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European Heart Journal Advance Access originally published online on September 20, 2007
European Heart Journal 2007 28(20):2438-2448; doi:10.1093/eurheartj/ehm369
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Transfer with GP IIb/IIIa inhibitor tirofiban for primary percutaneous coronary intervention vs. on-site thrombolysis in patients with ST-elevation myocardial infarction (STEMI): a randomized open-label study for patients admitted to community hospitals

Slawomir Dobrzycki1, Pawel Kralisz1,*, Konrad Nowak1, Przemyslaw Prokopczuk1, Waclaw Kochman1, Janusz Korecki2, Boguslaw Poniatowski2, Jerzy Zuk1, Ewa Sitniewska1, Hanna Bachorzewska-Gajewska1, Jerzy Sienkiewicz3 and Wlodzimierz J Musial2

1 Department of Invasive Cardiology, State Teaching Hospital, Medical University of Bialystok, Sklodowskiej 24a, 15-276 Bialystok, Poland
2 Department of Cardiology, State Teaching Hospital, Medical University of Bialystok, Poland
3 Department of Statistics and Medical Informatics, Medical University of Bialystok, Poland

Received 27 November 2006; revised 25 July 2007; accepted 3 August 2007; online publish-ahead-of-print 20 September 2007.

* Corresponding author. Tel: +48 857468496; fax +48 85 7468828. E-mail address: paqral{at}yahoo.com


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 Funding
 Acknowledgements
 References
 
Aims: Our study aimed to compare two reperfusion strategies in patients with ST-elevation myocardial infarction (STEMI) admitted initially to a community hospital without catheterization facilities.

Methods and results: Four hundred and one patients with STEMI admitted to community hospital (13 hospitals, radius 20–150 km from cath-lab) were randomized to on-site thrombolysis or to transport with tirofiban (10 µg/kg bolus i.v. + i.v. infusion 0.1 µg/kg/min) for primary PCI in single invasive centre. Primary endpoints were total mortality, recurrent MI (re-AMI), and stroke during 1 year follow-up. Delay to reperfusion defined as interval between admission and start of fibrinolysis or primary PCI was 35 and 145 min (P < 0.0001). Mean time of tirofiban administration to PCI in transfer group was: 122.3 ± 35.7 min. Mortality was not different during hospitalization and at 30th-day, with trend towards lower mortality at 1 year in transport group (12.5 vs. 7.0%, P = 0.061). There were no differences in the rate of re-AMI and stroke, with trend towards lower incidence of re-AMI in transfer group at 1 year (7.5 vs. 3.5%, P = 0.073). Composite of death/re-AMI/stroke was higher in on-site group during follow-up (15.5 vs. 8.0%, P = 0.019; 21.5 vs. 11.4%, P = 0.006, respectively, at 30th-day and 1 year).

Conclusion: Outcomes at 1 year follow-up suggest that transportation with adjunctive therapy with GP IIb/IIIa inhibitor tirofiban for primary PCI is superior to on-site thrombolysis for patient with STEMI presenting to hospital without catheterization facilities.

Key Words: ST-elevation myocardial infarction • Primary PCI • Thrombolysis • Transfer • Platelet GP IIb/IIIa • Tirofiban


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 Funding
 Acknowledgements
 References
 
Primary percutaneous coronary intervention (PCI) is currently the preferred reperfusion treatment in ST-elevation myocardial infarction (STEMI).1 However, the majority of patients present initially to hospitals without catheterization facilities. In this situation, there are two treatment options: rapid transfer to a tertiary centre for primary PCI or on-site fibrinolytic therapy. It has been demonstrated that primary PCI is superior to on-site thrombolysis even when transport to an angioplasty centre is necessary.2 Present guidelines underline that the time delay from symptom onset to treatment and the volume of procedures performed in PCI centre are essential in making a decision as to which strategy is to be applied.3,4

The delay of onset of primary angioplasty and prolonged ischaemia leading to necrosis caused by transportation may diminish the benefits of this strategy over thrombolysis.5 It seems to be the issue especially when the expected transfer time is long. Early restoration of infarct-related blood flow before primary PCI is associated with improved outcome.6 Treatment with GP IIb/IIIa inhibitors for transportation for primary PCI, with the potential to improve baseline blood flow in infarct-related artery (IRA), may be the option to hold the advantage of primary PCI in AMI treatment.7

The current study is a multi-centre prospective, randomized, open-label study to evaluate the impact of two reperfusion strategies on early and long-term outcomes in patients with STEMI admitted to a community hospital.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 Funding
 Acknowledgements
 References
 
Patients
Patients with STEMI, presented initially to a participating community hospital without primary PCI capabilities, were randomly assigned to on-site thrombolytic therapy or to transportation for primary PCI with adjunctive therapy with tirofiban. Thirteen participating hospitals are located in a radius of 20–150 km from the cath-lab. All primary PCI were conducted in the coordinating invasive centre in Bialystok.

Inclusion criteria
Inclusion criteria were patients with STEMI (typical chest pain >30 min, ST-elevation of Pardee wave type of ≥0.1 mV in at least two contiguous ECG leads and/or ≥0.2 mV in precordial leads) presented within 12 h of the onset of symptoms, age <80 years.

Exclusion criteria
Exclusion criteria were inability to give written informed consent, contraindications to fibrinolytic therapy, severe renal or hepatic failure, previous CABG, left bundle branch block in ECG recording.

Patients in cardiogenic shock were not randomized and were obligatorily transferred and treated with primary angioplasty.

Study protocol
Evaluation of eligibility for the study was performed by a physician in the hospital of admittance who subsequently contacted the coordinating centre by telephone. The consecutively enrolled patients were randomized to treatment groups in accordance with our database computer randomization programme. It took into account sex, age, and MI localization in ECG recording. Qualified patients (fulfilled criteria according to protocol) were described as male or female, < 50 years or 50–65 years or 65–75 years or >75 years, with anterior or other infarct. Each patient included in the study and characterized by pre-specified features was automatically coupled by the same consecutive patient in the other group, thus quickly providing an optimal balance between the two groups.

Patients assigned to transfer for primary PCI received heparin (fixed dose bolus i.v. 5.000 IU) and tirofiban (bolus i.v. of 10 µg/kg followed by i.v. infusion at a dose of 0.1 µg/kg/min) as soon as the randomization had been completed, tirofiban was continued during transportation, during PCI and after the procedure. There was no additional heparin for transport until the cath-lab, where, after ACT measurement before PCI, heparin was given (if needed) to keep the ACT at least at 300–350 s.8 Heparin was restarted in i.v. maintaining infusion after repeated measurement on average 4 h after procedure. It was maintained during tirofiban administration with APTT target value 70 s verified every 6–12 h. It was recommended to administer tirofiban at least 8 h after PCI procedure. We did not utilize LMWH during tirofiban administration. PCI was performed via the femoral artery with standard 6F catheters. PCI was performed even if the patient had clinical resolution of ischaemia and TIMI grade 3 flow on initial angiography with significant stenosis in IRA.

Stent implantation was encouraged and recommended. Ticlopidin or clopidogrel was given in case the stent was implanted. The arterial sheath was removed when APTT was <45 s after procedure and then heparin was restarted during tirofiban administration.

Patients assigned to fibrinolysis received a lytic drug in the hospital of admission. The study protocol did not define which drug had to be administered: the fibrinolytic was part of the admitting hospital’s standard of care. It was advised to administer LMWH (fraxiparine) if streptokinase was utilized or unfractionated heparin (UFH) if together with fibrin-specific lytic. Fibrinolytic treatment was initiated at the emergency room (ER) or the intensive cardiac care unit.

All patients in both groups received 325 mg of aspirin orally. Additional treatment was administered at the discretion of the physician. Rescue angioplasty was recommended if there was no resolution of ST-elevation and/or no pain resolution 2 h after lytic administration. Recurrent ischaemia in on-site group during hospitalization was treated invasively in the coordinating centre. However, in either case, the final decision on transfer to PCI centre was at the discretion of the physician in the admitting hospital.

The study was aimed to evaluate the reperfusion treatment in all hospitals in our region, so as to select and adopt the best strategy to a given clinical situation. Therefore, there was a second separate simultaneous randomization: for patients from Bialystok municipal hospitals (in a radius of less than 20 km). In this arm, all patients with STEMI were treated with primary angioplasty and were randomized to groups with and without tirofiban during PCI. In the first group, tirofiban was given according to the modified design: bolus i.v. of 10 µg/kg + infusion 0.4 µg/kg for the first 30 min + infusion at a dose of 0.1 µg/kg/min. The analysis of this part of our programme will be the subject of separate publication. Study design is shown in Figure 1.


Figure 1
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  		Figure 1 Design of the entire study. Grey bars correspond to the presented data.

 
The protocol of the study was approved by the local Bioethical Committee. Before randomization, written informed consents were obtained for all patients by a physician in the hospital of admittance.

Monitoring and follow-up
The exact times of presentation, evaluation, interhospital transportation, delay to treatment, and detailed timing of PCI were noted.

Major and minor bleeding was classified according to TIMI criteria.9

Recurrent MI was defined as a new increase in creatinine kinase of at least 50% of the prior value or of more than two times the upper limit of the normal value, accompanied by new ECG changes and/or chest pain recurrence. Stroke was defined as any new neurologic deficit lasting >24 h, and computed tomography was mandatory for stroke confirmation during index hospitalization.

Follow-up clinical examinations were performed in the outpatient clinic of the PCI coordinating centre at discharge, on the 30th day, and finally after 1 year.

Endpoints
The primary endpoints were total mortality, recurrent MI, and stroke during 1 year follow-up. The secondary endpoints were composite of death/re-AMI, death/re-AMI/stroke, and length of hospital stay (LOS).

Statistical analysis
The study was performed in accordance with an intention to treat (ITT) principle which is based on the initial treatment intent, not on the treatment eventually administered. Thereby assigned treatment was considered to have been received if thrombolytic therapy was initiated in patients assigned to thrombolytic therapy and if tirofiban and transfer was initiated with or without successive PCI in patients assigned to transfer for PCI. Based on assumed incidence of the primary endpoint (mortality) of 10% in on-site group and 5% in transfer group, sample size was estimated of 435 patients in each group to achieve 80% power to detect a difference between the group proportions of 0.05. The test statistic used is the two-sided Z test with pooled variance. The endpoint data were available in all randomized patients. Results are expressed as mean ± SD for normally distributed variables. Time intervals were reported as medians (lower Q1 and upper Q3 quartiles). The independent and the paired-samples two-sided t-tests were used to compare normally distributed continuous variables and Mann–Whitney U and the Wilcoxon signed-rank two-sided tests were used for not normally distributed. Differences in proportions were evaluated with {chi}2 or Fisher’s exact test. For mortality and composite endpoint, we presented Kaplan–Meier curves and results of log-rank tests. Results were considered to be statistically significant if P < 0.05. Analyses were done with SPSS (version 13.0). Thirty days and 1 year relative risk with two-sided asymptotic 95% CIs on proportions for primary and composite endpoints was calculated. Analyses were done with Review Manager 4.2.10.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 Funding
 Acknowledgements
 References
 
Baseline characteristics of the patients
During the study, from 1 February 2002 to 11 November 2003, a total of 476 STEMI patients were assessed for inclusion into the study. Four hundred and one patients were randomly assigned to either fibrynolytic treatment (on-site group, n = 200) or transfer for PCI with adjunctive therapy with tirofiban (transfer group, n = 201). A baseline clinical characteristic of both groups is presented in Table 1.


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  		Table 1 Baseline characteristics of the patients

 
Treatment
In 10 patients (four in on-site group and six in transfer group), the diagnosis of STEMI was false positive. All patients in on-site group received thrombolytic therapy—in all cases it was streptokinase. All patients in transfer group received tirofiban. Catheterization for primary PCI was not performed in one patient who died in the cath-lab of the invasive centre and in one patient who withdrew his consent in the invasive centre, after transfer, due to temporary resolution of ischaemic symptoms. PCI was not performed in 10 patients out of 199 who underwent catheterization. Of these three patients had MI confirmed by typical increase in necrotic enzymes and no significant stenosis in coronary arteries, and one patient received intracoronary thrombolysis (alteplase) due to thrombus in left main and left anterior descendent artery with TIMI 3 flow (Figure 2).


Figure 2
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  		Figure 2 Flow of community hospital patients through the trial.

 
The baseline flow in the IRA according to TIMI classification in transfer group is presented in Figure 3. Stent was implanted in 75.7% coronary interventions in transfer group. The procedural success (defined as TIMI flow 3 and residual stenosis <50%) was reached in 95.2% (180/189 coronary interventions).


Figure 3
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  		Figure 3 Flow in the infarct related artery according to TIMI classification in the transfer group (n = 199).

 
The pharmacological treatment at discharge differed with regard to ACEI assignment (Table 2).


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  		Table 2 Medications at hospital discharge

 
Time intervals
Majority of the patients in both groups were admitted within 3 h from MI onset (<2 h 48 vs. 55.7%, P = 0.12; <3 h 69.5 vs. 76.1%, P = 0.14;<4 h 81.5 vs. 85.6%, P = 0.27; in on-site and transfer groups, respectively). Delay to reperfusion was defined as interval between admission and the start of fibrinolysis or primary PCI after transport. All relevant time intervals are presented in Table 3. Forty-nine patients (24.4%) in transfer group had time between first medical contact and PCI below 90 min. Total time of tirofiban administration was 21.4 ± 7.9 h. The decision to prematurely stop the infusion was made on generally accepted indications (predominantly bleeding complications) or in those patients with false positive MI diagnosis with no significant stenosis.


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  		Table 3 Time intervals in study patients

 
Study endpoints
Early, 30 days and 1 year follow-up was completed for all patients (Table 4). In 7 patients in on-site group and 4 patients in transfer group, the information on 1 year follow-up was obtained by telephone. During hospitalization 17 (8.5%) patients died in on-site group vs. 9 patients (4.5%) in transfer group (P = 0.075). Mortality was not different between the two groups at 30th-day follow-up (9.0 vs. 5.0%, P = 0.113) with the trend towards lower mortality at 1 year follow-up in transfer group (12.5 vs. 7.0%, P = 0.061). There were no significant differences in the rate of re-AMI and stroke between the groups during the study, although there was a trend towards lower incidence of re-AMI in transfer group at 1 year follow-up (7.5 vs. 3.5%, P = 0.073). The composite of death/re-AMI/stroke was significantly higher in on-site group throughout the follow-up (15.5 vs. 8.0%, P = 0.019; 21.5 vs. 11.4%, P = 0.006, respectively, for on-site group and transfer group at 30th-day and 1 year follow-up). Patients randomized to transfer had a reduced hospital stay: 9.7 ± 4.3 days vs. 14.1 ± 5.5 days, P < 0.0001. Figure 4 shows 30-day mortality in transfer subgroups created with time delay from admission to start of reperfusion as a cut-off value. Figures 5 and 6 show results of pre-specified subgroup analyses of mortality and composite endpoint during 30-day and 1 year follow-up. Figure 7 shows the Kaplan–Meier curves for the mortality and event free survival.


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  		Table 4 Clinical outcome during hospitalization and at follow-up

 

Figure 4
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  		Figure 4 Thirty-day mortality in transfer subgroups created with time delay from admission to start of reperfusion as a cut-off value. PCI < 90 min, PCI >90 min, PCI < 145 min and PCI >145 min indicate transfer subgroups with 90 min (delay in accordance with the guidelines) and 145 min (median delay in transfer group) from admission to start of invasive reperfusion in transfer group, respectively.

 

Figure 5
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  		Figure 5 Relative risk (95% coronary intervention) for (A) mortality and (B) composite endpoint during 30-day follow-up.

 

Figure 6
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  		Figure 6 Relative risk (95% coronary intervention) for (A) mortality and (B) composite endpoint during 1 year follow-up.

 

Figure 7
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  		Figure 7 Kaplan–Meier estimates in on-site and transfer groups for (A) survival and (B) event-free survival (freedom from death, re-MI, stroke).

 
Complications during transfer
All patients randomized to transport were transferred to PCI centre. There was one ventricular fibrillation in emergency ambulance during transportation and two ventricular fibrillations in the ER of PCI centre. All these events were successfully treated with defibrillation. There was one death (mechanical dissociation of the heart) in cath-lab before the start of catheterization. There were two bleeding complications that required cessation of tirofiban; they were analysed as bleeding complications during hospitalization in transfer group.

Bleeding
Major bleeding during hospitalization occurred in 4 (2%) patients in on-site group and in 4 (2%) patients in transfer group (relative risk 1.01; 95% CI 0.25–4.08). In on-site group, three patients experienced a stroke due to intracranial hemorrhage (including one fatal stroke), one patient required blood transfusion due to gastrointestinal bleeding. In transfer group, there was one fatal tamponade and three blood transfusions due to gastrointestinal bleeding (one patient), and puncture site bleeding (two patients). Minor bleedings in on-site vs. transfer group were 13 (6.5%) vs. 8 (4.0%) (relative risk 1.63; 95% CI 0.69–3.85).

Non-protocol cardiac procedures
During index hospitalization, non-protocol catheterization was performed in 22 patients in on-site group and in 9 patients in transfer group (P = 0.015). The indications for catheterization were: (i) in on-site group, recurrence of ischaemia with ECG changes (13 patients), failure of thrombolysis (6 patients), recurrent MI (2 patients), other (1 patient); (ii) in transfer group, recurrent MI (5 patients; of these 4 patients due to acute stent thrombosis and 1 patient who initially withdrew consent for catheterization), recurrence of ischaemia with ECG changes (3 patients), other (1 patient). Non-protocol PCI was performed in 14 patients in on-site group compared with 6 patients in transfer group (P = 0.065). At 30-day follow-up, unscheduled catheterization was performed in 33 patients (16.5%) in thrombolytic group and in 10 patients (4.97%) in transfer group (P = 0.0002).

At 1 year, catheterization was performed in 86 (43%) vs. 27 (13.4%) patients (P < 0.0001), PCI procedures in 57 (28.5%) vs. 22 (11%) patients (P < 0.0001), coronary artery bypass surgery in 12 (6%) vs. 6 (3%) patients in on-site group vs. transfer group, respectively (P = 0.145).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 Funding
 Acknowledgements
 References
 
The purpose of our study was to evaluate the reperfusion therapy in our region. Thus, we intended to rationalize and justify the routine referral of all patients with STEMI for invasive treatment. In our centre, we started 24 h/7-day invasive treatment of STEMI patients in 1999. At the beginning, patients were referred from hospitals of Bialystok. In the next stage, we expanded the area of transfer to community hospitals located in the whole region (up to a radius of 150 km from the invasive centre). Based on retrospective data, we realized that transfer delays were disturbingly long and pre-treatment with potential to compensate for treatment delay was mandatory in these patients. In 1999–2001, we performed a pilot study with GP IIb/IIIa inhibitor tirofiban and we concluded that tirofiban was associated with improvement in coronary blood flow in IRA.10 Furthermore, there was some evidence that the effect of tirofiban before invasive treatment was dependent on the length of the time of drug administration.11 Therefore, we chose tirofiban as an adjunctive treatment for transferred patients in the design of the present study. Tirofiban had also an important advantage for its significantly lower cost compared with, for example, abciximab.

Meanwhile, the On-TIME trial, performed in 2001–2002 and published in 2004, found that early pre-treatment with tirofiban, despite improved patency (TIMI 2 or 3) and a better myocardial perfusion pre-PCI, had no beneficial effect on post-PCI angiographic or clinical outcome, when compared with late tirofiban administration.12 The On-TIME evaluated the hypothesis, which was first pointed out in ADMIRAL trial,13 that clinical benefit of IIb/IIIa platelet inhibitor prior to primary PCI may be dependent on time-period of drug infusion. Nevertheless, the later published pooled data of randomized trials of early (prior to transfer to the cath-lab) vs. late (at the time of PCI) administration of GP IIb/IIIa inhibitor showed significant improvement in normal coronary flow (TIMI 3) with favourable trend in mortality reduction.14

The authors hypothesized that limited efficacy of tirofiban in On-TIME trial may be explained by inadequate dosing to achieve the desired level of platelet inhibition. The hypothesis originates from the GOLD study which revealed that the extent of platelet aggregation inhibition is an independent predictor of major adverse cardiac events after PCI (MACE—death/MI/TVR). The highest risk of MACE was found in patients with suboptimal platelet inhibition measured within 10 min and 8 h after the initiation of treatment.15 In this regard, early tirofiban dosing (related to 10 µg/kg bolus) seemed to be vulnerable and remained under debate. Standard bolus of tirofiban 10 µg/kg, used in GOLD study as well as in On-Time and present study, was proved for insufficient platelet inhibition and was considered as being responsible for worse clinical outcome compared with other GP IIb/IIIa inhibitors.16 Subsequently, tirofiban with increased bolus to high-dose 25 µg/kg was found to be the most effective drug in achieving optimal early platelet inhibition,17,18 showing comparable angiographic and clinical outcome to abciximab with good safety profile.19 Nevertheless, despite favourable data, limited sample size of the studies with high-dose tirofiban performed so far do not allow for established clinical application in STEMI patients. At the same time, in accordance with GOLD study findings, maintaining infusions of tirofiban 0.15 mg/kg/min as in RESTORE trial20 or 0.1 mg/kg as in PRISM-Plus trial21 were related to comparable sufficient platelet inhibition. Therefore, in our study, we utilized maintaining infusion i.v. 0.1 mg/kg.

Abciximab trials showed enhancement in TIMI 3 in IRA along with longer time of administration (GRAPE—45 min infusion—TIMI 3 18%; SPEED—60 min infusion—TIMI 3 23%; TIMI 14–90 min infusion—TIMI 3 32%).22–24 Tirofiban trials, with smaller sample size, suggest the same rule.12,25 Total pre-treatment time with tirofiban was 79 min in the early group in On-TIME trial compared with 122 min in our study (transfer group). The rate of no-flow (TIMI 0 + 1), patent IRA (TIMI 2 + 3), was surprisingly comparable (57 vs. 56.3%; 43 vs. 43.7%, respectively, for the early group in On-TIME and the present study), and normal flow (TIMI 3) was slightly better in our study (19 vs. 26.6%). Bearing in mind the limitation of such comparison, one could suppose that evidently longer total time of tirofiban administration in our study, as compared with On-TIME study, might be responsible for the trend towards better TIMI 3 flow.

PRAGUE-2 study (streptokinase in hospital of admittance vs. immediate transport for primary PCI) reported the overall 30-day mortality as 10.0% in the thrombolytic group vs. 6.8% in the PCI group, and among ‘early presenters’ (<3 h from pain onset to admittance) 7.4 vs. 7.3%, respectively.26 Based on these results, the authors advanced a thesis, further confirmed in guidelines, that thrombolysis should be reserved for patients presenting within <3 h from symptom onset, with long, timely access to primary PCI. In our study, the overall 30-day mortality was slightly lower in both corresponding groups when compared with PRAGUE-2, and the difference, yet not statistically significant, was preserved among ‘early presenters’ (<3 h from pain onset to admittance)—8.6% in on-site group and 4.6% (relative risk 1.89; 95% CI 0.76–4.66) in transfer group. The total delay to treatment in our study (onset of symptoms to reperfusion therapy) was the same as in PRAGUE-2 study. But there were important differences that could possibly influence the outcome. First, it was the delay between administration of fibrinolytic and mechanical reperfusion with PCI. The benefit of primary PCI is lost once the delay between administration of fibrinolytic and balloon inflation during primary PCI exceeds 1 h.27 In PRAGUE-2, the difference between two treatments was 75 min and in our study it was 110 min. Therefore, one could expect the worse outcome in transfer group in our study, especially in ‘early presenters’. The important issue is that no patient received GP IIb/IIIa blocker before the intervention in PRAGUE-2 study. And if we look at TIMI-flow before PCI in transported groups, the rate of no-flow (TIMI 0 + 1), patent IRA (TIMI 2 + 3), and normal flow (TIMI 3) was in favour of patients in our study, transported with adjunctive tirofiban (69 vs. 56.3%; 31 vs. 43.7%, and 17 vs. 26.6%, respectively, for PRAGUE-2 study and present study). If we assume that tirofiban was responsible for the improvement in coronary blood flow, the results of the present study remain in line with previous findings that when reperfusion occurs before primary PCI, the outcomes are better.

On the other hand, ASSENT-4 trial revised the importance of open IRA before PCI as a major determinant of prognosis in STEMI. Full-dose tenecteplase, despite achieving increase in pre-procedural TIMI 3 flow in IRA (43% after median time 104 min), resulted in an increase in mortality, rates of re-infarction, TVR, and bleeding complications compared with PCI alone group.28 Also previous studies of facilitated PCI with thrombolytic therapy have not proved that significantly higher TIMI flow in IRA before PCI translates to a clear improvement in clinical outcome.23,29,30 The worse outcome in ASSENT-4 trial was attributed to the excess of thrombotic events, presumably induced by thrombolysis itself and/or not sufficiently prevented. Thus, ASSENT-4 trial underlined the importance of adjunctive antithrombotic treatment in periprocedural period. The occlusion of IRA due to thrombus formation is mediated primarily by platelets and specifically antiplatelet agents appear to be most important in the prevention of ischaemic events. Aspirin and clopidogrel are a must in primary PCI, and GP IIb/IIIa inhibitors, along with preventing both platelet aggregation and tissue-factor-induced thrombin generation might yield additional benefit. Although facilitated regimens of GP IIb/IIIa inhibitors alone have not shown this benefit so far, GP IIb/IIIa inhibitors seem to remain the only reasoned option for pharmacological facilitation of PCI in STEMI.31 However, the optimal dosing and timing of these drugs warrant further studies.

The rate of bleeding complications in transfer group was low and comparable with the previous studies with tirofiban.12,25 We did not utilize weight adjusted bolus of UFH; we chose the fixed dose to simplify transferring procedures. Our approach with medium dose bolus and additional UFH was supported by data by Chew et al.8 showing lower incidence of ischaemic events among patients with higher ACT values. However, this relationship has been questioned and it was shown that higher dose of UFH tends to cause more bleeding.32 If GP IIb/IIIa inhibitors are administered during PCI, both heparin dose reduction and heparin discontinuing after PCI can limit bleeding complications concurrently preserving effective antithrombotic activity.33,34

The LOS in our study was longer than usually reported in both groups. Randomized trials report mean LOS from 4.5 to 8 days in primary PCI patients and from 6 to 10 days in fibrinolytic patients.35–37 Registries, providing better insight into real life practice, show mean LOS of about 9 days.38 It must be remembered that all participating admitting hospitals in our study (with on-site group) were low volume, public, and non-profit—these are major features that contribute to lengthening the LOS. Furthermore, public funding and administrative factors in Poland, with no underlying economic pressure so far, do not favour the shortening of LOS in community hospitals.

Limitations
Our study has several limitations. First is the lytic drug used—streptokinase. Randomized trials proved t-PA-based fibrinolytics to be the most effective thus setting the standard in thrombolytic treatment. Nevertheless, streptokinase remains an alternative for many patients. In Poland, streptokinase is the prevailing fibrinolytic, mostly due to the fact that while preserving acceptable efficacy, it has incomparable lower costs. Another limitation, in view of studies published after completion of our study, is the lack of pre-treatment with clopidogrel both before fibrinolytic therapy39 and PCI.40 Furthermore, all transported patients were treated in a single invasive centre which, considering the relationship between centre characteristic and outcome, might have impact on results. Both groups differed regarding smoking status, previous AMI, and ACEI utilization and these differences were not taken into account in analysis. Finally, an important limitation is the small number of patients included in the study. We initialized the programme supported with a governmental grant and tirofiban was partly delivered free of charge by MSD, Poland. Further funding was intended to be secured by local authorities, but due to budget cuts it could not be maintained.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
Funding
 Acknowledgements
 References
 
Our study should be viewed as an endeavour to put the guidelines-recommended treatment into practice. Randomized trials proved undeniably the advantage of primary PCI over thrombolysis. Nevertheless, everyday practice yields challenges that may render this advantage impossible to reproduce. It can be overcome by adjusting available treatment as close to guidelines as possible. In our study, we proposed adjunctive treatment for transport with tirofiban and we reported that this strategy can be effective even when time of transfer is long. Outcomes at 1 year follow-up suggest that transportation with adjunctive therapy with GP IIb/IIIa inhibitor tirofiban for invasive treatment is superior to on-site thrombolysis for patients with STEMI presenting to hospital without catheterization facilities.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Funding
Acknowledgements
 References
 
The study was supported with an educational grant no. PCZ-012-22 CO-24/P05/2001 from The State Committee for Scientific Research of the Ministry of Science and Higher Education, Warsaw, Poland.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Funding
 Acknowledgements
References
 
The study was performed in the Department of Invasive Cardiology as co-ordinating centre; State Teaching Hospital, Medical University of Bialystok, Poland and in the Department of Cardiology, State Teaching Hospital, Medical University of Bialystok, Poland. Cooperating community hospitals were Voivod Hospital in Lomza, Voivod Hospital in Suwalki, community hospitals in Augustów, Dabrowa Bialostocka, Grajewo, Hajnówka, Knyszyn, Monki, Siemiatycze, Sejny, Sokólka, Wysokie Mazowieckie, Zambrów—all in the Podlasie region, Poland. The study drug tirofiban was partly delivered free of charge by MSD, Poland. We would like to extend our gratitude to physicians of community hospitals and ambulance teams for their contribution to the study.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Funding
 Acknowledgements
 References
 

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T. Huynh, S. Perron, J. O'Loughlin, L. Joseph, M. Labrecque, J. V. Tu, and P. Theroux
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