Effectiveness of pharmacological treatments for severe agitation in real-world emergency settings: protocol of individual-participant-data network meta-analysis.

BACKGROUND: Severe psychomotor agitation and aggression often require immediate pharmacological intervention, but clear evidence-based recommendations for choosing among the multiple options are lacking. To address this gap, we plan a systematic review and individual-participant-data network meta-analysis to investigate their comparative effectiveness in real-world emergency settings with increased precision. METHODS: We will include randomized controlled trials investigating intramuscular or intravenous pharmacological interventions, as monotherapy or in combination, in adults with severe psychomotor agitation irrespective of the underlying diagnosis and requiring rapid tranquilization in general or psychiatric emergency settings. We will exclude studies before 2002, those focusing on specific reasons for agitation and placebo-controlled trials to avoid concerns related to the transitivity assumption and potential selection biases. We will search for eligible studies in BIOSIS, CENTRAL, CINAHL Plus, Embase, LILACS, MEDLINE via Ovid, PubMed, ProQuest, PsycINFO, ClinicalTrials.gov, and WHO-ICTRP. Individual-participant data will be requested from the study authors and harmonized into a uniform format, and aggregated data will also be extracted from the studies. At least two independent reviewers will conduct the study selection, data extraction, risk-of-bias assessment using RoB 2, and applicability evaluation using the RITES tool. The primary outcome will be the number of patients achieving adequate sedation within 30 min after treatment, with secondary outcomes including the need for additional interventions and adverse events, using odds ratios as the effect size. If enough individual-participant data will be collected, we will synthesize them in a network meta-regression model within a Bayesian framework, incorporating study- and participant-level characteristics to explore potential sources of heterogeneity. In cases where individual-participant data are unavailable, potential data availability bias will be explored, and models allowing for the inclusion of studies reporting only aggregated data will be considered. We will assess the confidence in the evidence using the Confidence in Network Meta-Analysis (CINeMA) approach. DISCUSSION: This individual-participant-data network meta-analysis aims to provide a fine-tuned synthesis of the evidence on the comparative effectiveness of pharmacological interventions for severe psychomotor agitation in real-world emergency settings. The findings from this study can greatly be provided clearer evidence-based guidance on the most effective treatments. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023402365.

Efficacy of COVID-19 Oral antivirals in hospitalised oldest-old with high morbidity burden: a target trial emulation study.

BACKGROUND: Molnupiravir and nirmatrelvir-ritonavir are orally administered pharmacotherapies for mild to moderate COVID-19. However, the effectiveness of these drugs among very old (≥80 years), hospitalised patients remains unclear, limiting the risk-benefit assessment of these antivirals in this specific group. This study investigates the effectiveness of these antivirals in reducing mortality among this group of hospitalised patients with COVID-19. METHODS: Using a territory-wide public healthcare database in Hong Kong, a target trial emulation study was conducted with data from 13 642 eligible participants for the molnupiravir trial and 9553 for the nirmatrelvir-ritonavir trial. The primary outcome was all-cause mortality. Immortal time and confounding bias was minimised using cloning-censoring-weighting approach. Mortality odds ratios were estimated by pooled logistic regression after adjusting confounding biases by stabilised inverse probability weights. RESULTS: Both molnupiravir (HR: 0.895, 95% CI: 0.826-0.970) and nirmatrelvir-ritonavir (HR: 0.804, 95% CI: 0.678-0.955) demonstrated moderate mortality risk reduction among oldest-old hospitalised patients. No significant interaction was observed between oral antiviral treatment and vaccination status. The 28-day risk of mortality was lower in initiators than non-initiators for both molnupiravir (risk difference: -1.09%, 95% CI: -2.29, 0.11) and nirmatrelvir-ritonavir (risk difference: -1.71%, 95% CI: -3.30, -0.16) trials. The effectiveness of these medications was observed regardless of the patients' prior vaccination status. CONCLUSIONS: Molnupiravir and nirmatrelvir-ritonavir are moderately effective in reducing mortality risk among hospitalised oldest-old patients with COVID-19, regardless of their vaccination status.

Comparing the effectiveness of molnupiravir and nirmatrelvir-ritonavir in non-hospitalized and hospitalized COVID-19 patients with type 2 diabetes: A target trial emulation study.

AIMS: To compare the effectiveness of molnupiravir and nirmatrelvir-ritonavir for non-hospitalized and hospitalized COVID-19 patients with type 2 diabetes (T2DM). MATERIALS AND METHODS: Territory-wide electronic health records in Hong Kong were used to perform target trial emulation using a sequential trial approach. Patients (1) aged ≥18 years, (2) with T2DM, (3) with COVID-19 infection, and (4) who received molnupiravir or nirmatrelvir-ritonavir within 5 days of infection between 16 March 2022 and 31 December 2022 in non-hospital and hospital settings were included. Molnupiravir and nirmatrelvir-ritonavir initiators were matched using one-to-one propensity-score matching and followed for 28 days. Risk of outcomes was compared between groups by Cox regression adjusted for baseline characteristics. Subgroup analyses were performed on age (<70 years, ≥70 years), sex, Charlson comorbidity index (<4, ≥4), and number of COVID-19 vaccine doses (<2 doses, ≥2 doses). RESULTS: Totals of 17 974 non-hospitalized (8987 in each group) and 3678 hospitalized (1839 in each group) patients were identified. Non-hospitalized nirmatrelvir-ritonavir initiators had lower risk of all-cause mortality (absolute risk reduction [ARR] at 28 days 0.80%, 95% confidence interval [CI] 0.56-1.04; hazard ratio [HR] 0.47, 95% CI 0.30-0.73) and hospitalization (ARR at 28 days 4.01%, 95% CI 3.19-4.83; HR 0.73, 95% CI 0.66-0.82) as compared with molnupiravir initiators. Hospitalized nirmatrelvir-ritonavir initiators had reduced risk of all-cause mortality (ARR at 28 days 2.94%, 95% CI 1.65-4.23; HR 0.56, 95% CI 0.40-0.80) as compared with molnupiravir initiators. Consistent findings were found across all subgroups. CONCLUSIONS: The use of nirmatrelvir-ritonavir may be preferred to molnupiravir for COVID-19 patients with T2DM and without contraindication to either treatment.

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.

Lithium and the risk of fractures in patients with bipolar disorder: A population-based cohort study.

Lithium is considered to be the most effective mood stabilizer for bipolar disorder. Evolving evidence suggested lithium can also regulate bone metabolism which may reduce the risk of fractures. While there are concerns about fractures for antipsychotics and mood stabilizing antiepileptics, very little is known about the overall risk of fractures associated with specific treatments. This study aimed to compare the risk of fractures in patients with bipolar disorder prescribed lithium, antipsychotics or mood stabilizing antiepileptics (valproate, lamotrigine, carbamazepine). Among 40,697 patients with bipolar disorder from 1993 to 2019 identified from a primary care electronic health record database in the UK, 13,385 were new users of mood stabilizing agents (lithium:2339; non-lithium: 11,046). Lithium was associated with a lower risk of fractures compared with non-lithium treatments (HR 0.66, 95 % CI 0.44-0.98). The results were similar when comparing lithium with prolactin raising and sparing antipsychotics, and individual antiepileptics. Lithium use may lower fracture risk, a benefit that is particularly relevant for patients with serious mental illness who are more prone to falls due to their behaviors. Our findings could help inform better treatment decisions for bipolar disorder, and lithium's potential to prevent fractures should be considered for patients at high risk of fractures.

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.

Comparative effectiveness of combination therapy with nirmatrelvir-ritonavir and remdesivir versus monotherapy with remdesivir or nirmatrelvir-ritonavir in patients hospitalised with COVID-19: a target trial emulation study.

BACKGROUND: Remdesivir (Veklury, Gilead Sciences, Foster City, CA, USA) and nirmatrelvir-ritonavir (Paxlovid, Pfizer, New York, NY, USA) were reported to improve the outcome of patients with mild-to-moderate COVID-19 symptoms. Preclinical data suggest that nirmatrelvir-ritonavir might be more effective than remdesivir alone or in combination with nirmatrelvir-ritonavir for people at high risk of severe COVID-19. We aimed to assess the safety and effectiveness of combining remdesivir and nirmatrelvir-ritonavir compared with using each drug alone for adults hospitalised with COVID-19. METHODS: In this target trial emulation study, we used electronic health records of patients aged 18 years or older who received either combination treatment of nirmatrelvir-ritonavir and remdesivir or monotherapy of either drug between March 16 and Dec 31, 2022, within 5 days of hospitalisation for COVID-19 in Hong Kong. Inverse probability of treatment weighting was applied to balance baseline patient characteristics across the treatment groups. The primary outcome was all-cause mortality. Cox proportional hazards regression adjusting weighting was used to compare the risk of all-cause mortality, intensive care unit (ICU) admission, or ventilatory support for 90 days of follow-up between groups. FINDINGS: Between March 16 and Dec 31, 2022, 18 196 participants were identified from electronic health records and assigned to receive remdesivir (n=4232), nirmatrelvir-ritonavir (n=13 656), or nirmatrelvir-ritonavir and remdesivir (n=308). By applying an inverse probability of treatment weighting, a weighted sample composed of 18 410 recipients of nirmatrelvir-ritonavir and remdesivir combination treatment, 18 178 recipients of remdesivir monotherapy, and 18 287 recipients of nirmatrelvir-ritonavir monotherapy was obtained. After a median follow-up of 84 days (IQR 45-90), risk of mortality was lower in patients who received nirmatrelvir-ritonavir monotherapy (hazard ratio [HR] 0·18 [95% CI 0·15 to 0·20]; absolute risk reduction [ARR] -16·33% [95% CI -16·98 to -15·68]) or remdesivir and nirmatrelvir-ritonavir combination therapy (HR 0·66 [95% CI 0·49 to 0·89]; ARR -6·52% [95% CI -7·29 to -5·74]) than in patients who received remdesivir monotherapy. Similar results were observed for ICU admission or ventilatory support (nirmatrelvir-ritonavir monotherapy: HR 0·09 [95% CI 0·07 to 0·11]; ARR -10·04% [95% CI -10·53 to -9·56]; combination therapy: HR 0·68 [95% CI 0·42 to 1·12]; ARR -3·24% [95% CI -3·84 to -2·64]). Compared with combination therapy, nirmatrelvir-ritonavir monotherapy was associated with lower risk of mortality (HR 0·27 [95% CI 0·20 to 0·37]; ARR -9·81% [95% CI -10·39 to -9·24]) and ICU admission or ventilatory support (HR 0·13 [95% CI 0·08 to 0·22]; ARR -6·80% [95% CI -7·22 to -6·39]). INTERPRETATION: Our study highlighted the potential for reduced risk of mortality, ICU admission, or the need for ventilatory support in patients hospitalised with COVID-19 treated with nirmatrelvir-ritonavir as a monotherapy compared with treatment regimens based on nirmatrelvir-ritonavir and remdesivir combination therapy or remdesivir monotherapy. Further randomised controlled trials are needed to support the validity of the current results. FUNDING: The Health and Medical Research Fund Commissioned Research on COVID-19. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Effectiveness of post-COVID-19 primary care attendance in improving survival in very old patients with multimorbidity: a territory-wide target trial emulation.

OBJECTIVES: Older individuals with multimorbidity are at an elevated risk of infection and complications from COVID-19. Effectiveness of post-COVID-19 interventions or care models in reducing subsequent adverse outcomes in these individuals have rarely been examined. This study aims to examine the effectiveness of attending general outpatient within 30 days after discharge from COVID-19 on 1-year survival among older adults aged 85 years or above with multimorbidity. DESIGN: Retrospective cohort study emulating a randomised target trial using electronic health records. SETTING: We used data from the Hospital Authority and the Department of Health in Hong Kong, which provided comprehensive electronic health records, COVID-19 confirmed case data, population-based vaccination records and other individual characteristics for the study. PARTICIPANTS: Adults aged 85 years or above with multimorbidity who were discharged after hospitalisation for COVID-19 between January 2020 and August 2022. INTERVENTIONS: Attending a general outpatient within 30 days of last COVID-19 discharge defined the exposure, compared to no outpatient visit. MAIN OUTCOME MEASURES: Primary outcome was all-cause mortality within one year. Secondary outcomes included mortality from respiratory, cardiovascular and cancer causes. RESULTS: A total of 6183 eligible COVID-19 survivors were included in the analysis. The all-cause mortality rate following COVID-19 hospitalisation was lower in the general outpatient visit group (17.1 deaths per 100 person-year) compared with non-visit group (42.8 deaths per 100 person-year). After adjustment, primary care consultations within 30 days after discharge were associated with a significantly greater 1-year survival (difference in 1-year survival: 11.2%, 95% CI 8.1% to 14.4%). We also observed significantly better survival from respiratory diseases in the general outpatient visit group (difference in 1-year survival: 6.3%, 95% CI 3.5% to 8.9%). In a sensitivity analysis for different grace period lengths, we found that the earlier participants had a general outpatient visit after COVID-19 discharge, the better the survival. CONCLUSIONS: Timely primary care consultations after COVID-19 hospitalisation may improve survival following COVID-19 hospitalisation among older adults aged 85 or above with multimorbidity. Expanding primary care services and implementing follow-up mechanisms are crucial to support this vulnerable population's recovery and well-being.

Real-World Effectiveness and Safety of Tixagevimab-Cilgavimab: A Target Trial Emulation Study.

BACKGROUND: Immunocompromised individuals are at high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent severe or fatal coronavirus disease 2019 (COVID-19), yet they have suboptimal responses to mRNA and inactivated COVID-19 vaccines. The efficacy of tixagevimab-cilgavimab in reducing symptomatic SARS-CoV-2 infection was demonstrated in phase III clinical trials. Nevertheless, real-world data on the effectiveness and safety of tixagevimab-cilgavimab remain limited. OBJECTIVE: The aim was to evaluate the effectiveness and safety of tixagevimab-cilgavimab among immunocompromised individuals. METHODS: Adults who were immunocompromised or receiving immunosuppressive therapies were included in this target trial emulation using territory-wide electronic health records in Hong Kong. A sequential trial emulation approach was adopted to compare effectiveness and safety outcomes between individuals who received tixagevimab-cilgavimab and individuals who did not. RESULTS: A total of 746 tixagevimab-cilgavimab recipients and 2980 controls were included from 1 May 2022 to 30 November 2022. Tixagevimab-cilgavimab significantly reduced the risk of COVID-19 infection (hazard ratio [HR] 0.708, 95% confidence interval [CI] 0.527-0.951) during a median follow-up of 60 days. No significant difference was observed in the risk of COVID-19-related hospitalisation. Zero versus eight COVID-19 mortality cases and zero versus two severe COVID-19 cases were observed in tixagevimab-cilgavimab recipients and controls, respectively. Notably, significant risk reduction in COVID-19 infection was also observed among immunocompromised individuals who had been previously vaccinated with three or more doses of COVID-19 vaccine, or had no prior COVID-19 infection history. CONCLUSIONS: Tixagevimab-cilgavimab was effective in reducing COVID-19 infection among immunocompromised patients during the Omicron wave. Findings were consistent among individuals who previously received three or more doses of COVID-19 vaccine, or had no previous history of COVID-19 infection.

Cost-Effectiveness of Biosimilars vs Leflunomide in Patients With Rheumatoid Arthritis.

Importance: Among patients with rheumatoid arthritis (RA) who had an inadequate response to methotrexate, a treatment sequence initiated with biosimilar disease-modifying antirheumatic drugs (DMARDs) provides better clinical efficacy compared with conventional synthetic DMARDs recommended by current treatment guidelines; but its cost-effectiveness evidence remains unclear. Objective: To evaluate the cost-effectiveness of the treatment sequence initiated with biosimilar DMARDs after failure with methotrexate vs leflunomide and inform formulary listing decisions. Design, Setting, and Participants: This economic evaluation's cost-effectiveness analysis was performed at a Hong Kong public institution using the Markov disease transition model to simulate the lifetime disease progression and cost for patients with RA, using monetary value in 2022. Scenario and sensitivity analyses were performed to test the internal validity of the modeling conclusion. Participants included patients diagnosed with RA from 2000 to 2021 who were retrieved retrospectively from local electronic medical records to generate model input parameters. Statistical analysis was performed from January 2023 to March 2024. Interventions: The model assesses 3 competing treatment sequences initiated with biosimilar infliximab (CT-P13), biosimilar adalimumab (ABP-501), and leflunomide; all used in combination with methotrexate. Main Outcomes and Measures: Lifetime health care cost and quality-adjusted life-years (QALYs) of the simulated cohort. Results: In total, 25 099 patients with RA were identified (mean [SD] age, 56 [17] years; 19 469 [72.7%] women). In the base-case analysis, the lifetime health care cost and QALYs for the treatment sequence initiated with leflunomide were US $154 632 and 14.82 QALYs, respectively; for biosimilar infliximab, they were US $152 326 and 15.35 QALYs, respectively; and for biosimilar adalimumab, they were US $145 419 and 15.55 QALYs, respectively. Both biosimilar sequences presented lower costs and greater QALYs than the leflunomide sequence. In the deterministic sensitivity analysis, the incremental cost-effectiveness ratio (US$/QALY) comparing biosimilar infliximab sequence vs leflunomide sequence and biosimilar adalimumab sequence vs leflunomide sequence ranged from -15 797 to -8615 and -9088 to 10 238, respectively, all below the predefined willingness-to-pay threshold (US $48 555/QALY gain). In the probabilistic sensitivity analysis, the probability of treatment sequence initiated with leflunomide, biosimilar infliximab, and biosmilar adalimumab being cost-effective out of 10 000 iterations was 0%, 9%, and 91%, respectively. Conclusions and Relevance: In this economic evaluation study, the treatment sequences initiated with biosimilar DMARDs were cost-effective compared with the treatment sequence initiated with leflunomide in managing patients with RA who experienced failure with the initial methotrexate treatment. These results suggest the need to update clinical treatment guidelines for initiating biosimilars immediately after the failure of methotrexate for patients with RA.

Spontaneous bilateral pampiniform plexus thrombosis in a teenager.

Spontaneous pampiniform plexus thrombosis is an extremely rare condition. Its aetiology and pathophysiology are unknown, and its diagnosis remains challenging. We present the first case of an adolescent patient with bilateral spontaneous pampiniform plexus thrombosis. He presented with a 2-day history of bilateral testicular pain. Biochemical investigations were unremarkable, and the patient did not have any risk factors. Ultrasound of the scrotum demonstrated bilateral pampiniform plexus thrombosis. He was managed conservatively and repeat scrotal ultrasound 3 months later revealed complete resolution. This case adds to the minimal literature on spontaneous pampiniform plexus thrombosis, supporting diagnosis via scrotal ultrasound while recommending conservative management without the use of anticoagulation for patients with no pre-existing coagulopathy.

Comparative effectiveness and safety of BNT162b2 and CoronaVac in Hong Kong: A target trial emulation.

OBJECTIVES: To evaluate the difference between BNT162b2 and CoronaVac in vaccine effectiveness and safety. METHODS: This target trial emulation study included individuals aged ≥12 during 2022. Propensity score matching was applied to ensure group balance. The Cox proportional hazard model was used to compare the effectiveness outcomes including COVID-19 infection, severity, 28-day hospitalization, and 28-day mortality after infection. Poisson regression was used for safety outcomes including 32 adverse events of special interests between groups. RESULTS: A total of 639,818 and 1804,388 individuals were identified for the 2-dose and 3-dose comparison, respectively. In 2-dose and 3-dose comparison, the hazard ratios (95% confidence intervals [CI]) were 0.844 [0.833-0.856] and 0.749 [0.743-0.755] for COVID-19 infection, 0.692 [0.656-0.731] and 0.582 [0.559-0.605] for hospitalization, 0.566 [0.417-0.769] and 0.590 [0.458-0.76] for severe COVID-19, and 0.563 [0.456-0.697] and 0.457 [0.372-0.561] for mortality for BNT162b2 recipients versus CoronaVac recipients, respectively. Regarding safety, 2-dose BNT162b2 recipients had a significantly higher incidence of myocarditis (incidence rate ratio [IRR] [95% CI]: 8.999 [1.14-71.017]) versus CoronaVac recipients, but the difference was insignificant in 3-dose comparison (IRR [95% CI]: 2.000 [0.500-7.996]). CONCLUSION: BNT162b2 has higher effectiveness among individuals aged ≥12 against COVID-19-related outcomes for SARS-CoV-2 omicron compared to CoronaVac, with almost 50% lower mortality risk.

Comparison of safety and efficacy between Nirmatrelvir-ritonavir and molnupiravir in the treatment of COVID-19 infection in patients with advanced kidney disease: a retrospective observational study.

Background: Nirmatrelvir-ritonavir is used in patients with coronavirus disease 2019 (COVID-19) with normal or mild renal impairment (eGFR ≥30 ml/min per 1.73 m2). There is limited data regarding its use in advanced kidney disease (eGFR <30 ml/min per 1.73 m2). We performed a retrospective territory-wide observational study evaluating the safety and efficacy of nirmatrelvir-ritonavir when compared with molnupiravir in the treatment of patients with COVID-19 with advanced kidney disease. Methods: We adopted target trial emulation using data from a territory-wide electronic health record database on eligible patients aged ≥18 years with advanced kidney disease (history of eGFR <30 ml/min per 1.73 m2) who were infected with COVID-19 and were prescribed with either molnupiravir or nirmatrelvir-ritonavir within five days of infection during the period from 16 March 2022 to 31 December 2022. A sequence trial approach and 1:4 propensity score matching was applied based on the baseline covariates including age, sex, number of COVID-19 vaccine doses received, Charlson comorbidity index (CCI), hospitalisation, eGFR, renal replacement therapy, comorbidities (cancer, respiratory disease, myocardial infarction, ischaemic stroke, diabetes, hypertension), and drug use (renin-angiotensin-system agents, beta blockers, calcium channel blockers, diuretics, nitrates, lipid lowering agents, insulins, oral antidiabetic drugs, antiplatelets, immuno-suppressants, corticosteroids, proton pump inhibitors, histamine H2 receptor antagonists, monoclonal antibody infusion) within past 90 days. Individuals were followed up from the index date until the earliest outcome occurrence, death, 90 days from index date or the end of data availability. Stratified Cox proportional hazards regression adjusted with baseline covariates was used to compare the risk of outcomes between nirmatrelvir-ritonavir recipients and molnupiravir recipients which include (i) all-cause mortality, (ii) intensive care unit (ICU) admission, (iii) ventilatory support, (iv) hospitalisation, (v) hepatic impairment, (vi) ischaemic stroke, and (vii) myocardial infarction. Subgroup analyses included age (<70; ≥70 years); sex, Charlson comorbidity index (≤5; >5), and number of COVID-19 vaccine doses received (0-1; ≥2 doses). Findings: A total of 4886 patients were included (nirmatrelvir-ritonavir: 1462; molnupiravir: 3424). There were 347 events of all-cause mortality (nirmatrelvir-ritonavir: 74, 5.06%; molnupiravir: 273, 7.97%), 10 events of ICU admission (nirmatrelvir-ritonavir: 4, 0.27%; molnupiravir: 6, 0.18%), 48 events of ventilatory support (nirmatrelvir-ritonavir: 13, 0.89%; molnupiravir: 35, 1.02%), 836 events of hospitalisation (nirmatrelvir-ritonavir: 218, 23.98%; molnupiravir: 618, 28.14%), 1 event of hepatic impairment (nirmatrelvir-ritonavir: 0, 0%; molnupiravir: 1, 0.03%), 8 events of ischaemic stroke (nirmatrelvir-ritonavir: 3, 0.22%; molnupiravir: 5, 0.16%) and 9 events of myocardial infarction (nirmatrelvir-ritonavir: 2, 0.15%; molnupiravir: 7, 0.22%). Nirmatrelvir-ritonavir users had lower rates of all-cause mortality (absolute risk reduction (ARR) at 90 days 2.91%, 95% CI: 1.47-4.36%) and hospitalisation (ARR at 90 days 4.16%, 95% CI: 0.81-7.51%) as compared with molnupiravir users. Similar rates of ICU admission (ARR at 90 days -0.09%, 95% CI: -0.4 to 0.2%), ventilatory support (ARR at 90 days 0.13%, 95% CI: -0.45 to 0.72%), hepatic impairment (ARR at 90 days 0.03%, 95% CI: -0.03 to 0.09%), ischaemic stroke (ARR at 90 days -0.06%, 95% CI: -0.35 to 0.22%), and myocardial infarction (ARR at 90 days 0.07%, 95% CI: -0.19 to 0.33%) were found between nirmatrelvir-ritonavir and molnupiravir users. Consistent results were observed in relative risk adjusted with baseline characteristics. Nirmatrelvir-ritonavir was associated with significantly reduced risk of all-cause mortality (HR: 0.624, 95% CI: 0.455-0.857) and hospitalisation (HR: 0.782, 95% CI: 0.64-0.954). Interpretation: Patients with COVID-19 with advanced kidney disease receiving nirmatrelvir-ritonavir had a lower rate of all-cause mortality and hospital admission when compared with molnupiravir. Other adverse clinical outcomes were similar in both treatment groups. Funding: Health and Medical Research Fund (COVID1903010), Health Bureau, The Government of the Hong Kong Special Administrative Region, China.

Effectiveness of Molnupiravir and Nirmatrelvir-Ritonavir in CKD Patients With COVID-19.

Introduction: Even with effective vaccines, patients with CKD have a higher risk of hospitalization and death subsequent to COVID-19 infection than those without CKD. Molnupiravir and nirmatrelvir-ritonavir have been approved for emergency use, but their effectiveness for the CKD population is still unknown. This study was conducted to determine the effectiveness of these drugs in reducing mortality and severe COVID-19 in the CKD population. Methods: This was a target trial emulation study using electronic health databases in Hong Kong. Patients with CKD aged 18 years or older who were hospitalized with COVID-19 were included. The per-protocol average treatment effect among COVID-19 oral antiviral initiators, including all-cause mortality, intensive care unit (ICU) admission, and ventilatory support within 28 days, were compared to noninitiators. Results: Antivirals have been found to lower the risk of all-cause mortality, with Molnupiravir at a hazard ratio (HR) of 0.85 (95% confidence interval [CI], 0.77 to 0.95] and nirmatrelvir-ritonavir at an HR of 0.78 [95% CI, 0.60 to 1.00]. However, they do not significantly reduce the risk of ICU admission (molnupiravir: HR, 0.88 [95% CI, 0.59 to 1.30]; nirmatrelvir-ritonavir: HR, 0.86 [95% CI, 0.56 to 1.32]) or ventilatory support (molnupiravir: HR, 1.00 [95% CI, 0.76 to 1.33]; nirmatrelvir-ritonavir: HR, 1.01 [95% CI, 0.74 to 1.37]). There was a greater risk reduction in males and those with higher Charlson Comorbidity Index (CCI). The nirmatrelvir-ritonavir trial also showed reduced risk for those who had antiviral treatment and received 3 or more vaccine doses. Conclusion: Both molnupiravir and nirmatrelvir-ritonavir reduced mortality rates for hospitalized COVID-19 patients with CKD.

SABINA + Hong Kong: a territory wide study of prescribing trends and outcomes associated with the use of short-acting ß2 agonists in the Chinese population.

BACKGROUND: Excessive use of short-acting ß2 agonists (SABA) in patients with asthma continues to be a notable concern due to its link to higher mortality rates. Global relevance of SABA overuse in asthma management cannot be understated, it poses significant health risk to patients with asthma and imposes burden on healthcare systems. This study, as part of global SABINA progamme, aimed to describe the prescribing patterns and clinical outcomes associated with SABA use in the Chinese population. METHODS: Retrospective cohort study was conducted using anonymized electronic healthcare records of Clinical Data Analysis and Reporting System (CDARS) from Hong Kong Hospital Authority (HA). Patients newly diagnosed with asthma between 2011 and 2018 and aged ≥12 years were included, stratified by SABA use (≤2, 3-6, 7-10, or ≥11 canisters/year) during one-year baseline period since asthma diagnosis date. Patients were followed up from one-year post-index until earliest censoring of events: outcome occurrence and end of study period (31 December 2020). Cox proportional regression and negative binomial regression were used to estimate the mortality risk and frequency of hospital admissions associated with SABA use respectively, after adjusting for age, sex, Charlson Comorbidity Index (CCI), and inhaled corticosteroid (ICS) dose. Outcomes include all-cause, asthma-related, and respiratory-related mortality, frequency of hospital admissions for any cause, and frequency of hospital admissions due to asthma. RESULTS: 17,782 patients with asthma (mean age 46.7 years, 40.8% male) were included and 59.1% of patients were overusing SABA (≥ 3 canisters per year). Each patient was prescribed a median of 5.61 SABA canisters/year. SABA overuse during baseline period was associated with higher all-cause mortality risk compared to patients with ≤2 canisters/year. Association was dose-dependent, highest risk in those used ≥11 canisters/year (adjusted hazard ratio: 1.42, 95% CI: 1.13, 1.79) and 3-6 canisters/year (adjusted hazard ratio: 1.22, 95% CI: 1.00, 1.50). Higher SABA prescription volume associated with increased frequency of hospital admissions with greatest risk observed in 7-10 canisters/year subgroup (adjusted rate ratio: 4.81, 95% CI: 3.66, 6.37). CONCLUSIONS: SABA overuse is prevalent and is associated with increased all-cause mortality risk and frequency of hospital admissions among the patients with asthma in Hong Kong.

Development and validation of risk prediction model for recurrent cardiovascular events among Chinese: the Personalized CARdiovascular DIsease risk Assessment for Chinese model.

Aims: Cardiovascular disease (CVD) is a leading cause of mortality, especially in developing countries. This study aimed to develop and validate a CVD risk prediction model, Personalized CARdiovascular DIsease risk Assessment for Chinese (P-CARDIAC), for recurrent cardiovascular events using machine learning technique. Methods and results: Three cohorts of Chinese patients with established CVD were included if they had used any of the public healthcare services provided by the Hong Kong Hospital Authority (HA) since 2004 and categorized by their geographical locations. The 10-year CVD outcome was a composite of diagnostic or procedure codes with specific International Classification of Diseases, Ninth Revision, Clinical Modification. Multivariate imputation with chained equations and XGBoost were applied for the model development. The comparison with Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention (TRS-2°P) and Secondary Manifestations of ARTerial disease (SMART2) used the validation cohorts with 1000 bootstrap replicates. A total of 48 799, 119 672 and 140 533 patients were included in the derivation and validation cohorts, respectively. A list of 125 risk variables were used to make predictions on CVD risk, of which 8 classes of CVD-related drugs were considered interactive covariates. Model performance in the derivation cohort showed satisfying discrimination and calibration with a C statistic of 0.69. Internal validation showed good discrimination and calibration performance with C statistic over 0.6. The P-CARDIAC also showed better performance than TRS-2°P and SMART2. Conclusion: Compared with other risk scores, the P-CARDIAC enables to identify unique patterns of Chinese patients with established CVD. We anticipate that the P-CARDIAC can be applied in various settings to prevent recurrent CVD events, thus reducing the related healthcare burden.

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.

Drug-induced chylothorax as a rare pleural complication in dasatinib therapy for chronic myeloid leukaemia.

Chylothorax is a lymphatic chylous pleural effusion typically associated with traumatic (iatrogenic, non-iatrogenic) and non-traumatic (infections, malignancy, lymphatic disorders) aetiologies. Drug-induced chylothorax is uncommon and mostly reported in association with BCR-ABL tyrosine kinase inhibitor therapy.

Efficacy and safety of selinexor for patients with relapsed and refractory multiple myeloma: A meta-analysis.

PURPOSE: Selinexor is a first-in-class, oral selective-inhibitor-of-nuclear-export, granted accelerated approval by FDA (2019) for relapsed and refractory multiple myeloma (RRMM). We sought to quantitatively summarize the selinexor efficacy and safety in RRMM. METHODS: We searched PubMed, EMBASE, CENTRAL, clinicaltrial.gov, and google scholar, until May 2023, studies about selinexor use in RRMM. The outcome measures of interest were primarily efficacy outcomes, in addition to safety outcomes. Random-effect model analyses were performed, at statistical significance of P<0.05, using the RevMan software. RESULTS: Meta-analyses of eleven included clinical trials yielded a significant 56.21% overall clinical benefit, 46.91% overall response, 4.89% complete response, 23.41% very good partial response, 24.68% partial response, and 28.06% stable disease rates with selinexor. Due to safety reasons, selinexor caused significant increase in discontinuation rate, 16.80%. Subgroup analyses demonstrated higher efficacy with selinexor plus dexamethasone and proteasome inhibitor combinations than with selinexor alone. The multiple myeloma type, high cytogenetic risk, refractory state, and advanced disease state did not affect performance. Risk of selection, performance, and detection biases were unclear in the included trials. CONCLUSION: Selinexor led to significant positive responses with an acceptable safety profile in RRMM patients, despite higher rates of safety-related discontinuations. Selinexor-based combinations further enhanced response.

Risk of Incident Thyroid Dysfunction in the Post-Acute Phase of COVID-19: A Population-Based Cohort Study in Hong Kong.

OBJECTIVE: The evidence of thyroid dysfunction in the post-acute phase of SARS-CoV-2 infection is limited. This study aimed to evaluate the risk of incident thyroid dysfunction in the post-acute phase of COVID-19. METHODS: This retrospective, propensity-score matched, population-based study included COVID-19 patients and non-COVID-19 individuals between January 2020 and March 2022, identified from the electronic medical records of the Hong Kong Hospital Authority. The cohort was followed up until the occurrence of outcomes, death, or 31 January 2023, whichever came first. Patients with COVID-19 were 1:1 matched to controls based on various variables. The primary outcome was a composite of thyroid dysfunction (hyperthyroidism, hypothyroidism, initiation of antithyroid drug or levothyroxine, and thyroiditis). Cox regression was employed to evaluate the risk of incident thyroid dysfunction during the post-acute phase. RESULTS: A total of 84 034 COVID-19 survivors and 84 034 matched controls were identified. Upon a median follow-up of 303 days, there was no significant increase in the risk of diagnosed thyroid dysfunction in the post-acute phase of COVID-19 (hazard ratio [HR] 1.058, 95% confidence interval 0.979-1.144, P = .154). Regarding the secondary outcomes, patients with COVID-19 did not have increased risk of hyperthyroidism (HR 1.061, P = .345), hypothyroidism (HR 1.062, P = .255), initiation of antithyroid drug (HR 1.302, P = .070), initiation of levothyroxine (HR 1.086, P = .426), or thyroiditis (P = .252). Subgroup and sensitivity analyses were largely consistent with the main analyses. CONCLUSION: Our population-based cohort study provided important reassuring data that COVID-19 was unlikely to be associated with persistent effects on thyroid function.