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Randomized Trial of Warfarin Nomograms
- Michael J. Kovacs, MD, FRCPC; and
- Philip S. Wells, MD, FRCPC, MSc
- From London Health Sciences Centre, London, Ontario N6A 4G5, Canada, and Ottawa Hospital—Civic Campus; Ottawa, Ontario K1Y 4E9, Canada.
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IN RESPONSE:
We thank all of the correspondents for the interest in our article, which has initiated a strong and emotional debate. Given the strong shift, however, of treatment of acute thromboembolism to an outpatient setting using low-molecular-weight heparin, it is imperative to have a simple means to achieve therapeutic oral anticoagulation in an efficient, timely, and predictable fashion.
Much press has been given to the fact that the INR may predominantly reflect factor VII levels during initiation of oral anticoagulant therapy, but with concomitant primary therapy (that is, therapy with low-molecular-weight heparin), no clinical consequences have been reported. Perhaps our nomogram should not be employed if concomitant low-molecular-weight heparin therapy is not used, but there are no data to support this. Despite theoretical concerns using Bayesian modelling, we did not experience a greater rate of critically higher INRs in patients treated using the 10-mg nomogram, and there are no data showing that patients with cytochrome 2C9 require lower initiating doses despite requiring lower maintenance doses of warfarin. Speed may kill in automobiles, but no data prove that it kills with warfarin.
In our paper, we already stated that we cannot exclude a safety difference between the 5-mg and 10-mg warfarin initiation nomograms. It is probable that a study designed to detect differences in bleeding and recurrence would require a prohibitive sample size. We agree with Crowther and colleagues that the main reason for the differences between our study and theirs may be the patient samples. Until now, it was not apparent that they used primarily an inpatient population (including postoperative orthopedic prophylaxis) in their study. When we tried their nomogram in our outpatients, it was our impression that therapeutic anticoagulation was delayed, which was one impetus for our study.
We disagree with the concerns of Dr. Warkentin. Warfarin-induced skin necrosis is extremely rare and can occur in persons with and without protein C deficiency. No cases have been seen in our practices despite thousands of treated patients. Previous anecdotal case reports have linked this disorder to loading doses that were much higher than those used in our study or that were administered without concomitant heparin therapy. Moreover, we would argue that by achieving an INR in a quicker, more efficient fashion, the time exposure to heparin is shortened and, hence, the risk for heparin-induced thrombocytopenia is lower, especially when patients are treated only with low-molecular-weight heparin (1). Finally, venous limb gangrene has been associated with warfarin used unopposed in the treatment of heparin-induced thrombocytopenia (2), unlike in our study.
Although it is probable that very old or very small patients need lower initiating doses, this is not clear, and we did not exclude these patients. Ideally, there would be a nomogram for every type of patient, but that would not be practical. We believe a simple, standard ordering method will lead to better outcomes than the “on-call” person's best judgment. We have demonstrated that it is unnecessary to measure INRs every day. We suggest that other clinicians try our nomogram using our eligibility criteria (that is, outpatients of any age with venous thromboembolism, with or without cancer, regardless of medications) and judge for themselves how it works in their practices.
Michael J. Kovacs, MD, FRCPC
London Health Sciences Centre; London, Ontario N6A 4G5, Canada
Philip S. Wells, MD, FRCPC, MSc
Ottawa Hospital—Civic Campus; Ottawa, Ontario K1Y 4E9, Canada
The Editors welcome submissions for possible publication in the Letters section. Authors of letters should:
•Include no more than 300 words of text, three authors, and five references
•Type with double-spacing
•Send three copies of the letter, an authors' form signed by all authors, and a cover letter describing any conflicts of interest related to the contents of the letter.
Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified that the letter has been received. If the letter is selected for publication, the author will be notified about 3 weeks before the publication date. Unpublished letters cannot be returned.
Annals welcomes electronically submitted letters.
- Copyright ©2004 by the American College of Physicians
