Direct Oral Anticoagulants Research Articles

Direct oral anticoagulants or warfarin in patients with left ventricular thrombus: a meta-analysis of randomized clinical trials

Abstract Background/Introduction There are limited randomized controlled trials (RCTs) data on the use of direct oral anticoagulants (DOAC) versus warfarin in patients with left ventricular (LV) thrombus. Current AHA and ESC guidelines recommend oral anti-coagulants (either DOAC or warfarin) for 3 to 6 months without any preference. Purpose We aimed to compare outcomes with DOACs versus warfarin in patients with LV thrombus. Methods A comprehensive literature search was performed from inception to 02/01/2024 of the PubMed database. RCTs of adult patients comparing DOAC to warfarin were evaluated for mortality, major bleeding, stroke, and LV thrombus resolution. Meta-analytic Odds ratio (OR) with 95% confidence intervals (CI) were calculated using DerSimonian-Laird method. Results From 100 studies, four RCTs with 188 subjects (95 DOAC and 93 warfarin) were included with mean age of 53.4 years, 69.5% males, and mean follow up 5.03 months. There was no difference in mortality (OR= 0.67 [95% CI 0.15-3.06]; p=0.60; I2=0%; 3 trials), stroke (OR= 0.46 [95% CI 0.09-2.44]; p=0.37; I2=0%; 4 trials), major bleeding (OR= 0.43 [95% CI 0.12-1.55]; p=0.20; I2=0%; 4 trials), and LV thrombus resolution (OR= 1.33 [95% CI 0.45-3.95]; p=0.61; I2=0%; 2 trials) with use of DOAC compared to warfarin (Figure Panel A to D). Overall, there was no evidence of publication bias using either funnel plot or eggers test (p > 0.05). Conclusions In this meta-analysis of 4 RCTs, there was similar efficacy and safety of DOAC and warfarin in patients with LV thrombus. However, the evidence is limited by small sample size with lesser precision in the estimates. Future large-scale trials are needed to confirm these findings.

An external validation of DOAC score in patients with atrial fibrillation following transcatheter aortic valve replacement

Abstract Background Bleeding events, particularly in patients with atrial fibrillation (AF) and those with severe aortic stenosis undergoing transcatheter aortic valve replacement (TAVR), are a major clinical concern and are associated with a worse prognosis. The DOAC Score (1) has recently been introduced to predict bleeding risk in patients with AF taking direct oral anticoagulants (DOACs). However, further validation is required to confirm its ability. Objective This study aims to evaluate the predictive ability of the DOAC Score for bleeding events in Asian patients with AF undergoing TAVR. Methods In this multicentre, retrospective, observational cohort study, patients with AF who underwent TAVR were included. The data was obtained from the Japanese multicentre registry, which comprises 19 centres from 2013 to 2019. Bleeding was defined as any post-discharge bleeding after TAVR. The primary endpoint was the incidence of all bleeding events in 3 populations: the overall population, the DOAC cohort, and the vitamin K antagonist (VKA) cohort. Results This study included 1230 patients with a mean age of 84.6 ± 5.1 years, of whom 457 were males. Among them, 465 patients (37.8%) were treated with a VKA while the rest were treated with a DOAC. Patients were divided into three groups according to their DOAC Score: 380 patients (30.1%) were in the ≤ moderate risk group with a DOAC Score of 7 or less, 497 patients (40.4%) were in the high-risk group with a DOAC Score of 8 or 9, and 353 patients (28.7%) were in the very high-risk group with a DOAC Score over 10. The cumulative incidence of all bleeding at 5 years in the overall population was significantly different in the 3 risk groups: ≤ moderate: 8.4%, high-risk: 10.8%, very high-risk: 21.6%, respectively (p< 0.01). The incidence was also significantly different in the DOAC and VKA cohorts (p<0.01 and p=0.03, respectively). Conclusion The recently published DOAC Score is well predictive of bleeding risk in Asian patients with AF after TAVR. The score may be useful in predicting bleeding in patients taking both DOAC and VKA.Graphical abstract

Direct oral anticoagulants exhibit lower risks of mortality and bleeding compared to vitamin-k antagonists in atrial fibrillation patients on chronic hemodialysis: a meta-analysis

Abstract Background Atrial fibrillation (AF) is a common arrhythmia in patients with chronic kidney disease (CKD). Although direct oral anticoagulants (DOACs) are equally or more effective than vitamin K antagonists (VKAs) in patients with moderate CKD, evidence claiming the benefits of DOACs over VKAs in patients on hemodialysis (HD) is scarce. Purpose This meta-analysis aimed to assess the outcomes of patients with AF on chronic HD by comparing the clinical outcomes of DOACs versus VKAs. Methods A systematic literature search was conducted across various databases to retrieve studies focusing on efficacy and safety outcomes in patients with AF on chronic hemodialysis comparing DOACs and VKAs. Relative risks (RRs) with 95% confidence intervals (CIs) were pooled using the Mantel-Haenszel random-effects model in Review Manager 5.4. Statistical significance was set at p <0.05. Results Nine studies with 39, 831 patients were included. The risk of all-cause mortality [RR: 0.73; 95% CI: 0.60, 0.88; p=0.001], major bleeding [RR: 0.63; 95% CI: 0.52, 0.76; p<0.00001], gastrointestinal bleeding [RR: 0.67; 95% CI: 0.53, 0.85; p=0.0009], intracranial hemorrhage [RR: 0.57; 95% CI: 0.38, 0.84; p=0.004], all-cause stroke [RR: 0.64; 95% CI: 0.51, 0.81; p=0.0001], and ischemic stroke [RR: 0.53; 95% CI: 0.29, 0.96; p=0.04] were lower in the DOAC group than in the VKA group. The risk of cardiovascular-related death [RR: 1.34; 95% CI: 0.69, 2.60; p=0.39], and clinically relevant non-major bleeding [RR: 0.90; 95% CI: 0.75, 1.08; p=0.26] showed no significant differences. Conclusion The risks of all-cause stroke, ischemic stroke, all-cause mortality, major bleeding, gastrointestinal bleeding, and intracranial hemorrhage in the patients with AF undergoing chronic HD were lower in the DOAC group than in the VKA group. Further large-scale RCTs are needed to generate more robust evidence through adequately powered studies, leading to conclusive results that are applicable to real-world scenarios.

Direct Oral Anticoagulants versus Vitamin K Antagonists for the management of left ventricular thrombus after myocardial infarction: A meta-analysis

Abstract Background/Introduction Left ventricular (LV) thrombus formation is not an uncommon complication after acute myocardial infarction (AMI) in the modern era of early reperfusion. The optimal anticoagulation regimen in this clinical scenario remains poorly-defined. Purpose The present meta-analysis sought to investigate the efficacy and safety profile of direct oral anticoagulants (DOACs) compared with Vitamin K antagonists (VKAs) for the management of LV thrombus following AMI. Methods A systematic literature review was conducted in electronic databases to identify studies reporting efficacy and safety outcome data regarding the use of DOACs versus VKAs for patients with LV thrombus after MI. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated and random-effects meta-analyses were conducted to synthesize pooled ORs. Results Eight studies comprising a total of 605 patients were included (Table). DOACs were associated with an almost 2-fold higher likelihood for achieving thrombus resolution compared to VKAs (pooled OR 1.95 [1.25-3.04]; p =0.003, I2 =0 %), while they achieved a 70% lower risk for systemic embolism (pooled OR 0.30 [0.12-0.75]; p =0.01, I2 =0%). The use of DOACs was associated with a 54% lower risk for bleeding compared to VKAs (pooled OR 0.46 [0.26-0.84]; p =0.01, I2 =0 %). Overall, patients receiving DOACs had a 63% lower risk to reach the composite outcome of any bleeding, systemic embolism, cardiovascular hospitalization, or all-cause death, compared with patients using VKAs (pooled OR 0.37 [0.23-0.60]; p <0.0001, I2 =0%) (Figure). Conclusion DOACs appear to have a more favorable efficacy and safety profile compared to VKAs for the management of LV thrombus following AMI.Graphical abstractTable

Predictors and outcomes of intracranial hemorrhage in 58,000 patients with atrial fibrillation on oral anticoagulation: insights from COMBINE-AF

Abstract Background Among anticoagulated patients with atrial fibrillation (AF), intracranial hemorrhage (ICH) is the leading cause of bleeding-related death and disability. The COMBINE-AF database has patient-level data from four major randomized-controlled trials [ROCKET-AF (rivaroxaban), RE-LY (dabigatran), ENGAGE-TIMI 48 (edoxaban), ARISTOTLE (apixaban)] of direct oral anticoagulants (DOACs) versus warfarin in patients with AF. Purpose/Methods We investigated the rates, predictors, and mortality of ICH in patients randomized to DOAC (rivaroxaban, dabigatran, edoxaban, apixaban) or warfarin. ICH was subclassified as subdural or non-subdural (intracerebral, intraventricular, subarachnoid, epidural). Multivariable Cox models were used to identify predictors of ICH. Frequencies and fatality rates of ICH were calculated and displayed as Kaplan-Meier curves. Results In COMBINE-AF, there were 58,634 patients randomized to either DOAC (n=29,362) or warfarin (n=29,272). The mean age was 70.5 years, 37% were female, and 81% were White. The mean CHA2DS2-VASc score was 2.6, 43% of patients had a history of smoking, 31% had diabetes, and 29% had prior stroke/TIA. After a mean of 32 months, ICH occurred in 593 patients (1.01%, 0.58 per 100-patient years, 95% CI [0.54, 0.63]). The most significant independent predictors of ICH in order of importance were: treatment with warfarin, older age, prior stroke/TIA, enrollment in Asia, antiplatelet use at randomization, and history/risk of falls (Figure 1). Mortality after ICH was 48.4% (287/593 participants), with a majority of deaths (82%) occurring within 30 days of ICH event. Non-subdural ICH was more common than subdural ICH (73% vs 25%) and had a higher risk of death (Figure 2). Participants randomized to DOAC had a lower risk of both subdural and non-subdural ICH than those treated with warfarin; however, mortality rates after ICH were similar regardless of anticoagulant type. Conclusion ICH is an uncommon but devastating complication of oral anticoagulation in patients with atrial fibrillation. The mortality rate following ICH is high, particularly following non-subdural ICH. To reduce the risk of ICH, clinicians should consider using DOACs over warfarin and carefully evaluate the need for antiplatelet therapy, particularly in patients with other significant predictors of ICH such as prior stroke, advanced age, residence in Asia, and history of falls.Predictors of Intracranial Hemorrhage90-Day Mortality after ICH

Comparing the real-world and clinical trial bleeding rates associated with oral anticoagulation treatment for atrial fibrillation

Abstract Background The prevention of stroke in patients with atrial fibrillation (AF) involves the use of oral anticoagulation, commonly in the form of direct oral anticoagulants (DOAC). However, it comes with an increased risk of bleeding and therefore, counselling patients on their individual risk is important. Although majority of patients initiated on DOAC have been represented within the clinical trials, there are some cohorts which are under-represented in whom clinicians are unable to practice evidence-based medicine. Methods Utilising the pooled clinical trial (CT) data sourced from Medidata Enterprise Data Store, 5 recent open-label industry sponsored AF trials were compared with Real-World data (RWD) was sourced from the HealthVerity Marketplace with the occurrence of bleeding events as the primary outcome of interest. Results A total of 64,421 patients were included in the analysis, with 3207 patients from the clinical DOAC trials and 61,214 patients from the RWD cohort. Overall, the patients from RWD cohort had more co-morbidities, were older (72.2 ± 11.9 vs 65.3 ±10.7 years old, p<0.001), had higher mean CHA2DS2VASc (3.98 ± 1.9 vs 2.87 ± 1.73, p<0.001) and HAD-BLED scores (2.13 ± 1.02 vs 1/04 ± 0.93, p<0.001) when compared to the trial data. When comparing the incidence of first major bleed at 12 months post treatment initiation, rates in the RWD cohort was significantly higher (10.69 vs 18.97 per 100 person-years). The impact of comorbidities such as age, CHA2DS2VASc and HAD-BLED scores were similar in both cohorts, however, there was an under-representation of older, females and more co-morbid patients within the clinical trial cohort. Conclusion DOAC treated patients have higher bleeding incidence rate in the RWD cohort as compared to clinical trials. This can be explained by the older patient age group with more complex medical histories and higher HAS-BLED scores. The under-representation of higher risk patients and lower proportion of females within clinical trials should be addressed to better translate clinical trial data into real world clinical practice.

Cost differences between oral anticoagulation therapies in atrial fibrillation patients

Abstract Background Direct oral anticoagulants (DOACs) have largely replaced warfarin as the primary choice of oral anticoagulation (OAC) in atrial fibrillation (AF) patients. This study uses a nationwide registry data set to compare the health and social care costs of AF patients using different OAC therapies. We studied how these costs were distributed among different care services in the year following AF onset and how the costs develop in time before and after AF diagnosis. Methods This study is a part of the Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) research project, which includes data on patients with AF, combining registry data on primary and secondary care services as well as social services, drug purchases and laboratory data. We included all new-onset AF patients from 2011 to 2017 in Finland with an indication for OAC treatment. Patients were divided based on their first OAC purchase. Time in therapeutic range (TTR) values were assessed for warfarin patients, and they were divided into quartiles based on their TTR value. Standardized costs were determined for different health and social care contacts, accounting for hospital care, primary and ambulatory care, and long-term care. Drug costs were acquired from the Reimbursement for Prescription Medicines registry. Results A total of 130,745 patients (66,610 on warfarin, 32,996 on DOACs) were included. First-year total costs after onset of AF were €10,412 for rivaroxaban (n=13,320), €12,631 for apixaban (n=11,886), €10,706 for dabigatran (n=7,514) and €10,689 for edoxaban (n=366). Costs of care clustered near the diagnosis of AF (Figure 1). Costs for warfarin patients increased inversely with TTR, ranging from €10,945 in the highest TTR quartile (TTR over 82%) to €21,387 in the lowest (TTR under 57%). Average first-year costs for warfarin patients were €15,689, higher than DOAC patients by €3,058-€5,277 (Figure 2). Patients without any OAC had the highest first-year costs, €17,898. Patients with high risk of stroke had higher total costs both in patients using DOACS (€7,271 for patients with a CHA2DS2VA score of 1 vs €11,947 for patients with CHA2DS2VA 2+) and warfarin (€9,933 for CHA2DS2VA 1 vs €16,354 for CHA2DS2VA 2+). Drug costs averaged €1,541 for rivaroxaban, €1,659 for apixaban, €1,495 for dabigatran and €1,540 for edoxaban, and €986 warfarin users. Hospital care was the largest cost driver with 64% of total costs across the whole cohort, followed by primary care (19%), drug purchases (7%), social service costs (6%) and reimbursements for travel and private care (4%). Conclusions DOACs were superior to warfarin in a broad range of social and healthcare cost measures despite higher drug expenses. Patients on warfarin with low TTR and patients without any OAC had the highest cost of care.

Switching from warfarin to a DOAC in frail elderly asian patients with atrial fibrillation: a nationwide population-based study

Abstract Background Recently, switching international normalized ratio guided warfarin management to a direct oral anticoagulant (DOAC) was associated with more bleeding complications than maintaining warfarin in frail elderly patients with atrial fibrillation (AF). However, there is a paucity of information on whether these results could be applied to Asian patients with AF, who are known to have relatively low time in therapeutic range (TTR) levels. Purpose To evaluate the safety and effectiveness of switching from warfarin to a DOAC in frail elderly Asian patients with AF. Methods Using a Korean health insurance database, we included patients with AF who were prescribed warfarin between January 2013 and August 2015 without significant bleeding or thromboembolic events during the window period, specifically those aged 75 or older with a Hospital Frailty Risk Score of 5 or more. Those who switched to DOACs during the window period were categorized as the DOAC group and those who continued with warfarin were categorized as the warfarin group. The primary outcome was defined as the composite of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB), and secondary outcomes were defined as thromboembolic events, all-cause death, the composite of MB, CRNMB and ischemic stroke (so-called net clinical outcome [NCO]). The propensity score weighting method was utilized to compare the two groups. Results A total of 12,162 patients were included (8,108 with maintaining warfarin, 4,054 with switching to a DOAC). Baseline characteristics were well-balanced after the inverse probability of treatment weighting (mean age, 80 years; men, 50%; and mean CHA₂DS₂-VASc score, 5.6). Compared with maintaining warfarin, switching to a DOAC was associated with significantly higher risks of the primary outcome (hazard ratio [HR] 1.43, 95% confidence interval [CI] 1.09-1.87, p=0.01), thromboembolic events (1.28, 1.01-1.62, p=0.039), all-cause death (1.38, 1.15-1.66, p<0.001) and the NCO (1.26, 1.01-1.58, p=0.04). (Figure A, Figure B), whereas there was no difference in the risk of intracerebral hemorrhage (0.90, 0.50-1.60, p=0.7157). When comparing each DOAC with maintaining warfarin, switching to rivaroxaban was associated with a higher risk of the composite of MB and CRNMB (1.91, 1.38-2.64, p<0.001) and thromboembolic events (1.40, 1.03-1.91, p=0.034) than maintaining warfarin. Conclusion In line with the non-Asian population, switching to a DOAC was associated with a significantly higher risk of MB or CRNMB, thromboembolic events, all-cause death and NCO compared with maintaining warfarin in frail elderly Asian patients with AF. Therefore, even in Asians, switching to a DOAC should be considered more cautiously in patients who are stably managed on warfarin.

Optimal anticoagulant strategy for periprocedural management of atrial fibrillation ablation: a systematic review and network meta-analysis

Abstract Background This network meta-analysis was performed to rank the safety and efficacy of periprocedural anticoagulant strategies in patients undergoing atrial fibrillation ablation. Methods MEDLINE, EMBASE, CENTRAL, and Web of Science were searched to identify randomized controlled trials comparing anticoagulant regimens in patients undergoing atrial fibrillation ablation up to July 1, 2021. The primary efficacy and safety outcomes were thromboembolic and major bleeding events, respectively, and the net clinical benefit was investigated as the primary-outcome composite. Results Seventeen studies were included (n = 6950). The mean age ranged from 59 to 70 years; 74% of patients were men and 55% had paroxysmal atrial fibrillation. Compared with the uninterrupted vitamin-K antagonist strategy, the odds ratios for the composite of primary safety and efficacy outcomes were 0.61 (95%CI: 0.31–1.17) with uninterrupted direct oral anticoagulants, 0.63 (95%CI: 0.26–1.54) with interrupted direct oral anticoagulants, and 8.02 (95%CI: 2.35–27.45) with interrupted vitamin-K antagonists. Uninterrupted dabigatran significantly reduced the risk of the composite of primary safety and efficacy outcomes (odds ratio, 0.21; 95%CI, 0.08–0.55). Conclusion Uninterrupted direct oral anticoagulants are preferred alternatives to uninterrupted vitamin-K antagonists. Interrupted direct oral anticoagulants may be feasible as alternatives. Our results support the use of uninterrupted direct oral anticoagulants as the optimal periprocedural anticoagulant strategy for patients undergoing atrial fibrillation ablation.

Inappropriate dosing of direct oral anticoagulants in patients with atrial fibrillation undergoing percutaneous coronary intervention

Abstract Background Underdose (inappropriate low-dose) of direct oral anticoagulants (DOAC) is sometimes prescribed due to concerns of bleeding risk in patients with atrial fibrillation (AF). In AF patients with coronary artery disease requiring percutaneous coronary intervention (PCI), careful treatment is required to prevent bleeding events because of intensive antithrombotic therapy with a combination of oral anticoagulants and antiplatelet agents. Purpose The purpose of this study was to investigate the prevalence of underdose of DOAC and its impact on clinical outcomes in AF patients with coronary artery disease undergoing PCI. Methods This multicenter observational cohort study enrolled patients with AF on DOAC undergoing PCI between January 2015 and March 2021 at 15 institutions. Appropriateness of DOAC dose was determined according to the manufacturer's labeling recommendations in Japan. Clinical outcomes within 1 year, including major adverse cardiovascular events (MACE), all-cause mortality, ischemic stroke, and major bleeding events, were evaluated. Results Of 630 patients enrolled, 168 patients (26.7%) received underdose, 227 (36.0%) received appropriate low-dose, 213 (33.8%) received appropriate standard-dose, and 22 (3.5%) received overdose. Because of the extremely small number of patients in the overdose group, the primary analysis of the present study was a comparison between the underdose group (n=168) and the appropriate dose group (appropriate low-dose and standard-dose groups) (n=440). Although the incidence of MACE, all-cause mortality, and major bleeding events was not significantly different between the 2 groups (log-rank p=0.872, p=0.170, and p=0.725), ischemic stroke more frequently occurred in the underdose group compared with the appropriate dose group (log-rank p=0.010) (Figure 1). The multivariable Cox regression analysis determined underdose of DOAC as an independent predictor for ischemic stroke (adjusted HR 3.288, 95% CI: 1.189-9.088, p=0.022). Conclusions Compared with appropriate dose of DOAC, underdose was associated with a higher incidence of ischemic stroke, despite no significant difference in MACE, all-cause mortality, and major bleeding events, in AF patients undergoing PCI.Figure 1

The effect of oral anticoagulants on the incidence of dementia in patients with atrial fibrillation: a systematic review and meta-analysis

Abstract Background Atrial fibrillation (AF) is a common cardiac arrhythmia, with dementia being an increasingly recognised complication of this. Treatment with oral anticoagulant (OAC) therapy may be protective in developing this complication. Purpose This meta-analysis aims to investigate the validity of this hypothesis, whilst additionally exploring the effect of specific OAC medication subtypes on the incidence of dementia. Methods A comprehensive search of MEDLINE and Embase for relevant studies reporting the efficacy of OAC therapy for the incidence of dementia in patients with AF was conducted from its inception until March 2023. This included observational studies that reported odds ratio, risk ratio and hazard ratio for adult AF patients. Studies including patients with prior OAC use or prior history of dementia were excluded. Statistical analysis was performed using a random-effects model to calculate the pooled hazard ratio and their corresponding 95% confidence interval for all outcomes. Subgroup analyses were also performed according to the study design, presence of observational window, and prior history of stroke in patients. Results A total of 13 studies were included in the study. Although the heterogeneity was high in all comparisons, we demonstrated that OAC usage lowered the risk of developing dementia in AF patients when compared to the non-OAC cohort. Looking more specifically at medication subtypes, direct oral anticoagulants (DOACs) and vitamin K agonists (VKA) were both effective in reducing the likelihood of AF patients developing dementia when compared to non-OAC treatments. Conclusion Our meta-analysis confirms that administration of OAC and its subtypes (VKA and DOAC) are effective pharmacotherapies in managing dementia in patients with AF. These findings have important clinical implications for the management of AF patients and highlight the need for further investigation of the protective effects of OAC therapy on cognitive decline. Future research should explore the long-term effects of OAC therapy on cognitive function in AF patients.

Clinical outcomes of edoxaban treatment without parenteral anticoagulation therapy for acute venous thromboembolism: Insight from the COMMAND VTE Registry-2

Abstract Background Direct oral anticoagulants (DOACs) including edoxaban are currently widely used all over the world. Each DOAC has a specific usage for the treatment and second prevention of venous thromboembolism (VTE) in the acute phase as well as in the chronic phase. Edoxaban is recommended to be administered after an appropriate initial treatment including parenteral anticoagulation therapy such as heparin. However, because of the rapid anticoagulant effect of edoxaban after oral intake, some physicians could administer edoxaban initially without parenteral anticoagulation therapy in the daily clinical practice, which has not been investigated so far. Purpose The purpose of this study is to explore the effectiveness and safety of edoxaban treatment for VTE without initial parenteral anticoagulation therapy. Methods The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020. Of those, 1842 patients received edoxaban including 848 patients with pulmonary embolism (PE) and 994 patients with deep vein thrombosis (DVT) alone, who were divided into 2 groups based on the presence or absence of initial parenteral anticoagulation therapy with heparin. Propensity score matching (PSM) was performed to adjust for potential baseline differences in the 2 groups. Results PE and DVT patients with initial parenteral anticoagulation therapy with heparin accounted for 623 (73.5%) and 244 (24.5%), respectively. After the PSM, 195 pairs of PE patients and 226 pairs of DVT patients were matched. In PE patients, those matched by the PSM were relatively mild cases compared to the unmatched cases (simplified PESI score=0: 25.9% vs. 12.4%, P<0.001). Whereas, in DVT patients, those matched were relatively severe cases compared to unmatched cases (isolated distal DVT: 24.1% vs. 71.0%, P<0.001). In the matched cohort, there was no significant difference in baseline characteristics between the 2 groups, including simplified PESI score in PE patients and thrombus location profile in DVT patients. In both PE patients and DVT patients, the 30-day cumulative incidences of all-cause death were not significantly different between the 2 groups (PE patients: 3.7% vs. 2.6%, P=0.56; DVT patients: 2.7% vs. 4.5%, P=0.31). Similarly, the 30-day cumulative incidences of recurrent VTE and major bleeding were not significantly different between the 2 groups (recurrent VTE: PE patients: 0% vs. 0.5%, P=0.32; DVT patients: 0.6% vs. 0.9%, P=0.99; major bleeding: PE patients: 1.5% vs. 3.2%, P=0.32; DVT patients: 2.2% vs. 3.2%, P=0.54) Conclusion In this current real-world VTE registry, a certain number of patients received edoxaban without parenteral anticoagulation therapy, who did not show a signal of worse clinical outcomes.

Implementation of digital patient decision support tools for Atrial Fibrillation treatment: systematic review

Abstract Background/ Introduction Treating atrial fibrillation (AF) involves complex decisions. Digital patient decision-support tools can facilitate shared decision making by significantly reducing decisional conflict and improving patient knowledge [1,2]. Yet, implementation in clinical practice is lagging [3]. Purpose To systematically review trials of digital patient decision-support tools for AF treatment decisions, focusing on factors influencing their implementation in clinical practice. Methods We conducted a systematic review following Cochrane methods. EMBASE, MEDLINE and Scopus were searched from 2005 to 2023. Eligible randomised controlled trials and quasi-experimental trials that evaluated digital patient decision-support tools for AF treatment decisions were included. Two independent reviewers screened title and abstract, extracted data and assessed risk of bias. The implementation outcomes included a description of when and how the tool was used, as well as its characteristics and user satisfaction. Results Thirteen articles reporting on eleven studies (5 RCTs and 6 quasi-experimental trials) met the inclusion criteria (2,714 participants; mean age 71±4.2 years; 26% women; 92% with non-valvular AF, remaining not reported). Risk of bias was low for 2 studies, moderate for one and high for seven studies. All tools (n=11) focused on anticoagulation choice (1: warfarin vs no warfarin; 1: aspirin vs warfarin; 7: Direct Oral Anticoagulants (DOAC) vs antiplatelet or warfarin; 2: unspecified choice). The tools were used either pre-visit (at home or in the waiting room) or during the consultation (n=5). Tools were delivered using a mobile application (n=4), web-based application (n=5), or a desktop (n=2). Of the eleven tools, 2 could automatically calculate individualized stroke risk using data from electronic health records. Most articles reported favourable user feedback regarding use of the digital patient decision-support tools, such as high perceived usefulness, user-friendliness, and overall satisfaction. No significant difference was found in encounter times between intervention and control arms (2 RCTs). Four tools were publicly available and 3 were implemented in healthcare delivery beyond research. Conclusion Despite demonstrated efficacy in reducing decisional conflict and improving patient knowledge, as well as positive clinician and patient experience, only 3 tools were implemented in clinical practice beyond their trial. Future tools could better leverage digital capabilities to integrate with Electronic Health Records, automate stroke and bleeding risk calculations, and personalise content based on patient values and preferences. Additional robust trials and implementation studies are warranted to understand barriers and enablers to the use of these tools.

The incidence of death and risk factors for mortality following major bleeding in patients anticoagulated with factor Xa inhibitors: an observational study in the UK clinical setting (AXIOM UK)

Abstract Background Major bleeding (MB) in association with anticoagulant use results in significant mortality. Mortality can be directly attributed to bleeding, or may follow bleeding complications such acute kidney injury, myocardial infarction, stroke and other cardiovascular events. Most real-world data relating to bleeding mortality is derived from cohorts receiving vitamin-K antagonists. We investigated all-cause mortality (ACM) after MB in a large cohort anticoagulated with Factor Xa inhibitors (FXai), e.g. direct oral anticoagulants (DOAC) rivaroxaban, apixaban and low-molecular-weight heparins (LMWH). Purpose To describe incidence rates of and risk factors for ACM following MB in patients receiving FXai. To investigate MB related ACM by bleeding site, treatment indication, treatment subgroups and individual and cumulative time periods. Methods Retrospective cohort analysis of new users of FXai, between 2012-2020, for therapeutic indications including atrial fibrillation (AF), venous thromboembolism, bioprosthetic cardiac valves or adult congenital heart disease was conducted. MB was defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria. Incidence rates were reported per 100 person-years. Sub-distribution hazard ratios with 95% confidence intervals (95% CI) were estimated from Fine and Gray regression models accounting for competing risks. Results In 240,357 new users of FXai, 88% used an oral FXai. The most common FXai indication was AF (72%). There were 10,163 patients (4.2%) hospitalised for bleeding events during FXai use. Of these, 3,873 MB events (38%) fulfilled the ISTH definition of MB and 1312 died during 3,542 person years of follow-up (Table 1). ACM incidence rates varied by time, indication, bleeding subtype, and drug type. ACM occurred in 926 patients (23.9%) in the first month. Mortality rates were highest in the first month 607 (95% CI 568-647) per 100 person years, the rates then decreased over the year but remained elevated throughout the first year compared with subsequent years. Those receiving LMWH had higher ACM than those receiving a DOAC, but this was not significant in the adjusted risk factor analysis. Risk factors for ACM following bleeding included age ≥80, and a history of current smoking, myocardial infarction, congestive heart failure, peripheral artery disease, Stage 4 or 5 kidney disease, metastatic cancer, and intracranial haemorrhage. Age<60, bleeding following major trauma, and a history of anaemia were associated with lower risk of ACM (Table 2). Conclusions There is a significant incidence of ACM following MB among FXai users. The incidence rate of ACM in patients treated with FXai was highest in the first month after FXai initiation, declined during the first year and then plateaued. Multiple risk factors associated with ACM have been recognised and these could guide urgent therapies such as antidotes.

Haemorrhagic risk in elderly patients with atrial fibrillation that develop low platelet count during direct oral anticoagulant treatment: insights from the ATHERO-AF study

Abstract Background Bleeding risk in atrial fibrillation (AF) patients is complex and dynamic. Among others, thrombocytopenia has been suggested as a bleeding risk factors. No data on thrombocytopenia occurring during direct oral anticoagulants (DOACs) therapy are available. Purpose We investigated the incidence rate of thrombocytopenia and major bleeding (MB) in AF patients on DOACs. We also investigated whether the addition of incident thrombocytopenia to the HAS-BLED score might increase its predictive value compared to baseline HAS-BLED calculation. Methods 955 AF patients from the prospective ongoing ATHERO-AF study followed for a mean of 38.4±26.6 months. All patients were on DOACs. Thrombocytopenia was defined by a platelet count <150 x109/L registered during follow-up visits. MB events were defined according to ISTH definition and were recorded at each follow-up visit. Patients with thrombocytopenia at baseline were excluded. Multivariable Cox proportional hazards regression analysis was used to calculate the hazard ratio (HR) with 95% Confidence interval (95%CI) for each factor in relation to bleeding risk. Results Mean age was 77.3±9.0 years and 40.1% were women. During a follow-up, 139 patients developed thrombocytopenia with an incidence rate of 0.8% per year. We recorded no difference between thrombin and factor Xa inhibitors. During follow-up, 179 bleedings occurred, of which 80 were major. Patients experiencing bleedings were more likely to suffer from arterial hypertension, heart failure, anaemia and had higher CHA2DS2-VASc and HAS-BLED scores. At multivariable Cox proportional hazards regression analysis, factors associated with MB were incident thrombocytopenia (HR 1.995, 95%CI 1.211-3.288), antiplatelet use (HR 2.716 95%CI 1.269-5.816) and age (HR 1.033, 95%CI 1.003-1.064). The addition of incident thrombocytopenia to the HAS-BLED score increased the predictive value of baseline HAS-BLED in patients without thrombocytopenia for MB events (AUC from 0.54 to 0.61, p=0.016). Conclusion Incident thrombocytopenia is associated with an increased risk of MB. The addition of incident thrombocytopenia to the baseline HAS-BLED score increased its predictive value, suggesting that continuous bleeding risk evaluation of AF patients may provide additional prognostic information compared to the baseline only.

Monitoring anti-factor Xa activity in patients with chronic thromboembolic pulmonary hypertension treated with factor Xa inhibitors

Direct oral anticoagulants (DOACs) have been used clinically in patients with chronic thromboembolic pulmonary hypertension (CTEPH) for secondary prevention after acute venous thromboembolism, although the data are limited. We evaluated the effects of DOACs—especially factor Xa (FXa) inhibitors—by measuring anti-factor Xa activity (AXA). Fifty consecutive CTEPH patients treated with rivaroxaban, apixaban, or edoxaban were enrolled. Heparin-calibrated AXA was measured at peak and trough. The median peak heparin-calibrated AXA across all 50 patients was 1.90 IU/mL and was comparable among the three FXa inhibitors. At trough, heparin-calibrated AXA was significantly higher in apixaban-treated patients (median 0.70 IU/mL) than in those given rivaroxaban (median 0.11 IU/mL) or edoxaban (median 0.11 IU/mL, p < 0.001). Peak heparin-calibrated AXA was significantly lower with reduced-dosage FXa inhibitor (edoxaban 30 mg/day) than with the reference dosage (edoxaban 60 mg/day, apixaban 10 mg/day, or rivaroxaban 15 mg/day, p = 0.01). The heparin-calibrated AXA of both rivaroxaban and apixaban was strongly significantly correlated with the plasma concentration of each drug. The cumulative rate of major and clinically relevant non-major bleeding was significantly higher in patients with peak heparin-calibrated AXA ≥ 2.09 IU/mL. Heparin-calibrated AXA could provide useful information for treating CTEPH patients with FXa inhibitors.

Predictors of Ischemic Stroke in a cohort of patients with Chagas Cardiomyopathy: the CLOT-Chagas study

Abstract Introduction a high risk of embolic events characterizes Chronic Chagas Cardiomyopathy (CCC) due to the presence of structural alterations of the left ventricle, the high incidence of arrhythmias, and intrinsic coagulation disorders. Despite its relevance, there is limited information on factors associated with this type of embolic event in patients with CCC, with most studies designed as case-control studies. This study aimed to prospectively analyze independently associated factors with this population's Ischemic Stroke (IS). Materials and Methods A prospective study was conducted between 2019 and 2023 at a cardiovascular center's Heart Failure and Heart Transplant Clinic. Adult patients diagnosed with CCC were included, recording sociodemographic, clinical, and echocardiographic variables as potential predictors of IS. Patients were followed up for 18 months via telephone for outcome assessment. Multivariate logistic regression models were used to identify factors potentially associated with IS during follow-up. Results A total of 232 patients diagnosed with CCC were included (males: 54.9%; median age: 67 years), the majority of whom were receiving anticoagulant therapy (n=144; 62.1%), with DOACs being the most frequently prescribed type of anticoagulants (51%). During follow-up, 16 patients (6.9%) developed an IS. There was a trend towards a lower incidence of IS in patients treated with direct oral anticoagulants (6.8%) compared to those receiving Warfarin (11.5%); however, this difference was not statistically significant (p=0.584). In the multivariate regression analysis including all potential predictors of IS, only the presence of a ventricular aneurysm (RR 5.64; 95% CI 1.61-19.70, p=0.007) and the score obtained when applying the Pfeiffer cognitive impairment questionnaire (RR 0.56; 95% CI 0.42-0.75, p&amp;lt;0.001) were significantly associated with the outcome of IS, even after adjusting for age, sex, NYHA functional class, ejection fraction, and anticoagulant therapy. The model composed of ventricular aneurysms and the Pfeiffer questionnaire score showed adequate performance in predicting IS during follow-up (AUC 0.79). Conclusions and Discussion: The incidence of IS in this population was higher than reported in the literature for both CCC patients and those with heart failure from other etiologies. The finding of an association between the presence of ventricular aneurysms and IS has been previously reported; however, the association between the Pfeiffer cognitive test and the development of IS represents a novel observation that deserves validation in future studies for its applicability in the clinical setting.

Predictors of discordance in estimating the presence of chronic kidney disease among patients with atrial fibrillation and impact on prescription of anticoagulants and cardiovascular outcomes

Abstract Background In patients with atrial fibrillation (AF), the prevalence, predictors and clinical implications of a potential discordance in estimating the presence/absence of chronic kidney disease (CKD) according to Cockroft-Gault (CG) and CKD-EPI formulas remain unclear. Objective To examine patients characterized by discordance in evaluation of renal function, specifically with regard to the threshold for defining the presence of CKD according to an estimated glomerular filtration rate (eGFR) &amp;lt; 60 ml/min, in a large cohort of European AF patients, and to assess the association with prescriptions of oral anticoagulants (OAC) and the risks of adverse outcomes. Methods Data related to AF patients enrolled in a large European observational prospective registry with an average follow up of 645.2 days were analysed. We evaluated renal function for assessing the presence of CKD according to CG and CKD-EPI formulas and we categorized the population in four groups: eGFR ≥ 60 ml/min according both to CG and CKD-EPI (Concordant ≥ 60); &amp;lt; 60 ml/min according to both formulas (Concordant &amp;lt;60); CG &amp;lt;60 ml/min and CKD-EPI ≥60 ml/min (Discordant-CKD-EPI), CG ≥ 60 ml/min and CKD-EPI &amp;lt;60 ml/min (Discordant-CG). Logistic regression analyses were used to assess factors associated with a Discordant assessment of CKD and its association with OAC therapy. Cox regression analysis was used to determine association between categories and the risk of adverse outcome. The primary endpoint was a composite of all-cause death and major adverse cardiovascular events (MACEs). Results 8.786 patients with AF (mean age 68.70, SD 11.58 years; 40.9% female) were included in the analysis. 1360 (15.5%) of them had Discordant CKD assessment: 577 (6.6%) with Discordant-CKD-EPI and 783 (8.9%) with Discordant-CG. Increasing age, female sex and coronary artery disease (CAD) were associated with Discordant-CKD-EPI, while BMI and heart failure (HF) showed an inverse association (Figure 1). Conversely, BMI and HF were factors significantly associated with Discordant-CG. Discordant-CKD-EPI patients showed lower odds of being prescribed with OAC therapy (odds ratio [OR] 0.71, 95% confidence interval [CI] 0.54-0.95) with no significant differences regarding the type of OAC therapy (warfarin or direct oral anticoagulants). At Cox regression analysis, patients with Discordant-CKD-EPI showed a higher risk of composite endpoint events (Figure 2) and both Discordant-CKD-EPI and Discordant-CG patients were associated with a higher risk of all-cause death. Conclusions Age, BMI, female sex and comorbidities associated with AF (CAD and HF) significantly influenced the probability of having a discordant assessment of the presence of CKD, according to estimation of renal function impairment using CG or CKD-EPI formulas, respectively. A discordant assessment of CKD influenced the probability of being prescribed with OAC and was associated with a higher risk of adverse outcomes.Figure 1Figure2

The association between steroid use and recurrent venous thromboembolism: from the COMMAND VTE Registry-2

Abstract Background It is well known that use of oral steroids is a risk factor for development of venous thromboembolism (VTE). However, the impact of use of oral steroids on VTE recurrence has not been fully evaluated in the era of direct oral anticoagulants (DOAC), which has been a clinically relevant issue in the decision-making of anticoagulation strategies for patients who need oral steroids after VTE diagnosis. Purpose We aimed to investigate long-term clinical outcomes in VTE patients treated with oral steroids after VTE diagnosis in the DOAC era. Methods The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020. The current study population were divided into 2 groups according to the use of oral steroids after VTE diagnosis; the steroid group and the non-steroid group. We compared clinical characteristics, management strategies, and outcomes including recurrent VTE, major bleeding and all-cause death, between the 2 groups. Results Patients with steroids and those without accounted for 693 (13%) and 4,504 (87%), respectively. Patients with steroids more often had chronic kidney disease (29% vs. 18%, P&amp;lt;0.001), autoimmune disease (50% vs. 5.4%, P&amp;lt;0.001), thrombocytopenia (7.7% vs 4.9%, P=0.002), and anemia (64.4% vs 54.1%, P&amp;lt;0.001), whereas there was no significant difference in the mean age (68.5 vs. 67.6 years old, P=0.16), the prevalence of women (62% vs 58%, P=0.06), active cancer (30% vs. 29%, P=0.42), and history of VTE (8.4% vs 6.8%, P=0.12) between the 2 groups. The cumulative 5-year incidence of discontinuation of anticoagulation therapy were not significantly different between the 2 groups (61.5% vs. 58.5%, log-rank P=0.16). The cumulative 5-year incidences of recurrent VTE nor major bleeding were not significantly different between the 2 groups (10.4% vs. 9.4%, log-rank P=0.55; 16.9% vs. 13.3%, log-rank P=0.16, respectively). Even after adjusting confounders, the risks of recurrent VTE nor major bleeding were not significantly different (adjusted hazard ratio = 0.97, 95% confidence interval = 0.65-1.45, P = 0.89; adjusted hazard ratio = 1.12, 95% confidence interval = 0.84-1.50, P = 0.44). The cumulative 5-year incidences of all-cause death was significantly different between the 2 groups (44.2% vs. 30.2%, log-rank P&amp;lt;0.001). Even after adjusting confounders, the risk of all-cause death remained significantly different (adjusted hazard ratio = 1.82, 95% confidence interval = 1.56-2.12, P&amp;lt;0.001). Conclusions Use of oral steroids after VTE diagnosis was not significantly associated with an increased risk of VTE recurrence in the DOAC Era, which might suggest that there could be no major concerns on an increased risk of recurrent VTE with oral steroids after VTE diagnosis under appropriate anticoagulation therapy.

Clinical outcomes of edoxaban treatment in atrial fibrillation patients with high bleeding risk: insights from the ETNA-AF-China 1-year follow-up

Abstract Background In China and many other countries, anticoagulated atrial fibrillation (AF) patients with high bleeding risk often raises clinical concern; the optimal dose of direct oral anticoagulants (DOACs) preventing stroke/systemic embolic events (SEE) in those population remains unclear. Purpose To assess the effectiveness and safety of edoxaban treatment in Chinese AF patients with high bleeding risk, and to compare 60 mg vs 30 mg dose in this real-world registry. Methods ETNA-AF-China is a prospective, observational study conducted in 89 centres across Chinese Mainland enrolling AF patients receiving edoxaban. This subgroup analysis was based on 1-year follow-up data. Patients were categorized to high bleeding risk group who had a DOAC score ≥6 (age, creatinine clearance, underweight, history of stroke/TIA/SEE, diabetes, hypertension, antiplatelet use, NSAIDs use, history of major/critical bleeding, liver disease) at baseline, or moderate-to-low bleeding risk group meeting criteria of DOAC score &amp;lt;6. The safety, effectiveness, and composite outcomes were reported by comparison between patient subgroups using Cox proportional hazards models. Results Of 4883 patients with 1-year follow-up, 1534 (31.4%, 60 mg: n=518, 30 mg: n=1016) were identified as high bleeding risk and 3349 (68.6%) as moderate-to-low bleeding risk. As expected, patients with high bleeding risk were more often elderly (48.2% ≥80 years), had lower body weight, worse renal function, higher CHA2DS2-VASc score than those with moderate-to-low risk (Figure 1). In both high risk and moderate-to-low risk subgroups, patients receiving 60 mg edoxaban were younger, with better renal function, lower CHA2DS2-VASc score compared with 30 mg. Annualised event rates of major bleeding (HR 2.95, 95%CI 1.62–5.36), all cause death (3.42, 2.29–5.09), CV death (3.27, 1.52–7.04), major adverse cardiac events (MACE, 2.61, 1.69–4.02) and all NCOs were significant higher in patients with high bleeding risk compared with moderate-to-low risk (Figure 2). After multivariable adjustment, edoxaban dose of 60 mg other than 30 mg were associated with significantly lower rates of all cause death (adjusted HR 0.41, 0.18–0.90) and lower trend of NCO3 (0.51, 0.28–0.92) and NCO4 (0.51, 0.30–0.88) by composite of stroke/SEE, major bleeding and death events in high risk subgroup; no significant difference between edoxaban doses and stroke or bleeding outcomes with cumulative low event rates were observed. Conclusion In routine clinical care, AF patients at high bleeding risk faces worse outcomes of death events, MACE, as well as the composite outcomes over moderate-to-low risk patients. Among patients with high bleeding risk, edoxaban use showed effectiveness and safety with overall low incidence, and potential better survival, composite endpoint benefit could be associated with 60mg. Further investigation is ongoing.