Anisoylated Plasminogen Streptokinase Activator Complex (APSAC)

Abstract

APSAC ¹ is a new thrombolytic agent with advantages over conventional therapy such as streptokinase. In particular, it is suitable for intravenous administration over 4 to 5 minutes, in contrast with the prolonged infusion required with intravenous streptokinase, thus facilitating treatment of acute myocardial infarction outside a coronary care unit. Additionally, its fibrinolytic action is theoretically selective for fibrin associated with thrombi, which should minimise systemic fibrinolysis. However, in practice, systemic fibrinolysis does occur to some extent in most patients, but clinically significant haemorrhagic complications are rare. At the recommended dose of 30U injected intravenously over a period of 4 to 5 minutes in patients with acute myocardial infarction of less than 6 hours’ duration, reperfusion of occluded coronary arteries occurs in about 72% of patients (range 53 to 91% in individual studies). Subsequent reocclusion has been reported in 0 to 20% of patients in most studies, with an average reocclusion rate of around 10%. The reperfusion rate compares favourably with that reported for intracoronary streptokinase and has tended to be superior to that with intravenous streptokinase. Thus, APSAC is an important advance in thrombolytic therapy for patients with acute myocardial infarction. Of particular importance is its relative ease of administration, reducing the dependence on coronary care units with catheterisation facilities, and the associated costs and delays in implementing treatment. APSAC should result in effective thrombolytic therapy being rapidly introduced after acute myocardial infarction in a wider proportion of patients than was previously feasible. p-Anisoylated human plasminogen-streptokinase-activator complex (APSAC) is a new type of thrombolytic agent developed for the treatment of acute myocardial infarction. It is an acylated complex of streptokinase with human lys-plasminogen. Acylation of the catalytic site of the plasminogen molecule delays the formation of the active fibrinolytic enzyme plasmin, but has no influence on the lysine-binding sites involved in binding the complex to fibrin. Deacylation commences immediately after injection and continues in a controlled manner with the result that a certain percentage of the complex is bound to fibrin at the time of deacylation; plasmin formed in this situation is protected from neutralisation by circulating antiplasmins and is available for degradation of fibrin in thrombi. On the other hand, free plasmin formed from circulating deacylated complex is rapidly neutralised, until the neutralising capacity of the antiplasmins is surpassed. Experimental studies in animal models of venous thrombosis, and studies using relatively low doses of APSAC (up to 12.5U) in volunteers, confirmed that the drug had few significant systemic effects under these conditions. However, studies using higher doses (> 15U) in patients with acute myocardial infarction found a high incidence of fibrinogen degradation, depletion of plasminogen and antiplasmin concentrations, and changes in other coagulation indices. The influence of APSAC on these indices was equivalent to that of intravenous streptokinase 1,500,000IU. In vitro studies showed APSAC to have a thrombolytic potency 10 times that of streptokinase, and indicated that its thrombolytic action is dependent on fibrin-binding. This thrombolytic activity has been confirmed in vivo in experimentally prepared thrombi in rabbits and dogs. Extensive lysis of fresh thrombi followed single doses of APSAC. The streptokinase-plasminogen complex of APSAC dissociates at a slower rate than the deacylation rate, ensuring that the fibrinolytic activity of the drug is controlled by the latter. The deacylation half-life is about 105 minutes in human plasma or whole blood in vitro, and the plasma clearance half-life of fibrinolytic activity has been reported at 90 to 112 minutes in patients with acute myocardial infarction. Preliminary clinical studies with APSAC in patients with acute myocardial infarction employed intracoronary administration of doses from 5 to 30U. Reperfusion of occluded coronary arteries was achieved in 70 to 85% of such patients receiving doses of 15 to 30U within 6 hours of the onset of symptoms, with a mean time to reperfusion of 40 to 70 minutes. Subsequent reocclusion within 48 hours following intracoronary administration of APSAC in early dose-response studies occurred in about 20% of patients in whom initial reperfusion was confirmed. The site of infarction did not seem to influence the rate of reperfusion or reocclusion. The extended half-life of APSAC allows it to be administered as a single intravenous injection over 4 to 5 minutes, which offers several advantages over intracoronary administration. At a dose of 30U infused intravenously over a period of up to 5 minutes (the manufacturer’s recommended injection time is over 4 to 5 minutes), usually within 3 to 6 hours of the onset of symptoms, the rate of reperfusion varied among studies from 53 to 100% depending on the trial population, timing of drug administration and method of assessment. Reperfusion usually occurred within 60 minutes of drug infusion. In patients with angiographically confirmed occlusion of the infarct-related coronary vessel, APSAC produced reperfusion in a similar percentage of patients as intracoronary streptokinase 140,000 to 250,000IU, while in studies with post-treatment angiographic assessment only, APSAC tended to produce a higher patency rate than intravenous streptokinase l,500,000IU. Subsequent early reocclusion in studies involving intravenous administration of APSAC 30U occurred in about 10% of initially reperfused patients. In non-invasive studies APSAC proved a more effective therapy for acute myocardial infarction than an intravenous 5000U bolus dose, and subsequent infusion, of heparin (1000 U/hour). Current evidence suggests that early reperfusion after an acute myocardial infarction limits the extent of the infarction and improves both short and long term survival. In controlled clinical trials mortality within the first 30 days after myocardial infarction in patients treated with APSAC has been lower than in those treated with placebo (2 to 5% vs 16 to 27%), and not noteably different from the mortality in patients receiving alternative treatments (intracoronary or intravenous streptokinase, or heparin). No controlled trials have been performed to date to assess long term prognosis after APSAC therapy in patients with acute myocardial infarction. However, preliminary follow-up data on patients included in all clinical trials with APSAC indicate a mortality rate (at any time after therapy) of about 6%. Bleeding complications are the major concern with thrombolytic agents as a result of their general interference with haemostatic mechanisms. Clinical studies have revealed that APSAC does induce systemic fibrinolysis. However, clinically significant haemorrhagic complications have been rare. There have been a few cases of gastrointestinal and intracerebral haemorrhage in patients receiving doses of 30U, but otherwise bleeding has been limited primarily to puncture sites. Rapid intravenous administration of streptokinase results in a marked hypotensive response which demands that the drug be infused over an extended period. APSAC has been reported to induce a transient reduction in blood pressure in some patients, but generally acute administration over 4 to 5 minutes is not associated with adverse haemodynamic changes. Other side effects which have been reported with APSAC include flushing, dyspnoea, mild fibrile reactions, nausea/vomiting and occasionally skin rash, all of which may be symptoms of mild allergic reactions. The main advantages of APSAC over alternative thrombolytic drugs is its ease of administration by the intravenous route in patients with acute myocardial infarction. The recommended dose is 30U intravenously over 4 to 5 minutes enabling therapy to be implemented with a minimum of delay to a large proportion of patients with acute myocardial infarction. As with other thrombolytic agents, additional anticoagulation is desirable to reduce the rate of rethrombosis, but the optimum time for institution of such therapy has yet to be identified (in clinical trials it has ranged from 2 to 24 hours after infarction).