Table 4. Mediation analysis on effect of INR-variability on the increased risks of major adverse cardiovascular events and major bleeding complications in patients with chronic kidney disease in a nested case-control study.

Outcome	Crude OR (95% CI)	Adjusted OR 1 (95% CI)	Adjusted OR 2 (95% CI)	Adjusted OR 3 (95% CI)	Adjusted OR 4 (95% CI)
Stroke or TIA
No CKD (N = 91, of whom 67 unique)	ref	ref	ref	ref	ref
Moderate CKD (N = 90, of whom 70 unique)	0.76(0.36–1.61)	0.76(0.35–1.67)	0.79(0.36–1.76)	1.06(0.41–2.75)	1.02(0.40–2.56)
Severe CKD (N = 25, of whom 22 unique)	2.98(1.17–7.60)	2.56(0.92–7.10)	2.23(0.73–6.84)	1.96(0.50–7.74)	2.50(0.69–9.07)
MACE
No CKD (N = 210, of whom 125 unique)	ref	ref	ref	ref	ref
Moderate CKD (N = 205, of whom 134 unique)	1.21(0.74–1.98)	1.14(0.68–1.93)	1.15(0.66–1.99)	1.05(0.58–1.91)	1.10(0.62–1.96)
Severe CKD (N = 58, of whom 49 unique)	5.18(2.76–9.70)	5.07(2.57–10.02)	5.37(2.58–11.19)	3.58(1.59–8.03)	3.77(1.71–8.32)
Major bleeding
No CKD (N = 211, of whom 128 unique)	ref	ref	ref	ref	ref
Moderate CKD (N = 245, of whom 137 unique)	0.81(0.51–1.28)	0.76(0.47–1.23)	0.74(0.45–1.22)	0.88(0.52–1.52)	0.83(0.49–1.40)
Severe CKD (N = 60, of whom 42 unique)	2.08(1.12–3.85)	1.77(0.91–3.43)	1.82(0.93–3.56)	1.55(0.70–3.44)	1.57(0.72–3.40)
Major bleeding or MACE
No CKD (N = 361, of whom 179 unique)	ref	ref	ref	ref	ref
Moderate CKD (N = 419, of whom 192 unique)	0.87(0.62–1.25)	0.85(0.59–1.24)	0.87(0.59–1.27)	0.93(0.61–1.41)	0.88(0.59–1.34)
Severe CKD (N = 122, of whom 80 unique)	2.92(1.88–4.54)	2.61(1.64–4.16)	2.67(1.64–4.34)	2.49(1.40–4.41)	2.31(1.33–4.03)

Model 1 includes age, gender, hypertension, the use of platelet-inhibitors, diabetes mellitus and congestive heart failure.

Model 2 includes model 1 + INR VAR entire treatment period, Model 3 includes model 1 + INR variability over six months prior to event.

Model 4 includes model 1 + INR variability over three months prior to event.

Abbreviations: CKD  =  chronic kidney disease, MACE  =  major adverse cardiovascular event, OR  =  odds ratio, TIA  =  transient ischemic attack.