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Assessment of the Safety and Efficacy of a New Treatment Strategy for Acute Myocardial Infarction - ASSENT-4 PCI
Description:
The goal of the trial was to evaluate the safety and efficacy of full-dose thrombolysis immediately prior to primary percutaneous coronary intervention (PCI) compared with primary PCI alone among patients with ST elevation myocardial infarction (STEMI).
Study Design
Study Design:
Patients Enrolled: 1,667
Mean Follow Up: Six months (90 days reported to date)
Patient Populations:
Time from symptom onset within six hours, intent to perform primary PCI, and large infarct as documented by ST elevation of ≥6 mm
Primary Endpoints:
Composite of death, shock, or congestive heart failure (CHF) at 90 days
Secondary Endpoints:
Composite of death, shock, or CHF at 30 days; shock or CHF at 90 days; and single components of the composite endpoint
Drug/Procedures Used:
Patients with STEMI were randomized to full-dose tenecteplase (TNK) followed by primary PCI (n=829) or primary PCI alone (n=838). Glycoprotein (GP) IIb/IIIa inhibitors were allowed in the primary PCI arm at the discretion of the physician; however, GP IIb/IIIa inhibitors were only allowed for bail out use in the TNK+PCI group. Patients were to receive an intravenous (IV) bolus of unfractioned heparin (UFH) in both arms. UFH infusion during the PCI was not mandated in the TNK+PCI arm. Randomization could occur in the ambulance, at community hospitals, or at hospitals with on-site primary PCI.
Principal Findings:
The trial was to enroll 4,000 patients, but was discontinued early after enrollment of 1,667 patients. The median time from symptom onset to randomization was 140 minutes in the TNK+PCI group and 135 minutes in the PCI alone group; 20% of patients were randomized in the ambulance. PCI was performed in 91.1% of the primary PCI group and 87.1% of the TNK+PCI group (p=0.01), at a median of 104 minutes following TNK bolus administration. GP IIb/IIIa inhibitors were used more frequently in the PCI alone group both prior to the PCI (3.0% vs. 0.2%, p<0.001) and during the PCI (50% vs. 10%, p<0.001). Clopidogrel/ticlopidine was used in 63% of patients, while additional UFH was given in 70% of the primary PCI arm and 67% of the TNK+PCI arm.
TIMI grade 3 flow prior to PCI was present more frequently in the TNK+PCI arm (43% vs. 15%, p<0.001). Post-PCI patency (TIMI 2 or 3 flow) was slightly higher in the PCI alone group (98% vs. 95%).
At 90 days, the primary composite endpoint of death, CHF, or shock was higher in the TNK+PCI group (19% vs 13%, p=0.0055). There were no significant differences in the individual components of the composite, including death (7% vs 5%, p=0.141), shock (6% vs 5%, p=0.19) or CHF (12% vs 9%, p=0.064). Total stroke in-hospital occurred more often in the TNK+PCI group (1.8% vs. 0%, p<0.0001), as did ICH (1.0% vs. 0%, p=0.0037).
In a subgroup analysis by site of randomization, the greatest 90 day mortality difference by treatment group was seen in hospitals with on-site PCI (8.4% for TNK+PCI vs. 5.2% for PCI alone) with less difference in community hospitals (5.2% vs. 4.8%) and a shift in direction for patients enrolled in the ambulance (3.1% vs. 4.1%).
Interpretation:
Among patients with STEMI intended for primary PCI, administration of full-dose fibrinolytic (TNK) immediately prior to PCI was associated with an increase in the primary endpoint of death, shock, or CHF at 90 days compared with primary PCI alone.
A major potential confounder of the strategy of full-dose TNK followed by immediate PCI in the present study may be the lack of antiplatelet therapy, with <10% receiving a GP IIb/IIIa inhibitor and only 63% receiving clopidogrel/ticlopidine. While thrombolytic agents open the artery early, they can also be prothrombotic, as they can activate platelets. It should also be noted that while patients received up to a 4000 IU bolus of UFH in the TNK arm, they did not receive a maintenance infusion of heparin while awaiting PCI. Upstream administration of clopidogrel was not used in the study. While TIMI grade 3 flow was present more frequently in the TNK+PCI group than the primary PCI alone group, the rate of grade 3 flow was lower than in other contemporary fibrinolytic trials 90 minutes post-lytic administration, which were closer to 60% than the 44% seen in the present study.
The clinical event rates for death, stroke, and ICH in the TNK+PCI arm were nearly identical to those of other recent TNK studies, suggesting the TNK+PCI event rates were not excessively high, but rather that the primary PCI event rates were unexpectedly low. Compared to a recent meta-analysis by Keeley EC, et al., which reported a 7% mortality rate at 30 days and a 7% major bleeding rate in primary PCI trials, the primary PCI arm in the present study did have much lower rates (5% mortality and 4.4% major bleeding rate). It is not clear as yet why the PCI arm in this study behaved so differently than prior PCI studies included in the Keeley meta-analysis.
Other trials of upstream fibrinolytic therapy such as FINESSE are ongoing, and have not been stopped prematurely. Data from trials such as FINESSE are needed to further evaluate the hypothesis that upstream fibrinolysis might improve clinical outcomes among patients undergoing early PCI for STEMI.
References:
The ASSENT-4 PCI investigators. Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): randomised trial. Lancet 2006; epub before print.
Presented by Dr. Frans Van de Werf at the American Heart Association Scientific Sessions, Dallas, Texas, November 2005.
Presented by Dr. Frans Van de Werf at the European Society of Cardiology Hot Line Session, September 2005.
Keywords: Thrombolytic Therapy, Myocardial Infarction, Stroke, Platelet Aggregation Inhibitors, Hospitals, Community, Heparin, Ticlopidine, Fibrinolytic Agents, Platelet Membrane Glycoprotein IIb, Purinergic P2Y Receptor Antagonists, Percutaneous Coronary Intervention, Fibrinolysis, Tissue Plasminogen Activator, Platelet Glycoprotein GPIIb-IIIa Complex
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