More Options for Venous Thromboembolism Treatment
By Kirsten N. Kangelaris, MD
Kearon C, Ginsberg JS, Julian JA, et al. Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug 23;296(8):935-942.
The standard approach to using unfractionated heparin (UFH) in the treatment of acute venous thromboembolism as a bridge to warfarin therapy requires continuous intravenous infusion with frequent dose adjustments in response to measurements of activated partial thromboplastin time (aPTT). This therapy inevitably requires inpatient management. Subcutaneous administration of weight-based low molecular weight heparin (LMWH) has been the modality of choice for outpatient treatment of venous thromboembolism because it does not require laboratory monitoring. Its use has been limited by the high cost of treatment, however. A preliminary study, released in 2000 by the FIDO group (Fixed-Dose Heparin Investigators, Kearon and colleagues), suggested that subcutaneously administered UFH could be optimally dosed based on weight rather than monitoring aPTT levels.
This follow-up, randomized, open-label, adjudicator-blinded, multi-centered, non-inferiority trial enrolled 708 patients and compared fixed-dose, subcutaneously administered UFH to LMWH in acute deep venous thrombosis and pulmonary embolism. Administration in both groups was twice daily, subcutaneous, and weight-based. UFH was given as a first dose of 333 U/kg, followed by 250 U/kg every 12 hours. LMWH was administered at a dose of 100 IU/kg every 12 hours. Both treatments overlapped with three months of warfarin therapy, and both could be administered out of hospital.
Exclusion criteria were age <18, contraindication to subcutaneous therapy, active bleeding, life expectancy under three months, long-term anticoagulation therapy, pregnancy, and creatinine level >2.3 mg/dL.
The primary endpoints were efficacy as determined by recurrent venous thromboembolism within three months and safety as determined by major bleeding within 10 days of randomization. A secondary endpoint was relationship of efficacy and safety outcomes to aPTT levels measured on day two to three of therapy for the UFH group.
Results revealed that UFH was statistically non-inferior to LMWH by all endpoints, including treatment duration, efficacy, and safety. At three months, there was no significant difference between the groups in frequency of recurrent venous thromboembolism (3.8% UFH versus 3.4% LMWH), bleeding (1.1% UFH versus 1.4% LMWH), or death. There was no association between aPTT levels and recurrent venous thromboembolism or bleeding.
Limitations of the study included reduced enrollment from the initial study design, though power was adequate due to a lower than expected incidence of recurrent venous thromboembolism in both arms (~3.6% versus the expected 6%); possible biases related to open-label design; and more post-randomization exclusions in the UFH group versus the LMWH group.
In summary, fixed-dose, unmonitored, subcutaneous UFH appears to be an effective, safe alternative to LMWH as a bridge to warfarin therapy for venous thromboembolism. Clinically, this is relevant, because UFH is approximately 15 to 20 times less expensive than LMWH. The authors appropriately call attention to two developments in clinical practice that occurred during the course of the present study and that could potentially limit the use of UFH. These are 1) the dosing option for once-daily LMWH, which improves convenience, and 2) the preference for long-term LMWH therapy over warfarin for treating cancer patients with venous thromboembolism. Despite these exceptions, UFH may prove to be a viable and economic option for venous thromboembolism treatment.
In-Hospital MI Versus MI at Presentation
By Erin M. Galbraith, MD
Maynard C, Lowy E, Rumsfeld J, et al. The prevalence and outcomes of in-hospital acute myocardial infarction in the Department of Veterans Affairs Health System. Arch Intern Med. 2006 Jul 10;166(13):1410-1416.