Thrombin inhibition with inogatran for unstable angina pectoris: evidence for reactivated ischaemia after cessation of short-term treatment.
BACKGROUND: The acute coronary syndromes of unstable angina and non-Q-wave infarction are initiated by coronary plaque rupture and subsequent thrombus formation. Thrombin is central to this response as it activates platelets and the coagulation system. In an open design study we assessed the tolerability and safety of the low molecular weight thrombin inhibitor, inogatran, for unstable angina or non-Q-wave infarction. METHODS: Thirty-seven patients, treated within 72 h of symptoms, were allocated consecutively to groups to receive a 4 h infusion with one of three doses of inogatran. Thrombin generation and activity were measured with plasma markers at baseline, after the 4 h treatment period and 4 h later. Ischaemia was monitored using continuous vectorcardiography during the 4 h of treatment and during the subsequent 4 h after inogatran infusion had been stopped, to detect any increase in ischaemic events after the period of treatment. In addition, 12 patients received inogatran as an infusion for 72 h. RESULTS: Inogatran was tolerated well. There were no adverse haemodynamic effects or allergic reactions. Minor bleeding events were detected in 37% of the patients. The biochemical and vectorcardiographic findings indicated suppression of thrombin generation after the 4 h treatment period compared with baseline. During the first 4 h after inogatran treatment, thrombin activity and episodes of ischaemia were increased compared with during the treatment period. CONCLUSION: Inogatran was tolerated well and was safe, but its discontinuation was followed by a reactivation of thrombin activity and ischaemia. Whether this reactivation represented a rebound phenomenon, or merely resulted from the discontinuation of an effective therapy, cannot be established from the present study.