MedsScan Issue 3, 2024

These reviews provide updates on the international literature on therapeutics. Expert pharmacy practitioners — via AdPha’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. 

COMPOUNDING SERVICES

MedsScan editors for Compounding services SPG: Rachel Berry and Tammy Nguyen

Stability of two insulin eye drop formulations

Insulin eye drops are emerging as a treatment option for persistent epithelial corneal defects. Limited published stability data is currently available. The aim of this study was to assess physicochemical stability and in vitro tolerance of two insulin eye drop formulations, one in a commercially available artificial tears preparation, and one in sodium chloride 0.9%.

Insulin 1 IU/mL eye drops were prepared by diluting Actrapid insulin in sodium chloride 0.9% or Systane Ultra (propylene glycol based) artificial tears then stored in glass multi-dose eye dropper bottles. Insulin retained potency in sodium chloride 0.9% for 28 days stored at 2–8oC but potency decreased in artificial tears. Formulations were less stable at room temperature. This study also examined stability under various storage conditions likely to occur in real-life situations. As this study group have previously published two papers on safety and efficacy of insulin 1 IU/mL in propylene glycol-based artificial tears,1,2 this study included a case series of nine patients treated with the formulation in sodium chloride 0.9%. The results of this study are of relevance to practice, providing testing of two formulations in readily available preparations. In contrast to previous data, this study showed some degradation in a polyethylene glycol-based artificial tears formulation.

The results of this study provide evidence of stability and clinical efficacy and tolerability of a preservative free Actrapid eye drop formulation which can be implemented in clinical practice. Although physicochemical stability was observed in the preservative free formulation and the product was free from microbial growth during the study, current guidelines should be followed when assigning a product expiry to preservative free eye drops.

References

  1. Diaz-Valle D, Burgos-Blasco B, Gegundez-Fernandez JA, Garcia-Caride S, Puebla-Garcia V, Peña-Urbina P, et al. Topical insulin for refractory persistent corneal epithelial defects. Eur J Ophthalmol 2021; 31: 2280–2286.
  2. Diaz-Valle D, Burgos-Blasco B, Rego-Lorca D, Puebla-Garcia V, Perez-Garcia P, Benitez-Del-Castillo, et al. Comparison of the efficacy of topical insulin with autologous serum eye drops in persistent epithelial defects of the cornea. Acta Opthalmol 2022; 100: e912–e919.

Vicario-de-la-Torre M, Puebla-García V, Ybañez-García L, José Javier López-Cano, Miriam Ana González-Cela-Casamayor, Brugnera M, et al. Topical insulin eye drops: stability and safety of two compounded formulations for treating persistent corneal epithelial defects. Pharmaceutics 2024; 16: 580.

Meropenem stability in elastomeric infusion devices

The use of meropenem for outpatient parenteral antimicrobial therapy (OPAT) remains challenging due to limited chemical and physical stability in portable elastomeric infusion devices. Previous studies have yielded variable results, and a recommended dosing protocol is lacking. This study aimed to provide clinicians with guidance to appropriate dosing in the absence of an alternative, more stable antimicrobial agent.

The study evaluated two concentrations of meropenem (2 mg/mL and 25 mg/mL) diluted in sodium chloride 0.9% at three storage temperatures (2–8oC, 25oC and 32oC). Accufuser infusion devices were used. Chemical and physical stability were evaluated over 48 h using a validated high-performance liquid chromatography (HPLC) method. Adsorption to the device was calculated at the end of the experiment and remained below 1% for all samples. Meropenem was determined to be stable for 24 h only at low concentration under refrigerated storage. Higher concentrations and storage temperatures were less stable. A degradation product was noted after 2 h in the 25 mg/mL concentration and increased with increased storage time and temperature. No precipitation was seen, but a colour change was seen after 24 h at 25oC and 32oC and at 48 h at 2–8oC.

The key findings were that meropenem is not stable for OPAT use at higher concentrations and higher storage temperatures. Suggested dosing regimens are proposed for various doses, noting that these are in Accufuser brand devices which can be run at variable rates. Limitations of the study include controlled conditions, which do not accurately reflect real-life outpatient conditions and concentrations were chosen at either end of the clinically relevant range, but a midpoint concentration would be of value to compare stability over time and temperature. Further study at a controlled pH would also be a useful addition to the current data.

This study confirms the challenges with using continuous infusions of meropenem in an outpatient setting. However, care must be taken with extrapolation of data between different brand devices and concentrations not studied. The recommended administration protocols could help guide decision making in difficult clinical situations.

Esteban-Cartelle B, Serrano DR, Pérez Menéndez-Conde C, Vicente-Oliveros N, Álvarez-Díaz A, Abete JF, et al. Stability of meropenem in portable elastomeric infusion devices: which protocol should be implemented in clinical practice? Microbiol Spectr 2024; 12: e0206323.

Potential toxicity of excipients used in paediatric oral liquid formulations

It is often necessary to compound liquid formulations for paediatric and neonatal patients when commercial preparations are not available. Although data exists for the safety of the active compounds contained in these medicines, limited data is available on the safety of excipients used in these formulations and available data is often extrapolated from adult patients. Other work in this area includes the KIDS list (Key Potentially Inappropriate Drugs) containing active substances and excipients and the STEP database (Safety and Toxicity of Excipients for Paediatrics). Work in this area has led to the quantity of excipients of interest being listed in product information, where there are known toxicity concerns. The aim of this work was to contribute to the available toxicity date for excipients commonly found in paediatric oral liquid forms.

A compilation of 219 oral liquid forms used in paediatric and neonatal units in France was created. There was a mix of ready to use, and reconstituted formulations. From this list, toxicity data was reviewed from the STEP database for 16 common excipients, including propylene glycol, benzoic acid, polyethylene glycol, polysorbate 80 and sodium benzoate. The review identified that most formulations currently administered to paediatrics and neonates contain excipients of interest in dose ranges that can induce toxicity with long-term use. For instance, among the 219 formulations studied, 38 (37.6%) contain sodium benzoate, 23 (22.8%) contain aspartame and 14 (13.9%) contain ethanol.

This review provides an excellent summary of excipients used in compounding and their potential toxicity in paediatrics and neonates. This review is a recommended resource to carefully consider when formulating compounded oral liquid forms for paediatric and neonatal patients. Noting that this review was completed in France, there is some variation from excipients and formulations available in Australia. In addition, the data on the recommended maximum daily doses can be used to calculate quantities of excipients in Australian formulations.

Bobillot M, Delannoy V, Trouillard A, Kinowski JM, Sanchez-Ballester NM, Soulairol I. Potentially harmful excipients: state of the art for oral liquid forms used in neonatology and pediatrics units. Pharmaceutics 2024; 16: 119–9.

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DISPENSING AND DISTRIBUTION

MedsScan editors for Dispensing and distribution SPG: Anna Wood and Ashley Crawford

Understanding medication recycling practices in the hospital setting

There is currently a strong focus on waste reduction and sustainable practices within healthcare settings. Initiatives which address medication related waste generated within hospitals can contribute to positive environmental and financial outcomes. One such strategy involves return and reuse of medications supplied to clinical areas for inpatient use. The objective of this study was to gain an understanding of the adoption of this practice across hospital pharmacies in Canada.

A survey was conducted of eligible facilities across Canada in July and August of 2022. The survey aimed to determine the number of facilities utilising medication recycling processes, the influence of dosage form and packaging on medications recycled and identify recycling barriers.  Ninety-four percent of responding sites had a workflow to support the return and reuse of medication. However, whilst a high proportion of respondents indicated that medication recycling practices had been implemented, it was reported that between 30–50% of medications returned from clinical areas were not recycled. This was attributed to several factors including infection control concerns and time and resource constraints. There was also variation in extent of recycling across different dosage forms and packaging, with individually packaged tablets and capsules having a higher rate of recycling compared to multidose products.

The results of this study are limited by a low response rate and may not be a true representation of accepted practice across a wide range of facilities in Canada. Despite this, the results did highlight the potential for sites to reduce medication waste utilising medication recycling practices. It is also evident that medication presentation, packaging and handling has a substantial influence on the proportion of returned medications that are deemed suitable for reuse, and this warrants further exploration. Similar evaluation of inpatient medication recycling practices in the Australian hospital setting is necessary to understand local approaches and barriers to this process.

Zou B, Sung S, Drummond I, Tang L, Tejani AM. Understanding medication recycling practices in Canadian hospitals. Int J Pharm Pract 2024; 32: 311–315.

Medication supply operations: considerations for disaster preparedness and response

Potential disruptions to the medication supply chain have become increasingly of concern since the COVID-19 pandemic. Availability and timely access to medications is critical to contribute to positive patient outcomes. Medication supply operations represent a complex system with many different variables that require consideration in the event of a disaster. An understanding of each part of the process and leveraging off of lessons learnt from previous events is essential for adequately preparing the system to respond to potential disaster scenarios. This literature review aimed to identify and explore the relationships between different components of medication supply operations during disaster preparedness and responses and then use this information to develop a framework.

A literature search was performed using several different databases to identify relevant articles published up to 31st March 2023. Thirty-four articles met the inclusion criteria for further analysis. A variety of disaster types were represented inclusive of natural disasters and chemical, biological and nuclear incidents; however the majority of articles were focused on challenges faced during the COVID-19 pandemic. The 11 medication operations management components and 4 management support components identified were used to develop a framework outlining key requirements for both disaster preparedness and response phases. The authors also identified potential opportunities for enhancing disaster response through use of technology and collaborative networks.

The availability of a framework to support medication supply operations that has been formulated using information from various disaster response experiences is a valuable tool to assist in decision making but needs to be applied with local considerations in mind. It is important that there is continued research in this area to allow for expansion and refinement of strategies to support medication supply operations during times of crisis.

Ahmad Hamdi AH, Hatah E, Makmor Bakry M, Halim Basari A, Ahmad Hamdi N. Operations management of pharmaceutical supply during preparedness and disaster response: a scoping review. Int J Disaster Risk Reduct 2024; 103: 104296.

Use of Artificial Intelligence to reduce dispensing errors

Medication dispensing errors create a significant risk of patient harm. Data from the USA reports medication related harm costs their health system $42 billion each year and account for 5–6% of all hospitalisations. In Australia, medication misadventure, including dispensing errors have been reported to contribute to 250 000 hospitalisations annually.1 Artificial intelligence (AI) is demonstrating potential as one solution to improve medication safety, however the clinical uptake of this has been limited to date.

This study utilised a systems engineering approach to design an AI model to support the dispensing process within the American pharmacy environment. This ‘human factors’ approach considered 6 key aspects of the dispensing practice; person, tasks, tools and technologies, physical environment, organisational conditions and external environment to best inform how AI could support reducing medication errors. Experienced pharmacists were involved in a collaborative design process to refine the best approach for AI to assist in error reduction.

AI was proposed to assist with the visual identification step, to ensure the correct product had been dispensed when compared with the prescription. The study demonstrated a collaborative design process is necessary to achieve the desired safety benefits, with pharmacists reiterating that they would trust the AI process more if they understood what and how the AI checks were occurring. The recommended integration of AI into the dispensing process utilised a hybrid approach, where AI required less pharmacist involvement in dispensing checks for lower risk medications, compared with AI completing a safety pre-check for the pharmacist for high-risk medication dispensing.

While Australian dispensing processes typically use original pack dispensing, there is certainly benefit in considering the ways technology can support safe processes. Dispensing errors are commonly associated with incorrect drug or strength selection, and an AI check model may support error reduction, if trusted by pharmacists as another tool to improve patient care. This study demonstrates how that trust can be built.

References

  1. Pharmaceutical Society of Australia (PSA). Medicine Safety: Take Care. Canberra: PSA; 2019.

Zheng Y, Rowell B, Chen Q, Kim JY, Kontar RA, Yang XJ, Lester CA. Designing human-centered AI to prevent medication dispensing errors: focus group study with pharmacists. JMIR Form Res 2023; 7: e51921.

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EDUCATION AND EDUCATIONAL VISITING

MedsScan editors for Education and educational visiting SPG: Diana Bortoletto and Hilai Ahmadzai

Using Virtual Reality to promote patient empathy in pharmacy students

Physical limitations can negatively impact patients’ ability to manage medications. A patient-centric approach, including empathy, may improve patient outcomes. Reflection, didactic, role play and group discussion are effective learning modalities for empathy development. Virtual reality (VR) is a technology-enhanced simulation tool increasingly used in health professions’ curricula to engage current generations of learners.

This study, conducted at Auburn University’s Harrison College of Pharmacy in the United States of America, assessed first-year student pharmacists’ empathy before and after a colour-blindness VR simulation combined with a non-VR arthritis simulation. An anonymous pre- and post-survey, including the 15 item Kiersma-Chen Empathy Scale was used. A Presence scale and Virtual Reality Sickness questionnaire were also included in the post-survey.

Overall, 117 students completed surveys. Student empathy scores increased significantly from pre- to post-intervention in the cognitive domain (p < 0.001, 95% confidence interval [CI] 0.554–0.963), but not in the affective domain (p = 0.167). Within the Presence scale, 82% of learners felt the scenario was happening to them, 91% felt they were part of the action and 71% experienced the scenario as if it were real. Students had high levels of self-reported enjoyment (62%) and perceived usefulness to support learning (84%). 

Despite the study’s robustness and strength of results, there are several technological limitations addressed by authors. Overall costs, large open floor space and personnel requirement may also limit its use, as well as considerations around potential student physical and emotional harm.  Comparative studies of VR to conventional empathy learning modalities will be required to further support its use.

Garza KB, Davis B, Kelley J, Richardson A, Seals C, Hawkins G, et al. Assessing the effectiveness of virtual reality to promote empathy for patients through a mixed-methods study. Am J Pharm Educ 2024; 88: 100702.

The effect of learning models on student perceptions of empathy, engagement, knowledge and learning experience

Patient-Based Learning Models (PBLMs) describe the inclusion of real, virtual or fictional patients as tools in case-based, problem-based and simulation-based learning. This article explores the effect of different PBLMs on the student perceptions of empathy, engagement, knowledge and learning experience, which are considered the four pillars of PBLM.

Thirty-one second-year pharmacy students from Swansea University, United Kingdom, who had been exposed to nine different PBLMs participated in the study. The students were asked to rank their experience of the models based on the four pillars. The PBLMs included interacting with real patients on placement, in lecture theatres and on Zoom, watching pre-recorded videos of real patients, going through PowerPoint/workbook with scripted scenarios with and without simulated patients and lastly using Xerte software.

The study found that being on placement and real patient interactions were consistently rated as the most effective in all four pillars of learning including inciting empathy. PBLMs featuring some sort of interaction (physical, verbal or sight) with the patient were more preferred than scripted scenarios. Digital avatars were found to be more engaging than pre-recorded videos of real patients, while Xerte software, despite portraying a visual representation of the patient, was the least engaging. For knowledge building, integrated case studies featuring videos or avatars performed better than those without visual representations of patients. The overall learning experience mirrored the trends in engagement, with real patient interactions leading to the highest satisfaction. However, digital avatars and Zoom interactions with real patients also provided a moderately enriching experience.

This research serves as a guide for educators in selecting appropriate patient-based learning models. While real patient involvement is critical, particularly for developing empathy, other models, such as digital simulations, can also be effective for engagement and knowledge development.

Leigh L, Mok ZH. The effect of different patient-based learning models on student perceptions of empathy, engagement, knowledge, and learning experience. Med Tech 2024; [online ahead of print] https://doi.org/10.1080/0142159X.2024.2337254.

Continuing education models and statutory requirements for pharmacists

Continuing Professional Development (CPD) is essential for health practitioners, to maintain, enhance and expand their knowledge, expertise and competence, while also developing the personal and professional qualities necessary throughout their careers. Many countries mandate Continuing Professional Education (CPE) and CPD for the registration of pharmacists. This scoping review aimed to investigate global trends in CPE/CPD for pharmacists and how these trends align with statutory licensure requirements.

This review included twenty-four publications examining CPE/CPD, categorised by country income levels due to significant variations in the implementation of CPE/CPD models based on economic status. Although CPE/CPD is non-mandatory in some high-income and upper-middle-income countries, they are at the forefront of implementing CPD models. On the other hand, lower-income countries were found to be still developing their frameworks.

In terms of the mode of CPE/CPD delivery, face-to-face learning was the preferred format in 54.2% of the studies, followed by blended learning at 29.1%. Workplace learning and online learning were less favoured, with only 12.5% of studies mentioning workplace learning. The study highlighted the need to balance CPD requirements with demanding work schedules to prevent burnout.

The review concluded that diverse models of CPE/CPD and statutory requirements for pharmacists are evolving globally. They also highlighted a scarcity of literature on preferences for models and effective lifelong learning activities for pharmacists and emphasised the importance of ongoing research to refine and align CPD models with the evolving needs of the pharmacy profession, particularly in low- and middle-income countries to enhance inclusivity and effectiveness.

Ballaram S, Perumal-Pillay V, Suleman F. A scoping review of continuing education models and statutory requirements for pharmacists globally. BMC Med Educ 2024; 24: 343.

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EMERGENCY MEDICINE

MedsScan editor for Emergency medicine SPG: Jill Upton

Nitroglycerine (GTN) for SCAPE: how high?

This was an open label, single centre, parallel, randomised controlled trial with 54 participants at a tertiary care emergency department in India. It compared the efficacy of high-dose and low-dose nitroglycerine (GTN) in the treatment of patients with sympathetic crashing acute pulmonary oedema (SCAPE). High dose was defined as a 600–1000 microgram intravenous (IV) bolus followed by an IV infusion of 100 microgram/min. Low dose was defined as an IV infusion of 20–40 microgram/min without a bolus. The primary outcome was symptom resolution at 6 hours and 12 hours.

At 6 hours, symptom resolution was seen in 17 patients (65.4%) in the high-dose group, compared with 3 (11.5%) in the low-dose group (p < 0.001). At 12 hours, 88.5% of patients had a clinical resolution in the high-dose group versus 19.5% in low-dose group (risk difference 69.3%, 95% confidence interval [CI] 49.7% to 88.7%, p < 0.001)

Intubation rates, admission rates, length of hospital stay and major adverse cardiac events (MACE) at 30 days were all higher in the low-dose group. No hypotension was observed in either group and the only short-term adverse effect in both groups was headache (3 in the high-dose group and 11 in the low-dose group).

The study found that high dose GTN improved outcomes without significant side effects compared to low dose GTN. Further research should investigate the benefits of this approach across other healthcare settings.

Siddiqua N, Mathew R, Sahu AK, Jamshed N, Bhaskararayuni J, Aggarwal P, et al. High-dose versus low-dose intravenous nitroglycerine for sympathetic crashing acute pulmonary edema: a randomised controlled trial. Emerg Med J 2024; 41: 96–102.

Could tenecteplase be timeless?

Special contributor: Jasmine Walker

Intravenous thrombolysis with tenecteplase is used to treat acute ischaemic stroke causing measurable neurological deficit, within 4.5 hours of symptom onset, including in patients with large vessel occlusions (LVO). TIMELESS was a multicentre, double-blind, randomised, placebo-controlled trial that compared tenecteplase 0.25 mg/kg intravenous (IV) bolus, to placebo, administered at 4.5 to 24 hours after stroke onset, in patients with middle cerebral artery or internal carotid artery occlusion and salvageable tissue on brain imaging.

The primary outcome was the modified Rankin scale (mRS) at 90 days, as a measure of disability defined on a range of 0 (no symptoms) to 6 (death). Safety outcomes included death and symptomatic intracranial haemorrhage. Tenecteplase did not result in better clinical outcomes in comparison to placebo, median mRS 3 in both groups (95% CI 0.82–1.57, p = 0.45). Of 458 patients enrolled, a total of 73% of patients also underwent endovascular thrombectomy. There was no significant difference in mortality at 90 days or in the incidence of symptomatic intracerebral haemorrhage in either group.

This study adds to the literature on use of tenecteplase for patients with an LVO in an extended time window. In contrast to the previous demonstrated benefits of administration of tenecteplase within 4.5 hours in LVOs, tenecteplase did not improve clinical outcomes in comparison to placebo at 4.5 to 24 hours after stroke. Further research is required to identify benefits in specific patient sub-groups.

Albers GW, Jumaa M, Purdon B, Zaidi SF, Streib C, Shuaib A, et al. Tenecteplase for stroke at 4.5 to 24 hours with perfusion-imaging selection. N Engl J Med 2024; 390: 701–711.

Partnered discharge prescribing in the emergency department short stay unit

This prospective pre- and post-intervention study evaluated the impact of a collaborative pharmacist-medical officer discharge prescription planning model on the safe use of medications on discharge from the short stay unit (SSU) of an Australian emergency department (ED). It compared 163 prescriptions written before the intervention to 147 prescriptions written after the intervention.

Errors were defined and quantified using a Five Rights (5 Rs) method for medication administration (right patient, right medication, right dose/formulation, right duration, right indication). The primary outcome was the difference in the proportion of discharge prescriptions that met all the 5 Rs between the standard practice and Partnered Pharmacist Discharge Prescription Planning (PPDPP) phase. Secondary outcomes included difference in the time taken from discharge decision to prescription given to patients and to actual discharge (patient flow) and the rate of high-risk medicines prescribed.

The proportion of discharge prescriptions that met all the 5 Rs increased from 77 (47.2%) to 135 (91.8%) (P < 0.001) using this collaborative model. Although the intervention did not demonstrate a significant improvement in patient flow, the proportion of prescribed opioids decreased from 64 (28.3%) to 48 (16.2%) (P < 0.05) with the pharmacist model.

The study demonstrated that a collaborative model improves medication safety and patient care on discharge from the ED SSU. Further research should investigate the generalisability and optimal model of care in a multi-centre study.

Lee ES, Louey S, Bushby N, Levkovich B. Reducing medication errors on emergency department discharge: Evaluation of a collaborative pharmacist-medical officer discharge prescription planning model in a tertiary hospital emergency short stay unit. Emerg Med Australas 2024; 36: 563–570.

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GENERAL MEDICINE

MedsScan editors for General medicine SPG: Christina Hanciu, Gail Edwards and Marianne Jovanovic

Unveiling the SELECT Trial: semaglutide in obese patients without diabetes

Special Contributor: Reem Moussa

Obesity is prevalent in Australia and results in chronic conditions such as cardiovascular diseases (CVD), diabetes and chronic kidney disease (CKD). Current treatments for obesity have not been wholly successful and long lasting, however a novel approach being utilised is the medication semaglutide.

The SELECT trial was a randomised, double-blind trial exploring the effects of using subcutaneous semaglutide titrated up to 2.4 mg once weekly, on cardiac events in patients aged ≥45 years with a body mass index (BMI) ≥27 kg/m2 and prior CVD in the absence of diabetes, compared to placebo over 4 years. Clinically meaningful weight loss was defined as a 5% or more loss in weight.

At 104 weeks, the percentage of patients using semaglutide who achieved weight loss of ≥5% was 67.8%, compared with 21.3% in the placebo group. In the semaglutide group, 16.6% of patients discontinued treatment compared with 8.2% in the placebo group (p < 0.001). Also at week 104, in patients with a BMI <35 kg/m2, a reduced waist circumference (WC) to below the sex- and race-specific WC that is associated with increased cardiometabolic risk was observed in 41.2% of the semaglutide group compared with 18.0% of the placebo group. Additionally, a drop in BMI was recorded at 104 weeks in 52.4% of patients receiving semaglutide, compared with 15.7% in the placebo group. Treatment with semaglutide also produced a 20% reduction in major adverse cardiovascular events.

The SELECT trial shows that the level of weight loss achieved with semaglutide use paves the way for potentially reducing the health burden associated with obesity and its cardiovascular comorbidities. Results must be interpreted through the limitation that the formulation of semaglutide used is not available in Australia. Due to stock shortages, health professionals should select patients who would most benefit from preferential supply, perhaps now also considering patients at increased CVD risk.

Ryan DH, Lingvay I, Deanfield J, Kahn SE, Barros E, Burguera B, et al. Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. Nat Med 2024; 30: 2049–2057.

Intravenous hydrocortisone as an adjunctive therapy in community-acquired pneumonia

Special Contributor: Khadeeja Rawther 

Community Acquired Pneumonia (CAP) is Australia’s sixth leading cause of death. This multi-centre phase 3, double-blind study investigated whether administration of intravenous (IV) hydrocortisone reduces mortality in intensive care unit (ICU) admitted patients with severe CAP.   

The primary outcome was to assess whether hydrocortisone therapy reduced the risk of death at day 28 with a secondary outcome of death at day 98. Patients were randomly assigned to receive either hydrocortisone (n = 400) or placebo (n = 395), in addition to standard therapy which included antibiotics and supportive care. 

By day 28, death occurred in 6.25% (n = 25) patients in the hydrocortisone group, compared with 11.89% (n = 47) of patients in the placebo group. Similarly, death by day 98 occurred in 9.27% of patients (n = 36) in the hydrocortisone group and 14.65% of patients (n = 57) in the placebo group, showing a significant reduction in mortality in the treatment group (absolute difference -5.6%, p = 0.006). Patients who received hydrocortisone also had a lower rate of endotracheal intubation (18.0% vs 29.5% in the placebo group). The hydrocortisone group did not have an increased risk of hospital-acquired infections or gastrointestinal bleeding. However, an increased insulin requirement was evident in the hydrocortisone group, as expected with the adverse effect profile. 

The authors concluded that the administration of IV hydrocortisone in patients with severe CAP treated in ICU, resulted in a lower risk of death by day 28 and day 98 compared to placebo. However further research is required to explore the potential reversibility of hyperglycaemia, neuropsychological and neuromuscular adverse effects of corticosteroids.  

Dequin PF, Meziani F, Quenot J-P, Kamel T, Ricard J-D, Badie J, et al. Hydrocortisone in severe community-acquired pneumonia. N Engl J Med 2023; 388: 1931–1941.

Ferric carboxymaltose in heart failure with iron deficiency

Special Contributor: Harrison Kalma

Iron deficiency is a significant comorbidity in heart failure, particularly in those with reduced ejection fraction (HFrEF). Guidelines recommend ferric carboxymaltose (FCM) for quality-of-life improvement, but evidence for reducing hospitalisations and mortality is inconclusive. The HEART-FID trial aims to clarify FCM's role in this population.

A retrospective double-blind study compared FCM to placebo in iron-deficient heart failure patients HFrEF. The study enrolled 3065 patients across 281 centers in 14 countries between March 2017 and November 2021. The primary outcomes included a hierarchical composite of death within 12 months, hospitalisations for heart failure within 12 months and change from baseline at 6 months in the 6-minute walk test.

Results indicated a modest reduction in 12-month death rates (8.6% vs 10.3%), improved 6-month 6-minute walk distance (8 meters vs 4 meters), and fewer total hospitalisations within 12 months in the FCM arm (297 vs 332). The overall unmatched win ratio for the hierarchical composite was 1.10 (99% confidence interval 0.99–1.23, p = 0.02), below the US Food and Drug Administration approved significance level of 0.0099. Win ratios for death within 12 months and change in 6-month 6-minute walk distance were higher than placebo (1.2 and 1.11, respectively), while no difference was observed in hospitalisations within 12 months.

While no significant differences were observed, this study, along with previous trials, suggests potential FCM benefits in reducing cardiovascular death and heart failure hospitalisation. Further analysis is required to determine for which patients FCM elicits the greatest benefit. Considering the low risk and potential advantages, FCM treatment warrants consideration in iron-deficient HFrEF patients.

Mentz RJ, Jyotsna Garg MS, Rockhold FW, Butler J, De Pasquale CG, Ezekowitz JA, et al. Ferric carboxymaltose in heart failure with iron deficiency. N Eng J Med 2023; 389: 975–986.

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INFECTIOUS DISEASES

MedsScan editors for Infectious diseases SPG: Nadine Hillock and Minyon Avent

Comparison of three-times-daily versus four-times-daily tetracycline for Helicobacter pylori rescue treatment

This multicentre open-label, non-inferiority randomised controlled trial compared the efficacy and safety of different tetracycline doses in bismuth-containing quadruple rescue therapy for Helicobacter pylori (H. pylori) eradication. Adult patients (aged 18–70 years) were eligible for inclusion if H. pylori infection was confirmed via rapid urease test or 13C-urea breath test and a history of at least one (but no more than two) failed eradication treatment.

Four hundred and six patients were randomised (allocation concealed) to one of two 14-day treatment arms via computer-generated random sequencing. Physicians responsible for post-treatment follow up were blinded to treatment. Treatment regimens were esomeprazole 40 mg daily, bismuth 220 mg twice daily, amoxicillin 1 g twice daily, and either tetracycline 500 mg four times daily (QID) or 500 mg three times daily (TDS). The primary outcome was successful H. pylori eradication, defined as a negative 13C-urea breath test at 6 weeks after treatment completion. Compliance was defined as consuming at least 90% of prescribed dosage. The non-inferiority margin was set at 8%.

There were no significant differences in the baseline demographics, including age, gender, smoking status, alcohol consumption or previous failed antibiotic treatments. The Intention-to-treat (ITT) analysis of efficacy showed that three times daily was not inferior to four times daily; in 203 patients eradication rates were 91.1% (n = 185) in the TDS group compared to 90.2% (n = 183) in the QID group (difference 0.98%, 95% confidence interval [CI] -6.7% to 4.7%). Of the 203 patients included, treatment associated adverse events were significantly higher in the QID group with 33.5% (n = 68) reporting at least one adverse event, compared to 23.7% (n = 48) in the TDS group (p = 0.028). Compliance with treatment was 94.6% in the TDS group and 92.6% in the QID group with the difference not statistically significant (p = 0.42).

The investigators concluded that three-times-daily dosing of tetracycline was similar in efficacy to four-times-daily, while significantly reducing adverse events. This study suggests that TDS dosing may be more tolerable than the QID dosing currently recommended in clinical guidelines for H. pylori rescue treatment.

Han Z, Zhang Q, Mirza IA, Ding Y, Nan X, Zhao Q, et al. Efficacy of tetracycline three times daily was comparable to that of four times daily for Helicobacter pylori rescue treatment: a multicenter, noninferiority, randomised controlled trial. Helicobacter 2024; 29: e13102.

The ORACLE study: oral challenge versus routine care to assess low-risk penicillin allergy in intensive care patients

Conducted in four principal referral hospitals in Melbourne, the ORACLE study was an open-label, randomised controlled trial which aimed to establish the feasibility, safety and validity of direct enteral challenge for low-risk penicillin allergy in critically ill patients in the intensive care unit (ICU).

Adult ICU patients (≥18 years) with a documented penicillin allergy were identified by screening their electronic medical record. Patients were eligible for inclusion if their penicillin allergy was assessed as a PEN-FAST (Penicillin Allergy Decision Rule) score of less than 3 (low or very low risk of true penicillin allergy) and an expected duration of ICU stay of greater than 24 hours post-randomisation. Patients were ineligible for inclusion if pregnant, if death was imminent or inevitable during ICU stay, or if they had a history of anaphylaxis (non-penicillin related), idiopathic urticaria or mastocytosis. Patients were also excluded if they were on antihistamine therapy, receiving >0.1 μg/kg/min noradrenaline or any adrenaline therapy within previous 4 hours, receiving more than stress dose steroid therapy (i.e. >200 mg hydrocortisone daily, or equivalent) or if they had a high ventilator requirement if intubated. Primary outcomes were the proportion of eligible patients that consented to enrol (patient or treating team did not decline) and the proportion who experienced a penicillin-associated immune-mediated or serious adverse event.

Of the 533 patients screened, 403 patients were ineligible including 168 with a PEN-FAST score ≥3. One hundred and thirty patients met the inclusion criteria and of those, 80 patients were enrolled (62%). Patients were randomised (allocation concealed) to direct enteral challenge with 250 mg amoxicillin (or the penicillin they’d been documented as allergic to) or routine care. Participants were monitored for adverse events for 2 hours, with vital signs measured every 30 minutes. Patients in the intervention arm received a repeat penicillin challenge 48 hours after the initial challenge if the initial challenge was negative, and following discharge from ICU or resolution of critical illness.

No patients in the intervention group (n = 40) had an immune-mediated or severe adverse event during the 2-hour observation period following the initial enteral penicillin challenge. One patient developed an antibiotic-associated pruritic macular rash on the trunk 15 hours after amoxicillin challenge which resolved one hour after antihistamine administration. In the 40-patient intervention group, penicillin allergy labels were able to be removed in 39 (98%) of patients in the intervention arm. In-hospital use of any penicillin after randomisation was 13/40 (32%) of the intervention group and 4/40 (10%) of the control arm (odds ratio = 4.3; 95% CI 1.3 to 14.8, p = 0.33).

Based on the enrolment rate of 62% of eligible patients, the investigators deemed enteral challenge for low-risk penicillin allergy to be feasible in the ICU patient population. The authors acknowledged the low eligibility rate in this critical care patient population (24% of patients screened), which was primarily attributed to a PEN-FAST score ≥3, an ICU stay <24 hours or the need for high ventilatory or inotropic support.

Rose MT, Holmes NE, Eastwood GM, Vogrin S, James F, De Luca JF, et al. Oral challenge vs routine care to assess low-risk penicillin allergy in critically ill hospital patients (ORACLE): a pilot safety and feasibility randomised controlled trial. Intensive Care Med 2024; 50: 913–921.

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MENTAL HEALTH

MedsScan editors for Mental health SPG: Judy Longworth and Amy Sieff

Antidepressants and medical disease

Given that approximately 1 in 5 Australians have depression or anxiety1 it is also likely that they may also have a comorbid medical illness. Comorbid medical illnesses have traditionally been excluded from clinical trials and hence this paper aims to address a significant gap in the literature for patients with depression and comorbid medical illness. There is a wealth of information from this umbrella study looking at over 6587 references, especially in the attached tables from the PRISMA protocol and other statistical measures.

With the meta-analysis of the original trials for antidepressants being questioned for efficacy and poor effect sizes, risk needs to be taken into account when considering introducing another medication to a vulnerable population. The five main findings from this paper were:

  1. Antidepressants were more efficacious compared to placebo for depression in patients with comorbid medical illness
  2. Antidepressants demonstrated lower acceptability and adherence rates and higher risk of adverse effects than placebo
  3. Effect size varied widely across the identified medical illnesses, with those with comorbid illnesses of a cardiac nature being more likely to benefit from antidepressant treatment than those with other conditions such as back pain and brain injury
  4. For patients with comorbid medical disease there was an overall risk reduction in depression rates
  5. Moderate quality of systematic reviews but low quality randomised controlled trials.

Further good quality trials are needed, but this paper at least helps when trying to select options for an appropriate antidepressant medication for a patient with a particular medical comorbidity with some evidence for prior effectiveness in some populations. 

References

  1. Australian Institute of Health and Wellbeing. (AIHW). Prevalence and impact of mental illness. AIHW; 2024. Available from https://www.aihw.gov.au/mental-health/overview/prevalence-and-impact-of-mental-illness. Accessed 3 June 2024.

Köhler-Forsberg O, Stiglbauer V, Brasanac J, Chae WR, Wagener F, Zimbalski K, et al. Efficacy and safety of antidepressants in patients with comorbid depression and medical diseases: an umbrella systematic review and meta-analysis. JAMA Psychiatry 2023; 80: 1196–1207.

International use of clozapine

There is an associated burden to both patients and health infrastructure with clozapine due to frequent and mandatory haematological monitoring requirements. This likely contributes to underutilisation of clozapine, which is often the best option in treatment-resistant schizophrenia for improving quality of life and patient outcomes.1 Two recently published articles explore the use of clozapine in Finland and in Australia and New Zealand. This summary will discuss both articles.

An Australian and New Zealand retrospective analysis examined the incidence of neutropenia over a 32-year period for 26 630 patients. Of these patients, 1.2% had a serious neutropenic event (absolute neutrophil count < 1.0x109) leading to clozapine cessation and 0.8% had serious neutropenia unrelated to therapy without requiring cessation. The weekly incidence of serious neutropenia leading to cessation peaked at 9 weeks and then fell to an average of 0.001% at 104 weeks. The authors concluded that serious neutropenic events leading to cessation were highest in the first 18 weeks and became negligible after 2 years of clozapine exposure.

A Finnish study found that the absolute cumulative incidence of agranulocytosis for clozapine patients may be higher than that for non-clozapine antipsychotics (1.37% vs 0.13% respectively for the 22 year observation period); however the study also showed there was a significant decrease in the risk of neutropenia requiring cessation over time and noted the benefits of clozapine therapy.

Although the mechanism for the risk of serious neutropenic events is not fully understood, both of these studies demonstrate a reduction in risk after 6 months of clozapine therapy and suggest an equalisation with other antipsychotics in the long term. The data supports increasing calls for review and rationalisation of mandatory clozapine monitoring regimens in Australia, particularly after treatment has been established.

References

  1. Meltzer HY. Clozapine: balancing safety with superior antipsychotic efficacy. Clin Schizophr Relat Psychoses 2012; 6: 134–144.

Rubio JM, Kane JM, Tanskanen A, Tiihonen J, Taipale H. Long-term persistence of the risk of agranulocytosis with clozapine compared with other antipsychotics: a nationwide cohort and case–control study in Finland. Lancet Psychiatry 2024; 11: 443–450.

Northwood K, Myles N, Clark SR, Every-Palmer S, Kisley S, Warren N, et al. Evaluating the epidemiology of clozapine–associated neutropenia among people on clozapine across Australia and Aotearoa New Zealand: a retrospective cohort study. Lancet Psychiatry 2024; 11: 27–35.

Update: long-term ADHD medication use and cardiovascular disease risk

Recent literature has described the need for further studies examining the long-term relationship between medications for attention deficit hyperactivity disorder (ADHD) and cardiovascular disease (CVD) risk.1 This need is supported by the significantly increasing use of medicines for ADHD and a concurrent growing demand for assessment/diagnosis of consumers presenting with suspected adult-onset or previously undiagnosed ADHD.2

This paper describes a nested case-control study that included 278 027 participants with ADHD, from 6–64 years of age. The Swedish National Inpatient and Prescribed Drug registers were used to obtain data regarding incident diagnoses of ADHD, stimulant and non-stimulant ADHD medication dispensings and incident CVD diagnoses between 2007–2020. Exclusion criteria and matching were applied, yielding 10 388 participants for analysis.

Long-term ADHD medication use in this cohort was not associated with a statistically significant increase in the risk of heart failure, ischaemic heart disease, arrythmias, thrombosis or cerebrovascular disease. There were however increased risks of hypertension and arterial disease, particularly with stimulants and prolonged medication use.

Confounding factors in this study such as potential for undiagnosed/pre-clinical CVD, render it unable to confirm a causal link between long-term ADHD medications and increased CVD risk. Nonetheless, the results support judicious use of stimulant medications for ADHD, accompanied by ongoing blood pressure monitoring and CVD screening.

References

  1. Zhang L, Yao H, Li L, Du Rietz E, Andell P, Garcia-Argibay M, et al. Risk of cardiovascular disease associated with medications used in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. JAMA Netw Open 2022; 5: e2243597
  2. Suetani S, Kallapiran K, Scott JG. Have you been paying attention? Adult-onset attention-deficit hyperactivity disorder. Aust NZ J Psychiatry 2024; 58: 385–386.

Zhang L, Li L, Andell P, Garcia-Argibay M, Quinn PD, D’Onofrio BM, et al. Attention-deficit/hyperactivity disorder medication and long-term risk of cardiovascular diseases. JAMA Psychiatry 2024; 81: 178–187.

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NEPHROLOGY

MedsScan editor for Nephrology SPG: Laura Johnstone

The choice of blood pressure lowering medications in transplant recipients - do we know enough to choose the safest and most effective agent?

Special contributor: Hanh Tran

Background: Kidney transplant recipients often experience post-transplant hypertension, requiring control with antihypertensive agents. The selection of these agents can be constrained by a lack of robust evidence in current clinical practice guidelines and safety concerns. For example, calcium channel blockers (CCB) are preferred over angiotensin converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) (usual first line for hypertension according to guidelines), due to concerns of the latter agents’ potential adverse effects on graft function. Treatment decisions are also complicated by factors such as immunosuppressant complications, vascular injury and occlusion and pre-existing kidney disease, which also pose a significant risk for graft loss, cardiovascular events and other adverse outcomes.

Aim: This systematic review and network meta-analysis compared various antihypertensive agents used for kidney transplant recipients in randomised controlled trials (RCTs) to assess benefits and harms.

Method: A highly sensitive literature search from 1978–2023 identified 94 eligible RCTs from 26 countries involving 7547 participants, 2 studies also involved children. Patients studied had functioning kidney transplants and were on blood pressure (BP) lowering agents at any dose for at least 2 weeks. Two independent reviewers extracted a range of data. The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were followed to enable direct and indirect comparisons across studies, focusing on significant outcomes for patients with functioning kidney transplants. The primary outcome for effectiveness was graft loss, and for safety, medication withdrawal due to adverse effects.

Secondary outcomes included all-cause and cardiovascular mortality, cardiovascular diseases, acute transplant rejection, kidney injury-related parameters, quality of life, life participation, infection and cancer. Firstly, a random-effects pairwise meta-analysis estimated the direct effects of each BP agent compared to placebo or standard care, reporting effectiveness as odds ratios (OR) for dichotomous outcomes and mean differences (MD) or standardised mean differences (SMD) for continuous outcomes. Risk of bias and certainty of evidence were assessed using Cochrane risk bias tools. All available treatments within the global network were then compared using Frequentist network meta-analysis. Evidence of inconsistency within the network was determined by the ‘design-by-treatment’ interaction method, with a chi-squared test threshold of less than 0.05.

Results: Of the 94 eligible studies, 33 studies had 13% of participants (551 out of 4240) experience graft loss, and in 39 studies, 7.4% of participants (255 out of 3460) discontinued BP agents due to adverse events. No significant differences in the odds of these primary outcomes were observed between any class of BP-lowering agents compared to placebo or other classes. For secondary outcomes, the rates of all-cause death and cardiovascular death were 8.4% (388 out of 4618 participants in 41 studies) and 0.6% (19 out of 3158 participants in 34 studies), respectively. While ACEi and ARB showed higher odds ratios for causing hyperkalemia compared to CCB with low-certainty evidence (ACEi vs CCB: OR 5.48, 95% [confidence interval] CI 2.47–12.16; ARB vs. CCB: OR 8.67, 95% CI 2.65–28.36; ARB vs placebo: OR 4.12, 95% CI 1.63–10.42), no differences were found between any drug class and placebo or other classes for odds of all-cause or cardiovascular death and for effects of nonfatal myocardial infarction, acute transplant rejection, estimated glomerular filtration rate (eGFR), creatinine clearance, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) or cough. The BP-lowering agents studied included CCB, ACEi, ARB, aldosterone antagonists, alpha blockers, beta blockers, centrally acting vasodilators, direct renin inhibitors, mineralocorticoid receptor antagonists (MRA) and diuretics. Agents included were at any dose, used alone or in combination.  Despite a high or unclear risk of bias in most domains due to the large volume of studies, network plots for each outcome showed no evidence of global inconsistency except for MAP.

Key limitations: Only 2 out of 94 studies focused on paediatric transplant recipients, rendering the results of this systematic review inapplicable to this population. Most of the studies were of short duration, conducted up to 20 years ago, and lacked insight into key clinical outcomes such as mortality and cardiovascular complications. Many studies were noted by authors to have poor methodology and short-term follow up, which may reduce the certainty of estimated treatment effects.

Impact on practice: Concerns about the long-term adverse effects of ACEi and ARB on transplant outcomes compared to other BP agents remain based on clinician judgment rather than evidence. This follow up meta-analysis, which includes an additional 23 studies is consistent with previous findings; that ACEi and ARB do not alter the risk of graft loss, death, or doubling of serum creatinine when compared with placebo. Consequently, the evidence for comparative benefits and safety of BP lowering agents in adults and children remains inadequate to inform decisions regarding treatment, and future well-designed and adequately powered RCTs remain necessary.

Natale P, Palmer S, Jaure A, Saglimbene V, Iannone A, Sluiter A, et al. Blood pressure lowering for kidney transplant recipients: systematic review with network meta-analysis. J Hypertens 2024; 42: 848–855.

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ONCOLOGY AND HAEMATOLOGY

MedsScan editor for Oncology and haematology SPG: Hayley Vasileff

Pregnancy after breast cancer: suspending endocrine therapy

In this study, researchers sought to investigate the risk of breast cancer recurrence among women with hormone receptor–positive early breast cancer who temporarily suspend endocrine therapy to pursue pregnancy. This critical research addresses a significant gap in prospective data regarding the safety of interrupting endocrine therapy for women wishing to conceive post-breast cancer treatment.

The study employed a single-group trial design, enrolling 516 eligible women aged 42 years or younger, with stage I, II or III breast cancer, who had received adjuvant endocrine therapy for 18 to 30 months and wished to become pregnant. The primary endpoint was the incidence of breast cancer events during follow up, analysed after 1600 patient-years of follow up.

Results showed promising outcomes. Of the 497 women followed for pregnancy status, 74.0% experienced at least one pregnancy, with 63.8% having at least one live birth. The 3-year incidence of breast cancer events in the treatment-interruption group (8.9%) did not significantly differ from the control cohort (9.2%).

These findings suggest that temporary interruption of endocrine therapy to pursue pregnancy among select women with previous hormone receptor–positive early breast cancer does not pose a greater short-term risk of recurrent breast cancer compared to those who continue therapy. Although further research and follow up is required to assess the long-term safety of this approach, it offers hope and reassurance to young breast cancer survivors desiring pregnancy, providing crucial evidence to guide clinical decision-making in this vulnerable population.

Partridge AH, Niman SM, Ruggeri M, Peccatori FA, Azim Jr AE, Colleoni M, et al. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Eng J Med 2023; 388: 1645–1656.

Preventing chemotherapy-induced nausea and vomiting with lower dose olanzapine  

Special Contributor: Linda Nguyen

Olanzapine is recommended with triple antiemetic therapy to prevent chemotherapy-induced nausea and vomiting (CINV) with highly emetogenic chemotherapy. However, daytime somnolence is a significant and common adverse effect with the recommended 5–10 mg dose.

To determine the effects of lower dose olanzapine on CINV prevention and daytime somnolence, this single-centre, non-inferiority, randomised controlled trial investigated low dose (2.5 mg) versus standard dose (10 mg) olanzapine. Patients with solid tumours receiving doxorubicin with cyclophosphamide or high-dose cisplatin chemotherapy were included. Two hundred and sixty-seven patients received either olanzapine 2.5 mg or 10 mg orally at night for 4 days with triple antiemetic therapy (NK-1 receptor antagonist, 5HT3 receptor antagonist, dexamethasone).

Complete control of nausea in the overall phase (0–120 hours) was experienced by 45% (59/132) of patients in the 2.5 mg group versus 44% (59/135) in the 10 mg group (p = 0.87). Results were also comparable between the two groups for those who experienced complete control of nausea in the acute phase (0–24 hours) (50% vs 49%) and delayed phase (25–120 hours) (51% vs 59%). Daytime somnolence (any grade) in the overall phase was significantly reduced with the 2.5mg dose (65% vs 90%, p < 0.0001).

The authors concluded that olanzapine 2.5 mg was non-inferior in preventing CINV whilst significantly reducing daytime somnolence. This can benefit patients in practice by increasing tolerability and compliance, especially for those who are not candidates for the higher dose (eg. older age, other comorbidities). Further study is required, involving different patient populations, to confirm these results.

Bajpai J, Kapu V, Rath S, Kumar S, Sekar A, Patil P, et al. Low-dose versus standard-dose olanzapine with triple antiemetic therapy for prevention of highly emetogenic chemotherapy-induced nausea and vomiting in patients with solid tumours: a single-centre, open-label, non-inferiority, randomised, controlled, phase 3 trial. Lancet 2024; 25: 246–254.

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PAEDIATRICS AND NEONATOLOGY

MedsScan editor for Paediatrics and neonatology SPG: Rachael Worthington

Prevention of chronic lung disease of prematurity with AZTEC

Chronic lung disease of prematurity (CLD) is associated with significant mortality and life-long morbidity, with a multifactorial pathogenesis including pulmonary inflammation and colonisation by Ureaplasma spp., with the latter remaining controversial. Systematic reviews have revealed conflicting evidence on the utility of macrolide antibiotics in reducing the rates of chronic lung disease of prematurity (CLD) in at-risk preterm infants.

The AZTEC multicentre, double-blind, randomised, placebo-controlled trial conducted in 28 tertiary neonatal intensive care units in the United Kingdom, aimed to assess if the macrolide azithromycin improved survival without the development of physiologically-defined moderate or severe CLD in preterm infants. Infants were eligible if they were born at less than 30 weeks gestation and had received at least 2 h of either non-invasive or invasive respiratory support within 72 h of birth. Participants were recruited between 9 Oct 2019 and 22 March 2022 and were randomly allocated to receive ten days of intravenous azithromycin at 20 mg/kg per day for 3 days followed by 10 mg/kg for 7 days, or placebo, stratified by centre and gestational age at birth (<28 weeks vs ≥28 weeks). 

Of the 1505 eligible infants, 706 were not recruited, 799 (53.1%) underwent random allocation and of these, three infants were withdrawn, leaving 796 infants for analysis. The primary outcome was a composite outcome of survival without development of physiologically defined moderate or severe CLD at 36 weeks postmenstrual age. Outcomes and safety were analysed on an intention-to-treat basis (all randomly allocated infants, regardless of any post-randomisation events). Survival without moderate or severe CLD occurred in 166 (42%) of 394 infants in the intervention group and 179 (45%) of 402 in the placebo group (three-level adjusted odds ratio 0.84, 95% confidence interval [CI] 0.55–1.29, p = 0.43). Pulmonary Ureaplasma spp. colonisation did not influence treatment effect. Seven serious adverse events were reported for the azithromycin group (five graded as severe, two as moderate) and six serious adverse events were reported in the placebo group (two severe, two moderate and two mild) as assessed by the local principal investigators.

The authors concluded that, as prophylactic use of azithromycin did not improve survival without development of physiologically-defined CLD, regardless of Ureaplasma spp. colonisation, it should not be recommended in clinical practice.

Lowe J, Gillespie D, Aboklaish A, Lau TMM, Consoli C, Babu M, et al. Azithromycin therapy for prevention of chronic lung disease of prematurity (AZTEC): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Respir Med 2024; 12: 608–618.

Eosinophilic esophagitis diminished by dupilumab

Eosinophilic esophagitis frequently occurs in children and if untreated can lead to strictures, food impaction, failure to thrive and reduced quality of life. Dupilumab is a human monoclonal antibody that blocks interleukin-4 and interleukin-13 pathways and has demonstrated efficacy in five different type 2 inflammatory atopic diseases, including eosinophilic esophagitis in adults and adolescents.

This multicentre, phase 3 randomised, double blind, placebo-controlled trial sought to evaluate dupilumab in children aged 1–11 years of age with active eosinophilic esophagitis refractory to proton pump inhibitor therapy. One hundred and two participants were randomly assigned to higher exposure or lower exposure subcutaneous dupilumab regimen or to placebo for 16 weeks (Part A), then eligible patients in each dupilumab group continued the same regimen and those in the placebo groups were assigned to higher exposure or lower exposure dupilumab for 36 weeks (Part B). At each level of exposure, dupilumab was administered as one of four doses based on baseline body weight. The primary end point was histologic remission at week 16, with eight key histological, endoscopic and transcriptomic secondary end points tested hierarchically.

In Part A, histologic remission occurred in 25 of the 37 patients (68%) in the higher exposure group, in 18 of the 31 patients (58%) in the lower exposure group, and in 1 of the 34 patients (3%) in the placebo group (between the higher exposure regimen and placebo, 65 percentage point difference [95% CI 48–81, p < 0.001]; between the lower exposure regimen and placebo, 55 percentage point difference [95% CI 37–73, p < 0.001]). The higher exposure dupilumab regimen led to significant improvements in histologic, endoscopic, and transcriptomic measures when compared with placebo, which were retained through to week 52 in all patients. In Part A, the incidence of COVID-19, nausea, injection-site pain, and headache was at least 10 percentage points higher for patients who received either of the dupilumab doses compared with those who received placebo.

Serious adverse events were reported in 3 patients who received dupilumab during Part A and in 6 patients overall during Part B. Dupilumab resulted in histologic remission in a significantly higher percentage of children with eosinophilic esophagitis than placebo. The higher exposure dupilumab regimen also led to improvements in measures of key secondary end points when compared with placebo.

Chehade M, Dellon ES, Spergel JM, Collins MH, Rothenberg ME, Pesek RD, et al. Dupilumab for eosinophilic esophagitis in patients 1 to 11 years of age. N Engl J Med 2024; 390: 2239–2251.

Congenital Adrenal Hyperplasia treated with crinecerfont

Children with classic Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency, a rare autosomal recessive disorder characterised by impaired synthesis of cortisol and aldosterone, require treatment with supraphysiological doses of glucocorticoids, with associated glucocorticoid-related complications as sequelae. Phase 2 trials in adolescents and adults with CAH have demonstrated the potential therapeutic value of crinecerfont, a new oral corticotropin-releasing factor type 1 receptor antagonist.

This phase 3, multinational, randomised, double-blind, placebo-controlled trial sought to evaluate the efficacy in children 2–17 years of age with CAH. One hundred and three participants were randomly assigned to receive a weight stratified dose of crinecerfont or placebo for 28 weeks. The glucocorticoid dose was stabilised and maintained for 4 weeks, followed by 24 weeks of doses adjusted to a target of 8.0–10.0 mg/m2/day in hydrocortisone dose equivalents, while the androstenedione level was controlled. The primary efficacy end point was the change in androstenedione level from baseline to week 4, with the percent change in the glucocorticoid dose from baseline to week 28 while androstenedione control was maintained, evaluated as the secondary end point.

A total of 103 participants underwent randomisation, 69 were assigned to the crinecerfont group and 34 to the placebo group, with 100 (97%) remaining in the trial at 28 weeks. At baseline, the mean glucocorticoid dose was 16.4 mg/m2/day, and the mean androstenedione level was 431 ng/dl (15.0 nmol/L). At week 4, the androstenedione level substantially decreased in the crinecerfont group by 197 ng/dl (6.9 nmol/L) but increased in the placebo group by 71 ng/dl (2.5 nmol/L), with the least-squares mean difference of −268 ng/dl (−9.3 nmol/L), p < 0.001. The observed mean androstenedione value was 208 ng/dl (7.3 nmol/L) in the crinecerfont group, compared with 545 ng/dl (19.0 nmol/L) in the placebo group. At week 28, the mean glucocorticoid dose had decreased (while androstenedione control was maintained) by 18.0% with crinecerfont,but increased by 5.6% with placebo (least-squares mean difference, −23.5 percentage points, p < 0.001). Headache, pyrexia, and vomiting were the most common adverse events.

The results demonstrate that crinecerfont was superior to placebo in reducing elevated androstenedione levels in paediatric participants with CAH, with an associated decrease in the glucocorticoid dose to target physiologic levels while androstenedione control was maintained.

Sarafoglou K, Kim MS, Lodish M, Felner EI, Martinerie L, Nokoff NJ et al. for the CAHtalyst Pediatric Trial Investigators. Phase 3 trial of crinecerfont in pediatric Congenital Adrenal Hyperplasia. N Engl J Med 2024 391; 493–503.

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PAIN MANAGEMENT

MedsScan editor for Pain management SPG: Jeremy Szmerling

Australia’s annual overdose report 2023

The 2023 Annual Overdose Report (‘the Report’) highlights the rising overdose crisis, examining causes and trends. It aims to inform and mobilise healthcare professionals, urging pharmacists to engage in prevention and intervention efforts. The Report employs a comprehensive observational study design, analysing national overdose data from multiple sources. It examines demographic patterns, substances involved, and geographic trends. The report integrates data validated and compiled by the Australian Bureau of Statistics.

The Report reveals Australia's escalating drug overdose crisis, with 2231 drug-induced deaths in 2021, of which 75% were unintentional. Unintentional drug-induced deaths surpassed the road toll in 2014, with a 70.7% increase since 2001, outpacing population growth. Drug-induced deaths ranked as a leading cause of mortality across various age groups, disproportionately affecting Indigenous Australians, rural residents and men. Opioids remained the most common cause of unintentional drug-induced deaths in 2021 (45.7%). This was followed by unintentional fatalities linked to benzodiazepines (32.5%) and stimulants (27.5%), which have notably increased since 2001. Seven in ten unintentional drug-induced deaths involved two or more drug types. Non-fatal drug- and alcohol-related harm remained significant, with 151 797 hospitalisations and 162 874 ambulance attendances in 2020–21, predominantly due to alcohol.

This report underscores the critical role of pharmacists in both community and hospital settings in combating the overdose crisis. Australian pharmacists can leverage this information to enhance patient education on safe medication use, implement robust screening for substance misuse, and advocate for expanded access to naloxone. By participating in harm reduction strategies and supporting public health initiatives, pharmacists can significantly contribute to reducing overdose fatalities and improving patient outcomes.

Penington Institute. Australia’s annual Overdose report. Melbourne: Penington Institute; 2023. Available from: https://www.penington.org.au/wp-content/uploads/2023/08/PEN_Annual-Overdose-Report-2023_FINAL.pdf.

Standard of practice in pain management for pharmacy services

The purpose of the Standard of practice in pain management for pharmacy services (the Standard) is to describe the current best practice for the provision of pain management pharmacy services, and the role of pharmacists and pharmacy technicians. This Standard applies to all pharmacists working in pain management, irrespective of service type and location. The Standard supersedes the previous Standard of practice in pain management for pharmacy services and is read in conjunction with the SHPA Standards of practice for clinical pharmacy services. It was reviewed by SHPA members, the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine, the Australian Commission on Safety and Quality in Health Care, the Australian Pain Society, the Clinical Excellence Commission and Safer Care Victoria.

The Standard emphasises the integration of pain management pharmacists into interdisciplinary teams to enhance patient care through accurate medication histories, risk assessments, and tailored education. It stresses culturally responsive care, adherence to essential documents and policies, and continuous professional development. Key areas include analgesic stewardship, naloxone availability and opioid rotation and de-escalation. The Standard highlights the crucial requirements for staffing, training, and commitment to quality improvement and research to facilitate effective pain management. Pain management expertise reduces medication errors, increases patient satisfaction and improves pain management outcomes.

Pharmacist-led initiatives have demonstrated significant reductions in adverse events and healthcare resource utilisation. Interventions such as patient education and comprehensive medication management lead to better outcomes, including decreased opioid prescribing and minimised post-discharge opioid use. By considering patients' experiences and comorbidities, pharmacists optimise treatment plans and mitigate risks. Integrating pharmacists into interdisciplinary teams is crucial for effective pain management and minimising opioid-related harm.

Liu S, Bui T, Lee KK, Lim WS, Lim D, Onishko C, et al. Standard of practice in pain management for pharmacy services. J Pharm Pract Res 2024; 54: 74–93.

The impact of a multi-disciplinary analgesic stewardship program on optimising analgesic prescribing practices

Special contributor: James Peacock

Inappropriate prescribing of opioids remains a major Australian health issue leading to opioid-related harms and fatalities. This retrospective audit conducted at a major metropolitan health network in Victoria, aimed to assess the impact of a multidisciplinary analgesic stewardship program (AGS) on opioid prescribing appropriateness in general medicine and surgical units.

Electronic medical records of 100 adult inpatients were assessed during the first two months of implementation of the AGS program, between August–September 2022. A total of 51 opioid-naïve patients who’d been started on long-acting opioids for acute non-cancer pain underwent management and review by the AGS program. This resulted in the cessation of 89.7% of inappropriately prescribed long-acting opioids. Forty-nine patients admitted with opioids who were reviewed by the AGS program benefited from an average overall reduction in oral morphine equivalent daily dose (OMEDD) of 19.85 mg (95% confidence interval [CI] 10.3–29.4 mg, p < 0.05). Interventions or recommendations made by the AGS program included prescribing simple and/or adjunct analgesia, medications for analgesia side effects, ceasing inappropriate medication, changing medication dose or frequency, provision of weaning plans, referral to an Acute Pain Service or outpatient chronic pain team and GP review for deprescribing of analgesia. The AGS program's recommendations were fully or mostly implemented for 82% of patients, partially implemented for 7%, and not implemented at all for 11%.

This study highlights the significant impact of an AGS program on improving optimal analgesic prescribing practices to minimise unintended opioid-related harm. The results provide further evidence to support adoption of AGS programs in healthcare services to align with practice recommendations in national clinical care standards.

Szmerling J, Maleki S, Mar G, Goulopoulos A. Cultivating optimal analgesic prescribing practices in a metropolitan hospital network: evaluating an analgesic stewardship program. J Pharm Pract Res 2024; 54: 228–235.

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RESEARCH

MedsScan editors for Research SPG: Jacinta Johnson and Sid Patanwala

How to conduct and report guidelines and position, best practice and consensus statements

Guest contributor: Sam Malek

Evidence-based clinical practice guidelines are typically created by synthesising available research. However, an analysis of leading anaesthesia journals (2016–2020) found only seven of 51 guidelines met high scientific standards due to development challenges, inconsistent terminology and varied methodologies. This article provides recommendations for planning, executing and reporting clinical practice guidelines.

Core methodological aspects: Development groups should maintain process transparency and incorporate a range of experts, including clinicians from diverse backgrounds and relevant patient and consumer representatives. The experts involved should disclose any conflicts of interest. Evidence should be identified through systematic reviews and then evaluated by relevant stakeholders via a transparent process:

  • Guidelines should be evaluated and reported using quality assessment tools such as Appraisal of Guidelines Research and Evaluation (AGREE) II. This involves rigorous literature reviews and evidence synthesis, often using consensus-building methods such as Delphi, Evidence to Decision frameworks and risk of bias assessments. Recommendations should be graded with frameworks like Grading of Recommendations, Assessment, Development and Evaluations (GRADE), focusing on evidence quality, clinical outcomes, patient preferences and cost implications.
  • Consensus statements, while still largely relying on the same principles, depend on expert consensus rather than solely on systematic evidence synthesis, making them suitable for addressing specific or urgent clinical issues.
  • Position statements present opinions or policy positions of authorship groups or organisations based on relevant evidence and expert consensus. While not systematically graded, transparency in consensus methods is essential for clarity and credibility.
  • Best practice statements are developed for time-sensitive clinical scenarios where intervention benefits outweigh risks despite indirect or lack of evidence. Their methodology and reporting align with position statement guidelines, emphasising clear rationale and justification.

Published guidance aids in delivering consistent, high-quality clinical care by synthesising best practices from literature and expert consensus. This study acts as a methodological primer, discussing essential principles and providing references for future guidance development, thereby supporting uniformity and excellence in clinical care across diverse settings.

Wiles MD, El-Boghdadly K, Mariano ER. How to conduct and report guidelines and position, best practice and consensus statements. Anaesthesia 2024; 79: 542–547.

A practical guide for data extraction and systematic reviews

Prepared by Covidence in 2024, this guide aims to simplify data extraction for intervention systematic reviews, ensuring robust methodology regardless of the tool used. It includes definitions, practical advice, links to the Cochrane Handbook, downloadable templates and real-world examples.

Intervention systematic reviews use the PICO(T) framework to evaluate the effects of drugs or treatments, unlike alternative review types such as ‘scoping’ or ‘narrative’ reviews. Data extraction involves collecting and organising study information to facilitate comparisons, ensuring transparency and adherence to protocols. Quality assessment and risk of bias (RoB) are evaluated using tools like Cochrane RoB 2, RoB 1, ROBINS-I, the Newcastle-Ottawa Scale and the Critical Appraisal Skills Program (CASP) checklist.

Key points from the document include:

  • Use PICO(T) to guide data extraction and create templates and employ Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) for protocol reporting. PICO(T) stands for Population, Intervention, Comparison, Outcomes and Timepoints.
  • Capture detailed characteristics for outcomes, such as scale, metric, aggregation methods and timepoints, balancing ‘broad’ versus ‘narrow’ outcomes.
  • Results data can be dichotomous, continuous, count or ordinal, with specific effect measures for each type, such as risk ratio, odds ratio, or mean difference. It is also important to capture the degree of uncertainty (e.g. 95% confidence interval [CI], standard deviation [SD]).
  • Understand different study designs and how design may impact internal validity, generalisability, precision, accuracy and comparability.
  •  Organise your team, plan your approach, pilot templates and communicate and log regularly to address challenges.

This is a user-friendly guide featuring clear language, numerous examples and frequent summaries of complex concepts. The author recommends that researchers planning a systematic review utilise this guide in advance to effectively plan their study and create a streamlined data extraction template, thereby enhancing the reliability and efficiency of the review process.

Covidence. A practical guide: data extraction for intervention systematic reviews. Covidence. Melbourne: Veritas Health Innovations Ltd; 2024. Available from https://www.covidence.org/wp-content/uploads/2024/01/A_practical_guide-Data-Extraction_for_Intervention_Systematic_Reviews_2024.pdf.

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TRANSITIONS OF CARE AND PRIMARY CARE

MedsScan editors for Transitions of care and primary care SPG: Margaret Jordan and Ahmed Zeidan

Video vs telephone consultation: the telehealth showdown

The surge in telehealth during the COVID-19 pandemic led to increased use of telephone consultations (TC) and video consultations (VC) post-pandemic. This study compares these modalities in clinical, service and cost effectiveness. Comparing the effectiveness is crucial for pharmacists in home care and transitions of care. Caffery et al., conducted a systematic review of 79 studies from Embase, CINAHL and MEDLINE, focusing on clinical, service or economic outcomes. Studies based solely on clinician or patient preferences were excluded.

The findings highlighted the superior or equivalent outcomes of VC used by diverse healthcare professionals in various contexts. VC was found to be more effective or equivalent to TC in most studies. VC showed superior clinical outcomes in scenarios needing visual information, such as wound assessments and neurological evaluations. Additionally, VC was linked to better patient engagement, lower sub-acute care utilisation, and higher cost effectiveness despite higher incremental costs. TC was occasionally favoured for higher appointment completion rates and lower no-show rates.

The findings suggest that VC offers advantages over TC, particularly when visual assessments or patient engagement is crucial. One study suggested that VC should be prioritised over TC for pre-treatment medication histories, particularly during resource constraints exacerbated by COVID-19. However, the review notes mixed results in service outcomes, like appointment completion rates and consultation times.

These insights provide guidance for pharmacists in choosing telehealth modalities, favouring VC in scenarios requiring visual and non-verbal cues. Nonetheless, the choice should consider patient preference, access to technology, and digital literacy. Further research is needed to explore provider and patient preferences and the influence of telehealth modality on laboratory and radiology orders, comparing them to clinical guidelines.

Caffery LJ, Catapan SD, Taylor ML, Kelly JT, Haydon HM, Smith AC, Snoswell CL. Telephone versus video consultations: a systematic review of comparative effectiveness studies and guidance for choosing the most appropriate modality. J Telemed Telecare 2024 [online ahead of print] DOI: 10.1177/1357633X241232464.

Characteristics of randomised controlled trials that evaluate deprescribing interventions in older adults with polypharmacy

Deprescribing strategies involve tapering or ceasing harmful or unhelpful medications in an effort to optimise medicine regimens. The aim of this narrative review was to evaluate randomised controlled trials of deprescribing interventions in older adults, who were prescribed at least five medicines. The review comprised published completed or ongoing randomised controlled trials of deprescribing interventions, undertaken in adults aged 65 years or older. Articles were sourced from PubMed, Embase, ClinicalTrials.gov and the International Standard Randomised Controlled Trial Number Registry.

In all, 21 relevant completed studies were identified, where targeted settings comprised primary care (n = 15), hospitals (n = 4) or aged care facilities (n = 2). Four ongoing studies were identified, all occurring in primary care. Most interventions comprised medication reviews with additional components, such as shared decision-making or patient care prioritisation, collaboration with multidisciplinary teams, training of health professionals, clinical decision support tools, patient education materials and family involvement. Examples of outcomes included changes in Drug Burden Index, drug-related problems, mean number of medications prescribed per individual at six months, and number of hospitalisations within 12 months. Of the interventions, 11 effected at least one primary outcome, 6 did not effect primary outcomes but did effect at least one secondary outcome and 4 did not effect any primary or secondary outcomes. Of the ones that did not effect any outcomes, the interventions used were medication reviews (n = 2), clinical decision support tools (n = 1) and patient education materials (n = 1).

In Australia, there is an increasing focus on addressing the complexities of medicines management as older adults move across transitions of care. Several barriers exist at the patient, provider, and system levels, including fear of negative outcomes, lack of training for providers, lack of coordination activities between different settings and a healthcare culture focused on prescribing. Future efforts should address how these complex barriers impact deprescribing.

Hung A, Kim YH, Pavon JM. Deprescribing in older adults with polypharmacy. BMJ 2024; 385: e074892.

Embedding pharmacists where prescribing occurs is fundamental to deprescribing

An interdisciplinary team approach is ideal to support the supervised withdrawal of inappropriate medicines, especially for people with the burden of polypharmacy. Pharmacists in ambulatory care are well-placed to identify who may benefit from deprescribing, and to collaborate in the process.

This research comprised collation and synthesis of nine studies in which the role of the pharmacist in deprescribing was qualitatively evaluated. The perspectives of members of the multidisciplinary team — general practitioners, medical specialists, nurses and clinic personnel — as well as patients and carers were analysed. Only three studies analysed participants’ perspectives based on actual experience with pharmacist-led interventions. Barriers and enablers to pharmacists’ involvement in deprescribing were also explored.

Themes pertinent to deprescribing were the willingness of patients, fears of consequences, confidence or uncertainty around healthcare professionals’ roles, perceived capability and expertise of pharmacists, pharmacists providing the impetus and the value of pharmacists in medicines management. Fragmentation of care was noted to impair pharmacists’ deprescribing involvement, whereas collaboration and shared decision-making, and ensuring time and financial reimbursement were enablers. Additional barriers were contending with the status quo while strategies to enhance pharmacists’ involvement were having embedded roles in general practices and ready access to resources.

This research has relevance to Australian pharmacists’ evolving scope of practice. Three of the studies were Australian and all provided qualitative data based on participant’s lived experience, rather than perspectives only. Unsurprisingly, given most medicines contributing to polypharmacy are medically prescribed, a collaborative team approach in which the pharmacist was the expert contributor, was viewed as an enabler to deprescribing. The study provides qualitative evidence as to benefits of pharmacists in the interdisciplinary team, to achieve functional deprescribing.

Kassis A, Moles R, Carter S. Stakeholders' perspectives and experiences of the pharmacist's role in deprescribing in ambulatory care: a qualitative meta-synthesis. Res Social Adm Pharm 2024; 20: 697–712.

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