Real-world comparative effectiveness of dalteparin and enoxaparin for venous thromboembolism prophylaxis.

Venous thromboembolism (VTE) is a preventable cause of significant morbidity and mortality in hospitalized patients world-wide. In Australia, the low-molecular weight heparins (LMWHs) enoxaparin or dalteparin are usually used as first-line prophylaxis for VTE, though there is uncertainty whether dalteparin has the same effectiveness as enoxaparin in real-world settings. This is relevant because dalteparin is less renally cleared and may be more cost effective than enoxaparin. The aim of this study was to explore VTE event incidence in a general cohort of hospitalized adult inpatients who were prescribed enoxaparin or dalteparin for VTE prophylaxis. A retrospective observational study was conducted at a quaternary hospital in Brisbane, Australia, of patients who had experienced a hospital-acquired VTE from 1 September 2021 to 1 March 2023. Patients were identified from routinely collected data following an in-hospital VTE event, and further data was retrieved retrospectively from the integrated electronic Medical Record (ieMR). Incidence and type of VTE events, LMWH-prescribing patterns, and risk factors were assessed. The incidence of VTE events were similar across the dalteparin and enoxaparin cohorts (42.1 events/10 000 patients vs. 34.4 events/10 000 patients, respectively), although patients prescribed enoxaparin had a higher number of risk factors, particularly obesity and active cancer. Our research indicates comparable incidence of VTE in patients prescribed dalteparin compared with enoxaparin in an Australian hospital general cohort of adult inpatients. Dalteparin may be as effective as enoxaparin for VTE prophylaxis in a real-world cohort of patients, and as such dalteparin may be considered a suitable alternative to enoxaparin for VTE prophylaxis. Further research including large randomized controlled trials are required to confirm these results.

Experiences and learnings of pharmacists, students, and clinical assistants working collaboratively in a COVID-19 vaccination clinic: a qualitative study.

Background: The involvement of pharmacists and pharmacy clinical assistants (CAs) in hospital clinics has demonstrated benefits for improving medication safety and care delivery. Internationally, pharmacy staff played a crucial role in the safe storage, provision and administration of vaccines, as well as reinforcement of pharmacovigilance efforts during the COVID-19 pandemic. In Australia, healthcare providers collaborated to rapidly facilitate a phased COVID-19 vaccination program. The perspectives of the pharmacy team, including pharmacy students, involved in implementing novel health services are underexplored in the literature. Objective: To describe the key learnings in how a team of pharmacists, CAs and pharmacy students contributed to the COVID-19 vaccine service, and to explore their preparedness and experiences working at a vaccination clinic within a quaternary hospital. Method: This study involved semi-structured interviews with pharmacy students, CAs and pharmacists. All pharmacy staff who worked in the clinic were invited to participate in the study and a snowball strategy was used to maximise recruitment. The interviews were audio-recorded, transcribed, and analysed using inductive thematic techniques to identify major themes. Results: A total of 11 participants were interviewed including: four pharmacists, four CAs and three undergraduate students. Using thematic analysis, five main themes were identified: (1) Potential for student value and experiential learning; (2) Adaptive procedures and work practices in a rapidly changing environment; (3) Clear leadership, with role clarity, role expansion and interchangeability; (4) Supportive learning environment and (5) Stakeholder drivers for service delivery and to optimise societal benefit. These five themes often interacted with each other, highlighting the complexities of implementing and operating the service. Conclusions: The vaccine clinic service provided a novel and valuable opportunity for students, CAs, and pharmacists to work collaboratively, extending their scope of practice to contribute to better national health outcomes. Participants expressed their support for future initiatives involving pharmacy students and healthcare staff collaborating in hospital settings.

Evaluation of the Quality and Safety of Venous Thromboembolism Prophylaxis Among Gastroenterology Inpatients at a Tertiary Hospital in Australia.

Background and objective: Hospital acquired venous thromboembolisms (VTEs) are common and preventable. The Queensland Health VTE prophylaxis guidelines, developed in 2018, provide guidance for risk assessment, and prescribing of anticoagulation for prophylaxis and treatment of hospital inpatients. Currently, there are limited recommendations for gastroenterology patients. This study investigated the completion of VTE risk assessments, and the appropriateness of VTE prophylaxis regimens, in accordance with Queensland Health guidelines for gastroenterology patients. The quality and safety of VTE prophylaxis regimens was assessed based on their VTE risk and bleeding risk. Method: A retrospective study was conducted by obtaining a random sample of gastroenterology patients admitted to a tertiary Australian hospital, from 1st May 2019 and 1st May 2020, to determine the compliance of VTE risk assessment and thromboprophylaxis prescribing with state-wide VTE guidelines. The quality and safety of thromboprophylaxis was evaluated using the modified Caprini and HASBLED scores, and subsequent thromboprophylaxis-related complications. Results: Of the 94 patients reviewed, 68 did not have contraindications to thromboprophylaxis. Of these 68 patients, 32 (47%) had no VTE risk assessment recorded in their clinical records and were not prescribed any thromboprophylaxis during the hospitalization. There was no significant difference between thromboprophylaxis prescribing for patients with low VTE risk, compared to moderate to high VTE risk (P = .075). There was a trend for decrease in thromboprophylaxis prescribing as HASBLED bleeding risk score increased, and patients with moderate-high bleed risk were less likely to be prescribed thromboprophylaxis (P = .006). There were no thromboprophylaxis related complications identified. Conclusion: It is essential that all patients have a clearly documented risk assessment and are prescribed thromboprophylaxis according to best practice guidelines. The prescription of venous thromboembolism prophylaxis should continue to be individualized, with each patient assessed holistically.

Learning on the run - a qualitative, longitudinal study of pharmacy educators' experiences implementing a hospital pharmacy residency program.

BACKGROUND: A hospital pharmacy foundation residency training program has been introduced in Australia, modelled on residency programs established in other countries. The program aims to support the professional development of early-career hospital pharmacists, in both clinical and non-clinical roles. Pharmacy educators are usually tasked with the implementation and maintenance of this program. This qualitative, longitudinal study aimed to investigate hospital pharmacy educators' expectations, perceptions and experiences with implementing and developing their residency program. METHODS: Qualitative data were collected at two timepoints, approximately 24 months apart, using either focus groups or interviews with pharmacy educators who were directly involved in the implementation of the residency program at their respective hospitals. During the early phases of implementation, and approximately 24 months later, participants were asked about their experiences and expectations of the residency program as well as any changes that had occurred within the residency program over time. RESULTS: Four focus groups and three semi-structured interviews were held with pharmacy educators and senior pharmacists from different hospital settings. These were audio recorded and transcribed verbatim. Transcripts were inductively analysed via thematic analysis. Fifteen hospital pharmacy educators and senior hospital pharmacists participated in the initial focus groups and interviews, and seven educators were retained for follow-up. Four main themes were established from the discussions: participants had great expectations of a positive impact of the residency on their workplace and residents' professional development; substantial effort, support and resources were needed to implement and maintain a residency program; self-motivation and engagement is needed by residents to succeed and experience timely completion and career acceleration; and lastly a balance between standardisation, consistency and flexibility in delivering the residency needs to be found. The role of educators changed with the implementation of a residency, with the addition of more managerial and supervisory aspects. CONCLUSION: The Australian hospital pharmacy foundation residency program is a complex workplace training program with multiple factors and prerequisites influencing its implementation, development and outcomes. Pharmacy educators are central to the successful implementation and ongoing sustainability of a residency program. They may benefit from formal training and qualifications to support their role.

Estimation of cardiac QTc intervals in people prescribed antipsychotics: a comparison of correction factors.

Background: A prolonged electrocardiogram (ECG) QT interval is associated with cardiac events and increased mortality. Antipsychotics can prolong the QT interval. The QT interval requires correction (QTc) for heart rate using a formula or QT-nomogram. The QT and QTc can be calculated automatically by the ECG machine or manually; however, machine-measured QT(c) intervals may be inaccurate. Objective: We aimed to investigate the mean QTc and proportion of prolonged QTc intervals in people taking antipsychotic medicines. Methods: We conducted an observational retrospective chart review and data analysis of all consecutive patients taking antipsychotics, with an ECG record, admitted to the psychiatric unit of a large tertiary hospital in Brisbane, Australia, between 1 January 2017 and 30 January 2019. We investigated the mean QTc of people taking antipsychotics to determine differences using (a) machine versus manual QT interval measurement and (b) QTc correction formulae (Bazett, Fridericia, Framingham, Hodges and Rautaharju) and the QT-nomogram. We also determined the number of people with a prolonged QTc using different methods and compared rates of prolonged QTc with antipsychotic monotherapy and polypharmacy. Results: Of 920 included people, the mean (±SD) machine-measured, Bazett-corrected QT interval (recorded from the ECG) was 435 ms (±27), significantly longer (p < 0.001) than the mean manually measured corrected QT intervals with Fridericia 394 ms (±24), Framingham 395 ms (±22), Hodges 398 ms (±22) and Rautaharju 400 ms (±24) formulae. There were significantly more people with a prolonged QTc using machine-measured QT and the Bazett formula (12.0%, 110/920) when compared with manually measured QT and the Fridericia formula (2.2%, 20/920) or QT-nomogram (0.7%, 6/920). Rates of QTc prolongation did not differ between people taking antipsychotic polypharmacy compared with monotherapy. Conclusion: Machine-measured QTc using the Bazett formula overestimates the QTc interval length and number of people with a prolonged QTc, compared with other formulae and the QT-nomogram. We recommend manually measuring the QT and correcting with the Fridericia formula or QT-nomogram prior to modifying antipsychotic therapies.

CoMET: a randomised controlled trial of co-commencement of metformin versus placebo as an adjunctive treatment to attenuate weight gain in patients with schizophrenia newly commenced on clozapine.

BACKGROUND: There is limited evidence on interventions to minimise weight gain at clozapine commencement. We compared the effect of adjunctive metformin versus placebo at clozapine initiation. METHODS: People with schizophrenia commencing on clozapine were randomised to either metformin or placebo for 24 weeks. The primary outcome was difference in the change of body weight. Secondary outcomes included comparative rates of weight gain of more than 5%, overall weight gain/loss, and differences in metabolic and psychosis outcomes. RESULTS: The study was closed prematurely in March 2020 due to COVID-19 restrictions. Ten participants were randomised to each of the metformin and placebo groups. Eight metformin group and five placebo group participants completed the trial and were included in the analysis. The study was insufficiently powered to detect difference between the metformin and placebo groups for the primary outcome of change in weight (0.09 kg vs 2.88 kg, p = 0.231). In terms of secondary outcomes, people in the metformin group were significantly less likely to gain >5% of their body weight (12.5% vs 80%, p = 0.015) and were more likely to lose weight (37.5% vs 0% p = 0.024) compared to placebo. There was no difference between the groups in terms of adverse drug reactions (ADRs). CONCLUSION: While limited by the forced premature closure of the trial due to COVID19, the findings from this randomised controlled trial are promising. Clozapine and metformin co-commencement may be a promising treatment to prevent clozapine-associated weight gain, especially given the low rates of ADRs associated with metformin. This supports the consideration of use of metformin to prevent weight gain in people initiated on clozapine; however, further studies are needed to confirm this finding. TRIAL REGISTRATION: ACTRN12617001547336.

Metformin reduces 12-month change in body weight among people newly commenced on clozapine: a retrospective naturalistic cohort study.

BACKGROUND: People with schizophrenia have a 15-20-year reduction in life expectancy, driven in part by the metabolic effects of antipsychotics. Clozapine is associated with the highest rates of weight gain. As clozapine remains the most effective antipsychotic for treatment-resistant schizophrenia (TRS), identifying treatments to ameliorate clozapine-induced weight gain (CIWG) is urgently needed to reduce this morality gap. METHODS: We retrospectively analysed digital health records of patients with TRS aged 18-65 newly initiated on clozapine at four tertiary hospitals in south-east Queensland from 1 March 2017 to 30 June 2019. Our primary outcome was the effect of metformin on change in percentage bodyweight at 12 months after clozapine initiation, with secondary outcome being proportion with >5% or >7% bodyweight change. We also explored impact on bodyweight change of other variables including sex, tobacco smoking, type 2 diabetes (T2DM), age, clozapine level and dose and clozapine/norclozapine ratio. RESULTS: Among 90 patients initiated on clozapine, metformin use (n = 48) was associated with a smaller increase in percentage bodyweight (1.32% versus 5.95%, p = 0.031), lower rates of >7% gain in bodyweight (37.8% versus 63.0%, p = 0.025) but not >5% gain in bodyweight. Age below the median (32.0 years) was associated with greater bodyweight gain (5.55% versus 1.22%, p = 0.046). Sex, tobacco smoking, T2DM, clozapine dose and level and clozapine/norclozapine ratio were not associated with differences in change in bodyweight. CONCLUSION: In this small retrospective cohort study, use of metformin within 12-months of clozapine initiation was associated with a statistically and clinically significant reduction in CIWG. Although there is increasing evidence for the role of metformin to ameliorate bodyweight gain at time of clozapine initiation, our findings need replication and testing in a randomised controlled trial before recommending metformin co-commencement with clozapine as standard clinical practice.

Does Switching Antipsychotics Ameliorate Weight Gain in Patients With Severe Mental Illness? A Systematic Review and Meta-analysis.

OBJECTIVE: Obesity and adverse metabolic outcomes in patients with severe mental illness are clinically significant but potentially preventable. Importantly, the evidence for switching to antipsychotics to reduce cardiometabolic burden is unclear. METHOD: PubMED, Embase, PsycINFO, and Cochrane were searched from inception to March 8, 2020. Articles reporting weight and metabolic changes after antipsychotic switching vs staying on the previous antipsychotic were meta-analyzed both across and within group. RESULTS: Of 61 identified studies, 59 were meta-analyzed (40% rated high quality). In the switch-vs-stay pairwise meta-analyses, only aripiprazole significantly reduced weight (-5.52 kg, 95% CI -10.63, -0.42, P = .03), while olanzapine significantly increased weight (2.46 kg, 95% CI 0.34, 4.57, P = .02). Switching to aripiprazole also significantly improved fasting glucose (-3.99 mg/dl, 95% CI -7.34, -0.64, P = .02) and triglycerides (-31.03 mg/dl, 95% CI -48.73, -13.34, P = .0001). Dropout and psychosis ratings did not differ between switch and stay groups for aripiprazole and olanzapine. In before-to-after switch meta-analyses, aripiprazole (-1.96 kg, 95% CI -3.07, -0.85, P < .001) and ziprasidone (-2.22 kg, 95% CI -3.84, -0.60, P = .007) were associated with weight loss, whereas olanzapine (2.71 kg, 95% CI 1.87, 3.55, P < .001), and clozapine (2.80 kg, 95% CI 0.26, 5.34, P = .03) were associated with weight gain. No significant weight or other cardiometabolic changes were observed when switching to amisulpride, paliperidone/risperidone, quetiapine, or lurasidone. CONCLUSIONS: Switching antipsychotics to agents with lower weight gain potential, notably to aripiprazole and ziprasidone, can improve weight profile and other cardiometabolic outcomes. When choosing switch agents, both the weight gain potential of the pre- and post-switch antipsychotic must be considered. Antipsychotic switching in psychiatrically stable patients must be weighed against the risk of psychiatric worsening.

Unfractionated heparin dosing in obese patients.

Background The effect of obesity on the pharmacokinetics and pharmacodynamics of unfractionated heparin is not clearly understood, therefore to reduce the risk of bleeding, maximal dose (capped) nomograms are often used. This can lead to inadequate anticoagulation and increased mortality and morbidity. In Queensland, Australia, statewide nomograms recommend total-body-weight-based dosing, with capped initial bolus and maintenance doses. Objective To determine if current practices for unfractionated heparin dosing leads to inadequate anticoagulation in obese patients. Setting Princess Alexandra Hospital, Queensland, Australia. Method A retrospective audit of unfractionated heparin dosing in 200 patients divided into cohorts of; < 100 kg (defined as non-obese), 100-124.9 kg, 125-150 kg and > 150 kg, Main outcomes measured Mean maintenance doses in U/h and U/kg/h required to achieve two consecutive therapeutic activated partial thromboplastin times' and the corresponding time to achieve this endpoint. Results The mean ± standard deviation maintenance doses required to achieve two consecutive therapeutic activated partial thromboplastin times' in U/h were 1229 ± 316, 1673 ± 523, 2031 ± 596 and 2146 ± 846, and in U/kg/h were 16 ± 4.1, 15.1 ± 4.8, 14.9 ± 4.2 and 11.6 ± 4.2 for the weight cohorts respectively. The median time (inter-quartile range) to therapeutic activated partial thromboplastin times' for obese patients was 39 (21.5-56) h. Conclusions Our results suggest inadequate dosing in obese patients. We recommend the use of larger absolute doses (U/h) of nfractionated heparin but reduced uncapped total body weight-based doses-(U/kg/h) as patient weight increases.

Strategies to counter antipsychotic-associated weight gain in patients with schizophrenia.

Introduction: Patients living with schizophrenia have a marked risk of clinically significant weight gain and obesity compared to the general population. The risks have been highlighted following the introduction of second-generation antipsychotics. In turn, obesity is associated with a higher prevalence of cardiovascular disease, the most common cause of premature mortality in patients with schizophrenia.Areas covered: In this review, the authors outline possible mechanisms that induce obesity in patients with schizophrenia taking antipsychotics. The authors discuss the safety and effectiveness of three main approaches for attenuating antipsychotic-associated weight gain (AAWG), including lifestyle interventions, switching antipsychotics, and augmentation with other medications.Expert opinion: When selecting antipsychotics, effective treatment of psychotic symptoms should be highest priority but obesity and related metabolic comorbidities associated with antipsychotics should not be neglected. Further research into mechanisms of weight gain associated with antipsychotics will guide future treatments for AAWG and development of antipsychotics that produce minimal metabolic adverse effects. With current strategies only producing modest weight loss in already overweight and obese individuals, clinicians should transition to an approach where they aim to prevent weight gain when initiating antipsychotic treatment.

Evaluation of weight based enoxaparin dosing on anti-Xa concentrations in patients with obesity.

Current treatment dose of enoxaparin is based on total body weight (TBW), however dosage in obesity remains unclear. "Dose capping" commonly occurs if TBW > 100 kg minimising bleeding risk. However, this may result in under-dosing and increasing embolisation risk. The primary objective evaluated efficacy of current dosing strategies in obese patients and determined if resultant anti-Xa concentrations (aXaC) were therapeutic. The secondary objective was to investigate if an uncapped 0.75-0.85 mg/kg (TBW) twice daily dose, advocated by previous authors, results in therapeutic aXaC (0.5-1.0 IU/ml). This retrospective study included 133 patients with a median TBW of 128 kg, producing 59% therapeutic, 15% sub-therapeutic and 26% supra-therapeutic aXaC. Approximately 60% of patients in each dose group (< 0.75, 0.75-0.85 and > 0.85 mg/kg) had a therapeutic aXaC, however the percentage of sub-therapeutic versus supra-therapeutic was higher in the < 0.75 (27% vs 9%) and > 0.85 mg/kg (10% vs 34%) groups respectively. Most patients who weighed 100-119 kg (TBW) received doses > 0.85 mg/kg, however 32% had toxic aXaC. Those between 120 and 139 kg (TBW) had a high percentage of therapeutic aXaC (87%) when dosed < 0.75 mg/kg and a high percentage of supra-therapeutic aXaC (71%) when dosed > 0.85 mg/kg; although numbers were low. Dose reduction occurred in patients > 140 kg (TBW), however < 0.75 mg/kg resulted in higher percentage of sub-therapeutic aXaC (42%). Dosing at 0.75-0.85 mg/kg results in 62% of therapeutic, 14% sub-therapeutic and 24% supra-therapeutic aXaC. This appears to be a "safe" starting dose-range, however all obese patients should have aXaC monitoring due to high inter-patient variability.

Correction to: Clozapine-related neutropenia, myocarditis and cardiomyopathy adverse event reports in Australia 1993-2014.

The authors would like to change the statement found in the results section of the abstract from "There were five reported deaths from neutropenia and cardiomyopathy." to "There were five, 13, and two reported deaths from neutropenia, myocarditis, and cardiomyopathy, respectively."

CoMET: a protocol for a randomised controlled trial of co-commencement of METformin as an adjunctive treatment to attenuate weight gain and metabolic syndrome in patients with schizophrenia newly commenced on clozapine.

INTRODUCTION: Clozapine, while effective in treatment refractory schizophrenia, is associated with significant weight gain, heart disease and increased risk of type 2 diabetes mellitus (T2DM). Although there is evidence for weight loss with metformin for people with obesity who are already taking clozapine, there have been no published trials that have investigated the effect of metformin in attenuating weight gain at the time of clozapine initiation. METHODS AND ANALYSIS: A 24-week double-blind placebo-controlled trial of concomitant prescription of metformin at clozapine commencement. Eighty-six people being commenced on clozapine will be randomised to placebo or metformin (variable dose, up to 2 g/day). The primary outcome is comparative end point body weight, between the placebo and metformin groups. Secondary outcomes are comparative rates of conversion to T2DM, alteration of metabolic syndrome parameters, proportion gaining >5% body weight and changes in diet and appetite. We will additionally examine biomarkers associated with change in weight among trial participants. ETHICS AND DISSEMINATION: Ethics approval was granted by the Metro South Human Research Ethics Committee HREC/17/QPAH/538-SSA/17/QPAH/565. We plan to submit a manuscript of the results to a peer-reviewed journal, and present results at conferences, consumer forums and hospital grand rounds. TRIAL REGISTRATION NUMBER: ACTRN12617001547336; Pre-results.

Clozapine-related neutropenia, myocarditis and cardiomyopathy adverse event reports in Australia 1993-2014.

RATIONALE: Clozapine is the gold-standard medicine for treating refractory schizophrenia but there are some notable serious adverse events (AE). We aimed to analyse reported rates of clozapine cardiac and haematological AEs in Australia. METHODS: Using data from the Therapeutic Goods Administration, we examined all reported clozapine AEs (1993-2014) with a specific focus on neutropenia, myocarditis and cardiomyopathy. We related AEs to clozapine-dispensing data in Queensland, scaled up to Australia. RESULTS: There were 8561 AEs reported: neutropenia (13.7%), myocarditis (9.3%) and cardiomyopathy (3.8%). Reported rates of myocarditis and cardiomyopathy increased after 1999 following a myocarditis case series from Sydney. Cardiomyopathy AE rates have remained stable since then but myocarditis AEs have increased steadily. Neutropenia was more common in women, while cardiomyopathy and myocarditis were more common in men. There were five, 13, and two reported deaths from neutropenia, myocarditis, and cardiomyopathy, respectively. CONCLUSIONS: The rates of serious AEs (including deaths) are low and likely an underestimate of true rates and need to be considered by clinicians in balancing the risks and benefits. Continued education on the monitoring and treatment of these AEs for consumers, carers and health professionals is essential and reporting these to the relevant national reporting agency is crucial.

Treatment of clozapine-associated obesity and diabetes with exenatide in adults with schizophrenia: A randomized controlled trial (CODEX).

Clozapine causes obesity and type 2 diabetes (T2DM). Glucagon-like peptide-1 (GLP-1) receptor agonists (e.g. exenatide) can counter clozapine-associated GLP-1 dysregulation in animals, and may be beneficial in people on clozapine. This randomized, controlled, open-label, pilot trial evaluated weekly exenatide for weight loss among clozapine-treated obese adults with schizophrenia, with or without T2DM. A total of 28 outpatients were randomized to once-weekly extended-release subcutaneous exenatide or usual care for 24 weeks. The primary outcome was proportion of participants with >5% weight loss. All 28 participants completed the study; 3/14 in the exenatide group and 2/14 in the usual care group had T2DM. Six people on exenatide achieved >5% weight loss vs one receiving usual care (P = .029). Compared with usual care, participants on exenatide had greater mean weight loss (-5.29 vs -1.12 kg; P = .015) and body mass index reduction (-1.78 vs -0.39 kg/m2 ; P = .019), and reduced fasting glucose (-0.34 vs 0.39 mmol/L; P = .036) and glycated haemoglobin levels (-0.21% vs 0.03%; P = .004). There were no significant differences in other metabolic syndrome components. Exenatide may be a promising therapeutic agent for glycaemic control and weight loss in clozapine-treated people with obesity, and could assist in reducing clozapine-associated cardio-metabolic morbidity and mortality.