Journal reference: Kowey PR, Reiffel JA, Ellenbogen KA, et al. Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation. JAMA 2010; 304(21): 2363-72 ^[1]

Link: http://dx.doi.org/10.1001/jama.2010.1735

Published: 15 November 2010

Evidence cookie says...

High dose omega-3 fatty acids were not associated with a benefit in prevention of recurrent symptomatic atrial fibrillation (AF). The evidence is not definitive due to the narrow range of study participants (see more below). Nevertheless, GPs should avoid recommending ω-3 FA for treatment of atrial fibrillation unless contrary compelling evidence becomes available.

Article details:

Study design:

multicentre, double-blind randomised controlled trial

Study aim:

to evaluate the safety and efficacy of prescription omega-3 fatty acids (ω-3 FA) for the prevention of recurrent symptomatic atrial fibrillation (AF)

Study conclusion:

Among participants with paroxysmal AF, 24-week treatment with prescription omega-3 compared with placebo did not reduce recurrent AF over 6 months ^[1].

Critical appraisal:

Methodology (PICO):

Participants: who was studied?

• 663 patients
• 96 US centres
• age ≥ 18 years
• diagnosis of AF, either:
  • symptomatic paroxysmal AF
    • never been treated by long term pharmacological therapy
    • never had electrical cardioversion to revert AF
  • symptomatic persistent AF
    • previously successfully treated with pharmacotherapy
    • or, electrical cardioversion
    • current in sinus rhythm
• recently of symptoms:
  • at least 1 suspected or documented episode of symptomatic AF within 3 months of screening
  • and, at least 1 ECG documented episode of symptomatic AF within 12 months of screening
• exclusion criteria:
  • permanent AF
  • secondary AF
  • current use of anti-arrhythmic therapy
  • use of amiodarone within the past 6 months
  • prior ablation therapy
  • structural cardiac disorders
• baseline characteristics:
  • 56% male
  • mean age: 60.5 years, SD 12.26 years
  • mean BMI: 30.6, SD 7.29
  • race:
    • White: 92%
    • African American: 4%
  • medications:
    • ACEI or ARB: 39%
    • statin: 45%
  • last routine manual office BP: mmHg (standard deviation)
    • systolic BP: 126.2 (15.35)
    • diastolic BP: 74.9 (9.46)

Intervention: what was the exposure?

• week 1: loading dose of 8 g/day (8 capsules) of prescription omega-3 fatty acid (ω-3 FA)
• week 2 to week 24: 4 g/day (4 capsules) of ω-3 FA
• each capsule of ω-3 FA contained:
  • 465 mg of eicosapentaenoic acid (EPA)
  • 375 mg of docosahexaenoic acid (DHA)
• 6 month follow up
  • biweekly transtelephonic monitoring was used to document asymptomatic recurrences of AF and assess symptomatic events
• once a participant experienced the primary end point, additional therapies to maintain normal sinus rhythm were allowed

Comparator: what was the control/alternative?

• placebo capsules:
  • 1 g of corn oil
• dosing regimen and follow up the same as the intervention group

Outcomes: what was measured?

primary outcome:

• first symptomatic recurrence of AF or atrial flutter, from the first dose of the study drug, in the participants categorised with paroxysmal AF

secondary outcome:

• first symptomatic recurrence of AF or atrial flutter participants categorised with persistent AF
• first symptomatic recurrence of AF or atrial flutter in all participants as one group

Are the trial results valid?

Internal validity: Wikipedia

Were there sufficient participants in the trial?

Unclear.

• calculated total of 295 primary efficacy, or 220 primary events in the paroxysmal AF participants
  • 90% power, or 80% power respectively
  • to detect a hazard ratio (HR) of 0.682 for  ω-3 FA vs placebo
• 264 primary events accumulated (less than the a priori required 295 for 90% power, but more than for 80% power)
• the calculation used an estimated AF recurrence in the placebo group of 64.4%
  • however, the actual detected recurrence rate was 48%, this reduces the power of the study
• the assumed clinically important hazard ratio size was 0.682
  • this was admitted by the authors to have been an “aggressive” target
  • if there is a real effect from ω-3 FA, it is possible that the effect size is smaller; the study may be underpowered to detect this effect
• however, the results were non-statistically favouring placebo, more participants may not have made any substantial changes in the results

Was the assignment of patients to treatment randomised?

Yes.

• a clinical research organisation generated the randomisation schedule

Were the groups similar at the start of the trial?

Yes.

• there were no substantial baseline differences between groups (see Table 1, page 2366 ^[1])

Aside from the allocated treatment, were groups treated equally?

Yes.

Were all patients who entered the trial accounted for?

Yes.

• 584 (88%) of 663 participants randomised completed the study
• similar rates of drop outs between ω-3 FA group and placebo group

Intention to treat analysis?

• No; the primary analysis was a modified intention to treat analysis
  • 47 participants’ AF classification (paroxysmal to persistent AF or vice versa) changed after randomisation following review of source documentation
  • analyses restricted to participants with at least 1 post-randomisation transtelephonic monitoring ECG data transfer
• Note: the authors claim that their results was not substantially different to a performed (but unreported) intention to treat analysis of participants as originally randomised

Were measures objective or were the patients and clinicians kept blind to which treatment was received?

Yes.

• site personnel telephoned into an interactive voice response system to obtain a randomisation number
• patients, site personnel and clinicians were blinded to treatment assignment

What were the results?

Primary outcome

first recurrence of symptomatic AF or atrial flutter in participants with paroxysmal AF (ω-3 FA compared to placebo):

• hazard ratio (HR): 1.15 (95% CI, 0.90 – 1.46), P = 0.26
• interpretation:
  • no statistically significant result demonstrating a difference between ω-3 FA and placebo

Other outcomes:

first recurrence of symptomatic AF or atrial flutter (ω-3 FA compared to placebo) in any subgroup:

• no statistically significant difference found

Will the results help me care for my patient?

External validity: Wikipedia

Are the participants different to my patient?

• the study patients were older, obese, and predominately Caucasian Americans
• they were generally healthy
• they all had milder forms of primary atrial fibrillation that did not require continuing treatment with anti-arrhythmic medications
• structural heart disease was excluded as were secondary forms of atrial fibrillation and those who received previous radiofrequency ablation
• substantial proportion were receiving ACE inhibitor or ARB and/or a statin
• thus:
  • ambiguity remains regarding the effect of ω-3 FA in combination with other anti-arrhythmic drugs
  • ambiguity remains regarding the effect of ω-3 FA in more severe forms of atrial fibrillation
  • ambiguity remains regarding the effect of ω-3 FA in non-Caucasian populations

Is the treatment feasible?

• N/A; no clinically important effect associated with the intervention was detected

Were all the clinically important outcomes considered?

• the study did not examine AF-related endpoints such as stroke or cardiovascular death

Are the treatment benefits worth the potential harms/costs?

• N/A; no clinically important effect associated with the intervention was detected

Study weaknesses (summary)

• the study did not examine AF-related end points such as stroke or cardiovascular death
• assumed estimates in calculating the number of participants for the trial likely resulted in the trial being relatively underpowered
  • there is a potential type II error
• the most appropriate loading and maintenance dose to study was not known
• dietary information on participants’ fish consumption during the trial was not collected
  • however, serum EPA and DHA levels were measured and demonstrated a very substantial difference between the ω-3 FA group and placebo group
• the data collection technique could have underestimated asymptomatic AF recurrences

Study strengths (summary)

• consistent results when analysed using:
  • the pre-specified modified intention-to-treat analysis
  • using an independent academic statistician’s analysis including participants who were previously censored from the  protocol specified analysis
  • using an intention- to-treat analysis that included all randomised patients in the groups to which they were randomised
• large dose of ω-3 FA used; even if larger doses of ω-3 FA have a real effect, the treatment would become increasing infeasible
• good randomisation and blinding design
• study identified a group of participants who might benefit from an intervention where other anti-arrhythmic drugs may not be warranted due to side-effects; this improves the study’s generalisability

Biases and conflicts of interests

• all the authors have associations with numerous pharmaceutical companies
• Kowey PR (primary author) is a consultant for ClaxoSmithKline (GSK); and receiving honouraria  from GSK.
• funding for this trial was provided by GSK (original sponsor Reliant Pharmaceuticals was acquired by GSK in 2007)
• the sponsor designed the clinical trial in collaboration with the authors
• the sponsor conducted statistical analysis, reviewed the manuscript
• the “independent statistical analysis” was also funded by GSK
• this study should be considered at risk of funding bias
  • note: GSK produces both ω-3 FA capsules and various cardiac medications

Clinical relevance to primary health care

There has been substantial interest in the use of omega-3 fatty acids (ω-3 FA) in cardiovascular medicine. Limited data from smaller trials have indicated that ω-3 FA may be a potentially effective treatment for atrial fibrillation (AF).

This study demonstrates no association between the consumption of a high dose of prescription ω-3 FA capsules and recurrence of symptomatic atrial fibrillation, in participants with paroxysmal atrial fibrillation.

Caution should be taken when generalising these findings as there was a relatively narrow range of study participants. Specifically, the participants were older, predominately Caucasian, generally well, had milder forms of primary atrial fibrillation that did not require continuing anti-arrhythmic therapy, and were free from structural heart disease.  As such, the results of the study should not be considered definitive.

Nevertheless, unless contrary compelling evidence becomes available, Australian general practitioners in the primary health care setting should not recommend the use of ω-3 FA for the treatment of atrial fibrillation.

References

1. Kowey PR, Reiffel JA, Ellenbogen KA, et al. Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation. JAMA 2010; 304(21): 2363-72

Co-author: Michael Tam