RECOMBINANT HIRUDIN (HEW 023) PRODUCES STABLE ANTICOAGULATION UNAFFECTED BY CIRCADIAN VARIATION IN PATIENTS WITH THROMBOLYSIS FOR ACUTE MYOCARDIAL-INFARCTION

Background Circadian variations have been described for a number of ha emostatic and physiological factors, all of which might predispose tow ards clotting in the late morning. The anticoagulation effect of hepar in has been shown to respond in a circadian manner, resulting in minim al prolongation of the activated partial thromboplastin time (aPTT) in the morning. Methods Recombinant hirudin (HEW 023) given as a bolus o f 0.07, 0.1, 0.2 or 0.4 mg . kg(-1) followed by an infusion of 0.05, 0 .06, 0.1 or 0.15 mg . kg(-1) over 48 h was used as conjunctive therapy to thrombolysis with frontloaded recombinant tissue-type plasminogen activator (100 mg . 90 min(-1)) in 40 patients with acute myocardial i nfarction. APTT, activated clotting time and free hirudin plasma level s were determined at baseline and at 8, 12, 16, 20, 24, 32, 40 and 48 h. Results The prolongation of aPTT and activated clotting time was do se-dependent and stable. In 82.5% of the patients, aPTT values were ra nged between the highest and the lowest aPTT of <30 s. When the result s were divided into four time intervals (0000-0600, 0600-1200, 1200-18 00, 1800-2400) neither in the individual patients nor in the mean valu es of the four different dose groups was any significant circadian var iation in aPTT or activated clotting time prolongation observed. The p harmacokinetic studies of free hirudin plasma levels revealed no circa dian rhythm either. All but one patient (97.5%) had a patent vessel (T IMI grade 2/3) at the end of the hirudin infusion. Conclusions Recombi nant hirudin, in contrast to heparin, does not show any circadian vari ation in its anticoagulation effect. This might, in part, explain the more stable and predictable anticoagulation achieved by hirudin, which is associated with a reduced rate of reocclusions after thrombolysis.