Regulatory Decision Summary for Aggrastat

 

The evidence provided to support the proposed high dose bolus (HDB) tirofiban consisted of five studies involving 1,233 high risk NSTE-ACS patients undergoing PCI; with over half exposed to the HDB tirofiban. Two of the studies compared the efficacy of the HDB of tirofiban with placebo; the remainder compared HDB tirofiban with the two other GP IIb/IIIa inhibitors currently approved for use in Canada: abciximab and eptifibatide. All studies evaluated the major adverse cardiac events (MACE) outcome (incidence of death, nonfatal myocardial infarction or urgent target vessel revascularization TVR), an outcome directly linked to the currently approved indication for NSTE-ACS patients undergoing PCI.

The results of the clinical studies clearly indicate that the HDB of tirofiban is significantly better than placebo and not significantly different from abciximab. In the two tirofiban vs. placebo trials, patients on tirofiban had a significantly lower incidence of MACE. In the tirofiban vs. abciximab trials, there was no significant difference in the incidence of MACE between the two treatment groups.

The recently published randomized trial compared the three GP IIb/IIIa inhibitors in terms of their efficacy and safety among NSTE-ACS patients undergoing PCI. This study differed from the others as it compared all three GP IIb/IIIa inhibitors in terms of platelet inhibition, MACE at 30 days and bleeding events. Patients also received heparin and ASA along with loading doses of clopidogrel, prasugrel or ticagrelor. There were no statistically significant differences in platelet inhibition between the three GPIIb/IIIa inhibitors. For all three treatment groups, the median level of platelet inhibition achieved at 10 minutes was 97% which falls within the defined optimal dosing range. There was also no significant difference in the incidence of MACE or bleeding between treatment groups in this study and thus the findings concur with the other studies comparing HDB tirofiban with either abciximab or eptifabatide. The efficacy results from these studies indicate that the HDB of tirofiban is better than placebo and as effective as other GPIIa/IIIb inhibitors.

The major safety concerns associated with GPIIb/IIIa inhibitor use is bleeding and thrombocytopenia. A review of the safety data presented in the published studies indicated that there was no major safety concerns associated with the use of HDB tirofiban when compared to the currently approved low dose regimen or the other GP IIb/IIIa inhibitors approved for use in Canada. In the clinical studies, there were no reported cases of TIMI (Thrombolysis in Myocardial Infarction) major bleeding or any need for red blood cell transfusions among patients receiving the HDB of tirofiban and no significant differences in the incidence of TIMI bleeding among the GP IIb/IIIa inhibitors. The incidence of thrombocytopenia was also low, and no severe cases were reported. Post-market safety findings and signals from the PSURs were consistent with the safety data reported in the published studies.

 

In their response, the sponsor provided a thorough overview of recent HDB tirofiban clinical studies, post-market safety information and the subsequent evolution of treatment algorithms for high-risk NSTE-ACS patients undergoing early PCI as outlined in the American and European Treatment Guidelines. Based on the information provided within the original submission and the response to NON, the benefit/risk ratio is considered favorable for the high dose bolus of Aggrastat in high risk patients with NSTE-ACS undergoing PCI. Therefore, a Notice of Compliance was issued.