Anti-TNF (adalimumab) injection for the treatment of pain-predominant early-stage frozen shoulder: the Anti-Freaze-Feasibility randomised controlled trial.

OBJECTIVE: The Anti-Freaze-F (AFF) trial assessed the feasibility of conducting a definitive trial to determine whether intra-articular injection of adalimumab can reduce pain and improve function in people with pain-predominant early-stage frozen shoulder. DESIGN: Multicentre, randomised feasibility trial, with embedded qualitative study. SETTING: Four UK National Health Service (NHS) musculoskeletal and related physiotherapy services. PARTICIPANTS: Adults ≥18 years with new episode of shoulder pain attributable to early-stage frozen shoulder. INTERVENTIONS: Participants were randomised (centralised computer generated 1:1 allocation) to either ultrasound-guided intra-articular injection of: (1) adalimumab (160 mg) or (2) placebo (saline (0.9% sodium chloride)). Participants and outcome assessors were blinded to treatment allocation. Second injection of allocated treatment (adalimumab 80 mg) or equivalent placebo was administered 2-3 weeks later. PRIMARY FEASIBILITY OBJECTIVES: (1) Ability to screen and identify participants; (2) willingness of eligible participants to consent and be randomised; (3) practicalities of delivering the intervention; (4) SD of the Shoulder Pain and Disability Index (SPADI) score and attrition rate at 3 months. RESULTS: Between 31 May 2022 and 7 February 2023, 156 patients were screened of whom 39 (25%) were eligible. The main reasons for ineligibility were other shoulder disorder (38.5%; n=45/117) or no longer in pain-predominant frozen shoulder (33.3%; n=39/117). Of the 39 eligible patients, nine (23.1%) consented to be randomised (adalimumab n=4; placebo n=5). The main reason patients declined was because they preferred receiving steroid injection (n=13). All participants received treatment as allocated. The mean time from randomisation to first injection was 12.3 (adalimumab) and 7.2 days (placebo). Completion rates for patient-reported and clinician-assessed outcomes were 100%. CONCLUSION: This study demonstrated that current NHS musculoskeletal physiotherapy settings yielded only small numbers of participants, too few to make a trial viable. This was because many patients had passed the early stage of frozen shoulder or had already formulated a preference for treatment. TRIAL REGISTRATION NUMBER: ISRCTN 27075727, EudraCT 2021-03509-23, ClinicalTrials.gov NCT05299242 (REC 21/NE/0214).

The overlap between randomised evaluations of recruitment and retention interventions: An updated review of recruitment (Online Resource for Recruitment in Clinical triAls) and retention (Online Resource for Retention in Clinical triAls) literature.

BACKGROUND: The Online Resource for Recruitment in Clinical triAls (ORRCA) and the Online Resource for Retention in Clinical triAls (ORRCA2) were established to organise and map the literature addressing participant recruitment and retention within clinical research. The two databases are updated on an ongoing basis using separate but parallel systematic reviews. However, recruitment and retention of research participants is widely acknowledged to be interconnected. While interventions aimed at addressing recruitment challenges can impact retention and vice versa, it is not clear how well they are simultaneously considered within methodological research. This study aims to report the recent update of ORRCA and ORRCA2 with a special emphasis on assessing crossover of the databases and how frequently randomised studies of methodological interventions measure the impact on both recruitment and retention outcomes. METHODS: Two parallel systematic reviews were conducted in line with previously reported methods updating ORRCA (recruitment) and ORRCA2 (retention) with publications from 2018 and 2019. Articles were categorised according to their evidence type (randomised evaluation, non-randomised evaluation, application and observation) and against the recruitment and retention domain frameworks. Articles categorised as randomised evaluations were compared to identify studies appearing in both databases. For randomised studies that were only in one database, domain categories were used to assess whether the methodological intervention was likely to impact on the alternate construct. For example, whether a recruitment intervention might also impact retention. RESULTS: In total, 806 of 17,767 articles screened for the recruitment database and 175 of 18,656 articles screened for the retention database were added as result of the update. Of these, 89 articles were classified as 'randomised evaluation', of which 6 were systematic reviews and 83 were randomised evaluations of methodological interventions. Ten of the randomised studies assessed recruitment and retention and were included in both databases. Of the randomised studies only in the recruitment database, 48/55 (87%) assessed the content or format of participant information which could have an impact on retention. Of the randomised studies only in the retention database, 6/18 (33%) assessed monetary incentives, 4/18 (22%) assessed data collection location and methods and 3/18 (17%) assessed non-monetary incentives, all of which could have an impact on recruitment. CONCLUSION: Only a small proportion of randomised studies of methodological interventions assessed the impact on both recruitment and retention despite having a potential impact on both outcomes. Where possible, an integrated approach analysing both constructs should be the new standard for these types of evaluations to ensure that improvements to recruitment are not at the expense of retention and vice versa.

A systematic review of flurbiprofen 8.75 mg dose and risk of adverse events (excluding haemorrhagic) resulting from drug-drug interactions.

Background: Flurbiprofen 8.75 mg lozenges and oromucosal sprays are used for symptomatic relief of sore throat in patients aged 12 years and over. The documented adverse events of flurbiprofen use include those related to its pharmacological actions, namely, increased risk of haemorrhagic events, however other adverse events (such as nephrotoxicity and cardiac failure) have been known to occur. The likelihood of occurrence of adverse events increases when flurbiprofen is used concomitantly with some other medications. Therefore, the objective of this systematic review was to collate the current evidence on adverse events which occur with flurbiprofen 8.75 mg dose (any formulation), in particular as a result of interaction with other medicinal products, with a focus on non-haemorrhagic events. Methods: Systematic searches of the literature were conducted to identify literature on any formulation of flurbiprofen 8.75 mg up to the date of the electronic database search (data lock: 28 April 2020). Publications were screened to identify studies reporting non-haemorrhagic adverse events with flurbiprofen 8.75 mg and/or non-haemorrhagic adverse events in the comparator arm. Data extraction was performed for eligible studies according to pre-defined criteria and summarised in narratives, tables and figures. Risk of bias and certainty of evidence assessments were planned for each included study where results relating to the primary objective of the systematic review were available. Results: Of 1,528 publications identified by systematic literature searches, 26 met the inclusion criteria and were included in this review. None of these 26 studies contained information on non-haemorrhagic adverse events occurring as a result of a drug-drug interaction (interaction with concomitant medication used with flurbiprofen 8.75 mg), as per the primary objective and secondary objectives of the systematic review. Conclusion: Results from this systematic review on the risk of non-haemorrhagic events did not provide evidence for these events occurring as a result of interaction with other medicinal products. Additional appropriately designed studies would be required to confirm whether these findings suggest a true absence of risk or limitations in reporting.

NIMBUS study protocol: a single-centre feasibility study of non-invasive monitoring with bowel ultrasound in paediatric inflammatory bowel disease.

INTRODUCTION: Incidence of inflammatory bowel disease (IBD) is increasing in childhood and treatment increasingly targets mucosal healing. Monitoring bowel inflammation requires endoscopy or MRI enterography which are invasive, expensive and have long waiting lists.We aim to examine the feasibility of a non-invasive monitoring tool-bowel ultrasound (BUS)-in children with IBD and explore correlations with inflammatory markers and disease activity measures. Some BUS criteria have been found to correlate with these markers; however, this has not been validated in children.We aim to examine the feasibility of BUS for monitoring inflammation in this population; highlighting useful parameters for this purpose. We aim to inform a larger scale randomised controlled trial using BUS. METHODS AND ANALYSIS: This prospective observational feasibility study will be carried out over 24 months at the Noah's Ark Children's Hospital for Wales, Cardiff; with the endpoint recruitment of 50 participants. Children aged 2-18 years with a modified Porto criteria diagnosis of IBD will be included.Patients without IBD or who have previously undergone IBD-related surgery will be excluded; as will families unable to give informed consent.Ultrasound scan images and reports will be collected, as well as laboratory results and clinical outcomes.The primary aim will assess the feasibility of targeted BUS for disease monitoring; including recruitment statistics. The secondary aims will involve data collection and correlation analysis for targeted ultrasound parameters, biomarkers, disease activity scores and prediction of changes in treatment. The statistical methods will include: feasibility metrics, descriptive statistics, cross-tabulation and χ2 analysis, correlation analysis, regression analysis. ETHICS AND DISSEMINATION: Ethical approval is granted by NHS Research Ethics Committee. The sponsor is Cardiff and Vale University Health Board. We will publish the results in a peer-reviewed medical journal. TRIAL REGISTRATION NUMBER: NCT05673278.

Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure: An Exploratory Proof-of-Concept Trial.

Acute lung injury in COVID-19 results in diffuse alveolar damage with disruption of the alveolar-capillary barrier, coagulation activation, alveolar fibrin deposition and pulmonary capillary thrombi. Nebulized recombinant tissue plasminogen activator (rt-PA) has the potential to facilitate localized thrombolysis in the alveolar compartment and improve oxygenation. In this proof-of-concept safety study, adults with COVID-19-induced respiratory failure and a <300 mmHg PaO2/FiO2 (P/F) ratio requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care, between 23 April-30 July 2020 and 21 January-19 February 2021, respectively. Matched historical controls (MHC; n = 18) were used in C1 to explore efficacy. Safety co-primary endpoints were treatment-related bleeds and <1.0-1.5 g/L fibrinogen reduction. A variable dosing strategy with clinical efficacy endpoint and minimal safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40-60 mg rt-PA daily for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeds (one severe, three mild) in three patients were considered treatment related. There were no significant fibrinogen reductions. Greater improvements in mean P/F ratio from baseline to study end were observed in C1 compared with MHC (C1; 154 to 299 vs. MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in the P/F ratio occurred in NIRS patients (NIRS; 126 to 240 vs. IMV; 120 to 188) and fewer treatment days were required (NIRS; 7.86 vs. IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, with a trend towards improved oxygenation, particularly in the NIRS group. Randomized clinical trials are required to demonstrate the clinical effect significance and magnitude.

Novel approaches for leadless pacemaker implantation in the extra-cardiac Fontan cohort: Options to avoid leaded systems or epicardial pacing.

BACKGROUND: Fontan surgery, a palliative procedure for single ventricle patients, often leads to the need for permanent pacing. Epicardial pacing has limitations, while transvenous pacing carries risks in the Fontan circulation. This case series introduces a novel approach of leadless pacemaker implantation in the extra-cardiac Fontan (ECF) cohort to overcome these limitations. METHODS: The study includes four cases of leadless pacemaker (Micra™) implantation in patients with ECF. Procedures were performed under general anesthesia with guidance from trans-esophageal echocardiography. Various access routes were used, including trans-carotid and trans-fenestration approaches. Procedural details, parameters, and follow-up data were collected. RESULTS: All leadless pacemaker implantations were successful, with satisfactory electrical parameters and stable pacing postprocedural outcomes during short-term follow-up. One patient required closure of their fenestration for symptomatic desaturation post procedurally. CONCLUSIONS: Leadless pacemaker implantation via trans-carotid and trans-fenestration approaches appears to be a feasible back up option for pacing in Fontan patients where other options have been exhausted or there is a patient choice to avoid surgery. These techniques provide an option to avoid leaded systems or epicardial pacing, reducing the need for multiple thoracotomies and addressing challenges associated with surgical pacing leads. Further studies are needed to evaluate long-term outcomes and assess the broader application of leadless pacemakers in the Fontan population.

Delayed pregnancy detection and return to fertility with extended levonorgestrel-containing oral contraceptives: A real world setting cohort study.

PURPOSE: As part of the European risk management plan of a 91-day extended levonorgestrel-containing combined oral contraceptive (COCLNG ), a study was performed to assess its safety. This analysis was conducted to examine delayed pregnancy detection and return to fertility with extended combined oral contraceptives (COC). METHODS: We conducted a retrospective cohort study in new users of 91-day COCLNG or 28-day COCLNG within a US-based healthcare claims database from 2006 to 2017. Delayed pregnancy detection during current COCLNG exposure was defined as the time between estimated pregnancy start and first prenatal care encounter. Additionally, the time between estimated pregnancy start and COCLNG discontinuation was measured. To measure return to fertility, pregnancy rates were estimated among females who discontinued treatment. 91-day COCLNG users were propensity score-matched to 28-day COCLNG users. Hazard ratio for pregnancy was calculated using Cox proportional hazards models. RESULTS: The 91-day and 28-day COCLNG users had 25 593 and 76 586 treatment episodes, respectively. The median time to pregnancy detection was 64.5 and 61.0 days (p = 0.24) in users of 91-day COCLNG and 28-day COCLNG . The median exposure time to treatment after estimated pregnancy start was 54.0 and 38.0 days (p < 0.01). In the fertility analysis, pregnancy rates were 54.82 (95% CI, 50.05-59.93) and 69.30 (95% CI, 64.98-73.82) per 1000 person-years in extended COCLNG discontinuers and 28-day COCLNG discontinuers. The adjusted hazard ratio of pregnancy was 0.77 (95% CI, 0.69-0.85). CONCLUSIONS: Small differences were observed for pregnancy rates and delayed pregnancy detection between 91-day extended COCLNG and 28-day COCLNG , which may be related to the longer days' supply of extended COCLNG . Differences in the fertility analysis may be related to unmeasured residual confounding.

Long-term safety of extended levonorgestrel-containing oral contraceptives in the United States.

OBJECTIVES: To compare the safety profile of Seasonique, a 91-day levonorgestrel-containing combined oral contraceptive (COCLNG), to 28-day COCLNG regarding the risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE). STUDY DESIGN: A new user cohort study was conducted in a US health care database from 2006 to 2017. Each 91-day COCLNG treatment episode in females was matched to up to four 28-day COCLNG treatment episodes by propensity score. We identified VTE cases in either (1) an inpatient setting with ICD-9 and ICD-10 diagnosis codes of PE and/or DVT in the primary position, or (2) an outpatient setting with ICD-9 or ICD-10 diagnosis codes of DVT in conjunction with an anticoagulant medication dispensing or alteplase (thrombolytic) during the 30-day period following the date of DVT diagnosis. VTE was validated using medical records. We assessed the study endpoints in the two cohorts using incidence rates and Cox proportional hazards models adjusted for potential confounders. RESULTS: Of the 25,593 treatment episodes in 91-day COCLNG and 76,586 treatment episodes in 28-day COCLNG, 35 and 68 patients had VTEs, respectively, corresponding to a hazard ratio (HR) of 1.40 (95% confidence interval [CI], 0.90-2.19). The VTE algorithm had a positive predictive value of 76.4% (95% CI, 66.2%-84.8%). ATEs were recorded in 13 and 28 episodes, respectively, with a corresponding HR of 1.21 (95% CI, 0.58-2.53). CONCLUSIONS: These results do not indicate a significant difference between 91-day COCLNG and 28-day COCLNG in terms of VTE or ATE risk. IMPLICATIONS: Compared to use of 28-day COCLNG, use of 91-day extended COCLNG was not associated with a significant difference in risk of venous and arterial thromboembolism.

A Systematic Review of Flurbiprofen 8.75 mg Dose and Risk of Haemorrhagic Events.

Oral non-steroidal anti-inflammatory drugs (NSAIDs) are known to be associated with an increased risk of bleeding. The NSAID, flurbiprofen, in the form of 8.75 mg lozenge or oromucosal spray is indicated for the symptomatic relief of sore throat. Despite the low dose as compared to alternative flurbiprofen preparations, concerns have been raised regarding its safety in terms of haemorrhagic events. This systematic review was conducted to identify existing evidence on the risk of haemorrhagic events with flurbiprofen 8.75 mg dose (any formulation), particularly where this may be due to potential interactions with other medicinal products. The systematic review examined studies reporting haemorrhagic events in patients receiving flurbiprofen 8.75 mg dose. Six individual electronic databases were searched up to 28th April 2020. Records were initially screened for relevance followed by further review of potentially eligible studies. Data extraction was performed for eligible studies and risk of bias in studies was assessed. The search strategy identified 1093 individual records. Of these, 1038 records were excluded after initial review; the majority of these records related to flurbiprofen in alternative formulations with alternative doses (e.g., eye drops, skin patches, oral tablets) thus were not considered relevant for further review. The 55 remaining records related to flurbiprofen 8.75 mg dose (any formulation) or flurbiprofen lozenge/oromucosal spray where the dose was not specified. After further review, 52 of these records were not considered eligible. Thus, only three records were included in this systematic review. The three studies reported a total of five haemorrhagic events in patients taking flurbiprofen 8.75 mg lozenge; the corresponding risk in each of the studies was 8.33, 1.98 and 1.96%. Where possible, comparison of flurbiprofen 8.75 mg lozenge to placebo produced risk ratios of 0.96 (95% CI 0.07, 13.25) and 2.00 (95% CI 0.10, 118.0). This systematic review found limited evidence on the risk of haemorrhagic events with flurbiprofen when used at a dose of 8.75 mg. Counts were low across all studies and results comparing flurbiprofen and placebo treatment arms were non-significant. However, scarcity of studies and low certainty of evidence for the outcome of haemorrhagic events limits the conclusions of this systematic review.

Using the Mindfulness-Based Interventions: Teaching Assessment Criteria (MBI:TAC) in Supervision.

The Mindfulness-Based Interventions: Teaching Assessment Criteria (MBI:TAC) is a useful framework for supporting teacher development in the context of mindfulness-based supervision (MBS). It offers a framework that enhances clarity, develops reflexive practice, gives a structure for feedback, and supports learning. MBS is a key component of Mindfulness-Based Program (MBP) teacher training and ongoing good practice. Integrating the MBI:TAC within the MBS process adds value in a number of ways including: offering a shared language around MBP teaching skills and processes; framing the core pedagogical features of MBP teaching; enabling assessment of developmental stage; and empowering supervisees to be proactive in their own development. The paper lays out principles for integrating the MBI:TAC framework into MBS. The supervisor needs awareness of the ways in which the tool can add value, and the ways it can inadvertently interrupt learning. The tool enables skills clarification, but the learning process needs to remain open to spontaneous experiential discovery; it can enable structured feedback but space is also needed for open reflective feedback; and it can enable conceptual engagement with the teaching process but space is needed for the supervisee to experientially sense the teaching process. The tool needs to be introduced in a carefully staged way to create optimal conditions for learning at the various stages of the MBP teacher-training journey. Practical guidance is presented to consolidate and develop current practice. The principles and processes discussed can be generalized to other forms of reflective dialogue such as mentoring, tutoring and peer reflection groups.

Real world utilization of 91 day extended levonorgestrel-containing combined oral contraceptives in Europe: a multinational database study.

OBJECTIVE: As part of the risk management plan in Europe, this study was conducted to characterize drug utilization patterns of Seasonique, a 91 day extended levonorgestrel-containing combined oral contraceptive (COCLNG). METHODS: A retrospective observational study was conducted in France, Italy and Belgium using electronic medical record databases obtained from general practitioners (GPs) in all participating countries and gynecologists in France from 2015 to 2018. The study population included women receiving ≥1 prescription of 91 day COCLNG during the study period. Prescribing patterns of 91 day COCLNG were examined including: (1) treatment duration; (2) indication; (3) use of combined oral contraceptive (COC) before 91 day COCLNG initiation; and (4) switch from and to combined hormonal contraceptives (CHCs) or other contraceptives. RESULTS: Totals of 235, 220, 207 and 659 women using 91 day COCLNG were identified in French, Italian and Belgian GP, and French gynecologist databases, respectively. Across databases, 46-76% of women were prescribed a single 91 day COCLNG prescription and median treatment duration ranged from 3 to 6 months. The most common indication was contraception (42-81%), followed by menstrual migraines (2-14%). Use of COC during the 6 months prior to 91 day COCLNG initiation was 14% across GP databases, but was lower (8%) in the French gynecologist database. The frequency of switching from 91 day COCLNG to CHCs or other contraceptives was generally low (5-12%), with the highest proportion being among patients of French gynecologists. CONCLUSIONS: Findings indicate that 91 day COCLNG was prescribed for relatively short durations and predominantly as indicated for contraception. Most results were comparable across all participating countries. KEY POINTSFindings from this drug utilization study in European databases across general practitioners and French gynecologists confirmed that 91 day extended levonorgestrel-containing combined oral contraceptive (COCLNG) was prescribed for relatively short durations (median 3-6 months); predominantly for the intended indication of contraception.Combined oral contraceptive use during the 6 months prior to 91 day COCLNG initiation, and switching from 91 day COCLNG to combined hormonal contraceptives or other contraceptives, were generally low (14% or less).These findings were mostly consistent across participating countries.

Slow-Growing Pituitary Metastasis from Renal Cell Carcinoma: Literature Review.

BACKGROUND: Tumor metastasis to the pituitary is rare, most commonly reported with either breast or lung cancer metastasizing to the neurohypophysis. Pituitary metastases of renal cell carcinoma (RCC) are by contrast infrequently described even within this scarce literature. We present an illustrative case of RCC pituitary metastasis 15 years after radical nephrectomy for primary disease and a review of the published literature. CASE DESCRIPTION: A 69-year-old female was diagnosed with a large sellar mass with suprasellar extension. The initial radiologic diagnosis was most in keeping with pituitary macroadenoma, although prominent vascular flow voids were noted. Endoscopic endonasal transsphenoidal adenectomy was challenging on account of significant intraoperative hemorrhage from an unusually vascular tumor. Pathologic examination supported a diagnosis of metastatic clear cell renal carcinoma. Literature review identified 41 cases of RCC pituitary metastasis since 1984. The mean age at time of diagnosis with pituitary metastasis was 59.5 years (range 35-81 years, 73% male). Pituitary metastasis was the initial presentation of RCC in 10 patients. The median time from RCC diagnosis to pituitary metastasis was 1 year (range 0-27 years). Surgical resection was performed for 30 patients, of which 47% reported a highly vascular tumor. CONCLUSIONS: We highlight the potential for delayed metastasis to the pituitary to masquerade as a macroadenoma. Imaging consistent with rich vascularity should bring the diagnosis of RCC metastasis into the differential and is important to note when planning surgical resection in such cases.

Mild cognitive impairment: the Manchester consensus.

Given considerable variation in diagnostic and therapeutic practice, there is a need for national guidance on the use of neuroimaging, fluid biomarkers, cognitive testing, follow-up and diagnostic terminology in mild cognitive impairment (MCI). MCI is a heterogenous clinical syndrome reflecting a change in cognitive function and deficits on neuropsychological testing but relatively intact activities of daily living. MCI is a risk state for further cognitive and functional decline with 5-15% of people developing dementia per year. However, ~50% remain stable at 5 years and in a minority, symptoms resolve over time. There is considerable debate about whether MCI is a useful clinical diagnosis, or whether the use of the term prevents proper inquiry (by history, examination and investigations) into underlying causes of cognitive symptoms, which can include prodromal neurodegenerative disease, other physical or psychiatric illness, or combinations thereof. Cognitive testing, neuroimaging and fluid biomarkers can improve the sensitivity and specificity of aetiological diagnosis, with growing evidence that these may also help guide prognosis. Diagnostic criteria allow for a diagnosis of Alzheimer's disease to be made where MCI is accompanied by appropriate biomarker changes, but in practice, such biomarkers are not available in routine clinical practice in the UK. This would change if disease-modifying therapies became available and required a definitive diagnosis but would present major challenges to the National Health Service and similar health systems. Significantly increased investment would be required in training, infrastructure and provision of fluid biomarkers and neuroimaging. Statistical techniques combining markers may provide greater sensitivity and specificity than any single disease marker but their practical usefulness will depend on large-scale studies to ensure ecological validity and that multiple measures, e.g. both cognitive tests and biomarkers, are widely available for clinical use. To perform such large studies, we must increase research participation amongst those with MCI.

Evaluation of the incidence of bleeding in patients prescribed rivaroxaban for the treatment and prevention of deep vein thrombosis and pulmonary embolism in UK secondary care: an observational cohort study.

OBJECTIVES: To evaluate the short-term (12 weeks) safety and utilisation of rivaroxaban prescribed to new-user adult patients for the treatment of deep vein thrombosis and pulmonary embolism and for the prevention of recurrent deep vein thrombosis and pulmonary embolism in a secondary care setting in England and Wales. DESIGN: An observational cohort study using the technique of Specialist Cohort Event Monitoring. SETTING: The Rivaroxaban Observational Safety Evaluation study was conducted across 87 participating National Health Service secondary care trusts in England and Wales. PARTICIPANTS: 1532 patients treated with rivaroxaban for the prevention and treatment of deep vein thrombosis/pulmonary embolism from September 2013 to January 2016. INTERVENTIONS: Non-interventional postauthorisation safety study of rivaroxaban. PRIMARY AND SECONDARY OUTCOME MEASURES: (1) Risk of major bleeding in gastrointestinal, intracranial, and urogenital sites and (2) risk of all major and clinically relevant non-major bleeds. RESULTS: Of a total of 4846 patients enrolled in the study from September 2013 to January 2016, 1532 were treated with rivaroxaban for the prevention and treatment of deep vein thrombosis/pulmonary embolism. The median age of the deep vein thrombosis/pulmonary embolism cohort was 63 years, and 54.6% were men. The risk of major bleeding within the gastrointestinal, urogenital and intracranial primary sites was 0.7% (n=11), 0.3% (n=5) and 0.1% (n=1), respectively. The risk of major bleeding in all sites was 1.5% (n=23) at a rate of 8.3 events per 100 patient-years. CONCLUSIONS: In terms of the primary outcome risk of major bleeding in gastrointestinal, intracranial and urogenital sites, the risk estimates in the population using rivaroxaban for deep vein thrombosis/pulmonary embolism were low (<1%) and consistent with the risk estimated from clinical trial data and in routine clinical practice. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov Registry (NCT01871194); ENCePP Registry (EUPAS3979).

Incidence of major and clinically relevant non-major bleeding in patients prescribed rivaroxaban for stroke prevention in non-valvular atrial fibrillation in secondary care: Results from the Rivaroxaban Observational Safety Evaluation (ROSE) study.

INTRODUCTION: Although the direct oral anticoagulant rivaroxaban is recommended for stroke prevention in patients with non-valvular atrial fibrillation based on Phase III clinical trials, there is still a need for additional safety data from everyday clinical practice. The ROSE study was initiated to collect further information on the safety and utilisation of rivaroxaban in a broader range of patient groups in routine clinical practice. METHODS AND RESULTS: The ROSE study was conducted in hospitals in England and Wales. Consenting adults with non-valvular atrial fibrillation newly started on rivaroxaban were eligible and followed up for 12 weeks. Data was derived through secondary use of medical records. The primary outcome was major bleeding within gastrointestinal, urogenital and intracranial sites. A total of 4846 patients were enrolled in the study September 2013 to January 2016, 965 of which were treated with rivaroxaban for non-valvular atrial fibrillation. The median age in the rivaroxaban non-valvular atrial fibrillation cohort was 76 years, 53.6% were male. The median HAS-BLED score was 2 and the median CHA2DS2-VASc score was 4. The risk of major bleeding within each of the primary sites of gastrointestinal, urogenital and intracranial during the 12 week observation period was low (0.2%; n = 2). The risk of major bleeding in all sites was 1.0% (n = 10) at a rate of 5.5 events per 100 patient years. CONCLUSION: In terms of the primary outcome risk of major bleeding within gastrointestinal, urogenital and intracranial sites during the 12 week observation period, the risk estimates in the non-valvular atrial fibrillation rivaroxaban user population were low (<1%), and consistent with risk estimated from clinical trial data and in routine clinical practice.

Observational assessment of safety in seroquel (OASIS): a specialist cohort event monitoring (SCEM) study in England.

BACKGROUND: This study was designed to monitor the short-term (up to 12 weeks) use and safety of quetiapine (Seroquel) extended release (XL) and quetiapine immediate release (IR) prescribed to patients with a clinical diagnosis of schizophrenia, and/or manic episodes associated with bipolar disorder by psychiatrists under normal conditions of use. METHODS: A Specialist Cohort Event Monitoring (SCEM) study was conducted in England February 2010-April 2013. This observational cohort study recruited patients prescribed quetiapine XL within the secondary care setting by psychiatrists. A reference cohort of quetiapine IR users was also recruited. Baseline and 12 week observational data were collected from psychiatrists who abstracted information from medical records onto bespoke questionnaires. Data were collected on demographics, indication, past medical history, prescribing information and events of interest. Summary descriptive statistics were calculated. RESULTS: The final cohort consisted of 869 eligible patients; 646 XL users and 223 IR users. The majority of XL and IR users were female (56.2% and 55.6%, respectively), with a median age of 40 (interquartile range [IQR]: 29, 49) and 39 (IQR: 28, 50) years, respectively. The most frequent indication for treatment was Manic episodes associated with Bipolar Affective disorder (53.4% XL and 49.8% IR). Median index dose was 200 mg/day (IQR: 100, 300) for XL users and 50 mg/day (IQR: 50, 100) for IR users, while median final maintenance dose was 400mg/day (IQR: 250, 600) and 300 mg/day (IQR: 100, 400), respectively. The most frequently reported event of interest in both cohorts was sedation (n = 151, 23.9% XL cohort and n = 49, 23.0% IR cohort). CONCLUSION: Utilisation of quetiapine XL appeared to be in line with prescribing guidelines in terms of dose, and commonly reported events of interest were in concordance with the known safety profile. Overall, this SCEM study provided important information on the safety and utilisation of quetiapine XL in the secondary care setting in England.

Rationale and design of a European epidemiological post-authorization safety study (PASS) program: rivaroxaban use in routine clinical practice.

BACKGROUND: Rivaroxaban is a highly selective factor Xa inhibitor approved for use in Europe for multiple indications. STUDY DESIGN AND METHODS: The European rivaroxaban epidemiological post-authorization safety study (PASS) program consists of seven complementary observational studies. For four of the studies, data are obtained from health-care databases in the UK, the Netherlands, Germany, and Sweden. These database studies describe patterns of rivaroxaban use and patient characteristics over time, and investigate safety and effectiveness outcomes in new users of rivaroxaban using a cohort analysis and nested case-control analysis. To put these results in context, safety outcomes are also analyzed in new users of standard of care. In addition, a modified prescription event monitoring study conducted in the early post-launch phase in primary care, and two specialist cohort event monitoring studies that investigated rivaroxaban use in the secondary care hospital setting, systematically collected drug utilization and safety data via questionnaires completed by health-care professionals in the UK. DISCUSSION: The European rivaroxaban epidemiological PASS is a comprehensive program of complementary studies generating evidence from patients treated in routine clinical practice that will expand our understanding of the risk-benefit profile of rivaroxaban.

Lopinavir-Ritonavir in the Treatment of COVID-19: A Dynamic Systematic Benefit-Risk Assessment.

INTRODUCTION AND OBJECTIVE: COVID-19 is an ongoing, global public health crisis for which safe and effective treatments need to be identified. The benefit-risk balance for the use of lopinavir-ritonavir in COVID-19 needs to be monitored on an ongoing basis, therefore a systematic benefit-risk assessment was designed and conducted. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation; although initially this evaluation is likely to contain limited information, it is required because of the urgent unmet public need. Importantly, it allows additional data to be incorporated as they become available, and re-evaluation of the benefit-risk profile. METHODS: A systematic benefit-risk assessment was conducted using the Benefit-Risk Action Team (BRAT) framework. The exposure of interest was lopinavir-ritonavir treatment in severe COVID-19 compared to standard of care, placebo or other treatments. A literature search was conducted in PubMed and Embase to identify peer-reviewed papers reporting clinical outcomes. Two clinicians constructed a value tree and ranked key benefits and risks in order of considered clinical importance. RESULTS: We screened 143 papers from PubMed and 264 papers from Embase for lopinavir-ritonavir; seven papers were included in the final benefit-risk assessment. In comparison to standard of care, data for several key benefits and risks were identified for lopinavir-ritonavir. Time to clinical improvement was not significantly different for lopinavir-ritonavir in comparison to standard of care (hazard ratio 1.31, 95% confidence interval 0.95-1.80). From one study, there were fewer cases of acute respiratory distress syndrome with lopinavir-ritonavir compared with standard of care (13% vs 27%). There also appeared to be fewer serious adverse events with lopinavir-ritonavir (20%) vs standard of care (32%). Limited data were available for comparison of lopinavir-ritonavir to other treatments. CONCLUSIONS: Based on currently available data, there was no clear benefit for the use of lopinavir-ritonavir compared to standard of care in severe COVID-19. Risk data suggested a possible decrease in serious adverse events. There was a reduction in acute respiratory distress syndrome with lopinavir-ritonavir in one study. Overall, the benefit-risk profile for lopinavir-ritonavir in severe COVID-19 cannot be considered positive until further efficacy and effectiveness data become available.