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Acute intervention for myocardial infarction k ithough cardiology seems to be relatively young speciality - the Dutch Cardiology Association celebrated its seventieth birthday on 22 and 23 April of this year - acute interventions in the heart were already described in the Middle Ages. In the epic poem Parsifal, the tale of the search for the Holy Grail, an acute lifesaving intervention was described with great accuracy by Wolfiam von Eschenbach.' During one of his adventures Gawain, an impertnrbable hero following in the footsteps of King Arthur, encounters a woman under a linden tree on whose lap languishes a man who is seriously ill and short ofbreath. The description makes it dear that the patient is in a very bad condition. Gawain immediately recognises the symptoms and knows what he must do. The functioning ofthe patient's heart is being made impossible by blood in the pericardium as a result of being stabbed with a lance, an injury that is one of the occupational hazards of knighthood. Taking a reed from the riverbank Gawain carves a hollow tube. He then inserts the tube into the existing opening made by the lance to the heart of the patient. When he instructs the woman to suck hard on the tube, blood flows out and life flows back in. The episode is concluded with a few details about follow-up care and mention of the fact that the acute treatment must be followed by a brief admission to a suitable institution. I will attempt to explain to you that the significant characteristics of this tale are the cornerstones of the modern treatment of a myocardial infarction. So what are we told here? A patient is acutely ill, dose to death, but his life is saved quickly and efficiently. A number ofelements are noted. First of all the right diagnosis is made very rapidly, the condition is
immediately recognised and the knight seems to have great clinical skills. The establishment of the diagnosis is followed by intervention, without hesitation, to the point and with great skill. A specific type of follow-up care and a briefadmission were already elements in the care of the mediaeval patient. We try to organise this today as well, and in modern-day jargon we say that the life of this patient from Parsifal was saved by a combination of prehospital diagnostics and acute intervention followed by a short stay hospital admission and rehabilitation. Stab wounds were a veritable epidemic in the Middle Ages; sudden obstructions ofcoronary artenes with resulting myocardial infarction are one oftoday's epidemically occurring acute life-threatening conditions. Every year some 26,000 patients in Dutch hospitals are diagnosed as having had a myocardial infarction. Public screening has shown that in addition, a large group of patients die suddenly from the consequences of a heart attack before medical help has even reached them. So, acute myocardial infarction is a frequently occurring cause of death and in addition a great source ofmorbidity.
Although descriptions ofthe clinical picture of an acute infarction have already been published in the past, it is nonetheless mostly through electrocardiography that a diagnosis ofany reliability can be established in a living patient. The electrocardiogram still plays a key role in diagnostic terms.2 In the first halfof the last century the treatment ofacute myocardial infarction consisted of pain medication and long-term bed F. ZQilstra University Hospital Groningen E-mail: [email protected]
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rest. This changed in the 1960s, when it became possible to identify ventricular rhythm disturbances remotely using electrocardiographic monitonng equipment. This enabled physicians and nurses to establish the nature ofthe rhythm and ifnecessary use electrocardioversion or defibrillation to prevent the patient's acute demise. With the arrival on the scene of lidocaine and 1-blockers, it became possible to use medications to treat and prevent ventricular rhythm diturbances. Since that time the most important cause of death in patients with a myocardial infarction who are still alive when the ambulance reaches them has been heart failure. Heart failure is usualy caused by defective pump function as a result of too much damage to the heart musde. During the phase before the rhythm of the patient is monitored, ventricular fibrillation continues to be a frequently occurring cause of death. This is one of the reasons why it is desirable to make or keep the arrival time of ambulances short. Research into the placement and use by lay people of automatic external defibrillators, particularly in places where many people gather such as airports, stations, and sports fields, would appear to be a promising option in order to further decrease the number of deaths due to ventricular rhythm disturbances.3
The next large step forward was the application of thrombolytic therapy to open obstructed blood vessels. In 1976 Chazov described the intracoronary administration of streptokinase, with coronary angiography being used to delineate its effect.4 Earlier administration of intravenous streptokinase, by Sherry amongst others in the 1950s, was of limited value because the effect could not be evaluated.5 The ideas from Chazov's Russian publication were
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picked up in the West after Rentrop in Germany had published a comparable study.6 In that same year, during my housemanship, I subscribed to the New England Journal of Medicine. In the first edition that landed on my doormat, Gruntzig described the earliest applications of percutaneous transluminal coronary angioplasty or PTCA, the Dotter treatment.7 After many years of systematic preclinical work, he published the results that he had booked with patients starting in 1977. These results indeed transcended borders and broke records, even though in those first years a PTCA was certainly not a risk-free enterprise. The first acute PTCA in apatientwith a myocardial infarction was thus the treatment of a complication ofan elective PTCA for stable or unstable angina pectoris.
The treatment of myocardial infarction underwent a true revolution after it was clearly demonstrated in a few megatrials in the 1980s that intravenously administered thrombolysis is better in comparison with conservative therapy. The predominant belief in those years was that the obstructing thrombus had to be combated with thrombolytics. Then the underlying injury inside the infarcted vessel had to be dealt with using a PTCA. In various major American and European studies in the 1980s, however, it was noted that a systematic combination of thrombolysis and PTCA indeed caused complications but had no clear benefits. Although since that time this has certainly stayed open to discussion, both American and European guidelines indicate that thrombolysis must be followed by a basically conservative policy, with intervention only being desirable in patients with specific indications or justification for invasive diagnostics and therapy;8 I will get back to this later. The consistent elements in the treatment of acute myocardial infarction comprise rhythm monitoring, pain control, medications that
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influence coagulation by inhibiting the aggregation of blood platelets, and medications that have an antithrombin effect such as heparin. In addition some patients require treatment with 13-blockers and angiotensin-conversion enzyme inhibitors. At the same time, for each patient with a myocardial infarction a choice must be made between a pnimarily mechanical approach and a pnmarily pharmacological one, in order to effect reperfusion of the obstructed infarct-related artery. The mechanical approach consists of an acute coronary angiogram followed by a PTCA. The pharmacological strategy consists ofthe administration ofmodem thrombolytic medication administered as a bolus injection. In the beginning of the 1990s, the first comparative study between these two strategies was carried out and published in which to begin with thrombolysis was compared with 'plain old balloon angioplasty', percutaneous angioplasty with only a balloon.9 In later years came stents and new intravenously administered and very powerful platelet
aggregation inhibiting substances were added. In direct comparative studies since that time many thousands of patients have been studied and the advantages of primary angioplasty have consistently come to the fore in all studies, as shown in a recent meta-analysis in which the data from 23 randomised studies are summarised.'0 After 30 days there were two less deaths in every 100 patients treated with primary PCTA and one cerebrovascular accident and four repeat myocardial infarctions were prevented, in comparison with the patients who had undergone thrombolytic therapy in these studies. This means that per 14 treated patients a serious complication or death was prevented ifthe choice was for primary PTCA. This does not take away from the fact that in comparison with conservative treatment without reperfusion therapy, thrombolytic treatment gives a very solidly based reduction in short- and long-term mortality
after a myocardial infarction. A cautious estimate of the effect of primary PTCA compared with conservative treatment, that is to say without reperfusion therapy, is that in one out of ten patients a serious complication or death is prevented. That the primary PTCA strategy can be applied at a national level, with a few large centres serving an extended area, was demonstrated in a Danish study." The studywas carried out by five heart centres in cooperation with 24 referring hospitals in an area with over three ofthe five million residents of Denmark. Such a model, in which patients do not go to the nearest hospital but are brought directly to a centre for percutaneous angioplasty, could be easily organised in large parts of East and West Europe, North America and other developed areas of the world. Czech studies have confirmed this. Thus thrombolytic therapy has actually become a secondchoice therapy for if a primary PTCA is no option for logistical reasons.'2 Unfortunately it is true that the Netherlands are lagging far behind in comparison with large parts of the United States, France, Denmark, Germany and Poland, where 30 to 40% ofall acute infarctions are already being treated with primary PTCA. In the Netherlands, a continued bastion of thrombolysis supporters, only some 11% of acute infarctions were treated with PT CA in 2001. So we are losing to the Czech Republic in more than just football, and this despite a healthcare structure that makes it possible to fly trauma helicopters and rapidly carry out surgical intervention in response to a broad range of acute situations. So what makes a mechanical approach more effective than thrombolytic therapy? To answer this question, one must take a look at the pathogenesis ofacute coronary artery obstruction. The first description of the pathology is based on an obduction that was carried out in 1793 on a famous English surgeon, Sir James Hunter,, who died suddenly immediately after a fierce argument with the administrators of the
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hospital where he worked.'3 The organisation of care was at that time already literally and figuratively of vital significance. At this obduction an obstructed coronary arterywas found to be thrombotic. The connection between this type of finding, the clinical picture and the electrocardiogramwas described in 1912 and 1919 by Bryan Herrick'4 and in 1920 by Harold Pardee," both American internists. We now know that the occurrence of a rupture or the tearing of the covering layer of an atherosderotic plaque resulting in clot formation is a frequent complication of the complex illness atherosclerosis.'6 Small ruptures can very easily occur subclinically, larger ruptures lead to acute coronary syndromes such as unstable angina pectoris, acute myocardial infarction and sudden death. If an obstruction is caused by a freshly fonned dotwith little or no nonthrombotic obstruction, thrombolytic therapy is a rational approach that is usually reasonably effective. In 25 to 40% ofacute coronary artery obstructions, the however, thrombotic factor is not the most important component of the obstruction. Plaque rupture with characteristics of dissection, intramural haemorrhage, and the atheromatous material that can be released from a ruptured plaque can all, or jointly, suddenly completely obstruct the artery and cause an infarction that will not respond to thrombolytic therapy. Similarly, the embolisation of material from the ruptured plaque, with subsequent obstruction in the distal flow area of the plaque rupture, can cause an infarction, as was demonstrated in recent angiographic studies.'7 This type of obstruction does not show any 'staining' on coronary angiography and can only be cleared with balloon inflation and stenting. This also explains why ever more aggressive thrombolytic strategies do indeed increase the number of bleeding complications induding the dreaded intracerebral haemorrhage but do not cause more arteries to open. The current editor of the
American Journal of Cardiology described this splendidly in 1972 together with Buja'8 and in an editorial with the title: 'If I have an acute myocardial infirction take me to the hospital that has a cardiac catheterisation laboratory and open cardiac surgical facilities'.'9 Thus he was at that time ahead of the findings ofthe randomised studies ofthe last decade. In summary it can be stated that the pathogenetic model has been convincingly demonstrated: angioplasty is better than thrombolysis, particularly because nonthrombotic components of acute obstruction often play a significant role. This condusion immediately leads to the following two questions: how enduring is the advantage of PTCA with respect to thrombolysis and what price should we pay for it? In order to answer this question, I would like to address the study that we carried outin the 1990s in Zwolle in more detail, because for the time being this is the only study from which long-term results have been published.20 In the Zwolle study 395 patients with acute ST-segment elevation myocardial infarction were treated with either intravenous streptokinase or primary PTCA. After five years the deaths in the primary PTCA group were 13% and in the streptokinase group 24%. Ifwe look at the combination of deaths and nonfatal repeat myocardial infarctions, there is a clear difference in the first 30 days, plus later on more comp.lcations continue to occur m the streptokinase group. So the relative added value of PTCA increases somewhat with the passage oftime. On closer analysis it is noted that further divergence is particularly the result of two factors. Primary PTCA opens more vessels and the chance that those vessels will dose again later is small in comparison with thrombolysis. We know that after coronary angioplasty an obstruction can sometimes recur, but this does not lead to repeat myocardial infarctions or death. Restenosis after coronary angioplasty is a gradual
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process that may be the cause of symptoms or ischaemia, but usually does not cause a sudden complete obstruction of a blood vessel treated with a PTCA. After thrombolysis it is indeed true that signs ofmyocardial ischaemia or infarction do recur rather frequently, in the Zwolle study approximately twice as frequently as with PTCA-treated patients. So more open coronary arteries are the first factor that determines the long-term advantage of a PTCA. The second important factor is a direct consequence of this: in our study coronary angioplasty patients went home with a better ventricular function than the streptokinase patients. In the years after acute events, hospital admissions for heart failure occurred three times as frequently in the thrombolysis group, 27 versus 9% in the PTCA group. The significance of this difference can hardly be overestimated; ventricular function is the most important determinant of long-term survival and quality of life after a myocardial infarction. This also means that in economic terms primary PTCA should above all be viewed as an investment. The costs of coronary angioplasty dunng the first day after a myocardial infirction are, ofcourse, higher than those of thrombolysis. If, however, one makes up the financial balance after five years, the total costs per coronary angioplasty patient, including re-admissions, additional interventions, and medications are approximately E15,000, whereas the average thrombolysis patient has by then cost 416,000. The costs that are incurred on the first day are only a limited part of the total costs. Not only from the Zwolle figures but also from those of the Mayo clinic, the PAMI group and Pannley's group, one can deduce that opting for primary PTCA does not lead to an increase in costs in the long term. Progress in medicine sometimes means rising costs, but that does not apply to the treatment of acute myocardial infarction; the best treatment with the least chance of renewed symptoms and hospital admissions is also financially the
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healthiest policy. In this light we must also view the new, improved and more expensive stents. If as a result ofthese, patients spend fewer days in the hospital and require fewer additional procedures, then such an extra investment is quickly earned back. Whether the new generation of stents will actually live up to this promise remains to be seen. In which direction should the treatent and study ofmyocardial infacion proceed? The obstructed coronary artery must be opened up as rapidly as possible; this is clear. But attention must also be paid to the myocardium that depends upon the epicardial artery, which has been opened up again. In his inaugural speech in November 2001, Professor Dirk Jan van Veldhuisen outlined the significance of heart failure. In 60 to 70% of all patients with heart failure an old myocardial infarction is the cause of poor pump function of the left ventricle. So retaining and restoring ventricular function are the primary goals of the further studies to determine the best treatment for myocardial infarction. Systematic studies of additional mechanical treatment and improvements in the accompanying pharmacological therapy, for example with ,B-blockers and ACE inhibitors, are of great significance. In addition metabolic intervention with glucose, insulin and potassium is a promising strategy in an attempt to bring more cardiac muscle tissue through an acute episode viably. By intervening in a focused manner in the metabolism in the myocardial cells that are not yet irreparably damaged at the momentwhen the blood supply to an inflircted area recommences, the total damage may be limited. In the GIPS 1 study carried out earlier, the electrocardiographic data, as well as the findings of enzymatic infarct size and left ventricular ejection fraction, point in that direction.2' So in 2003 we commenced a large randomised study, called the GIPS 2, in 1050 patients with an acute myocardial infarction, who were of course also treated with reperfusion therapy. In
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addition to the Groningen University Hospital and the Isala Clinics in Zwolle, hospitals in Meppel, Dokkum, Emmen and Amsterdam are participating and a number of other hospitals are preparing to participate as well. Should this additional metabolic intervention prove effective, this will be a second illustration of my earlier postulate that progress in cardiology need not always lead to increased costs: glucose/insulin/potassium is an inexpensive treatment. Paradoxically enough, this makes obtaining the necessary funding for such a project more difficult, because there are no potential sponsors who can eam back an investment in the study in patient care after a positive result from the study. In order to execute this type ofstudy, support from various other spcialities is necessary. Good collaboration with internists both in Zwolle and in Groningen is one of the most important cornerstones ofthe GIPS projects, from which a PhD student can pluck the fruit this year. The clinical-chemical laboratory is on the one hand vital to daily practice while on the other hand delivers fundamental intermediary data with infarction scope enzymatic determinations that give us insight into the value of therapeutic approaches. This also applies with regard to nuclear medicine. Ventricular function quantification is vital to many studies. In addition, after the acute phase, for many patients a long-term treatment strategy can only be formulated with the aid of studies of ischaemia and vitality of the myocardium. The decision-making with regard to the policy to be followed takes place in daily multidisciplinary consultations between cardiologists and thoracic surgeons. Daily collaboration with thoracic surgery is the cornerstone of optimal care for many ofourpatients.
Some scientific topics in this area are not directly suited to clinical patientrelated studies. In Groningen, under the supervision ofProf&ssorWiekvan Gilst, fundamental studies in
experimental cardiology are being carried out in the department of clinical pharmacology. In the realm of stents and restenosis after PTCA, myocardial ischaemia and heart failure, much can be accomplished through interaction between preclinical and clinical studies. Collaboration with the Department ofRadiology, underthe management of Professor Matthijs Oudkerk, has also expanded within a short time into an important branch of study concerning stable coronary artery disease and acute coronary syndromes including myocardial infarction. Some patients with myocardial infarctions do not, alas, show the specific deviations on their electrocardiograms that are usually the basis for a rapid diagnosis. Modern CT techniques will be able to visualise whether and if so what type of coronary artery is blocked. If necessary, focused cardiac catheterisation with a subsequent PTCA can follow. Developments in the field ofmagnetic resonance, too, will lead to considerable progress in noninvasive cardiac imaging in the years to come. How should the findings from infarct studies from the last years be implemented, and what does this mean in terms of the organisation of care? In the years to come the most profitable direction for our patients would be to realise a change in the organisation of care based on the findings of infarct studies ofwhich I have painted you a picture. The tale ofthe mediaeval knight is our guiding principle here: early prehospital diagnostics at the first contact between the patient and caregivers are an essential first step. In the general practitioners, cardiologists of regional hospitals, and above all in the ambulance services under the leadership ofRonald de Vos,we have expert and motivated partners in the field. Since January of 2004 diagnostic testing pursuant to all major myocardial infirctions has been taking place in the ambulances ofour region, aunks to new equipment for electrocardiography and the focused
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training of ambulance personnel. Thus a diagnosis is established earlier and there is an opportunity to prepare our hospital for the reception of a patient. The time thus saved is approximately three-quarters of an hour, and in particular for patients with large infarctions in the anterior wall of the left ventride this yields a clearly demonstrated limitation of damage to the myocardium.22 In addition it is possible to start the patient on focused pharmacological therapy during his transport, in preparation for coronary angioplasty. In the context ofthe current status of scientific knowledge, the oral platelet aggregation inhibiting substances aspirin and dopidogrel and subcutaneous or intravenous heparin must be given. Above all, ifthe travel time is long, intravenous administration of a glycoprotein Ilb/IIIa blocker may be indicated. Upon acute admission to the hospital, dose collaboration between the catheterisation laboratories and the coronary care unit is a prerequisite; this is one of the many arguments in favour ofstrengthening the organisational link between these two departnents. For most patients this means that after acute treatment they will be monitored for a short period of time in our coronary care unit and then transferred to hospitals near their homes. For patients from the city of Groningen and the immediate environs, the Martini Hospital will often be used for dinical mobilisation and rehabilitation. Although this works well in daily practice, we are evaluating with cardiologists at the Martni Hospital what we could achieve in the more distant future thdugh more intensive collaboration between the two largest providers of acute cardiological care in the region. So we are adapting the organisation of care: what does this mean for the 26,000 myocardial infarction patients per year in Dutch hospitals? Approximately 16,000 of these patients present with acute symptoms and ECG deviations that are diagnostic for acute infarction:
ST elevations suggestive of acute ischaemia as a consequence of a complete obstruction of a coronary artery. These patients must be treated with reperfusion therapy. Some of them are currently already being treated with primary PTCA, the majority still with thrombolytic therapy. Unfortunately there are also still some unlucky ones who are not receiving either type of treatment. The most important factors that play a role in this situation are two persistent faulty concepts that are the mental legacy of the thrombolysis age. First of all the mistake is sometimes made of refraining from treating a patient because of his or her advanced age. Although, incidentally with justification, it is assumed that there is more likelihood of complications in the older patient, studies have shown that it is specifically the older patient who can benefit considerably from an acute intervention.23 Secondly the fact that the effect of thrombolysis decreases rather considerably with the passage of time plays a role. This can be explained: the clot continues to organise itself. Thus the chance that a blood vessel will open in response to thrombolytic therapy becomes smaller with time. The chance that you can still open up a vessel effectively a few hours later with a PTCA is, however, great. So it is rational to treat patients with primary PTCA if more than the classic six hours have passed, particularly if there are still signs of ongoing ischaemia, and particularly if the infarction is localised in the anterior wall of the left ventricle. This particularly applies for patients with haemodynamic problems. The SHOCK study has shown that in patients with myocardial infarction and serious hypotension, an open coronary artery is ofvital importance in the first 24 hours after the commencement of symptoms.?4
The number ofPTCAs carried outin patients with acute myocardial infarction will increase significantly. So the opening of the heart centres in Leeuwarden and Enschede is
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coming at the right time; both new centres can make great contributions to the treatment of myocardial infarction in the northern and eastern Netherlands. Notwithstanding this, for the time being some of the patients who have suffered an acute ST-elevation myocardial infarction will still be treatedwith thrombolysis; changes in the organisation of care take time. Should signs ofheart failure occur in the hours after thrombolytic therapy, there is a strong indication to carry out cardiac catheterisation after all. For most patients who have had thrombolytic therapy, no policy can be formulated at present on the basis of modern research data. Virtually no relevant data exist. In a recent editorial Bill O'Neill,25 one of the infirction PTCApioneers, argues in favour of approaching postthrombolysis patients with the same strategy as patients with acute coronary syndrome without ST elevation, perhaps not true 'evidencebased medicine' but indeed proof of good common sense. This brings me to the following and final topic that I would like to discuss with you. In the days after their acute presentation, a diagnosis of myocardial infarction will be established in approximately 10,000 patients, often on the basis of the results oflaboratory studies. In these patients electrocardiograms during the acute phase do not show evidence of myocardial infarction, that is to say no ST elevation. From the perspective of the treating physician these patients fall into the much larger group of patients who, after acute presentation, are diagnosed as having acute coronary syndrome without ST elevation, a very homogeneous group in which, according to O'Neill, we must also place post-thrombolytic patients. The American, European, and Dutch Associations of Cardiology have established separate guidelines for this group of patients.26 This is the ideal area for modern computer tomographic diagnostics to prove its added value. However the word CT does not yet appear in the guidelines for acute coronary syndrome.
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Some of these patients have symptoms that may fit with a myocardial infarction and sometimes later on this does prove to be true, but the electrocardiogram does not help us. In addition a large number of these patients have a form of unstable angina pectoris. The physician who is responsible for initial treatment must always be aware of other conditions that can simulate acute coronary syndrome. The differential diagnosis must consider myocarditis or pericarditis, conditions of organs in the upper abdomen, or pulmonary embolus. Here the clinical qualities ofthe physician are more important than most diagnostic techniques. Over the last few years a central role has evolved for the determination of troponin levels, a fast and sensitive method that can have consequences with regard to policy. Patients in whom myocardial ischaemia has been shown on the basis ofelectrocardiographic changes and/or troponins are eligible for coronary angiography and subsequent revascularisation by means of PTCA or cardiosurgical intervention. The remaining patients undergo exercise stress testing, stress ECHO, or nuclear studies. In the absence ofdemonstrated myocardial ischaemia an initially conservative policy is adhered to. Is this practical and patient-friendly? The ICTUS study, a project that was completed in 2003 in which a few dozen hospitals in the Netherlands including nearly all heart centres participated, revealed that the vast majority ofpatients who were initially treated conservatively, underwent cardiac catheterisation later on. In epidemiological terms the negative predictive value of the means that have been used thus far is therefore only moderate, or actually poor, in terms of risk stratification. If in the interest of stratification we apply a combination of history plus electrocardiogram plus troponin determination and subsequently, ifstill no signs of coronary disease are found, a computer tomogram, the patient can either continue on to the catheterisation room or go directly
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home. This does, ofcourse, initially cost a bit extra, but once again it will be proven to be a good investment: a shorter stay in the hospital, shorter amount of work missed due to illness, and fewer coronary angiographies in patients who eventually, after much diagnostic uncertainty, fortunately turn out not to have heart problems, but who have indeed been exposed to the risks ofinvasive diagnostics. M References Haage BD. The thoracocentesis in Wolfram von Eschenbach's 'Parsifal'. Wurzburg medical-bistorical tales 1984;2:79-99. 2 Zimetbaum PJ, Josephson ME. Current Concepts: Use ofthe electro-cardiogram in acute myocardial infarction. NEnglJMed 2003;348:933-40. 3 Weaver WD, Peberdy MA. Perspective: Defibrillators in public places - one step closer to home. N EngI J Med 2002; 347:1223-4. 4 Chazov EI, Matveeva LS, Mazaev AV, Sargin KE, Sadovskaia GV, Ruda MI. Intracoronary administration offibrinolysin in acute myocardial infarct. Ther Arkh 1976;48:8-19. 5 Fletcher AP, Alkjaersig N, Smyrniotis FE, Sherry S. The treatment ofpatients suffering from early myocardial infarction with massive and prolonged streptokinase therapy. Trans Assoc Am Physicians 1
1958;71:287-96. 6 Rentrop KP, Blanke H, Karsch KR, Wiegand V, Kostering H, Oster H, Leitz K Acute myocardial infarction: intracoronary application of nitroglycerin and streptokinase. Clin Cardiol 1979;5:54-63. 7 GnmtzigAR, SenningA, Siegenthaler WE. Non-operative dilatation of coronary artery stenosis: percutaneous transluminal coronary angioplasty. NEnglJMed 1979;
301:61-8. 8 Van de Werf F, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KA, et al, for the Task Force on the management of acute myocardial infarction of the European Society of Cardiology. Management of acute myocardial infarction in patients presentingwith ST-segment elevation. Eur
HeartJ2003;24:28-66. 9 Zijlstra F, de Boer MJ, Hoorntje JC, Reiffers S, Reiber JH, Suryapranata H. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med 1993;328:680-6. 10 Keeley EC, Boura JA, Grines CL. Primary angioplastyversus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative reviewof23 randomized trials.
Lancet2003;361:13-20. 11 Andersen HR, Nielsen 'IT, Rasmussen K, Theussen L, Kelbaek H, Thayssen P, et al, for the DANAMI-2 Investigators. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. NEnglJMed2003;349:73342.
12 Grines CL, Serruys P, O'Neill WW. Fibrinolytic therapy: is it a treatment ofthe past? Circulation 2003;107:2538-42. 13 Wlllius FA, Keys TE. Cardiac Classics. St Louis: CVMosbyCo; 1941:265,817. 14. Herrick JB. Thrombosis of the coronary arteries. JAMA 1919;72:387-90. 15 Pardee HEB. An electrocardiographic sign of coronary artery obstruction. Arch Intern Med 1920;26:244-7. 16 Davies MJ, Thomas A. Thrombosis and acute coronary artery lesions in sudden cardiac ischemic death. N Engl J Med 1984;310:1137-40. 17 Henriques JP, Zijlstra F, for the Zwolle myocardial infarction study group. Frequency and sequelae of ST elevation acute myocardial infarction caused by spontaneous distal embolization from unstable coronary lesions. Am J Cardiol 2003;91:708-11. 18 Roberts WC, Buja LM. The frequency and significance of coronary arterial thrombi and other observations in fatal acute myocardial infarction. A study of 107 necropsy patients.
AmJMed 1972;52:425-43.
19 Roberts WC. When I have an acute myocardial infarction take me to the hospital that has a cardiac catheterization laboratory and open cardiac surgical facilities. Am J Cardiol 1984;53:1410. 20 Zijlstra F, Hoorntje JC, de Boer MJ, Reiffers S, Miedema K, Ottervanger JP, et al. Long-term benefit ofprimary angioplasty as compared to thrombolytic therapy for acute myocardial infarction. NEnglJMed 1999;341:1413-9. 21 Van der Horst IC, Zijlstra F, van 't HofAW, Doggen CJ, de Boer MJ, Suryapranata H, et al. Glucose-insulin-potassium infusion in patients treated with primary angioplasty for acute myocardial infarction: the glucoseinsulin-potassium study, a randomized trial. JAm Coll Cardiol 2003;42:784-92. 22 Liem AL, van 't HofAWJ, Hoorntje JCA, de Boer MJ, Suryapranata H, Zijlstra F. Influence of treatment delay on infarct size and clinical outcome in patients with acute myocardial infarction treated with primary angioplasty. J Am Coll Cardiol 1998; 32:629-33. 23 De Boer MJ, Ottervanger JP, van 't Hof AW, Hoomtje JC, Suryapranata H, Zijlstra F. Reperfusion therapy in elderly patients with acute myocardial infarction: a randomized comparison of primary angioplasty and thrombolytic therapy. JAm Coll Cardiol 2002;39: 1723-8. 24 Hochman JS. Cardiogenic shock complicating acute myocardial infarction: expanding the paradigm. Circulation 2003; 107:2998-3002. 25 O'Neill WW. 'Watchful Waiting' after thrombolysis: It's time for a re-evaluation. JAm Coll Cardiol 2003;42:17-9. 26 Bertrand ME, Simoons ML, Fox KA, Wallentin LC, Hamm CW, McFadden E, et al. Task force on the management of acute coronary syndromes ofthe European society of cardiology. Management of acute coronary syndromes in patients presenting without persistent ST segment elevation. Eur HeartJ2002;23:1809-40.
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Acute intervention for myocardial infarction k ithough cardiology seems to be relatively young speciality - the Dutch Cardiology Association celebrated its seventieth birthday on 22 and 23 April of this year - acute interventions in the heart were already described in the Middle Ages. In the epic poem Parsifal, the tale of the search for the Holy Grail, an acute lifesaving intervention was described with great accuracy by Wolfiam von Eschenbach.' During one of his adventures Gawain, an impertnrbable hero following in the footsteps of King Arthur, encounters a woman under a linden tree on whose lap languishes a man who is seriously ill and short ofbreath. The description makes it dear that the patient is in a very bad condition. Gawain immediately recognises the symptoms and knows what he must do. The functioning ofthe patient's heart is being made impossible by blood in the pericardium as a result of being stabbed with a lance, an injury that is one of the occupational hazards of knighthood. Taking a reed from the riverbank Gawain carves a hollow tube. He then inserts the tube into the existing opening made by the lance to the heart of the patient. When he instructs the woman to suck hard on the tube, blood flows out and life flows back in. The episode is concluded with a few details about follow-up care and mention of the fact that the acute treatment must be followed by a brief admission to a suitable institution. I will attempt to explain to you that the significant characteristics of this tale are the cornerstones of the modern treatment of a myocardial infarction. So what are we told here? A patient is acutely ill, dose to death, but his life is saved quickly and efficiently. A number ofelements are noted. First of all the right diagnosis is made very rapidly, the condition is
immediately recognised and the knight seems to have great clinical skills. The establishment of the diagnosis is followed by intervention, without hesitation, to the point and with great skill. A specific type of follow-up care and a briefadmission were already elements in the care of the mediaeval patient. We try to organise this today as well, and in modern-day jargon we say that the life of this patient from Parsifal was saved by a combination of prehospital diagnostics and acute intervention followed by a short stay hospital admission and rehabilitation. Stab wounds were a veritable epidemic in the Middle Ages; sudden obstructions ofcoronary artenes with resulting myocardial infarction are one oftoday's epidemically occurring acute life-threatening conditions. Every year some 26,000 patients in Dutch hospitals are diagnosed as having had a myocardial infarction. Public screening has shown that in addition, a large group of patients die suddenly from the consequences of a heart attack before medical help has even reached them. So, acute myocardial infarction is a frequently occurring cause of death and in addition a great source ofmorbidity.
Although descriptions ofthe clinical picture of an acute infarction have already been published in the past, it is nonetheless mostly through electrocardiography that a diagnosis ofany reliability can be established in a living patient. The electrocardiogram still plays a key role in diagnostic terms.2 In the first halfof the last century the treatment ofacute myocardial infarction consisted of pain medication and long-term bed F. ZQilstra University Hospital Groningen E-mail: [email protected]
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rest. This changed in the 1960s, when it became possible to identify ventricular rhythm disturbances remotely using electrocardiographic monitonng equipment. This enabled physicians and nurses to establish the nature ofthe rhythm and ifnecessary use electrocardioversion or defibrillation to prevent the patient's acute demise. With the arrival on the scene of lidocaine and 1-blockers, it became possible to use medications to treat and prevent ventricular rhythm diturbances. Since that time the most important cause of death in patients with a myocardial infarction who are still alive when the ambulance reaches them has been heart failure. Heart failure is usualy caused by defective pump function as a result of too much damage to the heart musde. During the phase before the rhythm of the patient is monitored, ventricular fibrillation continues to be a frequently occurring cause of death. This is one of the reasons why it is desirable to make or keep the arrival time of ambulances short. Research into the placement and use by lay people of automatic external defibrillators, particularly in places where many people gather such as airports, stations, and sports fields, would appear to be a promising option in order to further decrease the number of deaths due to ventricular rhythm disturbances.3
The next large step forward was the application of thrombolytic therapy to open obstructed blood vessels. In 1976 Chazov described the intracoronary administration of streptokinase, with coronary angiography being used to delineate its effect.4 Earlier administration of intravenous streptokinase, by Sherry amongst others in the 1950s, was of limited value because the effect could not be evaluated.5 The ideas from Chazov's Russian publication were
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picked up in the West after Rentrop in Germany had published a comparable study.6 In that same year, during my housemanship, I subscribed to the New England Journal of Medicine. In the first edition that landed on my doormat, Gruntzig described the earliest applications of percutaneous transluminal coronary angioplasty or PTCA, the Dotter treatment.7 After many years of systematic preclinical work, he published the results that he had booked with patients starting in 1977. These results indeed transcended borders and broke records, even though in those first years a PTCA was certainly not a risk-free enterprise. The first acute PTCA in apatientwith a myocardial infarction was thus the treatment of a complication ofan elective PTCA for stable or unstable angina pectoris.
The treatment of myocardial infarction underwent a true revolution after it was clearly demonstrated in a few megatrials in the 1980s that intravenously administered thrombolysis is better in comparison with conservative therapy. The predominant belief in those years was that the obstructing thrombus had to be combated with thrombolytics. Then the underlying injury inside the infarcted vessel had to be dealt with using a PTCA. In various major American and European studies in the 1980s, however, it was noted that a systematic combination of thrombolysis and PTCA indeed caused complications but had no clear benefits. Although since that time this has certainly stayed open to discussion, both American and European guidelines indicate that thrombolysis must be followed by a basically conservative policy, with intervention only being desirable in patients with specific indications or justification for invasive diagnostics and therapy;8 I will get back to this later. The consistent elements in the treatment of acute myocardial infarction comprise rhythm monitoring, pain control, medications that
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influence coagulation by inhibiting the aggregation of blood platelets, and medications that have an antithrombin effect such as heparin. In addition some patients require treatment with 13-blockers and angiotensin-conversion enzyme inhibitors. At the same time, for each patient with a myocardial infarction a choice must be made between a pnimarily mechanical approach and a pnmarily pharmacological one, in order to effect reperfusion of the obstructed infarct-related artery. The mechanical approach consists of an acute coronary angiogram followed by a PTCA. The pharmacological strategy consists ofthe administration ofmodem thrombolytic medication administered as a bolus injection. In the beginning of the 1990s, the first comparative study between these two strategies was carried out and published in which to begin with thrombolysis was compared with 'plain old balloon angioplasty', percutaneous angioplasty with only a balloon.9 In later years came stents and new intravenously administered and very powerful platelet
aggregation inhibiting substances were added. In direct comparative studies since that time many thousands of patients have been studied and the advantages of primary angioplasty have consistently come to the fore in all studies, as shown in a recent meta-analysis in which the data from 23 randomised studies are summarised.'0 After 30 days there were two less deaths in every 100 patients treated with primary PCTA and one cerebrovascular accident and four repeat myocardial infarctions were prevented, in comparison with the patients who had undergone thrombolytic therapy in these studies. This means that per 14 treated patients a serious complication or death was prevented ifthe choice was for primary PTCA. This does not take away from the fact that in comparison with conservative treatment without reperfusion therapy, thrombolytic treatment gives a very solidly based reduction in short- and long-term mortality
after a myocardial infarction. A cautious estimate of the effect of primary PTCA compared with conservative treatment, that is to say without reperfusion therapy, is that in one out of ten patients a serious complication or death is prevented. That the primary PTCA strategy can be applied at a national level, with a few large centres serving an extended area, was demonstrated in a Danish study." The studywas carried out by five heart centres in cooperation with 24 referring hospitals in an area with over three ofthe five million residents of Denmark. Such a model, in which patients do not go to the nearest hospital but are brought directly to a centre for percutaneous angioplasty, could be easily organised in large parts of East and West Europe, North America and other developed areas of the world. Czech studies have confirmed this. Thus thrombolytic therapy has actually become a secondchoice therapy for if a primary PTCA is no option for logistical reasons.'2 Unfortunately it is true that the Netherlands are lagging far behind in comparison with large parts of the United States, France, Denmark, Germany and Poland, where 30 to 40% ofall acute infarctions are already being treated with primary PTCA. In the Netherlands, a continued bastion of thrombolysis supporters, only some 11% of acute infarctions were treated with PT CA in 2001. So we are losing to the Czech Republic in more than just football, and this despite a healthcare structure that makes it possible to fly trauma helicopters and rapidly carry out surgical intervention in response to a broad range of acute situations. So what makes a mechanical approach more effective than thrombolytic therapy? To answer this question, one must take a look at the pathogenesis ofacute coronary artery obstruction. The first description of the pathology is based on an obduction that was carried out in 1793 on a famous English surgeon, Sir James Hunter,, who died suddenly immediately after a fierce argument with the administrators of the
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hospital where he worked.'3 The organisation of care was at that time already literally and figuratively of vital significance. At this obduction an obstructed coronary arterywas found to be thrombotic. The connection between this type of finding, the clinical picture and the electrocardiogramwas described in 1912 and 1919 by Bryan Herrick'4 and in 1920 by Harold Pardee," both American internists. We now know that the occurrence of a rupture or the tearing of the covering layer of an atherosderotic plaque resulting in clot formation is a frequent complication of the complex illness atherosclerosis.'6 Small ruptures can very easily occur subclinically, larger ruptures lead to acute coronary syndromes such as unstable angina pectoris, acute myocardial infarction and sudden death. If an obstruction is caused by a freshly fonned dotwith little or no nonthrombotic obstruction, thrombolytic therapy is a rational approach that is usually reasonably effective. In 25 to 40% ofacute coronary artery obstructions, the however, thrombotic factor is not the most important component of the obstruction. Plaque rupture with characteristics of dissection, intramural haemorrhage, and the atheromatous material that can be released from a ruptured plaque can all, or jointly, suddenly completely obstruct the artery and cause an infarction that will not respond to thrombolytic therapy. Similarly, the embolisation of material from the ruptured plaque, with subsequent obstruction in the distal flow area of the plaque rupture, can cause an infarction, as was demonstrated in recent angiographic studies.'7 This type of obstruction does not show any 'staining' on coronary angiography and can only be cleared with balloon inflation and stenting. This also explains why ever more aggressive thrombolytic strategies do indeed increase the number of bleeding complications induding the dreaded intracerebral haemorrhage but do not cause more arteries to open. The current editor of the
American Journal of Cardiology described this splendidly in 1972 together with Buja'8 and in an editorial with the title: 'If I have an acute myocardial infirction take me to the hospital that has a cardiac catheterisation laboratory and open cardiac surgical facilities'.'9 Thus he was at that time ahead of the findings ofthe randomised studies ofthe last decade. In summary it can be stated that the pathogenetic model has been convincingly demonstrated: angioplasty is better than thrombolysis, particularly because nonthrombotic components of acute obstruction often play a significant role. This condusion immediately leads to the following two questions: how enduring is the advantage of PTCA with respect to thrombolysis and what price should we pay for it? In order to answer this question, I would like to address the study that we carried outin the 1990s in Zwolle in more detail, because for the time being this is the only study from which long-term results have been published.20 In the Zwolle study 395 patients with acute ST-segment elevation myocardial infarction were treated with either intravenous streptokinase or primary PTCA. After five years the deaths in the primary PTCA group were 13% and in the streptokinase group 24%. Ifwe look at the combination of deaths and nonfatal repeat myocardial infarctions, there is a clear difference in the first 30 days, plus later on more comp.lcations continue to occur m the streptokinase group. So the relative added value of PTCA increases somewhat with the passage oftime. On closer analysis it is noted that further divergence is particularly the result of two factors. Primary PTCA opens more vessels and the chance that those vessels will dose again later is small in comparison with thrombolysis. We know that after coronary angioplasty an obstruction can sometimes recur, but this does not lead to repeat myocardial infarctions or death. Restenosis after coronary angioplasty is a gradual
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process that may be the cause of symptoms or ischaemia, but usually does not cause a sudden complete obstruction of a blood vessel treated with a PTCA. After thrombolysis it is indeed true that signs ofmyocardial ischaemia or infarction do recur rather frequently, in the Zwolle study approximately twice as frequently as with PTCA-treated patients. So more open coronary arteries are the first factor that determines the long-term advantage of a PTCA. The second important factor is a direct consequence of this: in our study coronary angioplasty patients went home with a better ventricular function than the streptokinase patients. In the years after acute events, hospital admissions for heart failure occurred three times as frequently in the thrombolysis group, 27 versus 9% in the PTCA group. The significance of this difference can hardly be overestimated; ventricular function is the most important determinant of long-term survival and quality of life after a myocardial infarction. This also means that in economic terms primary PTCA should above all be viewed as an investment. The costs of coronary angioplasty dunng the first day after a myocardial infirction are, ofcourse, higher than those of thrombolysis. If, however, one makes up the financial balance after five years, the total costs per coronary angioplasty patient, including re-admissions, additional interventions, and medications are approximately E15,000, whereas the average thrombolysis patient has by then cost 416,000. The costs that are incurred on the first day are only a limited part of the total costs. Not only from the Zwolle figures but also from those of the Mayo clinic, the PAMI group and Pannley's group, one can deduce that opting for primary PTCA does not lead to an increase in costs in the long term. Progress in medicine sometimes means rising costs, but that does not apply to the treatment of acute myocardial infarction; the best treatment with the least chance of renewed symptoms and hospital admissions is also financially the
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healthiest policy. In this light we must also view the new, improved and more expensive stents. If as a result ofthese, patients spend fewer days in the hospital and require fewer additional procedures, then such an extra investment is quickly earned back. Whether the new generation of stents will actually live up to this promise remains to be seen. In which direction should the treatent and study ofmyocardial infacion proceed? The obstructed coronary artery must be opened up as rapidly as possible; this is clear. But attention must also be paid to the myocardium that depends upon the epicardial artery, which has been opened up again. In his inaugural speech in November 2001, Professor Dirk Jan van Veldhuisen outlined the significance of heart failure. In 60 to 70% of all patients with heart failure an old myocardial infarction is the cause of poor pump function of the left ventricle. So retaining and restoring ventricular function are the primary goals of the further studies to determine the best treatment for myocardial infarction. Systematic studies of additional mechanical treatment and improvements in the accompanying pharmacological therapy, for example with ,B-blockers and ACE inhibitors, are of great significance. In addition metabolic intervention with glucose, insulin and potassium is a promising strategy in an attempt to bring more cardiac muscle tissue through an acute episode viably. By intervening in a focused manner in the metabolism in the myocardial cells that are not yet irreparably damaged at the momentwhen the blood supply to an inflircted area recommences, the total damage may be limited. In the GIPS 1 study carried out earlier, the electrocardiographic data, as well as the findings of enzymatic infarct size and left ventricular ejection fraction, point in that direction.2' So in 2003 we commenced a large randomised study, called the GIPS 2, in 1050 patients with an acute myocardial infarction, who were of course also treated with reperfusion therapy. In
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addition to the Groningen University Hospital and the Isala Clinics in Zwolle, hospitals in Meppel, Dokkum, Emmen and Amsterdam are participating and a number of other hospitals are preparing to participate as well. Should this additional metabolic intervention prove effective, this will be a second illustration of my earlier postulate that progress in cardiology need not always lead to increased costs: glucose/insulin/potassium is an inexpensive treatment. Paradoxically enough, this makes obtaining the necessary funding for such a project more difficult, because there are no potential sponsors who can eam back an investment in the study in patient care after a positive result from the study. In order to execute this type ofstudy, support from various other spcialities is necessary. Good collaboration with internists both in Zwolle and in Groningen is one of the most important cornerstones ofthe GIPS projects, from which a PhD student can pluck the fruit this year. The clinical-chemical laboratory is on the one hand vital to daily practice while on the other hand delivers fundamental intermediary data with infarction scope enzymatic determinations that give us insight into the value of therapeutic approaches. This also applies with regard to nuclear medicine. Ventricular function quantification is vital to many studies. In addition, after the acute phase, for many patients a long-term treatment strategy can only be formulated with the aid of studies of ischaemia and vitality of the myocardium. The decision-making with regard to the policy to be followed takes place in daily multidisciplinary consultations between cardiologists and thoracic surgeons. Daily collaboration with thoracic surgery is the cornerstone of optimal care for many ofourpatients.
Some scientific topics in this area are not directly suited to clinical patientrelated studies. In Groningen, under the supervision ofProf&ssorWiekvan Gilst, fundamental studies in
experimental cardiology are being carried out in the department of clinical pharmacology. In the realm of stents and restenosis after PTCA, myocardial ischaemia and heart failure, much can be accomplished through interaction between preclinical and clinical studies. Collaboration with the Department ofRadiology, underthe management of Professor Matthijs Oudkerk, has also expanded within a short time into an important branch of study concerning stable coronary artery disease and acute coronary syndromes including myocardial infarction. Some patients with myocardial infarctions do not, alas, show the specific deviations on their electrocardiograms that are usually the basis for a rapid diagnosis. Modern CT techniques will be able to visualise whether and if so what type of coronary artery is blocked. If necessary, focused cardiac catheterisation with a subsequent PTCA can follow. Developments in the field ofmagnetic resonance, too, will lead to considerable progress in noninvasive cardiac imaging in the years to come. How should the findings from infarct studies from the last years be implemented, and what does this mean in terms of the organisation of care? In the years to come the most profitable direction for our patients would be to realise a change in the organisation of care based on the findings of infarct studies ofwhich I have painted you a picture. The tale ofthe mediaeval knight is our guiding principle here: early prehospital diagnostics at the first contact between the patient and caregivers are an essential first step. In the general practitioners, cardiologists of regional hospitals, and above all in the ambulance services under the leadership ofRonald de Vos,we have expert and motivated partners in the field. Since January of 2004 diagnostic testing pursuant to all major myocardial infirctions has been taking place in the ambulances ofour region, aunks to new equipment for electrocardiography and the focused
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training of ambulance personnel. Thus a diagnosis is established earlier and there is an opportunity to prepare our hospital for the reception of a patient. The time thus saved is approximately three-quarters of an hour, and in particular for patients with large infarctions in the anterior wall of the left ventride this yields a clearly demonstrated limitation of damage to the myocardium.22 In addition it is possible to start the patient on focused pharmacological therapy during his transport, in preparation for coronary angioplasty. In the context ofthe current status of scientific knowledge, the oral platelet aggregation inhibiting substances aspirin and dopidogrel and subcutaneous or intravenous heparin must be given. Above all, ifthe travel time is long, intravenous administration of a glycoprotein Ilb/IIIa blocker may be indicated. Upon acute admission to the hospital, dose collaboration between the catheterisation laboratories and the coronary care unit is a prerequisite; this is one of the many arguments in favour ofstrengthening the organisational link between these two departnents. For most patients this means that after acute treatment they will be monitored for a short period of time in our coronary care unit and then transferred to hospitals near their homes. For patients from the city of Groningen and the immediate environs, the Martini Hospital will often be used for dinical mobilisation and rehabilitation. Although this works well in daily practice, we are evaluating with cardiologists at the Martni Hospital what we could achieve in the more distant future thdugh more intensive collaboration between the two largest providers of acute cardiological care in the region. So we are adapting the organisation of care: what does this mean for the 26,000 myocardial infarction patients per year in Dutch hospitals? Approximately 16,000 of these patients present with acute symptoms and ECG deviations that are diagnostic for acute infarction:
ST elevations suggestive of acute ischaemia as a consequence of a complete obstruction of a coronary artery. These patients must be treated with reperfusion therapy. Some of them are currently already being treated with primary PTCA, the majority still with thrombolytic therapy. Unfortunately there are also still some unlucky ones who are not receiving either type of treatment. The most important factors that play a role in this situation are two persistent faulty concepts that are the mental legacy of the thrombolysis age. First of all the mistake is sometimes made of refraining from treating a patient because of his or her advanced age. Although, incidentally with justification, it is assumed that there is more likelihood of complications in the older patient, studies have shown that it is specifically the older patient who can benefit considerably from an acute intervention.23 Secondly the fact that the effect of thrombolysis decreases rather considerably with the passage of time plays a role. This can be explained: the clot continues to organise itself. Thus the chance that a blood vessel will open in response to thrombolytic therapy becomes smaller with time. The chance that you can still open up a vessel effectively a few hours later with a PTCA is, however, great. So it is rational to treat patients with primary PTCA if more than the classic six hours have passed, particularly if there are still signs of ongoing ischaemia, and particularly if the infarction is localised in the anterior wall of the left ventricle. This particularly applies for patients with haemodynamic problems. The SHOCK study has shown that in patients with myocardial infarction and serious hypotension, an open coronary artery is ofvital importance in the first 24 hours after the commencement of symptoms.?4
The number ofPTCAs carried outin patients with acute myocardial infarction will increase significantly. So the opening of the heart centres in Leeuwarden and Enschede is
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coming at the right time; both new centres can make great contributions to the treatment of myocardial infarction in the northern and eastern Netherlands. Notwithstanding this, for the time being some of the patients who have suffered an acute ST-elevation myocardial infarction will still be treatedwith thrombolysis; changes in the organisation of care take time. Should signs ofheart failure occur in the hours after thrombolytic therapy, there is a strong indication to carry out cardiac catheterisation after all. For most patients who have had thrombolytic therapy, no policy can be formulated at present on the basis of modern research data. Virtually no relevant data exist. In a recent editorial Bill O'Neill,25 one of the infirction PTCApioneers, argues in favour of approaching postthrombolysis patients with the same strategy as patients with acute coronary syndrome without ST elevation, perhaps not true 'evidencebased medicine' but indeed proof of good common sense. This brings me to the following and final topic that I would like to discuss with you. In the days after their acute presentation, a diagnosis of myocardial infarction will be established in approximately 10,000 patients, often on the basis of the results oflaboratory studies. In these patients electrocardiograms during the acute phase do not show evidence of myocardial infarction, that is to say no ST elevation. From the perspective of the treating physician these patients fall into the much larger group of patients who, after acute presentation, are diagnosed as having acute coronary syndrome without ST elevation, a very homogeneous group in which, according to O'Neill, we must also place post-thrombolytic patients. The American, European, and Dutch Associations of Cardiology have established separate guidelines for this group of patients.26 This is the ideal area for modern computer tomographic diagnostics to prove its added value. However the word CT does not yet appear in the guidelines for acute coronary syndrome.
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Some of these patients have symptoms that may fit with a myocardial infarction and sometimes later on this does prove to be true, but the electrocardiogram does not help us. In addition a large number of these patients have a form of unstable angina pectoris. The physician who is responsible for initial treatment must always be aware of other conditions that can simulate acute coronary syndrome. The differential diagnosis must consider myocarditis or pericarditis, conditions of organs in the upper abdomen, or pulmonary embolus. Here the clinical qualities ofthe physician are more important than most diagnostic techniques. Over the last few years a central role has evolved for the determination of troponin levels, a fast and sensitive method that can have consequences with regard to policy. Patients in whom myocardial ischaemia has been shown on the basis ofelectrocardiographic changes and/or troponins are eligible for coronary angiography and subsequent revascularisation by means of PTCA or cardiosurgical intervention. The remaining patients undergo exercise stress testing, stress ECHO, or nuclear studies. In the absence ofdemonstrated myocardial ischaemia an initially conservative policy is adhered to. Is this practical and patient-friendly? The ICTUS study, a project that was completed in 2003 in which a few dozen hospitals in the Netherlands including nearly all heart centres participated, revealed that the vast majority ofpatients who were initially treated conservatively, underwent cardiac catheterisation later on. In epidemiological terms the negative predictive value of the means that have been used thus far is therefore only moderate, or actually poor, in terms of risk stratification. If in the interest of stratification we apply a combination of history plus electrocardiogram plus troponin determination and subsequently, ifstill no signs of coronary disease are found, a computer tomogram, the patient can either continue on to the catheterisation room or go directly
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home. This does, ofcourse, initially cost a bit extra, but once again it will be proven to be a good investment: a shorter stay in the hospital, shorter amount of work missed due to illness, and fewer coronary angiographies in patients who eventually, after much diagnostic uncertainty, fortunately turn out not to have heart problems, but who have indeed been exposed to the risks ofinvasive diagnostics. M References Haage BD. The thoracocentesis in Wolfram von Eschenbach's 'Parsifal'. Wurzburg medical-bistorical tales 1984;2:79-99. 2 Zimetbaum PJ, Josephson ME. Current Concepts: Use ofthe electro-cardiogram in acute myocardial infarction. NEnglJMed 2003;348:933-40. 3 Weaver WD, Peberdy MA. Perspective: Defibrillators in public places - one step closer to home. N EngI J Med 2002; 347:1223-4. 4 Chazov EI, Matveeva LS, Mazaev AV, Sargin KE, Sadovskaia GV, Ruda MI. Intracoronary administration offibrinolysin in acute myocardial infarct. Ther Arkh 1976;48:8-19. 5 Fletcher AP, Alkjaersig N, Smyrniotis FE, Sherry S. The treatment ofpatients suffering from early myocardial infarction with massive and prolonged streptokinase therapy. Trans Assoc Am Physicians 1
1958;71:287-96. 6 Rentrop KP, Blanke H, Karsch KR, Wiegand V, Kostering H, Oster H, Leitz K Acute myocardial infarction: intracoronary application of nitroglycerin and streptokinase. Clin Cardiol 1979;5:54-63. 7 GnmtzigAR, SenningA, Siegenthaler WE. Non-operative dilatation of coronary artery stenosis: percutaneous transluminal coronary angioplasty. NEnglJMed 1979;
301:61-8. 8 Van de Werf F, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KA, et al, for the Task Force on the management of acute myocardial infarction of the European Society of Cardiology. Management of acute myocardial infarction in patients presentingwith ST-segment elevation. Eur
HeartJ2003;24:28-66. 9 Zijlstra F, de Boer MJ, Hoorntje JC, Reiffers S, Reiber JH, Suryapranata H. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med 1993;328:680-6. 10 Keeley EC, Boura JA, Grines CL. Primary angioplastyversus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative reviewof23 randomized trials.
Lancet2003;361:13-20. 11 Andersen HR, Nielsen 'IT, Rasmussen K, Theussen L, Kelbaek H, Thayssen P, et al, for the DANAMI-2 Investigators. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. NEnglJMed2003;349:73342.
12 Grines CL, Serruys P, O'Neill WW. Fibrinolytic therapy: is it a treatment ofthe past? Circulation 2003;107:2538-42. 13 Wlllius FA, Keys TE. Cardiac Classics. St Louis: CVMosbyCo; 1941:265,817. 14. Herrick JB. Thrombosis of the coronary arteries. JAMA 1919;72:387-90. 15 Pardee HEB. An electrocardiographic sign of coronary artery obstruction. Arch Intern Med 1920;26:244-7. 16 Davies MJ, Thomas A. Thrombosis and acute coronary artery lesions in sudden cardiac ischemic death. N Engl J Med 1984;310:1137-40. 17 Henriques JP, Zijlstra F, for the Zwolle myocardial infarction study group. Frequency and sequelae of ST elevation acute myocardial infarction caused by spontaneous distal embolization from unstable coronary lesions. Am J Cardiol 2003;91:708-11. 18 Roberts WC, Buja LM. The frequency and significance of coronary arterial thrombi and other observations in fatal acute myocardial infarction. A study of 107 necropsy patients.
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19 Roberts WC. When I have an acute myocardial infarction take me to the hospital that has a cardiac catheterization laboratory and open cardiac surgical facilities. Am J Cardiol 1984;53:1410. 20 Zijlstra F, Hoorntje JC, de Boer MJ, Reiffers S, Miedema K, Ottervanger JP, et al. Long-term benefit ofprimary angioplasty as compared to thrombolytic therapy for acute myocardial infarction. NEnglJMed 1999;341:1413-9. 21 Van der Horst IC, Zijlstra F, van 't HofAW, Doggen CJ, de Boer MJ, Suryapranata H, et al. Glucose-insulin-potassium infusion in patients treated with primary angioplasty for acute myocardial infarction: the glucoseinsulin-potassium study, a randomized trial. JAm Coll Cardiol 2003;42:784-92. 22 Liem AL, van 't HofAWJ, Hoorntje JCA, de Boer MJ, Suryapranata H, Zijlstra F. Influence of treatment delay on infarct size and clinical outcome in patients with acute myocardial infarction treated with primary angioplasty. J Am Coll Cardiol 1998; 32:629-33. 23 De Boer MJ, Ottervanger JP, van 't Hof AW, Hoomtje JC, Suryapranata H, Zijlstra F. Reperfusion therapy in elderly patients with acute myocardial infarction: a randomized comparison of primary angioplasty and thrombolytic therapy. JAm Coll Cardiol 2002;39: 1723-8. 24 Hochman JS. Cardiogenic shock complicating acute myocardial infarction: expanding the paradigm. Circulation 2003; 107:2998-3002. 25 O'Neill WW. 'Watchful Waiting' after thrombolysis: It's time for a re-evaluation. JAm Coll Cardiol 2003;42:17-9. 26 Bertrand ME, Simoons ML, Fox KA, Wallentin LC, Hamm CW, McFadden E, et al. Task force on the management of acute coronary syndromes ofthe European society of cardiology. Management of acute coronary syndromes in patients presenting without persistent ST segment elevation. Eur HeartJ2002;23:1809-40.
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