The safety of Aggrastat® (tirofiban hydrochloride) was studied in the PRISM, PRISM-PLUS, and RESTORE clinical trials.
In these studies, 1946 patients received Aggrastat® in combination with heparin and 2002 patients received Aggrastat® alone for about 3 days.
In clinical studies with the recommended regimen (25 mcg/kg bolus followed by a 0.15 mcg/kg/min maintenance infusion), Aggrastat® was administered in combination with aspirin, clopidogrel and heparin or bivalirudin to over 8000 patients for typically ≤ 24 hours.
The incidences of major and minor bleeding using the TIMI criteria in the PRISM-PLUS study are shown below.
(TIMI Criteria)‡ §
|Aggrastat® + Heparin
* 0.4 mcg/kg/min initial infusion; 0.10 mcg/kg/min maintenance infusion.
‡ Major = Hemoglobin drop of > 5.0 g/dL with or without an identified site, intracranial hemorrhage, or cardiac tamponade.
§ Minor = Hemoglobin drop of > 3.0 g/dL with bleeding from a known site, spontaneous gross hematuria, hematemesis or hemoptysis.
|Aggrastat® + Heparin||Heparin alone|
|Prior to Procedures||773||0.3||797||0.1|
The incidence rates of TIMI major bleeding in patients undergoing coronary artery bypass graft surgery (CABG) in PRISM-PLUS within one day of discontinuation of Aggrastat® were 17% on Aggrastat® plus heparin (N=29) and 35% on heparin alone (N=31).
Rates of major bleeds (including any intracranial, intraocular or retroperitoneal hemorrhage, clinically overt signs of hemorrhage associated with a drop in hemoglobin of > 3 g/dL or any drop in hemoglobin by 4 g/dL, bleeding requiring transfusion of ≥ 2 U blood products, bleeding directly resulting in death within 7 days or hemodynamic compromise requiring intervention) were consistent with the rates observed in subjects administered the PRISM-PLUS regimen of Aggrastat®.
There was a trend toward greater bleeding in ST segment elevation myocardial infarction (STEMI) patients treated with fibrinolytics prior to administration of Aggrastat® using the recommended regimen during rescue PCI.
SAVI-PCI compared clinical outcomes at 48 hours post-PCI (or hospital discharge, whichever came first) after treatment with short duration Aggrastat® or two different longer-infusion regimens of Aggrastat® or Integrilin® in patients undergoing PCI for elective or NSTE-ACS indications. Clinical outcomes (death, periprocedural myonecrosis, uTVR) and major bleeding (REPLACE-2) were reported.
|REPLACE-21,2 major||0 (0.0%)||4 (3.2%)||1 (0.5%)|
|REPLACE-21,2 minor||16 (7.7%)||13 (10.5%)||19 (9.4%)|
|REPLACE-21,2 major or|
|16 (7.7%)||15 (12.1%)†||20 (9.9%)|
CABG=Coronary Artery Bypass Graft; REPLACE-2=Randomized Evaluation in PCI Linking Angiomax to Reduced
The rate of REPLACE-2-defined major bleeding was significantly lower for Aggrastat® short infusion versus Aggrastat® long infusion (p=0.0093) and Integrilin® long infusion versus Aggrastat® long infusion (p=0.0394). Aggrastat® short infusion versus Integrilin® long infusion was statistically non-significant (p>0.05). The rate of REPLACE-2-defined minor bleeding or combined endpoint of REPLACE-2 major and minor bleeding between Aggrastat® short infusion, Aggrastat® long infusion, and Integrilin® long infusion arms was statistically non-significant (p>0.05 for all comparisons).
†Two patients in the Aggrastat® long infusion group experienced both a minor and major bleeding event at different timepoints, but prior to discharge.
REPLACE-2 Major Bleed: intracranial, intraocular, or retroperitoneal; overt blood loss with hemoglobin decrease 3 g/dL; any hemoglobin decrease 4 g/dL; transfusion of 2 U blood products. REPLACE-2 Minor Bleed: overt bleeding not meeting criteria for major bleeding.
|TIMI major1-3||0 (0.0%)||2 (1.6%)||1 (0.5%)|
|TIMI minor1-3||1 (0.5%)||3 (2.4%)||1 (0.5%)|
|TIMI major or minor1-3||1 (0.5%)||5 (4.0%)||2 (1.0%)|
|Thrombocytopenia*1-3||0 (0.0%)||1 (0.8%)||3 (1.5%)|
TIMI=Thrombolysis in Myocardial Infarction
The rate of the sum of TIMI major and minor bleeding was significantly lower for Aggrastat® short infusion versus Aggrastat® long infusion (p=0.0155). All other comparisons were statistically non-significant (p>0.05). The rates of thrombocytopenia was statistically non-significant between groups (p>0.05 for all comparisons). None of the thrombocytopenia events were severe (<50,000 cells/µL).
*Thrombocytopenia was assessed as a platelet count of <100,000 cells/µL, further divided into either severe thrombocytopenia (<50,000 cells/µL) or profound thrombocytopenia (<20,000 cells/µL) if applicable.
TIMI Major Bleeding: any intracranial bleeding (excluding microhemorrhages <10 mm evident only on gradient-echo MRI), clinical overt signs of hemorrhage associated with a decrease in hemoglobin of ≥5 g/dL, fatal bleeding (defined as a bleeding event that directly results in death within 7 days). TIMI Minor Bleeding: clinically overt (including imaging), resulting in decrease in hemoglobin concentration of 3 to <5 g/dL.
Aggrastat® is indicated to reduce the rate of thrombotic cardiovascular events (combined endpoint of death, myocardial infarction, or refractory ischemia/repeat cardiac procedure) in patients with non-ST elevation acute coronary syndrome (NSTE-ACS).