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• Adverse events in clinical trials with azathioprine for prevention of postoperative recurrence
  Hans Herfarth
  Published on: 3 April 2006

• Published on: 3 April 2006

  Adverse events in clinical trials with azathioprine for prevention of postoperative recurrence

  • Hans Herfarth, MD
  • Other Contributors:
    • Christine Tjaden, Milan Lukas, Florian Obermeier, Karin Dilger, Ralph Müller, Jürgen Schölmerich

  Dear Editor,

  We read with great interest the study by Ardizzone et al. (1) and the excellent review of Sands (2) commenting on the efficacy and side effects of azathioprine (AZA) in the therapy of ulcerative colitis. Ardiazonne et al. (1) observed in their investigator blinded study, which included patients with steroid dependent ulcerative colitis, more mild to moderate adverse events (AE) in azathioprine than i...

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  Dear Editor,

  We read with great interest the study by Ardizzone et al. (1) and the excellent review of Sands (2) commenting on the efficacy and side effects of azathioprine (AZA) in the therapy of ulcerative colitis. Ardiazonne et al. (1) observed in their investigator blinded study, which included patients with steroid dependent ulcerative colitis, more mild to moderate adverse events (AE) in azathioprine than in placebo treated patients (26% v 6%; p = 0.046). However, only two of 36 patients on AZA were withdrawn from the study because of AE. We would like to comment on the side effects of AZA, which we observed in a double-blind, double-dummy, randomized, prospective, multicentre study on the efficacy and safety of AZA (2.0-2.5 mg/kg/day) and mesalamine (5-ASA) (4 g/day) for prevention of postoperative endoscopic recurrence in Crohn´s disease. 79 patients (AZA: 42; 5-ASA: 37) were randomized within two weeks after surgery. TPMT genotyping was performed at baseline in order to exclude subjects with homozygous TPMT deficiency. However, the study was stopped prematurely because an interim analysis revealed that the hypothesis of superiority of AZA versus 5-ASA could not be tested with the planned sample size. In 37 patients (AZA: 18; 5-ASA: 19) who completed the study according to the protocol (treatment during one year) the primary study end point (treatment failure: severe endoscopic relapse, withdrawal due to clinical relapse or due to adverse drug reaction) was evaluated.

  Treatment failure was found to be equally high in each group (AZA: 9 of 18; 5-ASA: 9 of 19; p=1.00, two sided Fisher´s exact test). 6 of 18 patients on AZA and 2 of 19 patients on 5-ASA therapy were withdrawn because of adverse drug reactions (33% vs. 11%; p=0.12, two sided Fisher´s exact test); reasons were leukopenia/anemia (AZA: 1; 5-ASA: 1), elevated liver enzymes, arthralgia/myalgia, vomiting, abdominal pain, macroscopic fecal excretion of study medication (AZA: 1 each), and pancreatitis (5- ASA: 1). A clinical or a severe endoscopic relapse was observed in 3 of 18 patients on AZA therapy, and in 7 of 19 patients on 5-ASA therapy (17% vs. 37%; p=0.27, two sided Fisher´s exact test). Considering all 79 patients, AE were reported in about 70% of patients in each group (AZA: 29 of 42; 5-ASA: 26 of 37). Furthermore, in 3 of 42 “non-completers” an intolerable AE led to withdrawal (AZA: ileus; 5-ASA: cholezystitis, ankylosing spondylitis). Two further trials investigating the efficacy and side effects of AZA to prevent postoperative relapse of Crohn´s disease have been published recently (3, 4).

  In an open - label study by Ardizzone et al. (3), AE were observed more frequently (39% vs. 25%) in patients receiving AZA (2 mg/kg/day) than in those receiving 5-ASA (3 g/day). 15 of 69 patients in the AZA group and 6 of 69 patients in the 5- ASA group were withdrawn because of AE (22% vs. 9%; p=0.04); reasons for withdrawal were leukopenia/thrombocytopenia (AZA: 7; 5-ASA: 0), elevated liver enzymes (AZA: 4; 5-ASA: 1), pancreatitis (AZA: 3; 5-ASA: 0), epigastric intolerance (AZT: 1; 5-ASA: 2), and increased serum creatinine (AZT: 0; 5- ASA: 3). In a double-blind, placebo controlled trial by Hanauer et al. (4), 9 of 47 (19%) patients receiving a relatively low dose of 6-MP (50 mg/day), 6 of 44 (14%) patients receiving 5-ASA (3 g/day), and 4 of 40 (10%) patients on placebo were withdrawn from the study because of AE, respectively; reasons for withdrawal were diarrhea (6-MP: 2, 5-ASA: 2), leukopenia (6-MP: 2; 5- ASA: 0), alopecia (6-MP: 2; 5-ASA: 0), elevated liver enzymes (6-MP: 0; 5- ASA: 1), flatus, gastrointestinal bleeding, phlebitis (6-MP: 1 each), and allergic reaction, bowel obstruction, arthralgia (5-ASA: 1 each).

  In summary, we could not provide evidence for superiority of azathioprine over 5-ASA in our prospective clinical trial. In contrast to the above described trials we observed a higher rate of adverse drug reactions leading to withdrawal from the study in the azathioprine group. Placebo controlled trials are needed urgently to address the question of best postoperative immunosuppressive management (5). However, our observations indicate the difficulties that may arise in future trials for reaching an adequate statistical power to provide a valid answer to this question.

  References

  1. Ardizzone S, Maconi G, Russo A, et al. Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis. Gut 2006;55:47-53.

  2. Sands BE. Immunosuppressive drugs in ulcerative colitis: twisting facts to suit theories? 2006;55:437-441.

  3. Ardizzone S, Maconi G, Sampietro GM, et al. Azathioprine and mesalamine for prevention of relapse after conservative surgery for Crohn's disease. Gastroenterology 2004;127:730-40.

  4. Hanauer SB, Korelitz BI, Rutgeerts P, et al. Postoperative maintenance of Crohn's disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial. Gastroenterology 2004;127:723-9.

  5. Sandborn WJ, Feagan BG. The efficacy of azathioprine and 6- mercaptopurine for the prevention of postoperative recurrence in patients with Crohn's disease remains uncertain. Gastroenterology 2004;127:990-3.

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  Conflict of Interest:
  None declared.

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