Past, present and future considerations on low molecular weight heparin differentiation: an epilogue

This epilogue represents a final summary of the issues discussed and highlighted at the International Summit on Differentiation of Low Molecular Weight Heparins (LMWHs). International scientists and physicians presented and discussed the physicochemical differences between LMWHs, and concluded that different production processes result in the formation of distinct drugs with unique preclinical and clinical profiles. Important data was presented showing that different LMWHs continue to show marked differences in antithrombotic action, and pharmacokinetic and pharmacodynamic profiles measured in animal models. Human data also demonstrate that LMWHs are not bioequivalent. Moving to the clinical arena, it is clear that there are issues to be resolved regarding drug inequivalence. No apparent clinical efficacy differences have been observed in deep-vein thrombosis prophylaxis using a number of relatively low doses of LMWH. However, two studies have demonstrated clinical equivalence using different anti-Xa doses of LMWHs, strongly suggesting product inequivalence. This also suggests that anti-Xa doses are not reflective of the entire pharmacologic effects of LMWHs. It is unknown whether the higher dosages employed in the treatment of DVT will help provide evidence of clinical inequivalence. In the management of acute coronary syndromes, higher drug dosages than those used in prophylaxis have revealed an efficacy advantage; while two LMWHs have shown short-term improvement in acute coronary syndromes, only one provided a long-term treatment benefit, suggesting a drug-specific therapeutic advantage. This is in keeping with the position of the United States Food and Drug Administration and the World Health Organization, who regard each individual LMWH as a distinct drug requiring individual clinical trials for use in a specific clinical indication. In this epilogue, the chairpersons, Professors Jawed Fareed, Sylvia Haas and Arthur Sasahara, offer some final thoughts on this intriguing scientific and clinical issues of LMWH differentiation.