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Long-term use of low-dose aspirin for cancer prevention: A 20-year longitudinal cohort study of 1,506,525 Hong Kong residents.

Long-term use of low-dose aspirin has been demonstrated to reduce cancer risk, but the duration of necessary medication use remains uncertain. This study aimed to investigate the long-term chemoprotective effect of aspirin among the Chinese population. This population-based study included all aspirin users between 2000 and 2019. Aspirin users were age-sex matched with non-users at a 1:2 ratio. Cancer incidence and mortality were the main outcomes measured. Survival analyses with the Fine-Gray modelling were performed. The chemoprotective effects were measured by the sub-distribution hazard ratios (SHR) with control for the competing risks. A total of 538,147 aspirin users and 968,378 non-users were included, with a mean age of 64.8 years, 9,543,399 person-years of follow-up and 90% of users with 80 mg aspirin. The long-term use of aspirin was associated with a reduced risk of cancer (SHR 0.92, 95% CI 0.91-0.94) and a reduced risk of cancer mortality (SHR 0.80, 95% CI 0.79-0.82). Stronger chemopreventive effects were observed among those who used aspirin for more than 10 years, including risk reductions for lung (SHR 0.56, 95% CI 0.51-0.60), breast (SHR 0.34, 95% CI 0.29-0.38) and colorectal (SHR 0.37, 95% CI 0.33-0.40) cancers, but not for bladder cancer and leukaemia. Low-dose use of aspirin was associated with lower risk of cancer among Chinese. The association was even stronger for those using aspirin for more than 10 years. Prescription of aspirin may be started as early as at age of 40, as the chemoprotective effect also applied for early cancers.

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Prevalence, Behaviors, and Factors of Over-the-counter Aspirin Use in Hong Kong

Introduction: Aspirin can be used for cardiovascular disease prevention and analgesic use. Prevalence of over-the-counter (OTC) aspirin use remained unknown in Hong Kong. The study aimed to examine the prevalence of OTC aspirin use, participants health literacy level, and factors for OTC aspirin use in Hong Kong. Methods: This cross-sectional survey study was conducted in two phases from August 2021 to March 2024. Participants were recruited through inperson and online questionnaire distribution with convenient and snowball sampling. Health literacy was assessed using 12-item short-form health literacy instrument (HLS-SF12). Factors for OTC aspirin use were determined by multivariate logistic regression. Results: A total number of 1,215 participants were included in the study. The mean age was 63.2, whereas the majority (74.7%) were female. A total of 16.2% of respondents reported OTC aspirin use. The age-standardized prevalence of OTC aspirin use was 17.1% (95% confidence interval 15.1-19.3). The prevalence of OTC aspirin use was higher in participants who were ever prescribed aspirin (age-standardized prevalence 27.3% vs. 11.6%). Most users reported OTC aspirin use for symptomatic relief. Only half of the respondents (50.8%) reported knowledge of aspirin side effects, whereas most respondents (56.9%) obtained information on aspirin from their family members or friends. Higher health literacy level in health promotion was less likely to use OTC aspirin. Conclusion: Given the suboptimal rate of knowledge on medication side effects and major sources of information from family or friends, health literacy should be improved to ensure safe medication use in the Hong Kong population.

Dynamic Changes in ELF Score Predict Hepatocellular Carcinoma in Chronic Hepatitis B Patients Receiving Antiviral Treatment.

Enhanced liver fibrosis (ELF) score is a noninvasive assessment for liver fibrosis. We aimed to evaluate the performance of changes in ELF score 3 years apart in combination with liver stiffness measurement (LSM)-hepatocellular carcinoma (HCC) score to predict HCC in chronic hepatitis B (CHB) patients. This is a prospective cohort study. Patients who underwent transient elastography (TE) examinations and at intermediate or high risk of HCC defined by LSM-HCC score were invited to repeat the examination about 3 years later. Their serum samples at these two time points were retrieved to assess the ELF score changes. The primary endpoint was HCC. There were 445 CHB patients (males: 73.9%; mean age: 51.6 ± 10.3 years) who received two TE examinations and ELF scores. Among them, 252 (56.6%) and 193 (43.4%) patients were at intermediate and high HCC risk at first assessment defined by LSM-HCC score, respectively. Kaplan-Meier analysis showed that the changes in ELF score could stratify the HCC risk in both intermediate- and high-risk patients defined by LSM-HCC score (p  20%). Consistent findings were demonstrated in patients at both intermediate and high risk of HCC defined by LSM-HCC score. Dynamic changes in ELF score provided additional value to LSM-HCC score for stratifying HCC risk in CHB patients.

The Western and Chinese exercise training for blood pressure reduction among hypertensive patients: An overview of systematic reviews.

Hypertension remains the world's leading cause of premature death. Interventions such as exercise, diet modification, and pharmacological therapy remain the mainstay of hypertension treatment. Numerous systematic reviews and meta-analyses demonstrated the effectiveness of western exercises, such as aerobic exercise and resistance exercise, in reducing blood pressure in hypertensive patients. There is recently emerging evidence of blood pressure reduction with Chinese exercises, such as Tai Chi, Baduanjin, and Qigong. The current overview of systematic reviews aims to evaluate the quality and descriptively summarize the evidence for the effectiveness of western and Chinese exercises for hypertension management. Thirty-nine systematic reviews were included in this overview, with 15 of those being on Chinese exercise. Evidence suggests that exercise training, regardless of Western or Chinese exercise, generally reduced both systolic and diastolic blood pressure. High-intensity intermittent training did not further reduce blood pressure when compared to moderate-intensity continuous training. Conflicting results on the effectiveness of blood pressure reduction when comparing Chinese and Western exercise training were observed. This suggests the comparable effectiveness of Chinese exercise training, in particularly Tai Chi, to general or aerobic exercise training in terms of blood pressure reduction. The Chinese exercise modality and intensity may be more suitable for the middle-aged and elderly population.

Drug-drug interactions between direct-acting antivirals and co-medications: a territory-wide cohort study.

BackgroundThe increasing number of direct-acting antiviral (DAA) regimens along with limited number of subjects and co-medications involved in clinical trials results in drug-drug interactions (DDIs) with DAAs is to be determined. We aimed to examine the prevalence and degree of DDIs between DAAs and other co-medications in a territory-wide cohort of chronic hepatitis C virus (HCV) patients.MethodsDDIs were assigned to three risk categories: Category 1-no clinically significant DDI; category 2-potential clinically significant interaction (monitoring and caution required); category 3-contraindicated (should not be co-administered).ResultsOf 2981 patients (mean age 59.3 ± 12.3 years; male 60.6%), 810 (48.8%) had genotype 1 and 552 (33.2%) genotype 6 HCV among the 1661 patients with HCV genotype tested; 769 (25.8%) received sofosbuvir/velpatasvir, 510 (17.1%) sofosbuvir/ledipasvir, and 865 (29.0%) glecaprevir/pibrentasvir. More than one-fourth (26.3%) of the patients have polypharmacy (≥ 3 co-medications) in all patients, 27.0% in patients received sofosbuvir/velpatasvir, 25.1% in elbasvir/grazoprevir, and 21.2% in glecaprevir/pibrentasvir. 2037 (68.3%) patient experienced DDI (Category 2: 53.1%; Category 3: 15.2%). The commonest drugs leading to DDIs were calcium channel blockers (31.5%) and proton pump inhibitors (23.0%) in category 2; statins (10.2%), antiplatelet/anticoagulants (3.0%) and antipsychotics (2.9%) in category 3. Changing medication was the most common response from physicians in both category 2 and 3 DDIs.ConclusionThe commonest co-medications leading to contraindication during DAA treatment were statins and antipsychotics. Category 2 and 3 DDIs are often managed by appropriate dose adjustments or temporary discontinuation of relevant co-medications. Careful assessment for potential DDI before DAA use is mandatory to avoid potential harmful effects.

Tenofovir alafenamide is associated with improved alanine aminotransferase and renal safety compared to tenofovir disoproxil fumarate.

Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir for the treatment of chronic hepatitis B (CHB) infection. We aimed to evaluate the impact of switching to TAF on alanine aminotransferase (ALT) normalization and renal safety. We also described the indications of switching to TAF. Consecutive adult CHB patients switched from tenofovir disoproxil fumarate (TDF) dominant therapy to TAF for more than 12 months were identified retrospectively. A subgroup of patients newly switched to TAF was prospectively invited to perform transient elastography examination and dual-energy X-ray absorptiometry. The time of switching to TAF was defined as baseline. Among 393 patients in the retrospective cohort, the median ALT at month 12 was significantly lower (21.0 [16.0-29.9] U/L vs. 25.0 [19.0-34.0] U/L; p 2 vs. 68.5 ± 21.5 ml/min/1.73 m2 vs. 69.2 ± 21.5 ml/min/1.73 m2 , p = 0.002 (-12 m vs. baseline), p = 0.004 (baseline vs. 12 m)). In the prospective cohort, 103 patients switched to TAF because of age > 60 years (63.1%), bone diseases (54.4%), and renal alteration (42.7%). TAF is associated with ALT improvement and better renal safety than TDF dominant therapy in CHB patients. Most CHB patients switched to TAF because of advanced age, followed by bone disease and renal alteration.

Rise and fall of lung cancers in relation to tobacco smoking and air pollution: A global trend analysis from 1990 to 2012

Lung cancer remains the leading cancer in incidence and mortality in both genders and most countries. Global cancer statistics show a declining trend of lung squamous cell carcinoma (LSCC) but an uprising trend of lung adenocarcinoma (LADC). The reasons behind their opposite trends are unclear. This study aims to analyze the global trends of LSCC and LADC during 1990–2012 in relation to tobacco consumption and air pollution. Results show a 1% decline of smoking prevalence of 7 years ago is associated with a 9% (95% confidence interval: 8%, 10%) drop in the LSCC incidence globally, whereas a 0.1 μg/m3 increment of BC of 7 years ago is associated with a 12% (9%, 16%) increase in LADC incidence globally. Association between BC and LSCC (or LADC) is more prominent in females, with a 14% (7%, 20%) increase in LSCC [or 14% (11%, 19%) increase in LADC] incidence for a 0.1 μg/m3 increment of BC of 8 (or 6) years ago. Associations vary with different genders across different continents. For instance, concentration of BC is positively associated with incidence of both LSCC and LADC in Europe and North America, whereas concentration of sulfate is positively associated with LSCC incidence in Europe and Oceania, and with LADC incidence in Asia, Oceania and South America. We conclude global decreasing LSCC incidence is associated with the reduced tobacco consumption, whereas the global increasing LADC incidence is likely associated with air pollution. Various particulate species have divergent effects on LADC incidence in different continents.

May Measurement Month 2017-2019: A Community-Wide Opportunistic Blood Pressure Screening Campaign in Hong Kong.

INTRODUCTION: Hypertension is a modifiable risk factor for multiple cardiovascular diseases. Early identification and intervention of new cases are crucial to improve patients' outcomes. May Measurement Month (MMM) is an annual global synchronised blood pressure (BP) screening campaign. Participants can have their BP measured at the screening sites. It may be a possible way to identify undiagnosed hypertensive patients in the population. METHODS: It was a cross-sectional study of BP among Hong Kong adults. Multiple screening sites were set in local community pharmacies and on the campus of the Chinese University of Hong Kong. Participants were asked to fill in a questionnaire regarding their demographics, medical history, and social history. Then, they took at least one BP reading using an automated sphygmomanometer after sitting at for 5 minutes. Up to three BP readings were taken and recorded for each participant, with one-minute intervals between readings. RESULTS: A total of 3224 adults participated in MMM between 2017 and 2019. The average BP among the 3224 participants was 139.8/75.5 mmHg. The prevalence of hypertension was 2282 (70.8%), of which 635 (27.8%) were undiagnosed before MMM. Among the 1647 participants previously diagnosed with hypertension, 1007 (61.1%) had uncontrolled hypertension. CONCLUSION: A high number of cases can be identified with untreated, or treated but uncontrolled, hypertension from MMM. Citizens should be encouraged to check BP regularly and take follow-up actions if hypertension is suspected.

Antihypertensive treatments and risks of lung Cancer: a large population-based cohort study in Hong Kong.

BackgroundThere is a growing concern that the use of anti-hypertensives may be associated with an increased risk of cancer, but it remains uncertain for the association between anti-hypertensives and lung cancer risk, as well as their interaction with aspirin in chemoprotective effects.MethodsThe goal of this study is to assess the association between anti-hypertensives use and the risk of lung cancer, as well as the chemopreventive impacts from the combination usage of aspirin and anti-hypertensives. A retrospective cohort study was conducted based on all the public hospital electronic medical records in Hong Kong. Patients with prescription records of anti-hypertensives (ACEi/ARB, CCB, β-blocker,α-blocker) and/or aspirin were included as the exposure groups. Using the Cox proportional hazards model with inverse probability weighting, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for lung cancer risk from anti-hypertensives usage or combination usage of aspirin with anti-hypertensives. The likelihood ratio test and interaction model were adopted for exploring the interaction effects with aspirin.ResultsA total of 6592 and 84,116 lung cancer cases were identified from the groups of anti-hypertensives users and anti-hypertensives users with aspirin, respectively. The group of non-aspirin patients who received anti-hypertensives showed a significantly lower risk of lung cancer (HR: 0.63, 95% CI: 0.60-0.66), compared to those without anti-hypertensives. When aspirin and α-blocker were used simultaneously, it could lower the risk of lung cancer significantly (HR: 0.53, 95% CI: 0.34-0.84). Moreover, the lower risk of lung cancer persisted with a longer follow-up period of anti-hypertensives usage. Combination usage with aspirin in the users of ACEi/ARB, CCB, and α-blocker showed significant interaction effects. However, the smoking effect could not be eliminated in this analysis.DiscussionAnti-hypertensive treatment was associated with a lower risk of lung cancer, which is associated with the anti-hypertensives exposure period. The potential interaction on the chemopreventive influence from combination usage of α-blocker and aspirin might exist. More corroborations on these findings are needed to focus on the different settings in future studies.

Efficacy and safety comparing prasugrel/ticagrelor and clopidogrel in Hong Kong post-acute coronary syndrome patients-A 10-year cohort study.

BACKGROUND: Clinical evidence of prasugrel/ticagrelor in dual antiplatelet therapy (DAPT) in Asian acute coronary syndrome (ACS) population remains inconclusive. We aimed to compare the clinical efficacy and safety of prasugrel/ticagrelor compared to clopidogrel as part of DAPT in Hong Kong ACS population for 10 years. HYPOTHESIS: Prasugrel/ticagrelor, compared to clopidogrel, reduces risk of major adverse cardiovascular event (MACE) in Hong Kong ACS population. METHODS: The retrospective observational cohort study included patients admitted to seven institutions under Hospital Authority Hong Kong with diagnosis of ACS during 2008-2017. Risk of MACE, defined as composite of cardiovascular (CV) death, non-fatal myocardial infarction (MI) and non-fatal stroke, and risk of any bleeding leading to hospitalization were examined. Baseline characteristics difference was adjusted by propensity score (PS) matching. Adjusted Cox regression model was used to estimate hazard ratio of interested outcome. RESULTS: In PS matched cohort including 944 patients in each group, MACE risk reduction of 40% from 1 year to 5 years after index ACS event was observed in prasugrel/ticagrelor group (HR 0.60, 95% CI 0.39-0.91, p = .015). The risk reduction was highly driven by MI reduction (HR 0.54, 95% CI 0.33-0.91, p = .019). Lower bleeding risk was observed in prasugrel/ticagrelor group compared to clopidogrel from 1 year to 5 years (HR 0.46, 95% CI 0.21-1.00, p = .051). CONCLUSIONS: Prasugrel/ticagrelor showed MACE risk reduction over clopidogrel as part of DAPT up to 5 years after index event, while prasugrel/ticagrelor was not associated with increased bleeding risk.

Tryptophan and metabolites (serotonin and kynurenines) in posttraumatic stress disorder

It has become increasingly clear that trauma responses are defined less so by stressor-related factors and more so by individual-level factors, such as alterations in immune and inflammatory functioning. In this chapter, we begin with a summary and review of the prevalence, diagnostic characterization, and neurobiological etiology of Posttraumatic Stress Disorder (PTSD), presenting theory and research that describe the neuro-endocrinological, neurochemical, and neuroanatomical basis for PTSD. We then present evidence detailing the modulating and mediating roles of tryptophan derivatives (kynurenic acid, quinolinic acid, serotonin and melatonin) on the pathophysiology of disordered neurobiological and neuroinflammatory responses to fear/anxiety. Finally, we discuss both pharmacologic and non-pharmacologic therapeutic approaches that may be used in the treatment of PTSD.

Use of metformin and aspirin is associated with delayed cancer incidence.

BackgroundWhile the chemoprevention effect of aspirin is well-established, the effects of metformin in cancer prevention is still controversial. This study is to investigate the use of aspirin, metformin, or the combination of both is associated with delayed cancer incidence.MethodThis dataset is based on the electronic medical record of public hospitals in Hong Kong. Patients were classified into 1. aspirin user, 2. metformin user, 3. both aspirin and metformin user and 4. control group with neither aspirin nor metformin used. Aspirin and/or metformin must have been taken for over 6 months in the treatment group and cancer incidences was counted at least 6 months after exposure to such medications. The primary outcome of this study was overall incidence of cancer during the follow-up period. The secondary outcomes were cancer incidences of specific sites, including colon/rectum, liver, oesophagus, pancreas, stomach, lung, breast, kidney, bladder and prostate. Cox proportional hazards regression models were fitted to estimate hazard ratios of cancer risks. Inverse probability of treatment weighting was used to control for the medication effects.ResultsA total of 120,971 aspirin users, 11,365 metformin users, and 6630 aspirin plus metformin users, were identified. Compare to the control groups, those who used aspirin alone demonstrated a significant reduction in overall cancer risk (HR 0.80, 95% CI 0.73-0.87). Similarly, those who used metformin alone also showed an overall reduction in cancer risk (HR 0.79, 95% CI 0.71-0.88). Patients who received both aspirin and metformin showed the most significant reduction in overall cancer risk (HR 0.53, 95% CI 0.45-0.63). Metformin showed a significant reduction in cancer risk of lung, oesophagus and bladder.ConclusionThere is a similar decrease in overall cancer rate with the use of aspirin or metformin alone. A more significant reduction in overall cancer risk was found with the use of both agents.

Trends of prescribing adherence of antiplatelet agents in Hong Kong patients with acute coronary syndrome: a 10-year retrospective observational cohort study.

OBJECTIVES: The objective of this study is to examine the temporal trend of antiplatelet prescribing pattern during index hospitalisation discharge in Hong Kong (HK) acute coronary syndrome (ACS) population. DESIGN: The study is a retrospective observational cohort study. SETTING: The study retrieved data from electronic health record from Hospital Authority (HA), HK. PARTICIPANTS: The study included patients aged 18 years old or above, who were admitted to seven institutions under HA with diagnosis of ACS during 2008-2017. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the frequency of antiplatelet therapy prescription at the point of index hospitalisation discharge each year during 2008-2017. Association between demographics, baseline comorbidities, procedures and antiplatelet prescription were examined as secondary outcome using multivariate logistic regression model, with commonly used antiplatelet groups selected for comparison. RESULTS: Among the included 14 716 patients, 5888 (40.0%) discharged with aspirin alone, 6888 (46.8%) discharged with dual antiplatelet therapy (DAPT) with clopidogrel, and 973 (6.6%) discharged with DAPT with prasugrel/ticagrelor. Prescribing rate of aspirin alone decreased substantially from 56.8% in 2008 to 27.5% in 2017. Utilisation of DAPT with clopidogrel increased from 33.7% in 2008 to 52.7% in 2017. Use of DAPT with prasugrel/ticagrelor increased from 0.3% in 2010 to 15.3% in 2017. Compared with those prescribed with DAPT with clopidogrel, male patients (adjusted OR (aOR) 1.34, 95% CI 1.09 to 1.65), patients with non-ST-elevation myocardial infarction (aOR 2.50, 1.98 to 3.16) or ST-elevation myocardial infarction (aOR 3.26, 2.59 to 4.09), use of glycoprotein IIb/IIIa (aOR 3.03, 2.48 to 3.68) or undergoing percutaneous coronary intervention (aOR 3.85, 3.24 to 4.58) or coronary artery bypass graft (aOR 6.52, 4.63 to 9.18) during index hospitalisation, concurrent use of histamine-2 receptor antagonists (aOR 1.35, 1.10 to 1.65) or proton pump inhibitors (aOR 3.57, 2.93 to 4.36) during index hospitalisation discharge were more likely to be prescribed with DAPT with prasugrel/ticagrelor. Patients with older age (aOR 0.97, 0.96 to 0.97), diabetes (aOR 0.68, 0.52 to 0.88), chronic kidney disease (aOR 0.43, 0.22 to 0.85) or concurrent use of oral anticoagulant (aOR 0.16, 0.07 to 0.42) were more likely to received DAPT with clopidogrel. CONCLUSIONS: Use of DAPT with prasugrel/ticagrelor was suboptimal yet improving during 2008-2017 in HK patients with ACS. Considering DAPT, predictors for clopidogrel prescription, compared with prasugrel/ticagrelor, were consistent with identified risk factors of bleeding.

Warfarin control in Hong Kong clinical practice: a single-centre observational study.

IntroductionTime in therapeutic range (TTR) assesses the safety and effectiveness of warfarin therapy using the international normalised ratio. This study investigated the TTR in Hong Kong patients using both European and Japanese therapeutic ranges and patients' economic and clinical outcomes. Predictors of poor warfarin control and patient knowledge concerning warfarin therapy were assessed.MethodsA 5-month observational study with retrospective and prospective components was conducted in the Prince of Wales Hospital. The study examined electronic patient records of patients who received warfarin for at least 1 year during the period from January 2010 to August 2015. Patient knowledge was assessed via phone interview using the Oral Anticoagulation Knowledge (OAK) test.ResultsIn total, 259 patients were included; 174 completed the OAK test. The calculated mean TTR was 40.2±17.1% (European therapeutic range), compared with 49.1±16.1% (Japanese therapeutic range) [P<0.001]. Mean TTR was higher in patients with atrial fibrillation than in patients with prosthetic heart valve (P<0.001). The abilities of TTR to predict clinical and economic outcomes were comparable between European and Japanese therapeutic ranges. Patients with ideal TTR had fewer clinical complications and lower healthcare costs. Patients with younger age exhibited worse TTR, as did those with concurrent use of furosemide, famotidine, or simvastatin. Mean OAK test score was 54.1%. Only 24 (13.8%) patients achieved a satisfactory overall score of ≥75% in the test.ConclusionWarfarin use in Hong Kong patients was poorly controlled, regardless of indication. Patient knowledge concerning warfarin use was suboptimal; thus, additional patient education is warranted regarding warfarin.

Branded versus generic drug use in chronic disease management in Hong Kong-perspectives of health care professionals and the general public.

IntroductionThe aim of the present study was to evaluate the understanding of generic substitution among health care professionals and members of the general public ("general public") in Hong Kong.MethodsThis cross-sectional descriptive study was performed by using a self-completed anonymous questionnaire from March 2015 to May 2017. The questionnaire included demographic data, knowledge of generic drugs, experiences of generic substitution, and views on policy.ResultsA total of 2106 general public, 73 doctors, 22 nurses, and 50 pharmacists responded the questionnaire. In all, 41.2% of the general public was aware that generic drugs have the same active ingredients. Although a majority of the health care professionals knew that generic drugs have the same active ingredients (doctors: 79.5%; nurses: 86.4%; pharmacists: 98.0%), many were unaware of bioequivalence (doctors: 37.0%; nurses: 18.2%; pharmacists: 50.0%). "Efficacy" was ranked as the primary concern among all groups; a substantial portion of respondents reported experiencing adverse drug reactions upon generic substitution (general public: 26.6%; doctors: 23.3%; nurses: 9.1%; pharmacists: 42.0%). At least half of the general public, nurses, and pharmacists considered that patients should be given a choice for generic substitution. However, fewer than one-fifth of doctors and nurses and approximately one-third of pharmacists considered that patient consent was needed prior to generic substitution, compared with approximately two-thirds of the general public.ConclusionThe knowledge and perception of generic substitution remains low, both in the general public and among health care professionals. This knowledge deficit could potentially lead to different perspectives among stakeholders regarding generic substitution.

A platinum-based hybrid drug design approach to circumvent acquired resistance to molecular targeted tyrosine kinase inhibitors.

Three molecular targeted tyrosine kinase inhibitors (TKI) were conjugated to classical platinum-based drugs with an aim to circumvent TKI resistance, predominately mediated by the emergence of secondary mutations on oncogenic kinases. The hybrids were found to maintain specificity towards the same oncogenic kinases as the original TKI. Importantly, they are remarkably less affected by TKI resistance, presumably due to their unique structure and the observed dual mechanism of anticancer activity (kinase inhibition and DNA damage). The study is also the first to report the application of a hybrid drug approach to switch TKIs from being efflux transporter substrates into non-substrates. TKIs cannot penetrate into the brain for treating metastases because of efflux transporters at the blood brain barrier. The hybrids were found to escape drug efflux and they accumulate more than the original TKI in the brain in BALB/c mice. Further development of the hybrid compounds is warranted.

Interaction between digoxin and dronedarone in the PALLAS trial.

BackgroundElevated serum digoxin concentration can cause toxicity, including death. Dronedarone increases digoxin concentration by P-glycoprotein interaction. In Permanent Atrial Fibrillation Outcome Study Using Dronedarone On Top Of Standard Therapy Trial (PALLAS), dronedarone was associated with both increased cardiovascular death and heart failure in patients with permanent atrial fibrillation. The present analysis examines whether the dronedarone-digoxin interaction might explain these adverse outcomes.Methods and resultsSubgroup analysis was performed to compare outcomes of patients on digoxin at baseline or not. In PALLAS, 1619 patients were randomized to dronedarone and 1617 to placebo, of whom 544 (33.6%) and 526 (32.5%) were receiving digoxin, respectively. Median (Q1,Q3) digoxin serum concentration on day 7 was 1.1 (0.7,1.5) ng/mL on dronedarone and 0.7 (0.5,1.1) ng/mL on placebo (P<0.001). Among patients on digoxin, there were 15 (8.6%/year) cardiovascular deaths on dronedarone and 2 (1.2%/year) on placebo (adjusted hazard ratio, 7.31; 95% confidence interval, 1.66-32.20; P=0.009). Among patients not on digoxin, there were 6 cardiovascular deaths on dronedarone (1.7%/year) and 8 on placebo (2.2%/year; adjusted hazard ratio, 0.67; 95% confidence interval, 0.23-1.95; P=0.46; interaction P value 0.01). In patients on digoxin, there were 11 arrhythmic deaths on dronedarone and none on placebo; and in patients not on digoxin, there were 2 arrhythmic deaths on dronedarone and 4 on placebo (P value for interaction 0.002). There was no interaction between baseline digoxin use and the adverse effect of dronedarone on heart failure events.ConclusionsIn PALLAS, there was a strong effect of concurrent digoxin use on the adverse effect of dronedarone on cardiovascular death, but not on occurrence of heart failure.Clinical trial registrationhttp://www.clinicaltrials.gov. Unique identifier: NCT01151137.

Effect of clopidogrel added to aspirin in patients with atrial fibrillation.

BackgroundVitamin K antagonists reduce the risk of stroke in patients with atrial fibrillation but are considered unsuitable in many patients, who usually receive aspirin instead. We investigated the hypothesis that the addition of clopidogrel to aspirin would reduce the risk of vascular events in patients with atrial fibrillation.MethodsA total of 7554 patients with atrial fibrillation who had an increased risk of stroke and for whom vitamin K-antagonist therapy was unsuitable were randomly assigned to receive clopidogrel (75 mg) or placebo, once daily, in addition to aspirin. The primary outcome was the composite of stroke, myocardial infarction, non-central nervous system systemic embolism, or death from vascular causes.ResultsAt a median of 3.6 years of follow-up, major vascular events had occurred in 832 patients receiving clopidogrel (6.8% per year) and in 924 patients receiving placebo (7.6% per year) (relative risk with clopidogrel, 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.01). The difference was primarily due to a reduction in the rate of stroke with clopidogrel. Stroke occurred in 296 patients receiving clopidogrel (2.4% per year) and 408 patients receiving placebo (3.3% per year) (relative risk, 0.72; 95% CI, 0.62 to 0.83; P<0.001). Myocardial infarction occurred in 90 patients receiving clopidogrel (0.7% per year) and in 115 receiving placebo (0.9% per year) (relative risk, 0.78; 95% CI, 0.59 to 1.03; P=0.08). Major bleeding occurred in 251 patients receiving clopidogrel (2.0% per year) and in 162 patients receiving placebo (1.3% per year) (relative risk, 1.57; 95% CI, 1.29 to 1.92; P<0.001).ConclusionsIn patients with atrial fibrillation for whom vitamin K-antagonist therapy was unsuitable, the addition of clopidogrel to aspirin reduced the risk of major vascular events, especially stroke, and increased the risk of major hemorrhage. (ClinicalTrials.gov number, NCT00249873.)

Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

IMPORTANCE: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive. OBJECTIVE: To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONS: The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURES: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events. RESULTS: Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11 secondary outcomes. Serious adverse events were reported in 3.0% (32/1075) of participants in the convalescent plasma group and in 1.3% (12/905) of participants in the no convalescent plasma group. CONCLUSIONS AND RELEVANCE: Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support-free days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.