Edward Bessman, MD,
Chairman, Department of Emergency Medicine,
John Hopkins Bayview Medical Center; Assistant Professor,
Department of Emergency Medicine, Johns Hopkins
University
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Gary Setnik, MD,
Chair, Department of Emergency Medicine,
Mount Auburn Hospital; Assistant Professor, Division of
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John D Halamka, MD, MS,
Associate Professor of Medicine, Harvard
Medical School, Beth Israel Deaconess Medical Center; Chief
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Medical School; Attending Physician, Division of Emergency
Medicine, Beth Israel Deaconess Medical
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Chief Editor
David FM Brown, MD,
Associate Professor, Division of Emergency
Medicine, Harvard Medical School; Vice Chair, Department of
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Hospital
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Background
The initial diagnosis of acute coronary syndrome (ACS) is based on history, risk factors, and, to a lesser extent, ECG findings. The symptoms are due to myocardial ischemia, the underlying cause of which is an imbalance between supply and demand of myocardial oxygen.
Patients with ACS include those whose clinical presentations cover the following range of diagnoses: unstable angina, non–ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI). This ACS spectrum concept is a useful framework for developing therapeutic strategies.
View Image
A 50-year-old man with type 1 diabetes mellitus and hypertension presents after experiencing 1 hour of midsternal chest pain that began after eating a....
View Image
A 62-year-old woman with a history of chronic stable angina and a "valve problem" presents with new chest pain. She is symptomatic on arrival, complai....
Myocardial ischemia is most often due to atherosclerotic plaques, which reduce the blood supply to a portion of myocardium. Initially, the plaques allow sufficient blood flow to match myocardial demand. When myocardial demand increases, the areas of narrowing may become clinically significant and precipitate angina. Angina that is reproduced by exercise, eating, and/or stress and is subsequently relieved with rest, and without recent change in frequency or severity of activity that produce symptoms, is called chronic stable angina. Over time, the plaques may thicken and rupture, exposing a thrombogenic surface upon which platelets aggregate and thrombus forms. The patient may note a change in symptoms of cardiac ischemia with a change in severity or of duration of symptoms. This condition is referred to as unstable angina.
Patients with STEMI have a high likelihood of a coronary thrombus occluding the infarct artery. Angiographic evidence of coronary thrombus formation may be seen in more than 90% of patients with STEMI but in only 1% of patients with stable angina and about 35-75% of patients with unstable angina or NSTEMI. However, not every STEMI evolves into a Q-wave myocardial infarction (MI); likewise, a patient with NSTEMI may develop Q waves.
The excessive mortality rate of coronary heart disease is primarily due to rupture and thrombosis of the atherosclerotic plaque. Inflammation plays a critical role in plaque destabilization and is widespread in the coronary and remote vascular beds. Systemic inflammatory, thrombotic, and hemodynamic factors are relevant to the outcome. Evidence indicates that platelets contribute to promoting plaque inflammation as well as thrombosis. A new theory of unbalanced cytokine-mediated inflammation is emerging, providing an opportunity for intervention.
A less common cause of angina is dynamic obstruction, which may be caused by intense focal spasm of a segment of an epicardial artery (Prinzmetal angina). Coronary vasospasm is a frequent complication in patients with connective tissue disease. Other causes include arterial inflammation and secondary unstable angina. Arterial inflammation may be caused by or related to infection. Secondary unstable angina occurs when the precipitating cause is extrinsic to the coronary arterial bed, such as fever, tachycardia, thyrotoxicosis, hypotension, anemia, or hypoxemia. Most patients who experience secondary unstable angina have chronic stable angina as a baseline medical condition.
Spontaneous and cocaine-related coronary artery dissection remains an unusual cause of ACS and should be included in the differential diagnosis, especially when a younger female or cocaine user is being evaluated. An early clinical suspicion of this disease is necessary for a good outcome. Cardiology consultation should be obtained for consideration for urgent percutaneous coronary intervention.
Although rare, pediatric and adult ACS may result from the following (see Myocardial Infarction in Childhood):
ACS may occur with Marfan syndrome; Kawasaki disease; Takayasu arteritis; or cystic medial necrosis with aortic root dilatation, aneurysm formation, and dissection into the coronary artery.
Anomalous origin of the left coronary artery from the pulmonary artery may occur as unexplained sudden death in a neonate.
Coronary artery ostial stenosis may occur after repair of a transposition of the great arteries in the neonatal period.
An aberrant left main coronary artery with its origin at the right sinus of Valsalva may cause ACS, especially with exertion.
Traumatic myocardial infarction can occur in patients at any age.
Accelerated atherosclerosis is known to occur in cardiac transplant recipients on immunosuppressive therapy.
ACS may occur with progeria.
Irrespective of the cause of unstable angina, the result of persistent ischemia is MI.
Although the exact incidence of ACS is difficult to ascertain, hospital discharge data indicate that 1,680,000 unique discharges for ACS occurred in 2001.
International
In Britain, annual incidence rate of angina is estimated at 1.1 cases per 1000 males and 0.5 cases per 1000 females aged 31-70 years. In Sweden, chest pain of ischemic origin is thought to affect 5% of all males aged 50-57 years. In industrialized countries, annual incidence rate of unstable angina is approximately 6 cases per 10,000 people.
Mortality/Morbidity
When the only therapy for angina was nitroglycerin and limitation of activity, patients with newly diagnosed angina had a 40% incidence of MI and a 17% mortality rate within 3 months. A recent study shows that the 30-day mortality rate from ACS has decreased as treatment has improved, a statistically significant 47% relative decrease in 30-day mortality rate among newly diagnosed ACS from 1987-2000. This decrease in mortality rate is attributed to aspirin, glycoprotein (GP) IIb/IIIa blockers, and coronary revascularization via medical intervention or procedures.
Clinical characteristics associated with a poor prognosis include advanced age, male sex, prior MI, diabetes, hypertension, and multiple-vessel or left-mainstem disease.
Sex
Incidence is higher in males among all patients younger than 70 years. This is due to the cardioprotective effect of estrogen in females. At 15 years postmenopause, the incidence of angina occurs with equal frequency in both sexes. Evidence exists that women more often have coronary events without typical symptoms, which might explain the frequent failure to initially diagnose ACS in women.
Age
ACS becomes progressively more common with increasing age. In persons aged 40-70 years, ACS is diagnosed more often in men than in women. In persons older than 70 years, men and women are affected about equally.
Typically, angina is a symptom of myocardial ischemia that appears in circumstances of increased oxygen demand. It is usually described as a sensation of chest pressure or heaviness, which is reproduced by activities or conditions that increase myocardial oxygen demand.
Not all patients experience chest pain. Some present with only neck, jaw, ear, arm, or epigastric discomfort.
Other symptoms, such as shortness of breath or severe weakness, may represent anginal equivalents.
A patient may present to the ED because of a change in pattern or severity of symptoms. A new case of angina is more difficult to diagnose because symptoms are often vague and similar to those caused by other conditions (eg, indigestion, anxiety).
Patients may have no pain and may only complain of episodic shortness of breath, weakness, lightheadedness, diaphoresis, or nausea and vomiting.
Patients may complain of the following:
Palpitations
Pain, which is usually described as pressure, squeezing, or a burning sensation across the precordium and may radiate to the neck, shoulder, jaw, back, upper abdomen, or either arm
Exertional dyspnea that resolves with pain or rest
Diaphoresis from sympathetic discharge
Nausea from vagal stimulation
Decreased exercise tolerance
Patients with diabetes and elderly patients are more likely to have atypical presentations and offer only vague complaints, such as weakness, dyspnea, lightheadedness, and nausea.
Stable angina
Involves episodic pain lasting 5-15 minutes
Provoked by exertion
Relieved by rest or nitroglycerin
Unstable angina: Patients have increased risk for adverse cardiac events, such as MI or death. Three clinically distinct forms exist, as follows:
New-onset exertional angina
Angina of increasing frequency or duration or refractory to nitroglycerin
Angina at rest
Variant angina (Prinzmetal angina)
Occurs primarily at rest
Triggered by smoking
Thought to be due to coronary vasospasm
Elderly persons and those with diabetes may have particularly subtle presentations and may complain of fatigue, syncope, or weakness. Elderly persons may also present with only altered mental status. Those with preexisting altered mental status or dementia may have no recollection of recent symptoms and may have no complaints whatsoever.
As many as half of cases of ACS are clinically silent in that they do not cause the classic symptoms described above and consequently go unrecognized by the patient. Maintain a high index of suspicion for ACS especially when evaluating women, patients with diabetes, older patients, patients with dementia, and those with a history of heart failure.
Physical examination results are frequently normal. If chest pain is ongoing, the patient will usually lie quietly in bed and may appear anxious, diaphoretic, and pale.
Hypertension may precipitate angina or reflect elevated catecholamine levels due to either anxiety or exogenous sympathomimetic stimulation.
Hypotension indicates ventricular dysfunction due to myocardial ischemia, infarction, or acute valvular dysfunction.
Jugular venous distention
Third heart sound (S3) may be present.
A new murmur may reflect papillary muscle dysfunction.
Rales on pulmonary examination may suggest left ventricular (LV) dysfunction or mitral regurgitation.
Presence of a fourth heart sound (S4) is a common finding in patients with poor ventricular compliance due to preexisting ischemic heart disease or hypertension.
Troponin I is considered the preferred biomarker for diagnosing myocardial necrosis. Troponins have the greatest sensitivity and specificity in detecting MI, and elevated serum levels are considered diagnostic of MI. They also have prognostic value.
For early detection of myocardial necrosis, sensitivity of troponin is superior to that of the creatine kinase–MB (CK-MB). Troponin I is detectable in serum 3-6 hours after an MI, and its level remains elevated for 14 days.
Troponin is a contractile protein that normally is not found in serum. It is released only when myocardial necrosis occurs.
Troponin should be used as the optimum biomarkers for the evaluation of patients with ACS who have coexistent skeletal muscle injury.
Troponin T has similar release kinetics to troponin I, and levels remains elevated for 14 days. False-positive results may occur in patients with renal failure. Minor elevations in troponin T level also identify patients at risk for subsequent cardiac events.
Elevated troponin levels may also point to minor myocardial injury due to other causes. Zellweger et al described 4 patients with elevated troponin levels after supraventricular tachycardia without evidence of coronary artery disease and very low risk scores for ACS.[1] Similarly, Koller found that endurance athletes may show elevated serum troponin levels in the absence of ACS.[2]
CK-MB levels begin to rise within 4 hours after MI, peak at 18-24 hours, and subside over 3-4 days. A level within the reference range does not exclude myocardial necrosis.
The upper limit of normal for CK-MB is 3-6% of total CK. A normal level in the ED does not exclude the possibility of MI. A single assay in the ED has a 34% sensitivity for MI. Serial sampling over periods of 6-9 hours increases sensitivity to approximately 90%. Serial CK-MB over 24 hours detects myocardial necrosis with a sensitivity near 100% and a specificity of 98%.
Occasionally, a very small infarct is missed by CK-MB; therefore, troponin levels should be measured for patients suspected to have MI who have negative results from serial CK-MB tests.
One study looked at using the 2-hour delta (increase or decrease) of cardiac markers as 1 of 6 criteria in making the diagnosis of ACS and MI. According to one of the Erlanger criteria, an increase in the CK-MB level of 1.5 ng/mL or greater or an increase of the cardiac troponin I level of 0.2 ng/mL or greater over 2 hours in itself would allow one to make the provisional diagnosis of ACS with a high degree of sensitivity and specificity, even if the total levels were within the normal range. Patients with recent MI were also identified by a decreasing curve of CK-MB. Using this 2-hour delta of cardiac markers greatly reduces the number of cases of MI and ACS that are overlooked in patients who are then inappropriately discharged home.
Myoglobin, a low-molecular-weight heme protein found in cardiac and skeletal muscle, is released more rapidly from infarcted myocardium than troponin and CK-MB and may be detected as early as 2 hours after MI. Myoglobin levels, although highly sensitive, are not cardiac specific. They may be useful for early detection of MI when performed with other studies.
Cardiac markers should be used liberally to evaluate patients with prolonged episodes of ischemic pain, with new changes on ECG, or with nondiagnostic or normal ECGs in whom the diagnosis of ACS or MI is being considered.
Complete blood count is indicated to determine if anemia is a precipitant. Transfusion with packed red blood cells may be indicated.
A chemistry profile is indicated. Obtain a basic metabolic profile, including a check of blood glucose level, renal function, and electrolytes levels, for patients with new-onset angina. Potassium and magnesium levels should be monitored and corrected. Creatinine levels must be considered before using an angiotensin-converting enzyme (ACE) inhibitor.
Other biochemical markers
C-reactive protein (CRP) is a marker of acute inflammation. Patients without biochemical evidence of myocardial necrosis but elevated CRP level are at increased risk of an adverse event.
Interleukin 6 is the major determinant of acute-phase reactant proteins in the liver, and serum amyloid A is another acute-phase reactant. Elevations of either of these can be predictive in determining increased risk of adverse outcomes in patients with unstable angina.
Several other biomarkers have been investigated with variable sensitivity and specificity that include sCD40 ligand, myeloperoxidase, pregnancy-associated plasma protein-A, choline, placental growth factor, cystatin C, fatty acid binding protein, ischemia modified albumin, chemokines ligand-5 and -18 (mediators of monocyte recruitment induced by ischemia), angiogenin, SCUBE1 (a novel platelet protein), and others.[3, 4] In a study that included 107 patients presenting to an emergency department with chest pain, ischemia modified albumin was not found to have superior sensitivity and specificity over traditional biomarkers with a sensitivity of 0.86 and specificity of 0.49.[5]
In one study, patients presenting to the ED with suspected myocardial ischemia showing higher levels of inflammatory cytokines were associated with an increased risk of a serious cardiac event during the subsequent 3 months. However, the cytokines have limited ability to predict a serious adverse cardiac event.
Erythrocyte sedimentation rate rises above reference range values within 3 days and may remain elevated for weeks.
Serum lactase dehydrogenase level rises above the reference range within 24 hours of MI, reaches a peak within 3-6 days, and returns to the baseline within 8-12 days.
Chest radiograph may demonstrate complications of ischemia, such as pulmonary edema, or it may provide clues to alternative causes of symptoms, such as thoracic aneurysm or pneumonia.
Echocardiogram often demonstrates wall motion abnormalities due to ischemia. It is of limited value in patients whose symptoms have resolved or in those with preexisting wall motion abnormalities. However, echocardiogram may be useful in identifying precipitants for ischemia, such as ventricular hypertrophy and valvular disease.
Radionuclide myocardial perfusion imaging has been shown to have favorable diagnostic and prognostic value in this setting, with an excellent early sensitivity to detect acute myocardial infarction (MI) not achieved by other testing modalities.
A normal resting perfusion imaging study has been shown to have a negative predictive value of more than 99% in excluding MI. Observational and randomized trials of both rest and stress imaging in the ED evaluation of patients with chest pain have demonstrated reductions in unnecessary hospitalizations and cost savings compared with routine care.
Perfusion imaging has also been used in risk stratification after MI and for measurement of infarct size to evaluate reperfusion therapies. Novel "hot spot" imaging radiopharmaceuticals that visualize infarction or ischemia are currently undergoing evaluation and hold promise for future imaging of ACS. (See Myocardial Ischemia - Nuclear Medicine and Risk Stratification.)
Recent advances include CT coronary angiography and CT coronary artery calcium scoring.
The dual-source 64-slice CT scanners can do a full scan in 10 seconds and produce high-resolution images that allow fine details of the patient's coronary arteries to be seen. This technology allows for noninvasive and early diagnosis of coronary artery disease and thus earlier treatment before the coronary arteries become more or completely occluded. It allows direct visualization of not only the lumen of the coronary arteries but also plaque within the artery. Dual-source 64-slice CT scanning is being used with intravenous contrast to determine if a stent or graft is open or closed.
Whereas the use of CT coronary angiography (CTCA) as the primary noninvasive testing for coronary artery disease seems very attractive and is becoming more popular, the evidence for its diagnostic accuracy and clinical utility is still being evaluated in several prospective studies.[6]
However, preliminary evidence indicates that CTCA seems most valuable in patients with intermediate pretest probability of disease, because the test can distinguish which of these patients need invasive angiography.[7] In an observational study in the Netherlands, 517 patients were referred by their treating physicians for evaluation of chest symptoms using stress testing and CTCA in all patients. CTCA sensitivity approached 100% in patients with pretest probability of < 90% and was more accurate than stress testing. In patients with a low (< 20%) pretest probability of disease, negative stress test or CTCA results suggested no need for coronary angiography. In patients with an intermediate (20-80%) pretest probability, a positive CTCA result suggested need to proceed with ICA (posttest probability, 93% [95% CI, 92-93%]) and a negative result suggested no need for further testing (posttest probability, 1% [CI, 1-1%]).
These findings need to be confirmed before CTCA can be routinely recommended for these patients, since referral and verification bias might have influenced findings. Moreover, stress testing provides functional information that may add value to that from anatomical imaging.
CT coronary artery scoring is emerging as an attractive risk stratification tool in patients who are low risk for acute coronary syndrome. This imaging modality exposes the patient to very little radiation (1-2 msV). No contrast is needed, and the study does not have a requirement for heart rate.[8]
Technetium-99m (99mTc) tetrofosmin single-photon emission computed tomography (SPECT) is a useful method to exclude high-risk patients among patients with chest pain in the emergency department.
Resting cardiac magnetic resonance imaging (MRI) has exhibited diagnostic operating characteristics suitable for triage of patients with chest pain in the ED. Performed urgently to evaluate chest pain, MRI accurately detected a high fraction of patients with ACS, including patients with enzyme-negative unstable angina. MRI can identify wall thinning, scar, delayed enhancement (infarction), and wall motion abnormalities (ischemia). Coronary artery assessment may be coupled with magnetic resonance (MR) angiography in the future.
ECG is the most important ED diagnostic test for angina. It may show changes during symptoms and in response to treatment, which would confirm a cardiac basis for symptoms. It also may demonstrate preexisting structural or ischemic heart disease (left ventricular hypertrophy, Q waves). A normal ECG or one that remains unchanged from the baseline does not exclude the possibility that chest pain is ischemic in origin. Changes that may be seen during anginal episodes include the following:
Transient ST-segment elevations (fixed changes suggest acute MI) may be observed. In patients with elevated ST segments, consider LV aneurysm, pericarditis, Prinzmetal angina, early repolarization, and Wolff-Parkinson-White syndrome as possible diagnoses.
Dynamic T-wave changes (inversions, normalizations, or hyperacute changes) may be observed. In patients with deep T-wave inversions, consider CNS events or drug therapy with tricyclic antidepressants or phenothiazines.
ST depressions may be junctional, downsloping, or horizontal.
Diagnostic sensitivity may be increased by performing right-sided leads (V4 R), posterior leads (V8, V9), and serial recordings.
ECGs from 2 patients are shown below.
View Image
A 50-year-old man with type 1 diabetes mellitus and hypertension presents after experiencing 1 hour of midsternal chest pain that began after eating a....
View Image
A 62-year-old woman with a history of chronic stable angina and a "valve problem" presents with new chest pain. She is symptomatic on arrival, complai....
Generally, patients transported with chest pain should initially be managed under the assumption that the pain is ischemic in origin. Prehospital interventions should be guided by the nature of the presenting complaint, individual risk factors, and associated symptoms (eg, breathing difficulty, hemodynamic instability, appearance of ectopy). Airway, breathing, and circulation should be rapidly assessed with institution of CPR, ACLS-guided interventions, or other measures as indicated for the unstable patient.
Obtain intravenous access.
Administer supplemental oxygen.
Aspirin (162-325 mg) should be given in the field, chewed and swallowed.
Administer sublingual or aerosolized nitroglycerin if chest pain is ongoing and is believed to be cardiac in origin.
Additionally, recently, the AHA has published a statement on integrating prehospital ECGs into care for ACS patients (see AHA Publishes Statement on Integrating Prehospital ECGs Into Care for ACS Patients). Prehospital integration of ECG interpretation, when AMI is present, has been shown to decrease "door to balloon time," to allow paramedics to bypass non-PCI hospitals in favor of better equipped facilities, and to expedite care by allowing an emergency physician to activate the catheterization laboratory before patient arrival.
Prehospital thrombolysis allows eligible patients to receive thrombolysis 30-60 minutes sooner than if treatment were given in the ED; however, prehospital thrombolysis is still under investigation and has not become a trend due to unproven benefit and due to the increase in availability of percutaneous coronary intervention (PCI) in many medical centers as an alternative to thrombolysis for STEMI.
The ACS spectrum concept is a useful framework for developing therapeutic strategies. Antithrombin therapy and antiplatelet therapy should be administered to all patients with an ACS regardless of the presence or the absence of ST-segment elevation. Patients presenting with persistent ST-segment elevation are candidates for reperfusion therapy (either pharmacological or catheter based) to restore flow promptly in the occluded epicardial infarct-related artery. Patients presenting without ST-segment elevation are not candidates for immediate pharmacological reperfusion but should receive anti-ischemic therapy and PCI when appropriate. "Time is myocardium" is a dictum to be remembered as survival has been shown to correlate with time to reperfusion in patients with acute MI. Many centers set goals for, and routinely record, door-to-ECG, door-to-needle (thrombolytic therapy), or door-to-vascular access (for patients receiving PCI) times as measures of quality of care provided.
Rathore et al found that any delay in primary percutaneous coronary intervention after a patient with ST-elevation myocardial infarction (STEMI) arrives at hospital is associated with higher mortality.[9] In a prospective cohort study of 43,801 patients enrolled in the American College of Cardiology National Cardiovascular Data Registry, 2005-2006, longer door-to-balloon times were associated with a higher adjusted risk of in-hospital mortality, in a continuous nonlinear fashion (30 min = 3%, 60 min = 3.5%, 90 min = 4.3%, 120 min = 5.6%, 150 min = 7%, 180 min = 8.4%, P< 0.001). A reduction in door-to-balloon time from 90 minutes to 60 minutes was associated with 0.8% lower mortality, and a reduction from 60 minutes to 30 minutes was associated with a 0.5% lower mortality.
A recent study by Ryan et al sought to determine if point-of-care cardiac marker testing decreased length of stay in patients being evaluated for acute coronary syndrome in the ED.[10] Patients were randomized to 2 groups, with 1000 patients in each group: one having point-of-care markers and central laboratory markers and one having central laboratory markers only. Median time to discharge home was 4.6 hours (3.5-6.1 h) in central laboratory only patients and 4.5 hours (3.5-6.1 h) in the point-of-care patients.
Median time to transfer to an inpatient setting for admitted patients was 5.5 hours (4.2-7.5 h) in the central laboratory patients, and 5.4 hours (4.1-7.3 h) in point-of-care group patients. Time to transfer to the floor was reduced in the point-of-care group at one site, compared with the laboratory group (difference in medians 0.45 h; 95% confidence interval [CI] -0.14 to 1.04 h). Time to ED departure for discharged patients was higher in the point-of-care group than in the laboratory group (difference in medians 1.25 h; 95% CI 0.13 to 2.36 h) at one site.[10]
Results between the EDs varied, with one showing that point-of-care testing decreased time to admission, and another showing that point-of-care testing increased time to discharge. Ryan et al concluded that the potential effects of point-of-care testing in the ED for patient throughput should be considered in the full context of ED operations.
Goals of ED care are rapid identification of patients with STEMI, exclusion of alternative causes of nonischemic chest pain, and stratification of patients with acute coronary ischemia into low- and high-risk groups.
Obtain intravenous access, administer supplemental oxygen, and provide telemetry monitoring if these procedures have not already been accomplished in the prehospital phase. In addition, obtain a 12-lead ECG as soon as possible after arrival.
Complete a history and physical examination, with focus on risk factors for coronary ischemia; onset, duration, and pattern of symptoms; and early identification of complications of myocardial ischemia (eg, new murmurs, CHF).
Perform frequent reassessment of vital signs and symptoms in response to administered therapies.
Serial ECGs and continuous ST-segment monitoring may be useful.
Many EDs have an observation unit that may be an appropriate disposition for patients who meet admission criteria.
Medical therapy, as discussed in Medication, is indicated.
Treatment and evaluation guidelines are available from various sources including the American College of Emergency Physicians, American College of Chest Physicians, and National Academy of Clinical Biochemistry.[11, 12, 13]
Cardiology or interventional cardiology consultation may be indicated for patients with any of the following:
STEMI - Depending on the center, the patient may be a candidate for PCI, and immediate interventional cardiology consultation is indicated.
Ongoing symptoms highly suggestive of acute coronary ischemia and nondiagnostic ECG (eg, left bundle-branch block [LBBB])
Ongoing symptoms refractory to aggressive medical therapy
Hemodynamic instability
Evidence of acute valvular dysfunction
Shock
Known severe aortic stenosis and ongoing symptoms
Uncertainty of the diagnosis
The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial studied the impact of age on outcomes in moderate- and high-risk non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Outcomes were analyzed at 30 days and 1 year in 4 age groups, overall and among those undergoing percutaneous coronary intervention (PCI). Of 13,819 patients in the ACUITY trial, 3,655 (26.4%) were younger than 55 years of age, 3,940 (28.5%) were aged 55-64 years, 3,783 (27.4%) were aged 65-74 years, and 2,441 (17.7%) were 75 years or older. Older patients had more cardiovascular risk factors and had a higher acuity at presentation. Patients aged 75 years or older treated with bivalirudin alone had similar ischemic outcomes but significantly lower rates of bleeding compared with those treated with heparin and glycoprotein IIb/IIIa inhibitors overall and in the PCI subset.[14]
Another analysis from the ACUITY study data found patients with more than a 24-hour delay to cardiac catheterization had increased 30-day and 1-year mortality rates.[15]
The goals of treatment are to preserve patency of the coronary artery, augment blood flow through stenotic lesions, and reduce myocardial oxygen demand. All patients should receive antiplatelet agents, and patients with evidence of ongoing ischemia should receive aggressive medical intervention until signs of ischemia, as determined by symptoms and ECG, resolve.
The value of aspirin in primary prophylaxis for cardiovascular diseases was challenged in the Aspirin for Asymptomatic Atherosclerosis trial. In this double-blind randomized controlled trial, 28,980 men and women aged 50-75 years living in central Scotland, and recruited from a community health registry, who were free of clinical cardiovascular disease, but at higher risk of atherosclerosis and an increased risk of cardiovascular and cerebrovascular events based on low ankle brachial index (ABI), were given 100 mg aspirin (enteric coated) or placebo.
The primary end point was a composite of initial fatal or nonfatal coronary event or stroke or revascularization. Secondary end points included angina, intermittent claudication, or transient ischemic attack; as well as all-cause mortality. After a mean (SD) follow-up of 8.2 (1.6) years, none of the study end points showed statistically significant difference between groups. The rate of an initial event of major hemorrhage requiring admission to hospital was not also statistically different between the groups. Note though that this study was powered to detect a 25% proportional risk reduction in events, which may not have been achieved.[16, 17]
These agents inhibit the cyclooxygenase system, decreasing the level of thromboxane A2, which is a potent platelet activator. Antiplatelet therapy has been shown to reduce mortality rates by reducing the risk of fatal strokes and fatal myocardial infarctions.
Clinical Context:
Causes relaxation of the vascular smooth muscle via stimulation of intracellular cyclic guanosine monophosphate production, causing a decrease in blood pressure.
Clinical Context:
Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents recurrence of a clot after spontaneous fibrinolysis.
These agents have antiarrhythmic and antihypertensive properties as well as ability to reduce ischemia. They minimize the imbalance between myocardial supply and demand by reducing afterload and wall stress. In patients with acute MI, they have been shown to decrease infarct size as well as short- and long-term mortality, which is a function of their anti-ischemic and antiarrhythmic properties.
Clinical Context:
Excellent drug for use in patients at risk for complications from beta-blockers, particularly reactive airway disease, mild-to-moderate LV dysfunction, and peripheral vascular disease. Short half-life of 8 min allows for titration to desired effect with ability to stop quickly prn.
Glycoprotein (GP) IIb/IIIa antagonists prevent the binding of fibrinogen, thereby blocking platelet aggregation. Studies to date suggest that as a class, the addition of intravenous GP IIb/IIIa inhibitors to aspirin and heparin improves both early and late outcomes, including mortality, Q-wave MI, need for revascularization procedures, and length of hospital stay.
Currently, IIb/IIIb antagonists in combination with aspirin are considered standard antiplatelet therapy for patients at high risk for unstable angina. Adenosine diphosphate (ADP) antagonists are not considered standard therapy but may be used in patients unable to tolerate aspirin.
Clinical Context:
Chimeric human-murine monoclonal antibody. Binds to receptor with high affinity and reduces platelet aggregation by 80%. Inhibition of platelet aggregation persists for up to 48 h after end of infusion.
Abciximab has been approved for use in elective/urgent/emergent percutaneous coronary intervention.
Clinical Context:
Antagonist of the platelet GP IIb/IIIa receptor, which reversibly prevents von Willebrand factor, fibrinogen, and other adhesion ligands from binding to the GP IIb/IIIa receptor. End effect is the inhibition of platelet aggregation. Effects persist over duration of maintenance infusion and are reversed when infusion ends.
Clinical Context:
Nonpeptide antagonist of GP IIb/IIIa receptor. Reversible antagonist of fibrinogen binding. When administered IV, more than 90% of platelet aggregation inhibited.
Approved for use in combination with heparin for patients with unstable angina who are being treated medically and for those undergoing PCI.
Low molecular weight heparin (enoxaparin) has been shown to reduce cardiac ischemic events and death by as much as 15% in patients with unstable angina. The benefits appear to be sustained at 1 year, with a 13% reduction in patients requiring coronary artery bypass graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA) and a 15% reduction in death or AMI. These clinical effects have been reported with all patients also receiving aspirin.
One systematic review comparing low molecular weight heparin (LMWH) with unfractionated heparin found no significant difference in benefits between the two. The advantages of using LMWH over unfractionated heparin are ease of administration, absence of need for anticoagulation monitoring, safety profile, and potential for overall cost savings. Although 3 LMWHs are approved for use in the United States, only enoxaparin is currently approved for use in unstable angina. Lev et al found that the combination of eptifibatide with enoxaparin appears to have a more potent antithrombotic effect than that of eptifibatide and unfractionated heparin (UFH).[18]
Clinical Context:
LMWH is produced by partial chemical or enzymatic depolymerization of UFH. Binds to antithrombin III, enhancing its therapeutic effect. The heparin-antithrombin III complex binds to and inactivates activated factor X (Xa) and factor II (thrombin). LMWH differs from unfractionated heparin by having a higher ratio of antifactor Xa to antifactor IIa compared with UFH. Maximum antifactor Xa and antithrombin activities occur 3-5 h after administration.
Indicated for treatment of acute ST-segment elevation myocardial infarction (STEMI) managed medically or with subsequent percutaneous coronary intervention (PCI). Also indicated as prophylaxis of ischemic complications caused by unstable angina and non-Q-wave MI.
Hirudin is the prototype of direct thrombin inhibitors. Hirudin binds directly to the anion binding site and the catalytic sites of thrombin to produce potent and predictable anticoagulation.
Clinical Context:
When compared with unfractionated heparin in unstable angina trials, hirudin demonstrated a modest short-term reduction in the composite end point of death or nonfatal MI. Risk of bleeding is increased modestly. Currently, hirudin is indicated only in patients unable to receive heparin because of heparin-induced thrombocytopenia.
Clinical Context:
Synthetic analogue of recombinant hirudin. Inhibits thrombin. Used for anticoagulation in unstable angina undergoing PTCA. With provisional use of glycoprotein IIb/IIIa inhibitor (GPIIb/IIIa inhibitor) indicated for use as anticoagulant in patients undergoing PCI. Potential advantages over conventional heparin therapy include more predictable and precise levels of anticoagulation, activity against clot-bound thrombin, absence of natural inhibitors (eg, platelet factor 4, heparinase), and continued efficacy following clearance from plasma (because of binding to thrombin).
Two thienopyridines, clopidogrel and ticlopidine, are ADP antagonists that are approved for antiplatelet activity. Both have irreversible antiplatelet activity but take several days to manifest. A potential additive benefit exists when ADP antagonists are used in conjunction with aspirin.
These drugs may be considered alternatives to aspirin in patients intolerant or allergic to aspirin.
Literature continues to emerge regarding whether the use of proton pump inhibitors (PPIs) interferes with clopidogrel following MI.
Results from the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) found no apparent cardiovascular interaction between clopidogrel and omeprazole, even in high-risk subgroups. This study did not rule out a clinically meaningful difference in cardiovascular events resulting from PPI use. The authors noted several limitations of the study. The study was prematurely halted, and it used an investigational combination product of omeprazole and clopidogrel, therefore limiting its power to fully evaluate anticipated end results. Additionally, the confidence interval of the hazard ratio for cardiovascular events is wide; thus, the absence of omeprazole interacting with clopidogrel cannot be definitively determined.[19]
Some concern exists about possible interaction between proton pump inhibitors (PPIs) and clopidogrel, resulting in decreased effectiveness of clopidogrel. This concern was addressed in a nationwide retrospective cohort study in Denmark. Charlot et al found that combined use of PPIs and clopidogrel was not associated with increased adverse cardiovascular events over that observed for patients prescribed PPI alone.[20] For concomitant use of a PPI and clopidogrel among the cohort assembled at day 30 after discharge, the hazard ratio was 1.29 (95% confidence interval [CI], 1.17-1.42) for cardiovascular death or rehospitalization for MI or stroke. For use of a PPI in patients who did not receive clopidogrel, the hazard ratio was 1.29 (CI, 1.21-1.37). No statistically significant interaction between a PPI and clopidogrel (P = 0.72) was noted.
The cause of increased cardiovascular risk in all patients who received PPI may be explained by significant differences in baseline comorbid conditions. Although the authors used 2 different methods for statistical analysis trying to adjust for known differences, other unmeasured confounders as well as proxy assumptions may not have been accounted for.
The use of observational studies did not show clinical evidence for PPIs interfering with the effectiveness of clopidogrel, although the potential for observational studies to be misleading should be kept in mind. Use of ex vivo antiplatelet testing to examine the interaction may be potentially misleading.[21]
A consensus statement issued by the American College of Cardiology, American College of Gastroenterology, and American Heart Association in November 2010 addresses the issue of concomitant use of proton pump inhibitors (PPIs) and thienopyridine antiplatelet drugs.[22]
The group's findings and recommendations are listed below.
Clopidogrel reduces major CV events compared with placebo or aspirin.
Dual antiplatelet therapy with clopidogrel and aspirin, compared with aspirin alone, reduces major CV events in patients with established ischemic heart disease, and it reduces coronary stent thrombosis but is not routinely recommended for patients with prior ischemic stroke because of the risk of bleeding.
Clopidogrel alone, aspirin alone, and their combination are all associated with increased risk of GI bleeding.
Patients with prior GI bleeding are at highest risk for recurrent bleeding on antiplatelet therapy; other risk factors include advanced age, concurrent use of anticoagulants, steroids, or NSAIDs including aspirin, and Helicobacter pylori infection; risk increases as the number of risk factors increases.
Use of PPIs or histamine H2 receptor antagonists (H2RAs) reduces the risk of upper GI bleeding compared with no therapy; PPIs reduce upper GI bleeding to a greater degree than do H2Ras.
PPIs are recommended to reduce GI bleeding among patients with a history of upper GI bleeding; PPIs are appropriate in patients with multiple risk factors for GI bleeding who require antiplatelet therapy.
Routine use of either a PPI or an H2RA is not recommended for patients at lower risk of upper GI bleeding, who have much less potential to benefit from prophylactic therapy.
Clinical decisions regarding concomitant use of PPIs and thienopyridines must balance overall risks and benefits, considering both CV and GI complications.
Pharmacokinetic and pharmacodynamic studies, using platelet assays as surrogate endpoints, suggest that concomitant use of clopidogrel and a PPI reduces the antiplatelet effects of clopidogrel; the strongest evidence for an interaction is between omeprazole and clopidogrel; it is not established that changes in these surrogate endpoints translate into clinically meaningful differences.
Observational studies and a single randomized clinical trial have shown inconsistent effects on CV outcomes of concomitant use of thienopyridines and PPIs; a clinically important interaction cannot be excluded, particularly in certain subgroups, such as poor metabolizers of clopidogrel.
The role of either pharmacogenomic testing or platelet function testing in managing therapy with thienopyridines and PPIs has not yet been established.
Clinical Context:
Beneficial effects were noted in patients with UA after 2 wk of use in one randomized trial. When compared to controls, ticlopidine use decreased vascular deaths and nonfatal MIs.
Patients with unstable angina, ECG changes, or both should be admitted to a telemetry bed. A certain subset of patients with stable angina may be treated as outpatients with antianginal agents, but close follow-up is necessary.
Patients with symptoms refractory to aggressive medical treatment, shock, suspected or known aortic stenosis, or new or worsening mitral regurgitation are at high risk. Management for these patients should include the following: admission to an intensive care unit setting and cardiology consultation.
Intra-aortic balloon pump (IABP) and early angiography to delineate anatomy should be considered.
Antiplatelet and antianginal medications initiated in the ED should be continued. Subsequent dosing is determined by symptomatic response and tolerance of side effects.
The routine use of lidocaine as prophylaxis for ventricular arrhythmias in patients with ACS is not indicated. In MI, it has been shown to increase mortality rates. Lidocaine may be used for patients with complex ventricular ectopy or for patients with hemodynamically significant, nonsustained, or sustained ventricular tachycardia.
Mehta et al studied 3031 patients with acute coronary syndromes. Early intervention (coronary angiography ≤ 24 h after randomization; median time 14 h) in acute coronary syndromes did not differ greatly from delayed intervention (coronary angiography >24 h randomization; median time 50 h) in preventing the primary outcome (ie, composite of death, myocardial infarction, or stroke at 6 mo). Early intervention did reduce the rate of the secondary outcome (ie, death, myocardial infarction, or refractory ischemia at 6 mo) and improved the primary outcome in patients who were at highest risk (ie, Global Registry of Acute Coronary Events [GRACE] risk score >140).[23]
Patients with chronic stable angina may be considered for discharge after occurrence of the following:
Symptom duration is brief and identical to symptoms experienced in the past.
ECG is normal or unchanged.
Patient has access to timely follow-up with a primary care provider.
When in doubt, admit. The usual reason for a patient with chronic stable angina to present to the ED is a change in pattern or severity of symptoms, which makes their angina unstable.
A study by Bartholomew et al may be helpful in making the decision to admit or discharge. This prospective thrombolysis in myocardial infarction risk score (TIMI-RS) used 7 variables in patients with suspected ACS: (1) age older than 65 years, (2) 3 or more cardiac risk factors, (3) ST deviation, (4) aspirin use within 7 days, (5) 2 or more anginal events over 24 hours, (6) history of coronary stenosis, and (7) elevated troponin levels. Patients were contacted at 30 days, and data were collected concerning major adverse cardiac events.[24]
In patients presenting with chest pain, a higher TIMI-RS was associated with an increase in major adverse cardiac events within 30 days. The authors concluded that the 30-day event rate was 0% for a score of 1, 20% for a score of 2, 24% for a score of 3, 42% for a score of 4, 52% for a score of 5, and 70% for a score of 6 or 7 (p < 0.0001).
The TIMI-RS successfully differentiates early risk for major adverse cardiac events in a general population presenting with symptoms suggestive of ACS. A simple bedside calculation of the TIMI-RS provides rapid risk stratification, allowing facilitation of therapeutic decision-making in patients with symptoms suggestive of ACS and may be helpful with the patient's disposition.
Inpatient and outpatient medications may include the following:
Aspirin
Use clopidogrel as a substitute for patients unable to take aspirin because of a history of hypersensitivity or bleeding. Use a 300-mg loading dose, then 75 mg qd.
Nitrates
Use topical or oral nitrates for those who are discharged or for those who are stable inpatients.
Intravenous infusion is preferable for those admitted with unstable symptoms.
Beta-blockers
Metoprolol and propranolol are excellent choices for inpatient and outpatient management.
Use esmolol for inpatient treatment, particularly those at risk for adverse effects from beta-blockade.
Heparin: Use heparin for inpatient management of unstable angina. Some preliminary data suggest that LMWH is a safe and effective alternative.
Significant clustering of recurrent ischemic events occurs within 24 hours after cessation of both short-term UFH and enoxaparin treatment, and patients should be carefully monitored during that period. This early rebound may be prevented by continuation of a fixed dose of enoxaparin.
Consider transfer only for patients at particularly high risk and for those who are being evaluated in a center without access to timely cardiac catheterization, PTCA, or bypass.
High-risk criteria include the following:
Symptoms refractory to medical management
Hemodynamic instability, cardiogenic shock
New or worsening mitral regurgitant murmur
Known or suspected severe aortic stenosis
The risks of transferring these unstable patients must be carefully weighed against the benefits of transfer.
Deterrence/prevention of ACS may include the following:
Cessation of smoking
Assessment of lipid profile and dietary changes, where appropriate (Among patients who have recently had an ACS, an intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular events than a standard regimen.[25] )
Blood pressure control
Compliance with medications, particularly aspirin
Comprehensive risk assessment by primary care provider, including exercise tolerance test (ETT) for individuals at high risk and identification of structural heart disease (eg, left ventricular hypertrophy [LVH], aortic stenosis)
Supraventricular arrhythmias (rare complication of ischemia, may actually precipitate ischemic events)
Ventricular arrhythmias; simple and complex premature ventricular contractions (PVCs), and nonsustained ventricular tachycardia (NSVT)
Atrioventricular nodal blockade
Usually transient in setting of reversible ischemia
Treatment guided by location of block and hemodynamic stability
Ventricular rupture occurs in the interventricular septum or the LV free wall. This represents a catastrophic event with mortality rates greater than 90%. Prompt recognition, stabilization, and surgical repair are crucial to any hope of survival. An echocardiogram will usually define the abnormality, and a right heart catheterization may show an oxygenation increase with septal rupture.
Patients with angina either proceed to infarct or have their disease stabilized by medical and/or interventional therapies. Patients with angina are a heterogeneous group; therefore, prognosis varies with respect to stability of disease, demographics, comorbidity, and current intervention.
Patients with ACS with atrial fibrillation (AF) are associated with increased morbidity and mortality.[26]
Patients with ACS and diabetes mellitus, especially those with ST elevation, had increased in-hospital mortality rates. Among patients with ACS and diabetes mellitus, those receiving insulin had worse outcomes. Outcomes were similar for those on hypoglycemic medication or on diet alone.[27]
In chronic stable angina, prognosis is generally excellent. Factors that have been shown to impact prognosis include the following:
Aspirin reduces progression to both nonfatal MI and cardiac death.
Beta-blockers control anginal symptoms and reduce cardiac complications in patients with hypertension.
PTCA and revascularization improve the prognosis in high-risk patients.
Poor prognostic factors include male sex, diabetes, and hypertension.
In unstable angina, prognosis is determined by the ability to control symptoms acutely, preventing progression to AMI. Factors associated with a poorer prognosis include the following:
Evidence of myocardial necrosis, as determined by elevated troponin T level
Delays in angiography in patients at high risk (Early angiography allows for triage to medical therapy, PTCA, or revascularization.)
[Guideline] Storrow AB, Apple FS, Wu AH, Jesse R, Francis G, Christenson RH. Use of cardiac biomarkers for acute coronary syndromes. In: Laboratory medicine practice guidelines: evidence-based practice for point-of-care testing. Washington (DC): National Academy of Clinical Biochemistry (NACB). 2006;13-20.
Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. Oct 2010;363:
[Guideline] Abraham NS, Hlatky, MA, Antman EM, Bhatt DL, Bjorkman DJ, et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. J Am Coll Cardiol. Published online November 8, 2010:
A 50-year-old man with type 1 diabetes mellitus and hypertension presents after experiencing 1 hour of midsternal chest pain that began after eating a large meal. Pain is now present but is minimal. Aspirin is the single drug that will have the greatest potential impact on subsequent morbidity. In the setting of ongoing symptoms and ECG changes, nitrates titrated to 10% reduction in blood pressure and symptoms, beta-blockers, and heparin are all indicated. If the patient continues to have persistent signs and/or symptoms of ischemia, addition of a glycoprotein IIb/IIIa inhibitor should be considered.
A 62-year-old woman with a history of chronic stable angina and a "valve problem" presents with new chest pain. She is symptomatic on arrival, complaining of shortness of breath and precordial chest tightness. Her initial vital signs are blood pressure 140/90 mm Hg and heart rate is 98. Her ECG is as shown. She is given nitroglycerin sublingually, and her pressure decreases to 80/palpation. Right ventricular ischemia should be considered in this patient.
A 50-year-old man with type 1 diabetes mellitus and hypertension presents after experiencing 1 hour of midsternal chest pain that began after eating a large meal. Pain is now present but is minimal. Aspirin is the single drug that will have the greatest potential impact on subsequent morbidity. In the setting of ongoing symptoms and ECG changes, nitrates titrated to 10% reduction in blood pressure and symptoms, beta-blockers, and heparin are all indicated. If the patient continues to have persistent signs and/or symptoms of ischemia, addition of a glycoprotein IIb/IIIa inhibitor should be considered.
A 62-year-old woman with a history of chronic stable angina and a "valve problem" presents with new chest pain. She is symptomatic on arrival, complaining of shortness of breath and precordial chest tightness. Her initial vital signs are blood pressure 140/90 mm Hg and heart rate is 98. Her ECG is as shown. She is given nitroglycerin sublingually, and her pressure decreases to 80/palpation. Right ventricular ischemia should be considered in this patient.
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