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
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 . . . . . . . . . . . . . . . . . . . . . , . . . . . . . .
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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 resusci-tation, 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
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 opportu-nity, 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%. Half the deaths occur in the first 2 hours after the onset of symp-toms, and about two-thirds of deaths occur in the community)}] Hospital care starting several hours after the onset of symptoms can therefore have lit-tle 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 - resuscita-tion from ventricular fibrillation, pain relief with opiates, and thrombolysis.
1 .1 Resuscitation
If a rapid response is made to patients with sus-pected AMI, cardiac arrest will be encountered in about 5% of cases. If cardiac arrest is witnessed by a doctor with a defibrillator then the survival rate is better than 50%. Possession of a defibril-lator gives confidence, and enables the attending doctor to spend more time on stabilising the pa-tient's condition before transfer to hospital. A defi-brillator 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 be-ing: pain ~ autonomic response ~ hypotension and bradycardia ~ poor coronary perfusion ~ in-farct extension ~ pain. Relief of pain and anxi-ety with opiates, as well as being humane, breaks into this cycle and is life-saving.[7,8] General med-ical care, including opiate analgesia, treatment of
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vagal excess with atropine, correction of arrhyth-mias, 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 hos-pital4 to 5 hours after the onset of symptoms saves 20 to 30 per 1000 lives within a month. The ad-ditional 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 thrombo-lytic 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 ven-tricular fibrillation. 
2. Thrombolytic Therapy
2,1 Mechanism of Benefit
Most cases of AMI are due to coronary throm-bosis, often occurring at the site of a ruptured atheromatous plaque. Successful thrombolysis restores patency in the infarct-related artery. 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 in-farctJl5] Reperfusion occurring 4 hours or more af-ter onset is still beneficial, but by a different mech-anism: by that time it is too late for myocardial salvage to occur.
Drugs 50 (4) 1995
Guidelines for GPs Administering Thromboly~
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 fail-ure,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 and ASSET, entry was by clinical suspicion of AMI, and electrocardiographic (EeG) confirma-tion of the diagnosis was not required. In both trials there was evidence of benefit in those with-out 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 ten-dency 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 ex-pected, 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 signif-icance is no reason for denying treatment that is probably beneficial to patients with the charac-teristics 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
APSAC Intervention Mortality Study
AngloScandinavian 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 re-ductions were 40 and 18 lives per 1000, respec-tively.
2.2.2 The Time Effect There are strong reasons based on theory and
experiment for believing that the earlier thrombol-ysis is given, the greater the benefit. This time ef-fect would be expected to be powerful, and of great clinical importance. However, of the four largest randomised placebo-controlled trials of thrombo-lytic therapy, two show this effect (GISSI and ISIS-2), while two do not (AIMS and AS-SET).
In the FTT overview, subgroup analysis of 9 randomised trials of thrombolytic therapy shows a weak time effe