Acute Myocardial Infarction: Current Clinical Guidelines for Patient Evaluation,
July 4, 1999 33 minutes read
Acute Myocardial Infarction: Current Clinical Guidelines for Patient Evaluation, Thrombolysis, and Mortality Reduction
Part I: Laboratory Assessment, Stabilization, and Initial Drug Therapy
Authors: Gideon Bosker, MD, FACEP, Assistant Clinical Professor, Section of Emergency Medicine, Yale University School of Medicine, New Haven, CT; Associate Clinical Professor, Oregon Health Sciences University. David J. Robinson, MD, MS, Director of Research, Assistant Professor, Department of Emergency Medicine, University of Texas at Houston Medical School, Houston, TX; 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: Chuck Emerman, MD, Associate Professor of Emergency Medicine, Case Western Reserve University; Chairman of Emergency Medicine, MetroHealth Medical Center, Cleveland Clinic Foundation, Cleveland, OH.
Acute myocardial infarction (AMI) is the leading cause of death in the United States and most Western industrialized nations.1 In 1998, there were more than 1.6 million cases of AMI in the United States, and almost 500,000 associated deaths. 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 1994 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 such as t-PA in eligible 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 review provides an overview of current diagnostic and therapeutic approaches to AMI.4-7 The objectives are to provide a systematic approach to patient assessment, identify the clinical advantages of newer enzymatic tests for confirming the diagnosis of acute coronary ischemia, and review, in detail, the mortality reduction techniques—including pharmacotherapeutic and invasive procedures—supported by evidentiary clinical trials.8,9 Finally, a clinical algorithm outlining outcome-enhancing strategies for this life-threatening condition is presented. —The Editor
Overview of Clinical Principles: Diagnostic Criteria
In 1996, the American Heart Association and American College of Cardiology (AHA/ACC Guidelines) outlined three components necessary to establish the definitive diagnosis of AMI.10 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 65-69% 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. 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. (See Figure 1.) Atypical presentations for AMI may fail to satisfy the AHA/ACC criteria for the diagnosis of AMI. In these patients, repeat ECGs and enzymes can assist in establishing diagnosis.
Figure 1. Facts about Diagnosis and Misdiagnosis of AMI |
| • Approximately 25% of all AMIs go undetected ("silent heart attacks"), leaving patients at a higher risk of dying from a subsequent AMI. |
| • Approximately 27% of all patients who suffer AMIs die within one hour of the event ("sudden death"), usually before reaching an emergency room. |
| • Approximately 36% of AMI patients die immediately or within several days following onset of AMI. |
| • Each year, approximately 5 million people present in emergency rooms with chest pain; only 5-10% of these patients are actually experiencing an AMI. |
| • Only about one-half of patients who experience an AMI are actually diagnosed in time to permit meaningfully therapeutic intervention. |
| • Estimates are that more than 35,000 patients per year are wrongly discharged from emergency rooms because of failure to diagnose AMI; 8750 (about 25%) of these patients die or suffer life-threatening outcomes within 24 hours following discharge. |
| • Fewer than 25% of patients admitted to the hospital with ischemic-type chest discomfort are subsequently diagnosed as having had an AMI, adding significant costs to the health care system. |
| • Emergency department cases account for approximately 17% of all medical malpractice claims made; about 20% of these cases are attributable to failure to diagnose AMI. |
| Source: American Heart Association; Decision Resources, Inc. |
Risk Factors. Significant cardiac risk factors include hypertension, hyperlipidemia, diabetes, smoking, and a strong family history, which means a history of coronary artery disease (CAD) in early or mid-adulthood in a first-degree relative. 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 a history of infarction or angina.6-8
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.)
Table 1. Killip Classification | |
| Class I | |
| No clinical heart failure, < 5% mortality | |
| Class II | |
| Rales bilaterally in up to 50% of lung fields, isolated S3, good prognosis | |
| Class III | |
| Rales in all lung fields, acute mitral regurgitation, aggressive management required | |
| Class IV | |
| Cardiogenic shock: stuporous, systolic BP < 90, decreased urine output, pulmonary edema, and cold clammy skin; mortality near 80% | |
Inspiratory rales and an S3 gallop are associated with left-sided failure. Jugulovenous distentions (JVDs), 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. AHA/ACC guidelines state that "ST-segment elevation (equal to or greater than 1 mV) in contiguous leads provides strong evidence of thrombotic coronary arterial occlusion and makes the patient a candidate for immediate reperfusion therapy, either by fibrinolysis or primary percutaneous transluminal coronary angioplasty (PTCA). Symptoms consistent with AMI and new left bundle branch block (LBBB) should be managed like ST-segment elevation. In contrast, the patient without ST-segment elevation should not receive thrombolytic therapy. The benefit of primary PTCA in these patients remains uncertain."10
Although confirming AMI in the presence of LBBB can be difficult, certain findings can be useful for suggesting the diagnosis. For example, ongoing ischemia and infarction may be detected in the presence of LBBB.11,12 Either 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.12 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.
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 with 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 Table 2.) 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.
Table 2. Common Markers Used to Identify Acute Myocardial Infarction | |||
Marker | Initial Elevation after AMI |
Mean Time to Peak Elevations |
Time to Return to Baseline |
| Myoglobin | 1-4 h |
6-7 h |
18-24 h |
| CTnI | 3-12 h |
10-24 h |
3-10 d |
| CTnT | 3-12 h |
12-48 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; CPK-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. | |||
Although creatine kinase (CK)—in particular, the MB fraction of CK (CK-MB)—remains the most widely used enzyme marker and is still 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.4,13 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 (isoenzyme of CK with muscle subunits) 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 h) due to its 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%.14 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).14
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.15 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.
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 the small intestine, tongue, diaphragm, uterus, and prostate.13,16 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 h) 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.14
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 the 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).17 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 and 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 (longer 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 and 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.
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, AMI.18 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 be 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.19 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.18 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.19,20 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.21 In another trial, the sensitivity and specificity for AMI detection with CK-MB was 99% and 72%, vs. 100% and 69% for cTnT, respectively.22 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 ACI.19
Recent studies have focused on the high sensitivity of cTnT for detecting minimal myocardial damage and on its role as a tool for risk stratification prior to completed MI.21,23-25 The GUSTO-IIa subtrial of 755 patients evaluated patients with chest pain and attempted to characterize those with AMI vs. ACI.18 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.18 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 that 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.24 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.25 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.26 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.24-26
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.
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. (See Figure 2.) 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.)
Table 3. Treatment Recommendations for AMI | |
| Supportive Care with Management of Chest Pain | |
| • Patients should be placed in the most comfortable position, usually sitting up. | |
| • All patients should receive supplemental oxygen for a minimum of three hours. | |
| • Continue oxygen with titration to maintain pulse oximetry, 95% if hypoxic. | |
| • Patients with PaO2 less than 60 mmHg or significant acidosis should be intubated and ventilated. | |
| • Two large-bore IVs should be placed. Antecubital or large forearm sites are preferred. | |
| • Cardiac monitor and automatic blood pressure monitoring at frequent intervals. | |
| • Pain relief with nitroglycerin and morphine while maintaining adequate blood pressure (see text for precautions). | |
| Aspirin | |
| Inclusion | Clinical symptoms or suspicion of AMI |
| ECG confirmation is not required | |
| Exclusion | Aspirin allergy, active GI bleeding |
| Time Frame | Up to 24 hours of symptoms onset |
| Recommendation | ASA 160-325 mg chewable immediately and every day after; may use ASA per rectum if needed |
| Thrombolytics | |
| Inclusion | All patients with AHA/ACC criteria for thrombolytic infusion therapy |
| Exclusion | Active internal bleeding; history of cerebrovascular accident; recent intracranial or intraspinal surgery or trauma; intracranial neoplasm, arteriovenous malformation, or aneurysm; known bleeding diathesis; severe, uncontrolled hypertension |
| Time Frame | Up to six hours after chest pain begins |
| Recommendation | Front-loaded t-PA regimen 15 mg IV over 1-2 min, then 0.75 mg/kg IV up to 50 mg IV over 30 min, then 0.5 mg/kg IV up to 35 mg IV over 60 minutes |
| Beta-Blockade | |
| Inclusion | All patients with the diagnosis of AMI |
| Exclusion | See beta-blockade section in text for contraindications |
| Time Frame | Immediate upon diagnosis of AMI |
| Recommendation | Dosing according to specific beta-blocker used |
| Nitrates | |
| Inclusion | All patients with diagnosis of AMI |
| Exclusion | Nitrate allergy; patients on sildenafil (Viagra); severe hypotension; caution in right ventricular infarction |
| Time Frame | Immediate upon diagnosis of MI for management of chest pain, followed by continuous IV infusion |
| Recommendation | Dosing will vary according to route of administration and preparation used. Consult clinical protocols, many of which recommend the following: 0.4 mg NTG initially q 5 minutes, up to 3 doses. For persistent hypertension or chest pain, IV infusion of NTG at 10-20 mcg/min, titrating upward by 5-10 mcg/min q 5-10 minutes (maximum, 200 mcg/min). Slow or stop infusion if systolic BP < 90 mmHg |
| ACE Inhibitors | |
| Inclusion | All patients with the diagnosis of AMI |
| Exclusion | Killip class III or IV |
| History of renal failure, creatine > 2.5 mg/dL or hx | |
| Renal artery stenosis | |
| Hypotension with SBP < 100 | |
| Allergy to ACE inhibitor | |
| Time Frame | Up to 24 hours to initiate treatment, not necessary in ED |
| Recommendation | Captopril 12.5 mg po bid, may use test dose of 6.25 mg or lisinopril 5 mg po qd up to 10 mg qd as tolerated or lisinopril 2.5 mg po if SBP < 120 |
| Heparin | |
| Inclusion | Those patients receiving t-PA or those patients not receiving ASA |
| Exclusion | Hypersensitivity |
| Active internal bleeding | |
| Prolonged CPR | |
| Recent head trauma/CNS surgery/known intracranial neoplasm | |
| emorrhagic ophthalmic condition | |
| Time Frame | To be given concomitantly with t-PA |
| Recommendation | • With t-PA administration, begin weight-based IV heparin protocol to maintain a PTT at 1.5 to 2.0 ´ control for the next 48 hours |
| • Treatment beyond 48 hours is recommended only for those patients with a high risk for systemic or venous thromboembolism | |
| • In patients not receiving t-PA, weight-based heparin only for patients with high risk systemic emboli (large or anterior AMI, a-fib, previous embolus or known LV thrombus) for 48 hours to maintain a PTT at 1.5-2.0 ´ control | |
Supportive Care. Oxygen should be administered at a flow rate of at 2 L/min as required 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 is eligible and requires thrombolysis. Blood pressure should be monitored every 15 minutes until stable and then at least every four hours. Strict bedrest is advised.27
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.28 Morphine-induced hypotension typically occurs in volume-depleted patients but is uncommon in patients who remain in the supine position.28 Some cardiologists feel that morphine may mask ischemic pain and prefer to use nitrates or procedural interventions for pain management.
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.
Nitroglycerin is also indicated for persistent hypertension and congestive heart failure. NTG should be used with caution in patients with inferior-wall MI that is accompanied by right ventricular (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 (maximum, 200 mcg/min). Titrate to decrease the mean arterial pressure by 10% in normotensive patients and by 30% in those with hypertension. Slow or stop the infusion when the SBP drops below 90.27 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.27
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, the second International Study on Infarct Survival (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.29 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, which is most efficacious if given in the first four hours, are very substantial, as was demonstrated in more than 17,000 patients in the ISIS-2 trial. 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. A dose of 160-325 mg should be given on day 1 of AMI and continued indefinitely on a daily basis thereafter.10 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 a promising substitute for aspirin.
Beta Blockade. Beta-blockers have been shown to decrease mortality and to reduce infarct size in several clinical trials.30-32 The First International Study on Infarct Survival (ISIS-1) and the Metoprolol in Acute Myocardial Infarction (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.30 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.31 Beta-blockers also decrease recurrent ischemia and nonfatal reinfarction in patients treated with tissue plasminogen activator (t-PA).35 Contraindications to beta-blockade include allergy, significant bronchial hyperreactivity, bradycardia, hypotension, PR interval greater than 0.24 s, second- or third-degree AV block, pulmonary edema, insulin-dependent diabetes mellitus, severe peripheral vascular disease, or hypoperfusion.26
Heparin. The AHA/ACC criteria for using heparin are as follows:
• Class I:
• Patients undergoing percutaneous or surgical revascularization.
• Class IIa:
• Intravenously in patients undergoing reperfusion therapy with alteplase;
• Subcutaneously (7500 U bid) (intravenous heaprin is an acceptable alternative) in all patients not treated with thrombolytic therapy who do not have a contraindication to heparin. In patients who are at high risk for systemic emboli (large or anterior MI, atrial fibrillation [AF], previous embolus, or known LV thrombus), intravenous heparin is preferred;
• Intravenously in patients treated with nonselective thrombolytic agents (streptokinase, anistreplase, urokinase) who are at high risk for systemic emboli (large or anterior MI, AF, previous embolus, or known LV thrombus).
• Class IIb:
• Patients treated with nonselective thrombolytic agents, not at high risk, subcutaneous heparin, 7500-12,500 U bid until completely ambulatory.
• Class III:
• Routine intravenous heparin within six hours to patients receiving a nonselective fibrinolytic agent (streptokinase, anistreplase, urokinase) who are not at high risk for systemic embolism.10
ACE Inhibitors. Both the ISIS-4 trial33 and the GISSI-3 trial34-35 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 end points 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.36,37 In the LIMIT-2 trial, mortality reduction was 24% in the magnesium-treated group.36,37 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.33 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. Hypermagnesemia should be avoided and magnesium should not be administered when the serum creatine is above 3 or in patients with heart block. Despite 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 blockers. This class of drugs is not recommended in AMI.
Choosing a Thrombolytic Agent
Myocardial infarction (MI) is the direct consequence of thrombotic occlusion of a coronary artery. Therapeutic strategies focus on the rapid identification of the patient suffering acute coronary artery thrombosis, optimal reperfusion of the occluded artery, and prevention of subsequent complications, including reinfarction, bleeding, stroke, arrhythmic death, and heart failure.
Nine large placebo-controlled, randomized, clinical trials of more than 58,000 patients clearly demonstrated that intravenous fibrinolytic therapy confers a significant morbidity and mortality benefit in the treatment of patients with acute MI with ST elevation or bundle branch block.1 Despite an increased risk of hemorrhagic complications and stroke, this net benefit extended across all patient subgroups and was independent of all other outcome determinants. The clinical benefit was also more prominent the earlier treatment began. As a result, intravenous fibrinolytic therapy is the standard-of-care to which newer strategies are compared.
Subsequent studies have compared the effects of several available plasminogen activators, particularly recombinant tissue plasminogen activator (t-PA, alteplase) and streptokinase (SK). The GUSTO-1 trial ushered in the current era of intravenous fibrinolytic therapy by demonstrating a significant mortality benefit of the accelerated infusion of t-PA over SK.2
Determinants of Outcome in Acute MI
The primary determinants of outcome in acute MI are the baseline risk characteristics of the patient, the adequacy of flow in the reperfused artery, speed of reperfusion, the incidence of reocclusion of the infarct-related coronary artery, and the direct complications of the therapeutic intervention.
In a multivariate regression analysis of the data from the 41,021 patients in the GUSTO-1 trial, Lee and colleagues identified 16 baseline patient characteristics and their relative weights as independent predictors of 30-day mortality: age, systolic blood pressure, Killip class (degree of heart failure), heart rate, site of current infarction, prior infarction, the interaction of age with Killip class, height, time-to-treatment, diabetes, weight, smoking status, type of thrombolytic therapy, prior bypass surgery, hypertension, and prior cerebrovascular disease.3 Califf and associates then developed a model using a reduced set of these determinants that retained 90% of the predictive value of the original model.4 The most powerful variables predictive of 30-day mortality were as follows:
Although the other factors such as time-to-treatment or prior cerebrovascular disease may affect the physiologic status of the patient, the independent contribution is relatively small. The impact of age is nearly two orders of magnitude greater than the choice of lytic agent.
The patency of the infarct-related artery is an important determinant of outcome. Infarct-artery patency is described using angiographic criteria from the early Thrombolysis in Myocardial Infarction (TIMI) trials. TIMI grade 3 flow is essentially normal flow. TIMI grade 2 flow is reduced flow but considered adequate to prevent immediate cell death. TIMI grades 0 and 1 flow reflect either no or inadequate perfusion, respectively.
A substudy in the GUSTO-1 trial randomized 2431 patients to evaluate the angiographic determinants of outcome.5 Left ventricular (LV) function was strongly correlated with the 90-minute infarct-related artery patency. The patients with TIMI-3 flow had better LV function and myocardial wall motion at 90 minutes and seven days. The 30-day mortality for patients with TIMI-3 flow in the infarct-related artery was 4.4%, while the mortality in the patients with TIMI-2 flow was 7.4%.
A pooled analysis by Barbagelata and associates of angiographic studies performed after thrombolysis confirmed the findings of the GUSTO angiographic investigators.6 TIMI-3 flow is associated with a substantially lower rate of congestive heart failure, lower rate of recurrent ischemia, better LV function, and 30-50% lower mortality compared to TIMI-2 flow, which is in turn better than TIMI-0 or -1 flow.
t-PA vs. SK
Mortality. The GUSTO-1 trial (1993) used a new approach to the administration of t-PA by "accelerating" the administration of the fibrinolytic (using a weight-adjusted dose) over 90 minutes instead of the "standard" 180 minute t-PA dosage regimen and by giving intravenous heparin immediately. A significant mortality benefit of "accelerated" t-PA over streptokinase regimens was evident throughout all treatment groups. An analysis by Califf et al demonstrates that the absolute mortality benefit of t-PA vs. SK increases with increasing mortality risk.4 As a result, despite higher risks of treatment, the net mortality benefit of t-PA for the high-risk patient (e.g., elderly patient, anterior MI, and CHF) was predictably greater than for the low-risk patient (e.g., young patient with inferior MI without heart failure). The higher the risk, the greater the absolute mortality benefit of t-PA vs. SK. The mortality benefit of accelerated t-PA over SK is attributed to the higher rate of early infarct-related artery patency.
The angiographic substudy of GUSTO-1 revealed that accelerated t-PA produced a significantly higher rate of open vessels (TIMI 2 and 3 combined) of 81% and complete reperfusion (TIMI 3) of 54% at 90 minutes, compared to SK rates of 60% and 41%, respectively. The patency rates were not significantly different at 180 minutes between t- PA and SK. Most of the survival benefit of accelerated t-PA over SK in the GUSTO-1 trial appears to be largely due to this advantage of early patency.
Summary
Intravenous fibrinolytic therapy is the standard of care for eligible acute MI patients with ST elevation or bundle branch block. Treatment with the weight-adjusted accelerated t-PA protocol of GUSTO-1 provides a net absolute mortality benefit in all treatment groups as compared to SK.
References
1. Fibrinolytic Therapy Trialists’ Collaborative Group. Lancet 1994;343:311-322.
2. The GUSTO Investigators. N Engl J Med 1993;329:673-682.
3. Lee KL, et al. Circulation 1995;91: 1659-1668.
4. Califf RM, et al. Am Heart J 1997; 133:630-639.
5. The GUSTO Angiographic Investigators. N Engl J Med 1993;329:1615-1622.
6. Barbagelata NA, et al. Am Heart J 1997;133:273-282.
Author: William E. Davis, MD
References
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11. 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.
12. 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.
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14. 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.
15. 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.
16. 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;29:59-63.
17. 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.
18. 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.
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Physician CME Questions
1. The AHA/ACC Guidelines’ components necessary to establish the diagnosis of AMI include which of the following?
A. Chest pain suggestive of cardiac disease
B. ECG with characteristic changes suggestive of AMI
C. Elevation of cardiac-specific markers exceeding standard reference range
D. All of the above
E. None of the above
2. Chest pain is present in:
A. 95-99% of patients with AMI.
B. 85-99% of patients with AMI.
C. 75-79% of patients with AMI.
D. 65-69% of patients with AMI.
E. 55-59% of patients with AMI.
3. According to the article, which of the following is considered an independent variable for AMI?
A.Diaphoresis
B.Bradycardia
C.Tachycardia
D.Hypotension
4. On physical examination for AMI, which of the following suggest right-sided failure?
A. Peripheral edema
B. Hepatojugular reflux
C. Jugulovenous distentions
D. All of the above
5. Contraindications to thrombolytic therapy in AMI include:
A. known bleeding diathesis.
B. severe uncontrolled hypertensions.
C. history of recent cerebravascular accident.
D. recent intracranial injury.
E. All of the above
6. The most common causes for serum increases in total creatine kinase (TCK) remain non-cardiac in nature and include which of the following?:
A. Rhabdomylosis
B. Renal or endocrine disease
C. Systemic infections
D. All of the above
7. According to the article, TCK is sensitive for the early diagnosis of AMI.
A. True
B. False
8. Compared with patients with abnormal cTnI, those with negative troponin I results and normal ECGs during their chest pain evaluation have:
A. higher risk for future adverse cardiac events.
B. significantly lower risk for future adverse cardiac events
C. about the same risk for future adverse cardiac events.
D. none of the above.
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