Comprehensive assessment of radiation dose estimates for the CORE320 study.

Cardiopulmonar y Imaging • Original Research Rybicki et al. Radiation Dose Estimates

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Cardiopulmonary Imaging Original Research

Frank J. Rybicki1 Richard T. Mather 2 Kanako K. Kumamaru1 Jeffrey Brinker 3 Marcus Y. Chen 4 Christopher Cox 5 Matthew B. Matheson5 Marc Dewey 6 Marcelo F. DiCarli 7 Julie M. Miller 3 Jacob Geleijns 8 Richard T. George 3 Narinder Paul 9 John Texter 3 Andrea Vavere 3 Tan Swee Yaw 10 Joao A. C. Lima3 Melvin E. Clouse11 Rybicki FJ, Mather RT, Kumamaru KK, et al. Keywords: coronary angiography, coronary vessels, CT, radiation dose, SPECT DOI:10.2214/AJR.13.12375 Received November 28, 2013; accepted after revision April 12, 2014. M. Dewey, J. Brinker, C. Cox, M. F. DiCarli, R. T. George, J. M. Miller, T. S. Yaw, A. Vavere, J. A. C. Lima, N. Paul, and F. J. Rybicki report that their institutions receive grant support from Toshiba Medical Systems. M. Dewey, T. S. Yaw, and N. Paul are on the speakers bureau for Toshiba Medical Systems Corporation. M. Dewey and R. T. George report grant support from GE Healthcare; M. Dewey and J. A. C. Lima, from Bracco Diagnostics; M. Dewey, from European Regional Development Fund, German Heart Foundation, Guerbet, German Science Foundation, and German Federal Ministry of Education and Research.

Comprehensive Assessment of Radiation Dose Estimates for the CORE320 Study OBJECTIVE. The purpose of this study was to comprehensively study estimated radiation doses for subjects included in the main analysis of the Combined Non-invasive Coronary Angiography and Myocardial Perfusion Imaging Using 320 Detector Computed Tomography (CORE320) study (ClinicalTrials.gov identifier NCT00934037), a clinical trial comparing combined CT angiography (CTA) and perfusion CT with the reference standard catheter angiography plus myocardial perfusion SPECT. SUBJECTS AND METHODS. Prospectively acquired data on 381 CORE320 subjects were analyzed in four groups of testing related to radiation exposure. Radiation dose estimates were compared between modalities for combined CTA and perfusion CT with respect to covariates known to influence radiation exposure and for the main clinical outcomes defined by the trial. The final analysis assessed variations in radiation dose with respect to several factors inherent to the trial. RESULTS. The mean radiation dose estimate for the combined CTA and perfusion CT protocol (8.63 mSv) was significantly (p < 0.0001 for both) less than the average dose delivered from SPECT (10.48 mSv) and the average dose from diagnostic catheter angiography (11.63 mSv). There was no significant difference in estimated CTA–perfusion CT radiation dose for subjects who had false-positive or false-negative results in the CORE320 main analyses in a comparison with subjects for whom the CTA–perfusion CT findings were in accordance with the reference standard SPECT plus catheter angiographic findings. CONCLUSION. Radiation dose estimates from CORE320 support clinical implementation of a combined CT protocol for assessing coronary anatomy and myocardial perfusion.

C

ombined Non-invasive Coronary Angiography and Myocardial Perfusion Imaging Using 320 Detector Computed Tomography (CORE320) is a multicenter, multinational study conducted by centralized blinded analyses with 381 subjects [1, 2] that supports [3]

an integrated approach combining 320 × 0.5 mm detector row (Aquilion One, Toshiba Medical Systems) CT angiography (CTA) and myocardial perfusion CT to identify subjects with flow-limiting coronary artery disease (CAD). The main conclusion from the study was that patients with flow-limiting

1 Department of Radiology, Applied Imaging Science Laboratory, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis St, Boston, MA 02115. Address correspondence to F. J. Rybicki ([email protected]).

M. Dewey is on the speakers bureaus of Guerbet and Bayer Schering Pharma and consults for Guerbet.

2 3

Johns Hopkins Hospital and School of Medicine, Baltimore, MD.

R. T. George consults for ICON Medical Imaging and reports paid board membership for GE Healthcare and Astellas Pharma.

4

National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD.

WEB This is a web exclusive article. AJR 2015; 204:W27–W36

Toshiba Medical Research Institute, Vernon Hills, IL.

5

Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

6

Charité Medical School, Humboldt, Berlin, Germany.

7

Brigham and Women’s Hospital and Harvard Medical School, Boston, MA.

8

Leiden University Medical Center, Leiden, The Netherlands.

9

Toronto General Hospital, Toronto, Canada.

0361–803X/15/2041–W27

10

© American Roentgen Ray Society

11

National Heart Center, Singapore, Singapore.

Department of Radiology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.

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Rybicki et al. CAD were correctly identified with a combined 320-MDCT angiography and perfusion CT protocol. Radiation exposure is a key element in the integration of CT-based methods into the work flow for the evaluation of patients with clinical suspicion of CAD. In particular, it would be desirable for perfusion CT methods and a combined CTA plus perfusion CT study to have radiation doses comparable to, or less than, those of reference standard imaging. This secondary analysis focuses on the estimated radiation doses for subjects reported in the main analyses [3]. The collected CORE320 imaging, clinical, and demographic data provide a platform for comprehensive hypothesis testing related to CT radiation exposure. These data provide insights regarding the clinical implementation of integrated CT approaches for comprehensive CAD assessment. The purpose of this study was to comprehensively assess the radiation dose profile in CORE320. Four sets of analyses were conducted to compare radiation dose estimates according to imaging modality, patient characteristics that influence radiation exposure, published test characteristics from each of the 381 subjects included in the main analyses, and factors specific to the CORE320 methods. Subjects and Methods Subject Population CORE320 study is a prospective, diagnostic study performed at 16 centers in eight countries (ClinicalTrials.gov identifier NCT00934037). Adverse events were tracked, reported, and reviewed by an independent data safety and monitoring board. All centers received study approval from their local institutional review boards, and all patients gave written informed consent. The records of 381 of the total 436 eligible CORE320 subjects were available for analysis (Fig. 1). Comprehensive study inclusion criteria have been described elsewhere [2].

Image Acquisition Each of the 381 subjects underwent CT calcium scoring, coronary CTA, adenosine stress perfusion CT, SPECT, and catheter angiography. Calcium scoring plus a combined CTA and perfusion CT protocol was performed before catheter angiography, as was exercise or pharmacologic stress SPECT myocardial perfusion imaging (MPI). Subjects for whom SPECT MPI was not part of their clinical care underwent this study as part of the research protocol. Comprehensive protocol details have been described [1, 2].

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444 Patients consented 8 Screen failures 436 Eligible patients Imaging not performed 14 Invasive angiography not performed 6 CT and invasive angiography not performed 5 Stress CT not performed 1 Stress CT and SPECT not performed 1 SPECT and invasive angiography not performed 1 SPECT not performed 1 Stress CT, SPECT, and invasive angiography not performed

407 Eligible patients Technical failure 12 SPECT technical failure 3 Rest and stress CT technical failure 1 Invasive angiography technical failure

391 Eligible patients Stress CT incomplete imaging 6 Stress CT not performed 4 Stress CT could not be read

381 Eligible patients successfully completed imaging Fig. 1—Flowchart shows patient selection between eligible subjects (n = 436) and those who were included in main CORE360 analyses and are subjects in this radiation dose analysis. (Reproduced from Rochitte CE, George RT, Chen MY, et al. Computed tomography angiography and perfusion to assess coronary artery stenosis causing perfusion defects by single photon emission computed tomography: the CORE320 study. Eur Heart J 2014; 35 (17):1120–1130, by permission of Oxford University Press)

Radiation Dose Estimates A CORE320 radiation dose committee was formed to ensure comprehensive collection, analysis, and reporting of radiation dose estimates compiled by a centralized core laboratory. All 381 subjects had data regarding radiation dose available for analysis. Regarding catheter angiography, 14 subjects, the entire subpopulation from one of the recruiting sites, were excluded because the recorded data on radiation dose were considered unreliable after adjudication. For CT, the effective dose was estimated by recording the dose-length product and was converted to a whole-body effective dose estimate by use of the weighting factor k = 0.014 mSv/mGy ⋅ cm [4]. Whole-body effective dose was estimated for SPECT by use of the administered radiopharmaceutical dose and the methods of International Commission on Radiological Protection publication 80 [5]. For patients who received 99mTc-sestamibi, the administered activity in megabecquerels was converted to an estimated wholebody effective dose in millisieverts by use of a factor of 0.009 mSv/MBq at rest and 0.0079 mSv/ MBq during stress. The corresponding conversions for patients who received 99mTc-tetrofosmin were

0.0076 mSv/MBq at rest and 0.007 mSv/MBq during stress [6]. For catheter angiography, the effective dose was estimated from the dose area product (DAP) during the examination. The DAP (product of grays and square centimeters) was recorded from the console after completion of the diagnostic portion of the examination. For subjects who underwent an intervention, a second DAP at completion of the procedure was recorded. DAP values were converted to whole-body effective doses by use of standard methods with a conversion factor of 0.20 mSv/Gy ⋅ cm2 [7–9]. The whole-body effective dose was reported for all subjects and then individually among patients who had femoral access versus those who had upper extremity access.

CORE320 Radiation Dose Estimate Testing Analysis group 1: radiation stratified by imaging modality—The purposes in analysis group 1 were as follows: first, to evaluate the estimated radiation dose from combined CTA and perfusion CT with respect to SPECT MPI and with respect to the diagnostic portion of the catheter angiography and, second, to evaluate the summed radiation dose estimates from components of all CT acqui-

AJR:204, January 2015


Radiation Dose Estimates

Fig. 2—60-year-old woman with clinically suspected coronary artery disease. Representative images of coronary arteries and myocardium. A, Multiplanar reformatted image of left anterior descending coronary artery shows lesion in middle portion of artery. Estimated radiation dose is 2.7 mSv. B, Catheter angiogram corresponding to A. Estimated radiation dose is 2.6 mSv. C, Horizontal long-axis adenosine stress CT image of heart shows perfusion abnormality in anterior myocardium near apex. Estimated radiation dose is 4.7 mSv. D, SPECT image corresponding to C. Estimated radiation dose is 13 mSv.

A

B

C sitions (including scan planning, calcium scoring, and combined CTA and perfusion CT) with respect to the radiation dose from SPECT MPI and with respect to the radiation dose from the diagnostic portion of catheter angiography. Analysis group 2: relation between CT dose and patient-based parameters that typically influence CT radiation exposure—The purposes in analysis group 2 were as follows: first, to examine a correlation between patient body mass index (BMI) and estimated radiation dose from CT; second, to examine a correlation between the craniocaudal scan length required to encompass the heart and estimated radiation dose from CT; and third, to examine a correlation between the number of heartbeats used for CT acquisition and the estimated radiation dose from CT.

Analysis group 3: relation between radiation doses and subject-based outcomes—The purpose in analysis group 3 was as follows: Considering the per-subject diagnostic performance of combined CTA plus perfusion CT in detecting a hemodynamically significant lesion with respect to reference standard catheter angiography (> 50% stenosis) with a corresponding SPECT defect, to test the hypothesis that there is no significant correlation between the radiation dose delivered by CT and the study outcome (true-positive, truenegative, false-positive, false-negative) assigned to the subject. Analysis group 4: relation between radiation doses and CORE320 subject-based parameters, including demographic data and parameters specific to the protocol—The purposes in analy-

D sis group 4 were as follows: first, to test the hypothesis that there is no significant correlation between total radiation dose or radiation dose by modality and each of the three demographic parameters sex, age, and continent on which the patient underwent imaging; second, regarding SPECT data acquisition, to test the hypothesis that there is no difference in radiation dose estimates when subjects are separated into those who underwent SPECT for a clinical indication versus those who underwent research SPECT; third, regarding SPECT data acquisition, to test the hypothesis that there is no difference in radiation dose estimates with respect to the method by which stress was induced; and fourth, to test the hypothesis that there is no difference in radiation dose estimates among subjects who did



Rybicki et al. versus who did not have CAD, defined as positive for a subject if there were one or more coronary lesions with ≥ 50% stenosis found with quantitative coronary angiography applied to catheterization images and to examine whether subjects who underwent percutaneous coronary intervention (PCI) did not have higher radiation doses compared with subjects for whom PCI was not attempted.

Statistical Analyses Descriptive data included median and quartiles or mean and SD and percentages for categoric variables. The estimated radiation dose was treated as a continuous outcome variable in all analyses. Data were analyzed by univariate and multiple linear regression and analysis of variance. Each analysis included an examination of residuals as a check on the required assumptions of normally distributed errors with constant variance. For analyses involving repeated measurements of the same subjects, for example, by different imaging modalities, linear mixed models with a random subject effect were used. Where appropriate, p values were adjusted for multiplicity by use of the Tukey-Kramer method. For analysis groups 2 and 4, both individual and fully adjusted regression models were used to examine each predictor separately and to control for all other predictors of interest. Covariates for analysis group 4 included continent on which imaging was performed, sex, age, reason for SPECT (clinical indication vs research), method of stress induction (exercise vs pharmacologic), radiotracer (tetrofosmin vs sestamibi), stenosis ≥ 50% as found with quantitative coronary angiography, and attempted PCI. All covariates were examined for effects on to-

tal radiation dose, but only selected covariates were examined for effects on each individual radiation dose (CT, SPECT, and catheterization).

Results Analysis Group 1: Radiation Stratified by Imaging Modality The difference in mean radiation doses from the combined CTA and perfusion CT studies (8.63 mSv) (Table 1) and the total dose from CT (11.07 mSv) (Table 2) reflected the radiation from CT calcium scoring and the images used for planning. The combined CTA and perfusion CT radiation dose was statistically significantly (p < 0.0001) lower than the mean (10.48 mSv) from SPECT MPI and statistically significantly (p < 0.0001) lower than the mean from the diagnostic portion of conventional angiography (11.63 mSv). Considering the total radiation dose from all CT (Table 2), there was no statistically significant difference between the mean estimated dose from CT (11.07 mSv) and that from the reference standard modalities (Fig. 2).

TABLE 1: Mean Radiation Dose Estimates in Millisieverts for the CORE320 Imaging Modalities Radiation Source

Mean ± SD

CT calcium scoring

0.97 ± 0.56

CT angiography

3.54 ± 1.52

Myocardial perfusion CT

5.09 ± 1.41

CT total

11.07 ± 2.44

SPECT

10.48 ± 2.86

Catheterization

11.63 ± 7.12

Note—CT total includes CT angiography, perfusion CT, CT calcium scoring, and the images used for planning.

Analysis Group 2: Relation Between CT Dose and Patient-Based Parameters That Typically Influence CT Radiation Exposure For CTA, perfusion CT, and the combined CTA and perfusion CT protocol, higher radiation doses were delivered to subjects with a larger BMI, a greater craniocaudal scan length needed to encompass the heart, and

TABLE 2: Estimated Difference in Radiation Dose Estimates in Millisieverts Between CT Total, CT Angiography Plus Perfusion CT, SPECT, and Catheterization

Radiation Source

Estimated Difference From CT Angiography Plus Perfusion CT 0

CT angiography plus perfusion CT

p

Estimated Difference From CT Total

p

NA

NA

NA

SPECT

1.85

< 0.0001

−0.59

0.18

Catheterization

3.01

< 0.0001

0.57

0.20

Note—CT total includes CT angiography, perfusion CT, CT calcium scoring, and the images used for planning. NA = not applicable.

TABLE 3: CT Angiographic and Perfusion CT Radiation Dose Relations With Respect to Body Mass Index, Craniocaudal FOV, and Total Number of Heartbeats Used in the CT Acquisitions Radiation Source CT angiography

Perfusion CT

CT angiography plus perfusion CT

Covariate

Individual Estimated Effect

p

Multivariate Estimated Effect

p

BMI

0.04 (0.02)

0.04

0.08 (0.007)

< 0.0001

FOV

0.02 (0.008)

0.007

0.03 (0.003)

< 0.0001

No. of heartbeats

4.94 (0.14)

< 0.0001

5.15 (0.12)

< 0.0001

BMI

0.09 (0.01)

< 0.0001

0.07 (0.008)

< 0.0001

FOV

0.04 (0.007)

< 0.0001

0.05 (0.004)

< 0.0001

No. of heartbeats

2.40 (0.10)

< 0.0001

2.35 (0.08)

< 0.0001

BMI

0.13 (0.02)

< 0.0001

0.13 (0.01)

< 0.0001

FOV

0.06 (0.01)

< 0.0001

0.07 (0.005)

< 0.0001

No. of heartbeats

3.08 (0.13)

< 0.0001

3.13 (0.09)

< 0.0001

Note—Values in parentheses are standard error. Each covariate was first assessed individually for each radiation source then assessed multivariately with control for all covariates. All regression models, individual and multivariate, were adjusted for age and sex. In the CT angiography plus perfusion CT model, craniocaudal scan length was taken as the maximum value from CT angiography and perfusion CT, and number of heartbeats was taken as the sum of the values from CT angiography and perfusion CT. BMI = body mass index.

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total number of heartbeats used in the CT acquisition (Table 3). Analysis Group 3: Relation Between Radiation Doses and Subject-Based Outcomes The primary hypothesis in CORE320 entailed a per-subject diagnostic performance evaluation of combined CTA plus perfusion CT to detect a hemodynamically significant lesion; SPECT and catheterization data were the reference standard. Thus all 381 subjects were assigned one of four test characteristics (true-positive, true-negative, false-positive,

TABLE 4: Comparison Between CT Dose and the Test Characteristics of the CORE320 Primary Hypothesis Estimated Difference in CT Dose (mSv)

p

False-negative vs false-positive

−0.18 (0.68)

0.99

False-negative vs true-negative

−0.39 (0.67)

0.93

False-negative vs true-positive

−0.71 (0.67)

0.71

Comparison

False-positive vs true-negative

−0.22 (0.32)

0.91

False-positive vs true-positive

−0.53 (0.32)

0.35

True-negative vs true-positive

−0.32 (0.30)

0.72

Note—Overall p = 0.35. Values in parentheses are standard error.

TABLE 5: Median and Interquartile Range of Radiation Dose Estimates in Millisieverts for the CORE320 Imaging M odalities Stratified by Demographic Data, Parameters Specific to the Protocol, and Findings at C atheterization Characteristic

CT

SPECT

Catheterizationa

Totala

Sex Men (n = 251)

11.23 (9.39–12.72)

9.68 (9.10–12.62)

13.00 (8.64–19.80)

34.53 (29.76–41.52)

Women (n = 129)

10.31 (9.23–11.53)

11.52 (9.11–13.58)

10.30 (5.20–14.60)

30.87 (26.03–37.62)

North America (n = 89)

10.68 (9.11–12.51)

9.70 (9.38–12.04)

12.20 (8.20–16.40)

32.62 (28.14–39.23)

South America (n = 119)

11.92 (10.61–13.06)

13.02 (12.17–14.23)

9.70 (3.40–17.10)

35.49 (29.35–43.31)

Europe (n = 77)

10.55 (9.26–11.53)

5.14 (4.63–13.32)

11.34 (6.62–16.92)

29.41 (25.72–34.58)

Asia (n = 96)

10.02 (8.46–11.34)

9.10 (9.10–9.68)

14.60 (11.00–20.07)

34.10 (30.44–41.78)

Continent

Body mass index 9.65 (8.48–11.16)

9.68 (9.10–12.10)

9.60 (6.70–14.00)

30.48 (26.24–34.40)

25–29 (n = 157)

< 25 (n = 127)

10.98 (9.88–12.24)

9.75 (9.10–13.35)

12.00 (8.08–18.00)

34.34 (29.35–40.35)

30–34 (n = 78)

11.65 (10.76–12.72)

10.31 (9.10–12.95)

16.06 (9.90–22.00)

36.23 (31.15–45.34)

≥ 35 (n = 18)

12.55 (11.69–13.06)

13.03 (11.91–14.13)

14.30 (10.60–20.40)

40.93 (31.41–44.94)

Clinical (n = 157)

10.72 (9.26–12.19)

9.10 (5.19–11.81)

13.00 (9.17–20.07)

33.34 (28.41–40.51)

Research (n = 224)

10.98 (9.43–12.47)

10.69 (9.68–13.40)

11.00 (6.70–16.40)

32.89 (28.14–39.61)

SPECT Purpose

Method of stress Exercise (n = 124)

10.63 (9.14–11.87)

9.00 (4.91–9.10)

12.92 (8.82–20.27)

31.86 (27.21–40.35)

Pharmacologic (n = 256)

11.01 (9.45–12.65)

11.04 (9.68–13.51)

11.80 (7.11–16.80)

33.46 (28.86–40.24)

Sestamibi (n = 311)

10.91 (9.47–12.39)

9.97 (9.34–13.22)

11.83 (7.35–17.04)

32.65 (28.18–39.51)

Tetrofosmin (n = 38)

9.83 (8.30–11.25)

9.10 (9.10–9.10)

29.60 (11.78–43.16)

50.12 (29.94–65.07)

Radiotracer

Catheterization Percutaneous coronary intervention Not attempted (n = 319)

10.85 (9.33–12.39)

9.97 (9.10–13.16)

11.00 (6.96–15.40)

32.07 (27.86–37.72)

Attempted (n = 61)

10.97 (9.01–12.25)

9.51 (7.72–12.04)

22.48 (14.58–33.40)

40.63 (33.78–53.70)

No stenosis > 50% (n = 155)

10.77 (9.57–12.22)

9.97 (9.10–13.20)

9.80 (5.60–14.60)

31.26 (26.24–37.72)

Stenosis > 50% (n = 226)

10.94 (9.12–12.39)

9.69 (9.10–12.81)

13.20 (8.80–19.80)

Coronary stenosis 34.37 (29.77–42.03) (Table 5 continues on next page)


Rybicki et al.


TABLE 5: Median and Interquartile Range of Radiation Dose Estimates in Millisieverts for the CORE320 Imaging M odalities Stratified by Demographic Data, Parameters Specific to the Protocol, and Findings at C atheterization (continued) Characteristic

CT

SPECT

Catheterizationa

Totala

Catheterization Percutaneous coronary intervention Not attempted (n = 319)

10.85 (9.33–12.39)

9.97 (9.10–13.16)

11.00 (6.96–15.40)

32.07 (27.86–37.72)

Attempted (n = 61)

10.97 (9.01–12.25)

9.51 (7.72–12.04)

22.48 (14.58–33.40)

40.63 (33.78–53.70)

No stenosis > 50% (n = 155)

10.77 (9.57–12.22)

9.97 (9.10–13.20)

9.80 (5.60–14.60)

31.26 (26.24–37.72)

Stenosis > 50% (n = 226)

10.94 (9.12–12.39)

9.69 (9.10–12.81)

13.20 (8.80–19.80)

34.37 (29.77–42.03)

120 (n = 11)

8.86 (8.08–13.08)

11.37 (9.10–13.99)

9.30 (7.80–13.80)

35.51 (31.43–37.22)

128 (n = 30)

10.08 (8.04–11.01)

9.10 (9.10–9.72)

18.14 (12.00–45.54)

37.61 (31.79–53.67)

Coronary stenosis

CT CT angiography FOV (craniocaudal range)

140 (n = 273)

10.76 (9.23–11.99)

9.69 (9.10–12.78)

11.82 (7.20–17.04)

31.92 (27.86–39.23)

160 (n = 66)

12.75 (10.71–13.67)

12.58 (9.30–14.23)

11.25 (7.60–17.80)

35.89 (31.92–44.47)

120 (n = 9)

8.86 (8.42–13.08)

13.06 (9.05–13.99)

8.60 (7.80–10.00)

35.33 (31.43–35.68)

Perfusion CT FOV (craniocaudal range) 128 (n = 30)

10.05 (8.04–10.79)

9.26 (9.10–12.23)

15.30 (12.00–21.40)

35.57 (33.29–40.51)

140 (n = 273)

10.74 (9.17–11.99)

9.68 (9.10–12.70)

12.00 (7.35–17.80)

31.99 (27.83–40.22)

160 (n = 69)

12.67 (10.71–13.21)

12.57 (9.26–13.98)

10.70 (7.46–16.70)

35.65 (31.59–43.52)

1 (n = 352)

10.67 (9.17–11.99)

9.71 (9.10–12.94)

12.08 (7.80–18.00)

33.12 (28.41–40.24)

2 (n = 28)

15.06 (13.89–17.25)

9.97 (9.55–13.04)

8.30 (4.00–14.60)

34.29 (28.84–43.25)

1 (n = 110)

8.63 (8.08–9.63)

9.68 (9.00–12.10)

13.00 (9.20–17.26)

31.86 (27.86–36.07)

2 (n = 270)

11.45 (10.55–12.83)

9.97 (9.10–13.31)

11.26 (7.00–17.90)

33.93 (28.86–40.59)

Rest CT angiography no. of heartbeats

Stress perfusion CT no. of heartbeats

Note—Values in parentheses are interquartile range. aFourteen patients omitted because of unreliable doses for catheterization.

false-negative). There was no significant correlation between the radiation dose delivered by CT and the assigned test characteristic for the primary hypothesis (Table 4). Analysis Group 4: Relation Between Radiation Doses and CORE320 Subject-Based Parameters, Including Demographic Data and Parameters Specific to the Protocol Radiation doses for each modality stratified by individual subgroups are summarized in Table 5. The results of multivariate analyses (Table 6) showed that men received higher radiation doses for CT and for catheterization and thus had an overall higher radiation burden. Considering the cumulative radiation exposure (i.e., including combined CTA and perfusion CT, SPECT, and catheter angiography), subjects who were older did not receive a greater radiation dose than subjects who were younger (Table 6). The dose from

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CT significantly decreased with patient age. With subjects imaged in North America as reference, subjects imaged in South America had no significant difference in total radiation dose. The CT and SPECT doses were significantly higher than in North America, but radiation exposure from diagnostic catheterization was less. Subjects imaged in Europe had an overall lower total radiation dose than those imaged in North America. This total was driven by the lower SPECT doses. Considering SPECT, the radiation doses were comparable among subjects who underwent the study as part of clinical care as opposed to those who underwent research nuclear imaging. Subjects who received tetrofosmin radiotracer had higher similar exposure than those who were imaged with sestamibi. In keeping with the literature findings [10], subjects who underwent catheterization with upper extremity access (n =

179) had a statistically higher (p = 0.04) estimated catheterization radiation dose (mean, 15.23 ± 9.25 [SD] mSv) than the subjects who had femoral access (12.84 ± 10.68 mSv). Considering subjects with CAD defined by at least one lesion with > 50% stenosis determined with catheter angiography, the increase in radiation dose from catheterization alone and for the total dose estimate did not reach statistical significance in the multivariate analyses. However, subjects who underwent clinically indicated PCI in the catheterization laboratory had a greater radiation dose than subjects who did not, considering only the radiation associated with the diagnostic portion of conventional angiography. Discussion The main finding in this comprehensive radiation study of CORE320 subjects is that the radiation dose estimates of the com-


Radiation Dose Estimates TABLE 6: Effects of Demographic Characteristics, Parameters Specific to the Protocol, and Findings at Catheterization on Radiation Dose Estimates Individual Estimated Effect

p

Multivariate Estimated Effect

p

Continent South America

1.31 (0.32)

< 0.0001

1.47 (0.32)

< 0.0001

Continent Europe

−0.24 (0.36)

0.50

0.02 (0.34)

0.96

Continent Asia

−0.17 (0.35)

0.62

0.09 (0.33)

0.79

Male sex

1.26 (0.25)

< 0.0001

1.56 (0.24)

< 0.0001

Age

−0.06 (0.01)

< 0.0001

−0.04 (0.01)

0.004


2.30 (0.32)

< 0.0001

2.03 (0.33)

< 0.0001


Radiation Source CT (including CT angiography, perfusion CT, and CT calcium scoring)

SPECT

Catheterizationa

Totala

Covariate

Continent Europe

−2.72 (0.36)

< 0.0001

−2.02 (0.38)

< 0.0001

Continent Asia

−1.04 (0.36)

0.004

−0.42 (0.40)

0.30

Male sex

−0.59 (0.33)

0.07

−0.01 (0.26)

0.96

Age

−0.07 (0.02)

0.0001

0.00 (0.02)

0.95

Clinical SPECT

−2.58 (0.28)

< 0.0001

−0.30 (0.38)

0.43

Exercise stress

−3.03 (0.29)

< 0.0001

−1.35 (0.40)

0.0008

Tetrofosmin

−1.73 (0.49)

0.0004

−0.01 (0.47)

0.98


−4.67 (1.52)

0.002

−3.22 (1.50)

0.03

Continent Europe

−0.93 (1.60)

0.56

−0.41 (1.39)

0.77

Continent Asia

5.62 (1.69)

0.001

1.79 (1.77)

0.31

Male sex

5.88 (1.17)

< 0.0001

4.21 (0.99)

< 0.0001

Age

0.14 (0.07)

0.04

−0.005 (0.06)

0.93

Stenosis > 50%

5.97 (1.16)

< 0.0001

0.81 (1.08)

0.45

PCI attempted

14.50 (1.28)

< 0.0001

12.63 (1.32)

< 0.0001

Femoral entry

−2.47 (1.14)

0.03

−4.04 (1.26)

0.002


−0.63 (1.57)

0.69

−0.11 (1.54)

0.08

Continent Europe

−3.81 (1.69)

0.02

−2.71 (1.59)

0.07

Continent Asia

5.47 (1.76)

0.002

−0.31 (1.89)

0.02

6.15 (1.21)

< 0.0001

5.02 (1.05)

< 0.0001

−0.03 (0.07)

0.71

−0.03 (0.06)

0.34

Male sex Age Clinical SPECT

1.75 (1.23)

0.16

0.10 (1.55)

0.62

Exercise stress

0.76 (1.34)

0.57

−1.29 (1.66)

0.29

Tetrofosmin

14.79 (2.43)

< 0.0001

9.22 (2.31)

0.0004

Stenosis > 50%

6.10 (1.21)

< 0.0001

1.54 (1.12)

0.13

PCI attempted

12.02 (1.41)

< 0.0001

9.95 (1.43)

< 0.0001

Femoral entry

−5.24 (1.15)

< 0.0001

−5.05 (1.30)

0.0001

Note—Values in parentheses are standard error. Each covariate was first assessed individually for each radiation source then assessed multivariately with control for all covariates. All regression models, individual and multivariate, adjusted for body mass index. PCI = percutaneous coronary intervention. aFourteen patients omitted because of unreliable doses for catheterization.

bined CTA and perfusion CT protocol were comparable to those of SPECT. Although the total CT radiation dose (i.e., that from all CT, including planning, calcium scoring, and combined CTA and perfusion CT) was also comparable to that from diagnostic catheterization, specific conclusions regarding catheterization should be made with caution because the protocol included cine

runs for quantitative coronary angiographic research purposes. Thus our reported radiation dose estimates from catheterization are expected to be higher than in clinical practice with optimized technique. The global nature of our study exposed substantial differences in imaging strategies across continents. In one instance this was related to specific imaging policies. The reference dose

values for SPECT in Germany are substantially lower than they are elsewhere because of regulations of the German Federal Office for Radiation Protection. This condition resulted in significantly lower effective doses in Germany. In other instances, practice differences between centers likely contributed to the differences. Compared with those in North America, subjects in South America



Rybicki et al. had higher dose estimates for both CT and SPECT, but these increases were offset in the total estimated radiation doses because the catheterization exposure was lower. As of this writing, 36 clinical reports describe the use of rest and stress cardiac CT to evaluate CAD and myocardial perfusion and also include a report on radiation dose estimates [11–46]. The mean estimated radiation dose has a range of 5.0–19.4 mSv, except in one report of a 128-MDCT dual-source scanner with high-pitch ECG-synchronization (2.5 ± 2.1 mSv) [30]. Several other studies in the literature have shown some form of stress perfusion CT but did not also include an analysis of myocardial perfusion at rest. We found no previous data in the peer-reviewed literature regarding the multimodality radiation dose profiles for complete cardiac analyses with comparison with the doses required to obtain similar diagnostic information with other modalities in a carefully controlled prospective study. Among the five study reports describing rest and stress perfusion 320-MDCT and radiation estimates, the mean dose was 7.2– 14.9 mSv (conversion factor k = 0.014). There are several explanations for the variation in reported dose estimates. In addition to variation in the protocols, all previous studies had fewer subjects than in CORE320. Moreover, in some reports, it is not explicitly stated whether, or how, the radiation exposure from the localizers and image timing is included. Finally, to our knowledge, in no study have dose estimates been reported with respect to imaging results based on reference standard outcomes. Each of the four analysis groups provides important inferences regarding future advanced imaging strategies for combined CTA and perfusion CT. First, from a radiation dose perspective, implementation of combined CT protocols should not be limited by concerns regarding radiation. Although there were small (on the order of 1–3 mSv) differences between modalities, from a clinical perspective these are not likely to be relevant in the selection of an imaging study. Second, patientbased parameters, such as BMI and heart rate, influence combined CTA and perfusion CT radiation doses with trends similar to those recognized for coronary CTA alone. Third, CORE320 outcomes were not correlated to radiation doses. Specifically, subjects who received less radiation exposure did not have inferior test characteristics, and subjects who received greater radiation exposure did not have superior test characteristics. These findings support our combined CTA and perfusion CT

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protocol for clinical use as one that delivers appropriate, low radiation exposure for diagnostic purposes. Fourth, the CORE320 data have inherent global differences in imaging strategies, particularly with respect to SPECT and coronary catheterization. Because these modalities were used as the reference standard and were clinically driven, these differences were introduced into the data. From this analysis group we can conclude that there are variations in SPECT protocols. Considering coronary catheterization, subjects who are men and who have CAD are expected to receive higher radiation exposures than subjects who are women and who do not have CAD. Multivariate analyses showed that men received greater radiation exposure than women for both CT and catheterization. For CT, the protocol [1] was designed to image men with a higher tube current. The catheterization protocols were driven by practices at each center. Radiation dose optimization strategies for all modalities included in CORE320 will influence future work. For CT, benchmark data showed a reduction in radiation dose when 320-MDCT replaced 64-MDCT scanners [47, 48], and use of next-generation hardware [49] and iterative reconstruction technologies [50] will lead to large reductions in radiation dose. Results of early studies suggest that these will not compromise diagnostic accuracy. Additional methods [51–54] of extracting information on coronary blood flow do not entail additional radiation. Similar radiation dose reduction trends for SPECT will lower patient exposure in nuclear imaging [55]. In general, radiation exposure for catheterization is expected to be most dependent on the operator. As noted earlier, generalizations from CORE320 catheterization doses should be made with caution. Nonetheless, even without the application of iterative reconstruction for CTA, the CORE320 findings are in keeping with the large body of evidence that coronary CTA delivers less radiation dose than diagnostic conventional angiography. MR angiography and perfusion MRI also depict evidence of CAD [56, 57] and have high prognostic value [58]. MRI does not entail ionizing radiation and thus is attractive from a radiation exposure perspective [59]. However, MRI remains limited because routine high-quality coronary angiography is challenging. The image quality is, in our experience, inferior to that of CTA. Moreover, the acquisition time for comprehensive MR angiography and perfusion MRI is longer than that for CTA plus perfusion CT [60].

Our study had limitations. Although CORE320 is the largest study of perfusion CT in the literature, because of the rigorous acquisition over four imaging modalities, 55 of the total 436 recruited subjects were not included in the main analyses. All patient exclusions have been detailed [3]. Among the 55 patients, 13 were excluded for reasons related to CT scanning, and 12 were excluded for reasons related to SPECT. In clinical practice, this is likely to increase patient radiation exposure because repeat image acquisition is typically warranted. Among the 381 patients who were included in our analyses, only one subject needed repeat perfusion CT scanning (none needed repeat CTA), and for this subject the total radiation was included in the analyses. Regarding image acquisition, unlike combined CTA and perfusion CT protocols, SPECT protocols were not optimized owing to limitations in equipment across all sites. Modern software and hardware potentially allow significantly lower radiation doses than those delivered to the CORE320 subjects [61–63]. With respect to dose estimates, for CT we used dose-length product readings from the hardware and acknowledge that Monte Carlo estimations [64] are more precise, and necessary, for more accurate dose models. This same limitation applies to SPECT and coronary catheterization. However, although simplified, the approach used gives dose estimates that represent current clinical standards [65]. We also recognize that the radiation dose for an individual patient should be tailored to the patient’s habitus, clinical scenario, and image quality required for a clinical indication. We acknowledge that the association between BMI and individual effective radiation dose estimate will be strongly influenced by the imaging parameters, such as tube current. For CORE320 subjects, the specific, published [1] imaging guidelines were developed from the collective experience of the investigators and best practice from the literature. For CT, this involved the use of prospective ECG gating [66] with a relatively narrow phase window width [67] and a modest iodine load for CTA [68] and perfusion CT [41]. In lieu of radiation dose modulation, a BMI-based protocol delivered prespecified tube voltage and tube current on a per-subject basis. Conclusion A combined CT cardiac anatomy and myocardial perfusion protocol has an estimated subject radiation dose that is not sig-




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