Atrial fibrillation and frailty in older inpatients in Australia and Vietnam

Atrial fibrillation (AF) is a common health problem and a major risk factor for stroke in older people. As the world population is ageing, the increased prevalence of AF and AF-related stroke are growing public health concerns. There is marked heterogeneity amongst people aged over 65 years. Some of this may be captured by increasing chronological age. However, much of this variability is thought to be due to biological age or frailty, a state of vulnerability that can impact on the treatment and prognosis in older people with AF. The broad aim of this thesis was to investigate the impact of frailty on the pharmacological treatment and outcomes in older patients with AF. A dominant part of this thesis involved a prospective observational study in Australia about the impact of frailty on the pharmacological treatment, coagulation changes and outcomes in older inpatients with AF. In this study, a total of 302 inpatients aged ≥65 years with AF admitted to Royal North Shore Hospital, a tertiary referral teaching hospital in Sydney, Australia, was recruited. Of these, 134 patients participated in the sub-study on coagulation function. Chapters One, Two, Three are introduction, literature review and methods, respectively. Chapter Four describes the differences in clinical characteristics, pharmacological treatment and incidence of stroke and major bleeding over six months between the frail and the non-frail. Compared to the non-frail, frail participants were older, had more comorbidities and higher risk of strokes (as reflected by CHA2DS2-VASc score) but not haemorrhage (as reflected by HASBLED score). Upon discharge, 55.7% participants were prescribed anticoagulants (49.3% frail, 62.6% non-frail, p=0.02). Frail participants were less likely to be prescribed an anticoagulant and were more likely to receive digoxin upon discharge, although the impact of frailty on these prescriptions was reduced in multivariate analysis. Compared to previous studies in Australia, prescription of anticoagulants was higher in this study in older patients with AF, especially in the frail. A significant percentage of participants with AF received antiplatelets with no evidence of ischemic heart disease, suggesting that antiplatelets may be used for stroke prevention in AF although current guidelines do not recommend aspirin for stroke prevention in AF unless patients refuse the use of any oral anticoagulant. After six months, overall incidence of ischemic stroke was 2.1% and, in patients taking anticoagulants, incidence of major/severe bleeding was 6.3%, with no significant difference between frailty groups. The findings from Chapter Five established that in older inpatients with AF, frailty was associated with prolonged length of stay and increased all-cause mortality but not re-admission during six months after discharge. The coexistence of frailty and delirium during hospitalisation significantly increased the risk of mortality. Chapter Six and Chapter Seven report the two pilot studies testing the hypotheses of altered platelet function, coagulation function and responses to antithrombotic drugs in frail patients. In Chapter Six, platelet aggregation studies were performed using Whole Blood Impedance Aggregometry. While there was no significant relationship between frailty and platelet aggregation in participants not taking any antiplatelet drugs, there was a reduced responsiveness to aspirin in the frail amongst those taking aspirin. The observed reduced platelet responsiveness to aspirin in the frail supports the current guidelines that do not recommend aspirin for stroke prevention in AF, and raises a question about the risk benefit ratio of aspirin prescription in older patients with AF, which is usually commoner in the frail, in whom prescribers may be more concerned about using anticoagulants. In Chapter Seven, the Overall Haemostatic Potential and Calibrated Automated Thrombogram were used to globally assess coagulation function. Compared to non-frail participants, frail participants had significantly reduced fibrin generation, which may reflect decreased acute phase response in the frail. There was no difference on coagulation profiles between the frail and the non-frail on warfarin, suggesting that frail warfarinised patients are not at higher risk of bleeding which is consistent with the clinical follow up findings in Chapter Four. There have been few published studies about AF or frailty in developing countries; hence, this thesis also aimed to investigate the evidence about AF and frailty in developing countries with two systematic reviews and an observational study in Vietnam. Chapter Eight is a systematic review of epidemiology and management of AF in developing countries with a summary of 70 studies of AF in these countries. The prevalence of AF in the community-based studies ranged from 0.03% to 1.3%, while the prevalence of AF in hospital-based studies varied from 0.7% to 55.7%. The most common conditions associated with AF were hypertension and valvular heart disease. The prevalence of stroke in patients with AF ranged from 6.7% to 27%. The utilisation of anticoagulants was highly variable (2.7%-72.7%). There was a high prevalence of use of rate control therapies (55.3%-87.3%). Chapter Nine is a systematic review of frailty research in developing countries, with a total of 20 studies of frailty in these countries. The prevalence of frailty in community-dwelling older people ranged from 5.4% to 43.9%. The prevalence of frailty in hospitalised and institutionalised older people was from 32.3% to 49.3%. The prevalence of frailty in outpatient clinics was 27.8% to 71.3%. Fried frailty phenotype was the most commonly used definition of frailty in developing countries. Frailty was associated with increased mortality and comorbidities, decreased physical and cognitive function, and poor perceptions of health in these countries. In the reviews in Chapter Eight and Chapter Nine, there were no published studies of the pharmacological treatment of AF in older patients in Vietnam and no published studies related to frailty in Vietnam, a typical developing country with a rapidly ageing population. Chapter Ten presents a cross-sectional study of the prevalence of AF among older hospitalised patients in Vietnam and describes clinical characteristics and treatment of these patients. Of the 461 older patients recruited at the National Geriatric Hospital in Hanoi, Vietnam, during seven months, the prevalence of AF was 3.9%, which is similar to that reported in other countries. Amongst patients with AF, the most common medical conditions were hypertension (72.2%), followed by stroke (55.6%), heart failure (50.0%), type 2 diabetes (44.4%). The prevalence of frailty in patients with AF was 39%. Living alone (OR=10.2, 95% CI 1.5–70.1), having a habit of using vitamins at home as self-medication (OR=3.8, 95% CI 1.1–13.4), having heart failure (OR=31.3, 95% CI 9.6–101.8), and having type 2 diabetes (OR=3.5, 95% CI 1.2–10.7) were associated with the presence of AF on admission. All patients with AF had a high risk of stroke and 72.2% of them had a high risk of bleeding with anticoagulant medications. Only 22.2% were anticoagulated on admission and 22.2% upon discharge, with no difference between frail and non-frail patients. In conclusion, AF and frailty are growing public health concerns in developed countries as well as in the developing world. The studies in this thesis in Australia and Vietnam provide new evidence on the frequency, treatment and prognosis for patients with AF. Frailty was common in older patients with AF in both Australia and in Vietnam. In both countries there was evidence of sub-optimal use of anticoagulant medications: among frail people with AF in Australia and among all patients with AF in Vietnam. A large size, multi-centre prospective cohort study or pharmaco-epidemiological study using existing linked healthcare data looking at outcomes in frail and non-frail patients on anticoagulants is needed to derive accurate results about the impact of frailty on anticoagulation utilisation, efficacy and complications. Further clinical epidemiological research is needed on AF and frailty in developing countries such as Vietnam. Such research will become increasingly important as population ageing leads to rapidly increasing numbers of people with AF and/or frailty. The interaction between frailty and coagulation requires further laboratory investigation. More research is also needed to investigate the impact of frailty on responses to newer direct oral anticoagulants

A Trio Neural Model for Dynamic Entity Relatedness Ranking

Measuring entity relatedness is a fundamental task for many natural language processing and information retrieval applications. Prior work often studies entity relatedness in static settings and an unsupervised manner. However, entities in real-world are often involved in many different relationships, consequently entity-relations are very dynamic over time. In this work, we propose a neural networkbased approach for dynamic entity relatedness, leveraging the collective attention as supervision. Our model is capable of learning rich and different entity representations in a joint framework. Through extensive experiments on large-scale datasets, we demonstrate that our method achieves better results than competitive baselines.Comment: In Proceedings of CoNLL 201

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