Warfarin Dose Assessment Every 4 Weeks Versus Every 12 Weeks in Patients With Stable International Normalized Ratios: A Randomized Trial

Study Questions:

Is assessment of warfarin dosing every 12 weeks as safe as assessment every 4 weeks, in patients receiving warfarin therapy with stable international normalized ratios (INRs)?


The authors reported the results of a noninferiority, randomized trial of patients receiving long-term warfarin treatment with a target therapeutic INR range of 2.0-3.0 or 2.5-3.5. Subjects were eligible for the study if their warfarin dose had remained unchanged for the prior 6 months or longer, after continuous management by the same anticoagulation clinic. All subjects, and study and statistical personnel were blinded to treatment assignment. Subjects were randomized 1:1 to either dosing assessment every 12 weeks versus every 4 weeks. Subjects in the 12-week group underwent INR testing every 4 weeks, with sham INR results within the target range reported for two of the three 4-week periods. The primary outcome was time and therapeutic range (TTR). Also reported were the number of extreme INRs, changes in maintenance dose, major bleeding events, objectively verified thromboembolism, and death (secondary outcomes).


Of the 250 patients randomized, 226 completed the study, with the major indication for warfarin being atrial fibrillation (58% and 56% in the two groups), and with many subjects having undergone heart valve replacement (41% in both groups). TTR was 74.1% (standard deviation [SD] 18.8%) in the 4-week group compared with 71.6% (SD 20.0%) in the 12-week group (absolute difference, 2.5 percentage points [one-sided 97.5% upper confidence bound, 7.3 percentage points]; p = 0.020 for noninferiority for a 7.5 percentage point margin). There were fewer dose changes in the 12-week group versus the 4-week group (37.1% vs. 55.6%; absolute difference, 18.5 percentage points [95% CI, 6.1-30.0 percentage points]; p = 0.004). There were no differences between the groups in any other secondary outcomes.


The authors concluded that assessment of warfarin dosing every 12 weeks seems to be safe and noninferior to assessment every 4 weeks. They cautioned, however, that a comparison of INR testing, patient contact, and warfarin dose assessment every 12 weeks versus every 4 weeks would be necessary before INR testing every 12 weeks can be routinely recommended for practice.


Randomized trial data to evaluate clinical practice recommendations for the administration and monitoring of warfarin therapy are scarce. This randomized trial suggests that fewer dose changes, but no diminution in quality of care as measured by TTR, resulted from warfarin dosing assessment every 12 weeks versus the currently recommended dosing every 4 weeks. As the authors mention in their limitations and rightly point out in their conclusion, the interpretation of this study is significantly compromised by the fact that all subjects underwent testing and contact with clinic staff every 4 weeks. The only elements of care that differed between the two study groups were the frequency of actual INR testing performed. One very important component of warfarin monitoring anticoagulation clinics, possibly the most important component, is the regular patient contact, which provides built-in adherence reassurance. We therefore cannot infer from this study that less frequent patient monitoring is, in fact, noninferior.

Clinical Topics: Anticoagulation Management, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention

Keywords: Thromboembolism, Blood Coagulation, Warfarin, Cardiac Surgical Procedures, Drug Monitoring, Heart Valves, Hemorrhage

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