Oxycodone initiation in Australia (2014-2018): Sociodemographic factors and preceding health service use.

AIMS: Oxycodone is the most commonly prescribed strong opioid in Australia. This study describes health service antecedents and sociodemographic factors associated with oxycodone initiation. METHODS: Population-based new user cohort study linking medicine dispensings, hospitalizations, emergency department visits, medical services and cancer notifications from New South Wales (NSW) for 2014-2018. New users had no dispensings of any opioid in the preceding year. We analysed health service use in the 5 days preceding initiation and proportion of people on treatment over 1 year and fitted an area-based, multivariable initiation model with sociodemographic covariates. RESULTS: Oxycodone accounted for 30% of opioid initiations. Annually, 3% of the NSW population initiated oxycodone, and 5-6% were prevalent users; the new user cohort comprised 830 963 people. Discharge from hospital (39.3%), therapeutic procedures (21.4%) and emergency department visits (19.7%) were common; a hospital admission for injury (6.0%) or a past-year history of cancer (7.2%) were less common. At 1 year after initiation, 4.6% of people were using oxycodone. In the multivariable model, new use of oxycodone increased with age and was higher for people outside major cities, for example, an incidence rate ratio of 1.43 (95% confidence interval 1.36-1.51) for inner regional areas relative to major cities; there was no evidence of variation in rates of new use by social disadvantage. CONCLUSION: About half of new oxycodone use in NSW was preceded by a recent episode of hospital care or a therapeutic procedure. Higher rates of oxycodone initiation in rural and regional areas were not explained by sociodemographic factors.

A phase 3 double-blind study of the addition of tocilizumab vs placebo to cyclosporin/methotrexate GVHD prophylaxis.

We determined the efficacy of tocilizumab (TCZ) in preventing grade 2-4 acute graft-versus-host disease (aGVHD) in patients with acute leukemia or myelodysplasia undergoing matched sibling donor (MSD) or volunteer unrelated donor (VUD) allogeneic stem cell transplantation after myeloablative or reduced-intensity conditioning across 5 Australian centers. A total of 145 patients (50 MSD, 95 VUD) were randomly assigned to placebo or TCZ on day -1. All patients received T-cell-replete peripheral blood stem cell grafts and graft-versus-host disease (GVHD) prophylaxis with cyclosporin/methotrexate. A planned substudy analyzed the VUD cohort. With a median follow-up of 746 days, the incidence of grade 2-4 aGVHD at day 100 for the entire cohort was 36% for placebo vs 27% for TCZ (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.38-1.26; P = .23) and 45% vs 32% (HR, 0.61; 95% CI, 0.31-1.22; P = .16) for the VUD subgroup. The incidence of grade 2-4 aGVHD at day 180 for the entire cohort was 40% for placebo vs 29% for TCZ (HR, 0.68; 95% CI, 0.38-1.22; P = .19) and 48% vs 32% (HR, 0.59; 95% CI, 0.30-1.16; P = .13) for the VUD subgroup. Reductions in aGVHD were predominantly in grade 2 disease. For the entire cohort, transplant-related mortality occurred in 8% vs 11% of placebo-treated vs TCZ-treated patients, respectively (P = .56), and overall survival was 79% vs 71% (P = .27). Median day to neutrophil and platelet engraftment was delayed by 2 to 3 days in TCZ-treated patients, whereas liver toxicity and infectious complications were similar between groups. In this phase 3 randomized double-blind trial, TCZ showed nonsignificant trends toward reduced incidence of grade 2-4 aGVHD in recipients from HLA-matched VUDs but no improvements in long term-survival.

A data-informed approach using individualised dispensing patterns to estimate medicine exposure periods and dose from pharmaceutical claims data.

Pharmaceutical claims data are often used as the primary information source to define medicine exposure periods in pharmacoepidemiological studies. However, often critical information on directions for use and the intended duration of medicine supply are not available. In the absence of this information, alternative approaches are needed to support the assignment of exposure periods. This study summarises the key methods commonly used to estimate medicine exposure periods and dose from pharmaceutical claims data; and describes a method using individualised dispensing patterns to define time-dependent estimates of medicine exposure and dose. This method extends on important features of existing methods and also accounts for recent changes in an individual's medicine use. Specifically, this method constructs medicine exposure periods and estimates the dose used by considering characteristics from an individual's prior dispensings, accounting for the time between prior dispensings and the amount supplied at prior dispensings. Guidance on the practical applications of this method is also provided. Although developed primarily for application to databases, which do not contain duration of supply or dose information, use of this method may also facilitate investigations when such information is available and there is a need to consider individualised and/or changing dosing regimens. By shifting the reliance on prescribed duration and dose to determine exposure and dose estimates, individualised dispensing information is used to estimate patterns of exposure and dose for an individual. Reflecting real-world individualised use of medicines with complex and variable dosing regimens, this method offers a pragmatic approach that can be applied to all medicine classes.

The Effect of Renal Replacement Therapy and Antibiotic Dose on Antibiotic Concentrations in Critically Ill Patients: Data From the Multinational Sampling Antibiotics in Renal Replacement Therapy Study.

BACKGROUND: The optimal dosing of antibiotics in critically ill patients receiving renal replacement therapy (RRT) remains unclear. In this study, we describe the variability in RRT techniques and antibiotic dosing in critically ill patients receiving RRT and relate observed trough antibiotic concentrations to optimal targets. METHODS: We performed a prospective, observational, multinational, pharmacokinetic study in 29 intensive care units from 14 countries. We collected demographic, clinical, and RRT data. We measured trough antibiotic concentrations of meropenem, piperacillin-tazobactam, and vancomycin and related them to high- and low-target trough concentrations. RESULTS: We studied 381 patients and obtained 508 trough antibiotic concentrations. There was wide variability (4-8-fold) in antibiotic dosing regimens, RRT prescription, and estimated endogenous renal function. The overall median estimated total renal clearance (eTRCL) was 50 mL/minute (interquartile range [IQR], 35-65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (P < .05). The median (IQR) trough concentration for meropenem was 12.1 mg/L (7.9-18.8), piperacillin was 78.6 mg/L (49.5-127.3), tazobactam was 9.5 mg/L (6.3-14.2), and vancomycin was 14.3 mg/L (11.6-21.8). Trough concentrations failed to meet optimal higher limits in 26%, 36%, and 72% and optimal lower limits in 4%, 4%, and 55% of patients for meropenem, piperacillin, and vancomycin, respectively. CONCLUSIONS: In critically ill patients treated with RRT, antibiotic dosing regimens, RRT prescription, and eTRCL varied markedly and resulted in highly variable antibiotic concentrations that failed to meet therapeutic targets in many patients.

Temporal trends in co-morbidities and cardiometabolic risk factors at the time of type 2 diabetes diagnosis in the UK.

AIM: To evaluate temporal patterns in co-morbidities, cardiometabolic risk factors and a high atherosclerotic cardiovascular disease (ASCVD) risk population at type 2 diabetes (T2D) diagnosis by age groups and sex. MATERIALS AND METHODS: From the UK primary care database, 248,619 people with a new diagnosis of T2D during 2005-2016 were identified. Among people without ASCVD, high ASCVD risk was defined as two or more of current smoker, grade 2+ obesity, hypertension, dyslipidaemia or microvascular disease. Cardiometabolic multimorbidity (CMM) was defined as two or more of cardiovascular disease, microvascular disease, hypertension, dyslipidaemia, grade 2+ obesity or cancer. Temporal patterns in the distribution of cardiometabolic risk factors were evaluated. RESULTS: While the prevalence of ASCVD was stable over time (approximately 18%), 50% were identified to have a high ASCVD risk (26% and 38% in the 18-39 and 40-49 years age groups, respectively), with an increasing trend across all age groups. Overall, 51% had CMM at diagnosis, increasing during 2005-2016 for the 18-39 years age group by 14%-17%, for the 40-49 years age group by 27%-33%, for the 50-59 years age group by 41%-50%, for the 60-69 years age group by 56%-65%, and for the 70-79 years age group by 65%-80%. People with young-onset T2D had significantly higher HbA1c, body mass index and lipids at diagnosis (all p < .01). The proportions with an HbA1c of 7.5% or higher in the 18-39 and 40-49 years age groups were 58% and 54%, respectively, significantly and consistently higher over the last decade compared with those aged 50 years or older, with males having higher proportions of 15-26 and 10-18 percentage points, respectively, compared with females. CONCLUSIONS: CMM and high ASCVD risk have been increasing consistently across all age groups and in both sex, in particular CMM in those aged younger than 50 years. Our findings indicate that the European Society of Cardiology-European Association for the Study of Diabetes recommendations need to change to consider people with young-onset T2D as a high-risk group, as recommended in the Primary Care Diabetes Europe position statement.

Validation of the modified Glasgow Prognostic Score (mGPS) in recurrent ovarian cancer (ROC) - Analysis of patients enrolled in the GCIG Symptom Benefit Study (SBS).

BACKGROUND: Modified Glasgow Prognostic Score (mGPS) is predictive of survival in many advanced cancers, but has not been evaluated in recurrent ovarian cancer (ROC). The aim was to determine validity of mGPS in ROC, investigate its associations with health related quality of life (HRQL) and ECOG performance status (PS). METHODS: mGPS is based on serum C reactive protein (CRP) and albumin, with scores ranging from 0 (least) to 2 (most). HRQL was measured with EORTC QLQ C-30 and OV-28. χ2 tests for trend were used to examine the relationship between HRQL, PS and mGPS. Cox proportional hazards regression was used to assess associations between mGPS, HRQL, clinicopathological factors, and overall survival (OS). RESULTS: Inflammatory markers were available in 516 of 948 patients in GCIG SBS. 200(39%) had potentially platinum sensitive ROC with ≥3 lines of chemotherapy, 316(61%) had platinum resistant ROC. 282(55%), 123(24%), 111(22%) had mGPS of 0, 1, 2, respectively. Median OS (months) was 18.1, 9.6, and 6.6 for mGPS 0, 1, and 2 respectively. mGPS was an independent predictor of OS after adjusting for PS and platinum sensitivity (p<0.001). mGPS remained a predictor of OS after adjusting for physical function, role function, global health status, abdominal/GI symptoms, and multiple clinicopathologic factors (p=0.02). Worse PS and higher mGPS were associated with poorer HRQL (p<0.001). Higher mGPS was associated with worse HRQL, independent of PS. CONCLUSION: The mGPS is an independent predictor of OS in ROC after adjusting for HRQL and clinicopathological factors. Higher mGPS is associated with worse HRQL independent of PS. mGPS is simple, inexpensive and may be suitable for clinical practice, clinical trial patient selection and stratification.

Measuring what matters MOST: validation of the Measure of Ovarian Symptoms and Treatment, a patient-reported outcome measure of symptom burden and impact of chemotherapy in recurrent ovarian cancer.

PURPOSE: Gynecologic Cancer Intergroup Symptom Benefit Study (GCIG-SBS) Stage 2 aimed to review, revise, and validate a patient-reported outcome measure (PROM), the Measure of Ovarian Symptoms and Treatment concerns (MOST), developed in GCIG-SBS Stage 1 (MOSTv1, 35 items), and document recurrent ovarian cancer (ROC) symptom burden and benefit. METHODS: GCIG-SBS Stage 2 recruited patients with platinum-resistant/refractory ROC (PRR-ROC) or potentially platinum-sensitive ROC with ≥ 3 lines of prior chemotherapy (PPS-ROC ≥ 3). Patients completed MOSTv1, QLQ-C30, QLQ-OV28, and FACT-O/FOSI at baseline and before cycle 3 of chemotherapy (pre-C3), and global assessments of change (MOST-Change) pre-C3. Clinicians rated patients' cancer-related symptoms, performance status, and adverse events. Convergent and divergent validity (Spearman's correlations), discriminative validity (effect sizes between groups classified by clinician-rated characteristics), and responsiveness (paired t tests in patients expected to experience clinically meaningful change) were assessed. RESULTS: Of 948 recruits, 903 completed PROMs at baseline and 685 pre-C3. Baseline symptom burden was substantial for PRR-ROC and PPS-ROC ≥ 3. MOSTv2 has 24 items and five multi-item scales: abdominal symptoms (MOST-Abdo), disease or treatment-related symptoms (MOST-DorT), chemotherapy-related symptoms (MOST-Chemo), psychological symptoms (MOST-Psych), and MOST-Well-being. Correlations confirmed concurrent and divergent validity. Discriminative validity was confirmed by effect sizes that conformed with a priori hypotheses. MOST-Abdo was responsive to improvements in abdominal symptoms and MOST-Chemo detected the adverse effects of chemotherapy. CONCLUSIONS: The MOSTv2 validly quantifies patient-reported symptom burden, adverse effects, and symptom benefit in ROC, and as such is fit-for-purpose for clinical trials of palliative chemotherapy in ROC. Further research is required to assess test-retest reliability.

Reducing Uncertainty: Predictors of Stopping Chemotherapy Early and Shortened Survival Time in Platinum Resistant/Refractory Ovarian Cancer-The GCIG Symptom Benefit Study.

BACKGROUND: Clinicians and patients often overestimate the benefits of chemotherapy, and overall survival (OS), in platinum resistant/refractory ovarian cancer (PRROC). This study sought to determine aspects of health-related quality of life and clinicopathological characteristics before starting chemotherapy that were associated with stopping chemotherapy early, shortened survival, and death within 30 days of chemotherapy. MATERIALS AND METHODS: This study enrolled women with PRROC before starting palliative chemotherapy. Health-related quality of life was measured with EORTC QLQ-C30/QLQ-OV28. Chemotherapy stopped within 8 weeks of starting was defined as stopping early. Logistic regression was used to assess univariable and multivariable associations with stopping chemotherapy early and death within 30 days of chemotherapy; Cox proportional hazards regression was used to assess associations with progression-free and OS. RESULTS: Low baseline global health status (GHS), role function (RF), physical function (PF), and high abdominal/gastrointestinal symptom (AGIS) were associated with stopping chemotherapy early (all p < .007); low PF and RF remained significant after adjusting for clinicopathological factors (both p < .0401). Most who stopped chemotherapy early had Eastern Cooperative Oncology Group Performance Score 0-1 at baseline (79%); PF, RF, and GHS remained independently significant predictors of stopping chemotherapy early in this subgroup. Death within 30 days of chemotherapy occurred in 14%. Low GHS, RF, and PF remained significantly associated with death within 30 days of chemotherapy after adjusting for clinicopathological factors (all p < .012). CONCLUSION: Women with low GHS, RF, or PF before starting chemotherapy were more likely to stop chemotherapy early, with short OS. Self-ratings of GHS, RF, and PF could improve patient-clinician communication regarding prognosis and help decision-making in women considering chemotherapy for PRROC. IMPLICATIONS FOR PRACTICE: Measuring aspects of health-related quality of life when considering further chemotherapy in platinum resistant/refractory ovarian cancer (PRROC) could help identify women with a particularly poor prognosis who are unlikely to benefit from chemotherapy and could therefore be spared unnecessary treatment and toxicity in their last months of life. Self-ratings of global health status, role function, and physical function could improve patient-clinician communication regarding prognosis and help decision-making in women considering chemotherapy for PRROC.

Relationship of fibroblast growth factor 21 with baseline and new on-study microvascular disease in the Fenofibrate Intervention and Event Lowering in Diabetes study.

AIMS/HYPOTHESIS: Baseline circulating fibroblast growth factor 21 (FGF21) levels can predict total cardiovascular disease events in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. This paper describes the relationship of baseline FGF21 levels and new on-study microvascular disease in patients with type 2 diabetes from the FIELD study. METHODS: Baseline FGF21 levels were measured in plasma by enzyme-linked immunosorbent assay in 9697 study participants. Total microvascular disease was defined as the presence of any nephropathy, retinopathy, neuropathy and/or microvascular amputation. The relationship between FGF21 levels and microvascular disease was assessed by multivariable logistic regression. RESULTS: Higher baseline FGF21 levels were found in patients with baseline total microvascular disease (p<0.001). The association remained significant after adjusting for potential confounding factors (OR [95% CI] 1.13 [1.08, 1.19] per SD increase in log e -transformed FGF21 levels, p<0.001). Of 6465 patients without baseline total microvascular disease, 1517 developed new on-study total microvascular disease over 5 years of follow-up. Higher baseline FGF21 levels were associated with a higher risk of new on-study total microvascular disease after adjusting for potential confounding factors (OR [95% CI] 1.09 [1.02, 1.16] per SD increase in log e -transformed FGF21 levels, p=0.01). Addition of FGF21 levels in a model of new on-study total microvascular disease with established risk factors significantly, but modestly, increased the integrated discrimination improvement and the net reclassification improvement (both p < 0.01). CONCLUSIONS/INTERPRETATION: Higher baseline FGF21 levels are seen in patients with type 2 diabetes and established microvascular disease, and predict the future development of new microvascular disease.

Prescription opioid use among people with opioid dependence and concurrent benzodiazepine and gabapentinoid exposure: An analysis of overdose and all-cause mortality.

BACKGROUND: Studies investigating mortality risk associated with use of opioid analgesics, benzodiazepines, gabapentinoids, and opioid agonist treatment (OAT) among people with opioid dependence (PWOD) are lacking. This study addresses this gap using a cohort of 37,994 PWOD initiating opioid analgesics between July 2003 and July 2018 in New South Wales, Australia. METHODS: Linked administrative records provided data on dispensings, sociodemographics, clinical characteristics, OAT, and mortality. Cox proportional hazards models assessed associations between time-varying measures of individual and concurrent medicine use and OAT with all-cause mortality, accidental opioid overdose, non-drug induced accidents, and non-drug-induced suicide. Opioid analgesic dose effects, expressed as oral morphine equivalents (OMEs) per day, were also examined. OUTCOMES: During the study period, 3167 individuals died. Compared with no use, all medicines of interest were associated with increased accidental opioid overdose risk; hazard ratios (HR) ranged from 1.33 (95 % CI: 1.05-1.68) for opioid analgesic use to 6.10 (95 % CI: 4.11-9.06) for opioid analgesic, benzodiazepine and gabapentinoid use. Benzodiazepine use was associated with increased non-drug-induced accidents and non-drug-induced suicides. For all-cause mortality, all combinations of benzodiazepines and gabapentinoids with opioid analgesics were associated with increased risk (aHRs ranged from 1.35 to 2.73). For most medicines/medicine combinations, all-cause mortality risk was reduced when in OAT compared to out of OAT. Higher opioid analgesic doses were associated with increased all-cause mortality (e.g., 90-199 mg vs 1-49 mg OME per day: HR 1.90 [95 % CI: 1.52-2.40]). INTERPRETATION: The increased mortality risk associated with benzodiazepines and gabapentinoids among PWOD appear to be reduced when engaged in OAT. A greater focus on encouraging OAT engagement, providing overdose prevention education, and access and coverage of overdose antidotes is necessary to minimise the unintended consequences of medicines use in this population.

Age-Related Risk of Serious Fall Events and Opioid Analgesic Use.

Importance: Opioid analgesics may be associated with increased risk of falls, particularly among older adults. Objective: To quantify the age-related risk of serious fall events among adults prescribed opioids by opioid exposure, time from initiation, and daily dose. Design, Setting, and Participants: This population-based cohort study conducted in New South Wales, Australia, used data linking national pharmaceutical claims to national and state datasets, including information on sociodemographic characteristics, clinical characteristics, medicines use, health services utilization, and mortality (POPPY II study). It included adults (18 years or older) who initiated prescription opioid treatment, which was defined as no prior dispensing during the preceding 365 days, between January 1, 2005, and December 31, 2018. Data were analyzed from February to June 2023. Exposure: Time-dependent periods of opioid exposure were evaluated from dispensing records. Main Outcome and Measures: Serious fall events identified from emergency department, hospitalization, and mortality records. Negative binomial models were used to assess associations between time-dependent opioid exposure (overall, by time from initiation, and by dose), age, and risk of fall events. Models were adjusted for known fall risk factors, including other fall risk-increasing drugs, frailty risk, and prior serious fall events. Results: The cohort comprised 3 212 369 individuals who initiated prescription opioid treatment (1 702 332 women [53%]; median [IQR] age at initiation, 49 [32-65] years). Overall, 506 573 serious fall events were identified, including 5210 fatal falls. During exposure to opioids, the risk of serious fall events was elevated among all age groups; compared with the group aged 18 to 44 years, this risk was highest among those 85 years or older (adjusted incident rate ratio, 6.35; 95% CI, 6.20-6.51). Across all age groups, the first 28 days following opioid initiation was a time of increased serious fall risk; this risk increased with age. Among individuals aged 18 to 84 years, associations were identified between higher daily opioid doses and serious fall events. Conclusions and Relevance: The results of this cohort study suggest that prescription opioids were associated with increased risk of serious fall events among adults of all ages, with individuals 85 years or older at greatest risk. These risks should be considered when prescribing opioids, particularly for individuals with preexisting risk factors or when opioids are prescribed at higher doses. Targeted falls prevention efforts may be most effective within the first month following opioid initiation.

Do Patient Demographics and Performance Status Influence Opioid Dose in Cancer Pain?

Context: There is limited evidence on the role of objective parameters in influencing analgesic use in cancer pain management.Objective: To investigate the significance of objective parameters (age, male/female and performance status) in influencing opioid dose. Methods: We conducted a retrospective cross-sectional audit of adult inpatients with metastatic cancer at a major cancer centre from 1 January 2016 to 31 December 2018, who were prescribed slow release opioids for cancer pain on discharge. Main outcome measures were demographics (age, male/female and performance status), oral morphine equivalent daily dose (oMEDD) and adjuvant analgesic use. Results: Of the 7,747 eligible records, 215 patient records fulfilled inclusion criteria. Older patients (≥75 years) received half of the median oMEDD dose (30 mg) compared to their youngest counterparts (60 mg oMEDD in age ≤50 years) (P = .003). No significant differences were observed between oMEDD and male/female and performance status. Conclusion: Older patients are prescribed half the opioid dose compared to their younger counterparts. This highlights the importance of vigilance in opioid prescribing in the elderly in order to balance side effects with under treatment. Although no other significant relationships were observed, future studies comparing objective patient parameters with opioid prescription may uncover other at risk populations.

Does cancer type and adjuvant analgesic prescribing influence opioid dose?-a retrospective cross-sectional study.

Opioids are the backbone of cancer pain management. Minimal evidence exists examining the relationship between cancer type and opioid dose. Similarly, the use of adjuvant analgesics and its impact within an inpatient cancer setting is understudied. This study examined the influence of cancer type upon opioid dose, measured by oral morphine equivalent daily dose (oMEDD). The effect of adjuvant analgesics on patient oMEDD was also examined. This retrospective cross-sectional study examined records of 520 patients admitted to Royal Melbourne Hospital or Peter MacCallum Cancer Centre between 2016 and 2018 with advanced cancer. Number and dose of both opioid and adjuvant analgesics were collected along with demographic and cancer data. Comparisons of median oMEDD by cancer type [analysis of variance (ANOVA), non-parametric t-tests] and adjuvant analgesics (Kruskal-Wallis test) were performed. There were no statistically significant differences in oMEDD between the 12 cancer types (P=0.83; n=215). Patients co-prescribed pregabalin (n=102) and paracetamol (n=73) as adjuvant analgesics were on significantly higher daily oMEDD [60 mg (P=0.015), 90 mg (P<0.001), respectively]. Opioid dose did not differ significantly between cancer types. The observed use of adjuvant analgesics coincided with significantly higher oMEDD prescription which may relate to complex pain seen in this cohort of inpatients in a quarternary cancer centre. Future research should focus on pain type and aetiology, and pain scores in different cancer pain syndromes to determine the net effect of opioids and adjuvants in cancer pain prescribing.

Five-Year Trajectories of Prescription Opioid Use.

Importance: There are known risks of using opioids for extended periods. However, less is known about the long-term trajectories of opioid use following initiation. Objective: To identify 5-year trajectories of prescription opioid use, and to examine the characteristics of each trajectory group. Design, Setting, and Participants: This population-based cohort study conducted in New South Wales, Australia, linked national pharmaceutical claims data to 10 national and state data sets to determine sociodemographic characteristics, clinical characteristics, drug use, and health services use. The cohort included adult residents (aged ≥18 years) of New South Wales who initiated a prescription opioid between July 1, 2003, and December 31, 2018. Statistical analyses were conducted from February to September 2022. Exposure: Dispensing of a prescription opioid, with no evidence of opioid dispensing in the preceding 365 days, identified from pharmaceutical claims data. Main Outcomes and Measures: The main outcome was the trajectories of monthly opioid use over 60 months from opioid initiation. Group-based trajectory modeling was used to classify these trajectories. Linked health care data sets were used to examine characteristics of individuals in different trajectory groups. Results: Among 3 474 490 individuals who initiated a prescription opioid (1 831 230 females [52.7%]; mean [SD] age, 49.7 [19.3] years), 5 trajectories of long-term opioid use were identified: very low use (75.4%), low use (16.6%), moderate decreasing to low use (2.6%), low increasing to moderate use (2.6%), and sustained use (2.8%). Compared with individuals in the very low use trajectory group, those in the sustained use trajectory group were older (age ≥65 years: 22.0% vs 58.4%); had more comorbidities, including cancer (4.1% vs 22.2%); had increased health services contact, including hospital admissions (36.9% vs 51.6%); had higher use of psychotropic (16.4% vs 42.4%) and other analgesic drugs (22.9% vs 47.3%) prior to opioid initiation, and were initiated on stronger opioids (20.0% vs 50.2%). Conclusions and relevance: Results of this cohort study suggest that most individuals commencing treatment with prescription opioids had relatively low and time-limited exposure to opioids over a 5-year period. The small proportion of individuals with sustained or increasing use was older with more comorbidities and use of psychotropic and other analgesic drugs, likely reflecting a higher prevalence of pain and treatment needs in these individuals.

Cohort profile: POPPY II - a population-based cohort examining the patterns and outcomes of prescription opioid use in New South Wales, Australia.

PURPOSE: The POPPY II cohort is an Australian state-based cohort linking data for a population of individuals prescribed opioid medicines, constructed to allow a robust examination of the long-term patterns and outcomes of prescription opioid use. PARTICIPANTS: The cohort includes 3 569 433 adult New South Wales residents who initiated a subsidised prescription opioid medicine between 2003 and 2018, identified through pharmacy dispensing data (Australian Pharmaceutical Benefits Scheme) and linked to 10 national and state datasets and registries including rich sociodemographic and medical services data. FINDINGS TO DATE: Of the 3.57 million individuals included in the cohort, 52.7% were female and 1 in 4 people were aged ≥65 years at the time of cohort entry. Approximately 6% had evidence of cancer in the year prior to cohort entry. In the 3 months prior to cohort entry, 26.9% used a non-opioid analgesic and 20.5% used a psychotropic medicine. Overall, 1 in 5 individuals were initiated on a strong opioid (20.9%). The most commonly initiated opioid was paracetamol/codeine (61.3%), followed by oxycodone (16.3%). FUTURE PLANS: The POPPY II cohort will be updated periodically, both extending the follow-up duration of the existing cohort, and including new individuals initiating opioids. The POPPY II cohort will allow a range of aspects of opioid utilisation to be studied, including long-term trajectories of opioid use, development of a data-informed method to assess time-varying opioid exposure, and a range of outcomes including mortality, transition to opioid dependence, suicide and falls. The duration of the study period will allow examination of population-level impacts of changes to opioid monitoring and access, while the size of the cohort will also allow examination of important subpopulations such as people with cancer, musculoskeletal conditions or opioid use disorder.

Evaluation of a Large Scale Advance Care Planning Co-Design Education Program for Chinese-Speaking People in Australia.

BACKGROUND: Advance care planning (ACP) is important, however ethnic minorities have half the completion rates in the United States compared to Caucasian counterparts, and in Australia only 3.5% of advance directives were completed by those overseas-born.Educational intervention improves ACP knowledge and subsequent uptake. We evaluated immediate and longer-term outcomes of a co-designed ACP education toolkit in Chinese-speaking people in Victoria, Australia. METHODS: We conducted a cross-sectional survey of Chinese-speaking community members who participated in a co-designed Chinese ACP educational workshop. A self-selected subgroup were subsequently contacted 6 months later to determine longer-term outcomes. RESULTS: Of 519 attendees across 17 workshops, 325 (63%) completed the evaluation. The majority (63%;n = 206) were previously unaware of ACP. Perception of receipt of useful information positively correlated with motivation to undertake ACP (r = 0.3486, p < 0.001). Of the 70 participants who consented to follow up, 36% (n = 26) agreed to participate in structured telephone interviews. English speakers were more likely to have undertaken ACP (n = 6 vs n = 3). ACP completion was not associated with being a carer or suffering from cancer or chronic illness. CONCLUSIONS: This first Australian study evaluating ACP co-design education implementation outcomes in Chinese-speaking people supports that motivation to undertake ACP is related to knowledge, albeit a modest ACP uptake in a small follow up sample. Clinicians should note that this assists with ACP uptake, with likely downstream improved health outcomes. This co-designed toolkit could be helpful in increasing ACP uptake. Future engagement by Chinese language societies to overcome further barriers to ACP is needed.

The risk of postoperative deterioration of non-cardiac surgery patients with ICU referral status who are admitted to the regular ward: a retrospective observational cohort study.

BACKGROUND: Higher-risk surgical patients may not be admitted to the intensive care unit due to stable immediate post-operative status on review. The outcomes of this cohort are not well described. Our aim was to examine the subsequent inpatient course of intensive care unit -referred but not admitted surgical patients. METHODS: All patients aged ≥18 years who were referred but not admitted for post-operative management in a tertiary metropolitan intensive care unit following non-cardiac surgery between 1/7/2017 and 30/6/2018 were eligible for inclusion in this retrospective observational cohort study. Primary outcome was Medical Emergency Team activation. Secondary outcomes included unplanned intensive care unit admission; length of stay; and 30-day mortality. Risk of serious complications and predicted length of stay were calculated using the National Surgical Quality Improvement Program scoring tool. RESULTS: Fifteen of 60 patients (25%) had a MET-call following surgery, eight (13%) patients required unplanned intensive care unit admission, with median (IQR) time to Medical Emergency Team call 9 (6-13) hours. No patients died within 30-days. There was no significant difference between mean National Surgical Quality Improvement Program predicted and actual length of stay; after adjustment, National Surgical Quality Improvement Program predicted risk of serious complications was associated with unplanned intensive care unit admission (OR [95% CI] = 1.08 [1.00-1.16], p = 0.04), although not Medical Emergency Team calls. CONCLUSIONS: Post-operative deterioration occurs frequently, and early, in a cohort of high-risk surgical patients initially assessed as being safe for ward care. Changes to current triage models for post-operative intensive care unit admission may reduce the impact of complications in this high-risk group.

Right or Left Primary Site of Colorectal Cancer: Outcomes From the Molecular Analysis of the AGITG MAX Trial.

BACKGROUND: For metastatic colorectal cancer, previous reports have described differences in biology and outcome, including response to biologic agents, based on whether the primary tumor is right- or left-sided. We explored the molecular markers from the AGITG MAX trial. PATIENTS AND METHODS: The AGITG MAX trial was a randomized study comparing capecitabine versus capecitabine + bevacizumab versus capecitabine + bevacizumab + mitomycin C as first-line therapy in advanced colorectal cancer. Patients were classified as having right-sided (caecum to transverse colon) or left-sided (descending colon to rectum) disease according to anatomic location. Baseline characteristics and previously described molecular profiles were compared by side of primary tumor. Survival outcomes were analyzed by the Kaplan-Meier approach and proportional hazards regression modeling. RESULTS: Among the 471 patients, the location of primary tumor was known in 440 patients (93%). Molecular profile was known in 298 patients (63%). Twenty-eight percent had right-sided primary tumors. Major differences between right and left are as follows: female 49% versus 33% (P < .01), BRAF mutant 16% versus 3.5% (P ≤ .001), and phosphatase and tensin homolog (PTEN) loss 27.6% versus 53% (P = .01). There were no differences in RAS mutation, PIK3CA mutation, or high versus low expression of assessed angiogenic markers. Right-sided primary lesion predicted a poor outcome for median overall survival: right-sided disease 13.2 months versus left-sided disease 20 months (P = .001; hazard ratio [HR] = 0.67; 95% confidence interval [CI], 0.53-0.85), but not for progression-free survival (HR 0.96; 95% CI, 0.78-1.20). The relative treatment effect did not differ significantly according to location of primary tumor: right primary tumor HR (bevacizumab containing arm vs. capecitabine monotherapy arm) was 0.82 (95% CI, 0.54-1.22), and left primary HR (bevacizumab containing arm vs. capecitabine monotherapy arm) was 0.51 (95% CI, 0.4-0.63) (interaction P = .10). CONCLUSION: There are more negative prognostic factors in patients with right-sided primary tumors, in particular high BRAF mutations, and these patients have inferior overall survival compared to those with a left-sided primary tumor. There was no suggestion that side of primary site had any impact on bevacizumab effect on progression-free survival.

Performance of four published risk models to predict sentinel lymph-node involvement in Australian women with early breast cancer.

BACKGROUND: Sentinel lymph-node biopsy has reduced the need for extensive axillary surgery for staging. It still exposes women to associated morbidity. Risk models that use clinical and pathology information of the primary tumour to predict sentinel lymph-node metastasis may allow further improvements in care. This study assessed the performance of four published risk models for predicting sentinel lymph-node metastasis in Australian women with early breast cancer; including one model developed in an Australian population. METHODS: The Sentinel Node Biopsy Versus Axillary Clearance (SNAC) trial dataset was used to assess model discrimination by calculating the area under the receiver-operating-characteristic curve (AUC) and the false-negative rate for sentinel lymph-node metastasis using model-predicted risk cut-points of 10%, 20%, 30%, and calibration using Hosmer-Lemeshow tests and calibration plots. RESULTS: The sentinel node was positive in 248 of 982 (25.2%) women (158 macrometastasis, 90 micrometastasis). The AUCs of risk models ranged from 0.70 to 0.74 for prediction of any sentinel-node metastasis; 0.72 to 0.75 for macrometastasis. Calibration was poor for the three models developed outside of Australia (lack-of-fit statistics, P < 0.001). For women with a model-predicted risk of sentinel lymph-node metastasis ≤10%, observed risk was 0-13% (three models <10%), false-negative rate 0-9%; 1-17% of women were classified in this range. CONCLUSION: All four models showed good discrimination for predicting sentinel lymph-node metastasis, in particular for macrometastasis. With further development such risk models could have a role in the provision of reassurance to low risk women with normal nodes sonographicaally for whom no axillary surgery is contemplated.

Effect of fenofibrate on uric acid and gout in type 2 diabetes: a post-hoc analysis of the randomised, controlled FIELD study.

BACKGROUND: Gout is a painful disorder and is common in type 2 diabetes. Fenofibrate lowers uric acid and reduces gout attacks in small, short-term studies. Whether fenofibrate produces sustained reductions in uric acid and gout attacks is unknown. METHODS: In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, participants aged 50-75 years with type 2 diabetes were randomly assigned to receive either co-micronised fenofibrate 200 mg once per day or matching placebo for a median of 5 years follow-up. We did a post-hoc analysis of recorded on-study gout attacks and plasma uric acid concentrations according to treatment allocation. The outcomes of this analysis were change in uric acid concentrations and risk of on-study gout attacks. The FIELD study is registered with ISRCTN, number ISRCTN64783481. FINDINGS: Between Feb 23, 1998, and Nov 3, 2000, 9795 patients were randomly assigned to fenofibrate (n=4895) or placebo (n=4900) in the FIELD study. Uric acid concentrations fell by 20·2% (95% CI 19·9-20·5) during the 6-week active fenofibrate run-in period immediately pre-randomisation (a reduction of 0·06 mmol/L or 1 mg/dL) and remained -20·1% (18·5-21·7, p<0·0001) lower in patients taking fenofibrate than in those on placebo in a random subset re-measured at 1 year. With placebo allocation, there were 151 (3%) first gout events over 5 years, compared with 81 (2%) among those allocated fenofibrate (HR with treatment 0·54, 95% CI 0·41-0·70; p<0·0001). In the placebo group, the cumulative proportion of patients with first gout events was 7·7% in patients with baseline uric acid concentration higher than 0·36 mmol/L and 13·9% in those with baseline uric acid concentration higher than 0·42 mmol/L, compared with 3·4% and 5·7%, respectively, in the fenofibrate group. Risk reductions were similar among men and women and those with dyslipidaemia, on diuretics, and with elevated uric acid concentrations. For participants with elevated baseline uric acid concentrations despite taking allopurinol at study entry, there was no heterogeneity of the treatment effect of fenofibrate on gout risk. Taking account of all gout events, fenofibrate treatment halved the risk (HR 0·48, 95% CI 0·37-0·60; p<0·0001) compared with placebo. INTERPRETATION: Fenofibrate lowered uric acid concentrations by 20%, and almost halved first on-study gout events over 5 years of treatment. Fenofibrate could be a useful adjunct for preventing gout in diabetes. FUNDING: None.