Cohort profile: Using primary care data to understand Opioid Prescribing, Policy Impacts and Clinical Outcomes (OPPICO) in Victoria, Australia.

PURPOSE: The OPPICO cohort is a population-based cohort based on non-identifiable electronic health records routinely collected from 464 general practices in Victoria, Australia, created with the aim of understanding opioid prescribing, policy impacts and clinical outcomes. The aim of this paper is to provide a profile of the study cohort by summarising available demographic, clinical and prescribing characteristics. PARTICIPANTS: The cohort described in this paper comprises people who were aged at least 14 years at cohort entry, and who were prescribed an opioid analgesic at least once at participating practices for a total of 1 137 728 person-years from 1 January 2015 to 31 December 2020. The cohort was formed using the data collected from electronic health records through the Population Level Analysis and Reporting (POLAR) system. The POLAR data primarily consist of patient demographics, clinical measurements, Australian Medicare Benefits Scheme item numbers, diagnoses, pathology testing and prescribed medications. FINDING TO DATE: In total, the cohort consists of 676 970 participants with 4 389 185 opioid prescription records from 1 January 2015 to 31 December 2020. Approximately half (48.7%) received a single opioid prescription, and 0.9% received more than 100 opioid prescriptions. The mean number of opioid prescriptions per patient was 6.5 (SD=20.9); prescriptions for strong opioids accounted for 55.6% of all opioid prescriptions. FUTURE PLANS: The OPPICO cohort data will be used for various types of pharmacoepidemiological research, including examining the impact of policy changes on coprescription of opioids with benzodiazepines and gabapentin, and monitoring trends and patterns of other medication utilisation. Through data-linkage between our OPPICO cohort and hospital outcome data, we will examine whether policy changes for opioid prescribing lead to changes in prescription opioid-related harms, and other drug and mental health-related outcomes. TRIAL REGISTRATION NUMBER: EU PAS Register (EUPAS43218, prospectively registered).

A Systems-Based Analysis of Mono- and Combination Therapy for Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections.

Antimicrobial resistance is a global threat. As "proof-of-concept," we employed a system-based approach to identify patient, bacterial, and drug variables contributing to mortality in patients with carbapenem-resistant Klebsiella pneumoniae (CRKp) bloodstream infections exposed to colistin (COL) and ceftazidime-avibactam (CAZ/AVI) as mono- or combination therapies. Patients (n = 49) and CRKp isolates (n = 22) were part of the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE-1), a multicenter, observational, prospective study of patients with carbapenem-resistant Enterobacterales (CRE) conducted between 2011 and 2016. Pharmacodynamic activity of mono- and combination drug concentrations was evaluated over 24 h using in vitro static time-kill assays. Bacterial growth and killing dynamics were estimated with a mechanism-based model. Random Forest was used to rank variables important for predicting 30-day mortality. Isolates exposed to COL+CAZ/AVI had enhanced early bacterial killing compared to CAZ/AVI alone and fewer incidences of regrowth compared to COL and CAZ/AVI. The mean coefficient of determination (R2) for the observed versus predicted bacterial counts was 0.86 (range: 0.75 - 0.95). Bacterial subpopulation susceptibilities and drug mechanistic synergy were essential to describe bacterial killing and growth dynamics. The combination of clinical (hypotension), bacterial (IncR plasmid, aadA2, and sul3) and drug (KC50) variables were most predictive of 30-day mortality. This proof-of-concept study combined clinical, bacterial, and drug variables in a unified model to evaluate clinical outcomes.

Global Incidence of Frailty and Prefrailty Among Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.

Importance: Frailty is a common geriatric syndrome of significant public health importance, yet there is limited understanding of the risk of frailty development at a population level. Objective: To estimate the global incidence of frailty and prefrailty among community-dwelling adults 60 years or older. Data Sources: MEDLINE, Embase, PsycINFO, Web of Science, CINAHL Plus, and AMED (Allied and Complementary Medicine Database) were searched from inception to January 2019 without language restrictions using combinations of the keywords frailty, older adults, and incidence. The reference lists of eligible studies were hand searched. Study Selection: In the systematic review, 2 authors undertook the search, article screening, and study selection. Cohort studies that reported or had sufficient data to compute incidence of frailty or prefrailty among community-dwelling adults 60 years or older at baseline were eligible. Data Extraction and Synthesis: The methodological quality of included studies was assessed using The Joanna Briggs Institute's Critical Appraisal Checklist for Prevalence and Incidence Studies. Meta-analysis was conducted using a random-effects (DerSimonian and Laird) model. Main Outcomes and Measures: Incidence of frailty (defined as new cases of frailty among robust or prefrail individuals) and incidence of prefrailty (defined as new cases of prefrailty among robust individuals), both over a specified duration. Results: Of 15 176 retrieved references, 46 observational studies involving 120 805 nonfrail (robust or prefrail) participants from 28 countries were included in this systematic review. Among the nonfrail individuals who survived a median follow-up of 3.0 (range, 1.0-11.7) years, 13.6% (13 678 of 100 313) became frail, with the pooled incidence rate being 43.4 (95% CI, 37.3-50.4; I2 = 98.5%) cases per 1000 person-years. The incidence of frailty was significantly higher in prefrail individuals than robust individuals (pooled incidence rates, 62.7 [95% CI, 49.2-79.8; I2 = 97.8%] vs 12.0 [95% CI, 8.2-17.5; I2 = 94.9%] cases per 1000 person-years, respectively; P for difference < .001). Among robust individuals in 21 studies who survived a median follow-up of 2.5 (range, 1.0-10.0) years, 30.9% (9974 of 32 268) became prefrail, with the pooled incidence rate being 150.6 (95% CI, 123.3-184.1; I2 = 98.9%) cases per 1000 person-years. The frailty and prefrailty incidence rates were significantly higher in women than men (frailty: 44.8 [95% CI, 36.7-61.3; I2 = 97.9%] vs 24.3 [95% CI, 19.6-30.1; I2 = 8.94%] cases per 1000 person-years; prefrailty: 173.2 [95% CI, 87.9-341.2; I2 = 99.1%] vs 129.0 [95% CI, 73.8-225.0; I2 = 98.5%] cases per 1000 person-years). The incidence rates varied by diagnostic criteria and country income level. The frailty and prefrailty incidence rates were significantly reduced when accounting for the risk of death. Conclusions and Relevance: Results of this study suggest that community-dwelling older adults are prone to developing frailty. Increased awareness of the factors that confer high risk of frailty in this population subgroup is vital to inform the design of interventions to prevent frailty and to minimize its consequences.

Medications and Prescribing Patterns as Factors Associated with Hospitalizations from Long-Term Care Facilities: A Systematic Review.

BACKGROUND: Residents of long-term care facilities (LTCFs) are at high risk of hospitalization. Medications are a potentially modifiable risk factor for hospitalizations. OBJECTIVE: Our objective was to systematically review the association between medications or prescribing patterns and hospitalizations from LTCFs. METHODS: We searched MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and International Pharmaceutical Abstracts (IPA) from inception to August 2017 for longitudinal studies reporting associations between medications or prescribing patterns and hospitalizations. Two independent investigators completed the study selection, data extraction and quality assessment using the Joanna Briggs Institute Critical Appraisal Tools. RESULTS: Three randomized controlled trials (RCTs), 22 cohort studies, five case-control studies, one case-time-control study and one case-crossover study, investigating 13 different medication classes and two prescribing patterns were included. An RCT demonstrated that high-dose influenza vaccination reduced all-cause hospitalization compared with standard-dose vaccination (risk ratio [RR] 0.93; 95% confidence interval [CI] 0.88-0.98). Another RCT found no difference in hospitalization rates between oseltamivir as influenza treatment and oseltamivir as treatment plus prophylaxis (treatment = 4.7%, treatment and prophylaxis = 3.5%; p = 0.7). The third RCT found no difference between multivitamin/mineral supplementation and hospitalization (odds ratio [OR] 0.94; 95% CI 0.74-1.20) or emergency department visits (OR 1.05; 95% CI 0.76-1.47). Two cohort studies demonstrated influenza vaccination reduced hospitalization. Four studies suggested polypharmacy and potentially inappropriate medications (PIMs) increased all-cause hospitalization. However, associations between polypharmacy (two studies), PIMs (one study) and fall-related hospitalizations were inconsistent. Inconsistent associations were found between psychotropic medications with all-cause and cause-specific hospitalizations (11 studies). Warfarin, nonsteroidal anti-inflammatory drugs, pantoprazole and vinpocetine but not long-term acetylsalicylic acid (aspirin), statins, trimetazidine, digoxin or ß-blockers were associated with all-cause or cause-specific hospitalizations in single studies of specific resident populations. Most cohort studies assessed prevalent rather than incident medication exposure, and no studies considered time-varying medication use. CONCLUSION: High-quality evidence suggests influenza vaccination reduces hospitalization. Polypharmacy and PIMs are consistently associated with increased all-cause hospitalization.

The representativeness of direct oral anticoagulant clinical trials to hospitalized patients with atrial fibrillation.

PURPOSE: Trials of the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban and apixaban provide the basis for prescribing for the prevention of stroke and systemic embolism in atrial fibrillation (AF). The objective of this study was to assess the representativeness of the three pivotal DOAC randomized controlled trials of dabigatran, rivaroxaban and apixaban for unselected hospitalized patients with AF. METHODS: A cross-sectional study was undertaken. All patients discharged with AF between 2012 and 2015 from a large public hospital network in Melbourne, Australia, were identified. Inclusion and exclusion criteria from the DOAC trials were applied. The proportions of hospitalized patients with AF who would have been eligible for the dabigatran (RE-LY), rivaroxaban (ROCKET-AF) and apixaban (ARISTOTLE) trials were estimated, as was pooled eligibility for all three trials. Characteristics of eligible and ineligible patients were compared. RESULTS: For the 4734 patients, application of the inclusion and exclusion criteria resulted in 60.5, 52.6 and 35.8% eligibility for the trials of apixaban, dabigatran and rivaroxaban, respectively. Pooled eligibility across all three trials demonstrated that 33.4% of the patients would have been eligible for all three trials but 36.7% ineligible for any trial. Ineligible patients who met exclusion criteria were older and experienced more comorbidities. CONCLUSIONS: The apixaban and dabigatran trials may be the most representative of hospitalized patients with AF. The DOAC trial results can readily be extrapolated to, and guide prescribing for, at least two thirds of patients discharged from a large metropolitan health service in Australia.