Imaging of atherosclerosis: study design and cardiovascular risk prediction

Cardiovascular disease is still the leading cause of morbidity and mortality worldwide.1 The majority of cardiovascular disease events is caused by atherosclerosis. Atherosclerosis is a slow and progressive disease of the arterial wall that is on the pathway between the effects of exposure to risk factors and the occurrence of cardiovascular events.2 Even though atherosclerosis may remain clinically silent for decades, it can be non-invasively assessed from early to late stages of the disease process using different imaging techniques. B-mode ultrasound is one of those imaging techniques which is frequently used to assess atherosclerosis in a safe, inexpensive, reliable, and reproducible manner. B-mode ultrasound measurements of the carotid intima-media thickness (CIMT) is an accepted measure of atherosclerosis that has frequently been used in observational studies to study the causes and consequences of atherosclerosis. In addition, numerous randomized controlled trials have used CIMT as alternative endpoint for cardiovascular disease events to evaluate the effects of new interventions. The main advantage of using CIMT as an outcome variable in studies is the considerable increase in efficacy in sample size and duration of follow-up when compared to studies using morbidity and mortality as primary outcome. Nevertheless, while CIMT measurements are increasingly being used, there are still no accepted standards on the use of CIMT measurements in various research areas. Hence, choices in the design and analysis of a CIMT study are generally based on experience and expert opinion rather than on solid evidence. Even though some methodological issues have begun to be addressed, there are many outstanding topics that need to be further evaluated. Also, there is a need to further explore alternative B-mode ultrasound approaches to examine the effects of new interventions on atherosclerosis. In addition, there is growing interest in the use of imaging of atherosclerosis as tool to improve risk prediction for cardiovascular disease in clinical practice. Yet, there is no conclusive evidence on the use of imaging of atherosclerosis in clinical practice and the added value of imaging of atherosclerosis in risk prediction for cardiovascular events. The aim of this thesis is threefold. First, several outstanding topics in the design and analytical phase of a CIMT trial will be addressed. The results from these studies will provide evidence for the most optimal approach to design and statistically analyze a CIMT study into the early effects of a new intervention on atherosclerosis before the start of a large morbidity and mortality study. In the second part, some alternative measures of atherosclerosis are evaluated with respect to their usefulness to study the effect of drug therapy on atherosclerosis. Finally, the role of imaging of atherosclerosis in risk prediction for cardiovascular disease in the general population will be examined.