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The merits and limitations of carotid intima-media thickness

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The progression of carotid intima-media thickness has been an endpoint in several recent studies. CIMT has been shown to predict future risk of cardiovascular events and to be associated with progression of atherosclerosis.

Because large prospective, placebo-controlled, randomized studies evaluating cardiovascular events and/or death are costly and time-consuming, surrogate endpoints such as CIMT are often initially evaluated as an alternative.

Researchers with the ENHANCE study evaluated the effects of simvastatin-ezetimibe vs. simvastatin alone upon CIMT in patients with familial hypercholesterolemia. Results of the study did not show a difference in CIMT between groups, despite additional LDL lowering in the combination group. Limitations of this study included a longer duration of pretreatment with statins and a lower baseline CIMT (0.69 mm) compared to other studies.

A previous study, ASAP, compared atorvastatin 80 mg to simvastatin 40 mg upon the progression of CIMT over a period of two years. The average baseline CIMT was 0.92 mm. There was greater LDL reduction in the atorvastatin group associated with a decrease in CIMT of -0.031 mm while the simvastatin group had progression of +0.036 mm. However, a two year extension of this study failed to show any further decrease of CIMT in the atorvastatin group.

None of these studies were designed to evaluate cardiovascular outcomes. It is possible that the benefit of antihyperlipidemic medication upon CIMT is accrued early in the course of therapy. We do not know if there is additional benefit of further LDL lowering upon cardiovascular events independent of effect on CIMT. Finally, it is also unclear how the results of studies in individuals with a genetic defect of the LDL receptor should be extrapolated to the management of the more common polygenic dyslipidemia.

In my own practice, I offer CIMT as additional risk screening to selected patients. I strongly agree that we should focus on modification of traditional risk factors as per the current guidelines. If we maximize the number of patients reaching goals, we will save many lives and reduce health care costs.

However, even with aggressive therapy, patients may still be at risk. Emerging risk markers enable us to further fine tune therapy. For instance, I am hesitant to advocate decades of aggressive pharmacotherapy, based on a worrisome family history alone, in an otherwise low risk patient. On the other hand, it is inappropriate to wait until an event has occurred before initiating therapy. Additional information such as CIMT may encourage more aggressive and earlier intervention in certain individuals than we would consider based on traditional risk assessment alone.

Nevertheless, even though I am a “believer” in the merits of CIMT, I am also the first to admit that it is a surrogate marker and not a cardiovascular event. Before we pass final judgment on any therapy based on CIMT or other surrogate endpoints, we must await the results of large well-designed studies formally evaluating cardiovascular events and death.

For more information:

• Chambless LE, Heiss G, Folsom AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987-1993. Am J Epidemiol. 1997;146:483-494.
• Hodis HN, Mack WJ, LaBree L, et al. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med. 1998;128:262-269.
• Kastelein JJP, Akdim F, Stroes ESG, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358:1431-1443.
• Smilde TJ, van Wissen S, Awollersheim H, et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholeasterolaemia (ASAP): a prospective, randomized, double blind trial. Lancet. 2001;357:577-581.
• van Wissen S, Smilde TJ, Trip MD, et al. Long term safety and efficacy of high dose atorvastatin treatment in patients with familial hypercholesterolemia. Am J Cardiol. 2005;95:264-266.

(Dr. Repas discloses that he has received honoraria from or has been on the speakers bureaus of Abbott Laboratories; Daiichi Sankyo; GlaxoSmithKline; Merck & Co, Inc; Pfizer; and Takeda. He also admits to bias towards this technology after learning that his own CIMT was equivalent to that of a 17-year-old.)