- Email: [email protected]
Renal Function Considerations for Stroke Prevention in Atrial Fibrillation
Accepted Manuscript Renal function considerations for stroke prevention in atrial fibrillation John Fanikos, RPh, MBA, Allison E. Burnett, PharmD, Charles E. Mahan, PharmD, Paul P. Dobesh, PharmD PII:
S0002-9343(17)30481-3
DOI:
10.1016/j.amjmed.2017.04.015
Reference:
AJM 14073
To appear in:
The American Journal of Medicine
Received Date: 2 March 2017 Revised Date:
14 April 2017
Accepted Date: 18 April 2017
Please cite this article as: Fanikos J, Burnett AE, Mahan CE, Dobesh PP, Renal function considerations for stroke prevention in atrial fibrillation, The American Journal of Medicine (2017), doi: 10.1016/ j.amjmed.2017.04.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Renal function considerations for stroke prevention in atrial fibrillation
John Fanikos, RPh, MBA1; Allison E. Burnett, PharmD2; Charles E. Mahan, PharmD3; Paul P.
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Dobesh, PharmD3
Department of Pharmacy, Brigham and Women’s Hospital, Boston, MA; 2Department of
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Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM; 3College of Pharmacy, University of New Mexico Health Sciences Center, Presbyterian Healthcare Services,
Corresponding author: John Fanikos
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Department of Pharmacy Services
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Albuquerque, NM; 4College of Pharmacy, University of Nebraska Medical Center, Omaha, NE
Brigham and Women's Hospital 75 Francis Street
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Boston, MA, 02115, USA Phone: (617) 605-3237
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Email: [email protected]
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Funding sources: Funding for writing and editorial support was provided by Daiichi Sankyo. Conflict of interest: Charles Mahan has served as a consultant for Portola, Point of Care Software Solutions, Daiichi-Sankyo, Sanofi-Aventis, Boehringer Ingelheim, Johnson and
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Johnson, Polymedix Inc., LEO Pharma, and Eisai; and served as a speaker for Janssen, Bristol Myers Squibb, Pfizer, Sanofi-Aventis, Portola, and Boehringer Ingelheim. John Fanikos has served as a consultant for Boehringer Ingelheim and Portola. Allison Burnett has nothing to
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disclose. Paul Dobesh has served as a consultant for Janssen, Daiichi-Sankyo, Pfizer, Bristol-
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Myers Squibb, and Boehringer Ingelheim.
All authors were involved in writing the manuscript, had full control of content, and have seen and approved the submitted version.
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Running head: Renal function considerations for treatment in atrial fibrillation Keywords: Direct oral anticoagulants, atrial fibrillation
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Paper type: Review
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Abstract Renal impairment increases risk of stroke and systemic embolic events and bleeding in
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patients with atrial fibrillation. Direct oral anticoagulants have varied dependence on renal
elimination, magnifying the importance of appropriate patient selection, dosing, and periodic kidney function monitoring. In randomized controlled trials of nonvalvular atrial fibrillation,
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direct oral anticoagulants were at least as effective and associated with less bleeding compared with warfarin. Each direct oral anticoagulant was associated with reduced risk of stroke and
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systemic embolic events and major bleeding compared with warfarin in nonvalvular atrial fibrillation patients with mild or moderate renal impairment. Renal function decline appears less impacted by direct oral anticoagulants, which are associated with a better risk-benefit profile than warfarin in patients with declining renal function over time. Limited data address the risk-
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benefit profile of direct oral anticoagulants in patients with severe impairment or on dialysis.
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Atrial fibrillation and renal impairment Renal impairment is common in atrial fibrillation patients. In large registries, meta-
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analyses, and observational studies, roughly one-third of atrial fibrillation patients have mild to moderate renal dysfunction (estimated glomerular filtration rate [eGFR] 30–89 mL/min) or
chronic kidney disease,1-4 and up to 3% have severe renal dysfunction (eGFR <30 mL/min).5, 6 A
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recent European registry analysis reported up to 60% of atrial fibrillation patients have mild to moderate renal dysfunction (eGFR 30–79 mL/min) and up to 4% have severe renal impairment
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(eGFR <30 ml/min).7
Patients with atrial fibrillation and renal dysfunction are at increased risk of systemic embolic events (hazard ratio [HR] 1.49; P <0.001) and bleeding (HR 2.24; P <0.001) relative to those without chronic kidney disease.6 Relative stroke risk increases 7% with every 10
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mL/min/1.73 m2 decline in eGFR.8 An eGFR <60 mL/min/1.73 m2 is associated with a 43% higher risk of incident stroke.9 Proteinuria and reduced eGFR are associated with higher rates of thromboembolism in patients with nonvalvular atrial fibrillation, independent of other stroke risk
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factors.3 In the National Health and Nutrition Examination Survey, patients with chronic kidney disease had additional stroke risk factors including diabetes (40.4%), hypertension (31.0%), and
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cardiovascular disease (39.5%).10 Additionally, chronic kidney disease patients with atrial fibrillation are 67% more likely to progress to end-stage renal disease than those without atrial fibrillation.11
Finally, survival rates are reduced in patients with atrial fibrillation and renal disease.6, 12
Patients with chronic kidney disease have a higher risk of death from any cause (HR 2.37; P <0.001) and myocardial infarction (HR 2.00; P <0.001) than those without chronic kidney
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disease.6 Survival after incident atrial fibrillation decreases progressively with decreasing renal function (P <0.0001).12 Disruptions in platelet function and platelet-vessel wall interactions in
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patients with renal impairment may result in increased bleeding.
Assessment of renal function in clinical trials
Renal function can be estimated with the Modification of Diet in Renal Disease
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(MDRD)13 or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations,14 which provide eGFR, or the Cockcroft-Gault15 (C-G) equation, which estimates creatinine
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clearance (CrCl). While C-G using actual body weight may not be the best method for calculating renal function, it was used in all phase 3 direct oral anticoagulant trials. 13, 14, 16-20 Renal function cutoffs varied between trials, with a calculated CrCl of ≤30 mL/min for dabigatran, <30 mL/min for edoxaban and rivaroxaban, and serum creatinine >2.5 mg/dL or a
dysfunction.
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calculated CrCl of <25 mL/min for apixaban.17-20 All trials excluded patients with severe renal
Patient populations enrolled in these phase 3 nonvalvular atrial fibrillation studies also
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differed in risk for cardiac dysfunction, stroke, inclusion of patients with atrial flutter, and in timing of documentation of atrial fibrillation.21 The rivaroxaban and edoxaban trials included a
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larger percentage of patients with diabetes mellitus (40% and 36%, respectively) relative to those for dabigatran (23%) and apixaban (25%), which increases patient risk for bleeding and thrombosis, as well as a larger percentage of patients with heart failure (63% and 57% for rivaroxaban and edoxaban, respectively) relative to dabigatran (32%) and apixaban (35%).22 Mean patient CHADS2 (congestive heart failure, hypertension, age = 75 years, diabetes mellitus,
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stroke [doubled]) scores were highest in the rivaroxaban trial (3.5), followed by edoxaban (2.8), and the apixaban and dabigatran trials (2.1).22 Clinical trial calculations of CrCl were based on C-G and employed actual body weight;
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therefore, use of other equations may result in incorrect DOAC dosing. A large database study demonstrated renal function estimations other than C-G would result in a failure to reduce
rivaroxaban or edoxaban doses in 28% of patients, and 18% to 21% of doses among dabigatran
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patients.23 Additionally, apixaban dosing adjustments are based on serum creatinine, body
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weight, and age (components of CrCl) rather than CrCl directly.24
Direct oral anticoagulants in atrial fibrillation and renal impairment All direct oral anticoagulants undergo some degree of renal clearance with 80%, 50%, 36%, and 27% (ie, unchanged drug) of the absorbed doses of dabigatran, edoxaban, rivaroxaban,
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and apixaban, respectively, excreted in urine.24-27 As impaired renal function decreases drug clearance, prolongs half-life, and increases total exposure, it is important to follow dosing recommendations based on level of renal function (Figure 1).24-27
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Despite label recommendations, inappropriately reduced doses of direct oral anticoagulants are commonly prescribed in patients with mild-to-moderate renal dysfunction, a
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past medical history of bleeding events, and concomitant use of medications that increase bleeding risk.28 In a retrospective patient record review, approximately 60% of patients received a DOAC dose below manufacturer recommendations.28 Improper dose reduction may increase thrombotic risk, resulting in preventable strokes. A recent analysis of atrial fibrillation patients suggests direct oral anticoagulant over- and underdosing is associated with increased risk for adverse events.29 In an apixaban phase 3 trial subanalysis,19 patients with 1 criterion for dose
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reduction (age ≥80 years, weight ≤60 kg, or creatinine ≥1.5 mg/dL) had higher risk of stroke or systemic embolism and major bleeding relative to patients with no criteria for dose reduction during follow-up.30 However, in patients with 1 or no dose reduction criteria, apixaban 5 mg
warfarin.30
Patients with higher renal function (CrCl >80 mL/min)
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Effect of renal function on efficacy and safety of DOACs
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twice daily was associated with similar rates of systemic embolic events or bleeding relative to
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In patients with CrCl ≥80 mL/min, systemic embolic event rates for rivaroxaban (1.6 vs 1.7),27 apixaban (0.82 vs 0.94),31 and dabigatran (0.71 vs 1.05)32 were similar, and slightly numerically lower, compared with warfarin. Rates of systemic embolic events for edoxaban (1.28 vs 0.97)26 were similar, but slightly numerically higher compared to warfarin (Table 1,
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Figure 2). In a retrospective analysis of dabigatran claims data, relative to warfarin, the incidence of thromboembolism for patients with CrCl ≥90 mL/min/1.73m2 was 3.14 (95% confidence interval [CI] 1.11–8.88).33 In a post hoc subanalysis of patients with CrCl >95
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mL/min, once-daily edoxaban 60 mg trended toward lower efficacy for prevention of systemic embolic events relative to warfarin; however, the net clinical outcome was at least as favorable
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as warfarin across renal subgroups.34 Rivaroxaban was noninferior to warfarin for stroke and systemic embolism across the full range of baseline CrCl. However, patients with CrCl >95 mL/min had a numerically, although not significantly, higher rate of stroke or systemic embolic events per 100 patient years relative to warfarin (HR 1.47; 95% CI 0.81–2.68); the interaction was significantly different relative to patients with CrCl ≤95 mL/min, in whom a stroke risk reduction was observed (p = 0.033).35 Bleeding, measured as the composite of major or
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nonmajor clinically relevant bleeding, was similar for rivaroxaban and warfarin and there was no significant treatment interaction.35 There have been no peer-reviewed phase 3 subanalyses of the efficacy or safety of dabigatran or apixaban compared to warfarin in patients with CrCl >95
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mL/min. However, in a US Food and Drug Administration (FDA) statistical analysis, the HR for systemic embolic events for patients with a CrCl ≥80 was calculated as 0.71 for dabigatran, 0.89 for rivaroxaban, and 0.88 for apixaban.36 Interestingly, the HR for first ischemic stroke for these
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patients was 0.84 for dabigatran, 1.07 for rivaroxaban, and 1.35 for apixaban.37 In patients with CrCl ≥80 mL/min, bleeding rates for dabigatran (2.04 vs 2.43),27 apixaban (1.33 vs 1.66),31 and
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edoxaban (2.44 vs 2.85)32 were similar, and slightly numerically lower, compared with warfarin. Bleeding rates for rivaroxaban (3.0 vs 2.4)26 were similar, but slightly numerically higher compared with warfarin (Table 2, Figure 3).
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Patients with CrCl 50 to 80 ml/min (normal to mildly impaired function) In patients with CrCl 50 to 80 mL/min, DOACs are associated with a reduced risk of systemic embolic event (Table 1; Figure 2) and lower bleeding risk (Table 2; Figure 3) relative
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to warfarin.
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Patients with CrCl <50 mL/min
All direct oral anticoagulants reduced systemic embolic event risk to a greater extent than
warfarin in patients with moderate renal impairment (CrCl 30–50 mL/min) in individual trials (Table 1; Figure 2)24-27, 32, 34 and a meta-analysis (relative risk [RR] 0.79, 95% CI 0.66–0.94).38 In patients with moderate renal impairment, major bleeding risk was reduced with apixaban (HR 0.53; 95% CI 0.39–0.71)24, 39 and edoxaban (HR 0.76, 95% CI 0.58–0.98),4 34 relative to
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warfarin, but was similar to warfarin for dabigatran32 or rivaroxaban27 (Table 2; Figure 3). Per a meta-analysis of the pivotal trials, in patients with moderate renal impairment, DOACs were associated with a significant reduction in major bleeding compared with warfarin (RR 0.80, 95%
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CI 0.70–0.91).38 In a retrospective claims analysis, the incidence of systemic embolic events for all patients with eGFR <30–59 mL/min/1.73m2 taking dabigatran was calculated as 0.53 (95% CI 0.27–1.05) compared with warfarin.33
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Efficacy and safety data supporting the use of DOACs in patients with nonvalvular atrial fibrillation with severely impaired renal function or on hemodialysis are limited, thus their use
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has been supported by pharmacokinetic studies.24-27 Dosing recommendations for patients with end-stage renal disease vary among agents (Figure 1).
Based on pharmacokinetic/pharmacodynamics study outcomes, dabigatran doses should be reduced in patients with nonvalvular atrial fibrillation and a CrCl 15 to 30 mL/min and
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rivaroxaban and edoxaban doses reduced with a CrCl 15 to 50 mL/min.25, 27, 4 Apixaban doses should be reduced in patients with reduced renal function, provided body weight and/or age criteria are also met.24 A small phase 3 trial of Japanese patients with nonvalvular atrial
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fibrillation compared short-term safety of 15 mg edoxaban once daily in patients with severe renal impairment (CrCl ≥15–<30 mL/min) with 60 mg (30 mg reduced dose) edoxaban in
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patients with normal or mild renal impairment (CrCl ≥50 mL/min) over a 12-week period.40 In patients with severe renal insufficiency, edoxaban plasma concentrations following 15 mg edoxaban overlapped considerably compared with patients with normal/mild renal impairment receiving 30 or 60 mg edoxaban. No major bleeding episodes or thromboembolic events occurred. Predose plasma edoxaban concentrations in patients with severe renal impairment were significantly higher than in patients with normal or mild renal impairment administered 30 mg
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edoxaban, but similar to patients with normal/mild renal impairment receiving 60 mg edoxaban following 2 weeks of treatment. At 1-to-3 hours and 4-to-8 hours postdose, median plasma edoxaban concentrations in patients with severe renal impairment were similar to those with
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normal/mild renal impairment receiving 30 mg edoxaban, but significantly lower than patients with normal/mild renal impairment receiving 60 mg edoxaban following 2 weeks of treatment. The impact of renal function on apixaban was evaluated in an open-label, parallel-group,
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single-dose study enrolling 32 patients without nonvalvular atrial fibrillation, of whom 8 had normal renal function, 10 had mild renal impairment (CrCl >50–≤80 mL/min), 7 had moderate
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renal impairment (CrCl ≥30–≤50 mL/min), and 7 had severe renal impairment (CrCl <30 mL/min) but were not receiving dialysis.41 Renal impairment did not affect maximal plasma concentrations of apixaban following a single 10-mg dose; however, apixaban exposure increased with increasing renal impairment. A CrCl of 15 mL/min was estimated to result in a
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44% increase in exposure relative to patients with normal renal function. Apixaban activity, as measured by anti-FXa activity, was linearly correlated with apixaban concentration. No deaths or serious adverse events occurred during the study. The limited influence of renal function on
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apixaban pharmacokinetics and pharmacodynamics observed suggests that dose adjustment of apixaban is not required on the basis of renal function alone.
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Studies to date enrolled small numbers of patients and were not designed to evaluate or
measure plasma accumulation with repeated dosing. Additional data establishing the benefit/risk balance of DOACs in this group of patients are warranted.
Patients on hemodialysis
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Apixaban 5 mg twice daily is approved in the US for patients with end-stage renal disease maintained on intermittent hemodialysis. It is unknown whether this dose will lead to reduction of systemic embolic events and bleeding risk in patients with end-stage renal disease
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on dialysis.
A small open-label, single-dose study evaluated apixaban in 8 subjects with end-stage renal disease vs 8 subjects with normal renal function.42 Patients with end-stage renal disease
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were treated with apixaban 5 mg 2 hours prior to hemodialysis. After a 7-day washout, patients again received apixaban 5 mg immediately following hemodialysis. Dosing prior to a 4-hour
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session of hemodialysis increased apixaban clearance by 17% and decreased exposure by 14%, whereas administration of apixaban after hemodialysis produced a 36% increase in exposure relative to participants with normal renal function. Before and after hemodialysis, maximum plasma concentrations were approximately 20% and 10% lower, respectively, in subjects with
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end-stage renal disease compared with subjects with normal renal function. As apixaban exposure in patients with end-stage renal disease maintained on hemodialysis was similar to those with moderate to severe renal impairment, dose adjustment based solely on single-dose
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studies may not be warranted. However, single-dose studies may not reflect accumulation observed over multiple dosing in hemodialysis patients.
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Recently, steady-state exposure from multiple doses of apixaban 2.5 mg and 5.0 mg twice
daily was evaluated in 6 patients with nonvalvular atrial fibrillation and end-stage renal disease on stable hemodialysis. Following 8 days of apixaban 2.5 mg twice daily (phase 1), patients received apixaban 2.5 mg immediately prior to hemodialysis (phase 2); after a 5-day washout period, 5 patients who remained in the study received apixaban 5 mg twice daily for 8 days (phase 3).43 During phase 1, drug accumulation increased 2–5.4 times relative to the single first
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dose. However, steady-state exposure was similar to expected median values in patients indicated for a reduced dose but above the 10th percentile of expected values with full dose (5 mg twice daily) in patients without chronic kidney disease. Only 4% of drug was removed by
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dialysis. During phase 3, drug exposure increased 2–5.7 times relative to the steady state
achieved following 2.5 mg twice daily; mean exposure and trough levels exceeded the 90th
percentile relative to median values reported in patients without chronic kidney disease. The
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apixaban half-life was prolonged in patients with highest peak and exposure levels. One adverse event of minor bleeding was reported in a patient receiving apixaban 5 mg. These results suggest
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that the approved 5-mg twice-daily dose for this patient population can lead to supratherapeutic drug exposure.
An open-label, single-dose study evaluated 15 mg rivaroxaban in 8 patients with endstage renal disease on hemodialysis compared with 8 participants with normal renal function.44
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Rivaroxaban was administered to participants with end-stage renal disease 2 hours before hemodialysis. After a 7-to-14-day washout, rivaroxaban 15 mg was administered 3 hours after hemodialysis. After dialysis, rivaroxaban exposure was increased by 56% relative to subjects
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with normal renal function, whereas administration prior to dialysis decreased exposure 5%, relative to postdialysis exposure. Consistent with plasma levels, activity measured by anti-factor
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Xa inhibition was higher in end-stage renal disease patients than in healthy subjects. Changes in rivaroxaban pharmacokinetics and pharmacodynamics were comparable to patients with moderate to severe renal impairment, supporting use of the 15-mg dose. Rivaroxaban 15 mg once daily is approved for patients with end-stage renal disease maintained on intermittent hemodialysis. While once-daily rivaroxaban results in concentrations and pharmacodynamic
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activity similar to those observed in clinical development, it is unknown whether this dose will lead to comparable efficacy and safety results. In an open label study of 10 patients with end-stage renal disease, the effect of
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hemodialysis on exposure was evaluated following administration of a single oral edoxaban dose.45 Edoxaban exposures and total clearance were comparable when administered prior to a 4hour hemodialysis session or when administered off-dialysis (between sessions). This suggests
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hemodialysis minimally affects edoxaban clearance (less than 7%).26, 45 Again, however, this study included a small number of patients and did not evaluate drug accumulation with repeated
In patients with worsening renal function
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dosing over time, warranting additional data establishing risk and benefit.
Renal function declines over time.31, 46, 47 In the dabigatran trial, after an average of 30
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months, mean decline in eGFR (CKD-EPI) was significantly greater with warfarin than with dabigatran 150 mg twice daily (−3.68 vs −2.46 mL/min; P = 0.0002).46 Warfarin-treated patients had a larger decline in renal function relative to those treated with rivaroxaban (−4.3 vs −3.5
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mL/min; P <0.001).47 This highlights the need for monitoring of renal function at regular intervals, with appropriate dosage modifications as needed.
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Direct oral anticoagulants may have a better renal risk-benefit profile than warfarin in
patients with declining renal function, defined as >20% decrease in CrCl based on C-G.31, 47 In ROCKET AF, 26.3% of the analysis population experienced a ≥20% CrCl decline.47 Among patients with declining renal function over time, patients randomized to rivaroxaban had a lower rate of systemic embolic events relative to warfarin (HR 0.50; P = 0.05).47 However, this effect was not observed in those with stable renal function (HR 0.97). There was no difference between
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rivaroxaban and warfarin in the rate of major or nonmajor clinically relevant bleeding regardless of stability of renal function. In the apixaban trial, 13.6% of enrolled patients had ≥20% decline in CrCl.31 Apixaban was associated with a lower relative risk of systemic embolic events (HR
warfarin in patients with declining renal function over time.31
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Conclusion
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0.80; 95% CI, 0.51–1.24) and major bleeding (HR, 0.76; 95% CI, 0.54–1.07) compared with
Patients with renal impairment are at increased risk for thromboembolic and bleeding
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events, a risk that increases over time. In patients with nonvalvular atrial fibrillation with mild or moderate renal impairment, direct oral anticoagulants were associated with reduced risk of systemic embolic events and similar risk of major bleeding relative to warfarin. Less data supports the use of DOACs in patients with severe renal impairment or on hemodialysis. While
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there are FDA-approved dose recommendations for rivaroxaban and apixaban use in hemodialysis, these agents have not been adequately studied in chronic kidney disease. They, along with dabigatran and edoxaban, should be avoided whenever possible, despite labeling.
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Others have highlighted these concerns in “real world” populations.48 Edoxaban use is not approved for use in patients with CrCl ≥95 mL/min in the US.
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The direct oral anticoagulants may confer a better renal risk-benefit profile than warfarin
in those with declining renal function over time. Following dosing recommendations as calculated by C-G, utilizing actual body weight, is critical for avoiding improper dosing of patients. Additional assessments may be warranted to further assess use of DOACs in patients with very high or low renal function.
Acknowledgements 14
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Writing and editorial support was provided by Terri Schochet, PhD, of AlphaBioCom, LLC, and
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funded by Daiichi Sankyo.
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dose-reduced direct oral anticoagulant therapy. Am J Med. 2016;129:1198-1204. Steinberg BA, Shrader P, Thomas L, et al. Off-label dosing of non-vitamin K antagonist oral anticoagulants and adverse outcomes: The ORBIT-AF II Registry. J Am Coll Cardiol. 2016;68:2597-2604.
Alexander JH, Andersson U, Lopes RD, et al. Apixaban 5 mg twice daily and clinical
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30.
outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine: A secondary analysis of a randomized clinical trial. JAMA Cardiol.
31.
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2016;1:673-681.
Hijazi Z, Hohnloser SH, Andersson U, et al. Efficacy and safety of apixaban compared
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with warfarin in patients with atrial fibrillation in relation to renal function over time: Insights from the ARISTOTLE randomized clinical trial. JAMA Cardiol. 2016;1:451-
460.
32.
Hijazi Z, Hohnloser SH, Oldgren J, et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a
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RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation. 2014;129:961-970. 33.
Del-Carpio Munoz F, Yao X, Abraham NS, et al. Dabigatran versus warfarin in relation
34.
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to renal function in patients with atrial fibrillation. J Am Coll Cardiol. 2016;68:129-131. Bohula EA, Giugliano RP, Ruff CT, et al. Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 Trial. Circulation. 2016;134:24-36.
Lindner SM, Fordyce CB, Hellkamp AS, et al. Treatment Consistency Across Levels of
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35.
Baseline Renal Function With Rivaroxaban or Warfarin: A ROCKET AF (Rivaroxaban
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Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) Analysis. Circulation. 2017;135:1001-1003. 36.
US Food and Drug Administration. SAVAYSA (edoxaban) Tablets. FDA Draft Briefing
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Document for the Cardiovascular and Renal Drugs Advisory Committee. NDA 206316. Meeting date October 30, 2014. Available at: www.fda.gov/downloads/AdvisoryCommittees/.../Drugs/.../UCM420704.pdf. Accessed
US Food and Drug Administration. SAVAYSA (edoxaban) Tablets. Statistical Considerations for the Cardiovascular and Renal Drugs Advisory Committee. NDA
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37.
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2/27/17. 2014.
206316. Meeting date October 30, 2014. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drug s/CardiovascularandRenalDrugsAdvisoryCommittee/UCM421612.pdf. Accessed 2/27/17. 2014.
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38.
Del-Carpio Munoz F, Gharacholou SM, Munger TM, et al. Meta-analysis of renal function on the safety and efficacy of novel oral anticoagulants for atrial fibrillation. Am J Cardiol. 2016;117:69-75. Hohnloser SH, Hijazi Z, Thomas L, et al. Efficacy of apixaban when compared with
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39.
warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. 2012;33:2821-2830.
Koretsune Y, Yamashita T, Kimura T, Fukuzawa M, Abe K, Yasaka M. Short-term
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40.
safety and plasma concentrations of edoxaban in japanese patients with non-valvular
41.
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atrial fibrillation and severe renal impairment. Circ J. 2015;79:1486-1495. Chang M, Yu Z, Shenker A, et al. Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban. J Clin Pharmacol. 2016;56:637-645. 42.
Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, pharmacodynamics, and
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safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol. 2016;56:628-636. 43.
Mavrakanas TA, Samer CF, Nessim SJ, Frisch G, Lipman ML. Apixaban
44.
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Pharmacokinetics at Steady State in Hemodialysis Patients. J Am Soc Nephrol. 2017. Dias C, Moore KT, Murphy J, et al. Pharmacokinetics, pharmacodynamics, and safety of
45.
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single-dose rivaroxaban in chronic hemodialysis. Am J Nephrol. 2016;43:229-236. Parasrampuria DA, Marbury T, Matsushima N, et al. Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis.
Thromb Haemost. 2015;113:719-727.
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46.
Bohm M, Ezekowitz MD, Connolly SJ, et al. Changes in renal function in patients with atrial fibrillation: An analysis from the RE-LY Trial. J Am Coll Cardiol. 2015;65:24812493. Fordyce CB, Hellkamp AS, Lokhnygina Y, et al. On-Treatment Outcomes in Patients
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47.
With Worsening Renal Function With Rivaroxaban Compared With Warfarin: Insights From ROCKET AF. Circulation. 2016;134:37-47.
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Chan KE, Edelman ER, Wenger JB, Thadhani RI, Maddux FW. Dabigatran and
rivaroxaban use in atrial fibrillation patients on hemodialysis. Circulation. 2015;131:972-
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979.
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48.
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Figure Legends Figure 1: Dosing recommendations in the US based on kidney function measured by creatinine
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clearance, as per prescribing information.24-27 BID, twice daily; CrCl, creatinine clearance; QD, once daily; SCr, serum creatinine. aNot recommended for patients with CrCl <30 mL/min taking concomitant P-gp inhibitors; the dose should be reduced or avoided in patients with CrCl 30–50
c
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mL/min who use concomitant P-gp inhibitors. bShould be taken with the evening meal.
Apixaban should be reduced to a dose of 2.5 mg BID in patients for whom 2 of the following
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apply: serum creatinine >1.5 mg/dL, age ≥80 years old, body weight ≤60 kg; apixaban may be administered to patients on hemodialysis at a dose of 5 mg unless dose administration is warranted based on reduction criteria. dLabeling suggests rivaroxaban may be administered to patients on hemodialysis at a dose of 15 mg unless dose administration is warranted based on
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reduction criteria; however, as it has not been adequately studied in a large scale clinical trial, use in this population should be avoided whenever possible. eLabeling suggests apixaban may be administered to patients on hemodialysis at a dose of 5 mg unless dose administration is
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warranted based on reduction criteria; however, as it has not been adequately studied in a large scale clinical trial, use in this population should be avoided whenever possible.
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Figure 2: Rates of stroke or systemic embolism relative to warfarin for the DOACs stratified by renal function calculated by Cockroft-Gault.24, 26, 27, 32, 39 aFor CrCl 30–50 mL/min. CrCl, creatinine clearance; DOAC, direct oral anticoagulant. Figure 3: Rates of major bleeding relative to warfarin for the DOACs stratified by renal function calculated by Cockroft-Gault.24, 26, 27, 32, 34, 39 aFor CrCl 30–50 mL/min. CrCl, creatinine clearance; DOAC, direct oral anticoagulant.
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Table 1. Hazard ratios for rates of stroke or systemic embolism relative to warfarin for the DOACs stratified by renal function
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calculated by Cockroft-Gaulta2-4, 36, 38, 43
150-mg dose.
c
eGFR >50–≤80 mL/min.
d
e
eGFR≥30–≤50 mL/min.
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b
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range provided.
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CrCl >80 CrCl >50–95 CrCl >50–80 CrCl 30–50 mL/min mL/min mL/min mL/min % of HR % of HR % of HR % of HR total (95% CI) total (95% CI) total (95% CI) total (95% CI) enrolled enrolled enrolled enrolled in trial in trial in trial in trial Dabigatran36b 31.2 0.69 NR NR 18.5 0.48 45.8 0.65 c (0.43, 1.12) (0.31, 0.76)d (0.47, 0.88) 2e Rivaroxaban 22.0 0.93 NR NR 31.4 0.81 45.1 0.90 (0.67, 1.31) (0.60, 1.10) (0.70, 1.14) NR 0.79 Apixabanf 26.0g 0.87 NR 0.70 48.1g 0.78 g g g (0.61, 1.02) (0.60, 1.26) (0.48, 1.03)g (0.58, 1.04) Edoxaban4, 38h 37 1.33 58.3 0.78 19.5 0.87 43 0.68 (0.97, 1.81) (0.64, 0.96) (0.65, 1.18) (0.54, 0.86) a Comparisons should not be made across drugs within CrCl ranges; HR presented are for each DOAC vs warfarin within the CrCl
20 mg daily or 15 mg daily in patients with a CrCl of 15–50 mL/min once daily with the evening meal.
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f
5 mg twice daily or 2.5 mg twice daily for a subset of patients with 2 or more of the following criteria: age ≥80 years, body weight
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≤60 kg, serum creatinine ≥1.5 mg/dL. g
In patients with stable renal function over time.
h
60 mg daily or a 50% dose reduction to 30 mg daily for CrCl 30–50 mL/min, body weight of ≤60 kg, or use of a potent P-gp
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inhibitor.
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hazard ratio; NR, not reported; P-gp, P-glycoprotein.
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CI, confidence interval; CrCl, creatinine clearance; DOAC, direct oral anticoagulant; eGFR, estimated glomerular filtration rate; HR,
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Table 2. Hazard ratios for rates of major bleeding for the DOACs relative to warfarin stratified by renal function calculated by
Dabigatran36b
% of total enrolled in trial 31.3
HR (95% CI)
CrCl >50–95 mL/min
CrCl >50–80 mL/min
% of total enrolled in trial NR
% of total enrolled in trial 45.8
HR (95% CI)
HR (95% CI)
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CrCl >80 mL/min
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Cockroft-Gaulta2-4, 36, 38, 43 CrCl 30–50 mL/min
% of total enrolled in trial 18.4
HR (95% CI)
150-mg dose.
c
eGFR 50–<80 mL/min.
d
e
eGFR ≥30–≤50 mL/min.
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b
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range provided.
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0.90 NR 1.02 0.92 c (0.65, 1.25) (0.77, 1.34)d (0.75, 1.14) 2e Rivaroxaban 31.7 1.26 NR NR 22.4 1.03 45.7 0.94 (0.95, 1.67) (0.79, 1.35) (0.76, 1.15) Apixabanf3, 43 26.0g 0.80 NR 0.74 15.0 0.53 48.1g 0.76 g g g (0.60, 1.07) (0.61, 0.94) (0.39, 0.71) (0.62, 0.94) 4, 38h Edoxaban 37 0.86 58.3 0.89 19.5 0.76 43 0.88 (0.60, 1.22)i (0.75, 1.04) (0.58, 0.98) (0.73, 1.07) a Comparisons should not be made across drugs within CrCl ranges; HR presented are for each DOAC vs warfarin within the CrCl
20 mg daily or 15 mg daily in patients with a CrCl of 15–50 mL/min once daily with the evening meal.
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f
5 mg twice daily or 2.5 mg twice daily for a subset of patients with 2 or more of the following criteria: age ≥80 years, body weight
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≤60 kg, serum creatinine ≥1.5 mg/dL. g
In patients with stable renal function over time.
h
60 mg daily or a 50% dose reduction to 30 mg daily for CrCl 30–50 mL/min, body weight of ≤60 kg, or use of a potent P-gp
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inhibitor. i
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CrCl>80–95.
CI, confidence interval; CrCl, creatinine clearance; DOAC, direct oral anticoagulant; eGFR, estimated glomerular filtration rate; HR,
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hazard ratio; NR, not reported; P-gp, P-glycoprotein.
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Edoxaban
CrCl
CrCl mL/min
Rivaroxabanb
Dose
mL/min
CrCl Dose
>50–≤95
150 mg BID
75 mg BID
15 mg QD
50–15
2 of 3: 30 mg QD
<15
SCr >1.5 mg/dL Weight <60 kg
Avoid Use <15
Avoid Use Hemodialysis 15 mg
QDd
≥80 y 2.5 mg BID
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<15
5 mg BID
60 mg QD
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30–15
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50–15
Dose
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20 mg QD
Metric
Avoid Use
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>30
Dose
mL/min
>95
>50
Apixabanc
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Dabigatrana
Avoid Use
Hemodialysis
5 mg BIDe
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CrCl ≥80 mL/min
3 2
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% / year
4
1 n = 28 n = 41 Dabigatran
n = 65 n = 68 Rivaroxaban
n = 53 n = 61 Apixaban
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0
n = 92 n = 70 Edoxaban
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CrCl 50–<80 mL/min 3
1
% / year
4 3 2
n = 70 n = 103 Dabigatran
n = 125 n = 141
Rivaroxaban
n = 77 n = 98 Apixaban
n = 122 n = 176 Edoxaban
CrCl <50 mL/min
DOAC
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0
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2
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% / year
4
Warfarin
1 0
n = 36 n = 57 Dabigatran
n = 78 n = 96 Rivaroxabana
n = 45 n = 61 Apixaban
n = 82 n = 91 Edoxabana
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% / year
6 5 4 3 2 1 0
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n = 112 n = 89 Rivaroxaban
n = 83 n = 103 Apixaban
n = 57 n = 70 Edoxaban
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n = 81 n = 95 Dabigatran
n = 188 n = 209 Dabigatran
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CrCl 50–<80 mL/min
n = 176 n = 191 Rivaroxaban
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% / year
6 5 4 3 2 1 0
CrCl ≥80 mL/min
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% / year
6 5 4 3 2 1 0
n = 129 n = 116 Dabigatran
n = 136 n = 176 Apixaban
n = 136 n = 176 Edoxaban
CrCl <50 mL/min
n = 106 n =106 Rivaroxaban a
DOAC Warfarin
n = 82 n = 130 Apixaban
n = 100 n = 132 Edoxabana
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•
Dependence on renal elimination varies among direct oral anticoagulants; renal function may affect systemic drug exposure, efficacy and safety.
weight, is critical for optimizing patient outcomes.
In patients with NVAF with mild or moderate renal impairment, direct oral
anticoagulants were associated with a reduced risk of stroke/SEE and similar risk of
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major bleeding relative to warfarin.
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•
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Appropriate dosing by renal function, calculated by Cockcroft-Gault using actual body
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•
S0002-9343(17)30481-3
DOI:
10.1016/j.amjmed.2017.04.015
Reference:
AJM 14073
To appear in:
The American Journal of Medicine
Received Date: 2 March 2017 Revised Date:
14 April 2017
Accepted Date: 18 April 2017
Please cite this article as: Fanikos J, Burnett AE, Mahan CE, Dobesh PP, Renal function considerations for stroke prevention in atrial fibrillation, The American Journal of Medicine (2017), doi: 10.1016/ j.amjmed.2017.04.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Renal function considerations for stroke prevention in atrial fibrillation
John Fanikos, RPh, MBA1; Allison E. Burnett, PharmD2; Charles E. Mahan, PharmD3; Paul P.
1
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Dobesh, PharmD3
Department of Pharmacy, Brigham and Women’s Hospital, Boston, MA; 2Department of
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Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM; 3College of Pharmacy, University of New Mexico Health Sciences Center, Presbyterian Healthcare Services,
Corresponding author: John Fanikos
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Department of Pharmacy Services
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Albuquerque, NM; 4College of Pharmacy, University of Nebraska Medical Center, Omaha, NE
Brigham and Women's Hospital 75 Francis Street
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Boston, MA, 02115, USA Phone: (617) 605-3237
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Email: [email protected]
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Funding sources: Funding for writing and editorial support was provided by Daiichi Sankyo. Conflict of interest: Charles Mahan has served as a consultant for Portola, Point of Care Software Solutions, Daiichi-Sankyo, Sanofi-Aventis, Boehringer Ingelheim, Johnson and
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Johnson, Polymedix Inc., LEO Pharma, and Eisai; and served as a speaker for Janssen, Bristol Myers Squibb, Pfizer, Sanofi-Aventis, Portola, and Boehringer Ingelheim. John Fanikos has served as a consultant for Boehringer Ingelheim and Portola. Allison Burnett has nothing to
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disclose. Paul Dobesh has served as a consultant for Janssen, Daiichi-Sankyo, Pfizer, Bristol-
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Myers Squibb, and Boehringer Ingelheim.
All authors were involved in writing the manuscript, had full control of content, and have seen and approved the submitted version.
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Running head: Renal function considerations for treatment in atrial fibrillation Keywords: Direct oral anticoagulants, atrial fibrillation
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Paper type: Review
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Abstract Renal impairment increases risk of stroke and systemic embolic events and bleeding in
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patients with atrial fibrillation. Direct oral anticoagulants have varied dependence on renal
elimination, magnifying the importance of appropriate patient selection, dosing, and periodic kidney function monitoring. In randomized controlled trials of nonvalvular atrial fibrillation,
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direct oral anticoagulants were at least as effective and associated with less bleeding compared with warfarin. Each direct oral anticoagulant was associated with reduced risk of stroke and
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systemic embolic events and major bleeding compared with warfarin in nonvalvular atrial fibrillation patients with mild or moderate renal impairment. Renal function decline appears less impacted by direct oral anticoagulants, which are associated with a better risk-benefit profile than warfarin in patients with declining renal function over time. Limited data address the risk-
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benefit profile of direct oral anticoagulants in patients with severe impairment or on dialysis.
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Atrial fibrillation and renal impairment Renal impairment is common in atrial fibrillation patients. In large registries, meta-
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analyses, and observational studies, roughly one-third of atrial fibrillation patients have mild to moderate renal dysfunction (estimated glomerular filtration rate [eGFR] 30–89 mL/min) or
chronic kidney disease,1-4 and up to 3% have severe renal dysfunction (eGFR <30 mL/min).5, 6 A
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recent European registry analysis reported up to 60% of atrial fibrillation patients have mild to moderate renal dysfunction (eGFR 30–79 mL/min) and up to 4% have severe renal impairment
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(eGFR <30 ml/min).7
Patients with atrial fibrillation and renal dysfunction are at increased risk of systemic embolic events (hazard ratio [HR] 1.49; P <0.001) and bleeding (HR 2.24; P <0.001) relative to those without chronic kidney disease.6 Relative stroke risk increases 7% with every 10
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mL/min/1.73 m2 decline in eGFR.8 An eGFR <60 mL/min/1.73 m2 is associated with a 43% higher risk of incident stroke.9 Proteinuria and reduced eGFR are associated with higher rates of thromboembolism in patients with nonvalvular atrial fibrillation, independent of other stroke risk
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factors.3 In the National Health and Nutrition Examination Survey, patients with chronic kidney disease had additional stroke risk factors including diabetes (40.4%), hypertension (31.0%), and
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cardiovascular disease (39.5%).10 Additionally, chronic kidney disease patients with atrial fibrillation are 67% more likely to progress to end-stage renal disease than those without atrial fibrillation.11
Finally, survival rates are reduced in patients with atrial fibrillation and renal disease.6, 12
Patients with chronic kidney disease have a higher risk of death from any cause (HR 2.37; P <0.001) and myocardial infarction (HR 2.00; P <0.001) than those without chronic kidney
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disease.6 Survival after incident atrial fibrillation decreases progressively with decreasing renal function (P <0.0001).12 Disruptions in platelet function and platelet-vessel wall interactions in
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patients with renal impairment may result in increased bleeding.
Assessment of renal function in clinical trials
Renal function can be estimated with the Modification of Diet in Renal Disease
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(MDRD)13 or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations,14 which provide eGFR, or the Cockcroft-Gault15 (C-G) equation, which estimates creatinine
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clearance (CrCl). While C-G using actual body weight may not be the best method for calculating renal function, it was used in all phase 3 direct oral anticoagulant trials. 13, 14, 16-20 Renal function cutoffs varied between trials, with a calculated CrCl of ≤30 mL/min for dabigatran, <30 mL/min for edoxaban and rivaroxaban, and serum creatinine >2.5 mg/dL or a
dysfunction.
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calculated CrCl of <25 mL/min for apixaban.17-20 All trials excluded patients with severe renal
Patient populations enrolled in these phase 3 nonvalvular atrial fibrillation studies also
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differed in risk for cardiac dysfunction, stroke, inclusion of patients with atrial flutter, and in timing of documentation of atrial fibrillation.21 The rivaroxaban and edoxaban trials included a
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larger percentage of patients with diabetes mellitus (40% and 36%, respectively) relative to those for dabigatran (23%) and apixaban (25%), which increases patient risk for bleeding and thrombosis, as well as a larger percentage of patients with heart failure (63% and 57% for rivaroxaban and edoxaban, respectively) relative to dabigatran (32%) and apixaban (35%).22 Mean patient CHADS2 (congestive heart failure, hypertension, age = 75 years, diabetes mellitus,
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stroke [doubled]) scores were highest in the rivaroxaban trial (3.5), followed by edoxaban (2.8), and the apixaban and dabigatran trials (2.1).22 Clinical trial calculations of CrCl were based on C-G and employed actual body weight;
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therefore, use of other equations may result in incorrect DOAC dosing. A large database study demonstrated renal function estimations other than C-G would result in a failure to reduce
rivaroxaban or edoxaban doses in 28% of patients, and 18% to 21% of doses among dabigatran
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patients.23 Additionally, apixaban dosing adjustments are based on serum creatinine, body
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weight, and age (components of CrCl) rather than CrCl directly.24
Direct oral anticoagulants in atrial fibrillation and renal impairment All direct oral anticoagulants undergo some degree of renal clearance with 80%, 50%, 36%, and 27% (ie, unchanged drug) of the absorbed doses of dabigatran, edoxaban, rivaroxaban,
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and apixaban, respectively, excreted in urine.24-27 As impaired renal function decreases drug clearance, prolongs half-life, and increases total exposure, it is important to follow dosing recommendations based on level of renal function (Figure 1).24-27
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Despite label recommendations, inappropriately reduced doses of direct oral anticoagulants are commonly prescribed in patients with mild-to-moderate renal dysfunction, a
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past medical history of bleeding events, and concomitant use of medications that increase bleeding risk.28 In a retrospective patient record review, approximately 60% of patients received a DOAC dose below manufacturer recommendations.28 Improper dose reduction may increase thrombotic risk, resulting in preventable strokes. A recent analysis of atrial fibrillation patients suggests direct oral anticoagulant over- and underdosing is associated with increased risk for adverse events.29 In an apixaban phase 3 trial subanalysis,19 patients with 1 criterion for dose
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reduction (age ≥80 years, weight ≤60 kg, or creatinine ≥1.5 mg/dL) had higher risk of stroke or systemic embolism and major bleeding relative to patients with no criteria for dose reduction during follow-up.30 However, in patients with 1 or no dose reduction criteria, apixaban 5 mg
warfarin.30
Patients with higher renal function (CrCl >80 mL/min)
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Effect of renal function on efficacy and safety of DOACs
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twice daily was associated with similar rates of systemic embolic events or bleeding relative to
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In patients with CrCl ≥80 mL/min, systemic embolic event rates for rivaroxaban (1.6 vs 1.7),27 apixaban (0.82 vs 0.94),31 and dabigatran (0.71 vs 1.05)32 were similar, and slightly numerically lower, compared with warfarin. Rates of systemic embolic events for edoxaban (1.28 vs 0.97)26 were similar, but slightly numerically higher compared to warfarin (Table 1,
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Figure 2). In a retrospective analysis of dabigatran claims data, relative to warfarin, the incidence of thromboembolism for patients with CrCl ≥90 mL/min/1.73m2 was 3.14 (95% confidence interval [CI] 1.11–8.88).33 In a post hoc subanalysis of patients with CrCl >95
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mL/min, once-daily edoxaban 60 mg trended toward lower efficacy for prevention of systemic embolic events relative to warfarin; however, the net clinical outcome was at least as favorable
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as warfarin across renal subgroups.34 Rivaroxaban was noninferior to warfarin for stroke and systemic embolism across the full range of baseline CrCl. However, patients with CrCl >95 mL/min had a numerically, although not significantly, higher rate of stroke or systemic embolic events per 100 patient years relative to warfarin (HR 1.47; 95% CI 0.81–2.68); the interaction was significantly different relative to patients with CrCl ≤95 mL/min, in whom a stroke risk reduction was observed (p = 0.033).35 Bleeding, measured as the composite of major or
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nonmajor clinically relevant bleeding, was similar for rivaroxaban and warfarin and there was no significant treatment interaction.35 There have been no peer-reviewed phase 3 subanalyses of the efficacy or safety of dabigatran or apixaban compared to warfarin in patients with CrCl >95
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mL/min. However, in a US Food and Drug Administration (FDA) statistical analysis, the HR for systemic embolic events for patients with a CrCl ≥80 was calculated as 0.71 for dabigatran, 0.89 for rivaroxaban, and 0.88 for apixaban.36 Interestingly, the HR for first ischemic stroke for these
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patients was 0.84 for dabigatran, 1.07 for rivaroxaban, and 1.35 for apixaban.37 In patients with CrCl ≥80 mL/min, bleeding rates for dabigatran (2.04 vs 2.43),27 apixaban (1.33 vs 1.66),31 and
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edoxaban (2.44 vs 2.85)32 were similar, and slightly numerically lower, compared with warfarin. Bleeding rates for rivaroxaban (3.0 vs 2.4)26 were similar, but slightly numerically higher compared with warfarin (Table 2, Figure 3).
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Patients with CrCl 50 to 80 ml/min (normal to mildly impaired function) In patients with CrCl 50 to 80 mL/min, DOACs are associated with a reduced risk of systemic embolic event (Table 1; Figure 2) and lower bleeding risk (Table 2; Figure 3) relative
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to warfarin.
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Patients with CrCl <50 mL/min
All direct oral anticoagulants reduced systemic embolic event risk to a greater extent than
warfarin in patients with moderate renal impairment (CrCl 30–50 mL/min) in individual trials (Table 1; Figure 2)24-27, 32, 34 and a meta-analysis (relative risk [RR] 0.79, 95% CI 0.66–0.94).38 In patients with moderate renal impairment, major bleeding risk was reduced with apixaban (HR 0.53; 95% CI 0.39–0.71)24, 39 and edoxaban (HR 0.76, 95% CI 0.58–0.98),4 34 relative to
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warfarin, but was similar to warfarin for dabigatran32 or rivaroxaban27 (Table 2; Figure 3). Per a meta-analysis of the pivotal trials, in patients with moderate renal impairment, DOACs were associated with a significant reduction in major bleeding compared with warfarin (RR 0.80, 95%
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CI 0.70–0.91).38 In a retrospective claims analysis, the incidence of systemic embolic events for all patients with eGFR <30–59 mL/min/1.73m2 taking dabigatran was calculated as 0.53 (95% CI 0.27–1.05) compared with warfarin.33
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Efficacy and safety data supporting the use of DOACs in patients with nonvalvular atrial fibrillation with severely impaired renal function or on hemodialysis are limited, thus their use
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has been supported by pharmacokinetic studies.24-27 Dosing recommendations for patients with end-stage renal disease vary among agents (Figure 1).
Based on pharmacokinetic/pharmacodynamics study outcomes, dabigatran doses should be reduced in patients with nonvalvular atrial fibrillation and a CrCl 15 to 30 mL/min and
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rivaroxaban and edoxaban doses reduced with a CrCl 15 to 50 mL/min.25, 27, 4 Apixaban doses should be reduced in patients with reduced renal function, provided body weight and/or age criteria are also met.24 A small phase 3 trial of Japanese patients with nonvalvular atrial
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fibrillation compared short-term safety of 15 mg edoxaban once daily in patients with severe renal impairment (CrCl ≥15–<30 mL/min) with 60 mg (30 mg reduced dose) edoxaban in
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patients with normal or mild renal impairment (CrCl ≥50 mL/min) over a 12-week period.40 In patients with severe renal insufficiency, edoxaban plasma concentrations following 15 mg edoxaban overlapped considerably compared with patients with normal/mild renal impairment receiving 30 or 60 mg edoxaban. No major bleeding episodes or thromboembolic events occurred. Predose plasma edoxaban concentrations in patients with severe renal impairment were significantly higher than in patients with normal or mild renal impairment administered 30 mg
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edoxaban, but similar to patients with normal/mild renal impairment receiving 60 mg edoxaban following 2 weeks of treatment. At 1-to-3 hours and 4-to-8 hours postdose, median plasma edoxaban concentrations in patients with severe renal impairment were similar to those with
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normal/mild renal impairment receiving 30 mg edoxaban, but significantly lower than patients with normal/mild renal impairment receiving 60 mg edoxaban following 2 weeks of treatment. The impact of renal function on apixaban was evaluated in an open-label, parallel-group,
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single-dose study enrolling 32 patients without nonvalvular atrial fibrillation, of whom 8 had normal renal function, 10 had mild renal impairment (CrCl >50–≤80 mL/min), 7 had moderate
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renal impairment (CrCl ≥30–≤50 mL/min), and 7 had severe renal impairment (CrCl <30 mL/min) but were not receiving dialysis.41 Renal impairment did not affect maximal plasma concentrations of apixaban following a single 10-mg dose; however, apixaban exposure increased with increasing renal impairment. A CrCl of 15 mL/min was estimated to result in a
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44% increase in exposure relative to patients with normal renal function. Apixaban activity, as measured by anti-FXa activity, was linearly correlated with apixaban concentration. No deaths or serious adverse events occurred during the study. The limited influence of renal function on
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apixaban pharmacokinetics and pharmacodynamics observed suggests that dose adjustment of apixaban is not required on the basis of renal function alone.
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Studies to date enrolled small numbers of patients and were not designed to evaluate or
measure plasma accumulation with repeated dosing. Additional data establishing the benefit/risk balance of DOACs in this group of patients are warranted.
Patients on hemodialysis
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Apixaban 5 mg twice daily is approved in the US for patients with end-stage renal disease maintained on intermittent hemodialysis. It is unknown whether this dose will lead to reduction of systemic embolic events and bleeding risk in patients with end-stage renal disease
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on dialysis.
A small open-label, single-dose study evaluated apixaban in 8 subjects with end-stage renal disease vs 8 subjects with normal renal function.42 Patients with end-stage renal disease
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were treated with apixaban 5 mg 2 hours prior to hemodialysis. After a 7-day washout, patients again received apixaban 5 mg immediately following hemodialysis. Dosing prior to a 4-hour
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session of hemodialysis increased apixaban clearance by 17% and decreased exposure by 14%, whereas administration of apixaban after hemodialysis produced a 36% increase in exposure relative to participants with normal renal function. Before and after hemodialysis, maximum plasma concentrations were approximately 20% and 10% lower, respectively, in subjects with
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end-stage renal disease compared with subjects with normal renal function. As apixaban exposure in patients with end-stage renal disease maintained on hemodialysis was similar to those with moderate to severe renal impairment, dose adjustment based solely on single-dose
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studies may not be warranted. However, single-dose studies may not reflect accumulation observed over multiple dosing in hemodialysis patients.
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Recently, steady-state exposure from multiple doses of apixaban 2.5 mg and 5.0 mg twice
daily was evaluated in 6 patients with nonvalvular atrial fibrillation and end-stage renal disease on stable hemodialysis. Following 8 days of apixaban 2.5 mg twice daily (phase 1), patients received apixaban 2.5 mg immediately prior to hemodialysis (phase 2); after a 5-day washout period, 5 patients who remained in the study received apixaban 5 mg twice daily for 8 days (phase 3).43 During phase 1, drug accumulation increased 2–5.4 times relative to the single first
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dose. However, steady-state exposure was similar to expected median values in patients indicated for a reduced dose but above the 10th percentile of expected values with full dose (5 mg twice daily) in patients without chronic kidney disease. Only 4% of drug was removed by
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dialysis. During phase 3, drug exposure increased 2–5.7 times relative to the steady state
achieved following 2.5 mg twice daily; mean exposure and trough levels exceeded the 90th
percentile relative to median values reported in patients without chronic kidney disease. The
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apixaban half-life was prolonged in patients with highest peak and exposure levels. One adverse event of minor bleeding was reported in a patient receiving apixaban 5 mg. These results suggest
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that the approved 5-mg twice-daily dose for this patient population can lead to supratherapeutic drug exposure.
An open-label, single-dose study evaluated 15 mg rivaroxaban in 8 patients with endstage renal disease on hemodialysis compared with 8 participants with normal renal function.44
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Rivaroxaban was administered to participants with end-stage renal disease 2 hours before hemodialysis. After a 7-to-14-day washout, rivaroxaban 15 mg was administered 3 hours after hemodialysis. After dialysis, rivaroxaban exposure was increased by 56% relative to subjects
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with normal renal function, whereas administration prior to dialysis decreased exposure 5%, relative to postdialysis exposure. Consistent with plasma levels, activity measured by anti-factor
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Xa inhibition was higher in end-stage renal disease patients than in healthy subjects. Changes in rivaroxaban pharmacokinetics and pharmacodynamics were comparable to patients with moderate to severe renal impairment, supporting use of the 15-mg dose. Rivaroxaban 15 mg once daily is approved for patients with end-stage renal disease maintained on intermittent hemodialysis. While once-daily rivaroxaban results in concentrations and pharmacodynamic
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activity similar to those observed in clinical development, it is unknown whether this dose will lead to comparable efficacy and safety results. In an open label study of 10 patients with end-stage renal disease, the effect of
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hemodialysis on exposure was evaluated following administration of a single oral edoxaban dose.45 Edoxaban exposures and total clearance were comparable when administered prior to a 4hour hemodialysis session or when administered off-dialysis (between sessions). This suggests
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hemodialysis minimally affects edoxaban clearance (less than 7%).26, 45 Again, however, this study included a small number of patients and did not evaluate drug accumulation with repeated
In patients with worsening renal function
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dosing over time, warranting additional data establishing risk and benefit.
Renal function declines over time.31, 46, 47 In the dabigatran trial, after an average of 30
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months, mean decline in eGFR (CKD-EPI) was significantly greater with warfarin than with dabigatran 150 mg twice daily (−3.68 vs −2.46 mL/min; P = 0.0002).46 Warfarin-treated patients had a larger decline in renal function relative to those treated with rivaroxaban (−4.3 vs −3.5
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mL/min; P <0.001).47 This highlights the need for monitoring of renal function at regular intervals, with appropriate dosage modifications as needed.
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Direct oral anticoagulants may have a better renal risk-benefit profile than warfarin in
patients with declining renal function, defined as >20% decrease in CrCl based on C-G.31, 47 In ROCKET AF, 26.3% of the analysis population experienced a ≥20% CrCl decline.47 Among patients with declining renal function over time, patients randomized to rivaroxaban had a lower rate of systemic embolic events relative to warfarin (HR 0.50; P = 0.05).47 However, this effect was not observed in those with stable renal function (HR 0.97). There was no difference between
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rivaroxaban and warfarin in the rate of major or nonmajor clinically relevant bleeding regardless of stability of renal function. In the apixaban trial, 13.6% of enrolled patients had ≥20% decline in CrCl.31 Apixaban was associated with a lower relative risk of systemic embolic events (HR
warfarin in patients with declining renal function over time.31
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Conclusion
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0.80; 95% CI, 0.51–1.24) and major bleeding (HR, 0.76; 95% CI, 0.54–1.07) compared with
Patients with renal impairment are at increased risk for thromboembolic and bleeding
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events, a risk that increases over time. In patients with nonvalvular atrial fibrillation with mild or moderate renal impairment, direct oral anticoagulants were associated with reduced risk of systemic embolic events and similar risk of major bleeding relative to warfarin. Less data supports the use of DOACs in patients with severe renal impairment or on hemodialysis. While
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there are FDA-approved dose recommendations for rivaroxaban and apixaban use in hemodialysis, these agents have not been adequately studied in chronic kidney disease. They, along with dabigatran and edoxaban, should be avoided whenever possible, despite labeling.
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Others have highlighted these concerns in “real world” populations.48 Edoxaban use is not approved for use in patients with CrCl ≥95 mL/min in the US.
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The direct oral anticoagulants may confer a better renal risk-benefit profile than warfarin
in those with declining renal function over time. Following dosing recommendations as calculated by C-G, utilizing actual body weight, is critical for avoiding improper dosing of patients. Additional assessments may be warranted to further assess use of DOACs in patients with very high or low renal function.
Acknowledgements 14
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Writing and editorial support was provided by Terri Schochet, PhD, of AlphaBioCom, LLC, and
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funded by Daiichi Sankyo.
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26.
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Alexander JH, Andersson U, Lopes RD, et al. Apixaban 5 mg twice daily and clinical
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RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation. 2014;129:961-970. 33.
Del-Carpio Munoz F, Yao X, Abraham NS, et al. Dabigatran versus warfarin in relation
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to renal function in patients with atrial fibrillation. J Am Coll Cardiol. 2016;68:129-131. Bohula EA, Giugliano RP, Ruff CT, et al. Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 Trial. Circulation. 2016;134:24-36.
Lindner SM, Fordyce CB, Hellkamp AS, et al. Treatment Consistency Across Levels of
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Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) Analysis. Circulation. 2017;135:1001-1003. 36.
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206316. Meeting date October 30, 2014. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drug s/CardiovascularandRenalDrugsAdvisoryCommittee/UCM421612.pdf. Accessed 2/27/17. 2014.
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38.
Del-Carpio Munoz F, Gharacholou SM, Munger TM, et al. Meta-analysis of renal function on the safety and efficacy of novel oral anticoagulants for atrial fibrillation. Am J Cardiol. 2016;117:69-75. Hohnloser SH, Hijazi Z, Thomas L, et al. Efficacy of apixaban when compared with
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warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. 2012;33:2821-2830.
Koretsune Y, Yamashita T, Kimura T, Fukuzawa M, Abe K, Yasaka M. Short-term
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atrial fibrillation and severe renal impairment. Circ J. 2015;79:1486-1495. Chang M, Yu Z, Shenker A, et al. Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban. J Clin Pharmacol. 2016;56:637-645. 42.
Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, pharmacodynamics, and
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safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol. 2016;56:628-636. 43.
Mavrakanas TA, Samer CF, Nessim SJ, Frisch G, Lipman ML. Apixaban
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Pharmacokinetics at Steady State in Hemodialysis Patients. J Am Soc Nephrol. 2017. Dias C, Moore KT, Murphy J, et al. Pharmacokinetics, pharmacodynamics, and safety of
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single-dose rivaroxaban in chronic hemodialysis. Am J Nephrol. 2016;43:229-236. Parasrampuria DA, Marbury T, Matsushima N, et al. Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis.
Thromb Haemost. 2015;113:719-727.
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46.
Bohm M, Ezekowitz MD, Connolly SJ, et al. Changes in renal function in patients with atrial fibrillation: An analysis from the RE-LY Trial. J Am Coll Cardiol. 2015;65:24812493. Fordyce CB, Hellkamp AS, Lokhnygina Y, et al. On-Treatment Outcomes in Patients
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47.
With Worsening Renal Function With Rivaroxaban Compared With Warfarin: Insights From ROCKET AF. Circulation. 2016;134:37-47.
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Chan KE, Edelman ER, Wenger JB, Thadhani RI, Maddux FW. Dabigatran and
rivaroxaban use in atrial fibrillation patients on hemodialysis. Circulation. 2015;131:972-
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979.
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48.
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Figure Legends Figure 1: Dosing recommendations in the US based on kidney function measured by creatinine
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clearance, as per prescribing information.24-27 BID, twice daily; CrCl, creatinine clearance; QD, once daily; SCr, serum creatinine. aNot recommended for patients with CrCl <30 mL/min taking concomitant P-gp inhibitors; the dose should be reduced or avoided in patients with CrCl 30–50
c
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mL/min who use concomitant P-gp inhibitors. bShould be taken with the evening meal.
Apixaban should be reduced to a dose of 2.5 mg BID in patients for whom 2 of the following
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apply: serum creatinine >1.5 mg/dL, age ≥80 years old, body weight ≤60 kg; apixaban may be administered to patients on hemodialysis at a dose of 5 mg unless dose administration is warranted based on reduction criteria. dLabeling suggests rivaroxaban may be administered to patients on hemodialysis at a dose of 15 mg unless dose administration is warranted based on
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reduction criteria; however, as it has not been adequately studied in a large scale clinical trial, use in this population should be avoided whenever possible. eLabeling suggests apixaban may be administered to patients on hemodialysis at a dose of 5 mg unless dose administration is
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warranted based on reduction criteria; however, as it has not been adequately studied in a large scale clinical trial, use in this population should be avoided whenever possible.
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Figure 2: Rates of stroke or systemic embolism relative to warfarin for the DOACs stratified by renal function calculated by Cockroft-Gault.24, 26, 27, 32, 39 aFor CrCl 30–50 mL/min. CrCl, creatinine clearance; DOAC, direct oral anticoagulant. Figure 3: Rates of major bleeding relative to warfarin for the DOACs stratified by renal function calculated by Cockroft-Gault.24, 26, 27, 32, 34, 39 aFor CrCl 30–50 mL/min. CrCl, creatinine clearance; DOAC, direct oral anticoagulant.
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Table 1. Hazard ratios for rates of stroke or systemic embolism relative to warfarin for the DOACs stratified by renal function
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calculated by Cockroft-Gaulta2-4, 36, 38, 43
150-mg dose.
c
eGFR >50–≤80 mL/min.
d
e
eGFR≥30–≤50 mL/min.
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b
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range provided.
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CrCl >80 CrCl >50–95 CrCl >50–80 CrCl 30–50 mL/min mL/min mL/min mL/min % of HR % of HR % of HR % of HR total (95% CI) total (95% CI) total (95% CI) total (95% CI) enrolled enrolled enrolled enrolled in trial in trial in trial in trial Dabigatran36b 31.2 0.69 NR NR 18.5 0.48 45.8 0.65 c (0.43, 1.12) (0.31, 0.76)d (0.47, 0.88) 2e Rivaroxaban 22.0 0.93 NR NR 31.4 0.81 45.1 0.90 (0.67, 1.31) (0.60, 1.10) (0.70, 1.14) NR 0.79 Apixabanf 26.0g 0.87 NR 0.70 48.1g 0.78 g g g (0.61, 1.02) (0.60, 1.26) (0.48, 1.03)g (0.58, 1.04) Edoxaban4, 38h 37 1.33 58.3 0.78 19.5 0.87 43 0.68 (0.97, 1.81) (0.64, 0.96) (0.65, 1.18) (0.54, 0.86) a Comparisons should not be made across drugs within CrCl ranges; HR presented are for each DOAC vs warfarin within the CrCl
20 mg daily or 15 mg daily in patients with a CrCl of 15–50 mL/min once daily with the evening meal.
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f
5 mg twice daily or 2.5 mg twice daily for a subset of patients with 2 or more of the following criteria: age ≥80 years, body weight
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≤60 kg, serum creatinine ≥1.5 mg/dL. g
In patients with stable renal function over time.
h
60 mg daily or a 50% dose reduction to 30 mg daily for CrCl 30–50 mL/min, body weight of ≤60 kg, or use of a potent P-gp
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inhibitor.
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hazard ratio; NR, not reported; P-gp, P-glycoprotein.
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CI, confidence interval; CrCl, creatinine clearance; DOAC, direct oral anticoagulant; eGFR, estimated glomerular filtration rate; HR,
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Table 2. Hazard ratios for rates of major bleeding for the DOACs relative to warfarin stratified by renal function calculated by
Dabigatran36b
% of total enrolled in trial 31.3
HR (95% CI)
CrCl >50–95 mL/min
CrCl >50–80 mL/min
% of total enrolled in trial NR
% of total enrolled in trial 45.8
HR (95% CI)
HR (95% CI)
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CrCl >80 mL/min
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Cockroft-Gaulta2-4, 36, 38, 43 CrCl 30–50 mL/min
% of total enrolled in trial 18.4
HR (95% CI)
150-mg dose.
c
eGFR 50–<80 mL/min.
d
e
eGFR ≥30–≤50 mL/min.
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b
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range provided.
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0.90 NR 1.02 0.92 c (0.65, 1.25) (0.77, 1.34)d (0.75, 1.14) 2e Rivaroxaban 31.7 1.26 NR NR 22.4 1.03 45.7 0.94 (0.95, 1.67) (0.79, 1.35) (0.76, 1.15) Apixabanf3, 43 26.0g 0.80 NR 0.74 15.0 0.53 48.1g 0.76 g g g (0.60, 1.07) (0.61, 0.94) (0.39, 0.71) (0.62, 0.94) 4, 38h Edoxaban 37 0.86 58.3 0.89 19.5 0.76 43 0.88 (0.60, 1.22)i (0.75, 1.04) (0.58, 0.98) (0.73, 1.07) a Comparisons should not be made across drugs within CrCl ranges; HR presented are for each DOAC vs warfarin within the CrCl
20 mg daily or 15 mg daily in patients with a CrCl of 15–50 mL/min once daily with the evening meal.
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f
5 mg twice daily or 2.5 mg twice daily for a subset of patients with 2 or more of the following criteria: age ≥80 years, body weight
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≤60 kg, serum creatinine ≥1.5 mg/dL. g
In patients with stable renal function over time.
h
60 mg daily or a 50% dose reduction to 30 mg daily for CrCl 30–50 mL/min, body weight of ≤60 kg, or use of a potent P-gp
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inhibitor. i
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CrCl>80–95.
CI, confidence interval; CrCl, creatinine clearance; DOAC, direct oral anticoagulant; eGFR, estimated glomerular filtration rate; HR,
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hazard ratio; NR, not reported; P-gp, P-glycoprotein.
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Edoxaban
CrCl
CrCl mL/min
Rivaroxabanb
Dose
mL/min
CrCl Dose
>50–≤95
150 mg BID
75 mg BID
15 mg QD
50–15
2 of 3: 30 mg QD
<15
SCr >1.5 mg/dL Weight <60 kg
Avoid Use <15
Avoid Use Hemodialysis 15 mg
QDd
≥80 y 2.5 mg BID
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<15
5 mg BID
60 mg QD
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30–15
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50–15
Dose
SC
20 mg QD
Metric
Avoid Use
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>30
Dose
mL/min
>95
>50
Apixabanc
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Dabigatrana
Avoid Use
Hemodialysis
5 mg BIDe
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CrCl ≥80 mL/min
3 2
RI PT
% / year
4
1 n = 28 n = 41 Dabigatran
n = 65 n = 68 Rivaroxaban
n = 53 n = 61 Apixaban
SC
0
n = 92 n = 70 Edoxaban
M AN U
CrCl 50–<80 mL/min 3
1
% / year
4 3 2
n = 70 n = 103 Dabigatran
n = 125 n = 141
Rivaroxaban
n = 77 n = 98 Apixaban
n = 122 n = 176 Edoxaban
CrCl <50 mL/min
DOAC
AC C
0
TE D
2
EP
% / year
4
Warfarin
1 0
n = 36 n = 57 Dabigatran
n = 78 n = 96 Rivaroxabana
n = 45 n = 61 Apixaban
n = 82 n = 91 Edoxabana
ACCEPTED MANUSCRIPT
% / year
6 5 4 3 2 1 0
RI PT SC
n = 112 n = 89 Rivaroxaban
n = 83 n = 103 Apixaban
n = 57 n = 70 Edoxaban
M AN U
n = 81 n = 95 Dabigatran
n = 188 n = 209 Dabigatran
TE D
CrCl 50–<80 mL/min
n = 176 n = 191 Rivaroxaban
EP
% / year
6 5 4 3 2 1 0
CrCl ≥80 mL/min
AC C
% / year
6 5 4 3 2 1 0
n = 129 n = 116 Dabigatran
n = 136 n = 176 Apixaban
n = 136 n = 176 Edoxaban
CrCl <50 mL/min
n = 106 n =106 Rivaroxaban a
DOAC Warfarin
n = 82 n = 130 Apixaban
n = 100 n = 132 Edoxabana
ACCEPTED MANUSCRIPT
•
Dependence on renal elimination varies among direct oral anticoagulants; renal function may affect systemic drug exposure, efficacy and safety.
weight, is critical for optimizing patient outcomes.
In patients with NVAF with mild or moderate renal impairment, direct oral
anticoagulants were associated with a reduced risk of stroke/SEE and similar risk of
EP
TE D
M AN U
major bleeding relative to warfarin.
AC C
•
RI PT
Appropriate dosing by renal function, calculated by Cockcroft-Gault using actual body
SC
•