Time in the Therapeutic Range for Patients Taking Warfarin in Clinical Trials: Useful, but Also Misleading, Misused, and Overinterpreted.

Abstract

The time in the therapeutic range (an international normalized ratio [INR] between 2.0 and 3.0) (TTR) has been used as a measure of warfarin (W) therapy quality. Although generally useful in clinical care and better than other alternatives, in recent new oral anticoagulant (NOAC) versus W trials in atrial fibrillation (AF), its utility has been overvalued. TTRs have typically been assessed by the Rosendaal method1 (± variable alterations, such as including versus excluding the first 7 days on W and after stopping W), where the INR is assumed to change linearly from the last INR until the INR at next check. TTR indicates the days with INRs of 2.0 to 3.0 over total day counts using these integrated numbers. But, if an INR is 3.0, and time between checks is long (weeks), the calculated TTR will be falsely low. In real life, if a measured INR is out of range, the W dose is changed and within days the INR has increased. On average, it takes 3 days for W’s effect to reach a stable value when W concentrations are constant.2 For example, if W dosing were changed the day a physician learned an INR was 1.5, but an INR was not rechecked for a month, the INR would rise within days but, per Rosendaal, it would only slowly increase to the value at next check a month later (see Figure). Thus, if INR-recheck frequency differs, Rosendaal …