Murcia atrial fibrillation project II: protocol for a prospective observational study in patients with atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is characterised by a high stroke risk. Vitamin K antagonists (VKAs) are the most commonly used oral anticoagulants (OACs) in Spain, but their efficacy and safety depend on the time in therapeutic range of International Normalized Ratio (INR) 2.0-3.0 over 65%-70%. Unfortunately, the difficulties of maintaining an optimal level of anticoagulation and the complications of VKAs (particularly haemorrhagic ones), frequently lead to cessation of this therapy, which has been associated with higher risk of adverse events (AEs), including ischaemic stroke. Our aims are as follows: (1) to evaluate the quality of oral anticoagulation with VKAs, the prevalence of poor quality of anticoagulation, and to identify factors predisposing to poor quality anticoagulation; and (2) to identify patients who will stop OAC and to investigate what factors influence the decision of OAC withdrawal. METHODS AND ANALYSIS: Prospective observational cohort study including outpatients newly diagnosed with AF and naïve for OACs from July 2016 to June 2018 in an anticoagulation clinic. Patients with prosthetic heart valves, rheumatic mitral valves or valvular AF will be excluded. Follow-up will extend for up to 3 years. During this period, the INR results and changes in the anticoagulant therapy will be recorded, as well as all AEs, or any other information that would be relevant to the proper conduct of research. ETHICS AND DISSEMINATION: All patients were informed about the nature and purpose of the study, and the protocol was approved by the Ethics Committee of Hospital General Universitario Morales Meseguer (reference: EST:20/16). This is an observational study focusing on 'real life' practice and therefore all treatments and follow-up will be performed in accordance to the routine clinical practice with no specific interventions or visits. The results of our study will be disseminated by presentations at national and international meetings, and publications in peer-reviewed journals.

Refining Stroke and Bleeding Prediction in Atrial Fibrillation by Adding Consecutive Biomarkers to Clinical Risk Scores.

Background and Purpose- Current European guidelines for the management of atrial fibrillation suggest using biomarkers to refine the risk stratification process. However, it is unclear whether ≥2 biomarkers incrementally improve risk prediction beyond 1 biomarker alone. We investigated whether the predictive performance of CHA2DS2-VASc and HAS-BLED scores could be enhanced by incrementally adding consecutive different biomarkers in real-world atrial fibrillation patients taking vitamin K antagonists therapy. Methods- We included 940 atrial fibrillation patients stable on vitamin K antagonists (international normalized ratio, 2.0-3.0) for at least the previous 6 months. At inclusion, VWF (von Willebrand factor), high-sensitivity troponin T, NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity IL (interleukin)-6, fibrin monomers, and BTP (ß-trace protein) concentrations were quantified. During follow-up, all adverse events were recorded, and biomarkers were added to CHA2DS2-VASc and HAS-BLED scores depending on the C index. Results- During 6.5 (4.3-7.9) years, there were 98 ischemic strokes (1.60% per year) and 172 major bleeds (1.60% per year). After the addition of biomarkers, the predictive performance of CHA2DS2-VASc was not significantly increased, although the model with 3 biomarkers (ie, NT-proBNP+BTP+VWF) showed a low gain in sensitivity (integrated discrimination improvement, 2.70%; P<0.001). The predictive performance of HAS-BLED was enhanced in all biomarker-based models, with the best prediction shown by the model with 3 biomarkers (ie, VWF+NT-proBNP+high-sensitivity IL-6; C index, 0.600 [95% CI, 0.561-0.625] versus 0.639 [95% CI, 0.607-0.669]; P=0.025). This model also confirmed an increased sensitivity (integrated discrimination improvement, 5.20%; P<0.001) and positive reclassification (net reclassification improvement, 19.20%; P=0.020). Conclusions- By adding consecutive biomarkers, the predictive ability of CHA2DS2-VASc for ischemic stroke was not increased, whereas the predictive ability of HAS-BLED for major bleeding was only slightly enhanced. The net benefit and clinical usefulness of the biomarker-based models were marginal in comparison to the original scores based on clinical factors.

The SAMe-TT2R2 Score Predicts Poor Anticoagulation Control in AF Patients: A Prospective 'Real-world' Inception Cohort Study.

OBJECTIVES: International guidelines recommend that an average individual time in therapeutic range should be >65% to 70% for optimal efficacy and safety outcomes while taking a vitamin K antagonist. The Sex, Age (<60 years); Medical history (at least 2 of the following: hypertension, diabetes, coronary artery disease/myocardial infarction, peripheral arterial disease, congestive heart failure, previous stroke, pulmonary disease, hepatic or renal disease); Treatment (interacting drugs, eg, amiodarone for rhythm control) [all 1 point]; and the current Tobacco use (2 points) and Race (non-Caucasian; 2 points) (SAMe-TT2R2) score would help decision making by identifying those patients with newly diagnosed atrial fibrillation who could do well on vitamin K antagonists. The study objective was to validate the predictive value of the SAMe-TT2R2 score for discriminating those who would achieve a high time in the therapeutic range (≥65%) in a prospective "real-world" cohort of patients with atrial fibrillation initiating oral anticoagulation therapy with vitamin K antagonists. METHODS: We studied an inception cohort of consecutive patients with nonvalvular atrial fibrillation who initiated oral anticoagulation in our outpatient anticoagulation clinic. The baseline SAMe-TT2R2 score was calculated. At 6 months, we calculated the time in therapeutic range using a linear method. RESULTS: We included 459 patients, of whom 222 (47%) were male. Their median age was 76 years (interquartile range, 70-82 years), median Cardiac failure or dysfunction, Hypertension, Age over 75 years [Doubled], Diabetes, Stroke [Doubled] - Vascular disease, Age between 65-74 and Sex category [Female] (CHA2DS2-VASc) score was 4 (3-5), and median Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly (HAS-BLED) score was 3 (2-3). The median SAME-TT2R2 score was 2 (1-2). At 6 months, the mean ± standard deviation time in therapeutic range was 64% ± 17% overall, and 248 patients (54%) had a time in therapeutic range value >65%. Patients with a SAME-TT2R2 score 0 to 1 had a mean time in therapeutic range of 67% ± 18%, whereas patients with a SAME-TT2R2 score ≥2 had a mean time in therapeutic range of 61% ± 16% (P < .001). The odds ratio for having a low time in therapeutic range value was 2.10 (95% confidence interval, 1.44-3.06; P < .001) for those patients with a SAME-TT2R2 score ≥2. CONCLUSIONS: In a prospective "real-world" inception cohort of patients with atrial fibrillation initiating oral anticoagulation with acenocoumarol, we have validated the clinical value of the SAME-TT2R2 score for the identification of patients who would have poor-quality anticoagulation. Thus, rather than imposing a "trial of vitamin K antagonists" for such patients (and exposing such patients to thromboembolic risks), we can a priori identify those patients who can (not cannot) do well on a vitamin K antagonists. Such patients would benefit from additional strategies for improving anticoagulation control with vitamin K antagonists or alternative oral anticoagulant drugs.

Usefulness of N-terminal pro-B-type natriuretic Peptide levels for stroke risk prediction in anticoagulated patients with atrial fibrillation.

BACKGROUND AND PURPOSE: Oral anticoagulation is highly effective in reducing stroke and mortality in atrial fibrillation (AF). Several risk stratification schemes have been developed using clinical characteristics. Elevated levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) are important markers of increased mortality and morbidity in congestive heart failure and general community population. The aim of our study was to assess the predictive value of NT-proBNP levels in an unselected real-world cohort of anticoagulated patients with AF. METHODS: We studied 1172 patients (49% male; median age, 76 years) with permanent AF who were well stabilized on oral anticoagulation (international normalized ratio, 2.0-3.0). Plasma NT-proBNP levels were quantified at baseline. We recorded thrombotic and vascular events, mortality, and major bleeding. The best cutoff points were assessed by receiver-operating characteristic curves. RESULTS: Median levels (interquartile range) of NT-proBNP were 610 (318-1037) pg/mL. Median follow-up was 1007 (806-1279) days. On multivariate analysis, high NT-proBNP was significantly associated with the risk of stroke (hazards ratio, 2.71; P=0.001) and composite vascular events (acute coronary syndrome or acute heart failure; hazards ratio, 1.85; P=0.016), as well as a significant association with mortality (adjusted hazards ratio, 1.66; P=0.006). No association with bleeding was found (P=0.637). The integrated discrimination improvement (IDI) analysis demonstrated that NT-proBNP improved the Congestive heart failure, Hypertension, Age≥75 (doubled), Diabetes mellitus, Stroke (doubled)-Vascular disease and Sex category (female); CHA2DS2-VASc score for predicting embolic events (relative IDI, 2.8%; P=0.001) and all-cause death (relative IDI, 1.8%; P=0.001). CONCLUSIONS: In real-world cohort of anticoagulated patients with AF, NT-proBNP provided complementary prognostic information to an established clinical risk score (CHA2DS2-VASc) for the prediction of stroke/systemic embolism. NT-proBNP was also predictive of all-cause mortality, suggesting that this biomarker may potentially be used to refine clinical risk stratification in anticoagulated patients with AF.

Relation of the HAS-BLED bleeding risk score to major bleeding, cardiovascular events, and mortality in anticoagulated patients with atrial fibrillation.

BACKGROUND: Stroke risk in atrial fibrillation (AF) using oral vitamin K antagonists is closely related to bleeding risk. The HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR [international normalized ratio], elderly, drugs/alcohol concomitantly) bleeding score has demonstrated usefulness in assessing major bleeding risk in patients with AF. However, risk factors for warfarin-associated bleeding also predict stroke risk in patients with AF. We tested the usefulness of the HAS-BLED score for predicting both major bleeding and cardiovascular events in a cohort of anticoagulated patients with AF. METHODS AND RESULTS: We recruited 965 consecutive anticoagulated outpatients with permanent or paroxysmal AF who were stabilized for at least 6 months on oral anticoagulation (international normalized ratio, 2.0-3.0). Medical history and HAS-BLED score were assessed. Cox regression models were used to determine the association between clinical risk factors and bleeding episodes, adverse cardiovascular events, and mortality. The median HAS-BLED score was 2 (range, 0-6; 29% with a score ≥3 [ie, high risk]). Median follow-up was 861 days (range, 718-1016 days). Independent predictors for major bleeding were age ≥75 years (hazard ratio [HR], 1.74; 95% CI, 1.05-2.87; P=0.030), male sex (HR, 1.70; 95% CI, 1.03-2.80; P=0.036), renal impairment (HR, 2.12; 95% CI, 1.20-3.73; P=0.010), previous bleeding episode (HR, 6.00; 95% CI, 3.73-9.67; P<0.001), current alcohol consumption (HR, 2.28; 95% CI, 1.03-5.06; P=0.043), and concomitant malignant disease (HR, 2.17; 95% CI, 1.13-4.18; P=0.020). Independent predictors for adverse cardiovascular events were age >75 years (HR, 2.20; 95% CI, 1.40-3.46; P=0.001), heart failure (HR, 1.78; 95% CI, 1.20-2.86; P=0.001), and previous stroke (HR, 1.85; 95% CI, 1.20-2.86; P<0.001). The HAS-BLED score was highly predictive for major bleeding events (HR, 2.04; 95% CI, 1.68-2.49; P<0.001) and adverse cardiovascular events (HR, 1.51; 95% CI, 1.27-1.81; P<0.001). The incidence of both bleeding and adverse cardiovascular events was higher as HAS-BLED score increased, and crude bleeding rates only exceeded thrombotic events at a HAS-BLED score >3. The HAS-BLED score also predicted all-cause mortality (HR, 1.68; 95% CI, 1.40-2.01; P<0.001). CONCLUSIONS: The HAS-BLED score not only is useful in the assessment of bleeding risk, but also shows some predictive value for cardiovascular events and mortality in anticoagulated patients with AF, consistent with the relationship between thrombosis and bleeding. Nonetheless, the HAS-BLED score has been designed for predicting bleeding risk rather than thrombotic events per se, and specific risk scores for cardiovascular events and mortality should be applied for these events.