Efficacy of 5-Aminosalicylates in Ulcerative Colitis: Systematic Review and Meta-Analysis

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1 CLINICAL AND SYSTEMATIC S nature publishing group 601 Efficacy of 5-Aminosalicylates in Ulcerative Colitis: Systematic Review and Meta-Analysis Alexander C. Ford, MBChB, MD, MRCP 1, 2, Je an - Pau l Ach k ar, M D 3, Khurram J. Khan, MD, FRCPC 4, Su nand a V. Kane, M D, M SPH 5, Nichol as J. Ta l le y, M D, Ph D 6, John K. Marshall, MD, MSc, FRCPC 4 and Paul Moayyedi, BSc, MBChB, PhD, MPH, FRCP, FRCPC4 OBJECTIVES: METHODS: RESULTS: The efficacy of 5-aminosalicylic acids (5-ASAs) in ulcerative colitis (UC) has been studied previously in meta-analyses. However, several randomized controlled trials (RCTs) have been published recently, and no previous meta-analysis has studied the effect of 5-ASA dosage used. MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through December 2010). Eligible trials recruited adults with active or quiescent UC, comparing different doses of 5-ASAs with themselves or placebo. Dichotomous data were pooled to obtain relative risk (RR) of failure to achieve in active UC, and RR of relapse of disease activity in quiescent UC, with a 95 % confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference. The search identified 3,061 citations, and 37 RCTs were eligible. Of these, 11 compared 5-ASA with placebo in active UC, with the RR of no with 5-ASAs of 0.79 (95 % CI ; NNT = 6). Doses of 2.0 g / day were more effective than < 2.0 g / day for (RR = 0.91; 95 % CI ). There were 11 RCTs comparing 5-ASAs with placebo in preventing relapse of quiescent UC, with the RR of relapse of 0.65 (95 % CI ; NNT = 4). Doses of 2.0 g / day appeared more effective than < 2.0 g / day for preventing relapse (RR = 0.79; 95 % CI ). CONCLUSIONS: 5-ASAs are highly effective for inducing and preventing relapse in UC. Evidence suggests that doses of 2.0 g / day have greater efficacy, although doses > 2.5 g / day do not appear to lead to higher rates. Am J Gastroenterol 2011; 106: ; doi: /ajg ; published online 15 March 2011 INTRODUCTION Ulcerative colitis (UC), a chronic inflammatory condition of the gastrointestinal tract of unknown etiology, is a relatively common disorder in the United States, with an incidence of 7 9 per 100,000 people (1,2 ), and a prevalence of ~ per 100,000 (1 3 ). The disease tends to follow a relapsing and remitting course, with sufferers experiencing intermittent flare-ups of disease activity. The majority of these are treated with medical therapy, with surgery being reserved for life-threatening episodes of acute severe UC unresponsive to medical treatment, or for chronic active disease leading to impairment of normal activities of daily living and quality of life. For individuals with severe flare-ups of disease activity, there is evidence from randomized controlled trials (RCTs) that highdose corticosteroids are effective in this situation ( 4,5 ), whereas for those who experience regular flare-ups there are some data to suggest that the use of immunosuppressant drugs, such as azathioprine, reduce the likelihood of future relapse of disease activity and requirement for corticosteroids ( 6 8 ). However, both of these drug classes have unwanted, and in some cases potentially serious, side effects. Corticosteroids cause acne, weight gain, hyperglycemia, risk of opportunistic infection, and suppression of the hypothalamic pituitary adrenal axis, and their long-term use is associated with osteoporosis and cataracts, while the potential association between long-term immunomodulator use and malignancy is a concern. For individuals with milder disease, the risks associated with these therapies may therefore outweigh the intended benefits. 5-Aminosalicylic acids (5-ASAs) are thought to have a beneficial anti-inflammatory action in UC, via increased expression of 1 Leeds Gastroenterology Institute, Leeds General Infi rmary, Leeds, UK ; 2 Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK ; 3 Department of Gastroenterology and Hepatology, Center for Infl ammatory Bowel Disease, Cleveland Clinic, Cleveland, Ohio, USA ; 4 Gastroenterology Division, McMaster University, Health Sciences Center, Hamilton, Ontario, Canada ; 5 Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA ; 6 Faculty of Health, University of Newcastle, Newcastle, New South Wales, Australia. Correspondence: Alexander C. Ford, MBChB, MD, MRCP, Leeds Gastroenterology Institute, Leeds General Infi rmary, D Floor, Clarendon Wing, Great George Street, Leeds, LS1 3EX, UK. alexf12399@yahoo.com Received 22 November 2010; accepted 3 February by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

2 602 Ford et al. Box 1. Eligibility criteria Randomized controlled trials. Adults ( > 90 % of patients aged > 16 years) with ulcerative colitis (UC). Compared 5-aminosalicylic acid (5-ASA) drugs a with placebo or an alternative dose of the same 5-ASA drug. Minimum duration of therapy of 14 days in trials reporting induction of of active UC. Minimum duration of therapy of 6 months in trials reporting prevention of relapse of quiescent UC. Assessment of failure of in active UC, or relapse of disease activity in quiescent UC, at the last time point of assessment in the trial. b a Sulfasalazine, mesalamine, balsalazide, or olsalazine. b Preferably using endoscopic healing or evidence of endoscopic relapse, but if this outcome measure was not reported, then other measures were permissible according to a predefined hierarchy (Box 2). peroxisome proliferator-activated receptors in gastrointestinal epithelial cells ( 9 ). Previous systematic reviews and meta- analyses have suggested that these drugs, when given orally in UC, are effective in both inducing of mildly to moderately active disease and in preventing relapse of quiescent disease ( ). However, all of the previously published meta-analyses examining this issue were conducted by the same author, and there have been further RCTs reported in the interim. In addition, we have previously demonstrated errors in the conduct of systematic reviews and meta-analyses of pharmacological therapies for the treatment of irritable bowel syndrome ( 13 ), in terms of identifying eligible trials successfully, excluding ineligible RCTs, and extracting data. These errors led to significant over- or under-estimation of the efficacy of these therapies in some instances, and hence the validity of previous meta-analyses of the benefit of 5-ASAs in UC cannot be assumed. Furthermore, none of the meta-analyses previously conducted have studied the effect of using a higher dose of 5-ASA drug on the likelihood of achieving or preventing relapse. We have therefore conducted a systematic review and meta-analysis to assess the efficacy of 5-ASAs, compared with placebo, in both inducing of active UC and in preventing relapse of quiescent UC, and have performed analyses according to the dose of 5-ASA used, comparing high, standard, and low doses of the same 5-ASA drug in each RCT, where individual trials reported these data. METHODS Search strategy and study selection A search of the medical literature was conducted using MEDLINE (1966 to December 2010), EMBASE (1984 to December 2010), the Cochrane central register of controlled trials (Issue 4, October 2010), and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register. RCTs examining the effect of 5-ASA drugs in adult patients ( > 90 % of participants over the age of 16 years) with active or quiescent UC were eligible for inclusion ( Box 1 ). The first period of crossover RCTs were also eligible for inclusion. The control arm was required to receive either placebo or an alternative dose of the same 5-ASA drug. Duration of therapy had to be at least 14 days for induction of trials in active UC, and at least 6 months in prevention of relapse trials in quiescent UC. Trials using any dose of 5-ASA drug were considered eligible. Studies had to report either an assessment of failure of in active UC, or relapse of disease activity in quiescent UC at the last time point of assessment in the trial, preferably using evidence of endoscopic mucosal healing in induction of trials, or endoscopic relapse in prevention of relapse trials, but if this outcome measure was not reported, then other measures were permissible according to a predefined hierarchy ( Box 2 ). Trials of 5-ASAs in active UC that reported an improvement in disease activity as their only outcome were not eligible for inclusion. The first and senior authors of studies were contacted to provide additional information on trials where required. The literature search was performed as part of a broader exercise to inform the update of the American College of Gastroenterology s monograph for the management of inflammatory bowel disease. Specifically, studies on UC were identified with the terms ulcerative colitis, inflammatory bowel disease, or colitis (both as medical subject headings (MeSH) and free text terms). These were combined using the set operator AND with studies identified with the terms: sulfasalazine, mesalamine, or aminosalicylic acid (both as MeSH terms and free text terms), or the following free text terms: balsalazide, olsalazine, mesalazine, pentasa, asulfidine $, azulfadine $, azulfidine $, sulfasalazine $, salazopyrin $, salazosulfapyridine, 5-ASA, 5ASA, 5-aminosalicylic $, 5-aminosalicylate $, 5aminosalicylic $, or 5aminosalicylate $. Th ere were no language restrictions. Abstracts of the papers identified by the initial search were evaluated by the lead investigator for appropriateness to the study question. All potentially relevant papers were obtained and evaluated in detail. Foreign language papers were translated where necessary. Abstract books of conference proceedings between 2002 and 2009 were handsearched to identify potentially eligible studies published only in abstract form. The bibliographies of all identified relevant studies were used to perform a recursive search of the literature. Experts in the field were contacted to try to identify other unpublished studies. Articles were assessed independently by two investigators using predesigned eligibility forms, according to the eligibility criteria stated previously. Any disagreement between investigators was resolved by discussion with a third investigator. Outcome assessment The primary outcome assessed was the efficacy of 5-ASA drugs compared with placebo, or an alternative dose of the same 5-ASA drug, in terms of failure to achieve in active UC, and preventing relapse of disease activity in quiescent UC. Secondary outcomes included assessing adverse events occurring as a The American Journal of GASTROENTEROLOGY VOLUME 106 APRIL

3 5-ASAs in Ulcerative Colitis: A Meta-Analysis 603 Box 2. Data extraction methodology Outcome of interest : failure of in active ulcerative colitis (UC), and relapse of disease activity in quiescent UC. Hierarchy of reporting of outcomes used: UC : endoscopic evidence of complete (most stringent definition available, e.g., complete mucosal healing), endoscopic evidence and clinical assessment as complete, clinical assessment as complete, recognized scoring system of complete (e.g., Truelove and Witt), or other author-defined criteria for. UC relapse: endoscopic evidence of any degree of relapse, endoscopic evidence and clinical assessment as relapsed, clinical assessment as relapsed, recognized scoring system as relapsed (e.g., Truelove and Witt), or other author-defined criteria for relapse. Time of assessment : last time point of assessment in the trial. Denominator used: true intention-to-treat analysis, and if not available, then all evaluable patients. Studies identified in literature search (n = 3,061) Studies retrieved for evaluation (n = 137) Excluded (title and abstract revealed not appropriate) (n = 2,924) used, duration of therapy, compliance with therapy, number of individuals incurring each (or any) of the adverse events of interest, primary outcome measure used to define or relapse following therapy, and duration of follow-up. Data were extracted as intention-to-treat analyses, where all drop-outs are assumed to be treatment failures (i.e., failed to achieve in active UC trials, and disease activity relapsed in quiescent UC trials), wherever trial reporting allowed this. Excluded (n = 100) because: Not the comparison of interest = 61 Duplicate publication = 17 Not the outcome of interest = 11 Data not extractable = 5 Not the intervention of interest = 3 Review article = 1 Not an RCT = 1 Pooled analysis of 2 RCTs = 1 Assessment of risk of bias This was performed independently by two investigators, with disagreements resolved by discussion with a third investigator. Risk of bias was assessed as described in the Cochrane handbook ( 14 ), by recording the method used to generate the randomization schedule, the method used to conceal allocation, whether ing was implemented, what proportion of patients completed followup, whether an intention-to-treat analysis was extractable, and whether there was evidence of selective reporting of outcomes. RCTs of 5-ASAs in UC eligible (n = 37) 5-ASAs in active UC = 19 5-ASAs in quiescent UC = 18 Figure 1. Flow diagram of assessment of studies identifi ed in the systematic review. 5-ASA, 5-aminosalicylic acid; RCT, randomized controlled trial; UC, ulcerative colitis. result of therapy (overall numbers, as well as individual adverse events such as upper or lower gastrointestinal disturbances (nausea, vomiting, diarrhea), dermatological problems (rash), and systemic effects (myalgia, fever, headache, lethargy)). Data extraction All data were extracted independently by two investigators on to a Microsoft Excel spreadsheet (XP professional edition; Microsoft, Redmond, WA) as dichotomous outcomes ( or failure of in active UC, and relapse or no relapse of disease activity in quiescent UC) ( Box 2 ). In addition, the following clinical data were extracted for each trial, where available: demographic data of trial participants (age, gender, and ethnicity), UC characteristics (duration of UC, proportion with new-onset UC, distribution of UC, and severity of UC), number of centers, country of origin, geographical region, dosage and schedule of 5-ASA drug Data synthesis and statistical analysis Data were pooled using a random effects model to give a more conservative estimate of the effect of individual therapies, allowing for any heterogeneity between studies ( 15 ). The impacts of different interventions were expressed as a relative risk (RR) of failure to achieve with 95 % confidence intervals (CIs) in trials of therapy for active UC, or RR of relapse of disease activity in trials of therapy for quiescent UC with 5-ASA drug compared with placebo or, in trials that used one or more alternative doses of the same 5-ASA drug, between high-dose 5-ASA (defined as a total daily dose of > 2.5 g of 5-ASA), standard-dose 5-ASA (2.0 g to 2.5 g per day), and low-dose 5-ASA ( < 2.0 g per day). As balsalazide contains a lower absolute dose of active drug than other 5-ASAs, a total daily dose of < 6 g was classed as low dose, and a total daily dose of 6 g as standard dose. The last time point of assessment in the trial was used for analysis. The number needed to treat (NNT) and 95 % CIs were calculated from the reciprocal of the risk difference from the meta-analysis. Adverse events were summarized with relative risks, and a number needed to harm was calculated from the reciprocal of the risk difference. The results of individual studies can be diverse, and this inconsistency within a single meta-analysis can be quantified with a statistical test of heterogeneity to assess whether the variation across trials is due to true heterogeneity or chance. This quantity is termed I 2, and its value ranges from 0 to 100 %, with 0 % representing no 2011 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

4 604 Ford et al. Table 1. Characteristics of RCTs of 5-ASAs vs. placebo in inducing in active UC Study Country, and number of centers Disease distribution Criteria used to define Baron et al. ( 18 ) UK, 1 site Not reported Normal sigmoidoscopic appearances Dick et al. ( 19 ) UK, 1 site 68 % colitis, 32 % proctitis Normal or faintly granular mucosa at sigmoidoscopy Hetzel et al. ( 20 ) Australia, 1 site Not reported Normal or mildly hyperemic mucosa at sigmoidoscopy Schroeder et al. ( 21 ) USA, 1 site 23 % pancolitis, 77 % distal colitis Miner et al. ( 22 ) USA, multiple Not reported Clinical and endoscopic Sigmoidoscopic Sninsky et al. ( 23 ) USA, 9 Not reported Clinical and endoscopic Hanauer et al. ( 24 ) USA, % pancolitis, 68 % distal colitis Kamm et al. ( 25 ) Multinational, 49 Lichtenstein et al. ( 26 ) Multinational, % pancolitis, 76 % distal colitis 18 % pancolitis, 82 % distal colitis Sigmoidoscopic score of 4 out of 15 Modifi ed sigmoidoscopic score of 1 out of 3 with no mucosal friability Clinical and endoscopic Scherl et al. ( 27 ) USA, 55 Not reported Sigmoidoscopy score of 1 out of 3 Ito et al. ( 53 ) Japan, 53 Not reported UC DAI score 2 and a bloody stool score of 0 Number of patients 5-ASA used 40 Sulfasalazine 1 g q.i.d. for 1 week, then 500 mg q.i.d. for 2 weeks 44 Sulfasalazine 4 6 g per day Duration of therapy Methodology 3 Weeks Randomization unclear, stated, double 4 Weeks Randomization and stated, double 30 Olsalazine 1 g b.i.d. 6 Weeks Randomization stated, 87 Mesalamine (Asacol) 400 mg or 1.2 g q.i.d. 251 Mesalamine (Pentasa) 2 or 4 g daily 158 Mesalamine (Asacol) 1.6 g or 2.4 g daily 374 Mesalamine (Pentasa) 250 mg, 500 mg, or 1 g q.i.d. 343 Mesalamine (MMX) 2.4 g or 4.8 g o.d. or mesalamine (Asacol) 800 mg t.i.d. 280 Mesalamine (MMX) 1.2 g b.i.d. or 4.8 g o.d. 250 Balsalazide 3.3 g b.i.d. 229 Mesalamine (Asacol) 2.4 g or 3.6 g daily, mesalamine (Pentasa) 2.25 g daily 6 Weeks Randomization and stated, double,, and ing unclear 6 Weeks Randomization stated, and unclear, stated, double unclear, stated, double unclear, stated, double unclear, stated, double 5-ASA, 5-aminosalicylic acid; b.i.d., twice daily; o.d., once daily; q.i.d., four times daily; RCT, randomized controlled trial; t.i.d., three times daily; UC, ulcerative colitis; UC DAI; ulcerative colitis disease activity index. observed heterogeneity, and larger values indicating increasing heterogeneity. A value < 25 % was arbitrarily chosen to represent low levels of heterogeneity ( 16 ). We also evaluated heterogeneity using the χ 2 test with P values < 0.15 indicating statistically significant heterogeneity. Where the degree of statistical heterogeneity was greater than this between trial results in this meta-analysis, possible explanations were investigated using sensitivity analyses according to the dosage and duration of therapy, compliance with therapy, criteria used to define or relapse, duration of disease, proportion with new-onset disease, and high risk of bias and unclear risk of bias vs. low risk of bias trials, where trial reporting allowed this. These were exploratory analyses only, and may explain some of the observed variability, but the results should be interpreted with caution. Review Manager version (RevMan for Windows 2008, the Nordic Cochrane Centre, Copenhagen, Denmark) and StatsDirect The American Journal of GASTROENTEROLOGY VOLUME 106 APRIL

5 5-ASAs in Ulcerative Colitis: A Meta-Analysis ASA Placebo Risk ratio Risk ratio Study or subgroup Sulfasalazine Events Total Events Total Weight M-H, random, 95% CI Year M-H, random, 95% CI Baron % 0.58 (0.38, 0.87) 1962 Dick % 0.78 (0.58, 1.05) % 0.70 (0.52, 0.93) Heterogeneity: τ 2 = 0.01; χ 2 = 1.42, d.f. = 1 (P = 0.23); I 2 = 30% Test for overall effect: Z = 2.42 (P = 0.02) Mesalamine Schroeder Miner Sninsky Hanauer Lichtenstein Kamm Ito , Heterogeneity: τ 2 = 0.01; χ 2 = 20.65, d.f. = 6 (P = 0.002); I 2 = 71% Test for overall effect: Z = 4.35 (P < ) 10.6 % 8.7 % 15.2 % 9.8 % 13.0 % 6.0 % 11.3 % 74.6 % 0.84 (0.72, 0.99) 0.79 (0.65, 0.96) 0.92 (0.85, 1.01) 0.81 (0.68, 0.96) 0.79 (0.70, 0.90) 0.58 (0.45,.076) 0.72 (0.62, 0.84) 0.79 (0.71, 0.88) Olsalazine Hetzel Heterogeneity: not applicable Test for overall effect: Z = 1.26 (P = 0.21) % 3.1 % 0.77 (0.51, 1.16) 0.77 (0.51, 1.16) Balsalazide Scherl 2009 Heterogeneity: not applicable Test for overall effect: Z = 3.74 (P = ) % 14.1 % 0.82 (0.74, 0.91) (0.74, 0.91) Total (95% CI) % Heterogeneity: τ 2 = 0.01; χ 2 = 23.54, d.f. = 10 (P = 0.009); I 2 = 58% Test for overall effect: Z = 5.84 (P < ) Test for subgroup differences: not applicable 0.79 (0.73, 0.85) Favors 5-ASA Favors placebo 10 Figure 2. Forest plot of randomized controlled trials of 5-aminosalicylic acids (5-ASAs) vs. placebo in inducing in active ulcerative colitis (UC). M-H, Mantel-Haenszel. Table 2. Adverse events with 5-ASAs vs. placebo in inducing in active UC Adverse event Number of trials Total number of 5-ASA patients Number of 5-ASA patients experiencing event ( % ) Total number of placebo patients Number of placebo patients experiencing event ( % ) Relative risk 95 % Confidence interval Any (46.2) (43.4) Nausea or vomiting 7 1, (3.8) (3.0) Headache 7 1, (5.1) (6.3) Abdominal pain (1.9) (4.7) Rash (2.4) (2.3) Diarrhea (3.3) (5.5) ASA, 5-aminosalicylic acid; UC, ulcerative colitis. version (StatsDirect, Sale, Cheshire, UK) were used to generate Forest plots of pooled RRs and risk differences for primary and secondary outcomes with 95 % CIs, as well as funnel plots. The latter were assessed for evidence of asymmetry, and therefore possible publication bias or other small study effects, using the Egger test (17 ). RESULTS The search strategy employed to inform the American College of Gastroenterology monograph identified 3,061 citations, 2,924 of which were excluded after examining the title and abstract. There were a total of 137 articles reporting on efficacy of 5-ASAs in UC that were retrieved and evaluated in more detail. Of these, by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

6 606 Ford et al. Table 3. Characteristics of RCTs of high-dose 5-ASAs vs. standard-dose 5-ASAs in inducing in active UC Study Miglioli et al. ( 28 ) Miner et al. ( 22 ) Hanauer et al. ( 24 ) Hanauer et al. ( 30 ) D Haens et al. ( 31 ) Hanauer et al. ( 32 ) Country, and number of centers Italy, 8 USA, multiple USA, 20 USA and Canada, 55 UK, Holland, Belgium, 8 USA and Canada, 41 Kamm et al. ( 25 ) Multinational, 49 Lichtenstein et al. ( 26 ) Sandborn et al. ( 33 ) Multinational, 52 Multinational, 113 Disease distribution 15 % pancolitis, 42 % left-sided colitis, 43 % Not reported 30 % pancolitis, 70 % distal colitis 20 % pancolitis, 34 % left-sided colitis, 46 % 28 % pancolitis, 72 % left-sided colitis 24 % pancolitis, 30 % left-sided colitis, 46 % 23 % pancolitis, 77 % distal colitis 15 % pancolitis, 85 % distal colitis 16 % pancolitis, 35 % left-sided colitis, 48 % Criteria used to define Normal mucosa at colonoscopy Sigmoidoscopic Sigmoidoscopic score of 4 out of 15 Clinical and endoscopic Number of patients 5-ASA used 48 Mesalamine (Asacol) 800 mg or 1.2 g t.i.d. 168 Mesalamine (Pentasa) 2 or 4 g daily 192 Mesalamine (Pentasa) 500 mg or 1 g q.i.d. 268 Mesalamine (Asacol) 800 mg t.i.d. or 1.6 g t.i.d. UC DAI score 1 25 Mesalamine (MMX) 2.4 or 4.8 g o.d. Clinical and endoscopic Modifi ed sigmoidoscopic score of 1 out of 3 with no mucosal friability Clinical and endoscopic Clinical and endoscopic Ito et al. ( 53 ) Japan, 53 Not reported UC DAI score 2 and a bloody stool score of Mesalamine (Asacol) 800 mg t.i.d. or 1.6 g t.i.d. 257 Mesalamine (MMX) 2.4 g or 4.8 g o.d. or mesalamine (Asacol) 800 mg t.i.d. 187 Mesalamine (MMX) 1.2 g b.i.d. or 4.8 g o.d. 772 Mesalamine (Asacol) 800 mg t.i.d. or 1.6 g t.i.d. 196 Mesalamine (Asacol) 2.4 or 3.6 g daily, mesalamine (Pentasa) 2.25 g daily Duration of therapy Methodology 4 Weeks Randomization stated,,, and ing unclear and unclear, double 6 Weeks Randomization and unclear, double and unclear, double 6 Weeks Randomization and unclear, double unclear, stated, double unclear, stated, double 6 Weeks Randomization unclear, stated, double unclear, stated, double 5-ASA, 5-aminosalicylic acid; b.i.d., twice daily; o.d., once daily; q.i.d., four times daily; RCT, randomized controlled trial; t.i.d., three times daily; UC, ulcerative colitis; UC DAI; ulcerative colitis disease activity index. were excluded for various reasons, leaving 37 RCTs eligible for inclusion ( Figure 1 ) ( ). Of these, 19 separate RCTs reported the efficacy of 5-ASAs in inducing in active UC, 4 comparing 5-ASA with placebo ( 18 20,27 ), 8 comparing alternative doses of the same 5-ASA ( ), and 7 comparing alternative doses of the same 5-ASA, both with placebo and with each other ( 21 26,53 ). In addition, 18 trials studied efficacy of 5-ASAs in preventing relapse of quiescent UC, 11 of which were placebo controlled ( 36 45,52 ), and 7 compared alternative doses of the same 5-ASA drug ( 46 51,54 ). Efficacy and safety of 5-ASAs vs. placebo in inducing in active UC Th ere were 11 RCTs, including a total of 2,086 patients with mildly to moderately active UC, reporting rates with 5-ASA vs. placebo after 3 8 weeks of therapy ( 18 27,53 ). Only two trials were at low risk of bias ( 19,21 ). For detailed characteristics of individual trials, see Table 1. Remission of UC was not achieved in 887 (60.3 % ) of 1,470 patients randomized to receive 5-ASA, compared with 494 (80.2 % ) of 616 patients allocated to placebo. The RR of failure to achieve with 5-ASA compared with placebo in active UC was 0.79 (95 % CI , I 2 = 58 %, P = 0.009; Figure 2 ), and there was statistically significant funnel plot asymmetry (Egger test, P = 0.02), suggesting evidence of publication bias or other small study effects. The NNT with 5-ASAs to achieve in one patient with active UC was 6 (95 % CI 5 8). Overall, there was no statistically significant difference between the type of 5-ASA therapy used and efficacy at inducing in active UC (Cochrane Q = 1.11, P = 0.77). The American Journal of GASTROENTEROLOGY VOLUME 106 APRIL

7 5-ASAs in Ulcerative Colitis: A Meta-Analysis 607 Study or subgroup Miglioli 1990 Miner 1991 Hanauer 1993 Hanauer 2005 D Haens 2006 Lichtenstein 2007 Kamm 2007 Hanauer 2007 Sandborn 2009 Ito 2010 High dose 5-ASA Standard-dose 5-ASA Risk ratio Risk ratio Events Total Events Total Weight M-H, random, 95% CI Year M-H, random, 95% CI % 5.1% 5.4% 18.9% 2.2% 9.4% 2.1% 17.7% 30.0% 6.1% 0.84 (0.59, 1.19) 0.84 (0.64, 1.10) 0.93 (0.71, 1.21) 0.97 (0.86, 1.08) 1.15 (0.74, 1.77) 1.07 (0.88, 1.29) 0.63 (0.40, 0.98) 0.95 (0.84, 1.07) 1.00 (0.94, 1.07) 0.78 (0.61, 1.00) Total (95% CI) 1,124 1, Heterogeneity: τ 2 = 0.00; χ 2 = 12.35, d.f. = 9 (P = 0.19); I 2 = 27% Test for overall effect: Z = 1.51 (P = 0.13) 100.0% 0.95 (0.89, 1.02) Favors high-dose Favors standard-dose Figure 3. Forest plot of randomized controlled trials of high-dose 5-aminosalicylic acids (5-ASAs) vs. standard-dose 5-ASAs in inducing in active ulcerative colitis (UC). M-H, Mantel-Haenszel. When only the six RCTs that used 8 weeks of therapy were considered in the analysis ( 22,24 27,53 ), the effect of 5-ASAs on of UC remained (RR = 0.77; 95 % CI ), but the degree of heterogeneity between studies was of borderline statistical significance ( I 2 = 29 %, P = 0.22). When only the seven RCTs that used endoscopic healing to define were included in the analysis (18 20,22,24,25,27 ), the beneficial effect of 5-ASAs in inducing in active UC remained (RR = 0.76; 95 % CI ), and again the degree of heterogeneity observed was only borderline ( I 2 = 30 %, P = 0.20). Efficacy of sulfasalazine vs. placebo in inducing in active UC Two trials compared sulfasalazine with placebo in 84 patients with active UC ( 18,19 ). Remission data were reported after 3 to 4 weeks of therapy. Remission of UC was not achieved in 26 (63.4 % ) of 41 patients randomized to receive sulfasalazine, compared with 40 (93.0 % ) of 43 patients allocated to placebo. The RR of failure to achieve with sulfasalazine compared with placebo in active UC was 0.70 (95 % CI ; Figure 2 ), with the NNT to achieve in one patient of 3 (95 % CI 2 10). Efficacy of mesalamine vs. placebo in inducing in active UC In all, 7 trials, containing 1,722 patients, reported rates with mesalamine vs. placebo in active UC after 6 8 weeks of therapy ( 21 26,53 ). Remission of UC was not achieved in 724 (58.1 % ) of 1,247 patients randomized to receive mesalamine, compared with 364 (76.6 % ) of 475 patients allocated to placebo. The RR of failure to achieve with mesalamine compared with placebo in active UC was 0.79 (95 % CI ; Figure 2 ). Again, there was statistically significant heterogeneity between studies ( I 2 = 71 %, P = 0.002), and evidence of funnel plot asymmetry (Egger test, P = 0.02). Subgroup analyses according to dose of mesalamine used and criteria used to define did not reveal any obvious explanations for this heterogeneity, although when only the five RCTs that used 8 weeks of therapy were considered in the analysis there was only borderline heterogeneity observed ( I 2 = 27 %, P = 0.24) ( 22,24 26,53 ). The NNT with mesalamine to achieve in one patient with active UC was 6 (95 % CI 5 9). Efficacy of olsalazine vs. placebo in inducing in active UC Only one trial compared olsalazine with placebo in active UC ( 20 ), containing 30 patients. The trial reported rates after 6 weeks of therapy. There was no statistically significant difference detected between olsalazine and placebo in this study, with no in 10 (66.7 % ) of 15 patients randomized to olsalazine, compared with 13 (86.7 % ) of 15 receiving placebo (RR of failure to achieve with olsalazine vs. placebo = 0.77; 95 % CI ; Figure 2 ). There were, however, three trials that were excluded from our primary analysis, as they only described disease improvement rather than ( ). If these data were included in a sensitivity analysis, then olsalazine was superior to placebo (RR of no or improvement = 0.81; 95 % CI ), with no significant heterogeneity between studies ( I 2 = 0 %, P = 0.98). Efficacy of balsalazide vs. placebo in inducing in active UC A recently published trial compared balsalazide with placebo in 250 patients with active UC ( 27 ), reporting rates after 8 weeks of therapy. There appeared to be a benefit of balsalazide over placebo, with 127 (76.0 % ) of 167 patients failing to achieve with balsalazide vs. 77 (92.8 % ) of 83 with placebo (RR of failure to achieve with balsalazide vs. placebo = 0.82; 95 % CI , NNT = 6; 95 % CI 4 13; Figure 2 ). Adverse events with 5-ASAs vs. placebo in inducing in active UC Of the trials, 10 provided adverse events data for extraction (18 21,23 27,53 ). There was no statistically significant difference 2011 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

8 608 Ford et al. Table 4. Characteristics of RCTs of high- or standard-dose 5-ASAs vs. low-dose 5-ASAs in inducing in active UC Study Schroeder et al. ( 21 ) Country, and number of centers USA, 1 site Disease distribution 20 % pancolitis, 80 % distal colitis Riley et al. ( 34 ) UK, 3 5 % pancolitis, 17 % left-sided colitis, 78 % Miglioli et al. ( 28 ) Sninsky et al. ( 23 ) Hanauer et al. ( 24 ) Levine et al. ( 29 ) Italy, 8 12 % pancolitis, 40 % left-sided colitis, 48 % Criteria used to define Clinical and endoscopic Sigmoidoscopy score of 1 out of 4 Normal mucosa at colonoscopy USA, 9 Not reported Clinical and endoscopic USA, 20 USA and Puerto Rico, 15 Kruis et al. ( 35 ) Multinational, 60 D Haens et al. ( 31 ) UK, Holland, Belgium, 8 32 % pancolitis, 68 % distal colitis Not reported 20 % pancolitis, 34 % left-sided colitis, 46 % 24 % pancolitis, 74 % left-sided colitis Sigmoidoscopic score of 4 out of 15 Clinical and endoscopic Number of patients 5-ASA used 49 Mesalamine (Asacol) 400 mg or 1.2 g q.i.d. 41 Mesalamine (Asacol) 400 mg or 1.2 g b.i.d. 73 Mesalamine (Asacol) 400 mg, 800 mg, or 1.2 g t.i.d. 87 Mesalamine (Asacol) 1.6 or 2.4 g daily 284 Mesalamine (Pentasa) 250 mg, 500 mg, or 1 g q.i.d. 103 Balsalazide 750 mg or 2.25 g t.i.d. CAI Mesalamine 500 mg, 1 g, or 1.5 g t.i.d. UC DAI score 1 38 Mesalamine (MMX) 1.2, 2.4, or 4.8 g o.d. Duration of therapy Methodology 6 Weeks Randomization and stated, double 4 Weeks Randomization and 4 Weeks Randomization stated, unclear, double 6 Weeks Randomization stated, unclear, double and and and and 5-ASA, 5-aminosalicylic acid; b.i.d., twice daily; CAI, clinical activity index; o.d., once daily; q.i.d., four times daily; RCT, randomized controlled trial; t.i.d., three times daily; UC, ulcerative colitis; UC DAI; ulcerative colitis disease activity index. detected in the likelihood of experiencing any adverse event with 5-ASAs compared with placebo (RR = 1.02; 95 % CI ). The relative risk for each individual adverse event is provided in Table 2. There was no statistically significant difference detected in the frequency of any individual adverse event with 5-ASA vs. placebo, with the exception of a lower risk of abdominal pain with active therapy (RR = 0.44; 95 % CI ). Efficacy and safety of high-dose 5-ASAs vs. standard-dose 5-ASAs in inducing in active UC We identified 10 RCTs that compared a total daily dose of > 2.5 g of 5-ASA with a dose of 2 g to 2.5 g in 2,414 patients with active UC ( 22,24 26,28,30 33,53 ). All 10 trials used mesalamine, and followed patients up at 4 8 weeks. Of the RCTs, eight recruited patients with mildly to moderately active UC ( 22,24 26,30 32,53 ), one trial also recruited patients with severely active UC ( 28 ), and the final trial recruited only patients with moderately active disease ( 33 ). None of the trials were at low risk of bias. The detailed trial characteristics are provided in Table 3. When data were pooled, failure to achieve occurred in 777 (69.1 % ) of 1,124 patients randomized to high-dose 5- ASA, compared with 906 (70.2 % ) of 1,290 patients allocated to standard dose. The RR of failure to achieve with high-dose 5-ASA vs. standard dose in active UC was 0.95 (95 % CI ), with borderline statistically significant heterogeneity between trial results ( I 2 = 27 %, P = 0.19; Figure 3 ), and no evidence of funnel plot asymmetry (Egger test, P = 0.08). When risk difference was used as a summary statistic, in a post hoc sensitivity analysis, there was a statistically significant effect with high-dose 5-ASA being superior to standard-dose 5-ASA, although the effect was extremely modest (NNT = 25; 95 % CI = , P = 0.04). A total of seven trials provided extractable adverse events data ( 25,26,30 33,53 ), but data available for pooling were limited. There was no statistically significant difference detected in total number of adverse events (RR = 1.00; 95 % CI ), nausea or vomiting (RR = 0.65; 95 % CI ), headache (RR = 0.97; 95 % CI ), or abdominal The American Journal of GASTROENTEROLOGY VOLUME 106 APRIL

9 5-ASAs in Ulcerative Colitis: A Meta-Analysis 609 High/standard dose 5-ASA Low-dose 5-ASA Risk ratio Study or subgroup Mesalamine Events Total Events Total Weight M-H, random, 95% CI Year Schroeder % 0.84 (0.65, 1.09) 1987 Riley % 0.89 (0.60, 1.32) 1988 Miglioli % 0.83 (0.66, 1.04) 1990 Sninsky % 1.00 (0.87, 1.15) 1991 Hanauer % 0.90 (0.73, 1.11) 1993 Kruis % 0.81 (0.63, 1.04) 2003 D Haens % 0.78 (0.61, 0.99) % 0.89 (0.82, 0.97) Heterogeneity: τ 2 = 0.00; χ 2 = 5.37, d.f. = 6 (P = 0.50); I 2 = 0% Test for overall effect: Z = 2.73 (P = 0.006) Risk ratio M-H, random, 95% CI Balsalazide Levine Heterogeneity: not applicable Test for overall effect: Z = 0.16 (P = 0.87) % 20.8% 0.99 (0.84, 1.16) 0.99 (0.84, 1.16) 2002 Total (95% CI) Heterogeneity: τ 2 = 0.00; χ 2 = 6.75, d.f. = 7 (P = 0.46); I 2 =0% Test for overall effect: Z = 2.50 (P = 0.01) Test for subgroup differences: not applicable % 0.91 (0.85, 0.98) Favors high/standarddose Favors low-dose Figure 4. Forest plot of randomized controlled trials of high- or standard-dose 5-aminosalicylic acids (5-ASAs) vs. low-dose 5-ASAs in inducing in active ulcerative colitis (UC). M-H, Mantel-Haenszel. pain (RR = 0.82; 95 % CI ) with high- vs. standarddose 5-ASA. Efficacy and safety of high- or standard-dose 5-ASAs vs. lowdose 5-ASAs in inducing in active UC Th ere were eight RCTs that compared a total daily dose of 2 g of 5-ASA with < 2 g in 1,015 patients with active UC ( 21,23,24,28,29,31,34,35 ). Of these trials, seven used mesalamine ( 21,23,24,28,31,34,35 ), and the eighth used balsalazide ( 29 ). Follow-up was at 4 8 weeks. Of the trials, six recruited patients with mild to moderately active UC, but two also included patients with severely active disease ( 28,29 ). Only one RCT was at low risk of bias ( 21 ). The detailed trial characteristics are provided in Table 4. Overall, 380 (58.7%) of 647 patients receiving high- or standard-dose 5-ASA failed to achieve compared with 257 (69.8%) of 368 assigned to low-dose 5-ASA. The RR of failure to achieve was 0.91 (95% CI ), with no heterogeneity between trial results ( I 2 = 0 %, P = 0.46; Figure 4 ), but evidence of funnel plot asymmetry (Egger test, P = 0.02). The NNT with high- or standard-dose 5-ASA to achieve in one patient was 13 (95% CI 8 50). This beneficial effect appeared to be limited to mesalamine (RR = 0.89; 95 % CI , I 2 = 0 %, P = 0.50), with the NNT of 11 (95% CI 7 33). A total of six trials reported adverse events data ( 21,23,29,31, 34,35 ). There was no increase in overall adverse events (RR = 0.91; 95 % CI ), nausea or vomiting (RR = 1.04; 95 % CI ), headache (RR = 0.85; 95 % CI ), or abdominal pain (RR = 1.78; 95 % CI ) with high- or standarddose 5-ASA vs. low-dose 5-ASA. Efficacy and safety of standard-dose 5-ASAs vs. low-dose 5-ASAs in inducing in active UC There were six trials comparing a total daily dose of g of 5- ASA with < 2 g in 515 patients with active UC ( 23,24,28,29,31,34 ). None of the RCTs were at low risk of bias. There were 189 (72.1 % ) of 262 patients receiving standard-dose 5-ASA who failed to achieve, compared with 195 (77.1 % ) of 253 randomized to low-dose 5-ASA. The RR of failure to achieve with standard-dose 5-ASA was 0.95 (95 % CI ), with no statistically significant heterogeneity between studies ( I 2 = 0 %, P = 0.62), but evidence of funnel plot asymmetry (Egger test, P = 0.03). Adverse events data were provided by four of these six trials ( 23,29,31,34 ). Total numbers of adverse events (two trials: RR = 0.85; 95 % CI ) and individual adverse events such as nausea or vomiting (two trials: RR = 1.08; 95 % CI ) or headache (three RCTs: RR = 0.70; 95 % CI ) were no higher with standard- vs. low-dose 5-ASA, although there was a trend toward a higher incidence of abdominal pain with standarddose 5-ASA (three trials: RR = 2.12; 95 % CI ). Efficacy and safety of 5-ASAs vs. placebo in preventing relapse in quiescent UC We identified 11 trials of 5-ASAs vs. placebo in quiescent UC ( 36 45,52 ), containing a total of 1,502 patients, 849 of whom were randomized to receive 5-ASA, and 653 to placebo. Relapse data were reported between 6 and 12 months. Two of the RCTs were at low risk of bias (38,44 ). The detailed characteristics of individual trials are provided in Table 5. In total, 342 (40.3 % ) of 5-ASA patients relapsed compared with 409 (62.6 % ) of placebo patients (RR of relapse = 0.65; 95 % CI ), with significant heterogeneity between studies 2011 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

10 610 Ford et al. Table 5. Characteristics of RCTs of 5-ASAs vs. placebo in preventing relapse in quiescent UC Study Misiewicz et al. ( 36 ) Dissanayake and Truelove ( 37 ) Country, and number of centers Disease distribution Criteria used to define relapse UK, 1 site Not reported Hemorrhagic mucosa at sigmoidoscopy UK, 1 site Not reported Infl ammation on sigmoidoscopy Riis et al. ( 38 ) Denmark, 1 site Not reported Rectal bleeding for > 3 successive days or > 3 stools per day for > 5 successive days Sandberg- Gertzen et al. ( 39 ) Lauritsen et al. ( 40 ) Wright et al. ( 41 ) Miner et al. ( 42 ) The Mesalamine Study Group (MSG) ( 43 ) Hawkey et al. ( 44 ) Ardizzone et al. ( 45 ) Lichtenstein et al. ( 52 ) Sweden, 1 site Denmark, 3 South Africa, 1 site USA, multiple USA, 17 Multinational, 30 Italy, 1 site USA and Russia, % pancolitis, 51 % distal colitis, 8 % proctitis 27 % pancolitis, 46 % distal colitis, 27 % proctitis 20 % pancolitis, 80 % left-sided colitis or proctitis Bloody diarrhea and active infl ammation at sigmoidoscopy Recurrence of symptoms and endoscopic signs of infl ammation Recurrence of diarrhea felt by physician to warrant rectal or oral corticosteroid therapy Not reported Sigmoidoscopic index 5 out of 15, and 5 stools or rectal bleeding for 3 of 7 successive days 28 % pancolitis, 18 % left-sided colitis, 39 % Number of patients 5-ASA used 80 Sulfasalazine 500 mg q.i.d. 64 Sulfasalazine 500 mg q.i.d. 49 Sulfasalazine at dose previously taking 101 Olsalazine 500 mg b.i.d. 11 Sulfasalazine 1 g b.i.d. 101 Olsalazine 500 mg q.i.d. 205 Mesalamine (Pentasa) 1 g q.i.d. Endoscopic relapse 264 Mesalamine (Asacol) 400 mg b.i.d. or q.i.d. Not reported Sigmoidoscopic score of 1 out of 4, or rectal bleeding 3 consecutive days, or liquid stools for 1 week 20 % pancolitis, 35 % left-sided colitis, 45 % Increased stool frequency with blood or mucus and evidence of active disease at sigmoidoscopy Not reported Rectal bleeding score 1, and a mucosal appearance score 2 on the SDAI, a fl are, or initiation of medication previously used to treat a UC fl are 210 Mesalamine 400 mg q.i.d. 112 Mesalamine (Asacol) 400 mg t.i.d. 305 Mesalamine 1.5 g o.d. Duration of therapy Methodology 12 Months Randomization and 6 Months Randomization unclear, stated, double 6 Months Randomization and stated, double 6 Months Randomization and 6 Months Randomization stated, 12 Months Randomization and 12 Months Randomization and 6 Months Randomization stated, 6 Months Randomization and stated, double 12 Months Randomization and 6 Months Randomization and 5-ASA, 5-aminosalicylic acid; b.i.d., twice daily; o.d., once daily; q.i.d., four times daily; RCT, randomized controlled trial; SDAI, Sutherland disease activity index; t.i.d., three times daily; UC, ulcerative colitis. ( I 2 = 52 %, P = 0.02; Figure 5 ). There was no evidence of funnel plot asymmetry (Egger test, P = 0.15). The NNT with 5-ASAs to prevent one patient with quiescent UC relapsing was 4 (95 % CI 3 7). Overall, there was no statistically significant difference between the type of 5- ASA therapy used and efficacy at preventing relapse in quiescent UC (Cochrane Q = 1.23, P = 0.54). We conducted sensitivity analyses according to the criteria used to define relapse. Three trials, containing 408 patients, used endoscopic criteria ( 36,37,43 ). The RR of endoscopic relapse with 5-ASAs vs. placebo was 0.56 (95 % CI ), with statistically significant heterogeneity between studies ( I 2 = 76 %, P = 0.01), and the NNT of 4 (95 % CI 2 9). Also, six RCTs used a combination of clinical criteria and endoscopic findings in 944 patients ( 39,40,42,44,45,52 ). In this analysis, the beneficial effect of 5-ASAs in preventing relapse remained (RR = 0.59; 95 % CI ), but the observed heterogeneity The American Journal of GASTROENTEROLOGY VOLUME 106 APRIL

11 5-ASAs in Ulcerative Colitis: A Meta-Analysis ASA Placebo Risk ratio Study or subgroup Sulfasalazine Events Total Events Total Weight M-H, random, 95% CI Year Misiewicz % 0.58 (0.39, 0.87) 1965 Riis % 0.82 (0.32, 2.10) 1973 Dissanayake % 0.22 (0.08, 0.58) 1973 Lauritsen % 0.10 (0.01, 1.43) % 0.45 (0.23, 0.89) Heterogeneity: τ 2 = 0.22; χ 2 = 6.23, d.f. = 3 (P = 0.10); I 2 = 52% Test for overall effect: Z = 2.32 (P = 0.02) Risk ratio M-H, random, 95% CI Mesalamine Miner MSG Hawkey Ardizzone Lichtenstein Heterogeneity: τ 2 = 0.01; χ 2 = 6.93, d.f. = 4 (P = 0.14); I 2 = 42% Test for overall effect: Z = 5.42 (P < ) 17.1% 17.1% 13.2% 5.3% 13.1% 65.8% 0.56 (0.47, 0.68) 0.78 (0.65, 0.95) 0.68 (0.51, 0.90) 0.51 (0.28, 0.95) 0.65 (0.48, 0.86) 0.65 (0.56, 0.76) Olsalazine Sandberg-Gertzen 1986 Wright Heterogeneity: τ 2 = 0.13; χ 2 = 3.43, d.f. = 1 (P = 0.06); I 2 = 71% Test for overall effect: Z = 1.08 (P = 0.28) % 13.4% 19.1% 0.51 (0.29, 0.92) 0.91 (0.69, 1.21) 0.72 (0.40, 1.30) Total (95% CI) Heterogeneity: τ 2 = 0.03; χ 2 = 20.82, d.f. = 10 (P = 0.02); I 2 = 52% Test for overall effect: Z = 5.25 (P < ) Test for subgroup differences: not applicable 100.0% 0.65 (0.55, 0.76) Favors 5-ASA Favors placebo Figure 5. Forest plot of randomized controlled trials of 5-aminosalicylic acids (5-ASAs) vs. placebo in preventing relapse in quiescent ulcerative colitis (UC). M-H, Mantel-Haenszel; MSG, Mesalamine Study Group. between studies disappeared ( I 2 = 0 %, P = 0.59), with the NNT of 4 (95 % CI 2 6). Efficacy of sulfasalazine vs. placebo in preventing relapse in quiescent UC There were four trials of sulfasalazine vs. placebo for the prevention of relapse of quiescent UC ( 36 38,40 ), containing 204 patients reporting relapse data at 6 12 months. There were 28 (26.4 % ) of 106 patients randomized to sulfasalazine who relapsed, compared with 56 (57.1 % ) of 98 allocated to placebo. The RR of relapse with sulfasalazine compared with placebo was 0.45 (95 % CI ; Figure 5 ), with statistically significant heterogeneity between studies ( I 2 = 52 %, P = 0.10), and the NNT of 3 (95 % CI 2 8). Efficacy of mesalamine vs. placebo in preventing relapse in quiescent UC Of the trials five studied the efficacy of mesalamine in preventing relapse of quiescent UC in 1,096 patients ( 42 45,52 ). In total, 271 (42.2 % ) of 642 patients relapsed with mesalamine compared with 295 (65.0 % ) of 454 with placebo. The RR of relapse was significantly reduced with mesalamine therapy (RR = 0.65; 95 % CI ; Figure 5 ), with statistically significant heterogeneity between studies ( I 2 = 42 %, P = 0.14) and the NNT of 4 (95 % CI 3 8). Efficacy of olsalazine vs. placebo in preventing relapse in quiescent UC There were only two trials that used olsalazine in 202 patients with quiescent UC ( 39,41 ). Overall, 43 (42.6 % ) of 101 patients assigned to olsalazine relapsed compared with 58 (57.4 % ) of 101 allocated to placebo. There was no statistically significant difference detected between olsalazine and placebo in terms of preventing relapse of quiescent UC (RR = 0.72; 95 % CI ; Figure 5 ). Adverse events with 5-ASAs vs. placebo in preventing relapse in quiescent UC Only five trials provided extractable adverse events data ( 37,42 44,52 ). No statistically significant differences were detected in the incidence of total adverse events (RR of experiencing any adverse event = 0.98; 95 % CI ), nausea or vomiting (RR = 1.76; 95 % CI ), or headache (RR = 1.23; 95 % CI ) with 5-ASA vs. placebo. Efficacy and safety of high-dose 5-ASAs vs. standard-dose 5-ASAs in preventing relapse in quiescent UC There was only one trial that compared high-dose 5-ASA with standard-dose 5-ASA in preventing relapse in quiescent UC after 6 months of therapy ( 46 ), in 113 patients. Sigmoidoscopic relapse 2011 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

12 612 Ford et al. Table 6. Characteristics of randomized controlled trials of high- or standard-dose 5-ASAs vs. low-dose 5-ASAs in preventing relapse in quiescent UC Study Azad Khan et al. ( 46 ) Country, and number of centers Disease distribution Criteria used to define relapse Number of patients 5-ASA used UK, 1 site Not reported Sigmoidoscopic relapse 170 Sulfasalazine 1, 2, or 4 g daily Green et al. ( 47 ) UK, 4 33 % pancolitis, 40 % left-sided colitis, 27 % Travis et al. ( 48 ) Fockens et al. ( 49 ) UK and Sweden, 2 Holland, 12 Kruis et al. ( 50 ) Germany, 21 Paoluzi et al. ( 51 ) Italy, 1 site Kruis et al. ( 54 ) Multinational, % pancolitis, 48 % left-sided colitis, 17 % 22 % pancolitis, 28 % left-sided colitis, 50 % 40 % pancolitis, 34 % left-sided colitis, 24 % 23 % pancolitis, 77 % left-sided colitis Increased stool frequency for 1 week and friable mucosa or spontaneous hemorrhage at sigmoidoscopy Increase in bowel frequency with blood or mucus and active disease on sigmoidoscopy Clinical assessment and sigmoidoscopic score of > 2 out of Balsalazide 3 or 6 g daily 198 Olsalazine 500 mg, 1 g, or 2 g daily 169 Mesalamine (Pentasa) 500 mg or 1 g t.i.d. CAI 6 and EI > 4 89 Balsalazide 1.5 or 3 g b.i.d. Clinical or endoscopic relapse 156 Mesalamine (Asacol) 400 or 800 mg t.i.d. Not reported EI > Mesalamine (Salofalk) 3 g o.d., 1.5 g o.d., or 500 mg t.i.d. Duration of therapy Methodology 6 Months Randomization,, and ing unclear 12 Months Randomization and 12 Months Randomization,, and ing unclear 12 Months Randomization and 6 Months Randomization and 12 Months Randomization and unclear, single 12 Months Randomization and stated, double 5-ASA, 5-aminosalicylic acid; b.i.d., twice daily; CAI, clinical activity index; o.d., once daily; EI, endoscopic index; RCT, randomized controlled trial; t.i.d., three times daily; UC, ulcerative colitis. occurred in 5 (8.9 % ) of 56 patients assigned to 4 g of sulfasalazine per day, compared with 6 (10.5 % ) of 57 allocated to 2 g per day. Adverse events occurred in 21 (37.5 % ) of the 56 patients receiving 4 g of sulfasalazine, but total numbers of adverse events occurring with 2 g per day were not reported. Efficacy and safety of high- or standard-dose 5-ASAs vs. lowdose 5-ASAs in preventing relapse in quiescent UC We identified seven RCTs that compared a total daily dose of 5-ASA of 2 with < 2 g ( 46 51,54 ). Three trials used mesalamine ( 49,51,54 ), two used balsalazide ( 47,50 ), and one each used sulfasalazine ( 46 ) and olsalazine ( 48 ). Relapse data, in the 1,534 included patients, were reported between 6 and 12 months. One of the RCTs was at low risk of bias ( 54 ). In two trials, whether or not ing was employed was unclear ( 46,48 ), and a third trial was single ( 51 ). The detailed characteristics of individual trials are provided in Table 6. In total, 225 (34.7 % ) of 649 high- or standard-dose 5-ASA patients relapsed compared with 379 (42.8 % ) of 885 low-dose 5-ASA patients (RR of relapse = 0.79; 95 % CI ), with significant heterogeneity between studies ( I 2 = 59 %, P = 0.02; Figure 6 ). There was evidence of funnel plot asymmetry (Egger test, P = 0.03). The NNT with high- or standard-dose 5-ASAs to prevent one patient with quiescent UC relapsing was 10 (95 % CI 5 33). Of the individual 5-ASA drugs studied, only high- or standard-dose sulfasalazine appeared to be of benefit compared with low dose in one RCT (RR of relapse = 0.35; 95 % CI ), with no statistically significant difference detected between high- or standard-dose and low-dose mesalamine, olsalazine, and balsalazide. However, when the efficacies of the different types of 5-ASA were compared indirectly, there was no statistically significant difference in efficacy between them (Cochrane Q = 7.16, P = 0.07). Four trials reported adverse events data ( 48 50,54 ). Overall, adverse events occurred in 89 (38.3 % ) of 402 patients assigned to high- or standard-dose 5-ASA compared with 306 (43.8 % ) of 698 allocated to low-dose 5-ASA. The RR of adverse events was no higher with high- or standard-dose 5-ASA (1.09; 95 % CI ). Individual adverse events were not reported by any of the RCTs. Efficacy and safety of standard-dose 5-ASAs vs. low-dose 5-ASAs in preventing relapse in quiescent UC Five RCTs compared g of 5-ASA per day with < 2 g ( 46 48,50,51 ), and reported relapse rates between 6 and 12 months in 661 patients. None of the RCTs were at low risk of bias. There The American Journal of GASTROENTEROLOGY VOLUME 106 APRIL