Comparison of rivaroxaban and low molecular weight heparin in the treatment of cancer-associated venous thromboembolism: a Swedish national population-based register study.

BACKGROUND: Treating cancer-associated venous thromboembolism (CAT) with anticoagulation prevents recurrent venous thromboembolism (rVTE), but increases bleeding risk. OBJECTIVES: To compare incidence of rVTE, major bleeding, and all-cause mortality for rivaroxaban versus low molecular weight heparin (LMWH) in patients with CAT. METHODS: We developed a cohort study using Swedish national registers 2013-2019. Patients with CAT (venous thromboembolism within 6 months of cancer diagnosis) were included. Those with other indications or with high bleeding risk cancers were excluded (according to guidelines). Follow-up was from index-CAT until outcome, death, emigration, or end of study. Incidence rates (IR) per 1000 person-years with 95% confidence interval (CI) and propensity score overlap-weighted hazard ratios (HRs) for rivaroxaban versus LMWH were estimated. RESULTS: We included 283 patients on rivaroxaban and 5181 on LMWH. The IR for rVTE was 68.7 (95% CI 40.0-109.9) for rivaroxaban, compared with 91.6 (95% CI 81.9-102.0) for LMWH, with adjusted HR 0.77 (95% CI 0.43-1.35). The IR for major bleeding was 23.5 (95% CI 8.6-51.1) for rivaroxaban versus 49.2 (95% CI 42.3-56.9) for LMWH, with adjusted HR 0.62 (95% CI 0.26-1.49). The IR for all-cause mortality was 146.8 (95% CI 103.9-201.5) for rivaroxaban and 565.6 (95% CI 541.8-590.2) for LMWH with adjusted HR 0.48 (95% CI 0.34-0.67). CONCLUSIONS: Rivaroxaban performed similarly to LMWH for patients with CAT for rVTE and major bleeding. An all-cause mortality benefit was observed for rivaroxaban which potentially may be attributed to residual confounding. TRIAL REGISTRATION NUMBER: NCT05150938 (Registered 9 December 2021).

Lessons learned from a multi-data source research collaboration: The mirabegron post-authorization safety study program.

BACKGROUND: Many factors contribute to developing and conducting a successful multi-data source, non-interventional, post-authorization safety study (NI-PASS) for submission to multiple health authorities. Such studies are often large undertakings; evaluating and sharing lessons learned can provide useful insights to others considering similar studies. OBJECTIVES: We discuss challenges and key methodological and organizational factors that led to the delivery of a successful post-marketing requirement (PMR)/PASS program investigating the risk of cardiovascular and cancer events among users of mirabegron, an oral medication for the treatment of overactive bladder. RESULTS: We provide context and share learnings, including sections on research program collaboration, scientific transparency, organizational approach, mitigation of uncertainty around potential delays, validity of study outcomes, selection of data sources and optimizing patient numbers, choice of comparator groups and enhancing precision of estimates of associations, potential confounding and generalizability of study findings, and interpretation of results. CONCLUSIONS: This large PMR/PASS program was a long-term commitment from all parties and benefited from an effective coordinating center and extensive scientific interactions across research partners, scientific advisory board, study sponsor, and health authorities, and delivered useful learnings related to the design and organization of multi-data source NI-PASS.

Consistency between the National Patient Register and the Swedish Cancer Register.

PURPOSE: The Swedish National Patient Register (NPR) is widely used as a data source in epidemiological studies, but the consistency of all cancer diagnoses compared to the Swedish Cancer Register (SCR) remains unclear. Using NPR supplementary for detecting safety signals is beneficial due to shorter data extraction delays compared to using SCR alone. This study aims to evaluate the consistency of NPR for cancer diagnoses compared to SCR and its potential use in pharmacoepidemiology. METHODS: Patients with a cancer diagnosis recorded in SCR during 2018-2020 were included. To measure the consistency of NPR diagnoses with SCR as the gold standard, positive predictive value (PPV), and sensitivity were calculated. As an empirical example showing differences in identification of cancer diagnoses in NPR and SCR, two nested case-control studies for the association between antidiabetic medications and pancreatic cancer were repeated using the two registers. Conditional logistic regression was performed and the 95% confidence intervals (CIs) for the odds ratios (ORs) were checked for overlaps. RESULTS: For breast, male genital organs, and oral cancers consistency was high (PPV: 87.5%-97.4%, sensitivity: 82.2%-91.0%), while for female genital organs, thyroid, and ill-defined, secondary, and unspecified sites cancers it was low (PPV: 8.8%-90.0%, sensitivity: 19.9%-32.3%). All the CIs for the ORs from the nested case-control studies overlapped when pancreatic cancer was identified in NPR or SCR. CONCLUSION: Consistency of cancer diagnoses in NPR when compared to SCR depends on cancer type with higher consistency for some cancers and lower for others. Differences in diagnostic processes for different cancer types and coding of cancer in the two registers may explain part of the inconsistent results.

Estrogen-modulating treatment among mid-life women and COVID-19 morbidity and mortality: a multiregister nationwide matched cohort study in Sweden.

BACKGROUND: It has been repeatedly shown that men infected by SARS-CoV-2 face a twofold higher likelihood of dying, being hospitalized or admitted to the intensive care unit compared to women, despite taking into account relevant confounders. It has been hypothesized that these discrepancies are related to sex steroid hormone differences with estrogens being negatively correlated with disease severity. The objective of this study was therefore to evaluate COVID-19-related mortality and morbidity among peri- and postmenopausal women in relation to estrogen-containing menopause hormonal treatments (MHT). METHODS: This is a national register-based matched cohort study performed in Sweden between January 1 to December 31, 2020. Study participants comprised women over the age of 53 years residing in Sweden. Exposure was defined as prescriptions of local estrogens, systemic estrogens with and without progestogens, progestogens alone, or tibolone. MHT users were then compared with a matched cohort of non-users. The primary outcome consisted of COVID-19 mortality, whereas the secondary outcomes included inpatient hospitalizations/outpatient visits and confirmed SARS-CoV-2 infection. Multivariable adjusted Cox regression-derived hazard ratios (HRs) were calculated. RESULTS: Use of systemic estrogens alone is associated with increased COVID-19 mortality among older women (aHR 4.73, 1.22 to 18.32), but the association is no longer significant when discontinuation of estrogen use is accounted for. An increased risk for COVID-19 infection is further observed for women using combined systemic estrogens and progestogens (aHR 1.06, 1.00 to 1.13) or tibolone (aHR 1.21, 1.01 to 1.45). Use of local estrogens is associated with an increased risk for COVID-19-related death (aHR 2.02,1.45 to 2.81) as well as for all secondary outcomes. CONCLUSIONS: Systemic or local use of estrogens does not decrease COVID-19 morbidity and mortality to premenopausal background levels. Excess risk for COVID-19 morbidity and mortality was noted among older women and those discontinuing systemic estrogens. Higher risk for death was also noted among women using local estrogens, for which non-causal mechanisms such as confounding by comorbidity or frailty seem to be the most plausible underlying explanations. TRIAL REGISTRATION DETAILS: Not applicable.

Characteristics and hormonal contraception use patterns of levonorgestrel 13.5 mg intrauterine device users in Sweden 2014-2016.

OBJECTIVES: The levonorgestrel-releasing intrauterine device containing 13.5 mg of levonorgestrel (LNG 13.5 mg IUD), Jaydess, was approved for contraception by the European Medicines Agency in 2013. We aimed to describe the characteristics of new users of LNG 13.5 mg IUD in Sweden within the first 3 years after approval (2014-2016). STUDY DESIGN: We conducted an observational, population-based study using data from the Swedish national registers. Women with the first pharmacy dispensation of LNG 13.5 mg IUD between 2014 and 2016 were followed until December 31, 2020. Descriptive analyses included demographic characteristics, duration of the use of first-time LNG 13.5 mg IUD, and contraceptive switching patterns. RESULTS: We included 38,327 women, with mean age at first-time LNG 13.5 mg IUD use of 26 (SD: 7) years. Over 80% were prescribed LNG 13.5 mg IUD by a midwife. The most common comorbidities in the year prior to LNG 13.5 mg IUD use (2%-3% prevalence) were depression, anxiety, premenstrual syndrome, and menorrhagia. The median duration of first-time LNG 13.5 mg IUD use was 2.6 years, and after use, more than 50% of women opted to continue using a hormonal intrauterine device. CONCLUSIONS: In this postmarketing drug utilization study, there were over 38,000 first-time LNG 13.5 mg IUD users in Sweden between 2014 and 2016, with an estimated median duration of use of 2.6 years. First-time LNG 13.5 mg IUD users consisted mostly of young, healthy individuals with a history of hormonal contraceptive use. Over half of the women continued using a hormonal IUD after the first LNG 13.5 mg IUD. IMPLICATIONS: The median duration of LNG 13.5 mg IUD use was 2.6 years, approaching the 3-year indicated use limit. The majority of users continued with another hormonal intrauterine device after LNG 13.5 mg IUD use.

A global systematic overview of socioeconomic factors associated with antidiabetic medication adherence in individuals with type 2 diabetes.

BACKGROUND: Antidiabetic medication adherence is a key aspect for successful control of type 2 diabetes mellitus (T2DM). This systematic review aims to provide an overview of the associations between socioeconomic factors and antidiabetic medication adherence in individuals with T2DM. METHODS: A study protocol was established using the PRISMA checklist. A primary literature search was conducted during March 2022, searching PubMed, Embase, Web of Science, as well as WorldCat and the Bielefeld Academic Search Engine. Studies were included if published between 1990 and 2022 and included individuals with T2DM. During primary screening, one reviewer screened titles and abstracts for eligibility, while in the secondary screening, two reviewers worked independently to extract the relevant data from the full-text articles. RESULTS: A total of 15,128 studies were found in the primary search, and 102 were finally included in the review. Most studies found were cross-sectional (72) and many investigated multiple socioeconomic factors. Four subcategories of socioeconomic factors were identified: economic (70), social (74), ethnical/racial (19) and geographical (18). The majority of studies found an association with antidiabetic medication adherence for two specific factors, namely individuals' insurance status (10) and ethnicity or race (18). Other important factors were income and education. CONCLUSIONS: A large heterogeneity between studies was observed, with many studies relying on subjective data from interviewed individuals with a potential for recall bias. Several socioeconomic groups influencing medication adherence were identified, suggesting potential areas of intervention for the improvement of diabetes treatment adherence and individuals' long-term well-being.

The association between exposure to clozapine, olanzapine, and quetiapine and the outcomes perimyocarditis and heart failure: A population-based cohort study.

The risk of cardiac adverse events following clozapine use is debated and is unknown for the chemically related and widely used antipsychotics olanzapine and quetiapine. National Swedish registers were used to identify all patients 16-75 years old with antipsychotic dispensations between 2005 and 2018. The short-term outcome was a diagnosis of perimyocarditis (pericarditis and/or myocarditis) within two months of first dispensation, and the long-term outcome was heart failure (including cardiomyopathy) within three years. Cox regressions with time varying exposure were used to estimate hazard rates (HR) and their 95% confidence intervals (CI). A total of 201,045 individuals were included in the cohort. The risk of developing perimyocarditis during clozapine treatment tripled compared to no antipsychotic treatment (HR 3.4, CI 1.6-7.3), although the absolute rate remained comparably low. The long-term risk of heart failure during clozapine treatment was also elevated (HR 1.3, CI 1.1-1.7). Treatment with either or both olanzapine or quetiapine was not associated with an increased relative risk of perimyocarditis, or heart failure compared to no antipsychotic treatment. Clozapine use is therefore associated with a substantially elevated short-term risk of perimyocarditis and an increased risk of heart failure within three years.

Identification of irritable bowel syndrome in the Swedish National Patient Register: a validation study.

BACKGROUND AND OBJECTIVE: National patient registers are valuable in epidemiological studies. To ensure high-quality data for studies of irritable bowel syndrome (IBS), this study aimed to validate the ICD-10 code for IBS in the Swedish National Patient Register. METHODS: The positive predictive values (PPV) for IBS defined by the Rome criteria were calculated based on a review of medical records of randomly selected individuals with a first-ever diagnostic listing of IBS in the Swedish National Patient register in the year 2005 (Rome II criteria) or 2010 (Rome III criteria). KEY RESULTS: 340 medical records were reviewed (172 from 2005 and 168 from 2010). The majority of patients were females (74%), and the mean age was 42 years. IBS used in any type of department had a PPV of 76% (95% confidence interval 71-80%), which increased to 80% (76-84%) when we included individuals likely to have IBS but where information about some aspects of the Rome criteria was lacking in the medical record. Two highly specialized gastroenterological departments had the best PPV, 96%, while departments of internal medicine in general had a PPV of 82% (80-95%). The PPV for the IBS subtype was 62% (55-67%). The PPVs were not significantly different comparing the two time periods investigated. CONCLUSION AND INFERENCES: The validity of a register-based definition of IBS in the Swedish National Patient register is high and can be used to identify patients with IBS in observational research. The data source, i.e., type of hospital and department, influences reliability.

COVID-19 and comedications in atrial fibrillation-a case-control study in Stockholm.

To test the main hypothesis that anticoagulation reduces risk of hospitalization, intensive care unit (ICU) admission and death in COVID-19. Nested case-control study among patients with atrial fibrillation (AF) in Stockholm. COVID-19 cases were matched to five disease-free controls with same sex, born within ± 1 years. Source population was individuals in Stockholm with AF 1997-2020. Swedish regional and national registers are used. National registers cover hospitals and outpatient clinics, local registers cover primary care. Records were linked through the personal identity number assigned to each Swedish resident. Cases were individuals with COVID-19 (diagnosis, ICU admission, or death). The AF source population consisted of 179,381 individuals from which 7548 cases were identified together with 37,145 controls. The number of cases (controls) identified from hospitalization, ICU admission or death were 5916 (29,035), 160 (750) and 1472 (7,360). The proportion of women was 40% for hospitalization and death, but 20% and 30% for admission to ICU in wave one and two, respectively. Primary outcome was mortality, secondary outcome was hospitalization, tertiary outcome was ICU admission, all with COVID-19. Odds ratios (95% confidence interval) for antithrombotics were 0.79 (0.66-0.95) for the first wave and 0.80 (0.64-1.01) for the second wave. Use of anticoagulation among patients with arrythmias infected with COVID-19 is associated with lower risk of hospitalization and death. If further COVID-variants emerge, or other infections with prothrombotic properties, this emphasize need for physicians to ensure compliance among vulnerable patients.

Bleeding events among patients concomitantly treated with direct oral anticoagulants and macrolide or fluoroquinolone antibiotics.

Fluoroquinolones and macrolides may, due to a potential drug-drug interaction, increase the concentration of any concomitantly administered direct oral anticoagulant (DOAC) and thereby increase the risk of severe bleeding. However, clinical evidence for such an effect is scarce. The present study aimed to evaluate the association between the use of fluoroquinolones or macrolides and bleeding events in patients with concomitant DOAC use. This was a nationwide cohort study including 19 288 users of DOACs in 2008-2018 using information from Swedish national health registers. We compared the incidence of bleeding events associated with use of fluoroquinolones or macrolides using doxycycline as a negative control. Cox regression was used to calculate crude and adjusted hazard ratios (aHRs) in time windows of various length of follow-up after the start of antibiotic use. The incidence rates for fluoroquinolones and macrolides ranged from 12 to 24 and from 12 to 53 bleeding events per 100 000 patients in the investigated time windows. The aHRs (95% confidence interval) for use of fluoroquinolones and macrolides were 1.29 (0.69-2.44) and 2.60 (0.74-9.08) at the concomitant window, 1.31 (0.84-2.03) and 1.79 (0.75-4.29) at 30 days, and 1.34 (0.99-1.82) and 1.28 (0.62-2.65) at 150 days, respectively. With regard to fluoroquinolones, the present study suggests that the risk of bleeding when combined with DOACs, if any, is small. Codispensation of macrolides in patients on DOACs was not associated with an increased risk of bleeding. However, due to the small number of macrolide users, the results must be interpreted with caution.

Method of Hormonal Contraception and Protective Effects Against Ectopic Pregnancy.

OBJECTIVE: To estimate the incidence rates for ectopic pregnancy by contraceptive method in a cohort of women using hormonal contraception in Sweden between 2005 and 2016. METHOD: Women aged 15-49 years with a filled prescription for a hormonal contraceptive in the Swedish Prescribed Drug Register between 2005 and 2016 were included. For each woman, all exposed woman-years were allocated to treatment episodes depending on the method of contraception. Treatment time started on the day the prescription was filled and ended on the first day of the end of supply, new eligible dispensing, pregnancy-related diagnosis and its associated estimated last menstrual period, or removal procedure. Ectopic pregnancy was defined as having at least two records of International Classification of Diseases, Tenth Revision code O00-, including O00.0, O00.1, O00.2, O00.8, O00.9, within 30 days or one episode of O00- and one surgical procedure for ectopic pregnancy (NOMESCO Classification of Surgical Procedures code LBA, LBC, LBD, LBE, LBW). Incidence rates per 1,000 woman-years and 95% CIs were calculated for each method of contraception. RESULTS: The study included 1,663,242 women and 1,915 events of ectopic pregnancy. The incidence rate (95% CI) for ectopic pregnancy per method of hormonal contraception was estimated: 13.5-mg levonorgestrel (LNG) hormonal intrauterine device (IUD), 2.76 (2.26-3.35) per 1,000 woman-years; 52-mg LNG hormonal IUD, 0.30 (0.28-0.33) per 1,000 woman-years; combined oral contraception, 0.20 (0.19-0.22) per 1,000 woman-years; progestogen implants, 0.31 (0.26-0.37) per 1,000 woman-years; oral medium-dose progestogen (desogestrel 75 mg), 0.24 per 1,000 woman-years, (0.21-0.27); and oral low-dose progestogen (norethisterone 0.35 mg and lynestrenol 0.5 mg), 0.81 (0.70-0.93) per 1,000 woman-years. CONCLUSION: Hormonal contraception lowers the risk of ectopic pregnancy markedly. The incidence rate of ectopic pregnancy among women using a low-dose hormonal IUD (13.5 mg LNG) was substantially higher than that in women using other types of hormonal contraception. This study provides real-world evidence to inform best clinical practice for women-centered contraceptive counseling.

Rationale and performances of a data-driven method for computing the duration of pharmacological prescriptions using secondary data sources.

The assessment of the duration of pharmacological prescriptions is an important phase in pharmacoepidemiologic studies aiming to investigate persistence, effectiveness or safety of treatments. The Sessa Empirical Estimator (SEE) is a new data-driven method which uses k-means algorithm for computing the duration of pharmacological prescriptions in secondary data sources when this information is missing or incomplete. The SEE was used to compute durations of exposure to pharmacological treatments where simulated and real-world data were used to assess its properties comparing the exposure status extrapolated with the method with the "true" exposure status available in the simulated and real-world data. Finally, the SEE was also compared to a Researcher-Defined Duration (RDD) method. When using simulated data, the SEE showed accuracy of 96% and sensitivity of 96%, while when using real-world data, the method showed sensitivity ranging from 78.0 (nortriptyline) to 95.1% (propafenone). When compared to the RDD, the method had a lower median sensitivity of 2.29% (interquartile range 1.21-4.11%). The SEE showed good properties and may represent a promising tool to assess exposure status when information on treatment duration is not available.

The use of uncertain exposure-A method to define switching and add-on in pharmacoepidemiology.

PURPOSE: When defining exposure to pharmacological treatments in pharmacoepidemiology, register data often do not provide information regarding if a pharmacological treatment is a switch or an add-on. This study aims to compare two methods defining switching and add-on therapies and their impact on exposure-outcome associations. Additionally, to guide bias reduction, it aims to describe how the methods relate to immortal time bias and selection bias. METHODS: Cohort study using Swedish population-based health registers to identify antidepressant (AD) prescriptions as exposures while hospitalizations for psychiatric reasons were used as an empirical outcome example. The first method for exposure definition used conditioning on future exposure (FE), the second used the concept of uncertain exposure (UE). To estimate associations between outcome and exposure categories "Use of one AD," "Use of two or more ADs", and "UE" compared to "Unexposed," hazard ratios (HRs) and 95% confidence intervals were estimated using Cox regression adjusted for age and sex. RESULTS: Using the UE method, 7.2% of time periods were classified as "UE" with a notable proportion of psychiatric hospitalizations (7.7%) occurring during this time, while when using the FE method these hospitalizations were distributed over unexposed time and AD use time. The FE method resulted in slightly higher associations than the UE method. The highest HR was found during "UE": HR (95% CI) 5.54 (5.06-6.07). CONCLUSIONS: This study suggests that to reduce the potential immortal time bias, selection bias, and exposure misclassification inherent to the FE method, the UE method could be used for identifying switching and add-on therapies. If not used as a main exposure definition, the UE method may be used to investigate the impact of UE time in a sensitivity analysis.

Effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in atrial fibrillation: a Scandinavian population-based cohort study.

AIMS: Using Scandinavian population-based registries, we assessed risk of stroke/systemic embolism (SE) and bleeding with non-vitamin K antagonist oral anticoagulants compared with warfarin in anticoagulation-naïve patients with atrial fibrillation (AF). METHODS AND RESULTS: This historical cohort study included 219 545 AF patients [median age 74 years; 43% women; mean CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischaemic attack, vascular disease, age 65-74 years, sex category) score 3.3] initiating apixaban, dabigatran, rivaroxaban, or warfarin in Denmark, Norway, and Sweden (1 January 2013 to 31 December 2016). The primary endpoints were stroke/SE and major bleeding. The median follow-up times were 9.7 (3.9-21.5) months for stroke/SE and 9.6 (3.8-21.3) months for bleeding. Apixaban and warfarin initiators were older and had higher CHA2DS2-VASc scores compared with dabigatran and rivaroxaban initiators. After 1:1 propensity score matching, three cohorts were created: apixaban-warfarin (n = 111 162), dabigatran-warfarin (n = 56 856), and rivaroxaban-warfarin (n = 61 198). Adjusted hazard ratios (HRs) were estimated using a Cox regression. For stroke/SE, adjusted HRs against warfarin were 0.96 [95% confidence interval (CI): 0.87-1.06] for apixaban, 0.89 (95% CI: 0.80-1.00) for dabigatran, and 1.03 (95% CI: 0.92-1.14) for rivaroxaban. For major bleeding, the HRs against warfarin were 0.73 (95% CI: 0.67-0.78) for apixaban, 0.89 (95% CI: 0.82-0.97) for dabigatran, and 1.15 (95% CI: 1.07-1.25) for rivaroxaban. The results in the dabigatran cohort did not hold in all dose-defined subgroups. CONCLUSION: In this large Scandinavian study among AF patients initiating oral anticoagulation, those initiating dabigatran, apixaban, and rivaroxaban had similar rates of stroke/SE to patients initiating warfarin. Rates of major bleeding were lower with apixaban and dabigatran and higher with rivaroxaban, each compared with warfarin.

Patient characteristics and safety outcomes in new users of ticagrelor and clopidogrel-An observational cohort study in Sweden.

PURPOSE: We aimed to describe characteristics of new users of ticagrelor or clopidogrel following a recent coronary event, and to compare incidences of selected safety outcomes. METHODS: This observational cohort study used data from national Swedish registers. Patients first dispensed ticagrelor or clopidogrel (June 2011-December 2013) were identified from the Prescribed Drug Register and followed until censoring or 31 December 2014. Cohorts were restricted to patients with a recent coronary event-related hospital contact identified in the Patient Register. RESULTS: The study included 45 987 unique, naïve users of ticagrelor (73% men; mean age 66 years) or clopidogrel (69% men; mean age 69 years). Corresponding to indication, diagnoses before initiation were acute coronary syndrome (93%), myocardial infarction (76%), and percutaneous coronary intervention (69%). The most common medications used in the year before initiation of study therapy were antithrombotic agents (clopidogrel 62%, ticagrelor 43%), mainly low-dose acetylsalicylic acid. Ticagrelor users had a higher incidence (per 1000 person-years) of respiratory bleeding (24.6 [95% confidence interval (CI): 22.1-27.3]; vs clopidogrel users: 14.4 [13.1-15.8]) and dyspnea (25.9 [23.3-28.7]; vs clopidogrel users: 16.8 [15.4-18.4]). Epistaxis accounted for 83-93% of respiratory bleeds. Adjusted analyses found increased risks of gout and acute renal failure with ticagrelor. CONCLUSIONS: Clopidogrel users were older with a higher prevalence of concomitant medications than ticagrelor users. Our study showed increased incidences of dyspnea and respiratory bleeding (mainly epistaxis) among current ticagrelor users compared with clopidogrel users, and increased risks of gout and acute renal failure after adjustment.

Societal impact for patients with psoriasis: A nationwide Swedish register study.

BACKGROUND: Psoriasis is an immune-mediated chronic inflammatory disease having a significant negative health impact. Psoriasis has societal impact; loss of productivity has been estimated at approximately 10% and it may influence the patient's financial status. Relationships between quality of life, disease severity, and cost of care need exploration. Understanding the disease burden is important for health policy and research allocation. Few studies address the research gaps in socioeconomics, comorbidity, and medication use. OBJECTIVE: Observing differences in education, income, employment status, marital status, health care consumption, and drug utilization between patients with psoriasis and matched controls. METHODS: Cohort study following socioeconomics and health care consumption for all psoriasis patients from the Swedish patient register. All individuals with a first diagnosis of psoriasis in outpatient or inpatient care from 2002 to 2013 were followed until death, emigration, or end of the study. RESULTS: Overall, 109,803 patients were included (mean age 51.2 years, 53% women) and matched with 1.08 million controls. The levels of education and income were similar, but the proportion employed was significantly lower for patients with psoriasis. There was a tendency for fewer patients with psoriasis to be married. LIMITATIONS: Generalizability, lack of primary care diagnoses, and lack of early treatments (available from 2005). CONCLUSION: Understanding of the socioeconomic impact of psoriasis is extended by showing reductions in employment.

Risk factors of hospitalisation for thrombosis in adults with primary immune thrombocytopenia, including disease-specific treatments: a French nationwide cohort study.

We aimed to assess the risk factors of venous thrombosis (VT) and arterial thrombosis (AT) in adults with primary immune thrombocytopenia (ITP), particularly in relation to treatments. The population comprised all incident primary ITP adults in France between 2009 and 2017 (FAITH cohort; NCT03429660) built in the national health database. Outcomes were the first hospitalisation for VT and AT. Multivariable Cox regression models included baseline risk factors, time-varying exposure to ITP drugs, splenectomy and to cardiovascular drugs. The cohort included 10 039 patients. A higher risk of hospitalisation for VT was observed with older age, history of VT, history of cancer, splenectomy [hazard ratio (HR) 3·23, 95% confidence interval (CI) 2·26-4·61], exposure to corticosteroids (HR 3·55, 95% CI 2·74-4·58), thrombopoietin-receptor agonists (TPO-RAs; HR 2·28, 95% CI 1·59-3·26) and intravenous immunoglobulin (IVIg; HR 2·10, 95% CI 1·43-3·06). A higher risk of hospitalisation for AT was observed with older age, male sex, a history of cardiovascular disease, splenectomy (HR 1·50, 95% CI 1·12-2·03), exposure to IVIg (HR 1·85, 95% CI 1·36-2·52) and TPO-RAs (HR 1·64, 95% CI 1·26-2·13). Rituximab was not associated with an increased risk. These findings help to estimate the risk of thrombosis in adult patients with ITP and to select treatment.

Lessons Learned Using Real-World Data to Emulate Randomized Trials: A Case Study of Treatment Effectiveness for Newly Diagnosed Immune Thrombocytopenia.

Regulatory agencies are increasingly considering real-world evidence (RWE) to support label expansions of approved medicines. We conducted a comparative effectiveness study to emulate a proposed randomized trial of romiplostim vs. standard-of-care (SOC) therapy among patients with recently diagnosed (≤12 months) immune thrombocytopenia (ITP), that could support expansion of the romiplostim label. We discuss challenges that we encountered and solutions that were developed to address those challenges. Study size was a primary concern, particularly for romiplostim initiators, given the rarity of ITP and the stringent trial eligibility criteria. For this reason, we leveraged multiple data sources (Nordic Country Patient Registry for Romiplostim; chart review study of romiplostim initiators in Europe; Flatiron Health EMR linked with MarketScan claims). Additionally, unlike the strictly controlled clinical trial setting, platelet counts were not measured at regular intervals in the observational data sources, and therefore the end point of durable platelet response often used in trials could not be reliably measured. Instead, the median platelet count was chosen as the primary end point. Ultimately, while we observed a slightly higher median platelet count in the romiplostim group vs. SOC, precision was limited because of small study size (median difference was 11 × 109 /L (95% CI: -59, 81)). We underscore the importance of conducting comprehensive feasibility assessments to identify fit-for-purpose data sources with sufficient sample size, data elements, and follow-up. Beyond technical challenges, we also discuss approaches to increase the credibility of RWE, including systematic incorporation of clinical expertise into study design decisions, and separation between decision makers and the data.

Cardiovascular Risk in Users of Mirabegron Compared with Users of Antimuscarinic Treatments for Overactive Bladder: Findings from a Non-Interventional, Multinational, Cohort Study.

INTRODUCTION: During clinical trials, mirabegron, a ß3-adrenoreceptor agonist, was associated with increased vital signs vs placebo in patients with overactive bladder. OBJECTIVE: The purpose of this study was to compare incidence rates of adverse cardiovascular (CV) outcomes following mirabegron or antimuscarinic use. METHODS: We conducted an observational post-marketing safety study utilising real-world data. The study population was identified within five sources: Danish and Swedish National Registers, Clinical Practice Research Datalink (UK), Optum (USA) and Humana (USA). Episodes of time when patients were new users of mirabegron or antimuscarinics (October 2012-December 2018) were sourced from prescriptions and matched on propensity scores. Occurrences of major adverse cardiovascular events (MACE), acute myocardial infarction (AMI), stroke, CV mortality and all-cause mortality were identified. Outcome incidence rates and hazard ratios from Cox models were estimated. RESULTS: Overall, 152,026 mirabegron and 152,026 antimuscarinic episodes were matched. The population consisted of 63.1% women and 72.6% were ≥ 65 years old. There were no appreciable differences in the incidence rates of MACE, AMI or stroke between users of mirabegron and antimuscarinics. Incidence rates of CV mortality (hazard ratio 0.83, 95% confidence interval 0.73-0.95) and all-cause mortality (hazard ratio 0.80, 95% confidence interval 0.76-0.84) were no higher with mirabegron vs antimuscarinics. Results restricted to episodes at high risk for CV events or stratified by age (< 65 years, ≥ 65 years) or prior overactive bladder medication use were consistent with overall findings. CONCLUSIONS: This large, multinational study found no higher risk of MACE, AMI, stroke, CV mortality or all-cause mortality among users of mirabegron relative to users of antimuscarinics.

During clinical trials, mirabegron, which is a treatment for overactive bladder, was associated with small increases in heart rate and blood pressure. This study was conducted to compare the frequency of cardiac events following the use of mirabegron or antimuscarinics, a group of treatments also used to treat overactive bladder. We obtained the data for this study from four countries: Denmark, Sweden, the UK and the USA. We identified people who were new users of mirabegron or antimuscarinics from 2012 to 2018 using prescription or dispensing records. Occurrences of major cardiac events, heart attack, stroke, death due to cardiac events and death from any cause were evaluated. Overall, we identified 152,026 times when mirabegron or antimuscarinics were each used as new treatments. Most of the people in the study were women (63.1%) and at least 65 years old (72.6%). There were no notable differences between the treatment groups with regard to how often major cardiac events, heart attack or stroke occurred. Further, death due to cardiac events and death from any cause were no higher with mirabegron compared with antimuscarinics. We obtained similar results when the data were assessed for patients who were at high risk for cardiac events or split by age (less than 65 years or at least 65 years) or a history of overactive bladder medication use. In conclusion, this large study involving data from several countries found no higher risk of major cardiac events, heart attack, stroke or death among people prescribed mirabegron compared with antimuscarinics.

Use of intravenous iron and risk of anaphylaxis: A multinational observational post-authorisation safety study in Europe.

PURPOSE: This post-authorisation safety study estimated the risk of anaphylaxis in patients receiving intravenous (IV) iron in Europe, with interest in iron dextran and iron non-dextrans. Studies conducted in the United States have reported risk of anaphylaxis to IV iron ranging from 2.0 to 6.8 per 10 000 first treatments. METHODS: Cohort study of IV iron new users, captured mostly through pharmacy ambulatory dispensing, from populations covered by health and administrative data sources in five European countries from 1999 to 2017. Anaphylaxis events were identified through an algorithm that used parenteral penicillin as a positive control. RESULTS: A total of 304 210 patients with a first IV iron treatment (6367 iron dextran), among whom 13-16 anaphylaxis cases were identified and reported as a range to comply with data protection regulations. The pooled unadjusted incidence proportion (IP) ranged from 0.4 (95% confidence interval [CI], 0.2-0.9) to 0.5 (95% CI, 0.3-1.0) per 10 000 first treatments. No events were identified at first dextran treatments. There were 231 294 first penicillin treatments with 30 potential cases of anaphylaxis (IP = 1.2; 95% CI, 0.8-1.7 per 10 000 treatments). CONCLUSION: We found an IP of anaphylaxis from 0.4 to 0.5 per 10 000 first IV iron treatments. The study captured only a fraction of IV iron treatments administered in hospitals, where most first treatments are likely to happen. Due to this limitation, the study could not exclude a differential risk of anaphylaxis between iron dextran and iron non-dextrans. The IP of anaphylaxis in users of penicillin was consistent with incidences reported in the literature.