A Longitudinal Study of the Use and Effects of Fall-Risk-Increasing Drugs in Residential Aged Care.

OBJECTIVES: Fall-risk-increasing drugs (FRIDs)-psychotropics and cardiovascular disease (CVD) drugs-may elevate the risk of falling, with strong evidence observed in psychotropic FRIDs, whereas findings from cardiovascular disease (CVD) FRIDs remain inconclusive. Existing studies on FRIDs and falls are often hampered by methodologic limitations. Leveraging longitudinal observational data, we aimed to determine the long-term patterns of FRID use and their association with falls in residential aged care (RAC) homes. DESIGN: A retrospective longitudinal cohort study. SETTING AND PARTICIPANTS: A total of 4207 permanent residents newly admitted to 27 RAC homes in Sydney, Australia. METHOD: The outcomes were incidence of all and injurious falls. We measured exposure to each FRID over 60 months using the Proportion of Days Covered (PDC) metric. We used group-based multitrajectory modeling to determine concurrent usage patterns of psychotropics and CVD FRIDs and applied negative binomial regression to assess their associations with the outcomes. RESULTS: A total of 83.6% (n = 3516) and 77.3% (n = 3254) residents used psychotropic and CVD FRIDs, respectively. The PDC values ranged from 67.3% (opioids) to 86.9% (antidepressants) for specific psychotropics and 79.0% (α-adrenoceptor antagonists) to 89.6% (ß blockers) for CVD FRIDs. We identified 4 groups: group 1, low psychotropics-low CVDs use (16.7%, n = 701); group 2, low psychotropics-high CVDs (25.0%, n = 1054); group 3, high psychotropics-high CVDs (41.0%, n = 1723); and group 4, high psychotropics-low CVDs (17.3%, n = 729). Group 4 had a significantly higher rate of falls than the other groups for both outcomes, including relative to group 3, in which exposure to both FRID classes was high. CONCLUSIONS AND IMPLICATIONS: Our findings reveal concerningly high FRID use in RAC homes and highlight a critical difference in the impact of the 2 major FRID classes on falls. Psychotropics were strongly associated with falls, whereas the studied CVD FRIDs did not elevate risk of falling.

Developing a process to measure actual harm from medication errors in paediatric inpatients: From design to implementation.

AIMS: The potential harm associated with medication errors is widely reported, but data on actual harm are limited. When actual harm has been measured, assessment processes are often poorly described, limiting their ability to be reproduced by other studies. Our aim was to design and implement a new process to assess actual harm resulting from medication errors in paediatric inpatient care. METHODS: Prescribing errors were identified through retrospective medical record reviews (n = 26 369 orders) and medication administration errors through direct observation (n = 5137 administrations) in a tertiary paediatric hospital. All errors were assigned potential harm severity ratings on a 5-point scale. Multidisciplinary panels reviewed case studies for patients assigned the highest three potential severity ratings and determined the following: actual harm occurrence and severity level, plausibility of a link between the error(s) and identified harm(s) and a confidence rating if no harm had occurred. RESULTS: Multidisciplinary harm panels (n = 28) reviewed 566 case studies (173 prescribing related and 393 administration related) and found evidence of actual harm in 89 (prescribing = 22, administration = 67). Eight cases of serious harm cases were found (prescribing = 1, administration = 7) and no cases of severe harm. The panels were very confident in 65% of cases (n = 302) where no harm was found. Potential and actual harm ratings varied. CONCLUSIONS: This harm assessment process provides a systematic method for determining actual harm from medication errors. The multidisciplinary nature of the panels was critical in evaluating specific clinical, therapeutic and contextual considerations including care delivery pathways, therapeutic dose ranges and drug-drug and drug-disease interactions.

Can old drugs learn new tricks? Achieving registration and public subsidy listing for off-patent medicines with novel therapeutic applications.

With the increasing costs of drug development, repurposing of low-cost medicines for new indications has never been more important. However, there are multiple barriers to repurposing, particularly for off-patent medicines, and limited incentives for the pharmaceutical industry to sponsor registration and public subsidy listing. Here, we explore these barriers and their consequences and provide examples of successful repurposing strategies.

Short- and long-term effects of an electronic medication management system on paediatric prescribing errors.

Electronic medication management (eMM) systems are designed to improve safety, but there is little evidence of their effectiveness in paediatrics. This study assesses the short-term (first 70 days of eMM use) and long-term (one-year) effectiveness of an eMM system to reduce prescribing errors, and their potential and actual harm. We use a stepped-wedge cluster randomised controlled trial (SWCRCT) at a paediatric referral hospital, with eight clusters randomised for eMM implementation. We assess long-term effects from an additional random sample of medication orders one-year post-eMM. In the SWCRCT, errors that are potential adverse drug events (ADEs) are assessed for actual harm. The study comprises 35,260 medication orders for 4821 patients. Results show no significant change in overall prescribing error rates in the first 70 days of eMM use (incident rate ratio [IRR] 1.05 [95%CI 0.92-1.21], but a 62% increase (IRR 1.62 [95%CI 1.28-2.04]) in potential ADEs suggesting immediate risks to safety. One-year post-eMM, errors decline by 36% (IRR 0.64 [95%CI 0.56-0.72]) and high-risk medication errors decrease by 33% (IRR 0.67 [95%CI 0.51-0.88]) compared to pre-eMM. In all periods, dose error rates are more than double that of other error types. Few errors are associated with actual harm, but 71% [95%CI 50-86%] of patients with harm experienced a dose error. In the short-term, eMM implementation shows no improvement in error rates, and an increase in some errors. A year after eMM error rates significantly decline suggesting long-term benefits. eMM optimisation should focus on reducing dose errors due to their high frequency and capacity to cause harm.

"We face the same risk as the other health workers": Perceptions and experiences of community pharmacists in Indonesia during the COVID-19 pandemic.

In many countries, community pharmacies have played an important role during the COVID-19 pandemic, providing essential medicines and personal protective equipment (PPE), disseminating information on disease prevention and management, and referring clients to health facilities. In recognition of this, there are increasing calls for an improved understanding of the challenges and experiences faced by these providers during the COVID-19 pandemic, with a view to providing them with better support and guidance now and during future emergencies. Between January and February 2021 we conducted 21 qualitative interviews to explore the experiences, safety concerns, and attitudes of pharmacists and pharmacy technicians during the COVID-19 crisis in Indonesia, a country that has recorded more than four million cases since the start of the pandemic. Interview transcripts were analysed using thematic content analysis. Findings indicate that COVID-19 has had a significant impact on pharmacy practices in Indonesia. Most participants implemented preventive measures and adapted their business models to the changing circumstances. The shift to remote sales and home delivery allowed many pharmacies to maintain, and even increase their profit margins due to greater demand for medicines and PPE. However, many participants were concerned about the increased risk of infection due to limited social distancing and prolonged interactions with clients, many of whom displayed COVID-19 symptoms. Importantly, there was a general perception that the government did not sufficiently recognize these risks. In conclusion, the government should consider developing additional operational guidelines and regulatory frameworks to improve the safety, operation, and involvement of community pharmacies in the current pandemic response efforts and any future public health emergencies.

Precision medicine and clinical relevance in older people.

Precision medicine and clinical relevance in older people.

BT2 Suppresses Human Monocytic-Endothelial Cell Adhesion, Bone Erosion and Inflammation.

INTRODUCTION: Inflammation and bone erosion are processes key to the pathogenesis of rheumatoid arthritis, a systemic autoimmune disease causing progressive disability and pain, impacting around 1.3 million people in the United States alone. However, many patients do not respond sufficiently to existing therapies or benefit is not sustained and alternate therapeutic approaches are lacking. We recently identified the dibenzoxazepinone BT2, which inhibits ERK phosphorylation, from a high-throughput chemical screen and identified its ability to inhibit angiogenesis and vascular leakiness. METHODS: Here we evaluated BT2 for potential anti-inflammatory activity in in vitro models of human monocytic-endothelial cell adhesion, monocytic cell extravasation and collagen antibody-induced arthritis in mice. RESULTS: BT2 inhibits human monocytic cell adhesion to IL-1ß-treated human endothelial cells and inhibits monocytic transendothelial migration toward MCP-1. In mice rendered arthritic, single systemic administration of BT2 prevented footpad swelling, bone destruction and TRAP+ cells in the joints. BT2 suppressed inducible circulating levels of IL-1ß, IL-2 and IL-6 to normal levels without affecting levels of IL-4 or IL-10 among other cytokines. BT2 also inhibited the expression of pro-inflammatory adhesion molecules ICAM-1 and VCAM-1 in arthritic joints. There was no evidence of toxicity following intraperitoneal, gavage or intraarticular administration of BT2. CONCLUSION: BT2 is a novel small molecule inhibitor of joint inflammation, bone erosion, pro-inflammatory cytokine and adhesion molecule expression. This suggests the potential clinical utility of BT2 as a new anti-inflammatory agent.

Estriol serum levels in new and chronic users of vaginal estriol cream: A prospective observational study.

AIMS: To quantify estriol serum concentrations in "new" and "chronic users" of topical estriol cream using quantitative liquid chromatography tandem mass spectrometry. METHODS: In this singlecentre prospective observational study, postmenopausal women with urogynaecological complaints were enrolled: 40 had not used topical estriol previously ("new users") and 50 had been applying estriol cream for more than 12 weeks ("chronic users"). In "new users," serum estriol levels were measured at baseline and after 12 weeks use. Estriol cream 1 mg/g was used daily for 3 weeks, then twice weekly with applicator (group 1A) or digitally (group 1B) or three times per week digitally (group 1C). "Chronic users" applied the cream twice (n = 7) or three (n = 43) times per week. Serum samples were taken in the morning after using cream the previous night. The main outcome measures were estriol serum concentrations in "new" and "chronic users" of estriol cream. RESULTS: Baseline serum estriol concentrations were less than 5 pmol/L in all 40 "new users." At 12 weeks, the 12-hour serum estriol levels ranged from less than 5 to 494 pmol/L (median 22.8; Interquartile range [IQR] 9.2-108.5). Seven "new users" had levels more than 100 pmol/L. Most of the 50 "chronic users" also had 12-hour levels less than 100 pmol/L (median 15.1 pmol/L [IQR 2.7-33.9]: three had levels more than 100 pmol/L. CONCLUSIONS: This study reports serum estriol concentrations in a large number of "new" and "chronic users" of vaginal estriol cream, employing a novel highly sensitive and specific technique. Overall, the results are reassuring: 87% had 12-hour estriol levels less than 100 pmol/L.

Efficacy and harms of orally, intramuscularly or intravenously administered glucocorticoids for sciatica: A systematic review and meta-analysis.

BACKGROUND: Sciatica can be a debilitating condition and there is limited guidance on the use of glucocorticoids administered via the oral, intramuscular or intravenous route for this condition. These represent viable treatment options in the primary care setting. OBJECTIVE: To evaluate the evidence on efficacy and harms of oral, IM and IV glucocorticoid administration for sciatica. DATABASES AND DATA TREATMENT: MEDLINE, EMBASE, CENTRAL, CINAHL, PsycINFO (inception to October 2018) were searched for randomised placebo-controlled trials evaluating oral, IV or IM glucocorticoid administration for sciatica. Two authors extracted outcomes data. Continuous pain and disability outcomes were converted to a 0 (no pain/disability) to 100 (worst pain/disability) scale. Data were pooled using a random effects model. Overall quality of evidence was assessed using GRADE. Primary outcomes were leg pain and disability. Primary follow-up period was the immediate-term (<2 weeks from administration). We also considered adverse events. RESULTS: Nine trials were eligible. One study [n = 27] provided low quality evidence of a small reduction in disability with early administration of oral prednisone (within 1 week); MD -13.4 [-23.3, -3.5] but not for pain MD -2.5 [-16.9, 11.9]. There was low quality evidence from one study [n = 78] of moderate reduction in disability and small reduction in pain with early (within 72 hr of symptom onset) single intramuscular administration of methylprednisolone acetate; MD -24.5 [-38.8, -10.2] and -14.0 [-27.4, -0.6], respectively. There were no immediate-term benefits with IV administration. CONCLUSION: The effects of glucocorticoids on immediate-term leg pain or disability are uncertain. Future large high quality trials are needed to resolve this uncertainty.

STANDING Collaboration: a study protocol for developing clinical standards.

INTRODUCTION: Despite widespread availability of clinical practice guidelines (CPGs), considerable gaps continue between the care that is recommended ('appropriate care') and the care provided. Problems with current CPGs are commonly cited as barriers to providing 'appropriate care'.Our study aims to develop and test an alternative method to keep CPGs accessible and up to date. This method aims to mitigate existing problems by using a single process to develop clinical standards (embodied in clinical indicators) collaboratively with researchers, healthcare professionals, patients and consumers. A transparent and inclusive online curated (purpose-designed, custom-built, wiki-type) system will use an ongoing and iterative documentation process to facilitate synthesis of up-to-date information and make available its provenance. All participants are required to declare conflicts of interest. This protocol describes three phases: engagement of relevant stakeholders; design of a process to develop clinical standards (embodied in indicators) for 'appropriate care' for common medical conditions; and evaluation of our processes, products and feasibility. METHODS AND ANALYSIS: A modified e-Delphi process will be used to gain consensus on 'appropriate care' for a range of common medical conditions. Clinical standards and indicators will be developed through searches of national and international guidelines, and formulated with explicit criteria for inclusion, exclusion, time frame and setting. Healthcare professionals and consumers will review the indicators via the wiki-based modified e-Delphi process. Reviewers will declare conflicts of interest which will be recorded and managed according to an established protocol. The provenance of all indicators and suggestions included or excluded will be logged from indicator inception to finalisation. A mixed-methods formative evaluation of our research methodology will be undertaken. ETHICS AND DISSEMINATION: Human Research Ethics Committee approval has been received from the University of South Australia. We will submit the results of the study to relevant journals and offer national and international presentations.

OPAL: a randomised, placebo-controlled trial of opioid analgesia for the reduction of pain severity in people with acute spinal pain. Trial protocol.

INTRODUCTION: Low back pain and neck pain are extremely prevalent and are responsible for an enormous burden of disease globally. Strong analgesics, such as opioid analgesics, are recommended by clinical guidelines for people with acute low back pain or neck pain who are slow to recover and require more pain relief. Opioid analgesics are widely and increasingly used, but there are no strong efficacy data supporting the use of opioid analgesics for acute low back pain or neck pain. Concerns regarding opioid use are further heightened by the risks of adverse events, some of which can be serious (eg, dependency, misuse and overdose). METHODS AND ANALYSIS: OPAL is a randomised, placebo-controlled, triple-blinded trial that will investigate the judicious use of an opioid analgesic in 346 participants with acute low back pain and/or neck pain who are slow to recover. Participants will be recruited from general practice and randomised to receive the opioid analgesic (controlled release oxycodone plus naloxone up to 20 mg per day) or placebo in addition to guideline-based care (eg, reassurance and advice of staying active) for up to 6 weeks. Participants will be followed-up for 3 months for effectiveness outcomes. The primary outcome will be pain severity. Secondary outcomes will include physical functioning and time to recovery. Medication-related adverse events will be assessed and a cost-effectiveness analysis will be conducted. We will additionally assess long-term use and risk of misuse of opioid analgesics for up to 12 months. ETHICS AND DISSEMINATION: Ethical approval has been obtained. Trial results will be disseminated by publications and conference presentations, and via the media. TRIAL REGISTRATION NUMBER: ACTRN12615000775516: Pre-results.

Potentially inappropriate medications (PIMs) in older hospital in-patients: Prevalence, contribution to hospital admission and documentation of rationale for continuation.

AIM: To establish prevalence, sequelae and documentation of potentially inappropriate medication (PIM) use in older hospital in-patients. METHODS: Notes of all patients ≥65 years old, admitted to our tertiary teaching hospital (January 2013), were retrospectively reviewed, and the Screening Tool of Older Persons' potentially inappropriate Prescriptions applied. RESULTS: Amongst 534 patients, 54.8% (284) were on ≥1 PIM at admission, 26.8% on multiple; 60.8% were discharged on a PIM. Six percent of all admissions were potentially attributable to a PIM; falls associated with risk therapies were commonest (23/30), and often (65.2%) associated with serious injury. Pre-specified subgroup analysis (n = 100) identified 101 PIMs-at-discharge amongst 47 patients. In 82.2%, a clinical rationale for continued prescription was documented, with this communicated to the GP by letter in 71.1%. CONCLUSION: PIMs were common, and contributed to admission and injury. Hospitalisation provides an opportunity for medication rationalisation, and documentation of rationale for any PIM use.

Development of Preliminary Remission Criteria for Gout Using Delphi and 1000Minds Consensus Exercises.

OBJECTIVE: To establish consensus for potential remission criteria to use in clinical trials of gout. METHODS: Experts (n = 88) in gout from multiple countries were invited to participate in a web-based questionnaire study. Three rounds of Delphi consensus exercises were conducted using SurveyMonkey, followed by a discrete-choice experiment using 1000Minds software. The exercises focused on identifying domains, definitions for each domain, and the timeframe over which remission should be defined. RESULTS: There were 49 respondents (56% response) to the initial survey, with subsequent response rates ranging from 57% to 90%. Consensus was reached for the inclusion of serum urate (98% agreement), flares (96%), tophi (92%), pain (83%), and patient global assessment of disease activity (93%) as measurement domains in remission criteria. Consensus was also reached for domain definitions, including serum urate (<0.36 mm), pain (<2 on a 10-point scale), and patient global assessment (<2 on a 10-point scale), all of which should be measured at least twice over a set time interval. Consensus was not achieved in the Delphi exercise for the timeframe for remission, with equal responses for 6 months (51%) and 1 year (49%). In the discrete-choice experiment, there was a preference towards 12 months as a timeframe for remission. CONCLUSION: These consensus exercises have identified domains and provisional definitions for gout remission criteria. Based on the results of these exercises, preliminary remission criteria are proposed with domains of serum urate, acute flares, tophus, pain, and patient global assessment. These preliminary criteria now require testing in clinical data sets.

The management of severe hypertension in Australian general practice.

BACKGROUND: Severe hypertension (SHT) (Blood Pressure, BP ≥ 180/110 mmHg) is associated with considerable morbidity and mortality, yet little is known about how it is managed. The purpose of this study is to examine the management of SHT by Australian general practitioners (GPs) and to explore its variance across patient characteristics and clinical practices. METHODS: Review of electronic medical records for a year before and after a recorded measure of SHT in 7,499 patients by 436 GPs in 167 clinics throughout Australia during 2008-2009. Outcome measures included follow-up, referral, changes to antihypertensive drug treatment, and BP control (normotensive reading, BP < 140/90 mmHg, and whether subsequent recorded measures were also in the normal range--sustained normotension). RESULTS: Of 7,499 patients with an electronic BP record of SHT, 94% were followed up (median time 14 days); 8% were referred to an appropriate specialist (median time 89 days--2% within 7 days) and 86% were managed by GPs. GPs initiated or changed antihypertensive drugs in 5,398 patients (72% of cohort); of these, 46% remained hypertensive (4% with SHT) and 7% achieved sustained normotension; 6% had no further electronic BP records. The remaining 14% had no medication changes; among these, 43% remained hypertensive (5% with SHT) and 3% achieved sustained normotension; 32% had no further electronic BP records. Some outcome measures displayed a variance across GP clinics that was mostly unexplained by patient or practice characteristics. CONCLUSIONS: Most patients with SHT had at least one follow-up visit and 72% had initiation of, or changes to, antihypertensive drug treatment. Although most of the patients experienced some improvement, blood pressure control was poor. Some clinics showed better performance. Suggestions are made for the development of clinical standards to facilitate appropriate management of this dangerous condition.

Access to high cost medicines in Australia: ethical perspectives.

Access to "high cost medicines" through Australia's Pharmaceutical Benefits Scheme (PBS) is tightly regulated. It is inherently difficult to apply any criteria-based system of control in a way that provides a fair balance between efficient use of limited resources for community needs and equitable individual access to care. We suggest, in relation to very high cost medicines, that the present arrangements be re-considered in order to overcome potential inequities. The biological agents for the treatment of rheumatoid arthritis are used as an example by which to discuss the ethical issues associated with the current scheme. Consideration of ethical aspects of the PBS and similar programs is important in order to achieve the fairest outcomes for individual patients, as well as for the community.

The views of stakeholders on controlled access schemes for high-cost antirheumatic biological medicines in Australia.

BACKGROUND: In Australia, government-subsidised access to high-cost medicines is "targeted" to particular sub-sets of patients under the Pharmaceutical Benefits Scheme to achieve cost-effective use. In order to determine how this access system could be improved, the opinions of key stakeholders on access to biological agents for rheumatoid arthritis were explored. METHODS: Thirty-six semi-structured interviews were conducted with persons from relevant stakeholder groups. These were transcribed verbatim, and analysed thematically. RESULTS: Controlled access to expensive medicines was considered to be equitable and practical; however, there was disagreement as to the method of defining the target patient populations. Other concerns included timeliness of access, excessive bureaucracy, and the need for additional resources to facilitate the scheme. Collaboration between stakeholders was deemed important because it allows more equitable distribution of limited resources. The majority considered that stakeholder consultation should have been broader. Most wanted increased transparency of the decision-making process, ongoing and timely review of access criteria, and an increased provision of information for patients. More structured communication between stakeholders was proposed. CONCLUSION: The Pharmaceutical Benefit Scheme is adapting to meet the changing needs of patients. Provision of subsidised access to high-cost medicines in a manner that is affordable for individuals and society, and that is equitable and efficiently managed is challenging. The views of stakeholders on targeted access to anti-rheumatic biological medicines in Australia acknowledged this challenge and provided a number of suggestions for modifications. These could serve as a basis to inform the debate on how to change the processes and policies so as to improve the scheme.