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Gema Requena,1 Alexandrosz Czira,1 Victoria Banks,2 Robert Wood,2 Theo Tritton,2 Catherine Castillo,2 Jie Yeap,2 Rosie Wild,2 Chris Compton,1 Kieran J Rothnie,1 Felix JF Herth,3 Jennifer K Quint,4 Afisi S Ismaila5,6 1GSK, R&D Global Medical, Brentford, Middlesex, UK; 2Real-World Evidence, Adelphi Real World, Bollington, Cheshire, UK; 3Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg and Translational Lung Research Center Heidelberg, Heidelberg, Germany; 4National Heart and Lung Institute, Imperial College London, London, UK; 5Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 6Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: Gema Requena, Epidemiology, Value Evidence and Outcomes, R&D Global Medical, GSK, Brentford, Middlesex, UK, Tel +44 20 80476893, Email gema.x.requena@gsk.comPurpose: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with significant morbidity and mortality and increased economic healthcare burden for patients with COPD. Long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) dual therapy is recommended for patients receiving mono-bronchodilator therapy who experience exacerbations or ongoing breathlessness. This study compared two single-inhaler LAMA/LABA dual therapies, umeclidinium/vilanterol (UMEC/VI) and indacaterol/glycopyrronium (IND/GLY), on moderate-to-severe exacerbation rates in patients with COPD in England.Patients and Methods: This retrospective cohort study used linked primary care electronic health record data (Clinical Practice Research Datalink-Aurum) and secondary care data (Hospital Episode Statistics) to assess outcomes for patients with COPD who had a first prescription for single-inhaler UMEC/VI or IND/GLY (index date) between 1 January 2015 and 30 September 2019 (indexing period). Analyses compared UMEC/VI and IND/GLY on moderate-to-severe, moderate, and severe exacerbations, healthcare resource utilization (HCRU), and direct costs at 6, 12, 18, and 24 months, and time-to-first on-treatment exacerbation up to 24 months post-index date. Following inverse probability of treatment weighting (IPTW), non-inferiority and superiority of UMEC/VI versus IND/GLY were assessed.Results: In total, 12,031 patients were included, of whom 8753 (72.8%) were prescribed UMEC/VI and 3278 (27.2%) IND/GLY. After IPTW, for moderate-to-severe exacerbations, weighted rate ratios were < 1 at 6, 12, and 18 months and equal to 1 at 24 months for UMEC/VI; around the null value for moderate exacerbations and < 1 at all timepoints for severe exacerbations. UMEC/VI showed lower HCRU incidence rates than IND/GLY for all-cause Accident and Emergency visits and COPD-related inpatient stays and associated all-cause costs at 6 months post-indexing. Time-to-triple therapy was similar for both treatments.Conclusion: UMEC/VI demonstrated non-inferiority to IND/GLY in moderate-to-severe exacerbation reduction at 6, 12 and 18 months. These results support previous findings demonstrating similarity between UMEC/VI and IND/GLY on reduction of moderate-to-severe exacerbations.Plain Language Summary: Sudden exacerbations, or flare-ups, of chronic obstructive pulmonary disease (COPD) are linked with worsening health and increased risk of death, as well as increased healthcare costs for people with COPD. Long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) dual therapy is recommended for patients with COPD who take LAMA or LABA monotherapy but continue to experience flare-ups or ongoing breathlessness. This study compared two single-inhaler LAMA/LABA dual therapies, umeclidinium/vilanterol (UMEC/VI) and indacaterol/glycopyrronium (IND/GLY), in terms of flare-ups in patients with COPD in England.We used two linked databases of de-identified medical records from general practitioners and hospitals for patients with COPD who had a first prescription for UMEC/VI or IND/GLY between 1 January 2015 and 30 September 2019. We compared the two treatments on COPD flare-ups, healthcare resource utilization and related costs, and changes in medication over the 2 years following starting treatment.We found that the treatments were comparable for moderate-to-severe flare-ups. Patients taking UMEC/VI had less Accident and Emergency (A&E) visits in total and less inpatient stays related to their COPD, and had a lower overall cost of healthcare for A&E visits and inpatient stays than patients taking IND/GLY. Changes to treatment and time before their first flare-up were similar for all patients, regardless of their prescribed treatment.This study showed that UMEC/VI is as effective as IND/GLY at preventing moderate-to-severe flare-ups. These results support previous findings demonstrating similarity between UMEC/VI and IND/GLY in reducing the rate of moderate-to-severe exacerbations after starting treatment.Keywords: COPD dual therapy, LABA/LAMA new users, healthcare resource utilization, exacerbations, comparative effectiveness, single-inhaler dual therapy

Gema Requena,1 Alexandrosz Czira,1 Victoria Banks,2 Robert Wood,2 Theo Tritton,2 Catherine M Castillo,2 Jie Yeap,2 Rosie Wild,2 Chris Compton,1 Kieran J Rothnie,1 Felix Herth,3,4 Jennifer K Quint,5 Afisi S Ismaila6,7 1GSK, R&D Global Medical, Brentford, Middlesex, UK; 2Real-World Evidence, Adelphi Real World, Bollington, Cheshire, UK; 3Department of Pulmonology and Respiratory Care Medicine, Thoraxklinik at the University of Heidelberg, Heidelberg, Germany; 4Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research DZL, Heidelberg, Germany; 5National Heart and Lung Institute, Imperial College London, London, UK; 6Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 7Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: Gema Requena, GSK, R&D Global Medical, Brentford, Middlesex, UK, Tel +44 20 80476893, Email gema.x.requena@gsk.comPurpose: Routinely collected healthcare data on the comparative effectiveness of the long-acting muscarinic antagonist/long-acting β2-agonist combination umeclidinium/vilanterol (UMEC/VI) versus tiotropium bromide/olodaterol (TIO/OLO) for chronic obstructive pulmonary disease (COPD) is limited. This study compared rescue medication prescriptions in patients with COPD in England receiving UMEC/VI versus TIO/OLO.Patients and Methods: This retrospective cohort study used primary care data from the Clinical Practice Research Datalink Aurum database linked with secondary care administrative data from Hospital Episode Statistics. Patients with a COPD diagnosis at age ≥ 35 years were included (indexed) following initiation of single-inhaler UMEC/VI or TIO/OLO between July 1, 2015, and September 30, 2019. Outcomes included the number of rescue medication prescriptions at 12-months (primary), and at 6-, 18- and 24-months (secondary), adherence at 6-, 12-, 18- and 24-months post-index, defined as proportion of days covered ≥ 80% (secondary), and time-to-initiation of triple therapy (exploratory). Inverse probability of treatment weighting (IPTW) was used to balance potential confounding baseline characteristics. Superiority of UMEC/VI versus TIO/OLO for the primary outcome of rescue medication prescriptions was assessed using an intention-to-treat analysis with a p-value < 0.05.Results: In total, 8603 patients were eligible (UMEC/VI: n = 6536; TIO/OLO: n = 2067). Following IPTW, covariates were well balanced across groups. Patients initiating UMEC/VI had statistically significantly fewer (mean [standard deviation]; p-value) rescue medication prescriptions versus TIO/OLO in both the unweighted (4.84 [4.78] vs 5.68 [5.00]; p < 0.001) and weighted comparison (4.91 [4.81] vs 5.48 [5.02]; p = 0.0032) at 12 months; consistent results were seen at all timepoints. Adherence was numerically higher for TIO/OLO versus UMEC/VI at all timepoints. Time-to-triple therapy was similar between treatment groups.Conclusion: UMEC/VI was superior to TIO/OLO in reducing rescue medication prescriptions at 12 months after treatment initiation in a primary care cohort in England, potentially suggesting improvements in symptom control with UMEC/VI compared with TIO/OLO.Keywords: COPD treatment, LABA/LAMA, primary care setting, rescue medication, treatment escalation

Alexandrosz Czira,1 Gema Requena,1 Victoria Banks,2 Robert Wood,2 Theo Tritton,2 Catherine M Castillo,2 Jie Yeap,2 Rosie Wild,2 Chris Compton,1 Kieran J Rothnie,1 Felix Herth,3,4 Jennifer K Quint,5 Afisi S Ismaila6,7 1R&D Global Medical, GSK, Brentford, Middlesex, UK; 2Real-World Evidence, Adelphi Real World, Bollington, Cheshire, UK; 3Department of Pulmonology and Respiratory Care Medicine, Thoraxklinik at the University of Heidelberg, Heidelberg, Germany; 4Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research DZL, Heidelberg, Germany; 5National Heart and Lung Institute, Imperial College London, London, UK; 6Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 7Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: Alexandrosz Czira, Value Evidence and Outcomes, R&D Global Medical, GSK, Brentford, Middlesex, UK, Tel +44 7788 351610, Email alexandrosz.x.czira@gsk.comPurpose: To compare adherence to once-daily umeclidinium/vilanterol (UMEC/VI), a long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA), and twice-daily inhaled corticosteroids (ICS)/LABA single-inhaler dual therapy in patients with chronic obstructive pulmonary disease (COPD) in a primary care cohort in England.Patients and Methods: Active comparator, new-user, retrospective cohort study using CPRD-Aurum primary care data and linked Hospital Episode Statistics secondary care administrative data. Patients without exacerbations in the previous year were indexed on first/earliest prescription date of once-daily UMEC/VI or twice-daily ICS/LABA as initial maintenance therapy between July 2014-September 2019. Primary outcome: medication adherence at 12 months post-index, defined as proportion of days covered (PDC) ≥ 80%. PDC represented proportion of time over the treatment duration that the patient was theoretically in possession of the medication. Secondary outcomes: adherence at 6, 18, and 24 months post-index, time-to-triple therapy, time-to-first on-treatment COPD exacerbation, COPD-related and all-cause healthcare resource utilization (HCRU), and direct health-care costs. A propensity score was generated and inverse probability of treatment weighting (IPTW) was used to balance potential confounders. Superiority was defined as > 0% difference between treatment groups.Results: In total, 6815 eligible patients were included (UMEC/VI:1623; ICS/LABA:5192). At 12 months post-index, weighted odds of a patient being adherent were significantly greater with UMEC/VI versus ICS/LABA (odds ratio [95% CI]: 1.71 [1.09, 2.66]; p=0.0185), demonstrating superiority of UMEC/VI. Patients taking UMEC/VI were statistically significantly more adherent than those taking ICS/LABA at 6, 18, and 24 months post-index (p< 0.05). Differences in time-to-triple therapy, time-to-moderate COPD exacerbations, HCRU, and direct medical costs were not statistically significant between treatments after IPTW was applied.Conclusion: At 12 months post-treatment initiation, once-daily UMEC/VI was superior to twice-daily ICS/LABA in medication adherence among patients with COPD without exacerbations in the previous year, newly initiating dual maintenance therapy in England. The finding was consistent at 6, 18, and 24 months.Keywords: adherence, comparative effectiveness, chronic obstructive pulmonary disease (COPD) treatment, inhaled corticosteroid/long-actingβ2-agonist (ICS/LABA) dual therapy, long-acting muscarinic antagonist (LAMA)/LABA dual therapy

Gema Requena,1 Victoria Banks,2,&ast; Alexandrosz Czira,1 Robert Wood,2 Theo Tritton,2 Rosie Wild,2 Chris Compton,1 Afisi S Ismaila3,4 1Value Evidence and Outcomes, GSK, R&D Global Medical, Brentford, Middlesex, UK; 2Real-World Evidence, Adelphi Real World, Bollington, Cheshire, UK; 3Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 4Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada&ast;At the time of the studyCorrespondence: Gema Requena, Epidemiology, Value Evidence and Outcomes, R&D Global Medical, GSK, Middlesex, UK, Tel +44 20 80476893, Email gema.x.requena@gsk.comPurpose: Selection of treatments for patients with chronic obstructive pulmonary disease (COPD) may impact clinical outcomes, healthcare resource use (HCRU) and direct healthcare costs. We aimed to characterize these outcomes along with treatment patterns, for patients with COPD following initiation of single-inhaler long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) dual therapy in the primary care setting in England.Patients and Methods: This retrospective cohort study used linked primary care electronic medical record data (Clinical Practice Research Datalink-Aurum) and secondary care administrative data (Hospital Episode Statistics) in England to assess outcomes for patients with COPD who had a prescription for one of four single-inhaler LAMA/LABA dual therapies between 1st June 2015– 31st December 2018 (indexing period). Outcomes were assessed during a 12-month follow-up period from the index date (date of earliest prescription of a single-inhaler LAMA/LABA within the indexing period). Incident users were those without previous LAMA/LABA dual therapy prescriptions prior to index; this manuscript focuses on a subset of incident users: non-triple therapy users (patients without concomitant inhaled corticosteroid use at index).Results: Of 10,991 incident users included, 9888 (90.0%) were non-triple therapy users, indexed on umeclidinium/vilanterol (n=4805), aclidinium/formoterol (n=2109), indacaterol/glycopyrronium (n=1785) and tiotropium/olodaterol (n=1189). At 3 months post-index, 63.3% of non-triple therapy users remained on a single-inhaler LAMA/LABA, and 22.1% had discontinued inhaled therapy. Most patients (86.9%) required general practitioner consultations in the first 3 months post-index. Inpatient stays were the biggest contributor to healthcare costs. Acute exacerbations of COPD (AECOPDs), adherence, time-to-triple therapy, time-to-first on-treatment moderate-to-severe AECOPD, time-to-index treatment discontinuation, HCRU and healthcare costs were similar across indexed therapies.Conclusion: Patients initiating treatment with single-inhaler LAMA/LABA in primary care in England were unlikely to switch treatments in the first three months following initiation, but some may discontinue respiratory medication. Outcomes were similar across indexed treatments.Keywords: COPD, single-inhaler LAMA/LABA dual therapy, primary care setting, treatment patterns, clinical outcomes

David MG Halpin,1 Kieran J Rothnie,2 Victoria Banks,3 Alexandrosz Czira,2 Chris Compton,4 Robert Wood,3 Theo Tritton,3 Olivia Massey,3 Rosie Wild,3 Neil Snowise,5 Kirill Nikitin,2 Raj Sharma,4 Afisi S Ismaila,6,7 Claus F Vogelmeier8 1University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK; 2Value Evidence and Outcomes, R&D Global Medical, GSK, Brentford, UK; 3Real-World Evidence, Adelphi Real World, Bollington, UK; 4Global Medical, GSK, London, UK; 5Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King’s College, London, UK; 6Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 7Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada; 8Department of Medicine, Pulmonary and Critical Care Medicine, University of Marburg, Member of the German Center for Lung Research (DZL), Marburg, GermanyCorrespondence: David MG Halpin, University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, EX1 2LU, UK, Tel +44 (0)1392 201178, Email d.halpin@nhs.netPurpose: Triple therapy comprising a long-acting muscarinic antagonist, long-acting β2-agonist and inhaled corticosteroid is recommended for patients with chronic obstructive pulmonary disease (COPD) who continue to experience frequent exacerbations or symptoms whilst receiving dual therapy. Adherence and persistence to multiple-inhaler triple therapy (MITT) is known to be poor. This study assessed comparative adherence to single-inhaler triple therapy (SITT) versus MITT in a real-world setting in England.Patients and Methods: This was a retrospective cohort study using linked primary care (Clinical Practice Research Datalink Aurum) and secondary care (Hospital Episode Statistics [HES] Admitted Patient Care) data to identify patients with COPD who were newly initiated on SITT or MITT between November 2017 and June 2019. Eligible patients were aged ≥ 35 years and had a forced expiratory volume in 1 second/forced vital capacity < 0.7, linkage to HES and continuous registration with a general practitioner for 12 months pre- and 6 months post-initiation. Inverse probability of treatment weighting was used to balance baseline characteristics between cohorts. Adherence was measured using the proportion of days covered by days’ supply of SITT or MITT prescriptions. Persistence was measured with a gap of > 30 days between the end of a prescription and the following refill used to determine non-persistence.Results: Overall, 4080 SITT and 6579 MITT users comprised the study cohort. After weighting, the baseline characteristics between the cohorts were comparable (absolute standardized mean difference < 10%). SITT users had significantly higher adherence than MITT users at 6, 12, and 18 months post-initiation (p< 0.001 for all comparisons). Median persistence was higher among SITT users than MITT users (5.09 months vs 0.99 months).Conclusion: Patients with COPD in England initiating SITT had significantly better adherence and persistence compared with MITT initiators. These improvements continued at least 18 months following treatment initiation.Keywords: COPD, Clinical Practice Research Datalink, Hospital Episode Statistics, MITT, proportion of days covered, SITT

Gema Requena,1 Victoria Banks,2 Alexandrosz Czira,1 Robert Wood,2 Theo Tritton,2 Rosie Wild,2 Chris Compton,1 Maria Duarte,1 Afisi S Ismaila3,4 1Value Evidence and Outcomes, Epidemiology, GSK, R&D Global Medical, Brentford, Middlesex, UK; 2Real-world Evidence, Adelphi Real World, Bollington, Cheshire, UK; 3Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 4Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: Gema Requena, Epidemiology, Value Evidence and Outcomes, R&D Global Medical, GSK, Brentford, Middlesex, UK, Tel +44 20 80476893, Email gema.x.requena@gsk.comPurpose: Treatment pathways of patients with chronic obstructive pulmonary disease (COPD) receiving single-inhaler dual therapies remain unclear. We aimed to describe characteristics, prescribed treatments, healthcare resource use (HCRU) and costs of patients with COPD who initiated single-inhaler long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) dual therapy in primary care in England.Patients and Methods: Retrospective study using linked data from Clinical Practice Research Datalink Aurum and Hospital Episode Statistics datasets. Patients with COPD with ≥ 1 single-inhaler LAMA/LABA prescription between June 2015 and December 2018 (index) were included. Demographic and clinical characteristics, prescribed treatments, HCRU and costs were evaluated in the 12 months pre-index. Data are presented for patients not receiving concomitant inhaled corticosteroids at index (non-triple users).Results: Of 10,991 patients initiating LAMA/LABA, 9888 were non-triple users, of whom 21.3% (n=2109) received aclidinium bromide/formoterol, 18.1% (n=1785) received indacaterol/glycopyrronium, 12.0% (n=1189) received tiotropium bromide/olodaterol and 48.6% (n=4805) received umeclidinium/vilanterol. Demographic and clinical characteristics were similar across indexed therapies. LAMA monotherapy was the most frequently prescribed respiratory therapy at 12 (18.4– 25.8% of patients) and 3 months (23.9– 33.7% of patients) pre-index across indexed therapies; 42.5– 59.0% of patients were prescribed no respiratory therapy at these time points. COPD-related HCRU during the 12 months pre-index was similar across indexed therapies (general practitioner consultations: 62.0– 68.6% patients; inpatient stays: 19.3– 26.1% patients). Pre-index COPD-related costs were similar across indexed therapies, with inpatient stays representing the highest contribution. Mean total direct annual COPD-related costs ranged from £ 805–£ 1187.Conclusion: Characteristics of patients newly initiating single-inhaler LAMA/LABA dual therapy were highly consistent across indexed therapies. As half of non-triple users were not receiving respiratory therapy one year prior to LAMA/LABA initiation, there may be an opportunity for early optimization of treatment to relieve clinical burden versus current prescribing patterns in primary care in England.Keywords: COPD, initial maintenance therapy, primary care setting, patient characteristics, single-inhaler LAMA/LABA dual therapy, treatment patterns

Resistance to anticancer drugs is a major cause of failure of many therapeutic protocols. A variety of mechanisms have been proposed to explain this phenomenon. The exact mechanism depends upon the drug of interest as well as the tumor type treated. While studying a cell line selected for its resistance to cisplatin we noted that the cells expressed a >25,000-fold collateral resistance to methotrexate. Given the magnitude of this resistance we elected to investigate this intriguing collateral resistance. From a series of investigations we have identified an alteration in a membrane protein of the resistant cell as compared to the sensitive cells that could be the primary mechanism of resistance. Our studies reviewed here indicate decreased tyrosine phosphorylation of a protein (molecular mass = 66) in the resistant cells, which results in little or no transfer of methotrexate from the medium into the cell. Since this is a relatively novel function for tyrosine phosphorylation, this information may provide insight into possible pharmacological approaches to modify therapeutic regimens by analyzing the status of this protein in tumor samples for a better survival of the cancer patients.

Objective: Management of chronic obstructive pulmonary disease (COPD) with inhaled corticosteroid/long-acting β 2 -agonist (ICS/LABA) improves lung function and health status and reduces COPD exacerbation risk versus monotherapy. This study described treatment use, healthcare resource utilisation (HCRU), healthcare costs and outcomes following initiation of single-device ICS/LABA as initial maintenance therapy (IMT)., Design: Retrospective cohort study., Setting: Primary care, England., Data Sources: Linked data from the Clinical Practice Research Datalink Aurum and Hospital Episode Statistics datasets., Participants: Patients with COPD and ≥1 single-device ICS/LABA prescription between July 2015 and December 2018 were included., Primary and Secondary Outcome Measures: Treatment pathways, COPD-related HCRU and healthcare costs, COPD exacerbations, time to triple therapy, medication adherence (proportion of days covered ≥80%) and indexed treatment time to discontinuation. Data for patients without prior maintenance therapy history (IMT users) and non-triple users were assessed over a 12-month follow-up period., Results: Of 13 451 new ICS/LABA users, 5162 were IMT users (budesonide/formoterol, n=1056; beclomethasone dipropionate/formoterol, n=2427; other ICS/LABA, n=1679), for whom at 3 and 12 months post-index, 45.6% and 39.4% were still receiving any ICS/LABA. At >6 to ≤12 months, the proportion of IMT users with ≥1 outpatient visit (10.1%) and proportion with ≥1 inpatient stay (12.6%) had increased from those at 3 months (9.0% and 7.4%, respectively). Inpatient stays contributed most to total COPD-related healthcare costs. For non-triple IMT users, at 3 and 12 months post-index, 4.5% and 13.7% had ≥1 moderate-to-severe COPD exacerbation. Time to triple therapy initiation and time to discontinuation of index medication ranged from 45.9 to 50.2 months and 2.3 to 2.8 months between treatments. Adherence was low across all time points (21.5-27.6%). Results were similar across indexed therapies., Conclusions: In the year following treatment initiation, ICS/LABA adherence was poor and many patients discontinued or switched therapies, suggesting that more consideration and optimisation of treatment is required in England for patients initiating single-device ICS/LABA therapy., Competing Interests: Competing interests: AC, GR, CC and AI are employees of GSK and hold stock and shares at GSK. AI is also an unpaid part-time Professor at McMaster University. TT, RWood and RWild are employees of Adelphi Real World, which received funding from GSK to conduct the study, but not for manuscript development. VLB was an employee of Adelphi Real World at the time of the study and is currently an employee of Bayer AG UK, and holds stock and shares in Bayer AG UK. Adelphi Real World is a business that provides consulting and other research services to pharmaceutical, device, government and non-government organisations. Adelphi Real World employees work with a variety of companies and organisations and are expressly prohibited from receiving any payment or honoraria directly from these organisations for services rendered., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To create case definitions for confirmed COVID-19 diagnoses, COVID-19 vaccination status and three separate definitions of high risk of severe COVID-19, as well as to assess whether the implementation of these definitions in a cohort reflected the sociodemographic and clinical characteristics of COVID-19 epidemiology in England., Design: Retrospective cohort study., Setting: Electronic healthcare records from primary care (Clinical Practice Research Datalink, CPRD) linked to secondary care data (Hospital Episode Statistics) data covering 24% of the population in England., Participants: 2 271 072 persons aged 1 year and older diagnosed with COVID-19 in CPRD Aurum between 1 August 2020 and 31 January 2022., Main Outcome Measures: Age, sex and regional distribution of COVID-19 cases and COVID-19 vaccine doses received prior to diagnosis were assessed separately for the cohorts of cases identified in primary care and those hospitalised for COVID-19 (primary diagnosis code of ICD-10 U07.1 'COVID-19'). Smoking status, body mass index and Charlson Comorbidity Index were compared for the two cohorts, as well as for three separate definitions of high risk of severe disease used in the UK (National Health Service Highest Risk, PANORAMIC trial eligibility, UK Health Security Agency Clinical Risk prioritisation for vaccination)., Results: Compared with national estimates, CPRD case estimates under-represented older adults in both the primary care (age 65-84: 6% in CPRD vs 9% nationally) and hospitalised (31% vs 40%) cohorts, and over-represented people living in regions with the highest median wealth areas of England (20% primary care and 20% hospital admitted cases in South East vs 15% nationally). The majority of non-hospitalised cases and all hospitalised cases had not completed primary series vaccination. In primary care, persons meeting high-risk definitions were older, more often smokers, overweight or obese, and had higher Charlson Comorbidity Index score., Conclusions: CPRD primary care data are a robust real-world data source and can be used for some COVID-19 research questions, however, limitations of the data availability should be carefully considered. Included in this publication are supplemental files for a total of over 28 000 codes to define each of three definitions of high risk of severe disease., Competing Interests: Competing interests: KMA, LJM, MR, DM, JLN, CT, DM and JY are employees of Pfizer or Pfizer and may hold Pfizer stock or stock options. KKR and TT are employees of Adelphi Real World which has received consulting fees from Pfizer., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To quantify direct costs and healthcare resource utilisation (HCRU) associated with acute COVID-19 in adults in England., Design: Population-based retrospective cohort study using Clinical Practice Research Datalink Aurum primary care electronic medical records linked to Hospital Episode Statistics secondary care administrative data., Setting: Patients registered to primary care practices in England., Population: 1 706 368 adults with a positive SARS-CoV-2 PCR or antigen test from August 2020 to January 2022 were included; 13 105 within the hospitalised cohort indexed between August 2020 and March 2021, and 1 693 263 within the primary care cohort indexed between August 2020 and January 2022. Patients with a COVID-19-related hospitalisation within 84 days of a positive test were included in the hospitalised cohort., Main Outcome Measures: Primary and secondary care HCRU and associated costs ≤4 weeks following positive COVID-19 test, stratified by age group, risk of severe COVID-19 and immunocompromised status., Results: Among the hospitalised cohort, average length of stay, including critical care stays, was longer in older adults. Median healthcare cost per hospitalisation was higher in those aged 75-84 (£8942) and ≥85 years (£8835) than in those aged <50 years (£7703). While few (6.0%) patients in critical care required mechanical ventilation, its use was higher in older adults (50-74 years: 8.3%; <50 years: 4.3%). HCRU and associated costs were often greater in those at higher risk of severe COVID-19 than in the overall cohort, although minimal differences in HCRU were found across the three different high-risk definitions. Among the primary care cohort, general practitioner or nurse consultations were more frequent among older adults and the immunocompromised., Conclusions: COVID-19-related hospitalisations in older adults, particularly critical care stays, were the primary drivers of high COVID-19 resource use in England. These findings may inform health policy decisions and resource allocation in the prevention and management of COVID-19., Competing Interests: Competing interests: JY, KMA, MR, LJM, CT, TM, KN, DM, Tamuno Alfred, MA and JLN are employees of Pfizer and may hold stock or stock options. KKR, TT, PP, BEB and RW are employees of Adelphi Real World, which received funds from Pfizer to conduct the study and develop the manuscript., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Osteoarthritis (OA) affects 10% of adults in the UK. Despite over one-third of people with OA experiencing chronic pain, few studies have examined the population-level impact of chronic pain associated with OA. We compared resource-use and epidemiological outcomes in patients with mild, moderate and severe chronic OA-associated pain and matched controls without known OA., Design: Retrospective, longitudinal, observational cohort study (July 2008 to June 2019)., Setting: Electronic records extracted from Clinical Practice Research Datalink GOLD primary care linked to Hospital Episode Statistics (HES)., Participants: Patients (cases; n=23 016) aged ≥18 years with chronic OA-associated pain. Controls (n=23 016) without OA or chronic pain matched on age, sex, comorbidity burden, general practitioner practice and available HES data., Interventions: None., Primary and Secondary Outcome Measures: Total healthcare resource use (HCRU), direct healthcare costs in 0-12, 12-24 and 24-36 months postindex. Secondary outcomes included incidence and prevalence of chronic OA-associated pain and pharmacological management., Results: HCRU was consistently greater in cases versus controls for all resource categories during preindex and postindex periods. Across follow-up periods, resource use was greatest in patients with severe pain. In the first 12 months postindexing, mean total costs incurred by cases were four times higher versus matched controls (£256 vs £62); costs were approximately twice as high in cases vs controls for months 12-24 (£166 vs £86) and 24-36 (£150 vs £81; all p<0.0001). The incidence of new cases of chronic pain associated with OA was 2.64 per 1000 person-years; the prevalence was 1.4%., Conclusions: This study highlights the real-world cost of chronic pain associated with OA in cases versus matched controls. We included patients with mild, moderate and severe pain associated with OA, and showed HCRU in discrete 1-year time frames. The true economic burden of pain associated with OA is likely to be considerably higher when indirect costs are considered., Competing Interests: Competing interests: GC, PC and CL are employees of Pfizer UK, which provided funding for this study; HS was an employee of Pfizer UK during the conduct of the work; RW, LM and TT are employees of Adelphi Real World, which received funding from Pfizer and Eli Lilly & Company in connection with the development of this manuscript and who are paid consultants to Pfizer and Eli Lilly & Company; RK declares a personal financial interest in his employment by the University of Nottingham, which receives funding for his salary in part from the Primary Integrated Community Solutions Ltd. In the past 36 months, RK declares consultancy through his employment with the University of Nottingham to Pfizer and Mibe; AJD declares a personal financial interest in his employment with York Medical Group (YMG), and over the past 36 months with NHS111 and RCP (London), from whom he receives payment for his work as a part-time salaried GP with YMG, and over the past 36 months as a GP on the NHS111 COVID 19 Response and the NICE Gout Committee, respectively, and in his ownership and directorship of AD Outcomes. In the past 36 months, AJD declares the following personal financial interests through medical and health economics consultancy work for AD Outcomes for: Emotive (Agency), Grunenthal (UK), Grunenthal, Pfizer (UK), Pharmacy Magazine, Spink Health, Tilray (Portugal) and RCGP, as a racecourse doctor for various racecourses (Croft, Doncaster, Market Rasen, Newcastle, Pontefract, Redcar, Southwell and Thirsk) and as a locum GP with out-of-hours, NHS111 and urgent care work for Vocare part of Totally Plc. AJD has a non-personal financial interest in his roles as a Trustee of the Primary Care Rheumatology & Musculoskeletal Medicine (PCRMM) Society (Trustee from 2017 2020) and as Trustee of the UK Gout Society (ongoing). The PCRMM Society has received funding from multiple companies for its annual conference including from Pfizer (UK) in 2020. AJD's work as a Trustee of PCRMM Society and UK Gout Society and as GP Clinical Lead for the North of England Low Back Pain Group are voluntary and unpaid; DW declares a personal financial interest in his employment by the University of Nottingham, which receives funding for his salary from the UK Government, Sherwood Forest Hospitals NHS Foundation Trust and UKRI. He is Director UKRI/Versus Arthritis Advanced Pain Discovery Platform (personal pecuniary: paid by University of Nottingham as part of job plan, funded by UKRI), Honorary Consultant Rheumatologist at Sherwood Forest Hospitals NHS Foundation Trust (personal pecuniary; paid by University of Nottingham as part of job plan, funded by Sherwood Forest Hospitals) and Professor of Rheumatology, University of Nottingham (personal pecuniary; paid by University of Nottingham). In the past 36 months, DW declares the following non-personal financial interests: research support to the University of Nottingham from Versus Arthritis and National Institute for Health and care Research; grants from Pfizer, Eli Lilly and UCB Pharma; consultancy through his employment with the University of Nottingham to Pfizer, Eli Lilly, AbbVie, AKL R&D, Galapagos, Reckitt Benckiser Health and GlaxoSmithKline Plc, and responsibilities for investigator-led grants outside the work in this presentation held by the University of Nottingham from Pfizer, Lilly and UCB Pharma, and research grants from Versus Arthritis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (to University of Nottingham) from Pfizer and AbbVie., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Despite the high prevalence of chronic low back pain (CLBP) and osteoarthritis (OA), few estimates of the economic cost of these conditions in England have been published. The aim of the present analysis was to characterise the economic burden of moderate-to-severe pain associated with CLBP + OA and CLBP alone compared with general population-matched controls without CLBP or OA. The primary objective was to describe the total healthcare resource use (HCRU) and direct healthcare costs associated with the target patient populations. Secondary objectives were to describe treatment patterns and surgical procedures., Methods: This was a retrospective, observational cohort study of patients receiving healthcare indicative of moderate-to-severe chronic pain associated with CLBP, with or without OA. We used linked longitudinal data from the Clinical Practice Research Datalink GOLD and Hospital Episode Statistics (HES). Patients (cases) were matched 1 : 1 with controls on age, sex, comorbidity burden, GP practice, and HES data availability., Results: The CLBP-alone cohort comprised 13 554 cases with CLBP and 13 554 matched controls; the CLBP + OA cohort comprised 7803 cases with both OA and CLBP and 7803 matched controls. Across all follow-up periods, patients with CLBP alone and those with CLBP + OA had significantly more GP consultations, outpatient attendances, emergency department visits, and inpatient stays than controls (all p  < 0.0001). By 36 months after indexing, the mean (SD) per-patient total direct healthcare cost in the CLBP-alone cohort was £5081 (£5905) for cases and £1809 (£4451) for controls ( p  < 0.0001); in the CLBP + OA cohort, the mean (SD) per-patient total direct healthcare cost was £8819 (£7143) for cases and £2428 (£4280) for controls ( p  < 0.0001)., Conclusion: Moderate-to-severe chronic pain associated with CLBP-with or without OA-has a substantial impact on patients and healthcare providers, leading to higher HCRU and costs versus controls among people with CLBP alone or together with OA., Competing Interests: GC and PC are employees of Pfizer UK. CL was an employee of Pfizer UK at the time of the work and is now employed by Pfizer Aus. HS was an employee of Pfizer UK during the conduct of the work. RW and TT are employees of Adelphi Real World, which was contracted by Pfizer UK to conduct this study. RDK declares a personal financial interest in his employment by the University of Nottingham, which receives funding for his salary in part from the Primary Integrated Community Solutions Ltd. In the past 36 months, RDK declares the following nonpersonal financial interests: consultancy through his employment with the University of Nottingham to Pfizer Ltd. and Mibe Ltd. AJD declares a personal financial interest in his employment with York Medical Group (YMG), and over the past 36 months with NHS111 and RCP (London), from whom he receives payment for his work as a part-time salaried GP with YMG, and over the past 36 months as a GP on the NHS111 COVID-19 Response and the NICE Gout Committee, respectively, and in his ownership and directorship of AD Outcomes Ltd. In the past 36 months, AJD declares the following personal financial interests through medical and health economics consultancy work for AD Outcomes Ltd. for: Emotive (Agency) Ltd., Grunenthal (UK), Grunenthal (GmbH), Pfizer (UK), Pharmacy Magazine, Spink Health, Tilray (Portugal), and RCGP, as a racecourse doctor for various racecourses (Croft, Doncaster, Market Rasen, Newcastle, Pontefract, Redcar, Southwell, and Thirsk), and as a locum GP with out-of-hours, NHS111 and urgent care work for Vocare part of Totally Plc. AJD has a nonpersonal financial interest in his roles as a Trustee of the Primary Care Rheumatology and Musculoskeletal Medicine (PCRMM) Society (Trustee from 2017 to 2020) and as Trustee of the UK Gout Society (ongoing). The PCRMM Society has received funding from multiple companies for its annual conference including from Pfizer (UK) in 2020. AJD's work as a Trustee of the PCRMM Society and the UK Gout Society and as GP Clinical Lead for the North of England Low Back Pain Group are voluntary and unpaid; DAW declares a personal financial interest in his employment by the University of Nottingham, which receives funding for his salary from the UK Government, Sherwood Forest Hospitals NHS Foundation Trust, and UKRI. He is Director of the UKRI/Versus Arthritis Advanced Pain Discovery Platform (personal pecuniary: paid by the University of Nottingham as part of job plan, funded by UKRI), Honorary Consultant Rheumatologist at Sherwood Forest Hospitals NHS Foundation Trust (personal pecuniary; paid by the University of Nottingham as part of job plan, funded by Sherwood Forest Hospitals), and Professor of Rheumatology, University of Nottingham (personal pecuniary; paid by the University of Nottingham). In the past 36 months, DAW declares the following nonpersonal financial interests: research support to the University of Nottingham from Versus Arthritis and National Institute for Health and care Research; grants from Pfizer Ltd., Eli Lilly, and UCB Pharma; consultancy through his employment with the University of Nottingham to Pfizer Ltd., Eli Lilly, AbbVie Ltd., AKL R&D, Galapagos, Reckitt Benckiser Health Ltd., and GlaxoSmithKline Plc, and responsibilities for investigator-led grants outside the work in this presentation held by the University of Nottingham from Pfizer Ltd., Lilly Ltd. and UCB Pharma, and research grants from Versus Arthritis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (to University of Nottingham) from Pfizer Ltd. and AbbVie. The authors declare that they have no conflicts of interest., (Copyright © 2023 Greg Coates et al.)

Objective: Despite the prevalence of osteoarthritis (OA) in England, few studies have examined the health economic impact of chronic pain associated with OA. The aim of this study was to compare outcomes in patients with moderate-to-severe chronic pain associated with OA and matched controls without known OA., Design: Retrospective, longitudinal, observational cohort study., Setting: Electronic records extracted from the Clinical Practice Research Datalink GOLD primary care database linked to Hospital Episode Statistics (HES) data set., Participants: Patients (cases; n=5931) ≥18 years and with existing diagnosis of OA and moderate-to-severe pain associated with their OA, and controls matched on age, sex, comorbidity burden, general practitioner (GP) practice and availability of HES data., Interventions: None., Primary and Secondary Outcome Measures: Total healthcare resource use (HCRU) and direct healthcare costs during 0-6, 0-12, 0-24 and 0-36 months of follow-up. Secondary outcomes measures included pharmacological management and time to total joint replacement., Results: Patients with moderate-to-severe chronic pain associated with OA used significantly more healthcare services versus matched controls, reflected by higher HCRU and significantly higher direct costs. During the first 12 months' follow-up, cases had significantly more GP consultations, outpatient attendances, emergency department visits and inpatient stays than matched controls (all p<0.0001). Total mean costs incurred by cases during 0-12 months' follow-up were five times higher in cases versus controls (mean (SD): £4199 (£3966) vs £781 (£2073), respectively). Extensive cycling through pharmacological therapies was observed; among cases, 2040 (34.4%), 1340 (22.6%), 841 (14.2%), 459 (7.7%) and 706 (11.9%) received 1-5, 6-10, 11-15, 16-20 and >20 lines of therapy, respectively., Conclusions: This wide-ranging, longitudinal, observational study of real-world primary and secondary care data demonstrates the impact of moderate-to-severe chronic pain associated with OA in patients compared with matched controls. Further studies are required to fully quantify the health economic burden of moderate-to-severe pain associated with OA., Competing Interests: Competing interests: GC and PC are employees of Pfizer UK, which provided funding for this study. CL was an employee of Pfizer UK at the time of the work and is now employed by Pfizer Australia. HS was an employee of Pfizer UK during the conduct of the work. RW and TT are employees of Adelphi Real World, which received funding to conduct this study. RK declares a personal financial interest in his employment by the University of Nottingham, which receives funding for his salary in part from the Primary Integrated Community Solutions. In the past 36 months, RK declares consultancy through his employment with the University of Nottingham to Pfizer and Mibe. AJD declares a personal financial interest in his employment with York Medical Group (YMG), and over the past 36 months with NHS111 and RCP (London), from whom he receives payment for his work as a part-time salaried general practitioner (GP) with YMG, and over the past 36 months as a GP on the NHS111 COVID-19 Response and the NICE Gout Committee, respectively, and in his ownership and directorship of AD Outcomes. In the past 36 months, AJD declares the following personal financial interests through medical and health economics consultancy work for AD Outcomes for: Emotive (Agency), Grunenthal (UK), Grunenthal (GmbH), Pfizer (UK), Pharmacy Magazine, Spink Health, Tilray (Portugal) and RCGP, as a racecourse doctor for various racecourses (Croft, Doncaster, Market Rasen, Newcastle, Pontefract, Redcar, Southwell and Thirsk) and as a locum GP with out-of-hours, NHS111 and urgent care work for Vocare part of Totally. AJD has a non-personal financial interest in his roles as a Trustee of the Primary Care Rheumatology & Musculoskeletal Medicine (PCRMM) Society (Trustee from 2017 to 2020) and as Trustee of the UK Gout Society (ongoing). The PCRMM Society has received funding from multiple companies for its annual conference including from Pfizer (UK) in 2020. AJD’s work as a Trustee of PCRMM Society and UK Gout Society and as GP Clinical Lead for the North of England Low Back Pain Group are voluntary and unpaid. DW declares a personal financial interest in his employment by the University of Nottingham, which receives funding for his salary from the UK Government, Sherwood Forest Hospitals NHS Foundation Trust and UKRI. He is Director UKRI/Versus Arthritis Advanced Pain Discovery Platform (personal pecuniary: paid by University of Nottingham as part of job plan, funded by UKRI), Honorary Consultant Rheumatologist at Sherwood Forest Hospitals NHS Foundation Trust (personal pecuniary; paid by University of Nottingham as part of job plan, funded by Sherwood Forest Hospitals) and Professor of Rheumatology, University of Nottingham (personal pecuniary; paid by University of Nottingham). In the past 36 months DW declares the following non-personal financial interests: research support to the University of Nottingham from Versus Arthritis and National Institute for Health and care Research; grants from Pfizer, Eli Lilly, and UCB Pharma; consultancy through his employment with the University of Nottingham to Pfizer, Eli Lilly, AbbVie, AKL R&D, Galapagos, Reckitt Benckiser Health, and GlaxoSmithKline, and responsibilities for investigator-led grants outside the work in this presentation held by the University of Nottingham from Pfizer, Lilly and UCB Pharma, and research grants from Versus Arthritis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (to University of Nottingham) from Pfizer and AbbVie., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To compare adherence to once-daily umeclidinium/vilanterol (UMEC/VI), a long-acting muscarinic antagonist/long-acting β 2 -agonist (LAMA/LABA), and twice-daily inhaled corticosteroids (ICS)/LABA single-inhaler dual therapy in patients with chronic obstructive pulmonary disease (COPD) in a primary care cohort in England., Patients and Methods: Active comparator, new-user, retrospective cohort study using CPRD-Aurum primary care data and linked Hospital Episode Statistics secondary care administrative data. Patients without exacerbations in the previous year were indexed on first/earliest prescription date of once-daily UMEC/VI or twice-daily ICS/LABA as initial maintenance therapy between July 2014-September 2019. Primary outcome: medication adherence at 12 months post-index, defined as proportion of days covered (PDC) ≥80%. PDC represented proportion of time over the treatment duration that the patient was theoretically in possession of the medication. Secondary outcomes: adherence at 6, 18, and 24 months post-index, time-to-triple therapy, time-to-first on-treatment COPD exacerbation, COPD-related and all-cause healthcare resource utilization (HCRU), and direct health-care costs. A propensity score was generated and inverse probability of treatment weighting (IPTW) was used to balance potential confounders. Superiority was defined as >0% difference between treatment groups., Results: In total, 6815 eligible patients were included (UMEC/VI:1623; ICS/LABA:5192). At 12 months post-index, weighted odds of a patient being adherent were significantly greater with UMEC/VI versus ICS/LABA (odds ratio [95% CI]: 1.71 [1.09, 2.66]; p=0.0185), demonstrating superiority of UMEC/VI. Patients taking UMEC/VI were statistically significantly more adherent than those taking ICS/LABA at 6, 18, and 24 months post-index (p<0.05). Differences in time-to-triple therapy, time-to-moderate COPD exacerbations, HCRU, and direct medical costs were not statistically significant between treatments after IPTW was applied., Conclusion: At 12 months post-treatment initiation, once-daily UMEC/VI was superior to twice-daily ICS/LABA in medication adherence among patients with COPD without exacerbations in the previous year, newly initiating dual maintenance therapy in England. The finding was consistent at 6, 18, and 24 months., Competing Interests: AC, GR, CC, KJR, and ASI are employees of GSK and hold stock and shares at GSK. ASI also holds an unpaid faculty position at McMaster University in Canada. FH is an employee of the Translational Lung Research Center Heidelberg, part of the Germany lung research Foundation (DZL) and he also reports lecturing and adboard activities for GSK. JKQ holds a position at Imperial College London. CMC, TT, RWo, and RWi are employees of Adelphi Real World. VB is currently an employee of Bayer AG UK and holds stock and shares there. VB and JY were employees of Adelphi Real World at the time of the study. Adelphi Real World is a business that provides consulting and other research services to pharmaceutical, device, government, and non-government organizations, which received funding from GSK to conduct the study. Adelphi Real World employees work with a variety of companies and organizations and are expressly prohibited from receiving any payment or honoraria directly from these organizations for services rendered. The authors report no other conflicts of interest in this work., (© 2023 Czira et al.)

Purpose: Selection of treatments for patients with chronic obstructive pulmonary disease (COPD) may impact clinical outcomes, healthcare resource use (HCRU) and direct healthcare costs. We aimed to characterize these outcomes along with treatment patterns, for patients with COPD following initiation of single-inhaler long-acting muscarinic antagonist/long-acting β 2 -agonist (LAMA/LABA) dual therapy in the primary care setting in England., Patients and Methods: This retrospective cohort study used linked primary care electronic medical record data (Clinical Practice Research Datalink-Aurum) and secondary care administrative data (Hospital Episode Statistics) in England to assess outcomes for patients with COPD who had a prescription for one of four single-inhaler LAMA/LABA dual therapies between 1st June 2015-31st December 2018 (indexing period). Outcomes were assessed during a 12-month follow-up period from the index date (date of earliest prescription of a single-inhaler LAMA/LABA within the indexing period). Incident users were those without previous LAMA/LABA dual therapy prescriptions prior to index; this manuscript focuses on a subset of incident users: non-triple therapy users (patients without concomitant inhaled corticosteroid use at index)., Results: Of 10,991 incident users included, 9888 (90.0%) were non-triple therapy users, indexed on umeclidinium/vilanterol (n=4805), aclidinium/formoterol (n=2109), indacaterol/glycopyrronium (n=1785) and tiotropium/olodaterol (n=1189). At 3 months post-index, 63.3% of non-triple therapy users remained on a single-inhaler LAMA/LABA, and 22.1% had discontinued inhaled therapy. Most patients (86.9%) required general practitioner consultations in the first 3 months post-index. Inpatient stays were the biggest contributor to healthcare costs. Acute exacerbations of COPD (AECOPDs), adherence, time-to-triple therapy, time-to-first on-treatment moderate-to-severe AECOPD, time-to-index treatment discontinuation, HCRU and healthcare costs were similar across indexed therapies., Conclusion: Patients initiating treatment with single-inhaler LAMA/LABA in primary care in England were unlikely to switch treatments in the first three months following initiation, but some may discontinue respiratory medication. Outcomes were similar across indexed treatments., Competing Interests: AC, GR, CC, and ASI are employees of GSK and hold stock and shares at GSK. ASI is also a part-time member of the McMaster university faculty. TT, RWo and RWi are employees of Adelphi Real World, which received funding from GSK to conduct the study, but not for manuscript development. VB was an employee of Adelphi Real World at the time of the study, and is currently an employee of Bayer AG UK, and holds stock and shares in Bayer AG UK. Adelphi Real World is a business that provides consulting and other research services to pharmaceutical, device, government, and non-government organizations. Adelphi Real World employees work with a variety of companies and organizations and are expressly prohibited from receiving any payment or honoraria directly from these organizations for services rendered. The authors report no other conflicts of interest in this work., (© 2023 Requena et al.)

Introduction: Treatment pathways of patients with chronic obstructive pulmonary disease (COPD) receiving single-device dual therapies in England remain unclear. This study describes the characteristics of patients with COPD before initiating treatment with a single-device inhaled corticosteroid/long-acting β 2 -agonist (ICS/LABA) in primary care in England., Methods: This is a retrospective, descriptive study of linked primary and secondary healthcare data (Clinical Practice Research Datalink Aurum, Hospital Episode Statistics). Patients with COPD were indexed on first prescription of fixed-dose, single-device ICS/LABA (June 2015-December 2018). Demographics, clinical characteristics, prescribed treatments, healthcare resource use (HCRU) and direct healthcare costs were assessed over 12 months pre-index. Incident users (indexed on first ever prescription) could be non-triple users (no concomitant long-acting muscarinic antagonist at index); a subset were initial maintenance therapy (IMT) users (no history of pre-index maintenance therapy)., Results: Overall, 13 451 incident users (non-triple users: 7448, 55.4%; IMT users: 5162, 38.4%) were indexed on beclomethasone dipropionate/formoterol (6122, 45.5%), budesonide/formoterol (2703, 20.1%) or Other ICS/LABA combinations (4626, 34.4%). Overall, 20.8% of incident users had comorbid asthma and 42.6% had ≥1 moderate-to-severe acute exacerbation of COPD pre-index. Baseline characteristics were similar across indexed therapies. At 3 months pre-index, 45.3% and 35.4% of non-triple and IMT users were receiving maintenance treatment. HCRU and direct healthcare costs were similar across indexed treatments. Prescribing patterns varied regionally., Conclusion: Patient characteristics, prior treatments, prior COPD-related HCRU and direct healthcare costs were similar across single-device ICS/LABAs in primary care in England. A high proportion of patients were not receiving any respiratory medication pre-index, indicating that prescribing in primary care in England is more closely aligned with national guidelines than global treatment strategies. Comorbid asthma may have influenced prescribing decisions. Less than half of users had preindex exacerbations, suggesting that ICS/LABA is not being prescribed principally based on exacerbation history., Competing Interests: Competing interests: AC, GR, CC, MD and ASI are employees of GSK and hold stock and shares at GSK. ASI is also a part-time member of the McMaster University faculty. VB, TT, RWo and RWi are employees of Adelphi Real World (or were at the time of the study), which received funding from GSK to conduct the study. Adelphi Real World is a business that provides consulting and other research services to pharmaceutical, device, government and non-government organisations. Adelphi Real World employees work with a variety of companies and organisations and are expressly prohibited from receiving any payment or honoraria directly from these organisations for services rendered., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Treatment pathways of patients with chronic obstructive pulmonary disease (COPD) receiving single-inhaler dual therapies remain unclear. We aimed to describe characteristics, prescribed treatments, healthcare resource use (HCRU) and costs of patients with COPD who initiated single-inhaler long-acting muscarinic antagonist/long-acting β 2 -agonist (LAMA/LABA) dual therapy in primary care in England., Patients and Methods: Retrospective study using linked data from Clinical Practice Research Datalink Aurum and Hospital Episode Statistics datasets. Patients with COPD with ≥1 single-inhaler LAMA/LABA prescription between June 2015 and December 2018 (index) were included. Demographic and clinical characteristics, prescribed treatments, HCRU and costs were evaluated in the 12 months pre-index. Data are presented for patients not receiving concomitant inhaled corticosteroids at index (non-triple users)., Results: Of 10,991 patients initiating LAMA/LABA, 9888 were non-triple users, of whom 21.3% (n=2109) received aclidinium bromide/formoterol, 18.1% (n=1785) received indacaterol/glycopyrronium, 12.0% (n=1189) received tiotropium bromide/olodaterol and 48.6% (n=4805) received umeclidinium/vilanterol. Demographic and clinical characteristics were similar across indexed therapies. LAMA monotherapy was the most frequently prescribed respiratory therapy at 12 (18.4-25.8% of patients) and 3 months (23.9-33.7% of patients) pre-index across indexed therapies; 42.5-59.0% of patients were prescribed no respiratory therapy at these time points. COPD-related HCRU during the 12 months pre-index was similar across indexed therapies (general practitioner consultations: 62.0-68.6% patients; inpatient stays: 19.3-26.1% patients). Pre-index COPD-related costs were similar across indexed therapies, with inpatient stays representing the highest contribution. Mean total direct annual COPD-related costs ranged from £805-£1187., Conclusion: Characteristics of patients newly initiating single-inhaler LAMA/LABA dual therapy were highly consistent across indexed therapies. As half of non-triple users were not receiving respiratory therapy one year prior to LAMA/LABA initiation, there may be an opportunity for early optimization of treatment to relieve clinical burden versus current prescribing patterns in primary care in England., Competing Interests: AC, GR, CC, MD and ASI are employees of GSK and hold stock and shares at GSK. ASI is also a part-time member of the McMaster university faculty. VB, TT, RWo and RWi are employees of Adelphi Real World (or were at the time of the study), which received funding from GSK to conduct the study. Adelphi Real World is a business that provides consulting and other research services to pharmaceutical, device, government, and non-government organizations. Adelphi Real World employees work with a variety of companies and organizations and are expressly prohibited from receiving any payment or honoraria directly from these organizations for services rendered. Since concluding the study, VB left employment with Adelphi Real World and started full time employment with Bayer PLC., (© 2022 Requena et al.)

Objective: The aim of the study was to improve understanding of adherence and persistence to biologics, and their association with health-care resource utilization (HCRU), in Japanese patients with moderate to severe ulcerative colitis (UC)., Methods: Data were from Medical Data Vision, a secondary care administrative database. A retrospective, longitudinal cohort analysis was conducted of data from UC patients initiating biologic therapy between August 2013 and July 2016. Data collected for 2 years prior (baseline) and 2 years after (follow-up) the index date were evaluated. Patients completing biologic induction were identified, and adherence/persistence to biologic therapy calculated. HCRU, steroid, and immunosuppressant use during baseline and follow-up were assessed. Biologic switching during the follow-up was evaluated. Descriptive statistics (e.g., means and proportions) were obtained and inferential analyses (from Student's t tests, Fisher's exact tests, χ 2 tests, the Cox proportional hazard model, and negative binomial regression) were performed., Results: The analysis included 649 patients (adalimumab: 265; infliximab: 384). Biologic induction was completed by 80% of patients. Adherence to adalimumab was higher than that to infliximab ( p < 0.001). Persistence at 6, 12, 18, and 24 months was higher with infliximab than with adalimumab ( p < 0.05). Overall, gastroenterology outpatient visits increased, and hospitalization frequency and duration decreased, from baseline to follow-up. UC-related hospitalizations were fewer and shorter, and endoscopies fewer, in persistent than in nonpersistent patients, although persistent patients made more outpatient visits than nonpersistent patients. Hospitalization duration was lower in persistent than nonpersistent patients. Approximately 50% of patients received an immunosuppressant during biologic therapy; 5% received a concomitant steroid during biologic therapy. Overall, 17% and 3% of patients, respectively, received 2nd line and 3rd line biologics., Conclusions: Poor biologic persistence was associated with increased non-medication-associated HCRU. Effective treatments with high persistence levels and limited associated HCRU are needed in UC., Competing Interests: Joseph C. Cappelleri, Irene Modesto, Marco DiBonaventura, Timothy W. Smith, Sean Gardiner, and Irene Modesto are stockholders and employees of Pfizer Inc (who funded this study). At the time of conducting the study, Danielle Bargo and Takanori Tsuchiya were employees of Pfizer Inc. Theo Tritton and Tim Holbrook are employed by Adelphi Real World, which received funding from Pfizer in connection with the development of this manuscript. At the time of conducting the study, Daniel Bluff was an employee of Adelphi Real World., (Copyright © 2021 by S. Karger AG, Basel.)

Background: Limited real-world data exist on healthcare resource utilization (HCRU) and associated costs of patients with heart failure (HF) with reduced ejection fraction (HFrEF) and preserved EF (HFpEF), including urgent HF visits, which are assumed to be less burdensome than HF hospitalizations (hHFs) HYPOTHESIS: This study aimed to quantify the economic burden of HFrEF and HFpEF, via a retrospective, longitudinal cohort study, using IBM® linked claims/electronic health records (Commercial and Medicare Supplemental data only)., Methods: Adult patients, indexed on HF diagnosis (ICD-10-CM: I50.x) from July 2012 through June 2018, with 6-month minimum baseline period and varying follow-up, were classified as HFrEF (I50.2x) or HFpEF (I50.3x) according to last-observed EF-specific diagnosis. HCRU/costs were assessed during follow-up., Results: About 109 721 HF patients (22% HFrEF, 31% HFpEF, 47% unclassified EF; median 18 months' follow-up) were identified. There were 3.2 all-cause outpatient visits per patient-month (HFrEF, 3.3; HFpEF, 3.6); 69% of patients required inpatient stays (HFrEF, 80%; HFpEF, 78%). Overall, 11% of patients experienced hHFs (HFrEF, 23%; HFpEF, 16%), 9% experienced urgent HF visits (HFrEF, 15%; HFpEF, 12%); 26% were hospitalized less than 30 days after first urgent HF visit versus 11% after first hHF. Mean monthly total direct healthcare cost per patient was $9290 (HFrEF, $11 053; HFpEF, $7482)., Conclusions: HF-related HCRU is substantial among contemporary real-world HF patients in US Commercial or Medicare supplemental health plans. Patients managed in urgent HF settings were over twice as likely to be hospitalized within 30 days versus those initially hospitalized, suggesting urgent HF visits are important clinical events and quality improvement targets., (© 2021 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Introduction: Prophylactic treatment of severe hemophilia A is burdensome, requiring frequent intravenous injections. Extended half-life (EHL) factor VIII replacement therapies offer longer intervals between infusions while still meeting efficacy and safety outcomes; however, patient perspectives following long-term use of such products in the real-world remain unknown., Objective: We aimed to explore the importance of infusion frequency and the potential benefits of reduced infusion frequency among patients receiving prophylactic treatment with an EHL product (BAY 94-9027)., Methods: Patients with severe hemophilia A participating in the PROTECT VIII extension study were invited to participate in a semi-structured, concept elicitation 'exit' interview to discuss their experiences. Participants were recruited from Israel, The Netherlands, and the US. Interview transcripts were translated into English and analyzed using thematic analysis methods., Results: Sixteen participants (29-68 years of age) infusing with BAY 94-9027 once every 7 days, once every 5 days, or twice weekly were interviewed. Participants reported infusion frequency (alongside efficacy) as the most important treatment attribute influencing their satisfaction with therapy. Patient-reported benefits of reduced infusion frequency and longer duration of factor coverage included greater ability to participate in physical activities; better vein health; less time to schedule and administer factor VIII; reduced impact on work; and improved emotional well-being., Conclusions: This study provides rich insights into the experiences of patients with EHL products and the value of reduced infusion frequency. Such data could be of value to a range of stakeholders (e.g. regulators, payers) and facilitate patient-clinician discussions to promote tailored treatment decisions.

Anthracyclines are, above all, DNA intercalators, which induce genetic damage leading to cell death. However, increasing evidence firmly suggests that the underlying mechanism for anthracycline cytotoxicity is the induction of apoptosis through intracellular-mediated signaling pathways. Whether drug/DNA interaction is necessary for such apoptosis signaling is unknown. We investigated the cellular effects of the anthracyclines daunorubicin (DNR) and doxorubicin (DOX) using the myeloid leukemia cell line U937. By comparing free drug against agarose bead-immobilized drug iDNR and iDOX (which cannot accumulate within the cell), we observed that whereas both free and immobilized anthracyclines were cytotoxic, only the former induced apoptosis; the latter induced necrosis. Indeed, we did not observe ceramide generation, neutral sphingomyelinase activation, poly (ADP-ribose) polymerase cleavage, or other apoptotic events with iDNR or iDOX. However, both free and immobilized drug were similarly capable of triggering nuclear factor kappaB activation. These observations demonstrate that whereas activation of certain cellular signaling pathways can be achieved solely through membrane interaction, apoptosis signaling requires anthracycline internalization. These results also show that the initiation of cell survival pathways (illustrated by nuclear factor kappaB activation) is independent of intracellular drug/target interaction.

Asbestos fibers are human carcinogens with undefined mechanisms of action. In studies here, we examined signal transduction events induced by asbestos in target cells of mesothelioma and potential cell surface origins for these cascades. Asbestos fibers, but not their nonfibrous analogues, induced protracted phosphorylation of the mitogen-activated protein (MAP) kinases and extracellular signal-regulated kinases (ERK) 1 and 2, and increased kinase activity of ERK2. ERK1 and ERK2 phosphorylation and activity were initiated by addition of exogenous epidermal growth factor (EGF) and transforming growth factor-alpha, but not by isoforms of platelet-derived growth factor or insulin-like growth factor-1 in mesothelial cells. MAP kinase activation by asbestos was attenuated by suramin, which inhibits growth factor receptor interactions, or tyrphostin AG 1478, a specific inhibitor of EGF receptor tyrosine kinase activity (IC50 = 3 nM). Moreover, asbestos caused autophosphorylation of the EGF receptor, an event triggering the ERK cascade. These studies are the first to establish that a MAP kinase signal transduction pathway is initiated after phosphorylation of a peptide growth factor receptor following exposure to asbestos fibers.

We present studies which suggest that the cytotoxic action of Adriamycin (ADR) may involve intracellular pathways of vesicular transport. The movement of proteins or lipids from the endoplasmic reticulum to the plasma membrane via the Golgi organelle and associated compartments exhibits several temperature-sensitive steps between 15 degrees C and 20 degrees C. In this same temperature range, ADR loses its cytotoxic capacity. Using the inhibitor brefeldin A (BFA), we have investigated the possible role of intravesicular trafficking in the loss of ADR activity and the induction of protection from cytotoxicity at low temperature in L1210 cells. We show here that cells pretreated at 37 degrees C for 2 h with BFA could be protected from a subsequent exposure to ADR. The concentration causing 50% inhibition, determined by cloning in soft agar, was increased approximately 3.5 fold. L1210 cells could also be protected from the topoisomerase II inhibitors etoposide and amsacrine, but to a lesser extent; the concentration causing 50% inhibition for the latter inhibitors were increased 2-fold. Spectrofluorometric analysis of intracellular ADR accumulation revealed that there was no significant difference in the level of ADR in cells with or without BFA pretreatment. In addition, examination of ADR-induced cleavable complex formation by alkaline elution showed no significant difference in the level of DNA strand breaks in cells which had been pretreated with BFA even though there was a large difference in survival. Further examination of the persistence of DNA damage after a period of up to 6 h of repair revealed that cells which were pretreated with BFA removed DNA strand breaks at rates equivalent to those of cells which had received ADR directly. These results suggest that the protective effect induced by brefeldin A does not involve uptake, DNA damage, or repair but instead implicates protein or lipid interactions which may be independent of DNA damage and which may influence critical events that take place after the topoisomerase II-DNA complex has been formed.

Adriamycin is a cytotoxic drug which has enjoyed considerable success in the treatment of cancer. This agent has a bewildering variety of biological effects both within and on the surface of cells exposed to drug, and it has proved difficult to unambiguously assign a single mechanism of action. In this report we are able to separate intracellular and extracellular actions by taking advantage of the complete lack of Adriamycin-induced cytotoxicity at low temperature. For example, cells exposed to 100 microM Adriamycin at 0 degree C are not killed by the drug, even though this concentration is orders of magnitude higher than the concentration needed to cause 100% cell death at 37 degrees C. If cells exposed to 100 microM Adriamycin at 0 degree C are shifted to fresh drug-free medium at 37 degrees C, there is a time-dependent decrease in survival. However, if the drug-free medium contains calf thymus DNA (1.5 mg/ml) to act as a reservoir for Adriamycin binding of effluxed drug, there is no ensuing cytotoxicity. Thus, the results show that no matter how much drug is present inside the cell, there must also be extracellular drug available for membrane interaction in order to initiate nuclear DNA damage and the cytotoxic cascade.

The cytotoxic effects of anthracyclines and other chemotherapeutic agents were examined in normally aerated and hypoxic Sarcoma 180 and EMT6 tumor cells in vitro. Adriamycin, daunomycin, and mitomycin C were selectively toxic to hypoxic Sarcoma 180 cells. The augmented sensitivity was not the result of an increase in susceptibility of oxygen-deprived cells toward antitumor agents in general. 1,3-Bis(2-chloroethyl)-1-nitrosourea, for example, exhibited equal cytotoxicity toward normally aerated and hypoxic cells, while streptonigrin was selectively toxic toward normally aerated cells. The cellular levels of [3H]daunomycin in both Sarcoma 180 and EMT6 cells were not different under the two conditions of oxygenation, and no greater production of either the alcohol or aglycone metabolites of daunomycin occurred in hypoxic cells, compared with their normally aerated counterparts. In addition, analysis of cellular pellets for residual drug remaining after exhaustive extraction showed no significant difference between normally aerated and hypoxic cells. The effects of reoxygenation of hypoxic cells on their sensitivity to mitomycin C and to Adriamycin were studied in both Sarcoma 180 and EMT6 cells. The enhanced efficacy of mitomycin C as a cytotoxic agent observed under hypoxia was reversed after a 2-hr reoxygenation. In contrast, the augmented toxicity of Adriamycin toward hypoxic cells was not reversible in either cell line after 2 or 4 hr of reoxygenation. The results suggest that neither the formation of a reactive oxygen species nor direct involvement of an alkylating agent generated by drug metabolism is an obligatory step in the cytotoxic action of these anthracyclines.

We have used photoaffinity labeling to investigate the distribution and function of daunomycin binding sites in Sarcoma 180 cells. When native daunomycin is irradiated at 366 or 488 nm in the presence of cells, the drug is irreversibly incorporated into cellular molecules. The cellular acceptor for the photoincorporation cannot be extracted by chloroform-methanol nor can it be degraded by DNase. However, the drug acceptor is susceptible to trypsin digestion. These results show that the photoincorporation site is composed of protein but not of lipid or DNA. Furthermore, the fact that photoincorporation proceeds equally well at 0 degrees (where drug does not accumulate inside the cells) as compared to 37 degrees (where free drug concentrates in the cells) suggests that the labeling reaction occurs principally at the cell surface. The photolabeling process is not highly specific since it is not saturable at high drug concentrations and cannot be competed for by unlabeled daunomycin. When 2 X 10(5) daunomycin molecules are incorporated per Sarcoma 180 cell, the cells can still accumulate free drug. This result suggests that the photolabeling reaction does not occur at the drug transport locus. Photoincorporation of daunomycin also does not affect the viability of Sarcoma 180 cells, as judged by a cloning assay. Thus, there is probably no surface receptor for the drug which mediates cytotoxicity when occupied. This result is as expected from previous work predicting that the mechanism of daunomycin involves disruption of some generalized membrane property like fluidity. However, in a series of Sarcoma 180 sublines selected for increasing resistance to daunomycin, the photoincorporation increases in direct proportion to drug sensitivity. Consequently, daunomycin appears to be capable of photoaffinity labeling a cell surface protein which, although not directly involved in the mechanism of cytotoxicity is implicated in the expression of drug resistance.