Warfarin dose assessment every 4 weeks versus every 12 weeks in patients with stable international normalized ratios: a randomized trial.

BACKGROUND

Guidelines recommend that patients receiving warfarin undergo international normalized ratio (INR) monitoring every 4 weeks.

OBJECTIVE

To investigate whether assessment of warfarin dosing every 12 weeks is as safe as assessment every 4 weeks.

DESIGN

Noninferiority randomized trial. The randomization schedule (in a 1:1 ratio) was computer-generated, and allocation was concealed until the database was locked by using a centralized schedule. Patients, study and clinical personnel, adjudicators of clinical events, and the study statistician were blinded to treatment assignment. (ClinicalTrials.gov registration number: NCT00356759) SETTING: Single center in Hamilton, Ontario, Canada.

PATIENTS

250 patients receiving long-term warfarin therapy, whose dose was unchanged for at least 6 months; 226 completed the study.

INTERVENTION

Dosing assessment every 12 weeks (n = 124) compared with every 4 weeks (n = 126) for 12 months. Patients in the 12-week group were tested every 4 weeks; sham INRs within the target range were reported for two of the three 4-week periods.

MEASUREMENTS

Percentage of time in the therapeutic range (primary outcome) and number of extreme INRs, changes in maintenance dose, major bleeding events, objectively verified thromboembolism, and death (secondary outcomes).

RESULTS

The percentage of time in the therapeutic range was 74.1% (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 [1-sided 97.5% upper confidence bound, 7.3 percentage points]; noninferiority P = 0.020 for a 7.5-percentage point margin). Fewer patients in the 12-week group than in the 4-week group had any dose changes (37.1% vs. 55.6%; absolute difference, 18.5 percentage points [95% CI, 6.1 to 30.0 percentage points]; P = 0.004). Secondary outcomes did not differ between groups.

LIMITATIONS

Patients in the 12-week group had testing and contact with clinic staff every 4 weeks. The study was conducted at a single center and used surrogate outcomes.

CONCLUSION

Assessment of warfarin dosing every 12 weeks seems to be safe and noninferior to assessment every 4 weeks. A comparison of INR testing, patient contact, and warfarin dose assessment every 12 weeks versus every 4 weeks is necessary before INR testing every 12 weeks can be routinely recommended for practice.

PRIMARY FUNDING SOURCE

Physicians' Services Incorporated Foundation.