Received July 2, 2002;
accepted July 3, 2002
Correspondence: Petr Widimsk
, MD., PhD., FESC., Cardiocenter Vinohardy,
robárova 50, 100 34 Prague 10, Czech Republic.
Abstract
Background Primary percutaneous coronary intervention (PCI) is shown to be the most effective reperfusion strategy in acute myocardial infarction. The aim of this multicentre national randomized mortality trial was to test whether the nationwide change in treatment guidelines (transportation of all patients to PCI centres) was warranted.
Methods The PRAGUE-2 study randomized 850 patients with acute ST elevation myocardial infarction presenting within <12 h to the nearest community hospital without a catheter laboratory to either thrombolysis in this hospital (TL group, n=421) or immediate transport for primary percutaneous coronary intervention (PCI group, n=429). The primary end-point was 30-day mortality. Secondary end-points were: death/reinfarction/stroke at 30 days (combined end-point) and 30-day mortality among patients treated within 03 h and 312 h after symptom onset. Maximum transport distance was 120 km.
Results Five complications (1.2%) occurred during the transport. Randomizationballoon time in the PCI group was 97±27 min, and randomizationneedle time in the TL group was 12±10 min. Mortality at 30 days was 10.0% in the TL group compared to 6.8% mortality in the PCI group (P=0.12, intention-to-treat analysis). Mortality of 380 patients who actually underwent PCI was 6.0% vs 10.4% mortality in 424 patients who finally received TL (P<0.05). Among 299 patients randomized >3 h after the onset of symptoms, the mortality of the TL group reached 15.3% compared to 6% in the PCI group (P<0.02). Patients randomized within <3 h of symptom onset (n=551) had no difference in mortality whether treated by TL (7.4%) or transferred to PCI (7.3%). A combined end-point occurred in 15.2% of the TL group vs 8.4% of the PCI group (P<0.003).
Conclusions Long distance transport from a community hospital to a tertiary PCI centre in the acute phase of AMI is safe. This strategy markedly decreases mortality in patients presenting >3 h after symptom onset. For patients presenting within <3 h of symptoms, TL results are similar results to long distance transport for PCI.
Key Words: Acute myocardial infarction thrombolysis long distance transport coronary intervention coronary angioplasty stent
Introduction
Direct coronary angioplasty as the primary reperfusion therapy for acute myocardial infarctionwas first described by Meyer1 and Hartzler2 in 19823. Ten years later three randomized studies showed the superiority of primary angioplasty over thrombolysis when used within the same period after onset of symptoms.35 This was also confirmed by a meta-analysis of additional trials.6Currently there is no doubt that primary percutaneous coronary intervention (primary PCI) results in markedly lower in-hospital mortality79 anddecreased risk of reinfarction and stroke.310 However, the use of primary PCI as the treatmentof choice for all patients with acute myocardial infarction and ST segment elevations has notbecome routine. The explanation is complex:difficulties in the logistics of such an approach, large variation in PCI results between high- vs low-volume centres9,11 and the possible deleteriouseffects of substantial treatment delay on myocardial salvage and resulting left ventricular function.1214
The safety and feasibility of interhospital transportation of patients with acute myocardial infarction presenting initially to smaller hospitals without PCI facilities to the tertiary PCI centres was investigated by the LIMI study in the Netherlands15 and by the PRAGUE-1 study in the Czech Republic.16 Both these studies clearly proved the safety and feasibility of the transport and both had the same direction of results: transport for primary PCI was superior to immediate thrombolysis in the first hospital, and the combination strategy (thrombolysis during transport) was intermediate (inferior to transport alone, superior to thrombolysis alone). Transportation decreased the incidence of the combined clinical end-point (death/reinfarction/stroke at 30 days). Thus, immediately after the PRAGUE-1 study we started preparing for a much larger nationwide trial, with 30-day mortality as the only primary end-point: the PRAGUE-2 trial. The aim was to compare intravenous streptokinase vs immediate transport for primary PCI in patients with ST elevation myocardial infarction, admitted to hospitals without PCI facilities in the Czech Republic, where distance between primary hospitals and tertiary PCI centres does not exceed120 km.
Methods
The study protocol has been approved by the local ethical committees of all participating centres. The local ethical committee of the coordinating centre expressed concerns about the safety of long distance transport (i.e. not performing immediate thrombolysis) specifically in patients presenting within the initial 3 h after symptom onset. Thus, the committee required repeat interim reports about mortality to ensure that whenever a significant difference in favour of any group occurred the study would be stopped prematurely.
Infrastructure
The coordinating site was at the Cardiocenter,University Hospital Vinohrady, Prague, which was also one of the seven participating PCI centres. For at least 6 months before the start of the study inall seven PCI centres primary PCI was the only reperfusion strategy used in all patients presenting from their respective primary care region (these PCI centres had completely stopped using thrombolysis in their routine treatment of patients with acute myocardial infarction). Forty-one community hospitals without catheterization facilities were the primary sites. Patients were enrolled here into the study immediately after their initial ECG and after obtaining informed consent (Fig. 1).
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Examinations and follow-up
Complete clinical examination with ECG was performed on days 1, 2, 3, at discharge and on day 30. Echocardiography was performed at discharge and on day 30. Coronary angiography was performed in the PCI group immediately on arrival at the PCI centre. In the TL group (as well as any repeat angiography in the PCI group) it was performed according to routine clinical indication: postinfarction angina pectoris, reinfarction, rescue PTCAafter failed thrombolysis. Further 1-year follow-up is under way, but is not the subject of this paper.
Study end-points and definition
The primary end-point was mortality at 30 days. It was defined as death from any cause within 30 days after randomization. The secondary end-point was the presence of any serious clinical event (death/non-fatal reinfarction/non-fatal stroke) at 30 days. Furthermore, according to the suggestion of the ethical committee (see above), the 30-day mortality among subgroups of patients treated within 03 h and 312 h after symptom onset was added as a secondary end-point.
Stroke was defined as any new neurologic deficit lasting >24 h. Reinfarction was defined as recurrent symptoms of ischemia with new electrocardiographic changes and a rise in CK-MB. Optimal procedural success was defined as TIMI-3 flow and <30% stenosis after the intervention. Partial success (suboptimal result) was defined as TIMI-2 flow and/or >30% residual stenosis.
Statistic assessment
The calculated sample size was based on theexpected mortality rates, similar to those in the PRAGUE-1 study. The target sample size was thus planned for 1200 patients. Microsoft Excel andSystat software were used for the database and chi-square was used for the statistical analyses of the differences between the two groups.
Results
Study termination
The study was stopped prematurely by the ethical committee. The reason was 2.5-fold excess mortality in the TL group among patients treated after >3 h from symptom onset. The committee considered thrombolytic treatment without transportation to the PCI centre no longer justified in this subset of patients (i.e. those treated between312 h after symptom onset). There was also an increasing reluctance in the primary community hospitals to randomize the patients into the thrombolytic arm. These hospitals were increasingly asking for routine transportation of all patients with ST elevations during the study period.
Complications during transport
Four hundred and twenty-five patients (99%) in the PCI group were transported immediately after randomization to the PCI centre. The remaining four patients (1%) were not transported due to rapid haemodynamic deterioration into profound cardiogenic shock soon after randomization. All fourpatients were resuscitated and received thrombolysis, three of them died within the initial 24 h. They are analysed within the PCI group, based on the intention-to-treat principle. The distancesbetween primary hospitals and PCI centres varied between 5120 km. There were two deaths and three ventricular fibrillations (successfully treated with defibrillation in the emergency ambulance car, their further course was uneventful) during the transport (i.e. complications during the transport occurred in 1.2%).
The time delays and hospital stay
The treatment delays and transport time intervals are listed in Table 4and Fig. 2. The mean hospital stay duration in the TL group was 13±5 days and in the PCI group 11±4 days (P<0.05).
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Secondary end-points
Among 299 patients randomized after >3 h (mean5 h and 6 min) from symptom onset, the mortality was 15.3% in the TL group vs 6.0% in the PCI group (P<0.02). Among 551 patients randomized within<3 h (mean 1 h and 41 min) of symptom onset, the mortality was similar in both groups (7.4% inthe TL group vs 7.3% in the PCI group) (Fig. 4). The combined clinical end-point (death/reinfarction/stroke) occurred in 64 TL group patients (=15.2%) vs 36 PCI group patients (=8.4%, P<0.003). There were 13 (=3.1%) non-fatal reinfarctions in the TL group vs six (=1.4%) in the PCI group (ns). Non-fatal stroke occurred in nine (=2.1%) TL patients vs one (=0.2%) PCI patient (P<0.03).
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Left ventricular function
The mean echocardiographic left ventricular ejection fraction at 30 days was 51±9% in the TL group vs 50±8% in the PCI group (ns).
Discussion
Thirty-day mortality in the PCI group was almost exactly as expected based on the PRAGUE-1 study results (7%). However, mortality in the TL group was lower than expected 13%. Thus, the overall difference did not reach statistical significance. Nevertheless, the trend in favour of PCI strategy is clear. These data show a trend similar to that of DANAMI-2,30 where the mortality difference was smaller, possibly due to use of t-PA instead of streptokinase.
The first 3 h of myocardial infarction
The results showed no harm from transport-related delays in the subgroup of early presenters but did show a 2.5-fold increase in mortality among late presenters treated by thrombolysis. This is similar to the PCAT meta-analysis.17 These studies support the strategy of primary PCI for every patient for whom PCI is available with only a short delay, compared to thrombolysis (i.e. short transport distances or primary admissions to PCI centres) and for every patient (even with a need for long transport distance) presenting after >3 h from symptomonset. Thrombolysis should be reserved only for those patients presenting within <3 h from symptom onset, with long, timely access to primary PCI. The study results do not show a difference between thrombolysis and PCI among patients with a presentation time <3 h, but this is not a statistical proof of equivalence; it would require a much larger study.
Patients presenting between 312 h after the onset of symptoms
The high mortality among TL group patients presenting after >3 h confirms the previous experience,14,27 that thrombolysis is much less effective in these late presenters, while the effectivity of primary PCI is equal to the early presenters. The German MITRA/MIR registries showed no significant difference in mortality rates between primaryangioplasty and thrombolysis for prehospital delays of <3 h. However, when pre-hospital delay was>3 h, thrombolysis was independently associated with a higher mortality rate compared with primary angioplasty.18 Thus, the results of these studies support the change in the strategy for the late presentersroutine transfer for primary PCI should be the first choice. This is in accordance with the recent meta-analysis PCAT.17
Safety of transport in the acute phase of myocardial infarction
Several non-randomized observational reports1922 and two mentioned randomized trials15,16 confirmed the feasibility and safety of transporting patients with acute myocardial infarction to tertiary centres for primary (or rescue) coronary angioplasty. There is a little doubt now, that the interhospital transport of patients with ST elevation acute myocardial infarction does not present any additional risk for the patient. What is the maximal distance for transport, for which thebenefit of primary PCI will be offset by such an extensive time delay, that on-site thrombolysis will remain the preferable strategy? The published data are controversial in this respect. There is enough evidence that ischaemic time is related to infarct size and clinical outcome.2326 However, whiledelayed thrombolysis offers only very limitedpotential benefit to the patient,28 primary PCI performed later (i.e. between 312 h from the onset of symptoms) has a similar success rate and similar clinical outcome as in patients presenting within<3 h.2729
Role of centreloperator experience
The variation among seven PCI centres was 8797% for success rate and 2.8%9.1% for in-hospital mortality among non-study patients. This reflects mainly the differences in routine decision making: the centres with lower mortality tended to exclude some really terminally ill cardiogenic shockpatients or some elderly patients, while the centres with higher mortality rates do perform primary PCI in every patient without any age or terminal phase limits. However, the variation was relatively small and the results of all seven centres were similar among the study patients (where these differences could not have any influence, because the patients were randomized in other hospital). This is different from our previous experience16 and reflects the increasing workload of the PCI centres in the Czech Republic during the last 5 years, when primaryPCI became more frequent than thrombolysis as reperfusion therapy in the entire country.
Pharmacologic treatment before/after primary PCI
Another limitation of this study is that the thrombolytic arm was represented by streptokinase rather than more potent thrombolytic agents. Streptokinase was used because it is the routine treatment of myocardial infarction in the Czech Republic. However, the use of a more potent thrombolytic would probably not substantiallyaffect the main results of the study (the difference between tPA and streptokinase could be hardly expected in a population of 421 patients in the TL group). In the recently presented DANAMI-2 trial tPA was used and the study was also terminated prematurely due to the convincing clinical benefit in the PCI group.30
Implications for the current practice
The data favouring primary PCI as the best available reperfusion strategy for patients with acute myocardial infarction are sound. The change in clinical practice should be considered in three directions: (1) Patients with ST elevations in areas with PCI availability within 2030 min of transport time should always be transported directly from the emergency car/helicopter to the catheterization laboratory (avoiding delays in the small hospitals or emergency departments of the large hospitals). (2) When PCI cannot be started within 60 min of the ECG diagnosis, thrombolysis should be usedbut only for patients presenting within <3 h of symptom onset. The usefulness of immediate angiography/intervention routinely after thrombolysis in these patients remains to be established. And finally (3) all patients presenting between 312 h from symptom onset should be transported for primary PCI and thrombolysis should not be used in this subset of patients. The data from this study together with data from other randomized trials and myocardial infarction registries should be brought together and a modification of guidelines may be considered.
Appendix
The complete list of investigators
PCI centres (number of patients randomized to the PCI group in the respective cooperating primary community hospitals): Investigators
Cardiocenter, University Hospital Vinohrady, Prague (110 patients): Petr Widimský, MD., DrSc., FESC., (principal investigator of the study).Tomá Bud
ínský, MD., David Vorá
, MD. (Junior research coordinator of the study), JaroslavDvo
ák, MD., Ji
í Krupi
ka, MD., Libor Lisa, MD, Radovan Jirmá
, MD., Pavel Gregor, MD., DrSc., FESC., Rudolf
pa
ek, MD., PhD, Zbynek Straka, MD, PhD.
Cardiovascular Department I, University Hospital St. Anne, Brno (147 patients): Ladislav Groch, MD., Ivan Horá
ek, MD., Ota Hlinomaz, MD., Jan Sitar, MD., Libor Nechvátal, MD.
Cardiocenter, Hospital Podlesí, Tinec (72patients): Marian Branny, MD., Igor Nykl, MD., Ivo Varva
ovský, MD., Jind
ich
erný, MD., MarekRichter, MD.
Cardiology Clinic IKEM, Prague (45 patients): Michal elízko, MD., PhD., Bronislav Janek, MD., PhD., Ji
í Kettner, MD., PhD., Vladimír Karmazín, MD.
Cardiocenter, University Hospital Hradec Králové (35 patients): Josef t'ásek, MD., Pavel
ervinka, MD., Du
an
ernohorský, MD., Miroslav Brtko, MD., Vladimír Rozsíval MD., PhD., Ale
Herman, MD., PhD.
Cardiology Department, Hospital Na Homolce, Prague (15 patients): Pavel Formánek, MD., Petr Kmoníek, MD., Ond
ej Aschermann, MD.
Medical Department II, General University Hospital, Prague (5 patients): Michal Aschermann, MD., DrSc., Stanislav imek, MD., Ale
Linhart,MD., PhD., Franti
ek Holm, MD., Jan B
lohlávek, MD.
Community hospitals (with total randomizedpatients) and investigators (all are MD)
Tebí
(62 patients): Josef
tumar, Ji
í Carda, Ond
ej Toman, Pavel R
i
ka, Petr Kone
ný. Vy
kov (59 patients): Josef Veselý, Old
ich Synek, Franti
ek Adamec, Vladimír Foret, Ji
í Pinka.Nymburk (57 patients): Arno
t Václaví
ek, David Vencour, Michal Hudcovic, Pavel Fri
, Radka Sytarová, Hana
irová, Václav Hulínský. Haví
ov (57 patients): Miloslav Dur
ák, Eva Pederzoliová.Ivan
ice (49 patients): Petr Vale
, Miroslav
ech. Kutná Hora (42 patients): Venu
e
mejkalová, Alena Kadle
ková, Dana Ry
avá. Slaný (42patients): Gabriel Marcínek, Ond
ej
ermák, Jan Mácha. Mladá Boleslav (38 patients): Ji
í Kotou
, Tomá
Kubí
ek, Zbyn
k Ko
ek. Vala
ské Mezi
í
í (37 patients): Pavel Prod
lal, Marie Lí
eníková, Richard Wiesner. Vsetín (34 patients): Jaroslav Doubravský, Ji
í Ludva, Petr Palacký, RadmilaBohá
ová. Ti
nov (29 patients): Jaroslav Vykou
il, Jaroslav Svoboda. Havlí
k
v Brod (24 patients): Josef Málek, Ji
í
tefánek. Krom
í
(24 patients): Lumír Francek, Pavel T
e
tík. Chrudim (23patients): Josef Tuhý, Dalibor Ka
ík, MichalWysocki. Vyso
any (22 patients): Eva Kosová, Jan Kaufman. Uherské Hradi
t
(21 patients): Vladimír Okénka, Vladimír Klapal. Svitavy (20 patients): Ivana Kellnerová, Emilie Smr
ková. Bene
ov (19 patients): Václav Havlik, Martin Otava. Ho
ovice (17 patients): Eduard Kroupa. Pardubice (16patients): Marek Sychra. Roudnice nad Labem (14 patients): Ilona Ka
íková. B
eclav (14 patients): Jitka Siegelová. Boskovice (14 patients): Marie Lý
ková. FrýdekMístek (14 patients): Tomá
Gistinger. Brandýs nad Labem (13 patients):Richard Kobza. Tábor (12 patients): Jind
ichCharouzek. Louny (9 patients): Jan Semrád. Ji
in (nine patients): So
a Zají
ková. Liberec (7patients): Ji
í Kot'átko. Beroun (7 patients): Karel Sochor. Karviná (6 patients): Jan Bolek. NovýByd
ov (6 patients): Lud
k Beran. Jihlava (6patients): Zden
k Klimsa. Na Franti
ku (6patients): Ivo Jokl. Turnov (5 patients): Old
ich Honc
. Military Hospital Brno (5 patients): Tomá
Brabec. Military Hospital PragueSt
e
ovice (5patients): David Ru
ka.
eská Lípa (3 patients): Zden
k Holý. Na
i
kové (1 patient): Zden
k Felix. Kladno (1 patient): Ji
í Povolný. T
inecSosna (1 patient): Jan Bohá
.
Acknowledgments
The authors express thanks to the physicians, nurses and technicians of participating catheterization laboratories, coronary care units, community hospitals and regional emergency medical services.
Footnotes
* Appendix lists the investigators.
The study was partly supported by the project of MMT
R nr. 111200004.
References
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