Carotid intima-media thickness progression as surrogate marker for cardiovascular risk

In this paper – published in Circulation – we quantified the association between the intervention effects on carotid intima media thickness (cIMT) progression and the intervention effect on cardiovascular risk.

Therefore, we systematically reviewed the literature and collected aggregated literature based data and individual participant data from 119 randomised controlled trials involving a total of 100,667 individuals. Mean age of the participants was 62 years and 42% were female. The primary outcome was a combined cardiovascular endpoint defined as myocardial infarction, stroke, revascularisation procedures, or fatal cardiovascular disease. Over an average of 3.7 years of follow-up, 12,038 individuals developed the combined cardiovascular endpoint.

The primary analysis revealed that across all interventions, each 10 μm/year reduction of cIMT progression resulted in a relative risk for cardiovascular disease of 0.91 (95% credible interval: 0.87-0.94), with an additional relative risk for cardiovascular disease of 0.92 (95% credible interval: 0.87-0.97) being achieved independent of cIMT progression.

Furthermore, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/year would yield relative risks of 0.84 (95% credible interval: 0.75-0.93), 0.76 (95% credible interval: 0.67-0.85), 0.69 (95% credible interval: 0.59-0.79), or 0.63 (95% credible interval: 0.52-0.74).

In outcome-specific analyses, we identified relative risks per 10 μm/year slower cIMT progression of 0.88 (95% credible interval: 0.82-0.94) for myocardial infarction, 0.92 (95% credible interval: 0.86-1.00) for stroke, 0.90 (95% credible interval: 0.83-0.98) for revascularisation procedures, 0.91 (95% credible interval: 0.83-1.01) for fatal cardiovascular disease, and 0.96 (95% credible interval: 0.89-1.04) for all-cause mortality.

In subgroup analyses we did not find a significant difference in relative risks when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients.

Finally, we concluded that the extent of intervention effects on cIMT progression predicted the degree of cardiovascular risk reduction, which provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for cardiovascular risk in clinical trials.

The paper is available at

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