5-aminosalicylic acid agents for prevention of recurrent diverticulitis: A systematic review and meta-analysis

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1 bs_bs_banner doi: /jgh META ANALYSIS AND SYSTEMATIC REVIEW 5-aminosalicylic acid agents for prevention of recurrent diverticulitis: A systematic review and meta-analysis Seigo Urushidani,*, Akira Kuriyama and Masami Matsumura* *Division of General Medicine, Center for Community Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Departments of Emergency Medicine, Emergency and Critical Care Center, and General Medicine, Kurashiki Central Hospital, Kurashiki, Okayama, Japan Key words aminosalicylic acid, diverticulitis, mesalamine, recurrence. Accepted for publication 11 June Correspondence Dr Seigo Urushidani, Department of Emergency Medicine, Emergency and Critical Care Center, Kurashiki Central Hospital, Miwa, Kurashiki, Okayama , Japan. sei5uru4@gmail.com Disclosures: All authors have nothing to disclose. Abstract Background and Aim: Prevalence of colonic diverticulosis is increasing worldwide with age, and up to 25% of patients who have colonic diverticulosis might experience diverticulitis. However, a definitive approach of preventing recurrent diverticulitis remains unknown. 5-aminosalicylic acid (5-ASA) agents are anti-inflammatory agents and have been used to prevent recurrent diverticulitis, and there have been some randomized clinical trials (RCTs). However, the efficacy results for secondary prevention in uncomplicated diverticulitis differed across studies. Our aim was to clarify the efficacy and safety of 5-ASA agents in the prevention of recurrent diverticulitis. Methods: We searched MEDLINE, EMBASE, Web of Science, and the Cochrane library with no language restrictions. Two reviewers independently assessed and selected RCTs. The data were pooled using a random effect model and were presented in the pooled risk ratio (RR) and 95% confidence interval (CI). Cochrane s Q and I-squared statistics were used to assess heterogeneity. The protocol was registered at PROSPERO. Results: Seven articles with eight RCTs from 329 potentially relevant articles were included. 5-ASA agents were not superior to controls in preventing recurrent diverticulitis (RR 0.86, 95% CI 0.63 to 1.17, I 2 = 60%) and the incidence of adverse events was not different between 5-ASA agents and controls (RR 0.97, 95% CI 0.84 to 1.11, I 2 = 45%). However, some included studies were few in number of participants and substantial risk of bias. Conclusions: 5-aminosalicylic acid agents were not associated with prevention of recurrent diverticulitis. Introduction The prevalence of colonic diverticulosis is increasing worldwide. 1 The prevalence of colonic diverticulosis is also increasing with aging. 2 About 4% to 25% of patients who have colonic diverticulosis might experience diverticulitis in their lifetime. 2 5 Although the number of admissions due to diverticular bleeding decreased from 2000 to 2010, the number of admissions due to diverticulitis had tended to increase through 2008 in the United States. 6 In 2009, diverticulitis without hemorrhage was the third most common reason for hospitalization among gastrointestinal diseases, and if diverticular hemorrhage is added, these two conditions account for the largest number of gastrointestinal diseases and cost 2.6 billion dollars per year. 7 Treatments of diverticulitis include conservative treatments and surgery. From a retrospective chart review of uncomplicated diverticulitis patients who were managed without surgery, 23% experienced recurrence, 5% developed complicated diverticulitis, and 3% needed surgery. 8 Another retrospective cohort study also showed that 5-year cumulative incidence of readmission was 9.0% in patients who discharged with non-operative management after a first episode of diverticulitis. 9 Diverticulitis also influences quality of life (QOL). Health-related QOL was decreased, and the prevalence of depression was increased in patients who experienced a diverticulitis attack. 10 Thus, the prevention of recurrent acute diverticulitis is important from the perspective of medical expenses and patients QOL. Recently, several ways of preventing diverticulitis, such as a high-fiber diet, antibiotics, probiotics, surgery, and antiinflammatory agents, have been considered. 1 However, a definitive approach remains unknown. 5-aminosalicylic acid (5-ASA) agents are anti-inflammatory agents and used mainly in inflammatory bowel disease. Sulfasalazine had been made as drug for rheumatoid arthritis in the 1940s. 11 Sulfasalazine is a molecule of 5-ASA and sulfapyridine. However, because sulfapyridine has dose-dependent toxicity and a high incidence of side effects, use of sulfasalazine was limited. To resolve this problem, 5-ASA active moieties with a delayed release formulation such as mesalamine, olsalazine, and balsalazide have been developed. 11 Recently, 5-ASA agents have been used to prevent diverticulitis or symptomatic uncomplicated diverticular disease (SUDD), and there have been some randomized clinical trials (RCTs). However, the efficacy results for secondary prevention in uncomplicated diverticulitis differed from study to study. Our aim was, thus, to conduct a systematic review and clarify the efficacy and safety of 5-ASA agents in preventing recurrent diverticulitis. 12 Journal of Gastroenterology and Hepatology 33 (2018) 12 19

2 S Urushidani et al. 5ASA to prevent recurrent diverticulitis Methods The Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) statement 12 was followed, and the protocol was registered at PROSPERO (CRD ). MEDLINE, EMBASE, the Web of Science, and the Cochrane central register of controlled trials (CENTRAL) were searched for randomized trials of 5-ASA agents for preventing recurrent diverticulitis. The MEDLINE search strategy was: ( aminosalicylic acid OR mesalamine OR olsalazine OR balsalazide OR sulfasalazine) AND (diverticulitis OR diverticulosis OR diverticular disease OR diverticulum OR diverticular). The search strategy was adapted for each database. Unpublished studies were also searched using ClinicalTrials.gov. In addition, hand searches of references of retrieved studies were also performed. Attempts were made to contact original authors about unpublished data and unclear information. The authors were considered unresponsive, when three e- mails were sent and no reply was obtained. There were no language restrictions. The initial date of search was February 25, 2016, and it was updated on December 15, Randomized clinical trials that evaluated the efficacy and safety of 5-ASA agents for the prevention of recurrent diverticulitis were included. Patients were 18 years old or older, and they had a history of uncomplicated diverticulitis and remission. The diagnosis of diverticulitis was left to each study. The 5-ASA agents were sulfasalazine, mesalamine (or mesalazine), balsalazide, and olsalazine. The way of administration and the protocol were not restricted, and the duration of the studies was defined as the longest follow-up time. Comparators were placebo, no treatment, and the treatments that might not have a known effect for prevention of recurrence. Studies of only primary prevention of diverticulitis, studies of patients with complicated diverticulitis, and studies of patients with comprehensive symptomatic diverticular disease and SUDD were excluded. Crossover trials and nonrandomized trials were also excluded. Two authors (S. U. and A. K.) retrieved the data from the included studies according to a predetermined dataset independently. Items of the dataset were as follows: (i) patients characteristics (age and sex); (ii) study characteristics (country of origin, language, and inclusion and exclusion criteria); (iii) information about interventions (kinds of 5-ASA agents, way of administration, dose and protocol of administration, concomitant drugs, and study duration); and (iv) outcomes of interest. Primary outcomes were the number of patients with recurrent diverticulitis and time to recurrence. Secondary outcomes were QOL, subjective symptoms, and adverse events. The third author (M. M.) resolved any disagreements. Two authors (S. U. and A. K.) independently assessed the quality of included studies using Cochrane risk of bias tools. 13 If the assessment differed, the third author (M. M.) was consulted to achieve consensus. For dichotomous outcomes, the data were abstracted into two by two tables, and the relative risk (RR) was evaluated. For continuous outcomes, the weighted mean difference was evaluated. The standardized mean difference was calculated for heterogeneous scales such as QOL. In the main analysis of the diverticulitis recurrence, the denominators were all patients that belonged to one of the groups. We considered the dropouts of both 5-ASA group and controls as recurrence because many of the included studies underreported the reason of dropouts. Only for the study by Stollman et al., we included all patients that entered the followup period for the analysis of recurrent diverticulitis. A metaanalysis was performed with the available data. The data were pooled with a random effect model. 14 To assess heterogeneity, Cochrane s Q and I-squared statistics were used. 15 Substantial heterogeneity was considered present if I 2 was greater than 50%. A sensitivity analysis was performed by excluding the RCTs that administered antibiotics or probiotics as concomitant drugs. We conducted an additional sensitivity analysis that included only RCTs using computed tomography (CT) or ultrasonography (US) for the diagnosis of recurrent episodes. We conducted another two sets of sensitivity analyses, namely, the best-case and worst-case analysis. 13 In the best-case analysis, we considered that the participants in the 5-ASA group that dropped out of the study did not have the recurrent diverticulitis, while those in the control group had the recurrence. 13 The worst-case analysis was the converse. 13 If there were more than 10 included studies, publication bias was assessed using the funnel plot. If there were few outcomes despite author contact, the meta-analysis was not performed, and only the results of outcomes were reported. All analyses were calculated using Review Manager 5.3 ( download). Results Search results. A total of 329 potentially relevant articles (120 from MEDLINE, 118 from EMBASE, 67 from Web of Science, 24 from CENTRAL) were identified. Records were reviewed, and 69 related records were retrieved. After excluding duplicates and studies that did not meet the inclusion criteria, seven articles with eight RCTs were included: two meeting abstracts and five full published articles (Fig. 1) Characteristics of the included studies. The study characteristics are shown in Table 1. Four original authors were contacted about unclear data 16,18 22 ; two of four these authors replied, 18,19,21,22 and one author provided sufficient data. 18,19 Five of eight studies compared mesalamine with placebo. 16,17,21,22 One study administered balsalazide as a 5-ASA agent, and probiotics were administered both to the intervention group and the control group. 19 One study compared mesalamine, placebo, and mesalamine plus probiotics. 20 This study was different from the other seven studies in having a 9-month non-treatment observation period after 12 weeks of intervention. One study compared a combination of mesalamine and rifaximin with rifaximin alone. 18 For previous episodes of diverticulitis, four out of eight RCTs 17,20 22 performed CT or US, one RCT 18 used colonoscopy or double contrast X-ray, and the remaining one RCT 19 used colonoscopy. In PREVENT 1 and PREVENT 2 trials, the investigators performed CT, magnetic resonance imaging, US, sigmoidoscopy or colonoscopy, and barium enema to diagnose previous episodes of diverticulitis. 16 As diagnostic imagings for recurrent episodes of diverticulitis, five out of eight RCTs 16,17,21,22 performed CT or US. Risk of bias. The Cochrane risk of bias is presented in Table 2. Random sequence generation, allocation concealment, and Journal of Gastroenterology and Hepatology 33 (2018)

3 5ASA to prevent recurrent diverticulitis S Urushidani et al. Figure 1 Flow diagram of the study selection process. CENTRAL, Cochrane central register of controlled trials; DD, diverticular disease; RCT, randomized controlled trial; SUDD, symptomatic uncomplicated diverticular disease. blinding of outcome assessment were adequately reported in three studies (37.5%), two studies (25%), and one study (12.5%), respectively. Efficacy. All eight studies reported on recurrence The pooled data also showed that 5-ASA agents were not superior to controls (RR 0.86, 95% confidence interval [CI] 0.63 to 1.17, I 2 = 60%) (Fig. 2) All studies mentioned the time to recurrence Five of eight studies showed that there was no significant difference in the time to recurrence between 5-ASA agents and controls. 16,17,20,22 Raskin et al. reported that time to recurrence was significantly shorter for the groups to whom mesalamine were given (1.2 and 2.4 g) than for the placebo group in PREVENT2. 16 Because we could not obtain the sufficient data from the original investigators, we could not pool the data of time to recurrence. Two studies reported QOL. 16 Both PREVENT1 and PRE- VENT2 did not show differences in health-related QOL and EuroQol 5 dimensions between the 5-ASA group and the placebo group. Adverse events. All studies reported adverse events The pooled data of adverse events were shown in Table 3. The incidence of any adverse events was not different between 5-ASA agents and controls (RR 0.97, 95% CI 0.84 to 1.11, I 2 = 45%) ,20 For adverse events, the numbers of patients with gastrointestinal disorders were reported in four of eight studies. 5-ASA agents were not associated with gastrointestinal disorders (RR 1.05, 95% CI 0.83 to 1.32, I 2 = 33%). 16,18,20 In the same way, patient numbers for abdominal pain were reported in three studies. 16,18 The prevalence of abdominal pain was not significantly different between 5-ASA agents and controls (RR 1.44, 95% CI 0.72 to 2.90, I 2 = 54%). 16,18 Sensitivity analyses. Sensitivity analyses of the recurrence rate were performed (Table 4). In the best-worst case analysis, pooled data were as follows: RR 0.57, 95% CI 0.38 to 0.84, I 2 = 66% in the best-case analysis and RR 1.26, 95% CI 0.85 to 1.87, I 2 = 63% in the worst-case analysis. Comparing with the main analysis, there was no significant differences in the best-case and the worst-case analyses. There was also no significant difference when 5-ASA was compared with only placebo or usual care (RR 1.03, 95% CI 0.86 to 1.24, I 2 = 14%). 16,17,20 There was also no significant difference in pooled data from RCTs in which the diagnosis of recurrence was made by using US or CT (RR 1.05, 95% CI 0.85 to 1.29, I 2 = 30%). 16,17 The data from studies with low selection bias and low detection bias were pooled, and the results showed no significant difference. These sensitivity analyses did not show a significant difference, and these results were consistent with the primary analysis. Discussion The results of the present study suggest that the recurrence rate of diverticulitis was not different between the 5-ASA group and the control group. The results of sensitivity analyses for the recurrence rate were similar to the result of the primary analysis. Although two meeting abstracts 21,22 could not be included, they suggested that 5-ASA agents were not superior to placebo in the prevention of recurrent diverticulitis, and these conclusions were similar to those of the current meta-analysis. The current meta-analysis also showed that the incidence of adverse events was not different between the 5-ASA group and the control group. Traditionally, causes of diverticulitis included obstruction of diverticular sac with fecal stasis, fecalith, or poorly digested food components. These trigger barotrauma, mucosal abrasion, inflammation, and bacterial overgrowth. 1,23 Recently, low-grade inflammation, which pathologically mimics inflammatory bowel disease, was detected through diverticular biopsies. Persistent 14 Journal of Gastroenterology and Hepatology 33 (2018) 12 19

4 S Urushidani et al. 5ASA to prevent recurrent diverticulitis Table 1 Characteristics of included studies Study, year (country) Publication type Number of participants (% women) Patients characteristics and age Interventions and controls Study duration Reported outcomes Raskin et al PREVENT1 (USA) Raskin et al PREVENT2 (USA) Parente et al (Italy) Tursi et al (Italy) Tursi et al (Italy) Full 590 (47) - They had documented episodes - Mesalamine 1.2 g once daily plus three 104 weeks - Diverticulitis recurrencefree of acute diverticulitis previously. matching placebo per day proportion - 18 years of age or older - Mesalamine 2.4 g daily plus two - Time to recurrence matching placebo per day - Mesalamine 4.8 g daily plus one - Proportion of surgical matching placebo per day intervention - Placebo four tablets daily - HRQOL using the EQ-5D and HUI2 - Adverse events Full 592 (54) - They had documented episodes - Mesalamine 1.2 g once daily plus three 104 weeks - Diverticulitis recurrencefree of acute diverticulitis previously. matching placebo per day proportion - 18 years of age or older - Mesalamine 2.4 g daily plus two matching - Time to recurrence placebo per day Mesalamine 4.8 g daily plus one matching - Proportion of surgical placebo per day intervention Placebo four tablets daily - HRQOL using the Full 92 (51) - Patients who were treated for uncomplicated left-sided diverticulitis, within 12 months. Full 218 (40) - Patients who experienced at least two attacks of acute diverticulitis in the previous year. Full 30 (37) - Patients with acute uncomplicated diverticulitis - Mesalazine 800 mg one tablet bid for 10 days every month EQ-5D and HUI2 - Adverse events 24 months - Diverticulitis recurrence - 18 to 85 years old - Placebo one tablet bid for 10 days every month - Time to relapse - Therapy Impact Questionnaire - Additional drugs saving - Side effects - Rifaximin 400 mg bid plus mesalazine 800 mg tid for 7 days, followed by rifaximin 400 mg bid plus mesalazine 800 mg bid for 7 days every month to 79 years old - Rifaximin 400 mg bid for 7 days, followed by rifaximin 400 mg bid for 7 days every month. - First 10 days: balsalazide 2.25 g/day plus rifaximin 800 mg/day. Following 12 months: balsalazide 2.25 g for 10 days/month plus VSL#3 450 billion/day for 15 days every month. 12 months - Recurrent diverticulitis - Bowel habit - Symptoms - Side effects 12 months - Maintaining remission after attack - 47 to 75 years old - Overall scores - Symptoms (Continues) Journal of Gastroenterology and Hepatology 33 (2018)

5 5ASA to prevent recurrent diverticulitis S Urushidani et al. Table 1. (Continued) Study, year (country) Publication type Number of participants (% women) Patients characteristics and age Interventions and controls Study duration Reported outcomes Stollman et al (Italy) Kruis et al (Germany) Kruis et al (Germany) Full 117 (52) - Patients with acute diverticulitis diagnosed by CT Meeting abstract Meeting abstract - First 10 days: balsalazide 2.25 g daily plus rifaximin 800 mg/day. Following 12 months: VSL#3 450 billion/day for 15 days every month. - Standard care (i.e., antibiotics and dietary advice) with mesalamine 400 mg tab*6 (2.4 g) once daily during the first 10 to 14 days and added probiotic capsules (B. infantis 35624) once daily for 12 weeks to 85 years old - Standard care with mesalamine 400 mg tab*6 (2.4 g) once daily during the first 10 to 14 days and added placebo capsules once daily for 12 weeks. 330 (61) - Patients who were treated for uncomplicated left-sided diverticulitis, confirmed by CT within 6 months. - Standard care with placebo tab*6 once daily during the first 10 to 14 days and added placebo capsules once daily for 12 weeks. 12 weeks of treatment and 9 months of follow-up. - Global Symptomatic Score - Markers of inflammation - Requiring surgery for recurrence - Adverse events - Mesalamine granules daily 1.5 g 96 weeks - Proportion of recurrencefree patients at 48 and 96 weeks - 30 to 80 years - Mesalamine granules daily 3 g - Mean days with left lower quadrant pain per week 345 (59) - Patients who were treated for uncomplicated left-sided diverticulitis diagnosed by typical symptoms and cross-sectional imaging within 6 months. - Placebo - Adverse reactions - Mesalamine 3 g daily 48 weeks - Recurrence-free patients - 40 to 80 years old - Placebo 3 g daily - Mean time to recurrence - Left lower quadrant abdominal pain - Treatment-emergent adverse events bid, twice daily; CT, computed tomography; EQ-5D, EuroQol 5 dimensions; HRQOL, health-related quality of life; HUI2, Health Utility Index Mark 2; tid, three times daily. 16 Journal of Gastroenterology and Hepatology 33 (2018) 12 19

6 S Urushidani et al. 5ASA to prevent recurrent diverticulitis Table 2 Risk of bias of included studies Author year Random sequence generation Allocation concealment Blinding of participants and personnel Blinding of outcome assessment Incomplete outcome data Selective reporting Other bias Raskin PREVENT1 Low Unclear Low Unclear Low Low Low Raskin PREVENT2 Low Unclear Low Unclear Low Low Low Parente Unclear Low Low Unclear Unclear Low Low Tursi Unclear Unclear Low Unclear Low Unclear Low Tursi Unclear Unclear Low Unclear Low Unclear Unclear Stollman Low Low Low Low Low High Low Kruis Unclear Unclear Unclear Unclear Unclear Unclear Unclear Kruis Unclear Unclear Unclear Unclear Unclear Unclear Unclear inflammation may play a role in occurrence and recurrence of inflammatory complications of diverticular disease. 1,23,24 Thus, it was thought that anti-inflammatory agents such as 5-ASA agents could prevent recurrent diverticulitis. 11,24 A previous review conducted by Ünlü et al. included only two RCTs of 5-ASA agents. However, they did not pool the data, and the efficacy of 5-ASA Figure 2 Meta-analysis of studies on recurrence. CI, confidence interval; 5-ASA, 5-aminosalicylic acid agents. [Color figure can be viewed at wileyonlinelibrary.com] Table 3 Adverse events of 5-ASA agents Included studies No. of adverse events/total no. of participants Risk ratio (95% CI) Heterogeneity I 2 statistic 5-ASA Controls (P-value) Any adverse events 5 690/ / (0.84 to 0.11) 45% (0.12) Gastrointestinal disorders 4 386/ / (0.83 to 1.32) 33% (0.22) Abdominal pain 3 113/996 28/ (0.72 to 2.90) 54% (0.11) CI, confidence interval; No., number; 5-ASA, 5-aminosalicylic acid. Table 4 Summary of sensitivity analyses for recurrence of diverticulitis Included studies No. of recurrence/total no. of participants 5-ASA Controls Risk ratio (95% CI) Heterogeneity I 2 statistic (P-value) Best-case analysis 6 271/ / (0.38 to 0.84) 66% (0.01) Worst-case analysis 6 379/ / (0.85 to 1.87) 63% (0.24) 5-ASA compared with placebo or usual treatments 4 372/ / (0.86 to 1.24) 14% (0.32) Trials that used CT or US for the diagnosis of recurrence episodes 3 359/ / (0.85 to 1.29) 30% (0.24) Low risk of selection bias (random sequence generation) 3 358/ / (0.92 to 1.29) 0% (0.33) Low risk of selection bias (allocation concealment) 2 27/77 35/ (0.52 to 1.13) 0% (0.17) Low risk of selection bias (blinding of outcome assessors) 1 13/32 14/ (0.48 to 1.48) CI, confidence interval; CT, computed tomography; No., number; US, ultrasonography; 5-ASA, 5-aminosaiycylic acid. Journal of Gastroenterology and Hepatology 33 (2018)

7 5ASA to prevent recurrent diverticulitis S Urushidani et al. agents was still unclear. 25 The present study included eight RCTs and pooled the data, so it was the first meta-analysis of 5-ASA agents for the secondary prevention of diverticulitis. The numbers of previous diverticulitis episodes in patients of included RCTs differed across studies. Sallinen et al. indicated that the number of attacks might be an independent risk factor for uncomplicated recurrent diverticulitis. 26 However, because of the variety in the numbers of previous diverticulitis attacks, we failed to conduct subgroup analysis by the number of previous diverticulitis attacks. Studies that focus on the number of previous diverticulitis attacks might elucidate who will get benefitted with 5-ASA agents. The follow-up periods of RCTs included in our study ranged from 48 to 104 weeks. Trenti et al. conducted a large prospective study about the recurrence of diverticulitis after treating conservatively. 27 It showed that the median time to recurrence was 18 months (about 78 weeks). For RCTs included in our study, four trials 18 20,22 were less than 18 months and one trial was nearly 2 years 21 in length. Future study needs to follow up patients with at least one episode of diverticulitis for a period longer than 18 months. The present study has some strengths, including strict inclusion criteria. Diverticulitis is defined as macroscopic inflammation of diverticula with symptoms and complications. On the other hand, SUDD is defined as persistent symptoms caused by diverticula, with no overt macroscopic inflammation. 28 Thus, diverticulitis and SUDD are different, and both are subtypes of symptomatic diverticular disease. 28,29 Although some RCTs examining the prevention of diverticulitis with 5-ASA agents were identified, they were excluded because patients in these studies had comprehensive symptomatic diverticular disease or SUDD Recently, Khan et al. conducted a systematic review and meta-analysis of 5 RCTs. 37 However, one of the pooled studies 35 also included SUDD, beside acute diverticulitis. Therefore, their study did not simply examine the efficacy of mesalamine for prevention of recurrent diverticulitis. Moreover, they did not mention some of important RCTs about 5-ASA agents for preventing diverticulitis recurrence. 18,19 The present study has some limitations. First, the pooled results have moderate to substantial heterogeneity. One of the reasons for the heterogeneity might be the different protocols for 5-ASA administration. For example, 5-ASA agents were administered daily in PREVENT1 and PREVENT2, 16 but Tursi et al. and Parente et al. administered 5-ASA agents intermittently Moreover, Stollman et al. administered 5-ASA agents for only the first 12- week treatment period. 20 Another reason for the substantial heterogeneity might be concomitant drugs. In some studies, probiotics were administered concurrently, and antibiotics were also administered concurrently in some studies. 18,19 The data of studies in which concomitant drugs were administered to both the intervention group and the control group were pooled. From the study of Stollman et al., 20 the data of the mesalamine with probiotic group were excluded, and the data from only the mesalamine group and the only placebo group were pooled. Second, although the studies were carefully examined, the methodologies of some included studies were still unclear. There were also a small number of studies with a moderate to low risk of bias. Moreover, the participants of some included studies were few in number, and the results of these studies tended to show a larger effect. 38 Thus, the influence of these studies on the pooled data cannot be unconditionally ruled out. A future study should be large with a clear study procedure. We hope that the results of such high-quality studies will facilitate critical appraisals and interpretations about 5-ASA agents for preventing recurrent diverticulitis. When two ongoing studies 21,22 are published, this systematic review and meta-analysis will be updated. References 1 Tursi A. Advances in the management of colonic diverticulitis. CMAJ 2012; 184: Parks TG. Natural history of diverticular disease of the colon. Clin. Gastroenterol. 1975; 4: Stollman NH, Raskin JB. 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