Individual time within target range in patients treated with vitamin K antagonists: main determinant of quality of anticoagulation and predictor of clinical outcome. a retrospective study of 2300 consecutive patients with venous thromboembolism

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Abstract
The efficacy and safety of vitamin K antagonists (VKA) are related to the actual level of anticoagulation (given as the international normalized ratio, INR). It is often difficult to maintain an optimal INR over time. We assessed the clinical impact of the individual time spent within INR target range (ITTR) in 2304 consecutive patients with venous thromboembolism. Annual incidences of recurrent thromboembolism and major bleeding were 6·2% and 2·8% respectively. The relative risk (RR) of thromboembolism was 4·5 [95% confidence interval (CI) 3·1–6·6, P < 0·001] at INR < 2·0, for major bleeding it was 6·4 (2·5–16·1, P < 0·001) at INR > 5·0, compared with INR 2·0–3·0. Patients with ITTR < 45% were at higher risk than those with ITTR > 65% (RR 2·8, 1·9–4·3, P < 0·001), while no difference was demonstrated comparing ITTR 45–65% and ITTR > 65% (RR 1·2, 0·7–1·8, P = 0·54). Annual incidences of recurrent thromboembolism were 16·0%, 4·9% and 4·6% at ITTR < 45%, 45–60% and >65% respectively. For major bleeding these were 8·7%, 2·1% and 1·9% respectively. ITTR < 37% during the first 30 treatment days was highly predictive for the total treatment time ITTR < 45% (RR 24·2, 13·5–43·1, P < 0·001). In conclusion, ITTR can be used to identify patients on VKA at risk of recurrent thromboembolism or major bleeding. Since the 30-d ITTR is highly predictive for total treatment ITTR, these patients can be identified soon after start of treatment.