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Coronary Artery Calcium Imaging in the ROBINSCA Trial

Rationale and Objectives

To describe the rationale, design, and technical background of coronary artery calcium (CAC) imaging in the large-scale population-based cardiovascular disease screening trial (Risk Or Benefit IN Screening for CArdiovascular Diseases [ROBINSCA]).

Materials and Methods

First, literature search was performed to review the logistics, setup, and settings of previously performed CAC imaging studies, and current clinical CAC imaging protocols of participating centers in the ROBINSCA trial were evaluated. A second literature search was performed to evaluate the impact of computed tomography parameter settings on CAC score.

Results

Based on literature reviews and experts opinion an imaging protocol accompanied by data management protocol was created for ROBINSCA. The imaging protocol should consist of a fixed tube voltage, individually tailored tube current setting, mid-diastolic electrocardiography-triggering, fixed field-of-view, fixed reconstruction kernel, fixed slice thickness, overlapping reconstruction and without iterative reconstruction. The analysis of scans is performed with one type and version of CAC scoring software, by two dedicated and experienced researchers. The data management protocol describes the organization of data handling between the coordinating center, participating centers, and core analysis center.

Conclusion

In this paper we describe the rationale and technical considerations to be taken in developing CAC imaging protocol, and we present a detailed protocol that can be implemented for CAC screening purposes.

Introduction

Early detection of cardiovascular disease (CVD) followed by evidence-based treatment could potentially reduce CVD morbidity and mortality . Extent of coronary artery calcium (CAC) is a strong risk marker for coronary events, with evidence mainly derived from observational studies and from prospective nonrandomized studies . So far, there is no evidence that CAC imaging followed by treatment leads to a decrease in CVD morbidity and mortality as prospective randomized studies on CVD risk stratification based on CAC imaging combined with treatment are lacking. Consequently, European and North-American guidelines on CVD prevention still classify the evidence for CAC imaging at level IIb (“may be considered”) in asymptomatic adults at intermediate risk and mention that CAC imaging should not be uncritically used as a screening method . However, there is an ongoing debate on whether and how a randomized controlled trial (RCT) to determine the risk or benefit of screening for CVD by CAC imaging should be performed . Issues related to RCT in CVD screening by CAC imaging, regarding radiation safety, imaging protocols, and privacy, and ethical and economic considerations, have been addressed by many experts in the field of CAC imaging . A well-described study design is essential when performing an RCT in CVD screening by CAC imaging. Moreover, in the case of such a trial, CAC imaging will most likely be performed in multiple centers involving many operators, technicians, and analysts. To use the CAC score as a quantitative imaging biomarker in a trial, the CAC score needs to be accurate, consistent, reliable, and valid across computed tomography (CT) platforms, clinical sites, and over time , demanding development of a robust and well-fitted imaging protocol.

In this paper we describe the rationale, design, and technical background of CAC imaging within the framework of the Dutch large-scale population-based cardiovascular screening trial, ROBINSCA (Risk Or Benefit IN Screening for CArdiovascular Diseases).

The ROBINSCA Trial

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Figure 1, Overview of ROBINSCA (Risk Or Benefit IN Screening for CArdiovascular Diseases) trial. The flowchart shows the basic study design of the ROBINSCA trial.

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Materials and Methods

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Results

Imaging Protocols in Previous CAC Studies

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TABLE 1

Coronary Artery Calcium Imaging Studies and their Protocol Settings

Study Author Year N Scanner Type ECG Triggering Scan Mode Tube Voltage Tube Current Recon Analysis St. Francis Heart Study Arad et al. 2000 1238 EBCT (Imatron C-150XP) 80% R-R interval 100 ms/Slice — — 3.0 mm (Contiguous), FOV 35 cm Threshold: 130 HU  ≥2 adjacent pixels (≥0.93 mm 2 ) Arad et al. 2001 5582 EBCT (Imatron C-150XP) 80% R-R interval 100 ms/Slice — — 3.0 mm (Contiguous), FOV 26 cm, pixel area 0.51 mm 2 Threshold: 130 HU  ≥2 adjacent pixels CARDIA study Iribarren et al. 2000 374 EBCT ECG gated Scantime: 100 ms — — 3.0 mm ≥6 Adjacent pixels (≥2 mm 2 ) Carr et al. 2005 3044 See MESA Pro and retrospective

80% R-R interval — — Yan et al. 2006 2913 EBCT, MDCT — 2 Sequential scans — — 2.5–3.0 mm ≥6 Adjacent pixels (≥2 mm 2 ) South Bay Heart Watch Park et al. 2002 1461 EBCT (Imatron C-100) 80% R-R interval — — — 6.0 mm See MESA (≥4.1 mm 3 ) Qu et al. 2003 1312 EBCT (Imatron C-100) 80% R-R interval 100 ms Exposure — — 6.0 mm

3.0 mm ( n = 319 Validation purposes) See MESA Greenland et al. 2004 1461 (EB) CT — — — — 6.0 mm See MESA — Shaw et al.

Raggi et al. 2003

2004 10,377 EBCT (Imatron C-100, Imatron C-150) 60%–80% R-R interval 100 ms — — 3.0 mm Slice thickness

contiguous Threshold: 130 HU  ≥3 contiguous pixels (1.03 mm 3 ) — Kondos et al. 2003 8855 EBCT (Imatron C-100) 80% R-R interval 100 ms — — 3.0 mm, FOV 260 mm, 512 matrix, sharp kernel Threshold: 130 HU  ≥4 adjacent pixels (1.0 mm 2 ) Cooper Clinic Dallas Cheng et al. 2003 17,967 EBCT (Siemens Evolution C-150XP) — 100 ms — — 3.0 mm Slice thickness

2.0 mm Increment — LaMonte et al. 2005 10,746 EBCT — — — — — — Church et al. 2007 10,746 EBCT (Imatron C-150 XP, Imatron C-300) — — — — 3.0 mm Slice thickness

2.0 mm Increment — MESA Carr et al. 2005 6814 EBCT

MDCT Prospective, 80% R-R

Prospective, 50% R-R

Prospective, 50% R-R

Retrospective, 50% R-R Sequential mode

MDCT: 4 detect row

Sequential

Sequential

Sequential 130 kVp

140 kVp

120 kVp

120 kVp 63 mAs

50 mAs

106 mAs

320 mAs 3.0 mm, FOV 350 mm

2.5 mm, FOV 350 mm ≥5.5 mm 3

≥4.6 mm 3 Rotterdam Coronary Calcification Study Vliegenthart et al. 2005 1795 EBCT (Imatron C-150) 80% R-R interval 100 ms/slice — — 3.0 mm Threshold: 130 HU

≥2 adjacent pixels (0.65 mm 2 ) PACC project Taylor et al. 2005 2000 EBCT (Imatron C-150 LXP) 60%–80% R-R interval — — — 3.0 mm Slice thickness Threshold: 130 HU

≥4 contiguous pixels Framingham Heart Study Moselewski et al. 2005 612 8-Slice MDCT(Lightspeed Ultra GE) 50% R-R interval Sequential 120 kVp 320 mA

400 mA 2.5 mm Slice thickness

contiguous Threshold: 130 HU

≥3 connected pixels HNR, ECAC Schmermund et al. 2007 Ongoing EBCT (Imatron C-100, Imatron C-150) 80% R-R interval 100 ms 3.0 mm Slice thickness

Contiguous Threshold: 130 HU

≥4 contiguous pixels CONFIRM registry Min et al. 2011 27,125 MDCT, DSCT — — — — — — SCOT-HEART Newby et al. 2012 ~2070 64, 128, 320 MDCT — — — — — Threshold: 130 HU Jackson Heart Study Liu et al. 2012 2880 MDCT (Lightspeed 16 Pro, GE) — — — — — — NHLBI Family Heart study Robbins et al. 2014 1848 MDCT 50% R-R interval Sequential, 0.5 s gantry rotation, temporal res. 250–300 ms 120 kV 160 mAs 2.5 mm, FOV 350 mm Threshold: 130 HU

≥2 connected pixels (0.9 mm) ROMICAT II trial Pursnani et al. 2015 473 MDCT, DSCT

GE 64-Slice Lightspeed, GE Lightspeed VCT, Siemens 64-Slice Sensation, Siemens Dual Source 64-Slice Definition, Siemens Dual Source 128-Slice Flash, and Philips Brilliance 256-Slice iCT — — — — — — EURO-CCAD Nicoll et al. 2016 5515 MDCT — 4–256 slices — — 3.0 mm ≥4 Contiguous pixels CRESCENT Lubbers et al. 2016 242 CT — — — — — —

CARDIA, Coronary Artery Risk Development in Young Adults; CONFIRM, COroNary CT Angiography Evaluation For Clinical Outcomes: An InteRnational Multicenter Registry; CRESCENT, Computed Tomography vs. Exercise Testing in Suspected Coronary Artery Disease; CT, computed tomography; DSCT, dual-source computed tomography; EBCT, electron beam computed tomography; ECAC, Epidemiology of Coronary Calcification; ECG, electrocardiography; EURO-CCAD, European Calcific Coronary Artery Disease; FOV, field of view; MDCT, multidetector computed tomography; MESA, Multi-Ethnic Study of Atherosclerosis; PACC, Prospective Army Coronary Calcium; ROMICAT, Rule Out Myocardial Infarction using Computer Assisted Tomography; SCOT-HEART, Scottish COmputed Tomography of the HEART trial.

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Impact of Parameter Settings on CAC Score

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Screenee Characteristics

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Heart Rate and Vessel Displacement

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Electrocardiography (ECG) Triggering

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Tube Voltage

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Tube Current

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Slice Thickness and Increment

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Kernel/FOV

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Iterative Reconstruction

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Scoring Software

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Design CAC Imaging Protocol

Preparation

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Acquisition

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TABLE 2

CT Acquisition Protocol for CAC Scoring Scan

Scan Parameters CT Protocol A B Scan mode High pitch spiral Sequential Pitch 3.4 — Tube voltage (kVp) 120 Tube current (ref. mAs) 80 Rotation time (ms) 280 Collimation (mm) 128 × 0.6 Matrix 512 × 512 ECG triggering Prospective, 60% Dose modulation CareDose 4D → semi →enter ref mAs API Inspiratory breath-hold Direction Craniocaudal Upper limit Below carina Lower limit Apex/bottom edge heart

API, automated patient instruction; CAC, coronary artery calcium; CT, computed tomography; ECG, electrocardiography.

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Reconstruction

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TABLE 3

CT Reconstruction Protocol for CAC Scoring Scan

Reconstruction Parameters Protocols A and B Reconstruction 1 Reconstruction 2 Reconstruction 3 Slice thickness (mm) 3.0 1.5 3.0 Slice increment (mm) 1.5 1.0 1.5 FOV (mm) 250 250 Maximum Kernel b35f (sharp) Algorithm Filtered-back projection Window Mediastinum Window width (HU) 350 Window center (HU) 50

CAC, coronary artery calcium; CT, computed tomography; ECG, electrocardiography; FOV, field of view.

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Analysis

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Design Imaging Data Management

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Figure 2, Imaging data management of ROBINSCA (Risk Or Benefit IN Screening for CArdiovascular Diseases) trial. (1) The coordinating center schedules the participants per participating center. (2) A coronary artery calcium (CAC) scan is made, and all imaging data are transferred to the analyzing center. Image data are analyzed and (3) outcomes are transferred to the coordinating center, (4) which communicates this outcome including advice to the general practitioner (GP) and participant (and if necessary, a medical specialist is consulted). (5) Requests for CAC scans can be done at the coordinating center, (6) which anonymizes the request for the analyzing center. Next, (7) the CAC scan is transferred to the requesting specialist.

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TABLE 4

Incidental Findings on CT Scan for CAC Scoring That Are (Not) Reported to GP and Participant

Reported Not Reported Chest

Abdomen

CAC, coronary artery calcium; CT, computed tomography; GP, general practitioner.

TABLE 5

Cardiovascular Risk Stratification Based on the CAC Score

Calcium Score Extent of Atherosclerotic Coronary Artery Disease Cardiovascular Disease Risk 0 No identifiable plaque Low 1–10 Mild identifiable plaque Low 11–99 Definite, at least mild atherosclerotic plaque Low 100–399 Definite, at least moderate atherosclerotic plaque High ≥400 Extensive atherosclerotic plaque Very high

CAC, coronary artery calcium.

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Discussion

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Acknowledgments

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