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Editorial Comment Optimizing Thrombolytic Therapy of Acute Myocardial Infarction Eugene Braunwald, MD M ajor advances in medicine rarely burst upon the scene fully developed and immediately applicable to a large majority of the potential beneficiaries. More commonly, after the initial studies in which the clinical value of a new discovery is demonstrated, there is a period during which the precise indications are established and "tooling up" occurs. For example, following the development of the coronary care unit, coronary artery bypass grafting, and percutaneous transluminal coronary angioplasty, it took several years to work out the precise clinical indications for the use of each of these modalities, for the training of personnel, and for the manufacture of the equipment necessary for widespread application. Thrombolytic therapy of acute myocardial infarction has now reached the stage at which the clinical value of the technique for many patients has been clearly established and is no longer in dispute,12 and it is now undergoing clinical application. However, making this form of treatment available to all or nearly all patients with myocardial infarction who can benefit from it is now an important challenge. See p 1140 In 1989, approximately 700,000 patients with acute myocardial infarction were admitted to hospitals in the United States, but only 140,000 were treated with thrombolytic agents. The reasons for the failure of more than 500,000 patients to receive this treatment fall into four general categories: 1) uncertainty regarding where thrombolytic therapy should be delivered, 2) uncertainty regarding who can deliver thrombolytic therapy, 3) uncertainty regarding the criteria of eligibility for thrombolytic therapy, and 4) contraindications to thrombolytic therapy.
Where Should Thrombolytic Therapy Be Delivered? A large number of individuals, particularly in rural areas, simply cannot reach a facility at which thromThe opinions expressed in this editorial comment are not necessarily those of the editors or of the American Heart Association. From the Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston. Address for correspondence: Eugene Braunwald, MD, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.
bolytic therapy is provided in sufficient time for it to be maximally effective. This obstacle can be overcome by first recognizing that the administration of thrombolytic therapy does not require a tertiary medical center with facilities for cardiac catheterization, angioplasty, or coronary artery surgery. In the Thrombolysis in Myocardial Infarction (TIMI) II trial, the conservative strategy of "watchful waiting" following tissue-type plasminogen activator, intravenous heparin, and aspirin was found to be equivalent to an invasive strategy of catheterization.3 Moreover, patients assigned to the conservative strategy were admitted and treated in either tertiary centers or community hospitals without facilities for catheterization. The patients admitted to these two kinds of hospitals were similar, and there was no demonstrable difference in the outcome after 1 year of followUp.4 Thus, thrombolytic therapy can be as effectively and safely administered in a community hospital as in a tertiary medical center. The sites at which treatment can be begun could probably be extended to free-standing emergency departments and ambulatory health centers, physician offices, ambulances, and even patients' homes.5-9 However, after thrombolytic therapy is begun, it is important that patients be managed in a facility from which they can be promptly transferred to a tertiary care center should ischemia recur. Who Can Deliver Thrombolytic Therapy? Thrombolytic treatment, like most new forms of cardiac therapy, was first introduced by academic cardiologists in tertiary medical centers. However, in the United States, the majority of patients with acute myocardial infarction are managed not by cardiologists but by primary care internists or family practitioners. Just as these physicians successfully mastered the intricacies of the coronary care unit prior to the thrombolytic era, so they (as well as emergency medicine physicians) are now becoming familiar with the use of thrombolytic agents, their indications, contraindications, and adverse effects. Given the importance of prompt treatment and the limitations in the immediate availability of physicians, it is logical to also consider training nonphysicians - paramedics, nurses, emergency medical technicians, and physicians' assistants -in the delivery of this therapy.
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Braunwald Thrombolytic Therapy Weaver et al10 have developed an algorithm that allows trained paramedics, under the direction of a hospital-based physician, to identify in the field patients eligible for thrombolytic therapy. In patients potentially eligible for such therapy, the electrocardiogram can be transmitted by cellular telephone to the hospital. There it is interpreted by the physician who, after a brief consultation with the paramedic, can prescribe administration of a thrombolytic agent by telephone or radio. Weaver et al have shown that this approach can reduce strikingly the delay of beginning thrombolytic treatment. If such therapy were begun in the patient's home; an ambulance; or an infirmary in a factory, large office building, or sports stadium; a large majority of patients in the United States who need it should be able to benefit from prompt thrombolytic therapy. Just as the initial reluctance of allowing trained nurses to carry out ventricular defibrillation had to be overcome to realize the full potential of the coronary care unit, so the barrier to the delivery of thrombolytic therapy by nonphysicians must be surmounted to obtain maximum possible benefit from this mode of treatment. Which Patients Are Eligible for Thrombolytic Therapy? An important obstacle to the widespread application of thrombolytic therapy for acute myocardial infarction is the uncertainty regarding the boundaries of eligibility for this treatment. This uncertainty arises in part from the restrictive nature of the entry criteria into many of the trials of this therapy and blurring of the distinction between trial eligibility and clinical indications for the therapy. It is important to understand that studies designed to investigate the mechanisms of action of a therapy (i.e., "mechanistic" studies) usually have rigidly controlled eligibility criteria. For example, the TIMI II trial, which may be considered of this category, was restricted to patients less than 76 years of age with chest pain of less than 4 hours' duration and with electrocardiographic ST segment elevations,3 not because it was believed that no other patients with acute myocardial infarction could benefit from thrombolytic therapy but because it was thought that the specific questions of interest to the investigators could be answered best in the particular patient group selected; similar considerations hold for other mechanistic trials. In contrast, population-based trials such as the Second International Study of Infarct Survival (ISIS-2),2 with very broad inclusion criteria, no age limit, no special electrocardiographic criteria, and treatment up to 24 hours from the onset of pain, can be very helpful in defining the clinical usefulness of the intervention. Conversely, population-based trials inherently provide less information about the therapy's mechanism(s). When they are well planned, both types of trials are useful and complementary; both are usually needed before a therapeutic strategy is thoroughly understood for broad application.
1511
In this issue of Circulation, Karlson et al,11 as did previous investigators,12-'4 examine the important question of the percentage of patients with acute myocardial infarction who might be eligible for thrombolytic therapy. The unique feature of their study is that it provides an estimate of how many patients would be treated as two important inclusion criteria-delay time and admission electrocardiographic features-are varied. Among patients presenting with a clinical suspicion of acute myocardial infarction upon admission to the hospital and who subsequently developed a confirmed infarction, the percentage of patients eligible for thrombolytic therapy ranged from 27% to 77%, depending on the specific delay time and electrocardiographic eligibility criteria that were selected. Using rather strict eligibility criteria for thrombolytic therapy, Weaver et al also found that only 24% of patients with acute myocardial infarction would have been eligible for thrombolytic therapy by paramedics operating under physician guidance.10 There is uncertainty about the precise eligibility cutoff time. In the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) I trial, no benefit was found when thrombolytic therapy was administered more than 6 hours after the onset of symptoms.' However, the number of patients treated relatively late (i.e., 6-12 hours after symptom onset) was relatively small, thereby limiting the statistical significance of this finding. However, in ISIS-2, a much larger number of patients were enrolled 5-24 hours after the onset of pain, and the combination of streptokinase and aspirin reduced early mortality in this group by almost one third, from 13% to 9%!2,15 It is interesting to consider the mechanism of this impressive benefit of late therapy in ISIS-2. One possibility is that the therapy was applied not really late at all, but rather that the precise time of onset of myocardial infarction from clinical symptoms might not have been (and sometimes cannot be) estimated accurately. Many patients experienced prodromal pain, or a "stuttering" onset of infarction. Perhaps some of the patients who entered ISIS-2 relatively late had experienced several hours of unstable angina, during which the infarctrelated artery repeatedly closed and reopened before becoming totally occluded. A second possible explanation is that late vessel opening by the thrombolytic agent prevented death by a mechanism other than myocardial salvage.16"7 Benefit of late therapy in ISIS-2 is interesting, somewhat surprising, and potentially very important, and requires confirmation. Regardless of whether late thrombolytic therapy is actually beneficial, there is widespread agreement that it is most effective when administered as soon as possible after the onset of infarction. Of course, the timing of therapy depends on the interval between symptom onset and the time the patient reaches the medical care system (now usually the hospital emergency department) but in the future perhaps by the
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Circulation Vol 82, No 4, October 1990
time a paramedic reaches the patient.10 In the Multicenter Investigation of Limitation of Infarct Size (MILIS) trial, we observed that patients with acute myocardial infarction who presented to the hospital relatively late (more than 2 hours after the onset of myocardial infarction) were at relatively high risk (i.e., older patients, most often women and minorities, with a history of diabetes mellitus and congestive heart failure) than were early arrivers. Even more disturbing was the finding that patients receiving ,l-blockers and larger doses of nitrates, who might be expected to have had greater previous contact with the health care system, arrived later than did patients who had not received these drugs. Not surprisingly, late arrivers had a significantly higher in-hospital and 2-year mortality.18 Regrettably, the very patients who stand to benefit the most from early therapy reach the hospital later than do patients at lower risk. To ensure that patients receive thrombolytic therapy in a timely manner, a public education campaign must be mounted. Such a campaign should probably begin with the patients at highest risk of developing myocardial infarction (i.e., those with known coronary artery disease). Counseling such patients to immediately contact the medical care system when they experience symptoms of infarction should be done immediately upon the diagnosis of coronary artery disease and subsequently reinforced. In fact, there is evidence that a public education campaign can be useful in reducing the delay in presentation of patients experiencing acute myocardial infarction. Thus, Herlitz et al19 instituted a media campaign in Goteborg, Sweden, and found that the median delay time in patients developing infarction decreased from 3 to 2 hours. Of course, a public education campaign could be counterproductive if it caused flooding of already crowded emergency departments with large numbers of persons with nonischemic chest pain, thereby increasing the delay for patients with true ischemia. The aforementioned campaign in Goteborg did, in fact, initially cause a large influx of patients with nonischemic chest pain.19 As important as is the encouragement of patients with symptoms of acute myocardial infarction to seek early medical attention is the alacrity with which patients are triaged and treated once they reach a hospital. Unfortunately, unlike patients presenting with gunshot wounds or other causes of external bleeding, patients with chest pain must wait their turn, sometimes for hours, before being assessed in the emergency departments of many otherwise fine hospitals. Then there may be another delay until the patient is evaluated for thrombolytic therapy by a cardiologist; sometimes thrombolytic therapy is not begun until the patient has been transferred to the coronary care unit.20 When cumulative, such delays can be substantial and reduce greatly the potential benefit of this therapy. The second factor of eligibility for thrombolytic therapy considered by Karlson et all" (i.e., the electrocardiographic changes at presentation) is as
important as the delay time in selecting patients for thrombolytic therapy. The mechanistic studies of thrombolysis have focused on patients with ST segment elevation at presentation. Neither GISSI-1 nor ISIS-2 showed any benefit of thrombolytic therapy in patients with ST segment depression and non-Q wave myocardial infarction.12 Indeed, the early mortalities in such patients were very high even when they received such therapy (20.5% in GISSI-1 and 18.7% in ISIS-2). However, in both trials the examination of treatment effects according to ST segment deviation were posthoc subgroup analyses, with all of their attendant problems of interpretation. Therefore, the role, if any, of thrombolytic therapy in such patients should be addressed directly and prospectively. Indeed, this is now underway in the TIMI I1I trial, which focuses on the efficacy of thrombolytic therapy in patients presenting with acute ischemic syndromes accompanied by ST segment depression (i.e., non-Q wave myocardial infarction and unstable angina). The upper age limit of eligibility for thrombolytic therapy considered by Karlson et al (i.e., 75 years"l) also requires further investigation, since in the two largest population-based trials, one showed substantial benefit in older patients (ISIS-2)2 and the other showed no benefit (GISSI)1; it appears that the risk of bleeding in the elderly receiving thrombolytic therapy is higher than in younger patients.21,22 In any event, it is important to settle the question of whether an age ceiling should be set for thrombolytic therapy and, if so, what it should be. What Are the Contraindications to Thrombolytic Therapy? Finally, thrombolytic therapy is not carried out because of a broad range of contraindications.23 An active peptic ulcer, hypertension, a history of cerebrovascular disease, and a recent operation or cardiopulmonary resuscitation are commonly considered to be such contraindications. But what should be the strategy in the patient who has had bleeding from a peptic ulcer more than 2 years earlier? What about the patient with a history of serious hypertension whose blood pressure is now well controlled? Should the patient with a history of possible transient ischemic attacks be treated? Patients who have undergone recent cardiopulmonary resuscitation in particular appear to benefit from this therapy.24 Should this factor remain a contraindication? These situations commonly occur among patients with acute myocardial infarction. Conclusions Future clinical research of thrombolytic therapy in acute myocardial infarction will focus on the selection of the thrombolytic agent (or agents) of choice and the value of adjunctive therapeutic procedures such as newer antithrombin and antiplatelet agents, as well as on measures designed to limit reperfusion injury. In addition to these traditional areas of
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Braunwald Thrombolytic Therapy
research, there is now an urgent need to identify the patients in whom the benefits of thrombolytic therapy outweigh the adverse effects and in whom the therapy is cost effective.25 In addition, widespread but thoughtful professional and public educational campaigns are now in order to optimize this therapy. As is clear from the article by Karlson et al,11 our current lack of clear information on potential benefits might be responsible for a vast underutilization of appropriate treatment of acute myocardial infarction, a condition that remains the most important cause of death in hospitalized patients in the United States. Optimizing thrombolytic therapy will require the cooperation of the public, clinical investigators, and the cardiology community. Therefore, it is now appropriate that this country's three leading organizations representing these groups - the American Heart Association; the National Heart, Lung, and Blood Institute; and the American College of Cardiologyrise to the challenge of creating the conditions that allow for prompt thrombolytic therapy to the largest number of patients who might benefit from it. References 1. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI): Effectiveness of intravenous thrombolytic treatm-etnt in acute myocardial infarction. Lancet 1986; 1:397-402 2. ISIS-2 (Second Internationai 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: ISIS-2. Lancet 1988;
2:349-360 3. The TIMI Study Group: Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI) Phase II Trial. N Engl J Med 1989;320:618-627 4. Feit F, Mueller HS, Ross R, Herman MV, Hodges M, Knatterud G, the TIMI Group: Coronary angiography and angioplasty in the conservative arm of TIMI-IIB: A comparison of primary and satellite hospitals (abstract). Circulation
1989;80(suppl II):II-626 5. Koren G, Weiss AT, Hasin Y, Appelbaum D, Welber S, Rozenman Y, Lotan C, Mosseri M, Sapoznikov D, Luria MH, Gotsman MS: Prevention of myocardial damage in acute myocardial ischemia by early treatment with intravenous streptokinase. N Engl J Med 1985;313:1384-1389 6. Villemant D, Barriot P, Riou B, Bodenan P, Brunet F, Noto R, Monsallier J-F: Achievement of thrombolysis at home in cases of acute myocardial infarction. Lancet 1987;1:228-229 7. European Myocardial Infarction Project (EMIP) Subcommittee: Potential time saving with pre-hospital intervention in acute myocardial infarction. EurHeart J 1988;9:118-124 8. Roth A, Barbash GI, Hod H, Miller NI, Rath S, Modan M, Har-Zahav Y, Keren G, Bassan S, Kaplinsky E, Laniado S: Should thrombolytic therapy be administered in the mobile intensive care unit in patients with evolving myocardial infarction? A pilot study. JAm Coll Cardiol 1990;15:932-936
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9. Califf RM, Harrelson-Woodlief SL: At home thrombolysis. J
Am Coil Cardiol 1990;15:937-939 10. Weaver WD, Eisenberg MS, Martin JS, Litwin PE, Schaefer S, Ho MT, Kudenchuk P, Hallstrom AP, Cerqueira MD, Copass MK, Kennedy JW, Cobb LA, Ritchie JL: Myocardial Infarction Triage and Intervention Project: Phase I patient characteristics and feasibility of prehospital initiation of thrombolytic therapy. JAm Coll Cardiol 1990;15:925-931 11. Karlson BW, Herlitz J, Edvardsson N, Emanuelsson H, Sjolin M, Hjalmarson A: Eligibility for intravenous thrombolysis in suspected acute myocardial infarction. Circulation 1990; 82:1140-1146 12. Jagger JD, Murray RG, Davies MK, Littler WA, Flint EJ: Eligibility for thrombolytic therapy in acute myocardial infarction. Lancet 1987;1:34-35 13. Murray N, Lyons J, Layton C, Balcon R: What proportion of patients with myocardial infarction are suitable for thrombolysis? Br Heart J 1987;57:144-147 14. Lee TH, Weisberg MC, Brand DA, Rouan GW, Goldman L: Candidates for thrombolysis among emergency room patients with acute chest pain: Potential true- and false-positive rates. Ann Intem Med 1989;110:957-962 15. Peto R, Collins R, Sleight P: Wider inclusion criteria needed for thrombolytic therapy. Ann Intern Med 1989;111:540 16. Braunwald E: Myocardial reperfusion, limitation of infarct size, reduction of left ventricular dysfunction, and improved survival: Should the paradigm be expanded? Circulation 1989; 79:441-444 17. Califf RM, Topol EJ, Gersh BJ: From myocardial salvage to patient salvage in acute myocardial infarction: The role of reperfusion therapy. JAm Coll Cardiol 1989;14:1382-1388 18. Turi JG, Stone PH, Muller JE, Parker C, Rude RE, Raabe DE, Jaffe AS, Hartwell TD, Robertson TL, Braunwald E, the MILIS Study Group: Implications for acute intervention related to time of hospital arrival in acute myocardial infarction. Am J Cardiol 1986;58:203-209 19. Herlitz J, Hartford M, Blohm M, Karlson BW, Ekstrom L, Risenfors M, Wennerblom B, Luepker R, Holmberg S: Effect of a media campaign on delay times and ambulance use in suspected acute myocardial infarction. Am J Cardiol 1989; 64:90-93 20. Sharkey SW, Brunette DD, Ruiz E, Hession WT, Wysham DG, Goldenberg IF, Hodges M: An analysis of time delays preceding thrombolysis for acute myocardial infarction. JAMA 1989;262:3171-3174 21. Lew AS, Hanoch HOD, Cercek B, Shah PK, Ganz W: Mortality and morbidity rates of patients older and younger than 75 years with acute myocardial infarction treated with intravenous streptokinase. Am J Cardiol 1987;59:1-5 22. Chaitman BR, Knatterud GL, Stump D, Hamilton WP, Hillis LD, Dwyer JG, Solomon RE, the TIMI Investigators: Thrombolytic therapy for acute myocardial infarction in the elderly (abstract). Circulation 1988;78(suppl II):II-211 23. Althouse R, Maynard C, Olsufka M, Kennedy JW: Incidence of contraindications to thrombolysis in patients with myocardial infarction (abstract). Circulation 1988;78(suppl II):II-211 24. Califf RM, Topol EJ, Kereiakes DJ, Abbottsmith CW, George BS, Candela RJ, Aronson LG, Bauman RP, Ellis SG: Cardiac resuscitation should not be a contraindication to thrombolytic therapy for myocardial infarction (abstract). Circulation 1988;
78(suppl II):II-127 25. Laffel GL, Fineberg H, Braunwald E: A cost-effectiveness model for coronary thrombolysis/reperfusion therapy. J Am Coll Cardiol 1987;10:79B-90B
(Circulation 1990;82:1510-1513)
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Optimizing thrombolytic therapy of acute myocardial infarction. E Braunwald Circulation. 1990;82:1510-1513 doi: 10.1161/01.CIR.82.4.1510 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1990 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/82/4/1510.citation
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Editorial Comment Optimizing Thrombolytic Therapy of Acute Myocardial Infarction Eugene Braunwald, MD M ajor advances in medicine rarely burst upon the scene fully developed and immediately applicable to a large majority of the potential beneficiaries. More commonly, after the initial studies in which the clinical value of a new discovery is demonstrated, there is a period during which the precise indications are established and "tooling up" occurs. For example, following the development of the coronary care unit, coronary artery bypass grafting, and percutaneous transluminal coronary angioplasty, it took several years to work out the precise clinical indications for the use of each of these modalities, for the training of personnel, and for the manufacture of the equipment necessary for widespread application. Thrombolytic therapy of acute myocardial infarction has now reached the stage at which the clinical value of the technique for many patients has been clearly established and is no longer in dispute,12 and it is now undergoing clinical application. However, making this form of treatment available to all or nearly all patients with myocardial infarction who can benefit from it is now an important challenge. See p 1140 In 1989, approximately 700,000 patients with acute myocardial infarction were admitted to hospitals in the United States, but only 140,000 were treated with thrombolytic agents. The reasons for the failure of more than 500,000 patients to receive this treatment fall into four general categories: 1) uncertainty regarding where thrombolytic therapy should be delivered, 2) uncertainty regarding who can deliver thrombolytic therapy, 3) uncertainty regarding the criteria of eligibility for thrombolytic therapy, and 4) contraindications to thrombolytic therapy.
Where Should Thrombolytic Therapy Be Delivered? A large number of individuals, particularly in rural areas, simply cannot reach a facility at which thromThe opinions expressed in this editorial comment are not necessarily those of the editors or of the American Heart Association. From the Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston. Address for correspondence: Eugene Braunwald, MD, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.
bolytic therapy is provided in sufficient time for it to be maximally effective. This obstacle can be overcome by first recognizing that the administration of thrombolytic therapy does not require a tertiary medical center with facilities for cardiac catheterization, angioplasty, or coronary artery surgery. In the Thrombolysis in Myocardial Infarction (TIMI) II trial, the conservative strategy of "watchful waiting" following tissue-type plasminogen activator, intravenous heparin, and aspirin was found to be equivalent to an invasive strategy of catheterization.3 Moreover, patients assigned to the conservative strategy were admitted and treated in either tertiary centers or community hospitals without facilities for catheterization. The patients admitted to these two kinds of hospitals were similar, and there was no demonstrable difference in the outcome after 1 year of followUp.4 Thus, thrombolytic therapy can be as effectively and safely administered in a community hospital as in a tertiary medical center. The sites at which treatment can be begun could probably be extended to free-standing emergency departments and ambulatory health centers, physician offices, ambulances, and even patients' homes.5-9 However, after thrombolytic therapy is begun, it is important that patients be managed in a facility from which they can be promptly transferred to a tertiary care center should ischemia recur. Who Can Deliver Thrombolytic Therapy? Thrombolytic treatment, like most new forms of cardiac therapy, was first introduced by academic cardiologists in tertiary medical centers. However, in the United States, the majority of patients with acute myocardial infarction are managed not by cardiologists but by primary care internists or family practitioners. Just as these physicians successfully mastered the intricacies of the coronary care unit prior to the thrombolytic era, so they (as well as emergency medicine physicians) are now becoming familiar with the use of thrombolytic agents, their indications, contraindications, and adverse effects. Given the importance of prompt treatment and the limitations in the immediate availability of physicians, it is logical to also consider training nonphysicians - paramedics, nurses, emergency medical technicians, and physicians' assistants -in the delivery of this therapy.
Downloaded from http://circ.ahajournals.org/ at University of Oregon on March 18, 2015
Braunwald Thrombolytic Therapy Weaver et al10 have developed an algorithm that allows trained paramedics, under the direction of a hospital-based physician, to identify in the field patients eligible for thrombolytic therapy. In patients potentially eligible for such therapy, the electrocardiogram can be transmitted by cellular telephone to the hospital. There it is interpreted by the physician who, after a brief consultation with the paramedic, can prescribe administration of a thrombolytic agent by telephone or radio. Weaver et al have shown that this approach can reduce strikingly the delay of beginning thrombolytic treatment. If such therapy were begun in the patient's home; an ambulance; or an infirmary in a factory, large office building, or sports stadium; a large majority of patients in the United States who need it should be able to benefit from prompt thrombolytic therapy. Just as the initial reluctance of allowing trained nurses to carry out ventricular defibrillation had to be overcome to realize the full potential of the coronary care unit, so the barrier to the delivery of thrombolytic therapy by nonphysicians must be surmounted to obtain maximum possible benefit from this mode of treatment. Which Patients Are Eligible for Thrombolytic Therapy? An important obstacle to the widespread application of thrombolytic therapy for acute myocardial infarction is the uncertainty regarding the boundaries of eligibility for this treatment. This uncertainty arises in part from the restrictive nature of the entry criteria into many of the trials of this therapy and blurring of the distinction between trial eligibility and clinical indications for the therapy. It is important to understand that studies designed to investigate the mechanisms of action of a therapy (i.e., "mechanistic" studies) usually have rigidly controlled eligibility criteria. For example, the TIMI II trial, which may be considered of this category, was restricted to patients less than 76 years of age with chest pain of less than 4 hours' duration and with electrocardiographic ST segment elevations,3 not because it was believed that no other patients with acute myocardial infarction could benefit from thrombolytic therapy but because it was thought that the specific questions of interest to the investigators could be answered best in the particular patient group selected; similar considerations hold for other mechanistic trials. In contrast, population-based trials such as the Second International Study of Infarct Survival (ISIS-2),2 with very broad inclusion criteria, no age limit, no special electrocardiographic criteria, and treatment up to 24 hours from the onset of pain, can be very helpful in defining the clinical usefulness of the intervention. Conversely, population-based trials inherently provide less information about the therapy's mechanism(s). When they are well planned, both types of trials are useful and complementary; both are usually needed before a therapeutic strategy is thoroughly understood for broad application.
1511
In this issue of Circulation, Karlson et al,11 as did previous investigators,12-'4 examine the important question of the percentage of patients with acute myocardial infarction who might be eligible for thrombolytic therapy. The unique feature of their study is that it provides an estimate of how many patients would be treated as two important inclusion criteria-delay time and admission electrocardiographic features-are varied. Among patients presenting with a clinical suspicion of acute myocardial infarction upon admission to the hospital and who subsequently developed a confirmed infarction, the percentage of patients eligible for thrombolytic therapy ranged from 27% to 77%, depending on the specific delay time and electrocardiographic eligibility criteria that were selected. Using rather strict eligibility criteria for thrombolytic therapy, Weaver et al also found that only 24% of patients with acute myocardial infarction would have been eligible for thrombolytic therapy by paramedics operating under physician guidance.10 There is uncertainty about the precise eligibility cutoff time. In the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) I trial, no benefit was found when thrombolytic therapy was administered more than 6 hours after the onset of symptoms.' However, the number of patients treated relatively late (i.e., 6-12 hours after symptom onset) was relatively small, thereby limiting the statistical significance of this finding. However, in ISIS-2, a much larger number of patients were enrolled 5-24 hours after the onset of pain, and the combination of streptokinase and aspirin reduced early mortality in this group by almost one third, from 13% to 9%!2,15 It is interesting to consider the mechanism of this impressive benefit of late therapy in ISIS-2. One possibility is that the therapy was applied not really late at all, but rather that the precise time of onset of myocardial infarction from clinical symptoms might not have been (and sometimes cannot be) estimated accurately. Many patients experienced prodromal pain, or a "stuttering" onset of infarction. Perhaps some of the patients who entered ISIS-2 relatively late had experienced several hours of unstable angina, during which the infarctrelated artery repeatedly closed and reopened before becoming totally occluded. A second possible explanation is that late vessel opening by the thrombolytic agent prevented death by a mechanism other than myocardial salvage.16"7 Benefit of late therapy in ISIS-2 is interesting, somewhat surprising, and potentially very important, and requires confirmation. Regardless of whether late thrombolytic therapy is actually beneficial, there is widespread agreement that it is most effective when administered as soon as possible after the onset of infarction. Of course, the timing of therapy depends on the interval between symptom onset and the time the patient reaches the medical care system (now usually the hospital emergency department) but in the future perhaps by the
Downloaded from http://circ.ahajournals.org/ at University of Oregon on March 18, 2015
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Circulation Vol 82, No 4, October 1990
time a paramedic reaches the patient.10 In the Multicenter Investigation of Limitation of Infarct Size (MILIS) trial, we observed that patients with acute myocardial infarction who presented to the hospital relatively late (more than 2 hours after the onset of myocardial infarction) were at relatively high risk (i.e., older patients, most often women and minorities, with a history of diabetes mellitus and congestive heart failure) than were early arrivers. Even more disturbing was the finding that patients receiving ,l-blockers and larger doses of nitrates, who might be expected to have had greater previous contact with the health care system, arrived later than did patients who had not received these drugs. Not surprisingly, late arrivers had a significantly higher in-hospital and 2-year mortality.18 Regrettably, the very patients who stand to benefit the most from early therapy reach the hospital later than do patients at lower risk. To ensure that patients receive thrombolytic therapy in a timely manner, a public education campaign must be mounted. Such a campaign should probably begin with the patients at highest risk of developing myocardial infarction (i.e., those with known coronary artery disease). Counseling such patients to immediately contact the medical care system when they experience symptoms of infarction should be done immediately upon the diagnosis of coronary artery disease and subsequently reinforced. In fact, there is evidence that a public education campaign can be useful in reducing the delay in presentation of patients experiencing acute myocardial infarction. Thus, Herlitz et al19 instituted a media campaign in Goteborg, Sweden, and found that the median delay time in patients developing infarction decreased from 3 to 2 hours. Of course, a public education campaign could be counterproductive if it caused flooding of already crowded emergency departments with large numbers of persons with nonischemic chest pain, thereby increasing the delay for patients with true ischemia. The aforementioned campaign in Goteborg did, in fact, initially cause a large influx of patients with nonischemic chest pain.19 As important as is the encouragement of patients with symptoms of acute myocardial infarction to seek early medical attention is the alacrity with which patients are triaged and treated once they reach a hospital. Unfortunately, unlike patients presenting with gunshot wounds or other causes of external bleeding, patients with chest pain must wait their turn, sometimes for hours, before being assessed in the emergency departments of many otherwise fine hospitals. Then there may be another delay until the patient is evaluated for thrombolytic therapy by a cardiologist; sometimes thrombolytic therapy is not begun until the patient has been transferred to the coronary care unit.20 When cumulative, such delays can be substantial and reduce greatly the potential benefit of this therapy. The second factor of eligibility for thrombolytic therapy considered by Karlson et all" (i.e., the electrocardiographic changes at presentation) is as
important as the delay time in selecting patients for thrombolytic therapy. The mechanistic studies of thrombolysis have focused on patients with ST segment elevation at presentation. Neither GISSI-1 nor ISIS-2 showed any benefit of thrombolytic therapy in patients with ST segment depression and non-Q wave myocardial infarction.12 Indeed, the early mortalities in such patients were very high even when they received such therapy (20.5% in GISSI-1 and 18.7% in ISIS-2). However, in both trials the examination of treatment effects according to ST segment deviation were posthoc subgroup analyses, with all of their attendant problems of interpretation. Therefore, the role, if any, of thrombolytic therapy in such patients should be addressed directly and prospectively. Indeed, this is now underway in the TIMI I1I trial, which focuses on the efficacy of thrombolytic therapy in patients presenting with acute ischemic syndromes accompanied by ST segment depression (i.e., non-Q wave myocardial infarction and unstable angina). The upper age limit of eligibility for thrombolytic therapy considered by Karlson et al (i.e., 75 years"l) also requires further investigation, since in the two largest population-based trials, one showed substantial benefit in older patients (ISIS-2)2 and the other showed no benefit (GISSI)1; it appears that the risk of bleeding in the elderly receiving thrombolytic therapy is higher than in younger patients.21,22 In any event, it is important to settle the question of whether an age ceiling should be set for thrombolytic therapy and, if so, what it should be. What Are the Contraindications to Thrombolytic Therapy? Finally, thrombolytic therapy is not carried out because of a broad range of contraindications.23 An active peptic ulcer, hypertension, a history of cerebrovascular disease, and a recent operation or cardiopulmonary resuscitation are commonly considered to be such contraindications. But what should be the strategy in the patient who has had bleeding from a peptic ulcer more than 2 years earlier? What about the patient with a history of serious hypertension whose blood pressure is now well controlled? Should the patient with a history of possible transient ischemic attacks be treated? Patients who have undergone recent cardiopulmonary resuscitation in particular appear to benefit from this therapy.24 Should this factor remain a contraindication? These situations commonly occur among patients with acute myocardial infarction. Conclusions Future clinical research of thrombolytic therapy in acute myocardial infarction will focus on the selection of the thrombolytic agent (or agents) of choice and the value of adjunctive therapeutic procedures such as newer antithrombin and antiplatelet agents, as well as on measures designed to limit reperfusion injury. In addition to these traditional areas of
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Braunwald Thrombolytic Therapy
research, there is now an urgent need to identify the patients in whom the benefits of thrombolytic therapy outweigh the adverse effects and in whom the therapy is cost effective.25 In addition, widespread but thoughtful professional and public educational campaigns are now in order to optimize this therapy. As is clear from the article by Karlson et al,11 our current lack of clear information on potential benefits might be responsible for a vast underutilization of appropriate treatment of acute myocardial infarction, a condition that remains the most important cause of death in hospitalized patients in the United States. Optimizing thrombolytic therapy will require the cooperation of the public, clinical investigators, and the cardiology community. Therefore, it is now appropriate that this country's three leading organizations representing these groups - the American Heart Association; the National Heart, Lung, and Blood Institute; and the American College of Cardiologyrise to the challenge of creating the conditions that allow for prompt thrombolytic therapy to the largest number of patients who might benefit from it. References 1. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI): Effectiveness of intravenous thrombolytic treatm-etnt in acute myocardial infarction. Lancet 1986; 1:397-402 2. ISIS-2 (Second Internationai 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: ISIS-2. Lancet 1988;
2:349-360 3. The TIMI Study Group: Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI) Phase II Trial. N Engl J Med 1989;320:618-627 4. Feit F, Mueller HS, Ross R, Herman MV, Hodges M, Knatterud G, the TIMI Group: Coronary angiography and angioplasty in the conservative arm of TIMI-IIB: A comparison of primary and satellite hospitals (abstract). Circulation
1989;80(suppl II):II-626 5. Koren G, Weiss AT, Hasin Y, Appelbaum D, Welber S, Rozenman Y, Lotan C, Mosseri M, Sapoznikov D, Luria MH, Gotsman MS: Prevention of myocardial damage in acute myocardial ischemia by early treatment with intravenous streptokinase. N Engl J Med 1985;313:1384-1389 6. Villemant D, Barriot P, Riou B, Bodenan P, Brunet F, Noto R, Monsallier J-F: Achievement of thrombolysis at home in cases of acute myocardial infarction. Lancet 1987;1:228-229 7. European Myocardial Infarction Project (EMIP) Subcommittee: Potential time saving with pre-hospital intervention in acute myocardial infarction. EurHeart J 1988;9:118-124 8. Roth A, Barbash GI, Hod H, Miller NI, Rath S, Modan M, Har-Zahav Y, Keren G, Bassan S, Kaplinsky E, Laniado S: Should thrombolytic therapy be administered in the mobile intensive care unit in patients with evolving myocardial infarction? A pilot study. JAm Coll Cardiol 1990;15:932-936
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9. Califf RM, Harrelson-Woodlief SL: At home thrombolysis. J
Am Coil Cardiol 1990;15:937-939 10. Weaver WD, Eisenberg MS, Martin JS, Litwin PE, Schaefer S, Ho MT, Kudenchuk P, Hallstrom AP, Cerqueira MD, Copass MK, Kennedy JW, Cobb LA, Ritchie JL: Myocardial Infarction Triage and Intervention Project: Phase I patient characteristics and feasibility of prehospital initiation of thrombolytic therapy. JAm Coll Cardiol 1990;15:925-931 11. Karlson BW, Herlitz J, Edvardsson N, Emanuelsson H, Sjolin M, Hjalmarson A: Eligibility for intravenous thrombolysis in suspected acute myocardial infarction. Circulation 1990; 82:1140-1146 12. Jagger JD, Murray RG, Davies MK, Littler WA, Flint EJ: Eligibility for thrombolytic therapy in acute myocardial infarction. Lancet 1987;1:34-35 13. Murray N, Lyons J, Layton C, Balcon R: What proportion of patients with myocardial infarction are suitable for thrombolysis? Br Heart J 1987;57:144-147 14. Lee TH, Weisberg MC, Brand DA, Rouan GW, Goldman L: Candidates for thrombolysis among emergency room patients with acute chest pain: Potential true- and false-positive rates. Ann Intem Med 1989;110:957-962 15. Peto R, Collins R, Sleight P: Wider inclusion criteria needed for thrombolytic therapy. Ann Intern Med 1989;111:540 16. Braunwald E: Myocardial reperfusion, limitation of infarct size, reduction of left ventricular dysfunction, and improved survival: Should the paradigm be expanded? Circulation 1989; 79:441-444 17. Califf RM, Topol EJ, Gersh BJ: From myocardial salvage to patient salvage in acute myocardial infarction: The role of reperfusion therapy. JAm Coll Cardiol 1989;14:1382-1388 18. Turi JG, Stone PH, Muller JE, Parker C, Rude RE, Raabe DE, Jaffe AS, Hartwell TD, Robertson TL, Braunwald E, the MILIS Study Group: Implications for acute intervention related to time of hospital arrival in acute myocardial infarction. Am J Cardiol 1986;58:203-209 19. Herlitz J, Hartford M, Blohm M, Karlson BW, Ekstrom L, Risenfors M, Wennerblom B, Luepker R, Holmberg S: Effect of a media campaign on delay times and ambulance use in suspected acute myocardial infarction. Am J Cardiol 1989; 64:90-93 20. Sharkey SW, Brunette DD, Ruiz E, Hession WT, Wysham DG, Goldenberg IF, Hodges M: An analysis of time delays preceding thrombolysis for acute myocardial infarction. JAMA 1989;262:3171-3174 21. Lew AS, Hanoch HOD, Cercek B, Shah PK, Ganz W: Mortality and morbidity rates of patients older and younger than 75 years with acute myocardial infarction treated with intravenous streptokinase. Am J Cardiol 1987;59:1-5 22. Chaitman BR, Knatterud GL, Stump D, Hamilton WP, Hillis LD, Dwyer JG, Solomon RE, the TIMI Investigators: Thrombolytic therapy for acute myocardial infarction in the elderly (abstract). Circulation 1988;78(suppl II):II-211 23. Althouse R, Maynard C, Olsufka M, Kennedy JW: Incidence of contraindications to thrombolysis in patients with myocardial infarction (abstract). Circulation 1988;78(suppl II):II-211 24. Califf RM, Topol EJ, Kereiakes DJ, Abbottsmith CW, George BS, Candela RJ, Aronson LG, Bauman RP, Ellis SG: Cardiac resuscitation should not be a contraindication to thrombolytic therapy for myocardial infarction (abstract). Circulation 1988;
78(suppl II):II-127 25. Laffel GL, Fineberg H, Braunwald E: A cost-effectiveness model for coronary thrombolysis/reperfusion therapy. J Am Coll Cardiol 1987;10:79B-90B
(Circulation 1990;82:1510-1513)
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Optimizing thrombolytic therapy of acute myocardial infarction. E Braunwald Circulation. 1990;82:1510-1513 doi: 10.1161/01.CIR.82.4.1510 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1990 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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