August 15, 2008 (London, UK) — The addition of "high-bolus-dose" tirofiban (Aggrastat, Merck) to dual antiplatelet therapy in the prehospital setting significantly improved ST-segment resolution both before and after primary PCI in patients with acute ST-elevation MI (STEMI), in the placebo-controlled second Ongoing Tirofiban in Myocardial Evaluation (ON-TIME 2) trial.  Such triple antiplatelet therapy, given with unfractionated heparin before PCI, didn't seem to increase the risk of major bleeding.
There was a statistically significant reduction in a composite clinical end point with added tirofiban, but the trial wasn't powered for clinical outcomes, according to ON-TIME 2 investigators; ST-segment resolution is an indirect marker for myocardial reperfusion.
The findings, published in the August 16, 2008 issue of the Lancet, with first author Arnoud WJ van't Hof (Isala Klinieken, Zwolle, the Netherlands), had been preliminarily presented at the American College of Cardiology 2008 Scientific Sessions and were covered then by heartwire .
"The routine administration of glycoprotein [GP] IIb/IIIa blockers in patients with STEMI is a class 2a indication according to [US and European guidelines]," observe the authors, yet "large registry studies show that in real-world practice, GP IIb/IIIa blockers are given to only 25% to 30% of patients with STEMI, often for bailout situations." The current trial, they write, suggests that the drugs "should not be restricted to patients with complications after PCI, even in a setting in which high-dose clopidogrel is given well in advance of PCI."
Studies of prehospital GP IIb/IIIa inhibition in STEMI, usually with abciximab (ReoPro, Centocor/Eli Lilly), have been conducted primarily in Europe, where ambulances are often staffed by physicians. In ON-TIME 2, van't Hof et al write, "patients were diagnosed and immediately treated in the ambulance by either a physician or a dedicated well-trained paramedic. Diagnosis was correct in 94% of patients with computerized ECG algorithms only, without the need for transmission of the ECG to the hospital."
The trial randomized 491 patients in the Netherlands, Germany, and Belgium to receive the GP IIb/IIIa inhibitor as a 25-µg/kg bolus followed by a 0.15-µg/kg/min infusion for 18 hours--493 patients instead received placebo--on top of 600-mg oral clopidogrel and 500-mg IV aspirin along with 5000-IU heparin, all administered in-transit to a PCI center.
The entry criteria included MI symptoms for >30 minutes but <24 hours and ST-segment elevation >1 mV in two adjacent ECG leads. Patients with severe renal impairment or in shock were excluded.
Outcomes in ON-TIME 2
|Mean residual ST-deviation (mm)|
|1 h after PCI a||3.6||4.8||0.003|
|Major bleeding (%)b||19||14||0.36|
|Composite clinical end point (%)c||26.0||32.9||0.020|
a. Primary end point
b. Defined as clinical signs of hemorrhage associated with a >50 g/L decrease in hemoglobin or >15% decrease in hematocrit
c. At 30 days: death, recurrent MI, urgent target-vessel revascularization, or blinded bailout tirofiban
After the prehospital STEMI diagnosis, randomization took place a median of 75 minutes after symptom onset; it was a median of 55 minutes from the start of prehospital antithrombotic therapy to angiography.
"ON-TIME 2 tells us more than the benefit of high-dose tirofiban in primary PCI. The study reveals that high-dose clopidogrel is not effective enough and confirms the need for fast and strong platelet inhibition," according to Dr Gilles Montalescot (Universitaire Pitié-Salpêtrière, Paris, France) in an accompanying editorial . The trial, he writes, "reminds us also that the first contact with the patient must be rapid and medical. Until now, only well-organized prehospital systems have been able to provide such a service."
The trial was funded by Merck. Disclosures for its coauthors are in the report. Montalescot reports that his center "has received research grants from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, and Centocor," and he has consulted for Sanofi-Aventis, Eli Lilly, Bristol-Myers Squibb, Merck, GlaxoSmithKline, The Medicines Company, and Schering-Plough and received lecture fees from Sanofi-Aventis, Eli Lilly, Bristol-Myers Squibb, and GlaxoSmithKline.
van't Hof AWJ, ten Berg J, Heestermans T, et al. Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (ON-TIME 2): a multicentre, double-blind, randomised controlled trial. Lancet 2008; 372:537–546.
Montalescot G. Mechanical reperfusion: treat well, treat on time too. Lancet 2008; 372: 509-510.
Heartwire from Medscape © 2008 Medscape
Cite this: Steve Stiles. On-TIME 2 in Print: Acute STEMI Gains with Prehospital Triple Antiplatelet Therapy - Medscape - Aug 15, 2008.