Chest Pain Evaluation in t h e Em e r g e n c y D e p a r t m e n t Andrew J. Foy,
MD
a
, Lisa Filippone,
MD
b,
*
KEYWORDS Chest pain Myocardial infarction Acute coronary syndrome KEY POINTS Chest pain is a common chief complaint in the emergency department; approximately 9% of patients with chest pain are diagnosed with an acute coronary syndrome (ACS). ACS presents as a range of clinical conditions including unstable angina, non–STsegment elevation myocardial infarction (MI), ST-segment elevation MI, and sudden cardiac death. The patient history and electrocardiogram are very important for early recognition of ACS. Type I MI is owing to coronary artery thrombosis, whereas type II MI represents myocardial injury from a variety of underlying processes not related to intracoronary thrombosis. Advanced noninvasive testing in patients who rule out for ACS is low yield from a diagnostic standpoint and has not been found to improve patient outcomes.
INTRODUCTION
Chest pain accounts for 5.5 million or approximately 9% of all non–injury-related emergency department (ED) visits for adults in the United States each year.1 The development of catheter-based therapies and regional care networks allowing for rapid transfer of patients to centers with advanced treatment options has contributed to declining acute coronary syndrome (ACS) case fatality rates. Data from the Nationwide Inpatient Sample shows the overall case fatality in the United States for STsegment elevation myocardial infarction (STEMI) declined 3% between 1993 and 2009.2 A community study of patients hospitalized with incident myocardial infarction (MI) in Olmsted County, Minnesota, found the age- and sex-adjusted hazard ratio of death within 30 days for an MI occurring in 2006 compared with 1987 was 0.44.3 Despite improvements in the acute care of patients with ACS, it accounts for only a small percentage (9%) of all ED visits for chest pain4 and there is now concern that current diagnostic strategies could be contributing to the overtreatment of obstructive coronary artery disease (CAD) in patients presenting with chest pain without evidence a Division of Cardiology, Heart and Vascular Institute, Penn State Milton S. Hershey Medical Center, 500, University Drive, Hershey, PA 17033, USA; b Department of Emergency Medicine, Cooper Medical School of Rowan University, One Cooper Plaza, Camden, NJ 08103, USA * Corresponding author. E-mail address: [email protected]
Med Clin N Am - (2015) -–http://dx.doi.org/10.1016/j.mcna.2015.02.010 medical.theclinics.com 0025-7125/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
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of ACS. From 1999 through 2008, the use of advanced medical imaging in patients with chest pain increased 368%.1 This was largely undertaken in an effort to avoid missing ACS. However, although this strategy has indeed led to the increased detection and treatment of obstructive CAD, it has not translated into a reduction in cardiac events. A cross-sectional, population-based sample of Medicare patients from 1993 to 2001 found that overall hospitalizations for acute MI (AMI) remained flat at 8.7 per 1000 patients despite significant increases in imaging and revascularization rates.5 This article discusses the evaluation of patients presenting to the ED with chest pain and suspected ACS. It emphasizes important points of the pathophysiology, patient history, and physical examination, as well as clinical findings related to ACS. It will also discuss recommendations regarding ordering cardiac troponin (cTn) and the use of advanced noninvasive testing in this patient population. PATHOPHYSIOLOGY
The term ‘acute coronary syndrome’ refers to any condition that is brought on by a sudden reduction in blood flow to the heart. It represents a spectrum of clinical conditions including unstable angina, non–ST-segment elevation MI (NSTEMI), and STEMI. Unstable angina is characterized by an unstable pattern of ischemic cardiac discomfort without increased cTn levels or ST-segment elevation on the electrocardiogram (ECG). It may or may not present with horizontal or down-sloping ST depression or dynamic T-wave changes on the ECG. NSTEMI is characterized by increased cTn levels. It too may or may not present with evidence of ischemia on the ECG. STEMI is characterized by ST-segment elevation on the ECG owing to transmural (full-thickness) necrosis of the myocardial segment(s) involved. cTn may be negative in the early stage of STEMI because cell lysis and release of intracellular components into the bloodstream do not occur immediately upon myocardial cell death. AMI is defined by a 20% increase and/or decrease in cTn (I or T), the preferred myocardial biomarker, with 1 value exceeding the 99th percentile upper reference limit (URL) of a normal population.6 MI can result from a variety of clinical conditions and the etiology of AMI is important to differentiate because it significantly affects patient management. The Third Universal Definition of MI specifies 5 types (Table 1).6 For the purposes of patient evaluation and management, it is best to classify MI into 2 broad categories: (1) MI owing to acute coronary artery thrombosis or (2) MI not owing to acute coronary artery thrombosis, the causes of which are extensive (Box 1). The backbone of treatment for patients in the first category is administration of antiplatelet and anticoagulation therapy with or without percutaneous coronary intervention (PCI), which is intended to stabilize the process of acute thrombosis and restore coronary flow. Treatment for patients in the second category is directed at treating the underlying condition responsible for causing oxygen supply/demand imbalance or other myocardial injury (volume resuscitation, presser support, and antibiotics for patients in septic shock). Coronary artery thrombosis is caused usually by either atherosclerotic plaque rupture or plaque erosion. In each case, there is a loss of integrity in the protective covering over an atherosclerotic plaque, formed by a single layer of endothelial cells, thus exposing the thrombogenic components of the necrotic core to the bloodstream.7 The resulting intracoronary thrombus is composed of platelet aggregates layered with fibrin, red blood cells, and acute inflammatory cells.7 Plaque rupture or erosion often occurs at sites without significant luminal stenosis. One study of 3747 patients in the National Heart, Lung, and Blood Institute Dynamic Registry undergoing PCI found that 216 (5.8%) required additional PCI of the
Chest Pain Evaluation in the Emergency Department
Table 1 Universal classification of MI Type
Description
Type 1: Spontaneous MI
Related to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus; patient may or may not have underlying obstructive CAD.
Type 2: Ischemic imbalance
Oxygen supply cannot meet myocardial oxygen; owing to any condition that affects this relationship including tachycardia, hypotension, severe hypertension with or without LVH, tachyarrhythmias/bradyarrhythmias, anemia, acute bleeding, respiratory failure, or CHF; patient may or may not have underlying obstructive CAD.
Type 3: MI before biomarker evidence of cell death
Symptoms suggestive of AMI and new ischemic ECG changes before biomarker conversion such as in the early phase of STEMI.
Type 4a: Owing to PCI
Troponin rise >5 99th percentile URL in patients with normal baseline values (and no concern for AMI before PCI) or a rise of troponin >20% if the baseline values are elevated and are stable or falling.
Type 4b: Stent thrombosis
Evidence of stent thrombosis with an increase and/or decrease of cardiac biomarkers with 1 value >99th percentile URL.
Type 5: Owing to CABG
Cardiac biomarker increase >10 99th percentile URL in patients with normal baseline values.
Abbreviations: AMI, acute myocardial infarction; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CHF, congestive heart failure; ECG, electrocardiogram; LVH, left ventricular hypertension; MI, myocardial infarction; PCI, percutaneous coronary intervention; STEMI, STsegment elevation myocardial infarction; URL, upper reference limit.
nontarget lesion within 1 year of follow-up for new clinical symptoms.8 Although the degree of obstructive CAD during initial PCI was a strong predictor of future events, the majority of new lesions were less than 50% in severity at the time of the initial PCI.8 The fact that ACS often occurs at sites without significant luminal stenosis is probably 1 explanation for why contemporary PCI trials in patients with stable CAD have not prevented future MI compared with medical management alone. The “vulnerable plaque” theory identifies several important features of plaque morphology associated with increased odds of rupture and ACS. In 1 study of 1059 patients undergoing coronary CT angiography, the combination of positive remodeling and low-attenuation plaque was associated with a 22% risk of ACS over a mean follow-up of 27 months, whereas 1 feature alone was associated with a 3.7% risk and those with no features a 0.5% risk.9 Stable angina is not on the spectrum of ACS and is not considered a medical emergency. Stable angina is most often owing to intracoronary stenosis; however, it can be owing to other processes that compromise coronary flow, such as diastolic dysfunction. Ischemic discomfort follows a stable pattern, often remaining unchanged for months or years at a time, and is caused by the predictable mismatch in myocardial oxygen supply and demand that occurs with exertion and goes away promptly with rest or nitroglycerin. A recent study from a registry of patients with stable CAD found that those with stable angina and evidence of ischemia had a 4% risk of cardiovascular death, MI, or stroke over 2 years of follow-up.10 True stable angina is rarely encountered in the ED. In the Internet Tracking Registry of Acute Coronary Syndrome (i*trACS) registry only 1% of chest pain patients were
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Box 1 Causes of increased troponin not related to intracoronary thrombosis Injury related to supply/demand imbalance of myocardial tissue Tachyarrhythmias/bradyarrhythmias Aortic dissection or severe aortic valve disease Hypertrophic cardiomyopathy Cardiogenic, hypovolemia, or septic shock Severe respiratory failure Severe anemia Hypertension with or without left ventricular hypertension Coronary spasm Coronary embolism or vasculitis Coronary endothelial dysfunction without significant coronary artery disease Injury not related to myocardial ischemia Cardiac contusion, surgery, ablation, pacing, or defibrillator shocks Rhabdomyolysis with cardiac involvement Myocarditis Cardiotoxic agents (e.g., anthracyclines, herceptin) Multifactorial or indeterminate myocardial injury Heart failure Stress (Takotsubo) cardiomyopathy Severe pulmonary embolism or pulmonary hypertension Sepsis and critically ill patients Renal failure Severe acute neurologic diseases (e.g., stroke, subarachnoid) Hemorrhage Infiltrative diseases (e.g., amyloidosis, sarcoidosis) Strenuous exercise
found to have stable angina.4 Although stable angina is best treated by a cardiologist in the outpatient setting, it is recommended that providers err on the side of caution and consider most cases of characteristic angina in the ED setting as unstable. In conclusion, ACS presents as a range of clinical conditions caused by a sudden reduction in blood flow to the heart. AMI is defined by myocardial cell death that manifests as a rise or fall of greater than 20% in cTn with at least 1 value exceeding the 99th percentile URL. It is important to determine whether the etiology of AMI is owing to acute intracoronary thrombosis or another cause of myocardial injury, because this information directs appropriate patient management. PATIENT HISTORY AND PHYSICAL
A thorough history forms the cornerstone of diagnosis for patients who present to the ED with chest pain. In a prospective cohort study of all consecutive patients newly
Chest Pain Evaluation in the Emergency Department
admitted from the ED to 1 academic department of medicine over a 53-day period, researchers found that history alone was the most important modality in patients who were diagnosed correctly based on initial clinical data available on admission.11 A high-quality history enables the physician to form a pretest probability of disease. Once this is established, the predictive value of additional findings and tests can be interpreted correctly. Inadequate or inaccurate history taking and failure to appreciate the role pretest probability plays in diagnosing any particular condition exposes the physician to important cognitive biases, which can lead to disproportionate estimates of frequency and faulty Bayesian reasoning.12 The differential diagnosis of chest pain is broad. The Internet Tracking Registry of Acute Coronary Syndrome (i*trACS) is a multicenter registry of undifferentiated ED patients with suspected ACS that includes 15,608 patients, with 17,713 visits.4 Chest pain was the chief complaint in 71% of visits. “Chest pain not otherwise specified” and “other” represented the most common final diagnoses (70%), followed by unstable angina (6.3%), congestive heart failure (4.0%), STEMI (1.6%), pneumonia (1.5%), stable angina (1.2%), NSTEMI (1.0%), pulmonary embolism (PE; 0.4%), pericarditis (0.3%), and dissecting aneurysm (0.1%). Chest pain characteristics and related symptoms that are associated with increased odds of AMI include pain radiation to both arms (likelihood ratio [LR] 7.1), to the right shoulder (LR, 2.9), to the left arm (LR, 2.3), chest pain as the most important symptom (LR, 2.0), association with diaphoresis (LR, 2.0), and association with nausea or vomiting (LR, 1.9).13 It should be noted that nausea and vomiting as an isolated symptom(s) is not a predictor of AMI; however, patients with AMI will on rare occasion present with only gastrointestinal complaints. A recent multicenter observational study of 2475 consecutive patients presenting with acute chest pain to the ED found that chest pain aggravated by exertion and chest pain relieved with nitrates also increased the likelihood of AMI.14 Physical examination findings that are associated with increased odds of AMI include a third heart sound on auscultation (LR, 3.2), hypotension with systolic blood pressure of 80 mm Hg or lower (LR, 3.1), and pulmonary crackles on auscultation (LR, 2.1).13 Chest pain characteristics that decrease the probability of AMI are pleuritic chest pain (LR, 0.2), pain that is sharp or stabbing (LR, 0.3), pain that is positional (0 LR,.3), and pain reproduced by palpation (LR, 0.2–0.4).13 Studies that have examined selected cohorts of ACS patients have consistently found chest pain to be the most common presenting symptom. The populationbased MONICA/KORA Myocardial Infarction Registry included 568 women and 1710 men hospitalized with a first-ever AMI.15 Chest pain or feelings of pressure or tightness in the chest were reported in 93.5% of women and 94.2% of men.15 An analysis of the Euro Heart Survey, which included 10,253 patients with a discharge diagnosis of ACS, found that the vast majority of patients (>90%) presented with chest pain, either typical or atypical, and this was true regardless of age or gender.16 Other studies have found small differences in AMI presentation between men versus woman as well as younger versus older patients. In 1 observational study of 1015 patients younger than 55 years who were hospitalized for ACS, chest pain was the most common symptom in both sexes but women were more likely to present without chest pain than men (19% vs 14%, respectively).14 An observational study from the National Registry of Myocardial Infarction, 1994 to 2006, that included 1,143,513 patients found women were more likely than men to present without chest pain and so were older versus younger patients.17 Age was found to be a stronger determinant of different symptoms at AMI presentation than sex.17 It is also commonly taught that diabetic patients are less likely to present with symptoms of chest pain with ACS; however, there is little evidence to support this. McNulty and colleagues18 performed
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coronary balloon occlusion on 100 patients with and without type 2 diabetes and found no difference in the subjective perception of pain between groups; nor were there any differences between men and women. In summary, chest pain is the hallmark of ACS and specific characteristics of the pain significantly increase or decrease the odds of it. When the patient history is consistent with ischemic cardiac discomfort, physicians should retain a high index of suspicion for ACS despite the lack of objective evidence of ischemia. Finally, although slight differences remain in ACS presentation between men and women physicians should not lose sight of the bigger picture: chest pain is the primary symptom associated with ACS. CLINICAL FINDINGS Electrocardiogram
The ECG plays a major role in determining the initial management in patients presenting to the ED with complaints consistent with ACS. The recognition of an STEMI or an “STEMI equivalent” is the first decision point in the management of the patient presenting with an ACS complaint. The 2013 STEMI guidelines refer to a Joint Task Force Definition of MI. It defines diagnostic ST elevation as new elevation measured at the J point of 1 mm or greater (0.1 mV) in 2 contiguous leads, in all leads except V2 and V3.6,19 Given the differences in men and women different levels of elevation are accepted in leads V2 and V3. Abnormal elevation is defined as 2.5 mm or greater in men less than 40 years old, 2 mm or greater in men greater than 40 years old, and 1.5 mm or greater in women.6 Three additional ECG patterns deserve special mention in that they may require emergent reperfusion therapy. These are isolated ST depressions in the anterior leads concerning for transmural posterior MI, prominent “hyperacute T waves” in leads consistent with coronary circulation, and isolated ST elevation in aVR with diffuse ST depression. In a 2010 study of approximately 1200 patients looking at the clinical outcomes of patients presenting with isolated anterior segment depression, 26.2% had an occluded culprit artery with increased serum troponin levels.20 Of these patients, the culprit artery was the left circumflex in 48.4%, the left anterior descending artery in 33.8%, and the right coronary artery in 17.8%.20 Given the limitation of the standard 12-lead ECG for the evaluation of isolated posterior MI, 3 additional posterior leads (V7, V8, and V9) can be used to aid in diagnosis. In a study of 53 patients undergoing cardiac catheterization, the left circumflex artery was purposely occluded and serial recordings of ST deviation were performed. Compared with the standard 12lead ECG, the 15-lead ECG was more often able to detect the presence of any ST elevation of 0.5 mm or greater (odds ratio [OR], 2.6) and 1 mm or greater (OR, 2.2).21 Patients who present very early after acute occlusion of a coronary artery may not yet display ST segment elevation, but rather prominent T waves, often termed hyperacute T waves.22,23 This has been described in the literature in human subjects as early as 1934.24 In a subgroup study of one of the early thrombolytic trials, higher T waves were observed more frequently in patients with a shorter duration of symptoms (2.5 vs 3.3 hours).25 Patients who present with an ECG pattern of ST depression and isolated ST elevation in aVR while not meeting the criteria for acute STEMI are frequently managed with an early invasive strategy owing to the concern for left main or severe multivessel disease.26,27 In a multivariable analysis of NSTEMI patients, 140 of whom met this pattern, those with ST depression and isolated elevation in aVR showed an increased risk of culprit left main disease (OR, 4.7) and in-hospital cardiovascular mortality (OR,
Chest Pain Evaluation in the Emergency Department
5.6) compared with patients without any ST deviation. Patients with isolated ST depression did not demonstrate this risk. Additionally, at 1-year follow-up, ST depression and isolated ST elevation in aVR was a strong predictor of cardiovascular death (hazard ratio, 2.3).27 As mentioned, ST segment depressions can be observed with isolated posterior wall MI and in association with elevation in aVR. ST depressions may also be observed in association with STEMI, termed reciprocal ST change. However, ST segment depression alone may represent subendocardial ischemia. The morphology of ST segment depression that is most consistent with ischemia is horizontal or downsloping. The degree of depression considered significant is 0.5 mm or greater measured at the J point. Both the amount of depression and the extent of depression are associated with an increased risk of death.28,29 In a 2001 study looking at patients who were enrolled in the PARAGON-A study, patients whose presenting ECG had ST depression of 0.2 mm or greater had an OR of 5.7 for death at 1 year.30 Additionally, when those depressions involved more than 1 region, their risk of death increased with an OR of 9.2 compared with no ST segment depression.30 T wave inversions are encountered commonly in patients presenting with ACS. T wave inversion may present alone or with ST segment depression. Significant T wave inversions are generally 1 mm or greater in depth and occur in 2 or more contiguous leads. The prognostic importance of T wave inversion alone is not clear; however, 2 particular patterns of T wave inversion historically portent a high risk of anterior wall MI. This pattern described by de Zwann and colleagues31 in 1982 is referred to as Wellens’ warning. This pattern of either symmetric deep T wave inversion or a sharply biphasic T wave in the anterior precordial leads is treated with an early invasive strategy. Of note, this pattern often occurs after a chest pain episode and may normalize during recurrent pain episodes.31–33 There are many underlying conditions that confound the diagnosis of ACS. The presence of bundle branch blocks, left ventricular hypertrophy, paced rhythms, Brugada syndrome, left ventricular aneurysm, and early repolarization pattern all may have ST segment elevations on the baseline ECG. Similarly, ST depressions may be observed in bundle branch blocks, left ventricular hypertrophy, digitalis effect, and electrolyte abnormalities. Patients presenting with chest pain that is not ACS often have changes on their EGC. There are many ECG abnormalities described in patients with PE; these abnormalities include S1Q3T3, S1S2S3, right bundle branch block, low voltage, and right axis deviation. Additionally, T wave changes that may mimic ACS have been observed. In a study of 80 patients admitted with PE, 68% had an ischemic T wave pattern on their ECG (85% of patients with massive PE and 19% in nonmassive PE).34 In a more recent study of 127 patients, 40 diagnosed with PE and 87 diagnosed with ACS, negative T waves were seen in leads III and V1 in 88% of PE patients compared with only 1% of ACS patients.35 Patients presenting with chest pain owing to pericarditis may demonstrate several different ECG abnormalities. Classically, there is a progression through 4 stages. The first stage with ST segment elevation can be misinterpreted as STEMI. However, unlike STEMI, ST elevation in pericarditis is usually diffuse. Additionally, there may be PR depression identified most often in lead II.36 The opposite findings are observed in aVR in patients with pericarditis with PR elevation and ST depression. Patients with acute aortic dissection often have EGC changes that are consistent with myocardial ischemia or may present with clear ST elevation. In a recent study of 233 patients diagnosed with Stanford type A acute aortic dissection, approximately 50% of patients had ST–T wave changes (4% with ST elevation, 47% with ST
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depression and/or negative T waves).37 Patients in this study with ST–T wave changes had a poorer clinical condition and subsequent higher mortality when compared with patients who had normal or no significant ST–T changes on admission.37 In conclusion, the ECG is integral in the evaluation of the patient with suspected ACS. The patient’s presentation and risk factors for ACS as well as for other nonACS causes of chest pain should be interpreted in conjunction with the ECG to avoid misdiagnosis. Cardiac Troponin
cTn is the preferred biomarker for diagnosing AMI because of its superior sensitivity and specificity for detection of myocardial necrosis. It is an important part of the myocardial contractile apparatus and is released into the bloodstream, over time (from 30 minutes to 12 hours) after cardiomyocyte death.6 AMI is defined by an increase or decrease of greater than 20% in cTn with at least 1 value exceeding the 99th percentile URL. It must be kept in mind that despite the high specificity of cTn for myocardial necrosis, it is not specific for the cause of injury. Maag and colleagues38 found that in a large, undifferentiated cohort of patients who underwent cTn testing in the ED that when “chest pain” was not the chief complaint, an elevated cTn that met the definition for AMI was unlikely to be owing to type I MI (20%). However, when “chest pain” was the chief complaint, nearly all patients with an elevated cTn had a type I MI (OR, 7.3).38 Because this is an article on the evaluation of chest pain, we will not belabor this point. It suffices to say that, when chest pain is not the chief complaint, caution should be exercised in ordering cTn and interpreting the result. Physicians should be aware of the 99th percentile URL for the cTn assay used in their hospital because all cTn assays have different URLs. Ideally, a cTn assay should have a coefficient of variation of less than 10% above the 99th percentile URL. Levels below the 99th percentile URL are often reported. Failure to appreciate this concept could lead physicians to misinterpret normal cTn levels as significant elevations. Therefore, physicians must familiarize themselves with the performance characteristics of the cTn assay used in their laboratories. Serial measurements of cTn are necessary when cTn concentration is not elevated on admission because cTn may not be detectable in the blood within the first hours after myocardial injury.39 When myocardial ischemia is suspected and cTn is not initially detected, the current standard of care in the United States calls for a cTn to be drawn again in 6 to 9 hours, although precise timing is not defined. If the index of suspicion is high then a third sample should be drawn in 12 to 24 hours.39 IMAGING AND ADDITIONAL TESTING
In 2007, the American College of Cardiology and American Heart Association produced guidelines for the management of patients with unstable angina and NSTEMI. This report was developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society for Thoracic Surgeons.39 It was also endorsed formally by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. It states that, In patients with suspected ACS in whom ischemic heart disease is present or suspected, if the follow-up 12-lead ECG and cardiac biomarkers measurements are normal, a stress test (exercise or pharmacological) to provoke ischemia should be performed in the ED, in a chest pain unit, or on an outpatient basis in a timely
Chest Pain Evaluation in the Emergency Department
fashion (within 72 h) as an alternative to inpatient admission. Low-risk patients with a negative diagnostic test can be managed as outpatients. It was given a class I recommendation, meaning the “benefit >>> risk” and “procedure/treatment SHOULD be performed/administered.” However, it was also assigned a level C for estimate of certainty of treatment effect, meaning there is little if any evidence to support it outside of expert opinion. This recommendation has not been updated with the exception of a 2010 scientific statement from the American Heart Association, which adds that anatomic assessment, meaning coronary CT angiography, could be performed in place of stress testing.40 Despite these recommendations, significant questions remain with the most important being; Does our current practice improve patient outcomes? Several retrospective studies suggest the answer is “no.” Chan and colleagues41 performed a prospective cohort study on 832 consecutive patients who presented to a single ED with chest pain and were admitted to a non–intensive care telemetry bed over a 16-month period. Thirty-one percent of patients received either an inpatient or outpatient stress test in the form of exercise electrocardiography. At baseline, there were no differences between patients who received stress testing or not in respect to demographics, risk factors, risk scores (Acute Coronary Ischemia–Time Insensitive Predictive Instrument [ACI-TIPI] and Goldman), or specific clinical features of the chest pain, including location, quality, or associated symptoms.41 The authors found that more than 30 days of follow-up the overall rate of AMI among the cohort was low (
MD
a
, Lisa Filippone,
MD
b,
*
KEYWORDS Chest pain Myocardial infarction Acute coronary syndrome KEY POINTS Chest pain is a common chief complaint in the emergency department; approximately 9% of patients with chest pain are diagnosed with an acute coronary syndrome (ACS). ACS presents as a range of clinical conditions including unstable angina, non–STsegment elevation myocardial infarction (MI), ST-segment elevation MI, and sudden cardiac death. The patient history and electrocardiogram are very important for early recognition of ACS. Type I MI is owing to coronary artery thrombosis, whereas type II MI represents myocardial injury from a variety of underlying processes not related to intracoronary thrombosis. Advanced noninvasive testing in patients who rule out for ACS is low yield from a diagnostic standpoint and has not been found to improve patient outcomes.
INTRODUCTION
Chest pain accounts for 5.5 million or approximately 9% of all non–injury-related emergency department (ED) visits for adults in the United States each year.1 The development of catheter-based therapies and regional care networks allowing for rapid transfer of patients to centers with advanced treatment options has contributed to declining acute coronary syndrome (ACS) case fatality rates. Data from the Nationwide Inpatient Sample shows the overall case fatality in the United States for STsegment elevation myocardial infarction (STEMI) declined 3% between 1993 and 2009.2 A community study of patients hospitalized with incident myocardial infarction (MI) in Olmsted County, Minnesota, found the age- and sex-adjusted hazard ratio of death within 30 days for an MI occurring in 2006 compared with 1987 was 0.44.3 Despite improvements in the acute care of patients with ACS, it accounts for only a small percentage (9%) of all ED visits for chest pain4 and there is now concern that current diagnostic strategies could be contributing to the overtreatment of obstructive coronary artery disease (CAD) in patients presenting with chest pain without evidence a Division of Cardiology, Heart and Vascular Institute, Penn State Milton S. Hershey Medical Center, 500, University Drive, Hershey, PA 17033, USA; b Department of Emergency Medicine, Cooper Medical School of Rowan University, One Cooper Plaza, Camden, NJ 08103, USA * Corresponding author. E-mail address: [email protected]
Med Clin N Am - (2015) -–http://dx.doi.org/10.1016/j.mcna.2015.02.010 medical.theclinics.com 0025-7125/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
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of ACS. From 1999 through 2008, the use of advanced medical imaging in patients with chest pain increased 368%.1 This was largely undertaken in an effort to avoid missing ACS. However, although this strategy has indeed led to the increased detection and treatment of obstructive CAD, it has not translated into a reduction in cardiac events. A cross-sectional, population-based sample of Medicare patients from 1993 to 2001 found that overall hospitalizations for acute MI (AMI) remained flat at 8.7 per 1000 patients despite significant increases in imaging and revascularization rates.5 This article discusses the evaluation of patients presenting to the ED with chest pain and suspected ACS. It emphasizes important points of the pathophysiology, patient history, and physical examination, as well as clinical findings related to ACS. It will also discuss recommendations regarding ordering cardiac troponin (cTn) and the use of advanced noninvasive testing in this patient population. PATHOPHYSIOLOGY
The term ‘acute coronary syndrome’ refers to any condition that is brought on by a sudden reduction in blood flow to the heart. It represents a spectrum of clinical conditions including unstable angina, non–ST-segment elevation MI (NSTEMI), and STEMI. Unstable angina is characterized by an unstable pattern of ischemic cardiac discomfort without increased cTn levels or ST-segment elevation on the electrocardiogram (ECG). It may or may not present with horizontal or down-sloping ST depression or dynamic T-wave changes on the ECG. NSTEMI is characterized by increased cTn levels. It too may or may not present with evidence of ischemia on the ECG. STEMI is characterized by ST-segment elevation on the ECG owing to transmural (full-thickness) necrosis of the myocardial segment(s) involved. cTn may be negative in the early stage of STEMI because cell lysis and release of intracellular components into the bloodstream do not occur immediately upon myocardial cell death. AMI is defined by a 20% increase and/or decrease in cTn (I or T), the preferred myocardial biomarker, with 1 value exceeding the 99th percentile upper reference limit (URL) of a normal population.6 MI can result from a variety of clinical conditions and the etiology of AMI is important to differentiate because it significantly affects patient management. The Third Universal Definition of MI specifies 5 types (Table 1).6 For the purposes of patient evaluation and management, it is best to classify MI into 2 broad categories: (1) MI owing to acute coronary artery thrombosis or (2) MI not owing to acute coronary artery thrombosis, the causes of which are extensive (Box 1). The backbone of treatment for patients in the first category is administration of antiplatelet and anticoagulation therapy with or without percutaneous coronary intervention (PCI), which is intended to stabilize the process of acute thrombosis and restore coronary flow. Treatment for patients in the second category is directed at treating the underlying condition responsible for causing oxygen supply/demand imbalance or other myocardial injury (volume resuscitation, presser support, and antibiotics for patients in septic shock). Coronary artery thrombosis is caused usually by either atherosclerotic plaque rupture or plaque erosion. In each case, there is a loss of integrity in the protective covering over an atherosclerotic plaque, formed by a single layer of endothelial cells, thus exposing the thrombogenic components of the necrotic core to the bloodstream.7 The resulting intracoronary thrombus is composed of platelet aggregates layered with fibrin, red blood cells, and acute inflammatory cells.7 Plaque rupture or erosion often occurs at sites without significant luminal stenosis. One study of 3747 patients in the National Heart, Lung, and Blood Institute Dynamic Registry undergoing PCI found that 216 (5.8%) required additional PCI of the
Chest Pain Evaluation in the Emergency Department
Table 1 Universal classification of MI Type
Description
Type 1: Spontaneous MI
Related to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus; patient may or may not have underlying obstructive CAD.
Type 2: Ischemic imbalance
Oxygen supply cannot meet myocardial oxygen; owing to any condition that affects this relationship including tachycardia, hypotension, severe hypertension with or without LVH, tachyarrhythmias/bradyarrhythmias, anemia, acute bleeding, respiratory failure, or CHF; patient may or may not have underlying obstructive CAD.
Type 3: MI before biomarker evidence of cell death
Symptoms suggestive of AMI and new ischemic ECG changes before biomarker conversion such as in the early phase of STEMI.
Type 4a: Owing to PCI
Troponin rise >5 99th percentile URL in patients with normal baseline values (and no concern for AMI before PCI) or a rise of troponin >20% if the baseline values are elevated and are stable or falling.
Type 4b: Stent thrombosis
Evidence of stent thrombosis with an increase and/or decrease of cardiac biomarkers with 1 value >99th percentile URL.
Type 5: Owing to CABG
Cardiac biomarker increase >10 99th percentile URL in patients with normal baseline values.
Abbreviations: AMI, acute myocardial infarction; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CHF, congestive heart failure; ECG, electrocardiogram; LVH, left ventricular hypertension; MI, myocardial infarction; PCI, percutaneous coronary intervention; STEMI, STsegment elevation myocardial infarction; URL, upper reference limit.
nontarget lesion within 1 year of follow-up for new clinical symptoms.8 Although the degree of obstructive CAD during initial PCI was a strong predictor of future events, the majority of new lesions were less than 50% in severity at the time of the initial PCI.8 The fact that ACS often occurs at sites without significant luminal stenosis is probably 1 explanation for why contemporary PCI trials in patients with stable CAD have not prevented future MI compared with medical management alone. The “vulnerable plaque” theory identifies several important features of plaque morphology associated with increased odds of rupture and ACS. In 1 study of 1059 patients undergoing coronary CT angiography, the combination of positive remodeling and low-attenuation plaque was associated with a 22% risk of ACS over a mean follow-up of 27 months, whereas 1 feature alone was associated with a 3.7% risk and those with no features a 0.5% risk.9 Stable angina is not on the spectrum of ACS and is not considered a medical emergency. Stable angina is most often owing to intracoronary stenosis; however, it can be owing to other processes that compromise coronary flow, such as diastolic dysfunction. Ischemic discomfort follows a stable pattern, often remaining unchanged for months or years at a time, and is caused by the predictable mismatch in myocardial oxygen supply and demand that occurs with exertion and goes away promptly with rest or nitroglycerin. A recent study from a registry of patients with stable CAD found that those with stable angina and evidence of ischemia had a 4% risk of cardiovascular death, MI, or stroke over 2 years of follow-up.10 True stable angina is rarely encountered in the ED. In the Internet Tracking Registry of Acute Coronary Syndrome (i*trACS) registry only 1% of chest pain patients were
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Box 1 Causes of increased troponin not related to intracoronary thrombosis Injury related to supply/demand imbalance of myocardial tissue Tachyarrhythmias/bradyarrhythmias Aortic dissection or severe aortic valve disease Hypertrophic cardiomyopathy Cardiogenic, hypovolemia, or septic shock Severe respiratory failure Severe anemia Hypertension with or without left ventricular hypertension Coronary spasm Coronary embolism or vasculitis Coronary endothelial dysfunction without significant coronary artery disease Injury not related to myocardial ischemia Cardiac contusion, surgery, ablation, pacing, or defibrillator shocks Rhabdomyolysis with cardiac involvement Myocarditis Cardiotoxic agents (e.g., anthracyclines, herceptin) Multifactorial or indeterminate myocardial injury Heart failure Stress (Takotsubo) cardiomyopathy Severe pulmonary embolism or pulmonary hypertension Sepsis and critically ill patients Renal failure Severe acute neurologic diseases (e.g., stroke, subarachnoid) Hemorrhage Infiltrative diseases (e.g., amyloidosis, sarcoidosis) Strenuous exercise
found to have stable angina.4 Although stable angina is best treated by a cardiologist in the outpatient setting, it is recommended that providers err on the side of caution and consider most cases of characteristic angina in the ED setting as unstable. In conclusion, ACS presents as a range of clinical conditions caused by a sudden reduction in blood flow to the heart. AMI is defined by myocardial cell death that manifests as a rise or fall of greater than 20% in cTn with at least 1 value exceeding the 99th percentile URL. It is important to determine whether the etiology of AMI is owing to acute intracoronary thrombosis or another cause of myocardial injury, because this information directs appropriate patient management. PATIENT HISTORY AND PHYSICAL
A thorough history forms the cornerstone of diagnosis for patients who present to the ED with chest pain. In a prospective cohort study of all consecutive patients newly
Chest Pain Evaluation in the Emergency Department
admitted from the ED to 1 academic department of medicine over a 53-day period, researchers found that history alone was the most important modality in patients who were diagnosed correctly based on initial clinical data available on admission.11 A high-quality history enables the physician to form a pretest probability of disease. Once this is established, the predictive value of additional findings and tests can be interpreted correctly. Inadequate or inaccurate history taking and failure to appreciate the role pretest probability plays in diagnosing any particular condition exposes the physician to important cognitive biases, which can lead to disproportionate estimates of frequency and faulty Bayesian reasoning.12 The differential diagnosis of chest pain is broad. The Internet Tracking Registry of Acute Coronary Syndrome (i*trACS) is a multicenter registry of undifferentiated ED patients with suspected ACS that includes 15,608 patients, with 17,713 visits.4 Chest pain was the chief complaint in 71% of visits. “Chest pain not otherwise specified” and “other” represented the most common final diagnoses (70%), followed by unstable angina (6.3%), congestive heart failure (4.0%), STEMI (1.6%), pneumonia (1.5%), stable angina (1.2%), NSTEMI (1.0%), pulmonary embolism (PE; 0.4%), pericarditis (0.3%), and dissecting aneurysm (0.1%). Chest pain characteristics and related symptoms that are associated with increased odds of AMI include pain radiation to both arms (likelihood ratio [LR] 7.1), to the right shoulder (LR, 2.9), to the left arm (LR, 2.3), chest pain as the most important symptom (LR, 2.0), association with diaphoresis (LR, 2.0), and association with nausea or vomiting (LR, 1.9).13 It should be noted that nausea and vomiting as an isolated symptom(s) is not a predictor of AMI; however, patients with AMI will on rare occasion present with only gastrointestinal complaints. A recent multicenter observational study of 2475 consecutive patients presenting with acute chest pain to the ED found that chest pain aggravated by exertion and chest pain relieved with nitrates also increased the likelihood of AMI.14 Physical examination findings that are associated with increased odds of AMI include a third heart sound on auscultation (LR, 3.2), hypotension with systolic blood pressure of 80 mm Hg or lower (LR, 3.1), and pulmonary crackles on auscultation (LR, 2.1).13 Chest pain characteristics that decrease the probability of AMI are pleuritic chest pain (LR, 0.2), pain that is sharp or stabbing (LR, 0.3), pain that is positional (0 LR,.3), and pain reproduced by palpation (LR, 0.2–0.4).13 Studies that have examined selected cohorts of ACS patients have consistently found chest pain to be the most common presenting symptom. The populationbased MONICA/KORA Myocardial Infarction Registry included 568 women and 1710 men hospitalized with a first-ever AMI.15 Chest pain or feelings of pressure or tightness in the chest were reported in 93.5% of women and 94.2% of men.15 An analysis of the Euro Heart Survey, which included 10,253 patients with a discharge diagnosis of ACS, found that the vast majority of patients (>90%) presented with chest pain, either typical or atypical, and this was true regardless of age or gender.16 Other studies have found small differences in AMI presentation between men versus woman as well as younger versus older patients. In 1 observational study of 1015 patients younger than 55 years who were hospitalized for ACS, chest pain was the most common symptom in both sexes but women were more likely to present without chest pain than men (19% vs 14%, respectively).14 An observational study from the National Registry of Myocardial Infarction, 1994 to 2006, that included 1,143,513 patients found women were more likely than men to present without chest pain and so were older versus younger patients.17 Age was found to be a stronger determinant of different symptoms at AMI presentation than sex.17 It is also commonly taught that diabetic patients are less likely to present with symptoms of chest pain with ACS; however, there is little evidence to support this. McNulty and colleagues18 performed
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coronary balloon occlusion on 100 patients with and without type 2 diabetes and found no difference in the subjective perception of pain between groups; nor were there any differences between men and women. In summary, chest pain is the hallmark of ACS and specific characteristics of the pain significantly increase or decrease the odds of it. When the patient history is consistent with ischemic cardiac discomfort, physicians should retain a high index of suspicion for ACS despite the lack of objective evidence of ischemia. Finally, although slight differences remain in ACS presentation between men and women physicians should not lose sight of the bigger picture: chest pain is the primary symptom associated with ACS. CLINICAL FINDINGS Electrocardiogram
The ECG plays a major role in determining the initial management in patients presenting to the ED with complaints consistent with ACS. The recognition of an STEMI or an “STEMI equivalent” is the first decision point in the management of the patient presenting with an ACS complaint. The 2013 STEMI guidelines refer to a Joint Task Force Definition of MI. It defines diagnostic ST elevation as new elevation measured at the J point of 1 mm or greater (0.1 mV) in 2 contiguous leads, in all leads except V2 and V3.6,19 Given the differences in men and women different levels of elevation are accepted in leads V2 and V3. Abnormal elevation is defined as 2.5 mm or greater in men less than 40 years old, 2 mm or greater in men greater than 40 years old, and 1.5 mm or greater in women.6 Three additional ECG patterns deserve special mention in that they may require emergent reperfusion therapy. These are isolated ST depressions in the anterior leads concerning for transmural posterior MI, prominent “hyperacute T waves” in leads consistent with coronary circulation, and isolated ST elevation in aVR with diffuse ST depression. In a 2010 study of approximately 1200 patients looking at the clinical outcomes of patients presenting with isolated anterior segment depression, 26.2% had an occluded culprit artery with increased serum troponin levels.20 Of these patients, the culprit artery was the left circumflex in 48.4%, the left anterior descending artery in 33.8%, and the right coronary artery in 17.8%.20 Given the limitation of the standard 12-lead ECG for the evaluation of isolated posterior MI, 3 additional posterior leads (V7, V8, and V9) can be used to aid in diagnosis. In a study of 53 patients undergoing cardiac catheterization, the left circumflex artery was purposely occluded and serial recordings of ST deviation were performed. Compared with the standard 12lead ECG, the 15-lead ECG was more often able to detect the presence of any ST elevation of 0.5 mm or greater (odds ratio [OR], 2.6) and 1 mm or greater (OR, 2.2).21 Patients who present very early after acute occlusion of a coronary artery may not yet display ST segment elevation, but rather prominent T waves, often termed hyperacute T waves.22,23 This has been described in the literature in human subjects as early as 1934.24 In a subgroup study of one of the early thrombolytic trials, higher T waves were observed more frequently in patients with a shorter duration of symptoms (2.5 vs 3.3 hours).25 Patients who present with an ECG pattern of ST depression and isolated ST elevation in aVR while not meeting the criteria for acute STEMI are frequently managed with an early invasive strategy owing to the concern for left main or severe multivessel disease.26,27 In a multivariable analysis of NSTEMI patients, 140 of whom met this pattern, those with ST depression and isolated elevation in aVR showed an increased risk of culprit left main disease (OR, 4.7) and in-hospital cardiovascular mortality (OR,
Chest Pain Evaluation in the Emergency Department
5.6) compared with patients without any ST deviation. Patients with isolated ST depression did not demonstrate this risk. Additionally, at 1-year follow-up, ST depression and isolated ST elevation in aVR was a strong predictor of cardiovascular death (hazard ratio, 2.3).27 As mentioned, ST segment depressions can be observed with isolated posterior wall MI and in association with elevation in aVR. ST depressions may also be observed in association with STEMI, termed reciprocal ST change. However, ST segment depression alone may represent subendocardial ischemia. The morphology of ST segment depression that is most consistent with ischemia is horizontal or downsloping. The degree of depression considered significant is 0.5 mm or greater measured at the J point. Both the amount of depression and the extent of depression are associated with an increased risk of death.28,29 In a 2001 study looking at patients who were enrolled in the PARAGON-A study, patients whose presenting ECG had ST depression of 0.2 mm or greater had an OR of 5.7 for death at 1 year.30 Additionally, when those depressions involved more than 1 region, their risk of death increased with an OR of 9.2 compared with no ST segment depression.30 T wave inversions are encountered commonly in patients presenting with ACS. T wave inversion may present alone or with ST segment depression. Significant T wave inversions are generally 1 mm or greater in depth and occur in 2 or more contiguous leads. The prognostic importance of T wave inversion alone is not clear; however, 2 particular patterns of T wave inversion historically portent a high risk of anterior wall MI. This pattern described by de Zwann and colleagues31 in 1982 is referred to as Wellens’ warning. This pattern of either symmetric deep T wave inversion or a sharply biphasic T wave in the anterior precordial leads is treated with an early invasive strategy. Of note, this pattern often occurs after a chest pain episode and may normalize during recurrent pain episodes.31–33 There are many underlying conditions that confound the diagnosis of ACS. The presence of bundle branch blocks, left ventricular hypertrophy, paced rhythms, Brugada syndrome, left ventricular aneurysm, and early repolarization pattern all may have ST segment elevations on the baseline ECG. Similarly, ST depressions may be observed in bundle branch blocks, left ventricular hypertrophy, digitalis effect, and electrolyte abnormalities. Patients presenting with chest pain that is not ACS often have changes on their EGC. There are many ECG abnormalities described in patients with PE; these abnormalities include S1Q3T3, S1S2S3, right bundle branch block, low voltage, and right axis deviation. Additionally, T wave changes that may mimic ACS have been observed. In a study of 80 patients admitted with PE, 68% had an ischemic T wave pattern on their ECG (85% of patients with massive PE and 19% in nonmassive PE).34 In a more recent study of 127 patients, 40 diagnosed with PE and 87 diagnosed with ACS, negative T waves were seen in leads III and V1 in 88% of PE patients compared with only 1% of ACS patients.35 Patients presenting with chest pain owing to pericarditis may demonstrate several different ECG abnormalities. Classically, there is a progression through 4 stages. The first stage with ST segment elevation can be misinterpreted as STEMI. However, unlike STEMI, ST elevation in pericarditis is usually diffuse. Additionally, there may be PR depression identified most often in lead II.36 The opposite findings are observed in aVR in patients with pericarditis with PR elevation and ST depression. Patients with acute aortic dissection often have EGC changes that are consistent with myocardial ischemia or may present with clear ST elevation. In a recent study of 233 patients diagnosed with Stanford type A acute aortic dissection, approximately 50% of patients had ST–T wave changes (4% with ST elevation, 47% with ST
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depression and/or negative T waves).37 Patients in this study with ST–T wave changes had a poorer clinical condition and subsequent higher mortality when compared with patients who had normal or no significant ST–T changes on admission.37 In conclusion, the ECG is integral in the evaluation of the patient with suspected ACS. The patient’s presentation and risk factors for ACS as well as for other nonACS causes of chest pain should be interpreted in conjunction with the ECG to avoid misdiagnosis. Cardiac Troponin
cTn is the preferred biomarker for diagnosing AMI because of its superior sensitivity and specificity for detection of myocardial necrosis. It is an important part of the myocardial contractile apparatus and is released into the bloodstream, over time (from 30 minutes to 12 hours) after cardiomyocyte death.6 AMI is defined by an increase or decrease of greater than 20% in cTn with at least 1 value exceeding the 99th percentile URL. It must be kept in mind that despite the high specificity of cTn for myocardial necrosis, it is not specific for the cause of injury. Maag and colleagues38 found that in a large, undifferentiated cohort of patients who underwent cTn testing in the ED that when “chest pain” was not the chief complaint, an elevated cTn that met the definition for AMI was unlikely to be owing to type I MI (20%). However, when “chest pain” was the chief complaint, nearly all patients with an elevated cTn had a type I MI (OR, 7.3).38 Because this is an article on the evaluation of chest pain, we will not belabor this point. It suffices to say that, when chest pain is not the chief complaint, caution should be exercised in ordering cTn and interpreting the result. Physicians should be aware of the 99th percentile URL for the cTn assay used in their hospital because all cTn assays have different URLs. Ideally, a cTn assay should have a coefficient of variation of less than 10% above the 99th percentile URL. Levels below the 99th percentile URL are often reported. Failure to appreciate this concept could lead physicians to misinterpret normal cTn levels as significant elevations. Therefore, physicians must familiarize themselves with the performance characteristics of the cTn assay used in their laboratories. Serial measurements of cTn are necessary when cTn concentration is not elevated on admission because cTn may not be detectable in the blood within the first hours after myocardial injury.39 When myocardial ischemia is suspected and cTn is not initially detected, the current standard of care in the United States calls for a cTn to be drawn again in 6 to 9 hours, although precise timing is not defined. If the index of suspicion is high then a third sample should be drawn in 12 to 24 hours.39 IMAGING AND ADDITIONAL TESTING
In 2007, the American College of Cardiology and American Heart Association produced guidelines for the management of patients with unstable angina and NSTEMI. This report was developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society for Thoracic Surgeons.39 It was also endorsed formally by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. It states that, In patients with suspected ACS in whom ischemic heart disease is present or suspected, if the follow-up 12-lead ECG and cardiac biomarkers measurements are normal, a stress test (exercise or pharmacological) to provoke ischemia should be performed in the ED, in a chest pain unit, or on an outpatient basis in a timely
Chest Pain Evaluation in the Emergency Department
fashion (within 72 h) as an alternative to inpatient admission. Low-risk patients with a negative diagnostic test can be managed as outpatients. It was given a class I recommendation, meaning the “benefit >>> risk” and “procedure/treatment SHOULD be performed/administered.” However, it was also assigned a level C for estimate of certainty of treatment effect, meaning there is little if any evidence to support it outside of expert opinion. This recommendation has not been updated with the exception of a 2010 scientific statement from the American Heart Association, which adds that anatomic assessment, meaning coronary CT angiography, could be performed in place of stress testing.40 Despite these recommendations, significant questions remain with the most important being; Does our current practice improve patient outcomes? Several retrospective studies suggest the answer is “no.” Chan and colleagues41 performed a prospective cohort study on 832 consecutive patients who presented to a single ED with chest pain and were admitted to a non–intensive care telemetry bed over a 16-month period. Thirty-one percent of patients received either an inpatient or outpatient stress test in the form of exercise electrocardiography. At baseline, there were no differences between patients who received stress testing or not in respect to demographics, risk factors, risk scores (Acute Coronary Ischemia–Time Insensitive Predictive Instrument [ACI-TIPI] and Goldman), or specific clinical features of the chest pain, including location, quality, or associated symptoms.41 The authors found that more than 30 days of follow-up the overall rate of AMI among the cohort was low (
