Thrombolytic therapy

GENERAL CLINICAL ISSUES

acute myocardial infarction; thrombotytic theropy

ThrombolyticTherapy I

FFom the

Unive~'sity of Washington, Seattle;* U~iversity of Massachusetts, Worcester;~ University Antwerp, Belgium; ,~Washington University, St Louis, Missouri9 and the University of Vi~nia, Richmond#

Mickey S Eisenberg, MD, PhD* Richard V Aghababian,MD~ Leo Bossaert, MD, PhD* Allan S Jaffe, MD§ Joseph P Ornate, MD" W DouglasWeaver, MD*

All patients with symptoms and ECGfindings suggestive of acute myocardial infarction (AMI) should be considered for treatment with thrombolytic agents. The decision to use thrombolytic therapy is a clinical judgment based upon a weighing of the potential benefits versus the possible risks. The physician must take into account relative contraindications, age of the patient, area of jeopardized myocardium, and duration of symptoms. Health professionals involved in the care of AMI patients should develop written plans and protocols addressing the following matters: identification of patients with chest pain in the prehospital setting (this applies to hospitals that receive patients from emergency medical services systems), triage of patients in the emergency department, obtaining the 12qead electrocardiogram, determination of contraindications, authority for ordering thrombolytic therapy, and consultation for atypical cases. There also should be agreed standards for the time interval from arrival in the ED to administration of the thrombolytic agent, as well as a commitment to the prospective monitoring of procedures and times to assure continuous improvement. A time interval for treatment (arrival in ED to administration of drug) of 30 to 60 minutes should be achievable for patients who present with typical symptoms and ECGfindings. [Eisenberg MS, Aghababian RV, Bossaert L, Jaffe AS, 0rnato JP, Weaver WD: Thrombolytic therapy. Ann EmergMed February 1993;22 (pt 2):417-427.] OVERVIEW OF ISSUES All patients with symptoms and ECG findings suggestive of acute myocardial infarction (AMI)should be considered for treatment with thrombolytic agents, s The early administration of such agents has been shown to reduce morbidity and mortality in patients with typical findings of AMI. 2-so Maximum benefit requires administration of treatment as soon as possible after the onset of symptoms. >1o While the benefit of thrombolysis in cer-

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rain types of AMI is unequivocal, many unresolved and partially resolved issues remain. These issues involve defining the best criteria for selection of patients, how to achieve rapid initiation of therapy, the agents of choice, appropriate adjunctive treatments, and how best to consolidate treatment. The decision to use thrombolytic therapy is a clinical judgment based upon a weighing oJ the potential benefits versus the possible risks. The physician must take into account relative contraindications, age of the patient, area of jeopardized myocardium, and duration of symptoms. Following are general, diagnostic, therapeutic, and patient decision considerations associated with the use of thrombolytic agerits. General considerations include: Rapid diagnosis and initiation of therapy and an example of a model protocol. Diagnostic considerations include: How should the diagnosis of AMI be made? Who should identify patients and order treatment? Where should the diagnosis be made? How can delays to diagnosis be minimized? What defines the onset of AMI? Therapeutic considerations include: Who should and should not receive thrombolytic therapy? ~s there an age limit for thrombolytic therapy? When is the best time to initiate therapy? Where should treatment begin? Which thrombolytic agent should be used? What adjuncts to thrombolytic therapy should be used? Does thrombolytic therapy interfere with emergent coronary angioplasty? Is thrombolytic therapy preferred over direct coronary angioplasty? How should thrombolytic therapy be monitored? How should complications of thrombolytic therapy be managed? How can delays to therapy be minimized? Patient decision considerations include: How can the public seek help sooner for symptoms of AMI? Should patients use the emergency medical services (EMS) system or self-transport to hospital? General Considerations

Rapid Diagnosis and Initiation of Therapy Because the rapid initiation of treatment is essential to achieve optimal benefit, quick identification of candidates for treatment and rapid initiation of therapy is crucial. The best means to facilitate this is for health professionals involved in the care of AMI patients to prospectively develop written plans and protocols. 11,~2 Each locale should have its own protocol integrating the considerations of emergency physicians, cardiologists, internists, pharmacists, and nurses. If the hospital receives patients from a prehospitaI EMS program, the program should also be involved, Prospective planning should address the following matters: identification of patients with chest pain in the prehospital setting (this applies to hospitals that receive

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patients from EMS systems), triage of patients in the emergency department, obtaining the 12-lead electrocardiogram, determination of contraindications, authority for ordering thrombolytic therapy, and consultation for atypical cases. There should also be agreed standards for the time interval from arrival in the ED to administration of the thrombolytic agent, as well as a commitment to the prospective monitoring of procedures and times to assure continuous improvement. 13 Recent research has indicated that the median time to delivery of thrombolytic therapy, once the patient reaches the ED, is 90 minutes in the United States. 14-16 It is believed that, through comprehensive educational programs and collaborative prospective plans, a time to treatment of 30 to 60 minutes should be achievable for patients who present with typical symptoms and ECG findings. Model Protocol The following protocol is offered as an example of the ingredients that should be included in a hospital's thrombolytic therapy protocol. This is only an example, and each institution will have to develop its own protocol based on local resources, EMS responsibilities, and working relationships of health providers. The following protocol is for a hospital that receives patients from EMS systems and has supervisory responsibilities for medical control of EMS activities. EXAMPLE OF A MODEL PROTOCOL This protocol is intended to ensure the rapid ident~ication of patients with AMI, determination of eligibility for thrombolytic therapy, and administration of therapy. The following services, in conjunction with EM5 services, collaborated in the development of this protocol: emergency medicine, cardiology, nursing, and pharmacy. EMS RESPONSIBILITIE5: Paramedics will routinely obtain the following information for patients complaining of chest pain: Pain of probable cardiac origin? Pain persistent for 15 minutes or more? Age >30? Blood pressure: systolic <180, diastolic <11 O? Lack of cerebrovascular accident (CVA) or other serious central nervous system problem in the past six months? Lack of major surgery or trauma in the past two weeks? Lack of bleeding problems? Lack .of pregnancy? If yes is answered to all the above questions, a 12-lead ECG should be obtained and transmitted to the ED. If direct communication is not available, use radio or telephone and

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verbally report the ECG interpretation. If an ECG cannot be obtained, transport the patient immediately to the ED. TRIAGE IN THE ED: The Triage Nurse will determine the presence of chest pain. All patients with chest pain should immediately be taken by wheelchair to an intensive care stretcher. Verbal permission for care must be obtained by the Triage Nurse, with ED registration deferred to a relative or obtained at a later time, @er initiation of treatment. ED NURSING: Oxygen should be administered at 4 L/min flow. ECG monitor electrodes should be placed, and a 12lead ECG should be obtained without delay. The ECG should be interpreted by the responsible ED physician as soon as possible, as this currently is the most important diagnostic test in determining the need and type of treatment to be given. An IV line with D5W should be started concurrently with the 12-lead ECG. I.[ thrombolytic therapy is indicated, a second peripheral IV line should be placed. Blood samples can be drawn for determination of hematocrit and other baseline laboratory tests, including cardiac enzymes. Arterial puncture should be avoided when thrombolytic agents are anticipated. Monitoring of oxygen saturation with pulse oximett~y is preferred. If thrombolytic agents are administered, a repeat 12-lead ECG should be obtained at one and three hours @er treatment (more may be requested by the physician) in an effort to identify a subset of patients with reperfusion. A portable chest radiograph can be obtained if needed to exclude any contraindication (eg, aortic dissection) to the use of thrombolytic agents or in cases in which the diagnosis is uncertain. Otherwise, the radiograph should be obtained @er the initiation of treatment with thrombolytic agents. All patients with an AMI should be admitted to a critical care unit (CCU) or intensive care unit. ED PHYSICIAN: The ED physician is responsible for reviewing, as soon as possible @er arrival, the patient's history, physical findings, and ECG to determine eligibility for thrombolytic therapy and for rapid initiation of treatment, The ED physician may consult with other physicians who are on call for situations in which the indications or contraindications to thrombolysis are questionable or to interpret an ECG, if required, Either on-site help or a facsimile transmission of the ECG may serve this purpose. The emergency physician should consider the following in deciding whether to order thrombolytic therapy: likelihood of benefit (age, type, and location of ECG changes; duration of symptoms; contraindications), likelihood of risk (especially serious bleeding), history of prior infarction and or treatment with thrombolytics, evidence of pulmonary congestion, hypotension, or tachycardia.

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CONSULTANTS: A physician with expertise in the management of patients with AMI should be available to consult with the ED physician at any time of the day or night. PHARMACY." Thrombolytic agents should be available for immediate use in the ED. TIME GOALS: These protocols are intended to ensure the delivery of thrombolytic therapy to the majority of indicated patients no longer than 60 minutes @er either arrival in the ED or identification by the prehospital care provider. Ideally, time from arrival into the ED to administration of thrombolytic therapy should be 30 minutes or lessfor typical AMI patients. CONTINUOUS QUALITY IMPROVEMENT: Relevant information on all patients with AMI will be reviewed regularly in order to identify ways to improve the protocol. The overriding goal is to ensure better diagnosis and treatment of patients with AMI. Impediments to rapid diagnosis and therapy should be identified, and solutions should be implemented. Diagnostic Considerations How should the diagnosis of AMI be made? At present, the diagnosis of AMI is a clinical diagnosis based on the patient's signs and symptoms and appropriate ECG findings. The likelihood of AMI for any given history and physical examination increases with the presence of risk factors. Ventricular ectopy, sinus tachycardia, bradycardia, accelerated idioventricular rhythm, congestive heart failure, or presence of an S3 may be present but are not diagnostic of AMI. 17 While AMI and angina usually are associated with chest discomfort, both entities may be heralded by other signs and symptoms. In some cases, the associated signs and symptoms may be of greater concern to the patient than the chest discomfort. In general, chest discomfort is the most common symptom causing patients to seek medical care; however, other pain in other locations (such as the upper abdomen) may be the presenting symptom. Other symptoms such as hypotension, weakness, or confusion may be especially relevant in patients with extensive infarction and in diabetic and elderly patients. The acute chest discomfort associated with cocaine use may be due to noncardiac or cardiac causes (either due to transient ischemia caused by coronary spasm or due to infarction); ECG changes may be present. 17 When chest discomfort is present, differentiating unstable angina from AMI often can be done only retrospectively There is no evidence that thrombolytic treatment is of benefit to patients with unstable angina. It currently is not possible to use noninvasive means to distinguish angina

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from AMI objectively at the bedside of a patient with acute chest pain. However, most patients with unstable angina or non-Q wave AMI do not have ST segment elevation. Thus, in general, those who may benefit from thrombolytic agents can be distinguished by the ECG changes of ST elevation. ECG changes of ST elevation (>1 mm in two contiguous V leads or 1 mm in two limb reads) strongly suggest AMI and also define patients apt to benefit from thrombolytic agents. However, ST elevation is neither 100% sensitive nor 100% specific. Chest pain and ECG changes that persist despite nitroglycerin usually define the group most apt to benefit from thrombolytic agents. Patients presenting with possible ischemic heart-related pain should receive nitrates (subfingual, oraI spray, paste, or IV nitroglycerin). If ST elevation is present, and if the nitroglycerin leads to normalization of the ECG, thrombolytic therapy is not indicated (assuming the ECG remains normal). In more than 50% of AMIs, nondiagnostic ECG changes are present, and sequential ECG changes or cardiac enzyme measurements are required for diagnosis of AMI. ~S Patients with left bundle-branch heart block and typical signs and symptoms of infarction also may benefit from treatment with thrombolytic agents. 3 Serial ECGs are often useful in demonstrating dynamic changes or clarifying the clinical situation, and ECGs should be repeated 15 minutes after the original ECG if changes are equivocal or if ongoing ischemic pain is present. Laboratory evidence for the presence of AMI requires elevation of cardiac enzymes. The identification of the MB isoenzyme of creatine kinase (CK-MB) is the most widely used laboratory test for the diagnosis of AMI. 19-2~ As little as 1 to 2 grams of necrotic myocardium can be recognized with this laboratory test. However, triage based on a single CK-MB measurement is not sufficiently sensitive to recommend as a primary means of identifying patients who should receive thrombolytic therapy. Currently, these tests are not available in a timely fashion in most hospitals to be useful in determining initial treatment. Recent studies using isoform analyses of CK, myoglobin, troponin-t, and/or myosin light chains suggest possible improvement in rapid diagnosis; however, these studies are still investigational. 22-27 In general, although the sensitivity of these isoform analyses appears high, the specificity is only adequate, and the analytic techniques are not ready for widespread implementation. Immunochemical CK-MB methods have, in some studies, provided information on patients with chest pain who have nondiagnostic ECGs. However, the triage of patients with

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chest pain should be based more on the pattern of chest pain and hemodynamic stability than on laboratory tests. In the future, CK-MB isoforms or immunochemical techniques may play an important role in hospitals with ED holding areaswhere patients can be observed for a period and additional diagnostic information is collected. Such strategies can be used rationally to discharge or admit patients to CCU beds or arrange for additional diagnostic studies.2L 27 While the precise role of rapid immunochemical tests for AMI currently is being defined, there is general agreement that prolonged stays in the ED for patients with unstable angina or AMI should be discouraged if CCU beds are available. Echocardiography has been advocated for the diagnosis of AMI. Sensitivities as high as 90% have been reported in some studies. 2s However, echocardiography takes time, requires expertise for adequate acquisition and interpretation, and thus is useful in only a limited number of patients. Finally, the sensitivity and specificity also will vary substantially depending on the presence or absence of other preexisting cardiac abnormalities. Accordingly, the routine use of echocardiography to evaluate unselected patients with chest discomfort cannot be recommended. Nuclear magnetic resonance imaging, cine-computed tomography, and radionuclide imaging with coronary angiography are other useful techniques in documenting AMI, though none are or should be used routinely to evaluate patients presenting with possible AMI. While all of the above tests and findings may be useful in the eventual diagnosis of AMI, the major problem faced by the physician considering thrombolytic therapy is to identify rapidly those patients who should be treated with thrombolytic agents. In this situation, the major tools are the history, physical findings, and ECG. Echocardtography, angiography, and other diagnostic aids may be of benefit for occasional patients when the presentation is atypical or the findings are equivocal. Computer interpretation has the potential to aid the nonexpert electrocardiographer in selecting appropriate patients with probable AMI. To date, few studies have been done to determine the accuracy of various algorithms, and no standards of performance exist. However, one recent study showed that computer specificity was superior to either the electrocardiographer or emergency physician. ~s At present, although compute> interpreted systems are aids to interpretation, the ultimate responsibility for assessment of the ECG resides with the physician. Who should identify patients and order treatment? Because time from symptom onset to initiation of treat-

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ment is critical, the first physician to assume responsibility for patients with typical findings should make the diagnosis and initiate treatment with thrombolytic therapy when indicated. For a majority of patients, this will be the ED physician. In many European and Israeli communities, this may be the ambulance physician. If the first physician to have contact with the patient is not experienced in evaluating the eligibility for thrombolysis, consultation with someone more responsible for such evaluation should be obtained. It is essential that emergency physicians, cardiologists/internists, and other physicians involved in managing AMI patients develop written protocols that address the steps to be followed while identifying, stabilizing, and treating patients with AMI. The protocol should provide the treating physician with continuous access, when needed, to consultants with experience in the management of patients with atypical presentations of AMI, complicating medical problems, or potential contraindications to the use of thrombolytic therapy Where should the diagnosis be made? In the prehospital setting, ECGs obtained by paramedics and transmitted by phone line or by cellular phone to the emergency physician have been shown to reduce the time to treatment. 29 Given the accuracy of computer-interpreted ECGs, an approach (providing the EMS system assumes this responsibility) might be for paramedics to obtain a 12-lead ECG on all patients with chest pain and to relay verbally the computer-interpreted information to the basestation physician. This could be through usual modes of communications such as radio or telephone. The ECG simply may be used to prepare the ED to receive the patient and thus shorten the time to treatment, or, in some communities, the physician can order thrombolytic therapy to be administered directly at the scene, lo,3o-32 At present, the efficacy and cost-effectiveness of this latter approach have not been proved. Depending on the local community and its protocols, the physician can order thrombolytic therapy to be administered directly at the scene or may choose to wait for the patient's arrival in the ED. Should the strategy of prehospital diagnosis of AMI using 12-lead ECGs become routine? EMS systems will have to consider the time it takes to perform and transmit an ECG and whether this procedure will shorten the overall time to diagnosis and treatment of AMI. If it is determined that time can be shortened, the EMS system should consider whether the cost of such equipment is justified, given alternate demands for funds. For example, should an EMS system invest in 12-lead ECG machines or auto-

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matic external defibrillators for its first-responding units? Each EMS system, in conjunction with the medical director, must make this cost-effective determination for itself. The relative value of prehospital 12-lead ECGs will become more evident in the next few years. How can delays to diagnosis be minimized? The best means to minimize delays in the diagnosis of AMI is to have all EMS providers, ED staff, and primary care providers initially approach chest pain patients as medical emergencies. Prehospital protocols should be in place to ensure the expeditious management of patients with symptoms and findings consistent with AMI. Upon arrival in the ED, the patient with chest pain should be immediately triaged to an intensive care-type bed or stretcher; there should be no delays for registration. An ECG should be obtained immediately, concurrent with administration of oxygen and initiation of IV line access, while the patient's history and identification are obtained. The ECG machine should be available in the ED, and a nurse or physician should obtain the patient's ECG, unless an ECG technician is immediately at hand. The ECG must be reviewed immediately by a physician qualified to interpret ECGs. A physician should take the pertinent history from the patient. For patients with typical signs and symptoms, ED personnel should strive to achieve the goal of initiating thrombolytic therapy within 30 minutes of the patient's arrival. The goal for patients with atypical presentations should be treatment within 60 minutes. In some cases, these goals may not be achieved because of the need to verify data about the patient's medical history, prior ECGs, or current health status. The thrombolytic agent used in a particular institution should be available immediately in the ED; only in unusual circumstances should it have to be obtained from the pharmacy. There should be no delays resulting from obtaining chest radiographs or laboratory tests or requesting technical staff to obtain the ECG. What defines the onset of AMI? Because time is a critical variable in the decision whether to administer thrombolytic therapy, it is important that the physician be able to anchor in time the onset of symptoms associated with AMI. This is difficult in some instances, because the symptoms may not begin abruptly or severely A majority of patients present with prodromal symptoms that may be vagu e and difficult to characterize, such as not feeling well, vague discomfort, or epigastric or chest ache that may occur hours or even days preceding the acute event. In general, it is possible to mark the onset of the acute event. However, it is important that physicians realize that

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prodromal symptoms of subacute coronary occlusion often must be distinguished from the symptoms of total and persistent occlusion. In this situation, it is suggested that one estimate the time of onset as the time that the symptoms leading the patient to seek medical care began. For patients in whom it is uncertain how long symptoms have been present but in whom all other findings are otherwise typical, the weight of the decision should be on initiating treatment (in the absence of contraindications), especially in patients with anterior MI or complications of infarction.

Therapeutic Considerations Who should and should not receive thrombolytic therapy? Patients with symptoms of AMI who present in an appropriate period of time (generally within six hours of onset of acute symptoms) and have ST segment elevation or new left bundle-branch heart block on the ECG are felt to be the most appropriate candidates for thrombolytic therapy. Patients with ST segment depression have yet to be shown to benefit from thrombolytic therapy. The risk/benefit ratio of thrombolysis is unclear in patients who are treated later than six hours after the onset of chest pain. Patients whose ECGs are normal upon presentation do not benefit from thrombolytic therapy.2, 3 What are the contraindications to thrombolytic therapy? No set of contraindications can adequately anticipate every clinical circumstance. Thus, there may be exceptions to the following, It is generally accepted, however, that the absolute contraindications to the use of thrombolytic therapy are as follows: 1) active internal bleeding; 2) suspected aortic dissection; 3) prolonged (more than 5 to 10 minUtes) and/or traumatic CPR, particularly if endotracheal intubation has been performed; 4) recent head trauma or known intracranial neoplasm; 5) pregnancy; 6) severe persistent hypertension (>180 mm Hg systolic or >110 mm Hg diastolic) not readily responsive to pain relief or initial pharmacologic measures; 7) history of CVA in the past six months; 8) severe trauma or major surgery within the past two weeks. Relative contraindications should be considered on a case-by-case basis. In general, the following should mandate caution in the administration of thrombolytic therapy: 1) recent trauma or major surgery in the past two months;

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2) an initial blood pressure >180 mm Hg systolic or >110 mm Hg diastolic that is controlled by medical treatment; 3) active peptic ulcer or guaiac-positive stools; 4) history of CVA, tumor, injury, or brain surgery; 5) known bleeding disorder or current use of warfarin; 6) significant liver dysfunction or renal failure; 7) prior exposure to streptokinase or anistreplase during the preceding 12 months (for use of either of these agents only); 8) known cancer or other systemic illness in which thoracic, abdominal, or intracranial abnormalities are possible; or 9) brief (less than 5 to 10 minutes) CPR. To date, there is no evidence that thrombolytic therapy is beneficial in unselected patients with AMI accompanied by ST depression or in patients with unstable angina. The use of thrombolytic therapy in AMI associated with severe congestive heart failure or cardiogenic shock has not been shown to improve survival, although this issue has not been specifically studied. In facilities with catheterization laboratories, it is reasonable to obtain angiographic data (assuming the study can be done in a timely fashion) before deciding on therapy. Patients in cardiogenic shock should be managed at hospitals with catheterization capability. Is there an age limit for thrombolytic therapy? There is evidence that thrombolytic therapy can be beneficial in all age groups and, in some studies, especially in the elderly.3,33, 34 There is also an increased risk of complications in the elderly, particularly of intracranial bleeding. In general, most trials have enrolled patients less than 70 to 75 years of age. However, there is no absolute age limit by which patients should be excluded. For elderly patients with AMI, the administration of thrombolytic therapy should be considered on individual factors, including the potential benefit versus the risk. When is the best time to initiate thrombolytic therapy? The simple answer is the sooner the better. The majority of studies have demonstrated benefit from thrombolytic therapy administered up to six hours after the onset of symptoms. There is also a consensus that selected patients with recurrent episodes of ischemic chest discomfort (ie, stuttering infarction) may benefit) The results of studies to date do not support the routine use of thrombolytic drugs for patients with symptoms suggestive of complete thrombosis for six hours or longer. There is evidence that the risk of myocardial rupture may be increased in patients who are treated late after onset of chest pain. In general, the presence of ongoing pain and

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persistent ST segment elevation strengthens the decision to administer thrombolytic therapy in patients who present to the hospital late in the course of myocardial infarction. Where should treatment begin? No one questions the administration of thrombolytic therapy in the hospital; the question is whether thrombolytic therapy in the prehospital setting saves sufficient time to justify the extra risk of misdiagnosis. Studies currently under way in Seattle, King County, Washington (the MITI Trial) and Europe (EMIP Trial) are prospective, randomized, intervention trials designed specifically to answer this question.31, 32 For areas with sophisticated EMS systems, the early diagnosis by paramedics with computer.assisted ECG equipment facilitates treatment, but the cost-to-benefit ratio must be weighed against other needs in the EMS system (for example, communities without early defibrillation programs may consider purchase of automated external defibrillators a higher priority). At this time, data recommending the administration of thrombolytic therapy in the prehospital setting are insufficient, although several studies have shown that sophisticated EMS systems can identify appropriate patients with the help of ECGs and remote direction by a physician. Many communities in Europe and Israeb o utilize physicians on EMS ambulances; the use of thrombolytic agents in the prehospital setting is more widespread than in the United States, where EMS ambulances are staffed with paramedics and not physicians. Which thrombolytic agent should be used? Three thrombolytic agents are currently available for clinical use in the United States: streptokinase, anistreplase (APSAC), and alteplase (tPA) (Table). The agents appear to have equal efficacy, with some differences in, ease of administration, price, and antigenicity. Alteplase, unlike the other agents, is relatively fibrin-specific and causes less perturbation in circulating coagulation factors. It induces patency earlier than less fibrin-specific agents. To date, this specificity has not been shown to lower the risk of serious bleeding. Two large comparative trials of streptokinase and a standard three- to four-hour infusion of tPA have demonstrated no difference in overall effectiveness of the agents or in the reduction of mortality from transmural AMI. These trials either indicate the lack of primacy of early coronary patency as a determinant of benefit or may reflect the need to utilize adjunctive treatments (not done in the trials cited) to achieve previous documented increments in patency. Alternative infusion rates and combinations of these drugs are undergoing testing; however, both the benefit and risk of such treatment strategies are largely

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unknown to date. 33-39 What adjuncts to thrombolytic therapy should be used? ASPIRIN: The ISIS II trial showed that the combination of aspirin and streptokinase produced a greater reduction in mortality than did streptokinase or aspirin alone. 2 No such evaluation has been made for either anistreplase or tPA; however, it is widely held that aspirin is likely to have similar benefit. Aspirin, unless specifically contraindicated, should be given to all patients with AMI. HEPARIN: IV heparin is used commonly in the United States. It is essential for the maintenance of coronary patency with tPA) 9,4° Several studies support the concept that inadequate inhibition of clotting predicts the failure of treatment with all activators. Heparin also facilitates the rapidity of coronary recanalization with all activators. Subcutaneous heparin does not provide adequate levels of anticoagulation in a substantial number of patients. The effect of IV heparin, both in terms of saving lives and reducing bleeding complications, has yet to be defined. BETA BLOCKERS: IV beta blockers, if given very early, also have been shown to lower the risk of early re-infarction in low-risk patients. 41-~3 In one study, they also appeared to be associated with a lower risk of intracranial bleeding; this was not confirmed in another) 4

Table.

Comparison of thromboZyticagents Anistreplase (APSAC)*

Pro-urokinase (SCU-PA)*

Streptokinase

AIteplase (tPA)t

Plasma 90-120 min halflife of circulating fibrinolytic activity

15-20 min

5 min as bolus or 35 min as infusion

15-20rain

7 min as bolus or 35 rain as infusion

Standard doses

30 U bolus bolusdose over 5 rain 1.5 million

units over1 hr

100 mg over 3 million 3 hr unit bolus

60-80 mg over60-90 rain

Systemic lyric state

4-I-+

+'t"4"

+

4-+

Advantages proven

+++

proven effective, value, clot- nonantigenic selective, nonantigenic bower initial antigenicity, expensive, expensive patency, lower initial inconvenient antigenicity, patency, regimen expensive hypoteosion value, longacting

Disadvantages

Urokinase

proven value, inexpensive

clot selective, oenantigenic

investigational

*APSAC = anisoylated plasminogen-streptokinase activator complex. ttPA = tissue plasminogan activator. *SCU-PA = single-chain urokinase plasminogen activator.

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NITROGLYCERIN: It is reasonable to administer nitroglycerin immediately (by sublingual tablet, spray, or paste) to all patients in which angina or AMI is a possibility. Occasionally, patients who present with acute ST elevations on the ECG will respond promptly to nitroglycerin with normalization of the ECG and disapperance of pain. If the ECG remains normal, such patients probably should not receive thrombolytic therapy. CALCIUM CHANNEL BLOCKERS: Dihydropyridine calcium blockers have been shown to be detrimental in patients with AMI. There are inadequate data concerning the risks and/or benefits of the other calcium channel blockers for AMI.

Does thrombolytic therapy interfere with emergent coronary angioplasty? In those cases in which coronary patency has been restored by thrombolytic therapy, routine emergent angioplasty should not be performed to increase flow further, as such an approach has been shown to be of no benefit and increases the risk of complications from the procedure. 4x-45 The value of emergent angioplasty to restore patency in those in whom thrombolysis has failed has yet to be determined, but there is evidence that it may be beneficial in selected patients.46-4s The use of thrombolytic therapy increases the risk of bleeding, but it is not a contraindication to emergent angioplasty in those patients with symptoms of recurrent occlusion or ischemia. Will excessive bleeding occur in such situations? To date, there is no firm evidence that thrombolytic therapy increases serious bleeding risks associated with emergent angioplasty in patients with ongoing ischemia. In most instances, the incidence of bleeding, though greater, is easily controlled.

Is thrombolytic therapy preferred over direct coronary angioplasty? As yet, there is no large, published, direct comparison between the use of thrombolytic therapy and direct angioplasty for AMI. Passions and emotions justifying each strategy run high. There is consensus, however, that time is of the essence and that substantial delay, if associated with one approach versus the approach that can be initiated expeditiously, is to be avoided. .9 Of course, the option to perform emergent angioplasty is limited to select hospitals. We believe the decision ~whether routinely to use thrombolytic therapy or angioplasty" in those hospitals capable of performing emergent angioplasty should be a decision jointly made by cardiologists, emergency physicians, and staff physicians. Direct angioplasty should be considered a means for reperfusion in patients who have contraindications to thrombolytic drugs. There is a general consensus (based on case series data and historical controls) that patients who are hemo-

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dynamically compromised upon presentation (severe heart failure or shock) benefit from emergent angiography and mechanical reperfusion, if it can be done expeditiously. The use of thrombolytics in cardiogenic shock has not been definitively studied.

How should thrombolytic therapy be monitored? Patients receiving thrombolytic therapy should receive ECG monitoring. In addition, urine and stool should be tested for occult blood, and neurologic checks should be performed frequently. Usually, the first sign of an intracranial hemorrhage is a change in neu,rologic status. Any change in neurologic status should be evaluated with a thorough neurologic examination and a computed tomography scan. Noninvasive means (ECG and enzymes) to indicate reperfusion are under current investigation. 5o-54 Currently, there is no noninvasive means to accurately identify successful reperfhsion following treatment.

How should complications of thrombolytic therapy be managed? The most serious complications are bleeding, particularly intracerebral hemorrhage, or arrhythmias. When bleeding complications occur, the thrombolytic agent should be stopped if it is currendy being administered, tteparin also should be stopped. (Typically, complications are recognized 6 to 24 hours after the administration of thrombolytic therapy.) Fresh whole blood should be obtained for replacement if indicated. Occasionally, to reverse the effects of lyric therapy, cryoprecipitate, platelets, and ~-aminocaproic acid (Amicar) are required. The optimal replacement therapy has yet to be determined. Thus, any or all of these approaches may be justified, though in most instances of serious bleeding (except intracranial bleeding), blood transfusion is sufficient. Arrhythmias are treated in the usual fashion; no unique management of arrhythmias is associated with the use of thrombolytic therapy. Few data exist to support the use of prophylactic lidocaine in patients receiving thrombolytic agents, but it is commonly employed. No added risk for the occurrence of ventricular fibrillation has been observed following treatment. On the contrary, the risk of cardiac arrest is lower. How can delays to therapy be minimized? Rapid therapy requires rapid diagnosis, which is addressed separately. Once the diagnosis is made, all impediments to initiation of therapy should be removed. The patient must be informed of the therapeutic options, and an informed consent must be obtained. The agent should be immediately available for use, and the patient should be adequately prepared (such as starting a second IV line and ensuring adequate monitoring). Perhaps the best means to

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ensure rapid therapy is to prospectively review the cases in which thrombolytic therapy is used and to initiate a system of continuous quality improvement. This entails documentation of time intervals from arrival in the ED to delivery of drug, as well as all complications. There must be a willingness to ask "How can we improve the safety and speed in which thrombolytics are used?" Patient Decision Consideration How can the public seek help sooner for symptoms of AMI? Perhaps the largest component in the interval from onset of symptoms to delivery of thrombolytic therapy is the component of patient decision time. Studies have demonstrated this decision time to be a median of two hours. A host of factors contributes to the delay55-59; these range from denial of symptoms to fear to misperception of the signs and symptoms. Health education programs in Sweden have shown how increased public awareness can shorten the time from onset of symptoms to arrival in EDs. 59 However, the study also demonstrated an increase in the number of patients with chest pain of noncardiac origin coming to the hospital. Some health educators recommend that bystanders, friends, and relatives of the person with chest pain should be educated concerning the signs and symptoms of AMI in order to activate the EMS system or convince the person to seek medical care promptly. In addition, it is clear that response times are shorter when patients are in the company of family and friends. By urging the person with chest pain to "tell someone" of his or her symptoms, the bystander can assume responsibility for deciding to activate the EMS system. At this time, no data convincingly demonstrate a strategy for increasing public awareness and thereby shortening time from onset of symptoms to hospital-seeking behavior. Until such studies are performed, it seems reasonable and prudent to increase public awareness about the benefit of thrombolytic therapy for AMI in order to increase knowledge of the signs and symptoms of ischemia. Stressing the importance of seeking help early is important, as is the fact that effective new medications and therapies are available. The public should be educated to use the local EMS system for symptoms of chest pain rather than attempt to reach a primary care provider. The National Heart Attack Alert Program of the National Heart, Lung, and Blood Institute is a nationwide effort designed to encourage the public to seek care fast and to use the EMS system for chest pain symptoms. A study currently under way in King County. Washington (the Call Fast, Call 911 study) is a prospective, randomized community intervention to determine if public health messages are effective in shortening the time to seek medi-

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cal care and increasing the percentage of patients using the 911 system for chest pain symptoms. 6o Should patients use the EMS system for transport to hospital? The issue involved in self-transport versus the EMS system deals with a possible delay in waiting for EMS system transport versus the risk of transport by relatives, friends, or bystanders. Transport by the EMS system usually can ensure a rapid diagnosis of AMI, oxygen therapy, pain relief, ECG monitoring, and most importantly, the management of life-threatening arrhythmias such as ventricular fibrillation. Patients who choose non-EMS transport obviously have none of these benefits, and there are data indicating that it takes them longer to arrive at the hospitai. On the other hand, if the time to EMS transport is excessively long (eg, as in some rural communities), or if the patient is extremely close to a hospital, it may be prudent to consider transportation by automobile. It is difficult to measure the risks/benefits associated with each type of transport. Certainly, there is stress associated with getting into a car and driving through traffic, even if a relative or friend is the driver. Conversely, there is probably stress associated with hearing sirens an d having to wait for help to arrive. Patients should never drive themselves to the hospital unless no other means of transport is readily available. In general, we believe that the EMS system should be used by patients for symptoms of AMI. An education campaign to explain why EMS is important for the management of AMI may be beneficial. If, however, there is a delay of more than 15 minutes for arrival of EMS personnel, we believe that transport by a friend, relative, or bystander is a reasonable alternative. RESEARCH INITIATIVES

Additional research in each of the above issues will clarify matters. Research in thrombolytic therapy is Occurring on a massive scale, and new developments are occurring regularly. Perhaps the most difficult areas tO research are public education and the reasons people delay before seeking medical care. A better understanding of how and why people seek care following symptoms of AMI potentially can do much to shorten the time interval to receiving thrombolytic therapy. REFERENCES 1. ACC/AHATask Force: Guidelines for the early management of patients with acute myocardial infarction. J Am Celt Carflio11990;16:249-292. 2. Gruppo Itaiiano per Io Studio derla Streptochinasi Nell-lnfarto Miocardica {GISSI): Effectiveness of intravenousthrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397-402.

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36. White HD, Rivers JT, Maslowski AH, et al: Effect of intravenous streptokinase as compared wit~t nf tissue plasminogen activator on ]eft ventricdar function after first myocardial infarction. N Engl J Mad 1989;320:817-821. 36. Sleight P: Survival following thromboJytic therapy. EurHeartJ1990; II(suppl):l-4. 37. Neuhaus KL, Eeuerer W, Jeep-Tebbe S, et ah Improved thrombolysis with a modified dose regimen of recombinant tissue-type plasminogen activator. JAm Ceil Cardio11989;14:1566-1569. 38. Califf R, Topoi EJ, George BS, et al: Hemorrhagic complications associated with the use of intravenous tissue plasminogen activator in treatment ef acute myocardial infarction. Am J Med t 988;85:353-359.

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18. Kudenchuck PJ, Ha MT, Weaver WD, et ah Accuracy of the computer interpreted electrocardiography in selecting patients for thrombolytic therapy: The myocardial infarction, triage, and intervention trial. JAm Carl Cardio11991;17:1486-1491.

41. Pepine CJ: The importance of timing of thrombolytic therapy as shown in clinical trials. Clio Cardio11990;13 (suppl V111):12-17.

19. Ahumada G, Roberts R. Sobel BE: Evaluation of myocardial infarction with enzymatic indices. Prog CardiovascDis 1976;18:405-420.

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20. Lee TH, Weisberg MC, Cook EF, et ah Evaluation of creatine kinase and creatine kinase - MB for diagnosing myocardial infarction: Clinical impact in the emergency room. Arch Intern Mad 1987;147:115-121.

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44. Topoi EJ, Califf RM., Georges BS, et al: A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminog~ n activa~orin~acute myocardial infarction. N Engl J Mad 1987;317:581-588.

22. Kagen L, Scheidt S, Butt A: Serum myoglnbin in myocardial infarction: The "staccato phenomenon." Is acute myocardial infarction in man an intermittent event? Am J Med 1977;62:86-92.

45. Simoons ML, Arnold AER, Betriu A, et ak Thrombolysis with tissue plasminogen activator in acute myocardial infarction: No additional benefit from immediate percutaneous coronary angioplasty. Lancet 1988;1:197-202.

23. Gibler WB, Lewis LM, Erb RE: Early detection of acute myocardial infarction in patients presenting with chest pain and nondiagnostic EKGs: Serial CK-MB sampling in the emergency d apartment. Ann EmergMad 1990;19:1359-1396.

46. SWIFT (Should We Intervene Following Thrombelysis?) Study Group: SWIFT.trial of delayed elective intervention versus conservative treatment after thrombolysis with anistreplase in acute myocardial infarction. BrMedJ1991;302:555-560.

24. Puleo PR, Guedagno PA, Robert R, et al: Early diagnosis of acute myocardial infarction based an assay for subforms of creatine Idnase-MB. Circulation 1990;82:759-784.

47. Topoi EJ, Fung AY, Kline E, et al: Safety of helicopter transport and out-of-hospital intravenous fibrinolytic therapy in patients with evolving myocardial infarction. Cathet Cardiovasc Dingo 1986;12:151-155.

25. Jaffa AS, Serota H, Grace A, et al: Diagnostic changes in plasma creatine kinase isoforms early after the onset of acute myocardial infarction. Circulation 1986;74:105-109. 26. Katus HA, Yasuda T, Gold HK, et al: Diagnosis of acute myocardial infarction by detection of circulating cardiac myosin light chains. Am J Cardio11984;54:964-970.

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48. Ryan TJ, Faxon DP, Gunner RF, et ah Guidelines for percutaneous transluminal coronary angioplasty: A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee an Percutaneous Translumfnal Coronary Angioplasty). JAm CarlCardio11988;12:529-545.

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49. Rothbaum DA, LinnemeierTJ, Landin RJ, et al: Emergencypercutaneoustransluminal coronaryangieplasty in acute myocardial infarction: A three-year experience. JAm CellCard/el 1987;10:1264-1272. 50. Califf R, O'Neil W, Stack RS, et at: Fairureof simple clinical measurementsto predict perfusion status after intravenous thrombolysis. Ann InternMed1988;62:20-24. 51. Lewis B, GanzW, LarameeP, et al: Usefulnessof a rapid initiar increase in plasma creatine kinase activity as a marker of reperfusion during thrombolytic therapy for acute myocardial infarction. Am J Cordial1988;62:20-24.

57. Dracup K, Moser DK: Treatment-seekingbehavior among those with signs and symptoms of acute myocardial infarction. HeartLung1991;20:570-574. 58. Ho MT, EisenbergMS, Litwin PE, etal: Delay between onset of chest pain and seeking medical care: The effect of public education. Ann EmargMed1989;18:727-731. 59. Herlitz J, Hartford MN, Blohm M, et al: Effect of a media campaign on delay times and ambulance use in suspected acute myocardial infarction. Am J Cardie/1989;84:90-93. 60. National Heart Attack Alert Program: Patient/bystander recognition and action. Bethesda, MD: National Heart, Lung, and Blood Institute, June 1992.

52. Krucoff MW, Wagner NB, PopeJE, et al: The portable programmable microprocessor-driven real-time 12-lead electrocardiographic monitor: A preliminary report of a new device for the noninvasive detection of successful repoffusion or silent coronary reocclusion: Am J Cordial 1990;65:143-148.

Joseph Alpert, MD, Nisha C Chandra, MD, and Hiltrud S Mueller, MD, reviewed the manuscript and offered useful suggestions.

53. Puled PR, Perryman MB: Noninvasive detection of roperfusion in acute myocardial infarction based on plasma activity of creatine kinase-MB subforms. JAm Ceil Cardio/1991;17:1047-1052.

Address for reprints:

54. Abendschein DR, Ellis AK, EisenbergPR, et al: Prompt detection of coronary recanalization by analysis of rates of change ef concentrations of macromolecularmarkers in plasma. Coronary Artery Disease1991;2:201-212. 55. Alonzo A: The impact of the family and lay others on care-seekingduring life-threatening episodes of suspected coronary artery disease. Soc Sci Mad 1986;22:1297-t311.

Mickey Eisenberg, MD, PhB University of Washington Medical Center Emergency Medicine Services, RC-02 Seattle, Washington 98195

56. Wielgosz ATJ, Nolao RP, EarpJA, et al: Reasonsfor patients' delay in responseto symptoms of acute myocardial infarction. CanMedAssecJ 1988;139:853-887.

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