MedsScan Issue 1, 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

Stability of a sterile compounded morphine hydrogel application for treating painful skin ulcers

Alleviating skin ulcer pain is difficult. The use of morphine topically in a sterile hydrogel formation has been noted to achieve optimal pain relief via peripheral nociceptive nerve endings present while concurrently avoiding systemic adverse effects. This study from the Netherlands describes the method of compounding a 0.5% w/w morphine chloride hydrogel formulation, packing it in a sterile plastic prefillable syringe system BD Sterifill SCF, and steam sterilising it to give 20 months stability.

The study outlines the following process: 500 mg of morphine hydrochloride was dissolved in distilled water warmed to 80°C and mixed with 22 g Poloxamer 407 in a melamine mortar; then a mixture of 75 mg carmellose sodium and 20 g glycerol was added and mixed until homogenous; the cooled mixture was made up to 100 g with sterile water. The resulting mixture was refrigerated, which liquefied it and allowed air to escape; then 5 g of liquid was poured into each syringe. A total of three batches of 64 syringes were produced. Two syringes from each batch were used to carry out a bioburden test and the rest were sterilised for 15 min at 121°C in a rain system autoclave. They were stored between 15°C–25°C protected from light. European Pharmacopoeia grade pharmaceuticals, standards, tests and validated processes were used throughout the study. The membrane filtration method was utilised for the sterility test. Morphine levels were evaluated using a validated HPLC method, and measurements were taken monthly from a randomly selected sample from each batch for the three years.

The bioburden test of two batches showed no growth, while the third batch showed only three Colony Forming Units (CFU) which passed the hospital limit of 20 CFU attesting to no excessive contamination prior to sterilisation. Six syringes per batch were tested for sterility after the steam sterilisation and at 20 months, showing no growth in any sample. The morphine hydrochloride concentrations remained stable between 90%–110% for the 36 months.

There is currently no sterile morphine hydrochloride gel formulation in a ready to use container available on the market. This study presents stability and formulation information allowing its replication in a compounding pharmacy in Australia and improving the availability of a sterile morphine hydrogel to treat painful skin ulcers.

Jansen MMPM, Waas VPHV, Verzijl JM, Burger D. Development of a sterile morphine hydrogel for the local treatment of painful skin ulcers. Eur J Hosp Pharm 2021; 28:331–5.

Physicochemical stability of a novel tacrolimus ophthalmic formulation

A number of different inflammatory ophthalmic complaints are treated with tacrolimus as an immunosuppressant. Currently, commercially produced tacrolimus ophthalmic formulations that are safe are not available, limiting patient treatment options. This European study aimed to develop two different concentration formulations of tacrolimus ophthalmic solutions that are physicochemically stable.

The International Conference on Harmonisation (ICH) for stability studies and recommendations issued by the French Society of Clinical Pharmacy (SFPC) and by the Evaluation and Research Group on Protection in Controlled Atmosphere (GERPAC); as well as European Pharmacopeia standards were followed throughout the study. Ophthalmic solutions of 0.2 mg/mL and 1 mg/mL were prepared by dissolving tacrolimus powder in absolute ethanol and gently agitating it at room temperature, followed by the addition of Kolliphor EL (KEL) and vigorous mechanical mixing. Hydrogen phosphate–hyaluronate buffer solution was added to stabilise pH. Final solutions were filtered using a 0.22 µm filter Stericup, then aseptically repartitioned in an ISO 4.8 microbiological safety cabinet using a Baxter repeater pump. Then 5 mL aliquots were filled into low-density polyethylene multidose eye droppers with a sterility preserving system (Novelia nozzle).

Formulations were studied in the dark at 60 ± 5% relative humidity and 5 ± 3 °C, 25 ±1 °C and 35 ± 1 °C. On Day 0 (immediately after preparation) then at months 1, 2, 3, 4, 6, 8 and 9 (i.e., M1, M2, M3, M4, M6, M8, M9), four units at each temperature and each concentration were analysed. And additionally, for both concentrations, 28 days after eight months of storage at 5°C, a simulation of patient use was done as one drop used twice daily for one month (except weekends) with the drops tested for tacrolimus concentrations. The remaining solution also underwent full analysis including validated HPLC quantification, pH, osmolality, visual inspection, chromaticity and luminance analysis, sterility assay and the use of degradation kinetics during storage.

The stability of tacrolimus was affected by increased storage temperatures. All assay results for visual aspect, turbidity, micelle size, viscosity, pH and osmolality favoured a physicochemical stability of nine months at 5°C. Interestingly, a t90 value of 3.71 months was also calculated from degradation data.

This study provides useful stability data for tacrolimus eye drop formulation which could be prepared in a hospital pharmacy in Australia giving patients another potential option for ophthalmic treatment.

Barrieu M, Chennell P, Yessaad M, Bouattour Y, Wasiak M, Jouannet M, et al. Physicochemical Stability of a Novel Tacrolimus Ophthalmic Formulation for the Treatment of Ophthalmic Inflammatory Diseases. Pharmaceutics 2022; 14: 118.

90-day and in-use stability of ophthalmic voriconazole 10 mg/mL solution

Fungal keratitis can cause severe infectious keratitis requiring the immediate administration of antifungal eye drops to reduce the risk of damage and blindness. Natamycin 5% is the only eye drop formulation available commercially but it is only effective for superficial infections. This French study evaluates the physicochemical and microbiological stability of ophthalmic voriconazole solution which has good eye penetration and has a broad spectrum of activity.

Batches of voriconazole ophthalmic solution (10 mg/mL) were aseptically prepared by reconstituting 200 mg Voriconazole Arrow lyophilised powder for injection (has excipients) with 19 mL of water for injection. Aliquots of 10mL of this solution were filtered using a 0.22 µm filter and transferred to sterile High-Density-Polyethylene (HDPE) eye drop containers either with a sterile preserving cap by Novelia or without one using Pureflow technology sourced from CAT Laboratory. The International Conference on Harmonisation (ICH) for stability studies and recommendations issued by the French Society of Clinical Pharmacy (SFPC) and by the Evaluation and Research Group on Protection in Controlled Atmosphere (GERPAC); as well as European Pharmacopeia standards were utilised throughout the study. From the 24 samples stored at 2–8°C and protected from light, 12 were used for physicochemical analysis. The remaining 12 samples underwent sterility tests using the filtration method on Day 0 (D0) and Day 90 (D90); and additionally, 15 days after a simulated daily extraction of three drops (D90 + 15). An eye drop solution of 1 mL was filtered using 0.45 µm hydrophilic PVDF (Polyvinylidene Fluoride) (Merck Millipore) membrane, then rinsed, followed by incubation at 25°C and 37°C in 50 mL of trypticase soja broth for 14 days. A validated HPLC analytical method was used for stability testing in triplicate on three different batches. The stability was defined as concentration after 90 days staying between 90–110% of first concentration (100%).

Sterility was shown by zero growth for both containers at D0 and D90 and only for the sterile preserving cap container at D90 + 15. Of the three non-sterile preserving cap containers, one showed microbial growth. HPLC, particle counting, pH, osmolality and visual observation results were all found to be stable through D0–D90.

The absence of an effective broad spectrum commercial antifungal ophthalmic formulation contributes to a significant risk of blindness for patients with fungal keratitis. This study supplies a useful and easy method of preparing voriconazole eye drops aseptically in Australian hospitals that would greatly reduce this risk.

Khan A, A. Venet A, Bernadou J-M, Cresto S, Servant V, Boulestreau H, et al. Stability of voriconazole 10 mg/mL ophthalmic solution for 90 days. Pharm Technol Hosp Pharm 2022; 7: 20210010.

ELECTRONIC MEDICATION MANAGEMENT

MedsScan Editor for #eMM: James Grant

The future of big data: A review of the utilisation of big data in hospitals to create value

Special Contributor: Nadine Tey

The use of big data analytics (BDA) to improve processes and key decisions has been utilised in other sectors and industries, however little is known on the utilisation and impact of BDA in hospitals. This paper describes a scoping review aimed at providing an overview on the use of BDA in hospitals. A literature review was conducted, and 94 articles met the criteria for analysis. 

In healthcare, there are five BDA capabilities (traceability, interoperability, analytical capability, predictive capability, decision support capability) within the three steps of the BDA process (data acquisition, data analysis, data interpretation). A combination of capabilities is required to enable the full utilisation of BDA. The articles analysed had a range of combinations of capabilities studied. 

The BDA analytics created are used to drive value creation mechanisms (VCM), identify value targets, and pursue these targets with the aim of realising benefits. Of the five VCMs, the most common mechanism found in the literature was enabling discovery and experimentation. Improving the quality of decision-making was the most frequent value target, and can be applied to both clinical (e.g., drug-drug interactions, disease diagnosis) and administrative settings (e.g., resource allocation). Only a subset of articles described benefits, as most of the articles analysed are experimental, proof of concepts. 

There is a growing interest in the use of BDA in hospitals, and this study demonstrated that there is the potential for the utilisation of BDA to create value and result in benefits to healthcare organisations. However, there is currently still a knowledge gap between the potential utilisation of BDA and the actual impacts of doing so, and the authors recommend that this is the priority area for upcoming research.

Brossard PY, Minvielle E, Sicotte C. The path from big data analytics capabilities to value in hospitals: a scoping review. BMC Health Serv Res 2022; 22: 134.

A ‘patient-centric implementation strategy’ of an Electronic Medication Management System and the facilitators and barriers to a successful adoption

Special Contributor: Nadine Tey

This paper describes the implementation of an electronic medication management system (EMMS) in a major tertiary hospital in Sydney using focus groups to explore the facilitators and barriers to successful implementation and adoption of an EMMS. A unique patient-centric implementation strategy was used — with the guiding principle of ‘one patient, one chart’ — on the day of implementation, only new patients were started on the EMMS, with existing patients remaining on paper charts. 

Four focus groups of approximately 60 minutes each were conducted with doctors, nurses, pharmacists, and the implementation team (consisting of clinicians from various disciplines). Five themes and twenty-three sub-themes were identified and mapped to the four key constructs of the Unified Theory of Acceptance and Use of Technology (UTAUT) model. The majority of the sub-themes identified were facilitators to successful adoption. The five themes identified were: implementation strategy; organisational benefits; individual impact of EMMS; IT product; and organisation culture.

Few research studies focus on the implementation team’s perspective, and this provided unique yet critical insights on a successful implementation and adoption of an EMMS. Some factors identified by the implementation team included a strong clinical lead and stakeholder engagement, the role of administrative support, the importance of organisational readiness, and learning from the lessons of other organisations that have implemented an EMMS.

Vaghasiya MR, Penm J., Kuan KKY, Gunja N, Liu Y, Kim ED, et al. Implementation of an electronic medication management system in a large tertiary hospital: a case of qualitative inquiry. BMC Med Inform Decis Mak 2021; 21: 226. 

A novel way to generate hard numbers on how much interoperability exists between electronic health records

Interoperability goes beyond interfacing between two or more systems. It means a system has the same meaning and intent for the key, or all, concepts as the other system(s). Of course, different software, different configurations and challenges in using standardised concepts mean the theory is often removed from practice. This study set out to quantify how interoperable a sample of five systems in 68 sites actually were, by comparing six medicines and six laboratory tests between them (12 concepts total). 

Bernstam et al., note several challenges in even starting the analysis which was based around counting the total number of software submitted variants of the 12 concepts to judge variance per concept. Details such as capitalisation become an issue like eGFR (estimated glomerular filtration rate) and EGFR (epidermal growth factor receptor) though not in all cases (e.g., paracetamol vs Paracetamol). 

A matrix, checking if each concept at each of the 68 sites would be understood at the other sites, yielded an approximate 65% chance that the concept would be understood at a site using the same software, and an approximate 21% chance that it would be understood at a site with different software. The mathematics to this approach is novel and not yet validated in terms of general applicability. 

Interestingly, the approach was ‘raw concepts’ with some data cleaning to allow for capitalisation, as one example, rather than the standard concept that the raw ones could have been mapped onto, which is the common current practice for sending data or information between systems. Consequently, it will underestimate how interoperable, with standard mapping, these systems are at present. 

Bernstam EV, Warner JL, Krauss JC, Ambinder E, Rubinstein WS, Komatsoulis G, et al. Quantitating and assessing interoperability between electronic health records. J Am Med Inform Assoc 2022; 29: 753–60.

Back to top

GENERAL MEDICINE

MedsScan Editor for #SHPAGenMed: Gail Edwards

Heart failure pharmacotherapy in the frail population

Special Contributor: Sarah McPhee

The incidence of heart failure (HF) nearly triples in individuals over the age of 75 when compared to those aged 55–65 years. Patients included in HF specific pharmacotherapy clinical trials are more likely to be younger with significantly less comorbidities and on fewer medicines than HF patients seen in clinical practice.

This retrospective study explored the impact of HF specific medications (beta blockers, ACEi, ARBs and MRA) on clinical outcomes of frail patients who were hospitalised with HF. All frail adult patients (n = 1406) who were hospitalised with HF over a period of eight years at two tertiary hospitals were included in the study. Frailty status was determined by the use of a hospital frailty risk score (HFRS). Primary outcomes included the days alive and out of hospital (DAOH) at 90 days following discharge, 30-day and 180-day mortality, length of hospital stay (LOS) and 30-day readmissions. Of 1406 frail HF patients, 1025 (72.9%) received HF specific pharmacotherapy compared with 381 (27.1%) who did not. Frail patients on pharmacotherapy were more likely to have an increased DOAH compared to those not on pharmacotherapy. Both 30-day and 180-day mortality were significantly lower in frail patients on HF pharmacotherapy. There were no significant differences in LOS and 30-day readmissions.

This study found that frail HF patients were less likely to be on HF pharmacotherapy than non-frail patients. This study also demonstrated the benefits of prescribing HF specific pharmacotherapy in some frail patients, noting the importance of considering a patient’s full clinical picture and goals of care.

Sharma Y, Horwood C, Hakendorf P, Thompson C. Benefits of heart failure-specific pharmacotherapy in frail hospitalised patients: a cross-sectional study. BMJ Open 2022; 12: e059905.

Evening or morning dosing? Cardiovascular outcomes in adults with hypertension

Special Contributor: Sam Watts

Hypertension is a prognostic indicator for poor cardiovascular outcomes such as cardiovascular death, myocardial infarction, ischaemic stoke and haemorrhagic stroke. Overnight hypertension is a key predictor of poor cardiovascular outcomes, with evening dosing of medicines previously being reported to prevent long-term sequalae of hypertension more than morning dosing.

This prospective, randomised, open-label, blinded endpoint, controlled, parallel-group superiority trial recruited patients >18 years of age in the National Health Service in the United Kingdom diagnosed with hypertension and taking at least one antihypertensive agent. Night shift workers and patients with multiple daily doses of antihypertensives were excluded.

There was not a significant difference for cardiovascular outcomes between morning and evening dosing groups. The composite outcome of vascular death or hospitalisation for non-fatal myocardial infarction or non-fatal stroke, analysed as the time to first event, occurred in 362 (3.4%) patients in the evening dosing group compared to 390 (3.7%) assigned to morning dosing (unadjusted hazard ratio 0.95 [95% confidence interval 0·83–1.10]; p = 0.53).

Participants in the evening dosing group were slightly less likely to report falls (21.1% vs. 22.2%; p = 0.048).  Fewer patients reported one or more prespecified adverse events in the evening dosing group compared to morning (69.2% vs 70.5%; p = 0.041). Non-adherence to allocated dose timing at any point in the study was more common in those assigned to evening treatment than to morning treatment (39.0% vs 22.5%; p < 0.0001).

It can be concluded that the most effective dosing time to enhance adherence is one that suits the patient best. 

Mackenzie IS, Rogers A, Poulter NR, Williams B, Brown MJ, Webb DJ, et al. Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial. Lancet 2022; 400: 1417–25.

Safety and efficacy of rivaroxaban in patients with rheumatic disease-associated atrial fibrillation

Special Contributor: Krista Siason

In high-income countries, atrial fibrillation (AF) commonly develops due to advanced age, hypertension and ischaemic heart disease. However, in low-and middle-income countries, rheumatic heart disease remains an important cause of AF. AF increases the risk of embolic stroke. Trials have shown that non-vitamin K antagonist oral anticoagulants (non-VKAs) such as rivaroxaban are as effective as vitamin K antagonists (VKAs) for stroke prevention in AF. However, these trials excluded patients who had rheumatic disease-associated AF. The use of a non-VKA oral anticoagulant would be very useful in low- and middle-income countries where access to regular international normalised ratio (INR) monitoring and healthcare may be limited.

This randomised, noninferiority trial was conducted to investigate the safety and efficacy of rivaroxaban as compared to VKA therapy in patients with rheumatic disease-associated AF in Africa, Asia and Latin America. A total of 4565 patients were enrolled (mean age 50.5 years; 72.3% female) with 2292 patents assigned to the rivaroxaban group and 2273 patients to the VKA group. A primary outcome event (stroke, systemic embolism, myocardial infarction or death) occurred in 24.6% of patients in the rivaroxaban group and 19.8% in patients in the VKA group (proportional-hazards ratio, 1.25; 95% confidence interval [CI], 1.10–1.41). Rates of major bleeding did not differ significantly between the rivaroxaban group (1.8%) when compared to the VKA group (2.5%) (proportional-hazards ratio, 0.76; 95% CI, 0.51–1.15).

This trial showed that VKA therapy leads to lower rates of ischaemic stroke and mortality in patients with rheumatic heart disease-associated AF when compared to rivaroxaban without significantly increasing the rate of major bleeding. These results support the current guideline which recommends VKA therapy for stroke prevention in patients with rheumatic heart disease-associated AF.

Connolly SJ, Karthikeyan G, Ntsekhe M, Haileamlak A, El Sayeh A, El Ghamrawy A, et al. Rivaroxaban in rheumatic heart disease-associated atrial fibrillation. N Engl J Med 2022; 387: 978–98.

INFECTIOUS DISEASES

MedsScan Editor for #SHPAInfDis: Matthew Rawlins

Impact of infectious disease consultation for Pseudomonas aeruginosa bloodstream infection on health outcomes 

Special Contributor: Brett Coghill (Infectious Diseases Advanced Training Resident)

A retrospective cohort study from January 2012 through to December 2018 using the US Department of Veterans Affairs database, assessed the impact of Infectious Disease (ID) consults on the adequacy of treatment of Pseudomonas aeruginosa (PA) bloodstream infections (BSI) for adults. The primary outcomes were death in-hospital and 30-days after culture date. 

An ID consultation was determined by a clinical ID consult request within two weeks before or two weeks after the culture date, and only within a hospital admission timeframe. This time period was based on the usual treatment duration of two weeks for PA BSI. 

A total of 3256 patients had PA BSI, with 367 (11.3%) classified as multidrug resistant (MDR). The majority were male (97.5%), older than 65 years (71.2%) and white (70.9%). Half of the patients (50.8%, n = 1564) received at least one ID consult. Overall, the in-hospital and 30-day patient mortality was (23.3%, n = 759) and 26.0% respectively. The average time between the positive blood culture and ID consult was 2.5 days. After adjusting for risk factors, ID consultation for PA BSI reduced in-hospital death (odds ratio [OR], 0.47; 95% Confidence Interval [CI], 0.39–0.56), as well as 30-day mortality (OR, 0.51; 95% CI, 0.42–0.62). The mean time to ID consult did not differ for those who survived during hospitalisation, compared to those who did not (2.0 vs 2.1 days; P = 0.25), nor for those who survived at 30-days (2.0 vs 2.0 days; P = 0.56). 

ID consultation was associated with lower mortality among inpatients with PA BSIwho were veterans. Based on these findings, ID consults should be considered for all PA BSI patients. 

Ramanathan S, Albarillo FS, Fitzpatrick MA, Suda KJ, Poggensee L, Vivo A, et al. Infectious disease consults of Pseudomonas aeruginosa bloodstream infection and impact on health outcomes. Open Forum Infect Dis 2022; 9: ofac456.

PANORAMIC study of molnupiravir in COVID-19 outpatients with mild-moderate disease

A large, industry-funded, randomised, open-label study of 25 783 participants with mild-moderate COVID-19 in the community, evaluated the impact of molnupiravir. Patients were aged at least 50 years or were over 18 years old with comorbidities that put them at risk of severe disease and had confirmed COVID-19 for five days or less. Participants were randomised to molnupiravir 800 mg twice-daily plus usual care, or to usual care only and outcomes were self-recorded using an online diary. The primary outcome was all-cause hospitalisation or death within 28 days, analysed using Bayesian models. Secondary outcomes included time to self-reported recovery, time to alleviation of symptoms and adverse events. The primary analysis included 12 529 patients in the molnupiravir group and 12 525 in the usual care group. The mean age (standard deviation) was 56.6 years (12.6), 17 703 (69%) patients had comorbidities and 24 290 (94%) had received at least three vaccinations for COVID-19. There was no difference in hospitalisation or death between the groups; molnupiravir 105 (1%) versus usual care 98 (1%) adjusted odds ratio (aOR), 1.06 (95% Bayesian credible interval [BCI] 0.81–1.41; probability of superiority 0.33). The median time to first recovery was 10.4 days (95% BCI, 10.1–10.6) for molnupiravir recipients versus 14.6 days (95% BCI, 14.2–15.0) for usual care (hazard ratio 1.36 [95% BCI, 1.32–1.40]).  Serious adverse events were similar; 50 (0.4%) vs 45 (0.3%) and considered unrelated to molnupiravir. The median time to starting molnupiravir from symptom onset was three days (interquartile range 3–5).

The young, highly-vaccinated population make these results unsurprising, however there appears to be a self-reported benefit in symptom resolution with molnupiravir which may have been influenced by the open-label study design.

Butler CC, Hobbs FDR, Gbinigie OA, Rahman NM, Hayward G, Richards DB, et al. Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. Lancet 2022; 401: 281–93.

Managing antibiotics in pancreatitis with procalcitonin

A single-centre, prospective patient-blinded randomised controlled study in Manchester, UK was performed using a procalcitonin (PCT) algorithm to guide antibiotic use in adults with acute pancreatitis.

The PROCAP study randomly assigned adults 1:1 to PCT or usual care, according to disease severity and admission. In the PCT group, PCT testing occurred on days 0, 4, 7 and then weekly. A PCT of at least 1.0 nanogram(ng)/mL suggested the commencement or continuation of antibiotics, a result less than 1.0 ng/mL suggested not starting, or cessation of antibiotics. Antibiotics could be empirically commenced in the PCT group following PCT sampling. The primary outcome was the frequency of antibiotic prescribing during the index hospital admission. Secondary outcomes included: all-cause mortality; days of antibiotic use; infection of pancreatic necrosis; surgical or radiological intervention; 90-day survival; length of stay; and hospital readmission. Between July 2018 and Nov 2020, 369 patients were screened, and 260 patients were randomly assigned to PCT (n = 132) or usual care (n = 129).

Fewer patients in the PCT group were prescribed antibiotics, 59 (45%) versus the usual care group, 79 (63%), adjusted risk difference, -15.6% (95% confidence interval [CI], -27.0–-4.2; p = 0.0071). The odds ratio for the treatment effect was 0.49 (95% CI, 0.29–0.83; p = 0.0077). There were fewer mean (standard deviation) days of antibiotic use in the PCT group (4.5 [10.5] vs 5.8 [10.6]; -1.16 [95% CI, -2.10–-0.22]; P = 0.015). There were no differences in safety outcomes between the groups, including all-cause mortality (3% vs 2%; 0.69% [95% CI, -3.24–4.62]; P = 0.73).

It is often difficult to distinguish inflammation from bacterial infection in acute pancreatitis. This single-centre study suggests that a PCT-based algorithm could reduce antibiotic use in acute pancreatitis without patient harm.

Siriwardena AK, Jegastheeswaran S, Mason JM, PROCAP investigators.  A procalcitonin-based algorithm to guide antibiotic use in patients with acute pancreatitis (PROCAP): a single-centre, patient-blinded, randomised controlled trial. Lancet Gastroenterol Hepatol 2022; 7: 913–21.

The Infectious Diseases Leadership Committee would like to sincerely thank Matthew Rawlins for his dedication and contributions to MedsScan (formerly DrugScan) since 2010 and welcomes Nadine Hillock as incoming MedsScan Editor

Back to top

MENTAL HEALTH

MedsScan Editor for #SHPAMentalHealth: Judy Longworth

MedsScan Editor for #SHPAMentalHealth: Judy Longworth

Haloperidol for treatment of delirium in ICU patients

Haloperidol has long been the standard of care for delirium in Intensive Care Unit (ICU) settings. In this multicentre, placebo-controlled trial, randomly assigned delirious adults admitted to ICU were prescribed either intravenous haloperidol 2.5 mg three times daily plus when needed doses to maximum of 20 mg daily, or placebo. There were 1000 patients in the randomisation with 510 receiving haloperidol. Haloperidol or placebo were administered as long as delirium continued, and the primary outcome was the number of days alive and discharged out of hospital at 90 days after randomisation. In cases of uncontrollable delirium, additional rescue medications included propofol, benzodiazepines and α2 agonists.

In a literature review, it was concluded that the evidence for use of haloperidol for delirium is weak and evidence for effect is limited. Hence this trial aimed to investigate whether haloperidol use would lead to a greater number of days alive and out of hospital compared to placebo. This trial was conducted in 18 general ICUs in Europe. The screening tools used for twice daily screening were Confusion Assessment Method for the ICU (CAM-ICU) or the Intensive Care Delirium Screening Checklist (ICDSC).

Secondary analysis was carried out for additional predefined risk factors including traumatic brain injury, stroke, mental illness, neurodegenerative illness, alcohol over consumption, substance abuse, benzodiazepine use, tobacco smoking, predicted 90-day mortality and prior use of haloperidol.

There was no significant difference between the haloperidol group and placebo group with regards to  the number of days alive and out of hospital at 90 days after randomisation. Using a validated screening tool may contribute to the generalisation of this trial in other settings.

Andersen-Ranberg NC, Poulsen LM, Perner A, Wetterslev J, Estrup S, Hästbacka J, et al. Haloperidol for the treatment of delirium in ICU patients. N Engl J Med 2022; 387:2425–35.

Low dose quetiapine

Low-dose quetiapine is widely used for numerous off-label reasons outside licensed indications. Antipsychotics are associated with increased risk of cardiovascular morbidity and sudden cardiac death driven by metabolic abnormalities. This observational study hypothesised that low-dose quetiapine would be associated with increased risk of cardiovascular events compared to Z-drugs and to selective serotonin reuptake inhibitors (SSRIs). Data was collected from the Danish National Prescription Register as well as Danish National patient register and Danish Civil registration system including the Danish Cause of Death register.

A total of 515 133 patients were identified with a median age of 49 (Interquartile range [IQR], 36–93) and 58% of patients were female. After adjusting for baseline covariates, the risk of a major adverse cardiovascular event was significantly higher with low-dose quetiapine. Analysis of individual major cardiovascular events showed low-dose quetiapine was associated with an increased risk of cardiovascular death, but not non-fatal myocardial infarction; with a greater association of adverse cardiovascular events in females.

When compared to Z-drugs there is an increased risk of cardiovascular events; mainly death, and this was also confirmed when SSRIs were used as comparators. It was postulated that the increased risk among low-dose quetiapine patients is caused by dyslipidaemia. The risk increased with continuous treatment and in vulnerable populations.

Højlund M, Andersen K, Ernst MT, Correll CU, Hallas J. Use of low-dose quetiapine increases the risk of major adverse cardiovascular events: results from a nationwide active comparator-controlled cohort study. World Psychiatry 2022; 21: 444–51.

ADHD medication and risk of cardiovascular disease

Attention deficit/hyperactivity disorder medications, primarily the psychostimulants, have been associated with increased blood pressure and heart rate, with several papers in the 2010s indicating an increased risk of sudden death or ventricular arrhythmia, especially in adult populations.1 This is an updated analysis of the observational studies that investigated the association between ADHD medications and the risk of cardiovascular diseases (CVD) as well as a broader range of cardiovascular events such as hypertension, heart failure, and transient ischaemic attacks.

The study was conducted and reported using a standardised method — the Meta-analysis of observational studies epidemiology (MOOSE) — and quality assessment was done using Good Research for Comparative Effectiveness (GRACE v2), which is more specific for observational research. The study meta-analysed the relative risk in stratified age groups.

This meta-analysis included a wider range of cardiovascular outcomes than in previous studies. Finding no statistically significant association between ADHD medication use and CVD among children and adolescents, young and middle-aged adults or older adults, although the confidence interval could not exclude an increased risk.

Further long-term studies are needed to exclude the possible increased risk, but overall there can be greater confidence that the use of ADHD medication does not increase the risk of CVD, including for those patients with pre-existing CVD.

Zhang L, Yao H, Li L, Du Rietz E, Andell P, Garcia-Argibay M, et al. Risk of cardiovascular disease associated with medications used in attention-deficit/hyperactivity disorder: A systematic review and meta-analysis. JAMA Netw Open 2022; 5: e2243597.

References:

1. Schelleman H, Bilker WB, Kimmel SE, Daniel GW, Newcomb C, Guevara JP, et al. Methylphenidate and risk of serious cardiovascular events in adults. Am J Psychiatry 2012; 169: 178–85.

NEPHROLOGY

MedsScan Editor for #SHPA: Jess Lloyd

EMPA-KIDNEY; another pillar to slow chronic kidney disease progression

This highly anticipated publication provides additional certainty about the role of sodium-glucose transport protein 2 (SGLT2) inhibitors in prevention of chronic kidney disease (CKD) progression and the populations which derive the most benefits.

EMPA-KIDNEY was a double blind, placebo-controlled randomised control trial comparing empagliflozin 10 mg daily to placebo. It enrolled a broad range of the CKD population (estimated glomerular filtration rate [eGFR] down to 20 mL/min, 1.73 m2), including those with and without diabetes and albuminuria. The primary outcome was to determine the therapy’s impact on kidney disease progression and death due to cardiovascular causes. The trial was stopped early due to the meeting of efficacy outcomes during the interim analysis. This meant the mean follow up duration of the 6552 patients was quite short at only two years (interquartile range 1.5–2.4 years). The primary outcome occurred in 13.1% patients in the empagliflozin group vs 16.9% patients in the placebo group conferring a 28% risk reduction with good safety and tolerability of the treatment. The beneficial effects were preserved across different eGFR’s and in patients with and without diabetes, although the greatest benefit was seen in those with moderately increased albuminuria. The results of EMPA-KIDNEY add to those demonstrated by CREDENCE1 and DAPA-CKD2 solidifying the role of SGLT2 inhibitors in patients with CKD over a wide glomerular filtration rate (GFR) range and confirms the benefits are greatest in those with albuminuria. EMPA-KIDNEYshows that patients with lower baseline GFR and albuminuria still obtain benefit from SGLT2 inhibition. Given the public health implications and direct individual patient benefits achievable with these therapies, pharmacists should be pro-actively considering ways in which they can support the increased roll out and uptake of these therapies in their practice settings.

The EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med 2023; 388: 117–27.                                                                                                

References

  1. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380: 2295–306.
  2. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou F-F, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020; 383: 1436–46.

PAEDIATRICS AND NEONATOLOGY

MedsScan Editor for #SHPAPaedNeonate: Rachael Worthington

Hydroxyurea in SPRING for primary stroke prevention in children with sickle cell anaemia

In high-income countries, standard care for primary stroke prevention in children with sickle cell anaemia and abnormal transcranial Doppler velocities results in a 92% relative risk reduction of strokes but mandates initial monthly blood transfusion. This study tested the hypothesis that, in Africa, where regular blood transfusion is not feasible for most children, initial moderate-dose compared with low-dose hydroxyurea decreases the incidence of strokes for children with abnormal transcranial Doppler velocities.

SPRING was a double-blind, parallel-group, randomised, controlled, phase 3 trial of children aged 5–12 years with sickle cell anaemia with abnormal transcranial Doppler velocities conducted at three teaching hospitals in Nigeria. For randomisation, a permuted block allocation scheme with block sizes of four, stratified by sex and site was used. Allocation was concealed from all but the pharmacists and statisticians. Participants were assigned in a 1:1 ratio to low-dose (10 mg/kg per day) or moderate-dose (20 mg/kg per day) oral hydroxyurea taken once daily with monthly clinical evaluation and laboratory monitoring. The primary outcome was initial stroke or transient ischaemic attack, centrally adjudicated. The secondary outcome was all-cause hospitalisation. The intention-to-treat population was used for data analysis. The trial was stopped early for futility after a planned minimum follow-up of 3.0 years to follow-up for participants.

Between 2 August 2016 and 14 June 2018, 220 participants with median age 7.2 years (interquartile range [IQR] 5.5–8.9; 114 [52%] female) were randomly allocated and followed for a median of 2.4 years (IQR 2.0–2.8). All participants were Nigerian and were from the following ethnic groups: 179 (82%) people were Hausa; 25 (11%) were Fulani; and 16 (7%) identified as another ethnicity. In the low-dose hydroxyurea group, three (3%) of 109 participants had strokes, with an incidence rate of 1.19 per 100 person-years and in the moderate-dose hydroxyurea group five (5%) of 111 had strokes with an incidence rate of 1.92 per 100 person-years with an incidence rate ratio of 0.62 (95% confidence interval [CI] 0.10–3.20, p = 0.77). The incidence rate ratio of hospitalisation for any reason was 1.71 (95% CI 1.15–2.57, p = 0.0071), with higher incidence rates per 100 person-years in the low-dose group versus the moderate-dose group (27.43 vs 16.08). No participant had hydroxyurea treatment stopped for myelosuppression.

The authors concluded that compared with low-dose hydroxyurea therapy, participants treated with moderate-dose hydroxyurea had no difference in the stroke incidence rate. However, secondary analyses suggest that the moderate-dose group could lower incidence rates for all-cause hospitalisations. These findings provide an evidence-based guideline for the use of low-dose hydroxyurea therapy for children with sickle cell anaemia at risk of stroke.                                                         

Abdullahi SU, Jibir BW, Bello-Manga H, Gambo S, Inuwa H, Tijani AG, et al. Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): a double-blind, multicentre, randomised, phase 3 trial. Lancet Haematol 2022; 9: e26–e37.

Agomelatine appropriateness for major depressive disorder in Paediatrics

Major depressive disorder is a severe illness that frequently manifests before the age of 18 years, often recurring later in life. Paediatric medical treatment options are scarce. The melatonin receptor agonist and 5-hydroxytryptamine 2C receptor antagonist agomelatine is used to treat adults and could offer a new therapeutic option for paediatric patients. This study aimed to investigate the short-term antidepressant efficacy and safety of agomelatine in children and adolescents with major depressive disorder.

A 12 week, randomised, double-blind, parallel-group, multicentre, phase 3 trial was conducted in 46 specialist psychiatric units or centres in Bulgaria, Finland, Hungary, Poland, Romania, Russia, Serbia, South Africa and Ukraine. Participants (aged 7–17 years) were eligible if they were unresponsive to psychosocial therapy during the 3-week run-in period (Children's Depression Rating Scale–revised [CDRS-R] score of ≥45). Ethnicity was not recorded. The short-term antidepressant efficacy of agomelatine (10 mg or 25 mg per day) was investigated versus placebo with an active control (fluoxetine 10–20 mg depending on symptom severity) after 12 weeks of treatment in children (aged 7–11 years) and adolescents (12–17 years) with major depressive disorder. Patients were randomly assigned (1:1:1:1) to agomelatine 10 mg, agomelatine 25 mg, placebo, or fluoxetine via an interactive response system with permuted-block randomisation. Standardised manualised psychosocial counselling, developed for this trial, was initiated from selection and continued throughout the study, including the open-label extension. All people involved in the conduct of the clinical trial and patients were masked to treatment allocation. Study outcomes were measured using standardised interviews at each study visit.

The primary endpoint was change in CDRS-R raw score from baseline to week 12. Between 23 February 2016 and 14 January 2020, 466 individuals were assessed for eligibility and of 400 included patients, 396 (247 [62%] girls, 149 [38%] boys; mean age 13.7 years [standard deviation 2.7]) were analysed (full analysis set). The primary objective was met; 25 mg/day agomelatine (n = 94, with n = 102 receiving 10 mg/day) resulted in an improvement versus placebo (n = 101) in CDRS-R raw score of 4.22 (95% confidence interval [CI] 0.63–7.82; p = 0.040) at 12 weeks, with a similar effect for fluoxetine (n = 99), establishing assay sensitivity.

The overall effect was confirmed in adolescents (n = 317), but not in children (n = 79). No unexpected safety signals were observed with agomelatine, with no significant weight gain or effect on suicidal behaviours. The authors concluded that this study supports the efficacy of 25 mg/day agomelatine, in addition to psychosocial counselling, in treating adolescent patients with major depressive disorder, with no unexpected safety signals, providing another option in the limited psychopharmaceutical repertoire for management of major depressive disorder.

Arango C, Buitelaar JK, Fegert JM, Olivier V, Pénélaud PF, Marx U, et al. Safety and efficacy of agomelatine in children and adolescents with major depressive disorder receiving psychosocial counselling: a double-blind, randomised, controlled, phase 3 trial in nine countries. Lancet Psychiatry 2022; 9: 113–24.

The benefit of Beta Blockers for CPVT

Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk, but studies comparing individual β-blockers in sizeable cohorts are lacking. This study aims to assess the association between risk for arrhythmic events and type of β-blocker in a large cohort of symptomatic children with CPVT identified from two international registries.

Patients with CPVT, RYR2 variant–carrying symptomatic children (defined as syncope or sudden cardiac arrest before β-blocker initiation and age at start of β-blocker therapy <18 years) treated with a β-blocker were included in the study. Cox regression analyses with time-dependent covariates for β-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope. Three hundred and twenty-nine patients were included (median age at diagnosis, 12 [interquartile range, 7–15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8–12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective β-blocker (predominantly nadolol [n = 140] or propranolol [n = 70]) and 111 (33.7%) used a β1-selective β-blocker (predominantly atenolol [n = 51], metoprolol [n = 33], or bisoprolol [n = 19]) as initial β-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for β1-selective compared with nonselective β-blockers, HR, 2.04 (95% confidence interval [CI], 1.31–3.17); and HR, 1.99 (95% CI, 1.20–3.30), respectively. When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44–4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47–7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08–4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30–5.55]).

The authors concluded that β1-selective β-blockers were associated with a significantly higher risk of arrhythmic events in symptomatic children with CPVT compared with nonselective β-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred β-blocker for treating symptomatic children with CPVT.

Peltenburg PJ, Kallas D, Bos JM, Lieve KVV, Franciosi S, Roston TM et al. An international multicenter cohort study on β-blockers for the treatment of symptomatic children with catecholaminergic polymorphic ventricular tachycardia. Circulation 2022; 145: 333–44.

Semaglutide in Adolescents with Obesity

Young people with obesity are at risk of developing conditions such as dysglycaemia, hypertension, dyslipidaemia, nonalcoholic fatty liver disease and obstructive sleep apnea, alongside impairment in mental health and quality of life, with limited pharmacotherapeutic options for obesity management. A once-weekly, 2.4 mg dose of subcutaneous semaglutide, a glucagon-like peptide-1 receptor agonist, is used to treat obesity in adults, but assessment of the drug in adolescents has been lacking.

This multinational, double-blind, parallel-group, randomised, placebo-controlled trial enrolled adolescents (12 to <18 years of age) with obesity (a body-mass index [BMI] in the 95th percentile or higher) or with overweight (a BMI in the 85th percentile or higher) and at least one weight-related coexisting condition. Participants were randomly assigned in a 2:1 ratio to receive once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo for 68 weeks, plus lifestyle intervention. The primary end point was the percentage change in BMI from baseline to week 68; the secondary confirmatory end point was weight loss of at least 5% at week 68. A total of 201 participants underwent randomisation, and 180 (90%) completed treatment. All but one of the participants had obesity. The mean change in BMI from baseline to week 68 was -16.1% with semaglutide and 0.6% with placebo (estimated difference, -16.7 percentage points; 95% confidence interval [CI], -20.3–-13.2; P < 0.001). At week 68, a total of 95 of 131 participants (73%) in the semaglutide group had weight loss of 5% or more, as compared with 11 of 62 participants (18%) in the placebo group (estimated odds ratio, 14.0; 95% CI, 6.3–31.0; P < 0.001). Reductions in body weight and improvement with respect to cardiometabolic risk factors (waist circumference and levels of glycated hemoglobin, lipids [except high-density lipoprotein cholesterol], and alanine aminotransferase) were greater with semaglutide than with placebo. The incidence of gastrointestinal adverse events was greater with semaglutide than with placebo (62% vs 42%). Five participants (4%) in the semaglutide group and no participants in the placebo group had cholelithiasis. Serious adverse events were reported in 15 of 133 participants (11%) in the semaglutide group and in 6 of 67 participants (9%) in the placebo group.

The authors concluded that among adolescents with obesity, once-weekly treatment with a 2.4 mg dose of semaglutide plus lifestyle intervention resulted in a greater reduction in BMI than lifestyle intervention alone.

Weghuber D, Barrett T, Barrientos-Pérez M, Gies I, Hesse D, Jeppesen OK, et al. Once-weekly semaglutide in adolescents with obesity. N Engl J Med 2022; 387: 2245–57.

PAIN MANAGEMENT

MedsScan Editor for #SHPAPainMgmt: Shania Liu

Post-surgical pain — are opioids required?

Special contributor: Matthew Bianco

The surgical community is a well-documented contributor to the overuse of opioids globally. A key factor in the overprescribing of opioids stems from a poor understanding of post-surgery analgesia requirements.

Fiore et al. performed a systematic review and meta-analysis of randomised trials to evaluate differences in pain intensity on day one and vomiting up to 30 days post-discharge in patients receiving opioid or opioid-free analgesia. Secondary outcomes included differences in pain intensity at other timepoints post-discharge and rates of other side effects (dizziness, constipation, sedation, nausea).

There were 47 trials (n = 6607 patients) included, involving dental (63%), orthopaedic (47%), and general surgery (29%) procedures. Opioid prescribing was associated with no reduction in pain intensity compared with opioid-free analgesia on the first day after hospital discharge (weighted mean difference 0.01 cm; 95% confidence interval [95% CI], -0.26–0.27) or at other postoperative timepoints. Patients receiving opioid analgesia experienced higher rates of vomiting (relative risk = 4.5; 95% CI, 1.93–10.51) compared to those receiving non-opioid analgesia.

Opioid analgesia for post-surgical pain was associated with no improvement in pain intensity compared to simple analgesia (paracetamol and non-steroidal anti-inflammatories) while increasing rates of adverse effects. This research should guide clinical pharmacy practice to promote more judicious use of opioids among post-surgical patients on hospital discharge, which may reduce subsequent harms associated with opioid overuse.

Fiore Jr JF, El-Kefraoui C, Chay M-A, Nguyen-Powanda P, Do U, Olleik G, et al. Opioid versus opioid-free analgesia after surgical discharge: a systematic review and meta-analysis of randomised trials. Lancet 2022; 399(10343): 2280–93.

Risk factors for opioid-related harm after surgery

Special contributor: Sophie Stack

Opioids are commonly used to manage acute pain after surgery, but their use is limited by opioid-related adverse drug events (ORADEs) such as constipation and respiratory depression. This study aimed to identify the risk factors for ORADEs after surgery and the association between ORADEs and clinical outcomes including length of stay and hospital readmission.

This was a retrospective cohort study conducted between July 2016 and April 2020. Multivariate logistic regression was performed to determine whether there was a relationship between patient factors such as age or comorbidities and ORADEs. Propensity score matching was utilised to determine whether there was an association between experiencing ORADEs and clinical outcomes.  

Of the 17 886 surgical patients that received opioids postoperatively, 1814 patients (10.2%) experienced at least one ORADE. Risk factors for experiencing ORADEs included concurrent use of benzodiazepines or gabapentinoids, higher doses of opioids and older age. Patients experiencing ORADEs had longer lengths of hospital stays (rate ratio, 3.00; 95% confidence interval [CI], 2.97–3.04) but a similar rate of hospital readmission within 28 days after discharge (odds ratio, 0.89; 95% CI, 0.71–1.11).

This study provides unique insight into the incidence of adverse effects for patients prescribed opioids post-operatively. In practice going forward, opioids may be reconsidered in patients at an increased risk of adverse effects and alternative medications for pain relief should be considered. Future studies in this area could analyse the severity of ORADEs and whether this is related to patient factors to better inform safe analgesic prescribing after surgery.  

Yiu CH, Gnjidic D, Patanwala A, Fong I, Begley D, Khor KE, et al. Opioid-related adverse drug events in surgical patients: risk factors and association with clinical outcomes. Expert Opin Drug Saf 2022; 21: 1211–23.

Persistent Opioid Use after Discharge from Australian Hospitals

Special contributor: Abigail Corbett

Given the many harms associated with long-term opioid use, prolonged opioid use after discharge from Australian hospitals remains a pertinent issue. This study aimed to explore the rates of persistent opioid (≥3 months) use following discharge from Australian hospitals through a systematic review of the available literature.

Data were collected from a range of databases, including Embase, PubMed, Scopus, CINAHL, and International Pharmaceutical Abstracts. There were 13 studies included in the review. Twelve of the 13 included articles were of ‘good’ quality. The majority (n = 11) of the peer-reviewed literature focused on long-term opioids use among post-surgical patients, sourcing information from both dispensing data from the Pharmaceutical Benefits Scheme or Department of Veterans’ Affairs databases, and direct verbal follow-up with patients prospectively. Overall rates of persistent opioid use among surgical patients ranged from 3.9% to 10.5% at between two to four months following hospital discharge.

Whilst the rates of persistent opioid use in Australia do appear to be lower than those published in international literature, a high degree of heterogeneity exists in the methods, sources and time periods of data collection between international and Australian literature. As the first Australian systematic review of prolonged opioid prescribing and use after hospital discharge, a great necessity exists for future reviews of this nature expanding on opioid prescribing for varied clinical populations outside of post-surgical patients and with greater consistency in data collection methods and time points.

Suckling B, Patullo C, Liu S, James P, Donovan P, Patanwala A, et al. Persistent opioid use after hospital discharge in Australia: A systematic review. Aust Health Rev 2022; 46: 367–80.

Back to top