CIRCADIAN VARIATION IN THE EFFICACY OF TISSUE-TYPE PLASMINOGEN-ACTIVATOR

Background The frequency of onset of acute myocardial infarction follo ws a circadian pattern, with a peak incidence between 6:00 AM and noon . Circadian variations have been defined for platelet aggregation, pla sminogen-activator inhibitor, and a number of hemostatic and physiolog ical factors, all of which might predispose toward clotting in the lat e morning and thrombolysis in the evening. Thus, the hypothesis for th is retrospective analysis was that tissue-type plasminogen activator ( TPA) has greater efficacy when administered between noon and midnight, as measured by coronary patency 90 minutes after initiation of treatm ent. Methods and Results Seven hundred twenty-eight patients were enro lled in either of two studies in which TPA was administered under a un iform protocol for the treatment of acute myocardial infarction. Of th ese, 692 patients had qualifying arteriograms that allowed standardize d assessment by a core angiographic laboratory of the primary end poin t of 90-minute patency. TPA has a circadian pattern of efficacy, with greater TIMI grade 3 patency when administered between noon and midnig ht (P<.001). When TPA was given within 2 hours of symptoms (n=127), th e total patency was highest and there was a trend (P=.055) toward the greatest magnitude difference occurring between AM and PM patency. The onset of myocardial infarction was confirmed to have a marked circadi an variation with a peak incidence about 10:00 AM. The peak efficacy o f TPA was about 8:00 PM, representing a phase difference of about 10 h ours after peak infarction incidence. Conclusions There is a circadian variation in the ability of TPA to rapidly open coronary arteries, wi th highest efficacy between noon and midnight. This complements clinic al and in vitro knowledge of increased morning thrombosis and is conco rdant with knowledge of a fibrinolytic profile that is more favorable for evening lysis. This finding has implications for understanding the circadian pathophysiology of myocardial infarction and for its chrono therapy.