John Cairns, MD, FRCPC, FACC;Paul W. Armstrong, MD, FRCPC, FACC; ... David Sackett, FRSC, MD, MSc (Epid), FRCPC; Pierre Theroux, MD, FRCPC, FACC.
[ editorial * editorial
I
MAXIMIZING THE BENEFITS OF THROMBOLYTIC THERAPY FOR ACUTE MYOCARDIAL INFARCTION John Cairns, MD, FRCPC, FACC; Paul W. Armstrong, MD, FRCPC, FACC; Israel Belenkie, MD, FRCPC; Jack Hirsh, MD, FRCPC, FACCP; David E. Johnstone, MD, FRCPC, FACC; Merril Knudtson, MD, FRCPC; Michel Lemieux, MD, FRCSC, FACS; David Massel, MD, FRCPC; C. David Naylor, MD, DPhil, FRCPC; Louis Roy, MD, CSPQ, FACC; David Sackett, FRSC, MD, MSc (Epid), FRCPC; Pierre Theroux, MD, FRCPC, FACC
Thrombolytic therapy is a huge advance in the management of acute myocardial infarction (AMI). The results of large clinical trials over the past 9 years have unequivocally demonstrated its benefit: of every 1000 patients treated 30 will be saved, at a cost of two cases of nonfatal cerebral hemorrhage and seven of noncerebral major hemorrhage. The concurrent use of acetylsalicylic acid increases the benefit of thrombolytic therapy. Sales figures for thrombolytic agents indicate that their use in Canada is less than optimal and lags behind that in several European countries. Major educational efforts are needed to promote awareness of the efficacy of thrombolytic therapy and of optimal approaches for maximizing its potential benefit for patients with AMI.
On ne of the greatest advances ever made in the management of acute myocardial infarction (AMI) has evolved over the past 9 years. The early administration of an intravenous thrombolytic agent concurrently with acetylsalicylic acid (ASA) to patients with AMI can reduce the 1-month mortality by up to 50% in comparison with the mortality among patients given neither agent. The efficacy and safety of thrombolytic agents has been demonstrated unequivocally in a remarkable series of large clinical trials published since 1986.' Familiarity with these results and an understanding of their implications for the management of AMI is essential for physi-
Le traitement thr-ombolytique repr6sente un progres 6norme dans le traitemelnt de l'infarctoLs aigu du myocarde (IAM). Les r6sultats d'essais cliniques importants realises au cours des 9 derni&res annees en ont proove sans equivoque l'avantage: sur I 000 patients trait6s, 30 seront sauv6s, et il en coOtera deux cas dhnmorragie c6rebrale non mortelle et sept hbmorragies majeures non c6r6brales. L'utilisation simultan6e d'acide ac6tylsalicyliqUe renforce l'avantage offert par le traitement thrombolytiqLe. Les statistiques sur les ventes d'agents thrombolytiqLcs indiquent que leur utilisation n'atteint pas son niveaLl optimal et que le Canada a du retard sur plosieurs pays d'Europe a cet 5gard. D'importants efforts d'education simposent si lIon veut promouvoir Ia sensibilisation a l'efficacit& doL traitement thrombolytique et aux strategles optimales qui visent a maximiser lavantage que peuvent en tirer les patients victimes dun IAN!.
cians who treat these patients and administrators who make decisions about resource allocation. To promote such awareness, the Canadian Cardiovascular Society has recently completed a consensus exercise based on a rigorous evaluation of the literature and has published recommendations for the use of thrombolytic therapy.2 The primary pathogenetic role of the coronary thrombus was postulated by Herrick,3 who is generally credited as having made the first detailed clinical description of AMI. Hence, a clear rationale for the use of thrombolytic therapy influenced the design and conduct of the first published clinical trial of this treatment.4 Al-
Drs. Cairns and Hirsh are in the Department of Medicine, McMaster University, Hamilton, Ont; Dr. Armstrong is in the Department of Medicine, University of Alberta, Edmonton, Alta.; Drs. Belenkie and Itnudtson are in the Department of Medicine, University of Calgaly, Calgary, Alta; Dr. Johnstone is in the Department of Medicine, Dafhousie University, Halifax, NS; Dr. Lemieux is in the Department of Surgery and Dr. Roy is in the Department of Medicine, Universite Laval, Sainte-Foy, Que.; Dr. Massel is in the Department of Medicine, University of Western Ontario, London, Ont.; Dr. Naylor is in the Department of Preventive Medicine and Biostatistics, University of Toronto, Toronto, Ont.; Dr. Sackett is in the Department of Clinical Epidemiology, University of Oxford, Oxford, England; and Dr. Thdroux is in the Department of Medicine, Universite de Montrdal, Montreal, Que.
Repient requests to: Dr. John Cairns, Department of Medicine, McMaster University Health Sciences Centre, 1200 Main St. W, Hamilton ON L8N3Z5 -
For prescribing information see page 1012
CAN MED ASSOC J o MAR. 15, 1995; 152 (6)
though many randomized trials of intravenous therapy followed, five of them showing statistically significant benefit, the therapy was rarely used.5 By the late 1970s a renewed interest in thrombolytic therapy prompted a series of trials of intracoronary administration.6 Promising initial results, together with a formal meta-analysis of the preceding intravenous trials that suggested a marked benefit,5 prompted researchers to undertake several large randomized trials; these have provided definitive evidence of the efficacy and safety of coronary thrombolytic therapy.7-12 The first large trial involved a network of 176 coronary care units throughout Italy. Within 12 hours after the onset of symptoms patients with suspected AMI were randomly assigned either intravenous streptokinase or conventional therapy; an open-label study design was used. Results published in 1986 reported a fall in the inhospital mortality from 13% to 10.7% -a remarkable 18% reduction (p = 0.0002). The second International Study of Infarct Survival (ISIS-2) trial followed; at 417 hospitals in Europe, New Zealand, Australia, the United States and Canada a total of 17 181 patients with AMI were randomly assigned treatment with streptokinase or ASA, both agents in combination or neither.8 The researchers found that after 5 weeks the rate of vascular mortality was 23% lower among the patients given streptokinase alone (p < 0.00001), 21 % lower among those given ASA alone (p < 0.00001) and 39% lower among those given both (p < 0.00001) than among the patients given neither. After the publication of these findings in 1988, thrombolytic therapy began to be widely used. Thrombolytic agents are all plasminogen activators: they convert plasminogen, a proenzyme, to plasmin, which is then capable of cleaving fibrin and producing clot lysis.'3 The first thrombolytic agent to become available was streptokinase, an enzyme derived from B-hemolytic streptococcal culture. Streptokinase binds to circulating plasminogen; the resulting complex then converts circulating plasminogen to plasmin, which in turn produces lysis, not only of clots but also of circulating fibrinogen, giving rise to the so-called systemic fibrinolytic state. Anisoylated plasminogen streptokinase activator complex (APSAC) is a chemically prepared complex that is gradually activated in the plasma following intravenous administration. It offered theoretical advantages over streptokinase and was first subjected to major clinical evaluation in the placebo-controlled APSAC Intervention Mortality Study (AIMS),9"10 which demonstrated a 50.5% odds reduction of 30-day mortality (95% confidence interval [CI] 26% to 67%, p = 0.0006) with the use of APSAC. Tissue plasminogen activator (t-PA), which is pro820
CAN MED ASSOC J * 15 MARS 1995; 152 (6)
duced endogenously by endothelial cells and can be manufactured for therapeutic use by means of recombinant DNA technology (rt-PA), binds to fibrin and activates clot-bound plasminogen, leading to clot lysis with relatively minimal systemic effect. The AngloScandinavian Study of Early Thrombolysis (ASSET) trial, the results of which were published in 1988, was the first to evaluate this promising new thrombolytic agent in a large placebo-controlled trial." In this study the use of rt-PA was found to reduce the mortality at I month from 9.8% to 7.2%, a 26% relative risk reduction (95% ClI 1% to 39%, p = 0.0011). A recent overview of the results of all controlled randomized trials involving more than 1000 patients with suspected AMI has provided overwhelming evidence of the efficacy and safety of thrombolytic agents.12 Among the 58 600 patients included in these trials, mortality at 35 days was reduced from 11.5% to 9.6%, an 18% odds reduction (2p < 0.00001). Initially, there was some concern that the early benefits of thrombolytic therapy might eventually be lost as patients with incomplete infarction were exposed to the risk of recurrent myocardial infarction over subsequent months. However, follow-up over 5 years indicates that the initial gains of therapy have in fact not been lost."', The trials have clearly shown that the benefit of thrombolytic therapy increases the earlier it is administered after the onset of AMI.'2 This observation has prompted the conduct of clinical trials that, in aggregate, demonstrate a 17% reduction in mortality among patients whose thrombolytic therapy is initiated before admission to hospital.'5 Although such an approach is not likely to be an appropriate use of resources in North America, the overall evidence of an incremental benefit from early initiation of therapy has been a profound stimulus to the design of efficient diagnostic and therapeutic approaches to AMI."6 Because a bed in a coronary care unit is not likely to be immediately available, it is necessary to ensure that thrombolytic therapy can be initiated in the emergency department. Community hospitals that routinely accept responsibility for patients with AMI must develop the capacity to administer thrombolytic therapy as appropriate, given the fact that transfer to an acute care centre is likely to be impractical and will reduce the potential for benefit.' Thirty-fiveday mortality is reduced by about 24% among patients treated within 6 hours after onset of infarction and by about 14% among those treated between 7 and 12 hours after onset.'2 Although the earlier the treatment is started the greater the benefit, there are, surprisingly, some patients who may benefit from thrombolytic therapy even when it is not started until 13 to 24 hours after onset of symptoms. 12 Although the relative and absolute benefits of throm-
bolytic therapy vary considerably among various types of patients, the treatment is efficacious in patients of all ages and of either sex, in patients with anterior or inferior AMI, those with first or subsequent AMI and those with a wide range of presenting heart rates and blood pressures, except probably those with very high blood pressure.'2 Patients with ST-segment depression rather than STsegment elevation, or with normal electrocardiograms (even though they may have symptoms suggestive of AMI) do not benefit from thrombolytic therapy.12 It was anticipated that because of its somewhat greater fibrin specificity APSAC might cause less bleeding and, possibly, be more effective than streptokinase. The highly clot-specific rt-PA offered the promise of even greater efficacy and fewer complications from bleeding, hypotension and allergic reactions. However, the first large trials to compare these two agents directly showed no significant difference in efficacy, although there was some variation in the rates of reinfarction, cerebral hemorrhage and allergic reaction.' 20 The most recent trial2, demonstrated that, in comparison with conventional treatment with streptokinase, a regimen of accelerated-dose rt-PA achieved a 14% reduction in 30-day mortality. It has been calculated that the substantially greater cost of rt-PA results in an excess cost of $29 000 per year of life saved; this has prompted extensive debate as to the most appropriate choice of thrombolytic agent in various clinical settings.2"7 The most serious complication of thrombolytic therapy is cerebral hemorrhage. Thrombolytic therapy will save 30 of 1000 patients with suspected AMI who have ST-segment elevation or bundle-branch block and are treated within 12 hours after the onset of symptoms. There will be two episodes of nonfatal cerebral hemorrhage in the treated group, one of which will lead to permanent disability, and there will be roughly seven episodes of noncerebral major hemorrhage. 2 Although physicians must strive to minimize serious complications, their incidence is acceptable in the context of large reductions in mortality. A number of agents have been evaluated for use as an adjunct to thrombolytic therapy. 22 ASA used alone was shown to reduce 35-day mortality by almost as much as streptokinase; when used in combination with streptokinase, it was found to almost double the reduction in mortality.8 Intravenous heparin is routinely used along with rt-PA because of improved arterial patency demonstrated by clinical trials2 25 and the observed superiority of accelerated rt-PA plus intravenous heparin versus conventional-dose streptokinase plus heparin.2' Heparin does not appear to enhance the benefit of streptokinase.2,21 Recent trials have shown that among patients receiving thrombolytic therapy there was no significant reduc-
tion in mortality with early nitrate26 or magnesium therapy,27 whereas early therapy with an angiotensinconverting-enzyme inhibitor reduced the 35-day mortality by about 7%.28 An extensive series of studies evaluating various strategies for coronary angiography and prophylactic angioplasty showed no benefit.29
CONCLUSIONS Before 1986 thrombolytic therapy was rarely used in Canada for AMI. Subsequently, large placebo-controlled clinical trials have demonstrated that the three main thrombolytic agents achieved marked reductions in mortality that were augmented by concurrent therapy with ASA. The benefits of thrombolytic therapy can be enjoyed by a variety of patients regardless of age or sex, of whether the infarct is anterior or inferior, and of whether it is the first or a subsequent episode. These benefits are most marked when treatment is initiated soon after the onset of symptoms. It is likely that 70% to 80% of patients with AMI could benefit from thrombolytic therapy.30 However, 1993 sales figures indicated that in Canada no more than 38% of patients with AMI in hospital received a thrombolytic agent,3'32 a rate considerably below that in the United Kingdom, for example.30 It is clear that many more Canadian patients could be given thrombolytic therapy. Many patients who have already received such therapy could have derived greater benefit had it been initiated earlier after the onset of symptoms. The practice guidelines developed by the Canadian Cardiovascular Society should help to provide direction for physicians in the use of coronary thrombolytic therapy. Major educational efforts are needed to promote awareness among the public, health care administrators and emergency staff of the efficacy of thrombolytic therapy and of approaches to its administration that will maximize its potential benefit for patients with AMI.
1. Cairns JA: Coronary thrombolysis: mortality trials. Can J Cardiol 1993; 9: 490-497
2. Cairns J, Armstrong P, Belenkie I et al: The Canadian Consensus Conference on Coronary Thrombolysis - 1994 Update. Can J Cardiol 1994; 10: 517-529
3. Herrick JB: Clinical features of sudden obstruction of the coronary arteries. JAMA 1912; 59: 2015-2020 4. Fletcher AP, Sherry S, Alkjaersig N et al: The maintenance of a sustained thrombolytic state in man. II. Clinical observations on patients with myocardial infarction and other thromboembolic disorders. J Clin Invest 1959; 38: 1 1 11-1 119 CAN MED ASSOC J * MAR. 15, 1995; 152 (6)
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5. Yusuf S, Collins R, Peto R et al: Intravenous and intracoro nary fibrinolytic therapy in acute myocardial infarction: Overview of results on mortality, reinfarction and side effects from 33 randomized controlled trials. Eur Heart J 1985; 6: 556-585 6. Cairns JA, Fuster V, Kennedy JW: Coronary thrombolysis. Chest 1992; 102: 482S-507S 7. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI): Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; 1: 397-402
8. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group: Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction. Lancet 1988; 2: 349-360
9. AIMS Trial Study Group: Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet 1988; 1: 545-549 10. AIMS Trial Study Group: Long-term effects of intravenous anistreplase in acute myocardial infarction: final report of the AIMS study. Lancet 1990; 335: 427-431 11. Wilcox RG, Von der Lippe G, Olsson CG et al: Trial of tissue plasminogen activator for mortality reduction in acute
myocardial infarction. Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet 1988; 2: 525-530 12. Fibrinolytic Therapy Trialists' (F1T) Collaborative Group: Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomized trials of more than 1000 patients. Lancet 1994; 343: 311-322 13. Hirsh J: Mechanisms of action of thrombolytic drugs. Can J Cardiol 1993; 9: 485-486
19. International Study Group: In-hospital mortality and clinical course of 20 891 patients with suspected acute myocardial infarction randomised between alteplase and streptokinase with or without heparin. Lancet 1990; 336: 71-75
20. ISIS-3 Collaborative Group: ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and or aspirin plus heparin vs aspirin alone among 41 299 cases of suspected acute myocardial infarction. Lancet 1992; 339: 753-770 21. GUSTO investigators: An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673-682 22. Theroux P, Roy L: Coronary thrombolysis: adjuvant medical therapy. Can J Cardiol 1993; 9: 524-528 23. Bleich SD, Nichols TC, Schumacher RR et al: Effect of heparin on coronary arterial patency after thrombolysis with tissue plasminogen activator in acute myocardial infarction. Am J Cardiol 1990; 66: 1412-1417 24. Heparin-Aspirin Reperfusion Trial (HART) investigators: A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue-type plasminogen activator for acute myocardial infarction. N Engl J Med 1990; 323: 143 3-1437
25. European Cooperative Study Group (ECSG): The effect of early intravenous heparin on coronary patency, infarct size and bleeding complications after alteplase thrombolysis: results of a randomised double blind European Cooperative Study Group trial. Br Heart J 1992; 67: 122-128
26. ISIS Collaborative Group: ISIS-4: randomised study of oral isosorbide mononitrate in over 50 000 patients with suspected acute myocardial infarction. [abstract] Circulation 1993; 88 (suppl): 1-394
14. Baigent C, Collins R for the ISIS Collaborative Group: ISIS2: 4-year mortality follow-up of 17 187 patients after fibrinolytic and antiplatelet therapy in suspected acute myocardial infarction. [abstract] Circulation 1993; 88 (suppl): 11-291
27. ISIS Collaborative Group: ISIS-4: randomised study of intravenous magnesium in over 50 000 patients with suspected acute myocardial infarction. [abstract] Circulation 1993; 88 (suppl): 1-292
15. European Myocardial Infarction Project Group: Prehospital thrombolytic therapy in patients with suspected acute my-
28. ISIS Collaborative Group: ISIS-4: randomised study of oral captopril in over 50 000 patients with suspected acute myocardial infarction. [abstract] Circulation 1993; 88 (suppl): 1-394
ocardial infarction. NEngliJMed 1993; 329: 383-389 16. Pell ACH, Miller HC, Robertson CF et al: Effect of "fast track" admission for acute myocardial infarction on delay to
thrombolysis. BMJ 1992; 304: 83-87 17. Naylor CD, Bronskill S, Goel V: Cost-effectiveness of intravenous thrombolytic drugs for acute myocardial infarction.
Can J Cardiol 1993; 9: 553-558 18. Gruppo Italiano per lo Studio della Sopravvivenza nell'In farto Miocardicor GISSI-2: a factorial randomised trial of al teplase versus streptokinase and heparin versus no heparin 822
among 12,490 patients with acute myocardial infarction. Lancet 1990; 336: 65-71
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29. Knudtson M: Coronary thrombolysis: adjuvant coronary angioplasty. Can J Cardiol 1993; 9: 528-536 30. Ketley D, Woods KL: Impact of clinical trials on clinical practice: example of thrombolysis for acute myocardial infarction. Lancet 1993; 342: 891-894 31. Hospital Morbidity, 1989-90 (cat no 82-00351), vol 4, no 1, Health Reports, Statistics Canada, Ottawa, 1992
32. Drugstore and Hospital Audit, Intercontinental Medical Statistics Canada, data on file For
prescribing information
see
page 996 -*
