Delaying and Preventing Ischemic Events in Patient with Acute Coronary Syndromes using the platelet GP IIb/IIIa inhibitor lamifiban - PARAGON


Lamifiban and heparin for death/MI/revascularization in acute coronary syndromes.


Evaluate the benefit of different doses of lamifiban (a platelet IIb/IIIa antagonist) alone and in combination with heparin.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 2,282
Mean Follow Up: 1 year
Mean Patient Age: 66
Female: 35

Patient Populations:

Chest discomfort within the previous 12 hours
Transient or persistent ST-segment depression (≥ 0.5 mm) or T-wave inversion or transient (30 minutes) ST-segment elevation (≥ 0.5 mm).


Oral anticoagulants and INR >1.5 × control
Intravenous heparin and aPTT >85 seconds (not due to recent bolus)
Thrombolytic therapy within 24 hours
Active, significant bleeding
Contraindication to aspirin or heparin
Systolic blood pressure &ge 180 mm Hg or diastolic blood pressure ≥ 100 mm Hg despite treatment
Serum creatinine level >2.0 mg/dL (177 mcmol/L)
Platelet count <100 000/mm3;
Cerebrovascular accident within the past year
Any history of hemorrhagic stroke, tumor, or intracranial aneurysm
Angioplasty within the previous week
Gastrointestinal bleeding, major surgery, or trauma within 1 month
Women of childbearing potential unless pregnancy test was negative

Primary Endpoints:

Death or nonfatal myocardial infarction at 30 days.

Secondary Endpoints:

Death, Myocardial (re)infarction, Disabling stroke, Major bleeding, and Intermediate bleeding (red blood cell transfusion or >5g of hemoglobin drop without hemodynamic compromise) at 30 days.
Death and myocardial infarction at 6 months.
Death at 1-year follow-up.

Drug/Procedures Used:

Lamifiban (2x2 factorial design: low-dose [1 mcg/min] with and without heparin versus high-dose [5 mcg/min] with and without heparin) or to standard therapy (placebo and heparin).

Concomitant Medications:


Principal Findings:

A total of 758 patients were randomized to the placebo group, with 377 receiving low-dose lamifiban with heparin, 378 patients receiving low-dose lamifiban without heparin, 373 high-dose lamifiban with heparin, and 396 high-dose lamifiban without heparin.

The composite primary end point of death or nonfatal myocardial infarction at 30 days occurred in 11.7% of those receiving standard therapy, 10.6% receiving low-dose lamifiban, and 12.0% receiving high-dose lamifiban (P=0.668). No significant difference was noted between the control group and any lamifiban group at 30 days.

At 6-month follow-up, a substantial treatment effect was present. Three of the four lamifiban-treated groups had lower composite event rate compared to control. Death or nonfatal myocardial infarction at 6 months was lowered 23% by low-dose lamifiban with or without heparin (odds ratio, 0.73; 95% CI, 0.55 to 0.97) and 8% by high-dose lamifiban with or without heparin (odds ratio, 0.90; 95% CI, 0.69 to 1.18) compared with control. Patients receiving high-dose lamifiban with heparin had 30-day and 6-month outcomes similar to those of the control group.

There were more bleeding-related events among those receiving high-dose lamifiban. The combination of major and intermediate bleeding occurred in 5.5% of control patients, 6% of low-dose lamifiban patients, and 10.7% of high-dose lamifiban patients (P=0.002).

The combination of high-dose lamifiban and heparin resulted in more intermediate or major bleeding compared with control, (12.1% versus 5.5%; P=0.002) and a similar rate of ischemic events. Conversely, low-dose lamifiban and heparin yielded similar bleeding rates as in the control group but fewer ischemic events at 6 months (12.6% versus 17.9%; P=0.025).


At 6-month follow-up, a distinct treatment benefit was observed with lamifiban for the composite end point of death and nonfatal myocardial infarction. Compared with standard therapy, low-dose lamifiban resulted in a 23% lower event rate (P=0.027), and high-dose lamifiban resulted in a nonsignificant 8% reduction in events. The study was not adequately powered to draw clear conclusions regarding the benefit of heparin coadministration.

The improvement in outcomes at 6 months compared to 30 days may reflect passivation of unstable plaques. The exact mechanism underlying the time course of benefit observed in PARAGON remains to be elucidated. PARAGON was designed to identify an optimal treatment strategy of lamifiban and heparin to be further studied against standard therapy. A larger study of lamifiban, with dose adjustments for renal function, is ongoing.


1. Circulation. 1998;97:2386-95. Final results

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Anticoagulation Management and ACS

Keywords: Odds Ratio, Myocardial Infarction, Acute Coronary Syndrome, Follow-Up Studies, Platelet Aggregation Inhibitors, Heparin, Tyrosine

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