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Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn's disease

  1. Raffi Lev-Tzion1,*,
  2. Anne Marie Griffiths2,
  3. Oren Ledder1,
  4. Dan Turner1

Editorial Group: Cochrane IBD Group

Published Online: 28 FEB 2014

Assessed as up-to-date: 22 NOV 2013

DOI: 10.1002/14651858.CD006320.pub4


How to Cite

Lev-Tzion R, Griffiths AM, Ledder O, Turner D. Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn's disease. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD006320. DOI: 10.1002/14651858.CD006320.pub4.

Author Information

  1. 1

    Shaare Zedek Medical Center, Pediatric Gastroenterology Unit, Jerusalem, Israel

  2. 2

    The Hospital for Sick Children, Division of Gastroenterology, Hepatology & Nutrition, Toronto, ON, Canada

*Raffi Lev-Tzion, Pediatric Gastroenterology Unit, Shaare Zedek Medical Center, Jerusalem, Israel. raffilv@szmc.org.il.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 28 FEB 2014

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Characteristics of included studies [ordered by study ID]
Belluzzi 1996

MethodsDouble blind, placebo-controlled trial


ParticipantsN = 39 in each arm

All patients had CDAI < 150 at baseline with an increase in inflammatory markers


InterventionsEnteric coated, n-3 as timed release fatty acids (1.8 g/day of EPA, 0.9 g/day of DHA) versus identical placebo of 500 mg Miglyol 812


OutcomesRelapse rates over 1 year

Adverse events
Time to first relapse


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskBalanced block randomization scheme

The method of randomization was not described

Allocation concealment (selection bias)Unclear riskThe method of allocation concealment was not described

Blinding (performance bias and detection bias)
All outcomes
Low riskThe study medications were packed identically and labelled with each patient’s code number

There was no difference in odor between the fish-oil and placebo preparations, provided the capsules were not broken

Incomplete outcome data (attrition bias)
All outcomes
High riskParticipants who withdrew due to diarrrhea were not included in the relapse rate calculation and it is unclear whether they were included in lab results at the end of the study

Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Other biasLow riskThe study appears to be free of other sources of bias

Belluzzi 1997

MethodsDouble blind, placebo- controlled trial


ParticipantsN = 26 in the intervention arm and 24 in the control arm

Patients in remission one month following ileal resection


InterventionsEnteric coated, n-3 as timed release fatty acids (1.8 g/day of EPA, 0.9 g/day of DHA) versus identical placebo of 500 mg Miglyol 812


OutcomesClinical and endoscopic relapse rates over 1 year


NotesPublished in abstract form


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThe random list was prepared by the pharmacist of the company producing the product using a balanced block randomization scheme

The method of randomization was not described

Allocation concealment (selection bias)Low riskCentrallized pharmacy randomization

Blinding (performance bias and detection bias)
All outcomes
Low riskThe study medications were packed identically and labelled with each patient’s code number

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskOnly 16/26 in the n-3 arm and 15/24 in the control arm were assessed for the primary outcome (endoscopic recurrence) This might be due to exclusion of patients with clinical relapse but no explanation was given

Selective reporting (reporting bias)Low riskExpected outcomes were reported

Other biasLow riskThe study appears to be free of other sources of bias

Feagan 2008a

MethodsDouble blind, placebo-controlled trial (EPIC-1)


Participantsn = 183 in the intervention arm and 180 in the control arm

CDAI < 150 for at least three months and at least one exacerbation within the previous year


InterventionsEnteric coated, n-3 as timed release fatty acids (2.2 g/day of EPA, 0.8 g/day of DHA) versus identical placebo of 4 g/day medium-chain triglyceride oil

No new medications were allowed after randomization


OutcomesTime to relapse

1 year relapse rate

Adverse events

Change in CDAI

Change in SF-36


NotesBoth EPIC-1 and EPIC-2 were reported in one manuscript of Feagan 2008


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskEligible patients were randomly assigned, in a 1:1 ratio using a random number generator

Allocation concealment (selection bias)Low riskBoth studies used a central randomization procedure

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo

Neither the investigators nor the patients were aware of the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs balanced across intervention groups with similar reasons for withdrawal

Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Other biasLow riskThe study appears to be free of other sources of bias

Feagan 2008b

MethodsDouble blind, placebo- controlled trial (EPIC-2)


Participantsn = 187 in the intervention arm and 188 in the control arm

Steroid induced remission with CDAI < 150 after 8 weeks of treatment


InterventionsSimilar to the EPIC-1 trial; corticosteroids were tapered off over 8 weeks from randomization


OutcomesSame as for EPIC-1 above


NotesBoth EPIC-1 and EPIC-2 were reported in one manuscript (Feagan 2008)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskEligible patients were randomly assigned, in a 1:1 ratio using a random number generator

Allocation concealment (selection bias)Low riskBoth studies used a central randomization procedure

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo

Neither the investigators nor the patients were aware of the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs balanced across intervention groups with similar reasons for withdrawal

Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Other biasLow riskThe study appears to be free of other sources of bias

Lorenz-Meyer 1996

MethodsDouble blind, placebo-controlled trial


ParticipantsN = 70 in the intervention arm and 65 in the control arm

CDAI < 150 at baseline

Patients on a diet low in arachidonic acid and rich in fiber


InterventionsNon-enteric coated, n-3 as ethylesther (3.3 g/day of EPA and 1.8 g/day of DHA) versus identical placebo of corn oil


OutcomesRelapse rates over 1 year

Adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo of corn oil

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe study had a high drop-out rate, but the drop-out appeared to be balanced: 8/70 (11%) in the intervention arm and 7/65 (11%) in the control arm

Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Other biasLow riskThe study appears to be free of other sources of bias

Romano 2005

MethodsDouble blind, placebo-controlled trial


ParticipantsN = 18 in the intervention arm and 20 in the control arm

PCDAI < 20 at baseline


InterventionsEnteric coated n-3 as triglycerides (1.2 g/day of EPA and 0.6 g/day of DHA) versus placebo of olive oil

Both groups received 5-ASA (50 mg/kg/day)


OutcomesRelapse rates over 1 year

Time to first relapse


NotesPediatric study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot described

Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-out rate not specifically reported, but there appear to have been no drop-outs

Selective reporting (reporting bias)High riskLaboratory testing was performed as specified in the methods section, but no results are reported

Other biasLow riskThe study appears to be free of other sources of bias

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Bamba 2003Study enrolled patients with active Crohn's disease

Bjorkkjaer 2004N-3 treatment was for less than 6 months

Eivindson 2005Study enrolled patients with active Crohn's disease

Geerling 2000N-3 treatment was for less than 6 months

Lorenz 1989Study enrolled both patients with active and non-active Crohn's disease

Attempts to obtain data from the authors on the inactive patients only were unsuccessful

Mate 1991Non-randomized study

Nielsen 2005Study enrolled patients with active Crohn's disease

Sakurai 2002Study enrolled patients with active Crohn's disease

Seidman 2003Study enrolled patients with active Crohn's disease

Socha 2002Study enrolled patients with active Crohn's disease

Trebble 2004Study enrolled patients with active Crohn's disease

Trebble 2005Study enrolled patients with active Crohn's disease

Tsujikawa 2000Non-randomized study

 
Comparison 1. Omega-3 versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Relapse rate at one year (all studies)61039Risk Ratio (M-H, Random, 95% CI)0.77 [0.61, 0.98]

 2 Relapse rate at one year (enteric coated studies)5904Risk Ratio (M-H, Random, 95% CI)0.71 [0.54, 0.93]

 3 Relapse rate at one year (sensitivity analysis of Belluzi 1996)5904Risk Ratio (M-H, Random, 95% CI)0.77 [0.64, 0.93]

 4 Relapse rate at one year (enteric coated - risk difference)5904Risk Difference (M-H, Random, 95% CI)-0.17 [-0.30, -0.04]

 5 Relapse rate at one year (sensitivity analysis - excluding abstract study)4854Risk Ratio (M-H, Random, 95% CI)0.72 [0.54, 0.96]

 6 Relapse rate at one year (sensitivity analysis - excluding pediatric study)4866Risk Ratio (M-H, Random, 95% CI)0.71 [0.50, 1.01]

 7 Relapse rate at one year (all studies, rate in EPIC studies by survival estimates)61039Risk Ratio (M-H, Random, 95% CI)0.81 [0.66, 1.00]

 8 Relapse rate at one year (only EPIC studies)2738Risk Ratio (M-H, Random, 95% CI)0.88 [0.74, 1.05]

 9 Relapse at one year, survival analysis (Hazard Ratios of the EPIC studies)2hazard ratio (Random, 95% CI)0.87 [0.69, 1.09]

 10 Adverse events rate: Diarrhea4862Risk Ratio (M-H, Random, 95% CI)1.36 [1.01, 1.84]

 11 Adverse events rate: Upper GI symptoms (nausea, vomiting, halitosis, heartburn, dyspepsia, disgeusia and bloating)5999Risk Ratio (M-H, Random, 95% CI)1.65 [1.25, 2.18]

 
Summary of findings for the main comparison.

n-3 therapy compared with placebo for maintaining remission in CD

Patient or population: Crohn's disease patients in remission

Settings: adult and pediatric outpatient gastroenterology and IBD centers, single-center and multicenter; not stated in one study (Belluzzi 1997).

Intervention: n-3 or fish oil capsules

Comparison: placebo capsules

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

placebon-3 or fish oil capsules

Relapse rate at one year (all studies)Study populationRR 0.77

(0.61 to 0.98)
1039
(6 studies)
⊕⊝⊝⊝
very low2,3,4

471 per 10001363 per 1000
(287 to 462)

Relapse rate at one year (sensitivity analysis of Belluzi 1996)Study populationRR 0.77 (0.64 to 0.93)904
(5 studies)
⊕⊝⊝⊝
very low3,4,5

459 per 1000353 per 1000
(294 to 462)

Relapse rate at one year (only EPIC studies)Study populationRR 0.88 (0.74 to 1.05)738
(2 studies)
⊕⊕⊕⊝
moderate6
Well-designed and implemented studies, larger than all other studies combined

424 per 1000373 per 1000
(314 to 445)

Adverse events rate-DiarrheaStudy populationRR 1.36 (1.01 to 1.84)862
(4 studies)
⊕⊕⊕⊝
moderate7

140 per 1000190 per 1000
(141 to 258)

Adverse events rate- Upper GI (nausea, vomiting, halitosis, heartburn, dyspepsia, dysgeusia and bloating)Study populationRR 1.98 (1.38 to 2.85)999
(5 studies)
⊕⊕⊕⊝
moderate8

123 per 1000244 per 1000
(170 to 351)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio;RD: Risk Difference;OR: Odds Ratio; HR: Hazard Ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 The control group risk estimate comes from the control arm of the included studies.
2 Significant unexplained heterogeneity.
3 Likely publication bias is indicated by the absence of negative small studies.
4 Two of the studies in the analysis were at high risk of bias due to incomplete outcome data and selective reporting.
5 Sparse data (374 events).
6 Sparse data (294 events).
7 Sparse data (144 events).
8 Sparse data (167 events).
 
Table 1. Adverse events that were different between the intervention and control arms

StudyBelluzzi 1996Lorenz-Meyer 1996Romano 2005Feagan 2008; EPIC 1Feagan 2008; EPIC 2

Diarrhea -intervention vs control4/39 (10%) vs. 1/39 (3%)1/70 (1%) vs. 1/65 (2%)0/18 (0%) vs. 0/20 (0%)35/187 (19%) vs. 21/184 (11%)44/189 (23%) vs 37/188 (20%)

Halitosis, or heartburn -intervention vs control0/39 (0%) vs. 0/39 (0%)10/70 (14%) vs. 2/65 (3%)0/18 (0%) vs. 0/20 (0%)not reported but dysgeusia: 2/187 (1%) vs 1/184 (0.5%)not reported but dysgeusia: 10/189 (5%) vs. 2/188 (1%)

Nausea -intervention vs control0/39 (0%) vs. 0/39 (0%)0/70 (0%) vs. 0/65 (0%)0/18 (0%) vs. 0/20 (0%)17/187 (9%) vs. 4/184 (2%)30/189 (16%) vs. 19/188 (10%)

All upper GI symptoms -intervention vs. controls (halitosis, nausea, vomiting, dyspepsia, dysgeusia and bloating)0/39 (0%) vs. 0/39 (0%)10/70 (14%) vs. 2/65 (3%)0/18 (0%) vs. 0/20 (0%)27/187 (14%) vs..12/184 (6.5%)67/189 (35.5%) vs. 45/188 (24%)