Antithrombotic therapy in myocardial infarction and stable anginaBMJ 2002; 325 doi: https://doi.org/10.1136/bmj.325.7375.1287 (Published 30 November 2002) Cite this as: BMJ 2002;325:1287
- Gregory Y H Lip,
- Bernard S P Chin,
- Neeraj Prasad
Acute Q wave myocardial infarction
The use of thrombolytic treatment in acute myocardial infarction is now established beyond doubt. However, primary angioplasty is now proved to be an effective alternative and is used increasingly in preference to thrombolysis in many centres worldwide.
Current key issues relate to the clinical situations in which thrombolysis may be beneficial or contraindicated. For example, all patients with a history suggesting cardiac ischaemia and accompanying electrocardiographic changes indicating acute myocardial infarction should be considered for thrombolysis. However, patients with only ST segment depression on an electrocardiogram or with a normal electrocardiogram do not benefit from thrombolysis, and treatment should therefore be withheld. Exceptions to this are when there is evidence of new development of left bundle branch block or a true posterior myocardial infarction (shown by ST segment depression with dominant R waves present in leads V1 and V2). These situations require thrombolytic treatment.
Indications and contraindications for thrombolysis in acute myocardial infarction
Clinical history and presentation strongly suggestive of myocardial infarction within 6 hours plus one or more of: 1 mm ST elevation in two or more contiguous limb leads 2 mm ST elevation in two or more contiguous chest leads New left bundle branch block 2 mm ST depression in V1-4 suggestive of true posterior myocardial infarction
Patients presenting with above within 7-12 hours of onset with persisting chest pains and ST segment elevation
Patients aged <75 years presenting within 6 hours of anterior wall myocardial infarction should be considered for recombinant tissue plasminogen activator
Previous cerebral haemorrhage
Known history of cerebral aneurysm or arteriovenous malformation
Known intracranial neoplasm
Recent (within past 6 months) thromboembolic stroke
Active internal bleeding (excluding menstruation)
Patients previously treated with streptokinase or anisolated plasminogen streptokinase activator complex (APSAC or anistreplase) should receive recombinant tissue plasminogen activator, reteplase, or tenecteplase
Severe uncontrolled hypertension (blood pressure >180/110 mm Hg) on presentation or chronic severe hypertension
Current use of anticoagulants or known bleeding diathesis
Recent (within past 2-4 weeks) trauma including head injury or traumatic or prolonged (>10 minutes) cardiopulmonary resuscitation
Recent (within 3 weeks) major surgery, organ biopsy, or puncture of non-compressible vessel
Recent (within past 6 months) gastrointestinal or genitourinary or other internal bleeding
Active peptic ulcer disease
Thrombolytic treatment should be given within six hours of the onset of symptoms and electrocardiographic changes for patients to derive full benefit. Patients with persisiting pain and ST segment elevation may still benefit from thrombolysis up to 12 hours from the onset of symptoms. Beyond that, few patients will benefit, and there is no clear evidence of whether this benefit outweighs the risk of haemorrhage.
Thrombolytic treatment should be offered to all eligible patients presenting with an acute myocardial infarction regardless of age, sex, or site of infarct. In general, patients over 75 years and those with anterior myocardial infarction or previous heart attack have a higher mortality. Therefore, the absolute reduction in mortality in these patients will be greater. Many of the accepted contraindications (absolute and relative) come from observational studies only. Some conditions, such as diabetic proliferative retinopathy and menstruation, are no longer considered to be absolute contraindications.
Reperfusion of the artery affected by infarction occasionally fails with thrombolytic treatment. If this happens patients will have ongoing chest pain or acute electrocardiographic changes. In these instances the optimal management is still uncertain, although readministration of an alternative thrombolytic agent (“rescue thrombolysis”) or emergency percutaneous transluminal coronary angioplasty (“rescue” or “salvage” percutaneous transluminal coronary angioplasty) has been advocated. Rescue thrombolysis more than doubles the bleeding complications. Also, the limited data available showed benefit only in cases where plasma fibrinogen concentration was >1.0 g/l and where recombinant tissue plasminogen activator was given if initial streptokinase did not achieve 25% reduction of maximal ST elevation on the pretreatment electrocardiogram.
All thrombolytic agents are plasminogen activators. Streptokinase is the cheapest widely available agent. However, it is highly antigenic, and neutralising antibodies preclude use of this agent more than once in a patient. Thus, it should not be readministered after 48 hours from the initial infusion. Tenecteplase, reteplase, and recombinant tissue plasminogen activator (alteplase) have been shown to be as good as streptokinase in reducing mortality after acute myocardial infarction. They are suitable alternatives if a patient has already received streptokinase. In the GUSTO trial, recombinant tissue plasminogen activator produced greater mortality reduction than streptokinase, especially in patients aged under 75 years who presented within six hours of onset of anterior myocardial infarction. Patients presenting within six hours of inferior myocardial infarction accompanied by right ventricular infarct, haemodynamic compromise, or anterior wall extension may also benefit. Tenecteplase has the advantage of being easily administered as a single bolus injection.
The concurrent use of aspirin with a thrombolytic drug reduces mortality far more than either drug alone. In the ISIS-2 trial, streptokinase reduced mortality by 25%, aspirin by 23%, and the combination of aspirin with streptokinase by 42%. In addition, there was no increase in incidence of stroke or major bleeding by giving aspirin and streptokinase in combination.
The use of “full dose” heparin, either intravenously or by subcutaneous injections, is not warranted routinely after streptokinase (or anistreplase) infusion, with no difference in mortality during hospitalisation and an increased risk of cerebral haemorrhage and other major bleeding. Patients who may benefit from heparin treatment after streptokinase (or anistreplase) are those at high risk of developing thromboembolism. These patients include those with large infarctions, atrial fibrillation, or congestive cardiac failure.
Antithrombotic therapy in acute Q wave myocardial infarction and after myocardial infarction
All patients should receive
Aspirin 300 mg orally as soon as possible and 75-300 mg daily thereafter
Consideration for thrombolysis
β blockers, nitrates, and other standard antianginal drugs as appropriate
Choice of thrombolytic agents
Streptokinase 1.5 MU intravenously over an hour
Recombinant tissue plasminogen activator 15 mg intravenous bolus followed by 0.75 mg/kg (maximum 50 mg) infusion over 30 minutes, then at 0.5 mg/kg (maximum 35 mg) over 60 minutes
Reteplase 10 MU intravenous bolus, repeated once after 30 minutes
Tenecteplase 30-50 mg (according to body weight) intravenously over 10 seconds
Adjuvant heparin treatment
In all patients receiving recombinant tissue plasminogen activator—75 U/kg intravenous bolus with recombinant tissue plasminogen activator infusion, followed by 1000-1200 U/hour to maintain APTT ratio 1.5-2.0 for 48 hours
In all patients receiving reteplase or tenecteplase—75 U/kg intravenous bolus with first reteplase bolus, followed by 1000-1200 U/hour to maintain APTT ratio 1.5-2.0 for 48 hours
Prevention of systemic and venous thromboembolism
In all patients with acute myocardial infarction—low dose low molecular weight heparin until ambulatory
In patients receiving streptokinase at high risk of systemic or venous thromboembolism—measure APTT from four hours after thrombolysis. Start intravenous heparin at 1000-1200 U/hour once APTT ratio has fallen to less than 2.0. Continue for 48 hours, maintaining APTT at ratio 1.5-2.0. Alternatively, use low molecular weight heparin
In all patients at high risk of systemic or venous thromboembolism—heparin infusion may be continued beyond 48 hours or converted to 15 000 U subcutaneously twice daily (alternatively, use low molecular weight heparin) or to warfarin (INR 2-3) for up to three months
In patients with atrial fibrillation—warfarin treatment after heparin infusion should continue indefinitely
On the other hand, recombinant tissue plasminogen activator, tenecteplase, and reteplase have short half lives and thus have only small systemic fibrinolytic effects. The high reocclusion rates seen in patients given recombinant tissue plasminogen activator may be stopped by concomitant use of full dose heparin (for at least 24 hours). Several trials of angiographic patency have also reported a favourable synergistic effect of heparin after recombinant tissue plasminogen activator.
For patients with persistent risk factors for systemic embolisation, consideration should be given to starting oral warfarin or continuing heparin treatment as subcutaneous injections beyond 48 hours. All other patients should receive prophylactic heparin (unfractionated or low molecular weight heparin) until they are mobile to prevent venous thromboembolism. Finally, trials comparing the use of hirudin and heparin after recombinant tissue plasminogen activator showed hirudin to be no better than heparin at reducing cardiovascular deaths or reinfarction at 30 days.
Postmyocardial infarction and stable coronary artery disease
Data from the Antiplatelet Trialists' Collaboration, which analysed more than 100 trials and 100 000 patients, including 20 000 with acute myocardial infarction, confirmed that antiplatelet treatment reduced cardiovascular events in acute myocardial infarction by 25%, representing a two year treatment benefit in 36 out of 1000 patients treated.
Aspirin is the most widely used antiplatelet drug and is effective at doses from 75 to 300 mg daily in patients who have had myocardial infarction and those with stable coronary artery disease. Although there is no substantial difference in efficacy between lower and higher doses of aspirin within the stated range, higher doses are associated with greater side effects.
Dipyridamole and ticlopidine have both been compared with aspirin. Dipyridamole showed no benefit over aspirin in the PARIS trials. Ticlopidine may be slightly better than aspirin treatment but is associated with undesirable side effects such as neutropenia and thrombocytopenia. In the CAPRIE study, which compared clopidogrel with aspirin over two years in patients with vascular disease (ischaemic stroke, myocardial infarction, peripheral vascular disease), clopidogrel was slightly better in reducing the number of vascular events (5.32% v 5.83%, P=0.04). Importantly, clopidogrel was as well tolerated as aspirin. Therefore, it would be reasonable to give patients clopidogrel after acute myocardial infarction if aspirin were contraindicated or not tolerated.
Risk factors for systemic embolisation when anticoagulation should be considered
Large anterior wall myocardial infarction
Myocardial infarction complicated by severe left ventricular dysfunction
Congestive heart failure
Echocardiographic evidence of mural thrombus or left ventricular aneurysm
The glycoprotein IIb/IIIa antagonists have been tried in conjunction with thrombolysis in acute myocardial infarction, but the various regimens used in recent trials did not confer any additional benefit over conventional treatment. However, there was some evidence of more rapid and complete reperfusion, and these agents warrant further evaluation and refinement.
Long term anticoagulation with heparin followed by warfarin is not needed routinely except in patients at higher risk of venous or systemic thromboembolism.
Intracardiac thrombi usually occur within 48 hours after acute myocardial infarction and tend to embolise within the first few weeks. Low dose dalteparin has been shown to reduce the incidence of intramural thrombus (21.9% v 14.2%, P=0.03) in patients given thrombolytic treatments, although this is at a risk of small increase in minor bleeding complications. Thus, in patients at high risk of mural thrombus formation, dalteparin should be started as soon as possible after the diagnosis of acute myocardial infarction.
Warfarin should be continued for two to three months, except in the case of atrial fibrillation, when it may be maintained indefinitely. While a patient is taking warfarin, aspirin use may increase the risk of bleeding, but, pending further evidence, many clinicians still continue to use low dose aspirin for its antiplatelet effect. Although thrombus is commonly associated with left ventricular aneurysm (up to 60%), systemic emboli are uncommon (4-5%), and long term anticoagulation does not seem to further reduce the risk of systemic embolisation; thus, anticoagulant treatment is not currently indicated in these patients in the long term.
Cairns JA, Theroux P, Lewis D, Ezekowitz M, Meade TW. Antithrombotic agents in coronary artery disease. Chest 2001;119:228-52S
Collins R, MacMahon S, Flather M, Baigent C, Remvig L, Mortensen S, et al. Clinical effects of anticoagulant therapy in suspected acute myocardial infarction: systematic overview of randomised trials. BMJ 1996;313:652-9
ISIS-2 Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet1988;II:349-60
Oldroyd KG. Identifying failure to achieve complete (TIMI 3) reperfusion following thrombolytic treatment: how to do it, when to do it, and why it's worth doing. Heart 2000;84:113-
Mounsey JP, Skinner JS, Hawkins T, MacDermott AF, Furniss SS, Adams PC, et al. Rescue thrombolysis: alteplase as adjuvant treatment after streptokinase in acute myocardial infarction. Br Heart J1995;74:348-53
The GUSTO Investigators. An international randomized trial comparing 4 thrombolytic strategies for acute myocardial infarction. N Eng J Med 1993;329:673-82
National Institute for Clinical Excellence. Technology appraisal guideline no 52. Guidance on the use of drugs for early thrombolysis in the treatment of acute myocaardial infarction.London: NICE, 2002
Ohman EM, Harrington RA, Cannon CP, Agnelli G, Cairns JA, Kennedy JW. Intravenous thrombolysis in acute myocardial infarction. Chest2001;119:253-77S
Venous thromboembolism is often associated with acute myocardial infarction, although its incidence has fallen since the introduction of thrombolytic treatment. Although no trials have compared the efficacy of low molecular weight heparin with unfractionated heparin in preventing venous thromboembolism after acute myocardial infarction per se, it is likely that these agents are equally effective, and are increasingly used in clinical practice.
The box showing antithrombotic therapy in acute Q wave myocardial infarction and after myocardial infarction is adapted from the 6th ACCP consensus conference on antithrombotic therapy. The figure showing lives saved in relation to time of administration of thrombolytic treatment from onset of symptoms of chest pain is adapted from Collins R, et al, N Engl J Med 1997;336:847-60.
Bernard S P Chin is research fellow, and Gregory Y H Lip is professor of cardiovascular medicine at the haemostasis thrombosis and vascular biology unit, university department of medicine; Neeraj Prasad is a consultant cardiologist. All are based at City Hospital, Birmingham.
The ABC of antithrombotic therapy is edited by Gregory Y H Lip and Andrew D Blann, senior lecturer in medicine at the haemostasis thrombosis and vascular biology unit, university department of medicine, City Hospital, Birmingham. The series will be published as a book in spring 2003.