Evidence remains limited on the real-world prescription of very low-dose oral anticoagulation among frail patients with atrial fibrillation (AF). We described the practice patterns, effectiveness, and safety of very low-dose edoxaban (15 mg once daily).

Patients with AF prescribed edoxaban 15 mg once daily in 2 tertiary hospitals between 2016 and September 2022 were included. Baseline clinical characteristics and clinical outcomes of interest were thromboembolic and bleeding events.

A total of 674 patients were included (mean age 78.3±9.1, 49.7% aged ≥80 years, 49.3% women, median follow-up 1.0±1.2 years). Mean CHA2DS2-VASc score was 3.9±1.6, and the modified HAS-BLED score was 2.0±1.1. Between 2016 and 2022, the number of very low-dose edoxaban prescriptions increased. The main reasons for the prescription of very low-dose were low body weight (55.5% below 60 kg), anaemia (62.8%), chronic kidney disease (40.2%), active cancer (15.3%), concomitant anti-platelet use (26.7%), and prior major bleeding (19.7%). During a median follow-up duration of 8 (interquartile range 3-16) months, overall thromboembolic and bleeding events occurred in 16 (2.3%) and 88 (13.1%) patients, respectively. Compared to the expected event rates on the established risk scoring systems, patients receiving very low-dose edoxaban demonstrated a 61% reduction in ischemic stroke, a 68% reduction of ischemic stroke/transient ischemic attack/systemic embolism, whereas a 49% increase in major bleeding.

The prescription of very low-dose edoxaban was increased over time, attributable to various clinical factors. The use of very low-dose edoxaban reduced the expected risk of thromboembolic events.

Transcatheter aortic valve replacement (TAVR) recipients frequently have an indication for long-term oral anticoagulation, including atrial fibrillation or systemic thromboembolic disease. It remains unclear if there are differences in safety and effectiveness between direct oral anticoagulants (DOAC) and warfarin in this patient population.

Clinical outcomes were compared between TAVR recipients receiving DOACs or warfarin using data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (TVT) registry linked with Centers for Medicare & Medicaid Services claims data. The analysis included patients from the TVT registry who underwent successful TAVR and were discharged on either a DOAC or warfarin between January 2013 and May 2018. The primary outcome was any bleeding requiring hospitalization from discharge to 1 year. Secondary outcomes included all-cause mortality and stroke from discharge to 1 year. Multivariable Cox proportional hazards regression models were used to compare these outcomes between the 2 groups.

A total of 29,142 patients underwent TAVR and were discharged on oral anticoagulation, among whom 10,973 (37.7%) were discharged on a DOAC. The use of DOACs increased throughout the study period and exceed the use of warfarin by the final year (2018). The cumulative incidence of bleeding requiring hospitalization at 1 year (11.8% vs 15.2%, P < .001) and all-cause mortality (15.5% vs 17.5%, P < .001) was significantly lower in DOAC group while stroke (2.47% vs 2.39%, P = .64) was not statistically different between groups. In an adjusted model, the use of a DOAC as opposed to warfarin was associated with a significantly lower risk of bleeding requiring hospitalization (adjusted hazard ratio 0.49, 95% confidence interval 0.43-0.56), all-cause mortality (adjusted hazard ratio 0.61, 95% confidence interval 0.57-0.66), and stroke (adjusted hazard ratio 0.86, 95% confidence interval 0.81-0.92) (all P < .001).

In this analysis of TAVR recipients discharged on oral anticoagulation in a large U.S. registry, the use of a DOAC rather than warfarin was associated with a lower risk of bleeding requiring hospitalization, all-cause mortality, and stroke from discharge to 1 year. Future randomized studies will be necessary to establish the optimal choice of anticoagulant in TAVR patients.

Swift reversal of oral anticoagulation is deemed essential for the outcome of patients with anticoagulation-related critical bleeding. The aim of this systematic review was to evaluate the benefits and harms of prothrombin complex concentrate (PCC) in patients with oral anticoagulants-related critical bleeding.

For this systematic review CENTRAL, MEDLINE, Embase, LILACS, BIOSIS, Web of Science, and clinical trial registries were systematically searched. Clinical study reports were also requested from competent authorities. Eligible for inclusion were randomised clinical trials comparing PCC versus no intervention, placebo, or other reversal interventions in participants with critical bleeding related to ongoing treatment with vitamin K antagonist (VKA) or direct oral anticoagulants (DOAC). Pre-specified primary outcomes were all-cause mortality, health-related quality of life, and serious adverse events for which meta-analyses, Trial Sequential Analysis, and GRADE assessments were conducted.

Three trials, randomising a total of 291 participants, evaluated PCC against two different active comparators in participants with VKA-related critical bleeding, and two trials, randomising a total of 534 participants, evaluated PCC against two different active comparators in participants with factor Xa-related critical bleeding. Among participants with VKA-related critical bleeding, meta-analyses showed no evidence of a difference between PCC versus fresh frozen plasma (FFP) when assessing all-cause mortality (risk ratio [RR] 1.05; 95% confidence interval (CI) 0.27 to 4.05; low certainty), health-related quality of life (mean difference 1.04; 95% CI - 0.94 to 3.02; very low certainty), and serious adverse events (RR 1.33; 95% CI 0.94 to 1.88; very low certainty), but information is currently sparse. Among participants with factor Xa-related critical bleeding, PCC could not be shown superior or inferior to other reversal strategies (FFP or andexanet alfa) on any patient-relevant outcome, but information is currently sparse.

Among participants with VKA or DOAC-related critical bleeding, evidence from randomised clinical trials is currently insufficient to establish if PCC is superior or inferior versus other interventions in decreasing the risk of undesirable patient-relevant outcomes or improving health-related quality of life.

Background: Dose adjustments of direct-acting oral anticoagulants (DOACs) for atrial fibrillation are based on pivotal clinical trials assessing their effectiveness and safety in controlled settings. However, the appropriateness of these dosing strategies in real-world practice is uncertain. The purpose of this study is to compare the effectiveness and safety of dose-specific DOACs with those of warfarin. Methods: This study retrieved articles from MEDLINE, Embase, and CENTRAL until March 5, 2024. Primary outcomes were the incidence of stroke/systemic embolisms (S/SEs) and major bleeding (MB). Direct pairwise meta-analyses compared each dose-specific DOAC with warfarin. Heterogeneity was assessed using Higgin's I 2 and Q statistics, while publication bias was evaluated through funnel plots and Begg's and Egger's tests, with adjusted pooled estimates calculated via trim-and-fill and precision-effect estimate with standard error (PET-PEESE) methods. A network analysis was conducted, with additional comparisons made using a Bayesian random-effects model for indirect evidence. Results: A total of 32 studies with 2,332,770 patients were included. Both standard-dose (SD) and low-dose (LD) DOACs significantly reduced S/SE, except for LD apixaban and LD edoxaban. Rivaroxaban did not show significant difference in MB compared to warfarin. In East Asian patients, all doses of DOACs exhibited lower hazard ratios (HRs) for S/SE and MB than those observed in the primary analysis, with LD rivaroxaban significantly reducing MB, a finding not observed in the primary analysis. Rank probability analysis indicated that the dose-specific DOACs had different safety profiles and small but meaningful differences in effectiveness. SD apixaban (S/SE: second, MB: second) and edoxaban (S/SE: first, MB: fourth) and LD edoxaban (S/SE: fourth, MB: first) had high ranks. LD apixaban had the most significant difference in rank for S/SE from SD apixaban, ranking eighth compared to second. Conclusions: This study found that all DOACs provided comparable or superior effectiveness and safety to warfarin. SD apixaban, SD edoxaban, and LD edoxaban achieved a favorable balance between preventing S/SE and MB risk.

Little is known how individual time-in-therapeutic-range (TTR) impacts the effectiveness and safety of warfarin therapy compared to direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF).

To compare the effectiveness and safety of standard dose DOACs to warfarin in patients with AF, while categorizing warfarin treated patients into quartiles based on their individual TTR.

We conducted a nationwide study including all patients with new-onset AF between 2011 and 2018 in Finland. Hazard ratios (HR) were calculated using Cox regression analysis with the inverse probability of treatment weighted method to assess the risks of ischaemic stroke (IS), intracranial haemorrhage (ICH) and mortality for users of apixaban (n = 12,426), dabigatran (n = 4545), rivaroxaban (n = 12,950) and warfarin (n = 43,548).

The median TTR for warfarin users was 72%. Compared to the second best TTR quartile (reference), the risk of IS was higher in the two poorest TTR quartiles, and lower in the best TTR quartile and on rivaroxaban [2.35 (95% confidence interval, 1.85-2.85), 1.44 (1.18-1.75), 0.60 (0.47-0.77) and 0.72 (0.56-0.92)]. These differences were non-significant for apixaban and dabigatran. HR of ICH was 6.38 (4.88-8.35) and 1.87 (1.41-2.49) in the two poorest TTR groups, 1.44 (1.02-1.93) on rivaroxaban, and 0.58 (0.40-0.85) in the best TTR group compared to the reference group. Mortality was higher in the two poorest TTR groups and lowest in the best TTR group.

The outcome was unsatisfactory in the two lowest TTR quartiles - in half of the patients treated with warfarin. The differences between the high TTR groups and standard dose DOACs were absent or modest.

Background and objective Retrobulbar block is commonly used for providing effective anesthesia and akinesia for ophthalmic surgery. It can, however, lead to sight-threatening retrobulbar hemorrhage in very rare cases. The aim of this study was to evaluate retrobulbar block quality, to determine the prevalence of retrobulbar hemorrhage associated with these blocks, and to assess whether the use of antithrombotic agents in patients undergoing retrobulbar block for ophthalmic surgery was associated with retrobulbar hemorrhage. Methods This was a retrospective cohort study conducted on a registry of patients who underwent outpatient ophthalmic surgery at a tertiary care eye center. Adult patients who underwent ophthalmic surgery and received retrobulbar block between October 2014 and December 2021 were retrospectively included to evaluate retrobulbar hemorrhage prevalence and block quality between three groups according to antithrombotic agent use: non-therapeutic antithrombotic use, therapeutic antithrombotic use, and no antithrombotic use. Results Of 15,112 records included in final analyses, the median age was 73 with an interquartile range of 67-79 years. White patients totaled 9,813 (64.9%). Patients classified as having mild or major systemic disease before surgery totaled 8,178 (62.9%) and 4,216 (32.4%), respectively. Patients who had at least one comorbidity totaled 13,364 (88.4%). Regarding antithrombotic agent use, 5,856 (38.8%) patients used either one, two, or three medications. Of these, there were 4,183 (27.7%) patients who were therapeutic during the block procedure compared to a total of 10,929 (72.3%) who either did not use antithrombotics or did not use them therapeutically. There were seven (0.1%) retrobulbar hemorrhages among 15,112 patients overall, including two (0.1%) from the 4,183 (27.7%) therapeutic antithrombotic users and five (0.1%) from the 9,256 (61.2%) no antithrombotic users, with no significant differences between groups (p=0.621). Successful blocks totaled 13,364 (95.7%). Conclusions Retrobulbar hemorrhage from retrobulbar block in ophthalmic surgery patients is extremely rare, with these results showing no difference in the occurrence of retrobulbar hemorrhage between those using and not using antithrombotic medications. Therefore, it is recommended to continue antithrombotic medication use during ophthalmic procedures as they do not appear to increase the risk of retrobulbar hemorrhage.

The 2017 Japanese guidelines recommend continuing warfarin therapy during the perioperative period or discontinuing direct oral anticoagulants (DOACs) only on the day of endoscopic submucosal dissection for early gastric cancer. However, their safety has not been sufficiently explored. This study aimed to validate this management method.

This retrospective, multicenter study analyzed the characteristics and outcomes of patients who underwent gastric endoscopic submucosal dissection between July 2017 and June 2019. The patients were categorized according to the use of warfarin or DOACs.

Among the 62 eligible patients, 53 (85%) were male (median age, 76 years). Warfarin was used in 10 patients (16%) and DOACs in 52 patients (84%). Fourteen patients taking DOACs (27%) used concomitant antiplatelet agents, with seven patients (13%) continuing treatment at the time of the endoscopic procedure. No postprocedural bleeding occurred in patients receiving warfarin (0%), whereas 10 cases (19%) of bleeding occurred in patients receiving DOACs: rivaroxaban, 0% (0/22); dabigatran, 0% (0/2); edoxaban, 43% (6/14); and apixaban, 29% (4/14). The type of anticoagulant (P < 0.01) and continuation of antiplatelet therapy (P = 0.02) were risk factors for postprocedural bleeding in patients receiving DOACs. Intraprocedural bleeding requiring transfusion or symptomatic thromboembolic events were not reported.

Continuous warfarin therapy is preferred. DOAC withdrawal 1 day before a procedure is associated with a high bleeding rate, which may differ for different types of anticoagulants. The continuation of antiplatelet medications in patients receiving DOACs carries a high risk of bleeding and is a future challenge.

Background: The therapeutic effects of oral anticoagulant drugs for nonvalvular atrial fibrillation (NVAF) suggest that the three factor Xa (FXa) inhibitors may have distinct safety profiles, though this is not yet fully conclusive. This study investigated the current dosing of rivaroxaban, apixaban, and edoxaban by monitoring drug plasma concentration (PC) and coagulation activity from the viewpoint of the safety. Methods and results: This multicenter clinical study monitored the drug PC and two coagulation biomarkers (fibrinogen and fibrin monomer complex [FMC]) at peak and trough timing in 268 outpatients taking rivaroxaban (n = 72), apixaban (n = 71), and edoxaban (n = 125) for NVAF. Doses were adjusted based on the dose-adjustment criteria of each drug. Referencing our previous study, peak drug PC remained below the cut-off level for predicting bleeding events except in eight patients (rivaroxaban, n = 3; apixaban, n = 2; edoxaban, n = 3) in whom bleeding events occurred. Among them, two (one each on rivaroxaban and edoxaban) had a peak drug PC below the cut-off level. Drug PCs widely varied from peak to trough, whereas FMC levels, reflecting thrombin activity, remained within the normal range (<6.1 µg/mL) regardless of PC variations. These results indicated that the anticoagulant effects of these drugs persisted throughout the day regardless of the drug PC levels, dosage, and dosing frequency. Regarding the change over time in peak PC, the elevation over time developed more in rivaroxaban (29/57; 50.9%, p < 0.05) than in edoxaban (32/101; 31.7%), and rivaroxaban tended to accumulate more than edoxaban. Conclusions: Although drug PC levels of once-daily FXa inhibitors widely varied from peak to trough, FMC levels were maintained within the normal range without daily variations. Rivaroxaban also tended to accumulate over time. The results indicate the low risk of thrombotic events with once-daily FXa inhibitors and its correspondence to the twice-daily regimen.

Direct oral anticoagulant drugs (DOACs) are available in addition to warfarin for the treatment of patients with non-valvular atrial fibrillation (NVAF). Anticoagulants are useful for practical pharmacotherapy in Asian populations, but their responses are different from those in Caucasian populations. Therefore, we aimed to identify the most useful anticoagulant using a nationwide insurance claims database in Japan. We extracted information on patients with NVAF treated with DOACs or warfarin for the first time between September 2015 and February 2018 to conduct a retrospective observational cohort study using the claims database of Japan. We calculated hazard ratios (HR) of effectiveness and safety endpoints among DOACs or warfarin after adjusting for backgrounds by propensity scores (inverse probability weighting). Using negative control outcomes, we considered renal function as an unmeasured confounding factor. After adjusting for their backgrounds, patients treated with DOACs showed higher effectiveness endpoints (stroke or systemic embolism) than those treated with warfarin (HR; 0.72-0.81) and higher safety in terms of safety end points (clinically significant bleeding) (HR; 0.80-0.88). The net clinical benefit, which reflects the actual clinical usefulness, indicates the advantages of DOACs over warfarin (HR; 0.75-0.82). Dabigatran had lower usefulness than edoxaban and rivaroxaban in Japanese patients treated with NVAF, even after considering the unmeasured confounding factor of kidney function. Based on practical clinical data, edoxaban and rivaroxaban were the most useful anticoagulants in Japanese patients with NVAF.

Nursing home residents with atrial fibrillation are at high risk for ischemic stroke, but most are not treated with anticoagulants. This study compared the effectiveness and safety between oral anticoagulant (OAC) users and non-users.

We conducted a new-user retrospective cohort study by using Minimum Data Set 3.0 assessments linked with Medicare claims. The participants were Medicare fee-for-service beneficiaries with atrial fibrillation residing in US nursing homes between 2011 and 2016, aged ≥ 65 years. The primary outcomes were occurrence of an ischemic stroke or systemic embolism (effectiveness), occurrence of intracranial or extracranial bleeding (safety) and net clinical outcome (effectiveness or safety outcomes). Secondary outcomes included total mortality and a net clinical and mortality outcome. Cox proportional hazards and Fine and Grey models estimated multivariable adjusted hazard ratios (aHRs) and sub-distribution hazard ratios (sHRs).

Outcome rates were low (effectiveness: OAC: 0.86; non-users: 1.73; safety: OAC: 2.26; non-users: 1.75 (per 100 person-years)). OAC use was associated with a lower rate of the effectiveness outcome (sHR: 0.69; 95% Confidence Interval (CI): 0.61-0.77), higher rates of the safety (sHR: 1.70; 95% CI: 1.58-1.84) and net clinical outcomes (sHR: 1.20; 95% CI: 1.13-1.28) lower rate of all-cause mortality outcome (sHR: 0.60; 95% CI: 0.59-0.61), and lower rate of the net clinical and mortality outcome (sHR: 0.60; 95% CI: 0.59-0.61). Warfarin users, but not DOAC users, had a higher rate of the net clinical outcome versus OAC non-users.

Our results support the benefits of treatment with OACs to prevent ischemic strokes and increase longevity, while highlighting the need to weigh apparent benefits against elevated risk for bleeding. Results were consistent with net favorability of DOACs versus warfarin.

The study aimed to describe the patterns and trends of initiation, discontinuation, and adherence of oral anticoagulation (OAC) in patients with new-onset postoperative atrial fibrillation (POAF), and compare with patients newly diagnosed with non-POAF.

This retrospective cohort study identified patients newly diagnosed with atrial fibrillation or flutter between 2012 and 2021 using administrative claims data from OptumLabs Data Warehouse. The POAF cohort included 118 366 patients newly diagnosed with atrial fibrillation or flutter within 30 days after surgery. The non-POAF cohort included the remaining 315 832 patients who were newly diagnosed with atrial fibrillation or flutter but not within 30 days after a surgery. OAC initiation increased from 28.9% to 44.0% from 2012 to 2021 in POAF, and 37.8% to 59.9% in non-POAF; 12-month medication adherence increased from 47.0% to 61.8% in POAF, and 59.7% to 70.4% in non-POAF. The median time to OAC discontinuation was 177 days for POAF, and 242 days for non-POAF. Patients who saw a cardiologist within 90 days of the first atrial fibrillation or flutter diagnosis, regardless of POAF or non-POAF, were more likely to initiate OAC (odds ratio, 2.92 [95% CI, 2.87-2.98]; P <0.0001), adhere to OAC (odds ratio, 1.08 [95% CI, 1.04-1.13]; P <0.0001), and less likely to discontinue (odds ratio, 0.83 [95% CI, 0.82-0.85]; P <0.0001) than patients who saw a surgeon or other specialties.

The use of and adherence to OAC were higher in non-POAF patients than in POAF patients, but they increased over time in both groups. Patients managed by cardiologists were more likely to use and adhere to OAC, regardless of POAF or non-POAF.

Atrial fibrillation (AF) is a predominant contributor to morbidity and mortality, and stroke prevention remains the mainstay for the management of AF. The precise mechanism involved in thrombus formation remains unknown. However, factors such as stretch-induced fibrosis, endothelial dysfunction, disordered atrial contractions, and pro-thrombotic states have been postulated for the development of AF. Various risk assessment strategies have been acknowledged for determining the risk of stroke in AF, of which the congestive heart failure, hypertension, age ≥75, diabetes, stroke, vascular disease, age between 65-74, and female sex (CHA2DS2-VASc) score remains the ultimate risk stratification tool. For the longest time, vitamin K antagonists (VKA) were the only oral anticoagulants available but were associated with an increased risk of bleeding. Recently, direct oral anticoagulants (DOACs) were approved and considered more efficient and safer than or as secure as warfarin in stroke prevention and lowering intra-cranial bleeding events. The pharmacodynamics and pharmacokinetics of DOACs were also clarified in this article. This review article compiles current evidence-based data on the role of DOACs, uncovering their underlying mechanisms, and comparing their efficacy with warfarin in stroke prevention in AF.

Non-vitamin K antagonist oral anticoagulants (NOACs) have largely supplanted vitamin K antagonists (VKAs) for oral anticoagulation in non-valvular atrial fibrillation (NVAF). However, data on the real-world effectiveness of NOACs vs. phenprocoumon, a VKA widely used in Germany, are limited. The RELOADED study aimed to compare effectiveness of factor Xa NOACs and phenprocoumon in NVAF in clinical practice.

Patients who started on a factor Xa NOAC or phenprocoumon for NVAF during the study period were enrolled from the Institute for Applied Healthcare Research Berlin. Patients were followed from first prescription until the end of exposure or available data. Primary outcomes were analyzed by Cox proportional hazard regression models and included ischemic stroke and systemic embolism for effectiveness, and intracranial hemorrhage (ICH) for safety. Subgroups of interest were patients with diabetes and patients with renal impairment.

The total study population was 64,920; 36.3% of patients initiated phenprocoumon, 34.4% initiated rivaroxaban, 25.0% apixaban, and 4.4% edoxaban. Treatment with phenprocoumon is associated with a similar risk of ischemic stroke/systemic embolism as treatment with rivaroxaban or apixaban; while rivaroxaban (adjusted hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.43-0.75) and apixaban (adjusted HR 0.43, 95% CI 0.31-0.6) were associated with a lower risk of ICH compared to phenprocoumon in NVAF patients. The use of rivaroxaban and apixaban was associated with a lower risk of developing kidney failure in patients with diabetes or renal impairment in comparison to those treated with phenprocoumon.

The factor Xa NOACs rivaroxaban and apixaban demonstrated similar effectiveness and lower rates of ICH compared with phenprocoumon in this study.

The treatment landscape for CLL has undergone a profound transformation with the advent of targeted agents (TAs) like Bruton's Tyrosine Kinase inhibitors (BTKis) and BCL-2 inhibitors (BCL-2is). These agents target crucial cellular pathways in CLL, offering superior efficacy over traditional chemo-immunotherapy, which has led to improved progression-free and overall survival rates. This advancement promises enhanced disease control and potentially normal life expectancy for many patients. However, the journey is not without challenges, as these TAs are associated with a range of adverse events (AEs) that can impact treatment efficacy and patient quality of life. This review focuses on detailing the various AEs related to TA management in CLL, evaluating their frequency and clinical impact. The aim is to present a comprehensive guide to the effective management of these AEs, ensuring optimal tolerability and efficacy of TAs. By reviewing the existing literature and consolidating findings, we provide insights into AE management, which is crucial for maximizing patient outcomes in CLL therapy.

Atrial fibrillation (AF) represents a prevalent cardiac arrhythmia associated with increased risks of stroke and bleeding events, necessitating comprehensive risk assessment and management strategies.

This retrospective cohort research aimed to longitudinally analyze risk factors associated with stroke and bleeding incidents in patients diagnosed with AF, focusing on identifying predictive factors and their impact on patient outcomes.

The research enrolled 480 AF patients from a tertiary care center over an 18-month period (2021-2022). Baseline demographic, clinical, and medication data were collected from electronic health records. Patients were monitored for occurrences of stroke and bleeding events during follow-up. Cox proportional hazards models and Kaplan-Meier estimates were utilized to assess risk factor associations and cumulative event incidences, respectively.

A cohort of 480 AF patients, with a mean age of 65.4 years, was observed over 18 months. Stroke patients tended to be older (72.1 years), and bleeders slightly younger (68.8 years). Cox models revealed higher stroke risk in >70-year-olds (hazard ratio (HR): 1.85, 95% confidence interval (95% CI): 1.21-2.78, p < 0.001) and with prior stroke history (HR: 2.13, 95% CI: 1.45-3.12, p < 0.001). Prior stroke linked to bleeding risk (HR: 1.88, 95% CI: 1.26-2.81, p = 0.003). At six months, stroke incidence was 5.2%, bleeding 3.8%; at 18 months, 12.5% experienced strokes, 9.3% bleeding. These findings underscore age and prior stroke as vital predictors of adverse outcomes in AF patients.

This research reaffirms age and prior stroke as pivotal risk factors for adverse outcomes in AF patients. The findings emphasize the necessity for tailored risk stratification and interventions to mitigate stroke and bleeding risks, thereby enhancing patient care and prognosis in AF management.

The advent of direct oral anticoagulants (DOACs) marks a significant milestone in anticoagulant treatment. However, DOACs can exacerbate bleeding, which is challenging for the treating clinician, especially when combined with traumatic injury.

In major bleeding associated with DOACs, rapid reversal of the anticoagulant effects is crucial. Recent observational and nonrandomized interventional trials have demonstrated the effectiveness of the specific antidotes andexanet alfa and idarucizumab as well as the unspecific prothrombin complex concentrates (PCCs) to counteract the anticoagulant effects of DOACs. The European Society of Anaesthesiology and Intensive Care guideline for severe perioperative bleeding and the European trauma guideline propose divergent recommendations for the use of andexanet alfa and PCC to obtain hemostasis in Factor Xa inhibitor-related bleeding. The conflicting recommendations are due to limited evidence from clinical studies and the potential increased risk of thromboembolic complications after the administration of andexanet. Regarding dabigatran-associated major bleeding, both guidelines recommend the specific reversal agent idarucizumab as first-line therapy.

Current guidelines recommend specific antidots and PCCs in DOAC-related major bleeding. Prospective randomized trials comparing specific vs. nonspecific hemostatic agents in the perioperative setting are needed to evaluate the effectiveness and safety of the hemostatic agents.

In this research, we assessed mortality after major bleeding events in atrial fibrillation (AF) patients taking four direct oral anticoagulants (DOACs). Drawing data from the Taiwan National Health Insurance Research Database between 2016 and 2019, we focused on AF patients on DOACs who had major bleeding episodes. Using propensity score stabilized weighting, we established four comparable pseudo-DOAC groups. Among 2770 patients (460 dabigatran, 1322 rivaroxaban, 548 apixaban, 440 edoxaban), 85.3% were prescribed low-dose regimens. The 7-day mortality rate was 9.0%, surging to 16.0% by the 30th day. Compared with dabigatran, there was a distinct divergence in 7-day mortality of factor Xa inhibitors (p = 0.012), with hazard ratios of 1.83 (95% CI 1.11-3.00, p = 0.017) for rivaroxaban, 2.13 (95% CI 1.23-3.66, p = 0.007) for apixaban, and 2.41 (95% CI 1.39-4.19, p = 0.002) for edoxaban. This pattern remained consistent when analyzing the subgroup that received lower dosages of DOACs. In conclusion, factor Xa inhibitors were associated with a significantly higher risk of 7-day mortality following major bleeding events than dabigatran among AF patients.

Non-adherence to recommended secondary preventive anticoagulation in stroke patients with atrial fibrillation (AF) is a common phenomenon although the introduction of direct oral anticoagulants (DOACs) has simplified anticoagulation management for physicians as well as for patients.

We examined the adherence of secondary preventive anticoagulation in AF patients after re-integration in their social environment 6 to 12 weeks after stroke unit and rehabilitation clinic treatment and analyzed for predictors for adherence and non-adherence. We conducted a telephone survey in consecutive patients treated between January 2013 and December 2021 at our institutional stroke unit with an acute cerebrovascular ischemic event and we analyzed discharge letters of rehabilitation clinics of those patients not anticoagulated at follow-up. All patients had known or newly diagnosed AF and in all we had recommended secondary preventive anticoagulation.

Follow-up information about anticoagulant intake could be obtained in 1348 of 1685 patients (80.0%) treated within the study period. Anticoagulation rate was 91.5% with 83.6% of patients receiving DOACs and 7.9% receiving vitamin K antagonists (VKAs). Adherence to recommended anticoagulation was associated with intake of the recommended anticoagulant already at discharge (adjusted OR, 18.357; CI, 9.637 to 34.969), recommendation of a specific DOAC and dose (in contrast to "DOAC" as drug category) (adjusted OR, 2.971; CI, 1.173 to 7.255), a lower modified Rankin Scale at discharge (per point; adjusted OR, 0.813; CI, 0.663 to 0.996), younger age (per year; adjusted odds ratio [OR], 0.951; confidence interval [CI], 0.926 to 0.976), and the absence of peripheral vascular disease (adjusted OR, 0.359; CI, 0.173 to 0.746). In patients already anticoagulated at discharge adherence was 98.5%, irrespective of a patient's age, functional deficit at discharge, and peripheral vascular disease. Avoidable obstacles for non-adherence in patients not on anticoagulants at stroke unit discharge were (1) non-implementation of recommended anticoagulation by rehabilitation physicians predominantly in patients with moderate-severe or severe stroke disability (2.1%), (2) delegation of anticoagulation start from rehabilitation physicians to general practitioners/resident radiologists (1.3%), and (3) rejection of recommended anticoagulation because of patients' severe stroke disability (0.5%). Non-avoidable obstacles were contraindications to anticoagulation (2.1%) and patients' refusal (0.7%).

Commencing drug administration already during stroke unit hospitalization and providing an explanation for the selection of the recommended anticoagulant in discharge letters ensures high adherence at patients' re-integration in their social environment after acute stroke treatment. If drug administration cannot be commenced before discharge, education of rehabilitation physicians by stroke physicians and the involvement of stroke physicians into the post-stroke decision process might hinder avoidable obstacles.

The discontinuation of oral anticoagulants (OACs) remains as a significant concern in the management of atrial fibrillation (AF). The discontinuation rate may vary depending on management strategy, and physicians may also discontinue OACs due to concerns about patient satisfaction with their care. We aimed to assess the incidence of OAC discontinuation and its relationship to patients' health in an outpatient AF registry.

From a multicenter registry for newly recognized AF patients (n = 3313), we extracted 1647 (49.7%) patients with OACs and a CHA2DS2-Vasc score of ≥2. Discontinuation was defined as sustained cessation of OACs within a 1-year follow-up. We examined predictors associated with discontinuation and its relations to health status defined by the AFEQT questionnaire. Of the 1647 patients, 385 (23.6%) discontinued OACs after 1 year, with discontinuation rates varying across treatment strategies (15.3% for catheter ablation, 4.9% for rhythm control with antiarrhythmic drugs, and 3.0% for rate control). Successful rhythm control was associated with discontinuation in the catheter ablation (OR 6.61, 95% CI 3.00-14.6, p < 0.001) and antiarrhythmic drugs (OR 6.47, 95% CI 2.62-15.9, p < 0.001) groups, whereas the incidence of bleeding events within 1 year was associated with discontinuation in the rate control group. One-year AFEQT scores did not significantly differ between patients who discontinued OACs and those who did not in each treatment strategy group.

OAC discontinuation was common among AF patients with significant stroke risk but varied depending on the chosen treatment strategy. This study also found no significant association between OAC discontinuation and patients' health status.

Objective: A lack of clarity persists regarding the efficacy and risks associated with direct oral anticoagulants (DOACs) in end-stage renal disease (ESRD) patients with atrial fibrillation (AF) undergoing dialysis, primarily due to limited retrospective studies. Therefore, the objective of this study was to evaluate the existing data and propose a practical protocol for the clinical utilization of DOACs in ESRD patients with AF undergoing dialysis. Methods: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for clinical studies evaluating DOACs in ESRD patients with AF on dialysis published up to 2 February 2023. DOACs included warfarin, dabigatran, apixaban, edoxaban, and rivaroxaban. The outcomes were mortality, ischemic stroke, hemorrhagic stroke, any stroke, gastrointestinal bleeding, major bleeding, intracranial bleeding, and minor bleeding. Results: Compared with placebo, apixaban (HR = 0.97, 95% CI: 0.88-1.07), rivaroxaban (HR = 0.91, 95% CI: 0.76-1.10), and warfarin (HR = 0.96, 95% CI: 0.90-1.01) did not reduce mortality. Regarding direct comparisons of mortality, the comparisons of warfarin vs. apixaban (HR = 0.99, 95% CI: 0.92-1.06), placebo vs. warfarin (HR = 1.04, 95% CI: 0.99-1.11), and rivaroxaban vs. warfarin (HR = 0.96, 95% CI: 0.80-1.14) did not significantly reduce mortality. Based on the surface under the cumulative ranking curve, rivaroxaban (75.53%), warfarin (62.14%), and apixaban (45.6%) were the most effective interventions for managing mortality, and placebo (16.74%) was the worst. Conclusion: In conclusion, rivaroxaban demonstrated efficacy in reducing mortality and the incidence of ischemic stroke, gastrointestinal bleeding, and intracranial hemorrhage. Dabigatran is recommended for the prevention of hemorrhagic stroke. However, caution should be exercised due to the risk of major bleeding. Warfarin can effectively reduce minor bleeding but does not offer significant protection against gastrointestinal or intracranial bleeding. Apixaban was not recommended for mortality reduction or for preventing ischemic or hemorrhagic strokes. Further research will be necessary to establish specific clinical protocols.

There is substantial debate on the best method to reverse factor Xa-inhibitors in patients following traumatic brain injury (TBI). Prothrombin complex concentrates (PCC) have been used for this indication but their role has been questioned. This study reported failure rates with PCC in patients following TBI and as a secondary objective, compared 4-factor (4 F-PCC) and activated PCC (APCC).

Consecutive patients with TBI on factor Xa-inhibitors admitted to one of two trauma centers were retrospectively identified. Patients with penetrating TBI, delays in PCC administration (>6 h), receipt of tranexamic acid, factor VIIa or no follow up CT-scan were excluded. The primary outcome was treatment failure defined as hematoma expansion > 20% from baseline for SDH, EDH or IPH, a new hematoma not present on the initial CT scan or any expansion of a SAH or IVH. Hematoma expansion was further categorized as symptomatic or asymptomatic, designated by a change in the motor GCS score, neurologic exam or change ≥ 3 in NIH Stroke Scale. Multi-variate analysis was performed.

There were 43 patients with a mean age of 77 ± 13 years with primarily mild TBI (95%) after a ground level fall (79%). The mean dose was 41 ± 12 units/kg. Sixty percent received 4 F-PCC and 40% APCC. The incidence of treatment failure was 28% (12/43). Of the 12 patients with hematoma expansion, only 3 were symptomatic (9.3%). Hematoma expansion with 4 F-PCC and APCC were similar (27% vs. 29%,p = .859). Only sex was associated with hematoma expansion on multivariate analysis [OR (95% CI) = 6.7 (1.1 - 40.9)].

PCC was an effective option for factor Xa inhibitor reversal following TBI. The relationship between radiographic expansion and clinical expansion was poor.

There has been an increasing uptake of transcatheter left atrial appendage occlusion (LAAO) for stroke reduction in atrial fibrillation.

To investigate the perceptions and approaches among a nationally representative sample of physicians.

Using the American Medical Association Physician Masterfile, we selected a random sample of 500 physicians from each of the specialties: general cardiologists, interventional cardiologists, electrophysiologists, and vascular neurologists. The participants received the survey by mail up to three times from November 9, 2021 to January 14, 2022. In addition to the questions about experiences, perceptions, and approaches, physicians were randomly assigned to 1 of the 4 versions of a patient vignette: white man, white woman, black man, and black woman, to investigate potential bias in decision-making.

The top three reasons for considering LAAO were: a history of intracranial bleeding (94.3%), a history of major extracranial bleeding (91.8%), and gastrointestinal lesions (59.0%), whereas the top three reasons for withholding LAAO were: other indications for long-term oral anticoagulation (87.7%), a low bleeding risk (77.0%), and a low stroke risk (65.6%). For the reasons limiting recommendations for LAAO, 59.8% mentioned procedural risks, 42.6% mentioned "limiting efficacy data comparing LAAO to NOAC" and 32.8% mentioned "limited safety data comparing LAAO to NOAC." There was no difference in physicians' decision-making by patients' race, gender, or the concordance between patients' and physicians' race or gender.

In the first U.S. national physician survey of LAAO, individual physicians' perspectives varied greatly, which provided information that will help customize future educational activities for different audiences.

Although diverse practice patterns of LAAO have been documented, little is known about the reasoning or perceptions that drive these variations. Unlike prior surveys that were directed to Centers that performed LAAO, the current survey obtained insights from individual physicians, not only those who perform the procedures (interventional cardiologists and electrophysiologists) but also those who are closely involved in the decision-making and referral process (general cardiologists and vascular neurologists). The findings identify key evidence gaps and help prioritize future studies to establish a consistent and evidence-based best practice for AF stroke prevention.

Levetiracetam is widely used in post-stroke epilepsy. However, it is suspected to possess P-glycoprotein (P-gp) induction properties, and therefore, a potentially significant interaction with direct oral anticoagulants (DOACs). We aimed to search for ischemic stroke signals with levetiracetam and the DOACs.

In this retrospective pharmacovigilance study, we used the FAERS database to identify ischemic stroke events associated with DOACs and concomitant use of levetiracetam. We evaluated disproportionate reporting by the adjusted reporting odds ratio (adjROR) and the lower bound of the shrinkage 95% confidence interval. When shrinkage is positive, an increased risk of a specific adverse event occurrence is emphasized over the sum of the individual risks when these same drugs are used separately.

We identified 1841 (1.5%), 3731 (5.3%), 338 (4.9%), and 1723 (1.3%) ischemic stroke reports with apixaban, dabigatran, edoxaban, and rivaroxaban, respectively. The adjROR of the interaction effect was 3.57 (95% CI 2.81-4.58) between DOACs and levetiracetam. The shrinkage analysis detected an interaction between each of the DOACs and levetiracetam. The logistic model and shrinkage analysis failed to detect an interaction when queried for hemorrhagic stroke. A significant signal in the classical enzyme inducer, carbamazepine, strengthened our results (adjROR; 8.47, 95% CI 5.37-13.36).

Our study shows a strong signal for the levetiracetam interaction with the DOACs. Our findings suggest implementation of a drug monitoring strategy.

Andexanet alfa (AA) is approved for reversal of factor Xa inhibitor (FXaI) bleeds; however, there are limited reports of its use for gastrointestinal bleeding (GIB) in real-world populations. The objective of this study was to report real-world utilization and evaluation of the effectiveness of AA for FXaI-associated GIB.

This retrospective cohort study including consecutive patients receiving AA for FXaI-associated GIB (7/2018-2/2021). Demographics, blood product administration, hemostatic efficacy, rebleeding, thrombosis, and mortality rates were collected. Hemostatic efficacy (HE), based on corrected hemoglobin at 12 h compared to baseline, was categorized as excellent (<10% decrease), good (≤ 20% decrease), or poor (>20% decrease, > 2 units of additional coagulation intervention or death prior to repeat hemoglobin). Comparative transfusion requirements between efficacy groups was assessed by Wilcoxon-Rank test.

Twenty-two patients were included (64% male, median (IQR) age 76 years (67, 80). Most patients (59%, n = 13) were on apixaban, and the primary anticoagulation indication was atrial fibrillation (64%, n = 14). Median initial hemoglobin was 7.5 g/dL (IQR 6.4, 8.8) and 50% (n = 11) were upper GIB. Hemostatic efficacy was excellent in 46% (n = 10), good in 23% (n = 5), and poor in 32% (n = 7). There was no statistically significant difference in red blood cells (RBCs) received between those with excellent/good hemostasis (median 2, IQR 1 to 2) and those with poor hemostasis (median 4, IQR 1.5 to 4.5). Two patients (9%) had arterial thrombotic events within 30 days of reversal.

In this multicenter, single arm, real-world observational analysis of patients with factor Xa inhibitor associated GIB most patients achieved good hemostasis following administration of AA. There was a 9% 30-day thrombotic event rate. The lack of a control group limits the strength of the conclusions that can be drawn from this study.

Ischemic strokes (IS) occurring in patients taking non-vitamin K antagonist oral anticoagulants (NOACs) are becoming increasingly more frequent. We aimed to determine the clinical, echocardiographic, and neuroimaging markers associated with developing IS in patients taking NOACs for atrial fibrillation.

From a quaternary care center, clinical/radiologic data were collected from consecutive NOAC users with IS and age-matched controls without IS. Brain MRIs were reviewed for markers of cerebral small vessel disease. Variables with significant differences between groups were entered into a multivariable regression model to determine predictors of IS. Among IS patients, a Cox regression analysis was constructed to determine predictors of IS recurrence during follow-up.

112 patients with IS and 94 controls were included in the study. Variables significantly different between groups included apixaban use, dabigatran use, prior cerebrovascular events, hemoglobin A1c (HbA1c), left ventricular hypertrophy, left atrial volume index, and severe white matter hyperintensities. After multivariable adjustment, prior cerebrovascular events (aOR 23.86, 95% CI [6.02-94.48]), HbA1c levels (aOR 2.36, 95% CI [1.39-3.99]), left ventricular hypertrophy (aOR 2.73, 95% CI [1.11-6.71]) and left atrial volume index (aOR 1.05, 95% CI [1.01-1.08]) increased the risk of stroke, whereas apixaban use appeared to decrease the risk (aOR 0.38, 95% CI [0.16-0.92]). Malignancy was associated with IS recurrence (aHR 4.90, 95% CI [1.35-18.42]) after adjustment for age and chronic renal failure.

Prior cerebrovascular events, diabetes, left ventricular hypertrophy, and increased left atrial size are risk factors for developing an IS among NOAC users.

In randomised controlled trials (RCTs), bleeding outcomes are often assessed using definitions provided by the International Society on Thrombosis and Haemostasis (ISTH). Information relating to bleeding events in real-world evidence (RWE) sources are not identified using these definitions. To assist with accurate comparisons between clinical trials and real-world studies, algorithms are required for the identification of ISTH-defined bleeding events in RWE sources.

To present a novel algorithm to identify ISTH-defined major and clinically-relevant non-major (CRNM) bleeding events in a US Electronic Health Record (EHR) database.

The ISTH definition for major bleeding was divided into three subclauses: fatal bleeds, critical organ bleeds and symptomatic bleeds associated with haemoglobin reductions. Data elements from EHRs required to identify patients fulfilling these subclauses (algorithm components) were defined according to International Classification of Diseases, 9th and 10th Revisions, Clinical Modification disease codes that describe key bleeding events. Other data providing context to bleeding severity included in the algorithm were: 'interaction type' (diagnosis in the inpatient or outpatient setting), 'position' (primary/discharge or secondary diagnosis), haemoglobin values from laboratory tests, blood transfusion codes and mortality data.

In the final algorithm, the components were combined to align with the subclauses of ISTH definitions for major and CRNM bleeds. A matrix was proposed to guide identification of ISTH bleeding events in the EHR database. The matrix categorises bleeding events by combining data from algorithm components, including: diagnosis codes, 'interaction type', 'position', decreases in haemoglobin concentrations (≥ 2 g/dL over 48 hours) and mortality.

The novel algorithm proposed here identifies ISTH major and CRNM bleeding events that are commonly investigated in RCTs in a real-world EHR data source. This algorithm could facilitate comparison between the frequency of bleeding outcomes recorded in clinical trials and RWE. Validation of algorithm performance is in progress.

Over the past decade, the treatment landscape of chronic lymphocytic leukemia (CLL) has dramatically changed, shifting from cytotoxic chemotherapy to targeted therapies. Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of CLL and are increasingly applied in many other malignancies. However, ibrutinib, the first BTK inhibitor approved, is associated with serious toxicities, including atrial fibrillation in up to 38% of patients, ventricular arrhythmias, and other cardiovascular toxicities. Emerging data suggest several newer BTK inhibitors (eg, acalabrutinib, zanubrutinib) are still associated with cardiotoxic risks. This review examines the current state of evidence, including incidence rates, risk factors, mechanisms, and management strategies of cardiovascular toxicities with BTK inhibitors and other CLL therapies. We specifically focus on atrial fibrillation, ventricular arrhythmias/sudden death, hypertension, heart failure, bleeding, and stroke. We also touch on other emerging BTK therapies (eg, pirtobrutinib). Finally, we highlight key unanswered questions and future directions of research.

Objectives: Our objective was to analyse effectiveness and safety of oral anticoagulants (OAC) for stroke prevention in non-valvular atrial fibrillation. Material and methods: Population-based cohort study including adults initiating oral anticoagulants, either direct oral anticoagulants (DOAC) or vitamin K antagonists (VKA), during 2011-2020. Data source: SIDIAP, capturing information from the electronic health records of Primary Health Care in Catalonia, Spain. Study outcomes: stroke, cerebral and gastrointestinal (GI) haemorrhage, assessed by patients' subgroups according to different clinical characteristics. Results: We included 90,773 patients. Male sex, older than 75, previous event, peripheral artery disease, deep vein thrombosis, or receiving antiplatelets, antidiabetics or proton pump inhibitors (PPI) was associated with higher stroke risk. For DOAC-treated, treatment switch increased stroke risk, while being adherent had a protective effect. Men, antidiabetic treatment or a previous event increased the risk of cerebral bleeding. Receiving direct oral anticoagulants had a protective effect in comparison to vitamin K antagonists. For DOAC-treated, treatment switch increased, and adherence decreased the bleeding risk. Men, people with chronic kidney disease or a previous event posed an increased risk of gastrointestinal bleeding, whereas receiving PPI had a protective effect. For DOAC-treated, switch was associated with a higher bleeding risk. Conclusion: Being men, a previous event and DOAC-switch posed a higher risk for all study outcomes. direct oral anticoagulants had a protective effect against cerebral bleeding in comparison to vitamin K antagonists. Adherence to direct oral anticoagulants resulted in lower risk of stroke and cerebral bleeding. We found no differences in the risk of stroke and gastrointestinal bleeding when we compared direct oral anticoagulants vs. vitamin K antagonists.

Patients with atrial fibrillation (AF) experiencing ischemic stroke despite oral anticoagulation (OAC), i.e., breakthrough strokes, are not uncommon, and represent an important clinical subgroup in view of the consistently high risk of stroke recurrence and mortality. The understanding of the heterogenous potential mechanism underlying OAC failure is essential in order to implement specific therapeutic measures aimed at reducing the risk of recurrent ischemic stroke. However, due to the incomplete comprehension of this phenomenon and the limited available data, secondary stroke prevention in such high-risk patients represents a clinical dilemma. There are several available strategies to prevent ischemic stroke recurrence in AF patients with breakthrough stroke in the absence of competing causes unrelated to AF, and these include continuation or change in the type of OAC, addition of antiplatelet therapy, left atrial appendage closure, or any combination of the above options. However, due to the limited available data, the latest guidelines do not provide any specific recommendations about which of the above strategies may be preferred. This review describes the incidence, the clinical impact and the potential mechanisms underlying OAC failure in AF patients. Furthermore, the evidence supporting each of the above therapeutic options for secondary stroke prevention and the potential future directions will be discussed.

The conjunction of atrial fibrillation (AF) and venous thromboembolism (VTE) is common in clinical practice. Over the last 2 decades, a significant number of articles (2500) have been published about AF and VTE. To effectively analyze and present these vast amounts of information, this study uses bibliometric research methods to categorize and consolidate these publications. The number of publications has increased yearly, especially since 2012. The United States was the most prolific country, with 1054 studies published. The most productive institution was McMaster University. Gregory Y.H. Lip was the most prolific author. The keyword analysis identified that the research focuses from 2003 to 2014 were factor Xa inhibitor, dabigatran etexilate, direct thrombin inhibitor, double-blind, deep vein thrombosis, molecular weight heparin, stroke prevention, etc. From 2015 to 2016, research mainly focused on venous thromboembolism, antithrombotic therapy, anticoagulant, warfarin, atrial fibrillation, stroke, and pulmonary embolism. Studies during 2017 to 2022 focused on apixaban, direct oral anticoagulant, rivaroxaban, dabigatran, hemorrhage, edoxaban, medicine efficacy and safety, risk factors, clinical management, and vitamin K antagonists. Since 2018, novel oral anticoagulants have been the most commonly used keywords. On the whole, most studies of AF and VTE focus on pathogenesis and therapeutic drugs. The causal relationship between AF and VTE, the effectiveness and safety of novel oral anticoagulants in the treatments, the anticoagulant regimen of AF and VTE co-disease, and the treatment regimen for vulnerable populations such as the elderly or obese people were the focus of current research and will continue to be the central point of future research.

Background: There are no randomized trials comparing andexanet alfa and 4 factor prothrombin complex concentrate (4F-PCC) for the treatment of factor Xa inhibitor (FXa-I)-associated bleeds, and observational studies lack important patient characteristics. We pursued this study to demonstrate the feasibility of acquiring relevant patient characteristics from electronic health records. Secondarily, we explored outcomes in patients with life-threatening FXa-I associated bleeds after adjusting for these variables. Methods: We conducted a multicenter, chart review of 100 consecutive adult patients with FXa-I associated intracerebral hemorrhage (50) or gastrointestinal bleeding (50) treated with andexanet alfa or 4F-PCC. We collected demographic, clinical, laboratory, and imaging data including time from last factor FXa-I dose and bleed onset. Results: Mean (SD) age was 75 (12) years; 34% were female. Estimated time from last FXa-I dose to bleed onset was present in most cases (76%), and patients treated with andexanet alfa and 4F-PCC were similar in baseline characteristics. Hemostatic efficacy was excellent/good in 88% and 76% of patients treated with andexanet alfa and 4F-PCC, respectively (P = 0.29). Rates of thrombotic events within 90 days were 14% and 16% in andexanet alfa and 4F-PCC patients, respectively (P = 0.80). Survival to hospital discharge was 92% and 76% in andexanet alfa and 4F-PCC patients, respectively (P = 0.25). Inclusion of an exploratory propensity score and treatment in a logistic regression model resulted in an odds ratio in favor of andexanet alfa of 2.01 (95% confidence interval 0.67-6.06) for excellent/good hemostatic efficacy, although the difference was not statistically significant. Conclusion: Important patient characteristics are often documented supporting the feasibility of a large observational study comparing real-life outcomes in patients with FXa-I-associated bleeds treated with andexanet alfa or 4F-PCC. The small sample size in the current study precluded definitive conclusions regarding the safety and efficacy of andexanet alfa or 4F-PCC in FXa-I-associated bleeds.

Background Transcatheter closure of patent foramen ovale (PFO) has reduced the risk of recurrent stroke in patients with cryptogenic strokes in randomized clinical trials. Whether PFO closure in clinical practice is associated with similar benefit remains unknown. Methods and Results We identified patients with PFO and a history of ischemic stroke or transient ischemic attack who were treated with PFO closure or medical therapy in the OptumLabs database. The primary end point was recurrent ischemic stroke or systemic embolization. Secondary outcomes included mortality, all stroke, transient ischemic attack, and major bleeding. A total of 6668 propensity-matched patients were included (PFO closure n=4111; medical therapy n=2557). The incidence of stroke or systemic embolization per 100 person-years was 2.38 after PFO cohort and 2.99 with medical therapy (hazard ratio [HR], 0.85 [95% CI, 0.68-1.05], P=0.13). Mortality was lower in the PFO closure cohort (1.78 versus 2.59 per 100 person-years: HR, 0.69 [95% CI, 0.55-0.87], P=0.002). Falsification end points showed that this difference is unlikely to be completely explained by residual confounders. There were no significant differences between the groups in secondary end points including intracranial hemorrhage and major bleeding except for an increase in nonintracranial hemorrhage bleeding among patients treated with oral anticoagulation (1.42 versus 2.16 per 100 person-years: HR, 0.69 [95% CI, 0.48-0.99], P=0.043). The main end point was consistent in subanalyses including patients <60 years of age, patients with prior stroke, and those treated after the publication of the positive PFO trials in 2017. Conclusions In contemporary US practice, PFO closure is not associated with lower rates of recurrent ischemic stroke or systemic embolization compared with medical therapy. Potential reasons for this discrepancy warrant further investigation.

To assess potential impacts of formulary tier increases of apixaban-an efficacious oral anticoagulant (OAC) for preventing stroke in patients with atrial fibrillation (AF)-on patients' prescription drug plan (PDP) switching and OAC treatment patterns.

Nationwide claims data for Medicare beneficiaries with Parts A, B, and D (100% sample) were used to assess apixaban-treated AF patients who faced a formulary tier increase for apixaban in 2017 by their Part D PDP. Patients' out-of-pocket (OOP) costs for apixaban were described, along with PDP switching and OAC treatment patterns.

Among 1845 included patients, 97.7% had apixaban on tier 3 of their plan's formulary in 2016 and faced its increase to tier 4 for 2017. Approximately 4% (N = 81) of patients pre-emptively switched to a different PDP for 2017 with almost all switching to plans with apixaban on a lower formulary tier and 85.2% continuing apixaban treatment. Among the 96% (N = 1764) of patients who remained on the same PDP for 2017, over half (57.5%) continued apixaban treatment, despite increased OOP costs ($54 vs. $135 for a 30-day supply in 2016 vs. 2017). Only 12.4% of those who remained on the same plan for 2017 switched to another OAC, while as much as 30.1% discontinued OACs. These discontinuers exhibited higher comorbidity burdens than patients continuing on any OAC.

The majority of patients continued on apixaban despite higher OOP cost, suggesting patients' reluctance to change treatment for non-medical reasons; however, 30% of patients discontinued OAC treatment after higher apixaban tier placement.

Breakthrough acute ischemic stroke (AIS) in patients with known, nonvalvular Atrial Fibrillation (AF), on Direct Oral Anticoagulants (DOAC), is an ongoing clinical conundrum. Switching anticoagulants was shown to be ineffective in preventing recurrent AIS. Systematic, patient-level chart review of so-called "DOAC failures" may offer insight into this phenomenon.

We conducted an IRB-approved, 6-year, retrospective study of AIS admissions, already prescribed DOAC for known AF. We sought plausible, alternative reasons for the AIS using a novel classification schema, CLAMP: C for Compliance concerns, L for Lacunes (small-vessel disease), A for Arteriopathy (atherosclerosis, web, or vasculitis), M for Malignancy, and P for Patent Foramen Ovale (PFO). These categories were labeled as DOAC "Pseudo-failures." Conversely, absence of CLAMP variables were labeled as DOAC "Crypto-failures" conceivably from AF itself ("atriopathy") or pharmacokinetic/pharmacogenomic dysfunction (ie, altered DOAC absorption, clearance, metabolism, or genetic polymorphisms). Forward logistic regression analysis was performed on prespecified DOAC subgroups.

Of 4890 AIS admissions, 606 had AF, and 87 were previously prescribed DOAC (14.4% overall DOAC failure rate, 2.4% annualized over 6 years). Pseudo-failures comprised 77%: Compliance concerns (48.9%), Lacunes (5.7%), Arteriopathy (17.0%), Malignancy (26.1%), and PFO (2.3%). Crypto-failures comprised 23%, had lower CHADSVASc scores (AOR = .65, P = .013), and occurred more with rivaroxaban (41%) than apixaban (16%) or dabigatran (5.6%).

In AIS patients with known AF, DOAC Pseudo-failures, with identified alternate etiologies, are 3 times more likely than DOAC Crypto-failures. The CLAMP schema represents a novel approach to diagnostic classification and therapeutic adjustments in patients already prescribed DOAC for AF.

The impact of using direct-to-consumer wearable devices as a means to timely detect atrial fibrillation (AF) and to improve clinical outcomes is unknown.

Heartline is a pragmatic, randomized, and decentralized application-based trial of US participants aged ≥65 years. Two randomized cohorts include adults with possession of an iPhone and without a history of AF and those with a diagnosis of AF taking a direct oral anticoagulant (DOAC) for ≥30 days. Participants within each cohort are randomized (3:1) to either a core digital engagement program (CDEP) via iPhone application (Heartline application) and an Apple Watch (Apple Watch Group) or CDEP alone (iPhone-only Group). The Apple Watch Group has the watch irregular rhythm notification (IRN) feature enabled and access to the ECG application on the Apple Watch. If an IRN notification is issued for suspected AF then the study application instructs participants in the Apple Watch Group to seek medical care. All participants were "watch-naïve" at time of enrollment and have an option to either buy or loan an Apple Watch as part of this study. The primary end point is time from randomization to clinical diagnosis of AF, with confirmation by health care claims. Key secondary endpoint are claims-based incidence of a 6-component composite cardiovascular/systemic embolism/mortality event, DOAC medication use and adherence, costs/health resource utilization, and frequency of hospitalizations for bleeding. All study assessments, including patient-reported outcomes, are conducted through the study application. The target study enrollment is approximately 28,000 participants in total; at time of manuscript submission, a total of 26,485 participants have been enrolled into the study.

The Heartline Study will assess if an Apple Watch with the IRN and ECG application, along with application-facilitated digital health engagement modules, improves time to AF diagnosis and cardiovascular outcomes in a real-world environment.

ClinicalTrials.gov Identifier: NCT04276441.