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.

Predicting performance of the HAS-BLED and ORBIT bleeding risk scores in patients with atrial fibrillation treated with Rivaroxaban: Observations from the prospective EMIR Registry.

BACKGROUND: Assessing bleeding risk during the decision-making process of starting oral anticoagulation (OAC) therapy in atrial fibrillation (AF) patients is essential. Several bleeding risk scores have been proposed for vitamin K antagonist users but, few studies have focused on validation of these bleeding risk scores in patients taking direct oral anticoagulants (DOACs). The aim was to compare the predictive ability of HAS-BLED and ORBIT bleeding risk scores in AF patients taking rivaroxaban in the EMIR ('Estudio observacional para la identificación de los factores de riesgo asociados a eventos cardiovasculares mayores en pacientes con fibrilación auricular no valvular tratados con un anticoagulante oral directo [Rivaroxaban]) Study. METHODS AND RESULTS: EMIR Study was an observational, multicenter, post-authorization, and prospective study that involved AF patients under OAC with rivaroxaban at least 6 months before enrolment. We analysed baseline clinical characteristics and adverse events after 2.5 years of follow-up and validated the predictive ability of HAS-BLED and ORBIT scores for major bleeding (MB) events.We analysed 1433 patients with mean age of 74.2 ± 9.7 (44.5% female). Mean HAS-BLED score was 1.6 ± 1.0 and ORBIT score was 1.1 ± 1.2. The ORBIT score categorised a higher proportion of patients as 'low-risk' (87.1%) compared with 53.5% using the HAS-BLED score. There were 33 MB events (1.04%/year) and 87 patients died (2.73%/year). Both HAS-BLED and ORBIT had a good predictive ability for MB{Area under the curve (AUC) 0.770, [95% confidence interval (CI) 0.693-0.847; P <0.001] and AUC 0.765 (95% CI 0.672-0.858; P <0.001), respectively}. There was a non-significant difference for discriminative ability of the two tested scores (P = 0.930) and risk reclassification in terms of net reclassification improvement (NRI) -5.7 (95% CI -42.4-31.1; P = 0.762). HAS-BLED score showed the best calibration and ORBIT score showed the largest mismatch in calibration, particularly in higher predicted risk patients. CONCLUSION: In a prospective real-world AF population under rivaroxaban from EMIR registry, the HAS-BLED score had good predictive performance and calibration compared with ORBIT score for MB events. ORBIT score presented worse calibration than HAS-BLED in this DOAC treated population.

Under-prescription of novel antiplatelet drugs in patients with acute coronary syndrome and previous cardiovascular disease.

BACKGROUND: Patients with acute coronary syndrome (ACS) and previous cardiovascular disease (CVD) (stroke, peripheral arterial disease [PAD] or coronary artery disease [CAD]) are at high risk of serious events and mortality. Current clinical guidelines recommend new antiplatelet drugs (NADs) for high cardiovascular risk patients with ACS; however, these drugs are underused in different scenarios. METHODS: This study included 1717 ACS patients from 3 tertiary hospitals. Of them, 641 (37.33%) suffered from previous CVD: 149 patients with stroke, 154 patients with PAD and 541 patients with CAD. Bleeding, mortality and major adverse cardiac events (MACE) at 1 year of follow-up after hospital discharge were analyzed. RESULTS: NADs administration during hospital stay and at discharge was less frequent in patients with previous CVDs (P<0.001, for both). Cox analysis in this cohort of patients showed that clopidogrel prescription at discharge was independently associated with MACEs (HR: 1.59 [95% CI: 1.03-2.45]; P=0.036) and with death (HR: 1.99 [95% CI: 1.00-3.98]; P=0.049) in multivariate analysis. More specifically, when ticagrelor prescription at discharge was compared with clopidogrel, a significant death reduction was found in both, the univariate and the multivariate Cox analysis (HR: 4.54 [95% CI: 2.26-9.13]; P<0.001 and HR: 2.61 [95% CI: 1.16-5.90]; P=0.021, respectively). CONCLUSIONS: New antiplatelet drugs, especially ticagrelor, showed lower rates of mortality in patients with CVD without differences for bleeding. Despite the recommendations of current clinical guidelines for high risk patients with ACS, the use of NADs is very low in "real-life" patients with previous CVD.

Switching of Oral P2Y12 Inhibitor Treatment in Patients with Acute Coronary Syndrome: Prevalence, Predictors, and Prognosis.

BACKGROUND AND OBJECTIVE: Dual antiplatelet therapy is one of the main treatments in acute coronary syndrome (ACS). Switching antiplatelet agents may be necessary in some patients to improve efficacy or safety. The objective of this study was to determine the prevalence, predictors, and implications of clinical switching in patients during hospital admission and 1-year follow-up at discharge. METHODS: Observational, prospective, multicenter registry study in patients discharged following an admission for ACS and followed up for 1 year. We analyzed ischemic and bleeding events as well as treatment changes. RESULTS: We recruited 1717 patients; in-hospital switching occurred in 425 (24.8%): 15.1% to clopidogrel and 84.9% to newer antiplatelet drugs (prasugrel or ticagrelor). Those switched to newer antiplatelets were younger, with lower scores on the GRACE and CRUSADE scales, admitted more frequently for ST-elevation myocardial infarction and underwent more invasive management and percutaneous revascularization. The clinical cardiologist was responsible for most in-hospital switching to newer antiplatelets (79.6%). The loading dose of the second antiplatelet did not affect incidence of bleeding events. Post-discharge switching was infrequent (2%) and depended mainly on clinical indications; only 30% was related to a new ACS. CONCLUSIONS: In a contemporary registry with ACS, in-hospital switching of antiplatelet drugs was frequent. Those switched to newer antiplatelets were younger and admitted more frequently for ST-elevation myocardial infarction. Post-discharge switching was infrequent.