Infliximab treatment is linked to lower colectomy rates in patients with moderate to severe active ulcerative colitis, according to the results of a prespecified analysis from 2 randomized, double-blind, placebo-controlled trials reported in the October issue of Gastroenterology.
"Our purpose in this study was to see if the use of infliximab for ulcerative colitis would reduce the need for surgery," lead author William J. Sandborn, MD, from Mayo Clinic in Rochester, Minnesota, said in a news release. "We found that treatment with infliximab reduced the need for colectomy by 41% compared to patients treated with placebo."
In the Active Ulcerative Colitis Trial (ACT)-1 and ACT-2 multicenter, international trials of infliximab induction and maintenance treatment, 728 patients with moderately to severely active ulcerative colitis were randomly assigned to receive placebo or infliximab (5 or 10 mg/kg) intravenously at weeks 0, 2, and 6, then every 8 weeks through week 46 (ACT-1) or week 22 (ACT-2).
Using data from ACT-1, ACT-2, and associated sources, the investigators extracted information regarding colectomy, hospitalization, and types of surgery and procedure through 54 weeks after the first infusion. To determine time to colectomy, all data were combined in the prespecified analysis. The combined infliximab group and placebo were compared with use of the Kaplan-Meier product-limit method and log-rank test to estimate the cumulative incidence of colectomy.
"This study reports a prespecified analysis from the ACT-1 and ACT-2 data to ascertain whether infliximab reduces colectomy and hospitalization in moderate to severe ulcerative colitis in the outpatient setting," Dan Turner, MD, PhD, head of the Pediatric Gastroenterology and Nutrition Unit at Shaare Zedek Medical Center, the Hebrew University of Jerusalem in Jerusalem, Israel, told Medscape Gastroenterology when asked for independent comment. "The data of both studies have been combined in a time-to-event analysis. The study shows that patients treated with infliximab are less likely to require colectomy and hospitalization within 54 weeks of treatment."
Follow-up for colectomy was complete in 630 (87%) of 728 patients. In the remaining 13% of patients (98/728), median follow-up was 6.2 months. Through 54 weeks, the cumulative incidence of colectomy was 10% for infliximab and 17% for placebo (P = .02), with absolute risk reduction of 7%.
"One of the most feared outcomes for ulcerative colitis patients is surgical removal of the colon," Dr. Sandborn said. "Our research hopes to provide other treatment solutions for patients beyond surgery."
Patients treated with infliximab also fared better vs those receiving placebo in that they had fewer ulcerative colitis–related hospitalizations (40 vs 20; P = .003) and fewer surgeries or procedures (34 vs 21; P = .03) per 100 patient-years of treatment.
In the infliximab group, serious adverse events included serious infections, tuberculosis, histoplasmosis, listeriosis, and malignant disease.
"The results of this study bring important argument for using infliximab in moderate to severe outpatient ulcerative colitis as an induction and maintenance treatment," Dr. Turner said. "It brings to our attention that infliximab is beneficial, not only in reducing the score of clinical indices, but also in achieving a clinically important endpoint in ulcerative colitis, avoiding colectomy. This will likely support the steadily increasing use of antitumor necrosis factor therapy in ulcerative colitis, which somewhat lags after Crohn's disease."
However, Dr. Turner noted that the number needed to treat with infliximab to avoid 1 colectomy in 1 year was 15 overall and 20 in the standard 5-mg/kg group.
"Whether this and the reduced hospitalization rate outweigh the infliximab-related toxicity and cost is less certain," Dr. Turner said. "It is important to emphasize that these figures relate to outpatient patients who are at low risk for colectomy and not to those with severe disease pending colectomy who were excluded from the ACT studies and may have had higher absolute risk reduction. Colectomy should be carefully considered when initiating infliximab, [and the] predictors of colectomy, reported in this study and others, should be utilized in discussing the different alternatives at the time of infliximab initiation with the patients."
Strengths of this study noted by Dr. Turner were that it was "important, well designed and conducted" and that the findings "bring novel data important to decision making in clinical practice." In addition, the study used several rigorously collected datasets that ensured minimization of selection bias, resulting in a well-powered analysis on a homogeneous group of patients with reasonable rate of loss to follow-up.
"It is important to remember, however, that according to the eligibility criteria of the ACT studies, patients with severe disease who would have typically admitted for intravenous steroids were not included in this analysis," Dr. Turner said. "Thus, although the results of this study enforce the anecdotal knowledge that infliximab is beneficial in avoiding colectomy in ulcerative colitis, it does not necessarily prove superiority of infliximab in steroid-refractory, severe ulcerative colitis. Finally, despite the large sample size of the combined analysis, some of the subgroups in the secondary analyses are too small to draw definite conclusions."
A final caveat noted by Dr. Turner is the possibility that infliximab merely defers colectomy vs avoiding it.
"Longer studies are important to ascertain whether infliximab truly changes the natural history of the disease in the long run," Dr. Turner concluded. "Economical studies should determine the cost-effectiveness of infliximab treatment in the outpatient setting. Finally, well validated clinical rules that can predict the response to infliximab are needed for directing infliximab therapy to a selected group of patients who will benefit the most from the drug."
Dr. Sandborn provided consulting services for Centocor during the course of this research and received no personal compensation. Mayo Clinic received reimbursement for the services provided by Dr. Sandborn. Dr. Turner has disclosed no relevant financial relationships with Centocor in the last 2 years.
Medscape Medical News by Laurie Barclay, M.D., 10/14/09