PRACTICAL THERAPEUTICS Drugs 50 (4): 615-625, 1995 OOI2-6667/95/00HH)615/SII.QO/O ----------- ---© Adis International Limited. All rights reserved.

Guidelines for General Practitioners Administering Thrombolytics John Rawles Medicines Assessment Research Unit, University of Aberdeen, Foresterhill, Aberdeen, Scotland

Contents

Summary . . . . .. . ......... . 1. The Case for Prehospital Coronary Care

1.1 Resuscitation 1.2 Pain Relief ... . 1,3 Thrombolysis .. .

2. Thrombolytic Therapy 2.1 Mechanism of Benefit 2.2 Evidence of Efficacy from Clinical Trials

2.2.1 The Presenting Electrocardiogram (ECG) 2.2.2 The Time Effect ........... . 2.2.3 Comparison of Thrombolytic Agents

2.3 The Risks of Thrombolytic Therapy ..... 3. Diagnosis of Acute Myocardial Infarction (AMI) 4. Guidelines . . . . . . . . . , . . . . . , . . . . .

4.1 Practice Policy for Management of AMI 4.2 Indications for Thrombolytic Therapy. . .

4.2.1 Strong Clinical Suspicion of AMI .. 4.2.2 Chest Pain 20 Minutes to 12 Hours 4.2.3 Abnormal ECG .......... .

4.3 Contraindications to Thrombolytic Therapy . 4.3.1 Avoidance of Thrombolysis in Patients Without AMI 4.3.2 Avoidance of Cerebral Haemorrhage . . . . . . . . 4.3.3 Avoidance of Noncerebral Haemorrhage ..... 4.3.4 Previous Exposure to Streptokinase or Anistreplase .

4.4 Choice of Thrombolytic Agent 5. Conclusions . . . . . . . . . . . . . . . . . . . . . , . . . . . . . .

615 616 616 616 616 616 616 617 617 617 618 618 619 620 620 620 620 620 621 621 621 621 621 622 622 623

Summary Acute myocardial infarction (AMI) recognises no boundaries, and the patient's greatest need occurs at the interface between primary care and the hospital system. Ideally, the general practitioner, if summoned, should be able to provide resusci­tation, analgesia with opiates, and thrombolytic therapy. Thrombolytics should certainly be given to eligible patients by the general practitioner if an hour could be saved by so doing. Optimising the risk-benefit ratio for thrombolytic therapy given in the community is a challenge to clinical judgement. Experience with this

616 Rawles

potent treatment is best obtained under a degree of supervision, which could take the form of an audit of the prehospital management of suspected AMI.

With prehospital administration of thrombolytic therapy at the first opportu­nity, the chances of saving a life are better than I in 10, while the excess risk of a disabling stroke is about I in 1000.

1. The Case for Prehospital Coronary Care

Acute myocardial infarction (AMI) has a 28-day fatality rate of about 50%.[1] Half the deaths occur in the first 2 hours after the onset of symp­toms,[2] and about two-thirds of deaths occur in the community)}] Hospital care starting several hours after the onset of symptoms can therefore have lit­tle impact on the overall mortality from AMI. The patient's needs for medical care are immediate: there is no 'golden hour' within which appropriate medical help can be organised. Ideally, the first doctor summoned should be able to administer all 3 essential elements of coronary care - resuscita­tion from ventricular fibrillation, pain relief with opiates, and thrombolysis.

1 .1 Resuscitation

If a rapid response is made to patients with sus­pected AMI, cardiac arrest will be encountered in about 5% of cases.[4] If cardiac arrest is witnessed by a doctor with a defibrillator then the survival rate is better than 50%.[5] Possession of a defibril­lator gives confidence, and enables the attending doctor to spend more time on stabilising the pa­tient's condition before transfer to hospital. A defi­brillator should therefore be available whether or not thrombolytic therapy is given.

1.2 Pain Relief

Untreated, the patient with AMI may rapidly die from cardiogenic shock, a possible mechanism be­ing: pain ~ autonomic response ~ hypotension and bradycardia ~ poor coronary perfusion ~ in­farct extension ~ pain.[6] Relief of pain and anxi­ety with opiates, as well as being humane, breaks into this cycle and is life-saving.[7,8] General med­ical care, including opiate analgesia, treatment of

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vagal excess with atropine, correction of arrhyth­mias, and administration of aspirin (acetylsalicylic acid), is of overriding importance in the immediate management of AMI: it must not be overlooked in the rush to give thrombolytic therapy.

1 .3 Thrombolysis

Administration of thrombolytic therapy in hos­pital4 to 5 hours after the onset of symptoms saves 20 to 30 per 1000 lives within a month.[9] The ad­ditional benefit of prehospital thrombolysis may be as much as 60 to 80 lives saved per 1000 per hour of earlier treatment;[IO] I in 10 lives will be saved by prehospital thrombolysisJII] Giving thrombo­lytic therapy at the first opportunity is a matter of the utmost urgency. In terms of potential lives saved, it is as urgent as resuscitation from cardiac arrest. From every 1000 patients with AMI, more lives are likely to be lost by deferring thrombolysis until the patient enters hospital than would be lost by a similar delay in resuscitating those with ven­tricular fibrillation. [12]

2. Thrombolytic Therapy

2,1 Mechanism of Benefit

Most cases of AMI are due to coronary throm­bosis, often occurring at the site of a ruptured atheromatous plaque.[13] Successful thrombolysis restores patency in the infarct-related artery.[14] If reperfusion is established within 2 hours of onset, salvage of ischaemic myocardium is likely, and the infarct is smaller than it would have been without therapy. Following very early thrombolysis, within an hour of onset, there may be no detectable in­farctJl5] Reperfusion occurring 4 hours or more af­ter onset is still beneficial, but by a different mech­anism: by that time it is too late for myocardial salvage to occur.[16]

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A patent infarct-related artery confers electrical stability,[l7,18] so that ventricular fibrillation is less likely, and it helps in the healing process, reducing infarct expansion and progression to heart fail­ure,l19,20]

2.2 Evidence of Efficacy from Clinical Trials

An overview of all randomised clinical trials of more than 1000 patients has shown beyond doubt that thrombolytic therapy reduces mortality from AMI.l9] In patients presenting with ST elevation or bundle branch block up to 12 hours from symptom onset, 20 to 30 deaths per 1000 are prevented by thrombolytic therapy.

2.2. 1 The Presenting Electrocardiogram (ECG) In 2 major trials that each showed an overall

benefit from thrombolytic therapy, ISIS-2[21] and ASSET,[22] entry was by clinical suspicion of AMI, and electrocardiographic (EeG) confirma­tion of the diagnosis was not required. In both trials there was evidence of benefit in those with­out ST elevation on the presenting EeG, as well as in those with this abnormality. In ISIS-2, the presenting EeG was classified into 7 categories, and in patients given aspirin, all showed a ten­dency to benefit from thrombolytic therapy. The magnitude of the benefit was greatest for those with ST elevation in the anterior leads and least in those with ST depression. As would be ex­pected, only in the largest subgroups or in those where the benefit was greatest, was the benefit statistically significant.

Statistical significance in a subgroup analysis is as much a function of the size of the subgroup as of the magnitude of benefit: failure to reach signif­icance is no reason for denying treatment that is probably beneficial to patients with the charac­teristics of that subgroup. More weight should be attached to the trial result as a whole than to the subgroup analyses.

To decide whether patients are likely to benefit from thrombolytic therapy it should be considered whether they would have met the inclusion criteria for any of the trials of thrombolysis. If they are suspected of having AMI and would have been el-

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Glossary. List of clinical trials cited in this review which are commonly known by acronyms

AIMS

ASSET

EMERAS

EMIP

FIT

GISSI·2

GREAT

GUSTO

ISIS

APSAC Intervention Mortality Study

Anglo·Scandinavian Study of Early Thrombolysis

Estuio Mulicentrico Estreptoquinasa Republicas de America del Sur

European Myocardial Infarction Project

Fibrinolytic Therapy Triallists' Collaborative Group

Gruppo Italiano per 10 Studio della Soprawivenza nell'lnfarto Miocardico

Grampian Region Early Anistreplase Trial

Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries

International Study of Infarct Survival

LATE Late Assessment of Thrombolytic Efficacy

MITI Myocardial Infarction Triage and Intervention

igible for ISIS-2, the odds of their dying would be reduced by 25% with streptokinase - a little more if they had ST elevation and a little less if they had other EeG abnormalities. Absolute mortality re­ductions were 40 and 18 lives per 1000, respec­tively.

2.2.2 The Time Effect There are strong reasons based on theory and

experiment for believing that the earlier thrombol­ysis is given, the greater the benefit. This time ef­fect would be expected to be powerful, and of great clinical importance. However, of the four largest randomised placebo-controlled trials of thrombo­lytic therapy, two show this effect (GISSI[23] and ISIS-2[21]), while two do not (AIMS[24] and AS­SET[22]).

In the FTT overview, subgroup analysis of 9 randomised trials of thrombolytic therapy shows a weak time effect, with an estimated loss of benefit of 1.6 lives per 1000 per hour of delay to randomisation,l9] However, this estimate is incor­rect because of the false assumption that patients who present for treatment at different times after symptom onset have the same mortality risk. In fact, patients with more severe infarction tend to seek medical aid sooner,[25,26] and this behaviour

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acts as a confounding factor, masking the greater benefit of earlier thrombolysis.[27]

The outcome for patients with AMI treated as soon as they present at different times depends on the balance between greater severity of infarction with earlier presentation, and greater efficacy of thrombolytic therapy with earlier administration. This knowledge is important because it explains the apparent weakness of the time effect, and it constitutes a second reason for advocating early thrombolysis: the earlier the opportunity for treat­ment, the greater the efficacy of treatment and the greater the patient's need for it.

The magnitude of the benefit of earlier throm­bolysis cannot be determined by retrospective sub­group analysis of placebo-controlled trials, but can only be determined with a trial design in which patients are randomly allotted thrombolytic ther­apy on presentation prehospital, or later after ad­mission to hospital. Such trials are few in number and small in size, the three largest being EMIP,[28] MITI[l5] and GREAT.[29] None of these showed a statistically significant reduction of mortality at 1 month, but a meta-analysis of all randomised trials of prehospital thrombolysis shows a relative reduc­tion of mortality of 17% (p = 0.03) with prehospi­tal thrombolysis.[28]

The benefit/time gradient calculated from these 3 trials is 23 lives saved per 1000 per hour within 1 month PO] Follow-up of GREAT shows diver­gence of the mortality curves, with very substantial late mortality benefit from early thromboly­sis.llO,ll] For 30 months' follow-up, the benefit gra­dient for patients who present 1 hour after onset is 80 lives saved per 1000 per hour, so that the benefit of giving thrombolytic therapy at the first opportu­nity may be an absolute mortality reduction of more than 10%.

At the other end of the time-window for throm­bolysis, it has been shown in LATE[3l] and EMERAS[32] that there is modest benefit from thrombolysis up to 12 hours from onset, and pos­sibly later if there is florid evidence of infarction when patients are first seen 12 to 24 hours after onset.

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Rawles

2.2.3 Comparison of Thrombolytic Agents In ISIS-3, the 3 main thrombolytic agents, strep­

tokinase, anistreplase and tissue plasminogen acti­vator (t-PA) [as duteplase], were compared with each other.[33] There were no significant differ­ences between agents in all-cause mortality at 35 days or 6 months.

In GISSI-2, streptokinase was compared with t-PA (as alteplase).[34] With a composite end-point of death or severe left ventricular damage, no sig­nificant differences between the 2 thrombolytic agents were detected.

More recently, streptokinase has been compared with alteplase given as an initial bolus followed by a rapid infusion (,accelerated' regimen) in the GUSTO trial. l35] The accelerated regimen resulted in a mortality reduction of 10 in 1000 compared with streptokinase, at a cost of2 additional haemor­rhagic strokes.

There is relatively little published on the effi­cacy of urokinase in AMI,[36,37] but coronary artery patency rates were similar in a randomised study in which it was compared with t_PA.[38]

2.3 The Risks of Thrombolytic Therapy

Thrombolytic therapy is associated with an ex­cess risk of <1 % of noncerebral haemorrhage se­vere enough to be life-threatening or to require blood transfusion.l9] Such bleeds are seldom fatal, and have not been encountered prehospital. The risk of intracerebral haemorrhage is about 3 per 1000 for streptokinase, 6 per 1000 for anistreplase, and 7 per 1000 for t-PA.l33] The FTT overview showed that thrombolytic therapy was associated with about 4 extra strokes per 1000. Of these, two were associated with early death and so were al­ready accounted for in the overall mortality reduc­tion, one was moderately or severely disabling, and one was not.[9]

Apart from the use of t -PA, other factors increas­ing the risk of cerebral haemorrhage are advanced age, low bodyweight, known cerebrovascular dis­ease including previous stroke, uncontrolled hypertension, and a known bleeding tendency, in-

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eluding that resulting from the use of anticoagu­lants such as warfarinP9,40]

Cerebral haemorrhage, particularly where it re­sults in serious disability, may be considered the worst outcome, and hence the denominator in the risk-benefit ratio for thrombolytic therapy. It should be noted that the risk of cerebral haemor­rhage is not related to the time after onset when treatment is given. The risk-benefit ratio is there­fore enhanced by earlier administration. With pre­hospital administration of thrombolytic therapy at the first opportunity, the chances of saving a life are better than 1 in 10, while the excess risk of disabling stroke is about 1 in 1000.

When thrombolytic therapy is given in the com­munity, adverse events are infrequent and, apart from cardiac arrest, not a serious problem)29,41] There is a slightly increased risk of ventricular fibrillation following the injection[28] but doctors attending patients with AMI should be equipped to deal with this complication.

3. Diagnosis of Acute Myocardial Infarction (AMI)

In patients in whom AMI is strongly suspected by general practitioners, the diagnosis is sub­sequently confirmed in 64 to 78% ofpatients)29,41] Most of the others have unstable angina or chest pain of unknown cause. A few (2 to 4%) have a proven alternative diagnosis such as aortic dissec­tion or cholelithiasis.

Because of the risk of causing cerebral haemor­rhage or other serious harm in patients without AMI, who could not possibly benefit from throm­bolysis, this level of diagnostic accuracy is insuf­ficient for giving thrombolytic therapy. The ECG is the best and most convenient ancillary diagnos­tic aid, but it should be noted that it is not possible to be 100% certain of the final diagnosis when the patient is first seen.

There are 2 trade-offs that have to be consid­ered. First, the diagnosis will become more cer­tain with the passage of time, but the time taken to reach a diagnosis has to be balanced against the waning efficacy of treatment. Secondly,

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whatever the diagnostic method used, high speci­ficity has to be weighed against low sensitivity, and vice versa. Thus, extensive ST elevation in both anterior and inferior sites is highly specific for AMI, and very few patients with this abnormality will not have infarcts; however, this abnormality is seen in only a small minority of patients with AMI. On the other hand, some abnormality of the ECG is present in the vast majority of AMI patients, but some abnormality of the ECG will also be present in many patients with chest pain who do not have AMI.

A widely recommended precondition for thrombolytic therapy is ST segment elevation of 2mm in 2 adjacent chest leads, or lmm in 2 ad­jacent limb leads. While it may be appropriate in hospital, where the ECG recording may be re­peated, such a rigidly defined precondition is un­satisfactory for several reasons in the commu­nity, where a therapeutic decision has to be made on a single ECG recording. First, it is difficult to measure, there being a large inter-observer vari­ation in categorising a solitary ECG. Secondly, ST elevation is present at anyone time in only about half of patients with AMI. Thirdly, ST el­evation is labile, resolving and reappearing spontaneously. Elevation of the ST segment is therefore a most unsatisfactory precondition for such an important therapeutic decision.l42]

Also, the level of diagnostic certainty on which the decision to treat is made needs to be varied according to the time after onset when the patient is seen. 12 hours after onset the risk­benefit ratio of thrombolytic therapy is narrow, so only patients with florid evidence of AMI should be treated. But for patients seen in the community in the first hour, the risk-benefit ratio is very much more favourable, so the threshold for treatment may be lowered while maintaining an acceptable margin of safety. In this way a greater proportion of patients with AMI are able to benefit from thrombolytic therapy.

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4. Guidelines

4.1 Practice Policy for Management of AMI

Every practice should have a clear policy for managing patients with suspected AMI.[43] This policy should take account of local geography and the availability of ambulances, resuscitation equip­ment, trained paramedics and hospital facilities.

The practice receptionists should know to pass calls from patients with chest pain to a doctor with­out delay, and they should know what to do if a doctor is not immediately available. If it is practice policy to attend such calls, the doctor on call should be prepared to abandon consulting and go at once.

The practice information booklet should advise patients what to do in the event of chest pain, and patients with known ischaemic heart disease and their close associates should be made aware of the practice policy. Patients should be encouraged to call the doctor without delay, and to call for an ambulance.

If the doctor is unable to attend rapidly because of heavy traffic or other commitments, an emer­gency ambulance should be summoned on the patient's behalf. A dual response, with both ambul­ance and general practitioner attending, is prefera­ble to self-referral to the nearest accident and emer­gency department, because many patients with chest pain do not require hospital admission, there may be long delays in the emergency department, and general medical care and pain relief is not given until after transportation and arrival in hos­pital.

Adoption of a practice policy of giving throm­bolytic therapy should be guided mainly by the likely time-saving that would result. If the local hospital has not audited its 'door-to-needle' time or made any special effort to expedite thrombolysis, then delays in hospital of at least an hour may be assumed)44] If the journey time to hospital exceeds 30 minutes, or the combined journey time and hos­pital delay exceeds an hour, then prehospital thrombolysis would result in a worthwhile time saving.

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Rawles

Table I. Indications far prehospital thrombolysis

Strong clinical suspicion of acute myocardial infarction and characteristic pain unrelieved by nitrates lasting from 20 minutes to 12 hours and unequivocally abnormal electrocardiogram (ECG)

ST elevation - definite indication other abnormality - thrombolysis may be considered if patient is severely ill and ECG is grossly ischaemic and Short time since onset and long time until hospital review

Whatever policy is adopted by a practice, it is desirable that it has the full support of the local cardiologists and the health authority. The safe and proper use of thrombolytic therapy requires expe­rience that can only be obtained by practice. Ide­ally, as for all new skills, learning to use such po­tent therapy should be done under supervision, and this could take the form of an audit. The main ob­jective could be to comply with the guideline pro­posed by the British Heart Foundation - a 'call-to­needle time' of ideally less than 1 hour)43] Other aspects of management, such as use of aspirin and opioids, could also be monitored.

4.2 Indications for Thrombolytic Therapy

Indications for thrombolytic therapy are summarised in table I.

4.2. 1 Strong Clinical SuspiCion of AMI General practitioners' clinical diagnosis of AMI

is correct in about 75% of cases. Knowledge of the patient and their previous medical history is helpful in reaching a diagnosis, as are subtle clinical signs related to the feel of the patient's skin, appearance and demeanour, which all contribute to the doctor's 'gut feelings'. Unless the ECG is strongly support­ive, thrombolytic therapy should not be given in 'rule out' cases where the doctor is doubtful about the diagnosis, but chooses to refer the patient to hospital as a precaution.

4.2.2 Chest Pain Lasting 20 Minutes to 12 Hours The basis for the clinical diagnosis of AMI

should usually be characteristic chest pain. Unless the ECG shows unequivocal evidence of AMI, thrombolysis should not be used in patients who

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Guidelines for GPs Administering Thromboly~

collapse without chest pain, or in those in whom the chest pain has resolved spontaneously. Relief of pain by buccal nitrate spray given immediately on arrival would suggest unstable angina rather than AMI, and thrombolysis should be withheld unless the ECG shows unequivocal evidence of in­farction.

4.2.3 Abnormal ECG

Thrombolysis should not be given if the ECG is normal, or if an ECG has not been recorded. Pa­tients with conditions such as dissection of the aorta, pancreatitis or gastric perforation, which may mimic AMI, are most likely to be found amongst those who are seriously ill yet have a nor­mal ECG. Patients with the final diagnosis of AMI who have a normal ECG when first seen have a low mortality risk and are unlikely to benefit much from thrombolytic therapy. Thrombolysis may be given to them in hospital if the ECG on arrival there shows new evidence of AMI.

The presence of frank ST elevation is a clear indication for thrombolytic therapy, but for pa­tients with other abnormalities such as ST depres­sion, T wave peaking or inversion, or Q waves, thrombolysis should be a matter of clinical judge­ment. Factors to be considered are the severity of the illness, the degree of abnormality of the ECG, the time when the patient is seen, and the length of time before the patient reaches hospital, and the need for thrombolysis can be reviewed. If the pa­tient is seen within 2 hours of onset, is seriously ill, has a grossly ischaemic ECG and is 2 hours from hospital treatment, then the doctor should be in­clined to give thrombolytic therapy. But if the pa­tient is seen 8 hours after onset, is stable and has only minor abnormalities on the ECG, then therapy should be withheld.

Ideally, to develop clinical judgement, general practitioners' management of suspected AMI should be audited, and there should be a regular case review involving general practitioners and the cardiologist to whom patients with chest pain are referred.

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Table II. Gantraindications to prehospital thrombolysis

Normal electrocardiogram (EGG) [or EGG not available]

History of cerebrovascular accident

Known intracranial pathology

Uncontrolled hypertension (blood pressure >180/110mm Hg)

Bleeding disorder or anticoagulants

Surgery or major trauma within 10 days

Active gastrointestinal bleeding

Traumatic cardiopulmonary resuscitation

Streptokinase or anistreplase previously (>5 days) [not a contraindication if using urokinase or tissue plasminogen activator]

4.3 Contraindications to Thrombolytic Therapy

621

Contraindications to thrombolytic therapy are summarised in table II.

4.3. 1 Avoidance of Thrombolysis in Patients Without AMI

The main reason for the injunction to withhold thrombolytic therapy where the ECG is normal, or has not been recorded, is to minimise the exposure of patients without AMI to the risks of thrombo­lytic therapy, the most serious of which is life-long disability from cerebral haemorrhage.

4.3.2 Avoidance of Cerebral Haemorrhage The risk of cerebral haemorrhage in patients

with AMI is minimised by withholding thrombo­lytic therapy where there is a history of cerebrovas­cular disease, known intracranial pathology such as arteriovenous malformation or aneurysm, un­controlled hypertension, or a known bleeding dia­thesis including the use of anticoagulants such as warfarin.

4.3.3 Avoidance of Noncerebral Haemorrhage

The risk of noncerebral haemorrhage may be reduced by withholding thrombolytic therapy when there has been recent surgery or trauma, or when the patient is known to be bleeding into the gut, for example, from peptic ulceration or angio­dysplasia. It should be remembered, however, that the risk of dying from AMI far exceeds the risk of dying from gastrointestinal haemorrhage, and gen-

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Table III. Thrombolytic agents

Other names

Allergenic

Streptokinase

Yes

Anistreplase

APSAC

Yes

Tissue plasminogen activator

Alteplase (Duteplase - withdrawn)

No

Rawles

Urokinase"

No

Dose and means of administration

1.5 MIU by IV infusion over 1 hour in 50-200m I saline

30U by IV injection over 4-5 minutes

15mg IV bolus, then 0.75 mg/kg (not >50mg) over 30 minutes, then 0.5 mg/kg (not >35mg) over the next hour. Plus heparin 5000lU IV bolus then 1 000 I U/h

2 MIU by bolus IV injection

Storage

Acquisition cost (1995)

2-25°C

£80-85

a Named patient basis in the UK.

Abbreviation: IV = intravenous.

2-8°C

£495

erally the benefits of thrombolytic therapy will out­weigh the risks.

Many patients are denied thrombolytic therapy because they have had cardiopulmonary resuscita­tion; it should be given unless there is clear evi­dence of rib fracture. These are relative contraindi­cations, and giving thrombolytic therapy when there is an increased likelihood of non cerebral haemorrhage should be a matter of clinical judge­ment.

4.3.4 Previous Exposure to Streptokinase or Anistreplase A few days after administration of either strep­

tokinase or anistreplase (which contains streptoki­nase), the titre of antibodies to streptokinase rises and remains elevated for many months afterwards. A high level of anti streptokinase antibodies results in increased risk of allergic reactions, and by neu­tralising streptokinase may reduce the efficacy of a subsequent dose given for reinfarction.

The patient should be asked whether a card has been given recording previous exposure to strepto­kinase or anistreplase. It is recommended that these agents should not be given again if >5 days has elapsed since previous administration.

This contraindication does not apply to the non­antigenic thrombolytic agents urokinase and al­teplase, which may be given to patients who have had previous exposure to streptokinase or anis­treplase. Urokinase and alteplase may themselves be given repeatedly.

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<25°C <25°C

£750 £460

4.4 Choice of Thrombolytic Agent

The differences in efficacy and safety between thrombolytic agents appear to be trivial compared with the increased benefit of giving any agent ear­lier. The main considerations in selecting a throm­bolytic agent for use in general practice are there­fore convenience and cost (table III).

Streptokinase is the cheapest thrombolytic agent, but it has the disadvantage that it is given by slow intravenous infusion in a small fluid volume over an hour; a pump is desirable to control the rate of infusion. It is not convenient to set up a drip in the patient's home and keep it running while the patient is being transferred to hospital, but strepto­kinase could be infused where a general practi­tioner has access to beds in a community hospital with good resuscitation facilities. Younger patients may be later transferred to a district general hospi­tal for further investigation.

Alteplase is the most expensive thrombolytic agent, and is commonly reserved for reinfarction in patients who are likely to have antistreptokinase antibodies following previous use of streptokinase or anistreplase. Its expense, and the complicated infusion regimen, make it unsuitable for use by general practitioners at the moment. Adouble bolus regime which might be suitable for use by general practitioners is being developed.

Anistreplase and urokinase are both given by intravenous bolus injection. Anistreplase has been evaluated in large clinical trials conducted in hos-

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Guidelines for GPs Administering Thrombolytics - - - --

pital and in the community, and shown to be safe and effective. It has the disadvantage that it is an­tigenic and cross-reacts with streptokinase, and it has to be stored in a refrigerator. The doctor may therefore not have the drug to hand when it is needed.

Urokinase has been much less extensively used and evaluated than the other agents, and it is only available in the UK on a named-patient basis. It appears to have similar efficacy to t-PA. Urokinase is the most convenient thrombolytic agent for gen­eral practitioners to use because it is nonantigenic, is given as a bolus injection, and does not have to be refrigerated.

Compared with streptokinase given in hospital, the additional cost of giving anistreplase or uroki­nase in the community is fully justified by the ex­pected saving of life.

5. Conclusions

In 1991, the Clinical Resource and Audit Group (CRAG) of the Scottish Home and Health Depart­ment published a consensus statement on throm­bolytic therapy. [45] No firm recommendations regarding the use of this treatment by general prac­titioners were made because at that time the vari­ous trials of prehospital thrombolysis had not been completed or published.

The guidelines published herewith, and sum­marised in the Appendix, have been developed fol­lowing consultation with many cardiologists and general practitioners, and have been subject to peer review. They therefore represent a consensus view that incorporates the latest clinical trial evidence and opinion. These guidelines have been adopted by CRAG and will be made widely available to general practitioners in Scotland, where it is now the policy to encourage general practitioners work­ing 30 minutes or more from a district general hos­pital to give thrombolytic therapy themselves. The broad aim of this policy is to reduce the formidably high mortality rate from coronary heart disease in Scotland by initiating coronary care, including thrombolysis, in the community, starting with

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623

practices in the periphery where it will be most clearly beneficial.

It is hoped that these guidelines will be helpful to all general practitioners who are contemplating the use of thrombolytic therapy.

Appendix

Table AI. Brief Clinical Resource and Audit Group (CRAG) guidelines for administering thrombolytic therapy

1. Call from patient with chest pain

2. Acute myocardial infarction probable? - call ambulance

3. Go at once - remember defibrillator, ECG machine, thrombolytic agent

4. Take brief history - patient conscious with chest pain that sounds ischaemic

5. Give aspirin 300mg

6. Give glyceryl trinitrate by sublingual spray

7. Insert IV cannula

8. Patient still in pain? - give opiate and anti-emetic IV

9. Finish taking history. Brief examination - seek other diagnoses

10. Record and examine 12-lead ECG

11. Review indications for thrombolytic therapy: strong clinical suspicion of acute myocardial infarction and chest pain for 20 minutes to 12 hours and unequivocally abnormal ECG ST elevation - thrombolysis indicated other abnormality - thrombolysis may be considered if patient severely ill and ECG grossly ischaemic and short time since onset and long time until hospital review

12. Review contraindications to thrombolytic therapy: normal ECG (or ECG not available) history of cerebrovascular accident known intracranial pathology uncontrolled hypertension (> 180/11 Omm Hg) bleeding disorder or anticoagulants surgery or major trauma <10 days active gastrOintestinal bleeding traumatic CPR streptokinase or anistreplase previously (>5 days) [not a

contraindication to urokinase]

13. If indicated, give thrombolytic therapy IV (urokinase 2 MIU or anistreplase 30 IU)

14. Arrange hospital admission: say whether thrombolytic therapy given

15. Check analgesia, cardiac rate and rhythm, heart failure, IV cannula

16. Write referral letter: record details of drugs given, especially thrombolytic therapy

17. Stay with patient until ambulance arrives

18. Ensure that patient is monitored while being transferred

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References 1. Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, et al. Myocardial

infarction and coronary deaths in the World Health Organiza­tion MONICA project. Registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation 1994; 90: 583-612

2. Armstrong A, Duncan B, Oliver MF, et al. Natural history of acute coronary heart attacks. A community study. Br Heart J 1972;34:67-80

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10. Rawles JM. The magnitude of benefit from earlier thrombolysis in acute myocardial infarction. New evidence from the Grampian region early anistreplase trial (GREAT). BMJ. In press

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18. Bourke JP, Young AA, Richards DA, et al. Reduction in inci­dence of inducible ventricular tachycardia after myocardial

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Rawles

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19. Bonaduce D, Petretta M, Villari B, et al. Effects of late admin­istration of tissue-type plasminogen activator on left ventric­ular remodeling and function after myocardial infarction. J Am Col1 Cardiol 1990; 16: 1561-8

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27. Rawles J. Problems in quantifying the benefit of earlier throm­bolysis in acute myocardial infarction. Pharm Med. In press

28. The European Myocardial Infarction Project Group. Prehospital thrombolytic therapy in patients with suspected acute myo­cardial infarction. N Eng J Med 1993; 329; 383-9

29. GREAT Group. Feasibility, safety, and efficacy of domiciliary thrombolysis by general practitioners. BMJ 1992; 305: 548-53

30. Rawles JM. Treatment of myocardial infarction and angina [let­ter]. BMJ 1995; 310: 465

31. LATE Study Group. Late Assessment of Thrombolytic Efficacy (LATE) study with alteplase 6-24 hours after onset of acute myocardial infarction. Lancet 1993; 342: 759-66

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Drugs 50 (4) 1995

Guidelines for GPs Administering Thromboly~

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39. De Jaegere Pp, Arnold AA, Balk AH, et al. Intracranial hemor­rhage in association with thrombolytic therapy: incidence and clinical predictive factors. J Am Coli Cardiol 1992; 19: 289-94

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Errata

625

42. Adams J, Trent R, Rawles J, on behalf of the GREAT Group. Earliest electrocardiographic evidence of myocardial infarc­tion: implications for thrombolytic treatment. BMJ 1993; 307:409-13

43. Weston CFM, Penny WJ, Julian DG, on behalf of the British Heart Foundation Working Group. Guidelines for the early management of patients with myocardial infarction. BMJ 1994; 308: 767-71

44. Birkhead JS. Time delays in provision of thrombolytic treat­ment in six district hospitals. BMJ 1992; 305: 445-8

45. Clinical Resource and Audit Group. Thrombolytic therapy in the early treatment of acute myocardial infarction. Consensus statement. Edinburgh: The Scottish Office, 1991

Correspondence and reprints: Dr John Rawles, Medicines Assessment Research Unit, University of Aberdeen, Foresterhill, Aberdeen AB9 2ZD, Scotland.

Vol. 50, No.1, page 152: In section 5, Place of Sulfasalazine in Therapy, the next to last paragraph should read: 'In conclusion, sulfasalazine is an effective DMARD which offers a good trade-off between efficacy and toxicity in the treatment of RA. However, direct comparisons with methotrexate are yet to be conducted. Sulfasalazine may offer a more prompt onset of action ... '.

[Rains Cp, Noble S, Faulds D. SuIJasalazine: a review of its pharmacological properties and therapeutic efficacy in the treatment of rheumatoid arthritis. Drugs 1995; 50 (1): 137-56J

Vol. 50, No.3, page 434: In table VI the dosage of ceftriaxone in the studies by Thomas et al. and Niebuhr et al. should read Ceftriaxone 2g od (once daily).

[Adu A, Armour CL. Drug utilisation review (DUR) of the third generation cephalosporins: focus on ceftriaxone, ceftazidime and cefotaxime. Drugs 1995; 50 (3): 423-9J

© Adis Intemational Lim~ed. All rights reserved. Drugs 50 (4) 1995