The On-Time 2 trial Suggests Benefit with Early Administration of Tirofiban in the Ambulance following Acute Myocardial Infarction.

August 21, 2008 By Vijayalakshmi Kunadian MBBS MD MRCP [mailto:vkunadian@perfuse.org]

Lancet-Netherlands: Investigators from Europe demonstrate that early administration of high dose tirofiban in the ambulance improves ST segment resolution and clinical outcomes following acute myocardial infarction in the On-Time 2 trial.

Several strategies have been employed to improve outcomes following acute ST segment elevation myocardial infarction (STEMI). Rapid restoration of blood flow and improvement in myocardial perfusion is associated with improved clinical outcomes. Antiplatelet agents such as glycoprotein IIbIIIa inhibitors (GPIIbIIIa) have been demonstrated to reduce ischemic complications and improve clinical outcomes in the setting of primary percutaneous coronary intervention (PPCI) following acute STEMI.

The investigators in the On-Time 2 trial (Ongoing Tirofiban In Myocardial Infarction Evaluation) determined if early administration of high dose GPIIbIIIa inhibitor tirofiban in the ambulance improved ST segment resolution among patients who were due to undergo PPCI following an acute STEMI. This study consisted of 984 patients from 24 centers in 3 countries (Germany, Netherlands and Belgium) recruited between June 29, 2006 and November 13, 2007. Patients were randomized to receive either high dose tirofiban (n=491) or placebo (n=493) in the ambulance in addition to 500 mg of aspirin, 5000 IU of heparin and 600 mg of clopidogrel. The activated clotting time was maintained at 200 seconds during PCI. Tirofiban was administered at a dose of 25μg/kg bolus and 0.15μg/kg/minute maintenance infusion for 18 hours.

The inclusion criteria for this study consisted of STEMI patients who were suitable to undergo PPCI with symptoms of more than 30 minutes and less than 24 hours. Patients with renal failure, cardiogenic shock, persistent severe hypertension, patients with left bundle branch block, pregnant patients, those with life expectancy of less than one year and had contraindications to antiplatelet therapy were excluded from the study. The primary endpoint consisted of the extent of residual ST-segment deviation at 1 hour following PCI. The secondary endpoint consisted of a composite of death, recurrent myocardial infarction, urgent target vessel revascularization or bail-out use of tirofiban at 30 days.

Patients who were randomized to receive tirofiban had reduced incidence of TIMI flow grade 0 prior to PCI compared with placebo (41.8% vs. 49.8%, p=0.013). There was however, no difference in TIMI flow grades (p=0.618) and myocardial blush grades (p=0.227) following PCI. The occurrence of TIMI flow 0/1 or distal embolization following PCI was significantly reduced in the tirofiban group compared with the placebo group (6.2% vs. 10.3%, p=0.029). There was a significant reduction in cumulated ST segment deviation in the tirofiban group compared with the placebo group prior to angiography [10.9 (9.2) mm vs. 12.1 (9.4) mm, p=0.028] and 1 hour following PCI [3.6 (4.6) mm vs. 4.8 (6.3) mm, p=0.003). At one hour following PCI, 65.6% of patients in the tirofiban group and 60% of patients in the placebo group had complete (>70%) ST segment resolution (p=0.033).

There was also significant improvement in the secondary endpoints in the tirofiban group compared with the placebo group at 30 days (26% vs. 32.9%, p=0.020). This was mainly contributed by the reduced incidence of bail-out use of tirofiban in the tirofiban group (19.9% vs. 28.5%, p=0.002) in the setting of an increased occurrence of abrupt closure in the placebo group (2.2% vs. 0.2%, p=0.004). There was no significant difference in the incidence of major bleeding (4% vs. 2.9%, p=0.363) and the occurrence of thrombocytopenia (2% vs. 1.8%, p=0.806) between the tirofiban and placebo groups. The investigators recommend that early administration of tirofiban in the ambulance before the patient arrives in the cardiac catheterization laboratory might be beneficial and safe in the setting of acute myocardial infarction. The limitations of this study include the fact that a surrogate endpoint rather than clinical endpoint was used as the primary endpoint. It is also interesting to note that the improvement in ST segment resolution did not translate into improvements in myocardial blush grades following PCI. The authors also indicate that only 50-80% of patients who were screened were actually randomized in the study and hence limiting the applicability of the results of this trial for all patients.

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 * 1) http://wikidoc.org/index.php/High_dose_tirofiban_and_clopidogrel_are_safe_and_effective_in_the_ON-TIME-2_trial