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Azathioprine and 6-Mercaptopurine in Crohn Disease: A Meta-Analysis

David C. Pearson; Gary R. May; Gordon H. Fick; and Lloyd R. Sutherland
[+] Article and Author Information

From the University of Calgary, Calgary, Alberta, Canada. Requests for Reprints: Lloyd Sutherland, MD, Room 1751, Health Sciences Centre, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1 Canada. Grant Support: Dr. Pearson is a Glaxo Canada research fellow.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1995;123(2):132-142. doi:10.7326/0003-4819-123-2-199507150-00009
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Purpose: To assess the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn disease and the effectiveness of azathioprine in maintaining remission of quiescent disease.

Data Sources: Pertinent studies were selected from the MEDLINE database (1966 to May 1994), abstracts from major gastrointestinal meetings, and references from published articles and reviews.

Study Selection: Nine randomized, placebo-controlled trials of azathioprine or 6-mercaptopurine therapy were identified: Four addressed active disease, two addressed quiescent disease, and three had multiple therapeutic arms.

Data Extraction: Data were extracted by three independent observers on the basis of the intention-to-treat principle and were analyzed with logistic regression. Each study was given a quality score on the basis of predetermined criteria.

Data Synthesis: Compared with placebo, azathioprine or 6-mercaptopurine therapy had an odds ratio of response of 3.09 (95% CI, 2.45 to 3.91) in patients with active Crohn disease. When the single trial that used 6-mercaptopurine in active disease was excluded from the analysis, the odds ratio of response was 1.45 (CI, 1.12 to 1.87). No trials of quiescent disease used 6-mercaptopurine; the odds ratio of response in these trials of quiescent disease was 2.27 (CI, 1.76 to 2.93). For active disease, continuation of therapy for at least 17 weeks improved response (P = 0.03). For quiescent disease, a higher dose improved response (P = 0.008). Increased cumulative dose improved response in both groups (P < 0.001 for active disease and P = 0.01 for quiescent disease). A steroid-sparing effect was seen in active disease (odds ratio, 3.69 [CI, 2.12 to 6.42] and in quiescent disease (odds ratio, 4.64 [CI, 1.00 to 21.54]). Fistulae improved with therapy (odds ratio, 4.44 [CI, 1.50 to 13.20]). Adverse events requiring withdrawal from a trial, primarily allergy, leukopenia, pancreatitis, and nausea, were increased with therapy (odds ratio, 5.26 [CI, 2.20 to 12.60]).

Conclusions: Azathioprine and 6-mercaptopurine are effective in treating active Crohn disease and in maintaining remission. Cumulative dose was an important factor in predicting response. Adverse effects were more common among patients receiving therapy.

Figures

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Figure 1.
Odds ratio of response in randomized, controlled studies of azathioprine and 6-mercaptopurine for active disease.

The odds ratio (log scale) for each study is represented by the filled square, and the 95% CIs are represented by the horizontal bars. Values greater than 1.0 indicate a therapeutic benefit compared with placebo. The estimated common odds ratio for response was 3.09 (CI, 2.45 to 3.91). Study reference numbers are in parentheses. NCCDS = National Cooperative Crohn's Disease Study.

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Figure 2.
Odds ratio of response in randomized, controlled studies of azathioprine for maintenance therapy.

The odds ratio (log scale) for each study is represented by the filled square, and the 95% CIs are represented by the horizontal bars. Values greater than 1.0 indicate a therapeutic benefit compared with placebo. The estimated common odds ratio for response was 2.27 (CI, 1.76 to 2.93). Study reference numbers are in parentheses. NCCDS = National Cooperative Crohn's Disease Study.

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Figure 3.
Effect of cumulative dose in the therapy for active disease.

The odds ratio for each study is represented by the filled square, and the 95% CIs are represented by the vertical bars. Numbers in parentheses are the reference numbers for each study. The odds ratio of response is increased by 1.32 (CI, 1.25 to 1.38) with each 100 mg/kg body weight increase in cumulative dose.

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Grahic Jump Location
Figure 4.
Effect of cumulative dose in maintenance therapy.

The odds ratio for each study is represented by the filled square, and the 95% CIs are represented by the vertical bars. The numbers in parentheses are the reference numbers for each study. The odds ratio of response is increased by 1.19 (CI, 1.13 to 1.24) with each 100 mg/kg body weight increase in cumulative dose.

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