Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients.
Willeit P., Tschiderer L., Allara E., Reuber K., Seekircher L., Gao L., Liao X., Lonn E., Gerstein HC., Yusuf S., Brouwers FP., Asselbergs FW., van Gilst W., Anderssen SA., Grobbee DE., Kastelein JJP., Visseren FLJ., Ntaios G., Hatzitolios AI., Savopoulos C., Nieuwkerk PT., Stroes E., Walters M., Higgins P., Dawson J., Gresele P., Guglielmini G., Migliacci R., Ezhov M., Safarova M., Balakhonova T., Sato E., Amaha M., Nakamura T., Kapellas K., Jamieson LM., Skilton M., Blumenthal JA., Hinderliter A., Sherwood A., Smith PJ., van Agtmael MA., Reiss P., van Vonderen MGA., Kiechl S., Klingenschmid G., Sitzer M., Stehouwer CDA., Uthoff H., Zou Z-Y., Cunha AR., Neves MF., Witham MD., Park H-W., Lee M-S., Bae J-H., Bernal E., Wachtell K., Kjeldsen SE., Olsen MH., Preiss D., Sattar N., Beishuizen E., Huisman MV., Espeland MA., Schmidt C., Agewall S., Ok E., Aşçi G., de Groot E., Grooteman MPC., Blankestijn PJ., Bots ML., Sweeting MJ., Thompson SG., Lorenz MW., PROG-IMT and the Proof-ATHERO Study Groups .
BACKGROUND: To quantify the association between effects of interventions on carotid intima-media 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 used. The primary outcome was a combined CVD end point 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 2 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 end point. Across all interventions, each 10 μm/y 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/y 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), respectively. Results were similar 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. 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.