Oral 5‐aminosalicylic acid for induction of remission in ulcerative colitis Edited (no change to conclusions)

Abstract

Abstract Background

Oral 5‐aminosalicylic acid (5‐ASA) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. Previously, it was found that 5‐ASA drugs in doses of at least 2 g/day, were more effective than placebo but no more effective than SASP for inducing remission in ulcerative colitis. This updated review includes more recent studies and evaluates the efficacy and safety of 5‐ASA preparations used for the treatment of mild to moderately active ulcerative colitis.

Objectives

The primary objectives were to assess the efficacy, dose‐responsiveness and safety of oral 5‐ASA compared to placebo, SASP, or 5‐ASA comparators for induction of remission in active ulcerative colitis. A secondary objective of this systematic review was to compare the efficacy and safety of once daily dosing of oral 5‐ASA with conventional (two or three times daily) dosing regimens.

Search methods

A computer‐assisted literature search for relevant studies (inception to July 9, 2015) was performed using MEDLINE, EMBASE and the Cochrane Library. Review articles and conference proceedings were also searched to identify additional studies.

Selection criteria

Studies were accepted for analysis if they were randomized controlled clinical trials of parallel design, with a minimum treatment duration of four weeks. Studies of oral 5‐ASA therapy for treatment of patients with active ulcerative colitis compared with placebo, SASP or other formulations of 5‐ASA were considered for inclusion. Studies that compared once daily 5‐ASA treatment with conventional dosing of 5‐ASA (two or three times daily) and 5‐ASA dose ranging studies were also considered for inclusion.

Data collection and analysis

The outcomes of interest were the failure to induce global/clinical remission, global/clinical improvement, endoscopic remission, endoscopic improvement, adherence, adverse events, withdrawals due to adverse events, and withdrawals or exclusions after entry. Trials were separated into five comparison groups: 5‐ASA versus placebo, 5‐ASA versus sulfasalazine, once daily dosing versus conventional dosing, 5‐ASA versus comparator 5‐ASA, and 5‐ASA dose‐ranging. Placebo‐controlled trials were subgrouped by dosage. SASP‐controlled trials were subgrouped by 5‐ASA/SASP mass ratios. Once daily versus conventional dosing studies were subgrouped by formulation. 5‐ASA‐controlled trials were subgrouped by common 5‐ASA comparators (e.g. Asacol, Claversal, Salofalk and Pentasa). Dose‐ranging studies were subgrouped by 5‐ASA formulation. We calculated the relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention‐to‐treat basis.

Main results

Fifty‐three studies (8548 patients) were included. The majority of included studies were rated as low risk of bias. 5‐ASA was significantly superior to placebo with regard to all measured outcome variables. Seventy‐one per cent of 5‐ASA patients failed to enter clinical remission compared to 83% of placebo patients (RR 0.86, 95% CI 0.82 to 0.89). A dose‐response trend for 5‐ASA was also observed. No statistically significant differences in efficacy were found between 5‐ASA and SASP. Fifty‐four per cent of 5‐ASA patients failed to enter remission compared to 58% of SASP patients (RR 0.90, 95% CI 0.77 to 1.04). No statistically significant differences in efficacy or adherence were found between once daily and conventionally dosed 5‐ASA. Forty‐five per cent of once daily patients failed to enter clinical remission compared to 48% of conventionally dosed patients (RR 0.94, 95% CI 0.83 to 1.07). Eight per cent of patients dosed once daily failed to adhere to their medication regimen compared to 6% of conventionally dosed patients (RR 1.36, 95% CI 0.64 to 2.86). There does not appear to be any difference in efficacy among the various 5‐ASA formulations. Fifty per cent of patients in the 5‐ASA group failed to enter remission compared to 52% of patients in the 5‐ASA comparator group (RR 0.94, 95% CI 0.86 to 1.02). A pooled analysis of 3 studies (n = 1459 patients) studies found no statistically significant difference in clinical improvement between Asacol 4.8 g/day and 2.4 g/day used for the treatment of moderately active ulcerative colitis. Thirty‐seven per cent of patients in the 4.8 g/day group failed to improve clinically compared to 41% of patients in the 2.4 g/day group (RR 0.89; 95% CI 0.78 to 1.01). Subgroup analysis indicated that patients with moderate disease may benefit from the higher dose of 4.8 g/day. One study compared (n = 123 patients) Pentasa 4 g/day to 2.25 g/day in patients with moderate disease. Twenty‐five per cent of patients in the 4 g/day group failed to improve clinically compared to 57% of patients in the 2.25 g/day group (RR 0.44; 95% CI 0.27 to 0.71). A pooled analysis of two studies comparing MMX mesalamine 4.8 g/day to 2.4 g/day found no statistically significant difference in efficacy (RR 1.03, 95% CI 0.82 to 1.29). There were no statistically significant differences in the incidence of adverse events between 5‐ASA and placebo, once daily and conventionally dosed 5‐ASA, 5‐ASA and comparator 5‐ASA formulation and 5‐ASA dose ranging (high dose versus low dose) studies. Common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache and worsening ulcerative colitis. SASP was not as well tolerated as 5‐ASA. Twenty‐nine percent of SASP patients experienced an adverse event compared to 15% of 5‐ASA patients (RR 0.48, 95% CI 0.37 to 0.63).

Authors' conclusions

5‐ASA was superior to placebo and no more effective than SASP. Considering their relative costs, a clinical advantage to using oral 5‐ASA in place of SASP appears unlikely. 5‐ASA dosed once daily appears to be as efficacious and safe as conventionally dosed 5‐ASA. Adherence does not appear to be enhanced by once daily dosing in the clinical trial setting. It is unknown if once daily dosing of 5‐ASA improves adherence in a community‐based setting. There do not appear to be any differences in efficacy or safety among the various 5‐ASA formulations. A daily dosage of 2.4 g appears to be a safe and effective induction therapy for patients with mild to moderately active ulcerative colitis. Patients with moderate disease may benefit from an initial dose of 4.8 g/day.

Author(s)

Yongjun Wang, Claire E Parker, Tania Bhanji, Brian G Feagan, John K MacDonald

Abstract

Plain language summary

Oral 5‐aminosalicylic acid for the treatment of active ulcerative colitis

Sulfasalazine (SASP) has been used for treating ulcerative colitis for decades. SASP is made up of 5‐aminosalicylic acid (5‐ASA) linked to a sulfur molecule. Up to a third of patients treated with SASP have reported side effects, which are thought to be related to the sulfur part of the molecule. Common side effects associated with SASP include nausea, indigestion, headache, vomiting and abdominal pain. 5‐ASA drugs were developed to avoid the side effects associated with SASP. This review includes 53 randomized trials with a total of 8548 participants. Oral 5‐ASA was found to be more effective than placebo (fake drug). Although oral 5‐ASA drugs are effective for treating active ulcerative colitis, they are no more effective than SASP therapy. Patients taking 5‐ASA are less likely to experience side effects than patients taking SASP. Side effects associated with 5‐ASA are generally mild in nature, and common side effects include gastrointestinal symptoms (e.g. flatulence, abdominal pain, nausea, and diarrhea), headache and worsening ulcerative colitis. Male infertility is associated with SASP and not with 5‐ASA, so 5‐ASA may be preferred for patients concerned about fertility. 5‐ASA compounds are more expensive than SASP, so SASP may be the preferred option where cost is an important factor. 5‐ASA dosed once daily appears to be as effective and safe as conventionally dosed (two or three times daily) 5‐ASA. There do not appear to be any differences in effectiveness or safety among the various 5‐ASA formulations. A daily dosage of 2.4 g appears to be a safe and effective therapy for patients with mild to moderately active ulcerative colitis. Patients with moderate disease may benefit from an initial dose of 4.8 g/day.

Author(s)

Yongjun Wang, Claire E Parker, Tania Bhanji, Brian G Feagan, John K MacDonald

Reviewer's Conclusions

Authors' conclusions

Implications for practice

5‐ASA was superior to placebo and no more effective than SASP. It is possible that special populations of patients can benefit from 5‐ASA therapy. For example, the seminal fluid abnormalities associated with SASP can be reversed with the substitution of a 5‐ASA preparation in lieu of SASP (Riley 1987; Kjaergaard 1989). Nonetheless, it is clear that the newer 5‐ASA preparations have yet to be proven to be more clinically beneficial than SASP for the treatment of ulcerative colitis. The cost of oral 5‐ASA formulations exceeds that of SASP by three to four times. The decision to use 5‐ASA or SASP should consider tolerance to SASP and cost. Oral 5‐ASA administered once daily is as effective and safe as conventional dosing (twice or three times daily) for induction therapy in mild to moderately active ulcerative colitis. There do not appear to be any differences in efficacy or safety between the various formulations of 5‐ASA. Among patients with mildly active ulcerative colitis a dosage of 4 to 4.8 g/day does not appear to provide any additional benefit over a dosage of 2 to 2.4 g/day. Patients with severe symptoms and moderately active disease may benefit from an initial dosage of 4 to 4.8 g/day. When selecting among the various 5‐ASA formulations, physicians and patients should consider dose‐response data, adherence issues related to dose forms (size of dose form and total number of tablets or capsules per day), and price (Sandborn 2002a).

Implications for research

Future trials comparing the efficacy of oral 5‐ASA with placebo or SASP do not appear to be justified. There is little evidence to suggest that there is a difference in efficacy between the oral 5‐ASA drugs. Future trials should look at enhancing patient adherence with medication. Adherence to therapy is important for treatment success and may be an important predictor of relapse (Kane 2003; Kane 2001). Future trials could assess whether once daily dosing regimens improve adherence in the community. Future trials may be necessary to identify patients who will benefit from varying doses of MMX mesalamine or Salofalk.

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