Feasibility of cardiovascular population-based CT screening
Vonder, Marleen
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Publication date: 2018
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Vonder, M. (2018). Feasibility of cardiovascular population-based CT screening. Rijksuniversiteit Groningen.
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1
General introduction &
outline of the thesis
Population-based screening
The prevalence of cardiovascular disease (CVD), chronic obstructive pulmonary disease (COPD) and lung cancer, the ‘Big-3’ diseases, is high in the Netherlands, with an annual incidence of 123,200 (only coronary heart disease (CHD)), 50,600 and 12,600 respectively [1–3]. Furthermore, coronary disease, COPD and lung cancer are responsible for a relatively high disease burden, with disability adjusted live years (DAILY’s) of 5.0, 3.4 and 2.9 resulting from relatively high number of years lived with the disability (respectively 4.8, 3.1 and 0.2) and/or years of life lost (respectively 5.5, 4.2 and 9.5 years) [4]. Consequently, these Big-3 diseases together result in a high burden on the health system, and healthcare costs have risen to 10 billion euros annually [5]. Technological developments in CT allow to determine nodule volume, to quantify coronary artery calcium and to evaluate lung parenchyma with a single low-dose CT examination of the thorax [6–10]. Population-based low-dose CT screening for early detection of the Big-3 diseases followed by early treatment has high potential to cure the disease or to delay or stop progression of the disease, thereby reducing morbidity and mortality.
Of the three diseases, only CT lung cancer screening has proven survival benefit in long-term smokers, and it is likely that it will be implemented in Europe within the next 5 years [11,12]. Contrary, no randomized controlled trials (RCTs) have been performed yet that could show benefit of CT screening for CVD, nor for COPD. This thesis focuses on the feasibility of cardiovascular population-based CT screening.
Cardiovascular population-based screening
Although CHD is nowadays less than half of what it was in the 1980s in many countries in Europe due to preventive measures, many risk factors like obesity, diabetes mellitus etc. have been increased substantially [13]. Studies have shown that prevention measures are poorly implemented, resulting in prevailing CVD risk factors and consequently CVD events [14]. The 2016 European Guidelines recommend systematic cardiovascular risk assessment (CVD screening) in individuals at increased risk, like individuals with family history of premature CVD, hyperlipidaemia, smoking, high blood pressure, diabetes or raised lipid levels [13]. Within Europe, the SCORE method is used as the screening tool to estimate the 10 year risk of fatal CVD, relying on classical CVD risk factors like gender, smoking status, blood pressure and cholesterol level. Nevertheless, this method is recommended for cardiovascular risk management in individual patients, and not for population screening. While CVD risk
management by the SCORE method is a class 1 recommendation, so far no RCTs have been performed showing the added value of treatment following population based risk assessment by the SCORE method (level of evidence: C) [13].
Besides these classical risk factors, many studies have shown the added value or even superiority of coronary artery calcium (CAC) quantification: the imaging biomarker for CVD risk prediction [15–17]. An imaging biomarker is a decision parameter to assess disease presence, absence, activity, or outcome in individuals or groups with the disease process [18]. The presence and amount of coronary calcifications can be quantified by low-dose computed tomography (CT) and is expressed in a CAC (Agatston) score, which is a measure of subclinical CVD [19]. Validation and standardization of this measurement is essential to ensure that the quantitative measurements are accurate and precise [20]. For CAC scoring, technical and clinical validation has already been performed extensively and many population studies have shown the strong predictive value of the CAC score for coronary events [15,16]. So far, no large (population-based) randomized-controlled trials have been performed for cardiovascular CT screening followed by treatment of individuals at high CVD risk according to the CAC score. Hence, the clinical impact of CVD screening by CAC scoring combined with evidence-based treatment is unknown. Nevertheless, in several studies it was reported that CAC can improve medication and lifestyle adherence and can be cost-effective in specified populations [21].
Risk or benefit in screening for cardiovascular disease:
the ROBINSCA trial
There is an urgent need for large-scale population-based RCTs showing the impact of CVD screening followed by treatment in high risk individuals according to their CVD risk based on classical factors and/or based on CAC quantification. The goal of CVD screening is to stratify individuals with a high risk for CHD events, and to reduce the morbidity and mortality by offering these individuals treatment at an early stage to stop or delay progression of subclinical CVD. Although cost-effective preventive treatment options are available for cardiovascular diseases, there is no evidence from RCTs about the effectiveness of CVD screening in terms of the potential benefits, like reduction in CHD-related morbidity and mortality, reduction in overuse of statins and aspirin, and the harms, like radiation-induced related risks, overdiagnosis, overtreatment, and impact on quality of life.
In 2014, the Dutch population-based screening trial ‘ROBINSCA: Risk OR Benefit IN Screening for CArdiovascular disease’ started. The primary objectives of the trial are: “To establish whether screening for CVD by ‘classic’ risk factor assessment in
asymptomatic individuals followed by early treatment according to prevailing guidelines will reduce CHD mortality and morbidity with at least 15% compared with no screening after 5-years of follow-up” and “To establish whether screening for CAC using CT in asymptomatic individuals followed by treatment, according to prevailing consensus, will reduce CHD mortality and morbidity by at least 15% compared with screening with the ‘classic’ risk factor assessment after 5-years of follow-up” [22]. In the ROBINSCA
trial, approximately 39,000 participants are included and randomized (1:1:1) into three groups: intervention group A (screening for CVD risk by means of SCORE), intervention group B (screening for CVD risk by means of CT scanning to determine the CAC score) or control group (no screening). Eventually, the ROBINSCA trial will provide evidence whether cardiovascular population-based screening should be implemented or not, and whether this should be based on classical risk factor assessment or CAC quantification by CT.
Challenges in cardiovascular CT screening
One of the challenges in cardiovascular population-based CT screening is to secure imaging biomarker validity to perform proper risk stratification on one hand, while screening large populations at a radiation dose as low as possible on the other hand. CT screening of large populations requires a multi-center environment, involving different CT systems and many operators, technicians and analysts. In addition, radiation dose reduction has become more and more a priority in chest and non-contrast cardiac CT, especially in the case of usage in an asymptomatic healthy population [13,23,24]. Radiation dose reduction in population-based screening protocols can have great impact on the total radiation exposure of an entire population and related health risks. However, a highly variable environment and radiation dose reduction can impact biomarker validity and subsequently risk stratification and the effectiveness of a whole screening program. If these issues are appropriately controlled and the impact of radiation dose reduction is validated, reliable population-based low-dose cardiovascular CT screening can be assured while increasing the health benefit.
Outline of the thesis
The aim of this thesis is to determine the feasibility of radiation dose reduced cardiovascular population-based CT screening in order to increase the health benefits of screening.
The first part of the thesis focuses on the design of population-based CT screening trials. In Chapter 2, an overview of current evidence and CT protocols for early detection of CVD, lung cancer and COPD (Big-3 diseases) with low dose chest CT is provided. In this chapter the various options for combining the different dedicated CT protocols of each imaging biomarker are explored with the goal to reduce the radiation dose in combined Big-3 screening. Nonetheless, before Big-3 screening can be implemented, a RCT in CVD screening by CAC imaging combined with evidence-based treatment should be performed to prove whether CVD CT screening is effective or not. A well-described study design and a robust and well-fitting imaging protocol are essential when performing an RCT in CVD screening by CAC imaging. In Chapter 3 the rationale, design, and technical background of CAC imaging are described within the framework of the Dutch large-scale cardiovascular population-based screening trial, ROBINSCA. Continuous efforts to further optimize the CAC imaging protocol can be valuable to provide a cutting-edge imaging protocol to the market when CVD screening has been proven ready for wide-scale implementation. In Chapter 4, the impact of two scan modes on CAC quantification, risk stratification and dose in CAC scanning in ROBINSCA participants with a regular high heart rate are determined. Because of the screening nature of the ROBINSCA trial, no heart-rate lowering medication during scan acquisition can be used. In this chapter the impact of the scan-mode in participants with a high heart rate, is assessed to show the potential for dose reduction in CVD CT screening.
The second part of the thesis focuses on dose reduction as a function of imaging biomarker validity. So far, efforts for dose reduction were mainly focused on coronary CT angiography and have not been systematically implemented for CAC scoring. In Chapter 5 an overview of dose reduction techniques for CAC imaging is given. This chapter includes a systematic review to determine to what extent the radiation dose in CAC CT can be safely reduced without significantly impacting the CVD risk stratification. Several of these dose reduction techniques and combination of techniques are evaluated in Chapter 6 and Chapter 7 in more detail. Any new acquisition protocol that would be implementable in clinical practice should give at least comparable stratification results to the conventional protocol. Therefore, in these chapters the impact of these techniques on CAC quantification is examined to warrant
the validity of CAC as an imaging biomarker for CVD. Methods for dose reduction are not limited to setting and techniques available on a scanner, but dose reduction could also be achieved by comparing different types of CT systems while applying a similar CAC protocol. Besides, in large multi-center screening trials and in follow-up studies, it is often not possible to use exactly the same type of CT system. In Chapter 8, CAC quantification between three generations of dual-source computed tomography systems is compared to determine the variability between CT systems. Moreover, it provides a threshold above which CAC progression could be assessed in follow-up studies.
Finally, in Chapter 9 the main results presented in the previous chapters are discussed in a broader perspective and recommendations for future studies are given.
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