low-molecular-weight heparin

INTRODUCTION

Heparin (i.e., unfractionated heparin) combined with oral anticoagulant therapy has been the mainstay of both prophylaxis and treatment for patients who have venous thromboembolism or who are at risk of this condition. Low- molecular-weight (LMW) heparins have increasingly replaced unfractionated heparin in the treatment of deep vein thrombosis with or without pulmonary embolism. The use of LMW heparins beyond the acute treatment period of venous thromboembolism occurs for selected patients in whom oral anticoagulation with warfarin may not be appropriate, primarily patients who experience recurrent thrombosis while taking warfarin and patients with active cancer. Data also support the use of LMW heparin in acute coronary syndromes, and institutions commonly use these agents for such syndromes. LMW heparins are employed for other indications as well, such as bridging at the time of surgical procedures. For the vast majority of patients, weight-adjusted doses of LMW heparin can be administered subcutaneously once or twice daily without laboratory monitoring.

The LMW heparins vary slightly from one another in the distribution of the molecular weight species they contain and in their pharmacologic properties. LMW heparins are hydrophilic agents that are primarily distributed to the intravas- cular space. In adults, their volume of distribution is typically about 0.05 L/kg or about 4—6 L. Although some drugs (e.g., aminoglycosides) are dosed on an estimated lean or adjusted body weight in obese patients, the activity of LMW heparins does not appear to be significantly increased when these drugs are dosed on the basis of total body weight. Peak pharmaco­logic effect (based on anti-Xa levels) ranges from 3 to 5 h.
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Dosage recommendations for the 4 LMW heparins marketed in Canada are based on weight up to a maximum between about 83 and 120 kg. The dosage cap varies for each LMW heparin and for each indication (Table 1). In contrast, the regulatory agencies of many other countries have not placed a cap on the maximum dose.

tab 1

According to the 2004 Canadian Community Health Survey for nutrition, 23% of Canadian adults are obese, as defined by body mass index (BMI) of 30 kg/m2 or more. An unpublished survey of 480 patients referred for any indication to the Calgary Health Region Anticoagulation Management Service revealed that an average of 12.2% of patients weighed more than 100 kg. Given current practices and Canadian demographics, determination of the optimal dose of LMW heparins for patients with obesity is clinically relevant. It is reasonable to assume that achieving adequate levels of anticoagulation in obese patients who are taking LMW heparins will affect outcomes such as morbidity, mortality, and risk of recurrent thrombosis.

In assessing the level of anticoagulation, the concentration of LMW heparins cannot be measured directly. The activity of anti-Xa activity is the primary indirect measure of their anticoagulant effect. In the Winnipeg Regional Health Authority, therapeutic peak anti-Xa levels at 4 h after dose administration for patients with venous thromboembolism (including pulmonary embolism) are defined as 1.0-2.0 U/mL with once-daily dosing of LMW heparin and 0.5-1.0 U/mL with twice-daily dosing. Two concerns related to use of the anti-Xa level to measure anticoagulant effect are that optimal target peak anti-Xa levels for LMW heparins are not well defined and there is a lack of data to support a link between the anti-Xa level and the clinical outcome. In addition to the use of anti-Xa levels as an indirect marker of efficacy, there is evidence that higher anti-Xa levels are associated with an increased risk of major bleeding.
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Many patients who are taking LMW heparins weigh more than the maximum dosing weight defined by the Canadian monographs. A literature review was therefore undertaken to deter­mine the validity of the caps on treatment doses of LMW heparins marketed in Canada that have been set for obese patients.