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Treatment of cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplantation (alloHCT) patients with ganciclovir is complicated by toxicity and resistance. This study aimed to develop an intravenous ganciclovir population pharmacokinetic model for post-alloHCT patients and to determine dosing regimens likely to achieve suggested therapeutic exposure targets. We performed a prospective observational single-center pharmacokinetic study in adult alloHCT patients requiring treatment with intravenous ganciclovir for CMV viremia or disease. Samples were analyzed using a validated ultraperformance liquid chromatography method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R. Twenty patients aged 18 to 69 years were included in the study. A 2-compartment model with linear elimination from the central compartment and between occasion variability best described the data. Incorporating creatinine clearance (CLCR) estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and presence of continuous renal replacement therapy as covariates for ganciclovir clearance improved the model. Compared to current dosing recommendations, simulations demonstrated loading doses were required to achieve a target AUC24 of 80 to 120 mg.h/L on day 1 of induction therapy. Increased individualization of post-loading induction and maintenance doses based on CLCR is required to achieve the suggested exposures for efficacy (AUC24 >80/>40 mg.h/L for induction/maintenance) while remaining below the exposure thresholds for toxicity (AUC24

Background Allergy to opioids is the second most common drug allergy label in electronic health records (EHR). Adverse drug reactions (ADR) to opioids cause significant morbidity and contribute to healthcare costs, while incorrect opioid allergy labels may unnecessarily complicate patient management. Aims To examine the documentation of opioid ADR in a large-scale hospital-based EHR. Methods A cross-sectional retrospective review of EHR documentation of opioid ADR at four public hospitals in South Australia was conducted. Data were extracted from all ADR entries including the reported allergen, ADR category (allergy or intolerance) and reaction details. Expert criteria were used to determine consistency of ADR categorisation as allergy or intolerance. Results Of 86 727 unique ADR reports, there were 13 781 ADR to opioids with most being entered as allergy (n = 8913, 64.7%) rather than intolerance (n = 4868, 35.3%). The most commonly documented reactions were nausea/vomiting (n = 3912, 28%), rash (n = 647, 5%), itch (n = 642, 5%) and hallucinations (n = 527, 4%). There were 362 (3%) ADR labels of anaphylaxis. Of those ADR containing a reaction description (n = 11 868), 89% of reports entered as allergy had a reaction description that was consistent with intolerance and 8% of the entered intolerances had descriptions consistent with allergy when assessed using predefined criteria. Conclusions This large EHR-based study demonstrates the high rate of opioid ADR labels in EHR. The majority of these labels were for symptoms suggestive of pharmacological intolerance. Reactions consistent with true allergy were uncommon. Systematic review of ADR by a dedicated clinical service would improve the accuracy of documentation.

Direct oral anticoagulant (DOAC) use for stroke prevention in atrial fibrillation (AF) has dose reduction criteria including age, weight, serum creatinine, and creatinine clearance. There is a paucity of data for rates of inappropriate inpatient DOAC dosing in Australia. The objective was to determine the rates of inappropriate inpatient DOAC dosing in AF and identifying its associated underlying factors. We conducted a retrospective cross-sectional study from December 2013 to November 2019 across six South Australian public hospitals utilising a centralised electronic health record. Multivariate analysis was used to identify factors associated with underdosing of patients prescribed apixaban. Of 1882 inpatients, 544 (28.9 %) were inappropriately dosed. Underdosing was the most common form of inappropriate dosing with rates of 22.9 % (n = 295), 7.1 % (n = 7), and 25.1 % (n = 124) for apixaban, dabigatran, and rivaroxaban, respectively. Independent factors predictive of apixaban underdosing included higher age (adjusted odds ratio (aOR) 1.63 [95 % Confidence Interval (CI): 1.47–1.81]), higher serum creatinine (aOR 1.13 [95 % CI: 1.08–1.19]), higher total number of drugs on discharge (aOR 1.08 [95 % CI: 1.04–1.11]), and being already prescribed a DOAC on admission (aOR 1.63 [95 % CI: 1.12–2.38]). Nearly one quarter of all apixaban prescribing was inappropriately underdosed. Older patients with multimorbidity, frailty and polypharmacy present a challenge for clinicians in balancing risks of thromboembolism and bleeding. It is likely prescribers are more conservative in their apixaban dosing in this population. Clinicians should consider alternative drug regimens to avoid DOAC use at inappropriate doses at unknown safety and efficacy. Refereed/Peer-reviewed

Ganciclovir (GCV) and valganciclovir (VGCV) are the first-line agents used to prevent and treat cytomegalovirus (CMV) infection in allogeneic haematopoietic stem cell transplant (alloHCT) patients. The aim of this work was to describe available data for the clinical pharmacokinetics, pharmacodynamics and toxicodynamics of GCV and VGCV and the potential of a therapeutic drug monitoring strategy to improve outcomes in the alloHCT population. We systematically reviewed the pharmacokinetics (dose-exposure), pharmacodynamics (exposure-efficacy) and toxicodynamics (exposure-toxicity) of GCV and VGCV in alloHCT patients with CMV infection. Studies including alloHCT patients treated for CMV infection reporting the pharmacokinetics, pharmacodynamics and toxicodynamics of GCV or VGCV were searched for using the PUBMED and EMBASE databases from 1946 to 2019. Only studies involving participants > 12 years of age and available in the English language were included. A total of 179 patients were included in the 14 studies that met the inclusion criteria, of which 6 examined GCV pharmacokinetics only, while 8 also examined GCV pharmacodynamics and toxicodynamics. Reported pharmacokinetic parameters showed considerable interpatient variability and were different from other populations, such as solid organ transplant and human immunodeficiency virus-infected patients. Only one study found a correlation between neutropenia and elevated peak and trough GCV concentrations, with no other significant pharmacodynamic and toxicodynamic relationships identified. While therapeutic drug monitoring of GCV is performed in some institutions, no association between GCV therapeutic drug monitoring and clinical outcomes was identified. Further studies of the pharmacokinetics, pharmacodynamics and toxicodynamics of GCV/VGCV in alloHCT patients are required to identify a more robust therapeutic range and to subsequently quantify the potential value of therapeutic drug monitoring of GCV/VGCV in the alloHCT population.

Background: Polypharmacy has been associated with increased mortality but the contribution of different medication-related factors to this is unknown. Aims: The aim of this study was to identify demographic and medication-related predictors of mortality in the older population. Given the intrinsic link between polypharmacy and multimorbidity, the secondary aim was to examine if the medicines or underlying diseases predicted mortality. Methods: Patients aged ≥ 65 years from an outpatient multimorbidity clinic were included. Medication-related factors included the medicines count, high-risk medicines, inappropriate medicines duplication, and potential drug–drug and drug–disease interactions. Logistic regression was used to identify mortality predictors within a year of clinic discharge from the outpatient clinic. Patients attend the clinic until medications and comorbidity management have been optimised, at which point they are discharged from the clinic, and their General Practitioner provides ongoing care. Results: A total of 584 patients were included (median age 80.0 years) and 9.9% (n = 58) died within a year of discharge. Demographics, namely age (adjusted odds ratio [aOR] 1.05; 95% CI 1.01–1.09; p = 0.018) and being male (aOR 5.10; 95% CI 2.63–9.88; p < 0.001); chronic disease, namely heart failure (aOR 3.36; 95% CI 1.78–6.35; p < 0.001); and medication-related factors, namely the number of sedative and anticholinergic medicines (aOR 1.66; 95% CI 1.19–2.33; p = 0.003) predicted mortality in the study population. Conclusion: Whilst polypharmacy has been defined using the number of medicines in the literature, a combination of demographics, chronic disease and medications predicted mortality in our study. This provides guidance for the development of future tools and guidelines regarding the inclusion of key factors for identifying high-risk patients at risk of adverse health outcomes such as mortality. Refereed/Peer-reviewed

Background Warfarin is underutilised in frail older people because of the fear of bleeding complications. Drug interactions are an independent bleeding risk factor. However, the extent to which potential drug interactions are taken into account at warfarin therapy initiation in frail patients is not known. Objective The objective of this study was to investigate the use of potentially interacting drugs increasing the bleeding risk before and after warfarin initiation in frail and non-frail patients. Methods We conducted an observational study including inpatients aged ≥ 60 years initiated on warfarin in a tertiary hospital in Adelaide, South Australia. Frailty status was assessed with the Reported Edmonton Frail Scale. Medication charts were reviewed before and after warfarin initiation. Results In total, 151 patients (102 non-frail and 49 frail) were included. Before warfarin initiation, the use of clopidogrel and acetaminophen was more common in frail patients compared with non-frail patients (25.5% vs 10.2%, p = 0.0135, 63.8% vs 35.7% p = 0.0014, respectively). The use of non-steroidal anti-inflammatory drugs, 9.2% in non-frail patients and 6.4% in frail patients before warfarin initiation, was completely stopped after warfarin initiation in both groups. The use of antiplatelet drugs decreased from 56.1% in non-frail patients and 66.0 % in frail patients to 12.2% and 14.9%, respectively. Instead, the use of drugs affecting the metabolism of warfarin or vitamin K increased in both groups. No statistically significant difference was seen in the exposure to interacting drugs between study groups after warfarin initiation. Acetaminophen, senna glycosides and cytochrome P450 2C9 inhibiting drugs were the most common interacting drugs at discharge used in 49.0%, 18.4% and 20.4% of non-frail patients and 53.2%, 29.8% and 19.1% of frail patients, respectively. Conclusions The overall frequency of potential drug interactions was moderate and frail patients were not exposed to warfarin drug interactions more often than non-frail patients. Further studies in larger study populations are required to verify these results. Electronic supplementary material The online version of this article (10.1007/s40266-020-00755-0) contains supplementary material, which is available to authorized users.

Refereed/Peer-reviewed Medication-related harm can occur during transitions of care. Revised Home Medicines Review (HMR) and Residential Medication Management Review (RMMR) program rules were published in April 2020 which allowed provision for some hospital medical practitioners to refer at-risk patients for medication review. In turn, the Society of Hospital Pharmacists of Australia's (SHPA's) Transitions of Care and Primary Care Leadership Committee developed a framework to support hospitals facilitating Hospital-Initiated Medication Reviews (HIMRs) via three pathways: HMR, RMMR, and Hospital Outreach Medication Review. Following the compilation of draft barriers and enablers to implementation of the SHPA HIMR framework, refinement occurred after broad consultation with hospital- and primary care-based pharmacists with transitions of care experience. The finalised list of barriers and enablers can inform broadscale implementation of the SHPA HIMR framework to reduce medication-related harm when high-risk patients transition from hospital to primary care and aged care.

Background: Limited consensus exists on the optimal use of antifungal agents to prevent invasive fungal infection in the early post allogeneic hematopoietic stem cell transplant (alloHCT) period, particularly when patients cannot tolerate oral medication administration. Methods: We undertook a retrospective observational cohort study to assess the tolerability, efficacy, and cost of a new antifungal prophylaxis pathway at a major tertiary alloHCT centre. Patients aged ≥16 years who underwent alloHCT between February 2018 and October 2019 (cohort 1) or between April 2020 and November 2021 (cohort 2) were included. In both cohorts, first line prophylactic therapy was oral posaconazole. The second line drugs where oral therapy was unable to be administered were intravenous voriconazole (cohort 1) versus intravenous posaconazole (cohort 2). Results: There were 142 patients enrolled in the study, 71 in each cohort. The proportion of patients remaining on first-line prophylaxis or progressing to second-, third-, and fourth-line options was 22.5%, 39.4%, 29.6%, and 8.5% in cohort 1 and 39.4%, 59.2%, 1.4%, and 0% in cohort 2, respectively. The frequency of neuropsychiatric adverse events was significantly higher in cohort 1 compared to cohort 2 (49.3% vs. 19.8%, p = .0004). Occurrence of proven and probable fungal infections was not significantly different between cohorts. Antifungal drug expenditure was $359 935 (AUD) more in cohort 1 ($830 486 AUD) compared to cohort 2 ($477 149 AUD). Conclusion: The antifungal prophylaxis pathway used in cohort 2 resulted in reduced antifungal-associated adverse effects, less patients requiring progression to 3rd and 4th line prophylaxis and reduced antifungal drug costs. Refereed/Peer-reviewed

Objectives Assess Staphylococcus aureus (S. aureus) colonization in healthy Australian adults receiving an investigational S. aureus 3-antigen vaccine (SA3Ag). Methods In this phase 1, double-blind, sponsor-unblinded study, participants were randomized to receive a single dose (1 of 3 dose levels) of SA3Ag or placebo and a booster dose or placebo at 6 months. S. aureus isolates from nasal, perineal, and oropharyngeal swabs before and through 12 months post-vaccination were identified. Results Baseline S. aureus colonization prevalence was 30.6% (any site), with nasal carriage (27.0%) more common than oropharyngeal/perineal (3.2% each). Following initial vaccination (low-dose: 102; mid-dose: 101; high-dose: 101; placebo: 102) and booster (low-dose: 45; mid-dose: 44; high-dose: 27; placebo: 181), placebo and SA3Ag groups showed similar S. aureus carriage through 12 months. Most colonized participants (74.0%) were colonized by single spa types. Placebo and SA3Ag groups had similar persistence of colonization, with 19.6–30.7% due to single spa types. Acquisition was observed in mid- and high-dose recipients (∼20%) and low-dose and placebo recipients (∼12%). Vaccination resulted in substantial increases in antibodies to all 3 antigens, irrespective of carriage status. Conclusions Based on descriptive analyses of this small study, SA3Ag vaccination did not impact S. aureus acquisition or carriage. Carriage status did not impact antibody responses to SA3Ag.

There is evidence that heart failure (HF) patients who receive pharmacist care have better clinical outcomes.English-language peer-reviewed randomized controlled trials comparing the pharmacist-involved multidisciplinary intervention with usual care were included. We searched PubMed, MEDLINE, EMBASE, CINAHL, Web of Science, Scopus, and the Cochrane Library from inception through March 2017. Cochrane method for risk of bias was used to assess within and between studies. 18 RCTs (n = 4630) were included for systematic review, and 16 (n = 4447) for meta-analysis. Meta-analysis showed a significant reduction in HF hospitalizations {odds ratio (OR) 0.72 [95% confidence interval (CI) 0.55-0.93], P = .01, I2 = 39%} but no effect on HF mortality. Similarly, a significant reduction in all-cause hospitalizations [OR 0.76, 95% CI (0.60-0.96), P = .02, I2 = 52%] but no effect on all-cause mortality was revealed. The overall trend was an improvement in medication adherence. There were significant improvements in HF knowledge (P.05), but no significant improvements were found on health care costs and self-care.The pharmacist is a vital member of a multidisciplinary team in HF management to improve clinical outcomes. There was a great deal of variability about which specific intervention is most effective in improving clinical outcomes.

Background Clinicians prescribe high-cost medicines for rare diseases and nonapproved indications when conventional therapies have failed. Objective To examine the use of non-formulary high-cost medicines at an Australian public hospital. Methods Retrospective audit of individual patient use applications for nonformulary medicines costing more than $5000 AUD per year at a large tertiary referral hospital in Adelaide, South Australia over a 12-month study period from January 2015 to December 2015. Main outcome measures Total cost of non-formulary high-cost medicines, medication class, indications for use, level of supporting evidence and proposed monitoring outcomes. Results Eighty-seven individual patient use applications were examined. All except one were approved, at a total cost of $1,339,203 AUD. The most common drug classes were anti-CD20 (n = 33, 38%), combined antiretrovirals (n = 10, 11%) and TNF-alpha antagonists (n = 10, 11%). There were 56 indications for these medicines with the majority being inflammatory conditions (n = 52, 60%), followed by infections (n = 14, 16%) and malignancies (n = 14, 16%). Of the first-time individual patient use applications (n = 63), there were 25 applications (40%) that provided a case series as supporting evidence. Approximately half of new individual patient use applications (n = 32) proposed an objective monitoring outcome, but few (n = 13, 21%) contained sufficient information to allow a third party to determine efficacy of the medication. Conclusions Non-formulary high-cost medicines are being used for a broad range of indications based largely on low levels of evidence. Prospective definition of an adequate response to treatment and reporting of these outcomes is required to improve the evidence-base and to aid decision-making for subsequent treatment courses.

In animal, epidemiological, and human challenge studies, a pre-existing T-cell response to internal proteins of influenza A has been associated with improved virological and disease outcomes. The aim of this study was to assess whether inducing additional responses to conserved CD4 and CD8 T-cell antigens provides added benefit to standard influenza vaccination.We designed a phase 2b, randomised, placebo-controlled, double-blind trial of a recombinant viral-vectored vaccine (modified vaccinia Ankara expressing virus nucleoprotein and matrix protein 1; MVA-NP+M1), which has been shown to induce both CD4 and CD8 T cells, at eight outpatient clinical trial sites in Australia over two consecutive influenza seasons. We recruited non-immunosuppressed adults (≥18 years) who had received the 2019 quadrivalent influenza vaccine (QIV) vaccine within 28 days before study enrolment and randomisation (day 0). Participants were randomly assigned (1:1) according to a computer-generated random sequence to receive one dose of 1·5 × 10Between April 2 and June 14, 2019, 2152 adults were randomly allocated and received MVA-NP+M1 (n=1077) or placebo (n=1075), comprising the efficacy (ITT) analysis set. Participants were followed up throughout the 2019 Australia influenza season (May 1 to Oct 15, 2019). 419 (19·5%) of 2152 participants were aged 65 years or older. The incidence of laboratory-confirmed influenza did not differ between the MVA-NP+M1 group (35 of 1077 participants; 3·25% [95% CI 2·31-4·44]) and the placebo group (23 of 1075; 2·14% [1·39-3·14]; Fisher's exact p=0·14). 23 severe solicited local injection site reactions were reported in 13 (0·6%) of 2152 participants, 22 of which were reported in the MVA-NP + M1 group (in 12 [1·1%] participants). 100 severe systemic events were reported in 45 (4·2%) MVA-NP + M1 recipients, and 20 were reported in 14 (1·3%) placebo recipients. Three unsolicited grade 3 events in three participants (two headache and one nausea, all in the MVA-NP+M1 group) were deemed vaccine related. 21 serious adverse events were reported in 18 (1·7%) of 1077 participants in the MVA-NP+M1 group and 25 serious adverse events were reported in 22 (2·0%) of 1075 participants in the placebo group; none were considered vaccine related. The trial was stopped after one season for futility on the recommendation of the data monitoring committee.MVA-NP+M1 was well tolerated with no vaccine-associated serious adverse events. A vaccine designed to induce moderate T-cell responses to the cross-reactive internal proteins of influenza A did not lead to improved incidence when given within 28 days after standard QIV immunisation. A greater magnitude of T-cell response with a different vaccine or regimen, or localisation in the lungs via alternative delivery, such as intranasal or aerosol, might be successful and require further investigation.Vaccitech.

Direct oral anticoagulant (DOAC) use for stroke prevention in atrial fibrillation (AF) has dose reduction criteria including age, weight, serum creatinine, and creatinine clearance. There is a paucity of data for rates of inappropriate inpatient DOAC dosing in Australia. The objective was to determine the rates of inappropriate inpatient DOAC dosing in AF and identifying its associated underlying factors. We conducted a retrospective cross-sectional study from December 2013 to November 2019 across six South Australian public hospitals utilising a centralised electronic health record. Multivariate analysis was used to identify factors associated with underdosing of patients prescribed apixaban. Of 1882 inpatients, 544 (28.9 %) were inappropriately dosed. Underdosing was the most common form of inappropriate dosing with rates of 22.9 % (n = 295), 7.1 % (n = 7), and 25.1 % (n = 124) for apixaban, dabigatran, and rivaroxaban, respectively. Independent factors predictive of apixaban underdosing included higher age (adjusted odds ratio (aOR) 1.63 [95 % Confidence Interval (CI): 1.47-1.81]), higher serum creatinine (aOR 1.13 [95 % CI: 1.08-1.19]), higher total number of drugs on discharge (aOR 1.08 [95 % CI: 1.04-1.11]), and being already prescribed a DOAC on admission (aOR 1.63 [95 % CI: 1.12-2.38]). Nearly one quarter of all apixaban prescribing was inappropriately underdosed. Older patients with multimorbidity, frailty and polypharmacy present a challenge for clinicians in balancing risks of thromboembolism and bleeding. It is likely prescribers are more conservative in their apixaban dosing in this population. Clinicians should consider alternative drug regimens to avoid DOAC use at inappropriate doses at unknown safety and efficacy.

Background: Little is known about how clinicians assess polypharmacy in real-world practice. Objectives: To identify which medication-related factors influence clinicians’ ratings of polypharmacy, harm from medicines and deprescribing of medicines when presented with a patient’s list of medications and comorbidities.Setting: A novel website called What Is Polypharmacy Exactly (WIPE) was created with 50 de-identified real-world cases with varying numbers of comorbidities and medicines.Methods: Participants, consisting of physicians and pharmacists were asked to rate each case from zero (lowest) to 10 (highest) on three questions: i) degree of polypharmacy, ii) potential for medication-related harm and iii) potential to deprescribe medicines. Medication-related factors including medicines count, high-risk medicines, inappropriate duplication, drug-drug and drug-disease interactions were assessed. Multiple linear regression was used to determine which medication-related factors influenced median ratings for the three questions. Main outcome measures: The primary outcome measure was the median rating for the degree of polypharmacy for each case. Secondary outcome measures were the median rating for the potential for harm from medicines for each case and median rating for the potential to deprescribe medicines for each case. Results: Ninety-two clinicians were included in the study, comprising of 76.1% pharmacists (n=70) and 23.9% physicians (n=22). The comorbidity count (P=0.001), medicines count (PP=0.017), high-risk medicines (P=0.049), use of NSAIDs (P=0.032) and antihypertensives (P=0.040) were predictive of the perceived degree of polypharmacy. The comorbidity count (PPP=0.016) and high-risk medicines (P=0.036) were predictive of the recognised potential for medication-related harm. The medicines count (PP=0.017), benzodiazepine use (P=0.003) and antipsychotic use (P=0.039) were predictive of the recognised potential to deprescribe medicines. Conclusion: Whilst polypharmacy has traditionally been defined using the medicines count, our findings suggest that clinicians also consider other factors such as high-risk medicines and inappropriate medicines duplication to identify patients at risk of adverse outcomes. Future polypharmacy assessment tools should additionally include these factors.

Drug allergy is commonly reported in patient notes and electronic health records. The prevalence of self-reported drug allergy in the general Australian population has not previously been studied.To investigate the prevalence of self-reported drug allergy in the general adult population in South Australia.We surveyed a representative sample of the South Australian adult population regarding their own perception of drug allergy, including drug type and severity, as well as the use of medical alert devices. Data were weighted to correspond to age and sex of the South Australian population.Twenty-two percent of adults in South Australia consider themselves allergic to one or more drugs: 9.3% declared themselves to be allergic to penicillin, 5% to an antibiotic other than penicillin and 13% to one or more antibiotics. Drug allergy and penicillin allergy was significantly more prevalent in females and increased with age. Thirteen percent of those with an antibiotic allergy reported a severe reaction, of whom 27% wore a medical notification device. Of those allergic to penicillin, 75% had their index reaction more than 10 years ago and did not report severe features.Self-reported drug allergy is common in the general population, as it is in medical clinic and hospital populations. The majority of those reporting penicillin allergy would be considered low-risk and suitable for de-labelling procedures.

Refereed/Peer-reviewed Background: The use of cardiac implantable electronic devices (CIED), which includes pacemakers, implantable cardioverter-defibrillators (ICD), cardiac resynchronisation therapy pacemakers (CRT-P) and cardiac resynchronisation therapy defibrillators (CRT-D) has increased over the past 20 years, but there is a lack of real world evidence on the longevity of these devices in the older population which is essential to inform health care delivery and support clinical decisions. Methods and Results: We conducted a retrospective cohort study using data from the Australian Government Department of Veterans’ Affairs database. The cohort consisted of people who had a CIED procedure between 2005 and 2015. The cumulative risk of generator replacement/reoperations was estimated accounting for the competing risk of death. A total of 16,662 patients were included. In pacemaker recipients with an average age of 85 years, the 5-year risk of reoperation ranged from 2.8% in single chamber, 3.6% in dual chamber to 7.6% in CRT-P recipients, while the 5-year risk of dying with the index pacemaker in situ was 63% in single chamber, 46% in dual chamber and 56% in CRT-P recipients. In defibrillator recipients with an average age of 80 years, the 5-year risk of reoperation ranged from 11% in single chamber, 13% in dual chamber to 24% in CRT-D recipients, while the 5-year risk of dying with the index defibrillator in situ was 46% in single chamber, 40% in dual chamber and 41% in CRT-D recipients. Conclusion: In this cohort of older patients the 5-year risk of generator reoperation was low in pacemaker recipients whereas up to one in four CRT-D recipients would have a reoperation within 5 years.

Background Globally, chronic disease is a leading cause of illness, disability and death and an important driver of health system utilization and spending. Continuity of care is a significant component of quality healthcare. However, an association between nurse-led services, interventions, patient outcomes and continuity of care at the primary and secondary interface as an outcome, has not been established for people with chronic disease. Objective To identify the effectiveness of nurse–led services for people with chronic disease in achieving an outcome of continuity of care at the primary-secondary healthcare interface. Design Quantitative systematic review. Data sources Systematic searches of Medline, Cochrane, Embase, Emcare, JBI and Scopus databases were conducted of studies published between 1946 and May 2019 using the search terms “nurse”, “continuity of care” and “chronic disease”. Review methods Quality of the included studies was assessed using the Cochrane risk of bias tool for randomized controlled trials and Joanna Briggs Institute quality appraisal checklists. A second reviewer screened 10% of full text articles and all articles in critical appraisal. Studies were excluded from the review if they were of poor methodological quality or the description of the effect of the nurse-led service was inadequately reported. Results Fourteen studies were included in the review (n=4,090 participants). All studies incorporated recognized continuity of care interventions. The nurse-led services were associated with fewer hospitalizations, reduced by 2-8.9% and re-admissions reduced by 14.8-51% (n=886). Reporting of positive patient experiences and improvement in symptoms and lifestyle was also evident. An association of nurse-led services with improved continuity of care between primary and secondary health services as an outcome per se could not be concluded. Conclusion Nurse-led services for adults provide coordinated interventions that support continuity of care for people with chronic disease in both the primary and secondary healthcare settings that are associated with reduced hospitalizations or readmissions and patient satisfaction. However, the limited use of validated continuity of care outcome measurement tools precluded establishing correlations between interventions, patient outcomes and continuity of care as a specific outcome.

Objective: To collaboratively develop a model of nurse-led care, within a multidisciplinary team and support continuity of care at the primary-secondary interface for people with multimorbidity. Background: Existing models of care are frequently based on a medical model, designed to manage a single disease condition, and thus pose a significant challenge to provide healthcare for people with multimorbidity. Particular design elements for models of care affecting the primary-secondary interface have been previously demonstrated, however, these have not been applied to the development of a nurse-led model of care for people with multimorbidity. Study design and methods: This paper, the first in a series of two, is part of a broader action research study and reports on the development of a model which will subsequently be assessed in terms of feasibility to provide a nurse-led care coordination service for people with multi-morbidity. This paper reports on the first action research cycle and methodology including a literature search, stakeholder engagement forums, validation workshop, team meetings, and professional engagement and validation. Results: Data from two stakeholder forums were sorted into 257 ‘structure, process and outcome’ statements and 86 goal related statements. These were cross referenced with design elements on models of care from the literature and finally aggregated into themes. The aggregated themes were then integrated into a model of care for a nurse–led care coordination service. The model consists of an overarching component, 4 domains and 6 operational areas with underpinning criteria. Conclusion: Through stakeholder consultation, consideration of the strengths of previous models and building blocks, a new nurse-led model of care that provides a pathway for transitional healthcare management at the primary -secondary interface has been developed. Inclusion of governance and culture within the model’s domains enables the approach to be pragmatic and adaptable, contributing to the potential for successful change management and model implementation in the clinical workplace. Further evaluation and refinement of the model is planned and will be reported on, in part 2 of this two-part series. Implications for research, policy, and practice: These findings provide direction for model implementation and further research required regarding nurse-led models of care. The supporting documents, systems, and processes reported, positions the model to support change and guide clinical practitioners and nursing management working at the primary-secondary healthcare interface. The future success of model implementation could provide evidence for health workforce policy and coordinated healthcare management. What is already known about this topic: Particular design elements for models of care affecting the primary-secondary interface have been previously demonstrated. Interventions delivered at the primary-secondary care interface, particularly stepped care and models of shared care are effective for the management of depression. Established model design elements and interventions to improve continuity of care at the primary-secondary interface have not been applied to nurse- led models of care for chronic conditions and still require development within research settings. What this paper adds: A new person-centred nurse-led model of care coordination, with healthcare management activities intended to support and enable development of the person’s agency in their healthcare optimisation. A model with specific domains and criteria with the potential for application to nurse-led services across primary and secondary settings, for a range of patients. Inclusion of governance and culture as domains within the model, to enable the best possibility for change, model implementation and continuity of care between the primary-secondary healthcare interface.

BackgroundAdherence to guideline-directed medical therapy (GDMT) remains low particularly in elderly despite several approaches. Previous studies showed that heart failure (HF) patients who receive pharmacist-involved multidisciplinary care may have better clinical outcomes. We evaluated patient characteristics and the practice of receiving individual GDMT in chronic HF patients who attended multidisciplinary clinics.MethodsA retrospective audit of data of chronic HF patients presenting to two multidisciplinary outpatient clinics at a tertiary hospital between March 2005 and January 2017 was performed. Data were obtained from two clinics, a Multidisciplinary Ambulatory Consulting Service (MACS) clinic which uses a pharmacist-involved model of multidisciplinary care, and a General Cardiology Heart Failure Service (GCHFS) clinic which does not have the active involvement of a pharmacist.ResultsHF with mid-range ejection fraction (HFmrEF) subjects resembled the HF with preserved ejection fraction (HFpEF) patients in terms of age, heart rate (HR), systolic blood pressure (SBP) and having higher prevalence of polypharmacy whereas resembled with the HF with reduced ejection fraction (HFrEF) for the proportion of male distribution and prevalence of ischemic heart disease (IHD). Both the clinics had similar prescribing rates of GDMT and achieved maximal tolerated doses of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARB) in HFrEF, but significantly higher prescription of ACEIs/ARBs (70.5% v. 56.2%) was found in HFpEF patients in the MACS clinic. There was significantly lower rates of β-blockers and mineralocorticoid receptor antagonists (MRAs) prescription in HFrEF and HFpEF patients in both clinics. Use of digoxin in chronic atrial fibrillation (AF) was significantly higher in HFrEF patients (82.5% v. 58.5%), but number of people anticoagulated in presence of AF and prescription of diuretics were significantly lowered in MACS clinic in HFpEF patients. Age, anemia, chronic renal failure, SBP, HR and comorbidities were the significant predictors in a multivariate binary logistic regression for the utilization of GDMT.ConclusionsOur study concludes that pharmacist is an important member of a multidisciplinary team in the management of chronic heart failure. The other roles of the pharmacist within a multidisciplinary team, including continuity of care, medication compliance and prevention of adverse reactions need further research.

BACKGROUND It is well known that recommendations from electronic medication alerts are seldom accepted or acted on by users. Key factors affecting the effectiveness of medication alerts include system usability and alert design. Thus, human factors principles that apply knowledge of human capabilities and limitations are increasingly used in the design of health technology to improve the usability of systems. OBJECTIVE This study aims to evaluate a newly developed evidence-based self-assessment tool that allows the valid and reliable evaluation of computerized medication alerting systems. This tool was developed to be used by hospital staff with detailed knowledge of their hospital’s computerized provider order entry system and alerts to identify and address potential system deficiencies. In this initial assessment, we aim to determine whether the items in the tool can measure compliance of medication alerting systems with human factors principles of design, the tool can be consistently used by multiple users to assess the same system, and the items are easy to understand and perceived to be useful for assessing medication alerting systems. METHODS The Tool for Evaluating Medication Alerting Systems (TEMAS) was developed based on human factors design principles and consisted of 66 items. In total, 18 staff members recruited across 6 hospitals used the TEMAS to assess their medication alerting systems. Data collected from participant assessments were used to evaluate the validity, reliability, and usability of the TEMAS. Validity was assessed by comparing the results of the TEMAS with those of prior in-house evaluations. Reliability was measured using Krippendorff α to determine agreement among assessors. A 7-item survey was used to determine usability. RESULTS The participants reported mostly negative (n=8) and neutral (n=7) perceptions of alerts in their medication alerting system. However, the validity of the TEMAS could not be directly tested, as participants were unaware of any results from prior in-house evaluations. The reliability of the TEMAS, as measured by Krippendorff α, was low to moderate (range 0.26-0.46); however, participant feedback suggests that individuals’ knowledge of the system varied according to their professional background. In terms of usability, 61% (11/18) of participants reported that the TEMAS items were generally easy to understand; however, participants suggested the revision of 22 items to improve clarity. CONCLUSIONS This initial assessment of the TEMAS allowed the identification of its components that required modification to improve usability and usefulness. It also revealed that for the TEMAS to be effective in facilitating a comprehensive assessment of a medication alerting system, it should be completed by a multidisciplinary team of hospital staff from both clinical and technical backgrounds to maximize their knowledge of systems.

Aims/Background A fundamental part of all clinical trials is informed consent, reflecting the respect for the volunteer’s autonomy. Research participation is voluntary; therefore, certain aspects of the proposed study must be disclosed so that volunteers can make an informed decision. In this study, we aimed to examine the level of comprehension and recall of healthy volunteers from the informed consent process. Methods The study was carried out at a single phase I clinical trials unit. A questionnaire was administered to each volunteer to assess recall of important aspects of the study at the day-1 visit following the informed consent process. The questionnaire contained seven questions regarding study objectives, route, frequency and type of drug administration, adverse effects, number of subjects previously exposed and remuneration. One point was awarded for each correct answer. Results A total of 266 volunteers were administered the questionnaire. The mean total score (±standard deviation) for all volunteers was 4.5 ± 1.1 points out of 7, with a range of 0.8–6.7. For all 10 studies, 91% of volunteers responded correctly when answering about the route of administration, and 90% were able to accurately state the correct payment amount. Only 7% were able to repeat the aims of the study correctly. Conclusion The poor performance of our study volunteers raises concerns about recall of information prior to study drug administration. This has implications for the volunteer’s safety and ability to provide true informed consent. Interventions to improve recall prior to dosing should be undertaken.

Background: Medication errors are a leading cause of harm to patients in hospital that can be decreased by electronic medication management systems. Aims: This study determined the effects of electronic prescribing using the Enterprise Patient Administration System (EPAS) on prescribing errors and adverse drug reaction (ADR) documentation in South Australian public hospitals. Methods: A prospective structured medication chart audit was conducted before (in 2012) and after the implementation (in Dec 2014) of EPAS, comparing the paper-based National Inpatient Medication Chart (NIMC) with prescribing. All inpatients were eligible for inclusion in the study. Prescribing order errors were determined by the percentage of medication orders that had unclear, illegal or unsafe prescriptions. The quality of ADR documentation was assessed by the percentage of patients with correct documentation. Results: The total number of prescribing errors before and after the implementation of EPAS was 67.7 and 2.8 per 100 orders,respectively. The frequency of prescribing order errors due to unclear, illegal and unsafe prescriptions decreased to almost zero with EPAS. Prescriptions classified as unsafe due to incorrect dose, route of administration or dosing frequency decreased from 5.8% to 0.03% of medication orders before versus after EPAS implementation (p < 0.0001). Completed ADR documentation was similar between the paper-based NIMC and EPAS, but the percentage of patients with ADR alerts who required them was 100% in EPAS compared with 27% on the NIMC (p < 0.0001). Conclusions: E-prescribing using EPAS significantly decreased prescribing errors and increased ADR alerts. Continued implementation of electronic medication management systems is an important approach to improve medication safety. Refereed/Peer-reviewed

Stearoyl‐coenzyme A desaturase 1 (SCD‐1) in sebaceous glands is a key enzyme in the synthesis of monounsaturated fatty acids essential for acne development. GSK1940029 gel, a novel SCD‐1 inhibitor, is being developed as a potential treatment for acne. To assess the irritation potential, pharmacokinetics (PK), and safety of topical GSK1940029 to the skin of healthy adults, two interdependent studies were conducted in parallel. Study 1 (n = 54) investigated the irritation potential of GSK1940029 (0.3% and 1%, occluded application) to allow for its application to larger surface areas in study 2 (n = 39), which investigated the safety, tolerability, and PK of GSK1940029 after single and repeat doses as occluded and nonoccluded applications. GSK1940029 was not a primary or cumulative irritant after 2 and 21 days of dosing in study 1. In study 2, single and repeat applications of GSK1940029 (0.1% to 1%) doses were well tolerated with little or no influence on AUC and Cmax under occluded or unoccluded conditions. Systemic exposure increased proportionally with surface area and was higher in occluded conditions. Design of these interdependent studies allowed for the assessment of the irritation potential for topical GSK1940029 in parallel with the investigation of PK and safety profiles.

Rearranged during transfection (RET), a neuronal growth factor receptor tyrosine kinase, regulates the development of the sympathetic, parasympathetic, motor, and sensory neurons in the enteric nervous system. GSK3179106 is a RET kinase inhibitor that was administered in double-blind, randomized, placebo-controlled single-dose and repeat-dose studies in healthy subjects to investigate its pharmacokinetics and safety/tolerability. In the single-dose study (n = 16), GSK3179106 was dosed from 10 mg to 800 mg, including a food effect arm. In the repeat-dose study (n = 46), GSK3179106 was dosed for 14 days with food once daily (QD) from 5 mg to 100 mg and twice daily (BID) at 100 mg and 200 mg. With single fasted doses, bioavailability was low and less than dose proportional. A significant food effect was observed with a 100-mg QD dose. Drug exposure after QD and BID repeat dosing with food showed dose dependency up to 100 mg but was not dose proportional. There were no significant differences in exposure between 100-mg and 200-mg BID doses of GSK3179106. Accumulation was observed with both QD and BID dosing. Single doses up to 800 mg and repeat doses up to 400 mg were well tolerated with no safety concerns in healthy subjects.

There are four potential outcomes when a patient commences a new drug and its effects are assessed at the correct time. First, the new drug provides no clinical benefits and gives the patient intol...

Magnetic resonance imaging (MRI) is a widely used diagnostic tool with great benefits but has been considered contraindicated in people with cardiac implantable electronic devices (CIED). We investigated the occurrence of MRI in people with CIEDs and associated adverse events in a national cohort. Of 17,848 people included, 56 (0.3%) had at least one MRI; 16 of 16,102 (0.1%) with MRI non-compatible CIEDs and 40 of 1746 (2%) with MRI compatible CIEDs. Following MRI exposure, hospitalisations for potential serious adverse events were rare. Refereed/Peer-reviewed

Background The majority of patients with penicillin allergy labels tolerate penicillins. Inappropriate avoidance of penicillin is associated with increased hospitalisation, infections and healthcare costs. Aims To examine the documentation of penicillin adverse drug reactions (ADR) in a large-scale hospital-based electronic health record. Methods Penicillin ADR were extracted from 96 708 patient records in the Enterprise Patient Administration System in South Australia. Expert criteria were used to determine consistency of ADR entry and suitability for further evaluation. Results Of 43 011 unique ADR reports, there were 5023 ADR to penicillins with most being entered as allergy (n = 4773, 95.0%) rather than intolerance (n = 250, 5.0%). A significant proportion did not include a reaction description (n = 1052, 20.9%). Using pre-set criteria, 10.1% of reports entered as allergy had a reaction description that was consistent with intolerance and 31.0% of the entered intolerances had descriptions consistent with allergy. Virtually all ADR (n = 4979, 99.1%) were appropriate for further evaluation by history taking or immunological testing and half (50.7%, n = 2549) had documented reactions suggesting low-risk of penicillin allergy. Conclusion The frequency of penicillin allergy label in this data set is consistent with the known overdiagnosis of penicillin allergy in the hospital population. ADR documentation was poor with incomplete entries and inconsistent categorisation. The concepts of allergy and intolerance for ADR classification, whilst mechanistically valid, may not be useful at the point of ADR entry by generalist clinicians. Systematic evaluation of reported ADR is needed to improve the quality of information for future prescribers.