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Low-dose aspirin and metformin have been individually associated with a reduced risk of cancer. Whether their concurrent use in adults with type 2 diabetes mellitus (T2DM) is associated with a reduced risk of colorectal cancer (CRC) is unclear.Among individuals with T2DM taking metformin, we sought to evaluate the association between low-dose aspirin versus no aspirin and the risk of CRC.A multiple-database new-user cohort study of patients with T2DM taking metformin was conducted between 2007-2010 (Clinical Data Analysis and Reporting System [CDARS], Hong Kong) and 2007-2016 (The Health Improvement Network [THIN], UK). The primary outcome was incident CRC. Patients were followed from index date of prescription until the earliest occurrence of an outcome of interest, an incident diagnosis of any cancer, death, or until December 31, 2019. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Estimates were pooled using an inverse variance random effects model, and heterogeneity was assessed using IAfter one-to-one propensity-score matching, 57,534 patients were included (CDARS = 16,276; THIN = 41,258). The median (IQR) follow-up was 9.3 (6.5-10.7) years in CDARS and 3.2 (1.1-5.8) years in THIN. The concurrent use of low-dose aspirin and metformin was not associated with a lower risk of CRC compared to metformin only (HR = 0.89, 95% CI 0.75-1.05, ILow-dose aspirin was not associated with a lower risk of CRC in patients with T2DM taking metformin. Our study does not support the routine use of low-dose aspirin in this population. This article is protected by copyright. All rights reserved.

Background Oral anticoagulants (OACs) are high-risk medications often used in older people with complex medication regimens. This study was the first to assess the association between overall regimen complexity and bleeding in people with atrial fibrillation (AF) initiating OACs. Methods Patients diagnosed with AF who initiated an OAC (warfarin, dabigatran, rivaroxaban, apixaban) between 2010 and 2016 were identified from the Hong Kong Clinical Database and Reporting System. Each patient’s Medication Regimen Complexity Index (MRCI) score was computed. Baseline characteristics were balanced using inverse probability of treatment weighting. People were followed until a first hospitalization for bleeding (intracranial hemorrhage, gastrointestinal bleeding, or other bleeding) and censored at discontinuation of the index OAC, death, or end of the follow-up period, whichever occurred first. Cox regression was used to estimate hazard ratios (HR) between MRCI quartiles and bleeding during initiation and all follow-up. Results There were 19 292 OAC initiators (n = 9 092 warfarin, n = 10 200 direct oral anticoagulants) with a mean (standard deviation) age at initiation of 73.9 (11.0) years. More complex medication regimens were associated with an increased risk of bleeding (MRCI > 14.0–22.00: aHR 1.17, 95% confidence interval [CI] 0.93–1.49; MRCI > 22.0–32.5: aHR 1.32, 95%CI 1.06–1.66; MRCI > 32.5: aHR 1.45, 95%CI 1.13–1.87, compared to MRCI ≤ 14). No significant association between MRCI and bleeding risk was observed during the initial 30, 60, or 90 days of treatment. Conclusion In this cohort study of people with AF initiating an OAC, a more complex medication regimen was associated with higher bleeding risk over periods longer than 90 days. Further prospective studies are needed to assess whether MRCI should be considered in OAC prescribing.

Background Patients with bipolar disorder (BPD) are prone to engage in risk-taking behaviours and self-harm, contributing to higher risk of traumatic injuries requiring medical attention at the emergency room (ER).We hypothesize that pharmacological treatment of BPD could reduce the risk of traumatic injuries by alleviating symptoms but evidence remains unclear. This study aimed to examine the association between pharmacological treatment and the risk of ER admissions due to traumatic injuries. Methods Individuals with BPD who received mood stabilizers and/or antipsychotics were identified using a population-based electronic healthcare records database in Hong Kong (2001–2019). A self-controlled case series design was applied to control for time-invariant confounders. Results A total of 5040 out of 14 021 adults with BPD who received pharmacological treatment and had incident ER admissions due to traumatic injuries from 2001 to 2019 were included. An increased risk of traumatic injuries was found 30 days before treatment [incidence rate ratio (IRR) 4.44 (3.71–5.31), p < 0.0001]. After treatment initiation, the risk remained increased with a smaller magnitude, before returning to baseline [IRR 0.97 (0.88–1.06), p = 0.50] during maintenance treatment. The direct comparison of the risk during treatment to that before and after treatment showed a significant decrease. After treatment cessation, the risk was increased [IRR 1.34 (1.09–1.66), p = 0.006]. Conclusions This study supports the hypothesis that pharmacological treatment of BPD was associated with a lower risk of ER admissions due to traumatic injuries but an increased risk after treatment cessation. Close monitoring of symptoms relapse is recommended to clinicians and patients if treatment cessation is warranted.

Aims Concern about the cardiovascular safety of coronavirus disease 2019 (COVID-19) vaccines among individuals with cardiovascular disease (CVD) may lead to vaccine hesitancy. We sought to assess the association between two COVID-19 vaccines, BNT162b2 and CoronaVac, and the risk of major adverse cardiovascular events (MACE) in individuals with established CVD. Methods and results We identified individuals with a history of CVD before 23 February 2021 and a diagnosis of MACE between 23 February 2021 and 31 January 2022 in Hong Kong. MACE was defined as a composite of myocardial infarction, stroke, revascularization, and cardiovascular death. Electronic health records from the Hong Kong Hospital Authority were linked to vaccination records from the Department of Health. A self-controlled case-series method was used to evaluate the risk of MACE for 0–13 and 14–27 days after two doses of COVID-19 vaccine. We estimated incidence rate ratios (IRRs) to compare the risk of MACE between each risk period and the baseline period. A total of 229 235 individuals with CVD were identified, of which 1764 were vaccinated and had a diagnosis of MACE during the observation period (BNT162b2 = 662; CoronaVac = 1102). For BNT162b2, IRRs were 0.48 [95% confidence interval (CI) 0.23–1.02] for the first dose and 0.87 (95% CI 0.50–1.52) for the second dose during the 0–13 days risk period, 0.40 (95% CI 0.18–0.93) for the first dose and 1.13 (95% CI 0.70–1.84) for the second dose during the 14–27 days risk period. For CoronaVac, the IRRs were 0.43 (95% CI 0.24–0.75) for the first dose and, 0.73 (95% CI 0.46–1.16) for the second dose during the 0–13 days risk period, 0.54 (95% CI 0.33–0.90) for the first dose and 0.83 (95% CI 0.54–1.29) for the second dose during the 14–27 days risk period. Consistent results were found in subgroup analyses for different sexes, age groups and different underlying cardiovascular conditions. Conclusion Our findings showed no evidence of an increased risk of MACE after vaccination with BNT162b2 or CoronaVac in patients with CVD. Future research is required to monitor the risk after the third dose of each vaccine.

Aims Underutilization of guideline-directed heart failure with reduced ejection fraction (HFrEF) medications contributes to poor outcomes. Methods and results A pilot study to evaluate the safety and efficacy of a home-based remote monitoring system for HFrEF management was performed. The system included wearable armband monitors paired with the smartphone application. An HFrEF medication titration algorithm was used to adjust medication daily. The primary endpoint was HFrEF medication utilization at 120 days. Twenty patients (60.5 ± 8.2 years, men: 85%) with HFrEF were recruited. All received angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB)/angiotensin receptor-neprilysin inhibitor (ARNI) at recruitment; 45% received ≥50% maximal targeted dose (MTD) with % MTD of 44.4 ± 31.7%. At baseline, 90 and 70% received beta-adrenergic blocker and mineralocorticoid receptor antagonist (MRA), 35% received ≥50% MTD beta-adrenergic blocker with % MTD of 34.1 ± 29.6%, and 25% received ≥50% MTD MRA with % MTD of 25.0 ± 19.9%. At 120 days, 70% received ≥50% MTD ACEI/ARB/ARNI (P = 0.110) with % MTD increased to 64.4 ± 33.5% (P = 0.060). The proportion receiving ≥50% MTD ARNI increased from 15 to 55% (P = 0.089) with % MTD ARNI increased from 20.6 ± 30.9 to 53.1 ± 39.5% (P = 0.006*). More patients received ≥50% MTD MRA (65 vs. 25%, P = 0.011*) with % MTD MRA increased from 25.0 ± 19.9 to 46.2 ± 28.8% (P = 0.009*). Ninety-five per cent of patients had reduced NT-proBNP with the percentage reduction of 26.7 ± 19.7%. Conclusion Heart failure with reduced ejection fraction medication escalation with remote monitoring appeared feasible.

Evidence of the effectiveness of statins compared with fibrates for primary prevention of cardiovascular events is limited. Therefore, we assessed the comparative effectiveness of simvastatin versus gemfibrozil for primary prevention of major adverse cardiovascular events (MACE) and mortality.This territory-wide cohort study used electronic health records of simvastatin and gemfibrozil prescriptions from the Hong Kong Hospital Authority and compared simvastatin or gemfibrozil initiation. The primary outcome was MACE, defined as the composite of the first diagnosis of cardiovascular mortality, coronary heart disease, or stroke. Secondary outcomes were the individual components of MACE, all-cause mortality, and non-cardiovascular mortality. Inverse probability of treatment weighting on the propensity score was used to estimate hazard ratios (HRs).A total of 223,699 individuals (120,207 [53.7%] women; median follow-up 7.0 years [interquartile range 5.7-9.1]) who were prescribed simvastatin (n = 168,630) or gemfibrozil (n = 55,069) were included. Simvastatin was associated with a reduced risk of MACE (HR 0.90, 95% confidence interval [CI] 0.88-0.93), all-cause mortality (HR 0.88, 95% CI 0.86-0.90), cardiovascular mortality (HR 0.71, 95% CI 0.67-0.76), and non-cardiovascular mortality (HR 0.92, 95% CI 0.89-0.95). Associations for MACE varied according to baseline characteristics with gemfibrozil being associated with a reduced risk of MACE in men and patients with low baseline high-density lipoprotein (HDL) cholesterol ( 1.0 mmol/L).The results of this study showed better population-level effectiveness of simvastatin compared with gemfibrozil for the primary prevention of MACE; however, a definitive randomized controlled trial is required to compare simvastatin with gemfibrozil among patients with low HDL cholesterol, as they appear to obtain benefit with gemfibrozil.

Background and aims Lipid-modifying agents (LMAs) are increasingly used to reduce lipid levels and prevent cardiovascular events but the magnitude of their consumption in different world regions is unknown. We aimed to describe recent global trends in LMA consumption and to explore the relationship between country-level LMA consumption and cholesterol concentrations. Methods This cross-sectional and ecological study used monthly pharmaceutical sales data from January 2008 to December 2018 for 83 countries from the IQVIA Multinational Integrated Data Analysis System and total and non-high-density lipoprotein (non-HDL) cholesterol concentrations from the NCD Risk Factor Collaboration. Compound annual growth rate (CAGR) was used to assess changes in LMA consumption over time. Results From 2008 to 2018, use of LMAs increased from 7468 to 11,197 standard units per 1000 inhabitants per year (CAGR 4.13%). An estimated 173 million people used LMAs in 2018. Statins were the most used class of LMA and their market share increased in 75% of countries between 2008 and 2018. From 2013 to 2018, consumption of low-density lipoprotein lowering therapies increased (statins 3.99%; ezetimibe 4.01%; proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors 104.47%). Limited evidence supports a clear relationship between country-level changes in LMA consumption and mean total and non-HDL cholesterol concentrations in 2008 versus 2018. Conclusions Since 2008, global access to LMAs, especially statins, has improved. In line with international lipid guideline recommendations, recent trends indicate growth in the use of statins, ezetimibe, and PCSK9 inhibitors. Country-level patterns of LMA use and total and non-HDL cholesterol varied considerably.

Aims Frailty may be found in heart failure patients especially in the elderly and is associated with a poor prognosis. However, assessment of frailty status is time‐consuming, and the electronic frailty indices developed using health records have served as useful surrogates. We hypothesized that an electronic frailty index developed using machine learning can improve short‐term mortality prediction in patients with heart failure. Methods and results This was a retrospective observational study that included patients admitted to nine public hospitals for heart failure from Hong Kong between 2013 and 2017. Age, sex, variables in the modified frailty index, Deyo's Charlson co‐morbidity index (≥2), neutrophil‐to‐lymphocyte ratio (NLR), and prognostic nutritional index at baseline were analysed. Gradient boosting, which is a supervised sequential ensemble learning algorithm with weak prediction submodels (typically decision trees), was applied to predict mortality. Variables were ranked in the order of importance with a total score of 100 and used to build the frailty models. Comparisons were made with decision tree and multivariable logistic regression. A total of 8893 patients (median: age 81, Q1–Q3: 71–87 years old) were included, in whom 9% had 30 day mortality and 17% had 90 day mortality. Prognostic nutritional index, age, and NLR were the most important variables predicting 30 day mortality (importance score: 37.4, 32.1, and 20.5, respectively) and 90 day mortality (importance score: 35.3, 36.3, and 14.6, respectively). Gradient boosting significantly outperformed decision tree and multivariable logistic regression. The area under the curve from a five‐fold cross validation was 0.90 for gradient boosting and 0.87 and 0.86 for decision tree and logistic regression in predicting 30 day mortality. For the prediction of 90 day mortality, the area under the curve was 0.92, 0.89, and 0.86 for gradient boosting, decision tree, and logistic regression, respectively. Conclusions The electronic frailty index based on co‐morbidities, inflammation, and nutrition information can readily predict mortality outcomes. Their predictive performances were significantly improved by gradient boosting techniques.

Risk of suicide attempt, depression, anxiety and seizure and the association with statins is an ongoing debate. We aim to investigate the association between statins and the above neuropsychological outcomes, in specific pre- and post-exposure time windows.We identified patients aged 40-75 years old who were dispensed a statin between January 1, 2003 and December 31, 2012 from the Hong Kong Clinical Data AnalysisReporting System (CDARS), an electronic medical records database. Patients with new onset of suicide attempt, depression, anxiety and seizure were derived from the original dataset separately, in a self-controlled case series study design. A non-parametric spline-based self-controlled case series model was built to measure continuous changes of risk.We identified 396,614 statin users. The risk of each outcome was elevated prior to statin initiation with incidence rate ratios of 1.38 (95 % CI, 1.09-1.74) for suicide attempt, 1.29 (95 % CI, 1.15-1.45) for depression, 1.35 (95 % CI, 1.19-1.53) for anxiety, and 1.45 (95 % CI, 1.21-1.73) for seizure. The incidence rate ratios remained elevated after the initiation of statins during the first 90 and 91-365 days after statin prescription and decreased to the baseline level after 1 year of continuous prescription.CDARS includes prescription data but not adherence data, which could lead to misclassification of exposure periods.Our study does not support a direct association between statin use and suicide attempt, depression, anxiety and seizure, whose risks could be explained by cardiovascular events, for which statins were prescribed.

Background With accruing case reports on de novo or relapsing glomerular diseases (GD) following different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, we evaluated the risk of GD following BNT162b2 and CoronaVac vaccines. Methods A modified self-controlled case series analysis was conducted using anonymized, territory-wide SARS-CoV-2 vaccination records in Hong Kong. All Hong Kong residents aged 18 years or above with outcomes of interest were included. Outcomes of interest were GD, proteinuria or hematuria within 42 days following each dose of SARS-CoV-2 vaccines. Incidence per 100 000 doses of SARS-CoV-2 vaccines administered was calculated, and incidence rate ratios (IRRs) were estimated using conditional Poisson regression with seasonality adjustment. Results Between 23 February 2021 and 31 March 2022, 4062 patients had an incident diagnosis of GD, proteinuria or hematuria, with 2873 of them being vaccinated during the observation period. The incidences of the composite events 1–41 days after vaccination were 3.7 (95% CI 3.1–4.4) per 100 000 doses of BNT162b2 administered, and 6.5 (95% CI 5.7–7.5) per 100 000 doses CoronaVac administered. There was no significant increase in the risks of composite events following the first (BNT162b2: IRR = 0.76, 95% CI 0.56–1.03; CoronaVac: IRR = 0.92, 95% CI 0.72–1.19), second (BNT162b2: IRR = 0.92, 95% CI 0.72–1.17; CoronaVac: IRR = 0.88. 95% CI 0.68–1.14) or third (BNT162b2: IRR = 0.39. 95% CI 0.15–1.03; CoronaVac: IRR = 1.18. 95% CI 0.53–2.63) dose of SARS-CoV-2 vaccines. Conclusions There was no evidence of increased risks of de novo or relapsing GD with either BNT162b2 or CoronaVac vaccines.

This study aims to evaluate the causal association of blood pressure (BP) with cardiovascular diseases (CVDs). Two-sample Mendelian randomization was performed using a large genome-wide association study (n=299 024) and the UK Biobank cohort (n=375 256). We identified 327 and 364 single-nucleotide polymorphisms strongly and independently associated with systolic BP and diastolic BP, respectively, as genetic instruments to assess the causal association of BP with total CVD, CVD mortality, and 14 cardiovascular conditions. Nonlinearity was examined with nonlinear instrumental variable assumptions. Genetically predicted BP was significantly positively associated with total CVD (systolic BP, per 10 mm Hg: odds ratio [OR], 1.32 [95% CI, 1.25–1.40]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.15–1.26]). Similar positive causal associations were observed for 14 cardiovascular conditions including ischemic heart disease (systolic BP, per 10 mm Hg: OR, 1.33 [95% CI, 1.24–1.41]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.14–1.27]) and stroke (systolic BP, per 10 mm Hg: OR, 1.35 [95% CI, 1.24–1.48]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.12–1.28]). Nonlinearity Mendelian randomization test demonstrated linear causal association of BP with these outcomes. Consistent estimates were observed in sensitivity analyses, suggesting robustness of the associations and minimal horizontal pleiotropy. The linear positive causal association of BP and CVD was consistent with previous findings that lower BP is better, thus consolidating clinical knowledge on hypertension management in CVD risk reduction.

Three hundred million people living with rare diseases worldwide are disproportionately deprived of in-time diagnosis and treatment compared with other patients. This review provides an overview of global policies that optimize development, licensing, pricing, and reimbursement of orphan drugs.Pharmaceutical legislation and policies related to access and regulation of orphan drugs were examined from 194 World Health Organization member countries and 6 areas. Orphan drug policies (ODPs) were identified through internet search, emails to national pharmacovigilance centers, and systematic academic literature search. Texts from selected publications were extracted for content analysis.One hundred seventy-two drug regulation documents and 77 academic publications from 162 countries/areas were included. Ninety-two of 200 countries/areas (46.0%) had documentation on ODPs. Thirty-four subthemes from content analysis were categorized into 6 policy themes, namely, orphan drug designation, marketing authorization, safety and efficacy requirements, price regulation, incentives that encourage market availability, and incentives that encourage research and development. Countries/areas with ODPs were statistically wealthier (gross national income per capita = $10 875 vs $3950, P.001). Country/area income was also positively correlated with the scope of the respective ODP (correlation coefficient = 0.57, P.001).Globally, the number of countries with an ODP has grown rapidly since 2013. Nevertheless, disparities in geographical distribution and income levels affect the establishment of ODPs. Furthermore, identified policy gaps in price regulation, incentives that encourage market availability, and incentives that encourage research and development should be addressed to improve access to available and affordable orphan drugs.

BackgroundPrevious studies have reported an extremely unbalanced global access to opioid analgesics. We aimed to determine contemporary trends and patterns of opioid analgesic consumption at the global, regional, and national levels.MethodsWe analysed the global pharmaceutical sales data of 66 countries or regions from the IQVIA-Multinational Integrated Data Analysis System database on opioid analgesics between 2015 and 2019. Opioid analgesic consumption was measured in milligram morphine equivalent per 1000 inhabitants per day (MME per 1000/day). The global, regional, and national trend changes were estimated using linear regressions. Factors associated with consumption patterns and trend changes were explored in multivariable linear regression analyses.FindingsOverall opioid analgesic sales in the 66 countries or regions increased from 27·52 MME per 1000/day (16·63–45·54) in 2015 to 29·51 MME per 1000/day (17·85–48·79) in 2019 (difference per year 3·96%, 95% CI 0·26 to 7·80). Sales reduced yearly in North America (–12·84%; 95% CI –15·34 to –10·27) and Oceania (–2·96%; –4·20 to –1·70); increased in South America (28·69%; 7·18 to 54·53), eastern Europe (7·68%; 3·99 to 11·49), Asia (5·74%; 0·61 to 11·14), and western and central Europe (1·64%; 0·52 to 2·78); and did not differ in Africa or central America and the Caribbean. The global opioid consumption patterns were associated with country-level Human Development Index (p=0·040), cancer death rate excluding leukaemia (p=0·0072), and geographical location (pInterpretationGlobal opioid analgesic consumption increased from 2015 to 2019. The trend changes were distinctive across regions, which could reflect the different actions in response to known issues of opioid use and misuse. Disparities in opioid analgesic consumption remained, indicating potential inadequate access to essential pain relief in countries with low consumption.

Neuroleptic malignant syndrome (NMS) is a rare and acute adverse drug reaction associated with antipsychotic therapy. However, few data on the risk and epidemiology of NMS are available. The aim of this study was to ascertain the incidence risk and all-cause mortality of NMS associated with antipsychotic use, and to assess the association of recent antipsychotic exposure and NMS. We did a population-based study using data from the Hong Kong Hospital Authority’s Clinical Data Analysis and Reporting System database. Cases had a first diagnosis of NMS between 1 January 2004 and 30 November 2017. A case-crossover analysis was used to compare antipsychotic exposure 30 days before the diagnosis of NMS (index date) and a reference period 91–120 days before the index date. To adjust for potential time trends in antipsychotic exposure, we sampled from cases to match current cases and future cases, and further adjusted for select medications and acute medical conditions. 297,647 patients were prescribed antipsychotics, and the incidence risk of NMS was 0.11%. Of the 336 cases included in the case-crossover analysis, 20 (6%) died within 30 days after the index date; only one case had NMS recorded as the primary cause of death. When compared with the reference period, cases were more frequently prescribed multiple antipsychotics (15.8% vs 26.8%; standardized mean difference [SMD] 0.27) and short-acting injectable antipsychotics (3.6% vs 13.7%; SMD 0.37) during the 30 days prior to the diagnosis of NMS. Odds ratios for antipsychotic exposure in the case-crossover, case-crossover adjusted for time trend, and case-crossover adjusted for time trend and potential confounders analysis were 8.00 (95% confidence interval 3.42–18.69), 5.88 (2.46–14.04), and 4.77 (1.95–11.66). Our results suggest that recent use of antipsychotics is associated with NMS. Although a case-only design inherently controls for confounding by time-invariant factors, residual confounding by acute medical conditions with similar presentations to NMS cannot be fully excluded.

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.

Whether ACE (angiotensin-converting enzyme) inhibitors and angiotensin receptor blockers modify colorectal cancer risk remains controversial. We aimed to determine association between their use and colorectal cancer risk after a negative baseline colonoscopy. This is a territory-wide retrospective cohort study recruiting patients aged ≥40 who had undergone colonoscopy between 2005 and 2013. Exclusion criteria included colorectal cancer detected 3years (adjusted hazard ratio, 1.18 [95% CI, 0.88–1.57]); every single year increase in the drug use was associated with 5% reduction in adjusted hazard ratio risk. ACE inhibitors/angiotensin receptor blocker were associated with a lower colorectal cancer risk in a duration-response manner.

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.

Neurological and psychiatric (mental health) disorders have a large impact on health burden globally. Cognitive disorders (including dementia) and stroke are leading causes of disability. Mental health disorders, including depression, contribute up to one-third of total years lived with disability. The Neurological and mental health Global Epidemiology Network (NeuroGEN) is an international multi-database network that harnesses administrative and electronic medical records from Australia, Asia, Europe and North America. Using these databases NeuroGEN will investigate medication use and health outcomes in neurological and mental health disorders. A key objective of NeuroGEN is to facilitate high-quality observational studies to address evidence-practice gaps where randomized controlled trials do not provide sufficient information on medication benefits and risks that is specific to vulnerable population groups. International multi-database research facilitates comparisons across geographical areas and jurisdictions, increases statistical power to investigate small subpopulations or rare outcomes, permits early post-approval assessment of safety and effectiveness, and increases generalisability of results. Through bringing together international researchers in pharmacoepidemiology, NeuroGEN has the potential to be paradigm-changing for observational research to inform evidence-based prescribing. The first focus of NeuroGEN will be to address evidence-gaps in the treatment of chronic comorbidities in people with dementia.

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.

Background Studies have demonstrated that higher rates of antibiotic resistance are found in countries with higher antibiotic consumption. The global increase in antibiotic consumption is a major public health concern. Objectives The objective of this study was to describe the antibiotic dispensing patterns in public hospitals in Hong Kong from 2000 to 2015. Methods We acquired data on all hospital admissions with any antibiotics dispensed from 2000 to 2015 from the Hong Kong public hospitals. The annual proportion of hospital admissions with antibiotics dispensed was estimated and stratified by age group. An interrupted time series analysis was conducted to examine any potential change in tetracycline dispensing after the release of the new clinical practice guideline. Results A total of 35,535,506 antibiotic prescriptions were dispensed among 2,161,360 unique hospitalized patients from 2000 to 2015. Antibiotics were dispensed in 29.2% of all hospital admissions in the public hospitals, the annual proportions of hospital admissions with antibiotics dispensed increased over the study period from 27.87% in 2000 to 31.39% in 2015, ranging from 27.17 to 31.39%. However, a significant increase was only observed in age groups of 5–19, 20–44, and 85 years or above when stratifying by age. In the interrupted time series analysis, a change in trend was detected for tetracycline dispensing that coincided with the time of publication of the new clinical practice guideline. Conclusions We found that the overall volume of antibiotic use increased between 2000 and 2015. The rise in the dispensing of carbapenems in our study is concerning. The significant change in tetracycline use after being recommended as one of the preferred regimens demonstrated that the change in the clinical practice guideline had an immediate effect on the antibiotic prescribing practice in Hong Kong public hospitals.

Background: Individuals may still develop gastric cancer even after Helicobacter pylori eradication. We aimed to investigate statin effect on gastric cancer development in H. pylori–eradicated subjects. Methods: All adult subjects who were prescribed clarithromycin-based triple therapy between 2003 and 2012 were identified in this retrospective cohort study utilizing a territory-wide electronic healthcare database. Patients were observed from index date of H. pylori therapy, and censored at gastric cancer diagnosis, death, or December 2015 (study end date). Statin use was defined as ≥180-day use after index date. Exclusion criteria included gastric cancer diagnosed within the first year after index date, previous gastric cancer or gastrectomy, and H. pylori treatment failure. Subdistribution hazard ratio (SHR) of gastric cancer with statins was calculated by competing risk regression with propensity score (PS) analysis matching 19 variables (age, sex, comorbidities, and other drug usage, including proton pump inhibitors, nonsteroidal anti-inflammatory drugs, aspirin, cyclooxygenase-2 inhibitors, and metformin). Results: During a median follow-up of 7.6 years (interquartile range = 5.1–10.3), 169 (0.27%) of 63,605 patients developed gastric cancer at an incidence rate of 3.5 per 10,000 person-years. Among 22,870 PS-matched subjects, statins were associated with a lower gastric cancer risk (SHR = 0.34; 95% confidence interval, 0.19–0.61), in a duration– and dose–response manner (Ptrend < 0.05). Conclusions: Statins were associated with a lower gastric cancer risk in a duration– and dose–response manner among H. pylori–eradicated patients. Impact: This study provides evidence on the additional benefits of statins as chemopreventive agents against gastric cancer among H. pylori–eradicated patients.

Haloperidol remains a frequently prescribed first-generation antipsychotic. However, haloperidol-associated mortality risk by all causes, cardiovascular disease (CVD), and pneumonia compared with other antipsychotics is unknown. This study investigated the mortality risk associated with long-term haloperidol treatment versus that with other antipsychotics. We identified incident antipsychotic users from 2004 to 2014 in the Clinical Data Analysis and Reporting System (CDARS), a population-based clinical database managed by the Hong Kong Hospital Authority. We included patients who were aged ≥ 18 and received antipsychotics for any indication apart from terminal illnesses or management of acute behavioural disturbance. Patients on haloperidol and other antipsychotic agents (risperidone, quetiapine, olanzapine, chlorpromazine, aripiprazole, sulpiride, amisulpride, or trifluoperazine) were matched by propensity score. Hazard ratios (HRs) for all-cause mortality and death due to CVD and pneumonia were estimated with 95% confidence intervals (CIs) using a Cox proportional hazards model. In total, 136,593 users of antipsychotics were included. During a mean follow-up of 3.2 years, the incidence of all-cause mortality ranged from 186.8/1000 person-years for haloperidol to 10.4/1000 person-years for trifluoperazine. The risk of all-cause mortality was lower with non-haloperidol antipsychotics than with haloperidol, with HRs ranging from 0.68 (95% CI 0.64–0.72 [chlorpromazine]) to 0.43 (95% CI 0.36–0.53 [trifluoperazine]). Risperidone, quetiapine, sulpiride, chlorpromazine, aripiprazole, and trifluoperazine were associated with a significantly lower risk of pneumonia-related mortality. A significantly lower risk of CVD mortality was observed for risperidone, sulpiride, chlorpromazine, and quetiapine. Haloperidol was associated with increased overall mortality when compared with other antipsychotics in long-term follow-up. Treatment with haloperidol should be carefully considered, especially in older patients and patients at risk of CVD or pneumonia, since the risk of death appears to be lower with non-haloperidol agents.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of patients infected worldwide and indirectly affecting even more individuals through disruption of daily living. Long-term adverse outcomes have been reported with similar diseases from other coronaviruses, namely Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). Emerging evidence suggests that COVID-19 adversely affects different systems in the human body. This review summarizes the current evidence on the short-term adverse health outcomes and assesses the risk of potential long-term adverse outcomes of COVID-19. Major adverse outcomes were found to affect different body systems: immune system (including but not limited to Guillain-Barré syndrome and paediatric inflammatory multisystem syndrome), respiratory system (lung fibrosis and pulmonary thromboembolism), cardiovascular system (cardiomyopathy and coagulopathy), neurological system (sensory dysfunction and stroke), as well as cutaneous and gastrointestinal manifestations, impaired hepatic and renal function. Mental health in patients with COVID-19 was also found to be adversely affected. The burden of caring for COVID-19 survivors is likely to be huge. Therefore, it is important for policy makers to develop comprehensive strategies in providing resources and capacity in the healthcare system. Future epidemiological studies are needed to further investigate the long-term impact on COVID-19 survivors., GRAPHICAL ABSTRACT

Background Previous studies investigating potential cardiovascular adverse events of acid-suppressing drugs are susceptible to protopathic bias and confounding. We aimed to investigate the association between short-term risk of myocardial infarction (MI) and proton pump inhibitors (PPIs) using a self-controlled case series (SCCS) with an active comparator. Methods We conducted a SCCS using a population-wide database from Hong Kong from 2003–2014. Adult with ≥1 outpatient oral PPI prescription or H2 receptor antagonist (H2RA) and MI during the observation period were included. We used both simple ratio and effect modifier approaches to SCCS with active comparators to obtain comparator adjusted estimates. Results A total of 2802 and 1889 people with MI who had exposure to PPIs and H2RA were included respectively. We observed a higher risk of MI during days 1–14 following the start of PPI prescription (Incidence rate ratio (IRR): 2.30, 95% confidence interval (CI): 1.76–3.00) versus baseline. Similarly, we observed a higher risk of MI during days 1–14 following the start of H2RA prescription (IRR: 2.46, 95%CI: 1.92–3.16) versus baseline. In the novel SCCS analyses, comparator adjusted estimates were 0.93 (95%CI: 0.57–1.30) and 0.83 (95%CI: 0.58–1.20) during days 1–14 in simple ratio and effect modifier approach, respectively. Conclusions We observed no difference in risk of MI associated with PPIs compared with baseline using H2RA as the active comparator. The elevated risk of MI associated with PPIs is likely due to protopathic bias. More studies are required to explore the feasibility of using active comparators in SCCS to address protopathic bias in addition to confounding.