Does Carotid Intima-Media Thickness Regression Predict Reduction of Cardiovascular Events? A Meta-Analysis of 41 Randomized Trials

Abstract

Conclusion: Slowed progression or regression of carotid intima-media thickness (IMT) induced by drug therapy does not translate into reduction in clinical cardiovascular events. Summary: Carotid intima-media thickness (IMT) predicts cardiovascular events. IMT is therefore a potentially attractive biomarker as a therapeutic target in subjects at increased cardiovascular risk. IMT is considered a manifestation of subclinical atherosclerosis. It has been included in the list of organ damaged conditions in European Hypertensive Guidelines and in the European Prevention Guidelines. (Mancia G, et al. Eur Heart J 2007;28:1462-536, and Graham I, et al. Eur J Cardiovasc Prev Rehabil 2007;14 Suppl 2:e1-40). IMT changes have been employed as surrogate clinical end-points in randomized clinical studies of lipid lowering agents, antihypertensive agents, oral antidiabetic agents, and antioxidant drugs in subjects at intermediate to high cardiovascular risk. Information verifying whether changes in IMT were associated with consistent changes in cardiovascular risk profile would be relevant for interpretation of IMT variations and surrogate clinical-end points and for identifying therapeutic targets for cardiovascular therapies. The author's designed this meta-analysis to verify whether IMT regression is associated with reduced incidence of cardiovascular events. Cochrane and the Medline databases were searched for articles published until August 2009. Included articles were randomized trials that assessed carotid IMT at baseline and at follow-up and that also reported clinical end-points. A weighted random-affects analysis was used to determine a relationship between mean and maximum IMT changes and outcome. Baseline patient characters, cardiovascular risk profile, IMT at baseline and follow up and quality of the trials were also explored. Estimates and effects were calculated with a fixed-effects model, random-effects model or Peto method. There were 18,307 participants and 41 trials included in the analysis. There were significant reductions in coronary heart disease, cerebral vascular disease events and all cause death induced by active treatments in the trial. However, there was no significant relationship between IMT regression and coronary heart disease events (tau, 0.91; P = .37), cerebral vascular events (tau, −0.32; P = .75) and all cause death (tau, −0.41; P = .69). The association between IMT changes and clinical outcomes was not influenced by subject's baseline characters, cardiovascular risk profile, IMT at baseline, follow up or quality of the trials. Comment: The principle finding of the study is carotid IMT changes do not correlate with changes in major cardiovascular events that are induced by drug treatments in subjects at intermediate to high cardio vascular risk. The US Preventative Task Force considers correlation of IMT changes with clinical events to be unproven (Helfand M, et al. Ann Intern Med 2009;151:496-507). There may be many unknown determinates of IMT that reduce the clinical strength and statistical significance of IMT changes associated with cardiovascular outcomes when compared to more direct atherosclerotic risk factors. It may also be, that atherosclerosis in the carotid artery, is not generally representative of atherosclerosis throughout the body. Atherosclerotic plaques in the carotid artery grow longitudinally at twice the rate that they grow in thickness. Therefore, IMT may be a less sensitive measure of plaque evolution than total plaque burden (Mackinnon AD, et al. Stroke 2004;35:2150-4). The bottom line, however, is that while IMT increase indicates increased cardiovascular risk, changes in IMT induced by drug therapy do not appear to reflect clinical outcome.