Francesco Dentali, MD
In patients treated with warfarin who have stable international normalized ratios (INRs), is dose assessment every 12 weeks noninferior to assessment every 4 weeks?
Randomized, controlled, noninferiority trial. ClinicalTrials.gov NCT00356759.
Blinded* (patients, principal investigator, clinic and laboratory staff, event adjudication committee, and statistician).
Hospital-based anticoagulation clinic in Hamilton, Ontario, Canada.
250 patients ≥ 18 years of age (median age 70 to 72 y, 70% men) who were receiving long-term warfarin (therapeutic INR range 2.0 to 3.0 or 2.5 to 3.5) with a stable maintenance dose for ≥ 6 months, managed in the clinic for ≥ 6 months, and had prothrombin time (PT) measured at the hospital laboratory or designated private laboratory. Exclusion criteria included life expectancy < 1 year and lack of suitability for the study (e.g., psychiatric disorders, history of poor adherence).
Warfarin dose assessment every 12 weeks (n = 124) or every 4 weeks (n = 126). All patients had PT monitored every 4 weeks. Treating physicians in the 4-week group were given true INR values after every monitoring visit; those in the 12-week group were given 1 true INR value for 1 randomly selected 4-week period and sham INR values (1.8 to 3.5 for patients with a therapeutic INR range of 2.0 to 3.0, and 2.0 to 4.0 for those with a therapeutic INR range of 2.5 to 3.5) for the other two 4-week periods unless the INR value was extreme (< 1.5 or ≥ 4.5) or the patient had a clinical event or needed perioperative management. Clinic staff telephoned all patients every 4 weeks for dosing and to ask about clinical events or antibiotic therapy.
INR time in therapeutic range (TTR), number of extreme INRs, changes in maintenance warfarin dose, and clinical events (major bleeding, thromboembolism, and death).
90% (intention-to-treat analysis).
The main results are in the Table. The 12-week and 4-week groups did not differ for clinical events (major bleeding 1.6% vs 0.8%, P = 0.55; verified thromboembolic event 0% vs 0.8%, P = 0.32; death 1.6% vs 4.0%, P = 0.25).
In patients with stable international normalized ratios, assessing warfarin dose every 12 weeks was not inferior to assessing dose every 4 weeks for time in therapeutic range.
†INR = international normalized ratio; TTR = time in therapeutic range; other abbreviations defined in Glossary.
‡Criterion for noninferiority was met because upper 97.5% CI was < 7.5% (1-sided P = 0.02 for noninferiority).
§INR < 1.5 or ≥ 4.5.
Dentali F. Less-frequent warfarin dose assessment was noninferior for patients with stable INRs. Ann Intern Med. ;156:JC3–3. doi: 10.7326/0003-4819-156-6-201202210-02003
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Published: Ann Intern Med. 2012;156(6):JC3-3.
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