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. 2018 Jul 18;2018(7):CD003177. doi: 10.1002/14651858.CD003177.pub3

Sandhu 2016

Methods RCT, parallel 5 arms (combined groups 4 and 5 omega‐3‐acid ethyl esters (Lovaza) n‐3 ± raloxifene vs control groups 1 and 3 ± raloxifene), 24 months
Summary risk of bias: moderate or high
Participants Healthy postmenopausal women (50% normal weight, 30% overweight, 20% obese) with high breast density detected on their routine screening mammograms
N: 54 + 53 intervention, 53 + 53 control
Level of risk for CVD: low
Men: 0% intervention, 0% control
Mean age in years (SD): 56.56 (6.9) + 57.85 (5.1) intervention, 57.11 (5.9) + 57.68 (5.1) control
Age range: not reported
Smokers: 0% intervention, 0% control
Hypertension: not reported
Medications taken by at least 50% of those in the control group: not reported
Medications taken by 20%‐49% of those in the control group: not reported
Medications taken by some, but less than 20% of the control group: not reported
Location: USA
Ethnicity: not reported
Interventions Type: supplement (n‐3 capsules)
Comparison: EPA + DHA vs nil
Intervention: group 4, Lovaza 4 g per day. Lovaza is the FDA‐approved n‐3 FA formulation containing 465 mg of EPA + 375 mg of DHA per gram, total dose; 1860 mg/d EPA, 1500 mg/d DHA. Group 5 as group 4 plus 30 mg raloxifene/d. Dose: 3.36 g/d EPA + DHA
Control: group 1, no treatment; group 3, 30 mg raloxifene/d
Compliance: measured by pill count, recorded at follow‐up visits and further verified by serum fatty acids monitoring. Compliance was 94% (SE 2%) at 6 months and 97% (SE 2%) at 12 months. Only 2 participants had a compliance < 85% (84% and 81%).
Duration of intervention: 24 months
Outcomes Main study outcome: change in breast density
Dropouts: 5 intervention, 6 control
Available outcomes: cardiovascular events, breast cancer, lipids, dietary intake, plasma FAs, adverse events (including one incidence of hyperglycaemia)
Response to contact: yes
Notes The study had 5 arms: group 1, no treatment, control; group 2, raloxifene 60 mg orally daily; group 3, raloxifene 30 mg orally daily; group 4, Lovaza 4 g orally daily; and group 5, Lovaza 4 g/d plus raloxifene 30 mg orally daily. Data here is combined for groups 4 and 5 vs 1 and 3 for binary outcomes and group 1 vs 4 used for continuous outcomes
Study funding: GlaxoSmith Kline and Eli Lilly provided Lovaza and raloxifene, respectively. Funded by Susan G Komen for the Cure, KG081632 (A Manni) and pilot funds from the Penn State Hershey Cancer Institute (K El‐Bayoumy)
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Sandhu 2016 pg 276: "each study participant was randomly assigned with equal probability to one of the following five groups. A block randomization scheme was used to ensure balance treatment allocation during the course of enrolment."
Allocation concealment (selection bias) Unclear risk No description of concealment of allocation
Blinding of participants and personnel (performance bias) All outcomes High risk Open label
Blinding of outcome assessment (detection bias) All outcomes High risk Open label
Incomplete outcome data (attrition bias) All outcomes Low risk < 20% lost over 2 years, detailed reasons provided, no suggestion these are unbalanced
Selective reporting (reporting bias) High risk Biomarkers of oxidative stress (Urinary 8‐(isoprostane) F‐2α and 8OHdG, Lymphocyte 8‐OHdG, DNA etheno adducts), Urinary 2‐OHE1, 4‐OHE1, and 16α‐OHE1, Serum level of C‐reactive protein and IL‐6, Serum level of IGF‐I and IGFBP‐3, complete blood count mentioned in trial registry but not reported in Sandhu 2016. (More outcomes reported than in registry – diet, physical activity levels, adverse events)
Attention Low risk Participants assessed at baseline, 1‐year and 2‐year follow‐up
Compliance Unclear risk Measured by pill count, recorded at follow‐up visits and further verified by serum fatty acids monitoring. Compliance was 94% (SE 2%) at 6 months and 97% (SE 2%) at 12 months. Only 2 participants had a compliance < 85% (84% and 81%)
Other bias Low risk None noted