Low molecular weight heparin treatment of venous thromboembolism

Abstract

T HE ACCEPTED standard treatment for acute deep vein thrombosis (DVT) is initial continuous intravenous heparin~,2, 3 followed by long-term oral anticoagulant therapy. 4-s It has been possible to perform a series of randomized clinical trials to evaluate the various approaches to treatment of venous thrombosis, because accurate objective tests have become available to detect venous thromboembolism (VTE) 9-13 and the methodology for clinical trials has improved. Almost all of the uncertainties confronted by clinicians in the selection of an appropriate course of anticoagulant therapy have been resolved by these clinical trials, vs It has become common clinical practice to adjust the heparin dose to maintain the activated partial thromboplastin time (APT]?) within a defined therapeutic range, ie, between 1.5 and 2.5 times control. To prevent unacceptably high rates of recurrent VTE, adequate initial hepatin treatment, as judged by the APTT response, is required, a,5 The use of an APTT ratio of 1.5 as the lower limit of the therapeutic range is supported by data from clinical trials. ~,~4 The relative risk for recurrence of VTE was 15 to 1 for patients receiving inadequate initial heparin treatment (APTT ratio, < 1.5). 1 These findings were strongly supported by a more recent randomized trial comparing intravenous heparin and oral anticoagulants with oral anticoagulants alone for the initial treatment of proximal venous thrombosis. ~5 Recurrent VTE occurred in 20% of patients treated with oral anticoagulants alone compared with 6% for those who received initial intravenous heparin adjusted to maintain the APTT above 1.5 times control. Most of the symptomatic recurrences occurred after the first month of treatment. In contrast to the strong association between the subtherapeutic APTT response and recurrent VTE, evidence supporting the use of an upper limit of the therapeutic range is weak. The use of a heparin protocol assures that virtually all patients (98% to 99%) will achieve the therapeutic range for the APTT, thereby decreasing the likelihood of recurrent VTE. Using this protocol, many patients will have APTT values greater than 2.5 times control during their course of therapy. Review of the bleeding complications associated with this trial indicated that major bleeding occurred most frequently in patients because of the presence of underlying causes for bleeding (eg, recent surgery, peptic ulcer disease, and cancer) rather than as a result of an elevated APTT) 4 These findings show a lack of an association between the supratherapeutic APTT result (ratio, 2.5 or more) and the risk of clinically important bleeding complications. Recently, trials have shown that the duration of initial heparin therapy can be shortened from 10 to 14 days to approximately 5 days. 7,8 In an era of fiscal constraint, short-course heparin allows effective treatment without detracting from patient care and, by shortening the inhospital stay, offers a substantial financial bene fit. 16 If an approach for the initial treatment of proximal vein thrombosis is developed that can be administered on an outpatient basis and does not require laboratory monitoring, it would markedly simplify treatment and improve costeffectiveness. A conservative estimate of the number of hospital days that would be saved by an outpatient approach to initial therapy is 5 to 6 days. It has been estimated that such a decrease in the duration of hospitalization would result in savings to the health care system of at least 500 million dollars annually in the United States alone. 16 A number of randomized trials have compared the effectiveness and safety of heparin administered by the subcutaneous and continu-