EAL

HTN: Omega-3 Fatty Acids (2007)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To test the effect of a daily dose of 0.48g of eicosapentaenoic acid (EPA) plus 0.12g of gamma linoleic acid (GLA) on blood pressure (BP) in patients with high normal diastolic BP or stage 1 hypertension (diatsotlic BP of 85mm to 94mm Hg).

Inclusion Criteria:

Adults 30 to 54 years of age with average diastolic BP based on nine readings was 85 to 94mm Hg
Cholesterol level was below 6.72mmol per L (260mg per L).

Exclusion Criteria:

History of congenital heart disease
Stroke within the preceding six months
Cancer.

Description of Study Protocol:

Recruitment

Not discussed.

Design

Randomized placebo-controlled double-blinded clinical trial
Subjects were randomized to treatment (omega-3 fatty acid) group or control group receiving olive oil capsules daily for 12 weeks total
Baseline data was collected during a two- to four-month run-in period, consisting of demographic characteristics, medical history, self-report of health status, total cholesterol and baseline BP
Hypertension was defined as diastolic BP under 95mm Hg or being on antihypertensive medication
Compliance was measured by pill count
Change in diastolic and systolic BP and development of hypertension were determined at six and 12 weeks of intervention.

Blinding Used

Subjects were blinded as to which supplement (omega-3 or olive oil) they were receiving
Clinic staff were unaware of treatment status of subjects.

Intervention

Treatment group received a total dose of 0.48g of eicosapentaenoic acid (EPA) plus 0.12g of gamma linoleic acid (GLA) plus 80IU of vitamin E as eight capsules per day
The control group received capsules of olive oil with a total daily dose of less than one teaspoon.

Statistical Analysis

Data was analyzed on an intention-to-treat basis, with all randomized subjects analyzed regardless of treatment compliance. Baseline characeristics of of the treatment and control groups were compared using:

A two-sample T-test for means
The non-parametric Wilcoxon rank-sum test for medians
The chi square or Fiser's exact test for proportions.

"The effect of fatty acid supplementation on BP were evaluated by repeated measures analysis with a mixed linear regression model to control for the correlation of multiple BP measurements over time. Multivariate models controlled for race, gender, age, baseline BP, and other potentially confounding baseline characteristics."

The occurence of hypertension was analyzed with adjusted and unadjusted Cox proportional hazard models.

Data Collection Summary:

Timing of Measurements

Baseline measurements were taken during a two- to four-month run-in period

BP was measured again at six weeks and 12 weeks, following the run-in period

Three separate visits were conducted for the 12-week measurement, spaced one to two weeks apart

Six-week and 12-week measurements included weight and evaluation of side effects in addition to BP

Total cholesterol was measured at baseline and 12 weeks.

Dependent Variables

Variable One: Diastolic BP measured three times manually, using Korotkoff sounds in three-second intervals after patient had rested for five minutes

Variable Two: Systolic BP measured in the same manner as the diastolic BP

Variable Three: Development of hypertension (defined as diastolic BP above 160mmHg or systolic BP above 95mm Hg or use of antihypertensive medication).

Independent Variables

Variable One: Daily supplementation of 0.48g of EPA, 0.12g of GLA, 80IU of vitamin E

Variable Two: Daily supplementation of less than one teaspoon olive oil.

Control Variables

Age, education level, smoking status, history of BP medication use, history of elevated BP, alcohol intake at baseline

Age, race, gender, marital status, baseline diastolic and systolic BP, education level, marital status, smoking status for analysis at six and 12 weeks.

Description of Actual Data Sample:

Initial N: 103 (51 males) were initially randomized to treatment or control groups

Attrition (final N): 92 completed the study; attrition was not associated with treatment status

Ethnicity: 66% of the initial control group were white, 59% of the initial control group were white.

Other Relevant Demographics

Baseline Characteristics

Control Group

Treatment Group

College educated

64%

49%

Married

78%

59%

Current smoker

12%

8%

Alcohol intake (drinks per week)

4±5

3±7

Anthropometrics

Mean BMI of the treatment group: 29±4

Mean BMI of control group: 28±4.

Location

University of California at Davis and Johns Hopkins University.

Summary of Results:

Change in Systolic and Diastolic BP within Treatment Groups at Six and 12 Weeks and Differences in these Changes Between Treatment Groups

Omega-3 Fatty Acids

P

Olive Oil

P

Difference

Unadjusted Systolic BP; six weeks

-2.08±1.07

0.0542

-1.17±1.11

0.2954

-0.91
(-3.97, 2.15)

Unadjusted Systolic BP; 12 weeks

-1.21±0.89

0.1743

-1.56±0.90

0.0867

-0.34
(-2.17, 2.85)

Unadjusted Diastolic BP; six weeks

-1.55±0.81

0.0575

-2.12±0.84

0.0133

0.56
(-1.75, 2.87)

Unadjusted Diastolic BP; 12 weeks

-2.68±0.64

0.0001

-3.35±0.65

0.0001

0.68
(-1.12, 2.48)

Adjusted Systolic BP; six weeks

-2.11±1.08

0.0536

-1.15±1.13

0.3107

-0.97
(-4.09, 2.15)

Adjusted Systolic BP; 12 weeks

-1.23±0.91

0.1801

-1.54±0.92

0.0987

0.31
(-2.29, 2.91)

Adjusted Diastolic BP; six weeks

-1.46±0.80

0.0728

-2.26±0.83

0.0081

0.80
(-1.51, 3.11)

Adjusted Diastolic BP; 12 weeks

-2.58±0.62

0.0001

-3.45±0.63

0.0001

0.87
(-0.90, 2.65)

Values are mean±SE

Differences are mean with 95% CI. Difference values are reduction in BP in the omega-3 fatty acid group minus reduction in BP in the olive oil group. A negative number indicates omega-3 fatty acids decreased BP more than olive oil and a positive number indicates that olive oil decreased BP more than the omega-3 fatty acids.

Baseline characteristics and BP in the two groups were not statistically different

Compliance was similar in the two groups

Diastolic BP decreased in both groups over 12 weeks and there was not a difference in reduction between the two groups. This observation was similar at six weeks.

Systolic BP decreased in both groups by six and 12 weeks and there was not a difference in reduction between the two groups

The results for the changes in diastolic and systolic BP were similar when analyzed to control for age, race, gender and baseline diastolic and systolic BP

Changes in sytolic and diastolic BP at six weeks and 12 weeks were combined and analyzed for differences between the two groups, adjusting for age, race, gender and baseline diastolic or systolic BP. No differences were noted between the groups. This analysis was repeated with further adjustments for education level, marital status and current smoking status. Again, not differences were noted between the groups.

Other Findings

The relavite risk of hypertension was similar in the two groups (relative risk 0.3, 95% CI -0.4 to 4.8)

There was an increase in the number of subjects reporting increases in the side effect of belching in the omega-3 fatty acid group, compared to the control group, 40% vs. 19.2%; P=0.03.

Author Conclusion:

There was no significant effect of a daily low-dose EPA and GLA supplement on BP in patients with high normal diastolic BP or stage 1 hypertension (diastolic BP 85mm to 94mm Hg), following six or 12 weeks of treatment

The incidence of hypertension was also similar in the group consuming the fatty acid supplement and the control group consuming olive oil

This supplement cannot be recommended as adjuvent therapy to lower BP in patients with type 1 hypertension.

Funding Source:

Industry:

Eico Pharmaceuticals

Pharmaceutical/Dietary Supplement Company:

Reviewer Comments:

Did not control for physical activity or dietary intake.

This study is an example of 80IU of vitamin E supplementation having no effect on BP when given with omega-3 fatty acids.

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

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

4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes

Validity Questions

1. Was the research question clearly stated? Yes

1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes

1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes

1.3. Were the target population and setting specified? 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

2.2. Were criteria applied equally to all study groups? 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

3. Were study groups comparable? 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? 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

3.5. 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

4. Was method of handling withdrawals described? 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

4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes

4.4. Were reasons for withdrawals similar across groups? Yes

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

5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? 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

5.4. 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

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

6.2. 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

6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes

6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A

6.6. Were extra or unplanned treatments described? N/A

6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes

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? ???

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? No

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

7.5. Was the measurement of effect at an appropriate level of precision? Yes

7.6. Were other factors accounted for (measured) that could affect outcomes? No

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? ???

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

8.3. 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

8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No

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? No

9. Are conclusions supported by results with biases and limitations taken into consideration? No

9.1. Is there a discussion of findings? No

9.2. Are biases and study limitations identified and discussed? No

10. Is bias due to study's funding or sponsorship unlikely? Yes

10.1. Were sources of funding and investigators' affiliations described? Yes

10.2. Was the study free from apparent conflict of interest? Yes

Baseline Characteristics	Control Group	Treatment Group
College educated	64%	49%
Married	78%	59%
Current smoker	12%	8%
Alcohol intake (drinks per week)	4±5	3±7

	Omega-3 Fatty Acids	P	Olive Oil	P	Difference
Unadjusted Systolic BP; six weeks	-2.08±1.07	0.0542	-1.17±1.11	0.2954	-0.91 (-3.97, 2.15)
Unadjusted Systolic BP; 12 weeks	-1.21±0.89	0.1743	-1.56±0.90	0.0867	-0.34 (-2.17, 2.85)
Unadjusted Diastolic BP; six weeks	-1.55±0.81	0.0575	-2.12±0.84	0.0133	0.56 (-1.75, 2.87)
Unadjusted Diastolic BP; 12 weeks	-2.68±0.64	0.0001	-3.35±0.65	0.0001	0.68 (-1.12, 2.48)
Adjusted Systolic BP; six weeks	-2.11±1.08	0.0536	-1.15±1.13	0.3107	-0.97 (-4.09, 2.15)
Adjusted Systolic BP; 12 weeks	-1.23±0.91	0.1801	-1.54±0.92	0.0987	0.31 (-2.29, 2.91)
Adjusted Diastolic BP; six weeks	-1.46±0.80	0.0728	-2.26±0.83	0.0081	0.80 (-1.51, 3.11)
Adjusted Diastolic BP; 12 weeks	-2.58±0.62	0.0001	-3.45±0.63	0.0001	0.87 (-0.90, 2.65)

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
	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
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	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
	2.2.	Were criteria applied equally to all study groups?	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
3.	Were study groups comparable?		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?	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
	3.5.	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
4.	Was method of handling withdrawals described?		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
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	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
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	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
	5.4.	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
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
	6.2.	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
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	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?		???
	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?	No
	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
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	No
	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?		???
	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
	8.3.	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
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	No
	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?	No
9.	Are conclusions supported by results with biases and limitations taken into consideration?		No
	9.1.	Is there a discussion of findings?	No
	9.2.	Are biases and study limitations identified and discussed?	No
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes