Дисертації з теми "Atrial fibrillation; stroke; thrombogenesis"

Contemporary pacemakers allow quantification of atrial high-rate episodes (AHREs) and atrial fibrillation burden (AFB) accurately. It is generally believed that left atrial (LA) remodelling may precede the development of atrial arrhythmias (AA), and AHRE precede the clinical manifestation of atrial flutter or fibrillation. However, the relationship between LA remodelling with AHRE has not been studied. Furthermore, the relationship of AFB to progressive LA remodelling and how this relates to indices of thrombogenesis is unclear. The aim of my study is to investigate the inter-relationship between LA remodelling, AA burden and indices of thrombogenesis in patients with pacemakers. My findings suggest that the incidence of AHRE was 35%. Increased frequency of right ventricular pacing is associated with LA enlargement and reduced global left and right ventricular function. However, there was no clear association between the right atrial pacing with cardiac remodelling. The cumulative percentage right ventricular pacing and increased LA volume are associated with the development of AHREs, but AFB is independently associated with changes in LA function, left ventricular diastolic function and indices of platelet activation and thrombosis. In addition, I demonstrated the feasibility and reproducibility of a novel method of IACT measurement in patients with permanent pacemakers.

Background: The Framingham Study from 1991 showed a clear correlation between atrial fibrillation (AF) and ischemic stroke, where patients with AF had an almost fivefold increase in risk of stroke compared with patients without AF. Since then, several trials have evaluated different antithrombotic treatments to reduce the risk of stroke in patients with AF. Other trials have investigated factors that increase the risk of stroke in patients with AF and risk score systems have been developed to categorize patients into low or increased risk of stroke to help clinicians to decide which patients benefit from antithrombotic treatment and in whom it can be abstained, not to expose patients with low stroke risk to an increased risk of bleeding conferred by antithrombotic treatment. The aims of this thesis were: [1] to evaluate if a warfarin dosing algorithm can increase hit rate and decrease mean error compared with manually changed doses; [2] to assess the prevalence and net clinical benefit of aspirin as monotherapy for stroke prevention in AF; [3] to investigate the risk of thromboembolic and haemorrhagic complications within 30 days after electrical cardioversion (ECV) of AF in patients with and without oral anticoagulation (OAC) pre-treatment; and [4] to assess the proportion of patients discontinuing OAC after pulmonary vein isolation (PVI), identify factors predicting stroke after PVI and to investigate risk of complications after PVI with and without OAC. Materials and methods: All studies are retrospective and based on data from Swedish national quality registries. In paper I, data from Auricula was used to compare the resulting INR values after algorithmic warfarin dose suggestions and manually changed doses. In paper II data was extracted from the Swedish National Patient Register, the Dispensed Drugs Register and the Cause of Death Register. Patients with aspirin treatment were compared with patients without any antithrombotic treatment regarding risk of thromboembolic and haemorrhagic complications. In paper III data was collected from the Swedish National Patient Register and the Dispensed Drugs Register to examine risk of complications (thromboembolic and haemorrhagic events) within 30 days after cardioversion, comparing patients with and without oral anticoagulation pre-treatment. In paper IV data from six different Swedish national quality registries were used (Swedish Catheter Ablation Register, Auricula, Swedish National Patient Register, Dispensed Drugs Register, Cause of Death Register and Riksstroke). Patients undergoing pulmonary vein isolation (PVI) were investigated for adherence to guidelines regarding oral anticoagulation, predictors for stroke after PVI, as well as risk of ischemic stroke or intracranial haemorrhage after PVI in patients with and without treatment. Results: Paper I showed that a computerized dosing algorithm for warfarin in most cases perform as well or better compared with doses that have been changed manually, with a better hit-rate (0.72 vs. 0.67) and a lower mean error (0.44 vs. 0.48). Paper II showed that 32% of 182.678 patients with a diagnosis of AF were on monotherapy with aspirin for stroke prevention. A total of 115.185 patients were included, 58.671 with aspirin treatment and 56.514 without antithrombotic treatment at baseline. After stratification after CHA2DS2-VASc score and after multivariable adjustment, aspirin treatment did not confer a decrease in thromboembolic events. After propensity score mathcing, rate of ischemic stroke was 7.4%/year (95% CI 7.1-7.6) in aspirin treated patients and 6.6%/year (95% CI 6.4-6.9) in patients without antithrombotic treatment. In paper III 22.874 patients undergoing electrical cardioversion were included, 10.722 with and 12.152 without OAC pre-treatment. In patients with low stroke risk (CHA2DS2-VASc 0-1), no thromboembolic complication was seen within 30 days after cardioversion. In patients with CHA2DS2-VASc ≥2, the risk of thromboembolic complications was increased when no oral anticoagulation pre-treatment was used, results that remained after propensity score matching. No difference regarding haemorrhagic complications was seen. Paper IV included a total of 1585 patients undergoing PVI with a mean follow up of 2.6 years. Adherence to current guidelines regarding oral anticoagulation was good in patients with CHA2DS2-VASc ≥2. Previous ischemic stroke was a predictor for a new stroke after PVI. In patients with CHA2DS2-VASc ≥2 stroke risk was increased in patients discontinuing OAC compared to those continuing OAC (1,60%/year vs. 0.34%/year). Conclusion: Oral anticoagulation is still underutilized for prevention of stroke and systemic embolism in patients with atrial fibrillation. Patients with risk factors for stroke (CHA2DS2-VASc ≥2p) benefit from continuous oral anticoagulation treatment to prevent stroke, also in conjunction with electrical cardioversion and after pulmonary vein isolation. If warfarin is chosen, a computerised dosing algorithm can facilitate and standardize warfarin dosing and lead to better resulting INR values than manually changed doses. Aspirin should not be used for stroke prevention in patients with atrial fibrillation.

Hypertrophic cardiomyopathy (HCM) is an inherited myocardial disease associated with atrial fibrillation (AF) and thromboembolism (TE), which are related to adverse clinical outcomes and reduced survival. Current ESC and ACCF/AHA guidelines recommend anticoagulation in all patients with HCM and atrial fibrillation but the absolute risk of thromboembolism in patients with and without documented AF is unclear. The primary aim of this study was to derive and validate a model for estimating the risk of TE in HCM. Analyses were performed to determine predictors of AF and TE. Exploratory analyses assessed the performance of the CHA2DS2-VASc score and outcome with vitamin K antagonists (VKA). A further aim was to investigate the effect of AF on mortality and the efficacy of antiarrhythmic therapy in the development of AF.

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice with rapidly rising prevalence and incidence predominantly due to advancing age in Western populations. Of particular concern however is the strong relationship between AF and stroke. This relates to a number of factors, but there is an emerging body of evidence to suggest that AF confers a hypercoagulable state. Disruption of endothelial homeostasis (damage vs. repair) is thought to be central to this process. The endothelium appears to be damaged both by AF and various other vascular diseases (e.g. hypertension) that frequently co-exist with the arrhythmia, with similar disruption to endothelial repair (normally effected by endothelial progenitor cells). Endothelial damage seems to be an essential prerequisite to thrombogenesis in AF. Significantly, the endothelium also links a number of processes including inflammation, growth factors, the renin-angiotensin-aldosterone system among others, which may directly or indirectly lead to activation of the coagulation cascade. This thesis investigates the relationship between the temporal pattern of AF (paroxysmal, persistent, permanent) and established markers of endothelial dysfunction (vonWillebrand factor, vWf; soluble E-selectin, sEsel), angiogenesis (vascular Endothelial Growth Factor, VEGF), apoptosis (soluble Fas/Fas ligand, sFas/sFasL) and inflammation (C-reactive protein, CRP; Interleukin-6, IL-6) in AF with particular reference to circulating progenitor cells (CPCs) as a novel marker of endothelial health/angiogenesis. Additionally the impact of restoration of sinus rhythm using electrical cardioversion on these indices and the relevance of the AF arrhythmia burden in influencing these markers is investigated. In conclusion, the endothelium seems to be a central link through which all three components of Virchow’s triad interact in AF. This thesis finds a possible link for CPCs to interact with various other reported aberrancies of the hypercoagulable state in this process. Also reported is a modest alteration in CPC counts following restoration of sinus rhythm, however, only limited numbers of patients were assessed and this requires examination with a more in depth study. Finally, the thesis has also examined the role of paroxysmal AF in influencing surrogate markers of the hypercoagulable state, but failed to find any significant differences on the basis of the arrhythmia burden. These findings must however been considered in light of numerous study limitations, the most notable of which is limited statistical power.

Background: Atrial fibrillation (AF) is the most common arrhythmia in the adult population, affecting about 5% of the population over 65 years. Occurrence of AF is an independent risk factor for stroke, and together with other cardiovascular risk factors (CHADS2/CHA2DS2- VASc), the stroke risk increases. Since AF is often paroxysmal and asymptomatic (silent) it may remain undiagnosed for a long time and many AF patients are not discovered before suffering a stroke. Aims: To estimate the prevalence of previously undiagnosed AF in an out-of-hospital population with CHADS2 ≥1, in patients with an enlarged left atrium (LA) and of total AF prevalence in sleep apnea (SA) patients, conditions that have been associated with AF. To compare the efficacy of short intermittent ECG with continuous 24h Holter ECG in detecting arrhythmias. Methods: Patients without known AF recorded 10−30 second handheld ECG (Zenicor-EKG®) registrations during 14−28 days at home, both regular, asymptomatic registrations twice daily and when having cardiac symptoms. Recordings were transmitted through the in-built SIM card to an internet-based database. Patients with palpitations or dizziness/presyncope referred for 24h Holter ECG were asked to additionally record 30-second handheld ECG registrations during 28 days at home. Results: In the out-of-hospital population with increased stroke risk, previously unknown AF was diagnosed in 3.8% of 928 patients. Comparing AF detection in patients with an enlarged LA versus normal LA showed that eleven of 299 patients had AF. Five of these had an enlarged LA (volume/BSA). No statistical difference in AF prevalence was found between patients with enlarged and normal LA, 3.3% and 3.2% respectively, (p = 0.974). AF occurred in 7.6% of 170 patients with sleep apnea, in 15% of patients with sleep apnea ≥60 years, and in 35% of patients with central sleep apnea. AF prevalence was also associated with severity of sleep apnea, male gender and diabetes. Comparing the efficacy of arrhythmia detection in 95 patients with palpitations or dizziness/presyncope with continuous 24h Holter and short intermittent ECG, 24h Holter found AF in two and AV-block II in one patient, resulting in 3.2% relevant arrhythmias detected. Short intermittent ECG diagnosed nine patients with AF, three with PSVT and one with AV-block II, in total 13.7% relevant arrhythmias. (p = 0.0094). Conclusions: Screening in the out-of-hospital patient population (mean age 69.8 years) yielded almost 4% AF, making it seem worthwhile to screen older patients with increased stroke risk for AF with this method. Screening patients with LA enlargement (mean age 73.1 years) did not result in higher detection rates compared with the general out-of-hospital population. AF occurred in 7.6% of patients with sleep apnea, (mean age 57.6 years) and was associated with severity of sleep apnea, presence of central sleep apnea, male gender, age ≥60 years, and diabetes. Short intermittent ECG is more effective in detecting relevant arrhythmias than 24h Holter ECG in patients with palpitations or dizziness/presyncope.

Atrial fibrillation (AF) confers an independent increased risk of stroke and death. The stroke risk is very heterogeneous and current risk stratification models based on clinical variables, such as the CHADS2 and CHA2DS2VASc score, only offer a modest discriminating value. The aims of this thesis were to study cardiac biomarkers, cardiac troponin and natriuretic peptides e.g. N-terminal prohormone-B-type natriuretic peptide (NT-proBNP), and describe levels in AF patients, investigate the association with stroke or systemic embolism, cardiovascular event, major bleeding and mortality, and to assess how levels of cardiac biomarkers change over time. Cardiac troponin was analyzed with contemporary assays and high sensitivity assays. The study populations consisted of patients with atrial fibrillation and one risk factor for stroke included in the RE-LY (n=6189) and the ARISTOTLE (n=14892) biomarker substudies. Median follow-up time was 2.2 years and 1.9 years, respectively. In a subset of participants (n=2514) data from repeated measurements was available at three months. Cardiac troponin was detectable in 57.0% with the contemporary assay and 99.4% with the high sensitivity assay. NT-proBNP was elevated in approximately three quarters of the participants. In Cox models adjusted for established risk factors the cardiac biomarkers levels was independently associated with stroke or systemic embolism, cardiovascular events, and mortality. Only cardiac troponin was associated with major bleeding. In ROC analyses the prediction of stroke or systemic embolism, cardiovascular events, and mortality increased significantly by addition of cardiac troponin or NT-proBNP to the models. Persistent detectable cardiac troponin (contemporary assay) and elevated NT-proBNP levels were found in a large number of participants. Persistent detectable or elevated levels conferred significantly higher risk for stroke or systemic embolism, cardiovascular events, and mortality. By using both cardiac biomarkers simultaneously the risk stratification improved even further for all outcomes. In conclusion the analyses for the first time display that elevation of troponin I and NT-proBNP are common in patients with AF and independently related to increased risks of stroke, cardiovascular events and mortality. Persistent elevation of troponin and NT-proBNP indicate a worse prognosis than transient elevations or no elevations of either marker. The cardiac biomarkers added substantial improvements to existing risk stratification models.

Cardio-embolic stroke accounts for nearly a third of all ischaemic strokes. The most clinically important cardio-embolic sources are non-valvular atrial fibrillation (AF) and chronic heart failure. Strokes due to these conditions are associated with greater disability and more mortality, as compared to stroke of other aetiology. This thesis is aimed at addressing some of the challenges faced by clinicians when dealing with stroke in patients with AF or heart failure, using an extensive range of historical data. Chapter 1 provides an introduction to stroke, AF and heart failure, including current prevalences, aetiology, and their complex intertwine relationship. The current acute stroke management in patients with AF or heart failure is also outlined within the chapter. In chapter 2, the data sources and statistical methods that were common to the studies in the thesis are outlined. The justifications of using historical data in the absence of evidence from robust clinical trials are also detailed. Chapter 3 explores the relevance of antithrombotic treatment on patterns and outcomes of acute stroke patients with AF. A non-randomised cohort analysis was conducted using data from the Virtual International Stroke Trials Archive (VISTA). The associations of antithrombotic treatment with the modified Rankin scale (mRS) outcome, and the occurrence of recurrent stroke and symptomatic intracerebral haemorrhage, at 90 days after stroke were described. Combined sequential antithrombotic therapy (i.e. oral anticoagulant and antiplatelet treatment), was associated with favourable outcome on ordinal mRS and significantly lower risk of recurrent stroke, symptomatic intracerebral haemorrhage and mortality by day 90, compared to the patients who did not receive any antithrombotic treatment. The relative-risk of recurrent stroke and symptomatic intracerebral haemorrhage appeared highest in the first 2 days after stroke before attenuating to become constant over time. Thus, early introduction of oral anticoagulant treatment (2-3 days after stroke), and to a lesser extent antiplatelet agents, was associated with substantially fewer recurrent stroke events over the following weeks but with no excess risk of symptomatic intracerebral haemorrhage. Chapter 4 seeks to describe the current prescribing patterns in stroke survivors with AF, with particular emphasis on socio-demographic associations. A cross-sectional analysis of city-wide Glasgow primary care data for the year 2010, was conducted. This chapter highlights that oral anticoagulant treatment was under-used in this high risk population, especially those of older age and affected by deprivation. Strategies need to be developed to improve prescription of oral anticoagulant treatment. Chapter 5 investigates the incidence of stroke within the available heart failure trials spanning a 30 year period, according to AF status at baseline. Individual patient data were pooled from 11 trials conducted in patients with heart failure and reduced ejection fraction (HF-REF); and, 3 trials performed in patients with heart failure and preserved ejection fraction (HF-PEF). Stroke incidence has not significantly declined over time in patients with HF-REF enrolled to trials, despite greater use of evidence-based heart failure and oral anticoagulant therapies. However, anticoagulation proportions remain under 70% among HF-REF patients with documented AF. Similar trends of stroke incidence were observed for patients enrolled in HF-PEF trials. Some patients with heart failure but without atrial fibrillation may be at high risk of stroke and may potentially benefit from oral anticoagulant treatment. Chapter 6 provides a comprehensive description of the current incidence of and risk factors for stroke in patients with HF-REF but without AF. Data from two large and contemporary heart failure trials, the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiac- Heart Failure trial (GISSI-HF), were pooled to enable the analysis. The new simple clinical predictive model for stroke showed that about one-third of patients without AF have a risk of stroke similar to patients with AF. The predictive model was also validated in an independent large data set. The high risk of stroke in patients without AF might be reduced by individualised and safer oral anticoagulant treatment. Correspondingly, Chapter 7 explores the risk-model for stroke in a contemporary cohort of patients with HF-PEF but without AF. Data were pooled from the Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity- Preserved trial (CHARM-Preserved) and the Irbesartan in Heart Failure with Preserved Systolic Function trial (I-Preserve), for patients with ejection fraction ≥45% only. The analysis showed that the simple clinical model developed in Chapter 6, for patients with HF-REF, is also applicable to patients with HF-PEF. There are concerns that systemic thrombolysis might not achieve clinically-important outcome among chronic heart failure patients with acute ischaemic stroke. Chapter 8 evaluates the relevance of chronic heart failure on the outcome of acute stroke patients who received thrombolysis. A non-randomised cohort analysis was conducted using data obtained from the Virtual International Stroke Trials Archive (VISTA). The associations of outcome among chronic heart failure patients with thrombolysis treatment using the mRS distribution at day 90, stratified by presence of AF, were evaluated. Chronic heart failure was associated with a worse outcome with or without thrombolysis. However, acute stroke patients who received thrombolysis had more favourable outcome regardless of heart failure status, compared to their untreated peers. The findings should reassure clinicians considering systemic thrombolysis treatment in hyper-acute ischaemic stroke patients with chronic heart failure. This thesis has summarised and extended our knowledge of the complex relationship between stroke and the heart, focusing on atrial fibrillation and heart failure. It has answered many questions and generated many more. The reported studies may assist clinicians who are dealing with stroke in patients with atrial fibrillation or heart failure. These conditions are common and each carry poor prognosis. Thus, even small advances in their treatment may have a useful societal impact.

Background: Atrial fibrillation (AF) confers high risk of stroke, but often goes undiagnosed due to difficulties in its diagnosis. AF detection is important in post-stroke populations for secondary prevention and smartwatches have emerged as a promising modality for detecting AF, but little is known about their use in older adults who have experienced a stroke. Methods: This dissertation uses data from the Pulsewatch study, a two-phased trial assessing accuracy, usability, and adherence of smartwatch-based AF detection among older patients after stroke. Analyses performed include: descriptive statistics, linear and logistic regressions, qualitative and mixed-methods analyses, mixed effects modeling, and group-based trajectory modeling. Results: The Pulsewatch system was 91% accurate in detecting AF compared to a clinical gold-standard. Participants found the system easy to use, but indicated that streamlining the smartwatch’s functionalities to focus on passive cardiac monitoring is crucial. Improving battery life to allow for longer wear time would alleviate anxiety in some participants. Participants with previous experience using cardiac rhythm monitors rated the system lower on usability, but overwhelmingly preferred it to previous monitors due to the watch’s comfort, appearance, and convenience. Watch wear decreased over time, and we observed three distinct patterns of decline. No individual-level characteristics were associated with usability or adherence to watch wear. Conclusions: Smartwatches are promising for AF detection in older adults after stroke, though while they offer high accuracy and usability, adherence to wear is low. Strategies to encourage extended watch wear are necessary to realize the potential of smartwatches as a viable cardiac monitoring modality.

Class of 2015 Abstract
Objectives: Warfarin has historically been the anticoagulant used for the primary prevention of stroke in atrial fibrillation (AF), however three target specific oral anticoagulants, dabigatran, rivaroxaban, and apixaban, have recently been approved for use in this setting. Current literature lacks a comparison of these four drugs in relation to post-stroke outcomes, and this study aims to compare their performance in a natural setting. Methods: This retrospective cohort study identified stroke patients admitted to an academic medical center between January 2013 and December 2014 using the Quintiles, Inc.-American Heart Association Get With The Guidelines-Stroke database; pertinent data was collected from the database and patient electronic medical records. Primary endpoints measured were length of stay, 30-day readmission, and discharge disposition; secondary endpoints included rates of admission to the intensive care unit (ICU) and complications. Results: Of 940 stroke admissions, 53 ischemic stroke patients were identified as receiving an oral anticoagulant for stroke prevention in AF. The warfarin (n=40) and non-warfarin (dabigatran, rivaroxaban, and apixaban; n=13) groups were well matched regarding admission demographics, however patients taking warfarin were more likely to have an elevated INR at hospital admission (P=0.0053) and receive tPA (P=0.047). Patients in the warfarin group were also statistically significantly more likely to receive warfarin on discharge (P=0.004). No endpoints achieved statistical significance. Conclusions: No differences in post-stroke outcomes between warfarin and non-warfarin oral anticoagulants used for stroke prevention in AF were found.

The costs for stroke management and reduced health related quality of life (QoL) can extend throughout life as mental and physical disabilities are common. The aim of this thesis was to quantify this stroke-related burden with data from Riks-Stroke (RS), the Swedish stroke register. Costs for hospital and primary care, secondary drug prevention, home and residential care services, and production losses were estimated for first-ever stroke patients registered in the RS. The present value lifetime costs were estimated from the expected survival and discounted by 3%. Quality of life was estimated with the EQ-5D instrument on a subset of patients at 3 months after the index event and mapped to patient-reported outcome measures in the RS. Standard descriptive and analytic (multivariate regressions) statistical methods were used. The life-time societal present value cost per patient in 2009 was approximately €69,000 whereof home and residential care due to stroke was 59% and indirect costs for productivity losses accounted for 21% (year 2009 prices). Women had higher costs than men in all age groups. Treatment at stroke units had a low incremental cost per life-year gained compared to patients who were not treated at such facilities. The estimated disutility from stroke was greatest for women and the oldest, and compared to 1997 the cost per patient increased after a revised assumption. Hospitalisation costs were stable while long-term costs for ADL support increased in part due to a changed age structure. Patients with atrial fibrillation (AF; 24%) had €367 higher inpatient costs compared to non-AF stroke patients €8,914 (P<0.01; year 2001 prices). As the index case fatality was higher among AF patients, the cost difference was higher for patients surviving the first 28 days. A multivariate regression showed that AF, diabetes, stroke severity, and death during the 3-year follow-up period were independent cost drivers. Three regression techniques (OLS, Tobit, CLAD) were chosen for mapping EQ-5D utilities to patient-reported outcome measures in the RS. The mean utility was overestimated with all models and had lower variance than the original data. In conclusion, total societal lifetime cost for 22,000 first-ever stroke patients in 2009 amounted to €1.5 billion (whereof production losses were €314 million). About 56,600 QALYs were lost due to premature death and disability. Including a preference-based QoL instrument in the RS would allow cost-utility analyses, but it is important to control for confounders in comparator arms to avoid bias.

Stroke is a major cause of premature death and disability throughout the world and atrial fibrillation (AF) is one of the most common preventable causes of stroke. AF affects about 10% of individuals aged ≥80 years, but warfarin is substantially under-used in this age group despite being effective in preventing AF-related thromboembolic events. AF-related ischaemic strokes tend to be severe and incur high care costs, and non-cerebral systemic embolism secondary to AF is also a major clinical burden. Despite that, there are few population-based studies on AF-related ischaemic stroke, and no recent study of the burden of AF-related thromboembolism and the population impact of under-treatment. I have used data from the Oxford Vascular Study (OXVASC), a prospective, population-based incidence study of vascular disease in all territories, which was started in April 2002 and is on-going. The study population comprises of 92,728 individuals registered with 100 family physicians in nine general practices and uses multiple overlapping methods of “hot” and “cold” pursuit to achieve near-complete ascertainment of all patients with acute vascular events. There are several findings described by the research in this thesis which have important implications for public health and can be utilised to improve secondary prevention in stroke. First, I have shown that one-third of all incident embolic events were related to AF and 60% of AF-related embolic events occurred at ≥80 years. Second, I have shown that only 9% of patients aged ≥80 years with incident embolic event related to known prior AF were on premorbid warfarin, and consequently three quarters of those previously independent were dead or disabled six months post event. Third, I have shown that there has been no reduction in age-specific incidence of AF-related ischaemic stroke in Oxfordshire over the last 25 years. Fourth, I have shown that assuming age-specific incidence does not continue to rise, if prevention is not improved, the number of embolic events at age ≥80 years would be expected to treble by 2050 (72,975 AF-related embolic events), with 84% of events at all ages occurring at age ≥80. Fifth, I have shown through a meta-analysis that one in five incident strokes had a history of prior AF of which only 19% were on premorbid warfarin, and AF was related to one in three incident ischaemic strokes. Sixth, I have shown that 1 in 5 stroke patients with known prior AF subsequently became institutionalised and incurred high acute and long-term care costs. Seventh, I have shown that one in five patients with undetermined cerebral ischaemic event subsequently had AF-related late recurrent stroke. Eighth, I have shown that even though TIA or ischaemic stroke patients who subsequently turned out to have new AF at follow-up had significantly higher baseline NT-proBNP compared to non-AF group, its utility is limited by low sensitivity and specificity. Ninth, I have shown in another meta-analysis that the duration of cardiac monitoring after cerebral ischaemic events was the main determinant of the observed rate of pAF, and that 5-7 days of monitoring may be adequate in unselected patient populations. Finally, I have shown that using 5-day event loop recording in clinic patients with TIA and minor ischaemic stroke could detect 12% new AF and the delay in monitoring did not reduce the sensitivity of pAF detection.

Background Fewer than one-third of nursing home residents with atrial fibrillation were treated with the only available oral anticoagulant, warfarin, historically. Management of atrial fibrillation has transformed in recent years with the approval of 4 direct-acting oral anticoagulants (DOACs) since 2010. Methods Using the national Minimum Data Set 3.0 linked to Medicare Part A and D claims, we first described contemporary (2011-2016) warfarin and DOAC utilization in the nursing home population (Aim 1). In Aim 2, we linked residents to nursing home and county level data to study associations between resident, facility, county, and state characteristics and anticoagulant treatment. Using a new-user active comparator design, we then compared the incidence of safety (i.e., bleeding), effectiveness (i.e., ischemic stroke), and mortality outcomes between residents initiating DOACs versus warfarin (Aim 3). Results The proportion of residents with atrial fibrillation receiving treatment increased from 42.3% in 2011 to 47.8% as of December 31, 2016, at which time 48.2% of treated residents received DOACs. Demographic and clinical characteristics of residents using DOACs and warfarin were similar in 2016. Half of the 8,734 DOAC users received standard dosages and most were treated with apixaban (54.4%) or rivaroxaban (35.8%) in 2016. Compared with warfarin, bleeding rates were lower and ischemic stroke rates were higher for apixaban users. Ischemic stroke and bleeding rates for dabigatran and rivaroxaban were comparable to warfarin. Mortality rates were lower versus warfarin for each DOAC. Conclusions In nursing homes, DOACs are being used commonly and with equal or greater benefit than warfarin.

Objective: The primary objective of this study was to estimate the long-term cost-effectiveness of stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) in the United States using new anticoagulant therapies - dabigatran 150 mg, apixaban 5 mg, and rivaroxaban 20 mg - as well as the standard treatment, warfarin. Methods: A Markov decision-analysis model was constructed using data from clinical trials that evaluated the new oral anticoagulants relative to warfarin (apixaban 5 mg & ARISTOTLE, dabigatran 150 mg & RE-LY, and rivaroxaban 20 mg & ROCKET-AF) to compare the lifetime cost and quality-adjusted life expectancy. The Markov model target population was a hypothetical cohort of 70-year old patients with nonvalvular atrial fibrillation, an increased risk for stroke (CHADS₂ ≥ 1, or equivalent), a renal creatinine clearance (CrCl) of 50 or above, and no contraindication to anticoagulant therapy. Using pair-wise comparisons of each therapy, analyses were conducted to evaluate incremental cost-effectiveness ratios (ICERs), net monetary benefits (NMBs), lifetime costs, life-years, and quality-adjusted life-years (QALYs). Results: In the base case, warfarin had the lowest cost of $71,857 (95% confidence interval [CI]: $68,730, $77,452), followed by rivaroxaban 20 mg ($74,023; 95% CI: $70,943, $77,307), dabigatran 150 mg ($78,584; 95% CI: $75,277, $81,968), and apixaban 5 mg ($81,180; 95% CI: $78,642, $83,756). Apixaban 5 mg also yielded the highest QALY estimate, 8.63 (95% CI: 8.52, 8.72), followed by dabigatran 150 mg (8.55; 95% CI: 8.43, 8.67), rivaroxaban 20 mg (8.42; 95% CI: 8.31, 8.54), and warfarin (8.17; 95% CI: 8.1, 8.24). In a Monte Carlo probabilistic sensitivity analysis, apixaban 5 mg, dabigatran 150 mg, rivaroxaban 20 mg, and warfarin were cost effective in 45%, 37%, 19%, 0%, respectively, of the simulations using a willingness-to pay threshold of $50,000 per QALY gained. From the one-way sensitivity analyses, new anticoagulant (apixaban 5 mg, dabigatran 150 mg, rivaroxaban 20 mg) costs and probabilities associated with intracranial hemorrhage and stroke for patients receiving rivaroxaban 20 mg were identified as significant influential variables impacting model results. Conclusion: In patients with NVAF and an increased risk of stroke prophylaxis, apixaban 5 mg, dabigatran 150 mg, and rivaroxaban 20 mg may all be cost-effective alternatives to warfarin depending on pricing in the United States and neurologic events for rivaroxaban 20 mg.

The aim of this thesis was to explore variations in stroke prevention and the effect of prevention on outcome. The studies were based on patients registered in the Swedish Stroke Register between 2001 and 2009 and although used to different extents in each paper, additional information was retrieved through linkage to The National Patient Register, the Cause of Death Register, the Prescribed Drug Register and the Total Population Register. Cardiovascular risk factors were prevalent among ischemic stroke (IS) patients; however, they were not always prescribed the drugs recommended, and increasing age was an important negative predictor (Paper I). After IS, the rate of hemorrhage in patients prescribed antiplatelet agents (2.4 per 100 person-years) was double to results from randomized controlled trails, but was similar for patients prescribed warfarin (2.5 per 100 person-years).  Age ≥75 years and previous hemorrhage were associated with a moderately increased risk of future hemorrhage (Paper II). Among IS patients with atrial fibrillation, one-third was prescribed warfarin and two-thirds were prescribed antiplatelets. After adjustment for a propensity score (used to adjust for the non-randomized design), warfarin was associated with a reduced risk of death (0.67; 95% CI, 0.63-0.71) (Paper III). The rate of subsequent hemorrhagic stroke was 0.4 per 100 person-years and the risk did not change (HR 1.04; 95% CI, 0.73-1.48) when later years of the 2000s (inclusion period 2005-8: follow-up until 2009) was compared with earlier years (inclusion period 2001-4: follow-up until 2005) (Paper IV, cohort). Although the risk of first-ever hemorrhagic stroke more than doubled with warfarin than without, the risk did not change between 2006 and 2009 (Paper IV, case-control). In summary, the prescription of secondary preventive drugs varies with age, even though cardiovascular risk factors are prevalent in all ages. The risk of death and hemorrhage are affected by the type of antithrombotic prescribed. Therefore, it is important individual’s stroke and bleeding risks in stroke prevention are assessed.

Background Cerebrovascular disease remains one of the leading causes of morbidity and mortality globally. In South Africa, cerebrovascular disease was the fourth leading cause of death in 2016, responsible for 5.1 % of all deaths - the leading cause of death in individuals 65 years and older. Atrial fibrillation accounts for 15% of all strokes and a 25% of patients with AF-related stroke have this arrhythmia diagnosed at the time of the stroke. Objectives This study sets out to determine the prevalence of atrial fibrillation in patients with ischaemic stroke, as confirmed on CT scan, at a district level hospital in the Western Cape, South Africa. Methods This descriptive study was conducted at Mitchell’s Plain Hospital in Cape Town and data was collected over a year. Patients diagnosed with a stroke were identified from an electronic patient register and relevant radiology and clinical data was sourced retrospectively. The diagnosis of ischaemic stroke was confirmed by a CT scan report and ECGs were independently screened by two Emergency Physicians. Categorical data was described in percentages and descriptive statistics. Continuous variables were described by median and interquartile range (IQR). Statistical significance is defined as a p< 0.05. Categorical data was compared using the Fisher’s exact test. This project has been approved by UCT Human Research Ethics Committee [790/2018]. Results The proportion of adult patients with a diagnosis of stroke was 2%. Of those, 64% had ischaemic strokes, 9% had intracranial bleeds, 20% did not have a CT scan and 7% had stroke mimics. 11% of all participants with ischaemic stroke had atrial fibrillation, 67% of those presumed new. A total of 90 (22%) of all participants with ischaemic stroke was less than 51 years of age. The mortality rate was statistically higher in patients who had AF. Conclusion The results from this study suggests that screening practices to detect both Atrial Fibrillation in asymptomatic patients, as well as in those with an ischaemic stroke, are not effective. With the increasing population life expectancy, and prevalence of cardiovascular disease, the prevalence of AF and its complications will increase. Since the risk of stroke related to AF can be reduced significantly by oral anticoagulation, further studies should aim to explore barriers and challenges to effective screening.

Background: Atrial fibrillation (AF) is the most common arrhythmia and may be complicated by embolic stroke. It is also associated with a significant risk of heart failure and mortality. The burden of rheumatic heart disease remains great in the developing world. The prevalence of AF in those with rheumatic heart disease is in the order of 20% with a resultant 17-fold increased risk of embolic stroke. Over time, many other risk factors for stroke in the AF population have been described. Stroke risk stratification tools such as the CHADS₂ (Congestive heart failure, hypertension, age of 75 or older, diabetes mellitus or stroke/TIA) and CHA₂DS₂VASc (with the addition of a second age category, female gender, and peripheral artery disease) scores have been developed. These are used to assess the need for anticoagulation and have been well validated. These scores have traditionally excluded those patients with valvular AF. Valvular AF has not been studied extensively in the contemporary era. Oral anticoagulation had previously been advised in all patients with valvular AF. Little is known however about outcomes for stroke and mortality in this cohort of patients. Furthermore, the utilization of the CHADS₂ and CHA₂DS₂VASc scores may provide incremental benefit in prognostication and resultantly, both more diligent prescription of anticoagulation and improved outcomes. Objectives: The objectives of this study were as follows - 1. To determine the prevalence of AF in the Global Rheumatic Heart Disease Registry (the REMEDY study) and in the Groote Schuur Hospital (GSH) cohort. 2. To assess the demographic, social and clinical characteristics of patients with AF in the REMEDY study and in the GSH cohort. 3. To assess the frequency of CHADS₂ and CHA₂DS₂VASc risk factors in the GSH cohort and to calculate a CHADS₂ and CHA₂DS₂VASc score on each of the patients with AF. 4. To establish whether CHADS₂ and CHA₂DS₂VASc scores further increase the risk of stroke and death in this cohort of patients with valvular AF. Methods: This is a substudy of the Global Rheumatic Heart Disease Registry (the REMEDY study). We assessed those with AF from the entire cohort for prevalence and outcome data. Patients with ECG or Holter proven AF from the GSH cohort were further risk stratified using the CHADS₂ and CHA₂DS₂Vasc scores. Clinical data was obtained from folder reviews and telephonic interviews. The CHADS₂ and CHA₂DS₂Vasc scores for each patient in the GSH cohort were calculated. Patients were followed up for 2 years and information pertaining to death and stroke were obtained from folder reviews. These were then correlated with the CHADS₂ and CHA₂DS₂Vasc scores. Results: A total of 2624 REMEDY patients were analysed. Of these, 22% in the total cohort (586 of 2684 patients) and 38.2% in the GSH cohort (187 of 489 patients) had AF. These patients were older (35 years vs. 25 years, p<0.0001), more likely to be female (73.1% vs. 65.6%, p=0.001) and more frequently had a history of congestive heart disease (41.0% vs. 33.3%, p=0.001) when compared to those in sinus rhythm. They also had significantly more strokes (13.8% vs. 5%, p<0.0001) and a poorer NYHA class (NYHA III& IV 30.8% vs. 25.2%, p=0.002). The cohort with AF had more severely impaired left ventricular (LV) function compared to those in sinus rhythm (Ejection fraction (EF) 57% vs. 61%. P<0.0001). The presence of a larger left atrial (LA) size, spontaneous echo contrast and LA thrombus was much greater in the AF cohort. Of those patients in AF, only 68% had received a prescription for warfarin. The GSH cohort was risk stratified using the CHADS₂ and CHA₂DS₂VASc scores. Twenty-three percent of patients had a CHADS₂ score of 0 and 27.7% of 1. When the same cohort was scored using the CHA₂DS₂VASc score, only 5.4% had a score of 0; this difference was mainly driven by the additional category of female gender. The patients in our cohort were young (median age 28 years) and had few comorbidities. Despite this, patients with AF did significantly worse than those in sinus rhythm, with a stroke rate of 4.6% and a mortality rate of 13.1% observed at 2 years (compared to a 1.5% stroke rate and 5.5% mortality rate for those in sinus rhythm). The presence of any additional comorbidities significantly reduced survival in both the short and long term. Greater CHA₂DS₂VASc score categories (CHA₂DS₂VASc 1 and CHA₂DS₂VASc 2 or more) conferred an incrementally higher risk of death. Conclusion: In a contemporary cohort of patients with rheumatic heart disease, AF is common with a prevalence of 22-39%. These patients were older and exhibited features of more advanced disease both clinically and on echo, compared to their sinus rhythm counterparts. The mortality and stroke rates in the AF group were high despite the relatively young age of this cohort. Mortality and stroke increased significantly and incrementally with each greater CHA₂DS₂VASc score category. Given the differences in chronicity between RHD in the developed world (i.e., disease of older people) and RHD in developing countries (i.e., disease of the young), these results cannot be extrapolated to those living in the first world.

Background: The risk of ischaemic stroke in patients with atrial fibrillation (AF) and mechanical heart valve (MHV) prostheses can be reduced by oral anticoagulation (OAC), which increases the risk of serious bleeding. The aims of this thesis were [1] to find out how effective and safe warfarin is where treatment quality is high, i.e. Sweden, with proportion of time that patients spend within the therapeutic range (TTR) >70%, [2] whether there is evidence for administering low-molecular-weight heparin (LMWH) during temporary interruptions of OAC (bridging therapy), and whether non-vitamin K-dependent oral anticoagulants (NOACs) as a group, [3] or individually, [4] are more effective and safer than warfarin when used for stroke prevention in patients with AF. Materials and methods: All four studies were retrospective, based on the Swedish anticoagulation register Auricula, and done with merging of data from some or all of the National Patient Register, the Prescribed Drug Register, the Swedish Stroke Register (Riksstroke), and the Cause of Death Register. In studies 2–4, propensity score matching was performed to obtain treatment groups with similar risk profiles. Outcomes were defined as haemorrhages or thromboses requiring specialist care, or death. Haemorrhages were intracranial, gastrointestinal, or other. Thromboses were ischaemic stroke, systemic embolism, myocardial infarction, or venous thromboembolism (VTE). Study 1 described all patients on warfarin during 2006–2011, which was before the introduction of NOACs. Study 2 was a cohort study of all patients who had a planned interruption of warfarin during the same period. Study 3 included all 49,011 patients starting OAC for stroke prevention due to AF between 1 July 2011 and 31 December 2014, and study 4 all 64,382 patients with the same indication between 1 January 2013 and 31 December 2015. Results: Study 1 showed that for the 77,423 patients on warfarin with 217,804 treatment years, TTR was 77.4% for patients with AF, 74.5% with MHV, and 75.9% with VTE. Annual rates of intracranial bleeding were 0.38%, 0.51%, and 0.30%. In study 2, with 14,556 warfarin interruptions, the 30-day risk of a bleeding requiring specialist care was 0.64% for LMWH treated and 0.46% for controls. For patients with VTE as indication for OAC, bleeding rate with LMWH was significantly higher at 0.85% vs. 0.16% (hazard ratio 5.24, 95% confidence interval 1.39–19.77), but with no difference for patients with MHV or AF. The incidence of ischaemic complications was higher in the LMWH bridging group overall and for patients with MHV and AF, but not for patients with VTE. In study 3, for the 12,694 patients starting NOAC (10,392 treatment years) or matched warfarin patients (9,835 treatment years, TTR 70%) due to AF, annual incidence of ischaemic stroke and systemic embolism did not differ between the groups (1.35% vs. 1.58%), but risks of major bleedings and intracranial bleedings were significantly lower: 2.76% vs. 3.61% and 0.40% vs. 0.69%. In study 4, patients on individual NOACs (6,574 dabigatran, 8,323 rivaroxaban, 12,311 apixaban) were compared to 37,174 patients starting warfarin (in total 81,176 treatment years). No NOAC showed any difference in risk of ischaemic stroke or systemic embolism, but there were fewer intracranial bleedings, serious bleedings overall, and deaths for dabigatran and apixaban compared to warfarin. For patients starting rivaroxaban the risk of gastrointestinal bleeding was higher than for matched warfarin counterparts, with no significant differences in other bleeding risks, or mortality. Conclusions: Swedish warfarin treatment shows TTR levels that are high by international standards, correlating to low incidences of ischaemic and haemorrhagic events. LMWH bridging has not been proven beneficial, even for patients with MHV, meaning that bridging in general cannot be recommended. NOACs as a group were safer than high-quality warfarin treatment. Efficacy did not differ, even when comparing individual NOACs to warfarin, but there were fewer bleedings on dabigatran and apixaban. Although not more efficient than warfarin with a high TTR, NOACs should be the recommended first choice for OAC in AF, on the merit of lower bleeding risks.

Finansiär: Forskning och Utveckling, Region Västernorrland

La Fibrillazione Atriale è associata a un incremento di quattro-cinque volte del rischio di eventi cerebrovascolari, i quali sono ritenuti responsabili del 15% di tutti gli strokes. In questo contesto, alcuni studi clinici hanno suggerito che la stratificazione del rischio di stroke potrebbe essere sensibilmente migliorata utilizzando le informazioni emodinamiche sull'atrio sinistro e in particolare sull'auricola sinistra. L'obiettivo di questo studio è stato lo sviluppo di un modello fluidodinamico computazionale paziente specifico, il quale potrebbe quantificare le implicazioni emodinamiche della fibrillazione atriale su una base paziente-specifica. Questo modello potrebbe consentire un miglioramento della stratificazione del rischio di stroke del paziente e l'ottimizzazione della terapia. L'acquizione di dati CT dinamici cardiaci è stata utilizzata per derivare il modello anatomico 3D dell'atrio sinistro paziente specifico, tramite la progettazione e l'applicazione di un algoritmo di segmentazione. Successivamente, è stato sviluppato il modello computazionale per risolvere la fluidodinamica all'interno dell'atrio sinistro. I dati Doppler acquisiti in corrispondenza dell’ingresso delle vene polmonari e della valvola mitrale, in pazienti affetti da fibrillazione atriale, sono stati utilizzati per la definizione delle condizioni al contorno del modello fluidodinamico. In questa Tesi, verrà descritto in dettaglio il modello sviluppato e la applicazione di esso su due pazienti affetti da fibrillazione atriale persistente. I risultati hanno evidenziato che il modello ha restituito profili di velocità realistici e ha mostrato una riduzione nello svuotamento di sangue nell'auricola sinistra. Queste indicazioni confermano, mediante un modello computazionale fluidodinamico paziente-specifico, che la fibrillazione atriale aumenta il rischio di stroke a causa di un possibile ristagno di sangue, soprattutto in regioni specifiche, quali l'auricola sinistra.

Background Many risk factors for stroke are well characterized and might, at least to some extent, be similar for first-ever stroke and for recurrent stroke events. However, previous studies have shown heterogeneous results on predictors and rates of stroke recurrence. Patients who survive spontaneous intracerebral hemorrhage (ICH) often have compelling indications for antithrombotic (AT) treatment (antiplatelet (AP) and/or anticoagulant (AC) treatment), but due to controversy of the decision to treat, a large proportion of these patients are untreated. In the absence of evidence from randomized controlled trials (RCTs), there is need for more high- quality observational data on the clinical impact of, and optimal timing of AT in ICH survivors. The aims of this thesis were to assess time trends in stroke recurrence, to determine the factors associated with an increased risk of stroke recurrence – including socioeconomic factors – and to determine to what extent ICH survivors with and without atrial fibrillation (AF) receive AT treatment and to determine the optimal timing (if any) of such treatment.  Methods The population-based Monitoring Trends and Determinants of Cardiovascular Disease (MONICA) stroke incidence register was used to assess the epidemiology and predictors of stroke recurrence after ischemic stroke (IS) and ICH from 1995 to 2008 in northern Sweden. Riksstroke, the Swedish stroke register, linked with the National Patient Register and the Swedish Dispensed Drug Register, made it possible to identify survivors of first-ever ICH from 2005 to 2012 with and without concomitant AF to investigate to what extent these patients were prescribed AP and AC therapy. The optimal timing of initiating treatment following ICH in patients with AF 2005–2012 was described through separate cumulative incidence functions for severe thrombotic and hemorrhagic events and for the combined endpoint “vascular death or non-fatal stroke”. Riksstroke data on first-ever stroke patients from 2001 to 2012 was linked to the Longitudinal Integration Database for Health Insurance and Labour market studies to add information on education and income to investigate the relationship between socioeconomic status and risk of recurrence. Results Comparison between the cohorts of 1995–1998 and 2004–2008 showed declining risk of stroke recurrence (hazard ratio: 0.64, 95% confidence interval (CI): 0.52-0.78) in northern Sweden. Significant factors associated with an increased risk of stroke recurrence were age and diabetes. Following ICH, a majority (62%) of recurrent stroke events were ischemic.  The nationwide Riksstroke study confirmed the declining incidence, and it further concluded that low income, primary school as highest attained level of education, and living alone were associated with a higher risk of recurrence beyond the acute phase. The inverse effects of socioeconomic status on risk of recurrence did not differ between men and women and persisted over the study period. Of Swedish ICH-survivors with AF, 8.5% were prescribed AC and 36.6% AP treatment, within 6 months of ICH. In patients with AF, predictors of AC treatment were less severe ICH, younger age, previous anticoagulation, valvular disease and previous IS. High CHA2DS2-VASc scores did not seem to correlate with AC treatment. We observed both an increasing proportion of AC treatment at time of the initial ICH (8.1% in 2006 compared with 14.6% in 2012) and a secular trend of increasing AC use one year after discharge (8.3% in 2006 versus 17.2% in 2011) (p<0.001 assuming linear trends). In patients with high cardiovascular event risk, AC treatment was associated with a reduced risk of vascular death and non-fatal stroke with no significantly increased risk of severe hemorrhage. The benefit appeared to be greatest when treatment was started 7–8 weeks after ICH. For high-risk women, the total risk of vascular death or stroke recurrence within three years was 17.0% when AC treatment was initiated eight weeks after ICH and 28.6% without any antithrombotic treatment (95% CI for difference: 1.4% to 21.8%). For high-risk men, the corresponding risks were 14.3% vs. 23.6% (95% CI for difference: 0.4% to 18.2%). Conclusion Stroke recurrence is declining in Sweden, but it is still common among stroke survivors and has a severe impact on patient morbidity and mortality. Age, diabetes and low socioeconomic status are predictors of stroke recurrence. Regarding ICH survivors with concomitant AF, physicians face the clinical dilemma of balancing the risks of thrombosis and bleeding. In awaiting evidence from RCTs, our results show that AC treatment in ICH survivors with AF was initiated more frequently over the study period, which seems beneficial, particularly in high-risk patients. The optimal timing of anticoagulation following ICH in AF patients seems to be around 7–8 weeks following the hemorrhage.

OBJECTIVES: To assess cost effectiveness of anticoagulant clinics after FDA approval of New Oral Anticoagulants (NOACs) for preventing ischemic stroke in Atrial Fibrillation (AF) patients in the United States. METHODS: A decision tree was built to compare cost and effectiveness of 150mg dabigatran twice a day to adjusted dose of warfarin within anticoagulation clinic. The analysis was for one year using a societal perspective. The population in this analysis was a cohort of AF patients, ≥ 65 years old, with a CHADS2 score>2, and no contraindication to anticoagulation. RESULTS: The base case analysis showed that changing from warfarin with anticoagulant clinic to dabigatran without monitoring resulted in an additional $82,793 per QALY saved. Sensitivity analyses found that the model was sensitive to utilities of patients on warfarin. CONCLUSION: This study showed that substituting dabigatran for warfarin in this population was not within acceptable willingness to pay values for new therapy.

Background The prevalence and incidence of stroke are known to increase with age, which, combined with demographic change, means that very old patients with stroke are a growing patient group. Risk factors for incident stroke among very old people have not been widely investigated. The impact of depression on mortality in very old people who have had a stroke also remains unclear.  The aim of this thesis was to investigate the risk factors for incident stroke, the epidemiology of stroke and depression, and the consequences of having had a stroke regarding the risk of depression and mortality among very old people. Methods A randomly selected half of 85-, all 90-, and all ≥95-year-olds in certain municipalities in Västerbotten County, Sweden, and Pohjanmaa County, Finland were targeted in a population-based cohort study from 2000-2012. The 65-, 70-, 75-, and 80-year-olds in all the rural and random samples from the urban municipalities in the same counties were furthermore targeted in a survey in 2010. In the cohort study patients were assessed in their homes, by means of the 15-item Geriatric Depression Scale (GDS-15) and other assessment scales, as well as blood pressure measurements, several physical tests, and a review of medical diagnoses appearing in the medical charts. Incident stroke data were collected from medical charts guided by hospital registry records, cause of death records, and reassessments after 5 years. Depression was defined as a GDS-15 score ≥5. A clinical definition of all depressive disorders, based on assessment scale scores and review of medical charts was also used. A specialist in geriatric medicine evaluated the diagnoses. The survey included yes/no questions about stroke and depression status, and the 4-item Geriatric Depression Scale. Associations with mortality and incident stroke were tested using Cox proportional-hazard models.  Results In the ≥85-year-olds examined in 2005-2007 (n=601), the stroke prevalence was 21.5%, the prevalence of all depressive disorders was 37.8% and stroke was independently associated with depressive disorders (odds ratio 1.644, p=0.038). The prevalence of depression according to GDS-15 scores was 43.2% in people with stroke compared with 25.0% in people without stroke (p=0.001). However, in ≥85-year-olds examined in Sweden from 2000-2012 (n=955), from all past data collections in the study, depression was not independently associated with incident stroke.  In ≥65-year-olds who responded to a survey in 2010 (n=6098), the stroke prevalence rose with age from 4.7% among the 65- to 11.6% among the 80-year-olds (p<0.001). The prevalence of depression rose from 11.0% among the 65- to 18.1% among the 80-year-olds (p<0.001). In the group with stroke, depression was independently associated with dependence in personal activities of daily living and having a life crisis the preceding year, while in the non-stroke group, depression was independently associated with several additional demographic, social and health factors. In ≥85-year-olds examined in 2005-2007 with valid GDS-15 tests (n=452), having had a stroke was associated with increased 5-year mortality [hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.15-2.03]. Having had a stroke and depression was associated with increased 5-year mortality compared with having only stroke (HR 1.90, 95% CI 1.15-3.13), having only depression (HR 1.59, 95% CI 1.03-2.45), and compared with having neither stroke nor depression (HR 2.50, 95% CI 1.69-3.69). Having only stroke without a depression did not increase mortality compared with having neither stroke nor depression. In ≥85-year-olds examined in Sweden from 2000-2012 (n=955), from all past data collections in the study, the stroke incidence was 33.8/1000 person-years during a mean follow-up period of about three years. In a comprehensive multivariate model, atrial fibrillation (HR 1.85, 95% CI 1.07–3.19) and higher systolic blood pressure (SBP; HR 1.19, 95% CI 1.08–1.30 per 10-mmHg increase) were associated with incident stroke overall. In additional multivariate models, diastolic blood pressure (DBP) ≥90 mmHg (HR 2.45, 95% CI 1.47–4.08) and SBP ≥160 mmHg (v. <140 mmHg; HR 2.80, 95% CI 1.53–5.14) were associated with incident stroke. Conclusion The prevalence of both stroke and depression increased with age, and rates were especially high among very old people. Having had a stroke was independently associated with a higher prevalence of depression among very old people, however, depression was not independently associated with a higher incidence of stroke. Having had a stroke was associated with increased all-cause mortality among very old people, but only among those who were also depressed. High SBP (≥160 mmHg), DBP (≥90 mmHg) and atrial fibrillation were the only consistent independent risk factors for incident stroke among very old people.
I västvärlden inklusive Sverige så ökar gruppen av människor som uppnår åldern 80 år eller äldre. Människorna som uppnår denna mycket höga ålder har en hög förekomst av kardiovaskulära riskfaktorer, har ofta flera samtidiga sjukdomar och ofta funktionsnedsättningar. Medicinska behandlingsåtgärder är ofta mindre effektiva och förknippade med biverkningar i åldersgruppen. Stroke är en sjukdom som beror på skada av hjärnvävnad till följd av minskad blodtillhörsel till delar av hjärnan. Det är känt att såväl förekomsten av och insjuknandet i stroke ökar med stigande ålder. Den som drabbas av stroke löper risk att få en bestående funktionsnedsättning och att dö i förtid. En vanlig komplikation efter att ha drabbats av stroke är nedstämdhet eller depression. Vetenskapliga studier om stroke har tidigare negligerat mycket gamla människor, vilket i takt med den pågående demografiska utvecklingen framstått som allt mer orimligt. Det är ej helt klarlagt vilka riskfaktorer som leder till att insjukna med stroke i mycket hög ålder. Överdödligheten förknippad med att drabbas av depression efter stroke är också oklar i åldersgruppen. Det är också oklart vad som skiljer depression efter stroke från depression bland den övriga befolkningen av åldrade människor. Den populations-baserade kohortstudien GErontologisk Regional DAtabas (GERDA) inleddes år 2000 för att kartlägga faktorer förknippade med gott åldrande bland mycket gamla människor. Hälften av 85-åringarna, alla 90-åringar och alla ≥95-åringar i utvalda kommuner i Västerbotten erbjöds att delta i studien. Därefter har återbesök hos tidigare deltagare i sina nya åldersgrupper och rekrytering av nya deltagare genomförts vart femte år. Studien utvidgades med utvalda kommuner i Österbotten, Finland vid den första femårsuppföljningen. Datainsamlingen i studien bestod av demografiska frågor, skattningsskalor, blodtrycksmätning och kognitiva test genomförda vid ett hembesök i deltagarens hem, samt genomgång av journalhandlingar. År 2010 skickades även en enkät ut till 65-, 70-, 75- och 80-åringar i alla kommuner i Västerbotten och Österbotten. Enkäten innehöll frågor om demografi, hälsa, sjukdomar och intressen. Bland deltagarna i kohortstudien bestämdes förekomsten av tidigare stroke baserat på genomgång av journaluppgifter och uppgifter från hembesöken. Förekomsten av depression bestämdes baserat på poängsättning från en validerad skattningsskala för depression, samt baserat på en sammanvägning av journaluppgifter och skattningsskalor. En specialist i geriatrik fattade det slutliga beslutet om diagnoser. Insjuknande i stroke bestämdes baserat på journalgenomgång av individer med stroke-relaterade diagnoskoder i sjukhusregistret, i dödsorsaksregistret eller uppgift om stroke vid femårsuppföljningen i studien. Bland deltagarna i enkätstudien bestämdes förekomsten av tidigare stroke baserat på självrapportering, och förekomsten av depression bestämdes baserat på en sammanvägning av självrapportering och en skattningsskala för depression.  Förekomsten av stroke i enkätstudien steg med ålder, från 4.7% bland 65-åringar till 11.6% bland 80-åringar. Förekomsten av stroke var omkring 20% bland ≥85-åringar, med minimal variation mellan 85-, 90- och ≥95-åringar. Förekomsten av depression var högre bland dem med stroke jämfört med de övriga deltagarna, både gällande den sammavägda diagnosen och baserat endast på poängsättning. Stroke och sömnproblem var oberoende associerade med depression. Bland ≥65-åringar i enkätstudien var funktionsnedsättning och genomgången livskris associerade med depression hos dem med en tidigare stroke. Bland deltagare utan stroke var ett antal ytterligare externa faktorer, inklusive subjektiv upplevelse av dålig ekonomi och att inte ha någon att anförtro sig till, associerade med depression. Både stroke och depression var associerade med ökad dödlighet bland ≥85-åringar. De med stroke utan depression hade en dödlighet i linje med normalbefolkningen utan stroke eller depression. Förekomsten av samtidig stroke och depression var associerad med högre dödlighet än normalbefolkningen, jämfört med dem med enbart stroke eller enbart depression. Högt systoliskt blodtryck (≥160 mmHg), högt diastoliskt blodtryck (≥90 mmHg) och förmaksflimmer var oberoende riskfaktorer för att insjukna i stroke bland ≥85-åringarna. Sambandet mellan blodtryck och strokerisk försvagades ej hos människor med kognitiv eller funktionell nedsättning. Tidigare stroke, hjärtsvikt, kognitiv nedsättning, näringsbrist, depressiva symtom och låg gånghastighet var också associerade med att insjukna i stroke, men ej oberoende av varandra. Sammanfattningsvis så stiger förekomsten av stroke med åldern och är särskilt hög bland mycket gamla människor. Depression är betydligt vanligare hos mycket gamla människor med stroke, även justerat för störningsfaktorer. Depression är främst associerat med funktions-nedsättning hos människor med stroke, men med ett större antal externa faktorer hos människor utan stroke. Mycket gamla människor med stroke har särskilt hög dödlighet om de samtidigt är deprimerade, men en dödlighet i linje med normalbefolkningen om de inte är deprimerade. Högt systoliskt och diastoliskt blodtryck samt förmaksflimmer är viktiga och behandlingsbara orsaker till att drabbas av stroke i mycket hög ålder.

Objectives. (1) To develop a probability trade-off technique (PTOT) for determining the minimal clinically important difference (MCID) of warfarin therapy from the patients' perspective; (2) to estimate the MCID for the efficacy of warfarin to prevent stroke in the treatment of nonvalvular atrial fibrillation (NVAF) from the perspective of patients with this disease and who have experienced a course of warfarin therapy; (3) to assess two different methods of eliciting the patients' MCID. The two elicitation methods were: (1) ping-ponging (PP), in which the hypothetical efficacy of warfarin to prevent stroke was varied from one extreme to the other until the patients' MCID was determined; and (2) starting at known efficacy (SKE), in which the hypothetical efficacy was started at a midpoint value and then incrementally increased or decreased until the patients' MCID was determined. Conclusions. The MCID for this group of patients was much smaller than the known efficacy of warfarin to prevent stroke in patients with NVAF. The PTOT, using the flipchart approach, was well accepted and appeared to improve their knowledge of their disease, and its consequences and treatment. The method of elicitation used to determine the patients' MCIDs can have a clinically important effect on their responses. (Abstract shortened by UMI.)

La fibril·lació auricular (FA) és l’arítmia crònica més freqüent. S’associa amb una àmplia varietat de malalties cardiovasculars i les seves conseqüències clíniques més importants són un major risc d’ictus i mortalitat respecte a la població general. El maneig de la FA es porta a terme principalment des de l’Atenció Primària i està basat en la prevenció de l’ictus, el control farmacològic de la freqüència i del ritme cardíac i el maneig de les patologies cardiovasculars concomitants. Aquesta tesi forma part de l’estudi ESC-FA (Efectivitat, Seguretat i Costos en FA), que és un estudi de cohorts retrospectiu de base poblacional amb dades procedents dels registres electrònics de la història clínica d’Atenció Primària a Catalunya. L’estudi ESCFA va rebre finançament amb els ajuts a la Recerca Clínica Independent del 2011 del Ministerio de Sanidad, Política Social e Igualdad del Govern Espanyol. L’ESC-FA és un estudi amb quatre fases o subestudis; I a IV, i la tesi inclou els estudis I i II. Els resultats de l’estudi I es descriuen en un article publicat (article 1) i en un altre actualment en revisió per la seva publicació (article 2). Els resultats de l’estudi 2 estan publicats a l’article 3. La població d’estudi inclou totes les persones ≥18 anys amb diagnòstic de FA no valvular registrat a la base de dades SIDIAP (Sistema d’Informació pel Desenvolupament de la Investigació en Atenció Primària) durant el període 2007-2012, i que van iniciar tractament antitrombòtic (o van romandre sense aquest tractament) just després del diagnòstic de la FA. A l’estudi I es descriu l’ús d’antitrombòtics en 22 585 pacients amb FA no valvular, i s’avaluen l’efectivitat i seguretat d’aquests fàrmacs en condicions reals d’ús, abans de la introducció dels anticoagulants orals directes en el maneig d’aquesta patologia. Els nostres resultats principals inclouen: una població amb FA no valvular de característiques sociodemogràfiques i clíniques semblants a la població inclosa en altres estudis, una reducció del risc d’ictus en pacients tractats amb antagonistes de vitamina K i amb elevat risc de patir aquest esdeveniment (puntuacions de CHADS2 i CHA2DS2-VASc ≥2), un augment del risc d’ictus i d’hemorràgia digestiva en els pacients tractats amb antiagregants plaquetaris, i una reducció del risc de mortalitat per qualsevol causa tant amb antagonistes de vitamina K com amb antiagregants; respecte al grup de pacients no tractats amb antitrombòtics. A l’estudi II es descriu el maneig farmacològic de la freqüència i ritme cardíac en FA no valvular. El grup de fàrmacs més utilitzat van ser els β-blocadors, indicant probablement que l’estratègia de control de la freqüència cardíaca és l’alternativa més usada, tal i com es recomana com a teràpia d’elecció en el maneig de la FA crònica. Algunes fortaleses del nostre estudi inclouen la gran mostra de pacients estudiats, l’elevada representativitat de la població general, dades sociodemogràfiques i clíniques molt completes i llargs períodes de seguiment; tot en condicions reals d’ús. Es tracta d’un estudi molt rellevant al nostre entorn, donat què avalua el nombre real de pacients tractats amb antitrombòtics i els resultats clínics que se’n deriven del seu ús en termes d’incidència d’ictus, hemorràgies cerebrals i digestives, i mortalitat per qualsevol causa; abans d’avaluar aquests resultats incloent el grup d’anticoagulants orals directes que s’han començat a utilitzar en els últims anys. Algunes limitacions dels estudis desenvolupats amb dades procedents de registres electrònics de la història clínica són la informació faltant, l’infrarregistre, la informació no recollida sobre certes circumstàncies dels pacients en aquest tipus de registres, i els possibles confusors. La majoria d’aquestes limitacions es poden minimitzar amb l’ús de les tècniques estadístiques adequades, descrites als articles inclosos a la tesi.
Atrial fibrillation (AF) is the most common chronic arrhythmia. It is associated with a variety of cardiovascular conditions and the most important clinical consequences are higher risks of stroke and mortality than general population. AF management increasingly takes place in Primary Healthcare settings and it is based in stroke prevention, pharmacological control of heart rate and rhythm and handling of concomitant cardiovascular diseases. This thesis is part of the ESC-FA study (Effectiveness, Safety and Costs in AF), which is a population-based retrospective observational cohort study conducted with data from electronic health records from Primary Healthcare in Catalonia. ESC-FA study received funding through 2011 Grants for Independent Clinical Research from the Ministerio de Sanidad, Política Social e Igualdad from the Spanish Government. ESC-FA consists in four sub-studies; I to IV, and this thesis includes studies I and II. Study I results are reported in one published paper (paper 1) and in another paper which is currently under review (paper 2). Study II results are published in paper 3. The study population includes all individuals ≥18 years-old with a diagnosis of nonvalvular AF registered in SIDIAP (Information System for the Improvement of Research in Primary Care) database during 2007-2012, who started antithrombotic treatment (or remained without it) after AF diagnosis. In study I we describe antithrombotic use in 22 585 patients with non-valvular AF and assess effectiveness and safety of these drugs in real-use conditions before the introduction of direct oral anticoagulants in the management of the disease. Our main results showed: a non-valvular AF population with socio-demographic and clinical features similar to those in other populations, a reduction of stroke risk in patients treated with vitamin K antagonists who have higher risks of stroke (CHADS2 and CHA2DS2-VASc index ≥2), an increased risk of stroke and gastrointestinal haemorrhage with antiplatelets and a reduced risk of all-cause mortality with both vitamin K antagonists and antiplatelets, in comparison with patients who were not treated with any antithrombotics. In study II we describe heart rate and rhythm pharmacological management in nonvalvular AF patients. Mostly prescribed drugs were β-blockers, probably pointing out that rate control strategy is the most frequent alternative used, as widely recommended as first-line therapy for management of chronic AF. Some strengths of our study are the large number of patients included, representativeness for the general population, complete socio-demographic and health records, long follow-up, and real clinical practice data. This study has high relevance in our setting as it assesses the real number of patients treated with traditional antithrombotics and the clinical results of their use in terms of stroke, haemorrhages and mortality rates, before assessing these clinical results including direct oral anticoagulants, which have been authorized for non-valvular AF in the last years. Some weaknesses of observational studies conducted with electronic health records are missing or incomplete information, under-register of some health conditions, nonregistered information of some personal circumstances of patients and possible confounders. These limitations have been minimized using the appropriate statistical techniques described in the papers included.

Si bé la relació entre la fibril.lació auricular (FA) i els ictus isquèmics està ben establerta i demostrada, existeix escassa informació de l’associació entre arítmies supraventriculars diferents de la fibril.lació auricular i/o el flutter auricular i els ictus isquèmics. L’objectiu del treball és determinar si la taquicàrdia auricular que presenten pacients ingressats per ictus criptogènic es relaciona amb fibril.lació auricular o ictus durant el seguiment. Es van analitzar de forma retrospectiva dades de pacients consecutius ingressats amb ictus criptogènic, els quals es van sotmetre a un holter de 24 hores. Es van comparar pacients amb i sense salves auriculars en el holter en relació a la incidència de fibril.lació auricular, recurrència dels ictus i mortalitat cardiovascular durant 12 mesos i 4 anys de seguiment. Es van repetir totes les anàlisis després d’excloure els pacients que van rebre anticoagulació després de l’esdeveniment índex i a l’alta, per motius fora dels establerts en les guies de pràctica clínica i sota criteris del metge tractant. S’ha de destacar que aquest treball ha estat realitzat amb elements i proves diagnòstiques habituals i rutinàries en la pràctica clínica, i disponibles en la majoria de centres sanitaris. En total es van incloure 192 pacients (78 amb salves auriculars en el holter i 114 sense) no anticoagulats, i 16 pacients que van rebre anticoagulació a l’alta per sospita de FA, tot i que no demostrada (10 amb salves auriculars en el holter). Les característiques basals entre els dos grups no presentaven diferències significatives. Els pacients amb salves auriculars en el holter presentaven més incidència de FA, de recurrència d’ictus i de mortalitat cardiovascular als 12 mesos de seguiment, tot i que aquesta diferència només era evident en l’anàlisi excloent els pacients anticoagulats. La fibril.lació auricular continuava sent més elevada en el grup de pacients amb salves auriculars als 4 anys de seguiment. Com a conclusió, la presència de salves auriculars en el holter de 24 hores de pacients ingressats per ictus criptogènic pot identificar pacients amb alt risc per desenvolupar FA, recurrència d’ictus i mortalitat cardiovascular, en un període de seguiment relativament curt (12 mesos). Es pot arribar a la conclusió, després d’aquest treball, que els pacients amb alta sospita clínica de FA per la presència de salves auriculars en el holter, es podrien beneficiar de tractament anticoagulant a curt i llarg termini.
Although the relationship between atrial fibrillation (AF) or atrial flutter and ischemic stroke has been well established and demonstrated, there is few information about the association between supraventricular arrhythmias different from atrial fibrillation or atrial flutter and stroke. The aim of this study was to determine whether atrial tachycardia in patients hospitalized for cryptogenic stroke was associated with atrial fibrillation and recurrence of stroke during a period of follow-up. We retrospectively analysed consecutive patients with cryptogenic stroke who underwent 24-hour holter monitoring. We compared patients with and without atrial tachycardia on atrial fibrillation, recurrence of stroke and cardiovascular mortality during 12 months and after 4 years of follow-up. We repeated all analyses after excluding patients prescribed anticoagulation after discharge under physician criteria. It is worth to mention that subjects in our study underwent only conventional tests that are widely used and available in clinical practice. We included 192 patients (78 with atrial tachycardia and 114 without) non-anticoagulated, and 16 patients who received anticoagulation for suspected but unconfirmed atrial fibrillation after discharge (10 of them with atrial tachycardia). Baseline characteristics between both groups did not differ. Patients with atrial tachycardia had higher incidences of atrial fibrillation, recurrent stroke and cardiovascular mortality at 12 months of follow-up. The higher incidence of stroke and cardiovascular mortality in the group with atrial tachycardia was only seen in the analysis excluding anticoagulated patients. Atrial fibrillation was still more frequent in patients with atrial tachycardia at 4 years follow-up. So, in conclusion, the presence of atrial tachycardia in 24 hour holter monitoring of patients with cryptogenic stroke could identify patients with increased risk of atrial fibrillation, stroke recurrence and cardiovascular mortality, especially in the early follow-up period. Patients suffered from cryptogenic stroke and with highly clinically suspected atrial fibrillation for the presence of atrial tachycardia in holter, might benefit from anticoagulation.

Abstract The identification of risk factors for major adverse events after coronary artery bypass surgery is of main importance as it allows outcome prediction, facilitates preoperative patient selection and improves the quality of care. In the present clinical studies we have evaluated the impact of preoperative angiographic severity of a coronary artery disease and preoperative C-reactive protein (CRP) on the immediate outcome after coronary artery bypass surgery. We have reviewed the results of off-pump (OPCAB) versus conventional on-pump coronary artery bypass surgery (CCAB) in high risk patients. We have evaluated the impact of postoperative pulmonary artery blood temperature on the immediate outcome as well. In addition, we have investigated the incidence, timing and outcome of an atrial fibrillation (AF) related stroke after surgery. The multivariate analysis showed that among 2233 patients, the overall coronary angiographic score was predictive of postoperative death (p = 0.03; OR 1.027, 95% CI: 1.003–1.052) and of a low cardiac output syndrome (p = 0.04; OR 1.172, 95% CI: 1.010–1.218). The poor status of the proximal segment of the left circumflex coronary artery, the diagonal branches and the left obtuse marginal artery were most closely associated with adverse postoperative outcome. Patients (114/764) with a preoperative serum concentration of CRP ≥ 1.0 mg/dL had a higher risk of overall postoperative death (5.3% vs. 1.1%, p = 0.001), cardiac death (4.4% vs. 0.8%, p = 0.002), a low cardiac output syndrome (8.8% vs. 3.7%, p = 0.01). Among 179 high risk patients with an additive EuroSCORE6, the 30-day postoperative death and stroke rates were 7.5% and 6.0% in the OPCAB group, and 5.4% (p = 0.75) and 8.0% (p = 0.77) in the CCAB group, respectively. No significant differences were observed in other major outcome end-points between these non-randomised groups either. High pulmonary artery blood temperature on admission to the ICU among 1639 patients was significantly associated with an increased risk of overall postoperative death (p = 0.002), cardiac death (p = 0.03), and a low cardiac output syndrome (p < 0.0001), and was significantly correlated with prolonged length of the ICU stay (r = 0.095; p < 0.0001), and postoperative bleeding (ρ = –0.091; p = 0.001). Among 2,630 patients who underwent coronary artery bypass grafting (CABG), 52 (2.0%) experienced a postoperative stroke. Twelve out of these 52 patients (23.1%) died postoperatively. The ischemic cerebral event occurred after a mean of 3.7 days (0–33). In 19 patients (36.5%), atrial fibrillation preceded the occurrence of neurological complication. The angiographic severity of the coronary artery disease and the preoperative serum concentration of CRP predict postoperative outcome after a CABG operation. OPCAB can be performed safely in high-risk patients with results as satisfactory as those achieved with CCAB. CABG patients with a high pulmonary artery blood temperature on admission to the ICU seem to have a higher risk of postoperative adverse events. Atrial fibrillation occurring after coronary artery bypass grafting is a major determinant of a postoperative stroke.

INTRODUCCIÓ: La fibril·lació auricular (FA) es una de les arítmies més freqüents a nivell mundial. Es imprescindible detectar FA de forma precoç; es disposa de poques escales de risc per detectar FA. OBJECTIUS: Desenvolupar una escala clínica per estratificar el risc de desenvolupar FA entre pacients diabètics i hipertensos, aplicant-la posteriorment a població general. També, avaluar aquesta escala de risc de FA i la seva relació amb la incidència d’ictus isquèmic y la prevalença de deteriorament cognitiu. MATERIALS I MÈTODES: Estudi observacional, comunitari i multicèntric a les Terres de l'Ebre, el primer de 8.237 pacients diabètics i hipertensos; el segon de 46.706 pacients ≥ 65 anys en la població general. Al primer estudi es va realitzar una regressió de Cox per identificar predictors de FA i amb aquests es va crear una escala de risc de FA per quartils. Aquesta fórmula posteriorment es va aplicar a la població del segon estudi. RESULTATS: Els predictors de risc de FA van ser CHA2DS2VASc, edat, pes, freqüència cardíaca i sexe femení. Amb aquests es va crear una escala de risc de FA. El grup de major risc de FA del primer article es va caracteritzar per major edat (85,95±6,03, p<0,001), proporció de dones (85,2%, p<0,001), densitat d’incidència (DI) de FA (22,5/1.000 persones/any), DI d’ictus (3,5/1.000 persones/any), mortalitat total (22,7%, p<0,001) i per un NNS més baix (9). El grup de major risc de FA del segon article es va caracteritzar per major edat (87,5±7,4, p<0,001), proporció de dones (78,2%, p<0,001), DI de FA (17,0/1.000 persones/any), DI d’ictus (3,8/1.000 persones/any), deteriorament cognitiu (16,4%, p<0,001) i per un NNS més baix (19). CONCLUSIONS: Aquest model d’estratificació del risc permet discriminar aquells pacients en major risc de FA en cinc anys de seguiment que estan associats a una major incidència d’ictus i prevalença de deteriorament cognitiu.
INTRODUCCIÓN: La fibrilación auricular (FA) es una de las arritmias más frecuentes a nivel mundial. Es imprescindible detectar FA de forma precoz; se dispone de pocas escalas de riesgo para detectar FA. OBJETIVOS: Desarrollar un score clínico para estratificar el riesgo de FA entre pacientes diabéticos e hipertensos y aplicarlo posteriormente a población general. También, evaluar este score clínico de riesgo y su relación con la incidencia de ictus isquémico y la prevalencia de deterioro cognitivo. MATERIAL Y MÉTODOS: Estudio observacional, comunitario y multicéntrico en las Terres de l'Ebre, el primero de 8.237 pacientes diabéticos e hipertensos y el segundo de 46.706 pacientes ≥ 65 años en la población general. En el primer estudio se realizó una regresión de Cox para identificar predictores de FA y con estos se creó una escala de riesgo de FA por cuartiles. Está fórmula posteriormente se aplicó a la población del segundo estudio. RESULTADOS: Los predictores de riesgo de FA fueron CHA2DS2VASc, edad, peso, frecuencia cardíaca y sexo femenino (p<0,05). Con estos se creó la escala de riesgo de FA. El grupo de mayor riesgo de FA del primer artículo se caracterizó por una mayor edad (85,95±6,03, p<0,001), proporción de mujeres (85,2%, p<0,001), densidad de incidencia (DI) de FA (22,5/1.000 personas/año), DI de ictus (3,5/1.000 personas/año), mortalidad total (22,7%, p<0,001) y por un NNS más bajo (9). El grupo de mayor riesgo de FA del segundo artículo se caracterizó por una mayor edad (87,5±7,4, p<0,001), proporción de mujeres (78,2%, p<0,001), DI de FA (17,0/1.000 personas/año), DI de ictus (3,8/1.000 personas/año), deterioro cognitivo (16,4%, p<0,001) y por un NNS más bajo (19). CONCLUSIONES: Este modelo permite discriminar aquellos pacientes con mayor riesgo de FA en cinco años de seguimiento que están asociados a una mayor incidencia de ictus y prevalencia de deterioro cognitivo.
INTRODUCTION: Atrial fibrillation (AF) is one of the most frequent arrhythmias worldwide. It is essential to detect AF early; few risk scales are available to detect AF. OBJECTIVES: To develop a clinical score to stratify the risk of suffering AF among diabetic and hypertensive patients and subsequently apply it to the general population. Also, evaluate this clinical AF risk score and its relationship with the incidence of ischemic stroke and the prevalence of cognitive impairment. MATERIAL AND METHODS: Observational, community and multicenter study in Terres de l'Ebre, the first study of 8,237 diabetic and hypertensive patients and the second of 46,706 patients ≥ 65 years in the general population. In the first study, a Cox regression was performed to identify predictors of AF and with these a risk scale for AF was created by quartiles. Later, this formula was applied to the population of the second study. RESULTS: Risk predictors for AF were: CHA2DS2VASc, age, weight, heart rate and female sex. With these, the AF risk scale was created. The highest risk group for AF in the first article was characterized by older age (85.95±6.03, p<0.001), proportion of women (85.2%, p<0.001), incidence density (ID) of AF (22.5/1,000 people/year), ID of stroke (3.5/1,000 people/year), total mortality (22.7%, p<0.001) and lower NNS (9). The highest risk group for AF in the second article was characterized by older age (87.5±7.4, p<0.001), proportion of women (78.2%, p<0.001), ID of AF (17.0/1,000 people/year), ID of stroke (3.8/1,000 people/year), cognitive impairment (16.4%, p<0.001) and lower NNS (19). CONCLUSIONS: This risk stratification model makes it possible to discriminate those patients with a higher risk of AF in five years of follow-up who are associated with a higher incidence of stroke and higher prevalence of cognitive impairment

La FA és l’arítmia cardíaca més freqüent. És conegut el seu elevat potencial de produir esdeveniments tromboembòlics, com els ictus isquèmics. Aquests ictus cardioembòlics no solament són freqüents sinó també s’associen a una elevada morbi-mortalitat. És per aquest motiu que ens proposem estudiar-los en més profunditat. Així mateix, és conegut que no tots els pacients amb una FA tenen el mateix risc tromboembòlic. Diferents factors de risc cardiovasculars com l’edat avançada, la hipertensió arterial, la diabetis mellitus, entre d’altres, contribueixen a atorgar un risc anual de tromboembolisme. S’han creat múltiples escales per tal d’estratificar aquest risc. D’aquestes, la més emprada clàssicament ha estat la CHADS2 per la seva simplicitat. Però en el 2010 es publica l’escala CHA2DS2-VASc. El primer objectiu d’aquesta tesi és avaluar com classifica l’escala CHADS2 a una cohort de pacients en el moment previ al primer ictus isquèmic i comparar-ho amb la classificació si l’escala CHA2DS2-VASc hagués estat utilitzada. Els resultats d’aquest estudi mostren que la nova escala reclassifica a una gran part dels pacients que posteriorment pateixen un ictus, fora de la categoria de risc baix o intermedi, a una categoria on se’ls hauria d’haver indicat un tractament anticoagulant. Arrel de treballs com el nostre han canviat les recomanacions, tant en les guies europees com en les americanes, envers a l´ús de l’escala CHA2DS2-VASc per l’estratificació de risc. El segon objectiu ha estat avaluar l’ús d’aquesta nova escala CHA2DS2-VASc no només per estratificar el risc d’ictus sinó també la seva utilitat com a eina pronòstica en pacients que han patit un ictus isquèmic. Demostrem que per cada increment d’un punt en l’escala, s’incrementa un 36% la possibilitat de tenir un mal pronòstic als 3 mesos de l’ictus. En ambdues investigacions, trobem una baixa indicació de tractament anticoagulant en prevenció primària, en pacients d’alt risc, tot i l’efecte conegut clarament protector dels anticoagulants sobre la severitat de l’ictus, que es replica en el nostre estudi. La nostra línia d´investigació (amb el tercer treball) també s’ha orientat envers a la detecció d’un debut de fibril·lació auricular paroxística (FAp) un cop s’ha produït l’ictus, sobretot per la gran importància d’una correcta prevenció secundària, donat que la no detecció d’aquesta arítmia relega als pacients a un tractament clarament ineficient amb antiagregants plaquetaris. En la nostra cohort d’ictus isquèmics no seleccionats, que ingressen a la unitat d’ictus, diagnostiquem un 11.2% de FAp. Analitzem quins són els factors clínics que s’associen a aquest debut en un anàlisis bivariant i posteriorment multivariant (que són l’edat avançada, el sexe femení, la severitat inicial de l’ictus i la història prèvia d’insuficiència cardíaca congestiva). D’aquest anàlisis obtenim uns riscos de debut de FAp segons cada perfil clínic, que hem representat en unes taules de risc per a la seva fàcil i immediata interpretació a l’arribada del pacient.
AF is the most common cardiac arrhythmia in clinical practice, and is a well-known risk factor for cardiogenic embolism. These cardioembolic strokes are frequent and associated with a substantial increased risk of morbidity and mortality. However the risk of stroke and thromboembolism in AF patients is not homogeneous. Different risk factors such as advancing age, hypertension and diabetes mellitus, among others, contribute to the annual thromboembolic risk. Various stroke risk-stratification schemes have been developed for people with AF. The CHADS2 was probably the most often used because of its simplicity. But in 2010 a new scale was published: CHA2DS2-VASc. The first purpose of this thesis was to evaluate how CHADS2 classifies a cohort of patients previous to its first ischemic stroke and compare this risk stratification if the CHA2DS2-VASc scale would have been used. The results of this study showed that this new scale reclassifies a lot of patients out of the category of low-intermediate risk, into a category in which anticoagulation would have been indicated. Studies like ours changed recommendations of both European and U.S guidelines towards the use of the CHA2DS2-VASc score as the main scheme to assess patientís stroke risk. The second objective of our thesis was to evaluate the use of this new scale, not only for risk stratification, but also as prognosis tool in patients who suffered a stroke. We found that each point increase in the scale is associated with a 36% increase in the risk for poor 90-day outcome, independently of stroke severity. In both works, we found a low use of anticoagulation in primary prevention for high risk patients, despite its well-established protective effect, that we were able to replicate. Our research is also orientated towards the detection of a new paroxysmal atrial fibrillation (pAF) in stroke patients, since undetected pAF would lead to a suboptimal secondary prevention with antiplatelet agents. Therefore in the third work, in our cohort with unselected patients, who were admitted in the stroke unit, we detected 11.2% of pAF until de three-month visit. We analyzed which are the clinical risk factors associated to this new diagnosis in a bivariate and afterwards a multivariate analysis (which were advancing age, female sex, initial stroke severity and previous history of congestive heart failure). From this analysis we obtained a risk for new pAF detection for each vascular risk profile, that we represented into two risk charts for easy and immediately interpretation at patientís arrival.

Despite major advances in the treatment and prevention of atherosclerosis the last several decades, cardiovascular disease still accounts for the majority of deaths in Sweden. With the population getting older, more obese and with rising numbers of diabetics, the cardiovascular disease burden may increase further in the future. The focus in cardiovascular disease has shifted with time from calcification and narrowing of arteries to the biological processes within the atherosclerotic plaque. C-reactive protein (CRP) has emerged as one of many proteins that reflect a low grade systemic inflammation and is suitable for analysis as it is more stable and easily measured than most other inflammatory markers. Several large prospective studies have shown that CRP is not only an inflammatory marker, but even a predictive marker for cardiovascular disease. C-reactive protein is associated with several other risk factors for cardiovascular disease including obesity and the metabolic syndrome. Our study of twenty healthy men during a two week endurance cross country skiing tour demonstrated a decline in already low baseline CRP levels immediately after the tour and six weeks later. In a study of 200 obese individuals with impaired glucose tolerance randomised to a counselling session at their health care centre or a one month stay at a wellness centre, we found decreased levels of CRP in subjects admitted to the wellness centre. The effect remained at one, but not after three years of follow-up. In a prospective, nested, case-referent study with 308 ischemic strokes, 61 intracerebral haemorrhages and 735 matched referents, CRP was associated with ischemic stroke in both uni- and multivariate analyses. No association was found with intracerebral haemorrhages. When classifying ischemic stroke according to TOAST criteria, CRP was associated with small vessel disease. The CRP 1444 (CC/CT vs. TT) polymorphism was associated with plasma levels of CRP, but neither with ischemic stroke nor with intracerebral haemorrhage. A study on 129 patients with atrial fibrillation was used to evaluate whether inflammation sensitive fibrinolytic variables adjusted for CRP could predict recurrence of atrial fibrillation after electrical cardioversion. In multivariate iv models, lower PAI-1 mass was associated with sinus rhythm even after adjusting for CRP and markers of the metabolic syndrome. In conclusion, lifestyle intervention can be used to reduce CRP levels, but it remains a challenge to maintain this effect. CRP is a marker of ischemic stroke, but there are no significant associations between the CRP1444 polymorphism and any stroke subtype, suggesting that the CRP relationship with ischemic stroke is not causal. The fibrinolytic variable, PAI-1, is associated with the risk of recurrence of atrial fibrillation after electrical cardioversion after adjustment for CRP. Our findings suggest a pathophysiological link between atrial fibrillation and PAI-1, but the relation to inflammation remains unclear.

The overall aim of this thesis was to study the influence of physical activity on health. Risks and benefits of physical activity is of particular interest since there is a global trend of less physical activity among youths and adults. In order to investigate this aim we used a database from a large cross country ski race, Vasaloppet, with participants with a wide age range, and with both elite athletes and ordinary people who exercise and promote their health. The most serious risk of strenuous exercise is sudden death and it is challenging to identify preventive effects of major endemic diseases. Using epidemiological methodology we studied 200 000 Vasaloppet skiers and compared them with the general population. Based on personal identification numbers we added data from Swedish national personal and health registers, clinical registers as the cancer register, Swedeheart, or Swedish stroke register, and socioeconomic information from Statistics Sweden. In the Vasaloppet database we collected data on age, gender, finish time and number of races during the period 1989 to 2010. We evaluated risk of death during the race in two papers (I,II). During 90 years of annual races, cardiac arrest occurred in 20 skiers, of which five survived. The death rate is in average two per 100 000 skiers. We also studied the association with cancer incidence (paper III). The overall reduction of cancer was modest among skiers compared with the general population, but for cancers related to lifestyle the risks were markedly lower. We investigated the risk for recurrent myocardial infarction and found a 30% reduction among skiers (paper IV). In paper V we showed that skiers with a first stroke have a lower incidence of all-cause death. The skiers had a higher frequency of atrial fibrillation but had less severe stroke and no increased risk of recurrent stroke. Thus our data suggest that a lifestyle with a high level of physical activity may work as a protection after a cardiovascular event. Summary: The short excess mortality in endurance physical activity is by far outweighed by the long term protective effect of exercise in cardiovascular diseases and cancer.

The aim was to investigate associations of fitness and types and levels of physical activity with subsequent risk of cardiovascular disease. Four large-scale longitudinal cohort studies were used. The exposures were different measures related to physical activity and the outcomes were obtained through linkage to the Swedish In-Patient Register. In a cohort of 466 elderly men without pre-existing cardiovascular disease, we found that skeletal muscle morphology was associated with risk of cardiovascular events. A high amount of type I (slow-twitch, oxidative) skeletal muscle fibres was associated with lower risk of cardiovascular events and high amount of type IIx was associated with higher risk of cardiovascular events. This association was only seen among physically active men. Among 39,805 participants in a fundraising event, higher levels of both total and leisure time physical activity were associated with lower risk of heart failure. The associations were strongest for leisure time physical activity. In a cohort of 53,755 participants in the 90 km skiing event Vasaloppet, a higher number of completed races was associated with higher risk of atrial fibrillation and a higher risk of bradyarrhythmias. Further, better relative performance was associated with a higher risk of bradyarrhythmias. Among 1,26 million Swedish 18-year-old men, exercise capacity and muscle strength were independently associated with lower risk of vascular disease. The associations were seen across a range of major vascular disease events (ischemic heart disease, heart failure, stroke and cardiovascular death). Further, high exercise capacity was associated with higher risk of atrial fibrillation and a U-shaped association with bradyarrhythmias was found. Higher muscle strength was associated with lower risk of bradyarrhythmias and lower risk of ventricular arrhythmias. These findings suggest a higher rate of atrial fibrillation with higher levels of physical activity. The higher risk of atrial fibrillation does not appear to lead to a higher risk of stroke. In contrast, we found a strong inverse association of higher exercise capacity and muscle strength with vascular disease. Further, high exercise capacity and muscle strength are related to lower risk of cardiovascular death, including arrhythmia deaths. From a population perspective, the total impact of physical activity on cardiovascular disease is positive.

Atrial fibrillation (AF) is the commonest sustained heart rhythm disorder in clinical practice. Non-valvular AF confers a 5-fold increased risk of stroke. Stroke in AF is mainly due to thromboembolic phenomenon from the left atrium (LA). It is well known that atrial mechanical dysfunction contributes to thrombus formation. However, patients with AF are also known to exhibit a prothrombotic state and endothelial dysfunction, further contributing to this thromboembolic risk. There is debate as to whether the prothrombotic state and endothelial dysfunction seen in patients with AF are due to AF per se or the patients’ concurrent comorbidities. Chapter 2 examined the LA milieu in patients with lone non-valvular AF compared to patients with AF and comorbidities and controls. The study demonstrated increased platelet activation in the LA compared to the periphery in patients with lone AF. There was a step-wise increase in endothelial dysfunction in the lone AF cohort and AF with comorbidities compared to controls, indicating that both AF per se and its concurrent comorbidities contribute to endothelial dysfunction and thrombotic risk. Chapter 3 investigated the effect of rapid atrial rates in patients with AF compared to patients with supraventricular tachycardia. The study demonstrated rapid atrial rates increased LA platelet activation and thrombin generation in patients with AF. Left atrial thrombogenesis was markedly accentuated with atrio-ventricular dyssynchrony. In contrast, rapid atrial rates did not result in abnormal changes in patients with supraventricular tachycardia. These findings suggest rapid atrial rates, atrio-ventricular dyssynchrony and the abnormal substrate in patients with AF contribute to LA thrombogenesis in these patients. The relative contribution of the atrial rate or rhythm to LA thrombogenesis is unknown. Chapter 4 examined the effects of atrial rate and abnormal rhythm on LA thrombogenesis and demonstrated both rapid atrial rates and AF result in increased platelet activation and thrombin generation in the LA. However, AF also induced endothelial dysfunction and inflammation, not seen with rapid atrial rates alone. These findings suggest that while rapid atrial rates increase the thrombogenic risk, abnormal rhythm may further potentiate this risk. Catheter ablation therapy has emerged as an effective strategy for rhythm control in patients with AF. However, radiofrequency ablation is known to cause an increase in various markers of inflammation and patients are at risk of peri-procedural thromboembolic events. Chapter 5 examined inflammatory, myocardial injury and prothrombotic markers in AF patients undergoing catheter ablation during the peri-procedural period. The study demonstrated that patients exhibit an inflammatory response within the first few days post-ablation, and that this response predicted immediate AF recurrence. Prothrombotic markers were elevated one week post-ablation and may contribute to the increased peri-procedural thrombotic risk. Whether catheter ablation for AF confers a benefit on prevention of future thromboembolic stroke is a vital question. Chapter 6 demonstrated that successful catheter ablation and maintenance of sinus rhythm leads to a decrease in platelet activation and improvement in endothelial function. These findings suggest that the prothrombotic state in patients with AF can be reduced with successful maintenance of sinus rhythm following catheter ablation.
Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2012

Background: Atrial Fibrillation (AF) is the most common atrial arrhythmia affecting Australia and the world, with patients with AF known to be at a 5times higher risk of stroke than that of the normal population. The substrates of AF are also known to significantly impact of this risk of stroke. Mitral stenosis (MS) is one of the leading causes of valvular AF in the developing world. Enlargement of the LA is one of the most common structural changes that occurs in MS and is known to lead to fibrosis and oxidative stress. These alterations can also cause atrial electrical remodelling leading to the development of AF. Patients with MS have been shown to have an increase in thrombogenic properties which include platelet reactivity, inflammation and endothelial dysfunction. The precise mechanisms which underlie this phenomenon of atrial thrombus formation in AF are still unknown, furthermore it is also unknown if the substrate (cause) of AF influences the thromboembolic profile in AF patients. This thesis aims to evaluate the peripheral and atrial thrombogenic profile of both AF and the major substrate MS and their differing disease states alter the thrombus potential. Methods: A total of 166 patients were collected for this study, 55 patients undergoing a radiofrequency ablation as a curative procedure for paroxysmal AF, at the Royal Adelaide Hospital, Adelaide, 59 patients with mitral stenosis (MS)undergoing a balloon valvuloplasty at the Christian Medical Centre in Vellore, India, and 52 with aged matched control subjects, diagnosed with left sided accessory pathway supraventricular tachycardia (SVT) undergoing a routine elective electrophysiological study. Blood samples were collected from the peripheral, RA and LA circulation, during each of these procedures, for further analysis through flow cytometry, platelet aggregation and ELISA tests. Echocardiographic studies were used for atrial structure measurements. Results: We found that within the AF population there is increase in thrombogenic markers within the heart compared to the peripheral circulation. More interestingly when comparing the MS and AF populations each of the different factors involved in thrombogenesis is altered differently, with AF having an increase in platelet reactivity and endothelial function (ADMA and ET-1) and inflammation through VCAM-1 and ICAM-1. However of inflammation through MPO, CD40L and IL-6 and structural remodelling (MMP-9 and TIMP-1) were more pronounced within the MS population. Conclusion: This study has shown that AF and the valvular AF substrate mitral stenosis (MS) have two distinctly different mechanisms leading to atrial thrombus formation. This shows that MS as a substrate for valvular AF impacts on atrial thrombus formation through remodelling and inflammation whereas non valvular AF affects endothelial function and tissue inflammation. This illustrates that the pathophysiology of each of the diseases states is different when comparing it to the normal haemostatic properties of the heart within a control (SVT) population to determine if these factors are in fact altered from the norm.
Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2014

碩士
國立虎尾科技大學
工業管理系工業工程與管理碩士班
106
Stroke is a cerebrovascular obstructive or cerebrovascular rupture, resulting in damage to brain cells and neurological symptoms. Cause of stroke is very wide, about 10-15% is directly related to heart disease. The atrial fibrillation is clinically the most common type of arrhythmias. According to the prevalence survey, it is estimated that about 2% of the population have gotten atrial fibrillation. The chance of atrial fibrillation patients get stroke is more than five times the normal. Therefore, in this study, patients with atrial fibrillation in the database of an anonymous medical institution in Taiwan were adopted as research participants. Through the collection of relevant literature and interview with professional physicians to select the factors that affect the ischemic stroke, using particle swarm optimization, cross entropy and genetic algorithms logistic regression combined with back propagation neural network and support vector machines to construct six predictive models of ischemic stroke patients with atrial fibrillation. In addition, using weight of three algorithms combined with case-based reasoning technique to construct evaluation system of ischemic stroke patients with atrial fibrillation. Research results show that there are significant differences among six predictive models. Among these models, the best two models are constructed by particle swarm optimization that the average accuracy rate and the average area under the ROC curve are both over 88% and 0.85. For the evaluation system, there are no significant differences among three algorithms. Thus, three algorithms are all suitable for the weight of the evaluation system. The average accuracy and average area under the ROC curve are both over 85% and 0.80. The prediction models and evaluation system constructed in this study can provide medical institutions and relevant medical personnel as a reference for assisting diagnosis and evaluation. From the perspective of preventive medicine, there will be a help to early detection of diseases to avoid the consumption of medical resources.

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2018
Introdução: A fibrilhação auricular é uma arritmia frequente e uma causa major de AVC isquémico. O risco de AVC é avaliado através de scores como CHADS2 ou CHA2DS2VASc, podendo indicar o inicio de terapêutica trombo-profilática. A profilaxia do AVC com anticoagulantes orais tem uma eficácia conhecida, porém associada a um risco de hemorragia que não deve ser ignorado. Considerando que a formação de trombos está maioritariamente associada à aurícula esquerda, outras técnicas não farmacológicas estão a ser desenvolvidas de forma local. No caso do paciente também sofrer de doença hepática crónica, a eficácia e a segurança destas abordagens não está ainda esclarecida, sendo a escolha de como e quando começar terapêutica ainda difícil, considerando a pouca evidencia disponível. Métodos: Realizámos uma pesquisa em bases de dados como Medline Ovid (até janeiro de 2018) e a Cochrane Central Registry. Dos artigos selecionados apresentámos os nossos resultados em tabelas e analisámos o seu conteúdo. Finalmente elaborámos um algoritmo. Resultados: A terapêutica anticoagulante oral tradicional e os novos anticoagulantes orais parecem ser seguros para doentes com doença hepática ligeira e moderada, exceto o rivaroxaban e o edoxaban, cujo uso não está indicado em casos de doença moderada; os doentes devem sujeitar-se a controlos regulares dos níveis dos fármacos e das enzimas hepáticas. As técnicas de encerramento da aurícula esquerda são diversas e uma delas provou, num ensaio controlado e randomizado, ser não inferior à varfarina. Conclusões: Mais estudos devem ser realizados a fim de provar a eficácia e a segurança do uso de anticoagulantes em pacientes com doença hepática crónica com o fim de obter uma norma orientadora para a clínica. A oclusão da aurícula esquerda tem-se revelado promissora, porém nenhum estudo foi realizado especificamente em pacientes com cirrose, permanecendo a terapêutica anticoagulante como primeira linha. A alternativa local fica reservada aos doentes cuja anticoagulação está contraindicada.
Introduction: Atrial fibrillation is a common cardiac arrhythmia and a major cause of ischaemic stroke. Stroke risk can be accessed using scores like CHA2DS2VASc and thromboprophylatic therapy with oral anticoagulants might be indicated, whose efficacy is well proven. However it’s also linked to a risk of haemorrhage that cannot be neglected. Considering that thrombus formation is mainly linked to left atrial appendage, other nonpharmacological alternatives are being developed, as local therapies. However, evidence and experience about these approaches are lacking from patients with concomitant hepatic disease, making the decision on how and when to start therapy very delicate and stressful. Methodology: we conducted a research using data sources like Medline Ovid (until January 2018) and the Cochrane Central Registry. We presented our results from the selected articles in tables. Then we analysed our information and built an algorithm. Results: Traditional anticoagulant therapy and NOACs seem to be safe in patients with mild or moderate hepatic impairment, except for rivaroxaban and edoxaban, whose use is not advised for patients with moderate impairment. Nonetheless, patients should undergo regular monitoring of drug levels and hepatic enzymes. The LAAC techniques are several and one proved to be at least non-inferior to warfarin in a large randomized controlled trial. Conclusions: More studies are required to proof OAC’s efficacy and safety in patients with chronic hepatic disease (CHD), in order to build a guideline for clinicians. The left atrial appendage occlusion has revealed promising results but no study was yet conducted in patients with CHD. Anticoagulant therapy remains the first line for thromboprophylaxis, being LAAC reserved for patients with declared contraindications to OAC.

博士
國立陽明大學
臨床醫學研究所
104
Background and Objectives: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia which increases the risk of ischemic stroke by 4- to 5-fold. AF-related stroke has a worse prognosis and higher recurrence rate compared to non-AF related stroke. The risk of AF-associated stroke is not homogeneous and depends on patients’ age and comorbidities, which have resulted in clinical scores to aid risk stratification for AF patients. Oral anticoagulants (OACs) with warfarin or non-vitamin K antagonist OACs (NOACs) could reduce the risk of AF-related stroke by around 64%. The decision to prescribe OACs for AF patients should be based on individual risk of ischemic stroke which is estimated according to the clinical scores. However, data regarding the risk of ischemic stroke in Taiwan AF patients were lacking. We performed a serial studies to investigate the risk of ischemic stroke in Taiwan AF patients and determine which scoring system should be used. We also compared the risk of ischemic stroke of Taiwanese AF patients to that of Caucasians. Method: We used the “National Health Insurance Research Database” released by the Taiwan National Health Research Institutes. From year 1996-2011, a total of 354,649 AF patients aged ≥ 20 years were identified as study population. Among the study population, we excluded patients who received treatments with warfarin or any antiplatelet agents, including aspirin, clopidogrel, dipyridamole and ticlopidine. Finally, a total of 186,570 patients were enrolled into the study cohort. The study endpoint was the occurrence of ischemic stroke. Main Findings: 1. The annual risk of ischemic stroke for Taiwanese AF patients was around 3.71%. 2. CHA2DS2-VASc performed better than CHADS2 and ATRIA scores for stroke risk stratification, and should be the preferred scoring system for Taiwanese AF patients. 3. The CHA2DS2-VASc score could further refine stroke risk stratification among patients with a low CHADS2 or ATRIA score. 4. The risk of ischemic stroke for Taiwanese AF patients with a low CHA2DS2-VASc score was higher than that of Caucasians. 5. Not all risk factors in CHA2DS2-VASc score carried an equal risk, and age 65-74 was associated with the highest stroke rate. 6. AF males with only 1 risk factor having a CHA2DS2-VASc score of 1 had an annual stroke rate ranging between 1.96%-3.50% depending on the specific covariates composing the score. For AF females with one additional stroke risk factor (ie. CHA2DS2-VASc score of 2), the annual stroke rate ranged from 1.91% to 3.34%. For these patients, OACs should be considered for stroke prevention, and NOACs may be the preferred choices based on their better safety profiles. 7. Hyperuricemia/gout was a novel risk factor of ischemic stroke for AF patients, and may potentially refine the risk stratification system. 8. For Taiwanese patients aged 50 to 64 years, the annual stroke risk was 1.78%, which may exceed the threshold for OAC use for stroke prevention. The annual risk of ischemic stroke for AF patients age <50 years was 0.53%, which was truly low-risk, and OACs could be omitted. The age threshold for an increased risk of ischemic stroke in Taiwanese AF patients may be different from that of Caucasians. Conclusions: The risk of ischemic stroke of Taiwanese AF patients could be accurately estimated using the CHA2DS2-VASc score. OACs should be considered for stroke prevention for AF patients with 1 additional risk factor beyond gender. Whether the consideration of hyperuricemia/gout or resetting the age threshold at 50 years could refine current clinical risk stratification for Taiwanese AF patients deserves further study.

碩士
國立臺北護理健康大學
長期照護研究所
105
The study aimed to evaluate the relationship between prescribed medication and functional outcomes in patients with ischemic stroke and atrial fibrillation.We retrospectively recruited patient with from a medical center database in North Taiwan. Research tools was were: (1) National Institutes of Health Stroke Scale (NIHSS); (2) Modified Rankin scale (mRS); (3)Barthel Index( BI). The data was analyzed with IBM SPSS Statistical 23. This was a retrospective cross-sectional study. Patients to medical center database in North Taiwan from 2012 to 2015 were recruited and the study variable included: Demographic characteristics (age, sex, etc.)、the presence of Acute ischemic stroke with atrial fibrillation and the presence of vascular risk factors including coronary artery disease、 diabetes、 hypertension or dyslipidemia. The functional outcomes were represented by NIHSS,mRS and Barthel. The results showed that age、educational、low albumin, NIHSS in emergency were significantly.In addition, the study also found the dependency rates after 1 year were in groups taking oral vitamin k antagonists and new oral anticoagulants lower than the groups taking antiplatelet.

Objectives: To understand the efficacy and safety profile of early anticoagulation in Atrial Fibrillation (AF)-related acute ischemic stroke (AIS) and to evaluate the main predictors of ischemic and hemorrhagic complications. Materials and Methods: We retrospectively evaluated patients hospitalized in a stroke unit due to AF-related AIS, between 2017-2019. Patients were divided according to anticoagulation initiation timing (0-4 days, 5-14 days, no anticoagulation at day 14). We assessed the following outcomes at 90 days: composite embolic recurrence (intracranial or systemic), composite hemorrhagic events, and favorable functional outcome (modified Rankin Scale (mRS) score 0-2 or equal to prestroke). Results: We included 395 patients. Median age was 80. Anticoagulation was initiated at days 0-4 in 134(33.9%) patients, at days 5-14 in 100(25.3%) and not initiated by day 14 in 161(40.8%). Factors associated with earlier anticoagulation included lower previous mRS, valvular AF and lower National Institutes of Health Stroke Scale (NIHSS) at Stroke Unit discharge. Ischemic recurrence occurred in 33(8.3%) patients, with higher odds in non-anticoagulated patients at day 14 compared to the remainder groups (OR:2.49,95%CI 1.07-5.80 vs. 0-4 days and 5.12,95%CI 1.49-17.58 vs. 5-14 days). In patients who started anticoagulation (n=288), composite hemorrhagic events occurred in 31(10.8%), with no significant differences between groups. Favorable outcome occurred in 157(40.2%) patients, with higher odds in those anticoagulated at 0-4 days versus 5-14 days, independently of age, previous mRS and discharge NIHSS. Conclusions: Early anticoagulation was significantly associated with lower embolic recurrence and better functional outcome at 90 days, with no significant increased hemorrhagic risk.

Objectives: To understand the efficacy and safety profile of early anticoagulation in Atrial Fibrillation (AF)-related acute ischemic stroke (AIS) and to evaluate the main predictors of ischemic and hemorrhagic complications. Materials and Methods: We retrospectively evaluated patients hospitalized in a stroke unit due to AF-related AIS, between 2017-2019. Patients were divided according to anticoagulation initiation timing (0-4 days, 5-14 days, no anticoagulation at day 14). We assessed the following outcomes at 90 days: composite embolic recurrence (intracranial or systemic), composite hemorrhagic events, and favorable functional outcome (modified Rankin Scale (mRS) score 0-2 or equal to prestroke). Results: We included 395 patients. Median age was 80. Anticoagulation was initiated at days 0-4 in 134(33.9%) patients, at days 5-14 in 100(25.3%) and not initiated by day 14 in 161(40.8%). Factors associated with earlier anticoagulation included lower previous mRS, valvular AF and lower National Institutes of Health Stroke Scale (NIHSS) at Stroke Unit discharge. Ischemic recurrence occurred in 33(8.3%) patients, with higher odds in non-anticoagulated patients at day 14 compared to the remainder groups (OR:2.49,95%CI 1.07-5.80 vs. 0-4 days and 5.12,95%CI 1.49-17.58 vs. 5-14 days). In patients who started anticoagulation (n=288), composite hemorrhagic events occurred in 31(10.8%), with no significant differences between groups. Favorable outcome occurred in 157(40.2%) patients, with higher odds in those anticoagulated at 0-4 days versus 5-14 days, independently of age, previous mRS and discharge NIHSS. Conclusions: Early anticoagulation was significantly associated with lower embolic recurrence and better functional outcome at 90 days, with no significant increased hemorrhagic risk.

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2017
Background: Oral anticoagulation is essential following post-operative atrial fibrillation. Although warfarin is commonly used, its efficacy is dependent on the achievement of a time in therapeutic range above 65%. Non-vitamin K oral anticoagulants are an alternative option, however the optimal time to initiate post-operatively is unknown, due to 'recent surgery' often being cited as an exclusion criteria within phase III clinical trials. Purpose: To compare the management of oral anticoagulation for stroke prevention in postoperative atrial fibrillation after cardiothoracic surgery. Methods: An ambispective study was conducted at large tertiary centre analysing patients that developed postoperative atrial fibrillation after cardiothoracic surgery from January 2016 to January 2017 reviewing both patient and surgical data. Results: Sixty-four patients developed postoperative atrial fibrillation, of which 39 (60.9%) and 25 (39.1%) were prescribed warfarin and non-vitamin K oral anticoagulants (NOACs), respectively. 14 (51.9%) patients had a confirmed time in therapeutic range below 65%, reflecting poor anticoagulant control with warfarin. NOACs were initiated on an average of 8.36 ± 3.74 days post-operatively. 22 (62.9%) patients in the warfarin group and 13 (65.9%) patients in the NOAC group were confirmed to be in sinus rhythm six weeks after discharge. Among these patients, 14 (40.0%) stopped the anticoagulation after restoration of sinus rhythm, of which were more likely to continue if were receiving a NOAC. Conclusion: Whilst warfarin is commonly initiated for post-operative atrial fibrillation, a time in therapeutic range below 65% for warfarin shows that acute optimal anticoagulation management is difficult to achieve, especially for the short term patients that revert back in to sinus rhythm. NOACs may possibly be a more effective alternative, initiating eight days post operatively. However further studies need to be conducted to ensure optimal dose of these agents as well as the ideal timeframe to initiate anticoagulation in the acute post-operative phase.
Introdução: A fibrilhação auricular (FA) é a arritmia sustentada mais comum na prática clínica e está associada ao aumento da mortalidade e morbilidade, assim como a hospitalizações frequentes e à redução da qualidade de vida. A fibrilhação auricular pós-operatória (FAPO) é uma variante da FA clássica que se caracteriza pelo diagnóstico de um novo caso de FA, habitualmente auto-limitada, após realização de cirurgia-major (tipicamente cardíaca) em doentes que se encontravam em ritmo sinusal previamente ao procedimento cirurgico e sem historial clínico prévio desta arritmia. Estima-se que a FAPO ocorra em cerca de 30% das cirurgias-major. Neste sentido, a terapêutica anticoagulante é essencial como profilaxia para o acidente vascular cerebral, sendo que tanto os anticoagulantes orais não antagonistas da vitamina K (NACOs) (apixabano; dabigatrano; edoxabano; rivaroxabano) como os antagonistas da vitamina K (AVK) (varfarina; acenocumarol) se revelam eficazes na prevenção do acidente vascular cerebral na fibrilhação auricular. Embora a varfarina seja amplamente usada na prática clínica, a sua eficácia está dependente da manutenção da percentagem de tempo no intervalo terapêutico a um nível superior a 65%. Por sua vez, os NACOs revelam-se como uma alternativa à varfarina, sendo referidos como opção preferencial nos normativos das mais reconhecidas sociedades de cardiologia. No entanto, o tempo ideal para iniciar a terapêutica com estes agentes no perído pós-operatório carece de investigação, devido à exclusão desta população dos ensaios clínicos randomisados de fase III. Desta forma, no âmbito do programa Erasmus, este projeto foi desenvolvido durante os três meses em que tive a oportunidade de integrar o Departamento de Farmácia do Hospital St. Bartholomew sediado em Londres, Reino Unido. Tendo sido proposto pelo responsável deste departamento, este estudo teve como objetivo aprofundar o conhecimento relativamente ao tratamento ótimo e efetivo com anticoagulantes orais e, em última análise, permitir a otimização, eficácia e segurança destes agentes. Além disso, refletindo o importante papel do farmacêutico enquanto membro integrado numa equipa multidisciplinar de profissionais de saúde, este projeto permitiu de igual forma, a promoção da discussão com cirurgiões, médicos e enfermeiros acerca do potencial de possíveis mudanças a adotar futuramente na prática clínica de modo a garantir uma melhor gestão da FAPO, e consequentemente proporcionar os melhores cuidados em saúde a estes utentes. Objetivos: Este estudo teve como propósito comparar a gestão da terapêutica anticoagulante oral na fibrilhação auricular pós-cirurgia cardiotorácica. Deste modo, foram formuladas quatro questões de investigação: 1. Qual percentagem de pacientes prescritos com varfarina que demonstrou um tempo no intervalo terapêutico superior a 65%, seis semanas após a alta hospitalar? 2. Qual é a dosagem adequada de NACOs no período pós-operatório? 3. Qual é o momento ideal para iniciar terapêutica com NACOs no período pós-operatório? 4. Os anticoagulantes orais foram descontinuados nos doentes que revelaram reversão para ritmo sinusal seis semanas após a alta hospitalar? Assim, tendo como ponto de partida as questões supracitadas, foram definidos os seguintes objetivos específicos para este estudo: i) Avaliar a eficácia da varfarina no período pós-operatório; ii) Investigar as tendências e padrões na prática clínica em relação à NACOs (i.e., escolha do NACO prescrito, dosagem, período pós-operatório de iniciação terapêutica); iii) Esclarecer as características envolvidas na hipótese de considerar a redução da dose de NACOs, bem como o prazo ideal para iniciar a terapêutica com estes fármacos no período pós-operatório; iv) Identificar o número de doentes que revertem para ritmo sinusal (RS) seis semanas após a cirurgia cardiotorácica; v) Analisar as taxas de descontinuação de anticoagulantes orais, quando é verificada a reversão para RS. Métodos: Foi conduzido um estudo ambiespectivo em doentes que desenvolveram fibrilhação auricular pós operatória entre janeiro de 2016 e janeiro de 2017. O estudo compreendeu duas fases distintas; Uma retrospetiva e uma prospectiva (desenho ambiespectivo). As informações presentes nos registos médicos dos utentes submetidos a cirurgia entre os dias 1 de janeiro de 2016 e 31 de janeiro de 2017 foram avaliadas retrospectivamente para determinar a amostra de interesse para estudo com base nos critérios de eligibilidade definidos. Foram igualmente consultados retrospectivamente os registos de distribuição da farmácia e os relatórios de controlo de stocks para identificar todos os doentes com prescrições de varfarina ou novos anticoagulantes orais nas alas cardiotorácicas durante o período de coleção de dados. Foram assim constituídos dois coortes de exposição, de acordo com o subgrupo farmacoterapêutico adotado (AVK vs NACO). Foram analisados os registos de prescrição de fármacos e notas médicas eletrónicas, a fim de selecionar de entre os pacientes prescritos com estes anticoagulantes orais, os que foram dispensados do hospital com um diagnóstico confirmado de fibrilhação auricular pós-operatória. Dados demográficos, historial médico e estudos laboratoriais foram analisados. Foram definidas como variáveis de interesse, os valores de tempo no intervalo terapêutico especificamente para o grupo-varfarina; o NACO prescrito, respetiva dose e dia de inicio da terapêutica no período pós-operatório para o grupo-NACO; CHA2DS2‐VASc score, tendo sido realizada a estratificação de risco para tromboembolismo e acidente vascular cerebral para ambas as coortes através da análise dos fatores de risco individuais. A fase prospetiva decorreu desde 31 de Janeiro até 28 de abril de 2017 e serviu para recolher os dados das consultas de follow-up, realizadas em média cerca de seis semanas após cirurgia no Hospital St. Bartolomew. Através da consulta deste dados obteve-se assim informação sobre a reversão para ritmo sinusal (ou não), a consequente descontinuição dos anticoagulantes orais. Os valores de International Normalized Ratio (INR) que estão na origem do cálculo do tempo no intervalo terapêutico foram obtidos através de contactos estabelecidos com as clínicas de anticoagulação onde estes utentes realizavam as mediações do INR. Estes valores foram obtidos prospetivamente para os doentes que continuaram a terapia com varfarina e consequente monitorização de INR coincidente com a fase prospetiva do estudo. Os dados recolhidos foram analisados recorrendo a estatística descritiva univariada e bivariada. Os dados discretos são apresentados como frequências absolutas e relativas, enquanto que os dados contínuos são apresentados através da tendência central e medidas de dispersão, incluindo média, mediana e desvio padrão. A análise bivariada serviu para comparar as características dos utentes das duas coortes de doentes expostas aos dois diferentes tratamentos e verificar se as características dos doentes, nomeadamente o seu perfil de risco de AVC ou risco hemorrágico, poderiam justificar a sua inclusão num ou noutro grupo farmacoterapêutico. Dado o tamanho amostral e a distribuição não-normal dos dados, foram selecionados testes não-paramétricos; o chi-quadrado e a sua extensão peloo teste Exacto de Fisher foram utilizados para analisar dados categóricos e o teste Wilcoxon Mann-Whitney para analisar dados contínuos. O intervalo de confiança considerado foi de 95%. Todos os dados foram analisados usando o IBM Statistical Software Package for Social Sciences (SPSS, versão 24). O protocolo deste estudo foi aprovado pela Comissão de Ética do Hospital St. Bartolomew, sob o número 8021. Resultados: Sessenta e quatro utentes desenvolveram fibrilhação pós-operatória, dos quais 39 (60.9%) e 25 (39.1%) foram medicados com varfarina e NACOs, respetivamente. Foram obtidos 27 dados de valores de tempo no intervalo terapêutico (69% dos medicados com varfarina), sendo que 14 doentes (52%) demonstraram valores de tempo no intervalo terapêutico inferiores a 65%, refletindo fraco controlo e pouca eficácia da terapêutica anticoagulante com varfarina. No que concerne à iniciação de NACOs no período pós-operatório, foi revelado que a terapêutica com estes anticoagulantes teve inicio, em média, 8.36 ± 3.74 dias após realização do procedimento cirurgico. Relativamente à reversão para RS, 22 doentes (62.9%) do grupo da varfarina e 13 doentes (65.0%) do grupo dos NACOs tinham revertido para RS seis semanas após a alta hospitalar. De entre estes doentes, um total de 14 (40.0)% discontinuou os anticoagulantes orais após confirmação de ritmo sinusal. Conclusões: Alcançar um tempo no intervalo terapêutico superior a 65% revela-se desafiante e díficil de alcançar no que diz respeito à terapêutica com varfarina, sendo tal facto demonstrado pela proporção de pacientes que demonstraram valores que expressam a baixa eficácia deste agente, ainda que eventualmente resultante da sua utilização em contexto real onde questões associadas ao estilo de vida, inclusivamente alimentares e de adesão à terapêutica, poderão influenciar profundamente a capacidade de autogestão do doente. Deste modo, os anticoagulantes orais não antagonistas da vitamina K, iniciados oito dias após cirurgia cardiotorácica, podem constituir uma alternativa mais efetiva na tromboprofilaxia associada à fibrilhação auricular. No entanto, será prudente confirmar estes dados em amostras de maior dimensão dadas as limitações deste exercício académico. Estudos adicionais devem igualmente ser realizados de modo a estabelecer a dose ideal, bem como o período apropriado para iniciar a terapêutica anticoagulante com estes agentes na fase aguda do pós-operatório.

Objectives: To describe patient characteristics and evaluate costs and outcomes of novel oral anticoagulants compared to clinic-monitored warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation within the Scott & White Healthcare system. Methods: Patients with atrial fibrillation, CHADS₂ score ≥ 1, and a prescription claim for dabigatran, rivaroxaban, or warfarin between 2010 and 2012 were evaluated over 12 months. Patients in the warfarin cohort were enrolled in an Anticoagulation Clinic. Patients were matched 1:1 for age, CHADS₂, and gender for comparisons between groups. Baseline characteristics, medication adherence, occurrence of adverse events, and treatment costs were compared using inferential statistics. Anticoagulation control was assessed for patients in the warfarin cohort. Results: 141 and 471 patients met criteria for the novel cohort group and the warfarin group, respectively. After matching, 136 remained in each cohort. Prior to matching, compared to the warfarin cohort, the novel anticoagulant cohort had a higher proportion of male patients (63% versus 49%), and lower average CHADS₂ score (2.65 versus 3.30), while average age in both cohorts was similar (75 years). Matched cohorts had similar adherence rates (88% for novel versus 87% for warfarin). After matching, annual medication cost in 2014 US dollars for dabigatran or rivaroxaban averaged $2,658 (SD $1,494) compared to $1,066 (SD $633) for warfarin, including monitoring costs. Annual total all-cause healthcare costs averaged $23,711 (SD $22,910) for dabigatran or rivaroxaban, compared to $18,248 (SD $24,184) for warfarin. For the 95 warfarin patients with INR values, time in therapeutic range averaged 70.4%. Conclusion: Compared to clinic-monitored warfarin, more men than women were prescribed new oral anticoagulants and these patients averaged a lower CHADS₂ score. After matching, patient adherence was high and comparable between groups. Anticoagulation control for warfarin patients was similar to clinical trials. Annual medication cost was significantly greater for new oral anticoagulants than clinic-monitored warfarin, including INR monitoring costs. Total annual all-cause healthcare costs were significantly greater for patients taking new oral anticoagulants compared to warfarin, although too few adverse events occurred to draw conclusions regarding event rates and costs of ischemic stroke and major bleeds.
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