Transition of care (ToC) for patients following acute type 1 myocardial infarction or coronary revascularisation procedures is complex, often resulting in medication-related harm and hospital readmissions. Current ToC models lack comprehensive, system-wide approaches, especially in Australia, and often fail to address patient-centred needs and cultural considerations. This theoretical paper aims to outline a multidimensional implementation science approach that will underpin the design and implementation a pharmacy-led ToC intervention to reduce hospital readmissions and improve medication safety. Informed by Guyatt et al. (2021), the REduce hospital readmissions for high-risk CARDiology patients (RECARD) ToC model, will integrate six key elements: (1) guiding implementation with the Consolidated Framework for Implementation Research (CFIR), including a patient domain; (2) co-design with patients and healthcare professionals; (3) understanding local needs using Bradshaw’s taxonomy; (4) designing an evidence-informed intervention based on health behaviour theories; (5) planning and executing implementation using the Expert Recommendations for Implementing Change (ERIC) and the Behaviour Change Wheel (BCW); and (6) evaluating and sustaining the intervention using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. This approach will involve a pre-post interventional trial across three quaternary Queensland hospitals, informed by focus groups, semi-structured interviews, and Yarning circles to refine the literature-informed intervention design. We present our synthesised RECARD ToC model planned to be delivered as an “Adaptive ToC Pathway,” involving a collaborative team of pharmacists, nurse practitioners, and Indigenous health workers. The intervention will incorporate inpatient and post-discharge activities, tailored to local needs and patient preferences. The implementation plan will address barriers and enablers identified through stakeholder engagement, and RE-AIM will guide the evaluation. Our novel theory-informed approach, integrating CFIR, Bradshaw’s model, ERIC, BCW, and RE-AIM, provides a comprehensive framework for designing and implementing the RECARD ToC model. This will allow comparison of a prospective cohort receiving evidence-informed ToC activities to optimise medication management and patient safety, guided by a risk prediction model to predict unplanned readmissions due to medication harm within 30 days, with a retrospective historical cohort who received usual care. By understanding local needs and engaging stakeholders, this project seeks to create a sustainable and impactful intervention that addresses the gaps in current ToC practices, particularly for Indigenous populations, and enhances patient safety in the Australian healthcare setting. Not applicable.

The use of multi-national observational study in post-marketing safety assessment has been rising in recent years in parallel with the rapid development and adoption of electronic healthcare data (e.g., administrative claims, electronic health records) and novel statistical analysis methods to handle these data. Secondary use of routinely collected electronic health information has long been available to conduct pharmacoepidemiologic studies using data from millions of patients. Certain observational studies or surveillance activities, especially those investigating rare exposure or outcome or those designed to study specific patient subgroups (e.g., elderly, pediatric) or newly approved medical products, necessitate a multi-national approach. Other instances utilizing such study design include but not limited to (1) postmarketing study requested by multiple regulatory authorities; (2) multiple data systems chosen to complement each other (e.g., databases with long-term clinical outcome data combined with another that includes lab and radiology findings to allow case adjudication and/or algorithm validation); (3) multiple data sources needed to verify and replicate study findings. In this article, we share examples of multi-national postmarketing studies and discuss key pitfalls related to the design and analysis of such studies as well as strategies to mitigate biases.

BackgroundAlmost half of the dementia cases are preventable. Semaglutide treats several medical conditions that are risk factors for dementia.ObjectiveWe aim to investigate if semaglutide is associated with a decreased risk of dementia.MethodsWe conducted emulation target trials based on a nationwide population-based database of patient electronic health records (EHRs) in the US among 1,710,995 eligible patients with type 2 diabetes (T2D) comparing semaglutide with other antidiabetic medications. First-time diagnosis of Alzheimer's disease-related dementia (ADRD) including vascular dementia, frontotemporal dementia, Lewy body dementia and other dementias were examined using Cox proportional hazards and Kaplan-Meier survival analyses during a 3-year follow-up. Models were adjusted by propensity-score matching.ResultsWe show that semaglutide was associated with a significantly reduced risk of overall ADRD incidence with a hazard ratio ranging from 0.54 (0.49-0.59) compared with insulin, 0.67 (0.61-0.74) compared with metformin, to 0.80 (0.72-0.89) compared with older generation glucagon-like peptide-1 agonists (GLP-1RAs). The association varied for specific dementia types, with significantly reduced risk of vascular dementia and no evidence of associations with frontotemporal and Lewy body dementias.ConclusionsThese findings provide evidence supporting protective effects of semaglutide on dementias in patients with T2D. Future works are needed to establish the causal relationships through randomized clinical trials and to characterize the underlying mechanisms.

Concerns over reports of suicidal ideation associated with semaglutide treatment, a glucagon-like peptide 1 receptor (GLP1R) agonist medication for type 2 diabetes (T2DM) and obesity, has led to investigations by European regulatory agencies. In this retrospective cohort study of electronic health records from the TriNetX Analytics Network, we aimed to assess the associations of semaglutide with suicidal ideation compared to non-GLP1R agonist anti-obesity or anti-diabetes medications. The hazard ratios (HRs) and 95% confidence intervals (CIs) of incident and recurrent suicidal ideation were calculated for the 6-month follow-up by comparing propensity score-matched patient groups. The study population included 240,618 patients with overweight or obesity who were prescribed semaglutide or non-GLP1R agonist anti-obesity medications, with the findings replicated in 1,589,855 patients with T2DM. In patients with overweight or obesity (mean age 50.1 years, 72.6% female), semaglutide compared with non-GLP1R agonist anti-obesity medications was associated with lower risk for incident (HR = 0.27, 95% CI = 0.200.32–0.600.36) and recurrent (HR = 0.44, 95% CI = 0.32–0.60) suicidal ideation, consistent across sex, age and ethnicity stratification. Similar findings were replicated in patients with T2DM (mean age 57.5 years, 49.2% female). Our findings do not support higher risks of suicidal ideation with semaglutide compared with non-GLP1R agonist anti-obesity or anti-diabetes medications. A real-world retrospective cohort study provides evidence that semaglutide prescription is not associated with higher risks of suicide ideation when compared with other anti-obesity or anti-diabetic medications.

Cannabis is the most frequently used illicit drug in the United States with more than 45 million users of whom one-third suffer from a cannabis use disorder (CUD). Despite its high prevalence, there are currently no FDA-approved medications for CUD. Patients treated with semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) approved for treating type 2 diabetes (T2D) and for weight management have reported reduced desire to drink and smoke. Preclinical studies have shown that semaglutide decreased nicotine and alcohol consumption. Preclinical and preliminary clinical evidence of semaglutide’s potential beneficial effects on various substance use disorders led us to evaluate if it pertained to CUD. In this retrospective cohort study of electronic health records (EHRs) from the TriNetX Analytics Network, a global federated health research network of approximately 105.3 million patients from 61 large healthcare organizations in the US, we aimed to assess the associations of semaglutide with both incident and recurrent CUD diagnosis compared to non-GLP-1RA anti-obesity or anti-diabetes medications. Hazard ratio (HR) and 95% confidence intervals (CI) of incident and recurrent CUD were calculated for 12-month follow-up by comparing propensity-score matched patient cohorts. The study population included 85,223 patients with obesity who were prescribed semaglutide or non-GLP-1RA anti-obesity medications, with the findings replicated in 596,045 patients with T2D. In patients with obesity (mean age 51.3 years, 65.6% women), semaglutide compared with non-GLP-1RA anti-obesity medications was associated with lower risk for incident CUD in patients with no prior history CUD (HR: 0.56, 95% CI: 0.42–0.75), and recurrent CUD diagnosis in patients with a prior history CUD (HR: 0.62, 95% CI: 0.46–0.84). Consistent reductions were seen for patients stratified by gender, age group, race and in patients with and without T2D. Similar findings were replicated in the study population with T2D when comparing semaglutide with non-GLP-1RA anti-diabetes medications for incident CUD (HR: 0.40, 95% CI: 0.29–0.56) and recurrent CUD (HR: 0.66, 95% CI: 0.42–1.03). While these findings provide preliminary evidence of the potential benefit of semaglutide in CUD in real-world populations, further preclinical studies are warranted to understand the underlying mechanism and randomized clinical trials are needed to support its use clinically for CUD.

The ICH E17 guidelines (2014-2017) on Multiregional Clinical Trials (MRCT) was a joint effort by the regulators and industry to facilitate simultaneous global drug development and registration through taking a strategic approach for clinical trials. In other words, the objective was to reduce the time it takes to bringing medications to patients around the world through minimizing unnecessary duplication of local or regional studies, which may add the regulatory burden to cost and time of bringing new therapies to patients. Under the auspices of ICH, training materials were created and provided to various stakeholders. Despite the successful promotion of the benefits of ICH E17 MRCT guidelines across the different regions, the uptake of some concepts (e.g., pooling strategy) in the ICH E17 guidelines has been slow. This paper describes various factors which could affect the conduct of MRCT at a global level, including ambiguity in definition of "region" (in MRCT), new regulatory requirements to enroll a diverse patient population, the use of decentralized clinical trials, use of data sources other than randomized clinical trials (e.g., use of Real Word Data), and the impact of the COVID-19 pandemic on the conduct of MRCT.

INTRODUCTION:Emerging preclinical evidence suggests that semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA) for type 2 diabetes mellitus (T2DM) and obesity, protects against neurodegeneration and neuroinflammation. However, real-world evidence for its ability to protect against Alzheimer's disease (AD) is lacking. METHODS:We conducted emulation target trials based on a nationwide database of electronic health records (EHRs) of 116 million US patients. Seven target trials were emulated among 1,094,761 eligible patients with T2DM who had no prior AD diagnosis by comparing semaglutide with seven other antidiabetic medications. First-ever diagnosis of AD occurred within a 3-year follow-up period and was examined using Cox proportional hazards and Kaplan-Meier survival analyses. RESULTS:Semaglutide was associated with significantly reduced risk for first-time AD diagnosis, most strongly compared with insulin (hazard ratio [HR], 0.33 [95% CI: 0.21 to 0.51]) and most weakly compared with other GLP-1RAs (HR, 0.59 [95% CI: 0.37 to 0.95]). Similar results were seen across obesity status, gender, and age groups. DISCUSSION:These findings support further studies to assess semaglutide's potential in preventing AD. HIGHLIGHTS:Semaglutide was associated with 40% to 70% reduced risks of first-time AD diagnosis in T2DM patients compared to other antidiabetic medications, including other GLP-1RAs. Semaglutide was associated with significantly lower AD-related medication prescriptions. Similar reductions were seen across obesity status, gender, and age groups. Our findings provide real-world evidence supporting the potential clinical benefits of semaglutide in mitigating AD initiation and development in patients with T2DM. These findings support further clinical trials to assess semaglutide's potential in delaying or preventing AD.

Aortic stenosis (AS) is one of the most common valvular pathologies. Severe coronary artery disease (CAD) often coexists with AS. Transcatheter aortic valve implantation (TAVI) and percutaneous coronary intervention (PCI) have been established as alternatives to open surgical interventions. The data on the timing for the treatment of the 2 conditions are scarce and depend on multiple factors. This review compares the clinical outcomes of the concomitant versus staged PCI and TAVI for the treatment of AS and CAD. A systematic, electronic search was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines to identify relevant articles that compared outcomes of the staged versus concomitant approaches for the TAVI and PCI. Seven studies were included involving 3745 patients. We found no statistically significant difference in primary outcomes such as 30-day mortality [odds ratio (OR) = 0.78; 95% confidence interval (CI): 0.39–1.57] and secondary outcomes including length of hospital stay (mean difference = −4.74, 95% CI: −10.96 to 1.48), new-onset renal failure (OR = 0.83, 95% CI: 0.22–3.13), cerebrovascular accidents (OR = 1.28, 95% CI: 0.64–2.57), and intraoperative blood loss (OR = 0.83, 95% CI: 0.32–2.12). New pacemaker insertion was statistically significant in favor of the concomitant approach (OR = 0.78, 95% CI: 0.63–0.96). This analysis suggests that while the 2 approaches are largely comparable in terms of most outcomes, patients at risk of requiring a pacemaker postprocedure may benefit from a concomitant approach. In conclusion, concomitant TAVI + PCI approach is nonsuperior to the staged approach for the treatment of CAD and AS. This review calls for robust trials in the field to further strengthen the evidence.

This cohort study compares glucagon-like peptide 1 receptor agonists (GLP-1RAs) with 7 non–GLP-1RA antidiabetics among drug-naive patients with type 2 diabetes.

This cohort study uses emulation target trial methods to evaluate whether semaglutide is associated with lower rates of opioid overdose among patients with type 2 diabetes (T2D) and opioid use disorder (OUD).

Alcohol use disorders are among the top causes of the global burden of disease, yet therapeutic interventions are limited. Reduced desire to drink in patients treated with semaglutide has raised interest regarding its potential therapeutic benefits for alcohol use disorders. In this retrospective cohort study of electronic health records of 83,825 patients with obesity, we show that semaglutide compared with other anti-obesity medications is associated with a 50%-56% lower risk for both the incidence and recurrence of alcohol use disorder for a 12-month follow-up period. Consistent reductions were seen for patients stratified by gender, age group, race and in patients with and without type 2 diabetes. Similar findings are replicated in the study population with 598,803 patients with type 2 diabetes. These findings provide evidence of the potential benefit of semaglutide in AUD in real-world populations and call for further randomized clinicl trials. Anecdotal reports from patients prescribed semaglutide describe a reduced desire to drink. Here, the authors show that semaglutide is associated with a 50%-56% reduced risk for both the incidence and recurrence of alcohol use disorder in real-world populations.

BACKGROUND:Reports of reduced desire to smoke in patients treated with semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA) medication for type 2 diabetes mellitus (T2DM) and obesity, have raised interest about its potential benefit for tobacco use disorders (TUDs). OBJECTIVE:To examine the association of semaglutide with TUD-related health care measures in patients with comorbid T2DM and TUD. DESIGN:Emulation target trial based on a nationwide population-based database of patient electronic health records. SETTING:United States, 1 December 2017 to 31 March 2023. PARTICIPANTS:Seven target trials were emulated among eligible patients with comorbid T2DM and TUD by comparing the new use of semaglutide versus 7 other antidiabetes medications (insulins, metformin, dipeptidyl-peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors, sulfonylureas, thiazolidinediones, and other GLP-1RAs). MEASUREMENTS:The TUD-related health care measures (medical encounter for diagnosis of TUD, smoking cessation medication prescriptions, and smoking cessation counseling) that occurred within a 12-month follow-up were examined using Cox proportional hazards and Kaplan-Meier survival analyses. RESULTS:The study compared 222 942 new users of antidiabetes medications including 5967 of semaglutide. Semaglutide was associated with a significantly lower risk for medical encounters for TUD diagnosis compared with other antidiabetes medications, and was strongest compared with insulins (hazard ratio [HR], 0.68 [95% CI, 0.63 to 0.74]) and weakest but statistically significant compared with other GLP-1RAs (HR, 0.88 [CI, 0.81 to 0.96]). Semaglutide was associated with reduced smoking cessation medication prescriptions and counseling. Similar findings were observed in patients with and without a diagnosis of obesity. For most of the group comparisons, the differences occurred within 30 days of prescription initiation. LIMITATION:Documentation bias, residual confounding, missing data on current smoking behavior, body mass index, and medication adherence. CONCLUSION:Semaglutide was associated with lower risks for TUD-related health care measures in patients with comorbid T2DM and TUD compared with other antidiabetes medications including other GLP-1Ras, primarily within 30 days of prescription. These findings suggest the need for clinical trials to evaluate semaglutide's potential for TUD treatment. PRIMARY FUNDING SOURCE:National Institutes of Health.

"Guest editors’ note on special issue on application of estimand." Journal of Biopharmaceutical Statistics, ahead-of-print(ahead-of-print), pp. 1–2

A fundamental problem in the regulatory evaluation of a therapy is assessing whether the benefit outweighs the associated risks. This work proposes designing a trial that assesses a composite endpoint consisting of benefit and risk, hence, making the core of the design of the study, to assess benefit and risk. The proposed benefit risk measure consists of efficacy measure(s) and a risk measure that is based on a composite score obtained from pre-defined adverse events of interest (AEI). This composite score incorporates full aspects of adverse events of interest (i.e. the incidence, severity, and duration of the events). We call this newly proposed score the AEI composite score. After specifying the priorities between the components of the composite endpoint, a win-statistic (i.e. win ratio, win odds, or net benefit) is used to assess the difference between treatments in this composite endpoint. The power and sample size requirements of such a trial design are explored via simulation. Finally, using Dupixent published adult study results, we show how we can design a paediatric trial where the primary outcome is a composite of prioritized outcomes consisting of efficacy endpoints and the AEI composite score endpoint. The resulting trial design can potentially substantially reduce sample size compared to a trial designed to assess the co-primary efficacy endpoints, therefore it may address the challenge of slow enrollment and patient availability for paediatric studies.

ICH E9(R1) introduces the estimand framework to strengthen dialogues between sponsors and regulators during drug development. A well-structured benefit-risk assessment (BRA) framework also intends to facilitate communication among stakeholders. However, the estimand in ICH E9(R1) is written mainly from the perspective of a single measure of treatment effect in clinical trials. There is lack of systematic discussion on estimand in the context of BRA. This paper initiates the BRA discussion under the estimand framework. By identifying two types of BRA approaches, we summarize and discuss completed clinical trials, using the estimand language for BRA. Benefits and challenges of using estimand for BRA are also discussed.

BACKGROUND:In 2015, a Brisbane tertiary hospital's cardiac unit implemented a new model of multidisciplinary care (Better Cardiac Care (BCC)) for Aboriginal and Torres Strait Islander patients. Since then, clinical indicators for Aboriginal and Torres Strait Islander cardiac patients have improved, but the recipients' voices have not been heard. This research aimed to determine the acceptability and appropriateness, features of value, and opportunities for improvements in this model of care, from the perspective of patients and their family members.METHODS:This descriptive qualitative study employed a narrative methodology. BCC Health Workers contacted prospective participants; with consent, interested individuals were then contacted by the Aboriginal Research Officer (RO) who arranged yarning sessions and consent. Family members were also invited to share their stories of their loved ones' hospitalisation. Two researchers conducted the interviews, using a yarning approach. Inductive narrative analysis, informed by Aboriginal and Torres Strait Islander ways of Being, Knowing, and Doing, focused on enabling participants' stories to be heard and understood from their perspectives.RESULTS:Relationality was at the heart of the BCC model of care, particularly between patients and Aboriginal and Torres Strait Islander staff. The relationality included a responsibility for holistic care, extending beyond hospital discharge, although support and handover for family members required improvement. The Aboriginal and Torres Strait Islander staff understood the contextual and structural challenges faced by participants, including the disempowerment and racism experienced in healthcare. This understanding was shared with the BCC team who, in turn, protected, advocated for, and holistically supported participants through their cardiac health journeys.CONCLUSIONS:Empowering (and employing) Aboriginal and Torres Strait Islander staff, and relating to patients as people, enabled BCC to meet Aboriginal and Torres Strait Islander patient's needs and improve outcomes. The wider health system and health academia could benefit from exploring and valuing Aboriginal and Torres Strait Islander discourses of relationality.

A comprehensive review of relevant clinical literature on evidence-based recommendations and existing prediction models specific to lung cancer surgery was undertaken. Preoperative risk assessment parameters such as pulmonary function tests (PFT), cardiopulmonary exercise testing (CPET), Brunelli models, Thoracoscore and frailty were analyzed for predicting postoperative risk of complications.When assessing fitness for surgery, the primarily used PFT parameters such as predictive postoperative forced expiratory volume in one second (FEV1) and diffusion capacity for carbon monoxide (DLCO ) showed conflicting evidence in determining a positive correlation with postoperative mortality. CPET variables predicted higher complication risk when VO2peak < 10ml/kg/min, AT < 11ml/kg/min and ventilation/carbon dioxide production (VE/VCO2) was in range of 34-40. While a cardiac risk index like the Thoracic Revised Cardiac Risk Index (ThRCRI) predicted major cardiovascular compromise, a thoracic risk index like Thoracoscore proved imprecise. Lastly, frailty is used to risk stratify patients in clinical practice but a recognized validated model specific to thoracic surgery is non-existent.When considering patients for lung cancer surgery, some dilemma exists regarding the accuracy of clinical prediction models and their external validation. There is a pressing need for the development of a consolidated clinically robust risk stratification model to predict complications after thoracic resections.