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European Heart Journal 2003 24(1):28-66; doi:10.1016/S0195-668X(02)00618-8
Copyright © 2003 by the European Society of Cardiology.
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Task Force Report

Management of acute myocardial infarction in patients presenting with ST-segment elevation

The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology, Frans Van de Werf, Chair*, Diego Ardissino, Amadeo Betriu, Dennis V. Cokkinos, Erling Falk, Keith A.A. Fox, Desmond Julian, Maria Lengyel, Franz-Josef Neumann, Witold Ruzyllo, Christian Thygesen, S. Richard Underwood, Alec Vahanian, Freek W.A. Verheugt and William Wijns

Received August 6, 2002; accepted August 7, 2002 * Correspondence: Prof. dr. F. Van de Werf, Cardiology, Gasthuisberg University Hospital, Herestraat 49, B-3000 Leuven, Belgium.

Key Words: Acute myocardial infarction • drug therapy • ischaemic heart disease

Introduction
    The definition of acute myocardial infarction
    The pathogenesis of acute myocardialinfarction
    The natural history of acute myocardial infarction
    Aims of management
Emergency care
    Initial diagnosis and early risk stratification
    Relief of pain, breathlessness and anxiety
    Cardiac arrest
    Basic life support
    Advanced life support
Pre-hospital or early in-hospital care
    Restoring coronary flow and myocardial tissue reperfusion
    Fibrinolytic treatment
    Fibrinolytic regimens
    Percutaneous coronary interventions (PCI)
    Primary PCI
    PCI combined with fibrinolysis
    ‘Rescue’ PCI
    Assessing myocardial salvage by fibrinolysis or PCI
    GP IIb/IIIa antagonists and early PCI
    Coronary artery bypass surgery
    Pump failure and shock
    Heart failure
    Mild and moderately severe heart failure
    Severe heart failure and shock
    Mechanical complications: cardiac rupture and mitral regurgitation
    Free wall rupture
    Ventricular septal rupture
    Mitral regurgitation
    Arrhythmias and conduction disturbances
    Ventricular arrhythmias
    Supraventricular arrhythmias
    Sinus bradycardia and heart block
    Routine prophylactic therapies in the acute phase
    Management of specific types of infarction
    Right ventricular infarction
    Myocardial infarction in diabetic patients
Management of the later in-hospital course
    Ambulation
    Management of specific in-hospital complications
    Deep vein thrombosis and pulmonary embolism
    Intraventricular thrombus and systemic emboli
    Pericarditis
    Late ventricular arrhythmias
    Post-infarction angina and ischaemia
Risk assessment, rehabilitation and secondary prevention
    Risk assessment
    Timing
    Clinical assessment and further investigations
    Assessment of myocardial viability, stunning and hibernation
    Evaluation of risk of arrhythmia
    Rehabilitation
    Secondary prevention
Logistics of care
    Pre-hospital care
    The coronary (cardiac) care unit (CCU)
The current use of therapies tested by clinical trials
Recommendations
References

Introduction

The management of acute myocardial infarction continues to undergo major changes. Good practice should be based on sound evidence derived from well-conducted clinical trials. Because of the great number of trials on new treatments performed in recent years and because of new diagnostic tests, the European Society of Cardiology decided that it was opportune to upgrade the 1996 guidelines and appointed a Task Force. It must be recognized, that even when excellent clinical trials have been undertaken, their results are open to interpretation and that treatment options may be limited by resources. Indeed, cost-effectiveness is becoming an increasingly important issue when deciding upon therapeutic strategies.

In setting out these new guidelines, the Task Force has attempted to classify the usefulness or efficacy of the recommended routine treatments and the level of evidence on which these recommendations are based. The usefulness or efficacy of a recommended treatment will be presented as:

class I=evidence and/or general agreement that a given treatment is beneficial, useful and effective;
class II=conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the treatment;
IIa: weight of evidence/opinion is in favour of usefulness/efficacy;
IIb: usefulness/efficacy is less well established by evidence/opinion;
class III=evidence or general agreement that the treatment is not useful/effective and in some cases may be harmful.

The strength of evidence will be ranked according to three levels: level A, data derived from at least two randomized clinical trials; level B, data derived from a single randomized clinical trial and/or meta-analysis or from non-randomized studies; level C, consensus opinion of the experts based on trialsand clinical experience. As always with guidelines, they are not prescriptive. Patients vary so much from one another that individual care is paramount and there is still an important place for clinical judgment, experience and common sense.

The definition of acute myocardial infarction
Myocardial infarction can be defined from a number of different perspectives related to clinical, electrocardiographic (ECG), biochemical and pathologic characteristics.1 It is accepted that the term myocardial infarction reflects death of cardiac myocytes caused by prolonged ischaemia.

The ECG may show signs of myocardial ischaemia, specifically ST and T changes, as well as signs of myocardial necrosis, specifically changes in the QRS pattern. A working definition for acute evolving myocardial infarction in the presence of clinically appropriate symptoms has been established as (1) patients with ST-segment elevation, i.e. new ST-segment elevation at the J point with the cut-off points ≥0.2mV in V1through V3and ≥0.1mV in other leads, or (2) patients without ST-segment elevation, i.e. ST-segment depression or T wave abnormalities. Clinically established myocardial infarction may be defined by any Q wave in leads V1through V3, or Q wave ≥0.03s in leads I, II, aVL, aVF, V4, V5or V6.

Myocardial infarction can be recognized when blood levels of biomarkers are increased in the clinical setting of acute myocardial ischaemia. The preferred biomarker for myocardial damage is cardiac troponin (I or T) which has nearly absolute myocardial tissue specificity, as well as high sensitivity. The best alternative is CK-MB mass, which is less tissue-specific than cardiac troponin but its clinical specificity for irreversible injury is more robust. An increased value of cardiac troponin or CK-MB is defined as one that exceeds the 99th percentile of a reference population.

The present guidelines pertain to patients presenting with ischaemic symptoms and persistent ST-segment elevation on the ECG. The great majority of these patients will show a typical rise of biomarkers of myocardial necrosis and progressto Q-wave myocardial infarction. Separate guidelines2 have been developed by another Task Force of the European Society of Cardiology for patients presenting with ischaemic symptoms but without persistent ST-segment elevation.

The pathogenesis of acute myocardial infarction
An acute coronary syndrome is nearly always caused by a sudden reduction in coronary blood flow caused by atherosclerosis with thrombosis superimposed, with or without concomitant vasoconstriction.3 The clinical presentation and outcome depend on the location of the obstruction and the severity and duration of myocardialischaemia. In myocardial infarction with ST-segment elevation, occlusive and persistent thrombosis prevails. About 2/3 to 3/4 of fatal coronary thrombi are precipitated by sudden rupture of a vulnerable plaque (inflamed, lipid-rich plaque covered by a thin fibrous cap).4 Other poorly defined mechanisms such as plaque erosion account for the rest. As many as 3/4 of all infarct-related thrombi appear to evolve over plaques causing only mild-to-moderate stenosis prior to infarction and after thrombolysis.4 However,severe stenoses are more likely to undergo plaque events leading to infarction than mild ones.5 Myocardial infarction caused by complete coronary artery occlusion begins to develop after 15–30min of severe ischaemia (no forward or collateral flow) and progresses from the subendocardium to the subepicardium in a time-dependent fashion (the wave-front phenomenon). Reperfusion, including recruitment of collaterals, may save myocardium at risk from undergoing necrosis, and subcritical but persistent flow may extend the time-window for achieving myocardial salvage by complete reperfusion.

The thrombotic response to plaque disruptionis dynamic: thrombosis and thrombolysis, oftenassociated with vasospasm, occur simultaneously, causing intermittent flow obstruction and distal embolization.3,6 The latter leads to microvascular obstruction which may prevent successful myocardial reperfusion despite a patent epicardial infarct-related artery.7 In coronary thrombosis, the initial flow obstruction is usually due to platelet aggregation, but fibrin is important for the subsequent stabilization of the early and fragile platelet thrombus.6 Therefore, both platelets and fibrin are involved in the evolution of a persisting coronary thrombus.

The natural history of acute myocardial infarction
The true natural history of myocardial infarction is hard to establish for a number of reasons: the common occurrence of silent infarction, the frequency of acute coronary death outside hospital and the varying methods used in the diagnosis of the condition. Community studies8,9 have consistently shown that the overall fatality of acute heart attacks in the first month is between 30% and 50%, and of these deaths about one-half occur within the first 2h. This high initial mortality seems to have altered little over the last 30 years.10 By contrast with community mortality, there has been a profound fall in the fatality of those treated in hospital. Prior to the introduction of coronary care units in the 1960s, the in-hospital mortality seems to have averaged some 25–30%.11 A systematic review of mortality studies in the pre-thrombolytic era of the mid-1980s showed an average fatality of 18%.12 With the widespread use of fibrinolytic drugs, aspirin and coronary interventions the overall 1-month mortality has since been reduced to 6–7%, at least in those who participate in large-scale trials and qualify for fibrinolysis, aspirin and/or coronary interventions. In the recent European Heart Survey, mortality in patients presenting with ST-segment elevation acute coronary syndromes was 8.4% at 1 month.13 The WHO-MONICA investigators convincingly demonstrated that, also at the population level, the introduction of new treatments for coronary care was strongly linked with declining coronary event rates and 28-day case fatality.9

It was found many years ago that certain factors were predictive of death in patients admitted to hospital with myocardial infarction.11 Chief among these were age, previous medical history (diabetes, previous infarction), indicators of large infarct size, including site of infarction (anterior vs inferior), low initial blood pressure, Killip class on admission and the extent of ischaemia as expressed by ST-segment elevation and/or depression on the electrocardiogram. These factors remain operative today.14

Aims of management
While the primary concern of physicians is to prevent death, those caring for victims of myocardial infarction aim to minimize the patient's discomfort and distress and to limit the extent of myocardial damage. The care can be divided conveniently into four phases:

  1. Emergency care when the main considerations are to make a rapid diagnosis and early risk stratification, to relieve pain and to prevent or treat cardiac arrest.
  2. Early care in which the chief considerations are to initiate as soon as possible reperfusion therapy to limit infarct size and to prevent infarct extension and expansion and to treat immediate complications such as pump failure, shock and life-threatening arrhythmias.
  3. Subsequent care in which the complications that usually ensue later are addressed.
  4. Risk assessment and measures to prevent progression of coronary artery disease, new infarction, heart failure and death.

These phases may correspond to pre-hospital care, the emergency department or the coronary care unit (CCU), the post CCU and an ordinary ward, but there is much overlap and any categorization of this kind is artificial.

Emergency care

Initial diagnosis and early risk stratification
Rapid diagnosis and early risk stratification ofpatients presenting with acute chest pain areimportant to identify patients in whom early interventions can improve outcome. On the other hand, when the diagnosis of acute myocardialinfarction has been ruled out, attention can be focused on the detection of other cardiac or non-cardiac causes of the presenting symptoms.

A working diagnosis of myocardial infarction must first be made. This is usually based on the history of severe chest pain lasting for 20min or more, not responding to nitroglycerine. Important clues are a previous history of coronary artery disease, and radiation of the pain to the neck, lower jaw, or left arm. The pain may not be severe and, in the elderly particularly, other presentations such as fatigue, dyspnoea, faintness or syncope are common. There are no individual physical signs diagnostic of myocardial infarction, but most patients have evidence of autonomic nervous system activation (pallor, sweating) and either hypotension or a narrow pulse pressure. Features may also include irregularities of the pulse, bradycardia or tachycardia, a third heart sound and basal rales.

An electrocardiogram should be obtained as soon as possible. Even at an early stage, the ECG is seldom normal.15,16 In case of ST-segment elevations or new or presumed new left bundle-branch block, reperfusion therapy needs to be given and measures to initiate this treatment must be taken as soon as possible. However, the ECG is often equivocal in the early hours and even in proven infarction it may never show the classical features of ST-segment elevation and new Q waves. Repeated ECG recordings should beobtained and, when possible, the current ECG should be compared with previous records. Additional recordings of e.g. lead V7and V8may be helpful to make the diagnosis in selected cases (true posterior infarction). ECG monitoring should be initiated as soon as possible in all patients to detect life-threatening arrhythmias.

Blood sampling for serum markers is routinely done in the acute phase but one should not wait for the results to initiate reperfusion treatment. The finding of elevated markers of necrosis may sometimes be helpful in deciding to give reperfusion therapy (e.g. in patients with left bundle-branch block).

Two-dimensional echocardiography has become a useful bedside technique in the triage of patients with acute chest pain. Regional wall motion abnormalities occur within seconds after coronary occlusion well before necrosis.17 However, wall motion abnormalities are not specific for acute myocardial infarction and may be due to ischaemia or an old infarction. Two-dimensional echocardiography is of particular value for the diagnosis of other causes of chest pain such as acute aortic dissection, pericardial effusion or massive pulmonary embolism.18 The absence of wall motion abnormalities excludes major myocardial infarction. In difficult cases, coronary angiography may be helpful.

Myocardial perfusion scintigraphy has also been used successfully, though unfrequently, in the triage of patients presenting with acute chest pain.19,20 A normal resting technetium-99m myocardial perfusion scintigram effectively excludes major myocardial infarction. An abnormal acute scintigram is not diagnostic of acute infarctionunless it is known previously to have been normal, but it does indicate the presence of coronary artery disease and the need for further evaluation.

When the history, ECG and serum markers are not diagnostic of acute myocardial infarction the patient can proceed safely to stress testing for investigation of underlying coronary artery disease.


Summary: initial diagnosis of acute myocardial infarction

  • History of chest pain/discomfort.
  • ST-segment elevations or (presumed) new left bundle-branch block on admission ECG. Repeated ECG recordings often needed.
  • Elevated markers of myocardial necrosis (CK-MB, troponins). One should not wait for the results to initiate reperfusion treatment!
  • 2D echocardiography and perfusion scintigraphy helpful to rule out acute myocardial infarction.

 

Relief of pain, breathlessness and anxiety
Relief of pain is of paramount importance, not only for humane reasons but because the pain is associated with sympathetic activation which causesvasoconstriction and increases the workload of the heart. Intravenous opioids—morphine or, where available, diamorphine—are the analgesics most commonly used in this context (e.g. 4 to 8mg morphine with additional doses of 2mg at intervals of 5min until the pain is relieved); intramuscular injections should be avoided. Repeated dosesmay be necessary. Side effects include nausea and vomiting, hypotension with bradycardia, andrespiratory depression. Antiemetics may be administered concurrently with opioids. The hypotension and bradycardia will usually respond to atropine, and respiratory depression to naloxone, which should always be available. If opioids fail to relieve the pain after repeated administration, intravenous beta-blockers or nitrates are sometimes effective. Oxygen (2–4l.min–1by mask or nasal prongs) should be administered especially to those who are breathless or who have any features of heart failure or shock. Non-invasive monitoring of blood oxygen saturation greatly helps in deciding on the need for oxygen administration or, in severe cases, ventilatory support.

Anxiety is a natural response to the pain andto the circumstances surrounding a heart attack. Reassurance of patients and those closely associated with them is of great importance. If thepatient becomes excessively disturbed, it maybe appropriate to administer a tranquilliser, but opioids are frequently all that is required.


Summary: relief of pain, breathlessness and anxiety.

  • Intravenous opioids (e.g. 4 to 8mg morphine) with additional doses of 2mg at 5min intervals.
  • O2(2–4l.min–1) if breathlessness or heart failure.
  • Consider intravenous beta-blockers or nitrates if opioids fail to relieve pain.
  • Tranquilliser may be helpful.

 

Cardiac arrest
Basic life support
Those not trained or equipped to undertake advanced life support should start basic life support as recommended in the international guidelines 2000 for resuscitation and emergency cardiovascular care.21

Advanced life support
Trained paramedics and other health professionals should undertake advanced life support, as described in the international guidelines for cardiopulmonary resuscitation and emergencycardiovascular care.22

Pre-hospital or early in-hospital care

Restoring coronary flow and myocardial tissue reperfusion
For patients with the clinical presentation of myocardial infarction and with persistent ST-segment elevation or new or presumed new left bundle-branch block, early mechanical or pharmacological reperfusion should be performed unless clearcontraindications are present.

Fibrinolytic treatment
The evidence for benefit
More than 150 000 patients have been randomized in trials of thrombolysis vs control, or one fibrinolytic regimen compared with another.23–35 Forpatients within 12h of the onset of symptoms of infarction, the overall evidence for the benefit of fibrinolytic treatment is overwhelming.

According to the Fibrinolytic Therapy Trialists' (FTT) analysis for those presenting within 6h of symptom onset, arid ST-segment elevation or bundle-branch block, approximately 30 deaths are prevented per 1000 patients treated, with 20 deaths prevented per 1000 patients treated for those between 7 and 12h. Beyond 12h there is no convincing evidence of benefit for the group as a whole.23 The amount of ST-segment elevationrequired and the type of bundle-branch block were not specified in this meta-analysis. However, most of the trials included in the analysis used ST-segment elevations of ≥1mm or new or presumed new left bundle-branch block as entry criteria.

The ISIS-224 study demonstrated the important additional benefit of aspirin so that there was a combined reduction of approximately 50 lives per 1000 patients treated. There is remarkable consistency of benefit across pre-stratified subgroups. Overall, the largest absolute benefit is seen among patients with the highest risk, even though the proportional benefit may be similar.

In patients over 75 and treated within 24h the survival benefit shown in the FTT analysis was small and not statistically significant.22 Two recent registry-type studies36,37 questioned the benefit of fibrinolytic therapy in the elderly, with one of these studies even suggesting more harm than good.36 However, a recent re-analysis by the FTT secretariat indicates that in approximately 3300 patients over the age of 75 presenting within 12h of symptom onset and with either ST-segment elevation or bundle-branch block, mortality rates were significantly reduced by fibrinolytic therapy (from 29.4% to 26%, P=0.03).38

Time to treatment
Most benefit is seen in those treated soonest after the onset of symptoms. Analysis of studies in which more than 6000 patients were randomized to pre-hospital or in-hospital thrombolysis has shown significant reduction (range 15 to 20%) in early mortality with pre-hospital treatment.39–41 Thefibrinolytic overview23 reported a progressivedecrease of about 1.6 deaths per hour of delay per 1000 patients treated. In another meta-analysis of 22 trials42 a larger mortality reduction was found in patients treated within the first 2h (44% vs 20% for those treated later). These calculations, based on studies in which the time to treatment was not randomized, must be interpreted with cautionbecause the time to presentation is not random. Nevertheless they should be considered as an additional indirect support for pre-hospital initiation of fibrinolytic treatment. The availability of new fibrinolytic agents that can be given as a bolus (cfr. infra) should facilitate pre-hospital thrombolysis.

Hazards of fibrinolysis
Thrombolytic therapy is associated with a small but significant excess of approximately 3.9 extra strokes per 1000 patients treated23 with all ofthe excess hazard appearing on the first dayafter treatment. The early strokes are largelyattributable to cerebral haemorrhage; later strokes are more frequently thrombotic or embolic. There is a non-significant trend for fewer thrombo-embolic strokes in the later period in those treated with fibrinolysis: Part of the overall excess of stroke is among patients who subsequently die and is accounted for in the overall mortality reduction (1.9 excess per 1000). Thus, there is an excess of approximately two non-fatal strokes per 1000 surviving patients treated. Of these, half are moderately or severely disabling. Advanced age, lower weight, female gender, prior cerebrovascular disease or hypertension, systolic and diastolic hypertension on admission are significant predictors of intracranial haemorrhage.43–45 Major non-cerebral bleeds (bleeding complications requiring blood transfusion or that are life-threatening), can occur in 4% to 13% of the patients treated.33,46 The most common sources of bleeding are procedure-related. Independent predictors of non-cerebral bleeding are older age, lower weight and female gender, also in patients not undergoing percutaneous interventions.

Administration of streptokinase and anistreplase may be associated with hypotension, but severe allergic reactions are rare. Routine administration of hydrocortisone is not indicated. Where hypotension occurs, it should be managed bytemporarily halting the infusion, lying thepatient flat or elevating the feet. Occasionally atropine or intravascular volume expansion may be required.

Comparison of fibrinolytic agents
Neither the GISSI-2/International Trials27 nor the Third International Study of Infarct Survival(ISIS 3)25 found a difference in mortality between the use of streptokinase and tissue plasminogen activator or anistreplase. Furthermore, the addition of subcutaneous heparin did not reduce mortality compared with the use of no heparin. However, the GUSTO Trial (Global Utilisation of Streptokinase and Tissue Plasminogen Activator for occluded coronary arteries)28 employed an accelerated t-PA (tissue type plasminogen activator) regimen given over 90min29 rather than the previously conventional period of 3h. Accelerated t-PA with concomitant APTT (activated partial thromboplastin time) adjusted intravenous heparin was reported to result in 10 fewer deaths per 1000 patients treated. The risk of stroke is higher with t-PA or anistreplase than with streptokinase.24,28 In the GUSTO trial, there were three additional strokes per 1000 patients treated with accelerated t-PA and heparin in comparison with streptokinase and subcutaneous heparin,28 but only one of these survived with a residual deficit. In assessing the net clinical benefit, this must be taken into account with the reduced death rate in the t-PA group. Several variants of t-PA have been studied. Double-bolus r-PA (reteplase) does not offer any advantage over accelerated t-PA except for its ease of administration. Single-bolus weight-adjusted TNK-tPA (tenecteplase) is equivalent to accelerated t-PA for 30-day mortality and associated with a significantly lower rate of non-cerebral bleeds and less need for blood transfusion. Bolus fibrinolytic therapy may facilitate more rapid treatment in and out of the hospital and reduce the risk of medication errors. The choice of fibrinolytic agent will depend on an individual assessment of risk and benefit, and also on factors such as availability and cost.45 For late treated patients more fibrin-specific agents may be more effective.30,33,48

Clinical implications
Based upon the substantial evidence now accumulated, there is unequivocal benefit, in terms of morbidity and mortality for prompt treatment of acute myocardial infarction with fibrinolytic agents and aspirin, the two agents being additive in their effect. Where appropriate facilities exist, with trained medical or paramedical staff able to analyse on-site or to transmit the ECG to the hospital for supervision, pre-hospital fibrinolysis is recommended provided that the patient exhibits the clinical features of myocardial infarction andthe ECG shows ST-segment elevation or new or presumed new left bundle-branch block.

Unless clearly contraindicated, patients withinfarction, as diagnosed by clinical symptoms and ST-segment elevation or left bundle-branch block, should receive aspirin and fibrinolytic therapy with the minimum of delay. A realistic aim is to initiate fibrinolysis within 90min of the patient calling for medical treatment (‘call to needle’ time) or within 30min of arrival at the hospital (‘door to needle’ time). In patients withslowly evolving, or stuttering myocardial infarction, a series of ECGs or ST-segment monitoring, clinical assessments and repeat testing of serum markers should be performed to detect evolving infarction.

Fibrinolytic therapy should not be given topatients in whom infarction has been established for more than 12h, unless there is evidence of ongoing ischaemia, with the ECG criteria forfibrinolysis. Elderly patients without contraindications should be given fibrinolytic therapy when timely mechanical reperfusion can not be performed.

Contra-indications to fibrinolytic therapy
Absolute and relative contraindications to fibrinolytic therapy are shown in Table 1. It should be stressed that diabetes, and more particularly diabetic retinopathy, is not a contraindication tofibrinolytic therapy. Although traumatic resuscitation is considered to represent a relativecontraindication to thrombolysis, out-of-hospitalthrombolytic therapy may improve outcome ofpatients in whom initial conventional cardiopulmonary resuscitation was unsuccessful.49


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  		Table 1 Contraindications to fibrinolytic therapy

 
Fibrinolytic regimens
Dosages for the current fibrinolytic agents and the need for antithrombin co-therapy are provided in Table 2.


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  		Table 2 Fibrinolytic regimens for acute myocardial infarction

 
Re-administration of a fibrinolytic agent
If there is evidence of re-occlusion or reinfarction with recurrence of ST-segment elevation or bundle-branch block, further fibrinolytic therapy shouldbe given if mechanical reperfusion is not available.50 Streptokinase and anistreplase should not be re-administered since antibodies to streptokinase persist for at least 10 years, at levels which can impair its activity.51 Alteplase (t-PA) and its variants do not result in antibody formation.Re-administration of fibrinolytic agents may lead to excessive bleeding complications.

Adjunctive anticoagulant and antiplatelet therapy
The independent and additive benefits of aspirin have been described above. It is not clear whether aspirin works by enhancing fibrinolysis, preventing reocclusion or by limiting the microvascular effects of platelet activation. In studies on late reocclusion, aspirin was more effective in preventingrecurrent clinical events than in maintainingpatency.52 The first dose of 150–325mg should be chewed (no enteric-coated aspirin!), and a lower dose (75–160mg) given orally daily thereafter. If oral ingestion is not possible aspirin can be given intravenously (250mg).

Platelet aggregation is only partly inhibited by aspirin and progress has been made with the development of platelet glycoprotein IIb/IIIa inhibitors, which block the final pathway of platelet aggregation. Angiographic trials53–57 demonstrated that the combination of GP IIb/IIIa inhibitors with half-dose fibrinolytic and reduced doses of heparin, induces similar or slightly higher TIMI grade 3 flow rates when compared with full-dose fibrinolytic alone and is associated with more complete resolutionof ST-segment elevations, suggesting an improvement in tissue reperfusion. The clinical benefit and safety of these combinations has been tested in two large trials.58,59 No reductions in 30-day mortality or intracranial haemorrhage rates but lower rates of in-hospital reinfarction were observed, however, at the cost of an increase in (mostly spontaneous) non-cerebral bleeding complications especially in elderly patients. Therefore, the routine use of a reduced dose fibrinolytic with abciximab or other platelet glyco-protein IIb/IIIa inhibitors cannotbe recommended. Whether this combination therapy may be beneficial in specific subgroups of patients (for example those at high risk or those likely to undergo early PCI) needs to be further evaluated.

Heparin has been extensively used during and after fibrinolysis, especially with tissue plasminogen activator. Heparin does not improve immediate clot lysis60 but coronary patency evaluated in the hours or days following thrombolytic therapywith tissue plasminogen activator appears to be better with intravenous heparin.61,62 No difference in patency was apparent in patients treated with either subcutaneous or intravenous heparin and streptokinase.63 Prolonged intravenous heparin administration has not been shown to prevent reocclusion after angiographically proven successful coronary fibrinolysis.64 Heparin infusion after tissue plasminogen activator therapy may be discontinued after 24–48h. Close monitoring of intravenous heparin therapy is mandatory; aPTT values over 70s are associated with higher likelihood of mortality, bleeding and reinfarction.65 Although no randomized trials have beenperformed, there is evidence from recent trials suggesting that more frequent monitoring ofaPTT and a full weight adjustment of heparinmay decrease the risk of non-cerebral bleeding complications.59,66

Low-molecular-weight heparin is a subfraction of standard heparin. It has a number of theoretical advantages over standard heparin: better prevention of new thrombin generation due to its greater degree of factor-Xa inhibition, more predictable kinetics, less protein-binding, less platelet activation, a lower rate of thrombocytopenia and the lack of a need to monitor the aPTT. Low-molecular-weight heparins have been studied in large numbers of patients with non-ST-segment elevation acute coronary syndromes but only recently has testing begun in combination with fibrinolytic agents. Two earlier clinical studies suggest that dalteparin compared with heparin may reduce the risks of recurrent ischaemia67 and of ventricular thrombus formation, albeit at the expense of a higher rate of bleeding.68 In three more recent angiographicstudies69–71 enoxaparin or dalteparin were associated with a trend towards less reocclusion and/or more late patency of the infarct vessel. In the ASSENT-3 trial, the first large-scale trial with a low-molecular-weight heparin, enoxaparin (30mg i.v. bolus and 1mg.kg–1every 12h) given in association with tenecteplase for a maximum of7 days59 reduced the risk of in-hospital reinfarction or in-hospital refractory ischaemia when compared with heparin. There was no increase in intracranial haemorrhage rate and only a modest increase in non-cerebral bleeding complications when compared with heparin. Mortality at 30 days also tended to be lower with enoxaparin. However, in the ASSENT-3 PLUS trial71a prehospital administration of the same dose of enoxaparin resulted in a significant increase in intracranial haemorrhage rate when compared with heparin. This excess was only seen in patients ≥75 years. Larger studies (especially in the elderly) are needed beforerecommendations can be given on the use of enoxaparin or other low-molecular-weight heparins in combination with fibrinolytic agents.

In early studies, the direct thrombin inhibitors, hirudin, bivalirudin and argatroban, as an adjunct to fibrinolysis showed superior patencies at adecreased rate of bleeding compared with heparin.72–74 Nevertheless, in two large-scale clinical trials, hirudin showed no clear clinical benefit over heparin in patients given fibrinolytic therapy.75,76 A multicentre trial with bivalirudin in combination with streptokinase has recently been published.77 When compared with intravenous heparin no mortality reduction at 30 days but significantly fewer reinfarctions were seen with intravenous bivalirudin given for 48h at the cost of a modest and non-significant increase in non-cerebral bleeding complications. Bivalirudin is not approved in Europe. Recommended doses for heparin are given in Table 3.


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  		Table 3 Heparin co-therapy

 
Percutaneous coronary interventions (PCI)
The role of percutaneous coronary interventions (PCI) during the early hours of myocardial infarction can be divided into primary PCI, PCI combined with pharmacological reperfusion therapy, and ‘rescue PCI’ after failed pharmacological reperfusion.

Primary PCI
This is defined as angioplasty and/or stenting without prior or concomitant fibrinolytic therapy, and is the preferred therapeutic option when it can be performed within 90min after the first medical contact. It requires an experienced team, which includes not only interventional cardiologists, but also skilled supporting staff. This means that only hospitals with an established interventional cardiology programme should use primary PCI as a routine treatment option for patients presenting with the symptoms and signs of acute myocardial infarction. Lower mortality rates among patients undergoing primary PCI are observed in centres with a high volume of PCI procedures.78 For patients admitted to a hospital without catheterization facilities on site, a careful individual assessment should be made of thepotential benefits of mechanical reperfusion in relation to the risks and treatment delay of transportation to the nearest interventional catheterization laboratory. Recently the DANAMI-2 investigators have investigated whether a strategy of routine transfer to a tertiary care hospital for primary PCI is superior to in-hospital thrombolysis.79 Transfer times up to 3h from admission at community hospitals to arrival at the invasive centre were allowed per protocol. The observedmedian transport time by ambulance was <32min and the median time between arrival at the community hospital and start of PCI was <2h. A significant reduction in the combined end-point of death, reinfarction and stroke was found after 30 days in the transferred patients undergoing primary PCI (14.2% to 8.5%, P<0.002), while mortality reduction was not significant (8.6% vs 6.5%, P=0.20). In the CAPTIM study comparing pre-hospital (ambulance) fibrinolysis with primaryPCI, no significant difference was found for this combined end-point (8.2% vs 6.2%) and 30-day mortality was 1% higher in the primary PCI arm (3.8% vs 4.8%).80

Primary PCI is effective in securing and maintaining coronary artery patency and avoids some of the bleeding risks of fibrinolysis. Randomized clinical trials comparing timely performed primary PCI with fibrinolytic therapy in high-volume, experienced centres have shown more effective restorationof patency, less reocclusion, improved residualleft ventricular function and better clinical outcome.81–87 Routine coronary stent implantation in patients with acute myocardial infarction decreases the need for target-vessel revascularization but is not associated with significant reductions in death or reinfarction rates88,89 when compared with primary angioplasty.

Patients with contra-indications to fibrinolytic therapy have a higher morbidity and mortality than those eligible for this therapy.90 Primary PCI can be performed with success in a large majority of these patients.91 Primary PCI is the preferred treatment for patients in shock.

PCI combined with fibrinolysis
PCI performed as a matter of policy immediately after fibrinolytic therapy, in order to enhance reperfusion or reduce the risk of reocclusion, has proved disappointing in a number of earlier trialsall showing a tendency to an increased risk of complications and death.92–94 Increased experience and the availability of stents and more potent antiplatelet agents (glycoprotein IIb/IIIa receptor antagonists and thienopyridines) have made PCI following fibrinolysis effective and safe. A combined pre-hospital pharmacological and mechanical reperfusion strategy might prove to be beneficial95 and is currently under investigation.

‘Rescue PCI’
‘Rescue PCI’ is defined as PCI performed on a coronary artery which remains occluded despite fibrinolytic therapy. Limited experience from two randomized trials96,97 suggests a trend towards clinical benefit if the infarct-related vessel canbe recanalized at angioplasty. Although angioplasty success rates are high, an unsolved problem is the lack of reliable non-invasive methods for assessing patency of the infarct-relatedcoronary artery. Limited data from a number of studies indicate that transfer to a tertiary care hospital for rescue PCI can be performed safely.98 Coronary intervention in patients who received full-dose fibrinolytics and a glycoprotein IIb/IIIa antagonist may lead to excessive bleeding complications.

Assessing myocardial salvage by fibrinolysis or PCI
Although not commonly used in clinical practice, myocardial perfusion scintigraphy can be a valuable research technique for assessing the amount of myocardium salvaged by fibrinolysis or PCI. A technetium-99m perfusion tracer can be given intravenously before the intervention and imaging of the territory at risk is possible for up to 6h. Repeat injection and imaging in the recovery phase defines the final size of infarction and the amount of myocardium salvaged by comparison with the territory at risk.85,99

GP IIb/IIIa antagonists and early PCI
Randomized trials with abciximab as conjunctive antiplatelet therapy during PCI of the infarct-related coronary artery have been performed in recent years.89,100–102

The RAPPORT study102 showed that abciximab improves the immediate clinical outcome (death, myocardial infarction, and urgent revascularization) and decreases the need for ‘bail-out’ stenting. Haemorrhagic complications, however, were significantly increased in the abciximab group, likely as a result of relatively high heparin doses. In addition, the combined primary end-point of death, reinfarction, and any revascularization was not significantly improved by abciximab at 6 months. The role of abciximab during primary PCI has been further investigated in the ISAR-2, CADILLAC and ADMIRAL trials. In the ISAR-2 study101 the administration of abciximab and reduced-dose heparin during primary stenting was associated with a significant reduction in the composite of death, reinfarction and target lesion revascularization at 30 days but did not reduce angiographic restenosis rate. In the ADMIRAL study abciximab, given before catheterization, improved angiographic and clinical outcomes after primary stenting.100 In the largest study, the CADILLAC trial, a favourable effect of abciximab was only observed when abciximab was given duringprimary angioplasty but not during primary stenting.89

Thus the current data support the use of abciximab in primary angioplasty in combination with low-dose heparin. The routine administration of abciximab with primary stenting is still a matter of debate.

Coronary artery bypass surgery
The number of patients who need coronary artery bypass surgery in the acute phase of myocardial infarction is limited. It may, however, be indicated when PCI has failed, when there has been a sudden occlusion of a coronary artery during catheterization, if PCI is not feasible, in selected patients in cardiogenic shock or in association with surgeryfor a ventricular septal defect or mitral regurgitation due to papillary muscle dysfunction and rupture.


Reperfusion therapy
Recommendations
Class I
IIa
IIb
III
Level of evidence
Reperfusion therapy is indicated in all patients with history of chest pain/discomfort of <12h and associated with ST-segment elevation or (presumed) new bundle-branch block on the ECG X A
Primary PCI
•preferred treatment if performed by experienced team <90min after first medical contact X A
•indicated for patients in shock and those with contraindications to fibrinolytic therapy X C
•GP Ilb/IIIa antagonists and primary PCI
no stenting X A
with stenting X A
Rescue PCI
•after failed thrombolysis in patients with large infarcts X B
Fibrinolytic treatment
In the absence of contraindications (see Table 1) and if primary PCI cannot be performed within 90min after first medical contact by an experienced team pharmacological reperfusion should be initiated as soon as possible X A
•choice of fibrinolytic agent depends on individual assessment of benefit and risk, availability and cost
In patients presenting late (>4h after symptom onset) a more fibrin-specific agent such as tenecteplase or alteplase is preferred X B
For dosages of fibrinolytic and antithrombin agents see Tables 2 and 3
•pre-hospital initiation of fibrinolytic therapy if appropriate facilities exist X B
•readministration of a non-immunogenic lytic agent if evidence of reocclusion and mechanical reperfusion not available X B
•if not already on aspirin 150–325mg chewable aspirin (no enteric-coated tablets) X A
•with alteplase and reteplase a weight-adjusted dose of heparin should be given with early and frequent adjustments according to the aPTT X B
•with streptokinase heparin is optional
X

B

Pump failure and shock
The various haemodynamic states that can arise in myocardial infarction are tabulated in Table 4.In addition, heart failure may arise from arrhythmic or mechanical complications (see respective sections).


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  		Table 4 Clinical spectrum of haemodynamic states in myocardial infarction and their treatment

 
Heart failure
Left ventricular failure during the acute phase of myocardial infarction is associated with a poor short and long-term prognosis.103 The clinical features are those of breathlessness, sinus tachycardia, a third heart sound and pulmonary rales which are at first basal but may extend throughout both lung fields. However, pronounced pulmonary congestion can be present without auscultatory signs. Repeated auscultation of the heart and lung fields should be practised in all patients during the early period of myocardial infarction, together with the observation of other vital signs.

General measures include monitoring for arrhythmias, checking for electrolyte abnormalities, and for the diagnosis of concomitant conditions such as valvular dysfunction or pulmonary disease. Pulmonary congestion can be assessed by portable chest X-rays. Echocardiography is very useful in assessing the extent of myocardial damage, mechanical ventricular function and complications, such as mitral regurgitation and ventricular septal defect, which may be responsible for poor cardiac performance. In patients with severe heart failure or shock percutaneous or surgical revascularization can improve survival.

The degree of failure may be categorized according to the Killip classification:104 class 1: no rales or third heart sound; class 2: rales over less than 50% of the lung fields or third heart sound; class 3: rales over 50% of the lung fields; class 4: shock.

Mild and moderately severe heart failure
Oxygen should be administered early by mask or intranasally, but caution is necessary in the presence of chronic pulmonary disease. Monitoring blood oxygen saturation is recommended.

Minor degrees of failure often respond quicklyto diuretics, such as furosemide 20–40mg given slowly intravenously, repeated at 1–4 hourlyintervals, if necessary. If there is no satisfactoryresponse, intravenous nitroglycerine or oralnitrates are indicated. The dose should be titrated while monitoring blood pressure to avoid hypotension. ACE inhibitors should be initiated within 48h in the absence of hypotension, hypovolaemia or significant renal failure.

Severe heart failure and shock
Oxygen should be administered and a loop diuretic given as mentioned above. Unless the patient is hypotensive, intravenous nitroglycerine should be given, starting with 0.25µg.kg–1min–1, and increasing every 5min until a fall in blood pressure by 15mmHg is observed or the systolic blood pressure falls to 90mmHg. Consideration should be given to measuring the pulmonary artery and wedge pressures, and the cardiac output with a balloon flotation catheter with a view to obtaining a wedge pressure of less than 20mmHg and a cardiac index in excess of 2l.min–1.m–2.

Inotropic agents may be of value if there is hypotension. If signs of renal hypoperfusion are present, dopamine is recommended intravenously in a dosage of 2.5–5.0µg.kg–1min–1. If pulmonary congestion is dominant, dobutamine is preferred with an initial dosage of 2.5µg.kg–1min–1. This may be increased gradually at 5–10min intervalsup to 10µg.kg–1min–1or until haemodynamicimprovement is achieved.

The blood gases should be checked. Endotracheal intubation with ventilatory support may be indicated if an oxygen tension of more than 60mmHg cannot be maintained in spite of 100% oxygen delivered at 8–10l.min–1by mask and the adequate use of bronchodilators. Patients with acute heart failure may have stunned (reperfused myocardium but with delayed contractile recovery) or hypoperfused, viable myocardium. Identification and revascularization of hypoperfused myocardium can lead to improved ventricular function.

Cardiogenic shock
Cardiogenic shock is a clinical state of hypoperfusion characterized by systolic pressure <90mmHg and central filling pressure >20mmHg, or a cardiac index <1.8l.min–1.m–2. Shock is also considered present if intravenous inotropes and/or intraaortic balloon pump are needed to maintain a systolic blood pressure >90mmHg and a cardiac index of >1.8l.min–1.m–2. Early thrombolysis reduces the incidence of cardiogenic shock.

The diagnosis of cardiogenic shock should be made when other causes of hypotension have been excluded such as hypovolaemia, vasovagal reactions, electrolyte disturbance, pharmacological side effects, or arrhythmias. It is usually associated with extensive left ventricular damage, but may occur in right ventricular infarction (vide infra). Left ventricular function and associated mechanical complications should be evaluated by two-dimensional Doppler echocardiography. Haemodynamic assessment is usually performed with a balloon floating catheter. A filling pressure (pulmonary wedge) of at least 15mmHg should be aimed for with a cardiac index of >2l.kg–1min–1. Low-dose dopamine 2.5–5µg.kg–1min–1may be given to improve renal function and the additional administration of dobutamine 5–10µg.kg–1min–1should be considered.

Patients in cardiogenic shock can be assumed to be acidotic. Correction of acidosis is important as catecholamines have little effect in an acidmedium. Supportive treatment with a balloon pump is strongly recommended as a bridge tomechanical interventions.

Emergency PCI or surgery may be life-saving and should be considered at an early stage.105,106 If neither of these are available or can only be provided after a long delay, fibrinolytic therapy should be given.


Summary: pump failure and shock.

  • Diagnosis: chest X-ray, echocardiography, right heart catheterization.
  • Treatment of mild and moderately severe heart failure:
    O2
    furosemide: 20–40mg intravenously repeated at 1–4 hourly intervals if necessary
    nitrates: if no hypotension
    ACE inhibitors in the absence of hypotension, hypovolaemia or renal failure.
  • Treatment of severe heart failure:
    O2
    furosemide: cfr. supra
    nitrates if no hypotension
    inotropic agents: dopamine and/or dobutamine
    haemodynamic assessment with balloon floating catheter
    ventilatory support if inadequate oxygen tension
    consider early revascularization.
  • Treatment of shock:
    O2
    haemodynamic assessment with balloon floating catheter
    inotropic agents: dopamine and dobutamine
    ventilatory support if inadequate oxygen tension
    intraaortic balloon pump
    consider left ventricular assist devices and early revascularization.

 

Mechanical complications: cardiac rupture and mitral regurgitation
Free wall rupture
Acute free wall rupture
This is characterized by cardiovascular collapse with electromechanical dissociation i.e. continuing electrical activity with a loss of cardiac output and pulse. It is usually fatal within a few minutes, and does not respond to standard cardiopulmonaryresuscitation measures. Only very rarely is there time to bring the patient to surgery.

Subacute free wall rupture
In about 25% of cases, small quantities of blood reach the pericardial cavity and produce a progressive haemodynamic burden.107,108 The clinical picture may simulate reinfarction because of the recurrence of pain and re-elevation of ST segments, but more frequently there is sudden haemodynamic deterioration with transient or sustained hypotension. The classical signs of cardiac tamponade occur and can be confirmed by echocardiography. Although echocardiography is usually not able to show the site of rupture, it can demonstrate pericardial fluid with or without signs of tamponade. The presence of pericardial fluid alone is not sufficient to diagnose a subacute free wall rupture, because it is relatively common after acute myocardial infarction. The typical finding is an echo-dense mass in the pericardial space consistent with clot (haemopericardium). Immediate surgery should be considered depending on the clinical status. Pericardiocentesis may relieve tamponade in shock patients awaiting surgery.109

Ventricular septal rupture
Ventricular septal defect appears early after myocardial infarction, with an incidence of about 1–2% of all infarctions.110 Without surgery, the mortality is 54% within the first week, and 92% within the first year.111 The diagnosis, first suspected because of severe clinical deterioration, is confirmed by the occurrence of a loud systolic murmur, by echocardiography and/or by detecting an oxygen step-up in the right ventricle. Themurmur may, however, be soft or absent. Echocardiography reveals the location and size of the ventricular septal defect, the left-to-right shunt can be depicted by colour Doppler and further quantified by pulsed Doppler technique. Peak flow velocity across the rupture measured by continuous-wave Doppler can be used to estimate right ventricular (pulmonary) systolic pressure. Pharmacological treatment with vasodilators, such as intravenous nitroglycerine, may produce some improvement if there is no cardiogenic shock, but intra-aortic balloon counterpulsation is the most effective method of providing circulatory support while preparing for surgery. Urgent surgery offers the only chance of survival in large post-infarction ventricular septal defect with cardiogenic shock.112,113 Even if there is no haemodynamic instability early surgery is usually indicated, also because the defect may increase.114 Successful percutaneous closure of the ventricular septal defect has been reported but more experience is needed before it can be recommended.

Pre-operative coronary angiography should be performed. Bypass grafts are inserted as necessary. Predictors of poor postoperative outcome are cardiogenic shock, posterior location, right ventricular dysfunction, age, and long delay between septal rupture and surgery.111,112 Hospital mortality after surgery is estimated to be between 25% and 60%,114,115 and 95% of survivors are in NYHA class I or II.115

Mitral regurgitation
Mitral regurgitation is common after acute myocardial infarction. There are three mechanisms of acute mitral regurgitation in this setting: (1) mitral valve annulus dilatation due to left ventricular dilatation and dysfunction, (2) papillary muscle dysfunction usually due to inferior myocardial infarction, and (3) papillary muscle rupture. Papillary muscle rupture typically presents as a sudden haemodynamic deterioration. Due to the abrupt and severe elevation of left atrial pressure, the murmur is often soft. The severity of mitral regurgitation is best assessed by colour Doppler-echocardiography. The most frequent cause of partial or total papillary muscle rupture is a small infarct of the posteromedial papillary muscle in the right or circumflex artery distribution.117,118 In some patients transoesophageal echocardiography may be necessary to clearly establish thediagnosis.

Cardiogenic shock and pulmonary oedema with severe mitral regurgitation require emergency surgery. Intra-aortic balloon pump placement is helpful during preparation115 and coronary angiography should be performed.

Valve replacement is the procedure of choicefor rupture of the papillary muscle, although repair can be attempted in selected cases.119 If there isno rupture of the papillary muscle mechanical reperfusion of the infarct-related artery can be attempted.

Arrhythmias and conduction disturbances
Arrhythmias and conduction disturbances are extremely common during the early hours after myocardial infarction. In some cases, such as ventricular tachycardia, ventricular fibrillation and total atrioventricular block, these are life threatening and require immediate correction. Often arrhythmias are a manifestation of a serious underlying disorder, such as continuing ischaemia, pump failure, altered autonomic tone, hypoxia, electrolyte (e.g. hypokalaemia) and acid-base disturbances, that requires attention and corrective measures. The necessity for treatment and itsurgency depend mainly upon the haemodynamic consequences of the rhythm disorder.

Ventricular arrhythmias
Ventricular ectopic rhythms
Ventricular ectopic beats are almost universal on the first day, and complex arrhythmias (multiform complexes, short runs, or the R-on-T phenomenon) are common. Their value as predictors of ventricular fibrillation is questionable. No specific therapy is required.

Ventricular tachycardia
Runs of non-sustained ventricular tachycardia may be well tolerated and do not necessarily require treatment. More prolonged episodes may causehypotension and heart failure and may degenerate into ventricular fibrillation. Beta-blockers, unless contraindicated, are the first line of therapy. If the estimated risk for (recurrent) ventricular fibrillation is high, lidocaine is usually the drug of first choice: an initial loading dosage of 1mg.kg–1of intravenous lidocaine may be followed by half this dose every 8–10min to a maximum of 4mg.kg–1or a continuous infusion (1–3mg.min–1). Intravenous amiodarone (5mg.kg–1in the first hour to be followed by 900 to 1200mg.24h–1) may besuperior, however, especially in patients withrecurrent sustained ventricular tachycardia requiring cardioversion or in the case of ventricularfibrillation. Countershock is indicated if haemodynamically significant ventricular tachycardia persists. If no defibrillator is available, a precordial thump is worth trying.

It is important to differentiate true ventricular tachycardia from accelerated idioventricular rhythm, usually a harmless consequence of reperfusion, in which the ventricular rate is less than 120beats.min–1.

Ventricular fibrillation
Immediate defibrillation should be performed. The recommendations of the international guidelines 2000 for cardiopulmonary resuscitation andemergency cardiovascular care should be followed.21,22

Supraventricular arrhythmias
Atrial fibrillation complicates some 15–20% of myocardial infarctions, and is frequently associated with severe left ventricular damage and heart failure. It is usually self-limited. Episodes may last from minutes to hours, and are often repetitive. In many cases, the ventricular rate is not fast, the arrhythmia is well tolerated, and no treatment is required. In other instances, the fast rate contributes to heart failure and prompt treatment is needed. Beta-blockers and digoxin are effective in slowing the rate in many cases, but amiodarone may be more efficacious in terminating the arrhythmia.120 Countershock may also be used, but should only be employed if mandatory, since recurrences are so common.

Other supraventricular tachycardias are rare and usually self-limited. They may respond to carotid sinus pressure. Beta-blockers may be effective, if not contra-indicated, but verapamil is not recommended. Intravenous adenosine may be considered in this setting, if atrial flutter is ruled out and the haemodynamic status is stable; the ECG should be monitored during administration. Countershock should be employed if the arrhythmia is poorly tolerated.

Sinus bradycardia and heart block
Sinus bradycardia is common in the first hour,especially in inferior infarction. In some cases, opioids are responsible. It may be accompanied by quite severe hypotension, in which case it should be treated by intravenous atropine, starting with a dosage of 0.3–0.5mg, repeated up to a total of 1.5–2.0mg. Later in the course of myocardialinfarction, it is usually a favourable sign andrequires no treatment. Occasionally it may, however, be associated with hypotension. If it then fails to respond to atropine, temporary pacing may be advisable.

First-degree heart block needs no treatment
Type I second degree (Mobitz I or Wenckebach) AV (atrio-ventricular) block is usually associated with inferior infarction and seldom causes adverse haemodynamic effects. Should it do so, however, atropine should be given first; if this fails, pacing should be instituted.

Type II second degree (Mobitz II) and complete AV block are indications for the insertion of a pacing electrode, certainly if bradycardia causes hypotension or heart failure. If the haemodynamic disturbance is severe, consideration should be given to AV sequential pacing. The development of a new bundle-branch block or hemiblock usually indicates extensive anterior infarction. There is a high likelihood both for developing complete AV block as well as pump failure. The preventive placement of a temporary pacing wire may be warranted. Asystole may follow AV block, bi- or trifas-cicular block, or electrical countershock. Ifa pacing electrode is in place, pacing should be attempted. Otherwise, chest compression andventilation should be initiated, and transthoracic pacing started.

A transvenous pacing electrode should beinserted, as discussed above, in the presence of advanced AV block, and considered if bifascicular or trifascicular block develop. Some cardiologists prefer the subclavian route but this should be avoided following fibrinolysis or in the presence of anticoagulation. Alternative sites should be chosen in this situation.

Routine prophylactic therapies in the acute phase
Aspirin
Convincing evidence of the effectiveness of aspirin was demonstrated by the ISIS-2 trial,23 in whichit was shown that the benefits of aspirin andstreptokinase were additive.

There are few contra-indications to the use of aspirin, but it should not be given to those with a known hypersensitivity, bleeding peptic ulcer, blood dyscrasia, or severe hepatic disease. Aspirin may occasionally trigger bronchospasm in asthmatics. Unlike the situation with fibrinolysis, there is no clear evidence of a relationship between effectiveness and the time from the onset of symptoms. Nonetheless, aspirin should be given to all patients with an acute myocardial infarction as soon as possible after the diagnosis is deemed probable. This represents about 85–95% of those sustaining a myocardial infarction.

Anti-arrhythmic drugs
Although it has been demonstrated that lidocaine can reduce the incidence of ventricular fibrillation in the acute phase of myocardial infarction,121,122 this drug significantly increases the risk of asystole.122 A meta-analysis of 14 trials showed anon-significantly higher mortality in lidocaine-treated patients than in controls.123 The routine prophylactic use of this drug is not justified.

Beta-blockers
Many trials of intravenous beta-blockade havebeen undertaken in the acute phase of myocardial infarction, because of their potential to limit infarct size, reduce the incidence of fatal arrhythmias, and to relieve pain. Pooling of 28 trials124 of intravenous beta-blockade reveals an absolute reduction of mortality at 7 days from 4.3% to 3.7% or six lives saved per 1000 treated. These studies were conducted prior to the use of fibrinolytic agents or the performance of primary PCI. Two randomized trials of intravenous beta-blockade were undertaken since the widespread use of fibrinolysis.125,126 The number of events was too small to allow conclusions to be drawn. A post-hoc analysis of the use of atenolol in the GUSTO-I trial and a systematic review do not support the routine early intravenous use of beta-blockers.127,128 As discussed below, the use of beta-blockade in the acute phase of infarction in many countries is extremely low. There is a good case for the greater use of an intravenous beta-blocker when there is tachycardia (in the absence of heart failure), relative hypertension, or pain unresponsive to opioids. It may be prudent to test the patient's response to this form of therapy by first using a short-acting preparation. In most patients, however, oral beta-blockade will suffice.

Nitrates
A meta-analysis of 10 trials of early intravenous nitrate therapy conducted in 2041 patients showed a significant mortality reduction of about one-third.129 Each of the trials was small and with only 329 deaths in all, the results, although highly significant, had wide confidence limits. The GISSI-3130 trial tested a strategy of routine intravenous administration of nitrates vs selected administration because of ongoing ischaemia in 19 394 patients. No significant reduction in mortality was observed with the routine administration. The ISIS-4 trial,131 in which oral mononitrate was administered acutely and continued for 1 month, also failed to show a benefit. Furthermore, a benefit was not seen in the ESPRIM trial of molsidomine,132 a nitric oxide donor. The routine use of nitrates in the initial phase of myocardial infarction has, therefore, not convincingly been shown to be of value and is, therefore, not recommended.

Calcium antagonists
A meta-analysis of trials involving calcium antagonists early in the course of acute myocardial infarction showed a non-significant adverse trend.133 There is no case for using calciumantagonists for prophylactic purposes in the acute phase of myocardial infarction.

Angiotensin-converting enzyme (ACE) inhibitors
It is now well established that ACE inhibitors should be given to patients who have an impaired ejection fraction or who have experienced heart failure in the early phase. The GISSI-3,130 ISIS-4131 and Chinese Study134 have shown that ACE inhibitors started on the first day reduce mortality in the succeeding 4–6 weeks by a small but significant amount. The CONSENSUS II study,135 however, failed to show a benefit. This may have been due to the play of chance, or the fact that treatment was initiated early with an intravenous formulation. A systematic overview of trials of ACE inhibition early in acute myocardial infarction indicated that this therapy is safe, well tolerated and associated with a small but significant reduction in 30-day mortality with most of the benefit observed in the first week.131 There is now general agreement on starting ACE inhibitors in the first 24h if no contraindications are present.136 Opinions still differ as to whether to give ACE inhibitors to all patients or to high-risk patients only.

Magnesium
A meta-analysis of trials of magnesium therapy in acute myocardial infarction suggested a significant benefit,137,138 but the subsequent large ISIS-4trial131 did not support this, although it has been argued that the magnesium regimen in ISIS-4was not optimal. The large, recently presentedMAGIC trial confirmed the lack of benefit ofmagnesium.139

Glucose-insulin-potassium
There is experimental and limited clinical evidence that routine administration of glucose-insulin-potassium may favourably influence metabolism in the ischaemic myocardium and therefore confer a clinical benefit. Meta-analysis of the available data in 1928 patients suggests a 28% reduction in hospital mortality (95% CI, 10–43%). The number of lives saved per 1000 patients treated was 49 (95% CI, 14–83).140 Whether this inexpensive treatment should be routinely recommended depends on the results of an ongoing large mortality trial.


Routine prophylactic therapies in the acute phase
Recommendations
Class I
IIa
IIb
III
Level of evidence
•Aspirin: 150–325mg (no enteric-coated formulation) X A
•Intravenous beta-blocker: for all patients in whom it is not contraindicated X A
Oral beta-blockers: cfr. infra
•ACE inhibitors: oral formulation on first day
to all patients in whom it is not contraindicated X A
to high-risk patients X A
•Nitrates X A
•Calcium antagonists X B
•Magnesium X A
•Lidocaine


X
 B

Management of specific types of infarction

Right ventricular infarction
The recognition of right ventricular infarction is important because it may manifest itself as cardiogenic shock, but the appropriate treatmentstrategy is quite different from that for shock due to severe left ventricular dysfunction.

Right ventricular infarction may be suspected by the specific, but insensitive, clinical triad of hypotension, clear lung fields, and raised jugular venous pressure in a patient with inferior myocardialinfarction.141 ST-segment elevation in V4R is very suggestive of the diagnosis;142 this lead shouldcertainly be recorded in all cases of shock, if not done as a routine. Q waves and ST-segment elevation in V1–3also suggest the diagnosis. Echocardiography may confirm the diagnosis of right ventricular infarction by the following features: the right ventricle is dilated and hypokinetic to akinetic, the right atrium is also dilated and low velocity tricuspid regurgitation becomes significant due to tricuspid annulus dilatation.

When right ventricular infarction can be implicated in hypotension or shock, it is important to maintain right ventricular preload. It is desirable to avoid (if possible) vasodilator drugs such as the opioids, nitrates, diuretics and ACE inhibitors.Intravenous fluid loading is effective in many cases: initially, it should be administered rapidly, forexample at a rate of 200ml in 10min. It may require the infusion of 1–21 of normal saline in the first few h, and 200ml.h–1thereafter. Careful haemodynamic monitoring is required during intravenous fluid loading. Right ventricular infarction is often complicated by atrial fibrillation. This should be corrected promptly as the atrial contribution to right ventricular filling is important in this context. Likewise, if heart block develops, dual chamber pacing should be undertaken in spite of theincreased risk of catheter-induced ventricularfibrillation. There has been some question of the effectiveness of fibrinolytic therapy in right ventricular infarction,143 but it certainly seems appropriate in the hypotensive patient. Alternatively, direct PCI may result in rapid haemodynamicimprovement.144

Myocardial infarction in diabetic patients
Up to one quarter of all patients with myocardial infarction have diabetes and this figure is expected to increase. Importantly, diabetic patients may present with atypical symptoms and heart failure is a common complication. Diabetic patients who sustain a myocardial infarction still have doubled mortality compared to non-diabetic patients. There are indications that patients with diabetes do not receive the same extensive treatment as non-diabetics, presumably due to fear for treatment complications. Diabetes is not a contra-indication for fibrinolytic therapy, even in the presence of retinopathy. Furthermore, treatment with beta-blockers and ACE inhibitors seems to be even more effective than in non-diabetic patients and the risk for complications is negligible.145 The acute phase is often characterized by deterioration of the metabolic control and hyperglycaemia is an independent predictor of mortality. Strict attention to the glycaemic control by use of insulinglucose infusion followed by multiple-dose insulin treatment has been shown to reduce long-term mortality.146,147

Management of the later in-hospital course

Management of the later in-hospital phase will be determined by the amount of myocardial necrosis, the demographic characteristics of the patients and the presence or absence of co-morbidity. While the patient who became asymptomatic and with minimum myocardial damage may go home after a few days, particularly if the coronary anatomy is known, patients with significant left ventricular dysfunction or those who are at risk of new events require a longer hospitalization.

Ambulation
Patients with significant left ventricular damage should rest in bed for the first 12–24h, by which time it will be apparent whether the infarction is going to be complicated. In uncomplicated cases, the patient can sit out of bed late on the first day, be allowed to use a commode and undertake self-care and self-feeding. Ambulation can start the next day and such patients can be walking up to 200m on the flat, and walking up stairs within a few days. Those who have experienced heart failure, shock or serious arrhythmias should be kept in bed longer, and their physical activity increased slowly, dependent upon their symptoms and the extent of myocardial damage.

Management of specific in-hospital complications
Deep vein thrombosis and pulmonary embolism
These complications are now relatively uncommon after infarction, except in patients kept in bed because of heart failure. In such patients, they can be prevented by prophylactic doses of a low-molecular-weight heparin. When they occur they should be treated with therapeutic doses of alow-molecular-weight heparin, followed by oralanticoagulation for 3–6 months.

Intraventricular thrombus and systemic emboli
Echocardiography may reveal intraventricular thrombi, especially in patients with large anterior infarctions. If the thrombi are mobile or protuberant, they should be treated initially withintravenous unfractionated heparin or low-molecular-weight heparin and subsequently with oral anticoagulants for at least 3–6 months.

Pericarditis
Acute pericarditis may complicate myocardialinfarction and is associated with a worse outcome. It gives rise to chest pain that may be misinterpreted as recurrent infarction or angina. The pain is, however, distinguished by its sharp nature, and its relationship to posture and respiration. The diagnosis may be confirmed by a pericardial rub. If the pain is troublesome, it may be treated by high-dose oral or intravenous aspirin, non-steroidal anti-inflammatory agents, or steroids. A haemorrhagic effusion with tamponade is uncommon and is particularly associated with anticoagulant treatment. It can usually be recognized echocardiographically. Treatment is by peri