Table 2. Trials of oral anticoagulation in CKD.

RE-LY: Randomized Evaluation of Long-Term Anticoagulation Therapy; 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; ARISTOTLE: Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; INR:international normalized ratio; CrCl: creatinine clearance Numbers in bold represent significant differences of the investigated medication compared to warfarin. a: for non-inferiority; b: for superiority

	RE-LY [38]	ROCKET AF [39]	ARISTOTLE [40]
Drug	Dabigatran etexilate	Rivaroxaban	Apixaban
Study design	Phase 3, multicenter, prospective, open-label randomized trial: 18,113 patients with AF and one additional risk factor for stroke	Phase 3, multicenter, double-blind, double-dummy randomized trial: 14,264 patients with AF and elevated stroke risk	Phase 3, multicenter, double-blind, double-dummy randomized trial: 18,201 patients with AF and at least one additional risk factor for stroke
Dosage	110 mg resp. 150 mg dabigatran etexilate twice daily versus warfarin adjusted to an INR of 2.0 to 3.0	20 mg rivaroxaban per day resp. 15 mg/day rivaroxaban for patients with CrCl 30-49 ml/min versus warfarin adjusted to an INR of 2.0 to 3.0	5 mg apixaban twice daily resp. 2.5 mg apixaban twice daily for patients with serum creatinine ≥ 1.5 mg/dl (approx. CrCl ≤ 50 ml/min) versus warfarin adjusted to an INR of 2.0 to 3.0
Antiplatelet agents	Aspirin ≤100 mg per day Clopidogrel Ticlopidine Dipyridamole ASA/Dipyridamole	Aspirin ≤100 mg per day	Aspirin ≤165 mg per day Clopidogrel
Investigated CKD stages	CrCl <50 ml/min CrCl 50 - 79 ml/min CrCl ≥ 80 ml/min	CrCl 30 - 49ml/mg CrCl ≥ 50ml/min	CrCl ≤ 30 ml/min CrCl 30 - 50 ml/min CrCl <50 – 80 ml/min CrCl > 80 ml/min
Exclusion criteria with regard to creatinine clearance	<30 ml/min	<30 ml/min	<25 ml/min
Study Outcomes Primary efficacy outcome Primary safety outcome Secondary efficacy outcome	Stroke Systemic embolism Major hemorrhage Stroke Systemic embolism Death Myocardial infarction	Composite of stroke and systemic embolism Composite of major and non-major clinically relevant bleeding events Composite of stroke, non-central nervous system systemic embolism, cardiovascular death, myocardial infarction	Ischemic or hemorrhagic stroke Systemic embolism Major hemorrhage Death Myocardial infarction
Study Results
Primary efficacy outcome	Dabigatran Warfarin 110 mg: 1.53%/yra 1.69%/yr 150 mg: 1.11%/yra,b	Rivaroxaban Warfarin 15 mg: 2.32%/yr 2.77%/yr 20 mg: 1.57 %/yr 2.00%/yr	Apixaban Warfarin 1.27%/yra,b 1.60%/yr
Primary safety outcome	Dabigatran 110 mg: 2.71%/yra Warfarin 150 mg: 3.11%/yr 3.36%/yr	Rivaroxaban Warfarin 15 mg: 17.82%/yr 18.28%/yr 20 mg: 14.24%/yr 13.67%/yr	Apixaban Warfarin 2.13%/yr 3.09%/yr
Secondary efficacy outcome	Mortality Rate:
	Dabigatran Warfarin 110 mg: 3.75%/yr 4.13%/yr 150 mg: 3.64%/yr	Rivaroxaban Warfarin 15 mg: 5.58%/yr 6.54%/yr 20 mg: 3.55%/yr 4.16%/yr	Apixaban Warfarin 3.52%/yr 3.94%/yr
Outcome with regard to CKD	No significant difference in the treatment effect could be observed in patients with renal impairment	Patients with moderate renal impairment (CrCl <50ml/min) have higher rates of stroke and bleeding under both rivaroxaban and warfarin compared to patients with normal renal function. No superiority or non-inferiority of rivaroxaben versus warfarin could be demonstrated for patients with CrCl 30-49 ml/min	Patients with moderate to severe renal impairment (CrCl ≤50 ml/min) showed an even greater reduction in major bleeding events under apixaban compared to warfarin.