Reteplase

Abstract

Synopsis

Reteplase (BM 06.022; r-PA) is a recombinant peptide which consists of the kringle 2 and protease domains of human tissue-type plasminogen activator. It has been developed as a thrombolytic treatment for acute myocardial infarction (AMI). The half-life of reteplase allows administration as a double-bolus injection (second injection given 30 minutes after the first) rather than by the prolonged and, in some cases, more complex intravenous infusion regimens that are required for most other thrombolytic agents.

Reteplase produced rapid and effective coronary artery thrombolysis in a number of dose-finding and comparative studies. Double-bolus administration of reteplase 10U + JOU produced significantly higher coronary artery patency rates than accelerated alteplase (WOmg as a 1.5-hour infusion) in patients with AMI in the RAPID-II study. The 10U + 10U reteplase regimen produced a 35-day survival rate at least equivalent to that seen with a 1-hour infusion of streptokinase 1.5 million units in 5986 patients in the INJECT study, which was designed to demonstrate equivalence between treatments.

As with other thrombolytics, bleeding was the most common adverse event seen in reteplase recipients. No significant differences in the overall risk of haemorrhage were observed between reteplase and either accelerated alteplase or standard streptokinase treatment in clinical trials. The risk of stroke in reteplase recipients appears to be similar to that for other thrombolytic agents [1.2% incidence in 3288 patients treated with reteplase 10U + 10U in clinical trials (0.76% for haemorrhagic stroke)], although accurate statistical assessment of the relative risk is not possible for the data available to date.

Thus, reteplase is an effective thrombolytic agent which can be administered as a double-bolus injection regimen rather than as a prolonged infusion. Together with acquisition cost and general pharmacoeconomic data (which are not yet available), the results of GUSTO-III (a trial comparing double-bolus reteplase with accelerated alteplase in 15 000 patients) will have a major influence on the pattern of use of reteplase. In the meantime, data from the available clinical trials suggest that reteplase is a fast-acting and effective thrombolytic treatment for patients with AMI.

Pharmacodynamic Properties

Reteplase (BM 06.022; r-PA) is a 39.6kD, single-chain, nonglycosylated peptide which consists of amino acids 1 to 3 and 176 to 527 of native tissue-type plasminogen activator (t-PA). It contains the kringle 2 and protease domains of native t-PA, but lacks the kringle 1, finger and epidermal growth factor domains. Reteplase is produced by recombinant DNA technology in Escherichia coli and requires in vitro folding to become active.

Reteplase has lower in vitro affinity for fibrin than alteplase, probably because of the absence of the fibrin-binding finger domain which is part of native t-PA. It was less potent than alteplase for 50% clot lysis in vitro, but produced a similar maximum level of clot lysis in platelet-poor human plasma. Reteplase was a more potent thrombolytic than alteplase in canine models of coronary artery thrombosis. In addition, reteplase produced reperfusion significantly faster than alteplase, anistreplase, streptokinase or urokinase in canine models. In patients with acute myocardial infarction (AMI), reteplase reduced plasminogen levels to between 35 and 52% of baseline values, fibrinogen to between 36 and 61% of baseline and α2-antiplasmin to between 16 and 31% of baseline within 4 hours of treatment.

Pharmacokinetjc Properties

Maximum plasma concentrations of 2000 IU/ml (functional activity assay) and 4200 μg/L (detection of the reteplase antigen with a murine monoclonal antibody) were recorded after double-bolus intravenous administration of reteplase 10U + 10U (the recommended dose for clinical use) in patients with AMI. Data from healthy volunteers suggest that not all of the reteplase antigen in plasma is active. The initial half-life (t1/2α) of reteplase activity or antigen ranged from about 11 to 19 minutes in healthy volunteers or patients with AMI, compared with a typical t1/2α for alteplase of 5 minutes in other studies. Data from animal studies suggest that reteplase is cleared by both the liver and kidneys, but the latter route appears to be dominant. Inactivation of reteplase by components of blood or plasma also accounts for some of its elimination.

Clinical Efficacy

Reteplase produced rapid and effective coronary artery thrombolysis (as assessed by angiography) in dose-ranging and comparative studies in patients with AMI. In the RAPID-I study, double-bolus injection of reteplase 10U + 10U was significantly more effective than a 3-hour alteplase infusion, based on the rates of TIMI grade 3 (complete) patency at 60 and 90 minutes. There was no significant difference between the 2 treatments for the combined TIMI 2 and TIMI 3 (TIMI 2/3) flow rate at these times. Reteplase 10U + 10U produced more rapid thrombolysis than accelerated alteplase (100mg as a 1.5-hour infusion) in the RAPID-II study. Coronary artery patency rates were significantly greater with reteplase than with accelerated alteplase after 60 minutes [81.8 vs 66.1% (TIMI 2/3) and 51.2 vs 37.4% (TIMI 3)] and 90 minutes [83.4 vs 73.3% and 59.9 vs 45.2%]. The incidence of angiographically assessed reocclusion during hospitalisation was similar in reteplase (9.0%) and alteplase (7.0%) recipients.

Patients with AMI who received reteplase 10U + 10U had a 35-day survival rate at least equivalent to that seen with a 1-hour infusion of streptokinase 1.5 million units in the INJECT study (n = 5986). This multicentre trial was designed to show that the mortality rate for reteplase was not more than 1% greater than that for streptokinase; it was not sufficiently large to demonstrate superiority of one drug over the other. The 35-day mortality rate was 9.02% with reteplase and 9.53% with streptokinase, a difference of -0.51% (95% confidence interval -1.98 to 0.96%). Cardiogenic shock, heart failure, hypotension and atrial fibrillation occurred significantly less often in the reteplase group than in the streptokinase group.

Tolerability

Bleeding is the most common adverse event in reteplase recipients; about 21% of 3805 patients treated in clinical trials (3296 of whom had received reteplase 10U + 10U as a double bolus) experienced some type of bleeding. As with other thrombolytics, intracranial haemorrhage and haemorrhagic stroke are the most serious adverse events associated with reteplase. Stroke occurred in 1.2% of 3288 patients who received reteplase 10U + 10U in the RAPID-I, RAPID-II or INJECT studies (0.76% for haemorrhagic stroke). Bleeding events (of any sort) occurred in about 15 % of patients receiving either reteplase 10U + 10U or a 1 -hour infusion of streptokinase 1.5 million units in the INJECT trial. There were no significant differences between groups in the incidence of stroke (1.23 vs 1.00%) or haemorrhagic stroke (0.77 vs 0.37%). Similarly, no significant differences in any bleeding events were observed between reteplase 10U + 10U and alteplase given either as a 3-hour or a 1.5-hour infusion in RAPID-I or RAPID-II. However, it should be noted that the studies reported to date were not sufficiently large to allow accurate statistical analysis of differences in stroke rates. Data from 2400 patients treated with reteplase indicate that the drug is not antigenic.

Dosage and Administration

Reteplase treatment should be initiated as soon as possible after the onset of symptoms of AMI. The recommended dose is 2 separate 10U bolus injections, the second of which is given 30 minutes after the first. Reteplase recipients should also receive heparin and aspirin. Reteplase is currently recommended for coronary artery clot lysis, reduction of mortality and congestive heart failure and improvement in ventricular function in patients with AMI.