Table 8.

Annual rates of major bleeding in patients with normal and impaired renal function enrolled in NOAC phase III trials

Trial	Major bleeding in patients with eGFR ≥50 mL/min (%/year)		HR (95% CI)	Major bleeding in patients with eGFR 30–49 mL/min (%/year)		HR (95% CI)	P-value for interaction
	Intervention	Control		Intervention	Control
RE-LYa90	≥80 mL/min Dabigatran 110 mg 1.48	Warfarin 2.43	0.61 (0.44–0.84)	Dabigatran 110 mg 5.45	Warfarin 5.49	0.99 (0.77–1.28)	0.06
	Dabigatran 150 mg 2.04 50–79 mL/min Dabigatran 110 mg 2.84 Dabigatran 150 mg 3.35	Warfarin 2.43 Warfarin 3.70 Warfarin 3.70	0.84 (0.62–1.13) 0.76 (0.62–0.94) 0.91 (0.75–1.11)	Dabigatran 150 mg 5.50	Warfarin 5.49	1.01 (0.79–1.30)	0.64
AVERROESc91	≥60 mL/min Apixaban 5 mgb 0.9	Aspirin 81–324 0.8	1.1 (0.56–2.0)	<60 mL/min Apixaban 2.5–5 mgb 2.5	Aspirin 81–324 2.2	1.2 (0.65–2.1)	0.82
ARISTOTLEd92	>80 mL/min Apixaban 5 mgb 1.46	Warfarin 1.84	0.80 (0.61–1.04)	Apixaban 2.5–5 mgb 3.221	Warfarin 6.44	0.79 (0.55–1.14)	0.03
	>50–80 mL/min Apixaban 5 mgb 2.45	Warfarin 3.21	0.77 (0.62–0.94)
ROCKET-AFe93	Rivaroxaban 20 mg 3.39	Warfarin 3.17	1.07 (0.91–1.26)	Rivaroxaban 15 mg 4.49	Warfarin 4.70	0.95 (0.72–1.26)	0.48

ARISTOTLE, Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation; AVERROES, Apixaban VErsus acetylsalicylic acid to Reduce the Risk Of Embolic Stroke; 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.

^aRE-LY compared creatinine clearance ≥80 vs. 50–79 vs. <50 mL/min.

^bSerum creatinine >133 mmol/L plus aged ≥80 years or body weight ≤60 kg.

^cAVERROES compared eGF ≥60 vs. <60.

^dARISTOTLE compared eGFR ≤50 vs. >50–80 vs. >80 mL/min.

^eOn treatment analyses reported.