Innovations in pharmacovigilance studies of medicines in older people.

Pharmacovigilance is defined by the World Health Organization as "the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine/vaccine related problem". Pharmacovigilance studies are critical for detecting and assessing adverse events of medicines that may not have been observed in clinical trials. This activity is especially important in older people who are often excluded from clinical trials as they have multiple chronic conditions and use multiple medicines for longer durations than the clinical trials. In this narrative review we describe innovative methods in pharmacovigilance studies of medicines in older people that leverage the increasing availability of digital health technologies, electronic health records and real-world health data to identify and quantify medication related harms in older people.

Evolution of the data and methods in real-world COVID-19 vaccine effectiveness studies on mortality: a scoping review protocol.

BACKGROUND: Early evidence on COVID-19 vaccine efficacy came from randomised trials. Many important questions subsequently about vaccine effectiveness (VE) have been addressed using real-world studies (RWS) and have informed most vaccination policies globally. As the questions about VE have evolved during the pandemic so have data, study design, and analytical choices. This scoping review aims to characterise this evolution and provide insights for future pandemic planning-specifically, what kinds of questions are asked at different stages of a pandemic, and what data infrastructure and methods are used? METHODS AND ANALYSIS: We will identify relevant studies in the Johns Hopkins Bloomberg School of Public Health VIEW-hub database, which curates both published and preprint VE RWS identified from PubMed, Embase, Scopus, Web of Science, the WHO COVID Database, MMWR, Eurosurveillance, medRxiv, bioRxiv, SSRN, Europe PMC, Research Square, Knowledge Hub, and Google. We will include RWS of COVID-19 VE that reported COVID-19-specific or all-cause mortality (coded as 'death' in the 'effectiveness studies' data set).Information on study characteristics; study context; data sources; design and analytic methods that address confounding will be extracted by single reviewer and checked for accuracy and discussed in a small group setting by methodological and analytic experts. A timeline mapping approach will be used to capture the evolution of this body of literature.By describing the evolution of RWS of VE through the COVID-19 pandemic, we will help identify options for VE studies and inform policy makers on the minimal data and analytic infrastructure needed to support rapid RWS of VE in future pandemics and of healthcare strategies more broadly. ETHICS AND DISSEMINATION: As data is in the public domain, ethical approval is not required. Findings of this study will be disseminated through peer-reviewed publications, conference presentations, and working-papers to policy makers. REGISTRATION: https://doi.org/10.17605/OSF.IO/ZHDKR.

The weighted cumulative exposure method and its application to pharmacoepidemiology: A narrative review.

PURPOSE: The weighted cumulative exposure (WCE) method has been used in a number of fields including pharmacoepidemiology where it can account for intensity, duration and timing of exposures on the risk of an outcome. The method uses a data driven approach with flexible cubic B-splines to assign weights to past doses and select an aetiologically appropriate time window. Predictions of risk are possible for common exposure patterns encountered in real-world studies. The purpose of this study was to describe applications of the WCE method to pharmacoepidemiology and assess the strengths and limitations of the method. METHOD: A literature search was undertaken to find studies applying the WCE method to the study of medicines. Articles published in PubMed using the search term 'weighted cumulative exposure' and articles citing Sylvestre et al. (2009) in Google Scholar or Scopus up to March 2023 were subsequently reviewed. Articles were selected based on title and review of abstracts. RESULTS: Seventeen clinical applications using the data-driven WCE method with flexible cubic splines were identified in the review. These included 3 case-control studies and 14 cohort studies, of which 12 were analysed with Cox proportional hazards models and 2 with logistic regression. Thirteen studies used time windows of 1 year or longer. Of 11 studies which compared conventional models with the WCE method, 10 (91%) studies found a better fit with WCE models while one had an equivalent fit. The freely available 'WCE' software package has facilitated the applications of the WCE method with flexible cubic splines. CONCLUSIONS: The WCE method allows additional insights into the effect of cumulative exposure on outcomes, including the timing and intensity (dose) of the exposure on the risk. The flexibility of the method is particularly well suited to studies with long-term exposures that vary over time or where the current risk of an event is affected by how far the exposure is in the past, which is difficult to model with conventional definitions of exposure. Interpretation of the results can be more complex than for conventional models and would be facilitated by a standardised reporting framework.

Chronic Obstructive Pulmonary Disease Adverse Event Signals Associated with Potential Inhibitors of Glutathione Peroxidase 1: A Sequence Symmetry Analysis.

BACKGROUND AND OBJECTIVE: Prior molecular modelling analysis identified several medicines as potential inhibitors of glutathione peroxidase 1 (GPx1) which may contribute to development or progression of chronic obstructive pulmonary disease (COPD). This study investigates 40 medicines (index medicines) for signals of COPD development or progression in a real-world dataset. METHODS: Sequence symmetry analysis (SSA) was conducted using a 10% extract of Australian Pharmaceutical Benefits Scheme (PBS) claims data between January 2013 and September 2019. Patients must have been initiated on an index medicine and a medicine for COPD development or progression within 12 months of each other. Sequence ratios were calculated as the number of patients who initiated an index medicine followed by a medicine for COPD development or progression divided by the number who initiated the index medicine second. An adjusted sequence ratio (aSR) was calculated which accounted for changes in prescribing trends. Adverse drug event signals (ADEs) were identified where the aSR lower 95% confidence interval (CI) was greater than 1. RESULTS: Twenty-one of 40 (53%) index medicines had at least one ADE signal of COPD development or progression. Signals of COPD development, as identified using initiation of tiotropium, were observed for atenolol (aSR 1.32, 95% CI 1.23-1.42) and naproxen (aSR 1.14, 95% CI 1.06-1.23). Several signals of COPD progression were observed, including initiation of fluticasone propionate/salmeterol following initiation of atenolol (aSR 1.44, 95% CI 1.30-1.60) and initiation of aclidinium/formoterol following initiation of naproxen (aSR 2.21, 95% CI 1.34-3.65). CONCLUSION: ADE signals were generated for several potential GPx1 inhibitors; however, further validation of signals is required in large well-controlled observational studies.

Cardiovascular risk in rheumatoid arthritis patients treated with targeted synthetic and biological disease-modifying antirheumatic drugs: A multi-centre cohort study.

BACKGROUND: This study aimed to compare the cardiovascular safety of interleukin-6 inhibitors (IL-6i) and Janus Kinase inhibitors (JAKi) to tumour necrosis factor inhibitors (TNFi). METHODS: We conducted a retrospective cohort study using population-based electronic databases from Hong Kong, Taiwan and Korea. We identified newly diagnosed patients with rheumatoid arthritis (RA) who received b/tsDMARDs first time. We followed patients from b/tsDMARD initiation to the earliest outcome (acute coronary heart disease, stroke, heart failure, venous thromboembolism and systemic embolism) or censoring events (death, transformation of b/tsDMARDs on different targets, discontinuation and study end). Using TNFi as reference, we applied generalized linear regression for the incidence rate ratio estimation adjusted by age, sex, disease duration and comorbidities. Random effects meta-analysis was used for pooled analysis. RESULTS: We identified 8689 participants for this study. Median (interquartile range) follow-up years were 1.45 (2.77) in Hong Kong, 1.72 (2.39) in Taiwan and 1.45 (2.46) in Korea. Compared to TNFi, the adjusted incidence rate ratios (aIRRs) (95% confidence interval [CI]) of IL-6i in Hong Kong, Taiwan and Korea are 0.99 (0.25, 3.95), 1.06 (0.57, 1.98) and 1.05 (0.59, 1.86) and corresponding aIRR of JAKi are 1.50 (0.42, 5.41), 0.60 (0.26, 1.41), and 0.81 (0.38, 1.74), respectively. Pooled aIRRs showed no significant risk of cardiovascular events (CVEs) associated with IL-6i (1.05 [0.70, 1.57]) nor JAKi (0.80 [0.48, 1.35]) compared to TNFi. CONCLUSION: There was no difference in the risk of CVE among RA patients initiated with IL-6i, or JAKi compared to TNFi. The finding is consistent in Hong Kong, Taiwan and Korea.

Application of an Integrative Drug Safety Model for Detection of Adverse Drug Events Associated With Inhibition of Glutathione Peroxidase 1 in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Chronic Obstructive Pulmonary Disease is characterised by declining lung function and a greater oxidative stress burden due to reduced activity of antioxidant enzymes such as Glutathione Peroxidase 1. OBJECTIVES: The extent to which drugs may contribute to this compromised activity is largely unknown. An integrative drug safety model explores inhibition of Glutathione Peroxidase 1 by drugs and their association with chronic obstructive pulmonary disease adverse drug events. METHODS: In silico molecular modelling approaches were utilised to predict the interactions that drugs have within the active site of Glutathione Peroxidase 1 in both human and bovine models. Similarities of chemical features between approved drugs and the known inhibitor tiopronin were also investigated. Subsequently the Food and Drug Administration Adverse Event System was searched to uncover adverse drug event signals associated with chronic obstructive pulmonary disease. RESULTS: Statistical and molecular modelling analyses confirmed that the use of several registered drugs, including acetylsalicylic acid and atenolol may be associated with inhibition of Glutathione Peroxidase 1 and chronic obstructive pulmonary disease. CONCLUSION: The integration of molecular modelling and pharmacoepidemological data has the potential to advance drug safety science. Ongoing review of medication use and further pharmacoepidemiological and biological analyses are warranted to ensure appropriate use is recommended.

Reducing opioid use for chronic non-cancer pain in primary care using an evidence-based, theory-informed, multistrategic, multistakeholder approach: a single-arm time series with segmented regression.

BACKGROUND: Many countries have high opioid use among people with chronic non-cancer pain. Knowledge about effective interventions that could be implemented at scale is limited. We designed a national intervention that included audit and feedback, deprescribing guidance, information on catastrophising assessment, pain neuroscience education and a cognitive tool for use by patients with their healthcare providers. METHOD: We used a single-arm time series with segmented regression to assess rates of people using opioids before (January 2015 to September 2017), at the time of (October 2017) and after the intervention (November 2017 to August 2019). We used a cohort with historical comparison group and log binomial regression to examine the rate of psychologist claims in opioid users not using psychologist services prior to the intervention. RESULTS: 13 968 patients using opioids, 8568 general practitioners, 8370 pharmacies and accredited pharmacists and 689 psychologists were targeted. The estimated difference in opioid use was -0.51 persons per 1000 persons per month (95% CI -0.69, -0.34; p<0.001) as a result of the intervention, equating to 25 387 (95% CI 24 676, 26 131) patient-months of opioid use avoided during the 22-month follow-up. The targeted group had a significantly higher rate of incident patient psychologist claims compared with the historical comparison group (rate ratio: 1.37, 95% CI 1.16, 1.63; p<0.001), equating to an additional 690 (95% CI 289, 1167) patient-months of psychologist treatment during the 22-month follow-up. CONCLUSIONS: Our intervention addressed the cognitive, affective and sensory factors that contribute to pain and consequent opioid use, demonstrating it could be implemented at scale and was associated with a reduction in opioid use and increasing utilisation of psychologist services.

Prevalence and Preventability of Adverse Medicine Events in a Sample of Australian Aged-Care Residents: A Secondary Analysis of Data from the ReMInDAR Trial.

BACKGROUND: Aged care residents are vulnerable to the harmful effects of medicines; however, data on the prevalence and preventability of adverse medicine events in aged care residents are scarce. AIM: To determine the prevalence and preventability of adverse medicine events in Australian aged care residents. METHODS: A secondary analysis of data from the Reducing Medicine-Induced Deterioration and Adverse Reactions (ReMInDAR) trial was conducted. Potential adverse medicine events were identified and independently screened by two research pharmacists to produce a short-list of potential adverse medicine events. An expert clinical panel reviewed each potential adverse medicine to determine the likelihood that the event was medicine related (based on the Naranjo Probability Scale criteria). The clinical panel assessed preventability of medicine-related events using Schumock-Thornton criteria. RESULTS: There were 583 adverse events due to medicines, involving 154 residents (62% of the 248 study participants). There was a median of three medication-related adverse events (interquartile range [IQR] 1-5) per resident over the 12-month follow-up period. The most common medication-related adverse events were falls (56%), bleeding (18%) and bruising (9%). There were 482 (83%) medication-related adverse events that were preventable, most commonly falls (66% of preventable adverse medicine events), bleeding (12%) and dizziness (8%). Of the 248 residents, 133 (54% of the cohort) had at least one preventable adverse medicine event, with a median of 2 (IQR 1-4) preventable adverse medicine events per resident. CONCLUSION: In total, 62% of aged care residents in our study had an adverse medicine event and 54% had a preventable adverse medicine event in a 12-month period.

Impact of Introducing Infliximab Biosimilars on Total Infliximab Consumption and Originator Infliximab Prices in Eight Regions: An Interrupted Time-Series Analysis.

OBJECTIVE: We aimed to assess whether the introduction of the first infliximab biosimilar was associated with changes in overall infliximab consumption (originator and biosimilars) and price changes to the originator infliximab. METHODS: An interrupted time series analysis using infliximab sales data from 2010 to 2020 from the IQVIA Multinational Integrated Data Analysis System for eight selected regions: Australia, Canada, Hong Kong, Korea, India, Japan, the UK, and the USA. Quarterly measures of infliximab consumption and list prices were respectively defined as the number of standard units (SU)/1000 inhabitants and as 2020 USA dollars (USD)/SU. RESULTS: Following the introduction of infliximab biosimilars, overall infliximab consumption increased in Australia [immediate change: 0.145 SU/1000 inhabitants (P = 0.014); long-term change: 0.022 SU/1000 inhabitants per quarter (P < 0.001)], Canada [immediate change 0.415 (P = 0.008)], the UK [long-term change 0.024 (P < 0.001)], and Hong Kong [immediate change: 0.042 (P < 0.001)]. The list price of originator infliximab also decreased following biosimilar introduction in Australia [immediate change: - 187.84 USD/SU (P < 0.001); long-term change - 6.46 USD/SU per quarter (P = 0.043)], Canada [immediate change: - 145.58 (P < 0.001)], the UK [immediate change: - 34.95 (P = 0.010); long-term change: - 4.77 (P < 0.001)], and Hong Kong [long-term change: - 4.065 (P = 0.046)]. Consumption and price changes were inconsistent in India, Japan, Korea, and the USA. CONCLUSIONS: Introduction of the first infliximab biosimilar was not consistently associated with increased consumption across regions. Additional policy and healthcare system interventions to support biosimilar infliximab adoption are needed.

Precision public-health intervention for care coordination: a real-world study.

BACKGROUND: Health emergencies disproportionally affect vulnerable populations. Digital tools can help primary care providers find, and reach, the right patients. AIM: To evaluate whether digital interventions delivered directly to GPs' clinical software were more effective at promoting primary care appointments during the COVID-19 pandemic than interventions delivered by post. DESIGN AND SETTING: Real-world, non-randomised, interventional study involving GP practices in all Australian states. METHOD: Intervention material was developed to promote care coordination for vulnerable older veterans during the COVID-19 pandemic, and sent to GPs either digitally to the clinical practice software system or in the post. The intervention material included patient-specific information sent to GPs to support care coordination, and education material sent via post to veterans identified in the administrative claims database. To evaluate the impact of intervention delivery modalities on outcomes, the time to first appointment with the primary GP was measured; a Cox proportional hazards model was used, adjusting for differences and accounting for pre-intervention appointment numbers. RESULTS: The intervention took place in April 2020, during the first weeks of COVID-19 social distancing restrictions in Australia. GPs received digital messaging for 51 052 veterans and postal messaging for 26 859 veterans. The digital group was associated with earlier appointments (adjusted hazard ratio 1.38 [1.34 to 1.41]). CONCLUSION: Data-driven digital solutions can promote care coordination at scale during national emergencies, opening up new perspectives for precision public-health initiatives.

Antibiotic utilisation in primary and revision total hip replacement patients: A registry linkage cohort study of 106 253 patients using the Australian Orthopaedic Association National Joint Replacement Registry.

PURPOSE: Infection is a major complication following joint replacement (JR) surgery. However, little data exist regarding antibiotic utilisation following primary JR and how use changes with subsequent revision surgery. This study aimed to examine variation in antibiotic utilisation rates before and after hip replacement surgery in those revised for infection, revised for other reasons and those without revision. METHODS: This retrospective cohort analysis used linked data from the Australian Orthopaedic Association National Joint Replacement Registry and Australian Government Pharmaceutical Benefits Scheme. Patients were included if undergoing total hip replacement (THR) for osteoarthritis in private hospitals between 2002 and 2017. Three groups were examined: primary THR with no subsequent revision (n = 102 577), primary THR with a subsequent revision for reasons other than periprosthetic joint infection (PJI) (n = 3156) and primary THR with a subsequent revision for PJI (n = 520). Monthly antibiotic utilisation rates and prevalence rate ratios (PRRs) with 95% confidence intervals (CIs) were calculated in the 2 years pre- and post-THR. RESULTS: Prior to primary THR antibiotic utilisation was 9%-10%. After primary THR, antibiotic utilisation rates were higher among patients revised for PJI (PRR 1.69, 95% CI 1.60-1.79) compared to non-revised patients, while the utilisation rate was lower in patients revised for reasons other than infection (PRR 0.96, 95% CI 0.93-0.98). For those revised for infection, antibiotic utilisation post-revision surgery was two times higher than those revised for other reasons (PRR 2.16, 95% CI 2.08-2.23). Utilisation of injectable antibiotics including, vancomycin, flucloxacillin and cephazolin was higher in those revised for PJI patients 0-2 weeks following surgery but not in those revised for other reasons compared to the non-revised group. CONCLUSIONS: Ongoing antibiotic utilisation after primary surgery may be an early signal of problems with the THR and should be a prompt for primary care physicians to refer patients to specialists for further appropriate investigations and management.

No increased risk of cancer associated with metal-on-metal or ceramic-on-ceramic procedures compared to other bearing surfaces in patients with total hip arthroplasty: A nationwide linked registry cohort analysis of 167,837 patients.

OBJECTIVES: Studies have identified increased cancer risk among patients undergoing total hip arthroplasty (THA) compared to the general population. However, evidence of all-cause and site-specific cancer risk associated with different bearing surfaces has varied, with previous studies having short latency periods with respect to use of modern Metal-on-Metal (MoM) bearings. Using the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) linked to Australasian Association of Cancer Registries data, our aim was to evaluate risk of all-cause and site-specific cancer according to bearing surfaces in patients undergoing THA for osteoarthritis and whether risk increased with MoM bearings. METHODS: Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated by comparing number of observed cancer cases to expected number based on incidence rate in the Australian population. All-cause and site-specific cancer rates were calculated for all conventional stemmed THA (csTHA) and resurfacing THA (rsTHA) procedures performed for osteoarthritis. Cox proportional hazards models were used to compare cancer rates for MoM, ceramic-on-ceramic (CoC) and resurfacing procedures with a comparison group comprising metal-on-polyethylene (MoP) or ceramic-on-polyethylene (CoP) procedures. RESULTS: There were 156,516 patients with csTHA procedures and 11,321 with rsTHA procedures for osteoarthritis performed between 1999 and 2012. Incidence of all-cause cancer was significantly higher for csTHA (SIR 1.24, 95% CI 1.22-1.26) and rsTHA (SIR 1.74, 95% CI 1.39-2.04) compared to the Australian population. For csTHA, there was no significant difference in all-site cancer rates for MoM (Hazard Ratio (HR) 1.01, 95%CI 0.96-1.07) or CoC (HR 0.98, 95%CI 0.94-1.02) compared to MoP and CoP bearings. Significantly increased risk of melanoma, non-Hodgkins lymphoma, myeloma, leukaemia, prostate, colon, bladder and kidney cancer was found for csTHA and, prostate cancer, melanoma for rsTHA procedures when compared to the Australian population, although risk was not significantly different across bearing surfaces. CONCLUSIONS: csTHA and rsTHA procedures were associated with increased cancer incidence compared to the Australian population. However, no excess risk was observed for MoM or CoC procedures compared to other bearing surfaces.

Frailty trajectory over one year among residential aged care (nursing home) residents.

Objectives: Large population-based studies examining frailty trajectory found a linear increase in frailty over time. The pattern in which frailty changes over time for an individual person is less well-described. We examined the frailty trajectory of older adults living in aged-care in Australia. Materials and methods: This secondary study used data from a randomised controlled trial involving 39 aged-care facilities in Australia. The trial intervention was an on-going pharmacist-led intervention occurring every 8 weeks over 12 months aimed at preventing medicine-induced deterioration and adverse reactions. Frailty was assessed using the Frailty Index. Participants were categorised as non-frail, pre-frail and frail. Individual frailty trajectory over 12 months was visualised using the alluvial plot. Case notes were examined to explore reasons for any rapid transitions in frailty status. Results: A total of 248 participants was included. At baseline, 40.3% were non-frail and 59.7% were pre-frail. The proportion of participants who were non-frail and pre-frail decreased over time; 15.7% were frail at 6 months and 23.4% were frail at 12 months. Overall, twenty different combinations of frailty transitions were identified over 12 months. Retrospective analysis of case notes suggest that death or transition from non-frail to frail was often preceded by hospitalisation, falls, medication change or clinically significant deterioration in grip strength or cognition. Conclusion: The degree of frailty increased over time, but there were variations in the individual trajectories. Regular monitoring of events that precede changes in frailty status is needed to identify strategies to prevent further deterioration in residents' conditions.

Estimating incidence rates of periprosthetic joint infection after hip and knee arthroplasty for osteoarthritis using linked registry and administrative health data.

AIMS: The aim of this study was to estimate the 90-day periprosthetic joint infection (PJI) rates following total knee arthroplasty (TKA) and total hip arthroplasty (THA) for osteoarthritis (OA). METHODS: This was a data linkage study using the New South Wales (NSW) Admitted Patient Data Collection (APDC) and the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR), which collect data from all public and private hospitals in NSW, Australia. Patients who underwent a TKA or THA for OA between 1 January 2002 and 31 December 2017 were included. The main outcome measures were 90-day incidence rates of hospital readmission for: revision arthroplasty for PJI as recorded in the AOANJRR; conservative definition of PJI, defined by T84.5, the PJI diagnosis code in the APDC; and extended definition of PJI, defined by the presence of either T84.5, or combinations of diagnosis and procedure code groups derived from recursive binary partitioning in the APDC. RESULTS: The mean 90-day revision rate for infection was 0.1% (0.1% to 0.2%) for TKA and 0.3% (0.1% to 0.5%) for THA. The mean 90-day PJI rates defined by T84.5 were 1.3% (1.1% to 1.7%) for TKA and 1.1% (0.8% to 1.3%) for THA. The mean 90-day PJI rates using the extended definition were 1.9% (1.5% to 2.2%) and 1.5% (1.3% to 1.7%) following TKA and THA, respectively. CONCLUSION: When reporting the revision arthroplasty for infection, the AOANJRR substantially underestimates the rate of PJI at 90 days. Using combinations of infection codes and PJI-related surgical procedure codes in linked hospital administrative databases could be an alternative way to monitor PJI rates.Cite this article: Bone Joint J 2022;104-B(9):1060-1066.

Monoclonal antibodies and Fc-fusion protein biologic medicines: A multinational cross-sectional investigation of accessibility and affordability in Asia Pacific regions between 2010 and 2020.

Background: Monoclonal antibody (mAb) and Fc-fusion protein (FcP) are highly effective therapeutic biologics. We aimed to analyse consumption and expenditure trends in 14 Asia-Pacific countries/regions (APAC) and three benchmark countries (the UK, Canada, and the US). Methods: We analysed 440 mAb and FcP biological products using the IQVIA-MIDAS global sales database. For each year between 2010 and 2020 inclusive, we used standard units (SU) sold per 1000 population and manufacture level price (standardised in 2019 US dollars) to evaluate consumption (accessibility) and expenditure (affordability). Changes of consumption and expenditure were estimated using compound annual growth rate (CAGR). Correlations between consumption, country's economic and health performance indicators were measured using Spearman correlation coefficient. Findings: Between 2010 and 2020, CAGRs of consumption in each region ranged from 7% to 34% and the CAGRs of expenditure ranged from 9% to 31%. The median consumption of biologics was extremely low in lower-middle-income economies (0·29 SU/1000 population) compared with upper-middle-income economies (1·20), high-income economies (40·94) and benchmark countries (109·55), although the median CAGRs of biologics consumption in lower-middle-income economies (31%) was greater than upper-middle-income (14%), high-income economies (13%) and benchmark countries (9%). Consumption was correlated with GDP per capita [Spearman's rank correlation coefficient (r) = 0·75, p < 0·001], health expenditure as a percentage of total (r = 0·83, p < 0·001) and medical doctors' density (r = 0·85, p < 0·001). Interpretation: There have been significant increases in mAb and FcP biologics consumption and expenditure, however accessibility of biological medicines remains unequal and is largely correlated with country's income level. Funding: This research was funded by NHMRC Project Grant GNT1157506 and GNT1196900; Enhanced Start-up Fund for new academic staff and Internal Research Fund, Department of Medicine, LKS Faculty of Medicine, University of Hong Kong.

A comparison of survival models for prediction of eight-year revision risk following total knee and hip arthroplasty.

BACKGROUND: There is increasing interest in the development and use of clinical prediction models, but a lack of evidence-supported guidance on the merits of different modelling approaches. This is especially true for time-to-event outcomes, where limited studies have compared the vast number of modelling approaches available. This study compares prediction accuracy and variable importance measures for four modelling approaches in prediction of time-to-revision surgery following total knee arthroplasty (TKA) and total hip arthroplasty (THA). METHODS: The study included 321,945 TKA and 151,113 THA procedures performed between 1 January 2003 and 31 December 2017. Accuracy of the Cox model, Weibull parametric model, flexible parametric model, and random survival forest were compared, with patient age, sex, comorbidities, and prosthesis characteristics considered as predictors. Prediction accuracy was assessed using the Index of Prediction Accuracy (IPA), c-index, and smoothed calibration curves. Variable importance rankings from the Cox model and random survival forest were also compared. RESULTS: Overall, the Cox and flexible parametric survival models performed best for prediction of both TKA (integrated IPA 0.056 (95% CI [0.054, 0.057]) compared to 0.054 (95% CI [0.053, 0.056]) for the Weibull parametric model), and THA revision. (0.029 95% CI [0.027, 0.030] compared to 0.027 (95% CI [0.025, 0.028]) for the random survival forest). The c-index showed broadly similar discrimination between all modelling approaches. Models were generally well calibrated, but random survival forest underfitted the predicted risk of TKA revision compared to regression approaches. The most important predictors of revision were similar in the Cox model and random survival forest for TKA (age, opioid use, and patella resurfacing) and THA (femoral cement, depression, and opioid use). CONCLUSION: The Cox and flexible parametric models had superior overall performance, although all approaches performed similarly. Notably, this study showed no benefit of a tuned random survival forest over regression models in this setting.

The association between exacerbation of chronic obstructive pulmonary disease and timing of paracetamol use: a cohort study in elderly Australians.

BACKGROUND: In elderly populations, paracetamol may be used regularly for conditions such as osteoarthritis. Paracetamol has been associated with respiratory disease through a proposed mechanism of glutathione depletion and oxidative stress. Given that chronic obstructive pulmonary disease (COPD) is frequently co-morbid with osteoarthritis, this study investigated whether the dose and timing of paracetamol exposure may induce COPD exacerbations. METHODS: The study population was 3523 Australian Government Department of Veterans' Affairs full entitlement holders who had existing COPD on 1 January 2011, who were dispensed at least one prescription of paracetamol between 1 January 2011 and 30 September 2015, and had no paracetamol dispensed in the 6 months prior to 1 January 2011. The outcome was time to first hospitalisation for COPD exacerbation after initiation of paracetamol. A weighted cumulative exposure approach was used. RESULTS: The association between paracetamol exposure and COPD exacerbation was protective or harmful depending on the dose, duration, and recency of exposure. Compared to non-use, current use at the maximum dose of 4 g daily for 7 days was associated with a lower risk (HR = 0.78, 95% CI = 0.67-0.92) and a higher risk after 30 days (HR = 1.27, 95% CI = 1.06-1.52). Risk declined to baseline after 2 months. For past use, there was a short-term increase in risk on discontinuation depending of dose, duration and time since stopping. CONCLUSIONS: Patients and doctors should be aware of the possible risk of COPD exacerbation with higher dose paracetamol 1 to 6 weeks after initiation or discontinuation, but no increased risk after 2 months.

Effect of an ongoing pharmacist service to reduce medicine-induced deterioration and adverse reactions in aged-care facilities (nursing homes): a multicentre, randomised controlled trial (the ReMInDAR trial).

OBJECTIVE: To assess the effectiveness of a pharmacist-led intervention using validated tools to reduce medicine-induced deterioration and adverse reactions. DESIGN AND SETTING: Multicenter, open-label parallel randomised controlled trial involving 39 Australian aged-care facilities. PARTICIPANTS: Residents on ≥4 medicines or ≥1 anticholinergic or sedative medicine. INTERVENTION: Pharmacist-led intervention using validated tools to detect signs and symptoms of medicine-induced deterioration which occurred every 8 weeks over 12 months. COMPARATOR: Usual care (Residential Medication Management Review) provided by accredited pharmacists. OUTCOMES: Primary outcome was change in Frailty Index at 12 months. Secondary outcomes included changes in cognition, 24-hour movement behaviour by accelerometry, grip strength, weight, adverse events and quality of life. RESULTS: 248 persons (median age 87 years) completed the study; 120 in the interventionand, 128 in control arms. In total 575 pharmacist, sessions were undertaken in the intervention arm. There was no statistically significant difference for change in frailty between groups (mean difference: 0.009, 95% CI: -0.028, 0.009, P = 0.320). A significant difference for cognition was observed, with a mean difference of 1.36 point change at 12 months (95% CI: 0.01, 2.72, P = 0.048). Changes in 24-hour movement behaviour, grip strength, adverse events and quality of life were not significantly different between groups. Point estimates favoured the intervention arm at 12 months for frailty, 24-hour movement behaviour and grip strength. CONCLUSIONS: The use of validated tools by pharmacists to detect signs of medicine-induced deterioration is a model of practice that requires further research, with promising results from this trial, particularly with regards to improved cognition.

Implementation and Evaluation of a Digitally Enabled Precision Public Health Intervention to Reduce Inappropriate Gabapentinoid Prescription: Cluster Randomized Controlled Trial.

BACKGROUND: Digital technologies can enable rapid targeted delivery of audit and feedback interventions at scale. Few studies have evaluated how mode of delivery affects clinical professional behavior change and none have assessed the feasibility of such an initiative at a national scale. OBJECTIVE: The aim of this study was to develop and evaluate the effect of audit and feedback by digital versus postal (letter) mode of delivery on primary care physician behavior. METHODS: This study was developed as part of the Veterans' Medicines Advice and Therapeutics Education Services (MATES) program, an intervention funded by the Australian Government Department of Veterans' Affairs that provides targeted education and patient-specific audit with feedback to Australian general practitioners, as well as educational material to veterans and other health professionals. We performed a cluster randomized controlled trial of a multifaceted intervention to reduce inappropriate gabapentinoid prescription, comparing digital and postal mode of delivery. All veteran patients targeted also received an educational intervention (postal delivery). Efficacy was measured using a linear mixed-effects model as the average number of gabapentinoid prescriptions standardized by defined daily dose (individual level), and number of veterans visiting a psychologist in the 6 and 12 months following the intervention. RESULTS: The trial involved 2552 general practitioners in Australia and took place in March 2020. Both intervention groups had a significant reduction in total gabapentinoid prescription by the end of the study period (digital: mean reduction of 11.2%, P=.004; postal: mean reduction of 11.2%, P=.001). We found no difference between digital and postal mode of delivery in reduction of gabapentinoid prescriptions at 12 months (digital: -0.058, postal: -0.058, P=.98). Digital delivery increased initiations to psychologists at 12 months (digital: 3.8%, postal: 2.0%, P=.02). CONCLUSIONS: Our digitally delivered professional behavior change intervention was feasible, had comparable effectiveness to the postal intervention with regard to changes in medicine use, and had increased effectiveness with regard to referrals to a psychologist. Given the logistical benefits of digital delivery in nationwide programs, the results encourage exploration of this mode in future interventions.

The Risk of Preoperative Central Nervous System-Acting Medications on Delirium Following Hip or Knee Surgery: A Matched Case-Control Study.

INTRODUCTION: Medicines acting on the central nervous system can increase the risk of postoperative delirium, but the specific medicines associated with greatest risk remain unclear. OBJECTIVES: We aimed to examine the risk of individual central nervous system-acting medicines used preoperatively on delirium after hip or knee surgery. METHODS: A matched case-control study was conducted using data from the Australian Government Department of Veterans' Affairs. We included people aged 65 years or older who had knee or hip surgery between 2000 and 2019. People with hip or knee surgery who developed postoperative delirium were cases and controls were people with hip or knee surgery but who did not develop postoperative delirium. Use of medicines including anxiolytics, sedatives, and hypnotics, opioid analgesics and antidepressants prior to surgery was compared between cases and controls. RESULTS: A total of 2614 patient cases with postoperative delirium were matched by same sex, age (±2 years), and year of admission (±2 years) with 7842 controls without postoperative delirium. Cases were more likely to be exposed to nitrazepam (odds ratio [OR] = 1.81, 95% confidence interval [CI] 1.24-2.64), sertraline (OR = 1.50, 95% CI 1.20-1.87), mirtazapine (OR = 1.38, 95% CI 1.11-1.74), venlafaxine (OR = 1.42, 95% CI 1.02-1.98), citalopram (OR = 1.54, 95% CI 1.19-1.99), escitalopram (OR = 1.42, 95% CI 1.06-1.89) or fluvoxamine (OR = 5.01, 95% CI 2.15-11.68) prior to surgery than controls. At the class level, exposure to benzodiazepines (OR = 1.20, 95% CI 1.05-1.37) and antidepressants (OR = 1.64, 95% CI 1.47-1.83) prior to surgery was significantly higher in cases than in controls. The numbers needed to treat to harm for one additional delirium case were 43 for sertraline, 40 for citalopram, 57 for mirtazapine and 26 for nitrazepam. Whereas, the numbers needed to treat to harm were found to be 20 for sertraline, 17 for citalopram, 19 for mirtazapine and 10 for nitrazepam in the 85 years or older age group, indicating that the harmful effect of these medicines is pronounced as age advances. CONCLUSIONS: People who developed delirium following hip or knee surgery were more likely to be exposed to nitrazepam, sertraline, mirtazapine, venlafaxine, citalopram, escitalopram or fluvoxamine at the time of admission for surgery. Planning to reduce use of these medicines well prior to surgery may decrease the risk of postoperative delirium.