Table 2.

Summary of studies included in meta-analysis of safety of NOACs in CKD

Study, YearInterventionDoseMean TTR (INR 2–3) (%)aPatients in Renal Subgroups per Creatinine Clearance (n)Creatinine Clearance (ml/min)bStudy PopulationRenal Exclusion CriteriaAdditional Medications
ARISTOTLE, 20115Apixaban (Xa inhibitor) versus warfarin5 mg twice daily (apixaban) versus target INR of 2–3 (warfarin) or 2.5 mg twice daily versus target INR of 2–3c62.2≥81 ml/min: 7518Not providedPatients with AF or atrial flutter and at least 1 risk factor for strokeCreatinine>221 μmol/L or CrCl<25 ml/minNSAID and antiplatelet agents permitted
≥51–80 ml/min: 7567
>25–50 ml/min: 3017
Missing: 79
EINSTEIN-DVT, 20103(Acute)Rivaroxaban (Xa inhibitor) versus warfarin or acenocoumarold15 mg twice daily (rivaroxaban) for the first 3 wk, then 20 mg daily, versus target INR of 2–3 (VKA)57.7≥80 ml/min: 2363Not providedPatients with acute, symptomatic, objectively confirmed proximal DVT, without symptomatic pulmonary embolismCrCl<30 ml/minNSAID and antiplatelet use discouraged, but aspirin (up to 100 mg) and clopidogrel (75 mg daily) were permitted
≥50–79 ml/min: 792
>30–49 ml/min: 235
<30 ml/min: 15
Missing: 44
EINSTEIN-PE, 2012Rivaroxaban (Xa inhibitor) versus warfarin or acenocoumarold15 mg twice daily (rivaroxaban) for the first 3 wk, then 20 mg daily, versus target INR of 2–3 (VKA)62.7≥80 ml/min: 3172Not providedPatients with acute, symptomatic pulmonary embolism with objective confirmation, with or without symptomatic deep-vein thrombosisCrCl<30 ml/minNSAID and antiplatelet use discouraged, but aspirin (up to 100 mg) and clopidogrel (75 mg daily) were permitted
≥50–79 ml/min: 1230
>30–49 ml/min: 398
<30 ml/min: 6
Missing: 26
RECOVER, 2009Dabigatran (DTI) versus warfarin150 mg twice daily (dabigatran) versus dose-adjusted warfarin (target INR 2–3)e60≥80 ml/min: 1833Mean±SD for dabigatran: 105.8±40.7
Mean±SD for warfarin:104.4±39.9Patients with acute, symptomatic, objectively verified proximal DVTs of the legs or pulmonary embolismCrCl<30 ml/minAspirin (up to 100 mg daily) and antiplatelet agent use permitted
≥50–79 ml/min: 551
31–49 ml/min: 120
≤30 ml/min: 13
REMEDY, 20131Dabigatran (DTI) versus warfarin150 mg twice daily (dabigatran) versus dose-adjusted warfarin (target INR 2–3)65.3≥80 ml/min: 2103Mean±SD for dabigatran: 04.2±38.6
Mean±SD for warfarin:106.6±37.9Patients with a previous history of symptomatic, objectively verified proximal DVTs of the legs or pulmonary embolism enrolled in the RECOVER or RECOVER-II trialsCrCl<30 ml/minAspirin (up to 100 mg daily) and antiplatelet agent use permitted
≥50–79 ml/min: 617
31–49 ml/min:104
≤30 ml/min: 4
RE-LY, 20096Dabigatran (DTI) versus warfarin110 mg twice daily (dabigatran) versus dose-adjusted warfarin (target INR 2–3) or 150 mg twice daily (dabigatran) versus dose-adjusted warfarin (target INR 2–3)64≥80 ml/min: 5658Not providedPatients with AF or atrial flutter and at least one risk factor for strokeCrCl<30 ml/minAspirin (up to 100 mg daily) and antiplatelet agent use permitted
≥50–79 ml/min: 8597
30–49 ml/min: 3343
<30 ml/min: 77
ROCKET-AF, 20114Rivaroxaban (Xa inhibitor) versus warfarin15 mg daily (rivaroxaban) versus adjusted-dose warfarin (target INR 2–3)f55 (entire cohort) 57.7 (CrCl 30/49 ml/min)≥80 ml/min: 4518Median (IQR) for rivaroxaban:67 (52–88)
Median (IQR) for warfarin: 67 (52–86)Patients with nonvalvular AF and a moderate-to-high risk for stroke based on prior history of stroke or CHADS2 score of ≥2CrCl<30 ml/minAspirin (up to 100 mg daily) and antiplatelet agent use permitted
≥50–79 ml/min: 6723
31–49: ml/min 2970
J-ROCKET-AF, 20122Rivaroxaban (Xa inhibitor) versus warfarin10 mg daily (rivaroxaban) versus dose-adjusted warfaring65≥50 ml/min: 994Not providedJapanese patients with nonvalvular AF and a moderate-to-high risk for stroke based on prior history of stroke or CHADS2 score≥2CrCl<30 ml/minAspirin (up to 100 mg daily) and antiplatelet agent use permitted
<50 ml/min: 284
  • TTR, time in therapeutic range; AF, atrial fibrillation; NSAID, nonsteroidal anti-inflammatory drug; DVT, deep venous thrombosis; DTI, direct thrombin inhibitor; IQR, interquartile range; CHADS2: Risk score consisting of 1 point each for congestive heart failure, hypertension, age>75 years, diabetes, and 2 points for stroke; EINSTEIN-DVT, oral direct factor Xa inhibitor rivaroxaban in patients with acute symptomatic deep-vein thrombosis; EINSTEIN-PE, oral direct factor Xa inhibitor rivaroxaban in patients with acute symptomatic pulmonary embolism; REMEDY, a phase III, randomised, multi-center, double-blind, parallel-group, active controlled study to evaluate the efficacy and safety of oral dabigatran etexilate compared to warfarin (INR 2.0-3.0) for the secondary prevention of venous thromboembolism; ROCKET-AF, The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; J-ROCKET-AF, Evaluation of the Efficacy and Safety of Rivaroxaban (BAY59-7939) for the Prevention of Stroke and Noncentral Nervous System Systemic Embolism in Japanese With Nonvalvular Atrial Fibrillation.

  • a TTR reported for the entire cohort randomly assigned to VKA group for each trial, not the subset of patients with CKD.

  • b Pooled for the entire cohort in the trial.

  • c 2.5-mg doses were used in a subset of patients with two or more of the following criteria: age≥80 years, body weight≤60 kg, or a serum creatinine level≥1.5 mg/dl (133 μmol/L).

  • d Patients received enoxaparin at a dose of 1.0 mg/kg body weight twice daily and either warfarin or acenocoumarol, started within 48 hours after randomization. Enoxaparin was discontinued when the INR was ≥2.0 for 2 consecutive days and the patient had received at least 5 days of enoxaparin treatment.

  • e A parenteral anticoagulant (generally unfractionated heparin administered intravenously or low-molecular-weight heparin administered subcutaneously) was usually started before random assignment. The parenteral anticoagulant was stopped, once it had been given for at least 5 days and the true or sham INR was recorded as ≥2.0 on 2 consecutive days. Warfarin was started on the day of random assignment. Dabigatran was initiated within 2 hours before the time that the next dose of initial parenteral therapy would have been due or at the time of discontinuation of intravenous unfractionated heparin.

  • f Fifteen-milligram dose for CrCl<50 ml/min; 20 mg for CrCl≥50 ml/min.

  • g INR of 2.0–3.0 in patients aged<70 years or a reduced INR of 1.6–2.6 in patients aged≥70 years.