Rate Of Change In Carotid Intima-media Thickness Research Articles

Measuring effects on intima-media thickness: an evaluation of rosuvastatin in Chinese subjects with subclinical atherosclerosis\u2014design, rationale, and methodology of the METEOR-China study

BackgroundThe beneficial effect of statins on atherosclerosis and cardiovascular outcomes has been well established. The Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin (METEOR) global study demonstrated that a 2-year orally administered treatment with rosuvastatin 40 mg daily significantly slowed the progression of carotid intima-media thickness (CIMT) compared to placebo. The current METEOR-China study is designed to evaluate the effect of rosuvastatin 20 mg daily versus placebo on the progression of atherosclerosis measured by CIMT in asymptomatic Chinese subjects.MethodsThis is a phase 3, randomised, double-blind, placebo-controlled, multicentre parallel-group study. Asymptomatic Chinese subjects with a 10-year ischaemic cardiovascular disease (ICVD) risk < 10% will be recruited at 25 study sites. They will be treated with rosuvastatin 20 mg or placebo for 104 weeks. The primary endpoint is the annualised rate of change in CIMT measured by B-mode ultrasonography. Secondary endpoints include the annualised rate of change in CIMT at three different sections of the carotid artery and changes in the serum lipid profile. Safety parameters will also be assessed.ConclusionThe study will evaluate whether rosuvastatin 20 mg slows the progression of CIMT in asymptomatic Chinese subjects at low risk of ICVD.Trial registrationClinicalTrials.gov NCT02546323. Registered on September 10, 2015

Biologically implausible carotid intima–media thickness measurement values: effects on rate of change over time

Objective:Carotid intima–media thickness (CIMT) is a marker of atherosclerosis that is commonly used to assess the effect of therapeutic interventions. It is currently unclear to what extent biologically implausible values affect treatment effects. We evaluated the impact of biologically implausible CIMT values on the estimated rate of change in CIMT.Methods:Data were used from the METEOR (Measuring Effects on Intima–media Thickness: an Evaluation of Rosuvastatin) trial. METEOR was a randomized, placebo-controlled trial showing that rosuvastatin reduced the 2-year change in CIMT among low-risk individuals with subclinical atherosclerosis. In the main METEOR analysis, the data were analyzed without exclusion of biologically implausible data. In this post-hoc analysis, we constructed twelve definitions to define mildly or extremely biologically implausible values using distance from the interquartile range, median or mean. We evaluated the effect of removing implausible values on the estimated rate of change in CIMT.Results:The percentage of biologically implausible CIMT values ranged from 0.6% to 9.7%, depending on the definition used. Across all definitions, removal of biologically implausible CIMT values marginally reduced standard errors and did not change the primary outcome (i.e., a nonsignificant change in the rosuvastatin group, significant progression in the placebo group, and a statistically significant difference between treatment groups).Limitation:This study was focussed on the impact of implausible values in the analytical part of a CIMT study. Ultrasound images were not re-examined to determine whether an implausible measurement was due to measurement error or temporal morphological thickening,Conclusion:Removal of biologically implausible CIMT values marginally decreased the variability of the estimated rate of change in CIMT without having a large impact on the estimated rate of change.

Variability in the intima-media thickness measurement as marker for cardiovascular risk? Not quite settled yet.

For over two decades the measurement of carotid intima-media thickness (CIMT) has been applied in cardiovascular research. There is a wealth of evidence supporting its value. A thickened CIMT measurement does not lead directly to the occurrence of a myocardial infarction or stroke, but merely reflects what is going on in the vasculature of an individual. Similarly, the rate of change in CIMT over time is a reflection of how the development of atherosclerosis is altered over time. Both these CIMT measurements are reflections of cardiovascular risk (1,2).

Extensive or Restricted Ultrasound Protocols to Measure Carotid Intima-Media Thickness: Analysis of Completeness Rates and Impact on Observed Rates of Change Over Time

Ultrasound protocols to measure carotid intima-media thickness (CIMT) vary considerably with regard to carotid sites and angles that are assessed. Measurements from the carotid bifurcation and internal carotid artery are thought to be affected by large numbers of missing data. Actual published quantification of completeness rates and the relation with cardiovascular risk factors, however, is scarce. Also, it is currently unknown whether extensive ultrasound protocols including assessment of the carotid bifurcation and internal carotid artery add information in detecting rate of change in CIMT induced by drug therapy. These issues were addressed in this study using data from Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin (METEOR). In METEOR, carotid ultrasound examinations were performed twice before randomization, once each at 6, 12, and 18 months after randomization, and twice after 24 months of study treatment. B-mode ultrasound images were obtained from the near and far walls of the left and right common carotid artery, bifurcation, and internal carotid artery at five predefined angles. Completeness of CIMT data was assessed by carotid site and by angle. A site was considered complete when any of the five angles was measured. The relation between completeness at baseline and cardiovascular risk factors was assessed using logistic regression analyses. Ultrasound protocols with a reduced number of carotid sites and angles were retrospectively constructed, and differences in the rate of change in maximum CIMT between ultrasound protocols were compared. At each visit, CIMT measurements from all 12 carotid sites were available for >94% of the participants. Incompleteness was the highest for near wall of the internal carotid artery and for the extreme angles (60° and 300°). Of 12 risk factors examined, higher body mass index was related to incompleteness. Ultrasound protocols with a reduced number of angles resulted in similar estimates for the differences in rate of change in maximum CIMT. However, reductions in the number of sites gave results in the same direction but with different magnitudes and larger standard errors. High levels of complete data can be obtained with extensive ultrasound protocols that include measurement from the carotid bifurcation and internal carotid artery. A high body mass index contributes to incompleteness of CIMT measurements. Extensive ultrasound protocols are required to obtain the highest precision to observe a treatment effect and to fully cover the degree of atherosclerotic burden.

Attenuation of Rate of Change in Carotid Intima-Media Thickness by Lipid-Modifying Drugs

Measurements of carotid intima-media thickness (CIMT) are widely used in clinical research as a measure of atherosclerosis. Many randomized controlled trials (RCTs) have been performed using the rate of change in CIMT as the primary endpoint to study the efficacy of lipid-modifying therapies. The main advantage of using CIMT over the use of cardiovascular events as a primary endpoint is the greater efficiency and feasibility. The underlying assumption for the use of CIMT in trials is that the rate of change in CIMT achieved by a therapy reflects a change in the risk for cardiovascular events. We therefore set out to assess the evidence showing whether the rate of change in CIMT induced by lipid-lowering therapies has an impact on clinical outcomes, by reviewing the available evidence based on a search of the PubMed database. Solid evidence from observational studies shows that increased CIMT relates to an increase in cardiovascular risk. RCTs consistently demonstrate that the annual rate of change in CIMT is favourably affected by lipid-modifying therapies. One study investigating the relationship between the rate of change in CIMT and clinical events has been published and showed a positive relationship between these two outcomes. A published meta-analysis based on pooled CIMT data from statin trials has shown a positive relationship between attenuated rate of change in CIMT after statin therapy and clinical outcomes. However, methodological issues question the validity of the meta-analytical approach. The consistent agreement between results from CIMT trials and event trials on the effects of lipid-modifying therapies, however, clearly supports the presence of a relationship between changes in CIMT and clinical endpoints. Therefore, although direct evidence is scarce, the data overall on whether the attenuation of rate of change in CIMT by lipid-lowering therapies impact on clinical outcomes are supportive.

O3-1.4 Multiple imputation: panacea or placebo, the case of missing carotid intima-media thickness measurements in clinical trials

IntroductionWe assessed the added value of multiple imputation (MI) of missing values in longitudinal datasets with carotid intima-media thickness (CIMT) as primary endpoint subsequently analysed with linear mixed effects (LME)...

Effect of number of ultrasound examinations on the assessment of carotid intima–media thickness changes over time: the example of the METEOR study

To evaluate the effect of the number and positioning during follow-up of ultrasound examinations on the rate of change in carotid intima-media thickness (CIMT) using METEOR (Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin) as an example. METEOR was a randomized, placebo-controlled trial showing that rosuvastatin reduced progression of 2-year change in CIMT among low-risk patients with subclinical atherosclerosis. In the full METEOR protocol, ultrasound examinations were performed twice before randomization, once each at 6, 12, and 18 months after randomization, and then twice at the end of study at 24 months. For the present study, 17 study designs were retrospectively constructed with varying number and position of ultrasound examinations during the study. Differences in the rate of change in maximum CIMT between these study designs were compared. Variations in frequency of ultrasound visits gave results in the same direction and magnitude for the change in maximum CIMT for both groups (i.e. nonsignificant change for rosuvastatin and significant progression for placebo, and a significant difference between treatments). However, standard errors were larger when the number of exams reduced. This finding was consistent over different lengths of follow-up, sample sizes, and with CIMT measurements made on different locations. Protocols with different number and timing of ultrasound examinations minimally affect the direction and magnitude of treatment effects on the rate of change in CIMT. However, reductions in exam frequency increase standard errors of rates of change, suggesting larger sample sizes would be required to have the same level of statistical power.

Are changes in carotid intima-media thickness related to risk of nonfatal myocardial infarction? A critical review and meta-regression analysis

Carotid intima-media thickness (CIMT) is increasingly being used as a surrogate end point in randomized control trials (RCTs) of novel cardiovascular therapies. However, it remains unclear whether changes in CIMT that result from these therapies correlate with nonfatal myocardial infarction (MI). We performed a literature search of RCTs from 1990-2009 that used CIMT. Eligible RCTs (1) included quantitative and sequential assessments in CIMT at least 1 year apart and (2) reported nonfatal MI. Across RCTs, random-effects metaregression was employed to correlate differences in mean change in CIMT between treatment and control groups over time with the log odds ratios of developing nonfatal MI during follow-up. Overall, we identified 28 RCTs with 15,598 patients. Differences in mean change in CIMT over time between treatment and control groups correlated with developing nonfatal MI during follow-up: for each 0.01 mm per year smaller rate of change in CIMT, the odds ratio for MI was 0.82 (95% CI, 0.69 to 0.96; P = .018). Results were similar in subgroups of RCTs with >1 year follow-up (P = .018) and those with at least 50 subjects in the treatment group (P = .019). However, there was no significant relationship between mean change in CIMT and nonfatal MI in RCTs evaluating statin therapy or those with high CIMTs at baseline (P > .20 in both instances). Less progression in CIMT over time is associated with a lower likelihood of nonfatal MI in selected RCTs; however, these findings were inconsistent at times, suggesting caution in using CIMT as a surrogate end point.

Ultrasound protocols to measure carotid intima-media thickness in trials; comparison of reproducibility, rate of progression, and effect of intervention in subjects with familial hypercholesterolemia and subjects with mixed dyslipidemia

Background. Current ultrasound protocols to measure carotid intima-media thickness (CIMT) in trials rather differ. The ideal protocol combines high reproducibility with a high precision in the measurement of the rate of change in CIMT over time and with a precise estimate of a treatment effect. To study these aspects, a post-hoc analysis was performed using data from two randomized double-blind, placebo-controlled trials: one among 872 subjects with familial hypercholesterolemia (FH) and the other among 752 subjects with mixed dyslipidemia (MD), respectively. Participants were randomized to torcetrapib or placebo on top of optimal atorvastatin therapy.Methods. CIMT information was collected from the left and right carotid artery from two walls (the near and far wall) of three segments (common carotid, bifurcation, and internal carotid artery) at four different angles (right: 90, 120, 150, and 180 degrees on Meijer's carotid arc; left: 270, 240, 210, and 180 degrees, respectively). Based on combinations of these measurements, 60 different protocols were constructed to estimate a CIMT measure per participant (20 protocols for mean common CIMT, 40 protocols for mean maximum CIMT). For each protocol we assessed reproducibility (intra-class correlation coefficient (ICC), mean difference of duplicate base-line scans); 2-year progression rate in the atorvastatin group with its standard error (SE); and treatment effect (difference in rate of change in CIMT between torcetrapib and placebo) with its SE.Results. Reproducibility: ICC ranged from 0.77 to 0.91 among FH patients and from 0.68 to 0.86 among MD patients. CIMT progression rates ranged from −0.0030 to 0.0020 mm/year in the FH trial and from 0.00084 to 0.01057 mm/year in the MD trial, with SE ranging from 0.00054 to 0.00162 and from 0.00083 to 0.00229, respectively. The difference in CIMT progression rate between treatment arms ranged from −0.00133 to 0.00400 mm/year in the FH trial and from −0.00231 to 0.00486 mm/year in the MD trial. The protocol with the highest reproducibility, highest CIMT progression/precision ratio, and the highest treatment effect/precision ratio were those measuring mean common CIMT with measurements of the near and far wall at multiple angles. When the interest is in the mean maximum CIMT, protocols using multiple segments and angles performed the best.Conclusion. Our findings support the position that the number and specific combination of segments, angles, and walls interrogated are associated with differences in reproducibility, magnitude, and precision of progression of CIMT over time, and treatment effect. The best protocols were mean common CIMT protocols in which both the near and far walls are measured at multiple angles.Trial registration: ClinicalTrials.gov identifier: NCT00136981.Trial registration: ClinicalTrials.gov identifier: NCT00134264.

Recent Advances of Intervention to Inhibit Progression of Carotid Intima-Media Thickness in Patients With Type 2 Diabetes Mellitus

Type 2 diabetes is associated with a high cardiovascular morbidity and mortality. Recent advances of intervention studies in type 2 diabetes with use of carotid intima-media thickness (CIMT) measurement as a surrogate end point may allow for better understanding of the undetermined process of atherosclerosis, the effect of interventions, and the usefulness of CIMT to inhibit events of cardiovascular disease. Data were available from 11 studies (n=1578) in subjects with type 2 diabetes (including impaired glucose tolerance, n=132) that evaluated the effect of interventions on change in CIMT. The overall weighed rate of change in mean CIMT based on data among control groups (ie, type 2 diabetes without interventions) was 0.034 mm/y (95% CI, 0.029 to 0.039; median SD, 0.054), in which mean HbA(1c) was 7.86% (95% CI, 7.72 to 8.00; median SD, 1.5). A significant close correlation of HbA(1c) with rate of CIMT change was found (R(2)=0.35, P=0.01). Agents for lowering of blood glucose, platelet activation, or blood pressure significantly reduced the CIMT increase, independent of blood glucose control. This implies that other mechanisms of such agents to diminish CIMT increase should be explored. CIMT measurement may contribute to elucidating the short- and/or long-term effect of interventions on the rate of change in CIMT in relation to the levels of various risk factors. Although the method needs further standardization, pharmacological interventions are likely to inhibit progression of CIMT, leading to a reduction of cardiovascular events.