Warfarin started at 10 mg achieves therapeutic INR faster than 5 mg

Journal of Family Practice, Sept, 2003 by Alan Cementina, Eric A. Jackson

Kovacs MJ, Rodger M, Anderson DR, et al. Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular weight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial. Ann Intern Med 2003; 138:714-719.

* PRACTICE RECOMMENDATIONS

Starting warfarin with 10 mg rather than 5 mg achieves a therapeutic international normalized ratio (INR) >1.9 one day earlier (4.2 vs 5.6 days) in selected outpatients at low risk for major bleeding complications with confirmed acute venous thromboembolism.

This strategy saves the time and expense of 1 daily INR determination, and it may decrease the number of days that low-molecular-weight heparin is required by 1 day--although all patients in this study, due to the nature of the design, received a minimum of 5 days of low-molecular-weight heparin.

No conclusions regarding differences in safety or efficacy between the 10-mg and 5-mg nomogram can be drawn from the results of this study, as it was underpowered to detect differences in these important endpoints.

* BACKGROUND

Though not frequently undertaken by family physicians, the treatment of acute venous thromboembolism is now common in the outpatient setting. Patients are treated with a low-molecular-weight heparin, and warfarin is initiated within 24 hours.

This trial compares 2 dosing nomograms that may facilitate sale and timely initiation of warfarin.

* POPULATION STUDIED

Researchers at 4 Canadian thrombosis clinics enrolled 201 outpatients with confirmed acute venous thromboembolism. Patients ranged in age from 18 to 98 years (mean, 55.5 years), 16% being older than 75 years. After randomization, baseline characteristics of both treatment groups were similar, although the 10-mg group included more men.

Patients were excluded if they had a baseline INR greater than 1.4, had thrombocytopenia, recently received oral anticoagulation, or were at high risk for major bleeding. While the setting was different (specialty clinics), the patients were similar to those seen in family practice offices.

* STUDY DESIGN AND VALIDITY

Subjects were randomly assigned to receive warfarin induction using either a modified, previously developed nomogram (1) starting with 5 mg on the 2 days (n=97) or a new nomogram starting with 10 mg on the first 2 days (n=104). Warfarin was started on the first day of treatment with subcutaueous low-molecular-weight heparin, which was continued for at least 5 days until a therapeutic INR was achieved. Subsequent doses of warfarin were determined from the respective nomograms. INR values were checked on days 3, 4, and 5 in all patients, although the 10-mg nomogram did hot require an INR on day 4. Patients were followed for 90 days.

The methodology was very strong and included double-blinding (physician and patient) with concealed allocation (treatment details contained in opaque, sealed envelopes) and intention-to-treat analysis. The study was adequately powered to detect the primary endpoint (time to therapeutic INR), but was underpowered for secondary clinical endpoints.

* OUTCOMES MEASURED

The primary outcome was time in days to a therapeutic INR (>1.9). Secondary outcomes included the proportion of patients with an INR between 2.0 and 3.0 on day 5, total number of INR measurements, incidence of recurrent venous thromboembolism and major bleeding, and survival.

* RESULTS

Patients in the 10-mg group achieved a therapeutic INR 1.4 days earlier than those in the 5-mg group (P<.001) and many more patients in the 10-mg group than in the 5-mg group achieved a therapeutic INR by day 5 (83% vs. 46%; P<.001; number needed to treat=2.7). As a result, fewer INR assessments were performed in the 10-mg group than in the 5-mg group (8.1 vs. 9.1; P=.04). No significant differences were round between the 2 groups in recurrent venous thrombotic events, major bleeding episodes (1 in each group), or survival over the 90 days of follow-up, though the study was not large enough to find a small difference in rates if one exists.

REFERENCE

(1.) Crowther MA, Harrison L, Hirsh J. Warfarin: less may be better (Letter). Ann Intern Med 1997; 127:333.

Alan Cementina, MD, and Eric A. Jackson, PharmD, University of Connecticut School of Medicine and Saint Francis Hospital and Medical Center, Hartford, Conn. E-mail: ejackson2@stfanciscare.org.