10-Milligram Coumadin Loading for Outpatient Management of Deep-Vein Thrombosis

Abstract & Commentary

Synopsis: In this randomized outpatient clinical trial of anticoagulation nomograms for patients with acute deep-vein thrombosis, a 10-mg initial dose of warfarin (coumadin) proved superior to an initial 5-mg dose with regard to time reaching therapeutic INR. The scheme presented, including initial treatment with low-molecular-weight heparin, is immediately applicable to the outpatient management of DVT.

Source: Kovacs MI, et al. Ann Intern Med. 2003;138: 714-719.

The optimal method to achieve therapeutic anticoagulation in the outpatient setting has yet to be established. In the current report, outpatients with acute deep-vein thrombosis (DVT) were randomized to 1 of 2 nomograms that included loading with either 10 mg or 5 mg of coumadin. The study was undertaken at the clinics associated with 4 Canadian hospitals and was a randomized, double-blind (physician/patient) interventional trial. The clearly stated hypothesis was that patients receiving the 10-mg coumadin induction nomogram would achieve therapeutic international normalized ratios (INRs) more rapidly than those managed with a 5-mg coumadin nomogram. The question, of course, was whether this could be done without an increased risk of bleeding.

Consecutive patients (n = 201) with objectively confirmed acute DVT were treated with low-molecular weight heparin for a minimum of 5 days and until therapeutic INR (> 1.9) was achieved. Patients were randomly assigned to initially receive a 10-mg or 5-mg dose of coumadin.

Demographic characteristics were similar in both groups. Patients in the 10-mg group achieved therapeutic INR 1.4 days earlier than patients in the 5-mg group (P < .001). By day 5, 83% of those in the 10-mg group had reached the therapeutic INR compared with 46% in the 5-mg group (P < .001). There were no significant differences between the 2 groups in recurrent events, major bleeding, survival and number of INR measurements greater than 5.0. Kovacs and colleagues concluded that the 10-mg coumadin induction nomogram was superior to the 5-mg nomogram because it allows more rapid achievement of therapeutic INR.

Comment by William B. Ershler, MD

Outpatient management of DVT has become common practice in many communities because it decreases cost and is associated with improved quality of life.1 However, there are burdens on the patient, family, and clinic associated with daily injections of low-molecular-weight heparin and the need for frequent monitoring of INR. The minimum duration for LMWH therapy is 5 days,2,3 and although extension beyond this point is unlikely to be harmful, it adds expense and the additional inconvenience of needle injections. The current report provides convincing evidence that a 10-mg starting dose of coumadin is more effective than a 5-mg dose in achieving therapeutic INR in a timely way and without added toxicity.

The study was performed in an outpatient setting and is relevant most clearly for that setting. The nomogram employed involves INR determination at baseline, day 3, and day 5, with a prescribed dose adjustment on those days. For example, on day 3, those who had an INR of < 1.3 received 15 mg of coumadin on days 3 and 4, whereas others who had an INR of 1.7-1.9 would have coumadin doses reduced to 5 mg for days 3 and 4. In the hospital setting, there has been a suggestion that patients are more sensitive to coumadin, presumably on the basis of nutritional factors or the likelihood of antibiotics or other potential drug interactions,3 and at least 1 group has indicated that a 5-mg loading dose of coumadin is more effective4,5 in that setting.

Although there was no significant difference observed for recurrent DVT or bleeding, the current report was not adequately powered to conclude that these differences do not exist. Thus, the data must be reviewed with caution and additional, larger trials will be needed. Furthermore, the selection of patients for outpatient treatment of acute DVT is likely to exclude the sickest patients and those that are at greater risk for bleeding. Thus, the current report provides a very useful strategy for effective anticoagulation of acute DVT patients who are otherwise well enough to be treated in the outpatient setting. A copy of the nomogram, included as Figure 1 in the manuscript, may well be a useful addition to the clinic bulletin board.

Dr. Ershler, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.

References

1. Wells PS, et al. Ann Intern Med. 1998;158:1809-1812.

2. Levine M, et al. N Engl J Med. 1996;334:677-681.

3. Koopman MM, et al. N Engl J Med. 1996;334:682-687.

4. Krother MA, et al. Ann Intern Med. 1997;127:333.

5. Harrison L, et al. Ann Intern Med. 1997;126:133-136.