Drug Register Research Articles

Cross-sectional analysis of cardiovascular disease and risk factors in patients with spondyloarthritis: a real-life evidence from biostar nationwide registry

The association between spondyloarthritis and cardiovascular (CV) diseases is complex with variable outcomes. This study aimed to assess the prevalence rates of CV diseases and to analyze the impact of CV risk factors on CV disease in patients with spondyloarthritis. A multi-center cross-sectional study using the BioSTAR (Biological and Targeted Synthetic Disease-Modifying Antirheumatic Drugs Registry) database was performed on patients with spondyloarthritis. Socio-demographic, laboratory, and clinical data were collected. Patients with and without major adverse cardiovascular events (MACE) were grouped as Group 1 and Group 2. The primary outcome was the overall group’s prevalence rates of CV disease and CV risk factors. The secondary outcome was the difference in socio-demographic and clinical characteristics between the groups and predictive risk factors for CV disease. There were 1457 patients with a mean age of 45.7 ± 10.9 years. The prevalence rate for CV disease was 3% (n = 44). The distribution of these diseases was coronary artery disease (n = 42), congestive heart failure (n = 4), peripheral vascular disorders (n = 6), and cerebrovascular events (n = 4). Patients in Group 1 were significantly male (p = 0.014) and older than those in Group 2 (p < 0.001). There were significantly more patients with hypertension, diabetes mellitus, chronic renal failure, dyslipidemia, and malignancy in Group 1 than in Group 2 (p < 0.05). Smoking (36.7%), obesity (24.4%), and hypertension (13.8%) were the most prevalent traditional CV risk factors. Hypertension (HR = 3.147, 95% CI 1.461–6.778, p = 0.003), dyslipidemia (HR = 3.476, 95% CI 1.631–7.406, p = 0.001), and cancer history (HR = 5.852, 95% CI 1.189–28.810, p = 0.030) were the independent predictors for CV disease. A multi-center cross-sectional study using the BioSTAR (Biological and Targeted Synthetic Disease-Modifying Antirheumatic Drugs Registry) database was performed on patients with spondyloarthritis. Socio-demographic, laboratory, and clinical data were collected. Patients with and without major adverse cardiovascular events (MACE) were grouped as Group 1 and Group 2. The primary outcome was the overall group’s prevalence rates of CV disease and CV risk factors. The secondary outcome was the difference in socio-demographic and clinical characteristics between the groups and predictive risk factors for CV disease. There were 1457 patients with a mean age of 45.7 ± 10.9 years. The prevalence rate for CV disease was 3% (n = 44). The distribution of these diseases was coronary artery disease (n = 42), congestive heart failure (n = 4), peripheral vascular disorders (n = 6), and cerebrovascular events (n = 4). Patients in Group 1 were significantly male (p = 0.014) and older than those in Group 2 (p < 0.001). There were significantly more patients with hypertension, diabetes mellitus, chronic renal failure, dyslipidemia, and malignancy in Group 1 than in Group 2 (p < 0.05). Smoking (36.7%), obesity (24.4%), and hypertension (13.8%) were the most prevalent traditional CV risk factors. Hypertension (HR = 3.147, 95% CI 1.461–6.778, p = 0.003), dyslipidemia (HR = 3.476, 95% CI 1.631–7.406, p = 0.001), and cancer history (HR = 5.852, 95% CI 1.189–28.810, p = 0.030) were the independent predictors for CV disease. The prevalence rate of CV disease was 3.0% in patients with spondyloarthritis. Hypertension, dyslipidemia, and cancer history were the independent CV risk factors for CV disease in patients with spondyloarthritis.

P1073 Opioid use Before and After First Diagnosis of Crohn’s Disease: A Swedish Nationwide Cohort Study 2008-2020

Abstract Background The ongoing opioid misuse epidemic, initially sparked by over-prescription, presents challenges in managing severe pain in Crohn’s disease (CD). Despite associated negative effects, such as narcotic bowel syndrome and susceptibility to chronic use, opioids are frequently prescribed for CD patients. However, data on the evolution of opioid use before and after the initial CD diagnosis in a European context are limited. Methods This nationwide cohort study utilized the Swedish Patient Register to identify adults with a first CD diagnosis between 1 January 2008 and 31 December 2017, residing in Sweden at least two years before and three years after the diagnosis. For each CD patient, we included up to 10 reference individuals from the general population matched on birth year, sex, calendar year, and place of residence. Data on dispensed opioid prescriptions were retrieved from the National Prescribed Drug Register. Opioid use history was categorized into non-users (no dispensations), intermittent users (≥1 dispensation in 1–3 periods), and chronic users (≥1 dispensation in all periods) based on the four preceding six-month periods before the first CD diagnosis. Opioid use per six-month period was estimated from two years before to five years following CD diagnosis (corresponding index date for matched reference individuals) and coarsened exact matching was employed to account for confounding (birth year, sex, education, and history of psychiatric disorders and cancer). Results We included 12,539 incident CD patients and 116,073 matched reference individuals. During the two years before the first CD diagnosis, CD patients (and 3.9% vs 10.4% and 1.4%, respectively) were more often intermittent (22.3% vs 10.4%) or chronic (3.9% vs 1.4%) opioid users than matched reference individuals. Prior to diagnosis, opioid use per six-month period was twice as common among CD patients than in reference individuals. Following a peak in the first year after the diagnosis, the prevalence of dispensed opioids per six-month period stabilized at a three-fold level among CD patients (13.6%; 95% CI: 13.0, 14.3) compared with the reference individuals (5.5%; 95% CI: 5.4, 5.7) (Figure 1). The 6-month prevalence of opioid use five years after CD diagnosis was 7.6% (95% CI: 7.0, 8.2), 22.9% (95% CI: 21.1, 24.6), and 79.5.4% (95% CI: 73.2, 85.7) for CD patients classified as non-users, intermittent, or chronic users two years before diagnosis, respectively. Conclusion CD patients exhibited elevated opioid use two years before their initial diagnosis, which persisted at a three-fold level compared to matched reference individuals for five years post-diagnosis. This pattern persisted despite publicly-funded healthcare and modern CD therapy accessibility.

P827 Has opioid use increased among adults with Crohn’s disease? A Swedish Nationwide cohort Study 2008-2020

Abstract Background Chronic opioid use has turned into a global health challenge. Crohn’s disease (CD) patients may experience severe pain requiring opioids which could exacerbate CD symptoms and pose a risk of chronic use. The use of opioids among CD patients has not been explored on a national level. We compared the secular trends of opioid use among prevalent CD patients and matched reference individuals in Sweden. Methods This nationwide cohort study included adults with a prevalent CD diagnosis who lived in Sweden for at least 12 consecutive months at some point between 1 January 2008 and 31 December 2020. For each patient, up to 10 reference individuals from the general population were matched on birth year, sex, calendar year, and place of residence. We retrieved the data on dispensed opioid prescriptions (opioid use) from the National Prescribed Drug Register. We defined opioid use as ≥1 filled prescription per calendar year. We also estimated the annual prevalence of ≥1 dispensation of weak (codeine combinations, tramadol, and Dextropropoxifen) and/or strong opioids (Oxycodone, Morphine, Hydromorphone, Fentanyl, Buprenorphine, Tapentadol, and Petidin). Results We identified 43,155 adult CD patients and 418,218 reference individuals (Table 1). The prevalence of opioid use was stable from 2008-2016. However, between 2017 and 2020 it decreased from 19.7% (95% CI: 19.2, 20.2) to 16.9% (95% CI: 16.2, 17.7) and from 8.5% (95% CI: 8.4, 8.7) to 6.9% (95% CI: 6.7, 7.1) among CD patients and reference individuals, respectively (Figure 1a). However, between 2008 and 2020, the prescription of strong opioids more than doubled among both CD patients (increasing from 4.3% [95% CI: 4.1, 4.6] to 11.5% [95% CI: 11.1, 11.8]), and reference individuals (increasing from 1.3% [95% CI: 1.3, 1.4] to 5.4% [95% CI: 5.3, 5.5]) (Figure 1b). In 2020, the last year of the observation, compared with males, both female CD patients (20.3% [19.7, 20.8] vs 9.3% [9.2, 9.5]) and their matched reference individuals (15.3% [14.8, 15.9] vs 7.1% [6.9, 7.2]) had a higher prevalence of annual opioid use. The secular trends of overall opioid use and increasing use of strong opioids were similar for males and females (data not shown). Conclusion Annual opioid use among prevalent CD patients in Sweden, a country with publicly-funded healthcare and access to modern CD treatment, was two-fold higher than in the general population in the last 13 years. The annual opioid use remained stable from 2008-2016 and slightly decreased from 2017-2020 for CD patients and reference individuals. During the same period, the use of strong opioids more than doubled for CD patients and the general population.

Menopausal hormone therapy and risk of sarcoidosis: a population-based nested case–control study in Sweden

Sarcoidosis incidence peaks in women between 50 and 60 years old, which coincides with menopause, suggesting that certain sex hormones, mainly estrogen, may play a role in disease development. We investigated whether menopausal hormone therapy (MHT) was associated with sarcoidosis risk in women and whether the risk varied by treatment type. We performed a nested case–control study (2007–2020) including incident sarcoidosis cases from the Swedish National Patient Register (n = 2593) and matched (1:10) to general population controls (n = 20,003) on birth year, county, and living in Sweden at the time of sarcoidosis diagnosis. Dispensations of MHT were obtained from the Swedish Prescribed Drug Register before sarcoidosis diagnosis/matching. Adjusted odds ratios (aOR) of sarcoidosis were estimated using conditional logistic regression. Ever MHT use was associated with a 25% higher risk of sarcoidosis compared with never use (aOR 1.25, 95% CI 1.13–1.38). When MHT type and route of administration were considered together, systemic estrogen was associated with the highest risk of sarcoidosis (aOR 1.51, 95% CI 1.23–1.85), followed by local estrogen (aOR 1.25, 95% CI 1.11–1.42), while systemic estrogen-progestogen combined was associated with the lowest risk compared to never users (aOR 1.12, 95% CI 0.96–1.31). The aOR of sarcoidosis did not differ greatly by duration of MHT use. Our findings suggest that a history of MHT use is associated with increased risk of sarcoidosis, with women receiving estrogen administered systemically having the highest risk.

Definition of rheumatoid arthritis flare based on SDAI and CDAI

ObjectiveTo develop and validate definitions for disease flares in rheumatoid arthritis (RA) based on the quantitative Simplified and Clinical Disease Activity Indices (SDAI, CDAI).MethodsWe analysed RA treatment courses from the...

Safety of Macitentan for the Treatment of Portopulmonary Hypertension: Real-World Evidence from the Combined OPUS/OrPHeUS Studies.

Portopulmonary hypertension (PoPH) carries a worse prognosis than other forms of pulmonary arterial hypertension (PAH). Data regarding use of PAH-specific therapies in patients with PoPH are sparse as they are usually excluded from clinical trials. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles in patients with PoPH newly initiating macitentan in the USA using the OPUS/OrPHeUS combined dataset. OPUS was a prospective, US, multicenter, observational drug registry (April 2014-June 2020); OrPHeUS was a retrospective, US, multicenter chart review (October 2013-March 2017). Additional information regarding patients' liver disease was retrospectively collected for patients with PoPH in OPUS. The OPUS/OrPHeUS dataset included 206 patients with PoPH (median age 58years; 52.4% female), with baseline cirrhosis and liver test abnormalities reported in 72.8% and 31.6% of patients respectively. Macitentan was initiated as combination therapy in 74.8% of patients and median (Q1, Q3) exposure to macitentan was 11.9 (3.1, 26.0) months. One-year Kaplan-Meier estimates (95% confidence limit, CL) of patients free from all-cause hospitalization and survival were 48.6% (40.7, 56.0) and 82.2% (75.1, 87.4). Of the 96 patients with PoPH in OPUS, 29.2% were classified as in need of liver transplant due to underlying liver disease during the study; transplant waitlist registration was precluded because of PAH severity for 32.1% and 17.9% were transplanted. Hepatic adverse events (HAE) were experienced by 49.0% of patients; the most common being increased bilirubin (16.0%), ascites (7.3%), and hepatic encephalopathy (5.8%); 1.5% and 21.8% of patients discontinued macitentan as a result of HAE and non-hepatic adverse events. There were no unexpected safety findings in patients with PoPH treated with macitentan. These data add to the evidence supporting the safety and tolerability of macitentan in patients with PoPH. A graphical abstract is available with this article. OPsumit® Users Registry (OPUS): NCT02126943; OPsumit® Historical Users cohort (OrPHeUS): NCT03197688; www. gov .

Validation of a Novel Method to Assess the Clinical Quality of Information in Pregnancy-Related Pharmacovigilance Case Reports: A ConcePTION Project.

To assess the causal relationship between a medicinal product and a reported event, relevant information needs to be present. Information elements for assessing cases of exposure to medicinal products during pregnancy were predefined and used in a new tool to assess the quality of information. However, the extent in which the presence or absence of these predefined information elements is associated with the overall clinical quality of these cases, as evaluated by pharmacovigilance experts, remains uncertain. We aimed to validate a novel method to assess the clinical quality of information in real-world pregnancy pharmacovigilance case reports. The clinical quality of case reports regarding medicinal product exposure and pregnancy-related outcomes was appraised from spontaneous reports, literature, Teratology Information Services (UK and Switzerland), The Dutch Pregnancy Drug Register, the Gilenya pregnancy registry and the Enhanced PV programme of Novartis. Assessment was done by means of the novel standardised tool based on the presence and relevance of information, and by expert judgement. The novel tool was validated compared to the expert assessment as the gold standard expressed as the area under the receiver operating characteristic curves, after which the sensitivity and specificity were calculated using cross-tabulations. Inter-rater variability was determined by means of weighted Cohen's kappa. One hundred and eighty-six case reports were included. The clinical quality score as assessed by the novel method was divided into three categories with cut-off values of 45% (poor to intermediate) and 65% (intermediate to excellent). Sensitivity was 0.93 and 0.96 for poor to intermediate and intermediate to excellent, respectively. Specificity was respectively 0.52 and 0.73. Inter-rater variability was 0.65 (95% confidence interval 0.53-0.78) for the newly developed approach, and 0.40 (95% confidence interval 0.28-0.52) for the gold standard assessment. The tool described in this study using the presence and relevance of elements of information is the first designed, validated and standardised method for the assessment of the quality of information of case reports in pregnancy pharmacovigilance data. This method confers less inter-rater variability compared with a quality assessment by experts of pregnancy-related pharmacovigilance data.

Validation of diagnoses of liver disorders in users of systemic azole antifungal medication in Sweden

BackgroundLiver disorders are important adverse effects associated with antifungal drug treatment. However, the accuracy of Clinical International Classification of Diseases (ICD)-10 codes in identifying liver disorders for register based research is not well-established. This study aimed to determine the positive predictive value (PPV) of the ICD-10 codes for identifying patients with toxic liver disease, hepatic failure, and jaundice among patients with systemic antifungal treatment.MethodsData from the Swedish Prescribed Drug Register and the National Patient Register were utilized to identify adult patients who received systemic azole antifungal drugs and had a recorded diagnosis of toxic liver disease (K71.0, K71.1, K71.2, K71.6, K71.8, K71.9), hepatic failure (K72.0, K72.9), or jaundice (R17) between 2005 and 2016. The medical records of all included patients were reviewed. Prespecified criteria were used to re-evaluate and confirm each diagnosis, serving as the gold standard to calculate PPVs with 95% confidence intervals (95% CI) for each diagnostic group.ResultsAmong the 115 included patients, 26 were diagnosed with toxic liver disease, 58 with hepatic failure, and 31 with jaundice. Toxic liver disease was confirmed in 14 out of 26 patients, yielding a PPV of 53.8% (95% CI 33.4–73.4%). Hepatic failure was confirmed in 26 out of 38 patients, resulting in a PPV of 62.1% (95% CI 48.4–74.5%). The highest PPV was found in jaundice, with 30 confirmed diagnoses out of 31, yielding a PPV of 96.8% (95% CI 83.3–99.9%).ConclusionAmong patients who received azole antifungal treatment and were subsequently diagnosed with a liver disorder, the PPV for the diagnosis of jaundice was high, while the PPVs for toxic liver disease and hepatic failure were lower.

Risk of Death in Patients With Coronary Artery Disease Taking Nitrates and Phosphodiesterase-5 Inhibitors

BackgroundPhosphodiesterase-5 inhibitor (PDE5i) treatment for erectile dysfunction is associated with lower mortality compared with no treatment for erectile dysfunction after myocardial infarction (MI). There are conflicting results regarding the impact of PDE5i treatment on mortality in conjunction with nitrate medication. ObjectivesThe purpose of this study was to investigate the association between PDE5i treatment and cardiovascular outcomes in men with stable coronary artery disease treated with nitrate medication. MethodsUsing the Swedish Patient Register and the Prescribed Drug Register we included men with previous MI or revascularization in 2006-2013 who had 2 dispensed nitrate prescriptions within 6 months. Exposure was defined as at least 2 filled prescriptions of any PDE5i. We performed multivariable Cox proportional hazard regression to estimate HRs with 95% CIs for all-cause, cardiovascular, and noncardiovascular mortality, MI, heart failure, cardiac revascularization, and major cardiovascular events (MACE). ResultsIn total, 55,777 men were treated with nitrates and 5,710 men with nitrates and a PDE5i. The combined use of PDE5i treatment with nitrates was associated with higher mortality (HR: 1.39; 95% CI: 1.28-1.51), cardiovascular mortality (HR: 1.34; 95% CI: 1.11-1.62), noncardiovascular mortality (HR: 1.40; 95% CI: 1.27-1.54), MI (HR: 1.72; 95% CI: 1.55-1.90), heart failure (HR: 1.67; 95% CI: 1.48-1.90), cardiac revascularization (HR: 1.95; 95% CI: 1.78-2.13), and MACE (HR: 1.70; 95% CI: 1.58-1.83). ConclusionsThe use of a PDE5i in combination with nitrate medication in men with stable coronary artery disease may pose an increased hazard for cardiovascular morbidity and mortality. Careful patient-centered consideration before prescribing PDE5is to patients with cardiovascular disease using nitrate medication is warranted.

Prevalence of cardiovascular diseases and traditional cardiovascular risk factors in patients with rheumatoid arthritis: a real-life evidence from BioSTAR nationwide registry.

Patients with rheumatoid arthritis (RA) have increased morbidity and mortality due to cardiovascular (CV) comorbidities. The association of CV diseases (CVD) and traditional CV risk factors has been debated, depending on patient and RA characteristics. This study aimed to find the prevalence of CVD and CV risk factors in patients with RA. A multi-center cross-sectional study was performed on RA patients using the BioSTAR (Biological and Targeted Synthetic Disease-Modifying Antirheumatic Drugs Registry) in September 2022. Socio-demographic, clinical, and follow-up data were collected. Myocardial infarction, ischemic heart disease, peripheral vascular disorders, congestive heart failure, ischemic stroke, and transient ischemic attack were regarded as major adverse cardiovascular events (MACEs). CVD was defined as the presence of at least one clinical situation of MACE. Group 1 and Group 2 included patients with and without CVD. Prevalence rates of CVD and traditional CV risk factors were the primary outcomes. Secondary outcomes were the differences in the clinical characteristics between patients with and without CVD. An analysis of 724 patients with a mean age of 55.1 ± 12.8years diagnosed with RA was conducted. There was a female preponderance (79.6%). The prevalence rate of CVD was 4.6% (n = 33). The frequencies of the diseases in the MACE category were ischemic heart disease in 27, congestive heart failure in five, peripheral vascular disorders in three, and cerebrovascular events in three patients. The patients with CVD (Group 1) were significantly male, older, and had higher BMI (p = 0.027, p < 0.001, and p = 0.041). Obesity (33.4%) and hypertension (27.2%) were the two CV risk factors most frequently. Male sex (HR = 7.818, 95% CI 3.030-20.173, p < 0.001) and hypertension (HR = 4.570, 95% CI 1.567-13.328, p = 0.005) were the independent risk factors for CVD. The prevalence of CVD in RA patients was 4.6%. Some common risk factors for CVD in the general population, including male sex, older age, and hypertension, were evident in RA patients. Male sex and hypertension were the independent risk factors for developing CVD in patients with RA.

Immunomodulators as objects of the pharmaceutical market. Message III. The product conjuncture of immunosuppressants and their place in the state guarantees program of medical care of the population

Immunosuppressants (ІS) are used to prevent a number of autoimmune diseases, non-autoimmune inflammatory diseases and rejection of transplanted organs. Global ІS market is characterized by high growth rates.&#x0D; The aim of the work: analyze the immunosuppressants product nomenclature on the pharmaceutical market of Ukraine, as well as their characteristics from the point of view of state guarantees of medical care of the population.&#x0D; The research materials: the sources of special and scientific and methodical literature; The State Register of Drugs of Ukraine (as of February 1, 2023), the Register of Drugs that are subjects to reimbursement by the state guarantees program of medical care of the population, as of February 14, 2023. The methods of information search, analysis, generalization, and marketing research have been used.&#x0D; It has been established that 27 INN of immunosuppressants in the form of 134 trade names had been registered in Ukraine. Almost half of the studied drugs consisted of lenalidomide (23.13%), tacrolimus (15.67%) and mycophenolic acid (9.70%). Immunosuppressants are presented in the shape of 7 dosage forms, mostly in capsules (55.22%).&#x0D; It has been found that immunosuppressants are characterized by absolute import dependence, 127 foreign manufacturers from 27 countries have registered 133 trade names (99.25%), and the Ukrainian manufacturer (JSC "Farmak") - only one position (0.75%) and even that is from products in bulk. Germany is characterized as the country that has the highest production activity of immunosuppressants (22.83% of the enterprises had an indicator of production activity of 20.81%), and among the producers there are two pharmaceutical enterprises: Novartis Pharma Stein AG, Switzerland and Sinton Hispania S.L, Spain (production activity indicator 3.76% both).&#x0D; The Register of drugs subjects to reimbursement under the state guarantees program of medical care of the population has included 5 INN of immunosuppressants in the form of 21 trade names for people in the post-transplantation period. Four-fifths (80.95%) of them belong to expensive drugs, as evidenced by their retail price per package of UAH 1,000 or more. However, patients can receive 15 trade names free of charge, for the other 6 trade names patient’s payment ranges from 8.09 to 33.95% of retail value.&#x0D; The obtained results can serve as a prototype for the formation of the product nomenclature of drug manufacturers, wholesale pharmaceutical enterprises and pharmacies.

Improving Data Collection in Pregnancy Safety Studies: Towards Standardisation of Data Elements in Pregnancy Reports from Public and Private Partners, A Contribution from the ConcePTION Project.

The ConcePTION project aims to improve the way medication use during pregnancy is studied. This includes exploring the possibility of developing a distributed data processing and analysis infrastructure using a common data model that could form a foundational platform for future surveillance and research. A prerequisite would be that data from various data access providers (DAPs) can be harmonised according to an agreed set of standard rules concerning the structure and content of the data. To do so, a reference framework of core data elements (CDEs) recommended for primary data studies on drug safety during pregnancy was previously developed. The aim of this study was to assess the ability of several public and private DAPs using different primary data sources focusing on multiple sclerosis, as a pilot, to map their respective data variables and definitions with the CDE recommendations framework. Four pregnancy registries (Gilenya, Novartis; Aubagio, Sanofi; the Organization of Teratology Information Specialists [OTIS]; Aubagio, Sanofi; the Dutch Pregnancy Drug Register, Lareb), two enhanced pharmacovigilance programmes (Gilenya PRIM, Novartis; MAPLE-MS, Merck Healthcare KGaA) and four Teratology Information Services (UK TIS, Jerusalem TIS, Zerifin TIS, Swiss TIS) participated in the study. The ConcePTION primary data source CDE includes 51 items covering administrative functions, the description of pregnancy, maternal medical history, maternal illnesses arising in pregnancy, delivery details, and pregnancy and infant outcomes. For each variable in the CDE, the DAPs identified whether their variables were: identical to the one mentioned in the CDE; derived; similar but with a divergent definition; or not available. The majority of the DAP data variables were either directly taken (85%, n = 305/357, range 73-94% between DAPs) or derived by combining different variables (12%, n = 42/357, range 0-24% between DAPs) to conform to the CDE variables and definitions. For very few of the DAP variables, alignment with the CDE items was not possible, either because of divergent definitions (1%, n = 3/357, range 0-2% between DAPs) or because the variables were not available (2%, n = 7/357, range 0-4% between DAPs). Data access providers participating in this study presented a very high proportion of variables matching the CDE items, indicating that alignment of definitions and harmonisation of data analysis by different stakeholders to accelerate and strengthen pregnancy pharmacovigilance safety data analyses could be feasible.

Developing and externally validating multinomial prediction models for methotrexate treatment outcomes in patients with rheumatoid arthritis: results from an international collaboration

ObjectivesIn rheumatology, there is a clinical need to identify patients at high risk (>50%) of not responding to the first-line therapy methotrexate (MTX) due to lack of disease control or discontinuation due to adverse events (AEs). Despite this need, previous prediction models in this context are at high risk of bias and ignore AEs. Our objectives were to (i) develop a multinomial model for outcomes of low disease activity and discontinuing due to AEs 6 months after starting MTX, (ii) update prognosis 3-month following treatment initiation, and (iii) externally validate these models. Study Design and SettingA multinomial model for low disease activity (submodel 1) and discontinuing due to AEs (submodel 2) was developed using data from the UK Rheumatoid Arthritis Medication Study, updated using landmarking analysis, internally validated using bootstrapping, and externally validated in the Norwegian Disease-Modifying Antirheumatic Drug register. Performance was assessed using calibration (calibration-slope and calibration-in-the-large), and discrimination (concordance-statistic and polytomous discriminatory index). ResultsThe internally validated model showed good calibration in the development setting with a calibration-slope of 1.01 (0.87, 1.14) (submodel 1) and 0.83 (0.30, 1.34) (submodel 2), and moderate discrimination with a c-statistic of 0.72 (0.69, 0.74) and 0.53 (0.48, 0.59), respectively. Predictive performance decreased after external validation (calibration-slope 0.78 (0.64, 0.93) (submodel 1) and 0.86 (0.34, 1.38) (submodel 2)), which may be due to differences in disease-specific characteristics and outcome prevalence. ConclusionWe addressed previously identified methodological limitations of prediction models for outcomes of MTX therapy. The multinomial approach predicted outcomes of disease activity more accurately than AEs, which should be addressed in future work to aid implementation into clinical practice.

FC25: Use of antidepressants in older adults in Sweden 2006-2020

Objectives:Antidepressants are among the most prescribed medications in older adults. In this study we aimed to explore the trends in the use of antidepressants in older Swedish adults between 2006 and 2020.Methods:We conducted a retrospective repeated cross-sectional study, where we included all older adults (65 years and older) registered in the Swedish National Prescribed Drug Register between 2006 and 2020. We estimated the use of antidepressants in older people for each year, across the 21 Swedish regions.Results:The Swedish population of older adults increased from 1.2 million in 2006 to 1.7 million in 2020. There was an increase in antidepressant use from 12.4% in 2006 to 13.2% in 2019 and 13.8% in 2020. We found that the use of antidepressants varied across age groups, older adults 85+ had a higher use (18.2% in 2006, 18.2% in 2019 and 19.4% in 2020) compared to those 65-74 years of age (9.6% in 2006, 11.7% in 2019 and 12.2% in 2020).Individuals who used antidepressants were generally older (mean age = 77.7) and more often women, compared to individuals who did not use antidepressants (mean age =75.7). Moreover, individuals who used antidepressants also had a higher use of benzodiazepine compared to non-users (25.1% vs. 6.4% in 2006; 16.0% vs. 2.7% in 2019 and 15.6% vs. 2.5% in 2020), sleeping drugs (27.7% vs. 10.9% in 2006; 25.2% vs. 9.3% in 2019 and 24.6% vs. 8.9% in 2020), first generation antipsychotics (1.1% vs. 4.0% in 2006 and 0.3% vs. 1.3% in 2020) and second-generation antipsychotics (1.0% vs. 6.3% in 2006 and 0.8% vs. 6.3% in 2020).Citalopram was the most frequently used antidepressant. However, its use declined from 2006 to 2020 and instead we observed an increase in the use of mirtazapine and sertraline. The prescription of tricyclic antidepressants (TCA), selective monoamine-A inhibitors and lithium was relative stable over time.Overall, antidepressants were prescribed at doses close to the defined daily doses (DDD), except for TCA, mianserin, bupropion and venlafaxine which were often prescribed at lower doses.Conclusions:We found a slight increase in antidepressant prescription in Sweden between 2006 and 2020, with older adults 85 years and older using more antidepressants compared to those 65-74 years of age. Use of antidepressants was associated with increased use of benzodiazepines, sleeping drugs (zolpidem and zopiclone), as well as first- and second-generation antipsychotics. Citalopram was the most prescribed antidepressant, but its use has declined over time.

Income and Education Affect Prognosis and Treatment in Symptomatic Myeloma: A Population-Based Study on 8672 Multiple Myeloma Patients Diagnosed 2008-2021 from the Swedish Myeloma Registry

Introduction While survival in myeloma has improved with new treatment modalities, a substantial variation in mortality remains. This variation cannot entirely be explained by differences in known prognostic factors, such as age and genetic risk group. A link between socioeconomic factors and prognosis has gained attention during recent years, but most studies derive from populations with unequal access to health care. We tested whether income and education affects myeloma treatment and survival also in a country where nearly all health care is publicly funded. Materials and methods Study population The study base included all Swedish patients with symptomatic myeloma diagnosed between 2008 and 2021 (n=8672) and included in the Swedish Myeloma Registry. Data on stem cell transplants (HSCT) were retrieved from the 1-year follow-up form in the myeloma register. Data on lenalidomide, pomalidomide, and melphalan treatment were retrieved from the Swedish Prescribed Drug Register. Data on comorbidities were retrieved from the Swedish Patient Register and the Swedish Cancer Register and Charlson comorbidity index was constructed based on diagnoses registered within five years preceding myeloma diagnosis. Data on socioeconomic conditions were retrieved from the Integrated Database for Labor Market Research (LISA), held by Statistics Sweden. Education level was divided into three categories; primary school only (≤9 years), some college or university (≥13 years), or anything between these two (10-12 years). To avoid undue effect of outliers, personal and family income were grouped into highest quartile, lowest quartile and those in-between. Patients were followed in Swedish population statistics until death, permanent emigration or 31 st December 2022. Statistical analysis Analyses on overall survival were performed with Kaplan-Meier plots and with Cox proportional hazards models, yielding hazard ratios (HR) with 95% confidence intervals (95% CI) as measures of relative risk of death. Differences in treatment were assessed by Poisson regression. All p-values were two-sided and a value below 0.05 was considered statistically significant. All analyses were performed with SAS 9.4 statistical software (SAS Inc., Cary, NC). Ethical considerations The study has been approved by the Swedish Ethical Review Authority (2020-01729). All data were anonymized before analyses. Results Median survival was doubled in patients with higher education, compared with patients with primary school only (6.0 years vs 3.0 years). Similarly, patients in the highest family income quartile had a median survival of 7.5 years, compared to 2.8 years among patients from the lowest quartile (Figure 1). The survival differences were to some degree explained by differences at baseline, in particular age at diagnosis. In a multivariable proportional hazards regression, with adjustments for age group, sex, year of diagnosis and comorbidity index, low income patients had 40% higher risk of death than high income patients (HR 1.6, 95% CI 1.5-1.8) and patients with primary school only had 30% higher risk of death compared to patients with higher education (HR=1.4, 95% CI=1.3-1.5), p&amp;lt;0.0001 for both analyses. Patients with the highest family incomes were also more likely to have been treated with a stem cell transplant, a lenalidomide containing regimen, or a pomalidomide containing regimen, while patients with the lowest family incomes were more often treated with melphalan-prednisone based regimens (Table 1). Discussion Education and private economy are correlated with survival in myeloma, even in a country where the cost of health care is covered almost completely by taxes. The differences are not explained by age and comorbidities alone. Our data also suggest that doctors' choices of myeloma treatment are influenced by socioeconomic factors. The data indicate that myeloma survival could increase with more than a year if we could achieve the same results for all patients as we do with the wealthiest and most educated quartile.

The Dutch Pregnancy Drug Register: Suitable to Study Paternal Drug Exposures?

The Dutch Pregnancy Drug Register: Suitable to Study Paternal Drug Exposures?

A comparison of infants' birth defects self-reported by mothers with data provided by general practitioners: Data from the Dutch Pregnancy Drug Register.

Since the presence of a birth defect is often a primary outcome in drug-safety studies among pregnant women, researching the validity of data collection methods is imperative. The aim of this study is to compare self-reported birth defects in infants by mothers with the information provided by general practitioners (GP (singular) or GPs (plural)). Mothers who participated in the Dutch Pregnancy Drug Register reported information about possible birth defects of their infants via questionnaires. GPs were approached to provide information on possible birth defects of the same infants. All reported birth defects by mothers and GPs were blindly coded using the International Classification of Diseases, Tenth Revision (ICD-10) index and EUROCAT-classified as either a minor or major birth defect. Differences in reported birth defects between participants and GPs were assessed. Participants and GPs (N = 551) reported 67 and 53 birth defects respectively, leading to a total of 120 birth defects among 65 infants. When both the GP and the participant reported a birth defect, 76.9% of these birth defects (N = 60) were coded with an identical ICD-10 code. Information on the absence of a birth defect and the presence of a major birth defect was identically reported by the GP and the mother in almost all cases (98.2%). Of the major birth defects reported by the GP, 67% could be matched with information provided by the participant, for 33% contradicting information was reported. Self-reported questionnaire data on infants' birth defects from mothers yield fairly similar information compared to information obtained through GPs. Future studies should validate the accuracy of self-reported birth defects by mothers more extensively to improve the quality of drug safety studies during pregnancy.

Validating the risk of hypoparathyroidism after total thyroidectomy in a population-based cohort: plea for improved follow-up.

A previous nationwide study from Sweden showed that the rate of permanent hypoparathyroidism is high and under-rated in the Swedish Quality Register. This retrospective population-based study aimed to validate the rate and diagnosis of permanent hypoparathyroidism found in the previous study. A secondary aim was to assess the relationship between the rate of low parathyroid hormone (PTH) levels within 24 h after surgery and the rate of permanent hypoparathyroidism. All patients who underwent total thyroidectomy from 2005 to 2015 in a region of Sweden were included. Data were retrieved from local health records, the National Patient Registry, the Swedish Prescribed Drug Registry, and the Swedish Quality Register. A strict definition of permanent hypoparathyroidism was used, including biochemical data and attempts to stop the treatment. A total of 1636 patients were included. Altogether, 143 patients (8.7 per cent) developed permanent hypoparathyroidism. Of these, 102 (6.2 per cent) had definitive permanent hypoparathyroidism, whereas 41 (2.5 per cent) had possible permanent hypoparathyroidism, because attempts to stop the treatment were lacking (28) or patients were lost to follow-up (13). The agreement between the Swedish Quality Register and the chart review was 29.3 per cent. A proportion of 23.2 per cent with a PTH level below the reference value corresponded to a 6.7 per cent rate of permanent hypoparathyroidism. The risk of permanent hypoparathyroidism after total thyroidectomy is high. Some patients are overtreated because attempts to stop the treatment are lacking. Quality registers might underestimate the risk of permanent hypoparathyroidism. Approximately one-quarter of all patients with low PTH levels immediately after surgery developed permanent hypoparathyroidism.

Attention-Deficit/Hyperactivity Disorder Medications and Long-Term Risk of Cardiovascular Diseases

Use of attention-deficit/hyperactivity disorder (ADHD) medications has increased substantially over the past decades. However, the potential risk of cardiovascular disease (CVD) associated with long-term ADHD medication use remains unclear. To assess the association between long-term use of ADHD medication and the risk of CVD. This case-control study included individuals in Sweden aged 6 to 64 years who received an incident diagnosis of ADHD or ADHD medication dispensation between January 1, 2007, and December 31, 2020. Data on ADHD and CVD diagnoses and ADHD medication dispensation were obtained from the Swedish National Inpatient Register and the Swedish Prescribed Drug Register, respectively. Cases included individuals with ADHD and an incident CVD diagnosis (ischemic heart diseases, cerebrovascular diseases, hypertension, heart failure, arrhythmias, thromboembolic disease, arterial disease, and other forms of heart disease). Incidence density sampling was used to match cases with up to 5 controls without CVD based on age, sex, and calendar time. Cases and controls had the same duration of follow-up. Cumulative duration of ADHD medication use up to 14 years. The primary outcome was incident CVD. The association between CVD and cumulative duration of ADHD medication use was measured using adjusted odds ratios (AORs) with 95% CIs. Of 278 027 individuals with ADHD aged 6 to 64 years, 10 388 with CVD were identified (median [IQR] age, 34.6 [20.0-45.7] years; 6154 males [59.2%]) and matched with 51 672 control participants without CVD (median [IQR] age, 34.6 [19.8-45.6] years; 30 601 males [59.2%]). Median (IQR) follow-up time in both groups was 4.1 (1.9-6.8) years. Longer cumulative duration of ADHD medication use was associated with an increased risk of CVD compared with nonuse (0 to ≤1 year: AOR, 0.99 [95% CI, 0.93-1.06]; 1 to ≤2 years: AOR, 1.09 [95% CI, 1.01-1.18]; 2 to ≤3 years: AOR, 1.15 [95% CI, 1.05-1.25]; 3 to ≤5 years: AOR, 1.27 [95% CI, 1.17-1.39]; and >5 years: AOR, 1.23 [95% CI, 1.12-1.36]). Longer cumulative ADHD medication use was associated with an increased risk of hypertension (eg, 3 to ≤5 years: AOR, 1.72 [95% CI, 1.51-1.97] and >5 years: AOR, 1.80 [95% CI, 1.55-2.08]) and arterial disease (eg, 3 to ≤5 years: AOR, 1.65 [95% CI, 1.11-2.45] and >5 years: AOR, 1.49 [95% CI, 0.96-2.32]). Across the 14-year follow-up, each 1-year increase of ADHD medication use was associated with a 4% increased risk of CVD (AOR, 1.04 [95% CI, 1.03-1.05]), with a larger increase in risk in the first 3 years of cumulative use (AOR, 1.08 [95% CI, 1.04-1.11]) and stable risk over the remaining follow-up. Similar patterns were observed in children and youth (aged <25 years) and adults (aged ≥25 years). This case-control study found that long-term exposure to ADHD medications was associated with an increased risk of CVDs, especially hypertension and arterial disease. These findings highlight the importance of carefully weighing potential benefits and risks when making treatment decisions about long-term ADHD medication use. Clinicians should regularly and consistently monitor cardiovascular signs and symptoms throughout the course of treatment.

SGLT-2 inhibitors are associated with lower rates of mortality following myocardial infarction in patients with type 2 diabetes - A SWEDEHEART observational study

Abstract Introduction Secondary prevention following myocardial infarctions is critical in patients with type 2 diabetes due to the substantial risk of adverse events. Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce rates of heart failure hospitalisation and cardiovascular death in patients with type 2 diabetes in several randomised studies. We hypothesised that the cardiovascular benefits associated with SGLT2 inhibitors could be observed in patients with diabetes treated with SGLT2 inhibitors following myocardial infarction in a real-world setting. Methods We included all patients with type 2 diabetes with an eGFR &amp;gt;30 ml/min/1.73m2 discharged from the cardiac care unit following a type 1 acute myocardial infarction between 1 January 2018 to 15 February 2022 from the nationwide Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) registries and cross-referenced the registry to the National Prescribed Drug Register. We identified all patients with a redeemed SGLT2 inhibitor 365 days prior to admission or within 10 days after discharge from the cardiac care unit. The primary outcome measure was a composite of all-cause death and hospitalisation for heart failure within 1 year from hospital discharge. Follow-up started at discharge. Results The study included 12,502 patients, of whom 2,770 (22.2%) were treated with SGLT2 inhibitors. Patients who were prescribed SGLT2 inhibitors were younger but had more comorbidities. The primary endpoint occurred in 2,128 (17.0%) patients during the follow-up period. After adjustment for differences in baseline characteristics and medical therapy, the use of SGLT2 inhibitors was associated with a 15% lower rate of the primary outcome, with an adjusted hazard ratio (HR) of 0.85 (95% CI 0.75 – 0.97). This was primarily driven by a lower rate of all-cause mortality, with an adjusted HR of 0.63 (95% CI 0.51 – 0.79). However, no difference was observed in hospitalisations for heart failure, with an adjusted HR of 1.07 (95% CI 0.93 – 1.22). Conclusion Treatment with SGLT2 inhibitors after myocardial infarction in patients with type 2 diabetes was associated with a lower incidence of a composite outcome comprising of all-cause mortality or hospitalisation for heart failure. The lower observed rate appeared to be driven by a lower all-cause mortality rate in those treated with SGLT2 inhibitors.Baseline characteristicsCumulative incidence of the outcome