Direct thrombin inhibitors in cardiovascular disease

Heparin, the most widely used antithrombin, suffers several limitations, including high inter-individual variability of anticoagulant response, a nonlinear dose-response curve, inability to inactivate clot-bound thrombin, a requirement for endogenous cofactors and inactivation by platelet factor 4 and heparinase. These shortcomings may explain its suboptimal efficacy and safety in the prevention of arterial vessel occlusion. Heparin's drawbacks may be overcome by direct thrombin inhibitors. The development of these specific antithrombins has been a major therapeutic goal of the past decade. The high expectations generated by the use of these compounds in experimental models of arterial thrombosis appeared to be confirmed by the initial phase I and II clinical studies. However, large phase III trials have been highly discouraging: three trials with hirudin have been interrupted as a result of a high incidence of serious adverse events. Two of these trials were subsequently restarted at lower doses and did not support an incremental efficacy of hirudin over heparin. Two trials in the setting of angioplasty (one with hirudin and one with hirulog) have also failed to demonstrate the superiority of these compounds over heparin. Is this the result of a very narrow therapeutic range of these agents or the consequence of poor design of the phase II studies leading to the selection of inappropriate doses for the comparative efficacy trials? This review focuses on the clinical development of two specific antithrombins: hirudin and hirulog. The experimental pharmacology and human studies of Argatroban are discussed in a review by Fitzgerald and Murphy.