Unstable Angina: Year 2000 Update
Unstable Angina: Year 2000 Update
Multi-Modal Strategies For Reducing Mortality, Urgent Revascularization, and Adverse Cardiovascular Events
Authors: Elizabeth B. Jones, MD, Assistant Professor, Department of Emergency Medicine, The University of Texas Health Science Center at Houston; David J. Robinson, MD, Director of Research and Assistant Professor, Department of Emergency Medicine, The University of Texas—Houston Memorial Hermann Hospital; Medical Director, Diagnostic Observation Center, The University of Texas—Houston Memorial Hermann Hospital.
Peer Reviewer: Joseph C. Howton, MD, FACEP, Assistant Clinical Professor of Medicine, Division of Emergency Medicine, University of Washington Medical Center, Federal Way, WA.
Coronary heart disease (CHD) is the most important cause of mortality in the United States. Among acute coronary ischemic syndromes, acute myocardial infarction (AMI) is the leading single cause of death, with more than 1.5 million cases of AMI in 1996, and more than 500,000 associated deaths.1 Of the more than 95 million annual visits to the emergency department in the United States each year, nearly 8 million (8.4%) are because of chest pain.2 Not all of these patients, however, suffer from AMI; in fact, approximately 3 million of these individuals will have a non-cardiac diagnosis. Of the 5 million patients with a probable cardiac etiology, 20% will have an AMI, 16% will have unstable angina (USA), and 6% will die suddenly from a variety of causes.2
The economic impact of AMI is staggering. The estimated direct medical cost for a man is $31,000 for the first year of survival following the initial event and $1800 and $1300 for the next two years, respectively. The overall cost to manage the patients with acute coronary syndromes in the United States is estimated at more than $60 billion annually.3
As the principal manifestation of a wide spectrum of clinical conditions, ranging from angina, pneumonia, and AMI to pleurisy, muscle strain, and pulmonary embolism, chest pain remains one of the most common chief complaints among patients presenting to the emergency department. Some patients will have unequivocal electrocardiogram (ECG) and laboratory findings suggestive of an AMI, whereas others will have a non-cardiac diagnosis. However, most patients with cardiac-consistent pain who are 55 years or older and present without a fever will have an ischemic source for their chest complaints.
In the past, the emergency physician has used the history, presence of cardiac risk factors, and ECG to predict the patient’s likelihood of having USA. This approach lead to missed AMIs and missed chances to intervene early in the course of acute coronary ischemic syndromes. To decrease these errors, many emergency physicians have developed multi-modal strategies and strict protocols to definitively evaluate chest pain in the emergency department. To enhance detection of acute coronary ischemia, new cardiac markers, intra-departmental exercise testing, and coronary observation units may be used to improve the diagnostic accuracy of the ED physician.
The therapeutic landscape for USA has also changed. Over the past 10 years, new medications have been introduced that are especially useful in USA. In particular, the low-molecular-weight heparins have been shown to be as effective as conventional heparin and much easier to use; one agent, enoxaparin, has even been shown to be superior to unfractionated heparin. A new class of drug, the glycoprotein IIb/IIIa inhibitors, is now prescribed for some patients with USA, especially if they have failed traditional therapies.
With these issues in clear focus, this review examines diagnostic and therapeutic protocols useful in USA from the viewpoint of the emergency physician. Because it is usually not possible to separate cardiac from non-cardiac chest pain in the ED, the article discusses diagnosis and identification of patients at risk for complications of CHD in detail. State-of-the-art treatment and further ED evaluation are discussed, with emphasis on new medications and diagnostic strategies.
— The Editor
Introduction
CHD is the single most important cause of mortality in American men and women.1 Currently, 12 million Americans have a history of MI or angina or both. It is estimated that 7.2% of all Americans older than age 20 have CHD. In the year 2000, an estimated 1.1 million Americans will have new or recurrent coronary symptoms. In 1996, 476,124 Americans died of CHD, about one-half of them within one hour of the onset of symptoms.1
In the United States, significant health care resources have been devoted to the treatment of CHD, yielding impressive improvements in morbidity and mortality. For example, the death rate from CHD fell 27% from 1986 to 1996. Despite these reductions in mortality, in 1997, there were 429,000 hospital discharges with USA listed as the first diagnosis.4 USA, a condition intermediate in severity between stable, exertional angina and AMI, usually provides an opportunity to intervene before there is irreversible damage to the patient’s coronary architecture or myocardium. By correctly identifying and treating USA in the setting of coronary artery disease (CAD), the ED physician may prevent heart attack and death.
Unstable Angina: Clinical Classification
USA is a clinical syndrome rather than a discreet disease. Classically, USA has been characterized as accelerating angina or rest angina. This pattern has been observed by practitioners for years and has been noted to herald MI or sudden death. To enhance the consistency of the diagnosis and to provide more accurate measurement of clinical response to treatment, the Agency for Health Care Policy and Research (AHCPR) has issued clinical guidelines for USA that emphasize three distinct presentations: 1) rest angina; 2) new-onset angina; and 3) increasing angina.5 Rest angina is associated with anginal symptoms occurring at rest that last longer than 20 minutes and which have occurred within a week of presentation. New-onset angina is angina with onset within two months of presentation that occurs with walking 1-2 blocks or climbing one flight of stairs. Accelerating angina is angina that occurs more frequently, is longer in duration, or begins with less provocation.
The AHCPR definition of USA includes new-onset chest pain, non-Q wave MI, and post-infarction angina. Non-Q wave MI is included because it is initially impossible to differentiate these patients from those with traditional USA. In the ED, the clinical diagnosis of USA will also include patients in this group as well as some patients who ultimately prove not to have CHD. This is to be expected, since the intent of the AHCPR definition is "to include all patients with acute presentations with the exclusion only of those with reperfusion-eligible AMI."5 Accordingly, in the ED the patient is given the provisional diagnosis of USA based on a pattern of symptoms and the absence of AMI on ECG. This diagnosis is then revised as additional information becomes available.
Clinical Pathophysiology
In stable angina, chest pain occurs when myocardial oxygen demand exceeds the ability of the coronary artery to supply oxygenated blood. As a normal subject exercises, myocardial work increases, which is accompanied by an increase in myocardial oxygen demand. Normal coronary arteries dilate in response to this demand and coronary blood flow increases. In a subject with CHD, a fixed obstruction in a coronary artery limits blood flow through the diseased artery. Consequently, with exercise, myocardial oxygen demand increases while oxygen supply remains fixed, resulting in chest pain. With rest, myocardial oxygen demand falls below the upper limit of supply and pain is relieved.
The development of true USA implies a rather precipitous and critical reduction in coronary artery blood flow. Four possible causes of this diminution in coronary flow have been identified.6
1. Non-occlusive thrombosis on a pre-existing plaque. A pre-existing plaque is disrupted, resulting in a thrombus that doesn’t completely occlude the coronary artery.7 Non-occlusive thrombi have been identified on angiography and coronary angioscopy.8,9 This mechanism is the presumed etiology for the majority of patients with USA.
2. Coronary vasoconstriction. Coronary vasoconstriction is seen in Prinzmetal’s variant angina; it can be caused by adrenergic input, cold stimuli, or cocaine.10 Vasospasm may also explain ischemia associated with microcirculatory angina, in which small intramural branches of coronary vessels constrict and lead to pain, while epicardial arteries remain normal.11
3. Progressive coronary obstruction. The coronary artery progressively narrows until the stenosis is sufficiently severe to produce pain even at rest.12 This mechanism is observed when restenosis occurs following PTCA.
4. Coronary inflammation. New evidence suggests that inflammation plays a role in atherogenesis and thrombogenesis. Inflammatory markers, such as C-reactive protein and amyloid A, have been predictive of mortality and future cardiac events in unstable coronary syndromes.13-15 There is an association between Helicobactor pylori infection and CHD as well as an association between Chlamydia pneumoniae antibodies and CHD.16-19
It should be emphasized that extra-cardiac factors can increase myocardial oxygen demand and present as USA. In this regard, the clinician should search for precipitants of USA such as anemia, fever, hypoxia, arrhythmias, thyrotoxicosis, aortic stenosis, sympathomimetic drug therapy, and cocaine use.
While multiple mechanisms may play a role in the pathogenesis of USA, most often a non-occlusive thrombosis at the site of a pre-existing plaque is responsible for reducing coronary flow. In non-Q wave MI, it is postulated that complete occlusion occurs but lasts less than one hour.20 Alternatively, total coronary occlusion may occur in an area supplied by collaterals. This collateral blood flow limits the amount of myocardial necrosis. In both mechanisms, the amount of myocardial necrosis is limited, producing enzymatic evidence of infarction, but no Q waves.7
Prognosis
The precise prognosis is difficult to establish for USA because different studies have used different definitions of USA and, hence, different pools of patients. One trial followed all patients admitted to ICUs in Hamilton, Ontario, during 1979 and found 1.5% in-hospital mortality and a mortality rate of 16% at one year for patients with USA.21 Other studies have yielded similar numbers, with in-hospital mortality rates ranging from 0.2% to 1%21,22 and one year mortality rates ranging from 9% to 18%.22-25 As might be expected, the complication rates for non-Q wave MI are much higher. The TIMI IIIB trial found that patients with non-Q wave MI had a 70% higher risk of death or AMI at six weeks than those with USA (8.6% for those with non-Q wave MI vs 5% for those with USA).26 Similarly, in the GUSTO-IIb trial, which included 8001 patients with non-Q wave MI or USA, one-year mortality was 11.1% in the non-Q wave MI group vs. 7.0% in the USA group.27
Initial Patient Evaluation and Diagnostic Database
When a patient presents to the ED with chest pain, the physician has three immediate goals: 1) to quickly identify those with AMI who will benefit from reperfusion therapy, whether it be thrombolytic or procedural coronary intervention; 2) to identify those patients at risk for complications of CHD; and 3) identify patients with "intermediate" acute coronary ischemic syndromes (i.e., USA or NQMI) who will benefit from established therapeutic protocols using aspirin and low molecular weight heparin (LMWH).
This initial identification and clinical stratification of patients is important because of the limited window of opportunity for reperfusion therapy and because short-term complications of acute coronary syndromes (ACS) are common and serious. In this regard, the Multicenter Chest Pain Study examined 10,682 ED chest pain patients for events within 72 hours.28 ACS was diagnosed in 31%, AMI in 15%, and major events (malignant arrhythmias, cardiogenic shock or pulmonary edema requiring intubation, cardiac arrest or recurrent ischemia requiring revascularization) occurred in 4.5%. Another study evaluated 7157 consecutive patients presenting to one ED.29 Of these, 4690 were admitted, 921 (12.9% of those evaluated) had AMI within 72 hours and 18% of these died or suffered serious complications.
To perform this critical initial triage, the physician has three tools: history, physical exam, and ECG. Each is discussed in detail in sections following.
Clinical History. The time-honored, cardiac risk factors of family history, age, sex, smoking, diabetes mellitus, elevated cholesterol, and hypertension are often used by the ED physician to estimate the likelihood of CHD in the chest pain patient.30 However, these classic risk factors predict the lifetime risk of developing CHD, not the likelihood that this patient’s acute presentation is because of ACS. The Multicenter Chest Pain Study identified the following features as predictive of AMI: prior history of ischemic heart disease, pain worse than usual angina, pain similar to prior AMI, pain lasting more than one hour, and radiation to left shoulder or arm.31
In one study, age, the degree of clinical suspicion of AMI, a history of congestive heart failure (CHF), history of diabetes mellitus, and loss of consciousness were the best predictors of in-hospital mortality. A prospective validation of the Braunwald classification of USA patients identified age and diabetes mellitus as the only risk factors that were predictive of major adverse cardiac events.32 Based on these investigations, a prior history of CHD, diabetes mellitus, or history of CHF and age will be more predictive of acute events than the traditional risk factors for CHD.
Unfortunately, the patient who presents to the ED rarely presents with the textbook description of angina. More often, the patient’s story contains a combination of typical and atypical clinical features. In 1985, one study collected detailed histories in 596 patients presenting to the ED with chest pain.33 Among these patients, 104 had AMI and 143 had USA. While no single variable could predict AMI or USA, acute coronary ischemic disease was more likely to be the cause of chest pain in older patients, in men, and in those who described their pain as pressure, burning, indigestion, "a knot," suffocating, or "bricks."
Pain that was reproducible, pleuritic, or positional in character was less likely to be due to acute coronary ischemia, although none of these components could completely exclude AMI or USA. A similar study of 540 ED patients with chest pain found that age older than 65, retrosternal pain, radiation to both shoulders, and such associated symptoms as nausea, diaphoresis, and dyspnea were predictive of AMI.34 The Multicenter Chest Pain Study found stabbing pain, reproducible pain, and pain radiating to the back, legs or abdomen to negatively predict AMI, but not exclude it.31
Physical Exam. Physical exam results are most often normal in USA and, therefore, not very helpful in distinguishing ACS from non-cardiac causes of chest pain. Signs of myocardial dysfunction are helpful when present. Patients with a third heart sound, a fourth heart sound, or rales on ED physical examination are at significantly greater risk for serious cardiovascular complications.35 Tierney noted that heart rate and blood pressure did not differ between patients with AMI and those without AMI, but those with infarctions more often had cyanosis, rales, third heart sound, and diaphoresis.34
Chest pain reproduced by chest wall palpation is less likely to have a cardiac cause, but this finding does not exclude ACS. Reproducible chest pain may be found in up to 15% of patients with AMI.33,34 Physical exam should concentrate on finding signs of myocardial dysfunction, which may need to be treated and can predict adverse outcomes.
Electrocardiogram. The ECG is the single best test for initial evaluation of patients who present to the ED with acute chest pain.33 Accordingly, the ECG must be obtained promptly in all patients presenting to the ED with chest pain in order to identify those individuals who will benefit from thrombolytic therapy or emergent angioplasty. The ECG is also used to diagnose ischemia in those with atypical presentations, to suggest alternate diagnoses such as pulmonary embolus and pericarditis, and to help identify patients at risk for adverse events.
Employing strict criteria for AMI (ST elevation of at least 1 mm in two contiguous leads, pathologic Q waves, or LBBB not known to be old), the ECG, nevertheless, will miss many patients with AMI; conversely, nearly all patients identified as having AMI on ECG will have AMI confirmed as their final diagnosis. Applying strict ECG criteria, the Multicenter Chest Pain Study found a sensitivity of 61% (positive predictive value, 73%) and a specificity of 92% (negative predictive value, 92%) using ECG criteria for AMI.36
Unfortunately, it is difficult to generate comparable statistics for ECG-mediated diagnosis of USA, in part because there is no quantifiable "gold standard" for USA. Moreover, USA is a "transitional" acute coronary ischemic syndrome, and therefore, its presence can only be suggested by correlating clinical symptoms characteristic of angina with ECG evidence of underlying ischemia that has not evolved to the myocardial infarction.
Nevertheless, specific ECG changes may help clarify the clinical picture and suggest the presence of USA. For example, transient ST- or T-wave changes that develop during an episode of angina and then resolve as symptoms resolve, strongly suggest USA and the presence of severe CHD.5 Even in the absence of anginal symptoms, an ECG that reveals ST-segment depression greater than 1 mm, T-wave inversion 1 mm or greater, and deeply inverted symmetrical precordial T-waves suggests ischemia. Old pathological Q-waves indicate a prior AMI. Non-specific ST- and T-wave changes (ST-deviation or T-wave inversion less than 1 mm) are less helpful. One study found non-specific changes in 24% of patients with USA and in 32% of patients not diagnosed with ACS.33
The ECG changes of ischemia are present in less than one-third of those with ACS, but when present, they offer useful prognostic information. Multiple studies have shown that transient ST segments shifts greater than 1 mm or transient T-wave inversions coincident with anginal symptoms, as well as non-transient ST-depression and significant T-wave inversions, can predict AMI and major cardiac events.31,36-38 In the TIMI III registry, new ST-segment deviation of 1 mm or greater was present in 14.3% of 1416 patients admitted with USA, isolated T-wave inversion in 21.9%, and LBBB in 9%. At one-year follow-up, death or MI had occurred in 11% of the patients with ST-segment deviation and in 6.8% with new, isolated T-wave inversion as compared with 8.2% with no ECG changes.39 From a practical, clinical perspective any ECG changes, especially those suggestive of acute coronary ischemia, should prompt consideration of intervention in patients presenting with angina-like chest pain.
It should be stressed that a normal ECG cannot exclude ACS or even AMI. One major trial found that 4.1% of patients with a normal ECG had AMI or USA.33 Another study noted that 6% of 1576 patients admitted for ACS with a normal ECG had AMI confirmed prior to discharge.40 Although an ECG cannot definitively rule out AMI, a normal ECG is a good prognostic factor. Three studies found the risk of life-threatening events to be 0-0.6% during the hospitalization of chest-pain patients with a normal ECG upon admission.41-43 Accordingly, a normal ECG is an independent predictor of good outcome.
Although the ECG is useful for directing treatment and triage of ED chest pain patients, it has well-documented limitations. First, the ECG is a limited sample of a complex clinical event. The ECG is more likely to be diagnostic if obtained while the patient is symptomatic. Second, the ECG will be difficult to interpret in the presence of baseline abnormalities such as LBBB, LVH, and early repolarization. Third, the ECG does not sample all areas of the heart well and may not detect small areas of ischemia. Finally, the ECG is only as good as its interpreter. One investigator found ST-elevation in 25% of patients who were sent home with AMI.44 The ECG should be read carefully and repeated as the clinical situation changes, especially with recurrent chest pain.
Cardiac Markers. Among cardiac markers used for diagnosis of acute coronary ischemia, creatinine kinase (CK) is the best-studied marker of myocardial necrosis. CK is an enzyme that reversibly converts creatinine phosphate and adenosine diphosphate to creatinine and adenosine triphosphate (ATP). CK consists of three isoenzymes: CK-MM, which is found mostly in skeletal muscle, but also in heart muscle; CK-BB, which is found in kidney and brain tissue; and CK-MB, which is found in highest concentration in the myocardium. Myocardial necrosis releases both CK-MM and CK-MB. For each unit of CK-MB released from damaged heart muscle, 4-5 units of CK-MM are released.45
The sensitivity of a single CK-MB drawn in the ED varies from 34% to 96%, depending on how long after the onset of symptoms the sample is drawn.45 CK-MB is elevated 6-10 hours after cessation of coronary blood flow to an area of myocardium. CK Index (CK-MB/total CK) over 12-24 hours is currently the test of choice for diagnosis of AMI.
CK-MB has limitations as a diagnostic tool. It is insensitive before six hours and after 48-72 hours, and loses some specificity due to the presence of small amounts of CK-MB in other tissues. These disadvantages have lead to the investigation of other serum makers for the diagnosis of AMI. Notable among other markers is myoglobin, a heme protein present in all muscle tissue. It is released within two hours of the onset of AMI, but may be elevated in many conditions other than AMI.
In contrast, the troponin complex is part of the contractile apparatus of all muscle cells. The myocardial troponin complex contains three subunits—T, I, and C. Cardiac troponin T and I (TnT and TnI) are specific to the myocardium. TnI and TnT persist in the serum 4-7 days longer than CK. Because of this, troponin measurements have largely supplanted LDH for the late diagnosis of AMI.
In the absence of ST-elevation and/or Q waves, elevated CK-MB levels have been used to distinguish USA from non-Q wave MI. Troponin I and T have been shown to predict subsequent AMI and death in patients with USA. A 1998 meta-analysis of studies evaluating the predictive value of TnT and TnI in USA confirms this.46 Eleven studies followed a total of 2847 USA patients for a median of 30 days. Elevated TnT conferred an odds ratio of 2.7 for the risk of AMI or death. Nine studies of 1901 patients with a median follow-up of 42 days were compiled for the meta-analysis of TnI in USA. The meta-analysis revealed a cumulative odds ratio of 4.2 for AMI or death in USA patients with elevated TnI during the follow-up period.45
Tables 1 and 2 summarize those factors from the history, physical exam, ECG, and initial enzymes, which predict high and low risk of complications.
| Table 1. Predictors of High Risk of Complications in Unstable Angina |
| History |
| • Prior CAD |
| • Pain worse than usual or like prior MI |
| • Pressure, burning, or indigestion-like pain |
| • Pain > 1 hour, but < 48 hours |
| • Radiation to left or both shoulders |
| • Nausea, diaphoresis, or dyspnea |
| • High clinical suspicion |
| • History of CHF, DM, or loss of consciousness |
| • Age: M > 60, F > 70 |
| Physical exam |
| • S3 or S4 |
| • Rales |
| • Cyanosis |
| • Diaphoresis |
| ECG |
| • Transient ST depression, T-wave inversion, or ST elevation during pain |
| • ST segment depression > 1 mm |
| • Marked symmetrical T-wave inversion in multiple precordial leads |
| Laboratory |
| • Elevated CK-MB |
| • Elevated cardiac index (CK-MB/total CPK) |
| • Elevated troponin I or T |
| Table 2. Predictors of Low Risk of Complications in Unstable Angina |
| • Reproducible chest pain |
| • Pleuritic chest pain |
| • Stabbing pain |
| • Radiation to back, legs, or abdomen |
| • Normal ECG |
Pharmacotherapy for Unstable Angina: Evidence-Based Interventions
Acute therapy for USA can be conveniently divided into anti-ischemic therapy, anti-platelet therapy, and anti-thrombotic therapy. Treatment priority should be given to aspirin and anticoagulant therapy, as these are supported by strong evidentiary trials demonstrating reduction of AMI and death. Table 3 presents commonly used medications and recommended dosing. If aggressive medical management fails to stabilize the patient and relieve symptoms, emergent cardiac catherization should be considered. (See Figure 1.)
| Table 3. Medications for Unstable Angina | ||||
| Medication | Route | Dose | Frequency | Contraindications |
| Aspirin | PO | 81-325 mg | daily | Major hemorrhage, distinct allergy |
| Heparin | IV | 80 U/kg IV bolus | 18 U/kg/h infusion | Active hemorrhage |
| LMWH Enoxaparin | SC | 1 mg/kg SC | q 12 hours | Active hemorrhage, pre-disposition to hemorrhage |
| GRI (GIIb/IIa receptor inhibitor) abciximab | IV | 0.25 mg/kg IV bolus | 10 mcg/min infusion x 12 hours | Active hemorrhage, pregnancy, predisposition to hemorrhage |
| Nitroglycerin | SL to chest wall IV | 0.4 mg one-half - 2 in. 50 mg in 250 D5W | q 5 min x 3 q 8 hours 10-20 mcg/min (3-6 mL/h), titrate to relieve pain, keep SBP > 90 | SBP < 90 |
| Metoprolol | IV | 5 mg | q 5 min x 3 | COPD, CHF, AV block, asthma, hypotension, bradycardia |
| Morphine | IV | 2-5 mg | q 5-30 min prn | Allergy, hypotension |
| Diltiazem | IV | bolus: 20 mg over 2 min | infusion: 5-15 mg/h | AV block, CHF, bradycardia, hypotension |
Anti-Platelet Therapy—Aspirin. First introduced in the 18th century, aspirin is the most widely used antiplatelet agent. Aspirin blocks the action of cyclooxygenase, which catalyzes the conversion of arachidonic acid to prostaglandin endoperoxides, the precursor of thromboxane A2. Thromboxane A2 promotes platelet aggregation, amplifies other platelet modulators, and is a mild vasoconstrictor. Aspirin inhibits more than 93% of thromboxane A2 activity within 15 minutes of low-dose administration, but does not block thrombin-induced platelet aggregation. Aspirin does not inhibit shear-induced platelet aggregation a pathologic process which can occur with the plaque disruption and frequently precedes AMI and other ACSs, including USA.
Aspirin remains the least expensive and safest antithrombotic agent shown to be effective for AMI and ACS. Importantly, this agent is effective in both the acute (USA, AMI) and chronic (post-infarction) phase of cardiovascular disease. During the acute phase of coronary occlusion, aspirin reduces the risk of fatal and nonfatal AMI by about 71%, and by 52% at two years.47,48 To evaluate the cardioprotective properties of aspirin, the VA Cooperative Study Group randomized 1266 male patients admitted with USA to treatment with 325 mg aspirin per day or placebo.49 There was a 51% reduction in both fatal and nonfatal AMI in the aspirin group at 12 weeks. Unfortunately, there are no randomized trials to suggest a specific aspirin dose for ACS, but most trials for acute coronary disease and AMI suggest starting daily doses at 75-324 mg/d.50 The ISIS-2 trial reported a starting dose of at least 160 mg followed by 80-324 mg daily for long-term, post-acute management of USA.51
Given its favorable risk benefit-to-risk ratio, documented benefits, and attractive cost, the ACC/AHA task force on heart disease has recommended that all patients with suspect USA should receive aspirin (160-325 mg) unless there is a definite contraindication (i.e., life-threatening hemorrhage or a history of hypersensitivity to the drug).2 An additional rationale for the early use of aspirin in USA is its well-documented, independent benefit in AMI. Administration of aspirin to all patients with USA ensures that those patients with AMI initially classified as USA will be benefit from the cardioprotective properties of acute aspirin therapy.
Unfractionated Heparin (UFH) and Low Molecular Weight Heparin. Atherosclerotic plaque disruption associated with endothelial shearing results in thrombin generation and platelet activation. Heparin facilitates the action of circulating antithrombin III, an enzyme that inhibits thrombin and several other activated factors essential for the clotting cascade. Heparin’s advantage over aspirin in USA results from its direct antithrombin action. Although this action prevents new clot formation, it does not dissolve existing thrombus.
Five trials have evaluated the effectiveness of unfractionated heparin (UFH) in the management of USA.47,50,52 A 1989 double-blind trial randomized 479 patients with USA into groups receiving aspirin, UFH, both, or neither.52 All treatment arms experienced significantly fewer AMIs than the placebo group. There were no significant differences between treatment groups, but the combination of aspirin and UFH was associated with more episodes of serious bleeding (3.3% vs 1.7%). In a similarly designed investigation enrolling 796 men, the RISC trials of 1990 reported that aspirin reduced the risk of AMI and death while heparin had no significant influence on the event rate.47 It was noted, however, that the group treated with heparin and aspirin had the lowest event rate during the first five days following onset of ischemic symptoms.
The latest study to address the use of heparin compared UFH with aspirin in 484 USA patients using a randomized, double-blind design.53 Patients were followed for 5.7 ± 3.3 days. AMI occurred in 0.8% of those treated with heparin and 3.7% of those receiving aspirin. A follow-up of his 1989 study of 479 patients reported reactivation of angina following discontinuation of therapy in significantly more patients who had received heparin than in those treated with aspirin or heparin and aspirin.54 From these data, while it is not clear which is the better agent, or what precise advantage combination confers, it is clear that both heparin and aspirin are beneficial in USA.
There are no clear data to support continuous infusion of UFH over intermittent injection for USA, but the ACC/AHA guidelines recommend continuous infusion since it may reduce bleeding complications. The current recommended dosing is a bolus of 80 units/kg followed by a continuous infusion of 18 units/kg/hr to maintain an aPTT of 1.5-2.5 times control.2
It should be stressed that UFH has several disadvantages as an antithrombotic agent. For example, at therapeutic levels, it can lead to thrombin formation by activating platelets. Also, thrombin generation has been reported after discontinuation of UFH. UFH is difficult to administer because it requires continuous intravenous infusions and frequent monitoring of aPTT. The incidence of heparin-induced thrombocytopenia (HIT) is significant, and is greater in patients receiving GIIB/IIIA antiplatelet receptor inhibitors.
Low Molecular Weight Heparins. To circumvent these limitations and pitfalls of UFH, and also to evaluate the possibility of improving patient outcomes in ACS, LMWHs, such as enoxaparin, have been intensively studied as a possible replacement for UFH in patients with USA and other acute coronary ischemic syndromes, including NQMI. From a pathophysiological perspective, LMWHs are more potent inhibitors of thrombin generation than UFH and are resistant to inhibition by activated platelets. The antithrombotic activity provided by LMWHs stabilizes the plaque, allowing the healing plaque to develop a smooth muscle layer with less disruption and dminished plaque propagation rates. This process is referred to as passification. Other benefits that LMWHs possess as compared to UFH include relatively simple dosing, ease of administration, limited requirements for further blood monitoring, and a more predictable anticoagulant effect.55-57
The rationale for use of LMWHs in acute coronary ischemic syndromes is supported by a number of evidentiary trials; in fact, the use of LMWHs in USA has been evaluated in five large trials.58 The FRISC (Fragmin during Instability in Coronary Artery Disease) compared ASA and placebo vs. ASA and dalteparin.59 The addition of LMWH within 72 hours of presentation with ACS resulted in significantly fewer deaths, a reduced risk of myocardial infarction, and fewer urgent revascularization procedures than placebo. By 150 days, however, LMWH and ASA were no better than ASA alone.
The FRIC (Fragmin in Unstable Coronary Artery Disease) did not demonstrate any benefits from LMWH (dalteparin) over standard UFH using the same three end points (death, MI, urgent revascularization) in either the acute phase (6 days) or the chronic phase (40 days).60 The FRAXIS trial infused nadroparin for 6 or 14 days vs. UFH for six days.61 At 90-day follow-up, no significant reduction in recurrent angina, MI, or urgent revascularization was achieved by extending the course of the LMWH. In contrast, studies with other LMWHs, in particular, enoxaparin (Lovenox), have yielded more favorable results, with some analyses and trials suggesting superiority compared to UFH.
Enoxaparin. The ESSENCE trial was designed to compare the long-term benefits of short courses (48 hr to 8 d) of enoxaparin and UFH.62 The ESSENCE trial evaluated the same end points used in FRISC and FRIC at one year. Enoxaparin significantly reduced the 30-day combined end points from 32.2% with UFH to 27.0%. Statistically significant benefits with enoxaparin were observed at one year following the acute event (P = 0.022).
The TIMI 11B trial compared enoxaparin with UFH in patients with USA and non-Q wave MI.63 The trial included an additional bolus of LMWH (enoxaparin) at enrollment and an extended treatment arm. The extended arm continued LMWH for 43 days after enrollment. Enoxaparin provided statistically significant reductions in coronary revascularization procedures, MI, and death as compared with UFH at eight days and at 43 days. No further relative decrease in end points occurred with the extended outpatient enoxaparin treatment, although the reductions in end points persisted at one year following therapy.
The investigators of the ESSENCE and TIMI 11B trials attempted to determine whether enoxaparin had a positive effect on the composite occurrence of death, MI, or recurrent angina at pre-specified time periods after treatment. They also wanted to determine the effect that enoxaparin had on the composite double end point of death and MI.
In this regard, both the ESSENCE and TIMI 11B trials showed that enoxaparin significantly reduced the occurrence of death, MI, or urgent revascularization in patients with USA/NQMI. However, neither study independently examined enough patients to detect significant differences between enoxaparin and UFH on outcomes other than the triple end points of both trials. Accordingly, to provide a more statistically sound estimate of the effect of enoxaparin has on death and serious cardiovascular events, a prospective meta-analysis of the ESSENCE and TIMI 11B trials was performed.64 This allowed data from both studies to be combined to potentially yield more important results that might have been missed by small studies due to small sample size. The meta-analysis of ESSENCE and TIMI 11B was possible because of the similarities between the two study populations.
In the meta-analysis, the odds ratio (OR) for enoxaparin vs. UFH, along with its 95% confidence interval (CI), was estimated for each end point of interest from the pooled data from the ESSENCE and TIMI 11B trials. Specifically, the end points of interest included all-cause mortality, recurrent myocardial infarction, urgent revascularization, and major hemorrhage. The OR and CI were estimated at day 2 (period of direct comparison of UFH vs enoxaparin); day 8 (end of acute phase management); day 14 (time of ascertainment of primary end point in ESSENCE); and day 43 (end of outpatient phase in TIMI 11B).64
Results of this meta-analysis showed that enoxaparin provided a statistically significant reduction in the occurrence of composite double (death/MI) and triple end points (death/MI/recurrent vascularization).64 Of clinical importance is that these benefits were confirmed without a significant increase in the incidence of major bleeding, although there was a slight increase in minor hemorrhage in those treated with enoxaparin.
The investigators suggest that the increased efficacy of enoxaparin as compared to UFH in treating patients with USA/NQMI may be the result of several pharmacologic differences between enoxaparin and UFH. Among the advantages associated with enoxparin are the following: better bioavailability; specificity of binding to factor Xa; and less sensivity to inhibition of platelet factor 4.
In summary, enoxaparin is the only LMWH that in prospective, clinical, and meta-analaysis trials has consistently demonstrated superiority over UFH in the management of UA and NQMI. Although large trials comparing the LMWHs to each other are lacking, in all studies LMWHs were at least as beneficial as UFH. However, only enoxaparin has demonstrated benefit over UFH in two trials, which enrolled more than 7000 patients, perhaps because of its higher Xa to antifactor IIa activity.56 Consequently, LMWHs, especially enoxaparin, should be considered for all patients presenting with ACS without ST segment elevations.65 Based on these studies, a number of authorities, consensus guidelines, and clinical reviews have encouraged clinicians to use enoxaparin as the preferred agent (rather than UFH) for managing patients with USA and non-Q-wave MI.
Platelet Glycoprotein IIb/IIIa Receptor Inhibitors (GRIs). Platelet glycoprotein IIb/IIIa receptor inhibitors (GRIs) are a new therapeutic class representing one of the most potent antiplatelet modalities developed for coronary syndromes. The glycoprotein IIb/IIIa receptor complex, found on the platelet surface, develops high affinity for fibrinogen and von Willebrand’s factor when activated. Fibrinogen and von Willebrand’s factor bind glycoprotein IIb/IIIa on adjacent platelets, resulting in platelet adhesion. The GRIs were designed to block the glycoprotein IIb/IIIa receptor because this is the final common pathway for platelet aggregation.66 The drug design mimics the fibrinogen binding sequence of the IIb/IIIa receptors synthetically or by monoclonal antibody to the receptor (abciximab, Reopro). Although GRIs inhibit platelet aggregation, they do not inhibit platelet adhesion or dissolve existing thrombus.
Eptifibatide and tirofiban are small molecules that competitively bind the IIb/IIIa receptor and have a 2- to 3-hour half-life. Abciximab, a monoclonal antibody, has a high affinity for the IIb/IIIa receptor, which results in a long (12-24 hour) half-life. The most common side effects of GRIs are bleeding complications. Antibodies do develop to abciximab, leading to concerns about anaphylaxis, thrombocytopenia, and reduced effectiveness with readministration of the drug.67 At this point, these potential reactions have not been reported, but the number of patients having repeat courses of abciximab is probably small.
Early trials studied the benefits of GRIs for patients prior to invasive percutaneous coronary interventions (PCI) such as coronary angioplasty. The EPIC trial added abciximab infusions to heparin and ASA prior to PCI.68 The abciximab treatment group enjoyed a 62% reduction in death, MI, and unplanned revascularization procedures at 30 days (P = 0.14), which did not achieve statistical signifiance. Abciximab without heparin did not effectively reduce composite end points after angioplasty. The abciximab and heparin treatment-arm resulted in higher rates of bleeding in this trial, but it is unknown if the bleeding was due to abciximab or heparin.
Two additional trials (EPILOG and CAPTURE) treated all patients with weight-adjusted heparin and randomized patients to receive abciximab or placebo prior to PCI.67,69 Results of both trials reported significant reductions in composite end points that were similar to EPIC at 30 days, without increased risks of major bleeding. In CAPTURE, 1265 refractory USA patients received abciximab and weight-based heparin prior to PCI. Progression to AMI prior to PTCA decreased from 2.1% (placebo) to 0.6% (GRI), P = 0.029. Significant triple end point reductions were noted through 30 days (P = 0.012), but not at six months. Similar short-term risk reductions prior to PCI were reported with eptifibatide and tirofiban (IMPACT-II, and RESTORE).70,71 However, only abciximab reported significant reduction in infarction or worsening ischemia both prior to and following PCI.
Trials using GRIs prior to PCI suggest that the addition of a GRI, specifically abciximab, along with weight-adjusted heparin and ASA, should be considered in any ACS patient who requires urgent PCI. Studies evaluating the combination of abciximab and enoxaparin also are progress.
The efficacy of intravenous GRIs for ACS (MI without ST segment elevation and USA) is reported in a number of large trials. The PRISM trial compared tirofiban to heparin in 3232 patients presenting with ACS.72 The composite end points of death, MI, or urgent revascularization were reduced from 5.6% to 3.8% (P = 0.01) with tirofiban at 48 hours. However, no composite end point reductions persisted at 30 days.
The PRISM-PLUS trial randomized 1915 patients with severe non-Q wave ACS to either treatment with tirofiban, heparin, or both.73 The primary end points of death, AMI, or refractory ischemia were reduced at seven days in the tirofiban/heparin group (12.9%) when compared with heparin alone (17.9%, P = 0.004). PRISM-PLUS reported sustained significant reductions in death and MI at 30 days with the tirofiban/heparin combination (8.7%) vs. heparin (11.9%, P = 0.02), as well as a 14% reduction of further events by 60 days. The tirofiban-alone arm was discontinued due to excessive mortality.
The PURSUIT trial of 10,948 patients with ACS compared low-dose eptifibatide, high-dose eptifibatide, and heparin.74 High-risk presentations, including those with elevated myocardial markers or ST segment elevations, were enrolled. The low-dose arm of the trial was discontinued after interim analysis supported safety with higher-doses. Heparin was encouraged in the GRI arm. Results indicated a significant reduction in nonfatal MI and death in the GRI group (5.9%) vs. placebo (7.9%, P = 0.001). These results remained significant at seven days. For those requiring PCI, the benefits extended to 30 days.
An analysis of data from the three ACS trials enrolling patients without persistent ST elevation (CAPTURE, PURSUIT, and PRISM-PLUS) concluded that the three trials combined (n = 6125) resulted in a 2.5% rate of death or nonfatal MI during the GRI infusion period vs. 3.8% for placebo (n = 6171).75 The results imply a 34% relative reduction (P < 0.001) in adverse coronary events when using GRIs along with aspirin and heparin. The results of the ACS trials clearly demonstrate benefits from early aggressive medical intervention in ACS with or without ST segment elevations.65,76 Reduced MI and death rates with GRIs are demonstrated prior to PCI, during the immediate post intervention period, and extending at least to 30 days. However, long-term benefits are not always reproducible. Given the cost of the GRIs and the lack of cost-benefit data, it is prudent to limit GRI use to patients at high risk for adverse cardiac events.76 As there are no trials comparing GRIs to each other, we cannot recommend a particular agent, except for abciximab prior to PCI.
Anti-Ischemic Therapy
Oxygen. Oxygen is commonly given to all patients with chest pain; interestingly, there is no evidence that this agent improves clinical outcomes when used on a routine basis. Accordingly, oxygen should be reserved for those patients with suspected or confirmed respiratory distress and in those with hypoxemia documented by pulse oximetry.
Nitroglycerin. Nitroglycerin was first used for the relief of angina in 1879.77 Nitroglycerin relaxes vascular smooth muscle in veins, arteries, and arterioles. It causes systemic venous pooling, resulting in decreased preload and decreased myocardial oxygen demand. It may also vasodilate coronary arteries, thereby improving myocardial oxygen supply. The decreased preload may cause hypotension in patients with marginal BP, right ventricular infarct, or inferior MI. This is usually easily treated with a bolus of normal saline.
There are only small studies evaluating use of nitrates in USA. These studies (along with years of clinical experience) indicate that nitrates relieve angina and prevent recurrence. Although there is no evidence that nitrates improve prognosis in USA, a meta-analysis compiling multiple small trials of nitroglycerin in AMI demonstrates a 35% reduction in mortality.78 Current standard therapy for patients presenting to the ED with possible ACS is up to 0.3-0.4 mg sublingually nitroglycerin doses as tolerated by blood pressure. If SL dosing does not relieve pain, IV nitroglycerin should be initiated. The drip should be titrated to relieve symptoms while maintaining systolic BP over 90 mmHg.
Morphine. Morphine is a powerful analgesic. It also has some anxiolytic effects and may reduce preload through vasodilation. The effectiveness of morphine has not been well evaluated, but it may be used when nitrates do not relieve pain and while other therapies are being started.
Beta-Blockers. Beta-blockers reduce myocardial oxygen demand by lowering heart rate and myocardial contractility. Beta-blockers have been shown to reduce mortality and reinfarction in post-MI patients. They have been shown to reduce the frequency of symptoms in patients with stable angina. Such evidence from large studies is not available for beta-blockers in USA. However, a meta-analysis of randomized trials of beta-blockers in USA found a 13% reduction of the risk of AMI in patient with USA started acutely on beta-blockers.79
Propranolol, metoprolol, or atenolol may all be given by slow IV push. A typical protocol to establish beta-blockade is 5 mg metoprolol IV every 5 minutes for a total of 15 mg. Esmolol is an ultra-short-acting agent, which is given by continuous infusion. It may be used for patients with relative contra-indications to beta-blockade such as COPD or mild CHF. Beta-blockers should not be given in the presence of hypotension, bradycardia, or bradyarrhythmia.
Calcium channel blockers. Calcium channel blockers are a diverse group of agents that inhibit calcium movement through slow channels in cardiac and smooth muscle cell membranes. In angina, they prevent vasospasm and decrease myocardial oxygen demand by decreasing afterload, contractility, and heart rate. They may also cause AV node blockade and peripheral vasodilation leading to hypotension. There are few data on the efficacy of calcium channel blockers in USA. Several studies have demonstrated an increase in AMI and mortality when short-acting nifedipine was used alone.80,81 These effects were prevented when the patients were pre-treated with beta-blockers,81,82 and these adverse effects may be unique to short-acting nifedipine. In a 1985 randomized trial comparing diltiazem to propranolol, both agents reduced the number of chest pain episodes. Mortality and AMI rates were similar at five months.83
The suggestion that AMI and mortality rates actually increase when nifedipine is used alone, coupled with the small amount of evidence about channel blocker use in USA, limits the use of the agents in USA. Their proven benefit is limited to symptom control. Calcium channel blockers, preferably diltiazem, should be used only after nitrates and beta-blockers have failed to relieve symptoms.5
Procedural Coronary Intervention
Emergent Cardiac Catheterization and Revascularization. The precise role of emergent (< 6 hours after the precipitating event) catheterization and revascularization in USA is unclear. In the TIMI IIIB trial, 744 of 1473 patients with USA or non-Q wave MI underwent catheterization within 36 hours of admission. No significant coronary obstruction was found in 19%, one-vessel disease was identified in 38%, two-vessel disease in 29%, three-vessel disease in 15% and left main disease in 4%.84 Therefore, a significant number of ED patients initially diagnosed with USA would not benefit from emergent catheterization.
The MATE trial was specifically designed to address the issue of whether routine emergent angiography is of benefit in the ED patient with a preliminary diagnosis of ACS.85 Two hundred-one patients with suspected ACS who were not eligible for thrombolysis were randomized to conservative therapy or angiography as soon as possible. Patients underwent angiography a mean of seven hours after presentation. Of these 111 patients, 58% underwent PTCA or CABG. There was an initial reduction in adverse events (recurrent ischemia and death) in the invasive group, but at the median follow-up of 21 months there was no reduction in rehospitalization, procedure use, or death. In the conservative treatment group, 60% underwent out-of-protocol angiography, and 59% of those patients underwent PTCA or CABG, making the data somewhat difficult to interpret.
In the heterogeneous population of ED patients tentatively diagnosed with ACS, there is no clear benefit that can be ascribed to routine emergent angiography. The current strategy is to direct high-risk patients to early (within 48 hours) catheterization and moderate- to low-risk patients to medical management with provocative testing. Emergent catheterization with revascularization as indicated is recommended for any patient whose pain persists longer than one hour after initiation of aggressive medical therapy or for any patient with recurrent ischemia despite aggressive medical therapy.5
Progressive Evaluation of Acute Coronary Syndromes: The Role of the Intra-Departmental Testing
AHCPR standards published in 1994 recommend that patients with presumed USA who are at high risk of complications be admitted to the CCU.5 Those with moderate risk of complications should be treated in the CCU or an intermediate care area. Patients at low risk for complications who retain a working diagnosis of USA may be discharged for an expeditious (within 72 hour) outpatient work-up.
For the ED physician, sending this low-risk group home can be problematic. For example, the rate of missed MI has been documented to be between 1.9% and 4%.44,84 Missed MI accounts for about 10% of closed malpractice claims and 25% of the cost of closed claims.86 Furthermore, it is often difficult for the patient to get a timely work-up. As a result, the ED physician has an incentive to be very conservative when evaluating chest pain in the ED. These concerns, coupled with the impracticality of admitting every chest pain patient to the CCU, have lead ED physicians to develop strategies to further evaluate the low-risk patient in the ED.
Resting Sestamibi Imaging. Sestamibi imaging is useful in the ED because after technetium-99m-labeled sestamibi (Tc-sestamibi) is taken up by myocardium in proportion to regional blood flow and this uptake remains stable for several hours. Consequently, Tc-sestamibi can be injected in the ED while the patient is having pain and scanned several hours later. In the largest study reporting the use of ED sestamibi, one team of investigators divided 1187 consecutive patients presenting to the ED with chest pain into five groups: AMI on ECG, AMI or USA, probable USA, possible USA, and non-cardiac chest pain.87 Patients with probable or possible USA underwent rest sestamibi. Injection was given with pain when possible. Sensitivity and specificity for AMI were 100% and 78%, respectively. At one year, 42% of the 100 patients with abnormal scans experienced death, AMI, or revascularization. In contrast, in the 338 patients with normal scans there were no deaths of MIs at one year, and only 3% underwent revascularization.
ED sestamibi is a promising technology, but it is expensive, inconvenient, and not yet sufficiently tested. For routine use in the ED, there must be personnel able to process radioactive materials and radiologists must be available to read nuclear scans. Potentially unstable patients must be moved to the nuclear medicine department. Sestamibi is expensive at $500-$800, but it costs less than admission or missed MI. The true utility of sestamibi is presently unknown. Larger studies are needed to establish its appropriate role in the ED.
ECG Exercise Stress Testing. The ECG exercise test is inexpensive, widely available, and easy to interpret. Compared to cardiac catheterization, the sensitivity and specificity of 1 mm ST depression during the ECG exercise test are 50-70% for single vessel disease, and 80-90% for three-vessel disease.88 This sensitivity and specificity rate, however, falls as the pre-test probability of disease falls. Furthermore, the ECG exercise test can’t be interpreted in patients with baseline ECG abnormalities due to LVH, LBBB, or digoxin, and it can’t be performed in those patients who can’t exercise.
Traditionally, patients with suspected USA have not been stressed prior to complete exclusion of AMI. Recently, three studies have investigated the possibility that it is safe to immediate stress a very low-risk subset of chest pain patients.89-91 In one trial, 212 low-risk patients were exercised without measuring enzymes prior to the test. Fifty-nine percent of the patients had negative tests, 29% were non-diagnostic, and 13 patients were positive.90 Further evaluation confirmed CAD in 57% of those with a positive test. At 30-day follow-up no patients had died and none with a negative test had any cardiac event. These studies are interesting because the cost in dollars and in time was much less than with traditional inpatient evaluation. Larger studies are needed to recommend this approach for routine use.
Chest Pain Observation Unit. ED Chest Pain Observation Units have been created in the last decade to provide rapid and safe work-up of potential USA patients at low risk for adverse events. Typically, the patient has ECG-monitoring for twelve hours, a rapid schedule of cardiac enzymes to rule out MI in 9-12 hours, and a provocative test if no AMI is diagnosed. The unit is usually protocol-directed and supervised by ED physicians. Multiple studies have established that these units are safe and effective and provide faster and less expensive evaluations for low risk patients than traditional hospitalization.92-96 One study achieved similar results for patients at intermediate risk.97
Continuous 12-lead ECG Monitoring. An adjuvant to telemetry monitoring used in some chest-pain observation units is 12-lead ECG monitoring. The patient wears 12 leads and the monitor acquires and analyzes a 12-lead ECG every 20 seconds. One sample ECG is saved every 20 minutes. An alarm sounds if ST-segment elevation or depression is detected. The clinician can then view the alarm ECG and stored ECGs. Case reports and anecdotal experiences confirm that these systems can detect AMI before the development of symptoms. In one trial of patients at low risk for USA, the positive predictive value for ST-segment changes identified was less than 50%.68 In the ED, continuous ST-segment monitoring may provide an early warning of AMI, but because of the low positive predictive value of an alarm event, the physician must compare alarm ECGs with baseline ECGs and interpret any changes in light of clinical and laboratory data.
Provocative Testing. In most chest pain observation unit protocols, a provocative test is performed after the patient rules out for MI. Exercise ECG is an inexpensive, widely available test, which is useful for diagnosis of CAD. When the patient is able to exercise, is not on digoxin, and has a normal baseline ECG, it is almost as accurate as exercise-imaging tests for identifying left main and three-vessel disease.98 Furthermore, patients who can exercise to a high workload without evidence of ischemia have a favorable prognosis when treated medically. Even though 20% of these patients will have three-vessel disease,99 prognosis for this subset of patients is excellent.100
Imaging modalities such as thallium, sestamibi, or echocardiography have higher sensitivity than the exercise ECG, are able to localize ischemic regions, and measure LV function; but, they are more expensive. In the low-risk observation patient, ECG stress testing should be the procedure of choice.5,101 An imaging technique should be added when the baseline ECG is abnormal or the patient is taking digoxin. Selection of the particular imaging technique depends on local availability and expertise. When the patient cannot exercise, pharmacological stress with adenosine, dipyridamole or dobutamine must be provided. These agents do not reliably provoke ECG changes, so an imaging technique is always used with pharmacological stress (e.g., dobutamine echocardiography, adenosine sestamibi). Figure 2 is an algorithm designed to assist with provocative test selection.
The results of stress testing may be used to triage patients. A cardiologist should evaluate patients with positive tests or poor exercise tolerance. Non-diagnostic or equivocal exercise ECG tests are repeated with imaging and pharmacological stress, if needed. When evaluating stress test results, it is important to remember that no provocative test can completely exclude CAD. All patients evaluated in the chest pain observation unit should be referred to their primary care doctor for risk modification. Aspirin should be considered in all discharged patients. Patients with moderate risk for cardiac complications, but normal stress testing, should be treated for presumed CAD with risk-modification, aspirin, nitrates, and other agents as determined by their primary care physician.
Clinical Triage Strategy. One study evaluating the usefulness of sestamibi divided all ED patients presenting with chest pain into five groups.87 This is a useful way to think of these patients. Level 1 patients (AMI) meet ECG requirements for thrombolysis and need emergent revascularization. Level 2 patients (AMI or USA) have ECG evidence of ischemia or are at high risk for cardiac complications. Level 3 patients (probable USA) have non-specific ECG findings and/or moderate risk of cardiac complications. Level 4 patients (possible USA) have normal ECG findings and low risk for complications. Level 5 patients have noncardiac chest pain. Table 4 presents criteria and treatment recommendations for each group.
| Table 4. Management and Triage of Emergency Department Chest Pain Syndromes | ||||
| Category | Criteria | Medications to consider | Medications | Disposition |
| I. Acute myocardial infarction | 1mm ST elevation in 2 or more contiguous leads or new LBBB in symptomatic patient | ASA, nitroglycerin, TPA (or PTCA), UFH | Morphine | CCU |
| II. Unstable angina | Accelerating or rest pain with known CAD, post MI pain, chest pain with new 1 mm ST depression in 2 or more contiguous leads or reversible T wave inversions, chest pain with CHF or hypotension | ASA, nitroglycerin, LMWH (enoxaparin); or as second-line alternative: heparin (UFH) | Morphine, GRI, (especially prior to PCI), beta-blocker, diltiazem | CCU |
| III. Probable unstable angina | Typical symptoms with non-specific ECG changes or history of diabetes mellitus or multiple risk factors | ASA, nitrates, beta-blocker | Enoxaparin or UFH, morphine | Telemetry unit or ED observation unit |
| IV. Possible unstable angina | Low risk patient with typical | ASA, nitrates | ED observation unit or discharge with rapid outpatient work-up symptoms with normal ECG or atypical symptoms with nonspecific ECG changes | |
| V. Non-cardiac chest pain | Atypical symptoms in very low risk patient or symptoms explained by another diagnosis | Treat other cause of pain, discharge or admit as indicated by diagnosis | ||
Summary
Chest pain is a common patient presentation encountered in emergency medicine. The majority of these patients will not be suffering from an AMI, although they may be at risk for life-threatening complications. New technologies and strategies for evaluating these patients are now available. Cardiac troponins, observation units, and ED stress testing extend the diagnostic ability and therapeutic decision tree of the ED physician. In addition, multi-modal pharmacotherapy relying on aspirin and enoxaparin has become the new standard for initial medical management, with the use of abciximab when intensification is required or PCI is anticipated.
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Physician CME Questions
73. All of the following factors have been identified as predictors of high risk of complications from USA, except?
A. Burning or indigestion-like pain
B. Hypertension
C. Rales
D. Diaphoresis
E. Transient ST depression
74. AMI may be excluded by which of the following?
A. A normal ECG
B. A negative cardiac catherization
C. Initial negative CK-MB, troponin I, and troponin T
D. ECG that is unchanged from baseline
E. Negative serial CK-MBs over 9-12 hours
75. Reproducible chest pain may be found in what percentage of patients with AMI?
A. 0%
B. 5%
C. 15%
D. 25%
E. 35%
76. All of the following are true regarding myoglobin and troponins I and T except:
A. both I and T are specific to the myocardium.
B. myoglobin is the earliest cardiac marker released in AMI, but is not very specific for AMI.
C. LDH is used for the diagnosis of AMI 3-7 days after the event.
D. elevated Troponin I and T in patients with USA are associated with higher risk of AMI and death.
E. a single CK-MB drawn in the ED should not be used to exclude the diagnosis of AMI.
77. All of the following are true of aspirin therapy except:
A. Aspirin lyses existing clot in the coronary artery.
B. Aspirin is the least toxic anti-thrombotic agent for AMI and ACS.
C. In USA, aspirin may reduce AMI at 12 weeks and one year.
D. The usual dose of aspirin in ACS is 82-325 mg, not enteric-coated, chewed.
E. Aspirin blocks the action of cyclooxygenase, which ultimately limits thromboxane A production.
78. Unfractionated heparin has the following advantage over low-molecular-weight heparins:
A. ease of dosing.
B. more predictable anti-coagulant effect.
C. proven superiority in USA.
D. more easily reversed.
E. fewer requirements for monitoring.
79. Which of the following is true of platelet glycoprotein IIb/IIIa receptor inhibitors?
A. They inhibit platelet adhesion and dissolve existing thrombus.
B. All are monoconal antibodies and have a long half-life.
C. They are indicated in all patients with USA.
D. They should not be used with heparin or aspirin.
E. They should be considered in any ACS patient who undergoes urgent angioplasty.
80. A 35-year-old truck driver from out-of-town who smokes presents to the ED complaining of two episodes of chest discomfort with mild exertion in the last two days. He has no pain now and ECG is normal. What is the best course of treatment?
A. Urgent cardiac catheterization
B. Aspirin therapy and referral to his primary care doctor
C. Rapid rule-out of AMI and provocative testing
D. Reassurance that the pain is non-cardiac
E. Aspirin, enoxaparin, nitroglycerin, and CCU admission
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