MedsScan: Issue 4, 2022

These reviews provide updates on the international literature on therapeutics. Expert pharmacy practitioners – via SHPA’s Specialty Practice Groups – scan major peer-reviewed journals in areas relevant to Australian pharmacy practice and present precis on major clinical trials, important pharmacoepidemiology studies and pharmacoeconomic research, and other updates relevant to practice. Interested readers are encouraged to explore the original publications in greater detail.

ABORIGINAL AND TORRES STRAIT ISLANDER HEALTH

GRIT Liaison for #SHPAIndigenous: Nicola Maddern

Community-driven health research

In 2018, at a Hot North conference in Waiben (Thursday Island), the community called for a research agenda that was locally driven, empowering, and would remove the sense of exploitation, disrespectfulness and lack of benefit to the people that had been present in research for decades.

Researchers from the Australian Institute of Tropical Health and Medicine worked with a group of Elders and senior health providers to develop a research program that focused on both health and cultural needs, to address the aim of promotion of research skills through a “learning-by-doing approach”. Workshops were undertaken in 2019 to progress this work. The four workshops covered the following topics: Asking the right questions; Ways to address the questions in an ethical and cultural context; Collecting and handling the information; and What to do with the results.

Overall, the response to the workshops was positive and the participants were given the opportunity to develop and refine their own research questions and consider how this would be translated into real health outcomes.

COVID-19 put a halt to the work in this space and highlighted one of many challenges when conducting research in a community-driven manner. Funding and acceptance in the community were also flagged as ongoing challenges. It was felt that this model may benefit the broader research community if these challenges could be overcome.

With the recent release of the updated Australian Institute of Aboriginal and Torres Strait Islander Studies (AIATSIS) code of ethics1, it is great to see some researchers ahead of the game and incorporating the key principles of this code into practice: integrity, self-determination, Indigenous leadership, impact and value and, sustainability and accountability.

Wapau H, Kris E, Roeder L, McDonald M on behalf of the Australian Institute of Tropical Health and Medicine Torres Strait Community-Driven Research Collaboration. Community-driven health research in the Torres Strait. Aust J Prim Health 2022; 28: 289–95.

References

  1. Australian Institute of Aboriginal and Torres Strait Islander Studies (AIATSIS). AIATSIS Code of Ethics for Aboriginal and Torres Strait Islander Research. Canberra: AIATSIS; 2020.

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CLINICAL TRIALS

GRIT Liaison for #SHPAClinTrials: June Challen

The health and economic impact of investigator-initiated clinical trials

In Australia, from 2006–2015, more than 10 000 clinical trials were conducted through Australian clinical trial networks (CTNs), including more than 5 million participants. While the proportion of funding for non-industry sponsored investigator-initiated clinical trials (IITs) is relatively small, these studies account for more than half of Australia’s clinical trial activity. IITs have had a major impact on the improvements of health care quality and outcomes.

This article illustrates the key findings and recommendations from an evaluation conducted with a selected group of three well-established CTNs on the overall health and economic impact of IITs weighing benefits against clinical trial and network costs. This is the first such analysis conducted of the role of CTNs in the Australian health sector. The evaluation found that funding provided to run a portfolio of IITs did not cover the total costs within either a CTN or at an individual IIT level, and in-kind funding support was relied upon to make up the shortfall. The authors highlight that such support is at capacity in many instances and at risk of exhaustion. The authors argue that reliance on such support undermines the timeliness, volume and international competitiveness of clinical research in Australia.

The joint ACTA/ACSQHC Working Group. The value proposition of investigator-initiated clinical trials conducted by networks. Med J Aust 2021: 214: 159–61.e1.

Speed or rigour? The pressure to produce results and unethical COVID-19 research

Ivermectin — used to treat a range of parasitic diseases — was tested as a possible treatment and prevention for COVID-19. Initial research from randomised trials and systematic reviews suggested large benefits from the drug, including reduced hospital admissions and improved survival rates.

This editorial notes that of 26 major ivermectin trials for COVID-19, more than one third of them contained serious errors or possible fraud. Meyerowitz-Katz et al., also discuss two recent ivermectin research ethics scandals.1 The authors argue it “is both unethical and a waste of resources to conduct drug research in an emergency that is of such low quality that no conclusions can be drawn about the drug’s efficacy”.

The authors acknowledge that times of global health crisis can put pressure on researchers to “act quickly” and this can “lead researchers to cause harm”. However, fast and informative trials can be run during a pandemic.  Meyerowitz-Katz et al., note that the Recovery trial allowed clinicians to quickly and efficiently discard ineffective treatments while adopting effective ones (such as dexamethasone).2 The editorial concludes by indicating that the urgency of a pandemic is not an excuse for poorly designed studies, ethical misconduct or the violation of human rights.

Meyerowitz-Katz G, Wieten S, Medina Arellano, MdJ, Yamey G. Unethical studies of ivermectin for covid-19. BMJ 2022; 377 :o917

References

  1. Dyer O. Covid-19: Mexico City gave ivermectin kits to people with covid in “unethical” experiment. BMJ 2022; 376: 0453.
  2. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med 2021; 25: 693–704.

Phase 1 trials and the experiences of patient-participants

Phase 1 drug trials are treatment options for patients with advanced disease, however the decision to participate in a clinical trial is complex. For some patients with advanced disease, their priorities may change to a focus on quality rather than quantity of life, while for others survival is their goal   and access to phase 1 trials may be seen by them to offer hope by giving access to new treatments. It has been suggested that such patients experience enhanced vulnerability.

This review brings together the qualitative evidence of patients’ experiences of participating in phase 1 oncology trials, exploring their decisions to take part and the impact of these trials on patient wellbeing. A comprehensive literature search was undertaken and studies were critically appraised and data extracted. Qualitative results were analysed using thematic synthesis. Three main themes were identified across 13 studies: decision-making and joining the trial; experiences of taking part in the trial; and hope and coping. This synthesis shows hope of therapeutic benefits as a primary motivator to trial participation and continuation, with altruism a secondary concern. The apparent bias towards treatment benefit presents an ethical challenge to models of informed consent in phase 1 trials. Escritt et al., discuss that hope is essential when facing terminal illness and indicate that medical teams must maintain a careful balance between realism and hope.

The authors conclude that these findings challenge information-based models of consent, favouring coping frameworks which account for the role of hope and meaning-making during serious illness.

Escritt K, Mann M, Nelson A, Harrop E. Hope and meaning-making in phase 1 oncology trials: a systematic review and thematic synthesis of qualitative evidence on patient- participant experiences. Trials 2022; 23: 409.

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CRITICAL CARE

GRIT Liaison for #SHPACritCare: Lucy Arno

Population pharmacokinetics of levetiracetam and dosing evaluation in critically ill patients with normal or augmented renal function

Levetiracetam is frequently used in critical care, both for treatment and prophylaxis of seizures, because of its ease of use and safety profile compared with other agents. Bilbao-Meseguer et al., evaluated the adequacy of levetiracetam dosing in intensive care unit patients with normal or augmented renal clearance using population modelling and simulation. Augmented renal clearance (ARC) is common in populations with traumatic brain injury and subarachnoid haemorrhage who are also commonly treated with levetiracetam. ARC is relevant to levetiracetam as it is primarily renally excreted.

All included patients had measured creatinine clearance (CrCl) > 50 mL/min. Of the included patients (n = 27), 37% had ARC (CrCl > 130 mL/min). Each patient received a dose of 500, 1000 or 1500 mg of levetiracetam every 12 hours, infused over 30 minutes. Blood samples were taken pre dose, at the end of the infusion (30 minutes) and at the end of the dosing interval (12 hours). Additional samples were taken within the intervals of 1–2 hours, 3–5 hours and 6–8 hours. Plasma concentrations were determined by a high-performance liquid chromatography assay. Pharmacokinetic parameters were determined, and modelling was completed using numerous covariates. Dosing simulations were completed using the developed model.

It is noted that the target concentration range for levetiracetam is not well established (and there is no differentiation between treatment or prophylaxis). The authors used a reference range of 12–46 mg/L.

The modelling indicated that CrCl had the most significant effect on levetiracetam clearance. The investigators found that 500 mg twice daily is inadequate to achieve target concentrations in the studied population, with even the maximum approved dose (1500 mg twice daily) being possibly inadequate in the ARC group. For patients with normal renal function, the investigators suggest that 500 mg three times a day or 1000 mg twice daily could be required.

Bilbao-Meseguer I, Barrasa H, Asín-Prieto E, Alarcia-Lacalle A, Rodríguez-Gascón A, Maynar J, et al. Population pharmacokinetics of levetiracetam and dosing evaluation in critically ill patients with normal or augmented renal function. Pharmaceutics 2021; 13(10): 1690.

The Kids Are Alright: A multifaceted approach to reduce paediatric delirium in a Paediatric Intensive Care Unit (PICU)

Special contributor: Kieran Behan

Delirium, immobilisation, and heavy sedation are major contributors to paediatric post-intensive care syndrome. However, interventions to minimise their incidence and optimise functional outcomes can be difficult to implement. This observational study evaluated the feasibility and safety of a bundle of measures prioritising delirium screening and treatment, early mobilisation and benzodiazepine-limited sedation.

Outcomes were measured in pre- and post-implementation phases. Patients requiring admission for < 72 hours were excluded.  Children in the post-implementation cohort were significantly younger than those in the pre-implementation phase, however other characteristics were evenly matched.  Delirium screening was evaluated using the Connell Assessment of Paediatric Delirium scale. Early mobilisation was performed and a new sedation protocol, limiting the use of benzodiazepines, was adopted.

In the pre- and post-implementation phases, 137 and 88 patients were enrolled, respectively. High rates of delirium screening (90.9%), benzodiazepine-limited sedation (81.1%) and early mobilisation (70.4%) were achieved in the post-implementation phase. The overall incidence of delirium was 23%. Compared to the pre-implementation period, significantly less benzodiazepines were used in the post-implementation period [0.83 vs 0.74, p = 0.0001], whilst dexmedetomidine use was increased [0.53 vs 2.64, p = 0.0001]. There was a non-significant reduction in opioid use in the post-implementation period. Mobilisation was significantly higher. Duration of mechanical ventilation, length of stay and iatrogenic withdrawal syndrome were significantly lower in the post-implementation period.

This study has shown that implementation of a bundle of evidenced based interventions is feasible and safe, with further studies required to determine the impact of long-term patient outcomes, as well as the financial impact. These findings are likely to be applicable to the Australian PICU setting.

Di Nardo M, Boldrini F, Broccati F, Cancani F, Satta T, Stoppa F, et al. The LiberAction project: Implementation of a pediatric liberation bundle to screen delirium, reduce benzodiazepine sedation, and provide early mobilization in a human resource-limited Pediatric Intensive Care Unit. Front Pediatr 2021; 8: 788997.

Thinking about antiseizure medications? Why it's time to check interactions

Special contributor: Brigitte Catalano

Antiseizure drug (ASD) polypharmacy is commonly utilised in intensive care units (ICUs) to control status epilepticus (SE). Consequently, this introduces an increased risk of drug-drug interactions (DDI) — for both ASDs and regular chronic medications (RCM) — which can result in reduced efficacy or toxicity. ICU guidelines lack extensive investigation into ASD DDI.

 A retrospective, observational bi-centric cohort study of SE patients in two ICUs in France was completed over a four-year period (2016–2020). A total of 431 patients were observed for DDI (290 males/141 females; age 57 +/- 17 years). DDIs were classified into three categories: moderate, major and severe; defined by two open access DDI database programs. Each patient recorded a potential DDI. Overall, 5504 were recorded: moderate = 4871 (89%), major = 562 (10%) and severe = 16 (1%). Pharmacokinetic (CYP450) and pharmacodynamic (increased sedation) accounted for 36% and 64% of DDIs, respectively.

Common patient profiles admitted to ICUs for SE included: epileptic or brain trauma patients (n = 177), withdrawal syndrome (n = 155), older patients with comorbidities including hypertension (71%), cardiovascular disorders (70%), diabetes mellitus (36%) and renal failure (29%) (n = 70) and self-poisoned patients with mental health history (n = 29).

Potential DDI were found between ASD-ASD (33%), ASD-RCM (47%) and ASD-ICU treatments (20%).  Major to severe DDIs mostly occurred in ASD-regular chronic medications. Higher risk factors for DDIs included increased length of stay in ICU and an increase in  the number of medications prescribed. This study excluded patients with cardiac arrest or recent neurosurgery, however these patient cohorts are commonly seen in ICUs. Clinicians and pharmacists are recommended to recognise risk factors for these patient cohorts in ICUs and utilise DDI checkers to prevent sequalae.

Le Roux C, Destère A, Hervy S, Lloret-Linares C, Reignier J, Caillet P, et al. Potential drug–drug interactions when managing status epilepticus patients in intensive care: A cohort study. Br J Clin Pharmacol 2022; 88: 2408–18.

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EDUCATION AND EDUCATIONAL VISITING

GRIT Liaison for #SHPAEdu: Michelle Hansen

Intellectual Humility and Collaborative Practice

Interprofessional care is a coordinated approach to healthcare in which multiple professions work together to provide patient care. Whilst the importance of interprofessional collaboration on patient care has long been recognised, barriers to this practice still exist. In this commentary, the authors discuss the concept of intellectual humility, how this virtue relates to interprofessional collaboration and how this can be taught to pharmacy students.

The cognitive phenomenon of intellectual humility involves the ability to recognise that “one’s beliefs and opinions might be incorrect”.  It has been proposed that intellectual humility is comprised of four core dimensions including, open-mindedness, intellectual modesty, corrigibility and engagement. By mapping each of these dimensions against the competency domains for interprofessional collaboration, it can be seen how intellectual humility may provide benefit in facilitating collaborative practice.

Suggested strategies to teach intellectual humility to pharmacy students include the use of self-assessments, simulated patient cases, evaluation of behaviours and role modelling. The success of these strategies could then be evaluated by using reflective writing as a form of self-assessment. Further research on the effectiveness of teaching intellectual humility is recommended to measure its impact on behaviours and interprofessional practice.

Interprofessional collaborative practice is a focus for healthcare that is recognised nationally and internationally. The alignment of intellectual humility with the principles of interprofessional collaboration suggests that training pharmacy students on this behaviour may assist in preparing them for collaborative practice.

de la Peña I, Koch J. Teaching Intellectual Humility is Essential in Preparing Collaborative Future Pharmacists. Am J Pharm Educ 2021; 85: 1007–11.

Entrustable Professional Activities

Entrustable Professional Activities (EPAs) were introduced in health professional education in 2007 as a method of assessing competency and determining the required level of supervision for undertaking tasks in clinical practice. Being a relatively new concept, evidence in this space is still growing with further evaluation of the use of EPAs recommended. This review aims to describe how EPAs are currently being used to support education of health professionals with an emphasis on their use within pharmacy.

A database search was undertaken to identify articles published between January 2011 and March 2021 that related to medical education, pharmacy education and entrustable professional activities. The 243 articles found were each screened and reviewed by one author with 21 articles identified for inclusion in the review. A narrative review was performed which identified three key themes including, frameworks for the development of EPAs, implementation and evaluation of EPAs for workplace learning and gaps in knowledge and future directions for EPAs.

The review highlighted that there is currently no standard approach or method used in the development, implementation or evaluation of EPAs. A standardised approach to EPAs has been recommended with the importance of involving key stakeholders and aligning with existing curriculum and competency frameworks recognised. Further work and research in this space is warranted to ensure EPAs and utilised successfully for pharmacy education.

Abeyaratne C, Galbraith K. A Review of Entrustable Professional Activities in Pharmacy Education. Am J Pharm Educ 2021; 86: 8872.

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EMERGENCY MEDICINE

GRIT Liaison for #SHPAEmergMed: Amy Thomson and Libby Currey

A novel bedside test to aid direct oral anticoagulant (DOAC) risk assessment

Serum DOAC concentrations are not routinely available in Australia. It is sometimes crucial to know if a patient has a therapeutic concentration of DOAC systemically to guide decision making around the management of hemorrhage, stroke or emergency surgery.

Örd et al., evaluated a DOAC Dipstick test, a bedside DOAC urinalysis. This clinical pilot study aimed to evaluate the uses and limitations of this new test and determine the consistency of visual analysis vs DOASENSE Reader analysis of the DOAC Dipstick pads. Plasma and urine samples of 23 patients taking DOACs and 10 volunteers not taking any anticoagulants were collected and assessed by chromogenic substrate assays and by urine DOAC Dipstick. A threshold plasma DOAC concentration of ≥ 30 ng/mL was chosen to indicate a positive result based on previous studies.

The DOAC Dipstick and the Reader gave positive results in all 23 patients, with two having plasma concentrations < 30 ng/mL. The interobserver agreement rates for visual analysis of urine and the DOASENSE Reader analysis in the DOACs group were 91% and 100% respectively, and 100% for the control group in both analysing methods. The abnormalities of urine colour did not affect the result.

The DOAC Dipstick test provides a rapid result that is considered easy to interpret and can be performed at the bedside. However, further investigations are needed to find the lowest concentration of DOACs that can be detected and the effect of time between last drug intake and urine sampling. In conclusion, DOAC Dipstick may be an easy and effective way to detect the presence of DOACs in urine for emergencies, and with DOASENSE Reader for a consistent analysis. Further studies confirming its practical application in clinical scenarios is required.

Örd L, Marandi T, Märk M, Raidjuk L, Kostjuk J, Banys V, et al. Evaluation of DOAC dipstick test for detecting direct oral anticoagulants in urine compared with a clinically relevant plasma threshold concentration. Clin Appl Thromb Hemost 2022; 28: 10760296221084307.

Understanding the FAKTs about fentanyl in rapid sequence intubation 

Special contributor: Taylor Gerritzen

Rapid sequence induction (RSI) commonly occurs in the emergency department (ED). Many factors must be considered when selecting medications to perform this procedure.  

The FAKT trial was a multicentre, randomised double blind placebo-controlled trial conducted at five NSW hospitals. The trial compared fentanyl vs placebo, used in combination with ketamine and rocuronium, for rapid sequence intubation of adults in the ED. The primary outcome was the proportion of patients with a systolic blood pressure (SBP) outside pre-specific parameters (SBP 110–150) within 10 minutes post administration.

In the fentanyl group, 66% (92/140) of patients met the primary outcome versus 65% (89/137) in the placebo group (difference = 1%, 95% confidence interval [CI], −10–12%) showing no statistical difference between groups (p=0.86). Fentanyl was more likely to cause hypotension with 29% of patients having at least one SBP measurement less than 100 mmHg compared to 16% of the placebo group (difference = 13%, 95% CI, 3–23%). The placebo group was more likely to become hypertensive with 69% having a SBP measurement more than 150 mmHg compared to 55% of the fentanyl group (difference = 14%, 95% CI, 3–24%).

There were a number of limitations with the trial, including the heterogenous patient study group. Hypotension may be driven by, and may be more clinically important in, certain patient groups. Additionally, patients such as those with multi-trauma will have higher analgesic requirements necessitating the use of fentanyl and managing the potential risk of hypotension. Further research should focus on specific subgroups to assist with determining clinical relevance. 

Ferguson I, Buttfield A, Burns B, Reid C, Shepherd S, Milligan J, et al. Fentanyl versus placebo with ketamine and rocuronium for patients undergoing rapid sequence intubation in the emergency department: The FAKT study—A randomized clinical trial. Acad Emerg Med 2022; 29: 719–28.

Droperidol for Paediatric Agitation

Special contributor: Grace Said

Acute agitation in children poses significant risks to patients, carers and healthcare workers. Paediatric studies of the safety and efficacy of droperidol for acute agitation are crucial to guide medication choice, whilst promoting patient and staff safety.

This systematic review evaluated the effectiveness and safety of droperidol use for the management of acute agitation in acute care settings in patients 7 to 21 years of age. Four hundred and thirty-one articles were identified, six articles met inclusion criteria: one prospective observational study, three retrospective observational studies, and two case reports.

Droperidol intramuscular/intravenous was administered to 198 patients. Most patients achieved adequate sedation within 15 minutes after a single dose of droperidol. Furthermore, in Page et al., during 102 presentations, only 1% (n=1) failed to achieve sedation.1 Szwak et al., demonstrated 86.6% of cases resulted in effective sedation defined as sleeping, calm, resting, cooperative or quiet.2 A mean duration of sedation of 58.5 ± 29.1 minutes was also recorded.3

In terms of safety outcomes, no arrythmias were recorded in any children. Hypotension was occasionally noted, typically not requiring intervention. Dystonic reactions were recorded in five of 198 patients, all cases responded to standard care. One case of respiratory depression was recorded following administration to an alcohol intoxicated patient.

Despite promising results evaluated within this review, limitations include risk of bias from observational study types, lack of dosing protocol, and absence of direct comparisons with other medications for acute agitation in paediatrics. Future research should consider dosing protocols and standardised outcomes to measure effectiveness and safety, allowing for comparable data.

Ramsden SC, Pergjika A, Janssen AC, Mudahar S, Fawcett A, Walkup JT, et al. A systematic review of the effectiveness and safety of droperidol for pediatric agitation in acute care settings. Acad Emerg Med 2022 [preprint].

References

  1. Page CB, Parker LE, Rashford SJ, Isoardi KZ, Isbister GK. A prospective study of the safety and effectiveness of droperidol in children for prehospital acute behavioral disturbance. Prehospital Emerg Care 2019; 23: 519–26.
  2. Szwak K, Sacchetti A. Droperidol use in pediatric emergency department patients. Pediatr Emerg Care 2010; 26: 248–50.
  3. Joshi PT, Hamel L, Joshi ART, Capozzoli JA. Use of droperidol in hospitalized children. J Am Acad Child Adolesc Psychiatry 1998; 37: 228–30.

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GERIATRIC MEDICINE

GRIT Liaison for #SHPAGeri: Alex Ho Yin Chan and David Nguyen

Antihypertensive drug treatments in older adults

Special contributor: Samantha Fraser

Optimal blood pressure (BP) control in older adults is an ongoing controversial issue with limited studies conducted to assess optimal treatment targets. Although these studies have had significant influence on hypertension management guidelines, clinicians remain uncertain on its applicability in older patients with frailty and multimorbidity.

Bogaerts et al., provides an overview of the thresholds and targets of antihypertensive drug therapy for older adults in current guidelines through a search of PubMed, Embase, Emcare, and five guideline databases. Guidelines were selected if they included numerical thresholds for initiation or target values of antihypertensive drug therapy in the context of primary prevention, and specific advice concerning antihypertensive drug therapy in older adults.

Researchers identified 42 guidelines for primary prevention, 34 of which made recommendations for BP management in ageing and/or frailty. Twenty guidelines recommended a higher target of systolic BP (SBP) for octogenarians in comparison with the general population and three recommended a lower target. Eighteen guidelines recommended targeting a SBP < 150 mmHg, while four endorsed targets of SBP lower than 130 to 120 mmHg. Only three guidelines gave specific thresholds and targets in frailty.

This systematic review highlights a lack of concordance in recommended blood pressure targets for older people, despite being broadly based on similar evidence such as the Systolic Blood Pressure Intervention Trial (SPRINT). In routine practice, clinicians should use a number of assessments and screening tools to identify frailty and multimorbidity, and tailor blood pressure management based on patients’ health priorities and risks.

Bogaerts JMK, van Ballmoos LM, Achterberg WP, Gussekloo J, Streit S, van der Ploeg MA, et al. Do we AGREE on the targets of antihypertensive drug treatments in older adults: a systematic review of guidelines on primary prevention of cardiovascular diseases. Age Ageing 2021; 51: 1–14.

Electronic decision support for deprescribing reduces potentially inappropriate medications prescribed at discharge but not adverse drug events at 30-days post-discharge

Special contributor: Elizabeth Manias

While deprescribing contributes to harm reduction in older patients, there has been limited research conducted on how it impacts adverse drug events (ADEs) after hospital discharge. This study’s aim was to evaluate the effect of an electronic deprescribing decision support tool on ADEs in the first 30 days post-discharge among older patients.

The step-wise cluster randomised controlled trial was conducted in 11 acute care hospitals. The intervention involved an electronic decision support tool, which provided individualised reports with deprescribing recommendations to the health care team. Usual care involved patients receiving a best possible medication history and medication reconciliation on admission and discharge. ADEs were checked using a structured telephone interview with patients or their proxies at 30 days post-discharge.

Overall, 6633 patients (median [range] age, 78 [72–85] years) participated with 2742 control patients and 2247 intervention patients completing interviews. Of the control patients, 138 (5.0%) patients experienced an ADE post-discharge compared with 111 (4.9%) intervention patients (adjusted risk difference [aRD], −0.8%; 95% confidence interval [CI], −2.9–1.4%), which was statistically insignificant. At discharge, deprescribing of potentially inappropriate medications was statistically significant between the two groups, with 795 (29.8%) in the control group of 2667 participants and 1249 (55.4%) in the intervention group of 2256 participants (aRD, 22.2%; 95% CI, 16.9–27.4%).

Results demonstrated an electronic decision support tool can be used to improve deprescribing at discharge, with no accompanying increase in adverse drug withdrawal events. Further research with sufficiently powered sample sizes and examination of longer term ADEs is needed.  

McDonald EG, Wu PE, Rashidi B, Goodwin Wilson M, Bortolussi-Courval É, Atique A, et al. The MedSafer Study—electronic decision support for deprescribing in hospitalized older adults: a cluster randomized clinical trial. JAMA Intern Med 2022; 182: 265–73.

Are we there yet? How long until bisphosphonates are of benefit in postmenopausal women with osteoporosis?

Special contributor: Jacqueline Parkinson

Bisphosphonates have been shown to reduce the fracture risk in post-menopausal women with osteoporosis. However, in older multimorbid patients with limited life expectancy, bisphosphonates may not be commenced when the potential benefits are unclear. This meta-analysis aimed to determine the time to benefit (TTB) of bisphosphonate therapy for the prevention of non-vertebral and other fractures among postmenopausal women with osteoporosis. Data was extracted from 10 studies that met the inclusion criteria and pooled to estimate the absolute risk reduction (ARR) and TTB.

Overall, 23 384 subjects (mean [SD] age 63 [7] to 74 [3] years) were included in the analysis. It was found that to prevent one non-vertebral fracture, 100 post-menopausal women would need to take bisphosphonate therapy for 12.4 months (95% confidence interval [CI], 6.3–18.4 months). To prevent one hip fracture, 200 post-menopausal women with osteoporosis would need to take bisphosphonate therapy for 20.3 months (95% CI, 11–29.7 months). To prevent one clinical vertebral fracture, 200 post-menopausal women with osteoporosis would need to take bisphosphonate therapy for 12.1 months (95% CI, 6.4–17.8 months). It concluded that post-menopausal women with life expectancy of 1–2 years are unlikely to benefit from starting a bisphosphonate.

Unfortunately, the doses used in this study were inconsistent with Australian practice, and patients with older age and multi-morbidity were mostly excluded from the studies limiting extrapolation to this population. This meta-analysis supports the consideration of TTB when prescribing bisphosphonate therapy.

Deardorrff WJ, Cenzer I, Nguyen B, Lee SJ. Time to benefit of bisphosphonate therapy for the prevention of fractures among postmenopausal women with osteoporosis: A meta-analysis of randomized clinical trials. JAMA Intern Med 2022; 182: 33–41.

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MEDICINES INFORMATION

GRIT Liaison for #SHPAMedsInfo: Helen Trenerry

Are abnormal blood glucose levels (BGL) associated with cardiovascular and renal complications in hospitalised COVID-19 patients?

Complications from COVID-19 are associated with diabetes, obesity, increased age, cardiovascular disease, hypertension, and minority ethnic groups. This study investigated the association between admission BGL and cardiovascular and renal complications in patients admitted to hospital for the treatment of COVID-19.

A multicentre, prospective study of 36 269 adults hospitalised with COVID-19 recorded BGL on admission and classified patients with hypoglycaemia (≤3.9 mmol/L), normoglycaemia (4-11 mmol/L), or hyperglycaemia (≥11.1 mmol/L). Sex, age, obesity, ethnic group and pre-existing diabetes were recorded. Logistic regression models were used to investigate an association of BGL with cardiovascular and renal complications.

Cardiovascular and renal complications occurred in 10 421 (28.7%) patients admitted with COVID-19 of whom 55% survived and 45% died. There was a non-linear relationship between BGL and cardiovascular or renal complications with a nadir at BGL of 4.9–6.4 mmol/L, and an increased risk in patients with hypoglycaemia and hyperglycaemia. Patients under 69 years of age and those without diabetes had a higher risk of cardiovascular and renal complications. At very high BGL, this risk was reversed and increased in those aged 69 years or older and/or with pre-existing diabetes. There was no modifying effect of sex or obesity on admission BGL and any complications.

There was an increased risk of COVID-19 cardiovascular and renal complications in patients hospitalised with both high and low BGL with risk being higher in younger patients and those without diabetes. Routine glucose screening on admission can identify these high-risk patients and optimisation of BGL may improve COVID-19 outcomes.

Norris T, Razieh C, Yates T, Zaccardi F, Gillies CL, Chudasama YV, et al. Admission blood glucose level and its association with cardiovascular and renal complications in patients hospitalized with COVID-19. Diabetes Care 2022; 45: 1132–40.

Can statins be safely used during pregnancy? 

Statins are first line treatment for hyperlipidaemia. Statins are generally avoided in pregnancy due to a possible negative impact on the development of the placenta and interference with foetal development. This study reported maternal use of statins during pregnancy and perinatal outcomes.

In this retrospective cohort study of 1 443 657 pregnant women,  469 women were dispensed statins during pregnancy for hyperlipidaemia and 4690 women with no statin exposure during pregnancy were the age-matched controls. Statin exposure (divided into lipophilic and hydrophilic statins) was defined as at least seven days of use. Maternal age and presence of diabetes or hypertension were recorded. The primary outcome was congenital malformations. A subgroup analysis of women with preconceptual statin use for more than three months was performed.

Statin exposure during pregnancy was not associated with an increase in congenital anomalies. The statin-exposed group had more babies with low birth weight (RR 1.51[95% CI, 1.05–2.16]), preterm birth (RR, 1.99[95% CI, 1.46–2.71]) and a lower one-minute Apgar score (RR 1.83 [95% CI, 1.04–3.20]). The statin-exposed group had a higher incidence of diabetes and hypertension. The subgroup analysis showed no association between periconceptual use of statins for hyperlipidaemia and adverse perinatal outcomes.

The lack of association of statins with congenital anomalies gives support for their use in women with high-risk hyperlipidaemia during pregnancy. Statin exposure during pregnancy increases the risk of low birth weight and preterm labour. This needs to be weighed against the risk of accelerated atherosclerosis in the child due to gestational hyperlipidaemia.

Chang JC, Chen YJ, Chen IC, Lin WS, Chen YM, Lin CH. Perinatal outcomes after statin exposure during pregnancy. JAMA Netw Open 2021; 4(12): e2141321.

Development of a standardised severity rating scale to assess drug interactions

Drug interaction resources rate interactions according to their severity to aid in interpretation. However, the same drug-drug interaction may be inconsistently rated between resources causing ambiguity among users. This study aimed to develop and validate a standardised tool for consistent interpretation across drug interaction resources.

A panel of doctors and pharmacists selected eight frequently used drug interaction resources and then compiled a list of 20 common drug interactions. They reviewed the severity rating categories of each of the resources and then developed a standardised rating scale for mild, moderate and severe drug interactions. They then reassigned the severity rating of their standardised scale to the 20 drug interactions in the eight resources. Overall consistency among all the drug interaction resources was assessed as well as consistency between individual resources and the new standardised rating scale.

There were 14 different severity rating categories in the eight drug interaction resources. Use of the standardised severity rating scale showed improvement (based on Fleiss’ kappa score from 0.047 to 0.176) in the overall consistency between the drug interaction resources. The Cohen’s kappa score improved from 0.082 (poor agreement) to 0.198 (equal to fair agreement) for consistency between individual drug interaction resources and the standardised severity rating scale.

Medicines information pharmacists are often asked to interpret the significance of drug interactions due to conflicting or inconsistent information across drug interaction resources. Use of this standardised severity rating scale can aid in the assessment and interpretation of drug interactions between resources.

Shariff A, Belagodu Sridhar S, Abdullah Basha N, Bin Thaleth Alshemeili SSH, Ahmed Aljallaf Alzaabi NA. Development and validation of standardized severity rating scale to assess the consistency of drug-drug interaction severity among various drug information resources. Res Social Adm Pharm 2022; 18: 3323–8.

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NEPHROLOGY

GRIT Liaison for #SHPANeph: Jess Lloyd

Testing ‘TESTING’  – IgA nephropathy and methylprednisolone

IgA nephropathy (IgAN) is the most common glomerulonephritis and it is estimated that 25% of patients with this condition will reach end-stage kidney disease (ESKD) after 10 years. Although the pathogenesis of IgAN is not completely understood, based on current research there is a plausible rationale for using immunomodulators like glucocorticoids despite previous smaller studies not showing a benefit.1

The Therapeutic Effects of Steroids in IgA Nephropathy Global (TESTING) trial began enrolment in 2012, at a time when there were no registered therapies specifically for IgAN. It was an international multicentre double-blind randomised clinical trial comparing oral methylprednisolone weaned over approximately six months vs placebo in patients with IgAN at high risk of disease progression. The primary composite outcome was kidney failure: death due to kidney disease or 40% reduction in eGFR. The methylprednisolone dose was initially given at 0.6–0.8 mg/kg but an excess rate of serious infection-related adverse events halted the study and an amended reduced dose protocol of 0.4 mg/kg was used when the study resumed.

A total of 503 patients were randomised with the mean follow up of 4.2 years. The primary outcome occurred in 74 participants in the methylprednisolone group (28.8%) compared to 106 (43.1%) in the placebo group. There were more serious adverse events in participants randomised to methylprednisolone mainly attributable to the higher doses initially used.

The TESTING trial provides evidence that steroids can impact on clinically relevant endpoints in patients with IgAN however, the treatment landscape has changed significantly since this trial began. The recent Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial showed clear benefit with dapagliflozin in patients proteinuric CKD, with the benefits consistent when analysis was limited to patients who specifically had IgAN.2 There has also been an accelerated approval in the USA for an oral targeted-release budesonide product, the first registered therapy for IgAN. Both therapies have more favourable safety profiles and should be considered as add-on therapies for patients with IgAN with proteinuria despite optimal ACEI/ARB dosing. Access to targeted-release budesonide remains limited in Australia, but dapagliflozin has recently gained PBS listing for use in CKD.

Lv J, Wong MG, Hladunewich MA, Jha V, Hooi LS, Monaghan H, et al. Effect of oral methylprednisolone on decline in kidney function or kidney failure in patients with IgA nephropathy: The TESTING randomized clinical trial. JAMA 2022; 327: 1888–98.

References

  1. Rauen T, Eitner F, Fitzner C, Sommerer C, Zeier M, Otte B, et al. Intensive supportive care plus immunosuppression in IgA nephropathy. N Engl J Med 2015; 373: 2225–36.
  2. Wheeler DC, Toto RD, Stefánsson BV, Jongs N, Chertow GM, Greene T, et al. A pre-specified analysis of the DAPA-CKD trail demonstrates the effects of dapaglifozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int 2021; 100: 215–24.

Voclosporin: a lupus nephritis miracle or an expensive mirage?

Special Contributor: Reanna McFarland

Current treatments for lupus nephritis can have considerable side effects, with many patients struggling to reach complete remission. Voclosporin, a novel calcineurin inhibitor, has been found to have a more reliable pharmacokinetic profile and oral bioavailability, making it an attractive option for patients who would otherwise require regular therapeutic drug monitoring. This phase 3 trial aimed to determine the drug’s efficacy and safety in the treatment of lupus nephritis.

This multicentre double-blind randomised controlled trial compared voclosporin 23.7 mg twice daily versus placebo, in combination with mycophenolate and low-dose prednisone in patients with active lupus nephritis. The primary outcome was a complete renal response at 52 weeks, defined as urine PCR ≤ 0.5 mg/mg, eGFR ≥ 60 mL/min (or no more than a 20% decrease)​, nil requirement for rescue medications and a prednisone dose of 10 mg/day or less in the last eight weeks.

A total of 179 patients were assigned to voclosporin and 178 patients assigned to placebo.​ Complete renal response after 52 weeks was achieved in 41% of the voclosporin patients compared with 23% of the placebo patients (odds ratio 2.65; 95% confidence interval, 1.64–4.27; P < 0.0001). There was no significant difference in adverse events or death.

While the results seem promising, the sample size from each site was small and some study features cause us to question the real-world significance. It’s difficult to ascertain whether the surrogate marker of proteinuria is a direct effect of the podocyte-stabilising activity of the calcineurin inhibitor. Therefore, it’s not clear if the protein-lowering effect and resulting renal response is sustained after ceasing the drug. Data was not gathered on the use of protein-lowering sodium glucose lowering transport 2 inhibitors, and half the patients were newly established on mycophenolate at the start of the study — the effect of which is not clear. The current proposed cost of voclosporin is USD $144175 per year, making it largely cost prohibitive when compared to current treatments.

Voclosporin has been incorporated in the recent update to the Kidney Disease: Improving Global Outcomes guidelines.1 However, it is not approved for use nor available in Australia as it is not clear if the benefits seen in this trial justify the cost of this novel treatment.

Rovin BH, Onno Teng YK, Ginzler EM, Arriens C, Caster DJ, Romero-Diaz J, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2021; 397: 2070–80.

References

  1. Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO Guidelines. KDIGO; 2016. Available from < https://kdigo.org/guidelines/>.

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PAEDIATRICS AND NEONATOLOGY

GRIT Liaison for #SHPAPaedNeonate: Rachael Worthington

PREDNOS2 Low-Dose Prednisolone Preventing Nephrotic Syndrome in Children with an upper respiratory tract infection

Most children with steroid-sensitive nephrotic syndrome have relapses that are triggered by upper respiratory tract infections. Four small trials, mostly in children already taking maintenance corticosteroid in countries of different upper respiratory tract infection epidemiology, showed that giving daily low-dose prednisone/prednisolone for 5–7 days during an upper respiratory tract infection reduces the risk of relapse. This randomised double-blind placebo-controlled study aimed to determine if these findings were replicated in a large UK population of children with relapsing steroid-sensitive nephrotic syndrome on different background medication or none. A cost-effectiveness analysis was also included in this study.  

A total of 365 children with relapsing steroid-sensitive nephrotic syndrome (mean age 7.6 ± 3.5 years) were recruited from a total of 122 UK paediatric departments and randomised (1:1) according to a minimisation algorithm based on background treatment. Eighty children completed 12 months of follow-up without an upper respiratory tract infection. Thirty-two children were withdrawn from the trial (14 prior to an upper respiratory tract infection), leaving a modified intention-to-treat analysis population of 271 children (134 and 137 children in the prednisolone and placebo arms, respectively). At the start of an upper respiratory tract infection, children received six days of prednisolone (15 mg/m2) or an equivalent dose of placebo.

The primary outcome was the incidence of first upper respiratory tract infection-related relapse following any upper respiratory tract infection over 12 months. The secondary outcomes were the overall rate of relapse, changes in background treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, change in Achenbach Child Behaviour Checklist score and quality of life. Analysis was by intention-to-treat principle. The cost-effectiveness analysis used trial data and a decision-analytic model to estimate quality-adjusted life-years and costs at one year, which were then extrapolated over 16 years. There were 384 upper respiratory tract infections and 82 upper respiratory tract infection-related relapses in the prednisolone arm, and 407 upper respiratory tract infections and 82 upper respiratory tract infection-related relapses in the placebo arm. The number of patients experiencing an upper respiratory tract infection-related relapse was 56 (42.7%) and 58 (44.3%) in the prednisolone and placebo arms, respectively (adjusted risk difference –0.024, 95% confidence interval [CI], –0.14–0.09; p = 0.70).

There was no evidence that the treatment effect differed when data were analysed according to background treatment. There were no significant differences in secondary outcomes between treatment arms. Giving daily prednisolone at the time of an upper respiratory tract infection was associated with increased quality-adjusted life-years (0.9427 vs. 0.9424) and decreased average costs (£252 vs £254), when compared with standard care. The cost saving was driven by background therapy and hospitalisations after relapse. The finding was robust to sensitivity analysis. A larger number of children than expected did not have an upper respiratory tract infection and the sample size attrition rate was adjusted accordingly during the trial.

The authors concluded that giving six days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of steroid-sensitive nephrotic syndrome in UK children. However, there was an economic benefit from lower treatment costs overall which were associated with background therapy and relapse, and the health-related quality-of-life impact of having a relapse.

Christian MT, Webb NJA, Woolley RL, Afentou N, Mehta S, Frew E, et al. Daily low-dose prednisolone to prevent relapse of steroid-sensitive nephrotic syndrome in children with an upper respiratory tract infection: PREDNOS2 RCT. Health Technol Assess 2022; 26: 1–94.

Analysis of Adverse Drug Events in paediatric intensive care units (PICUs) 

This study aimed to assess the incidence, nature, preventability and severity of adverse drug events (ADEs) across three paediatric intensive care units (PICUs) in England. A prospective observational cohort study was conducted across three PICUs over a three-month period during 2019. Included patients were aged ≤ 18 years and stayed in a PICU for a minimum of 24 hours. Identification of suspected ADEs was performed by trained PICU pharmacists. A multidisciplinary expert panel assessed causality, preventability and severity of events.

A total of 302 patients were included and 62 ADEs were confirmed (definite/probable causality). One in six patients experienced one or more ADEs. The estimated incidences of ADEs were 20.5 per 100 patients (95% CI, 15.3–27.5) and 16.7 per 1000 patient-days (95% CI, 9.3–29.9). Of the 62 ADEs confirmed: 58.1% (n=36) were judged preventable by the expert panel; 46.8% (n=29) were commonly involved with medicines prescribing; and 67.7% (n=42) caused temporary patient harm. Further, medications for the central nervous system (n=14, 22.6%), infections (n=13, 20.9%) and the cardiovascular system (n=12, 19.4%) were commonly implicated in the 62 ADEs. Multivariable analysis revealed that patients who stayed in PICU for ≥ 7 days (odds ratio [OR] 6.29; 95% CI, 2.42–16.32) were more likely to experience an ADE compared to patients with a stay of 1–6 days.

Alghamdi et al., concluded that ADEs are common in PICUs in England and most of them may be preventable. There is a strong association between ADE occurrence and duration of PICU stay, which represents a target for remedial interventions. Exploring contributory factors to preventable ADEs is now necessary to inform preventive policies.

Alghamdi AA, Keers RN, Sutherland A, Hann M, Gray J, Mason G, et al. Incidence and nature of adverse drug events in paediatric intensive care units: A prospective multicentre study. Br J Clinical Pharmacol 2021; 88: 2213–22.

CAP-IT appropriate amoxycillin dose and duration

The optimal dose and duration of oral amoxicillin for children with community-acquired pneumonia (CAP) are unclear. This study sought to determine whether lower-dose amoxicillin is noninferior to higher dose and whether three-day treatment is noninferior to seven days in children with community-acquired pneumonia discharged from an emergency department, observational unit, or inpatient ward within 48 hours. Eight-hundred and twenty-four children, aged six months and older, with clinically diagnosed CAP, treated with amoxicillin on discharge from emergency departments and inpatient wards of 28 hospitals in the UK and one in Ireland — between February 2017–April 2019, with last trial visit on 21 May 2019 — were enrolled in this multicentre, randomized, 2×2 factorial noninferiority study. Children were randomised 1:1 to receive oral amoxicillin at a lower dose (35–50 mg/kg/d; n=410) or higher dose (70–90 mg/kg/d; n=404), for a shorter duration (3 days; n = 413) or a longer duration (7 days; n = 401).

The primary outcome was clinically indicated antibiotic re-treatment for respiratory infection within 28 days after randomisation. The noninferiority margin was 8%. Secondary outcomes included severity/duration of 9 parent-reported CAP symptoms, 3 antibiotic-related adverse events, and phenotypic resistance in colonising Streptococcus pneumoniae isolates. Of 824 participants randomised into 1 of the 4 groups, 814 received at least 1 dose of trial medication (median [IQR] age, 2.5 years [1.6–2.7]; 421 [52%] males and 393 [48%] females), and the primary outcome was available for 789 (97%) participants. For lower vs higher dose, the primary outcome occurred in 12.6% with lower dose vs 12.4% with higher dose (difference, 0.2% [1-sided 95% CI, –∞–4.0%]), and in 12.5% with 3-day treatment vs 12.5% with 7-day treatment (difference, 0.1% [1-sided 95% CI, –∞–3.9]). Both groups demonstrated noninferiority with no significant interaction between dose and duration (p = 0.63). Of the 14 prespecified secondary end points, the only significant differences were 3-day vs 7-day treatment for cough duration (median 12 days vs 10 days; hazard ratio [HR], 1.2; 95% CI, 1.0–1.4; p = 0.04) and sleep disturbed by cough (median, 4 days vs 4 days; HR, 1.2; 95% CI, 1.0–1.4; p = 0.03). Among the subgroup of children with severe CAP, the primary end point occurred in 17.3% of lower-dose recipients vs 13.5% of higher-dose recipients (difference, 3.8%; 1-sided 95% CI, –∞–10%; p value for interaction = 0.18) and in 16.0% with 3-day treatment vs 14.8% with 7-day treatment (difference, 1.2%; 1-sided 95% CI, –∞–7.4%; p value for interaction = 0.73).

The authors concluded that among children with CAP discharged from an emergency department or hospital ward within 48 hours, lower-dose outpatient oral amoxicillin was noninferior to higher dose, and 3-day duration was noninferior to 7 days, with regard to need for antibiotic re-treatment. However, disease severity, treatment setting, prior antibiotics received and acceptability of the noninferiority margin require consideration when interpreting the findings.

Bielicki JA, Stöhr W, Barratt S, Dunn D, Naufal N, Roland D, et al. Effect of amoxicillin dose and treatment duration on the need for antibiotic re-treatment in children With community-acquired pneumonia: The CAP-IT randomized clinical trial. JAMA 2021; 326: 1713–24.

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PALLIATIVE CARE

GRIT Liaison for #SHPAPalliative: Josephine To, Vicki Poulier and Pascale Dettwiller

Effect of antipsychotic use on survival in advanced cancer

The risks of antipsychotics in a range of patient groups are well known including the risk of decreased survival when used to managed terminal delirium in advanced cancer patients.

This secondary analysis of a prospective multicentre observational study focused on the use of antipsychotics and any dose-response effect on mortality rates after initiation for management of delirium in advanced cancer patients. Antipsychotics were prescribed according to the doctor’s usual practice and dose was recorded on day three as oral chlorpromazine equivalents (OCE).

There were 422 patients included in the analysis, who were divided into low dose (less than 100 mg/day OCE, n = 231), moderate dose (100–200 mg/day OCE, n = 122) and high dose (greater than 200 mg/day OCE, n = 69) groups. Haloperidol was the most commonly prescribed antipsychotic and median survival following any antipsychotic initiation was 11 days (95% confidence interval [CI] 10–13 days). High dose was associated with a significantly higher risk of shorter survival compared to low dose (adjusted hazard ratio [HR] 1.46; 95% CI, 1.08–1.09) particularly for atypical antipsychotics.

Despite being a multicentre prospective study, the observational nature limits its applicability and generalisability. The use of haloperidol is consistent with Australian palliative care practice and the lower risk of decreased survival suggests that this should be preferred over an atypical antipsychotic. Low doses with careful titration and monitoring should continue to be best practice to minimise any possible effect on survival. 

Yokomichi N, Maeda I, Morita T, Yoshiuchi K, Ogawa A, Hisanaga T, et al. Association of antipsychotic dose with survival of advanced cancer patients with delirium. J Pain Symptom Manage 2022; 64: 28–36.

Considering antimicrobial stewardship in end-of-life care

Antibiotics may be used in palliative care to suppress symptoms but evidence of benefit is limited, and the associated treatment burden can be significant, which may not align with expressed goals of care. This retrospective study reviewed the use of antibiotics in 66 006 adults admitted to hospice care in the USA.

Participants (n = 6080, 9.2%) were prescribed antibiotics on admission to hospice with 85% over 65 years of age, 45% were male, and included a range of non-cancer palliative diagnoses. Infection was documented in 70.7% of patients on admission with 29.3% having greater than one infectious diagnosis. The most frequently reported were sepsis (39%) and pneumonia (26%). Only 11.4% of patients with a diagnosed infection had an antibiotic prescribed on admission, although 8.8% without a diagnosis also had an antibiotic prescribed on admission. The most frequently prescribed antibiotics were quinolones (22%), cephalosporins (20%) and penicillins (16%), with 21% given intravenously.

The retrospective design is a limitation to the study and the results did include antibiotics prescribed for long-term prophylaxis. Use of data linkage and coding data may not capture all the relevant information. The nature of the US healthcare system and use of hospice care does limit extrapolation to the Australian context. This original work highlights the need for antibiotic stewardship in the palliative care setting in conjunction with goals of care discussions with patients and carers.

Lanz TL, Noble BN, McPherson ML, Tija H, Colangeli HN, Ferris RE, et al. Frequency and characteristics of patients prescribed antibiotics on admission to hospice care. J Pall Med 2022; 25: 584–90.

Understanding why opioid conversion calculators should be used with caution

Opioid conversion calculators (OCCs) are common in clinical practice, providing ease of use at the point of care, and avoiding manual dose calculations. However, clinicians with limited understanding of opioid conversion methodology may overlook important patient clinical factors when determining the new opioid dose regimen.

This study of 62 postgraduate students in a palliative care program were asked to use OCCs of their choice in three clinical scenarios. Calculations were compared to the most used OCC (Practical Pain Management [PPM]) and a manually calculated dose determined by consensus of three pharmacists.

There was large variability in calculated doses across all three scenarios when compared to PPM and the consensus dose. In scenario A, median OCC doses were all significantly higher than the consensus dose. In scenario B, one OCC calculated a median dose almost ten times lower than the consensus dose. In scenario C, there was no significant difference in mean dose between the OCCs, but the median dose was higher compared to the consensus dose. There was variation in recommended breakthrough doses and any dose reductions required for incomplete cross tolerance.

OCCs perform a mathematical calculation, and while most include dose reductions, clinicians must understand the principles of dose conversion so they can interpret and determine appropriateness for each individual patient. Of note, some of the calculations involved doses higher than those typically seen in the Australian setting. Scenario C involved a methadone conversion and the commonly used OCCs in Australia (such as the calculator developed by the Faculty of Pain Medicine, ANZCA) recommend seeking specialist advice rather than providing a calculation. Nonetheless, the conclusion that clinicians be able to manually calculate dose conversions and to use any OCC with caution is appropriate.

Costantino RC, Barlow A, Gressler LE, Zarzabal LA, Tao D, McPherson ML. Variability among online opioid conversion calculators performing common palliative care conversions. J Pall Med 2022; 25: 549–55.

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RURAL AND REMOTE PRACTICE

GRIT Liaison for #SHPARuralRemote: Caitlin Hardman

Rural Pharmacist Recruitment and Retention

Special Contributor: Susan Trevillian

Securing equitable access to health services for rural and remote populations continues to be a challenge for governments and policy-makers. Retention is of particular importance in rural and remote regions where there are high staff turnover rates, reduced pharmacist numbers and reliance on temporary staff. Despite several incentives in training, funding and targeted programs, there remains a maldistribution and undersupply of pharmacists in rural and remote areas.

The aim of this systematic review was to comprehensively identify the factors associated with recruitment and retention of the pharmacist workforce in rural and remote settings. A systematic search of the primary research literature examining recruitment and retention factors for the pharmacist workforce in rural and remote settings was conducted. Five main themes associated with recruitment and retention of pharmacists in rural practice were identified: geographic and family-related; economic and resources; scope of practice or skills development; the practice environment; and community and practice support factors.

In contrast to other allied health professionals, this study highlighted personal satisfaction and professional satisfaction as specific motivators for pharmacists. Personal satisfaction is influenced by the extent to which the rural setting caters to their individual and familial needs, especially in terms of lifestyle, education, recreation and community support. Whereas professional satisfaction is mostly associated with opportunities for continuing career development, enhanced practice scope and experiences, positive inter- and intra-disciplinary relationships,and satisfactory financial benefits. These factors should be taken into consideration when developing interventional strategies to resolve rural pharmacist workforce recruitment and retention shortfalls. 

Terry D, Phan H, Peck B, Hills D, Kirschbaum, Bishop J, et al. Factors contributing to the recruitment and retention of rural pharmacist workforce: a systematic review. BMC Health Serv Res 2021; 21: 1052.

Partnered Pharmacist Medication Charting in Rural Practice

The Partnered Pharmacist Medication Charting (PPMC) model was developed to reduce the incidence of medication errors in an acute setting. In this proactive model of care, a pharmacist who has completed the PPMC competency package training (credentialing) charts pre-admission medication and venous thromboembolism (VTE) prophylaxis, in collaboration with the admitting medical officer, for patients admitted to either an emergency short stay unit or a general medicine unit. Reconciliation of the medication chart is performed by the unit pharmacist within 24 hours. The collaboration between medical officer and pharmacist — a key feature of the PPMC model — allows for better integration of the skills and expertise of pharmacists and other clinicians, reduced duplication of effort, and consequently reduced medication errors.

The aim of this study was to evaluate the impact of the PPMC model on medication errors and inpatient length of hospital stay in general medical patients admitted to rural and regional hospitals. There were 1361 medication charting errors identified during pre-intervention and 80 in the post- intervention. Of the 669 patients who received standard medical charting during the pre-intervention period, 446 (66.7%) patients had at least one medication error identified compared to 64 patients (9.5%) using PPMC model (p < 0.001). The median (interquartile range) inpatient length of stay was 4.8 days (2.7–10.8) in the pre-intervention period and 3.7 days (2.0–7.0) among patients that received PPMC (p < 0.001). Expansion of a collaborative medication‐charting model to reduce length of hospital stay and medication errors can have a large impact in rural and remote areas.

Tong EY, Hua PU, Edwards G, Van Dyk E, Yip G, Mitra B, et al. Partnered pharmacist medication charting (PPMC) in regional and rural general medical patients. Aust J Rural Health 2022; 30: 593–600.

Rural Patient Satisfaction with Telepharmacy

Transition of care is known to be a hazardous time, and a key focus of hospital pharmacy services is to reduce medication errors on admission to and discharge from hospital, via Medication Reconciliation. On discharge, the patient’s Best Possible Medication History (BPMH) — gathered on admission — is routinely compared with medicines initiated, discontinued or changed during the admission, in order to provide the patient with an updated and revised medication list. This list is known as the Best Possible Medication Discharge Plan (BPMDP).

In an underserviced rural and remote community hospital in Canada, pharmacists explored using a mobile Double robotic platform (Double Robotics, Redwood City, California, USA) to provide BDMDP where in-person hospital pharmacy services were unavailable. Patients in the small rural/remote 12-bed community hospital between September 2017 and January 2019, who were at high risk of hospital readmission, and of preventable medication-related adverse events, were asked about their experience and perceptions of the pharmacist-led, real-time BPDMP (using telepresence robot technology) during their discharge.

Of 368 patients assessed for eligibility by the pharmacist, 47 were assessed by hospital nurses as eligible for a BPDMP (a non-mandatory component of the hospital discharge process). Of those 47 patients, 24 were successfully contacted and offered a discharge interview with the pharmacist, and 9 completed the discharge medication interview using the Double robotic technology. Of those 9 patients, 8 (89%) completed a satisfaction survey regarding their experience, with 80% positive, 13% undecided and 7% describing a negative experience.

Language barriers, available technology, bandwidth and lack of on-site support for the robot were noted as factors that hindered the success of interviews with the pharmacist.

Newman P, Dhaliwall S, Bains S, Polyakova O, McDonald K. Patient satisfaction with a pharmacist-led best possible medication discharge plan via tele-robot in a remote and rural community hospital. Can J Rural Med 2021; 26: 151–9

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TRANSITIONS OF CARE AND PRIMARY CARE

GRIT Liaison for #SHPATransitionCare: Deirdre Criddle, Margaret Jordan and Ahmed Zeidan

Putting clinical pharmacy on the country health agenda: Implementing a virtual model in a rural and remote setting

Small community rural hospitals with low inpatient numbers and low emergency presentations rarely have access to onsite clinical pharmacists. A virtual clinical pharmacy service (VCPS) was established to provide a model of care comprising supportive  technologies to enable implementation into rural hospital practice.

The pharmacy team was virtual and decentralised with staff residing in the larger regional centres of Dubbo and Orange in New South Wales, providing a service to eight rural hospitals. Videoconferencing was used to to support delivery of core clinical pharmacy services including Best Possible Medication History (BPMH), medication reconcilation at transitions of care, medication review, interprofessional team meetings, patient-friendly medication lists, antimicrobial stewardship and patient and clinical education. Activity measures included 574 site-requested consults, 4406 clinical and medication reviews and 580 discharge medication reviews delivered to 1306 patients over a 12 month period.

The irregular conduct of virtual pharmacy was identified as potentially disruptive for local staff, particularly during periods of high activity or low staffing levels. Additionally the VCPS was reliant on the availability of onsite staff to take telephone or video calls, arrange patient consultations and act on clinical recommendations. This challenge was partially mitigated by the pharmacist providing the service being aware of the local pressures, rearranging consults and having clear escalation pathways for urgent issues. Some hospitals utilised administrative staff to reduce the impact on nursing staff. The model evolved organically as clinical staff experienced the benefits of the VCPS and associated time-saving.

The ability to identify and prioritise patients across multiple sites remains a challenge and has been flagged as an element that needs improvement. Nevertheless, this study showed the value of VCPS as a model of care that is scalable and appropriate for rural and remote health facilities.

Chambers B, Fleming C, Packer A, Botha L, Hawthorn G, Nott S. Virtual clinical pharmacy services: A model of care to improve medication safety in rural and remote Australian health services. Am J Health Syst Pharm 2022; 79: 1376–84.

Equitable delivery of patient care by general practice pharmacists: developing standards of practice

Pharmacist integration into Australian general practice is a nascent scope of practice. Although international standards for pharmacy professionals are available, a gap was identified for the delivery of polypharmacy and chronic disease medication reviews by general practice clinical pharmacists (GPCPs).

A modified Nominal Group Technique process was employed for structured idea generation. Input was collated from an expert group, comprised of experienced GPCPs (n = 4) and a sample of the 159 GPCPs from 260 Scottish practices invited to participate. Following a round-robin for ideas generation, clarification and rankings, two rounds of Delphi questionnaires were used to obtain consensus of proposed standards.

The majority of GPCPs provided responses in the final Delphi phase, after which 44 standards proposed were accepted, across seven categories: skills; environment; qualifications; qualities and behaviours; knowledge; process; and experience. The standards concentrated on effective communication, patient-centredness and the ability to manage complex patients. Leadership and teamwork featured as well as the ability to work independently. New standards were identified that were specific to complex polypharmacy and chronic disease medication reviews in general practice.

The intention behind formulating GPCP standards was for contractual reasons, as a new three-tiered process had been proposed in Scotland to optimise patient care and free up GP capacity. Levels 1 and 2 of the GCCP standards comprised core and advanced services, and Level 3 — ‘additional specialist’ services — required definition. For the developing role in Australia, aspiration would be for our GPCPs to provide equivalent level 3 services, and therefore be evaluated against the majority of these standards, with the obvious discrepancy in the recognition as independent prescribers. This research is timely given the impetus of Australian professional pharmacy organisations to update or develop standards, particularly in developing scopes of practice.

Earle-Payne K, Forsyth P, Johnson CF, Harrison H, Robertson S, Weidmann AE. The standards of practice for delivery of polypharmacy and chronic disease medication reviews by general practice clinical pharmacists: a consensus study. Int J Clin Pharm 2022; 44: 663–72.

Prioritising tailored medication communication with older patients across transitions of care

Special contributor: Elizabeth Manias

As older patients move across transitions of care, they interact with health professionals of different disciplines in diverse healthcare settings. Often these interactions are associated with communication breakdown, which can lead to medication-related problems and patient harm.

This perspectives paper identified how conversations between health professionals and patients are largely disorganised and unplanned — these are called “fleeting conversations”. When health professionals communicate about medications, they place greater emphasis on information exchange about medications rather than providing opportunities for older patients and families to participate in shared decision-making activities. Several factors also contribute to difficulties in facilitating engagement with older patients, including those with complex medication regimens, those with mental health problems or disabilities, individuals of low health literacy or socioeconomic backgrounds, as well as Aboriginal and Torres Strait Islander people and people from migrant backgrounds. Making time to facilitate interactive and individualised conversations across transitions of care will enable increased understanding about patients’ and families’ priorities in managing medications.

Health professionals, including pharmacists, should consider using diverse communication strategies in an effort to reduce the occurrence of fleeting conversations. Communicating about medications needs to occur for the whole patient journey from admission to discharge, rather than concentrating this activity prior to hospital discharge. Interactions should be individualised to the patient’s particular needs, using information in large font type in easy-to-understand language, the patient’s own language, diagrams, photographs of medications, video resource materials and case scenarios. Interactions with various health professionals such as nurses, doctors, physiotherapists and speech pathologists can help to identify how the medication regimen can fit within the patient’s daily living activities. Decision aids can also be helpful in encouraging patients to ask questions and to be informed about their medications.

Taking time to convert fleeting conversations into tailored, meaningful interactions is helpful in encouraging patient and family participation in medication communication across transitions of care.

Manias E, Hughes C, Woodward-Kron RE, Jorm CM, Ozavci G, Bucknall TK. More than a fleeting conversation: Managing medicines communication across transitions of care. Med J Aust 2022; 217: 176–7.

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WOMEN’S AND NEWBORN HEALTH

GRIT Liaison for #SHPAWomenNewborn: Kate Luttrell

Reducing the pain of opioid consumption post-caesarean section

Caesarean section is a frequently performed surgical procedure, and the use of opioid analgesics is common in the postoperative period.

A retrospective cohort study was conducted in the USA in women undergoing caesarean section. A quality improvement initiative was implemented, aiming to minimise post-caesarean opioid usage. This involved creating an electronic order set that maximised non-opioid analgesics, nursing education, data-driven nursing feedback and physician education. Investigators reviewed opioid use six-months before and after implementation to assess the prescribing of opioids postpartum, and on discharge.

Following implementation, median inpatient opioid use decreased from 75 mg to 30 mg morphine milligram equivalents (MMEs) per admission, a reduction of over 60% (p < 0.001). The proportion of opioid-free admissions significantly increased from 12.6% pre-intervention to 30.7% (p < 0.001). Additionally, there were less opioids prescribed on discharge, and more patients discharged without an opioid prescription. Importantly, despite this reduction in opioid use, pain scores slightly decreased post-intervention, showing it is possible to reduce opioid consumption without adversely affecting pain control.

This study was conducted in the USA where the risk of chronic opioid use has been reported to affect one in 300 women who fill an opioid prescription after caesarean section.1 However, Australia also has increasing rates of opioid prescribing. Many Australian hospitals have developed innovative strategies to minimise opioid use, although there is a noticeable lack of evidence within an obstetric setting. Additionally, neonatal opioid exposure through breast milk has been linked to infant central nervous system depression and death.2 Minimising maternal opioid use postpartum has the potential to reduce infant risk through exposure to breast milk.

This study addresses this research gap and provides potential strategies that could be successfully implemented in an Australian obstetric unit.

Llarena NC, Krivanek K, Yao M, Kim DD, Devarajan J, Ayad S, et al. A multimodal approach to reducing post-caesarean opioid use: a quality improvement initiative. BJOG: Int J Obstet Gy 2022; 129: 1583–90.

References

  1. Bateman BT, Franklin JM, Bykov K, Avorn J, Shrank WH, Brennan TA, et al. Persistent opioid use following cesarean delivery: patterns and predictors among opioid-naïve women. Am J Obstet Gynecol 2016; 215: 353.e1–353.e18.
  2. Lam J, Kelly L, Ciszkowski C, Landsmeer MLA, Nauta M, Carleton BC, et al. Central nervous system depression of neonates breastfed by mothers receiving oxycodone for postpartum analgesia. J Pediatr 2012; 160: 33–37.e2.

Prevalence and significance of gestational cannabis use in an Australian setting

Cannabis is one of the most commonly used non-prescribed psychoactive substances during pregnancy, and its prevalence appears to be increasing. This study aimed to assess the prevalence of gestational cannabis use within an Australian setting and identify any associated pregnancy and neonatal outcomes.

A retrospective observational study was conducted at a tertiary hospital in Perth, Western Australia, reviewing pregnant women delivering in 2019. Maternal self-reporting identified substance use during pregnancy, including cannabis. Multivariate logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for various birth outcomes, including preterm birth and low birthweight (LBW).

Among 3104 pregnant women, gestational cannabis use was reported by 1.6% of patients. Gestational cannabis use (OR; 3.3, 95% CI, 1.6–6.7) and tobacco smoking (OR; 2.2, 95% CI, 1.5–3.6) were both associated with increased odds of LBW, a finding that persisted with multivariate logistic regression analysis adjusted for various factors. Combined cannabis and tobacco use further increased the likelihood of LBW (adjusted OR; 3.9, 95% CI, 1.6–9.3).

While addressing an important gap in existing literature by providing Australian data, these findings likely underestimate prevalence rates, as women with known substance use are routinely referred early to a Women and Newborn Drug and Alcohol Service and would not be included in these data. By relying on self-reporting of cannabis use, and not classifying dose or trimester-specific usage, these results do not allow for dose- or trimester-specific associations.

Given concurrent tobacco and cannabis use is common, this study highlights the need for targeted public health interventions to optimise health outcomes for both mother and neonate.

Dunn ML, Bradley C, Ayonrinde OA, Van Rooyen DM, Tait RJ, White SW, et al. The prevalence and significance of gestational cannabis use at an Australian tertiary hospital. Aust N Z J Obstet Gynaecol 2022; 1–7 [preprint].

Is prenatal exposure to triptans associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD)?

Migraine is most prevalent in women of reproductive age, with triptans commonly prescribed for treatment. Information about the safety of triptans during pregnancy is limited, particularly for long-term outcomes, such as child neurodevelopment.

This Norwegian population-based cohort study used registry data from 1999–2008 to identify children born to women reporting migraine or triptan use in the six months before or during pregnancy. Diagnosis and dispensed ADHD medicines were used to identify children with ADHD, as well as the presence of ADHD symptoms at five years of age. Exposed children were compared with two groups of unexposed children whose mothers reported migraine (1) during pregnancy and (2) before pregnancy only.

Of 10 167 offspring with an ADHD diagnosis, 832 children had prenatal triptan exposure (8.2%). Statistical analysis showed children with prenatal triptan exposure had no increased risk of ADHD diagnosis compared with unexposed children whose mothers had migraine during pregnancy (weighted hazard ratio [HR]; 1.16, 95% CI, 0.78–1.74) and those whose mothers had migraine only before pregnancy (weighted HR; 1.28, 95% CI, 0.84–1.94). There were no differences in ADHD symptom scores between exposed and unexposed children.

Despite the frequency of migraine in pregnancy, women may discontinue triptan use due to concerns about their safety and rely on less effective options, causing more pain1 and risk of pregnancy complications.2,3

This study adds to the literature on the safety of triptan use during pregnancy, which may be reassuring for women. However, due to the limited sample size, investigators were unable to assess triptan use by trimester or examine specific triptans to aid prescribing decisions.

Harris GM, Wood M, Ystrom E, Nordeng H. Association of maternal use of triptans during pregnancy with risk of attention-deficit/hyperactivity disorder in offspring. JAMA Netw Open 2022; 5: e2215333.

References

  1. Marchenko A, Etwel F, Olutunfese O, Nickel C, Koren G, Nulman I. Pregnancy outcome following prenatal exposure to triptan medications: a meta-analysis. Headache 2015; 55: 490–501.
  2. Tauqeer F, Wood M, Hjorth S, Lupattelli A, Nordeng H. Perinatal use of triptans and other drugs for migraine–a nationwide drug utilization study. PLoS One 2021; 16: e0256214.
  3. Skajaa N, Szépligeti SK, Xue F, Sørensen HT, Ehrenstein V, Eisele O, et al. Pregnancy, birth, neonatal, and postnatal neurological outcomes after pregnancy with migraine. Headache 2019; 59: 869–79.

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