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Reteplase

A Review of its Use in the Management of Thrombotic Occlusive Disorders

  • Adis Drug Evaluation
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Summary

Abstract

Reteplase (Retavase®) is a plasminogen activator, mimicking endogenous tissue plasminogen activator (t-PA), a serine protease, converting plasminogen to plasmin and thereby precipitating thrombolysis. It is a third-generation recombinant form of t-PA that operates in the presence of fibrin (i.e. it is fibrin specific).

Reteplase can be administered as a bolus dose (nonweight-based) rather than an infusion, which promotes rapid and safe administration. The ease of administration of this reteplase dosage regimen (two 10U bolus doses, each over 2 minutes, 30 minutes apart) is conducive to prehospital initiation of thrombolytic treatment in patients with ST-segment elevation myocardial infarction (STEMI), which reduces the time to treatment, a critical factor in improving long-term survival.

In large randomized clinical trials of patients with STEMI, reteplase was superior to alteplase for coronary artery patency (according to TIMI [thrombolysis in myocardial infarction] flow) at 60 and 90 minutes, but there was no significant difference between agents for mortality rate and incidence of intracranial bleeding. The 35-day mortality rates were equivalent for reteplase and streptokinase recipients; there was reduced incidence of some cardiac events with reteplase versus streptokinase, but a greater incidence of hemorrhagic stroke.

Reteplase has also shown thrombolytic efficacy (in nonapproved indications) as a catheter-directed intra-arterial or intravenous infusion for peripheral vessel occlusions, as 5-minute bolus doses (in 1U increments) for acute ischemic stroke, as a low-dose solution for occluded catheters or grafts, and as an intravenous double bolus for massive pulmonary embolism. Across studies in these indications, the incidence of bleeding complications associated with reteplase treatment appeared to be similar to that associated with other thrombolytic agents.

With its efficacy, and the ease of administration of the bolus doses potentially minimizing dosage errors when treatment is administered under time pressure, reteplase is a valuable option for pre- or in-hospital thrombolytic treatment in patients with STEMI, and is a useful thrombolytic for the treatment of the other thrombotic occlusive disorders described.

Pharmacoloaic Properties

Reteplase, a single-chain, nonglycosylated peptide, is a fibrin-specific recombinant plasminogen activator that contains the kringle 2 and protease domains of native t-PA, but lacks the kringle 1, fibronectin finger, and epidermal growth factor domains. It exerts its thrombolytic action by catalyzing the conversion of the inactive proenzyme plasminogen to the active protease plasmin, which degrades the fibrin matrix of the thrombus. Reteplase has a fibrin-specific activity and, in animal models of thrombosis, is a more potent thrombolytic than alteplase, and produces reperfusion significantly faster than alteplase, streptokinase, or urokinase. In patients with acute myocardial infarction (AMI), reteplase decreased levels of fibrinogen, plasminogen, and α2-antiplasmin. In these patients, a double-bolus (10U + 10U; 30 minutes apart) dose of reteplase produced relatively greater alterations in hemostatic variables than a single bolus (10U) dose. A paradoxical activation of the coagulation system seen after reteplase treatment is blunted in a beneficial fashion when reduced-dose reteplase is combined with abciximab in AMI patients.

Pharmacokinetic studies in healthy volunteers have suggested that not all of the reteplase antigen in plasma was active. In healthy volunteers, the apparent volume of distribution of reteplase activity during the terminal elimination phase was ≈ 6L, which, like that of alteplase, approximates plasma volume. Reteplase has a longer activity half-life (12.6 minutes) than that of alteplase (<5 minutes), and is cleared via the kidneys and liver.

Therapeutic Efficacy

Patients with acute STEMI receiving reteplase, administered as two intravenous 10U bolus doses 30 minutes apart, achieved superior patency rates at 60 and 90 minutes after treatment initiation compared with alteplase recipients (in terms of TIMI [thrombolysis in myocardial infarction] grade 2 or 3, or grade 3 flow) in the RAPID II study, and similar patency rates (TIMI grade 2 or 3 flow) to those of alteplase recipients in the RAPID I trial. However, the 30-day mortality rates for these two agents were not significantly different in the GUSTO III study (7.47% vs 7.24%). The 35-day mortality rates for reteplase and streptokinase recipients in the INJECT study were considered equivalent (9.02% vs 9.53%), based on the rate with reteplase being ≤1% lower than that for streptokinase and the upper limit of the confidence interval ≤1%.

The shorter the time to reperfusion for patients with STEMI the greater the survival rate; reteplase treatment reduced the median door-to-needle time by 32 minutes in the ER-TIMI 19 study, which also led to earlier ST-segment resolution.

Including the antiplatelet agent abciximab in the reteplase regimen and halving the reteplase dose (in the GUSTO V trial of patients with STEMI) maintained efficacy relative to full-dose reteplase monotherapy but provided little benefit. There was no between-group difference in the 30-day mortality rate (5.6% vs 5.9%), thereby demonstrating the noninferiority of combination therapy versus full-dose monotherapy. There was also no difference between treatment groups for 1-year mortality. However, patients receiving combination treatment had a significantly lower combined incidence of death or nonfatal reinfarction (7.4% vs 8.8%; p = 0.0011), and a lower incidence of urgent (i.e. within 6 hours) percutaneous coronary intervention (PCI) than the monotherapy group (5.6% vs 8.6%; p < 0.0001), and they also experienced significantly fewer complications of MI up to day 7.

The combination of reteplase (half-dose) and abciximab facilitated PCI in patients with STEMI; at 30 days, there was clinical success (freedom from death, reinfarction, urgent revascularization, major bleeding, or transfusion) in 85.4% of patients who underwent early (at time of first angiography) PCI and in 70.4% of those who did not undergo early PCI.

In patients with peripheral arterial thrombotic occlusions, intra-arterial administration of catheter-directed reteplase 0.25 U/h infused for a mean ≈29 hours was associated with thrombolytic success in 84% of procedures. The benefit of adding abciximab (0.25 mg/kg bolus, then 0.125 μg/kg/min [maximum 10 μg/min] as a 12-hour infusion) to a reteplase regimen (0.1–1.0 U/h) for peripheral vessel occlusions was demonstrated in the RELAX trial by rates of complete thrombolysis of 50–80% versus 16–50% with reteplase alone, and shorter median infusion times (17–28 hours vs 22.5–42 hours). The combination of reteplase with abciximab had similar recanalization rates to those of urokinase with abciximab (each combination administered as an intra-arterial, catheter-directed pulsed spray), but the mean infusion time was longer with the reteplase combination (APART trial).

Intra-arterial reteplase administered up to 9 hours after symptom onset has demonstrated efficacy in acute ischemic stroke in small noncomparative studies, and there are preliminary investigations of the combination of reteplase and abciximab in this indication. Results of preliminary noncomparative studies also suggest efficacy, with few complications, for low-dose reteplase for the restoration of blood flow in occluded central venous catheters or hemodialysis catheters and grafts, and limited data suggest similar efficacy for reteplase (intravenous double-bolus dose) and alteplase (infusion over 2 hours) in patients with massive pulmonary embolism.

Tolerability

As With other systemic thrombolytic therapies, bleeding (intracranial bleeding, hemorrhagic stroke, other internal bleeding, and superficial bleeding from puncture/catheter or surgical sites) constitutes a serious safety issue, and is the most common adverse effect of reteplase administration. The proportions of patients with STEMI experiencing at least one bleed were similar for reteplase (10U + 10U) and comparators (15.8% vs 16.6% streptokinase recipients [INJECT study], 30.5% vs 30.8% of alteplase recipients [GUSTO III study], and 47.4% vs 47.9% of alteplase recipients [pooled results of the angiographic RAPID trials]). Overall, the puncture/ injection site was generally the most common bleeding site associated with full-dose reteplase therapy, but these bleeds were mild.

Reteplase and alteplase recipients experienced similar incidences of intracranial hemorrhage or severe or life-threatening bleeding in the large GUSTO III trial, despite a numerically and relatively lower incidence of intracranial hemorrhage with reteplase than with alteplase in the earlier smaller (RAPID) trials of vessel patency. The incidence, severity and sites of other bleeding events were similar for reteplase and alteplase in these trials.

Compared with streptokinase, reteplase was associated with a higher incidence of hemorrhagic stroke, but the incidence, severity, and site of other bleeding events was similar for both agents (INJECT study in patients with STEMI).

Also in patients with STEMI, half-dose reteplase with abciximab was associated with a similar incidence of intracranial bleeding to that of full-dose reteplase monotherapy, but a greater incidence of nonintracranial bleeding.

In patients with peripheral arterial occlusions, the incidence of major bleeding complications with reteplase monotherapy administered for thrombolysis increased with dose. The addition of abciximab to the reteplase regimen in the RELAX trial was associated with a numerically greater incidence of major bleeding and need for blood transfusion compared with reteplase alone. Major complications (including bleeding) at 30 days occurred in numerically fewer recipients of a reteplase and abciximab combination than in recipients of urokinase plus abciximab, although there were more minor complications associated with the reteplase combination.

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Notes

  1. The use of trade names is for identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Adis International Inc., 770 Township Line Road, Suite 300, Yardley, PA, 19067, USA

    Dene Simpson, M. Asif A. Siddiqui & Lesley J. Scott

  2. School of Pharmacy, Creighton University, Omaha, Nebraska, USA

    Daniel E. Hilleman

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  1. Dene Simpson
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  2. M. Asif A. Siddiqui
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  3. Lesley J. Scott
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Correspondence to Dene Simpson.

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Various sections of the manuscript reviewed by: E. R. Bates, University of Michigan Medical Center, Ann Arbor, Michigan, USA; D. L. Bhatt, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA; E. Boersma, University Hospital Rotterdam, Rotterdam, The Netherlands; J. French, Department of Medicine, South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia; M. Ohman, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA; S. R. Steinhubl, Division of Cardiology, University of Kentucky, Lexington, Kentucky, USA.

Data Selection p ]Sources: Medical literature published in any language since 1980 on ‘reteplase’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE, and AdisBase search terms were ‘reteplase’. Searches were last updated 1 August 2006.

Selection: Studies in patients with thromboembolic disorders or central venous/hemodialysis catheter occlusion who received reteplase. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Reteplase, plasminogen activators, acute myocardial infarction, peripheral arterial occlusion, acute ischemic stroke, central catheter occlusion, central hemodialysis catheter occlusion, pulmonary embolism, pharmacodynamics, pharmacokinetics, tolerability.

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Simpson, D., Siddiqui, M.A.A., Scott, L.J. et al. Reteplase. Am J Cardiovasc Drugs 6, 265–285 (2006). https://doi.org/10.2165/00129784-200606040-00007

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