State-of-the-Art Evaluation of Emergency Department Patients Presenting With Potential Acute Coronary Syndromes
Abstract
It is well established that clinicians cannot use clinical judgment alone to determine whether an individual patient who presents to the emergency department has an acute coronary syndrome. The history and physical examination do not distinguish sufficiently between the many conditions that can cause acute chest pain syndromes. Cardiac risk factors do not have sufficient discriminatory ability in symptomatic patients presenting to the emergency department. Most patients with non–ST-segment–elevation myocardial infarction do not present with electrocardiographic evidence of active ischemia. The improvement in cardiac troponin assays, especially in conjunction with well-validated clinical decision algorithms, now enables the clinician to rapidly exclude myocardial infarction. In patients in whom unstable angina remains a concern or there is a desire to evaluate for underlying coronary artery disease, coronary computed tomography angiography can be used in the emergency department. Once a process that took ≥24 hours, computed tomography angiography now can rapidly exclude myocardial infarction and coronary artery disease in patients in the emergency department.
Introduction
About 20 million patients present with symptoms possibly suggestive of acute coronary syndrome (ACS) to emergency departments (ED) in North America and Europe each year.1–3 Patients with ACS and acute myocardial infarction (AMI) present with a wide variety of symptoms such as chest pain, shortness of breath, weakness, nausea, vomiting, and even fatigue, making the diagnosis difficult. Demographics, cardiac risk factors, chest pain characteristics, and physical examination can assist disposition decisions but are insufficient to identify who does and does not have an ACS.4–7 Some patients may have objective evidence of a clear-cut diagnosis, but the majority do not.8 The majority ultimately will be found not to have ACS, but symptoms caused by noncardiac and often benign disorders such as musculoskeletal pain, pleuritis, or gastroesophageal reflux make the rapid rule-out of ACS more difficult and result in huge medical expenses. Safe and early rule-out of ACS contributes to more efficient and high-value healthcare delivery.
History and Physical Examination
Clinical features, alone or in combination with an ECG, are poorly predictive for AMI (Table 1).9,10 In addition, they have variable reliability. Features classically associated with a lower probability of AMI such as pleuritic, positional, and sharp chest pain have poor to fair interphysician reliability (κ=0.27–0.44),11 whereas high-risk features (radiation to left arm, substernal location, and history of AMI) are more reliable (κ=0.74–0.89).11
| Clinical Feature | Likelihood Ratio(95% CI) |
|---|---|
| Increased likelihood of AMI | |
| Described as pressure | 1.3 (1.2–1.5) |
| Pain in chest or left arm | 2.7* |
| Chest pain radiation | |
| To right arm or shoulder | 4.7 (1.9–12) |
| To left arm | 2.3 (1.7–3.1) |
| To both left and right arm | 7.1 (3.6–14.2) |
| To both arms or shoulders | 4.1 (2.5–6.5) |
| Chest pain most important symptom | 2.0* |
| Chest pain associated with exertion | 2.4 (1.5–3.8) |
| Worse than previous angina or similar to prior AMI | 1.8 (1.6–2.0) |
| History of MI | 1.5–3.0† |
| Nausea or vomiting | 1.9 (1.7–2.3) |
| Diaphoresis | 2.0 (1.9–2.2) |
| Third heart sound | 3.2 (1.6–6.5) |
| Hypotension (systolic BP <80 mm Hg) | 3.1 (1.8–5.2) |
| Pulmonary crackles | 2.1 (1.4–3.1) |
| Decreased likelihood of AMI | |
| Pleuritic chest pain | 0.2 (0.1–0.3) |
| Described as sharp | 0.3 (0.2–0.5) |
| Positional chest pain | 0.3 (0.2–0.5) |
| Reproduced by palpation | 0.3 (0.2–0.4) |
| Inframammary location | 0.8 (0.7–0.9) |
| Not associated with exertion | 0.8 (0.6–0.9) |
AMI indicates acute myocardial infarction; BP, blood pressure; and CI confidence interval.
*
Data not available to calculate CIs.
†
In heterogeneous studies, the likelihood ratios are reported as ranges. Likelihood ratios tell us how much to modify our suspicion for a particular test result. The positive likelihood ratio tells us how much to increase the probability of disease when the test is positive. The negative likelihood ratio tells us how much to decrease when the test is negative.
Traditional cardiac risk factors, derived from population-based longitudinal cohort studies of asymptomatic patients, are poor predictors of risk for AMI or ACS in symptomatic patients in the ED.6,7 Similarly, the physical examination seldom is useful for distinguishing patients with ACS from patients with noncardiac chest pain.
Trials of medications, once thought to be useful, now are known to be unable to rule in or rule out ACS. Relief of symptoms with either nitroglycerin or a “gastrointestinal cocktail” occurs with similar frequency whether symptoms are related to or unrelated to myocardial ischemia.12,13
Knowledge of a previously normal stress test should not affect clinical decision making in the ED because patients with a prior normal stress test are at the same risk of 30-day adverse cardiovascular events as patients who have not previously undergone stress testing.14,15 Stress testing does not assess whether nonobstructive plaque existing at the time of the test will subsequently rupture, leading to ischemia.
On the other hand, prior invasive coronary angiography results are useful for risk stratification of patients. Patients with no or minimal (<25%) stenosis have an excellent long-term prognosis, with 90% free from single-vessel disease and >98% free from myocardial infarction nearly a decade later.16,17 Thus, recent coronary angiography with normal or minimally diseased vessels makes the possibility of an ACS extremely unlikely, unlike a recent negative stress test, which is still associated with a 5% event rate at 30 days.14
The ECG
The ECG is the most important initial diagnostic instrument used for detecting ACS because it is the quickest means of objectively diagnosing acute ST-segment–elevation myocardial infarction (STEMI). Characteristic patterns such as ST-segment elevations or depressions, T-wave changes in anatomic distributions, a new bundle-branch block, and Q waves can all provide information on the timing, severity, and location of a lesion. However, the sensitivity of ST-segment elevation for diagnosing AMI is poor. Non-STEMI and unstable angina (UA) can occur with only nonspecific changes or with no change at all on ECG.18
Misinterpretation or misclassification of the ECG can hinder the diagnosis of AMI. Misclassifications rates range from 5.9% to 29%.19,20 False-positive interpretations of the ECG occur in at least 11% to 14% of presumed STEMI cases.21,22 Although it is true that the more significant the ECG abnormalities are, the more likely the patient is to have AMI, UA, and serious cardiovascular complications, patients with normal or nonspecific ECGs still have a 5% to 28% incidence of ACS. New electrocardiographic evidence of ischemia increases the risk of AMI to 25% to 73% and the UA risk from 14% to 43%; however, ischemic changes alone lack a high degree of specificity.4,23 Thus, the standard 12-lead ECG is useful for risk stratification of patients with potential ACS but is not definitive. The addition of the right-sided precordial lead V4R in the setting of acute inferior myocardial infarction helps detect RV involvement.
Biomarkers
The clinical assessment, even with an ECG, is not sufficient to diagnose or exclude AMI and ACS in most patients, and thus the addition of blood tests to measure the concentration of cardiac troponin (cTn) T or I forms the cornerstone for the early diagnosis of AMI. Clinicians use cTn values to estimate the likelihood of AMI and the short-term risk of adverse cardiovascular outcomes, including death.
Advances in assay technology have led to a refinement in the clinical ability to detect and quantify myocardial injury.1–3,24–60 These assays increase diagnostic accuracy at presentation, substantially reduce the “troponin-blind” interval, and have allowed the recent development of several novel strategies for the early rule-out or rule-in of AMI.1–3,24–61 These assays are labeled sensitive when able to detect cTn in ≈20% to 50% of healthy individuals. Assays are labeled as highly sensitive if they detect a level in >50% of apparently healthy subjects and they have a coefficient of variation of <10% at the 99th percentile upper reference limit of the assay. High-sensitivity assays can accurately detect cTn at a lower levels than older-generation assays, giving them higher sensitivity for the detection of AMI at presentation, which means that the time interval to the second measurement of high-sensitivity (hs) cTn can be significantly shortened, thereby reducing the time to diagnosis and improving efficiency in the ED.1–3,24–33
Although hs-cTn assays have been used in Europe, Australia, New Zealand, Canada, and many other developed countries since 2010, they have not yet received approval for use in the United States. High-sensitivity and sensitive cTn assays quantify the amount of cardiomyocyte damage and therefore should be interpreted as quantitative variables. The higher the cTn level is, the higher the likelihood of AMI is. For levels in the normal range, the same concept applies: The lower the cTn blood concentration is, the lower the likelihood of AMI is.
In an oversimplification, hs-cTn (and sensitive cTn) assays often are criticized for having a lower positive predictive value (PPV) for AMI. This relates to the use of the 99th percentile as a cutoff level, not the assay itself. The use of the 99th percentile, mandated by the universal definition, allows both the detection of AMI earlier after presentation and the detection of small AMIs. However, these beneficial effects are at least partly counterbalanced by a more challenging differential diagnosis resulting from mild elevations in cTn associated with myocardial injury unrelated to AMI (eg, resulting from chronic cardiac disorders).
It also is critical to note that there are no false-positive troponin elevations; all reflect myocardial injury and all portend a worse prognosis than otherwise similar patients without a troponin elevation. This is true regardless of whether the patient has heart failure, renal failure, gastrointestinal bleeding, sepsis, respiratory disease, pulmonary embolism, subarachnoid hemorrhage, or stroke or the patient is asymptomatic without known cardiovascular disease.40 Any troponin is always worse than no troponin, and more troponin is always worse than less troponin.40
Compared with non-STEMI patients, individuals with UA do not experience myocardial necrosis, have a substantially lower acute risk of death and/or major arrhythmias, and seem to derive less benefit from intensified antiplatelet therapy and early invasive strategy.41 Several biomarker strategies rely on serial troponin testing. Specifically, the European Society of Cardiology (ESC) has a 0- and 1-hour algorithm and a 0- and 2-h algorithm. These novel strategies have been fine-tuned to detect AMI but not UA.
It is important to highlight 5 points for the application of biomarker-based strategies in clinical practice: First, they should be used only in conjunction with full clinical assessment, including a pretest probability assessment to identify patients at high risk who are not candidates for early discharge. Second, these are risk stratification strategies rather than definitive diagnostic strategies, so additional tests (eg, invasive coronary angiography, computed tomography [CT] angiography [CTA], stress testing, perfusion imaging, or echocardiography) may be necessary for a definite diagnosis. Third, these strategies do not apply to everyone. The percentage of patients in whom they can be applied varies widely from ≈9.8% to 77%. In particular, they do not apply to patients who present so early that the troponin would not be elevated, even in the setting of AMI, nor do they apply to patients with short-lived episodes of ischemic pain who have UA without myocardial necrosis. Fourth, they can be applied only after the initial ECG has excluded a STEMI. Some apply only to patients with a completely normal ECG; others allow also for mild and nonspecific ECG abnormalities. Fifth, these strategies should optimally be embedded in the local standard ED operating procedures.
Three algorithms use the absolute change between 2 measurements of cTn in addition to the actual concentrations to take advantage of the full diagnostic information provided. Rising or falling cTn levels differentiate acute from chronic myocardial injury. Absolute rather than relative changes seem to be the best metric to differentiate AMI from other causes of chest pain.36–39 The larger the absolute cTn change within 1, 2, or 3 hours is, the higher the likelihood of the presence of AMI is.36–39
Among the multitude of other biomarkers evaluated for the early diagnosis of AMI, only copeptin seems to have some clinical relevance.3,42–47 Copeptin, the c-terminal part of the vasopressin prohormone, is secreted stoichiometrically with arginine-vasopressin from the neurohypophysis and seems to quantify the individual endogenous stress level in multiple medical conditions, including AMI.3,42–47 Because endogenous stress seems to be nearly invariably present at the onset of AMI, copeptin helps to improve the sensitivity of cTn at early ED presentation.3,42–47 The less sensitive the cTn assay is, the higher the incremental value of copeptin for the early rule-out of AMI is.3,42–47 The incremental value may be substantial if a conventional cTn assay is used that is unable to measure around the 99th percentile (eg, most point-of-care assays) but very small if a sensitive or hs-cTn assay is used. The incremental benefits of copeptin exist within the first 2 hours of arrival, after which a second troponin achieves the same sensitivity for AMI. Copeptin has neither disease (AMI) nor organ (heart) specificity and therefore is helpful only in the AMI rule-out process.42–47 It is not useful to rule in AMI.
Biomarker-Based Strategies for Rapid Rule-Out or Rule-In of AMI
Six biomarker-based strategies have been studied and validated in large, methodologically robust, multicenter diagnostic studies including several thousand patients. The main performance metrics of the studies include safety (quantified by the negative predictive value [NPV] and sensitivity for AMI) and efficacy (percentage of patients identified) for rule-out, as well as the PPV and specificity for AMI (Table 2). Two of these strategies require the use of a predefined risk score (0- and 3-hour ESC algorithm and 2-hour advanced diagnostic protocol [ADP]), and the remaining 4 strategies do not.
| Very Low cTn | cTn and Copeptin | 0- and 1-h Algorithm | 0- and 2-h Algorithm | 2-h ADP | 0- and 3-h ESC | |
|---|---|---|---|---|---|---|
| Clinical scoring system | None | None | None | None | TIMI score ≤1 ECG normal at 0 and 2 h | GRACE <140 and pain free |
| Blood draws, n | 1 | 1 | 2* | 2* | 2* | 2* |
| Indication | Rule out | Rule out | Rule out and rule in | Rule out and rule in | Rule out | Rule out and rule in |
| NPV for AMI, % | 98–100 | 92.4–9996–99 with hs-cTn | 99.1–100 | 99.5–99.9 | 99.1–100† | 99.6–100 |
| Eligible population size | +(+) | ++ | +++ | +++ | ++ | ++(+) |
| Biomarker rule-out criteria‡ | ||||||
| Using hs-cTnT | hs-cTnT <5 ng/L | hs-cTnT <14 ng/L AND copeptin <10 pmol/L | hs-cTnT<12 ng/L AND 1-h Δ <3 | hs-cTnT <14 ng/L at 0 and 2 h AND 2-h Δ <4 | hs-cTnT <14 ng/L at 0 and 2 h | hs-cTnT <14 ng/L at 0 and 3 h |
| Using hs-cTnI | hs-cTnI <2–5 ng/L | hs-cTnI <26 ng/L AND copeptin <10 pmol/L | hs-cTnI <5 ng/L AND 1-h Δ <2 | hs-cTnI <6 ng/L at 0 and 2 h AND 2-h Δ <2 | hs-cTnI <26 ng/L at 0 and 2 h | hs-cTnI <26 ng/L at 0 and 3h |
| Biomarker rule-in criteria | ||||||
| Using hs-cTnT | hs-cTnT ≥52 ng/L OR 1-h Δ ≥5 | hs-cTnT ≥53 ng/L OR 2-h Δ ≥10 | ||||
| Using hs-cTnI | hs-cTnI ≥52 ng/L OR 1-h Δ ≥5 | hs-cTnI ≥64 ng/L OR 2-h Δ ≥15 | ||||
| Feasibility | High | Low; Requires 2 biomarkers requiring different analyzers | High | High | Medium; Requires use of TIMI score | Medium; Requires GRACE score |
ACS indicates acute coronary syndrome; ADP, accelerated diagnostic protocol; AMI, acute myocardial infarction; cTn, cardiac troponin; ED, emergency department; ESC, European Society of Cardiology; GRACE, Global Registry of Acute Coronary Events; hs-cTn, high-sensitivity cardiac troponin; NPV, negative predictive value; and TIMI, Thrombolysis in Myocardial Infarction. Eligible population size is quantified by the percentage of consecutive patients with chest pain eligible for this early triage strategy: +, ≈20%; ++, ≈40%; and +++, ≈50% to 75%.
*
For some patients, only 1 blood draw will be necessary.
†
For major adverse cardiac events (death, AMI, major arrhythmias).
‡
Characteristics are provided for the hs-cTnT (Elecsys) and hs-cTnI (Architect). Cutoff levels differ for other hs-cTn assays becoming available for clinical use in the future.
0- and 3-Hour ESC Algorithm
AMI is ruled out if concentrations of hs-cTn remain in the normal range at presentation and at 3 hours later and if the patient fulfills 2 additional requirements: to be pain-free and to be at low risk of in-hospital mortality as quantified by a GRACE (Global Registry of Acute Coronary Events) score <140.48 In patients presenting >6 hours after chest pain onset in whom the onset can be reliably quantified, a single blood draw at presentation is considered sufficient.26,41 Patients are considered ruled in if they have a clearly elevated hs-cTn blood concentration at presentation or if the 3-hour sample shows a relevant change. This approach has been recommended by the ESC since 201141 and is the standard of care in many institutions in Europe (Figure, A). This approach to ruling out AMI appears to be safe for all hs-cTn assays and likely many sensitive cTn assays.49 Assuming a 1-hour turn-around time for hs-cTn, this approach facilitates a disposition decision within ≈4 hours of presentation.
0- and 2-Hour ESC Algorithm
This approach using hs-cTn achieves a high NPV and sensitivity by also taking into account absolute concentration changes within 2 hours.35,50,51 The lack of a relevant absolute change from presentation to 2 hours, in conjunction with the fact that both baseline and 2-hour hs-cTn concentrations are within the normal range, obviates the need to use a predefined risk score and allows one to safely rule out AMI even in patients with mild, nonspecific ECG abnormalities. This strategy allows the rapid rule-out of AMI in up to 60% of patients.35,52 Moreover, this strategy includes a rule-in algorithm that provides a PPV of >75% for AMI and allows the early rule-in of ≈10% to 15% of patients with acute chest pain within 2 to 3 hours of presentation.
0- and 1-Hour ESC Algorithm
The concept of the 0- and 1-hour algorithm is identical to that of the 0- and 2-hour algorithm and is based exclusively on information provided by hs-cTn blood concentrations, which are assay dependent.31,37,53–56 Again, the 1-hour algorithm obviates the need for formal use of risk scores and allows safe rule-out of AMI even in patients with mild, nonspecific ECG abnormalities. This strategy is very effective and allows an accurate disposition for ≈75% of patients: 60% rule-out and 15% rule-in of AMI. Given an average turn-around time for hs-cTn of ≈1 hour, this strategy facilitates clinical decision making within 2 to 3 hours of ED presentation for many patients. In patients assigned to observation (Figure, A), clinical decision making still requires the 3-hour measurement; in these “observe zone” individuals, final disposition can be made 4 to 5 hours after arrival.
Dual-Marker Strategy Combining cTn and Copeptin at the Time of Arrival
The dual-marker strategy combining cTn and copeptin takes advantage of the reciprocal release kinetics of both biomarkers. The combination provides incremental diagnostic value compared with a single cTn concentration when conventional cTn assays are used, albeit with a much smaller incremental benefit observed with the use of hs-cTn assays.42–48 The NPV achieved in patients negative for both markers depends on the sensitivity of the cTn assay. Use of the 99th percentile for hs-cTnT or cTnI and a low cutoff for copeptin (eg, <10 pmol/L) achieves an NPV of 96% to 99% in studies with an AMI prevalence of 10% to 22%.44–46,57 This strategy also has been successfully applied in a multicenter, open-label, randomized, controlled trial (RCT) in which a conventional cTn assay was used in the majority of patients in both arms. The main limitations of this strategy are the complexities related to adding a copeptin analyzer in the laboratory and a slightly lower NPV compared with the other strategies.44–46,57,58 Two other caveats for the proper use of copeptin deserve attention. First, elevated copeptin concentrations have a very poor specificity for AMI, which creates challenges in patients with a normal first cTn but elevated copeptin. Second, in AMI, copeptin blood concentrations decline rapidly after the onset of chest pain and render its diagnostic utility low in patients presenting >6 hours after the onset of chest pain.44–46,57,58
Undetectable/Very Low Levels of hs-cTn at the Time of Arrival
Very low blood concentrations of hs-cTn at presentation have a very high (98%–100%) NPV for AMI. Because the lower limit of detection is assay dependent and varies among the clinically available hs-cTn assays, defining very low concentrations using a distribution of the normal range (eg, <40% percentile of healthy individuals) may be the preferred metric to identify biologic-equivalent values. Four large studies and a recent meta-analysis have provided consistent results for hs-cTnT, whereas 2 studies showed comparable findings for 3 hs-cTnI assays.29–34,55–60 Because the release of cTn is a time-dependent phenomenon, this approach should be used only in patients with a chest pain onset of at least 2 to 3 hours before ED presentation. In the 2015 ESC guidelines, this approach is recommended in combination with the 0- and 1-hour algorithm as the preferred rule-out strategies because of an excellent balance between speed and accuracy.41 Because it requires only a single blood draw of an inexpensive and widely available biomarker (outside the United States), this approach has unique simplicity.
Observe Zone
Although most rapid AMI diagnostic strategies provide guidance for the rule-out only, 3 strategies also provide detailed guidance for the rule-in of AMI (0- and 3-hour ESC algorithm, 0- and 2-hour algorithm, 0- and 1-hour algorithm). In addition to the rule-out and rule-in zone, these strategies leave up to a third of patients in an observe-zone. These patients are often elderly men with pre-existing coronary artery disease (CAD) and high long-term mortality. Continued serial sampling of cTn may be appropriate, with follow-up risk assessment with functional stress imaging, coronary CTA, or other diagnostic testing to help determine whether these patients may have AMI, ACS, or underlying coronary disease.
Evidence, Methodological Considerations, and Translation Into Clinical Practice
Although the continuous evaluation and possible further refinement of these strategies are necessary, appreciation of the methodology of large, prospective, multicenter diagnostic studies with meticulous and central adjudication of a final diagnosis of AMI and rather unbiased enrollment led to the strong position of the ESC advocating widespread clinical adoption. Diagnostic studies allow the precise quantification of the diagnostic performance (accuracy, sensitivity, NPV, specificity, PPV) of novel biomarkers or novel diagnostic algorithms compared with the final adjudicated diagnosis as the reference. Ideally, they are further supported by RCTs, which can add, for example, important insights into cost-effectiveness. Unfortunately, large, appropriately powered (eg, for recurrent AMI or mortality during long-term follow-up) RCTs in the diagnostic field are extremely rare. In fact, not a single such RCT has ever been performed evaluating the use of biomarkers, ECG variables, or any other inexpensive diagnostic tools in the diagnosis of AMI.
Patient Admission Despite Rule-Out Triage by the Algorithm
The disposition recommendation provided by the novel biomarker-based strategies should be used in conjunction with all other diagnostic and prognostic information available to the physician in the ED. These algorithms were designed only to safely rule out AMI and do not address the other disorders that still require admission such as UA, pulmonary embolism, aortic dissection, or pneumonia. To appropriately detect these conditions, other diagnostic tests (such as CT scans) not included in these strategies may be necessary in some patients.
Combining Troponin With Risk Scoring Systems for Accelerated Diagnostic Pathways
Clinical decision aids have become popular to overcome cognitive biases that affect the clinician’s ability to accurately predict pretest probability of disease. Physicians have difficulty in estimating risks of diseases and frequently err toward overestimation. Accelerated decision-making processes incorporating such aids can be used to facilitate safe early discharge.
Chest pain risk scoring tools in combination with cTn testing have had considerable success in identifying low-risk patients who may be suitable for early discharge (Tables 3 and 4).61–76 Although most of the research in this area is observational, there have been 2 single-center RCTs, and there has been widespread implementation of such strategies in Australasia. The Australian state of Queensland and the country of New Zealand, with combined populations of nearly 10 million people, now have fully adopted accelerated diagnostic pathways. The strategy in Queensland (and some New Zealand sites) is based on the use of a contemporary assay such as is available in the United States rather than a high-sensitivity troponin assay.
| Rule | Characteristics of Risk Score | Early Discharge Criteria |
|---|---|---|
| Modified Goldman score and Trust ADP | 8 Criteria each worth 1 point: typical new-onset chest pain at rest; pain the same as previous myocardial infarction; pain not relieved by nitroglycerin spray within 15 min; pain lasting >60 min; pain occurring with increasing frequency; hypotension; acute shortness of breath; pain within 6 wk of a myocardial infarction or revascularization | Total score ≤1, nonischemic ECG, hs-cTn <14 ng/L |
| HEART score | 5 Criteria each graded 0, 1, or 2: history, ECG, age, risk factors, troponin | Total score ≤3 |
| North American Chest Pain Rule | Absence of new ischemia on ECG, no history of coronary disease, not typical pain, age <40 y, and initial cTn negative; if age is 41–50 y, add repeat troponin at 6 h | |
| Vancouver Chest Pain Algorithm | Absence of ongoing pain, angina; physical findings consistent with heart failure, murmur, or hemodynamic instability; ischemic ECG, and elevated cTn | |
| EDACS | 4 Different categories with variable point assignments | Total score ≤16, no new ischemia on ECG, both 0- and 2-h cTn negative |
| Age groups, history of premature CAD, or 4 risk factors, 4 symptoms associated with pain, sex | ||
| Range of scores usually requiring computer or a smartphone application | ||
| MACS Clinical Decision Rule | 5 CAD symptoms; nonischemic ECG and negative serial biomarker tests (hs-cTn and H-FABP) | |
| Modified TIMI score | 5 criteria each worth one point: age, ≥3 CAD risk factors, known CAD, ASA in past 7 d, recent severe angina | ASPECT, ADAPT |
ADAPT indicates 2-Hour Accelerated Diagnostic Protocol to Assess Patients With Chest Pain Symptoms Using Contemporary Troponins as the Only Biomarker; ADP, accelerated diagnostic pathway; ASA, acetylsalicylic acid/aspirin; ASPECTS, Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis; CAD, coronary artery disease; cTn, cardiac troponin; EDACS, Emergency Department Assessment Chest Pain Score; H-FABP, heart-type fatty acid binding protein; hs-cTn, high-sensitivity cardiac troponin; MACS, Manchester Acute Coronary Syndromes; and TIMI, Thrombolysis in Myocardial Infarction.
| Decision Aid | n | Low Risk, % | Sensitivity, % | NPV, % | MACEs, % | TroponinAssay |
|---|---|---|---|---|---|---|
| Modified TIMI score=0 | ||||||
| ASPECT ADP62 | 3582 | 9.8 | 99.3 | 99.1 | 11.8 | C |
| ADAPT ADP63 | 1975 | 20 | 99.7 | 99.7 | 15.3 | C |
| Modified TIMI score=0 or 1 | ||||||
| ADAPT cohort65 | 1635 | 40 | 99.2 | 99.7 | 15.1 | H |
| APACE cohort65 | 909 | 39 | 99.4 | 99.7 | 17.2 | H |
| Modified Goldman score | ||||||
| TRUST ADP66 | 960 | 39.8 | 98.8 | 99.7 | 10.1 | H |
| HEART score | ||||||
| Backus et al67 | 880 | 34.4 | 98.1 | 99.0 | 18.0 | C |
| Mahler et al68 | 1070 | 84.5 | 58.3 | 99.4 | 1.2 | C |
| Six et al69 | 2906 | 28.2 | 96.3 | 98.3 | 12.9 | C |
| Mahler et al70 | 141 | 46.8 | 100 | 100 | 6 | C |
| North American Chest Pain Rule | ||||||
| Hess et al71 | 2718 | 18 | 100 | 100 | 12.0 | C |
| Vancouver Chest Pain Algorithm | ||||||
| Scheuermeyer et al72 derivation | 763 | 14.5 | 100 | 100 | 21.6 | H |
| Scheuermeyer et al72 validation | 906 | 20.4 | 99.2 | 99.5 | 13.1 | H |
| Cullen et al73 | 1635 | 13.0 | 99.1 | 98.6 | 20.4 | H |
| Cullen et al73 | 1635 | 12.8 | 98.8 | 98.1 | 20.4 | C |
| MACS Clinical Decision Rule | ||||||
| Body et al74 derivation | 698 | 35.5 | 99.4 | 99.6 | 22.5 | H |
| Body et al74 validation | 463 | 27.0 | 98.0 | 98.4 | 21.2 | H |
| EDACS | ||||||
| Than et al75 derivation | 1974 | 42.2 | 99.0 | 99.6 | 15.5 | C |
| Than et al75 validation | 608 | 51.3 | 100 | 100 | 12.9 | C |
| Canada76 | 763 | 41.0 | 100 | 100 | 17.4 | C |
ADAPT indicates 2-Hour Accelerated Diagnostic Protocol to Assess Patients With Chest Pain Symptoms Using Contemporary Troponins as the Only Biomarker; ADP, accelerated diagnostic protocol; APACE, Advantageous Predictors of Acute Coronary Syndromes Evaluation; ASPECTS, Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis; C, contemporary; EDACS, Emergency Department Assessment of Chest Pain Score; H, high sensitivity; MACE, major adverse cardiac event; MACS, Manchester Acute Coronary Syndromes; NPV, negative predictive value; and TIMI, Thrombolysis in Myocardial Infarction.
The TIMI (Thrombolysis In Myocardial Infarction) score was developed from a high-risk group of patients but subsequently validated for use in the ED setting.61 The ASPECT (Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis) pathway62 (online-only Data Supplement) combined a modified TIMI risk score of 0 with a nonischemic electrocardiogram at 0 and 2 hours and multibiomarker point-of-care testing and was able to classify ≈10% of patients with chest pain as low risk for 30-day major adverse cardiac events with a >99% NPV (Table 4). The ADAPT study (2-Hour Accelerated Diagnostic Protocol to Assess Patients With Chest Pain Symptoms Using Contemporary Troponins as the Only Biomarker)63 involved the Australasian ASPECT cohorts using just central laboratory contemporary cTns such as those available in the United States (instead of multiple biomarker testing). This study resulted in twice as many patients classified as low risk with an improved sensitivity and NPV (99.7%) (Table 4). The effectiveness of the ADAPT pathway was then validated in an RCT64 and has been widely implemented in Queensland, Australia.
A modified ADAPT rule, incorporating results from a highly sensitive troponin assay in patients with a TIMI score of 0 or 1, found that ≈40% of patients could be identified as low risk with >99% sensitivity and NPV. This was further validated in the independent APACE (Advantageous Predictors of Acute Coronary Syndromes Evaluation) study (Table 4) cohort.65
A modified Goldman risk score recently was incorporated into an accelerated diagnostic pathway67 (Table 3 and the online-only Data Supplement) in which patients were determined suitable for early discharge after a single high-sensitivity troponin measured on arrival at the ED (TRUST study). This validation study classified a percentage of patients as low risk (39.8%) similar to the ADAPT and APACE studies with good sensitivity (98.8%) and NPV (99.7%; Table 4).63,65,66
The HEART score67 was derived on the basis of clinical logic and simplicity rather than statistical derivation from a prospective trial. The manner in which the score was developed is interesting. Jacob Six, a cardiologist from Utrecht, the Netherlands, was undertaking teaching rounds with medical students. In the process of ward rounds, he taught students that the key factors to consider when assessing patients with chest pain were their history, ECG results, age, risk factors, and troponin test result (Table 3). He then realized that these factors actually formed a good mnemonic, and work began to determine whether a related score would be useful in clinical practice.
Backus et al67 tested the score on 880 patients, yielding a 98.1% sensitivity and a 41.6% specificity. Mahler et al68 tested the HEART score on a registry cohort of 1070 patients. In this population, the score achieved a 58.3% sensitivity and an 85.0% specificity; however, it must be noted that this population had a very low prevalence of disease (1%), meaning that only a small number of false-positive results (5 cases) had a large influence on the sensitivity. In 2013, a retrospective validation was published using data from 2906 patients from the Asia-Pacific ASPECT study in which the prevalence of major adverse cardiac events was 12.9%.69 In this analysis, the sensitivity was 96.3%. In 2013, a validation published from 10 centers in the Netherlands had a combined major adverse cardiac event prevalence of 17%, also resulting in a sensitivity of 96.3%.69 In this study, the ECG criteria were modified slightly, with 2 points also being given for negative T waves. Both analyses required retrospective determination of history parameter of the score from other data fields. There has now been a small RCT using a modified version of the HEART score that used structured criteria to categorize history and excludes patients from being classified as low risk if there is a positive troponin result from blood sampling at 0 and 3 hours from arrival at the ED.70 In this study, the prevalence of major adverse cardiac events was 6%, and the sensitivity for major adverse cardiac events for 141 patients randomized to the modified HEART pathway was 100%.
The original troponin criteria were based on the contemporary non–high-sensitivity Beckman Access AccuTroponin I assay with a threshold for positivity of 0.04 μg/L (40 ng/L). Clinicians wishing to use the HEART score should be judicious about how best to use troponin results within the score. First, it would seem that using serial troponin samples improves the sensitivity; however, prospective studies on this approach are limited. Second, it is important to recognize that all troponin assays are different from each other, and it is not clear whether the points-allocated approach for the troponin component will be the same for every troponin assay. Because several adaptations exist for using the HEART score, differences should be considered in its implementation.
In a derivation study, the North American Chest Pain Rule (Table 3 and the online-only Data Supplement)71 was 100% sensitive for a cardiac event within 30 days and categorized 18% of patients as safe for early discharge (Table 4). The model was internally validated with statistical bootstrapping techniques but has not yet been validated in an external data set.
The new Vancouver Chest Pain Diagnostic Algorithm was derived from a single cohort implementation study with careful monitoring of patient outcomes.72 Clinicians used their own judgment to classify patients as low risk or to continue observing and testing troponin. More than 70% of patients were classified as low risk with high sensitivity. When it was later assessed on an Australasian population with the use of high-sensitivity and contemporary troponin assays,73 considerably fewer patients (13%) were classified as low risk. With the use of the high-sensitivity assay, the diagnostic sensitivity for ACS was 99.1%, specificity was 16.1%, PPV was 23.3%, and NPV was 98.6%. With the use of a contemporary non–high-sensitivity troponin assay, 208 patients (12.6%) were eligible for early discharge, with 4 of these patients being diagnosed with ACS for a sensitivity of 98.8%.
The Manchester Acute Coronary Syndromes (MACS) Decision Rule74 differs from other accelerated chest pain diagnostic pathways in that it incorporates testing of a heart-type fatty acid binding protein in addition to high-sensitivity troponin. Biomarker concentrations are considered continuous variables, and computer software is required to calculate the probability of a major adverse cardiac event occurring within 30 days. The need for an additional assay that is not commonly available and computer software makes this unlikely to be adopted widely.
The EDACS-ADP (Emergency Department Assessment of Chest Pain Score Accelerated Diagnostic Pathway) decision aid was derived from 2 Australasia centers as preplanned parallel research to the observational ADAPT study.75 Data were prospectively collected for 37 candidate variables commonly used in clinical care or reported as having value in predicting AMI among ED patients.75 This protocol was validated and tested for reproducibility with prospectively collected data from separate cohorts of patients from the same centers. In the derivation and validation cohorts, the EDACS-ADP classified >40% of patients as low risk with high sensitivity.75 A subsequent validation of the EDACS-ADP using a Canadian cohort of patients classified a similar proportion of patients as low risk with optimal sensitivity and NPV.76 The EDACS-ADP has been validated in an RCT77 and is now being used in multiple hospitals in New Zealand and Australia.
Clinical decision aids with or without clinical gestalt have the potential to be important tools in the assessment of patients presenting to the ED with possible AMI, and accelerated decision-making processes incorporating such aids can be used to facilitate safe early discharge. Clinicians or departments thinking of adopting an ADP for local implementation should carefully decide on the outcome of importance (ie, early rule-out of AMI versus rule-out of ACS). Consideration also should be given to the prevalence of the disease in the hospitals where ADPs were studied. An ADP that was developed and tested in a low-prevalence population must be transferred with caution to a setting where the disease prevalence is high, and for this reason, it is important to consider both the sensitivity and the NPV of the rule-out strategy. The pathways based on ADAPT, EDACS, and HEART have the most extensive evidence base behind them.
Assessment of CAD or Myocardial Ischemia in the ED
Guidelines from both Europe and the United States recommend not just ruling out AMI but also risk stratifying patients who present with potential ACS and evaluating them for CAD.41,78 Biomarker approaches detect AMI but will not be able to detect UA, which, by definition, lacks myocardial necrosis. When concerns about UA remain after ascertainment of negative biomarkers, further assessment of inducible ischemia or detection of CAD is important. Although most commonly done through the use of cardiac catheterization for the highest-risk patients and 24- to 72-hour stress testing for many low- to intermediate-risk patients, coronary CTA has been found to have a high degree of diagnostic accuracy with the additional benefit of facilitating safe and expeditious discharge of low- to intermediate-risk patients without significant CAD directly from the ED.
Coronary CTA
Coronary CTA is an appropriate option for the evaluation of low- to intermediate-risk patients with chest pain syndromes in the ED.79 It has a high degree of diagnostic accuracy; is predictive of acute, 30-day, and 1 year event rates; and can safely and more rapidly facilitate discharge from the ED for patients who present with a potential ACS.
Accuracy
A systematic review of 41 studies totaling 2515 patients indicated a sensitivity of 95% and specificity of 85% for the detection of obstructive CAD in all types of scanners combined.80
Short-Term Outcomes
It has been well demonstrated that a negative coronary CTA (defined as maximal stenosis <50% in all vessels) predicts freedom from 30-day myocardial infarction, coronary revascularization, and cardiovascular death. In a recent meta-analysis of studies of 1559 patients with symptoms suggestive of ACS who presented to an ED, the sensitivity was 93.3%, specificity was 89.9%, PPV was 48.1%, and NPV was 99.3% for 30-day cardiovascular events.81
Two RCTs of ≥1000 patients have confirmed the benefit of this approach.82,83 The ACRIN-PA (American College of Radiology Imaging Network) 4005 multicenter trial randomized 1370 low- to intermediate-risk ED patients to either coronary CTA or traditional care.82 Patients with a negative coronary CTA (<50% maximal stenosis) were free from cardiac death or myocardial infarction at 30 days (upper limit of the 95% confidence interval, 0.57%). Additionally, the coronary CTA–based strategy doubled the discharge rate (50% versus 23%) and shortened the length of stay (18 versus 25 hours) while identifying more patients with coronary disease (9% versus 3%) and simultaneously reducing the likelihood of a negative catheterization. Similarly, the ROMICAT-II study (Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography) was a multicenter RCT comparing the effectiveness of coronary CTA evaluation and standard evaluation.83 Patients who received CT evaluation had a shorter length of stay and were more likely to be discharged from the ED (47% versus 12%). Overall, there were no differences in clinical adverse events between the 2 groups and no undetected ACS at 28 days. These data support the recommendations that patients with a maximal stenosis of <50% can be safely discharged home from the ED.
Longer-Term Outcomes
Hollander et al84 evaluated 588 low-risk patients who received coronary CTA in the ED. Of the 481 patients with <50% stenosis in any vessel who also did not have depressed left ventricular function, 53 patients (11%) were rehospitalized and 51 patients (11%) received further diagnostic testing (stress or catheterization) during the subsequent year. Only 1 patient died (0.2%) and there was no AMI during this time period.84 Hadamitzky et al85 enrolled 1256 consecutive patients with suspected CAD undergoing 64-slice coronary CTA and observed them prospectively for the occurrence of cardiac death, myocardial infarction, or UA requiring hospitalization. In the 802 patients without any stenosis >50%, only 1 case of UA occurred during the initial 90 days. Within a median of 18 months, there were only 4 events in these 802 patients (<0.5%), whereas there were 17 events in the 348 patients (5%) with obstructive CAD.85
The ACRIN-PA 4005 study followed up 1285 patients for 1 year and found that only 1 of the 640 patients with a negative coronary CTA on presentation had an adverse event.86
Compared with the traditional care arm, patients randomized to coronary CTA had similar rates of ED revisits, hospital admissions, and subsequent cardiac testing.86
Two smaller studies focused on low- to intermediate-risk patients with chest pain. The ROMICAT trial (Rule Out Myocardial Infarction Using Computer Assisted Tomography) reported 2-year outcomes for their cohort in 368 ED patients with acute chest pain, negative initial troponin, and a nonischemic ECG.87 Cumulative probability of 2-year events increased across strata for CAD, but none occurred in patients without disease (no CAD, 0%; nonobstructive CAD, 4.6%; obstructive CAD, 30.3%).
In a European cohort of 227 patients with 2.3 years of follow-up, there were no cardiovascular events in the 96 patients without CAD (0%), 2 events in the 76 patients with nonobstructive CAD group (2.6%), and 11 in the 55 patients (20%) with obstructive CAD.88 Abdulla et al89 conducted a meta-analysis that included 5675 patients who were mostly intermediate to high risk in 10 studies with a mean follow-up of 21 months. The event rate was 0.5% in 2045 patients with normal CTA, 3.5% in 2068 patients with nonobstructive CAD, and 16% in 1562 patients with obstructive CAD.
Thus, it seems clear that a negative coronary CTA is associated with a very low event rate and that discharge directly from the ED is safe in the short and longer term.
Calcium Score Alone
The role of coronary artery calcium score (CACS) alone or in combination with angiography remains the subject of some debate. The American College of Cardiology Foundation/American Heart Association 2007 clinical expert consensus document on coronary artery calcium scoring by CT evaluated 6 published reports in 27 622 patients, none of whom were symptomatic ED patients.90 The relative risk for myocardial infarction or death over 3 to 5 years was increased 4.3-fold for any measurable calcium compared with a CACS of 0. Patients without detectable calcium (or a CACS of 0) have a very low rate of death from coronary heart disease or myocardial infarction (0.4%) within this time frame. In contradiction, Gottlieb et al91 evaluated 291 patients who were undergoing coronary CTA and invasive coronary angiography, of whom most (95%) patients were at intermediate to high probability of obstructive CAD. A total of 72 patients had a CACS of 0, among whom 14 (19%) had at least 1 stenosis ≥50%. Chang et al92 found that 4 of 17 patients (24%) with a CACS of 0 still had CAD. Within the CONFIRM registry (Coronary Computed Tomography Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry), >5000 patients had a CACS of 0, yet 16% of these patients still had evidence of CAD on coronary CTA.93 Freedom from CACS does not appear to provide enough information to effectively risk stratify patients in the ED for acute events.
Application in Practice
The Society of Cardiovascular Computed Tomography guidelines on the use of coronary CTA for patients presenting with acute chest pain to the ED provide detailed recommendations for patient selection, site requirements, imaging, scanning, and reader requirements, as well as details on patient preparation.94
Coronary CTA is not ideal for all low- to intermediate-risk patients. Up to one-third of patients may not qualify for imaging because of contrast allergy, renal insufficiency, unresolved tachycardia, or inability to receive β-blockade for heart rate control. The ideal patient is not known to be free of disease or to definitely have underlying coronary disease and but will be considered low- to intermediate-risk without significant contraindications (Table 5). Typical patients may have a TIMI score of 0 to 2 (or equivalent other scoring system) or may be at higher risk but have had a negative stress test in the past 6 to 12 months, therefore benefiting from a different assessment of potential underlying disease.
| Indications |
| ECG negative or indeterminate for myocardial ischemia |
| Low to intermediate pretest likelihood by risk stratification tools |
| TIMI score of 0–2 (low risk) ideal or TIMI score of 3–4 (intermediate) in some cases |
| HEART score <3 |
| ≥1 Negative troponin values, including point-of-care assays |
| Equivocal or inadequate previous functional testing during index ED or within previous 6 mo |
| Equivocal indications |
| High clinical likelihood of ACS by clinical assessment and standard risk criteria (eg, TIMI score >4) |
| Previously known CAD |
| Known calcium score >400 |
| Relative contraindications |
| History of allergic reaction to iodinated contrast |
| GFR <60 mL·min−1·1.73 m−2 |
| Factors likely to lead to nondiagnostic scans; specifics will vary with scanner technology and site capabilities |
| Heart rate greater than site maximum for reliably diagnostic scans after β-blockers (usually 70–80 bpm) |
| Contraindications to β-blockers and heart rate not controlled |
| Atrial fibrillation or other markedly irregular rhythm |
| BMI >39 kg/m2 |
| Absolute contraindications |
| Known ACS |
| GFR <30 mL·min−1·1.73 m−2 unless on long-term dialysis |
| Previous anaphylaxis after iodinated contrast administration |
| Previous episode of contrast allergy after adequate steroid/antihistamine preparation |
| Pregnancy |
ACS indicates acute coronary syndrome; BMI, body mass index; CAD, coronary artery disease; CTA, computed tomography angiography; ED, emergency department; GFR, glomerular filtration rate; and TIMI, Thrombolysis in Myocardial Infarction.
There is a concern that the use of coronary CTA may be associated with an increased risk of coronary angiography and revascularization than seen with stress testing, but the ACRIN-PA study suggested more appropriate use of cardiac catheterization because there was a lower rate of angiographically negative coronary arteries in the coronary CTA group.82
Providers must continue to interpret test results in conjunction with clinical judgment. Finding coronary disease on a coronary CTA does not mean that the coronary disease is the cause of the symptoms. Although it is possible to help clarify the relevance of CAD detected by calculating fractional flow reserve on coronary CTA images, the duration of time required to process these images (up to 6 hours) makes fractional flow reserve not practical in ED patients. Similarly, reversible ischemia on a stress test does not mean that the patient has ischemic heart disease because low-risk patients have a high false-positive rate.
Future studies need to help determine which patients with coronary CTA demonstrating coronary disease benefit from interventions. Additionally, future studies need to determine the role of coronary CTA in patients with low-grade troponin elevations and in patients who do have rising or falling patterns with serial measurements.
Same-Day Stress Testing
Although a complete review of stress testing in the outpatient and hospital setting is beyond the scope of this review, it is worth noting that stress testing also can be done rapidly after negative biomarkers are obtained.95–97 Amsterdam et al96 found stress testing after a single negative biomarker to be safe. Kirk et al95 demonstrated that stress testing in ED patients with chest pain without the use of serum biomarkers was safe, but the study was small and biomarkers are universally obtained early in the clinical course of patients with potential ACS. A report on 856 patients receiving stress testing after 2 troponin values 2 hours apart found this approach to be safe and efficient.97
Resting Sestamibi Imaging
Resting sestamibi imaging is useful for early risk stratification of patients with potential ACS. The use of early resting sestamibi imaging can reduce unnecessary hospitalizations among patients without ACS without reducing appropriate admissions for patients with ACS.98 Tatum et al99 found no AMIs or deaths within 12 months in 338 patients with normal scans, whereas an abnormal scan was associated with 50-fold increased risk of AMI, 14.5-fold increased risk of 30-day revascularization, and 30-fold increased risk of death over 12 months.
There are, however, significant practical issues preventing widespread implementation. Radioisotope preparation in batches makes use in a single patient costly. Decreased accuracy occurs if injection does not occur during or shortly after pain, making timely injection essential. Timely injection by certified nuclear technologists is difficult to attain at most sites.
Cardiovascular Magnetic Resonance Imaging
Cardiovascular magnetic resonance imaging has been proven to be a reliable and well-tolerated tool and is useful after ACS to focus on remodeling or for diagnosis of diseases such as myocarditis. However, in the setting of acute chest pain in the ED where rapid diagnosis is required, it is not practical. Its use in other settings is beyond the scope of this review.
Echocardiography
Resting echocardiography has insufficient sensitivity and poor specificity for the detection of AMI. It cannot distinguish old from new infarcts. Larger areas of infarction and more depressed left ventricular function predict a higher likelihood of cardiovascular complications and an increased mortality. The predictive properties of stress echocardiography and myocardial perfusion imaging are similar with respect to AMI and the presence of CAD but are typically outpatient or next-day tests and are not usually done in the ED.
No Objective Testing
An increasingly common school of thought is that objective testing for ischemia or coronary disease in some low-risk patients who currently receive testing is not necessary because it has not been shown to lower event rates or to improve outcomes compared with accelerated biomarker-based protocols alone. Unfortunately, there have not been any randomized trials comparing testing with no-testing strategies, and such a trial would require a prohibitively large number to demonstrate a difference between groups. Foy et al100 found no difference in the hospitalization rate or AMI at 7 and 190 days between patients who did and did not have an imaging test during the ED visit using a private insurance claims database. They concluded that deferral of noninvasive testing for these patients may be reasonable. This no-testing approach might miss an opportunity for long-term CAD risk assessment and intervention (ie, statins) and does not take into account the high likelihood of an ED patient with chest pain presenting again within the next year. Additionally, it is not guideline compliant because current practice guidelines recommend testing for CAD after exclusion of myocardial infarction.
Conclusions
It is well established that the clinician cannot use clinical judgment alone to determine whether an individual patient who presents to the ED has an ACS. The improvement in cTn assays, especially in conjunction with clinical decision algorithms, now enables the clinician to rapidly exclude myocardial infarction. In patients in whom UA remains a concern or there is a desire to evaluate for underlying CAD, coronary CTA can be used in the ED. Although this process once took ≥24 hours, patients can now have myocardial infarction and CAD rapidly excluded in the ED.
Supplemental Material
File (circ_circulationaha-2016-021886_supp2.pdf)
- Download
- 836.11 KB
References
1.
Thygesen K, Mair J, Katus H, Plebani M, Venge P, Collinson P, Lindahl B, Giannitsis E, Hasin Y, Galvani M, Tubaro M, Alpert JS, Biasucci LM, Koenig W, Mueller C, Huber K, Hamm C, Jaffe AS; Study Group on Biomarkers in Cardiology of the ESC Working Group on Acute Cardiac Care. Recommendations for the use of cardiac troponin measurement in acute cardiac care. Eur Heart J. 2010;31:2197–2204. doi: 10.1093/eurheartj/ehq251.
2.
Thygesen K, Mair J, Giannitsis E, Mueller C, Lindahl B, Blankenberg S, Huber K, Plebani M, Biasucci LM, Tubaro M, Collinson P, Venge P, Hasin Y, Galvani M, Koenig W, Hamm C, Alpert JS, Katus H, Jaffe AS; Study Group on Biomarkers in Cardiology of ESC Working Group on Acute Cardiac Care. How to use high-sensitivity cardiac troponins in acute cardiac care. Eur Heart J. 2012;33:2252–2257. doi: 10.1093/eurheartj/ehs154.
3.
Möckel M, Searle J, Hamm C, Slagman A, Blankenberg S, Huber K, Katus H, Liebetrau C, Müller C, Muller R, Peitsmeyer P, von Recum J, Tajsic M, Vollert JO, Giannitsis E. Early discharge using single cardiac troponin and copeptin testing in patients with suspected acute coronary syndrome (ACS): a randomized, controlled clinical process study. Eur Heart J. 2015;36:369–376. doi: 10.1093/eurheartj/ehu178.
4.
Lee TH, Cook EF, Weisberg M, Sargent RK, Wilson C, Goldman L. Acute chest pain in the emergency room: identification and examination of low-risk patients. Arch Intern Med. 1985;145:65–69.
5.
Zucker DR, Griffith JL, Beshansky JR, Selker HP. Presentations of acute myocardial infarction in men and women. J Gen Intern Med. 1997;12:79–87.
6.
Jayes RL, Beshansky JR, D’Agostino RB, Selker HP. Do patients’ coronary risk factor reports predict acute cardiac ischemia in the emergency department? A multicenter study. J Clin Epidemiol. 1992;45:621–626.
7.
Han JH, Lindsell CJ, Storrow AB, Luber S, Hoekstra JW, Hollander JE, Peacock WF IV, Pollack CV, Gibler WB. Cardiac risk factor burden and its association with acute coronary syndrome. Ann Emerg Med. 2007;49:145–152.
8.
Hollander JE, Robey JL, Chase MR, Brown AM, Zogby KE, Shofer FS. Relationship between a clear-cut alternative noncardiac diagnosis and 30-day outcome in emergency department patients with chest pain. Acad Emerg Med. 2007;14:210–215. doi: 10.1197/j.aem.2006.09.053.
9.
Panju AA, Hemmelgarm BR, Guyatt GH, Simel DL. Is this patient having a myocardial infarction. JAMA. 1998;280:1256–1263.
10.
Swap CJ, Nagurney JT. Value and limitations of chest pain history in the evaluation of patients with suspected acute coronary syndromes. JAMA. 2005;294:2623–2629. doi: 10.1001/jama.294.20.2623.
11.
Hickam DH, Sox HC, Sox CH. Systematic bias in recording the history in patients with chest pain. J Chronic Dis. 1985;38:91–100.
12.
Diercks DB, Boghos E, Guzman H, Amsterdam EA, Kirk JD. Changes in the numeric descriptive scale for pain after sublingual nitroglycerin do not predict cardiac etiology of chest pain. Ann Emerg Med. 2005;45:581–585. doi: 10.1016/j.annemergmed.2004.12.009.
13.
Wrenn K, Slovis CM, Gongaware J. Using the “GI cocktail”: a descriptive study. Ann Emerg Med. 1995;26:687–690.
14.
Nerenberg RH, Shofer FS, Robey JL, Brown AM, Hollander JE. Impact of a negative prior stress test on emergency physician disposition decision in ED patients with chest pain syndromes. Am J Emerg Med. 2007;25:39–44. doi: 10.1016/j.ajem.2006.05.027.
15.
Shaver KJ, Marsan RJ, Sease KL, Shofer FS, Sites FD, Hollander JE. Impact of a negative evaluation for underlying coronary artery disease on 1 year resource utilization for patients admitted with potential acute coronary syndromes. Acad Emerg Med. 2005:11:1272–1277.
16.
Pitts WR, Lange RA, Cigarroa JE, Hillis LD. Repeat coronary angiography in patients with chest pain and previously normal coronary angiogram. Am J Cardiol. 1997;80:1086–1087.
17.
Papanicolaou MN, Califf RM, Hlatky MA, McKinnis RA, Harrell FE, Mark DB, McCants B, Rosati RA, Lee KL, Pryor DB. Prognostic implications of angiographically normal and insignificantly narrowed coronary arteries. Am J Cardiol. 1986;58:1181–1187.
18.
Lau J, Ioannidis JP, Balk EM, Milch C, Terrin N, Chew PW, Salem D. Diagnosing acute cardiac ischemia in the emergency department: a systematic review of the accuracy and clinical effect of current technologies. Ann Emerg Med. 2001;37:453–460. doi: 10.1067/mem.2001.114903.
19.
Brady WJ, Perron A, Ullman E. Errors in emergency physician interpretation of ST-segment elevation in emergency department chest pain patients. Acad Emerg Med. 2000;7:1256–1260.
20.
Vijayaraghavan R, Yan AT, Tan M, Fitchett DH, Georgescu AA, Hassan Q, Langer A, Goodman SG; Canadian Acute Coronary Syndromes Registry Investigators. Local hospital vs. core-laboratory interpretation of the admission electrocardiogram in acute coronary syndromes: increased mortality in patients with unrecognized ST-elevation myocardial infarction. Eur Heart J. 2008;29:31–37. doi: 10.1093/eurheartj/ehm503.
21.
Sharkey SW, Berger CR, Brunette DD, Henry TD. Impact of the electrocardiogram on the delivery of thrombolytic therapy for acute myocardial infarction. Am J Cardiol. 1994;73:550–553.
22.
Larson DM, Menssen KM, Sharkey SW, Duval S, Schwartz RS, Harris J, Meland JT, Unger BT, Henry TD. “False-positive” cardiac catheterization laboratory activation among patients with suspected ST-segment elevation myocardial infarction. JAMA. 2007;298:2754–2760. doi: 10.1001/jama.298.23.2754.
23.
Selker HP, Zalenski RJ, Antman EM, Aufderheide TP, Bernard SA, Bonow RO, Gibler WB, Hagen MD, Johnson P, Lau J, McNutt RA, Ornato J, Schwartz JS, Scott JD, Tunick PA, Weaver WD. An evaluation of technologies for identifying acute cardiac ischemia in the emergency department: a report from a National Heart Attack Alert Program Working Group. Ann Emerg Med. 1997;29:13–87.
24.
Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Thygesen K, Alpert JS, White HD, Jaffe AS, Katus HA, Apple FS, Lindahl B, Morrow DA, Chaitman BA, Clemmensen PM, Johanson P, Hod H, Underwood R, Bax JJ, Bonow RO, Pinto F, Gibbons RJ, Fox KA, Atar D, Newby LK, Galvani M, Hamm CW, Uretsky BF, Steg PG, Wijns W, Bassand JP, Menasché P, Ravkilde J, Ohman EM, Antman EM, Wallentin LC, Armstrong PW, Simoons ML, Januzzi JL, Nieminen MS, Gheorghiade M, Filippatos G, Luepker RV, Fortmann SP, Rosamond WD, Levy D, Wood D, Smith SC, Hu D, Lopez-Sendon JL, Robertson RM, Weaver D, Tendera M, Bove AA, Parkhomenko AN, Vasilieva EJ, Mendis S; Writing Group on the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction; ESC Committee for Practice Guidelines (CPG). Third universal definition of myocardial infarction. Eur Heart J. 2012;33:2551–2567. doi: 10.1093/eurheartj/ehs184.
25.
Reichlin T, Hochholzer W, Bassetti S, Steuer S, Stelzig C, Hartwiger S, Biedert S, Schaub N, Buerge C, Potocki M, Noveanu M, Breidthardt T, Twerenbold R, Winkler K, Bingisser R, Mueller C. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med. 2009;361:858–867. doi: 10.1056/NEJMoa0900428.
26.
Keller T, Zeller T, Peetz D, Tzikas S, Roth A, Czyz E, Bickel C, Baldus S, Warnholtz A, Fröhlich M, Sinning CR, Eleftheriadis MS, Wild PS, Schnabel RB, Lubos E, Jachmann N, Genth-Zotz S, Post F, Nicaud V, Tiret L, Lackner KJ, Münzel TF, Blankenberg S. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med. 2009;361:868–877. doi: 10.1056/NEJMoa0903515.
27.
Keller T, Zeller T, Ojeda F, Tzikas S, Lillpopp L, Sinning C, Wild P, Genth-Zotz S, Warnholtz A, Giannitsis E, Möckel M, Bickel C, Peetz D, Lackner K, Baldus S, Münzel T, Blankenberg S. Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction. JAMA. 2011;306:2684–2693. doi: 10.1001/jama.2011.1896.
28.
Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe AS, Katus HA. Analytical validation of a high-sensitivity cardiac troponin T assay. Clin Chem. 2010;56:254–261. doi: 10.1373/clinchem.2009.132654.
29.
Haaf P, Drexler B, Reichlin T, Twerenbold R, Reiter M, Meissner J, Schaub N, Stelzig C, Freese M, Heinzelmann A, Meune C, Balmelli C, Freidank H, Winkler K, Denhaerynck K, Hochholzer W, Osswald S, Mueller C. High-sensitivity cardiac troponin in the distinction of acute myocardial infarction from acute cardiac noncoronary artery disease. Circulation. 2012;126:31–40. doi: 10.1161/CIRCULATIONAHA.112.100867.
30.
Reiter M, Twerenbold R, Reichlin T, Haaf P, Peter F, Meissner J, Hochholzer W, Stelzig C, Freese M, Heinisch C, Breidthardt T, Freidank H, Winkler K, Campodarve I, Gea J, Mueller C. Early diagnosis of acute myocardial infarction in the elderly using more sensitive cardiac troponin assays. Eur Heart J. 2011;32:1379–1389. doi: 10.1093/eurheartj/ehr033.
31.
Reiter M, Twerenbold R, Reichlin T, Benz B, Haaf P, Meissner J, Hochholzer W, Stelzig C, Freese M, Heinisch C, Balmelli C, Drexler B, Freidank H, Winkler K, Campodarve I, Gea J, Mueller C. Early diagnosis of acute myocardial infarction in patients with pre-existing coronary artery disease using more sensitive cardiac troponin assays. Eur Heart J. 2012;33:988–997. doi: 10.1093/eurheartj/ehr376.
32.
Apple FS. A new season for cardiac troponin assays: it’s time to keep a scorecard. Clin Chem. 2009;55:1303–1306. doi: 10.1373/clinchem.2009.128363.
33.
Rubini Gimenez M, Twerenbold R, Reichlin T, Wildi K, Haaf P, Schaefer M, Zellweger C, Moehring B, Stallone F, Sou SM, Mueller M, Denhaerynck K, Mosimann T, Reiter M, Meller B, Freese M, Stelzig C, Klimmeck I, Voegele J, Hartmann B, Rentsch K, Osswald S, Mueller C. Direct comparison of high-sensitivity-cardiac troponin I vs. T for the early diagnosis of acute myocardial infarction. Eur Heart J. 2014;35:2303–2311. doi: 10.1093/eurheartj/ehu188.
34.
Reichlin T, Twerenbold R, Reiter M, Steuer S, Bassetti S, Balmelli C, Winkler K, Kurz S, Stelzig C, Freese M, Drexler B, Haaf P, Zellweger C, Osswald S, Mueller C. Introduction of high-sensitivity troponin assays: impact on myocardial infarction incidence and prognosis. Am J Med. 2012;125:1205–1213.e1. doi: 10.1016/j.amjmed.2012.07.015.
35.
Reichlin T, Cullen L, Parsonage WA, Greenslade J, Twerenbold R, Moehring B, Wildi K, Mueller S, Zellweger C, Mosimann T, Rubini Gimenez M, Rentsch K, Osswald S, Müller C. Two-hour algorithm for triage toward rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T. Am J Med. 2015;128:369–379.e4. doi: 10.1016/j.amjmed.2014.10.032.
36.
Reichlin T, Irfan A, Twerenbold R, Reiter M, Hochholzer W, Burkhalter H, Bassetti S, Steuer S, Winkler K, Peter F, Meissner J, Haaf P, Potocki M, Drexler B, Osswald S, Mueller C. Utility of absolute and relative changes in cardiac troponin concentrations in the early diagnosis of acute myocardial infarction. Circulation. 2011;124:136–145. doi: 10.1161/CIRCULATIONAHA.111.023937.
37.
Reichlin T, Schindler C, Drexler B, Twerenbold R, Reiter M, Zellweger C, Moehring B, Ziller R, Hoeller R, Rubini Gimenez M, Haaf P, Potocki M, Wildi K, Balmelli C, Freese M, Stelzig C, Freidank H, Osswald S, Mueller C. One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T. Arch Intern Med. 2012;172:1211–1218. doi: 10.1001/archinternmed.2012.3698.
38.
Haaf P, Drexler B, Reichlin T, Twerenbold R, Reiter M, Meissner J, Schaub N, Stelzig C, Freese M, Heinzelmann A, Meune C, Balmelli C, Freidank H, Winkler K, Denhaerynck K, Hochholzer W, Osswald S, Mueller C. High-sensitivity cardiac troponin in the distinction of acute myocardial infarction from acute cardiac noncoronary artery disease. Circulation. 2012;126:31–40. doi: 10.1161/CIRCULATIONAHA.112.100867.
39.
Mueller M, Biener M, Vafaie M, Doerr S, Keller T, Blankenberg S, Katus HA, Giannitsis E. Absolute and relative kinetic changes of high-sensitivity cardiac troponin T in acute coronary syndrome and in patients with increased troponin in the absence of acute coronary syndrome. Clin Chem. 2012;58:209–218. doi: 10.1373/clinchem.2011.171827.
40.
Hollander JE. Managing troponin testing [printed online ahead of print June 25, 2016]. Ann Emerg Med. doi: 10.1016/j.annemergmed.2016.05.023. http://www.annemergmed.com/article/S0196-0644(16)30203-7/abstract. Accessed June 1, 2016.
41.
Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P, Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S, Baumgartner H, Gaemperli O, Achenbach S, Agewall S, Badimon L, Baigent C, Bueno H, Bugiardini R, Carerj S, Casselman F, Cuisset T, Erol Ç, Fitzsimons D, Halle M, Hamm C, Hildick-Smith D, Huber K, Iliodromitis E, James S, Lewis BS, Lip GY, Piepoli MF, Richter D, Rosemann T, Sechtem U, Steg PG, Vrints C, Luis Zamorano J. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting Without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J. 2016;37:267–315. doi: 10.1093/eurheartj/ehv320.
42.
Maisel A, Mueller C, Neath SX, Christenson RH, Morgenthaler NG, McCord J, Nowak RM, Vilke G, Daniels LB, Hollander JE, Apple FS, Cannon C, Nagurney JT, Schreiber D, deFilippi C, Hogan C, Diercks DB, Stein JC, Headden G, Limkakeng AT, Anand I, Wu AH, Papassotiriou J, Hartmann O, Ebmeyer S, Clopton P, Jaffe AS, Peacock WF. Copeptin helps in the early detection of patients with acute myocardial infarction: primary results of the CHOPIN trial (Copeptin Helps in the early detection Of Patients with acute myocardial INfarction). J Am Coll Cardiol. 2013;62:150–160. doi: 10.1016/j.jacc.2013.04.011.
43.
Balmelli C, Meune C, Twerenbold R, Reichlin T, Rieder S, Drexler B, Rubini MG, Mosimann T, Reiter M, Haaf P, Mueller M, Ernst S, Ballarino P, Alafify AA, Zellweger C, Wildi K, Moehring B, Vilaplana C, Bernhard D, Merk S, Ebmeyer S, Freidank H, Osswald S, Mueller C. Comparison of the performances of cardiac troponins, including sensitive assays, and copeptin in the diagnostic of acute myocardial infarction and long-term prognosis between women and men. Am Heart J. 2013;166:30–37. doi: 10.1016/j.ahj.2013.03.014.
44.
Keller T, Tzikas S, Zeller T, Czyz E, Lillpopp L, Ojeda FM, Roth A, Bickel C, Baldus S, Sinning CR, Wild PS, Lubos E, Peetz D, Kunde J, Hartmann O, Bergmann A, Post F, Lackner KJ, Genth-Zotz S, Nicaud V, Tiret L, Münzel TF, Blankenberg S. Copeptin improves early diagnosis of acute myocardial infarction. J Am Coll Cardiol. 2010;55:2096–2106. doi: 10.1016/j.jacc.2010.01.029.
45.
Raskovalova T, Twerenbold R, Collinson PO, Keller T, Bouvaist H, Folli C, Giavarina D, Lotze U, Eggers KM, Dupuy AM, Chenevier-Gobeaux C, Meune C, Maisel A, Mueller C, Labarère J. Diagnostic accuracy of combined cardiac troponin and copeptin assessment for early rule-out of myocardial infarction: a systematic review and meta-analysis. Eur Heart J Acute Cardiovasc Care. 2014;3:18–27. doi: 10.1177/2048872613514015.
46.
Wildi K, Zellweger C, Twerenbold R, Jaeger C, Reichlin T, Haaf P, Faoro J, Giménez MR, Fischer A, Nelles B, Druey S, Krivoshei L, Hillinger P, Puelacher C, Herrmann T, Campodarve I, Rentsch K, Steuer S, Osswald S, Mueller C. Incremental value of copeptin to highly sensitive cardiac troponin I for rapid rule-out of myocardial infarction. Int J Cardiol. 2015;190:170–176. doi: 10.1016/j.ijcard.2015.04.133.
47.
Mueller C. Biomarkers and acute coronary syndromes: an update. Eur Heart J. 2014;35:552–556. doi: 10.1093/eurheartj/eht530.
48.
Giannitsis E, Kehayova T, Vafaie M, Katus HA. Combined testing of high-sensitivity troponin T and copeptin on presentation at prespecified cutoffs improves rapid rule-out of non-ST-segment elevation myocardial infarction. Clin Chem. 2011;57:1452–1455. doi: 10.1373/clinchem.2010.161265.
49.
Druey S, Wildi K, Twerenbold R, Jaeger C, Reichlin T, Haaf P, Rubini Gimenez M, Puelacher C, Wagener M, Radosavac M, Honegger U, Schumacher C, Delfine V, Kreutzinger P, Herrmann T, Moreno Weidmann Z, Krivoshei L, Freese M, Stelzig C, Isenschmid C, Bassetti S, Rentsch K, Osswald S, Mueller C. Early rule-out and rule-in of myocardial infarction using sensitive cardiac Troponin I. Int J Cardiol. 2015;195:163–170. doi: 10.1016/j.ijcard.2015.05.079.
50.
Than M, Aldous S, Lord SJ, Goodacre S, Frampton CM, Troughton R, George P, Florkowski CM, Ardagh M, Smyth D, Jardine DL, Peacock WF, Young J, Hamilton G, Deely JM, Cullen L, Richards AM. A 2-hour diagnostic protocol for possible cardiac chest pain in the emergency department: a randomized clinical trial. JAMA Intern Med. 2014;174:51–58. doi: 10.1001/jamainternmed.2013.11362.
51.
Meller B, Cullen L, Parsonage WA, Greenslade JH, Aldous S, Reichlin T, Wildi K, Twerenbold R, Jaeger C, Hillinger P, Haaf P, Puelacher C, Kern V, Rentsch K, Stallone F, Rubini Gimenez M, Ballarino P, Bassetti S, Walukiewicz A, Troughton R, Pemberton CJ, Richards AM, Chu K, Reid CM, Than M, Mueller C. Accelerated diagnostic protocol using high-sensitivity cardiac troponin T in acute chest pain patients. Int J Cardiol. 2015;184:208–215. doi: 10.1016/j.ijcard.2015.02.006.
52.
Boeddinghaus J, Reichlin T, Cullen L, Greenslade JH, Parsonage WA, Hammett C, Pickering JW, Hawkins T, Aldous S, Twerenbold R, Wildi K, Nestelberger T, Grimm K, Rubini-Gimenez M, Puelacher C, Kern V, Rentsch K, Than M, Mueller C. Two-hour algorithm for triage toward rule-out and rule-in of acute myocardial infarction by use of high-sensitivity cardiac troponin I. Clin Chem. 2016;62:494–504. doi: 10.1373/clinchem.2015.249508.
53.
Reichlin T, Twerenbold R, Wildi K, Rubini Gimenez M, Bergsma N, Haaf P, Druey S, Puelacher C, Moehring B, Freese M, Stelzig C, Krivoshei L, Hillinger P, Jäger C, Herrmann T, Kreutzinger P, Radosavac M, Weidmann ZM, Pershyna K, Honegger U, Wagener M, Vuillomenet T, Campodarve I, Bingisser R, Miró Ò, Rentsch K, Bassetti S, Osswald S, Mueller C. Prospective validation of a 1-hour algorithm to rule-out and rule-in acute myocardial infarction using a high-sensitivity cardiac troponin T assay. CMAJ. 2015;187:E243–E252. doi: 10.1503/cmaj.141349.
54.
Rubini Gimenez M, Twerenbold R, Jaeger C, Schindler C, Puelacher C, Wildi K, Reichlin T, Haaf P, Merk S, Honegger U, Wagener M, Druey S, Schumacher C, Krivoshei L, Hillinger P, Herrmann T, Campodarve I, Rentsch K, Bassetti S, Osswald S, Mueller C. One-hour rule-in and rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I. Am J Med. 2015;128:861–870.e4. doi: 10.1016/j.amjmed.2015.01.046.
55.
Body R, Carley S, McDowell G, Jaffe AS, France M, Cruickshank K, Wibberley C, Nuttall M, Mackway-Jones K. Rapid exclusion of acute myocardial infarction in patients with undetectable troponin using a high-sensitivity assay. J Am Coll Cardiol. 2011;58:1332–1339. doi: 10.1016/j.jacc.2011.06.026.
56.
Rubini Giménez M, Hoeller R, Reichlin T, Zellweger C, Twerenbold R, Reiter M, Moehring B, Wildi K, Mosimann T, Mueller M, Meller B, Hochgruber T, Ziller R, Sou SM, Murray K, Sakarikos K, Ernst S, Gea J, Campodarve I, Vilaplana C, Haaf P, Steuer S, Minners J, Osswald S, Mueller C. Rapid rule out of acute myocardial infarction using undetectable levels of high-sensitivity cardiac troponin. Int J Cardiol. 2013;168:3896–3901. doi: 10.1016/j.ijcard.2013.06.049.
57.
Zhelev Z, Hyde C, Youngman E, Rogers M, Fleming S, Slade T, Coelho H, Jones-Hughes T, Nikolaou V. Diagnostic accuracy of single baseline measurement of Elecsys troponin T high-sensitive assay for diagnosis of acute myocardial infarction in emergency department: systematic review and meta-analysis. BMJ. 2015;350:h15.
58.
Body R, Burrows G, Carley S, Cullen L, Than M, Jaffe AS, Lewis PS. High-sensitivity cardiac troponin t concentrations below the limit of detection to exclude acute myocardial infarction: a prospective evaluation. Clin Chem. 2015;61:983–989. doi: 10.1373/clinchem.2014.231530.
59.
Bandstein N, Ljung R, Johansson M, Holzmann MJ. Undetectable high-sensitivity cardiac troponin T level in the emergency department and risk of myocardial infarction. J Am Coll Cardiol. 2014;63:2569–2578. doi: 10.1016/j.jacc.2014.03.017.
60.
Shah AS, Anand A, Sandoval Y, Lee KK, Smith SW, Adamson PD, Chapman AR, Langdon T, Sandeman D, Vaswani A, Strachan FE, Ferry A, Stirzaker AG, Reid A, Gray AJ, Collinson PO, McAllister DA, Apple FS, Newby DE, Mills NL; High-STEACS investigators. High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study. Lancet. 2015;386:2481–2488. doi: 10.1016/S0140-6736(15)00391-8.
61.
Hess EP, Agarwal D, Chandra S, Murad MH, Erwin PJ, Hollander JE, Montori VM, Stiell IG. Accuracy of the TIMI risk score in emergency department patients with potential acute coronary syndromes: a systematic review and meta-analysis. Can Med Assoc J. 2010;182:1039–1044.
62.
Than M, Cullen L, Reid CM, Lim SH, Aldous S, Ardagh MW, Peacock WF, Parsonage WA, Ho HF, Ko HF, Kasliwal RR, Bansal M, Soerianata S, Hu D, Ding R, Hua Q, Seok-Min K, Sritara P, Sae-Lee R, Chiu TF, Tsai KC, Chu FY, Chen WK, Chang WH, Flaws DF, George PM, Richards AM. A 2-h diagnostic protocol to assess patients with chest pain symptoms in the Asia-Pacific region (ASPECT): a prospective observational validation study. Lancet. 2011;377:1077–1084. doi: 10.1016/S0140-6736(11)60310-3.
63.
Than M, Cullen L, Aldous S, Parsonage WA, Reid CM, Greenslade J, Flaws D, Hammett CJ, Beam DM, Ardagh MW, Troughton R, Brown AF, George P, Florkowski CM, Kline JA, Peacock WF, Maisel AS, Lim SH, Lamanna A, Richards AM. 2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial. J Am Coll Cardiol. 2012;59:2091–2098. doi: 10.1016/j.jacc.2012.02.035.
64.
Than M, Aldous S, Lord SJ, Goodacre S, Frampton CM, Troughton R, George P, Florkowski CM, Ardagh M, Smyth D, Jardine DL, Peacock WF, Young J, Hamilton G, Deely JM, Cullen L, Richards AM. A 2-hour diagnostic protocol for possible cardiac chest pain in the emergency department: a randomized clinical trial. JAMA Intern Med. 2014;174:51–58. doi: 10.1001/jamainternmed.2013.11362.
65.
Cullen L, Mueller C, Parsonage WA, Wildi K, Greenslade JH, Twerenbold R, Aldous S, Meller B, Tate JR, Reichlin T, Hammett CJ, Zellweger C, Ungerer JP, Rubini Gimenez M, Troughton R, Murray K, Brown AF, Mueller M, George P, Mosimann T, Flaws DF, Reiter M, Lamanna A, Haaf P, Pemberton CJ, Richards AM, Chu K, Reid CM, Peacock WF, Jaffe AS, Florkowski C, Deely JM, Than M. Validation of high-sensitivity troponin I in a 2-hour diagnostic strategy to assess 30-day outcomes in emergency department patients with possible acute coronary syndrome. J Am Coll Cardiol. 2013;62:1242–1249. doi: 10.1016/j.jacc.2013.02.078.
66.
Carlton EW, Cullen L, Than M, Gamble J, Khattab A, Greaves K. A novel diagnostic protocol to identify patients suitable for discharge after a single high-sensitivity troponin. Heart. 2015;101:1041–1046. doi: 10.1136/heartjnl-2014-307288.
67.
Backus BE, Six AJ, Kelder JC, Mast TP, van den Akker F, Mast EG, Monnink SH, van Tooren RM, Doevendans PA. Chest pain in the emergency room: a multicenter validation of the HEART Score. Crit Pathw Cardiol. 2010;9:164–169. doi: 10.1097/HPC.0b013e3181ec36d8.
68.
Mahler SA, Hiestand BC, Goff DC, Hoekstra JW, Miller CD. Can the HEART score safely reduce stress testing and cardiac imaging in patients at low risk for major adverse cardiac events? Crit Pathw Cardiol. 2011;10:128–133. doi: 10.1097/HPC.0b013e3182315a85.
69.
Six AJ, Cullen L, Backus BE, Greenslade J, Parsonage W, Aldous S, Doevendans PA, Than M. The HEART score for the assessment of patients with chest pain in the emergency department: a multinational validation study. Crit Pathw Cardiol. 2013;12:121–126. doi: 10.1097/HPC.0b013e31828b327e.
70.
Mahler SA, Riley RF, Hiestand BC, Russell GB, Hoekstra JW, Lefebvre CW, Nicks BA, Cline DM, Askew KL, Elliott SB, Herrington DM, Burke GL, Miller CD. The HEART Pathway randomized trial: identifying emergency department patients with acute chest pain for early discharge. Circ Cardiovasc Qual Outcomes. 2015;8:195–203. doi: 10.1161/CIRCOUTCOMES.114.001384.
71.
Hess EP, Brison RJ, Perry JJ, Calder LA, Thiruganasambandamoorthy V, Agarwal D, Sadosty AT, Silvilotti ML, Jaffe AS, Montori VM, Wells GA, Stiell IG. Development of a clinical prediction rule for 30-day cardiac events in emergency department patients with chest pain and possible acute coronary syndrome. Ann Emerg Med. 2012;59:115–125.e1. doi: 10.1016/j.annemergmed.2011.07.026.
72.
Scheuermeyer FX, Wong H, Yu E, Boychuk B, Innes G, Grafstein E, Gin K, Christenson J. Development and validation of a prediction rule for early discharge of low-risk emergency department patients with potential ischemic chest pain. CJEM. 2014;16:106–119.
73.
Cullen L, Greenslade JH, Than M, Brown AF, Hammett CJ, Lamanna A, Flaws DF, Chu K, Fowles LF, Parsonage WA. The new Vancouver Chest Pain Rule using troponin as the only biomarker: an external validation study. Am J Emerg Med. 2014;32:129–134. doi: 10.1016/j.ajem.2013.10.021.
74.
Body R, Carley S, McDowell G, Pemberton P, Burrows G, Cook G, Lewis PS, Smith A, Mackway-Jones K. The Manchester Acute Coronary Syndromes (MACS) decision rule for suspected cardiac chest pain: derivation and external validation. Heart. 2014;100:1462–1468. doi: 10.1136/heartjnl-2014-305564.
75.
Than M, Flaws D, Sanders S, Doust J, Glasziou P, Kline J, Aldous S, Troughton R, Reid C, Parsonage WA, Frampton C, Greenslade JH, Deely JM, Hess E, Sadiq AB, Singleton R, Shopland R, Vercoe L, Woolhouse-Williams M, Ardagh M, Bossuyt P, Bannister L, Cullen L. Development and validation of the Emergency Department Assessment of Chest Pain Score and 2 h accelerated diagnostic protocol. Emerg Med Australas. 2014;26:34–44. doi: 10.1111/1742-6723.12164.
76.
Flaws D, Than M, Scheuermeyer S, Christenson J, Boychuk B, Greenslade J, Aldous S, Hammett C, Parsonage W, Deely J, Pickering J, Cullen L. External validation of the Emergency Department Assessment of Chest Pain Score Accelerated Diagnostic Pathway (EDACS-ADP) [published online ahead of print July 12, 2016]. Emerg Med J. doi: https://doi.org/10.1136/emermed-2015%E2%80%93205028. http://emj.bmj.com/content/early/2016/07/12/emermed-2015-205028.long. Accessed June 1, 2016.
77.
Than MP, Pickering JW, Aldous SJ, Cullen L, Frampton CM, Peacock WF, Jaffe AS, Goodacre SW, Richards AM, Ardagh MW, Deely JM, Florkowski CM, George P, Hamilton GJ, Jardine DL, Troughton RW, van Wyk P, Young JM, Bannister L, Lord SJ. Effectiveness of EDACS versus ADAPT accelerated diagnostic pathways for chest pain: a pragmatic randomized controlled trial embedded within practice. Ann Emerg Med. 2016;68:93–102.e1. doi: 10.1016/j.annemergmed.2016.01.001.
78.
Amsterdam EA, Wenger NK, Brindis RG, Casey DE, Ganiats TG, Holmes DR, Jaffe AS, Jneid H, Kelly RF, Kontos MC, Levine GN, Liebson PR, Mukherjee D, Peterson ED, Sabatine MS, Smalling RW, Zieman SJ; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons; American Association for Clinical Chemistry. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64:e139–e228. doi: 10.1016/j.jacc.2014.09.017.
79.
Emergency Department Patients With Chest Pain Writing Panel, Rybicki FJ, Udelson JE, Peacock WF, Goldhaber SZ, Isselbacher EM, Kazerooni E, Kontos MC, Litt H, Woodard PK; Emergency Department Patients With Chest Pain Rating Panel; Appropriate Utilization of Cardiovascular Imaging Oversight Committee. 2015 ACR/ACC/AHA/AATS/ACEP/ASNC/NASCI/SAEM/SCCT/SCMR/SCPC/SNMMI/STR/STS appropriate utilization of cardiovascular imaging in emergency department patients with chest pain: a joint document of the American College of Radiology Appropriateness Criteria Committee and the American College of Cardiology Appropriate Use Criteria Task Force. J Am Coll Radiol. 2016;13:e1–e29.
80.
Janne d’Othée B, Siebert U, Cury R, Jadvar H, Dunn EJ, Hoffmann U. A systematic review on diagnostic accuracy of CT-based detection of significant coronary artery disease. Eur J Radiol. 2008;65:449–461. doi: 10.1016/j.ejrad.2007.05.003.
81.
Takakuwa KM, Keith SW, Estepa AT, Shofer FS. A meta-analysis of 64-section coronary CT angiography findings for predicting 30-day major adverse cardiac events in patients presenting with symptoms suggestive of acute coronary syndrome. Acad Radiol. 2011;18:1522–1528. doi: 10.1016/j.acra.2011.08.013.
82.
Litt HI, Gatsonis C, Snyder B, Singh H, Miller CD, Entrikin DW, Leaming JM, Gavin LJ, Pacella CB, Hollander JE. Safety of CT angiography for rapid “rule-out” of acute coronary syndrome. N Engl J Med. 2012;366:1393–1403.
83.
Hoffmann U, Truong QA, Schoenfeld DA, Chou ET, Woodard PK, Nagurney JT, Pope JH, Hauser TH, White CS, Weiner SG, Kalanjian S, Mullins ME, Mikati I, Peacock WF, Zakroysky P, Hayden D, Goehler A, Lee H, Gazelle GS, Wiviott SD, Fleg JL, Udelson JE; ROMICAT-II Investigators. Coronary CT angiography versus standard evaluation in acute chest pain. N Engl J Med. 2012;367:299–308. doi: 10.1056/NEJMoa1201161.
84.
Hollander JE, Chang AM, Shofer FS, Collin MJ, Walsh KM, McCusker CM, Baxt WG, Litt HI. One-year outcomes following coronary computerized tomographic angiography for evaluation of emergency department patients with potential acute coronary syndrome. Acad Emerg Med. 2009;16:693–698. doi: 10.1111/j.1553-2712.2009.00459.x.
85.
Hadamitzky M, Distler R, Meyer T, Hein F, Kastrati A, Martinoff S, Schömig A, Hausleiter J. Prognostic value of coronary computed tomographic angiography in comparison with calcium scoring and clinical risk scores. Circ Cardiovasc Imaging. 2011;4:16–23. doi: 10.1161/CIRCIMAGING.110.955351.
86.
Hollander JE, Gatsonis C, Greco EM, Snyder BS, Chang AM, Miller CD, Singh H, Litt HI. Coronary computed tomography angiography versus traditional care: comparison of one-year outcomes and resource use. Ann Emerg Med. 2016;67:460–468.e1. doi: 10.1016/j.annemergmed.2015.09.014.
87.
Schlett CL, Banerji D, Siegel E, Bamberg F, Lehman SJ, Ferencik M, Brady TJ, Nagurney JT, Hoffmann U, Truong QA. Prognostic value of CT angiography for major adverse cardiac events in patients with acute chest pain from the emergency department: 2-year outcomes of the ROMICAT trial. JACC Cardiovasc Imaging. 2011;4:481–491. doi: 10.1016/j.jcmg.2010.12.008.
88.
Carrigan TP, Nair D, Schoenhagen P, Curtin RJ, Popovic ZB, Halliburton S, Kuzmiak S, White RD, Flamm SD, Desai MY. Prognostic utility of 64-slice computed tomography in patients with suspected but no documented coronary artery disease. Eur Heart J. 2009;30:362–371. doi: 10.1093/eurheartj/ehn605.
89.
Abdulla J, Asferg C, Kofoed KF. Prognostic value of absence or presence of coronary artery disease determined by 64-slice computed tomography coronary angiography a systematic review and meta-analysis. Int J Cardiovasc Imaging. 2011;27:413–420. doi: 10.1007/s10554-010-9652-x.
90.
Greenland P, Bonow RO, Brundage BH, Budoff MJ, Eisenberg MJ, Grundy SM, Lauer MS, Post WS, Raggi P, Redberg RF, Rodgers GP, Shaw LJ, Taylor AJ, Weintraub WS, Harrington RA, Abrams J, Anderson JL, Bates ER, Grines CL, Hlatky MA, Lichtenberg RC, Lindner JR, Pohost GM, Schofield RS, Shubrooks SJ, Jr, Stein JH, Tracy CM, Vogel RA, Wesley DJ; American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography); Society of Atherosclerosis Imaging and Prevention; Society of Cardiovascular Computed Tomography. ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain. Circulation. 2007;115:402–426. doi: https://doi.org/10.1161/CIRCULATIONAHA.107.181425
91.
Gottlieb I, Miller JM, Arbab-Zadeh A, Dewey M, Clouse ME, Sara L, Niinuma H, Bush DE, Paul N, Vavere AL, Texter J, Brinker J, Lima JA, Rochitte CE. The absence of coronary calcification does not exclude obstructive coronary artery disease or the need for revascularization in patients referred for conventional coronary angiography. J Am Coll Cardiol. 2010;55:627–634. doi: 10.1016/j.jacc.2009.07.072.
92.
Chang AM, Le J, Matsuura AC, Litt HI, Hollander JE. Does coronary artery calcium scoring add to the predictive value of coronary computed tomography angiography for adverse cardiovascular events in low-risk chest pain patients? Acad Emerg Med. 2011;18:1065–1071. doi: 10.1111/j.1553-2712.2011.01173.x.
93.
Chow BJ, Small G, Yam Y, Chen L, Achenbach S, Al-Mallah M, Berman DS, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng V, Chinnaiyan KM, Delago A, Dunning A, Hadamitzky M, Hausleiter J, Kaufmann P, Lin F, Maffei E, Raff GL, Shaw LJ, Villines TC, Min JK; CONFIRM Investigators. Incremental prognostic value of cardiac computed tomography in coronary artery disease using CONFIRM: COroNary computed tomography angiography evaluation for clinical outcomes: an InteRnational Multicenter registry. Circ Cardiovasc Imaging. 2011;4:463–472. doi: 10.1161/CIRCIMAGING.111.964155.
94.
Raff GL, Chinnaiyan KM, Cury RC, Garcia MT, Hecht HS, Hollander JE, O’Neil B, Taylor AJ, Hoffmann U; Society of Cardiovascular Computed Tomography Guidelines Committee. SCCT guidelines on the use of coronary computed tomographic angiography for patients presenting with acute chest pain to the emergency department: a report of the Society of Cardiovascular Computed Tomography Guidelines Committee. J Cardiovasc Comput Tomogr. 2014;8:254–271. doi: 10.1016/j.jcct.2014.06.002.
95.
Kirk JD, Turnipseed S, Lewis WR, Amsterdam EA. Evaluation of chest pain in low-risk patients presenting to the emergency department: the role of immediate exercise testing. Ann Emerg Med. 1998;32:1–7.
96.
Amsterdam EA, Kirk JD, Diercks DB, Lewis WR, Turnipseed SD. Immediate exercise testing to evaluate low-risk patients presenting to the emergency department with chest pain. J Am Coll Cardiol. 2002;40:251–256.
97.
Soremekun OA, Hamedani A, Shofer FS, O’Conor KJ, Svenson J, Hollander JE. Safety of a rapid diagnostic protocol with accelerated stress testing. Am J Emerg Med. 2014;32:124–128. doi: 10.1016/j.ajem.2013.10.020.
98.
Udelson JE, Beshansky JR, Ballin DS, Feldman JA, Griffith JL, Handler J, Heller GV, Hendel RC, Pope JH, Ruthazer R, Spiegler EJ, Woolard RH, Selker HP. Myocardial perfusion imaging for evaluation and triage of patients with suspected acute cardiac ischemia: a randomized controlled trial. JAMA. 2002;288:2693–2700.
99.
Tatum JL, Jesse RL, Kontos MC, Nicholson CS, Schmidt KL, Roberts CS, Ornato JP. Comprehensive strategy for the evaluation and triage of the chest pain patient. Ann Emerg Med. 1997;29:116–125.
100.
Foy AJ, Liu G, Davidson WR, Sciamanna C, Leslie DL. Comparative effectiveness of diagnostic testing strategies in emergency department patients with chest pain: an analysis of downstream testing, interventions, and outcomes. JAMA Intern Med. 2015;175:428–436. doi: 10.1001/jamainternmed.2014.7657.
Information & Authors
Information
Published In
Copyright
© 2016 American Heart Association, Inc.
History
Published online: 16 August 2016
Published in print: 16 August 2016
Keywords
Subjects
Authors
Disclosures
Dr Hollander has received research grants from the National Institute of Health, Patient Centered Outcome Research Institute, Alere, Siemens, Trinity, and Roche. He has received consulting honoraria from Janssen and Novartis.
Dr Mueller has received research grants from the Swiss National Science Foundation, European Union, Swiss Heart Foundation, Cardiovascular Research Foundation Basel, Abbott, Alere, AstraZeneca, Beckman Coulter, Biomerieux, Brahms, Nanosphere, 8sense, Critical Diagnostics, Roche, Siemens, Singulex, Sphingotec, and Department of Internal Medicine of the University Hospital Basel, as well as speaker/consulting honoraria from Abbott, Alere, AstraZeneca, BG Medicine, Biomerieux, BRAHMS, Cardiorentis, Daiichi Sankyo, Radiometer, Roche, Novartis, Sanofi, Singulex, and Siemens.
Dr Than has received grants from the Health Research Council of New Zealand and the Christchurch Cardio-Endocrine Research Group. He has received honoraria from Beckman, Abbott, and Alere.
Metrics & Citations
Metrics
Citations
Download Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.
- Artificial intelligence in ECG analysis - future or present?, Emergency Medical Service, 11, 2, (105-109), (2024).https://doi.org/10.36740/EmeMS202402106
- Rol de las troponinas de alta sensibilidad en el paciente con dolor torácico, Medicina Crítica, 38, 4, (304-306), (2024).https://doi.org/10.35366/118222
- To Be, or Not to Be … Pectoral Angina? The Pain Is the Same, but the Etiology Is Different—A Case Report, Life, 14, 9, (1066), (2024).https://doi.org/10.3390/life14091066
- High-Sensitivity Troponin: Finding a Meaningful Delta, Journal of Cardiovascular Development and Disease, 11, 10, (318), (2024).https://doi.org/10.3390/jcdd11100318
- Dolor torácico: de las guías a la práctica clínica, Radiología, (2024).https://doi.org/10.1016/j.rx.2024.05.002
- Rapid Acute Coronary Syndrome Evaluation Over One Hour With High-Sensitivity Cardiac Troponin I: A United States-Based Stepped-Wedge, Randomized Trial, Annals of Emergency Medicine, 84, 4, (399-408), (2024).https://doi.org/10.1016/j.annemergmed.2024.04.024
- Biomarkers: Revolutionizing disease monitoring and therapeutic strategies, Public Health and Toxicology Issues Drug Research, Volume 2, (1-25), (2024).https://doi.org/10.1016/B978-0-443-15842-1.00002-8
- Identification of Coronary Culprit Lesion in ST Elevation Myocardial Infarction by Using Deep Learning, IEEE Journal of Translational Engineering in Health and Medicine, 11, (70-79), (2023).https://doi.org/10.1109/JTEHM.2022.3227204
- Machine learning and myocardial infarction diagnosis: sometimes you can’t make it on your own, European Heart Journal, 44, 35, (3309-3310), (2023).https://doi.org/10.1093/eurheartj/ehad467
- Troponin in early presenters to rule out myocardial infarction, European Heart Journal, 44, 30, (2846-2858), (2023).https://doi.org/10.1093/eurheartj/ehad376
- See more
Loading...
View Options
Login options
Check if you have access through your login credentials or your institution to get full access on this article.
Personal login Institutional LoginPurchase Options
Purchase this article to access the full text.
eLetters(0)
eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.
Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.