Cohort Entry Date Research Articles

Cancer Risk Among Patients With Multiple Sclerosis: A 10-Year Nationwide Retrospective Cohort Study.

Previous literature has been diverging on cancer risk in people with multiple sclerosis (PwMS). Therefore, this study compared the risk of cancer in PwMS and a matched sample from the French general population. This 10-year nationwide retrospective matched cohort study (2012-2021) used data from the national French administrative health care database (99% coverage of the French population) to determine the time to the first incident cancer. PwMS were identified using their long-term disease (LTD) status, hospitalizations, and multiple sclerosis (MS)-specific drug reimbursements. The control population was matched 4:1 on age, sex, residence, insurance scheme, and cohort entry date. Participants were included if they had no history of cancer in the 3 years before inclusion. Patients with cancer were identified through LTD status, hospitalizations, chemotherapy, radiotherapy, or prostate cancer-specific drug reimbursements. Overall and cancer location-specific hazard ratios (HRs) for the first incident cancer were obtained from Fine and Gray models, and age- and sex-stratified estimates were reported. Participation in cancer screening through the 3 national programs (breast, colorectal, and cervical) were compared between groups. Cancer incidence was 799 per 100,000 person-years (PYs) (n = 8,368) among the 140,649 PwMS and 736 per 100,000 PYs (n = 31,796) among the 562,596 matched controls (70.8% of women; follow-up: 7.6 ± 3.2 years). A small overall risk increase was observed for PwMS (HR 1.06, 95% CI 1.03-1.08), mostly in women (HR 1.08, 95% CI 1.05-1.11). Risk varied by cancer types and was lower for prostate (HR 0.80, 95% CI 0.73-0.88), breast (HR 0.91, 95% CI 0.86-0.95), and colorectal (HR 0.90, 95% CI 0.84-0.97) cancer and higher for bladder (HR 1.71, 95% CI 1.54-1.89), brain (HR 1.68, 95% CI 1.42-1.98), and cervical (HR 1.24, 95% CI 1.12-1.38) cancer in PwMS. Cancer risk was higher in PwMS younger than 55 years (HR 1.20, 95% CI 1.15-1.24) but decreased in PwMS aged 65 years and older (HR 0.89, 95% CI 0.85-0.94). This trend was found in all cancer locations. There were fewer PwMS getting screened than controls (all programs), with a particularly pronounced difference among those aged 65 years and older. Cancer risk was slightly increased in PwMS, particularly for urogenital cancers, possibly due to surveillance bias. Risk fluctuated depending on age, perhaps due to varying generational screening practices (i.e., diagnosis neglect in the older PwMS) and risk factors.

The risk of acute infection in association with first ever diagnosed depression: a cohort study.

To assess the risk of acute infections in patients with first ever diagnosed depression compared to patients with no diagnosed depression in a primary-care database. We conducted a cohort study using the UK CPRD GOLD database (2000-2019). We identified patients aged 18 years or older with a recorded Read code for depression (cohort entry date) and compared them to patients with no Read codes for depression using risk set sampling. Comparison groups were frequency-matched on age and sex, and comparison patients were required to have ≥ 1 general practitioner (GP) contact within 14 days before cohort entry. The primary outcome was a composite of outpatient diagnosed acute infections, including respiratory, gastrointestinal, urogenital infections and septicemia) within the two-years after cohort entry. We applied propensity score fine stratification and estimated incidence rates and IR ratios (IRR) using negative binomial regression. In a weighted population of 285,922 patients with diagnosed depression and 285,921 comparison patients, the IR of acute infections was 97.3/1000 person-years (py) in patients with and 83.7/1000 py in patients with no diagnosed depression. The weighted IRR of acute infection was 1.18 (95% CI 1.16-1.20) comparing those with and with no diagnosed depression. Excluding patients with baseline comorbidities yielded an IRR even closer to the null: 1.07 (95% CI, 1.04-1.09). Our results suggest that patients with diagnosed depression are not at a meaningfully increased risk of acute infections compared to patients with no diagnosed depression. Slightly increased overall relative risks of infections can be explained by residual differences in health care utilization and by the severity of comorbidities.

Non-alcoholic fatty liver disease risk with GLP-1 receptor agonists and SGLT-2 inhibitors in type 2 diabetes: a nationwide nested case–control study

BackgroundNon-alcoholic fatty liver diseases (NAFLDs)/non-alcoholic steatohepatitis (NASH) are the most common liver disorders among patients with type 2 diabetes. Newer classes of glucose-lowering agents (GLAs), such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is), have been shown to improve liver-related biomarkers. However, their effects on the development of NAFLD/NASH remain inconclusive.MethodsA nested case–control study was conducted using Taiwan’s National Health Insurance Research Database for 2011–2018. Patients aged ≥ 40 years, diagnosed with type 2 diabetes, having stable non-insulin GLA use, and without NAFLD/NASH history were included. Patients with incident NAFLD/NASH were matched up to 10 randomly sampled controls based on individual’s age, gender, cohort entry date, type 2 diabetes diagnosis date, and disease risk score. Conditional logistic regression analyses were employed to estimate the association between liver risk and treatment exposure. Dose-response analysis was also performed.ResultsThere were 621,438 study patients included for analysis. During 1.8 years of median follow-up, the incidence of NAFLD/NASH was 2.7 per 1000 person-years. After matching, 5,730 incident NAFLD cases (mean age: 57.6 years, male: 53.2%) and 45,070 controls (57.7 years, 52.7%) were identified. Using GLP-1RAs or SGLT2is was associated with an insignificantly lower NAFLD/NASH risk (i.e., odds ratios [95% CIs]: 0.84 [0.46–1.52] and 0.85 [0.63–1.14], respectively) and increased cumulative SGLT2i doses were significantly associated with a reduced NAFLD/NASH risk (0.61 [0.38–0.97]).ConclusionGLP-1RA and SGLT2i therapies in type 2 diabetes patients might prevent NAFLD/NASH development, with a significantly lower risk related to greater treatment exposure.

Trajectories of disease severity and their clinical outcome in real-world patients with systemic lupus erythematosus

ObjectiveSystemic lupus erythematosus (SLE) is characterised by variability of disease activity patterns over time. This study aimed to investigate the trajectories of SLE disease severity patterns, identify clinical and demographic variables, and assess the association between trajectories of SLE disease severity and all-cause mortality. MethodsA retrospective cohort of newly diagnosed patients with SLE was established using the Korean nationwide healthcare claims information database between 1st January 2008 and 31st December 2016. Using group-based trajectory modelling (GBTM), they were clustered based on the trajectory of SLE disease severity patterns during a two-year follow-up from the cohort entry date. We performed Cox proportional hazards models to compare the mortality between trajectories of SLE disease severity patterns. ResultsA total of 8901 patients with SLE were included in the analysis from 2008 to 2016. Five distinct SLE disease severity trajectories were identified as optimal: consistently severe (4.6 %), mild-then-moderate (11.6 %), moderate-then-mild (15.1 %), consistently moderate (30.4 %), and consistently mild (38.3 %). Patients with consistently mild disease severity were more likely to be older; those with consistently severe disease severity were more likely to be male with more comorbidities than other groups. Compared to the consistently mild disease severity, the other trajectory groups showed a higher risk of all-cause mortality. ConclusionThrough GBTM, dynamic two-year severity trajectories of newly diagnosed SLE were identified. Patients’ demographics and comorbidities attributed to changes in SLE severity trajectories, which may inform evidence for clinical decision-making.

Real-world evidence from Germany and the United States: Treatment initiation on low-efficacy versus high-efficacy therapies in patients with multiple sclerosis

BackgroundThe hit-hard-and-early (HHAE) strategy where treatment is initiated with high-efficacy therapies opposed to low-efficacy therapies presents a potential paradigm shift in multiple sclerosis (MS) management. This study aimed to assess the adoption of the HHAE strategy in Germany and the United States (US) from 2020 to 2022 based on real-world data. MethodsThe analysis was based on longitudinal, patient-level data from Germany and the US. For Germany, data was extracted from the Permea platform covering approximately 44 % of all German community pharmacy dispensing. For the US, data from the Komodo Healthcare Map™ was utilized, covering medical benefit data from around 88 % of the US patient population. Patients ≥18 years old and who had at least 2 prescriptions for MS-related disease-modifying drugs (DMDs) between January 2020 and December 2022 were included. To approximate therapy beginners, a washout period of one year before treatment start was applied, excluding all patients who had an MS-related DMD prescription or claim in 2019. Cohort entry date was the day of the first MS-related DMD dispense or claim. DMDs were classified as high-efficacy and low-efficacy based on the Multiple Sclerosis Therapy Consensus Group (MSTCG). Group differences were assessed with two-sided χ2-square and t-tests. Results29,604 MS therapy beginners were identified in the German and 49,791 MS therapy beginners were identified in the US dataset. 29.6 % of MS therapy beginners in Germany and 61.6 % in the US followed the HHAE strategy. Between 2020 and 2022, a significant 14 % increase in the HHAE strategy was observed in both countries (p < 0.0001). High-efficacy therapy beginners switched from their initially prescribed therapy less frequently than low-efficacy therapy beginners: 6.9 % of high-efficacy vs. 19.5 % of low-efficacy therapy beginners in Germany (p < 0.0001) and 5.5 % of high-efficacy vs. 25.0 % low-efficacy therapy beginners in the US (p < 0.0001) switched from their first prescribed DMD. ConclusionBetween 2020 and 2022, the adoption of the HHAE strategy increased in both countries, with the US exhibiting nearly double the adoption rates. High-efficacy therapy beginners were less likely to switch from their initially prescribed medication than low-efficacy therapy beginners. Real world evidence can provide valuable insights into rapidly changing treatment patterns in patients with MS.

Long-Term Use of Oral Corticosteroids and Safety Outcomes for Patients With Atopic Dermatitis

The use of oral corticosteroids for prolonged periods may be associated with adverse events (AEs). Nevertheless, the risk of AEs with oral corticosteroids, especially among patients with atopic dermatitis (AD), has not been comprehensively investigated and lacks evidence on duration of treatment. To assess the association between long-term exposure to oral corticosteroids and AEs among adult patients with AD. This nested case-control study used data from the Health Insurance Review and Assessment Service database of South Korea between January 1, 2012, and October 31, 2021, which included 1 year prior to the cohort entry date of January 1, 2013, for assessing exclusion criteria and baseline characteristics, and 1 year after the study end date of October 31, 2020, to ensure a minimum duration for assessing exposure. Among the population of adults with AD, patients diagnosed with any of 11 AEs were matched with patients who had never received a diagnosis of any of the 11 AEs. Long-term use of oral corticosteroids was defined as cumulative supply of more than 30 days or more than 90 days of oral corticosteroid prescription per year. We used multivariable conditional logistic regression analyses to measure the risk of 11 individual outcomes (osteoporosis, fracture, type 2 diabetes, hyperlipidemia, hypertension, myocardial infarction, stroke, heart failure, avascular necrosis, cataract, or glaucoma) as the composite outcome, controlling for potential confounders. We further classified the composite outcome to individual outcomes to evaluate the AE-specific risk. Among 1 025 270 patients with AD between 2013 and 2020, 164 809 cases (mean [SD] age, 39.4 [14.8]; 56.9% women) were matched with 328 303 controls (mean [SD] age, 39.3 [14.7]; 56.9% women) for sex, age, cohort entry date, follow-up duration, and severity of AD, where the balance of most baseline characteristics was achieved. A total of 5533 cases (3.4%) and 10 561 controls (3.2%) were exposed to oral corticosteroids for more than 30 days, while 684 cases (0.4%) and 1153 controls (0.4%) were exposed to oral corticosteroids for more than 90 days. Overall, there was no increased risk of AEs with use of oral corticosteroids for more than 30 days (adjusted odds ratio [AOR], 1.00; 95% CI, 0.97-1.04), whereas the risk was slightly higher with use of oral corticosteroids for more than 90 days (AOR, 1.11; 95% CI, 1.01-1.23). The small elevation in experiencing an AE was observed with each cumulative or consecutive year of ever long-term use. This case-control study found a slightly increased risk of AEs associated with use of oral corticosteroids for more than 90 days per year, which warrants future research to fully elucidate the observed findings.

Adverse event comparison between glucagon-like peptide-1 receptor agonists and other antiobesity medications following bariatric surgery.

To compare the incidence of adverse events (AEs) related to antiobesity medications (AOMs; glucagon-like peptide-1 receptor agonists [GLP-1RAs] vs. non-GLP-1RAs) after bariatric surgery. This single-centre retrospective cohort included patients (aged 16-65 years) who had undergone laparoscopic Roux-en-Y gastric bypass or sleeve gastrectomy (cohort entry date) and initiated AOMs. Participants were categorized as users of US Food and Drug Administration (FDA)-approved, off-label, or GLP-1RA AOMs if documented as receiving the medication on or after cohort entry date. Non-GLP-1RA AOMs were phentermine, orlistat, topiramate, canagliflozin, dapagliflozin, empagliflozin, naltrexone, bupropion/naltrexone and phentermine/topiramate. GLP-1RA AOMs included: semaglutide, dulaglutide, exenatide and liraglutide. The primary outcome was AE incidence. Logistic regression was used to determine the association of AOM exposure with AEs. We identified 599 patients meeting our inclusion criteria, 83% of whom were female. Their median (interquartile range [IQR]) age was 47.8 (40.9-55.4) years. The median duration of surgery to AOM exposure was 30 months. GLP-1RAs use was not associated with higher odds of AEs: adjusted odds ratio (aOR) 1.1 (95% confidence interval [CI] 0.5-2.6) and aOR 1.1 (95% CI 0.6-2.3) for GLP-1RA versus FDA-approved and off-label AOM use, respectively. AOM initiation ≥12 months after surgery was associated with lower risk of AEs compared to <12 months (aOR 0.01 [95% CI 0.0-0.01]; p < 0.001). Our results showed that GLP-1RA AOMs were not associated with an increased risk of AEs compared to non-GLP-1RA AOMs in patients who had previously undergone bariatric surgery. Prospective studies are needed to identify the optimal timeframe for GLP-1RA initiation.

Late mortality and chronic health conditions in long-term survivors of nasopharyngeal cancers: The 20-year follow-up of territory-wide Hong Kong Nasopharyngeal Cancer Survivor Study (HKNPCSS).

12045 Background: The survival rate of patients with nasopharyngeal cancer (NPC) has significantly improved in the last decade. However, there are only a few studies that have quantified the long-term morbidity and mortality that follow NPC treatment. This study aims to analyze the chronic health conditions, all-cause mortality, and cause-specific mortality among NPC survivors. Methods: The Hong Kong NPC Survivor Study (HKNPCSS) is a retrospective cohort study conducted across all six oncology centers in Hong Kong. It included longitudinal follow-up of 5-year survivors diagnosed with NPC between 1997 to 2015. We compared the standardized mortality ratio (SMRs) of 7893 survivors to a matched population in terms of age, sex, and calendar year. We also calculated the frequencies of chronic conditions of 7893 survivors and 23679 healthy individuals with matched age, sex, and date of cohort entry. Chronic health conditions were classified using the Common Terminology Criteria for Adverse Events. Cox proportional hazard models were used to estimate hazard ratios (HRs) for chronic health conditions. Results: The mean age of NPC survivors was 49.1 years, while healthy individuals had a mean age of 50.5 years. Among the 7893 NPC survivors, the 20-year cumulative all-cause mortality was 34.0% (95% CI, 29.1%-38.9%), with 1668 (59.9%) of 2785 deaths attributed to health-related causes. The SMR for NPC survivors compared to the general population was 3.81 (95% CI, 3.67-3.95), with the highest SMRs observed for pulmonary (SMR: 6.18, 95% CI, 5.73-6.64) and cardiovascular (SMR: 2.12, 95% CI, 1.90-2.36) causes. Among the survivors, 59.2% (n=4674) had severe, life-threatening, or fatal (grade 3-5) health conditions, with a 20-year cumulative incidence of 59.0% (95% CI, 56.4%-61.5%). The adjusted hazard ratio (HR) of grade 3-5 chronic condition in NPC survivors, compared to healthy cohorts, was 7.02 (95% CI, 6.64-7.42). Gastrointestinal (HR: 20.7), hearing, visual, and nasal (HR: 15.4), and neurological (HR: 8.39) conditions had the highest risks. Intensity modulated radiotherapy (IMRT), compared to non-IMRT, was associated with reduced risks of all-cause mortality (HR: 0.83, 95% CI, 0.74-0.91) and a trend towards reduced grade 3-5 chronic health conditions (HR: 0.89, 95% CI, 0.75-1.05). Conclusions: Even 20 years after diagnosis, NPC survivors still face increased risks of late mortality and morbidity. The findings emphasize the need for a comprehensive survivorship program to improve outcomes for NPC survivors.

Hepatocellular carcinoma surveillance among people living with hepatitis B in Senegal (SEN-B): insights from a prospective cohort study

Chronic hepatitis B virus (HBV) infection is the predominant cause of hepatocellular carcinoma in west Africa, yet data on the incidence of HBV-related hepatocellular carcinoma remain scarce. We aimed to describe the uptake and early outcomes of systematic ultrasound-based hepatocellular carcinoma screening in SEN-B, which is a prospective HBV cohort in Senegal. In this prospective cohort study, we included treatment-naive, HBsAg-positive individuals who were referred to the two infectious diseases clinics (the Department of Tropical and Infectious Diseases and Ambulatory Treatment Center) at Fann University Hospital of Dakar, Senegal, between Oct 1, 2019, and Oct 31, 2022. All participants resided within the Dakar region. Participants underwent abdominal ultrasound, transient elastography, and clinical and virological assessments at inclusion and every 6 months. Liver lesions at least 1 cm in diameter on ultrasound were assessed using four-phase CT, MRI, or liver biopsy. Adherence to hepatocellular carcinoma surveillance was measured using the proportion of time covered, calculated by dividing the cumulative months covered by abdominal ultrasound examinations by the overall follow-up time, defined as the number of months from the date of cohort entry until the last recorded visit, hepatocellular carcinoma diagnosis, or death. Optimal adherence was defined as a proportion of time covered of 100%. Overall, 755 (99·6%) of 758 participants had at least one abdominal ultrasound performed. The median age of the enrolled participants was 31 years (IQR 25-39), 355 (47·0%) of 755 participants were women, and 82 (10·9%) had a family history of hepatocellular carcinoma. 15 (2·0%) of 755 individuals were HBeAg positive, 206 (27·3%) of 755 individuals had HBV DNA of more than 2000 IU/mL, and 27 (3·6%) of 755 had elastography-defined liver cirrhosis. Of ten (1·3%) participants with a focal lesion at least 1 cm at initial assessment, CT or MRI ruled out hepatocellular carcinoma in nine, whereas imaging and subsequent liver biopsy confirmed one patient with hepatocellular carcinoma. Two further patients with hepatocellular carcinoma were diagnosed at study presentation due to the presence of portal thrombosis on ultrasound. Excluding the three participants with hepatocellular carcinoma identified at baseline, 752 participants were eligible for screening every 6 months. Median follow-up time was 12 months (IQR 6-18) and the median number of ultrasounds per patient was 3 (2-4). During 809·5 person-years of follow-up, one incident hepatocellular carcinoma was reported, resulting in an incidence rate of 1·24 cases per 1000 person-years (95% CI 0·18-8·80). Overall, 702 (93·0%) of 755 participants showed optimal hepatocellular carcinoma surveillance, but this proportion decreased to 77·8% (42 of 54 participants) after 24 months. Hepatocellular carcinoma screening is feasible in HBV research cohorts in west Africa, but its longer-term acceptability needs to be evaluated. Long-term hepatocellular carcinoma incidence data are crucial for shaping tailored screening recommendations. Swiss National Science Foundation, the Swiss Cancer Research Foundation, the National Cancer Institute, and Roche Diagnostics. For the French translation of the abstract see Supplementary Materials section.

Epidemiology of Diabetic Kidney Disease among US Veterans.

With a large number of patients and high mortality, diabetic kidney disease (DKD) imposes a significant burden on US health care. Although diabetes is the leading cause of chronic kidney disease and complications, the epidemiology of DKD in the contemporary US veteran population is generally unknown. We aimed to estimate the rate of DKD progression and to measure the general epidemiology of DKD in the United States veteran population. We performed a retrospective observational research using electronic health-care records and administrative databases. The DKD patient cohort was abstracted from the Veterans Health Administration health-record data from January 2016 to March 2022. We defined DKD patients using the laboratory test data based on Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines. Summary statistics include the five-year cumulative incidence of progression to an advanced stage from the DKD stage at the cohort entry date and prevalence at a series of single time points. A total of 685,288 patients (male [96%], mean age 62 years, Caucasian [64%], non-Hispanic [87%]) met our eligibility criteria. The 5-year cumulative incidence of progression to an advanced DKD stage or all-cause death from DKD stages G1 A2/A3, G2 A2/A3, G3a, and G3b were 52.0%, 47.4%, 50.5%, and 60.9%, respectively. In sum, 594,082 patients were classified as moderate or high risk as per KDIGO guidelines in 2021, and stages G3a and G3b accounted for 51.2% and 25.3%, respectively, of cases. More than half of DKD patients underwent a stage progression or death within 5 years. A substantial number of DKD patients at an earlier stage might be left undetermined. The study findings warrant a revision of DKD patient identification and management in US veterans.

Concomitant Use of Selective Serotonin Reuptake Inhibitors With Oral Anticoagulants and Risk of Major Bleeding

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressants associated with a small increased risk of major bleeding. However, the risk of bleeding associated with the concomitant use of SSRIs and oral anticoagulants (OACs) has not been well characterized. To assess whether concomitant use of SSRIs with OACs is associated with an increased risk of major bleeding compared with OAC use alone, describe how the risk varies with duration of use, and identify key clinical characteristics modifying this risk. A population-based, nested case-control study was conducted among patients with atrial fibrillation initiating OACs between January 2, 1998, and March 29, 2021. Patients were from approximately 2000 general practices in the UK contributing to the Clinical Practice Research Datalink. With the use of risk-set sampling, for each case of major bleeding during follow-up, up to 30 controls were selected from risk sets defined by the case and matched on age, sex, cohort entry date, and follow-up duration. Concomitant use of SSRIs and OACs (direct OACs and vitamin K antagonists [VKAs]) compared with OAC use alone. The main outcome was incidence rate ratios (IRRs) of hospitalization for bleeding or death due to bleeding. There were 42 190 patients with major bleeding (mean [SD] age, 74.2 [9.3] years; 59.8% men) matched to 1 156 641 controls (mean [SD] age, 74.2 [9.3] years; 59.8% men). Concomitant use of SSRIs and OACs was associated with an increased risk of major bleeding compared with OACs alone (IRR, 1.33; 95% CI, 1.24-1.42). The risk peaked during the initial months of treatment (first 30 days of use: IRR, 1.74; 95% CI, 1.37-2.22) and persisted for up to 6 months. The risk did not vary with age, sex, history of bleeding, chronic kidney disease, and potency of SSRIs. An association was present both with concomitant use of SSRIs and direct OACs compared with direct OAC use alone (IRR, 1.25; 95% CI, 1.12-1.40) and concomitant use of SSRIs and VKAs compared with VKA use alone (IRR, 1.36; 95% CI, 1.25-1.47). This study suggests that among patients with atrial fibrillation, concomitant use of SSRIs and OACs was associated with an increased risk of major bleeding compared with OAC use alone, requiring close monitoring and management of risk factors for bleeding, particularly in the first few months of use.

The risk of acute infections in new users of antidepressants: An observational cohort study

BackgroundPreclinical studies suggested that drugs that functionally inhibit acid sphingomyelinase (FIASMA)may enhance immune cell longevity and potentially offer protection against infections. Many antidepressants have shown FIASMA activity. MethodsWe conducted a cohort study using primary-care data from the UK-based Clinical Practice Research Datalink (2000−2021). We assessed the association of composite diagnosed acute infections in new users of fluoxetine, sertraline, paroxetine, or venlafaxine aged 18–80 years compared to citalopram. We compared SARS-CoV-2 infections between groups in a secondary analysis. We estimated incidence rates (IR) and IR ratios (IRR) of acute infections in four pairwise comparisons using negative binomial regression. We applied propensity score (PS) fine stratification to control for confounding. ResultsIn the PS-weighted cohorts, we included 353,138 fluoxetine, 222,463 sertraline, 69,963 paroxetine, 32,608 venlafaxine, and between 515,996 and 516,583 new citalopram users. PS-weighted IRs ranged between 76.8 acute infections /1000 person-years (py) (sertraline) and 98.9 infections/1000 py (citalopram). We observed PS-weighted IRRs around unity for paroxetine (0.97, 95 % CI, 0.95–1.00), fluoxetine (0.94, 95 % CI, 0.92–0.95), and venlafaxine (0.90, 95 % CI, 0.87–0.94) vs citalopram. Reduced IRR for sertraline vs citalopram (0.84, 95 % CI, 0.82–0.85), became null within subgroups by cohort entry date. In the analysis of SARS-CoV-2 infection, no statistically relevant risk reduction was seen. LimitationsAnalysis not limited to patients with diagnosed depression, possible underestimation of infection incidence, and unclear FIASMA activity of citalopram. ConclusionsFluoxetine, sertraline, paroxetine, and venlafaxine were not associated with a reduced risk of acute infection when compared with the presumably weak FIASMA citalopram.

Vascular Endothelial Growth Factor Inhibitors and the Risk of Aortic Aneurysm and Aortic Dissection

Vascular endothelial growth factor pathway inhibitors (VPIs) pose a concern for aortic aneurysm (AA) and aortic dissection (AD), signaling potential vascular disease development. To investigate VPI-associated AA and AD. This case-control study with a nested design used full population data from a national claims database in Taiwan between 2011 and 2019. Eligible participants were aged 20 years or older with kidney, hepatic, gastrointestinal, or pancreatic cancer diagnosed between January 1, 2012, and December 31, 2019. The first cancer diagnosis date was defined as the cohort entry date. Cases were patients who received a diagnosis of AA or AD in hospitalizations or emergency visits between the cohort entry date and December 31, 2019. Controls were matched by ratio (up to 1:5) based on age, sex, cancer type, cohort entry date, and the index date (ie, the first AA or AD event date). Data analysis was performed between January 2022 and December 2023. Use of the oral VPIs sorafenib, sunitinib, and pazopanib between cohort entry date and index date. In the primary analysis, AA and AD were evaluated compositely, while in the secondary analyses, they were evaluated separately. Adjusted odds ratios (aORs) were calculated using conditional logistic regression to assess the association with VPI use (sorafenib, sunitinib, and pazopanib) considering various VPI exposure windows and cumulative use. A total of 1461 cases were included (mean [SD] age, 73.0 [12.3] years; 1118 male patients [76.5%]), matched to 7198 controls. AA or AD risk increased with a VPI exposure of 100 days or less before the index date (aOR, 2.10; 95% CI, 1.40-3.15), mainly from VPI-associated AD (aOR, 3.09; 95% CI, 1.77-5.39). Longer VPI duration (68 days or more: aOR, 2.64; 95% CI, 1.66-4.19) and higher cumulative dose (61 or more defined daily doses: aOR, 2.65; 95% CI, 1.66-4.23) increased the risk. The use of the 3 study VPIs (sorafenib, sunitinib, and pazopanib) was associated with an increased risk of AA and AD in patients with cancer, essentially all of the risk from VPI-associated AD. Future studies are needed to determine the risk factors of VPI-associated AA and AD, as well as to establish a class effect.

Pregnancy Outcomes in Living Kidney Donors: Protocol of a Population-Based Cohort Study in Three Canadian Provinces.

A substantial proportion of living kidney donors are women of childbearing age. Some prior studies report a higher risk of gestational hypertension and pre-eclampsia in living kidney donors compared with nondonors. Further research is needed to better quantify the risk of adverse maternal, fetal/infant, and neonatal outcomes attributable to living kidney donation. To determine the risk of hypertensive disorders of pregnancy, including gestational hypertension, pre-eclampsia, and eclampsia, and other maternal and fetal/infant outcomes in living kidney donors compared with a matched group of nondonors of similar baseline health. Protocol for a population-based, matched cohort study using Canadian administrative health care databases. The protocol will be run separately in 3 provinces, Ontario, Alberta, and British Columbia, and results will be combined statistically using meta-analysis. The cohort will include women aged 18 to 48 years who donated a kidney between July 1992 and March 2022 and had at least one postdonation singleton pregnancy of ≥20 weeks gestation between January 1993 and February 2023. We expect to include at least 150 living kidney donors with over 200 postdonation pregnancies from Ontario and a similar number of donors and pregnancies across Alberta and British Columbia combined. Nondonors will include women from the general population with at least one pregnancy of ≥20 weeks gestation between January 1993 and February 2023. Nondonors will be randomly assigned cohort entry dates based on the distribution of nephrectomy dates in donors. The sample of nondonors will be restricted to those aged 18 to 48 years on their cohort entry dates with delivery dates at least 6 months after their assigned entry dates. A concern with donor and nondonor comparisons is that donors are healthier than the general population. To reduce this concern, we will also apply 30+ exclusion criteria to further restrict the nondonor group so that they have similar health measures at cohort entry as the donors. Donor and nondonor pregnancies will then be matched (1:4) on 5 potential confounders: delivery date, maternal age at delivery date, time between cohort entry and delivery date, neighborhood income quintile, and parity at delivery date. The primary outcome will be a composite of maternal gestational hypertension, preeclampsia, or eclampsia. Secondary maternal outcomes will include components of the primary outcome, early pre-eclampsia, severe maternal morbidity, cesarean section, postpartum hemorrhage, and gestational diabetes. Fetal/infant/neonatal outcomes will include premature birth/low birth weight, small for gestational age, neonatal intensive care unit admission, stillbirth, and neonatal death. The primary unit of analysis will be the pregnancy. We will compute the risk ratio of the primary composite outcome in donors versus nondonors using a log-binomial mixed regression model with random effects to account for the correlation within women with multiple pregnancies and within matched sets of donors and nondonors. We will perform the statistical analyses within each province and then combine aggregated results using meta-analytic techniques to produce overall estimates of the study outcomes. Due to regulations that prevent individual-level records from being sent to other provinces, we cannot pool individual-level data from all 3 provinces. Compared to prior studies, this study will better estimate the donation-attributable risk of adverse maternal, fetal/infant, and neonatal outcomes. Transplant centers can use the results to counsel female living donor candidates of childbearing age and to inform recommended practices for the follow-up and care of living kidney donors who become pregnant.

Comparison of Acute Health Care Utilization Between Patients Receiving In-Center Hemodialysis and the General Population: A Population-Based Matched Cohort Study From Ontario, Canada.

Patients receiving maintenance hemodialysis have multiple comorbidities and are at high risk of presenting to the hospital. However, the incidence and cost of acute health care utilization in the in-center hemodialysis population and how this compares with other populations is poorly understood. To determine the rate, pattern, and cost of emergency department visits and hospitalizations in patients receiving in-center hemodialysis compared with a matched general population. Population-based matched cohort study. We used linked administrative health care databases from Ontario, Canada. We included 25 379 patients (incident and prevalent) receiving in-center hemodialysis between January 1, 2010, and December 31, 2018. Patients were matched on birth date (±2 years), sex, and cohort entry date using a 1:4 ratio to 101 516 individuals from the general population. Our primary outcomes were emergency department visits (allowing for multiple visits per individual) and hospital admissions from the emergency department. We also assessed all-cause hospitalizations, all-cause readmissions within 30 days of discharge from the original hospitalization, length of stay for hospital admissions (including multiple visits per individual), and the financial cost of these admissions. We presented the rate, percentage, median (25th, 75th percentiles), and incidence rate per 1000 person-years for emergency department visits and hospitalizations. Individual-level health care costs for emergency department visits and all-cause hospitalization were estimated using resource intensity weights multiplied by the cost per weighted case. Patients receiving in-center hemodialysis had substantially more comorbidities (eg, diabetes) than the matched general population. Eighty percent (n = 20 309) of patients receiving in-center hemodialysis had at least 1 emergency department visit compared with 56% (n = 56 452) of individuals in the matched general population, over a median follow-up of 1.8 years (25th, 75th percentiles: 0.7, 3.6) and 5.2 (2.5, 8.4) years, respectively. The incidence rate of emergency department visits, allowing for multiple visits per individual, was 2274 per 1000 person-years (95% confidence interval [CI]: 2263, 2286) for patients receiving in-center hemodialysis, which was almost 5 times as high as the matched general population (471 per 1000 person-years; 95% CI: 469, 473). The rate of hospital admissions from the emergency department and the rate of all-cause hospital admissions in the in-center hemodialysis population was more than 7 times as high as the matched general population (hospital admissions from the emergency department: 786 vs 101 per 1000 person-years; all-cause hospital admissions: 1056 vs 139 per 1000 person-years). The median number of all-cause hospitalization days per patient year was 4.0 (0, 16.5) in the in-center hemodialysis population compared with 0 (0, 0.5) in the matched general population. The cost per patient-year for emergency department visits in the in-center hemodialysis population was approximately 5.5 times as high as the matched general population while the cost of hospitalizations in the in-center hemodialysis population was approximately 11 times as high as the matched general population (emergency department visits: CAN$ 1153 vs CAN$ 209; hospitalizations: CAN$ 21 151 vs CAN$ 1873 [all costs in 2023 CAN$]). External generalizability and we could not determine whether emergency department visits and hospitalizations were preventable. Patients receiving in-center hemodialysis have high acute health care utilization. These results improve our understanding of the burden of disease and the associated costs in the in-center hemodialysis population, highlight the need to improve acute outcomes, and can aid health care capacity planning. Additional research is needed to address the risk of hospitalization after controlling for patient comorbidities. This is not applicable as this is a population-based matched cohort study and not a clinical trial.

High-Throughput Computing to Automate Population-Based Studies to Detect the 30-Day Risk of Adverse Outcomes After New Outpatient Medication Use in Older Adults with Chronic Kidney Disease: A Clinical Research Protocol.

Safety issues are detected in about one third of prescription drugs in the years following regulatory agency approval. Older adults, especially those with chronic kidney disease, are at particular risk of adverse reactions to prescription drugs. This protocol describes a new approach that may identify credible drug-safety signals more efficiently using administrative health care data. To use high-throughput computing and automation to conduct 700+ drug-safety cohort studies in older adults in Ontario, Canada. Each study will compare 74 acute (30-day) outcomes in patients who start a new prescription drug (new users) to a group of nonusers with similar baseline health characteristics. Risks will be assessed within strata of baseline kidney function. The studies will be population-based, new-user cohort studies conducted using linked administrative health care databases in Ontario, Canada (January 1, 2008, to March 1, 2020). The source population for these studies will be residents of Ontario aged 66 years or older who filled at least one outpatient prescription through the Ontario Drug Benefit (ODB) program during the study period (all residents have universal health care, and those aged 65+ have universal prescription drug coverage through the ODB). We identified 3.2 million older adults in the source population during the study period and built 700+ initial medication cohorts, each containing mutually exclusive groups of new users and nonusers. Nonusers were randomly assigned cohort entry dates that followed the same distribution of prescription start dates as new users. Eligibility criteria included a baseline estimated glomerular filtration rate (eGFR) measurement within 12 months before the cohort entry date (median time was 71 days before cohort entry in the new user group), no prior receipt of maintenance dialysis or a kidney transplant, and no prior prescriptions for drugs in the same subclass as the study drug. New users and nonusers will be balanced on ~400 baseline health characteristics using inverse probability of treatment weighting on propensity scores within 3 strata of baseline eGFR: ≥60, 45 to <60, <45 mL/min per 1.73 m2. We will compare new user and nonuser groups on 74 clinically relevant outcomes (17 composites and 57 individual outcomes) in the 30 days after cohort entry. We used a prespecified approach to identify these 74 outcomes. In each cohort, we will obtain eGFR-stratum-specific weighted risk ratios and risk differences using modified Poisson regression and binomial regression, respectively. Additive and multiplicative interaction by eGFR category will be examined. Drug-outcome associations that meet prespecified criteria (identified signals) will be further examined in additional analyses (including survival, negative-control exposure, and E-value analyses) and visualizations. The initial medication cohorts had a median of 6120 new users per cohort (interquartile range: 1469-38 839) and a median of 1 088 301 nonusers (interquartile range: 751 697-1 267 009). Medications with the largest number of new users were amoxicillin trihydrate (n = 1 000 032), cephalexin (n = 571 566), prescription acetaminophen (n = 571 563), and ciprofloxacin (n = 504,374); 19% to 29% of new users in these cohorts had an eGFR <60 mL/min per 1.73 m2. Despite our use of robust techniques to balance baseline indicators and to control for confounding by indication, residual confounding will remain a possibility. Only acute (30-day) outcomes will be examined. Our data sources do not include nonprescription (over-the-counter) drugs or drugs prescribed in hospitals and do not include outpatient prescription drug use in children or adults <65 years. This accelerated approach to conducting postmarket drug-safety studies has the potential to more efficiently detect drug-safety signals in a vulnerable population. The results of this protocol may ultimately help improve medication safety.

Long-Term Safety of Roflumilast in Patients with Chronic Obstructive Pulmonary Disease, a Multinational Observational Database Cohort Study.

This study evaluated the long-term safety of roflumilast in patients with chronic obstructive pulmonary disease or chronic bronchitis using electronic healthcare databases from Germany, Norway, Sweden, and the United States (US). The study population consisted of patients aged ≥40 years who had been exposed to roflumilast and a matched cohort unexposed to roflumilast. The matching was based on sex, age, calendar year of cohort entry date (2010-2011, 2012, or 2013), and a propensity score that included variables such as demographics, markers of chronic obstructive pulmonary disease (COPD) severity and morbidity, and comorbidities. In comparison to the unexposed matched cohort (never use), three exposure definitions were used for the exposed matched cohort: ever use, use status (current, recent, past use), and cumulative duration of use. The main outcome was 5-year all-cause mortality. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CI). 112,541 unexposed and 23,239 exposed patients across countries were included. Some variables remained unbalanced after matching, indicating higher COPD disease severity among the exposed patients. Adjusted HRs of 5-year all-cause mortality for "ever use" of roflumilast, compared to "never use", were 1.12 (95% CI, 1.08-1.17) in Germany, 1.00 (95% CI, 0.92-1.08) in Norway, 0.98 (95% CI, 0.92-1.04) in Sweden, and 1.16 (95% CI, 1.12-1.20) in the US. Compared to never users, there was a decrease in 5-year mortality risk observed among "current users" in Germany (HR: 0.93, 95% CI: 0.88-0.98), Norway (HR: 0.77, 95% CI: 0.67-0.87), and Sweden (HR: 0.80, 95% CI: 0.73-0.88). There was no observed increase in 5-year mortality risk with the use of roflumilast in Sweden or Norway. A small increase in 5-year mortality risk was observed in Germany and the US in the ever versus never comparison, likely due to residual confounding by indication.

Diagnosis patterns among diverse populations with mild cognitive impairment and Alzheimer’s disease: A large nationwide electronic health record cohort study

AbstractBackgroundWith recent advances and emerging research on diagnostic biomarkers and evolving diagnostic criteria, practitioners managing patients with cognitive complaints operate within a complex, changing environment. Although some evidence is available on the importance of prompt diagnosis, little information exists on the diagnostic process used in real‐world settings among diverse populations. This study’s objective was to characterize diagnosis patterns among adults with mild cognitive impairment (MCI), Alzheimer’s disease (AD), and/or dementia in the United States, and stratify by gender, age and race/ethnicity.MethodThis retrospective observational cohort study utilized the Optum® Market Clarity database from January 1, 2017–September 30, 2021. Eligible individuals had ≥1 diagnosis of MCI, AD, and/or dementia in their electronic health records or ≥2 diagnosis codes separated by ≥30 days in claims data, had ≥12 months of continuous enrollment before the cohort entry date, and had ≥1 day of continuous healthcare plan enrollment after the index date. Demographic information and the occurrence of diagnostic tests were also obtained from electronic medical records and insurance claims. Descriptive statistics were calculated and stratified by demographic factors.ResultA total of 179,419 newly diagnosed MCI cases, 81,267 AD cases, and 338,739 dementia cases were identified. The mean age at MCI, AD, or dementia diagnosis was similar overall for males and females. Among Caucasians, the mean age of MCI diagnosis was 70.5±14.8 for females and 69.8±14.5 for males. Among African Americans, the mean age at MCI diagnosis was 66.3±15.4 for females and 63.6±16.1 for males. PET scans and CSF biomarker screening occurred less often than MRI and CT (MCI: PET 0.6%, CSF 1.6%, MRI 16.6%, CT 17.5%; AD: PET 0.5%; CSF 0.9%; MRI 9.0%; CT 18.4%; dementia: PET 0.2%; CSF 1.6%; MRI 9.5%; CT 25.9%).ConclusionThe mean age at MCI, AD, and dementia diagnosis varied by demographic groups. The diagnosis of MCI, AD, and dementia remains largely clinical, with low use of brain imaging or CSF biomarkers. This knowledge of the patient populations and diagnostic experiences in a real‐world setting allows for greater understanding and growth to improve diagnosis across diverse groups and lead to faster support.

Association of anticholinergic drug exposure with the risk of dementia among older adults in Japan: The LIFE Study.

Several studies have investigated that anticholinergic drugs cause cognitive impairment. However, the risk of dementia associated with anticholinergics has not been extensively investigated in the super-aging society of Japan. We conducted this study to assess the association between anticholinergic drugs and the risk of dementia in older adults in Japan. This nested case-control study used data from the Longevity Improvement & Fair Evidence Study, which includes claim data in Japan from 2014 to 2020. We included 66,478 cases of diagnosed dementia and 328,919 matched controls aged ≥65years, matched by age, sex, municipality, and cohort entry year. Primary exposure was the total cumulative anticholinergic drugs prescribed from cohort entry date to event date or matched index date, which was the total standardized daily doses for each patient, calculated by adding the total dose of different types ofanticholinergic drugs in each prescription, divided by the World Health Organization-defined daily dose values. Odds ratios for dementia associated with cumulative exposure to anticholinergic drugs were calculated using conditional logistic regression adjusted for confounding variables. The mean (standard deviation) age at index date was 84.3 (6.9), and the percentage of women was 62.1%. From cohort entry date to event date or matched index date, 18.8% of the case patients and 13.7% of the controls were prescribed at least one anticholinergic drug. In the multivariable-adjusted model, individuals with anticholinergic drugs prescribed had significantly higher odds of being diagnosed with dementia (adjusted odds ratio, 1.50 [95% confidence interval, 1.47-1.54]). Among specific types of anticholinergic drugs, a significant increase in risk was observed with the use of antidepressants, antiparkinsonian drugs, antipsychotics, and bladder antimuscarinics in a fully multivariable-adjusted model. Several types of anticholinergic drugs used by older adults in Japan are associated with an increased risk of dementia. These findings suggest that the underlying risks should be considered alongside the benefits of prescribing anticholinergic drugs to this population.

VOC-Free Status Among Patients with Sickle Cell Disease Following Allogeneic Hematopoietic Stem Cell Transplant: A Cohort Study of Medicaid Enrollees

Background: Sickle cell disease (SCD) is characterized by recurrent acute vaso-occlusive crises (VOCs), which diminish patient quality-of-life, contribute to end-organ damage and failure, and increase mortality. Currently, approved therapies for SCD are only partially effective and do not fully eliminate VOCs. Allogeneic hematopoietic stem cell transplant (HSCT) is the only known curative option for patients with SCD, however, HSCT is available to &amp;lt;20% of patients who have a matched sibling donor and is associated with significant risks, such as graft-versus-host disease. Autologous gene therapies that have the potential to provide a one-time functional cure to patients with SCD are currently in pivotal trials. The primary endpoint for these pivotal studies is the proportion of patients who become VOC-free for ≥12 months after treatment. Absence of VOCs for ≥12 months is expected to predict long-term efficacy. Given this, we evaluated patients with SCD in the national US Medicaid database who underwent allogeneic-HSCT to determine whether VOC-free status at 12 months was predictive of VOC-free status at 18 and 24 months after HSCT. Methods: A cohort of patients with SCD who had a record of allogeneic HSCT with at least 12 months of continuous Medicaid enrollment during 2000-2014 was identified. The date of HSCT was defined as the cohort entry date and the covariate assessment window was the 12 months continuous enrollment period preceding the cohort entry date. A VOC event was identified using ICD-9 diagnosis codes in hospitalization and ER visit claims for Hb-SS disease with crisis, other acute pain crisis, acute chest syndrome, priapism, and splenic sequestration. The cohort was further restricted to patients who had ≥24 months of follow-up after cohort entry to accurately assess VOC outcomes. Diagnosis codes associated with the delivery of healthcare and pharmacy claims were used to identify patient characteristics and outcomes of interest. Primary study outcome was the proportion of patients with no VOCs at 6 months, 12 months, 18 months, and 24 months after allogeneic HSCT. Results: During the study period, 44,685 patients with SCD were identified, out of whom 103 patients had undergone allogeneic HSCT, were enrolled for ≥12 months in the Medicaid program and had ≥24 months of follow-up after HSCT. Mean (SD) age was 10.3 (7.2) years, with 55.3% being male and majority (67%) Black. Patients had an average of 2.7 (SD, 7.9) VOC events during the 12-month period prior to HSCT. The most common (&amp;gt;10%) baseline comorbidities were chronic cardiac disease (42.7%), infections (36.9%), chronic pulmonary disease (31.1%), and acute chest syndrome (12.6%). Among the cohort of 103 patients who had undergone HSCT, 79% (n=81) were VOC-free by 12 months. Furthermore, among patients who were VOC-free at 12 months, 91% (n=74) were VOC-free at 18 months and 90% (n=73) were VOC-free at 24 months. Conclusions: This population-based study provides valuable information regarding long-term VOC-free status among patients with SCD who have undergone allogeneic HSCT in routine clinical care. Our findings suggest that patients with SCD who are VOC-free by 12 months post-HSCT are highly likely to stay VOC-free for longer durations (i.e. 18 and 24 months) after HSCT.