Methods

This study was a post hoc analysis of the Treatment With Statin on Atheroma Regression Evaluated by Intravascular Ultrasound With Virtual Histology (TRUTH) study. The TRUTH study was a prospective, open-labeled, randomized, multicenter trial performed at 11 Japanese centers to compare the effects of 8-month treatment with pitavastatin and pravastatin on coronary atherosclerosis using virtual histology (VH) intravascular ultrasound (IVUS). Briefly, 164 patients with angina pectoris were randomized to either pitavastatin (4 mg/day, intensive lipid-lowering) or pravastatin (20 mg/day, moderate lipid-lowering) therapy after successful percutaneous coronary intervention (PCI) under VH-IVUS guidance. Follow-up IVUS was performed after 8 months of statin therapy.

The inclusion criteria were analyzable IVUS data obtained at PCI and at 8-month follow-up as well as adequate serum volume in frozen samples for various measurements. One hundred and one patients were included in this study. We compared the effects of serum n-3 to n-6 PUFA ratios on coronary atherosclerosis in patients treated with pitavastatin and pravastatin.

The TRUTH study was conducted in accordance with the Declaration of Helsinki and with the approval of the ethical committees of the 11 participating institutions. Each patient enrolled in the study provided written informed consent.

The IVUS procedure has been documented in detail previously. Briefly, after PCI of the culprit lesion, IVUS was performed for angiographic lesions with <50% lumen narrowing on the distal and proximal sides of the culprit lesion. An IVUS catheter (Eagle Eye Gold; Volcano Corporation, San Diego, California) was used, and a motorized pullback device was used to withdraw the transducer at 0.5 mm/s. During pullback, grayscale IVUS was recorded, and raw radiofrequency data were captured at the top of the R wave using a commercially available IVUS console (IVG3; Volcano Corporation, San Diego, California). After 8 months of statin therapy, IVUS examination was repeated in the same coronary artery using the same type of IVUS catheter used at baseline.

All baseline and follow-up IVUS core laboratory analyses were performed by an independent and experienced investigator (M. T.) in a blinded manner. Before IVUS analysis, baseline and follow-up IVUS images were reviewed side by side on a display, and the distal and proximal ends of the target segment were identified on the basis of the presence of reproducible anatomic landmarks such as the side branch, vein, and stent edge. Plaques <5 mm from the PCI site were excluded because mechanical interventions affect atheroma measurements. Manual contour detection of the lumen and external elastic membrane was performed for each frame. Quantitative IVUS grayscale analysis was performed according to the guidelines of the American College of Cardiology and European Society of Cardiology. VH-IVUS data analysis was based on grayscale border contour calculation, and relative and absolute amounts of different coronary artery plaque components were measured using IVUSLab version 2.2 (Volcano Corporation).

Serum lipid levels and inflammatory markers had already been measured at baseline and 8 months after treatment with statins. The serum levels of EPA, DHA, arachidonic acid (AA), and dihomogamma-linolenic acid in conserved frozen samples obtained at baseline and at 8-month follow-up were measured annually by a central laboratory (BML Inc., Kawagoe, Japan). Briefly, serum lipids were extracted using Folch’s procedure. Next, using tricosanoic acid (C23:0) as an internal standard, fatty acids were methylated with boron trifluoride and methanol. The methylated fatty acids were analyzed using a capillary gas chromatograph (GC-2010; Shimadzu Corporation, Kyoto, Japan) and a BPX70 capillary column (0.25-mm internal diameter × 30 m; SGE International Ltd., Melbourne, Australia).

The necessary sample size of the TRUTH trial was estimated on the basis of the assumption that changes in plaque composition are accompanied by changes in plaque volume. The percentage change in plaque volume was estimated on the basis of a previous report, and it was 11.5% in the pitavastatin group and 5.3% in the pravastatin group. The standard deviation of plaque volume percentage changes after statin therapy was 12.8%. On the basis of these factors, the required sample size was 69 patients in each group to achieve 80% power using a 2-sided, 2-sample Student t test at a significance level of 5%. Assuming that 10% of patients would drop out of the study, the sample size per group determined to be 77 patients.

Statistical analysis was performed using StatView version 5.0 (SAS Institute Inc., Cary, North Carolina). Results are expressed as mean ± SD. Differences in continuous variables between the 2 groups were compared using unpaired Student t tests when variables showed a normal distribution and the Mann-Whitney U tests when they did not. Differences in continuous variables within each group were compared using paired Student t tests when variables showed a normal distribution and the Wilcoxon signed rank-sum tests when they did not. Univariate regression analysis was performed to determine the predictors for percentage changes in plaque volume, including nominal variables (i.e., gender, coronary artery disease status, hypertension, diabetes mellitus, and smoking) and numerical variables (i.e., age; percentage changes in low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and high-sensitivity C-reactive protein levels; changes in the DHA/AA ratio). The variables with a p <0.1 in univariate analysis were entered into multivariate models. Statistical significance was set at p <0.05.

Results

The baseline characteristics of the subjects are shown in Table 1 . Pitavastatin and pravastatin were used to treat 51 and 50 patients, respectively. None of the baseline characteristics were significantly different between the 2 groups, except for the frequency of calcium channel blocker use. Serum low-density lipoprotein cholesterol levels decreased significantly in both groups (pitavastatin group, −41%, p <0.0001; pravastatin group, −28%, p <0.0001). The mean low-density lipoprotein cholesterol level at 8-month follow-up was significantly lower in the pitavastatin group (72 mg/dl vs 95 mg/dl, p <0.0001).

Changes in the n-3 to n-6 PUFA ratios at 8-month follow-up are shown in Figure 1 . The DHA/AA ratio (−0.14, p = 0.0002) and EPA+DHA/AA ratio (−0.12, p = 0.03) decreased significantly in the pitavastatin group, whereas decreases in these ratios were not significant in the pravastatin group. There was a significant difference in the change of the DHA/AA ratio between the 2 groups. No significant changes were observed in the EPA/AA ratio in either group.

Changes in the n-3 to n-6 PUFA ratios in patients treated with pitavastatin and pravastatin. Decreases in the DHA/AA and EPA+DHA/AA ratios were significant in the pitavastatin group but not in the pravastatin group. There was a significant difference in change of the DHA/AA ratio between the 2 groups. * p <0.05, ** p <0.001 compared with baseline.

We assessed the correlations between the percentage change in plaque volume and changes in the n-3 to n-6 PUFA ratios. Although there were no significant correlations between the percentage change in plaque volume and changes in the n-3 to n-6 PUFA ratios in the pitavastatin group ( Figure 2 ), the percentage change in plaque volume was significantly negatively correlated with changes in the DHA/AA ratio (r = −0.404, p = 0.004) and EPA+DHA/AA ratio (r = −0.350, p = 0.01) in the pravastatin group ( Figure 3 ).

Correlations between the percentage change in plaque volume and changes in the n-3 to n-6 PUFA ratios in patients treated with pitavastatin. No significant correlations were observed between the percentage change in plaque volume and changes in the n-3 to n-6 PUFA ratios.

Correlations between the percentage change in plaque volume and changes in the n-3 to n-6 PUFA ratios in patients treated with pravastatin. Significant negative correlations were observed between the percentage change in plaque volume and changes in the DHA/AA and EPA+DHA/AA ratios.

Among the n-3 to n-6 PUFA ratios, we used the DHA/AA ratio in the regression model, because this ratio produced the greatest correlation coefficient with the percentage change in plaque volume among the n-3 to n-6 PUFA ratios in the pravastatin group. Multivariate regression analysis showed that age (β = 0.306, p = 0.02), the presence of diabetes mellitus (β = 0.250, p = 0.048), and changes in the DHA/AA ratio (β = −0.423, p = 0.001) were significantly associated with percentage change in plaque volume in the pravastatin group ( Table 2 ).

Table 2

Predictors of percentage change in plaque volume

Variable	Pitavastatin				Pravastatin
	Univariate		Multivariate		Univariate		Multivariate
	r	p Value	β	p Value	r	p Value	β	p Value
Age	0.249	0.08	0.210	0.14	0.247	0.08	0.306	0.02
Gender	0.037	0.8			−0.096	0.51
Coronary artery disease status	−0.254	0.07	−0.217	0.12	0.118	0.42
Hypertension	0.118	0.41			0.114	0.43
Diabetes mellitus	−0.123	0.39			0.239	0.09	0.250	0.048
Percentage change in low-density lipoprotein cholesterol	−0.073	0.61			−0.024	0.87
Percentage change in high-density lipoprotein cholesterol	−0.171	0.23			−0.078	0.59
Percentage change in high-sensitivity C-reactive protein	0.089	0.53			−0.027	0.85
Smoking	−0.177	0.21			−0.135	0.35
Change in DHA/AA ratio	−0.047	0.75			−0.404	0.004	−0.423	0.001

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