Summary
Background
Compared with administration in the catheterization laboratory, early treatment with glycoprotein IIb/IIIa inhibitors provides benefits to patients with ST-segment elevation myocardial infarction who undergo primary percutaneous intervention. Whether this benefit is maintained on top of a 600 mg loading dose of clopidogrel is unknown.
Methods
In a multicentre, controlled, randomized study, 320 patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention received a high-dose bolus of tirofiban given either in the ambulance (prehospital group) or in the catheterization laboratory. The primary endpoint was a TIMI flow grade 2–3 of the infarct-related vessel at initial angiography. Secondary endpoints included ST-segment resolution 1 h after percutaneous coronary intervention and peak serum troponin I concentration.
Results
Tirofiban was administered 48 (95% confidence interval 21.4–75.0) min earlier in the prehospital group. At initial angiography, the combined incidence of TIMI 2–3 flow was 39.7% in the catheterization-laboratory group and 44.2% in the prehospital group ( p = 0.45). No difference was found on postpercutaneous intervention angiography or peak troponin concentration. Complete ST-segment resolution 60 min after the start of intervention was 55.4% in the catheterization-laboratory group and 52.6% in the prehospital group ( p = 0.32).
Conclusion
Prehospital initiation of high-dose bolus tirofiban did not improve significantly initial TIMI 2 or 3 flow of the infarct-related artery or complete ST-segment resolution after coronary intervention compared with initiation of tirofiban in the catheterization laboratory ( NCT00538317 ).
Résumé
Contexte
L’administration d’un anti-GPIIb/IIIa très en amont de l’admission en salle de cathétérisme augmente le taux de reperfusion des patients qui bénéficient d’une angioplastie primaire. La persistance du bénéfice de cette administration précoce chez des patients qui reçoivent en préhospitalier une dose de 600 mg de clopidogrel n’est pas connue.
Méthodes
Dans cette étude multicentrique, contrôlée et randomisée, 320 patients présentant un STEMI et bénéficiant d’une angioplastie primaire ont reçu une dose de charge de 600 mg de clopidogrel et du tirofiban soit dans l’ambulance (groupe pré-Hosp) soit directement en salle de cathétérisme (groupe cath Lab). Le critère de jugement principal était un flux TIMI 2–3 dans l’artère coronaire coupable lors de la première injection. Les critères de jugement secondaires incluaient la résolution du sus-décalage du segment ST une heure après l’angioplastie primaire et le pic de troponine I.
Résultats
Le tirofiban a été administré 48 minutes (IC95 % : 21,4–75,0) plus tôt dans le groupe pré-Hosp. À l’angiographie initiale, la proportion des flux TIMI 2–3 était de 39,7 % dans le groupe cath Lab et de 44,2% dans le groupe pré-Hosp ( P = 0,45). Aucune différence significative n’a été observée entre les deux groupes pour les résultats angiographiques postprocédure ou le pic de troponine I. La résolution complète du sus-décalage du segment ST, 60 minutes après l’angioplastie était de 55,4 % dans le groupe cath Lab contre 52,6 % dans le groupe pré-Hosp ( p = 0,32).
Conclusion
Comparée à une administration en salle de cathétérisme, l’administration préhospitalière du tirofiban en plus d’une dose de charge de 600 mg de clopidogrel n’améliore ni les valeurs initiales de flux TIMI 2 ou 3 dans l’artère responsable de l’infarctus, ni l’évolution du sus-décalage du segment ST en postprocédure d’angioplastie.
Abbreviations
STEMI
ST-segment elevation myocardial infarction
AMI
acute myocardial infarction
PCI
percutaneous coronary intervention
GP IIb/IIIa
glycoprotein IIb/IIIa
TIMI
thrombolysis in myocardial infarction
IRA
infarct-related artery
On-TIME2
Ongoing tirofiban in myocardial infarction evaluation2
BRAVE 3
Bavarian reperfusion alternatives evaluation-3
Introduction
In patients undergoing primary percutaneous intervention (PCI), glycoprotein (GP) IIb/IIIa inhibitors improve angiographic and clinical outcome and are a class IIa recommendation . Compared with administration in the catheterization laboratory (cath lab), early initiation of GP IIb/IIIa inhibitors in the emergency department or the ambulance had been associated with a better recanalization rate .
Most studies comparing early and late administration of GP IIb/IIIa inhibitors were performed before the generalization of adjuvant antiplatelet aggregation with high loading-dose clopidogrel. Loading with 600 mg of clopidogrel provides a high degree of platelet-aggregation inhibition within a short time . With a 600 mg clopidogrel regimen, prehospital administration of high-dose tirofiban was associated with an improved ST-segment resolution compared with placebo .
However, prehospital tirofiban has not been compared with tirofiban given in the cath lab in the modern era of adjuvant antiplatelet therapy in patients undergoing primary PCI. It is not only a clinical question but also an organizational problem. If applied widely, the systematic prehospital administration of GP IIb/IIIa inhibitors would raise the cost and complexity of prehospital protocols for the management of ST-segment elevation myocardial infarction (STEMI). We therefore performed a multicentre, prospective randomized trial to evaluate the extent of the benefit of prehospital tirofiban compared with cath-lab tirofiban on top of a high loading-dose of clopidogrel in patients undergoing primary PCI.
Methods
Study patients
The study recruited out-of-hospital patients managed by mobile intensive care units (MICU) staffed by a physician. The study was conducted within the organization of the RESCUe and RESURCOR networks that associate 12 tertiary cardiology centres with a round-the-clock catheterization laboratory, six medical dispatching centres and 20 MICU services. Patients were eligible for inclusion if they presented within 12 h after the onset of symptoms of myocardial infarction, i.e., characteristic pain lasting for at least 30 min and not responsive to nitrates, and electrocardiographic ST-segment elevation ≥ 0.2 mV in two or more contiguous precordial leads or 0.1 mV for limb leads. Patients were excluded if they were known to have haemorrhagic diathesis; were pregnant; had any allergy or contraindication to heparin, aspirin or tirofiban; suffered from severe renal or hepatic insufficiency; had had major surgery within the past month; had any sign of cerebral ischaemic disease for < 1 month or non-ischaemic disease whatever its date; had received oral anticoagulant treatment, a fibrinolytic or a GP IIb/IIIa antagonist within the past 7 days; had uncontrolled hypertension, severe conduction disorder or cardiogenic shock; or if duration of transfer to the hospital (entrance to the cath lab) was to exceed 1 h.
The study protocol was approved by the hospital and regional ethics committees. Oral informed consent was required in the ambulance and written consent was obtained from all patients no later than the time of catheterization.
Randomisation and treatment strategies
After initial screening and patient consent, open-label randomisation was conferred at the site of initial management (usually at home or at the patient’s workplace) to high-dose tirofiban in the ambulance (prehospital group) or in the catheterization laboratory (cath-lab group). Randomisation was done in dispatching medical centres according to a computer-generated random sequence enclosed in scratch cards.
All patients received, in the prehospital setting, a loading dose of 600 mg of clopidogrel, a 60 IU/kg intravenous (IV) heparin bolus (maximum dose 5000 IU) and 250–500 mg aspirin (oral or IV). Patients were transported immediately to the hospital for coronary angiography and angioplasty whenever possible.
Open-label tirofiban was administered as soon as possible at the site of initial management in patients assigned to the prehospital group, and at the admission to the cath lab before vascular access in those assigned to the cath-lab group. A loading dose of 25 μg/kg was administered in 3 min followed by an infusion of 0.15 μg/kg per min for 18–24 h.
Angioplasty was performed according to local standards with the intention of re-establishing blood flow in the infarct-related artery as soon as possible.
Electrocardiograms, biological data and procedural reports were collected and analysed centrally. Data on coronary angiograms were reported by the investigators. If discrepancies appeared between the case-report form and the procedural report, a request was sent to the investigator for further details. Electrocardiograms were recorded at presentation, on admission to the cath-lab and 1 h after PCI or angiography if no PCI was performed. They were collected and analysed centrally according to the same protocol by two trained research monitors unaware of the therapeutic strategy. ST-segment elevation was measured in all leads to the nearest 0.5 mm at 60 ms after the J point with hand-held callipers. ST-segment resolution was defined as the ratio between cath-lab or 60 min post-PCI values and the initial sum of ST-segment elevation.
Creatine kinase and troponin I concentrations were measured on admission, after the procedure, and every 6 h for 24 h, then every day until discharge.
Endpoints
The primary endpoint was the presence of TIMI 2 or 3 flow in the culprit artery during the first injection in coronary angiography. Secondary endpoints were sum residual ST-segment deviation and the frequency of ST-segment resolution 60 min after the angioplasty, creatine kinase and troponin peak serum concentrations. ST-segment resolution was considered complete when > 70% from baseline. To allow comparison with previous studies , residual ST-segment deviation was stratified as 0 mm, 1–3 mm, 4–6 mm and > 6 mm. Peak creatine kinase and peak troponin were defined as the highest creatine kinase and troponin I serum concentrations within the first 48 h. Clinical and safety endpoints were in-hospital death, reinfarction, acute stent thrombosis or major bleeding. Major bleeding was defined as signs of haemorrhage associated with a drop in haemoglobin > 50 g/L, excluding patients who underwent coronary artery bypass graft surgery.
Statistical analysis
Continuous data are presented as mean with standard deviation or median with 25th and 75th quartiles unless otherwise stated. Comparisons were made with Student’s t -test or the Mann-Whitney U test. Discrete data are summarized as frequencies and comparisons were made with Pearson’s c 2 test or Fisher’s exact test. The c 2 test was also used to test for trends in various grades of TIMI flow, ST-segment resolution and residual ST-segment elevation. A subgroup analysis was performed in patients managed early (before the median time from symptom onset to arrival in the MICU) or later (after the median time). Statistical analysis was performed on the basis of intention-to-treat. A p -value of < 0.05 was considered statistically significant.
Based on the results of a previous meta-analysis , the initial sample size calculation was 300 patients with a 5% alpha risk and an 80% power to detect a 16% difference in the primary endpoint. The study population was set to 320 patients. Since some patients were wrongly randomised due to errors in the dispatching centre or withdrew their informed consent before angiography, the recruitment was increased to 337 patients to reach at least 155 patients in each group. Incorrectly randomised patients were excluded from all analyses. The SAS software (Windows V 9.1) was used for all analyses.
The study is registered, number NCT00538317 .
Results
Clinical data
From July 2007 to July 2008, 320 patients with an out-of-hospital diagnosis of STEMI and planned primary PCI were included and assigned randomly to prehospital tirofiban ( n = 164) or cath-lab tirofiban ( n = 156) ( Fig. 1 ).
