This standard practice is now being challenged by the development of low-molecular-weight heparins, which are manufactured by depolymerization of unfractionated heparin. The concept behind the development of these refined compounds is that inhibition of activated coagulation factor X (Xa) is crucial for the antithrombotic activity of heparins. Unlike unfractionated heparin, which has equivalent activity against both factor Xa and thrombin, low-molecular-weight heparins have greater activity against factor Xa. Therefore, it is expected that low-molecular-weight heparins will be associated with anti-thrombotic activity at least equal to that of unfractionated heparin, whereas the risk for hemorrhage is smaller. However, the most important advantages of low-molecular-weight heparins are their superior pharmacokinetic properties. Compared with unfractionated heparin, they bind less to plasma proteins, blood cells, and the endothelium, resulting in nearly complete bioavailability, longer half-life, and more predictable anticoagulant response [5, 6]. This allows once- or twice-daily subcutaneous administration of low-molecular-weight heparins adjusted for body weight without the need for laboratory monitoring. Evidence also suggests that the risk for heparin-induced thrombocytopenia is smaller with low-molecular-weight heparins [7].

We briefly review the research evidence on the clinical use of low-molecular-weight heparin in patients with deep venous thrombosis and pulmonary embolism. We then explore the pragmatic question of the proper clinical indications for use of low-molecular-weight heparin therapy today, and we look at clinical situations in which one should be more cautious in the use of these compounds.

The role of low-molecular-weight heparins in the treatment of acute deep venous thrombosis has been assessed in at least nine clinically similar randomized studies of high methodologic quality. In a pooled analysis of these trials, which included a total of about 3500 patients, fixed-dose subcutaneous low-molecular-weight heparin was similar to or better than continuous, intravenous, dose-adjusted unfractionated heparin for reducing the incidence of symptomatic recurrent venous thromboembolism during 3 to 6 months of follow-up (odds ratio, 0.75 [95% CI, 0.55 to 1.01]; P = 0.06) [8-10]. Two randomized studies with clinical follow-up compared initial therapy with unmonitored low-molecular-weight heparin with unfractionated heparin in patients with acute symptomatic pulmonary embolism. Almost 900 patients were studied, and the pooled odds ratio for symptomatic recurrent venous thromboembolism over 3 months was 0.91 (CI, 0.42 to 1.97; P = 0.81) [9, 10]. In these studies, low-molecular-weight heparin was also administered subcutaneously in a dose identical to that used in the treatment of patients with deep venous thrombosis. When all studies of patients with deep venous thrombosis or pulmonary embolism were combined, the occurrence of clinically important hemorrhage was reduced significantly in the low-molecular-weight heparin recipients (odds ratio, 0.55 [CI, 0.34 to 0.89]; P = 0.02) [8-10].

Because low-molecular-weight heparins are administered by subcutaneous injection in unmonitored, weight-adjusted dosing, two randomized studies and one cohort study evaluated the potential of self-treatment with low-molecular-weight heparin out of hospital. These studies in patients with symptomatic, usually proximal deep venous thrombosis revealed that self-treatment with low-molecular-weight heparin had an efficacy and safety similar to those of intravenous unfractionated heparin administered in the hospital. Approximately 30% to 50% of the patients who received low-molecular-weight heparin were fully treated at home, 10% to 25% were admitted to the hospital for the entire treatment period, and the remainder were discharged after 1 to 3 days in the hospital [11-13]. The potential for out-of-hospital treatment with low-molecular-weight heparins makes strategies that use these compounds potentially cost-effective, despite the higher costs of fractionated heparins.

Most studies of low-molecular-weight heparin in patients with venous thromboembolism have used two subcutaneous injections of the agent daily. However, studies comparing a once-daily with a twice-daily regimen indicate that the two regimens have similar efficacy and safety [13, 14].

What are the implications of these findings for the practicing clinician? For most patients with acute deep venous thrombosis, including those with proximal venous thrombosis and those with risk factors for recurrent disease or cancer, there is sufficient evidence that low-molecular-weight heparins are an effective and safe alternative to intravenous unfractionated heparin. However, it should be recognized that in the above-mentioned studies, about 15% of the eligible patients with deep venous thrombosis were excluded because they had clinically suspected pulmonary embolism, previous deep venous thrombosis, or an expected high risk for bleeding. Although the results of the randomized studies can probably be extrapolated to these patients, it is uncertain whether low-molecular-weight heparin treatment is the most appropriate option for these patients.

The efficacy and safety of home treatment in patients with deep venous thrombosis who do not have clinically overt pulmonary embolism have been shown to be similar to those of treatment with unfractionated heparin in the hospital. Therefore, treatment at home throughout the entire course of therapy or after a few days in the hospital should be considered in patients who understand the implications of such treatment. Most patients are able to inject themselves; alternatively, a family member or a visiting nurse can give the injections. It must be emphasized that care outside the hospital increases pressure on community agencies to provide proper anticoagulant therapy and that these agencies must be prepared for this task.

For patients with proven pulmonary embolism, it is less clear whether low-molecular-weight heparins can be recommended as a replacement for unfractionated heparin. Findings in patients with pulmonary embolism will probably not differ much from those in patients with deep venous thrombosis. As of now, only two studies have been performed, and more data are needed to justify a change in clinical practice.

In conclusion, for patients with symptomatic deep venous thrombosis, low-molecular-weight heparin seems to be the preferred therapy on the basis of its demonstrated efficacy coupled with ease of administration, lack of need for laboratory monitoring, and decreased risk for bleeding. Out-of-hospital treatment is appropriate for most of these patients. For patients with symptomatic pulmonary embolism, growing evidence shows that low-molecular-weight heparin may be the best option, but more data are needed. Although unfractionated heparin has dominated the treatment of venous thromboembolism for more than 80 years, it seems increasingly likely that the fractionated preparations of this classic drug will take over this role.