I. Acute Coronary Syndrome: What every physician needs to know
Heart disease, which includes acute coronary syndromes (ACS), is the leading cause of death in the United States. Chest pain is a common complaint in patients at primary care offices, emergency departments, and inpatient medical services. However, the majority of patients with chest pain will not have ACS. Patients must be appropriately stratified according to risk of ACS so that proper treatment can occur quickly.
Risk assessment is not a single procedure, but rather an ongoing process that requires an intensive initial evaluation and serial measurements of ECGs and cardiac biomarkers. Risk stratification must consider the chances that the patient’s symptoms are due to ACS and the patient’s risk for adverse outcomes if they are experiencing ACS. Simultaneously, high risk ACS mimics, such as pulmonary embolism and aortic dissection, must be considered and appropriately ruled out.
Although there is a typical pattern of ACS symptoms, the absence of these symptoms, or the presence of atypical symptoms, is not enough to rule out ACS.
The rapid acquisition and interpretation of an ECG is a mandatory first step in the evaluation of suspected ACS to rule out ST elevation myocardial infarction (STEMI).
Acute coronary syndromes are divided into three categories. ST segment elevation myocardial infarction (STEMI) refers to complete or near complete occlusion of an epicardial coronary artery, generally due to atherosclerotic plaque rupture and resultant thrombosis. It is defined electrocardiographically by >1mm ST segment elevation in two or more anatomically contiguous leads on the ECG. Death of the myocardial tissue is progressing in STEMI, and worsens the longer reperfusion is delayed.
Non-ST segment elevation myocardial infarction (NSTEMI) refers to myocardial cell death in the absence of diagnostic criteria for STEMI. Controversy exists regarding the necessity of rapid reperfusion in NSTEMI, although the American College of Cardiology / American Heart Association (ACC/AHA) guidelines do recommend an early interventional strategy for those patients with evidence of myocardial necrosis, as demonstrated by elevated cardiac biomarkers.
Unstable angina refers to symptoms that are due to impaired blood flow through the coronary arteries that is inadequate to meet metabolic demands, but not to the degree that actual cell death is occurring. The typical classifications of unstable angina are: a) new onset, severe angina, b) anginal symptoms occurring at rest or with minimal activity, or c) crescendo angina – symptoms occurring with increasing frequency, that require less exertion than previously to provoke, or more nitroglycerin to alleviate than before. Transient ST segment elevation, ST segment depression, or t-wave inversion may occur, but may also be absent. Biomarkers are, by definition, not elevated in unstable angina.
The initial ECG may be normal in 50% of patients ultimately diagnosed with ACS.
II. Diagnostic confirmation: are you sure your patient has ACS?
Two of the three categories of ACS have definite diagnostic criteria with regards to the presence of myocardial infarction. STEMI is defined by >1mm/0.1mV elevation of the ST segment in two or more contiguous leads on an ECG.
The 2007 Universal Definition of MI consists of a typical rise and fall of cardiac biomarkers (troponin preferred) accompanied by
symptoms of ischemia
ECG changes indicative of ischemia
development of Q waves
imaging evidence of new loss of viable myocardium or new wall motion abnormality
In absence of ST elevation or elevated cardiac biomarkers, it may be difficult to diagnose acute coronary syndrome. Even in the setting of coronary catheterization, it may be difficult to determine if a visualized coronary lesion is responsible for the symptoms.
A. History part I: pattern recognition
The classic symptoms for acute coronary syndrome include left sided or substernal chest pain or heaviness, radiating to the jaw or shoulder, accompanied by diaphoresis, nausea and vomiting, and dyspnea, worsened by exertion and relieved by rest or nitroglycerin. Some patients, including the elderly, women, and diabetics, may present with atypical symptoms, including fatigue, abdominal pain, weakness, and nausea in the absence of chest pain.
Physical signs are rarely helpful in the diagnosis of ACS. Rarely, papillary muscle necrosis and rupture may result in a new mitral regurgitation murmur. Acute cardiogenic shock may accompany STEMI or NSTEMI with pallor, hypotension, and altered mentation.
B. History part 2: prevalence
Traditional risk factors help identify patients at risk for developing CAD, although they are of limited value in determining whether the patient presenting with acute chest pain is experiencing ACS. The original Framingham criteria were investigated as predictors of developing CAD over a 10 year surveillance period.
Age, male sex, diabetes, hypercholesterolemia, and smoking increase the risk of developing CAD, which in turn increases the risk of an ACS event. Unfortunately, this does not mean that the absence of CAD risk factors equals the absence of risk for ACS. Research demonstrates that the additive attributable risk for ACS due to the presence of CAD risk factors is low when compared to the risk when the patient presents with symptoms of ACS. While traditional risk factors are useful for primary care management and prevention, they are less useful in the acute assessment and risk stratification of a patient presenting with symptoms concerning for ACS.
C. History part 3: competing diagnoses that can mimic ACS
Pulmonary Embolism – occurs across all adult age ranges, whereas ACS increase in incidence after the age of 40. Pain is frequently pleuritic in nature. D-dimer testing provides a very sensitive but non-specific screening test for pulmonary embolism. In a patient at low-to-moderate risk for pulmonary embolism, a negative quantitative d-dimer can effectively rule out the disease.
Aortic Dissection – pain is generally excruciating, sharp, and radiating to the back. If the coronary ostia are involved, ECG changes may occur. Anticoagulation can be disastrous with aortic dissection, so a high index of suspicion is warranted.
Pericarditis – pain is frequently sharp, pleuritic, and positional, with relief upon sitting forward. A pericardial friction rub will be pathognomonic, but can be transient and not present during assessment. PR segment depression on the ECG is also a specific but insensitive marker for pericardial involvement. Elevation of cardiac biomarkers indicates the presence of myocarditis.
Gastrointestinal disorders – the alimentary tract can mimic ACS symptoms, with root causes that range from benign (reflux disease) to disastrous (perforated viscera). Conversely, ACS can mimic GI disorders, with many patients presenting with epigastric pain, nausea, and vomiting as their anginal equivalent. Improvement in pain with the administration of the classic “GI cocktail” is not a reliable indicator that ACS is absent.
Pneumonia – pneumonia typically presents with fever, cough, and dyspnea with sputum production. Comorbidities, such as COPD with chronic dyspnea and sputum production but an increase in chest discomfort, may complicate the assessment. Likewise, severe infection may cause metabolic demands that exceed myocardial capacity, resulting in myocardial necrosis (elevated troponin) that is not due to true ACS/coronary plaque rupture.
Musculoskeletal chest pain – the presence of a precipitating traumatic event is helpful in making this diagnosis, as is reproduction of pain with specific movements or precise palpation along defined muscle tracts. However, a substantial portion of patients with ongoing cardiac ischemia will have chest wall tenderness on exam, and so this finding is non-specific.
Anxiety disorder – depression and anxiety frequently accompany cardiac disease. Unless the patient is quite young, with very atypical features, anxiety should remain a diagnosis of exclusion. The onset of symptoms with emotional distress is not sufficient to attribute the patient’s chest pain to psychiatric disease as opposed to cardiac disease.
D. Physical examination findings
Due to sequelae of ACS
Papillary muscle rupture may present with an acute mitral regurgitation murmur.
Ischemic heart disease may lead to myocardial dysfunction, which may lead to signs and symptoms of acute heart failure.
Cardiogenic shock may present with pulmonary edema, pallor, diaphoresis, or altered mental status.
E. What diagnostic tests should be performed?
An immediate 12 lead ECG should be performed to determine the presence or absence of STEMI or new LBBB. Other ECG-based sequelae of ischemia could include conduction blocks (3
rd degree AV blocks, hemifascicular blocks) or profound bradycardia.
Right ventricular infarction and posterior wall infarction will not present with ST – segment elevation on the traditional 12 lead ECG. Right ventricular infarction may, however, manifest itself as ST segment depression in the lateral leads. If right ventricular infarction is suspected, a right sided ECG can be performed with leads V3 – V6 placed over the right chest in analogous positions to the left sided leads.
Posterior wall infarction will be evidenced by ST segment depression in leads V1 – V3. An upright t-wave in these leads in the setting of ST segment depression is strongly suggestive of posterior wall infarction, as opposed to subendocardial ischemia. A prominent R-wave in V1-V3 is also suggestive of posterior wall infarction.
The initial ECG is normal or non-specific in nearly 50% of all patients eventually diagnosed with myocardial infarction by biomarker criteria. Serial ECGs should be obtained while symptoms concerning for ACS are ongoing in order to detect potential progression to STEMI.
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Outside of suspected STEMI, cardiac biomarkers must be evaluated in the setting of suspected ACS. These are intracellular proteins that are released into circulation upon myocardial necrosis. They may be energy enzymes (CK, CK-MB) or structural proteins (troponin, myoglobin). Cardiac troponin (either I or T) is preferred for the initial diagnosis of ACS due to its superior sensitivity and specificity. CK-MB can be used for diagnosing re-infarction, or if cardiac troponin is not available. CK should not be used by itself to diagnose MI. Myoglobin may detect MI earlier than troponin; however, it is not specific to cardiac myocytes and elevation can also occur with skeletal muscle injury or renal failure.
Given that the rise of biomarkers is time-dependent from the point of myocardial necrosis, serial measurements are often required to detect infarction, especially if the patient presents promptly after the onset of symptoms. Unfortunately, the optimum timing for laboratory draws or selection of biomarkers has not been defined. Conflicting studies have advocated for troponin-only strategies vs. multimarker panels, and various timing regimens (repeat draws at 2,3,4,6, or 8 hours) have been described. It should be noted that previous studies advocating multimarker panels (troponin plus CK-MB or myoglobin or both) were tested against early generation troponin assays. Current troponin assays in clinical use are substantially more sensitive than previous iterations, and are detectable in the first few hours after infarction.
However, serial biomarker testing utilizing currently available assays will, at best, detect myocardial infarction with necrosis and cell lysis. There are no biomarkers that have been validated for the detection of cardiac ischemia as opposed to infarction. Therefore, there remains a population of suspected ACS patients that will not have a definitive diagnosis established with serial biomarkers and ECGs alone.
In addition to cardiac biomarker testing, further laboratory studies may assist in identifying ACS mimics or in characterizing comorbidities that could complicate further diagnosis and treatment.
A complete blood count. Anemia may precipitate anginal symptoms due to supply/demand mismatch and is a risk factor for adverse outcomes in ACS. Thrombocytopenia may affect choice of anticoagulants.
A basic metabolic profile should be obtained and electrolyte abnormalities addressed.
Renal function testing (with abnormal renal function identified by elevated blood urea nitrogen and serum creatinine values) will identify a patient at risk for contrast mediated nephrotoxicity if cardiac catheterization or CT scan with intravenous contrast is required. Elevated creatinine has also been identified as a risk factor for adverse outcome in ACS.
D-dimer testing is necessary when a pulmonary embolism is suspected.
Natriuretic peptide testing may be considered, as elevated BNP is linked to a poor long term outcome in ACS. However, neither BNP nor n-terminal proBNP have been shown to assist with acute diagnosis or risk stratification.
JCAHO lists serum lipid measurement within 24 hours as a core measure for patients presenting with myocardial infarction. This is an assay of limited use in the ED setting, affecting neither diagnosis nor immediate prognosis.
Urine drug screen testing may identify the presence of cocaine or methamphetamine as precipitants of cardiac ischemia.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
If acute STEMI is suspected, initiating reperfusion (either fibrinolysis or primary PCI) should not be delayed for chest x-ray. The exception to this is suspected acute aortic dissection as the etiology for the patient’s STEMI. In this scenario, it is reasonable to obtain an immediate portable chest x-ray to look for evidence of aortic dissection: widened mediastinum, pleural effusion, tracheal deviation due to hematoma, etc. If suspicion is strong enough, a CT scan focusing on the aorta may be required to evaluate the aortic anatomy. Avoid delay in reperfusion for STEMI. However, initiating fibrinolysis or anticoagulation for an acute aortic dissection can be disastrous.
When evaluating the patient without STEMI, chest radiography should be obtained to explore alternate diagnoses (aortic dissection, pneumothorax, pneumonia, rib fractures) or comorbidities (cardiomegaly, pulmonary edema). PA and lateral imaging provides more detail and may be preferred if the patient is hemodynamically stable; otherwise, a portable AP chest x-ray should be obtained.
CT angiography has emerged as the diagnostic test of choice for suspected pulmonary embolism (PE) with either a high clinical suspicion or elevated d-dimer testing. Ventilation-perfusion (VQ) scanning is an alternative when there are contrast contraindications, such as renal insufficiency or dye allergy, and was the mainstay of PE diagnosis for years before the advent of CT angiography. However, VQ scanning will not provide information regarding alternate diagnoses, such as occult pneumonia or aortic dissection, that can be discovered on CT.
The management for this condition is as follows:
STEMI- local reperfusion protocol (fibrinolysis, local PCI, or transfer for primary PCI) should be initiated immediately upon identification.
High risk ACS- high risk features or a high risk for adverse outcomes per validated risk stratification score such as TIMI or GRACE. Plan for early interventional strategy.
Intermediate risk ACS- non-ischemic ECG and biomarkers, clinically stable, but still at risk per risk stratification tool. May consider early conservative strategy and diagnostic protocol.
Low risk ACS- negative ECG and biomarkers, low risk per risk stratification tool. Consider accelerated diagnostic protocol
The American College of Cardiology / American Heart Association guidelines for NSTEMI / unstable angina list the following characteristics as indicative of a high risk presentation:
dynamic ECG changes
elevated cardiac biomarkers
sustained ventricular tachycardia
recurrent ischemic chest pain despite ongoing medical management
pulmonary edema or new mitral regurgitation murmur
recent PCI (less than 6 months) or previous CABG
established systolic heart failure (EF<40%)
In addition, the ACC/AHA guidelines recommend the calculation of a risk stratification score as part of the initial assessment of a patient with suspected ACS. Validated scores include GRACE, PURSUIT, and TIMI models. Given the simplicity of calculating a TIMI score, and given that TIMI has been validated in an ED population of non-specific chest pain, the TIMI score is preferred by the author.
Patients with high risk features or at high risk for adverse outcomes per risk stratification score should receive aggressive medical management (at least dual antiplatelet therapy and anticoagulation), admission to an inpatient unit, and cardiac catheterization with the intent to perform PCI, preferably within 24 hours of presentation.
Patients without high risk features but with increased risk for ACS as characterized by a validated risk stratification score may be managed utilizing an initially conservative strategy and diagnostic protocol. In this strategy, anticoagulation and antiplatelet therapy should be initiated while the patient is monitored for high risk features (hemodynamic instability, refractory angina) followed by stress testing to determine the need for diagnostic angiography. A conservative strategy should also be pursued in those patients who would not consent to PCI regardless of findings on angiography or those with a poor life expectancy due to comorbidities such that they would not expect to receive a survival benefit with PCI.
Patients with a low risk for ACS, as characterized by a low risk stratification score, but not clearly non-cardiac chest pain, should undergo an accelerated diagnostic protocol in an observation setting, including serial evaluations such as biomarkers and ECG. Once infarction has been ruled out, guidelines recommend provocative stress testing or coronary CTA. This may be done as part of the initial observation stay, or as an outpatient if timely (<72 hours) stress testing can be assured. The decision to proceed with diagnostic angiography is based on stress testing results.
A. Immediate management
While completing risk stratification, the clinician should actively manage the patient’s symptoms to alleviate angina, minimize myocardial demand, and maximize blood delivery to the myocardium by inhibiting platelet aggregation and thrombus formation. All ACS medications carry a risk profile, whether hemodynamic compromise or increased bleeding risk, and the clinician must balance patient needs and the risk of adverse effects of medication.
The classic agent to treat angina is nitroglycerin, which affects both peripheral and coronary vasodilatation and increases oxygen delivery to the myocardium by reversing coronary artery vasospasm. In addition, it will reduce both preload and, to a lesser extent, afterload, reducing myocardial oxygen demand. In the setting of concomitant use of phosphodiesterase inhibitors, such as erectile dysfunction medication, however, a precipitous blood pressure drop may occur, and nitroglycerin use is contraindicated.
Likewise, with right ventricular ischemia/infarction, the reduction in preload produced by nitroglycerin can severely compromise right ventricular function via the Starling curve, and again a precipitous drop in blood pressure can occur. Nitroglycerin is effective at ameliorating anginal pain, but this goal should not be pursued at the expense of hemodynamic compromise. If the patient is already hypotensive, is using phosphodiesterase inhibitors, or right ventricular involvement is suspected, nitroglycerin should be avoided. It also should be noted that there are no large randomized controlled trials that have demonstrated a reduction in mortality with nitroglycerin use in ACS.
Morphine is the recommended analgesic for refractory angina. Hypotension may occur via an anaphylactoid, histamine-mediated pathway, and nausea, vomiting, and respiratory depression may occur. Retrospective cohort studies have demonstrated an association between morphine use and mortality in ACS. The mechanism of this relationship has not been defined, but it is postulated that opiate use may mask identification of recurrent ischemia. Alternately, the use of morphine instead of specific anginal therapy may mark the clinician’s inappropriately low suspicion for ACS. However, these are speculations, and the relationship between opiate use and mortality has not been fully explored.
Beta-blockers, calcium channel blockers, and ACE inhibitors
Beta-blockade decreases heart rate and blood pressure, contributing to a decreased myocardial oxygen demand. However, the use of beta blockers early in the management of ACS has been de-emphasized in recent years subsequent to the COMMIT trial, which studied intravenous metoprolol in the setting of AMI. Although there have been a number of benefits noted with beta blocker use, early mortality was noted due to patients developing cardiogenic shock. Therefore, recommendations have shifted to the use of oral beta blockers within the first 24 hours after presentation, when hemodynamic stability has been assessed. Intravenous beta-blockade can be considered in the setting of substantial hypertension.
Beta blockade should be avoided in those with heart failure, cardiogenic shock, conduction abnormalities, and active bronchospasm. In addition, when beta-blockers are used, there is a theoretical risk of unopposed alpha-mediated vasoconstriction in the setting of acute cocaine toxicity. In the case of continued angina and hypertension when beta-blockers are contraindicated, a non-dihydropyridine calcium channel blocker, such as verapamil or diltiazem, can be considered. As with beta blockers, patients at risk for or who are experiencing cardiogenic shock should not receive calcium channel blockers.
Angiotensin converting enzyme (ACE) inhibitors have multiple beneficial effects in patients with structural heart disease and impaired systolic function. In patients with ACS and impaired ejection fraction (EF<40%), and in the absence of chronic renal failure, shock, or hypotension, an ACE inhibitor should be administered within the first 24 hours of presentation.
It is the author’s preference that, in the absence of substantial hypertension with tachycardia, one should refrain from administering upstream beta blockers. Tachycardia may represent a precursor to incipient cardiogenic shock. If the patient requires stress testing, beta-blockade may interfere with achieving an adequate heart rate, rendering the stress test less than diagnostic.
In order to prevent further thrombus formation and propagation on the surface on a ruptured, unstable plaque, both antiplatelet and anticoagulant agents should be administered in high and intermediate risk patients with suspected or confirmed ACS. Antiplatelet agents work on the various receptors on the platelet surface to inhibit successful platelet aggregation, whereas anticoagulants will target the thrombin-fibrin cascade along different points, depending on the agent. The use of these medications requires balancing the preservation of coronary artery blood flow with the increased risk of bleeding associated with them.
There are a variety of potential agents that can be used in various combinations in this patient population. The strongest recommendation the authors can make is for the emergency department and cardiology teams to sit down and determine an explicit protocol as to which drugs will be used in which patients, based on clinical presentation. This is especially critical when an emergency department is served by multiple cardiologists/cardiology groups. Having to adjust medication regimens based on which cardiologist is on call, instead of patient-based characteristics, is a recipe for error.
The SYNERGY trial indicates that crossing over between different pharmacologic agents increases the chances of drug interactions and bleeding risk. In SYNERGY, patients who went from low molecular weight heparin to unfractionated heparin, or vice versa, had a substantially increased risk of an adverse bleeding event. Getting everyone involved and coming up with an acceptable evidence based pharmacologic protocol for patients based on their risk profile is in the patient’s best interest.
Specific agent classes and their indications are listed below. For a detailed discussion of the evidence supporting each drug and class, see the latest edition of the ACC/AHA guidelines for the management of patients with unstable angina/NSTEMI.
Aspirin is the first choice for platelet inhibition in suspected cases of ACS. Its effects are rapid and predictable, and the side effect profile for acute usage is benign. All patients presenting with suspected ACS should receive 162-325 mg of aspirin unless they are allergic. In the case of aspirin allergy, the current guidelines recommend clopidogrel (300 mg loading dose, then 75 mg daily) as a substitute.
This class of oral medications includes thienopyridines (clopidogrel, prasugrel) as well as the non-thienopyridine agent ticagrelor. These medications all block platelet aggregation via competitive inhibition of the ADP-receptor on the platelet surface. Early upstream administration, prior to angiography, has demonstrated benefit with these agents, although prasugrel has not been studied with upstream use prior to cardiac catheterization in non-ST segment elevation ACS. The main adverse event associated with these drugs is bleeding, predominantly during coronary artery bypass grafting (CABG) when required for ACS not amenable to PCI. Of note, prasugrel carries a black box warning for patients over 75 years old and those with a history of previous TIA or stroke due to an increased risk of stroke in these subpopulations in initial studies.
This class of agents is also recommended for ACS patients undergoing an initially conservative management strategy who are at high to intermediate risk for ACS. Unless there is an allergy-based contraindication, aspirin should be used concomitantly to provide dual-agent antiplatelet activity.
Glycoprotein IIb/IIIa antagonists
This class of intravenous medications includes abciximab, eptifibatide, and tirofiban, and acts to impair platelet aggregation by competitive antagonism at the surface glycoprotein IIb/IIIa (GP IIb/IIIa) receptor. In the setting of a planned interventional strategy where the patient is going to undergo angiography within hours of presentation, it is reasonable to hold off on upstream administration of a GP IIb/IIIa inhibitor until the coronary anatomy is defined and the decision to proceed with PCI has been made. However, when it is anticipated that angiography will be delayed, dual antiplatelet therapy (either aspirin + ADP receptor antagonist or aspirin + GP IIb/IIIa inhibitor) or triple antiplatelet therapy (an agent from each class) should be initiated in patients with high risk ACS.
Authors’ preferred agents
Generally, we initiate aspirin and an ADP receptor antagonist in the setting of high risk ACS in the ED, given that the EARLY ACS trial demonstrated no benefit to upstream initiation vs. cath lab provisional use of eptifibatide. The effect of intravenous GP IIb/IIIa inhibitors is quite rapid, as opposed to the time required for oral absorption of the ADP receptor antagonists. Therefore, our protocol utilizes early administration of dual platelet therapy so as to ensure adequate inhibition as soon as possible. We find that the event rate of high risk ACS patients without STEMI going on to urgent CABG is quite low, and so we do not withhold dual platelet inhibition for that concern.
Heparin is a polysaccharide that catalyzes and enhances native antithrombin activity, which then inhibits a number of components in the coagulation cascade. Unfractionated heparin (UFH) consists of polysaccharide chains of vary lengths and densities, whereas low molecular weight heparin (LMWH) products have been refined to isolate smaller chains.
In general, the anticoagulant effect of LMWH is more predictable, not requiring laboratory monitoring, But it is more dependent on renal clearance for elimination. The anticoagulation effect of UFH is less predictable, requiring frequent PTT monitoring and infusion rate adjustment. LMWH do not affect the PTT and thus cannot be monitored by standard laboratory assays. However, factor Xa assays can be used if available and necessary to assess the extent of anticoagulant activity provided by LMWH. In general, trials have supported the efficacy of LMWH over UFH, but the ACC/AHA guidelines do acknowledge the concern of some interventional cardiologists that LMWH activity cannot be titrated in the catheterization lab during PCI.
As stated above, the SYNERGY trial inadvertently demonstrated that crossing patients from a LMWH to UFH without an adequate washout period substantially increases the risk of bleeding. Therefore, if a transition is planned for angiography with intent to perform PCI, it is recommended that at least 8 hours lapse between the last dose of LMWH and the initiation of UFH. Evidence suggests that PCI can be performed safely with LMWH, without a transition to UFH.
Direct thrombin inhibitors
Drugs in this class block thrombin without native antithrombin as a substrate. In the US, bivalirudin is the primary clinical agent in this class. Bivalirudin has not been studied outside of an angiography-based strategy, and therefore cannot be recommended for use in an early, conservative management setting. Evidence suggests that this agent is best suited for initiation in the cath lab. It also strongly suggests that dual antiplatelet therapy with aspirin and an ADP receptor antagonist be initiated prior to the use of bivalirudin in the cath lab due to increased rates of ischemic events when bivalirudin was utilized as monotherapy in the ACUITY trial.
Factor Xa inhibitors
Fondaparinux is the only agent in this class currently approved in the United States for ACS. Fondaparinux is a competitive inhibitor of factor Xa in the coagulation cascade, but it does not act against thrombin that is already in the coronary thrombus. In the OASIS V study, fondaparinux had substantially fewer bleeding events and demonstrated improved ischemic outcomes when compared to an enoxaparin/UFH regimen. This was at the expense of a three-fold higher incidence of intraprocedural, catheter-associated thrombus, however. This agent that has not been studied in a conservative, management strategy, and therefore is not particularly suited to upstream ED administration.
Authors’ preferred agents
Given the evidence supporting the efficacy of LMWH over UFH, the authors’ recommend LMWH use in high and intermediate risk patients with suspected ACS, especially if a conservative strategy is selected, with some reservations. First, in patients with renal insufficiency, UFH may be preferred due to impaired clearance of LMWH. Second, if the patient is going urgently from the ED to the cath lab, the time required for LMWH to be absorbed from subcutaneous administration and demonstrate effective anticoagulation may make UFH a superior choice. In addition, if the use of bivalirudin is preferred in the catheterization laboratory, UFH upstream allows a smoother transition to bivalirudin use if PCI is indicated. We do not recommend upstream use of either bivalirudin or fondaparinux, although these agents may be utilized in the catheterization lab if warranted.
B. Physical examination tips to guide management
Physical examination findings that would be suggestive of deterioration include:
rales from pulmonary edema
new mitral valve murmur
bradycardia (especially with right coronary involvement affecting the sinoatrial pacemaker)
While on anticoagulation, the physician should monitor for signs of bleeding, including:
altered mental status
rectal bleeding, melena, or hematemesis
back or hip pain, suggestive of potential retroperitoneal hematoma
bleeding at the site of vascular access catheters
C. Laboratory tests to monitor response to, and adjustments in, management
Serial cardiac biomarkers should be monitored until at least 6 hours after the onset of symptoms to detect the typical rise associated with myocardial infarction. For patients receiving unfractionated heparin infusion, partial thromboplastin time (PTT) should be monitored while on the infusion so infusion rates can be adjusted to therapeutic effect. Most heparin protocols utilize q6 hour draws. In addition, complete blood count with platelets should be monitored daily when patients are receiving anticoagulation. Hemoglobin / hematocrit should be followed for bleeding, and platelets should be monitored for the development of heparin induced thrombocytopenia.
D. Long-term management
Low risk patients
After the initial risk stratification assessment, a substantial portion of patients will be deemed low risk for ACS (negative initial cardiac biomarkers, non-ischemic ECG, and low risk stratification score). These patients should receive serial assessment via repeat biomarker measurement, repeat ECG, and either coronary imaging or stress testing with or without cardiac imaging (echocardiography, nuclear scintigraphy).
An increasing body of literature evaluates the use of coronary CTA in low risk chest pain populations to non-invasively evaluate the coronary anatomy. The intent is that, in the absence of elevated cardiac biomarkers and ECG changes, a lack of substantial coronary plaque will render the diagnosis of acute coronary syndrome highly unlikely. There are technical requirements that may inhibit the widespread adoption of this modality, including the fact that a high-speed multidetector CT is required for optimal imaging quality and radiation minimization, expertise in image interpretation may not be widely available, and the patient must be able to tolerate IV contrast and beta-blockade sufficient to produce bradycardia during the imaging process. However, in the appropriate setting, obstructive coronary artery disease can be effectively ruled out in a non-invasive fashion.
The goal of stress testing is to objectively determine supply and demand mismatch. A continuous ECG is monitored as increasing demand is placed on the cardiovascular system. Typically a graded treadmill protocol is used, but pharmacologic agents can be administered in lieu of actual exercising.
Per the ACC guidelines on the management of low risk chest pain, ECG stress testing alone (without confirmatory imaging) may be considered in patients with good functional capacity. However, the sensitivity of the ECG component of stress testing for predicting coronary stenosis is approximately 75%. The authors prefer a testing strategy that incorporates echocardiography or nuclear scintigraphy. The use of either increases the sensitivity of stress testing substantially over ECG stress tests alone. Their sensitivity for predicting coronary stenosis ranges from 85%-90%.
The goal of stress testing is to decrease the likelihood that the patient’s symptoms are due to coronary stenosis. In a patient with an appropriately low pre-test probability of disease, perfect sensitivity is not required to decrease the post-test probability of disease to acceptable limits if the test is negative.
Stress cardiac MRI
Stress cardiac MRI combines outstanding detail of the cardiac structures with the ability to determine perfusion defects. Generally, pharmacologic agents are required to generate the stress, as standard treadmills cannot operate near the MRI magnets as they contain too many ferromagnetic components. Research is ongoing in order to delineate the precise role of cardiac MRI in the risk stratification process. The increased sensitivity and accuracy over conventional stress imaging is tempered by the restricted availability of this technology.
The serial presenter
Sometimes a patient has presented multiple times with symptoms suggesting ACS, but has had a previous negative workup. There are a few special points to consider in this case. First, what does a “normal cath” mean? A patient may report a previous negative cardiac catheterization that, upon further review, is actually positive for coronary artery disease that did not warrant mechanical intervention at that time. As a large number of MI arise from non-obstructive plaques, the presence of non-obstructive CAD on a previous anatomic study should encourage the physician to maintain ACS in the differential. Generally, acute plaque rupture with downstream thrombus showering will manifest itself with elevated biomarkers.
Second, when a patient has had a stress test in the past year, the following points must be considered:
Was the stress test done properly? Did the patient have an appropriately elevated heart rate such that the test could have been diagnostic?
Was the right study done? ECG stress without imaging is insufficient to rule out ACS in a patient presenting emergently with potential symptoms of angina.
Was the previous stress test wrong? Stress testing can accurately stratify low risk populations. A patient with high risk features may warrant further testing despite a previously negative stress test. If the previous testing was a functional study (stress echo), consider a perfusion (cardiac MRI, nuclear perfusion) or an anatomic study (coronary CT, cardiac catheterization), and vice versa.
Stress testing identifies a lesion large enough to limit blood flow. In the absence of plaque rupture, it is unlikely that a patient will develop a de novo obstructing plaque large enough to affect a stress test within the course of a few months to a year. Therefore, if a recent stress test was adequate, doing another is unlikely to produce results that will alter management. Consider serial ECG and biomarker measurement without repeating a provocative study in a patient at low risk for disease.
E. Common pitfalls and side-effects of management
The primary pitfall of ACS risk stratification and evaluation is to not consider the diagnosis in the first place. The literature suggests we inadvertently send home 1%-4% of AMI patients from the ED. Atypical presentations in the elderly, females, and diabetics can fail to alert the clinician to the possibility of ACS. A reasonable index of suspicion should be maintained for the possibility that the 60 year old with nausea and vague malaise is actually experiencing myocardial ischemia.
There is as of yet no evidence that demonstrates the effective utility of a single troponin measurement, even with highly sensitive troponin assays, in ruling out all forms of acute coronary syndrome. Emerging evidence suggests that high-sensitivity troponins will be detectable quite early in the setting of NSTEMI. However, a plaque that is substantial enough to cause ischemic symptoms and consequences, but not actual infarction and cell death, will not be detected by a single troponin drawn after the onset of symptoms. One common practice is to utilize a single troponin draw after 6 to 8 hours of constant chest pain. We suggest that the reliability of this strategy is tied to the reliability of the patient’s ability to discern and report consistency of pain and the absence of waxing and waning symptoms.
Undertreatment of high risk individuals is also a concern. As the interval from presentation to intervention increases, so does the patient benefit realized from appropriately aggressive antiplatelet and anticoagulation regimens initiated early in the ED and hospital course. Treatment initiated in the ED is frequently carried into the inpatient setting, so the physician in the ED does have an opportunity to positively influence the future care of the admitted patient.
The primary complication associated with anticoagulation and antiplatelet agents is bleeding. Altered mental status, headache, and vomiting may indicate an intracranial hemorrhage. Vascular access sites should be monitored for hematoma formation. Serial hemoglobin measurements should be obtained if occult blood loss is suspected. Heparin-based products may induce an immune reaction causing sensitization to platelets (heparin induced thrombocytopenia, or HIT). The risk is low (<1%) overall and lower in patients exposed to low molecular weight heparins as compared to unfractionated heparin. Many of these agents are cleared renally, and dosing should be adjusted in patients with renal insufficiency.
Beta-blockers, calcium channel blockers, ACE inhibitors, and nitroglycerin all may cause a drop in blood pressure, especially in patients with right ventricular ischemia. Cardiogenic shock may develop in extreme cases. Fluid boluses should be utilized to support preload. Vasopressors may be required to provide support until revascularization can be achieved. These medications should be avoided in patients with pre-existing hypotension or cardiogenic shock.
Rarely, beta-blockers may precipitate bronchospasm in patients with uncontrolled COPD/asthma. There is also a theoretic risk of critical hypertension and vasospasm when pure beta-blockers are administered in the setting of acute cocaine toxicity.
ACE inhibitors and ARBs may precipitate hyperkalemia in the context of renal insufficiency. Infrequently, angioedema may occur with the use of ACE/ARB medications. This is a non-antigen mediated response, and traditional anaphylactic treatments have little effect. Expectant management and prompt airway control when warranted are the mainstays of treatment.
IV. Management with co-morbidities
Multiple comorbidities may affect how ACS is managed, depending on the severity of the comorbidity. For example, patients with limited life expectancy due to advanced malignancy or dementia will be unlikely to benefit from aggressive ACS management, and the focus of therapy would therefore be on comfort measures as opposed to aggressive revascularization. In general, however, comorbidities that are not an immediate threat to life expectancy should only affect the care plan in modest fashion. That is, high risk patients should still receive aggressive pharmacologic therapy.
Renal failure / renal insufficiency
ACE inhibitors may be contraindicated
unfractionated heparin may be preferred over low molecular weight heparin
intravenous contrast exposure should be limited where possible, and isosmolar agents are preferred
renally cleared drugs should be dose adjusted
patients with diabetes should receive an ACE inhibitor (or ARB if ACE is not tolerated) if not contraindicated due to renal insufficiency
glycemic control should be maintained during hospitalization
V. Patient safety and quality measures
Physician quality reporting system
This set of measures, reported to the Centers for Medicare & Medicaid Services (CMS), provides financial incentives to providers meeting guideline-based quality recommendations. There are a variety of medical conditions and targeted interventions about which the provider can report data. One that is relevant to ACS includes aspirin on arrival for AMI. This is the percentage of patients with an ED discharge diagnosis of AMI who received aspirin in the ED (or have documented receipt in the 24 hours prior to the ED presentation). Explicit documentation of appropriate contraindications for aspirin use is sufficient to remove a patient from the reporting requirement.
In addition, a 12-lead ECG performed for non-traumatic chest pain is also relevant to suspected ACS. This is the percentage of ED patients over the age of 40 with a diagnosis that includes non-traumatic chest pain who received a 12-lead ECG.
Recently retired measures include beta-blocker on arrival for AMI.
Institution-level quality metrics
It is obvious that results attributed to an institution are generated from the actions of individuals. Therefore, while publicly reported performance data may not refer specifically to individual results, we are all responsible for providing evidence-based, guideline recommended elements of medical care. While the institutional-level data may not be publicly attributed to your performance, your hospital administration monitors these metrics at the individual level.
Hospital-Inpatient measures relevant to the ED management of patients with suspected or confirmed ACS are included under the category of AMI. The majority of the measures relevant to the ED setting are in reference to STEMI. v However, aspirin use applies to NSTEMI as well. These measures apply to patients that are admitted to the hospital directly from the ED. The care of patients transferred to another hospital for inpatient care must meet the standards set by the Hospital-Outpatient metrics, discussed below.
AMI – 1: aspirin at arrival: This measure applies to both non-STEMI and STEMI. Patients should receive aspirin therapy, either given within 24 hours of arrival (by patient or by EMS) in the ED or within 24 hours after presentation. Patients with an explicitly documented contraindication for aspirin use will be excluded from this measure.
AMI – 7: median time to fibrinolysis: This measure applies to patients with STEMI or new left bundle branch block (LBBB) on the initial ECG that receive fibrinolytics as the primary treatment. If the initial ECG does not show STEMI, but the patient develops STEMI, this measure will not apply. If the patient was transferred from another hospital, designated as comfort care only, or if there are explicitly documented reasons for a delay (cardiac arrest, patient refusal, diagnostic uncertainty regarding the STEMI), the measure will also not apply.
AMI – 7a: fibrinolysis within 30 minutes of arrival: The proportion of patients as defined above who receive fibrinolysis within 30 minutes of arrival to the ED.
AMI – 8: median time to primary PCI:This measure applies to patients with STEMI or new left bundle branch block (LBBB) on the initial ECG that receive PCI as the primary treatment. If the initial ECG does not show STEMI, but the patient goes on to develop STEMI, this measure will not apply. If the patient was transferred in from another hospital, designated as comfort care only, or if there are explicitly documented reasons for a delay (cardiac arrest, patient refusal, diagnostic uncertainty regarding the STEMI), the measure will not apply.
AMI – 8a: primary PCI received within 90 minutes of arrival: The proportion of patients as defined above who receive primary PCI within 90 minutes of arrival to the ED.
In addition, CMS monitors two outcomes-based measures relative to AMI: 30-day all-cause mortality rates after AMI, and 30-day all-cause readmission rates after discharge for AMI. Providing solid, evidenced-based care is the best thing that ED-based providers can do to contribute to preventing 30 day mortality. The 30-day readmission metric, however, may result in increased pressure on EDs to not readmit patients after AMI who may benefit from hospitalization. It should be noted that an observation stay with subsequent discharge will not count against the readmission rate. Typically, ED-based observation units are used to provide care to patients at low risk for suspected ACS, not patients with recent AMI and a potential need for readmission. How the role of the ED in preventing readmissions evolves is certainly not clear at this time, and there is no widely applicable standard process.
Hospital-Outpatient measures apply to patients initially seen in the ED with chest pain of suspected ACS origin or AMI and who are then transferred to another facility, either to a general hospital or a federal (VA) facility. Certain measures that apply to those patients with chest pain of suspected ACS origin will also apply to those patients who are discharged or leave against medical advice. These measures DO NOT APPLY if the patient is admitted from the ED to the inpatient setting without a transfer.
OP-1: median time to fibrinolysis: This measure applies to patients with STEMI or new left bundle branch block (LBBB) on the initial ECG that receive fibrinolytics as their primary treatment. If the initial ECG does not show STEMI, but the patient develops STEMI, this measure will not apply. If the patient was transferred from another hospital, designated as comfort care only, or if there are explicitly documented reasons for a delay (cardiac arrest, patient refusal, diagnostic uncertainty regarding the STEMI), the measure will also not apply.
OP-2: fibrinolytic therapy received within 30 minutes: The proportion of patients as defined above who receive fibrinolysis within 30 minutes of arrival to the ED.
OP-3: median time to transfer to another facility for acute coronary intervention:This metric reports the door-in to door-out time for patients transferred for primary PCI for STEMI or new LBBB. Patients who receive primary fibrinolysis who are then transferred are not included in this measure.
OP-4: aspirin at arrival: This measure applies both to patients with AMI as well as to patients with chest pain of suspected ACS origin. Patients should receive aspirin therapy within 24 hours of arrival (by patient or by EMS) in the ED or within 24 hours after presentation. Patients with an explicitly documented contraindication for aspirin use will be excluded from this measure.
OP-5: median time to ECG: This measure applies both to patients with AMI as well as to patients with chest pain of suspected ACS origin. This metric reports the interval from patient arrival at the ED to ECG acquisition.
OP-16: troponin results received in 60 minutes: This measure applies both to patients with AMI as well as to patients with chest pain of suspected ACS origin. This metric reports the proportion of patients who have a troponin result returned in 60 minutes from the time arrival.
A. Appropriate prophylaxis and other measures to prevent readmission
Secondary prevention of acute coronary syndrome after an initial event incorporates multiple approaches, including:
Lifestyle modification- patients should quit smoking, increase physical activity levels, and maintain a healthy weight.
Beta blockade is indicated in all patients recovering from an ACS event, in the absence of contraindications.
ACE inhibition- patients with a history of diabetes or heart failure should be discharged on an ACE inhibitor (or ARB if ACE is not tolerated). Consider an ACE/ARB in those patients without diabetes or heart failure.
Aspirin is indicated in all patients recovering from an ACS event, absent allergy or elevated bleeding risks.
An ADP-receptor antagonist should be prescribed at discharge, with the duration of therapy as:
At least 1 month for patients who were medically managed
At least 1 month, and preferably up to a1 year for those patients receiving a bare metal stent
At least 1 year for all patients receiving a drug-eluting stent.
A statin should be prescribed at discharge for all ACS patients, regardless of LDL level.
Diabetes and hypertension should be appropriately monitored and treated.
B. What is the evidence for specific management and treatment recommendations?
The quality of the evidence for management of ACS ranges from high quality, randomized, placebo controlled, double blind studies to consensus-based recommendations. The best summary of the available evidence can be found in the guidelines and scientific statements issued jointly by the American College of Cardiology and the American Heart Association. Recommendations are graded both on the strength of the recommendation and the level of evidence. These guidelines are updated every few years, and are easily accessed electronically. Citations for the most recent recommendations are below:
Anderson, JL, Adams, CD, Antman, EM. “2011 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines”. Circulation. vol. 123. 2011. pp. e426-e579.
Amsterdam, EA, Kirk, JD, Bluemke, DA. “Testing of low-risk patients presenting to the emergency department with chest pain: a scientific statement from the American Heart Association”. Circulation. vol. 122. 2010. pp. 1756-76.
Kushner, FG, Hand, M, Smith, SC. “2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines”. J Am Coll Cardiol. vol. 54. 2009. pp. 2205-41.
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- I. Acute Coronary Syndrome: What every physician needs to know
- II. Diagnostic confirmation: are you sure your patient has ACS?
- A. History part I: pattern recognition
- B. History part 2: prevalence
- C. History part 3: competing diagnoses that can mimic ACS
- D. Physical examination findings
- E. What diagnostic tests should be performed?
- III. Management
- A. Immediate management
- B. Physical examination tips to guide management
- C. Laboratory tests to monitor response to, and adjustments in, management
- D. Long-term management
- E. Common pitfalls and side-effects of management
- IV. Management with co-morbidities
- V. Patient safety and quality measures
- A. Appropriate prophylaxis and other measures to prevent readmission
- B. What is the evidence for specific management and treatment recommendations?