Approach Considerations
Simply put, the two fundamental questions in the approach to the patient with possible angina are the following:
-
Is this coronary artery disease (CAD)? (That is, what is the diagnosis, or what does the patient have?)
-
How dangerous is this? (That is, what is the prognosis, or what is the risk of something bad happening next?)
Therefore, a brief history and physical examination, resting 12-lead electrocardiography (ECG), and a blood draw for evaluation of cardiac enzymes should be accomplished expeditiously.
The following laboratory studies are recommended within the first 24 hours in the evaluation of a patient with unstable angina:
-
Serial cardiac biomarker assays
-
Hemoglobin level
-
Serum chemistry panel
-
Lipid panel
Numerous cardiac biomarker assays are currently available for the diagnosis of myocardial cell necrosis. Some of these, especially the troponin assays, are powerful prognostic tools as well and serve as important guides to the aggressiveness of approach.
Urinary proton nuclear magnetic resonance (1H NMR) spectroscopy–based metabolomic profiling appears to have the potential for identifying diagnostic biomarkers in the investigation of unstable angin pectoris metabolic signatures. [24]
Investigators have demonstrated enhanced expression of toll-like receptors 2 and 4 (TLR-2 and TLR-4) on platelets in patients with acute coronary syndrome, which has potential clinical implications for prophylactic and therapeutic targets. [25]
Perform chest radiography to evaluate patients for signs of congestive heart failure (CHF) and for other causes of chest symptoms, such as pneumothorax, pulmonary infection or masses, pulmonary hypertension, and mediastinal widening.
Missed diagnosis
Patients in whom the diagnosis of myocardial infarction (MI) or unstable angina has been missed and those who are sent home from the emergency department (ED) have, respectively, a 2-fold and a 1.7-fold increased risk of death, compared with those who were admitted to the hospital. [23] This a public health issue. Indeed, up to 20% of the millions of dollars awarded in malpractice suits against ED practitioners is for missed acute coronary syndrome (ACS). [23]
A related study reported that nearly one third (32%) of patients with ACS have normal levels (< 14 ng/L) of high-sensitivity cardiac troponin (hs-cTnT) when they present to the ED with acute chest pain. [26] The majority of these patients had unstable angina. In addition, although the death rates of patients with normal hs-cTnT levels were significantly lower 1 year later than those of patients with elevated hs-cTnT levels, their acute MI rates were significantly higher.
Although eliminating missed diagnoses of acute ischemic syndromes is impossible without undue hospitalization rates and costs, this problem could be minimized by the following means:
-
Addressing factors or preconceptions that obscure the correct diagnosis in women and nonwhite patients, subgroups that are at higher risk for a missed diagnosis
-
Recognition of angina equivalents, particularly in elderly patients
-
More careful history taking to account for recent changes in the character or course of anginal symptoms
-
Use of confirmatory point-of-care cardiac enzyme assays that have a high negative predictive value in patients with nonspecific or normal ECG findings
-
Predischarge stress testing in stable patients at low risk who have a moderate likelihood of CAD
-
Awareness that absence of ECG findings or early cardiac enzyme elevation does not automatically preclude the possibility of acute ischemia, because these are merely snapshots of particular points in the course of a dynamic process
Basic Blood Studies
The complete blood cell (CBC) count helps in ruling out anemia as a secondary cause of acute coronary syndrome (ACS). Leukocytosis has prognostic value in the setting of acute myocardial infarction (MI). Early changes in platelet size and number appear to occur in those with ACS. [27] In a prospective study of 134 patients with ACS (unstable angina, non-ST elevation MI [NSTEMI], STEMI), investigators found that platelets and mean platelet volume decreased within 3 hours of admission, whereas at 72 hours and 7 days, these values increased only in those with acute MI. [27]
Close monitoring of potassium and magnesium levels is important in patients with ACS because low levels may predispose them to ventricular arrhythmias. Routine measurement of serum potassium levels and prompt correction are recommended.
A creatinine level is also needed, particularly if cardiac catheterization is considered. Use of N -acetylcysteine and adequate hydration can help prevent contrast material–induced nephropathy. [28]
Myeloperoxidase levels may be potentially useful in differentiating patients with ACS from those with chest pain from other causes. A single emergency department retrospective study (September to December 2015) of all patients older than 18 years with nontraumatic chest pain evaluated serial measurements of troponin and myeloperoxidase on admission and at 6 hours and found statistically significant differences not only in myeloperoxidase concentration at admission and at 6 hours for patients diagnosed with ACS as well as non-ACS patients, but also among ACS patients and those with heart disease other than coronary artery disease at the same time points. [29]
Cardiac Biomarkers
Creatine kinase, CK-MB, and troponin
Absolute elevations of creatine kinase and its MB isoenzyme (CK-MB) or troponin levels are highly specific evidence of myocardial cell death and distinguish non−ST-elevation MI (NSTEMI) from unstable angina (see the image below.)
Unstable Angina. Time course of elevations of serum markers after acute myocardial infarction. CK = creatine kinase; CK-MB = creatine kinase MB fraction; LDH = lactate dehydrogenase.
In addition, biomarkers alone or as part of accelerated diagnostic protocols (ADP) may reduce the number of patients with a missed diagnosis of NSTEMI who are at increased risk for major adverse cardiac events.
Furthermore, such approaches may facilitate early discharge from the ED in patients who have a low short-term risk of a major cardiac event, as reported by the ASPECT (ASia-Pacific Evaluation of Chest pain Trial) investigators. [30] However, the trial did not fully address the potentially important influence of cultural differences in chest pain perception and time to presentation.
The current standard of care includes drawing blood for total CK-MB levels every 6-8 hours during the first 24 hours. In addition, it is important to determine cardiac-specific troponin (T or I) levels at least twice, 6-8 hours apart, because these markers may initially be negative, especially within 2-4 hours of chest pain. If patients have persistent or recurrent symptoms or if the index of suspicion is high, additional measurements of CK-MB, or troponin if initially negative, should be considered.
Troponin I levels of 0.4 ng/mL or higher or troponin T levels of 0.1 ng/mL or higher are considered positive and have been associated with higher short-term and midterm mortality. Outcomes in troponin-positive patients have been improved by aggressive treatment strategies that include early cardiac catheterization. The temporal trends of these assays are helpful in interpreting difficult cases, and mild elevations of CK-MB or troponins from a lower baseline with subsequent falls in levels strongly indicate the occurrence of myonecrosis.
Troponin levels also may still capture evidence of a cardiac event in patients who delay their presentation to the hospital, because the serum half-life of troponin is longer than that of CK-MB and can remain elevated for 7-14 days after an event. Owing to their kinetics, however, cardiac troponins, once elevated, are much less useful in evaluating recurrent chest pain with myocardial injury, whereas CK-MB levels permit detection of reinfarction.
Because measurement of troponin is a very sensitive assay that detects myocardial injury or necrosis in the absence of CAD (eg, in critically ill or septic patients), newer mechanistic criteria have been put forth for a universal definition of MI by a joint task force of the European Society of Cardiology (ESC), the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and the World Heart Federation (WHF). [31]
Fundamentally, this universal definition tries to identify patients in whom there may be an ACS wherein investigation or intervention might improve outcome (type I, or “spontaneous MI”). [31] Such an individual is distinguished from the patient in an intensive care unit (ICU) who has a type 2 MI or troponin elevation that is related to myocardial necrosis due to a supply-demand mismatch (eg, anemia, tachycardia, respiratory failure, or hypotension due to sepsis).
Although elevated troponins portend a graver prognosis for all of these cohorts, the latter patients are unlikely to benefit from an ischemia workup—and may indeed be harmed by an invasive strategy. [31]
There are also data suggesting that troponin T may be falsely elevated with major injury to skeletal muscles. Furthermore, qualitative bedside troponin assay results may be difficult to interpret in patients with renal insufficiency.
Brain natriuretic peptide
The TACTICS/TIMI (Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy/Thrombolysis In Myocardial Infarction)-18 substudy showed that brain (B-type) natriuretic peptide (BNP) is an independent predictor of short- and long-term mortality and risk of CHF in patients presenting with unstable angina. [32]
Elevated BNP levels have also been linked to more significant coronary artery lesions in patients with unstable angina, including patients with greater left anterior descending (LAD) artery involvement.
Note: Although BNP levels may add incremental information to the assessment of patients with unstable angina, they should be used in context with other cardiac markers to guide medical decision making. The cost-effectiveness of routine use of multiple cardiac biomarkers has not been established.
Combination with C-reactive protein
In the future, a combination of levels of troponin (a biomarker of myocardial necrosis), N-terminal pro-B-type natriuretic peptide (NT-proBNP) (an indicator of elevated left ventricular end-diastolic pressure and wall stress), and C-reactive protein (CRP) (an estimate of extent of systemic inflammation) may prove useful for predicting the outcome of patients with ACS.
Nitric oxide
Levels of endothelial nitric oxide appears to have potential as a novel biomarker in predicting coronary complexity in patients with unstable angina. In a study that aimed to compare nitric oxide levels with the Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score in terms of predicting coronary complexity and the treatment decision for unstable angina pectoris in the emergency department, investigators found lower mean nitric oxide levels in those with unstable angina than control subjects, and that nitric oxide levels were negatively correlated with the SYNTAX score and treatment decision. [33] Decreased nitric oxide levels were noted in those who underwent coronary artery bypass graft surgery compared with those who underwent coronary angiography and those who underwent percutaneous coronary intervention.
Electrocardiography
The first line of assessment in any patient with suspected unstable angina is the 12-lead ECG, which should be obtained within 10 minutes of the patient’s arrival in the ED. The diagnostic accuracy of an ECG is enhanced if a prior tracing is available for comparison. Serial ECG recordings taken every 15-30 minutes are recommended if the patient’s chest pain continues and ECG changes are not noted in the initial or subsequent recordings. [34]
The highest-risk ECG findings (ST-segment elevation or new left bundle branch block) necessitate immediate triage for revascularization therapy. Peaked T waves may also indicate early MI.
The next level of high-risk patients includes those with ST depression greater than 1 mm on ECG. Approximately 50% of patients with this finding have subendocardial myocardial necrosis. The presence of ST-segment depression portends relatively high in-hospital, 30-day, and 1-year mortalities, irrespective of cardiac biomarker level.
New or reversible ST-segment deviation of 0.5 mm or more from baseline was associated with a higher incidence (15.8% vs 8.2%) of 1-year death or MI in the TIMI-III Registry ECG Ancillary study. [19]
Primary T wave changes are neither sensitive nor specific for ischemia, but they become an important clue in the context of the patient’s symptoms or if the QRS to T-wave angle is greater than 60°. Isolated symmetric T-wave inversion does not appear to carry additional adverse prognosis.
Wellens syndrome
Wellens syndrome refers to specific ECG abnormalities in the precordial T-wave segment, which are associated with critical stenosis of the proximal LAD coronary artery. De Zwaan, Wellens, and colleagues in the early 1980s recognized this subset of patients with unstable angina who had specific precordial T-wave inversions and subsequently developed a large anterior wall MY. [35] Wellens syndrome is also referred to as LAD coronary T-wave syndrome. [36] Syndrome criteria include the following:
-
Characteristic T-wave changes
-
A history of anginal chest pain
-
Normal or minimally elevated cardiac enzyme levels
-
An ECG without Q waves, without significant ST elevation, and with normal precordial R-wave progression
Recognition of this ECG abnormality is of paramount importance because LAD coronary T-wave syndrome represents a preinfarction stage of CAD that often progresses to a devastating anterior wall infarction.
Echocardiography
If available on a prompt basis, echocardiography can provide a quick evaluation of left ventricular function either for prognosis (which is worse when the left ventricular ejection fraction [LVEF] is less than 40%) or for diagnosis, as when new segmental wall motion abnormality is detected (eg, in postinfarction or postrevascularization chest pain in which baseline left ventricular function is known). However, it must be kept in mind that small infarcts may not be apparent on the echocardiogram.
Important causes of chest pain, such as aortic stenosis and hypertrophic obstructive cardiomyopathy (HOCM), can be readily detected by echocardiography.
Transesophageal echocardiography is highly recommended if the clinical picture suggests the possibility of a valvular or mechanical complication of MI or if the patient is not following the expected hospital course.
Transesophageal echocardiography, computed tomography angiography (CTA), or magnetic resonance angiography (MRA) is invaluable when aortic dissection is being ruled out.
SPECT and MRI
The sensitivity of single-photon emission computed tomography (SPECT) is sufficient to detect infarcts of at least 10 g, but magnetic resonance imaging (MRI) with gadolinium enhancement may depict infarcts as small as 1-5 g.
MRI has emerging applications for identifying ischemia (space-time maps of impaired blood arrival), infarction (wall thinning, scar, or delayed enhancement), and wall-motion abnormalities that may be coupled with coronary artery MRA in the future.
MRI is well established as a means of detecting myocardial scarring of as little as 1%, which is a powerful prognostic factor. [37, 38] It is also well established for detecting and characterizing complications of MI. MRI may find wall-motion abnormalities and infarcts missed by echocardiography, whether because of the higher resolution and full coverage of MRI, because of echocardiography dropout from the lungs or ribs, or because of the angle dependence of echocardiography, which may miss the affected area, such as the real apex.
Myocardial Perfusion Imaging
Myocardial perfusion imaging is a valuable method for triaging patients with chest pain in the ED. Myocardial perfusion imaging at rest is highly sensitive for detecting acute MI, and it can be supplemented with provocative testing after infarction is excluded. However, the results of clinical trials can be applied only in centers with proven reliability and experience.
Exercise Testing
Exercise testing is not typically performed in the acute phase of unstable angina or in subjects with recent rest angina. However, subjects in whom disease activity becomes controlled after several days of medical therapy may safely undergo stress testing before hospital discharge.
When feasible, predischarge testing is preferential to testing weeks to months after discharge because no prognostic value is lost with early testing and because a relatively high proportion of adverse cardiac events occur earlier rather than later.
Predischarge exercise tests add independent prognostic information to known important clinical descriptors, such as recurrent rest pain and evolutionary T-wave changes. For example, patients who had a reversible defect on nuclear stress testing had a 25% incidence of death or MI at 1 year, compared with an incidence of only 2% for those with a negative scan. [39] Among men, shorter exercise duration, lower maximal rate-pressure product, and exercise-induced angina or ST-segment depression have correlated with unfavorable outcome. [40]
Although the negative predictive value is on the order of 90% across the board for all modalities of stress tests, the positive predictive value is poor (16-19%) for exercise or adenosine stress tests and only moderately better (31-48%) for the imaging stress tests.
Many chest pain centers are evaluating early stress testing for expeditious triage of low-risk patients. The ERASE Chest Pain (Emergency Room Assessment of Sestamibi for Evaluation of Chest Pain) randomized clinical trial compared usual care with usual care plus a resting perfusion scan in patients with and ECG that was normal or nondiagnostic for ischemia. [40] There was a 32% reduction in the odds of being unnecessarily admitted to the hospital, without sacrifice of safety, in nonischemic patients who underwent early nuclear perfusion scanning.
No large studies comparing the performance characteristics of the different stress-testing modalities in the specific setting of unstable angina are available.
-
Unstable Angina. Pathogenesis of acute coronary syndromes.
-
Unstable Angina. Thrombolysis in Myocardial Infarction (TIMI) Risk Score correlates with major adverse outcome and effect of therapy with low-molecular-weight heparin. ARD = absolute risk difference; ESSENCE = Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events; No. = number; NNT = number needed to treat.
-
Unstable Angina. Algorithm for initial invasive strategy. ASA = acetylsalicylic acid (aspirin); GP IIb/IIIa= glycoprotein IIb/IIIa; IV = intravenous; LOE = level of evidence; UA/NSTEMI = unstable angina/non–ST-segment elevation myocardial infarction; UFH = unfractionated heparin. (Adapted from 2007 ACC/AHA UA/NSTEMI Guidelines.)
-
Unstable Angina. Algorithm for initial conservative strategy. ASA = acetylsalicylic acid (aspirin); EF = ejection fraction; GP IIb/IIIa= glycoprotein IIb/IIIa; IV = intravenous; LOE = level of evidence; LVEF = left ventricular ejection fraction; UA/NSTEMI = unstable angina/non–ST-segment elevation myocardial infarction. (Adapted from 2007 ACC/AHA UA/NSTEMI Guidelines.)
-
Unstable Angina. Rate and timing of revascularization for patients with unstable angina using invasive versus conservative approach (FRagmin during InStability in Coronary artery disease [FRISC] II).
-
Unstable Angina. Time course of elevations of serum markers after acute myocardial infarction. CK = creatine kinase; CK-MB = creatine kinase MB fraction; LDH = lactate dehydrogenase.
Tables
- Table 1. Patient Characteristics, GUARANTEE Versus CRUSADE Trials
- Table 2. Demographic Characteristics of Patients in International OASIS-2 Registry
- Table 3. Thirty-Day Clinical Outcome in Patients With Acute Coronary Syndromes in Clinical Trials
- Table 4. Braunwald Classification of Unstable Angina
- Table 5. Recommendations for Selection of Preferred Management Strategy
Characteristics |
GUARANTEE, 1995-96 [12] |
CRUSADE, 2001-06 [13] |
Mean age (y) |
62 |
69 |
Patients >65 y (%) |
44 |
– |
Female (%) |
39 |
40 |
Hypertension (%) |
60 |
73 |
Diabetes mellitus (%) |
26 |
33 |
Current smoker (%) |
25 |
– |
Hypercholesterolemia (%) |
43 |
50 |
Previous stroke (%) |
9 |
– |
Previous MI (%) |
36 |
30 |
Previous angina (%) |
66 |
– |
CHF (%) |
14 |
18 |
Previous coronary intervention (%) |
23 |
21 |
Previous coronary bypass surgery (%) |
25 |
19 |
CHF = congestive heart failure; CRUSADE = Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association guidelines; GUARANTEE = Global Unstable Angina Registry and Treatment Evaluation; MI = myocardial infarction. |
||
Characteristics [15] |
Australia |
Brazil |
Canada |
Hungary |
Poland |
United States |
|
General |
Number of patients |
1899 |
1478 |
1626 |
931 |
1135 |
918 |
Mean age (y) |
65 |
62 |
66 |
65 |
63 |
66 |
|
Women (%) |
37 |
42 |
37 |
45 |
40 |
37 |
|
Clinical |
NQMI presentation (%) |
7 |
7 |
14 |
22 |
17 |
16 |
Abnormal ECG (%) |
74 |
91 |
82 |
95 |
97 |
87 |
|
Select treatments |
Beta blocker (%) |
67 |
53 |
73 |
67 |
59 |
57 |
Calcium blocker (%) |
59 |
51 |
53 |
52 |
43 |
59 |
|
Invasive procedures (index hospitalization) |
Cardiac catheterization (%) |
24 |
69 |
43 |
20 |
7 |
58 |
PCI (%) |
7 |
19 |
16 |
5 |
0.4 |
24 |
|
CABG (%) |
4 |
20 |
10 |
7 |
0.4 |
17 |
|
CABG = coronary artery bypass grafting; ECG = electrocardiographic; NQMI = non-Q wave myocardial infarction; OASIS = Organization to Assess Strategies for Ischemic Syndromes; PCI = percutaneous coronary intervention. |
|||||||
Study |
Year |
Number of Patients |
Death (%) |
Myocardial Infarction (%) |
Major Bleed (%) |
TIMI-3 |
1994 |
1,473 |
2.5 |
9.0 |
0.3 |
GUSTO-IIb |
1997 |
8,011 |
3.8 |
6.0 |
1.0 |
ESSENCE |
1998 |
3,171 |
3.3 |
4.5 |
1.1 |
PARAGON-A |
1998 |
2,282 |
3.2 |
10.3 |
4.0 |
PRISM |
1998 |
3,232 |
3.0 |
4.2 |
0.4 |
PRISM-PLUS |
1998 |
1,915 |
4.4 |
8.1 |
1.1 |
PURSUIT |
1998 |
10,948 |
3.6 |
12.9 |
2.1 |
TIMI-11B |
1999 |
3,910 |
3.9 |
6.0 |
1.3 |
PARAGON-B |
2000 |
5,225 |
3.1 |
9.3 |
1.1 |
Pooled |
40,167 |
3.5 |
8.5 |
1.5 |
|
ESSENCE = Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events; GUSTO-IIb = Global Utilization of Streptokinase and TPA (tissue plasminogen activator) for Occluded Coronary Arteries; PARAGON-A = Platelet IIb/IIIa Antagonism (lamifiban) for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network; PARAGON-B = Platelet IIb/IIIa Antagonism (lamifiban) for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network; PRISM = Platelet Receptor Inhibition in Ischemic Syndrome Management; PRISM-PLUS = Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Angina Signs and Symptoms; PURSUIT = Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; TIMI-11B = Thrombolysis in Myocardial Infarction Clinical Trial 11B; TIMI-3 = Thrombolysis in Myocardial Infarction Clinical Trial 3. |
|||||
Characteristic |
Class/Category |
Details |
Severity |
I |
Symptoms with exertion |
II |
Subacute symptoms at rest (2-30 days prior) |
|
III |
Acute symptoms at rest (within prior 48 hr) |
|
Clinical precipitating factor |
A |
Secondary |
B |
Primary |
|
C |
Postinfarction |
|
Therapy during symptoms |
1 |
No treatment |
2 |
Usual angina therapy |
|
3 |
Maximal therapy |
| Preferred Strategy | Patient Characteristic/Clinical Risk |
Immediate Invasive Strategy (< 2 hours) |
Refractory angina |
| Signs/symptoms of heart failure or new or worsening mitral regurgitation | |
| Hemodynamic instability or cardiogenic shock | |
| Recurrent angina/ischemia at rest or with low-level activities despite intensive medical therapy | |
| Sustained ventricular tachycardia or ventricular fibrillation | |
| Ischemia-Guided Strategy | Low-risk score (eg, TIMI 0 or 1, GRACE < 109) |
| Low-risk Tn-negative female | |
| Patient or physician preference in the absence of high-risk features | |
Early Invasive Strategy (< 24 hours) |
GRACE score >140 |
| Rise or fall in Tn compatible with myocardial infarction | |
| New or presumably new ST-segment depression | |
Delayed Invasive Strategy (24-72 hours) |
Diabetes mellitus |
| Renal insufficiency (GFR < 60 mL/min/1.73m2) | |
| Reduced LV systolic function (LVEF < 40%) | |
| Early postinfarction angina | |
| PCI within 6 months | |
| Prior CABG | |
| GRACE score 109-140; TIMI Score ≥2 | |
| ACC/AHA = American College of Cardiology/American Heart Association; CABG = coronary artery bypass grafting; GFR = glomerular filtration rate; GRACE = Global Registry of Acute Coronary Events; LV = left ventricle; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention; TIMI = Thrombolysis in Myocardial Infarction Clinical Trial; Tn = troponin. | |
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