Journal reference: Galan P, Kesse-Guyot E, Czernichow S, et al. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. BMJ 2010; 341:c6273 ^[1]

Link: http://dx.doi.org/10.1136/bmj.c6273

Published: 29 November 2010

Evidence cookie says...

B-vitamin and low dose omega-3 fatty acid supplements are not associated with better vascular outcomes in people with ischaemic heart disease and stroke. The routine use of these interventions for secondary prevention of cardiovascular disease is not supported by the evidence base. Clinical attention should be directed at known efficacious therapies that lower cardiovascular risk. Note: the study findings are likely applicable within some limitations. See below for more details.

More details:

Article details

Study design:

multicentre, double blind, randomised controlled trial

Study aim:

to investigate whether dietary supplements of B-vitamins (folate, vitamin B6, and vitamin B12) or omega-3 fatty acids (eicosapentanoic acid and docosahexaenoic acid), or both, could prevent cardiovascular events in patients with a history of ischaemic heart disease or stroke

Methods summary:

• large French study: Supplémentation en Folates et Omega-3 (SU.FOL.OM3) trial
• recruitment through a network of cardiologists, neurologists and other physicians at 257 centres throughout France
• between 1 February 2003 and 1 June 2007
• inclusion criteria:
  • aged 45-80 years
  • acute coronary event within 12 months prior to randomisation
  • or cerebral ischaemic event with the prior 12 months
• exclusion criteria:
  • age < 45 years or > 85 years
  • ill defined diagnosis of cardiovascular disease
  • inability or unwillingness to comply with study treatment
  • diseases or treatment that might interfere with metabolism of homocysteine or omega-3 (ω-3) fatty acids
    • treatment with methotrexate
    • chronic renal failure (plasma creatinine > 200 μmol/L or creatine clearance < 40 mL/min
• randomisation:
  • computerised block sequence stratified by three age groups, sex, prior disease at enrolment, and recruitment centre
  • participants were randomly assigned (in the blocks) to receive:
    • B-vitamins alone
      • 5-methyltetrahydrofolate (5-methyl-THF) 560 μg
      • vitamin B6 3 mg
      • vitamin B12 20 μg
    • ω-3 fatty acids alone
      • 600 mg
      • eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) at 2:1 ratio
    • both treatments
    • double placebo
• blinding:
  • patients, clinicians, trial coordinators and outcome investigators were blinded to treatment allocation
  • participant allocation and study treatment provision was managed by a statistical coordinating centre
  • study treatment was given in the form of two capsules to be taken daily
• assessment:
  • 6 monthly mailed questionnaires to participants
  • non-mandatory visit scheduled annually
  • participants unwilling or unable to attend and did not return questionnaires were telephoned by study physicians
  • participant GPs, cardiologists and neurologists were asked to report any relevant health events 6 monthly
  • where any possible event was suspected, the investigators sought all relevant medical records for review
  • treatment compliance by self reported questionnaires
  • blood samples:
    • all participants at baseline (2501)
    • a sample of participants at 12 months (2147)
    • a sample of participants at end of the trial (1160)
• outcomes:
  • primary outcome:
    • first major cardiovascular event
      • non-fatal myocardial infarction
      • stroke
      • sudden death within one hour of onset of acute symptoms in the absence of violence or accident
      • aortic dissection
  • secondary outcomes:
    • acute coronary syndrome without myocardial infarction
    • coronary revascularisation procedure (coronary artery bypass graft or angioplasty)
    • cardiac arrhythmia
    • cardiac failure
    • cardiac surgery of any kind
    • transient ischaemic attack (TIA)
    • deep vein thrombosis (DVT)
    • pulmonary embolism (PE)
    • carotid artery surgery or angioplasty
    • peripheral artery surgery or angioplasty
    • any vascular procedure
    • all cause mortality
  • all events were adjudicated by two independent committees of cardiologists and neurologists (blinded to treatment allocation)
• statistical analysis:
  • power calculation made a priori
    • planned enrolment of 2500 participants with average follow-up of 5 years
    • > 90% power to detect a 10% reduction in the relative risk of major vascular events associated with B-vitamins or ω-3 fatty acids
  • participants contributed person time up to (whichever was first):
    • date of diagnosis of primary outcome
    • or, date of last completed questionnaire
    • or, 1 July 2009
  • intention to treat analyses

Results summary:

• 3374 assessed for eligibility → 2501 randomised
  • of the 873 not included:
    • 337 did not meet inclusion criteria
    • 536 refused to participate (~18% of those who met inclusion criteria)
  • a further 145 patients withdrew consent or were lost to follow up
  • that is, about 78% of the participants who met inclusion criteria reached the end of the trial
• 2501 randomised were divided evenly between the 4 treatment groups
• no significant differences in baseline characteristics
• high level of compliance for the returned questionnaires: ≥ 94% at 6, 12, 24 months and end of trial
• 86% of those who returned the questionnaire reported compliance with study treatment (≥ 80% of the allocated treatment)
• mean 4.2 years of follow up
  • this was less than the planned average length of follow up (5 years)

Primary endpoint:

• 6.3% of participants experienced the primary outcome (major cardiovascular event)
  • 6.1% of the participants in the placebo group
  • this was less than the estimation used in the power calculation (8.7%)
• allocation to B-vitamins was not associated with any significant effect on the primary endpoint
• allocation to ω-3 fatty acids was not associated with any significant effect
• the combination was not associated with any significant effect

Secondary endpoints:

• allocation to B-vitamins was associated with:
  • fewer stroke events:
    • hazard ratio (HR) = 0.57 (95% CI, 0.33-0.97), P = 0.04
  • higher risk of all cause mortality:
    • HR 1.55 (95% CI 1.07-2.25), P = 0.02
• allocation to ω-3 fatty acids had no significant effect on any secondary endpoints

B-vitamin and ω-3 fatty acids on blood profiles:

• allocation to B-vitamins:
  • ↓ 19% homocysteine compared to placebo at end of trial
  • ↑ 146% serum folate
  • ↑ 35% serum vitamin B12
  • ↑ 116% plasma vitamin B6
• allocation to ω-3 fatty acids:
  • ↑ 37% in plasma concentrations at one year compared to placebo

Study conclusion:

This study does not support the routine use of dietary supplements containing B vitamins or omega 3 fatty acids for prevention of cardiovascular disease in people with a history of ischaemic heart disease or ischaemic stroke, at least when supplementation is introduced after the acute phase of the initial event.

Participants:

• study performed in France – ethnic Western European
• 2501 participants randomised of 3374 assessed
  • 1987 (79%) men
  • 514 (21%) women
• age:
  • men: mean 60.9 years, SD 8.8 years
  • women: mean 63.2 years, SD 9.7 years
• prior conditions:
  • 1150 (46%) myocardial infarction
  • 713 (28%) acute coronary syndrome without myocardial infarction
  • 638 (26%) ischaemic stroke
• median time between prior acute event and randomisation was 101 days
• median follow-up time was 4.7 years (mean 4.2 years, SD 1.0 years)
• baseline characteristics
  • balanced across all four study groups
  • current smokers ~ 11%
  • former smokers ~ 61%
  • BP ~ 131/82
  • BMI ~ 27.2
  • lipid lower agents ~ 85%
  • aspirin or antiplatelet agents ~ 94%
  • total cholesterol ~ 4.5 mmol/L
  • HDL cholesterol ~ 1.2 mmol/L
  • LDL cholesterol ~ 2.7 mmol/L

Methodological weaknesses

• the study does not clearly describe the recruitment procedure apart from that it was through a “network of cardiologists, neurologists and other physicians” ^[1]
  • the median time between prior acute event and randomisation was 101 days; this suggests that patients were assessed for eligibility during follow up/rehabilitation period of the acute event, but this is a supposition only
  • it is possible that there is an unknown/undescribed recruitment bias that threatens the external validity of the findings
• the study was underpowered for the primary outcome:
  • mean follow up achieved was 4.2 years (power calculated planned for 5 years)
  • the primary outcome occurred less frequently than expected, 6.1% of the participants in the placebo group (power calculated based on estimation of 8.7% in the placebo group)
  • relatively wide confidence intervals
• blood tests:
  • it was performed in only a subset of the participants at 12 months and at end of trial; presumably on those who attended clinic follow up
    • it is possible that these patients were also more compliant in taking their study medication and thus the blood profiles are not representative of those of the entire cohort
  • blood tests for ω-3 fatty acids were only performed at baseline and at 1 year
    • there are no objective measures to confirm medication compliance or whether the supplement had a significant effect on plasma ω-3 fatty acid levels by the end of trial
• the 6 monthly self-reported questionnaires are subject to recall bias
• the dose of EPA and DHA used in the ω-3 fatty acid groups (600 mg total) is relatively low
• the study does not provide evidence on whether starting secondary prevention with B-vitamins or ω-3 fatty acids in the acute period has any effect
• few women in the study; limited conclusions can be made about these interventions in women

Methodological strengths

• rigorous randomisation and blinding procedure
• high reported level of compliance with return of questionnaires and consumption of the study medication
• few patients lost to follow up
• study performed in a population with widespread folate fortified foods or consumption of folate supplements
• use of a more naturally occurring form of folate (5-methyl-THF)
• demonstration of effect of both folate and ω-3 fatty acids in blood profiles

Biases and conflicts of interests

• potential conflicts of interest: supplements provide free of charge by the following companies:
  • Merck Eprova AG: 5-methyltetrahydrofolate
  • Roche Laboratory: vitamins B6 and B12
  • Pierre Fabre: ω-3 fatty acids
• no other obvious conflicts of interests declared by the authors

Clinical relevance to primary health care

This was a well conducted study on whether there is an effect of B-vitamins and omega-3 (ω-3) fatty acids on major vascular outcomes in a population with previous ischaemic heart disease or stroke. The number of participants and the length of the trial limits its statistical power. Nevertheless, the cautious conclusion made by the study authors appears to be valid and can be generalised to the primary health care population with some caveats. This study does not support the use of B-vitamins or ω-3 fatty acids as a form of secondary prevention for ischaemic heart disease and stroke.  The caveats:

• the study does not have sufficient power to detect a relative risk benefit from either interventions of a magnitude of 10% or less
• the study does not provide any evidence on the use of higher doses of ω-3 fatty acids
• the study does not provide any evidence on the use of these interventions for secondary prevention commencing in the acute period
• caution must to taken in generalising the results to women due to the low number of female participants

In the analysis of secondary endpoints, participants allocated to the B-vitamins arm were associated with few strokes but a higher total mortality. These results are of unclear clinical significance given the relatively small number of patients who had these outcomes. Furthermore, these results need to be taken in the context of existing results from larger studies designed to examine B-vitamins, stroke and mortality; a recent meta-analysis of studies that lowered homocysteine with B-vitamins did not find an effect on vascular outcomes or all-cause mortality ^[2].

For the Australian general practitioner in the primary health care setting, there is little evidence that B-vitamin supplements or low dose of ω-3 fatty acids (in the order of one fish-oil capsule a day) are useful for secondary prevention of cardiovascular disease. Neither intervention can be supported. Clinical attention should be directed instead at known efficacious therapies that lower cardiovascular risk.

References

1. Galan P, Kesse-Guyot E, Czernichow S, et al. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. BMJ 2010; 341:c6273
2. Clarke R, Halsey J, Lewington S, et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37,485 individuals. Arch Intern Med. 2010;170(18):1622-1631