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Meta-Analysis
. 2018 Apr 1;4(4):CD000542.
doi: 10.1002/14651858.CD000542.pub3.

Enteral nutritional therapy for induction of remission in Crohn's disease

Neeraj Narula  1 , Amit Dhillon, Dongni Zhang, Mary E Sherlock, Melody Tondeur, Mary Zachos
Affiliations
Meta-Analysis

Enteral nutritional therapy for induction of remission in Crohn's disease

Neeraj Narula et al. Cochrane Database Syst Rev. .

Abstract

Background: Corticosteroids are often preferred over enteral nutrition (EN) as induction therapy for Crohn's disease (CD). Prior meta-analyses suggest that corticosteroids are superior to EN for induction of remission in CD. Treatment failures in EN trials are often due to poor compliance, with dropouts frequently due to poor acceptance of a nasogastric tube and unpalatable formulations. This systematic review is an update of a previously published Cochrane review.

Objectives: To evaluate the effectiveness and safety of exclusive EN as primary therapy to induce remission in CD and to examine the importance of formula composition on effectiveness.

Search methods: We searched MEDLINE, Embase and CENTRAL from inception to 5 July 2017. We also searched references of retrieved articles and conference abstracts.

Selection criteria: Randomized controlled trials involving patients with active CD were considered for inclusion. Studies comparing one type of EN to another type of EN or conventional corticosteroids were selected for review.

Data collection and analysis: Data were extracted independently by at least two authors. The primary outcome was clinical remission. Secondary outcomes included adverse events, serious adverse events and withdrawal due to adverse events. For dichotomous outcomes, we calculated the risk ratio (RR) and 95% confidence interval (CI). A random-effects model was used to pool data. We performed intention-to-treat and per-protocol analyses for the primary outcome. Heterogeneity was explored using the Chi2 and I2 statistics. The studies were separated into two comparisons: one EN formulation compared to another EN formulation and EN compared to corticosteroids. Subgroup analyses were based on formula composition and age. Sensitivity analyses included abstract publications and poor quality studies. We used the Cochrane risk of bias tool to assess study quality. We used the GRADE criteria to assess the overall quality of the evidence supporting the primary outcome and selected secondary outcomes.

Main results: Twenty-seven studies (1,011 participants) were included. Three studies were rated as low risk of bias. Seven studies were rated as high risk of bias and 17 were rated as unclear risk of bias due to insufficient information. Seventeen trials compared different formulations of EN, 13 studies compared one or more elemental formulas to a non-elemental formula, three studies compared EN diets of similar protein composition but different fat composition, and one study compared non-elemental diets differing in glutamine enrichment. Meta-analysis of 11 trials (378 participants) demonstrated no difference in remission rates. Sixty-four per cent (134/210) of patients in the elemental group achieved remission compared to 62% (105/168) of patients in the non-elemental group (RR 1.02, 95% CI 0.88 to 1.18; GRADE very low quality). A per-protocol analysis (346 participants) produced similar results (RR 1.04, 95% CI 0.91 to 1.18). Subgroup analyses performed to evaluate the different types of elemental and non-elemental diets (elemental, semi-elemental and polymeric) showed no differences in remission rates. An analysis of 7 trials including 209 patients treated with EN formulas of differing fat content (low fat: < 20 g/1000 kCal versus high fat: > 20 g/1000 kCal) demonstrated no difference in remission rates (RR 1.03; 95% CI 0.85 to 1.26). Very low fat content (< 3 g/1000 kCal) and very low long chain triglycerides demonstrated higher remission rates than higher content EN formulas. There was no difference between elemental and non-elemental diets in adverse event rates (RR 1.00, 95% CI 0.63 to 1.60; GRADE very low quality), or withdrawals due to adverse events (RR 1.29, 95% CI 0.80 to 2.09; GRADE very low quality). Common adverse events included nausea, vomiting, diarrhea and bloating.Ten trials compared EN to steroid therapy. Meta-analysis of eight trials (223 participants) demonstrated no difference in remission rates between EN and steroids. Fifty per cent (111/223) of patients in the EN group achieved remission compared to 72% (133/186) of patients in the steroid group (RR 0.77, 95% CI 0.58 to 1.03; GRADE very low quality). Subgroup analysis by age showed a difference in remission rates for adults but not for children. In adults 45% (87/194) of EN patients achieved remission compared to 73% (116/158) of steroid patients (RR 0.65, 95% CI 0.52 to 0.82; GRADE very low quality). In children, 83% (24/29) of EN patients achieved remission compared to 61% (17/28) of steroid patients (RR 1.35, 95% CI 0.92 to 1.97; GRADE very low quality). A per-protocol analysis produced similar results (RR 0.93, 95% CI 0.75 to 1.14). The per-protocol subgroup analysis showed a difference in remission rates for both adults (RR 0.82, 95% CI 0.70 to 0.95) and children (RR 1.43, 95% CI 1.03 to 1.97). There was no difference in adverse event rates (RR 1.39, 95% CI 0.62 to 3.11; GRADE very low quality). However, patients on EN were more likely to withdraw due to adverse events than those on steroid therapy (RR 2.95, 95% CI 1.02 to 8.48; GRADE very low quality). Common adverse events reported in the EN group included heartburn, flatulence, diarrhea and vomiting, and for steroid therapy acne, moon facies, hyperglycemia, muscle weakness and hypoglycemia. The most common reason for withdrawal was inability to tolerate the EN diet.

Authors' conclusions: Very low quality evidence suggests that corticosteroid therapy may be more effective than EN for induction of clinical remission in adults with active CD. Very low quality evidence also suggests that EN may be more effective than steroids for induction of remission in children with active CD. Protein composition does not appear to influence the effectiveness of EN for the treatment of active CD. EN should be considered in pediatric CD patients or in adult patients who can comply with nasogastric tube feeding or perceive the formulations to be palatable, or when steroid side effects are not tolerated or better avoided. Further research is required to confirm the superiority of corticosteroids over EN in adults. Further research is required to confirm the benefit of EN in children. More effort from industry should be taken to develop palatable polymeric formulations that can be delivered without use of a nasogastric tube as this may lead to increased patient adherence with this therapy.

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Conflict of interest statement

Neeraj Narula has no known declarations of interest to declare.

Amit Dhillon has no known declarations of interest to declare.

Dongni Zhang has no known declarations of interest to declare.

Mary Sherlock has served as an advisory board member for Abbvie and Jannsen and received travel expenses from Abbvie to attend an IBD meeting in 2015.

Melody Tondeur has no known declarations of interest to declare.

Walter Reinisch has served as a speaker, a consultant or an advisory board member for Abbott Laboratories, Abbvie, Aesca, Amgen, AM Pharma, Aptalis, Astellas, Astra Zeneca, Avaxia, Bioclinica, Biogen IDEC, Bristol‐Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Grünenthal, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Robarts Clinical Trial, Schering‐Plough, Setpointmedical, Shire, Takeda, Therakos, Tigenix, UCB, Vifor, Yakult, Zyngenia, and 4SC.

Mary Zachos has served as an advisory board member for Abbvie, Janssen and Ferring.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 1 Remission rate ‐ Intention‐to‐treat.
1.2
1.2. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 2 Remission rate ‐ Per‐protocol.
1.3
1.3. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 3 Remission rate ‐ sensitivity analysis excluding studies at high risk of bias.
1.4
1.4. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 4 Remission rate ‐ elemental versus polymeric enteral feeds.
1.5
1.5. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 5 Remission rate ‐ elemental versus semi‐elemental.
1.6
1.6. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 6 Remission rate ‐ sensitivity analysis elemental vs polymeric, excluding studies at high risk of bias.
1.7
1.7. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 7 Remission rate ‐ sensitivity analysis elemental vs semi‐elemental, excluding studies at high risk of bias.
1.8
1.8. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 8 Remission rate ‐ elemental vs non‐elemental enteral feeds: sensitivity analysis including abstract.
1.9
1.9. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 9 Remission rate ‐ Protein composition: polymeric vs glutamine‐enriched polymeric.
1.10
1.10. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 10 Remission rate ‐ Comparison of fat content: very low fat vs high fat.
1.11
1.11. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 11 Remission rate ‐ Comparison of fat content: low fat vs high fat.
1.12
1.12. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 12 Remission rate ‐Type of fat in non‐elemental feeds: n9 rich feeds.
1.13
1.13. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 13 Remission rate ‐ Type of fat in non‐elemental feeds: n6 rich feeds.
1.14
1.14. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 14 Remission rate ‐ Comparision of LCT content: low % LCT (<10%) vs high % LCT (>10%).
1.15
1.15. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 15 Remission rate ‐ Comparison of LCT content with alternate cut‐off (15%LCT).
1.16
1.16. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 16 Remission rate ‐ Comparison of LCT content with alternate cut‐off (5% LCT).
1.17
1.17. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 17 Adverse events.
1.18
1.18. Analysis
Comparison 1 Elemental versus non‐elemental enteral feeds, Outcome 18 Withdrawal due to adverse events.
2.1
2.1. Analysis
Comparison 2 Enteral nutrition versus corticosteroids, Outcome 1 Remission rate ‐ Intention‐to‐treat.
2.2
2.2. Analysis
Comparison 2 Enteral nutrition versus corticosteroids, Outcome 2 Remission rate ‐ Per‐protocol.
2.3
2.3. Analysis
Comparison 2 Enteral nutrition versus corticosteroids, Outcome 3 Remission rate ‐ sensitivity analysis including abstracts.
2.4
2.4. Analysis
Comparison 2 Enteral nutrition versus corticosteroids, Outcome 4 Remission rate ‐ sensitivity analysis excluding studies at high risk of bias.
2.5
2.5. Analysis
Comparison 2 Enteral nutrition versus corticosteroids, Outcome 5 Remission rate ‐ sensitivity analysis excluding trials with concurrent therapy.
2.6
2.6. Analysis
Comparison 2 Enteral nutrition versus corticosteroids, Outcome 6 Remission rate ‐ published studies only semi‐elemental diet vs steroid.
2.7
2.7. Analysis
Comparison 2 Enteral nutrition versus corticosteroids, Outcome 7 Remission rate ‐ polymeric diet vs steroids.
2.8
2.8. Analysis
Comparison 2 Enteral nutrition versus corticosteroids, Outcome 8 Remission rate ‐ elemental diet vs steroids.
2.9
2.9. Analysis
Comparison 2 Enteral nutrition versus corticosteroids, Outcome 9 Adverse events.
2.10
2.10. Analysis
Comparison 2 Enteral nutrition versus corticosteroids, Outcome 10 Withdrawal due to adverse events.
See this image and copyright information in PMC

Update of

References

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References to studies excluded from this review

Afzal 2005a {published data only}
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Akobeng 2002 {published data only}
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References to ongoing studies

NCT00265772 {published data only}
    1. NCT00265772. Phase IV Study Comparing a Nutritional Anti‐Inflammatory Treatment to Steroids for Pediatric Crohn's Disease ‐ the Molecular Basis. clinicaltrials.gov/show/NCT00265772 (accessed 3 August 2017).
NCT01728870 {published data only}
    1. NCT01728870. Comparison of Partial Enteral Nutririon (Modulen) With a Unique Diet to Exclusive Enteral Nutrition (Modulen) for the Treatment of Pediatric Crohn's Disease. A Prospective Randomized Controlled Trial. clinicaltrials.gov/show/NCT01728870 (accessed 3 August 2017).
NCT02056418 {published data only}
    1. NCT02056418. A Randomized, Controlled, Single‐blind Study of Effects of Enteral Nutrition and Corticosteroid on Intestinal Flora in Induction Remission of Crohn Disease in Adult. clinicaltrials.gov/show/NCT02056418 (accessed 23 July 2017).
NCT02231814 {published data only}
    1. NCT02231814. Pilot Study of Partial Enteral Nutrition With a Unique Diet for the Treatment of Adult Patients With Crohn's Disease. clinicaltrials.gov/show/NCT02231814 (accessed 3 August 2017).
NCT02843100 {published data only}
    1. NCT02843100. Diet for Induction and Maintenance of Remission and Re‐biosis in Crohn's Disease. clinicaltrials.gov/show/NCT02843100 (accessed 3 August 2017).
NCT03176875 {published data only}
    1. NCT03176875. Comparison of Partial and Exclusive Enteral Nutrition in the Treatment of Active Childhood‐onset Crohn's Disease. clinicaltrials.gov/show/NCT03176875 accessed 3 bAugust 2017.

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References to other published versions of this review

Zachos 2001
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