J o u r n a l o f C a r d i o v a s c u l a r C o m p u t e d T o m o g r a p h y 8 ( 2 0 1 4 ) 9 0 e9 6
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofCardiovascularCT.com
Clinical Trial Design
Rationale and design of the PREDICT (Plaque Registration and Evaluation Detected In Computed Tomography) registry Hideya Yamamoto MD, PhDa, Kazuo Awai MD, PhDb, Sachio Kuribayashi MD, PhDc, Yasuki Kihara MD, PhDa,*; on behalf of the PREDICT Investigators a
Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan b Department of Diagnostic Radiology, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan c Department of Diagnostic Radiology, Keio University School of Medicine, Tokyo, Japan
article info
abstract
Article history:
Background: At least two-thirds of cases of acute coronary syndrome are caused by
Received 13 June 2013
disruption of an atherosclerotic plaque. The natural history of individual plaques is
Received in revised form
unknown and needs to be established.
10 September 2013
Objectives: The Plaque Registration and Evaluation Detected In Computed Tomography
Accepted 16 December 2013
(PREDICT) registry is a prospective, multicenter, longitudinal, observational registry. This registry was designed to examine the relationships among coronary CT angiography (CTA)
Keywords:
findings and clinical findings, mortality, and morbidity. The relationships among
Coronary CT angiography
progression of coronary atherosclerosis, including changes in plaque characteristics on
Prognosis
coronary CTA, and serum lipid levels and modification of coronary risk factors will also be
Coronary plaque
evaluated.
Multicenter
Methods: From October 2009 to December 2012, 3015 patients who underwent coronary
Changes in plaque characteristics
CTA in 29 centers in Japan were enrolled. These patients were followed for 2 years. The primary end points were considered as all-cause mortality and major cardiac events, including cardiac death, nonfatal myocardial infarction, and unstable angina that required hospitalization. The secondary end points were heart failure that required administration of diuretics, target vessel revascularization, cerebral infarction, peripheral arterial disease, and invasive coronary angiography. Blood pressure, serum lipid, and C-reactive protein levels and all cardiovascular events were recorded at 1 and 2 years. If the initial coronary CTA showed any stenosis or plaques, follow-up coronary CTA was scheduled at 2 years to determine changes in coronary lesions, including changes in plaque characteristics. Conclusion: Analysis of the PREDICT registry data will clarify the relationships between coronary CTA findings and cardiovascular mortality and morbidity in a collaborative
Conflict of interest: The authors report no conflict of interest. * Corresponding author. E-mail address: [email protected] (Y. Kihara). 1934-5925/$ e see front matter ª 2014 Society of Cardiovascular Computed Tomography. All rights reserved. http://dx.doi.org/10.1016/j.jcct.2013.12.004
J o u r n a l o f C a r d i o v a s c u l a r C o m p u t e d T o m o g r a p h y 8 ( 2 0 1 4 ) 9 0 e9 6
91
multicenter fashion. This trial is registered at www.clinicaltrials.gov as NCT 00991835. ª 2014 Society of Cardiovascular Computed Tomography. All rights reserved.
1.
Introduction
Coronary CT angiography (CTA) with the use of 64 or more detector rows is a recently introduced noninvasive method of evaluating coronary artery disease (CAD) with high diagnostic accuracy for the detection or exclusion of obstructive CAD.1,2 Coronary CTA findings about the presence and extent of CAD were reported to be strong predictors of cardiovascular events.3,4 Coronary CTA is also expected to be a useful tool for evaluating plaque characteristics because it can visualize the structure of coronary vessels and morphologic features of coronary plaques.5,6 Acute coronary syndrome is mainly attributable to the acute rupture of vulnerable plaques, characterized by positive remodeling with lipid-rich, thin fibroatheroma and subsequent thrombus formation.7,8 Several studies that used intravascular ultrasonography have reported that coronary positive vessel remodeling (PR), low-attenuation plaques (LAPs), and spotty calcification are associated with plaque vulnerability.9e11 Therefore, it is crucial to detect and stabilize rupture-prone plaques noninvasively to prevent cardiovascular events. The characteristics of coronary plaques are hypothesized to predict future coronary events. The Plaque Registration and Evaluation Detected In Computed Tomography (PREDICT) registry was developed to provide a database of coronary CTA findings that could be used to identify risk factors for cardiac events. This report describes the rationale and design of the PREDICT registry.
2.
Methods
2.1.
Overall study design
The PREDICT registry is a prospective, multicenter, observational registry designed to examine the relationships among coronary CTA findings and clinical findings, mortality, and specific events in patients with clinically suspected and proven CAD (Fig. 1). This registry uses a novel collaborative design that merges similar prospectively enrolled cohorts from 29 hospitals in Japan. This study is registered at www. clinicaltrials.gov as NCT 00991835.
2.2.
Study objectives
The primary objective of the PREDICT registry is to examine the relationships among coronary CTA findings and demographic data, clinical data, and events caused by CAD in the 3015 enrolled patients. Specifically, the registry data will be analyzed to identify specific coronary CTA findings that can predict cardiovascular events during the next 2 years and to clarify the associations between plaque characterization on coronary CTA and culprit lesions at the time of presentation of acute coronary syndrome. The secondary objectives of the PREDICT registry include the following: to examine the relationships among coronary CTA findings and clinical risk factors and therapeutic interventions for CAD and to evaluate relationships among
Fig. 1 e Chart of study design. CTA, CT angiography; ECG, electrocardiogram.
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J o u r n a l o f C a r d i o v a s c u l a r C o m p u t e d T o m o g r a p h y 8 ( 2 0 1 4 ) 9 0 e9 6
serum lipid levels, plasma glucose levels, hemoglobin A1c levels, and renal function and changes in coronary plaques during the 2-year follow-up period. The details of the secondary objectives are shown in Table 1.
2.3.
Ethical considerations
The institutional review board of each participating institution reviewed and approved the study protocol and other documents. All subjects gave written informed consent for inclusion.
2.4.
Targeted population
The targeted population included patients with suspected or known CAD aged 20 years who were referred to an outpatient clinic and underwent coronary CTA. The exclusion criteria were as follows: (1) irregular heart rhythm or tachycardia (>90 beats/min), (2) iodine allergy, (3) chronic kidney disease (serum creatine levels: male patients, >1.4 mg/dL, female patients, >1.1 mg/dL), (4) prior coronary artery bypass grafting, (5) implanted pacemaker or cardioverterdefibrillator, (6) ST-elevation myocardial infarction (MI) or hemodynamically unstable, (7) severe heart failure (New York Heart Association class IV) or cardiogenic shock, (8) inability to hold breathing, (9) advanced malignancy, and (10) prior stenting of bilateral coronary arteries.
2.5.
Participating centers
Twenty-nine centers contributed data from patients who underwent coronary CTA of 64 or more detector rows. Data collection activity began in October 2009 with the goal of enrolling 3015 patients, and this was achieved in December 2012.
2.6.
Patient recruitment and evaluation
All patients underwent coronary CTA as directed by a physician. Data describing patient characteristics were prospectively collected at the time of the coronary CTA examination, including demographic information, targeted medical history,
and cardiovascular risk factors. Data were recorded with sitespecific case report forms. Data about the indications for coronary CTA and the characteristics of any chest pain were also recorded. Blood pressure, body mass index (calculated at weight divided by height squared; kg/m2), and waist circumference were measured, and electrocardiography (ECG) was performed. Blood was drawn to measure the leukocyte count; serum levels of lipids, creatinine, uric acid, and C-reactive protein; plasma glucose levels, and hemoglobin A1c levels.
2.7.
Patient follow-up
Patient information was obtained by direct or telephone interviews with patients or their families by dedicated physicians at each participating center. All enrolled patients were followed for the primary end points of all-cause mortality and major cardiac events, including cardiac death, nonfatal MI, and unstable angina that required hospitalization. Acute MI was defined as an increase in cardiac enzyme levels with symptoms suggestive of cardiac ischemia and new STeT changes or Q waves on ECG.12 Unstable angina was defined according to the Braunwald classification.13 In cases of acute coronary syndrome (acute MI and unstable angina), the culprit lesion was determined by dedicated physicians on the basis of on ECG, echocardiographic, and invasive coronary angiographic findings. Other events, including target vessel revascularization, heart failure that required administration of diuretics, cerebrovascular disease, aortic disease, peripheral arterial disease, and invasive coronary angiography, were also recorded. Elective coronary revascularization on the basis of coronary CTA findings was defined as early if it was performed 130 HU in a native image, or greater than the contrast-enhanced vessel lumen in a contrast-enhanced image. The presence and extent of each type of plaque are determined for each subject. The coronary plaque characteristics on coronary CTA are evaluated as previously described by determining the minimum CT number and vascular remodeling index.6,10 The outer circumference of the vessel and the lumen are manually traced. Vascular remodeling is assessed by using the remodeling index (proximal reference cross-sectional vessel area/ lesion cross-sectional vessel area) in cross-sectional images.17 The minimum CT number is determined for each plaque by setting at least 5 regions of interest (each region ¼ 1 mm2) in
94
J o u r n a l o f C a r d i o v a s c u l a r C o m p u t e d T o m o g r a p h y 8 ( 2 0 1 4 ) 9 0 e9 6
each area of plaque. If an NCP or PCP is observed, plaque volume (mm3) is measured. The napkin-ring sign was defined as a low attenuation plaque core surrounded by a circumferential area of higher attenuation.18 Adjacent coronary calcifications are evaluated by measurement of the length and width and are categorized as spotty, medium, or large, as previously reported.10 Spotty calcification measuring 50% stenosis. Measurement of plaque CT number is affected by tube voltage, the concentration of iodinated contrast agent in the lumen, and the presence of calcified lesions near the plaque.25 Evaluation of PR is not affected by these factors and therefore may be a more reliable method for assessing NCPs than evaluation of LAPs. Because the PREDICT registry includes information on serum lipid levels and medication use at the time of coronary CTA, these data can be used to evaluate relationships between coronary events and coronary risk management, such as lipid-lowering therapy or changes in serum lipid levels. Serial studies that used intravascular ultrasonography found that regression of coronary atherosclerosis induced by intensive statin therapy is related to reduced levels of low-density lipoprotein cholesterol.26,27 Studies that used coronary CTA reported changes in coronary plaque volume and other plaque characteristics in patients receiving lipid-lowering therapy with statins.28,29 The effect of management of diabetes mellitus on the progression of coronary atherosclerosis on coronary CTA and outcomes will also be analyzed by using the PREDICT data. The effects of intensive glucose-lowering therapy on cardiovascular events and mortality in patients with diabetes have not been definitively established.30 Furthermore, specific coronary atherosclerotic findings on coronary CTA in patients with diabetes will be evaluated.
4.
Conclusion
The PREDICT registry data will help to clarify the relationships between coronary CTA findings and the risks of mortality and other hard events in a collaborative multicenter fashion. The unique ability of coronary CTA to examine plaque characteristics other than the severity of stenosis will provide unique prognostic insights into CAD risk stratification in a manner that was not previously possible. The findings of the PREDICT registry analyses will be valuable for the creation of guidelines for coronary CTA indications, as well as for designing future randomized controlled trials.
Acknowledgments This study was supported by grants from the Ministry of Health, Labour and Welfare, Japan (H20-Clinical ResearchGeneral-015). A list of the PREDICT investigators and participating centers is provided in the Appendix.
J o u r n a l o f C a r d i o v a s c u l a r C o m p u t e d T o m o g r a p h y 8 ( 2 0 1 4 ) 9 0 e9 6
Appendix 4.
Assessment of coronary CTA findings 5.
Toshiro Kitagawa, Yoji Urabe, Hiroshi Tsushima, and Toshiharu Oka (Hiroshima University) were principal investigators. 6.
Assessment of coronary CTA image quality Masahiro Jinzaki (Keio University) was principal investigator. 7.
Participating centers of the PREDICT investigators Norihiko Ohashi and Hiroto Utsunomiya: Hiroshima University; Shunichi Miyazaki and Kazuhiro Kobuke: Kinki University; Tomohiro Kawasaki: Shin-Koga Hospital; Hiroyuki Daida, Eriko Matsunaga, and Ryoko Kinoshita: Juntendo University; Takashi Fujii: Hiroshima General Hospital; Yasuyuki Tomohiro and Eiji Kunita: Kure Kyosai Hospital; Aki Sato: Megumino Hospital; Yasuhiko Hayashi and Tomokazu Okimoto: Tsuchiya General Hospital; Hideo Himeno and Hideto Yano: Fujisawa City Hospital; Takeshi Kondo and Shinichiro Fujimoto: Takase Clinic; Akira Yamashina and Masaharu Hirano: Tokyo Medical University; Yoshihiro Yokoi and Kyohei Yamaji: Kokura Memorial Hospital; Noriko Inoue: Hiroshima Atomic Bomb Casualty Council Health Management & Promotion Center; Keigo Dote, Masaya Kato, and Shota Sasaki: Hiroshima City Asa Hospital; Masaki Kawamura: Yokkaichi Social Insurance Hospital; Hideo Yoshino and Haruhisa Ishiguro: Kyorin University; Shuntaro Ikeda: Uwajima City Hospital; Atsushi Hirayama and Nobuyuki Fujii: Nippon University; Osamu Doi: Shizuoka Prefecture General Hospital; Shota Fukuda and Kenei Shimada: Osaka Ekiseikai Hospital; Toshiro Miura and Tomoko Nawa: Yamaguchi University Graduate School of Medicine; Kengo Tanabe: Mitsui Memorial Hospital; Teruhito Mochizuki and Akira Kurata: Ehime University; Hiroshi Morishita: Morishita Clinic; Naoya Matsumoto: Nippon University; Yuichi Sato: Kurosawa Clinic; and Hiroshi Ohta: Itabashi Chuo Medical Center.
8.
9.
10.
11.
12.
13.
14.
references 15. 1. Miller JM, Rochitte CE, Dewey M, et al. Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med. 2008;359:2324e2336. 2. Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol. 2008;52:1724e1732. 3. Bamberg F, Sommer WH, Hoffmann V, et al. Meta-analysis and systematic review of the long-term predictive value of assessment of coronary atherosclerosis by
16.
17.
95
contrast-enhanced coronary computed tomography angiography. J Am Coll Cardiol. 2011;57:2426e2436. Hulten EA, Carbonaro S, Petrillo SP, Mitchell JD, Villines TC. Prognostic value of cardiac computed tomography: a systemic review and meta-analysis. J Am Coll Cardiol. 2011;57:1237e1247. Motoyama S, Kondo T, Sarai M, et al. Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. J Am Coll Cardiol. 2007;50:319e326. Kitagawa T, Yamamoto H, Horiguchi J, et al. Characterization of noncalcified coronary plaques and identification of culprit lesions in patients with acute coronary syndrome by 64-slice computed tomography. JACC Cardiovasc Imaging. 2009;2:153e160. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92:657e671. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000;20:1262e1275. Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes: an intravascular ultrasound study. Circulation. 2000;101:598e603. Kitagawa T, Yamamoto H, Ohashi N, et al. Comprehensive evaluation of noncalcified coronary plaque characteristics detected using 64-slice computed tomography in patients with proven or suspected coronary artery disease. Am Heart J. 2007;154:1191e1198. Jinzaki M, Okabe T, Endo A, et al. Detection of attenuated plaque in stable angina with 64-multidetector computed tomography: a comparison with intravascular ultrasound. Circ J. 2012;76:1182e1189. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD. Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction. Circulation. 2012;126:2020e2035. Braunwald E, Antman EM, Beasley JW, et al. American College of Cardiology. American Heart Association. Committee on the Management of Patients With Unstable Angina. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarctiondsummary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol. 2002;40:1366e1374. Hadamitzky M, Distler R, Meyer T, et al. Prognostic value of coronary computed tomographic angiography in comparison with calcium scoring and clinical risk scores. Circ Cardiovasc Imaging. 2011;4:16e23. Raff GL, Abidov A, Achenbach S, et al. Society of Cardiovascular Computed Tomography. SCCT guidelines for the interpretation and reporting of coronary computed tomographic angiography. J Cardiovasc Comput Tomogr. 2009;3:122e136. Tung MK, Cameron JD, Casan JM, et al. Radiation dose in 320-slice multidetector cardiac CT: a single center experience of evolving dose minimization. J Cardiovasc Comput Tomogr. 2013;7:157e166. Hoffmann U, Moselewski F, Cury RC, et al. Predictive value of 16-slice multidetector spiral computed tomography to detect significant obstructive coronary artery disease in patients at high risk for coronary artery disease: patient-versus segment-based analysis. Circulation. 2004;110:2638e2643.
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18. Seifarth H, Schlett CL, Nakano M, et al. Histopathological correlates of the napkin-ring sign plaque in coronary CT Angiography. Atherosclerosis. 2012;224:90e96. 19. Motoyama S, Sarai M, Harigaya H, et al. Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol. 2009;54:49e57. 20. Min JK, Dunning A, Lin FY, et al. CONFIRM Investigators. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: an International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol. 2011;58:849e860. 21. Russo V, Zavalloni A, Bacchi-Reggiani ML, et al. Incremental prognostic value of coronary CT angiography in patients with suspected coronary artery disease. Circ Cardiovasc Imaging. 2010;3:351e359. 22. Narula J, Nakano M, Virmani R, et al. Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and noninvasive detection of vulnerable plaques. J Am Coll Cardiol. 2013;61:1041e1051. 23. American College of Cardiology Foundation Task Force on Expert Consensus DocumentsMark DB, Berman DS, Budoff MJ, et al. ACCF/ACR/AHA/NASCI/SAIP/SCAI/SCCT 2010 expert consensus document on coronary computed tomographic angiography: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation. 2010;121:2509e2543.
24. Yamamoto H, Kitagawa T, Ohashi N, et al. Noncalcified atherosclerotic lesions with vulnerable characteristics detected by coronary CT angiography and future coronary events. J Cardiovasc Comput Tomogr. 2013;7:192e199. 25. Cademartiri F, Mollet NR, Runza G, et al. Influence of intracoronary attenuation on coronary plaque measurements using multislice computed tomography: observations in an ex vivo model of coronary computed tomography angiography. Eur Radiol. 2005;15:1426e1431. 26. Nissen SE, Tuzcu EM, Schoenhagen P, et al. REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071e1080. 27. Nissen SE, Nicholls SJ, Sipahi I, et al. ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556e1565. 28. Inoue K, Motoyama S, Sarai M, et al. Serial coronary CT angiography-verified changes in plaque characteristics as an end point: evaluation of effect of statin intervention. JACC Cardiovasc Imaging. 2010;3:691e698. 29. Kitagawa T, Yamamoto H, Horiguchi J, et al. Effects of statin therapy on non-calcified coronary plaque assessed by 64-slice computed tomography. Int J Cardiol. 2011;150:146e150. 30. Action to Control Cardiovascular Risk in Diabetes Study GroupGerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545e2559.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofCardiovascularCT.com
Clinical Trial Design
Rationale and design of the PREDICT (Plaque Registration and Evaluation Detected In Computed Tomography) registry Hideya Yamamoto MD, PhDa, Kazuo Awai MD, PhDb, Sachio Kuribayashi MD, PhDc, Yasuki Kihara MD, PhDa,*; on behalf of the PREDICT Investigators a
Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan b Department of Diagnostic Radiology, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan c Department of Diagnostic Radiology, Keio University School of Medicine, Tokyo, Japan
article info
abstract
Article history:
Background: At least two-thirds of cases of acute coronary syndrome are caused by
Received 13 June 2013
disruption of an atherosclerotic plaque. The natural history of individual plaques is
Received in revised form
unknown and needs to be established.
10 September 2013
Objectives: The Plaque Registration and Evaluation Detected In Computed Tomography
Accepted 16 December 2013
(PREDICT) registry is a prospective, multicenter, longitudinal, observational registry. This registry was designed to examine the relationships among coronary CT angiography (CTA)
Keywords:
findings and clinical findings, mortality, and morbidity. The relationships among
Coronary CT angiography
progression of coronary atherosclerosis, including changes in plaque characteristics on
Prognosis
coronary CTA, and serum lipid levels and modification of coronary risk factors will also be
Coronary plaque
evaluated.
Multicenter
Methods: From October 2009 to December 2012, 3015 patients who underwent coronary
Changes in plaque characteristics
CTA in 29 centers in Japan were enrolled. These patients were followed for 2 years. The primary end points were considered as all-cause mortality and major cardiac events, including cardiac death, nonfatal myocardial infarction, and unstable angina that required hospitalization. The secondary end points were heart failure that required administration of diuretics, target vessel revascularization, cerebral infarction, peripheral arterial disease, and invasive coronary angiography. Blood pressure, serum lipid, and C-reactive protein levels and all cardiovascular events were recorded at 1 and 2 years. If the initial coronary CTA showed any stenosis or plaques, follow-up coronary CTA was scheduled at 2 years to determine changes in coronary lesions, including changes in plaque characteristics. Conclusion: Analysis of the PREDICT registry data will clarify the relationships between coronary CTA findings and cardiovascular mortality and morbidity in a collaborative
Conflict of interest: The authors report no conflict of interest. * Corresponding author. E-mail address: [email protected] (Y. Kihara). 1934-5925/$ e see front matter ª 2014 Society of Cardiovascular Computed Tomography. All rights reserved. http://dx.doi.org/10.1016/j.jcct.2013.12.004
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91
multicenter fashion. This trial is registered at www.clinicaltrials.gov as NCT 00991835. ª 2014 Society of Cardiovascular Computed Tomography. All rights reserved.
1.
Introduction
Coronary CT angiography (CTA) with the use of 64 or more detector rows is a recently introduced noninvasive method of evaluating coronary artery disease (CAD) with high diagnostic accuracy for the detection or exclusion of obstructive CAD.1,2 Coronary CTA findings about the presence and extent of CAD were reported to be strong predictors of cardiovascular events.3,4 Coronary CTA is also expected to be a useful tool for evaluating plaque characteristics because it can visualize the structure of coronary vessels and morphologic features of coronary plaques.5,6 Acute coronary syndrome is mainly attributable to the acute rupture of vulnerable plaques, characterized by positive remodeling with lipid-rich, thin fibroatheroma and subsequent thrombus formation.7,8 Several studies that used intravascular ultrasonography have reported that coronary positive vessel remodeling (PR), low-attenuation plaques (LAPs), and spotty calcification are associated with plaque vulnerability.9e11 Therefore, it is crucial to detect and stabilize rupture-prone plaques noninvasively to prevent cardiovascular events. The characteristics of coronary plaques are hypothesized to predict future coronary events. The Plaque Registration and Evaluation Detected In Computed Tomography (PREDICT) registry was developed to provide a database of coronary CTA findings that could be used to identify risk factors for cardiac events. This report describes the rationale and design of the PREDICT registry.
2.
Methods
2.1.
Overall study design
The PREDICT registry is a prospective, multicenter, observational registry designed to examine the relationships among coronary CTA findings and clinical findings, mortality, and specific events in patients with clinically suspected and proven CAD (Fig. 1). This registry uses a novel collaborative design that merges similar prospectively enrolled cohorts from 29 hospitals in Japan. This study is registered at www. clinicaltrials.gov as NCT 00991835.
2.2.
Study objectives
The primary objective of the PREDICT registry is to examine the relationships among coronary CTA findings and demographic data, clinical data, and events caused by CAD in the 3015 enrolled patients. Specifically, the registry data will be analyzed to identify specific coronary CTA findings that can predict cardiovascular events during the next 2 years and to clarify the associations between plaque characterization on coronary CTA and culprit lesions at the time of presentation of acute coronary syndrome. The secondary objectives of the PREDICT registry include the following: to examine the relationships among coronary CTA findings and clinical risk factors and therapeutic interventions for CAD and to evaluate relationships among
Fig. 1 e Chart of study design. CTA, CT angiography; ECG, electrocardiogram.
92
J o u r n a l o f C a r d i o v a s c u l a r C o m p u t e d T o m o g r a p h y 8 ( 2 0 1 4 ) 9 0 e9 6
serum lipid levels, plasma glucose levels, hemoglobin A1c levels, and renal function and changes in coronary plaques during the 2-year follow-up period. The details of the secondary objectives are shown in Table 1.
2.3.
Ethical considerations
The institutional review board of each participating institution reviewed and approved the study protocol and other documents. All subjects gave written informed consent for inclusion.
2.4.
Targeted population
The targeted population included patients with suspected or known CAD aged 20 years who were referred to an outpatient clinic and underwent coronary CTA. The exclusion criteria were as follows: (1) irregular heart rhythm or tachycardia (>90 beats/min), (2) iodine allergy, (3) chronic kidney disease (serum creatine levels: male patients, >1.4 mg/dL, female patients, >1.1 mg/dL), (4) prior coronary artery bypass grafting, (5) implanted pacemaker or cardioverterdefibrillator, (6) ST-elevation myocardial infarction (MI) or hemodynamically unstable, (7) severe heart failure (New York Heart Association class IV) or cardiogenic shock, (8) inability to hold breathing, (9) advanced malignancy, and (10) prior stenting of bilateral coronary arteries.
2.5.
Participating centers
Twenty-nine centers contributed data from patients who underwent coronary CTA of 64 or more detector rows. Data collection activity began in October 2009 with the goal of enrolling 3015 patients, and this was achieved in December 2012.
2.6.
Patient recruitment and evaluation
All patients underwent coronary CTA as directed by a physician. Data describing patient characteristics were prospectively collected at the time of the coronary CTA examination, including demographic information, targeted medical history,
and cardiovascular risk factors. Data were recorded with sitespecific case report forms. Data about the indications for coronary CTA and the characteristics of any chest pain were also recorded. Blood pressure, body mass index (calculated at weight divided by height squared; kg/m2), and waist circumference were measured, and electrocardiography (ECG) was performed. Blood was drawn to measure the leukocyte count; serum levels of lipids, creatinine, uric acid, and C-reactive protein; plasma glucose levels, and hemoglobin A1c levels.
2.7.
Patient follow-up
Patient information was obtained by direct or telephone interviews with patients or their families by dedicated physicians at each participating center. All enrolled patients were followed for the primary end points of all-cause mortality and major cardiac events, including cardiac death, nonfatal MI, and unstable angina that required hospitalization. Acute MI was defined as an increase in cardiac enzyme levels with symptoms suggestive of cardiac ischemia and new STeT changes or Q waves on ECG.12 Unstable angina was defined according to the Braunwald classification.13 In cases of acute coronary syndrome (acute MI and unstable angina), the culprit lesion was determined by dedicated physicians on the basis of on ECG, echocardiographic, and invasive coronary angiographic findings. Other events, including target vessel revascularization, heart failure that required administration of diuretics, cerebrovascular disease, aortic disease, peripheral arterial disease, and invasive coronary angiography, were also recorded. Elective coronary revascularization on the basis of coronary CTA findings was defined as early if it was performed 130 HU in a native image, or greater than the contrast-enhanced vessel lumen in a contrast-enhanced image. The presence and extent of each type of plaque are determined for each subject. The coronary plaque characteristics on coronary CTA are evaluated as previously described by determining the minimum CT number and vascular remodeling index.6,10 The outer circumference of the vessel and the lumen are manually traced. Vascular remodeling is assessed by using the remodeling index (proximal reference cross-sectional vessel area/ lesion cross-sectional vessel area) in cross-sectional images.17 The minimum CT number is determined for each plaque by setting at least 5 regions of interest (each region ¼ 1 mm2) in
94
J o u r n a l o f C a r d i o v a s c u l a r C o m p u t e d T o m o g r a p h y 8 ( 2 0 1 4 ) 9 0 e9 6
each area of plaque. If an NCP or PCP is observed, plaque volume (mm3) is measured. The napkin-ring sign was defined as a low attenuation plaque core surrounded by a circumferential area of higher attenuation.18 Adjacent coronary calcifications are evaluated by measurement of the length and width and are categorized as spotty, medium, or large, as previously reported.10 Spotty calcification measuring 50% stenosis. Measurement of plaque CT number is affected by tube voltage, the concentration of iodinated contrast agent in the lumen, and the presence of calcified lesions near the plaque.25 Evaluation of PR is not affected by these factors and therefore may be a more reliable method for assessing NCPs than evaluation of LAPs. Because the PREDICT registry includes information on serum lipid levels and medication use at the time of coronary CTA, these data can be used to evaluate relationships between coronary events and coronary risk management, such as lipid-lowering therapy or changes in serum lipid levels. Serial studies that used intravascular ultrasonography found that regression of coronary atherosclerosis induced by intensive statin therapy is related to reduced levels of low-density lipoprotein cholesterol.26,27 Studies that used coronary CTA reported changes in coronary plaque volume and other plaque characteristics in patients receiving lipid-lowering therapy with statins.28,29 The effect of management of diabetes mellitus on the progression of coronary atherosclerosis on coronary CTA and outcomes will also be analyzed by using the PREDICT data. The effects of intensive glucose-lowering therapy on cardiovascular events and mortality in patients with diabetes have not been definitively established.30 Furthermore, specific coronary atherosclerotic findings on coronary CTA in patients with diabetes will be evaluated.
4.
Conclusion
The PREDICT registry data will help to clarify the relationships between coronary CTA findings and the risks of mortality and other hard events in a collaborative multicenter fashion. The unique ability of coronary CTA to examine plaque characteristics other than the severity of stenosis will provide unique prognostic insights into CAD risk stratification in a manner that was not previously possible. The findings of the PREDICT registry analyses will be valuable for the creation of guidelines for coronary CTA indications, as well as for designing future randomized controlled trials.
Acknowledgments This study was supported by grants from the Ministry of Health, Labour and Welfare, Japan (H20-Clinical ResearchGeneral-015). A list of the PREDICT investigators and participating centers is provided in the Appendix.
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Appendix 4.
Assessment of coronary CTA findings 5.
Toshiro Kitagawa, Yoji Urabe, Hiroshi Tsushima, and Toshiharu Oka (Hiroshima University) were principal investigators. 6.
Assessment of coronary CTA image quality Masahiro Jinzaki (Keio University) was principal investigator. 7.
Participating centers of the PREDICT investigators Norihiko Ohashi and Hiroto Utsunomiya: Hiroshima University; Shunichi Miyazaki and Kazuhiro Kobuke: Kinki University; Tomohiro Kawasaki: Shin-Koga Hospital; Hiroyuki Daida, Eriko Matsunaga, and Ryoko Kinoshita: Juntendo University; Takashi Fujii: Hiroshima General Hospital; Yasuyuki Tomohiro and Eiji Kunita: Kure Kyosai Hospital; Aki Sato: Megumino Hospital; Yasuhiko Hayashi and Tomokazu Okimoto: Tsuchiya General Hospital; Hideo Himeno and Hideto Yano: Fujisawa City Hospital; Takeshi Kondo and Shinichiro Fujimoto: Takase Clinic; Akira Yamashina and Masaharu Hirano: Tokyo Medical University; Yoshihiro Yokoi and Kyohei Yamaji: Kokura Memorial Hospital; Noriko Inoue: Hiroshima Atomic Bomb Casualty Council Health Management & Promotion Center; Keigo Dote, Masaya Kato, and Shota Sasaki: Hiroshima City Asa Hospital; Masaki Kawamura: Yokkaichi Social Insurance Hospital; Hideo Yoshino and Haruhisa Ishiguro: Kyorin University; Shuntaro Ikeda: Uwajima City Hospital; Atsushi Hirayama and Nobuyuki Fujii: Nippon University; Osamu Doi: Shizuoka Prefecture General Hospital; Shota Fukuda and Kenei Shimada: Osaka Ekiseikai Hospital; Toshiro Miura and Tomoko Nawa: Yamaguchi University Graduate School of Medicine; Kengo Tanabe: Mitsui Memorial Hospital; Teruhito Mochizuki and Akira Kurata: Ehime University; Hiroshi Morishita: Morishita Clinic; Naoya Matsumoto: Nippon University; Yuichi Sato: Kurosawa Clinic; and Hiroshi Ohta: Itabashi Chuo Medical Center.
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references 15. 1. Miller JM, Rochitte CE, Dewey M, et al. Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med. 2008;359:2324e2336. 2. Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol. 2008;52:1724e1732. 3. Bamberg F, Sommer WH, Hoffmann V, et al. Meta-analysis and systematic review of the long-term predictive value of assessment of coronary atherosclerosis by
16.
17.
95
contrast-enhanced coronary computed tomography angiography. J Am Coll Cardiol. 2011;57:2426e2436. Hulten EA, Carbonaro S, Petrillo SP, Mitchell JD, Villines TC. Prognostic value of cardiac computed tomography: a systemic review and meta-analysis. J Am Coll Cardiol. 2011;57:1237e1247. Motoyama S, Kondo T, Sarai M, et al. Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. J Am Coll Cardiol. 2007;50:319e326. Kitagawa T, Yamamoto H, Horiguchi J, et al. Characterization of noncalcified coronary plaques and identification of culprit lesions in patients with acute coronary syndrome by 64-slice computed tomography. JACC Cardiovasc Imaging. 2009;2:153e160. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92:657e671. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000;20:1262e1275. Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes: an intravascular ultrasound study. Circulation. 2000;101:598e603. Kitagawa T, Yamamoto H, Ohashi N, et al. Comprehensive evaluation of noncalcified coronary plaque characteristics detected using 64-slice computed tomography in patients with proven or suspected coronary artery disease. Am Heart J. 2007;154:1191e1198. Jinzaki M, Okabe T, Endo A, et al. Detection of attenuated plaque in stable angina with 64-multidetector computed tomography: a comparison with intravascular ultrasound. Circ J. 2012;76:1182e1189. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD. Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction. Circulation. 2012;126:2020e2035. Braunwald E, Antman EM, Beasley JW, et al. American College of Cardiology. American Heart Association. Committee on the Management of Patients With Unstable Angina. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarctiondsummary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol. 2002;40:1366e1374. Hadamitzky M, Distler R, Meyer T, et al. Prognostic value of coronary computed tomographic angiography in comparison with calcium scoring and clinical risk scores. Circ Cardiovasc Imaging. 2011;4:16e23. Raff GL, Abidov A, Achenbach S, et al. Society of Cardiovascular Computed Tomography. SCCT guidelines for the interpretation and reporting of coronary computed tomographic angiography. J Cardiovasc Comput Tomogr. 2009;3:122e136. Tung MK, Cameron JD, Casan JM, et al. Radiation dose in 320-slice multidetector cardiac CT: a single center experience of evolving dose minimization. J Cardiovasc Comput Tomogr. 2013;7:157e166. Hoffmann U, Moselewski F, Cury RC, et al. Predictive value of 16-slice multidetector spiral computed tomography to detect significant obstructive coronary artery disease in patients at high risk for coronary artery disease: patient-versus segment-based analysis. Circulation. 2004;110:2638e2643.
96
J o u r n a l o f C a r d i o v a s c u l a r C o m p u t e d T o m o g r a p h y 8 ( 2 0 1 4 ) 9 0 e9 6
18. Seifarth H, Schlett CL, Nakano M, et al. Histopathological correlates of the napkin-ring sign plaque in coronary CT Angiography. Atherosclerosis. 2012;224:90e96. 19. Motoyama S, Sarai M, Harigaya H, et al. Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol. 2009;54:49e57. 20. Min JK, Dunning A, Lin FY, et al. CONFIRM Investigators. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: an International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol. 2011;58:849e860. 21. Russo V, Zavalloni A, Bacchi-Reggiani ML, et al. Incremental prognostic value of coronary CT angiography in patients with suspected coronary artery disease. Circ Cardiovasc Imaging. 2010;3:351e359. 22. Narula J, Nakano M, Virmani R, et al. Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and noninvasive detection of vulnerable plaques. J Am Coll Cardiol. 2013;61:1041e1051. 23. American College of Cardiology Foundation Task Force on Expert Consensus DocumentsMark DB, Berman DS, Budoff MJ, et al. ACCF/ACR/AHA/NASCI/SAIP/SCAI/SCCT 2010 expert consensus document on coronary computed tomographic angiography: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation. 2010;121:2509e2543.
24. Yamamoto H, Kitagawa T, Ohashi N, et al. Noncalcified atherosclerotic lesions with vulnerable characteristics detected by coronary CT angiography and future coronary events. J Cardiovasc Comput Tomogr. 2013;7:192e199. 25. Cademartiri F, Mollet NR, Runza G, et al. Influence of intracoronary attenuation on coronary plaque measurements using multislice computed tomography: observations in an ex vivo model of coronary computed tomography angiography. Eur Radiol. 2005;15:1426e1431. 26. Nissen SE, Tuzcu EM, Schoenhagen P, et al. REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071e1080. 27. Nissen SE, Nicholls SJ, Sipahi I, et al. ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556e1565. 28. Inoue K, Motoyama S, Sarai M, et al. Serial coronary CT angiography-verified changes in plaque characteristics as an end point: evaluation of effect of statin intervention. JACC Cardiovasc Imaging. 2010;3:691e698. 29. Kitagawa T, Yamamoto H, Horiguchi J, et al. Effects of statin therapy on non-calcified coronary plaque assessed by 64-slice computed tomography. Int J Cardiol. 2011;150:146e150. 30. Action to Control Cardiovascular Risk in Diabetes Study GroupGerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545e2559.
