Association of COVID-19 with acute and post-acute risk of multiple different complications and mortality in patients infected with omicron variant stratified by initial disease severity: a cohort study in Hong Kong.

BACKGROUND: Few studies have attempted to use clinical and laboratory parameters to stratify COVID-19 patients with severe versus non-severe initial disease and evaluate age-specific differences in developing multiple different COVID-19-associated disease outcomes. METHODS: A retrospective cohort included patients from the electronic health database of Hong Kong Hospital Authority between 1 January 2022 and 15 August 2022 until 15 November 2022. The cohort was divided into three cohorts by age (≤ 40, 41-64, and ≥ 65 years old). Each age cohort was stratified into four groups: (1) COVID-19 critically exposed group (ICU admission, mechanical ventilation support, CRP > 80 mg/L, or D-dimer > 2 g/mL), (2) severely exposed group (CRP 30-80 mg/L, D-dimer 0.5-2 g/mL, or CT value < 20), (3) mildly-moderately exposed group (COVID-19 positive-tested but not fulfilling the criteria for the aforementioned critically and severely exposed groups), and (4) unexposed group (without COVID-19). The characteristics between groups were adjusted with propensity score-based marginal mean weighting through stratification. Cox regression was conducted to determine the association of COVID-19 disease severity with disease outcomes and mortality in the acute and post-acute phase (< 30 and ≥ 30 days from COVID-19 infection) in each age group. RESULTS: A total of 286,114, 320,304 and 194,227 patients with mild-moderate COVID-19 infection; 18,419, 23,678 and 31,505 patients with severe COVID-19 infection; 1,168, 2,261 and 10,178 patients with critical COVID-19 infection, and 1,143,510, 1,369,365 and 1,012,177 uninfected people were identified in aged ≤ 40, 40-64, and ≥ 65 groups, respectively. Compared to the unexposed group, a general trend tending towards an increase in risks of multiple different disease outcomes as COVID-19 disease severity increases, with advancing age, was identified in both the acute and post-acute phases. Notably, the mildly-moderately exposed group were associated with either insignificant risks (aged ≤ 40) or the lowest risks (aged > 40) for the disease outcomes in the acute phase of infection (e.g., mortality risk HR (aged ≤ 40): 1.0 (95%CI: 0.5,2.0), HR (aged 41-64): 2.1 (95%CI: 1.8, 2.6), HR (aged > 65): 4.8 (95%CI: 4.6, 5.1)); while in the post-acute phase, these risks were largely insignificant in those aged < 65, remaining significant only in the elderly (age ≥ 65) (e.g., mortality risk HR (aged ≤ 40): 0.8 (95%CI: (0.5, 1.0)), HR (aged 41-64): 1.1 (95%CI: 1.0,1.2), HR (aged > 65): 1.5 (95%CI: 1.5,1.6)). Fully vaccinated patients were associated with lower risks of disease outcomes than those receiving less than two doses of vaccination. CONCLUSIONS: The risk of multiple different disease outcomes in both acute and post-acute phases increased significantly with the increasing severity of acute COVID-19 illness, specifically among the elderly. Moreover, future studies could improve by risk-stratifying patients based on universally accepted thresholds for clinical parameters, particularly biomarkers, using biological evidence from immunological studies.

Trajectory of haemoglobin A1c and incidence of cardiovascular disease in patients with type 2 diabetes mellitus.

AIM: To evaluate the association between changes in haemoglobin A1c (HbA1c) and the concurrent incidence of cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM) patients. METHOD: We conducted a retrospective cohort study among T2DM patients with HbA1c measurement after T2DM diagnosis between August 2009 and September 2010. The patients were classified into six subgroups based on baseline HbA1c (<7%; 7%-7.9%; ≥8%) and age (<65; ≥65 years), and then clustered into classes by HbA1c trajectory and CVD incidence over the 12-year follow-up period using joint latent class mixture models. We explored the HbA1c trajectories and CVD incidences in each latent class. Multinomial logistic regression was used to compare the baseline characteristics among different latent classes. RESULTS: A total of 128 843 T2DM patients were included with a median follow-up period of 11.7 years. Ten latent classes were identified in patients with baseline HbA1c ≥ 8% and age <65 years, while seven classes were identified in the other five groups. Among all the identified latent classes, patients with fluctuating HbA1c trajectories, characterized by alternating periods of increase and decrease, had higher CVD incidences. Male patients, and patients with higher baseline HbA1c and use of antidiabetic drugs were more likely to have a fluctuating HbA1c trajectory. More specifically, patients aged < 65 years with younger age or a smoking habit, and patients aged ≥ 65 years with a longer duration of T2DM were more likely to have a fluctuating HbA1c trajectory. CONCLUSION: We found that T2DM patients with fluctuating HbA1c trajectories could have a higher CVD risk. Different trajectory-associated characteristics in age subgroups highlight the need for individualized management of T2DM patients.

Optimizing physician-encounter frequency for type 2 diabetes patients in primary care based on cardiovascular risk assessment: A target trial emulation study.

AIM: To investigate whether the physician-encounter interval for patients with type 2 diabetes (T2D) can be optimized from 2-3 to 4-6 months among those with a calculated 10-year cardiovascular disease (CVD) risk score of less than 20% without compromising their long-term outcomes. MATERIALS AND METHODS: Using territory-wide public electronic medical records in Hong Kong, we emulated a target trial to compare the effectiveness of the physician-encounter intervals of 4-6 versus 2-3 months for T2D patients without prior CVDs and with a predicted risk for CVDs of less than 20% (i.e. those patients not in the high-risk category). Propensity score matching was used to emulate the randomization of participants at baseline, where 42 154 matched individuals were included for analysis. The marginal structural model was applied to estimate the hazard ratio (HR) for CVD incidence and all-cause mortality, the incidence rate ratio of secondary and tertiary care utilization, as well as the between-group differences in HbA1c, blood pressure and cholesterol levels. RESULTS: During a follow-up period of up to 12 (average: 5.1) years, there was no significantly increased risk of CVD in patients with physician-encounter intervals of 4-6 months compared with those patients with physician-encounter intervals of 2-3 months (HR [95% confidence interval {CI}]: 1.01 [0.90, 1.14]; standardized 10-year risk difference [95% CI]: -0.1% [-0.7%, 0.6%]), nor for all-cause mortality (HR: 1.00 [0.84, 1.20]; standardized 10-year risk difference: -0.1% [-0.5%, 0.3%]). Additionally, there was no observable difference in the utilization of secondary and tertiary care or key clinical parameters between these two follow-up frequencies. CONCLUSIONS: For T2D patients with a calculated 10-year CVD risk of less than 20%, the interval of regular physician encounters can be optimized from 2-3 to 4-6 months without compromising patients' long-term outcomes and saving substantial service resources in primary care.

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.

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.

Development and validation of 10-year risk prediction models of cardiovascular disease in Chinese type 2 diabetes mellitus patients in primary care using interpretable machine learning-based methods.

AIM: To develop 10-year cardiovascular disease (CVD) risk prediction models in Chinese patients with type 2 diabetes mellitus (T2DM) managed in primary care using machine learning (ML) methods. METHODS: In this 10-year population-based retrospective cohort study, 141 516 Chinese T2DM patients aged 18 years or above, without history of CVD or end-stage renal disease and managed in public primary care clinics in 2008, were included and followed up until December 2017. Two-thirds of the patients were randomly selected to develop sex-specific CVD risk prediction models. The remaining one-third of patients were used as the validation sample to evaluate the discrimination and calibration of the models. ML-based methods were applied to missing data imputation, predictor selection, risk prediction modelling, model interpretation, and model evaluation. Cox regression was used to develop the statistical models in parallel for comparison. RESULTS: During a median follow-up of 9.75 years, 32 445 patients (22.9%) developed CVD. Age, T2DM duration, urine albumin-to-creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), systolic blood pressure variability and glycated haemoglobin (HbA1c) variability were the most important predictors. ML models also identified nonlinear effects of several predictors, particularly the U-shaped effects of eGFR and body mass index. The ML models showed a Harrell's C statistic of >0.80 and good calibration. The ML models performed significantly better than the Cox regression models in CVD risk prediction and achieved better risk stratification for individual patients. CONCLUSION: Using routinely available predictors and ML-based algorithms, this study established 10-year CVD risk prediction models for Chinese T2DM patients in primary care. The findings highlight the importance of renal function indicators, and variability in both blood pressure and HbA1c as CVD predictors, which deserve more clinical attention. The derived risk prediction tools have the potential to support clinical decision making and encourage patients towards self-care, subject to further research confirming the models' feasibility, acceptability and applicability at the point of care.

Age-specific Multimorbidity Patterns and Burden on All-Cause Mortality and Public Direct Medical Expenditure: A Retrospective Cohort Study.

OBJECTIVE: To evaluate age-specific multimorbidity patterns and morbidity burden on mortality and healthcare expenditure across age groups. PATIENTS AND METHODS: Retrospective observational study between January 1, 2009 to December 31, 2017 using electronic health records in Hong Kong: Individuals were stratified by age (< 50, 50-64, 65-79, ≥ 80), and sub-classified by number of morbidities (0, 1, 2, 3, ≥ 4) out of 21 common chronic conditions. Clustering analyses were conducted to identify specific patterns of multimorbidity. Association between the number as well as combinations of morbidities and all-cause mortality and public expenditure was examined. RESULTS: 4,562,832 individuals with a median follow-up of 7 years were included. Mental disorders were the top morbidities among young individuals, while cardiovascular diseases were prevalent in the elderly. An increased number of morbidities was associated with a greater relative risk for mortality and medical expenditure, and this relationship was stronger among younger patients. Compared to individuals in the same age group without morbidity, the hazard ratios (HR; 95% CI) of all-cause mortality in patients aged < 50 and ≥ 80 with two comorbidities 3.81 (3.60-4.03) and 1.38 (1.36-1.40), respectively, which increased to 14.22 (9.87-20.47) and 2.20 (2.13-2.26), respectively, as the number of morbidities increased to ≥ 4. The stroke-hypertension cluster was shown to be associated with the highest HR of mortality 2.48 (2.43-2.53) among all identified clusters arising from the clustering analysis. CONCLUSION: Given the stronger association between multimorbidity and all-cause mortality and greater opportunity costs in younger populations, prevention and management of early-onset multimorbidity are warranted. (248 words).

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.

Long-term statin use and risk of cancers: a target trial emulation study.

BACKGROUND AND OBJECTIVES: Controversy exists regarding potential cancer risks associated with long-term statin use. This study aimed to use real-world data to investigate the association between cancer incidence and sustained statin use over a 10-year period. METHODS: Using territory-wide public electronic medical records in Hong Kong, we emulated a sequence of nested target trials on patients who met indications for statin initiation in each calendar month from January 2009 to December 2011. Statin initiators and noninitiators were matched in a 1:1 ratio to mimic the randomization of eligible person-trials at baseline. Pooled logistic regression was applied to obtain the hazard ratios for the cancer incidence of statin initiation in intention-to-treat analysis, with the adjustment of baseline confounders and the inverse probability weighting accounting for the postbaseline confounders in per-protocol analysis. RESULTS: Among 8,560,051 eligible person-trials, 119,715 noninitiators were matched to 119,715 initiators for analysis. Over the 10-year study period, the estimated hazard ratio of overall cancer incidence was 0.96 (0.87, 1.05), and the standardized 10-year risk difference was -0.4% (-1.3%, 0.4%) in the per-protocol analysis. For the cancer subtypes of interest (ie, breast cancer, colorectal cancer, hematological cancer, pancreatic cancer, prostate cancer, urothelial carcinoma, and lung cancer), the 10-year risk differences ranged from -0.3% to 0.2% in the per-protocol analysis. No observable risk change for cancer was found in all patient subgroups with regards to their sex, age (<70/≥70 years), Charlson Comorbidity Index (≤4/>4), and statin indication. CONCLUSION: Statin use has no impact on cancer incidence over a 10-year follow-up period, including all cancer subtypes of interest and patient subgroups with regards to sex, age, comorbidities, and statin indications.

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.

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.

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.

Associations and attributable burden between risk factors and all-cause and cause-specific mortality at different ages in patients with hypertension.

It remains unclear the age-specific associations of risk factors with deaths and mortality burden attributable across age. In a territory-wide retrospective cohort, 1,012,228 adults with hypertension were identified. Comorbidities including diabetes, chronic kidney disease (CKD), cardiovascular disease (CVD), heart failure, and cancer, and risk factors including current smoking and suboptimal control of blood pressure (BP), glucose and low-density lipoprotein cholesterol were defined. Associations of comorbidities/risk factors with all-cause and cause-specific mortality across age groups (18-54, 55-64, 65-74, and ≥75 years) were assessed. Population attributable fractions were also quantified. During a median follow-up of 10.7 years, 244,268 (24.1%) patients died, with pneumonia (7.2%), cancer (5.1%), and CVD (4.2%) being the leading causes. Despite increasing deaths with age, relative risk of mortality related to comorbidities/risk factors decreased with age; similar patterns were found for cause-specific mortality. The assessed risk factors accounted for 24.0% (95% CI 22.5%, 25.4%) deaths, with highest proportion in the youngest group (33.5% [28.1%, 38.5%] in 18-54 years vs 19.4% [17.0%, 21.6%] in ≥75 years). For mortality burden, CKD was the overall leading risk factor (12.7% [12.4%, 12.9%]) with higher proportions in older patients (11.1-13.1% in ≥65 years), while diabetes was the leading risk factor in younger patients (15.9-13.5% in 18-54 years). The association of comorbidities or risk factors with mortality is stronger in younger patients with hypertension, despite lower absolute mortality in young patients than in the elderly. Leading risk factors differed across age, highlighting the importance of targeted and precise risk management.

Benefits and Risks Associated With Statin Therapy for Primary Prevention in Old and Very Old Adults : Real-World Evidence From a Target Trial Emulation Study.

BACKGROUND: There is little consensus on using statins for primary prevention of cardiovascular diseases (CVDs) and all-cause mortality in adults aged 75 years or older due to the underrepresentation of this population in randomized controlled trials. OBJECTIVE: To investigate the benefits and risks of using statins for primary prevention in old (aged 75 to 84 years) and very old (aged ≥85 years) adults. DESIGN: Sequential target trial emulation comparing matched cohorts initiating versus not initiating statin therapy. SETTING: Territory-wide public electronic medical records in Hong Kong. PARTICIPANTS: Persons aged 75 years or older who met indications for statin initiation from January 2008 to December 2015 were included. Participants with preexisting diagnosed CVDs at baseline, such as coronary heart disease (CHD), were excluded from the analysis. Among 69 981 eligible persons aged 75 to 84 years and 14 555 persons aged 85 years or older, 41 884 and 9457 had history of CHD equivalents (for example, diabetes) in the respective age groups. INTERVENTION: Initiation of statin therapy. MEASUREMENTS: Incidence of major CVDs (stroke, myocardial infarction, or heart failure), all-cause mortality, and major adverse events (myopathies and liver dysfunction). RESULTS: Of 42 680 matched person-trials aged 75 to 84 years and 5390 matched person-trials aged 85 years or older (average follow-up, 5.3 years), 9676 and 1600 of them developed CVDs in each age group, respectively. Risk reduction for overall CVD incidence was found for initiating statin therapy in adults aged 75 to 84 years (5-year standardized risk reduction, 1.20% [95% CI, 0.57% to 1.82%] in the intention-to-treat [ITT] analysis; 5.00% [CI, 1.11% to 8.89%] in the per protocol [PP] analysis) and in those aged 85 years or older (ITT: 4.44% [CI, 1.40% to 7.48%]; PP: 12.50% [CI, 4.33% to 20.66%]). No significantly increased risks for myopathies and liver dysfunction were found in both age groups. LIMITATION: Unmeasured confounders, such as lifestyle factors of diet and physical activity, may exist. CONCLUSION: Reduction for CVDs after statin therapy were seen in patients aged 75 years or older without increasing risks for severe adverse effects. Of note, the benefits and safety of statin therapy were consistently found in adults aged 85 years or older. PRIMARY FUNDING SOURCE: Health Bureau, the Government of Hong Kong Special Administrative Region, China, and National Natural Science Foundation of China.

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.

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.

Effects of SARS-CoV-2 infection on incidence and treatment strategies of hepatocellular carcinoma in people with chronic liver disease.

BACKGROUND: Chronic liver disease (CLD) was associated with adverse clinical outcomes among people with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. AIM: To determine the effects of SARS-CoV-2 infection on the incidence and treatment strategy of hepatocellular carcinoma (HCC) among patients with CLD. METHODS: A retrospective, territory-wide cohort of CLD patients was identified from an electronic health database in Hong Kong. Patients with confirmed SARS-CoV-2 infection [coronavirus disease 2019 (COVID-19)+CLD] between January 1, 2020 and October 25, 2022 were identified and matched 1:1 by propensity-score with those without (COVID-19-CLD). Each patient was followed up until death, outcome event, or November 15, 2022. Primary outcome was incidence of HCC. Secondary outcomes included all-cause mortality, adverse hepatic outcomes, and different treatment strategies to HCC (curative, non-curative treatment, and palliative care). Analyses were further stratified by acute (within 20 d) and post-acute (21 d or beyond) phases of SARS-CoV-2 infection. Incidence rate ratios (IRRs) were estimated by Poisson regression models. RESULTS: Of 193589 CLD patients (> 95% non-cirrhotic) in the cohort, 55163 patients with COVID-19+CLD and 55163 patients with COVID-19-CLD were included after 1:1 propensity-score matching. Upon 249-d median follow-up, COVID-19+CLD was not associated with increased risk of incident HCC (IRR: 1.19, 95%CI: 0.99-1.42, P = 0.06), but higher risks of receiving palliative care for HCC (IRR: 1.60, 95%CI: 1.46-1.75, P < 0.001), compared to COVID-19-CLD. In both acute and post-acute phases of infection, COVID-19+CLD were associated with increased risks of all-cause mortality (acute: IRR: 7.06, 95%CI: 5.78-8.63, P < 0.001; post-acute: IRR: 1.24, 95%CI: 1.14-1.36, P < 0.001) and adverse hepatic outcomes (acute: IRR: 1.98, 95%CI: 1.79-2.18, P < 0.001; post-acute: IRR: 1.24, 95%CI: 1.13-1.35, P < 0.001), compared to COVID-19-CLD. CONCLUSION: Although CLD patients with SARS-CoV-2 infection were not associated with increased risk of HCC, they were more likely to receive palliative treatment than those without. The detrimental effects of SARS-CoV-2 infection persisted in post-acute phase.

COVID-19 vaccine effectiveness against the Omicron variant of SARS-CoV-2 in multimorbidity: A territory-wide case-control study.

Multimorbidity entails a higher risk of SARS-CoV-2 infection and COVID-19 complications. We examined vaccine effectiveness (VE) stratified by multimorbidity using a case-control study of territory-wide electronic health records in Hong Kong. Cases of infection (testing positive), hospitalization, and mortality were identified from January to March 2022. Controls were matched by age, sex, outpatient attendance/hospitalization date, and Charlson Comorbidity Index. We demonstrated a consistently good VE among people with increased multimorbidity burden; even more so than among those with minimal such burden. There was also a significantly greater VE after a third dose of BNT162b2 or CoronaVac against infection. The difference in VE between those with multimorbidity and those without was less pronounced for hospitalization, and such difference for COVID-19-related mortality was negligible. In conclusion, VE of both examined vaccines against SARS-CoV-2 infection among people with more complex multimorbidity burden is significant. Further vaccine roll-out should prioritize people with multimorbidity.

Prognostic Utility of Left Atrial Strain From MRI Feature Tracking in Ischemic and Nonischemic Dilated Cardiomyopathy: A Multicenter Study.

BACKGROUND. MRI-based prognostic evaluation in patients with dilated cardiomyopathy (DCM) has historically used markers of late gadolinium enhancement (LGE) and feature tracking (FT)-derived left ventricular global longitudinal strain (LVGLS). Early data indicate that FT-derived left atrial strain (LAS) parameters, including reservoir, conduit, and booster, may also have prognostic roles in such patients. OBJECTIVE. The purpose of our study was to evaluate the prognostic utility of LAS parameters, derived from MRI FT, in patients with ischemic or nonischemic DCM, including in comparison with the traditional parameters of LGE and LVGLS. METHODS. This retrospective study included 811 patients with ischemic or nonischemic DCM (median age, 60 years; 640 men, 171 women) who underwent cardiac MRI at any of five centers. FT-derived LAS parameters and LVGLS were measured using two- and four-chamber cine images. LGE percentage was quantified. Patients were assessed for a composite outcome of all-cause mortality or heart failure hospitalization. Multivariable Cox regression analyses including demographic characteristics, cardiovascular risk factors, medications used, and a wide range of cardiac MRI parameters were performed. Kaplan-Meier analyses with log-rank tests were also performed. RESULTS. A total of 419 patients experienced the composite outcome. Patients who did, versus those who did not, experience the composite outcome had larger LVGLS (-6.7% vs -8.3%, respectively; p < .001) as well as a smaller LAS reservoir (13.3% vs 19.3%, p < .001), LAS conduit (4.7% vs 8.0%, p < .001), and LAS booster (8.1% vs 10.3%, p < .001) but no significant difference in LGE (10.1% vs 11.3%, p = .51). In multivariable Cox regression analyses, significant independent predictors of the composite outcome included LAS reservoir (HR = 0.96, p < .001) and LAS conduit (HR = 0.91, p < .001). LAS booster and LGE were not significant independent predictors in the models. LVGLS was a significant independent predictor only in a model that initially included LAS booster but not the other LAS parameters. In Kaplan-Meier analysis, all three LAS parameters were significantly associated with the composite outcome (p < .001). CONCLUSION. In this multicenter study, LAS reservoir and LAS conduit were significant independent prognostic markers in patients with ischemic or nonischemic DCM, showing greater prognostic utility than the currently applied markers of LVGLS and LGE. CLINICAL IMPACT. FT-derived LAS analysis provides incremental prognostic information in patients with DCM.