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Carotid Intima-Media Thickness Progression to Predict Cardiovascular Events in the General Population (The PROG-IMT Collaborative Project): A Meta-Analysis of Individual Participant Data
Study Questions:
Is there an association between individual progression of carotid intima-media thickness (cIMT) and cardiovascular event risk?
Methods:
The authors assembled a large cIMT progression data set, employing a meta-analysis of published studies that included at least two ultrasound visits measuring cIMT, within longitudinal studies of general population samples, and clinical follow-up that recorded myocardial infarction (MI), stroke, death, vascular death, or a combination of these endpoints. Data sets underwent central plausibility checks, and the original study teams collaborated in an individual participant data meta-analysis. Subjects with prior MI or stroke were excluded to assess the association between cIMT progression and risk of incident cardiovascular events using Cox regression analysis. The authors pooled log hazard ratios per standard deviation difference by random-effects meta-analysis.
Results:
The authors included 16 of 21 eligible studies, with 36,984 participants, and a mean follow-up of 7.0 years. In these studies, there were 1,519 MIs, 1,339 strokes, and 2,028 combined endpoints (MI, stroke, vascular death). The yearly cIMT progression derived from the two recorded ultrasound visits was not associated with the combined endpoint (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.94-1.00) after adjusting for age, sex, and mean common carotid artery IMT, or after adjusting for vascular risk factors (HR, 0.98; 95% CI, 0.95-1.01). Sensitivity analyses also found no association with the combined endpoint. There was, however, an association between cIMT and cardiovascular risk, after adjusting for age, sex, mean common carotid artery IMT progression, and vascular risk factors (HR, 1.16; 95% CI, 1.10-1.22). Among 3,439 subjects in three studies for which four ultrasound scans were performed, cIMT progression did not correlate between examinations (reproducibility correlations between r = -0.06 and r = -0.02).
Conclusions:
The authors concluded that the association between cIMT progression assessed from two ultrasound scans and cardiovascular risk in the general population remains unproven. The authors further opined that no conclusion could be derived for the use of cIMT progression as a surrogate in clinical trials.
Perspective:
This carefully performed, individual data meta-analysis further calls into question the use of cIMT progression as a surrogate endpoint for cardiovascular events. Although there are epidemiologic data suggesting an association between cIMT and cardiovascular risk in general (and this study found the same), the use of wall thickness progression as an individual risk factor has been previously questioned. The current data suggest that there is no good evidence to support using cIMT progression as a surrogate risk factor for clinical events. The unstable nature of measures of cIMT, as well as the high degree of interobserver variability, has caused many to question the validity of this surrogate endpoint. The data in the current study should temper the interpretation of previous clinical trials that have used cIMT progression as endpoints.
Keywords: Myocardial Infarction, Stroke, Follow-Up Studies, Biomarkers, Carotid Intima-Media Thickness, Cardiology, Cardiovascular Diseases, Carotid Artery Diseases, Risk Factors, Disease Progression
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