Oral 5‐aminosalicylic acid for maintenance of remission in ulcerative colitis New search for studies and content updated (no change to conclusions)

Abstract

Abstract Background

Oral 5‐aminosalicylic acid (5‐ASA; also known as mesalazine or mesalamine) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. In an earlier version of this review, we found that 5‐ASA drugs were more effective than placebo for maintenance of remission of ulcerative colitis (UC), but had a significant therapeutic inferiority relative to SASP. In this version, we have rerun the search to bring the review up to date.

Objectives

To assess the efficacy, dose‐responsiveness, and safety of oral 5‐ASA compared to placebo, SASP, or 5‐ASA comparators for maintenance of remission in quiescent UC and 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

We performed a literature search for studies on 11 June 2019 using MEDLINE, Embase, and the Cochrane Library. In addition, we searched review articles and conference proceedings.

Selection criteria

We included randomized controlled trials with a minimum treatment duration of six months. We considered studies of oral 5‐ASA therapy for treatment of participants with quiescent UC compared with placebo, SASP, or other 5‐ASA formulations. We also included studies that compared once‐daily 5‐ASA treatment with conventional dosing of 5‐ASA and 5‐ASA dose‐ranging studies.

Data collection and analysis

We used standard methodological procedures expected by Cochrane. The primary outcome was the failure to maintain clinical or endoscopic remission. Secondary outcomes were adherence, adverse events (AE), serious adverse events (SAE), withdrawals due to AEs, and withdrawals or exclusions after entry. Trials were separated into five comparison groups: 5‐ASA versus placebo, 5‐ASA versus SASP, once‐daily dosing versus conventional dosing, 5‐ASA (balsalazide, Pentasa, and olsalazine) versus comparator 5‐ASA formulation (Asacol and Salofalk), and 5‐ASA dose‐ranging. We calculated the risk ratio (RR) and 95% confidence interval (CI) for each outcome. We analyzed data on an intention‐to‐treat basis, and used GRADE to assess the overall certainty of the evidence.

Main results

The search identified 44 studies (9967 participants). Most studies were at low risk of bias. Ten studies were at high risk of bias. Seven of these studies were single‐blind and three were open‐label.

5‐ASA is more effective than placebo for maintenance of clinical or endoscopic remission. About 37% (335/907) of 5‐ASA participants relapsed at six to 12 months compared to 55% (355/648) of placebo participants (RR 0.68, 95% CI 0.61 to 0.76; 8 studies, 1555 participants; high‐certainty evidence). Adherence to study medication was not reported for this comparison. SAEs were reported in 1% (6/550) of participants in the 5‐ASA group compared to 2% (5/276) of participants in the placebo group at six to 12 months (RR 0.60, 95% CI 0.19 to 1.84; 3 studies, 826 participants; low‐certainty evidence). There is probably little or no difference in AEs at six to 12 months' follow‐up (RR 0.93, 95% CI 0.73 to 1.18; 5 studies, 1132 participants; moderate‐certainty evidence).

SASP is more effective than 5‐ASA for maintenance of remission. About 48% (416/871) of 5‐ASA participants relapsed at six to 18 months compared to 43% (336/784) of SASP participants (RR 1.14, 95% CI 1.03 to 1.27; 12 studies, 1655 participants; high‐certainty evidence). Adherence to study medication and SAEs were not reported for this comparison. There is probably little or no difference in AEs at six to 12 months' follow‐up (RR 1.07, 95% CI 0.82 to 1.40; 7 studies, 1138 participants; moderate‐certainty evidence).

There is little or no difference in clinical or endoscopic remission rates between once‐daily and conventionally dosed 5‐ASA. About 37% (717/1939) of once‐daily participants relapsed over 12 months compared to 39% (770/1971) of conventional‐dosing participants (RR 0.94, 95% CI 0.88 to 1.01; 10 studies, 3910 participants; high‐certainty evidence). There is probably little or no difference in medication adherence rates. About 10% (106/1152) of participants in the once‐daily group failed to adhere to their medication regimen compared to 8% (84/1154) of participants in the conventional‐dosing group (RR 1.18, 95% CI 0.72 to 1.93; 9 studies, 2306 participants; moderate‐certainty evidence). About 3% (41/1587) of participants in the once‐daily group experienced a SAE compared to 2% (35/1609) of participants in the conventional‐dose group at six to 12 months (RR 1.20, 95% CI 0.77 to 1.87; moderate‐certainty evidence). There is little or no difference in the incidence of AEs at six to 13 months' follow‐up (RR 0.98, 95% CI 0.92 to 1.04; 8 studies, 3497 participants; high‐certainty evidence).

There may be little or no difference in the efficacy of different 5‐ASA formulations. About 44% (158/358) of participants in the 5‐ASA group relapsed at six to 18 months compared to 41% (142/349) of participants in the 5‐ASA comparator group (RR 1.08, 95% CI 0.91 to 1.28; 6 studies, 707 participants; low‐certainty evidence).

Authors' conclusions

There is high‐certainty evidence that 5‐ASA is superior to placebo for maintenance therapy in UC. There is high‐certainty evidence that 5‐ASA is inferior compared to SASP. There is probably little or no difference between 5‐ASA and placebo, and 5‐ASA and SASP in commonly reported AEs such as flatulence, abdominal pain, nausea, diarrhea, headache, and dyspepsia. Oral 5‐ASA administered once daily has a similar benefit and harm profile as conventional dosing for maintenance of remission in quiescent UC.

Author(s)

Alistair Murray, Tran M Nguyen, Claire E Parker, Brian G Feagan, John K MacDonald

Abstract

Plain language summary

Oral 5‐aminosalicylic acid compounds for maintaining remission in ulcerative colitis 

What was the aim of this review? 

The aim of this Cochrane Review was to find out if oral 5‐aminosalicylic acid (also known as mesalazine or mesalamine) helps maintain remission and prevent relapse in people with ulcerative colitis. Ulcerative colitis is an inflammatory bowel disease that results in long‐lasting inflammation of the colon. Some common symptoms include bloody diarrhea, abdominal and rectal pain, weight loss, fatigue and fever. The review authors collected and analyzed all relevant studies to answer this question and found 44 studies.

How up‐to‐date is this review? 

The review authors searched for studies that had been published up to June 2019.

What was studied in the review? 

The researchers examined whether oral 5‐aminosalicylic acid was better than a placebo (a fake medication), other comparator 5‐aminosalicylic acid formulations, sulfasalazine, different dose levels of oral 5‐aminosalicylic acid, and once‐daily dosing compared to conventional dosing in people with ulcerative colitis. The outcomes included clinical or endoscopic (where a long, thin tube is directly entered into the bowel) remission, adherence to medication regimen, and side effects from the medication.

What were the main results of the review? 

The review authors found 44 relevant studies (9967 participants). These studies compared oral 5‐aminosalicylic medications to placebo, comparator 5‐aminosalicylic acid formulations, sulfasalazine, different dose levels of oral 5‐aminosalicylic acid, and once‐daily dosing compared to conventional dosing.

Eight studies (1555 participants) assessed the effectiveness of oral 5‐aminosalicylic acid compared to placebo. The studies found oral 5‐aminosalicylic acid was more effective than placebo for maintaining clinical or endoscopic remission (high‐certainty evidence). Twelve studies (1655 participants) assessed the effectiveness of sulfasalazine compared to 5‐aminosalicylic acid. The studies found sulfasalazine to be slightly more effective compared to 5‐aminosalicylic acid (high‐certainty evidence). Ten studies (3910 participants) assessed the effectiveness of once‐daily compared to conventional dosing (twice daily). The studies found there was probably no difference between the groups for maintaining clinical or endoscopic remission (moderate‐certainty evidence). An additional analysis of adherence to study medication was also done on once‐daily versus conventional dosing. The results showed there was probably no difference in adherence to taking medication between the two dosing groups (moderate‐certainty evidence). Six studies (1781 participants) assessed oral 5‐aminosalicylic acid (e.g. balsalazide, Pentasa, and olsalazine) compared to other 5‐aminosalicylic acid formulations (e.g. Asacol and Salofalk). The studies found there was probably no difference in clinical or endoscopic remission between the 5‐aminosalicylic acid and the 5‐aminosalicylic acid comparator groups (low‐certainty evidence).

There is probably little or no evidence of a difference in commonly reported side effects between 5‐aminosalicylic acid and any of the comparators. Commonly reported side effects included flatulence, abdominal pain, nausea, diarrhea, headache, dyspepsia (indigestion), and nasopharyngitis (inflammation of the nasal passages).

Author(s)

Alistair Murray, Tran M Nguyen, Claire E Parker, Brian G Feagan, John K MacDonald

Reviewer's Conclusions

Authors' conclusions

Implications for practice

It is clear that oral 5‐aminosalicylic acid (5‐ASA) preparations have yet to be proven to be more clinically beneficial than sulfasalazine (SASP). Male infertility is associated with SASP and not with 5‐ASA (Kjaergaard 1989; Riley 1987), so 5‐ASA may be preferred for patients concerned about fertility. 5‐ASA therapy is more expensive than SASP, so SASP may be the preferred option where cost is an important factor. Patients who are intolerant to SASP may prefer 5‐ASA. Oral 5‐ASA administered once daily is as effective and safe as conventional dosing (twice or three times daily) for maintenance of remission in quiescent ulcerative colitis. Once‐daily dosing does not appear to enhance adherence in the clinical trial setting. There may be little or no difference in efficacy or safety between the various formulations of 5‐ASA. When selecting among the various 5‐ASA formulations, physicians and patients should consider dose‐response data, adherence issues, and price (Sandborn 2002a).

Implications for research

With limited research funding, careful thought should be given prior to commissioning new trials of 5‐ASA preparations for the treatment of quiescent ulcerative colitis. Future trials comparing 5‐ASA with placebo or SASP may not be justified. There does not appear to be any difference in efficacy or safety between the various formulations of 5‐ASA. However, the overall certainty of the evidence from the studies examining differences in efficacy between various 5‐ASA formulations was low due to sparse data and risk of bias. 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. Future trials could assess whether once‐daily dosing regimens improve adherence in the community.

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