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Budesonide for induction of remission in Crohn's disease

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Abstract

Background

Corticosteroids continue to play a central role in induction of remission in active Crohn's disease. However, their use comes at a price of significant adverse effects when used repeatedly or for extended periods. Newer corticosteroid agents with limited systemic bioavailability offer a tantalizing option, if they can be shown to be efficacious and safer than conventional corticosteroids. Budesonide is the main alternative corticosteroid currently available in an enteric formulation.

Objectives

To evaluate the effectiveness of oral budesonide for the treatment of acute flares of Crohn's disease. A secondary but important endpoint was to evaluate the adverse effect profile.

Search methods

The following sources were used to search the literature for potentially relevant papers and trials.
1. A computer‐assisted search of the on‐line bibliographic database MEDLINE from 1986 onwards.
2. Hand searching the reference lists of trials and review articles identified by means of the computer‐ assisted search.
3. Proceedings from major gastrointestinal meetings were manually searched from 1990 onwards.
4. Contact with the relevant pharmaceutical companies that have been involved in the development of budesonide.

Selection criteria

Potentially relevant articles were reviewed in an independent unblinded fashion by two authors to determine if they met the criteria specified below:

1) Study population: Patients of any age with acutely active Crohn's disease, as defined by a CDAI > 150.

2) Methodology: Randomized double blind controlled trials comparing budesonide to a control treatment. Patients in the control arm may have received placebo, conventional corticosteroids, 5‐aminosalicylic acid or sulfasalazine.

3) Outcome measures: Clinical remission was the outcome measure of interest. The definition of remission was usually a CDAI < 150 by 8 to 16 weeks of therapy.

Data collection and analysis

Eligible articles were reviewed in duplicate and the results of the primary research trials were abstracted onto specially designed data extraction forms. The proportion of patients achieving remission in the active treatment and control groups of each study were derived from the data provided in the original research papers. Where possible, data were broken down based on site of disease or other strata used by the individual trials.

Statistical analysis
Data extracted from the original research articles were converted, where necessary, into individual 2 x 2 tables (remission versus no remission x budesonide versus control) for each of the individual studies. Where available, individual 2 x 2 tables for strata within studies were also used. The presence of significant heterogeneity among studies was tested for using the chi‐square test. Because this is a relatively insensitive test for the presence of heterogeneity, a p‐value of 0.10 was regarded as statistically significant. Where p < 0.10 the data from the individual studies were still combined but the pooled results were interpreted with caution. The 2 x 2 tables were synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel. A fixed effects model was used for the pooling of data. The analysis was performed initially by combining data from all trials to estimate the response rate to budesonide therapy. The analysis was also performed by combining only studies with comparable control groups.

Main results

Eight studies were deemed eligible for review.

Efficacy
Budesonide was superior to placebo for induction of remission with a pooled odds ratio for the two placebo‐controlled trials of 2.85 (95% CI 1.67 ‐ 4.87). A single trial comparing budesonide with mesalamine demonstrated an odds ratio of 2.80 (95% CI 1.50 ‐ 5.20) in favour of budesonide over mesalamine for induction of remission in active Crohn's disease. However, budesonide was inferior to conventional corticosteroids (prednisone or prednisolone) for induction of remission with a pooled odds ratio for the five trials of 0.69 (95% CI 0.51 ‐ 0.95).

Safety
The two trials comparing budesonide versus placebo (Greenberg 1994; Tremaine 2002) showed no difference between study groups for proportion of reported corticosteroid‐related adverse effects with the pooled odds ratio for both trials of 0.98 (95% CI 0.58 ‐ 1.67). Five trials comparing budesonide versus prednisone showed the budesonide study group had fewer reported corticosteroid‐related adverse effects than the prednisone study group (pooled odds ratio was 0.38 (95% CI 0.28 ‐ 0.53).

Authors' conclusions

With disease in the ileum or ascending colon, budesonide offers an effective therapy which is somewhat less efficacious but with fewer adverse effects than conventional corticosteroids (e.g. prednisone, prednisolone, or 6‐methylprednisolone).

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Plain language summary

Budesonide is effective for the treatment of active Crohn's disease

Budesonide (9 mg/day for 8 to 10 weeks) is effective for the treatment of active Crohn's disease in the terminal ileum and/or ascending colon. Budesonide is more effective than mesalamine (a 5‐ASA drug) for the treatment of active Crohn's disease. Budesonide is somewhat less effective than conventional corticosteroids (e.g. prednisone, prednisolone, or 6‐methylprednisolone) for the treatment of active Crohn's disease. However, short term treatment (8 to 10 weeks) with budesonide has fewer side effects than conventional corticosteroids. Further work is required to evaluate the long‐term consequences of continued budesonide treatment. Budesonide treatment may be appropriate for patients with previous experience with corticosteroid‐related side effects or for patients in whom potential corticosteroid‐related side effects may be of greater importance than the expected difference in effectiveness when compared to conventional corticosteroids.