Is Keeping the Colon the Ultimate Marker of Success in Ulcerative Colitis?
Article Outline
See “Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab,” by Sandborn WJ, Rutgeerts P, Feagan BG, et al, on page 1250.
The chronic, relapsing nature of ulcerative colitis (UC) imparts substantial morbidity and decline in health-related quality of life. The advent of anti-tumor necrosis factor (TNF) therapy has revolutionized medical therapy in the inflammatory bowel diseases. Infliximab, which was introduced for the medical management of Crohn's disease in 1998, has efficacy in inducing and maintaining clinical remission in moderate-to-severe UC.1 Over the last several years, infliximab has gained increasing use as an alternative to cyclosporine and surgery for the management of steroid-refractory severe and fulminant UC.2 However, determining the place of anti-TNF therapy in the overall hierarchy of medical therapy in UC necessitates exploring infliximab's potential impact on a broader spectrum of long-term outcomes, including colectomy and hospitalization.
The influence of infliximab on long-term need for colectomy remains largely unknown. In recent population-based studies, between 9% and 21% of UC patients eventually underwent proctocolectomy over a 10-year course of disease.3, 4, 5 Proctocolectomy is considered curative, and ileal pouch anal anastomosis (IPAA), the procedure of choice, frequently leads to improvement in quality of life.6, 7 However, with its multitude of complications, IPAA is hardly the ideal panacea. The 10-year cumulative rates of pouchitis and small bowel obstruction are 48% and 22%, respectively.8 Over 10 years, as many as 8%–10% of IPAA recipients develop chronic complications that require pouch excision or defunctioning ileostomy.9 The pouch procedure may increase the risk of infertility by 3-fold, and thus may have devastating consequences for women of child-bearing age.10 The risk of colectomy without IPAA does not confer the same degree of fertility reduction. Nonetheless, a medical alternative to surgery or one that delays the need for surgery, while minimizing adverse effects, remains highly desirable. Corticosteroids and cyclosporine and infliximab, in steroid-refractory cases, can delay surgery during hospitalization for an acute flare, but nearly a half of these patients ultimately require colectomy during long-term follow-up.11, 12 Thus, until now, there have been no data to suggest that medical therapy is able to avert surgery in UC.
In this issue of Gastroenterology, investigators from the ACT-1 and ACT-2 multicenter trials report long-term data on colectomy and hospitalizations among patients with moderate-to-severe UC randomized to infliximab (either 5 or 10 mg/kg) or placebo.13 Over a 54-week follow-up period, there was a 7% absolute reduction in risk of colectomy in the infliximab versus placebo group (10% vs 17%, respectively). The study also demonstrated that patients receiving infliximab compared with placebo had lower rates of UC-related hospitalizations (20 vs 40 per 100 patient-years) and surgeries or procedures (21 vs 34 per 100 patient-years) during this same period.
This study is the first to present prospective data on colectomy outcomes associated with infliximab use in UC. The authors are to be congratulated on their excellent follow-up data. In any study, following patients longer than a few months presents significant logistical challenges. The authors report complete data on 87% of study subjects through 54 weeks. Given the large number of study subjects across several centers, this is quite an achievement. Thus, we have what seems to be striking and statistically significant results. However, do these new findings provide enough evidence to change current approaches to treatment in UC?
It is important to note that this study population was deliberately selected to be a group that was at relatively low risk for colectomy, which was not the study's primary end point. Consequently, the number needed to treat (NNT) with infliximab to prevent 1 colectomy during the 54-week study period was 14. Although this NNT is acceptable, it is higher than the 3–4 needed to treat with infliximab to achieve a clinical response in the same study population.1 Moreover, if the 95% confidence interval for colectomy (0.01–0.12) is considered, the true reduction in absolute risk lies somewhere between 1% and 12%. The clinician is left to determine if a reduction in colectomy in this range is adequate to recommend this treatment, especially given that another treatment option, colectomy, is widely available with demonstrated efficacy.
Unanswered in this study is the hypothesis generating question (from their subgroup analysis) as to whether this effect was due largely to patients treated with high-dose (10 mg/kg) infliximab. What dose of infliximab should be used? Should 5 mg/kg be recommended as a starting with escalation to 10 mg/kg if no treatment response is achieved, or should the 10 mg/kg dose be used to provide the (potential) greatest chance for improvement? The cost considerations with a doubling of drug costs at the higher dose are considerable, particularly when one considers the NNT of 14 to prevent 1 colectomy. Moreover, if the confidence interval is used as a best and worst case scenario, the NNT could be as low as 8 or as high as 100! This study provides data for effect at 54 weeks. In this chronic disease, patients embarking on this therapy may remain on it for many years. Data are not yet available on the safety and efficacy of open-ended infliximab use in UC.
In this low-risk (for colectomy) UC population, maintaining and achieving disease remission seems to be a much more powerful driving force for using infliximab than preventing colectomy. Additionally, infliximab may have a much greater impact on preventing colectomy among hospitalized patients with severe or fulminant UC. Because its side effect profile is more favorable than that of cyclosporine, it has a burgeoning role in the inpatient treatment of severe and fulminant colitis. Unfortunately, prospective colectomy outcomes in this population are lacking. Retrospective data assessing the impact of infliximab treatment in severe or fulminant colitis have failed to show efficacy after 1 year of follow-up.11 These studies were limited by small sample size and potential treatment selection bias. However, the results from the current study, given the fundamentally lower risk of colectomy in the study population compared with hospitalized patients, cannot be generalized to acute or fulminant colitis.
The choice of colectomy as an end point is an attractive, quantifiable, and objective outcome when assessing interventions for UC; unlike disease activity, which fluctuates instantaneously over time, it is a more cumulative measure reflecting how well the disease has been controlled over longer periods of time. There are, however, several caveats to using colectomy as a measure of effectiveness. First, the indication for colectomy in UC is most frequently refractory chronic active disease.14 Therefore, most colectomies for UC are inherently elective or semi-elective. Colectomy is curative and therefore a reasonable alternative to life-long medical therapy. This is in contrast with Crohn's disease, where the indication for surgery is typically undertaken when other medical alternatives are no longer available. Even among acutely ill hospitalized UC patients, a nationwide analysis from the United States has shown substantial geographic variation in the rates of in-hospital colectomy, suggesting a degree of subjectivity in the decision-making process.15 Thus, in addition to infliximab's efficacy, other factors such as patient and physician preference and accessibility to expert surgeons may also significantly contribute toward the decision of whether or not to undergo colectomy. Although the follow-up data from ACT-1 and ACT-2 demonstrate infliximab's modest efficacy in reducing colectomy, it does not capture the essence of patient and physician preference.
This most recent report from the ACT-1 and ACT-2 studies also raises the issue of infliximab's potential role as a first-line agent in the treatment of moderate-to-severe UC. Currently, corticosteroid therapy followed by maintenance therapy, often with azathioprine or 6-mercaptopurine, is considered by most to be the initial first-line therapy in moderate-to-severe UC.16 However, demonstration of reduction of colectomy and health resource utilization is a distinct advantage infliximab has over azathioprine. These health outcomes are, however, insufficient to support a paradigm shift toward earlier infliximab use in moderate-to-severe UC owing to many of the limitations associated with colectomy as an end point. The ability to achieve and maintain remission remains the primary goal of medical therapy. We need to await the completion of the UC-SUCCESS trial, comparing infliximab and azathioprine combination therapy with infliximab and azathioprine monotherapy to establish the optimal timing to initiate anti-TNF therapy.
How might the results from this study be used to counsel a patient? Given a patient with characteristics similar to those in the study, the 1-year risk of needing a colectomy is around 17%. Treatment with infliximab compared with a placebo reduces this risk to 10%. It would take treating 14 similarly affected patients to prevent 1 colectomy. The risks of rare, serious adverse outcomes (infection, cancer, or demyelinating disease) with this treatment must be discussed and balanced with the potential benefits. In addition, the cost and risks associated with no treatment remain significant, including the need for hospitalization and/or colectomy. Costs savings from decreased health utilization need to be weighed against the costs of infliximab in future studies using formal costs and cost-effectiveness analyses.
It remains important to remember that colectomy is not necessarily a bad outcome in UC. Patients with UC and an intact colon remain at future increased risk for colorectal cancer. Moreover, this 1-year study does not define overall patient risk for the future development of medication-related side effects, including serious infections and/or other, nongastrointestinal cancers. The clinician is left to balance the benefits, costs, and risks of long-term infliximab treatment with those of colectomy. These deficiencies underscore the importance of population-based inflammatory bowel disease registries and health administrative data in assessing population health outcomes such as colectomy over follow-up periods much longer than 1 year. Although these observational studies are susceptible to a multitude of biases, health outcomes researchers are developing innovative analytic techniques to circumvent these limitations.17 Importantly, their purpose should be to complement and not supplant data from randomized clinical trials.
The current study provides objective data showing that infliximab reduces the need for colectomy in outpatients with moderate to severe UC over a period of 1 year. Future studies are needed to determine the infliximab dose most appropriate to achieve this end point, establish the durability of this improvement, and define the economics of long-term infliximab use in UC. The current study supports the use of infliximab in outpatients with moderate-to-severe UC for reducing need for colectomy. The question remains, is colectomy the enemy in UC?
References
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- Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology. 2005;128:1805–1811
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- J ileal pouch-anal anastomosis for chronic ulcerative colitis: complications and long-term outcome in 1310 patients. Br J Surg. 1998;85:800–803
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- Three-fold increased risk of infertility: a meta-analysis of infertility after ileal pouch anal anastomosis in ulcerative colitis. Gut. 2006;55:1575–1580
- Colectomy rate in acute severe ulcerative colitis in the infliximab era. Dig Liver Dis. 2008;40:821–826
- Colectomy rate in steroid-refractory colitis initially responsive to cyclosporin: a long-term retrospective cohort study. BMC Gastroenterol. 2007;7:13;13
- Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab. Gastroenterology. 2009;137:1250–1260
- Inflammatory bowel disease characteristics among African Americans, Hispanics, and non-Hispanic Whites: characterization of a large North American cohort. Am J Gastroenterol. 2006;101:1012–1023
- Racial and geographic variations in colectomy rates among hospitalized ulcerative colitis patients. Clin Gastroenterol Hepatol. 2006;4:1507–1513
- American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. 2006;130:935–939
- Analysis of observational studies in the presence of treatment selection bias: effects of invasive cardiac management on AMI survival using propensity score and instrumental variable methods. JAMA. 2007;297:278–285
Conflicts of interest The authors disclose the following: Dr Nguyen has served on advisory boards for Schering-Plough, Canada, and Abbott Pharmaceuticals before the writing of this editorial. Dr Nguyen was not involved with the design or conduct of the ACT-1 or ACT-2 trials nor does he have any collaborative relationship with any of the investigators. There was no communication or input from any of the investigators or from any pharmaceutical company with regards to the contents of this editorial.
Dr Prather has served as a consultant for Proctor and Gamble. Dr Prather was not involved with the design or conduct of the ACT-1 or ACT-2 trials nor does she have any current or prior collaborative relationship with any of the investigators or the sponsor of the study. There was no communication or input from any of the investigators or from any pharmaceutical company with regards to the contents of this editorial.
PII: S0016-5085(09)01489-9
doi:10.1053/j.gastro.2009.08.024
© 2009 AGA Institute. Published by Elsevier Inc. All rights reserved.
Refers to article:
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Colectomy Rate Comparison After Treatment of Ulcerative Colitis With Placebo or Infliximab
, 13 July 2009
