Table 5. Mediation analysis on effect of time within therapeutic range 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)	0.94(0.41–2.13)	1.31(0.52–3.37)	1.01(0.40–2.56)
Severe CKD (N = 25, of whom 22 unique)	2.98(1.17–7.60)	2.56(0.92–7.10)	1.95(0.64–5.88)	2.49(0.65–9.55)	2.46(0.68–8.88)
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)	1.16(0.67–2.01)	1.06(0.58–1.93)	1.11(0.62–1.98)
Severe CKD (N = 58, of whom 49 unique)	5.18(2.76–9.70)	5.07(2.57–10.02)	4.98(2.42–10.23)	3.26(1.45–7.34)	3.42(1.55–7.55)
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)	0.73(0.44–1.21)	0.87(0.51–1.50)	0.83(0.49–1.41)
Severe CKD (N = 60, of whom 42 unique)	2.08(1.12–3.85)	1.77(0.91–3.43)	1.55(0.79–3.07)	1.48(0.67–3.29)	1.50(0.68–3.28)
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)	0.93(0.62–1.40)	0.96(0.63–1.46)	0.93(0.62–1.40)
Severe CKD (N = 122, of whom 80 unique)	2.92(1.88–4.54)	2.61(1.64–4.16)	2.22(1.27–3.88)	2.37(1.33–4.21)	2.22(1.27–3.88)

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

Model 2 includes model 1 + time within therapeutic range over entire treatment period, Model 3 includes model 1 + time within therapeutic range over six months prior to event, Model 4 includes model 1 + time within therapeutic range over three months prior to event.

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