Effectiveness and safety of apixaban and rivaroxaban vs warfarin in patients with atrial fibrillation and chronic kidney disease

Table 1 Demographic and clinical characteristics of cohorts of new oral anticoagulation therapy users with stage III chronic kidney disease after inverse probability of treatment weighting from 2013 to 2017 (mean ± SD, %)

	IPTW warfarin and rivaroxaban 15 mg		IPTW warfarin and rivaroxaban 20 mg		IPTW warfarin and apixaban 2.5 mg		IPTW warfarin and apixaban 5.0 mg
	Warfarin (n = 3335)	Rivaroxaban 15 mg (n = 744)	Warfarin (n = 3335)	Rivaroxaban 20 mg (n = 1064)	Warfarin (n = 3335)	Apixaban 2.5 mg (n = 1674)	Warfarin (n = 3335)	Apixaban 5.0 mg (n = 2082)
Age (yr)	82.9 ± 8.6	82.8 ± 7.7	80.1 ± 10.8	79.1 ± 8.2	84.3 ± 8.3	84.5 ± 7.2	80.4 ± 10.2	80.2 ± 7.8
Female sex	56.5	56.5	54.8	52.3	58.2	59.0	54.3	53.9
CHA2DS2-VASc	4.1 ± 1.4	4.1 ± 1.3	3.9 ± 1.5	3.9 ± 1.5	4.2 ± 1.4	4.2 ± 1.3	3.9 ± 1.5	3.8 ± 1.3
CHADS2 score	3.0 ± 1.2	3.0 ± 1.2	2.8 ± 1.3	2.9 ± 1.2	3.0 ± 1.2	3.0 ± 1.1	2.9 ± 1.3	2.8 ± 1.1
HAS-BLED score	3.5 ± 1.3	3.5 ± 1.3	3.3 ± 1.5	3.4 ± 1.4	3.5 ± 1.3	3.5 ± 1.2	3.3 ± 1.4	3.3 ± 1.2
Charlson-Deyo Comorbidity Index	5.9 ± 3.4	6.0 ± 3.6	5.7 ± 3.5	5.9 ± 3.6	5.9 ± 3.4	5.8 ± 3.2	5.7 ± 3.5	5.7 ± 3.4
Frailty score	18.6 ± 6.2	18.6 ± 5.9	17.7 ± 6.7	17.6 ± 6.3	18.8 ± 6.2	18.8 ± 5.8	17.7 ± 6.6	17.5 ± 6.1
Comorbidities (including the index hospitalization and the three years prior to cohort entry)
Hypertension	86.2	86.5	83.9	85.2	86.9	86.9	84.5	84.0
Coronary artery disease	64.7	65.1	62.0	62.7	64.1	62.5	61.2	58.4
Acute myocardial infarction	21.1	20.3	18.9	17.5	20.9	20.9	18.8	15.8
Chronic heart failure	56.2	56.7	53.4	54.2	56.1	56.6	53.3	53.6
Cardiomyopathy	7.9	8.3	7.7	8.7	7.4	7.1	8.2	7.8
Other cardiac dysrhythmias	18.8	19.0	17.8	16.4	19.2	19.4	18.2	18.0
Valvular heart disease	26.1	27.1	24.9	24.6	25.7	25.6	23.5	22.3
Stroke/TIA	16.9	17.2	16.0	17.3	16.8	16.1	15.9	15.0
Peripheral vascular disease	27.7	27.5	26.6	25.9	27.3	26.2	25.6	23.2
Dyslipidemia	54.4	53.3	54.2	55.8	53.9	54.0	55.5	53.8
Diabetes	45.1	46.1	46.4	49.9	43.1	42.7	47.3	46.9
Major bleeding	38.5	38.3	37.0	39.3	38.3	37.0	36.2	34.8
Major intracranial bleeding	3.7	3.7	3.5	5.7	3.9	3.5	4.2	3.8
Major gastrointestinal bleeding	8.3	9.5	7.9	7.7	8.7	8.1	7.9	7.9
Other sites of major bleeding	32.0	30.9	30.9	32.4	31.8	31.2	29.8	28.8
Liver disease	2.6	2.8	2.9	2.9	2.5	2.4	2.7	2.5
Chronic obstructive pulmonary disease/asthma	44.0	44.2	46.0	49.7	42.2	42.1	44.5	45.3
Depression	11.8	11.5	12.2	11.8	11.7	11.4	12.1	11.9
Medical procedures (three years prior to cohort entry)
Cardiac catheterization	5.0	5.4	5.2	5.3	5.0	4.9	6.4	6.4
Percutaneous coronary intervention-stent	4.1	3.9	3.8	4.1	3.8	4.0	4.1	4.0
Coronary artery bypass grafting	0.6	0.5	0.8	0.7	0.5	0.5	1.2	1.2
Implantable cardiac device	0.1	0.1	< 0.1	< 0.1	< 0.1	0.0	< 0.1	0.0
Medications (two weeks prior to cohort entry)
Statin	51.0	51.2	51.1	52.9	50.0	47.9	50.6	50.4
Antiplatelet	8.7	8.5	8.1	8.9	8.3	7.4	8.1	7.9
Low-dose ASA	35.3	35.5	34.8	35.2	35.6	34.9	33.9	33.4
Proton pump inhibitors	49.7	49.6	47.8	46.9	50.0	49.1	46.4	44.7
NSAIDs	0.9	0.9	1.3	1.6	0.9	1.0	1.2	1.2
Digoxin	9.3	10.6	9.1	10.1	9.2	9.0	8.9	8.7
Amiodarone	9.6	9.3	8.6	6.1	9.3	9.8	8.8	8.0
Antidepressants	10.5	10.1	10.4	10.5	10.6	10.3	10.2	10.4
Beta-blockers	62.5	63.1	61.4	61.1	63.8	62.8	62.4	62.5
Calcium channel blockers	42.9	42.6	41.9	39.8	42.7	43.2	41.4	41.0
Inhibitors of the renin-angiotensin system	37.5	36.9	38.1	38.5	38.0	36.5	38.0	38.3
Diuretics	60.5	60.3	61.4	61.0	61.0	60.8	60.3	60.4
Loop diuretics	56.2	55.8	57.0	54.4	56.4	56.7	55.4	56.3
Antidiabetics	27.4	28.0	28.7	30.3	26.5	25.8	29.2	29.3
Health medical services (one year prior to cohort entry)
Consultations with specialist physicians	1.2 ± 2.4	1.2 ± 1.9	1.2 ± 2.5	1.2 ± 2.3	1.2 ± 2.4	1.2 ± 2.2	1.2 ± 2.6	1.2 ± 1.8
Consultations with family physicians	1.3 ± 3.3	1.3 ± 2.8	1.2 ± 3.1	1.2 ± 2.5	1.3 ± 3.4	1.4 ± 3.0	1.2 ± 3.2	1.2 ± 2.6
Emergency visits	3.4 ± 3.1	3.4 ± 2.9	3.4 ± 3.4	3.5 ± 3.0	3.4 ± 3.1	3.5 ± 2.9	3.4 ± 3.3	3.3 ± 2.8
Health hospital services (three years prior to cohort entry)
All-cause hospital admission	2.5 ± 2.1	2.5 ± 2.0	2.5 ± 2.4	2.6 ± 2.2	2.4 ± 2.0	2.5 ± 1.9	2.5 ± 2.3	2.4 ± 2.0

ASA: Acetylsalicylic acid; CKD: Chronic kidney disease; IPTW: Inverse probability of treatment weighting; NSAIDs: Nonsteroidal anti-inflammatory drugs; OAC: Oral anticoagulant; TIA: Transient ischemic attack.

Table 2 Sensitivity analysis of negative controls after inverse probability of treatment weighting in an on-treatment analysis

	Incident rate of rivaroxaban 15 mg 100 PY (95%CI)	Incident rate of warfarin 100 PY (95%CI)	HR (95%CI)1	P value
Diabetes complications	1.1 (0.2-2.0)	1.1 (0.6-1.5)	1.02 (0.40-2.60)	0.96
	Incident rate of rivaroxaban 20 mg 100 PY (95%CI)	Incident rate of warfarin 100 PY (95%CI)	HR (95%CI)1	P value
Diabetes complications	1.5 (0.6-2.4)	1.0 (0.6-1.5)	1.48 (0.72-3.06)	0.29
	Incident rate of apixaban 2.5 mg 100 PY (95%CI)	Incident rate of warfarin 100 PY (95%CI)	HR (95%CI)1	P value
Diabetes complications	0.8 (0.3-1.3)	1.2 (0.8-1.7)	0.66 (0.31-1.41)	0.28
	Incident rate of apixaban 5.0 mg 100 PY (95%CI)	Incident rate of warfarin 100 PY (95%CI)	HR (95%CI)	P value
Diabetes complications	0.7 (0.2-1.1)	1.4 (0.9-1.9)	0.49 (0.24-1.02)	0.06

A significant value is for P < 0.05 vs warfarin.

¹For the negative control, we assessed the risk of diabetic complications (ICD-9: 250.1-250.9, 357.2, and 366.41; ICD-10: E10-E14 excluding E10.9, E11.9, E12.9, E13.0, and E14.9).

CI: Confidence interval; HR: Hazard ratio; PY: Person-years.

Table 3 E-values for significant comparisons in an on-treatment analysis after inverse probability of treatment weighting of new oral anticoagulant users with stage III chronic kidney disease

	Hazard ratio (95%CI)	E value corresponding to the CI bound closest to 1	E value for hazard ratio point estimate1
Apixaban 2.5 mg vs warfarin
Safety composite	0.65 (0.43-0.99)	1.11	2.45
Apixaban 5.0 mg vs warfarin
Effectiveness composite	0.76 (0.65-0.88)	1.53	1.96
All-cause mortality	0.61 (0.43-0.88)	1.53	2.66

¹E-value for hazard used the point estimate instead of the bound closest to 1.

CI: Confidence interval.