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

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

Determine the effect of a high dose of n-3 fatty acids given after an acute myocardial infarction (MI) on subsequent cardiac events and serum lipids.

Inclusion Criteria:
  • Verified MI by World Health Organization criteria
  • Older than 18 years of age
  • Discontinuation of regular supplementation of fish oil products
  • Informed consent.
Exclusion Criteria:
  • Assumed noncompliance to protocol
  • Expected survival less than two years because of severe heart failure, malignancy or other reasons
  • Ongoing GI bleeding or verified stomach ulcer
  • Thrombocytopenia or platelets less than 100 L to 109 per L
  • Liver insufficiency
  • Participation in another study
  • Residence outside recruitment area of study.
Description of Study Protocol:

Subjects with acute MI were recruited from a hospital center in Norway between September, 1995 and December, 1996. Patients were randomly assigned to receive either four grams of Omacor-R* (two gelatin capsules) or corn oil (two gelatin capsules) twice a day over 12 to 24 months. 

*Omacor-R: 850mg to 882mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in an average ratio of EPA to DHA of one to two (or the same amount of corn oil). Each capsule contained an additional 4.0mg a-tocopherol. 

A detailed patient history was obtained and a clinical exam was performed at baseline. ECG verified MI location. 

Treatment was initiated four to eight days after an acute MI, after inclusion and collection of baseline blood samples. Subjects were followed until the study ended in 1997. Follow-up occurred at six weeks, six months, one year, 18 months, and two years after start of treatment. All cardiac events and ongoing medication were recorded. The median follow-up time was 1.5 years (range: one day to two years).

 

 

Data Collection Summary:

At each follow-up period the following were performed:

  • Recording of cardiac events including cardiac death, resuscitation, recurrent MI and unstable angina
  • Recording of revascularization and death from other causes
  • Blood tests for serum lipid concentrations
  • ECG. 

Blinding

Subjects and researchers were blinded to treatment assignment.

 

Description of Actual Data Sample:

300 patients were recruited from one hospital.

No mention of drop-outs, although 82% of those receiving n-3 fatty acids and 86% receiving corn oil fulfilled the criteria for complete compliance after six weeks.

Demographics and Clinical Information by Treatment Group

 

n-3

Corn Oil

P

Gender (N, %)

0.25

   Male

115

76.7%

123

82.0%

   Female

35

23.3%

27

18%

Mean Age at MI (Range)

64.4

(28.9 to 86.7)

63.6

(29.3 to 87.7)

0.56

Mean BMI (Range)

25.9

(16.9 to 41.8)

26.0

(19.4 to 33.6)

0.87

Smoking Status [N (%)]     0.80
Non-smoker 34 (22.7) 39 (26.0)  
Ex-smoker 57 (38.0) 54 (36.0)  
Current Smoker 59 (39.3) 57 (38.0)  

Mean Systolic BP (Range)

124.5

(90 to 195)

122.1

(80 to 190)

0.30

Fish Oil Before Inclusion (N, %)

0.28

   No

104

69.8%

113

75.3%

   Yes

45

30.2%

37

24.7%

No significant group differences in demographics, clinical characteristics, MI location or drug use.

Summary of Results:

N=42 (28%) of patients in the n-3 group and N=36 (24%) in the corn oil group had at least one cardiac event during the follow-up period.

Distribution of Events by Treatment Group

 

n-3

Corn Oil

P

 

N (%)

N (%)

 

Number of Cardiac Events

 

 

0.74

   0

108 (72.0)

114 (76.0)

 

   1

27 (18.0)

20 (13.3)

 

   2

8 (5.3)

9 (6.0)

 

   >3

7 (4.7)

7 (4.7)

 

Most Serious Cardiac Event

 

 

0.97

   Cardiac Death

8 (19.0)

8 (22.2)

 

   Resuscitation

1 (2.4)

1 (2.8)

 

   Recurrent MI

15 (35.7)

11 (30.6)

 

   Unstable Angina

18 (42.9)

16 (44.4)

 

No significant differences between groups in number, type or severity of event.

 

 

No. of Events

HR (95%CI)

n-3 vs. Corn Oil

 

n-3

CO

Cardiac death

8

8

1.02 (0.38, 2.71)

Resuscitation

1

2

---

Cardiac death or resuscitation

9

9

1.01 (0.40, 2.55)

Total mortality

   Cardiac or non-cardiac death

11

11

1.02 (0.44, 2.36)

   Death or   resuscitation

12

12

1.02 (0.46, 2.27)

The number of cardiac events were highest in the n-3 group, but no overall significant differences between the groups for single or combined cardiac events were found. 

The overall Hazard Ratio (HR) for fatal or nonfatal cardiac event was 1.19 times higher in the n-3 group vs. the corn oil group. Adjustment for sex, age, smoking status, BMI, fish oil supplementation before inclusion, average number of fish meals per week and diabetes did not notably affect the HR for the combined cardiac event. 

Changes in Plasma Lipid Profile over Study Period

 

Inclusion Value

12 Months

Average Change per Month

 

mmol/L*

%

%

Total Cholesterol

   n-3

5.94 (1.18)

-11.14

-0.69

   CO

5.99 (1.20)

-6.18

-0.55

   P

0.53

HDL-C

   n-3

1.08 (0.30)

19.10

1.11

   CO

1.16 (0.35)

7.22

0.55

   P

0.0016

TG

   n-3

1.64 (0.82)

-18.57

-1.30

   CO

1.55 (0.81)

18.85

0.35

   P

<0.0001

  • Total Cholesterol: Significant overall decrease, no intergroup differences
  • HDL-C: Significant overall increase, significantly greater increase in n-3 group
  • TG: Differed significantly between groups, n-3 group decreased significantly.
Author Conclusion:

The total number of cardiac events was highest in the n-3 group, although no significant differences were found between the treatment groups in number, type or severity of cardiac event, including cardiac death. 

We observed no beneficial effect on the hazard of different cardiac events after an acute MI of a high dose of n-3 fatty acids compared with corn oil despite a favorable effect on serum TG and HDL-C.

It is possible that the high doses of concentrated n-3 fatty acids exceeded some optimal threshold level, outweighing the beneficial effect or even leading to an adverse effect.

Competing interventions, including aspirin, may have masked the potential to demonstrate an effect of n-3 fatty acids.

Funding Source:
Industry:
Pharmacia Upjohn (Oslo Norway), Pronova Oslo Norway)
Pharmaceutical/Dietary Supplement Company:
Reviewer Comments:

Subject pool from one hospital only. Likely to receive same treatment protocols for cardiac events, making the population more homogenous. However, this makes the study generalizable primarily to individuals within this geographic area. 

Researchers did not address how they measured compliance to supplement protocol. No measurement of plasma EPA and DHA, supplement logs, etc. Lack of significance between groups could potentially be related to noncompliance.

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) No
  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%.) No
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? 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
  5.1. 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? No
  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? 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
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? ???
  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? ???
  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
  8.1. 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)? 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? No
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes