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Comparisons between Novel Oral Anticoagulants and Vitamin K Antagonists in Patients with CKD Ziv Harel,* Michelle Sholzberg,† Prakesh S. Shah,‡ Katerina Pavenski,† Shai Harel,* Ron Wald,* Chaim M. Bell,§ and Jeffrey Perl* *Division of Nephrology, and The Keenan Research Centre in the Li Ka Shing Knowledge Institute, and †Division of Hematology, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; and ‡Department of Pediatrics and § Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

ABSTRACT Novel oral anticoagulants (NOACs) (rivaroxaban, dabigatran, apixaban) have been approved by international regulatory agencies to treat atrial fibrillation and venous thromboembolism in patients with kidney dysfunction. However, altered metabolism of these drugs in the setting of impaired kidney function may subject patients with CKD to alterations in their efficacy and a higher risk of bleeding. This article examined the efficacy and safety of the NOACs versus vitamin K antagonists (VKAs) for atrial fibrillation and venous thromboembolism in patients with CKD. A systematic review and meta-analyses of randomized controlled trials were conducted to estimate relative risk (RR) with 95% confidence interval (95% CIs) using a random-effects model. MEDLINE, Embase, and the Cochrane Library were searched to identify articles published up to March 2013. We selected published randomized controlled trials of NOACs compared with VKAs of at least 4 weeks’ duration that enrolled patients with CKD (defined as creatinine clearance of 30–50 ml/min) and reported data on comparative efficacy and bleeding events. Eight randomized controlled trials were eligible. There was no significant difference in the primary efficacy outcomes of stroke and systemic thromboembolism (four trials, 9693 participants; RR, 0.64 [95% CI, 0.39 to 1.04]) and recurrent thromboembolism or thromboembolism-related death (four trials, 891 participants; RR, 0.97 [95% CI, 0.43 to 2.15]) with NOACs versus VKAs. The risk of major bleeding or the combined endpoint of major bleeding or clinically relevant nonmajor bleeding (primary safety outcome) (eight trials, 10,616 participants; RR 0.89 [95% CI, 0.68 to 1.16]) was similar between the groups. The use of NOACs in select patients with CKD demonstrates efficacy and safety similar to those with VKAs. Proactive postmarketing surveillance and further studies are pivotal to further define the rational use of these agents. J Am Soc Nephrol 25: 431–442, 2014. doi: 10.1681/ASN.2013040361

The introduction of the novel oral anticoagulants (NOACs) rivaroxaban (Xarelto, Bayer, Munich Germany), apixaban (Elequis, Pfizer, Bristol-Myers Squibb), and dabigatran (Pradax/Pradaxa/Prazaxa, Boehringer Ingelheim) as alternatives to vitamin Kantagonists (VKAs) has been met with enthusiasm among clinicians. These agents are currently available for prophylaxis J Am Soc Nephrol 25: 431–442, 2014

and treatment of venous thromboembolism (VTE) and for prophylaxis of stroke and systemic thromboembolism in the setting of atrial fibrillation. Furthermore, they have demonstrated similar or greater efficacy and safety in relation to conventional anticoagulants in large trials.1–6 NOACs differ from traditional oral VKAs mechanistically and pharmacokinetically.

Dabigatran directly inhibits the final effector of coagulation, thrombin (factor IIa), while rivaroxaban and apixaban directly inhibit the rate-limiting step of coagulation, factor Xa activation. Thrombin and factor Xa are targeted by the NOACs for anticoagulant therapy given their roles in clot formation.7,8 Advantages of the NOACs include their rapid onset of action, shorter half-lives, lack of requirement for regular laboratory monitoring, and absence of food interactions compared with VKAs. Although the NOACs differ in their degree of kidney excretion, their elimination is differentially impaired with worsening kidney function, with accumulating levels predisposing patients to an increased risk of bleeding events.9,10 CKD is increasing in prevalence and is associated with an increased risk of atrial fibrillation and venous thrombosis, both of which are indications for NOAC use.11,12 In North America, these agents have been approved by the US Food and Drug Administration and Health Canada for use in patients with varying degrees of kidney dysfunction. However, these agencies have extrapolated the

Published online ahead of print. Publication date available at www.jasn.org. Correspondence: Dr. Ziv Harel, St. Michael’s Hospital, 61 Queen Street, 7th Floor, Toronto, ON M5C 2T2, Canada. Email: [email protected] Copyright © 2014 by the American Society of Nephrology

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efficacy and safety data from the NOAC trials and approved dabigatran and rivaroxaban for use in patients with more severe CKD, despite the exclusion of such patients from the trials (Table 1).13–18 Serious bleeding has been reported with the NOACs in patients with CKD.19,20 The increasing popularity of the NOACs, combined with the lack of a specific antidote in the face of hemorrhage, creates a potential “perfect storm” for adverse bleeding events in patients with CKD. As such, it is important to determine the efficacy and safety of these agents among patients with CKD in order to guide the rational use of these agents. We carried out a systematic review and meta-analysis comparing the efficacy and bleeding risk with the use of NOACs compared with conventional VKA therapy in patients with CKD.

duplicate citations, 1848 citations were evaluated, of which 151 were reviewed in detail. We excluded 19 other randomized controlled trials (RCTs). Two had results that were embargoed (Long-Term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation [RELY-ABLE] and Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism [RECOVER] II studies),21,22 pending future publication, one had information that the authors could not release (ARISTOTLE-J [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation])23 because of confidentiality agreements with the drug sponsor (Pfizer Japan), and 16 did not meet our inclusion criteria because of ineligible comparator groups. Eight eligible RCTs were identified and included in this review (Figure 1).2–6,24–26

RESULTS

Study Participants and Interventions

A total of 3354 screened citations met the search criteria. After exclusion of 1506

Table 2 summarizes the characteristics of the included studies and participants. Of the eight included studies, four

compared rivaroxaban with vitamin K antagonists (two compared rivaroxaban with warfarin,2,4 two compared rivaroxaban with acenocoumarol3,25), three studies compared dabigatran with warfarin,1,6,24 and one study compared apixaban with warfarin.5 Four trials involved anticoagulation for atrial fibrillation2,4–6 and four for treatment of VTE disease.1,3,24,25 The dosing regimens for each of the NOACs varied according to the trial (Table 2). VKA doses were titrated to a target international normalized ratio (INR) of 2–3 in all trials, but one trial modified the INR target to 1.6–2.5 for patients aged 70 years or older. For participants randomly assigned to VKAs, all trials provided the mean time in the therapeutic range (TTR) for the entire cohort (range, 55%–65.3%); however, only one trial4 provided additional information for patients with CKD (57.7%). Most trials excluded patients with a history of severe kidney dysfunction (defined by the Cockcroft–Gault equation as a creatinine clearance [CrCl],30 ml/min in five trials and ,25 ml/min in one trial). All trials

Table 1. Regulatory agency recommendations for NOACs in patients with CKD Agency Health Canada

US Food and Drug Administration

Drug Apixaban Atrial fibrillation and VTE: CrCl=30–50 ml/min: No dose adjustment required; i.e., 5 mg orally twice daily except for: Cr.132 mmol/L Age.80 yr Weight ,60 kg (if any of the above, use 2.5 mg orally twice daily) Contraindicated if CrCl,25 ml/min Atrial fibrillation and VTE: CrCl=30–50 ml/min: No dose adjustment required; i.e., 5 mg orally twice daily except for: Cr .132 mmol/L Age.80 yr Weight,60 kg (if any of the above, use 2.5 mg orally twice daily) Contraindicated if CrCl,15 ml/min

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Dabigatran Atrial fibrillation: CrCl=30–50 ml/min: 150 mg orally twice daily

Contraindicated if CrCl,30 ml/min

Atrial fibrillation and VTE: CrCl.30 ml/min: 150 mg orally twice daily CrCl=15–30 ml/min: 75 mg orally twice daily Contraindicated if CrCl,15 ml/min

Rivaroxaban Atrial fibrillation: CrCl=30–49 ml/min: 15 mg orally once daily

Contraindicated if CrCl,30 ml/min VTE: CrCl=30–49 ml/min: 15 mg orally twice daily321 d, then 20 mg orally once daily Contraindicated if CrCl,30 ml/min Atrial fibrillation: CrCl=30–49 ml/min: 15 mg orally once daily CrCl=15–29 ml/min: 15 mg orally once daily Contraindicated if CrCl,15ml/min VTE: CrCl=30–49 ml/min: 15 mg orally twice daily321 d then 20 mg orally once daily Contraindicated if CrCl,30 ml/min

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Outcomes

Efficacy The primary efficacy outcome for atrial fibrillation was stroke (ischemic or hemorrhagic) or systemic embolism. Four studies (n=9693) reported on the outcome of stroke or systemic embolism in atrial fibrillation populations with CKD (CrCl#50 ml/min) (Table 3).2,4–6 Of these, one study compared apixaban with a VKA (n=3005), one study compared dabigatran with a VKA (n=3471), and two compared rivaroxaban with a VKA (n=3217). The risk of stroke or systemic embolism did not significantly differ between patients randomly assigned to the NOACs and those assigned to VKAs (relative risk [RR], 0.64 [95% confidence interval (95% CI), 0.39 to 1.04]; I2=82%) (Figure 2A). Atrial Fibrillation.

The primary efficacy outcome for VTE was recurrent thromboembolism and thromboembolism-related death. We identified four studies (n=891), which reported on recurrent thromboembolism and related death in VTE populations with CKD (CrCl#50 ml/min) (Table 3). Two compared dabigatran with a VKA (n=237), and two compared rivaroxaban with a VKA (n=654). The risk of recurrent thromboembolism or thromboembolism-related death did not significantly differ between participants randomly assigned to NOACs and those assigned to VKAs (RR, 0.97 [95% CI, 0.43 to 2.15]; I2=0%) (Figure 2B). VTE.

Figure 1. Flow of studies through review. Of the 3354 studies identfied, eight were included in the systematic review and meta-analysis.

Adverse Events The primary bleeding outcome was major bleeding or a combined bleeding endpoint (major bleeding or clinically relevant nonmajor bleeding [CRNB]). Eight studies reported on the outcome of major bleeding or the combined bleeding endpoint in patients with CKD (CrCl#50 ml/min) (Figure 3A, Table 3).2–6,24,25 Of these eight studies, two reported major bleeding and combined bleeding events,4,5 three reported only combined bleeding events,2,3,25 and three reported only major bleeding events.6,24 All studies compared one of the NOACs with a VKA (n=10,616). Four studies compared rivaroxaban

Primary Bleeding Outcome.

permitted concurrent antiplatelet therapy. All studies included frequent safety assessments for bleeding and reported predefined safety outcomes. Risk of Bias

The overall risk of bias among included studies was low (Supplemental Table 1). Seven studies described the methods for generation of the randomization sequence and details about allocation concealment. All studies reported blinding of participants and investigators, but only seven provided sufficient detail on J Am Soc Nephrol 25: 431–442, 2014

the methods used to mask study staff, participants, and assessors. This is unlikely to affect safety outcomes, however, because these were based on predefined standardized criteria. Safety events were monitored and recorded for all included studies, and definitions were provided a priori. Withdrawal rates for all studies were ,20%. All included studies were industry sponsored (Bayer Schering Pharma, Johnson & Johnson, and OrthoMcNeil for rivaroxaban; Boehringer Ingelheim for dabigatran; and BristolMyers Squibb and Pfizer for apixaban).

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Dabigatran (DTI) versus warfarin

RECOVER, 2009

150 mg twice daily (dabigatran) versus dose-adjusted warfarin (target INR 2–3)e

Rivaroxaban (Xa 15 mg twice daily inhibitor) versus (rivaroxaban) for warfarin or the first 3 wk, then acenocoumarold 20 mg daily, versus target INR of 2–3 (VKA)

EINSTEIN-PE, 2012

5 mg twice daily Apixaban (Xa (apixaban) versus inhibitor) versus target INR of 2–3 warfarin (warfarin) or 2.5 mg twice daily versus target INR of 2–3c EINSTEIN-DVT, Rivaroxaban (Xa 15 mg twice daily 20103(Acute) (rivaroxaban) for inhibitor) versus the first 3 wk, then warfarin or 20 mg daily, versus acenocoumarold target INR of 2–3 (VKA)

ARISTOTLE, 20115

Study, Year

60

62.7

Patients with acute, symptomatic, objectively confirmed proximal DVT, without symptomatic pulmonary embolism Patients with acute, symptomatic pulmonary embolism with objective confirmation, with or without symptomatic deep-vein thrombosis Patients with acute, symptomatic, objectively verified proximal DVTs of the legs or pulmonary embolism $80 ml/min: 1833 $50–79 ml/min: 551 31–49 ml/min: 120 #30 ml/min: 13

Mean6SD for dabigatran: 105.8640.7 Mean6SD for warfarin: 104.4639.9

$80 ml/min: 3172 Not provided $50–79 ml/min: 1230 .30–49 ml/min: 398 ,30 ml/min: 6 Missing: 26

Not provided

$80 ml/min: 2363 $50–79 ml/min: 792 .30–49 ml/min: 235 ,30 ml/min: 15 Missing: 44

57.7

Study Population Patients with AF or atrial flutter and at least 1 risk factor for stroke

Creatinine Clearance (ml/min)b

$81 ml/min: 7518 Not provided $51–80 ml/min: 7567 .25–50 ml/min: 3017 Missing: 79

Patients in Renal Subgroups per Creatinine Clearance (n)

62.2

Mean TTR (INR 2–3) (%)a

Table 2. Summary of studies included in meta-analysis of safety of NOACs in CKD Additional Medications

CrCl,30 ml/min

CrCl,30 ml/min

CrCl,30 ml/min

Aspirin (up to 100 mg daily) and antiplatelet agent use permitted

NSAID and antiplatelet use discouraged, but aspirin (up to 100 mg) and clopidogrel (75 mg daily) were permitted

NSAID and antiplatelet use discouraged, but aspirin (up to 100 mg) and clopidogrel (75 mg daily) were permitted

NSAID and antiplatelet Creatinine.221 agents permitted mmol/L or CrCl,25 ml/min

Renal Exclusion Criteria

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ROCKET-AF, 20114

64 110 mg twice daily (dabigatran) versus dose-adjusted warfarin (target INR 2–3) or 150 mg twice daily (dabigatran) versus dose-adjusted warfarin (target INR 2–3) Rivaroxaban (Xa 15 mg daily 55 (entire inhibitor) versus (rivaroxaban) cohort) 57.7 warfarin versus adjusted(CrCl 30/49 dose warfarin ml/min) (target INR 2–3)f

RE-LY, 20096

Dabigatran (DTI) versus warfarin

150 mg twice daily (dabigatran) versus dose-adjusted warfarin (target INR 2–3)

Dabigatran (DTI) versus warfarin

REMEDY, 20131

65.3

Dose

Mean TTR (INR 2–3) (%)a

Intervention

Study, Year

Table 2. Continued

Mean6SD for dabigatran: 04.2638.6 Mean6SD for warfarin: 106.6637.9

Creatinine Clearance (ml/min)b Patients with a previous history of symptomatic, objectively verified proximal DVTs of the legs or pulmonary embolism enrolled in the RECOVER or RECOVER-II trials Patients with AF or atrial flutter and at least one risk factor for stroke

Study Population

Patients with $80 ml/min: 4518 Median (IQR) for nonvalvular $50–79 ml/min: 6723 rivaroxaban:67 AF and a 31–49: ml/min 2970 (52–88) moderate-toMedian (IQR) for high risk for warfarin: 67 stroke based (52–86) on prior history of stroke or CHADS2 score of $2

$80 ml/min: 5658 Not provided $50–79 ml/min: 8597 30–49 ml/min: 3343 ,30 ml/min: 77

$80 ml/min: 2103 $50–79 ml/min: 617 31–49 ml/min:104 #30 ml/min: 4

Patients in Renal Subgroups per Creatinine Clearance (n)

CrCl,30 ml/min

CrCl,30 ml/min

CrCl,30 ml/min

Renal Exclusion Criteria

Aspirin (up to 100 mg daily) and antiplatelet agent use permitted

Aspirin (up to 100 mg daily) and antiplatelet agent use permitted

Aspirin (up to 100 mg daily) and antiplatelet agent use permitted

Additional Medications

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Dose

65

Mean TTR (INR 2–3) (%)a $50 ml/min: 994 ,50 ml/min: 284

Patients in Renal Subgroups per Creatinine Clearance (n) Not provided

Creatinine Clearance (ml/min)b Renal Exclusion Criteria

CrCl,30 ml/min Japanese patients with nonvalvular AF and a moderateto-high risk for stroke based on prior history of stroke or CHADS2 score$2

Study Population Aspirin (up to 100 mg daily) and antiplatelet agent use permitted

Additional Medications

TTR, time in therapeutic range; AF, atrial fibrillation; NSAID, nonsteroidal anti-inflammatory drug; DVT, deep venous thrombosis; DTI, direct thrombin inhibitor; IQR, interquartile range; CHADS2: Risk score consisting of 1 point each for congestive heart failure, hypertension, age.75 years, diabetes, and 2 points for stroke; EINSTEIN-DVT, oral direct factor Xa inhibitor rivaroxaban in patients with acute symptomatic deep-vein thrombosis; EINSTEIN-PE, oral direct factor Xa inhibitor rivaroxaban in patients with acute symptomatic pulmonary embolism; REMEDY, a phase III, randomised, multi-center, double-blind, parallelgroup, active controlled study to evaluate the efficacy and safety of oral dabigatran etexilate compared to warfarin (INR 2.0-3.0) for the secondary prevention of venous thromboembolism; ROCKET-AF, The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; J-ROCKET-AF, Evaluation of the Efficacy and Safety of Rivaroxaban (BAY59-7939) for the Prevention of Stroke and Noncentral Nervous System Systemic Embolism in Japanese With Nonvalvular Atrial Fibrillation. a TTR reported for the entire cohort randomly assigned to VKA group for each trial, not the subset of patients with CKD. b Pooled for the entire cohort in the trial. c 2.5-mg doses were used in a subset of patients with two or more of the following criteria: age$80 years, body weight#60 kg, or a serum creatinine level$1.5 mg/dl (133 mmol/L). d Patients received enoxaparin at a dose of 1.0 mg/kg body weight twice daily and either warfarin or acenocoumarol, started within 48 hours after randomization. Enoxaparin was discontinued when the INR was $2.0 for 2 consecutive days and the patient had received at least 5 days of enoxaparin treatment. e A parenteral anticoagulant (generally unfractionated heparin administered intravenously or low-molecular-weight heparin administered subcutaneously) was usually started before random assignment. The parenteral anticoagulant was stopped, once it had been given for at least 5 days and the true or sham INR was recorded as $2.0 on 2 consecutive days. Warfarin was started on the day of random assignment. Dabigatran was initiated within 2 hours before the time that the next dose of initial parenteral therapy would have been due or at the time of discontinuation of intravenous unfractionated heparin. f Fifteen-milligram dose for CrCl,50 ml/min; 20 mg for CrCl$50 ml/min. g INR of 2.0–3.0 in patients aged,70 years or a reduced INR of 1.6–2.6 in patients aged$70 years.

10 mg daily J-ROCKET-AF, Rivaroxaban (Xa (rivaroxaban) inhibitor) versus 20122 versus dosewarfarin adjusted warfaring

Study, Year

Table 2. Continued

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with a VKA (n=3903),2–4 three compared dabigatran with warfarin (n=3708),6,24 and one compared apixaban with warfarin (n=3005).5 Bleeding risk did not differ among patients randomly assigned to receive NOACs versus those receiving VKAs (RR, 0.89 [95% CI, 0.68 to 1.16]). The primary safety outcome exhibited substantial heterogeneity (I2=68%). Secondary Bleeding Outcomes. Secondary bleeding outcomes were major bleeding, combination of major bleeding and CRNB, and intracranial hemorrhage. Five studies reported major bleeding events (n=9683),4–6,24 and five studies reported combined bleeding events (major bleeding and CRNB) (n=6908) (Supplemental Figures 1 and 2, Table 3).2–5 The risk of major bleeding was no different among patients given NOACs than among those given VKAs (RR, 0.82 [95% CI, 0.57 to 1.17]; I2=75%). Similarly, the risk of combined bleeding (major bleeding and CRNB) did not differ (RR, 0.88 [95% CI, 0.64 to 1.19]; I2=81%). Three atrial fibrillation studies reported intracranial hemorrhage events (n=9446). The risk of intracranial hemorrhage was significantly lower among patients given NOACs than among those given VKAs (hazard ratio, 0.38 [95% CI, 0.18 to 0.79]; I 2 =72%). As was seen with the primary safety outcome, all secondary safety outcomes demonstrated substantial levels of heterogeneity.

Subgroup and Sensitivity Analyses

We were unable to conduct a majority of our planned subgroup analyses (age, sex, dose of NOAC used) from the available data because patient-level data could not be obtained. Given differences in CrCl cut-points between the trials, we were unable to assess the risk of our primary and secondary outcomes according to our predefined CrCl tertiles. Therefore, we restricted comparisons to patients with moderate or severe kidney dysfunction (CrCl#50 ml/min) to those with normal kidney function (CrCl$80 ml/min). We found the risks of stroke and systemic thromboembolism or recurrent thromboembolism or thromboembolism-related deaths were

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Table 3. Number of primary and secondary events/total in included studies for the primary efficacy outcomes, and bleeding outcomes

Study, Year

ARISTOTLE, 2012 EINSTEIN-DVT, 2010 EINSTEIN-PE, 2012 RECOVER, 2009 REMEDY, 2013 RE-LY, 2009 ROCKET-AF, 2011 J-ROCKET, 2012

Stroke and Systematic Embolism

Recurrent Thromboembolism or ThromboembolismRelated Death

Combined Bleeding Endpoint

Major Bleeding

CRNB

DTI/FXa

Warfarin

DTI/FXa

Warfarin

DTI/FXa

Warfarin

DTI/FXa

Warfarin

DTI/FXa

Warfarin

54/1493 NA NA NA NA 84/2379 50/1481 5/141

69/1512 NA NA NA NA 103/1092 60/1452 6/143

NA 4/121 7/211 0/60 1/59 NA NA NA

NA 6/129 5/193 0/69 1/49 NA NA NA

123/1493 13/120 26/209 NA NA NA 336/1498 42/141

211/1512 10/128 34/192 NA NA NA 341/1472 35/143

73/1493 NA NA 4/60 2/59 244/2379 99/1498 NA

142/1512 NA NA 2/69 3/49 116/1092 100/1472 NA

50/1493 NA NA NA NA NA 261/1498 NA

69/1512 NA NA NA NA NA 259/1472 NA

DTI, direct thrombin inhibitor; FXa, factor Xa inhibitor; NA, not available.

There was no statistically significant difference in bleeding risk among patients treated with rivaroxaban or dabigatran compared with those treated with VKA (RR with rivaroxaban, 1.00 [95% CI, 0.79 to 1.26]; RR with dabigatran, 0.97 [95% CI, 0.79 to 1.19]). We could not perform meta-analysis on the risk of bleeding associated with apixaban because only a single study on this agent was included in our review (Figure 3). The L’Abbé plot failed to demonstrate any significant heterogeneity in the risk of bleeding among patients treated with NOACs compared with those treated with VKAs (Supplemental Figure 5). Figure 2. (A) There was no significant difference in the risk of stroke and systemic thromboembolism among participants with a CrCl#50 ml/min given a NOAC versus a VKA (RR, 0.64; 95% CI, 0.39–1.04). (B) There was no significant difference in the risk of recurrent thromboembolism or thromboembolism-related death among participants with a CrCl#50 ml/ min given a NOAC versus a VKA (RR, 0.97; 95% CI, 0.43–2.15).

similar in both groups: for stroke and systemic thromboembolism—RR, 0.64 (95% CI, 0.39 to 1.04) for CrCl# 50 ml/min and RR, 0.89 (95% CI, 0.89 to 1.16) for CrCl$80 ml/min); for recurrent thromboembolism or thromboembolismrelated death—RR, 0.97 (95% CI, 0.43 to 2.15) for CrCl# 50 ml/min and RR, 0.93 (95% CI, 0.57 to 1.51) for CrCl$80 ml/ min) (Supplemental Figure 3). We also found the risk of bleeding (primary safety outcome) to be the same in both groups (RR, 0.89 [95% CI, 0.68 to 1.16] for CrCl# 50 ml/min and RR, 0.91 [95% CI, 0.81 to 1.03] for CrCl$80 ml/min). In patients with CrCl$80 ml/min, dabigatran led to J Am Soc Nephrol 25: 431–442, 2014

less bleeding than did warfarin (RR, 0.72 [95% CI, 0.57 to 91]), whereas in patients with CrCl#50 ml/min, bleeding was the same in both groups (RR, 0.97 [95% CI, 0.79 to 1.19]) (Figure 3B). There was no difference in the risk of bleeding (RR, 0.87 [95% CI, 0.62 to 1.22]) among patients with CKD and atrial fibrillation who were treated with the NOACs compared with those treated with VKAs and among patients treated for acute deep venous thrombosis/pulmonary embolism or those receiving extended therapy for secondary VTE prophylaxis (RR, 0.93 [95% CI, 0.57 to 1.51]) (Supplemental Figure 4).

Publication Bias

No evidence of publication bias for the primary outcome was suggested by visual inspection of the funnel plots (Supplemental Figure 6).

DISCUSSION

In this systematic review, we identified no difference in the risk of stroke and systemic thromboembolism, recurrent thromboembolism or thromboembolism-related death, or bleeding among patients with CKD who received NOACs compared with those who received VKAs in the setting of chronic nonvalvular atrial fibrillation or venous thromboembolism. To date, no published systematic reviews or meta-analyses have evaluated the efficacy and safety of NOACs compared Novel Oral Anticoagulants

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Figure 3. (A) Overall, there was no significant difference in the risk of bleeding among participants with a CrCl#50 ml/min given a NOAC versus a VKA (RR, 0.89; 95% CI, 0.68– 1.16). This result persisted in subgroup analysis for rivaroxaban and dabigatran. (B) Overall, there was no difference in the risk of bleeding among participants with a CrCl$80 ml/min given a NOAC versus a VKA (RR, 0.91; 95% CI, 0.81–1.03). In subgroup analysis, participants given dabigtran had a significantly lower risk of bleeding compared to those given a VKA (RR, 0.72; 95% CI, 0.57–0.91).

with VKAs, specifically in patients with CKD (CrCl#50 ml/min). Recent metaanalyses of studies containing participants encompassing a broad spectrum of kidney function have yielded discordant conclusions with respect to the risk of stroke or 438

thromboembolic events and bleeding in users of NOACs compared with users of VKAs.26–29 These differences may result from clinical and methodologic heterogeneity between the studies, including variability in the indication for NOAC, dose of

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NOAC, duration of therapy, and baseline patient characteristics and differences in study inclusion criteria. In contrast to our review, the aforementioned analyses studied pooled patient populations, which largely included patients with normal kidney function. Our study demonstrated that among patients with CKD, defined as a CrCl#50 ml/min, no significant difference in efficacy between NOACs and VKAs exists. This finding may be a consequence of the quality of anticoagulation in the studies included in our review, as demonstrated by an increased TTR with an INR of 2–3 in these studies. Studies have shown that the degree of TTR is strongly correlated with improved clinical outcomes, including stroke prevention and bleeding risk.30 Indeed, pooled results from the trials included in our review indicated that patients had a higher mean TTR (61.5%) than that noted in routine clinical practice (55%).31 This result, along with the close follow-up of patients randomly assigned to VKAs in the included trials and a potentially less severe burden of comorbid illness, may have accounted for the lack of a significant difference between the NOAC and VKA groups in terms of stroke prevention. We found no significant difference in the primary bleeding outcome or in major bleeding and CRNB events in patients with CKD (CrCl#50 ml/min). This is surprising given the differential degree of renal excretion of each of the NOACs. Although dabigatran is highly renally excreted (80%), rivaroxaban (35%) and apixaban (25%) are less so. We would, therefore, have expected a graded risk of bleeding with worsening renal function in patients given NOACs, with the magnitude of the effect being greatest for dabigatran, followed by rivaroxaban and then apixaban. Our combining the three different NOACs into a single class probably obscured such differences in bleeding risk. Interestingly, in our analysis of bleeding risk stratified by renal status (CrCl#50 ml/min and CrCl$80 ml/ min), we found a significant decrease in bleeding risk for patients with a CrCl#50 ml/min given apixaban but J Am Soc Nephrol 25: 431–442, 2014

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not for those with a CrCl$80 ml/min. This finding has also been noted by Hohnloser et al. and may be explained by baseline differences in apixaban dose.32 Specifically, although patients with a CrCl#50 ml had characteristics that may have increased their risk for bleeding (increased age, greater comorbidity, and prior bleeding events), a substantial proportion were given a lower dose of apixaban (2.5 mg versus 5 mg), which may have modified this relationship. We did, however, demonstrate a significant decrease in bleeding risk associated with normal kidney function in patients receiving dabigatran, which may be due to the pharmacokinetic properties of dabigatran such that it does not accumulate in patients with normal renal function and thus mitigates the risk of bleeding. Taken together, there was substantial heterogeneity in most of our efficacy and safety outcome measures. Given that we pooled studies consisting of diverse patient populations that were prescribed NOACs for different indications, noticeable clinical and statistical heterogeneity was expected. Although including such a diverse group of studies may have increased the generalizability of our review, it may have also biased the results. Moreover, the heterogeneity in the pharmacokinetics of the individual NOACs may have also affected our results. For example, because dabigatran is primarily renally excreted, it may accumulate in individuals with CKD, thereby leading to a more robust anticoagulation effect compared with those without CKD, as demonstrated in our study. To account for clinical heterogeneity among studies, we performed several subgroup analyses, including one restricted to studies in which the indication for anticoagulation was atrial fibrillation or treatment of VTE. This allowed us to limit our analysis to two populations, each with similar indications for therapy. As was seen in our primary analysis, this analysis found no difference in the bleeding risk among NOAC users compared with VKA users. Defining a balance between safety and efficacy in patients with CKD treated J Am Soc Nephrol 25: 431–442, 2014

with anticoagulation is challenging, especially given the increased tendency of these patients for both bleeding and thrombosis.33 Currently, there is no definitive measure to estimate the risk of bleeding in patients with CKD in whom anticoagulant therapy is contemplated. Bleeding risk scores, such as HAS-BLED and HEMORR(2)HAGES, have poor predictive power and limited clinical utility.34 Although there are multiple reports of serious bleeding events in patients with impaired kidney function taking dabigatran,19,20,35 our study identified no increased risk of our primary bleeding endpoint with use of this agent or any other NOAC in patients with CKD. However, patients given the NOACs did have a significantly lower risk of intracranial hemorrhage. Several reasons may explain this finding, including unmeasured baseline differences in bleeding risk among the different study groups, differences in TTR among patients with CKD in the atrial fibrillation studies, the enrollment of patients with less severe kidney dysfunction in the ARISTOTLE5 and Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY)6 trials, and the close follow-up of study participants. All of these may have modified risk factors for bleeding complications, including AKI development. AKI would cause a sudden decrease in kidney function and hence the rapid accumulation of the NOACs, particularly for those for which the kidneys are the major route of excretion, such as dabigatran.36,37 Our findings need to be interpreted within the limitations of the study design. We pooled the results of a group of studies that were not intended to explore bleeding outcomes in a subgroup of patients with CKD. As a result, the 95% CIs for RRs of bleeding events in some of the included studies were wide and thus provide a more conservative estimate of safety and efficacy. We did not have access to patient-level data or the rates of major bleeding events for some of the included studies. We addressed this limitation using a combined endpoint consisting of major bleeding or the combination of major bleeding or CRNB in our primary

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analysis. Such an approach may have led us to overestimate bleeding risks, but analysis of our secondary outcomes paralleled the results of our primary endpoint. We also pooled studies of NOACs from different classes, which could have obscured the differences in bleeding risk, despite our best attempt to mitigate this by subgroup analysis stratifying bleeding risk by class of NOAC. Moreover, our definition of CKD was based on the Cockcroft–Gault formula, which is not as accurate as such GFR-estimating equations as the Modification of Diet in Renal Disease and CKD-Epidemiology Collaboration formulas, and may have led to misclassification of patients’ CKD status.38 Finally, our included studies had strict inclusion criteria, which limited the generalizability of our results. Collectively, the NOACs have demonstrated efficacy and safety similar to those of the VKAs in patients with moderate CKD (CrCl, 30–50 ml/min); however, trials evaluating the effect of these agents on important clinical outcomes in patients with more severe CKD, including patients undergoing dialysis, are lacking. Despite this, the US Food and Drug Administration has extrapolated the efficacy and safety data for patients with moderate CKD and approved dabigatran, apixaban, and rivaroxaban for use in patients with severe CKD (CrCl, 15–30 ml/min).13–15 Although the Food and Drug Administration considers the use of these agents in such patients to be “safe” on the basis of pharmacokinetic data, such a practice may be associated with an increased risk of adverse bleeding events. Indeed, patients with CKD have underlying abnormalities in hemostasis, are more likely to be elderly, and have an increased risk for developing AKI, the onset of which may be insidious—all reasons that can acutely increase the bleeding risk associated with NOAC use.39–41 This risk is further compounded by the lack of a specific antidote to reverse the anticoagulant effect of the NOACs.42 Because our review included only RCTs that enrolled carefully selected populations that were closely monitored, the application of our findings into Novel Oral Anticoagulants

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real-word practice must be done with relative caution. There is a reasonable chance of an increased risk of bleeding in such settings, especially given the wide 95% CIs associated with the bleeding outcomes in our review. As such, the use of the NOACs in patients with moderate CKD (CrCl, 30–50 ml/min) should be individualized by taking into account the potential for an increased risk of bleeding, particularly with compounds that are primarily renally excreted, such as dabigatran. Should clinicians choose to use the NOACs in patients with moderate CKD, close monitoring of kidney function is paramount; clinicians should note that any decline in kidney function may place patients at a higher risk of bleeding. Finally, given the danger of extrapolating the findings of landmark clinical trials to patients who may be at an increased risk of adverse events, we, in contrast to the opinion of the same governmental regulatory agencies, do not suggest using these agents in patients with more severe renal dysfunction (CrCl,30 ml/min), including those undergoing dialysis. In clinical trials, the use of NOACs in patients with moderate CKD demonstrated efficacy and safety similar to those seen with VKAs. As the use of these novel agents increases, their safety in usual clinical practice will be important to monitor, and clinicians who prescribe them to patients with moderate CKD should carefully monitor kidney function and recognize the potential for adverse effects.

CONCISE METHODS We conducted a systematic review and metaanalysis conforming to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.43

Search Strategy We used a strategy developed with a health informatics specialist tosearch Ovid MEDLINE (1948–March 2013), Embase (1980–March 2013), and the Cochrane Central Register of Controlled Trials (1993–March 2013) (Supplemental Appendix). No language restrictions were applied, and we reviewed the 440

bibliographies of identified articles to locate further eligible studies. In addition, to identify ongoing or completed trials, we searched the Clinical Trials Registry (www.clinicaltrials. gov); the clinical trial databases of Boehringer Ingelheim, Bristol-Myers Squibb, and Bayer; and abstracts from the past 3 years presented at conferences of the American Society of Nephrology.

Study Selection and Validity Assessment We included all RCTs of at least 4 weeks’ duration that involved the three NOACs currently marketed in Canada (dabigatran, apixaban, or rivaroxaban) and provided data on thromboembolic and bleeding complications relative to therapy with VKAs in patients with CKD. In line with the trials included in our review, CKD was defined as a calculated CrCl of #50 ml/min by the Cockcroft–Gault equation. Where necessary, we contacted corresponding authors for additional missing data. All dosing regimens of dabigatran, apixaban, rivaroxaban, and VKAs evaluated in the included trials were considered. For the VTE trials, all patients received initial therapy with enoxaparin or unfractionated heparin for up to 10 days. Given that we focused on long-term outcomes, we included these trials because we believed the number of early events during this 10-day period would be negligible; furthermore, this practice constitutes the current standard of care for the management of acute VTE.44 Where more than one publication of a trial existed or when a retrospective subgroup analysis was published, we used the most detailed publication. Case reports, case series, cohort studies, cross-sectional studies, casecontrol studies, cost-effectiveness reports, letters, commentaries, reviews, and editorials were also excluded. Two authors (Z.H. and J.P.) scanned titles and abstracts for initial selection. Selected studies were reviewed in full and were independently assessed for eligibility by the same two reviewers. Discrepancies were resolved by consensus.

Outcome Measures The primary efficacy outcome for patients with chronic nonvalvular atrial fibrillation consisted of the composite of stroke (ischemic or

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hemorrhagic) or systemic embolism. For patients with VTE, the primary efficacy outcome consisted of the composite of recurrent thromboembolism and thromboembolism-related death. Stroke was uniformly defined as a sudden focal neurologic deficit of presumed cerebrovascular cause that persisted beyond 24 hours and was not due to another identifying cause, and systemic embolism was defined as an acute vascular occlusion of an extremity or organ, documented by imaging, surgery, or autopsy. 4–6 Recurrent thromboembolism was defined in all trials as the composite of deep vein thrombosis or nonfatal or fatal pulmonary embolism.1,3,24,25 The primary bleeding outcome consisted of bleeding events: major bleeding or a combined bleeding endpoint (major bleeding or CRNB events) if the study did not report major bleeding as an adverse event in the CKD subgroup or if the study provided insufficient information to allow calculation of major bleeding events. The secondary bleeding outcomes were major bleeding events, the combination of major bleeding and CRNB events, and intracranial hemorrhage (for patients enrolled in the atrial fibrillation trials). Bleeding events were defined according to International Society on Thrombosis and Haemostasis criteria.45

Assessment of Risk of Bias Two reviewers (Z.H. and J.P.) independently assessed the risk of bias in the included studies without blinding to authorship or journal using the predefined checklist of the Cochrane Database of Systematic Reviews.46 The checklist assessed risk of bias in sequence generation, allocation concealment, blinding, attrition, selection, and other areas. In particular, because we were assessing the risk of adverse outcomes, for the domain of attrition we evaluated studies for attrition in reporting outcomes of interest and not the primary outcome of the study. In the domain of other biases, we determined whether an assessment of adverse effects was planned a priori. The classification in each category was yes, no, or unclear. We carried out an overall assessment of the risk of bias on the basis of the responses for the selected criteria. Discrepancies were resolved by consensus and involvement of the other authors. J Am Soc Nephrol 25: 431–442, 2014

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Data Extraction and Synthesis Two reviewers (Z.H. and J.P.) independently extracted data by using custom data extraction forms. Disagreements were resolved by consensus. Original data from the included trials were used, and all analyses were conducting using Review Manager (RevMan), version 5 (Copenhagen, The Nordic Cochrane Centre, The Cochrane Collaboration). Because direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban) have similar mechanisms—both act by inhibiting a single coagulation enzyme—we combined data across drug classes. We calculated RRs along with 95% CIs for all outcome variables. Because we anticipated clinical and statistical heterogeneity, we used a random-effects model because it accounts, to some extent, for variability within and between studies. Statistical heterogeneity was assessed using the Cochrane Q test (significance set at 0.01) and by I2 values. We weighted the studies in our meta-analysis using inverse variance. We evaluated publication bias using the funnel plot method.

Subgroup and Sensitivity Analysis We planned subgroup analyses to assess for clinical heterogeneity on the basis of characteristics of study populations and interventions. These characteristics included age, sex, kidney function (stratified by cut-points of calculated CrCl [#50 ml/min (moderate to severe), .50–79 ml/min (mild), and $80 ml/ min (normal)] as reported in the included trials), indication for anticoagulation (atrial fibrillation versus treatment of VTE), and type and dose of NOAC (rivaroxaban, apixaban, or dabigatran) used. To further account for heterogeneity in the bleeding risk in the included studies, we created a L’Abbé plot and plotted the observed proportion of bleeding events of the VKA group against the observed proportion of bleeding events of the NOAC group.

ACKNOWLEDGMENTS We thank Ms. Elizabeth Uleryk (librarian) and Ms. Teruko Kishibe (archivist/information specialist) for developing the search strategy and performing the search. Z.H. and J.P. had full access to all of the data in the study and take responsibility for the J Am Soc Nephrol 25: 431–442, 2014

integrity of the data and the accuracy of the data analysis. Z.H. is supported by a fellowship award funded by team grant OTG-88591 from the Canadian Institutes of Health Research.

DISCLOSURES

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This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10. 1681/ASN.2013040361/-/DCSupplemental.

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