SECURE has been designed to test the hypothesis that combination therapy with cilostazol and probucol is more effective in reducing plaque volume than cilostazol monotherapy. The effectiveness of probucol against atherosclerosis has been demonstrated in previous clinical trials. In the Fukuoka Atherosclerosis Trial (FAST), the patient group treated with probucol (500 mg/day) showed significantly reduced intima media thickness in the common carotid artery compared to the control group . In an IVUS substudy of the Canadian Antioxidant Restenosis Trial (CART-2), significant atherosclerosis regression was observed in patients treated with the probucol analog succinobucol, whereas no significant change in plaque volume occurred in the placebo group . In the Probucol Observational Study Illuminating Therapeutic Impact on Vascular Events (POSITIVE), long-term probucol treatment effectively prevented secondary cardiovascular events in a higher-cardiovascular-risk heterozygous familial hypercholesterolemia population without causing severe adverse effects . Cilostazol has also demonstrated diverse antiatherogenic properties in previous studies [11–14]. Recent animal studies have suggested that probucol and cilostazol may synergize in the prevention of atherosclerosis by suppressing inflammatory reaction and promoting cholesterol efflux [18, 19].
In the SECURE study, in addition to changes in plaque volume, we will also evaluate the potential of combination therapy to stabilize coronary plaques by altering their composition. Virtual Histology, a software system that enables a spectral analysis of radiofrequency backscatter IVUS, was recently developed to analyze plaque composition, providing information on fibrous, fibrofatty, dense calcium, and necrotic core components . VH findings have been validated using various human atherosclerotic plaque tissues . Different statins and darapladip, a direct lipoprotein-associated phospholipase A(2) inhibitor, have shown coronary plaque-stabilizing effects by reducing the necrotic core [22–25]. The SECURE study will also confirm whether the combination therapy is superior to cilostazol alone in decreasing neointimal hyperplasia after implantation of a drug-eluting stent. Previous studies have shown that both probucol and cilostazol are effective in preventing restenosis after PCI with or without stent implantation [2, 10, 32]. In addition, Sekiya et al.  demonstrated that cilostazol and probucol combination therapy reduced restenosis after stent implantation more effectively than either cilostazol or probucol alone.
Another focus of the SECURE study is on changes in lipid composition associated with probucol and cilostazol combination therapy. Generally, high LDL and low HDL cholesterol levels are regarded as major risk factors for coronary artery disease. However, within LDL and HDL cholesterols are subfractions with different particle sizes and different roles in the metabolism of lipids [33, 34]. Although still controversial, small, dense LDL is thought to be more atherogenic in conjunction with other features of metabolic syndrome, such low HDL and high triglyceride levels . Generally, the larger triglyceride-rich HDL2 subfraction is thought to confer better protection against coronary artery disease than the small HDL3 fraction . In a recent trial, the CETP inhibitor torcetrapib, which raised HDL-C levels by approximately 70%, showed a paradoxical increase in cardiovascular disease outcomes . Thus, a simple elevation of HDL cholesterol levels does not necessarily translated into protection from atherosclerosis. Probucol is thought to reduce HDL cholesterol by enhancing reverse cholesterol transport through increased expression of the hepatic HDL-receptor SR-B1 and activation of CETP [4–6]. Hepatic over-expression of SR-B1 increases hepatic uptake of HDL cholesterol resulting in increased biliary excretion of cholesterol. Probucol is known to increase the levels and activity of CETP [4, 5]. Activation of CETP increases transfer of cholesterol esters from HDL to triglyceride-rich lipoprotein particles in exchange for triglyceride, thereby reducing the circulating HDL cholesterol concentration. Whether CETP is anti- or proatherogenic is currently not fully understood. Potential antiatherogenic roles of CETP include HDL remodeling, with increased efflux of lipid-poor apolipoprotein A-I in exchange for cholesterol; and shuttling of cholesteryl esters to apolipoprotein B-containing lipoproteins, namely LDL, intermediate density lipoprotein (IDL), and very low density lipoprotein (VLDL), for excretion by the liver. In the SECURE study, we will investigate lipid parameters, such as LDL and HDL subfractions, and apolipoprotein A1 and B, as well as total cholesterol, triglyceride, HDL, and LDL. In addition, we will evaluate the effects of probucol and cilostazol combination therapy on the atherosclerosis biomarkers, oxidized LDL, VCAM-1, and vWF.
Possible major limitations of the SECURE study will be the relatively small number of study population and the short interval duration for follow-up IVUS study. However, several small clinical studies have shown significant plaque reduction with change of plaque composition despite relatively short period (6 or 12 months) of follow-up [22, 23, 25]. Thus, if probucol combined with cilostazol has strong antiatherosclerotic effects as shown in previous clinical and experimental studies, we think the SECURE study will be able to demonstrate them in terms of the primary or secondary endpoints.
In conclusion, the SECURE study will be the first double-blind, randomized, controlled multicenter clinical trial using VH-IVUS to investigate the effects of probucol and cilostazol combination therapy on the progression and composition of coronary artery plaques. Furthermore, the SECURE study will deliver important information on the effects of combination therapy on lipid composition and biomarkers related to atherosclerosis, thereby providing insight into the mechanisms underlying the prevention of atherosclerosis progression by cilostazol and probucol.