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.
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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 effect, with an estimated loss of benefit of 1.6 lives per 1000 per hour of delay to randomisation,l9] However, this estimate is incor-rect 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.
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 treat-ment, the greater the efficacy of treatment and the greater the patient's need for it.
The magnitude of the benefit of earlier throm-bolysis cannot be determined by retrospective sub-group analysis of placebo-controlled trials, but can only be determined with a trial design in which patients are randomly allotted thrombolytic ther-apy on presentation prehospital, or later after ad-mission to hospital. Such trials are few in number and small in size, the three largest being EMIP, MITI[l5] and GREAT. 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 reduc-tion of mortality of 17% (p = 0.03) with prehospi-tal thrombolysis.
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 diver-gence of the mortality curves, with very substantial late mortality benefit from early thromboly-sis.llO,ll] For 30 months' follow-up, the benefit gra-dient 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 opportu-nity may be an absolute mortality reduction of more than 10%.
At the other end of the time-window for throm-bolysis, it has been shown in LATE[3l] and EMERAS that there is modest benefit from thrombolysis up to 12 hours from onset, and pos-sibly later if there is florid evidence of infarction when patients are first seen 12 to 24 hours after onset.
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2.2.3 Comparison of Thrombolytic Agents In ISIS-3, the 3 main thrombolytic agents, strep-
tokinase, anistreplase and tissue plasminogen acti-vator (t-PA) [as duteplase], were compared with each other. There were no significant differ-ences between agents in all-cause mortality at 35 days or 6 months.
In GISSI-2, streptokinase was compared with t-PA (as alteplase). With a composite end-point of death or severe left ventricular damage, no sig-nificant 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 haemor-rhagic strokes.
There is relatively little published on the effi-cacy 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.
2.3 The Risks of Thrombolytic Therapy
Thrombolytic therapy is associated with an ex-cess risk of
Guidelines for GPs Administering Thromboly~
eluding that resulting from the use of anticoagu-lants such as warfarinP9,40]
Cerebral haemorrhage, particularly where it re-sults 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 haemor-rhage is not related to the time after onset when treatment is given. The risk-benefit ratio is there-fore enhanced by earlier administration. With pre-hospital 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 com-munity, 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 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 sub-sequently 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 dissec-tion or cholelithiasis.
Because of the risk of causing cerebral haemor-rhage or other serious harm in patients without AMI, who could not possibly benefit from throm-bolysis, this level of diagnostic accuracy is insuf-ficient for giving thrombolytic therapy. The ECG is the best and most convenient ancillary diagnos-tic aid, but i...