Fatty Acids in Statin Users vs Non-Users With MI History
Fatty Acids in Statin Users vs Non-Users With MI History
The Alpha Omega Trial is a multicentre, double-blind, placebo-controlled trial of low doses of n-3 fatty acids (400 mg/day EPA–DHA and/or 2 g/day ALA) on the risk of fatal and non-fatal major cardiovascular events. The trial was approved by a central medical Ethics Committee (Haga Hospital, Leyenburg, The Hague, The Netherlands) and by the Ethics Committee at each participating hospital. All subjects signed informed consent before entering the study. Details of the Alpha Omega Trial have been described elsewhere. Briefly, 4837 free-living Dutch post-MI patients aged 60–80 years were randomized to receive one of four margarines: an EPA–DHA-enriched, an ALA-enriched, an EPA–DHA plus ALA-enriched margarine or a placebo margarine. Patients were enrolled from April 2002 through December 2006 and were followed for an average of 41 months.
At baseline, anthropometric measures were obtained and blood pressure, heart rate, lipid and glucose levels were determined. Information on demographic variables, lifestyle habits, current health status and medical history were collected by self-administered questionnaires. Baseline measurements were repeated after 20 months of the intervention in a random sample of 810 participants, and after 41 months in the 2531 participants who completed the trial before 1 January 2009. For the remaining participants, due to budgetary constraints, physical examination and blood sampling were not repeated and data were collected by questionnaires at the end of follow-up.
Questionnaires on medication use were filled out by all participants at baseline and after 41 months. Subjects were asked to record changes in medication use in a structured diary, and medication was checked during structured telephone interviews after 12 and 24 months. All drugs were coded according to the Anatomical Therapeutic Chemical (ATC) classification by two of the authors (S.R.B.M.E. and O.H.K.). Subjects who reported the use of statins (ATC codes C10AA and C10B) at all measurements (at baseline and at 12-, 24-, and after on average 41-month follow-up) were classified as statin users. Those who were not using statins at any time point were classified as non-users. Subjects who initiated or stopped statin therapy during the trial and inconsistent statin users who used statins at some, but not all, time points were excluded.
The vital status of the participants was monitored via a computerized link with municipal registries. For patients who experienced a fatal event during follow-up, general practitioners, hospitals, and family members were approached to ascertain the primary and contributing causes of death. The occurrence of non-fatal major cardiovascular events (MI, cardiac arrest, and stroke) and cardiac interventions (percutaneous coronary intervention and coronary artery bypass grafting) was monitored by annual telephone interviews conducted by research staff and verified against hospital records. The primary endpoint of this study was the rate of major cardiovascular events, which comprised fatal CVDs, non-fatal MI, non-fatal cardiac arrest, non-fatal stroke, and cardiac interventions (percutaneous coronary intervention and coronary artery bypass grafting).
Demographic and health characteristics of the participants who received the different margarines, stratified for statin users and non-users, were compared by using Student's t-test or the Mann–Whitney U-test for continuous variables and the χ-test for nominal variables.
Uni- and multivariable general linear regression models were used to assess differences in changes in lipid levels over time among statin users and non-users randomized to n-3 fatty acid supplementation or placebo. Uni- and multivariable Cox's proportional hazard models were used to estimate hazard rate ratios (HR) for major cardiovascular events with the placebo group as reference. Fixed effects in the models were the n-3 fatty acids and the use of statins. To test whether the effect of EPA–DHA and/or ALA differed between patients with and without statins, the product term of n-3 fatty acids and statins was added to the models.
In the multivariable models, we adjusted for age, gender, and diabetes mellitus. In addition, we checked whether inclusion one by one of other potential confounding variables altered the relationship of EPA–DHA and/or ALA with major cardiovascular events by ≥10%. We selected the following potential confounders: baseline levels of body mass index, current smoking (yes/no), physical activity level (≥5 or <5 days/week engaged in physical activity with a Metabolic Equivalent TASK score>3), self-reported history of stroke, dietary EPA–DHA intake, alcohol consumption (≥1 or <1 glass/week), ratio of total to HDL cholesterol, serum triglyceride levels, systolic blood pressure, current use of blood pressure-lowering medication (ATC codes C02, C03, C07, C08, and C09), antithrombotic agents (B01), and hormone replacement therapy (G03).
Methods
Study Population
The Alpha Omega Trial is a multicentre, double-blind, placebo-controlled trial of low doses of n-3 fatty acids (400 mg/day EPA–DHA and/or 2 g/day ALA) on the risk of fatal and non-fatal major cardiovascular events. The trial was approved by a central medical Ethics Committee (Haga Hospital, Leyenburg, The Hague, The Netherlands) and by the Ethics Committee at each participating hospital. All subjects signed informed consent before entering the study. Details of the Alpha Omega Trial have been described elsewhere. Briefly, 4837 free-living Dutch post-MI patients aged 60–80 years were randomized to receive one of four margarines: an EPA–DHA-enriched, an ALA-enriched, an EPA–DHA plus ALA-enriched margarine or a placebo margarine. Patients were enrolled from April 2002 through December 2006 and were followed for an average of 41 months.
At baseline, anthropometric measures were obtained and blood pressure, heart rate, lipid and glucose levels were determined. Information on demographic variables, lifestyle habits, current health status and medical history were collected by self-administered questionnaires. Baseline measurements were repeated after 20 months of the intervention in a random sample of 810 participants, and after 41 months in the 2531 participants who completed the trial before 1 January 2009. For the remaining participants, due to budgetary constraints, physical examination and blood sampling were not repeated and data were collected by questionnaires at the end of follow-up.
Assessment of Statin Use
Questionnaires on medication use were filled out by all participants at baseline and after 41 months. Subjects were asked to record changes in medication use in a structured diary, and medication was checked during structured telephone interviews after 12 and 24 months. All drugs were coded according to the Anatomical Therapeutic Chemical (ATC) classification by two of the authors (S.R.B.M.E. and O.H.K.). Subjects who reported the use of statins (ATC codes C10AA and C10B) at all measurements (at baseline and at 12-, 24-, and after on average 41-month follow-up) were classified as statin users. Those who were not using statins at any time point were classified as non-users. Subjects who initiated or stopped statin therapy during the trial and inconsistent statin users who used statins at some, but not all, time points were excluded.
Endpoint
The vital status of the participants was monitored via a computerized link with municipal registries. For patients who experienced a fatal event during follow-up, general practitioners, hospitals, and family members were approached to ascertain the primary and contributing causes of death. The occurrence of non-fatal major cardiovascular events (MI, cardiac arrest, and stroke) and cardiac interventions (percutaneous coronary intervention and coronary artery bypass grafting) was monitored by annual telephone interviews conducted by research staff and verified against hospital records. The primary endpoint of this study was the rate of major cardiovascular events, which comprised fatal CVDs, non-fatal MI, non-fatal cardiac arrest, non-fatal stroke, and cardiac interventions (percutaneous coronary intervention and coronary artery bypass grafting).
Statistical Analysis
Demographic and health characteristics of the participants who received the different margarines, stratified for statin users and non-users, were compared by using Student's t-test or the Mann–Whitney U-test for continuous variables and the χ-test for nominal variables.
Uni- and multivariable general linear regression models were used to assess differences in changes in lipid levels over time among statin users and non-users randomized to n-3 fatty acid supplementation or placebo. Uni- and multivariable Cox's proportional hazard models were used to estimate hazard rate ratios (HR) for major cardiovascular events with the placebo group as reference. Fixed effects in the models were the n-3 fatty acids and the use of statins. To test whether the effect of EPA–DHA and/or ALA differed between patients with and without statins, the product term of n-3 fatty acids and statins was added to the models.
In the multivariable models, we adjusted for age, gender, and diabetes mellitus. In addition, we checked whether inclusion one by one of other potential confounding variables altered the relationship of EPA–DHA and/or ALA with major cardiovascular events by ≥10%. We selected the following potential confounders: baseline levels of body mass index, current smoking (yes/no), physical activity level (≥5 or <5 days/week engaged in physical activity with a Metabolic Equivalent TASK score>3), self-reported history of stroke, dietary EPA–DHA intake, alcohol consumption (≥1 or <1 glass/week), ratio of total to HDL cholesterol, serum triglyceride levels, systolic blood pressure, current use of blood pressure-lowering medication (ATC codes C02, C03, C07, C08, and C09), antithrombotic agents (B01), and hormone replacement therapy (G03).