- Email: [email protected]
Usefulness of Computed Tomographic Coronary Angiography in Patients With Acute Chest Pain With and Without High-Risk Features
Usefulness of Computed Tomographic Coronary Angiography in Patients With Acute Chest Pain With and Without High-Risk Features Benjamin J.W. Chow, MDa,c,*, Phil Joseph, MDa, Yeung Yam, BSca, Malek Kass, MDa, Li Chen, MScb, Rob S. Beanlands, MDa,c, and Terrence D. Ruddy, MDa,c The accuracy of 64-slice computed tomographic coronary angiography (CTA) and its ability to direct revascularization in patients with acute chest pain syndrome (ACPS) was investigated. A total of 107 patients with ACPS presenting to the emergency department and referred to cardiology were prospectively enrolled and underwent CTA. From the clinical features, the patients were categorized as having high-risk acute coronary syndrome features or no high-risk features. At the treating physician’s discretion, the patients underwent risk stratification with either invasive coronary angiography (ICA) or technetium-99m single photon emission computed tomography. All tests were interpreted by experts unaware of the clinical information. All 52 patients with high-risk acute coronary syndrome features underwent ICA. Of the 55 patients with no high-risk features, 36 underwent single photon emission computed tomography and 19 underwent ICA. The patients were followed up until a decision regarding revascularization was made. Compared with ICA, the operating characteristics of CTA (per-patient analysis) were excellent, with a sensitivity of 98% (95% confidence interval [CI] 87% to 100%), specificity of 100% (95% CI 85% to 100%), positive predictive value of 100% (95% CI 90% to 100%), and negative predictive value of 97% (95% CI 80% to 100%). The agreement between CTA and routine testing (single photon emission computed tomography or ICA) was very good ( ⴝ 0.94). CTA correctly identified 40 patients (100%) who underwent revascularization and 61 (91.0%) who were treated medically ( ⴝ 0.88, 95% CI 0.79 to 0.97). In conclusion, CTA might represent a single modality that could be used to triage a wide spectrum of patients with ACPS and could have the potential to rule out coronary disease and identify those who might require revascularization. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;106:463– 469) Computed tomographic coronary angiography (CTA) is an emerging diagnostic tool for the detection of coronary artery disease (CAD) in patients with stable symptoms.1–3 However, mounting data supports the use of CTA for both stable patients and those presenting to the emergency department with acute chest pain syndromes (ACPS).4 –11 The high sensitivity and negative predictive value of CTA enables it to rule out obstructive CAD and potentially eliminate the need for hospital admission or additional cardiac testing. Similarly, if proved to be accurate in patients with obstructive CAD, CTA might have a role in directing patient treatment. The present study prospectively assessed the potential accuracy of CTA in a wide spectrum of patients
a
Department of Medicine, Division of Cardiology, and bCardiovascular Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada; and cDepartment of Radiology, University of Ottawa and Ottawa Hospital, Ottawa, Ontario, Canada. Manuscript received January 8, 2010; manuscript received and accepted March 25, 2010. Dr. Chow is supported by the Canadian Institutes of Health Research New Investigator Award No. MSH-83718. This study was supported in part by the Ontario Research Fund, Ontario, Canada, Imaging for Cardiovascular Therapeutics Project No. RE02-038, Ontario, Canada, the Canada Foundation for Innovation No. 11966, Canada, and by an investigator initiated research grant from GE Healthcare (Princeton, New Jersey). *Corresponding author: Tel: (613) 761-4044; fax: (613) 761-4929. E-mail address: [email protected] (B.J.W. Chow). 0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.03.058
with ACPS compared to routine testing and CTA’s ability to direct patient revascularization therapy. Methods From October 2006 to June 2008, nonconsecutive patients presenting to the emergency department with ACPS and referred to cardiology for cardiac investigations or follow-up were prospectively enrolled and categorized as (1) having high-risk acute coronary syndrome features (HRACS) or (2) without high-risk features (i.e., low- or intermediate-risk patients). HR-ACS was defined as an accelerating pattern or a prolonged episode (⬎20 minutes) or recurrent episodes of chest pain at rest or with minimal effort within the preceding 24 hours and an elevated troponin or electrocardiographic changes consistent with ischemia (ST-segment depression of ⱖ0.1 mV or transient [⬍20 minutes] ST-segment elevation of ⱖ0.1 mV).12 Patients were excluded because of age ⬍18 years, an allergy or contraindication to contrast agents, refractory angina requiring urgent/emergent invasive coronary angiography (ICA), pregnancy, a history of coronary revascularization, atrial fibrillation, frequent ectopy, an uncontrolled heart rate, or the inability to perform a 20-second breath hold. All patients with HR-ACS were treated with an invasive strategy and underwent ICA. The patients without high-risk features underwent examination at the discretion of the www.ajconline.org
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treating physician and were either referred for ICA or technetium-99m single photon emission computed tomographic myocardial perfusion imaging. CTA for the present study was performed before all ICA. For patients undergoing single photon emission computed tomography, the timing of CTA was determined by test availability. All patients provided informed consent, and the institutional human research ethics board approved the protocol. The medical history and laboratory test results were recorded for all patients. Using the National Cholesterol Education Program/ Adult Treatment Panel III guidelines, the cardiac risk factors were collected. Hypertension was defined as blood pressure ⬎140/90 mm Hg or if the patient was taking antihypertensive medication. The diagnosis of dyslipidemia was determined by the fasting lipid profile results or drug treatment of hyperlipidemia. Before image acquisition, the patients received metoprolol, targeting a heart rate of ⱕ65 beats/min, and nitroglycerin 0.8 mg sublingually. A biphasic timing bolus (Visipaque 320 or Omnipaque 350, GE Healthcare, Princeton, New Jersey) was used to calculate the transit time.2,11 Final images were acquired using a triphasic protocol (100% contrast, 40%/60% contrast/saline, and 40 ml saline). The contrast volume and infusion rate (5 to 8 ml/s) were individualized according to the scan time and patient body habitus. Retrospective electrocardiographic-gated data sets were acquired using the GE volume computed tomographic scanner (GE Healthcare, Milwaukee, Wisconsin) at 64 ⫻ 0.625 mm slice collimation, a gantry rotation of 350 ms (300 to 800 mA, 120 kVp), with electrocardiographic-gated tube modulation and a pitch (0.16 to 0.24) that was individualized to the patient’s heart rate. The computed tomographic data sets were reconstructed with a slice thickness of 0.625 mm (0.4 mm increment) using the cardiac phases with the least cardiac motion. The images were postprocessed using the GE Advantage Volume Share Workstation (GE Healthcare) and visually interpreted by an expert observer unaware of the clinical data. A 17-segment model of the coronary arteries and a 4-point grading score (normal, mild [⬍50%], moderate [50% to 69%], and severe [ⱖ70%]) were used to evaluate coronary stenosis.2,11 Using the computed tomographic angiographic coronary anatomy, lesion characteristics, and target vessels, the patients were allocated to a revascularization strategy (medical therapy, percutaneous coronary intervention, or coronary artery bypass grafting). Significant obstructive CAD was defined as ⱖ70% luminal diameter stenosis or ⱖ50% left main stenosis. High-risk CAD was defined as left main stenosis of ⱖ50%, triple vessel CAD of ⱖ70%, or 2-vessel disease (ⱖ70%) with one vessel the proximal left anterior descending artery. ICA was performed according to the clinical routine.12,13 Using the same grading system as for CTA, all invasive coronary angiograms were reviewed by 2 observers unaware of the clinical data or computed tomographic angiographic results. Recognizing that the decision for revascularization is often influenced by clinical information, the blinded ICA observers allocated patients to a “theoretical” revascularization strategy according to the findings from ICA (anatomy)
Table 1 Patient characteristics Variable Age (years) Men Thrombolysis In Myocardial Infarction score* Median Range Global Registry of Acute Cardiac Events score* Median Range Creatinine (mol/L) Diabetes mellitus Current smoker Dyslipidemia Hypertension Previous coronary artery disease Abnormal troponin level Imaging heart rate (beats/min) Radiation dose (mSv)
All Patients (n ⫽ 107)
HR-ACS (n ⫽ 52)
No-HR (n ⫽ 55)
54 ⫾ 10 73 (68%)
55 ⫾ 10 41 (79%)
53 ⫾ 9 32 (58%)
1 0–2
2 1–3
0 0–1
99 75–112 85 ⫾ 50 11 (10%) 31 (29%) 53 (50%) 46 (43%) 9 (8%) 49 (47%)† 56 ⫾ 6 15 ⫾ 3
112 100–128 91 ⫾ 71 6 (12%) 19 (37%) 25 (48%) 18 (35%) 9 (17%) 46 (89%) 58 ⫾ 6 15 ⫾ 3
78 67–96 78 ⫾ 14 5 (9%) 12 (22%) 28 (51%) 28 (51%) 0 (0%) 3 (6%)† 55 ⫾ 5 15 ⫾ 3
Data are presented as mean ⫾ SD or number (%). * Three patients were excluded because of insufficient information. † Troponin values were not recorded in 2 patients in no high-risk features group. No-HR ⫽ no high-risk features.
alone (medical therapy, percutaneous coronary intervention, or coronary artery bypass surgery). Nonobstructive CAD on ICA was allocated to medical therapy and obstructive CAD was allocated to a revascularization strategy. Patients with high-risk coronary anatomy were allocated to coronary artery bypass grafting. Technetium-99m (tetrofosmin) single photon emission computed tomographic myocardial perfusion imaging was performed according to the clinical routine.3 In brief, a 1-day rest–stress protocol was used. Patients unable to exercise underwent vasodilator stress (dipyridamole 0.142 mg/kg/min for 5 minutes). Image acquisition was performed on dual-headed cameras using low-energy, high-resolution collimators and a 15% energy window centered on the 140-keV photopeak. Electrocardiographic-gated single photon emission computed tomographic data were acquired for 180° (25 s/projection for 60 projections) and reconstructed with filtered back-projection using a 64 ⫻ 64 matrix. All single photon emission computed tomographic images were reviewed by 2 observers unaware of the clinical data and computed tomographic angiographic results. The findings were considered abnormal in the presence of perfusion abnormalities not attributable to attenuation artifact, the presence of transient ischemic dilation, or the presence of increased lung uptake. To determine the accuracy of the CAD diagnosis, CTA was compared with routine testing (ICA or single photon emission computed tomography). The need for ICA after single photon emission computed tomography and all treatment decisions (medical therapy or revascularization) after single photon emission computed tomography and ICA were left to the discretion of the physician who was unaware of the computed tomographic
Coronary Artery Disease/CTA and ACPS
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Figure 1. Study population.
angiographic results. All patients were followed up until a clinical decision regarding therapy or revascularization had been made, and all revascularization decisions were made without knowledge of the results from CTA. Along with the “actual” (clinical) revascularization decision, the patients were allocated to a “theoretical” revascularization strategy according the findings from ICA (anatomy) alone without clinical data. Patients with high-risk CAD and suitable distal target vessels were allocated to coronary artery bypass grafting. Patients with high-risk CAD but not amenable to complete revascularization with coronary artery bypass grafting and patients with nonhighrisk CAD with suitable target lesions were allocated to percutaneous coronary intervention. Patients without obstructive CAD and patients with CAD not amenable to revascularization were allocated to medical therapy. Statistical analyses were performed using Statistical Analysis Systems, version 9.1.3 (SAS Institute, Cary, North Carolina). Continuous outcomes are presented as the mean ⫾ SD and categorical outcomes as frequencies with percentages. Agreements between categorical variables were assessed using analysis. Results A total of 108 patients were prospectively enrolled, but 1 patient did not undergo CTA because of a heart rate ⬎65 beats/min. The final study included 107 patients (52 HRACS and 55 without high-risk features; Table 1). All 52 patients with HR-ACS underwent ICA. Of the 55 patients without high-risk features, 36 underwent technetium-99m single photon emission computed tomography and 19 underwent ICA. During the study period, 4 patients initially evaluated using technetium-99m single photon emission
computed tomography subsequently underwent ICA. Thus, 23 (42%) of the 55 patients without high-risk features in the present study underwent ICA (Figure 1). A total of 75 patients underwent ICA (52 HR-ACS and 23 without high-risk features). The operating characteristics of CTA for the detection of anatomic obstructive CAD (left main diameter stenosis of ⱖ50% or ⱖ70% in any other vessel), with a per-patient analysis, were excellent (Table 2). CTA was similarly accurate in the HR-ACS population (Table 2). Examining an anatomic threshold of ⱖ50% diameter stenosis in any vessel, the operating characteristics of CTA compared to ICA, in a per-patient analysis, were equally excellent (Table 3). Using a vessel-based analysis (left main artery of ⱖ50% and left anterior, circumflex, and right coronary arteries of ⱖ70%), CTA demonstrated very good operating characteristics in the 75 patients who had undergone ICA (sensitivity of 89%, 95% confidence interval [CI] 80% to 95%), specificity of 94% (95% CI 90% to 97%), positive predictive value of 83% (95% CI 73% to 91%), and negative predictive value of 96% (95% CI 93% to 98%). Using a vesselbased analysis and a threshold of ⱖ50% for obstructive CAD, the sensitivity, specificity, positive predictive value, and negative predictive value for CTA was 92% (95% CI 83% to 96%), 87% (95% CI 82% to 91%), 75% (95% CI 65% to 82%), and 96% (95% CI 92% to 98%), respectively. The accuracy of CTA in all 107 patients and the agreement between CTA and “routine testing” for the diagnosis of CAD were very good ( ⫽ 0.94). Of the 36 patients who underwent single photon emission computed tomography, myocardial perfusion was normal in all but 1 patient, yet 4 patients were referred for ICA.
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Table 2 Accuracy of computed tomographic angiography (CTA) (patient-based analysis) compared to invasive coronary angiography (ICA) and routine testing (left main stenosis ⱖ50% or ⱖ70% in any other vessel) Variable All patients*
True Positive
True Negative
False Positive
False Negative
Sensitivity
Specificity
Positive Predictive Value
Negative Predictive Value
107
46
59
0
2
0.96
75
46
29
0
0
1.00
52
35
17
0
0
1.00
46/48 96% (5–99%) 46/46 100% (90 –100%) 35/35 100% (88 –100%)
59/59 100% (92–100%) 29/29 100% (85–100%) 17/17 100% (77–100%)
46/46 100% (90 –100%) 46/46 100% (90 –100%) 35/35 100% (88 –100%)
59/61 97% (88 –99%) 29/29 100% (85–100%) 17/17 100% (77–100%)
Data in parentheses are 95% confidence intervals. * Prevalence of CAD 45%. † Prevalence of CAD 67%.
Table 3 Accuracy of computed tomographic angiography (CTA) (patient-based analysis) compared to invasive coronary angiography (ICA) and routine testing (stenosis ⱖ50% in any vessel) Variable All patients* Patients undergoing coronary angiography Patients with high-risk acute coronary syndrome†
Patients (n)
True Positive
True Negative
False Positive
False Negative
Sensitivity
Specificity
Positive Predictive Value
Negative Predictive Value
107
47
51
6
3
0.83
75
47
23
4
1
0.85
52
35
13
3
1
0.81
47/50 94% (83–98%) 47/48 99% (88 –100) 35/36 97% (84 –100%)
51/57 90% (78 –96%) 23/27 85% (65–95%) 13/16 81% (54 –95%)
47/53 89% (76 –95%) 47/51 92% (80 –98%) 35/38 92% (78 –98%)
51/54 94% (84 –99%) 23/24 96% (77–100%) 13/14 93% (64 –100%)
Data in parentheses are 95% confidence intervals. * Prevalence of CAD 47%. † Prevalence of CAD 69%.
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Patients undergoing coronary angiography Patients with high-risk acute coronary syndrome†
Patients (n)
Coronary Artery Disease/CTA and ACPS
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Table 4 Agreement of computed tomographic angiography (CTA) with clinical revascularization decisions
not significantly different from those of CTA allocation (p ⫽ 0.501).
CTA
Discussion
Clinical Revascularization Decision Medical Therapy
Revascularization
61 6
0 40
Medical therapy Revascularization
Sensitivity 100% (95% CI 89 –100%), specificity 91% (95% CI 80 – 96%), negative predictive value 100% (95% CI 93–100%), positive predictive value 87% (95% CI 73–95), ⫽ 0.88 (95% CI 0.79 – 0.97). Table 5 Agreement between computed tomographic angiography (CTA) and mode of clinical revascularization CTA
Medical therapy Percutaneous coronary intervention Coronary artery bypass grafting
Clinical Revascularization Decision Medical Therapy
Percutaneous Coronary Intervention
Coronary Artery Bypass Grafting
61 5
0 25
0 2
1
5
8
⫽ 0.78 (95% CI 0.66 – 0.89).
All 4 patients (3 of whom had normal myocardial perfusion) had severe CAD requiring revascularization (Figure 1). At follow-up, 67 patients had been treated medically and 40 had undergone revascularization (30 percutaneous coronary intervention and 10 coronary artery bypass grafting). Of the 75 patients referred for ICA, 40 (53%) required revascularization. No significant CAD was identified in 17 (33%) of the 52 patients clinically identified as HR-ACS. CTA correctly identified all 40 patients (100%) who underwent revascularization, but incorrectly allocated 6 patients to revascularization who were subsequently treated medically ( ⫽ 0.88; 95% CI 0.79 to 0.97; Table 4). CTA correctly predicted the mode of treatment (medical therapy, percutaneous coronary intervention, or coronary artery bypass grafting) in 94 (88%) of the 107 patients ( ⫽ 0.78; 95% CI 0.66 to 0.89) and correctly allocated 25 (83%) of 30 patients to percutaneous coronary intervention and 8 (80%) of 10 to coronary artery bypass grafting (Table 5). Of the 75 patients referred for ICA, CTA predicted the need for “actual” revascularization with a sensitivity and specificity of 100% (95% CI 89% to 100%) and 83% (95% CI 65% to 93%), respectively and a negative and positive predictive value of 100% (95% CI 85% to 100%) and 87% (95% CI 73% to 95%), respectively, with very good agreement ( ⫽ 0.84; 95% CI 0.71 to 0.96). Also, very good agreement ( ⫽ 0.89; 95% CI 0.79 to 0.99) was found between the “theoretical” allocation by ICA to “actual” revascularization. Using “actual” revascularization as the reference standard, the operating characteristics of “theoretical” ICA allocation (sensitivity, specificity, and positive and negative predictive value of 98%, 95% CI 85% to 100%; 91%, 95% CI 76% to 98%; 92%, 95% CI 79% to 98%; and 97%, 95% CI 83% to 100%), respectively were
Patients with ACPS represent a significant proportion of emergency department visits. Attractive to clinicians would be a single modality that could be used for all patients with ACPS. Our study results suggest that CTA might be useful in a wide spectrum of patients with ACPS, not only in ruling out disease, but also for guiding revascularization therapy. Many ACPS studies have focused on patients at lower clinical risk and have demonstrated the ability of CTA to rule out CAD.7,8 Limited data are available evaluating the role of CTA in patients with ACPS with a greater likelihood of non–ST-segment elevation acute coronary syndromes.7,8 Our study has expanded on previous studies by examining the utility of CTA in a broader spectrum of patients with ACPS. In patients with ACPS, noninvasive and invasive tests are used for diagnosis, risk stratification, and guiding revascularization strategies. CTA appears to accurately identify patients with ACPS who required revascularization. Recognizing that factors other than the anatomy contribute to revascularization decisions, we compared the accuracy of CTA and “theoretical” revascularization decisions (using the anatomy from ICA alone) to the “actual” revascularization outcomes. Both had similar agreement to “actual” revascularization ( ⫽ 0.84 for CTA and ⫽ 0.89 for ICA). Although CTA accurately identified patients who required revascularization, it was slightly less accurate in assigning specific revascularization strategies (percutaneous coronary intervention vs coronary artery bypass grafting; kappa ⫽ 0.78). Additional studies are needed to determine the role of CTA to guide specific revascularization therapy. The early invasive strategy for patients with HR-ACS has been recommended and accepted in clinical practice.14,15 However, several acute coronary syndrome studies have demonstrated that a significant proportion of patients (22% to 45%) with ACS do not require revascularization or are not revascularization candidates.16 –18 Our results have confirmed that a significant proportion of patients (17 [33%]) with HR-ACS did not have obstructive CAD, highlighting that some patients presenting with HR-ACS might benefit from CTA by avoiding ICA. Such a strategy could prove useful at centers without direct access to ICA. We had one false-negative finding on CTA in 1 woman with dissection of a distal vessel that was treated medically. During image acquisition, this patient had a premature extrasystole, resulting in a suboptimal study. However, she was kept in our analysis to ensure that our results would reflect the “real-world” experience. Delaying revascularization is a concern when using CTA for patients with HR-ACS. However, de Winter et al19 demonstrated that, in patients with HR-ACS, a selectively invasive strategy resulted in clinical outcomes similar those with an early invasive strategy. Moreover, in patients presenting with ACS, delaying in-hospital revascularization for ⬎36 hours did not influence death, nonfatal myocardial infarction, or stroke. A subgroup analysis supported earlier revascularization for reducing recurrent ischemia in those
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with a Global Registry of Acute Coronary Events score of ⱖ141. Although our patients were deemed to have HR-ACS primarily from troponin elevation or electrocardiographic ST-segment changes, the median Thrombolysis In Myocardial Infarction risk score was 2, and the median Global Registry of Acute Coronary Events score was 112. Therefore, if performed in a timely manner, CTA could safely be used to risk stratify patients with ACS if at a “lower” clinical risk and might be most useful at centers without immediate access to ICA. The need to reduce patient radiation exposure is increasing. Our study has demonstrated that CTA can be used as a single modality to rule out obstructive CAD in patients with ACPS with and without high-risk features. Recognizing that patients with obstructive CAD on CTA will likely proceed to ICA, radiation-sparing techniques are desirable. We acknowledge that using CTA in patients with HR-ACS could lead to additional radiation exposure if the patients subsequently underwent ICA. However, several potential benefits of this strategy could offset the radiation exposure and the additional lifetime risk of cancer. In our select population, ⬎30% of patients could have avoided ICA and the risks associated with ICA (i.e., death, stroke, myocardial infarction, and vascular complications). As this technology matures, it might be possible for some patients with high-risk coronary anatomy to proceed directly to coronary artery bypass grafting, further avoiding the risks of ICA. Acknowledging the limitations of our sample size, we estimated that a sample size of 239 would be needed to detect a “true” of 0.9 versus a “null” of 0.8, using a 1-sided test (90% power, p ⫽ 0.05) in a population with equal proportions of patients with normal and abnormal findings. We also recognize that revascularization decisions are determined from numerous factors, including patient symptoms, patient and physician preference, the presence of other co-morbidities, and local practice patterns. Understanding this potential bias, the agreement of “theoretical” and “actual” allocations was assessed, and the agreement was not significantly different statistically from that of CTA and the “theoretical” allocations. Because a small number of patients were referred for coronary artery bypass grafting, our ability to make definitive conclusions regarding CTA’s ability to direct patients directly to coronary artery bypass grafting was limited. Also, we were unable to screen all patients presenting to the emergency department with ACPS and thus could not exclude the potential for referral bias. A larger randomized controlled trial is needed to assess the utility of CTA in patients with ACPS, its ability to direct revascularization, and its effect on patient outcomes. CTA might not be useful in all patients with ACPS, because patients with HR-ACS are more likely to be older and to have concomitant co-morbidities (renal insufficiency, atrial fibrillation) and severe coronary calcification. Of concern are patients with renal insufficiency who are at a greater risk of contrast-induced nephropathy with 2 contrast loads. The careful selection of patients with normal renal function should minimize such events, and we observed no adverse renal events during our study. Although our results are encouraging, we would advocate that CTA be used in a select ACPS population.
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a
Department of Medicine, Division of Cardiology, and bCardiovascular Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada; and cDepartment of Radiology, University of Ottawa and Ottawa Hospital, Ottawa, Ontario, Canada. Manuscript received January 8, 2010; manuscript received and accepted March 25, 2010. Dr. Chow is supported by the Canadian Institutes of Health Research New Investigator Award No. MSH-83718. This study was supported in part by the Ontario Research Fund, Ontario, Canada, Imaging for Cardiovascular Therapeutics Project No. RE02-038, Ontario, Canada, the Canada Foundation for Innovation No. 11966, Canada, and by an investigator initiated research grant from GE Healthcare (Princeton, New Jersey). *Corresponding author: Tel: (613) 761-4044; fax: (613) 761-4929. E-mail address: [email protected] (B.J.W. Chow). 0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.03.058
with ACPS compared to routine testing and CTA’s ability to direct patient revascularization therapy. Methods From October 2006 to June 2008, nonconsecutive patients presenting to the emergency department with ACPS and referred to cardiology for cardiac investigations or follow-up were prospectively enrolled and categorized as (1) having high-risk acute coronary syndrome features (HRACS) or (2) without high-risk features (i.e., low- or intermediate-risk patients). HR-ACS was defined as an accelerating pattern or a prolonged episode (⬎20 minutes) or recurrent episodes of chest pain at rest or with minimal effort within the preceding 24 hours and an elevated troponin or electrocardiographic changes consistent with ischemia (ST-segment depression of ⱖ0.1 mV or transient [⬍20 minutes] ST-segment elevation of ⱖ0.1 mV).12 Patients were excluded because of age ⬍18 years, an allergy or contraindication to contrast agents, refractory angina requiring urgent/emergent invasive coronary angiography (ICA), pregnancy, a history of coronary revascularization, atrial fibrillation, frequent ectopy, an uncontrolled heart rate, or the inability to perform a 20-second breath hold. All patients with HR-ACS were treated with an invasive strategy and underwent ICA. The patients without high-risk features underwent examination at the discretion of the www.ajconline.org
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treating physician and were either referred for ICA or technetium-99m single photon emission computed tomographic myocardial perfusion imaging. CTA for the present study was performed before all ICA. For patients undergoing single photon emission computed tomography, the timing of CTA was determined by test availability. All patients provided informed consent, and the institutional human research ethics board approved the protocol. The medical history and laboratory test results were recorded for all patients. Using the National Cholesterol Education Program/ Adult Treatment Panel III guidelines, the cardiac risk factors were collected. Hypertension was defined as blood pressure ⬎140/90 mm Hg or if the patient was taking antihypertensive medication. The diagnosis of dyslipidemia was determined by the fasting lipid profile results or drug treatment of hyperlipidemia. Before image acquisition, the patients received metoprolol, targeting a heart rate of ⱕ65 beats/min, and nitroglycerin 0.8 mg sublingually. A biphasic timing bolus (Visipaque 320 or Omnipaque 350, GE Healthcare, Princeton, New Jersey) was used to calculate the transit time.2,11 Final images were acquired using a triphasic protocol (100% contrast, 40%/60% contrast/saline, and 40 ml saline). The contrast volume and infusion rate (5 to 8 ml/s) were individualized according to the scan time and patient body habitus. Retrospective electrocardiographic-gated data sets were acquired using the GE volume computed tomographic scanner (GE Healthcare, Milwaukee, Wisconsin) at 64 ⫻ 0.625 mm slice collimation, a gantry rotation of 350 ms (300 to 800 mA, 120 kVp), with electrocardiographic-gated tube modulation and a pitch (0.16 to 0.24) that was individualized to the patient’s heart rate. The computed tomographic data sets were reconstructed with a slice thickness of 0.625 mm (0.4 mm increment) using the cardiac phases with the least cardiac motion. The images were postprocessed using the GE Advantage Volume Share Workstation (GE Healthcare) and visually interpreted by an expert observer unaware of the clinical data. A 17-segment model of the coronary arteries and a 4-point grading score (normal, mild [⬍50%], moderate [50% to 69%], and severe [ⱖ70%]) were used to evaluate coronary stenosis.2,11 Using the computed tomographic angiographic coronary anatomy, lesion characteristics, and target vessels, the patients were allocated to a revascularization strategy (medical therapy, percutaneous coronary intervention, or coronary artery bypass grafting). Significant obstructive CAD was defined as ⱖ70% luminal diameter stenosis or ⱖ50% left main stenosis. High-risk CAD was defined as left main stenosis of ⱖ50%, triple vessel CAD of ⱖ70%, or 2-vessel disease (ⱖ70%) with one vessel the proximal left anterior descending artery. ICA was performed according to the clinical routine.12,13 Using the same grading system as for CTA, all invasive coronary angiograms were reviewed by 2 observers unaware of the clinical data or computed tomographic angiographic results. Recognizing that the decision for revascularization is often influenced by clinical information, the blinded ICA observers allocated patients to a “theoretical” revascularization strategy according to the findings from ICA (anatomy)
Table 1 Patient characteristics Variable Age (years) Men Thrombolysis In Myocardial Infarction score* Median Range Global Registry of Acute Cardiac Events score* Median Range Creatinine (mol/L) Diabetes mellitus Current smoker Dyslipidemia Hypertension Previous coronary artery disease Abnormal troponin level Imaging heart rate (beats/min) Radiation dose (mSv)
All Patients (n ⫽ 107)
HR-ACS (n ⫽ 52)
No-HR (n ⫽ 55)
54 ⫾ 10 73 (68%)
55 ⫾ 10 41 (79%)
53 ⫾ 9 32 (58%)
1 0–2
2 1–3
0 0–1
99 75–112 85 ⫾ 50 11 (10%) 31 (29%) 53 (50%) 46 (43%) 9 (8%) 49 (47%)† 56 ⫾ 6 15 ⫾ 3
112 100–128 91 ⫾ 71 6 (12%) 19 (37%) 25 (48%) 18 (35%) 9 (17%) 46 (89%) 58 ⫾ 6 15 ⫾ 3
78 67–96 78 ⫾ 14 5 (9%) 12 (22%) 28 (51%) 28 (51%) 0 (0%) 3 (6%)† 55 ⫾ 5 15 ⫾ 3
Data are presented as mean ⫾ SD or number (%). * Three patients were excluded because of insufficient information. † Troponin values were not recorded in 2 patients in no high-risk features group. No-HR ⫽ no high-risk features.
alone (medical therapy, percutaneous coronary intervention, or coronary artery bypass surgery). Nonobstructive CAD on ICA was allocated to medical therapy and obstructive CAD was allocated to a revascularization strategy. Patients with high-risk coronary anatomy were allocated to coronary artery bypass grafting. Technetium-99m (tetrofosmin) single photon emission computed tomographic myocardial perfusion imaging was performed according to the clinical routine.3 In brief, a 1-day rest–stress protocol was used. Patients unable to exercise underwent vasodilator stress (dipyridamole 0.142 mg/kg/min for 5 minutes). Image acquisition was performed on dual-headed cameras using low-energy, high-resolution collimators and a 15% energy window centered on the 140-keV photopeak. Electrocardiographic-gated single photon emission computed tomographic data were acquired for 180° (25 s/projection for 60 projections) and reconstructed with filtered back-projection using a 64 ⫻ 64 matrix. All single photon emission computed tomographic images were reviewed by 2 observers unaware of the clinical data and computed tomographic angiographic results. The findings were considered abnormal in the presence of perfusion abnormalities not attributable to attenuation artifact, the presence of transient ischemic dilation, or the presence of increased lung uptake. To determine the accuracy of the CAD diagnosis, CTA was compared with routine testing (ICA or single photon emission computed tomography). The need for ICA after single photon emission computed tomography and all treatment decisions (medical therapy or revascularization) after single photon emission computed tomography and ICA were left to the discretion of the physician who was unaware of the computed tomographic
Coronary Artery Disease/CTA and ACPS
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Figure 1. Study population.
angiographic results. All patients were followed up until a clinical decision regarding therapy or revascularization had been made, and all revascularization decisions were made without knowledge of the results from CTA. Along with the “actual” (clinical) revascularization decision, the patients were allocated to a “theoretical” revascularization strategy according the findings from ICA (anatomy) alone without clinical data. Patients with high-risk CAD and suitable distal target vessels were allocated to coronary artery bypass grafting. Patients with high-risk CAD but not amenable to complete revascularization with coronary artery bypass grafting and patients with nonhighrisk CAD with suitable target lesions were allocated to percutaneous coronary intervention. Patients without obstructive CAD and patients with CAD not amenable to revascularization were allocated to medical therapy. Statistical analyses were performed using Statistical Analysis Systems, version 9.1.3 (SAS Institute, Cary, North Carolina). Continuous outcomes are presented as the mean ⫾ SD and categorical outcomes as frequencies with percentages. Agreements between categorical variables were assessed using analysis. Results A total of 108 patients were prospectively enrolled, but 1 patient did not undergo CTA because of a heart rate ⬎65 beats/min. The final study included 107 patients (52 HRACS and 55 without high-risk features; Table 1). All 52 patients with HR-ACS underwent ICA. Of the 55 patients without high-risk features, 36 underwent technetium-99m single photon emission computed tomography and 19 underwent ICA. During the study period, 4 patients initially evaluated using technetium-99m single photon emission
computed tomography subsequently underwent ICA. Thus, 23 (42%) of the 55 patients without high-risk features in the present study underwent ICA (Figure 1). A total of 75 patients underwent ICA (52 HR-ACS and 23 without high-risk features). The operating characteristics of CTA for the detection of anatomic obstructive CAD (left main diameter stenosis of ⱖ50% or ⱖ70% in any other vessel), with a per-patient analysis, were excellent (Table 2). CTA was similarly accurate in the HR-ACS population (Table 2). Examining an anatomic threshold of ⱖ50% diameter stenosis in any vessel, the operating characteristics of CTA compared to ICA, in a per-patient analysis, were equally excellent (Table 3). Using a vessel-based analysis (left main artery of ⱖ50% and left anterior, circumflex, and right coronary arteries of ⱖ70%), CTA demonstrated very good operating characteristics in the 75 patients who had undergone ICA (sensitivity of 89%, 95% confidence interval [CI] 80% to 95%), specificity of 94% (95% CI 90% to 97%), positive predictive value of 83% (95% CI 73% to 91%), and negative predictive value of 96% (95% CI 93% to 98%). Using a vesselbased analysis and a threshold of ⱖ50% for obstructive CAD, the sensitivity, specificity, positive predictive value, and negative predictive value for CTA was 92% (95% CI 83% to 96%), 87% (95% CI 82% to 91%), 75% (95% CI 65% to 82%), and 96% (95% CI 92% to 98%), respectively. The accuracy of CTA in all 107 patients and the agreement between CTA and “routine testing” for the diagnosis of CAD were very good ( ⫽ 0.94). Of the 36 patients who underwent single photon emission computed tomography, myocardial perfusion was normal in all but 1 patient, yet 4 patients were referred for ICA.
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Table 2 Accuracy of computed tomographic angiography (CTA) (patient-based analysis) compared to invasive coronary angiography (ICA) and routine testing (left main stenosis ⱖ50% or ⱖ70% in any other vessel) Variable All patients*
True Positive
True Negative
False Positive
False Negative
Sensitivity
Specificity
Positive Predictive Value
Negative Predictive Value
107
46
59
0
2
0.96
75
46
29
0
0
1.00
52
35
17
0
0
1.00
46/48 96% (5–99%) 46/46 100% (90 –100%) 35/35 100% (88 –100%)
59/59 100% (92–100%) 29/29 100% (85–100%) 17/17 100% (77–100%)
46/46 100% (90 –100%) 46/46 100% (90 –100%) 35/35 100% (88 –100%)
59/61 97% (88 –99%) 29/29 100% (85–100%) 17/17 100% (77–100%)
Data in parentheses are 95% confidence intervals. * Prevalence of CAD 45%. † Prevalence of CAD 67%.
Table 3 Accuracy of computed tomographic angiography (CTA) (patient-based analysis) compared to invasive coronary angiography (ICA) and routine testing (stenosis ⱖ50% in any vessel) Variable All patients* Patients undergoing coronary angiography Patients with high-risk acute coronary syndrome†
Patients (n)
True Positive
True Negative
False Positive
False Negative
Sensitivity
Specificity
Positive Predictive Value
Negative Predictive Value
107
47
51
6
3
0.83
75
47
23
4
1
0.85
52
35
13
3
1
0.81
47/50 94% (83–98%) 47/48 99% (88 –100) 35/36 97% (84 –100%)
51/57 90% (78 –96%) 23/27 85% (65–95%) 13/16 81% (54 –95%)
47/53 89% (76 –95%) 47/51 92% (80 –98%) 35/38 92% (78 –98%)
51/54 94% (84 –99%) 23/24 96% (77–100%) 13/14 93% (64 –100%)
Data in parentheses are 95% confidence intervals. * Prevalence of CAD 47%. † Prevalence of CAD 69%.
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Patients undergoing coronary angiography Patients with high-risk acute coronary syndrome†
Patients (n)
Coronary Artery Disease/CTA and ACPS
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Table 4 Agreement of computed tomographic angiography (CTA) with clinical revascularization decisions
not significantly different from those of CTA allocation (p ⫽ 0.501).
CTA
Discussion
Clinical Revascularization Decision Medical Therapy
Revascularization
61 6
0 40
Medical therapy Revascularization
Sensitivity 100% (95% CI 89 –100%), specificity 91% (95% CI 80 – 96%), negative predictive value 100% (95% CI 93–100%), positive predictive value 87% (95% CI 73–95), ⫽ 0.88 (95% CI 0.79 – 0.97). Table 5 Agreement between computed tomographic angiography (CTA) and mode of clinical revascularization CTA
Medical therapy Percutaneous coronary intervention Coronary artery bypass grafting
Clinical Revascularization Decision Medical Therapy
Percutaneous Coronary Intervention
Coronary Artery Bypass Grafting
61 5
0 25
0 2
1
5
8
⫽ 0.78 (95% CI 0.66 – 0.89).
All 4 patients (3 of whom had normal myocardial perfusion) had severe CAD requiring revascularization (Figure 1). At follow-up, 67 patients had been treated medically and 40 had undergone revascularization (30 percutaneous coronary intervention and 10 coronary artery bypass grafting). Of the 75 patients referred for ICA, 40 (53%) required revascularization. No significant CAD was identified in 17 (33%) of the 52 patients clinically identified as HR-ACS. CTA correctly identified all 40 patients (100%) who underwent revascularization, but incorrectly allocated 6 patients to revascularization who were subsequently treated medically ( ⫽ 0.88; 95% CI 0.79 to 0.97; Table 4). CTA correctly predicted the mode of treatment (medical therapy, percutaneous coronary intervention, or coronary artery bypass grafting) in 94 (88%) of the 107 patients ( ⫽ 0.78; 95% CI 0.66 to 0.89) and correctly allocated 25 (83%) of 30 patients to percutaneous coronary intervention and 8 (80%) of 10 to coronary artery bypass grafting (Table 5). Of the 75 patients referred for ICA, CTA predicted the need for “actual” revascularization with a sensitivity and specificity of 100% (95% CI 89% to 100%) and 83% (95% CI 65% to 93%), respectively and a negative and positive predictive value of 100% (95% CI 85% to 100%) and 87% (95% CI 73% to 95%), respectively, with very good agreement ( ⫽ 0.84; 95% CI 0.71 to 0.96). Also, very good agreement ( ⫽ 0.89; 95% CI 0.79 to 0.99) was found between the “theoretical” allocation by ICA to “actual” revascularization. Using “actual” revascularization as the reference standard, the operating characteristics of “theoretical” ICA allocation (sensitivity, specificity, and positive and negative predictive value of 98%, 95% CI 85% to 100%; 91%, 95% CI 76% to 98%; 92%, 95% CI 79% to 98%; and 97%, 95% CI 83% to 100%), respectively were
Patients with ACPS represent a significant proportion of emergency department visits. Attractive to clinicians would be a single modality that could be used for all patients with ACPS. Our study results suggest that CTA might be useful in a wide spectrum of patients with ACPS, not only in ruling out disease, but also for guiding revascularization therapy. Many ACPS studies have focused on patients at lower clinical risk and have demonstrated the ability of CTA to rule out CAD.7,8 Limited data are available evaluating the role of CTA in patients with ACPS with a greater likelihood of non–ST-segment elevation acute coronary syndromes.7,8 Our study has expanded on previous studies by examining the utility of CTA in a broader spectrum of patients with ACPS. In patients with ACPS, noninvasive and invasive tests are used for diagnosis, risk stratification, and guiding revascularization strategies. CTA appears to accurately identify patients with ACPS who required revascularization. Recognizing that factors other than the anatomy contribute to revascularization decisions, we compared the accuracy of CTA and “theoretical” revascularization decisions (using the anatomy from ICA alone) to the “actual” revascularization outcomes. Both had similar agreement to “actual” revascularization ( ⫽ 0.84 for CTA and ⫽ 0.89 for ICA). Although CTA accurately identified patients who required revascularization, it was slightly less accurate in assigning specific revascularization strategies (percutaneous coronary intervention vs coronary artery bypass grafting; kappa ⫽ 0.78). Additional studies are needed to determine the role of CTA to guide specific revascularization therapy. The early invasive strategy for patients with HR-ACS has been recommended and accepted in clinical practice.14,15 However, several acute coronary syndrome studies have demonstrated that a significant proportion of patients (22% to 45%) with ACS do not require revascularization or are not revascularization candidates.16 –18 Our results have confirmed that a significant proportion of patients (17 [33%]) with HR-ACS did not have obstructive CAD, highlighting that some patients presenting with HR-ACS might benefit from CTA by avoiding ICA. Such a strategy could prove useful at centers without direct access to ICA. We had one false-negative finding on CTA in 1 woman with dissection of a distal vessel that was treated medically. During image acquisition, this patient had a premature extrasystole, resulting in a suboptimal study. However, she was kept in our analysis to ensure that our results would reflect the “real-world” experience. Delaying revascularization is a concern when using CTA for patients with HR-ACS. However, de Winter et al19 demonstrated that, in patients with HR-ACS, a selectively invasive strategy resulted in clinical outcomes similar those with an early invasive strategy. Moreover, in patients presenting with ACS, delaying in-hospital revascularization for ⬎36 hours did not influence death, nonfatal myocardial infarction, or stroke. A subgroup analysis supported earlier revascularization for reducing recurrent ischemia in those
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with a Global Registry of Acute Coronary Events score of ⱖ141. Although our patients were deemed to have HR-ACS primarily from troponin elevation or electrocardiographic ST-segment changes, the median Thrombolysis In Myocardial Infarction risk score was 2, and the median Global Registry of Acute Coronary Events score was 112. Therefore, if performed in a timely manner, CTA could safely be used to risk stratify patients with ACS if at a “lower” clinical risk and might be most useful at centers without immediate access to ICA. The need to reduce patient radiation exposure is increasing. Our study has demonstrated that CTA can be used as a single modality to rule out obstructive CAD in patients with ACPS with and without high-risk features. Recognizing that patients with obstructive CAD on CTA will likely proceed to ICA, radiation-sparing techniques are desirable. We acknowledge that using CTA in patients with HR-ACS could lead to additional radiation exposure if the patients subsequently underwent ICA. However, several potential benefits of this strategy could offset the radiation exposure and the additional lifetime risk of cancer. In our select population, ⬎30% of patients could have avoided ICA and the risks associated with ICA (i.e., death, stroke, myocardial infarction, and vascular complications). As this technology matures, it might be possible for some patients with high-risk coronary anatomy to proceed directly to coronary artery bypass grafting, further avoiding the risks of ICA. Acknowledging the limitations of our sample size, we estimated that a sample size of 239 would be needed to detect a “true” of 0.9 versus a “null” of 0.8, using a 1-sided test (90% power, p ⫽ 0.05) in a population with equal proportions of patients with normal and abnormal findings. We also recognize that revascularization decisions are determined from numerous factors, including patient symptoms, patient and physician preference, the presence of other co-morbidities, and local practice patterns. Understanding this potential bias, the agreement of “theoretical” and “actual” allocations was assessed, and the agreement was not significantly different statistically from that of CTA and the “theoretical” allocations. Because a small number of patients were referred for coronary artery bypass grafting, our ability to make definitive conclusions regarding CTA’s ability to direct patients directly to coronary artery bypass grafting was limited. Also, we were unable to screen all patients presenting to the emergency department with ACPS and thus could not exclude the potential for referral bias. A larger randomized controlled trial is needed to assess the utility of CTA in patients with ACPS, its ability to direct revascularization, and its effect on patient outcomes. CTA might not be useful in all patients with ACPS, because patients with HR-ACS are more likely to be older and to have concomitant co-morbidities (renal insufficiency, atrial fibrillation) and severe coronary calcification. Of concern are patients with renal insufficiency who are at a greater risk of contrast-induced nephropathy with 2 contrast loads. The careful selection of patients with normal renal function should minimize such events, and we observed no adverse renal events during our study. Although our results are encouraging, we would advocate that CTA be used in a select ACPS population.
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17. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998;339:436 – 443. 18. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998;338:1488 –1497. 19. de Winter RJ, Windhausen F, Cornel JH, Dunselman PHJM, Janus CL, Bendermacher PEF, Michels HR, Sanders GT, Tijssen JG, Verheugt FW; Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) Investigators. Early invasive versus selectively invasive management for acute coronary syndromes. N Engl J Med 2005;353:1095–1104.