Federated analyses of multiple data sources in drug safety studies.

PURPOSE: Studies of rare side effects of new drugs with limited exposure may require pooling of multiple data sources. Federated Analyses (FA) allow real-time, interactive, centralized statistical processing of individual-level data from different data sets without transfer of sensitive personal data. METHODS: We review IT-architecture, legal considerations, and statistical methods in FA, based on a Swedish Medical Products Agency methodological development project. RESULTS: In a review of all post-authorisation safety studies assessed by the EMA during 2019, 74% (20/27 studies) reported issues with lack of precision in spite of mean study periods of 9.3 years. FA could potentially improve precision in such studies. Depending on the statistical model, the federated approach can generate identical results to a standard analysis. FA may be particularly attractive for repeated collaborative projects where data is regularly updated. There are also important limitations. Detailed agreements between involved parties are strongly recommended to anticipate potential issues and conflicts, document a shared understanding of the project, and fully comply with legal obligations regarding ethics and data protection. FA do not remove the data harmonisation step, which remains essential and often cumbersome. Reliable support for technical integration with the local server architecture and security solutions is required. Common statistical methods are available, but adaptations may be required. CONCLUSIONS: Federated Analyses require competent and active involvement of all collaborating parties but have the potential to facilitate collaboration across institutional and national borders and improve the precision of postmarketing drug safety studies.

Susceptibility to SARS-Cov-2 infection and risk for severe COVID-19 in patients with prostate cancer on androgen deprivation therapy.

Androgen deprivation therapy (ADT) has been hypothesized to protect against COVID-19, but previous observational studies of men with prostate cancer on ADT have been inconsistent regarding mortality risk from coronavirus disease 2019 (COVID-19). Using data from the Prostate Cancer data Base Sweden (PCBaSe), we identified a cohort of 114 547 men with prevalent prostate cancer on the start of follow-up in February 2020, and followed them until 16 December 2020 to evaluate the association between ADT and time to test positive for COVID-19. Among men testing positive for COVID-19, we used regression analyses to estimate the association between ADT and risk of COVID-19-related hospital admission/death from any cause within 30 days of the positive test. In total, 1695 men with prostate cancer tested positive for COVID-19. In crude analyses, exposure to ADT was associated with a 3-fold increased risk of both testing positive for COVID-19 infection and subsequent hospital admission/death. Adjustment for age, comorbidity and prostate cancer risk category substantially attenuated the associations: HR 1.3 (95% CI: 1.1-1.5) for testing positive for COVID-19, and OR 1.4 (95% CI: 1.0-1.9) for risk of subsequent hospital admission/death. In conclusion, although these results suggest increased risks of a positive COVID-19 test, and COVID-19-related hospital admission/death in men on ADT, these findings are likely explained by confounding by old age, cancer-associated morbidity and other comorbidities being more prevalent in men on ADT, rather than a direct effect of the therapy.

Optimized diagnosis-based comorbidity measures for all-cause mortality prediction in a national population-based ICU population.

BACKGROUND: We aimed to optimize prediction of long-term all-cause mortality of intensive care unit (ICU) patients, using quantitative register-based comorbidity information assessed from hospital discharge diagnoses prior to intensive care treatment. MATERIAL AND METHODS: Adult ICU admissions during 2006 to 2012 in the Swedish intensive care register were followed for at least 4 years. The performance of quantitative comorbidity measures based on the 5-year history of number of hospital admissions, length of stay, and time since latest admission in 36 comorbidity categories was compared in time-to-event analyses with the Charlson comorbidity index (CCI) and the Simplified Acute Physiology Score (SAPS3). RESULTS: During a 7-year period, there were 230,056 ICU admissions and 62,225 deaths among 188,965 unique individuals. The time interval from the most recent hospital stays and total length of stay within each comorbidity category optimized mortality prediction and provided clear separation of risk categories also within strata of age and CCI, with hazard ratios (HRs) comparing lowest to highest quartile ranging from 1.17 (95% CI: 0.52-2.64) to 6.41 (95% CI: 5.19-7.92). Risk separation was also observed within SAPS deciles with HR ranging from 1.07 (95% CI: 0.83-1.38) to 3.58 (95% CI: 2.12-6.03). CONCLUSION: Baseline comorbidity measures that included the time interval from the most recent hospital stay in 36 different comorbidity categories substantially improved long-term mortality prediction after ICU admission compared to the Charlson index and the SAPS score. Trial registration ClinicalTrials.gov ID NCT04109001, date of registration 2019-09-26 retrospectively.

Population-based estimates of age and comorbidity specific life expectancy: a first application in Swedish males.

INTRODUCTION: For clinical decision-making, an estimate of remaining lifetime is needed to assess benefit against harm of a treatment during the remaining lifespan. Here, we describe how to predict life expectancy based on age, Charlson Comorbidity Index (CCI) and a Drug Comorbidity Index (DCI), whilst also considering potential future changes in CCI and DCI using population-based data on Swedish men. METHODS: Simulations based on annual updates of vital status, CCI and DCI were used to estimate life expectancy at population level. The probabilities of these transitions were determined from generalised linear models using prostate cancer-free comparison men in PCBaSe Sweden. A simulation was performed for each combination of age, CCI, and DCI. Survival curves were created and compared to observed survival. Life expectancy was then calculated as the area under the simulated survival curve. RESULTS: There was good agreement between observed and simulated survival curves for most ages and comorbidities, except for younger men. With increasing age and comorbidity, there was a decrease in life expectancy. Cross-validation based on six regions in Sweden also showed that simulated and observed survival was similar. CONCLUSION: Our proposed method provides an alternative statistical approach to estimate life expectancy at population level based on age and comorbidity assessed by routinely collected information on diagnoses and filled prescriptions available in nationwide health care registers.

An Aggregated Comorbidity Measure Based on History of Filled Drug Prescriptions: Development and Evaluation in Two Separate Cohorts.

BACKGROUND: The ability to account for comorbidity when estimating survival in a population diagnosed with cancer could be improved by using a drug comorbidity index based on filled drug prescriptions. METHODS: We created a drug comorbidity index from age-stratified univariable associations between filled drug prescriptions and time to death in 326,450 control males randomly selected from the general population to men with prostate cancer. We also evaluated the index in 272,214 control females randomly selected from the general population to women with breast cancer. RESULTS: The new drug comorbidity index predicted survival better than the Charlson Comorbidity Index (CCI) and a previously published prescription index during 11 years of follow-up. The concordance (C)-index for the new index was 0.73 in male and 0.76 in the female population, as compared with a C-index of 0.67 in men and 0.69 in women for the CCI. In men of age 75-84 years with CCI = 0, the median survival time was 7.1 years (95% confidence interval [CI] = 7.0, 7.3) in the highest index quartile. Comparing the highest to the lowest drug comorbidity index quartile resulted in a hazard ratio (HR) of 2.2 among men (95% CI = 2.1, 2.3) and 2.4 among women (95% CI = 2.3, 2.6). CONCLUSIONS: A new drug comorbidity index based on filled drug prescriptions improved prediction of survival beyond age and the CCI alone. The index will allow a more accurate baseline estimation of expected survival for comparing treatment outcomes and evaluating treatment guidelines in populations of people with cancer.

Risk of cardiovascular events in men on abiraterone or enzalutamide combined with GnRH agonists: nation-wide, population-based cohort study in Sweden.

BACKGROUND: Men with prostate cancer (PCa) on gonadotropin-releasing hormone agonists (GnRH) have an increased risk of cardiovascular disease (CVD) compared to men with PCa not on GnRH as well as compared with PCa-free men. Whether the addition of androgen receptor targeted (ART) drugs to GnRH further increases CVD risk, remains to be fully elucidated. MATERIAL AND METHODS: We investigated risk of CVD for men with castration resistant PCa (CRPC) on GnRH plus ART; abiraterone or enzalutamide vs 5,127 and 12,079 respective matched comparator men on GnRH in Prostate Cancer data Base Sweden (PCBaSeTraject) 4.1 between 1 June 2015 and 31 December 2018. PCBaSeTraject links National Prostate Cancer Register of Sweden to other healthcare registries and demographic databases. We conducted multivariable Cox proportional hazard models adjusting for PCa risk category, Charlson comorbidity index (CCI), insulin or statin use, civil status, level of education, history of CVD events and number of CVD drugs, with any incident or fatal CVD as the outcome. RESULTS AND CONCLUSION: 1,310 men were treated with abiraterone and 3,579 with enzalutamide. In multivariable analysis, CVD risk was increased in men on abiraterone (hazard ratio (HR): 1.19; 95% confidence interval (CI): 1.03-1.38) and in men on enzalutamide (HR: 1.10; 95% CI: 1.01-1.20). Men with a recent CVD (<12 months) including both men on ART as well as comparators had a much higher probability of a new CVD vs men with no prior CVD. CVD risk was mildly increased in men with PCa on GnRH plus abiraterone or enzalutamide vs comparator men on GnRH. Residual confounding and detection bias may at least partly explain this association.

Change in risk for narcolepsy over time and impact of definition of onset date following vaccination with AS03 adjuvanted pandemic A/H1N1 influenza vaccine (Pandemrix) during the 2009 H1N1 influenza pandemic.

PURPOSE: To estimate risk for narcolepsy in defined time windows following exposure to adjuvanted A(H1N1) pandemic vaccine (Pandemrix) and impact of different definitions of index date for the narcolepsy diagnosis. METHODS: Vaccine exposure in approximately 30% of the Swedish population in 2009 was linked to information on narcolepsy diagnosis retrieved from the national patient registry. Cases were verified by a systematic chart review. Poisson regression was used to compare incidence in defined time windows following vaccination. RESULTS: Of 266 cases of narcolepsy identified, 25% (66/266) were prevalent cases with symptom onset documented before vaccine exposure. Incident cases had a median time interval between first symptom and the date recorded in the patient registry of 64 weeks (IQR 39-107) when vaccinated (N = 182) and 65 weeks (IQR 51-72) when unvaccinated (N = 16). With first symptom defining index date, the adjusted risk for narcolepsy in younger patients was increased 14 times during the first year after vaccination, three times elevated the second year, but with no detectable increased risk more than 2 years after vaccination exposure. Using the index date from the patient registry, the adjusted increase in risk was about seven times elevated for all three time intervals. CONCLUSIONS: The magnitude of the estimated increased risk for narcolepsy following exposure to the A(H1N1) pandemic vaccine is highly dependent on the method used to determine the index date for disease onset. The sometimes very long and potentially variable interval from first symptom to a health care registry diagnosis complicates estimations of risk.

Multivariable models using administrative data and biomarkers to adjust for case mix in the ICU.

BACKGROUND: Routinely collected laboratory biomarkers could improve control of confounding from disease severity in non-interventional studies of general intensive care unit (ICU) patients. Their ability to predict both short- and long-term mortality was evaluated. METHODS: The performance of age, sex, Charlson co-morbidity index, and baseline values of ten predefined blood biomarkers as predictors of 30-day and 1-year mortality was evaluated in 5505 general ICU stays. RESULTS: Regression models based on age, sex, Charlson index, and biomarkers were somewhat less accurate in predicting 30-day mortality (c-index 0.83, Brier score 0.27) compared to the SAPS II score (c-index = 0.88, Brier score = 0.09) and in predicting 1-year mortality (c-index = 0.82, Brier score = 0.31) compared to the SAPS II score (c-index = 0.85, Brier score = 0.13). Cystatin C improved predictive ability slightly compared to creatinine, but age and Charlson comorbidity index were more important predictors. Using multiple imputation to replace missing biomarker values notably improved predictive ability of the models. CONCLUSIONS: Automatically collected baseline variables are almost as predictive of both short- and long-term mortality in general ICU patients, as the SAPS II score. This can facilitate internal control of confounding in non-interventional studies of mortality using administrative data.

Increased availability of paracetamol in Sweden and incidence of paracetamol poisoning: using laboratory data to increase validity of a population-based registry study.

PURPOSE: To estimate the incidence trend and outcome of paracetamol poisoning, in relation to increased availability of paracetamol from non-pharmacy outlets in 2009. METHOD: Patients' serum paracetamol results over 14 years (2000-2013) from 20 (out of 21) regions in Sweden were linked to national registers of hospital care, cause of death, and prescriptions. Paracetamol poisonings were defined by serum paracetamol levels, hospital diagnoses, or cause of death. The change in incidence of poisonings following increased availability of paracetamol was analysed by using segmental regression of time series. RESULTS: Of the 12 068 paracetamol poisonings, 85% were classified as intentional self-harm. Following increased availability from non-pharmacy outlets, there was a 40.5% increase in the incidence of paracetamol poisoning, from 11.5/100 000 in 2009 to 16.2/100 000 in 2013. Regression analyses indicated a change in the trend (p < 0.0001) but not an immediate jump in the incidence (p = 0.5991) following the increased availability. Adjusting for trends in hospital episodes for self-harm, suicides, and the sales volume of paracetamol did not influence the result. All-cause mortality at 30 days (3.2%) did not change over time. CONCLUSIONS: The incidence of paracetamol poisoning in Sweden has increased since 2009, contrasting the decreased incidence in the period of 2007-2009. The change in trend was temporally associated with the introduction of availability of paracetamol from non-pharmacy outlets but did not appear to be related to sales volume of paracetamol or general trends in self-harm or suicides. © 2017 Commonwealth of Australia. Pharmacoepidemiology and Drug Safety © 2017 John Wiley & Sons, Ltd.

Acute myocardial infarction: a comparison of short-term survival in national outcome registries in Sweden and the UK.

BACKGROUND: International research for acute myocardial infarction lacks comparisons of whole health systems. We assessed time trends for care and outcomes in Sweden and the UK. METHODS: We used data from national registries on consecutive patients registered between 2004 and 2010 in all hospitals providing care for acute coronary syndrome in Sweden and the UK. The primary outcome was all-cause mortality 30 days after admission. We compared effectiveness of treatment by indirect casemix standardisation. This study is registered with ClinicalTrials.gov, number NCT01359033. FINDINGS: We assessed data for 119,786 patients in Sweden and 391,077 in the UK. 30-day mortality was 7·6% (95% CI 7·4-7·7) in Sweden and 10·5% (10·4-10·6) in the UK. Mortality was higher in the UK in clinically relevant subgroups defined by troponin concentration, ST-segment elevation, age, sex, heart rate, systolic blood pressure, diabetes mellitus status, and smoking status. In Sweden, compared with the UK, there was earlier and more extensive uptake of primary percutaneous coronary intervention (59% vs 22%) and more frequent use of ß blockers at discharge (89% vs 78%). After casemix standardisation the 30-day mortality ratio for UK versus Sweden was 1·37 (95% CI 1·30-1·45), which corresponds to 11,263 (95% CI 9620-12,827) excess deaths, but did decline over time (from 1·47, 95% CI 1·38-1·58 in 2004 to 1·20, 1·12-1·29 in 2010; p=0·01). INTERPRETATION: We found clinically important differences between countries in acute myocardial infarction care and outcomes. International comparisons research might help to improve health systems and prevent deaths. FUNDING: Seventh Framework Programme for Research, National Institute for Health Research, Wellcome Trust (UK), Swedish Association of Local Authorities and Regions, Swedish Heart-Lung Foundation.

Natural History of Nonmetastatic Prostate Cancer Managed With Watchful Waiting.

Importance: It is uncertain to what extent watchful waiting (WW) in men with nonmetastatic prostate cancer (PCa) and a life expectancy of less than 10 years is associated with adverse consequences. Objective: To report transitions to androgen deprivation therapy (ADT), castration-resistant prostate cancer (CRPC), death from PCa, or death from other causes in men treated with a WW strategy. Design, Setting, and Participants: This nationwide, population-based cohort study included men with nonmetastatic PCa diagnosed since 2007 and registered in the National Prostate Cancer Register of Sweden with WW as the primary treatment strategy and with life expectancy less than 10 years. Life expectancy was calculated based on age, the Charlson Comorbidity Index (CCI), and a drug comorbidity index. Observed state transition models complemented observed data to extend follow-up to more than 20 years. Analyses were performed between 2022 and 2023. Exposure: Nonmetastatic PCa. Main Outcomes and Measures: Transitions to ADT, CRPC, death from PCa, and death from other causes were measured using state transition modeling. Results: The sample included 5234 men (median [IQR] age at diagnosis, 81 [79-84] years). After 5 years, 954 men with low-risk PCa (66.2%) and 740 with high-risk PCa (36.1%) were still alive and not receiving ADT. At 10 years, the corresponding proportions were 25.5% (n = 367) and 10.4% (n = 213), respectively. After 10 years, 59 men with low-risk PCa (4.1%) and 221 with high-risk PCa (10.8%) had transitioned to CRPC. Ten years after diagnosis, 1330 deaths in the low-risk group (92.3%) and 1724 in the high-risk group (84.1%) were from causes other than PCa. Conclusions and Relevance: These findings suggest that the WW management strategy is appropriate for minimizing adverse consequences of PCa in men with a baseline life expectancy of less than 10 years.

Development and validation of a multi-dimensional diagnosis-based comorbidity index that improves prediction of death in men with prostate cancer: Nationwide, population-based register study.

Assessment of comorbidity is crucial for confounding adjustment and prediction of mortality in register-based studies, but the commonly used Charlson comorbidity index is not sufficiently predictive. We aimed to develop a multidimensional diagnosis-based comorbidity index (MDCI) that captures comorbidity better than the Charlson Comorbidity index. The index was developed based on 286,688 men free of prostate cancer randomly selected from the Swedish general population, and validated in 54,539 men without and 68,357 men with prostate cancer. All ICD-10 codes from inpatient and outpatient discharges during 10 years prior to the index date were used to define variables indicating frequency of code occurrence, recency, and total duration of related hospital admissions. Penalized Cox regression was used to predict 10-year all-cause mortality. The MDCI predicted risk of death better than the Charlson comorbidity index, with a c-index of 0.756 (95% confidence interval [CI] = 0.751, 0.762) vs 0.688 (95% CI = 0.683, 0.693) in the validation cohort of men without prostate cancer. Men in the lowest vs highest MDCI quartile had distinctively different survival in the validation cohort of men with prostate cancer, with an overall hazard ratio [HR] of 5.08 (95% CI = 4.90, 5.26). This was also consistent within strata of age and Charlson comorbidity index, e.g. HR = 5.90 (95% CI = 4.65, 7.50) in men younger than 60 years with CCI 0. These results indicate that comorbidity assessment in register-based studies can be improved by use of all ICD-10 codes and taking related frequency, recency, and duration of hospital admissions into account.

Declining hip fracture burden in Sweden 1998-2019 and consequences for projections through 2050.

We aimed to estimate the absolute and age-standardized number of hip fractures in Sweden during the past two decades to produce time trends and future projections. We used nationwide register data from 1998 to 2019 and a validated algorithm to calculate the annual absolute and age-standardized number of incident hip fractures over time. The total hip fracture burden was 335,399 incident events over the 22 years, with a change from 16,180 in 1998 to 13,929 in 2019, a 14% decrease. One decade after the index hip fracture event, 80% of the patients had died, and 11% had a new hip fracture. After considering the steady growth of the older population, the decline in the age-standardized number of hip fractures from 1998 through 2019 was 29.2% (95% CI 28.1-30.2%) in women and 29.3% (95% CI 27.5-30.7%) in men. With a continued similar reduction in hip fracture incidence, we can predict that 14,800 hip fractures will occur in 2034 and 12,000 in 2050 despite doubling the oldest old (≥ 80 years). Without an algorithm, a naïve estimate of the total number of hip fractures over the study period was 539,947, with a second 10-year hip fracture risk of 35%. We note an ongoing decline in the absolute and age-standardized actual number of hip fractures in Sweden, with consequences for future projections.

Triggers for transition from active surveillance to radical treatment of prostate cancer 2008-2020 - a case-control study.

OBJECTIVE: To examine associations between objective signs of progression (triggers) and transition from active surveillance (AS) to radical treatment for prostate cancer (PC). PATIENTS AND METHODS: This case-control study included men with low- or favourable intermediate-risk PC in the region of Halland, with data from The National Prostate Cancer Register (NPCR), Sweden, starting AS between 2008 and 2020. Cases were men who transitioned to radical treatment. For each case, 10 controls who remained in AS were selected without further matching. Triggers for transition to treatment were histopathological progression, magnetic resonance imaging (MRI) progression and increases in prostate-specific antigen (PSA) levels. We compared the probabilities for triggers between cases and controls, in 2008-2014 and 2015-2020, using logistic regression. RESULTS: Amongst 846 men, we identified 98 cases in 2008-2014 and 172 cases in 2015-2020. Histopathological progression was associated with transition, most strongly in the later period (2008-2014: odds ratios [OR] 6.88, 95% confidence interval [CI] 3.69-12.80; and 2015-2020: OR 75.29, 95% CI 39.60-143.17). MRI progression was associated with transition in 2015-2020 (OR 6.38, 95% CI 2.70-15.06), whereas an increase in PSA was weakly associated with transition in the early period. The absence of triggers was associated with no transition (2008-2014: OR 0.24, 95% CI 0.15-0.40, and 2015-2020: OR 0.09, 95% CI 0.06-0.14). The probability of no trigger was 27% in cases 2015-2020. CONCLUSION: The increase in association between histopathological trigger and transition to treatment indicates increased quality of AS. Still, amongst men treated from 2015 to 2020, 27% transitioned without any trigger.

Choice of imputation method for missing metastatic status affected estimates of metastatic prostate cancer incidence.

OBJECTIVES: To study how handling missing data on M stage in a clinical cancer register affects estimates of incidence of metastatic prostate cancer. STUDY DESIGN AND SETTING: Estimates of age-standardized incidence of metastatic prostate cancer were obtained by the use of data in a population-based clinical cancer register in Sweden and using four methods for imputation of missing M stage. Adjusted survival was used to compare men with known and imputed M stage. RESULTS: The proportion of men with missing M stage was high (66%) and varied according to the risk group and over calendar time. The estimated incidence of metastatic disease varied depending on imputation method, with all methods indicating a decreasing incidence over time. A combination of deterministic imputation (DI) and multiple imputation (MI) produced adjusted survival curves for men with imputed M stage that best resembled the survival for men with known M stage. CONCLUSIONS: Plausible estimates of incidence of metastatic prostate cancer in clinical cancer registers can be obtained by the use of a combination of DI of missing M stage and MI.

Uptake of doublet therapy for de novo metastatic castration sensitive prostate cancer: a population-based drug utilisation study in Sweden.

BACKGROUND: Randomised controlled trials have demonstrated prolonged survival with new upfront treatments in addition to standard androgen deprivation therapy (ADT) in men with de novo metastatic castration-sensitive prostate cancer. We describe patient characteristics, time trends and regional differences in uptake of these new treatment strategies in clinical practice. MATERIAL AND METHODS: This descriptive study consisted of men registered in the National Prostate Cancer Register of Sweden from 1 January 2018 to 31 March 2022 with de novo metastatic castration-sensitive prostate cancer defined by the presence of metastases on imaging at the time of diagnosis. Life expectancy was calculated based on age, Charlson Comorbidity Index and a Drug Comorbidity Index. RESULTS: Within 6 months from diagnosis, 57% (1,677/2,959) of men with de novo metastatic castration-sensitive prostate cancer and more than 3 years of life expectancy had received docetaxel, abiraterone, enzalutamide, apalutamide and/or radiotherapy. Over time, there was a 2-fold increase in uptake of any added treatment, mainly driven by a 6-fold increase in use of abiraterone, enzalutamide or apalutamide, with little change in use of other treatments. CONCLUSIONS: Slightly more than half of men diagnosed with de novo metastatic castration-sensitive prostate cancer and a life expectancy of at least 3 years received additions to standard ADT as recommended by national guidelines in 2019-2022 in Sweden. There was a 2-fold increase in use of these treatments during the study period; however, efforts to further increase adherence to guidelines are warranted.

Survival Trend in Individuals With De Novo Metastatic Prostate Cancer After the Introduction of Doublet Therapy.

Importance: Recently, life-prolonging treatments for patients with advanced prostate cancer have been introduced in clinical practice. Objective: To investigate if the introduction of doublet therapy is associated with changes in survival on a population-basis. Design, Setting, and Participants: This nationwide population-based cohort study used data from the Prostate Cancer data Base Sweden from 2008 to 2020. Men registered with de novo metastatic castration-sensitive prostate cancer (mCSPC) were included. Exposure: The proportion of men with mCSPC who received doublet therapy, ie, androgen deprivation therapy plus androgen receptor pathway inhibitor drugs or chemotherapy was assessed. Main Outcomes and Measures: Standardized overall survival, taking age, comorbidity, and cancer characteristics into consideration, was estimated by use of a parametric survival model. Results: A total of 11 382 men were included in this study (median [IQR] age, 74.0 [68-81] years). There was a shift toward less advanced prostate cancer during the study period with a decrease in median (IQR) prostate-specific antigen at diagnosis in men with mCSPC from 145 (39-571) ng/mL to 107 (27-426) ng/mL. Upfront treatment with doublet therapy in these men simultaneously increased from 1% (7 of 991) in 2016 to 44% (402 of 922) in 2020. The adjusted 5-year overall survival increased from 26% (95% CI, 25%-28%) from 2008 to 2012 to 35% (95% CI, 31%-40%) from 2017 to 2020. During the first 5 years after diagnosis, there was an increase in mean survival of 6 months, from 2.7 (95% CI, 2.6-2.8) years from 2008 to 2012 to 3.2 (95% CI, 3.1-3.1) years from 2017 to 2020. Conclusions and Relevance: In parallel with improvements in treatment of advanced prostate cancer, a clinically meaningful increase in mean survival was observed in men with de novo mCSPC in Sweden between 2008 and 2020 in this study.

Use of Antiepileptic Drugs and Risk of Prostate Cancer: A Nationwide Case-Control Study in Prostate Cancer Data Base Sweden.

An inverse association between use of antiepileptic drugs (AEDs) and prostate cancer (PCa) has been suggested, putatively due to the histone deacetylases inhibitory (HDACi) properties of the AEDs. In a case-control study in Prostate Cancer data Base Sweden (PCBaSe), PCa cases diagnosed between 2014 and 2016 were matched to five controls by year of birth and county of residence. AED prescriptions were identified in the Prescribed Drug Registry. Odds ratios (ORs) and 95% confidence intervals for risk of PCa were estimated using multivariable conditional logistic regression, adjusted for civil status, education level, Charlson comorbidity index, number of outpatient visits, and cumulative duration of hospital stay. Dose responses in different PCa risk categories and HDACi properties of specific AED substances were further explored. 1738/31591 (5.5%) cases and 9674/156802 (6.2%) controls had been exposed to AED. Overall, users of any AED had a reduced risk of PCa as compared to nonusers (OR: 0.92; 95% CI: 0.87-0.97) which was attenuated by adjustment to healthcare utilisation. A reduced risk was also observed in all models for high-risk or metastatic PCa in AED users compared to nonusers (OR: 0.89; 95% CI: 0.81-0.97). No significant findings were observed for dose response or HDACi analyses. Our findings suggest a weak inverse association between AED use and PCa risk, which was attenuated by adjustment for healthcare utilisation. Moreover, our study showed no consistent dose-response pattern and no support for a stronger reduction related to HDAC inhibition. Further studies focusing on advanced PCa and PCa treatments are needed to better analyse the association between use of AED and risk of PCa.