The PROG-IMT project: Individual progression of carotid intima media thickness as a surrogate for vascular risk.

• Applicant: Professor Dr. Matthias Wolfgang Lorenz
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology ; Epidemiology and Medical Biometry/Statistics ; Cardiology, Angiology
• Term: from 2010 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 147846926

Carotid Intima Media Thickness (IMT) is an ultrasound biomarker of early atherosclerosis. Single-time IMT is predictive of future vascular events, such as myocardial infarction or stroke. IMT progression, derived from at least two ultrasound scans, is frequently perceived to be a surrogate of vascular risk; and it is often used in randomized controlled trials and in pathophysiological studies. Current evidence for the surrogacy of IMT progression for the risk of clinical vascular endpoints is sparse and inconsistent.The submitted project aims at assessing the association between IMT progression and vascular risk, and the criteria of surrogacy, with current state-of-the-art methods of individual participant data (IPD) meta-analysis. This analysis is organized within a large, effective and fast growing international collaboration, led by the applicant. Based on informed estimations, approximately 200 RCTs that are eligible for our meta-analysis exist worldwide. 53 of these already joined our collaboration, and shared their datasets. Our projections - based on six years' experience with similar data - show that approximately 100 additional RCTs will cooperate within the next two years.Eligible trials are identified with an extensive search of PubMed, EMBASE and other databases of clinical trials, handsearch of the reference lists of all identified papers, PubMed research of review articles on IMT and handsearch of their reference lists, and personal contacts of all study group members. Inclusion criteria are (i) RCT with interventional arm and placebo or standard treatment arm, (ii) prospective longitudinal study design, (iii) investigation of lipid-lowering agents, antihypertensive drugs, or any other type of intervention when at least five trials studying this intervention type are available with the necessary data, (iv) well-defined and disclosed inclusion criteria and recruitment strategy, (v) at least two ultrasound visits where carotid IMT was determined, and (vi) a clinical follow-up recording MI, stroke, or death or several of these.Acquired datasets are kept in the coordination centre (Frankfurt), where harmonization and plausibility checks are done. Uniform datasets are transferred to the statistics centre (Cambridge). The analyses are managed in close cooperation between Frankfurt and Cambridge, and interpreted together.For the meta-analysis, the Daniels & Hughes approach will be used, where the association between the intervention effect on the surrogate marker (difference in mean IMT progression) and the intervention effect on the clinical endpoint (log hazard ratio of a Cox regression model) is modeled with a bivariate normal distribution, and fitted with a Bayesian model. The IPD meta-analysis enables us to allow for the imprecision of IMT progression, and for the within-trial correlation of IMT progression and log hazard ratio of CVD.

• DFG Programme: Research Grants
• Participating Persons: Privatdozent Dr. Matthias Sitzer; Professor Dr. Helmuth Steinmetz