Use of direct thrombin inhibitors in acute coronary syndrome

Objective: This paper examines the rationale for using direct thrombin inhi bitors in the management of acute coronary syndrome (ACS). Background: With traditional management of ACS using aspirin and unfraction ated heparin (UH), refractory angina and new myocardial infarction (MI) con tinue to develop. Growing understanding of the pathophysiology of ACS has l ed to the search for more effective therapies directed toward preventing fo rmation of fibrin- and platelet-rich thrombi in the coronary arteries. Curr ent pharmacologic approaches include use of direct thrombin inhibitors (lep irudin, 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 c ompared 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 effecti ve as UH in preventing complications after percutaneous coronary interventi on (11.4% vs 12.2%; NS) and carried a lower bleeding risk (7.8% vs 19.2%; N S); however, its use in the management of ACS has not been studied. Desirud in used at low doses (0.1-mg/kg bolus + 0.1 mg/kg/h) in large-scale clinica l 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). H owever, its therapeutic index was narrow, since it was associated with sign ificantly 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 mo rbidity and mortality have not been demonstrated. Until further data are av ailable, direct thrombin inhibitors should be restricted to use as a possib le alternative in patients who require anticoagulant therapy but experience UH-induced thrombocytopenia.