Regarding "The safety, efficacy, and pharmacoeconomics of low-dose alteplase compared with urokinase for catheter-directed thrombolysis of arterial and venous occlusions"

We read with interest the article by Sugimoto et al (J Vasc Surg 2003;37:512-7) reporting that continuous overnight infusion of low-dose tissue plasminogen activator (t-PA) combined with subtherapeutic dosage of heparin is equally efficacious and safe compared with urokinase for treatment of arterial occlusive disease and deep vein thrombosis. We would like to point out that both of these diseases and the effect of anticoagulant therapy demonstrate significant temporal variation, which should not be overlooked in planning studies and interpreting their results. Like many other acute cardiovascular events, acute arterial occlusion of the limbs and pulmonary embolism exhibit a circadian pattern of occurrence, with higher incidence in the morning. This morning excess appears to be related to increased platelet aggregability and reduced endogenous fibrinolysis during this time. Opposite circadian patterns, characterized by lower levels of tissue-type plasminogen- activator and higher values of t-PA and higher values of t-PA inhibitor-1, with variations up to 250%, have been reported. On the other hand, circadian changes in anticoagulant effect of heparin, even when infused intravenously at a constant rate, have been reported. Activated partial thromboplastin time (aPTT), thrombin time (TT), and coagulation factor Xa inhibition assay achieve maximal values at night, with differences between night and morning values of almost 50% for aPTT, 60% for TT, and 40% for factor Xa inhibition assay. As a consequence, a constant dose could have poor effects in the morning and enhance the risk for bleeding at night. A morning increase in resistance to thrombolysis performed to treat acute myocardial infarction has also been reported with both intracoronary urokinase and intravenous t-PA. In light of these data, it appears that, in comparing the efficacy and safety of various thrombolytic therapies, an imbalance in onset time of the event or time of administration of anticoagulant or fibrinolytic agent could justify possible differences in clinical outcome. Tailoring thrombolytic therapy and adjusting dosages according to the high-risk time of onset of acute events could lead to better results in providing patency, reduced dosages during low-risk times, and less adverse hemorrhagic effects, and save drugs and money, as well.