Opioid analgesia for acute low back pain and neck pain (the OPAL trial): a randomised placebo-controlled trial.

BACKGROUND: Opioid analgesics are commonly used for acute low back pain and neck pain, but supporting efficacy data are scarce. We aimed to investigate the efficacy and safety of a judicious short course of an opioid analgesic for acute low back pain and neck pain. METHODS: OPAL was a triple-blinded, placebo-controlled randomised trial that recruited adults (aged ≥18 years) presenting to one of 157 primary care or emergency department sites in Sydney, NSW, Australia, with 12 weeks or less of low back or neck pain (or both) of at least moderate pain severity. Participants were randomly assigned (1:1) using statistician-generated randomly permuted blocks to guideline-recommended care plus an opioid (oxycodone-naloxone, up to 20 mg oxycodone per day orally) or guideline-recommended care and an identical placebo, for up to 6 weeks. The primary outcome was pain severity at 6 weeks measured with the pain severity subscale of the Brief Pain Inventory (10-point scale), analysed in all eligible participants who provided at least one post-randomisation pain score, by use of a repeated measures linear mixed model. Safety was analysed in all randomly assigned eligible participants. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000775516). FINDINGS: Between Feb 29, 2016, and March 10, 2022, 347 participants were recruited (174 to the opioid group and 173 to the placebo group). 170 (49%) of 346 participants were female and 176 (51%) were male. 33 (19%) of 174 participants in the opioid group and 25 (15%) of 172 in the placebo group had discontinued from the trial by week 6, due to loss to follow-up and participant withdrawals. 151 participants in the opioid group and 159 in the placebo group were included in the primary analysis. Mean pain score at 6 weeks was 2·78 (SE 0·20) in the opioid group versus 2·25 (0·19) in the placebo group (adjusted mean difference 0·53, 95% CI -0·00 to 1·07, p=0·051). 61 (35%) of 174 participants in the opioid group reported at least one adverse event versus 51 (30%) of 172 in the placebo group (p=0·30), but more people in the opioid group reported opioid-related adverse events (eg, 13 [7·5%] of 174 participants in the opioid group reported constipation vs six [3·5%] of 173 in the placebo group). INTERPRETATION: Opioids should not be recommended for acute non-specific low back pain or neck pain given that we found no significant difference in pain severity compared with placebo. This finding calls for a change in the frequent use of opioids for these conditions. FUNDING: National Health and Medical Research Council, University of Sydney Faculty of Medicine and Health, and SafeWork SA.

Geographic variation in sodium-glucose cotransporter 2 inhibitor and glucagon-like peptide-1 receptor agonist use in people with type 2 diabetes in New South Wales, Australia.

AIM: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and cardio-renal outcomes for people with type 2 diabetes (T2D). However, geographic and socio-economic variation in use is not well understood. METHODS: We identified 367 829 New South Wales residents aged ≥40 years who dispensed metformin in 2020 as a proxy for T2D. We estimated the prevalence of use of other glucose-lowering medicines among people with T2D and the prevalence of SGLT2i and GLP-1RA use among people using concomitant T2D therapy (i.e. metformin + another glucose-lowering medicine). We measured the prevalence by small-level geography, stratified by age group, and characterized by remoteness and socio-economic status. RESULTS: The prevalence of SGLT2i (29.7%) and GLP-1RA (8.3%) use in people with T2D aged 40-64 increased with geographic remoteness and in areas of greater socio-economic disadvantage, similar to other glucose-lowering medicines. The prevalence of SGLT2i (55.4%) and GLP-1RA (15.4%) among people using concomitant T2D therapy varied across geographic areas, with lower SGLT2i use in more disadvantaged areas and localized areas of high GLP-1RA use (2.5 times the median). Compared with people aged 40-64 years, the prevalence of SGLT2i and GLP-1RA use was lower in older age groups, but with similar patterns of variation across geographic areas. CONCLUSIONS: The prevalence of SGLT2i and GLP-1RA use varied by geography, probably reflecting a combination of system- and prescriber-level factors. Socio-economic variation in GLP-1RA use was overshadowed by localized patterns of prescribing. Continued monitoring of variation can help shape interventions to optimize use among people who would benefit the most.

A potential novel treatment for cirrhosis-related ascites: Empagliflozin is safe and tolerable in advanced chronic liver disease.

AIMS: Advanced chronic liver disease and advanced chronic liver disease-related ascites have a high mortality. The pharmacological treatment of ascites and fluid overload has changed little over time. Empagliflozin, a sodium-glucose cotransporter type 2 inhibitor is an untested potential novel treatment in cirrhosis, as it has survival benefits in heart failure, which has similar pathophysiological fluid overload mechanisms. Before investigating empagliflozin's potential benefit in cirrhosis, its safety must be addressed. METHODS: Ten participants (five each with compensated or decompensated advanced chronic liver disease, based on Child-Pugh class) received empagliflozin 10 mg orally daily for 4 weeks with 2 weeks follow-up. Empagliflozin safety, pharmacokinetics and pharmacodynamics were investigated. RESULTS: In total, eight patients (80%) reported an adverse event, and three patients (30%) experienced a serious adverse event, one of which was attributed to empagliflozin. Overall, the frequency of adverse events was similar to previous phase 3 trials of gliflozins. Higher plasma empagliflozin concentrations did not significantly increase the risk of adverse events. CONCLUSIONS: Four-week treatment with empagliflozin was safe and well tolerated in patients with advanced chronic liver disease. These preliminary data support assessment of long-term treatment on disease-related and mortality outcomes in patients with cirrhosis through randomized control trials.

Estimation of adherence to urate-lowering therapy in people living with gout using Australia's Pharmaceutical Benefits Scheme and patient-reported dosing.

AIMS: The aim of this study was to estimate adherence to urate-lowering therapy (ULT), predominately allopurinol, from Australia's Pharmaceutical Benefits Scheme (PBS) claims database in association with (1) patient-reported doses and (2) World Health Organization's (WHO) defined daily doses (DDD), namely, allopurinol (400 mg/day) or febuxostat (80 mg/day). METHODS: Proportion of days covered (PDC) was calculated in 108 Gout App (Gout APP) trial participants with at least two recorded ULT dispensings in an approximately 12-month period before provision of intervention or control apps. Adherence was defined as PDC ≥80%. We measured the correlation between the two methods of calculating PDC using a Wilcoxon signed rank test. Agreement between ULT-taking status (self-reports) and ULT-dispensed status (PBS records) was tested with Cohen's kappa (κ), and positive and negative percent agreement. RESULTS: Allopurinol was prescribed in 93.5% of participants taking ULT. Their self-reported mean daily dose (SD) was 291 (167) mg/day. Mean PDC (SD) for allopurinol was 83% (21%) calculated using self-reported dose, and 63% (24%) using WHO's DDD. Sixty-three percent of allopurinol users were identified as adherent (PDC ≥80%) using self-reported dose. There was good agreement between self-reported ULT use and PBS dispensing claims (κ = 0.708, P < .001; positive percent agreement = 90%, negative percent agreement = 82%). CONCLUSIONS: Participant-reported allopurinol daily doses, in addition to PBS dispensing claims, may enhance confidence in estimating PDC and adherence compared to using DDD. This approach improves adherence estimations from pharmaceutical claims datasets for medications where daily doses vary between individuals or where there is a wide therapeutic dose range.

Evaluation of Published Population Pharmacokinetic Models to Inform Tacrolimus Therapy in Adult Lung Transplant Recipients.

BACKGROUND: The applicability of currently available tacrolimus population pharmacokinetic models in guiding dosing for lung transplant recipients is unclear. In this study, the predictive performance of relevant tacrolimus population pharmacokinetic models was evaluated for adult lung transplant recipients. METHODS: Data from 43 lung transplant recipients (1021 tacrolimus concentrations) administered an immediate-release oral formulation of tacrolimus were used to evaluate the predictive performance of 17 published population pharmacokinetic models for tacrolimus. Data were collected from immediately after transplantation up to 90 days after transplantation. Model performance was evaluated using (1) prediction-based assessments (bias and imprecision) of individual predicted tacrolimus concentrations at the fourth dosing based on 1 to 3 previous dosings and (2) simulation-based assessment (prediction-corrected visual predictive check; pcVPC). Both assessments were stratified based on concomitant azole antifungal use. Model performance was clinically acceptable if the bias was within ±20%, imprecision was ≤20%, and the 95% confidence interval of bias crossed zero. RESULTS: In the presence of concomitant antifungal therapy, no model showed acceptable performance in predicting tacrolimus concentrations at the fourth dosing (n = 33), and pcVPC plots displayed poor model fit to the data set. However, this fit slightly improved in the absence of azole antifungal use, where 4 models showed acceptable performance in predicting tacrolimus concentrations at the fourth dosing (n = 33). CONCLUSIONS: Although none of the evaluated models were appropriate in guiding tacrolimus dosing in lung transplant recipients receiving concomitant azole antifungal therapy, 4 of these models displayed potential applicability in guiding dosing in recipients not receiving concomitant azole antifungal therapy. However, further model refinement is required before the widespread implementation of such models in clinical practice.

'We are somehow fixated on this being a diabetes drug': a qualitative study exploring the views of cardiologists and nephrologists about sodium-glucose cotransporter 2 inhibitor initiation.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are now indicated for heart failure and chronic kidney disease (CKD), irrespective of the presence of diabetes. Hence, cardiologists and nephrologists have an important role in initiating these drugs. AIMS: To explore cardiologists' and nephrologists' perspectives regarding initiating SGLT2i and their safety monitoring practices when initiating SGLT2i. METHODS: Purposive and snowball approaches were used to recruit participants working in diverse areas in New South Wales, Australia. Semi-structured interviews were conducted with 12 cardiologists and 12 nephrologists. Interviews were conducted until thematic saturation was reached. Emergent themes were identified from transcripts. An iterative general inductive approach was used for data analysis. RESULTS: There was a reluctance amongst most non-heart-failure subspecialist cardiologists to initiate SGLT2i. Reasons included the perception of SGLT2i as diabetes drugs, concern about side effects, lack of experience and issues with follow-up. In contrast, nephrologists reported feeling confident to initiate SGLT2i. Nephrologists varied in their opinions about the severity of CKD at which SGLT2i initiation was reasonable and monitoring of renal function following initiation. Government subsidisation was an important factor in the decision to prescribe SGLT2i to people without diabetes. CONCLUSIONS: Our findings highlight the complex transition from the perception of SGLT2i as diabetes drugs to cardiometabolic and reno-protective agents. Interdisciplinary collaboration may enable greater confidence amongst specialists to initiate SGLT2i, including in patients with CKD. Additionally, there is a need for clear and detailed guidance about SGLT2i prescription in patients with renal dysfunction and renal function monitoring following SGLT2i initiation.

The experiences and perspectives of people with gout on urate self-monitoring.

INTRODUCTION: Gout management remains suboptimal despite safe and effective urate-lowering therapy. Self-monitoring of urate may improve gout management, however, the acceptability of urate self-monitoring by people with gout is unknown. The aim of this study was to explore the experiences of urate self-monitoring in people with gout. METHODS: Semistructured interviews were conducted with people taking urate-lowering therapy (N = 30) in a 12-month trial of urate self-monitoring in rural and urban Australia. Interviews covered the experience of monitoring and its effect on gout self-management. Deidentified transcripts were analysed thematically. RESULTS: Participants valued the ability to self-monitor and gain more understanding of urate control compared with the annual monitoring ordered by their doctors. Participants indicated that self-monitoring at home was easy, convenient and informed gout self-management behaviours such as dietary modifications, hydration, exercise and medication routines. Many participants self-monitored to understand urate concentration changes in response to feeling a gout flare was imminent or whether their behaviours, for example, alcohol intake, increased the risk of a gout flare. Urate concentrations were shared with doctors mainly when they were above target to seek management support, and this led to allopurinol dose increases in some cases. CONCLUSION: Urate self-monitoring was viewed by people with gout as convenient and useful for independent management of gout. They believed self-monitoring achieved better gout control with a less restricted lifestyle. Urate data was shared with doctors at the patient's discretion and helped inform clinical decisions, such as allopurinol dose changes. Further research on implementing urate self-monitoring in routine care would enable an evaluation of its impact on medication adherence and clinical outcomes, as well as inform gout management guidelines. PATIENT OR PUBLIC CONTRIBUTION: One person with gout, who was not a participant, was involved in the study design by providing feedback and pilot testing the semistructured interview guide. In response to their feedback, subsequent modifications to the interview guide were made to improve the understandability of the questions from a patient perspective. No additional questions were suggested.

Effects of Allopurinol on the Progression of Chronic Kidney Disease.

BACKGROUND: Elevated serum urate levels are associated with progression of chronic kidney disease. Whether urate-lowering treatment with allopurinol can attenuate the decline of the estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease who are at risk for progression is not known. METHODS: In this randomized, controlled trial, we randomly assigned adults with stage 3 or 4 chronic kidney disease and no history of gout who had a urinary albumin:creatinine ratio of 265 or higher (with albumin measured in milligrams and creatinine in grams) or an eGFR decrease of at least 3.0 ml per minute per 1.73 m2 of body-surface area in the preceding year to receive allopurinol (100 to 300 mg daily) or placebo. The primary outcome was the change in eGFR from randomization to week 104, calculated with the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. RESULTS: Enrollment was stopped because of slow recruitment after 369 of 620 intended patients were randomly assigned to receive allopurinol (185 patients) or placebo (184 patients). Three patients per group withdrew immediately after randomization. The remaining 363 patients (mean eGFR, 31.7 ml per minute per 1.73 m2; median urine albumin:creatinine ratio, 716.9; mean serum urate level, 8.2 mg per deciliter) were included in the assessment of the primary outcome. The change in eGFR did not differ significantly between the allopurinol group and the placebo group (-3.33 ml per minute per 1.73 m2 per year [95% confidence interval {CI}, -4.11 to -2.55] and -3.23 ml per minute per 1.73 m2 per year [95% CI, -3.98 to -2.47], respectively; mean difference, -0.10 ml per minute per 1.73 m2 per year [95% CI, -1.18 to 0.97]; P = 0.85). Serious adverse events were reported in 84 of 182 patients (46%) in the allopurinol group and in 79 of 181 patients (44%) in the placebo group. CONCLUSIONS: In patients with chronic kidney disease and a high risk of progression, urate-lowering treatment with allopurinol did not slow the decline in eGFR as compared with placebo. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; CKD-FIX Australian New Zealand Clinical Trials Registry number, ACTRN12611000791932.).

Patient factors and health outcomes associated with illness perceptions in people with gout.

OBJECTIVE: Illness perceptions are views and beliefs formed in response to a health threat which may influence self-management behaviours and chronic disease outcomes. Despite effective medication, sub-optimal outcomes in gout are common. This study aimed to quantitatively investigate illness perceptions in gout to examine how illness perceptions relate to health outcomes. METHODS: Data were obtained from a randomised-controlled trial where people with gout (n = 493) completed surveys measuring illness perceptions (Brief Illness Perception Questionnaire (B-IPQ)), gout flares, medication adherence, health-related quality of life, healthcare utilisation and productivity, alongside serum urate blood tests at baseline, 6- and 12-month follow-ups. Multivariable linear regression identified patient factors independently associated with each B-IPQ item score. Logistic and linear regression, adjusted for age and sex, determined whether baseline B-IPQ items could predict current and future health outcomes. RESULTS: Younger individuals and those with severe gout were more likely to experience pessimistic illness perceptions at baseline. Optimistic illness perceptions were associated with lower odds of having at least one flare in the preceding 6 months. Every 1-point increase in B-IPQ treatment control, indicating the optimistic view that gout is treatable, decreased the odds of a recent flare prior to baseline by 33% (OR : 0.67; 95%CI : 0.53,0.85; p< 0.001) and prior to 12-month follow-up by 15% (OR : 0.85; 95%CI : 0.76,0.96; p= 0.01). Pessimistic illness perceptions also predicted poorer medication adherence, health-related quality of life and productivity but not serum urate levels. CONCLUSION: Modifying pessimistic illness perceptions, including, but not limited to, patient education, may promote prudent self-management behaviours and better outcomes in gout. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry; https://www.anzctr.org.au/; ACTRN12616000455460.

Blood, dose recommendation reports and phone calls: Experiences of a therapeutic drug monitoring advisory service for vancomycin.

Dose-prediction software is recommended to enable area under the curve over 24 h (AUC24 )-guided dosing of the antibiotic vancomycin. However, uncertainty remains about how best to implement software in the clinic. We describe the activity, over 18 months, of a consultative therapeutic drug monitoring Advisory Service (the Service) for vancomycin that used dose-prediction software alongside clinical expertise, identifying factors that influence attainment of therapeutic targets. Of the 408 vancomycin dose reports provided for 182 courses of therapy, most (57%) recommended a dose change. The majority (82.8%, 193/233) of recommended dose adjustments were accepted by treating teams. A dose report was not published for 125 courses of therapy, with reasons including patient in intensive care unit or service error. An estimated 26.6 h of staff time was allocated to Service activities each month. Publication of a dose report facilitated attainment of therapeutic targets (P = .002). Software integration could improve Service outcomes, avoiding errors and reducing staff workload.

Optimizing adherence to allopurinol for gout: patients' perspectives.

AIMS: Poor adherence to allopurinol among people with gout contributes to suboptimal gout management. This study sought to understand the facilitators and barriers to allopurinol adherence across the three stages of medication adherence, and patient perspectives on strategies to improve adherence, including self-monitoring urate concentration. METHODS: Semi-structured interviews were conducted with 26 people with gout, previously or currently taking allopurinol. De-identified verbatim transcripts were thematically analysed using an inductive and deductive approach. RESULTS: Facilitators of adherence during allopurinol initiation were motivation to prevent gout flares and trust in the advice of their healthcare professionals (HCPs). Reluctance to commence long-term medication was a barrier to allopurinol initiation. Believing in the effectiveness and necessity of allopurinol and reminder systems were facilitators of implementation. Barriers to implementation included forgetfulness, gout flares and limited feedback on allopurinol's effectiveness. Patients discontinued therapy when allopurinol was perceived as ineffective or unnecessary. Discontinuation coincided with patients experiencing gout flares while adhering to allopurinol and receiving suboptimal advice about gout management. Patients identified receiving accurate advice from HCPs and regular urate monitoring for feedback on allopurinol's effectiveness as potential strategies to improve adherence. Perceived benefits of self-monitoring urate as a strategy to promote adherence included the ability to self-manage gout and make informed decisions about allopurinol therapy with their HCP. CONCLUSION: Patient perceptions of the effectiveness and necessity of allopurinol influenced intentional adherence during medication initiation, implementation and discontinuation. Strategies that inform patients of their urate control and provide accurate medical advice have the potential to improve adherence to allopurinol.

Adaptation of a population pharmacokinetic model to inform tacrolimus therapy in heart transplant recipients.

AIM: Existing tacrolimus population pharmacokinetic models are unsuitable for guiding tacrolimus dosing in heart transplant recipients. This study aimed to develop and evaluate a population pharmacokinetic model for tacrolimus in heart transplant recipients that considers the tacrolimus-azole antifungal interaction. METHODS: Data from heart transplant recipients (n = 87) administered the oral immediate-release formulation of tacrolimus (Prograf®) were collected. Routine drug monitoring data, principally trough concentrations, were used for model building (n = 1099). A published tacrolimus model was used to inform the estimation of Ka , V2 /F, Q/F and V3 /F. The effect of concomitant azole antifungal use on tacrolimus CL/F was quantified. Fat-free mass was implemented as a covariate on CL/F, V2 /F, V3 /F and Q/F on an allometry scale. Subsequently, stepwise covariate modelling was performed. Significant covariates influencing tacrolimus CL/F were included in the final model. Robustness of the final model was confirmed using prediction-corrected visual predictive check (pcVPC). The final model was externally evaluated for prediction of tacrolimus concentrations of the fourth dosing occasion (n = 87) from one to three prior dosing occasions. RESULTS: Concomitant azole antifungal therapy reduced tacrolimus CL/F by 80%. Haematocrit (∆OFV = -44, P < .001) was included in the final model. The pcVPC of the final model displayed good model adequacy. One recent drug concentration is sufficient for the model to guide tacrolimus dosing. CONCLUSION: A population pharmacokinetic model that adequately describes tacrolimus pharmacokinetics in heart transplant recipients, considering the tacrolimus-azole antifungal interaction was developed. Prospective evaluation is required to assess its clinical utility to improve patient outcomes.

The safe use of metformin in heart failure patients both with and without T2DM: A cross-sectional and longitudinal study.

AIMS: This study investigated the safe use of metformin in patients with (1) type 2 diabetes mellitus (T2DM) and heart failure on metformin, and (2) heart failure without T2DM and metformin naïve. METHODS: Two prospective studies on heart failure patients were undertaken. The first was a cross-sectional study with two patient cohorts, one with T2DM on metformin (n = 44) and one without T2DM metformin naive (n = 47). The second was a 12-week interventional study of patients without T2DM (n = 27) where metformin (500 mg immediate release, twice daily) was prescribed. Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were compared between cohorts. Univariable and multivariable analysis analysed the effects of variables on plasma lactate concentrations. RESULTS: Plasma metformin and lactate concentrations mostly (99.9%) remained below safety thresholds (5 mg/L and 5 mmol/L, respectively). Metformin concentration had no significant relationship with lactic acidosis safety markers. In the interventional study, New York Heart Association (NYHA) II (P < .03) and III (P < .001) grading was associated with higher plasma lactate concentrations, whereas male sex was associated with 47% higher plasma lactate concentrations (P < .05). The pharmacokinetics of heart failure patients with and without T2DM were similar. CONCLUSIONS: We observed no unsafe plasma lactate concentrations in patients with heart failure treated with metformin. Metformin exposure did not influence plasma lactate concentrations, but NYHA class and sex did. The pharmacokinetics of metformin in heart failure patients are similar irrespective of T2DM. These findings may support the safe use of metformin in heart failure patients with and without T2DM.

Evaluation of the Prescribing Skills Assessment implementation, performance and medical student experience in Australia and New Zealand.

AIMS: The UK Prescribing Safety Assessment was modified for use in Australia and New Zealand (ANZ) as the Prescribing Skills Assessment (PSA). We investigated the implementation, student performance and acceptability of the ANZ PSA for final-year medical students. METHODS: This study used a mixed-method approach involving student data (n = 6440) for 2017-2019 (PSA overall score and 8 domain subscores). Data were also aggregated by medical school and included student evaluation survey results. Quantitative data were analysed using descriptive and multivariate analyses. The pass rate was established by a modified Angoff method. Thematic analyses of open-ended survey comments were conducted. RESULTS: The average pass rate was slightly higher in 2017 (89%) which used a different examination to 2018 (85%) and 2019 (86%). Little difference was identified between schools for the PSA overall performance or domain subscores. There was low intercorrelation between subscores. Most students provided positive feedback about the PSA regarding the interface and clarity of questions, but an average of 35% reported insufficient time for completion. Further, 70% on average felt unprepared by their school curricula for the PSA, which is in part explained by the low prescribing experience; 69% reported completing ≤10 prescriptions during training. CONCLUSION: The ANZ PSA was associated with high pass rates and acceptability, although student preparedness was highlighted as a concern for further investigation. We demonstrate how a collaboration of medical schools can adapt a medical education assessment resource (UK PSA) as a means for fulfilling an unmet need.

Trends in use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) in Australia in the era of increased evidence of their cardiovascular benefits (2014-2022).

PURPOSE: To investigate trends in SGLT2i and GLP-1RA use in Australia in the era of increased evidence of their cardiovascular benefits. METHODS: We used national dispensing claims for a 10% random sample of Australians to estimate the number of prevalent and new users (no dispensing in the prior year) of SGLT2i or GLP-1RA per month from January 2014 to July 2022. We assessed prescriber specialty and prior use of other antidiabetic and cardiovascular medicines as a proxy for evidence of type 2 diabetes (T2D) and cardiovascular conditions, respectively. RESULTS: We found a large increase in the number of prevalent users (216-fold for SGLT2i; 11-fold for GLP-1RA); in July 2022 approximately 250,000 Australians were dispensed SGLT2i and 120,000 GLP-1RA. Most new users of SGLT2i or GLP-1RA had evidence of both T2D and cardiovascular conditions, although from 2022 onwards, approximately one in five new users of SGLT2i did not have T2D. The proportion of new users initiating SGLT2i by cardiologists increased after 2021, reaching 10.0% of initiations in July 2022. Among new users with evidence of cardiovascular conditions, empagliflozin was the most commonly prescribed SGLT2i, while dulaglutide or semaglutide was the most common GLP-1RA. CONCLUSION: SGLT2i and GLP-1RA use is increasing in Australia, particularly in populations with higher cardiovascular risk. The increased use of SGLT2i among people without evidence of T2D suggests that best-evidence medicines are adopted in Australia across specialties, aligning with new evidence and expanding indications.

Medication use and hospital-acquired acute kidney injury: an electronic health record-based study.

BACKGROUND AND AIMS: Medications remain an important contributor to the development of acute kidney injury (AKI). This study aimed to examine associations between (i) administration of medications known to reduce glomerular filtration rate (GFR), that is, GFR modifiers and subsequent hospital-acquired AKI; and (ii) potentially medication-related AKI and patient adverse outcomes. METHODS: A retrospective cohort study utilising electronic health record data of patients admitted to a tertiary hospital in Australia in 2015. Timing of medication administration was compared with timing of AKI development. AKI cases were identified using an algorithm based on serum creatinine level changes. Multilevel regression models were applied with adjustment for relevant demographic and clinical factors. RESULTS: Among 11 503 admissions, AKI was identified in 955 patients (8.3%) and 637 (66.7% of 955) were preceded by administration of a GFR modifier. Patients without prior AKI were 17% more likely to develop AKI after administration of these medications (adjusted odds ratio 1.17, 95% confidence interval (CI) 1.003-1.37). Older age and comorbidity with diabetes, acute myocardial infarction, peripheral vascular disease, liver cirrhosis and multiple myeloma were also significant predictors. Patients with potentially medication-related AKI were 11.69 times more likely to die in hospital (95% CI 7.84-17.43) and stayed 3.49 times longer in hospital (95% CI 3.26-3.73), compared with those without AKI. CONCLUSIONS: Administration of medications contributing to the reduction of GFR is associated with an increased risk of hospital-acquired AKI and worse patient outcomes. Caution is required when prescribing these medications to patients at risk of developing AKI, and monitoring patients for deterioration is needed if administered.

Optimizing the dosing of vancomycin in patients receiving intermittent haemodialysis with low-flux filters, and the potential impact of dosing software.

AIM: Iterative approaches to vancomycin dosing (e.g., dosing when trough concentrations <15-20 mg/L) can be inadequate. Computer-guided dosing may be superior but has not been evaluated in patients with kidney failure receiving replacement therapy. We evaluated vancomycin concentrations using a hospital protocol and a pharmacokinetic software. We measured vancomycin clearance by the FX8 low-flux filter because data are absent. METHODS: We retrospectively reviewed records of adults with kidney failure requiring replacement therapy receiving vancomycin and dialysed with the FX8 low-flux filter, and calculated the proportion of pre-dialysis concentrations that were within, above or below a specified range. One and two-compartment models in the pharmacokinetic software were assessed by computing mean prediction error (MPE) and root mean square error (RMSE) of observed versus predicted concentrations. Vancomycin extracorporeal clearance was prospectively determined using the extraction method. RESULTS: In 24 patients (34 courses; 139 paired observed and predicted concentrations), 62/139 (45%) pre-dialysis concentrations were 15-25 mg/L, 29/139 (21%) were above, and 48/139 (35%) were below. MPE for the one-compartment model was -0.2 mg/L, RMSE 5.3 mg/L. MPE for the two-compartment model was 2.0 mg/L, RMSE 5.6 mg/L. Excluding the first paired concentrations, the subsequent MPE (n = 105) using one-compartment model was -0.5 mg/L, RMSE 5.6 mg/L. The MPE for the two-compartment model was 2.1 mg/L, RMSE 5.8 mg/L. The median extracorporeal clearance was 70.7 mL/min (range: 10.3-130.3; n = 22). CONCLUSIONS: Vancomycin dosing was suboptimal and the pharmacokinetic software was not sufficiently predictive. These may improve with a loading dose. The substantial removal of vancomycin by low-flux filters is not accounted for by the models tested.

Influence of Inflammatory Cytokines IL-1ß and IFNγ on Sarcoplasmic Aggregation of p62 and TDP-43 in Myotubes.

Skeletal muscle of patients with sporadic inclusion body myositis (sIBM) presents with inflammation, including upregulation of inflammatory cytokines such as interferon γ (IFNγ). Non-inflammatory features are also observed, like the sarcoplasmic accumulation of proteins including TDP-43 and p62. This study aimed to investigate the effect of IFNγ and interleukin 1-ß (IL-1ß) on TDP-43 and p62 aggregation in vitro. Primary human myotubes were treated with IL-1ß (20 ng/mL) and IFNγ (750 ng/mL) separately or combined for 48 hr. Sarcoplasmic TDP-43 aggregates and p62 puncta were assessed using image analysis for size, frequency, and colocalization with each other. Total protein expression of TDP-43, p62 and LC3 was assessed using western blotting. The subcellular localization of TDP-43 was also analyzed using image analysis. Combined IL-1ß and IFNγ treatment increased puncta size of p62 compared to control (0.49 ± 0.13 µm2 versus 0.28 ± 0.06 µm2), without affecting puncta frequency or p62 expression but with an increased LC3II/LC3I ratio, suggesting autophagic alterations. IL-1ß or IFNγ did not alter p62 puncta size or frequency, suggesting a combined insult of multiple inflammatory mediators is necessary to cause p62 alterations. IL-1ß increased p62 protein expression in an autophagy-independent manner. None of the cytokine treatments affected TDP-43 protein expression, size, or frequency of TDP-43 aggregates or localization, suggesting IL-1ß and IFNγ may influence TDP-43 processing in human skeletal muscle cells. TDP-43 was localized to the sarcoplasm under control conditions, suggesting this may not be a pathological feature. Overall, sIBM-like TDP-43/p62 features were not triggered by IL-1ß and/or IFNγ.

Is evidence of effectiveness a driver for clinical decision support selection? A qualitative descriptive study of senior hospital staff.

Limited research has focused on understanding if and how evidence of health information technology (HIT) effectiveness drives the selection and implementation of technologies in practice. This study aimed to explore the views of senior hospital staff on the role evidence plays in the selection and implementation of HIT, with a particular focus on clinical decision support (CDS) alerts in electronic medication management systems. A qualitative descriptive design was used. Twenty senior hospital staff from six Australian hospitals in New South Wales and Queensland took part in a semistructured interview. Interviews were audio-recorded and transcribed, and a general inductive content analysis approach was used to identify themes. Participants acknowledged the importance of an evidence base, but reported that selection of CDS alerts, and HIT more broadly, was rarely underpinned by evidence that technologies improve patient care. Instead, investments in technologies were guided by the expectation that benefits will be achieved, bolstered by vendor assurances, and a perception that implementation of HIT is unavoidable. Postponing implementation of a technology until an evidence base is available was not always feasible. Although some technologies were seen as not requiring an evidence base, stakeholders viewed evidence as extremely valuable for informing decisions about selection of CDS alerts. In the absence of evidence, evaluation or monitoring of technologies postimplementation is critical, particularly to identify new errors or risks associated with HIT implementation and use. Increased transparency from vendors, with technology evaluation outcomes made directly available to healthcare organizations, may result in less reliance on logic, intuition, and vendor assertions and more evidence-based selection of HIT.

Ongoing challenges of off-label prescribing.

Off-label prescribing refers to prescribing that is not concordant with the indications, doses, routes of administration or patient groups included in the Australian approved product information. Off-label prescribing is common, especially for vulnerable patient groups who tend to be excluded from clinical trials, such as children and pregnant women. There may be increased risk of prescriber liability if the patient experiences an adverse event following off-label prescription, particularly when supporting evidence or guidelines are lacking. There may be additional costs to the patient if the medicine is not subsidised for the off-label indication. Prescribers should ensure patients are aware when a medicine is being prescribed off label, and informed of potential benefits and harms. Alternative pathways for approval of new indications, doses and patient groups may reduce the need for off-label prescribing.