Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Most patients with irritable bowel syndrome (IBS) are managed in primary care. When first-line therapies for IBS are ineffective, the UK National Institute for Health and Care Excellence guideline suggests considering low- dose tricyclic antidepressants as second-line treatment, but their effectiveness in primary care is unknown, and they are infrequently prescribed in this setting. METHODS: This randomised, double-blind, placebo-controlled trial (Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment [ATLANTIS]) was conducted at 55 general practices in England. Eligible participants were aged 18 years or older, with Rome IV IBS of any subtype, and ongoing symptoms (IBS Severity Scoring System [IBS-SSS] score ≥75 points) despite dietary changes and first-line therapies, a normal full blood count and C-reactive protein, negative coeliac serology, and no evidence of suicidal ideation. Participants were randomly assigned (1:1) to low-dose oral amitriptyline (10 mg once daily) or placebo for 6 months, with dose titration over 3 weeks (up to 30 mg once daily), according to symptoms and tolerability. Participants, their general practitioners, investigators, and the analysis team were all masked to allocation throughout the trial. The primary outcome was the IBS-SSS score at 6 months. Effectiveness analyses were according to intention-to-treat; safety analyses were on all participants who took at least one dose of the trial medication. This trial is registered with the ISRCTN Registry (ISRCTN48075063) and is closed to new participants. FINDINGS: Between Oct 18, 2019, and April 11, 2022, 463 participants (mean age 48·5 years [SD 16·1], 315 [68%] female to 148 [32%] male) were randomly allocated to receive low-dose amitriptyline (232) or placebo (231). Intention-to-treat analysis of the primary outcome showed a significant difference in favour of low-dose amitriptyline in IBS-SSS score between groups at 6 months (-27·0, 95% CI -46·9 to -7·10; p=0·0079). 46 (20%) participants discontinued low-dose amitriptyline (30 [13%] due to adverse events), and 59 (26%) discontinued placebo (20 [9%] due to adverse events) before 6 months. There were five serious adverse reactions (two in the amitriptyline group and three in the placebo group), and five serious adverse events unrelated to trial medication. INTERPRETATION: To our knowledge, this is the largest trial of a tricyclic antidepressant in IBS ever conducted. Titrated low-dose amitriptyline was superior to placebo as a second-line treatment for IBS in primary care across multiple outcomes, and was safe and well tolerated. General practitioners should offer low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies, with appropriate support to guide patient-led dose titration, such as the self-titration document developed for this trial. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme (grant reference 16/162/01).

Patients' Experiences After CKD Diagnosis: A Meta-ethnographic Study and Systematic Review.

BACKGROUND: Chronic kidney disease (CKD) is often asymptomatic at first diagnosis, and awareness of CKD is low in the general population. Thus, individuals who are unexpectedly identified as having CKD may struggle to adjust to living with this diagnosis. This study aims to synthesize qualitative research exploring patients' views and experiences of a CKD diagnosis and how they adjust to it. STUDY DESIGN: Systematic review and meta-ethnography. SETTING & POPULATION: Adult patients with CKD stages 1 to 5. SEARCH STRATEGY & SOURCES: MEDLINE, PsycINFO, CINAHL, Embase, and Web of Science were searched from the earliest date available to November 2015. Qualitative studies were selected that explored patients' views and experiences of a CKD diagnosis and their adjustment. ANALYTICAL APPROACH: Meta-ethnography was adopted to synthesize the findings. RESULTS: 10 studies involving 596 patients with CKD from secondary-care settings were included. 7 key themes were identified: a challenging diagnosis, diverse beliefs about causation, anticipated concerns about progression, delaying disease progression, unmet informational needs, psychosocial impact of CKD, and adjustment to life with CKD. LIMITATIONS: Limited to views and experiences of participants in included studies, which were mostly conducted in high-income countries. Studies not written in English were excluded. Transferability of findings to other populations may be limited. CONCLUSIONS: This review highlights variation in patients' understanding of CKD, an overall lack of information on the trajectory of CKD, and a need for psychosocial support, especially in later stages, to help patients adjust to living with CKD. Future research that acknowledges CKD as a condition with diverse complicating morbidities and explores how patients' information and psychosocial needs vary according to severity and comorbid conditions would be beneficial. This will support delivery of easily understandable, timely, and targeted information about CKD, as well as practical advice about recommended lifestyle changes.