963 research outputs found
A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome
No full textFull author list omitted for brevity. For full list of authors see article.BACKGROUND: Endocrine-cerebro-osteodysplasia (ECO) syndrome [MIM:612651] caused by a recessive mutation (p.R272Q) in Intestinal cell kinase (ICK) shows significant clinical overlap with ciliary disorders. Similarities are strongest between ECO syndrome, the Majewski and Mohr-Majewski short-rib thoracic dysplasia (SRTD) with polydactyly syndromes, and hydrolethalus syndrome. In this study, we present a novel homozygous ICK mutation in a fetus with ECO syndrome and compare the effect of this mutation with the previously reported ICK variant on ciliogenesis and cilium morphology. RESULTS: Through homozygosity mapping and whole-exome sequencing, we identified a second variant (c.358G > T; p.G120C) in ICK in a Turkish fetus presenting with ECO syndrome. In vitro studies of wild-type and mutant mRFP-ICK (p.G120C and p.R272Q) revealed that, in contrast to the wild-type protein that localizes along the ciliary axoneme and/or is present in the ciliary base, mutant proteins rather enrich in the ciliary tip. In addition, immunocytochemistry revealed a decreased number of cilia in ICK p.R272Q-affected cells. CONCLUSIONS: Through identification of a novel ICK mutation, we confirm that disruption of ICK causes ECO syndrome, which clinically overlaps with the spectrum of ciliopathies. Expression of ICK-mutated proteins result in an abnormal ciliary localization compared to wild-type protein. Primary fibroblasts derived from an individual with ECO syndrome display ciliogenesis defects. In aggregate, our findings are consistent with recent reports that show that ICK regulates ciliary biology in vitro and in mice, confirming that ECO syndrome is a severe ciliopathy
Drug-related problems (DRPs) in emergency department (ED) visits and the impact of the pharmacist-initiated analgesia pathway (PIAP) intervention for adult patients of a teaching hospital of Hong Kong
No full textDrug-Related Problems (DRPs) are substantial causes of hospital admissions to the Emergency Department (ED). It is estimated that approximately 5 to 35% of hospital admissions are due to DRPs. However, little is known about the incidence, preventability and severity of DRPs resulting in ED visits in Hong Kong. Besides, delayed administration of analgesia is another DRP due to the overcrowding in EDs. Literature reviews have shown that advanced trained pharmacists may support the clinical workload of ED, especially in pain management. Hence, we sought to evaluate the incidence, severity, preventability and types of drug-related visits to ED as well as the impact of pharmacist in acute pain management through multidisciplinary model in the setting of Hong Kong.
There are two chapters of this study. For chapter one, a retrospective, observational study was performed by reviewing the electronic patient records of 2,000 samples in a teaching hospital of Hong Kong over eight-month period. An emergency physician and a pharmacist were responsible for assessing and classifying all cases. For chapter two, we undertook a pre-intervention trial (September-October 2016) and post-intervention trial (November-
December 2016) in the ED of the Queen Mary Hospital (QMH). The intervention comprised development and implementation of a comprehensive Pharmacist-Initiated Analgesia Pathway (PIAP), in which the pharmacist was authorized to assess and administer paracetamol to eligible patients prior to doctors’ consultations. The primary outcome was patient satisfaction towards ED pain management during their stays in the department. Secondary outcomes were time to analgesia and the reductions in the pain scores at different time points after the dosing of paracetamol.
We included 1,849 cases (mean age, 65.9 years; female 57.6%). Of these, 127 cases (6.9%; 95% Cl 5.74-7.28%) were deemed drug-related. 57 cases of these 127 cases (44.9%; 95% Cl 36.25-53.55%) were considered preventable. Severity was classified as mild in 19 cases (15.0%; 95% Cl 8.8-21.2%), moderate in 98 cases (77.2%; 95% Cl 69.9-84.5%) and severe in 6 cases (4.7%; 95% CI 1.03-8.41%). The most common reasons of DRP ED visits were ADRs and nonadherence, whereas the most common inflicting medications were anti-diabetics (21.2%) and cardiovascular agents (44.9%). For chapter two, 55 patients were enrolled in both the pre- and post-intervention periods. Patient sex, mean age and triage pain score did not differ significantly between the groups (p > 0.05). At post-intervention, the proportion of parents who was satisfied or very satisfied with their overall pain management trended upwards was 88.9% vs. 52.8% at pre-intervention periods (p<0.05). The median time to analgesia was significantly reduced (33 min vs 173 min; p < 0.001).
A significant portion of ED visits (about 7 in 100 ED visits) was attributed to DRPs of which most 44.9% were preventable. The PIAP significantly reduced waiting the lag time to analgesia, which was also associated with higher levels of patient satisfaction. Strategies should be provided to minimize the occurrence of preventable DRPs and pharmacists may enhance the pain management in the ED in Hong Kong.published_or_final_versionPharmacology and PharmacyMasterMaster of Philosoph
Real-world evidence of the incidence of endocrine-related disorders following COVID-19 vaccination and SARS-CoV-2 infection
No full textThe coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has highlighted the urgent need for the rollout of vaccination programme to reduce virus transmission and alleviate disease severity. Although COVID-19 vaccinations have proven effective against infection, hospitalisation and severe diseases, concerns have emerged regarding the incidence of adverse events, including endocrine-related disorders following vaccination. Moreover, the expression of angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor, has been discovered in the endocrine system, raising concerns about developing endocrine-related disorders following SARS-CoV-2 infection. Population-based epidemiological studies are imperative for evaluating the safety of COVID-19 vaccines, understanding the impact of SARS-CoV-2 infection, and formulating the benefit-risk profile of COVID-19 vaccines in relation to endocrine health.
To address these knowledge gaps, COVID-19 vaccination and infection records from the Department of Health (DH) and electronic medical records (EMRs) from the Hong Kong Hospital Authority (HA) were used to investigate the incidence of endocrine-related disorders, focusing mainly on diabetes mellitus, thyroid dysfunction, and major osteoporosis fracture, following COVID-19 vaccination and SARS-CoV-2 infection.
The first study evaluated the risk of new-onset diabetes following COVID-19 vaccination and SARS-CoV-2 infection, employing a cohort study design. The findings indicated an increased risk of incident diabetes following SARS-CoV-2 infection (Hazard Ratio [HR]=1.23, P < 0.001), even with the prevailing Omicron variants, albeit at a lower risk. No increase in the risk of incident diabetes was observed following COVID-19 vaccination. Instead, fully vaccinated individuals might suppress the risk of incident diabetes following SARS-CoV-2 infection. The second study assessed the risk of thyroid dysfunction in individuals vaccinated with BNT162b2 or CoronaVac. Thyroid dysfunction includes the initiation of anti-thyroid drugs or levothyroxine, hyperthyroidism, hypothyroidism, Graves' disease, and thyroiditis. Using a self-controlled case series (SCCS) design, this study found no elevated risk of thyroid dysfunction during the post-vaccination period, indicating the safety of COVID-19 vaccines for thyroid health. The third study explored the risk of incident thyroid dysfunction in the post-acute phase (the period beyond 30 days after the first positive COVID-19 test) of COVID-19. This population-based cohort study provided important reassuring data that COVID-19 is unlikely to be associated with persistent effects on thyroid function. The fourth study investigated the incidence of major osteoporotic fractures following SARS-CoV-2 infection in individuals aged 50 and older. This study found an increased risk of major osteoporotic fractures (HR=1.22, P < 0.001) and falls (HR=1.28, P < 0.001) that persisted after infection and in the following months, underscoring the lasting impact of COVID-19 on bone health in older adults.
This thesis provides real-world evidence that COVID-19 vaccines do not increase the risk of major endocrine-related disorders, supporting the safety profile of BNT162b2 or CoronaVac vaccines. Furthermore, our findings emphasize the critical role of getting fully vaccinated in protecting against incident diabetes following SARS-CoV-2 infection. Along with the noted increased risk of incident major osteoporotic fractures after SARS-CoV-2 infection, future surveillance studies are essential to ascertain the long-term risk of endocrine-related disorders following infection.published_or_final_versionPharmacology and PharmacyDoctoralDoctor of Philosoph
Use and safety of medications associated with peptic ulcer disease and gastrointestinal bleeding
No full textAsian population are shown to be associated with higher risks of peptic ulcer disease (PUD) and/or gastrointestinal bleeding (GIB). As the decrease of Helicobacter Pylori infection led to a decline of the prevalence of PUD/GIB worldwide, medication use became a crucial superimposing factor for PUD/GIB. To date, the research findings are still unclear or inconclusive on the association of calcium channel blockers (CCBs) and non-vitamin K antagonists (NOACs) with PUD/GIB, or the role of gastroprotective agents (GPAs) in the prophylaxis of medication-associated PUD/GIB. This thesis contains four parts of pharmacoepidemiological studies and aims to assess the risk of PUD/GIB associated with the aforementioned medication use, and to investigate the prophylactic role of GPAs including histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs).
First, we conducted a meta-analysis using Review Manager to investigate the association between CCB use and the risk of GIB. The meta-analysis, including four randomized controlled trials (RCTs) and thirteen observational studies, suggested a modest association with a relative risk (RR) of 1.17 (95%CI 1.01-1.36). However, this is of weak clinical significance as results from neither RCTs nor subgroup analyses supported this association.
Unlike CCBs, nonsteroidal anti-inflammatory drugs (NSAIDs) are known to be the most common risk factor for PUD/GIB. To investigate the dosage effect of H2RAs in preventing NSAID-associated PUD, we conducted a population-based retrospective cohort study using the Clinical Data Analysis and Reporting System (CDARS) database on adult patients (≥ 18 years) in Hong Kong between 2009 and 2012. Among the 102 042 NSAID users, 76% were on low-dose H2RA and 24% were on high-dose, and the RR of PUD was 0.32 (95%CI 0.13-0.79) in high-dose compared to low-dose.
Besides NSAIDs, NOACs are another class of well-known medications potentially increasing GIB risk. The up-to-date meta-analysis of observational studies in the third part of this thesis suggested that dabigatran was associated with a modest increased risk of GIB as compared to warfarin (RR1.21, 95%CI 1.05-1.39). Lastly, our CDARS-based retrospective cohort study showed that among the 5041 new users of dabigatran from 2010-2013, 124 (2.5%) developed GIB during follow-up (4.2/100 patient-years). Aged ≥75 year (IRR, incident rate ratio 2.47, 95%CI 1.66–3.68), history of PUD/GIB (IRR 2.31, 95%CI 1.54–3.46), and concomitant use of aspirin (IRR1.52, 95%CI 1.03–2.24) were risk factors for GIB. Concomitant use of H2RAs/PPIs reduced the risk of GIB significantly (IRR, 0.52; 95% CI, 0.35–0.77).
In summary, our study found that CCB is unlikely to be associated with GIB clinically and current practice should not be affected. It is important to ensure high-dose H2RA is prescribed as it showed greater effectiveness compared to low-dose for the prophylaxis of NSAID-induced PUD. Dabigatran should be used with caution and concurrent GPAs use should be encouraged, especially for patients at high risk of GIB. The heterogeneity between studies (especially observational studies) in the meta-analyses and the inherent limitations of CDARS as electronic medical database are the major limitations of this study.published_or_final_versionPharmacology and PharmacyDoctoralDoctor of Philosoph
Dementia in observational studies using electronic health records : opportunities and challenges with pharmacoepidemiology
No full textDementia is a global health challenge that currently affects more than 50 million people internationally with increasing prevalence. Evidence to support safe medication use in people living with dementia and therapies that may reduce the risk its development can help to facilitate healthy ageing and address the growing dementia burden.
Studies of dementia face challenges such as requiring a long period of follow-up due to the gradual nature of its development, a lack of consistent dementia diagnosis definitions, and potential confounding bias when making comparisons between different groups of older people with different degrees of frailty and disease states. Although randomised controlled trials are the gold standard of investigating the effectiveness of interventions, their interpretation in studies of dementia are limited due to their restricted study samples in terms of size, age, and follow-up time. Therefore, alternative study types that can circumvent the weaknesses of clinical trials, such as observational studies, are crucial in bridging the knowledge gap in dementia research.
The aim of the thesis is to investigate several topics surrounding safe medication use related to dementia and highlight opportunities and challenges in using observational study designs within this disease area. The data used in the studies included in this thesis were electronic health records extracted from the population-wide database managed by the Hong Kong Hospital Authority. Two of the studies were collaboration projects with the addition of electronic health records from the United Kingdom, Sweden, and Australia.
Observational studies applying pharmacoepidemiologic methods were conducted in populations of people with dementia or with dementia as an outcome, with COVID-19 vaccines and antihypertensive drugs being medicines of interest. Studies included were an analysis of COVID-19 vaccine adverse events in people with dementia, multinational studies on prescribing trends of antihypertensive drugs in people with dementia and the association of the use of different antihypertensive drug classes and the risk of incident dementia, and the application of high-dimensional propensity scores as a method to mitigate confounding bias.
The findings of these studies comprised of evidence supporting the safe use of COVID-19 vaccines in people with dementia, descriptions and analyses of antihypertensive prescribing practices, and head-to-head comparisons between the use of different antihypertensive drug classes and the risk of incident dementia. Angiotensin-II receptor blockers were found to have a reduced risk of incident dementia compared to angiotensin-converting enzyme inhibitors in a large, multinational cohort study setting with a relatively long follow-up of more than five years. The high-dimensional propensity score method was also successfully implemented using electronic health records in Hong Kong in a proof of concept study to improve confounding control between the antihypertensive class comparison groups in older people.
To build on the findings presented in this thesis, future studies are needed, such as studies aiming to elucidate the mechanisms of antihypertensives in dementia risk reduction, and advances in study methods to reliably evaluate the relationships between these medicines and dementia.published_or_final_versionPharmacology and PharmacyDoctoralDoctor of Philosoph
Real-world evidence of cardiovascular complications following COVID-19 vaccines
No full textThe vaccines were considered essential in lessening the severity of the disease and slowing the transmission of COVID-19 during the pandemic. Due to stringent enrolment requirements and a shorter follow-up, the safety evidence from randomised clinical trials of COVID-19 vaccines may not be sufficient, especially in the expedited programs. Therefore, it is important to conduct post-marketing safety surveillance with real-world data for a comprehensive understanding of vaccine safety profiles, especially for novel vaccines with mRNA platforms.
Cardiovascular diseases (CVD) have been identified as intriguing adverse complications due to the higher incidence observed after COVID-19 infection. Yet, safety evaluation on CVD events following COVID-19 vaccination remains limited. This thesis aims to estimate the relative risks of three CVD major complications, including thromboembolic events, haemorrhagic stroke, and carditis associated with the administration of mRNA (BNT162b2) and inactivated (CoronaVac) vaccines. Additionally, it compares the absolute risk of these events between the COVID-19 vaccines and infection.
This thesis utilised three real-world databases in Hong Kong to answer the above research questions: 1) electronic health records (EHR) for all government-subsidised public hospitals and clinics, 2) a database for the sole public mass COVID-19 vaccination program, and 3) a territory-wide COVID-19 infection recording system. The vaccine safety on CVDs was assessed using the Self-Controlled Case Series (SCCS) design. By facilitating within-individual comparison, this approach mitigates the influence of time-invariant confounding factors. However, the outcomes of interest in this thesis may violate the event-dependent exposure and event-dependent observation assumptions for a standard SCCS. To address this, a modified SCCS approach was adopted, and it identified a higher risk of haemorrhagic stroke and carditis following the BNT162b2 vaccine compared to referent windows. The CoronaVac vaccination does not carry a higher risk of these CVD complications. Importantly, the absolute risks following both vaccines were significantly lower than those observed after COVID-19 infection.
A further focus of the thesis is the younger population, which was found to have a higher risk of carditis following their second dose of BNT162b2. To address the above issue, the thesis explores the impact of an interval extending between the first and second doses of BNT162b2 on carditis risk and its effectiveness. Two nested case-control study designs were utilised, and it discovered that prolonging the BNT162b2 vaccine's interdose interval can lower the incidence of carditis in the younger while preserving protection against COVID-19 infections.
In summary, this thesis offers an in-depth analysis of the CVD safety profile of COVID-19 vaccinations in the Hong Kong population, including both the inactivated and mRNA platforms. Although a higher relative risk of CVD events was observed after mRNA vaccination, the absolute risk is lower after vaccination than infection. Adjusting the dosing schedule can help optimise the balance between safety and effectiveness among the younger. Besides, a modified SCCS is more appropriate for safety identification when assumption violations exist. This knowledge is vital for ensuring the safe and effective implementation of COVID-19 vaccination programs, ultimately contributing to the global efforts in combating the COVID-19 pandemic.published_or_final_versionPharmacology and PharmacyDoctoralDoctor of Philosoph
Real-world effectiveness of pharmacotherapies for the prevention of severe and fatal COVID-19
No full textCoronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was a global health emergency that led to significant morbidity and mortality. In early 2022, the emergence of the Omicron variant resulted in widespread outbreaks even in regions with prior success of controlling the pandemic, including Hong Kong where an unusually high COVID-19 fatality rate was observed at the time. This may be attributed to low vaccination coverage among older individuals and vaccine hesitancy.
Various pharmacotherapies to prevent severe and fatal illness from COVID-19 were developed, including vaccines (BNT162b2, CoronaVac), monoclonal antibodies for pre-exposure prophylaxis (tixagevimab-cilgavimab), and oral antivirals for preventing disease progression after infection (molnupiravir, nirmatrelvir-ritonavir). Knowledge gaps remained regarding their effectiveness against the Omicron variant and among patients encountered in real-world practice. Firstly, randomised trials of COVID-19 vaccines were mainly conducted before Omicron emerged among healthier populations. Considering immune evasion of the Omicron variant and higher prevalence of risk factors for severe COVID-19, further investigation into vaccine effectiveness during an Omicron outbreak among the general population and high-risk groups was needed. Secondly, immunocompromised individuals may have suboptimal response to COVID-19 vaccines and require additional therapies for prevention. Although tixagevimab-cilgavimab reduced symptomatic SARS-CoV-2 infection among unvaccinated adults before Omicron emerged, data among vaccinated, immunocompromised individuals during an Omicron outbreak was not available. Thirdly, although randomised trials showed efficacy of molnupiravir and nirmatrelvir-ritonavir in non-hospitalised patients for the treatment of COVID-19, data among vaccinated, hospitalised adults were limited. These unanswered questions could hinder the adoption of these pharmacotherapies in practice.
In this thesis, observational studies were conducted using electronic medical records databases in Hong Kong, to generate real-world evidence to address the aforementioned questions. The key findings were that: (i) BNT162b2 and CoronaVac were effective in reducing the risks of COVID-19-related hospitalisation, critical illness, and mortality during an Omicron BA.2 outbreak, and timely administration of a third dose could further reduce such risks despite a decline in vaccine effectiveness over time, (ii) tixagevimab-cilgavimab was effective in reducing the risk of SARS-CoV-2 infection among immunocompromised individuals during an Omicron BA.2/BA.5-dominant period; and (iii) molnupiravir and nirmatrelvir-ritonavir were effective in reducing the risk of mortality among patients hospitalised for COVID-19. Consistent results were observed among older people and those with multiple comorbidities.
This research provided evidence to promote vaccination among older individuals with chronic diseases, by instilling confidence towards the effectiveness of COVID-19 vaccines and raising awareness on the importance of receiving booster doses, thereby reducing vaccine hesitancy. The findings bridged evidence gaps regarding the effectiveness of CoronaVac against Omicron, and the optimal window for receiving a booster dose. The results also demonstrated the role of tixagevimab-cilgavimab for pre-exposure prophylaxis among the immunocompromised population in regions where Omicron BA.2/BA.5 remained dominant, and informed clinical practice and policies regarding the use of oral antivirals among vaccinated adults hospitalised for COVID-19. Last but not least, methodologies employed in this thesis can be adapted for timely evaluation of real-world effectiveness of vaccines and other preventive pharmacotherapies in future infectious disease pandemics.published_or_final_versionPharmacology and PharmacyDoctoralDoctor of Philosoph
Use and effectiveness of lipid-modifying drugs
No full textLipid-modifying drugs are widely used to reduce elevated cholesterol concentrations,
an important modifiable cause of atherosclerotic cardiovascular disease (ASCVD).
Despite their widespread use, recent international trends in lipid-modifying drug
utilization—especially for statins and proprotein convertase subtilisin/kexin type 9
(PCSK9) inhibitors—have not been quantified. Also, it remains uncertain whether
statin treatment and achieving very low concentrations of low-density lipoprotein (LDL)
and non-high-density lipoprotein (non-HDL) cholesterol are associated with a reduced
risk of cardiovascular events and mortality for primary prevention of ASCVD in Chinese
adults.
To address these knowledge gaps, pharmaceutical sales data was used to describe
trends in lipid-modifying drug utilization in 83 countries. Electronic health record
data from Hong Kong was used to describe local statin prescription trends and to
conduct two cohort studies assessing the effectiveness of lipid-modifying drugs for
primary prevention of ASCVD. The first cohort study directly compared simvastatin
and gemfibrozil initiation, while the second assessed concentrations of LDL cholesterol
and non-HDL cholesterol two years after statin initiation.
From 2008 to 2018, the overall global consumption of lipid-modifying drugs increased
at an annual compound rate of 4.13%. Since the approval PCSK9 inhibitors in 2015,
the United States has experienced the largest utilization of and expenditure on these
drugs. In Hong Kong, the prescribing of statins for primary prevention has increased
rapidly and consistently since 2004.
The cohort studies found that simvastatin was associated with a reduced risk of
major adverse cardiovascular events (MACE) and all cause mortality compared with
gemfibrozil. In statin-treated individuals, LDL cholesterol < 2.6 mmol/L and non-
HDL cholesterol < 3.4 mmol/L were associated with a reduced risk of MACE and all
cause mortality. The magnitude of the association was generally larger for non-HDL
cholesterol than LDL cholesterol, remaining consistent in sensitivity analyses using a
three-month and one-year landmark.
This thesis addressed a significant gap in our knowledge of lipid-modifying drug
utilization and the effectiveness of statins and gemfibrozil for primary prevention.
The findings show improved global access to lipid-modifying drugs, especially statins.
Disparities in PCSK9 inhibitor utilization among regions may be a barrier to an adequate
response to the burden of disease caused by elevated LDL cholesterol. Increased
prescribing of statins in Hong Kong has likely contributed to the observed decline in
age-standardized deaths from cardiovascular diseases since 2004. Because ASCVD is a
major cause of death in Hong Kong, using statins to achieve a non-HDL cholesterol <
3.4 mmol/L within 3 months of treatment initiation could reduce residual cardiovascular
risk in primary prevention.
This research suggests that achieving lower absolute concentrations of non-HDL cholesterol and LDL cholesterol with statins reduces the risk of cardiovascular events and
mortality in Chinese adults. It can inform clinicians about the prescribing of lipid-
modifying drugs and monitoring of treatment response in Asians. Future studies
could include a pragmatic randomized trial for primary prevention to assess the risk
of cardiovascular events between patients assigned to a non-HDL cholesterol < 3.4
mmol/L—using a combination of lipid-modifying drugs—versus usual care.published_or_final_versionPharmacology and PharmacyDoctoralDoctor of Philosoph
Effectiveness and safety of new oral anticoagulants in patients with nonvalvular atrial fibrillation
No full textAtrial fibrillation (AF) is the most common heart rhythm disorder affecting over 33 million people worldwide. It is a leading cause of stroke, making up one-fourth of all strokes encountered in clinical practice. For many decades, warfarin and other vitamin K antagonist oral anticoagulants have been the only effective treatment for stroke prevention in AF. However, their use is limited by the narrow therapeutic range, multiple drug/food interactions, and concerns for bleeding risk. These limitations posed several challenges to clinical management, contributing to the underuse of oral anticoagulants. The utilisation of oral anticoagulants has not been systematically compared between ethnicities; however, it is generally believed that oral anticoagulants are mostly underused among Asians, as they tend to prescribe conservatively due to concerns for bleeding risk.
The large unmet need for better anticoagulation options has prompted the development of new oral anticoagulants (NOACs). Dabigatran was the first NOAC approved for clinical use, which has a comparable efficacy of stroke prevention and fewer drug/food interactions as compared to warfarin. However, evidence on bleeding risk has been inconclusive: some studies suggested a higher risk of bleeding with dabigatran, while some studies reported lower or no increased risk. In addition, a recent animal study suggested that dabigatran use may be associated with a lower risk of osteoporotic fractures when compared to warfarin. However, no similar study was conducted in humans.
To address the above knowledge gaps, this thesis had three main objectives: (1) to examine the local utilisation pattern of oral anticoagulants in patients with AF; (2) to compare the bleeding risk between dabigatran and warfarin; and (3) to compare the risk of osteoporotic fractures between dabigatran and warfarin.
The studies described in this thesis utilised the population-wide database managed by the Hong Kong Hospital Authority, whose service is accessible to over 7 million people in Hong Kong. The results revealed that: (1) among patients with AF and a high risk of stroke, only 23% received oral anticoagulants, and 61% received antiplatelet drugs alone perceivably as a strategy to reduce bleeding risk. Notably, further analyses showed that the use of antiplatelet drugs did not result in fewer bleeding events, but was associated with a higher risk of stroke and mortality when compared to warfarin; (2) Dabigatran use was associated with a comparable incidence of bleeding but a higher risk of 30-day recurrent bleeding, suggesting closer monitoring of patients after hospital discharge may be beneficial to improve the safety of dabigatran use; (3) Dabigatran use was associated with a lower risk of osteoporotic fractures when compared to warfarin, which raised an opportunity to reduce fracture risk in patients requiring anticoagulation therapy.
This was the largest pharmacoepidemiological study that examined the use of oral anticoagulants among Southern Chinese. The study findings suggest the need to optimise oral anticoagulation therapy in patients with AF. It also provided novel data to facilitate a better understanding of the place of NOACs in the current management of AF.published_or_final_versionPharmacology and PharmacyDoctoralDoctor of Philosoph
Investigating the effectiveness, safety and preferences of low-dose aspirin for the primary prevention of colorectal cancer
No full textAspirin is a widely used drug with multiple indications and a well-known safety profile. Colorectal cancer is the third most common cancer in the world, with more than 1.4 million new cases in 2020. The literature has pointed to the possibility of an association between low-dose aspirin use and a lower the risk of colorectal cancer; however, a number of recent studies have reported conflicting findings. Furthermore, the studies mainly included a general population without a focus on individuals who may benefit the most from low-dose aspirin use, especially those who are not routinely prescribed low-dose aspirin for the secondary prevention of cardiovascular disease. The studies also mainly represented a predominantly Caucasian population.
To address these knowledge gaps, this thesis had three main objectives: (1) to evaluate the safety and effectiveness of low-dose aspirin for the primary prevention of colorectal cancer in patients without atherosclerotic cardiovascular disease in Hong Kong; (2) to evaluate the safety and effectiveness of low-dose aspirin for the primary prevention of colorectal cancer in patients with type 2 diabetes in Hong Kong and the United Kingdom; (3) to elicit the preferences of the general public and clinicians in Hong Kong on the use of low-dose aspirin for the primary prevention of colorectal cancer.
The research described in this thesis utilized two large electronic health records data from Hong Kong and the United Kingdom to conduct retrospective cohort studies as well as primary data obtained from a survey representing the Hong Kong population to conduct a cross-sectional study. The main findings of the research were: (1) low-dose aspirin is associated with a lower risk of colorectal cancer in patients without established cardiovascular disease, however low-dose aspirin was also associated with an increased bleeding risk except for patients concurrently taking proton pump inhibitors or H2 receptor antagonists; (2) in patients with type 2 diabetes, low-dose aspirin was not associated with a lower risk of colorectal cancer and was associated with an increased risk of bleeding even in the subgroup of patients concurrently taking a proton pump inhibitor or H2 receptor antagonist; (3) individuals from the public valued a clinician recommendation the most when making the decision on whether to initiate low-dose aspirin for the primary prevention of colorectal cancer. A decrease in colorectal cancer risk was the second most important factor which was valued more than an increase in bleeding risk. As for clinicians, a decrease in colorectal cancer risk was valued slightly more than an increase in bleeding risk.
This is the first research to evaluate the association of low-dose aspirin and the risk of colorectal cancer specifically in patients without atherosclerotic cardiovascular disease and in patients with type 2 diabetes mellitus. The findings of this research suggest that low-dose aspirin could be prescribed for the primary prevention of colorectal cancer, but only in certain individuals in which the benefits outweigh the risks. The findings also suggest that individuals who are prescribed low-dose aspirin for the primary prevention of colorectal cancer will be willing to take it.published_or_final_versionPharmacology and PharmacyDoctoralDoctor of Philosoph
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