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British Medical Bulletin 59:89-112 (2001)
© 2001 Oxford University Press
The acute management of myocardial infarction
Academic Department of Cardiology, University Hospitals Leicester, Leicester, UK
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Abstract |
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Acute myocardial infarction (AMI) is a common and potentially fatal condition. Primary prevention by reducing the risk of developing coronary atheroma disease has had an important effect on the incidence of the disease. However, for many, the first clinical presentation of their coronary atheroma is the development of acute coronary occlusion1
. The acute nature of such presentation is the result of the dynamic nature of the plaque event. Thus while measures such as increasing public education in areas of primary prevention are always important it needs to be recognised that real differences in outcome need to and can be made even once the event has occurred. Individuals developing chest pain need to be encouraged to present early, especially if they have a history of ischaemic heart disease. Once they have arrived at point of medical contact, rapid triage, early diagnosis and the institution of therapies designed to reduce the extent of myocardial damage are paramount. |
Introduction |
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While evidence-based use of established treatments is important, the urgency with which they are instituted may also be critical. Much of what is practised has become standard management for a number of years so it is easy to presume that the current management of acute myocardial infarction is optimal. This is not the case and many contentious issues remain. This article will address some of these.
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The natural history of AMI |
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In the UK, acute myocardial infarction accounts for up to 250,000 deaths each year with 150,000 admissions to hospital. Many deaths thus occur before help arrives, with up to 30% occurring within the first 2 h. Many of these deaths are due to malignant arrhythymias. To date, out-of-hospital mortality has changed little. However, the establishment of coronary care units in the 1960s showed that having access to defibrillators had a significant impact on outcome once the patient had reached hospital, with an overall reduction in mortality from about 30% to about 20%. The importance of having defibrillators available has thus been recognised and more than 20 airline companies now have such equipment (and trained staff) available. Some have suggested that defibrillators should be made available wherever the public are (shopping malls, football stadia). It will be interesting to see if prehospital mortality changes. It has been estimated that the lives of 29/1000 patients can be saved by out of hospital resuscitation and that 86% of these patients are discharged from hospital when the arrest is witnessed compared to 34% when it is not2
. However, to date, the most important therapeutic impact has been with the introduction of thrombolytic in-hospital therapy in the 1980s and this reduced mortality further, currently estimated to be 10–20%3. This is still a worryingly high figure and the reasons for it being so high need to be examined. |
Understanding the pathology of AMI: impact on early strategies |
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 TopFootnotesAbstractIntroductionThe natural history of... Understanding the pathology of... Managing the patient with...Initial managementOpening the artery: the...Summary and conclusionsReferences |
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Important studies by Davies4
, Conti5 and others helped explain clinical progression or regression in patients with coronary disease and identified targets for therapy. In essence, these authors described the coronary arteries from patients who had died following acute coronary syndromes. It became clear that the primary event was plaque disruption, the consequences of which depended on the patient's response to it6. Thus, following a plaque event, unstable angina (through the continuing presence of thrombus), stable angina (incorporation of the thrombus) or acute vessel closure could all result (Fig. 1). While factors such as initial severity of luminal narrowing clearly influence outcome, the dynamic theory of coronary syndrome pathology meant that having a plaque that significantly reduced the arterial lumen was not essential. The patient can suffer a very prothrombogenic response to the plaque event, especially for example, if they are smokers or have high lipid levels, both of which increase platelet aggregation.
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The development of these concepts, by placing the thrombus central to the clinical problem was important for a number of reasons. First, it confirmed various clinical observations. As early as 1980, de Wood had undertaken sequential angiography on patients with acute myocardial infarction (AMI). He reported a 90% thrombotic occlusion (suggesting that thrombus was not formed after infarction), but more importantly showed spontaneous recanalisation by demonstrating a 54% occlusion rate only, in those studied 12–24 h after onset. More importantly, it became clear that the first presentation of AMI was not necessarily preceded by symptoms of angina. The cornerstone of treatment thus became dissolution of the thrombus which had formed after a plaque event, so-called thrombo- or fibrinolysis. However, the acute management of AMI involves other important therapeutic measures as well.
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Managing the patient with acute coronary occlusion |
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The aims of managing patients with acute infarction are quite simple. They can be divided into those aimed at treating the patient's symptoms and those that will influence prognosis. Thus relieving pain and anxiety are critical. At the same time, limiting myocardial cell death and so preventing myocardial damage in order to reduce the impact on prognosis should be the absolute end-point of therapeutic strategies. Thus once a patient has sought medical help, the goals are early diagnosis, rapid symptom relief and imperative reperfusion. There remain a number of issues that need to be discussed before these absolute goals can be achieved in all patients.
Prehospital thrombolysis
Since the availability of defibrillators and thrombolysis have been shown to influence outcome, the first priority when managing someone with a suspected infarct is to ensure rapid access to these. Public education strategies aimed at ensuring that those with chest pain summon help quickly are vitally important, especially if the patient is at higher risk as, for example are those with previous angina. Since loss of muscle cells starts to become irreversible following 45 min of ischaemia7, and death is common within the first 2 h, speed is critical. While provision of immediate care will need to reflect local conditions (such as whether the area is urban or rural), evidence suggests that patients' needs may be best served by them calling for an ambulance or for the general practitioner (GP) to call an ambulance, rather than the GP going to the patient and assessing them first. Local arrangements should be discussed and agreed between the GPs, the ambulance service and representatives from the hospital medical staff. Local guidelines should be drawn up, adhered to, and audited. A number of rural areas now have early triage systems in place. In some areas of the UK providers of care are looking at delivering thrombolysis by appropriately trained paramedics. Setting up of such a system requires a number of prerequisites. First, it requires enthusiasm from ambulance crews and the emergency services administrators. Second, there needs to be the ability to diagnose accurately the presence of an AMI, which may involve electronic transmission of ECGs to the hospital or full paramedic training in ECG diagnosis, or both. Finally, there needs to be demonstration through the audit process not only of an increase in rapidity of thrombolytic delivery but also of better outcomes with no increase in incidence of adverse side effects.
Acute management following arrival in hospital The aim of all treatments is to reduce the impact of coronary artery occlusion on the myocardium. Speed is of the essence. A system that allows immediate triage of patients with chest pain is vital. The first contact should be with someone experienced in directing the patient towards the immediate management of their infarct. In some hospitals, this is an accident and emergency nurse, in some there is an admission ward evaluation, and in others the patient is seen on the coronary care unit. Whichever system is used, it should be structured and audited such that standard guideline directives (e.g. door-to-needle time) are met. Once the diagnosis has been made on history and ECG, then the patient needs to be in an area where monitoring and treatment can be undertaken, expeditiously and safely.
If the patient has not yet received pain relief, then this is a mandatory first step. Pain often exacerbates anxiety, which in turn increases catecholamine release and peripheral increase in systemic resistance. Pain should be relieved using intravenous opiate. Morphine, in the form of diamorphine (2.5–5 mg, repeated if necessary) should be given. Since opiate analgesia can induce vomiting, metoclopramide (10 mg i.v.) or cyclazine (50 mg i.v.) should also be given. Oxygen administration and obtaining venous access are early important actions.
Establishing an early diagnosis is important in order to start appropriate treatment. Thus a history of severe chest pain lasting for greater than 15 min, unrelieved by GTN should raise a high index of suspicion but so should less obvious presentations such as pain predominantly in the jaw or teeth, or in one or both arms or occasionally unusual presentations such as syncope. Breathlessness may be the presenting complaint in the elderly.
An ECG may confirm the diagnosis and help determine whether thrombolysis is indicated. It should be remembered that an apparently normal early ECG does not exclude myocardial infarction. Repeated ECGs may help show changes. In the thrombolysis trials, patients with the ECG changes of left bundle branch block, anterior ST elevation (Fig. 2) and inferior ST elevation in association with a history of chest pain were all shown to benefit from thrombolytic therapy. ST depression, equivocal T wave changes and normal ECGs were not. Patients with other ECG changes may still have acute manifestations of ischaemic heart disease and, in the era of glycoprotein IIb/IIIa (GPIIb/IIIa) receptor blockers, the use of markers such as troponin tests may be essential. Thus, where there is a difficulty in making a diagnosis, early evaluation of standard cardiac enzymes or measurement of troponin, especially in those with stuttering syndromes may help. Measurement of troponin T or I (myocardial myofibrillar proteins) may be a specific and rapid aid to such diagnoses8. How troponin testing influences the appropriateness of thrombolytic therapy in those without standard ECG changes has not been established. Since standard enzyme measurement usually takes too long and since the thrombolytic trials indicated that those patients who clearly benefit are those with obvious ECG changes (rather than patients whose diagnosis continues to be equivocal), it becomes clear that it is at the point of ECG diagnosis that thrombolytic therapy is mandated, provided there are no contra-indications.
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Thrombolysis
The aim of all therapies should be the early, complete and maintained patency of the infarct related artery. Currently, in the UK and elsewhere, thrombolysis remains the cornerstone of treatment, but percutaneous coronary intervention has a role to play and may become increasingly used in the future.
If there is a suspicion that the patient is suffering an acute infarct, then an aspirin (150 mg) should be given9 (chewing it is an effective method of absorption). Aspirin has been shown to have an independent influence on 30-day mortality. If the patient presents to a unit that does not have a policy of direct intervention, then once the diagnosis is confirmed on ECG, a thrombolytic should be administered without delay.
Natural thrombolysis occurs via the action of plasmin on fibrin thrombi. Plasmin is formed from plasminogen by cleavage of a single peptide bond. Plasmin is a non-specific protease and dissolves coagulation factors as well as fibrin based clots. Three thrombolytic agents are currently available. Streptokinase (SK) forms a non-covalent link with plasminogen. The resultant conformational change exposes the active site on plasminogen to induce the formation of plasmin. Tissue plasminogen activator (tPA) is a serine protease and binds directly to fibrin via a lysine site, activating fibrin-bound plasminogen. The theoretical advantages of tPA are its increased specificity and potency because of its direct affect on fibrin-bound plasminogen. It should have a greater effect than streptokinase on vessel patency which should translate into better clinical outcome. Being the product of recombinant DNA technology, there should be no allergic reaction. Unlike SK which because of neutralising antibody production can be used only once, tPA can be used repeatedly. Some of these theoretical advantages translate into definite clinical benefit with tPA but not all. Reteplase, a modified plasminogen activator, theoretically designed to overcome some of the limitations of tPA by having an increased resistance to breakdown, has now been introduced as an alternative to tPA as has TNK-PA.
There is true evidence of benefit from thrombolytic treatment. More than 100,000 patients have been randomised in large clinical trials testing thrombolytic agent against controls or against other thrombolytic agents; these trials have been summarised in the Fibrinolytic Therapy Trialists Collaborative Group10. The overall relative risk reduction in 35-day mortality with treatment was 18% (P <0.00001). The mortality at this time point was reduced from about 13% in controls to about 8–9% with treatment. However, in real life where the population is older than in the trials, the true mortality may be higher in treated patients with figures up to 18–20% thought likely.
Despite this, the beneficial effect of thrombolytic therapy still holds for those presenting within 12 h of onset of symptoms. This holds true irrespective of age, sex, history of hypertension or diabetes, or previous MI. It is clear, however, that the earlier patients are treated, the better. Administration of a thrombolytic saves about 30 lives in a 1000 in those presenting within 6 h of symptom onset, but only 20 lives per 1000 when patients receive treatment 6–12 h after symptom onset. After 12 h, there appears to be only a small and statistically uncertain benefit. The LATE Trial, for example, clearly showed lack of benefit 12 h after onset of symptoms11. Judging the onset of symptoms can be difficult and may be influenced by collateral flow from another artery. If, for example, a patient presents with stuttering symptoms over 24 h or so, but has had severe pain over a few hours and then has an appropriately abnormal ECG, thrombolytic treatment should be seriously considered. Many patients do not have optimal outcome from treatment because too little notice is taken of the symptoms. The specific question ‘from the history is it likely that this patient with this diagnostic ECG will benefit from thrombolytic therapy’ is too infrequently asked.
Thrombolytic dissolution of extracardiac thrombus that was perhaps maintaining the cerebral vascular integrity can lead to strokes. The overall risk of stroke is about 1.2% in treated patients compared to 0.8% in controls, an overall excess risk of 4 per 1000 treated patients (P <0.00001). There is some suggestion that patients who suffer cerebral haemorrhage may do so because of a general lytic ooze. Risk factors for ICH, such as hypertension and age have been well established. While the risk is clearly greater in the elderly, the overall benefit from lytic therapy exceeds the risk in these patients.
Prehospital thrombolysis has been shown to reduce the cardiac mortality compared to in-hospital thrombolysis by 17% (P = 0.03) almost certainly by reducing the mean time to treatment by about 1 h12. Despite this, prehospital thrombolysis has, in general, not been taken up for logistical reasons. Some of these are now being seriously addressed through the use of paramedics and strategies designed to provide treatment expeditiously and safely before reaching hospital.
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Initial management |
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Agents that should be given Care of the patient during their in-hospital stay involves continued monitoring for arrhythymias, careful daily clinical examination for new murmurs indicating the presence of mitral regurgitation or VSD, and examination to detect early signs of heart failure.
Apart from aspirin, the only adjunctive medication shown to improve outcome when administered acutely is intravenous ß-blockade (ISIS-1) trial13. Given within 12 h of onset of the infarct intravenous ß-blocker reduced a composite end-point of death, cardiac arrest and re-infarction (P <0.002). The benefit was most evident in the first 2 days following administration (25% reduction), most likely due to a reduction in ventricular fibrillation and cardiac rupture. It should be given to patients with inappropriate tachycardia and hypertension. It is generally underused.
The benefits of continuing ß-blockers in the longer term have been well established. It has been suggested that a ß-blocker given only in the acute phase is in itself a strategy that has no longer term benefit. In an overview published in the British Medical Journal in 1999, Freemantle and colleagues reviewed 82 ß-blocker trials. Overall, the longer term trials indicate the pooled OR as being 0.77 (95% CI, 0.69–0.85). Over 2 years, 42 patients would need to be treated with ß-blockers to avoid one death, whereas 292 patients would need to be treated over the same period with antiplatelet agents to achieve the same benefit14. There appears to be no time cut-off after which ß-blockers no longer benefit, so it would seem that these agents need to be continued indefinitely.
A number of studies15,16 have demonstrated that early administration of an ACE inhibitor in unselected patients improves outcome. Even in the absence of any clinical signs of heart failure, early (day 1) treatment improves outcome (Table 1). Subgroup analysis of GISSI-3 and ISIS-4 indicate greater benefit in high-risk patients treated after day 1. Continued treatment improves longer term outcome. In a meta-analysis, Domanski17 reviewed 15 trials (15,104 patients). ACE inhibitor administration significantly reduced the risk of death (OR, 0.83; 95% CI, 0.71–0.97), cardiovascular death (OR, 0.82; 95% CI, 0.69–0.97) and sudden cardiac death (OR, 0.80; 95% CI, 0.70–0.92). The recent HOPE study showed that treatment with ramipril (n = 651) resulted in a lower primary end-point (14%) compared to placebo (17.8%; RR, 0.78; 95% CI, 0.70–0.86; P < 0.001)18, and has raised the profile of this particular ACE inhibitor.
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Agents tested and shown not to be of benefit Nitrates
Nitrates might be expected to have a beneficial effect in acute myocardial infarction by dilating arterial resistance vessels, venous capacitance vessels and coronary arteries and so opening up collaterals. Reducing afterload and preload, reduced wall tension and oxygen demand are also theoretical benefits. Nitrates are also known to affect platelet aggregation. However, in the ISIS-4 trial15
, the 35-day mortality was 7.34% in the group treated for 4 weeks with isosobide mononitrate versus 7.54% in controls. Benefit was also not shown in the GISSI-3 trial46.
Magnesium
Small studies and a larger trial based in Leicester (LIMIT-2) suggested a benefit from use of magnesium. However, in the larger ISIS-4 trial no benefit was seen. Controversy continues, however, since in the LIMIT-2 study not all patients received thrombolysis whereas all did in ISIS-4. The magnesium was also administered at different times. Thus a small advantage from magnesium may be being masked in the patients treated with thrombolysis. Advocates would argue that magnesium is beneficial only if present at appropriate blood levels at the time of reperfusion, i.e. it needs to be given early. Longer-term surveillance of the LIMIT–2 patients by the investigators suggests a continued benefit (K Woods, personal communication).
Prophylactic anti-arrhythmic agents
A number of studies have shown a trend towards an increase in mortality in patients given class IB agents prophylactically. This does not mean that an individual patient with a ventricular arrhythmia should not be considered for a drug like lignocaine. That stated, there is also some data to suggest that those patients with frequent premature ventricular beats (10 h) or repetitive (>1 run ventricular tachycardia) do better at 2-year follow-up treated with amioderone in terms of resuscitated ventricular death or arrhythmic death (4.5% versus 6.9% placebo; RRR, 34.3%; 95% CI, 1.9–66.8; P <0.03)19. Further, a meta-analysis of 13 trials (8 in patients with a history of AMI, 5 in patients with a history of congestive heart failure total; n = 6500) indicated that amioderone provides a modest reduction in all-cause mortality, death from arrhythmia or sudden death20.
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Opening the artery: the absolute goal |
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Thrombolytics In theory, tPA and reteplase should be more effective agents at opening coronary arteries than SK. This has been supported in a number of angiographic studies which showed a higher percentage of patients with patent arteries after tPA treatment than with SK (
70% versus 35%). There followed a number of studies that set out to compare the clinical efficacy of the two agents. Neither the GISSI-2 study21 nor the ISIS-3 study found any difference in 30-day mortality rate (8.5% SK versus 8.9% tPA) and (10.6% for SK and 10.3% for tPA, respectively). In the GUSTO trial, a more aggressive regimen was used, the so-called front loaded tPA. This produced a small, but significant, benefit favouring tPA (6.3% versus 7.3%; P >0.04). There was, however, an excess of strokes with this accelerated or front loaded regimen (0.72% for tPA versus 0.54% for SK) which translates into 5 or 6 new haemorrhagic strokes per 1000 treated. Combining deaths and strokes, there was still a benefit favouring tPA (6.9 % versus 7.8%)22. In the UK, streptokinase remains the first line treatment for most AMIs. This is because the advantage for tPA is modest at most and tPA is expensive compared to SK, allowing more patients to be treated overall for the same amount of money. Since streptokinase neutralising antibodies are formed from about day 4 onwards, then tPA will need to be administered should the patient re-infarct after this time. This accounts for about 20% of the market. Based on the GUSTO trial there are also patients who should receive tPA first time out. They include the younger patient, those presenting early and in those with larger, and in particular anterior, infarcts.
The lack of any large difference in clinical outcome between tPA and SK despite the difference in angiographic patency needs to be explained. tPA being locally effective has little systemic thrombolytic effects (for example on circulating plasminogen). It is, however, very specific which is the likely cause for the excess in strokes. It has a short half-life compared to SK. It has been clearly shown in animal models of arterial thrombotic occlusion that opening of the vessel by administration of tPA may be followed by early reclosure, perhaps within minutes. The 90-min angiogram cannot reflect the consequent re-occlusion of the artery, which will happen less with SK which has a longer half-life. Thus, the increased early patency with tPA may not translate into a decrease in 30-day mortality. The short half-life of tPA means that heparin should be co-administered and continued for 24 h, although true benefit has never actually been proven. The addition of subcutaneous heparin to streptokinase produced no improvement in outcome in the GISSI-2 trial and was associated with an excess of bleeding. In the GUSTO trial, the addition of subcutaneous or i.v. heparin made no difference to outcome in the SK groups, but it is indirectly assumed that the addition of heparin to the tPA group in this study contributed to its benefit.
What to give
In the absence of previous administration, the first line thrombolytic in the UK is streptokinase: 1.5 million units are given in 100 ml 5% dextrose or 0.9% saline over 30–60 min. Side-effects and complications with streptokinase include hypotension, but severe allergic reactions are rare. Routine hydrocortisone is not required and hypotension should be managed simply by lying the patient flat, raising their legs and administering atropine or volume expanders if necessary. The infusion should be temporarily halted.
If SK has been given >5 days previously, then tPA as a 15 mg bolus followed by 50 mg over 60 min and the residual 35 mg over a further 30 min or reteplase (10 IU bolus + a further 10 IU after 30 min) should be given. Choice between these two agents will be based on hospital or individual policy. Trials comparing efficacy show equivalence, which is interesting considering reteplase was ‘designed’ to have advantages over standard thrombolytics.
It should also be remembered that, during the early stages of thrombolysis, patients are at risk of bleeding and care about placing temporary pacing wires and arterial sampling for blood gases should be paramount. If the patient has a spontaneous bleed large enough to be life-threatening, then the infusion should be stopped, fresh frozen plasma given and, if necessary, i.v. aprotinin (4 mg/kg) administered, with or without tranexamic acid (25 mg/kg orally 6 hourly).
Thrombolysis should not be given if standard contra-indications are present (Table 2).
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In the ISIS-2 trial, aspirin (
150 mg) was shown to have an effect additional to streptokinase and should be continued at this dose indefinitely.
Problems with thrombolysis
The ‘open artery’ theory suggests that the short- and longer-term outcome after acute infarction is determined by the degree of patency obtained with treatment following initial vessel closure, and that when optimal patency is achieved it is also maintained. In other words, benefit is lost if the vessel re-occludes. Degree of patency is graded according to the TIMI classification, where TIMI flow 0 = total closure and TIMI flow 3 = flow equivalent to that in unaffected arteries. A number of studies have clearly shown that longer-term outcome correlates with the TIMI flow seen, especially at 90-min angiogram. For example, data from the angiographic study arm of the GUSTO trial23 clearly demonstrate that patients with TIMI grade 0 flow (i.e. complete occlusion) at 90-min angiogram had a 30-day mortality of 8.4%, whereas in those with TIMI grade 3 this was only 4%.
Other non-randomised data are available to support the belief that the better the patency the better the long-term outcome. Thus a retrospective meta-analysis of 4607 patients showed that mortality was 3.7% for TIMI grade 3 flow, but 6.6% (P <0.0003) for TIMI grade 2 and 9.2% (P <0.0001) for TIMI 0/1 flow24. Five and ten year follow-up suggests a continued benefit in those patients with initial grade 3 flow25.
There are two problems with thrombolytic therapy. Thrombolytic therapy alone is unable to produce ‘adequate patency’. TIMI grade 3 flow is seen in only 54% of patients treated with front loaded tPA and in only 30% with SK. Thus thrombolysis with current agents appears to have a therapeutic plateau. This may be due to a number of factors: atheromatous bulk, degree of intimal disruption or lytic resistance being some.
The second problem with current thrombolytic regimens is vessel re-occlusion. A number of studies have compared early (usually the 90 min patency) with late patency to determine the re-occlusion rate. Re-occlusion is a time-related phenomenon, and reaches an astonishing, albeit plateaued, rate of 30% by 3 months26. Reasons for this include re-release of thrombin, residual prothrombogenic plaque and activation of coagulation factors V and VIII by plasmin. Patients who have re-occluded have a much lower 1-year event-free survival (83% versus 63%; P < 0.001) and the 3-year event rate is 73% in the re-occluded group versus 33% in the group whose arteries are patent at 3 months.
Current goals are aimed at dealing with these two problems: optimal TIMI flow and re-occlusion. Strategies include the development of new thrombolytics, altering adjunctive therapy or by treating the occluded artery mechanically with balloon angioplasty and stenting.
Can adjunctive therapy help?
New thrombolytics
Various investigators have studied tPA mutants or variants of tPA. These agents may possess altered resistance to inhibitors such as plasminogen activator inhibitor-1 (PAI-1) or require binding to fibrin to become active. Other approaches have involved altering thrombolytic molecules to reduce their plasma clearance, although such modifications may lessen their thrombolytic effectiveness. One mutant produced by an alteration at the kringle 2 region of the tPA molecule appears to have a prolonged half-life, which may prove to be of value27. Some early trials in patients using tPA mutants have shown promise. Whether these and other mutants, such as those with increased resistance to plasma inhibitors, are any better in clinical practice than current agents is as yet unclear and will need to be tested in large, randomised, clinical trials against tPA.
Reteplase or rPA, a non-glycosylated deletion mutant of wild-type tPA, was the first member of the third generation thrombolytics and is one successful variant of tPA. Unfortunately, patency rates have been shown to be no greater with reteplase than with tPA and choice between these agents is frequently a commercial one.
Naturally occurring thrombolytics such as the vampire bat plasminogen activator (bat-PA) have also attracted attention. This latter agent is similar to human tPA but does not have a plasmin-sensitive processing site. It thus appears resistant to PAI-1 (one inhibitor of tPA) and has greater fibrin selectivity than tPA. Experimental data have shown that bat-PA is efficacious without activating systemic plasminogen and thus may partly circumvent bleeding complications associated with thrombolytics. Clinical trials were planned and are still awaited.
Staphylokinase is a protein with known profibrinolytic properties and is produced by Staphylococcus aureus. A recombinant form (STAR) has been produced and observed in experimental studies to be less immunogenic, but more active, against platelet-rich arterial clots than streptokinase. This agent has now been evaluated in small published clinical trials. STAR (10–20 mg) given intravenously over 30 min to patients with acute myocardial infarction resulted in similar coronary recanalisation rates to accelerated tPA, but without any fibrinogen breakdown (i.e. significantly more fibrin-specific than accelerated tPA)28. However, all patients developed STAR-neutralising antibodies from the second week after treatment, suggesting that, at least in man, this agent may not be as hypo-allergenic as originally hoped.
All these agents will need testing against current best therapy, tPA, in large trials. The TIMI patency of all the newer thrombolytics compared to those currently available is shown in Figure 3. Perhaps the most promising new agent is tenecteplase (single bolus) TNK-tPA which has been tested in the ASSENT-2 and ASSENT–3 trials29,30. It has slower plasma clearance, better fibrin specificity and high resistance to plasminogen-activator inhibitor 1. It seems easier to administer than tPA, and this may be its main advantage.
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In vitro and ex vivo work is starting in our laboratory to assess whether there is increased efficacy of thrombolytic when it is targeted to the thrombus using monoclonal antibodies, with the aim of increasing local concentration and reducing side-effects. In theory, a systemic injection of targeted thrombolytic would be concentrated at site of the infarct.
Adjunctive therapy
Heparin has limitations as an antithrombin: it needs a cofactor, has little action against bound thrombin and can be inactivated. Three large clinical trials designed to evaluate the value of hirudin (a powerful direct antithrombin originally extracted from the leech) in the setting of myocardial infarction have been undertaken and reported in 1994 (GUSTO-II, TIMI-9 and HIT-III)31–33. Given with tPA, the dose of hirudin used in these trials was as an intravenous bolus of 0.6 mg/kg, followed by a fixed dose infusion of 0.2 mg/kg/h for 96 h (GUSTO-II) or 72–120 h (TIMI-9). It became clear to the Event and Safety Committees during the trials, however, that bleeding, and in particular intracerebral haemorrhage, was occurring to excess in patients given hirudin. In the HIT-III trial, the incidence of haemorrhagic stroke was 3.4% in the hirudin group and 0% in the heparin group. These trials were stopped.
The TIMI-9 and GUSTO-II trials were then restarted using lower doses of hirudin (0.1 mg/kg bolus and 0.1 mg/kg/h infusion) and the lessons from the first trials on the need for APTT monitoring were incorporated (APTT value 2–3 times baseline). Unfortunately, early reports suggest that at this dose of hirudin no benefits may be seen. This suggests that the therapeutic window for these agents is very narrow. These studies taught us that increases in patency rates may come only at the cost of extra bleeding.
GPIIb/IIIa antagonists
Regardless of the mechanism of activation, the final common pathway for platelet aggregation is the cross-linking of platelets through fibrinogen bound to GPIIb/IIIa. The importance of GPIIb/IIIa has been known for many years because of the evidence that Glanzmann's thrombasthenia (GT), an hereditary deficiency of GPIIb/IIIa, results in a moderately severe bleeding tendency. Early animal studies with monoclonal antibodies to GPIIb/IIIa demonstrated the potent antiplatelet effects accruing from blocking the binding of fibrinogen to activated GPIIb/IIIa. This has lead to a number of fibrinogen receptor antagonists currently in various stages of clinical application. Their value in interventional cardiology and in the management of acute coronary syndromes has been proven in various well-controlled trials. Since the overall aim is to attempt to reduce thrombotic occlusion and since thrombus in the arterial system is both platelet initiated and platelet propagated, then these agents have come under some scrutiny to see if there is any benefit in the setting of acute infarction. Thus phase I studies and early safety pilot studies have shown an increase in TIMI grade 3 patency at 60 and 90 min when half dose thrombolytic was given in combination with glycoprotein IIb/IIIa receptor blocker (Fig. 4)34–36.
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These studies have led to the initiation and recently reported GUSTO-V (previously GUSTO-IV) study37
, which tested the efficacy and safety of half-dose reteplase with full-dose GPIIb/IIIa (a chimeric monoclonal antibody abciximab aka ReoPro). Taking into account the ICH rate for the antithrombin trials and the implied narrow therapeutic window, these studies implied it was possible to predict that the complication rates would form an important part of the trial report. This the ‘non-inferiority’ trial study of 16,588 patients was published in The Lancet in June 200135. It showed that the mortality rate for the full-dose reteplase was 5.9% (n = 488), and for the half-dose reteplase plus full-dose abciximab was 5.6% (n = 468) – clearly no mortality benefit. There was, however, a significant benefit for the combined end point of ‘death, re-infarction and need for coronary intervention’ (20.6% for lytic alone group versus 16% for lytic plus abciximab; OR, 0.75; CI, 0.69–0.81; P <0.0001). Re-infarction was the significant factor driving this combined end point benefit (3.5% reteplase versus 2.3% half-dose reteplase plus abciximab; P <0.0001). However, not only was this an open label trial, but re-infarction was investigator determined. Additionally, there was a cost for the reduction in this softer end-point with an increase in bleeding for the combined therapy group, some of which were severe and spontaneous (combined therapy 1.1% versus reteplase alone 0.5%; P <0.0001); any bleeding occurred in 24.6% versus 11.4% reteplase alone; P <0.0001. What did this trial tell us? It confirmed that the therapeutic window for agents or combinations is narrow. However, there is some suggestion from this trial, albeit unpublished, that those patients who went onto angioplasty did better if they were on the combined treatment. However, medication to produce maximal patency may have limited potential. It is likely that a trial comparing Clopidogrel (the so-called ‘super-aspirin’) with aspirin will be compared with aspirin alone after myocardial infarction. There will always be patients who fail thrombolytic therapy for mechanical reasons such as atheroma bulk or large spontaneous intimal disruption (Fig. 5). Perhaps mechanical strategies are better.
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Primary angioplasty Grade 3 TIMI flow can only be achieved in 54% of patients with thrombolysis; perhaps it will be shown to be more with lytic therapy plus powerful antiplatelet agent. Currently, however, the only treatment shown to be better than thrombolysis is to open the artery at the time of presentation with balloon angioplasty (plus stent; Fig. 6). A number of studies, albeit with small numbers, have shown that if a patient can be taken to the catheter laboratory within 12 h and the artery successfully opened and dilated, TIMI grade 3 flow can be obtained in 80–97% of cases38
. Short- and long-term survival and morbidity have been improved compared to thrombolysis. Re-occlusion of the vessel remains a real problem with thrombolytic therapy (reaching 30–40% by 3–6 months, and remaining at 25% at 1 year). The comparable 3–6 month vessel patency after primary angioplasty is much higher (87–91%)39. Pooled data from the various thrombolytic trials not surprisingly suggest a worse longer term outcome compared to direct angioplasty (death 6.4% versus 2.5%; re-infarction 7.9% versus 2.0%; stroke 2.5% versus 0.3%; death and/or re-infarction 13.1% versus 4.3%, respectively). Recurrent ischaemia in the three comparative trials (MAYO clinic, PAMI-I and Zwolle) varied between 27% and 36% for thrombolytic-treated patients and between 9% and 15% for direct angioplasty patients. The 2-year event-free survival (i.e. no myocardial infarction, cardiac death or need for re-intervention) for the PAMI-I trial patients was reported to be 85%, indicating that the early separation of the outcome curves for thrombolytic-treated and angioplasty-treated patients is maintained.
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However, there are difficulties with these trials. The small numbers of centres and patients results in wide confidence intervals. The data, therefore, have been pooled and evaluated on the basis of ‘high’ and ‘low’ risk patients. It would appear that the high-risk patients (older age, larger infarcts and anterior infarcts) benefit both in terms of mortality and re-infarction from direct angioplasty, whereas the low-risk group benefit only in terms of re-infarction. The GUSTO-IIb study40
failed to demonstrate longer term benefit. This was undoubtedly due, in part, to inadequate angioplasty. More recent trials in which stenting has been employed have shown significant improvement in immediate patency rates which may be the critical factor.
The same factors that influence benefit in thrombolytic treatment need also to be considered in primary angioplasty. Thus Cannon et al41 found that in 27,080 patients treated with primary angioplasty, the door-to-balloon time was a significant factor in mortality outcome (adjusted odds of mortality OR, 1.41; 95% CI, 1.08–1.84; P = 0.01 for door-to-balloon time > 2 h: and OR, 1.61; 95% CI, 1.25–2.08; P < 0.001 for > 3 h). Others have asserted that even late after the event, primary PCI may beneficially influence left ventricular re-modelling42; this is not current practice in the absence of recurrent symptoms or ECG changes, however.
The most important factor determining an improved outcome in patients undergoing intervention for acute myocardial infarction appears to be the use of stents. In a small study, Maillard found the 6-month event-free survival rates were 81.2% in those stented versus 72.7%43. The major study, however, was published by the Beaumont Hospital group. They studied patients who only received PCI for the primary treatment of their infarct. The acute result was significantly better in the stented group. The 6-month event-free survival rate was also higher in the stented group (12.6% n= 452 versus PTCA 20.1% n = 448; P <0.01)44.
There are now compelling data to suggest that the addition of glycoprotein IIb/IIIa inhibitor to the strategy (the ADMIRAL trial) improves outcome even further45.
What are the advantages of primary angioplasty?
Although still a matter for debate, the case for direct angioplasty for acute MI appears compelling, particularly for selected high-risk cases presenting within 12 h to an hospital with a catheter laboratory. It appears as effective or more effective than thrombolysis with significantly lower risk of stroke and lower risk of the high mortality risk associated with cerebral bleeding (stroke – PTCA = 0.7% versus lytic = 2.0%; OR, 0.35; 95% CI, 0.14–0.77; P = 0.007: intracerebral – haemorrhage PTCA = 0.1% versus lytic = 1.1%; OR, 0.07; 95% CI, 0.0–0.42; P <0.001). These figures do not of course take account of current strategies that incorporate glycoprotein IIb/IIIa receptor blocker use. Importantly, intervention deals with the stenosis which lytic agents cannot do. There are data to support the concept that the greater the residual stenosis the more likely the artery will re-occlude46. Failure of reperfusion is more likely with lytic therapy when there is significant atheroma bulk or severe disruption of the plaque. Finally, knowing the state of the coronary arteries allows for better triage of patients post-infarct. Thus the normal 5–7 day in-patient stay may be reduced if the infarct-related artery is open and we know the rest of the arteries are normal47.
What are the problems with primary angioplasty?
Primary and rescue angioplasty may be being undertaken in patients who are unwell and the best outcomes may require the most experienced operators. In a retrospective study, Magid et al48 showed the benefits of primary angioplasty outweighed those of thrombolysis in high and intermediate volume centres, but not in low volume centres ( high volume – mortality 3.4% PTCA versus 5.4% thrombolysis; P < 0.001: low volume centres – 6.2% versus 5.9%; P = 0.58). Poor outcome for patients with cardiogenic shock remains high no matter what treatment is instigated. Cost-effectiveness data are less available for the current interventional strategy of using stents and glycoprotein IIb/IIIa receptor blocker, than for just balloon angioplasty.
While better early patency rates can be achieved with primary PTCA which translates into improved clinical outcome, both in the short and medium-term, this treatment is not available to all. The problem is that most patients are admitted to hospitals without interventional facilities. There is neither the personnel nor financial resources to place such facilities in all hospitals receiving AMI patients.
Dealing with the thrombolysis versus angioplasty for AMI problem
There are a number of options. Some have advocated a policy of thrombolysis followed by angiography in all patients with angioplasty when indicated (occlusion or significant residual stenosis in the infarct-related artery). Thus Ross49 found a tPA patency rate of 61% on arrival on the catheter table which was increased to 77% after intervention. Others believe that, in the current resource-limited climate, primary angioplasty for acute infarction cannot be delivered and that angiography and angioplasty where indicated should be reserved for those who demonstrate failure of lytic therapy. There are two UK trials on-going of such a policy. The first, the MERLIN trial50, has reported preliminary data. In 179 patients undergoing emergency angiography for failed thrombolysis, 156 were deemed to need angioplasty. Providing at least TIMI grade 2 flow was attained (124/135 patients), they showed the mortality was low (5.9%). In the 11 patients in whom TIMI grade 2 flow was not successful, the mortality was very high at 48%. Interestingly, re-infarction or need for revascularisation was 37% in the 41 patients deemed not to need intervention following their angiogram. In the second ongoing trial, the UK-based British Heart Foundation funded on-going REACT trial, patients shown on 90 min ECG to have failed thrombolysis (failure of resolution ST to 
50%) were randomised to conservative therapy, second thrombolytic or intervention.
Whether high risk patients will do better receiving thrombolysis at their admission hospital or primary angioplasty after transfer to another hospital is also currently being tested both in the UK and in Europe.
Yet others are developing strategies for early out-of-hospital triage. Thus, on arrival at a patient suffering chest pain, the paramedic would record an ECG and electronically transmit it to a dedicated co-ordinator in a dedicated catheter laboratory. The patient would then be received to this laboratory and undergo angiography and intervention if necessary. Such concepts will need serious resource examination
Understanding that there are significant benefits that can be attributed having an open artery is important51. While current measures of patency may be deemed crude in that the TIMI grade flow only measure epicardial flow rather than perfusion52, this is currently the best indicator in that it has correlated well with short, medium and longer term outcome. There are data to support the benefit of an open artery on short-term commonly recognised complications such as electrical instability53. However, whatever the initial treatment prognosis for the infarct, be it lytic or primary PTCA, certain complications occur and need to be treated since these too may influence prognostic outcome.
The most important action, taking account of what has been stated about the importance of having an open artery is that if a patient either fails to settle after thrombolysis (on-going pain or recurrent ECG changes) intervention (with transfer if necessary, for so-called rescue angioplasty) remains an important option54.
The future is likely to see the advent of facilitated PCI (percutaneous coronary intervention). In this scenario, a rapid onset-of-action lytic (tPA or TNK-PA) will be given as soon as possible (including in ambulances). The additive benefits of subcutaneous heparin and/or glycoprotein IIb/IIIa inhibitors (ASSENT-3)30 will be utilised and the patient will either undergo coronary angiography and intervention on arrival at the hospital or careful assessment of success of medical treatment be undertaken prior to consideration for coronary angiography. Of course the practicality, bleeding and other side-effect risk and cost effectiveness of such strategies will need to be tested in appropriately conducted clinical trials. Trial data suggest mortality is about 5–6%. Real life mortality in 2001 according to registries such as the GRACE Registry and EuroASPIRE suggest it is closer to 10–12%. Even so, the numbers of patients required to prove benefit with such aggressive interventions will need to be very large.
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Summary and conclusions |
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Effective opening of the infarct-related artery is of paramount importance. It saves lives in the short, medium and long-term and reduces complications. Thrombolytic therapy with adjunctive aspirin has significantly improved the outcome following acute myocardial infarction. It is cheap and relatively safe. It must be given as early as possible. On-going efforts in public education about the need to recognise the implications of chest pain particularly in those with increased risk factors or who already have angina is imperative in order to reduce the delay in administration of thrombolytics. Beyond this there remains a need to optimise the vessel patency rate since this definitively correlates with both early and longer term survival. New thrombolytics are becoming available, which may improve patency. These agents, however, will need to be tested against current regimens in large clinical trials. Testing of the new antithrombins for reducing vessel re-occlusion in such a setting have indicated that these agents have a relatively narrow therapeutic window. We await the assessment of half-dose thrombolytics with full dose glycoprotein IIb/IIIa receptor blockers. Primary angioplasty may prove the definitive treatment for myocardial infarction in selected cases such as young or elderly patients with anterior infarction, provided the procedure can be undertaken early enough to be of benefit. Limited resources may be the inhibiting factor in wide-spread use of this treatment modality. However, ways to provide primary angioplasty to appropriate patients and importantly in a cost-effective manner should be the strategic aim over the next few years. Facilitated angioplasty may become a strategy to be tested. Early assessment of the thrombolysed patients or triage at the prehospital stage is the way forward.
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Footnotes |
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Correspondence to: Mr A H Gershlick, Academic Department of Cardiology, Clinical Sciences Building, Glenfield Hospital, University Hospitals Leicester, Leicester LE3 9QP, UK
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