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Ischaemic heart disease is a major health problem in the western world. In many cases the first symptom of this disorder is acute myocardial infarction (AMI). The clinical spectrum of AMI is broad: it may be immediately complicated by sudden cardiac death, or it may occur silently. The consequences of myocardial infarction for society are enormous, and include the cost of hospitalisation, medication, angioplasty, coronary surgery and rehabilitation as well as expenses for disability compensation and early retirement. Finally, the psychological sequelae of being struck with a heart attack are long lasting and often lifelong.
EARLY MANAGEMENT OF AMI
Since the patient with suspected AMI is at high risk for sudden coronary death, emergency measures should be taken: immediate monitoring of the electrocardiographic heart rhythm, venous access, and rapid transportation to a hospital. The initial measures are summarised in box 1.
Box 1 Initial measures in patients with acute ST elevation myocardial infarction
Electrocardiographic monitoring of heart rhythm
Introduction of venous cannula
Rapid transportation to a hospital, preferably with a catheterisation laboratory
Relief of pain and anxiety
Reduction of myocardial ischaemia by sublingual or buccal glyceryl trinitrate
Initiation of reperfusion therapy when appropriate
β-blockade (preferably oral)
Aspirin (chewed 100–200 mg), clopidogrel 300 mg (age >75 years: 75 mg) and heparin (5000 units intravenous (iv) bolus followed by iv drip at an activated partial thromboplastin time (aPTT) of 2–3 times control, or iv bolus low molecular weight heparin: 30 mg enoxaparin (>75 years: no bolus, but a subcutaneous injection of 0.75 mg/kg)
Patients with suspected AMI should be transferred to a hospital with a coronary care unit and preferably a catheterisation laboratory. Proper triage can be performed in those institutions with subsequent appropriate treatment for the patient. In some areas pre-hospital triage can be accomplished, where pre-hospital fibrinolytic therapy can be instituted.1 2 Depending on the local situation, time to fibrinolytic treatment can be shortened by 30–150 min, leading to better survival and preservation of left ventricular function. However, in most areas the infrastructure for pre-hospital fibrinolysis with transtelephonic or computer assisted electrocardiographic diagnosis are lacking. In those areas rapid transportation is even more pressing.
The routine use of glyceryl trinitrate in AMI is questionable. However, in patients with suspected myocardial infarction, the administration of glyceryl trinitrate may abort the development of myocardial necrosis and, in this case, glyceryl trinitrate is therapeutic. In two large randomised clinical trials the routine use of glyceryl trinitrate patch or isosorbide mononitrate led to a 5% relative reduction of mortality, which is at the brink of statistical significance.3 4 Although in the majority of patients routine glyceryl trinitrate may not be helpful, it may be useful in a subset of patients and its risk is almost nil.
Fibrinolytic therapy has become the greatest step forward in the early management of acute ST segment elevation myocardial infarction (fig 1). It has also become clear that fibrinolytic therapy beyond 6 h after symptom onset is only marginally beneficial.5 6 The indication for fibrinolytic therapy has to be weighed against the absolute or relative contraindications. The earlier the patient is presented and the larger the area at risk at the presenting ECG, the more beneficial fibrinolytic therapy is (fig 2) and the more contraindications are relative. The later the patient is presented and the smaller the area at risk, the least fibrinolytic therapy is beneficial and the more contraindications are stringent. The risk of fibrinolytic therapy is in its inherent bleeding complications. The most severe bleeding complication is the occurrence of cerebral haemorrhage. This is seen in about 0.5% of patients treated with fibrinolysis.7 Risk factors for the development of cerebral bleeding following fibrinolytic therapy are low body weight (<65 kg), female gender, hypertension, and the use of oral anticoagulants before fibrinolysis. Other bleeding complications are gastrointestinal bleeding and haemorrhage following arterial punctions. In most cases these bleeding complications can be managed conservatively and have a rather good prognosis.
A second problem after fibrinolytic therapy is the occurrence of reocclusion.8 Reocclusion is seen in about 10% of cases in hospital and about 30% in the year following fibrinolysis. So far, no specific drug or intervention has proven to be efficacious against reocclusion. The currently used aspirin and heparin (see below) are important in the management of patients undergoing fibrinolytic therapy, but their efficacy against reocclusion is not proven. Finally, fibrinolytic agents may be immunogenic. This is especially seen with streptokinase and streptokinase derived agents such as anistreplase. The recombinant endogenous plasminogen activator tissue plasminogen activator (rt-PA), or alteplase, has a low incidence of immunologic reactions and can be given to patients with streptokinase allergy or in patients who have had streptokinase before. A mutant of rt-PA can be given as single bolus (tenecteplase, or TNK-tPA).
The cost of fibrinolytic agents is considerable: streptokinase costs about US$100 (€75, £70), and rt-PA/TNK-tPA about US$2000 (€1500, £1400). However, these agents have different early (90 min) recanalisation rates: over 50% for front loaded tissue rt-PA/bolus TNK-tPA versus only 30–35% for streptokinase. Since early patency is correlated with early survival,9 not only is the initial cost of the fibrinolytic drug important. Early patients with a large myocardial infarction benefit more from a drug with a high early patency rate than patients presenting late with a small myocardial infarction. Given the above, fibrin specific fibrinolytics are preferred.
The clear alternative to fibrinolytic therapy in the reperfusion strategy of ST segment elevation AMI is primary coronary angioplasty. This therapy has a clinical benefit over the optimal fibrinolytic strategy.10 The major drawback of primary angioplasty is its limited availability and treatment delay. The delay is caused by preparation of the catheterisation laboratory and mobilisation of personnel to perform the procedure. Moreover, when patients have to be transferred for primary angioplasty, the delay can be considerable. During this delay patients may be treated with a lower dose of a fibrinolytic to speed up reperfusion before angioplasty (facilitated angioplasty). The initial cost of primary angioplasty is higher than fibrinolytic therapy, but the patency achieved is superior to fibrinolytic therapy—up to 90%.11 The risk of fibrinolytic therapy is higher than that of primary angioplasty, since cerebral bleeding is absent with primary angioplasty. Widespread application of primary angioplasty largely depends on the cost a community is willing to spend on the acute care of ST segment elevation myocardial infarction.
The choice of reperfusion strategy mainly depends on the time interval between first medical contact and the availability of a skilled catheterisation laboratory team to perform primary percutaneous coronary intervention (PCI).12 It is now generally agreed that the time window should be <2 h. If PCI cannot be performed within that time window, lytic therapy as initial treatment is preferred (fig 3).
The update of the European guidelines with regard to reperfusion therapy is summarised in table 1.
Patients with acute prolonged ischaemia at rest should be treated with β-blockade to reduce ischaemia. Since oral β-blockade takes at least 30 min to become clinically effective in reducing of heart rate and blood pressure, intravenous β-blockade may be given, especially in patients with acute transmural myocardial ischaemia. β-blockade is associated with better hospital survival,13 probably due to reduction of myocardial ischaemia and reinfarction, but also because of myocardial rupture.14 Metoprolol (10 mg intravenously) and atenolol (5 mg intravenously) are registered as intravenous agents in AMI. Intravenous β-blockade can be given, but must always be followed by oral β-blockade. Also, in the current era of reperfusion therapy, intravenous followed by oral β-blockade has been shown to be beneficial in the reduction of recurrent myocardial infarction, but not death.15 Cardiogenic shock is seen more often after intravenous β-blockade,15 suggesting that a slow start of this therapy is preferred.
Aspirin should be administered intravenously or orally to all patients presenting with prolonged myocardial ischaemia at rest. For acute coronary syndromes with and without ST segment elevation, aspirin has been shown to reduce (re)infarction and death by 30–50%.16 A loading dose of aspirin is probably necessary to block platelet thromboxane A2 biosynthesis completely. The first dose should be preferably 200 mg or more. Subsequent dosing can be between 75–325 mg daily. Acute treatment with the platelet adenosine diphosphate receptor antagonist clopidogrel has also been shown to reduce (recurrent) myocardial infarction in patients presenting with acute coronary syndromes with ST segment elevation, who are already treated with aspirin.17 These results with the agent are probably due to better early coronary patency.18 Blockers of the final common pathway of the platelet aggregation, the glycoprotein IIb/IIIa receptor antagonists, are of little value when given routinely to patients with acute coronary syndromes with ST segment elevation treated with aspirin and a fibrinolytic.19 Only patients undergoing primary angioplasty benefit from these expensive agents, that are given intravenously.20 The update of antiplatelet therapy in the European guidelines is summarised in table 1.
The role of heparin in acute coronary syndromes with ST segment elevation21 is less clear than in non-ST elevation acute coronary syndromes.22 Extracranial bleeding is increased with heparin. Two large trials with low molecular weight heparin in conjunction with fibrinolysis showed supremacy of low molecular heparin over unfractionated heparin, irrespective of the fibrinolytic used.23 24 As an alternative to (low molecular weight) heparin the subcutaneous pentasaccharide fondaparinux has been introduced. In patients without reperfusion therapy and those undergoing fibrinolysis, fondaparinux reduced significantly death and reinfarction compared to standard therapy (heparin, low molecular weight heparin, or no anticoagulant), but in primary angioplasty fondaparinux has shown no advantage over heparin.25 As an alternative to (low molecular weight) heparin the intravenous direct thrombin blocker bivalirudin has been introduced in reperfusion therapy. However, in a large trial bivalirudin in conjunction with streptokinase showed little benefit over heparin.26 On the other hand, when given in primary PCI as an alternative to the combination of heparin and glycoprotein IIb/IIIa blockers, bivalirudin halved the bleeding rate and significantly reduced 30 day mortality.27 The update of anticoagulant treatment in the European guidelines is summarised in table 1.
Other pharmacological measures
Routine antiarrhythmic therapy in prevention of ventricular arrhythmia is not indicated in patients with AMI. They may even be counterproductive. Lidocaine given to patients with AMI significantly prevents the occurrence of ventricular fibrillation but does induce asystole.28 Furthermore, lidocaine is a negative inotropic drug, may induce seizures, and in case of total atrioventricular block asystole can be induced. Routine administration of angiotensin converting enzyme (ACE) inhibitors significantly reduces mortality and morbidity, but the effect is small.3 4 Patients with overt heart failure at hospital admission may gain more benefit from this treatment as well as those who develop congestive heart failure in the early hours and days after onset of AMI.29 Magnesium sulfate as a routine treatment in AMI is not beneficial either.3
Box 2 Prognostic parameters at hospital admission in patients presenting with acute ST elevation myocardial infarction
Age: prognosis decreases with age
Gender: females have a worse prognosis than males
Heart rate: heart rate over 100 beats/min indicates a poor prognosis
Cardiogenic shock: has a very high early mortality
Congestive heart failure: indicates a poor prognosis even when treated successfully
ST segment deviation: the more ST segment deviation or Q wave formation, the larger the infarct and the worse the prognosis
Enzymes: not admission enzymes, but evolving rise in cardiac enzymes estimate infarct size
The role of primary angioplasty in acute coronary syndromes with ST segment elevation has been discussed above. Patients in cardiogenic shock or severe congestive heart failure may benefit the most from early angiography followed by emergency revascularisation.30 Also, in patients who have been treated with fibrinolytic therapy, an early routine invasive procedure within 24 h is beneficial,31 because reocclusion is not uncommon and sometimes severe residual stenosis remains after fibrinolytic therapy (fig 3). However, a routine angioplasty of an occluded culprit lesion beyond 72 h after infarction does not prevent recurrent infarction or death in the short and long term.32 In patients with recurrent ischaemia despite optimal anti-ischaemic and antithrombotic therapy, and in those with failed reperfusion by ECG, early coronary angiography followed by angioplasty or coronary surgery, if appropriate, is always indicated (fig 3). It should be noted that coronary surgery in patients with evolving myocardial infarction is correlated with a high mortality.
Mortality in patients experiencing an AMI is the highest during the early minutes of symptom onset. Ventricular arrhythmia is believed to be the cause of this very early fatal outcome of myocardial infarction. About 25% of patients with an AMI die in the first hour after symptom onset and often before medical or paramedical personnel have arrived on the scene. Even patients who develop ventricular fibrillation just before the arrival of (para)medical personnel have a poor prognosis, although they may arrive alive in the hospital.33 Patients alive at ambulance arrival or at hospital admission still face a considerable risk of ventricular fibrillation. Patients who develop ventricular fibrillation in the early hours of AMI, although properly defibrillated, have a worse in-hospital prognosis than those who do not develop ventricular fibrillation.34 The mechanisms involved are not quite clear and infarct size may play a role, but this is controversial. After hospital discharge, patients who have had ventricular fibrillation have the same prognosis as those without ventricular fibrillation.
ST elevation myocardial infarction (STEMI) and the new ESC guidelines: key points
Major changes with regard to reperfusion therapy in STEMI
Maximal acceptable time delay between first medical contact and first balloon inflation extended from 90 min to 120 min.
After fibrinolysis coronary angiography between 3–24 h is mandatory.
Major changes with regard to antithrombotic therapy in STEMI
Aspirin, clopidogrel and heparin are now standard of care in patients awaiting primary PCI.
In the catheterisation laboratory, use of glycoprotein IIb/IIIa blockers is recommended in primary PCI.
Clopidogrel has become standard of care in patients undergoing fibrinolysis.
Other important prognostic parameters at hospital admission are listed in box 2. Both clinical and biochemical markers may indicate an early prognosis for the patient with AMI. Ineligibility for reperfusion therapy has a much worse prognosis than patients who are eligible and do receive it. Failure of reperfusion therapy (persistence of pain and ST segment elevation) indicates the same worse prognosis in patients not receiving reperfusion therapy. Recurrent myocardial ischaemia is a sign of multivessel coronary artery disease, especially in the absence of reperfusion therapy. Those patients need urgent angiography and revascularisation, if possible (see above).
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SUMMARY AND FUTURE DEVELOPMENTS
AMI is still the major cause of death in the western world. However, its incidence is declining in the USA and western Europe, the reason for which is not completely clear. It is possible that improved prevention plays a role. Yet, the mortality and morbidity due to AMI is still high, possibly because the delay to treatment has not significantly decreased. Delay on the part of the patient contacting the emergency services is still the major contributor to the delay in receiving treatment and has barely changed, even after large public campaigns. Pre-hospital delay can be dramatically improved by pre-hospital fibrinolysis, and in-hospital delay by better infrastructure.
AMI is probably caused by rupture of an atherosclerotic plaque followed by coronary thrombosis. The abrupt impairment of myocardial blood flow in a large segment of the left ventricular myocardium immediately leads to electrical instability and loss of systolic and diastolic function. These electromechanical complications largely contribute to the early mortality and morbidity. The best diagnostic tool for AMI is the patient’s history followed by supportive diagnostics such as electrocardiography. Biochemical markers are sensitive and specific, but appear in the plasma several hours after symptom onset, and thus they do not contribute significantly to early patient triage. Both the treatment and prognosis of patients with AMI can be improved. The widespread introduction of pre-hospital triage and improvement of in-hospital infrastructure to shorten in-hospital delay will lead to better treatment and thus better prognosis of patients with AMI. The widespread introduction of primary angioplasty for AMI requires costly infrastructure and high personnel costs. Finally, the prevention of atherosclerosis is the key to lowering the incidence of myocardial infarction. Improvement in lifestyle and possibly better drugs to lower plasma cholesterol and other mechanistic factors involved in the development of atherosclerosis will all help to reduce the prevalence of this epidemic.
Large US registry of ST elevation myocardial infarction (STEMI) patients evaluating time delays in reperfusion therapy (fibrinolysis or primary PCI) on the one hand and hospital mortality on the other in 192 509 patients.
Large trial of short term early clopidogrel without loading dose in Chinese STEMI patients with and without reperfusion therapy (mainly fibrinolysis), showing less reinfarction and a mortality benefit for early clopidogrel without an excess bleeding risk.
Randomised trial of short term clopidogrel (with 300 mg loading dose) and aspirin versus aspirin alone on early infarct vessel patency in 3491 STEMI patients undergoing fibrinolysis, showing better patency and no increased bleeding risk.
Meta-analysis of trials evaluating heparin versus control in STEMI patients undergoing fibrinolysis addressing the role for anticoagulation during fibrinolysis.
Largest randomised trial of enoxaparin versus unfractionated heparin in 20 506 STEMI patients undergoing fibrinolysis, showing a reduction in reinfarction (but not death) with an acceptable rate of excess bleeding.
Trial of fondaparinux versus control (intravenous heparin or no heparin) in 12 092 STEMI patients, showing a significant reduction of death, reinfarction and stroke in patents undergoing fibrinolysis or no reperfusion therapy, but no benefit in those undergoing primary PCI. Fondaparinux proved safer than control therapy.
First large trial to evaluate intravenous direct thrombin blockade versus the combination heparin and platelet glycoprotein IIb/IIIa blockers in 3602 STEMI patients undergoing primary PCI, showing a large reduction in bleeding with bivalirudin with a 30 day mortality benefit.
Largest published trial of an immediate (mean 2.3 h) invasive versus a conservative strategy after fibrinolysis in 597 STEMI patients showing a reduction in reinfarction.
Large trial evaluating percutaneous opening of occluded infarct vessels 3–8 days after STEMI in 2166 patients showing no clinical benefit over a conservative approach.
Competing interests: In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conflicts of interest that might cause a bias in the article. The author has undertaken research contracts and consulting work, and received speaker fees, from various pharmaceutical companies.
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