Low-molecular-weight heparins and heparinoids

To the Editor: The recent "New Drugs, Old Drugs" review of low molecular weight heparins (LMWH) and heparinoids1 provides a timely reminder of the limitations of studies that support the use of these agents in preventing venous thromboembolism (VTE), particularly in orthopaedic surgery.

A new class of anticoagulants has recently been released in Australia and is being promoted as being more effective than LMWH in preventing VTE. However, while several randomised controlled trials suggest that fondaparinux reduces the risk of asymptomatic deep vein thrombosis (DVT) in patients undergoing hip and knee replacement surgery,2,3 there is currently no evidence to suggest that it reduces the risk of symptomatic VTE.

Fondaparinux is a synthetic penta-saccharide that selectively binds to antithrombin III, enhancing the neutralisation of factor Xa and inhibiting generation of thrombin and subsequent clot formation.2 Unlike LMWH, fondaparinux does not appear to affect platelet function, thus potentially reducing bleeding tendencies and avoiding the risk of immune-mediated thrombocytopenia.

The main problem facing researchers who study VTE prophylaxis in patients undergoing orthopaedic surgery is that, while asymptomatic DVT is common, symptomatic VTE is rare. The rate of fatal pulmonary embolism in patients undergoing hip replacement surgery is 0.1%–0.2% in those who receive no prophylaxis.4 Trials to demonstrate a reduction in symptomatic VTE are not performed because huge sample sizes are required to show a statistically significant difference in outcome (50 000 patients would need to be enrolled in a trial to show a reduction in the rate of fatal pulmonary embolism from 0.2% to 0.1% with 80% power). If such a difference could be shown, it would probably be clinically irrelevant to an orthopaedic surgeon performing 50 joint replacements a year.

Although asymptomatic DVT is used as a surrogate endpoint for trials that support VTE prophylaxis, the natural history of asymptomatic DVT is poorly documented. There is some evidence to suggest that asymptomatic DVT is not associated with an increased risk of subsequent chronic venous insufficiency,5 and the association between asymptomatic DVT and subsequent clot propagation and embolisation is not well established.

Further information on the natural history of asymptomatic DVT must be obtained before the clinical relevance of results from current studies of VTE prophylaxis can be determined. Until then, the clinical relevance of studies comparing the use of "new drugs" with "old drugs" in preventing VTE in orthopaedic surgery cannot be assessed.