The TIMI 9b and GUSTO IIb Trials and the "Thrombin Hypothesis"

The "thrombin hypothesis" proposes that the clinical outcome of patients with unstable angina or acute myocardial infarction (MI) is related to the degree of thrombin inhibition, with greater inhibition resulting in improved outcome. Two recent trials (TIMI 9b and GUSTO IIb) tried to test this hypothesis by randomizing 15,000 patients with MI or unstable angina to a 3-to-5 day intravenous administration of either the powerful thrombin inhibitor hirudin, or standard heparin. In both studies, after 30 days, there was no significant difference in the rates of death or nonfatal infarction between the 2 treatment arms. More than one reason may explain these findings. In both trials the anticoagulant regimens were carefully tailored to prevent excessive bleeding complications and to achieve a predetermined level of efficacy, as measure by aPTT. It is possible that similar aPTTs and similar bleeding rates will result in similar clinical outcomes, regardless of the anticoagulant agent used. It is also possible that patients already receiving fibrinolytic drugs and aspirin did not derive such additional thrombolytic benefit from anticoagulants to compensate for the increased bleeding risk associated with their use. Finally, thrombin may not always play the crucial role that has been attibuted to it: marked thrombin generation may occur only in subgroups of patients, or as a secondary response to a primary trigger that fails to be antagonized by antithrombin therapy or that re-emerges after stopping treatment. The true role played by anticoagulants in the management of acute coronary syndromes is not clear from TIMI 9b or GUSTO IIb because neither study included a control group not receiving anticoagulants. These trials, however, raise important issues that deserve further investigation: for example, the definition of what drives thrombin generation in patients with acute coronary syndromes and the identification of possible subgroups of patients deriving true clinical benefit from anticoagulant therapy.