Correspondence
Long-Term Anticoagulant Therapy
N Engl J Med 2003; 349:1976-1977November 13, 2003
- Article
To the Editor:
Schulman (Aug. 14 issue)1 states that a starting dose of 15 mg of warfarin daily is effective and reduces the duration of heparin treatment. This strategy of giving higher initial doses of warfarin requires clarification. Most studies demonstrating the superiority of higher loading doses have included only outpatients. Inpatients are more sensitive to warfarin therapy because of poor dietary status and the concomitant use of broad-spectrum antibiotics that decrease vitamin K absorption from enteric flora. Studies have shown both that because inpatients are more sensitive to warfarin, they do not require a higher loading dose2 and that higher loading doses are associated with overanticoagulation.3 Higher loading doses may lead to a hypercoagulable state in the first three days by markedly suppressing protein C levels and, as compared with lower loading doses, are associated with a much higher incidence of unwanted hypocoagulability, as manifested by an international normalized ratio (INR) greater than 3.0.
Since low-molecular-weight heparin facilitates outpatient therapy, the need to decrease the duration of heparin therapy is less of an issue. Further studies are required to determine the appropriate starting dose of warfarin for inpatients.
3 ReferencesMarc S. Itskowitz, M.D.
Allegheny General Hospital, Pittsburgh, PA 15212
mitskowi@wpahs.org 1
Schulman S . Care of patients receiving long-term anticoagulant therapy. N Engl J Med 2003;349:675-683
Full Text | Web of Science | Medline2
Kovacs MJ ,Cruickshank M ,Wells PS , et al. Randomized assessment of a warfarin nomogram for initial oral anticoagulation after venous thromboembolic disease. Haemostasis 1998;28:62-69
Medline3
Crowther MA ,Ginsberg JM ,Kearon C , et al. A randomized trial comparing 5-mg and 10-mg warfarin loading doses. Arch Intern Med 1999;159:46-48
CrossRef | Web of Science | Medline
Author/Editor Response
My statement that 15 mg of warfarin daily appears to be effective and safe is based on a study reported in 1984.1 At that time, all patients with venous thromboembolism were treated as inpatients until treatment with an intravenous infusion of unfractionated heparin could be discontinued. Neither in our study (with 169 patients) nor in a recent study (with 201 patients), which demonstrated more rapid achievement of an INR with 10 mg than with 5 mg as the initial dose,2 was there any clinical evidence of more thrombotic or hemorrhagic complications with the higher dose.
The use of laboratory parameters as proof of excessive anticoagulation is less convincing, since the clinical importance of an INR value slightly above 3.0 during the first days of treatment with vitamin K antagonists is unknown, and it is mainly a result of a more rapid depression of factor VII.1 This is the single coagulation factor for which many prothrombin-time reagents are most sensitive. Moreover, because of the difference in the responses of thromboplastin reagents to the reduction of vitamin K–dependent coagulation factors, the INR values are more variable and less reliable during the initial phase of treatment than during long-term anticoagulant therapy.3
3 ReferencesSam Schulman, M.D.
Karolinska Hospital, S-171 76 Stockholm, Sweden1
Schulman S ,Lockner D ,Bergstrom K ,Blomback M . Intensive initial oral anticoagulation and shorter heparin treatment in deep vein thrombosis. Thromb Haemost 1984;52:276-280
Web of Science | Medline2
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
Web of Science | Medline3
McKernan A ,Thomson JM ,Poller L . The reliability of international normalized ratios during short-term oral anticoagulant treatment. Clin Lab Haematol 1988;10:63-71
Medline
