Introduction. * Corresponding author. Tel: þ ; fax: þ address:

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1 European Heart Journal Supplements (2005) 7 (Supplement K), K36 K40 doi: /eurheartj/sui076 A quantitative analysis of the benefits of pre-hospital infarct angioplasty triage on outcome in patients undergoing primary angioplasty for acute myocardial infarction Arnoud W.J. van t Hof 1 *, Henri van de Wetering 2, Nicolette Ernst 1, Frans Hollak 2, Frank de Pooter 3, Harry Suryapranata 1, Jan C.A. Hoorntje 1, Jan-Henk E. Dambrink 1, Marcel Gosselink 1, Felix Zijlstra 1, and Menko-Jan de Boer 1 on behalf of the On-TIME study group 1 Isala Klinieken, Department of Cardiology, Locatie Weezenlanden, Zwolle, The Netherlands 2 Ambulance Service Region IJsselvecht, The Netherlands 3 Region Noord West Veluwe, The Netherlands KEYWORDS Acute myocardial infarction; Primary angioplasty; Pre-hospital care; Reperfusion Primary coronary angioplasty has been shown to be a very effective reperfusion modality in patients with acute myocardial infarction (MI). However, the time from diagnosis to therapy is often very long, often due to interhospital transfer of the patient. This study evaluates the effect of improving logistics by early infarct diagnosis in the ambulance (ambulance group) and subsequent transportation to a percutaneous coronary intervention (PCI) centre without visiting a nearby non-pci clinic (referred group). Pre-hospital infarct diagnosis and triage in the ambulance (n ¼ 209) were compared with triage at a referral non-pci centre (n ¼ 258) in patients included in the On-TIME (Ongoing Tirofiban In Myocardial infarction Evaluation) study. Baseline characteristics of the two patient groups did not differ significantly, with the exception of a higher prevalence of males in the ambulance group. The ambulance group had a significantly shorter time to treatment (177 vs. 208 min; P, 0.01), a higher initial patency rate (44 vs. 35%; P ¼ 0.045), a better extent of myocardial reperfusion (myocardial blush grade 3: 59 vs. 47%; P ¼ 0.02), a trend toward a higher prevalence of aborted MI (15 vs. 10%; P ¼ 0.08), and a significantly lower rate of death or re-mi at 1 year of follow-up (3 vs. 10%; P ¼ 0.004). It was concluded that early, pre-hospital infarct diagnosis in the ambulance with immediate transportation to the nearest PCI centre is associated with a shorter time to treatment and improved angiographic and clinical outcomes compared with referral from a non-pci centre in patients who are candidates to undergo primary angioplasty for acute MI. Introduction Primary coronary angioplasty has been shown to be a very effective reperfusion modality in patients with acute * Corresponding author. Tel: þ ; fax: þ address: v.r.c.derks@isala.nl myocardial infarction (MI), 1,2 even when additional transport is necessary to a percutaneous coronary intervention (PCI) centre. 3 The decision that a patient is a candidate for transportation to a PCI centre, together with the arrangement of ambulance transport (so called indoor outdoor time), often takes considerable time. In DANAMI 2 (Danish Trial in Acute MI-2), it took a median & The European Society of Cardiology All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 Early triage in acute myocardial infarction K37 of 45 min to decide and arrange referral to the PCI centre, despite the ideal logistic in which the presenting ambulance waited for the decision to transfer. 4 This extra delay might be prevented by pre-hospital infarct diagnosis and triage, in which patients who are candidates for primary angioplasty are immediately transported to the PCI centre. This study compares pre-hospital infarct diagnosis and triage in the ambulance with triage at a referral non-pci centre in patients included in the On-TIME (Ongoing Tirofiban In Myocardial Infarction Evaluation) study a multicentre, placebo-controlled, randomized trial to address the issue of early initiation of tirofiban in patients transferred to undergo primary coronary angioplasty. Forty-one per cent of patients included in On-TIME was randomized in the ambulance after computerized infarct diagnosis. Methods The design, inclusion criteria, and exclusion criteria of the On-TIME study have been described previously. 5 In brief, patients were eligible if they had chest pain for.30 min, together with.0.2 mv (anterior MI) or 0.1 mv (non-anterior MI) of ST-elevation in two contiguous echocardiogram (ECG) leads. Primary angioplasty could be performed within 6 h of the start of symptoms. Patients aged.80, women aged,50, patients who were treated with thrombolytic therapy in the previous 24 h, those receiving warfarin or acenocoumarol within the last 7 days, and those with a contraindication to glycoprotein (GP) IIb/IIIa 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 from all patients by either a physician or a specialized ambulance nurse. The day after the angioplasty procedure, written informed consent was requested. Patients were randomized to either early (before transportation) or late (in the catheterization laboratory) initiation of tirofiban. Emergency transportation was performed after preinformation of arrival of the patient at the catheterization laboratory. Enrolling PCI centres were experienced interventional cardiology centres. Recruitment and randomization in the ambulance were initiated only after a period of training in prehospital infarct diagnosis and care for at least 6 months. Computer diagnosis in the ambulance was made on the basis of a fixed algorithm, which has been described previously. 6,7 Time to diagnosis was defined as the time from symptom onset to infarct diagnosis (first ECG); transportation delay was defined as the time from randomization to arrival at the PCI centre; and total ischaemic time was defined as the time from symptom onset to first balloon inflation. All angiographic and electrocardiographic parameters were analysed by an independent core laboratory (Diagram Zwolle, The Netherlands) and scored by one observer who was unaware of randomization or outcome data. Cumulative ST-segment deviation was defined as the sum of ST-elevation and depression from all 12 ECG leads, as measured 60 ms after the J-point. ST-segment elevation resolution was calculated as described previously. 8 Before transportation, all patients received 500 mg of aspirin and 5000 IU of unfractionated heparin intravenously. Post-PCI, all patients were treated with clopidogrel (300 mg loading dose followed by 75 mg daily for 1 month), aspirin, betablockade, statin therapy, and angiotensin-converting enzyme inhibition. Follow-up was assessed via a planned 30-day visit at the outpatient department and a planned telephonic interview at 1 year. Total death from all causes was recorded. Aborted MI was defined as prolonged chest pain with typical evolutionary ECG changes, coupled with an unstable coronary lesion on the angiogram but without a rise in creatine kinase (CK) of.3 times the upper limit of normal (ULN). Recurrent MI was defined as a new increase in the CK-myocardial bound fraction of more than three times ULN, whether accompanied by chest pain and/or ECG changes, and present in two separate blood samples. Statistical analysis Statistical analysis was performed with the SPSS 10.0 statistical package. All non-continuous angiographic variables were analysed using the x 2 test or Fisher s exact test. Continuous variables were analysed using the analysis of variance or Mann Whitney U test (time variables). Risk stratification was based on the previously described thrombolysis in MI (TIMI) risk criteria. 9 Because of the small number of patients with myocardial blush grade (MBG) 3 pre-pci, the combined incidence of MBG 2 and 3 was reported. Results In the On-TIME study, 40 patients (8%) were randomized at an emergency room of one of the PCI centres, 258 patients (51%) were transported from referral hospitals (referred group), and 209 patients (41%) were diagnosed in the ambulance (ambulance group). The latter two groups form the basis of this report. Baseline characteristics did not differ significantly between the groups with the exception of a greater proportion of males in the ambulance group (Table 1 ). Total ischaemic time was significantly shorter in patients recruited in the ambulance. The percentage of patients who underwent balloon inflation within 2 h of the onset of symptoms was significantly higher in patients after triage in the ambulance (Table 2 ). Patients recruited in the ambulance more often had a patent (TIMI 2 or 3 flow) infarct-related vessel at initial angiography and a higher rate of coronary bypass grafting as initial reperfusion modality. Angiographic and clinical outcomes are described in Table 3. The rate of TIMI 3 flow after PCI did not differ between the two groups, but the percentage of patients with MBG 3 was significantly higher in patients recruited in the ambulance than those in the referred group (59 vs. 47%; P ¼ 0.02). Aborted MI was present in 15% of the ambulance group and in 10% of the referred group (P ¼ 0.08). The combination of death/recurrent MI or stroke at 30 days of follow-up occurred in 4.0% of the referred group, when compared with 2.0% of the ambulance group. At 1 year of follow-up, death or recurrent MI occurred in 10.4% of referred patients vs. 3.4% of patients recruited in the ambulance (P ¼ 0.004). Table 4 shows the effect of

3 K38 Arnoud W.J. van t Hof et al. Table 1 Characteristics and treatment of patients included in the study Baseline Referred group (n ¼ 258) Ambulance group (n ¼ 209) Age (years + SD) Male gender (%) 77 (198/258) 85 (177/209) Diabetes (%) 9 (22/257) 13 (26/208) Hypertension (%) 29 (75/257) 26 (53/208) Smoking a (%) 66 (165/251) 64 (131/205) Anterior MI (%) 46 (115/251) 46 (90/194) Previous MI (%) 10 (25/256) 7 (14/208) Previous CABG (%) 1.6 (4/257) 2.4 (5/208) Previous PCI (%) 4.3 (11/257) 5.8 (12/208) Killip class.1 b (%) 16 (36/233) 19 (35/188) TIMI risk score.3 (%) 42 (108/258) 46 (96/209) Electrocardiographic Cumulative ST-elevation (mm + SD) Cumulative ST-deviation (mm + SD) Angiographic Multivessel disease c (%) 59 (133/226) 51 (101/198) Pre-PCI TIMI 2,3 d (%) 35 (88/253) 44 (86/195) Treatment PCI (%) 90 (228/254) 87 (179/206) CABG (%) 1.6 (4/254) 5.3 (11/206) Other (%) 8.7 (22/254) 7.8 (16/206) CABG, coronary artery bypass grafting; LM, left main. a Current or previous smoking. b Defined as systolic blood pressure,100 mmhg or heart rate.100 beats per min. c Two- or three-vessel disease or LM disease. d TIMI risk score as described by Morrow et al. 9 Table 2 Time delays Referred group Ambulance group Time to diagnosis a 105 (62 149) 75 (48 131) Time to randomization 23 (15 32) 28 (23 34) NS Transportation delay 45 (38 56) 20 (15 26),0.001 Ischaemic time b 208 ( ) 177 ( ),0.001 Percentage treated within 2 h of symptom onset 7% (16/232) 23% (47/203),0.001 Median in minutes (25 75 percentiles). a Time from symptom onset to infarct diagnosis (first electrocardiogram). b Time from symptom onset to first balloon inflation. early initiation of tirofiban in the two different groups. In patients recruited in the ambulance, a significantly higher initial patency was found in patients pre-treated with tirofiban. The effect on thrombus reduction was also most evident in patients who received tirofiban early in the ambulance. Discussion This study showed that patients in whom infarct diagnosis and triage are made in the ambulance and who are immediately transferred to the PCI centre have a shorter time to treatment and a more favourable outcome than patients who are triaged and referred from a non-pci centre. It shows that further streamlining of logistics, in which an unnecessary visit to a non-pci centre is prevented, saves time and may lead to improved patient outcome. The results show that, in particular, presentation delay is shorter in patients who are diagnosed in the ambulance. Of the ambulance patients, 23% underwent angioplasty within 2 h of the onset of symptoms compared with only 7% of patients who were referred from other centres (P, 0.001). In addition, the ambulance group showed a higher initial patency. This shorter time to treatment, together with a higher initial recanalization rate, is probably the reason for the higher number of patients with an aborted MI in the ambulance group.

4 Early triage in acute myocardial infarction K39 Table 3 Aborted infarction, angiographic, electrocardiographic, and clinical outcomes Referred group Ambulance group Aborted MI a (%) 10 (24/246) 15 (31/204) 0.08 Angiographic outcome post-pci TIMI 3 (%) 91 (209/230) 91 (161/177) MBG 3 (%) 47 (106/225) 59 (104/177) Clinical outcome at 30 days Death (%) Re-MI (%) Death/re-MI (%) Clinical outcome at 1 year Death (%) Re-MI (%) Death/re-MI (%) a Defined as prolonged chest pain with typical evolutionary electrocardiographic changes, coupled with an unstable coronary lesion on the angiogram but without a rise in creatine kinase of more than three times the upper limit of normal. Table 4 Effects of early (pre-transportation) or late (catheterization laboratory) administration of tirofiban. Initial patency Early (n ¼ 130) Late (n ¼ 128) Referred group Pre-PCI (%) TIMI 2,3 (%) 36 (47/129) 33 (41/124) 0.57 MBG 2,3 (%) 27 (34/128) 22 (27/122) 0.42 Post-PCI TIMI 3 (%) 88 (102/116) 94 (107/114) 0.12 Early (n ¼ 103) Late (n ¼ 106) Ambulance group (n ¼ 103) (n ¼ 106) Pre-PCI TIMI 2,3 (%) 52 (50/97) 37 (36/98) 0.04 MBG 2,3 (%) 36 (33/92) 22 (21/97) 0.03 Post-PCI TIMI 3 (%) 92 (78/85) 90 (83/92) 0.72 The finding that patients diagnosed and triaged in the ambulance have a higher initial patency than those transferred from a non-pci centre was also reported in a previous study. 7 The very early administration of aspirin and heparin might be the reason for the higher recanalization rate in these patients. From Table 4, it is also clear that the early administration of tirofiban is more effective in patients recruited in the ambulance, possibly because the occlusive thrombus is less organized when the patient is treated early after the onset of symptoms. In thrombolytic trials, the concept of increased effectivity with shorter duration of symptoms is well recognized and is known as the golden hour ; this concept might explain the better outcome seen in patients treated with pre-hospital thrombolysis than in those given thrombolysis in hospital. 10 Myocardial reperfusion With regard to epicardial reperfusion, no difference in post-pci TIMI 3 flow was seen between the two groups. However, the rate of normalized myocardial blush (MBG 3) was significantly higher in the ambulance group than in the referred group, suggesting that, in particular, myocardial reperfusion was better in this group of patients. This is probably due to the shorter time to treatment in this group, as previous studies have shown that ischaemic time is an independent predictor of the extent of myocardial reperfusion. 11,12 Clinical implications The most recent version of the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the treatment of patients with STelevation acute MI (STEMI) state that a pre-hospital 12- lead ECG should be made by Advanced Cardiac Life Support providers in all patients suspected of STEMI (class IIa, level of evidence B) and that all patients with a high risk of dying should immediately be transferred to the PCI centre (class IIa, level of evidence B). 13 The study reported here shows that the implementation of these guidelines might further improve outcome, merely by reducing time to treatment, especially in those patients at high risk of adverse events. These high-risk patients, in particular, might benefit from a further reduction in time to treatment. 14 Limitations This study is not a randomized comparison between triage in the ambulance and triage at a referral centre. It would no longer be ethical to conduct such a trial as this would mean that treatment delay would deliberately be increased in one arm. In the ambulance group, total ischaemic time was significantly shorter than in the referred group, but the shorter transportation time in this group could have been a contributory factor.

5 K40 Arnoud W.J. van t Hof et al. Referred patients travelled a median of 41 km to the PCI centre, whereas ambulance patients were transported a median of 24 km. It is difficult to differentiate which part of this reduced transportation distance is due to improved logistics and which is due to a possible shorter distance to the PCI centre. Conclusions In patients who are candidates for primary angioplasty for acute MI, pre-hospital infarct diagnosis and triage is associated with shorter time to treatment, a higher initial patency, and better angiographic and clinical outcomes after PCI compared with triage and referral from a non-pci centre. All efforts should, therefore, be made to implement pre-hospital infarct diagnosis, triage, and therapy in the care of patients with an acute MI. Acknowledgement This study was supported by an unrestricted grant from Merck & Co., USA. We wish to thank all ambulance personnel for their contribution to this study. Conflict of interest: The On-TIME trial was supported by an unrestricted grant from Merck & Co., USA. Dr van t Hof has received speaker fees for various presentations about the results of the trial. Appendix I Members of the On-TIME study group 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. Ambulance Coordinators: F. Hollak (Ambulance Dienst Regio IJssel Vecht), F. de Pooter (Ambulance Dienst Regio Noord West Veluwe). Referral Centre Coordinators: 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 Coordinators: 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). References 1. Zijlstra F, Hoorntje JCA, de Boer MJ et al. Long-term benefit of primary angioplasty as compared with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1999;341: Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361: Dalby M, Bouzamondo A, Lechat P et al. Transfer for primary angioplasty versus immediate thrombolysis in acute myocardial infarction: a meta-analysis. Circulation 2003;108: Andersen HR, Nielsen TT, Rasmussen K et al. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003;349: van t Hof AW, Ernst N, de Boer MJ et al. 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. Eur Heart J 2004;25: Grijseels EW, Bouten MJ, Lenderink T et al. Pre-hospital thrombolytic therapy with either alteplase or streptokinase. Practical applications, complications and long-term results in 529 patients. Eur Heart J 1995;16: Ernst NMSKJ, de Boer MJ, van t Hof AWJ et al. Pre-hospital triage for angiography-guided therapy for acute myocardial infarction. Netherlands Heart J 2004;12: van t Hof AW, Liem A, de Boer MJ et al. Clinical value of 12-lead electrocardiogram after successful reperfusion therapy for acute myocardial infarction. Zwolle Myocardial infarction Study Group. Lancet 1997;350: Morrow DA, Antman EM, Charlesworth A et al. TIMI risk score for ST-elevation myocardial infarction: a convenient, bedside, clinical score for risk assessment at presentation: an intravenous npa for treatment of infarcting myocardium early II trial substudy. Circulation 2000;102: Boersma E, Akkerhuis M, Simoons ML. Primary angioplasty versus thrombolysis for acute myocardial infarction. N Engl J Med 2000;342: van t Hof AW, Liem A, Suryapranata H et al. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade. Zwolle Myocardial Infarction Study Group. Circulation 1998;97: De Luca G, van t Hof AW, de Boer MJ et al. Time-to-treatment significantly affects the extent of ST-segment resolution and myocardial blush in patients with acute myocardial infarction treated by primary angioplasty. Eur Heart J 2004;25: ACC/AHA Guidelines for the management of patients with ST-elevation myocardial infarction-executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 Guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol 2004;44: De Luca G, Ernst N, Zijlstra F et al. Preprocedural TIMI flow and mortality in patients with acute myocardial infarction treated by primary angioplasty. J Am Coll Cardiol 2004;43: