Although the clinical benefit of statins have been demonstrated in both genders, gender differences in the response to statin therapy on plaque morphologic changes have not been reported. A total of 66 nonculprit plaques from 46 patients who had serial image acquisition at baseline, 6 months, and 12 months by both optical coherence tomography and intravascular ultrasound (IVUS) were included. Patients were treated with atorvastatin 60 mg (AT60) or 20 mg (AT20). The baseline characteristics were similar between women (n = 16) and men (n = 30) except for age (59.3 ± 6.8 vs 52.5 ± 10.6 years, p = 0.027) and smoking status (12.5% vs 70.0%, p <0.001). The change in fibrous cap thickness (FCT) at 12 months was significant in both groups (108.8 ± 87.4 μm, p <0.001, 91.3 ± 70.1 μm, p <0.001, respectively) without significant difference between the groups (p = 0.437). The percent change in mean lipid arc at 6 months was significantly greater in women than that in men (−12.8 ± 18.8% vs −1.56 ± 21.8%, p = 0.040). In women, the percent change of FCT in the AT20 group was similar to that in the AT60 group (182.5 ± 199.5% vs 192.9 ± 149.7%, p = 0.886). However, in men, the percent change of FCT in the AT20 group was significantly smaller than that in the AT60 group (92.2 ± 90.5% vs 225.9 ± 104.3%, p <0.001). No significant change in percent atheroma volume by IVUS was seen at 12 months in both women and men. In conclusion, statin therapy was effective in both genders for plaque stabilization at 12-month follow-up. High-intensity statin therapy may be particularly important in men.
Although the clinical benefit of intensive lipid-lowering therapy with statins has been demonstrated in both women and men for secondary prevention, the difference in vascular response to statins between genders has not been reported. Recently, we conducted a prospective randomized study that aimed to test the effect of high- and moderate-intensity statins on plaque morphologies assessed by both optical coherence tomography (OCT) and intravascular ultrasound (IVUS). The high-intensity statins demonstrated better efficacy on the improvement of fibrous cap thickness (FCT) over moderate-intensity dose statins after 12 months of therapy. In the present study, we aimed to study whether (1) statins are equally effective in both men and women and (2) high-intensity statins are better than moderate-intensity statins in both genders for plaque stabilization.
Methods
This study is a substudy of an open-label, single-blinded, single-center randomized trial. Briefly, in this trial, the effect of 2 different intensities of statins (atorvastatin 60 mg [AT60] and atorvastatin 20 mg [AT20]) on the morphologic changes of 66 lipid-rich plaque from 46 patients was serially assessed by both OCT and IVUS at baseline, 6 months, and 12 months (see Supplementary Methods ). The main finding of the trial was that a greater change of FCT was observed in the AT60 group than in the AT20 group, whereas plaque burden by IVUS did not change significantly in either group. In the present study, we further investigated the impact of gender difference on the change of plaque morphologies in this cohort.
OCT image acquisition was performed using a time domain M3 system or a frequency domain C7 system. All procedures were performed after an intracoronary administration of 100 to 200 μg of nitroglycerin. OCT image analysis was performed by 2 experienced investigators in a laboratory of Massachusetts General Hospital who were blinded to clinical information using off-line software (Light Lab Imaging Inc., Westford, Massachusetts). When there was discordance between the investigators, a consensus reading was obtained from a third independent investigator. Qualitative and quantitative analyses were performed at 1-mm intervals. Landmarks including stent edge, calcification, and side branches were used to confirm the range of target plaques. All plaque morphologies were analyzed using previously established criteria (see Supplementary Methods ). At baseline, FCT was measured at its thinnest part 3 times and the average value was calculated. At follow-up, FCT was measured at the same site as it was measured at baseline. Thin-cap fibroatheroma (TCFA) was defined as a lipid plaque occupying ≥2 quadrants and FCT ≤65 μm. A microchannel was defined as a small black hole with a diameter of 50 to 100 μm that was present on at least 3 consecutive frames.
IVUS images were obtained by a commercially available system (iLab 1.3; Boston Scientific, Fremont, California) and 40 MHz, 2.6 Fr catheters. After intracoronary administration of nitroglycerin 100 to 200 μg, automatic pull-back was performed at 0.5 mm/s from at least 10 mm distal to the target plaque. Off-line analysis was performed using dedicated software (EchoPlaque; Indec Systems, Mountain View, California). All analyses were performed in accordance with the standards of the American College of Cardiology and the European Society of Cardiology. The chronological changes in normalized total atheroma volume and percent atheroma volume (PAV) were evaluated (see Supplementary Methods ).
Categorical variables are presented as counts and proportions and were compared using either a chi-square test or Fisher’s exact test. Continuous variables are presented as mean ± SD or median (25th to 75th percentiles). Data with normal distribution were analyzed with ANOVA and Bonferroni correction for multiple comparisons, otherwise nonparametric analysis was used. Generalized estimating equations were used to take into account the within-subject correlation attributable to multiple plaques analyzed within a single subject. All analyses were performed using SPSS 17.0 (SPSS, Chicago, Illinois). The statistical significance was considered as a 2-sided p value <0.05.
Results
Baseline clinical characteristics are listed in Table 1 . The mean age was significantly higher in women than in men. The current smoking rate was significantly less frequent in women than in men. Other baseline clinical characteristics were similar between the 2 groups. Laboratory findings at baseline, 6 months, and 12 months are summarized in Table 2 . In both women and men, the low-density lipoprotein-cholesterol (LDL-C) level significantly decreased after 12 months. The absolute change of LDL-C values during 12 months was significantly greater in men than in women (−50.2 ± 24.4 vs −32.0 ± 30.4 mg/dl, p = 0.016) ( Supplementary Table 1 ). The value of high-sensitivity C-reactive protein significantly decreased after 12 months in both groups.
| Variable | Women (n=16) | Men (n=30) | p value |
|---|---|---|---|
| Age (years) | 59 ± 7 | 52 ± 11 | 0.027 |
| Clinical presentation | 0.167 | ||
| ST-segment elevation myocardial infarction | 3 (19%) | 8 (27%) | |
| Non-ST-segment elevation acute coronary syndrome | 7 (44%) | 18 (60%) | |
| Stable angina pectoris | 6 (38%) | 4 (13%) | |
| Risk factors | |||
| Hypertension | 11 (69%) | 16 (53%) | 0.312 |
| Dyslipidemia | 4 (25%) | 11 (37%) | 0.421 |
| Diabetes mellitus | 7 (44%) | 13 (43%) | 0.978 |
| Smoking | 2 (13%) | 21 (70%) | <0.001 |
| Prior percutaneous coronary intervention | 3 (19%) | 5 (17%) | 0.859 |
| Prior myocardial infarction | 4 (25%) | 7 (23%) | 0.900 |
| Medication during follow-up | |||
| Atorvastatin 60 mg/20 mg | 10 (63%)/6 (38%) | 17 (57%)/13 (43%) | 0.700 |
| Aspirin | 16 (100%) | 29 (97%) | 0.460 |
| Clopidogrel | 16 (100%) | 29 (97%) | 0.460 |
| Beta blocker | 12 (75%) | 18 (60%) | 0.309 |
| ACEI/ARB | 9 (56%) | 11 (37%) | 0.202 |
| Variable | Baseline (n=46) | 6 months (n=46) | 12 months (n=46) | p value | ||
|---|---|---|---|---|---|---|
| Baseline vs. 6M | 6M vs. 12M | Baseline vs. 12M | ||||
| Women (n=16) | ||||||
| Low density lipoprotein (mg/dl) | 117 ± 23 | 81 ± 23 | 89 ± 29 | <0.001 | 0.184 | 0.002 |
| High density lipoprotein (mg/dl) | 52 ± 10 | 49 ± 12 | 51 ± 17 | 0.361 | 0.656 | 0.574 |
| Ratio of Low/High density lipoprotein | 2 ± 1 | 2 ± 0 | 2 ± 1 | 0.013 | 0.344 | 0.062 |
| High sensitivity C-reactive protein (μg/L) | 3 [1 – 6] | 1 [0 – 2] | 1 [0 – 1] | 0.011 | 0.575 | 0.005 |
| Men (n=30) | ||||||
| Low density lipoprotein (mg/dl) | 112 ± 26 | 64 ± 24 | 64 ± 21 | <0.001 | 0.977 | <0.001 |
| High density lipoprotein (mg/dl) | 46 ± 11 | 42 ± 11 | 42 ± 11 | 0.071 | 0.540 | 0.029 |
| Ratio of Low/High density lipoprotein | 3 ± 1 | 2 ± 1 | 2 ± 1 | <0.001 | 0.703 | <0.001 |
| High sensitivity C-reactive protein (μg/L) | 3 [1 – 12] | 1 [0 – 1] | 1 [0 – 1] | 0.002 | 0.826 | 0.001 |
Quantitative and qualitative assessment of plaque morphologies by OCT are summarized in Table 3 . FCT gradually increased over 12 months in both groups without significant difference between the groups (108.8 ± 87.4 vs 91.3 ± 70.1 μm, p = 0.437) ( Supplementary Table 2 ). The prevalence of TCFA significantly decreased from baseline to 12-month follow-up in women and men. In women, the prevalence of microchannels significantly decreased from baseline to 12 months, whereas the difference was not significant in men. The percent changes of plaque morphologies assessed by OCT are summarized in Figure 1 and Supplementary Table 3 . In the first 6 months, the percent change of mean lipid arc was significantly greater in women than in men (−12.8 ± 18.8% vs −1.56 ± 21.8%, p = 0.040) because of the difference in AT60 group (−20.9 ± 14.6% vs −0.02 ± 21.1%, p = 0.002) ( Supplementary Figures 1 and 2 ), although the difference in the percent change of FCT was not statistically significant (141.1 ± 173.6% vs 91.3 ± 107.4%, p = 0.200).
| Variable | Baseline (n=66) | 6 months (n=66) | 12 months (n=66) | p value | ||
|---|---|---|---|---|---|---|
| Baseline vs. 6M | 6M vs. 12M | Baseline vs. 12M | ||||
| Women (n=24) | ||||||
| Fibrous cap thickness (μm) | 62 ± 23 | 139 ± 95 | 171 ± 93 | <0.001 | 0.013 | <0.001 |
| Maximum lipid arc (º) | 237 ± 65 | 229 ± 71 | 194 ± 72 | 0.410 | 0.001 | <0.001 |
| Mean lipid arc (º) | 173 ± 53 | 155 ± 55 | 142 ± 60 | 0.027 | 0.016 | 0.001 |
| Thin-cap fibroatheroma | 17 (71%) | 4 (17%) | 1 (4%) | 0.001 | 0.126 | <0.001 |
| Macrophage | 17 (71%) | 18 (75%) | 17 (71%) | 0.647 | 0.545 | 1.000 |
| Microchannel | 12 (50%) | 8 (33%) | 5 (21%) | 0.025 | 0.183 | 0.009 |
| Calcification | 9 (38%) | 10 (42%) | 9 (38%) | 0.559 | 0.176 | 0.795 |
| Cholesterol crystal | 3 (13%) | 3 (13%) | 1 (4%) | 1.000 | 0.203 | 0.203 |
| Men (n=42) | ||||||
| Fibrous cap thickness (μm) | 60 ± 18 | 113 ± 65 | 151 ± 75 | <0.001 | <0.001 | <0.001 |
| Maximum lipid arc (º) | 248 ± 75 | 231 ± 76 | 209 ± 74 | 0.059 | 0.001 | <0.001 |
| Mean lipid arc (º) | 185 ± 56 | 177 ± 56 | 160 ± 54 | 0.171 | 0.006 | <0.001 |
| Thin-cap fibroatheroma | 31 (74%) | 12 (29%) | 4 (10%) | <0.001 | 0.001 | <0.001 |
| Macrophage | 32 (76%) | 25 (60%) | 24 (57%) | 0.030 | 0.797 | 0.155 |
| Microchannel | 17 (41%) | 15 (36%) | 12 (29%) | 0.663 | 0.680 | 0.490 |
| Calcification | 18 (43%) | 19 (45%) | 16 (38%) | 0.327 | 0.411 | 0.787 |
| Cholesterol crystal | 13 (31%) | 11 (26%) | 5 (12%) | 0.634 | 0.066 | 0.060 |
Quantitative assessment of plaque morphologies by IVUS are summarized in Table 4 . No significant change of PAV was observed in both women and men.
| Variable | Baseline (n=66) | 6 months (n=66) | 12 months (n=66) | p value | ||
|---|---|---|---|---|---|---|
| Baseline vs. 6M | 6M vs. 12M | Baseline vs. 12M | ||||
| Women (n=24) | ||||||
| Normalized total atheroma volumes (mm 3 ) | 99 ± 50 | 98 ± 45 | 98 ± 48 | 0.779 | 0.781 | 0.579 |
| Percent atheroma volume (mm 3 ) | 55 ± 8 | 55 ± 8 | 55 ± 9 | 0.581 | 0.827 | 0.788 |
| Men (n=42) | ||||||
| Normalized total atheroma volumes (mm 3 ) | 103 ± 36 | 97 ± 35 | 99 ± 34 | 0.003 | 0.462 | 0.131 |
| Percent atheroma volume (mm 3 ) | 57 ± 10 | 57 ± 10 | 57 ± 9 | 0.798 | 0.978 | 0.677 |
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