SummaryBackgroundResults of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects.MethodsFOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762.FindingsBetween Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months.InterpretationFluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function.FundingUK Stroke Association and NIHR Health Technology Assessment Programme.

Background and aimsIn the UK, treatments for patients with moderately to severely active ulcerative colitis who have an inadequate response to conventional therapies comprise four biological therapies—the tumour necrosis factor inhibitor (TNFi) agents adalimumab, golimumab and infliximab and the anti-integrin vedolizumab—and an orally administered small molecule therapy, tofacitinib. However, there have been few head-to-head studies of these therapies. This study aimed to compare the clinical and cost-effectiveness of tofacitinib with biological therapies.MethodsA systematic literature review was conducted to identify all relevant randomised controlled trial (RCT) evidence. Clinical response, clinical remission and serious infection rates were synthesised using network meta-analysis (NMA). The results were used to compare the cost-effectiveness of tofacitinib and biologics with conventional therapy, using a Markov model, which incorporated lifetime costs and consequences of treatment from a UK National Health Service perspective. Analyses were conducted separately for TNFi-naïve and TNFi-exposed populations.ResultsSeventeen RCTs were used in the NMAs. There were no statistically significant differences among biological therapies and tofacitinib for either TNFi-naïve or TNFi-exposed patients. In TNFi-naïve patients, all therapies were more efficacious than placebo. In TNFi-exposed patients, only tofacitinib was significantly more efficacious than placebo as induction therapy, and only tofacitinib and vedolizumab were significantly more efficacious than placebo as maintenance therapies. There were no significant differences in serious infection rates among therapies. The incremental cost-effectiveness ratios for tofacitinib versus conventional therapy were £21 338 and £22 816 per quality-adjusted life year (QALY) in the TNFi-naïve and TNFi-exposed populations, respectively. TNFi therapies were dominated or extendedly dominated in both populations. Compared with vedolizumab, tofacitinib was associated with a similar number of QALYs, at a lower cost.ConclusionTofacitinib is an efficacious treatment for moderately to severely active ulcerative colitis and is likely to be a cost-effective use of NHS resources.

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Objectives: Clostridium-difficile (c-diff) bacterium infect the large intestine causing symptoms ranging from pain and discomfort to diarrhea and life-threatening inflammation. While more than half a million Americans are impacted yearly, the most at risk are older adults or those with immune related disorders being treated with a biologic. Methods: From the 2014 Medicare MedPAR dataset, 70589 cases of c-diff were reported. A Bayesian network was utilized with primary nodes for surgery performed connected to length of stay (LOS) of 7+ days as well as death in hospital. Secondary nodes of a radiology test occurring, gender, and age of 80+ were included. Conditional probabilities were assessed and then updated when death was observed. Results: LOS for c-diff was exponentially distributed where l = 0.158. 66.08% of patients were female and 41.25% where 80+ years old. 2.145% of the c-diff patients died while in hospital, where 69.44% of those that died had surgery performed and 35.26% of those that survived had surgery. The median LOS was 7 days for those that died and 5 for those that survived, where 22% of those that did not have surgery and 49.2% that had surgery had a LOS of 7+ days. When death was observed, 52% of patients had a LOS of 7+ days and 71% had surgery, suggesting that surgery occurring is directly impacting both length of stay and death. 77% of those that had surgery had a radiology test performed, 63% were female, and 61% were 80+ years old. Conclusions: This analysis highlights the heavy hospital resource utilization of patients diagnosed with c-diff and the heavy burden of infection in the oldest age brackets of beneficiaries. Multiple pharmaceutical companies have c-diff vaccines in development that may help alleviate some of this burden. Results from this analysis highlight the unmet need in older Medicare patients.