European Heart Journal (1990) 11, (Supplement F), 43-47
Pre-hospital thrombolysis, is it useful? *A. D.
CASTAIGNE, | C H . HERVE, *A.-M. DUVAL-MOUUN *J.-L. DUBOIS-RANDE AND D. LELLOUCHE
'Cardiology Department and fSAMU Necker H&pital, Paris, France
94, Hopital Henri Mondor,
tM.
GAILLARD,
Creteil and fSAMU
75,
Thrombolytic treatment efficacy is greater when the delay between onset of pain and treatment is short. One way to shorten this delay is to give treatment at home, but one cannot recommend this technique if it has not been demonstrated first, that pre-hospital thrombolysis is feasible and safe, and second, that it is useful. We have been able to demonstrate that pre-hospital thrombolysis with APSAC is feasible and safe. Our findings are similar to those of other teams using other drugs. Whether pre-hospital thrombolysis is useful has not been adequately assessed; and we consider that first, the benefit of pre-hospital vs in-hospital thrombolysis must be determined, and second, the results of a study involving many centres, with various levels of training, practicing pre-hospital thrombolysis must be examined. Two large scale studies are currently being performed. One in Seattle, uses left ventricular ejection fraction as the major end-point, whereas the other, the European Myocardial Infarction Project, (EMIP) is using total mortality. Data currently available indicate that pre-hospital thrombolysis with APSAC is feasible, easy and safe. We hope that we will very soon be able to answer the last question: is it useful?
Introduction It has been shown that thrombolytic treatment reduces early and 1 year mortality after myocardial infarction11"4'. It has been suggested in the GISSI and ISIS-2 trials that the earlier the treatment is given the greater the mortality reduction. So cardiologists are now faced with the question of how to shorten the delay between onset of pain and treatment. Education of patients and physicians seems to be one way to shorten the delay between onset of pain and contact with a team able to give thrombolytic treatment. Nevertheless, two delays remain constant: delay due to transport from home to hospital; and in-hospital delays. In order to reduce those two factors, Koren et a/.151 demonstrated that thrombolytic treatment might be given outside the hospital. In that study, the
decision to treat was made by cardiologists working in the ambulance. But cardiologists do not usually work in mobile care systems. Thus, to give treatment before admission to a coronary care unit, responsibility needs to be transferred from cardiologists to other physicians working in mobile care units. In this paper we will briefly summarize our experience with pre-hospital thrombolysis161, review other reports and discuss the usefulness of pre-hospital treatment. Hie Val-de-Marne study of pre-hospital thrombolysis
In France, physicians working in mobile care units are usually anaesthesiologists not specifically trained for cardiac emergencies. Our preliminary study was planned to assess the feasibility of pre-hospital thrombolysis. Address for correspondence: A. D. Castaigne, Hdpital We wanted to know whether anaethesiologists working in mobile care units are able to make Henri Mondor, F 94010, Creteil, France. 0195-668X/90/OF043 + 05 $03.00/0
© 1990 The European Society of Cardiology
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on April 10, 2016
KEY WORDS: Thrombolytic therapy, myocardial infarction, emergencies, mobile care unit, APSAC.
44
A. D. Castaigne et al. placebo at home; and events during the pre-hospital phase. Within 2 years, 320 patients with acute myocardial infarction were screened, and a total of 100 were included in the trial. Of those 100 patients, 57 received APSAC at home, 36 received APSAC in hospital and seven did not receive thrombolytic treatment. The reasons for this have been explained previously161. Of the 100 patients included in the trial, 88 had typical myocardial infarction, as shown by enzymatic release and ECG criteria. Two patients died between home injection (one APSAC, one placebo) and hospital arrival; they had a typical myocardial infarction, as shown by clinical and ECG criteria, complicated by cardiogenic shock. Seven patients had typical chest pain and typical ECG signs, but enzymatic elevation did not reach the upper limit of normal values. In these seven patients, the infarctrelated artery was severely stenosed and a mild hypokinesia was seen on left ventriculogram. They were treated within 75 min of pain onset; the final diagnosis was aborted myocardial infarction. For three patients, the diagnosis of recent acute myocardial infarction was ruled out. One had an old anterior infarct with left ventricular aneurysm, ventricular tachycardia, chest pain but no new myocardial infarction. One had an ischaemic cardiomyopathy, anginal pain, old ECG abnormalities but no recent myocardial infarction. One had coronary spasm with transient enzymatic release but without myocardial infarction. Finally, all of the 100 patients had an acute coronary syndrome and the decision to give them a thrombolytic treatment was not in error. As regards timing of treatment, there was an average of 65 min between onset of pain and call to the mobile care unit, an average of 12 min between call and arrival of the mobile care unit, an average of 54 min between arrival of the mobile care unit and at-home injection, and an average of 60 min between at-home and in-hospital injections for patients receiving placebo. The median delay between pain onset and at-home injection was 131 min; the median delay between pain onset and in-hospital treatment for patients receiving placebo was 190 min. The delay of 60min between at-home and in-hospital injection was analysed. Approximately 30 min were accounted for by transport
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on April 10, 2016
the correct decisions regarding thrombolytic therapy, whether pre-hospital thrombolysis delays the patient's arrival in the coronary care unit, whether pre-hospital thrombolysis is safe, and how many minutes are saved by pre-hospital treatment. The first part of our study was a simulation and education study. Over a 1-year period anaesthesiologists had to complete a form for each case of acute chest pain. The two main questions were: Was the diagnosis correct? and If thrombolytic treatment had been available in the ambulance would the physician have used it adequately? Within 1 year, 294 patients with acute chest pain possibly due to coronary artery disease were evaluated at home by an anaesthesiologist working in a mobile care unit. Among the 294 patients, 282 had either unstable angina or acute myocardial infarction and the diagnosis of acute coronary syndrome made at home was correct. Thus, the false-positive rate was low (12 out of 294). Among those 294 cases the anaesthesiologists indicated that they would have used thrombolytic treatment in 62 cases; the decision was judged correct in all the cases. At the end of this first part, it was anticipated that the risk of incorrect administration of a thrombolytic agent was very low, and a randomized trial was begun. The randomized trial compared pre-hospital thrombolysis with in-hospital thrombolysis with APSAC. Patients less than 75 years old, with typical signs of myocardial infarction and no contra-indication to thrombolytic treatment were included in the study. They were first seen by the anaesthesiologist working in the mobile care unit, and if they were eligible they were randomly assigned to the placebo or APSAC group. After receiving placebo or APSAC, patients were referred to one of the participating coronary care units where the code was broken. If the patient had received placebo at home the coronary care unit physician had to decide whether thrombolytic treatment was necessary. Coronary angiography was performed and left ventricular ejection fraction was measured within 48 h of admission. The study end points included: diagnostic accuracy; delay between phone call to emergency medical service and arrival in coronary care unit for patients included in or excluded from the trial; delay between at-home and in-hospital injection for patients having received
Is pre-hospital thrombolysis useful?
Pre-bospHal thrombolysis: other studies Pre-hospital thrombolysis has been tested by other teams. Here we examine whether these experiences help us with regard to efficacy criteria. The relevant studies have been, to our knowledge, mainly published as abstracts during recent international meetings. They can be classified into three types: feasibility only. In these studies, the aim was only to show that the physician working in the mobile care unit is able to make a correct decision regarding thrombolytic treatment. feasibility with estimation of time gain. In these studies, a control group (randomized or not) allows the time gain to be estimated.
feasibility with estimation of time gain and efficacy criteria. In these studies, left ventricular ejection fraction was measured in the two groups. FEASIBILITY
This is the common aim of all the above studies; incorrect administration of thrombolytic treatment is very rarely reported and is certainly less frequent than reported in the ASSET trial1*1. This reflects the fact that when a pre-hospital thrombolysis program is undertaken, a mobile care unit team is specifically trained, correct ECG recordings are usually available, and restrictive ECG criteria are defined. The consequence is a very low rate of false-positive inclusions. However, some patients with myocardial infarction and non-typical ECG alterations are not included in those trials. As one of the goals of pre-hospital thrombolysis is to increase the number of patients receiving thrombolytic treatment, it is of serious concern that non-typical myocardial infarction cannot benefit from pre-hospital thrombolysis. TIME GAIN
All the above studies have been conducted in urban areas, the time gain has been estimated to be between 32 min (Marseille, France) and 74 min (Paris, France). Three randomized studies have been published and time gain was 34 min for Roth, 60 min in our study and 68 min for MacNeill16-8". This time gain is due partly to the suppression of transport-delay and partly to the avoidance of in-hospital delay. In-hospital delays seem to be a worldwide problem, and various attempts have been made to reduce them and to start thrombolytic treatment in the emergency room rather than the coronary care unit. It is our experience that the main cause of in-hospital delay is the time taken to find a physician able to take responsibility for starting thrombolytic treatment, so to reduce in-hospital delays it is, again, necessary to transfer the responsibility from cardiologists—well-trained but not usually present in the emergency room—to physicians always present in the emergency room. This question is associated with that of transferring responsiblity from cardiologists to physicians working in mobile care units. This issue is encountered whenever we consider options for reducing the delay.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on April 10, 2016
and 30min in-hospital. In hospital delays are discussed elsewhere'71. Finally we analysed the delay between phone call and arrival at the coronary care unit for patients included in the study and for patients excluded from the study; the delays were 135 min and 132 min, respectively. In our emergency medical system, an injection of APSAC at home does not induce an additional delay to arrival at the coronary care unit. The clinical development of these 100 patients was carefully monitored. During the pre-hospital phase, hypotension occurred in seven patients, two of whom had received placebo, five APSAC (Eminase®); six had a posterior wall myocardial infarction; two patients had nausea, vomiting and an allergic reaction, possibly due to eminase; no bleeding occurred during the pre-hospital phase; Holter monitoring conducted during the pre-hospital phase showed that arrhythmia frequencies and types were similar in the two groups. A total of 89 patients underwent coronary angiography. Patency rate was 72%. Left ventricular ejection fraction was 56-7% for the pre-hospital group and 53-4% for the in-hospital group; The difference is not significant. A total of five patients died, three of whom had been treated at home, and two in hospital. The results of our study allow us to conclude that pre-hospital thrombolysis with APSAC is easy to perform, feasible and safe if the mobile care unit team is specifically trained. Since so few patients were studied, data on left ventricular ejection fraction and mortality cannot be analysed.
45
46
A. D. Castaigne et al.
THE SEATTLE STUDY
APSAC, streptokinase and alteplase have been used in studies of pre-hospital thrombolysis. The known safety profiles of these drugs do not seem to be modified by pre-hospital use.
The myocardial infarction triage and intervention project is a prospective evalution of feasibility and benefit of paramedic administration of t-PA|10). Paramedics working in mobile care units have to examine each patient with chest pain. When the probability of acute coronary syndrome is high and when there is no contra-indication to thrombolytic treatment, an ECG is performed and is sent by phone to Seattle where a cardiologist helps to take the decision to include the patient in the study. Patients included receive either t-PA at home or t-PA in hospital. The two end-points of the study are the ability of this system to give the correct decision and the left ventricular ejection fraction. A total of 800 patients will be included in the study, which began in October 1988.
EFFICACY OF PRE-HOSPITAL THROMBOLYSIS
Only three randomized studies have been published giving data on left ventricular ejection fraction and mortality46-89'. In our study, and in the study by McNeill there is a trend toward better ejection fraction for patients treated at home: 56-7 vs 53-4 and 50-3 vs 47-6, respectively. In the study by Roth, the reverse is true (57% for patients treated at home and 59% for patients treated in hospital)1"1. As regards in-hospital mortality among the 257 patients included in the three trials, 16 died, eight in each group.
Hie European Myocardial Infarction Project CONCLUSION
These data show that pre-hospital thrombolysis is feasible, safe and probably practicable in many emergency medical systems if the question of transferring responsibility from cardiologists is adequately solved. Nevertheless, efficacy for pre-hospital thrombolysis has not been demonstrated. Assessment of pre-bospital thrombolysis efficacy We believe that pre-hospital thrombolysis efficacy must be adequately assessed. Thrombolytic treatment efficacy has been demonstrated in coronary care units in which the decision to treat was made by cardiologists. The only study in which the decision to treat was made without ECG data had a high rate of false-positive diagnosis (around 30%)'41, so we cannot be sure that rapid and widespread introduction of pre-hospital thrombolysis will not induce the same error rate. More generally, when the location of treatment and the physician in charge of the decision are altered, it cannot be certain that treatment efficacy will not be modified. Any new treatment has to be evaluated; similarly, any new way of giving the treatment has to be evaluated, and the only way to evaluate a treatment is to perform a randomized trial with enough patients to assess efficacy according to accepted criteria. Two such trials are currently being performed.
This is a multicentre multination study in which member states of the European Economic Community are involved. Its main objective is to evaluate the benefit/risk ratio of pre-hospital thrombolysis compared with in-hospital thrombolysis with total mortality as the major end-point. The organization is not uniform as mobile care units are dissimilar in different areas of Europe, but the general principles are as follows. (1) Patients may be recruited if they have a high probability of acute myocardial infarction. (2) Randomization is stratified according to ECG signs—patients with STsegment elevation are in group A, patients without ST-segment elevation are in group B. (3) Patients are randomly allocated at home to APSAC 30 units or placebo; on arrival in-hospital the other treatment is given if the diagnosis of acute myocardial infarction is confirmed. The entire process is double-blind. Thus, all patients receive APSAC 30 units, half of them at home and half in hospital. (4) Local standard care for myocardial infarction is then applied and no specific therapeutic agent or exploration is applied. (5) Two major end-points will be evaluated: whether the diagnosis of acute myocardial infarction is correct, and whether there is a difference in mortality between the two groups. It has been calculated that 10 000 patients will be necessary to answer the second question. The trial began in France in January 1989 and, by
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on April 10, 2016
SAFETY OF PRE-HOSPITAL THROMBOLYSIS
Is pre-hospital thrombolysis useful?
August 1989, 800 patients had been included. The trial will begin in the other countries by September 1989. We hope that the study will be completed in 1991.
[3] [4]
CONCLUSION
[5]
[6] [7] [8]
References [1] GISSI. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; i: 397-401. [2] ISIS-2 Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17187 cases of suspected acute
[9] [10]
myocardial infarction; ISIS-2. Lancet 1988; ii: 34961. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after myocardial infarction. Lancet 1988; i: 545-9. Wilcox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction: Anglo-Scandinavian Study of Early Thrombolysis. Lancet 1988; ii: 52530. Koren G, Weiss AT, Hasin Y, Appclbaum D, Welber S. Prevention of myocardial damage in acute myocardial ischemia by early treatment with intravenous streptokinase. N Engl J Med 1985; 313:1384-9. Castaigne AD, Herve Ch, Duval-Moulin AM et al. PTehospital use of APSAC: results of a placebocontrolled study. Am J Cardiol 1989; 64: 30A-33A. Chamberlain DA. In-hospital delays. Eur Heart J 1990; 11 (Suppl F): 000-000. Roth A, Brabash a , Hod H. Should rt-PA be administrated by the mobile intensive care unit team? Circulation 1988; 78 (Suppl): 189 (Abstr). McNeill A, Cunningham S, Flannery D et al. Preadmission recombinant tissue plasminogen activator. Eur Heart J 1988; 9 (Suppl 1): 214 (Abstr). Kennedy JW, Weaver WD. Potential use of thrombolytic therapy before hospitalisation. Am J Cardiol 1989; 64: 8A-11A.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on April 10, 2016
Feasibility of pre-hospital thrombolysis has been demonstrated. APSAC is very easy to use in mobile care units since a continuous infusion is unnecessary. The question of efficacy is a major one since if it were demonstrated that pre-hospital is the better way to give thrombolytic treatment, it would be necessary to modify emergency medical services in many cities in order to make the transfer of responsibility from cardiologists to other physicians possible.
47
Pre-hospital thrombolysis, is it useful? *A. D.
CASTAIGNE, | C H . HERVE, *A.-M. DUVAL-MOUUN *J.-L. DUBOIS-RANDE AND D. LELLOUCHE
'Cardiology Department and fSAMU Necker H&pital, Paris, France
94, Hopital Henri Mondor,
tM.
GAILLARD,
Creteil and fSAMU
75,
Thrombolytic treatment efficacy is greater when the delay between onset of pain and treatment is short. One way to shorten this delay is to give treatment at home, but one cannot recommend this technique if it has not been demonstrated first, that pre-hospital thrombolysis is feasible and safe, and second, that it is useful. We have been able to demonstrate that pre-hospital thrombolysis with APSAC is feasible and safe. Our findings are similar to those of other teams using other drugs. Whether pre-hospital thrombolysis is useful has not been adequately assessed; and we consider that first, the benefit of pre-hospital vs in-hospital thrombolysis must be determined, and second, the results of a study involving many centres, with various levels of training, practicing pre-hospital thrombolysis must be examined. Two large scale studies are currently being performed. One in Seattle, uses left ventricular ejection fraction as the major end-point, whereas the other, the European Myocardial Infarction Project, (EMIP) is using total mortality. Data currently available indicate that pre-hospital thrombolysis with APSAC is feasible, easy and safe. We hope that we will very soon be able to answer the last question: is it useful?
Introduction It has been shown that thrombolytic treatment reduces early and 1 year mortality after myocardial infarction11"4'. It has been suggested in the GISSI and ISIS-2 trials that the earlier the treatment is given the greater the mortality reduction. So cardiologists are now faced with the question of how to shorten the delay between onset of pain and treatment. Education of patients and physicians seems to be one way to shorten the delay between onset of pain and contact with a team able to give thrombolytic treatment. Nevertheless, two delays remain constant: delay due to transport from home to hospital; and in-hospital delays. In order to reduce those two factors, Koren et a/.151 demonstrated that thrombolytic treatment might be given outside the hospital. In that study, the
decision to treat was made by cardiologists working in the ambulance. But cardiologists do not usually work in mobile care systems. Thus, to give treatment before admission to a coronary care unit, responsibility needs to be transferred from cardiologists to other physicians working in mobile care units. In this paper we will briefly summarize our experience with pre-hospital thrombolysis161, review other reports and discuss the usefulness of pre-hospital treatment. Hie Val-de-Marne study of pre-hospital thrombolysis
In France, physicians working in mobile care units are usually anaesthesiologists not specifically trained for cardiac emergencies. Our preliminary study was planned to assess the feasibility of pre-hospital thrombolysis. Address for correspondence: A. D. Castaigne, Hdpital We wanted to know whether anaethesiologists working in mobile care units are able to make Henri Mondor, F 94010, Creteil, France. 0195-668X/90/OF043 + 05 $03.00/0
© 1990 The European Society of Cardiology
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on April 10, 2016
KEY WORDS: Thrombolytic therapy, myocardial infarction, emergencies, mobile care unit, APSAC.
44
A. D. Castaigne et al. placebo at home; and events during the pre-hospital phase. Within 2 years, 320 patients with acute myocardial infarction were screened, and a total of 100 were included in the trial. Of those 100 patients, 57 received APSAC at home, 36 received APSAC in hospital and seven did not receive thrombolytic treatment. The reasons for this have been explained previously161. Of the 100 patients included in the trial, 88 had typical myocardial infarction, as shown by enzymatic release and ECG criteria. Two patients died between home injection (one APSAC, one placebo) and hospital arrival; they had a typical myocardial infarction, as shown by clinical and ECG criteria, complicated by cardiogenic shock. Seven patients had typical chest pain and typical ECG signs, but enzymatic elevation did not reach the upper limit of normal values. In these seven patients, the infarctrelated artery was severely stenosed and a mild hypokinesia was seen on left ventriculogram. They were treated within 75 min of pain onset; the final diagnosis was aborted myocardial infarction. For three patients, the diagnosis of recent acute myocardial infarction was ruled out. One had an old anterior infarct with left ventricular aneurysm, ventricular tachycardia, chest pain but no new myocardial infarction. One had an ischaemic cardiomyopathy, anginal pain, old ECG abnormalities but no recent myocardial infarction. One had coronary spasm with transient enzymatic release but without myocardial infarction. Finally, all of the 100 patients had an acute coronary syndrome and the decision to give them a thrombolytic treatment was not in error. As regards timing of treatment, there was an average of 65 min between onset of pain and call to the mobile care unit, an average of 12 min between call and arrival of the mobile care unit, an average of 54 min between arrival of the mobile care unit and at-home injection, and an average of 60 min between at-home and in-hospital injections for patients receiving placebo. The median delay between pain onset and at-home injection was 131 min; the median delay between pain onset and in-hospital treatment for patients receiving placebo was 190 min. The delay of 60min between at-home and in-hospital injection was analysed. Approximately 30 min were accounted for by transport
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on April 10, 2016
the correct decisions regarding thrombolytic therapy, whether pre-hospital thrombolysis delays the patient's arrival in the coronary care unit, whether pre-hospital thrombolysis is safe, and how many minutes are saved by pre-hospital treatment. The first part of our study was a simulation and education study. Over a 1-year period anaesthesiologists had to complete a form for each case of acute chest pain. The two main questions were: Was the diagnosis correct? and If thrombolytic treatment had been available in the ambulance would the physician have used it adequately? Within 1 year, 294 patients with acute chest pain possibly due to coronary artery disease were evaluated at home by an anaesthesiologist working in a mobile care unit. Among the 294 patients, 282 had either unstable angina or acute myocardial infarction and the diagnosis of acute coronary syndrome made at home was correct. Thus, the false-positive rate was low (12 out of 294). Among those 294 cases the anaesthesiologists indicated that they would have used thrombolytic treatment in 62 cases; the decision was judged correct in all the cases. At the end of this first part, it was anticipated that the risk of incorrect administration of a thrombolytic agent was very low, and a randomized trial was begun. The randomized trial compared pre-hospital thrombolysis with in-hospital thrombolysis with APSAC. Patients less than 75 years old, with typical signs of myocardial infarction and no contra-indication to thrombolytic treatment were included in the study. They were first seen by the anaesthesiologist working in the mobile care unit, and if they were eligible they were randomly assigned to the placebo or APSAC group. After receiving placebo or APSAC, patients were referred to one of the participating coronary care units where the code was broken. If the patient had received placebo at home the coronary care unit physician had to decide whether thrombolytic treatment was necessary. Coronary angiography was performed and left ventricular ejection fraction was measured within 48 h of admission. The study end points included: diagnostic accuracy; delay between phone call to emergency medical service and arrival in coronary care unit for patients included in or excluded from the trial; delay between at-home and in-hospital injection for patients having received
Is pre-hospital thrombolysis useful?
Pre-bospHal thrombolysis: other studies Pre-hospital thrombolysis has been tested by other teams. Here we examine whether these experiences help us with regard to efficacy criteria. The relevant studies have been, to our knowledge, mainly published as abstracts during recent international meetings. They can be classified into three types: feasibility only. In these studies, the aim was only to show that the physician working in the mobile care unit is able to make a correct decision regarding thrombolytic treatment. feasibility with estimation of time gain. In these studies, a control group (randomized or not) allows the time gain to be estimated.
feasibility with estimation of time gain and efficacy criteria. In these studies, left ventricular ejection fraction was measured in the two groups. FEASIBILITY
This is the common aim of all the above studies; incorrect administration of thrombolytic treatment is very rarely reported and is certainly less frequent than reported in the ASSET trial1*1. This reflects the fact that when a pre-hospital thrombolysis program is undertaken, a mobile care unit team is specifically trained, correct ECG recordings are usually available, and restrictive ECG criteria are defined. The consequence is a very low rate of false-positive inclusions. However, some patients with myocardial infarction and non-typical ECG alterations are not included in those trials. As one of the goals of pre-hospital thrombolysis is to increase the number of patients receiving thrombolytic treatment, it is of serious concern that non-typical myocardial infarction cannot benefit from pre-hospital thrombolysis. TIME GAIN
All the above studies have been conducted in urban areas, the time gain has been estimated to be between 32 min (Marseille, France) and 74 min (Paris, France). Three randomized studies have been published and time gain was 34 min for Roth, 60 min in our study and 68 min for MacNeill16-8". This time gain is due partly to the suppression of transport-delay and partly to the avoidance of in-hospital delay. In-hospital delays seem to be a worldwide problem, and various attempts have been made to reduce them and to start thrombolytic treatment in the emergency room rather than the coronary care unit. It is our experience that the main cause of in-hospital delay is the time taken to find a physician able to take responsibility for starting thrombolytic treatment, so to reduce in-hospital delays it is, again, necessary to transfer the responsibility from cardiologists—well-trained but not usually present in the emergency room—to physicians always present in the emergency room. This question is associated with that of transferring responsiblity from cardiologists to physicians working in mobile care units. This issue is encountered whenever we consider options for reducing the delay.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on April 10, 2016
and 30min in-hospital. In hospital delays are discussed elsewhere'71. Finally we analysed the delay between phone call and arrival at the coronary care unit for patients included in the study and for patients excluded from the study; the delays were 135 min and 132 min, respectively. In our emergency medical system, an injection of APSAC at home does not induce an additional delay to arrival at the coronary care unit. The clinical development of these 100 patients was carefully monitored. During the pre-hospital phase, hypotension occurred in seven patients, two of whom had received placebo, five APSAC (Eminase®); six had a posterior wall myocardial infarction; two patients had nausea, vomiting and an allergic reaction, possibly due to eminase; no bleeding occurred during the pre-hospital phase; Holter monitoring conducted during the pre-hospital phase showed that arrhythmia frequencies and types were similar in the two groups. A total of 89 patients underwent coronary angiography. Patency rate was 72%. Left ventricular ejection fraction was 56-7% for the pre-hospital group and 53-4% for the in-hospital group; The difference is not significant. A total of five patients died, three of whom had been treated at home, and two in hospital. The results of our study allow us to conclude that pre-hospital thrombolysis with APSAC is easy to perform, feasible and safe if the mobile care unit team is specifically trained. Since so few patients were studied, data on left ventricular ejection fraction and mortality cannot be analysed.
45
46
A. D. Castaigne et al.
THE SEATTLE STUDY
APSAC, streptokinase and alteplase have been used in studies of pre-hospital thrombolysis. The known safety profiles of these drugs do not seem to be modified by pre-hospital use.
The myocardial infarction triage and intervention project is a prospective evalution of feasibility and benefit of paramedic administration of t-PA|10). Paramedics working in mobile care units have to examine each patient with chest pain. When the probability of acute coronary syndrome is high and when there is no contra-indication to thrombolytic treatment, an ECG is performed and is sent by phone to Seattle where a cardiologist helps to take the decision to include the patient in the study. Patients included receive either t-PA at home or t-PA in hospital. The two end-points of the study are the ability of this system to give the correct decision and the left ventricular ejection fraction. A total of 800 patients will be included in the study, which began in October 1988.
EFFICACY OF PRE-HOSPITAL THROMBOLYSIS
Only three randomized studies have been published giving data on left ventricular ejection fraction and mortality46-89'. In our study, and in the study by McNeill there is a trend toward better ejection fraction for patients treated at home: 56-7 vs 53-4 and 50-3 vs 47-6, respectively. In the study by Roth, the reverse is true (57% for patients treated at home and 59% for patients treated in hospital)1"1. As regards in-hospital mortality among the 257 patients included in the three trials, 16 died, eight in each group.
Hie European Myocardial Infarction Project CONCLUSION
These data show that pre-hospital thrombolysis is feasible, safe and probably practicable in many emergency medical systems if the question of transferring responsibility from cardiologists is adequately solved. Nevertheless, efficacy for pre-hospital thrombolysis has not been demonstrated. Assessment of pre-bospital thrombolysis efficacy We believe that pre-hospital thrombolysis efficacy must be adequately assessed. Thrombolytic treatment efficacy has been demonstrated in coronary care units in which the decision to treat was made by cardiologists. The only study in which the decision to treat was made without ECG data had a high rate of false-positive diagnosis (around 30%)'41, so we cannot be sure that rapid and widespread introduction of pre-hospital thrombolysis will not induce the same error rate. More generally, when the location of treatment and the physician in charge of the decision are altered, it cannot be certain that treatment efficacy will not be modified. Any new treatment has to be evaluated; similarly, any new way of giving the treatment has to be evaluated, and the only way to evaluate a treatment is to perform a randomized trial with enough patients to assess efficacy according to accepted criteria. Two such trials are currently being performed.
This is a multicentre multination study in which member states of the European Economic Community are involved. Its main objective is to evaluate the benefit/risk ratio of pre-hospital thrombolysis compared with in-hospital thrombolysis with total mortality as the major end-point. The organization is not uniform as mobile care units are dissimilar in different areas of Europe, but the general principles are as follows. (1) Patients may be recruited if they have a high probability of acute myocardial infarction. (2) Randomization is stratified according to ECG signs—patients with STsegment elevation are in group A, patients without ST-segment elevation are in group B. (3) Patients are randomly allocated at home to APSAC 30 units or placebo; on arrival in-hospital the other treatment is given if the diagnosis of acute myocardial infarction is confirmed. The entire process is double-blind. Thus, all patients receive APSAC 30 units, half of them at home and half in hospital. (4) Local standard care for myocardial infarction is then applied and no specific therapeutic agent or exploration is applied. (5) Two major end-points will be evaluated: whether the diagnosis of acute myocardial infarction is correct, and whether there is a difference in mortality between the two groups. It has been calculated that 10 000 patients will be necessary to answer the second question. The trial began in France in January 1989 and, by
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on April 10, 2016
SAFETY OF PRE-HOSPITAL THROMBOLYSIS
Is pre-hospital thrombolysis useful?
August 1989, 800 patients had been included. The trial will begin in the other countries by September 1989. We hope that the study will be completed in 1991.
[3] [4]
CONCLUSION
[5]
[6] [7] [8]
References [1] GISSI. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; i: 397-401. [2] ISIS-2 Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17187 cases of suspected acute
[9] [10]
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Feasibility of pre-hospital thrombolysis has been demonstrated. APSAC is very easy to use in mobile care units since a continuous infusion is unnecessary. The question of efficacy is a major one since if it were demonstrated that pre-hospital is the better way to give thrombolytic treatment, it would be necessary to modify emergency medical services in many cities in order to make the transfer of responsibility from cardiologists to other physicians possible.
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