Angina Pectoris in Emergency Medicine

Angina pectoris (AP) represents the clinical syndrome occurring when myocardial oxygen demand exceeds supply. The term is derived from Latin; the literal meaning is "the choking of the chest;" angere, meaning "to choke" and pectus, meaning "chest." The first English-written account of recurrent angina pectoris was by English nobleman Edward Hyde, Earl of Clarendon. He described his father as having, with exertion, "a pain in the left arm…so much that the torment made him pale".[1] The first description of angina as a medical disorder came from William Heberden. Heberden, a prodigious physician, made many noteworthy contributions to medicine during his career. He presented his observations on "dolor pectoris" to the Royal College of Physicians in 1768. Much of his classic description retains its validity today.[2]

Angina pectoris has a wide range of clinical expressions. The symptoms most often associated to angina pectoris are substernal chest pressure or tightening, frequently with radiating pain to the arms, shoulders, or jaw. The symptoms may also be associated with shortness of breath, nausea, or diaphoresis. Symptoms stem from inadequate oxygen delivery to myocardial tissue. No definitive diagnostic tools that capture all patients with angina pectoris exist. This, combined with its varied clinical expression, makes angina pectoris a distinct clinical challenge to the emergency physician. The disease state can manifest itself in a variety of forms, including the following:

• Stable angina pectoris is classified as a reproducible pattern of anginal symptoms that occur during states of increased exertion.

• Unstable angina pectoris (UA) manifests either as an increasing frequency of symptoms or as symptoms occurring at rest.

• Prinzmetal angina or variant angina occurs as a result of transient coronary artery spasms. These spasms can occur either at rest or with exertion. Unlike stable or unstable angina, no pathological plaque or deposition is present within the coronary arteries that elicits the presentation. On angiography, the coronary arteries are normal in appearance with spasm on angiography.

• Cardiac syndrome X occurs when a patient has all of the symptoms of angina pectoris without coronary artery disease or spasm.

Our overall understanding of the pathophysiology of myocardial ischemic syndromes has greatly expanded over the past two decades. The primary dysfunction in angina pectoris is decreased oxygen delivery to myocardial muscle cells. The two predominant mechanisms by which delivery is impaired appear to be coronary artery narrowing and endothelial dysfunction. Any other mechanism that affects oxygen delivery can also precipitate symptoms.

Extracardiac causes of angina include, but are by no means limited to, anemia, hypoxia, hypotension, bradycardia, carbon monoxide exposure, and inflammatory disorders.[3] The end result is a shift to anaerobic metabolism in the myocardial cells. This is followed by a stimulation of pain receptors that innervate the heart. These pain receptors ultimately are referred to afferent pathways, which are carried in multiple nerve roots from C7 through T4. The referred/radiating pain of angina pectoris is believed to occur because these afferent pathways also carry pain fibers from other regions (eg, the arm, neck, and shoulders).

Coronary artery narrowing

Coronary artery narrowing appears to be the etiology of cardiac ischemia in the preponderance of cases. This has clinical significance when atherosclerotic disease diminishes or halts blood flow through the coronary arterial circulation, interfering with normal laminar blood flow. The significance of even a small change in the diameter of a blood vessel can be profound. The Poiseuille law predicts this outcome—the rate of flow is decreased exponentially by any change in the radius of the lumen. As with a smaller pediatric airway, even relatively minute changes in diameter have dramatic consequences in flow rates. Thus, when a lumen is narrowed by one fifth, the flow rate is decreased by about one half. This predicts that even a small change in a coronary artery plaque size can affect the oxygenation through that vessel's territory.

The epicardial vessel, where atherosclerosis often takes place, has the capacity to dilate via autoregulatory mechanisms to respond to increased demand. Angina occurs as this compensatory mechanism is overwhelmed either by large plaques (typically considered 70% or greater obstruction) or by significantly increased myocardial demand.[4]

Endothelial factors

Endothelial factors also play an important role in angina pectoris. During sympathetic stimulation, the endothelium is subjected to mediators of both vasoconstriction and vasodilatation. Alpha-agonists (catecholamines) directly cause vasoconstriction, while endothelial nitrous oxide synthase creates nitrous oxide (NO), which counteracts this constricting force via vasodilatation.

In the diseased coronary artery, NO production is reduced or absent. In this setting, the catecholamine drive can overwhelm the autoregulatory mechanisms. In addition, the endothelium of the plaque-laden artery may, in itself, be dysfunctional. This limits the ability of the intra-arterial endothelium to produce mediators, which, in a healthy artery, would protect against further vasoconstriction, assist dilatation, and provide protection from platelet aggregation. Small lesions in these vessels may produce incompletely obstructing aggregates of platelets. This would further impede flow through the affected vessel.[4]

In the diseased heart, these two factors, coronary artery narrowing and endothelial dysfunction, synergistically result in reduced oxygen delivery to the myocardium. The net result is angina pectoris.

Extrinsic factors

Extrinsic factors can also play a role in specific circumstances. The oxygen-carrying capacity of blood is based on a number of factors. The most important of which is the amount of hemoglobin. Any alteration in the ability of blood to carry oxygen can precipitate angina. Anemia of any degree can result in anginal symptoms. Given a scenario where demand is increased, such as climbing a flight of stairs, increased stress, or even sexual intercourse, the anginal symptoms may appear.[5] Abnormal hemoglobin, such as methemoglobin, carboxyhemoglobin, or any of a number of hemoglobinopathies, creates an environment at greater risk for precipitating angina.

Other extrinsic factors that affect hemoglobin formation, such as lead poisoning or iron-deficiency states, also lead to a similar decrease in oxygen-carrying capacity. Any mechanism that impedes oxygen delivery to the red blood cells has a similar effect. Therefore, any number of pulmonary causes, such as pulmonary embolism, pulmonary fibrosis or scarring, pneumonia, or congestive heart failure, can exacerbate angina. A decreased oxygen environment, such as travel to a higher elevation, has similar consequences due to the decrease in concentration of atmospheric oxygen.

Variant angina

The etiology of variant angina is currently not well understood. Research suggests that inflammatory mediators may result in focal coronary artery vasospasm. Another possibility is that perfusion is decreased through microvascular circulation. Spasm or intermittent narrowing of this microscopic lumen may result in transient areas of hypoperfusion and oxygen deprivation.[6]

Syndrome X

Syndrome X is the triad of angina pectoris, a positive ECG stress test result, and a normal coronary angiogram. The pathophysiology of this disease is not well understood. Many theories exist as to the underlying pathology. Decreased oxygenation of the underlying myocardium may be the result of impaired vasodilatation, dysfunctional smooth muscle cells, poor or deficient microvascular circulation, or even structural problems on a cellular level (eg, an inappropriately functioning sodium ion channel).[6]

United States statistics

An average of 3.4 million US adults older than 40 years experience angina each year. Between 2007 and 2010, there were a total of 2.3 million office visits per year for angina.[7]

An estimated 720,000 American adults will have a new coronary event (MI or CHD death), with an estimated 335,000 experiencing recurrent events.[8]

Conservative 2016 data show 18,000 angina pectoris discharges from hospitals.[8]

Race-, sex-, and age-related demographics

The National Heart, Lung, and Blood Institute (NHLBI) note that the prevalence of angina pectoris is highest in non-Hispanic whites and non-Hispanic blacks (7.6% and 7.4% respectively), followed by Hispanics (6.2%) and Asian or Pacific Islanders (3.6%). This information includes patients aged ≥20 years in the 50 US states, the District of Columbia, Puerto Rico, and the US Virgin Islands.[8]

The overall prevalence for angina is 3.6% in US adults ≥20 years of age. Among US adults aged 40-59 years, the age-adjusted prevalence of angina pectoris (AP) is nearly equal in men and women (6.1% and 6.2% respectively); in those aged 60-79 years and 80 years and older, it is higher men than women.[8]

The incidence of new and recurrent angina increases with age but then declines at around 85 years.

The prognosis of each patient is dependent upon individual factors and the progression of their underlying disease.

The majority of coronary attacks are NOT preceded by long-standing angina pectoris (AP) (only 18%).[7]

Morbidity/mortality

Cardiovascular diseases, including heart disease and stroke, account for more than one third (33.6%) of all US deaths.[7]

Coronary heart disease is the single greatest killer of American men and women.[7]

In 2010, the total costs of cardiovascular diseases in the United States were estimated to be $444 billion, with treatment of these diseases accounting for about $1 of every $6 spent on US healthcare.[7]

Complications

Complications may occur from the progression of the patient's underlying disease or from failure to intervene. Unfortunately, even the testing for underlying disease (eg, stress testing, angiography) can lead to complications including progression to myocardial infarction and renal failure. The risks and benefits of testing and treatment must be determined for and discussed with each patient.

Classically, angina presents as substernal chest discomfort that occurs with exertion, but it also may occur at rest. The discomfort is frequently described as a pressure or heaviness. Other commonly used adjectives for anginal pain include dull, aching, or squeezing. Pain may radiate to one or both arms, to one or both shoulders, or to the neck or jaw. Symptoms are highly variable. The entity cannot be expected to present with the classic triad of chest pressure with exertion radiating to the left arm. The diversity of disease expression is likely related to a patient's age, sex, race, and culture.

The caveat is to have a high index of suspicion for the disease. Many factors influence the expression of anginal symptoms. Familiar terms such as anginal equivalent and atypical chest pain are frequently used in these cases. In addition, systemic diseases, such as diabetes mellitus or chronic pain syndromes, may alter presenting anginal symptoms; while other diseases, such as prior cerebral vascular accident or dementia, may limit the patient's reporting of symptoms. A pain-free variant of angina—sometimes referred to as silent chest pain—also exists. These patients can present with complaints of shortness of breath, nausea, altered mentation, or abdominal pain.[9]

Chest discomfort quality

Which of the following describes the patient's chest discomfort?

• Pain

• Pressure

• Squeezing

• Dullness

• Burning

• Heaviness

• Absent chest discomfort (eg, dyspnea, vomiting, altered sensorium)

Location

Which of the following is the site of the patient's chest pain (often diffuse to any location of C7-T4 dermatomes)?

• Retrosternal or substernal

• Inframammary

• Left sided

• Right sided

• Upper abdominal

• Shoulder, neck, arm

• Teeth, jaw, lower face (above C7 unclear etiology)

• Back, scapular region

Radiation

Which of the following areas does the patient's chest pain radiate to?

• Unilateral or bilateral arms

• Unilateral or bilateral shoulders

• Back

• Neck

• Jaw, ear, or lower face

Temporal

Which of the following describes the temporal relationship of the chest pain?

• Onset to maximum discomfort is progressive: With exertion (with or without increasing frequency) or at rest

• Alleviation to relief is progressive

• Alleviation mediators may include oxygen, nitroglycerin, reduction of stressful activity, pain medication, and the placebo effect (eg, "GI cocktail")

Severity

Which of the following describes the patient's pain severity?

• Mild to severe (1/10 to >10/10)

• "Like my heart pain" - Patients in the emergency department (ED) may refer to the pain as being consistent with prior heart pains.

The physical examination may reveal signs of a hyperadrenergic state. One might observe tachycardia, tachypnea, hypertension, and/or diaphoresis. In addition, ischemia may lead to the presence of crackles due to the loss in contractility with subsequent pulmonary edema or a reduction in the S1 intensity.[10]

That said, no definitive examination findings suggest angina. Much of the information obtained from the physical examination may suggest other comorbidities that place the patient at higher risk for anginal symptoms (eg, chronic obstructive pulmonary disease [COPD], tachycardia, pale conjunctiva). Therefore, the physical examination is necessary to qualify the patient's current physical state and comorbidities. In this manner, the emergency physician obtains a baseline physical examination. Also, as mentioned, comorbid illnesses that affect the patient's level of cardiac, pulmonary, and circulatory function can be assessed.

As with many presentations to the emergency department, the physical examination in angina pectoris also serves as a marker for response to therapy. Important comorbidities that can be identified on physical examination include aortic stenosis, gastrointestinal bleeding, and airway obstruction. Unfortunately, no examination findings are pathognomonic for angina pectoris. In addition, no physical examination findings rule out the disease state.

Of note, while the reproducibility of chest wall pain with palpation may lower the likelihood of angina, this alone cannot rule out angina or myocardial infarction.[11, 12]

The laboratory workup of patients with angina includes the following tests:

• CBC (anemia, leukocytosis may suggest an alternative diagnosis)

• BUN and creatinine level, if intravenous contrast is anticipated

• Cardiac enzyme levels, if positive may suggest non–ST-segment elevation myocardial infarction (NSTEMI); negative results do not rule out ischemia

• Coagulation studies, if anticoagulation or antiplatelets are anticipated

• Type and screen, if surgery or transfusions are considered

Electrolyte levels are of virtually no value unless the patient is on a diuretic and concern for an abnormality exists.

Chest radiography is used to rule out an alternative diagnosis or contributing factors (eg, pneumothorax [PTX], pneumonia [PNA], congestive heart failure); it is also used to evaluate the aorta prior to anticoagulant administration.

Computed tomography (CT) scanning of the chest may be considered for evaluation of aortic or pulmonary disease; if evaluating the aorta, include the abdominal aorta. Of note, the forthcoming "triple rule out CT scan" exposes the patient to an exorbitantly high dose of radiation and should only be used in certain circumstances.

Limited CT coronary scans may help to reduce the posttest probability of coronary artery disease while utilizing potentially less radiation exposure than the "triple rule out scan." Coronary artery calcification suggests the presence of an atherosclerotic plaque. Calcium scores are determined by the density of calcium and the total area. Higher calcium scores may suggest a higher risk of current or future adverse cardiac events. Multiple sites are currently conducting trials to see if this modality will benefit patients in the emergency department.

Bamberg et al found that, in patients with acute chest pain and an inconclusive initial evaluation (nondiagnostic electrocardiographic findings, negative cardiac biomarkers), age and gender can serve as simple criteria to select patients who would derive the greatest diagnostic benefit from coronary computed tomographic angiography (CTA).[16] In an observational cohort study in 368 low-risk patients, positive findings on 64-slice coronary CTA led to restratification to high risk, and negative findings led to restratification to very low risk, in men younger than 55 years and women younger than 65 years. In contrast, in women older than 65 years and men older than 55 years, a negative result on CTA did not result in restratification to a low-risk category.

Nuclear imaging should include V/Q (PE evaluation) and resting sestamibi. (In the appropriate clinical setting, a normal study in a patient with ongoing chest pain may rule out myocardial ischemia.[17] ).

ECG results may be normal or show signs of ischemia. Main use is to establish a baseline and R/O acute ST-segment elevation myocardial infarction (STEMI).

Intraluminal coronary artery sonography (ICAS) is a highly invasive modality that may provide additional information to a patient's coronary artery anatomy and disease. Coronary atherosclerosis, which does not result in coronary artery narrowing, may be missed by conventional forms of coronary angiography. If clinically suspected, ICAS may be utilized to detect the presence or absence of such lesions. ICAS is not readily available; as such, it is highly unlikely that ICAS will be utilized from the emergency department in the foreseeable future.

The use of stress cardiac MRI in an observation unit may be a cost-saving alternative to inpatient management for emergency department patients with chest pain. In a randomized study in 110 patients, Miller et al reported that an observation unit strategy with stress cardiac MRI reduced median hospitalization cost by approximately $588, with no cases of missed acute coronary syndrome.[18]

While the recent ROMICAT trial showed the introduction of coronary CT imaging improved efficiency of the emergency clinical workup in comparison to the traditional ED care, patients who underwent cardiac CT imaging had increased subsequent workups and incurred a higher radiation burden without any reduction in overall cost.[19]

Often, patients with angina pectoris rest or lie down to alleviate the pain. If the patient is not naive to cardiac disease, he or she may have access to nitroglycerin. Often, the patient uses nitroglycerin at home to palliate his or her symptoms. A patient who has known stable angina often is able to report what exacerbates the condition and what (as well as how often) is a "normal" number of tablets for him or her to use prior to alleviation of anginal symptoms. Patients are often instructed by their physicians that the use of more than 3 tablets of nitroglycerin necessitates a higher level of care (eg, calling for an ambulance). Some patients are instructed to take aspirin as well. A knowledgeable patient who reports a change in the pattern or presentation of his or her symptoms should be suspected as having worsening or unstable angina. However, any patient who presents to the ED with symptoms of angina should be assessed promptly for signs of acute myocardial infarction (AMI).

Most prehospital care for angina pectoris consists of administering nitroglycerin, oxygen, and aspirin. The ability to obtain a prehospital ECG is becoming more prevalent.

In the ED, the patient who complains of chest discomfort needs to be immediately assessed for AMI as well as other high-risk diagnoses (eg, aortic dissection, pulmonary embolism). Vital in this assessment is an early ECG and a rapid history and physical examination. Should this initial encounter not reveal a definitive diagnosis, then a more focused history and physical examination needs to be performed. Serial ECGs, especially in the setting of changing symptoms, is imperative. Labeling the ECGs with the patient's level of pain is often useful. A consecutive series of ECGs taken when a patient is having "10/10" pain, "3/10" pain, and "0/10" pain may yield valuable information that would not be readily apparent with an isolated cardiogram. Continuous telemetry monitoring is recommended for higher-risk patients.[20]

The patient who presents with chest pain is presumed to have underlying clinically significant cardiac pathology (ie, unstable angina or NSTEMI).

The initial treatment consists of administration of oxygen, aspirin, nitroglycerin, morphine, and a beta-blocker. Given an altered, yet nondiagnostic ECG and no contraindications, further treatment with heparin (low-molecular weight or unfractionated), clopidogrel, or other antiplatelet agents may be initiated. Most often, an additional abnormal marker (eg, an elevated serum troponin, myoglobin, or CPK level) will be verified prior to antiplatelet therapy.

For persistent symptoms unresponsive to initial therapy, glycoprotein inhibitors can be considered. These appear to demonstrate an additional benefit in the patient population who will be undergoing cardiac catheterization (PCI).[21] Persistent pain, in spite of this treatment, suggests either AMI or an alternative diagnosis. In the case of AMI, angioplasty or thrombolytics should be administered if available and not contraindicated. 

Atypical presentations of angina, unfortunately, are often diagnosed retrospectively. This subset of patients is identified either when their condition progresses to STEMI or through elevated serum marker levels or cardiac dysrhythmia (often ventricular tachycardia or fibrillation). It cannot be understated that the variance of expression of angina pectoris makes it imperative that the clinician have a high level of suspicion for the disease. Little value exists in relying on a constancy of expression or on ECG, history, or physical examination alone for making the diagnosis. Angina pectoris should be considered as well as an extensive differential diagnosis, in just about any patient who presents to the ED with chest pain with or without other nonspecific complaints.

Syndrome X and Prinzmetal angina are not diagnosed in the ED, but the patient's medical records or primary care physician may be helpful in recognizing these disorders.

Consultation

In the setting of unstable angina or AMI, consultation with a cardiologist is warranted.

Hospitalization

Admission is indicated for patients with unstable angina. Patients with angina pectoris who are admitted for alternative reasons do not routinely require telemetry monitoring.

Low-risk, pain-free patients who are admitted with nondiagnostic ECGs and negative cardiac marker results, often do not require telemetry monitoring as inpatients.

Patients admitted with UA/NSTEMI will likely undergo percutaneous transluminal coronary angioplasty (PTCA) if clinically indicated. If catheterization is not available, hospital transfer is suggested.

Transfer

Transfer of the high-risk patient to an active catheterization center is recommended. This may be done from the inpatient setting after the patient has been stabilized in the ED.

Follow-up

Any discharged patient with suspected angina should have close primary or cardiology follow-up care.

In late August 2020, the European Society of Cardiology (ESC) released their updated guidelines for the diagnosis and management of non ST-elevation (NSTE) acute coronary syndrome (ACS).[22, 23] The updates place increased reliance on high-sensitivity cardiac troponin testing (hs-cTn) for diagnosis, embrace coronary computed tomography (CT) imaging to rule out lower-risk patients, as well as highlight the need for personalized antiplatelet regimens, systems of care, and quality improvement. Key messages are below.

Diagnosis

Chest discomfort without persistent ST-segment elevation (NSTE-ACS) is the main symptom that initiates the diagnostic and therapeutic chain. The myocardial pathology consists of cardiomyocyte necrosis, measured by troponin release, or, less often, myocardial ischemia without cell damage (unstable angina). Those with unstable angina have a much lower death risk and benefit less from an aggressive pharmacologic and invasive approach.

Troponin assays and other biomarkers

The ESC recommends Hs-cTn assays over less sensitive assays (higher diagnostic accuracy, same low cost). Note that many cardiac conditions other than myocardial infarction (MI) also result in cardiomyocyte injury and can raise cTn levels.

Biomarkers such as creatine kinase myocardial band (CK-MB) and copeptin may be clinically relevant in specific circumstances when used with non hs-cTn T or I (T/I). There is a more rapid post-MI reduction of CK-MB, and it may have an added value for detecting early reinfarction. Routine use of copeptin is recommended as an additional biomarker for the early exclusion of MI in the infrequent setting of unavailable hs-cTn assays.

Rapid “rule-in” and “rule-out” algorithms

Use of hs-cTn assays (higher sensitivity, diagnostic accuracy) can shorten the time interval to the second cTn assessment for detecting MI at presentation. Recommendations include using the 0 h/1 h algorithm (best option, blood draw at 0 h and 1 h) or the 0 h/2 h algorithm (second-best option, blood draw at 0 h and 2 h). Use of the 0 h/1 h and 0 h/2 h algorithms with clinical and electrocardiographic (ECG) findings aid in identifying appropriate candidates for early discharge and outpatient management.

Hs-cTn confounders

Four clinical variables affect hs-cTn levels besides the presence/absence of MI, as follows:

• Age: Up to 300% differences in concentration between healthy very young versus “healthy” very old individuals
• Renal dysfunction: Up to 300% differences in concentration between otherwise healthy patients with very high versus very low estimated glomerular filtration rate (eGFR)
• Chest pain onset: Over 300%
• Sex: About 40%

Ischemic and bleeding risk assessments

Initial cTn levels add prognostic information about short- and long-term mortality to clinical and ECG variables (higher hs-cTn levels raise mortality risk). Measure serum creatinine and eGFR in all patients with NSTE-ACS; they are prognostic factors and key elements of the Global Registry of Acute Coronary Events (GRACE) risk score (superior assessment to subjective physician assessment for the occurrence of death or MI). Natriuretic peptides may add incremental prognostic information and may aid in risk stratification.

Academic Research Consortium for High Bleeding Risk (ARC-HBR) is a pragmatic approach for evaluating bleeding risk (includes the most recent trials of HBR patients previously excluded from clinical trials of dual antiplatelet therapy [DAPT] duration or intensity). The PRECISE-DAPT (PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent DAPT) score may be used to guide and inform decision making on DAPT duration with a modest predictive value for major bleeding. Their value in improving patient outcomes remains unclear.

Noninvasive imaging

After MI has been excluded, elective noninvasive/invasive imaging may still be indicated based on clinical assessment. Coronary CT angiography (CCTA) may be an option in those with a low-to-modest clinical likelihood of unstable angina as a normal scan excludes coronary artery disease (CAD): It has a high negative predictive value (NPV) to rule out ACS (by excluding CAD) and a positive outcome in patients presenting to the emergency department with a low-to-intermediate pretest probability for ACS and a normal CCTA. Upfront imaging with CCTA also reduces the need for invasive coronary angiography (ICA) in high-risk patients. Other imaging options based on risk evaluation include stress imaging by cardiac magnetic resonance imaging (CMRI), stress echocardiography, or nuclear imaging.

Risk Stratification for an Invasive Approach

The ESC recommends an early routine invasive approach within 24 hours of admission for NSTEMI (based on hs-cTn levels, GRACE risk score >140, and dynamic new/presumably new ST-segment changes) to improve major adverse cardiac events and possibly early survival. Highly unstable patients require immediate invasive angiography based on hemodynamic status, arrhythmias, acute heart failure, or persistent chest pain. For all other clinical presentations, a selective invasive approach may be performed based on noninvasive testing or clinical risk assessment.

Revascularization Strategies

The main technical aspects of percutaneous coronary intervention (PCI) in NSTE-ACS patients do not differ from the invasive assessment and revascularization strategies for other manifestations of CAD. Radial access is the recommended and preferred approach in NSTE-ACS patients undergoing invasive assessment with or without PCI. As NSTE-ACS commonly involves multivessel disease, base the determination of revascularization timing and completeness on the functional relevance of all stenoses, patient age and comorbidities, general clinical condition, and left ventricular function.

MI With Nonobstructive Coronary Arteries (MINOCA)

MINOCA comprises a heterogeneous group of underlying causes potentially involving both coronary and noncoronary pathologic conditions, with the latter including cardiac and extra-cardiac disorders. By consensus, myocarditis and Takotsubo syndrome are excluded. CMRI, a key diagnostic tool, identifies the underlying cause in over 85% of patients and the subsequent appropriate treatment.

Spontaneous Coronary Artery Dissection

Spontaneous coronary artery dissection is a nonatherosclerotic, nontraumatic, or iatrogenic separation of the coronary arterial tunics due to vasa vasorum hemorrhage or intimal tear. It comprises up to 4% of all ACS but has a higher reported incidence (22-35% of ACS) in women younger than age 60 years. Intracoronary imaging is very useful for the diagnosis and treatment strategy. Medical treatment remains to be established.

Pretreatment With P2Y12 Receptor Inhibitors

Due to a lack of established benefit, the ESC does not recommend routine pretreatment with a P2Y12 receptor inhibitor in NSTE-ACS patients with unknown coronary anatomy and a planned early invasive management. However, it may be considered in selected cases and based on the patient’s bleeding risk.

Posttreatment APT

Barring contraindications, DAPT consisting of a 12-month regimen of a potent P2Y12 receptor inhibitor plus aspirin is generally recommended, regardless of the stent type. DAPT duration can be shortened (< 12 months), extended (>12 months), or modified by switching DAPT or de-escalation, based on individual clinical judgment according to the patient’s ischemic and bleeding risks, the occurrence of adverse events, comorbidities, co-medications, and the availability of the respective drugs.

Triple Antithrombotic Therapy (TAT)

In at least 6-8% of patients undergoing PCI, long-term oral anticoagulation is indicated and should be continued. For eligible patients, non-vitamin K antagonist oral anticoagulants (NOACs) are preferred over vitamin K antagonists (VKAs). The ESC recommends dual antithrombotic therapy (DAT) with a NOAC for stroke prevention and single antiplatelet therapy (SAPT) (clopidogrel is preferred) as the default strategy up to 12 months after a short period up to 1 week of TAT (NOAC + DAPT). TAT may be prolonged up to 1 month when the ischemic risk outweighs the bleeding risk.

Guidelines for the management of non–ST-elevation acute coronary syndromes (NSTE-ACS) have been issued by the European Society of Cardiology (ESC) in 2014 and the American Heart Association/American College of Cardiology (AHA/ACC) in 2014. A summary of these guidelines are below.

In 2014, the AHA/ACC published a full revision of their 2007 guidelines which included the following key changes[24] :

• Because unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI) are on a pathophysiologic continuum and are often indistinguishable, they are considered together in the 2014 guidelines

• To more clearly convey this physiology-based patient-management approach, the guideline has replaced the term "initial conservative management" with "ischemia-guided strategy"

• Cardiac troponin assays may improve the diagnosis of myocardial necrosis

• High-intensity statins should be used in patients with overt cardiovascular disease

• Risk stratification tools in these patients include the Thrombolysis in Myocardial Infarction (TIMI) risk score and the Global Registry of Acute Coronary Events (GRACE) risk score

In 2015, the ESC released its guidelines which define unstable angina as "myocardial ischemia at rest or minimal exertion in the absence of cardiomyocyte necrosis."[25]

Evaluation

The 2014 AHA/ACC revised guidelines include the following recommendations for evaluation of patients with suspected ACS[24] :

Class I

Patients with suspected ACS should be risk stratified based on the likelihood of ACS and adverse outcome(s) to decide on the need for hospitalization and assist in the selection of treatment options. (Level of evidence: B)

Patients with suspected ACS and high-risk features such as continuing chest pain, severe dyspnea, syncope/presyncope, or palpitations should be referred immediately to the emergency department (ED) and transported by emergency medical services when available. (Level of evidence: C)

In patients with chest pain or other symptoms suggestive of ACS, a 12-lead electrocardiogram (ECG) should be performed and evaluated for ischemic changes within 10 minutes of the patient’s arrival at an emergency facility. (Level of evidence: C)

Serial ECGs (eg, 15- to 30-minute intervals during the first hour) should be performed to detect ischemic changes if the initial ECG is not diagnostic but the patient remains symptomatic. (Level of evidence: C)

Serial cardiac troponin I or T levels (when a contemporary assay is used) should be obtained at presentation and 3 to 6 hours after symptom onset in all patients who present with symptoms consistent with ACS to identify a rising and/or falling pattern of values. If the time of symptom onset is ambiguous, the time of presentation should be considered the time of onset for assessing troponin values. (Level of evidence: A)

Additional troponin levels should be obtained beyond 6 hours after symptom onset in patients with normal troponin levels on serial examination when changes on ECG and/or clinical presentation confer an intermediate or high index of suspicion for ACS. (Level of evidence: A)

Class IIa

It is reasonable to give low-risk patients who are referred for outpatient testing daily aspirin, short-acting nitroglycerin, and other medication if appropriate (eg, beta blockers), with instructions about activity level and clinician follow-up. (Level of evidence: C)

Observe patients with symptoms consistent with ACS without objective evidence of myocardial ischemia (nonischemic initial ECG and normal cardiac troponin) in a chest pain unit or telemetry unit with serial ECGs and cardiac troponin levels at 3- to 6-hour intervals. (Level of evidence: B)

For patients with possible ACS who have normal serial ECGs and cardiac troponin levels, it is reasonable to obtain a treadmill ECG (level of evidence: A), stress myocardial perfusion imaging, or stress echocardiography before discharge or within 72 hours after discharge (level of evidence: B).

In patients with possible ACS and a normal ECG, normal cardiac troponin levels, and no history of coronary artery disease (CAD), it is reasonable to initially perform (without serial ECGs and troponin levels) coronary computed tomography angiography to assess coronary artery anatomy (level of evidence: A) or rest myocardial perfusion imaging with a technetium-99m radiopharmaceutical to exclude myocardial ischemia (level of evidence: B).

The 2015 ESC guidelines are in general agreement with the 2014 AHA/ACC. Additional Class I recommendations are summarized below.[25]

Base the diagnosis and initial short-term ischemic and bleeding risk stratification on a combination of clinical history, symptoms, vital signs, other physical findings, ECG, and laboratory results. (Level of evidence: A)

Measure cardiac troponin levels with sensitive or high-sensitivity assays, and obtain the results within 60 minutes. (Level of evidence: A)

A rapid rule-out protocol at 0 h and 3 h if high-sensitivity cardiac troponin tests are available. (Level of evidence: B)

A rapid rule-out and rule-in protocol at 0 h and 1 h if a high-sensitivity cardiac troponin test with a validated 0 h/1 h algorithm is available. Additional testing after 3 to 6 hours is indicated if the first two troponin measurements are not conclusive and the clinical condition is still suggestive of ACS. (Level of evidence: B)

Continuous rhythm monitoring should be performed until the diagnosis of NSTEMI is established or ruled out. (Level of evidence: C)

In the absence of signs or symptoms of ongoing ischemia, rhythm monitoring in unstable angina may be considered in selected patients (eg, suspicion of coronary spasm or associated symptoms suggestive of arrhythmic events).

Selection of management strategy

Determination of the preferred management strategy depends on the patient’s clinical characteristics and clinical risk. The AHA/ACC and ESC provide similar recommendations for selection of the preferred management strategy which are summarized in Table 5 below.[24, 25]

Table 5.  Recommendations for Selection of Preferred Management Strategy (Open Table in a new window)

Initial hospital care

The 2014 AHA/ACC recommendations for initial hospital care are summarized below.[24]

Oxygen

Administer supplemental oxygen only with oxygen saturation below 90%, respiratory distress, or other high-risk features for hypoxemia. (Class I; level of evidence C)

Nitrates

Administer sublingual nitroglycerin (NTG) every 5 minutes three times for continuing ischemic pain, and then assess need for intravenous (IV) NTG. (Class I; level of evidence: C)

Administer IV NTG for persistent ischemia, heart failure (HF), or hypertension. (Class I; level of evidence: B)

Nitrates are contraindicated with recent use of a phosphodiesterase inhibitor. (Class III; level of evidence: B)

Analgesic therapy

IV morphine sulfate may be reasonable for continued ischemic chest pain despite maximally tolerated anti-ischemic medications. (Class IIb; level of evidence: B)

Nonsteroidal anti-inflammatory agents (NSAIDs) (except aspirin) should not be initiated and should be discontinued because of the increased risk of a major adverse cardiac event associated with their use. (Class III; level of evidence: B)

Beta-adrenergic blockers

Initiate oral beta blockers in the absence of HF, low-output state, risk for cardiogenic shock, or other contraindications to beta blockade. (Class I; level of evidence: A)

Use sustained-release metoprolol succinate, carvedilol, or bisoprolol for beta-blocker therapy with concomitant NSTE-ACS, stabilized HF, and reduced systolic function. (Class I; level of evidence: C)

Re-evaluate to determine subsequent eligibility in patients with initial contraindications to beta blockers. (Class I; level of evidence: C)

It is reasonable to continue beta-blocker therapy in patients with normal LV function with NSTE-ACS. (Class IIa; level of evidence: C)

IV beta blockers are potentially harmful when risk factors for shock are present. (Class III; level of evidence: B)

Calcium channel blockers (CCBs)

CCBs are recommended for ischemic symptoms when beta blockers are not successful, are contraindicated, or cause unacceptable side effects. (Class I; level of evidence: C)

Long-acting CCBs and nitrates are recommended for patients with coronary artery spasm. (Class I; level of evidence: C)

Administer initial therapy with nondihydropyridine CCBs with recurrent ischemia and contraindications to beta blockers in the absence of LV dysfunction, increased risk for cardiogenic shock, PR interval above 0.24 s, or second- or third-degree atrioventricular block without a cardiac pacemaker. (Class I; level of evidence: B)

Administer oral nondihydropyridine calcium antagonists with recurrent ischemia after use of beta blocker and nitrates in the absence of contraindications. (Class I; level of evidence: C)

Immediate-release nifedipine is contraindicated in the absence of a beta blocker. (Class III; level of evidence: B)

Cholesterol management

Initiate or continue high-intensity statin therapy in patients with no contraindications. (Class I; level of evidence: A)

Obtain a fasting lipid profile in patients with NSTE-ACS, preferably within 24 hours of presentation. (Class IIa; level of evidence: C)

Angiotensin-converting enzyme (ACE) inhibitors (ACEIs)

Class I

ACEIs should be started and continued indefinitely in all patients with an LVEF) below 0.40 and in those with hypertension, diabetes mellitus, or stable chronic kidney disease (CKD), unless contraindicated. (Level of evidence: A)

Angiotensin receptor blockers are recommended in patients with heart failure or MI with LVEF below 0.40 who are intolerant to ACEIs. (Level of evidence: A)

Aldosterone blockade is recommended in post–MI patients who are without significant renal dysfunction or hyperkalemia who are receiving therapeutic doses of ACEI and beta blocker and have an LVEF below 0.40, diabetes mellitus, or heart failure. (Level of evidence: A)

Antiplatelet therapy

Recommendations for initial antiplatelet/anticoagulation therapy in patients with NSTE-ACS are summarized below.[24]

Aspirin

Nonenteric-coated, chewable aspirin (162 mg to 325 mg) should be given to all patients without contraindications as soon as possible after presentation, and a maintenance dose of aspirin (81 mg/d to 325 mg/d) should be continued indefinitely. (Class I; level of evidence A)

In patients who are unable to take aspirin because of hypersensitivity or major gastrointestinal intolerance, a loading dose of clopidogrel followed by a daily maintenance dose should be administered. (Class I; level of evidence B)

Anticoagulation

Anticoagulation, in addition to antiplatelet therapy, is recommended for all patients irrespective of the initial treatment strategy. Treatment options (all Class I) include:

• Subcutaneous (SC) enoxaparin for duration of hospitalization or until percutaneous coronary intervention (PCI) is performed (Level of evidence: A)
• Bivalirudin until diagnostic angiography or PCI is performed in patients with early invasive strategy only (Level of evidence: B)
• SC fondaparinux for the duration of hospitalization or until PCI is performed (Level of evidence: B)
• IV unfractionated heparin (UFH) for 48 h or until PCI is performed (Level of evidence: B)

IV fibrinolytic treatment is not recommended in patients with NSTE-ACS. (Class III, level of evidence: A)

Dual antiplatelet therapy

In 2016, the ACC/AHA released updated guidelines on the duration of dual antiplatelet therapy (DAPT) in patients with CAD. In this focused update, the term and acronym DAPT is used to specifically to refer to combination antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor). Key recommendations for patients with NSTE-ACS treated with DAPT are summarized below.[26] :

Class I

For all patients treated with DAPT, a daily aspirin dose of 81 mg (range, 75 mg to 100 mg) is recommended. (Level of evidence: B-R)

After bare metal stent (BMS) or drug-eluting stent (DES) implantation, P2Y12 inhibitor therapy (clopidogrel, prasugrel, or ticagrelor) should be given for at least 12 months. (Level of evidence: B-R)

For patients who subsequently undergo CABG after coronary stent implantation, P2Y12 inhibitor therapy should be resumed postoperatively so that DAPT continues until the recommended duration of therapy is completed. (Level of evidence: C-EO)

In patients who undergo CABG, P2Y12 inhibitor therapy should be resumed after CABG to complete 12 months of DAPT therapy. (Level of evidence: C-LD)

Class IIa

After coronary stent implantation, it is reasonable to use ticagrelor in preference to clopidogrel for maintenance P2Y12 inhibitor therapy. (Level of evidence: B-R)

After coronary stent implantation in patients who are not at high risk for bleeding complications and who do not have a history of stroke or transient ischemic attack (TIA), it is reasonable to choose prasugrel over clopidogrel for maintenance P2Y12 inhibitor therapy. (Level of evidence: B-R)

Class IIb

In patients treated with coronary stent implantation who have tolerated DAPT without a bleeding complication and who are not at high bleeding risk, continuation of DAPT (clopidogrel, prasugrel, or ticagrelor) for longer than 12 months may be reasonable. (Level of evidence: A)

After DES implantation, patients who develop a high risk of bleeding, or are at high risk of severe bleeding complication, or develop significant overt bleeding, discontinuation of P2Y12 inhibitor therapy after 6 months may be reasonable. (Level of evidence: C-LD)

Class III

Prasugrel should not be administered to patients with a prior history of stroke or TIA. (Level of evidence: B-R)

Hospital discharge and follow-up

The 2014 AHA/ACC guidelines include the following Class 1 recommendations for posthospital care[24] :

Medications required in the hospital to control ischemia should be continued after hospital discharge in patients with NSTE-ACS who do not undergo coronary revascularization, patients with incomplete or unsuccessful revascularization, and patients with recurrent symptoms after revascularization. Titration of the doses may be required. (Level of evidence: C)

All patients should be given sublingual or spray NTG with verbal and written instructions for its use. (Level of evidence: C)

Before hospital discharge, patients should be informed about symptoms of worsening myocardial ischemia and Ml, and they should be given verbal and written instructions about how and when to seek emergency care for such symptoms. (Level of evidence: C)

For patients who have initial angina lasting more than 1 minute, NTG (1 dose sublingual or spray) if angina does not subside within 3 to 5 minutes; call 9-1-1 immediately to access emergency medical services. (Level of evidence: C)

If the pattern or severity of angina changes, suggesting worsening myocardial ischemia (eg, pain is more frequent or severe or is precipitated by less effort or occurs at rest), patients should contact their clinician without delay to assess the need for additional treatment or testing. (Level of evidence: C)

Before discharge, patients should be educated about modification of cardiovascular risk factors. (Level of evidence: C)

Diabetes

The 2014 AHA/ACC guidelines recommend that treatment in the acute phase of NSTE-ACS and decisions to perform stress testing, angiography, and revascularization should be similar in patients with and without diabetes mellitus. (Level of evidence: A)

The 2015 ESC guidelines offer the following recommendations[25] :

Class I

Screen all patients for diabetes and monitor blood glucose levels frequently in patients with known diabetes or admission hyperglycemia. (Level of evidence: C)

Administer the same antithrombotic treatment in diabetic and nondiabetic patients. (Level of evidence: C)

An invasive strategy is recommended over noninvasive management. (Level of evidence: A)

Monitor renal function for 2-3 days after coronary angiography or PCI in patients with baseline renal impairment or on metformin. (Level of evidence: C)

In patients undergoing PCI, new-generation DESs are recommended over BMSs. (Level of evidence: A)

In patients with stabilized multivessel CAD and an acceptable surgical risk, CABG is recommended over PCI. (Level of evidence: A)

Class IIa

Glucose-lowering therapy should be considered in ACS patients with blood glucose above 10 mmol/L (>180 mg/dL), with the target adapted to comorbidities, whereas episodes of hypoglycemia should be avoided. (Level of evidence: C)

Less stringent glucose control should be considered in patients with more advanced cardiovascular disease, older age, longer diabetes duration, and more comorbidities. (Level of evidence: C)

The goal of all of the following medications is either to improve myocardial oxygen and glucose supply or to reduce myocardial oxygen and glucose demand.

The use of thrombolytics in unstable angina and NSTEMI are not useful and potentially harmful. They should be reserved for use in STEMI when indicated.[27]

Class Summary

These agents inhibit platelet aggregation.

Aspirin (Anacin, Bayer Aspirin, Ascriptin)

Aspirin inhibits platelet cyclooxygenase-1, which blocks the formation of thromboxane A2, thus inhibiting platelet aggregation. Aspirin is arguably the most cost-effective medication in medicine.

Clopidogrel (Plavix)

Selectively inhibits adenosine diphosphate (ADP) binding to platelet receptor and subsequent ADP-mediated activation of glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation.

May have a positive influence on several hemorrhagic parameters and may exert protection against atherosclerosis not only through inhibition of platelet function but also through changes in the hemorrhagic profile.

May have additive effect when used in combination with aspirin. Useful alternative therapy in patients with a salicylate allergy.

Ticlopidine (Ticlid)

A thienopyridine that irreversibly alters the platelet membrane and inhibits platelet aggregation. Second-line antiplatelet therapy for patients who cannot tolerate or fail aspirin therapy. Toxicity includes neutropenia and diarrhea.

Class Summary

These agents relieve chest discomfort by improving myocardial oxygen supply, which, in turn, dilate epicardial and collateral vessels, improving blood supply to the ischemic myocardium.

Nitroglycerin topical (Nitro-Bid, Deponit)

Reduces preload and ventricular pressures, thus reducing myocardial oxygen demand. NTG also promotes coronary vasodilatation, which promotes improved myocardial blood flow. Reflex tachycardia may be harmful, concomitant beta-blocker usage may offset this reaction.

Class Summary

These agents reduce pain, which decreases sympathetic stress, in addition to providing some preload reduction.

Morphine sulfate (Astramorph, MS Contin, MSIR)

Reduces pain and possibly anxiety associated with angina pectoris. Use judiciously in setting of hypotension.

Class Summary

This category of drugs has the potential to suppress ventricular ectopy due to ischemia or excess catecholamines. In the setting of myocardial ischemia, beta-blockers have antiarrhythmic properties and reduce myocardial oxygen demand, secondary to elevations in heart rate and inotropy.

Metoprolol (Lopressor, Toprol XL)

These agents decrease myocardial oxygen demand by reducing heart rate, contractility, and arterial pressure. Shown to improve survival in patients with MI.

Class Summary

When beta-blockade is contraindicated in the setting of continuing angina, a nondihydropyridine calcium antagonist (eg, verapamil, diltiazem) may be used as initial therapy in the absence of severe LV dysfunction or other contraindications (see ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction).

Though controversial, long-acting nifedipine may have some benefit in stable angina.[28]

Verapamil (Calan SR, Covera-HS, Verelan)

During depolarization, inhibits calcium ion from entering slow channels or voltage-sensitive areas of vascular smooth muscle and myocardium.

Diltiazem (Cardizem CD, Dilacor, Tiazac)

During depolarization, inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. Serum calcium levels remain unchanged. The resultant decrease in intracellular calcium inhibits the contractile processes of myocardial smooth muscle cells, resulting in dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue.

Decreases conduction velocity in AV node. Also increases refractory period via blockade of calcium influx. This, in turn, stops reentrant phenomenon.

Decreases myocardial oxygen demand by reducing peripheral vascular resistance, reducing heart rate by slowing conduction through SA and AV nodes, and reducing LV inotropy.

Class Summary

Anticoagulants interfere with platelet aggregation and clot formation thus reducing arterial clot burden and promoting continued myocardial oxygen and glucose delivery. These agents do not digest present clots, they help prevent secondary formation during and after spontaneous fibrinolysis. Often, the decision of when and which anticoagulant to use is decided jointly by the emergency physician and cardiologist.

Heparin

Unfractionated heparin potentiates the effect of antithrombin, an enzyme that inactivates factors IIa, IXa, and Xa. This leads to an anticoagulant effect. Because of a relatively narrow therapeutic window, laboratory monitoring is required.

Enoxaparin (Lovenox)

Low molecular weight heparin produced by partial chemical or enzymatic depolymerization of unfractionated heparin (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).

Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis.

Advantages include intermittent dosing and decreased requirement for monitoring. Heparin anti–factor Xa levels may be obtained if needed to establish adequate dosing.

LMWH differs from UFH by having a higher ratio of antifactor Xa to antifactor IIa compared with UFH.

Class Summary

These agents block the GP IIb/IIIa receptor on platelets. Once the platelet is activated, these receptors change configuration, facilitating fibrinogen and ligand binding. GP IIb/IIIa receptor binding of fibrinogen is the final step leading to platelet aggregation. Thus, these agents stymie platelet aggregation.

Abciximab (ReoPro)

Chimeric human-murine monoclonal antibody approved for use in elective/urgent/emergent percutaneous coronary intervention. Binds to receptor with high affinity and reduces platelet aggregation by 80% for up to 48 h following infusion.

Eptifibatide (Integrilin)

Antagonist of the platelet glycoprotein (GP) IIb/IIIa receptor, which reversibly prevents von Willebrand factor, fibrinogen, and other adhesion ligands from binding to the GP IIb/IIIa receptor. Inhibits platelet aggregation. Effects persist over duration of maintenance infusion and are reversed when infusion ends.

Tirofiban (Aggrastat)

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.

Oxygen

Promotes a higher PaO2, thus improving myocardial oxygen delivery