The effect of three different doses of a thrombin inhibitor, inogatran, with UFH for unstable coronary disease was evaluated by the Thrombin Inhibition in Myocardial Ischemia (TRIM) study group (77). In the study, 1209 patients admitted to the hospital with suspected UA or NQWMI were randomly assigned double-blind treatment with inogatran, a selective low-molecular-weight thrombin inhibitor, or UFH given as a bolus. Initial treatment was followed by a 3-d infusion with either a low, medium, or high dose of inogatran, or UFH. The primary composite end point was death, incidence of MI, refractory angina, or recurrent angina after 7 d. Secondary end points were as above after 3 and 30 d. Median activated aPTTs after 24 h were 36, 44, and 53 s for low, medium-, and high-dose inogatran groups, respectively, compared with an aPTT of 54 s in the UFH group. At the end of the 3-d infusion period, patients receiving UFH had significantly fewer composite events than did inogatran-treated patients (p = 0.01). However, after 7 d, the event rate with respect to the primary outcome did not differ between the treatment groups. Death and MI occurred significantly less frequently in the UFH treatment group than in the three inogatran groups after 3 d (p < 0.05). After 7 d, although event rates continued to be lower in the UFH group, differences between groups were not statistically significant. Again, after 30 d, there were no significant differences in event rates between the four treatment groups. Within 7 d of treatment, major bleeding occurred in 1.1% of patients, with no differences between treatment groups. Therefore, during the study-drug infusion, none of the inogatran doses were better than UFH in preventing ischemic events. Nor was there a relationship between event rate and inogatran dosage. Consequently, despite a clear dose effect with respect to the prolongation of aPTT, this study did not indicate that inogatran's efficacy would improve at higher doses. Lastly, after withdrawal of UFH and inogatran treatment, event rates increased, suggesting a rebound effect.
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