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Patency trials with reteplase (r-PA): what do they tell us?
1Medizinische Klinik III (Kardiologie, Angiologie und Pulmonologie, Heidelberg, Germany.
Insights
Reteplase, administered as a 10 + 10 U double bolus, significantly improves early reperfusion in acute myocardial infarction patients compared to alteplase. This enhanced thrombolytic therapy shows improved artery patency without increasing complication risks.
Area of Science:
- Cardiology
- Pharmacology
- Thrombolytic Therapy
Background:
- Thrombolytic therapy reduces mortality and morbidity in acute myocardial infarction (AMI).
- Therapeutic benefit correlates with reperfusion completeness (TIMI grade 3 flow) and timeliness.
- Reteplase (r-PA) is a tissue plasminogen activator (t-PA) deletion mutant.
Purpose of the Study:
- To compare the efficacy of different reteplase (r-PA) regimens against standard recombinant tissue plasminogen activator (alteplase) regimens.
- To determine the optimal r-PA regimen for clinical thrombolysis in AMI.
Main Methods:
- Two large-scale, randomized studies (RAPID-1 and RAPID-2) were conducted.
- Patients received aspirin and intravenous heparin.
- Reteplase regimens were compared with conventional and accelerated alteplase regimens.
Main Results:
- A 10 + 10 U double bolus of reteplase was more effective than other r-PA doses and conventional alteplase (RAPID-1).
- Significantly higher rates of infarct-related artery patency (TIMI grade 2 or 3 flow) at 90 minutes were observed with reteplase (83.4%) versus alteplase (73.3%) (p=0.03) in RAPID-2.
- Complete patency (TIMI grade 3 flow) at 90 minutes was also greater with reteplase (59.9%) than alteplase (45.2%) (p=0.01).
- Early reperfusion (TIMI grade 2 or 3 flow at 60 minutes) was significantly higher with reteplase (81.8%) vs alteplase (66.1%) (p=0.01).
- 35-day mortality rates were similar (4.1% for reteplase vs 8.4% for alteplase, p=NS).
- Severe bleeding and hemorrhagic stroke rates did not differ significantly between reteplase and alteplase.
Conclusions:
- Reteplase, as a 10 + 10 U double bolus, achieves significantly higher rates of early reperfusion.
- Reteplase is associated with fewer acute coronary interventions compared to front-loaded alteplase.
- The benefits of reteplase are achieved without an increased risk of complications.
Abstract:
Thrombolytic therapy has been shown to reduce mortality and morbidity after acute myocardial infarction. Therapeutic benefit seems to be directly correlated with completeness of reperfusion (Thrombolysis in Myocardial Infarction [TIMI] grade 3 flow) of the infarct-related coronary artery, as well as the timeliness of reperfusion. To determine which regimen of reteplase (r-PA), a deletion mutant of wild-type tissue plasminogen activator (t-PA), is most effective for clinical thrombolysis, several reteplase regimens were compared with the most successful standard regimens of recombinant t-PA (alteplase) in 2 large-scale, randomized studies. All patients received aspirin and intravenous heparin. In the Reteplase Angiographic Phase II International Dose Finding Trial (RAPID-1), results in 606 randomized patients showed that a 10 + 10 U double bolus of reteplase was more effective than a 15 U single bolus, a 10 + 5 double bolus, or conventional alteplase (100 mg over 3 hours). In the Reteplase versus Alteplase Patency Investigation During Acute Myocardial Infarction (RAPID-2) trial, results in 324 patients showed that significantly more patients achieved patency of the infarct-related artery (TIMI grade 2 or 3 flow) at 90 minutes with reteplase (10 + 10 U double bolus) than with accelerated alteplase (100 mg over 90 minutes): 83.4% versus 73.3%, respectively (p = 0.03). The incidence of complete patency (TIMI grade 3 flow) at 90 minutes was likewise greater with reteplase than with accelerated alteplase (59.9% vs 45.2%, respectively; p = 0.01). At 60 minutes, the incidence of TIMI grade 2 or 3 flow was also significantly higher with reteplase than with alteplase (81.8% vs 66.1%, respectively; p = 0.01), as was the incidence of TIMI grade 3 flow (51.2% vs 37.4%, respectively; p < 0.031). The 35-day mortality rate was 4.1% for reteplase and 8.4% for alteplase (p = not significant). Reteplase and alteplase did not differ significantly with regard to the occurrence of severe bleeding (12.4% vs 9.7%, respectively) or hemorrhagic stroke (1.2% vs 1.9%, respectively). The results of these trials show that reteplase, given as a 10 + 10 U double bolus, achieves significantly higher rates of early reperfusion of the infarct-related coronary artery and is associated with significantly fewer acute coronary interventions when compared with front-loaded alteplase. The benefits of reteplase are achieved without any apparent increased risk of complications.