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The effect of the pre-hospital initiation of a glycoprotein 2b/3a recepter blocker in patients undergoing primary angioplasty for acute myocardial infarction. Results of the Ongoing Tirofiban in Myocardial Infarction Evaluation (On-TIME) 2 Trial.

Clinical Trial Update I

Acute Coronary Syndromes (ACS)

Presenter report:

Van 't Hof, Arnoud W J (Netherlands)

The On-TIME 2 trial consisted of 2 study phases: an open label run-in phase and a placebo-controlled double blind phase. Results of the double blind phase showed improved ST resolution after PCI in patients pre-treated with (High Bolus Dose (HBD), 25 μg/kg bolus, 0.15 μg/kg/min infusion) tirofiban. In order to evaluate the effect in certain subgroups and to evaluate the effect on clinical outcome, we performed a pooled analysis of the 2 study phases.

Briefly, patients with STEMI were randomised pre-hospital (either in the ambulance or at a referral centre) to high dose bolus tirofiban infusion (SHDB, 25 μg/kg/3 min and 0.15 μg/Kg/min for 18-24 hours) or placebo or no tirofiban on top of aspirin (500 mg), heparin (5000 IU) and clopidogrel (600 mg).

Between June 16, 2004, and June 29, 2006, 414 patients were randomised in the open label phase at 2 centres in one country followed by the randomisation of 984 patients in the double blind phase at 24 centres in 3 countries from June 29, 2006 to November 13, 2007. The primary end-point was residual ST segment deviation, 1 hour after primary coronary angioplasty. Secondary end points were initial TIMI 3 flow of the infarct related vessel and myocardial blush grade after PCI. TIMI frame count after PCI and aborted myocardial infarction, defined as the absence of a rise in Creatine Kinase (CK) were exploratory end points. By combining the 2 study phases, with 1398 randomised patients, the trial had 70% power to detect a 40% relative reduction in major adverse cardiac events (MACE, from 8% to 4.8%) at 30 days follow-up. This pooled analysis was pre-specified in the statistical plan of the study. All electrocardiographic and angiographic parameters were evaluated and analysed by an independent core lab (Diagram, Zwolle, NL). All clinical events were evaluated by an independent clinical event committee. All analyses were according to the intention to treat principle.

Baseline characteristics of the patients in both study phases were similar. Ninety-six (96) percent of patients were randomised after pre-hospital infarction diagnosis in the ambulance, 75 minutes after the onset of symptoms (IQR 45-146). The time to diagnosis was significantly longer in the 38 (2.7%) patients referred from a non-PCI clinic (125 minutes, IQR 61-210, p<0.007).

The mean residual ST deviation before PCI (11.4 ± 9.4 mm versus 12.4 ± 9.4 mm, p=0.020) and 1 hour after PCI (3.7 ± 5.2 mm  versus 4.8 ± 6.0 mm, p<0.008) was significantly lower for patients pre-treated with HBD Tirofiban (pre-PCI). A TIMI frame count <19 was present in 50% of patients pre-treated with HBD tirofiban versus 44% in the no-tirofiban group (p=0.07). Aborted myocardial infarction was present in 14% in the tirofiban group as compared to 10% in the no-tirofiban group (p=0.04).

At 30 days follow-up, the incidence of MACE was significantly lower after early tirofiban treatment (5.8% versus 8.6%, p=0.043). Total mortality was borderline significantly lower (2.2 versus 4.1%, p=0.051). No significant difference in major (3.4% versus 2.9%, p=0.58) or minor bleeding (5.9% versus 4.4%, p=0.21) was found. The combined incidence of death/re-MI/urgent TVR/stroke/major bleeding (net clinical outcome) was 8.0% in the tirofiban group as compared to 11.6% in the no-tirofiban group (p=0.024).

Patients who were diagnosed shortly after the onset of symptoms (within <75 minutes) had the greatest benefit of (HBD) tirofiban pre-treatment. Patients who were diagnosed early had significantly better initial TIMI 3 flow (28% versus 20%, p=0.02), more abortion of MI (17% versus 10%, p=0.01), and a significant reduction in MACE (4.3% versus 8.1%, p=0.04) and mortality (1.2% versus 3.3%, p=0.06), whereas patients who received tirofiban relatively late after the onset of symptoms had less benefit (no significant improvement in initial TIMI 3 flow (17% versus 20%, p=0.40), less effect on aborted MI (11% versus 10%, p=0.71), and less reduction in MACE (7.0% versus 7.9%, p=0.66) or mortality (2.9% versus 3.5%, p=0.64).

This pooled analysis of the 2 study phases of the On-TIME 2 trial showed that in patients with STEMI, early pre-hospital initiation of (HBD) tirofiban resulted in a significantly higher percentage of patients with aborted myocardial infarction. In addition, clinical outcome was improved, without a significant increase in bleeding, thereby improving net clinical outcome. Pre-hospital tirofiban pre-treatment is especially effective when given early after the onset of symptoms and therefore the administration should not be delayed until arrival of the patient in the cath-lab.

Discussant report:

Ardissino, Diego (Italy)


The On-TIME Investigators are to be complimented for the design of their trial and for the excellent organization that led to pre-hospital diagnosis and enrolment of 96% of the patients with a median time from the onset of symptoms to randomization of 75 minutes and a transportation time of 55 minutes, with a total ischemic time of 166 minutes. This is an outstanding achievement, made possible only by a long standing experience in the treatment of myocardial infarction and a perfect organization.

However, the results are rather disappointing. If we focus on the primary end point, the 1 mm of residual amount of total ST segment deviation difference between patients receiving high dose tirofiban in the ambulance compared with those receiving bail out drug in the cath-lab is at the very least an unsatisfactory result . A trend towards the reduction of a clinically meaningful end point is obtained by pooling the data of the ON TARGET preparation (open label and in 2 highly committed centers) and ONTARGET 2 (double blind and in 24 centers), but this operation is questionable from a methodological point of view. In 2008, after a long standing debate on whether GP IIb/IIIa antagonists should be administered in patients undergoing primary PCI, we need solid data on clinically meaningful end points with a careful evaluation of the risk /benefit ratio and cost/effectiveness, as well as transferability of the data to the real world.


Report prepared by : A.W.J van ‘t Hof, MD, PhD, Isala Klinieken, dpt of Cardiology, Zwolle, the Netherlands




Clinical Trial Update I

Notes to editor

This congress report accompanies a presentation given at the ESC Congress 2008. Written by the author himself/herself, this report does not necessarily reflect the opinion of the European Society of Cardiology.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.