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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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.

Cardiovascular risk in patients receiving ranibizumab for exudative age-related macular degeneration: a nationwide self-controlled case-series study.

AIMS: To identify the association between ranibizumab and risk of stroke and acute myocardial infarction (AMI) in patients with exudative age-related macular degeneration (AMD). METHODS: We identified patients aged ≥45 years who received ranibizumab for exudative AMD from the Korean National Health Insurance database. Of these, we selected patients suffering stroke or AMI for the self-controlled case series. We estimated incidence rate ratios (IRR) for stroke or AMI by comparing incidence rates of ranibizumab-exposed periods to that of baseline using conditional Poisson regression. The risks of haemorrhagic and ischaemic strokes were also calculated separately. RESULTS: Among 33 134 patients receiving ranibizumab, 2397 patients had stroke or AMI. The risk of stroke (IRR=0.83, 95% CI 0.75 to 0.91) was not increased during the overall exposed period; however, there was a marginally elevated risk in ≥57 days exposed period (IRR=1.14, 95% CI 1.001 to 1.31). When analysing by the types of stroke, no increased risks of haemorrhagic (IRR=1.01, 95% CI 0.80 to 1.26) and ischaemic stroke (IRR=0.78, 95% CI 0.71 to 0.86) were observed during the exposed period, although the risks of ischaemic and haemorrhagic stroke were slightly elevated during ≥57 days exposed period. We could not find an association between ranibizumab and AMI. CONCLUSIONS: Ranibizumab intravitreal injections did not increase the overall risk of stroke or AMI. Although the cardiovascular risk in patient receiving ranibizumab seems to be low, continuous monthly use of ranibizumab for high-risk patients should be judged carefully.

Reducing medicine-induced deterioration and adverse reactions (ReMInDAR) trial: study protocol for a randomised controlled trial in residential aged-care facilities assessing frailty as the primary outcome.

INTRODUCTION: Many medicines have adverse effects which are difficult to detect and frequently go unrecognised. Pharmacist monitoring of changes in signs and symptoms of these adverse effects, which we describe as medicine-induced deterioration, may reduce the risk of developing frailty. The aim of this trial is to determine the effectiveness of a 12-month pharmacist service compared with usual care in reducing medicine-induced deterioration, frailty and adverse reactions in older people living in aged-care facilities in Australia. METHODS AND ANALYSIS: The reducing medicine-induced deterioration and adverse reactions trial is a multicentre, open-label randomised controlled trial. Participants will be recruited from 39 facilities in South Australia and Tasmania. Residents will be included if they are using four or more medicines at the time of recruitment, or taking more than one medicine with anticholinergic or sedative properties. The intervention group will receive a pharmacist assessment which occurs every 8 weeks. The pharmacists will liaise with the participants' general practitioners when medicine-induced deterioration is evident or adverse events are considered serious. The primary outcome is a reduction in medicine-induced deterioration from baseline to 6 and 12 months, as measured by change in frailty index. The secondary outcomes are changes in cognition scores, 24-hour movement behaviour, grip strength, weight, percentage robust, pre-frail and frail classification, rate of adverse medicine events, health-related quality of life and health resource use. The statistical analysis will use mixed-models adjusted for baseline to account for repeated outcome measures. A health economic evaluation will be conducted following trial completion using data collected during the trial. ETHICS AND DISSEMINATION: Ethics approvals have been obtained from the Human Research Ethics Committee of University of South Australia (ID:0000036440) and University of Tasmania (ID:H0017022). A copy of the final report will be provided to the Australian Government Department of Health. TRIAL REGISTRATION NUMBER: Australian and New Zealand Trials Registry ACTRN12618000766213.

CRISTAL: protocol for a cluster randomised, crossover, non-inferiority trial of aspirin compared to low molecular weight heparin for venous thromboembolism prophylaxis in hip or knee arthroplasty, a registry nested study.

INTRODUCTION: Venous thromboembolism (VTE) is a serious complication following hip arthroplasty (HA) and knee arthroplasty (KA). This study aims to determine whether aspirin is non-inferior to low molecular weight heparin (LMWH) in preventing symptomatic VTE following HA and KA. METHODS AND ANALYSIS: This is a cluster randomised, crossover, non-inferiority, trial nested within the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR). The clusters will consist of Australian hospitals performing at least 250 HA and/or KA procedures per annum. All adult patients undergoing HA or KA will be included. The intervention will be aspirin, orally, 85-150 mg daily. The comparator will be LMWH (enoxaparin) 40 mg, subcutaneously, daily. Both drugs will commence within 24 hours postoperatively and continue for 35 days after HA and 14 days after KA. Each hospital will be randomised to commence with aspirin or LMWH and then crossover to the alternative treatment after meeting the recruitment target. Data will be collected through the AOANJRR via patient-reported surveys. The primary outcome is symptomatic VTE within 90 days post surgery, verified by AOANJRR staff. The primary analysis will include only patients undergoing elective primary total hip arthroplasty and total knee arthroplasty for osteoarthritis. Secondary outcomes will include symptomatic VTE for all HA and KA (including partial and revision) within 90 days, readmission, reoperation, major bleeding and death within 90 days and reoperation, death and patient-reported pain, function and health status at 6 months. If aspirin is found to be inferior, a cost-effectiveness analysis will be conducted. The study will aim to recruit 15 562 patients from 31 hospitals. ETHICS AND DISSEMINATION: Ethics approval has been granted. Trial results will be submitted for publication. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12618001879257, pre-results) and is endorsed by the Australia and New Zealand Musculoskeletal Clinical Trials Network.

Persistence with opioids post discharge from hospitalisation for surgery in Australian adults: a retrospective cohort study.

OBJECTIVE: To determine time to opioid cessation post discharge from hospital in persons who had been admitted to hospital for a surgical procedure and were previously naïve to opioids. DESIGN, SETTING AND PARTICIPANTS: Retrospective cohort study using administrative health claims database from the Australian Government Department of Veterans' Affairs (DVA). DVA gold card holders aged between 18 and 100 years who were admitted to hospital for a surgical admission between 1 January 2014 and 30 December 2015 and naïve to opioid therapy prior to admission were included in the study. Gold card holders are eligible for all health services that DVA funds. MAIN OUTCOME MEASURES: The outcome of interest was time to cessation of opioids, with follow-up occurring over 12 months. Cessation was defined as a period without an opioid prescription that was equivalent to three times the estimated supply duration. The proportion who became chronic opioid users was defined as those who continued taking opioids for greater than 90 days post discharge. Cumulative incidence function with death as a competing event was used to determine time to cessation of opioids post discharge. RESULTS: In 2014-2015, 24 854 persons were admitted for a surgical admission. In total 3907 (15.7%) were discharged on opioids. In total 3.9% of those discharged on opioids became chronic users of opioids. The opioid that the patients were most frequently discharged with was oxycodone; oxycodone alone accounted for 43%, while oxycodone with naloxone accounted for 8%. CONCLUSIONS: Opioid initiation post-surgical hospital admission leads to chronic use of opioids in a small percentage of the population. However, given the frequency at which surgical procedures occur, this means that a large number of people in the population may be affected. Post-discharge assessment and follow-up of at-risk patients is important, particularly where psychosocial elements such as anxiety and catastrophising are identified.

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.

Risk of chronic opioid use in older persons with pre-existing anxiety.

OBJECTIVE: Work that has shown a relationship between anxiety and chronic opioid use has not focused on older people specifically, despite the additional risks in older populations. This study aimed to understand whether anxiety prior to opioid initiation increased the likelihood of chronic opioid use over time in persons aged 60 years or older. DESIGN: Administrative claims data were used to calculate time between initiation of opioids and a first chronic episode of opioid use. Patients were classified as having a history of anxiety if they were dispensed medicines in the anxiolytics class or had a hospitalization event for anxiety prior to treatment with an opioid. Proportional hazards models were used to compare the likelihood of experiencing a chronic episode of opioid use between those with and without a history of anxiety. RESULTS: The cohort was 15,000 persons, of which, 5,076 (34 percent) had history of anxiety. Those with anxiety prior to their first opioid dispensing were 30 percent more likely to have an episode of chronic use after adjustment for age, gender, number of comorbidities, and prior surgery (HR = 1.30, 95% CI = 1.16-1.47). The risk of a chronic episode in patients who had surgery prior to initiation of an opioid was 60 percent greater in those with anxiety compared to no anxiety (HR = 1.60, 95% CI = 1.21-2.11) and 24 percent greater in those with anxiety but no prior surgery (HR = 1.24, 95% CI = 1.08-1.42). CONCLUSIONS: A significant proportion of older people will have a chronic episode of opioid use. This risk is increased where a history of anxiety is present.

Prior experience with cardiovascular medicines predicted longer persistence in people initiated to combinations of antihypertensive and lipid-lowering therapies: findings from two Australian cohorts.

PURPOSE: Many studies of persistence involving fixed dose combinations (FDCs) of cardiovascular medicines have not adequately accounted for a user's prior experience with similar medicines. The aim of this research was to assess the effect of prior medicine experience on persistence to combination therapy. PATIENTS AND METHODS: Two retrospective cohort studies were conducted in the complete Pharmaceutical Benefits Scheme prescription claims dataset. Initiation and cessation rates were determined for combinations of: ezetimibe/statin; and amlodipine/statin. Initiators to combinations of these medicines between April and September 2013 were classified according to prescriptions dispensed in the prior 12 months as either: experienced to statin or calcium channel blocker (CCB); or naïve to both classes of medicines. Cohorts were stratified according to formulation initiated: FDC or separate pill combinations (SPC). Cessation of therapy over 12 months was determined using Kaplan-Meier survival analysis. Risk of cessation, adjusted for differences in patient characteristics was assessed using Cox proportional hazard models. RESULTS: There were 12,169 people who initiated combinations of ezetimibe/statin; and 26,848 initiated combinations of amlodipine/statin. A significant proportion of each cohort were naïve initiators: ezetimibe/statin cohort, 1,964 (16.1%) of whom 81.9% initiated a FDC; and amlodipine/statin cohort, 5,022 (18.7%) of whom 55.4% initiated a FDC. Naïve initiators had a significantly higher risk of ceasing therapy than experienced initiators regardless of formulation initiated: ezetimibe/statin cohort, naïve FDC versus experienced FDC HR=3.0 (95% CI 2.8, 3.3) and naïve SPC versus experienced SPC HR=4.4 (95% CI 3.8, 5.2); and amlodipine/statin cohort naïve FDC versus experienced FDC HR=2.0 (95% CI 1.8, 2.2) and naïve SPC versus experienced SPC HR=1.5 (95% CI 1.4, 1.6). CONCLUSION: Prescribers are initiating people to combinations of two cardiovascular medicines without prior experience to at least one medicine in the combination. This is associated with a higher risk of ceasing therapy than when combination therapy is initiated following experience with one component medicine. The use of FDC products does not overcome this risk.

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.

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.

Preoperative medication use and postoperative delirium: a systematic review.

BACKGROUND: Medications are frequently reported as both predisposing factors and inducers of delirium. This review evaluated the available evidence and determined the magnitude of risk of postoperative delirium associated with preoperative medication use. METHODS: A systematic search in Medline and EMBASE was conducted using MeSH terms and keywords for postoperative delirium and medication. Studies which included patients 18 years and older who underwent major surgery were included. The methodological quality of included studies was assessed independently by two authors using the Newcastle-Ottawa quality assessment scale for cohort studies. RESULTS: Twenty-nine studies; 25 prospective cohort, three retrospective cohort and one post hoc analysis of RCT data were included. Only four specifically aimed to assess medicines as an independent predictor of delirium, all other studies included medicines among a number of potential predictors of delirium. Of the studies specifically testing the association with a medication class, preoperative use of beta-blockers (OR = 2.06[1.18-3.60]) in vascular surgery and benzodiazepines RR 2.10 (1.23-3.59) prior to orthopedic surgery were significant. However, evidence is from single studies only. Where medicines were included as one possible factor among many, hypnotics had a similar risk estimate to the benzodiazepine study, with one significant and one non-significant result. Nifedipine use prior to cardiac surgery was found to be significantly associated with delirium. The non-specific grouping of psychoactive medication use preoperatively was generally higher with an associated two-to-seven-fold higher risk of postoperative delirium, while only two studies included narcotics without other agents, with one significant and one non-significant result. CONCLUSIONS: There was a limited number of high quality studies in the literature quantifying the direct association between preoperative medication use and postsurgical delirium. More studies are required to evaluate the association of specific preoperative medications on the risk of postoperative delirium so that comprehensive guidelines for medicine use prior to surgery can be developed to aid delirium prevention. TRIAL REGISTRATION: This systematic review has been registered on PROSPERO International prospective register of systematic reviews (Registration number: CRD42016051245 ).