Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk
Authors: Willeit Peter , Tschiderer Lena , Allara Elias , Reuber Kathrin , Seekircher Lisa , Gao Lu , Liao Ximing , Lonn Eva , Gerstein Hertzel C. , Yusuf Salim , Brouwers Frank P. , Asselbergs Folkert W. , van Gilst Wiek , Anderssen Sigmund A. , Grobbee Diederick E. , Kastelein John J.P. , Visseren Frank L.J. , Ntaios George , Hatzitolios Apostolos I. , Savopoulos Christos , Nieuwkerk Pythia T. , Stroes Erik , Walters Matthew , Higgins Peter , Dawson Jesse , Gresele Paolo , Guglielmini Giuseppe , Migliacci Rino , Ezhov Marat , Safarova Maya , Balakhonova Tatyana , Sato Eiichi , Amaha Mayuko , Nakamura Tsukasa , Kapellas Kostas , Jamieson Lisa M. , Skilton Michael , Blumenthal James A. , Hinderliter Alan , Sherwood Andrew , Smith Patrick J. , van Agtmael Michiel A. , Reiss Peter , van Vonderen Marit G.A. , Kiechl Stefan , Klingenschmid Gerhard , Sitzer Matthias , Stehouwer Coen D.A. , Uthoff Heiko , Zou Zhi-Yong , Cunha Ana R. , Neves Mario F. , Witham Miles D. , Park Hyun-Woong , Lee Moo-Sik , Bae Jang-Ho , Bernal Enrique , Wachtell Kristian , Kjeldsen Sverre E. , Olsen Michael H. , Preiss David , Sattar Naveed , Beishuizen Edith , Huisman Menno V. , Espeland Mark A. , Schmidt Caroline , Agewall Stefan , Ok Ercan , Aşçi Gülay , de Groot Eric , Grooteman Muriel P.C. , Blankestijn Peter J. , Bots Michiel L. , Sweeting Michael J. , Thompson Simon G. , Lorenz Matthias W. ,   For the PROG-IMT and the Proof-ATHERO Study Groups
Published: June 2020

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.