Use of direct thrombin inhibitors in acute coronary syndrome

Objective: This paper examines the rationale for using direct thrombin inhibitors in the management of acute coronary syndrome (ACS). Background: With traditional management of ACS using aspirin and unfractionated heparin (UH), refractory angina and new myocardial infarction (MI) continue to develop. Growing understanding of the pathophysiology of ACS has led to the search for more effective therapies directed toward preventing formation of fibrin- and platelet-rich thrombi in the coronary arteries. Current pharmacologic approaches include use of direct thrombin inhibitors (lepirudin, desirudin, and bivalirudin). Methods: We reviewed all published clinical trials abstracted in MEDLINE(R) from 1966 to April 2000, excluding pilot studies enrolling <500 patients. Results: Use of lepirudin at medium doses (0.4-mg/kg bolus + 0.15 mg/kg/h) resulted in lower rates of death, new MI, and refractory angina at 7 days compared with UH (3.0% vs 6.5%; P = 0.047), although the incidence of minor bleeding was increased (7.6% vs 4.5%; P < 0.05). Bivalirudin was as effective as UH in preventing complications after percutaneous coronary intervention (11.4% vs 12.2%; NS) and carried a lower bleeding risk (7.8% vs 19.2%; NS); however, its use in the management of ACS has not been studied. Desirudin used at low doses (0.1-mg/kg bolus + 0.1 mg/kg/h) in large-scale clinical trials in patients with acute MI treated with alteplase or streptokinase appeared to be at least as effective as UH (8.9% vs 9.8% at 30 days; NS). However, its therapeutic index was narrow, since it was associated with significantly more moderate bleeding (8.8% vs 7.7%; P < 0.05). Conclusions: All clinical trials to date have studied relatively short-term use (3-5 days) of direct thrombin inhibitors, and long-term benefits on morbidity and mortality have not been demonstrated. Until further data are available, direct thrombin inhibitors should be restricted to use as a possible alternative in patients who require anticoagulant therapy but experience UH-induced thrombocytopenia.