Ongoing Tirofiban in Myocardial Infarction Evaluation 2 Trial - On-TIME 2

Description:

The goal of this trial was to evaluate prehospital treatment with tirofiban compared with placebo in patients with ST-elevation myocardial infarction (STEMI) who are anticipated to undergo primary percutaneous coronary intervention (PCI).

Hypothesis:

Prehospital treatment with tirofiban would be more effective in improving ST-segment resolution in patients anticipated to undergo primary PCI.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded

Patients Enrolled: 986
Mean Follow Up: 30 days
Mean Patient Age: 62 years

Patient Populations:

Patients with STEMI who presented to a non-PCI center

Exclusions:

  • Severe renal dysfunction
  • Cardiogenic shock
  • Severe hypertension
  • Contraindication to anticoagulation or increased risk of bleeding
  • Left bundle branch block
  • Pregnant women or women who were breast-feeding
  • Life expectancy <1>

Primary Endpoints:

  • Extent of residual ST-segment deviation 1 hour after PCI
  • For pooled analysis: MACE at 30 days (death, recurrent MI, or urgent TVR)

Secondary Endpoints:

  • Percentage of patients with >3 mm ST-segment elevation 60 minutes after PCI
  • Composite of death, recurrent MI, urgent target vessel revascularization, or thrombotic bailout
  • TIMI grade 3 flow in the infarct-related vessel at initial angiography
  • Major bleeding
  • Occurrence of hemorrhage, transfusions, stroke, thrombocytopenia, and serious adverse events

Drug/Procedures Used:

Patients with STEMI who presented to a non-PCI center were randomized to tirofiban (25-mcg/kg bolus and 0.15-mcg/kg/min maintenance infusion) or no tirofiban (phase 1), or placebo (phase 2) prior to transfer for primary PCI. Patients in the placebo/no tirofiban arm received provisional tirofiban in the catheterization laboratory.

Concomitant Medications:

All patients received aspirin (500 mg intravenously), clopidogrel (600 mg orally), and unfractionated heparin (5000 U intravenously).  An additional 2500 U of heparin was administered prior to PCI if the activated clotting time (ACT) was <200 seconds.

Principal Findings:

A total of 1,398 patients were randomized, 414 in phase I or the open-label phase, and 984 in phase II or the double-blind phase. Of these, 709 were assigned to tirofiban, and 689 to placebo or no tirofiban. Due to the difference in study design, a difference in the use of bail-out tirofiban was found between the study phases: 41.8% in the open-label phase versus 24.2% in the double-blind phase.

Most patients (96%) were diagnosed and randomized in an ambulance, with a false-positive diagnosis in 5.8% of the patients. The median time from the onset of chest pain to medical contact was 77 minutes. The median transportation distance was 25 km. Angiography was performed in 98% and 99% of the tirofiban and placebo groups, respectively, with a median time from study medication to angiography of 55 minutes. Thrombolysis in Myocardial Infarction (TIMI) 3 flow before PCI was noted in 20.9% of the patients, with no difference between the two groups.

In the double-blind phase, the primary outcome, cumulative ST-deviation before angiography, occurred in 10.9% of the tirofiban group versus 12.1% of the placebo group (p = 0.028). Persistent 3 mm ST-elevation 1 hour after PCI occurred in 38.1% of the tirofiban group and 45.1% of the placebo group (p = 0.035). Among the subgroups tested—women, diabetics, and patients with a relatively long time until angiography (>55 minutes) and relatively short duration of chest pain (<77 minutes)—appeared to have better ST-resolution with tirofiban.

The incidence of the secondary outcomes for tirofiban versus placebo was: 2.3% versus 4.0% for death (p = 0.14), 2.7% versus 2.9% for recurrent MI (p = 0.86), 0.2% versus 1.5% for stroke (p = 0.069), and 3.8% versus 4.2% for urgent target vessel revascularization (TVR) (p = 0.76). Thrombotic bailout occurred in 19.9% of the tirofiban group and 28.5% of the placebo group (p = 0.002), and abrupt vessel closure occurred in 0.2% versus 2.2% (p = 0.004), respectively.

Major bleeding occurred in 4.0% of the tirofiban group and 2.9% of the placebo group (p = 0.36) and minor bleeding was 6.1% versus 4.4% (p = 0.23), respectively.

In the pooled analysis, the incidence of the composite endpoint was 5.8% in the tirofiban group, compared with 8.6% in the placebo/no tirofiban group (odds ratio 0.65, 95% confidence interval 0.43-0.99, p = 0.04). The incidence of 30-day mortality (2.2% vs. 4.1%, p = 0.051), recurrent MI at 30 days (1.9% vs. 2.3%, p = 0.66), 1-year mortality (3.7% vs. 5.8%, p = 0.08), major bleeding (3.4% vs. 2.9%, p = 0.58), and minor bleeding (5.9% vs. 4.4%, p = 0.21) was similar in the two groups. Stroke was significantly lower in the tirofiban arm (0.3% vs. 1.4%, p = 0.03). In the subgroup analysis, of patients who had a short ischemic time (time from symptom onset until diagnosis) ≤75 minutes, initial TIMI 3 flow was noted in 27.4% versus 19.4% of the patients in the tirofiban and placebo/no tirofiban groups, respectively (p < 0.05).

Interpretation:

Among patients who presented to a non-PCI hospital with STEMI and were treated with aspirin, clopidogrel 600 mg, and heparin, the initiation of upstream tirofiban and transfer for PCI resulted in significant improvement in ST-segment resolution as well as 30-day major adverse cardiac event (MACE) rates, with a trend towards improved mortality at 30 days and 1 year. There was also significantly less thrombotic bailout and abrupt vessel closure with the upstream use of tirofiban. Although bleeding was numerically higher with tirofiban, it was not statistically significant, despite pretreatment with high-dose clopidogrel.

These are interesting results, but are unlikely to change current management for STEMI patients regarding the upstream use of glycoprotein IIb/IIIa inhibitors. For one, the clinical outcomes were derived from pooled analysis of open-label and double-blind phases, with the former being more susceptible to various biases. The exact mechanism of benefit is also unclear. TIMI 3 flow before PCI was similar between the two arms, and similar to that noted in the FINESSE trial with abciximab (which showed no difference in clinical outcomes). That said, it is possible that small molecule glycoprotein IIb/IIa inhibitors such as tirofiban are better at facilitating PCI than abciximab. This will need to addressed in future trials.

References:

Berg JM, van’t Hof AW, Dill T, et al., on behalf of the On-TIME 2 Study Group. Effect of early, pre-hospital initiation of high bolus dose tirofiban in patients with ST-segment elevation myocardial infarction on short- and long-term clinical outcome. J Am Coll Cardiol 2010;55:2446-2455.

Van’t Hof AW, Ten Berg J, Heestermans T, et al., on behalf of the Ongoing Tirofiban In Myocardial infarction Evaluation (On-TIME) 2 Study Group. Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (On-TIME 2): a multicentre, double-blind, randomized controlled trial. Lancet 2008;372:537-46.

Results of the ON-TIME 2 Trial: Prehospital Tirofiban in STEMI. Presented by Dr. Christian Hamm at the SCAI-ACC i2 Summit/American College of Cardiology Annual Scientific Session, Chicago, IL, March/April 2008.

Clinical Topics: Anticoagulation Management, Invasive Cardiovascular Angiography and Intervention

Keywords: Odds Ratio, Myocardial Infarction, Stroke, Platelet Aggregation Inhibitors, Heparin, Ticlopidine, Immunoglobulin Fab Fragments, Fibrinolytic Agents, Angioplasty, Balloon, Coronary, Tyrosine, Purinergic P2Y Receptor Antagonists, Chest Pain, Catheterization, Confidence Intervals, Diabetes Mellitus


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