Low- vs. standard-dose coronary artery calcium scanning

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1 European Heart Journal Cardiovascular Imaging (2015) 16, doi: /ehjci/jeu218 Low- vs. standard-dose coronary artery calcium scanning Harvey S. Hecht 1 *, Maria Eduarda Menezes de Siqueira 2, Matthew Cham 1, Rowena Yip 1, Jagat Narula 1, Claudia Henschke 1, and David Yankelevitz 1 1 Icahn School of Medicine at Mount Sinai, Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1030, New York, NY , USA; and 2 DASA/Delboni R. Dr. Diogo de Faria, Vila Clementino São Paulo - SP, Brazil Received 2 June 2014; accepted after revision 12 September 2014; online publish-ahead-of-print 7 November 2014 Aims This study was designed to assess the accuracy of coronary artery calcium scans (CACS) acquired at radiation doses below mammography and low-dose lung scanning, compared with standard-dose CACS.... Methods CACS was performed in 102 consecutive patients at 120 kvp; all were imaged at standard-dose mas levels ranging from and results 30 to 80 mas determined by their weight, with iterative reconstruction (IR) level 3, and at 50% of the standard-dose mas with IR level 7 to compensate for the expected increased noise with lower mas. The low- vs. standard-dose mas was vs mas (P, ), and the radiation exposure was vs msv (P, ). The Agatston score correlation between the low and high dose was excellent (r ¼ 0.998, P, ) over a range of scores from 0 to The weighted kappa for agreement of standard CAC risk categories was 0.95 (95% CI ). The mean of the differences between individual low- and standard-dose Agatston scores was , lower than the reported variability of two scans performed with the same mas.... Conclusion There was excellent agreement of CACS-based risk classification at low and standard doses, with lower interscan variability than with reported identical doses. The low-dose CACS radiation exposure was less than the approved screening tools of mammography and low-dose lung scanning Keywords Coronary artery calcium Radiation Atherosclerosis Introduction As the popularity of coronary artery calcium scanning (CACS) and its inclusion in guidelines and appropriateness criteria for risk assessment in asymptomatic patients have increased, 1 3 so has the concern regarding the radiation dose from computed tomography in general and CACS in particular. 4 Even though the CACS radiation exposure has steadily decreased from.5 msv in the era of retrospective acquisitions to a recommended radiation dose average of msv with prospective scanning, 5 theoretical projections of cancers emanating from computed tomography scanning have alarmed the public and physicians as well. In addition, radiation was cited as one of the reasons for downgrading risk assessment of asymptomatic patients by CACS to a class IIb recommendation by the 2013 American College of Cardiology/American Heart Association Guideline. 6 Consequently, in keeping with the ALARA (as low as reasonably achievable) mandate, and with the ESC principle that each patient should get the right imaging exam, at the right time, with the right radiation dose, 7 this study was designed to determine the effects on calcified plaque measurements of decreasing the radiation dose by 50% compared with standard state-of-the-art scanning, to levels below low-dose lung scanning 8 and mammography. 9 Methods Patient population The study was designed to evaluate consecutive patients presenting for clinically indicated coronary CT studies, either calcium scanning alone or coronary calcium together with coronary CTA. To ensure adequate sampling over a full range of calcium scores, and specifically to avoid the normal preponderance of 0 calcium scores, the number of 0 CAC patients was limited to,25% of the total. Consequently, with a planned total of 100 patients, after the 24th consecutive 0 CAC patient was imaged, only those patients who had.0 CAC on the standard-dose protocol proceeded to the low-dose imaging. A total of 102 consecutive patients, with the above modification, were imaged. * Corresponding author. Tel: ; Fax: , harvey.hecht@mountsinai.org, hhecht@aol.com Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 Low- vs. standard-dose coronary artery calcium scanning 359 Scanning protocols After informed consent was obtained, the patients were imaged on a 256-slice CT scanner (Philips Brilliance ict, Philips Healthcare, Best, The Netherlands). All scans were acquired at the presenting heart rate (HR) without administration of beta-blocking medication, with prospective ECG-gating (Step & Shoot Cardiac, Philips Healthcare) at 75% of the R R interval, with a collimation of mm, gantry rotation time of 270 ms, standard cardiac filter, 3 mm slice thickness, and a tube voltage of 120 kv. The standard-dose scan was performed first and was immediately followed by the low-dose acquisition without change in patient or scanner position. The standard- and low-dose protocols differed in two parameters: mas and degree of iterative reconstruction (IR; idose, Philips Healthcare). The mas standard-dose protocol varied by patient weight: 30 mas for,68.2 kg, 50 mas for kg, and 80 mas for.90.9 kg. The low-dose protocol employed 50% of the standard-dose mas: 15 mas for,68.2 kg, 25 mas for kg, and 40 mas for.90.9 kg. For noise reduction purposes, IR level 3 has replaced filtered back projection in our standard CAC scanning protocol based on phantom 10 and patient (submitted for publication) studies confirming the comparable results of IR3 and filtered back projection, with significant improvement in the signal-to-noise ratio. To mitigate the anticipated increased noise likely to be associated with the lower mas, the IR was increased to level 7 in the low-dose protocol. Calcification was defined as a plaque with an area of at least 1.03 mm 2 with a density of 130 Hounsfield units (HU). Coronary, aortic (including aortic valvular), and mitral annular calcifications were measured by a single experienced observer according to the method of Agatston et al. 11 Volume and mass scores were calculated as well. Intra-observer variability was determined by recalculating 30 randomly selected studies with CAC.0 after a 1-month interval, without the knowledge of prior measurements. The mean radiation effective dose was estimated by using the dose length product (DLP) multiplied by asthe conversion factor. 12 Signal and noise were measured by placing a 100 mm 2 circular region of interest in identical positions in the ascending aorta of the standard- and low-dose scans; the average and 1 SD of HU were recorded and the signal-to-noise ratio was calculated by dividing the average HU by the standard deviation. Image quality was determined on a 4-point scale: 4 ¼ excellent, 3 ¼ good, 2 ¼ fair, and 1 ¼ poor. Statistical analysis The distribution of demographic, clinical characteristics, and comorbidities for patients was calculated. The standard- and low-dose CT scans were reviewed to determine the CT acquisition parameters and the radiation dose obtained using computed tomography dose index (CTDI), DLP, and the effective dose in msv. The calcium scores were divided into the standard risk categories of 0, 1 10, , , and.400 and the low- and standard-dose classifications were compared using the x 2 statistics. Paired t-test was used to compare the differences between the low and standard dose within each of the five categories. Additional analyses included determination of the correlation of the CACS parameters between the two scans and the intra-observer variability. Informed consent was obtained from all patients, and the study was approved by the Institutional Review Board of Mount Sinai Medical Center. Results The patient characteristics are given in Table 1. The mean age was 62.6 years, 63% were male, mean BMI was 26.8 kg/m 2, 55% were Table 1 Patients characteristics (N 5 102) Age (years, mean + SD) Sex Male 63 62% Female 39 38% Race African 8 8% Asian 1 1% Caucasian 79 77% Hispanic 14 14% BMI (kg/m 2, mean + SD) Height (m) Weight (lb), % % % Weight (mean + SD) Heart rate (bpm, mean + SD) Diabetes mellitus 32 31% Hypertension 51 50% Cholesterol 59 58% Family history 32 31% Smoking 11 11% Asymptomatic 60 59% Chest pain 36 35% Dyspnoea 12 12% between 68.2 and 90.9 kg, and mean HR was 63.8 bpm; 60% were asymptomatic. Scan parameters and quality All patients were imaged at 120 kvp with an average current of and mas (P, ), and a scan length of and (P ¼ 0.32) in the low- and standard-dose groups, respectively. The dose length product and effective dose were significantly lower in the low dose compared with the standard-dose group ( vs mgy/cm, P, and vs msv, P, ). There was significantly lower noise ( vs HU, P, ), and a higher signal-to-noise ratio in the low- vs. standard-dose groups. There were no differences in scan length and quality between the two doses. Examples of standard- and low-dose scans in patients of different body habitus and CAC scores are shown in Figure 1. The low-dose scans are easily identified by their smoother, less noisy appearance produced by the higher IR level, which translates into significantly lower noise levels without change in signal intensity (Table 2). Coronary artery calcium scanning Table 3 compares the classification of the low- and standard-dose scans into the five CACS categories. The weighted kappa for agreement of standard CAC risk categories was 0.95 (95% CI ). All of the 24 lowest risk 0 CAC patients by standard dose had 0 CAC with low-dose imaging, and all of the 17 high risk.400

3 360 H.S. Hecht et al. Figure 1 Examples of standard- and low-dose scans in patients of varying body habitus and CAC scores. All studies were acquired at 120 kvp; the IR level was three in the standard-dose and seven in the low-dose scans. The low-dose scans are always smoother and less noisy in appearance, reflecting their higher IR level, which is achieved without loss of signal intensity.(a) Standard- (left) and low-dose (right) scans in a 57-year-old male with a BMI of 27.8 kg/m 2.(B) Standard- (left) and low-dose (right) scans in a 65-year-old female with a BMI of 19.5 kg/m 2.(C) Standard- (left) and low-dose (right) scans in a 52-year-old female with a BMI of 51.8 kg/m 2. CAC were high risk with both doses. In the low-to-intermediate CAC risk groups, 87% were in exact agreement. Table 4 summarizes the comparison of the actual Agatston scores within each of these five categories. As expected, the differences were greater with increasing calcium scores. The correlation of Agatston scores between the low and high dose was excellent (r ¼ 0.998, P, ), with similar excellent agreement for the volume and mass scores. There were significant differences in the Agatston scores: vs (P ¼ 0.001) for standard vs. low dose (Table 2). However, the clinical

4 Low- vs. standard-dose coronary artery calcium scanning 361 Table 2 results Comparison of standard- and low-dose scan Standard dose Low dose P-value N N kv mas , Radiation CTDI , DLP (mgy/cm) , Effective dose (msv) , Scan length Signal Noise , Signal/noise , Quality Total CAC Agatston Volume Mass LM Agatston Volume Mass LAD Agatston Volume Mass LCX Agatston Volume Mass RCA Agatston Volume Mass Aortic Agatston Volume Mass Mitral Agatston Volume Mass Percentile CTDI, computed tomography dose index; DLP, dose length product; CAC, coronary artery calcium; LAD, left anterior descending; LCX, left circumflex; LM, Left main; RCA, right coronary artery. significance of the difference was virtually nil (Table 3). The volume ( vs , P ¼ 0.06) and mass scores ( vs , P ¼ 0.03) had slightly better agreement between standard- and low-dose acquisitions (Table 2). Differences in age- and gender-based calcium percentiles were not significant ( vs , P ¼ 0.06; Table 2). There were no significant differences in the Agatston scores for the individual vessels, except for the RCA, or for aortic and mitral calcification (Table 2). The mean of the differences between individual low- and standarddose Agatston scores was ; differences within the individual risk groups in patients with.0 CAC ranged from in the 1 10 low-risk group to in the.400 high-risk group (Table 4). The percentage difference between the scans was %; the standard deviation is disproportionately influenced by small absolute but large percentage differences in the lower CAC groups. Intra-observer variability was negligible: the two measurements had an excellent correlation (r ¼ 0.999, P, ), with a % difference between them. Discussion In an era of increasing focus on the primary prevention of coronary artery disease, the role of CACS in risk prediction has assumed great importance. According to the ACC/AHA Class IIa recommendations, 40 million Americans in the intermediate risk group are appropriate candidates, as are low-risk patients with a family history of premature coronary artery disease and all diabetic patients.40 years of age. 1,2 Thus, there is an increasing imperative to minimize the radiation to which many millions are likely to be exposed, both for patient safety and to reduce barriers to patient and physician acceptance attributable to the negative, often sensationalistic, press coverage. This study is the first to demonstrate that low-dose scans have results equivalent to standard-dose CACS, at one-third of the guideline recommended effective radiation exposure 5 to an average of 0.37 msv, a level well below that of the 0.7 msv of mammography 9 and 0.65 msv of low-dose lung scanning. 8 Prior studies Earlier reports evaluating attempts to reduce CACS effective radiation dose have employed two approaches: reducing kv and reducing mas. In the first category, Nakazato et al. compared CAC and volume scores from a dual-source scanner in 60 patients (28 with 0 CAC) acquired at 120 kvp and 150 mas, using 130 HU as the calcium cut-off, with scans acquired at 100 kvp and 180 mas, using a phantom-derived 147 HU for definition of calcified plaques. 13 They noted an excellent agreement, with a Agatston score difference and k-value of The 120 kvp mean effective radiation dose was lower (1.17 vs msv, P, ). Similar excellent correlations were achieved with calcium volume scores. However, their low-dose radiation exposure was three times greater than in the present study, 47% of the patients had 0 CAC compared with 24% in the present study, and recalibration of the standard calcium attenuation threshold of 130 HU is required to establish the 100 kv threshold for each scanner, posing an obstacle to widespread use. In another 120 vs. 100 kvp study, Marwan et al. 14 evaluated 150 patients (46% with 0 CAC) with a high-pitch dual-source scanner and fixed current of 80 mas, using both 130 and 147 HU as the calcium threshold in the 120 kv arm. They reported an excellent agreement (r ¼ 0.99), with systematic overestimation in the 100 kv arm at both

5 362 H.S. Hecht et al. Table 3 Comparison of coronary calcium categories: standard vs. low dose Calcium score Total Agatston score (low dose) Total... Total Agatston score (standard dose) Total % CI Simple kappa 0.90 ( ) Weighted kappa 0.95 ( ) Table 4 Comparison of standard- and low-dose Agatston scores within CAC risk groups N Standard (HU) Low (HU) Standard low (HU) Mean + SD Mean + SD Mean + SD... Total Agatston score (standard dose) Standard low Mean + SD Variability Mean + SD 24.3% % calcium thresholds for both Agatston and volume scores, but a significant reduction in effective radiation dose from 0.3 to 0.2 msv. However, recalibration for 100 kvp is required, 46% of the patients had 0 CAC, and the low-radiation results are only applicable to the high-pitch scanner. In the reduced mas category, 33 patients were imaged on a fourdetector CT scanner at 140 kvp, with two consecutive scans of either 40 or 80 mas compared with 150 mas. 15 The differences in CACS were quite large: and % for the 40 and 80 mas compared with 150 mas, respectively; calcium volume scores were slightly closer. A radiation dose was not reported. Dey et al. 16 compared CACS in 66 patients (20 with 0 CAC) imaged on a dual-source scanner at 120 kv, with mas of 150 vs. either 120 mas for BMI.30 kg/m 2 or 85 mas for BMI 30 kg/m 2. There was an excellent correlation (r ¼ 1.0) for both Agatston and volume scores, mean differences of and % in Agatston and volume scores, respectively, and a dose reduction from 1.7 to 1.1 msv. This dose level is three times that of the present study, and there were only 36 patients with.0 CAC, compared with 78 in the present report. Interscan variability Of great importance is the interscan variability in this report that is less than published for two scans at identical kv and mas repeated one after the other without change in patient position. Using a fourdetector scanner in 50 patients, the CACS variability was %. 17 In 4054 patients in MESA, 18 the interscan variability of five different MDCT scanners ranged from 16 to 24% compared with 4.3% in the present study, with percentage agreement for the presence of CAC.0 from 93.0 to 96.3% compared with 97% in this report. Current and noise Whereas the guidelines require a voltage of 120 kvp, 4 there are no specific recommended mas levels. Rather, the current is based on achieving noise levels,20 HU for small- and medium-sized patients and,23 HU in large patients. 5 Whether laboratories conform to this recommendation is unknown, and it is quite likely that there are a variety of unvalidated protocols in use. In the current study, the average noise levels were significantly lower in the low-dose compared with the high-dose group ( vs , P, ), representing the more than compensatory effect of the increased IR level for the otherwise to be expected increased noise attributable to lower mas. This is reflected in the virtually identical image quality in both groups without loss of accuracy, and particularly by the perfect agreement for 0 calcium scores, in which group higher noise from lowering the mas would very likely have produced false positive.0 scores were it not for the higher IR level. To achieve noise reduction at standard-dose levels, IR3 had already replaced filtered back projection in our laboratory, validated by (i) anthropomorphic phantom studies demonstrating excellent

6 Low- vs. standard-dose coronary artery calcium scanning 363 agreement of CAC scores with IR level 3 compared with standard filtered back projection reconstruction, with mean + SD for seven calcium rods of vs Agatston units; 10 and (ii) the weighted kappa of (95% CI ) for the agreement in 100 consecutive patients at standard-dose levels between CACS reconstructed with FBP and IR3 for the risk classification scores of 0, 1 10, , , and.400. In addition, mean Agatston values of and were noted for FBP and IR3, respectively (submitted for publication). The current study extends these findings by demonstrating that further noise reduction by increasing the IR level to 7 can maintain the accuracy of the CACS, despite halving the current and radiation dose. Limitations of the study Universal applicability is required for dose reduction to be widely implemented. The current protocol fits this criterion: mas reduction is universally available without need for recalibration of the standard calcium attenuation threshold of 130 HU, and IR algorithms have become standard. However, the current results differ from those reported with different IR algorithms, that is, Adaptive Statistical Iterative Reconstruction, GE Healthcare, 19 Sinogram-Affirmed Iterative Reconstruction, and Siemens Healthcare, 20 with which there were significantly lower CAC at each level of IR, very likely reflecting differences in the reconstruction algorithms. Further studies with different CT systems will be needed to extend our results to the other IR algorithms and allow for dose reduction irrespective of the vendor. The next generation will employ model-based algorithms with even greater noise reduction, which are currently under investigation, and will have to be validated for each vendor. In addition, confirmation of our findings in a larger patient population would be valuable. The 50% reductions in mas levels and radiation exposure are not necessarily the maximum that can effectively be achieved without loss of accuracy. Future protocolswill addressthis issue. The use of IR inthe standard protocol is not addressed in guidelines, which followed the development of these algorithms. However, we have previously validated the excellent agreement between filtered back projection and IR. 10 Implications This validation of low-dose CACS represents a potential major step in its incorporation into the medical mainstream by minimizing concerns regarding radiation exposure. Whether or not the cancer concerns from the already low CACS radiation exposure are justified, the major reduction in dose to 0.37 msv can only enhance its acceptability and utilization. This very low dose is best viewed in the context of the US Preventive Services Task Force approved screening for breast and lung cancer, with exposures of 0.7 and 0.65 msv, respectively. 8,9 In contrast, low-dose CACS can be performed at 50% of the radiation of these screening tools. The ability to perform low-dose CACS with widely available scanners and reconstruction algorithms may accelerate its designation as a screening test for coronary artery disease. Conflict of interest: H.S.H. Philips Medical Systems Consultant, J.N. Philips Medical Systems and General Electric Research Grants, D.Y. patents for measurement of chest nodules. Funding The research was funded in part by the Flight Attendant Medical Research Institute. References 1. 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