Exploring the readiness of the Irish healthcare system to adopt advanced therapies: a scoping review protocol.

Aim: Advanced therapy medicinal products (ATMPs) are medicines for human use that are based on genes, tissues or cells. They offer groundbreaking new opportunities for the treatment of disease and injury. However, ATMP adoption requires adjustments to current clinical practices and frameworks. This study investigates the readiness of the Irish healthcare system to adopt licensed ATMPs. Materials & methods: Scoping review, guided by the preferred reporting items for systematic reviews and meta-analyses - scoping review extension. A systematic search of English articles from 2013 to 2023 (published and grey literature) will be conducted. Results: Findings will be presented via narrative summary, graphical and tabular formats. Discussion: Review findings will be discussed in the context of recommendations that will inform national policy and strategy on the adoption of ATMPs in Ireland.

This study examines whether Ireland's healthcare system is ready to use new kinds of medicines called advanced therapy medicinal products (ATMPs). These medicines are made from genes, tissues or cells and can be effective in treating certain diseases. However, delivering these medicines might mean changing current practices in clinics and hospitals.A scoping review will examine publications from 2013 to 2023 that focus on this topic. Results will be reported via narrative summary, graphs and tables. A discussion of the findings will be completed to inform recommendations for preparing the Irish healthcare system to deliver ATMPs.Ethics and dissemination: Ethical approval is not required for this scoping review. Findings will be disseminated through publication, stakeholder meetings and public engagement.

Risk Factors and Modifiers for Cardiovascular Disease Assessment of Patients with Heterozygous Familial Hypercholesterolaemia.

Background: The assessment of the risk of cardiovascular disease (CVD) in patients with heterozygous familial hypercholesterolemia (HeFH) is determined by conventional risk factors. However, factors modifying CVD, or risk modifiers, beyond conventional risk factors may inform their CVD risk assessment and the subsequent use of new therapies. This work identifies and characterises patients within a lipid clinic cohort with regards to conventional CVD risk factors and risk modifiers with a focus on those with HeFH. Methods: A study of consecutive adult patients attending our specialist lipid clinic was performed over a six-month period. The patient data recorded included demographics, clinical characteristics, risk factors and risk modifiers, biochemical profiles and genetic testing results. Risk modifiers were identified based on ESC/EAS guidance, and those with HeFH were compared to those without. Results: A total of 370 patients were included. Of these, 98 HeFH patients were identified (26%). Then, 52% of HeFH patients were stratified into the very-high risk category due to the presence of CVD risk factors. Risk modifiers were present in 73%. These included a family history of premature CVD (56%), obesity (28%), a sedentary lifestyle (13%) and a major psychiatric disorder (12%). Compared to the rest of the cohort, those with HeFH were less likely to have hypertension and more likely to have a family history of premature CVD. Conclusions: Half of patients with HeFH are categorised as having very high CV risk. Consideration of risk modifiers, particularly a family history of premature CV disease, increases this very-high-risk category further. This may have implications for the clinical application and access to novel treatments.

Patient perspectives about treatment preferences for obesity with complications.

Objective: Obesity and many of its comorbidities can be improved by nutritional therapy, lifestyle modification, pharmacotherapy, and surgical intervention. Relatively little is known about patients' preferences for the range of obesity treatments. The present study was undertaken to identify factors that may influence these preferences. By evaluating patient-preferred treatment options and factors influencing patients, treatment adherence and efficacy may be improved. Our objective was to identify factors that influence patient preferences and subsequent choice of obesity treatment among those seeking treatment for obesity-related complications. Methods: Participatory action research, using purposeful sampling, was used to recruit 33 patients with obesity complications. Recruitment took place in specialist clinics for non-alcoholic fatty liver disease, diabetes, hypertension, and chronic kidney disease. Sixteen males and 17 females aged 18-70 years with a BMI>35 kg/m2 were recruited. Prior to the interview, participants watched a 60-min video explaining nutritional therapies, pharmacotherapies, and surgical therapies in equipoise. Data were collected in one-to-one semi-structured interviews using zoom or the telephone; reflective thematic analysis was used. Results: Four themes emerged: 1) structural factors, 2) autonomy, 3) interaction with formal care, and 4) the emotional and physical consequences of obesity. 39% of participants preferred nutritional therapy with support from medical professionals. 27% chose bariatric surgery. 24% chose pharmacotherapy alone, while 6% chose pharmacotherapy combined with nutritional therapy, 3% of participants wanted no intervention. Conclusion: The challenges can be addressed by increasing support for healthcare professionals toward enhancing both their knowledge and the health literacy of patients. Future research should focus on improving access to treatment pathways for patients as well as developing health literacy programs and educational programs for healthcare professionals.

Changes in anticoagulation practice in subjects admitted with stroke associated with atrial fibrillation, following introduction of direct oral anticoagulants over 2013-2021.

BACKGROUND: The adoption of direct oral anticoagulants (DOACs) has changed practice in prevention of stroke in atrial fibrillation (AF). We used Irish data national data on stroke and anticoagulation therapy over 9 years to investigate changes in anticoagulation practice and potential consequences on stroke prevalence and thrombolysis. METHODS: AF, anticoagulation, thrombolysis, and stroke data from the Irish National Audit of Stroke (INAS) 2013-2021 were reviewed. The proportion of patients with ischemic stroke (IS) and intracerebral hemorrhage (IH) with known AF admitted on anticoagulation was determined. Effects on age distribution in the population and thrombolysis practice were assessed. RESULTS: AF data were available on 34,630 of 35,241 individuals (98.3%) included in INAS; median age was 74 years and 56% were male. AF was found in 10,016 (28.9%, 9059 IS, 957 IH). 6313 had known AF prior to stroke (63.1%). The proportion all total IS due to AF decreased by 15.3% (31.3%-26.5%, chi-square = 24.6, p < 0.0001). The proportion of IH did not change significantly (21.6%-20.2%, chi-square = 1.8, p = 0.18). Over the 9 years, 3875 (38.6%) of the subjects with AF were recorded as receiving anticoagulants at admission. In 2013, 4.4% of AF-associated strokes were admitted on a DOAC and 21.4% on warfarin; by 2021, 44.1% were receiving a DOAC and 6.2% warfarin. There was a strong inverse correlation between the proportion of anticoagulated stroke patients and the total proportion of AF-associated strokes over time (r = -0.82, p = 0.006). In contrast, no correlation was found between increasing DOAC usage and IH (r = 0.14, p = 0.71). Increased anticoagulation usage correlated with a reduction in patients ⩾ 80 years (r = -0.83, p = 0.006) and also correlated with a relative reduction of 30.1% in subjects thrombolysed <4 h from onset (r = -0.89, p = 0.001). CONCLUSION: DOACs have led to increased use of anticoagulation, but warfarin use fell by two-thirds. There has been a reduction in the proportion of AF-associated IS without a noticeable increase in IH. Increased anticoagulation correlated with reduced numbers of strokes in those >80 years and in the proportion of patients thrombolysed.

The Effect of Semaglutide on Blood Pressure in Patients without Diabetes: A Systematic Review and Meta-Analysis.

(1) Background: Recent advances in the pharmacological treatment of obesity with glucagon-like peptide-1 receptor agonists (GLP-1 RA) highlight the potential to target excess body weight to improve blood pressure (BP). This review aimed to determine the BP reduction in trials of semaglutide for weight reduction in patients without diabetes. (2) Methods: Relevant studies were identified via a search of research databases. Studies were screened to include randomized controlled trials (RCTs) of semaglutide versus a placebo in adults. Pooled and sensitivity analyses were performed, and risk of bias was assessed. (3) Results: six RCTs, with 4744 participants, were included in the final analysis. At baseline, the cohorts in these studies had a mean BP in the normotensive range. The mean difference in systolic BP was -4.83 mmHg (95% CI: -5.65 to -4.02), while that for diastolic BP was -2.45 mmHg (95% CI: -3.65 to -1.24). All included studies were of a high methodological quality. (4) Conclusions: A clinically significant reduction in BP was evident following semaglutide treatment in normotensive populations without diabetes. The effect of semaglutide in those with obesity and hypertension is as yet undetermined. Targeting excess body weight may be a novel therapeutic strategy for these patients.

The DA VINCI study: is Ireland achieving ESC/EAS guideline-directed LDL-C goals?

BACKGROUND: The EU-wide, cross-sectional observational study of lipid-lowering therapy (LLT) use in secondary and primary care (DA VINCI) assessed the proportion of patients achieving low-density lipoprotein cholesterol (LDL-C) goals recommended by the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines and provided an insight into regional use of LLT in Europe, including Ireland. AIMS: This analysis focuses on data from patients in Ireland who participated in the DA VINCI study. METHODS: The DA VINCI study enrolled patients receiving LLT at primary and secondary care sites across 18 European countries between June 2017 and November 2018. The study assessed the achievement of risk-based 2016 and 2019 ESC/EAS LDL-C goals. This subgroup analysis aimed to evaluate LDL-C goal attainment in an Irish cohort of primary and secondary care patients. RESULTS: In total, 198 patients from Ireland were enrolled from three primary care and three secondary care centres. Most patients were White and male, and were receiving moderate- or high-intensity statin therapy (most frequently atorvastatin or rosuvastatin). Few patients (< 10%) were receiving combination therapy of statin and ezetimibe. Approximately 60% of patients achieved their 2016 ESC/EAC LDL-C goals while less than half the patients achieved their 2019 ESC/EAS goals. Approximately half of secondary prevention patients achieved their 2016 ESC/EAS goals and only 20% of secondary prevention patients achieved their 2019 ESC/EAS goals. CONCLUSIONS: These results highlight the disparity between dyslipidaemia management in clinical practice in Ireland and guideline recommendations. TRIAL REGISTRATION: ENCePP; EU PAS 22,075; date registered 06 February 2018.

Clinical characteristics of two groups commonly referred to an Irish hypertension service-patients with resistant hypertension and young adults with hypertension.

BACKGROUND: The management of hypertension is primarily performed in primary care settings in many health systems. However, two groups of patients often require specialist input: patients with resistant hypertension (RH) and young adults with hypertension. AIMS: To elucidate these groups by examining the characteristics of patients attending an Irish hypertension service, thus informing future management of hypertension. METHODS: Patients were recruited at consecutive hypertension clinics at St James Hospital, Dublin from July to September 2019. Following patient consent, patient data were recorded to identify patient characteristics as well as the results of investigations, blood pressure (BP) measurements and the anti-hypertensive treatment of the study participants which were then analysed. RESULTS: Two hundred thirty-six patients were included in the study. Compared to those without RH, the RH group were more likely to be obese (OR 2.59 [95% CI 1.06 to 6.33]), to have cardiovascular disease (OR 3.07 [95% CI 1.56 to 6.02]) and to have a non-dipping BP pattern (OR 3.86 [95% CI 1.57 to 9.47]). Young adults comprised 27% of the cohort. Forty-seven percent of these patients were obese, 15.9% had hypertension in pregnancy and 22.2% had chronic headaches. Despite being prescribed less anti-hypertensives (1.41 vs 2.28; p < 0.05), the majority of young patients had a BP less than 140/90 mmHg, comparing favourably with older patients (OR 2.25 [95% CI 1.20 to 4.27]). CONCLUSION: This contemporary study highlights the high prevalence of obesity among RH patients and young adults with hypertension. Findings suggest that programs to combat hypertension must include interventions to address obesity.

Referrals to, and characteristics of patients attending a specialist hypertension clinic.

The management of hypertension is suboptimal in Ireland and internationally. The role of a specialist hypertension clinic is not always defined but an analysis of the reasons for referral are likely informative. Also, a description of the clinical characteristics of patients with hypertension will inform requirements for comprehensive hypertension management in the community and secondary care. Patients were recruited at consecutive hypertension clinics at St James Hospital, Dublin from July to September 2019. Reasons for referral, clinical characteristics of patients, their investigations and treatment were analyzed. 236 patients were included in the study. The majority of patients, 83%, were obese or overweight. A family history of hypertension was a frequent finding with 70.8% of patients reporting same. 26.7% of patients were under the age of 40. 78% of referrals were from primary care and the most referrals were to investigate secondary causes of hypertension or because the patient was ≤40 years of age. Calcium channel blockers were the treatment most frequently prescribed (51.7%). Clinic blood pressure for the cohort was 137/81 mmHg and this was replicated by their ambulatory BP. This insight into the contemporary management of hypertension highlights the frequency of obesity and a positive family history in those with hypertension. Most referrals were consistent with international guidance though deviations were evident. Findings suggest a national program for hypertension with greater focus on public health interventions and better resourcing of primary care is required.

Collaboration, supervision and patient safety in the era of COVID-19: an analysis of medical wards and ICU.

AIMS: COVID-19 resulted in significant changes across medical wards and ICU in St James's Hospital Dublin. This included the implementation of ward-based medical teams (WBMT). The purpose of this study was to identify how these structural changes affected inter-professional collaboration, supervision and patient safety. METHODS: Questionnaires were distributed to doctors working on medical wards and ICU at the height of the first wave of COVID-19. The sense of collaboration, patient safety and supervision were assessed. RESULTS: Fifty-three doctors took part in the study. Thirty-three (62%) felt that collaboration was better than normal. Forty-six (87%) of participants described supervision as "good" or "excellent". Thirty-one out of 40 participants (77%) felt that patient safety was better than normal. DISCUSSION: Implementation of WBMT may result in improved sense of collaboration, supervision and patient safety during COVID-19; however, the increased sense of solidarity and comradery felt during the initial surge make drawing these conclusions challenging.

The association between increasing oral anticoagulant prescribing and atrial fibrillation related stroke in Ireland.

AIMS: Recent increases in the number of patients with atrial fibrillation (AF) prescribed oral anticoagulants (OAC) are evident in Ireland and internationally, largely due to the availability of direct oral anticoagulants (DOACs). This study aimed to determine the rate of stroke in the context of increasing anticoagulation utilisation, with a focus on AF-related ischaemic stroke (IS). METHODS: Dispensing data for OACs were identified for the period 2010-2018 as well as hospital discharges for IS (2005-2018). Irish National Stroke Register data were used to elucidate the characteristics of patients with acute ischaemic stroke. RESULTS: The number of patients prescribed OACs increased by 94% from 2010-2018 with a significant change from 2013 (ß = 2.57, P = .038), associated with a large increase in the number of patients on DOACs. There was 3.3-fold increase in expenditure on OACs nationally from 2013 to 2018, of which 94% was DOAC related. Using the 2013 timepoint, ischaemic stroke rates until 2018 did not show a significant deviation from the previous trend (ß = 0.00, P = .898). The percentage of AF-related ischaemic stroke was stable from 2013 to 2017 with a 4.5% decrease in 2018. The percentage of ischaemic stroke patients with previously diagnosed AF decreased from 2013 to 2018; however, there was an increase in the percentage of ischaemic strokes while on OAC in this cohort. CONCLUSION: Large increases in OAC utilisation have not resulted in changes in ischaemic stroke rates at a national level. The percentage of ischaemic strokes with a previous diagnosis of AF has decreased indicating a possible benefit from greater OAC utilisation. However, the percentage presenting with an ischaemic stroke while on OAC treatment is increasing. The increase in patients presenting with stroke while treated with OAC may largely reflect the national increase in patients prescribed DOACs but the findings raise concerns about treatment failures. The real-world effectiveness of DOACs requires further examination.

Estimating the Theoretical Cost Implications of Funding New Drugs Considered Not to Be Cost-Effective.

This study aims to estimate the theoretical excess expenditure that would be incurred by the Irish state-payer, should drugs be reimbursed at their original asking ("list") price rather than at a price at which the drug is considered cost-effective. In Ireland, all new drugs are evaluated by the National Centre for Pharmacoeconomics. For this study, drugs that were submitted by pharmaceutical companies from 2012 to 2017 and considered not cost-effective at list price were reviewed. A total of 43 such drugs met our inclusion criteria, and their pharmacoeconomic evaluations were further assessed. The price at which the drug could be considered cost-effective (cost-effective price) at the upper cost-effectiveness threshold used in Ireland (€ 45 000/quality adjusted life-year) was estimated for 18 drugs with an available cost-effectiveness model. Then, for each drug, the list price and cost-effective price (both per unit) were both individually applied to 1 year of national real-world drug utilization data. This allowed the estimation of the expected expenditures under the assumptions of list price paid and cost-effective price paid. The resulting theoretical excess expenditure, the expenditure at list price minus the expenditure at the cost-effective price, was estimated to be €108.2 million. This estimate is theoretical because of the confidentiality of actual drug prices. The estimation is calculated using the list price and likely overestimates the actual excess expenditure, which would reduce to zero if cost-effective prices are agreed. Nevertheless, this estimate illustrates the importance of a process to assess the value of new drugs so that potential excess drug expenditure is identified.

Assessment of an electronic patient record system on discharge prescribing errors in a Tertiary University Hospital.

BACKGROUND: Prescribing error represent a significant source of preventable harm to patients. Prescribing errors at discharge, including omission of pre-admission medications (PAM), are particularly harmful as they frequently propagate following discharge. This study assesses the impact of an educational intervention and introduction of an electronic patient record (EPR) in the same centre on omission of PAM at discharge using a pragmatic design. A survey of newly qualified doctors is used to contextualise findings. METHODS: Discharge prescriptions and discharge summaries were reviewed at discharge, and compared to admission medicine lists, using a paper-based chart system. Discrepancies were noted, using Health Information and Quality Authority guidelines for discharge prescribing. An educational intervention was conducted. Further review of discharge prescriptions and discharge summaries took place. Following introduction of an EPR, review of discharge summaries and discharge prescriptions was repeated. A survey was administered to recently qualified doctors (interns), and analysed using descriptive statistics and thematic analysis. RESULTS: Omission of PAM as prescribed or discontinued items at discharge occurs frequently. An educational intervention did not significantly change prescribing error rates (U = 1255.5, p = 0.206). EPR introduction did significantly reduce omission of PAM on discharge prescribing (U = 694, p < 0.001), however there was also a reduction in the rate of deliberate discontinuation of PAM at discharge (U = 1237.5, p = 0.007). Survey results demonstrated that multiple sources are required to develop a discharge prescription. Time pressure, access to documentation and lack of admission medicine reconciliation are frequently cited causes of discharge prescribing error. CONCLUSION: This study verified passive educational interventions alone do not improve discharge prescribing. Introduction of EPR improved discharge prescribing, but negatively impacted deliberate discontinuation of PAM at discharge. This is attributable to reduced access to key sources of information used in formulating discharge prescriptions, and separation of the discontinuation function from the prescribing function on the EPR discharge application.

Efficacy and Safety of Armolipid Plus®: An Updated PRISMA Compliant Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials.

Armolipid Plus® is a multi-constituent nutraceutical that claims to improve lipid profiles. The aim of this PRISMA compliant systematic review and meta-analysis was to globally evaluate the efficacy and safety of Armolipid Plus® on the basis of the available randomized, blinded, controlled clinical trials (RCTs). A systematic literature search in several databases was conducted in order to identify RCTs assessing the efficacy and safety of dietary supplementation with Armolipid Plus®. Two review authors independently identified 12 eligible studies (1050 included subjects overall) and extracted data on study characteristics, methods, and outcomes. Meta-analysis of the data suggested that dietary supplementation with Armolipid Plus® exerted a significant effect on body mass index (mean difference (MD) = -0.25 kg/m2, p = 0.008) and serum levels of total cholesterol (MD = -25.07 mg/dL, p < 0.001), triglycerides (MD = -11.47 mg/dL, p < 0.001), high-density lipoprotein cholesterol (MD = 1.84 mg/dL, p < 0.001), low-density lipoprotein cholesterol (MD = -26.67 mg/dL, p < 0.001), high sensitivity C reactive protein (hs-CRP, MD = -0.61 mg/L, p = 0.022), and fasting glucose (MD = -3.52 mg/dL, p < 0.001). Armolipid Plus® was well tolerated. This meta-analysis demonstrates that dietary supplementation with Armolipid Plus® is associated with clinically meaningful improvements in serum lipids, glucose, and hs-CRP. These changes are consistent with improved cardiometabolic health.

Effect of an Online Reimbursement Application System on Prescribing of Lidocaine 5% Medicated Plaster in the Republic of Ireland.

BACKGROUND: The lidocaine 5% medicated plaster, Versatis®, has one therapeutic indication listed on the Summary of Product Characteristics-symptomatic relief of post-herpetic neuralgia (PHN) in adults. Increased expenditure on Versatis® suggests that there is considerable off-label use. To support the appropriate use of Versatis®, the Health Service Executive's Primary Care Reimbursement Service (PCRS) introduced a reimbursement application system for Versatis® from 1 September 2017. OBJECTIVE: The aim of this study was to investigate the effect of introducing a reimbursement application system on Versatis® prescribing under the General Medical Services (GMS) scheme. METHODS: This study was carried out using prescription dispensing data from the PCRS pharmacy claims database. We carried out segmented linear regression to assess changes in the Versatis® prescribing rate per 1000 GMS eligible population, before and after the introduction of the online reimbursement application system. RESULTS: The results of the segmented regression analysis show that there was a statistically significant level (- 4.91, p < 0.001) and trend change (- 0.69, p < 0.001) in the rate of Versatis® prescribing post-introduction of the reimbursement application system. In the year prior to the introduction of the system, 2016, the annual GMS expenditure on Versatis® lidocaine 5% patches was over €27 million, whereas the GMS expenditure in 2018 was reduced to just over €2 million. CONCLUSION: In our study, a substantial decrease in the dispensing of Versatis® was seen after the implementation of a reimbursement application system. Prescribing of Versatis® should be restricted to patients with a diagnosis of PHN not only to reduce costs, but to ensure evidence-based use of this medication.

Sacubitril/valsartan (Entresto) utilisation and prescribing patterns in the context of a reimbursement application system.

AIMS: Entresto (sacubitril/valsartan) is used to treat symptomatic chronic heart failure with reduced ejection fraction. Given its high potential budget impact, the Health Services Executive introduced a reimbursement application system (RAS) to ensure its appropriate use. The aim of this study was to evaluate the utilisation of Entresto in Ireland and compare patient characteristics to those of the pivotal PARADIGM-HF trial. METHODS: We used dispensed claims data from the Primary Care Reimbursement Services, clinical data obtained from the RAS, and data from published studies of Entresto utilisation. Differences in the baseline characteristics in the study populations vs the Entresto arm of the PARADIGM-HF trial were analysed. We also investigated cardiovascular medication use in the 6 months pre- and post-Entresto initiation. RESULTS: In 2018, there were 1043 individuals receiving Entresto, corresponding to an expenditure of €1.2 million. Patients prescribed Entresto in Ireland were older, had lower left ventricular ejection fraction and were more symptomatic than those in the PARADIGM-HF trial. Irish patient characteristics were reflective of Entresto-treated populations in other real-world studies. More than 63% of patients were commenced on the lowest Entresto dose. Entresto initiation was associated with a reduction in the use of other medications for heart failure. CONCLUSION: The utilisation of Entresto has been steadily increasing in Ireland since its reimbursement approval. The expenditure in the first year was substantially lower than predicted, and the RAS is an example of how health technology management can facilitate appropriate and cost-effective use of medicines.

Safety Evaluation of α-Lipoic Acid Supplementation: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Clinical Studies.

Alpha-lipoic acid (ALA) is a natural short-chain fatty acid that has attracted great attention in recent years as an antioxidant molecule. However, some concerns have been recently raised regarding its safety profile. To address the issue, we aimed to assess ALA safety profile through a systematic review of the literature and a meta-analysis of the available randomized placebo-controlled clinical studies. The literature search included EMBASE, PubMed Medline, SCOPUS, Google Scholar, and ISI Web of Science by Clarivate databases up to 15th August 2020. Data were pooled from 71 clinical studies, comprising 155 treatment arms, which included 4749 subjects with 2558 subjects treated with ALA and 2294 assigned to placebo. A meta-analysis of extracted data suggested that supplementation with ALA was not associated with an increased risk of any treatment-emergent adverse event (all p > 0.05). ALA supplementation was safe, even in subsets of studies categorized according to smoking habit, cardiovascular disease, presence of diabetes, pregnancy status, neurological disorders, rheumatic affections, severe renal impairment, and status of children/adolescents at baseline.