Uptake of new antidiabetic medicines in 11 European countries.

BACKGROUND: Several new antidiabetic medicines (GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors) have been approved by the European Medicines Agency since 2006. The aim of this study was to evaluate the uptake of new antidiabetic medicines in European countries over a 10-year period. METHODS: The study used IQVIA quarterly value and volume sales data January 2006-December 2016. The market uptake of new antidiabetic medicines together with intensity of prescribing policy for all antidiabetic medicines were estimated for Austria, Croatia, France, Germany, Hungary, Italy, Poland, Slovenia, Spain, Sweden, and the United Kingdom. The following measures were determined: number of available new active substances, median time to first continuous use, volume market share, and annual therapy cost. RESULTS: All countries had at least one new antidiabetic medicine in continuous use and an increase in intensity of prescribing policy for all antidiabetic medicines was observed. A tenfold difference in median time to first continuous use (3-30 months) was found. The annual therapy cost in 2016 of new antidiabetic medicines ranged from EUR 363 to EUR 769. Among new antidiabetic medicines, the market share of DPP-4 inhibitors was the highest. Countries with a higher volume market share of incretin-based medicines (Spain, France, Austria, and Germany) in 2011 had a lower increase in intensity of prescribing policy. This kind of correlation was not found in the case of SGLT-2 inhibitors. CONCLUSIONS: This study found important differences and variability in the uptake of new antidiabetic medicines in the included countries.

The association between medication or alcohol use and the incidence of frailty: a retrospective cohort study.

BACKGROUND: Understanding potentially modifiable factors that influence the risk of frailty is a key concern for the management of this urgent contemporary public health challenge. This study evaluates the association between the use of various medications or alcohol and the incidence of frailty among older adults. METHODS: This study was a retrospective cohort study on older adults (≥ 65 years) using data from the longitudinal Survey of Health, Ageing and Retirement in Europe (SHARE survey, 28 countries). Medication use was measured as taking several different groups of medications. Alcohol use was assessed with SHARE questions corresponding to AUDIT-C. The outcome measure was the incidence of frailty after two years, defined by frailty index (FI) and frailty phenotype (FP). A multiple logistic regression model was used to evaluate the association with adjustment for several potential confounding factors. RESULTS: Of the 14,665 FI-population participants, 1800 (12.3%) developed frailty within two years. Of the 8133 FP-population participants, 2798 (34.4%) developed pre-frailty and 247 (3.0%) developed frailty within two years of baseline. After adjustment for potential confounding variables, non-hazardous alcohol use (adjusted OR; 95% CI for the FI-population: 0.68; 0.60-0.77) and hazardous alcohol use (0.80; 0.68-0.93) are associated with lower incidence of frailty compared to no alcohol use. The odds of frailty are increased when taking medications; the largest effect size was observed in older adults taking medication for chronic bronchitis (adjusted OR; 95% CI for the FI-population: 2.45; 1.87-3.22), joint pain and other pain medication (2.26; 2.00-2.54), medication for coronary and other heart disease (1.72; 1.52-1.96), medication for diabetes (1.69; 1.46-1.96), and medication for anxiety, depression and sleep problems (1.56; 1.33-1.84). Additionally, the risk of frailty was increased with stroke, Parkinson's disease and dementia. CONCLUSIONS: Taking certain groups of medication was associated with increased incidence of frailty and pre-frailty, which might be due to either medication use or the underlying disease. Alcohol use was associated with a lower risk of pre-frailty and frailty compared to no alcohol use, which might be due to reverse causality or residual confounding. There was no significant interaction effect between medication groups and alcohol use on frailty incidence.

Improved adherence with Medicines Use Review service in Slovenia: a randomized controlled trial.

BACKGROUND: Based on several existing patient-oriented activities, Medicines Use Review (MUR) service was standardized and officially adopted in Slovenia in 2015. Service aims to provide adherence support and ensure safe and effective medicines use. Therefore, the aim of the study was to evaluate the benefits of MUR in Slovenia, primarily the impact on medication adherence. METHODS: A randomised controlled trial was performed in community pharmacies to compare MUR with standard care. Patients were randomised into either the test (patients received MUR by a certified MUR provider at visit 1), or control group. The study primary outcome was self-reported adherence to multiple medications, assessed by electronic ©Morisky Widget MMAS-8 Software at the first visit (V1) and after 12 weeks (V2). A sub-analysis of intentional and unintentional non-adherence was performed. MUR impact was defined as the relative difference in ©MMAS-8 score after 12 weeks between the test and control group. A multiple linear regression model was used to predict MUR impact based on baseline adherence (low versus medium and high). Several secondary outcomes (e.g. evaluation of drug-related problems (DRPs)) were also assessed. RESULTS: Data from 153 (V1) and 140 (V2) patients were analysed. Baseline adherence was low, moderate and high in 17.6, 48.4 and 34.0% patients, respectively. In the low adherence subpopulation, test group patients showed a 1.20 point (95% CI = 0.16-2.25) increase in total ©MMAS-8 score (p = 0.025) compared to control group patients. A 0.84 point (95% CI = 0.05-1.63) increase was due to intentional non-adherence (p = 0.038), and a 0.36 point (95% CI = - 0.23-0.95) was due to unintentional non-adherence (p = 0.226). Additionally, statistically significant decrease in the proportion of patients with manifested DRPs (p < 0.001) and concerns regarding chronic medicines use (p = 0.029) were revealed. CONCLUSION: MUR service in Slovenia improves low medication adherence and is effective in addressing DRPs and concerns regarding chronic medicines use. TRIAL REGISTRATION: ClinicalTrials.gov - NCT04417400 ; 4th June 2020; retrospectively registered.

Inhalation technique and asthma outcomes with different corticosteroid-containing inhaler devices.

Objective: Inhaler devices must be used correctly to ensure the effectiveness of the asthma treatment. This study evaluated inhalation technique across different types of corticosteroid-containing inhaler devices as well as health outcomes in patients with asthma. Methods: In a cross-sectional study, we evaluated inhaler technique by observing patients' handling of the inhaler devices and using checklists for four inhaler types, namely Diskus (n = 52), pressure metered dose inhalers (pMDIs; n = 41), Turbuhaler (n = 36) and Twisthaler (n = 16). We also collected data on patients' characteristics, asthma therapy, exacerbations, medication adherence (8-item Morisky Medication Adherence Scale), asthma control (Asthma Control Test) and quality of life (Saint George Respiratory Questionnaire). Results: In total, we included 145 patients. The mean (SD) age of the patients was 54.5 (18.9) years and 57% were female. The majority of the patients (70%) made at least one error in their inhalation technique. Patients using Turbuhaler performed the highest number of elements correctly, followed by pMDIs, Twisthaler and Diskus. Patients with Diskus or Twisthaler had better adherence compared with patients using pMDIs or Turbuhaler. Patients using Twisthaler had better asthma outcomes than patients using the other device types. Conclusions: Most patients with asthma made mistakes when handling their inhaler devices, especially those using Diskus. However, in addition to the device type being used, patients' characteristics, asthma therapy and medication adherence also played an important role in achieving good health outcomes.

Patient Access to Medicines for Rare Diseases in European Countries.

BACKGROUND: The number of authorized orphan and non-orphan medicines for rare diseases has increased in Europe. Patient access to these medicines is affected by high costs, weak efficacy/safety evidence, and societal value. European health care systems must determine whether paying for expensive treatments for only a few patients is sustainable. OBJECTIVES: This study aimed to evaluate patient access to orphan and non-orphan medicines for rare diseases in 22 European countries during 2005 to 2014. METHODS: Medicines for rare diseases from the Orphanet list, authorized during 2005 to 2014, were searched for in the IMS MIDAS Quarterly Sales Data, January 2005 - December 2014 (IQVIA, Danbury, CT). The following three measures were determined for each country: number of available medicines, median time to continuous use, and medicine expenditure. A medicine was considered available if uninterrupted sales within a 1-year period were detected. RESULTS: From 2005 to 2014, 125 medicines were authorized and 112 were found in the search. Of those, between 70 (63%) and 102 (91%) were available in Germany, the United Kingdom, Italy, France, and the Scandinavian countries. These countries were also the fastest to enable continuous use (3-9 mo). Only 27% to 38% of authorized medicines were available in Greece, Ireland, Bulgaria, Romania, and Croatia, which took 1 to 2.6 years to begin continuous use. A country's expenditure on medicines for rare diseases in 2014 ranged between €0.2 and €31.9/inhabitant. CONCLUSIONS: Patient access to medicines for rare diseases varies largely across Europe. Patients in Germany, Scandinavian countries, Switzerland, France, and the United Kingdom can access larger numbers of medicines in shorter time.

Decision-making criteria for medicine reimbursement in Slovenia: an expert panel discussion.

BACKGROUND: Rational and transparent Health Technology Assessment and reimbursement decision-making are crucial for healthcare system sustainability. A part of the reimbursement process are decision-making criteria which should be clearly defined. METHODS: The study aimed to obtain an insight into understanding and relevance of potential criteria for the medicine reimbursement decision-making process in Slovenia. A semi-structured guided focus panel was performed in June 2017 with five Slovenian experts covering principal healthcare system sectors. First, criteria understanding and relevance for medicine reimbursement decision-making were discussed. Second, healthcare priorities and societal values affecting decision-making were debated. The analysis was carried out with NVivo 11 by two independent researchers who coded the verbatim transcript in three coding steps based on the experts' interpretations and original ideas. RESULTS: Seven decision-making criteria were derived. Among those, the impact a disease has on the lives of patient family and caregivers and the indirect medicine benefit for them were new aspects comparing to the existing criteria set in Slovenia. The experts expressed that the same decision-making criteria are relevant for evaluating any health technology, allowing for different criteria weights. They also suggested a system that would allow re-evaluation of reimbursement decisions once real-world clinical data are available. CONCLUSIONS: As proposed by the international frameworks and tools, the Slovenian healthcare experts consider including multiple aspects more ethical and comprehensive than considering a single criterion, e.g. cost-effectiveness, existing in some healthcare systems. They recognize that in the existing decision-making process, health perspectives of the public represent a largely missed aspect.

Influence of generic reference pricing on medicine cost in Slovenia: a retrospective study.

AIM: To assess the impact of the generic reference pricing (GRP) system on the prices and cost of medicines in Slovenia approximately 8 years after its introduction in 2003 and before the implementation of the therapeutic reference pricing system. METHODS: A retrospective study of all medicines (N=789) included in the GRP system on January 31, 2012 was performed. Medicine prices and cost were analyzed between January 31, 2012 and December 31, 2013 after every update (N=11) of the maximum reimbursable price (MRP) and were compared to the price and cost on January 31, 2012 (index date). Time trends of different types of medicine prices (maximum allowed price, MRP, and actual wholesale price) were graphically analyzed, and actual wholesale price adjustments to the MRP changes and the budget impact of the GRP were assessed. RESULTS: In the 2-year study period, the long-term performance of the GRP system was associated with an approximate 45% decrease in the average MRP or an approximate 20% cost reduction. For each MRP update period, the GRP reduced the cost based on the maximum allowed price for approximately 30%. The wholesale price adjustments were mostly made for medicines priced above the MRP and reduced patients' out-of-pocket cost. CONCLUSIONS: In the long term, the GRP system effectively reduced medicine prices and the cost of reimbursed products.

Effects of synbiotic fermented milk containing Lactobacillus acidophilus La-5 and Bifidobacterium animalis ssp. lactis BB-12 on the fecal microbiota of adults with irritable bowel syndrome: A randomized double-blind, placebo-controlled trial.

We conducted a randomized double-blind, placebo-controlled multicentric study to investigate the influence of a synbiotic fermented milk on the fecal microbiota composition of 30 adults with irritable bowel syndrome (IBS). The synbiotic product contained Lactobacillus acidophilus La-5, Bifidobacterium animalis ssp. lactis BB-12, Streptococcus thermophilus, and dietary fiber (90% inulin, 10% oligofructose), and a heat-treated fermented milk without probiotic bacteria or dietary fiber served as placebo. Stool samples were collected after a run-in period, a 4-wk consumption period, and a 1-wk follow-up period, and were subjected to real-time PCR and 16S rDNA profiling by next-generation sequencing. After 4wk of synbiotic (11 subjects) or placebo (19 subjects) consumption, a greater increase in DNA specific for L. acidophilus La-5 and Bifidobacterium animalis ssp. lactis was detected in the feces of the synbiotic group compared with the placebo group by quantitative real-time PCR. After 1wk of follow-up, the content of L. acidophilus La-5 and B. animalis ssp. lactis decreased to levels close to initial levels. No significant changes with time or differences between the groups were observed for Lactobacillus, Enterobacteriaceae, Bifidobacterium, or all bacteria. The presence of viable BB-12- and La-5-like bacteria in the feces resulting from the intake of synbiotic product was confirmed by random amplification of polymorphic DNA (RAPD)-PCR. At the end of consumption period, the feces of all subjects assigned to the synbiotic group contained viable bacteria with a BB-12-like RAPD profile, and after 1wk of follow-up, BB-12-like bacteria remained in the feces of 87.5% of these subjects. The presence of La-5-like colonies was observed less frequently (37.5 and 25% of subjects, respectively). Next-generation sequencing of 16S rDNA amplicons revealed that only the percentage of sequences assigned to Strep. thermophilus was temporarily increased in both groups, whereas the global profile of the fecal microbiota of patients was not altered by consumption of the synbiotic or placebo. In conclusion, daily consumption of a synbiotic fermented milk had a short-term effect on the amount and proportion of La-5-like strains and B. animalis ssp. lactis in the fecal microbiome of IBS patients. Furthermore, both synbiotic and placebo products caused a temporary increase in fecal Strep. thermophilus.

Contribution of Slovenian community pharmacist counseling to patients' knowledge about their prescription medicines: a cross-sectional study.

AIM: To assess patients' knowledge about prescription medicines they are taking and their view on how much community pharmacist counseling contributed to their knowledge. METHODS: An observational study was designed to obtain information about patients' knowledge, their view on pharmacist counseling, and physicians'/pharmacists' provision of information. This study used a specifically designed questionnaire, which served as an interview guide. 400 patients picking up a prescription medicine were structurally interviewed upon leaving one of the 20 randomly chosen Slovenian pharmacies. The interviews took place in November and December 2013. RESULTS: Patients were familiar with general information about the medicines and their application (93%-100% of patients). Knowledge about considerations (16% of patients) and adverse effects (20% of patients) was limited. Factors associated with patient knowledge were physicians'/pharmacists' adequate provision of information (ß=0.259), patient's age (ß=- 0.149), patient's education (ß=0.100), and prescription type (ß=-0.104). Patients' responses were mostly consistent with the Summaries of Product Characteristics (72%-96% of responses). However, 42% of responses to the question about taking medicine with meals were incorrect. Pharmacists routinely informed the patients about medication purpose, dose, application rate, and timing of medication (in 72%, 89%, 89%, and 77% of cases, respectively). Other information was rarely offered. Patients with new prescriptions received significantly more counseling (pharmacist counseling score 5.9, 5.2, and 4.7 of maximum 10 for new, regular, and refill prescriptions, respectively, P=0.001) and obtained adequate labeling (69%, 26%, and 17% of patients for new, regular and refill prescriptions, respectively, P<0.001) than patients with regular or refill prescriptions. CONCLUSION: Patients were familiar with basic information about administration of their prescription medicines, but lacked knowledge about medication safety. This could be attributed to pharmacist counseling, which primarily focused on medicine use instructions.

The cost of systemic therapy for metastatic colorectal carcinoma in Slovenia: discrepancy analysis between cost and reimbursement.

BACKGROUND: The aim of the study was to estimate the direct medical costs of metastatic colorectal cancer (mCRC) treated at the Institute of Oncology Ljubljana and to question the healthcare payment system in Slovenia. METHODS: Using an internal patient database, the costs of mCRC patients were estimated in 2009 by examining (1) mCRC direct medical related costs, and (2) the cost difference between payment received by Slovenian health insurance and actual mCRC costs. Costs were analysed in the treatment phase of the disease by assessing the direct medical costs of hospital treatment with systemic therapy together with hospital treatment of side effects, without assessing radiotherapy or surgical treatment. Follow-up costs, indirect medical costs, and nonmedical costs were not included. RESULTS: A total of 209 mCRC patients met all eligibility criteria. The direct medical costs of mCRC hospitalization with systemic therapy in Slovenia for 2009 were estimated as the cost of medications (cost of systemic therapy + cost of drugs for premedication) + labor cost (the cost of carrying out systemic treatment) + cost of lab tests + cost of imaging tests + KRAS testing cost + cost of hospital treatment due to side effects of mCRC treatment, and amounted to €3,914,697. The difference between the cost paid by health insurance and actual costs, estimated as direct medical costs of hospitalization of mCRC patients treated with systemic therapy at the Institute of Oncology Ljubljana in 2009, was €1,900,757.80. CONCLUSIONS: The costs paid to the Institute of Oncology Ljubljana by health insurance for treating mCRC with systemic therapy do not match the actual cost of treatment. In fact, the difference between the payment and the actual cost estimated as direct medical costs of hospitalization of mCRC patients treated with systemic therapy at the Institute of Oncology Ljubljana in 2009 was €1,900,757.80. The model Australian Refined Diagnosis Related Groups (AR-DRG) for cost assessment in oncology being currently used is probably one of the reasons for the discrepancy between pay-outs and actual costs. We propose new method for more precise cost assessment in oncology.

Sedative load and anticholinergic burden among older adults in Slovenia over a decade: Potential for optimization of pharmacotherapy.

This study investigates the 10-year trend in the sedative and anticholinergic burden among older adults in Slovenia, with the aim of identifying opportunities to optimize pharmacotherapy in this population. A retrospective drug utilization analysis was conducted based on a national anonymized database of dispensed prescriptions from 2009 to 2019. The study employed the sedative load model and the anticholinergic cognitive burden scale to assess the sedative and anti cholinergic burden, respectively. The findings indicate that in 2019, 45.6 % and 40.8 % of older adults (≥ 65 years) used sedative and anticholinergic medications, respectively. A high sedative load and a clinically significant anticholinergic burden were observed in a considerable proportion of older adults (13.2 % and 11.2 %, respectively, in 2019). The age-standardized prevalence of sedative load and anti-cholinergic burden significantly decreased over the 10-year study period by 5.6 % and 1.7 %, respectively (absolute difference), while the prevalence of clinically significant anticholinergic burden remained stable. Notably, the age groups 85-89 years and above 90 years had an increase in the proportion of individuals with a clinically significant anticholinergic burden over the years. These results emphasize the need for targeted interventions, particularly in the oldest age groups, to promote safe and effective medication use among older adults.

Effectiveness of pharmacist-led medication reconciliation on medication errors at hospital discharge and healthcare utilization in the next 30 days: a pragmatic clinical trial.

Transitions of care often lead to medication errors and unnecessary healthcare utilization. Medication reconciliation has been repeatedly shown to reduce this risk. However, the great majority of evidence is limited to the provision of medication reconciliation within clinical trials and countries with well-established clinical pharmacy. Thus, this pragmatic, prospective, controlled trial evaluated the effectiveness of routine pharmacist-led medication reconciliation compared to standard care on medication errors and unplanned healthcare utilization in adult general medical patients hospitalized in a teaching hospital in Slovenia. All patients hospitalized in a ward where medication reconciliation was integrated into routine clinical practice were included in the intervention group and received admission and discharge medication reconciliation, coupled with patient counselling. The control group consisted of randomly selected patients from the remaining medical wards. The primary study outcome was unplanned healthcare utilization within 30 days of discharge, and the secondary outcomes were clinically important medication errors at hospital discharge and serious unplanned healthcare utilization within 30 days of discharge. Overall, 414 patients (53.4% male, median 71 years) were included-225 in the intervention group and 189 in the control group. In the intervention group, the number of patients with clinically important medication errors at discharge was significantly lower (intervention vs control group: 9.3% vs 61.9%). Multiple logistic regression revealed that medication reconciliation reduced the likelihood of a clinically important medication error by 20-fold, while a higher number of medications on admission was associated with an increased likelihood. However, no significant differences were noted in any and serious unplanned healthcare utilization (intervention vs control group: 33.9% vs 27.8% and 20.3% vs 14.6%, respectively). The likelihood of serious healthcare utilization increased with the age of the patient, the number of medications on admission and being hospitalized for an acute medical condition. Our pragmatic trial confirmed that medication reconciliation, even when performed as part of routine clinical practice, led to a substantial reduction in the risk of clinically important medication errors at hospital discharge but not to a reduction in healthcare utilization. Medication reconciliation is a fundamental, albeit not sufficient, element to ensure patient safety after hospital discharge. Clinical Trial Registration: https://clinicaltrials.gov/search?id=NCT06207500, identifier NCT06207500.

Deprescribing: An umbrella review.

This umbrella review examined systematic reviews of deprescribing studies by characteristics of intervention, population, medicine, and setting. Clinical and humanistic outcomes, barriers and facilitators, and tools for deprescribing are presented. The Medline database was used. The search was limited to systematic reviews and meta-analyses published in English up to April 2022. Reviews reporting deprescribing were included, while those where depre-scribing was not planned and supervised by a healthcare professional were excluded. A total of 94 systematic reviews (23 meta--analyses) were included. Most explored clinical or humanistic outcomes (70/94, 74 %); less explored attitudes, facilitators, or barriers to deprescribing (17/94, 18 %); few focused on tools (8/94, 8.5 %). Reviews assessing clinical or humanistic outcomes were divided into two groups: reviews with deprescribing intervention trials (39/70, 56 %; 16 reviewing specific deprescribing interventions and 23 broad medication optimisation interventions), and reviews with medication cessation trials (31/70, 44 %). Deprescribing was feasible and resulted in a reduction of inappropriate medications in reviews with deprescribing intervention trials. Complex broad medication optimisation interventions were shown to reduce hospitalisation, falls, and mortality rates. In reviews of medication cessation trials, a higher frequency of adverse drug withdrawal events underscores the importance of prioritizing patient safety and exercising caution when stopping medicines, particularly in patients with clear and appropriate indications.

Psychometric evaluation of the 5-item Medication Adherence Report Scale questionnaire in persons with multiple sclerosis.

The 5-item Medication Adherence Report Scale (MARS-5) is a reliable and valid questionnaire for evaluating adherence in patients with asthma, hypertension, and diabetes. Validity has not been determined in multiple sclerosis (MS). We aimed to establish criterion validity and reliability of the MARS-5 in persons with MS (PwMS). Our prospective study included PwMS on dimethyl fumarate (DMF). PwMS self-completed the MARS-5 on the same day before baseline and follow-up brain magnetic resonance imaging (MRI) 3 and 9 months after treatment initiation and were graded as highly and medium adherent upon the 24-cut-off score, established by receiver operator curve analysis. Health outcomes were represented by relapse occurrence from the 1st DMF dispense till follow-up brain MRI and radiological progression (new T2 MRI lesions and quantitative analysis) between baseline and follow-up MRI. Criterion validity was established by association with the Proportion of Days Covered (PDC), new T2 MRI lesions, and Beliefs in Medicines questionnaire (BMQ). The reliability evaluation included internal consistency and the test-retest method. We included 40 PwMS (age 37.6 ± 9.9 years, 75% women), 34 were treatment-naive. No relapses were seen during the follow-up period but quantitative MRI analysis showed new T2 lesions in 6 PwMS. The mean (SD) MARS-5 score was 23.1 (2.5), with 24 PwMS graded as highly adherent. The higher MARS-5 score was associated with higher PDC (b = 0.027, P<0.001, 95% CI: (0.0134-0.0403)) and lower medication concerns (b = -1.25, P<0.001, 95% CI: (-1.93-(-0,579)). Lower adherence was associated with increased number (P = 0.00148) and total volume of new T2 MRI lesions (P = 0.00149). The questionnaire showed acceptable internal consistency (Cronbach α = 0.72) and moderate test-retest reliability (r = 0.62, P < 0.0001, 95% CI: 0.33-0.79). The MARS-5 was found to be valid and reliable for estimating medication adherence and predicting medication concerns in persons with MS.

Public's perspective on COVID-19 adenovirus vector vaccines after thrombosis with thrombocytopenia syndrome (TTS) reports and associated regulatory actions - A cross-sectional study in six EU member states.

OBJECTIVE: In 2021, thrombosis with thrombocytopenia syndrome (TTS) was confirmed by the European Medicines Agency (EMA) as a rare side effect of the COVID-19 adenovirus vector vaccines Vaxzevria® and Jcovden®. This study aimed to describe the public's knowledge of TTS and how it affected the willingness to be vaccinated with COVID-19 vaccines and other vaccines in six European countries. METHODS: From June to October of 2022, a multi-country cross-sectional online survey was conducted in Denmark, Greece, Latvia, Netherlands, Portugal, and Slovenia. The minimum target of participants to be recruited was based on the size of the country's population. The results were analysed descriptively. RESULTS: In total, 3794 respondents were included in the analysis; across the six countries, 33.3 %-68.3 % reported being familiar with signs and symptoms of TTS, although 3.1-61.4 % of those were able to identify the symptoms correctly. The reported changes in willingness to be vaccinated against COVID-19 and with other vaccines varied per country. The largest reported change in the willingness to be vaccinated with Vaxzevria® and Jcovden® was observed in Denmark (61.2 %), while the willingness to be vaccinated with other COVID-19 vaccines changed most in Slovenia (30.4 %). The smallest decrease in willingness towards future vaccination against COVID-19 was reported in the Netherlands (20.9 %) contrasting with the largest decrease observed in Latvia (69.1 %). CONCLUSION: Knowledge about TTS seemed to have influenced the public's opinion in Europe resulting in less willingness to be vaccinated with Vaxzevria® and Jcovden®. Willingness for vaccination against COVID-19 with other vaccines and widespread use of vaccines to prevent other diseases also differed and seemed to be determined by the approaches taken by national health authorities when reacting to and communicating about COVID-19 vaccination risks. Further investigation of optimal risk communication strategies is warranted.

Medication adherence and health outcomes in persons with multiple sclerosis treated with dimethyl fumarate.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that particularly affects people in their 30s. Oral disease-modifying therapy (DMT) offers a simple dosage form, good efficacy and safety. Dimethyl fumarate (DMF) is a frequently prescribed oral DMT medication worldwide. The aim of this study was to evaluate the impact of medication adherence on health outcomes in Slovenian persons with MS treated with DMF. METHODS: Our retrospective cohort study included persons with relapsing-remitting MS on DMF treatment. The medication adherence was evaluated by AdhereR software package using the proportion of days covered (PDC) measure. The threshold was set at 90%. Health outcomes after treatment initiation were represented by relapse occurrence, disability progression and occurrence of active (new T2 and T1/Gadolinium (Gd) enhancing) lesions between first two outpatient visits and first two brain magnetic resonance imaging (MRI), respectively. For each health outcome a separate multivariable regression model was built. RESULTS: The study included 164 patients. Their mean age (SD) was 36.7 (8.8) years, and the majority of patients were women (114 or 70%). Eighty-one patients were treatment naive. The mean (SD) PDC value was 0.942 (0.08) and 82% of patients were considered adherent above the 90% threshold. Older age (OR 1.06 per one year, P = 0.017, 95% CI (1.01-1.11)) and treatment naivety (OR 3.93, P = 0.004, 95% CI (1.64-10.4)) were related to higher adherence. In the 6-year follow-up period after DMF treatment initiation, 33 patients experienced a relapse. Among those, 19 required an emergency visit. Sixteen patients had a 1-point disability progression on the Expanded Disability Status Scale (EDSS) score between two consecutive outpatient visits. Thirty-seven patients were found to have active lesions between first and second brain MRI. Medication adherence showed no impact on relapse occurrence or disability progression. Lower medication adherence (10% lower PDC) was associated with higher occurrence of active lesions (OR 1.25, P=0.038, 95% CI: 1.01-1.56). Higher disability prior to DMF initiation was related to a higher risk for relapse occurrence and EDSS progression. CONCLUSION: Our study showed high medication adherence among Slovenian persons with relapse-remitting MS on DMF treatment. Higher adherence was associated with lower incidence of the radiological progression of MS. Interventions for improving medication adherence should be intended for younger patients with higher disability prior treatment with DMF and those switching from alternative DMTs.

Medication persistence among people with multiple sclerosis in Slovenia treated with dimethyl fumarate.

Objective: Multiple sclerosis is a chronic, demyelinating inflammatory disease of the central nervous system. Medication persistence is defined as an interval between the initiation and last dose of the applied medication and presents a useful surrogate marker of a stable disease course. This observational study aimed to evaluate medication persistence and discontinuation reasons in Slovenian people with multiple sclerosis treated with dimethyl fumarate.Methods: Our retrospective cohort study evaluated people with relapsing-remitting multiple sclerosis treated with dimethyl fumarate as an initial monotherapy or switched from injectable disease-modifying therapy medication between 2014 and 2021. Medication dispenses were extracted from the Slovenian National Institute of Public Health Outpatient Medication Database. The medication persistence criterion was based on the treatment gap. Patients exceeding a 60-day gap were considered nonpersistent. The median time to discontinuation was assessed using survival analyses. Considering discontinuation reasons, patients were further divided into safety and inefficacy groups. Due to the high probability of adverse effects, patients exceeding a 60-day gap were included in the safety group, but definite discontinuation reason remains unknown. The impact of covariates was evaluated by Cox regression.Results: A total of 269 patients were included (183 women, mean age 37 years). During the 7-year follow-up period, 123 (45.7%) patients discontinued treatment. The median time to discontinuation was 5.6 years. After 1, 2, and 5 years of treatment, 84%, 77%, and 57% of patients were found to be persistent, respectively. All patients older than 30 years (p = 0.0013) and among them, those in the inefficacy group (p = 0.037) were more likely to be persistent.Conclusions: The results of our study proved a high persistence rate among our patients. The most frequent discontinuation reason was gastrointestinal adverse effects. Medication persistence requires interventions in younger patients with an unstable disease course.

Pharmacist-led clinical medication review service in primary care: the perspective of general practitioners.

BACKGROUND: An advanced level medication review service (CMR) is systematically reimbursed and available nationwide in Slovenian primary care since 2016. CMR is performed by clinical pharmacists (CP). Close collaboration with general practitioner (GP) is required as they perform patient selection and make clinical decisions regarding patient's medication. METHODS: A prospective observational study was conducted in 2018 aiming to evaluate the perspective of GPs on the implementation of pharmacist-led medication review service in Community Health Care Centre Ljubljana, Slovenia. GPs of the patients, who provided written informed consent were invited for the interviews. The semi-structured interview consisted of 5 open ended questions addressing reasons for referral of the patients, implementation of CP recommendations and the GPs' perspective of the service in general. Interviews were audio recorded with GPs written consent, transcribed verbatim and inductive content analysis was performed in NVivo11 Pro. RESULTS: In total 38 interviews with 24 GPs were performed. The emerged themes were nested under 3 main domains representing Donabedian model of quality healthcare - structure, process, outcomes. The service structure is built on broad pharmacotherapy knowledge as the main CP competency, good accessibility, and complementarity of healthcare professions. Patients are mainly referred to the CMR due to polypharmacotherapy, however in majority there is a more in-depth reason behind (e.g., adverse events, etc.). Lack of time to recognize eligible patients and additional workload to study and implement the recommendations present the major challenges in the service process and therefore low number of referrals. CPs recommendations are mostly accepted, although the implementation time varies. When recommendation addresses medicines prescribed by a clinical specialist, the CMR report is forwarded to them for decision regarding implementation. The empowerment of the patients in medicines use was emphasized as the major benefit of the CMR, which consequently supports and enhances the quality of GP's patient care. Transferability of recommendations to similar cases and high satisfaction with the service of GPs and patients, were mentioned. CONCLUSION: GPs experiences with CMR are encouraging and supportive and present a base for further growth of the service.

Pharmacy network and access to medicines in selected eastern European countries: comparative analysis.

AIM: To analyze the pharmacy network (structure and resources) in Bulgaria, Croatia, Serbia, and Slovenia and its relation to public expenditures for medicines. METHODS: We performed a cross-sectional study using the officially published data for the period 2003-2008 in four selected countries. Data sources were relevant national institutions. RESULTS: In 2008, Serbia had 27.5, Bulgaria 66.8, Croatia 59.5, and Slovenia 71.2 pharmacists per 100000 inhabitants. There was a significant difference in the number of pharmacists per 100000 inhabitants between all countries except between Bulgaria and Slovenia. The number of inhabitants per one pharmacy was significantly different between all observed countries. The expenditures for medicines per capita in 2008 were between €30.34 in Bulgaria to €137.03 in Slovenia, with a significant difference between all countries except between Bulgaria and Serbia. The number of pharmacists per 100000 inhabitants and expenditures for medicines per capita were positively correlated in all observed countries, except in Bulgaria. CONCLUSION: There were significant difference in the structure and availability of the pharmacy service in all selected countries. Expenditures for medicines were positively correlated with the number of pharmacists in all countries, except in Bulgaria. Our findings could be valuable to national regulatory bodies for the creation of national drug policies.

Risk of lower extremity amputations in patients with type 2 diabetes using sodium-glucose co-transporter 2 inhibitors.

AIMS: To compare the influence of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP-4i) on the risk of lower extremity amputations in patients with type 2 diabetes in Slovenia. METHODS: This retrospective cohort study included patients aged 40 years or more who were administered a newly introduced SGLT2i or DPP-4i between June 2014 and June 2018. Patients treated with insulin at baseline and patients with a history of amputation were excluded. Patients were matched in a 1:1 ratio using propensity score matching. Survival analysis was performed; hazard ratio (HR) and ratios of cumulative hazards at 1, 2, 3, and 4 years were estimated. On-treatment and intention-to-treat approaches were used. RESULTS: The study cohort (mean age: 64 years) consisted of 2,939 new users of SGLT2i (empagliflozin, 59%; dapagliflozin, 41%) matched to 2,939 new users of DPP-4i. In the on-treatment analysis (median follow-up of 2 years), the incidence of amputations was higher in SGLT2i than in DPP-4i users (4.2 vs. 2.7 per 1,000 patient years), resulting in a HR of 1.58 (95% CI 0.85-2.92; p = 0.145). An intention-to-treat analysis yielded to similar HR of 1.86 (95% CI: 1.10-3.14; p = 0.020). There was no difference in amputation rates in the first two years, but SGLT2i users had a 2.81-fold higher (95% CI: 1.63-4.84; p = 0.007) cumulative hazard of amputation at 4 years than did DPP-4i users. CONCLUSIONS: Compared with DPP-4i use, SGLT2i use did not result in a statistically significant higher overall risk of lower extremity amputations. However, the results suggest that SGLT2i may increase the risk of amputation with long-term use.