Acute Myocardial Infarction: Clinical Guidelines for Patient Evaluation
Acute Myocardial Infarction: Clinical Guidelines for Patient Evaluation and Mortality Reduction
Authors: David J. Robinson, MD, MS, Research Fellow and Clinical Instructor, Division of Emergency Medicine, University of Maryland Medical Systems, Baltimore, MD.
David A. Jerrard, MD, FACEP, Associate Professor of Surgery Medicine and Clinical Director, Emergency Care Services, Veterans' Affairs Hospital, Baltimore, MD.
Dick C. Kuo, MD, Assistant Professor, Division of Emergency Medicine, University of Maryland Medical Center, Baltimore, MD.
Peer Reviewer: Charles Emerman, MD, Associate Professor of Emergency Medicine, Case Western Reserve University, Cleveland, OH.
Acute myocardial infarction (AMI) is the leading cause of death in the United States and most Western industrialized nations. In 1993, there were more than 1.5 million cases of AMI in the United States, and almost 500,000 associated deaths.1 Forty-six percent of AMIs occurred in those younger than 65 years. AMI most commonly occurs from a sudden thrombotic occlusion at the site of a ruptured or fissured atherosclerotic plaque.2 The coronary artery occlusion leads to characteristic chest pain and impending infarction. Preservation of functional myocardium correlates best with future morbidity and mortality.
Few argue that early identification of AMI, prevention of evolving infarction, and, if possible, restoration of coronary perfusion improve outcomes in patients with AMI. A 1987 study of 205,000 AMIs demonstrated significant improvements in mortality and morbidity with early, aggressive management.3 Clearly, the ED physician must be prepared to recognize indications for emergent, mortality-reducing interventions in patients with AMI. Prompt execution of appropriate treatment strategies will preserve myocardium, reduce complications, and produce significant reductions in mortality and morbidity.
With these clinical issues in clear focus, this issue provides an overview of current diagnostic and therapeutic approaches to AMI. The objective is to provide a systematic approach to patient assessment, to identify the clinical advantages of newer enzymatic tests for confirming the diagnosis of acute coronary ischemia, and to review in detail the mortality reduction techniques-including pharmacotherapeutic and invasive procedures-supported by evidentiary clinical trials. Finally, a clinical algorithm outlining outcome-enhancing strategies for this life-threatening condition is presented.
-The Editor
Overview of Clinical Principles
Diagnostic Criteria. In 1983, the World Health Organization (WHO) outlined the components necessary to establish the definitive diagnosis of acute myocardial infarction (AMI).4,5 This triad consists of chest pain suggestive of cardiac disease, an ECG with characteristic changes suggesting myocardial infarction, and cardiac-specific biochemical markers exceeding the standard reference ranges in a pattern consistent with AMI. Two of the three findings are necessary to diagnose AMI. Presently, this group of findings is considered the "gold standard" for diagnosis.
History. Chest pain is present in 80-85% of patients with AMI and is characteristically ischemic in nature, although a large number of patients report "atypical" chest pain with known ischemic disease. Atypical pain presentations in AMI include pleuritic, sharp, burning, or reproducible chest pain, as well as pain referring to the back, abdomen, neck, or arm. Dyspnea is commonly seen in cardiac chest pain and is a presenting symptom in more than 15% of AMIs. Atypical or nonspecific pain or anginal equivalents such as dyspnea, nausea, vomiting, palpitations, syncope, stroke, or depressed mental status may be the only complaints in those presenting with AMI, especially in the elderly. Atypical presentations for AMI may fail to satisfy the WHO criteria for the diagnosis of AMI. In these patients, a high index of suspicion based on history and cardiac risk factors should be maintained until confirmatory enzyme results are available.
Risk Factors. Significant cardiac risk factors include hypertension, hyperlipidemia, diabetes, smoking, and a strong family history. It is well-known that cocaine use also presents some degree of risk for AMI due to its association with coronary vasospasm. Other minor risk factors may include type A personality, obesity, male sex, and a sedentary lifestyle. However, several studies have failed to confirm some of these factors as independent variables significantly contributing to AMI, except for a prior history of infarction or angina.6,7,8
Physical Examination. Physical examination of the patient with AMI reveals such abnormal signs as a tachy- or bradycardia, other arrhythmias, hyper- or hypotension, and tachypnea. Diaphoresis strongly suggests cardiac chest pain and is considered an independent variable for AMI.7 Up to 60% of patients with AMI present with diaphoresis.9
The Killip classification provides a quantitative assessment of cardiopulmonary function by correlating physical findings with patient outcomes in AMI. It is useful for predicting future morbidity and mortality and may help guide medical management. (See Table 1.)
Inspiratory rales and an S3 gallop are associated with left-sided failure. Jugulovenous distentions (JVD), hepatojugular reflux, and peripheral edema suggest right-sided failure. An S4 denotes decreased left ventricular compliance and possible pump failure. A systolic murmur may indicate ischemic mitral regurgitation or ventricular septal defect (VSD).
Electrocardiogram (ECG). Although the ECG is highly specific for diagnosis of AMI, the initial ECG reveals diagnostic ST elevations in only 40% of patients who eventually have a confirmed AMI. Historically, AMI trials have adopted the following criteria for inclusion in thrombolytic protocols (GISSI).
1. Greater than or equal to 1 mm ST elevation or depression in any limb lead.
2. Greater than or equal to 2 mm ST elevation in any precordial lead.
These criteria provide a specificity of 94% but with sensitivity in the range of 40%.9
The specificity for detecting AMI increases when the following criteria are adopted. (All ECG findings new, or no old tracing available).10
1. Greater than or equal 1 mm ST elevation or abnormal Q waves in greater than or equal to two leads
2. At least 1 mm ST depression in at least two leads
3. Other ST or T wave changes of ischemia or strain including ST depression greater than 1 mm and T wave inversions
Regardless of which criteria are used, about 3% of those diagnosed with AMI had a completely normal or nonspecific ECG in this study.10 (See section on selecting patients for thrombolysis on page 62.)
Other ECG presentations for AMI are listed in Table 2. Other ECG findings suggestive of AMI should always be considered, including the presence of a new left-bundle branch block (LBBB). Although confirming AMI in the presence of LBBB can be difficult, certain findings can be useful for suggesting the diagnosis. For example, however, ongoing ischemia and infarction may be detected in the presence of LBBB. 11 A deflection of the J point (and ST segment) in the direction of the major QRS complex, or an elevation of the ST segment of more than 7-8 mm opposite the direction of the major QRS complex, suggests AMI. These findings have a sensitivity of greater than 50% and are about 90% specific for detecting acute myocardial injury.11 The presence of Q waves in leads I, AVL, V5, and V6 is also a reliable sign of AMI in LBBB.
The diagnosis of myocardial injury in patients with artificial ventricular pacemakers can be difficult due to the abnormal sequence of ventricular excitation. In this subgroup of patients, the presence of new ST and T wave changes in the presence of a paced ventricular rhythm should be considered abnormal until proven otherwise.
Common patterns of ECG-lead ST elevations help identify the location of the myocardial damage. For example, ST-T wave elevations in I, AVL, and V1-V3 suggest anterior infarction, depressed ST segments in V1 and V2 suggest posterior-wall MI or an inferior-wall AMI with posterior extension, and ST elevations leads II, III, and AVF characteristically suggest inferior-wall infarction. ST segments may be falsely elevated in many conditions including myocarditis, ventricular aneurysms, LVH, LBBB, early repolarization, hypothyroidism, and hyperkalemia.
Table 1. Killip Classification
Laboratory Markers: Diagnostic and Prognostic Indications
General Principles. Enzyme markers are routinely used for the detection and management of AMI. Serum markers enhance the sensitivity for early detection of myocardial necrosis and ischemia as compared to the ECG. They also help determine the time of cardiac injury, especially when used in combination with other cardiac markers. It should be stressed that enzyme- and muscle-based cardiac markers vary in their performance characteristics, sensitivity, and specificity. (See Figure 1.) To maximize the usefulness of these assays, the emergency physician must be aware of the specificity of cardiac markers for myocardial tissue, its release pattern, its half-life in plasma, and the period of time after release during which the marker remains detectable in serum. Analyzing temporal patterns of multiple markers can improve detection of myocardial ischemia and/or infarction and can help characterize the time of onset, progression, and extent of myocardial damage.
Although creatine kinase (CK)-in particular, the MB fraction of CK (CK-MB)-remains the most widely used enzyme marker, and is still the sine qua non for the diagnosis of AMI, other cardiac markers have received considerable attention. Among the most clinically promising in this regard are troponin I and troponin T, which exhibit both sensitivity and specificity for the diagnosis of AMI. At present, these protein markers should not be considered replacements for CK-MB for the identification and management of AMI, but they are extremely useful adjuncts and can provide considerable information that helps quantify and prognosticate a patient's risk for complications, morbidity, and mortality associated with AMI.
Creatine Kinase (CK). CK is an ubiquitous enzyme found in nearly all tissues. The cardiac-specific dimer, CK-MB, however, is present almost exclusively in myocardium, although it represents only 15-30% of total cardiac enzyme activity.4,12 The most common causes for serum increases in total creatine kinase (TCK) remain non-cardiac in nature and include trauma, rhabdomyolysis, hyperthermia, vigorous physical activity, renal or endocrine disease, systemic infections, or any disease state causing destruction to muscle tissue. However, in the setting of chest pain in the absence of trauma, an elevated TCK level increases the likelihood that myocardial necrosis is present.
The majority of CK enzymes detected from myocardial injury result from CK-MM released from damaged cells. Accordingly, TCK, which is the measured sum of CK-MM, -MB, and -BB (found predominantly in brain tissue), is often elevated in MI. General reference ranges for normal TCK levels are less than 70 U/L. For AMI, the mean time required to exceed the reference range is 4.75 hours (range, 3.50-5.25 hrs.) due to its rather large size and slow release ratio. Consequently, TCK is not sensitive for the early diagnosis of AMI. At four hours, the sensitivity of TCK is only 44%, while the specificity is 82%.13 Specificity improves to nearly 100% by 10 hours. TCK levels peak at about 13 hours (range, 11.5-15.8 h) and remain elevated for 72 hours (range, 50-96 h).13
Conversely, insufficient TCK elevations should not be used to exclude the diagnosis of AMI. In fact, patients with small muscle mass (i.e., an elderly female with small muscle mass, or a non-Q wave MI) may not release sufficient quantities of CK to exceed the laboratory reference range. Therefore, in the presence of suspected AMI, the ED physician should not rely on normal TCK values to exclude AMI.14 Instead, a ratio of serum CK-MB to TCK (CK-MB/ TCK ´ 100%) should be calculated. A "cardiac index" ratio exceeding 3-5% (or a CK-MB mass assay/TCK ratio of 2.5% or greater) represents a disproportionately high concentration of CK-MB isoenzyme in the blood, which, in turn, suggests cardiac necrosis.5 High levels of TCK released from muscle after trauma or rhabdomyolysis can also release large amounts of CK-MB, producing false positive CK-MB interpretations. In this scenario, a cardiac index less than the cutoff value supports a non-cardiac etiology for elevated TCK. Regardless, an elevated cardiac index in a patient presenting with non-traumatic chest pain or with ECG changes suggesting cardiac involvement, confirms AMI by the WHO criteria.
Table 2. ECG Findings Suggesting AMI
|
ECG FINDING |
POSITIVE PREDICTIVE VALUE |
SPECIFICITY |
|
>1 mm ST elevation or Q waves in two leads |
76% |
45.0% |
|
New ischemia or strain >1 mm, ST depression in > two leads |
38% |
20.0% |
|
Other new ST or T wave changes of new ischemia or strain |
21% |
14.0% |
|
Old infarction, ischemia or strain |
8% |
5.0% |
|
Other new or old abnormality |
5% |
5.0% |
|
Nonspecific ST-T changes only |
5% |
7.0% |
|
Normal |
2% |
3.4% |
|
Note: See text for information on detecting AMI in the presence of a bundle branch block |
||
CK-MB Subunits. Subunits of CK, CK-MB, -MM, and -BB, are high molecular-weight (86,000 D) markers associated with a slow release into the blood from damaged cells. Although CK-MB is produced almost exclusively in the myocardium, trace amounts of activity are also found in small intestine, tongue, diaphragm, uterus, and prostate.12,15 Elevated CK-MB enzyme levels are observed in the serum 2-6 hours after MI, but may not be detected until up to 12 hours after the onset of symptoms. The mean time to exceed reference standard is about 4.5 hours, which reflects the slow release kinetics of this enzyme. Peak CK-MB levels are observed from 12-24 hours (mean, 18 hours) after AMI, and the enzyme is cleared from the bloodstream within 48-72 hours.
Various laboratory techniques are used to separate and identify cardiac specific CK-MB subforms from the non-specific CK-MM and -BB isoforms.The laboratory directly or indirectly measures CK-MB release. Indirect calculations of the amount of CK-MB enzymatic activity in the presence of substrate are reported in units of activity per liter (IU/L). This technique uses electrophoresis and is referred to as CK-MB activity. Monoclonal antibody techniques have greatly improved both specificity and sensitivity for detection of AMI by providing direct measurements of CK-MB mass. Mass assays are reported in mcg/L. Generally, the mass assay is more sensitive for detection of AMI and should be requested from the laboratory service. Both processes are limited by delayed enzyme release from damaged myocardial cells. Sensitivity for detection of AMI approaches 100% at 10-12 hours, but is only about 57% for the mass assay and about 32% for CK-MB activity during the first four hours.13
Assays of CK-MB isoforms, CK-MB1 and CK-MB2, separate two isoelectric forms of CK-MB. CK-MB2 values greater than 2.6 IU/L and CK-MB2 to CK-MB1 ratios greater than 1.7 are indicative of myocardial necrosis. These isoforms are released simultaneously into blood at 2-6 hours following AMI. However, increased isoform ratios can be detected in the serum earlier than CK-MB isoenzyme alone, increasing the sensitivity for early AMI detection and identification over standard CK-MB assays (at 6 hours, 91% sensitivity for subunits vs. 62% for CK-MB).16 Unfortunately, these assays are not available at all institutions, and are technically difficult tests requiring special equipment.
Other enzymes and/or enzyme panels including such markers as myoglobin, troponin T and I are often employed to enhance detection of early AMI until confirmatory levels of CK-MB are achieved. Accordingly, it is not advisable to discharge a patient with suspected cardiac chest pain until the CK-MB measurements supercede the duration of chest pain symptoms by at least nine hours, more if the patient has ongoing chest pain. This corresponds to the expected peak CK-MB level. Given these kinetics, patients who have a discrete episode of chest pain, followed by a pain-free course of at least nine hours who also have normal CK-MB measurements throughout this period do not have AMI. However, this "rapid rule out" does not exclude the presence of acute cardiac/coronary ischemia. Admission for stress testing or direct coronary angiography may be necessary in those with continued atypical chest pain suspicious for a cardiac etiology, regardless of CK-MB levels.
Figure 1. Common Markers Used to Identify Myocardial Infarction
|
Marker |
Initial Elevation after AMI |
Mean Time to Peak Elevations |
Time to Return to Baseline |
|
Myglobin |
1-4 h |
6-7 h |
18-24 h |
|
cTnI |
3-12 h |
10-24 h |
3-10 d |
|
cTnT |
3-12 h |
12 h-48 h |
5-14 d |
|
CKMB |
4-12 h |
10-24 h |
48-72 h |
|
CKMBiso |
2-6 h |
12 h |
38 h |
|
LD |
8-12 h |
24-48 h |
10-14 d |
cTnI, cTnT = troponins of cardiac myofibrils; -MB, MM = tissue isoforms of creatine kinase; LD = lactate dehydrogenase.
Adapted from: Adams JE III, Abendschein DR, Jaffee S. Biochemical markers of myocardial injury: Is MB creatine kinase the choice for the 1990s? Circulation 1993;88:750-763.
Troponin T and I. Acute coronary syndromes reflect a continuum of ischemic syndromes that range from silent ischemia to unstable angina and non Q-wave MI, and, finally, acute MI.17 Some of these syndromes represent reversible myocardial insult. For example, unlike AMI, acute cardiac ischemia (ACI), if it is detected in its early stages, may be amenable to medical or surgical management. In other words, interventions that successfully prevent evolution from ischemia to completed myocardial infarction may pressed into service to reduce morbidity and mortality.
Not surprisingly, new techniques that can detect and confirm ischemic myocardial insult prior to irreversible damage are being given high priority in emergency medicine. In this regard, protein subunits derived from muscle tissue have gained recognition as promising markers. During muscle contraction, thick filaments of myosin and thin filaments of actin slide across each as a result of calcium-mediated ATP-dependent contraction. Released calcium binds to a 'complex' of three proteins on the tropomyosin filament, troponin C, T, and I, which regulates muscle contraction.
Proteins of troponin T and I have been purified from myocardial tissue, allowing the development of cardiac specific immunoassays.18 Because the amino acid sequence for troponin C is identical in all tissues, it is not useful as a cardiac marker. Unlike CK-MB or myoglobin, the troponins T and I are cardiac-specific structural proteins, and therefore are not normally detectable in blood without myocardial insult. False positive results do not occur with skeletal muscle disease, exercise, non-cardiac trauma, or renal failure, as they would would with creatine kinase.
Cardiac-specific troponin T (cTnT) is a qualitative assay with a turnaround time of 30 minutes; it is also available as a rapid bedside assay. Cardiac troponin I (cTnI) is a quantitative assay with a processing time of about one hour. Troponin assays require only a single test, whereas two tests are required to interpret elevated creatine kinase, total creatine kinase, and CK-MB.17 Also, since cTnT remains elevated in serum up to 14 days (more than 5 times longer than CK-MB), and cTnI for 3-7 days after infarction, normal troponin results can provide information during the evaluation of patients with sustained chest pain.
Sensitivity and Specificity. Detection of cTnT or cTnI should be considered a positive finding. However, small measured quantities may suggest a "microinfarction," or even unstable angina, rather than a significant MI. After myocardial damage, cTnT and cTnI are released in a temporal fashion similar to that of CK-MB.18,19 Initial troponin levels are usually first detected at 2-4 hours after AMI. The sensitivity of cTnT for AMI detection at two, four, eight, and greater than eight hours is 33%, 50%, 75%, and 86%, respectively. In contrast, specificity of cTnT between four and eight hours post AMI was 100%; it is 95% at two hours and 86% after eight hours.20 In another trial, the sensitivity and specificity for AMI detection with CK-MB was 99% and 72%, vs. 100% and 69% for cTnT.21 However, troponin assays may have a lower specificity than CK-MB for "true" AMI, since significant amounts of troponins can be detected with small myocardial insults, now referred to as acute cardiac ischemia (ACI).18
Recent studies have focussed on the high sensitivity that cTnT has for detecting minimal myocardial damage and on its role as a tool for risk stratification prior to completed MI.20,22-24 The GUSTO-IIa subtrial of 755 patients evaluated patients with chest pain and attempted to characterize those with AMI vs. ACI.17 With a mean symptom-to-initial-sampling time of 3.5 hours, 36% of patients had cTnT elevations compared to 32% with elevated CK-MB. The 30-day mortality of those with elevated cTnT greater than 0.1 ng/mL was 11.8% vs. 3.9% in the negative cTnT group.17 This study suggests that cTnT may help stratify post-AMI patients into those at high risk for cardiac-related mortality.
Other studies involving ACI suggest elevated cTnT more closely correlates with 30-day mortality than CK-MB or ECG. In a trial of 183 unstable angina patients with cTnT levels drawn 12 and 24 hours after admission, increased rates of cardiac death and angioplasty during the two-year follow-up period were reported in patients in the positive cTnT group.23 Also, patients with a positive cTnT who have had AMI ruled by traditional criteria appear at greater risk for short-term adverse events including cardiac arrest, AMI, arrhythmia, and recurrent angina than those with a negative cTnT.24 Finally, patients with negative troponin I results and normal ECGs during their chest pain evaluation have significantly lower risk for future adverse cardiac events than those with abnormal cTnI.25 These trials suggest that cTnT and cTnI may be reliable prognostic markers for myocardial insult, and may be useful in risk stratifying those non-AMI patients with unstable angina.23-25
Because ACI is on the continuum that terminates in AMI, the value of troponin markers for the management of AMI is in evolution. Both markers are as reliable as CK-MB for detection of AMI, but may also be positive in acute coronary syndromes, what some call a "preinfarction state." At present, it does not appear that cTnT or cTnI should supplant CK-MB assay for identification of AMI, but these markers should help risk stratify those not identified for AMI by traditional means. Since AMI represents only a small percentage of patients presenting with chest pain, the utility of troponin in this setting requires more thorough evaluation.
Table 3. Guidelines for Thrombolytic Therapy in AMI
Guidelines for Mortality Reduction: Non-thrombolytic Agents
The goal of management in AMI is to prevent evolution of infarction, reduce myocardial necrosis, minimize complications, and ultimately reduce short- and long-term mortality. Diagnostic confirmation should be followed promptly by reperfusion whenever possible. Inclusionary and exclusionary criteria for thrombolysis should be assessed by the ED physician as soon as possible, and this intervention should be integrated with all aspects of care in a concise and effective manner. (See Table 3.)
Supportive Care. Oxygen should be administered at a flow rate of at 2 L/min for three hours and continued if pulse oximetry is less than 90%.26 The patient should be placed on a cardiac monitor and blood drawn for baseline laboratory studies. At least two IVs are helpful, especially if the patient requires thrombolysis. Blood pressure should be monitored every 30 minutes until stable and then at least every four hours. Strict bedrest is advised.26
Pain Control. Administer morphine sulfate 2-4 mg IV every 5-10 minutes to blunt the sympathetic response to pain and anxiety. Doses approaching 25-30 mg may be necessary to achieve adequate pain relief.27 Morphine-induced hypotension typically occurs in volume-depleted patients but is uncommon in patients who remain in the supine position.27
Nitroglycerin. Sublingual nitroglycerin (NTG) may improve ischemic chest pain but can also cause headaches. Initially, give up to three doses of 0.4 mg sublingual NTG every five minutes. Intravenous NTG drips are usually required to treat prolonged chest pain. Excessive NTG administration decreases blood pressure and may cause marked hypotension. Although NTG is beneficial in reducing chest pain associated with AMI and has been shown to reduce mortality in unstable angina, its benefits in AMI remain questionable. (See Figure 1.) The studies are conflicting. In selected subgroups of patients, such as those with anterior AMI, if treatment with IV NTG is started early and hypotension is avoided, infarct size may be reduced and subsequent mortality improved.28 However, one large, randomized trial, GISSI-3, showed no reduction in mortality with NTG as compared to placebo.29,30 In another meta-analysis of earlier trials, there is a suggestion that nitrates reduced the odds of death after AMI by 35%.31
In the setting of AMI, nitroglycerin is indicated for persistent hypertension and congestive heart failure. NTG should be used with caution in patients with inferior-wall MI that is accompanied by RV infarction, hypovolemia, or hypotension. For persistent hypertension, start an infusion of intravenous NTG at 10-20 mcg/min, titrating upward by 5-10 mcg/min every 5-10 minutes (max 200 mcg/min). Titrate to decrease the mean arterial pressure by 10% in normotensive patients and 30% in those with hypertension. Slow or stop the infusion when the SBP drops below 90.26 If clinically significant hypotension occurs with IV NTG administration, discontinue the drug, drop the head of the bed, and administer fluids as needed. Atropine may be appropriate if severe hypotension persists.26
Aspirin. The benefits of aspirin therapy for reducing mortality after MI and in the setting of unstable angina are substantiated by numerous trials. The largest, ISIS-2, demonstrated a 20% reduction in mortality (P < 0.001), which resulted in prevention of 25 early deaths for every 1000 patients with suspected AMI.32 Those individuals who were treated with aspirin for one month following AMI experienced nearly twice the reduction from further deaths, reinfarctions, and strokes than the group randomized to placebo. These benefits were independent of thrombolytic or heparin administration, and do not appear dose dependent (initial dose of at least 160 mg/d).
The benefits of aspirin are so substantial-as demonstrated in more than 17,000 patients in the ISIS-2 trial-that it is unlikely that this drug will be excluded from any future trials of AMI management. In the absence of contraindications (allergy, active GI bleeding, or recent intracranial hemorrhage), aspirin should be administered to all patients presenting with cardiac chest pain in the ED. For the rare patient with a contraindication to aspirin, another antiplatelet drug, such as ticlopidine, should be administered. Newer agents that block the final common pathway for platelet aggregation (IIB/IIIA inhibitors) are in clinical trials and may be a promising substitute for aspirin in the future.
Beta Blockade. Beta blockers have been shown to decrease mortality and to reduce infarct size in several clinical trials.33-35 The ISIS-1 and the MIAMI trial are the most important trials showing benefits from this intervention. In ISIS-1, 16,027 patients were randomized to receive IV atenolol or placebo. There was a significant, relative decrease in mortality rates (3.89% mortality rate in the drug group vs. 4.57% placebo) in the first week, and at one year (10.7% vs. 12%) following AMI. Overall, beta-blocker use during AMI can be expected to produce about an 11% reduction in mortality.33 The MIAMI trial included 5778 patients; a definitive AMI was confirmed in 4127 patients. Oral metoprolol was administered in doses ranging from 15-200 mg daily for 15 days. The metoprolol group had a mortality rate of 4.3% vs. 4.9% for the placebo group, demonstrating a 13% relative decrease in mortality. High-risk patients had a 29% lower mortality rate than control.34 Beta-blockers also decrease recurrent ischemia and nonfatal reinfarction in patients treated with tPA.35 Contraindications to beta-blockade include allergy, significant bronchial hyperreactivity, bradycardia, hypotension, LV failure, PR interval greater than 0.24 s, second- or third-degree AV block, IDDM, severe peripheral vascular disease, or hypoperfusion.26
Heparin. Although heparin is commonly used for management of chest pain, there is still some skepticism as to whether or not it confers mortality-reducing benefits. Intravenous heparin has been shown to increase the rate of late coronary artery patency when given with tPA.36 In addition, IV heparin and high-dose subcutaneous (SC) heparin, 12,500 SC bid, appear to reduce mortality, regardless of thrombolytic use.37 However, because of increased bleeding complications, IV or high-dose SC heparin is usually limited to patients with large anterior MI or those that may develop mural thrombus. Those patients not given IV or high-dose SC may be given low-dose heparin (5000 SC bid) to prevent deep venous thrombosis.
The GISSI-1 and ISIS-2 trials left the decision to use heparin to the physician.32,38 Supported by data from the more recent GUSTO trials,39,40 heparin administration is standard with tPA-use today. However, the GISSI-2 and ISIS-341,42 trials suggested that only patients treated with streptokinase (SK), and not those treated with tPA, benefit from heparin therapy. However, subsequent studies have reported different results when IV heparin is used in conjunction with tPA. In contrast, when IV heparin-as compared with SC heparin-is used in conjunction with SK, it does not appear to offer mortality benefits and may increase complications.43 Therefore, the routine use of IV heparin cannot be recommended with SK. Despite the lack of evidence in AMI trials, heparin is still indicated in the setting of unstable angina and ACI syndromes.
ACE Inhibitors. Both the ISIS-4 trial44 and the GISSI-3 trial29,30 have shown increased survival in patients with AMI who are given an oral ACE inhibitor within the first 24 hours. In the GISSI-3 trial, which consisted of 19,394 patients, patients were randomized to lisinopril or placebo for six weeks after AMI. Patients were followed and evaluated for death or severe ventricular dysfunction for six months after their AMI. ACE-inhibitors reduced the incidence of combined endpoints from 19.3% (placebo) to 18.1% (treatment group). ISIS-4 enrolled 58,050 patients and compared mortality rates for oral captopril, oral mononitrate, and IV magnesium. Captopril was given as a 6.25 mg initial dose and titrated up to 50 mg PO bid for one month. Mortality rates at five weeks were significantly better with ACE-inhibitors (7.19%) than with placebo (7.69%). ACE-inhibitors are recommended within the first 24 hours of AMI, but are not necessarily required for the initial ED management of AMI.
Magnesium. Intravenous magnesium was shown to be beneficial in the LIMIT-2 study of 2316 patients, as well as in a meta-analysis trial consisting of seven other smaller trials that analyzed 3566 patients.45,46 In the LIMIT-2 trial, mortality reduction was 24% in the magnesium-treated group.45,46 The overall mortality rates for AMI were 7.8% in the magnesium group vs. 10.3% in the placebo group. However, magnesium failed to reduce AMI mortality in the large, prospective and randomized ISIS-4 trial.44 Enrolling 58,050 patients, ISIS-4 failed to confirm mortality-reducing benefits associated with magnesium.
These differences may be attributed to variations in magnesium dosages and to the acuity of its administration. In the ISIS-4 trial, magnesium was not administered until the completion of thrombolytic therapy. In light of the inconsistencies between available studies, other trials may still be indicated. Hypermagnesmia should be avoided and magnesium should not be administered when the serum creatine is above 3 or in patients with heart block. Despite the fact that magnesium appears to be a relatively benign drug, it is not recommended by most authorities for routine administration in AMI at this time.
Calcium Channel Blockers. No benefits have been attributed to calcium channel blocker for acute management of AMI. In fact, significant increases in mortality have been reported in patients with heart failure or depressed left ventricular function, especially with short-acting calcium channel blocker. This class of drugs is not recommended in AMI.
Table 4. Contraindications to Thrombolytic Therapy
|
RELATIVE |
|
|
Active internal bleeding |
Prior allergic reaction to SK or APSAC |
|
Anticoagulation or bleeding disorder |
Prior exposure to above agents |
|
Aortic dissection |
|
|
Hemorrhagic CVA within the last 6 months |
Hemorrhagic retinopathy |
|
Prolonged CPR |
|
|
Uncontrolled hypertension |
Recent major surgery |
|
>180 systolic or >120 diastolic |
Ischemic CVA |
|
Major surgery or trauma less than two weeks |
Pregnancy |
|
Cerebral aneurysm, AVM or neoplasm |
Thrombolytics: Mortality-Reducing Options
Introduction. Plasmin is the complex that facilitates lysis of a coronary thrombus that precipitates AMI. Thrombolytic therapy enhances the conversion of plasminogen to plasmin, thereby inducing clot lysis. Plasminogen is an inactive proteolytic enzyme that is found in plasma and bound to fibrin in thrombi.47 Tissue plasminogen activator (tPA) essentially induces clot-specific lysis by cleaving bound plasminogen to the active form, plasmin, which then degrades fibrin to degradation products. These degradation products have antiplatelet and anticoagulant effects and also reduce viscosity. All tPA derivatives share similar risks and benefits, and have the same contraindications. (See Table 4.) The major limitation of all available plasminogen activators is that they generate active thrombin and stimulate platelet aggregation, which necessitates therapy with antithrombin and antiplatelet drugs in order to maintain arterial patency.
Streptokinase. Streptokinase (SK) is produced from b-hemolytic Streptococci cultures. Intravenous SK acts on inactive plasminogen to produce the active enzyme plasmin. This, in turn, leads to fibrin lysis and thrombus dissolution, but is not clot-specific.48 Reports of IV and intracoronary SK use were first published in 1958 and 1976 respectively.48,49 It was demonstrated in the early 1980s that SK could recanalize an acutely occluded coronary artery in a living patient.50 European, placebo-controlled megatrials such as GISSI-1 and ISIS-2 showed that mortality in patients with AMI could be reduced 23% and 30% respectively, by administering IV SK within six hours of the onset of chest pain.32,38 Subsequent studies have also shown benefit in those patients with stuttering chest pain or who give a description of chest pain of long duration.51
The current recommended dose of IV SK is 1.5 million units given over 60 minutes. A drawback to SK is its antigenicity. In a recent GUSTO trial, 5.7 percent of patients developed allergic reactions, and 13% had sustained hypotension. Because of this potential, it is not recommended for use in those with recent Streptococcal throat infection or readministration to those who have had previous use in the prior 12 months. In these individuals, the use of a nonantigenic thrombolytic agent such as tPA is recommended.52
Tissue Plasminogen Activator. The first reported clinical use of tPA was in 1984.53 Tissue plasminogen activator is a naturally occurring enzyme found in vascular endothelial cells. This agent converts plasminogen to plasmin. At low doses, tPA is characterized as clot-specific because of its propensity to bind to any new thrombus within the coronary artery lumen. Although tPA tends to activate the systemic fibrinolytic system less than SK, the higher doses of tPA required for reperfusion have been associated with a higher risk of intracranial bleeding than SK.53,54 This risk may be heightened because of the concomitant use of heparin when tPA is used.
Studies have shown that tPA is more effective than SK in reopening occluded arteries early in an acute event.57 At three hours, 24 hours, and three weeks, however, patency rates are similar between the two agents.42,54,57 GISSI-2, ISIS-3, and GUSTO-I compared data from more than 100,000 patients and revealed no mortality difference between tPA and SK.38,40,41
Previously, tPA was dosed at 100 mg over three hours, with 60 mg given in the first hour. The remaining 40 mg was given in equal doses over the next two hours. The accelerated tPA schedule consisting of a 15 mg bolus, then 0.75 mg/kg (up to 50 mg) for the next 30 minutes and then 0.5 mg/kg (up to 35 mg) for the next 60 minutes has replaced the older method as the preferred method of administration.38 Increased bleeding complications have not been seen with this front-loaded regimen. The coronary recanalization rate at 90 minutes is approximately 79% vs. 40% for SK and 63% for APSAC.55,56 Overall, "front-loaded" tPA saves one additional life per 100 patients as compared to SK (GUSTO trials), but increases the rate of intracranial hemorrhage and costs more than seven times that of SK.39,41,51
APSAC. Anisoylated plasminogen streptokinase activator complex (APSAC) also activates plasminogen molecules to lyse fibrin. Similar to SK in this respect, APSAC is antigenic. Hypotension and allergic reactions may occur. The major advantage of APSAC over SK or tPA is the ease of IV bolus administration: a single 30 U IV bolus given over five minutes.56 It has roughly 4-6 hours of fibrinolytic activity.
Reteplase. Reteplase (r-PA) is a non-glycosylated deletion mutant of wild-type tPA. Reteplase is administered as a double bolus infusion of 10 megaunits (10 U) 30 minutes apart. Outcomes data from the large GUSTO-III trial support its efficacy as an alternative to tPA.58 Reteplase has a longer half-life than tPA and does not require weight-based infusion calculations like tPA. Its cost is similar to tPA. The 30-day mortality data from GUSTO-III was not statistically different for r-PA (7.43%) and front-loaded tPA (7.22%). Additionally, this trial of 15,000 reported no significant differences between r-PA and tPA in stroke, death, or disabling stroke rates.58
Choice of Thrombolytic Agents. The choice of a thrombolytic agent for a given clinical situation is a matter of controversy. Prior to GUSTO-I, neither GISSI-2 nor ISIS-3, which enrolled more than 60,000 subjects demonstrated a significant, overall mortality difference between SK and tPA, or, for that matter, between the use of these agents and anisestreptelase. GISSI-2 randomized 20,891 patients within six hours of pain onset to receive either tPA or SK plus subcutaneous heparin started 12 hours after thrombolysis, or no heparin.41 The study failed to show any significant reduction in mortality, reinfarction, or stroke in patients given heparin vs. no heparin. There was no significant mortality difference between tPA and SK. The ISIS-3 trial randomized 41,299 patients within 24 hours of onset of suspected MI to either tPA, APSAC, or SK, and to either subcutaneous heparin or no heparin.42 There was no difference in 35-day survival among thrombolytic agents. A higher incidence of stroke, most likely due to hemorrhage, was noted in the tPA group.
In response to these trials, proponents of tPA argued that intravenous, and not subcutaneous, heparin should have been used in these trials. Intravenous heparin resulted in higher rates of sustained arterial patency in smaller angiographic trials. It was also noted that infarct-related arteries could be opened more quickly with front-loaded or accelerated tPA administration that was given over 90 minutes rather than over three hours. This regimen resulted in an improved infarct-artery patency rate of 85% at 90 minutes, versus 70 % with the usual method.56
The GUSTO-I trial, a randomized comparison of the two most widely used agents, SK and tPA, suggested that the accelerated intravenous infusion of tPA resulted in reduced mortality compared with IV SK. An angiographic subanalysis of the GUSTO-I trial revealed that the superiority of front-loaded alteplase was linked to a higher frequency of early patency (90 minutes) and more complete reperfusion.40 The best patency rates were recorded in those under the age of 75 years, in patients with anterior wall infarction, and in those treated less than four hours after onset of infarction.
Although many experts felt GUSTO-I supported tPA over SK as the thrombolytic of choice for AMI,59 there were criticisms of the GUSTO-I study. The lack of front-loaded SK regimen as well as the increased access of some patients to PTCA and CABG was felt to have possibly biased mortality outcomes.39,60,61 Despite these concerns, front-loaded tPA has become the standard reference thrombolytic agent. Reteplase was studied in GUSTO-III. It offers ease of administration, but provides no statistical benefits over tPA (GUSTO-III). Its efficacy is equivalent to that of tPA and should be considered an alternate thrombolytic agent, depending on cost and availability.
Percutaneous Coronary Angioplasty (PTCA). One of the most important debates in emergency medicine is whether pharmacologic therapy (thrombolysis) or mechanical therapy (PTCA) is the preferred strategy for achieving reperfusion with AMI. In this regard, the Primary Angioplasty in Myocardial Infarction (PAMI) Study Group reported a lower combined incidence of reinfarction and death in the hospital in those treated with percutaneous transluminal angioplasty (PTCA) vs. patients treated with thrombolytic therapy.62 Patients who received PTCA also had a lower incidence of intracranial bleeding (0% vs 2%).
However, preliminary results from GUSTO II-b revealed that there was no statistical difference in mortality rates after 30 days. These differences may reflect heterogeneity in door-to-balloon time. In PAMI, 60 minutes was the usual time from door to balloon. In GUSTO II-b, the time was 114 minutes. The Myocardial Infarction Triage and Intervention (MITI) trial reported no difference in mortality, either in hospital or in the long-term.63 Because 14 of the 19 hospitals in this study were community based, it quite possible that the data didn't properly reflect the "high volume expert centers." Outcomes may vary considerably secondary to the expertise of the interventionist. In 1997, it was concluded that in New York, at least, both hospital and cardiologist PTCA volume are inversely related to in-hospital mortality rate and same stay CABG surgery rate. The lowest same-stay CABG surgery rates were achieved with annual cardiologist PTCA volumes of 75 or more and annual hospital PTCA volumes between 600 and 999.64
Current recommendations that favor PTCA over thrombolytic administration include the ability to perform PTCA within 60-90 minutes of AMI, use in patients (such as the elderly) at high risk for intracranial bleeding, and in individuals who fail to qualify for thrombolytic therapy. In those situations where PTCA will not be available for more than 60 to 90 minutes, thrombolytics should be considered the primary mortality-reducing intervention. In the hands of experienced operators, PTCA may provide superior short-term outcomes and is highly recommended in those patients with cardiogenic shock. It would appear that the success of PTCA is very much dependent on the volume of procedures that is performed by the hospital or operator. Recent data suggest that the lowest mortality rates of patients undergoing PTCA are reported when the center and the cardiologist perform in excess of 400 and 200 cases, respectively, each year.64 Until more definitive comparative data become available, the goal should be to maximize the speed and efficiency of both approaches.
Complications of Thrombolysis
Bleeding is the most common adverse effect associated with thrombolysis and may occasionally lead to death.65,66 Most complications occur at vascular access sites and rarely require transfusions. Other sites would include GI, GU and intracranial locations. Contraindications to thrombolytics include active bleeding from any of these sites. (See Table 4.) A review of complications that may occur within 10 hours after IV tPA is initiated reveal that 19% of patients experienced minor bleeding, 3% had neurologic deficits, and 3% had major bleeding. Major bleeding involved the GI tract or was defined as a 15% drop in hematocrit. Two patients (2%) had intracranial bleeding, and 3% had hypotension that required treatment.67
Despite the increased incidence of hemorrhagic stroke after thrombolytic therapy, the overall incidence of stroke is similar whether or not thrombolytic therapy is administered. The difference, of course, is that most strokes in AMI patients who have not received thrombolytics are of the nonhemorrhagic variety.66,68 However, in one trial, the mortality in patients who developed a cerebrovascular accident (CVA) as a result of thrombolytic therapy quadrupled.69 The study also showed that those with prior CVAs, intermittent transient ischemic attacks, or any history of neurologic disease had an increased frequency of intracranial hemorrhage. The risk of intracranial hemorrhage with tPA use increased in patients older than 65 years, those with hypertension, or if their weight was less than 70 kg. GUSTO-I, ISIS-3 and GISSI-1 trials reported an increased risk of hemorrhagic CVAs for tPA compared with SK. Focal neurologic deficits mandate immediate CT scan. If positive, thrombolytic therapy should be discontinued.
Adverse effects may occur in up to 50% of patients treated with SK. Hypotension commonly occurs but it is usually responsive to IV fluids and doesn't necessitate halting the SK infusion.70 Bronchospasm, urticaria, and serum sickness may occur in up to 20% of patients.71 Since anaphylactic reactions are rare, pretreatment with antihistamines and corticosteroids is not necessary. Systemic bleeding has been noted to occur slightly more frequently with SK vs. tPA, but tPA is associated with a higher incidence of intracranial hemorrhage than SK.41
Punctured vessels that bleed secondarily to thrombolytics usually respond to direct pressure. It may occasionally be necessary to stop the anticoagulant and thrombolytic if bleeding from these vessels continues unabated or worsens. Transfusion may be required. Protamine sulfate, in a dose of 1 mg per 100 u of heparin, may be given to shorten the half-life of heparin. Cryoprecipitate (10-15 bags) may be employed as well if bleeding does not respond. Continuing hemorrhage would require fresh frozen plasma (2-6 units). Platelets may also be administered to gain control of hemorrhage. Epsilon-amino caproic acid, or anti-fibrinolytic agent, has been recommended in cases of intracranial hemorrhage. However, thrombolytic complications have resulted from its use.
Selecting Patients for Thrombolysis
ECG Criteria. Traditionally, ST elevation in limb and chest leads has been an essential criterion for initiating thrombolytic therapy. Unfortunately, many patients with AMI do not present with ST elevation at the time of infarct, thus precluding thrombolytic use for patients without ST elevation. In the TEAHAT study, mortality was decreased in patients given thrombolytics who had ST elevation, but was increased in individuals with ST depression.72 Other trials have looked at the subset of patients who present without a diagnostic ECG. GISSI-1 revealed that patients with ST depression treated with SK had a higher mortality rate. Patients with ST depression and a LBBB also did not benefit from thrombolysis with SK.42 However, patients with elevation of the ST segment in two or more leads by at least 1 mm (0.1 mV) or a new bundle branch block with a history suggesting AMI benefited from thrombolytics.41 Patients with ST depression are not considered candidates for thrombolytics.
Hypertension. Historically, acute hypertension was considered a contraindication to thrombolytic use because elevated blood pressure is associated with a higher rate of hemorrhagic CVA. Studies have supported this rationale.73 The risk of ICH is significantly greater when the presenting BP at time of AMI is 180/110 mmHg or greater. The TIMI-2 trial demonstrated that aggressive reduction in blood pressure with beta-blockade therapy decreased the incidence of hemorrhagic CVA in patients with AMI in whom tPA was administered.67 Those with anterior AMI are most likely to experience hypertension and might benefit from IV beta-blockade. However, paradoxical blood pressure depression is more commonly seen after administration of nitroglycerine and morphine. Elderly patients presenting with AMI and hypertension are a high risk for intracranial hemorrhage (ICH).74 A benefit to risk ratio must be considered when administering thrombolytics in this population.
CPR. A number of studies have touted the safety of thrombolysis in patients who have received CPR.75,76 A 1991 report was more cautious in its recommendation. The authors suggest a possible increase in major bleeding episodes.77 The benefit to risk ratio must be calculated on an individual basis. More recent recommendations suggest that thrombolytics may be administered, if CPR was performed for less than 10 minutes.78 Musculoskeletal trauma such as broken ribs may complicate thrombolytic therapy after prolonged CPR and should be considered a risk factor for continued bleeding.
Patient Age. Currently, it would appear that, despite higher morbidity and mortality as compared to younger patients who receive thrombolytics, the number of lives saved in those older than 75 years of age is greater than those younger than age 75.79 This appears to contradict earlier thinking regarding the dangers of thrombolysis in the elderly. However, many comorbid conditions in this age group can preclude or diminish the attractiveness of thrombolytic use in the elderly. (See Table 4.) Age older than 65 increases the odds of intracranial hemorrhage,80,81 as well as of nonhemorrhagic stroke. But absolute mortality reductions, nevertheless, are still recorded in clinical trials in which low risk elderly patients who presenting with AMI are treated with thrombolytic agents.79 Rates of ICH after tPA in the elderly with fewer than two of the following risk factors on presentation generally are regarded as acceptable thrombolytic candidates in clinical trials: age greater than 65, weight less than 70 kg, and hypertension on admission are about 1%.74 Despite many studies, no clear guidelines have been established for thrombolytics in the elderly. PTCA appears to be an excellent option in this age group.
Treatment Time. A number of studies have shown that mortality rates drop precipitously when thrombolytic agents are given as soon as possible after coronary artery occlusion. The prehospital MITI trial group noted early thrombolytic treatment within 70 minutes reduced mortality to 1.2%, compared to 9% for those patients who waited for more than 70 minutes to begin treatment.82 GISSI-1 demonstrated a mortality reduction of 50% when thrombolytic therapy was given one hour or less after onset of symptoms.7 A meta-analysis of 60,000 patients by the Fibrinolytic Therapy Trialists Collaborative Group reported an increase of 1.6 lives/1000 lost with each hour delay.83
At one time, it was felt that thrombolytics might confer no benefit if given beyond six hours of symptom onset. GISSI-1 revealed no benefit in mortality reduction beyond six hours with SK.38 However, ISIS-2, the LATE trial, and the EMRAS trial32,60 demonstrated mortality benefits if thrombolytics were administered within 12 hours. Only ISIS-2 suggested any benefit beyond this 12-hour window. It appears, then, that the recommended time to treat should be 12 hours in those with diagnostic ECGs and continued symptoms. A major finding of the recent GUSTO III study, however, is that the time from symptom onset to thrombolytic therapy administration averages nearly three hours. This represents no improvement since 1990.
Thrombolysis vs. PTCA. Survival and LV function are clearly improved with early administration of IV thrombolytics. Clot-specific agents such as tPA are more costly but have produced a greater percentage of early patency than non-clot specific agents (i.e, SK).43 This likely equates with a greater reduction in AMI-associated mortality. Front-loaded regimens of tPA may provide better patency rates and are now supported as the regimen of choice by most institutions. Agents such as rPA provide convenient dosing regimens but have essentially similar patency rates as tPA.84 The best responses to tPA are reported in patients younger than 75 years and in those experiencing anterior AMI, but the risk for intracranial hemorrhage is increased with tPA over SK, particularly in older age groups.
Some have argued that SK is the agent of choice in individuals older than 75 and in those with inferior AMI. The GUSTO-I trial, although limited by statistical power, suggests that SK may be the appropriate agent for those patients presenting four hours after symptom onset, while tPA may be better if administered within four hours of onset.39 Although the debate still persists as to which thrombolytic is ideal, all agree that too few individuals receive thrombolytic treatment or receive it quickly enough. The time from onset of symptoms to definitive management has not changed in the last seven years. Thrombolysis is still a major reperfusion strategy if it is given in a timely fashion.
Studies support PTCA as the most effective therapy in cardiogenic shock and in patients in whom attempts with thrombolysis are not successful. Debate continues as to which modality, primary PTCA or thrombolytics, is the best first-line treatment for other patients AMI. Primary PTCA may be favored over thrombolytics assuming the hospital and interventional cardiologist have adequate experience and PTCA can be initiated within 60 minutes of arrival to the hospital. However, since fewer than 20% of U.S. hospitals have an angioplasty suite or the capability to staff one in rapid fashion, thrombolysis remain a primary modality in the majority of hospital EDs.
Managing Complications of AMI
Arrhythmias. ACLS protocols are readily available for the management of arrhythmias encountered in the setting of AMI. Immediate defibrillation is the treatment of choice for V-fib or hemodynamically unstable ventricular tachycardia (VT). Ventricular ectopy is common in the setting of AMI and should not be routinely treated. Lidocaine may be used for the treatment of frequent ( 5/minute) VPDs, multifocal VPDs, or those that may induce VT or V-fib. Procainamide may be used if lidocaine is ineffective, although hypotension and widening of the QRS complex may be observed.
Accelerated idioventricular rhythm (AIVR) often occurs after thrombolysis has produced coronary reperfusion. This wide complex escape rhythm may occur when the sinus rate falls to less than 60. This rhythm usually requires no specific treatment and lidocaine should be avoided, inasmuch as ventricular suppression may lead to symptomatic bradycardia or asystole. If there is hemodynamic instability or if this rhythm is associated with VF or VT, atropine or overdrive pacing may be used.
Supraventricular rhythms are also encountered. Persistent sinus tachycardia may suggest a poor prognosis. The underlying causes (fever, pain, anxiety, hypovolemia, CHF) should be treated and, if necessary, treatment with judicious amounts of a beta-blocker is indicated. PSVT is uncommon but should be treated with synchronized cardioversion if the patient is unstable. Stable patients may require standard pharmacologic management as appropriate. Atrial fibrillation and flutter may be treated with IV diltiazem, verapamil, or propranolol, but if the patient is unstable, synchronized cardioversion is the treatment of choice. Atrial fibrillation with a rapid ventricular rate should also be cardioverted. Unstable atrial fibrillation with ventricular rates below 100 may require transvenous pacing before cardioversion to prevent asystole.
Sinus bradycardia is associated with inferior MI and should be treated with atropine if associated with symptoms of decreased cardiac output. Temporary pacing is indicated for any unstable patient that fails to respond to atropine, or develops a high grade heart block. Mobitz type II requires pacing regardless of symptoms and third-degree AV block requires emergent transvenous pacing, as these patients may readily progress to asystole.
Pump Failure. Pump failure is usually the result of decreased left ventricular systolic function or decreased compliance of the left ventricle. Acute mitral regurgitation, VSD, or exacerbation of existing valvular disease may also result in pulmonary edema or shock. Mild heart failure may be treated with furosemide but hypovolemia and hypotension should be avoided. Topical or low-dose IV nitrates may be of some benefit by reducing left ventricular filling pressures. ACE inhibitors may be used in patients with heart failure, but hypotension must be avoided. Initially, hypovolemia should be treated with fluids. These patients will have a low pulmonary capillary wedge pressure (PCWP) and a low cardiac index. Patients with volume overload or decreased left ventricular compliance can be treated with diuretics or nitrates. Swan-Ganz catheters are helpful in the management of patients with pump failure to measure CI and PCWP, but are rarely available in the ED. Advanced management in the critical care unit is recommended in patients with pump dysfunction in the setting of AMI.
The mortality of patients with cardiogenic shock is greater than 75%. Cardiogenic shock usually reflects infarction involving more than 50% of left ventricular mass. This may reflect an acute event or cumulative old and new infarctions. Left ventricular dysfunction, typically associated with decreased cardiac output and elevated PCWP, might temporarily benefit from alpha and beta agonists. Intravenous dopamine starting at 0.5-1.0 mcg/kg/min is helpful in cases of severe shock (< 80mmHg sbp). Doses higher than 10 mcg/kg/min may induce vasoconstriction, which is deleterious to ischemic or infarcting tissue. Dobutamine is most effective when hypertension is secondary to low cardiac output. Dobutamine at 2.5 to 15.0 mcg/kg/min primarily affects b-1 receptors, but also has smaller affects on peripheral b-2 and a-receptors. Dobutamine increases cardiac output, decreases peripheral resistance and increases perfusion. Unsuccessful use of vasopressors may dictate the need for an intra-aortic balloon pump. This may provide temporary left ventricular assistance.
Right ventricular infarction (RVI) occurs in approximately 30-50% of posterior-inferior infarctions.85 Hypotension, low PCWP, and intolerance to nitrates characterize decreased right ventricular propulsion. Right-sided precordial leads such as V4R exhibiting ST segment elevation indicate RVI. In RVI, a high right ventricular filling pressure must be supported by administration of fluids to maintain adequate left ventricular filling pressures. Clinically, RVI is usually recognized by evidence of impedance to right ventricular filling (elevated neck pains, quiet lung fields). Rarely, patients with RVI may present with cardiogenic shock reflecting concomitant left ventricular dysfunction. Use of Swan-Ganz monitoring techniques may be required to distinguish left ventricular forward failure or cardiogenic shock from hypovolemia, or RVI. Dobutamine may be needed as for inotropic augmentation in selected cases.
Summary
Aggressive methods to detect and treat AMI are imperative to reduce mortality among the 1.5 million patients with AMI each year. The history and physical exam can be invaluable in aiding diagnosis. The electrocardiogram and serum enzyme markers (CK-MB) continue to be the mainstay in AMI detection, although newer cardiac markers show promise as ancillary aids.
Once diagnosis of AMI is confirmed, management should be aggressive and systematic. Thrombolytic agents such as SK or tPA (front-loaded) can reduce mortality significantly and should be administered promptly in eligibile candidates. Adjunctive agents such as beta blockers, ACE-inhibitors, and aspirin have also been shown to decrease mortality. Mechanical means to open obstructed coronary arteries should be given preferential consideration provided the facility has significant PTCA experience and can perform this procedure in an expedient manner.
References
1. Gillum RF. Trends in acute myocardial infarction and coronary heart disease in the United States. J Am Coll Cardiol 1994;23:1273-1277.
2. Davies MJ, Thomas AC. Plaque fissuring-the cause of acute myocardial infarction, sudden ischemic death and crescendo angina. Br Heart J 1985;53:363-373.
3 McClellan M, McNeill BJ, Newhouse JP, et al. Does more intensive treatment of acute myocardial infarction in the elderly reduce mortality? Analysis using instrument variables. JAMA 1994;272:859-866.
4. Gillum RF, Formann SP, Prineas RJ, et al. International diagnostic criteria for acute myocardial infarction and stroke. Am Heart J 1984;108:150-158.
5. Apple FS. Acute myocardial infarction and coronary reperfusion: Serum cardiac markers for the 1990s. Am J Clin Pathol 1992;97:217-226.
6. Goldman L, Cook EF, Brand DA, et al. A computer protocol to predict myocardial infarction in emergency department patients with chest pain. N Engl J Med 1988;318:797-803.
7. Tierney WM, Roth BJ, Psaty B, et al. Predictors of myocardial infarction in emergency room patients. Crit Care Med 1985;13:526-531.
8. Pozen MW, D'Agostino RB, Selker HP, et al. A predictive instrument to improve coronary care unit admission practices in acute ischemic heart disease: a prospective multicenter clinical trial. N Engl J Med 1984;310:1273-1278.
9. Gruppo Italiano per lo Studio della Sopravivenza nell' Infarcto Miocardico. Comparison of frequency, diagnosis, and prognostic significance of pericardial involvement in acute myocardial infarction treated with and without thrombolytics. Am J Cardiol 1993;71:1377-1381
10. Rouan GW, Lee TH, Cook EF, et al. Clinical characteristics and outcome of acute myocardial infarction in patients with initially normal or nonspecific electrocardiograms (a report from the Multi-center Chest Pain Study). Am J Cardiol 1989;64:1087-1092.
11. Fesmire F. ECG diagnosis of acute myocardial infarction in the presence of left bundle branch block in patients undergoing continuous ECG monitoring. Ann Emerg Med 1995;26:69-72.
12. Howanitz JH, Howanitz PJ, eds. Laboratory Medicine: Test Selection and Interpretation. New York, Churchill Livingstone 1991:25-39.
13. Mair J, Artner-Dworzak E, Dienstl A, et al. Early detection of acute myocardial infarction by measurement of mass concentration of creatine kinase-MB. Am J Cardiol 1991;68:1545-1549.
14. Hong RA, Licht JD, Wei JY, et al. Elevated CK-MB with normal total creatine kinase in suspected myocardial infarction: associated clinical findings and early prognosis. Am Heart J 1986;111:1041-1046.
15. Selker HP, Zalenski RJ, Antman EM, et al. An evaluation of technologies for identifying acute cardiac ischemia in the emergency department: executive summary of a National Heart Attack Alert Program Working Group Report. Ann Emerg Med 1997;29:1:59-63.
16. Puleo PR, Guadagno PA, Roberts R, et al. Early diagnosis of acute myocardial infarction based on assay for subforms of creatine kinase-MB. Circulation 1990;82:759-764.
17. Ohman EM, Armstrong PW, Christenson RH, et al. Cardiac troponin T levels for risk stratification in acute myocardial ischemia. N Engl J Med 1996;335:1333-1341.
18. Christenson RH, Newby LK, Ohman EM. Cardiac markers in the assassment of acute coronary syndromes. The strategy of the chest pain units (in emergency departments) in the war against heart attacks: Proceedings from the first Maryland Chest Pain Center Research Conference. Maryland Med J 1997:Suppl 12;18-25.
19. deWinter RJ, Koster RW, Sturk A, et al. Value of myoglobin, troponin T, and CK-MB mass in ruling out an acute myocardial infarction in the emergency room. Circulation 1995;92:3401-3407.
20. Antman EM, Grudzien C, Sacks DB. Evaluation of a rapid bedside assay for detection of serum cardiac troponin T. JAMA 1995;273:1279-1282.
21. Ravkilde J, Horder M, Gerhart W, et al. Diagnostic performance and prognostic value of serum troponin T in suspected acute myocardial infarction. Scan J Clin Lab Invest 1993;53:677-685.
22. Wu Ah, Abbas SA, Green S, et al. Prognostic value of cardiac troponin T in unstable angina pectoris. Am J Cardiol 1995;76:970-972.
23. Stubbs P, Collinson P, Moseley D, et al. Prospective study of the role of cardiac troponin T in patients admitted with unstable angia. BMJ 1996;313:262.
24. Green GG, Beaudreau RW, Chan DW. Use of troponin T and creatine kinase-MB subunit levels for risk stratification of emergency department patients with possible myocardial ischemia. Ann Emerg Med 1998;31:19-29.
25. Hamm CW, Goldmann BU, Heeschen C, et al. Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I. N Engl J Med 1997;337:1648-1653.
26. Ryan TJ, Anderson JL, Antman EM, et al. ACA/AHA Guidelines for the management of patients with acute myocardial infarction. A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction) J Am Coll Cardiol 1996;28:1328-1428.
27. Antman EM. General hospital management. In: Julian DG, Braunwald E, eds. Management of Acute Myocardial Infarction. London, England: WB Saunders Co Ltd; 1994:42-44.
28. Jugduff BL, Warnica JW. Intravenous Nitroglycerin therapy to limit myocardial infarct size, expansion, and complications. Effect of timing, dosage, and infarct location. Circulation 1988;78:906-919.
29. Gruppo Italiano per lo Studio della Sopravivenza nell' Infarcto Miocardico. GISSI-3: Effects of lisinopril and transdermal glyceryl trinitrate singly and together on six-week mortality and ventricular function after acute myocardial infarction. Lancet 1994;343(8906):1115-1122.
30. GISSI-3 Investigators. Six month effects of early treatment with lisinopril and transdermal glyceryl trinitrate singly and together withdrawn six weeks after acute myocardial infarction: the GISSI-3 trial. J Am Coll Cardiol 1996;27(2):337-44.
31. Yusuf S, Collins R, MacMahon S, et al. Effect of intravenous nitrates on mortality in acute myocardial infarction: An overview of the randomized trials. Lancet 1988;1:1088-1092.
32. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349-360.
33. ISIS-1 (First International Study of Infarct Survival) in Collaborative Group. Randomised trial of intravenous atenolol among 16027 cases of suspected acute myocardial infarction. Lancet 1986;2(8498):57-66.
34. The MIAMI Trial Research Group. Metoprolol in acute myocardial infarction (MIAMI). A randomized placebo-controlled international trial. Eur Heart Journal 1985;6:199-226.
35. 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.
36. HART. A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction. Heparin Aspirin Reperfusion Trial. New Engl J Med 1990;323:1433-1437.
37. SCATI. Randomized controlled trial of subcutaneous calcium-heparin in acute myocardial infarction. Studio Sella Cacipamina nell Angina enella Trombosi Venticolare nell Infarcto. Lancet 1989;2:182-186.
38. GISSI. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397-402.
39. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673-682.
40. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary artery patency, ventricular function and survival after acute myocardial infarction. New Engl J Med 1993;329:1615-1622.
41. GISSI-2. A factorial randomized trial of alteplase versus streptokinase and heparin versus no heparin among 12490 patients with acute myocardial infarction. Lancet 1990;336:65-71.
42. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomized comparison of streptokinase vs. tissue plasminogen activator vs. anistreplase and of aspirin plus heparin vs. aspirin alone among 41299 cases of suspected acute myocardial infarction. Lancet 1992;339:753-770.
43. GUSTO investigators: The effects of tissue plasminogen activator, streptokinase, or both on coronary artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993;329:1615-1622.
44. ISIS-4 Collaborative Group. A randomized factorial trial assessing early oral captopril, oral mononitrate and intravenous magnesium sulphate in 58050 patients with suspected acute myocardial infarction. Lancet 1995;345:669-682.
45. Woods KL, Fletcher S, Roffe C, et al. Intravenous magnesium sulphate in suspected acute myocardial infarction: Results of the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2). Lancet 1992;339:1553-1558.
46. Woods KL, Fletcher S. Long-term outcome after intravenous magnesium sulphate in suspected acute myocardial infarction: The second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2). Lancet 1994;343:816-819.
47. Marder V. Relevance of changes in blood and coagulation parameters during thrombolytic therapy. Am J Med 1987;83:15.
48. Fletcher A, Alkajaerstig N, Smyrniotis F. The treatment of patients suffering from early myocardial infarction with massive and prolonged streptokinase therapy. Trans Assoc Am Phys 1958;71:287.
49. Chazav E, Matteeva L, Mazadev A. Intracoronary administration of fibrinolysis in acute myocardial infarction. Ter Arkh 1976;48:8.
50. Rentrop P, Blanke H, Karsch K. Selective intracoronary thrombolysis in acute myocardial infarction and unstable angina pectoris. Circulation 1981;63:307.
51. Brett J. Late assessment of thrombolytic efficacy with alteplase (rt-Pa) six-24 hours after onset of acute myocardial infarction. Aust N Z J Med 1993;23:745-748.
52. Dykewicz, M, McGrath K, Davison R. Identification of patients at risks for anaphylaxis due to streptokinase. Arch Intern Med 1986;146:305-307.
53. Vandewerf, Ludbrook P, Bergman S: Coronary thrombolysis with tissue plasminogen activator in patients with evolving myocardial infarction. N Engl J Med 1984;310:609-613.
54. Rao A, Pratt C, Berke A. Hemorrhagic manifestations and changes plasma fibrinolytic system in patients treated with tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;11:1
55. Granger C, White H, Bates E. A pooled analysis of coronary artery patency and left ventricular function after intravenous thrombolysis for acute myocardial infarction. Am J Cardiol 1994;74:1220-1226.
56. Newhaus K, von Essen R, Tebbe U. Improved thrombolysis in acute myocardial infarction with front-loaded administration of alteplase: Results of the rt-Pa - APSAC patency study (TAPS). J Am Coll Cardiol 1992;19:885-891.
57. Sherry S, Marder V. Streptokinase and recombinant tissue plasminogen activator are equally effective in treating acute myocardial infarction. Ann Intern Med 1991;144:417-423.
58. Bode C, Smalling R, Berg G. Randomized comparison of coronary thrombolysis achieved with double-bolus retaplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarct. Circulation 1996;94:891-898.
59. O'Neill W, Weintraub R, Grines C. et al. A prospective placebo-controlled randomized trial of intravenous streptokinase and angioplasty therapy of acute myocardial infarction. Circulation 1992;86:1710-1717.
60. EMERAS Collaborative Group. Randomised trial of late thrombolysis in patients with suspected acute myocardial infarction. Lancet 1993;342:767.
61. Ridker P, O'Donnell C, Marder V, et al. A response to "holding GUSTO up to the light." Ann Intern Med 1994;120:882-888.
62. Grines C, Browne K, Marco J, et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1993;328:673-679.
63. Every N, Parsons L, Hlatky M, et al. A comparison of thrombolytic therapy with primary coronary angioplasty for acute myocardial infarction. N Eng J Med 1996;335,1253-1262.
64. Hannan E, Racz M, Ryan T, et al. Coronary angioplasty volume-outcome relationships for hospitals and cardiologists. JAMA 1997;277:892-898.
65. Blankenship J, Almquist A. Cardiovascular complications of thrombolytic therapy in patients with a mistaken diagnosis of acute myocardial infarction. J Am Coll Cardiol 1989;14:1579-1582.
66. Eleff S, Borel C, Bell W. Acute management of intracranial hemorrhage in patients receiving thrombolytic therapy case reports. Neurosurgery 1990;26: 867-869.
67. Bovill E, Terrin M, Stump D, et al. Hemorrhagic events during therapy with tissue plasminogen activator, heparin and aspirin for acute myocardial infarction: Results of the TIMI, phase II trial. Ann Intern Med 1991;115:256-265.
68. Maggioni A, Franzosi M, Santoro E, et al. The risk of stroke in patients with acute myocardial infarction after thrombolytic and antithrombotic treatment. N Engl J Med 1992;327:1-6.
69. Maggioni A, Franzosi M, Farina M, et al: Cerebrovascular events after myocardial infarction: Analysis of the GISSI trial. BMJ 1991;302:1428-1431
70. Bednarczyk E, Sherlock S, Farah M, et al. Anaphylactic reaction to streptokinase with first exposure: Case report and review of the literature. Ann Pharmacother 1989;23:869.
71. Schweitzer D, vander Wall, Bosker H. Serum sickness-like illness as a complication after streptokinase therapy for acute myocardial infarction. Cardiology 1991;78:68-71.
72. Risenfors M, Zukauskiene I, Albertsson P, et al. Early thrombolytic therapy in suspected acute myocardial infarction-role of electrocardiogram: Results from the TEAHAT Study. J Intern Med 1991;734(Suppl):19-25.
73. Anderson J, Karagounis L, Allen A, et al. Older age and elevated blood pressure are risk factor for intracerebral hemorrhage after thrombolysis. Am J Cardiol 1991;68:166-170.
74. 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 (TIMI) phase II trial. N Engl J Med 1989; 320:618-627.
75. Cross S, Lee H, Rawles J, et al. Safety of thrombolysis in association with cardiopulmonary resuscitation. BMJ 1991;303:1241-1242.
76. Scholz K. Frequency of complications of cardiopulmonary resuscitation after thrombolysis during acute myocardial infarction. Am J Cardiol 1992;69:724-728.
77. Tenaglia A, Califf R, Candela R, et al. Thrombolytic therapy in patients requiring cardiopulmonary resuscitation. Am J Cardiol 1991;68:15.
78. Habib G. Current status of thrombolysis in acute myocardial infarction. Chest 1995;107:528-534.
79. Krumholz H, Pasternak R, Weinstein M, et al. Cost-effectiveness of thrombolytic therapy with streptokinase in elderly patients with suspected acute myocardial infarction. N Engl J Med 1992;327:7-13.
80. Simoons ML, Maggioni AP, Knatterud G, et al. Individual risk assessment for intracranial heamorrhage during thrombolytic therapy. Lancet 1993;342:1523-1528.
81. De Jaegere PP, Arnold AA, Balk AH, et al. Intracranial hemorrhage in association with thrombolytic therapy: incidence and clinical predictive factors. J Am Coll Cardiol 1992;19:289-294.
82. Weaver W, Cerqueira M, Hallstrom A, et al. Prehospital initiated vs. hospital-initiated thrombolytic therapy: The Myocardial Infarction Triage and Intervention Trial. JAMA 1993;270:1211-1216.
83. Fibrinolytic Therapy Trialists Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: Collaborative overview of early mortality and major morbidity results from all randomized trials of more than 1000 patients. Lancet 1994;343;311-321.
84. Recent Developments in Coronary Intervention: GUSTO-III and other Highlights from ACC '97. In: Clinical Challenges in Acute Myocardial Infarction. Roberts R, McCabe JB, eds. 1997;7:1-11.
85. Zehender M, Kasper W, Kander E, et al. Right ventricular infarction as an independent predictor of prognosis after acute inferior infarction. N Engl J Med 1993;328:982-988.
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