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

Background The frequency of onset of acute myocardial infarction follows a circadian pattern, with a peak incidence between 6:00 AM and noon. Circadian variations have been defined for platelet aggregation, plasminogen-activator inhibitor, and a number of hemostatic and physiological factors, all of which might predispose toward clotting in the late morning and thrombolysis in the evening. Thus, the hypothesis for this 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 treatment. Methods and Results Seven hundred twenty-eight patients were enrolled in either of two studies in which TPA was administered under a uniform protocol for the treatment of acute myocardial infarction. Of these, 692 patients had qualifying arteriograms that allowed standardized assessment by a core angiographic laboratory of the primary end point of 90-minute patency. TPA has a circadian pattern of efficacy, with greater TIMI grade 3 patency when administered between noon and midnight (P<.001). When TPA was given within 2 hours of symptoms (n=127), the 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 circadian variation with a peak incidence about 10:00 AM. The peak efficacy of TPA was about 8:00 PM, representing a phase difference of about 10 hours after peak infarction incidence. Conclusions There is a circadian variation in the ability of TPA to rapidly open coronary arteries, with highest efficacy between noon and midnight. This complements clinical and in vitro knowledge of increased morning thrombosis and is concordant 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 chronotherapy.