EAL

DLM: Omega-3 Fatty Acids (2009-2010)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To determine whether coronary mortality or morbidity in men less than 70 years old with angina can be reduced by an intake of oily fish or fish oil that provides about 3 g of eicosapentaenoic acid (EPA) weekly and/or by increased intake of fruits, vegetables, and oats providing 8 grams soluble fiber per day.

Inclusion Criteria:

Males under 70 years being treated for angina.

Exclusion Criteria:

Men denying ever having exertional chest pain or discomfort
Men waiting for coronary artery bypass surgery
Men who already ate oily fish 2x/week
Men who could not tolerate oily fish or fish oil
Men w/serious illness or likelihood of moving from area

Description of Study Protocol:

Recruitment- Participants recruited between 1990-92, 1993-96 (break due to interruption in funding). Potential subjects completed medical and dietary questionnaires; height, weight, blood pressure (BP) obtained; blood sample taken for cholesterol measurement to determine final participant pool.

Design- Randomized, controlled factorial trial

Blinding used- dietitian (blinded) - randomly assigned subjects to groups using previously prepared envelopes

Intervention- Subjects meeting inclusion criteria randomly assigned to 1 of 4 groups described below:

fish– advised to eat 2 or more portions oily fish per week or take up to 3g fish oil as a total or partial substitute if they disliked fish.
- subrandomization of fish group to receive either fish advice or fish oil capsules occurred during second phase of trial
fruit/vegetable/oat– advised to eat 4-5 portions of fruit and vegetables daily (apart from potatoes), drink at least 1 glass natural orange juice per day to increase vitamin C intake, and increase oat intake in order to consume at least 8 g soluble fiber per day
both – subjects advised to eat both fish and fruit/vegetable/oats
control– “sensible eating” with no specific dietary advice

If BMI>30kg/m² patients were given weight-reduction advice . Smokers were urged to quit.

Participants were seen at 6 months and questionnaires repeated. In group related subsets, plasma eicosapentaenoic acid (EPA) and ß-carotene obtained at baseline and 6 months.

Three years after the last subject was recruited, a questionnaire was sent to update medications. This also served to check that deaths were recorded.

Deaths were found using National Health Service register. Deaths due to cardiac causes were followed up with information from hospital records, relatives or other sources to determine suddenness of death. Unwitnessed deaths were excluded from analysis unless found within an hour of being known to be asymptomatic.

Statistical Analysis- all analysis by intention to treat

Weighted mean and SD for intakes of EPA, vitamin C, kcal, total fat, saturated fat, PUFA at baseline and 6 months
Mean and SD for plasma EPA concentrations and beta-carotene levels
Adjusted Hazard Ratios (AHR) used to determine mortality (covariates included age, smoking, previous MI, history of high blood pressure, diabetes, BMI, serum cholesterol, medication, and fruit consumption).
Power analysis revealed 3000 subjects were needed to detect mortality reduction from 13% to 10% over a 5 year period at 80% power and P<0.05.

Data Collection Summary:

Timing of Measurements

Height, weight, BP, serum cholesterol measured at baseline.
Medical and dietary questionnaires to participants at baseline and 6 months. (Dietary questionnaires derived from questionnaires that had been previously validated against 7-day weighed dietary records).
- In second phase of trial, dietary questionnaire was administered to only 10% of subjects.
Plasma EPA and b-carotene measured at baseline and 6 months in appropriate subsets.

Comliance checked by sending dietary charts to participants with pre-paid return envelopes. Those who did not return it, or who indicated poor compliance were contacted by a dietitian for encouragement.

Dependent variables

Mortality-
- overall deaths
- cardiac deaths
- sudden deaths

Independent variables

dietary fish intake or fish oil capsules
fruit, vegetable, and oat intake (soluble fiber)

Control variables

age
smoking status
previous MI
hx of hypertension
diabetes
serum cholesterol
medication use (b-blockers, nitrates, digoxin, lipid-lowering drugs, anticoagulants and diuretics)

Description of Actual Data Sample:

Initial N: 3114 males (1111 in phase 1, 2003 in phase 2)

n=764 fish group
n=779 fruit group
n=807 both fish and fruit group
n=764 neither/sensible eating group

Attrition (final n):

Subject characteristics at baseline- Mean (SD)

Age: 61.0-61.2 (6.3-6.9)

Ethnicity: Welsh

Other relevant demographics: none given

Anthropometrics: BMI 28.0-28.2 (3.9-4.2)

Location: Wales, UK

Other:

Cholesterol (mmol/dL)- 6.35-6.43 (1.1-1.19)
Systolic BP 141.3-142.3 (22.3-22.9)
Diastolic BP 84.3-85.1 (12.4-13.1)
21.6-25.1% smokers in each group
48.3-52.2% w/previous heart attack
39.5-42.5% on b-blockers

*Differences between groups exist for hx of heart attack, b-blocker usage, hx of hypertension. Age, BMI, BP similar between groups.

Summary of Results:

Mean intake of fish in fish group as EPA g/week (SD):

Baseline: 0.67 (0.53)
6 Months: 3.62 (1.35)
Change: 2.65 (1.35)
95% CI for change: 2.36, 2.94

Change in EPA concentrations in subgroups: Significant rise in EPA concentrations from baseline to six months in subjects given fish advice (n=39) of 1.23 mg/dL (SD=3.29; 95% CI 0.16, 2.30) w/a non-significant decline in subjects not given fish advice (n=29) of -0.16 mg/dL (SD=1.53; 95% CI -0.75, 0.44).

Deaths in relation to dietary advice (2-way analysis, fish vs no fish and fruit vs no fruit)

	All Fish	No Fish	All Fruit	No fruit
N	1571	1543	1586	1528
Total # of deaths (%)	283 (18.0) p=0.08	242 (15.7)	275 (17.3) p=0.07	250 (16.4)
# of cardiac deaths (%)	180 (11.5) p=0.02	139 (9.0)	158 (10.0) p=0.60	161 (10.5)
# of sudden deaths (%)	73 (4.6) p=0.02	47 (3.0)	61 (3.9) p=0.98	59 (3.8)

Subjects given fish advice had a significantly higher mortality from cardiac and sudden death; fruit advice had no effect.

Mortality of subjects advised about fish: AHR relative to subjects not advised about diet

	Fish Advice		Fruit Advice
	AHR (95%CI)	P-Value	AHR (95% CI)	P-Value
All deaths	1.15 (0.96, 1.36)	0.13	1.12 (0.94, 1.34)	0.2
Cardiac deaths	1.26 (1.00, 1.58)	0.047	1.00 (0.80, 1.25)	1.0
Sudden deaths	1.54 (1.06, 2.23)	0.025	1.01 (0.70, 1.46)	0.94

*above adjusted for age, smoking, previous MI, hx of high BP, DM, BMI, cholesterol, medication

Survival analysis of subjects advised on dietary fish or fish oil: AHR relative to subjects given no fish advice

	Dietary Fish n=1109			Fish Oil (n=462)
	n	AHR (95% CI)	P-Value	n	AHR	P-Value
All deaths	198	1.13 (0.94, 1.37)	P=0.2	85	1.19 (0.92, 1.54)	P=0.19
Cardiac deaths	121	1.20 (0.93, 1.53)	P=0.16	59	1.45 (1.05, 1.99)	P=0.024
Sudden deaths	49	1.43 (0.95, 2.15)	P=0.086	24	1.84 (1.11, 3.05)	P=0.018

*above adjusted for age, smoking, previous MI, hx of high BP, DM, BMI, cholesterol, medication

Dietary fish group includes all subjects allocated to fish group, even those who chose to take fish oil capsules instead of fish, but excludes the subrandomized fish oil group.

Author Conclusion:

Simple dietary advice increases the intake of some components (fish), but does not affect others (fruits and vegetables). There was a higher risk of cardiac death in men advised to eat oily fish. It was particularly apparent in those who took fish oil capsules.

Funding Source:

Industry:

Seven Seas Ltd, Novex Phaarma Ltd,

Food Company:

Pharmaceutical/Dietary Supplement Company:

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

In phase one of the study, subject were instructed to consume 2 portions oily fish per day or to take up to 3 g of fish oil (Maxepa) as a partial or total subsitute.

Authors gave numerous possible explanations for increase in deaths within the fish group.

Dietary advice was given at baseline and 6 months, and fish/fish oil capsule intake, and plasma EPA levels measured at baseline and 6 months. Authors assume fish group followed the advice of increased intake for a longer term, but this was not assessed, so it is difficult to determine whether advice was followed after the first 6 months. Dietary charts were sent in the mail to determine compliance, but the article does not state when these were sent.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
	1.	Was the research question clearly stated?	Yes
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
	1.3.	Were the target population and setting specified?	Yes
	2.	Was the selection of study subjects/patients free from bias?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
	3.	Were study groups comparable?	No
3.	Were study groups comparable?		No
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	No
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	No
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
	4.	Was method of handling withdrawals described?	Yes
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	???
	4.4.	Were reasons for withdrawals similar across groups?	???
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
	5.	Was blinding used to prevent introduction of bias?	Yes
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	???
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	???
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
	6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?	Yes
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	No
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	No
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	No
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	No
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
	7.	Were outcomes clearly defined and the measurements valid and reliable?	Yes
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
	8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	Yes
	9.	Are conclusions supported by results with biases and limitations taken into consideration?	Yes
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
	10.	Is bias due to study's funding or sponsorship unlikely?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes