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Platelet IIb/IIIa Antagonist for the Reduction of Acute coronary syndrome events in a Global Organization Network - PARAGON B
Description:
This randomized, double blind, placebo controlled trial compared 30 day outcomes between patients treated with the GP IIb/IIIa inhibitor lamifiban plus standard therapy compared to standard therapy alone in the setting of ACS without persistent ST elevation.
Hypothesis:
Patients treated with lamifiban would have a 25% reduction in the 30 day primary composite endpoint compared with placebo patients.
Study Design
Study Design:
Patients Enrolled: 5225
Mean Follow Up: 30 day for composite; 1 year for death
Mean Patient Age: >=21 years
Female: 34
Patient Populations:
Hospitalized for ACS; Age >=21 years; >=1 episode of cardiac ischemic pain at rest lasting >=10 minutes <12 hours before randomization; and one of the following (1) tansient or persisent ST segment depression >0.5 mm, transient ST segment elevation >0.5mm, or definite T wave inverion or (2) CK-MB, troponin T or troponin I >ULN
Exclusions:
active bleeding; impaired hemostatsis; increased bleeding risk; contraindication to aspirin or heparin; planned fibrinolysis or GP IIb/IIIa inhibition; GP IIb/IIIa inhibition within 1 week; LBBB or pacemaker use; estimated creatinine clearance <30 mL/min; serious comorbid disease likely to limit survival; current enrollment in trials of other investigational drugs or devices
Primary Endpoints:
30 day composite of death, MI, or severe recurrent ischemia
Secondary Endpoints:
30 day composite of death or MI 30 day individual endpoints of death, MI, and severe recurrent ischemia 7 day triple composite 7 day composite of death or MI 6 month composite of death or MI 1 year death
Drug/Procedures Used:
Lamifiban IV (500 ug bolus + <=72 hour infusion) plus standard heparin and aspirin therapy vs placebo plus standard therapy of heparin and aspirin. Lamifiban infusion dose was titrated to achieve a target plasma lamifiban concentration between 18 and 42 ng/mL and was adjusted for renal function. IV unfractionated heparin dosing was 5000 U bolus + 1000 U/h infusion for pts weighing >80 kg and 60 U/kg bolus + 12 U/kg/h infusion for pts weighing <=80 kg. Asprin dosing was 150-325 mg at enrollment and daily thereafter.
Principal Findings:
The primary end point of death, MI or severe recurrent ischemia occurred in 11.8% of lamifiban-treated patients and in 12.8% of placebo-treated patients by 30 days (OR, 0.914; 95% CI, 0.769 to 1.087; P=0.329). Kaplan Meier curves showed no difference in death or MI rates by 6 months (14% in lamifiban-treated patients vs 15% in placebo-treated patients, p=0.28). Treatment effect did not differ significantly by the performance or timing of PCI. Intermediate bleeding was more common in lamifiban-treated patients (14.0% vs 11.5%, p=0.002), but intracranial hemorrhage and thrombocytopenia were not increased. In a prosepective subgroup analysis among patients troponin positive at baseline, lamifiban was associated with a significant reduction in the primary endpoint (from 19.4% to 11.0%, p=0.01). No treatment effect was seen in troponin negative patients (11.2% vs 10.8%, p=0.86).
Interpretation:
Lamifiban did not significantly effect clinical outcomes in patients with non–ST-elevation acute coronary syndromes treated with concomitant heparin and aspirin, despite titration to targeted plasma concentrations. This was unlike PARAGON-A, where a significant relation was seen between plasma concentrations and outcomes. Treatment benefit with lamifiban was observed in patients who were troponin-positive at enrollment, indicating its effect may differ in higher risk populations.
References:
Circulation 2002;105:316-321. (main results) Circulation 2001;103:2891-2896. (Troponin substudy)
Keywords: Acute Coronary Syndrome, Intracranial Hemorrhages, Platelet Aggregation Inhibitors, Troponin I, Heparin, Troponin T, Tyrosine, Thrombocytopenia, Platelet Glycoprotein GPIIb-IIIa Complex
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