The association of hematological markers with occurrence of thrombotic and bleeding events following left atrial appendage occlusion.

Introduction Patients undergoing left atrial appendage occlusion (LAAO) are at increased risk for bleeding or thromboembolic events. Concurrently, biomarkers are of growing importance in risk stratification for atrial fibrillation patients. We aimed to evaluate the association of hematological markers and clinical characteristics with the occurrence of thromboembolic and bleeding events following LAAO. Methods Seven implanting centers retrospectively gathered data on hematological markers (i.e. platelet count (PC), mean platelet volume (MPV), and fibrinogen) prior LAAO. Prespecified thromboembolic and major bleeding outcomes were collected and the association with pre-procedural hematological markers and clinical characteristics was evaluated using Cox regression analysis. Results In total, 1315 patients were included (74±9 years, 36% female, CHA2DS2-VASc 4.3±1.5, HAS-BLED 3.3±1.1). Over a total follow-up duration of 2682 patient years, 77 thromboembolic events and 107 major bleeding events occurred after LAAO. Baseline PC was the only biomarker showing a signal for a relation to thromboembolic events (HR 1.18, 95% CI: 1.00-1.39) per 50*109 increment, p=0.056). Thrombotic event rates, including device-related thrombus, increased within higher PC quartiles. Thromboembolism was associated with age (HR 1.05, 95% CI: 1.00-1.10, per year increase) and prior thromboembolism (HR 2.08, 95% CI: 1.07-4.03), but with none of the biomarkers in multivariate analysis. No association of any of the hematological markers with major bleeding was observed. Major bleeding following LAAO was associated with prior major bleeding (HR 5.27, 95% CI: 2.71-10.22), renal disease (HR 1.93, 95% CI: 1.17-3.18) and discharge on dual antiplatelet therapy (HR 1.71, 95% CI: 1.05-2.77). Conclusion Most thrombotic events occurred in the highest PC quartile, but no association of any of the hematological markers with thromboembolism or major bleeding was observed in our analysis. In multivariate analysis, older age and prior thromboembolism were associated with thromboembolism. Prior major bleeding, renal disease and discharge on DAPT were multivariate predictors of major bleeding after LAAO.

Left Atrial Appendage Occlusion in Patients With Anticoagulation Failure vs Anticoagulation Contraindication.

BACKGROUND: Left atrial appendage occlusion (LAAO) provides mechanical cardioembolic protection for atrial fibrillation (AF) patients who cannot use oral anticoagulation therapy (OAT). Patients with a thrombotic event despite OAT are at high risk for recurrence and may also benefit from LAAO. OBJECTIVES: This study sought to investigate the efficacy of LAAO in AF patients with a thrombotic event on OAT compared to: 1) LAAO in AF patients with a contraindication for OAT; and 2) historical data. METHODS: The international LAAO after stroke despite oral anticoagulation (STR-OAC LAAO) collaboration included patients who underwent LAAO because of thrombotic events on OAT. This cohort underwent propensity score matching and was compared to the EWOLUTION (Evaluating Real-Life Clinical Outcomes in Atrial Fibrillation Patients Receiving the WATCHMAN Left Atrial Appendage Closure Technology) registry, which represents patients who underwent LAAO because of OAT contraindications. The primary outcome was ischemic stroke. Event rates were compared between cohorts and with historical data without OAT, yielding relative risk reductions based on risk scores. RESULTS: Analysis of 438 matched pairs revealed no significant difference in the ischemic stroke rate between the STR-OAC LAAO and EWOLUTION cohorts (2.5% vs 1.9%; HR: 1.37; 95% CI: 0.72-2.61). STR-OAC LAAO patients exhibited a higher thromboembolic risk (HR: 1.71; 95% CI: 1.04-2.83) but lower bleeding risk (HR: 0.39; 95% CI: 0.18-0.88) compared to EWOLUTION patients. The mortality rate was slightly higher in EWOLUTION (4.3% vs 6.9%; log-rank P = 0.028). Relative risk reductions for ischemic stroke were 70% and 78% in STR-OAC LAAO and EWOLUTION, respectively, compared to historical data without OAT. CONCLUSIONS: LAAO in patients with a thrombotic event on OAT demonstrated comparable stroke rates to the OAT contraindicated population in EWOLUTION. The thromboembolic event rate was higher and the bleeding rate lower, reflecting the intrinsically different risk profile of both populations. Until randomized trials are available, LAAO may be considered in patients with an ischemic event on OAT.

Mechanisms and Prediction of Ischemic Stroke in Atrial Fibrillation Patients.

Atrial fibrillation (AF) is the most common arrhythmia in adults worldwide and represents an important burden for patients, physicians, and healthcare systems. AF is associated with substantial mortality and morbidity, due to the disease itself and its specific complications, such as the increased risk of stroke and thromboembolic events associated with AF. The temporal relation between AF episodes and stroke is nonetheless incompletely understood. The factors associated with an increased thromboembolic risk remain unclear, as well as the stroke risk stratification. Therefore, in this review, we intend to expose the mechanisms and physiopathology leading to intracardiac thrombus formation and stroke in AF patients, together with the evidence supporting the causal hypothesis. We also expose the risk factors associated with increased risk of stroke, the current different risk stratification tools as well as future prospects for improving this risk stratification.

Long-term outcomes of successful left atrial appendage occlusion with focus on stroke prevention: 10-year follow-up of a single-center registry.

Background: Percutaneous left atrial appendage occlusion (LAAO) is an alternative to anticoagulation in the prevention of stroke in patients with nonvalvular atrial fibrillation, especially in patients with a contraindication for oral anticoagulation therapy (OAT). Objective: The study sought to obtain long-term patient outcomes after successful LAAO in everyday clinical practice. Methods: In this single-center registry spanning over 10 years, data of all consecutive patients that underwent percutaneous LAAO were collected. Observed thromboembolic and major bleeding event rates after successful LAAO during follow-up were compared with expected event rates based on CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65-74 years, sex category) and HAS-BLED (hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs or alcohol) scores. Furthermore, anticoagulation and antiplatelet use during follow-up was evaluated. Results: Of 230 patients scheduled for LAAO (38% women, 69.5 ± 8.2 years of age, CHA2DS2-VASc score 3.9 ± 1.6, HAS-BLED score 2.9 ± 1.0), 218 patients had a successful implantation (95%) with a follow-up duration of 5.2 ± 3.1 years. The procedure was combined with catheter ablation in 52% of the patients. Fifty thromboembolic complications (24 ischemic stroke, 26 transient ischemic attack) were observed during follow-up in 40 (18%) of 218 patients. Ischemic strokes occurred with a rate of 2.1 per 100 patient-years, accounting for a 66% relative risk reduction compared with the CHA2DS2-VASc predicted event rate. Device-related thrombus was observed in 5 (2%) patients. Sixty-five nonprocedural major bleeding complications occurred in 24 (11%) of 218 patients with a rate of 5.7 per 100-patient years, which is comparable to estimated HAS-BLED-bleeding rates under OAT use. At end of follow-up 71% of all patients were on single antiplatelet or no antiplatelet or anticoagulation treatment, while 29% were on OAT. Conclusion: Thromboembolic event rates during long-term follow-up after successful LAAO remained consistently lower than expected supporting the efficacy of LAAO.

COMPARE LAAO: Rationale and design of the randomized controlled trial "COMPARing Effectiveness and safety of Left Atrial Appendage Occlusion to standard of care for atrial fibrillation patients at high stroke risk and ineligible to use oral anticoagulation therapy".

BACKGROUND: Left atrial appendage occlusion (LAAO) provides an alternative to oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation (AF). In patients with a long-term or permanent contraindication for OAC randomized controlled trial (RCT) data is lacking. STUDY OBJECTIVES: To assess the efficacy and safety of LAAO in AF patients who are ineligible to use OAC. The co-primary efficacy endpoint is (1) time to first occurrence of stroke (ischemic, hemorrhagic, or undetermined) and (2) time to first occurrence of the composite of stroke, transient ischemic attack (TIA), and systemic embolism (SE). The primary safety endpoint is the 30-day rate of peri-procedural complications. STUDY DESIGN: This is a multicenter, investigator-initiated, open-label, blinded endpoint (PROBE), superiority-driven RCT. Patients with AF, a CHA2DS2-VASc score ≥2 for men and ≥3 for women and a long-term or permanent contraindication for OAC will be randomized in a 2:1 fashion to the device- or control arm. Patients in the device arm will undergo percutaneous LAAO and will receive post-procedural dual antiplatelet therapy (DAPT) per protocol, while those in the control arm will continue their current treatment consisting of no antithrombotic therapy or (D)APT as deemed appropriate by the primary responsible physician. In this endpoint-driven trial design, assuming a 50% lower stroke risk of LAAO compared to conservative treatment, 609 patients will be followed for a minimum of 1 and a maximum of 5 years. Cost-effectiveness and budget impact analyses will be performed to allow decision-making on reimbursement of LAAO for the target population in the Netherlands. SUMMARY: The COMPARE LAAO trial will investigate the clinical superiority in preventing thromboembolic events and cost-effectiveness of LAAO in AF patients with a high thromboembolic risk and a contraindication for OAC use. NCT TRIAL NUMBER: NCT04676880.

Hemostatic biomarkers and antithrombotic strategy in percutaneous left atrial interventions: State-of-the-art review.

Atrial septal defect, persistent foramen ovale and the left atrial appendage are nowadays often percutaneously closed with implantable devices. These interventions may be complicated by thromboembolic events and the perfect post-procedural antithrombotic management is still under investigation. The mechanisms leading to left atrial device-related thrombus and thromboembolic complications are not fully understood. Biomarkers of coagulation activation are elevated following percutaneous device placement, peaking within one month and returning to baseline values after three months. By contrast, platelet reactivity shows no post-procedural increase. This suggests that an optimal antithrombotic regimen should perhaps include (oral) anticoagulation therapy rather than the currently more frequently prescribed antiplatelet-based regimen. Furthermore, biomarkers of endothelial activation, fibrinolysis, and on-treatment platelet reactivity may be of value in predicting device-related thrombus and bleeding and guide future medical strategy, facilitating personalized medicine.

Interplay between temporal and spatial dispersion of repolarization in the initiation and perpetuation of torsades de pointes in the chronic atrioventricular block dog.

Ventricular arrhythmias, consisting of single ectopic beats (sEB), multiple EB (mEB), and torsades de pointes (TdP, defined as ≥5 beats with QRS vector twisting around isoelectric line) can be induced in the anesthetized chronic atrioventricular block (CAVB) dog by dofetilide (IKr blocker). The interplay between temporal dispersion of repolarization, quantified as short-term variability (STV), and spatial dispersion of repolarization (SDR) in the initiation and perpetuation of these arrhythmias remains unclear. Five inducible (≥3 TdPs/10 min) CAVB dogs underwent one mapping experiment and were observed for 10 min from the start of dofetilide infusion (0.025 mg/kg, 5 min). An intracardiac decapolar electrogram (EGM) catheter and 30 intramural cardiac needles in the left ventricle (LV) were introduced. STVARI was derived from 31 consecutive activation recovery intervals (ARIs) on the intracardiac EGM, using the formula: [Formula: see text]. The mean SDR3D in the LV was determined as the three-dimensional repolarization time differences between the intramural cardiac needles. Moments of measurement included baseline (BL) and after dofetilide infusion before first 1) sEB (occurrence at 100 ± 35 s), 2) mEB (224 ± 96 s), and 3) non-self-terminating TdP (454 ± 298 s). STVARI increased from 2.15 ± 0.32 ms at BL to 3.73 ± 0.99 ms* before the first sEB and remained increased without further significant progression to mEB (4.41 ± 0.45 ms*) and TdP (5.07 ± 0.84 ms*) (*P < 0.05 compared with BL). SDR3D did not change from 31 ± 11 ms at BL to 43 ± 13 ms before sEB but increased significantly before mEB (68 ± 7 ms*) and to TdP (86 ± 9 ms*+) (+P < 0.05 compared with sEB). An increase in STV contributes to the initiation of sEB, whereas an increase in SDR is important for the perpetuation of non-self-terminating TdPs.NEW & NOTEWORTHY This study compared two well-established electrophysiological parameters, being temporal and spatial dispersion of repolarization, and provided new insights into their interplay in the arrhythmogenesis of torsades de pointes arrhythmias. Although it confirmed that an increase in temporal dispersion of repolarization contributes to the initiation of single ectopic beats, it showed that an increase in spatial dispersion of repolarization is important for the perpetuation of non-self-terminating torsades de pointes arrhythmias.