Efficacy of biological therapies and small molecules in moderate to severe ulcerative colitis: systematic review and network meta-analysis.

OBJECTIVE: Biological therapies and small molecules continue to be evaluated in moderate to severely active ulcerative colitis, but are often studied in placebo-controlled trials, meaning their relative efficacy and safety is unknown. We examined this in a network meta-analysis. DESIGN: We searched the literature to October 2021 to identify eligible trials. We judged efficacy using clinical remission, endoscopic improvement, or clinical response, and according to previous exposure or non-exposure to antitumour necrosis factor (TNF)-α therapy. We also assessed safety. We used a random effects model and reported data as pooled relative risks (RRs) with 95% CIs. Interventions were ranked according to their P-score. RESULTS: We identified 28 trials (12 504 patients). Based on failure to achieve clinical remission, upadacitinib 45 mg once daily ranked first versus placebo (RR 0.73; 95% CI 0.68 to 0.80, P-score 0.98), with infliximab 5 mg/kg and 10 mg/kg second and third, respectively. Upadacitinib ranked first for clinical remission in both patients naïve to anti-TNF-α drugs (RR 0.69; 95% CI 0.61 to 0.78, P-score 0.99) and previously exposed (RR 0.78; 95% CI 0.72 to 0.85, P-score 0.99). Upadacitinib was superior to almost all other drugs in these analyses. Based on failure to achieve endoscopic improvement infliximab 10 mg/kg ranked first (RR 0.61; 95% CI 0.51 to 0.72, P-score 0.97), with upadacitinib 45 mg once daily, second, and infliximab 5 mg/kg third. Upadacitinib was more likely to lead to adverse events, but serious adverse events were no more frequent, and withdrawals due to adverse events were significantly lower than with placebo. Infections were significantly more likely with tofacitinib than placebo (RR 1.41; 95% CI 1.03 to 1.91). CONCLUSION: In a network meta-analysis, upadacitinib 45 mg once daily ranked first for clinical remission in all patients, patients naïve to anti-TNF-α drugs and patients previously exposed. Infliximab 10 mg/kg ranked first for endoscopic improvement. Most drugs were safe and well tolerated.

The Comparative Efficacy of Chlorhexidine Gluconate and Povidone-iodine Antiseptics for the Prevention of Infection in Clean Surgery: A Systematic Review and Network Meta-analysis.

OBJECTIVE: There is uncertainty around preoperative skin antisepsis in clean surgery. Network meta-analysis provides more precise estimates than standard pairwise meta-analysis and can rank interventions by efficacy, to better inform clinical decisions. BACKGROUND: Infection is the most common and costly complication of surgery. The relative efficacy of CHG and PVI based skin antiseptics in clean surgery remains unclear. METHODS: We searched for randomized or nonrandomized studies comparing the effect of different preparations of CHG and PVI on the dichotomous outcome of surgical site infection. We included studies of adults undergoing clean surgery. We excluded studies concerning indwelling vascular catheters, blood sampling, combination antiseptics or sequential applications of different antiseptics. We performed a network meta-analysis to estimate the relative efficacy of interventions using relative risks (RR). RESULTS: We included 17 studies comparing 5 antiseptics in 14,593 individuals. The overall rate of surgical site infection was 3%. Alcoholic CHG 4%-5% was ranked as the most effective antiseptic as it halved the risk of surgical site infection when compared to aqueous PVI [RR 0.49 (95% confidence interval 0.24, 1.02)] and also to alcoholic PVI, although uncertainty was larger [RR 0.51 (95% confidence interval 0.21, 1.27)]. Adverse events related to antiseptic application were only observed with patients exposed to PVI. CONCLUSIONS: Alcoholic formulations of 4%-5% CHG seem to be safe and twice as effective as PVI (alcoholic or aqueous solutions) in preventing infection after clean surgery in adults. Our findings concur with the literature on contaminated and clean-contaminated surgery, and endorse guidelines worldwide which advocate the use of alcoholic CHG for preoperative skin antisepsis. REGISTRATION: PROSPERO ID CRD42018113001.

Safety and Outcomes of Different Surgical Techniques for Cubital Tunnel Decompression: A Systematic Review and Network Meta-analysis.

Importance: Cubital tunnel syndrome is the second most common compressive neuropathy, affecting 6% of the population. Numerous different operations are performed globally to treat it; however, prior conventional (pairwise) meta-analyses have been unable to determine which procedure is associated with the best outcomes and fewest complications. Objective: To evaluate which operation for cubital tunnel syndrome is associated with the greatest likelihood of symptomatic cure. Data Sources: PubMed, EMBASE, and CENTRAL were searched from database inception to March 2, 2019, with no restrictions on the setting or design of studies. Study Selection: Experimental and observational studies directly comparing the outcomes of at least 2 surgical treatments for adults with primary cubital tunnel syndrome were included. Case reports were excluded, and when comparative studies had subgroups with 1 participant, the single-participant subgroup was excluded. The treatments had to be in situ decompression with or without medial epicondylectomy or an anterior subcutaneous, subfascial, intramuscular, or submuscular transposition. The access could be open, minimally invasive, or endoscopic. The comparator could be sham surgery or any operation mentioned earlier. Data Extraction and Synthesis: Data were extracted by 2 independent reviewers, following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline and the PRISMA Network Meta-analysis extension statement. Network meta-analysis was used to estimate the relative efficacy and safety associated with interventions using relative risks. Surgical techniques were ranked by their probability of being the best (P score) and interpreted in terms of their clinical impact. Main Outcomes and Measures: The primary outcome was response to treatment (ie, symptomatic improvement). The secondary outcomes were perioperative complications, reoperation, and recurrence. Results: A total of 30 studies of 2894 limbs undergoing 8 different operations were included. Across the studies, 56% of participants were men, the mean (SD) age was 48 (8) years, and patients had symptoms for a mean (SD) of 15 (7) months. Overall, 87% (95% CI, 92%-91%) of patients improved with surgery; all forms of in situ decompression were more effective than any type of transposition procedure; for example, open in situ decompression with epicondylectomy was associated with higher success rates than subcutaneous transposition (relative risk, 1.13; 95% CI, 1.01-1.25). Postoperatively, 3% (95% CI, 2%-4%) of patients developed complications, and in situ decompressions were ranked as the least risky, although there was considerable uncertainty in this outcome. Overall, 2% (95% CI, 1%-3%) of patients required reoperation; open in situ decompression was associated with the fewest reoperations; in comparison, submuscular transposition was associated with 5 times the risk of reoperation (relative risk, 5.08; 95% CI, 2.06-12.52). During surveillance, 3% (95% CI, 1%-4%) of patients developed recurrence, and open in situ decompression with epicondylectomy was ranked as the safest operation, although there was uncertainty in the estimates. Conclusions and Relevance: In this network meta-analysis, open in situ decompression (with or without medial epicondylectomy) appeared to be the safest operation and also was associated with the best outcomes for patients with primary cubital tunnel syndrome. Future research should focus on better defining this disorder and developing core outcome measures.

Causes of Post-Colonoscopy Colorectal Cancers Based on World Endoscopy Organization System of Analysis.

BACKGROUND & AIMS: Postcolonoscopy colorectal cancer (PCCRC) is CRC diagnosed after a colonoscopy in which no cancer was found. A consensus article from the World Endoscopy Organization (WEO) proposed an approach for investigating and categorizing PCCRCs detected within 4 years of a colonoscopy. We aimed to identify cases of PCCRC and the factors that cause them, test the WEO system of categorization, quantify the proportion of avoidable PCCRCs, and propose a target rate for PCCRCs detected within 3 years of a colonoscopy that did not detect CRC. METHODS: We performed a retrospective analysis of 107 PCCRCs identified at a single medical center in England from January 1, 2010, through December 31, 2017 using coding and endoscopy data. For each case, we reviewed clinical, pathology, radiology, and endoscopy findings. Using the WEO recommendations, we performed a root-cause analysis of each case, categorizing lesions as follows: possible missed lesion, prior examination adequate; possible missed lesion, prior examination inadequate; detected lesion, not resected; or likely incomplete resection of previously identified lesion. We determined whether PCCRCs could be attributed to the colonoscopist for technical or decision-making reasons, and whether the PCCRC was avoidable or unavoidable, based on the WEO categorization and size of tumor. The endoscopy reporting system provided performance data for individual endoscopists. RESULTS: Of the PCCRCs identified, 43% were in high-risk patients (those with inflammatory bowel disease, previous CRC, previous multiple large polyps, or hereditary cancer syndromes) and 66% were located distal to the hepatic flexure. There was no correlation between postcolonoscopy colorectal tumor size and time to diagnosis after index colonoscopy. Bowel preparation was poor in 19% of index colonoscopies, and only 36% of complete colonoscopies had adequate photodocumentation of completion. Development of 73% of PCCRCs was determined to be affected by technical endoscopic factors, 17% of PCCRCs by administrative factors (follow-up procedures delayed/not booked by administrative staff), and 27% of PCCRCs by decision-making factors. Twenty-seven percent of PCCRCs were categorized as possible missed lesion, prior examination adequate; 58% as possible missed lesion, prior examination inadequate; 8% as detected lesion, not resected; and 7% as incomplete resection of previously observed lesion; 89% were deemed to be avoidable. CONCLUSIONS: In a retrospective analysis of PCCRCs, using the WEO system of categorization, we found 43% to occur in high-risk patients; this might be reduced with more vigilant surveillance. Measures are needed to reduce technical, decision-making, and administrative factors. We found that 89% of PCCRCs may be avoidable. If half of avoidable PCCRCs could be prevented, the target rate of 2% for the PCCRC-3y (cancer diagnosed between 6 and 36 months after index colonoscopy) benchmark would be achievable.

Efficacy of pharmacological therapies in patients with IBS with diarrhoea or mixed stool pattern: systematic review and network meta-analysis.

OBJECTIVE: Over half of patients with IBS have either diarrhoea (IBS-D) or a mixed stool pattern (IBS-M). The relative efficacy of licenced pharmacological therapies is unclear in the absence of head-to-head trials. We conducted a network meta-analysis to resolve this uncertainty. DESIGN: We searched MEDLINE, Embase, Embase Classic, the Cochrane central register of controlled trials, and Clinicaltrials.gov through January 2019 to identify randomised controlled trials (RCTs) assessing the efficacy of licenced pharmacological therapies (alosetron, eluxadoline, ramosetron and rifaximin) in adults with IBS-D or IBS-M. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Efficacy and safety of all pharmacological therapies were reported as a pooled relative risk with 95% CIs to summarise the effect of each comparison tested. Treatments were ranked according to their p score. RESULTS: We identified 18 eligible RCTs (seven alosetron, five ramosetron, two rifaximin and four eluxadoline), containing 9844 patients. All were superior to placebo for the treatment of IBS-D or IBS-M at 12 weeks, according to the Food and Drug Administration (FDA)-recommended endpoint for trials in IBS. Alosetron 1 mg twice daily was ranked first for efficacy, based on the FDA-recommended composite endpoint of improvement in both abdominal pain and stool consistency, effect on global symptoms of IBS and effect on stool consistency. Ramosetron 2.5µg once daily was ranked first for effect on abdominal pain. Total numbers of adverse events were significantly greater with alosetron 1 mg twice daily and ramosetron 2.5µg once daily, compared with placebo. Rifaximin 550 mg three times daily ranked first for safety. Constipation was significantly more common with all drugs, except rifaximin 550 mg three times daily. CONCLUSION: In a network meta-analysis of RCTs of pharmacological therapies for IBS-D and IBS-M, we found all drugs to be superior to placebo, but alosetron and ramosetron appeared to be the most effective.

Relative Efficacy of Tegaserod in a Systematic Review and Network Meta-analysis of Licensed Therapies for Irritable Bowel Syndrome With Constipation.

Irritable bowel syndrome (IBS) is a chronic functional bowel disorder affecting 1 in 10 people and associated with poor psychological health, reduced quality of life, and increased health care expenditure.1 The etiology is complex and incompletely understood.2 Approximately one-third of patients have IBS with constipation (IBS-C),1 for which there are licensed therapies available in the United States. We summarized comparative efficacy of these in a recent network meta-analysis of randomized controlled trials (RCTs).3 Tegaserod, a 5-hydroxytryptamine-4 receptor agonist, approved by the Food and Drug Administration (FDA) for IBS-C, was withdrawn in 2007 after a small excess number of cerebrovascular and cardiovascular ischemic events in patients taking the drug.4 However, since our network meta-analysis, it has been reintroduced in the United States. It is therefore important to understand its efficacy relative to other available licensed therapies for IBS-C.

Variation in post-colonoscopy colorectal cancer across colonoscopy providers in English National Health Service: population based cohort study.

OBJECTIVES: To quantify post-colonoscopy colorectal cancer (PCCRC) rates in England by using recent World Endoscopy Organisation guidelines, compare incidence among colonoscopy providers, and explore associated factors that could benefit from quality improvement initiatives. DESIGN: Population based cohort study. SETTING: National Health Service in England between 2005 and 2013. POPULATION: All people undergoing colonoscopy and subsequently diagnosed as having colorectal cancer up to three years after their investigation (PCCRC-3yr). MAIN OUTCOME MEASURES: National trends in incidence of PCCRC (within 6-36 months of colonoscopy), univariable and multivariable analyses to explore factors associated with occurrence, and funnel plots to measure variation among providers. RESULTS: The overall unadjusted PCCRC-3yr rate was 7.4% (9317/126 152), which decreased from 9.0% in 2005 to 6.5% in 2013 (P<0.01). Rates were lower for colonoscopies performed under the NHS bowel cancer screening programme (593/16 640, 3.6%), while they were higher for those conducted by non-NHS providers (187/2009, 9.3%). Rates were higher in women, in older age groups, and in people with inflammatory bowel disease or diverticular disease, in those with higher comorbidity scores, and in people with previous cancers. Substantial variation in rates among colonoscopy providers remained after adjustment for case mix. CONCLUSIONS: Wide variation exists in PCCRC-3yr rates across NHS colonoscopy providers in England. The lowest incidence was seen in colonoscopies performed under the NHS bowel cancer screening programme. Quality improvement initiatives are needed to address this variation in rates and prevent colorectal cancer by enabling earlier diagnosis, removing premalignant polyps, and therefore improving outcomes.

Efficacy of drugs in chronic idiopathic constipation: a systematic review and network meta-analysis.

BACKGROUND: There are several drugs available for the treatment of chronic idiopathic constipation, but their relative efficacy is unclear because there have been no head-to-head randomised controlled trials. We did a network meta-analysis to compare the efficacy of these therapies in patients with chronic idiopathic constipation. METHODS: We searched Medline, Embase, Embase Classic, and the Cochrane Central Register of Controlled Trials for randomised controlled trials published from inception to week 3 June, 2019, to identify randomised controlled trials assessing the efficacy of drugs (osmotic or stimulant laxatives, elobixibat, linaclotide, lubiprostone, mizagliflozin, naronapride, plecanatide, prucalopride, tegaserod, tenapanor, or velusetrag) in adults with chronic idiopathic constipation. Participants had to be treated for a minimum of 4 weeks, and we extracted data for all endpoints preferentially at 4 weeks, 12 weeks, or both. Trials included in the analysis reported a dichotomous assessment of overall response to therapy (response or no response to therapy). We pooled the data using a random effects model, and reported efficacy and safety of all treatments as a pooled relative risk (RR) with 95% CIs to summarise the effect of each comparison tested. To rank treatments, we used P-scores, which measure the extent of certainty that a treatment is better than another treatment, averaged over all competing treatments. FINDINGS: We identified 33 eligible randomised controlled trials of drugs, comprising 17 214 patients. Based on an endpoint of failure to achieve three or more complete spontaneous bowel movements (CSBMs) per week, the stimulant diphenyl methane laxatives bisacodyl and sodium picosulfate, at a dose of 10 mg once daily, were ranked first at 4 weeks (RR 0·55, 95% CI 0·48-0·63, P-score 0·99), and prucalopride 2 mg once daily ranked first at 12 weeks (0·82, 0·78-0·86, P-score 0·96). When response to therapy was defined as falilure to achieve an increase of one or more CSBM per week from baseline, diphenyl methane laxatives at a dose of 10 mg once daily ranked first at 4 weeks (0·44, 0·37-0·54, P-score 0·99), with prucalopride 4 mg once daily ranked first at 12 weeks (0·74, 0·66-0·83, P-score 0·79), although linaclotide 290 µg once daily and prucalopride 2 mg once daily had similar efficacy (P-scores of 0·76 and 0·71, respectively). Bisacodyl ranked last in terms of safety for total number of adverse events and abdominal pain (P-score 0·08). INTERPRETATION: Almost all drugs studied were superior to placebo, according to either failure to achieve three or more CSBMs per week or or failure to achieve an increase of one or more CSBM per week over baseline. Although diphenyl methane laxatives ranked first at 4 weeks, patients with milder symptoms might have been included in these trials. Prucalopride ranked first at 12 weeks, and many of the included trials recruited patients who previously did not respond to laxatives, suggesting that this drug is likely to be the most efficacious for patients with chronic idiopathic constipation. However, because treatment duration in most trials was 4-12 weeks, the long-term relative efficacy of these drugs is unknown. FUNDING: None.

Management of benign oesophageal strictures.

Benign oesophageal strictures are an important gastrointestinal condition that can cause substantial morbidity. There are many different aetiologies and each case needs careful evaluation and individualised treatment. Management usually involves targeting therapy to the underlying cause, but oesophageal dilatation is an important part of the algorithm. The recent British Society of Gastroenterology guidelines provide advice on the use of dilatation for benign strictures and cover patient preparation, the dilatation procedure and disease-specific considerations. This article provides a summary of the key messages from the guidelines and applies them to routine clinical practice. It also includes practical advice on the clinical assessment, investigation and management of benign oesophageal strictures and gives an approach to the management of refractory strictures. Areas where evidence is sparse and further research is needed are highlighted.

Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: systematic review and network meta-analysis.

OBJECTIVE: Opioids are increasingly prescribed in the West and have deleterious GI consequences. Pharmacological therapies to treat opioid-induced constipation (OIC) are available, but their relative efficacy is unclear. We performed a systematic review and network meta-analysis to address this deficit in current knowledge. DESIGN: We searched MEDLINE, EMBASE, EMBASE Classic and the Cochrane central register of controlled trials through to December 2017 to identify randomised controlled trials (RCTs) of pharmacological therapies in the treatment of adults with OIC. Trials had to report a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Efficacy and safety of pharmacological therapies was reported as a pooled relative risk (RR) with 95% CIs to summarise the effect of each comparison tested and ranked treatments according to their P-score. RESULTS: Twenty-seven eligible RCTs of pharmacological therapies, containing 9149 patients, were identified. In our primary analysis, using failure to achieve an average of ≥3 bowel movements (BMs) per week with an increase of ≥1 BM per week over baseline or an average of ≥3 BMs per week, to define non-response, the network meta-analysis ranked naloxone first in terms of efficacy (RR=0.65; 95% CI 0.52 to 0.80, P-score=0.84), and it was also the safest drug. When non-response to therapy was defined using failure to achieve an average of ≥3 BMs per week, with an increase of ≥1 BM per week over baseline, naldemedinewas ranked first (RR=0.66; 95% CI 0.56 to 0.77, P score=0.91) and alvimopan second (RR=0.74; 95% CI 0.57 to 0.94, P-score=0.71). CONCLUSION: In network meta-analysis, naloxone and naldemedine appear to be the most efficacious treatments for OIC. Naloxone was the safest of these agents.

Decreasing Risk of First and Subsequent Surgeries in Patients With Crohn's Disease in England From 1994 through 2013.

BACKGROUND & AIMS: Gastrointestinal (GI) surgery is an important part of the treatment algorithm for patients with Crohn's disease (CD) that is complicated or does not respond to medical therapy. Cohort studies from Denmark and Canada have shown that the risk of primary surgery is decreasing but there is a lack of contemporary data on subsequent resections. We examined trends in first and second GI resections in patients with CD. METHODS: We performed a retrospective cohort study using the United Kingdom primary care database ResearchOne, collecting data from patients with Crohn's disease from 1994 through 2013. We compared rates of first and second GI resections with etiological factors. RESULTS: Among 3059 incident cases of CD, 13%, 21%, and 26% of the patients underwent surgical resections after 1, 5, and 10 years, respectively. Of patients with an initial resection, 20% required an additional operation when followed for 10 years after the initial resection. We found a significant reduction in first surgery, from 44% to 21% after 10 years of disease, from 1994 to 2003 (χ2 for trend, P < .05). There was a significant reduction in second resections, in a 10-year follow-up period, from 40% in 1994 to 17% in 2003 (χ2 for trend, P < .05). Duration of disease, younger age at diagnosis, smoking, and immunomodulator use were positively associated with first surgeries. Duration of disease was significantly associated with the risk of undergoing a second resection. CONCLUSION: In a retrospective analysis of a United Kingdom primary care database, we observed a significant reduction in first and subsequent GI surgeries among patients with CD over the past 20 years in England.

Systematic Review and Network Meta-Analysis of Medical Therapies to Prevent Recurrence of Post-Operative Crohn's Disease.

BACKGROUND AND AIMS: Surgery is an important treatment for Crohn's disease [CD], but recurrence occurs in up to 80% of individuals post-operatively. The efficacy of several drugs to prevent post-operative recurrence has been studied in previous meta-analyses, but a number of randomized controlled trials [RCTs] have recently been published. We therefore performed an updated systematic review and network meta-analysis to investigate this issue. METHODS: We performed a comprehensive literature search through to July 2018 to identify RCTs investigating the endoscopic and clinical recurrence of CD at 12 months post-operatively. We performed a random-effects network meta-analysis to produce a pooled relative risk [RR] with 95% confidence intervals [CIs]. We ranked the treatments according to their P-score. RESULTS: We included 10 RCTs, containing 751 patients, in our primary analysis of endoscopic recurrence of CD at 12 months. Anti-tumour necrosis factor [TNF]-α therapies were significantly better than placebo, either alone [P-score 0.98, RR 0.13; 95% CI 0.04-0.39] or in combination with 5-aminosalicylates [5-ASAs] [P-score 0.81, RR 0.30; 95% CI 0.12-0.75], or 5-nitroimidazoles [P-score 0.75, RR 0.40; 95% CI 0.23-0.69]. Combination therapy with a thiopurine and 5-nitroimidazole was also more effective than placebo [P-score 0.59, RR 0.56; 95% CI 0.40-0.80], as was thiopurine monotherapy [P-score 0.31, RR 0.84; 95% CI 0.74-0.94]. However, neither 5-nitroimidazoles nor 5-ASAs alone were superior to placebo. CONCLUSIONS: In network meta-analysis, anti-TNF-α therapies alone, or in combination, appear to be the best medications for preventing endoscopic post-operative recurrence of CD.

Efficacy of Secretagogues in Patients With Irritable Bowel Syndrome With Constipation: Systematic Review and Network Meta-analysis.

BACKGROUND & AIMS: Several secretagogues have been approved for the treatment of irritable bowel syndrome with constipation (IBS-C). However, their relative efficacy is unclear because there have been no head-to-head randomized controlled trials. We conducted a network meta-analysis to compare their efficacies in patients with IBS-C. METHODS: We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane Central Register of Controlled Trials through June 2018 to identify randomized controlled trials assessing the efficacy of secretagogues in adults with IBS-C. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random-effects model. Efficacy and safety of secretagogues were reported as a pooled relative risk with 95% confidence interval to summarize the effect of each comparison tested, and treatments were ranked according to their P score. RESULTS: We identified 15 eligible randomized controlled trials of secretagogues that included 8462 patients. Linaclotide, lubiprostone, plecanatide, and tenapanor were superior to placebo for the treatment of IBS-C. Linaclotide (290 µg once daily) was ranked first in efficacy based on the end point recommended by the Food and Drug Administration for trials in IBS-C, the primary end point used in each trial, abdominal pain, and complete spontaneous bowel movements. Tenapanor (50 mg twice daily) was ranked first for decreasing bloating. Total numbers of adverse events were significantly larger with linaclotide (290 and 500 µg once daily) and plecanatide (3 mg once daily) compared with placebo. However, plecanatide 6 mg once daily ranked first for safety. Diarrhea was significantly more common with all drugs, except lubiprostone (8 µg twice daily). Nausea was significantly more common in patients who received lubiprostone. CONCLUSIONS: In a network analysis of randomized controlled trials of secretagogues for IBS-C, we found all drugs to be superior to placebo. Efficacy was similar among individual drugs and dosages for most end points. However, data were extracted at the 12-week time point, so the long-term relative efficacy of these drugs is unknown.

Comparative efficacy of treatments for Clostridium difficile infection: a systematic review and network meta-analysis.

BACKGROUND: Several new treatments for Clostridium difficile infections have been investigated. We aimed to compare and rank treatments for non-multiply recurrent infections with C difficile in adults. METHODS: We did a random effects network meta-analysis within a frequentist setting to obtain direct and indirect comparisons of trials. We searched MEDLINE, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for published and unpublished trials from the creation of these databases until June 30, 2017. We included randomised controlled trials of treatments for non-multiply recurrent infections with confirmed C difficile in adults (at least 18 years) that reported both primary cure and recurrence rates, and we used the Cochrane Risk of Bias tool to appraise trial methods. For our analysis, we extracted the total numbers of patients with primary cure and recurrence from published and unpublished reports. The primary outcome was sustained symptomatic cure, defined as the number of patients with resolution of diarrhoea minus the number with recurrence or death. FINDINGS: Of 23 004 studies screened, 24 trials, which comprised 5361 patients and 13 different treatments, were included in the analysis. The overall quality of evidence was rated as moderate to low. For sustained symptomatic cure, fidaxomicin (odds ratio 0·67, 95% CI 0·55-0·82) and teicoplanin (0·37, 0·14-0·94) were significantly better than vancomycin. Teicoplanin (0·27, 0·10-0·70), ridinilazole (0·41, 0·19-0·88), fidaxomicin (0·49, 0·35-0·68), surotomycin (0·66, 0·45-0·97), and vancomycin (0·73, 0·56-0·95) were better than metronidazole. Bacitracin was inferior to teicoplanin (0·22, 0·06-0·77) and fidaxomicin (0·40, 0·17-0·94), and tolevamer was inferior to all drugs except for LFF571 (0·50, 0·18-1·39) and bacitracin (0·67, 0·28-1·58). Global heterogeneity of the entire network was low (Cochran's Q=15·70; p=0·47). INTERPRETATION: Among the treatments for non-multiply recurrent infections by C difficile, the highest quality evidence indicates that fidaxomicin provides a sustained symptomatic cure most frequently. Fidaxomicin is a better treatment option than vancomycin for all patients except those with severe infections with C difficile and could be considered as a first-line therapy. Metronidazole should not be recommended for treatment of C difficile. FUNDING: None.