Yared Santa-Ana-Tellez

Although isolated reports indicate widespread use of benzodiazepines and benzodiazepine-related drugs (BZRDs) in the Baltic States, utilisation patterns remain poorly described. We examined utilisation patterns of benzodiazepines and BZRDs in Estonia, Latvia, and Lithuania. A drug utilisation study was conducted using nationwide prescription databases from the Baltic states between 2019 and 2023. Dispensed benzodiazepine and BZRD prescriptions were identified using Anatomical Therapeutic Chemical codes: anxiolytic benzodiazepines (N05BA); hypnotic benzodiazepines (N05CD); antiepileptic benzodiazepines (N03AE); and BZRDs (N05CF). Annual incidence and prevalence per 1,000 inhabitants were calculated. Therapeutic intensity was assessed as defined daily doses (DDDs) per user per year. Between 2019 and 2023, incidence of benzodiazepine and BZRD use declined in Estonia (from 40.8 to 32.8 users/1,000 inhabitants), remained stable in Latvia (46.5-48.9 users/1,000 inhabitants), and fluctuated in Lithuania (44.4-56.8 users/1,000 inhabitants). Prevalence decreased in Estonia from 103.0 to 94.0 users/1,000 inhabitants, but increased in Latvia and Lithuania until 2022, followed by a decline in 2023 to 102.0 and 117.6 users/1,000 inhabitants. Incidence and prevalence of all benzodiazepine and BZRD classes declined in Estonia. Although antiepileptic benzodiazepine use declined in Latvia and Lithuania, BZRD use increased. In Lithuania, prevalence of hypnotic and anxiolytic benzodiazepines increased. In 2023, therapeutic intensity reached 121 DDDs/user in Estonia, 92 DDDs/user in Latvia, and 97 DDDs/user in Lithuania. Benzodiazepine and BZRD use remained high in the Baltic states. Estonia showed the lowest prevalence but highest therapeutic intensity. In Latvia and Lithuania, overall use changed little. Continuous monitoring of prescribing practices is warranted.

Purpose: Prescribing recommendations, communication programmes, and mandatory electronic prescribing were implemented in Lithuania to promote responsible use of benzodiazepines and benzodiazepine-related drugs (BZRDs). We assessed the impact of policy measures on benzodiazepine/BZRD prescribing patterns in Lithuania. Methods: We analysed utilisation of oral benzodiazepines/BZRDs in Lithuania from 2018 to 2024, using national prescription data and wholesale medicines data. Benzodiazepines/BZRDs included (1) anxiolytic benzodiazepines; (2) hypnotic benzodiazepines; and (3) BZRDs. The policy intervention period spanned from November 1, 2020, to July 1, 2021. We used ARIMA models to assess monthly incidence, prevalence, and long-term use prevalence (≥ 180 days) per 1,000 inhabitants. Besides, the numbers of defined daily doses (DDDs) prescribed and sold to pharmacies per 1,000 inhabitants were studied. We estimated baseline slopes, step changes after implementation, and changes in slopes after implementation. Results: In total, 717,590 patients received 6,974,059 prescriptions for benzodiazepines or BZRDs. Prior to implementing the policy measures, there were upward trends in incidence, prevalence, and long-term use prevalence across all classes. Following the implementation, monthly incidence stabilised and prevalence decelerated for anxiolytic benzodiazepines and BZRDs. The prevalence of hypnotic benzodiazepines showed a significant immediate reduction after implementation. Long-term use prevalence continued to increase for all benzodiazepine/BZRD classes after implementation of the policy. Before the policy measures were implemented, monthly DDDs sold to pharmacies were gradually declining for anxiolytic benzodiazepines, but were stable for other classes. In contrast, monthly DDDs prescribed were increasing across all classes. Following the policy measures, immediate reductions in DDDs sold to pharmacies were observed, without changes in slopes. The prescribed and sold DDDs converged after implementing the policy measures. Conclusion: From a public health perspective, the policy measures implemented in 2020 and 2021 had only a limited impact on the prescribing patterns of benzodiazepines and BZRDs in Lithuania. They continued to be used long-term, highlighting the persistence of potentially irrational prescribing.

Understanding drug utilization is essential for informed decision-making in national healthcare and for enabling comparisons across countries. In Mexico, the limited research in this field may be attributed to the lack of awareness and accessibility of existing data sources. Addressing this gap requires a comprehensive inventory of data sources for Drug Utilization Research (DUR). The purpose of this study was to develop an inventory of electronic data sources available in Mexico for DUR, outlining their characteristics, strengths, and limitations. From 2019 to 2024, specialists in pharmacoepidemiology and healthcare systems research conducted online searches for DUR data sources, including official websites of the Mexican government and public health institutions. A literature review was also performed for country-specific data sources in articles published between 2000 and 2023. Data sources were independently searched, screened, and selected by independent reviewers, with disagreements resolved through consensus. A descriptive analysis of selected databases was conducted, focusing on accessibility, geographical coverage, data aggregation level, health sector type, data source type, and setting. The analysis included twenty data sources, of which only four were publicly available. These databases offer insights into various aspects of drug utilization, primarily owned by social security institutions (twelve). Only four contain data from the private healthcare sector. Regarding data source type, five focused on procurement, twelve on prescription, two on pharmacovigilance, and one on drug disposal. Mexico faces notable challenges in accessible data for DUR especially in non-social security institutions and the private sector. This study underscores the urgent need to improve healthcare data accessibility and research in Mexico, to drive evidence-informed decision-making regarding medicines utilization.

Aims: In 2013, risk minimization measures (RMMs) were introduced in Europe to address the increased cardiovascular risk linked to diclofenac. This study aimed to assess the impact of those RMMs on analgesic use.Methods: Primary care data from CPRD GOLD (UK) were used. Patients newly diagnosed with musculoskeletal disorders during 2010–2019 were categorized into 4 cohorts, according to their diagnosis: acute (inflammatory) musculoskeletal conditions, chronic arthritic conditions, secondary arthritic conditions, or other painful conditions. The impact of the RMMs was studied using interrupted time series and survival analyses. Analyses were stratified by cardiovascular risk: (i) no risk factors or contraindications mentioned by RMMs; (ii) at least 1 risk factor; and (iii) at least 1 contraindication (prior cardiovascular events).Results: In total, 1 798 885 patients were included, with >28% having at least 1 cardiovascular risk factor and >7% having at least 1 contraindication for diclofenac. Initiation of diclofenac was already decreasing before the RMMs, but the RMMs were associated with a further immediate decrease in 2 cohorts (from −0.9 to −1.6%). No substantial difference in impact was observed depending on cardiovascular risk. The time from diagnosis to analgesic treatment increased after RMMs implementation, especially in patients with chronic arthritic conditions: median time increased from 4.2 to 7.6 months [95% confidence interval 4.0–4.5 and 7.4–7.8, respectively].Conclusion: The observed decrease of diclofenac initiation was unrelated to patients' cardiovascular risk. Continued prescribing of systemic diclofenac to patients with contraindications suggests limited impact of RMMs. Increased time from diagnosis to analgesic treatment suggests broader changes in analgesic prescribing practices.

Purpose: Fluoroquinolones are antibiotics associated with adverse events that prompted the European Medicines Agency to implement risk minimization measures (RMMs) in 2018/19 and 2020. Our aim is to assess the RMMs' impact on antibiotic prescriptions in primary care during 2014–2023.Methods: We assessed antibiotic prescriptions using CPRD GOLD (the United Kingdom, UK) and PHARMO (the Netherlands, NL). Prescriptions were assessed for fluoroquinolones and alternative antibiotics. The impact of RMMs on prescribing was assessed with interrupted time series (ITS) using monthly prescription rates per 10 000 person‐years (MPTPY).Results: Between 2014 and 2023, we identified cohorts of 4.0 (UK) and 0.9 million (NL) antibiotic users. Fluoroquinolones were prescribed to initiate 1.5% (UK) to 5.8% (NL) of the treatment episodes.Fluoroquinolone prescribing before the RMMs slowly decreased in the UK and was stable in the NL. The 2018/19 RMMs were associated with a steady downward post‐RMMs trend in incident use of fluoroquinolones (MPTPY −0.7 [UK] and −0.8 [NL]) and opposite changes after 2020 RMMs (MPTPY 0.6 [UK] and 1.8 [NL]).The 2018/2019 RMMs were linked with increasing trends for other antibacterials (J01XX) in both countries and other beta‐lactam antibacterials in the UK, but most antibiotics had decreasing trends post‐RMMs in both countries. After the 2020 RMMs, some antibiotic groups showed upward trends.Conclusion: The risk minimization measures in 2018/2019 were associated with a moderate decrease in fluoroquinolone prescribing, with no further decrease after 2020 RMMs. There was no sustained increase in other antibiotic prescribing, suggesting that overprescribing was negligible as an unintended impact of RMMs.

Aims: Studies assessing the impact of pharmacovigilance regulatory interventions often focus on the expected (or intended) outcomes, while any possible unintended impact may be overlooked. The update of the Good Pharmacovigilance Practice guideline in 2017 elaborated on impact assessment, emphasizing the need also to assess possible unintended impact. This systematic literature review investigated how often the unintended impact of regulatory interventions was considered in publications of studies investigating pharmacovigilance regulatory interventions in Europe.Methods: We conducted a systematic review of the literature on MEDLINE and EMBASE from 1 January 2012 to 28 February 2022 to identify publications that investigated the impact of regulatory interventions in Europe. The primary outcome of the study was the number of publications reporting assessments of unintended impact. In addition, we studied the characteristics of these publications, including the type of outcomes assessed, the analytical methods applied and the type of data used.Results: In total, 96 publications were included in the analysis. The unintended impact of pharmacovigilance regulatory interventions was investigated in 23 of 96 publications (24%). The drug classes most frequently studied in the publications assessing unintended impact of regulatory interventions were oral glucose‐lowering drugs (n = 6, 26%), opioids (n = 4, 17%), antidepressants (n = 4, 17%) and antipsychotics (n = 3, 13%). The reported methods to assess the unintended impact were interrupted time series (n = 10, 43%) and descriptive statistics with or without significance testing (n = 2 [9%] and n = 9 [39%], respectively). The outcomes selected for unintended impact assessments included the use of other drugs (n = 16, 70%), health outcomes (n = 8, 35%) and behavioural changes (n = 4, 17%). Most of the publications reported on the use of electronic health record databases (n = 13, 57%) or claims databases (n = 13, 57%), while registries were used in 4 publications (17%).Conclusion: The unintended impact of pharmacovigilance regulatory interventions was reported in only a quarter of identified publications. There was no apparent increase in attention to unintended impact assessments after the update of the Good Pharmacovigilance Practice guidelines.

Purpose: Drug utilization research (DUR) contributes to inform policymaking and to strengthen health systems. The availability of data sources is the first step for conducting DUR. However, documents that systematize these data sources in Latin American (LatAm) countries are not known. We compiled the potential data sources for DUR in the LatAm region.Methods: A network of DUR experts from nine LatAm countries was assembled and experts conducted: (i) a website search of the government, academic, and private health institutions; (ii) screening of eligible data sources, and (iii) liaising with national experts in pharmacoepidemiology (via an online survey). The data sources were characterized by accessibility, geographic granularity, setting, sector of the data, sources and type of the data. Descriptive analyses were performed.Results: We identified 125 data sources for DUR in nine LatAm countries. Thirty‐eight (30%) of them were publicly and conveniently available; 89 (71%) were accessible with limitations, and 18 (14%) were not accessible or lacked clear rules for data access. From the 125 data sources, 76 (61%) were from the public sector only; 46 (37%) were from pharmacy records; 43 (34%) came from ambulatory settings and; 85 (68%) gave access to individual patient‐level data.Conclusions: Although multiple sources for DUR are available in LatAm countries, the accessibility is a major challenge. The procedures for accessing DUR data should be transparent, feasible, affordable, and protocol‐driven. This inventory could permit a comparison of drug utilization between countries identifying potential medication‐related problems that need further exploration.

Aims: Acenocoumarol is a vitamin‐K antagonist (VKA) primarily used in certain countries (e.g. India, Netherlands, Spain). The half‐life of acenocoumarol is similar to that of non‐VKA oral anticoagulants (NOAC), unlike warfarin, and this could affect comparative effectiveness and safety (CES). However, data on CES for NOAC come almost exclusively from studies using warfarin as the comparator. We aimed to assess outcomes of NOAC and acenocoumarol in people with non‐valvular atrial fibrillation (NVAF) in real‐world clinical practice.Methods: This is a population‐based retrospective cohort study. All new users of oral anticoagulants from November 2011 to December 2015 with NVAF were included (n = 41,560). Data were obtained by linking several health electronic records of the Valencia region, Spain. Incidence rates were estimated. We used the inverse probability of treatment weighted Cox analysis to control for indication bias when assessing the risk of effectiveness and safety outcomes for each NOAC compared with acenocoumarol. Several sensitivity analyses were performed.Results: We did not find differences in the risk of mortality, ischaemic stroke or any gastrointestinal bleeding. However, we did find a decreased risk of intracranial haemorrhage for dabigatran (HR: 0.34, 95% CI 0.20–0.56) and rivaroxaban (HR: 0.55, 95% CI 0.35–0.85) as compared to acenocoumarol. In subanalyses, apixaban showed a higher risk of ischaemic stroke in high‐risk persons (≥75 years and CHA2DS2‐VASC score ≥ 2).Conclusions: No differences in clinical outcomes were found between NOAC and acenocoumarol overall, although dabigatran and rivaroxaban showed a lower risk of intracranial haemorrhage. Findings on the potential inferiority of specific NOAC in high‐risk subgroups should be studied further.

Worldwide, there is growing evidence that quality of international normalized ratio (INR) control in atrial fibrillation patients treated with Vitamin K Antagonists (VKA) is suboptimal. However, sex disparities in population-based real-world settings have been scarcely studied, as well as patterns of switching to second-line Non-VKA oral anticoagulants (NOAC). We aimed to assess the quality of INR control in atrial fibrillation patients treated with VKA in the region of Valencia, Spain, for the whole population and differencing by sex, and to identify factors associated with poor control. We also quantified switching to Non-VKA oral anticoagulants (NOAC) and we identified factors associated to switching. This is a cross-sectional, population-based study. Information was obtained through linking different regional electronic databases. Outcome measures were Time in Therapeutic Range (TTR) and percentage of INR determinations in range (PINRR) in 2015, and percentage of switching to NOAC in 2016, for the whole population and stratified by sex. We included 22,629 patients, 50.4% were women. Mean TTR was 62.3% for women and 63.7% for men, and PINNR was 58.3% for women and 60.1% for men (p<0.001). Considering the TTR<65% threshold, 53% of women and 49.3% of men had poor anticoagulation control (p<0.001). Women, long-term users antiplatelet users, and patients with comorbidities, visits to Emergency Department and use of alcohol were more likely to present poor INR control. 5.4% of poorly controlled patients during 2015 switched to a NOAC throughout 2016, with no sex differences. The quality of INR control of all AF patients treated with VKA in 2015 in our Southern European region was suboptimal, and women were at a higher risk of poor INR control. This reflects sex disparities in care, and programs for improving the quality of oral anticoagulation should incorporate the gender perspective. Clinical inertia may be lying behind the observed low rates of switching in patient with poor INR control.

Objective: To assess the impact of mandatory offer of generic substitution, introduced in South Africa in May 2003, on private sector sales of generic and originator medicines for chronic diseases.Methods: Private sector sales data (June 2001 to May 2005) were obtained from IMS Health for proton pump inhibitors (PPIs; ATC code A02BC), HMG‐CoA reductase inhibitors (statins; C10AA), dihydropyridine calcium antagonists (C08CA), angiotensin‐converting enzyme inhibitors (ACE‐I; C09AA) and selective serotonin reuptake inhibitors (SSRIs; N06AB). Monthly sales were expressed as defined daily doses per 1000 insured population per month (DDD/TIM). Interrupted time‐series models were used to estimate the changes in slope and level of medicines use after the policy change. ARIMA models were used to correct for autocorrelation and stationarity.Results: Only the SSRIs saw a significant rise in level of generic utilisation (0.2 DDD/TIM; P < 0.001) and a fall in originator usage (−0.1 DDD/TIM; P < 0.001) after the policy change. Utilisation of generic PPIs fell (level 0.06 DDD/TIM, P = 0.048; slope 0.01 DDD/TIM, P = 0.043), but utilisation of originator products also grew (level 0.05 DDD/TIM, P < 0.001; slope 0.003, P = 0.001). Generic calcium antagonists and ACE‐I showed an increase in slope (0.01 DDD/TIM, P = 0.016; 0.02 DDD/TIM, P < 0.001), while the originators showed a decrease in slope (‐0.003 DDD/TIM, P = 0.046; −0.01 DDD/TIM, P < 0.001). There were insufficient data on generic statin use before the policy change to allow for analysis.Conclusion: The mandatory offer of generic substitution appeared to have had a quantifiable effect on utilisation patterns in the 2 years after May 2003. Managed care interventions that were already in place before the intervention may have blunted the extent of the changes seen in this period. Generic policies are an important enabling provision for cost‐containment efforts. However, decisions taken outside of official policy may anticipate or differ from that policy, with important consequences.