Effectiveness and safety of continuous low-molecular-weight heparin versus switching to direct oral anticoagulants in cancer-associated venous thrombosis.

Given the existing uncertainty regarding the effectiveness and safety of switching from low-molecular-weight heparin (LMWH) to direct oral anticoagulants (DOACs) in patients with cancer-associated venous thrombosis (CAT), we conducted a comprehensive population-based cohort study utilizing electronic health database in Hong Kong. A total of 4356 patients with CAT between 2010 and 2022 were included, with 1700 (39.0%) patients switching to DOAC treatment. Compared to continuous LMWH treatment, switching to DOACs was associated with a significantly lower risk of hospitalization due to venous thromboembolism (HR: 0.49 [95% CI = 0.35-0.68]) and all-cause mortality (HR: 0.67 [95% CI = 0.61-0.74]), with no significant difference in major bleeding (HR: 1.04 [95% CI = 0.83-1.31]) within six months. These findings provide reassurance regarding the effectiveness and safety of switching from LMWH to DOACs among patients with CAT, including vulnerable patient groups.

Direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer-associated venous thrombosis: a cost-effectiveness analysis.

Background: Direct oral anticoagulants (DOACs) have demonstrated clinical benefits and better patient adherence over low-molecular-weight heparin (LMWH) in treating patients with cancer-associated venous thrombosis (CAT). We aimed to compare the cost-effectiveness of DOACs against LMWH in patients with CAT from the perspective of the Hong Kong healthcare system. Methods: A Markov state-transition model was performed to estimate the incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALYs) for DOACs and LMWH in a hypothetical cohort of 10,000 patients with CAT over a 5-year lifetime horizon. The model was primarily based on the health states of no event, recurrent venous thromboembolism, bleeding, and death. Transition probabilities, relative risks, and utilities were derived from the literature. Resource cost data were obtained from the Hong Kong Hospital Authority. Deterministic and probabilistic sensitivity analyses tested the robustness of the results. Results: Relative to LMWH, DOACs were associated with increased QALYs (1.52 versus 1.50) at a lower medical cost of USD 2,232 versus 8,224 in five years. The cost of LMWH was the main contributor to the outcome. Out of 10,000 simulated cases, DOACs were dominant in 15.8% and cost-effective in 42.1%, at the willingness-to-pay threshold of USD 148,392 per additional QALY. Conclusions: DOACs were associated with greater QALY improvements and lower overall costs compared to LMWH. Accounting for uncertainty, DOACs were between cost-effective and dominant in 57.9% of cases. DOACs are a cost-effective alternative to LMWH in the management of CAT in Hong Kong.

Proton pump inhibitors associated with severe COVID-19 among two-dose but not three-dose vaccine recipients.

BACKGROUND AND AIM: Proton pump inhibitors (PPIs) may increase the risk of COVID-19 among non-vaccinated subjects via various mechanisms, including gut dysbiosis. We aimed to investigate whether PPIs also affect the clinical outcomes of COVID-19 among vaccine recipients. METHODS: This was a territory-wide cohort study of 3 272 286 vaccine recipients (aged ≥ 18 years) of ≥ 2 doses of either BNT162b2 or CoronaVac. Exclusion criteria included prior gastrointestinal surgery, immunocompromised status, and prior COVID-19. The primary outcome was COVID-19, and secondary outcomes included COVID-19-related hospitalization and severe infection (composite of intensive care unit admission, ventilatory support, and/or death). Covariates include age, sex, the Charlson Comorbidity Index, comorbidities, and concomitant medication use. Subjects were followed from index date (first dose of vaccination) until outcome occurrence, death, additional dose of vaccination, or March 31, 2022. Exposure was pre-vaccination PPI use (any prescription within 90 days before the index date). Propensity score (PS) matching and a Poisson regression model were used to estimate the adjusted incidence rate ratio (aIRR) of outcomes with PPI use. RESULTS: Among 439 154 PS-matched two-dose vaccine recipients (mean age: 65.3 years; male: 45.7%) with a median follow-up of 6.8 months (interquartile range: 2.6-7.9), PPI exposure was associated with a higher risk of COVID-19 (aIRR: 1.08; 95% confidence interval [95% CI]: 1.05-1.10), hospitalization (aIRR: 1.20; 95% CI: 1.08-1.33), and severe infection (aIRR: 1.57; 95% CI: 1.24-1.98). Among 188 360 PS-matched three-dose vaccine recipients (mean age: 62.5 years; male: 49.0%; median follow-up: 9.1 months [interquartile range: 8.0-10.9]), PPIs were associated with higher infection risk (aIRR: 1.11; 95% CI: 1.08-1.15) but not other outcomes. CONCLUSIONS: Although PPI use was associated with a higher COVID-19 risk, severe infection was limited to two-dose but not three-dose vaccine recipients.

Risks of COVID-19-related hospitalisation and mortality among individuals with mental disorders following BNT162b2 and CoronaVac vaccinations: A case-control study.

Concerns have been raised regarding potential weaker vaccine immunogenicity with higher immune suppression for individuals with pre-existing mental disorders. Yet, data on the effectiveness of COVID-19 vaccinations among this vulnerable population are limited. A case-control study was conducted to investigate the risks of COVID-19-related hospitalisation and mortality among individuals with mental disorders following one to three doses of BNT162b2 and CoronaVac vaccinations in Hong Kong. Data were extracted from electronic health records, vaccination and COVID-19 confirmed case records. Conditional logistic regression was applied with adjustment for comorbidities and medication history. Subgroup analyses were performed with stratification: by age (< 65 and ≥ 65) and mental disorders diagnosis (depression, schizophrenia, anxiety disorder, and bipolar disorder). Two doses of BNT162b2 and CoronaVac significantly reduced COVID-19-related hospitalisation and mortality. Further protection for both outcomes was provided after three doses of BNT162b2 and CoronaVac. The vaccine effectiveness magnitude of BNT162b2 was generally higher than CoronaVac, but the difference diminished after the third dose. Individuals with mental disorders should be prioritised in future mass vaccination programmes of booster doses or bivalent COVID-19 vaccines. Targeted strategies should be developed to resolve the reasons behind vaccine hesitancy among this population and increase their awareness on the benefits of vaccination.

Antibiotic Use Prior to COVID-19 Vaccine Is Associated with Higher Risk of COVID-19 and Adverse Outcomes: A Propensity-Scored Matched Territory-Wide Cohort.

Background: Antibiotics may increase the risk of COVID-19 among non-vaccinated subjects via probable gut dysbiosis. We aimed to investigate whether antibiotics also affect the clinical outcomes of COVID-19 vaccine recipients. Methods: This was a territory-wide cohort study of 3,821,302 COVID-19 vaccine recipients (aged ≥ 18 years) with ≥2 doses of either BNT162b2 or CoronaVac. Exclusion criteria included prior COVID-19, prior gastrointestinal surgery, and immunocompromised status. The primary outcome was COVID-19 infection and secondary outcomes included COVID-19-related hospitalization and severe infection (composite of intensive care unit admission, ventilatory support, and/or death). Exposure was pre-vaccination antibiotic use (within 180 days of first vaccine dose). Covariates included age, sex, Charlson Comorbidity Index, and concomitant medication use. Subjects were followed from the index date (first dose vaccination) until outcome occurrence, death, an additional dose of vaccination, or 15 November 2022. Propensity score (PS) matching and a Poisson regression model were used to estimate the adjusted incidence rate ratio (aIRR) of outcomes with antibiotic use. Results: Among 342,338 PS matched three-dose vaccine recipients (mean age: 57.4 years; male: 45.1%) with a median follow-up of 13.6 months (IQR: 9.2-16.3), antibiotics were associated with a higher risk of COVID-19 infection (aIRR: 1.16;95% CI: 1.14-1.19), hospitalization (aIRR: 1.75;95% CI: 1.65-1.86), and severe infection (aIRR: 1.60; 95% CI: 1.21-2.11). Notably, antibiotic use was associated with a higher risk of severe infection and death among CoronaVac recipients (aIRR: 1.62 95% CI: 1.18-2.22 and aIRR: 2.70, 95% CI: 1.54-4.73 for the two secondary outcomes, respectively), but not BNT162b2 recipients. Conclusions: Pre-vaccination use of antibiotics was associated with a higher risk of COVID-19 infection, hospitalization, and severe disease outcomes.

Vaccine effectiveness of BNT162b2 and CoronaVac against SARS-CoV-2 omicron infection and related hospital admission among people with substance use disorder in Hong Kong: a matched case-control study.

BACKGROUND: People with substance use disorder have a high risk of SARS-CoV-2 infection and subsequent poor outcomes. Few studies have evaluated COVID-19 vaccine effectiveness among people with substance use disorder. We aimed to estimate the vaccine effectiveness of BNT162b2 (Fosun-BioNTech) and CoronaVac (Sinovac) against SARS-CoV-2 omicron (B.1.1.529) infection and related hospital admission in this population. METHODS: We did a matched case-control study using electronic health databases in Hong Kong. Individuals diagnosed with substance use disorder between Jan 1, 2016, and Jan 1, 2022, were identified. People aged 18 years and older with SARS-CoV-2 infection from Jan 1 to May 31, 2022, and people with COVID-19-related hospital admission from Feb 16 to May 31, 2022, were included as cases and were matched by age, sex, and previous clinical history with controls from all individuals diagnosed with substance use disorder who attended the Hospital Authority health services: up to three controls for SARS-CoV-2 infection and up to ten controls for hospital admission. Conditional logistical regression was used to evaluate the association between vaccination status (ie, one, two, or three doses of BNT162b2 or CoronaVac) and the risk of SARS-CoV-2 infection and COVID-19-related hospital admission, adjusted for baseline comorbidities and medication use. FINDINGS: Among 57 674 individuals with substance use disorder, 9523 people with SARS-CoV-2 infections (mean age 61·00 years, SD 14·90; 8075 [84·8%] males and 1448 [15·2%] females) were identified and matched to 28 217 controls (mean age 60·99 years, 14·67; 24 006 [85·1%] males and 4211 [14·9%] females), and 843 people with COVID-19-related hospital admissions (mean age 70·48 years, SD 14·68; 754 [89·4%] males and 89 [10·6%] females) were identified and matched to 7459 controls (mean age 70·24 years, 13·87; 6837 [91·7%] males and 622 [8·3%] females). Data on ethnicity were not available. We observed significant vaccine effectiveness against SARS-CoV-2 infection for two-dose BNT162b2 vaccination (20·7%, 95% CI 14·0-27·0, p<0·0001) and three-dose vaccination (all BNT162b2 41·5%, 34·4-47·8, p<0·0001; all CoronaVac 13·6%, 5·4-21·0, p=0·0015; BNT162b2 booster after two-dose CoronaVac 31·3%, 19·8-41·1, p<0·0001), but not for one dose of either vaccine or two doses of CoronaVac. Significant vaccine effectiveness against COVID-19-related hospital admission was detected after one dose of BNT162b2 vaccination (35·7%, 3·8-57·1, p=0·032), two-dose vaccination (both BNT162b2 73·3%, 64·3 to 80·0, p<0·0001; both CoronaVac 59·9%, 50·2-67·7, p<0·0001), and three-dose vaccination (all BNT162b2 86·3%, 75·6-92·3, p<0·0001; all CoronaVac 73·5% 61·0-81·9, p<0·0001; BNT162b2 booster after two-dose CoronaVac 83·7%, 64·6-92·5, p<0·0001), but not after one dose of CoronaVac. INTERPRETATION: For both BNT162b2 and CoronaVac, two-dose or three-dose vaccination was protective against COVID-19-related hospital admission and the booster dose provided protection against SARS-CoV-2 infection among people with substance use disorder. Our findings confirm the importance of booster doses in this population during the period dominated by the omicron variant. FUNDING: Health Bureau, the Government of the Hong Kong Special Administrative Region.

BNT162b2 or CoronaVac Vaccinations Are Associated With a Lower Risk of Myocardial Infarction and Stroke After SARS-CoV-2 Infection Among Patients With Cardiovascular Disease.

Background COVID-19 vaccines have demonstrated effectiveness against SARS-CoV-2 infection, hospitalization, and mortality. The association between vaccination and risk of cardiovascular complications shortly after SARS-CoV-2 infection among patients with cardiovascular disease remains unknown. Methods and Results A case-control study was conducted with cases defined as patients who had myocardial infarction or stroke within 28 days after SARS-CoV-2 infection between January 1, 2022 and August 15, 2022. Controls were defined as all other patients who attended any health services and were not cases. Individuals without history of cardiovascular disease were excluded. Each case was randomly matched with 10 controls according to sex, age, Charlson comorbidity index, and date of hospital admission. Adjusted odds ratio with 95% CI was estimated using conditional logistic regression. We identified 808 cases matched with 7771 controls among all patients with cardiovascular disease. Results showed that vaccination with BNT162b2 or CoronaVac was associated with a lower risk of myocardial infarction or stroke after SARS-CoV-2 infection with a dose-response relationship. For BNT162b2, risk decreased from 0.49 (95% CI, 0.29-0.84) to 0.30 (95% CI, 0.20-0.44) and 0.17 (95% CI, 0.08-0.34) from 1 to 3 doses, respectively. Similar trends were observed for CoronaVac, with risk decreased from 0.69 (95% CI, 0.57-0.85) to 0.42 (95% CI, 0.34-0.52) and 0.32 (95% CI, 0.21-0.49) from 1 to 3 doses, respectively. Conclusions Vaccination with BNT162b2 or CoronaVac is associated with a lower risk of myocardial infarction or stroke after SARS-CoV-2 infection among patients with cardiovascular disease.

Evolving Trends in Consumption of Direct Oral Anticoagulants in 65 Countries/Regions from 2008 to 2019.

BACKGROUND: Direct oral anticoagulants (DOACs) have been increasingly utilised over warfarin. However, little is known about the relative consumption trends and costs of each DOAC at the global level. METHODS: An ecological study using pharmaceutical sales data from IQVIA-MIDAS database was used to estimate consumption and cost of individual DOACs in 65 countries from 2008 to 2019. Consumption was estimated from the volume of DOACs sold, expressed as defined-daily-dose/1000-inhabitants/day (DDDTID). Compound and absolute annual growth rates were reported to quantify consumption changes over time. Costs were estimated as manufacturer price per day-of-therapy. RESULTS: Global consumption of dabigatran, rivaroxaban, apixaban and edoxaban were 0.31, 1.05, 1.08 and 0.78 DDDTID, respectively, in Q2-2019, compared to 0.23, 0.54, 0.21 and 0.03 in Q2-2015, with highest consumption in Western Europe, Northern Europe and Oceania (18.2, 14.07, 13.14 DDDTID). In most countries (46/65, 70%), rivaroxaban contributed to most DOAC consumption (35%-100%), whereas dabigatran accounted for less than one-third. Edoxaban accounted for < 20% of the total in Northern America and Europe but contributed significant proportions in Japan (28.58%) and South Korea (31.37%). Longer median time-to-adoption from FDA approval for apixaban and edoxaban was observed. Costs of all DOACs were ~2-4 times higher in the USA, Puerto Rico and Thailand than in other countries. CONCLUSIONS: Regional differences exist in consumption pattern and trends of individual DOACs over the past decade. Consumption of rivaroxaban and apixaban overtook dabigatran in most countries, whereas use of edoxaban remains limited except in East Asian countries. The USA pays higher prices for DOACs than other countries.

Safety of BNT162b2 or CoronaVac COVID-19 vaccines in patients with heart failure: A self-controlled case series study.

Background: COVID-19 vaccines are important for patients with heart failure (HF) to prevent severe outcomes but the safety concerns could lead to vaccine hesitancy. This study aimed to investigate the safety of two COVID-19 vaccines, BNT162b2 and CoronaVac, in patients with HF. Methods: We conducted a self-controlled case series analysis using the data from the Hong Kong Hospital Authority and the Department of Health. The primary outcome was hospitalization for HF and the secondary outcomes were major adverse cardiovascular events (MACE) and all hospitalization. We identified patients with a history of HF before February 23, 2021 and developed the outcome event between February 23, 2021 and March 31, 2022 in Hong Kong. Incidence rate ratios (IRR) were estimated using conditional Poisson regression to evaluate the risks following the first three doses of BNT162b2 or CoronaVac. Findings: We identified 32,490 patients with HF, of which 3035 were vaccinated and had a hospitalization for HF during the observation period (BNT162b2 = 755; CoronaVac = 2280). There were no increased risks during the 0-13 days (IRR 0.64 [95% confidence interval 0.33-1.26]; 0.94 [0.50-1.78]; 0.82 [0.17-3.98]) and 14-27 days (0.73 [0.35-1.52]; 0.95 [0.49-1.84]; 0.60 [0.06-5.76]) after the first, second and third doses of BNT162b2. No increased risks were observed for CoronaVac during the 0-13 days (IRR 0.60 [0.41-0.88]; 0.71 [0.45-1.12]; 1.64 [0.40-6.77]) and 14-27 days (0.91 [0.63-1.32]; 0.79 [0.46-1.35]; 1.71 [0.44-6.62]) after the first, second and third doses. We also found no increased risk of MACE or all hospitalization after vaccination. Interpretation: Our results showed no increased risk of hospitalization for HF, MACE or all hospitalization after receiving BNT162b2 or CoronaVac vaccines in patients with HF. Funding: The project was funded by a Research Grant from the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region (Ref. No. COVID19F01). F.T.T.L. (Francisco T.T. Lai) and I.C.K.W. (Ian C.K. Wong)'s posts were partly funded by the D24H; hence this work was partly supported by AIR@InnoHK administered by Innovation and Technology Commission.

Low-dose aspirin does not lower the risk of colorectal cancer in patients with type 2 diabetes taking metformin.

BACKGROUND: 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. OBJECTIVE: Among individuals with T2DM taking metformin, we sought to evaluate the association between low-dose aspirin versus no aspirin and the risk of CRC. METHODS: A multiple-database new-user cohort study of patients with T2DM taking metformin was conducted between 2007 and 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 31 December 2019. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Estimates were pooled using an inverse variance random effects model, and heterogeneity was assessed using I2 . RESULTS: After 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, I2  = 0%). CONCLUSION: Low-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.

Association between statins and the risk of suicide attempt, depression, anxiety, and seizure: A population-based, self-controlled case series study.

BACKGROUND: 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. METHODS: 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 Analysis & Reporting 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. RESULTS: 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. LIMITATIONS: CDARS includes prescription data but not adherence data, which could lead to misclassification of exposure periods. CONCLUSIONS: 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.

Global Consumption Trend of Antifungal Agents in Humans From 2008 to 2018: Data From 65 Middle- and High-Income Countries.

BACKGROUND: Understanding the trend of global antifungal agent consumption could assist with identification of global healthcare policy inadequacies and promote accessibility and availability of antifungal agents. METHODS: Using pharmaceutical sales data from the IQVIA-multinational integrated data analysis system database, we assessed use of systemic antifungal agents in humans in 27 middle- and 38 high-income countries from 2008 through 2018. RESULTS: Consumption of systemic antifungal agents increased from 0.50 (in 2008) to 0.92 defined daily dose (DDD)/1000 inhabitants/day (in 2018), with a compound annual growth rate of 6.2%. High-income countries remain major consumers of antifungal agents with large variance in quantities consumed, with a gradual decline in consumption in recent years. Consumption in middle-income countries increased. Itraconazole (0.32 DDD/1000 inhabitants/day), terbinafine (0.30 DDD/1000 inhabitants/day), and fluconazole (0.23 DDD/1000 inhabitants/day) were the most commonly used antifungal agents in middle- and high-income countries in 2018. Following incorporation into the World Health Organization Essential Medicines List, itraconazole consumption in middle-income countries surged. Consumption of ketoconazole slowly declined, with 5.04% annual decrease, probably due to labelling changes in 2013 to reflect hepatotoxicity concerns. The use of polyenes (0.004 DDD/1000 inhabitants/day) and echinocandins (0.003 DDD/1000 inhabitants/day) were lowest among all the antifungal drug classes. CONCLUSION: Global consumption of triazoles and terbinafine has gradually increased in middle- and high-income countries. Life-saving antifungal agents, including echinocandins and polyenes, are available only parenterally and may be underutilized, mainly in middle-income countries. Future research on country-specific epidemiology is warranted to guide health policy coordination to ensure equitable access to appropriate use of antifungal agents.

Association of Long-Acting Injectable Antipsychotics and Oral Antipsychotics With Disease Relapse, Health Care Use, and Adverse Events Among People With Schizophrenia.

Importance: Evidence for improved clinical outcomes with long-acting injectable antipsychotics (LAIAs) vs oral antipsychotics (OAs) is limited in Asian populations and special patient groups, including older people (>65 years), people with substance use, and early initiators of LAIAs. Objective: To compare the risk of disease relapse, health care use, and adverse events associated with the use of LAIAs vs OAs among people in Hong Kong with schizophrenia. Design, Setting, and Participants: In this self-controlled case series study, individuals with a diagnosis of schizophrenia who were prescribed LAIAs and OAs between January 1, 2004, and December 31, 2019, were identified from the Clinical Database Analysis and Reporting System of the Hong Kong Hospital Authority. Data analysis was conducted from May to August in 2021. Exposures: Use of LAIAs vs OAs. Main Outcomes and Measures: Risk of disease relapse (hospitalizations for psychiatric disorders, hospitalizations for schizophrenia, and suicide attempts), health care use (all-cause emergency department visits and hospitalizations), and adverse events (hospitalizations for somatic disorders, hospitalizations for cardiovascular diseases, and extrapyramidal symptoms) between the period in which patients were treated with LAIAs and the period in which patients were treated with OAs were compared using Poisson regression. Results: Of the 70 396 individuals with schizophrenia (37 200 women [52.8%]; mean [SD] age, 44.2 [15.8] years), 23 719 (33.7%) were prescribed both LAIAs and OAs. Compared with OAs, LAIAs were associated with a lower risk of hospitalizations for any cause (n = 20 973; incidence rate ratio [IRR], 0.63 [95% CI, 0.61-0.65]), hospitalizations for psychiatric disorders (n = 19 283; IRR, 0.52 [95% CI, 0.50-0.53]), hospitalizations for schizophrenia (n = 18 385; IRR, 0.53 [95% CI, 0.51-0.55]), and incident suicide attempts (n = 1453; IRR, 0.56 [95% CI, 0.44-0.71]). During full treatment with LAIAs, there was a reduction in hospitalizations for somatic disorders (n = 15 396; IRR, 0.88 [95% CI, 0.85-0.91]), hospitalizations for cardiovascular diseases (n = 3710; IRR, 0.88 [95% CI, 0.81-0.96]), and extrapyramidal symptoms (n = 22 182; IRR, 0.86 [95% CI, 0.82-0.91]) compared with full treatment with OAs. No significant difference was found for emergency department visits. Similar associations were observed during the subsequent treatment periods (beyond 90 days) and among older people and those with substance use, except for an increased risk of extrapyramidal symptoms among older people when initiating LAIAs (first 90 days). Compared with late initiators, early LAIA initiators had a greater reduction in these outcome events. Conclusions and Relevance: This self-controlled case series study of people in Hong Kong with schizophrenia suggests that LAIAs were associated with a lower risk of disease relapse and hospitalization than OAs, without an increased risk of adverse events. Clinicians should more broadly consider the long-term use of LAIAs for Chinese people with schizophrenia, especially early in the course of illness.

Association between BNT162b2 or CoronaVac COVID-19 vaccines and major adverse cardiovascular events among individuals with cardiovascular disease.

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.

Safety of two-dose COVID-19 vaccination (BNT162b2 and CoronaVac) in adults with cancer: a territory-wide cohort study.

BACKGROUND: The World Health Organization has defined a list of adverse events of special interest (AESI) for safety surveillance of vaccines. AESI have not been adequately assessed following COVID-19 vaccination in patients with cancer contributing to vaccine hesitancy in this population. We aimed to evaluate the association between BNT162b2 and CoronaVac vaccines and the risk of AESI in adults with active cancer or a history of cancer. PATIENTS AND METHODS: We conducted a territory-wide cohort study using electronic health records managed by the Hong Kong Hospital Authority and vaccination records provided by the Department of Health. Patients with a cancer diagnosis between January 1, 2018, and September 30, 2021, were included and stratified into two cohorts: active cancer and history of cancer. Within each cohort, patients who received two doses of BNT162b2 or CoronaVac were 1:1 matched to unvaccinated patients using the propensity score. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for AESI 28 days after the second vaccine dose. RESULTS: A total of 74,878 patients with cancer were included (vaccinated: 25,789 [34%]; unvaccinated: 49,089 [66%]). Among patients with active cancer, the incidence of AESI was 0.31 and 1.02 per 10,000 person-days with BNT162b2 versus unvaccinated patients and 0.13 and 0.88 per 10,000 person-days with CoronaVac versus unvaccinated patients. Among patients with history of cancer, the incidence was 0.55 and 0.89 per 10,000 person-days with BNT162b2 versus unvaccinated patients and 0.42 and 0.93 per 10,000 person-days with CoronaVac versus unvaccinated patients. Neither vaccine was associated with a higher risk of AESI for patients with active cancer (BNT162b2: HR 0.30, 95% CI 0.08-1.09; CoronaVac: 0.14, 95% CI 0.02-1.18) or patients with history of cancer (BNT162b2: 0.62, 95% CI 0.30-1.28; CoronaVac: 0.45, 95% CI 0.21-1.00). CONCLUSIONS: In this territory-wide cohort study of patients with cancer, the incidence of AESI following vaccination with two doses of either BNT162b2 or CoronaVac vaccines was low. The findings of this study can reassure clinicians and patients with cancer about the overall safety of BNT162b2 and CoronaVac in patients with cancer, which could increase the COVID-19 vaccination rate in this vulnerable group of patients.

COVID-19 Vaccination Preferences of University Students and Staff in Hong Kong.

Importance: COVID-19 has required universities to rapidly develop vaccination policies for students and staff, yet little is known about the preferences of these individuals toward vaccination. Objective: To quantify student and staff preferences for COVID-19 vaccination at a university in Hong Kong. Design, Setting, and Participants: A cross-sectional online survey study was conducted from July 20 to September 21, 2021, before the announcement of a campus-wide vaccine mandate. A survey of 42 451 eligible university students and staff used discrete-choice experiment methods to quantify 7 attributes of COVID-19 vaccination: risk of a mild or moderate adverse event after vaccination, risk of a severe adverse event after vaccination, efficacy against COVID-19 infection, efficacy against severe manifestation of COVID-19 infection, duration of protection after vaccination, incentive for completing vaccination, and out-of-pocket costs. Main Outcomes and Measures: A mixed logit regression model was used to estimate the preferences of attributes for COVID-19 vaccines and marginal willingness to pay (mWTP) adjusted for background characteristics, role, vaccination, and COVID-19 infection status of family or friends, adverse event status after vaccination among family and friends of participants, and scenario block. Results: Among 42 451 eligible university students and staff invited, 3423 individuals completed the survey (mean [SD] age, 27.1 [9.9] years; 2053 [60.0%] women). Participants included 2506 students (73.2%) and 917 staff (26.8%), with a response rate of 8.1%. Quarantine-free travel was preferred (ß = 0.86; 95% CI, 0.72-0.99; mWTP: $235.9; 95% CI, $190.3-$294.2), followed by efficacy against any COVID-19 infection (ß = 0.30; 95% CI, 0.29-0.32; mWTP: $84.1; 95% CI, $71.8-$100.8), against severe manifestation of COVID-19 infection (ß = 0.25; 95% CI, 0.24-0.27; mWTP: $69.7; 95% CI, $465-$653), and risk of severe adverse events following vaccination (ß = -0.24; 95% CI, -0.27 to -0.21; mWTP: -$66.8; 95% CI, -$81.5 to -$55.3). Participants were less concerned about protection duration (ß = 0.17; 95% CI, 0.15-0.18; mWTP: $46.0; 95% CI, $38.6-$56.2) and risk of mild to moderate adverse events (ß = -0.12; 95% CI, -0.13 to -0.10; mWTP: -$32.7; 95% CI, -$41.2 to -$26.4). Conclusions and Relevance: Preference of all attributes were significant and were considered important by the participants for vaccine decision-making. Insights drawn could assist policy makers in future vaccination decisions, such as campus vaccine mandate and requirement of a third dose.

Cost-Effectiveness of Midazolam Versus Haloperidol Versus Olanzapine for the Management of Acute Agitation in the Accident and Emergency Department.

OBJECTIVES: A multicenter randomized clinical trial in Hong Kong Accident and Emergency (A&E) departments concluded that intramuscular (IM) olanzapine is noninferior to haloperidol and midazolam, in terms of efficacy and safety, for the management of acutely agitated patients in A&E setting. Determining their comparative cost-effectiveness will further provide an economic perspective to inform the choice of sedative in this setting. METHODS: This analysis used data from a randomized clinical trial conducted in Hong Kong A&E departments between December 2014 and September 2019. A within-trial cost-effectiveness analysis comparing the 3 sedatives was conducted, from the A&E perspective and a within-trial time horizon, using a decision-analytic model. Sensitivity analyses were also undertaken. RESULTS: In the base-case analysis, median total management costs associated with IM midazolam, haloperidol, and olanzapine were Hong Kong dollar (HKD) 1958.9 (US dollar [USD] 251.1), HKD 2504.5 (USD 321.1), and HKD 2467.6 (USD 316.4), respectively. Agitation management labor cost was the main cost driver, whereas drug costs contributed the least. Midazolam dominated over haloperidol and olanzapine. Probabilistic sensitivity analyses supported that midazolam remains dominant > 95% of the time and revealed no clear difference in the cost-effectiveness of IM olanzapine versus haloperidol (incremental cost-effectiveness ratio 667.16; 95% confidence interval -770.89, 685.90). CONCLUSIONS: IM midazolam is the dominant cost-effective treatment for the management of acute agitation in the A&E setting. IM olanzapine could be considered as an alternative to IM haloperidol given that there is no clear difference in cost-effectiveness, and their adverse effect profile should be considered when choosing between them.

Postmarketing safety of orphan drugs: a longitudinal analysis of the US Food and Drug Administration database between 1999 and 2018.

BACKGROUND: Information about the specific regulatory environment of orphan drugs is scarce and inconsistent. Uncertainties surrounding the postmarketing long-term safety of orphan drugs remain. This study aimed to evaluate the labelling changes of orphan drugs and to identify postmarketing safety-associated approval factors. METHODS: This retrospective cohort study includes all drugs with orphan drug designation approved by the Center for Drug Evaluation and Research of the US Food and Drug Administration between 1999 and 2018. Main outcomes are safety-related labelling changes up to 31 December 2019. We defined any safety-related labelling changes as postmarketing safety events (PMSE). Safety-related withdrawals, suspensions, and boxed warnings were further categorised as severe postmarketing safety events (SPSE). Outcome measurements include frequencies of PMSE, SPSE, and association between approval factors and the occurrence of safety events. RESULTS: Amongst the 214 drugs identified with orphan drug designation (25.7% biologics), 83.6% were approved through at least one expedited programme, and 29.4% were approved with boxed warnings. During a median follow-up of 6.74 years since approval, 69.2% and 14.5% of the analysed orphan drugs had PMSE and SPSE, respectively. Safety-related withdrawal (0%, 0/214), suspended marketing (0.46%, 1/214) and new boxed warnings are uncommon (3.7%, 8/214). The safety-related labelling changes were more frequent in the drugs approved with boxed warnings [Incidence rate ratio (IRR): 1.95 (1.02-3.73)] and approved for long-term use [IRR: 2.76 (1.52-5.00)]. CONCLUSIONS AND RELEVANCE: In this long-term postmarketing analysis, approximately 70% of FDA-approved orphan drugs had safety-related labelling changes although severe safety events were rare. While maintaining early access to orphan drugs, the drug regulatory body has taken timely regulatory action with postmarketing surveillance to ensure patient safety.

Erratum: Drug Repurposing for the Treatment of COVID-19: A Knowledge Graph Approach.

[This corrects the article DOI: 10.1002/adtp.202100055.].

Psychotropic medicine consumption in 65 countries and regions, 2008-19: a longitudinal study.

BACKGROUND: The WHO Comprehensive Mental Health Action Plan 2013-2030 encourages routine collection and reporting of a set of essential mental health indicators, including the availability of psychotropic medicines. The global monitoring of country-level psychotropic medicine consumption trends can provide information on the extent of the availability of psychotropic medicines. The primary objective of this study was to investigate global trends in psychotropic medicines consumption from 2008 to 2019 across 65 countries and regions according to country income level and geographical region. METHODS: In this longitudinal trends study, we used pharmaceutical sales data from the IQVIA-Multinational Integrated Data Analysis System (IQVIA-MIDAS). We analysed monthly sales data of psychotropic medicines between Jan 1, 2008, and Dec 31, 2019. Total psychotropic medicine consumption included sales of antidepressants, antipsychotics, tranquilisers, sedatives or hypnotics, and mood stabilisers. Population estimates of each country or region (eight lower-middle-income countries, 19 upper-middle-income countries, and 38 high-income countries) were based on the UN World Population Prospects 2019 report. Average annual sales trends of psychotropic medicines, expressed as defined daily dose (DDD) per 1000 inhabitants per day, were estimated using a random-effects model adjusted for income level and region. Relative changes in the annual consumption of psychotropic medicines by income, expressed as DDD per 1000 inhabitants per day, were assessed as percentage change for each medicine class. FINDINGS: Psychotropic medicine sales increased from 28·54 DDD per 1000 inhabitants per day in 2008 to 34·77 DDD per 1000 inhabitants per day in 2019, corresponding to a 4·08% (95% CI 2·96-5·21) relative average increase annually. The absolute annual increase was greater in high-income countries (3·31 DDD per 1000 inhabitants per day, 95% CI 3·01-3·61) compared with upper-middle-income countries (1·94 DDD per 1000 inhabitants per day, 1·45-2·44) and low-middle-income countries (0·88 DDD per 1000 inhabitants per day, 0·62-1·13; p<0·0001). The relative average annual increase in psychotropic medicine sales from 2008 to 2019 was greater in upper-middle-income countries (7·88%, 95% CI 6·99-8·77) than in lower-middle-income countries (2·90%, 2·40-3·39) and high-income countries (1·02%, 0·80-1·24). In 2019, the regional consumption of psychotropic medicines varied greatly, with the highest sales of all psychotropic medicine classes reported in northern America (167·54 DDD per 1000 inhabitants per day) and lowest sales reported in Asia (5·59 DDD per 1000 inhabitants per day). 17 countries had very low consumption of psychotropic medicines in 2019, including high-income countries and countries with a high prevalence of mental disorders. INTERPRETATION: The consumption of psychotropic medicines has increased over a 12-year period, and although the absolute growth rate was highest in high-income countries, the relative growth is highest in middle-income countries and especially upper-middle-income countries. Disparities in psychotropic medicine consumption of countries can only partly be explained by geographical location and income. Greater efforts are needed to increase the availability of psychotropic medicines in countries with very low consumption, which is probably due to financial or cultural reasons as well as scarcity of trained health-care professionals to prescribe psychotropic medicines. FUNDING: None.