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Internet and telephone intervention to support patients discontinuing longterm antidepressants in primary care: the REDUCE research programme including RCT
Background: There is significant concern about increasing long-term antidepressant use in Western countries, much of which is not evidence-based. Median duration of treatment is more than 2 years in the United Kingdom, and more than 10% of adults are taking antidepressants, risking potentially significant adverse effects, particularly for older patients. Objectives: To develop internet-and telephone-based support for practitioners and patients, through a process of co-design, and to determine its effectiveness and cost-effectiveness in helping people discontinue antidepressants without increasing depression, in a randomised controlled trial. Design: Two systematic reviews (one qualitative); qualitative interviews with patients; qualitative interviews and focus groups with healthcare practitioners; co-production of online interventions with patients and practitioners; feasibility randomised controlled trial; definitive non-inferiority cluster randomised controlled trial with health economic evaluation; and quantitative and qualitative process evaluations. A booklet and video version of the patient intervention was also developed in Urdu. Setting: Primary care (131 general practices in England and Wales). Participants: Adults on antidepressant treatment for more than 1 year for a first episode of depression, or more than 2 years for recurrent depression, who were no longer depressed or judged to be at significant risk of relapse. Interventions: Tailored internet support (ADvisor for patients, and ADvisorHP for health professionals), plus three telephone support calls from psychological well-being practitioners. Primary outcome: Depressive symptoms on the Patient Health Questionnaire-9 items questionnaire at 6 months. Secondary outcomes: Depressive symptoms over 12 months, antidepressant discontinuation, anxiety, quality of life, withdrawal symptoms, adverse events, mental well-being, patient enablement, patient satisfaction, health service use and costs over 12 months. Sample size: The original sample size calculation gave a target of 402 patients for 90% power with one-sided significance of 2.5% to determine non-inferiority of the intervention, within 2 points on the Patient Health Questionnaire-9 items. This was reduced to 360 on finding a significant correlation between baseline and follow-up values for the Patient Health Questionnaire-9 items part-way through the trial. Randomisation: Remote cluster randomisation of practices by computerised sequence generation, with minimization by practice size, urban/rural location and deprivation index. Blinding: Participants and researchers could not be blinded given the pragmatic open design, but self-complete measures avoided observer rating bias, and analyses were conducted blind. Analyses: Linear mixed modelling was used to determine differences in outcomes, adjusting for previous depression, baseline outcome values, baseline anxiety, sociodemographic characteristics, and practice as a random effect. Primary analysis was performed by intention to treat, with per-protocol and complier-average sensitivity analyses. Multiple imputation was used to account for missing values. Qualitative interviews: Semistructured topic guides were used for interviews and focus groups, informed by normalisation process theory, which were audio-recorded, transcribed verbatim and analysed using reflexive thematic analysis. Results: Systematic reviews, qualitative interviews and focus groups indicated that barriers to discontinuing treatment include a fear of relapse of depression and withdrawal symptoms. If practitioners do not broach possible discontinuation, patients will usually continue treatment without questioning it. Patients wanted information on antidepressant mechanisms and effects, withdrawal symptoms and coping strategies. Practitioners wanted guidance on initiating discontinuation, antidepressant tapering regimens, and distinguishing withdrawal from relapse. The definitive trial randomised 330 patients (5% of those approached; 178 in intervention practices and 152 in controls), of whom 275 (83%) were followed up at 6 months, and 240 (73%) at 12 months. Mean Patient Health Questionnaire-9 items scores were slightly higher among controls at 6 months [5.0 vs. 4.0; adjusted difference 1.07 (95% confidence interval 0.09 to 2.06; p = 0.033)]. Antidepressant discontinuation rates at 6 months were slightly higher in the intervention arm, but not significantly (45.5% vs. 41.9% in the control arm). Antidepressant withdrawal symptoms and mental well-being were significantly better in the intervention arm. There were no significant differences in anxiety, quality of life, adverse events, patient enablement, or satisfaction with care. The adjusted mean cost of services used was lower in the intervention arm by −£69 (95% confidence interval −£77 to £207). The incremental cost-effectiveness ratio was a mean saving of −£2839 per quality-adjusted life-year gained (95% confidence interval −£30,024 to £22,227). The probability of the intervention being cost-effective compared to review alone, at the National Institute for Health and Care Excellence thresholds of societal willingness to pay of £20,000 and £30,000 per quality-adjusted life-year, was > 89% for both. Qualitative interviews suggested advice to taper slowly, and information on the difference between relapse and withdrawal symptoms, contributed significantly to the success of the interventions. Participants were well and willing to attempt antidepressant discontinuation, and general practitioners excluded people considered at high risk of relapse of depression. This may explain why more than 40% of participants in each arm discontinued. The results may not generalise to an unselected sample of people on long-term antidepressants, including people at greater risk of relapse. Conclusions: Comparatively high rates of discontinuation of long-term antidepressants are achievable through enabling patients, who are ready to consider stopping them, to get tapering advice and support from their general practitioners. Tailored internet and psychologist telephone support may help protect patients coming off long-term antidepressants against depressive and withdrawal symptoms, and conserve mental well-being. The interventions appear highly costeffective at thresholds for societal willingness to pay used by the National Institute for Health and Care Excellence. Trial registration: Workstream 4 (feasibility trial) is registered as International Standardised Randomised Controlled Trial Number ISRCTN15036829 and Workstream 5 (definitive trial of effectiveness and cost-effectiveness) is registered as ISRCTN12417565.
Subclinical Postpartum Renal Structure After Hypertensive Pregnancy Disorders.
BACKGROUND: Hypertensive pregnancies are associated with increased risks of renal failure in pregnancy and later life. However, traditional markers of renal function normalize postpartum, making identification of those at future disease risk difficult. We studied whether the type and severity of hypertensive pregnancy associated with postpartum renal structure. METHODS: One hundred twenty-five women from interventional trials (61 preeclamptic, 33 gestational hypertension, and 31 normotensive pregnancy), aged ≥18 years, were imaged using magnetic resonance imaging 6 to 12 months postpartum. Anthropometric, demographic, blood pressure, and blood sample data were collected during pregnancy and postpartum. Kidney volume indexed to body surface area and corticomedullary differentiation were compared between groups using a 1-way ANCOVA, whereas associations with other outcomes were assessed using correlation tests. RESULTS: Postpartum total kidney volume indexed to body surface area was smaller in women who had preeclampsia compared with those who had gestational hypertension or a normotensive pregnancy (P=0.049). Total kidney volume postpartum correlated with estimated glomerular filtration rate at delivery (P<0.001). However, smaller volumes were not explained by reduced corticomedullary differentiation, which only differed in women with gestational hypertension compared with preeclamptic (P=0.02) and normotensive women (P=0.007). There were no associations between renal measures and blood pressure during or after pregnancy. CONCLUSIONS: At 6 to 12 months postpartum, preeclamptic women have smaller kidney volumes than women with gestational hypertension or normotensive pregnancies. These smaller volumes relate to lower renal function at delivery but not corticomedullary differentiation, which only differed in women with gestational hypertension. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT04273854 and NCT05434195.
Eradication of Helicobacter pylori for prevention of aspirin-associated peptic ulcer bleeding in adults over 65 years: the HEAT RCT.
BACKGROUND: Peptic ulcers in patients on aspirin are associated with Helicobacter pylori infection. We investigated whether H. pylori eradication would protect against aspirin-associated ulcer bleeding. METHODS: The Helicobacter Eradication Aspirin Trial was a randomised placebo-controlled trial (European Union Drug Regulating Authorities Clinical Trials 2011-003425-96), conducted in United Kingdom primary care using routinely collected clinical data. Consenting participants aged ≥ 60 years prescribed aspirin ≤ 325 mg but not ulcerogenic or gastroprotective medication underwent C13 urea breath testing for H. pylori. Those with a positive test were randomised to receive either a combination of clarithromycin 500 mg, metronidazole 400 mg and lansoprazole 30 mg, or placebos twice daily for 7 days. The primary outcome, time to death or hospitalisation due to peptic ulcer bleeding, was analysed using a Cox proportional hazards model. FINDINGS: Between 14 September 2012 and 22 November 2017, 30,166 participants underwent H. pylori breath testing, 5367 had a positive result, 5352 were randomised to an intention-to-treat population of 2677 (eradication) and 2675 (placebo) and followed up for a median of 5.0 years (interquartile range 3.9-6.4). Statistical analysis of the primary outcome showed an overall hazard ratio of 0.69 [95% confidence interval 0.38 to 1.25; p = 0.22], but there was a significant departure from the proportional hazards assumption (p = 0.0068), requiring analysis split at the median time to event: 2.5 years. There was a significant reduction in the primary outcome in the eradication treatment group in the first 2.5 years (hazard ratio 0.35, 95% confidence interval 0.14 to 0.89; p = 0.028) but not the second period (hazard ratio 1.31, 95% confidence interval 0.55 to 3.11). The number needed to treat (first period) was 238 (95% confidence interval 184 to 1661). Results in the first 2.5 years remained significant when accounting for the competing risk of death (p = 0.028). During the study period, 657 participants died (306 in the eradication group and 351 in the controls group; hazard ratio 0.86, 95% confidence interval 0.74 to 1.01; p = 0.058). Malignancy was the most common cause of death and largely accounted for the numerical difference between the treatment groups. A health economic analysis found proactive screening not cost-effective, since the monetised benefits of the intervention in preventing a peptic ulcer bleed failed to outweigh the costs. INTERPRETATION: Helicobacter pylori eradication protects against aspirin-associated peptic ulcer bleeding, but this may not be sustained or cost-effective when applied non-selectively to our study population. The possibility that H. pylori eradication, on a background of aspirin use, might affect death from malignancies warrants further evaluation. LIMITATIONS AND FUTURE WORK: Studying subjects already established on aspirin probably contributed to the low event rate. A future study should investigate subjects starting on aspirin when the event rate is higher. TRIAL REGISTRATION: This trial is registered as ISRCTN10134725; ClinicalTrials.gov number NCT01506986. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 09/55/52) and is published in full in Health Technology Assessment; Vol. 29, No. 42. See the NIHR Funding and Awards website for further award information.
Recent-onset atrial fibrillation: challenges and opportunities.
Atrial fibrillation (AF) is increasingly diagnosed early, close to its first occurrence due to: (i) increased public awareness with self-screening; (ii) health care initiatives including population screening and opportunistic case finding; and (iii) increased use and surveillance of implantable cardiac devices. At its onset, AF is often low burden, and cardiovascular co-morbidities may be absent or at an early stage. Thus, the management of recent-onset AF has become an issue of growing importance. Professional guidelines have traditionally focused on anticoagulant thromboprophylaxis, generally recommending a cautious approach to rhythm control, and priority has been given to rate control to alleviate symptoms. In recent guidelines, the importance of managing lifestyle and co-morbidities has increased. The AF-SCREEN collaboration proposes that a vigorous approach to active management of recent-onset AF may be warranted. This includes addressing co-morbidities and promoting healthy lifestyles to prevent the emergence or progression of AF and associated cardiovascular disease, as well as the initiation of active rhythm control ± anticoagulation to prevent AF-related morbidity and mortality, including stroke and heart failure (HF). Intuitively, intervention early after AF onset would be beneficial since lifestyle and co-morbidity management, plus rhythm control and anticoagulation, are important contributors to improved outcomes in patients with established AF, but robust evidence is lacking for recent-onset AF. There is a delicate balance between achieving favourable outcomes such as preventing strokes, HF and AF progression vs the complications and potential adverse effects of interventions. Given the serious long-term consequences, innovative approaches are necessary to determine the value and risks of initiating active therapy very early in the course of AF. More data are needed to guide the best management of recent-onset AF, bearing AF burden in mind. Long-term studies using large national databases linked to electronic medical records and rhythm monitoring devices offer excellent opportunities. Shorter-term studies focusing on reducing AF burden to slow AF progression and studies focusing on outcomes such as HF could be used in both randomized clinical trials and observational cohort studies.
How often should self-monitoring of blood pressure be repeated? A secondary analysis of data from two randomized controlled trials.
BACKGROUND: Little evidence exists around the optimal frequency of self-monitoring of blood pressure (BP). Testing too frequently can lead to erroneous management changes due to random "noise" leading to raised measurements by chance. This study used recent trial data to evaluate self-monitored BP over time, aiming to determine how frequently patients should self-monitor. METHODS: Data from patients with home BP ≤135/85 mmHg on stable medication in the self-monitoring groups of two trials were analysed using a mixed effects model. The primary outcome was mean change in BP per month. Secondary outcomes included intra-individual BP variability, and probability of truly raised BP over time. RESULTS: 232 participants from HOMEBP, and 582 participants from TASMINH4 were included. The mean changes in systolic BP per month per study were -0.1 mmHg [standard deviation (SD) 0.6 mmHg], and -0.2mmHg [SD 0.7 mmHg], respectively. Intra-individual systolic variability (SD) per month was 4.7 and 5.1 mmHg respectively. Using TASMINH4 data, from a starting systolic BP of 130 mmHg, re-testing BP after 6 months resulted in a probability of 18% that BP ≥135 mmHg, with a 25% probability that this reflected truly raised BP; after 12 months the probability of a raised reading was 26% with a 65% probability this reflected a true rise. CONCLUSIONS: In the absence of medication changes, there was very little change in mean self-monitored BP per month, with larger variability within an individual's monthly submitted readings. For people with initially controlled BP and stable medication, repeating self-monitoring at 12 months is likely to be appropriate in guiding management.
Cognitive Therapy for PTSD: Updating Memories and Meanings of Trauma
In the initial days and weeks after a traumatic event, most people will experience at least some symptoms of posttraumatic stress disorder (PTSD) such as intrusive memories, sleep disturbance, feeling emotionally numb, or being easily startled (Rothbaum et al. 1992). Most people will recover in the ensuing months, but for some the symptoms persist, often for years. What prevents these people from recovering? A lesson that we learned in treating and interviewing many trauma survivors is that what people find most distressing about a traumatic event varies greatly from person to person. Understanding the personal meanings of trauma and their relationship with features of trauma memories appears key to helping people with PTSD.
Risk stratification of childhood infection using host markers of immune and endothelial activation in Asia (Spot Sepsis): a multi-country, prospective, cohort study.
BACKGROUND: Prognostic tools for febrile illnesses are urgently required in resource-constrained community contexts. Circulating immune and endothelial activation markers stratify risk in common childhood infections. We aimed to assess their use in children with febrile illness presenting from rural communities across Asia. METHODS: Spot Sepsis was a prospective cohort study across seven hospitals in Bangladesh, Cambodia, Indonesia, Laos, and Viet Nam that serve as a first point of contact with the formal health-care system for rural populations. Children were eligible if aged 1-59 months and presenting with a community-acquired acute febrile illness that had lasted no more than 14 days. Clinical parameters were recorded and biomarker concentrations measured at presentation. The primary outcome measure was severe febrile illness (death or receipt of organ support) within 2 days of enrolment. Weighted area under the receiver operating characteristic curves (AUC) were used to compare prognostic accuracy of endothelial activation markers (ANG-1, ANG-2, and soluble FLT-1), immune activation markers (CHI3L1, CRP, IP-10, IL-1ra, IL-6, IL-8, IL-10, PCT, soluble TNF-R1, soluble TREM1 [sTREM1], and soluble uPAR), WHO danger signs, the Liverpool quick Sequential Organ Failure Assessment (LqSOFA) score, and the systemic inflammatory response syndrome (SIRS) score. Prognostic accuracy of combining WHO danger signs and the best performing biomarker was analysed in a weighted logistic regression model. Weighted measures of classification were used to compare prognostic accuracies of WHO danger signs and the best performing biomarker and to determine the number of children needed to test (NNT) to identify one additional child who would progress to severe febrile illness. The study was prospectively registered on ClinicalTrials.gov, NCT04285021. FINDINGS: 3423 participants were recruited between March 5, 2020, and Nov 4, 2022, 18 (0·5%) of whom were lost to follow-up. 133 (3·9%) of 3405 participants developed severe febrile illness (22 deaths, 111 received organ support; weighted prevalence 0·34% [95% CI 0·28-0·41]). sTREM1 showed the highest prognostic accuracy to identify patients who would progress to severe febrile illness (AUC 0·86 [95% CI 0·82-0·90]), outperforming WHO danger signs (0·75 [0·71-0·80]; p<0·0001), LqSOFA (0·74 [0·69-0·78]; p<0·0001), and SIRS (0·63 [0·58-0·68]; p<0·0001). Combining WHO danger signs with sTREM1 (0·88 [95% CI 0·85-0·91]) did not improve accuracy in identifying progression to severe febrile illness over sTREM1 alone (p=0·24). Sensitivity for identifying progression to severe febrile illness was greater for sTREM1 (0·80 [95% CI 0·73-0·85]) than for WHO danger signs (0·72 [0·66-0·79]; NNT=3000), whereas specificities were comparable (0·81 [0·78-0·83] for sTREM1 vs 0·79 [0·76-0·82] for WHO danger signs). Discrimination of immune and endothelial activation markers was best for children who progressed to meet the outcome more than 48 h after enrolment (sTREM1: AUC 0·94 [95% CI 0·89-0·98]). INTERPRETATION: sTREM1 showed the best prognostic accuracy to discriminate children who would progress to severe febrile illness. In resource-constrained community settings, an sTREM1-based triage strategy might enhance early recognition of risk of poor outcomes in children presenting with febrile illness. FUNDING: Médecins Sans Frontières, Spain, and Wellcome. TRANSLATIONS: For the Arabic and French translations of the abstract see Supplementary Materials section.
Racialised experience of detention under the Mental Health Act: a photovoice investigation.
BACKGROUND: The rates of compulsory admission and treatment (CAT) are rising in mental health systems in the UK. Persistent disparities have been reported among migrants, and black and ethnic minorities in Europe and North America for decades. Lived experience data can provide novel insights to reduce coercive care. METHODS: We purposively sampled people within 2 years of receiving CAT, to maximise diversity by age, sex, ethnicity and different 'sections' of the Mental Health Act (England and Wales) from eight health systems in England. Using participatory photovoice workshops, we assembled images, captions and reflective narratives, which were transcribed and subjected to thematic and intersectional analyses. The interpretation privileged lived experiences of participants and peer researchers alongside the research team. Preventive insights informed a logic model to reduce CAT. RESULTS: Forty-eight ethnically diverse people contributed over 500 images and 30 hours of recorded narratives. A significant proportion of participants reported multimorbidity, adverse childhood experiences and carer roles. Their experiences indicated insufficient co-ordination to prevent CAT despite early help seeking; they were not taken seriously or believed when seeking help. Dismissive responses and even hostility from professionals and unnecessary police involvement were distressing, stigmatising and risked criminalisation. Participants wanted more (a) advocacy given in crisis, (b) trauma-informed therapeutic and creative support from inpatient into community settings, (c) family and carer involvement and (d) more information about how to negotiate care options, appeals, restriction and seclusion. Practitioners were felt to lack the essential skills to care for racialised and traumatised people subjected to CAT. CONCLUSIONS: We propose a lived experience logic model for the practice, policy and legislative solutions to reduce epistemic injustice, CAT and criminalising care.
Risk of repeat self-harm among individuals presenting to healthcare services: development and validation of a clinical risk assessment model (OxSET).
BACKGROUND: A self-harm episode is a major risk factor for repeat self-harm. Existing tools to assess and predict repeat self-harm have major methodological limitations, and few are externally validated. OBJECTIVE: To develop and validate a risk assessment model of repeat self-harm up to 6 months after an episode of non-fatal self-harm that resulted in an emergency visit to hospital or specialised care. METHODS: Using Swedish national registers, we identified 53 172 people aged≥10 years who self-harmed during 2008-2012. We allocated 37 523 individuals to development (2820 or 7.5% repeat self-harm incidents within 6 months) and 15 649 to geographic validation (1373 repeat episodes) samples, based on region of residence. In a temporal validation of people who self-harmed during 2018-2019, we identified 25 036 individuals (2886 repeat episodes). We fitted a multivariable accelerated failure time model to predict risk of repeat self-harm. FINDINGS: In the external validations (n=40 685), rates of repeat self-harm were 8.8%-11.5% over 6 months. The final model retained 17 factors. Calibration and discrimination were similar in both validation samples, with observed-to-expected ratio=1.15 (95% CI=1.09 to 1.21) and c-statistic=0.72 (95% CI=0.70 to 0.73) in the geographical validation. At 6 months and a 10% risk cut-off, sensitivity was 51.5% (95% CI=48.8% to 54.2%) and specificity was 80.7% (95% CI=80.1% to 81.4%) in geographic validation; corresponding values were 56.9% (95% CI=55.1% to 58.7%) and 76.0% (95% CI=75.5% to 76.6%) in temporal validation. Discrimination was slightly worse at the 1-month prediction horizon (c-statistics of 0.66-0.68). CONCLUSIONS: Using mostly routinely collected data, simple risk assessment models and tools can provide acceptable levels of accuracy for repeat of self-harm. CLINICAL IMPLICATIONS: This risk model (OXford SElf-harm repeat tool) may assist clinical decision-making.
Precision computerised cognitive behavioural therapy (cCBT) intervention for adolescents with depression (SPARX-UK): protocol for the process evaluation of a pilot randomised controlled feasibility trial.
INTRODUCTION: While digital technologies can increase the availability and access to evidence-based interventions, little is known about how users engage with them and the mechanisms associated with effective outcomes. Process evaluations are an important component in understanding the aforementioned factors. The 'SPARX-UK' study is a randomised controlled pilot and feasibility trial evaluating personalised human-supported (from an 'eCoach') vs a self-directed computerised cognitive behavioural therapy intervention (cCBT), called SPARX (Smart, Positive, Active, Realistic, X-factor thoughts), aimed at adolescents with mild to moderate depression. We are comparing supported vs self-directed delivery of SPARX to establish which format should be used in a proposed definitive trial of SPARX. The control is a waitlist group. We will conduct a process evaluation alongside the trial to determine how the intervention is implemented and provide context for interpreting the feasibility trial outcomes. We will also look at the acceptability of SPARX and how users engage with the intervention. This protocol paper describes the rationale, aims and methodology of the SPARX-UK trial process evaluation. METHODS AND ANALYSIS: The process evaluation will use a mixed-methods design following the UK Medical Research Council's 2015 guidelines, comprising quantitative and qualitative data collection. This will include analysing data usage of participants in the intervention arms; purposively sampled, semi-structured interviews of adolescents, parents/guardians, eCoaches and clinicians/practitioners from the SPARX-UK trial; and analysis of qualitative comments from a survey from those who dropped out early from the trial. Quantitative data will be analysed descriptively. We will use thematic analysis in a framework approach to analyse qualitative data. Quantitative and qualitative data will be mixed and integrated to provide an understanding of how the intervention was implemented and how adolescents interacted with the intervention. This process evaluation will explore the experiences of adolescent participants, parents/guardians, eCoaches and clinicians/practitioners in relation to a complex digital intervention. ETHICS: Ethical approval was granted by the National Health Service (NHS) Health Research Authority South West - Cornwall & Plymouth Research Ethics Committee (Ethics Ref: 22/SW/0149). DISSEMINATION: Contextualising how the intervention was implemented, and the variations in uptake and engagement, will help us to understand the trial findings in greater depth. The findings from this process evaluation will also inform the decision about whether and how to proceed with a full randomised controlled trial, as well as the development of more effective interventions which can be personalised more precisely via varying levels of human support. We plan to publish the findings of the process evaluation and the wider project in peer-reviewed journals, as well as disseminate via academic conferences. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN15124804. Registered on 16 January 2023, https://www.isrctn.com/ISRCTN15124804.