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

Citation:
 
Study Design:
Class:
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Quality Rating:
Research Purpose:

To determine whether omega-3 PUFAs have beneficial antiarrhythmic effects in patients with a history of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF).

Inclusion Criteria:

Patients at six medical centers in the US were eligible for entry if they were receiving an implantable cardioverter defibrillator (ICD) for an electrocardiogram-documented episode of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) that was not the result of acute myocardial infarction or a reversible cause of who had a preexisting ICD and had received ICD therapy for an episode of electrogram-documented VT or VF within the previous three months.

Exclusion Criteria:
  • Patients taking class I or class III antiarrhythmic medications
  • Patients who ate more than one fatty fish (salmon, Chilean sea bass, sardine, herring, or mackerel) meal per week or who had taken flaxseed oil, cod liver oil or fish oil supplements in the last month.
Description of Study Protocol:

Recruitment

Not described in detail. Patients from six US medical centers were enrolled from February, 1999 until January, 2003. 

Design

Randomized, double-blind, placebo-controlled trial.

Blinding Used

A printout of each episode of ICD therapy was reviewed by the local investigator and by a member of the electrogram committee, both of whom were blinded to the treatment assignment of the patient. 

Intervention

Patients were randomly assigned to receive a total dosage of 1.8g per day of fish oil, consisting of 42% eicosapentaenoic acid (EPA) and 30% docosahexaenoic acid (DHA) or placebo (olive oil, 73%; oleic acid, 12%; palmitic acid, 0%, EPA and DHA). Follow-up was completed by July, 2003. Follow-up consisted of monthly clinic visits at the enrolling center for the first three months and every three months thereafter. At each visit, participants were asked to report anticipated, unanticipated and serious adverse events. Implantable cardioverter defibrillator programming was left to the discretion of the attending cardiologist, and the slowest heart rate programmed to trigger ICD therapy was tracked. At all visits, ICD memory was checked for occurrence of episodes of ICD therapy. Blood was drawn for lipid analysis at baseline and months one, two, three, six, 12, 18, and 24.

Statistical Analysis

All analyses were performed based on intention to treat. The baseline characteristics of patients randomized to receive fish oil vs. placebo were compared using the T-test and the Chi-square test as appropriate. Differences in percentage of total plasma and red blood cell membrane and fatty acids over time were determined using separate mixed-model analysis of variance models. The initial value was used as a covariate to control for any differences at baseline, with the most appropriate covariance structure selected using the Akaike information criterion. Least square-adjusted means were estimated and compared for all analysis of variance effects; a Tukey adjustment was applied within analyses to account for multiple comparisons. All analyses were performed with SAS software, versions eight and nine. 

Actuarial analyses were performed using the Kaplan-Meier method, and the statistical significance of observed differences was determined using the log-rank test. Survival is presented as percentage (standard error). For the primary analysis of time to first arrhythmia and the secondary analysis of time to first VT and VF analysis in patients with VT at study entry, a plot of the natural logarithm of the negative of the natural logarithm of survival vs. the natural logarithm of survival was reviewed to assess the proportional hazards assumption. 

As a secondary analysis, a Cox proportional hazards model was used to assess the significance of the primary outcome controlling for other baseline characteristics. Variable selection was performed with these baseline characteristics, using all possible regression models with the score statistic and stepwise addition of variables. The treatment group was then added to the best model to determine if it was a significant predictor after controlling for significant baseline characteristics. To determine if compliance modified the primary analysis, all repeated measurements of plasma and red blood cell membrane omega-3 PUFA levels were analyzed as time-dependent covariates using the Cox proportional hazards model. The Anderson-Gill application of the Cox proportional hazards model was used to assess the effect of treatment group on the number of days with recurrent VT and VF events. That is, each day on which a patient had VT or VF was modeled as an event. For example, if a patient experienced arrhythmias on days one, three and five, each of these three arrhythmias was included in the model with the time measured from the last recorded arrhythmia. 

Data Collection Summary:

Timing of Measurements

Follow-up consisted of monthly clinic visits at the enrolling center for the first three months and every three months thereafter.

Dependent Variables

  • Variable One: Time to first episode of VT or VF leading to ICD therapy (each episode of ICD therapy was reviewed by the local investigator and a member of the electrogram committee, both were blinded to the treatment assignment of the patient; the episodes were classified VT, VF, atrial fibrillation, supraventricular tachycardia oversensing, or unknown)
  • Variable Two: Time to days with recurrent episodes of VT or VF leading to ICD therapy (each day a patient had VT or VF was counted as an event and included in analyses)
  • Variable Three: Time to first use of antiarrhythmic medication (number of days before initiation of antiarrhythmic medication)
  • Variable Four: Change in defibrillation threshold, inducibility of VT or VF and the ventricular effective refractor period from baseline to three months (measured a subsample of 49 patients using electrophysiologic testing through the ICD at implantation and again three months later).

Independent Variables

Treatment of 1.8g per day of fish oil or placebo of olive oil (compliance measured by testing red blood cell membrane plasma n-3 fatty acids).

Control Variables

  • Ethnicity (measured by asking participants to classify themselves)
  • Dietary counseling (given throughout study to counsel participants to not change their intake of fish and to follow the AHA step I low-fat diet).
Description of Actual Data Sample:

 

  • Initial N: 200 (172 male, 28 female)
  • Attrition (final N): 157 (17 patients assigned to fish oil and 26 assigned to placebo stopped study medication prior to the end of the trial because of adverse effects or unrelated severe illness)
  • Age [mean (SD)]: Placebo, 62 (13); Fish oil, 63 (13)
  • Ethnicity: Caucasian; placebo, 97; fish oil, 94
  • Other relevant demographics: The baseline demographics of patients assigned to fish oil and those randomized to placebo were well balanced.
  • Anthropometrics: The baseline demographics of patients assigned to fish oil and those randomized to placebo were well balanced.
  • Location: Six centers across the US.

 

Summary of Results:

Baseline Characteristics

There were no significant differences in serious adverse events in patients assigned to fish oil compared with those assigned to placebo, with the possible exception of an excess of hospitalizations for neurologic events in patients assigned to placebo. 

Red Blood Cell and Plasma Omega-3 PUFA Levels

At baseline, there was no difference in plasma or red blood cell membrane plasma omega-3 fatty acids (DHA plus EPA), expressed as a percentage of total fatty acids, between patients assigned to placebo and fish oil. Baseline fatty acid levels were 1.9% in patients assigned to fish oil, rising significantly to 4.4% by one month, with no significant change thereafter through 24 months. Red blood cell membrane levels in patients assigned to fish oil rose significantly, from 4.7% at baseline to 6.8% at one month, and continued to increase to 8.3% at three months, with no significant change thereafter. Patients assigned to placebo had no significant change in plasma or red blood cell omega-3 fatty acid levels over 24 months of follow-up. Plasma and red blood cell membrane omega-3 fatty acid levels in patients assigned to fish oil were higher than levels in patients assigned to placebo at all follow-up time points (P<0.001). There was no difference over time or between groups in the plasma or red blood cell membrane levels of the two primary components of the placebo, oleic acid and palmitic acid.

Time to First Episode of VT or VF 

During follow-up, patients received ICD therapy for a total of 45 VF episodes and 901 VT episodes. Other episodes of ICD therapy included 47 for atrial fibrillation, 124 for supraventricular tachycardia, two for oversensing and 31 that could not be classified. 

 

Six months

%(%SE)

12 months

%(%SE)

24 months

%(%SE)

P-value

Percent having ICD therapy for VT and VF

 

 

 

 

     Fish oil

45(5)

51(5)

65(5)

 

     Placebo

36(5)

41(5)

59(5)

0.19

Percent of patients with qualifying arrhythmia at study entry: incidence of VT and VF treated

 

 

 

 

     Fish oil

61(6)

66(6)

79(6)

 

     Placebo

37(6)

43(6)

65(6)

0.007

Regardless of ejection fraction, the group assigned to fish oil tended to have a shorter time to first episode of ICD therapy for VT or VF than those assigned to placebo.

Given the predictive value of presenting arrhythmia on the primary endpoint, a post-hoc analysis of time to first VT and first VF episode was performed. There was a trend toward an increased risk of VT in patients assigned to fish oil but no apparent effect on the risk of VF. In multivariate analysis, an ejection fraction less than 40% (hazard ratio, 1.7; 95% CI, 1.1 to 2.5) and VT as the qualifying arrhythmia (hazard ratio, 2.0; 95% CI, 1.3 to 3.1) were the independent predictors of time to ICD therapy for VT and VF. When treatment assignment was added to this model, the fish oil group had a hazard ratio of 1.4 (95% CI, 0.96 to 2.0).

Secondary Endpoints

An actuarial analysis of the time to recurrent episodes of VT and VF (i.e., time to each day on which an arrhythmia occurred) showed a significant increase in the incidence of days with episodes of ICD therapy for VT or VF in patients assigned to fish oil (P<0.001). Patients assigned to fish oil had ICD therapy for VT and VF on a mean of 3.5 (SE, 0.6) days compared with 2.2 (0.5) days for patients assigned to placebo over the two-year study.

To investigate whether compliance may have affected the results, analyses were performed of time to first episode of VT or VF using plasma or red blood cell membrane omega-3 PUFA levels as time-dependent covariates. These analyses showed no significant association between (P>0.20) omega-3 PUFA levels and time to first episode of VT or VF. During follow-up, class I or class III antiarrhythmic medications were initiated for 12% (3%), 22% (4%) and 29% (5%) of patients assigned to fish oil at six, 12, and 24 months, respectively, compared with 13% (3%), 15% (4%) and 25% (5%) in patients assigned to placebo (P=0.45). There was no difference in the results of electrophysiologic testing between patients assigned to fish oil vs. placebo.

Author Conclusion:

This study was undertaken to better understand the previously observed reduction in sudden death mortality after myocardial infarction associated with fish oil supplementation. The fact that we were not able to demonstrate an antiarrhythmic effect of fish oil does not call into question the potential benefits of fish oil or dietary fish intake in patients who have had a myocardial infarction. Instead, our results suggest that the mechanism of benefit, if due to antiarrhythmic properties, may not be due to the suppression of reentrant VT or VF. The lack of benefit and the suggestion that fish oil supplementation may increase the risk of VT or VF in some patients with ICD can reasonably be interpreted as evidence that the routine use of fish oil supplementation in patients with ICD and recurrent ventricular arrhythmias should be avoided. 

Funding Source:
Reviewer Comments:
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? Yes
  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? Yes
  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? Yes
  6.6. Were extra or unplanned treatments described? Yes
  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? 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? 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
  8.1. 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? N/A
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