MedsScan Issue 3, 2023

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.

COMPOUNDING SERVICES

MedsScan Editor for #SHPACompound: Shalini Kassam

Comparing the preparation time and productivity in compounding parenteral hazardous drugs using different manual and robotic aseptic compounding methods

There is increasing demand for hazardous parenteral drugs preparation in hospital pharmacies accompanied by growing scarcity of qualified personnel. This Dutch study of three hospitals compared three aseptic preparation methods: manual software-supported compounding; robotic compounding (OLVG); and combined robotic and manual compounding without software support. The compounding times of each drug, production capacity and direct labour costs not investigated previously were documented.

St Antonius Hospital provided the manual software-supported compounding method data. Amsterdam University Medical Centre (UMC) data was obtained for a manual volumetric compounding method from one location and a manual volumetric compounding combined with the robotic system from the second. The OLVG provided robotic system data and individual compounding times were determined only. Robot compounding times were obtained for two months. Times for each of the four compounding process phases were tabulated: preparation before the start of the compounding; actual compounding; the release of the preparation; and the cleaning procedure. The compounding times of nine different oncology drugs, which could be compounded either way, were investigated. Average timing for each drug preparation was taken from a minimum of three preparations made by at least three different personnel. Drugs investigated were cyclophosphamide, paclitaxel and pemetrexed, carboplatin, cisplatin, cytarabine, doxorubicin, fluorouracil, irinotecan and oxaliplatin. Production capacity and direct labour costs analysis was undertaken.

Individually, manual compounding with software support was the fastest compounding method at 3:31 min (standard deviation 2:00); this was 1:03 min and 1:26 min faster than robotic compounding at OLVG and Amsterdam UMC respectively, and 1:33 min faster than the manual compounding method without software support. The total compounding process lasted 6:44 min with robotic compounding, 6:48 min with manual compounding with support, and 9:48 min with manual compounding without software support. The before compounding, cleaning times and use of software support contributed to the time saved. The production for one compounding day was 15 preparations for manual compounding with and without software support, and 57 preparations for just robotic compounding. With the combined method, a more realistic figure of 30 preparations was observed with direct labour costs per preparation of €5.21, as opposed to €13.18 for manual.

Studying phase times and productivity provided a more realistic value of savings possible using robotic compounding appropriately and provided a useful calculation method which would be of benefit to Australian hospital pharmacies.

Geersing TH, Pourahmad DM, Lodewijk F, Franssen EJF, Knibbe CAJ, Crul M. Analysis of production time and capacity for manual and robotic compounding scenarios for parenteral hazardous drugs. Eur J Hosp Pharm 2023: 1–6 [published online before print].

Practical recommendations for the manipulation of kinase inhibitor formulations to age-appropriate dosage forms

Many kinase inhibitors (KIs) are now used off-label in paediatrics cancers. These solid oral drug forms frequently require manipulation to achieve appropriate individualised dosing. There is minimal information on stability or bioavailability data for dosage form manipulation from manufacturers. Most KIs have poor solubility increasing the risk of underdosing or overdosing from resulting altered pharmacokinetics (PKs). This systematic review on dosage form manipulation offers practical considered recommendations for 15 most frequently used KIs in paediatric oncology and proposes a decision support tool to assess other KIs similarly.   

A literature search was conducted with PubMed, Cochrane and Embase. KI stability studies were collected using these keywords (including synonyms): bosutinib; cabozantinib; cobimetinib; crizotinib; dabrafenib; dasatinib; entrectinib; imatinib; larotrectinib; nilotinib; ponatinib; ruxolitinib; selumetinib; sunitinib; trametinib; paediatrics; oncology; pharmacokinetics; formulation manipulation; and enteral tube administration. Duplicates were eliminated and remaining articles screened and cross-referenced to include studies not elicited in the initial search. Drug information from the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were examined for formulation choices and PK data. Two categories were selected for recommendations for manipulation of the solid oral dosage form to either (A) a compounded crushed tablet or opened capsule or (B) an oral liquid. A level of evidence (LoE) was allotted to each KI in each category. LoE 1 was given if there was a liquid or extemporaneous option or appropriate bioequivalence studies available. LoE 2–4 was allocated based on PK study type, similarity of PK parameters of manipulated KIs, EMA/FDA bioequivalence data, or case report description of KI formulation manipulation. LoE5 was assigned for theoretical PK considerations or bioequivalence data of unlicensed drugs. Larotrectinib and dasatinib were designated LoE1 for both categories while imatinib and ruxolitinib were designated LoE1 for category B, but LoE5 for category A. Sunitinib was the only KI designated LoE2 for both categories. The remainder were designated LoE4 or LoE5.

Until sufficient information is available for dose manipulation of KIs, and appropriate licenced paediatric formulations are available, this review is useful in assisting with clinical care decision making on formulation manipulation of KIs for essential paediatric use in Australia. Interpretation of this review must be undertaken in conjunction with the manufacturers information and therapeutic drug monitoring must be considered to ensure clinical efficacy.

Bernsen EC, Hogenes VJ, Nuijen B, Hanff LM, Huitema ADR, Diekstra MHM. Practical recommendations for the manipulation of kinase inhibitor formulations to age–appropriate dosage forms. Pharmaceutics 2022; 14: 2834.

3D printing of paracetamol suppositories: an automated manufacturing technique for individualised therapy

Suppositories and pessaries are commonly used when the oral route is not an option. The traditional size and shape of a suppository is limited by moulds available and due to its complex manufacturing technique, inconsistencies in content uniformity may arise. Three-dimensional printing (additive manufacturing) is a modern technique gaining traction in pharmaceutical manufacturing and options of customisable moulds, use of polyvinyl alcohol and layering techniques offer advantages of individualisation and different drug release properties.

This study aimed to use syringe-based, semi-solid 3D printing technology to develop an automated manufacturing process for customisable suppositories with reproducible quality and to meet individual patient needs. Two standard suppository bases, water-soluble polyethylene glycol (PEG) and lipophilic hard fat (HF) were used. The PEG base was melted and extruded from a syringe and mixed with the dissolved paracetamol (10%) while the HF base was layered as pastilles incorporating paracetamol (10%) in the centre, into syringes. The syringe was then heated in a water bath at 37°C and shaken vigorously to homogenise the preparation and cooled until it solidified into the varied sizes and shape moulds. Traditionally moulded suppositories with and without paracetamol were also prepared and characterised similarly for comparison. Three designs (standard, hollow and small) were created for 3D printing using computer-aided design software. The previously prepared syringes containing paracetamol in PEG or HF were heated inside the metal cylinder of the 3D printer to reach a flowable, but highly viscous consistency. The extruded strands were deposited on a printing plate which had blue painter’s tape on it and formed the desired shape layer-by-layer via movements of the printing plate and underwent continuous cooling for solidification. 3D printed suppositories were compared to the moulded ones by analysing visual appearance, uniformity of mass and content, diametrical dimension, breaking force and release behaviour.

Although bullet-shaped, 3D printed suppositories were observed to be textured with slightly thickened starting and end points compared to the smoother moulded ones. The suppositories withstood similar forces before fracturing, regardless of size and manufacturing technique. The mean drug content recovery rates were in the range of 95.9–99.7% for all batches, with a slightly lower mean content for the moulded HF suppository. The drug release was relatively constant for all suppositories but the rate of release for the hollow one was faster and lower for the small size one, but relatively, rates were all similar.

This study determined that 3D printing could be used for on-demand small scale manufacturing of tailored individualised suppositories by adjusting dose, size or shape. This could be a good option for hospital pharmacy manufacturing in Australia. Extensive details regarding the manufacturing process, associated considerations and possible future use were discussed.

Domsta V, Krause J, Weitschies W, Seidlitz A. 3D Printing of paracetamol suppositories: An automated manufacturing technique for individualized therapy. Pharmaceutics 2022; 14: 2676.

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DISPENSING AND DISTRIBUTION

MedsScan Editors for #SHPADispense: Ashley Crawford and Anna Wood

Can dispense tracking software improve availability of medicines for inpatients?

Delayed administration of medicines can have significant implications for patient outcomes, particularly when delayed medicines are time critical. Additionally, re-dispensing inpatient medicines has both cost and efficiency consequences for the pharmacy and hospital network. Dispense tracking software is a mechanism for tracing the location of dispensed inpatient medicines, but does it improve pharmacy efficiency without compromising on patient care?

This study was a prospective, pre-post implementation trial to evaluate the dispense tracking software implementation in an American paediatric hospital. Tracking occurred by scanning the dispensed item on departure from the pharmacy department, and then scanning the item again on delivery to the patient care area. The trial was focused on intravenous (IV) preparations. The trial intended to demonstrate whether this software reduced the requirement for re-dispensing of medicines. A survey of pharmacy staff was conducted to consider their satisfaction with the new process.

In the three months post implementation of the tracking software, there was an overall decrease of 1.7% in the number of re-dispensed doses, which equated to approximately 243 less re-dispenses per month. It is unclear whether this is a significant result. Nineteen percent of pharmacy employees who used the software completed the survey. The majority felt the software was beneficial for patient safety and was easy to use, however half of survey participants reported that the software didn’t reduce the number of enquiries from nursing staff about missing medicines. The study had several limitations, including that the survey only sought feedback from pharmacy staff, the small number of survey respondents, limiting the tracking to IV doses and no statistical analysis of the significance of the result.

Tracking systems have the potential to reduce the workload and cost associated with re-dispensing items from the pharmacy, however this study doesn’t provide robust evidence to support this. Staff however, reported satisfaction with this new system and perceived safety benefits. In the Australian setting, hospitals could learn from the limitations outlined in this study when developing and evaluating similar systems. Potentially, the data gained from a tracking system may also allow pharmacy departments to further analyse the efficiency of workflows, but any such system needs to be collaboratively developed with nursing colleagues.

Gunter Z, Lawson N, Bondarenka C. Impact of dispense tracking software on inpatient pharmacy operations. J Pharm Technol 2022; 38: 88–94.

Utilisation of a framework to assess the impact of medicine shortages

There has been an increased prevalence of supply chain disruptions following the COVID-19 pandemic, resulting in nationwide medicine shortages. If not managed appropriately, medicine shortages can have a detrimental impact on patient care due to interruptions in treatment. A review of the total number of medicine shortages alone fails to recognise that a shortage of one medicine may have a greater impact than shortage of another. A mechanism for assessing the impact of medicine shortages is important for enabling health professionals and government bodies to prioritise and manage their responses accordingly. 

This study reviewed a sample of reported medicine shortages in the Netherlands from 2012–2015. A shortage was defined as “a marketing authorization for human use that is nationally unavailable for at least 2 weeks”. Impact was evaluated utilising an EHCO-based framework, which assesses the economic, clinical and humanistic outcomes (EHCO) of the shortage. This involved an assessment of each shortage against five elements: availability of an alternative product; underlying disease; susceptibility of the patient; costs; and number of patients affected. A total of 324 shortages were assessed, representing 18% of all reported shortages within the study period. Ratings varied across different medicines, with disease and cost scoring as high impact most frequently across the data set. No shortages were rated as having a high impact across all five elements however, close to 10% of shortages did have this rating applied across multiple criteria. These results demonstrate that there are multiple factors that influence the impact of a medicine shortage that require consideration.

To gain a more comprehensive understanding of how this style of framework can be applied to the assessment of medicine shortages, it would be pertinent to conduct similar studies using more recent data and across other countries. One of the limitations of this study was that ratings were assigned primarily by one researcher. Given that many elements involved in the evaluation process may be open to interpretation, the inclusion of multiple assessors would yield more robust results. Further exploration is required before an ECHO-based framework can be more widely adopted; however this early evidence demonstrates the potential benefits of this type of approach.

Postma DJ, Notenboom K, De Smet PA, Leufkens HG, Mantel-Teeuwisse AK. Medicine shortages: Impact behind numbers. J Pharm Policy Pract 2023; 16: 1–12.

Assessing the impact of a medicine recovery and reuse program

Waste reduction and sustainable practises are of increasing importance across all facets of healthcare, including medicine management. Changes to medicine regimens often result in individuals having medicines in their homes that they no longer use and are encouraged to return to pharmacies for safe disposal. Current regulations in Australia prohibit the reuse of in-date medicines returned by patients due the potential safety risks to associated with loss of product integrity and tampering. However, there is some evidence available from other countries that suggests that a proportion of these medicines could be considered suitable for reuse. Overseas, different medicine reuse programs have been established specifically aimed at the redistribution of unwanted medicines to vulnerable patient populations. The aim of these programs is to facilitate access to medicines for those in need, contribute to cost savings related to medicine expenditure and reduce medicine-related waste.

This article focuses on one such program established in 2017 in Italy, aimed at recovering and reusing medicines in the hospital setting. Certain medicines were automatically considered outside of scope for reuse based on their therapeutic class and specificity of their storage parameters as stipulated by Italian law. Suitability for reuse was determined based on physical inspection of the pack by a pharmacist against pre-determined guidelines. A warehouse worker and an administrative worker were also required to facilitate logistical and recordkeeping activities associated with the program.

The impact of the program on cost savings was reviewed for a three-year period from 2017–2020.  A total of 10 450 packs of medicine were assessed as being appropriate for redistribution. This represented just over half of the total number of packs donated, with a combined estimated retail value of €1 300 000. The labour costs to coordinate the program across the total study period were estimated to be €75 806. This was based on the assumption that each of the three team members were required to work five hours per week on average to complete the necessary program tasks. 

This study demonstrates the cost savings and reduction in waste associated with implementation of a medicine reuse program. However, there are many complexities that require careful consideration and further exploration before similar programs could be more widely adopted in other countries, especially given that this practise is not currently supported by the World Health Organization Guidelines for Medicine Donation.1 Further data relating to the quality and integrity of medications returned by patients from a broader range of countries and healthcare settings is also crucial to alleviate patient safety concerns.

Gianino MM, Cotugno V, Scattaglia M, Colasanto I, Scaldaferri M, Cattel F. Medicine recovery and reuse in a hospital setting: a lesson from Italy. Int J Pharm Pract 2022; 30: 554–8.

References

  1. World Health Organization (WHO). Guidelines for medicine donations: Revised 2010. Geneva: WHO; 2011. Available from https://www.who.int/publications/i/item/9789241501989.

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EDUCATION AND EDUCATIONAL VISITING

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

Investigating preceptor experiences with cultural intelligence in pharmacy education

Cultural intelligence (CI) by healthcare professionals is critical for addressing health disparities and supporting patients’ spectrum of need. Acknowledging that the teaching strategies of preceptors are influenced by their own experiences and priorities, little is known about how they create or manage culturally relevant situations to support students, as they interact with patients during experiential training.

This exploratory study aimed to provide an understanding of pharmacy preceptors’ self-efficacy in teaching CI and how they applied the Cultural Intelligence Framework (CIF) during experiential training to enhance students’ CI. The CIF consists of four domains: cultural awareness; cultural knowledge; cultural practice; and cultural desire. A convergent parallel mixed methods approach was utilised where quantitative data were collected through a 10-item survey measuring the preceptors’ confidence (n = 24) on a Likert scale. Qualitative data were collected through focus groups or individual interviews of pharmacy preceptors (n = 10) from the University of North Carolina.

The research identified a degree of variability in preceptor teaching efficacy. Preceptors recognised the importance of learners’ self-awareness in promoting open dialogue and understanding cultural components of care. They also emphasised the need to address social determinants of health and avoid generalisations about specific cultural groups. Despite the importance of teaching cultural practice, preceptors reported challenges in finding practical resources for this domain, leading to lower self-efficacy when teaching. In addition to aligning CI goals with learning opportunities, the study suggests various teaching practices including self-assessment, reflection, metacognition, and using diverse patient cases to enhance students’ CI.

Although the study has limitations such as a small sample size and limited generalisability, it contributes valuable insights into teaching CI and highlight the need to address curricular gaps in CI. Further research regarding practical applicability in curriculums is needed to support student learning and enhance their cultural intelligence during training.

Li A, Minshew LM, Williams C, White C, Fassett KT, McLaughlin JE. Investigating preceptor experiences with cultural intelligence in pharmacy education. Res Social Adm Pharm 2023; 19: 622–7.

Australian pharmacy student perceptions on the ideal pharmacist preceptor

Experiential placements are integral to pharmacy students’ skills development and quality of placement is highly dependent on preceptors’ competency and role preparedness. This study focused on pharmacy students’ perceptions on the ideal preceptor roles and attributes with the aim of informing the design of a pharmacist preceptor training program.

The study was conducted at James Cook University, Australia. A mixed method design included an online student survey and focus groups. The survey contained 21 preceptor roles and 15 attributes statements to be answered on 5-point Likert importance scales. Focus groups further explored opinions. Surveys were analysed using descriptive statistics while interviews were thematically analysed.

Thirty-seven students completed the survey. Twelve students participated across three focus groups. The three most important preceptor roles identified by 81.6 % of participants were effective student communication, providing clear explanations, and demonstrating good decision making and evidence-based practice. The three most important skills and attributes were: effective communicator and counsellor (89.5%), enthusiasm and student support (84.2%) and effective student engagement (76.4%). Managing student conflict was seen as least important. A significant association was found between year level and the importance of familiarity with pharmacy curriculum (p = 0.017) and meeting educational expectations (p = 0.036). There was overall strong agreement between quantitative and qualitative findings on the ideal preceptor roles and attributes.

Despite the study being conducted at a single university, and hence not representative of all Australian pharmacy students, it provides valuable insight into students’ perceptions on preceptor roles and attributes. Most of the preceptor roles and attributes students identified as important are not a surprise to experienced placement preceptors. However, university curriculum may not always be known by preceptors and/or supervising hospital ward pharmacists. Preceptor training focused on building good preceptor–student relationships, as well as appropriate preceptor competency standards, including curriculum knowledge, will assist in meeting the challenges of future pharmacy graduates.

Knott, GJ, Mylrea MF, Glass, BD. Pharmacy student perceptions of the roles and attributes of pharmacist preceptors in Australia. Pharmacy (Basel) 2022; 10: 169.

Interprofessional collaboration and communication by hospital pharmacist trainees

Exposure to interprofessional education (IPE) to support health professional trainees to work within shared-care practice settings is typically conducted in campus-environments rather than inside hospitals’ social systems where interprofessional care is delivered. Little is known about pharmacist trainee interprofessional competency development and performance during workplace-based learning. This study aimed to explore pharmacist trainees’ experience with collaborator and communicator competency roles during team-based workplace-based learning.

Twenty-five fourth year pharmacy students from University of British Columbia, Canada, maintained written diaries reflecting on interprofessional collaboration and communication during an eight-week hospital clerkship. Diary entries and transcripts from semi-structured follow-up interviews were analysed from the social constructivist perspective using reflective thematic analysis and matched to pharmacy and interprofessional competency frameworks.

Most collaborator and communicator roles outlined in pharmacy and interprofessional competency frameworks were represented in diaries but were predominantly between the pharmacist trainee and physicians. Intra- and interprofessional communications were mostly information exchange and patient handovers were largely absent. Three main themes emerged of how interprofessional collaboration and communication are enacted in hospital practice: limited interaction with different health professionals; opportunities for authentic collaborative care, such as information sharing; and perceived interprofessional competency development through recurrent deliberate practice. Pharmacist trainees were largely satisfied with the opportunities afforded to develop interprofessional communication and collaboration.

The authors suggested that university campus-based IPE programs are often manufactured teams of convenience that will infrequently or never practically collaborate as professionals in practice. It poses the question; are students’ experiences actual authentic hospital pharmacy practice models or is their narrow expectations of interprofessional competency development readily met through physician and nurse encounters? Research is required to understand the Australian IPE experience. Further investigations to determine whether limited scope of interprofessional communication and collaboration impairs quality patient care may also help.

Wilbur K, Teunissen PW, Scheele F, Driessen EW, Yeung J, Pachev G. Pharmacist trainees narrow scope of interprofessional collaboration and communication in hospital practice. J Interprof Care 2023; 37: 428–37.

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ELECTRONIC MEDICATION MANAGEMENT

MedsScan Editor for #eMM: James Grant

Technology to support real-time medicine clinical decision support

This article presents a study on a real-time medicine clinical decision support (CDS) technology and process trialled over nine months in two hospitals (with a total of 2000 inpatient beds) in France. The technology utilised data feeds from the hospitals electronic systems (including medication orders, pathology and medical history) and a set of 71 rules to trigger a CDS ‘alert’. 

Interestingly, rather than the rules directly triggering an alert to the user, a staffed process was implemented, whereby a pharmacist reviewed the triggered scenario and either resolved it themselves if within their scope or forwarded it onto a prescriber. It is unclear if this was a 24-hour service though it seems not, given only one pharmacist was undertaking the role. 

Overall, the system seemed to have high sensitivity (showed true positives) and high specificity (hid true negatives) given there were 52 867 patient encounters at the hospital during the study and 1508 alerts were raised for pharmacist or prescriber intervention. This represents a 2.8% chance of one alert per patient when the average inpatient is presumably on many medicines. Of those alerts sent through to the prescriber (n = 540) there was 40% acceptance (change therapy), 40% decline (no change) and 20% undocumented output. 

Factoring in the workflow of the study, this was not a ‘real time’ CDS intervention in the typical sense. The data feeds were at best updated hourly (real time usually means data is available within three seconds) and the medical history was a monthly extract that was then loaded into the rules logic. 

Potier et al. make noteworthy calls for collaboration and improved interoperability between hospitals and countries, and they used recognised terminologies such as SNOMED-CT, ICD-10 and ATC for their rules, and the ability to share via Microsoft Excel as part of their work. Just like the goal in Australia, they state that a national repository of medicine CDS triggers should be created to reduce duplication of effort and standardise the level of care. 

Potier A, Dufay E, Dony A, Divoux E, Arnoux L-A, Boschetti E, et al. Pharmaceutical algorithms set in a real time clinical decision support targeting high-alert medications applied to pharmaceutical analysis. Int J Med Inform 2022; 160: 104708.

Influencing nurses’ adoption of information and communication technology

This review aimed to explore factors influencing nurses’ adoption of information and communication technology (ICT). The review had the typical biases seen in the majority of studies, including being North American and a focus on predominantly qualitative studies. Papers reviewed did cover barcoded medication administration and tele-medicine ICT, alongside electronic health record technologies.

Having healthcare staff involved from the beginning through to the end of the initiative implementing the technology was a positive influence on adoption and uptake. The paper was unable to provide more specific details on how much time spent co-developing and co-implementing was sufficient or how it could be structured (e.g., simply meeting together or having health professions in the ‘ICT team’ or vice versa). 

Coffetti et al. reported that it was key to have management support for the uptake. A local change champion, often an early adopter person, was also positively associated with adoption being successful. Providing training in groups, rather than one-on-one, was another beneficial factor in staff learning the new system. Change resistant cultures and having too much change at once — leading to workload challenges —were negatively associated with uptake of the new technology. 

Overall, the review concluded that a gradual implementation process of the ICT system(s), involvement from care professionals throughout the implementation process, and team trainings are important factors when adopting information and communication technology. 

Coffetti E, Paans W, Roodbol PF, Zuidersma J. Individual and team factors influencing the adoption of information and communication technology by nurses: A systematic review. Comput Inform Nurs 2022; 41: 205–14.

Attitudes towards using blockchain and machine learning in electronic prescriptions

This survey was undertaken to evaluate the attitudes of patients, pharmacists and prescribers toward potential features of using blockchain technology to improve upon existing approaches to providing electronic prescriptions (ePrescriptions). The authors note the need to involve all affected parties in a healthcare decision and as such, they made a deliberate choice to recruit a larger number of patients into the survey than previous work. The survey population comprised 284 respondents in the patient group (n = 226 respondents), 39 in the pharmacist group (n = 34 respondents) and 27 (n = 26 respondents) in the prescriber group.

Blockchain technology effectively makes the transfer of data or information more transparent and independently verifiable. As a decentralised platform, many different computers undertake checks that new blocks (data) have been added in the right way; it is nearly impossible for a malicious actor to prevent any and all of the computers on the network from doing their checks. In this context, a prescriber (their software) adds a block of data for an ePrescription into the network. The patient goes to the pharmacy of their choice and uses their token to show the pharmacy (their software) which ePrescriptions to dispense. Each of these connections to the ePrescription block are recorded and traced. 

The survey showed a positive attitude toward the theoretical blockchain ePrescription system with supportive responses from 72% (n = 163) of the 226 respondents in the patient group, 70.5% (n = 24) of the 34 respondents in the pharmacist group and 73% (n = 19) of the 26 respondents in the prescriber group. The pharmacist (70%, n = 24) and prescriber (85%, n = 22) groups had a positive attitude toward using machine learning algorithms to generate alerts regarding prescribed medicines to enhance the safety of medicines prescribing and prevent medication errors. Whilst the theoretical changes were viewed positively, 88.1% (n = 199) of the 226 patient respondents agreed that the current ePrescription system transfers their electronic prescriptions securely and keeps their information private. 

There was support for the use of near field communication (NFC) technology to enforce a physical locality check (i.e. the patient with the token is within 4 cm of the pharmacy software or device), though ad hoc feedback was recorded, with pharmacists noting their patients would like to order their prescriptions online to reduce in-store waiting. 

Aldughayfiq B, Sampalli S. Patients’, pharmacists’, and prescribers’ attitude toward using blockchain and machine learning in a proposed ePrescription system: Online survey. JAMIA Open 2022; 5: ooab115.

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INFECTIOUS DISEASES

MedsScan Editor for #SHPAInfDis: Nadine Hillock

Duration of post-op antibiotics for complex appendicitis

An open-label, randomised trial was performed across 15 hospitals in the Netherlands to determine whether a 2-day regimen of post-operative antibiotics was non-inferior to a 5-day regimen, with regard to infectious complications and mortality after appendectomy. Patients ≥8 years old were eligible for inclusion if diagnosed with complex appendicitis, defined as the presence of necrosis, perforation or abscess, as assessed intraoperatively. The antibiotics administered were cefuroxime (1500 mg three times daily) or ceftriaxone (2 g daily), in addition to metronidazole 500 mg three times daily and were initiated within 8 h after surgery. Doses were adjusted according to weight for patients aged 8–17 years. A single dose of gentamicin was allowed if required, in case of sepsis. The non-inferiority margin was set at 7.5%.

One thousand and five patients were included in the intention-to-treat analysis. Baseline characteristics of both groups of patients were similar. Nine hundred and fifty-five (95%) patients underwent appendectomy laparoscopically. The primary composite endpoint (intra-abdominal abscess, surgical site infection or mortality within 90 days of surgery) occurred in 10% (n = 51) of the 2-day group (comprised of 502 patients) and 8% (n = 41) of the 5-day group (comprised of 503 patients). The absolute risk difference, adjusted for age and severity of appendicitis, was 2% (95% confidence interval [CI], -1.6–5.6). This was not in excess of the pre-specified non-inferiority margin of 7.5%, finding the 2-day course non-inferior to 5-day. The rate of complications and reinterventions was similar in both groups. Adverse effects to antibiotics were less common in the 2-day group (9% vs 22%; odds ratio, [OR] 0.34; 95% CI, 0.24–0.50). Total length of hospital stay (including readmissions) was shorter in the 2-day group (median 3 days vs 5 days) however re-admission was more common (12% vs 6%; OR, 2.14; 95% CI, 1.34–3.40).

While non-inferiority of the 2-day regimen was demonstrated for laparoscopic appendectomy, it is not clear whether the results are applicable to open appendectomy due to insufficient patients (n = 50, 5%). Further adequately powered studies are required in this patient population.

de Wijkerslooth EML, Boerma E-JG, van Rossem CC, van Rosmalen J, Baeten CIM, Beverdam FH, et al. 2 days versus 5 days of postoperative antibiotics for complex appendicitis: A pragmatic, open-label, multicentre, non-inferiority randomised trial. Lancet 2023; 401: 366–76.

Oral prophylaxis after colorectal surgery

The Comparison of Intravenous versus Combined Oral and Intravenous Antimicrobial Prophylaxis (COMBINE) trial was a multicentre, randomised, double-blind placebo-controlled trial conducted in 11 French hospitals. Eligible patients were scheduled for elective colorectal surgery (either laparoscopic or open), did not have an active bacterial infection at the time of surgery, and had not received antibacterial treatment in the two weeks prior. The primary outcome was surgical site infection within 30 days.

Nine hundred and sixty patients were enrolled, of which 926 were included in the intention-to-treat analysis. All patients received cefoxitin 2 g intravenously (IV) at least 30 minutes prior to surgical incision as prophylaxis, with an additional dose for surgeries ≥2 h. Patients were randomised to receive 1 g oral ornidazole or placebo 12 h prior to surgery. From 463 patients, mechanical bowel preparation (MBP) was conducted in 33% (n = 153) of the ornidazole group and 35% (n = 160) of the placebo group.

Analysis of data from the intention-to-treat population found that a single oral dose of 1 g ornidazole significantly reduced the risk of surgical site infection by 30 days (relative risk [RR] = 0.60; 95% CI, 0.45–0.80; p = 0.001).

There were however major limitations with this study. Midway through the study, the IV prophylaxis protocol was amended to include 1 g IV metronidazole, an antimicrobial with similar anaerobic cover to ornidazole. Six patients in each group received IV metronidazole. Fifty-eight patients in the intention-to-treat population deviated from the study protocol including receipt of an unspecified non-trial IV antibiotic. Obese patients (BMI > 35 kg/m2) who have greater risk of SSI were excluded. MBP was not randomised, rather at the discretion of the surgeon. In patients who did not undergo MBP, there was no significant difference in surgical site infection between oral prophylaxis and placebo (RR = 0.83; 95% CI, 0.58–1.19).

While this study reported a benefit of administering an oral nitroimidazole prior to colorectal surgery, it is unclear whether these results are relevant to the Australian setting where IV anaerobic cover is routinely recommended.

Futier E, Jaber S, Garot M, Vignaud M, Panis Y, Slim K, et al (on behalf of COMBINE study group). Effect of oral antimicrobial prophylaxis on surgical site infections after elective colorectal surgery: Multicentre, randomised, double blind, placebo controlled trial. BMJ 2022; 379: e071476

Antifungal dosing in patients on extracorporeal membrane oxygenation

This narrative review aimed to review the published evidence to determine the potential impact of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics (PK) of antifungal drugs to inform dosing requirements in critically ill adult patients on ECMO. Critically ill patients commonly exhibit altered PK including increased drug volume of distribution (Vd) and altered clearance. Sequestration of antifungal drugs onto the ECMO circuit may further increase the apparent Vd, with the extent of sequestration being determined by multiple factors related to the antifungal drug and the ECMO circuit.

The authors conducted a PubMed literature search, including pharmacokinetic or dosing studies up to July 2022, excluding animal and non-English studies. The majority of identified papers were ex vivo experiments, case reports and observational studies. For many antifungals there were insufficient or conflicting data however the available studies suggest that for the azole antifungals, moderate to significant loss to ECMO sequestration may occur with voriconazole, posaconazole and isavuconazole. Therapeutic Drug Monitoring (TDM)-guided dosing may assist for some azole antifungals to prevent sub-optimal blood concentrations during ECMO. For the echinocandin class, the available data suggests that Vd is increased due to moderate ECMO circuit loss for these antifungals. Moderate sequestration onto the ECMO circuit is also likely for liposomal amphotericin based on the available data.

The review highlights the paucity of published literature in this complex patient population. ECMO may further exacerbate altered pharmacokinetics in critically ill patients and this comprehensive narrative provides a useful overview of the various factors to consider in order to minimise the risk of underdosing (and therapeutic failure) or supratherapeutic concentrations (and toxicity) of antifungals.

Lyster H, Shekar K, Watt K, Reed A, Roberts JA, Abdul-Aziz, MH. Antifungal dosing in critically ill patients on extracorporeal membrane oxygenation. Clin Pharmacokinet 2023; 62: 931–42.

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LEADERSHIP AND MANAGEMENT

MedsScan Editors fpr #SHPALeadership: Jessica Toleman and Ed Anderson

Leadership and health care worker wellbeing

Healthcare worker (HCW) wellbeing and engagement are influenced by leadership. Good leadership can have a positive impact on safety climate, error reporting culture, adverse events and employee wellbeing. The Leadership scale of the Safety, Communication, Operational Reliability, and Engagement (SCORE) survey is a measure of common workplace issues.

A cross-sectional observational study of 16 797 survey respondents was undertaken. A SCORE survey was conducted across 31 hospitals in 2015 in Michigan, USA. The aim of this study was to understand the correlation (if any) between modifiable leadership behaviour domains (Local Leadership ‘LL’ scores) (e.g. level of accessibility to leaders and provision of regular feedback) and well-established measures of wellbeing, safety culture and engagement.

Overall, increasing LL scores (i.e. more perceived access to leaders and more regular provision of communication and feedback) correlated with positive improvements in safety climate, teamwork climate, emotional exhaustion, perceived workload and intentions to leave/resign. Each 10-point increase in LL was associated with a 28.3% reduction in the odds of emotional exhaustion (burnout), 51.9% reduction in the odds of concerning safety climate, 35.7% reduction in the odds of concerning teamwork climate, 9.7% reduction in odds of high perceived workload, and 20.1% reduction in the odds of intention to leave/resign.

Local leadership behaviours are measurable and strongly associated with established domains of health care worker wellbeing, safety culture, and engagement. Development of leadership behaviours by pharmacy leaders may lower healthcare worker emotional exhaustion (burnout) and lead to an improved safety climate, better teamwork climate, and lower perceived workload and intentions to leave in the workplace.

Tawfik DS, Adair KC, Palassof S, Sexton JB, Levoy E, Frankel A, et al. Leadership Behavior Associations with Domains of Safety Culture, Engagement, and Health Care Worker Well-Being. Jt Comm J Qual Patient Saf 2023; 49: 156–65.

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MEDICINES INFORMATION

MedsScan Editor for #SHPAMedsInf: Helen Trenerry

Comparison of medicine information resources on COVID-19 medications in pregnancy and lactation

Infection with COVID-19 during pregnancy has resulted in significant respiratory complications, increased mortality and a higher risk of adverse outcomes such as pre-eclampsia, low birth weight and preterm birth. Clinicians seek reliable information on the safety of COVID-19 medicines during pregnancy and lactation.

Four expert reviewers analysed the information on 16 COVID-19 medicines from various medicine information resources (texts and online databases) for scope, completeness and consistency. Resources included Briggs, UpToDate, Drugs.com, Micromedex, Medscape, Portable Electronic Physician Information Database (PEPID) and LactMed. Resources were rated for each medicine into six recommendation categories to evaluate consistency between resources.

PEPID, UpToDate and Drugs.com achieved the highest scope scores while Micromedex and Drugs.com scored the highest for completeness. There was only slight agreement in recommendations and information between the resources for use of these medicines during pregnancy and lactation, especially for the newer medicines. Agreement by the reviewers rated from poor to fair for the categories of ‘not classifiable’ and ‘individual benefit-risk assessment’ and moderate for the ‘can be used’, ‘should not be used’ and ‘no available information’ categories.

Completeness was based on information on the safety of the medicine in pregnancy and/or lactation, breast milk concentrations, reproductive risk/fertility and pregnancy category or recommendation. LactMed was the sole lactation resource (information for all 16 medicines) but rated poorly for completeness as there was no information for pregnancy or reproductive risk/fertility. There are inconsistencies in information resources for COVID-19 medicines in pregnancy and lactation. Medicine information pharmacists are essential for the interpretation of information about the safety of medicines in pregnancy and lactation.

Shareef J, Sridhar SB, Bhupathyraaj M, Shariff A, Thomas S, Karattuthodi MS. Assessment of the scope, completeness, and consistency of various drug information resources related to COVID-19 medications in pregnancy and lactation. BMC Pregnancy Childbirth 2023; 23: 296.

Physicians’ perceptions of the impact of pharmacists in ambulatory care clinics

Clinical pharmacists have expanded their scope as integral members of the ambulatory care clinic team. They work with doctors and other healthcare providers (HCPs) to optimise medicine use and patient care. Information on patients’ experiences with a pharmacist has been published but little information is available on HCPs perceptions of the value of a pharmacist on the work environment in ambulatory care clinics.

Semi-structured interviews were conducted with 14 HCPs to identify themes for questions to be included in a survey. This survey was then sent to 202 potential participants at six sites. Participants ranked their level of agreement (using a Likert scale) on how a clinical pharmacist impacts the work environment, workload and level of burnout. They also rated the services provided by the clinical pharmacist and their utilisation of these services.

Forty-three (of 48) surveys returned were analysed (21% response rate). The clinical pharmacist had a positive impact on work environment, workload, work-related stress and burnout.  Clinical pharmacists are a knowledgeable resource, reducing the health care providers (HCPs) time spent by sharing patient care responsibilities. HCPs who were moderate to high utilisers of the pharmacy services had a more positive perception of their impact. Work commitments limited availability and impacted utilisation of clinical pharmacists in clinics.

HCPs working collaboratively with clinical pharmacists in ambulatory care clinics perceive a positive impact on their workload and associated work-related stress and burnout. Clinical pharmacists are a valuable resource to HCPs for medicines information and optimising patient care.

Elliott AN, Buzzard LN, Villa KR, Gadbois NR. Physicians’ and advanced practice providers’ perceptions of the impact of embedded clinical pharmacists on the work environment in ambulatory care clinics. Am J Health Syst Pharm. 2023; 80: 200–6.

Multiple switching of biosimilars: Is it safe and effective?

There are increasing numbers of biosimilars on the market resulting in switching from the originator product. The most common reason for switching is the cheaper cost of the biosimilar, although it may also occur for clinical reasons and/or patient acceptability. A single switch from the originator to the biosimilar was most common but now, with several biosimilars available for any one originator, multiple switches are also occurring.

A literature review of PubMed was conducted to assess the safety and effectiveness of multiple switches between the originator and/or biosimilars. Studies that included a single switch, guidelines or expert opinions were excluded. Descriptive analysis methods were used to report safety and efficacy in these studies.

Fifteen studies (11 observational and four clinical trials) involving multiple biosimilar switching were considered. Most (80%) of the studies evaluated double switching, while only three studies evaluated more than two switches. Inflammatory bowel disease (IBD) and psoriasis were the most common conditions (12 of 15 studies) where switching of biosimilars occurred. Seven studies reported switching with an infliximab biosimilar. In 14 out of 15 studies, economic reasons were used for justification of switching with a biosimilar. The effectiveness and safety of two or more switches with biosimilars was comparable to patients who had no, or only one switch.

There is limited information on more than two switches with biosimilars and the evidence for double switching is strongest with IBD and psoriasis. More evidence is needed to establish the safety of multiple switching with biosimilars, especially with epoetin and in the oncology-haematology space.

Lasala R, Abrate P, Zovi A, Santolen F. Safety and effectiveness of multiple switching between originators and biosimilars: Literature review and status report on interchangeability. Ther Innov Regul Sci 2023; 57: 352–64.

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MENTAL HEALTH

MedsScan Editor for #SHPAMentalHealth: Judy Longworth

Long-term use of methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder

This paper solves a long-time deficit in the lack of long-term studies into the adverse effects of methylphenidate on growing children and adolescents. The study was set up under the auspices of the European Medicines Authority and conducted in 25 European child and adolescent mental health centres. Participants were aged 6–17 years (average 9.28 years) during 2012 - 2016. Attention-deficit/hyperactivity disorder (ADHD) was diagnosed according to the DSM-IV criteria with minimal inclusion and exclusion criteria to ensure generalisability of the study.

A total of 756 participants were recruited to the methylphenidate group, 391 participants to the no-methylphenidate but diagnosed ADHD, and 263 participants to the control group. There was high loss to follow-up with only 53.5% attending the final visit at two years. Psychometric parameters used included the SNAP-IV (Swanson, Nolan and Pelham IV rating scale) and the SDQ (Strengths and Difficulties Questionnaire).  

Overall, contrary to the findings of previously reported meta-analyses of methylphenidate studies, there was no difference in the effects on growth (height and weight trajectories) in the methylphenidate group versus the other groups, suggesting that treatment with methylphenidate for 2 years is safe. There was also no increased risk of psychiatric or neurological adverse effects detected, although higher levels of suicidal behaviours were shown in the methylphenidate group compared with the no-methylphenidate group, prior to the study, which may be attributed to increased severity of ADHD and indicate the need to assess and medicate.

Although further long-term studies are needed, this goes someway to fulfilling a need, but as with many paediatric medicines the long-term consequences of continued use are not always reported.

Man KKC, Häge A, Banaschewski T, Inglis S, 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.

British Association for Psychopharmacology recommendations for the management of catatonia

These are the most recent British Association for Psychopharmacology guidelines, and are open access and available as pdfs at www.bap.org.uk. These cover the many forms of catatonia that may be referred to a mental health practitioner from child and adolescent to geriatric, as well as neurodevelopmental (autism), pregnancy and considerations for physical illness conditions in kidney, liver and lung disease. Catatonia presents as a wide range of clinical signs but there is no gold standard biomarker. Response to benzodiazepines is considered a surrogate biomarker but this can also be non-universal.

As signs of catatonia are not uncommon and can occur in many medical, as well as psychiatric conditions, a standard definition for this paper was required. The consensus definition for catatonia was based on the presence of three or more catatonic signs as in DSM-5-TR or ICD-11. As well as describing the clinical features of catatonia, there is a list of important medical conditions that may underlie catatonia. Assessment for the presence of catatonia is also described, as is the evaluation of treatment with psychometric testing, with the different tests also evaluated.

Treatments evaluated included the use of lorazepam and other GABA-ergic medicines, as well as electroconvulsive therapy and emerging therapies including NMDA receptor antagonists, such as amantadine and memantine, as well as the use of dopamine receptor antagonists and partial agonists.

Throughout the guidelines, there are recommendations for the overall treatment and evaluation of catatonia that are useful for any medical practitioner. This reference could be handy when developing local guidelines for catatonia or for designing research aimed at generating a more robust evidence base for treatment.

Rogers JP, Oldham MA, Fricchione G, Norrthoff G, Wilson JE, Mann SC et al Evidence-based consensus guidelines for the management of catatonia: Recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2023; 37: 327–69.

Impact of psilocybin and methylenedioxymethamphetamine on mental, behavioural or developmental disorders

Effective from 1 July 2023, the Australian scheduling of both psilocybin and methylenedioxymethamphetamine (MDMA) was changed to allow for prescribing of MDMA for post-traumatic stress disorder (PTSD), and psilocybin for treatment resistant depression (TRD).1 This down-scheduling has resulted in much discussion as alluded to in Rossell et al. and Kisely.2,3

This paper is a comprehensive literature review covering the latest information about the use of both medications using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Resulting in review and analysis of eight studies for MDMA and six for psilocybin and for clinical conditions including PTSD, TRD, obsessive-compulsive disorder, social anxiety in adults with autism, and anxiety or depression in life-threatening disease (LTD).

The eight studies for MDMA (n = 212 participants) included six for PTSD and all were parallel arm randomised controlled trials. MDMA was well tolerated in all studies with the five most common adverse effects being anxiety, fatigue, jaw clenching, reduced appetite and headache, all immediately after administration. The six studies for psilocybin covered anxiety, depression, obsessive-compulsive disorder and long standing or treatment resistant depression. Reported adverse effects were similar to those reported with MDMA and there was a significantly better response seen than the response seen with escitalopram in the comparison study.

Study bias was not optimal and included bias in allocation, follow-up and funding across the studies. However, in highly supported and structured environments, including intense psychotherapy, especially with MDMA, it appears that the interaction between the mechanisms of action of both agents and concurrent psychotherapy contributed to the success of therapy. Further research given the study limitations will need to be carried out to ensure the long-term viability of these treatments.

Kisely S, Connor M, Somogyi AA, Siskind D. A systematic literature review and meta-analysis of the effect of psilocybin and methylenedioxymethamphetamine on mental, behavioural or developmental disorders. Aust N Z J Psychiatry 2023; 57: 362–78.

References

  1. Therapeutic Goods Administration. Change to classification of psilocybin and MDMA to enable prescribing by authorised psychiatrists. Canberra: Commonwealth of Australia; 2023. Available from https://www.tga.gov.au/news/media-releases/change-classification-psilocybin-and-mdma-enable-prescribing-authorised-psychiatrists. Accessed 26 June 2023.
  2. Kisely S. The down-scheduling of MDMA and psilocybin(e): Too fast and too soon. Aust N Z J Psychiatry 2023; 57: 933–4.
  3. Rossell SL, Meikle SE, Williams ML, Castle DJ. Why didn’t the TGA consult with Australian researcher and clinicians with experience in psilocybin-assisted psychotherapy for treatment-resistant major depressive disorder? Aust N Z J Psychiatry 2023; 57: 935–6.

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NEPHROLOGY

MedsScan Editor for #SHPA: Jess Lloyd

Impact of sodium bicarbonate on slowing graft function decline in Swiss kidney transplant patients

Special contributor: Teana Brewster-O’Brien

Correction of metabolic acidosis with oral sodium bicarbonate in non-transplant chronic kidney disease is recommended by kidney health organisations to delay loss of kidney function. It has been argued that evidence of reduction in injury and rate of decline as a result of sodium bicarbonate administration is of low certainty.1 In the Preserve-Transplant study, Mohebbi et al., investigated the efficacy of this intervention for the kidney transplant cohort. 

Preserve-Transplant was prospective, single-blinded, randomised and placebo-controlled. It compared the efficacy of oral sodium bicarbonate supplementation or placebo on delaying progression of estimated Glomerular Filtration Rate (eGFR) loss in 242 kidney transplant patients. The primary endpoint was eGFR slope over the two-year treatment period. Patients aged 18 and over with a serum bicarbonate of 22 mmol/L or less and a stable graft over one year old were included. The baseline mean eGFR for both cohorts was 47.7 mL/min (placebo) and 48.2 mL/min (control).

Sodium bicarbonate did not delay decline of eGFR for kidney transplant recipients with metabolic acidosis (mean difference in estimated GFR slope 0.032 mL/min per 1.73 m2 per year; 95% CI –1.644–1.707) despite correcting metabolic acidosis. There was no difference in the primary endpoint between cohorts and there was no beneficial effect of sodium bicarbonate seen in subgroup analysis. The mean sodium bicarbonate dose was six tablets (3000 mg).  Rates of hypertension and fluid overload were similar and while infrequent, hypokalaemia occurred at a higher rate in the sodium bicarbonate group. 

This is the first study to evaluate the efficacy of sodium bicarbonate in preventing functional decline of kidney transplants due to metabolic acidosis. It highlights that evidence for the chronic kidney disease (CKD) population may not be directly translatable to those with CKD post-transplant. While the intervention did not demonstrate benefit in delaying eGFR decline, the study was not designed to measure the impact on reducing progression of bone disease and hyperkalaemia.

A reduction in use of sodium bicarbonate post-transplant will reduce tablet burden, regimen complexity and patient costs. The application of the results of this clinical trial should be explored by pharmacists working in Australian transplant units.

References

  1. Chen W, Levy DS, Abramowitz MK. Acid base balance and progression of kidney disease. Semin Nephrol 2019: 39: 406–17.

Mohebbi N, Ritter A, Wiegand A, Graf N, Dahdal S, Sidler D, et al. Sodium bicarbonate for kidney transplant recipients with metabolic acidosis in Switzerland: A multicentre, randomised, single-blind, placebo-controlled, phase 3 trail. Lancet 2023; 401: 557–67.

More weight added to the STOP-ACEi (angiotensin-converting enzyme inhibitors) debate

Special Contributor: Xanthe Cross

Data from previous trials has been inconsistent regarding whether the use of renin angiotensin system (RAS) inhibitors is nephroprotective in patients with advanced chronic kidney disease (CKD).1,2,3,4

STOP-ACEi (angiotensin-converting enzyme inhibitors) was a multi-centre, open label, randomised controlled clinical trial comparing continuation to discontinuation of RAS inhibitors in advanced CKD. The trial enrolled adults over 18 years of age with progressive stage 4–5 CKD. The primary endpoint was to determine whether discontinuing RAS inhibitors in this population would increase or stabilise estimated Glomerular Filtration Rate (eGFR). At three years, among the 411 patients enrolled, the mean eGFR was 12.6 ± 0.7 mL/min/1.73m2 in the discontinuation group and 13.3 ± 0.6 mL/min/1.73m2 in the continuation group (difference, -0.7; 95% confidence interval [CI], -2.5–1.0; P = 0.42). The discontinuation of RAS inhibitors was not associated with a significant between-group difference in the long-term rate of decrease in the eGFR. Adverse events were similar in the discontinuation group and continuation group with respect to cardiovascular events (108 vs 88) and deaths (20 vs 22).

The STOP-ACEi trial showed that discontinuation of RAS inhibitors in patients with advanced and progressive CKD did not lead to a clinically relevant change in the eGFR or a between-group difference in the long-term rate of decline in eGFR. This was a large UK study with limited ethnic diversity, and thus the applicability to wider populations is unknown. In an Australian context, there is limited data to direct practice considering Aboriginal and Torres Strait Islander peoples.

The decision to continue or discontinue RAS inhibitors should be made in the context of the individual patient, considering factors such as blood pressure control, electrolytes, proteinuria, tolerability and cardiovascular risk profile. Pharmacists are well placed to provide evidence-based advice on the risks and benefits of continuation or otherwise of RAS inhibitors to assist with risk mitigation in this highly complex patient population.

References

  1. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851–60.
  2. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin converting–enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329: 1456–62.
  3. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861–9.
  4. Ahmed AK, Kamath NS, El Kossi M, El Nahas AM. The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced chronic kidney disease. Nephrol Dial Transplant 2010; 25: 3977–82.

Bhandari S, Mehta S, Khwaja A, Cleland JGF, Ives N, Brettell E, et al. Renin-angiotensin system inhibition in advanced chronic kidney disease. N Engl J Med 2022; 387: 2021–32.

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PAIN MANAGEMENT

MedsScan Editor for #SHPAPainMgmt: Shania Liu

Comparing the risk of persistent postoperative pain between discharge opioids

Special contributor: Crystal Ucarer

Opioids are prescribed in 70% of surgical patients, with 1 in 6 Australian adults utilising opioids each year. Although immediate release (IR) formulations are recommended post operatively, long term use may lead to adverse outcomes such as an increased risk of falls, constipation, opioid dependence, and opioid-induced hyperalgesia. This observational study by Lam et al. examined prescription data across hospital and community settings in Australia.

The study used logistic regression models to compare the rates of persistent opioid use, with primary outcomes measured at 3 and 6 months post- operatively for oxycodone, tapentadol and mixed opioid prescriptions on discharge. The study assessed 122 836 patients between 2016 and 2021. Opioid release profiles were considered and dose escalation was deemed significant if the dose increased to 120% of the oral morphine equivalent dose at 6 months. Comorbidities and factors associated with increased risk of persistent opioid use included: preoperative opioid use, female gender, history of alcohol or nicotine dependence and psychotropic use.

At the 3-month milestone, 2.3% of opioid-naïve and 27.24% of opioid-experienced patients continued to receive opioids for postoperative pain. Whereas, at the 6-month milestone, 0.5% of opioid-naïve and 17% of opioid-experienced patients continued to use opioids. The prevalence of dose escalation for IR formulations was evident in both opioid-naïve and -experienced patients at 11.1% and 21.6% respectively. Overall, tapentadol displayed a significantly lower odds ratio (OR) compared with oxycodone, with lower persistence in both opioid-naïve (OR = 0.81; 95% confidence interval [CI] 0.69–0.94) and -experienced patients (OR = 0.91; 95% CI 0.71–0.93) at both milestones, regardless of the formulation type.

The findings of this study may be utilised in future practice as, compared to oxycodone, tapentadol is preferred in patients with risk factors, especially preoperative opioid use, discharge on modified-release opioids and for orthopaedic surgery.

Lam T, Xia T, Biggs N, Treloar M, Cheng O, Kabu K, et al. Effect of discharge opioid on persistent postoperative opioid use: a retrospective cohort study comparing tapentadol with oxycodone. Anaesthesia 2023; 78: 420–31.

Machine learning to target prolonged postoperative opioid use

Special contributor: Gabrielle Widjaja

Opioid misuse is a rising burden on the healthcare system and prescription opioids are routinely prescribed after orthopaedic surgery. Machine learning is a type of artificial intelligence that can be implemented to extract patient risk factors that may predict prolonged postoperative opioid use. These risk factors may then open the opportunity for individualised patient interventions.

This paper was a systematic review of PubMed, EMBASE, and Web of Science to identify literature that analysed the application of machine learning to predict prolonged postoperative opioid use after orthopaedic procedures. Krivicich et al. found a total of 10 studies that utilised machine learning models in spinal (40%), knee (30%) and hip (30%) surgery. Rates of prolonged opioid use after orthopaedic surgery ranged from 4.3% to 40.9%. Machine learning models across the studies identified several risk factors for prolonged postoperative opioid use, including preoperative opioid use, preoperative antidepressant use, and preoperative benzodiazepine use. Age was also cited as a risk factor, however, specified age groups at risk varied across the literature.

Although predictive modelling still requires external validation, machine learning can play a valuable role in developing individualised patient care and assisting with reduction in the rate of prolonged opioid use.

Krivicich LM, Jan K, Kunze KN, Rice M, Nho SJ. Machine learning algorithms can be reliably leveraged to identify patients at high risk of prolonged postoperative opioid use following orthopedic surgery: a systematic review. HSS Journal 2023 [published online before print].

Organisational interventions and their effect on appropriate opioid prescribing upon hospital discharge

Special contributor: Prue Anderson

Opioids are still prescribed in amounts that are in excess of patients’ needs on hospital discharge. This excess of opioids within the community has led to a rise in negative effects such as opioid misuse, overdose, dependence and tolerance. 

In light of this inappropriate opioid prescribing, Phinn et al. performed a systematic review to examine the effectiveness of opioid-prescribing organisational interventions, among all patients upon hospital discharge. Due to a rapid increase in opioid overdose deaths after 2010, this study only included research articles published during the last 10 years that reported quantitative outcomes of organisation-led interventions specifically targeting appropriate opioid prescribing for non-cancer pain upon hospital discharge.

There were 43 studies included, of which 16 introduced multifaceted interventions, 13 implemented local guidelines, 11 utilised educational interventions and 3 studies re-programmed electronic medical records to decrease the default supply of opioids upon discharge. The largest reduction in opioid prescribing upon hospital discharge was seen guidelines and protocols were implemented to guide and improve opioid prescribing, which saw reductions in number of patients discharged with an opioid of up to 93%. Other interventions (e.g., prescriber education) reduced opioid prescribing on hospital discharge by 20-59%.

The implementation of prescribing guidelines, improving prescriber education, and decreasing default opioid prescription quantities were all effective in improving appropriate opioid prescribing for patients upon hospital discharge. While multimodal interventions produced significant reductions in discharge opioid prescribing, the extent of prescribing reduction was similar with simpler interventions that are more cost-effective and easily employed within existing hospital systems. This research highlights that the role of hospital pharmacists could be further utilised by contributing to the development of standardised guidelines and protocols that guide discharge planning and ultimately reduce inappropriate opioid prescribing.  

Phinn K, Liu S, Patanwala AE, Penm J. Effectiveness of organizational interventions on appropriate opioid prescribing for noncancer pain upon hospital discharge: a systematic review. Br J Clin Pharmacol 2023; 89: 982–1002.

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RESEARCH

MedsScan Editors for #SHPAResearch: Sid Patanwala and Jacinta Johnson

The Granada Statements: Guidance for pharmacy practice research

In June 2022, a group of editors of pharmacy practice journals met in Granada, Spain. The editors aimed to improve the quality of articles that are published by pharmacy practice researchers by providing a set of recommendations to journals. The intent was to strengthen pharmacy practice as a discipline. This event was driven by the acknowledgement of challenges related to pharmacy practice research, which were impeding progress of the discipline and having deleterious impacts on researchers within the field.

Based on consensus opinion, the editors provided 18 recommendations pertaining to six topic areas. Some key recommendations pertained to establishing standardised terminology to describe pharmacy practice research. Researchers should strategically use existing Medical Subject Headings (MeSH) terms within titles and abstracts. This will improve the visibility and retrieval of pertinent studies for policymaking. The importance of peer review was highlighted with suggestions for engagement of peer reviewers, provision of adequate credit and editorial oversight. The recommendations highlighted the academic environment that incentivises researchers based on journal impact metrics, which are not synonymous with research quality. Researchers can enable change within their institutions to wisely utilise such metrics. They emphasised that authors should consider pharmacy practice journals for their ‘best’ work to advance the discipline, and for editors to guide authors to the most appropriate journals based on scope. The hope of these recommendations is to advance pharmacy practice as a scientific discipline.

Fernandez-Llimos F, Desselle S, Stewart D, Garcia-Cardenas V, Babar ZU, Bond C, et al. Improving the quality of publications in and advancing the paradigms of clinical and social pharmacy practice research: The Granada statements. Res Social Adm Pharm 2023; 19: 830–5.

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