Higher than 80% of coronary heart disease-related mortality occurs in patients ≥65 years of age. Guidelines recommend low-density lipoprotein (LDL) cholesterol targets for these at-risk patients; however, few clinical studies have evaluated lipid-lowering strategies specifically in older adults. This multicenter, 12-week, randomized, double-blind, parallel-group trial evaluated the efficacy and safety of the usual starting dose of ezetimibe/simvastatin (10/20 mg) versus atorvastatin 10 or 20 mg and the next higher dose of ezetimibe/simvastatin (10/40 mg) versus atorvastatin 40 mg in 1,289 hypercholesterolemic patients ≥65 years of age with or without cardiovascular disease. Patients randomized to ezetimibe/simvastatin had greater percent decreases in LDL cholesterol (−54.2% for 10/20 mg vs −39.5% and −46.6% for atorvastatin 10 and 20 mg, respectively; −59.1% for 10/40 mg vs −50.8% for atorvastatin 40 mg; p <0.001 for all comparisons) and the number attaining LDL cholesterol <70 mg/dl (51.3% for 10/20 mg, 68.2% for 10/40 mg) and <100 mg/dl (83.6% for 10/20 mg; 90.3% for 10/40 mg) was significantly larger compared to those receiving atorvastatin for all prespecified dose comparisons (p <0.05 to <0.001). A significantly larger percentage of high-risk patients achieved LDL cholesterol <70 mg/dl on ezetimibe/simvastatin 10/20 mg (54.3%) versus atorvastatin 10 mg (10.9%, p <0.001) or 20 mg (28.9%, p <0.001) and ezetimibe/simvastatin 10/40 mg (69.2%) versus atorvastatin 40 mg (38.2%, p <0.001), and a significantly larger percentage of intermediate-risk patients achieved LDL cholesterol <100 mg/dl on ezetimibe/simvastatin 10/20 mg (82.1%) versus atorvastatin 10 mg (59.3%, p <0.05). Improvements in non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and lipoprotein ratios were significantly greater with ezetimibe/simvastatin than atorvastatin for all comparisons (p <0.01 to <0.001). High-density lipoprotein cholesterol and triglyceride results were variable. All treatments were generally well tolerated. In conclusion, ezetimibe/simvastatin provided significantly greater improvements in key lipid parameters and higher attainment of LDL cholesterol targets than atorvastatin, with comparable tolerability.
Use of ezetimibe in combination with statins inhibits cholesterol absorption and synthesis, and produces larger decreases in low-density lipoprotein (LDL) cholesterol and more frequent attainment of recommended LDL cholesterol concentrations than statins alone. These results suggest that coadministration of ezetimibe with statins may provide a useful treatment option for patients with dyslipidemia, although data for combined therapy in older patients are limited. The present study is the first evaluation of the ezetimibe/simvastatin combination tablet designed to assess LDL cholesterol-lowering efficacy and safety exclusively in older adults. The primary objective of this study was to compare the usual starting dose of ezetimibe/simvastatin (10/20 mg) to atorvastatin 10 and 20 mg and the next highest dose of ezetimibe/simvastatin (10/40 mg) to atorvastatin 40 mg in hypercholesterolemic patients ≥65 years of age at moderately high risk, high risk, or with coronary heart disease (CHD).
Methods
This 12-week, multicenter, randomized, double-blind, 5-arm parallel-group study of Vytorin in the Elderly (VYTELD) was conducted in men and women ≥65 years with hyperlipidemia from November 8, 2007 to March 23, 2009. The protocol (Study Protocol 128) was approved by appropriate institutional review boards, and all participants provided written informed consent ( http://clinicaltrials.gov , identifier NCT00535405 ).
Participants included in this study were at moderately high risk or high risk (with CHD or CHD risk equivalents) with or without atherosclerotic vascular disease (AVD; including a history of myocardial infarction, stable angina, coronary artery procedures, evidence of clinically significant myocardial ischemia, peripheral arterial disease, abdominal aortic aneurysm, or carotid artery disease) with LDL cholesterol levels ≥130 mg/dl (3.36 mmol/L), triglyceride levels ≤350 mg/dl (3.96 mmol/L), liver transaminases (alanine aminotransferase and aspartate aminotransferase) ≤1.5 times the upper limit of normal (ULN) with no active liver disease, and creatine kinase levels ≤2 times ULN. Patients with prespecified cardiovascular diseases (congestive heart failure; unstable angina pectoris; myocardial infarction, coronary artery bypass surgery, angioplasty, or uncontrolled peripheral artery disease ≤3 months of placebo run-in; uncontrolled hypertension), intestinal malabsorption or renal disease, uncontrolled endocrine or metabolic diseases, or treatment with prohibited concomitant therapies (i.e., potent P450 3A4 inhibitors; cyclosporine, danazol or fusidic acid; systemic corticosteroids; anti-obesity medication with <3-month stabilization) were excluded from the trial. Patients were drug naive (moderately high risk, high risk, or with CHD) or rendered free of cholesterol-lowering drugs through a 6- to 8-week wash-out period (moderately high-risk patients only). After a 3-week single-blind placebo run-in period, patients meeting eligibility requirements were assigned randomly using a central interactive voice response system to 1 of 5 equally sized treatment groups, ezetimibe/simvastatin combination tablet (10/20 or 10/40 mg) or atorvastatin (10, 20, or 40 mg) for 12 weeks. Balance across treatment groups was achieved by stratification of patients by baseline LDL cholesterol levels: ≥130 to <160 mg/dl (≥3.36 to <4.14 mmol/L), ≥160 to <190 mg/dl (≥4.14 to <4.91 mmol/L), and ≥190 mg/dl (≥4.91 mmol/L). Enrollment was monitored and restricted when required to ensure that ≥25% of randomized patients were ≥75 years old. All patients were instructed to follow a cholesterol-lowering diet throughout the study. All study personnel, including investigators and study site personnel, patients, monitors, and central laboratory personnel, remained blinded to treatment allocation until the study was complete, the review of the patient-level data was finished, and the data file was locked.
The primary efficacy measurement was percent change from baseline LDL cholesterol after 12 weeks of treatment. Secondary efficacy measurements were assessed at 12 weeks and included the percentage of patients achieving an LDL cholesterol level (1) <70 mg/dl (1.81 mmol/L), (2) <100 mg/dl (2.59 mmol/L) for moderately high/high-risk patients without AVD and <70 mg/dl for high risk patients with AVD; (3) <100 mg/dl, (4) <70 mg/dl for high-risk patients, or (5) <70 mg/dl for high-risk patients with AVD. Additional secondary end points included assessment at 12 weeks of the percentage of patients achieving an LDL cholesterol level <100 mg/dl for moderately high/high-risk patients without AVD and percent change from baseline in total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, very LDL cholesterol, apolipoprotein B, apolipoprotein A-I, total cholesterol/HDL cholesterol ratio, LDL cholesterol/HDL cholesterol ratio, apolipoprotein B/apolipoprotein A-I ratio, non-HDL cholesterol/HDL cholesterol ratio, and high-sensitivity C-reactive protein.
Primary and secondary efficacy analyses included all randomized patients with a baseline evaluation and ≥1 valid post-baseline evaluation. Mean percent change from baseline in LDL cholesterol after 12 weeks of treatment (primary end point) was analyzed using an analysis of covariance mixed model with terms for treatment, baseline LDL cholesterol, study week (6 and 12), treatment-by-study week interaction, and random subject effects. Binary secondary end points were analyzed with a logistic regression model using a Generalized Estimating Equation method with terms for treatment, baseline LDL cholesterol, study week (6 and 12), and treatment-by-study week interaction. Additional secondary end points measuring percent change from baseline in lipid parameters (except for triglycerides, very LDL cholesterol, and high-sensitivity C-reactive protein) were evaluated using the analysis of covariance mixed model. Analysis of triglycerides and very LDL cholesterol were based on a nonparametric analysis of covariance model using ranks based on normal scores of percent change with terms for treatment and baseline triglyceride or very LDL cholesterol levels. High-sensitivity C-reactive protein was analyzed using a longitudinal data analysis method. Hochberg’s procedure was used to control the Type I error rate at the 0.05 level for primary and secondary hypotheses. Multiplicity control for the additional secondary efficacy end points was achieved using the false discovery rate procedure.
Safety was evaluated by monitoring clinical adverse events in all treated patients and laboratory adverse events in patients with ≥1 on-treatment measurement. Prespecified safety parameters of special interest constituted the safety end points of this study and included alanine aminotransferase and/or aspartate aminotransferase consecutive elevations ≥3, ≥5, and ≥10 times ULN and creatine kinase elevations ≥10 times ULN with and without muscle symptoms. Adverse reactions were classified into clinical categories including gastrointestinal, gallbladder, hepatitis, and allergic disorders or rash. Inferential testing for statistical significance provided p values and 95% confidence intervals for between-treatment group comparisons using the Miettinen and Nurminen method. Ninety-five percent confidence intervals for between-group differences were determined for other adverse events occurring in ≥1% of patients within ≥1 treatment group.
For the 3 primary hypotheses in this study, 242 evaluable patients per treatment and dose were anticipated, which would provide >99% power to detect a 10% treatment difference in LDL cholesterol for ezetimibe/simvastatin 10/20 mg versus atorvastatin 10 mg and a 95% power to detect a 5% treatment difference for ezetimibe/simvastatin 10/20 mg versus atorvastatin 20 mg and ezetimibe/simvastatin 10/40 mg versus atorvastatin 40 mg, assuming a SD of 15% and a significance level of 0.05 (2-sided). Thus, overall power to test the primary hypotheses was expected to be 90%. A fixed-sequence testing approach was used to control for multiplicity across the primary and secondary hypotheses; the approach requires that secondary hypotheses be tested only if ≥1 of the primary hypotheses was met, and only treatment group comparisons found to be significant for the primary end point would be compared for the secondary end points. Secondary hypotheses were tested in the order listed in the study protocol, and only those treatment group comparisons found to be significant were tested in the next set of hypotheses. Hochberg’s procedure was used for each set of hypotheses to control the Type I error rate at the 0.05 level.
Results
The flow of participants through the study is shown in Figure 1 . Of the 2,223 patients screened, 1,289 were randomized with 773 assigned to atorvastatin and 516 assigned to ezetimibe/simvastatin. Overall, 6.6% of patients in the atorvastatin group discontinued the study; 1.9% due to adverse events, 0.6% lost to follow-up, 0.3% due to physician decision, 0.5% due to protocol violation, 0.3% due to termination of treatment by the sponsor, and 3.0% withdrew consent. For the ezetimibe/simvastatin group, 9.3% of patients discontinued the study; 3.1% due to adverse events, 1.0% lost to follow-up, 0.6% due to physician decision, 0.6% due to protocol violation, and 4.1% withdrew consent. Compliance was high for all treatment regimens, with 91% of pooled atorvastatin groups and 91% of pooled ezetimibe/simvastatin groups achieving >95% compliance with study therapy.
Baseline characteristics and risk factors were generally similar across treatment groups ( Table 1 ). Median age of participants in this study was 71 years, and 29% were ≥75 years old. Most randomized patients were white (84%) and women (63%). Of the 1,289 randomized patients, 57% had CHD or CHD risk equivalents, 32% were at high risk with AVD, 25% were at high risk without AVD, 44% were at moderately high risk, and 58% had metabolic syndrome. Baseline lipid parameters and high-sensitivity C-reactive protein were generally well balanced between therapies ( Table 2 ). Although the inclusion criterion for LDL cholesterol was ≥130 mg/dl, 25 patients (4.9%) receiving ezetimibe/simvastatin and 43 patients (5.6%) receiving atorvastatin had baseline LDL cholesterol levels <130 mg/dl due to a mismatch of LDL cholesterol measurement units (millimoles per liter vs milligrams per deciliter) programmed into the interactive voice response system and the units used at some study sites.
| Characteristic | A10 (n = 257) | E10/S20 (n = 259) | A20 (n = 259) | E10/S40 (n = 257) | A40 (n = 257) |
|---|---|---|---|---|---|
| Men | 85 (33%) | 113 (44%) | 84 (32%) | 104 (40%) | 94 (36%) |
| Women | 172 (67%) | 146 (56%) | 175 (68%) | 153 (60%) | 163 (63%) |
| Age (years) | 72.1 ± 5.7 | 71.8 ± 5.5 | 71.7 ± 5.2 | 72.2 ± 5.6 | 72.1 ± 5.1 |
| 65–69 | 94 (37%) | 98 (38%) | 109 (42%) | 96 (37%) | 94 (37%) |
| 70–74 | 88 (34%) | 85 (33%) | 81 (31%) | 91 (35%) | 83 (32%) |
| 75–79 | 45 (18%) | 56 (22%) | 46 (18%) | 40 (16%) | 55 (21%) |
| >79 | 30 (12%) | 20 (8%) | 23 (9%) | 30 (12%) | 25 (10%) |
| Race | |||||
| Asian | 10 (4%) | 6 (2%) | 12 (5%) | 8 (3%) | 10 (4%) |
| Black | 2 (1%) | 2 (1%) | 8 (3%) | 6 (2%) | 9 (4%) |
| Other | 21 (8%) | 27 (10%) | 30 (12%) | 29 (11%) | 28 (11%) |
| White | 224 (87%) | 224 (87%) | 209 (81%) | 214 (83%) | 210 (82%) |
| Body mass index (kg/m 2 ) | 27.8 ± 4.3 | 28.4 ± 4.8 | 28.4 ± 4.3 | 28.0 ± 5.6 | 28.7 ± 4.8 |
| Metabolic syndrome ⁎ | 151 (59%) | 141 (54%) | 156 (60%) | 144 (56%) | 156 (61%) |
| National Cholesterol Education Program (Adult Treatment Panel III) risk category | |||||
| High risk † | 146 (57%) | 152 (59%) | 144 (56%) | 142 (56%) | 144 (56%) |
| Coronary heart disease | 30 (12%) | 45 (17%) | 40 (15%) | 44 (17%) | 32 (12%) |
| Moderately high risk ‡ | 111 (43%) | 107 (41%) | 115 (44%) | 114 (44%) | 113 (44%) |
| Diabetes | 25 (10%) | 39 (15%) | 41 (16%) | 38 (15%) | 31 (12%) |
| Baseline low-density lipoprotein cholesterol (mg/dl) | |||||
| <130 | 15 (6%) | 13/257 (5%) | 13/257 (5%) | 12 (5%) | 15/255 (6%) |
| ≥130–<160 | 104 (41%) | 113/257 (44%) | 111/257 (43%) | 121 (47%) | 102/255 (40%) |
| ≥160–<190 | 89 (35%) | 82/257 (32%) | 91/257 (35%) | 92 (36%) | 85/255 (33%) |
| ≥190 | 49 (19%) | 49/257 (19%) | 42/257 (16%) | 32 (13%) | 53/255 (21%) |
⁎ Metabolic syndrome defined as satisfying ≥3 of the following: waist circumference >102 cm (men) or >88 cm (women), triglycerides ≥150 mg/dl, high-density lipoprotein cholesterol <40 mg/dl (men) or <50 mg/dl (women), blood pressure ≥130/85 mm Hg or taking antihypertensive medication, fasting glucose ≥100 mg/dl or taking increased glucose medication.
† Coronary heart disease or coronary heart disease risk equivalents as defined by National Cholesterol Education Program (Adult Treatment Panel III) guidelines; 10-year risk >20%.
‡ At least 2 risk factors as defined by National Cholesterol Education Program (Adult Treatment Panel III) guidelines; 10-year risk 10% to 20%.
| Baseline, mean ± SD | A10 (n = 249–257) ⁎ | E10/S20 (n = 253–258) ⁎ | A20 (n = 248–257) ⁎ | E10/S40 (n = 253–257) ⁎ | A40 (n = 245–256) ⁎ |
|---|---|---|---|---|---|
| Low-density lipoprotein cholesterol (mg/dl) | 167 ± 34 | 166 ± 30 | 165 ± 29 | 163 ± 29 | 168 ± 30 |
| Total cholesterol (mg/dl) | 253 ± 39 | 250 ± 36 | 250 ± 35 | 247 ± 34 | 253 ± 37 |
| Triglycerides (mg/dl) † | 154 ± 74 | 132 ± 67 | 148 ± 71 | 141 ± 64 | 153 ± 93 |
| High-density lipoprotein cholesterol (mg/dl) | 53 ± 13 | 54 ± 14 | 54 ± 14 | 53 ± 13 | 53 ± 13 |
| Non-high-density lipoprotein cholesterol (mg/dl) | 200 ± 37 | 196 ± 32 | 197 ± 33 | 194 ± 32 | 201 ± 35 |
| Very low-density lipoprotein cholesterol (mg/dl) † | 31 ± 15 | 27 ± 14 | 30 ± 14 | 28 ± 13 | 31 ± 18 |
| Apolipoprotein B (mg/dl) | 148 ± 29 | 145 ± 26 | 146 ± 25 | 144 ± 25 | 149 ± 28 |
| Apolipoprotein A-I (mg/dl) | 160 ± 28 | 159 ± 27 | 159 ± 28 | 156 ± 27 | 158 ± 27 |
| Low-density lipoprotein cholesterol/high-density lipoprotein cholesterol | 3.3 ± 1.0 | 3.3 ± 0.9 | 3.3 ± 0.9 | 3.3 ± 0.9 | 3.4 ± 1.0 |
| Total cholesterol/high-density lipoprotein cholesterol | 5.0 ± 1.2 | 4.9 ± 1.1 | 4.9 ± 1.2 | 4.9 ± 1.2 | 5.1 ± 1.3 |
| Non-high-density lipoprotein cholesterol/high-density lipoprotein cholesterol | 4.0 ± 1.2 | 3.9 ± 1.1 | 3.9 ± 1.2 | 3.9 ± 1.2 | 4.1 ± 1.3 |
| Apolipoprotein B/apolipoprotein A-I | 1.0 ± 0.3 | 0.9 ± 0.2 | 1.0 ± 0.3 | 1.0 ± 0.2 | 1.0 ± 0.3 |
| High-sensitivity C-reactive protein (mg/L) † | 2.3 ± 3.3 | 2.0 ± 2.7 | 2.3 ± 2.5 | 2.2 ± 2.7 | 2.2 ± 2.6 |
⁎ Number of all randomized patients evaluated (varied slightly within each treatment group).
† Median ± robust SD (SD calculated as interquartile range divided by 1.075, where interquartile range is the third quartile minus the first quartile).
Ezetimibe/simvastatin produced a significantly greater percent decrease from baseline LDL cholesterol after 12 weeks of therapy than atorvastatin for all prespecified dose comparisons ( Table 3 ). In addition, a significantly larger percentage of patients achieved LDL cholesterol levels <70 mg/dl and <100 mg/dl with ezetimibe/simvastatin than with atorvastatin for all doses compared ( Figure 2 ). Analysis based on risk showed that a significantly larger percentage of high-risk patients reached target LDL cholesterol levels <70 mg/dl with ezetimibe/simvastatin compared to atorvastatin for all dose comparisons ( Figure 2 ). Combined analysis of LDL cholesterol level attainment based on AVD status (<100 mg/dl for patients without AVD and <70 mg/dl for patients with AVD) showed that a significantly larger proportion of patients reached the specified LDL cholesterol target with ezetimibe/simvastatin than with atorvastatin at all prespecified dose comparisons ( Figure 2 ). When analyzed individually, attainment of an LDL cholesterol level <70 mg/dl by patients with AVD was significantly greater for ezetimibe/simvastatin 10/20 mg versus atorvastatin 10 mg and ezetimibe/simvastatin 10/40 mg versus atorvastatin 40 mg, whereas a numerically larger but nonsignificant difference was seen between ezetimibe/simvastatin 10/20 mg and atorvastatin 20 mg ( Figure 2 ). For patients without AVD, achievement of an LDL cholesterol level <100 mg/dl was significantly more frequent for those taking ezetimibe/simvastatin 10/20 mg versus atorvastatin 10 mg, and the results were similar for the remaining 2 comparisons ( Figure 2 ).
| Parameter | Percent Change From Baseline ⁎ | Treatment Difference † | ||||||
|---|---|---|---|---|---|---|---|---|
| A10 (n = 242) ‡ | E10/S20 (n = 232) ‡ | A20 (n = 238) ‡ | E10/S40 (n = 236) ‡ | A40 (n = 239) ‡ | E10/S20 vs A10 | E10/S20 vs A20 | E10/S40 vs A40 | |
| Low-density lipoprotein | −39.5 | −54.2 | −46.6 | −59.1 | −50.8 | −14.7 †† | −7.5 †† | −8.2 †† |
| Total cholesterol | −27.9 | −37.8 | −33.3 | −41.0 | −35.9 | −9.9 †† | −4.5 †† | −5.1 †† |
| Non-high-density lipoprotein cholesterol | −36.4 | −49.9 | −43.0 | −54.0 | −46.3 | −13.5 †† | −6.9 †† | −7.6 †† |
| High-density lipoprotein cholesterol | 4.6 | 7.0 | 3.8 | 7.3 | 5.2 | 2.4 | 3.3 # | 2.1 |
| Triglycerides § | −21.5 | −24.4 | −24.9 | −25.9 | −27.7 | −3.7 ⁎⁎ | −0.2 | −0.3 |
| Very low-density lipoprotein § | −22.0 | −25.0 | −25.0 | −26.3 | −26.8 | −3.8 # | −0.3 | 0.2 |
| Apolipoprotein B | −30.1 | −41.0 | −34.5 | −44.7 | −39.0 | −10.9 †† | −6.5 †† | −5.7 ⁎⁎ |
| Apolipoprotein A-I | 4.1 | 3.9 | 2.1 ∥ | 4.4 | 1.2 | −0.2 | 1.7 ∥ | 3.2 |
| Low-density lipoprotein/high-density lipoprotein cholesterol | −41.4 | −56.2 | −47.7 | −61.3 | −52.0 | −14.7 †† | −8.5 †† | −9.4 †† |
| Total cholesterol/high-density lipoprotein cholesterol | −30.3 | −41.1 | −35.0 | −44.5 | −37.6 | −10.8 †† | −6.2 †† | −6.9 †† |
| Non-high-density lipoprotein cholesterol/high-density lipoprotein cholesterol | −38.3 | −52.1 | −44.1 | −56.5 | −47.5 | −13.8 †† | −7.9 †† | −9.0 †† |
| Apolipoprotein B/apolipoprotein A-I | −31.7 | −42.0 | −37.1 | −46.8 | −39.2 | −10.3 †† | −4.9 ⁎⁎ | −7.7 †† |
| High-sensitivity C-reactive protein ¶ | −16.6 | −21.3 | −10.2 | −26.8 | −31.3 | −4.7 | −11.0 | 4.5 |
† Differences in least squares mean values for E10/S20 minus A10, E10/S20 minus A20, and E10/S40 minus A40.
‡ Number of patients in full analysis set population (varied slightly within each treatment group).
§ Nonparametric results (medians) are presented for triglycerides and very low-density lipoprotein.
∥ The apolipoprotein A-I value for 1 subject was identified as an extreme outlier (5 mg/dl—not clinically plausible) and excluded from the analysis.
¶ Longitudinal data analysis results are presented for high-sensitivity C-reactive protein.
Ezetimibe/simvastatin therapy resulted in significantly greater decreases in total cholesterol, non-HDL cholesterol, apolipoprotein B, and all lipid/lipoprotein ratios (LDL cholesterol/HDL cholesterol, total cholesterol/HDL cholesterol, non-HDL cholesterol/HDL cholesterol, apolipoprotein B/apolipoprotein A-I) than atorvastatin for all prespecified treatment comparisons ( Table 3 ). Increases in HDL cholesterol were significantly greater for ezetimibe/simvastatin 10/20 mg than atorvastatin 20 mg and numerically larger but not significantly different when comparing ezetimibe/simvastatin 10/20 mg to atorvastatin 10 mg or ezetimibe/simvastatin 10/40 mg to atorvastatin 40 mg. Decreases in triglycerides and very LDL cholesterol were significantly greater for ezetimibe/simvastatin 10/20 mg than atorvastatin 10 mg, and were not different for all other prespecified dose comparisons ( Table 3 ). There was no significant difference in percent change in apolipoprotein A-I and high-sensitivity C-reactive protein between ezetimibe/simvastatin and atorvastatin for any of the prespecified dose comparisons ( Table 3 ). The greater LDL cholesterol-lowering efficacy of ezetimibe/simvastatin versus atorvastatin was generally consistent across all prespecified subgroups of age, gender, race, diabetes mellitus/metabolic syndrome, and baseline LDL cholesterol and consistent with the decreases seen for the entire cohort ( Figure 3 ). Results for some subgroups, however, were limited by sample size (black [n = 2 to 9], Asian [n = 6 to 12], baseline LDL cholesterol <130 mg/dl [n = 11 to 14]).
