Table 4.

Subgroup analyses of randomized, controlled trials of direct-acting oral anticoagulants for stroke prevention in CKD stages 3–5 nondialysis with atrial fibrillation

StudySponsor, PublicationYearInterventionControlaCKD Stage 3 eGFR≤60 ml/m (n of N, %)CKD Stage 4/5 eGFR<30–25 ml/m (n/N, %)Follow-Up (yr)Primary Efficacyb in CKD, HR (95% CI)Primary Safetyc in CKD, HR (95% CI)
RE-LYBoehringer Ingelheim Pharmaceutical2009Dabigatran 110 or 150 mg twice a dayWarfarin3554 of 17,951 (19.8)None, eGFR<30 excluded2.00.73 (0.46 to 1.14)0.99 (0.74 to 1.33)
ARISTOTLEBristol-Myers Squibb, Pfizer2010Apixaban 5 or 2.5 mg twice a daydWarfarin3017 of 18,122 (17.0)270 of 3017 (8.9%) eGFR 30–25, eGFR<25 or Cr>2.5 mg/dl excluded1.80.81 (0.51 to 1.28)a0.50 (0.36 to 0.70)
AVERROESBristol-Myers Squibb and Pfizer2011Apixaban 5 or 2.5 mg twice a daydAspirin 81–325 mg1697 of 5599 (30.3)None, eGFR<25 or Cr>2.5 mg/dl excluded1.10.45 (0.32 to 0.62)1.13 (0.74 to 1.75)
ROCKET AFJohnson & Johnson, Bayer Pharmaceutical2011Rivaroxaban 15 mg every dayWarfarin2950 of 14,264 (20.7)None, eGFR<30 excluded1.90.84 (0.57 to 1.26)0.96 (0.69 to 1.33)
J-ROCKET AFYakuhin Bayer Pharmaceutical2012Rivaroxaban 10 mg every dayWarfarin284 of 1278 (22.2)None, eGFR<30 excluded2.50.81 (0.22 to 2.96)0.89 (0.33 to 2.38)
ENGAGE AF-TIMI 48Daiichi Sankyo Pharma2013Edoxaban 30 mg every dayWarfarin2860 of 14,071 (23.9)None, eGFR<30 excluded2.80.85 (0.53 to 1.36)0.75 (0.54 to 1.06)
Overalle0.81 (0.65 to 1.00)0.79 (0.59 to 1.04)
  • HR, hazard ratio; 95% CI, 95% confidence interval; RE-LY, Randomized Evaluation of Long-term Anticoagulation Therapy; ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; Cr, serum creatinine; AVERROES, Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Strokes in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment; ROCKET-AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; J-ROCKET AF, Japan Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial; ENGAGE AF-TIMI 48, Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48.

  • a Warfarin dose adjusted to INR range of 2.0–3.0. All studies allowed ≤100 or ≤165 mg/d of aspirin. All were sponsor open and double blinded, except RE-LY 2009 in which warfarin was unblinded.

  • b Primary efficacy outcome was all-cause stroke (ischemic or hemorrhagic) and/or systemic thromboembolism.

  • c The primary safety outcome was major bleeding, defined as clinically overt bleeding accompanied by ≥1 of the following: hemoglobin drop ≥2 g/dl over 24 h, transfusion ≥2 U of packed red cells, critical location (intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal), or fatality.

  • d Dose determined according to ≥2 of the criteria: (1) age≥80 yr, (2) body wt ≤60 kg, or (3) serum creatinine≥1.5 mg/dl.

  • e Cochrane review all of the above studies excluding AVERROES (46).