José Miguel Rivera-Caravaca

Assessing Bleeding Risk in Atrial Fibrillation Patients: Comparing a Bleeding Risk Score Based Only on Modifiable Bleeding Risk Factors against the HAS-BLED Score. The AMADEUS Trial

Background The HAS-BLED (hypertension, abnormal renal/liver function, previous stroke, bleeding history or predisposition, labile international normalized ratio [INR], elderly and drugs/alcohol consumption) score has been validated in several scenarios but the recent European guidelines does not recommend any clinical score to assess bleeding risk in atrial fibrillation (AF) patients and only focus on modifiable clinical factors. Purpose The aim of this study was to test the hypothesis that the HAS-BLED score would perform at least similarly to an approach only based on modifiable bleeding risk factors (i.e. a ‘modifiable bleeding risk factors score’) for predicting bleeding events. Methods We performed a comparison between the HAS-BLED score and the new ‘modifiable bleeding risk factors score’ in a post hoc analysis in 4,576 patients included in the AMADEUS trial. Results After 347 (interquartile range, 186–457) days of follow-up, 597 patients (13.0%) experienced any clinically relevant bleeding event and 113 (2.5%) had a major bleeding. Only the HAS-BLED score was significantly associated with the risk of any clinically relevant bleeding (Coxs analysis for HAS-BLED ≥ 3: hazard ratio 1.38; 95% confidence interval [CI], 1.10–1.72; p = 0.005). The ‘modifiable bleeding risk factors score’ ≥ 2 were non-significantly associated with any clinical relevant bleeding. The two scores had modest ability in predicting bleeding events. The HAS-BLED score performed best in predicting any clinically relevant bleeding (c-indexes for HAS-BLED, 0.545 [95% CI, 0.530–0.559] vs. the ‘modifiable bleeding risk factors score’, 0.530 [95% CI, 0.515–0.544]; c-index difference 0.015, z-score = 2.063, p = 0.04). The HAS-BLED score with one, two and three modifiable factors performed significantly better than the ‘modifiable bleeding risk factors scores’ with one, two and three modifiable risk factors. Conclusion When compared with an approach only based on modifiable bleeding risk factors proposed by European Society of Cardiology (ESC) AF guidelines, the HAS-BLED score performed significantly better in predicting any clinically relevant bleeding in this clinical trial cohort. While modifiable bleeding risk factors should be addressed in all AF patients, the use of a formal bleeding risk score (HAS-BLED) has better predictive value for bleeding risks, and would help decision-making in identifying ‘high risk’ patients for scheduling reviews and follow-up.

Does von Willebrand factor improve the predictive ability of current risk stratification scores in patients with atrial fibrillation

Von Willebrand factor (vWF) is a biomarker of endothelial dysfunction. We investigated its role on prognosis in anticoagulated atrial fibrillation (AF) patients and determined whether its addition to clinical risk stratification schemes improved event-risk prediction. Consecutive outpatients with non-valvular AF were recruited and rates of thrombotic/cardiovascular events, major bleeding and mortality were recorded. The effect of vWF on prognosis was calculated using a Cox regression model. Improvements in predictive accuracy over current scores were determined by calculating the integrated discrimination improvement (IDI), net reclassification improvement (NRI), comparison of receiver-operator characteristic (ROC) curves and Decision Curve Analysis (DCA). 1215 patients (49% males, age 76 (71–81) years) were included. Follow-up was almost 7 years. Significant associations were found between vWF and cardiovascular events, stroke, mortality and bleeding. Based on IDI and NRI, addition of vWF to CHA2DS2-VASc statistically improved its predictive value, but c-indexes were not significantly different. For major bleeding, the addition of vWF to HAS-BLED improved the c-index but not IDI or NRI. DCA showed minimal net benefit. vWF acts as a simple prognostic biomarker in AF and, whilst its addition to current scores statistically improves prediction for some endpoints, absolute changes and impact on clinical decision-making are marginal.

Long‐Term Stroke Risk Prediction in Patients With Atrial Fibrillation: Comparison of the ABC‐Stroke and CHA2DS2‐VASc Scores

Background The ABC‐stroke score (age, biomarkers [N‐terminal fragment B‐type natriuretic peptide, high‐sensitivity troponin], and clinical history [prior stroke/transient ischemic attack]) was proposed to predict stroke in atrial fibrillation (AF). This score was derived/validated in 2 clinical trial cohorts in which patients with AF were highly selected and carefully followed‐up. However, the median follow‐up was 1.9 years in the trial cohort; therefore, its long‐term predictive performance remains uncertain. This study aimed to compare the long‐term predictive performances of the ABC‐stroke and CHA 2 DS 2‐VASc (cardiac failure or dysfunction, hypertension, age ≥75 [doubled], diabetes mellitus, stroke [doubled]—vascular disease, age 65 to 74 years and sex category [female]) scores in a cohort of anticoagulated patients with AF. Methods and Results We recruited 1125 consecutive patients with AF who were stable on vitamin K antagonists and followed‐up for a median of 6.5 years. ABC‐stroke and CHA 2 DS 2‐VASc (cardiac failure or dysfunction, hypertension, age ≥75 [doubled], diabetes mellitus, stroke [doubled]—vascular disease, age 65 to 74 years and sex category [female]) scores were calculated and compared. Median CHA 2 DS 2‐VASc and ABC‐stroke scores were 4 (interquartile range 3–5) and 9.1 (interquartile range 7.3–11.3), respectively. There were 114 ischemic strokes (1.55% per year) at 6.5 years. The C‐index of ABC‐stroke at 3.5 years was significantly higher than CHA 2 DS 2‐VASc (0.663 versus 0.600, P=0.046), but both C‐indexes were nonsignificantly different at 6.5 years. Integrated discrimination improvement showed a small improvement (<2%) in sensitivity at 3.5 and 6.5 years with ABC‐stroke. For ABC‐stroke, net reclassification improvement was nonsignificantly different at 3.5 years, and showed a negative reclassification at 6.5 years compared with CHA 2 DS 2‐VASc. Decision curve analyses did not show a marked improvement in clinical usefulness of the ABC‐stroke score over the CHA 2 DS 2‐VASc score. Conclusions In anticoagulated patients with AF followed‐up over a long‐term period, the novel ABC‐stroke score does not offer significantly better predictive performance compared with the CHA 2 DS 2‐VASc score.

Temporal Trends in the Use of Antiplatelet Therapy in Patients With Acute Coronary Syndromes

Background: Current clinical guidelines of acute coronary syndromes (ACS) recommend the use of potent antiplatelet therapy, prasugrel or ticagrelor, because both drugs consistently reduce cardiovascular events. Purpose: The aim of this study was to examine temporal changes in the use of optimal antiplatelet therapy in patients with ACS. Methods: A total of 1717 consecutive patients admitted for ACS in 3 tertiary hospitals from February 2014 to December 2015 were enrolled. We divided these 23 months into 4 semesters: period I (0-5 months), period II (6-11 months), period III (12-17 months), and period IV (17-23 months). Demographic, clinical, and treatment data were collected both at admission and at discharge. Results: Treatment with clopidogrel remained constant throughout the periods (52%, 50%, 44%, and 50% for periods I, II, III, and IV, respectively), whereas a progressive increase in ticagrelor treatment was observed (15%, 25%, 26%, and 28%; P = .001). Indeed, new P2Y12 agents showed an increase from 47% at the first semester to 65% in patients with ST-segment elevation myocardial infarction (STEMI), and in patients younger than 75 years from 36% to 53%. However, for patients older than 75 years, diabetic, and patients with end-stage kidney disease, clopidogrel was the second most commonly used antiplatelet agent. Conclusion: In this real-life registry of patients with ACS, we observed there is still a high rate of use of clopidogrel, despite guidelines recommendations, and our analyses also showed a trend toward the use of ticagrelor. Patients who received new antiplatelet agents were patients with STEMI, younger than 75 years, and with less comorbidities. However, the use of ticagrelor and prasugrel remains low, highlighting a therapeutic inertia with considerable gap between evidence-based clinical guidelines and daily clinical practice.

Quality of oral anticoagulation with vitamin K antagonists in ‘real-world’ patients with atrial fibrillation: a report from the prospective multicentre FANTASIIA registry

Aims The efficacy and safety of oral anticoagulation (OAC) using the vitamin K antagonists (VKA) are closely associated with the quality of anticoagulation, reflected by time in therapeutic range (TTR). The SAMe-TT2R2 is a risk score developed to predict the quality of anticoagulation control among VKA users. To analyse the quality of anticoagulation and its clinical determinants based on different methods in a prospective cohort of atrial fibrillation patients on VKA treatment participating in the multicentre Spanish observational registry FANTASIIA. Methods and results Estimated TTR was calculated from Rosendaal, direct method, international normalized ratio variability, and NICE criteria. Time in therapeutic range values were compared for those patients with a SAMe-TT2R2 score 0-2 and >2. One thousand four hundred and seventy patients were analysed (56.4% male, mean age 74.1 ± 9.5 years). Mean TTR was 61.5 ± 25.1 with Rosendaal and 64.7 ± 24.2 with direct method. There was a high correlation between both methods (ρ = 0.805). The prevalence of poor anticoagulation control was 55%. Diabetes mellitus [odds ratio (OR) 1.38; P = 0.008], peripheral artery disease (PAD, OR 1.62; P = 0.048), and HAS-BLED (OR 1.13; P = 0.022) were independently associated with TTR < 70%. SAMe-TT2R2 score 0-2 had a higher mean TTR than patients with SAMe-TT2R2 >2 (P = 0.044), with a specificity of > 90% for predicting TTR < 70%. Patients with TTR < 70% had higher risk of events (21.7 vs. 16.8%; P = 0.021). Conclusion In a multicentre prospective registry, 55% of AF patients had poor anticoagulation control with diabetes mellitus, PAD, and HAS-BLED being independently associated with TTR < 70%. A high SAMe-TT2R2 scores had a high specificity for predicting a TTR < 70% as an indicator of poor quality anticoagulation.

MiR-146a Regulates Neutrophil Extracellular Trap Formation That Predicts Adverse Cardiovascular Events in Patients With Atrial Fibrillation

Objective— Atrial fibrillation (AF) patients experience adverse cardiovascular events (ACEs) despite anticoagulant therapy. We reported that rs2431697 of miR-146a, a negative regulator of inflammation, predicts ACEs in patients with AF. The relationship between neutrophil extracellular traps and thrombogenesis is known. Thus, our aim was to evaluate the role of neutrophil extracellular trap compounds as prognostic markers of ACEs in AF and to study whether miR-146a affects NETosis. Approach and Results— We included 336 steadily anticoagulated AF patients with a median follow-up of 7.9 years (interquartile range, 7.3–8.1) and 127 healthy subjects. The reviewed ACEs included stroke (ischemic/embolic), acute coronary syndrome, acute heart failure, and global or vascular death. We quantified cell-free DNA and NE (neutrophil elastase) at diagnosis. Rs2431697 was genotyped. Neutrophils from human and mice were seeded to analyze shed cell-free DNA and H3cit (citrullinated histone 3) after activation. In human plasmas, higher NE levels (>55.29 ng/mL), but not cell-free DNA, were independently associated with higher risk of all-cause mortality (hazard ratio, 2.24; 95% CI, 1.36–3.68), cardiovascular mortality (hazard ratio, 4.77; 95% CI, 1.11–20.47), and composite cardiovascular events (hazard ratio, 1.84; 95% CI, 1.01–3.76). In patients, NE levels were associated with rs2431697 (TT: 51.82±2.73 versus CC: 40.01±3.05 ng/mL; P=0.040). In vitro, both human (TT for rs2431697) and miR-146a−/− mice neutrophils yielded higher levels of cell-free DNA and H3cit than CC or wild-type cells, respectively. Conclusions— NE activity can provide new ACE prognostic information in AF patients. These findings provide evidence of a potential role of miR-146a in neutrophil extracellular trap generation and cardiovascular risk in AF.

Enhancing the ‘real world’ prediction of cardiovascular events and major bleeding with the CHA2DS2-VASc and HAS-BLED scores using multiple biomarkers

Abstract Background: Atrial fibrillation (AF)-European guidelines suggest the use of biomarkers to stratify patients for stroke and bleeding risks. We investigated if a multibiomarker strategy improved the predictive performance of CHA2DS2-VASc and HAS-BLED in anticoagulated AF patients. Methods: We included consecutive patients stabilized for six months on vitamin K antagonists (INRs 2.0–3.0). High sensitivity troponin T, NT-proBNP, interleukin-6, von Willebrand factor concentrations and glomerular filtration rate (eGFR; using MDRD-4 formula) were quantified at baseline. Time in therapeutic range (TTR) was recorded at six months after inclusion. Patients were follow-up during a median of 2375 (IQR 1564–2887) days and all adverse events were recorded. Results: In 1361 patients, adding four blood biomarkers, TTR and MDRD-eGFR, the predictive value of CHA2DS2-VASc increased significantly by c-index (0.63 vs. 0.65; p = .030) and IDI (0.85%; p < .001), but not by NRI (−2.82%; p < .001). The predictive value of HAS-BLED increased up to 1.34% by IDI (p < .001). Nevertheless, the overall predictive value remains modest (c-indexes approximately 0.65) and decision curve analyses found lower net benefit compared with the originals scores. Conclusions: Addition of biomarkers enhanced the predictive value of CHA2DS2-VASc and HAS-BLED, although the overall improvement was modest and the added predictive advantage over original scores was marginal. Key Messages Recent atrial fibrillation (AF)-European guidelines for the first time suggest the use of biomarkers to stratify patients for stroke and bleeding risks, but their usefulness in real world for risk stratification is still questionable. In this cohort study involving 1361 AF patients optimally anticoagulated with vitamin K antagonists, adding high sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, interleukin 6, von Willebrand factor, glomerular filtration rate (by the MDRD-4 formula) and time in therapeutic range, increased the predictive value of CHA2DS2-VASc for cardiovascular events, but not the predictive value of HAS-BLED for major bleeding. Reclassification analyses did not show improvement adding multiple biomarkers. Despite the improvement observed, the added predictive advantage is marginal and the clinical usefulness and net benefit over current clinical scores is lower.

Non-vitamin K antagonist oral anticoagulants: impact of non-adherence and discontinuation

ABSTRACT Introduction: Non-Vitamin K Antagonist Oral Anticoagulants (NOACs) are at least as effective as vitamin K antagonists (VKAs) reducing thromboembolism and mortality in atrial fibrillation (AF). These ‘fixed-dose regimen’ drugs are characterized by not requiring routine monitoring or dosage adjustment. Stroke prevention with OAC is indicated in AF patients with CHA2DS2-VASc ≥2 (≥3 in females) and NOACs are recommended in preference to VKAs. However, underuse, premature discontinuation of treatment and non-adherence to guidelines is common, and independently associated with higher stroke risk and all-cause mortality. Areas covered: In this review, we provide an overview of the impact of under or overdosing NOACs in AF patients. We debate the current adherence to AF-guidelines, the reasons involved in non-adherence and discontinuation, as well as the limitations found by patients and physicians about the use of NOACs. Expert opinion: The more convenient non-monitored and fixed-dose regimen of NOACs might improve patients’ adherence but may hinder the identification of patients with poor adherence or discontinuation. Since there are several reasons for OAC underuse, future strategies to improve adherence should be implemented, that include more and better education about AF and stroke risk, as well as and specific information about the potential consequences of non-adherence to OAC.

A Propensity Score Matched Comparison of Clinical Outcomes in Atrial Fibrillation Patients Taking Vitamin K Antagonists: Comparing the “Real-World” vs Clinical Trials

Objective: To investigate the incidence and risk of adverse clinical outcomes in a “real‐world” cohort of patients with atrial fibrillation (AF) anticoagulated with vitamin K antagonists (VKAs) from the Murcia AF Project in comparison with the warfarin arm of the randomized clinical trial (RCT) AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation). Patients and Methods: We included 1361 patients with AF from the Murcia AF Project (recruitment from May 1, 2007, to December 1, 2007) and 2293 from the AMADEUS trial (started in September 2003 and primary completed in March 2006), all taking VKA treatment. After propensity score matching (PSM), we investigated differences in rates and risks of several events, including major bleeding, ischemic stroke, and all‐cause mortality at 365 (interquartile range, 275‐428) days of follow‐up. Results: After PSM there were 1324 patients for the comparative analysis, whereby annual event rates for most adverse events were significantly higher in the “real‐world” population. Cox regression analyses demonstrated that the risk of primary outcomes was also increased in the “real‐world” (vs RCT: hazard ratio [HR], 6.32; 95% CI, 2.84‐14.03 for major bleeding; HR, 3.56, 95% CI, 1.22‐10.42 for ischemic stroke; HR, 5.13, 95% CI, 3.02‐8.69 for all‐cause mortality). The risk of all other adverse events was higher in the real‐world cohort, except for cardiovascular mortality. Conclusion: This study comparing the Murcia AF Project and the AMADEUS trial demonstrates that there is a great heterogeneity in both populations, which is translated into a higher risk of several adverse outcomes in the real‐world cohort, including major bleeding, ischemic stroke, and mortality.

Disparities in the Estimation of Glomerular Filtration Rate According to Cockcroft‐Gault, Modification of Diet in Renal Disease‐4, and Chronic Kidney Disease Epidemiology Collaboration Equations and Relation With Outcomes in Patients With Acute Coronary Syndrome

Background A simple method to assess renal function is the estimated glomerular filtration rate, and it shows prognostic implications. However, it remains unknown which equation should be used in patients with acute coronary syndrome. We compared the ability and correlation of the Cockcroft‐Gault, Modification of Diet in Renal Disease‐4 (MDRD‐4), and Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equations and their predictive performance for major adverse cardiovascular events, all‐cause mortality, and major bleeding in a cohort of patients with acute coronary syndrome. Methods and Results Multicenter prospective registry involving 1699 consecutive patients with acute coronary syndrome from 3 tertiary institutions. At entry, renal function was assessed using the Cockcroft‐Gault, MDRD‐4, and CKD‐EPI‐creatinine equations. During 12 months of follow‐up, we recorded all major adverse cardiovascular events (composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal ischemic stroke), bleeding events (Bleeding Academic Research Consortium classification), and all‐cause mortality. Receiver operating characteristic curve comparisons demonstrated that Cockcroft‐Gault equation had higher predictive ability compared with MDRD‐4 equation for major adverse cardiovascular events (0.651 versus 0.616; P=0.023), major bleeding (0.600 versus 0.551; P=0.005), and all‐cause mortality (0.754 versus 0.717; P=0.033), as well as higher predictive ability compared with CKD‐EPI equation for major bleeding (0.600 versus 0.564; P=0.018). Integrated discrimination improvement and net reclassification improvement analyses showed superior discrimination and reclassification of Cockcroft‐Gault equation. Decision curve analyses graphically demonstrated higher net benefit and clinical usefulness of the Cockcroft‐Gault equation in comparison with MDRD‐4 and CKD‐EPI equations. Conclusions In patients with acute coronary syndrome, the Cockcroft‐Gault equation presented superior predictive ability for major adverse cardiovascular events, major bleeding, and all‐cause mortality compared with MDRD‐4 equation, and superior predictive ability for major bleeding compared with CKD‐EPI equation. The Cockcroft‐Gault equation also showed higher net benefit and clinical usefulness.