Carotid Intima-media Thickness Measurements

INTRODUCTION Cardiovascular disease (CVD) is the leading cause of death worldwide and contributes considerably to morbidity.[123] The underlying cause is atherosclerosis.[4] The development of new preventive therapies is one of the steps to control the CVD epidemic. It is increasingly demanded that promising therapies be evaluated in trials using cardiovascular (CV) morbidity and mortality (M and M) as a primary outcome.[5] M and M trials, however, are very costly, often multicenter studies requiring thousands of participants, and with a long follow-up period. There is great interest in alternative endpoints that can be used as a valid alternative or proxy for CV M and M alternative endpoints (surrogate endpoints) allow for the evaluation of novel therapies in randomized controlled trials within a shorter timeframe, fewer participants, at lower costs, and with a shorter time to availability of trial results when compared to an M and M trial. These studies may show a direct effect on atherosclerosis progression and in the same time may serve to direct or exclude subsequent large M and M trials. A measure of atherosclerosis is intuitively a suitable alternative endpoint for CVD events as atherosclerosis is the disease between exposure to risk factors and the majority of CV events. Atherosclerosis can be noninvasively assessed from early to late stages of the disease process using different imaging techniques.[6789] B-mode ultrasound is one of those imaging techniques and has been used to obtain quantitative measurements of the carotid intima-media thickness (CIMT) and as such provides estimates for an individual on the absolute value (presence) and its change over time.[1011] CIMT has been suggested to be an adequate alternative measurement for CV events (surrogate endpoint) in intervention studies.[1011] Prentice and Boissel have proposed several criteria [Supplementary Table 1] for a surrogate endpoint that should have been met before it could be validly used.[12] We set out to review literature and provide evidence for the validity of CIMT measurements as an alternative measurement for atherosclerosis elsewhere in the arterial system and for CV events.Supplementary Table 1: Criteria that markers must meet to be considered as valid surrogates for clinical endpoints according to Boissel and Prentice (12)VALIDITY, CONCEPT AND REPRODUCIBILITY OF THE MEASUREMENT Validity In 1986, Italian investigators reported for the first time the results of an in vitro study which compared direct measurements of arterial wall thickness by gross and microscopic examination with B-mode real-time imaging of those same specimens.[13] Several studies followed. The overall conclusion was that CIMT measurements of the far wall closely relate to the true biological thickness of the vessel wall, whereas near wall CIMT measurements are an approximation of the true wall thickness.[1415161718] Since then, the number of scientific publication has increased steadily [Figure 1] and CIMT is currently one of the most widely used noninvasive measures of atherosclerosis employed by clinicians and clinical investigators, both to quantify the extent of subclinical disease and to monitor change over time.Figure 1: The number of publications (y-axis) using “carotid intima-media thickness (not animal)” in the title or abstract as assessed using PubMed database (http://www.ncbi.nlm.nih.gov/sites/entrez), by year of publication (x-axis), (December 16, 2014).Acquisition of the images Typically, the carotid artery is classified into three segments, each approximately 10 mm in length [Figure 2].[19] The most proximal segment, the 1 cm straight segment of the carotid artery immediately prior to the bifurcation, is the common carotid artery (CCA). Its distal boundary is identified by a divergence of the near and far walls as the artery begins to divide into its internal and external branches. This focal widening of the bifurcation extends over approximately 1 cm and is labeled the carotid bulb or bifurcation (CB). The distal margin is defined by the tip of the flow divider separating the diverging internal carotid artery (ICA) and external carotid artery. The final segment that is frequently examined is the proximal 1 cm of the ICA.Figure 2: A typical B-mode ultrasound image from the carotid artery.[19]As indicated in Figure 3, CIMT has been assessed in a several ways, varying in side (left carotid artery, right carotid artery, or both), segment (common, bifurcation, and internal), wall (near wall and far wall on the image), and in angles (60, 90, 120, 150, 180, 210, 240, 270, and 300) by using an external arc for positioning (Meijer Carotid ArcR).[20] Some studies measure CIMT only once and choose an image in which the interfaces are most clear (i.e., single optimal B-mode image).[21] Others searches for the point with the thickest CIMT (e.g., the highest burden of atherosclerosis).[22] Others choose from multiple optimal B-mode images,[23] or measure the CIMT from multiple images that were obtained from various standardized angles of interrogation [Figure 4]. The latter, using the Meijer Carotid Arc approach, allows for measurement at exactly the same location over time.[23] It is important to realize that each measurement approach has its own specific characteristics. Since atherosclerosis is asymmetrically distributed across the carotid artery, selectively measuring only one angle is likely to ignore the asymmetric nature of the disease.[2425] Furthermore, each measurement approach has its own characteristics with respect to the assessment of atherosclerosis progression, as previously shown.[26] Finally, also measurement error or missing values tend to vary across the measurement approaches.[2728]Figure 3: Graphical representation of the circumferential assessment of the artery sites. The angle values from 60 to 180 represent the standardized angles of interrogation. BIFUR: Carotid bifurcation; CCA: Common carotid artery; ECA: External carotid artery; ICA: Internal carotid artery.[29]Figure 4: The Meijer Carotid Arc that allows for assessment of angles specific images.[23]Actual measurement of the images Ultrasound images in CIMT studies are typically acquired at the study site, stored digitally, and send to a reading laboratory for offline reading. At the core lab, typically quality control and quality assurance typically takes place first before the actual readings can start. These actual readings can be performed using several different edge detection methods (semi-automatic or manual).[29] Semi-automated edge detection is more often applied in settings where only the CCA is examined while manual edge detection is usually applied in settings where the carotid bifurcation and the ICA are also measured.[30] The main difference between semi-automated edge detection and manual edge detection, however, is the actual manual drawing of the lines on the interfaces with manual edge detection. With semi-automatic edge detection, the reader still may adjust or modify the automatically drawn lines when the reader judges that the lines were incorrectly placed. A major advantage of semi-automated edge detection programs, besides being less resource intensive and time-consuming, may be the reduction in variability in CIMT readings as a result of reduction in the variability between readers and reduction of change in reading behavior over time (reader drift).[30] Many investigators have a clear view on this topic, mostly based on personal experience. Yet, there is little published evidence on this topic. Two recent studies indicated that manual and semi-automated edge detection of far wall common CIMT both result in high reproducibility, and largely show similar relations to CV risk factors, rates of change, and treatment effects.[3031] Hence, choices between semi-automated and manual reading software for CIMT studies likely should be based on logistical and cost considerations rather than differences in expected data quality in populations with a low burden of atherosclerotic disease. Reproducibility of the measurement for an individual With reproducibility is meant that when an individual is measured today, the obtained value should be similar to that obtained tomorrow or next week. Between visit, reproducibility covers all sources that may affect the CIMT measurement: Position of the patient, image acquisition, reader variability, and within-patient variability in, for example, blood pressure or heart rate. Although difficult to quantify, due to a wide variation in reporting of reproducibility results, it seems that the reproducibility of the CIMT measurements has improved considerably over the years.[32] Studies reporting on the intraclass correlation coefficient (ICC), showed that the ICC ranged from 0.60 to 0.75 in studies conducted during the late eighties.[3334353637] whereas, more recent studies reported an ICC between 0.80 and 0.95.[383940] Of note, it seems that in studies that started as an observational study the reproducibility was less than in studies focuses on measuring progression.[4142] A number of reports from randomized controlled trials recently addressed the reproducibility of CIMT measurements based on various ultrasound protocols.[2843444546] In these trials, the ultrasound protocols were based on an assessment of both sides, all three segments, both walls and at least eight angles. With those data points, the interest was in providing the best balance between reproducibility, magnitude of CIMT change over time and its associated precision, and magnitude of effect of the intervention on CIMT change over time and its associated precision. RELATIONS WITH ESTABLISHED CARDIOVASCULAR RISK FACTORS There is a wealth of evidence on the relation between unfavorable level of risk factors and increased CIMT. We made no attempt to refer to all the available publications on that issue. Most of the evidence comes from cross-sectional studies. Traditional risk factors such as ageing, male gender, elevated blood pressure, increased body mass index, high low-density lipoprotein (LDL) cholesterol, low high-density lipoprotein (HDL) cholesterol, diabetes mellitus, and smoking have shown to be related to increased CIMT.[47484950515253545556] These relations also hold for individuals with an Asian ancestry.[57585960616263] In addition, increased CIMT has been associated with abnormalities in other organ systems such as the presence of white matter lesions in the brain,[64] left ventricular hypertrophy.[656667] renal disease,[68] and endothelial dysfunction measured at the level of the brachial artery.[69] Data on risk factors and change in CIMT or change in risk factors and change in CIMT is less readily available.[70717273] The Atherosclerosis Risk In Communities study in one of the earliest reports showed that baseline levels of established risk factors (such as diabetes, hypertension, LDL, and HDL cholesterol) were related to increased progression on CIMT.[70] RELATION WITH ATHEROSCLEROSIS THE A of studies evaluated the relation between CIMT and presence of atherosclerotic abnormalities elsewhere in the arterial were shown for the presence of atherosclerotic abnormalities in the carotid bifurcation and the the the of the lower and the In a recent most of the studies out of showed a between CIMT and assessed atherosclerosis with correlation in the of Of is to realize that these reported between carotid atherosclerosis and atherosclerosis are of similar magnitude to those shown in studies. Several studies at the relation between CIMT and showed similar of In studies using relations are between left main atherosclerosis and CIMT with correlation between and In the between CIMT and atherosclerosis in various studies the that CIMT measurements are atherosclerosis AND THE RELATION WITH CARDIOVASCULAR Several large observational studies the relation of CIMT with In published a review and of eight studies that reported on the of CIMT to CV points, the three a of for a of reported that for an absolute CIMT difference of the risk of by and the risk by There is a number of studies performed in with an Asian results with those in over studies that were performed with or and with and CVD risk factors, showed that increased CIMT to increased CV of established risk AND OF In Table an is of several trials that have been performed to the of on the of change in CIMT. In those trials, the of change in CIMT over time was the primary The majority have evaluated the of These trials the to measure change over time in which is a to differences across treatment Table 2: and results of CIMT trials on different therapies and with results from mortality and mortality trials from and the trials in which the of A are compared to are all trials, for reported a effect of on of change in CIMT. In a of trials on different was associated with a change in CIMT of mm to of trials showed that the difference in the of change in CIMT between and was mm to A review by to identified randomized controlled trials using different with a follow-up of This individuals showed that the difference in progression between and or for the common CIMT was mm performed a of the and a database to to studies with a or other on The trials that atherosclerotic disease at the subclinical and provide evidence that CIMT measurements are to show the of A point of interest and is that the effect of on of change in CIMT to be different across different carotid walls and segments, which for assessment of from different carotid in OF AND CARDIOVASCULAR have that data should available that a change in CIMT to change in risk of CV events. In in the clinical trial such an is as a final of the evidence to the CIMT measurement for in Yet, studies to that are difficult to as first to show the of an intervention on of change in CIMT and next have and follow-up time this to the of measured CIMT change to for subsequent in CVD most trials with CIMT data on the of change in CIMT for the of events the trial was these CIMT trials were for evaluation of events. data on change in CIMT by or blood pressure therapies and change risk for CV events is very The only published is the Atherosclerosis The trial that of change in CIMT. The trial was over an of the conclusion of to the of events. The trial showed a lower of change in common CIMT over time was related to a lower risk of an with an common CIMT progression of a CVD risk compared to those with a common CIMT progression of mm or The risk for those with progression rates between and mm was increased and the risk for those with progression rates between and mm was increased In to this performed a that across the trials, was associated with an of CIMT progression of to the same performed a which a risk reduction of for CVD events. In this approach, the the CIMT to the reduction of events. In addition, the recently published on the of change in CIMT and was based on a change in CIMT in observational in common CIMT rather than the of relation between the of change in common CIMT and risk of CV events was The reproducibility between the first and the CIMT measurement was low coefficient The a recent observational performed in in with or more risk factors, and was to CIMT in common CIMT of mm was related to an increased risk of CV events of The CIMT based on the change in segment showed a progression of of one that was related to an in risk of In a of with diabetes of CV events CIMT was assessed more than by were and for CV showed that the change in CIMT was associated with CV with a of using the of CIMT change of as were published to this using data from published The have been of in the and the of the of of trials out with and very different risk of measurements from a wide of that a common of for using and the Hence, the of these should be considered At direct quantitative evidence to the reduction in CIMT progression rates in a reduction in clinical is Yet, the of such the CIMT measurement for in trials on atherosclerosis and reduction of CV OF AND Prentice and Boissel have proposed several criteria [Supplementary Table 1] for a surrogate that should have been met before it could be validly In the have addressed in the criteria by Prentice and from the Table The criteria is more difficult to it studies in which data on the on the CIMT change and on clinical events are all in one This of data is only from as performed by showed a between and CV events of in the for the of change in the was to and no This that in CIMT may for of the effect of on CV events. 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A of however, may be the In studies that several between the first CIMT measurements and the CIMT a may in the estimates of the of change, due to change over time in measuring of reading of the core may affect rates of change in should affect treatment as readers are for of the and is likely to affect both treatment and the difference between the treatment should In all images of one individual are at the of the trial and CIMT is from all images in a time by one data on this however, in the of carotid ultrasound have been in a in measurement in edge detection point of CIMT The major advantage of CIMT is that it is noninvasive and can be as often as It provides a measure all have a carotid It is also to and the is widely A relation between and increased CIMT is CIMT has been shown to relate the atherosclerotic abnormalities elsewhere in the arterial increased CIMT events in both populations from and those from Asian Furthermore, has been shown to affect CIMT progression within in trials with results with clinical events trials. 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