The direct thrombin inhibitor, hirudin, was tested in two trials. The TIMI 9B trial randomized patients receiving thrombolytic therapy for acute myocardial infarction to receive hirudin or heparin. The GUSTO IIB trial randomized patients with or without electrocardiographic ST-segment elevation (i.e. thrombolytic- and non-thrombolytic-eligible patients). In the combined trials at 30 days there was a non-significant 14% reduction in myocardial infarction, but no effect on mortality. There are a number of factors in these two trials, including dose selection, timing of administration and duration of drug therapy, that may have led to an underestimate of the potential benefits of hirudin. Further trials are therefore required to test the thrombin hypothesis.