Heparin and low-molecular-weight heparin therapy for venous thromboembolism: will unfractionated heparin survive?

Abstract

Recent improvements in clinical trials methodology and the use of accurate objective tests to detect venous thromboembolism (VTE) have made it possible to carry out a series of randomized trials to evaluate various treatments for VTE. The results of these trials have resolved many of the uncertainties a clinician confronts in selecting the appropriate course of anticoagulant therapy. These trials have shown that the intensity of both initial heparin treatment and long-term anticoagulant therapy must be sufficient to prevent unacceptable rates of recurrence of VTE. Patients with proximal deep vein thrombosis who receive inadequate anticoagulant therapy have a risk of clinically evident, objectively documented recurrent VTE that approaches 20% to 25%. The need for adequate therapy with heparin and the importance of monitoring blood levels of the effect of heparin have been established. The importance of achieving adequate heparinization was suggested by a nonrandomized trial in 1972 and randomized trials in the 1980s have confirmed this finding. Furthermore, randomized trials have demonstrated the importance of achieving adequate heparinization early in the course of therapy. Unfractionated heparin by continuous intravenous infusion has provided an effective therapy for more than half a century, but the need to monitor therapy and establish therapeutic levels is a fundamental problem. It is evident that validated heparin protocols are more successful in establishing adequate heparinization than intuitive ordering by the clinician. However, even with the best of care using a heparin protocol, some patients treated with intravenous heparin will receive subtherapeutic treatment. In this context, subtherapeutic treatment reflects a practical limitation of the use of unfractionated heparin, rather than a poor standard of care. Furthermore, it is recognized that the practical difficulties associated with heparin administration are compounded by the substantive practical difficulties of standardizing activated partial thromboplastin time (aPTT) testing and the therapeutic range. Our findings have emphasized the confounding effect that initial heparin treatment has on long-term outcome. In all trials of long-term treatment, it is imperative that the initial therapy is of adequate intensity and duration; failure to administer adequate initial treatment may lead to a poor outcome that is falsely attributed to the long-term therapy under evaluation. Treatment with low-molecular-weight heparin (LMWH), which does not require monitoring or dose finding, has largely replaced unfractionated heparin for the initial management of VTE. Efficacy in terms of recurrent VTE or extension of thrombus has been at least as good with LMWH as unfractionated heparin and there is evidence that the incidence of major bleeding, heparin-induced thrombocytopenia, and osteoporosis are less with LMWH as compared with unfractionated heparin. Although unfractionated heparin may survive as a treatment option for acute VTE, its use has been largely supplanted by LMWH.