ml/min: not recommended

Atrial fibrillation CrCl >50 ml/min: 20 mg p.o. daily CrCl ¼ 15–50 ml/min: 15 mg p.o. daily CrCl <15 ml/min: contraindicated

Apixaban

25%

Atrial fibrillation 5 mg p.o. b.i.d. unless 2/3 are met:

Atrial fibrillation and VTE 5 mg p.o. b.i.d. unless 2/3 are met:

 

Age 80 years Body weight 60 kg, Serum Cr >132 mmol/l If met: then 2.5 mg p.o. b.i.d. CrCl <25 ml/min: contraindicated VTE 10 mg p.o. b.i.d. 7 days followed by 5 mg p.o. b.i.d. No dose adjustment in patients with CrCl >30 ml/min CrCl <29 ml/min: contraindicated

Age 80 years Body weight 60 kg, Serum Cr >132 mmol/lo If met: then use 2.5 mg p.o. b.i.d. CrCl <25 ml/min: contraindicated

Edoxaban

50%

Atrial fibrillation and VTE 60 mg p.o. daily unless one at least of following criteria met:

Atrial fibrillation and VTE CrCl 15–50 ml/min : 30 mg p.o. daily CrCl <15 ml/min: contraindicated

 

CrCl 30–50 ml/min Body weight 60 kg, Concomitant use of P-gp inhibitors (except amiodarone and verapamil) If met: then 30 mg p.o. daily CrCl <30 ml/min: contraindicated

b.i.d., twice daily; CI, contraindicated; Cr, creatinine; CrCl, creatinine clearance in ml/min; FDA, Food and Drug Administration; NOAC, novel oral anticoagulants; p.o., orally; USA, United States of America; VTE, venous thromboembolism.

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Novel oral anticoagulants in CKD Ashley and Sood

standard and reduced dosing to reflect patients with normal and reduced eGFRs [5,35–45] (Table 1). Nonetheless, our understanding of the efficacy and safety of NOACs in CKD and end-stage kidney disease (ESKD) is still underdeveloped. The major trials that evaluated NOACs excluded patients with a creatinine clearance (CrCl) less than 25–30 ml/ min and on dialysis; patients that are at the highest risk of atrial fibrillation, stroke, and VTE [2,13,14,22]. Secondly, little data is available regard- ing, which anticoagulant is most appropriate for patients with CKD and ESKD. This review explores recent work on NOACs in patients with CKD.

RECENT TRIALS

The landmark trials assessing the efficacy and safety NOAC have led to a paradigm shift of the

management of atrial fibrillation and VTE from VKAs to NOACs. The American Heart Association (AHA) and the Canadian Cardiovascular Society recognize NOACs as preferable or equivalent thera- pies to warfarin for the management of nonvalvular atrial fibrillation [46,47]. The American College of Chest Physicians (CHEST) identifies NOACs as preferable long-term anticoagulants in noncancer- related DVT and pulmonary embolism [48]. Recent studies have re-analysed data from these landmark trials focusing on reduced eGFRs and its effects on the efficacy and safety of NOACs [34 & ,49 & ,50]. A recent study [34 & ] conducted a post hoc anal- ysis of The Rivaroxaban versus Warfarin in Non- valvular Atrial Fibrillation (ROCKET-AF) [27] trial (Table 2). The investigators reanalyzed the patients with at least four creatinine measurements at set intervals. Worsening renal function was defined as a

Table 2. Summary of select major NOAC trials

 

Doses

Design summary

Summary of outcomes

ROCKET-AF, 2011

Rivaroxaban:

NVAF with moderate-to-high stroke or CHADS 2 at least 2

Stroke and SE Rivaroxaban 1.7/100 pt. yr. Warfarin 2.2/100 pt year hazard ratio 0.79 (95% CI 0.66–0.96) Major and non-major bleeding

20

mg daily OR

15

mg daily a

Warfarin:

Dose adjusted (target INR 2–3)

Renal exclusion criteria CrCl < 30 ml/min Population

 

N

¼ 14 264

Rivaroxaban 20.7% Warfarin 20.3% hazard ratio 1.03 (0.96–1.11)

Rivaroxaban ¼ 6958

Warfarin: 7004

ARISTOTLE, 2011

Apixaban 5 mg OR 2.5 mg twice daily b Warfarin Dose adjusted (target INR 2–3)

NVAF or AFlut with

at least one stroke risk factor Renal Exclusion Criteria Serum Cr 221 m mol/l or CrCl <25 ml/min Population

Stroke or SE Apixaban 1.27% per year Warfarin 1.6% per year hazard ratio 0.79 (95% CI 0.66–0.95) Major bleeding Apixaban 2.13% per year

 

N

¼ 18 201

Warfarin 3.09% per year hazard ratio 0.69 (95% CI 0.60–0.80)

Apixaban ¼ 9120 Warfarin ¼ 9081

ENGAGE AF- TIMI 48, 2013

HDE c

NVAF with CHADS 2 at least 2 Renal exclusion criteria CrCl <30 ml/min Population

Stroke or SE Warfarin 1.50% per year HDE 1.18% per year LDE 1.61% per year

60

mg daily

 

LDE

30

mg

N

¼ 21 105

Warfarin versus HDE hazard ratio 0.79, 97.5% CI 0.63–0.99 Warfarin versus LDE hazard ratio 1.07, 97.5% CI 0.63–0.99 Major bleeding Warfarin 3.43% per year HDE 2.75% per year LDE 1.61% Warfarin versus HDE hazard ratio 0.80, 95% CI 0.71–0.91 Warfarin versus LDE hazard ratio 0.47, 95% CI 0.41–0.55

Warfarin Dose adjusted (target INR 2–3)

HDE e ¼ 7035 LDE f ¼ 7034 Warfarin ¼ 7036

AFlut, atrial flutter; CHADS 2 , risk score consisting of one point each for congestive heart failure, hypertension, age greater than 75 years, diabetes, and two points for stroke; CrCl, creatinine clearance (in millilitres per minute); HDE, high-dose edoxaban; INR, international normalized ratio; LDE, low-dose edoxaban; NI, noninferiority; NVAF, nonvalvular atrial fibrillation; SE, systemic embolism. a Patients with CrCl 30–49 ml/min. b Reduced dosing for patients who met 2/3 criteria: at least 80 years old, 60 kg or less, Serum Cr 133–220 m mol/l. c For either high-dose or lose-dose edoxaban, the dose was halved if any criteria met: CrCl 30–50 ml/min; 60 kg or less; the concomitant use of verapamil or quinidine.

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Epidemiology and prevention

deterioration of more than 20% of CrCl from screen- ing measurement at any time during the study period. Participants with worsening renal function on rivaroxaban had a reduction in stroke or systemic embolism compared with worsening renal function on warfarin (hazard ratio 0.50, 95% CI 0.27–0.93; P ¼ 0.05). This was not observed in the stable renal function population. No significant difference between participants with worsening renal function on rivaroxaban or warfarin in regard to safety was appreciated.

inferences about which NOAC is preferable in CKD a difficult task.

RESULTS FROM RECENT NETWORK META-ANALYSES

A recent meta-analysis assessed the efficacy of

NOACs against warfarin in regards to efficacy in

CKD [51 && ] (Table 3). Investigators found [51 && ] a 21% reduction in the odds of stroke or systemic VTE

for high-dose NOACs compared with warfarin (0.79,

A similar study [49 & ] re-analysed the data of the Apixaban for Reduction in Stroke and Other Throm- boembolic Events in Atrial Fibrillation (ARISTOTLE) trial [25] (Table 2). The investigators [49 & ] divided participants into three groups based on renal func- tion (eGFR > 80 ml/min, eGFR 50–80 ml/min, eGFR < 49 ml/min) and a fourth group for patients with worsening renal function (eGFR deterioration > 20%). Patients randomized to apixaban had improved outcomes independent of renal function. Worsening renal function was associated with over- all worse outcomes irrespective of baseline renal function. However, the relative risk of stroke or systemic embolism (hazard ratio 0.80, 95% CI 0.51–1.24; P ¼ 0.86), ischemic or unspecified stroke

95% CI 0.67–0.94). A 29% reduction was found between high-dose NOACs and low-dose groups (0.71, 95% CI 0.57–0.89). The investigators then conducted a network analysis to assess the [51 && ] comparative effectiveness of dose anticoagulants in patients with atrial fibrillation and CKD (CrCl 25– 30 50 ml/min; Table 3). Only dabigatran 150 mg was statistically superior to warfarin in reducing the efficacy outcome (OR 0.56, 95% CI 0.36–0.86). Other NOACs were comparable with VKA for stroke and VTE reduction. Three recent meta-analyses assessed NOACs rel- ative safety against warfarin. Two meta-analyses demonstrated NOACs to have a superior safety pro- file than warfarin in the CKD population [33,51 && ]

(hazard ratio 0.88, 95% CI 0.52–1.48, P ¼ 0.94) and major bleeding (hazard ratio 0.76, 95% CI 0.54– 1.07, P ¼ 0.73) was lower in participants randomized

(Table 3). One study [51 && ] found the incidence of major bleeding was lower with NOACs than with warfarin in a dose-dependent fashion (OR 0.61, 95%

to apixaban compared with warfarin.

CI

0.50–0.74 for low-dose NOACs and OR 0.74, 95%

The ENGAGE AF-TIMI 48 (Effective Anticoagu-

CI

0.65–0.86 for full/single-dose NOACs, both as

lation with Factor Xa Next Generation in Atrial Fibrillation – Thrombolysis in Myocardial Infarc- tion Study 48) trial [41] assessed the efficacy and safety of edoxaban against warfarin (Table 2). Inves- tigators [50] conducted a subgroup analysis based on high-dose edoxaban (HDER) or low-dose edoxaban (LDER) regimens versus dose-adjusted warfarin [tar-

compared with warfarin). Other investigators [33] (Table 3) found that the composite risk of major bleeding was reduced by 19% in patients with reduced eGFRs taking NOACs compared with VKAs (RR 0.81; 95% CI 0.71–0.93). This effect held for patients with mild (RR 0.81, 95% CI 0.73–0.90) and moderate kidney disease (RR 0.82, 95% CI 0.72–

get international normalized ratio (INR) 2.0–3.0] and kidney function (CrCl 30–50 ml/min; CrCl 51–95 ml/min; CrCl > 95 ml/min). The primary effi- cacy outcomes, for both HDER and LDER compared with warfarin for CrCl 30–50 ml/min and CrCl 50–

0.94).

One study [52] (Table 3) did not demonstrate a statistically significant difference between patients on NOACs against VKAs in both minor kidney disease (CrCl 50–80 ml/min; RR 0.87 [95% CI

95 ml/min were not statistically significant.

Major

0.81–0.93]) and moderate kidney disease (CrCl

bleeding was significantly reduced for both HDER and LDER whenever compared with warfarin for both the reduced renal function groups. Further, HDER and LDER versus warfarin was statistically significant in reducing composite outcomes of stroke, systemic embolism, major bleeding, or death at CrCl 30–50 ml/min and CrCl 51–95 ml/min. These post hoc analyses continue to demon- strate the efficacy and safety of NOACs in patients with CKD or worsening kidney function. However, the relatively small numbers of the subgroup anal- yses and focus on only one NOAC per study makes

< 25–49 ml/min; RR 0.83 [95% CI 0.68–1.02]) in regards to safety. However, whenever individual NOACs were analysed in subgroup analysis, apixa- ban and edoxaban were associated with a decreased risk for major bleeding in patients with a CrCl less than 50 ml/min (apixaban – RR 0.52; CI 0.40–0.68; edoxaban – RR 0.77; CI 0.40–0.68) [52]. Whenever the atrial fibrillation population was analysed sepa- rately, NOACs were associated with lower risk of major bleeding as compared with VKAs for CrCl 50–80 ml/min (RR 0.89, 95% CI 0.81–0.97). In VTE sub-group, patients on NOACs experienced a

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Novel oral anticoagulants in CKD Ashley and Sood

Afib, atrial fibrillation; Apx, apixaban; CI, confidence interval; CKD, chronic kidney disease; CrCl, creatinine clearance in millilitres per min ute; Dab, dabigatran; Edx, edoxaban; eGFR, estimated glomerular filtration

mg twice daily; edoxaban high dose ¼ 60 mg daily; low dose ¼ 30 mg day.

bleeding to VKA: hazard ratio 0.76, 95%

superior to VKA: hazard ratio 0.37, 95%

95% CI 0.75–0.95 CrCl < 50 ml/min NOACs associated with nonsignificant decrease risk

NOACs associated with nonsignificant decrease risk

significant Edx: OR 0.85,

significant Edx: OR 0.75,

VKA CrCl 50–80 ml/min: RR 0.43, 95% CI 0.33–0.56

95% CI 0.59–0.96 Hemorrhagic stroke NOACs were associated with decrease risk versus

CrCl < 50 ml/min: RR 0.42, 95% CI 0.30–0.61

in subgroup

Mod CKD: RR 0.82, 95% CI 0.72–0.94

CI 0.73–0.90

CI 0.61–0.93;

CI 0.37–0.65;

CKD: were RR not 0.81, greatly 95% influenced

0.68–1.02)

0.81–0.93)

group

Efficacy outcomes not assessed

Efficacy outcomes not assessed

Only (RR OR apx 0.87, 0.76, and 95% edx 95% CI statistically

Only (RR OR apx 0.83, 0.49, and 95% edx 95% CI statistically

0.75–0.88

venous ¼ 110 thromboembolism.

95% CI in NOAC

and Riv hemorrhage

and Riv superior

bleeding ml/min

0.25–0.48

0.64–0.88

RR 19% Major 0.81, reduction bleeding

Life threatening

Major 50–80

Mild analyses

Intracranial

Results

CI

CI

Apx:

Apx:

CrCl

low dose

Dab

Dab

daily, VTE,

antagonist;

X

150 mg K twice

X

X

dose ¼ vitamin

X

X

risk; VKA,

X

X

RR, relative high

regimens (dabigatran

X

X

CrCl80ml/min ¼ 40230 CrCl 50–80 ml/min ¼ 40681

CrCl < 50 ml/min ¼ 13996 Exclusion Criteria CrCl < 30ml/min

had two Riv, dosing rivaroxaban;

Afib and VTE NOACS versus VKA subsequent network analysis with indirect

comparison

eGFR 25–50 ml/min Exclusion criteria:

eGFR 50–80 ml/min Mod CKD:

Total N ¼ 44 563 NOACs ¼ 22 327 VKA ¼ 22 236 Mild CKD:

N ¼ 94879

Dialysis patients

Total NOAC

dose; Mod, each moderate;

Table 3. Review of meta-analyses

dose; LD, and low edoxaban

ENGAGE AF

EINSTEIN PE

Hokusai-VTE

ROCKET-AF

ROCKET-AF

ARISTOTLE

ARISTOTLE

EINSTEIN

AMPLIFY

RE-LY

RE-LY

a Note HD, that high dabigatran

Raccah et al. [52 && ]

Bai et al. [33]

rate;

Ando and ARISTOTLE ENGAGE et Capranzano al. [51 && ] AF-TIMI 48 RE-LY ROCKET-AF Afib
Ando and
ARISTOTLE
ENGAGE
et Capranzano
al. [51 && ]
AF-TIMI 48
RE-LY
ROCKET-AF
Afib and CrCl < 50ml/min
On either NOAC a or VKA
NOACS versus VKA
subsequent network
analysis with indirect
X
X
X
X
X
Stroke/VTE:
Full-dose NOACS
Vs. VKA
21% reduction
(OR 0.79, LD NOACS
95% CI 0.67–0.94)
J-ROCKET-AF
comparison
versus.
Total NOAC
N ¼ 13,878
29% HD reduction
0.71, 95%
CI 0.57–0.89)
Major Bleeding reduction versus VKA
Dose-dependent
LD NOAC versus VKA
OR 0.61, 95% CI 0.50–0.74
Full Dose NOAC versus VKA
OR 0.74, 95% CI 0.65–0.86
Individual NOACs versus VKA
On VKA ¼ 5604
On NOAC ¼ 8274
Dab
was only (OR NOAC
statistically
superior to
Only significant
and Edx 95% HD CI statistically
VKA (OR 0.56, CI 0.36–0.86)
Apx:
OR Apx 0.49,
0.37–0.66
EdxLD: OR 0.36, 95% CI 0.26–0.50
Apx significant reduction versus other
NOACs

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Epidemiology and prevention

significantly lower risk of major bleeding for CrCl 50–80 ml/min (RR 0.84, 95% CI 0.74–0.94). Two studies conducted subsequent network analyses to determine a safety profile between NOACs [51 && ,52]. The first study found [51 && ] NOACs were associated with lower incidence of major bleed- ing in a dose-dependent fashion. However, only apixaban and high-dose edoxaban were associated with less major bleeding amongst high-dose regi- mens (apixaban – OR 0.49, 95% CI 0.37–0.66; edoxaban high dose – OR 0.72, 95% CI 0.55– 0.96) compared with warfarin. Amongst full-dose NOACs, only apixaban and high-dose edoxaban reduced major bleeding (versus dabigatran 150 mg: OR 0.49, 95% CI 0.33–0.72; versus rivarox- aban: OR 0.60, 95% CI 0.38–0.93). Similar results were seen in another recent meta- analysis by [52] (Table 3). Investigators found that in patients in whom atrial fibrillation or VTE and a CrCl less than 50 ml/min, apixaban as the only NOAC superior to VKA in terms of reducing bleed- ing (OR 0.49; 95% CI 0.37–0.65). However, low-dose edoxaban regimens were not included in the analysis. Cumulatively, these studies continue to affirm that NOACs, as a class of drugs, offer either an equivalent [11,52] or superior safety [33,51 && ] and efficacy profile than VKAs in patients with impaired kidney function. Further, network meta-analyses support NOACs as equivalent or superior to VKAs in preventing stroke and systemic embolism [51 && ]. In particular, dabigatran 150 mg daily and apixaban seem to be the most efficacious in patients with atrial fibrillation and a CrCl of 25–30 to 50 ml/ min and apixaban has been identified as a particu- larly well tolerated medication in the CKD popula- tion for both atrial fibrillation and VTE.

REAL-WORLD SAFETY AND EFFECTIVENESS OF NOVEL ORAL ANTICOAGULANTS IN CHRONIC KIDNEY DISEASE

Randomized control trials (RCTs) are useful for assessing the safety and efficacy of medications for the purposes of regulatory approval. However, the rigors of RCTs can sometimes limit their gener- alizability to the larger population that would ben- efit from a therapy. This is particularly true for NOACs as patients with CKD were underrepresented in the major trials [11,14,30]. Postmarketing surveil- lance or observational studies offer rigorous and complementary evidence to RCTs [53,54] as they provide real-world data on prescribing practices and safety. They also identify real-world concerns that could not be identified within the confines of an

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RCT [30]. These studies have been particularly important for NOACs [30] to establish as alterna- tives to VKAs [28–32] for patients with CKD and atrial fibrillation or VTE. As the only Food and Drug Administration (FDA)-approved NOAC for use with CrCl less than 15 ml/min, apixaban is the only NOAC studied in the hemodialysis population [55]. A retrospective cohort study assessing multidose apixaban in patients with ESRD on hemodialysis identified a weak correlation (correlation coefficient < 0.4) between higher cumulative apixaban exposure (P ¼ 0.03), number of hemodialysis sessions (P < 0.01), and hospital length of stay (P < 0.01) [55]. These results challenge the FDA guidelines and encourage prudence in the use of apixaban in patients with ESRD. Other observational studies, however, have found apixaban to be similar in efficacy and safety to warfarin. In a small, retrospective cohort study, Stanton et al. [56] identified that patients with ESRD and NVAF had equal rates of ischemic stroke (7.5% in both groups). No recurrent VTEs occurred between either group. Further, apixaban was associ- ated with a lower rate of bleeding (9.6 versus 17.8% in the VKA group). Investigators [57] compared apixaban and warfarin in patients with ESRD under- going chronic hemodialysis for the treatment or prevention of VTE. Again, there was no statistically significant difference between apixaban and warfa- rin regarding major bleeding, clinically relevant nonmajor bleeding; or minor bleeding. These stud- ies are limited by their small sample size and clinical context making the generalizability of these studies difficult [56,57]. Recent observational studies have continued to demonstrate rivaroxaban and dabigatran as similar or superior alternatives to VKAs in the CKD popu- lation. In a study of patients with nonvalvular atrial fibrillation (NVAF) either on rivaroxaban or warfa- rin, investigators [58] found that rivaroxaban had significantly lower rates of stroke (1.9/100 person- years) versus warf arin (4.2/100 person-years; haz- ard ratio 0.41, 95% CI 0.21–0.80) as well as lower composite events of stroke, VTE, and myocardial infarction (hazard ratio 0.64, 95% CI 0.44–0.91). In a subgroup analysis of diffe rent creatinine clearan- ces ( <50 ml/min; > 50–80 ml/min; 80 ml/min), only CrCl less than 50 ml (876 participants total; 429 randomized to rivaroxaban) was statistically superior to warfarin (hazard ratio 0.09, 95% CI 0.01–0.72). There was no difference in outcomes between rivaroxaban (7.3 /100 person-years) and warfarin (7.4/100 person-years; hazard ratio 0.64, 95% CI 0.44–0.91) with regard to major bleeding.

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Novel oral anticoagulants in CKD Ashley and Sood

A recent population-based nested case–control study focusing on the safety of dabigatran and rivar- oxaban versus warfarin in moderate CKD (median eGFR 38 ml/min per 1.73m 2 ) in Ontario, Canada [59] could not find a statistical different risk of major hemorrhage compared with warfarin (dabigatran:

OR 1.15, 95% CI 0.91–0.45; rivaroxaban: OR 1.22, 95% CI 0.83–1.79) [59]. The investigators [60] conducted a nationwide cohort study of the rates of stroke prevention in dose-reduced NOACs versus in the CKD population with NVAF versus warfarin and included a reduced dose subgroup analysis based patients on age (age 80) and/or renal disease. Notably, researchers did not have access to eGFR or creatinine clearance at the time of treatment initiation. A ‘reasonable clini- cal assumption’ was made as to why the NOAC was dose-reduced participants (an assumption that would likely lead to significant misclassification). Apixaban was associated with higher 1-year rates of ischaemic stroke or systemic embolism com- pared with warfarin (hazard ratio 1.24, 95% CI 1.00– 1.55). Rivaroxaban was associated with a significant decrease in rates (hazard ratio 0.63, 95% CI 0.69– 1.24) of stoke or systemic embolism. Dabigatran and apixaban had lower rates of composite bleeding in comparison with warfarin (dabigatran: hazard ratio 078, 95% CI 0.61–0.99; apixaban: hazard ratio 0.81, 95% CI 0.69–0.94). Rivaroxaban had similar bleed- ing rates to warfarin (hazard ratio 1.00, 95% CI 0.81–1.24). The results of Nielsen et al. [60] contin- ues to demonstrate NOACs, and in particular, rivar- oxaban as well tolerated alternatives to warfarin. In conjunction with post hoc analyses of major trials and meta-analyses, real-world observational studies provides another layer of complimentary evidence that NOACs are efficacious and well toler- ated options in the management of NVAF and VTE in CKD compared with warfarin.

CONCLUSION

The relationship between CKD, atrial fibrillation, stroke, and VTEs are intimately linked. This poses challenges for clinicians balancing risks of bleeding with stroke and systemic embolism. The evidence for supporting the use of NOACs in CKD is slowly increasing. In particular, apixaban has been identi- fied as an ideal alternative to VKAs such as warfarin. However, the conclusions are limited by the lack of RCTs studying patients with CrCl less than 30 ml/ min as well as head-to-head comparisons of NOACs. Given their popularity, ease of use, and consistency in research settings, it is anticipated that NOAC use will continue to rise in patients with CKD.

Acknowledgements

None.

Financial support and sponsorship M.M.S. is provided funding by the Jindal Research Chair for the Prevention of Kidney Disease.

Conflicts of interest There are no conflicts of interest.

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