A core outcome set for localised prostate cancer effectiveness trials

Objective: To develop a core outcome set (COS) applicable for effectiveness trials of all interventions for localised prostate cancer. Background: Many treatments exist for localised prostate cancer, although it is unclear which offers the optimal therapeutic ratio. This is confounded by inconsistencies in the selection, definition, measurement and reporting of outcomes in clinical trials. Subjects and methods: A list of 79 outcomes was derived from a systematic review of published localised prostate cancer effectiveness studies and semi-structured interviews with 15 prostate cancer patients. A two-stage consensus process involving 118 patients and 56 international healthcare professionals (HCPs) (cancer specialist nurses, urological surgeons and oncologists) was undertaken, consisting of a three-round Delphi survey followed by a face-to-face consensus panel meeting of 13 HCPs and 8 patients. Results: The final COS included 19 outcomes. Twelve apply to all interventions: death from prostate cancer, death from any cause, local disease recurrence, distant disease recurrence/metastases, disease progression, need for salvage therapy, overall quality of life, stress urinary incontinence, urinary function, bowel function, faecal incontinence, sexual function. Seven were intervention-specific: perioperative deaths (surgery), positive surgical margin (surgery), thromboembolic disease (surgery), bothersome or symptomatic urethral or anastomotic stricture (surgery), need for curative treatment (active surveillance), treatment failure (ablative therapy), and side effects of hormonal therapy (hormone therapy). The UK-centric participants may limit the generalisability to other countries, but trialists should reason why the COS would not be applicable. The default position should not be that a COS developed in one country will automatically not be applicable elsewhere. Conclusion: We have established a COS for trials of effectiveness in localised prostate cancer, applicable across all interventions which should be measured in all localised prostate cancer effectiveness trials

Comprehensive dissection of prevalence rates, sex differences, and blood level-dependencies of clozapine-associated adverse drug reactions

Clozapine is often underused due to concerns about adverse drug reactions (ADRs) but studies into their prevalences are inconclusive. We therefore comprehensively examined prevalences of clozapineassociated ADRs in individuals with schizophrenia and demographic and clinical factors associated with their occurrence. Data from a multi-center study (n=698 participants) were collected. The mean number of ADRs during clozapine treatment was 4.8, with 2.4% of participants reporting no ADRs. The most common ADRs were hypersalivation (74.6%), weight gain (69.3%), and increased sleep necessity (65.9%), all of which were more common in younger participants. Participants with lower BMI prior to treatment were more likely to experience significant weight gain (>10%). Constipation occurred more frequently with higher clozapine blood levels and doses. There were no differences in ADR prevalence rates between participants receiving clozapine monotherapy and polytherapy. These findings emphasize the high prevalence of clozapine-associated ADRs and highlight several demographic and clinical factors contributing to their occurrence. By understanding these factors, clinicians can better anticipate and manage clozapine-associated ADRs, leading to improved treatment outcomes and patient well-being

Milrinone for cardiac dysfunction in critically ill adult patients: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis

Milrinone is an inotrope widely used for treatment of cardiac failure. Because previous meta-analyses had methodological flaws, we decided to conduct a systematic review of the effect of milrinone in critically ill adult patients with cardiac dysfunction. This systematic review was performed according to The Cochrane Handbook for Systematic Reviews of Interventions. Searches were conducted until November 2015. Patients with cardiac dysfunction were included. The primary outcome was serious adverse events (SAE) including mortality at maximum follow-up. The risk of bias was evaluated and trial sequential analyses were conducted. The quality of evidence was assessed by the Grading of Recommendations Assessment, Development and Evaluation criteria. A total of 31 randomised clinical trials fulfilled the inclusion criteria, of which 16 provided data for our analyses. All trials were at high risk of bias, and none reported the primary composite outcome SAE. Fourteen trials with 1611 randomised patients reported mortality data at maximum follow-up (RR 0.96; 95% confidence interval 0.76-1.21). Milrinone did not significantly affect other patient-centred outcomes. All analyses displayed statistical and/or clinical heterogeneity of patients, interventions, comparators, outcomes, and/or settings and all featured missing data. The current evidence on the use of milrinone in critically ill adult patients with cardiac dysfunction suffers from considerable risks of both bias and random error and demonstrates no benefits. The use of milrinone for the treatment of critically ill patients with cardiac dysfunction can be neither recommended nor refuted. Future randomised clinical trials need to be sufficiently large and designed to have low risk of bias