Tailoring Treatment With Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel - 3T/2R
The goal of the trial was to evaluate if tirofiban would reduce the incidence of myocardial infarction (MI) after percutaneous coronary intervention (PCI) among poor responders to aspirin and/or clopidogrel.
Intensification of antiplatelet therapy by tirofiban among poor responders to aspirin or clopidogrel would reduce MI.
- Placebo Controlled
Patients Screened: 1,277
Patients Enrolled: 263
Mean Follow Up: 30 days
Mean Patient Age: 69 years
Mean Ejection Fraction: 57%
- Patients undergoing PCI for indications including low-risk non-ST-elevation acute coronary syndromes
- Poor response to aspirin and/or clopidogrel, as assessed by VerifyNow and P2Y12 assays
- Contraindication to a glycoprotein IIb/IIIa inhibitor
- Troponin I or T elevation >3× ULN 48 hours after PCI
- Troponin I or T elevation more than 1 or 5× ULN 48 hours after PCI
- CK-MB isoenzyme elevation more than 1, 3, or 5× ULN 48 hours after PCI
- Major adverse cardiac events at 30 days
- Stent thrombosis
Patients undergoing PCI were screened for poor response to aspirin and/or clopidogrel. Poor responders were then randomized to tirofiban (n = 132) or placebo (n = 131).
Patients received aspirin, clopidogrel (75 mg daily for at least 7 days, or 300 mg at least 6 hours before PCI, or 600 mg at least 2 hours before PCI), and unfractionated heparin, or bivalirudin. Among patients who received tirofiban, the dose was 25 µg/kg for 3 minutes, followed by 0.15 µg/kg/min for 14-24 hours.
Overall, 263 patients were randomized. There was no difference in baseline characteristics between the groups. The incidence of diabetes was approximately 26%, prior MI was 43%, stable angina was 42%, and multivessel disease was present in 73%. The median number of stents per patient was one, median stent length was 27 mm, the proportion of patients who received stents was 92%, approximately 46% of procedures were performed by radial approach, and the use of unfractionated heparin was 98%. Approximately 15% of patients were poor responders to aspirin, 27% were poor responders to clopidogrel, and 9% were poor responders to both.
The primary outcome, troponin I or T elevation >3× the upper limit of normal (ULN) occurred in 20.4% of the tirofiban group versus 35.1% of the placebo group (p = 0.009). There was no difference in the primary outcome among the various subgroups that were tested. Creatinine kinase (CK)-MB isoenzyme was reduced by tirofiban according to the level of cardiac biomarker (CK-MB > ULN, p < 0.001; CK-MB >3× ULN, p = 0.09; CK-MB >5× ULN, p = 0.05).
Tirofiban reduced major adverse cardiac events at 30 days (3.8% vs. 10.7%; p = 0.031). There were no major bleeds in either group.
The use of tirofiban was beneficial in reducing post-procedural MI within 48 hours among poor responders to aspirin and/or clopidogrel. The high incidence of troponin elevation in the placebo group attests to the seriousness of poor antiplatelet response. Tirofiban also reduced major adverse cardiac events at 30 days, driven by the reduction in MI. Major bleeding events did not occur in either group.
Tirofiban was not tested among patients with a good antiplatelet response; however, the ISAR-REACT trial documented that a glycoprotein IIb/IIIa inhibitor (abciximab) is not required among stable patients pretreated with clopidogrel undergoing elective PCI. The concept of tailoring pharmacological therapy among poor responders to clopidogrel was also studied with the VASP phosphorylation index. In that study, additional clopidogrel was administered to poor responders and was associated with reduced adverse cardiac events. From a safety standpoint, additional clopidogrel might be more attractive than administering a glycoprotein IIb/IIIa inhibitor.
Although these results are intriguing, this study will need to be validated in a larger trial. Moreover, these two approaches to poor antiplatelet response (additional clopidogrel or the use of a glycoprotein IIb/IIIa inhibitor) will need to be compared against each other. It is also unknown what the best mechanism is to test for poor antiplatelet response.
Valgimigli M, Campo G, de Cesare N, et al. Intensifying platelet inhibition with tirofiban in poor responders to aspirin, clopidogrel, or both agents undergoing elective coronary intervention. Results from the double-blind, prospective, randomized tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel study. Circulation 2009;119:3215-22.
Main Results of the Tailoring Treatment with Tirofiban in patients showing Resistance to aspirin and/or Resistance to clopidogrel Study (3T/2R). Presented by Dr. Marco Valgimigli at the European Society of Cardiology Congress, Munich, Germany, August/September 2008.
Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Anticoagulation Management and ACS, Interventions and ACS, Chronic Angina
Keywords: Myocardial Infarction, Acute Coronary Syndrome, Platelet Aggregation Inhibitors, Angina, Stable, Heparin, Coronary Disease, Ticlopidine, Immunoglobulin Fab Fragments, Creatinine, Tyrosine, Percutaneous Coronary Intervention, Stents, Troponin I, Diabetes Mellitus, Platelet Glycoprotein GPIIb-IIIa Complex
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