Background: To quantify the association between effects of interventions on carotid intimamedia thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. Methods: We systematically collated data from randomized controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were utilized. The primary outcome was a combined CVD endpoint defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the two using a Bayesian meta-regression approach. Results: We analyzed data of 119 randomized controlled trials involving 100,667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12,038 patients developed the combined CVD endpoint. Across all interventions, each 10 μm/year reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% credible interval 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/year would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74). Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary vs. secondary prevention trials, type of cIMT measurement, and proportion of female patients. Conclusions: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.

Background Dickkopf‐1 and sclerostin have been implicated in atherosclerosis and vascular calcification. We aimed to quantify the association of their serum levels with incident cardiovascular disease ( CVD ) in the general population. Methods and Results Among 706 participants of the prospective, population‐based Bruneck Study, mean±SD of serum levels were 44.5±14.7 pmol/L for dickkopf‐1 and 47.1±17.5 pmol/L for sclerostin. The primary outcome was a composite CVD end point composed of ischemic or hemorrhagic stroke, transient ischemic attack, myocardial infarction, angina pectoris, peripheral vascular disease, and revascularization procedures. Over a median follow‐up duration of 15.6 years, 179 CVD events occurred. For the primary CVD outcome, multivariable‐adjusted hazard ratios ( HR s) per SD higher level were 1.20 for dickkopf‐1 (95% CI , 1.02–1.42; P =0.028) and 0.92 for sclerostin (95% CI, 0.78–1.08; P =0.286). Secondary outcome analyses revealed that the association of dickkopf‐1 was primarily driven by ischemic and hemorrhagic stroke (67 events; HR, 1.37; 95% CI, 1.06–1.78; P =0.017), whereas no increase in risk was observed for transient ischemic attack (22 events; HR, 0.87; 95% CI, 0.53–1.44; P =0.593), myocardial infarction (45 events; HR, 1.10; 95% CI, 0.78–1.54; P =0.598), or for other CVD (45 events; HR, 1.25; 95% CI, 0.88–1.76; P =0.209). Conclusions In this prospective, population‐based study, elevated baseline levels of dickkopf‐1, but not sclerostin, were independently associated with incident cardiovascular events, which was mainly driven by stroke. Our findings support the hypothesis of a role of dickkopf‐1 in the pathogenesis of CVD .

Background Carotid intima‐media thickness and carotid plaque are well‐established imaging markers used to capture different stages of the atherosclerotic disease process. We aimed to quantify to which extent carotid intima‐media thickness predicts incidence of first‐ever carotid plaque. Materials and methods Two independent reviewers conducted a comprehensive literature search of PubMed and Web of Science. To be eligible for inclusion, prospective studies were required to involve participants free of carotid plaque at baseline and report on the association of baseline carotid intima‐media thickness with development of first‐ever carotid plaque. Study‐specific relative risks and 95% confidence intervals were collected and pooled using random‐effects meta‐analysis. Results We identified seven relevant prospective studies involving a total of 9341 participants. Individuals were recruited between 1987 and 2012, average age at baseline was 54 years, and 63% were female. Studies reported on 1288 incident first‐ever carotid plaques, occurring over an average maximum follow‐up of 8.7 years. When individuals in the top fourth of baseline carotid intima‐media thickness distribution were compared with those in the bottom fourth, the pooled relative risk for incidence of first‐ever carotid plaque was 1.78 (95% confidence interval: 1.53‐2.07, P < .001, I2 = 2.8%). The strength of association was not modified by mean baseline age, proportion of female participants, length of follow‐up, year of baseline, and geographical location of the studies. Conclusions In general population studies, elevated baseline carotid intima‐media thickness is associated with incidence of carotid plaque in individuals free of carotid plaque at baseline.