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To compare the effect of plant stanol ester spread with a placebo spread on cholesterol in patients taking statin therapy, but who still had elevated low density lipoprotein (LDL) cholesterol.

• At least 20 years of age
• LDL cholesterol level more than 130mg per dL
• Triglyceride (TG) levels more than 350mg per dL
• A stable regimen of atorvastatin calcium, pravastatin sodium, simvastatin or lovastatin
• With no change in dosage or frequency of administration for a minimum of 90 days before study entry.

• Gastrointestinal (GI) disorders or previous GI surgery
• History of myocardial infarction (MI) or stroke within three months before study entry
• Diabetes requiring insulin use or concurrent use of other cholesterol-reducing products within 30 days before enrollment.

• A randomized, double blind, placebo-controlled clinical trial over eight weeks, with six additional weeks of follow-up after discontinuation of the spread from September 1998 through September 1999
• Sample size was calculated to detect a mean difference of 8% between groups for change in LDL cholesterol from baseline to eight weeks, with 90% power
• The two primary outcomes were changes in serum total cholesterol and LDL cholesterol levels. Participants were randomized to one of two study groups.
• The outcome variables and covariables at zero (baseline), two, four and eight weeks over the treatment phase of the study and after an additional six weeks of follow-up were assessed. Primary outcome variables were the mean of blood chemistry analyses on two separate venous blood samples collected within a one-week period at baseline and again at week eight.
• Height, weight, heart rate and blood pressure and calculated BMI as kg per m². Participants completed a health questionnaire, which included items on family history of premature CAD, cigarette smoking, exercise habits and alcohol intake.
• Within one week after the baseline examination, detailed dietary information was obtained by an unannounced 24-hour recall involving a computer-assisted telephone interview
• Diet information collected during the 24-hour recalls was analyzed using food database 14A, nutrient database 29, and software version 4.01 (Minnesota Nutrition Data System, Nutrition Coordinating Center, University of Minnesota, Minneapolis, Minnesota). These dietary assessments were repeated at the end of the treatment phase.
• Participants randomly assigned to consume either a spread containing plant stanol esters (stanol) or a placebo spread (placebo). Randomization was stratified according to type (atorvastatin, pravastatin, simvastatin or lovastatin) of statin therapy. The two spread preparations were indistinguishable in color, taste, absorbable fat content and caloric value.
• The canola oil-based spreads, packaged into individual, foil-sealed packets of eight grams of spread, were composed primarily of the following major fatty acids: 16:0 (8.0%), 18:0 (6.6%), 18:1 (49.7%), 18.2 (29.3%) and 18:3 (4.8%).
• The average dietary fat quantities of one packet of spread included 6.0g total fat, 0.9g saturated fat, 2.8g monounsaturated fat, 1.9g polyunsaturated fat and 0.4g trans fat. Each 8g portion of active spread contained 1.7g plant stanol esters of which 1g was the plant stanol component.
• The plant stanol esters were manufactured by the esterification of plant stanols with fatty acid alcohol esters obtained from food-grade refined, bleached and deodorized canola oil
• Subjects received a two-week supply of spread with instructions to substitute three servings of normally consumed spread per day with the study spread while continuing with their statin therapy regimen and maintaining their usual diet for eight weeks. Plant stanol ester intake was targeted to be 5.1g per day, providing 3g per day of plant stanol.
• Participants recorded their daily statin dose(s) and spread consumption in diaries provided by staff. Participants received an additional two-week supply of their assigned spread at subsequent visits.
• Study center personnel reviewed participants’ diaries for compliance with spread consumption and statin regimen
• Participants were withdrawn if their compliance with both at week two (week zero to two interval) was more than 66% of the prescribed dose. Participants also returned unused packets of spread to the study center as an additional device to monitor compliance. We also collected information from participants at each visit regarding any adverse events they had experienced since their last visit.

Data Analysis

• All available data for statistical comparisons between intervention groups was used, with persons grouped as originally randomized. Differences were evaluated between intervention groups at baseline by the chi-square test or Fisher’s exact test for categorical variables and by one-way analysis of variance for continuous variables. Efficacy analyses only were conducted on subjects randomized to an intervention group who also met compliance requirements (taking more than 66% of the prescribed doses for both their statin and spread) at the end of week two. Subjects who failed to provide data at a time point were excluded from the analysis at that time point.
• Additional analyses was conducted on all randomized participants using the last observation-carried-forward method. Treatment responses were summarized as mean percent changes from baseline levels and used T-tests to assess the significance of the observed changes.
• Within-treatment group changes from week eight to the follow-up assessment six weeks later were evaluated by paired T-tests. Differences were assessed in outcomes between treatments by comparing percent changes from baseline to weeks two, four and eight. Two-way analysis of variance (treatment, clinical center) was used to detect treatment differences at each time point.

• 24-hour recall diet
• Height, weight, heart rate and blood pressure and calculated body mass index (BMI) as kg per m². Participants completed a health questionnaire, which included items on family history of premature coronary artery disease (CAD), cigarette smoking, exercise habits and alcohol intake.
• Total cholesterol, HDL cholesterol, TG and LDL cholesterol at zero, two, four and eight weeks intervention.

A total of 167 subjects were randomly assigned to treatment and 142 subjects completed the study.

• Stanol group:
  • N: 48 males, 35 females
  • Mean age: 55 years
  • Ethnicity: 86% White, 12% African-American, 2% other
  • BMI: 24% less than 25kg per m² ; 39% 25 to 29.9kg per m²; 37% at least 30kg per m²
  • Mean LDL: 147mg per dL
• Placebo group:
  • N: 52 males, 32 females
  • Mean age: 57 years
  • Ethnicity: 91% White, 6% African-American, 4% other
  • BMI: 24% less than 25kg per m²;  46% 25 to 29.9kg per m²; 30% at least 30kg per m²
  • Mean LDL: 149mg per dL
• Groups did not differ in amount or type of statin.

Subjects were excluded due to:

• Non-compliance (five in stanol group,  two placebo)
• Adverse events (three, three)
• Subject request (five, seven)
• Loss to follow-up (one in stanol group).

• There were significant reductions from baseline in levels of total cholesterol and LDL cholesterol at weeks two, four and eight for both the stanol and placebo groups
• There was a subsequent significant increase in both total and LDL cholesterol during the six-week follow-up after spread use was discontinued
• Significant reductions in total and LDL cholesterol occurred by week two, and there was little further change at weeks four or eight. The stanol ester spread group had significantly greater mean reductions from baseline for total and LDL cholesterol than did the placebo spread group at two, four and eight weeks. Changes from baseline for both experimental groups were comparable for women and men for both total and LDL cholesterol.
• Changes from baseline to weeks two, four and eight for all 167 randomized participants using the last observation- carried-forward approach. Net between-group differences remained highly significant (P<0.001) at all measurement points for both serum total cholesterol and LDL cholesterol.
• There were no significant changes in HDL cholesterol or triglycerides in either of the spread groups for any time point or for comparison between groups
• Between-group differences from baseline in total and LDL cholesterol levels did not differ in the two treatment groups between baseline and week eight and were similar and consistent across all statin medications
• There were no statistically significant changes for any of these variables in either the stanol ester or placebo groups over the course of the study. Likewise, no changes were observed for body weight, blood pressure or resting heart rate.
• Both spreads well tolerated
• The stanol ester group had a 10% greater reduction in LDL cholesterol than those in the placebo group at eight weeks. (P<0.0001 to P<0.001). No effect of statin dose or type, other dietary factors or BMI.
• See table below
• When treatment was discontinued, TC and LDL-C levels increased so that at six weeks without treatment, values in the placebo group were not significantly different from baseline.  Values in the stanol group were still mildly, but significantly lowered at six weeks.

Comparison of Absolute Changes in TC and LDL-C from Baseline to Week Eight for Stanol and Placebo Spread Groups

Stanol Group			Placebo Group
Baseline	Week 8	Change	Baseline	Week 8	Change	Treatment  Ddifference	ANOVA  P-value
Total Cholesterol mg/dL			Total Cholesterol mg/dL
232	205	-27	231	220	-11	-16 (-7%)	0.001
LDL Cholesterol mg/dL			LDL Cholesterol mg/dL
146	122	-24	148	138	-10	-14 (-10%)	0.001

• LDL cholesterol reductions in participants with cardiovascular disease at baseline (MI, stroke, or bypass surgery less than three months before enrollment in the study).
• For these participants, LDL cholesterol reductions from baseline were 22% in the stanol group and 8% in the placebo group. Of the 12 participants with coronary heart disease in the stanol group, five (42%) had LDL cholesterol less than 130mg per dL at eight weeks and two subjects (15%) of the placebo group had LDL cholesterol ,less than 130mg per dL at eight weeks (P=0.202, Fisher’s exact test).
• Safety data concerning all reported adverse events and treatment-related adverse events clearly indicate that the product was safe and well tolerated, with no significant differences between the two treatment groups. Most of the reported adverse events were of either mild (23 stanol, 24 placebo) or moderate (12 stanol, eight placebo) intensities. Four subjects reported serious adverse events.Six subjects discontinued owing to adverse events. One participant in the stanol group reported dyspepsia.

• Consumption of a canola oil spread that provided 5.1g per day of plant stanol esters lowered TC and LDL-C more effectively than the same spread without stanol in participants on a stable regimen of a statin. Reduction of lipids was somewhat greater than expected with doubled dose of statin.
• Our large, double-blind, placebo-controlled study convincingly confirms that an incremental lowering of LDL cholesterol by about 10% was achieved by adding a stanol ester spread to the daily diet in persons taking a stable dose of a statin, and this effect was seen in all four statins included in this study. There were few serious adverse events and the distribution of adverse events was comparable in both study groups. The stanol ester spread was safe and well tolerated.
• Our results suggest that incorporating plant stanol ester spread into the diets of statin-treated patients results in significant additional reductions in LDL cholesterol, even when the intake of saturated fatty acids and dietary cholesterol are already at recommended levels.

Industry:	McNeil Consumer Healthcare Food Company:
University/Hospital:	Jefferson Medical College, Mayo Clinic, University of Texas Southwestern Medical Center
Not-for-profit	0 Foundation associated with industry:

• Study was quite thorough in controlling and analyzing possibly confounding variables. Because the sample included both men and women of various ethnicity, the generalizability is great.
• The composition of the placebo spread was not reported including its nutrient composition. A group without any use of spread including only stable medications need to be included in the study.
• When the stanols were discontinued, still you see mild significant lowering of cholesterol was observed. This might be due to cholesterol lowering drugs, hence a group of subjects without spread is necessary. Is cholesterol lowered in all the subjects in stanol group? There is a difference from baseline to eight weeks, but there is no significant difference between the weeks.
• It is interesting to note that the percent change from baseline for total cholesterol at four weeks and eight weeks and for LDL cholesterol at four weeks and eight weeks is the same and there is no difference between four weeks and eight weeks. This needs an explanation. In future trials, it is better not to include all the categories of CVD and stroke including CABG.
• This is a case-controlled study also based on the selection of the population in the study.