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.

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.

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.

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.

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.

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.

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.

Cardiac Implantable Electronic Devices: Reoperations and the Competing Risk of Death.

BACKGROUND: The use of cardiac implantable electronic devices (CIED), which includes pacemakers, implantable cardioverter-defibrillators (ICD), cardiac resynchronisation therapy pacemakers (CRT-P) and cardiac resynchronisation therapy defibrillators (CRT-D) has increased over the past 20 years, but there is a lack of real world evidence on the longevity of these devices in the older population which is essential to inform health care delivery and support clinical decisions. METHODS AND RESULTS: We conducted a retrospective cohort study using data from the Australian Government Department of Veterans' Affairs database. The cohort consisted of people who had a CIED procedure between 2005 and 2015. The cumulative risk of generator replacement/reoperations was estimated accounting for the competing risk of death. A total of 16,662 patients were included. In pacemaker recipients with an average age of 85 years, the 5-year risk of reoperation ranged from 2.8% in single chamber, 3.6% in dual chamber to 7.6% in CRT-P recipients, while the 5-year risk of dying with the index pacemaker in situ was 63% in single chamber, 46% in dual chamber and 56% in CRT-P recipients. In defibrillator recipients with an average age of 80 years, the 5-year risk of reoperation ranged from 11% in single chamber, 13% in dual chamber to 24% in CRT-D recipients, while the 5-year risk of dying with the index defibrillator in situ was 46% in single chamber, 40% in dual chamber and 41% in CRT-D recipients. CONCLUSION: In this cohort of older patients the 5-year risk of generator reoperation was low in pacemaker recipients whereas up to one in four CRT-D recipients would have a reoperation within 5 years.

A data visualisation method for assessing exposure misclassification in case-crossover studies: the example of tricyclic antidepressants and the risk of hip fracture in older people.

BACKGROUND: The case-crossover design is suited to medication safety studies but is vulnerable to exposure misclassification. Using the example of tricyclic antidepressants and the risk of hip fracture, we present a data visualisation tool for observing exposure misclassification in case-crossover studies. METHODS: A case-crossover study was conducted using Australian Government Department of Veterans' Affairs claims data. Beneficiaries aged over 65 years who were hospitalised for hip fracture between 2009 and 2012 were included. The case window was defined as 1-50 days pre fracture. Control window one and control window two were defined as 101-150 and 151-200 days pre fracture, respectively. Patients were stratified by whether exposure status changed when control window two was specified instead of control window one. To visualise potential misclassification, each subject's tricyclic antidepressant dispensings were plotted over the 200 days pre fracture. RESULTS: The study population comprised 8828 patients with a median age of 88 years. Of these subjects, 348 contributed data to the analyses with either control window. The data visualisation suggested that 14% of subjects were potentially misclassified with control window one while 45% were misclassified with control window two. The odds ratio for the association between tricyclic antidepressants and hip fracture was 1.18 (95% confidence interval = 0.91-1.52) using control window one, whereas risk was significantly increased (odds ratio = 1.43, 95% confidence interval = 1.11-1.83) using control window two. CONCLUSIONS: Exposure misclassification was less likely to be present with control window one than with an earlier control window, control window two. When specifying different control windows in a case-crossover study, data visualisation can help to assess the extent to which exposure misclassification may contribute to variable results.

Suitability of databases in the Asia-Pacific for collaborative monitoring of vaccine safety.

INTRODUCTION: Information regarding availability of electronic healthcare databases in the Asia-Pacific region is critical for planning vaccine safety assessments particularly, as COVID-19 vaccines are introduced. This study aimed to identify data sources in the region, potentially suitable for vaccine safety surveillance. This manuscript is endorsed by the International Society for Pharmacoepidemiology (ISPE). METHODS: Nineteen countries targeted for database reporting were identified using published country lists and review articles. Surveillance capacity was assessed using two surveys: a 9-item introductory survey and a 51-item full survey. Survey questions related to database characteristics, covariate and health outcome variables, vaccine exposure characteristics, access and governance, and dataset linkage capability. Other questions collated research/regulatory applications of the data and local publications detailing database use for research. RESULTS: Eleven databases containing vaccine-specific information were identified across 8 countries. Databases were largely national in coverage (8/11, 73%), encompassed all ages (9/11, 82%) with population size from 1.4 to 52 million persons. Vaccine exposure information varied particularly for standardized vaccine codes (5/11, 46%), brand (7/11, 64%) and manufacturer (5/11, 46%). Outcome data were integrated with vaccine data in 6 (55%) databases and available via linkage in 5 (46%) databases. Data approval processes varied, impacting on timeliness of data access. CONCLUSIONS: Variation in vaccine data availability, complexities in data access including, governance and data release approval procedures, together with requirement for data linkage for outcome information, all contribute to the challenges in building a distributed network for vaccine safety assessment in the Asia-Pacific and globally. Common data models (CDMs) may help expedite vaccine safety research across the region.

Proton pump inhibitors may contribute to progression or development of chronic obstructive pulmonary disease-A sequence symmetry analysis approach.

WHAT IS KNOWN AND OBJECTIVE: Proton pump inhibitors (PPIs), used to treat and prevent gastro-oesophageal conditions, are well-tolerated but have been associated with risk including pneumonia. The extent to which initiation of PPIs can contribute to other respiratory conditions such as chronic obstructive pulmonary disease (COPD) is largely unknown. METHODS: A sequence symmetry analysis (SSA) approach was applied to the Australian Department of Human Services, Pharmaceutical Benefits Scheme 10% extract. Participants were aged 45 years and older and were dispensed PPIs (ATC Codes A02BC01, A02BC02, A02BC03, A02BC04 and A02BC05) and long-acting bronchodilators (LABDs) for COPD (ATC Codes R03BB04 (PBS Item Code 10509D and 08626B), R03BB05, R03BB06, R03BB07 and R03AC18 (PBS Item Code 05137J and 05134F)) between 2013 and 2019. The analysis included patients initiated on an LABD within 12 months before or after their first prescription of a PPI. The crude sequence ratio (cSR) was calculated as the number of patients prescribed their first LABD after starting a PPI divided by the number of patients prescribed their first LABD before starting a PPI. Calculation of the adjusted sequence ratio (aSR) accounted for prescribing trends over time in initiation of each of the medicines. A signal was identified where the aSR lower 95% confidence interval (CI) was greater than one. RESULTS AND DISCUSSION: Initiation of omeprazole was associated with a 29% increased risk of initiating a LABD (ASR = 1.29 95% CI 1.22-1.36). Initiation of esomeprazole, rabeprazole, pantoprazole or lansoprazole was associated with 25%, 15%, 8% and 8% increased risk, respectively. WHAT IS NEW AND CONCLUSION: There is an established association between gastro-oesophageal reflux disease and COPD which has been confirmed by implementation of a sequence symmetry-based approach which demonstrated that PPI initiation is potentially associated with progression or exacerbation of COPD. The impact PPI use has directly on this association requires further investigation.

Does a Prescription-based Comorbidity Index Correlate with the American Society of Anesthesiologists Physical Status Score and Mortality After Joint Arthroplasty? A Registry Study.

BACKGROUND: When analyzing the outcomes of joint arthroplasty, an important factor to consider is patient comorbidities. The presence of multiple comorbidities has been associated with longer hospital stays, more postoperative complications, and increased mortality. The American Society of Anesthesiologists (ASA) physical status classification system score is a measure of a patient's overall health and has been shown to be associated with complications and mortality after joint arthroplasty. The Rx-Risk score is another measure for determining the number of different health conditions for which an individual is treated, with a possible score ranging from 0 to 47. QUESTIONS/PURPOSES: For patients undergoing THA or TKA, we asked: (1) Which metric, the Rx-Risk score or the ASA score, correlates more closely with 30- and 90-day mortality after TKA or THA? (2) Is the Rx-Risk score correlated with the ASA score? METHODS: This was a retrospective analysis of the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) database linked to two other national databases, the National Death Index (NDI) database and the Pharmaceutical Benefits Scheme (PBS), a dispensing database. Linkage to the NDI provided outcome information on patient death, including the fact of and date of death. Linkage to the PBS was performed to obtain records of all medicines dispensed to patients undergoing a joint replacement procedure. Patients were included if they had undergone either a THA (119,076 patients, 131,336 procedures) or TKA (182,445 patients, 215,712 procedures) with a primary diagnosis of osteoarthritis, performed between 2013 and 2017. We excluded patients with missing ASA information (THA: 3% [3055 of 119,076]; TKA: 2% [4095 of 182,445]). This left 127,761 primary THA procedures performed in 116,021 patients (53% [68,037 of 127,761] were women, mean age 68 ± 11 years) and 210,501 TKA procedures performed in 178,350 patients (56% [117,337 of 210,501] were women, mean age 68 ± 9 years) included in this study. Logistic regression models were used to determine the concordance of the ASA and Rx-Risk scores and 30-day and 90-day postoperative mortality. The Spearman correlation coefficient (r) was used to estimate the correlation between the ASA score and Rx-Risk score. All analyses were performed separately for THAs and TKAs. RESULTS: We found both the ASA and Rx-Risk scores had high concordance with 30-day mortality after THA (ASA: c-statistic 0.83 [95% CI 0.79 to 0.86]; Rx-Risk: c-statistic 0.82 [95% CI 0.79 to 0.86]) and TKA (ASA: c-statistic 0.73 [95% CI 0.69 to 0.78]; Rx-Risk: c-statistic 0.74 [95% CI 0.70 to 0.79]). Although both scores were strongly associated with death, their correlation was moderate for patients undergoing THA (r = 0.45) and weak for TKA (r = 0.38). However, the median Rx-Risk score did increase with increasing ASA score. For example, for THAs, the median Rx-Risk score was 1, 3, 5, and 7 for ASA scores 1, 2, 3, and 4, respectively. For TKAs, the median Rx-Risk score was 2, 4, 5, and 7 for ASA scores 1, 2, 3, and 4, respectively. CONCLUSION: The ASA physical status and RxRisk were associated with 30-day and 90-day mortality; however, the scores were only weakly to moderately correlated with each other. This suggests that although both scores capture a similar level of patient illness, each score may be capturing different aspects of health. The Rx-Risk may be used as a complementary measure to the ASA score. LEVEL OF EVIDENCE: Level III, therapeutic study.

Data linkage in pharmacoepidemiology: A call for rigorous evaluation and reporting.

PURPOSE: The purpose of this paper is to provide guidance on the evaluation of data linkage quality through the development of a checklist for reporting key elements of the linkage process. METHODS: Responding to a call for manuscripts from the International Society for Pharmacoepidemiology (ISPE), a working group including international representation from the academic, industry, and contract research, and regulatory sectors was formed to develop a checklist for evaluation of data linkage performance and reporting data linkage specifically for pharmacoepidemiologic research. This checklist expands on the reporting of studies conducted using observational routinely collected health data specific to pharmacoepidemiology (RECORD-PE) guidelines. RESULTS: A key aspect of data linkage evaluation for pharmacoepidemiology is to articulate how a linkage process was performed and its accuracy in terms of validation and verification of the resulting linked data. This study generates a checklist, which covers domains including data sources, linkage variables, linkage methods, linkage results, and linkage evaluation. For each domain, specific recommendations provide a clear and transparent assessment of the linkage process. CONCLUSIONS: Linking data sources can help to enrich analytic databases to more accurately define study populations, enable adjustment for confounding, and improve the capture of health outcomes. Clear and transparent reporting of data linkage processes will help to increase confidence in the evidence generated from these data by allowing researchers and end users to critically assess the potential for bias owing to the data linkage process.

Mesh use in urogynaecological procedures between 2005 and 2016: An Australian cohort study.

BACKGROUND: Pelvic organ prolapse (POP) and stress urinary incontinence (SUI) are common conditions. The use of mesh in the surgical treatment of these conditions in Australia is unclear. AIM: To examine the use of mesh in POP and SUI procedures in an Australian national cohort of older women. METHODS: We conducted a population-based cohort study using data from the Australian Government Department of Veterans' Affairs (DVA) database. The cohort consisted of older women who had POP and SUI procedures between 1 July, 2005 and 31 December, 2016. Women who received mesh were identified by matching device billing codes with the Australian Government's Prosthesis List. RESULTS: In total, 3129 women experienced 3472 hospitalisations for POP and SUI procedures, with 74% of the women aged 75 years and older. There were 2276 (66%) hospitalisations with single POP repairs, 608 (18%) with single SUI procedures and 588 (17%) with concomitant POP and SUI procedures. Mesh was used in 23% of single procedures for POP, in 89% of single procedures for SUI and in 90% of concomitant POP and SUI procedures. The use of mesh in POP procedures decreased from a peak of 33% in 2008 down to 8% by 2016, whereas the use of mesh in SUI procedures increased from 77% in 2006 to 91% by 2016. CONCLUSION: Mesh was commonly used in SUI procedures, whereas use of mesh in POP repair was less common and the use decreased rapidly after 2011, when warnings about use of mesh in POP were first issued.

Antipsychotic polypharmacy in older Australians.

ABSTRACTBackground:Antipsychotics are commonly used, and the rate of use is highest, among those aged 65 years or over, where the risk of adverse events is also high. Up to 20% of younger adults use more than one antipsychotic concurrently; however there are few studies on the prevalence of antipsychotic polypharmacy in older people. We aimed to analyze antipsychotic use in elderly Australians, focusing on the prevalence of antipsychotic polypharmacy and the use of medicines to manage adverse events associated with antipsychotics. METHODS: A cross-sectional study was conducted using Australian Department of Veterans' Affairs (DVA) administrative claims data for the period 1 March 2014 to 30 June 2014. Veterans dispensed at least one antipsychotic medicine during the study period was included. We determined the number of participants dispensed antipsychotic polypharmacy and the number of participants dispensed medicines to manage antipsychotic side effects. RESULTS: There were 7,412 participants with a median age of 86 years. Fifty-one percent (n=3,784) were women and 48% (n=3,569) lived in residential aged-care. Fifty one participants (0.7%) were dispensed anticholinergic medicines indicated for the management of antipsychotic-associated extrapyramidal movement disorders and eight (0.1%) were dispensed medicines for the management of hyperprolactinemia. Five percent of participants (n=365) received dual antipsychotics. Dual antipsychotic users were more likely to be under the care of a psychiatrist or to have had a mental health hospitalization than those using a single antipsychotic. CONCLUSIONS: Antipsychotic polypharmacy occurred in one in 20 elderly persons, indicating that there is room for improvement in antipsychotic use in elderly patients.

Reducing hypnotic use in insomnia management among Australian veterans: results from repeated national interventions.

BACKGROUND: The Australian Government Department of Veterans' Affairs (DVA) Veterans' Medicines Advice and Therapeutics Education Services (Veterans' MATES) programme conducted two intervention (March 2009, follow-up intervention June 2012) both of which aimed to reduce hypnotic use among Australian veterans. We evaluated the effectiveness of the interventions, and estimated the associated health consequences. METHODS: Both interventions targeted veterans who had been dispensed hypnotics prior to the intervention. Patient-specific prescriber feedback containing patient details and the volume of hypnotics dispensed, along with tailored educational information, was mailed to general practitioners. Veterans, pharmacists and directors of care in residential aged care facilities were mailed tailored educational information. Interrupted time-series and segmented regression modelling were used to determine the effect of the two interventions on the rate of hypnotics dispensing. The cumulative patient-months of hypnotic treatment avoided as a result of the interventions was calculated. We estimated improvements in health consequences of as a result of hypnotic treatment avoided based on the results of cohort studies in the same population identifying the association between hypnotic and sedative use on the outcomes of falls, and confusion. RESULTS: After the first Veterans' MATES intervention in March 2009, hypnotic use declined by 0.2% each month, when compared to the baseline level (p = 0.006). The intervention effect was attenuated after one year, and use of hypnotics was found to increase by 0.2% per month after March 2010. Following the second intervention in June 2012, there was a further significant decline in use of 0.18% each month over the 12 months of follow up (p = 0.049). The cumulative effect of both interventions resulted in 20,850 fewer patient-months of treatment with hypnotics. This cumulative reduction in hypnotic use was estimated to lead to a minimum of 1 fewer hospital admissions for acute confusion and 7 fewer hospital admissions due to falls. CONCLUSIONS: The Veterans' MATES insomnia interventions which involved multiple stakeholders were effective in reducing hypnotic use among older Australians. Repetition of key messages led to sustained practice change.

Persistent Opioid Use Following Total Knee Arthroplasty: A Signal for Close Surveillance.

BACKGROUND: Prolonged opioid use following total knee arthroplasty (TKA) has not been extensively studied. METHODS: A cohort study of primary TKA for osteoarthritis using an integrated healthcare system and Total Joint Replacement Registry (January 2008-December 2011) was conducted. Opioid use during the first year after TKA was the exposure of interest and cumulative daily oral morphine equivalent (OME) amounts were calculated. Total postsurgical OME per 90-day exposure periods were categorized into quartiles. The end point was aseptic revision surgery. Survival analyses were conducted and hazard ratios (HRs) were adjusted for age, gender, prior analgesic use, opioid-related comorbidities, and chronic pain diagnoses. RESULTS: A total of 24,105 patients were studied. After the initial 90-day postoperative period, 41.5% (N = 9914) continued to use opioids. Also, 155 (0.6%) revisions occurred within 1 year and 377 (1.6%) within 5 years. Compared to patients not taking any opioids, patients using medium-low to high OME after the initial 90-day period had a higher adjusted risk of 1-year revision, ranging from HR = 2.4 (95% confidence interval, 1.3-4.5) to HR = 33 (95% confidence interval, 10-110) depending on the OME and time period. CONCLUSION: Patients who require opioids beyond 90 days after TKA warrant close follow-up.

Magnetic Resonance Imaging in People With Cardiac Implantable Electronic Devices: A Population Based Cohort Study.

Magnetic resonance imaging (MRI) is a widely used diagnostic tool with great benefits but has been considered contraindicated in people with cardiac implantable electronic devices (CIED). We investigated the occurrence of MRI in people with CIEDs and associated adverse events in a national cohort. Of 17,848 people included, 56 (0.3%) had at least one MRI; 16 of 16,102 (0.1%) with MRI non-compatible CIEDs and 40 of 1746 (2%) with MRI compatible CIEDs. Following MRI exposure, hospitalisations for potential serious adverse events were rare.