Elsevier

The Lancet

Volume 372, Issue 9638, 16–22 August 2008, Pages 537-546
The Lancet

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Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (On-TIME 2): a multicentre, double-blind, randomised controlled trial

https://doi.org/10.1016/S0140-6736(08)61235-0Get rights and content

Summary

Background

The most effective magnitude and timing of antiplatelet therapy is important in patients with acute ST-elevation myocardial infarction (STEMI). We investigated whether the results of primary coronary angioplasty (PCI) can be improved by the early administration of the glycoprotein IIb/IIIa blocker tirofiban at first medical contact in the ambulance or referral centre.

Methods

We undertook a double-blind, randomised, placebo-controlled trial in 24 centres in the Netherlands, Germany, and Belgium. Between June 29, 2006, and Nov 13, 2007, 984 patients with STEMI who were candidates to undergo PCI were randomly assigned to either high-bolus dose tirofiban (n=491) or placebo (N=493) in addition to aspirin (500 mg), heparin (5000 IU), and clopidogrel (600 mg). Randomisation was by blinded sealed kits with study drug, in blocks of four. The primary endpoint was the extent of residual ST-segment deviation 1 h after PCI. Analysis was by intention to treat. The trial is registered, number ISRCTN06195297.

Findings

936 (95%) patients were randomly assigned to treatment after a prehospital diagnosis of myocardial infarction in the ambulance. Median time from onset of symptoms to diagnosis was 76 min (IQR 35–150). Mean residual ST deviation before PCI (10·9 mm [SD 9·2] vs 12·1 mm [9·4], p=0·028) and 1 h after PCI (3·6 mm [4·6] vs 4·8 mm [6·3], p=0·003) was significantly lower in patients pretreated with high-bolus dose tirofiban than in those assigned to placebo. The rate of major bleeding did not differ significantly between the two groups (19 [4%] vs 14 [3%]; p=0·36).

Interpretation

Our finding that routine prehospital initiation of high-bolus dose tirofiban improved ST-segment resolution and clinical outcome after PCI, emphasises that further platelet aggregation inhibition besides high-dose clopidogrel is mandated in patients with STEMI undergoing PCI.

Funding

Merck (USA).

Introduction

Early and complete restoration of blood flow in the infarct-related vessel after acute myocardial infarction is associated with improved survival and clinical outcomes.1, 2, 3 Both short-term and long-term outcomes are better after primary percutaneous coronary angioplasty (PCI) than after fibrinolytic therapy for acute myocardial infarction.4, 5, 6 The benefits of PCI have mostly been attributed to accelerated and improved myocardial reperfusion.3

Platelet activation and aggregation have a crucial role in the cascade of events leading to myocardial infarction, and in the thrombotic complications that can accompany PCI. Insufficient inhibition of platelet aggregation at the time of PCI correlates with increased likelihood of major cardiovascular adverse events after such a procedure.7 Antiplatelet therapy, therefore, is an important component of medical therapy for patients with acute myocardial infarction. Triple antiplatelet treatment—including aspirin, a thienopyridine, and a glycoprotein IIb/IIIa blocker—is recommended for high-risk patients with non-ST-segment elevation acute coronary syndromes.8 Although many studies have reported beneficial results of routine treatment with a glycoprotein IIb/IIIa blocker shortly before PCI,9, 10 the additional value of early prehospital IIb/IIIa blockade in addition to dual antiplatelet therapy, including high-dose clopidogrel in patients with acute myocardial infarction, has not been established. Similarly, the most effective timing of administration of antiplatelet and antithrombotic drugs in this setting is still being investigated.11, 12

We investigated whether the results of PCI can further be improved by the early administration of the glycoprotein IIb/IIIa blocker tirofiban at first medical contact in the ambulance or referral centre.

Section snippets

Study design and patients

The Ongoing Tirofiban in Myocardial Evaluation (On-TIME) 2 trial was a prospective, multicentre, placebo-controlled, randomised, clinical trial. The rationale and design of the study has been described previously.13 Study enrolment was from June 29, 2006, to Nov 13, 2007, at 24 participating centres in three countries (the Netherlands, Germany, and Belgium). The study population consisted of patients with ST-elevation myocardial infarction (STEMI) who were candidates to undergo primary PCI.

Results

Figure 1 shows the trial profile. 491 patients were randomly assigned to tirofiban and 493 to placebo. Baseline clinical and angiographic characteristics of the patients were much the same between the groups (table 1). 936 (95%) patients were included and randomly assigned after prehospital diagnosis of myocardial infarction in the ambulance at a median of 75 min (IQR 44–147) after the onset of symptoms. Median time from symptom onset to diagnosis in the 48 (5%) patients who were referred from

Discussion

This study shows that in patients with STEMI, routine prehospital initiation of a glycoprotein IIb/IIIa blocker in addition to aspirin, heparin, and high-dose clopidogrel, improves ST-segment resolution before and after PCI. This finding was associated with an improved outcome free from adverse angiographic or clinical events at 30-day follow-up, without a significant increase in major bleeding.

The routine administration of glycoprotein IIb/IIIa blockers in patients with STEMI is a class IIa

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