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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. Refereed/Peer-reviewed

Refereed/Peer-reviewed Background and objective: Increasing age, male sex and various chronic conditions have been identified as important risk factors for poor outcomes from COVID-19. The aim of this study was to examine the prevalence of risk factors for poor outcomes due to COVID-19 infection in an older population. Methods: The proportion of the population with one or more risk factors and the prevalence of individual risk factors and multiple risk factors were calculated among Department of Veterans' Affairs (DVA) clients aged >= 70 years. Results: There were 103,422 DVA clients included. Of these, 79% in the community and 82% in residential aged care had at least one risk factor for poor outcomes from COVID-19. Hypertension was most prevalent, followed by chronic heart and airways disease. Over half had >= 2 risk factors, and one in five had >= 3 risk factors across multiple body systems. Discussion: A substantial proportion of older Australians are at risk of poor outcomes from COVID-19 because of their multimorbid risk profile. These patients should be prioritised for proactive monitoring to avoid unintentional harm due to potential omission of care during the pandemic.

Older people might be embarrassed to talk about falling as they worry this may be judged as a loss of their ability to live independently. Ask older patients, at least yearly, if they ever feel unsteady on their feet or if they have fallen Consider whether medicines may be contributing to feelings of unsteadiness or falling. Drugs such as benzodiazepines and selective serotonin reuptake inhibitors, particularly if taken together, are associated with a risk of falling and hip fracture Review the patient’s treatment regimen to see if there are drugs that are no longer required. Psychotropic drugs should usually be tapered gradually so that adverse effects can be minimised Involve a range of health professionals to identify and manage the risk of falls. Help patients stay physically active, independent and socially connected Keywords: antipsychotics, benzodiazepines, deprescribing, opioids, selective serotonin reuptake inhibitors Introduction In Australia, an estimated 30% of people aged over 65 years living in the community and 50% of residents of aged-care facilities fall at least once a year.1,2 The resultant harm is significant. In 2018, the estimated number of Australians aged 50 years and over who were hospitalised for a hip fracture was 28,000.3 An estimated 5% of those who sustain a hip fracture die in hospital, and more than 10% are discharged from hospital to an aged-care facility. More than 50% experience a persistent mobility-related disability one year after their injury.4 Falls typically result from multiple interacting factors. The more factors present, the more likely the person is to fall.1 Medicines are a modifiable risk factor. Adverse effects such as drowsiness, dizziness, blurred vision, confusion or postural hypotension may all contribute to falls.5,6 The association between psychotropic drugs and the increased risk of hip fracture is well recognised.7,8 This is likely to be even greater when psychotropic drugs are used in combination.

Renal function testing should be performed prior to initiating medicines that require dose adjustment in renal impairment, with ongoing monitoring in continued use, particularly in older people. There is little evidence regarding the extent to which renal function monitoring is performed in older Australians dispensed medicines requiring renal function monitoring.The aim of this study was to determine the extent of renal function testing in older people dispensed medicines requiring renal function monitoring.A retrospective analysis of administrative claims data from the Australian Government Department of Veterans' Affairs was conducted for people aged 65 years or older who were dispensed one or more medicines requiring renal function monitoring, from 1 June 2019 to 30 September 2019, to investigate the proportion of people with a claim for a pathology test that included creatinine levels in the 6-12 months before or after dispensing of a medicine requiring renal function monitoring.There were 100,113 people who were dispensed at least one medicine requiring renal function monitoring during the study period, of whom 15% had a history of renal impairment and 16% had diabetes mellitus. Sixty-one percent had a claim for a test in the prior 6 months; this increased to 80% of participants with a claim for a test in the prior 12 months. The rate of claims for testing was lower in aged care facility residents compared with people living in the community (54% vs 62% in the previous 6 months; p 0.001), and was higher in people with diabetes (75% vs 58%; p 0.001), history of renal impairment (91% vs 59%; p 0.001) or heart failure (77% vs 60%; p 0.001) compared with those without these conditions.Medicines that require renal function monitoring are commonly used in older Australians, and while the majority have claims for tests that include renal function, some are missing out.

Objective: To determine the prevalence of medication- related hospitalisations pre-ceded by potentially suboptimal processes of care in aged care residents Method: We conducted a retrospective analysis of administrative claims data from the Australian Government Department of Veterans’ Affairs (DVA). We identified all hospital admissions for aged care residents between 1 July 2014 and 30 June 2019. The proportion of hospital admissions preceded by potentially suboptimal medication- related processes of care was determined Results: A total of 18874 hospitalisations were included, and 46% were preceded by potentially suboptimal medication- related care. One- quarter of fracture admissions occurred in residents at risk of fracture who were not using a medicine to prevent fracture, and 87% occurred in residents using falls- risk medicines. Thirty per cent of heart failure admissions occurred in patients who were not using an angiotensin- converting enzyme inhibitor or angiotensin receptor blocker Conclusion: Nearly half of hospital admissions were preceded by potentially sub-optimal medication- related processes of care. Interventions to improve use of medi-cines for aged care residents in these areas are warranted. Refereed/Peer-reviewed

Objective To determine whether differences in combination DTaP vaccine types at 2, 4 and 6 months of age were associated with mortality (all-cause or non-specific), within 30 days of vaccination. Design Observational nationwide cohort study. Setting Linked population data from the Australian Childhood Immunisation Register and National Death Index. Participants Australian infants administered a combination trivalent, quadrivalent or hexavalent DTaP vaccine (DTaP types) between January 1999 and December 2010 at 2, 4 and 6 months as part of the primary vaccination series. The study population included 2.9, 2.6, & 2.3 million children in the 2, 4 and 6 month vaccine cohorts, respectively. Main outcome measures Infants were evaluated for the primary outcome of all-cause mortality within 30 days. A secondary outcome was non-specific mortality (unknown cause of death) within 30 days of vaccination. Non-specific mortality was defined as underlying or other cause of death codes, R95 ‘Sudden infant death syndrome’, R96 ‘Other sudden death, cause unknown’, R98 ‘Unattended death’, R99 ‘Other ill-defined and unspecified cause of mortality’ or where no cause of death was recorded. Results The rate of 30 day all-cause mortality was low and declined from 127.4 to 59.3 deaths per 100,000 person-years between 2 and 6 month cohorts. When compared with trivalent DTaP vaccines, no elevated risk in all-cause or non-specific mortality was seen with any quadrivalent or hexavalent DTaP vaccines, for any cohort. Conclusion Use of routine DTaP combination vaccines with differing disease antigens administered during the first six months of life is not associated with infant mortality.

Background Four-component meningococcal B (4CMenB) vaccine is licensed in many countries but has had limited use in adolescents despite this age group being at increased risk of meningococcal disease. Objectives To assess the safety profile of two doses of 4CMenB in adolescents. Methods Cluster randomised controlled trial of senior school students in South Australia (SA) with participating schools randomised to intervention (4CMenB) or control. Vaccine safety was monitored using the South Australian Vaccine Safety Surveillance System (SAVSS), a spontaneous reporting system for adverse events following immunisation (AEFI) with enhanced follow-up of AEFI. Results 58,637 doses of 4CMenB vaccine were administered to 30,522 students (median age 16 years) during 2017–2018. Of 18,348 and 12,174 students vaccinated in 2017 and 2018, 97.3% and 84.3%, respectively, received both scheduled doses (N = 28,115). 193 AEFI in 187 students were reported with a reporting rate of 0.32% (95%CI: 0.28–0.39%). Seventy individuals sought medical review, including nine serious adverse events. 98% (166/169) of those who were contactable for AEFI follow-up (87.6% 169/193) reported resolution of the event. Most common AEFI were injection site reaction (126/193), headache (99/193) and nausea (61/193). AEFI were more frequently reported in females (aOR = 1.409 (95%CI: 1.002, 1.980)), schools with high level of educational advantage (adjusted Odds Ratio (aOR) = 1.515 (95%CI: 1.005, 2.284)), following first dose (aOR = 1.619 (95%CI: 1.168, 2.244)), and in 2017 (aOR = 1.437 (95%CI: 1.001, 2.064)). Reported AEFI declined with increasing age (aOR = 0.771 (95%CI: 0.673, 0.883)). Conclusion In this largest post-licensure use of 4CMenB in adolescents, the low AEFI reporting rate provides real-world evidence of 4CMenB safety in this age group. (ClinicalTrials.gov number: NCT03089086).

Background: Frailty and medicine-related problems are common among the elderly and have been associated with an increased risk of adverse outcomes. However, there has been limited research on the association between frailty and medicines use. Aim: To determine the distribution of frailty among older people who used medicines and to examine the difference in frailty scores over time with continuation or discontinuation of specific medicines. Methods: The study population was from the Australian Longitudinal Study of Ageing (ALSA). The data used in the analysis were collected in 1992 (wave 1) and in 1995 (wave 3). Frailty scores were assessed at both waves using a modified version of the Frailty Index. Non-parametric tests were used to examine the difference in the distribution of frailty scores in relation to medicines used at baseline. Medicine use was categorised into continued or stopped by comparing use at wave 3 to use at baseline. A t-test was used to compare the mean changes in frailty scores between the two groups, with a p-value of

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. Refereed/Peer-reviewed

Background: Medicines are potentially modifiable risk factors for postoperative delirium. However, the extent to which preoperative medicines are included in risk prediction models (RPMs) is unknown. Objective: This systematic review aimed to assess the extent of inclusion of preoperative medications in RPMs for postoperative delirium. Methods: Articles were systematically searched from MEDLINE, EMBASE and CINAHL using Medical Subject Headings (MeSH) where possible and keywords for postoperative delirium and prediction model. Studies published until May 2017 with a primary outcome of postoperative delirium that developed an RPM containing preoperative patient information were considered. Where a study had two cohorts, a derivation and a validation cohort, findings from the derivation cohort were extracted and reported. Results: Eighteen prospective and one retrospective cohort studies were included for review. Of the 19 studies, only nine considered preoperative medication data, with medications appearing as predictor variables in five models. There was wide variability in the factors included in the final models, with the most frequent predictors being age and cognitive impairment, appearing in 13 (68%) and 11 (58%) RPMs, respectively. Conclusion: While medications are commonly cited risk factors for delirium, they are not adequately considered when developing RPMs. Future studies aiming to develop an RPM for postoperative delirium should include preoperative medication data as a potential predictor variable because of the modifiable nature of medication use and its impact on other factors commonly in models, such as cognition. Refereed/Peer-reviewed

Background Antidepressants are associated with adverse effects such as sedation and hypotension, which can result in falls and fractures. Few studies have assessed the risk of hip fracture due to mirtazapine, and no known studies have assessed whether the risk of hip fracture is higher in patients taking other antidepressant medicines in combination with mirtazapine. Objectives This study aimed to examine the risk of hip fracture in older people due to mirtazapine use as well as switching between or concurrently using mirtazapine and other antidepressants. Method A matched case–control study was conducted. Cases were people aged over 65 years who were eligible for Australian Government Department of Veterans’ Affairs (DVA) benefits and who sustained a hip fracture between 2009 and 2012. Each case was matched with up to four randomly selected controls of the same gender and age (± 2 years). Multivariable conditional logistic regression was used to estimate associations between antidepressant use and hip fracture. In order to assess whether combined antidepressant effects differed from the sum of individual effects, the relative excess risk due to interaction (RERI) was calculated. Results The study population comprised 8828 cases and 35,310 controls. The median age of these participants was 88 years and 63% were women. The risk of hip fracture was increased for mirtazapine (continuous use: odds ratio [OR] 1.27, 95% confidence interval [CI] 1.12–1.44). The combinations associated with increased odds of hip fracture were addition of selective serotonin reuptake inhibitors (SSRIs) to mirtazapine (OR 11, 95% CI 2.2–51; RERI 7.7, 95% CI −9.0 to 24), addition of tricyclic antidepressants (TCAs) to mirtazapine (OR 14, 95% CI 1.4–132; RERI 12, 95% CI −19 to 43) and continuous use of both SSRIs and mirtazapine (OR 2.4, 95% CI 1.4–4.2; RERI 0.4, 95% CI −0.9 to 1.7). RERIs indicated that the effect of each antidepressant pair equalled the sum of the effects of individual antidepressant use. There was no evidence of dispensing of lower strength mirtazapine upon introducing TCAs and SSRIs. Conclusions Our results show elevated risk of hip fracture following use of mirtazapine alone and in combination with other antidepressants. The overlapping use of antidepressants may reflect the treatment of comorbidities (e.g. anxiety), switching from mirtazapine to other antidepressants, or add-on therapy. Our results highlight the risks of employing add-on therapy or switching antidepressants in older people, providing further evidence to support cautious cross-tapering where switching between antidepressants is required. Electronic supplementary material The online version of this article (doi:10.1007/s40801-017-0120-y) contains supplementary material, which is available to authorized users.

Background Few studies have assessed the risk of hip fracture following concurrent use of psychoactive medicines, and none has investigated combinations with selective serotonin reuptake inhibitors. Objectives To assess the risk of hip fracture in older people as a result of concurrent use of selective serotonin reuptake inhibitors and other psychoactive medicines. Methods A matched case–control design was employed. Cases were Australian Government Department of Veterans’ Affairs beneficiaries aged over 65 years who experienced a hip fracture between 2009 and 2012. Each case was matched with up to four randomly selected controls of the same age (±2 years) and sex. Medicine-hip fracture associations were estimated via conditional logistic regression. The relative excess risk due to interaction (RERI) was calculated to determine whether combined effects differed from the sum of individual effects. Results There were 8828 cases and 35,310 controls. The median age of subjects was 88 years and 63% were women. The risk of hip fracture was elevated for all medicines assessed individually, most notably selective serotonin reuptake inhibitors (initiation: odds ratio [OR] = 2.7, 95% confidence interval [CI] 2.1, 3.6) and opioids (initiation: OR = 2.3, 95% CI 1.9, 2.9). Combinations associated with an increased odds of hip fracture included addition of benzodiazepines to selective serotonin reuptake inhibitor therapy (OR = 3.0, 95% CI 1.9, 4.8; RERI = 0.9, 95% CI −0.5, 2.3), concurrent use of both opioids and selective serotonin reuptake inhibitors (OR = 2.2, 95% CI 1.9, 2.6; RERI = 0.1, 95% CI −0.3, 0.5), addition of opioids to selective serotonin reuptake inhibitor therapy (OR = 3.2, 95% CI 1.8, 5.5; RERI = −0.1, 95% CI −2.0, 1.7), and initiation of both benzodiazepines and selective serotonin reuptake inhibitors (OR = 4.7, 95% CI 1.7, 13; RERI = 1.3, 95% CI −3.8, 6.3). The RERI results suggested that the effect of each of these medicine combinations equalled the sum of the effects of individual medicine use. Conclusions In older people, the concurrent use of selective serotonin reuptake inhibitors and other psychoactive medicines increased the risk of hip fracture as much as the sum of the risks owing to individual medicine use. Our results highlight the need for prescribers to consider the sedative burden of medicines in each older patient as well as the potential for an additive risk of hip fracture when initiating additional psychoactive therapy.

Objectives: To examine the risk of dementia associated with posttraumatic stress disorder (PTSD) and the contribution of antipsychotic use to this risk. Design: Retrospective cohort study Setting: Australia. Administrative claims data from the Australian Government Department of Veterans' Affairs were used. Participants: Male Vietnam veterans aged 55 to 65 at baseline (2001-02) with no preexisting dementia diagnosis (N = 15,612). Measurements: The association between PTSD and dementia was assessed over 12 years of follow-up. Dementia was identified as a hospital diagnosis, dementia record in service disability data, or dispensing of medicines for dementia. Cox-proportional hazards models were used, with age as the time-scale. Results were stratified according to baseline antipsychotic use. Results: No greater risk of dementia was observed with PTSD. In veterans who received antipsychotics, dementia risk was significantly higher than in those who did not (hazard ratio (HR) = 2.1, 95% confidence interval (CI) = 1.4-3.3). Dementia risk was significantly greater in veterans hospitalized for PTSD who received antipsychotics (HR = 2.2, 95% CI = 1.1-4.6) and veterans without PTSD who received antipsychotics (HR = 4.3, 95% CI = 2.1-8.6) than in those without PTSD with no antipsychotic use. Conclusion: Antipsychotic use may be a contributor to dementia risk. These findings should be interpreted with caution because the study design was observational. Further research using prospective study designs in settings where diagnostic data, cognitive function, and disease severity are available are required. Refereed/Peer-reviewed

Background and purpose: It is unclear whether metal particles and ions produced by mechanical wear and corrosion of hip prostheses with metal-on-metal (MoM) bearings have systemic adverse effects on health. We compared the risk of heart failure in patients with conventional MoM total hip arthroplasty (THA) and in those with metal-on-polyethylene (MoP) THA. Patients and methods — We conducted a retrospective cohort study using data from the Australian Government Department of Veterans’ Affairs health claims database on patients who received conventional THA for osteoarthritis between 2004 and 2012. The MoM THAs were classified into groups: Articular Surface Replacement (ASR) XL Acetabular System, other large-head (LH) (> 32 mm) MoM, and small-head (SH) (≤ 32 mm) MoM. The primary outcome was hospitalization for heart failure after THA. Results: 4,019 patients with no history of heart failure were included (56% women). Men with an ASR XL THA had a higher rate of hospitalization for heart failure than men with MoP THA (hazard ratio (HR) = 3.2, 95% CI: 1.6–6.5). No statistically significant difference in the rate of heart failure was found with the other LH MoM or SH MoM compared to MoP in men. There was no statistically significant difference in heart failure rate between exposure groups in women. Interpretation: An association between ASR XL and hospitalization for heart failure was found in men. While causality between ASR XL and heart failure could not be established in this study, it highlights an urgent need for further studies to investigate the possibility of systemic effects associated with MoM THA. Refereed/Peer-reviewed

Background: Most studies assessing the effect of central nervous system (CNS)-acting medicines on cognitive disturbances have focused on the use of individual medicines. The impact on cognitive function when another CNS-acting medicine is added to a patient's treatment regimen is not well known. Objective: To determine risk of hospitalization for confusion, delirium, or dementia in older people associated with increasing numbers of CNS-acting medicines taken concurrently, as well as the number of standard doses taken each day (measured as defined daily doses). Design: Retrospective cohort study, from July 2011 to June 2012, using health claims data. Setting: Australian veteran population. Participants: A total of 74,321 community-dwelling individuals aged 65 years and over, who were dispensed at least 1 CNS-acting medicine in the year before study entry. Patients with prior hospitalization for confusion or delirium, and those with dementia or receiving palliative care, were excluded. Main outcome measure: Hospitalization for confusion, delirium, or dementia. Results: Over the 1-year study period, 401 participants were hospitalized with confusion, delirium, or dementia. Adjusted analyses showed the risk of hospitalization was 2.4 times greater with the use of 2 CNS-acting medicines compared with no use [incident rate ratio (IRR) 2.39, 95% confidence interval (CI) 1.79-3.19, P < .001], and more than 19 times greater when 5 or more CNS-acting medicines were taken concurrently (IRR 19.35, 95% CI 11.10-33.72, P < .001). Similarly, the risk of hospitalization was significantly increased among patients taking between 1.0 and 1.9 standard doses per day (IRR 2.64, 95% CI 1.99-3.50, P < .001) and between 2.0 and 2.9 standard doses per day (IRR 3.43, 95% CI 2.07-5.69, P < .001) compared with no use. Conclusions: Use of multiple CNS-acting medicines or higher doses is associated with an increased risk of hospitalization for confusion, delirium, or dementia. Health care professionals need to be alert to the contribution of CNS-acting medicines among patients presenting with confusion or delirium and consider strategies to reduce treatment burden where possible. Refereed/Peer-reviewed

Aim To determine the prevalence of frailty in a cohort of older Australians. Methods Frailty status of the 2087 participants of the Australian Longitudinal Study of Ageing was assessed based on the questionnaire responses at the baseline interview. Frailty status and prevalence were assessed using four measures: two unidimensional measures (the Frailty Phenotype and Simplified Frailty Phenotype) and two multidimensional measures (Frailty Index and Prognostic Frailty Score). Agreement between the four measures was determined. Results The multidimensional measures identified more people as frail (17.5 and 49.4%) than did the unidimensional (2 and 8.8%). There was little agreement between the measures; only 0.5% of the participants were identified as frail by all four measures. Conclusions The apparent prevalence of frailty varied when different measures were used. It is important for clinicians and researchers to be aware that different frailty measures may identify different groups of older people as frail.

Background Prescription sequence symmetry analysis (PSSA) is a signal detection method for adverse drug events. Its capacity to consistently detect adverse drug events across different settings has not been tested. We aimed to determine the consistency of PSSA results for detecting positive and negative control adverse drug events across different settings. Methods Using a distributed network model, we analyzed prescription dispensing data using PSSA in Australia, Hong Kong, Japan, Korea, and Taiwan. Positive control was amiodarone and thyroxine, as a marker of amiodarone-induced hypothyroidism, a known adverse event with a clear temporal relationship to amiodarone initiation. Negative controls were amiodarone and allopurinol, as a marker of amiodarone-induced gout and thyroxine and allopurinol, as a marker of thyroxine-induced gout. Gout is not recorded as an adverse event in product information for either medicine. Adjusted sequence ratios (ASR) were calculated for each country. Pooled estimates were obtained by using the generic inverse variance method. Results A positive association was identified between amiodarone and thyroxine in all settings with a pooled ASR 2.63 (95% confidence interval (CI) 1.47–4.72). Temporal analysis showed the effect occurred within the first few weeks of treatment. No significant associations were found for the negative controls in any setting; pooled ASR were 0.76 (95%CI 0.62–0.93) and 0.98 (95%CI 0.85–1.12) for amiodaroneallopurinol and thyroxine-allopurinol, respectively. Conclusion Despite different health settings, different populations, and different patterns of medicine utilization, PSSA gave consistent estimates across countries for a well-known positive association and two negative control adverse events. © 2015 The Authors Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd. key words—prescription symmetry analysis; pharmacovigilance; amiodarone; hyperthyroidism; pharmacoepidemiology

PURPOSE: Many factors can increase the risk of hip fracture, including medicines. Traditional observational studies have assessed the risk, but results may be confounded by unmeasured factors. The case-crossover design is an alternative approach that controls for patient-specific, time-invariant confounding factors. This study aimed to assess associations between psychoactive medicines and hip fracture in the elderly using the case-crossover method. METHODS: Data were sourced from the Australian Government Department of Veterans' Affairs healthcare claims database. The study population comprised beneficiaries aged over 65 years who were hospitalised for hip fracture between 2009 and 2012. The case-crossover method was used to compare individuals' medicine exposure immediately before hip fracture (case window) with their exposure at an earlier time (control window). Conditional logistic regression was employed to quantify associations between medicine use and hip fracture. Alternative exposure windows were assessed in sensitivity analyses. RESULTS: Eight thousand eight hundred twenty-eight patients were hospitalised for hip fracture. Their median age was 88 years, and 63% were female. Odds of hip fracture were increased for opioids (odds ratio [OR] = 1.62, 95% confidence interval [CI] = 1.42-1.84), selective serotonin reuptake inhibitors (OR = 1.54, 95% CI = 1.28-1.86) and antipsychotics (OR = 1.47, 95% CI = 1.21-1.80). There was no significant association for tricyclic antidepressants in the primary analysis (OR = 1.18, 95% CI = 0.91-1.52), but there was a significant association in the sensitivity analysis using an alternative, earlier control window (OR = 1.43, 95% CI = 1.11-1.83). CONCLUSIONS: Increased risk of hip fracture in older people was found for opioids, selective serotonin reuptake inhibitors and antipsychotics. The choice of control window influenced the result for tricyclic antidepressants. Copyright © 2015 John Wiley & Sons, Ltd. Language: en

Objective To examine the association between benzodiazepine use and the risk of dementia. Design, setting, and participants We conducted a retrospective cohort study, using a nationwide healthcare database of South Korea (2002–2016). The participants included new users of benzodiazepines aged ≥50 years, with no prior prescription record of benzodiazepines or a history of dementia within the previous 5 years (2002–2006). Methods Outcome was defined as an incident dementia with specified algorithms using diagnosis and prescription records, with the application of a 5-year lag-time following the index date during which outcomes were censored. We used a multivariable Cox proportional hazard model to estimate hazard ratio (HR) and the 95% confidence interval (CI). Comorbidities and comedications were treated as time-varying covariates in 90-day windows, and an active comparator was used to reduce potential bias from confounding by indication. Active comparators were defined as new-users of antidepressants. Results Our final participants included 616,256 patients, after propensity score estimation and matching on a 1:1 ratio. We observed a 23% increase in the risk of dementia in benzodiazepine users, compared with that in nonusers, over a mean follow-up period of 5.5 years (HR 1.23, 95% CI 1.14–1.32). A consistent finding was observed when the lag-time duration was extended to 7 years, revealing a close to null association (HR 1.17, 95% CI 1.04–1.30). When new-users of antidepressants were used as the active comparator, no increase in the risk of dementia with benzodiazepines was observed over 7 years (HR 1.01, 95% CI 0.81–1.27). Conclusions and implications A significant association was observed between benzodiazepine use and the risk of dementia, compared with nonusers. However, a null or negative association was observed with the use of the active comparator, suggesting the absence of a causal association between dementia and benzodiazepine use.

Background: Risperidone is the only antipsychotic approved in Australia for the management of the behavioural and psychological symptoms of dementia (BPSD). In June 2015, the Australian Government Therapeutic Goods Administration (TGA) amended the indication to restrict use in BPSD to patients with Alzheimer&rsquo, s dementia for a maximum twelve-week duration. We aimed to determine whether the rate and duration of risperidone use for BPSD decreased following the regulatory changes. Methods: we conducted a study using the Australian Government Department of Veterans&rsquo, Affairs administrative claims data and Pharmaceutical Benefits Scheme (PBS) 10% sample data. We included people aged 65 years or older and compared the rate and duration of risperidone use before and after the TGA labelling changes. Results: There was a sustained decrease in the trend of risperidone use for BPSD following the TGA labelling changes, with a monthly decrease of 1.7% in the aged care population, 0.5% in the community living population and 1.5% in the general older Australian population. Overall, in the 24 months post the TGA changes the reduction in the rate of use of risperidone ranged from 20% to 28% lower than compared to what the rate would have been without the TGA changes. The median duration of use of risperidone in aged-care residents decreased from 338 days in the year prior to the TGA labelling changes, to 240 days per person in the year after the changes. Conclusion: The TGA labelling changes were associated with a significant reduction in the rate of use of risperidone for BPSD in veterans living in both the aged care and community settings, and in the general older Australian population. The labelling changes were also associated with a reduced duration of risperidone use in aged care residents, although for most people the duration of use still exceeded the recommended 12-week maximum duration.

Background Hip fracture impacts on quality of life and may lead to premature death. In Australia, the extent of use of medicines that increase risk of falls or hip fracture in at-risk older people is not known. Aim To determine the use of medicines associated with falls or hip fracture before hip fracture and whether medicine use changed after hip fracture. Method Data from the Australian Department of Veterans' Affairs healthcare claims database were used. The cohort included patients aged > 65 years who were hospitalised for hip fracture in 2009. Percentages of patients using medicines associated with falls or hip fracture were calculated in the 6 weeks before hospitalisation for hip fracture. McNemar's test was used to assess changes in medicines used before admission and after discharge from hospital. Results 2235 patients with a median age of 87 years had hip fractures in 2009. At least 1 medicine that increases risk of falls or hip fracture was used by 84% of patients before admission. Of the drug classes that increase risk of falls or hip fracture, the 4 most commonly dispensed before admission were antihypertensives (63%), antidepressants (29%), benzodiazepines (26%) and opioids (19%). After discharge, the use of antipsychotics (p < 0.0001), opioids (p < 0.0001), benzodiazepines (p = 0.0009) and antidepressants (p = 0.01) increased significantly. Conclusion Most older patients used at least 1 medicine that increases the risk of falls or hip fracture before and after hip fracture. Antipsychotic, opioid, benzodiazepine and antidepressant use increased significantly after hospital discharge.

Purpose To undertake a multi-country study to investigate the risk of acute hyperglycaemia with antipsychotic use. Methods Using a distributed network model with a common minimal data set, we performed a prescription sequence symmetry analysis (PSSA) to investigate the risk of acute hyperglycaemia associated with antipsychotic initiation. Incident insulin prescriptions were used as a proxy indicator of acute hyperglycaemia. Participating countries and population datasets included Australia (300,000 persons), Japan I (300,000 persons), Japan II (200,000 persons), Korea (53 million persons) Taiwan (1 million persons), Sweden (9 million persons), USA-Public (87 million persons) and USA-Private (47 million persons). Results Olanzapine showed a trend towards increased risk in most databases, with a significant association observed in the USA-Public database (Adjusted sequence ratio (ASR)=1.14; 95% Confidence Interval (CI) 1.10–1.17) and Sweden (ASR=1.53; 95% CI 1.13–2.06). Null or negative associations were observed for haloperidol, quetiapine and risperidone. Conclusion Acute hyperglycaemia appears to be associated with olanzapine use, however, this effect was only observed in two large databases. Despite different patterns of utilization of both antipsychotics and insulin, PSSA analysis results for individual antipsychotic medicines were qualitatively similar across most countries. PSSA, used in conjunction with existing methods, may provide a simple and timely method further supporting multi-national drug safety monitoring. Copyright © 2013 John Wiley & Sons, Ltd. key words—Asian Pharmacoepidemiology Network (AsPEN); distributed network model; multi-national collaboration; antipsychotics; hyperglycaemial; prescription sequence symmetry analysis; pharmacoepidemiology

Purpose To determine the validity of sequence symmetry analysis (SSA) method to detect adverse drug reactions from an administrative claims database. Methods Published randomised controlled trials (RCTs) of 19 medicines were identified through search databases, product information (PI) or the US Food and Drug Administration Web site. All adverse events (AEs) in the RCTs and the PI for the medicines were extracted. AEs were considered ‘gold standard positive events’ if they were reported as being statistically significant events in adequately powered RCTs. The remaining AEs were considered ‘gold standard negative events’ if the event was not listed as an AE in the PI for that medicine or any other medicine in its class. Indicators of AEs were identified by consensus from two clinical researchers. SSA was run for each medicine–indicator pair using four different time windows: 3, 6, 9 and 12 months. Results A total of 120 randomised placebo controlled trials were reviewed for the 19 tested medicines. A total of 165 medicine–indicator pairs (44 positive and 121 negative events) were identified and tested by SSA. At the 12-month time window, the sensitivity, specificity, positive and negative predictive values of SSA were 61% (95%CI 0.46–0.74), 93% (95%CI 0.87–0.96), 77% (95%CI 0.61–0.88) and 87% (95%CI 0.80–0.92), respectively. Using a 3-month time window, the SSA had a lower sensitivity (52%). Conclusions The SSA technique was found to have moderate sensitivity and high specificity for detecting ADRs. These results suggest that SSA is a potential tool for detecting ADRs using administrative claims data that could complement existing pharmacosurveillance methods. Copyright © 2013 John Wiley & Sons, Ltd.

Purpose: To identify the extent of use of medicines recommended to be used with caution in glaucoma patients with specified comorbidities and to determine evidence of associated harm. Methods: Retrospective cohort analysis from administrative claims data and prescription/event sequence symmetry analysis. Participants: Australian Government Department of Veterans' Affairs treatment card holders dispensed glaucoma eye-drops. Main outcome measures: Proportion of veterans with glaucoma and diabetes, airways disease, heart failure, ischemic heart disease or depression, dispensed glaucoma eye drops which should be used with caution. For harms, outcome measures were hospitalizations for airways disease and heart disease. Results: The cohort analysis included 25,984 veterans. Of these, 88% with airways disease were dispensed glaucoma eye drops with the potential to aggravate airways disease, 43% with heart failure were dispensed topical beta-blockers and 49% with depression received glaucoma eye drops which should be used cautiously in those with depression. We found increased risk of initiation of inhaled beta-agonist following timolol (adjusted sequence ratio (ASR) 1.48, 99% CI 1.22-1.78) and latanoprost (ASR 1.24, 99% CI 1.11-1.38) initiation. We found increased risk of inhaled corticosteroid initiation following initiation of timolol (ASR 1.43, 99% CI 1.13-1.81). There was increased risk of antidepressant initiation following timolol initiation (ASR 1.24, 99% CI 1.07-1.43), and latanoprost (ASR 1.16, 99% CI 1.03-1.31). There was also increased risk of hospitalization for bradycardia following timolol initiation (ASR 2.22,99% CI 1.15-4.31). Conclusion: Use of glaucoma eye drops recommended to be used with caution in co-morbidities is common and was associated with adverse outcomes. Awareness of co-morbidities is required in the selection and prescription of glaucoma eye drops. Refereed/Peer-reviewed

Since 2004, the Department of Veterans’ Affairs (DVA) has funded the Veterans’ Medicines Advice and Therapeutics Education Services (MATES) program. The main intervention of the program is quarterly targeted patient-specific prescriber feedback. The feedback comprises a list of relevant medications dispensed to each patient and notes about potential medicationrelated problems specific to the intervention. Supportive educational material is provided to assist general practitioners (GPs) resolve these medication-related problems. Veterans identified in the GP mailing are sent an educational brochure highlighting medication issues and encouraging them to speak with their doctor. To enable pharmacists to support this practice change, educational material is also provided to all pharmacies and accredited pharmacists. The most recent of the 28 interventions implemented to date have addressed osteoporosis, opioid-induced constipation and urinary incontinence. Overall, program materials have been mailed to 249 454 veterans, 34 527 GPs and around 8000 pharmacies and accredited pharmacists. Evaluation has demonstrated a doubling of home medicines review (HMR) rates in the veteran population. Analyses of the DVA data have reported a 45% reduction in hospitalisation for heart failure following HMR among veterans with heart failure (adjusted hazard ratio [HR] 0.6; 95% confidence interval [CI] 0.4–0.8), and a 79% reduction in hospitalisation for haemorrhage (HR 0.2; 95%CI 0.05–0.9) 2 to 6 months after an HMR in veterans dispensed warfarin. Veterans’ MATES has resulted in clinically significant improvements in medication and health service use. J Pharm Pract Res 2011; 41: 316-19.

Darren J Costain, Sarah L Whitehouse, Nicole L Pratt, Stephen E Graves, Philip Ryan, and Ross W Crawford

E. E. Roughead, J. D. Barratt, E. Ramsay, N. Pratt, P. Ryan, R. Peck, G. Killer, and A. L. Gilbert

Purpose To examine the prescribing of prochlorperazine secondary to the prescribing of a medicine which could lead to symptoms for which prochlorperazine is indicated and commonly used. Given the range of potential hypotensive, sedative, dystonic and other extra-pyramidal side effects associated with prochlorperazine, its association with hip fracture was also examined. Methods Prescription/event sequence symmetry analyses were undertaken from 1st January 2003 to 31st December 2006, using administrative claims data from the Department of Veterans' Affairs, Australia. This method assesses asymmetry in the distribution of an incident event (either prescription of another medicine or hospitalization) before and after the initiation of prochlorperazine. Crude and adjusted sequence ratios (ASR) with 95% confidence intervals (CI) were calculated. Results A total of 34 235 persons with incident use of prochlorperazine were identified during the study period. Statistically significant positive associations were found for a number of commonly used medicines, including cardiovascular medicines, NSAIDs, opioids and sedatives and the subsequent initiation of prochlorperazine that ranged from 1.07 (95%CI 1.01–1.14) for diuretics to 1.50 (95%CI 1.40–1.61) for statins. Prescription event analysis showed a 49% (95%CI 1.19–1.86) increased risk of hospitalisation for hip fracture following dispensing of prochlorperazine. Conclusions Prescribers should consider the possible contributing role of newly initiated medicines with the potential to cause of dizziness, and where possible address this through dose reduction or cessation of the medicine, rather than prescribing prochlorperazine. Copyright © 2010 John Wiley & Sons, Ltd.

Many observational studies in the general population have demonstrated an increased risk of adverse events associated with NSAIDs, including gastrointestinal bleeds, congestive heart failure, acute renal failure, hypertension and acute myocardial infarction. Few studies, however, have explored outcomes in populations considered to be more vulnerable to their effects. To determine the rate of adverse events requiring hospitalization that are associated with NSAIDs in two high-risk veteran populations and the general veteran population. In this retrospective cohort study, we identified veterans being dispensed medicines for diabetes mellitus (diabetes cohort), those receiving renin-angiotensin system medicines and frusemide (furosemide) concurrently (ACE inhibitors/angiotensin II type 1 receptor antagonists [angiotensin receptor blockers; ARBs] and frusemide cohort), or at least one other medicine (general population/reference cohort). The primary endpoint was hospitalization with a primary diagnosis of congestive heart failure, gastrointestinal ulcer, acute renal failure, acute myocardial infarction or hypertension. Hospitalization rates during the period of non-exposure and the 30-day period after a subject was first dispensed an NSAID were compared using Poisson regression. There was a significant increase in risk of all hospitalizations of interest in the exposed period compared with the unexposed period in the diabetes cohort (incidence rate ratio [IRR] 1.31; 95% CI 1.08, 1.60), ACE inhibitor/ARB and frusemide cohort (IRR 1.34; 95% CI 1.13, 1.58) and reference cohort (IRR 1.47; 95% CI 1.30, 1.66). The incidence rates demonstrate that for every 10 000 veterans treated for 30 days with NSAIDs, there were 20 extra hospitalizations in the diabetes population, 30 additional hospitalizations in the ACE inhibitor/ARB and frusemide cohort and 6 extra hospitalizations in the reference population compared with those not treated with NSAIDs. NSAID use is associated with an increased risk of hospitalization in all groups, with similar risk ratio estimates. However, the clinical implications were greater in the high-risk populations, in which more hospitalizations were observed. Consideration may need to be given to differential presentation of risk information to clinicians.

Risk factors were investigated for revision for dislocation in primary total hip arthroplasties (THAs) between September 1, 1999, and December 31, 2004, as reported by the Australian Orthopaedic Association National Joint Replacement Registry. For 65992 primary THAs, the only initial diagnoses with significantly increased relative risk (RR) of revision for dislocation compared to osteoarthritis were fractured neck of femur (RR, 2.03; P b .001), rheumatoid arthritis (RR, 2.01; P b .01), and avascular necrosis (RR, 1.57; P b .05). A total of 58109 primary THAs for osteoarthritis were investigated for effect of age group, sex, and fixation method. There were 428 (0.7%) revisions for dislocation, 369 (0.8%) with a cementless acetabulum, and 59 (0.6%) with cemented acetabulum (RR, 1.59; P b .01). There is a significantly increasing risk of revision for dislocation as head size decreases (P b .001). Cementless acetabula, particularly with smaller heads, have a higher rate of revision for dislocation.

What is already known about this subject • Previous cross-sectional studies have demonstrated underuse of cardiovascular medicines in the population with diabetes. What this study adds • Trends are changing over 5 years with increasing use of medicines affecting the angiotensin–renin system, lipid-lowering medicines and antiplatelets in the Australian veteran population, in line with recommended practice. Aim To determine trends over 5 years in cardiovascular medicine use in the Australian veteran population with diabetes Methods An observational study. All veterans dispensed medicines indicative of diabetes between 2000 and 2005 were identified from the Veterans Affairs pharmacy claims dataset. Concurrent dispensings of angiotensin-converting enzyme inhibitor (ACEI), lipid-lowering medicines and antiplatelets were assessed. Results ACEI/angiotensin II receptor blocker use has risen from 46% to 67% in the veteran population dispensed medicines indicative of diabetes. Lipid-lowering medicines have increased from 33% to 58% and antiplatelets from 28% to 50%. Conclusion The increasing use of cardiovascular medicines in the diabetes population is suggestive of improved treatment practices over time, consistent with guidelines and quality use of medicines initiatives.

Objectives: To update the analysis of the cohort mortality and cancer incidence study of employees in the Australian petroleum industry. Methods: Employees of Australian Institute of Petroleum member companies were enrolled in the cohort in four industry-wide surveys between 1981 and 1999. Mortality of 16 547 males and 1356 females was determined up to 31 December 2001 and cancer incidence to 31 December 2000. Cause specific mortality and cancer incidence were compared with those of the Australian population by means of standardised mortality ratios (SMRs) and standardised incidence ratios (SIRs). Associations between increased incidence of specific cancers and employment in the petroleum industry were tested by trends according to period of first employment, duration of employment, latency, and hydrocarbon exposure, adjusting for personal smoking history where appropriate. Results: There was a significant elevation of the incidence of mesothelioma (SIR 1.77, 95% CI 1.05 to 2.79), melanoma (SIR 1.37, 95% CI 1.19 to 1.58), and prostate cancer (SIR 1.18, 95% CI 1.04 to 1.34). The SIRs of all leukaemias and of acute non-lymphocytic leukaemia (ANLL) were not significantly different from unity, but all 11 ANLL cases were clustered in the middle to high hydrocarbon exposure categories. Tanker drivers had a significantly elevated incidence of kidney cancer (12 cases v 5.84 expected, SIR 2.05, 95% CI 1.06 to 3.59). Lung cancer incidence was significantly reduced (SIR 0.69, 95% CI 0.57 to 0.83) Conclusions: Most cases of mesothelioma are probably related to past exposure to asbestos in refineries. No occupational cause has been identified for the excess of melanoma, or prostatic or bladder cancer. The possibility of a causal relationship between cancer of the kidney and hydrocarbon exposure warrants further study. It is uncertain whether benzene exposures, particularly past levels of exposure, have been high enough to cause ANLL.

Objective: To determine whether proton-pump inhibitor (PPI) use is associated with hospitalisations for pneumonia and with antibiotic use. Design and setting: Historical cohort study in the Australian veteran population, conducted from 1 January 2002 to 30 December 2006, comparing veterans exposed to PPIs with those not exposed Participants: All 185 533 veterans who were Gold Card holders (ie, eligible for all health services subsidised by the Department of Veterans’ Affairs) and aged 65 years and over at 1 January 2002 and had been prescribed at least one medicine in the previous 6 months. Main outcome measures: The primary endpoint was hospitalisation for pneumonia. Secondary endpoints included hospitalisation for bacterial pneumonia and dispensings of antibiotics commonly used to treat respiratory tract infections. Results: After adjustment for potential confounders, we found an increased risk of hospitalisation for pneumonia among those exposed to PPIs compared with the unexposed group (rate ratio [RR], 1.16; 95% CI, 1.11–1.22). The risk was not increased for bacterial pneumonia (RR, 1.13; 95% CI, 0.98–1.31), which made up 8% of pneumonia cases. An increased risk of antibiotic dispensings was observed among those exposed to PPIs (RR, 1.23; 95% CI, 1.21–1.24). Conclusions: PPI dispensings were found to be associated with a small but significant increased risk of hospitalisation for pneumonia. While the increased risk is small, the prevalent use of PPIs means that many people could be affected Refereed/Peer-reviewed

Objective: To determine the risk of stroke associated with non-steroidal anti-inflammatory drug (NSAID) use. Design, setting and participants: Retrospective cohort study of 162 065 Australian veterans with incident dispensing of an NSAID between 1 January 2001 and 31 December 2008, using prescription event sequence symmetry analysis. Main outcome measures: Hospitalisation for stroke, ischaemic stroke or haemorrhagic stroke. Results: The absolute risk of stroke was low: 7.1/1000 people/year. Incident use of NSAIDs was associated with a 1.88 times increased risk (95% CI, 1.70-2.08) of hospitalisation for stroke (ischaemic or haemorrhagic) following first ever dispensing of an NSAID. This equates to an increased absolute risk of 13.4 strokes/1000 people/year. Significant positive associations between starting an NSAID and having a hospitalisation for stroke were found for most NSAIDs, with adjusted sequence ratios ranging from 1.44 (95% CI, 1.16-1.80) for indomethacin to 1.80 (95% CI, 1.59-2.04) for rofecoxib. Conclusions: Incident use of NSAIDs was associated with an increased risk of stroke. Increased awareness of the potential for serious adverse cardiovascular events, together with individual assessment of cardiovascular risk, careful deliberation of the balance between risk and benefits and appropriate supervision, is required when initiating NSAID therapy. Refereed/Peer-reviewed

Objectives. To determine the natural history of infant spilling (regurgitation/vomiting) during the first 2 years of life and to determine the relationship between infant spilling and gastroesophageal reflux (GER) symptoms at 9 years of age. Methods. A prospective birth cohort was followed with daily symptom diaries during the first 2 years of life and reviewed at 9 years of age (range: 8–11 years). The prevalence of infant spilling during the first 2 years of life, the prevalence of GER symptoms between 8 and 11 years of age (mean age: 9.7 years), relative risk of infant spilling predisposing to GER symptoms at 9 years of age, and prevalence of maternal GER symptoms and relationship with infant spilling and GER at 9 years of age were measured. Results. A total of 693 children who represented 83% of an original sample of 836 children and were followed for 2 years from birth with daily symptom diaries were contacted at 9 (8–11) years of age. Spilling of most feeds each day was common in infancy and reached a peak prevalence of 41% between 3 and 4 months of age and thereafter declined to < 5% between 13 and 14 months of age. Infants with spilling on 90 days or more during the first 2 years of life (classified as frequent spilling) were more likely to have GER symptoms at 9 years of age. Children with frequent infant spilling, compared with those with no spilling, had a relative risk of 2.3 (95% confidence interval [CI]: 1.3–4.0) of 1 or more GER symptoms at 9 years of age, 4.6 (95% CI: 1.5–13.8) for heartburn, 2.7 (95% CI: 1.4–5.5) for vomiting, and 4.7 (95% CI: 1.6–14.0) for acid regurgitation. Gender, breastfeeding, and environmental tobacco smoke exposure were not significant factors related to infant spilling. Prepregnancy smoking and smoking in the same room as the child at the 9-month and 18-month follow-ups had a significant effect on GER symptoms at 9 years of age. Infant spilling and GER at 9 years of age were significantly related to maternal GER symptoms but not to paternal GER symptoms. Conclusions. Spilling in infancy is very common, but the majority of children settle by 13 to 14 months of age. However, those with frequent spilling (>90 days) are more likely to have GER symptoms at 9 years of age. In addition, a maternal history of GER was significantly related both to infant spilling and to GER at 9 years, suggesting that a genetic component may be involved. Physicians should consider studying children with a history of frequent infant spilling to determine whether this group is at increased risk for GER disease.