Effect of statin treatment on the risk of cancer in patients with heart failure: A target trial emulation study.

PURPOSE: A recent observational study suggested statins could reduce cancer diagnosis in patients with heart failure (HF). The findings need to be validated using robust epidemiological methods. This study aimed to evaluate the effect of statin treatment on the risk of cancer in patients with HF. METHODS: We conducted two target trial emulations using primary care data from IQVIA Medical Research Database-UK (2000 to 2019) with a clone-censor-weight design. The first emulated trial addressed the treatment initiation effect: initiating within 1 year versus not initiating a statin after the HF diagnosis. The second emulated trial addressed the cumulative exposure effect: continuing a statin for ≤3 years, 3-6 years, and >6 years after initiation. The study outcomes were any incident cancer and site-specific cancer diagnoses. Weighted pooled logistic regression models were used to estimate 10-year risk ratios (RR). 95% confidence intervals (CIs) were estimated using non-parametric bootstrapping. RESULTS: The first emulated trial showed that, compared to no statin, statins did not reduce the cancer risk in patients with HF (RR, 1.05; 95% CI, 0.94-1.15). The second emulated trial showed that, compared to treatment ≤3 years, statins with longer durations did not reduce the cancer risk (3-6 years: RR, 0.94; 95% CI, 0.70-1.33. >6 years: RR, 0.97; 95% CI, 0.79-1.26). No significant risk difference was observed on any site-specific cancer diagnoses. CONCLUSIONS: The results from the target trial emulations suggest that statin treatment is not associated with cancer risk in patients with HF.

Treatment with methylphenidate and the risk of fractures among children and young people: A systematic review and self-controlled case series study.

AIMS: Animal studies suggest that methylphenidate treatment for around 3 months may lead to less mineralized and weaker appendicular bones. A systematic review was conducted to summarize the evidence from observational studies, and a self-controlled case series study was used to compare the risk before and after treatment initiation. METHODS: Literature search was conducted using PubMed, Embase and the Cochrane Library to identify observational studies on methylphenidate and fractures. We also conducted a self-controlled case series study with individuals aged 5-24 years who received methylphenidate treatment and experienced fractures from 2001 to 2020 in Hong Kong. Incidence rate ratios and 95% confidence intervals were calculated by comparing the incidence rate in the methylphenidate-exposed period compared with nonexposed period. RESULTS: Six cohort studies and 2 case-control studies were included in the systematic review. For all-cause fractures, studies found a 39-74% lower risk in treated-attention deficit hyperactivity disorder (ADHD) group compared with untreated ADHD but no difference between stimulants and nonstimulants. Differences between sexes and treatment duration were also found-significant results were shown in males and those with longer treatment duration. Among 43 841 individuals with ADHD medication before the year 2020, 2023 were included in the self-controlled case series analysis. The risks of fractures were lower by 32-41% in different treatment periods when compared with 6 months before treatment initiation. CONCLUSION: Methylphenidate treatment may lower the risk of all-cause fractures from both study designs; however, further evidence is needed about the treatment duration and sex effect. Conclusions on stress fractures are not yet established, and further research is required.

Maternal Benzodiazepines and Z-Drugs Use during Pregnancy and Adverse Birth and Neurodevelopmental Outcomes in Offspring: A Population-Based Cohort Study.

INTRODUCTION: The use of benzodiazepines and/or z-drugs in women of childbearing age has increased. OBJECTIVE: The aim of the study was to evaluate whether gestational benzodiazepine and/or z-drug exposure is associated with adverse birth and neurodevelopmental outcomes. METHODS: A population-based cohort including mother-child pairs from 2001 to 2018 in Hong Kong was analysed to compare gestationally exposed and nonexposed children on the risk of preterm birth, small for gestational age, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) through logistic/Cox proportional hazards regression with a 95% confidence interval (CI). Sibling-matched analyses and negative control analyses were applied. RESULTS: When comparing gestationally exposed with gestationally nonexposed children, the weighted odds ratio (wOR) was 1.10 (95% CI = 0.97-1.25) for preterm birth and 1.03 (95% CI = 0.76-1.39) for small for gestational age, while the weighted hazard ratio (wHR) was 1.40 (95% CI = 1.13-1.73) for ASD and 1.15 (95% CI = 0.94-1.40) for ADHD. Sibling-matched analyses showed no association between gestationally exposed children and their gestationally nonexposed siblings for all outcomes (preterm birth: wOR = 0.84, 95% CI = 0.66-1.06; small for gestational age: wOR = 1.02, 95% CI = 0.50-2.09; ASD: wHR = 1.10, 95% CI = 0.70-1.72; ADHD: wHR = 1.04, 95% CI = 0.57-1.90). Similarly, no significant differences were observed when comparing children whose mothers took benzodiazepines and/or z-drugs during pregnancy to children whose mothers took benzodiazepines and/or z-drugs before but not during pregnancy for all outcomes. CONCLUSIONS: The findings do not support a causal relationship between gestational benzodiazepines and/or z-drugs exposure and preterm birth, small for gestational age, ASD, or ADHD. Clinicians and pregnant women should carefully balance the known risks of benzodiazepines and/or z-drugs use against those of untreated anxiety and sleep problems.

Risk of hospitalization for upper gastrointestinal bleeding in Helicobacter pylori eradicated patients newly started on warfarin or direct oral anticoagulants: A population-based cohort study.

BACKGROUND: To investigate risks of hospitalization for upper gastrointestinal bleeding (UGIB) in H. pylori-eradicated patients newly started on warfarin or direct oral anti-coagulants (DOACs). METHODS: We identified all patients who had previously received H. pylori eradication therapy or were found to have no H. pylori on endoscopy and were then newly started on warfarin or DOACs from a population-based electronic healthcare database. Primary analysis was the risk of UGIB between warfarin and DOACs users in H. pylori-eradicated patients. Secondary analysis included the UGIB risk between H. pylori-eradicated and H. pylori-negative patients who were newly started on warfarin or DOACs. The hazard ratio (HR) of UGIB was approximated by pooled logistic regression model incorporating the inverse propensity of treatment weightings with time-varying covariables. RESULTS: Among H. pylori-eradicated patients, DOACs had a significantly lower risk of UGIB (HR: 0.26, 95% CI 0.09-0.71) compared with warfarin. In particular, lower UGIB risks with DOACs were observed among older (≥65 years) patients, female, those without a history of UGIB or peptic ulcer, or ischemic heart disease, and non-users of acid-suppressive agents or aspirin. Secondary analysis showed no significant difference in UGIB risk between H. pylori-eradicated and H. pylori-negative patients newly started on warfarin (HR: 0.63,95% CI 0.33-1.19) or DOACs (HR: 1.37, 95% CI 0.45-4.22). CONCLUSIONS: In H. pylori-eradicated patients, new users of DOACs had a significantly lower risk of UGIB than new warfarin users. Furthermore, the risk of UGIB in new warfarin or DOACs users was comparable between H. pylori-eradicated and H. pylori-negative patients.

Trends of polypharmacy among older people in Asia, Australia and the United Kingdom: a multinational population-based study.

BACKGROUND: Polypharmacy among older people represents a global challenge due to its association with adverse drug events. The reported prevalence of polypharmacy varies widely across countries, and is particularly high in Asian countries. However, there is no multinational study using standardised measurements exploring variations in prescribing trends. OBJECTIVE: To compare polypharmacy trends in older people in Asia, Australia and the United Kingdom. DESIGN: Multinational, retrospective, time-trend, observational study using a common study protocol. SETTING: Outpatient and community settings. SUBJECTS: All individuals aged ≥ 65 years between 2013 and 2016. METHODS: We defined polypharmacy as the concomitant use of ≥5 medications for ≥45 days per year. We estimated the annual prevalence of polypharmacy and calculated average annual percentage change (AAPC) to assess the time trends. RESULTS: A total of 1.62 million individuals were included in this study. The highest prevalence of polypharmacy was observed in Hong Kong (46.4%), followed by Taiwan (38.8%), South Korea (32.0%), the United Kingdom (23.5%) and Australia (20.1%) in 2016. For the time trend, the Asian region showed a steady increase, particularly in Hong Kong and South Korea (AAPC: Hong Kong, 2.7%; South Korea, 1.8%; Taiwan, 1.0%). However, Australia and the United Kingdom showed a decreasing trend (Australia, -4.9%; the United Kingdom, -1.1%). CONCLUSIONS: Polypharmacy prevalence in older people was higher in Hong Kong, Taiwan and South Korea, with an increasing trend over time, compared with Australia and the United Kingdom. Our findings underline the necessity to monitor polypharmacy among older people in Asia by conducting government-level interventions and introducing medicine-optimisation strategies.

Comparative Effectiveness and Safety Between Apixaban, Dabigatran, Edoxaban, and Rivaroxaban Among Patients With Atrial Fibrillation : A Multinational Population-Based Cohort Study.

BACKGROUND: Current guidelines recommend using direct oral anticoagulants (DOACs) over warfarin in patients with atrial fibrillation (AF), but head-to-head trial data do not exist to guide the choice of DOAC. OBJECTIVE: To do a large-scale comparison between all DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) in routine clinical practice. DESIGN: Multinational population-based cohort study. SETTING: Five standardized electronic health care databases, which covered 221 million people in France, Germany, the United Kingdom, and the United States. PARTICIPANTS: Patients who were newly diagnosed with AF from 2010 through 2019 and received a new DOAC prescription. MEASUREMENTS: Database-specific hazard ratios (HRs) of ischemic stroke or systemic embolism, intracranial hemorrhage (ICH), gastrointestinal bleeding (GIB), and all-cause mortality between DOACs were estimated using a Cox regression model stratified by propensity score and pooled using a random-effects model. RESULTS: A total of 527 226 new DOAC users met the inclusion criteria (apixaban, n = 281 320; dabigatran, n = 61 008; edoxaban, n = 12 722; and rivaroxaban, n = 172 176). Apixaban use was associated with lower risk for GIB than use of dabigatran (HR, 0.81 [95% CI, 0.70 to 0.94]), edoxaban (HR, 0.77 [CI, 0.66 to 0.91]), or rivaroxaban (HR, 0.72 [CI, 0.66 to 0.79]). No substantial differences were observed for other outcomes or DOAC-DOAC comparisons. The results were consistent for patients aged 80 years or older. Consistent associations between lower GIB risk and apixaban versus rivaroxaban were observed among patients receiving the standard dose (HR, 0.72 [CI, 0.64 to 0.82]), those receiving a reduced dose (HR, 0.68 [CI, 0.61 to 0.77]), and those with chronic kidney disease (HR, 0.68 [CI, 0.59 to 0.77]). LIMITATION: Residual confounding is possible. CONCLUSION: Among patients with AF, apixaban use was associated with lower risk for GIB and similar rates of ischemic stroke or systemic embolism, ICH, and all-cause mortality compared with dabigatran, edoxaban, and rivaroxaban. This finding was consistent for patients aged 80 years or older and those with chronic kidney disease, who are often underrepresented in clinical trials. PRIMARY FUNDING SOURCE: None.

Effectiveness of Facebook Groups and Pages on Participant Recruitment Into a Randomized Controlled Trial During the COVID-19 Pandemic: Descriptive Study.

BACKGROUND: In response to the unprecedented challenges posed by the COVID-19 pandemic, conventional recruitment approaches were halted, causing the suspension of numerous clinical trials. Previously, Facebook (Meta Platforms, Inc) has emerged as a promising tool for augmenting participant recruitment. While previous research has explored the use of Facebook for surveys and qualitative studies, its potential for recruiting participants into randomized controlled trials (RCTs) remains underexplored. OBJECTIVE: This study aimed to comprehensively examine the effectiveness of using Facebook groups and pages to facilitate participant recruitment during the COVID-19 pandemic for an RCT on the effectiveness of a remote parenting program, 1-2-3 Magic, in families who have children with attention-deficit/hyperactivity disorder (ADHD) in the United Kingdom. METHODS: We disseminated 5 Facebook posts with an attached digital flyer across 4 prominent ADHD UK support groups and pages run by the National Attention Deficit Disorder Information and Support Services, reaching an audience of around 16,000 individuals over 2 months (January 7 to March 4, 2022). Eligibility criteria mandated participants to be parents or caregivers of a child with diagnosed ADHD aged 12 years or younger, be residing in the United Kingdom, have access to stable internet, and have a device with the Zoom (Zoom Video Communications) app. Participants were required to have never attended 1-2-3 Magic training previously. Prospective participants expressed their interest through Microsoft Forms (Microsoft Corporation). The trial aimed to recruit 84 parents. It is important to note that the term "parent" or "caregiver" in the RCT and in this study within a trial refers to anybody who has legal responsibility for the child. RESULTS: Overall, 478 individuals registered their interest through Microsoft Forms within the stipulated 2-month window. After the eligibility check, 135 participants were contacted for a baseline meeting through Zoom. The first 84 participants who attended a baseline meeting and returned a completed consent form were enrolled. Subsequently, another 16 participants were added, resulting in a final sample of 100 participants. This recruitment strategy incurred negligible expenses and demanded minimal human resources. The approach yielded favorable outcomes by efficiently attracting eligible participants in a condensed time frame, transcending geographical barriers throughout the United Kingdom, which would have been tedious to achieve through traditional recruitment methods. CONCLUSIONS: Our experience demonstrated that digital flyers posted in the targeted Facebook groups were a cost-effective and quick method for recruiting for an RCT, which opened during the COVID-19 pandemic when lockdown restrictions were in place in the United Kingdom. Trialists should consider this low-cost recruitment intervention for trials going forward, and in the case of a global pandemic, this novel recruitment method enabled the trial to continue where many have failed. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 15281572; https://www.isrctn.com/ISRCTN15281572.

Effects of Phosphodiesterase-5 Inhibitors in Patients with Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis.

Chronic obstructive pulmonary disease (COPD) is a major burden of healthcare worldwide. We aimed to determine the effects of PDE-5 inhibitors on clinical outcomes and haemodynamic parameters in patients with COPD. A PROSPERO-registered systematic review and meta-analysis (identification number CRD42021227578) were performed to analyse the effects of PDE-5 inhibitors in patients with COPD. Data were sourced from MEDLINE, EMBASE, Cochrane Register of Controlled Trials and "ClinicalTrials.gov." Randomised controlled trials (RCTs) comparing PDE-5 inhibitors with control in patients with COPD were included. Quality assessment was carried out using the Cochrane Collaboration's tool for assessing the risk of bias in randomised trials. The pooled mean difference of 6-minute walk distance (6MWD) and mean pulmonary arterial pressure based on inverse variance estimation were analysed with a fixed-effect model or random-effects model meta-analysis. Nine RCTs involving 414 patients were included in the review. There was no significant difference in 6MWD (mean difference = 22.06 metres, 95% confidence interval (CI), -5.80 to 49.91). However, there was a statistically significant difference between PDE-5 inhibitor and control groups in mean pulmonary artery pressure (mean difference = -3.83 mmHg, 95% CI, -5.93 to -1.74). Headaches were the most common adverse event, occurring significantly in the PDE-5 inhibitor intervention group (odds ratio 3.83, 95% CI, 1.49 to 9.86). This systematic review indicates that PDE-5 inhibitors do not improve exercise capacity despite some possible improvements in haemodynamic parameters in COPD patients.

Treatment with direct oral anticoagulants or warfarin and the risk for incident diabetes among patients with atrial fibrillation: a population-based cohort study.

BACKGROUND: Diabetes mellitus is a common comorbidity of atrial fibrillation (AF), which can complicate the management of AF. The pharmacology of oral anticoagulants (OACs) have been implicated in pathogenesis of diabetes, but the relationship between different OACs and risk of diabetes remains unexamined. This study aimed to evaluate the risk of diabetes with use of different OACs in AF patients. METHODS: Population-based retrospective cohort study using an electronic healthcare database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with AF from 2014 through 2018 and prescribed OACs were included and followed till December 31, 2019. Inverse probability of treatment weighting based on the propensity score (PS) is used to address potential bias due to nonrandomized allocation of treatment. The risks ofdiabetes were compared between different new OAC users using propensity score-weighted cumulative incidence differences (CID). RESULTS: There were 13,688 new users of OACs (warfarin: n = 3454; apixaban: n = 3335; dabigatran: n = 4210; rivaroxaban: n = 2689). The mean age was 75.0 (SD, 11.2), and 6,550 (47.9%) were women. After a median follow-up of 0.93 years (interquartile range, 0.21-1.92 years), 698 incident diabetes cases were observed. In Cox-regression analysis, dabigatran use was significantly associated with reduced risk of diabetes when compared with warfarin use [HR 0.69 (95% CI 0.56-0.86; P < 0.001)], with statistically insignificant associations observed for use of apixaban and rivaroxaban. The corresponding adjusted CIDs at 2 years after treatment with apixaban, dabigatran, and rivaroxaban users when compared with warfarin were - 2.06% (95% CI - 4.08 to 0.16%); - 3.06% (95% CI - 4.79 to - 1.15%); and - 1.8% (- 3.62 to 0.23%). In head-to-head comparisons between women DOAC users, dabigatran was also associated with a lower risk of diabetes when compared with apixaban and rivaroxaban. CONCLUSIONS: Among adults with AF receiving OACs, the use of dabigatran had the lowest risk of diabetes when compared with warfarin use.

Global trends in symptomatic medication use against dementia in 66 countries/regions from 2008 to 2018.

BACKGROUND AND PURPOSE: The aim was to determine trends and patterns of symptomatic medication used against dementia in 66 countries and regions. METHODS: This was a cross-sectional study that used the wholesale data from the IQVIA Multinational Integrated Data Analysis System database. Sale data for symptomatic medication against dementia from 66 countries and regions from 2008 to 2018 were analysed and stratified by income level (low/middle-income countries [LMICs], n = 27; high-income countries [HICs], n = 37; regions, n = 2). The medication use volume was estimated by defined daily dose (DDD) per 1000 inhabitants per day (World Health Organization DDD harmonized the size, strength and form of each pack and reflects average dosing). Changes in medication use over time were quantified as percentage changes in compound annual growth rates (CAGRs). RESULTS: Total symptomatic medication against dementia sales increased from 0.85 to 1.33 DDD per 1000 inhabitants per day between 2008 and 2018 (LMICs 0.094-0.396; HICs 3.88-5.04), which is an increase of CAGR of 4.53% per year. The increase was mainly driven by the LMICs (CAGR = 15.42%) in comparison to the HICs (CAGR = 2.65%). The overall medication use from 2008 to 2018 increased for all four agents: memantine (CAGR = 8.51%), rivastigmine (CAGR = 6.91%), donepezil (CAGR = 2.72%) and galantamine (CAGR = 0.695%). In 2018, the most commonly used medication globally was donepezil, contributing to 49.8% of total use volume, followed by memantine (32.7%), rivastigmine (11.24%) and galantamine (6.36%). CONCLUSION: There was an increasing trend in the use of symptomatic medications against dementia globally, but the use remained low in LMICs. Interventions may be needed to support the medication use in some countries.

Patterns and factors influencing oral anticoagulant prescription in people with atrial fibrillation and dementia: Results from UK primary care.

AIMS: Oral anticoagulant (OAC) is recommended for preventing stroke in atrial fibrillation (AF). However, the OAC utilisation in AF patients with dementia or cognitive impairment (CI) is limited. This study aimed to examine the prevalence of OAC prescriptions in AF patients with dementia/CI and to identify factors associated with OAC treatment within 180 days after dementia/CI diagnosis. METHODS: Using The Health Improvement Network database, the annual trends of OAC between 2000 and 2015 were calculated. Multivariable logistic regression was performed to identify factors associated with OAC treatment. RESULTS: The prevalence rate of OAC prescriptions increased from 6.1% in 2000 to 45.9% in 2015. Among OAC users, the proportion of direct oral anticoagulants (DOACs) use increased significantly from 0.1% in 2011 to 33.8% in 2015 (P-trend < 0.001), while the proportion of vitamin K antagonist use decreased by 28.6% from 100% in 2000 to 71.4% in 2015 (P-trend < 0.001). In the multivariable analysis, younger age, very old age, female sex, higher Charlson Comorbidity Index, having a HAS-BLED score ≥3, a history of intracranial bleeding, falls and polypharmacy were significantly associated with lower odds of receiving OAC. CONCLUSIONS: In UK primary care, OAC use increased from 2000 to 2015 in AF patients with dementia/CI, with a substantial increase in use of DOACs. Characteristics related to frailty are associated with lower odds of OAC prescription. Given the increasing use of DOACs in patients with dementia/CI, further studies are needed to investigate the safety and effectiveness of DOACs in this important patient group.

Non-vitamin K oral anticoagulants and risk of fractures: a systematic review and meta-analysis.

AIMS: Comparative fracture risk for non-vitamin K antagonist oral anticoagulants (NOACs) and vitamin K antagonists (VKAs) among patients with atrial fibrillation (AF) remains unclear. This study aimed to provide summary relative risk (RR) estimates for associations between NOACs vs. VKAs and fracture risk. METHODS AND RESULTS: PubMed, EMBASE, and Cochrane Library were searched from 2010 to 26 May 2020. Observational studies investigating the association between NOACs vs. VKAs and fracture risk in patients with AF were included. The adjusted effect estimates were pooled using the DerSimonian-Laird random effects models. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and the Meta-analysis of Observational Studies in Epidemiological (MOOSE) guidelines were followed. Five observational studies comprising 269 922 patients and 4289 fractures were included. Non-vitamin K antagonist oral anticoagulants use was associated with a lower risk of any fractures compared to VKAs use, with moderate heterogeneity [pooled RR = 0.83, 95% confidence interval (CI): 0.75-0.92, P < 0.001, I2 = 73.0%]. When comparing individual NOAC to VKAs, a statistically significant lower risk of any fractures was found for rivaroxaban (pooled RR = 0.79, 95% CI: 0.71-0.88, P < 0.001, I2 = 55.2%) and apixaban (pooled RR = 0.75, 95% CI: 0.60-0.92, P = 0.007, I2 = 54.5%), but not dabigatran (pooled RR = 0.87, 95% CI: 0.74-1.01, P = 0.061, I2 = 74.6%). No differences were observed in all head-to-head comparisons between NOACs. CONCLUSION: This large meta-analysis suggests that NOACs use was associated with a lower risk of fractures compared with VKAs. Fracture risks were similar between NOACs. These findings may help inform the optimal anticoagulant choice for patients with AF at high risk of fracture.

Subgingival microbiota of dogs with healthy gingiva or early periodontal disease from different geographical locations.

BACKGROUND: Periodontal disease is the most common oral disease of dogs worldwide and results from a complex interplay between plaque bacteria, the host and environmental factors. Recent studies have enhanced our understanding of the associations between the plaque microbiota and canine periodontal disease. These studies, however, were limited in their geographical reach. Thus associations between the canine oral microbiota and geographical location were investigated by determining the composition of subgingival plaque samples from 587 dogs residing in the United Kingdom (UK), United States of America (USA), China and Thailand using 454-pyrosequencing. RESULTS: After quality filtering 6,944,757 sequence reads were obtained and clustering of these at ≥98% sequence resulted in 280 operational taxonomic units (OTUs) following exclusion of rare OTUs (present at < 0.05% in all four countries). The subgingival plaque from dog populations located in the UK, USA, China and Thailand had a similar composition although the abundance of certain taxa varied significantly among geographical locations. Exploration of the effect of clinical status and age revealed a marked similarity among the bacteria associated with increased age and those associated with gingivitis: Young dogs and those with no gingivitis were dominated by taxa from the phyla Bacteroidetes and Proteobacteria whereas older dogs and those with moderate gingivitis were dominated by members of the Firmicutes. The plaque microbiota of small breed dogs was found to significantly differ to medium and large breeds and was dominated by species belonging to the Firmicutes. CONCLUSIONS: The bacterial associations with health, gingivitis and periodontitis were conserved across dogs from the UK, USA, China and Thailand. These bacterial signatures of periodontal health and disease have potential as biomarkers for disease detection.

Association Between Treatment With Apixaban, Dabigatran, Rivaroxaban, or Warfarin and Risk for Osteoporotic Fractures Among Patients With Atrial Fibrillation: A Population-Based Cohort Study.

BACKGROUND: It is unclear whether anticoagulant type is associated with the risk for osteoporotic fracture, a deleterious complication of anticoagulants among patients with atrial fibrillation (AF). OBJECTIVE: To compare the risk for osteoporotic fracture between anticoagulants. DESIGN: Population-based cohort study. SETTING: Territory-wide electronic health record database of the Hong Kong Hospital Authority. PARTICIPANTS: Patients newly diagnosed with AF between 2010 and 2017 who received a new prescription for warfarin or a direct oral anticoagulant (DOAC) (apixaban, dabigatran, or rivaroxaban). Follow-up ended on 31 December 2018. MEASUREMENTS: Osteoporotic hip and vertebral fractures in anticoagulant users were compared using propensity score-weighted cumulative incidence differences (CIDs). RESULTS: There were 23 515 patients identified (3241 apixaban users, 6867 dabigatran users, 3866 rivaroxaban users, and 9541 warfarin users). Overall mean age was 74.4 years (SD, 10.8), ranging from 73.1 years (warfarin) to 77.9 years (apixaban). Over a median follow-up of 423 days, 401 fractures were identified (crude event number [weighted rate per 100 patient-years]: apixaban, 53 [0.82]; dabigatran, 95 [0.76]; rivaroxaban, 57 [0.67]; and warfarin, 196 [1.11]). After 24-month follow-up, DOAC use was associated with a lower risk for fracture than warfarin use (apixaban CID, -0.88% [95% CI, -1.66% to -0.21%]; dabigatran CID, -0.81% [CI, -1.34% to -0.23%]; and rivaroxaban CID, -1.13% [CI, -1.67% to -0.53%]). No differences were seen in all head-to-head comparisons between DOACs at 24 months (apixaban vs. dabigatran CID, -0.06% [CI, -0.69% to 0.49%]; rivaroxaban vs. dabigatran CID, -0.32% [CI, -0.84% to 0.18%]; and rivaroxaban vs. apixaban CID, -0.25% [CI, -0.86% to 0.40%]). LIMITATION: Residual confounding is possible. CONCLUSION: Among patients with AF, DOAC use may result in a lower risk for osteoporotic fracture compared with warfarin use. Fracture risk does not seem to be altered by the choice of DOAC. These findings may help inform the benefit-risk assessment when choosing between anticoagulants. PRIMARY FUNDING SOURCE: The University of Hong Kong and University College London Strategic Partnership Fund.

Adverse event profile for immunotherapy agents compared with chemotherapy in solid organ tumors: a systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Immunotherapy agents are an innovative oncological treatment modality and as a result their use has expanded widely. Understanding the treatment-related adverse events (AEs) of these drugs compared with traditional chemotherapy is crucial for clinical practice. DESIGN: A systematic review of studies indexed in Medline (PubMed), Embase, Web of Science, and the Cochrane Databases from January 2000 to 14 February 2019 was conducted. Randomized clinical trials comparing immunotherapy [cytotoxic T-lymphocyte protein-4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death-ligand 1 (PD-L1)] with standard-of-care chemotherapy in the treatment of advanced solid-organ neoplasms were included if AEs were reported as an outcome. Primary outcome was AEs ≥ grade 3 in severity. Secondary outcomes were proportion of overall AEs, treatment discontinuation due to AEs, deaths due to AEs, and specific AEs [fatigue, diarrhea, acute kidney injury (AKI), colitis, pneumonitis, and hypothyroidism]. Paule-Mandel pooling and a random effects model were used to produce odds ratios (ORs) for measures of effects. RESULTS: Among 10 598 abstracts screened, we included 22 studies involving 12 727 patients. In the immunotherapy group, 16.5% of patients developed an AE ≥ grade 3 in severity, compared with 41.09% in the chemotherapy arm [OR = 0.26, 95% confidence interval (CI) 0.19-0.35, I2 = 92%]. Patients receiving immunotherapy also had lower odds of developing an AE overall (OR = 0.35, 95% CI 0.28-0.44; I2 = 77%), terminating therapy due to an AE (OR = 0.55, 95% CI 0.39-0.78, I2 = 80%), or dying from a treatment-related AE (OR = 0.67, 95% CI 0.46-0.98, I2 = 0%). When treated with chemotherapy versus immunotherapy, patients more frequently experienced fatigue (25.10% versus 15.83%), diarrhea (14.97% versus 11.13%), and AKI (1.79% versus 1.31%). However, colitis (1.02% versus 0.26%), pneumonitis (3.36% versus 0.36%), and hypothyroidism (6.82% versus 0.37%) were more common in those treated with immunotherapy. CONCLUSIONS: Treatment of advanced solid-organ malignancies with immunotherapy compared with traditional chemotherapy is associated with a lower risk of AEs.

Association Between Nonvitamin K Antagonist Oral Anticoagulants or Warfarin and Liver Injury: A Cohort Study.

INTRODUCTION: The risk of liver injury in patients with atrial fibrillation (AF) using nonvitamin K antagonist oral anticoagulants (NOACs) has not been previously examined using liver function tests as the primary outcome in the real-world setting. This study assessed the association between NOACs (dabigatran, rivaroxaban, and apixaban) and warfarin and the risk of liver injury, as defined by laboratory tests. METHODS: Patients newly diagnosed with AF and prescribed NOACs or warfarin between 2010 and 2016, identified using the Hong Kong Clinical Database and Reporting System, were matched on age, sex, health status scores, comorbidities, and medications by propensity score on a 1:1 ratio. Risk of liver injury, defined as laboratory test values >3 times the upper limit of normal of alanine aminotransferase or aspartate aminotransferase and >2 times the upper limit of normal of total bilirubin, was compared between NOAC and warfarin users using Cox proportional hazards regression. RESULTS: After propensity score matching, 13,698 patients were included, of which 141 (2.1%) NOAC users and 232 (3.4%) warfarin users developed liver injury. The hazard ratio (HR) for NOAC vs warfarin users was 0.71 (95% confidence interval: 0.58-0.89). When comparing individual NOACs, only dabigatran (hazard ratio: 0.63; 95% confidence interval: 0.48-0.82) was associated with a lower risk of liver injury. DISCUSSION: Among patients with AF, NOACs as a group, and dabigatran alone were associated with a significantly lower risk of laboratory-based liver injury when compared with warfarin. However, liver injury occurs more frequently in real-world practice than in NOAC randomized controlled trials.

Gastrointestinal bleeding risk with rivaroxaban vs aspirin in atrial fibrillation: A multinational study.

PURPOSE: Comparative gastrointestinal bleeding (GIB) risk between rivaroxaban and low-dose aspirin is unknown in patients with atrial fibrillation (AF). This study investigated GIB risk with rivaroxaban vs aspirin among two separate AF cohorts in Hong Kong and the United Kingdom, using a common protocol approach. METHODS: This was a population-based cohort study using separate data from the Clinical Data Analysis and Reporting System (CDARS) of the Hong Kong Hospital Authority (2010-2018) and The Health Improvement Network (THIN) database in the United Kingdom (2011-2017). Patients with AF newly prescribed aspirin or rivaroxaban were included. Cox proportional hazards regression was used to compare GIB risks for rivaroxaban vs aspirin, accounting for confounders using propensity score fine stratification approach. RESULTS: In CDARS, 29 213 patients were included; n = 1052 (rivaroxaban), n = 28 161 (aspirin). Crude GIB event rates per 100 patient-years in CDARS were 3.0 (aspirin) and 2.6 (rivaroxaban). No difference in GIB risk was observed between rivaroxaban and aspirin overall (HR = 1.04, 95%CI = 0.76-1.42), and in dose-stratified analyses (HR = 1.21, 95%CI = 0.84-1.74 [20 mg/day]; HR = 0.80, 95%CI = 0.44-1.45 [≤15 mg/day]). In THIN, 11 549 patients were included, n = 3496 (rivaroxaban) and n = 8053 (aspirin). Crude GIB event rates were 1.3 (aspirin) and 2.4 (rivaroxaban) per 100 patient-years. No difference in GIB risk was observed between rivaroxaban and aspirin overall (HR = 1.40, 95%CI = 1.00-1.98) and low-dose rivaroxaban (≤15 mg/day) (HR = 1.00, 95%CI = 0.56-1.30), but increased GIB risk was observed for rivaroxaban 20 mg/day vs aspirin (HR = 1.57, 95%CI = 1.08-2.29). CONCLUSION: In patients with AF, GIB risk was comparable between aspirin and rivaroxaban ≤15 mg/day. GIB risk for rivaroxaban 20 mg/day vs aspirin remains uncertain and warrants further investigation.

Trazodone use and risk of dementia: A population-based cohort study.

BACKGROUND: In vitro and animal studies have suggested that trazodone, a licensed antidepressant, may protect against dementia. However, no studies have been conducted to assess the effect of trazodone on dementia in humans. This electronic health records study assessed the association between trazodone use and the risk of developing dementia in clinical practice. METHODS AND FINDINGS: The Health Improvement Network (THIN), an archive of anonymised medical and prescribing records from primary care practices in the United Kingdom, contains records of over 15 million patients. We assessed patients from THIN aged ≥50 years who received at least two consecutive prescriptions for an antidepressant between January 2000 and January 2017. We compared the risk of dementia among patients who were prescribed trazodone to that of patients with similar baseline characteristics prescribed other antidepressants, using a Cox regression model with 1:5 propensity score matching. Patients prescribed trazodone who met the inclusion criteria (n = 4,716; 59.2% female) were older (mean age 70.9 ± 13.1 versus 65.6 ± 11.4 years) and were more likely than those prescribed other antidepressants (n = 420,280; 59.7% female) to have cerebrovascular disease and use anxiolytic or antipsychotic drugs. After propensity score matching, 4,596 users of trazadone and 22,980 users of other antidepressants were analysed. The median time to dementia diagnosis for people prescribed trazodone was 1.8 years (interquartile range [IQR] = 0.5-5.0 years). Incidence of dementia among patients taking trazodone was higher than in matched users of other antidepressants (1.8 versus 1.1 per 100 person-years), with a hazard ratio (HR) of 1.80 (95% confidence interval [CI] 1.56-2.09; p < 0.001). However, our results do not suggest a causal association. When we restricted the control group to users of mirtazapine only in a sensitivity analysis, the findings were very similar to the results of the main analysis. The main limitation of our study is the possibility of indication bias, because people in the prodromal stage of dementia might be preferentially prescribed trazodone. Due to the observational nature of this study, we cannot rule out residual confounding. CONCLUSIONS: In this study of UK population-based electronic health records, we found no association between trazodone use and a reduced risk of dementia compared with other antidepressants. These results suggest that the clinical use of trazodone is not associated with a reduced risk of dementia.

All-cause pneumonia in children after the introduction of pneumococcal vaccines in the United Kingdom: A population-based study.

PURPOSE: To explore the impact of pneumococcal conjugate vaccines (PCVs) in preventing childhood pneumonia in the United Kingdom. METHODS: We carried out a population-based study to assess the trend of all-cause pneumonia in children aged under 10 years between 2002 and 2012. Data were obtained from the IMS Disease Analyser, a primary care database in the United Kingdom. Three time periods were defined to estimate monthly incidence: pre-PCV7 (January 2002 to August 2006), post-PCV7 (September 2006 to March 2010), and post-PCV13 (April 2010 to December 2012). Interrupted time series analysis (ITS) was performed to assess any immediate change or gradual change in the monthly incidence of pneumonia between prevaccination and postvaccination introduction. RESULTS: A total of 4228 children with at least one all-cause pneumonia episode were identified. The overall annual incidence rate of all-cause pneumonia declined by 37% from 3.8 episodes/1000 person-years in 2002 to 2.4 episodes/1000 person-years in 2012. Results of ITS analyses indicated that the incidence did not decline immediately after the introduction of PCV7 and PCV13. The incidence declined gradually in children aged under 2 years (IRR = 0.98; 95% CI, 0.97-0.99) post PCV7 and levelled off during post PCV13 (IRR = 1.00; 95% CI, 0.99-1.02). No significant changes in incidence trend was observed in children aged 2 to 4 years (IRR = 0.86; 95% CI, 0.68-1.07) and 5 to 9 years (IRR = 0.92; 95% CI, 0.73-1.15) after PCV13 introduction. CONCLUSIONS: In the United Kingdom, the incidence of all-cause pneumonia in children under 2 years declined after the introduction of PCV7 and levelled off in the first 2 years of introduction of PCV13. Continual monitoring is warranted to assess the population impact of PCV13 in preventing childhood pneumonia in the long term.

Haemoglobin concentrations in pregnancy and respiratory and allergic outcomes in childhood: Birth cohort study.

BACKGROUND: Limited epidemiological evidence suggests that low maternal iron status and anaemia in pregnancy may increase the risk of childhood respiratory and allergic outcomes. OBJECTIVES: To investigate the relation between maternal haemoglobin concentrations in pregnancy and childhood respiratory and allergic outcomes. METHODS: In the Avon Longitudinal Study of Parents and Children (ALSPAC), we examined associations of maternal haemoglobin concentrations (g/dL) in pregnancy with hayfever, eczema, wheezing, doctor-diagnosed asthma, allergic sensitisation and total IgE at 7 years, and with lung function at 8-9 years in the offspring, after controlling for potential confounders (N = 3234-5335). RESULTS: Maternal haemoglobin was not associated with offspring hayfever, eczema, wheezing or asthma. However, the first haemoglobin measurement in pregnancy (<18 weeks' gestation) and the last measurement (>28 weeks' gestation) were negatively associated with allergic sensitisation (adjusted odds ratio [95% CI] per g/dL 0.91 [0.83 to 0.99] and 0.90 [0.83 to 0.98], respectively). The last haemoglobin measurement was also negatively associated with total IgE (adjusted geometric mean ratio 0.94 [0.88 to 0.99]). Anaemia (haemoglobin <11 g/dL) in late pregnancy was negatively associated with forced vital capacity (difference in standard deviation score -0.07 [-0.13 to -0.01]). CONCLUSIONS AND CLINICAL RELEVANCE: Lower maternal haemoglobin in pregnancy may be a risk factor for allergic sensitisation, elevated IgE and lower FVC in childhood, which may reflect effects of lower prenatal iron status. However, maternal haemoglobin was not associated with risk of childhood asthma or other allergic disorders.