Serendipity of post-hoc surrogate marker research

This editorial refers to ‘Paradoxical progression of atherosclerosis related to low-density lipoprotein reduction and exposure to ezetimibe’†, by A.J. Taylor et al. , on page 2939 The prerequisites under which ‘novel’ compounds have to show cardiovascular benefit on top of statin therapy have raised the bar for clinical endpoint studies. B-mode ultrasound measurement of the carotid intima media thickness (cIMT) is the best validated imaging modality and most widely used surrogate endpoint in intervention studies to evaluate treatment efficacy in the progression of atherosclerosis.1 In contrast to the overwhelming evidence of epidemiological trials linking increased cIMT to cardiovascular risk, the evidence for a direct relationship between decreasing cIMT progression and lowering cardiovascular risk is, however, less clear.Taylor and colleagues performed a post-hoc analysis in the Arbiter 6-HALTS trial in which they explored the relationship between treatment effects and cIMT change in 159 patients randomized to ezetimibe.2 Ezetimibe is a cholesterol absorption inhibitor (CAI) which lowers LDL cholesterol (LDL-c) both as monotherapy (LDL-c reduction 17.2–22.3%) and on top of statin therapy (further LDL-c reduction 5–27%). The Arbiter-6 HALTS study was discontinued prematurely after an interim analysis at 14 months showing that niacin reduced cIMT progression whereas ezetimibe showed no change in cIMT.3 In a subsequent publication, the authors confirmed a neutral effect of ezetimibe on mean cIMT change (–0.0016 ± 0.0024 mm; P = 0.88) with a …