Clinical challenges in the management of atrial fibrillation – studies on overanticoagulation and risk scores

Background: In addition to stroke prevention with oral anticoagulation (OAC), comprehensive management of atrial fibrillation (AF) involves several important aspects. The aim of this thesis is to bring new and practical information on AF management to guide clinicians in challenging situations. Unsuccessful electrical cardioversion (ECV), excessive warfarin anticoagulation (EWA) during warfarin treatment and the limitations of CHA2DS2-VASc and HAS-BLED scores in risk stratification are the specific clinical challenges addressed in this thesis. Methods: The studies are based on three distinct datasets, all collected retrospectively by reviewing patient records. The FinCV (study I) data included 5,713 ECVs in 2,868 patients from two university hospitals and one central hospital in Finland during 2003-2010. The EWA Study data (studies II and III) included all patients on warfarin for AF, from 2003 to 2015 in the Turku University Hospital region, who suffered an EWA episode (defined as INR ≥9). The FibStroke data (study IV) was collected at four hospitals in Finland. All patients with a diagnosis of AF / Atrial flutter and either an ischemic stroke or an intracranial bleed between the years 2003–2012 were included. Results: 1) A scoring system was created to predict unsuccessful ECV. The predictive score parameters were Age, not the First AF, Cardiac failure, Vascular disease, and Short interval from previous AF episode (AF-CVS). 2) A total of 412 patients with EWA were identified, of whom 25.5% suffered a bleed. Of the many observed predictors of EWA, the strongest were alcohol abuse and impaired renal function. 3) Of the 412 EWA episodes, non-bleeding symptoms were recorded in 40.0% of patients and in 34.5% the EWA was a coincidental finding without symptoms. The 30-day mortality rate was high (9.2% to 32.7%). 4) Ischemic strokes occurred more often than intracranial bleedings in patients on OAC in each (CHA2DS2-VASc and HAS-BLED) score category, except HAS-BLED score >4. Conclusions: The risk of ECV failure and early recurrence of AF can be predicted with simple clinical characteristics. EWA can be predicted with several risk factors, many of which are modifiable. Bleeds are not the major determinant of the poor prognosis of EWA, as coincidental INR ≥9 findings also associate with high mortality. In patients with AF, ischemic strokes are more common than intracranial bleedings irrespective of CHA2DS2-VASc score, HAS-BLED score ≤4, or use of oral anticoagulation.Eteisvärinän hoidon kliinisiä haasteita – liiallinen antikoagulaatio ja riskilaskureiden käyttö Tausta: Antikoagulaatiohoidolla toteutetun aivohalvausriskin pienentämisen lisäksi eteisvärinän kokonaisvaltaiseen hoitoon liittyy useita tärkeitä seikkoja. Tämän väitöskirjatyön tarkoituksena on saada uutta tietoa eteisvärinän hoidon käytännön ongelmakohdista ja tuottaa uusia keinoja niiden hoitamiseksi. Väitöskirjatyössä käsiteltäviin ongelmakohtiin lukeutuvat sähköisen kardioversion epäonnistuminen, liiallinen antikoagulaatiotaso, sekä CHA2DS2-VASc ja HAS-BLED –riskilaskureiden käyttöön liittyvät rajoitukset. Metodit: Osatutkimukset perustuvat kolmeen takautuvasti potilastietojärjestelmistä kerättyyn tietokantaan. FinCV-aineistoon (osatyö I) lukeutuu 5713 sähköistä kardioversiota 2868 potilaalla kahdesta yliopistosairaalasta ja yhdestä keskussairaalasta vuosina 2003-2010. EWA-aineistossa (osatyöt II ja III) sisältää kaikki varfariinia käyttävät eteisvärinäpotilaat vuosilta 2003-2015 Turun yliopistollisen keskussairaalan vaikutusalueelta, joilla todettiin korkea INR taso (≥9). FibStroke-aineisto (osatyö IV) sisältää kaikki aivohalvauksen tai kallonsisäisen vuodon sairastaneet eteisvärinä- ja eteislepatuspotilaat neljästä suomalaisesta sairaalasta vuosilta 2003-2012. Tulokset: Ensimmäisessä työssä kehitettiin eteisvärinän sähköisen kardioversion epäonnistumista ennakoiva riskilaskuri. Laskurin riskitekijöihin lukeutuvat ikä, aiempi eteisvärinä, sydämen vajaatoiminta, verisuonisairaus, sekä eteisvärinän lyhyt uusiutumisviive. Toisessa työssä tunnistettiin 412 INR≥9 episodin kokenutta potilasta, joista 25.5%:lla tilaan liittyi verenvuoto. Useista tunnistetuista riskitekijöistä voimakkaimmiksi todettiin runsas alkoholin käyttö ja munuaisten vajaatoiminta. Kolmannessa työssä INR≥9 episodien kliiniseksi ilmenemismuodoksi todettiin muu oire kuin verenvuoto 40.0%:lla ja 34.5%:lla se ilmeni oireettomana sattumalöydöksenä. Lisäksi 30 päivän kuolleisuus todettiin korkeaksi (9.2% - 32.7%). Neljännessä työssä antikoaguloiduilla eteisvärinäpotilailla iskeemisen aivohalvauksen todettiin olevan yleisempi komplikaatio kuin kallonsisäinen vuoto riippumatta CHA2DS2-VASc ja HAS-BLED riskipisteistä, pois lukien HAS-BLED > 4 pistestatus. Päätelmät: Sähköisen kardioversion epäonnistumista ja eteisvärinän uusiutumista voidaan ennakoida. Samoin INR≥9 tapahtumalle on useita riskitekijöitä, joista osaan voidaan vaikuttaa. Näihin tapahtumiin liittyvä kuolleisuus ei selity verenvuodoilla, sillä myös oireettomina niihin liittyy korkea kuolleisuus. Eteisvärinäpotilailla iskeemiset aivohalvaukset ovat kallonsisäisiä vuotoja yleisempiä riippumatta antikoagulaatiohoidosta, CHA2DS2-VASc, sekä HAS-BLED ≤4 pistestatuksest

Association of Heart Rate With Troponin Levels Among Patients With Symptomatic Atrial Fibrillation

This cohort study investigates heart rate and cardiac troponin levels in patients admitted to the emergency department with symptomatic atrial fibrillation.Non peer reviewe

Association of CHA2DS2-VASc Score with Long-Term Incidence of New-Onset Atrial Fibrillation and Ischemic Stroke after Myocardial Infarction

The CHA2DS2-VASc score is a reliable tool used to estimate the risk of ischemic stroke (IS) in patients with atrial fibrillation (AF). Few tools exist for the prediction of new-onset AF (NOAF) after myocardial infarction (MI) and its relation to IS. We studied the usefulness of CHA2DS2-VASc in predicting NOAF and IS in a long-term follow-up after MI. Consecutive MI patients without baseline AF (n = 70,922; mean age: 68.2 years), discharged from 20 hospitals in Finland during 2005-2018, were retrospectively studied using national registries. The outcomes of interest after discharge were NOAF- and IS-assessed with competing risk analyses at one and ten years. The median follow-up was 4.2 years. The median baseline CHA2DS2-VASc score was 3 (IQR 2-5). The likelihood of both NOAF and NOAF-related IS increased stepwise with this score at one and ten years (all p 2DS2-VASc scores ≥6 points. The cumulative incidence of IS was 15.2% in patients with NOAF vs. 6.2% in patients without AF at 10 years after MI (adj. sHR 2.12; CI 1.98-2.28; p p 2DS2-VASc score is a simple tool used to estimate the long-term risk of NOAF and IS after MI in patients without baseline AF. Coronary bypass surgery is associated with an increased NOAF incidence after MI.</p

Prevalence of High Bleeding Risk among Hospitalized Suspected NSTEMI Patients

In recent years, guidelines for the management of acute coronary syndromes (ACS) have placed more emphasis on identifying patients at high bleeding risk (HBR). We set out to investigate the prevalence of HBR patients according to the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria in hospitalized patients with suspected non-ST-segment elevation myocardial infarction (NSTEMI). Consecutive patients were retrospectively enrolled between January and June 2019 from the emergency department (ED) of a tertiary hospital. The discharge diagnosis and baseline data were manually collected using electronic patient records and database searches. Patients with non-cardiac diagnoses were excluded. Overall, 212 patients were included in the study. A total of 146 (68.9%) patients were diagnosed with NSTEMI (Type 1), 47 (22.2%) with unstable angina pectoris (UAP) and 19 (9.0%) with "other." HBR was detected in 47.6% (n = 101) of all patients. Common criteria for HBR among ACS patients were age (40.4%), chronic kidney disease (33.7%), and the use of oral anticoagulation medicines (20.2%). In conclusion, nearly half of the patients hospitalized for ACS fulfilled HBR criteria. According to contemporary guidelines, the management of HBR patients differs from that of non-HBR patients, and thus, a more comprehensive screening for HBR may be considered in clinical practice

Frequency of cardioversions as an additional risk factor for stroke in atrial fibrillation - the FinCV-4 study

BackgroundPatients with atrial fibrillation (AF) are selected for oral anticoagulation based on individual patient characteristics. There is little information on how clinical AF burden associates with the risk of ischaemic stroke or systemic embolism (SSE). The aim of this study was to explore the association of the frequency of cardioversions (CV) as a measure of clinical AF burden on the long-term SSE risk, with a focus on patients at intermediate stroke risk based on CHA(2)DS(2)-VASc score. For these patients, additional SSE risk stratification by assessing CV frequency may aid in the decision on whether to initiate oral anticoagulation.MethodsThis retrospective analysis of FinCV Study from years 2003-2010 included 2074 patients who were not using any oral anticoagulation (long term or temporary) after CVs and undergoing a total of 6534 CVs for AF from emergency departments of three hospitals. Two study groups were formed: high CV frequency (mean interval between CVs 12 months).ResultsA total of 107 SSEs occurred during a mean follow-up of 5.4 years. The event rates per 100 patient-years were 1.82 and 0.67 in high versus low CV frequency groups, respectively. After adjustment for CHA(2)DS(2)-VASc score, CV frequency independently predicted SSE (HR, 2.87 [95% CI, 1.47 to 5.64]; p = .002) at 3 years. Competing risk analysis also identified CV frequency (sHR, 2.70 [95% CI, 1.38-5.31]; p = .004) as an independent predictor for SSE. In patients with CHA(2)DS(2)-VASc score 1 and low CV frequency, the SSE risk was only 0.08 per 100 patient-years.ConclusionsFrequency of CVs for symptomatic AF episodes provides additional information on stroke risk in AF patients with CHA(2)DS(2)-VASc score 1. Key messages This retrospective study offers a unique opportunity to observe the natural course of AF patients with infrequent episodes of clinical arrhythmia when they were not using OAC (before introduction of CHA(2)DS(2)-VASc score). Stroke or systemic embolism rate was very low (0.08 per 100 patient-years) in patients with one CHA(2)DS(2)-VASc point who visited the emergency room for cardioversion less than once a year. Frequency of cardioversions can be used for additional risk stratification in patients at intermediate risk of stroke based on CHA(2)DS(2)-VASc score.</p

Mechanocardiography in the Detection of Acute ST Elevation Myocardial Infarction: The MECHANO-STEMI Study

Novel means to minimize treatment delays in patients with ST elevation myocardial infarction (STEMI) are needed. Using an accelerometer and gyroscope on the chest yield mechanocardiographic (MCG) data. We investigated whether STEMI causes changes in MCG signals which could help to detect STEMI. The study group consisted of 41 STEMI patients and 49 control patients referred for elective coronary angiography and having normal left ventricular function and no valvular heart disease or arrhythmia. MCG signals were recorded on the upper sternum in supine position upon arrival to the catheterization laboratory. In this study, we used a dedicated wearable sensor equipped with 3-axis accelerometer, 3-axis gyroscope and 1-lead ECG in order to facilitate the detection of STEMI in a clinically meaningful way. A supervised machine learning approach was used. Stability of beat morphology, signal strength, maximum amplitude and its timing were calculated in six axes from each window with varying band-pass filters in 2–90 Hz range. In total, 613 features were investigated. Using logistic regression classifier and leave-one-person-out cross validation we obtained a sensitivity of 73.9%, specificity of 85.7% and AUC of 0.857 (SD = 0.005) using 150 best features. As a result, mechanical signals recorded on the upper chest wall with the accelerometers and gyroscopes differ significantly between STEMI patients and stable patients with normal left ventricular function. Future research will show whether MCG can be used for the early screening of STEMI.</p

Clinical manifestations and outcomes of severe warfarin overanticoagulation: from the EWA study

Introduction: Severe warfarin overanticoagulation is a risk factor for bleeding, but there is little information on its manifestations, prognosis and factors affecting the outcome. We describe the manifestations and clinical outcomes of severe warfarin overanticoagulation in a large group of patients with atrial fibrillation (AF).Material and methods: All international normalized ratio (INR) samples (n = 961,431) in the Turku University Hospital region between 2003 and 2015 were screened. A total of 412 AF patients with INR ≥9 were compared to 405 patients with stable warfarin anticoagulation for AF. Electronic patient records were manually reviewed to collect comprehensive data.Results: Of the 412 patients with INR ≥9, bleeding was the primary manifestation in 105 (25.5%). Non-bleeding symptoms were recorded in 165 (40.0%) patients and 142 (34.5%) had no symptoms. A total of 17 (16.2%) patients with a bleed and 67 (21.8%) without bleeding died within 30 days after the event. Intracranial haemorrhage strongly predicted death within 30 days. Other significant predictors were non-bleeding symptoms, active malignancies, recent bleed, history of myocardial infarction, older age, renal dysfunction and a recent treatment episode.Conclusions: Bleeds are not the major determinant of the poor prognosis in severe overanticoagulation, as coincidental INR ≥9 findings also associate with high mortality.</p

Subtype of atrial fibrillation and the outcome of transcatheter aortic valve replacement: The FinnValve Study

Whether the subtype of atrial fibrillation affects outcomes after transcatheter aortic valve replacement for aortic stenosis is unclear. The nationwide FinnValve registry included 2130 patients who underwent primary after transcatheter aortic valve replacement for aortic stenosis during 2008–2017. Altogether, 281 (13.2%) patients had pre-existing paroxysmal atrial fibrillation, 651 (30.6%) had pre-existing non-paroxysmal atrial fibrillation and 160 (7.5%) were diagnosed with new-onset atrial fibrillation during the index hospitalization. The median follow-up was 2.4 (interquartile range: 1.6–3.8) years. Paroxysmal atrial fibrillation did not affect 30-day or overall mortality (p-values >0.05). Non-paroxysmal atrial fibrillation demonstrated an increased risk of overall mortality (hazard ratio: 1.61, 95% confidence interval: 1.35–1.92; p0.05). In conclusion, non-paroxysmal atrial fibrillation and new-onset atrial fibrillation are associated with increased mortality after transcatheter aortic valve replacement for aortic stenosis, whereas paroxysmal atrial fibrillation has no effect on mortality. These findings suggest that non-paroxysmal atrial fibrillation rather than paroxysmal atrial fibrillation may be associated with structural cardiac damage which is of prognostic significance in patients with aortic stenosis undergoing transcatheter aortic valve replacement.Peer reviewe

Usefulness of the CHA2DS2-VASc and HAS-BLED Scores in Predicting the Risk of Stroke Versus Intracranial Bleeding in Patients With Atrial Fibrillation (from the FibStroke Study)

CHA2DS2-VASc and HAS-BLED scores stratify the risk of thromboembolic and bleeding events respectively in patients with atrial fibrillation. There is only little information on how they differentiate which of the 2 clinically most important complications (ischemic stroke [IS] or an intracranial bleeding [IB]) the patient is more prone to suffer.We evaluated both scores in patients with either of these major complications. The FibStroke Study collected data on all patients with atrial fibrillation with either an IS or an IB event between 2003and 2012 in 4 Finnish hospital districts. Individual electronic patient records were manually reviewed to collect the study data. To assess the relative risk of IS and IB, an IS/IBratio was calculated by dividing the absolute number of ISs with the absolute number of IBs within each score category. A total of 3,816 (82.7%) ISs and 798 (17.3%) IBs were detected in 3,909 patients. In general, ISs occurred more often than IBs in patients on oral anticoagulation in each score category (ratio 1.6 to 5.1). The ratio decreased below 1, however,only with very high HAS-BLED scores (>4). Moreover, 221 ISs and 53 IBs occurred in patients with HAS-BLED > CHA2DS2-VASc, of whom only 19.7% were on anticoagulation. In conclusion, IS was the predominant intracranial event irrespective of CHA2DS2-VASc score, HAS-BLED score ≤4, or use of oral anticoagulation, also in patients with low estimated thromboembolic risk (CHA2DS2-VASc 0 to 1). Furthermore, the HAS-BLED score predicted the excess of IBs over ISs only at very high-risk levels.</p

Incidence and predictors of excessive warfarin anticoagulation in patients with atrial fibrillation-The EWA study

Vitamin K antagonist warfarin is widely used in clinical practice and excessive anticoagulation is a well-known complication of this therapy. Little is known about permanent and temporary predictors for severe overanticoagulation. The aim of this study was to investigate the occurrence and predicting factors for episodes with very high (>= 9) international normalized ratio (INR) values in warfarin treated patients with atrial fibrillation (AF). Excessive Warfarin Anticoagulation (EWA) study screened all patients (n = 13618) in the Turku University Hospital region with an INR >= 2 between years 2003-2015. Patients using warfarin anticoagulation for AF with very high (>= 9) INR values (EWA Group) were identified (n = 412 patients) and their characteristics were compared to a control group (n = 405) of AF patients with stable INR during long-term follow-up. Over 20% (n = 92) of the EWA patients had more than one event of very high INR and in 105 (25.5%) patients EWA led to a bleeding event. Of the several temporary and permanent EWA risk factors observed, strongest were excessive alcohol consumption in 9.6% of patients (OR 24.4, 95% CI 9.9-50.4, p<0.0001) and reduced renal function (OR 15.2, 95% CI 5.67-40.7, p<0.0001). Recent antibiotic or antifungal medication, recent hospitalization or outpatient clinic visit and the first 6 months of warfarin use were the most significant temporary risk factors for EWA. Excessive warfarin anticoagulation can be predicted with several permanent and temporary clinical risk factors, many of which are modifiable