Facilitation of primary coronary angioplasty by early start of a glycoprotein 2b/3a inhibitor: results of the ongoing tirofiban in myocardial infarction evaluation (On-TIME) trial

Arnoud W.J van't Hofa,*, Nicolette Ernsta, Menko-Jan de Boera, Rob de Winterb, Eric Boersmac, Ton Buntd, Sonia Petronioe, A.T Marcel Gosselinka, Walter Japf, Frans Hollakg, Jan C.A Hoorntjea, Harry Suryapranataa, Jan-Henk E Dambrinka and Felix Zijlstraa on behalf of the On-TIME study group

a Isala Klinieken, Locatie Weezenlanden, Department of Cardiology, Groot Wezenland 20, 8011 JW Zwolle, The Netherlands
b Academic Medical Centre, Department of Cardiology, Amsterdam, The Netherlands
c Erasmus Medical Centre, Department of Cardiology, Rotterdam, The Netherlands
d Merck & Co., Inc., Whitehouse Station, NJ, USA
e Ospedale di Cisanello, University Hospital, Department of Cardiology, Pisa, Italy
f Gelre Ziekenhuizen, Department of Cardiology, Apeldoorn, The Netherlands
g Ambulance Dienst, Regio IJsselvecht, Zwolle, The Netherlands

Received March 24, 2004; revised April 5, 2004; accepted April 6, 2004 * Corresponding author. Tel.: +31-384242198; fax: +31-384243222
E-mail address: v.r.c.derks{at}isala.nl

See page 807 for the editorial comment on this article.1


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Statistical analysis
 Results
 Discussion
 Limitations
 Conclusion
 References
 
Aim Although primary angioplasty is effective despite additional transportation delay, improved patency before PCI might be obtained by starting pharmacological pre-treatment before transportation.

Methods and Results From June 2001 to November 2002, 507 patients with acute myocardial infarction, who were transferred to a PCI centre, were randomised to early, pre-hospital initiation of Tirofiban (Early) or to initiation in the catheterisation laboratory (Late). The primary end-point was TIMI flow grade 3 of the infarct-related vessel (IRV) at initial angiography, as assessed by an independent core-lab. The effect of Tirofiban on each TIMI flow component, the presence of thrombus at initial angiography and pre-PCI myocardial blush grade were secondary end-points. A large proportion of patients (41%) was diagnosed and randomised in the ambulance, without intervention of a physician. In the Early group, Tirofiban was administered a median of 59 min (range 11–178 min) earlier than in the Late group. At initial angiography, TIMI 3 flow was present in 19% the Early group and in 15% in the Late group (). The combined incidence of TIMI 2 or 3 flow was present in 43% in the Early group and in 34% in the Late group, respectively (). Thrombus or a fresh occlusion was present in 60% and 73% in the Early and Late group, respectively (). A pre-PCI myocardial blush grades 2 or 3 was more often present in the Early group (30% vs. 22%, ). However, no difference in TIMI 3 flow or myocardial blush grade was found between the groups, post-PCI. At one-year follow-up, the combined incidence of death or recurrent MI was not different between the groups (7.0% vs. 7.0%, ).

Conclusion Early initiation of Tirofiban did not improve initial TIMI 3 flow of the IRV significantly. Despite a better patency (TIMI 2 or 3 flow), a lower prevalence of thrombus or fresh occlusion and a better myocardial perfusion in the infarct-related region pre-PCI, no beneficial effect on post-PCI angiographic or clinical outcome was found, as compared to initiation of Tirofiban in the catheterisation laboratory.

Key Words: Primary angioplasty • Anti-platelet therapy • Reperfusion


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Statistical analysis
 Results
 Discussion
 Limitations
 Conclusion
 References
 
Primary coronary angioplasty has been shown to be an effective re-perfusion modality in patients with an acute myocardial infarction (MI) both at short and at long-term, follow-up.1,2 Most patients, however, present at hospitals without angioplasty facilities and therefore have to be transported to a percutaneous coronary intervention (PCI) centre. A recent meta-analysis showed a significant benefit for the combination of death, recurrent MI and stroke, even after transportation to a PCI centre.3 The majority of this evidence came from the DANAMI-2 and PRAGUE-2 trials, which showed that transportation of acute MI patients is safe and that clinical outcome was superior in patients who underwent angioplasty, despite the additional transportation delay.4,5 The question remains whether pharmacological pre-treatment, with the aim to improve initial patency during transportation and before intervention, might further improve outcome.

Retrospective analyses suggest that angioplasty success and outcome is better in patients with an open (thrombolysis in myocardial infarction (TIMI) 2 or 3 flow) infarct-related vessel (IRV) before the angioplasty procedure.6,7 The ideal drug, or combination of drugs, that may safely and effectively improve patency and thereby facilitate primary angioplasty, has yet to be found. Non-randomised trials demonstrated that pre-treatment with glycoprotein 2b/3a blockers for 10–60 min is associated with patency rates (TIMI 2 or 3 flow) varying from 35% to 55%.8–11

The current study is a multi-centre prospective, randomised, placebo-controlled trial, to evaluate the efficacy of Tirofiban pre-treatment, in addition to both aspirin and heparin, on the initial TIMI flow of the IRV in patients transported to undergo primary angioplasty.


    Methods
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 Abstract
 Introduction
 Methods
 Statistical analysis
 Results
 Discussion
 Limitations
 Conclusion
 References
 
Patient population
Inclusion criteria for the trial were the presence of chest pain for more than 30 min, together with more than 0.2 mV (anterior MI) or 0.1 mV (non-anterior MI) of ST-elevation in two contiguous ECG leads and the ability to perform primary angioplasty within 6 h after the onset of symptoms. Patients over 80 years of age, women less than 50 years of age, patients who were treated with thrombolytic therapy in the previous 24 h, patients on warfarin or acenocoumarol within the last seven days and patients with a contra-indication to glycoprotein 2b/3a blockade were excluded. Patients with severe heart failure or cardiogenic shock (Killip class III or IV) and patients who were on haemodialysis were also excluded. The protocol was approved by each institution's Review Board or Ethical Committee. Before transportation, oral informed consent was obtained for all patients by either a physician or a specialised ambulance nurse. The day after the angioplasty procedure, written informed consent was requested.

Study protocol
The double-blinded study design is depicted in Fig. 1. Before transportation, all patients received an intravenous bolus of 5000 IU unfractionated heparin together with 250 mg of aspirin intravenously. Randomisation was to an IV bolus of Tirofiban (Merck & Co., Inc., Whitehouse Station, NJ, USA, 10 µg/kg) followed by a maintenance infusion (0.15 µg/kg/min) or an IV bolus and infusion of placebo. Randomisation (in blocks per institution) was accomplished by selecting sealed study drug kits in sequential order.



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Fig. 1 Design of the study.

 
Emergency transportation was performed after pre-informed arrival of the patient at the catheterisation laboratory. At coronary angiography, the initial injection was used to assess TIMI flow of the IRV. After coronary angiography, but before angioplasty, all patients received a second bolus of study drug intravenously (Tirofiban in case of initial treatment with placebo and placebo in case of initial treatment with Tirofiban). After this second bolus of study drug, all patients were treated with open label Tirofiban (maintenance infusion, 0.15 µg/kg/min) for 24 h. Post-PCI, all patients were treated with Clopidogrel (300 mg loading dose followed by 75 mg daily for one month), aspirin, ß-blockade, statin therapy and ACE-inhibition.

Enrolling PCI centres were experienced interventional cardiology centres. Recruitment and randomisation in the ambulance was initiated only after a period of training in pre-hospital infarct diagnosis and care for at least six months.

Definitions
Presentation delay was defined as the time from symptom-onset to infarct diagnosis (first ECG). Indoor-Outdoor Time was defined as the time from infarct diagnosis to start of transportation. Pre-treatment time was defined as the time between the first bolus of active study drug and first balloon inflation. Total ischaemic time was defined as time from symptom-onset to first balloon inflation.

Bleeding complications were closely monitored clinically and by serial determinations of haemoglobin. Special observation of the catheter insertion site for prolonged bleeding or hematoma was performed. Major bleeding was defined as a fall in haemoglobin of >=2.0 mmol/l and the need for transfusion of two or more units of blood, corrective surgery or both, or as bleeding that resulted in documented intra-cranial or retro-peritoneal haemorrhage. Minor bleeding was defined as a fall in haemoglobin of >=2.0 mmol/l without the need for a transfusion. A further specification was made in coronary artery bypass grafting (CABG) related and non-CABG related major and minor bleeding. Total death from all causes was recorded. Recurrent MI was defined as a new increase in creatinine kinase (CK)-MB fraction of more than three times the upper limit of normal, whether accompanied by chest pain and/or ECG changes and present in two separate blood samples or not.

Angiographic core laboratory
All angiographic parameters were analysed by an independent core-lab (Diagram Zwolle, The Netherlands) and scored by one observer who was unaware of randomisation or outcome data. According to the protocol of the core-lab, 10% of angiograms were routinely evaluated by a second independent observer. In this study, a random sample of 56 (11%) films were reviewed, and agreement for pre-PCI TIMI flow was present in 54/56 angiograms (96%). For the entire cohort, doubt was present in 12 cases (2,5%) and a second observer reviewed the film after which consensus was reached in all cases. The IRV was selected based on electrocardiographic localisation of ischaemia and angiographic appearance of the lesion. Judgement of IRV flow was made on the initial contrast injection according to the TIMI classification.12 Successful angioplasty was defined as a less than 50% diameter stenosis and TIMI 3 flow of the IRV. Intra-coronary thrombus was defined as the presence of an intra-luminal non-calcified central filling defect or lucency surrounded by contrast material seen in multiple projections, or the persistence of contrast material within the lumen.13 In the case of an abrupt total occlusion of the IRV, without the presence of thrombus as defined above, the lesion was scored as a fresh occlusion. Corrected TIMI frame count and myocardial blush grade were defined as previously described.14,15 Pre-PCI myocardial blush grade was assessed using the same criteria as defined for post-PCI evaluation.


    Statistical analysis
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 Abstract
 Introduction
 Methods
 Statistical analysis
 Results
 Discussion
 Limitations
 Conclusion
 References
 
Sample size calculation
The primary hypothesis of the trial was that pre-treatment with Tirofiban will increase the incidence of TIMI grade 3 flow at initial angiography prior to PCI, compared to placebo. As the entrance criteria, concomitant therapy, and primary end-point for the trial were similar to those in the GRAPE trial,9 it was expected that pre-treatment with Tirofiban would result in an increase in TIMI 3 flow from 10% to 20%. With 80% power, and an of 0.05, 438 patients were needed to show a significant difference in the incidence of the primary end-point. To account for drop-outs and false positive infarct diagnoses in the ambulance, we planned to stop the study after inclusion of 500 patients.

The effect of Tirofiban pre-treatment on each TIMI flow component, on the presence of thrombus or fresh occlusion at initial angiography and on pre-PCI myocardial blush grade were secondary end-points.

Final analysis
The primary efficacy variable and all other non-continuous angiographic variables were analysed using the test or Fisher exact test. The TIMI frame count and other continuous variables were analysed using analysis of variance or the Mann–Whitney U test (time variables). For subgroup analyses, continuous variables were divided into two categories, with the 50th percentile set as the cut-off point. Risk stratification was based upon the previously described TIMI risk criteria.16 A patient was defined as high risk if the TIMI risk score was three or higher. Odds ratios and 95% confidence intervals (CIs) were calculated. Because of the small number of patients with blush grade 3 pre-PCI, the combined incidence of blush grades 2 and 3 was reported. All patients were analysed, including those who never received the drug, or in whom the procedure could not be performed, according to the intention-to-treat principle. All significance testing and confidence intervals were two-sided.


    Results
 Top
 Abstract
 Introduction
 Methods
 Statistical analysis
 Results
 Discussion
 Limitations
 Conclusion
 References
 
From June 2001 to November 2002, 507 patients were randomised to either pre-hospital initiation of Tirofiban (Early group, ) or to cath-lab initiation of Tirofiban (Late group, ). Baseline characteristics are described in Table 1. Two hundred and fifty-eight patients (51%) were transported from referral hospitals and 209 (41%) were diagnosed and included in the ambulance. 40 patients (8%) were included at the emergency department of one of the PCI centres. During the study period, the ambulance organisation screened 354 eligible patients, from which 209 were randomised (59%). Patients were excluded because of older age (), late presentation (), use of oral anti-coagulation medication (), Killip class2 (), contra-indication to Tirofiban (), coma (), a very short distance to the PCI centre (), doubt about the infarct diagnosis () or for other reasons ().


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Table 1 Baseline and angiographic characteristics

 
No differences in time delays between the groups were present (Table 2). Pre-treatment time was a median of 59 min longer (range 11–178 min) in the Early group patients as compared to patients in the Late group.


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Table 2 Time delays

 
In 14 patients (3%), a false positive infarct diagnosis was made, most often due to misinterpretation of the computer algorithm in the ambulance. The primary end-point could be assessed in 487 of the 493 patients (99%) with a confirmed diagnosis of acute myocardial infarction. Two patients died before angiography and no interpretation of initial TIMI flow could be made in four patients due to a missing film or poor quality of the angiogram. TIMI-3 flow was found in 19% (46/243) in the Early group and in 15% (36/244) in the Late group (). The distribution of the individual components of TIMI flow pre-PCI, the percentage of patients with combined TIMI 2 or 3 flow pre-PCI and other angiographic parameters pre- and post-PCI are described in Table 3. The odd ratios and 95% CI for TIMI 3 flow in the different subgroups are depicted in Fig. 2.


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Table 3 Angiographic outcome pre- and post-PCI

 


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Fig. 2 Odd ratios and 95% CI for TIMI 3 flow of the IRV at initial angiography.

 
At initial angiography, intra-coronary thrombus was present in 25% in the Early group and in 32% in the Late group (). The combined incidence of thrombus or fresh occlusion was present in 60% and 73% in the Early and Late group, respectively (, Table 3). A myocardial blush grade 2 or 3 pre-PCI was more often found in the patients pre-treated with Tirofiban during transportation (30% vs. 22%, ).

After initial angiography, 89% of patients underwent PCI and 3% of patients were candidates for by-pass surgery because of severe three-vessel disease. The remainder of the patients (8%) were treated conservatively. PCI was successful in 90% and 91% in the Early and Late group, respectively. Stents were used in 73% of patients, with no significant difference between the groups (Early, 72%, vs. Late, 74%, ). No difference in myocardial blush grade or TIMI frame count post-PCI was observed between the groups. In 7% (36/490) of patients an intra-aortic balloon pump was inserted because of pump failure and/or severe three vessel or left main disease.

In Table 4, angiographic outcome is described according to initial TIMI flow, myocardial blush grade or the presence or absence of thrombus. Patients with TIMI 0 or 1 flow, or with myocardial blush grade 0 or 1 pre-PCI, had significantly lower blush grades and higher frame counts after PCI compared to patients with initial TIMI 2 or 3 flow or MBG 2 or 3.


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Table 4 Angiographic outcome after PCI according to initial TIMI flow, initial myocardial blush grade or the presence or absence of thrombus or fresh occlusion

 
Thirty day- and one-year follow-up were available in 492 (97%) and 489 (96%) patients, respectively, and is described in Table 5. Fifteen patients withdrew informed consent most often on the second day of admission, when written confirmation of acutely given oral consent was requested. At 30-day follow-up, 11 patients had died (2.2%); 9 patients in the Early group (3.7%), and two in the Late group (0.8%, ). Major bleeding occurred in 44/492 patients (9.0%) from which 25 events (57%) were blood transfusions related to the CABG procedure. No differences in bleeding were observed between the groups. No intra-cranial bleeding event occurred during treatment with Tirofiban.


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Table 5 Clinical outcome at short and long-term follow-up

 
At one-year follow-up, mortality was no longer different between the Early and Late groups (4.5% vs. 3.7%, respectively, ) and the combined incidence of death, or re-MI was present in 7.0% of patients in both groups.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Statistical analysis
 Results
 Discussion
 Limitations
 Conclusion
 References
 
This study showed that the initiation of Tirofiban at a median of 59 min before angiography, did not significantly improve initial TIMI 3 flow, as compared to placebo pre-treatment. Although analysis of the secondary end-points showed that early initiation of Tirofiban was associated with a significantly better patency (TIMI 2 or 3 flow), a significantly lower thrombus load, and a better MBG before PCI, no difference in post-PCI angiographic or clinical outcome was found when compared to the patients who received Tirofiban only a few minutes before PCI.

Comparison with other studies
The ADMIRAL study showed that most of the beneficial effect of Abciximab (a chimeric mouse-human monoclonal antibody directed against the glycoprotein 2b/3a receptor) was obtained when the 2b/3a blocker was given before arrival in the hospital in the ambulance, whereas there was little or no effect when the Abciximab was given in the cath-lab.17 In the On-TIME trial this hypothesis was further evaluated: all patients received a 2b/3a blocker before PCI, half of them received Tirofiban at the pre-hospital phase and half of them in the cath-lab, shortly before PCI. However, the spectacular benefit associated with early initiation, as found in ADMIRAL, could not be reproduced in our study.

Two smaller studies had the same design as On-TIME and found conflicting results. One found a significantly higher TIMI 3 flow rate in patients who received Tirofiban in the emergency room a median of 26 min earlier than the group who received Tirofiban in the cath-lab.18 The other study did not find a benefit in initial TIMI 2 or 3 flow (52% vs. 48%) when Abciximab was administered in the ambulance.19 However, both these studies were small (2x50 patients) and lacked adequate power calculation.

Possible explanation for lack of significant difference
One possible explanation for the lack of efficacty of Tirofiban in improving TIMI 3 flow may be the fact that Tirofiban, in the dose given in this study (10 µg/kg bolus, 0.15 µg/kg/min maintenance infusion) was inadequate. Although this dosage is higher than that used in the PRISM-PLUS study, studies on the inhibition of platelet aggregation show that, particularly shortly after administration, inadequate inhibition of platelets is present.20 It took at least 2 h before platelet inhibition was at the desired level of 90–95%. In our study, Tirofiban was given a median of 59 min before angiography, which therefore might not be sufficient. In the subgroup analysis in Fig. 2, there is indeed a trend towards better efficacy when the drug is given for more than 60 min before angiography. Using this theory, one would expect even greater insufficiency of platelet aggregation inhibition in the group of patients, who received Tirofiban only a few minutes before PCI. This control group of patients, however, did very well, with a high incidence of post-PCI TIMI 3 flow and normal myocardial blush and a very favourable clinical outcome.

Pre-PCI myocardial re-perfusion
In this study, we also evaluated the effect of pre-treatment with Tirofiban on the extent of myocardial perfusion before PCI. The myocardial blush grade pre-PCI was assessed using the same criteria as has been described to evaluate post-PCI re-perfusion.15 Early initiation of Tirofiban was associated with a higher incidence of myocardial blush grade 2 or 3 as compared to late initiation. In the entire study population, TIMI 2 or 3 flow was present in 38% of patients, whereas myocardial blush grade 2 or 3 was present in only 26% of patients, again showing that epicardial patency is not equivalent to myocardial re-perfusion. Pre-PCI MBG turned out to be a relatively strong predictor of post-PCI angiographic outcome (Table 4).

Is an open IRV before PCI that important?
It is known that a high-thrombus load may negatively influence the outcome of PCI and is associated with a high risk of no-reflow or distal embolisation.21–23 The better pre-PCI epicardial and myocardial re-perfusion and the reduced presence of thrombus, however, did not improve outcome post-PCI. No difference in TIMI flow, MBG or frame count was found between the groups after PCI. This finding is consistent with previous trials, which studied the effect of pre-treatment or PCI facilitation on outcome. In the PACT, LIMI, PRAGUE-1 and the recently presented BRAVE trial, no improvement in angiographic outcome post-PCI was observed, despite a significantly higher initial patency rate.24–27 Similarly, after the early administration of aspirin and heparin, no difference in angiographic outcome was observed, despite an 11% higher absolute patency rate (31% vs. 20%) at the initial angiogram.28 In our study, a better angiographic outcome after PCI only became apparent when analysis was performed according to initial patency, MBG or according to the presence or absence of thrombus or fresh occlusion, reflecting a 100% absolute difference in patency. It is probable that primary PCI remains very effective, despite a completely occluded IRV before angiography: only a 5% absolute difference (6% relative difference) in success of the PCI was found between patients with an occluded IRV, as opposed to patients who present with an open IRV (Table 4). This explains the lack of difference in mortality between low risk patients who present with an open IRV as compared to patients who present with an occluded IRV.29 Therefore, it is highly optimistic to expect a difference in angiographic or clinical outcome when a relatively small difference in initial patency is found as in our trial.

Clinical outcome
Overall clinical outcome was very good in this study. Thirty day and one year mortality was 2.2% and 4.1%, respectively. Although very high-risk patients were excluded, 16% had signs of heart failure on admission and 44% of patients had a TIMI risk score of 3 or higher, which is comparable to most studies which included patients eligible for thrombolysis. The short time to treatment, particularly in the patients recruited in the ambulance, might have attributed to this observation, as it was recently shown that `every minute counts', also in patients treated with primary angioplasty.30

At 30-day follow-up, a significantly higher death rate was found in the Early group. This is probably due to a combination of chance, especially with the low mortality rate as found in this study, and a borderline non-significantly higher age (63 vs. 61 years, ). The difference in mortality was unexpected, also because no difference in post-PCI angiographic outcome was found between the groups. Both TIMI flow and MBG after PCI are important predictors of clinical outcome. At one-year follow-up, the difference in mortality was no longer present. Again, it should be emphasised that this study was not designed to detect a difference in angiographic or clinical outcome. According to the data of Stone et al.,7 more than 10000 patients are needed to detect an absolute 1% mortality benefit associated with a 20% difference in initial patency.

Risk of intra-cranial bleeding
No patient had an intra-cranial bleeding during treatment with Tirofiban. In DANAMI-2 and PRAGUE-2, in which no pre-treatment (besides aspirin and heparin) during transportation was given, primary PCI was associated with a more favourable clinical outcome than on-site thrombolysis.4,5 This was partly due to a lower rate of intra-cranial bleeding in the patients who underwent primary angioplasty. A recent overview showed that 11 intra-cranial bleeding episodes per 1000 patients treated are prevented by primary angioplasty compared to thrombolysis.31 One should be aware not to lose part of the beneficial effect of primary angioplasty by pre-treating patients at high risk of (intra-cranial) bleeding, such as elderly female patients, especially when a combination of 2b/3a inhibition and reduced dose thrombolysis is given.32


    Limitations
 Top
 Abstract
 Introduction
 Methods
 Statistical analysis
 Results
 Discussion
 Limitations
 Conclusion
 References
 
This study excluded very high-risk patients (elderly patients, patients with renal failure or cardiogenic shock, or patients with contra-indication for 2b/3a therapy). Therefore, the study findings may not be extrapolated to patients of this category. Future studies on facilitated PCI should focus on the high-risk population, which may specifically benefit from an open IRV before PCI.29


    Conclusion
 Top
 Abstract
 Introduction
 Methods
 Statistical analysis
 Results
 Discussion
 Limitations
 Conclusion
 References
 
A median of 1 h of pre-treatment with Tirofiban did not significantly improve TIMI 3 flow of the IRV at initial angiography. Despite an improved patency (TIMI 2 or 3 flow), a lower prevalence of thrombus, or fresh occlusion, and a better myocardial perfusion in the infarct-related region pre-PCI, no beneficial effect on post-PCI angiographic or clinical outcome was found, as compared to initiation of Tirofiban in the catheterisation laboratory, a few minutes before PCI.

On-TIME Committee members

Writing Committee: A.W.J. van't Hof, M.J. de Boer, F Zijlstra.

Steering Committee: M.J. de Boer, E. Boersma, A.J. van Boven, R. Buirma (Non-Voting member), J. Dille, A.W.J. van't Hof, R.J. de Winter.

Co-ordinating Centre: Diagram BV, Zwolle, The Netherlands.

Clinical Event Committee: N. Ernst, VAWM Umans.

Angiographic Core Laboratory: D. Amo, Diagram, Zwolle, The Netherlands.

Statistical Analysis: E. Boersma, E. Kolkman.

Ambulance Co-ordinators: F. Hollak (Ambulance Dienst Regio IJssel Vecht), F. de Pooter (Ambulance Dienst Regio Noord West Veluwe).

Referral Centre Co-ordinators: T. Bouwmeester (Winschoten), R. Brons (Meppel), R. Dijkgraaf (Harderwijk), W. Jap (Apeldoorn), M.J. de Leeuw (Assen), A. Mosterd (Amersfoort), C. Oei (Heerenveen), J. Saelman (Hoogeveen).

PCI Centre Co-ordinators: The Netherlands: J.M. ten Berg (Nieuwegein), A.J. van Boven (Groningen), J.H.E. Dambrink (Zwolle), R.J. de Winter (Amsterdam); Italy: S. Petronio (Pisa).Investigators (in order of numbers enrolled):

The Netherlands: F. Hollak, Ambulance dienst RAV IJssel Vecht, Zwolle (173). W. Jap, Gelre Ziekenhuizen, locatie Juliana, Apeldoorn (86). R. Dijkgraaf, St. Jansdal Ziekenhuis, Harderwijk (52). C. Oei, Ziekenhuis "de Tjongerschans", Heerenveen (39). F. de Pooter, RAD Nw. Veluwe, Elburg (37). J.H.E. Dambrink, Isala klinieken, Zwolle (23). M.J. de Leeuw, Wilhelmina Ziekenhuis, Assen (22). J. Saelman, Bethesda ziekenhuis, Hoogeveen (19). T. Bouwmeester, Sint Lucas Ziekenhuis, Winschoten (15). P. Hoogslag, Diaconessenhuis, Meppel (13). R.J. de Winter, AMC, Amsterdam (11). A. Mosterd, Algemeen Christelijk Ziekenhuis Eemland, Lokatie de Lichtenberg, Amersfoort (11).

Italy: G. Amorose, Ospedale di Cisanello, University Hospital, Pisa (6).


    Acknowledgments
 
This study was supported with an educational grant from Merck & Co.


    Footnotes
 
1 10.1016/j.ehj.2004.04.010 Back


    References
 Top
 Abstract
 Introduction
 Methods
 Statistical analysis
 Results
 Discussion
 Limitations
 Conclusion
 References
 

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