MedsScan Issue 1, 2024

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. 

CARDIOLOGY

MedsScan editor for #SHPACardiology: Adam Livori

Special contributor: Judy Duong

Decongestion with acetazolamide in acute decompensated heart failure across the spectrum of left ventricular ejection fraction: a prespecified analysis from the ADVOR trial

The ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial has demonstrated that acetazolamide — a carbonic anhydrase inhibitor acting on the proximal tubular sodium, — improved decongestion. Further investigation was required to assess the effects of this therapy across the spectrum of left ventricular ejection fraction (LVEF).

The analysis (stratified based on LVEF ≤ 40% or > 40%), was of the ADVOR trial which was a randomised  double-blind, placebo-controlled trial that enrolled 519 patients with acute heart failure (HF), clinical signs of volume overload (such as oedema, pleural effusion or ascites), N-terminal pro-B-type natriuretic peptide (NT-proBNP) > 1000 ng/L or B-type natriuretic peptide (BNP) > 250 ng/mL, to receive intravenous acetazolamide (500 mg once daily) or placebo in addition to standardised intravenous loop diuretics.  

The median LVEF was 45% (25th–75th percentile; 30%–55%) with 224 (43%) of the 519 patients having an LVEF < 40% and 42% of patients with an LVEF of > 50%. The primary end point of successful decongestion (defined as the absence of signs of volume overload within 3 days from randomisation without the need for mandatory escalation of decongestive therapy because of poor urine output), was achieved in those receiving acetazolamide (odds ratio [OR] 1.77, 95% confidence interval [CI] 1.18–2.63, P = 0.005; all P values for interaction > 0.401). No statistical treatment effect modification was found using LVEF categories as LVEF randomisation strata or as HF categories. Randomisation toward acetazolamide was associated with decreased risk for poor diuretic response without treatment effect modification per HF type. The lengths of stay were also shorter in those receiving treatment overall (geometric mean, 8.8 [8.0–9.5] days versus 9.9 [9.1–108] days, respectively: geometric mean ratio, 0.89 [0.81–0.98]; P = 0.016), with no statistical treatment effect modification found on the beneficial treatment effect of acetazolamide to length of stay for LVEF strata, HF categories or LVEF on a continuous scale. Additionally, an exploratory endpoint of all-cause and hospitalisation at three months was also undertaken between treatment groups (hazard ratio [HR] 1.11, 95% CI 0.67–1.84, P = 0.639). These findings were similar in patients with heart failure with reduced ejection fraction (HFrEF), heart failure with mid-range ejection faction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF). In the ADVOR trial, a doubling of creatinine was a predefined safety end point, and was not more frequent in patients randomised to acetazolamide, however, in this analyses, patients treated with acetazolamide had modest increases in creatinine during the treatment phase. This was more pronounced in patients with HFrEF.

Acetazolamide is effective in reducing congestion when added to high dose intravenous loop diuretics. The authors conclude that ‘the universal feature of congestion in HFrEF, HFmrEF and HFpEF may be beneficially influenced by acetazolamide, despite known pathophysiologic and baseline differences in these subtypes of HF.’ This therapy also decreases length of stay without specific treatment effect modification by baseline LVEF.  Some limitations to this prespecified analysis include that the ADVOR trial was only powered to test the treatment effect in the overall study cohort and LVEF was reported by site investigators and not by a core laboratory.

Martens P, Dauw J, Verbrugge FH, Nijst P, Meekers E, Nunes Augusto Jr S, et al. Decongestion with acetazolamide in acute decompensated heart failure across the spectrum of left ventricular ejection fraction: a prespecified analysis from the ADVOR trial. Circulation 2023; 147: 201–11.

Bempedoic acid: a novel lipid lowering treatment option for statin-intolerant patients

Special contributor: David Lui

Limited effective treatment options exist for patients that are intolerant to statin therapy or who fail to achieve recommended target levels on maximum therapy without the presence of familial hypercholesterolemia or established cardiovascular disease. Whilst there are several alternative oral cholesterol lowering agents available, none have been able to demonstrate significant improvements in cardiovascular outcomes.

The CLEAR (Cholesterol Lowering via Bempedoic Acid [ECT1002], an ACL-inhibiting Regimen) Outcomes trial was conducted as a double-blind, randomised placebo-controlled trial involving patients who either had or were considered high risk for cardiovascular disease and were statin ‘intolerant’, being unable or unwilling to take statins due to adverse effects.

Randomised patients (n = 13 970) received bempedoic acid 180 mg daily (n = 6992) and 6978 patients received placebo. The primary outcome of major cardiovascular events consisted of nonfatal myocardial infarction, nonfatal stroke, coronary revascularisation or cardiovascular death, with patients followed up for a median of 40.6 months. Results showed the primary composite end point vs placebo was 11.7% vs 13.3% with a hazard ratio 0.87 and 95% confidence interval 0.79–0.96 (p = 0.004).

This study was able to demonstrate an absolute reduction in major cardiovascular events including death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke or coronary revascularisation in patients who were unable or unwilling to take statins compared to placebo. Bempedoic acid provides an alternative oral treatment option that is effective in lowering lipid levels as well as decreasing the risk of cardiovascular disease.

Nissen SE, Lincoff AM, Brennan D, Ray KK, Mason D, Kastelein JJP, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Eng J Med 2023; 388: 1353–64.

Dapagliflozin use in patients with heart failure with preserved ejection fraction

Special contributor: Marcelle Appay

There are few pharmacological therapies to treat patients with heart failure (HF) with preserved ejection fraction (HFpEF). According to Peikert et al., the EMPEROR-Reduced, and DAPA-HF trials demonstrate that sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce mortality and hospitalisation in heart failure patients with reduced and preserved left ventricular ejection fraction (LVEF) of <40%, with the DAPA-HF trial showing the efficacy and safety of dapagliflozin across a broad spectrum of age in patients with heart failure with reduced ejection fraction. The DELIVER trial aimed to determine if dapagliflozin is effective in patients with HFpEF, across a broad age spectrum and regardless of diabetes status.

Peikert et al. randomised 6263 patients to receive either 10 mg dapgliflozin or placebo in a multicentre, double blinded, randomised controlled trial. The patients’ usual heart failure medicines were continued, and they were followed up for a median of 2.3 years. Patients had to have stable heart failure (HF), evidence of structural heart disease and an elevated natriuretic peptide level to be eligible.

Time-to-event analysis using a Cox proportional-hazards model was used to evaluate the primary endpoint of worsening heart failure (defined as hospitalisation or urgent clinic visit) or cardiovascular death. The primary outcome for dapagliflozin vs placebo was: 16.4% vs 19.5% (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.73–0.92, p < 0.001).  This benefit appeared to be comparable regardless of the patient’s diabetes status or if the LVEF was greater than or less than 60%, and was largely powered by hospitalisation and urgent clinic visits over cardiovascular death. The secondary outcome of all-cause mortality also demonstrated a benefit of 15.9% vs 16.8% (HR 0.94, 95% CI 0.83–1.07, p > 0.05).

This trial demonstrated that dapagliflozin is superior to placebo in improving HF outcomes in HFpEF patients as an add-on therapy to standard treatment. These results are congruent with the EMPEROR-Preserved trial which examined empagliflozin in the same patient population and thus suggests that this may be a drug class effect. It is important to note that dapaglifozin is not listed on the Pharmaceutical Benefits Scheme (PBS) for this patient population, however empaglifozin is (as of 1 November 2023).

Peikert A, Martinez FA, Vaduganathan M, Claggett BL, Kulac IJ, Desai AS, et al. Efficacy and safety of dapagliflozin in heart failure with mildly reduced or preserved ejection fraction according to age: the DELIVER trial. Circ Heart Fail 2022; 15: e010080.

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DISPENSING AND DISTRIBUTION

MedsScan editors for #SHPADispense: Ashley Crawford and Anna Wood

Do Automated Dispensing Cabinets improve governance of controlled drug storage?

The security of Automated Dispensing Cabinets (ADCs) is an often-promoted benefit of installing this technology. Many hospitals are continuing to consider the place of ADCs to improve patient safety and medication accountability, however the evidence for the impact of these devices on the governance of controlled drugs is still emerging.

This study presented the results of an exploratory, mixed methods assessment of how an ADC contributes to the governance of controlled drugs in an Australian hospital setting. The study undertook structured observations, auditing, interviewing and review of incident reporting to develop conclusions on the role of ADCs in supporting four domains of controlled drug governance: safekeeping; documenting transactions; monitoring; and reporting and investigating. For the auditing aspect of the study, pre- and post-implementation data was available.

For each of the areas of controlled drug governance, the ADC had both supportive features and some challenges. For example, the safekeeping of controlled medicines was supported by fingerprint access, however there are limitations to the medicines that can be stored in the ADC, resulting in hybrid storage systems. Documentation was improved by ADCs alerting users to potentially erroneous transactions, but the return process for unwanted medicines is more complicated than in the paper system. The researchers identified that it is difficult to report on efficiency gains with ADCs in the governance of controlled drugs. Perceptions of the ADCs implementation were that it saved time, however the ADC also created new workflows and shifts in the distribution of tasks.

Reporting the impact of ADCs in supporting governance of controlled drugs is complicated. While ADCs can significantly support many aspects of controlled drugs governance when compared with paper systems, this technology has also led to new governance challenges. As more becomes known about the challenges for ADC storage of controlled drugs in the Australian context, it is anticipated there will be demand for the technology to adapt and improve.  

Lichtner V, Progmet M, Gates P, Franklin BD. Automatic dispensing cabinets and governance of controlled drugs; an exploratory study in an intensive care unit. Eur J Hosp Pharm 2023; 30: 17–23.

A priority-based replenishment approach for in-pharmacy robotic dispensers can improve efficiencies in dispensing

Robotic dispensing systems are becoming more routinely utilised across Australian pharmacies in both community and hospital settings. The use of dispensing robotics can improve storage and dispensing safety and efficiency, however the replenishment of medicines into the robotics is completed manually. This highlights an opportunity to systematise the replenishment approach to ensure prescription efficiency is not compromised by stock outages within the robotics.

This paper explores a systems-engineering approach to developing a priority-based refill policy for robotic dispensing systems. It is hypothesised that the frequency of stock outages will be reduced when a priority model, developed using inventory and demand data, directs refilling of robotic dispensing systems. This article reports on a 3D simulation model which has been developed to analyse the system performance in a priority-based approach, when compared with traditional low-medium-high priority replenishment models. This 3D simulation software allowed the researchers to test their hypothesis that the frequency of stock outages is reduced with this alternative replenishment model.

The limitations of standard refill practice for pharmacy robotics are that refill processes are typically reactive to errors or out of stocks. The authors’ proposed alternative utilises future demand to influence replenishment processes. The comparison of these approaches in the simulation environment was able to demonstrate that the priority-based approach was able to prevent over 90% of inventory shortages within the robotics and reduce the frequency of dispensing delays by almost 80%.

The applicability of the mathematical model presented to the Australian hospital setting is perhaps limited, noting the style and scale of replenishment frequently vary from that presented here. However, applying the principle to consider both inventory and future demand to the refill of robotics is something pharmacies and robotic suppliers should investigate further. It is also interesting for pharmacists to consider the role systems specialists can play to support optimisation of pharmacy practices, particularly as automation continues to be adopted.

Cao N, Marcus A, Altarawneh L, Kwon S. 2023. Priority-based replenishment policy for robotic dispensing in central fill pharmacy systems: a simulation-based study. Health Care Manag Sci 2023; 26: 344–362.

Approaching the challenge of reducing interruptions in a hospital pharmacy using resilience engineering and systems thinking

Interruptions during the dispensing process are known to contribute to the occurrence of medication errors, which have the potential to negatively impact patient safety. Identifying causative factors and successfully implementing strategies aimed at reducing interruptions is a challenge faced by many pharmacy departments.

This study focused on the utilisation of resilience engineering and systems thinking methodologies to identify improvement measures to address the frequency of interruptions observed in an inpatient dispensing unit in a hospital pharmacy in Japan. Feedback from staff indicated that major contributing factors were contact with staff from the inpatient units via telephone calls and serving at the counter. The aim of this project was to reduce interruptions originating from these two sources.

The first phase of the study explored the interaction between the two systems involved, the Pharmacy dispensing unit and the inpatient unit, using a causal loop diagram. Workload data from Pharmacy IT systems, data about the frequency and type of phone calls and staff interviews provided insight into performance adjustments adopted by staff to allow for tasks to be completed. This provided an understanding of how individuals work within the environment and adapt to different scenarios. The data demonstrated that adaptive behaviour of both pharmacy staff and inpatient unit staff contributed to the number of telephone calls and physical presentations to pharmacy. Addressing the information gap between the two areas about the status of medicine preparation and delivery was identified as a key to reducing interruptions. 

The second phase of the study focused on the implementation of strategies aimed at improving the availability of information and access to dispensed medicines for inpatient unit staff. Three different improvement measures were implemented in a staggered approach between 2017 and 2020 and resulted in a significant reduction in telephone enquiries and an overall decrease in total interruptions. However, there was no information provided to suggest if this subsequently had any influence over the number of reported dispensing errors.

Whilst this study is limited to one site, it provides an example of what can be achieved by adopting a resilience engineering and systems thinking approach to solving a problem. It demonstrates the value of assessing how different systems interact rather than only considering a single work units’ processes in isolation.

Kojima T, Kinoshita N, Kitamura H, Tanaka K, Tokunaga A, Nakagawa S, et al. Effect of improvement measures in reducing interruptions in a Japanese hospital pharmacy using a synthetic approach based on resilience engineering and systems thinking. BMC Health Serv Res 2023; 23: 331.

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EDUCATION AND EDUCATIONAL VISITING 

MedsScan editors for #SHPAEdu&EduVisiting: Diana Bortoletto and Hilai Ahmadzai

Academic resilience in pharmacy education in the United Kingdom: applying love and breakup letter methodology

Pharmacy students in the United Kingdom (UK) are reported to have lower academic resilience, a trait indicative of wellbeing and academic success, compared to other disciplines. Academic resilience is associated with improved self-confidence and is protective against burnout and emotional exhaustion. While previous studies on pharmacy students’ resilience used quantitative methodologies, this pilot study used a novel approach of understanding the students’ lived experience through love and breakup letter methodology (LBM).

The study was conducted on eight (female n = 7) final year undergraduate pharmacy students, at one UK university, who were invited to participate in an online focus group. The participants were asked to write a love and/or breakup letter to their resilience, in relation to their experiences over the course of their degree. The participants were then asked to read their letters out loud, with the content of the letters being used to generate further discussion during the focus group.

Thematic analysis of the letters and the discussions demonstrated negative emotions with three meta-themes where the curriculum was described as:

  • Gaslighting for undermining their self-esteem
  • Controlling for taking up too much space leaving them with little opportunity for things outside of studies
  • Abusive due to the constant fear of failure in assessments which was perceived to be damaging to their academic resilience.

While the authors highlight LBM as a way to gain insight into the psyche of pharmacy students and a useful method of honest student-led dialogue, there are many limitations to this study including the small sample size and the overwhelming female majority of participants, affecting the transferability of their findings. Furthermore, common predictors of academic resilience such as self-efficacy, control, planning and persistence were absent in the participants of this study. Thus, highlighting a potential predisposition to lower academic resilience.

Mawdsley A, Willis SC. Academic resilience in UK pharmacy education – a pilot study applying love and break up letters methodology. BMC Med Educ 2023; 23: 441.

Clinical decision making and cognitive processes

Clinical decision making (CDM) is a series of step-by-step cognitive processes and skills that pharmacists apply in daily clinical practice to provide patient-centred care. Although CDM is a core professional activity for pharmacists and a skill that develops over time with experience, there are no universal CDM frameworks or models. Additionally, little is known about how pharmacist educators transfer this skill when teaching and training others.

In this qualitative study conducted in the Netherlands, 16 pharmacists from different care settings including community, hospital and outpatient were engaged in semi-structured, face-to-face interviews to better understand pharmacist CDM. Using an interview guide, the participants were asked questions in relation to the cognitive processes they used in clinical decision making in their day-to-day practice, and how they taught this skill to others.

The authors reported that participants struggled to clearly articulate their cognitive processes often going back and forth in their explanation of these steps. Thematic analysis of the data identified 21 themes. These themes were then organised into eight steps forming a theoretical model that illustrates the cognitive processes used by pharmacists for CDM. These eight steps include (1) problem and demand for care consideration, (2) information collection, (3) clinical reasoning, (4) clinical judgement, (5) shared decision-making, (6) implementation, (7) outcomes evaluation and (8) reflection.


This study confirms that CDM is dynamic in nature and a skill that pharmacists develop with experience. However, the study helps provide a theoretical model that can make these seemingly automatic processes more structured and explicit which may assist pharmacy educators when teaching CDM.

Mertens JF, Kempen TGH, Koster ES, Deneer VHM, Bouvy ML, van Gelder T. Cognitive processes in pharmacists’ clinical decision-making. Res Social Adm Pharm 2024; 20: 105–114.

Artificial intelligence, natural learning processing and large language models in higher education and research

Artificial intelligence (AI) has become part of modern society, revolutionising approaches to education and research. Large Language models (LLMs) — such as the Generative Pretrained Transformer (GPT) — are emerging Natural Language Processing (NLP) technologies, focusing on how computers and human language interact. This review article introduces these fundamental concepts, aiming to foster greater reader comprehension and to demonstrate how AI can revolutionise education and research.

AI tools in higher education can be applied to educational support, automating grading and assessment, strengthening curriculum design and cultivating mental health support. Some of the resultant benefits include developing adaptive learning systems, reducing subjectivity and bias, developing personalised learning plans and offering a safe environment. While AI and NLP offer various advantages, they present certain challenges, such as reduction in human interaction, models generating answers for students in assignments and tests, and reducing engagement in authentic learning. Similarly, AI technology can be applied to research with its own benefits and limitations as discussed by the authors.

As the education and research landscape evolves, adopting AI tools and innovative learning approaches is vital for cultivating a flexible and adaptive environment. AI technology is expected to profoundly affect pharmacy education. Personalised learning experiences tailored to each student’s needs, interest and preference could become common place. AI tools may also facilitate pharmacy curriculum development and simultaneously align it with job market needs. While these technologies have considerable potential to support teaching and learning, their use must be carefully managed and supplemented with strategies that encourage genuine understanding and critical thinking in order to learn informed decision making independently.

Alqahtani T, Badreldin HA, Alrashed M, Alshaya AI, Alghamdi SS, Bin Saleh K, et al. The emergent role of artificial intelligence, natural learning processing, and large language models in higher education and research. Res Social Adm Pharm 2023; 19: 1236–1242.

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ELECTRONIC MEDICATION MANAGEMENT

MedsScan editor for #SHPAeMM: James Grant

Reducing errors and improving workflows when sometimes the system doesn’t help: an analysis of eMM changes over time

The introduction of electronic medication management (eMM) systems is known to provide features to support medication safety, as well as introducing new risk factors. This analysis sought to review the mitigations that an eMM implementer utilised to handle these new risk factors. New risk factors introduced by digitising medications management include the incorrect selection of order components, failure to modify inappropriate defaults and misuse of system functions such as clinical decision support (CDS).

These new system-related factors are not the result of purely technical issues, and reflect incompatibilities between system design and end user factors. End users report that eMM systems introduce extra steps to complete tasks compared with paper records, amongst other usability issues. These lead to clinicians adopting workarounds, such as the use of free-text (unstructured) notes and fields to communicate ordering information when they experience an unsuitable and inflexible design in the system’s codified (and intended) inputs.

Over a 4-year period, 147 distinct changes were made across 3 sites within New South Wales. The most frequent purpose for a change was to prevent medication errors (24% of total); followed by optimising a workflow (22%) and to mirror ‘work as done’ on paper (16%). The contents of the changes were adding drop-down options (14% of total), additional information on screen (8%) and modifying phrasing of text (8%). Using the APINCH (Antimicrobials, Potassium and other electrolytes, Insulin, Narcotics and other sedatives, Chemotherapeutic agents, Heparin and other anticoagulants) classification system, 37% of the total changes occurred to these high-risk medications. The analysis also showed a shift in the reasons for making a change over time. Where optimising workflows was a common reason in the earlier part of the 4-year timeframe, expanding scope and functionality for new services was the more common reason during year 4 of the time period.

This is a useful review for services considering the adoption of eMM, who can learn from the experiences of established digital health providers and jump ahead of the changes made to avoid system-related errors. It is also useful information to consider in longer-term digital sites to assess if the summarised changes made have also been applied, where relevant, to their own environment.

Kinlay M, Ho LMR, Zheng WY, Burke R, Juraskova I, Moles R, et al. Electronic medication management systems: analysis of enhancements to reduce errors and improve workflow. Appl Clin Inform 2021; 12: 1049–1060.

Will patients adopt novel technologies to monitor medication adherence?

Special contributor: Jillian Campbell

Medication adherence (and more specifically, non-adherence) by patients is a significant concern for clinicians, particularly those engaged in clinical trials. Finding new ways to support patients to successfully take their medicines as prescribed and record accurate information about adherence is an interesting field of research with significant potential benefits for patients.

This study assessed the usability of the innovative ‘ID-Cap System’ aimed at monitoring medication adherence in patients. Using a simulated environment, the study evaluated how participants interacted with ‘digital pills’, wearable sensors and accompanying smartphone applications. The research used a human factors approach to assess potential errors or challenges that could impact user safety.

The ID-Cap System uses an ingestible sensor placed inside the medication capsule, which activates a radio signal upon dissolution in the gastrointestinal tract. This signal, received by a patient-worn reader on a lanyard, syncs with a smartphone app and forwards the ingestion event data to a cloud-based server for clinician monitoring. The sensor is excreted naturally after each dose. The study only used a simulation prototype, not linked to the study participant’s actual regular medication usage but did include diverse participants that were representative of future users. People who do not use smartphones were excluded from the study. Tasks were meticulously chosen through risk analysis to cover crucial and frequently performed actions essential for the system’s correct operation.

The ID-Cap System had low numbers of repeated user errors, showing it was relatively easy to learn without too much assistance. It had higher tolerability than previous designs that had the reader in a patch adhered to the skin.

While the study’s small sample size and short session limit comprehensive evaluation, it highlights the system’s promise. It suggests the impending role of digital pill monitoring in clinical trials, offering insights into patient adherence and system usability. Conclusively, these findings underscore the importance of user-friendly monitoring systems for medication adherence, which is crucial for clinical trials and routine patient care.

Baumgartner SL, Buffkin Jr DE, Rukavina E, Jones J, Weiler E, Carnes TC. A novel digital pill system for medication adherence measurement and reporting: usability validation study. JMIR Hum Factors 2021; 8: e30786.

Imperfect data in electronic health records: categorisation and detection

The promise of digital healthcare is large, yet delivery is delayed. This article delves into the challenges in leveraging the ‘big’ data from electronic health records (EHR) which has been one of the more touted benefits of digitisation. With appropriate health data and analytics there are many advantages to be seen in automated decision support, improving care and making predictions about patient outcomes.

Yet such benefits are challenging, due to concerns over the reliability of digital health data. For example, a clinician may enter a non-sensible value, e.g., a space character, into a mandatory field in order to progress through an electronic form. It is widely acknowledged that digital health data is severely impacted by accuracy and completeness concerns. Time then needs to be invested in cleaning data to reduce these concerns and risks, making the cost-benefit realisation poorer than  initially thought. High integrity data is of key importance in health as it influences clinical decision-making, both in real-time and the long-term.

This article identifies six patterns of imperfection: (1) double trouble (non-unique); (2) not the real truth (incorrect); (3) not the whole picture (incomplete); (4) mixing sand and gravel (granularity); (5) passing the sniff test (implausibility); and (6) shifting shape (non-concordance). Whilst patterns 1–3 will be familiar to readers, the other patterns may bear further explanation. Granularity, or rather mixed granularity, is an issue of not recording details at the same ‘level’ within a given part of the record. An example would be documenting a home medicine item as ‘aspirin’ and an inpatient order as ‘aspirin 100 mg tablets, 100 mg in the morning’. The difference in detail level makes it harder, if not impossible, to be sure during clinical reconciliation, that the appropriate conversion has happened.

Implausibility is an issue of context compared to the recorded data. The example provided in the article is a complex surgical procedure that has a duration of 5 minutes given the timestamps of its start and finish. The time values entered are valid and the name of the procedure matches the drop-down list of available surgeries. However, anyone reading that record would realise it’s highly unlikely to be correct; though no individual field has an invalid entry. At an aggregate level this leads to biased or questionable findings.

Non-concordance is an issue of similar words being used in different systems to represent the same real-world entity. An example would be documenting that the patient is taking ‘CBZ 400 mg’, ‘Tegretol 400’ and ‘Carbamazepine 400 milligrams’ in three different parts of a clinical information system (or across three different information systems). The lack of concordance leads to confusing or diffused findings. Based on the example, there would be no way from the raw data to tally a true total of carbamazepine use, or even mentions in the records, even if it happened to be the most commonly used medicine in an area.

The article does provide some means to technically assess health databases for the six patterns and support detection, and intervention, before ill-informed decisions can be made — or data dismissed altogether. Based on the numbers provided it seems their pattern recognition did not yield a large number of affected records in the site sample analysed and so implementation of these techniques would need to be weighed against existing processes used by data managers, data analysts and business intelligence teams.

Goel K, Sadeghianasl S, Andrews R, ter Hofstede AHM, Wynn MT, Kapugama Geeganage D, et al. Digital health data imperfection patterns and their manifestations in an Australian digital hospital. In: Bui TX (editor) Proceedings of the 56th annual Hawaii International Conference on Systems Sciences, HICSS 2023. Honolulu: University of Hawai’i; 2023. pp: 3235–3244. Available from: https://eprints.qut.edu.au/237500/1/115730037.pdf. Accessed 20 February 2024.

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INFECTIOUS DISEASES

MedsScan editor for #SHPAInfDis: Nadine Hillock

The ATTACK trial: sulbactam-durlobactam versus colistin for Acinetobacter baumannii-calcoaceticus complex infections

Conducted across 16 countries, the ATTACK trial was an industry-funded, two-part study completed in July 2021; Part A was a randomised, active-controlled, open-label non-inferiority trial. Sulbactam-durlobactam, a new β-lactam-β-lactamase antibacterial combination, was compared with colistin for efficacy and safety, both in combination with imipenem-cilastatin for the treatment of patients with severe infections caused by carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (ABC). Part B was a single-arm study for patients with colistin-resistant ABC.

Adult patients (≥18 years old) were eligible for inclusion if diagnosed with hospital-acquired pneumonia (HAP), ventilator-associated bacterial pneumonia (VAP) or bloodstream infections, confirmed to be caused by ABC based on sputum, respiratory or blood cultures within 72 hours before randomisation. Eligible patients had an Acute Physiology and Chronic Health Evaluation (APACHE) II score of 10–30 or a Sequential Organ Failure Assessment (SOFA) score of <12.

Patients were randomised (allocation concealed) to either sulbactam-durlobactam (1 g-1 g every 6 hours, infused over 3 hours) or colistin (loading dose of 2.5–5.0 mg/kg [75 000–150 000 IU/kg] followed by 2.5 mg/kg [75 000 IU/kg] every 12 hours, infused over 30 minutes).  Both groups received concomitant imipenem-cilastatin (1 g-1 g every 6 hours, infused over 1 hour) to ensure coverage of non-ABC co-infecting pathogens. Doses were adjusted according to renal function, and treatment duration was 7–14 days. The primary endpoint was 28-day all-cause mortality, and the non-inferiority margin was set at 20%.

One hundred and eighty-one patients were randomly assigned for treatment and 125 were included in the modified intention-to-treat (ITT) efficacy analysis (63 in the sulbactam-durlobactam group and 62 in the colistin group). Mortality rates at 28 days were 12/63 (19%) in the sulbactam-durlobactam group compared with 20/62 (32%) in the colistin group (difference 13.2%, 95% confidence interval [CI] -30.0–3.5). The investigators concluded that sulbactam-durlobactam in combination with imipenem-cilastatin was not inferior to colistin and imipenem-cilastatin in patients with severe, life-threatening carbapenem-resistant ABC infections. Notable limitations of this study however, include the low prevalence of female patients (25.7%), and the imbalance of age (sulbactam-durlobactam arm were a younger patient cohort). As all patients in this study were administered concomitant therapy with a carbapenem, it is unclear if the mortality outcomes would be similar if sulbactam-durlobactam were to be used as monotherapy in this patient group.

Kaye KS, Shorr AF, Wunderink RG, Du B, Poirier GE, Rana K, et al. Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with serious infections caused by Acetobacter baumannii-clacoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferioirity clinical trail (ATTACK). Lancet Infect Dis 2023; 23: 1072–1084.

Continuous vs intermittent meropenem administration in critically ill patients with sepsis

The MERCY trial was a multi-centre, double-blind, randomised controlled trial conducted across 26 hospitals to determine whether continuous infusion of meropenem reduced mortality and emergence of pandrug-resistant, or extensively drug-resistant bacteria, compared to intermittent administration in critically ill patients with hospital-acquired sepsis. Patients were included if aged ≥18 years old, admitted to an intensive care unit (ICU) and requiring meropenem treatment for sepsis or septic shock. Patients were excluded if they refused consent, had previous carbapenem therapy, had very low probability of survival (SAPS [Simplified Acute Physiology Score] II score ≥65 points) or severe immunosuppression. Six hundred and seven patients met the inclusion criteria and were allocated to a treatment arm via computer-generated randomisation. Patients, treating physicians and study investigators were blinded to treatment allocation. Pharmacists and ICU nurses were not blinded, nor involved in data collection or analysis.

Baseline characteristics were similar: the median SOFA score was 9 (interquartile range [IQR] 6–11) in both groups and both groups had been in ICU for a median of five days prior to randomisation. Of the 303 patients in the continuous administration group 73% (n = 218) received concurrent antibiotics and of the 304 patients in the intermittent administration group, 74% (n = 225) patients received concurrent antibiotics.

There was no significant difference for the primary composite outcome of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28 (47% in continuous vs 49% in intermittent [risk ratio [RR] 0.96, 95% CI 0.81–1.13, p = 0.60]). There was also no significant difference in the secondary outcome of 90-day mortality (30% in continuous vs 33% in intermittent [RR 1.00, 95% CI 0.83–1.21, p = 0.97]). The emergence of drug-resistant bacteria at 28 days was similar in both groups (24% in continuous vs 25% in intermittent [RR 0.94, 95% CI 0.71–1.26, p = 0.70]).

Published pharmacokinetic studies have shown that prolonged administration time maximises time above the minimal inhibitory concentration, which may translate to increased efficacy of β-lactam antibiotics. Despite this study finding of no significant benefit in mortality outcomes with continuous infusions in critically ill patients with sepsis, there was also no evidence of harm. A key limitation of the study was the large proportion of patients in both groups who were administered concomitant antibiotics (e.g., glycopeptides, fluoroquinolones, aminoglycosides, cefepime) which may have impacted the findings. Although this is the largest randomised controlled trial published to date, comparing continuous meropenem administration to intermittent administration, the authors acknowledge it may have been underpowered to detect a smaller treatment effect than expected based on meta-analysis of published literature. This study also found no evidence to support the theory that prolonged or continuous infusions of meropenem may reduce the risk of antimicrobial resistance.

Monti G, Bradic N, Marzaroli M, Konkayev A, Forminskiy E, Kotani Y, et al. Continuous vs intermittent meropenem administration in critically ill patients with sepsis: the MERCY randomised clinical trial. JAMA 2023; 330: 141–151.

The Australian surgical antibiotic prophylaxis (ASAP): placebo-controlled vancomycin and cefazolin surgical antibiotic prophylaxis trial

The ASAP trial was a randomised, double-blind, parallel, superiority, placebo-controlled trial comparing cefazolin plus vancomycin surgical prophylaxis with cefazolin alone, in joint replacement surgery conducted in 11 Australian hospitals between January 2019 and October 2021.

All enrolled patients received standard surgical prophylaxis with cefazolin 2 g within 60 minutes of incision. Patients were randomly allocated to either the intervention arm, 1.5 g vancomycin (1 g for patients <50kg), or the comparator arm, normal saline (placebo) which was commenced within 2 hours of incision. The primary outcome was surgical site infection (SSI) at 90 days (superficial, incisional, deep or organ space infection). Safety outcomes included acute kidney injury, hypersensitivity reactions, and death by any cause at 180 days. The primary outcome analysis was conducted on the intention-to-treat (ITT) population (all randomised patients who consented, underwent surgery and were not withdrawn by the surgeon).

Four thousand, two hundred and thirty-nine patients were recruited (2118 randomised to vancomycin and 2121 to placebo) and 4113 were included in the modified ITT population (2,233 knee replacement, 1,850 hip and 50 shoulder). Allocation was concealed via computer-generated randomisation. Patients, surgeons, the research team and the end-point adjudication committee were all blinded. Known methicillin-resistant Staphylococcus aureus (MRSA) colonisation was an exclusion criterion, however 24 patients with MRSA were recruited. Demographics of each group were similar, with the majority of surgeries being primary (89.9% in vancomycin and 90.3% in placebo). Pre-operative Staphylococcus aureus colonisation was detected in 1089 patients: 543 methicillin-sensitive Staphylococcus aureus (MSSA) and 7 MRSA in the vancomycin group and 526 MSSA and 17 MRSA in the placebo group. Four hundred and ninety-eight (26.8%) patients were colonised with methicillin-resistant Staphylococcus epidermidis (MRSE) in the vancomycin group, compared to 483 (25.6%) in the placebo group.

There were 163 SSIs overall, most were superficial (n = 148). There was no significant difference in SSIs between the groups: SSIs occurred in 91 (4.5%) of 2044 patients in the vancomycin group and 72 (3.5%) of 2069 in the placebo group (RR 1.28, 95% CI 0.94–1.73, p = 0.11). Among knee replacement patients, SSIs occurred in 5.7% of the vancomycin group and 3.7% of placebo (RR 1.52, 95% CI 1.04–2.23). For hips, SSIs occurred in 3.0% of the vancomycin group and 3.1% placebo (RR 0.98, 95% CI 0.59–1.63). In shoulder arthroplasty, the only SSI occurred in the placebo group. Of the 15 deep or organ-space SSIs that occurred overall, 7 were in the vancomycin group and 8 in the placebo group (RR 0.89, 95% CI 0.32–2.44). In the sub-group analysis of patients with known colonisation with a resistant staphylococcal species (MRSE or MRSA), SSIs occurred in 4.2% (25/590) of patients in the vancomycin group at 90 days and in 2.8% (16/577) of patients  in placebo (RR 1.53, 95% CI 0.82–2.83).

The adverse event rate was similar in both groups, 15.1% in the vancomycin group and 15.3% in the placebo. Hypersensitivity reactions were more frequent in the vancomycin group (RR 2.20, 95% CI 1.08–4.49). Acute kidney injury was less common in the vancomycin group (RR 0.57, 95% CI 0.39–0.83) compared with placebo.

The ASAP trial shows that in patients without known MRSA colonisation, vancomycin plus cefazolin surgical prophylaxis is not superior to cefazolin alone for the prevention of SSIs in arthroplasty patients. However, the main limitation is the small number of included patients at higher risk for MRSA (e.g. undergoing revision surgery). Over three quarters of patients were screened for MRSA and excluded if colonised. Only 3 of the 11 sites did not screen for Staphylococcus aureus.

Although no substantial difference between the vancomycin and placebo groups was reported in the subgroup of patients with preoperative colonisation with a resistant staphylococcal species, the 90-day follow up period may not be long enough to detect SSIs due to Staphylococcus epidermidis, including MRSE, as a considerable proportion of infections due to Staphylococcus epidermidis occur between 90 days to one year following surgery. Extension of the follow-up time post-surgery would provide further insight into the longer-term surgical outcomes of these patients.

Peel TN, Astbury S, Cheng AC, Paterson DL, Buising KL, Spelman T, et al. Trial of vancomycin and cefazolin as surgical prophylaxis in arthroplasty. N Eng J Med 2023; 389: 1488–1498.

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MENTAL HEALTH

MedsScan editor for #SHPAMentalHealth: Judy Longworth

Changing guidelines: challenges managing illicit substance presentations in emergency departments

Given the increase in patients presenting to emergency departments after ingestion of illicit substances, this scoping review may provide some background for developing consistent guidelines. Emergency departments have a significant burden with presentations of illicit drug-induced psychosis and if admitted, for the total health system. As these patients can be agitated and aggressive as well as experiencing hallucinations and delusions, there is a significant work health and safety issue for all involved with their care. Current guidelines include the use of antipsychotics and benzodiazepines, as well as promethazine in United Kingdom guidelines. Primarily, the utilised guidelines are for the management of acute behavioural disturbances in mental health settings, rather than specific for those intoxicated with illicit drugs in an emergency department setting.

Further study is needed to evaluate non-pharmacological, non-coercive de-escalation strategies and oral therapies, aiming for the least restrictive approach. However, achieving this is challenging due to the acute nature of presentations. As the pharmacological nature of the illicit substances also changes over time, this also needs to be incorporated into guidelines. When examining the current available guidelines there is provision for use of both mechanical and chemical restraint but in a world where their use is frowned upon, new adequate guidelines need to be established.

Au RT, Hotham E, Suppiah V. Guidelines and treatment for illicit drug related presentations in emergency departments: a scoping review. Australas Psychiatry 2023; 31: 625–634.

Metformin: why not?

Second-generation antipsychotics (SGAs) and dopamine-serotonin antagonists continue to be used by children and adolescents in neurodiverse and conduct disordered populations, and have a propensity for associated weight gain. Resultantly, a method for controlling this weight gain may be advantageous.

Although there have been at least five trials investigating the use of metformin for the associated weight gain in children and adolescents also taking SGAs, the uptake of this adjuvant therapy has not followed. This paper looks at a review of an electronic medical record database covering children and adolescents 6–17 years old and taking a SGA continuously for 90 days. For analysis, adjuvant metformin users were classified as those that had at least one week overlap between SGA and metformin prescriptions. Comparisons were with non-metformin users, as well as obese (BMI z -core >1.64) non-metformin users.

The study showed that amongst paediatric SGA recipients, only 2.9% received adjuvant metformin. These recipients were more likely to be female adolescents and have a prehistory of polycystic ovarian syndrome or family history of diabetes mellitus and 20% of adjuvant metformin users were switched to an SGA with a lower propensity for weight gain. Further studies are needed to identify the optimum time to introduce metformin in paediatric studies either when initiating an SGA or when significant weight gain has occurred.

Chen H, Lyu N, Chan W, De La Cruz A, Calarge C. Utilization and predictors of adjuvant metformin for children and adolescents on mixed receptor antagonists (second-generation antipsychotics). J Am Acad Child Adolesc Psychiatry 2023; 62: 1245–1255.

Can deprescribing psychotropic medicines reduce challenging behaviours in people with intellectual disabilities?

The final report of the Royal Commission into Violence, Abuse, Neglect and Exploitation of People with a Disability reports on the need to curb the use of chemical restraint for challenging behaviours1 and this paper may help in working towards that goal. Challenging behaviours — defined in this paper as culturally abnormal behaviours placing a person at risk of harm to themselves and others — can significantly impact on the day-to-day lives of people with intellectual disabilities. The review extended a previous adult only review (1990–2016) to include all psychotropic medicines used by children or adults since 2016.

This review included patients in both inpatient and community settings. The primary outcomes were changes in challenging behaviours and secondary outcomes included quality of life measures. Although necessary for replication, there is very little consistent use of psychometric measures to evaluate pre- and post-results. Across all the study types evaluated, there was incomplete reporting of rates of complete deprescribing to discontinuation or at least 50% reduction in dosage. Evidence does suggest that deprescribing can have positive effects on physical health, but generally most studies did not follow the patient for any extended time after discontinuation, so no long-term effects can be noted. The most frequently deprescribed medicines were both typical and atypical antipsychotics but the rate of use of pro re nata (PRN) medications was incompletely reported. There is discrepancy in the method of deprescribing, ranging from sudden withdrawal to tapering of dosage over 28 weeks.

This is a comprehensive systematic review with a good reference list for ongoing reference to, whilst establishing guidelines for deprescribing of psychotropic medications. But the need for continued follow up after deprescribing and acknowledgement of nocebo/placebo effect might also be necessary.

References

  1. Royal Commission into Violence, Abuse, Neglect and Exploitation of People with Disability. Final Report. Canberra: Commonwealth of Australia; 2023. Available from https://disability.royalcommission.gov.au/publications/final-report. Accessed 19 February 2024.

Adams D, Hastings RP, Maidment I, Shah C, Langdon PE. Deprescribing psychotropic medicines for behaviours that challenge in people with intellectual disabilities: a systematic review. BMC Psychiatry 2023; 23: 202.

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NEPHROLOGY

MedsScan editor for #SHPANephrology: Jess Lloyd

Endothelin receptor antagonists: the next frontier or a fluid foe?

Special contributor: Jeffrey Van

Angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and sodium-glucose transport protein 2 (SGLT2) inhibitors are now standard therapy to slow progression of proteinuric chronic kidney disease (CKD). Endothelin receptor antagonists (ERAs) such as zibotentan have been proposed as another potential treatment option. However, ERAs are not without risk, with previous trials demonstrating a higher risk of fluid retention, heart failure, and discontinuation due to adverse effects.1–4 These trials did not include SGLT2 inhibitors as part of standard therapy.

ZENITH-CKD was a randomised, double-blind, active-controlled, multicentre clinical phase 2b trial. Adults over the age of 18 with CKD (eGFR >20 mL/min per 1.73 m2) with a urinary albumin-to-creatinine ratio (UACR) of 150–5000 mg/g (17–565 mg/mmol) were randomised to three groups: dapagliflozin 10 mg and placebo daily; dapagliflozin 10 mg and zibotentan 0.25 mg daily; and dapagliflozin 10 mg and zibotentan 1.5 mg daily. Participants were also required to be stable on an ACE inhibitor or ARB for at least 4 weeks prior to screening.

At week 12, the percentage mean change from baseline UACR was -28.3% in the placebo group, -47.7% in the zibotentan 0.25 mg group, and -52.5% in the zibotentan 1.5 mg group. Favourable effects on systolic blood pressure, low-density lipoprotein (LDL) and an improvement in haemoglobin A1C were also noted in the zibotentan groups. Discontinuation rates were higher in the zibotentan groups (12% for both) vs placebo (4%). More patients met the pre-specified unfavourable fluid retention end point in the zibotentan groups with six cases of heart failure reported across both groups.

This trial demonstrated that a combination of low dose zibotentan 0.25 mg daily in combination with dapagliflozin 10 mg daily, decreased UACR compared with dapagliflozin 10 mg daily and placebo, without major side effects in patients with CKD already on an ACE inhibitor or ARB. Fluid overload remains a concern with zibotentan, even when combined with dapagliflozin. An upcoming phase 3 trial will be valuable in confirming long term data around its safety and efficacy for kidney outcomes.

References

  1. Mann JF, Green D, Jamerson K, Ruilope LM, Kuranoff SJ, Littke T, Viberti G; ASCEND Study Group. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol. 2010 Mar;21(3):527-35
  2. de Zeeuw D, Coll B, Andress D, Brennan JJ, Tang H, Houser M, et al. The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy. J Am Soc Nephrol. 2014 May;25(5):1083-93
  3. Heerspink HJL, Parving HH, Andress DL, Bakris G, Correa-Rotter R, Hou FF et al. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet. 2019 May;393(10184): 1937-47
  4. Heerspink HJL, Radhakrishnan J, Alpers CE, Barratt J, Bieler S, Diva U, et al. Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial. Lancet. 2023 May 13;401(10388):1584-1594

Heerspink HJL, Kiyosue A, Wheeler DC, Lin M, Wijkmark E, Carlson G, et al. Zibotentan in combination with dapagliflozin compared with dapagliflozin in patients with chronic kidney disease (ZENITH-CKD): a multicentre, randomised, active-controlled, phase 2b, clinical trial. Lancet 2023; 402: 2004–2017.

PROTECT people from IgA nephropathy with a novel non-immunosuppressant target

Special contributor: Eamonn Butler

Immunoglobulin A nephropathy (IgAN) is a leading cause of chronic kidney disease (CKD) and kidney failure.1 Proteinuria >1 g/day is a strong predictor of CKD progression.1 Non-immunosuppressant treatment that reduces proteinuria is preferred (renin-angiotensin system inhibition [RASI], sodium-glucose transport protein 2 inhibition [SGLT2i]), due to the higher risk of adverse events associated with immunosuppressants, as seen with steroid use in the TESTING trial.1–3 Endothelin receptor antagonists have been proposed as an additional therapeutic option for patients with proteinuric kidney diseases including IgAN.

This contribution summarises two recent articles reporting on the PROTECT study. The PROTECT randomised control trial, recruited adult IgAN patients with proteinuria >1 g/day, despite 12 weeks of maximised RASI. Patients were randomised to either sparsentan — a novel, non-immunosuppressive, dual endothelin and angiotensin receptor antagonist — or irbesartan. The primary outcome was proteinuria change between groups at 36 weeks, with secondary outcomes including CKD progression at 110 weeks.   

Two hundred and two patients were recruited to each group. The mean age was 46 years (standard deviation [SD] 12.4), mean eGFR was 57 mL/min per 1.73 m2 (SD 24.0) and median proteinuria was 1.8 g/day (interquartile range [IQR] 1.3–2.8). At 36 weeks, proteinuria in the sparsentan group reduced by 49.8% compared with 15.1% in the irbesartan group (p < 0.0001). Complete proteinuria remission (<0.3 g/day) occurred in 21% vs 8% (p = 0.0005), and partial remission (<1 g/day) in 70% vs 44% (p < 0.0001), in the sparsentan vs irbesartan group, respectively. CKD progression was slower in the sparsentan group (weeks 6–110, eGFR -2.7 vs -3.8 mL/min per 1.73 m2 per year [p = 0.037]).   

Sparsentan was well tolerated, with a similar frequency of serious adverse events and treatment discontinuations noted in both groups. No patients had to stop treatment because of oedema or heart failure (complications previously reported with endothelin receptor antagonists), however, higher rates of dizziness (15% vs 6%) and hypotension (13% vs 4%) were noted in the sparsentan group. Limitations of this study include an underrepresentation of Black and Hispanic patients, subtypes of focal segmental glomerulosclerosis (FSGS) potentially representing different responses and there being no differences in eGFR at 108 weeks despite a reduction in proteinuria at 36 weeks. This trial represents an important and exciting development for people with IgAN, already receiving accelerated US regulatory approval. Longer term results will become available from the extension to 270 weeks, and the safety and efficacy of combining sparsentan with SGLT2i’s is currently being investigated. 

References

  1. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int 2021; 100(4S): S1–S276.
  2. Wheeler DC, Toto RD, Stefánsson BV, Jongs N, Chertow GM, Greene T et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int 2021; 100: 215–224.
  3. 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: 1888–1898.

Heerspink HJL, Radhakrishnan J, Alpers CE, Barratt J, Bieler S, Diva U, et al. Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial. Lancet 2023; 401: 1584–1594.

Rovin BH, Barratt J, Heerspink HJL, Alpers CE, Bieler S, Chae DW, et al. Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial. Lancet 2023; 402: 2077–2090.

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PAEDIATRICS AND NEONATOLOGY

MedsScan editor for #SHPAPaedNeonate: Rachael Worthington

SCOUTing for Short-Course Therapy for Urinary Tract infections in children

Urinary tract infections (UTIs) are the most common bacterial infections worldwide and are a frequent indication for antibiotic therapy in both children and adults, as they can potentially result in both short-term and long-term morbidity including sepsis, acute kidney injury, kidney scarring and hypertension. The American Academy of Pediatrics recommends 7 to 14 days of antibiotic therapy to treat acute febrile UTIs (pyelonephritis) and to reduce the potential for long-term sequelae. Until now, robust clinical trials defining the optimal duration of therapy for UTIs in children have been very limited, with a paucity of paediatric-specific comparative data.

The Short-Course Therapy for Urinary Tract infections (SCOUT) randomised, clinical non-inferiority study was conducted at two children’s hospitals from May 2012–August 2019, to compare the efficacy of standard-course and short-course therapy for children with UTI. Children aged 2 months to 10 years with UTI exhibiting clinical improvement after five days of antimicrobials were included. Interventions included a further five days of antimicrobials (standard-course therapy) or five days of placebo (short-course therapy), with data analysed from January 2020–February 2023. Six hundred and sixty-four randomised children (639 female [96%]; median age, 4 years) were included in the primary outcome analysis, defined as symptomatic UTI at or before the first follow-up visit (day 11 to 14). Two of 328 assigned to standard-course (0.6%) and 14 of 336 assigned to short-course (4.2%) had treatment failure (absolute difference of 3.6% with upper bound 95% confidence interval of 5.5.%). Secondary outcomes included UTI after the first follow-up visit, asymptomatic bacteriuria, positive urine culture and gastrointestinal colonisation with resistant organisms. The short-course therapy cohort were more likely to have asymptomatic bacteriuria or a positive urine culture at or by the first follow-up visit. No differences were observed between groups in rates of UTI after the first follow-up visit, incidence of adverse events, or incidence of gastrointestinal colonisation with resistant organisms.

The authors concluded that, whilst treatment failure rates were low in both groups, standard-course therapy had lower rates of treatment failure than short-course therapy, which could be considered as an option for children exhibiting clinical improvement after five days of antimicrobial treatment.

Zaoutis T, Shaikh N, Fisher BT, Coffin SE, Bhatnagar S, Downes KJ, et al. Short-Course Therapy for Urinary Tract infections in children: The SCOUT randomized clinical trial. JAMA Pediatr 2023; 177: 782–9.

ARTIC-PC Challenges Prescribing of Antibiotics for lower respiratory tract infections in Children in Primary Care

There is little randomised evidence to support the effectiveness of antibiotics in treating uncomplicated lower respiratory tract infections (LRTI) in children, either overall, or in key clinical subgroups in which antibiotic prescribing is common. This placebo-controlled trial, inclusive of qualitative, observational and cost-effectiveness studies sought to estimate the clinical effectiveness and cost-effectiveness of amoxicillin for uncomplicated LRTI in children both overall and in clinical subgroups in general practices in the United Kingdom.

The primary outcome was the duration in days of symptoms rated moderately bad or worse, measured using a validated diary. Participants were children aged 1–12 years with acute uncomplicated LRTI, randomised to receive 50 mg/kg/day of oral amoxicillin in divided doses for 7 days, or placebo. Children who were not randomised could participate in a parallel observational study. Semi-structured telephone interviews explored the views of 16 parents and 14 clinicians, and throat swabs were analysed using multiplex polymerase chain reaction. Four hundred and thirty-two children were randomised (antibiotics n = 221; placebo n = 211). The duration of moderately bad symptoms was similar in the antibiotic and placebo groups overall (median of 5 and 6 days, respectively; hazard ratio 1.13, 95% confidence interval 0.90–1.42), with similar results for subgroups and including antibiotic prescription data from the 326 children in the observational study. Secondary outcomes were symptom severity on days 2–4, symptom duration, re-consultations for new or worsening symptoms, complications, side effects and resource use. Re-consultations for new or worsening symptoms, illness progression requiring hospital assessment or admission and side effects were similar in the two groups. Complete-case (n = 317) and per-protocol (n = 185) analyses were similar, with antibiotic effectiveness not impacted by the presence of bacteria. National Health Service (NHS) costs per child were slightly higher (antibiotics, £29; placebo, £26), with no difference in non-NHS costs (antibiotics, £33; placebo, £33). A model predicting complications with seven variables had good discrimination and calibration. Parents found it difficult to interpret symptoms and signs and often consulted to receive a clinical examination and reassurance, but acknowledged that antibiotics should be used only when necessary.

The authors concluded that, whilst the study was underpowered to detect small benefits in key subgroups, amoxicillin for uncomplicated lower respiratory tract infections in children is unlikely to be clinically effective or cost-effective.  A reduction in parents’ expectations for antibiotics during the study supports the need for clear communication and access to information about the self-management of their child’s illness.

Little P, Francis NA, Stuart B, O’Reilly G, Thompson N, Becque T, et al. Antibiotics for lower respiratory tract infection in children presenting in primary care: ARTIC-PC RCT. Health Technol Assess 2023; 27(9): 1-9.

ADDUCE Assesses the long-term effects of methylphenidate

Methylphenidate is the most frequently prescribed medicine for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents in many countries, and whilst short-term efficacy, tolerability and safety have been evaluated, limited data exists around long-term safety and tolerability. The ADDUCE naturalistic, longitudinal, controlled study was conducted in 27 European child and adolescent mental health centres in the United Kingdom, Germany, Switzerland, Italy and Hungary to investigate the safety of methylphenidate over a 2-year period in relation to growth and development, psychiatric health, neurological health and cardiovascular function in children and adolescents.

Participants were recruited into three cohorts: medication-naive ADHD patients who intended to start methylphenidate treatment (methylphenidate group), medication-naive ADHD patients who did not intend to start any ADHD medication (no-methylphenidate group) and a control group without ADHD. Eligibility criteria for inclusion were children, aged 6–17 years, with ADHD diagnosed by a qualified clinician according to the DSM-IV criteria and, in the control group, children who had scored less than 1.5 on average on the Swanson, Nolan and Pelham IV rating scale for ADHD items, and whose hyperactivity score on the parent-rated Strengths and Difficulties Questionnaire was within the normal range (<6). Participants were excluded if they had previously taken any ADHD medications but remained eligible if they had previously taken, or were currently taking, other psychotropic drugs.

The primary outcome was height velocity standard deviation [SD] score (estimated from at least two consecutive height measurements, normalised with reference to the mean and SD of a population of the same age and sex). One thousand, four hundred and ten participants were enrolled (756 in the methylphenidate group, 391 in the no-methylphenidate group and 263 in the control group) between 1 February 2012–31 January 2016. The methylphenidate and no-methylphenidate groups differed in ADHD symptom severity and other characteristics, with propensity scores used to account for the effect of variables. There was little evidence of an effect on growth (24 months height velocity SD score difference -0.07 (95% confidence interval -0.18–0.04, p = 0.20) or increased risk of psychiatric or neurological adverse events in the methylphenidate group compared with the no-methylphenidate group. Pulse rate and systolic and diastolic blood pressure were higher in the methylphenidate group compared with the no-methylphenidate group after 24 months of treatment. No serious adverse events were reported during the study. The results suggest that there is no evidence that long-term treatment with methylphenidate for two years leads to reductions in growth, but that pulse and blood pressure changes, although relatively small, require regular monitoring.

Man KKC, Häge A, Banachewski T, Inglis SK, Buitelaar J, Carucci S et al. Long-term safety of methylphenidate in children and adolescents with ADHD: 2-year outcomes of the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study. Lancet Psychiatry 2023; 10: 323–33.

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PAIN MANAGEMENT

MedsScan editor for #SHPAPainMgmt: Shania Liu

Buprenorphine patches for postoperative pain: what does the literature say?

While transdermal buprenorphine is not considered a first-line option for postoperative pain management, it may be considered for some patients for whom an anticipated duration of pain is expected, such as those with significant burns or traumatic injuries. This systematic review and meta-analysis examined the efficacy and safety of transdermal buprenorphine for postoperative pain compared to alternative analgesics or placebo.

There were 15 studies examining the use of transdermal buprenorphine for postoperative pain. Comparators included fentanyl (n = 2), tramadol (n = 5), celecoxib (n = 3), diclofenac (n = 3) and placebo (n = 2). Meta-analysis showed no difference in pain intensity between transdermal buprenorphine 10 microgram/hour and fentanyl 25 microgram/hour (standardised mean difference -0.03, 95% confidence interval [CI] -0.86–0.081, p = 0.95). Transdermal buprenorphine 10 microgram/hour was associated with less pain than celecoxib 200 mg twice a day (standardised mean difference -0.32, 95% CI -0.58–-0.05, p = 0.02) and placebo (standardised mean difference -2.29, 95% CI -4.32–-0.27, p = 0.03).

The authors conclude there appears to be limited evidence supporting the use of transdermal buprenorphine over other analgesics for the management of postoperative pain.

Aguilar B, Penm J, Liu S, Patanwala AE. Efficacy and safety of transdermal buprenorphine for acute postoperative pain: a systematic review and meta-analysis. J Pain 2023; 24: 1905–1914. 

Safety of modified-release opioid use after joint replacement surgery

Modified-release opioids are routinely prescribed for acute postoperative pain after total hip or knee replacement surgery, despite recommendations against the use of modified-release opioids for acute pain. This study aimed to examine the impact of modified-release opioid use on adverse events after hip or knee replacement compared with immediate-release opioid use.

Electronic medical record data from three hospitals in New South Wales, Australia, was analysed. Patients who received modified-release opioids with when-required immediate-release opioids were matched to patients who received immediate-release opioids only, to account for baseline differences between these groups (such as opioid dose received). After patients were matched, those who received modified-release opioids experienced a higher incidence of opioid-related adverse events compared with patients given immediate-release opioids only (20.5%, 71/347 vs 12.7%, 44/347; difference in proportions 7.8% [95% CI 2.3–13.3%]).

This study highlights that patients given modified-release opioids after hip or knee replacement surgery are at a higher risk of adverse events. Hospital pharmacists may play a key role in encouraging safer prescribing practices for the management of pain after joint replacements.

Liu S, Patanwala AE, Naylor JM, Levy N, Knaggs R, Stevens JA, et al. Impact of modified-release opioid use on clinical outcomes following total hip and knee arthroplasty: a propensity score-matched cohort study. Anaesthesia 2023; 78: 1237–1248.

Is there a role for opioids for the management of acute low back and neck pain?

Opioid analgesics are often used for acute low back and neck pain, despite limited evidence to support their use. This randomised placebo-controlled clinical trial aimed to examine the efficacy and safety of a short course of opioid analgesics for acute low back and neck pain.

The trial included adults presenting to one of 157 primary care sites or emergency departments in Sydney, Australia, who experienced 12 weeks or less of low back or neck pain, of at least moderate pain intensity. Participants were randomised to receive either oxycodone-naloxone up to 20 mg daily with standard care, or placebo with standard care. The primary outcome was pain intensity at 6 weeks after randomisation. There were 347 participants recruited into the trial (49% female), with 11% lost to follow up (151 intervention and 159 control patients included in the primary analysis). At 6 weeks, there was no significant difference in pain intensity between patients given an opioid and those given placebo (adjusted mean difference 0.53, 95% CI -0.00–1.07, p = 0·051).

The authors concluded that opioids should not be recommended for acute low back or neck pain. Thus, hospital pharmacists should discourage the use of opioid analgesics for acute low back or neck pain due to limited benefit compared with placebo.

Jones CMP, Day RO, Koes BW, Latimer J, Maher CG, McLachla AJ, et al. Opioid analgesia for acute low back pain and neck pain (the OPAL trial): a randomised placebo-controlled trial. Lancet 2023; 402 (10398): 304-12.

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RESEARCH

MedsScan editors for #SHPAResearch: Jacinta Johnson and Asad Patanwala

Identifying barriers and facilitators for research engagement among hospital pharmacists and pharmacy technicians in Australia

Hospital pharmacists often exhibit a keen interest in research, yet this interest doesn't always translate into active participation. Moreover, there's limited insight into the factors affecting pharmacy technicians' engagement in research. This study aimed to explore the barriers and drivers influencing hospital pharmacy staff's involvement in practice-based research, utilising the Capability, Opportunity, Motivation-Behaviour (COM-B) model. In this context, practice-based research refers to integrated research activities that directly arise from and contribute to the day-to-day clinical practice and operations within the pharmacy setting.

In a cross-sectional survey involving a broad sample from 19 hospitals within a statewide hospital pharmacy service, key findings mapped to the following COM-B components emerged:

  • Reflective motivation — both pharmacists and pharmacy technicians expressed a strong desire to engage in research that was driven by the aspiration to improve patient care, self-development, and recognition
  • Physical opportunity — a lack of time for research and competing work roles posed significant barriers, particularly in the setting of staff shortages
  • Psychological capability — insufficient skills and mentorship hindered research involvement, emphasising the importance of educational and mentorship programs
  • Social opportunity — Managerial support and a conducive departmental research culture emerged as facilitators, enhancing the engagement of both pharmacists and technicians.

The study found subtle distinctions in research motivators between hospital pharmacists and pharmacy technicians, suggesting tailored strategies may be required for each group. A lower proportion of technicians were motivated by problems that need solving or a desire to prove a theory and a greater proportion were motivated by colleagues doing research.

These insights could be used with the Behaviour Change Wheel to devise targeted interventions to enhance hospital pharmacy staff's involvement in practice-based research, ultimately improving patient care and the quality of pharmacy services.

Johnson J, Blefari C and Marotti S. Application of the COM-B model to explore barriers and facilitators to participation in research by Australian hospital pharmacists and pharmacy technicians: a cross-sectional mixed-methods survey Res Social Adm Pharm 2024; 20: 43–53.

Writing a compelling abstract: how to enhance your scholarly writing

This narrative review highlights the importance of an effective abstract; to provide an initial impression for readers and reviewers of scholarly work. Abstracts are often the only part of a manuscript that is read and so, it is important for the abstract to be well written, clear and concise. The authors provide a systematic approach to writing an abstract and have outlined eight steps for early career researchers and pharmacists to write a high-quality abstract including: getting prepared for writing; authorship; and formulating an effective title.

According to Dupree et al. the title should be dynamic, catch the attention of the audience and engage readers. They describe the usual abstract formats and how to write individual sections such as the introduction, method, results and conclusion. For example, the introduction should capture the problem and importance of the research. The method section answers the question ‘what did you do?’ and includes details about the study design, patient population and endpoints. Many readers want to know the study findings and often skim over the abstract, which makes the results section very important. This is usually the longest section of the abstract and is expected to provide key details such as the sample size and include quantitative results of the primary and secondary endpoints if applicable. The conclusions integrate the previous sections and provide an interpretation of the findings without overstating the results or ignoring personal biases.

This review includes examples of abstracts for journal, conference and grant submissions as these can vary. Finally, it is important to proofread the abstract thoroughly before submission. This narrative review serves as a useful guide for pharmacists, provides embedded examples and includes best practices that will help early career researchers.

Dupree LH, Casapao AM. Research and scholarly methods: writing abstracts. J Am Coll Clin Pharm 2023; 6: 1146–1155.

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TRANSITIONS OF CARE AND PRIMARY CARE

MedsScan editors for #SHPATransitionCare: Ahmed Zeidan, Margaret Jordan and Deirdre Criddle 

A new frontier in caring for older people: evaluating the pharmacist's impact 

A recent study conducted through a Victorian tertiary hospital explored the introduction of a clinical pharmacist into its Residential In-Reach (RIR) service, focusing on deprescribing and reducing the use of inappropriate medications (PIMs). RIR services offer acute care directly to aged care facility residents to avoid hospital visits and involve multidisciplinary teams that include nurses and geriatricians.  

Employing a pre-post observational design, the research aimed to assess the effect of pharmacist-led medication reviews on the practice of deprescribing. Notably, the findings indicated a significant reduction not only in the overall number of PIMs as identified through Screening Tool of Older People's Prescriptions criteria version 2 (STOPP v2), and the Drug Burden Index (DBI) following the pharmacist’s intervention, but also in medicines prescribed without a clear clinical indication. These results suggest a decrease in inappropriate prescribing and associated medication risks. However, there was no significate change in the prescribing of psychotropic medicines. 

The inclusion of clinical pharmacists in multidisciplinary teams, particularly within RIR services, appears to offer a promising approach to optimising medicines management for older people. The lack of change in psychotropic medicine prescribing likely reflects the challenges of altering long-standing treatment regimens and the clinical caution associated with deprescribing psychotropics, especially in short-term acute care settings like RIR services. While the study presents a positive outlook for the role of pharmacists in reducing the challenges of polypharmacy, it also calls for further investigation into the long-term sustainability of these interventions and their broader impact on patient well-being and system-wide healthcare outcomes. 

Hui JH, Parikh S, Kouladjian O'Donnell L, McInerney B, Dillon L, Poojary S, et al. Pharmacist-led medication review in a residential in-reach service leads to deprescribing. J Pharm Pract Res 2023; 42: 675–682. 

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