Acute myocardial infarction: early treatment

Summary
Acute myocardial infarction is a common cause of death. Most of the deaths are due to ventricular fibrillation occurring soon after the onset of ischaemia. Once the patient reaches hospital, the major aim of treatment is to decrease the size of the infarct. Fibrinolytic therapy with streptokinase or tissue plasminogen activator (tPA) restores coronary patency and significantly reduces mortality. Aspirin is mandatory unless there are absolute contraindications to its use. Heparin is optional with streptokinase but necessary with tPA. ACE inhibitors and intravenous beta blockers are beneficial in acute myocardial infarction and intravenous glyceryl trinitrate probably has a role. Calcium channel blockers and magnesium should not be used routinely.

Introduction
Myocardial infarction is one of the most common causes of death in Australia. The majority of patients that die develop ventricular fibrillation before they can obtain medical attention.

This means that the most important measure to reduce deaths is to educate people about the symptoms and signs of acute myocardial infarction. Patients must get near a defibrillator as soon as possible. Once the patient is in a situation where sudden death can be prevented, the important issue is reducing the size of the myocardial infarct, and in this, drug therapy has a major role to play.

Aetiology
Acute myocardial infarction is caused by the complete occlusion of a coronary artery with thrombus. The thrombus occurs at the site of a plaque which has ruptured, exposing its inner core and thus promoting thrombus formation.

Aim of treatment
Early treatment aims to reduce the extent of myocardial damage. As the myocardium is damaged by a diminished oxygen supply due to the obstructed coronary artery, infarct size can be reduced in two ways:

• dissolution of the thrombus to restore coronary blood flow
• decreasing myocardial oxygen consumption

Restoration of flow
This has become the main aim of treatment as it reduces the mortality significantly.1,2 Flow is normally restored using drug therapy - fibrinolytic agents (e.g. streptokinase, tissue plasminogen activator), antiplatelet agents (e.g. aspirin) and antithrombins (e.g. heparin). Recently, coronary angioplasty (PTCA) has been used to restore flow mechanically.

The speed at which the flow is restored is important. For every hour of delay, the effect of therapy diminishes and mortality increases.

Decreasing myocardial oxygen consumption
The benefit of therapy aimed at decreasing myocardial oxygen consumption is considerably less than the benefit of restoration of flow. Decreased oxygen consumption is achieved by lowering heart rate, blood pressure and cardiac filling pressures. Beta blockers, glyceryl trinitrate and possibly ACE inhibitors work in this way.

Initial treatment

Aspirin
All patients with a suspected myocardial infarction should be given aspirin. It is a powerful antiplatelet drug, with a rapid effect, which reduces mortality by 20%.² Aspirin, 150-300 mg, should be swallowed as early as possible. General practitioners should give aspirin or advise the patient to take an aspirin when they are called by a patient who may be suffering a myocardial infarction. There is no need to wait for an electrocardiograph (ECG). If the patient has not already taken aspirin, it should be given in the ambulance or emergency room.

Fibrinolytic therapy
The mainstay of treatment is fibrinolytic therapy. This is given to dissolve the thrombus in the artery and restore flow. There are two fibrinolytic drugs commonly used in Australia - streptokinase and tissue plasminogen activator (tPA).

Fibrinolytic therapy should be given to all patients with appropriate indications and no contraindications (Table 1).

The indications for fibrinolytic therapy are symptoms of myocardial ischaemia, of less than 12 hours' duration, with ECG changes of ST elevation or left bundle branch block. Patients without these ECG changes should not be given fibrinolytic therapy.³

Table 1 Indications and contraindications for fibrinolytic therapy Indications

within 12 hours of onset of chest pain lasting for at least 30 minutes

ECG changes of ST elevation of at least 1 mm in two or more contiguous leads, or left bundle branch block

Contraindications

cerebral event within 6 months

major trauma including surgery within 1 month

bleeding peptic ulcer within 2 months

uncontrolled hypertension

non-compressible vascular puncture

The concern with fibrinolytic therapy is bleeding. The most feared form of bleeding is intracerebral bleeding which is usually fatal. Therefore, patients with contraindications (Table 1) should be considered for acute PTCA. Uncontrolled hypertension is a relative contraindication and attempts should be made to lower the blood pressure below 175 mmHg systolic and 100 mmHg diastolic. A history of an ulcer or recent cardio-pulmonary resuscitation is not an absolute contraindication.

Streptokinase
Streptokinase produces generalised systemic fibrinolysis and is the drug most commonly used in Australia. Despite reducing mortality by 25%^1,2, only about 30% of patients have their coronary flow restored to normal within 90 minutes of treatment. This increases to over 50% by 3 hours and up to 80% by 5-7 days.⁴

An intravenous infusion of 1.5 million units is given over 30-60 minutes. Most patients will develop hypotension if streptokinase is given quickly, but this is usually easily overcome by slowing the infusion and giving fluid.

Streptokinase is derived from Streptococci and will produce an antibody reaction. These antibodies appear after 2-3 days and persist for some years. The presence of antibodies reduces the efficacy of subsequent doses of streptokinase and increases the potential for anaphylaxis. The present consensus is that streptokinase should be used only once per patient.⁵ All patients should be informed about being treated with streptokinase and ideally given a card or other form of record so that this information is available should they have another infarction.

Tissue plasminogen activator (tPA)
As tPA specifically binds to thrombus, it produces local fibrinolysis. It does not have the same systemic effects as streptokinase.

Clot dissolution occurs more promptly with tPA than streptokinase restoring patency at 90 minutes in 55% of patients.⁴ However, by 3 hours and 5-7 days there is no major difference in patency in patients treated with streptokinase or tPA. This improved early patency results in slightly improved mortality (6.3% tPA versus 7.1% streptokinase).⁶

Compared with streptokinase, tPA appears to cause more bleeding and, in particular, produces a higher incidence of cerebral bleeding. There are 2-3 extra strokes per 1000 patients treated and one of these patients dies from their stroke. Therefore, care should be taken with patients at risk of stroke, the elderly and those with high blood pressure.

Despite the increased risk of stroke, the net clinical benefit is greater with tPA in nearly all subgroups of patients. For every 1000 patients treated with tPA, there will be 10 extra survivors at the cost of one patient surviving with disability from a stroke.

tPA is not used in all patients because of its cost - approximately $1900 compared with $150 for streptokinase. The current consensus in Australia is that tPA should be utilised in

• patients who have previously had streptokinase
• patients aged less than 75 years having large myocardial infarctions who arrive within 4 hours of the onset of symptoms.⁵

The treatment regimen is shown in Table 2.

Table 2 tPA regimen
Bolus	Maintenance
15 mg	0.75 mg/kg over 30 minutes (not to exceed 50 mg) then 0.5 mg/kg over 60 minutes (not to exceed 35 mg)

Heparin
Heparin is an antithrombin agent. It has been utilised with both fibrinolytic drugs and given subcutaneously and intravenously.

Heparin and streptokinase
There is contention about the routine use of heparin with streptokinase. There has been no apparent benefit on mortality of subcutaneous versus no heparin7 and no benefit of intravenous heparin versus subcutaneous heparin.6 Equally, the addition of routine intravenous or subcutaneous heparin does not appear to do any harm. Not giving routine heparin has the benefit that clotting studies are not necessary and this may be particularly advantageous in smaller hospitals without 24-hour laboratory facilities. However, heparin may be required for clinical reasons e.g. large infarcts, ongoing ischaemia.

Intravenous heparin is given as a 5000 unit bolus followed by 1000 units per hour intravenously, adjusted after 24 hours according to the activated partial thromboplastin time (APTT). (APTT measurements are little use in the first 24 hours as streptokinase also raises the APTT.)

Heparin and tPA
Currently, it is believed that heparin should be given with tPA. The standard regimen is an initial bolus of 5000 units, followed by an infusion of 1000 units per hour adjusted after 6 hours for APTT.

ACE inhibitors
ACE inhibitors reduce the mortality of myocardial infarction and this benefit is seen within the first 30 days. Issues in relation to the use of ACE inhibitors are:

• whether they should be given to all patients or only those with large infarcts
• when they should be given

Most Australian cardiologists give ACE inhibitors only to patients with large infarcts and those with clinical signs of left ventricular failure. Captopril 6.25 mg, or equivalent low doses of another ACE inhibitor, should be used as a first dose and, if tolerated, the dose increased to at least 25 mg twice daily of captopril or the equivalent dose of the alternatives. Current consensus is that they should be given as early as feasible when the patient is haemodynamically stable.

Beta blockers
Intravenous beta blockers such as atenolol, metoprolol and timolol reduce the incidence of arrhythmias, infarct size and mortality. As the effect is relatively small, they are not widely used.

Beta blockers can be given if the patient is haemodynamically stable with a heart rate above 50 beats per minute and systolic blood pressure above 100 mmHg.

The standard regimen is atenolol 5 mg intravenously over 5 minutes followed 10 minutes later by a further 5 mg. Oral beta blockade is commenced 30 minutes later. Many centres use only oral beta blockade (atenolol 50 mg, metoprolol 50 mg) commenced as soon as possible after admission.

Much of the data on beta blockers was obtained before the widespread use of thrombolytic therapy. It is likely that the relative improvement in outcome would be the same in patients treated with thrombolysis, but it is possible that the absolute magnitude of the benefit would be reduced.

Glyceryl trinitrate
Intravenous glyceryl trinitrate reduces preload and after load and may help to keep the coronary vessels open. In small studies, intravenous glyceryl trinitrate for 24 hours reduced mortality, but this has not been confirmed by large trials. Intravenous glyceryl trinitrate can be used routinely or only for ongoing chest pain or left ventricular failure (the standard dose is 5 microgram/minute and this can be titrated against the blood pressure).

Oral nitrates should not be used routinely as they are of no benefit.

Other drugs
Treatment with a calcium channel blocker or magnesium should not be used routinely in patients with acute myocardial infarction as trials have not shown them to be beneficial.

Pain relief is important and should not be forgotten while administering thrombolytic therapy or other drugs. Intravenous morphine titrated slowly, starting at 2.5 mg until adequate relief is obtained, is the most appropriate drug. Intramuscular injection should be avoided. Oxygen therapy is thought to be beneficial, although there have been no trials to confirm this.

Summary
The early treatment of acute myocardial infarction consists of ensuring the patient is in an environment in which defibrillation is possible and then reducing the size of the potential infarct by re-opening the occluded coronary artery. Aspirin should be commenced out of hospital and fibrinolytic therapy given as soon as possible after the diagnosis is confirmed by ECG.

Dr Aylward is the National Co-ordinator for the GUSTO group in Australia.