Curr Treat Options Cardio Med (2016) 18:62 DOI 10.1007/s11936-016-0484-4

Imaging (Q Truong, Section Editor)

Coronary CT Angiography in the Emergency Department: Current Status Kavitha M. Chinnaiyan, MD, FACC* Gilbert L. Raff, MD, FACC Address * Department of Cardiology, William Beaumont Hospital, 3601 W. 13 Mile Road, Royal Oak, MI, 48073, USA Email: [email protected]

* Springer Science+Business Media New York 2016

This article is part of the Topical Collection on Imaging Keywords Imaging I Acute chest pain I Acute coronary syndrome I Coronary CT angiography

Opinion statement Acute chest pain (ACP) represents a clinical as well as economic challenge, often resulting in time-consuming, expensive evaluations to avoid missed diagnosis of acute coronary syndromes (ACSs). Coronary CT angiography (CTA) is an attractive noninvasive technique for use in the emergency department (ED) due to its high accuracy and negative predictive value. Recent studies have demonstrated that coronary CTA can aid in safe, rapid, and cost-efficient triage of these patients. Additional applications of plaque characterization, fractional flow analysis, and CT perfusion imaging hold promise in providing incremental data in patients with suspected ACS. In this review, we examine the data for the use of coronary CTA in acute chest pain, novel applications of the technology, and best practice for its use in the ED.

Introduction The 2011 National Hospital Medical Care Survey from the Centers for Disease Control and Prevention reported that 5.8 % of over 136 million emergency department (ED) visits in the USA were for acute chest pain (ACP) [1]. Of all patients presenting to the ED with ACP, nearly 75 % are diagnosed with non-cardiac or non-ischemic cardiac problems and less than 20 % of the remaining meet the criteria for acute coronary syndromes (ACSs) [2–4]. Increasing rates of obesity, diabetes, high-fat dietary changes, and an aging demographic profile

worldwide led to a rising prevalence of coronary artery disease (CAD) presenting to the ED [5]. The challenge for physicians caring for patients with acute chest pain is the accurate and efficient triage of the minority of patients with ACS or other potentially fatal conditions, while safely and economically handling the large numbers of patients in need of seemingly urgent attention. ED crowding per se has been associated with increased adverse outcomes for ACP patients, and consequently, more rapid triage has both health and economic

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consequences [6]. Frequently, these patients are admitted to the hospital or specialized (Bchest pain^) units for extended observation with various diagnostic strategies including serial EKGs, cardiac enzymes, and often, noninvasive stress testing [7–12]. Even with an approach of extensive testing at such high costs, 2–8 % of patients have a missed diagnosis of ACS or are inappropriately discharged home with a

doubling of mortality and risk for litigation [13, 14]. Thus, a safe, rapid, and accurate testing modality that can detect the presence of coronary artery disease (CAD) in patients with acute chest pain and facilitate clinical decision-making is highly attractive. This review will examine the role of coronary CT angiography (CTA) in acute chest pain, its challenges and drawbacks as well as future directions for its use.

Accuracy of coronary CTA in acute chest pain CT technology has rapidly evolved since the early 2000 to its current standing as the most sensitive noninvasive test for detection of CAD. With a spatial resolution of ≤0.6 mm and 64–320 slices, state-of-the art technology enables the evaluation of coronary arteries in most patients without limiting artifacts. The accuracy of coronary CTA for assessing the presence and severity of coronary atherosclerosis compared to invasive coronary angiography (ICA) has been reported in over 30 published studies encompassing more than 2000 patients [15]. Compared to other noninvasive modalities, coronary CTA with contemporary generation scanners has the highest sensitivity (99–100 %) in reference to ICA as the gold standard [16]. With the present scanner technology, the probability of detecting any CAD is greater than 90 % if the maximal internal thickness of the plaque is determined to be 91 mm on intravascular ultrasound [17]. A meta-analysis of the accuracy of coronary CTA to detect ACS in patients with chest pain (9 studies, N = 1349) demonstrated a sensitivity of 95 % and specificity of 87 % [18]. The absence of coronary atherosclerosis on coronary CTA results in a negative predictive value close to 100 %. These data have resulted in a Class IIa, Level of Evidence B recommendation for the use of coronary CTA in patients with acute chest pain with low-to-intermediate pretest likelihood of ACS and inconclusive initial EKG and biomarkers [19]. However, the presence of significant stenosis has only moderate diagnostic accuracy for ACS since the clinical presentation of an acute event may not always be associated with a stenotic lesion [20]. The low positive predictive value of significant stenosis on CTA can be improved with the evaluation of plaque morphology, myocardial perfusion, or left ventricular function [20].

Coronary CTA versus standard of care in the ED A large body of evidence has been published supporting early coronary CTA as a rapid, accurate, safe, and efficient diagnostic strategy in the triage of low-tointermediate-risk ACP patients in the ED [19–22]. Based on the premise that coronary CTA facilitates rapid triage of patients with acute chest pain, several randomized controlled studies were designed to examine the efficiency and safety of this approach compared to standard of care. In these studies conducted across 4–16 US sites, 10–15 % of patients presenting to the ED with chest pain were enrolled and clinical decisions were made by referring caregivers.

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The CT-STAT trial randomized 749 low-risk patients to coronary CTA or to standard of care with stress myocardial perfusion imaging (MPI) [21]. Compared to those in the MPI arm, patients undergoing coronary CTA as the first test had a significantly shorter time to diagnosis (2.9 vs. 6.2 h, p G 0.0001). Importantly, both approaches were equally safe, with similar rates of major adverse cardiac events (MACE) in those with normal index tests (0.8 vs. 0.4 %, p = 0.29). The ACRIN study randomized 1392 patients (TIMI risk scores of 0–2) to coronary CTA or traditional care (with or without stress testing), with safety as the primary outcome [22]. All patients were low-risk, with 0 % adverse event rate among the 640 patients with negative coronary CTA. Patients undergoing coronary CTA had nearly 2-fold rate of direct ED discharge (49.6 vs. 22.7 %, p G 0.0001), with significantly shorter lengths of stay (18 vs. 24.8 h, p G 0.001). CAD was diagnosed more frequently in the CTA group compared to the traditional care group (9 vs. 3.5 %). The ROMICAT II trial randomized 1000 patients with ACP to coronary CTA or standard ED evaluation, with the intent to determine if the former would result in decreased hospital length of stay. Patients in the CTA arm had significantly shorter lengths of stay (23.2 vs. 30.8 h, p = 0.001), almost 3-fold higher rate of direct discharge from the ED (46.7 vs. 12.4 %, p = 0.001) and significant reduction in time to diagnosis (10.4 vs. 18.7 h, p = 0.0001). Other studies have demonstrated that a coronary CTA-based triage is more cost-effective compared to other strategies for triage, such as stress echocardiography [23]. CT-STAT and ROMICAT II also examined the cost-effectiveness of coronary CTA in the ED. In CT-STAT, a nearly 40 % reduction in total ED costs was noted in the CTA arm. In ROMICAT II, the 18 % reduction in ED costs were compensated by increased costs during hospitalization, driven by the finding of obstructive CAD on CTA. It remains unclear if the increased coronary revascularizations resulting from initial CTA leads to improved long-term outcomes. In summary, these three large multicenter, randomized controlled studies demonstrated that in low-to-intermediate-risk patients with ACP, use of coronary CTA is safe and results in shorter length of stay and shorter time to diagnosis.

Prognostic value of coronary CTA The presence of subclinical atherosclerosis is known to be the strongest predictor of cardiac events [24, 25]. Coronary CTA has the distinct advantage of detection of subclinical CAD compared to other noninvasive imaging modalities. Several studies have examined the prognostic value of coronary CTA in ACP, demonstrating that patients without CAD are event-free over a 2-year follow-up period [26]. In ROMICAT I, patients with obstructive disease had a high risk of adverse events over a 2-year follow-up period of nearly 30 %. While patients no CAD on CTA have no events during intermediate-term follow-up, patients with nonobstructive disease have a slightly increased risk of nearly 5 % (ROMICAT I). Similarly, a CTA-based triage in the ACRIN-PA study did not result in increased resource utilization during a follow-up period of 1 year. Moreover, negative CTA results at the time of ED triage resulted in G1 % MACE rate [27]. Although several studies have examined the prognostic value of coronary CTA in patients with or without known coronary disease [24, 28],

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Curr Treat Options Cardio Med (2016) 18:62 comparative studies of long-term outcomes in large ED populations triaged via different approaches has not been evaluated.

BTriple rule out^ protocols in the ED The acquisition of three-dimensional from the entire thorax within the field of view results in the possibility of ruling out the three most potentially fatal causes of chest pain: CAD, acute aortic disease, and pulmonary embolism. Coronary CTA is useful to detect non-cardiac findings that could explain presenting symptoms in nearly one in six patients without CAD [29]. Specialized Btriple rule out^ protocols employ the use of a tri-phasic contrast injection and a caudal-cranial or cranial-caudal (or in succession) acquisition with a wider scan length to include the aortic arch. Such an acquisition results in excellent contrast opacification of the three vascular beds in question: the pulmonary and coronary arteries and the aorta [30–32]. Triple rule out protocols can be useful in clinical scenarios where more than one of the Bbig three^ diagnoses may be equally likely. In such situations, such expedited protocols may intuitively decrease time to diagnosis, costs, and cumulative radiation dose. However, such clinical situations must be assessed on a case-by-case basis since these protocols are associated with significantly higher radiation and contrast doses. Considering the very low yield of occult pulmonary or aortic disease when compared to coronary CTA studies, routine use of triple rule out scans in patients with ACP without specific clinical is not recommended [33–36]. Comparative effectiveness research is much needed in the arena of triple rule out cardiac CT scans. Until further evidence, it remains as an Buncertain^ indication in the current appropriate use criteria for cardiac CT [19].

Challenges in ED triage: beyond stenosis degree Having the ability to detect CAD is an excellent clinical advantage. However, what the results mean for a patient and the caregiver in terms of preventive measures can be an accompanying challenge due to the complex pathophysiology of ACS. In general, there are two pathways for the development of ACS. In the first, ACS is the result of progressive luminal narrowing due to plaque progression, resulting in an oxygen supply-demand mismatch in the myocardium. The luminal narrowing is considered significant if greater than 70 %, although neither the oxygen supply-mismatch nor patient outcomes depend solely on it [37]. Therefore, in the ED, when Bsevere disease^ (970 % stenoses) is demonstrated on coronary CTA, the clinical pathway is clear. Hospital admission and/or further invasive or noninvasive work-up are warranted. Similarly, in the absence of any atherosclerosis on coronary CTA, the disposition is also clear. In these situations, the etiology for the patient’s symptoms is not ACS, and if other serious diagnoses have been considered and excluded, immediate discharge is appropriate [38]. Triage decisions in the ED are not as clear in patients with intermediate disease noted on CTA, i.e., stenosis in the 25–70 % range. This has to do with the second pathway for ACS, where luminal narrowing is the result of rupture or erosion of a n u nderlying atherosclero tic plaqu e [ 3 9] . S e v e ra l

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pathophysiological mechanisms are proposed for the vulnerability of a plaque for rupture, including inflammation. Vulnerable plaques are at high-risk for the clinical presentation of ACS and consist of characteristic morphologic features such as a large necrotic lipid core, small calcified nodules and a thin fibrous cap [40]. High-risk plaques are usually associated with high overall atherosclerotic burden, but not always associated with severe stenosis. In up to 20 % of ACS events, no significant stenosis is noted on ICA [41].

Plaque assessment by coronary CTA A distinct advantage of coronary CTA is the potential to identify highrisk plaques in both obstructive and nonobstructive lesions. In addition to differentiating calcified from non-calcified plaques, CTA can detect low attenuation (G30 HU), positive vessel remodeling and spotty calcifications with excellent correlation to intravascular imaging as well as histology. Positive remodeling and low attenuation are particularly useful in classification of plaques as high-risk for ACS [37, 38] (Fig. 1). Other high-risk plaque features that have been identified are ulceration and intra-plaque dye penetration, with excellent correlation with invasive angiography. The ROMICAT II study demonstrated that independent of angiographic assessment of stenosis severity and clinical risk evaluation, high-risk plaque features on CTA increased the likelihood of ACS. Large-

Fig. 1. A Btwo-feature positive^ atherosclerotic plaque with low attenuation and positive remodeling seen on coronary CTA (a, b) and invasive coronary angiography (c) in the left anterior descending artery in a patient with acute chest pain.

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Curr Treat Options Cardio Med (2016) 18:62 scale studies are required to investigate the role of plaque assessment in the ED diagnostic pathways.

Contemporary practice of coronary CTA for acute chest pain In this section, we describe the practical implementation of the 2014 SCCT Guidelines on the use of CTA for Patients Presenting with ACP to the ED [42••], the multi-society 2015 Appropriate Utilization of Cardiovascular Imaging in ED Patient with Chest Pain [43••], and with the clinical experience since 2004 at Beaumont Health System. Our institution currently performs approximately 1500 CTA examinations annually on ED patients with ACP. Coronary CTA has several important limitations that affect its usefulness in the triage of ED patients with ACP. The advent of newer CT technology has resulted in major breakthroughs in scanning protocols, radiation dose, and resolution of artifacts. However, the lack of availability of up to date scanning equipment may require additional attention to patient preparation and choosing appropriate protocols. Radiation exposure is a significant consideration of coronary CTA use with a non-negligible lifetime attributable risk of cancer. The risk of exposure should be weighed against potential benefits, especially in sensitive populations such as women under 45 years of age. Significant technological advances over the last few years have resulted in exponential decrease in total radiation exposure from cardiac CT [44]. Conscientious and meticulous patient preparation to lower heart rate, ECG dose-modulation, lowered tube voltage, prospective gating, and use of newer technology such as the high-pitch or 320-slice (single heart-beat acquisitions) have resulted in 970 % dose reduction since the early and evolving application of CT for coronary angiography [44].

Patient selection Approximately 20 % of ACP patients are suitable for CTA evaluation. The research trials previously cited focused on patients with low-tointermediate pretest likelihood of ACS. While high-risk patients are considered to have Buncertain^ appropriateness by the 2010 AUC [45], our practice is to discourage use of CTA in these patients, primarily due to concern that CTA will not be definitive or will delay urgent therapy in patients with definite ACS. Therefore, all patients must have history, physical, EKG, and initial troponin without evidence of ACS. The concern about patients with high-pretest likelihood without ACS is that CTA is likely to reveal multiple anatomic abnormalities, and it will require functional evaluation either with stress testing or invasive evaluation to define whether the lesions seen are causative or Binnocent bystanders^ to chest pain caused by other pathology. Due to its high sensitivity and negative predictive value, coronary CTA is most useful in patients in whom a binary decision of whether CAD is present is likely to encourage early ED discharge. Therefore, prior coronary stents, bypass grafts, myocardial infarction, or other evidence of definite CAD usually precludes the use of CTA as a primary diagnostic strategy. That said, in selected instances, cardiologists may decide to use CTA specifically to

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define the patency of grafts or stents, realizing that native vessel anatomy is likely to show lesions that may require further work-up. Further selection considerations revolve around patient safety and image quality. Patients with renal dysfunction or pregnancy, inability to tolerate beta-blockers, atrial fibrillation or markedly irregular rhythm or definite serious contrast allergy, inability to cooperate with breath holding, or extreme obesity represent reasons to defer CTA. The scanner hardware temporal resolution is an important consideration; for example, our institution has the means to successfully image irregular heart rates, but this may not be possible or practical with other scanners. Women of childbearing age with atypical symptoms must be carefully considered for coronary CTA given its risk of radiation exposure.

Patient preparation and scan protocoling Successful implementation of CTA in the ED requires an experienced team to prepare the patient, as this phase is critical to a high rate of interpretability and acceptable median radiation doses. A common hurdle to the use of coronary CTA in ACP patients is inadequate heart rate control prior to the scan; prolonged preparation time in the real-world setting can result in much longer time to diagnosis compared to published studies. Additionally, because ECG-gating is critical to coronary imaging, any arrhythmias, ectopy, or ECG artifacts may result in degradation of image quality. The high doses of beta-blockers (100 to 200 mg of oral metoprolol, supplemented by intravenous doses of 15– 30 mg as needed) used to lower heart rates require experienced nurses or physician evaluation and monitoring. It was common in the early years of our experience to have patients prepped with 25 mg orally or 15 mg intravenously by ED nurses, resulting in hours of delay or image inadequacy. Currently, we have an experienced radiology nurse supervising all patient preparation who advises nurses in the ED about particular cases. These nurses are backed up by the interpreting physician on call, who is available to guide preparation and protocoling difficult cases. It is vitally important to inform patients of the typical sensations during an examination and the strict requirement to avoid breathing or other motion. Breathing instructions should be practiced just before the examination. The target heart rate is driven primarily by the temporal resolution of the scan hardware that is available and will range from mid-50 to mid70 beats/min depending on the scanner model. Our institution uses a standard order set included in our electronic medical record that is automatically generated whenever a coronary CTA is ordered. In general, even patients with heart rates of low 60 s will receive 100 mg of oral metoprolol to suppress a surge in the heart rate with contrast administration. All patients receive nitroglycerin unless specific contraindications exist. Scan protocols routinely use prospective-triggering for patients at target heart rates. This is the most robust low-radiation scan mode. Irregular and high heart rates demand retrospective EKG-current

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Curr Treat Options Cardio Med (2016) 18:62 modulation, often with a Bwide^ window of 40–80 % of the R-R cycle length. Obesity increases radiation scatter within the patient’s body and consequently degrades image quality due to a reduction of the signalto-noise ratio, diminishing the diagnostic accuracy of coronary CTA. Patient selection according to body habitus will vary based upon available scanner technology. Recent technical advances have enabled obtaining diagnostic quality images in the obese [46].

Interpretation, reporting, and patient management It is important for credentialed interpreting physicians to have considerable experience in real-world non-emergent CTA prior to initiating independent interpretation and management of acutely ill patients. As previously mentioned, interpreting physicians must be available for preparing and protocoling of difficult cases whenever patients are scanned, thus scanning is not done on shifts when physicians are not available. Our ED service operates 12 h per day (8 a.m.–8 p.m.). During night hours, patients are selected and prepped but scanning is only initiated when interpreting physicians are available. In our institution, a cloudbased workstation platform is used by physicians outside the hospital on evenings and weekends. This has proven to be safe and reliable for over a decade. A standardized template for interpretation is available in our electronic medical record, and its use is encouraged. Our standards include interpretation and reporting all coronary segments and quantitative stenosis grading using the quartile system recommended by the SCCT Guidelines as further modified by the new Coronary Artery DiseaseReporting and Data Systems expert consensus document [47••, 48]. Lesions may be described in detail as to the degree of calcification and the presence of lesion complexity in terms of lucency, positive remodeling, spotty calcification, Bnapkin ring^ configuration, and plaque erosion or ulceration, as these findings have important clinical implications beyond stenosis grade. However, it should be noted that it is important to communicate and educate referring physicians who may not be familiar with CT terminology such as positive remodeling, spotty calcification, and Bnapkin ring^ configuration and management of such CT findings in the context of nonobstructive disease. Our institution requires reporting ED CTAs as a STAT procedure with a turnaround time within 1 h of scan completion. ED staff is called about all results, including the finding of no CAD. One aim is to maximize the efficiency of discharge of normal or mildly abnormal patients, but such communication improves the management of patients with abnormal results. The understanding of CTA findings is highly variable among ED staff and referring physicians in general. Terms such as Bmoderate^ stenosis are of little use alone, prompting the need for numerical scoring such as 50–69 % stenosis, but even such precision results in widely varying management results unless verbally communicated. This is even truer of lesion morphology and complexity. Thus, management discussion between referring ED staff and interpreting

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physicians is particularly encouraged. Non-coronary cardiac and noncardiac findings should be included in the body of the report, with particular attention to those that might explain the patient’s presenting symptomatology, for example, aortic dissection, pericardial effusion, pulmonary embolus, and pneumonia. At our institution, CTAs are over-read by radiologists for non-cardiac findings.

Future directions: assessing hemodynamic significance of coronary stenoses An important consideration of coronary CTA, particularly relevant in the ED, is that it delineates only anatomy, and can therefore only infer the impact of any given luminal narrowing on coronary blood flow. Anatomical assessment of the coronaries is most clinically reassuring when the vessels are normal or have minimal disease, and may reliably predict the physiological significance of very severe stenoses. However, anatomic data by itself is limited in assessing the physiological significance of stenoses of Bintermediate severity^ (25–70 % diameter stenoses). Recent post hoc analyses of the FAME study data have shown poor correlation between perceived angiographic percent stenosis and confirmed hemodynamic significance via fractional flow reserve [49]. Thus, whether such anatomically defined lesions are responsible for symptoms, or are Binnocent bystanders^ requires adjudication by physiological determination of coronary blood flow [50]. Fractional flow reserve (FFR) by application of computational fluid dynamics to standard scans has recently been shown to be of value in patients with ambiguous findings on coronary CTA (Fig. 2). A recent meta-analysis of three large FFRCT trials demonstrated its superior specificity compared to CTA alone, with a shift in the area under the receiver operating curve from 0.742 to 0.891 [27]. In the PLATFORM trial, 61 % of scheduled ICA procedures were canceled after the FFRCT results were made available to referring physicians [28]. Thus, FFRCT may be of particular promise in selecting appropriate patients for ICA while detecting nonobstructive disease for preventive measures, though at this time is not feasible for ED patients given the 1- to 2-day turnaround time. Functional imaging with CT perfusion (CTP) is another area of immense research. Dynamic perfusion scanning is the most clinically favorable technique, where the inflow and outflow of the contrast in the left ventricle is assessed [51]. In patients with stenosis that is in the intermediate range, CTP increases the specificity to 89 % from 69 % by CTA alone [52]. However, CTP results in higher radiation dose compared to FFRCT that does not require additional image acquisitions. The prospective multicenter CREDENCE study [53] designed to test CTA against stress testing using invasive FFR as the gold standard will combine stenosis severity, plaque characteristics, and FFRCT results along with measures of functional testing to determine the totality of information from each test type to diagnosis hemodynamically significant CAD. Similar to FFRCT, CTP is not clinically feasible for the ED cohort at this time.

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Fig. 2. A comparison of two patients with similar proximal left anterior descending artery proximal lesions, but with very different FFRCT findings. In the first patient (a), coronary CTA showed a 50–70 % proximal LAD stenosis and the FFRCT value was 0.71, suggesting that the stenosis was flow-limiting stenosis with FFRCT of 0.71 in the LAD and 0.72 in the diagonal. There is an immediate transition from blue to red on FFRCT. The patient underwent successful percutaneous revascularization. In the second patient (b), coronary CTA showed remarkably similar anatomy to the previous example with a 50–70 % proximal LAD stenosis and a 25–49 % distal stenosis. In this case, however, the FFRCT result was 0.84 in the LAD, and the patient was discharged without further testing.

Conclusions Coronary CTA has revolutionized the evaluation of low-to-intermediate-risk patients with ACP with decreased time to diagnosis, length of stay, and expedited triage in the ED. Coronary CTA-based triage results in efficient

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downstream resource and cost utilization. Novel technologies to assess hemodynamic significance of intermediate-severity lesions on coronary CTA may further expedite time to diagnosis, avoiding unnecessary downstream testing. Plaque characterization on coronary CTA moves the field beyond stenosis degree to identify vulnerable patients and to implement preventive measures. Although this technology holds great promise, the risk of radiation exposure must be carefully considered in patient selection.

Compliance with Ethical Standards Conflict of Interest Kavitha M. Chinnaiyan and Gilbert L. Raff declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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