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Influence of Renal Function on the Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety of Non–Vitamin K Antagonist Oral Anticoagulants

  • Matthew R. Weir
    Correspondence
    Correspondence: Address to Matthew R. Weir, MD, Division of Nephrology, N3W143, University of Maryland Medical Center, 22 S Greene St, Baltimore, MD 21201.
    Affiliations
    Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
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  • Reinhold Kreutz
    Affiliations
    Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Clinical Pharmacology and Toxicology, Berlin, Germany
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      Abstract

      With the growing integration of non–vitamin K antagonist oral anticoagulants (NOACs) into clinical practice, questions have arisen regarding their use in special populations, including groups that may have been underrepresented in clinical trials. Patients with renal impairment, particularly in the lower echelons of renal function, are one such group. In an effort to elucidate the current evidence regarding the use of NOACs in patients with renal impairment, a systematic assessment of the literature was performed. The MEDLINE database was interrogated for studies and analyses evaluating the influence of renal function on the pharmacokinetics, pharmacodynamics, efficacy, and safety of NOACs published from January 1, 2000, through August 2, 2017. The 82 relevant publications retrieved highlight the diversity in the NOAC class regarding the impact of renal function on drug clearance, drug exposures, and clinical trial outcomes. In several large clinical trials, subgroup analyses revealed no significant differences when patients were stratified by creatinine clearance as a measure of renal function. Efficacy findings, in particular, were largely aligned with the overall population in the included studies. However, relative risks of bleeding were shown to vary, sometimes driven by changes in bleeding event rates in the comparator arm (eg, warfarin, enoxaparin). With few exceptions, minimal influence of mild renal impairment was observed on the relative efficacy and safety of NOACs. Taken together, the evidence suggests that the presence of renal impairment merits careful consideration of anticoagulant choice but should not deter physicians from appropriate use of NOACs.

      Abbreviations and Acronyms:

      AF (atrial fibrillation), BID (twice daily), CKD (chronic kidney disease), CL/F (apparent total clearance after oral administration), CrCL (creatinine clearance), CYP3A4 (cytochrome P450 3A4), DVT (deep vein thrombosis), eGFR (estimated glomerular filtration rate), ESRD (end-stage renal disease), HR (hazard ratio), NOAC (non–vitamin K antagonist oral anticoagulant), OD (once daily), PE (pulmonary embolism), PK (pharmacokinetics), PD (pharmacodynamics), THA (total hip arthroplasty), TKA (total knee arthroplasty), UFH (unfractionated heparin), VKA (vitamin K antagonist), VTE (venous thromboembolism)
      Article Highlights
      • The influence of renal impairment on the pharmacokinetic, pharmacodynamic, efficacy, and safety profiles of non–vitamin K antagonist oral anticoagulants (NOACs) varies among individual members of the drug class.
      • Except for severe renal impairment (creatinine clearance <30 mL/min per 1.73m2 for dabigatran and <15 mL/min per 1.73m2 for factor Xa inhibitors), NOAC use is not restricted in patients with renal dysfunction.
      • Renal function should be assessed before initiating and during treatment with oral anticoagulants (whether NOACs or other agents), and the presence and degree of renal impairment should guide an appropriate therapeutic regimen and dosing.
      Non–vitamin K antagonist oral anticoagulants (NOACs) have become a standard option for the management of thromboembolic disease and thromboprophylaxis across a variety of clinical indications. Commensurate with the integration of NOACs into routine care and the epidemiologic overlap among at-risk groups, the likelihood of encountering patients with renal impairment who may be candidates for treatment with a NOAC is high,
      • Kooiman J.
      • van de Peppel W.R.
      • van der Meer F.J.
      • Huisman M.V.
      Incidence of chronic kidney disease in patients with atrial fibrillation and its relevance for prescribing new oral antithrombotic drugs.
      • Antonucci E.
      • Poli D.
      • Tosetto A.
      • et al.
      The Italian START-Register on anticoagulation with focus on atrial fibrillation.
      yet there remains uncertainty regarding the utility, selection, and dosing of NOACs in this population.
      • Pattullo C.S.
      • Barras M.
      • Tai B.
      • McKean M.
      • Donovan P.
      New oral anticoagulants: appropriateness of prescribing in real-world setting.
      Indeed, inappropriate use or dosing of NOACs based on renal function is not uncommon
      • Pattullo C.S.
      • Barras M.
      • Tai B.
      • McKean M.
      • Donovan P.
      New oral anticoagulants: appropriateness of prescribing in real-world setting.
      • Isaacs A.N.
      • Doolin M.
      • Morse C.
      • Shiltz E.
      • Nisly S.A.
      Medication utilization evaluation of dabigatran and rivaroxaban within a large, multi-center health system.
      and can have potentially serious ramifications.
      • Smythe M.A.
      • Forman M.J.
      • Bertran E.A.
      • Hoffman J.L.
      • Priziola J.L.
      • Koerber J.M.
      Dabigatran versus warfarin major bleeding in practice: an observational comparison of patient characteristics, management and outcomes in atrial fibrillation patients.
      Given the clinical uncertainty, some studies have advocated use of vitamin K antagonists (VKAs) rather than NOACs in patients with impaired renal function.
      • Stollberger C.
      • Finsterer J.
      Pipe dreams about apixaban for stroke prevention in renal impairment.
      This may be an oversimplification because differences in the effect of renal function on individual NOACs are anticipated based on the unique pharmacological properties of the various drugs.
      The purpose of this review was to examine the current body of literature to (1) determine the effects of renal function on the clinical pharmacology (pharmacokinetics [PK] and pharmacodynamics [PD]), efficacy, and safety of individual NOACs and (2) ascertain how these findings might influence clinical practice.

      Identification of Relevant Publications

      Two search methods were used to identify publications that explored the influence of renal function on the clinical pharmacology, efficacy, and safety of established, guideline-recommended NOAC agents (apixaban, dabigatran, edoxaban, and rivaroxaban). Both searches involved interrogation of the MEDLINE database for articles reporting results from prospective clinical trials, subgroup analyses, or PK studies published in English from January 1, 2000, through August 2, 2017. The first search focused on publications with a clear inclusion of renal function analyses. To prevent missing relevant studies in which renal function was not described in the abstract or key words, a second search was performed with the renal terms removed and the type of study limited to phase 2 or 3 clinical trials.
      Results from the 2 searches were combined and duplicate publications removed. Retrospective studies, articles that evaluated NOACs as a group (rather than individual agents), studies of unapproved indications, and publications unrelated to the clinical pharmacology, efficacy, or safety of NOACs as they relate to renal function were excluded from the review. Primary publications from secondary or subgroup analyses were included if they were used to source study information and were found to contain relevant renal function analyses. Search terms and a schematic of the publication selection process are presented in the Supplemental Figure (available online at http://www.mayoclinicproceedings.org).

      Apixaban

      Influence of Renal Function on Apixaban PK/PD

      Elimination of apixaban, a direct factor Xa inhibitor, occurs via renal and nonrenal pathways, with 27% of total drug clearance accounted for by renal excretion.
      Chang et al
      • Chang M.
      • Yu Z.
      • Shenker A.
      • et al.
      Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban.
      evaluated the clinical pharmacology after administration of a single apixaban 10-mg dose in patients with mild, moderate, or severe renal impairment compared with healthy volunteers. Decreases in renal function were shown to modestly increase apixaban systemic exposure (area under the plasma concentration-time curve), with predicted increases of 16%, 29%, and 38% corresponding to 24-hour creatinine clearance (CrCL) values of 65, 40, and 25 mL/min, respectively, compared with a reference CrCL of 100 mL/min.
      Similar results were reported in a single-dose study of apixaban 5 mg administered to patients with end-stage renal disease (ESRD) and healthy volunteers.
      • Wang X.
      • Tirucherai G.
      • Marbury T.C.
      • et al.
      Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis.
      Apixaban exposure increased by 36% in patients with ESRD compared with healthy volunteers. This is consistent with values estimated by Chang et al
      • Chang M.
      • Yu Z.
      • Shenker A.
      • et al.
      Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban.
      at a CrCL of 25 mL/min (ie, severe renal impairment). Hemodialysis in patients with ESRD had minimal effect on apixaban exposure (14% decrease),
      • Wang X.
      • Tirucherai G.
      • Marbury T.C.
      • et al.
      Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis.
      which is likely owing to the relatively high protein binding of apixaban.
      Steady-state PK was explored by Mavrakanas et al
      • Mavrakanas T.A.
      • Samer C.F.
      • Nessim S.J.
      • Frisch G.
      • Lipman M.L.
      Apixaban pharmacokinetics at steady state in hemodialysis patients.
      in a multiple-dose study of apixaban (2.5 and 5.0 mg twice daily [BID] administered during separate study periods) in 7 patients with nonvalvular atrial fibrillation (AF) and ESRD undergoing hemodialysis. Significant increases in apixaban exposure were observed from day 1 to day 8 of treatment with both doses (P≤.03) and can be attributed to significant accumulation in this population. The increase in exposure with the 5.0-mg dose was considered supratherapeutic, and that of the 2.5-mg dose was comparable with standard dosing in patients with AF and normal renal function (5.0 mg BID). Hemodialysis removed only 4% of the drug (on par with the 7% reported in the single-dose study
      • Wang X.
      • Tirucherai G.
      • Marbury T.C.
      • et al.
      Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis.
      ).
      A population PK analysis showed a correlation between apparent total clearance after oral administration (CL/F) of apixaban and CrCL, but the effect was generally modest.
      • Byon W.
      • Sweeney K.
      • Frost C.
      • Boyd R.A.
      Population pharmacokinetics, pharmacodynamics, and exploratory exposure-response analyses of apixaban in subjects treated for venous thromboembolism.
      Severe renal impairment (CrCL of 15 to <30 mL/min) was predicted to decrease CL/F by 36% and increase exposure by 56%, whereas in mild (CrCL of 50-80 mL/min) or moderate (CrCL of 30 to <50 mL/min) renal impairment, the commensurate increases in exposure were 17% and 34%, respectively.

      Influence of Renal Function on Apixaban Efficacy and Safety

      The largest of the efficacy and safety studies identified for apixaban was ARISTOTLE, which randomized more than 18,000 patients with AF and at least 1 additional stroke risk factor to treatment with apixaban 5 mg BID or warfarin
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      (Table).
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Hylek E.M.
      • Held C.
      • Alexander J.H.
      • et al.
      Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): predictors, characteristics, and clinical outcomes.
      • Alexander J.H.
      • Andersson U.
      • Lopes R.D.
      • et al.
      Apixaban 5 mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine: a secondary analysis of a randomized clinical trial.
      • Hijazi Z.
      • Hohnloser S.H.
      • Andersson U.
      • et al.
      Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Eikelboom J.W.
      • Connolly S.J.
      • Gao P.
      • et al.
      Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease.
      • Lip G.Y.
      • Connolly S.
      • Yusuf S.
      • et al.
      Modification of outcomes with aspirin or apixaban in relation to CHADS(2) and CHA(2)DS(2)-VASc scores in patients with atrial fibrillation: a secondary analysis of the AVERROES study.
      • Coppens M.
      • Synhorst D.
      • Eikelboom J.W.
      • Yusuf S.
      • Shestakovska O.
      • Connolly S.J.
      Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial.
      • Pineo G.F.
      • Gallus A.S.
      • Raskob G.E.
      • et al.
      Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups.
      • Nakamura M.
      • Nishikawa M.
      • Komuro I.
      • et al.
      Apixaban for the treatment of Japanese subjects with acute venous thromboembolism (AMPLIFY-J Study).
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      Apixaban for extended treatment of venous thromboembolism.
      • Liu X.
      • Thompson J.
      • Phatak H.
      • et al.
      Extended anticoagulation with apixaban reduces hospitalisations in patients with venous thromboembolism: an analysis of the AMPLIFY-EXT trial.
      • Hijazi Z.
      • Hohnloser S.H.
      • Oldgren J.
      • et al.
      Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis.
      • Hori M.
      • Fukaya T.
      • Kleine E.
      • et al.
      Efficacy and safety of dabigatran etexilate vs. warfarin in Asian RE-LY patients according to baseline renal function or CHADS2 score.
      • Böhm M.
      • Ezekowitz M.D.
      • Connolly S.J.
      • et al.
      Changes in renal function in patients with atrial fibrillation: an analysis from the RE-LY trial.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials.
      • Majeed A.
      • Goldhaber S.Z.
      • Kakkar A.
      • et al.
      Bleeding events with dabigatran or warfarin in patients with venous thromboembolism.
      • Giugliano R.P.
      • Ruff C.T.
      • Braunwald E.
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      • Eisen A.
      • Giugliano R.P.
      • Ruff C.T.
      • et al.
      Edoxaban vs warfarin in patients with nonvalvular atrial fibrillation in the US Food and Drug Administration approval population: an analysis from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial.
      • Bohula E.A.
      • Giugliano R.P.
      • Ruff C.T.
      • et al.
      Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 trial.
      • Goette A.
      • Merino J.L.
      • Ezekowitz M.D.
      • et al.
      Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial.
      • Buller H.R.
      • Decousus H.
      • Grosso M.A.
      • et al.
      Hokusai-VTE Investigators
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Fox K.A.
      • Piccini J.P.
      • Wojdyla D.
      • et al.
      Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment.
      • Goodman S.G.
      • Wojdyla D.M.
      • Piccini J.P.
      • et al.
      Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation).
      • Wong K.S.
      • Hu D.Y.
      • Oomman A.
      • et al.
      Rivaroxaban for stroke prevention in East Asian patients from the ROCKET AF trial.
      • Fordyce C.B.
      • Hellkamp A.S.
      • Lokhnygina Y.
      • et al.
      On-treatment outcomes in patients with worsening renal function with rivaroxaban compared with warfarin: insights from ROCKET AF.
      • Lindner S.M.
      • Fordyce C.B.
      • Hellkamp A.S.
      • et al.
      Treatment consistency across levels of baseline renal function with rivaroxaban or warfarin: a ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) analysis.
      • Hori M.
      • Matsumoto M.
      • Tanahashi N.
      • et al.
      Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation: the J-ROCKET AF study.
      • Hori M.
      • Matsumoto M.
      • Tanahashi N.
      • et al.
      Safety and efficacy of adjusted dose of rivaroxaban in Japanese patients with non-valvular atrial fibrillation: subanalysis of J-ROCKET AF for patients with moderate renal impairment.
      • Hori M.
      • Matsumoto M.
      • Tanahashi N.
      • et al.
      Rivaroxaban vs. warfarin in Japanese patients with non-valvular atrial fibrillation in relation to age.
      • Uchiyama S.
      • Hori M.
      • Matsumoto M.
      • et al.
      Net clinical benefit of rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation: a subgroup analysis of J-ROCKET AF.
      • Turpie A.G.
      • Lassen M.R.
      • Eriksson B.I.
      • et al.
      Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty: pooled analysis of four studies.
      • Bauersachs R.
      • Berkowitz S.D.
      • Brenner B.
      • et al.
      EINSTEIN Investigators
      Oral rivaroxaban for symptomatic venous thromboembolism.
      • Buller H.R.
      • Prins M.H.
      • Lensin A.W.
      • et al.
      EINSTEIN-PE Investigators
      Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
      • Wang Y.
      • Wang C.
      • Chen Z.
      • et al.
      Rivaroxaban for the treatment of symptomatic deep-vein thrombosis and pulmonary embolism in Chinese patients: a subgroup analysis of the EINSTEIN DVT and PE studies.
      • Bauersachs R.M.
      • Lensing A.W.
      • Prins M.H.
      • et al.
      Rivaroxaban versus enoxaparin/vitamin K antagonist therapy in patients with venous thromboembolism and renal impairment.
      • Weitz J.I.
      • Lensing A.W.A.
      • Prins M.H.
      • et al.
      Rivaroxaban or aspirin for extended treatment of venous thromboembolism.
      Patients with severe renal impairment—defined in this study by a serum creatinine concentration greater than 2.5 mg/dL (to convert to μmol/L, multiply by 88.4) or CrCL less than 25 mL/min—were excluded. A reduced dose (2.5 mg BID) was applied in patients who fulfilled 2 or more of the following criteria: serum creatinine level greater than 1.5 mg/dL, age 80 years or older, or body weight of 60 kg or less. Thus, patients with renal impairment alone received the normal 5-mg apixaban dose. In the overall population, apixaban demonstrated superiority to warfarin in preventing stroke or systemic embolism and was associated with lower rates of bleeding and mortality. Results for the primary outcome (stroke or systemic embolism) were consistent across renal function subgroups (Figure 1A)
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Hijazi Z.
      • Hohnloser S.H.
      • Andersson U.
      • et al.
      Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Eikelboom J.W.
      • Connolly S.J.
      • Gao P.
      • et al.
      Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease.
      • Coppens M.
      • Synhorst D.
      • Eikelboom J.W.
      • Yusuf S.
      • Shestakovska O.
      • Connolly S.J.
      Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial.
      ; however, patients with impaired renal function (CrCL ≤50 mL/min) seemed to have experienced the greatest reduction in major bleeding (Figure 1B).
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Alexander J.H.
      • Andersson U.
      • Lopes R.D.
      • et al.
      Apixaban 5 mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine: a secondary analysis of a randomized clinical trial.
      • Hijazi Z.
      • Hohnloser S.H.
      • Andersson U.
      • et al.
      Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Eikelboom J.W.
      • Connolly S.J.
      • Gao P.
      • et al.
      Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease.
      • Coppens M.
      • Synhorst D.
      • Eikelboom J.W.
      • Yusuf S.
      • Shestakovska O.
      • Connolly S.J.
      Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial.
      Subsequent analysis of major bleeding confirmed a greater reduction in risk with apixaban vs warfarin in patients with renal dysfunction.
      • Hylek E.M.
      • Held C.
      • Alexander J.H.
      • et al.
      Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): predictors, characteristics, and clinical outcomes.
      Patients with serum creatinine levels greater than 1.5 mg/dL but no other criteria for dose reduction were also found to derive similar benefit from apixaban 5 mg compared with that of the overall population
      • Alexander J.H.
      • Andersson U.
      • Lopes R.D.
      • et al.
      Apixaban 5 mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine: a secondary analysis of a randomized clinical trial.
      (Figure 1B).
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Alexander J.H.
      • Andersson U.
      • Lopes R.D.
      • et al.
      Apixaban 5 mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine: a secondary analysis of a randomized clinical trial.
      • Hijazi Z.
      • Hohnloser S.H.
      • Andersson U.
      • et al.
      Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Eikelboom J.W.
      • Connolly S.J.
      • Gao P.
      • et al.
      Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease.
      • Coppens M.
      • Synhorst D.
      • Eikelboom J.W.
      • Yusuf S.
      • Shestakovska O.
      • Connolly S.J.
      Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial.
      TableCharacteristics of and Renal Dysfunction Representation in Randomized Controlled Efficacy and Safety Studies
      AF = atrial fibrillation; BID = twice daily; CrCL = creatinine clearance; DVT = deep vein thrombosis; OD = once daily; PE = pulmonary embolism; THA = total hip arthroplasty; TKA = total knee arthroplasty; UFH = unfractionated heparin; VTE = venous thromboembolism.
      Study and conditionsTreatment groupsPatients (No. [%])
      Normal function (CrCL >80 mL/min)Mild dysfunction (CrCL >50-80 mL/min)Moderate dysfunction (CrCL >30-50 mL/min)Severe dysfunction (CrCL ≤30 mL/min)
      Apixaban
       ARISTOTLE
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Hylek E.M.
      • Held C.
      • Alexander J.H.
      • et al.
      Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): predictors, characteristics, and clinical outcomes.
      • Alexander J.H.
      • Andersson U.
      • Lopes R.D.
      • et al.
      Apixaban 5 mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine: a secondary analysis of a randomized clinical trial.
      • Hijazi Z.
      • Hohnloser S.H.
      • Andersson U.
      • et al.
      Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
      Apixaban 5 mg BID
      Apixaban dose reduced to 2.5 mg BID for patients with 2 or more of the following criteria: age 80 years or older, weight of 60 kg or less, or serum creatinine concentration of at least 1.5 mg/dL (to convert to μmol/L, multiply by 88.4). Overall, 428 patients (5%) in ARISTOTLE and 179 (6%) in AVERROES received the 2.5-mg dose.
      (n=9120)
      3761 (41.2)3817 (41.9)1365 (15.0)137 (1.5)
      AF and ≥1 stroke risk factorWarfarin (n=9081)3757 (41.4)3770 (41.5)1382 (15.2)133 (1.5)
       AVERROES
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Eikelboom J.W.
      • Connolly S.J.
      • Gao P.
      • et al.
      Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease.
      • Lip G.Y.
      • Connolly S.
      • Yusuf S.
      • et al.
      Modification of outcomes with aspirin or apixaban in relation to CHADS(2) and CHA(2)DS(2)-VASc scores in patients with atrial fibrillation: a secondary analysis of the AVERROES study.
      • Coppens M.
      • Synhorst D.
      • Eikelboom J.W.
      • Yusuf S.
      • Shestakovska O.
      • Connolly S.J.
      Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial.
      Apixaban 5 mg BID
      Apixaban dose reduced to 2.5 mg BID for patients with 2 or more of the following criteria: age 80 years or older, weight of 60 kg or less, or serum creatinine concentration of at least 1.5 mg/dL (to convert to μmol/L, multiply by 88.4). Overall, 428 patients (5%) in ARISTOTLE and 179 (6%) in AVERROES received the 2.5-mg dose.
      (n=2808)
      2021 (36.1)2374 (42.4)1198 (21.4)
      AF and ≥1 stroke risk factorAspirin (n=2791)
       ADVANCE-2 and -3
      • Pineo G.F.
      • Gallus A.S.
      • Raskob G.E.
      • et al.
      Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups.
      Apixaban 2.5 mg BID (n=4236)2646 (62.5)1303 (30.8)217 (5.1)
      Elective TKA or THAEnoxaparin (n=4228)2609 (61.7)1347 (31.9)220 (5.2)
       AMPLIFY-J
      • Nakamura M.
      • Nishikawa M.
      • Komuro I.
      • et al.
      Apixaban for the treatment of Japanese subjects with acute venous thromboembolism (AMPLIFY-J Study).
      Apixaban 10/5 mg BID (n=40)20 (50.0)18 (45.0)1 (2.5)1 (2.5)
      Symptomatic DVT or PE (with or without DVT)UFH/warfarin (n=40)14 (35.0)17 (42.5)5 (12.5)3 (7.5)
       AMPLIFY-EXT
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      Apixaban for extended treatment of venous thromboembolism.
      • Liu X.
      • Thompson J.
      • Phatak H.
      • et al.
      Extended anticoagulation with apixaban reduces hospitalisations in patients with venous thromboembolism: an analysis of the AMPLIFY-EXT trial.
      Apixaban 2.5 mg BID (n=840)
      Patients with estimated CrCL less than 40 mL/min were randomly assigned to receive apixaban 2.5 mg BID or placebo.
      595 (70.8)174 (20.7)47 (5.6)1 (0.1)
      Symptomatic DVT or PE (with or without DVT)Apixaban 5 mg BID (n=813)580 (71.3)168 (20.7)41 (5.0)3 (0.4)
      Placebo (n=829)564 (68.0)194 (23.4)44 (5.3)2 (0.2)
      Dabigatran
       RE-LY
      • Hijazi Z.
      • Hohnloser S.H.
      • Oldgren J.
      • et al.
      Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis.
      • Hori M.
      • Fukaya T.
      • Kleine E.
      • et al.
      Efficacy and safety of dabigatran etexilate vs. warfarin in Asian RE-LY patients according to baseline renal function or CHADS2 score.
      • Böhm M.
      • Ezekowitz M.D.
      • Connolly S.J.
      • et al.
      Changes in renal function in patients with atrial fibrillation: an analysis from the RE-LY trial.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      Dabigatran 110 mg BID (n=6015)5826 (32.2)
      Based on the Cockcroft-Gault equation.
      8766 (48.4)
      Based on the Cockcroft-Gault equation.
      3505 (19.4)
      Based on the Cockcroft-Gault equation.
      AF and ≥1 stroke risk factorDabigatran 150 mg BID (n=6076)3880 (21.4)
      Based on the Chronic Kidney Disease Epidemiology Collaboration equation.
      10697 (59.1)
      Based on the Chronic Kidney Disease Epidemiology Collaboration equation.
      3374 (18.6)
      Based on the Chronic Kidney Disease Epidemiology Collaboration equation.
      Warfarin (n=6022)
       RE-NOVATE, RE-NOVATE II
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials.
      Dabigatran 220 mg OD (n=2156)1056 (64.5)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      495 (30.2)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      82 (5.0)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      5 (0.3)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      Elective THAEnoxaparin 40 mg (n=2157)1061 (64.5)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      508 (30.9)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      72 (4.4)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      4 (0.3)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
       RE-COVER, RE-COVER II
      • Majeed A.
      • Goldhaber S.Z.
      • Kakkar A.
      • et al.
      Bleeding events with dabigatran or warfarin in patients with venous thromboembolism.
      Dabigatran 150 mg BID (n=2553)1861 (72.9)538 (21.1)114 (4.5)12 (0.5)
      Symptomatic DVT or PEWarfarin (n=2554)1837 (71.9)562 (22.0)123 (4.8)11 (0.4)
      Edoxaban
       ENGAGE AF-TIMI 48
      • Giugliano R.P.
      • Ruff C.T.
      • Braunwald E.
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      • Eisen A.
      • Giugliano R.P.
      • Ruff C.T.
      • et al.
      Edoxaban vs warfarin in patients with nonvalvular atrial fibrillation in the US Food and Drug Administration approval population: an analysis from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial.
      • Bohula E.A.
      • Giugliano R.P.
      • Ruff C.T.
      • et al.
      Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 trial.
      Edoxaban 60 mg
      Edoxaban dose reduced by half in patients with estimated CrCL of 30 to 50 mL/min, a body weight of 60 kg or less, or concomitant use of verapamil or quinidine (potent P-glycoprotein inhibitors).
      (n=7035)
      5656 (80.4)1379 (19.6)
      AF and CHADS2 ≥2Edoxaban 30 mg
      Edoxaban dose reduced by half in patients with estimated CrCL of 30 to 50 mL/min, a body weight of 60 kg or less, or concomitant use of verapamil or quinidine (potent P-glycoprotein inhibitors).
      (n=7034)
      5700 (81.0)1334 (19.0)
      Warfarin (n=7036)5675 (80.7)1361 (19.3)
       ENSURE-AF
      • Goette A.
      • Merino J.L.
      • Ezekowitz M.D.
      • et al.
      Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial.
      Edoxaban 60 mg
      Edoxaban dose reduced by half in patients with estimated CrCL of 30 to 50 mL/min, a body weight of 60 kg or less, or concomitant use of verapamil or quinidine (potent P-glycoprotein inhibitors).
      (n=1095)
      643 (58.7)304 (27.8)83 (7.6)
      AF undergoing electrical cardioversionEnoxaparin-warfarin (n=1104)636 (57.6)315 (28.5)76 (6.9)
       Hokusai-VTE
      • Buller H.R.
      • Decousus H.
      • Grosso M.A.
      • et al.
      Hokusai-VTE Investigators
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
      Edoxaban 60 mg
      Edoxaban dose reduced by half in patients with estimated CrCL of 30 to 50 mL/min, a body weight of 60 kg or less, or concomitant use of verapamil or quinidine (potent P-glycoprotein inhibitors).
      (n=4118)
      3850 (93.5)268 (6.5)
      Symptomatic DVT or PE (with or without DVT)Warfarin (n=4122)3849 (93.4)273 (6.6)
      Rivaroxaban
       ROCKET AF
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Fox K.A.
      • Piccini J.P.
      • Wojdyla D.
      • et al.
      Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment.
      • Goodman S.G.
      • Wojdyla D.M.
      • Piccini J.P.
      • et al.
      Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation).
      • Wong K.S.
      • Hu D.Y.
      • Oomman A.
      • et al.
      Rivaroxaban for stroke prevention in East Asian patients from the ROCKET AF trial.
      • Fordyce C.B.
      • Hellkamp A.S.
      • Lokhnygina Y.
      • et al.
      On-treatment outcomes in patients with worsening renal function with rivaroxaban compared with warfarin: insights from ROCKET AF.
      • Lindner S.M.
      • Fordyce C.B.
      • Hellkamp A.S.
      • et al.
      Treatment consistency across levels of baseline renal function with rivaroxaban or warfarin: a ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) analysis.
      Rivaroxaban 20 mg OD
      Rivaroxaban dose reduced to 15 mg daily in patients with CrCL of 30 to 49 mL/min at baseline (n=1474; 21%).
      (n=7131)
      2285 (32.3)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      3298 (46.6)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      1490 (21.1)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      AF and CHADS2 ≥2Warfarin (n=7133)2222 (31.4)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      3400 (48.0)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      1459 (20.6)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
       J-ROCKET AF
      • Hori M.
      • Matsumoto M.
      • Tanahashi N.
      • et al.
      Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation: the J-ROCKET AF study.
      • Hori M.
      • Matsumoto M.
      • Tanahashi N.
      • et al.
      Safety and efficacy of adjusted dose of rivaroxaban in Japanese patients with non-valvular atrial fibrillation: subanalysis of J-ROCKET AF for patients with moderate renal impairment.
      • Hori M.
      • Matsumoto M.
      • Tanahashi N.
      • et al.
      Rivaroxaban vs. warfarin in Japanese patients with non-valvular atrial fibrillation in relation to age.
      • Uchiyama S.
      • Hori M.
      • Matsumoto M.
      • et al.
      Net clinical benefit of rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation: a subgroup analysis of J-ROCKET AF.
      Rivaroxaban 15 mg OD
      Rivaroxaban dose reduced to 10 mg daily in patients with CrCL of 30 to 49 mL/min at baseline (n=141; 22%).
      (n=639)
      170 (26.6)328 (51.3)141 (22.1)
      AF and CHADS2 ≥2Warfarin (n=639)168 (26.3)328 (51.3)143 (22.4)
       RECORD1, 2, 3, 4
      • Turpie A.G.
      • Lassen M.R.
      • Eriksson B.I.
      • et al.
      Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty: pooled analysis of four studies.
      Rivaroxaban 10 mg OD (n=6356)3617 (59.1)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      2093 (34.2)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      409 (6.7)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      Elective TKA or THAEnoxaparin (n=6373)3598 (58.5)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      2114 (34.4)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      437 (7.1)
      Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
       EINSTEIN DVT
      • Bauersachs R.
      • Berkowitz S.D.
      • Brenner B.
      • et al.
      EINSTEIN Investigators
      Oral rivaroxaban for symptomatic venous thromboembolism.
      Rivaroxaban 15//20 mg (n=1731)1193 (68.9)393 (22.7)115 (6.6)6 (0.3)
      Symptomatic proximal DVT without symptomatic PEEnoxaparin/warfarin (n=1718)1170 (68.1)399 (23.2)120 (7.0)9 (0.5)
       EINSTEIN PE
      • Buller H.R.
      • Prins M.H.
      • Lensin A.W.
      • et al.
      EINSTEIN-PE Investigators
      Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
      Rivaroxaban 15/20 mg (n=2419)1555 (64.3)637 (26.3)207 (8.6)4 (0.2)
      Symptomatic PE with or without DVTEnoxaparin/warfarin (n=2413)1617 (67.0)593 (24.6)191 (7.9)2 (<0.1)
       EINSTEIN DVT, EINSTEIN PE
      • Wang Y.
      • Wang C.
      • Chen Z.
      • et al.
      Rivaroxaban for the treatment of symptomatic deep-vein thrombosis and pulmonary embolism in Chinese patients: a subgroup analysis of the EINSTEIN DVT and PE studies.
      • Bauersachs R.M.
      • Lensing A.W.
      • Prins M.H.
      • et al.
      Rivaroxaban versus enoxaparin/vitamin K antagonist therapy in patients with venous thromboembolism and renal impairment.
      Rivaroxaban 15/20 mg (n=4150)2772 (66.8)1036 (25.0)323 (7.8)10 (0.2)
      Symptomatic DVT or PEEnoxaparin/warfarin (n=4131)2797 (67.7)1001 (24.2)313 (7.6)11 (0.3)
       EINSTEIN CHOICE
      • Weitz J.I.
      • Lensing A.W.A.
      • Prins M.H.
      • et al.
      Rivaroxaban or aspirin for extended treatment of venous thromboembolism.
      Rivaroxaban 20 mg OD (n=1107)787 (71.1)279 (25.2)40 (3.6)1 (0.1)
      Symptomatic proximal DVT or PE and 6-12 mo of anticoagulationRivaroxaban 10 mg OD (n=1127)774 (68.7)302 (26.8)49 (4.3)2 (0.2)
      Aspirin 100 mg (n=1131)790 (69.8)277 (24.5)63 (5.6)1 (0.1)
      a AF = atrial fibrillation; BID = twice daily; CrCL = creatinine clearance; DVT = deep vein thrombosis; OD = once daily; PE = pulmonary embolism; THA = total hip arthroplasty; TKA = total knee arthroplasty; UFH = unfractionated heparin; VTE = venous thromboembolism.
      b Apixaban dose reduced to 2.5 mg BID for patients with 2 or more of the following criteria: age 80 years or older, weight of 60 kg or less, or serum creatinine concentration of at least 1.5 mg/dL (to convert to μmol/L, multiply by 88.4). Overall, 428 patients (5%) in ARISTOTLE and 179 (6%) in AVERROES received the 2.5-mg dose.
      c Patients with estimated CrCL less than 40 mL/min were randomly assigned to receive apixaban 2.5 mg BID or placebo.
      d Based on the Cockcroft-Gault equation.
      e Based on the Chronic Kidney Disease Epidemiology Collaboration equation.
      f Numbers (percentages) of patients based on those assessed in subgroup analyses; values for the overall population are not presented.
      g Edoxaban dose reduced by half in patients with estimated CrCL of 30 to 50 mL/min, a body weight of 60 kg or less, or concomitant use of verapamil or quinidine (potent P-glycoprotein inhibitors).
      h Rivaroxaban dose reduced to 15 mg daily in patients with CrCL of 30 to 49 mL/min at baseline (n=1474; 21%).
      i Rivaroxaban dose reduced to 10 mg daily in patients with CrCL of 30 to 49 mL/min at baseline (n=141; 22%).
      Figure thumbnail gr1
      Figure 1Relative efficacy and safety of apixaban in renal function subgroups.
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Alexander J.H.
      • Andersson U.
      • Lopes R.D.
      • et al.
      Apixaban 5 mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine: a secondary analysis of a randomized clinical trial.
      • Hijazi Z.
      • Hohnloser S.H.
      • Andersson U.
      • et al.
      Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Eikelboom J.W.
      • Connolly S.J.
      • Gao P.
      • et al.
      Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease.
      • Coppens M.
      • Synhorst D.
      • Eikelboom J.W.
      • Yusuf S.
      • Shestakovska O.
      • Connolly S.J.
      Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial.
      • Pineo G.F.
      • Gallus A.S.
      • Raskob G.E.
      • et al.
      Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups.
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      Apixaban for extended treatment of venous thromboembolism.
      Forest plots of hazard ratios and 95% CIs for (A) stroke and systemic embolism in atrial fibrillation (AF) clinical trials,
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Hijazi Z.
      • Hohnloser S.H.
      • Andersson U.
      • et al.
      Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Eikelboom J.W.
      • Connolly S.J.
      • Gao P.
      • et al.
      Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease.
      • Coppens M.
      • Synhorst D.
      • Eikelboom J.W.
      • Yusuf S.
      • Shestakovska O.
      • Connolly S.J.
      Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial.
      (B) major bleeding in AF clinical trials,
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Alexander J.H.
      • Andersson U.
      • Lopes R.D.
      • et al.
      Apixaban 5 mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine: a secondary analysis of a randomized clinical trial.
      • Hijazi Z.
      • Hohnloser S.H.
      • Andersson U.
      • et al.
      Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Eikelboom J.W.
      • Connolly S.J.
      • Gao P.
      • et al.
      Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease.
      • Coppens M.
      • Synhorst D.
      • Eikelboom J.W.
      • Yusuf S.
      • Shestakovska O.
      • Connolly S.J.
      Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial.
      (C) major venous thromboembolism (VTE)
      • Pineo G.F.
      • Gallus A.S.
      • Raskob G.E.
      • et al.
      Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups.
      or recurrent VTE and all-cause death
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      Apixaban for extended treatment of venous thromboembolism.
      in deep vein thrombosis (DVT) prophylaxis or VTE treatment clinical trials, and (D) major bleeding
      • Pineo G.F.
      • Gallus A.S.
      • Raskob G.E.
      • et al.
      Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups.
      or major and clinically relevant nonmajor bleeding
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      Apixaban for extended treatment of venous thromboembolism.
      in DVT prophylaxis or VTE treatment clinical trials. Relative risk values for the ADVANCE-2, -3 safety analysis were calculated from event rates provided by Pineo et al.
      • Pineo G.F.
      • Gallus A.S.
      • Raskob G.E.
      • et al.
      Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups.
      aCreatinine clearance as determined by the Cockcroft-Gault equation. bEstimated glomerular filtration rate (eGFR) as determined by the Chronic Kidney Disease Epidemiology Collaboration equation. All definitions and renal function categories are maintained as used in the original studies. CKD = chronic kidney disease. To convert creatinine values to μmol/L, multiply by 88.4.
      During 12 months of follow-up in the ARISTOTLE trial, 13.6% of patients experienced worsening renal function, defined as a decline in estimated glomerular filtration rate (eGFR) of at least 20%.
      • Hijazi Z.
      • Hohnloser S.H.
      • Andersson U.
      • et al.
      Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
      Treatment assignment did not seem to influence observed renal function changes. In patients with worsening renal function, greater relative reductions in risk of stroke or systemic embolism and in major bleeding rates were maintained with apixaban vs warfarin (Figure 1A and B).
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Alexander J.H.
      • Andersson U.
      • Lopes R.D.
      • et al.
      Apixaban 5 mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine: a secondary analysis of a randomized clinical trial.
      • Hijazi Z.
      • Hohnloser S.H.
      • Andersson U.
      • et al.
      Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Eikelboom J.W.
      • Connolly S.J.
      • Gao P.
      • et al.
      Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease.
      • Coppens M.
      • Synhorst D.
      • Eikelboom J.W.
      • Yusuf S.
      • Shestakovska O.
      • Connolly S.J.
      Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial.
      In AVERROES, patients with AF at increased risk for stroke who were not candidates for VKA therapy were randomized to treatment with apixaban 5 mg BID or low-dose aspirin.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      Renal impairment exclusion and dose reduction criteria followed those of ARISTOTLE. Overall, apixaban was found to decrease risk of stroke or systemic embolism without significantly increasing rates of major bleeding or intracranial hemorrhage compared with aspirin. Primary efficacy and safety outcomes were comparable across renal function subgroups (Figure 1A and B).
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Alexander J.H.
      • Andersson U.
      • Lopes R.D.
      • et al.
      Apixaban 5 mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine: a secondary analysis of a randomized clinical trial.
      • Hijazi Z.
      • Hohnloser S.H.
      • Andersson U.
      • et al.
      Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Eikelboom J.W.
      • Connolly S.J.
      • Gao P.
      • et al.
      Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease.
      • Coppens M.
      • Synhorst D.
      • Eikelboom J.W.
      • Yusuf S.
      • Shestakovska O.
      • Connolly S.J.
      Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial.
      Subsequent analyses reported similar findings in patients with stage III chronic kidney disease (CKD) (eGFR of 30-59 mL/min per 1.73 m2) compared with patients with preserved renal function (eGFR of ≥60 mL/min per 1.73 m2)
      • Eikelboom J.W.
      • Connolly S.J.
      • Gao P.
      • et al.
      Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease.
      and among renal function strata in patients who had previously tried and failed VKA therapy
      • Coppens M.
      • Synhorst D.
      • Eikelboom J.W.
      • Yusuf S.
      • Shestakovska O.
      • Connolly S.J.
      Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial.
      (Figure 1A and B).
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Alexander J.H.
      • Andersson U.
      • Lopes R.D.
      • et al.
      Apixaban 5 mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine: a secondary analysis of a randomized clinical trial.
      • Hijazi Z.
      • Hohnloser S.H.
      • Andersson U.
      • et al.
      Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Eikelboom J.W.
      • Connolly S.J.
      • Gao P.
      • et al.
      Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease.
      • Coppens M.
      • Synhorst D.
      • Eikelboom J.W.
      • Yusuf S.
      • Shestakovska O.
      • Connolly S.J.
      Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial.
      In addition, an analysis by Lip and colleagues
      • Lip G.Y.
      • Connolly S.
      • Yusuf S.
      • et al.
      Modification of outcomes with aspirin or apixaban in relation to CHADS(2) and CHA(2)DS(2)-VASc scores in patients with atrial fibrillation: a secondary analysis of the AVERROES study.
      found that risk of stroke was increased in patients with renal dysfunction (eGFR <60 mL/min per 1.73 m2) who received aspirin, whereas no such increase was observed in the apixaban treatment group.
      The ADVANCE-2 and ADVANCE-3 clinical trials examined venous thromboembolism (VTE) prophylaxis with apixaban 2.5 mg BID vs enoxaparin 40 mg once daily (OD) in patients undergoing elective total knee arthroplasty (TKA) or total hip arthroplasty (THA).
      • Pineo G.F.
      • Gallus A.S.
      • Raskob G.E.
      • et al.
      Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups.
      Notably, CrCL less than 30 mL/min was an exclusion criterion in both studies. No significant differences in VTE or major bleeding rates were observed among renal function subgroups (Figure 1C
      • Pineo G.F.
      • Gallus A.S.
      • Raskob G.E.
      • et al.
      Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups.
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      Apixaban for extended treatment of venous thromboembolism.
      and data not shown). However, there did seem to be a reduced risk of major and clinically relevant nonmajor bleeding with apixaban vs enoxaparin in patients with CrCL of 51 to 80 mL/min, which was not observed in other renal function subgroups (Figure 1D).
      • Pineo G.F.
      • Gallus A.S.
      • Raskob G.E.
      • et al.
      Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups.
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      Apixaban for extended treatment of venous thromboembolism.
      Two studies of apixaban for the treatment of VTE were identified: AMPLIFY-J
      • Nakamura M.
      • Nishikawa M.
      • Komuro I.
      • et al.
      Apixaban for the treatment of Japanese subjects with acute venous thromboembolism (AMPLIFY-J Study).
      and AMPLIFY-EXT.
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      Apixaban for extended treatment of venous thromboembolism.
      Both studies excluded patients with severe renal impairment (CrCL <25 mL/min). The AMPLIFY-J study randomized 80 Japanese patients with symptomatic proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) (with or without DVT) to receive treatment with apixaban (10 mg BID for 7 days, followed by 5 mg BID for 23 weeks) or unfractionated heparin/warfarin.
      • Nakamura M.
      • Nishikawa M.
      • Komuro I.
      • et al.
      Apixaban for the treatment of Japanese subjects with acute venous thromboembolism (AMPLIFY-J Study).
      In this small cohort, no difference was observed in recurrent VTE rates between treatment groups, although the major and clinically relevant nonmajor bleeding rate was lower with apixaban. Results were consistent in the predefined renal subgroup analyses. In AMPLIFY-EXT, patients with symptomatic DVT or PE (with or without DVT) who had completed 6 to 12 months of anticoagulation therapy received apixaban 2.5 or 5.0 mg BID or placebo for 12 months.
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      Apixaban for extended treatment of venous thromboembolism.
      The risk of the composite efficacy end point of symptomatic recurrent VTE and all-cause mortality was consistent in renal function subgroups with that of the overall population (Figure 1C).
      • Pineo G.F.
      • Gallus A.S.
      • Raskob G.E.
      • et al.
      Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups.
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      Apixaban for extended treatment of venous thromboembolism.
      Lower rates of hospitalization were also observed with apixaban vs placebo regardless of renal function.
      • Liu X.
      • Thompson J.
      • Phatak H.
      • et al.
      Extended anticoagulation with apixaban reduces hospitalisations in patients with venous thromboembolism: an analysis of the AMPLIFY-EXT trial.
      Bleeding outcomes were comparable among renal function subgroups, although the small numbers of patients with moderate renal impairment and the low event rates suggest caution in interpretation of these data
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      Apixaban for extended treatment of venous thromboembolism.
      (Figure 1D).
      • Pineo G.F.
      • Gallus A.S.
      • Raskob G.E.
      • et al.
      Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups.
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      Apixaban for extended treatment of venous thromboembolism.

      Dabigatran

      Influence of Renal Function on Dabigatran PK/PD

      Elimination of dabigatran, a direct thrombin inhibitor, occurs predominantly via renal excretion (80%).
      Of all the NOACs, the PK of dabigatran depends most critically on renal function. In the pivotal dabigatran PK study, drug exposure was 1.5, 3.2, and 6.3 times greater in patients with mild, moderate, or severe renal impairment, respectively, compared with healthy individuals.
      • Stangier J.
      • Rathgen K.
      • Stahle H.
      • Mazur D.
      Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study.
      The mean half-life of dabigatran increased with decreasing renal function, resulting in an approximately 2 times longer half-life in patients with severe renal impairment (CrCL <30 mL/min) compared with those without renal insufficiency.
      An early population PK analysis by Trocóniz et al
      • Trocóniz I.F.
      • Tillmann C.
      • Liesenfeld K.H.
      • Schafer H.G.
      • Stangier J.
      Population pharmacokinetic analysis of the new oral thrombin inhibitor dabigatran etexilate (BIBR 1048) in patients undergoing primary elective total hip replacement surgery.
      reported overlapping simulation-predicted dabigatran drug concentration-vs-time profiles for patients with normal renal function and those with mild, moderate, or severe renal impairment. In addition, using data from a phase 3 study (RE-LY), simulations by Liesenfeld et al
      • Liesenfeld K.H.
      • Lehr T.
      • Dansirikul C.
      • et al.
      Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial.
      predicted similar exposures with 75 mg BID in patients with severe renal impairment to those of 150 mg BID in patients with normal renal function. The RE-LY study compared 2 doses of dabigatran (110 and 150 mg BID) with warfarin for the prevention of stroke and systemic embolism in patients with AF and at least 1 additional stroke risk factor
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      (Table).
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Hylek E.M.
      • Held C.
      • Alexander J.H.
      • et al.
      Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): predictors, characteristics, and clinical outcomes.
      • Alexander J.H.
      • Andersson U.
      • Lopes R.D.
      • et al.
      Apixaban 5 mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine: a secondary analysis of a randomized clinical trial.
      • Hijazi Z.
      • Hohnloser S.H.
      • Andersson U.
      • et al.
      Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Eikelboom J.W.
      • Connolly S.J.
      • Gao P.
      • et al.
      Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease.
      • Lip G.Y.
      • Connolly S.
      • Yusuf S.
      • et al.
      Modification of outcomes with aspirin or apixaban in relation to CHADS(2) and CHA(2)DS(2)-VASc scores in patients with atrial fibrillation: a secondary analysis of the AVERROES study.
      • Coppens M.
      • Synhorst D.
      • Eikelboom J.W.
      • Yusuf S.
      • Shestakovska O.
      • Connolly S.J.
      Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial.
      • Pineo G.F.
      • Gallus A.S.
      • Raskob G.E.
      • et al.
      Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups.
      • Nakamura M.
      • Nishikawa M.
      • Komuro I.
      • et al.
      Apixaban for the treatment of Japanese subjects with acute venous thromboembolism (AMPLIFY-J Study).
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      Apixaban for extended treatment of venous thromboembolism.
      • Liu X.
      • Thompson J.
      • Phatak H.
      • et al.
      Extended anticoagulation with apixaban reduces hospitalisations in patients with venous thromboembolism: an analysis of the AMPLIFY-EXT trial.
      • Hijazi Z.
      • Hohnloser S.H.
      • Oldgren J.
      • et al.
      Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis.
      • Hori M.
      • Fukaya T.
      • Kleine E.
      • et al.
      Efficacy and safety of dabigatran etexilate vs. warfarin in Asian RE-LY patients according to baseline renal function or CHADS2 score.
      • Böhm M.
      • Ezekowitz M.D.
      • Connolly S.J.
      • et al.
      Changes in renal function in patients with atrial fibrillation: an analysis from the RE-LY trial.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials.
      • Majeed A.
      • Goldhaber S.Z.
      • Kakkar A.
      • et al.
      Bleeding events with dabigatran or warfarin in patients with venous thromboembolism.
      • Giugliano R.P.
      • Ruff C.T.
      • Braunwald E.
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      • Eisen A.
      • Giugliano R.P.
      • Ruff C.T.
      • et al.
      Edoxaban vs warfarin in patients with nonvalvular atrial fibrillation in the US Food and Drug Administration approval population: an analysis from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial.
      • Bohula E.A.
      • Giugliano R.P.
      • Ruff C.T.
      • et al.
      Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 trial.
      • Goette A.
      • Merino J.L.
      • Ezekowitz M.D.
      • et al.
      Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial.
      • Buller H.R.
      • Decousus H.
      • Grosso M.A.
      • et al.
      Hokusai-VTE Investigators
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Fox K.A.
      • Piccini J.P.
      • Wojdyla D.
      • et al.
      Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment.
      • Goodman S.G.
      • Wojdyla D.M.
      • Piccini J.P.
      • et al.
      Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation).
      • Wong K.S.
      • Hu D.Y.
      • Oomman A.
      • et al.
      Rivaroxaban for stroke prevention in East Asian patients from the ROCKET AF trial.
      • Fordyce C.B.
      • Hellkamp A.S.
      • Lokhnygina Y.
      • et al.
      On-treatment outcomes in patients with worsening renal function with rivaroxaban compared with warfarin: insights from ROCKET AF.
      • Lindner S.M.
      • Fordyce C.B.
      • Hellkamp A.S.
      • et al.
      Treatment consistency across levels of baseline renal function with rivaroxaban or warfarin: a ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) analysis.
      • Hori M.
      • Matsumoto M.
      • Tanahashi N.
      • et al.
      Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation: the J-ROCKET AF study.
      • Hori M.
      • Matsumoto M.
      • Tanahashi N.
      • et al.
      Safety and efficacy of adjusted dose of rivaroxaban in Japanese patients with non-valvular atrial fibrillation: subanalysis of J-ROCKET AF for patients with moderate renal impairment.
      • Hori M.
      • Matsumoto M.
      • Tanahashi N.
      • et al.
      Rivaroxaban vs. warfarin in Japanese patients with non-valvular atrial fibrillation in relation to age.
      • Uchiyama S.
      • Hori M.
      • Matsumoto M.
      • et al.
      Net clinical benefit of rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation: a subgroup analysis of J-ROCKET AF.
      • Turpie A.G.
      • Lassen M.R.
      • Eriksson B.I.
      • et al.
      Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty: pooled analysis of four studies.
      • Bauersachs R.
      • Berkowitz S.D.
      • Brenner B.
      • et al.
      EINSTEIN Investigators
      Oral rivaroxaban for symptomatic venous thromboembolism.
      • Buller H.R.
      • Prins M.H.
      • Lensin A.W.
      • et al.
      EINSTEIN-PE Investigators
      Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
      • Wang Y.
      • Wang C.
      • Chen Z.
      • et al.
      Rivaroxaban for the treatment of symptomatic deep-vein thrombosis and pulmonary embolism in Chinese patients: a subgroup analysis of the EINSTEIN DVT and PE studies.
      • Bauersachs R.M.
      • Lensing A.W.
      • Prins M.H.
      • et al.
      Rivaroxaban versus enoxaparin/vitamin K antagonist therapy in patients with venous thromboembolism and renal impairment.
      • Weitz J.I.
      • Lensing A.W.A.
      • Prins M.H.
      • et al.
      Rivaroxaban or aspirin for extended treatment of venous thromboembolism.
      Patients with CrCL less than 30 mL/min were excluded from the study. Use of the 75-mg dose in patients with severe renal impairment was further supported by simulations performed by Hariharan and Madabushi
      • Hariharan S.
      • Madabushi R.
      Clinical pharmacology basis of deriving dosing recommendations for dabigatran in patients with severe renal impairment.
      and Lehr et al.
      • Lehr T.
      • Haertter S.
      • Liesenfeld K.H.
      • et al.
      Dabigatran etexilate in atrial fibrillation patients with severe renal impairment: dose identification using pharmacokinetic modeling and simulation.
      Use of a 75-mg BID regimen (as well as 110- and 150-mg BID regimens) was also tested in simulations of patients undergoing maintenance hemodialysis.
      • Liesenfeld K.H.
      • Clemens A.
      • Kreuzer J.
      • Brueckmann M.
      • Schulze F.
      Dabigatran treatment simulation in patients undergoing maintenance haemodialysis.
      All of the BID dosing regimens resulted in higher exposures than predicted for the typical RE-LY patient. In contrast, simulated exposures with dabigatran 75 and 110 mg OD were more aligned with the prototypical RE-LY patient.
      Only recently, the PK of lower-dose dabigatran (75 mg BID) was directly measured in an open-label, single-center study that enrolled 16 patients with severe renal impairment (CrCL of 15-30 mL/min).
      • Kooiman J.
      • van der Hulle T.
      • Maas H.
      • et al.
      Pharmacokinetics and pharmacodynamics of dabigatran 75 mg b.i.d. in patients with severe chronic kidney disease.
      During the 7.5-day treatment period, mean steady-state drug exposures were comparable with model-predicted values. The study also demonstrated that dabigatran 75 mg BID in patients with severe renal impairment is not associated with drug accumulation beyond 5 days of treatment.
      A single-arm, open-label study assessed dabigatran 150 mg OD in patients undergoing elective TKA or THA who had moderate renal impairment.
      • Eriksson B.I.
      • Mikuska Z.
      • Feuring M.
      • et al.
      An open-label study of the pharmacokinetics and pharmacodynamics of dabigatran etexilate 150mg once daily in Caucasian patients with moderate renal impairment undergoing primary unilateral elective total knee or hip replacement surgery.
      Trough dabigatran concentrations in this population were similar to previous reports in patients with mild renal impairment.
      Dabigatran has been studied in patients with ESRD receiving hemodialysis but with an eye toward removing circulating drug levels in those with a bleeding emergency rather than assessing clinical utility. Hemodialysis has proved to be an effective means to remove dabigatran from the circulation.
      • Stangier J.
      • Rathgen K.
      • Stahle H.
      • Mazur D.
      Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study.
      • Khadzhynov D.
      • Wagner F.
      • Formella S.
      • et al.
      Effective elimination of dabigatran by haemodialysis: a phase I single-centre study in patients with end-stage renal disease.
      • Wilson J.A.
      • Goralski K.B.
      • Soroka S.D.
      • et al.
      An evaluation of oral dabigatran etexilate pharmacokinetics and pharmacodynamics in hemodialysis.
      Multiple studies and population PK models have reported a strong correlation between CrCL and dabigatran CL/F, as well as an increase in dabigatran exposure in patients with renal impairment.
      • Stangier J.
      • Rathgen K.
      • Stahle H.
      • Mazur D.
      Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study.
      • Trocóniz I.F.
      • Tillmann C.
      • Liesenfeld K.H.
      • Schafer H.G.
      • Stangier J.
      Population pharmacokinetic analysis of the new oral thrombin inhibitor dabigatran etexilate (BIBR 1048) in patients undergoing primary elective total hip replacement surgery.
      • Liesenfeld K.H.
      • Lehr T.
      • Dansirikul C.
      • et al.
      Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial.
      • Hariharan S.
      • Madabushi R.
      Clinical pharmacology basis of deriving dosing recommendations for dabigatran in patients with severe renal impairment.
      • Eriksson B.I.
      • Dahl O.E.
      • Ahnfelt L.
      • et al.
      Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I.
      • Dansirikul C.
      • Lehr T.
      • Liesenfeld K.H.
      • Haertter S.
      • Staab A.
      A combined pharmacometric analysis of dabigatran etexilate in healthy volunteers and patients with atrial fibrillation or undergoing orthopaedic surgery.
      • Reilly P.A.
      • Lehr T.
      • Haertter S.
      • et al.
      The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy).
      • Shimomura D.
      • Nakagawa Y.
      • Kondo H.
      • et al.
      Relationship between plasma dabigatran concentration and activated partial thromboplastin time in Japanese patients with non-valvular atrial fibrillation.
      • Matsuda S.
      • Imazu T.
      • Kimura R.
      • et al.
      Dosage adjustment of dabigatran etexilate based on creatinine clearance in patients with cardioembolic stroke or atrial fibrillation.
      • Tomita H.
      • Araki T.
      • Kadokami T.
      • et al.
      Factors influencing trough and 90-minute plasma dabigatran etexilate concentrations among patients with non-valvular atrial fibrillation.
      Commensurate effects on efficacy and safety are possible because anticoagulant activity is linearly related to plasma dabigatran concentration.
      • Khadzhynov D.
      • Wagner F.
      • Formella S.
      • et al.
      Effective elimination of dabigatran by haemodialysis: a phase I single-centre study in patients with end-stage renal disease.
      • Shimomura D.
      • Nakagawa Y.
      • Kondo H.
      • et al.
      Relationship between plasma dabigatran concentration and activated partial thromboplastin time in Japanese patients with non-valvular atrial fibrillation.
      • Tomita H.
      • Araki T.
      • Kadokami T.
      • et al.
      Factors influencing trough and 90-minute plasma dabigatran etexilate concentrations among patients with non-valvular atrial fibrillation.

      Influence of Renal Function on Dabigatran Efficacy and Safety

      In the RE-LY study, dabigatran 110 mg produced similar reductions in stroke and systemic embolism to those of warfarin, with a lower rate of major bleeding.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      Dabigatran 150 mg decreased the risk of stroke or systemic embolism more than warfarin but had a comparable rate of major bleeding. In the original assessment, wherein CrCL was estimated using the Cockcroft-Gault equation, the results for the primary efficacy and safety end points were consistent across renal function subgroups (Figure 2A and B ).
      • Hijazi Z.
      • Hohnloser S.H.
      • Oldgren J.
      • et al.
      Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis.
      • Hori M.
      • Fukaya T.
      • Kleine E.
      • et al.
      Efficacy and safety of dabigatran etexilate vs. warfarin in Asian RE-LY patients according to baseline renal function or CHADS2 score.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      However, a subsequent assessment, in which renal function was estimated using the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease Study Group equations, detected a significant interaction (P<.05) between treatment and renal function such that a notable reduction in major bleeding was observed with either dose of dabigatran compared with warfarin in patients with an eGFR of at least 80 mL/min per 1.73 m2 but not in patients with renal impairment (Figure 2B
      • Hijazi Z.
      • Hohnloser S.H.
      • Oldgren J.
      • et al.
      Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis.
      • Hori M.
      • Fukaya T.
      • Kleine E.
      • et al.
      Efficacy and safety of dabigatran etexilate vs. warfarin in Asian RE-LY patients according to baseline renal function or CHADS2 score.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      and data not shown). No interaction was found between treatment effects (either efficacy or safety) and renal function in a subsequent Asian subgroup analysis; however, CrCL was calculated using the Cockcroft-Gault equation in this analysis.
      • Hori M.
      • Fukaya T.
      • Kleine E.
      • et al.
      Efficacy and safety of dabigatran etexilate vs. warfarin in Asian RE-LY patients according to baseline renal function or CHADS2 score.
      Figure thumbnail gr2
      Figure 2Relative efficacy and safety of dabigatran in renal function subgroups.
      • Hijazi Z.
      • Hohnloser S.H.
      • Oldgren J.
      • et al.
      Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis.
      • Hori M.
      • Fukaya T.
      • Kleine E.
      • et al.
      Efficacy and safety of dabigatran etexilate vs. warfarin in Asian RE-LY patients according to baseline renal function or CHADS2 score.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials.
      • Majeed A.
      • Goldhaber S.Z.
      • Kakkar A.
      • et al.
      Bleeding events with dabigatran or warfarin in patients with venous thromboembolism.
      Forest plots of hazard ratios and 95% CIs for (A) stroke and systemic embolism in atrial fibrillation (AF) clinical trials,
      • Hijazi Z.
      • Hohnloser S.H.
      • Oldgren J.
      • et al.
      Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis.
      • Hori M.
      • Fukaya T.
      • Kleine E.
      • et al.
      Efficacy and safety of dabigatran etexilate vs. warfarin in Asian RE-LY patients according to baseline renal function or CHADS2 score.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      (B) major bleeding in AF clinical trials,
      • Hijazi Z.
      • Hohnloser S.H.
      • Oldgren J.
      • et al.
      Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis.
      • Hori M.
      • Fukaya T.
      • Kleine E.
      • et al.
      Efficacy and safety of dabigatran etexilate vs. warfarin in Asian RE-LY patients according to baseline renal function or CHADS2 score.
      (C) total venous thromboembolism (VTE) and all-cause mortality in deep vein thrombosis (DVT) prophylaxis clinical trials,
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials.
      and (D) major and clinically relevant nonmajor bleeding in VTE treatment clinical trials.
      • Majeed A.
      • Goldhaber S.Z.
      • Kakkar A.
      • et al.
      Bleeding events with dabigatran or warfarin in patients with venous thromboembolism.
      Data for Eriksson et al
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials.
      are absolute risk differences (the difference in the proportion of patients with an event) rather than hazard ratios.
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials.
      aCreatinine clearance as determined by the Cockcroft-Gault equation. bEstimated glomerular filtration rate as determined by the Chronic Kidney Disease Epidemiology Collaboration equation. All definitions and renal function categories are maintained as used in the original studies.
      Böhm et al
      • Böhm M.
      • Ezekowitz M.D.
      • Connolly S.J.
      • et al.
      Changes in renal function in patients with atrial fibrillation: an analysis from the RE-LY trial.
      conducted an analysis of changes in renal function during RE-LY. Over a 30-month observation period, significantly greater mean ± SE declines in renal function were observed in patients who received warfarin (GFR, –3.68±0.24 mL/min) compared with either dabigatran 110 mg (GFR, –2.57±0.24 mL/min; P=.0009 vs warfarin) or dabigatran 150 mg (GFR, –2.46±0.23 mL/min; P=.0002 vs warfarin).
      • Böhm M.
      • Ezekowitz M.D.
      • Connolly S.J.
      • et al.
      Changes in renal function in patients with atrial fibrillation: an analysis from the RE-LY trial.
      The effect of renal function on efficacy and safety measures was also evaluated in a pooled analysis from RE-NOVATE and RE-NOVATE II.
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials.
      Patients in both studies received dabigatran (150 or 220 mg) or enoxaparin 40 mg OD for DVT prevention after elective THA. Because RE-NOVATE II did not include the 150-mg dose, only the 220-mg dose was evaluated in the pooled analysis. Reductions in VTE and all-cause mortality (the primary efficacy outcome) were consistent across renal function strata (Figure 2C).
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials.
      An observational study of dabigatran 150 mg OD was recently conducted in patients with moderate renal impairment undergoing elective TKA or THA.
      • Samama C.M.
      • Rosencher N.
      • Kleine E.
      • et al.
      Observational study of dabigatran etexilate 150mg in patients with moderate renal impairment undergoing elective total hip or knee replacement.
      In this study, the rates of major bleeding (2.1%) and symptomatic VTE or death (0.7%) were low, suggesting that the lower dosing regimen may be appropriate for patients with moderate renal impairment.
      The effects of renal function on bleeding risk were described in 2 pooled analyses. Using data from the RE-LY, RE-COVER, RE-COVER II, RE-MEDY, and RE-SONATE trials, Majeed et al
      • Majeed A.
      • Hwang H.G.
      • Connolly S.J.
      • et al.
      Management and outcomes of major bleeding during treatment with dabigatran or warfarin.
      reported that patients who experienced major bleeding while receiving dabigatran had lower mean CrCL values compared with those who experienced major bleeding while taking warfarin. No significant interaction was found between treatment and renal function subgroup with respect to bleeding events in a separate pooled analysis from the RE-COVER and RE-COVER II trials, which compared dabigatran and warfarin for the treatment of symptomatic proximal DVT or PE (Figure 2D).
      • Majeed A.
      • Goldhaber S.Z.
      • Kakkar A.
      • et al.
      Bleeding events with dabigatran or warfarin in patients with venous thromboembolism.

      Edoxaban

      Influence of Renal Function on Edoxaban PK/PD

      The direct factor Xa inhibitor edoxaban is eliminated via renal and nonrenal pathways, with approximately 50% of total clearance accounted for by renal clearance.
      Edoxaban area under the plasma concentration-time curve increases with decreasing renal function, with 32%, 74%, and 72% higher levels of exposure reported in patients with mild, moderate, and severe renal impairment, respectively, compared with healthy individuals.
      • Parasrampuria D.A.
      • Truitt K.E.
      Pharmacokinetics and pharmacodynamics of edoxaban, a non-vitamin K antagonist oral anticoagulant that inhibits clotting factor Xa.
      To offset the increased exposure, a 50% dose reduction in patients with moderate or severe renal impairment was suggested by Salazar et al
      • Salazar D.E.
      • Mendell J.
      • Kastrissios H.
      • et al.
      Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation.
      and Yin et al
      • Yin O.Q.
      • Tetsuya K.
      • Miller R.
      Edoxaban population pharmacokinetics and exposure-response analysis in patients with non-valvular atrial fibrillation.
      based on PK model predictions. However, using data from clinical trials in which the dose reduction was applied in patients with moderate renal impairment, 2 subsequent population PK analyses determined that the resulting exposures from this dose reduction were lower than those of patients receiving a standard edoxaban dose.
      • Niebecker R.
      • Jonsson S.
      • Karlsson M.O.
      • et al.
      Population pharmacokinetics of edoxaban in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism: the Hokusai-VTE phase 3 study.
      • Krekels E.H.
      • Niebecker R.
      • Karlsson M.O.
      • et al.
      Population pharmacokinetics of edoxaban in patients with non-valvular atrial fibrillation in the ENGAGE AF-TIMI 48 study, a phase III clinical trial.
      In patients with moderate renal impairment who were given a dose reduction (30 mg OD) in the Hokusai-VTE study, clinically relevant bleeding was lower than in the 60-mg OD dose group (7.91% and 8.60%, respectively), although recurrent VTE occurred more frequently (1.77% and 1.57%, respectively).
      • Nyberg J.
      • Karlsson K.E.
      • Jonsson S.
      • et al.
      Edoxaban exposure-response analysis and clinical utility index assessment in patients with symptomatic deep-vein thrombosis or pulmonary embolism.
      A third modeling analysis determined that in patients with severe renal impairment, a dose reduction to 30 mg OD resulted in similar predicted exposure levels to those of patients with normal or mild renal impairment receiving the standard 60-mg OD dose.
      • Shimizu T.
      • Tachibana M.
      • Kimura T.
      • Kumakura T.
      • Yoshihara K.
      Population pharmacokinetics of edoxaban in Japanese atrial fibrillation patients with severe renal impairment.
      Clinical data supporting dose reduction come from a 12-week open-label study in which Japanese patients with nonvalvular AF and severe renal impairment received edoxaban 15 mg OD and patients with normal renal function or mild renal impairment were randomized to receive edoxaban 30 or 60 mg OD.
      • Koretsune Y.
      • Yamashita T.
      • Kimura T.
      • Fukuzawa M.
      • Abe K.
      • Yasaka M.
      Short-term safety and plasma concentrations of edoxaban in Japanese patients with non-valvular atrial fibrillation and severe renal impairment.
      Plasma concentrations, bleeding rates, and biomarker profiles were comparable among the treatment groups.
      Use of edoxaban in patients with ESRD on hemodialysis was investigated in an open-label study in which patients received a single dose of edoxaban 15 mg either 2 hours before dialysis or on off-dialysis days.
      • Parasrampuria D.A.
      • Marbury T.
      • Matsushima N.
      • et al.
      Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis.
      Hemodialysis resulted in a slight decrease in edoxaban exposure compared with observations in the off-dialysis population, but not enough to justify a change in dose.
      Multiple population PK analyses detected a significant correlation between CrCL and edoxaban CL/F.
      • Salazar D.E.
      • Mendell J.
      • Kastrissios H.
      • et al.
      Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation.
      • Yin O.Q.
      • Tetsuya K.
      • Miller R.
      Edoxaban population pharmacokinetics and exposure-response analysis in patients with non-valvular atrial fibrillation.
      • Krekels E.H.
      • Niebecker R.
      • Karlsson M.O.
      • et al.
      Population pharmacokinetics of edoxaban in patients with non-valvular atrial fibrillation in the ENGAGE AF-TIMI 48 study, a phase III clinical trial.
      • Rohatagi S.
      • Mendell J.
      • Kastrissios H.
      • et al.
      Characterisation of exposure versus response of edoxaban in patients undergoing total hip replacement surgery.
      Correlations were also observed between model-predicted increases in edoxaban exposure and degree of renal impairment, with the greatest elevations in the lowest tier of CrCL.
      • Salazar D.E.
      • Mendell J.
      • Kastrissios H.
      • et al.
      Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation.
      • Jonsson S.
      • Simonsson U.S.
      • Miller R.
      • Karlsson M.O.
      Population pharmacokinetics of edoxaban and its main metabolite in a dedicated renal impairment study.

      Influence of Renal Function on Edoxaban Efficacy and Safety

      Three edoxaban clinical trials assessed efficacy and safety based on renal function: ENGAGE AF-TIMI 48, ENSURE-AF, and Hokusai-VTE (Table).
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Hylek E.M.
      • Held C.
      • Alexander J.H.
      • et al.
      Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): predictors, characteristics, and clinical outcomes.
      • Alexander J.H.
      • Andersson U.
      • Lopes R.D.
      • et al.
      Apixaban 5 mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine: a secondary analysis of a randomized clinical trial.
      • Hijazi Z.
      • Hohnloser S.H.
      • Andersson U.
      • et al.
      Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Eikelboom J.W.
      • Connolly S.J.
      • Gao P.
      • et al.
      Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease.
      • Lip G.Y.
      • Connolly S.
      • Yusuf S.
      • et al.
      Modification of outcomes with aspirin or apixaban in relation to CHADS(2) and CHA(2)DS(2)-VASc scores in patients with atrial fibrillation: a secondary analysis of the AVERROES study.
      • Coppens M.
      • Synhorst D.
      • Eikelboom J.W.
      • Yusuf S.
      • Shestakovska O.
      • Connolly S.J.
      Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial.
      • Pineo G.F.
      • Gallus A.S.
      • Raskob G.E.
      • et al.
      Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups.
      • Nakamura M.
      • Nishikawa M.
      • Komuro I.
      • et al.
      Apixaban for the treatment of Japanese subjects with acute venous thromboembolism (AMPLIFY-J Study).
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      Apixaban for extended treatment of venous thromboembolism.
      • Liu X.
      • Thompson J.
      • Phatak H.
      • et al.
      Extended anticoagulation with apixaban reduces hospitalisations in patients with venous thromboembolism: an analysis of the AMPLIFY-EXT trial.
      • Hijazi Z.
      • Hohnloser S.H.
      • Oldgren J.
      • et al.
      Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis.
      • Hori M.
      • Fukaya T.
      • Kleine E.
      • et al.
      Efficacy and safety of dabigatran etexilate vs. warfarin in Asian RE-LY patients according to baseline renal function or CHADS2 score.
      • Böhm M.
      • Ezekowitz M.D.
      • Connolly S.J.
      • et al.
      Changes in renal function in patients with atrial fibrillation: an analysis from the RE-LY trial.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials.
      • Majeed A.
      • Goldhaber S.Z.
      • Kakkar A.
      • et al.
      Bleeding events with dabigatran or warfarin in patients with venous thromboembolism.
      • Giugliano R.P.
      • Ruff C.T.
      • Braunwald E.
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      • Eisen A.
      • Giugliano R.P.
      • Ruff C.T.
      • et al.
      Edoxaban vs warfarin in patients with nonvalvular atrial fibrillation in the US Food and Drug Administration approval population: an analysis from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial.
      • Bohula E.A.
      • Giugliano R.P.
      • Ruff C.T.
      • et al.
      Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 trial.
      • Goette A.
      • Merino J.L.
      • Ezekowitz M.D.
      • et al.
      Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial.
      • Buller H.R.
      • Decousus H.
      • Grosso M.A.
      • et al.
      Hokusai-VTE Investigators
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Fox K.A.
      • Piccini J.P.
      • Wojdyla D.
      • et al.
      Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment.
      • Goodman S.G.
      • Wojdyla D.M.
      • Piccini J.P.
      • et al.
      Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation).
      • Wong K.S.
      • Hu D.Y.
      • Oomman A.
      • et al.
      Rivaroxaban for stroke prevention in East Asian patients from the ROCKET AF trial.
      • Fordyce C.B.
      • Hellkamp A.S.
      • Lokhnygina Y.
      • et al.
      On-treatment outcomes in patients with worsening renal function with rivaroxaban compared with warfarin: insights from ROCKET AF.
      • Lindner S.M.
      • Fordyce C.B.
      • Hellkamp A.S.
      • et al.
      Treatment consistency across levels of baseline renal function with rivaroxaban or warfarin: a ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) analysis.
      • Hori M.
      • Matsumoto M.
      • Tanahashi N.
      • et al.
      Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation: the J-ROCKET AF study.
      • Hori M.
      • Matsumoto M.
      • Tanahashi N.
      • et al.
      Safety and efficacy of adjusted dose of rivaroxaban in Japanese patients with non-valvular atrial fibrillation: subanalysis of J-ROCKET AF for patients with moderate renal impairment.
      • Hori M.
      • Matsumoto M.
      • Tanahashi N.
      • et al.
      Rivaroxaban vs. warfarin in Japanese patients with non-valvular atrial fibrillation in relation to age.
      • Uchiyama S.
      • Hori M.
      • Matsumoto M.
      • et al.
      Net clinical benefit of rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation: a subgroup analysis of J-ROCKET AF.
      • Turpie A.G.
      • Lassen M.R.
      • Eriksson B.I.
      • et al.
      Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty: pooled analysis of four studies.
      • Bauersachs R.
      • Berkowitz S.D.
      • Brenner B.
      • et al.
      EINSTEIN Investigators
      Oral rivaroxaban for symptomatic venous thromboembolism.
      • Buller H.R.
      • Prins M.H.
      • Lensin A.W.
      • et al.
      EINSTEIN-PE Investigators
      Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
      • Wang Y.
      • Wang C.
      • Chen Z.
      • et al.
      Rivaroxaban for the treatment of symptomatic deep-vein thrombosis and pulmonary embolism in Chinese patients: a subgroup analysis of the EINSTEIN DVT and PE studies.
      • Bauersachs R.M.
      • Lensing A.W.
      • Prins M.H.
      • et al.
      Rivaroxaban versus enoxaparin/vitamin K antagonist therapy in patients with venous thromboembolism and renal impairment.
      • Weitz J.I.
      • Lensing A.W.A.
      • Prins M.H.
      • et al.
      Rivaroxaban or aspirin for extended treatment of venous thromboembolism.
      ENGAGE AF-TIMI 48 randomized patients with AF and CHADS2 of 2 or greater to receive edoxaban 60 mg OD, edoxaban 30 mg OD, or warfarin.
      • Giugliano R.P.
      • Ruff C.T.
      • Braunwald E.
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      Patients with CrCL less than 30 mL/min were excluded from the study, and the edoxaban dose was reduced by 50% in patients with CrCL of 30 to 50 mL/min in both dosing groups. In the overall population, treatment with either dose of edoxaban reduced the risk of stroke or systemic embolism and was associated with lower rates of bleeding and mortality compared with warfarin. Those in the higher edoxaban dose group who received a reduction due to renal impairment, the decline in bleeding observed with edoxaban was further augmented.
      • Eisen A.
      • Giugliano R.P.
      • Ruff C.T.
      • et al.
      Edoxaban vs warfarin in patients with nonvalvular atrial fibrillation in the US Food and Drug Administration approval population: an analysis from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial.
      When parsed into groups with CrCL of 30 to 50 mL/min vs greater than 50 mL/min, the relative efficacy was equivalent (Figure 3A).
      • Eisen A.
      • Giugliano R.P.
      • Ruff C.T.
      • et al.
      Edoxaban vs warfarin in patients with nonvalvular atrial fibrillation in the US Food and Drug Administration approval population: an analysis from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial.
      • Bohula E.A.
      • Giugliano R.P.
      • Ruff C.T.
      • et al.
      Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 trial.
      Yet, exploratory analyses suggest some decline in benefit at higher CrCL levels (hazard ratio [HR], 0.78; 95% CI, 0.64-0.96 for CrCL >50-95 mL/min; HR, 1.36; 95% CI, 0.88-2.10 for CrCL >95 mL/min) in the comparison between edoxaban and warfarin.
      • Bohula E.A.
      • Giugliano R.P.
      • Ruff C.T.
      • et al.
      Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 trial.
      The Food and Drug Administration has limited approval of high-dose edoxaban to patients with a CrCL of 95 mL/min or lower based on the increased risk of ischemic stroke in patients with CrCL greater than 95 mL/min in this trial.
      Figure thumbnail gr3
      Figure 3Relative efficacy and safety of edoxaban in renal function subgroups.
      • Bohula E.A.
      • Giugliano R.P.
      • Ruff C.T.
      • et al.
      Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 trial.
      • Goette A.
      • Merino J.L.
      • Ezekowitz M.D.
      • et al.
      Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial.
      • Buller H.R.
      • Decousus H.
      • Grosso M.A.
      • et al.
      Hokusai-VTE Investigators
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
      Forest plots of hazard ratios and 95% CIs for (A) stroke and systemic embolism in atrial fibrillation (AF) clinical trials,
      • Bohula E.A.
      • Giugliano R.P.
      • Ruff C.T.
      • et al.
      Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 trial.
      • Goette A.
      • Merino J.L.
      • Ezekowitz M.D.
      • et al.
      Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial.
      (B) major bleeding
      • Bohula E.A.
      • Giugliano R.P.
      • Ruff C.T.
      • et al.
      Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 trial.
      or major and clinically relevant nonmajor bleeding
      • Goette A.
      • Merino J.L.
      • Ezekowitz M.D.
      • et al.
      Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial.
      in AF clinical trials, (C) recurrent venous thromboembolism (VTE) in VTE treatment clinical trials,
      • Buller H.R.
      • Decousus H.
      • Grosso M.A.
      • et al.
      Hokusai-VTE Investigators
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
      and (D) major and clinically relevant nonmajor bleeding in VTE treatment clinical trials.
      • Buller H.R.
      • Decousus H.
      • Grosso M.A.
      • et al.
      Hokusai-VTE Investigators
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
      Relative risk values for the ENSURE-AF efficacy and safety analyses were calculated from event rates provided by Goette et al.
      • Goette A.
      • Merino J.L.
      • Ezekowitz M.D.
      • et al.
      Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial.
      All definitions and renal function categories are maintained as used in the original studies.
      ENSURE-AF compared edoxaban 60 mg OD with enoxaparin/warfarin in patients with nonvalvular AF undergoing cardioversion.
      • Goette A.
      • Merino J.L.
      • Ezekowitz M.D.
      • et al.
      Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial.
      The edoxaban dose was reduced to 30 mg OD in patients with CrCL of 15 to 50 mL/min. In the overall cohort, rates of thromboembolism and major bleeding were similar with edoxaban and enoxaparin/warfarin. No difference in the primary efficacy end point (composite of stroke, systemic embolism, myocardial infarction, and cardiovascular mortality), major bleeding, or net clinical benefit was observed across CrCL strata (Figure 3A and B
      • Bohula E.A.
      • Giugliano R.P.
      • Ruff C.T.
      • et al.
      Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 trial.
      • Goette A.
      • Merino J.L.
      • Ezekowitz M.D.
      • et al.
      Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial.
      and data not shown).
      Hokusai-VTE examined treatment with heparin followed by edoxaban 60 mg OD or warfarin in patients with symptomatic DVT or PE (with or without DVT).
      • Buller H.R.
      • Decousus H.
      • Grosso M.A.
      • et al.
      Hokusai-VTE Investigators
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
      Edoxaban dose was reduced to 30 mg OD in patients with CrCL of 30 to 50 mL/min. Edoxaban was noninferior to warfarin in terms of the primary end point (recurrent symptomatic VTE; P<.001 for noninferiority) and was associated with significantly less major or clinically relevant nonmajor bleeding compared with warfarin (P=.004 for superiority). The relative efficacy of edoxaban vs warfarin was maintained across renal function subgroups (Figure 3C and D).
      • Buller H.R.
      • Decousus H.
      • Grosso M.A.
      • et al.
      Hokusai-VTE Investigators
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.

      Rivaroxaban

      Influence of Renal Function on Rivaroxaban PK/PD

      Rivaroxaban, a direct factor Xa inhibitor, is eliminated through renal excretion (approximately one-third of active drug) as well as by fecal/biliary routes.
      The effect of renal function on rivaroxaban clearance was found to be moderate, even in the context of severe renal impairment.
      • Kubitza D.
      • Becka M.
      • Mueck W.
      • et al.
      Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct factor Xa inhibitor.
      Among patients with mild, moderate, or severe renal impairment enrolled in a dedicated PK study, rivaroxaban exposure after a single 10-mg dose was 44%, 52%, and 64% higher, respectively, compared with healthy individuals.
      • Kubitza D.
      • Becka M.
      • Mueck W.
      • et al.
      Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct factor Xa inhibitor.
      Two studies explored rivaroxaban dosing in patients with ESRD undergoing maintenance hemodialysis.
      • De Vriese A.S.
      • Caluwe R.
      • Bailleul E.
      • et al.
      Dose-finding study of rivaroxaban in hemodialysis patients.
      • Dias C.
      • Moore K.T.
      • Murphy J.
      • et al.
      Pharmacokinetics, pharmacodynamics, and safety of single-dose rivaroxaban in chronic hemodialysis.
      The first study reported that administration of a single dose of rivaroxaban 10 mg in patients receiving hemodialysis resulted in comparable drug exposure levels (by indirect comparison) to that of rivaroxaban 10 mg in patients with moderate or severe renal impairment in a previous study.
      • De Vriese A.S.
      • Caluwe R.
      • Bailleul E.
      • et al.
      Dose-finding study of rivaroxaban in hemodialysis patients.
      In addition, the study demonstrated that there was no accumulation of rivaroxaban after dosing for 1 week. In the second study, a single dose of rivaroxaban 15 mg was administered to patients receiving hemodialysis and matched healthy volunteers.
      • Dias C.
      • Moore K.T.
      • Murphy J.
      • et al.
      Pharmacokinetics, pharmacodynamics, and safety of single-dose rivaroxaban in chronic hemodialysis.
      A direct comparison indicated an increase in exposure by 56% in patients undergoing hemodialysis,
      • Dias C.
      • Moore K.T.
      • Murphy J.
      • et al.
      Pharmacokinetics, pharmacodynamics, and safety of single-dose rivaroxaban in chronic hemodialysis.
      which is consistent with known effects in patients with moderate-to-severe renal impairment who were not undergoing dialysis.
      • Kubitza D.
      • Becka M.
      • Mueck W.
      • et al.
      Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct factor Xa inhibitor.
      In both studies, hemodialysis did not appreciably reduce plasma rivaroxaban concentrations, likely owing to high protein binding.
      • De Vriese A.S.
      • Caluwe R.
      • Bailleul E.
      • et al.
      Dose-finding study of rivaroxaban in hemodialysis patients.