Pharmacologic Reperfusion for AMI: Combining GPIIb/IIIa Inhibitors with Reduced Dose Fibrinolytics
Abstract & Commentary
Source: Lincoff MA, et al, for the GUSTO V Investigators. Mortality at 1 year with combination platelet glycoprotein IIb/IIIa inhibition and reduced-dose fibrinolytic therapy vs conventional fibrinolytic therapy for AMI. GUSTO V randomized trial. JAMA 2002;288:2130-2135.
Current pharmacologic reperfusion for acute myocardial infarction (AMI) primarily involves the administration of fibrinolytic therapy. While these agents clearly have shown benefit in terms of rapid reperfusion and survival, they also are associated with higher rates of vessel reocclusion, reinfarction, and need for revascularization when compared with mechanical reperfusion strategies. Recently, investigators have focused on combining fibrinolytic agents with platelet inhibitors, such as the glycoprotein IIb/IIIa inhibitor agents (GPI), to reduce these complications and improve clinical outcome.
This study reports the one-year mortality findings of the large GUSTO V trial, which compared a platelet GPI (abciximab) combined with half-dose fibrinolytic therapy (reteplase) against full-dose fibrinolytic therapy alone for the treatment of AMI. In GUSTO V, 16,588 patients with AMI within six hours of presentation and ST elevation or new left bundle-branch block on ECG were randomized to receive either standard reteplase (two 10-U boluses) or half-dose reteplase (two 5-U boluses) with abciximab (0.25 mg/kg bolus, followed by 0.125 mg/kg/min infusion for 12 hours). Previously reported results found no difference in 30-day mortality (5.9% vs 5.6%, p = 0.43), but lower rates of nonfatal reinfarction (2.3% vs 3.5%, p < 0.001), need for urgent revascularization (5.6% vs 8.6%, p < 0.001), and nonfatal cardiac complications in the abciximab combination group compared to standard reteplase, respectively.1
In this study, investigators followed up on 8257 of 8328 (99.1%) patients in the abciximab combination group, and 8196 of 8260 (99.2%) of the reteplase alone group at one year after treatment. All-cause mortality at one year was equivalent between the two groups (8.38% vs 8.38%, p > 0.99). Mortality rates were higher among patients who experienced reinfarction (22.6 % vs 8.0%, p < 0.001), but this difference did not affect overall mortality between the two treatment groups. Moreover, the assigned treatment group did not significantly influence time of mortality.
The investigators conclude that the combination of GPI with reduced-dose reteplase is neither superior nor inferior to standard reteplase monotherapy with regards to overall long-term mortality.
Commentary by Theodore C. Chan, MD, FACEP
The industry-sponsored GUSTO-V trial is the largest randomized study comparing low-dose fibrinolytic therapy combined with a platelet GPI against standard fibrinolytic treatment alone for AMI. Earlier reported results showed that despite no difference in mortality, there was benefit with the combined approach seen in lower nonfatal reinfarction rates and other nonfatal cardiac complications. This study now reports no long-term mortality difference at one year despite these benefits.
In theory, combining a fibrinolytic agent, which disrupts thrombus, and a GPI, which prevents platelet adhesion and aggregation, would provide an optimal synergistic approach to pharmacologic reperfusion. Studies have found that this combination improves vessel patency earlier for AMI patients, but has yet to demonstrate any impact on mortality, as evidenced by these results.
Interestingly, GUSTO V demonstrated that patients who experience reinfarction within the first 30 days are more likely to die within one year (14.6% absolute difference). The combination therapy group had a lower rate of reinfarction (1.2% absolute difference) reported in the initial GUSTO V.1 These findings together would suggest a 0.18% mortality benefit for the combination therapy, a difference too small to be statistically significant in this study.
While the results of GUSTO V were disappointing, a number of other industry-sponsored studies are underway to investigate the utility of combining fibrinolysis with GPIs. The recently published ASSENT-3 trial reported that tenecteplase with either the low molecular weight heparin, enoxaparin, or abciximab reduced rates of reinfarction and refractory ischemia—but not necessarily 30-day mortality—in AMI patients.2 Other combination studies, such as INTEGRITI, FASTER, and ENTIRE, are utilizing different fibrinolytics and GPIs (such as eptifibatide and tirofiban), as well as different dosing strategies with heparin to see if such synergy can demonstrate clinical benefit in the future.
Dr. Chan, Associate Clinical Professor of Medicine, Emergency Medicine, University of California, San Diego, is on the Editorial Board of Emergency Medicine Alert.
References
1. Topol EJ, et al, for the GUSTO V Investigators. Reperfusion therapy for AMI with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: The GUSTO V randomized trial. Lancet 2001;357:1905-1914.
2. ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: The ASSENT-3 randomised trial in AMI. Lancet 2001;358:605-613.
Current pharmacologic reperfusion for acute myocardial infarction primarily involves the administration of fibrinolytic therapy. Recently, investigators have focused on combining fibrinolytic agents with platelet inhibitors, such as the glycoprotein IIb/IIIa inhibitor agents, to reduce complications and improve clinical outcome.
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