How soon can warfarin be started after thrombolytic treatment of embolic stroke with alteplase (Act

Fråga: How soon can warfarin be started after thrombolytic treatment of embolic stroke with alteplase (Actilyse)?

Sammanfattning: Alteplase has a short pharmacokinetic half-life and also a relatively short duration of effect. It has a different mechanism of action than warfarin, which also has a slow onset of effect. Therefore it should be possible to start warfarin when it is reasonably certain that no hemorrhagic complication of thrombolysis has occured.

Svar: Alteplase is recombinant human tissue plasminogen activator (rtPA). It has a half-life of 3-11 minutes in alpha-phase. The concentration is less than 10% of Cmax after after 20 minutes. The terminal half-life is 30-40 minutes. Its mechanism of action is to cleave plasminogen to plasmin, which degrades fibrin. By binding to fibrin, which also binds plasminogen, the affinity between rtPA and plasminogen can be enhanced. Twenty-four hours after alteplase plasminogen, plasmin, fibrin and fibrinogen have returned to 80% of normal (1,2).

Warfarin acts as a vitamin-K antagonist and primarily inhibits the formation of coagulation factor II, VII, IX and X. The half-lives of these factors are 4-50 hours (shortest for factor VII and longest for factor II). Thus anticoagulative effect is reached after 3-5 days of therapy (1,3).

There are no controlled studies on the interaction between thrombolytics and anticoagulants. In patients on warfarin, there is an increased risk of bleeding complications after thrombolysis for myocardial infarction (3). However, there are case-reports of intraarterial thrombolysis after cerebral infarction in patients on warfarin with an INR of 1,7-2,0 (4).

Most studies where thrombolysis has been followed by oral anticoagulants seem to have started the anticoagulant within 0-48 hours after thrombolysis (5,6,7,8). Most of these studies are after myocardial infarction (6,7,8), but one is after deep venous thrombosis (5). We have not found any study where thrombolysis has been followed by oral anticoagulants in cerebrovascular disease. Fass 2005 Dollery C Sir, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone; 1999 Harder S, Klinkhardt U. Thrombolytics: Drug Interactions of clinical significance. Drug Saf 2000;23(5):391-399 Linfante I, Reddy AS, Andreone V, Caplan LR, Selim M, Hirsch JA. Intra-arterial thrombolysis in patients treated with warfarin. Cerebrovasc Dis 2005;19:133-135. Goldhaber SZ, Meyerovitz MF, Green D, Vogelzang RL, Citrin P, Heit J, et al. Randomized controlled trial of tissue plasminogen activator in proximal deep venous thrombosis. Am J Med 1990;88:235-40. Grip L, Rydén L. Late streptokinase infusion and antithrombotic treatment in myocardial infarction reduce subsequent myocardial ischemia. Am Heart J 1991;121:737-45. Julian DG, Chamberlain DA, Pocock SJ. A comparison of aspirin and anticoagulation following thrombolysis for myocardial infarction (the AFTER study): a multicentre unblinded randomised clinical trial. Br Med J 1996;313:1429-31. Williams MJ, Stewart RA. Coronary artery flow ten weeks after myocardial infarction or unstable angina: effects of combined warfarin and aspirin therapy. Int J Cardiol 1999;69:19-25.