Direct Oral Anticoagulants Research Articles

Comparative Safety and Effectiveness of Heparin vs. Direct Oral Anticoagulants in Patients with Cirrhosis and ESKD

Comparative Safety and Effectiveness of Heparin vs. Direct Oral Anticoagulants in Patients with Cirrhosis and ESKD

Incidence and long-term outcomes of upper limb deep vein thrombosis associated with intracardiac devices: analysis of bleeding, recurrence, and sequelae.

Pacemakers (PM) and implantable cardioverter-defibrillators are vital devices in contemporary clinical practice, but their growing adoption poses challenges. Complications, including lead migration, infections, and post-implantation venous thrombosis, underscore the importance of comprehensive investigation. This retrospective observational study enrolled patients diagnosed with upper limb deep vein thrombosis (DVT) secondary to intracardiac devices at a tertiary hospital from 2015 to 2022. The aim of the study was to determine the incidence and long-term outcomes (bleeding, DVT recurrence and sequelae) in these patients. Across the study period, 2681 intracardiac devices were implanted, with 12 cases of upper limb DVT documented. The majority of patients were male (91.7%), with a mean age of 63.92 years. DVT occurred in patients with PM (50%), implantable cardioverter-defibrillators (25%) and implantable cardioverter-defibrillators with Cardiac Resynchronization Therapy (25%). Treatment encompassed low-molecular-weight heparin (91.7%) during the acute episode and long-term anticoagulation with direct oral anticoagulants (75%) or vitamin K antagonists (25%). Over a mean follow-up period of 33.17 months, half of the patients exhibited long-term sequelae, notably collateral circulation (66.7%). Remarkably, no thrombosis recurrences were observed during follow-up. However, one patient (8.3%) experienced a major bleeding event during treatment, and one patient (8.3%) required device removal (PM) due to persistent symptoms. This study revealed upper limb DVT occurred in 0.45% of patients after intracardiac device implantation. Rate of thrombosis recurrence was low during follow-up. Although half of the patients developed long-term sequelae, the need for prolonged anticoagulant therapy in these cases remains uncertain.

Ten tips to manage oral anticoagulation in hemodialysis patients with atrial fibrillation

ABSTRACT Patients with chronic kidney disease (CKD) have a high incidence and prevalence of atrial fibrillation (AF). While general treatment strategies for AF may largely be transferred to patients with mild to moderate CKD, patients with advanced CKD—particularly hemodialysis (HD) patients—with AF pose substantial therapeutical challenges to cardiologists and nephrologists. The arguably greatest dilemma is the very limited evidence on appropriate strategies for prevention of stroke and systemic embolism in HD patients with AF, since the risk for both thromboembolic events without oral anticoagulation and severe bleeding events with oral anticoagulation are substantially increased in advanced CKD, compared with the general population. Thus, the benefit to risk ratio of either vitamin K antagonists or direct oral anticoagulants is less evident in HD than in non-CKD patients with AF. As a multidisciplinary panel of clinicians, we here propose 10 tips that may help our colleagues to navigate between the risk of undertreatment—exposing CKD patients with AF to a high stroke risk—and overtreatment—exposing the very same patients to a prohibitively high bleeding risk. These tips include ideas on alternative risk stratification strategies and novel treatment approaches that are currently in clinical studies—such as factor XI inhibitors or left atrial appendage closure—and may become game-changers for HD patients with AF.

The anticoagulant effects of milvexian, a novel small molecule factor XIa inhibitor, are neutralized by activated prothrombin complex concentrates and recombinant factor VIIa in human plasma and whole blood in vitro

BackgroundThe development of anticoagulants that provide antithrombotic efficacy without a concomitant bleeding risk remains an unmet clinical need in thrombosis. Although direct oral anticoagulants (DOACs) have a reduced incidence of major bleeding compared with warfarin, they still carry a bleeding risk, resulting in a suboptimal therapeutic index. Epidemiologic data suggest that inhibiting activated factor (F)XI may offer an improved safety profile with respect to bleeding risk compared with current-generation DOACs. Additionally, a phase II trial of milvexian in patients undergoing elective total knee replacement demonstrated robust dose-dependent efficacy with no statistically significant increase in bleeding. Nevertheless, the ability to rapidly and effectively correct FXIa inhibitor–induced anticoagulation may still be important in situations where patients experience uncontrolled bleeding or require emergency surgery. ObjectivesWe assessed the ability to normalize the anticoagulant effects of the novel small molecule FXIa inhibitor milvexian (BMS-986177/JNJ-70033093) in vitro using commercially available prohemostatic agents. MethodsMilvexian-associated anticoagulation and correction was evaluated in activated partial thromboplastin time clotting assays, thromboelastography, and kaolin-initiated thrombin generation assays. ResultsActivated prothrombin complex concentrates (PCCs) and recombinant factor (rF)VIIa corrected the anticoagulant effects of milvexian in activated partial thromboplastin time clotting assays, thromboelastography, and kaolin-initiated thrombin generation assays. In contrast, other agents including PCCs, rFIX, and rFVIII demonstrated either modest or no correction of milvexian-associated anticoagulation. ConclusionThis study demonstrated that currently available activated PCCs and rFVIIa normalize anticoagulation induced by milvexian in vitro. The clinical utility of these agents remains to be established.

Comparative Effectiveness and Safety of Direct Oral Anticoagulants vs Warfarin among Nursing Home Residents with Atrial Fibrillation: A Retrospective Cohort Study

ObjectiveResidents of nursing homes are usually excluded from clinical trials, including trials to assess treatments for common conditions such as nonvalvular atrial fibrillation (NVAF). We aimed to quantify the real-world comparative safety and effectiveness of direct-acting oral anticoagulants (DOACs) vs warfarin among nursing home residents with NVAF. DesignRetrospective cohort study using 100% national Minimum Data Set and linked Medicare claims from January 2011 through December 2018. Setting and ParticipantsLong-term care nursing home residents aged ≥66 years enrolled in fee-for-service Medicare. We included individuals diagnosed with NVAF newly initiating oral anticoagulants. MethodsWe identified exposure to DOACs (apixaban, dabigatran, rivaroxaban, and edoxaban) vs warfarin. Outcomes were hospitalization for ischemic stroke/systemic embolism, major bleeding, pneumonia (negative control outcome), and all-cause death. We used inverse probability of treatment weighting competing risk regression models for clinical outcomes and Cox proportional hazards regression for all-cause death. ResultsOf 38,983 individuals newly initiating anticoagulants, 19,366 (49.7%) initiated DOACs and 19,617 (50.3%) initiated warfarin. In the inverse probability of treatment weighting analysis, compared with warfarin, there was no statistically significant association between DOAC use and ischemic stroke/systemic embolism [4.5 vs 4.7 events per 100 person-years; adjusted hazard ratio (aHR), 0.94; 95% CI, 0.84–1.05] or major bleeding (12.6 vs 12.4 events per 100 person-years; aHR, 1.03; 95% CI, 0.96–1.10). DOACs use was associated with a modest but statistically significant lower risk of all-cause death (48.1 vs 49.0 events per 100 person-years; IPTW analysis aHR, 0.95; 95% CI, 0.91–0.98). Conclusions and ImplicationsAmong nursing home residents with NVAF, DOACs and warfarin were associated with a similar risk of ischemic stroke/systemic embolism and major bleeding. However, the use of DOACs was associated with a slightly reduced risk of all-cause mortality.

Direct oral anticoagulant approvals by four major regulatory agencies: a cross-sectional analysis of premarket and postmarket evidence

ObjectivesTo compare the premarket and postmarket evidence of safety and efficacy of direct oral anticoagulants approved for stroke prevention in atrial fibrillation patients across four major regulatory agencies.DesignCross-sectional.SettingEuropean Medicines Association...

Safety and efficacy of direct oral anticoagulants in chronic kidney disease: a meta-analysis

BackgroundDirect oral anticoagulants (DOACs) have emerged as the first-line therapy for venous thromboembolism and stroke prophylaxis in atrial fibrillation. As DOACs are partially excreted renally, their safety in patients with chronic kidney disease (CKD) is unclear. ObjectivesTo synthesize primary evidence on the safety profile of DOACs in patients with CKD. MethodsWe searched MEDLINE and Embase from inception to June 2023 for randomized and nonrandomized cohort studies comparing DOACs with vitamin K antagonists (VKAs) in CKD patients. Screening and data collection were conducted in duplicate. The primary safety outcome was major bleeding, defined by International Society on Thrombosis and Haemostasis criteria, stratified by CKD severity. Meta-analysis was done using the Mantel–Haenszel random-effects model, presented as odds ratios (ORs) with corresponding 95% CIs. ResultsOf the 2355 articles captured in the literature search, 25 nonrandomized studies (n = 6832) and 6 randomized studies (n = 66,898) were included. DOACs reduced major bleeding compared with VKAs in all subgroups (stage 4: OR, 0.73; 95% CI, 0.58, 0.93; stage 5/renal replacement therapy: OR, 0.70; 95% CI, 0.50, 0.98; stage unspecified: OR, 0.72; 95% CI, 0.63, 0.83). Apixaban and rivaroxaban both reduced major bleeding in stage 5/renal replacement therapy patients (apixaban: OR, 0.66; 95% CI, 0.52, 0.85; rivaroxaban: OR, 0.58; 95% CI, 0.35, 0.94). ConclusionIn this meta-analysis, DOACs reduced major bleeding compared with VKAs in stage 4, stage 5/renal replacement therapy, and CKD stage unspecified patients. Future analysis should evaluate the impact of specific DOACs and dosage on safety and efficacy in this population.

Knowledge, Attitudes, and Practices of Prescribing Doctors Towards Direct Oral Anticoagulants: First Cross-sectional Study from Sudan

Background: During recent years, the prescription rates of direct oral anticoagulants (DOACs) have increased rapidly worldwide. Little is known about situation of DOACs in Sudan. Therefore, this study was conducted to assess prescribing doctors’ knowledge, attitude, and practice level regarding DOACs. Methods: A cross-sectional, hospital-based study was conducted at three large hospitals in Khartoum, Sudan. The doctors were recruited from a wide range of disciplines such as cardiology, surgery, and nephrology. A four-section questionnaire consisting of questions on demographics, knowledge, attitude, and practice was designed and administered. Results: A total of 100 doctors responded over a period of four months, 52% of them were found to correlate with a low level of knowledge. Moreover, 56% and 81% of the doctors demonstrated inappropriate attitude and practice levels, respectively. With regard to switching protocols between DOACs and warfarin, the majority of the doctors did not have sufficient information when converting from rivaroxaban to warfarin and vice versa. Conclusion: The overall knowledge, attitudes, and practices of prescribing doctors regarding the use of the DOACs were found to be inadequate and insufficient for maintaining high therapeutic outcomes in patients necessitating anticoagulants agents. A well-structured educational program about DOACs is urgently needed.

Comparison of Oral Anticoagulants vs. Warfarin for Stroke Prevention in Atrial Fibrillation: A Meta-Analysis

Background: Atrial fibrillation (AF) significantly increases the risk of ischemic stroke, necessitating effective anticoagulation therapy. Warfarin has been the standard treatment, but direct oral anticoagulants (DOACs) have emerged as a safer and more effective alternative.Objective: To compare the efficacy and safety of DOACs versus warfarin in stroke prevention among AF patients.Methods: A comprehensive literature search was conducted in PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus following PRISMA guidelines. Randomized controlled trials and observational studies comparing DOACs (dabigatran, rivaroxaban, apixaban, edoxaban) with warfarin in AF patients were included. Primary outcomes were ischemic stroke or systemic embolism, and secondary outcomes included all-cause mortality, major bleeding, intracranial hemorrhage (ICH), and gastrointestinal bleeding. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a random-effects model.Results: A total of 35 studies involving 172,350 patients were analyzed. DOACs significantly reduced ischemic stroke or systemic embolism (HR: 0.78, 95% CI: 0.72–0.84, p < 0.001) and all-cause mortality (HR: 0.85, 95% CI: 0.79–0.92, p = 0.002). Major bleeding risk was lower (HR: 0.88, 95% CI: 0.80–0.96, p = 0.005), but gastrointestinal bleeding was higher (HR: 1.20, 95% CI: 1.10–1.30, p < 0.001).Conclusion: DOACs provide superior efficacy and safety in stroke prevention compared to warfarin, despite a higher risk of gastrointestinal bleeding.

Selection of Home Treatment and Identification of Low-Risk Patients With Pulmonary Embolism Based on Simplified Pulmonary Embolism Severity Index Score in the Era of Direct Oral Anticoagulants.

The simplified Pulmonary Embolism Severity Index (sPESI) score could help identify low-risk patients with pulmonary embolism for home treatment. However, the application of the sPESI score and selection for home treatment have not been fully evaluated in the direct oral anticoagulants era. The COMMAND VTE (Contemporary Management and Outcomes in Patients With Venous Thromboembolism) Registry-2 is a multicenter registry enrolling consecutive patients with acute symptomatic venous thromboembolism. The current study population consists of 2496 patients with hemodynamically stable pulmonary embolism (2100 patients [84%] treated with direct oral anticoagulants), who were divided into 2 groups: sPESI scores of 0 and ≥1. We investigated the 30-day mortality, home treatment prevalence, and factors predisposing to home treatment using the Kaplan-Meier method and logistic regression model. Patients with an sPESI score of 0 accounted for 612 (25%) patients, and only 17% among 532 patients with out-of-hospital pulmonary embolism were treated at home. The cumulative 30-day mortality was lower in patients with an sPESI score of 0 than the score of ≥1 (0% and 4.8%, log-rank P<0.001). There was no patient with 30-day mortality with an sPESI score of 0. Independent factors for home treatment among out-of-hospital pulmonary embolism patients with an sPESI score of 0 were no transient risk factors for venous thromboembolism, no cardiac biomarker elevation, and direct oral anticoagulants use in the acute phase. The 30-day mortality rate was notably low in an sPESI score of 0. Nevertheless, only a minority of patients with an sPESI score of 0 were treated at home between 2015 and 2020 after the introduction of direct oral anticoagulants for venous thromboembolismin Japan.

Pulmonary Embolism and Right Ventricular Dysfunction: Mechanism and Management.

Pulmonary embolism (PE) occurs when thrombi from deep vein thrombosisdislodge and obstruct pulmonary arteries, raising pulmonary artery pressure and straining the right ventricle. This strain can lead to right ventricular dysfunction (RVD), characterized by reduced cardiac output, impaired contractility, and potential development of chronic thromboembolic pulmonary hypertension. Clinically, PE may present with symptoms such as dyspnea, pleuritic chest pain, and tachycardia. Diagnosis is typically confirmed through computed tomography pulmonary angiography, biomarkers like D-dimer and cardiac troponins, and clinical scoring systems. Acute management focuses on hemodynamic support, including intravenous fluids and vasopressors, and may involve anticoagulation with low-molecular-weight heparin or direct oral anticoagulants. Severe cases may require systemic anticoagulation, catheter-directed techniques, and surgeries like pulmonary endarterectomy. Long-term management involves continued anticoagulation tailored to individual risk factors, with ongoing monitoring to prevent recurrence. Effective early diagnosis and management are crucial, as severe PE can significantly increase mortality and lead to serious complications. This review explores the pathophysiology, diagnosis, and management of PE and RVD.

Assessing Direct Oral Anti-Coagulant And Therapeutic Low Molecular Weight Heparin Prescriptions At A University Teaching Hospital

Abstract Background A 2017-2018 survey identified anti-thrombotics as the most commonly implicated agents in reported medication incidents across Irish acute hospitals [State Claims Agency, 2020, Medication Incidents Report (2017-2018)]. Of the top 10 anti-thrombotics reported, 2 were Low Molecular Weight Heparins (LMWHs) and 3 were Direct Oral Anti-Coagulants (DOACs). 3 years after the survey results were published, we audited our hospital's compliance with the Health Service Executive's guidelines for prescribing DOACs and LMWHs. Methods Over 3 consecutive weeks, data was collected by doctors and clinical pharmacists across 6 wards and the intensive and coronary care units. In-patients on a DOAC or therapeutic LMWH were chosen for kardex and laboratory result review. Results 83 patients were included. The average age was 79 years. 81%(n=67) were on a DOAC. 91% were being treated for non-valvular atrial fibrillation (NVAF), 3% for pulmonary embolism (PE), 3% for deep vein thrombosis and 3% had no indication documented. 33%(n=22) had indications for dose reduction but only 77%(n=17) of them were prescribed the appropriate reduced dose. 3%(n=2) had no dose reduction indications but were inappropriately prescribed a reduced dose. 3%(n=2) were on dialysis, 1%(n=1) had their creatinine clearance persistently below 15ml/min and 1%(n=1) inappropriately received once daily dosing of apixaban for 3 days. 19%(n=16) of all participants were on therapeutic LMWH. Treatment indications included acute coronary syndrome in 63%, suspected PE in 19%, newly diagnosed NVAF in 6% and bridging anti-coagulation while a DOAC is temporarily held in 13%. 6%(n=1) were inappropriately prescribed an under-dose. Conclusion Overall, there was an error rate of 16%(n=11) in DOAC prescriptions and 6%(n=1) in LMWH prescriptions. To address this, we propose an educational intervention for prescribers and the introduction of e-prescriptions with built-in alerts for errors. We plan to re-audit once these recommendations are implemented.

Retracted: Risk of Haemorrhage Associated with Direct Oral Anticoagulation Versus Anti-platelet Therapy: A Systematic Review and Meta-Analysis

Abstract Background Among patients with atrial fibrillation, clinicians often prescribe anti-platelet therapy rather than oral anticoagulation which may relate to a concern that direct oral anticoagulants (DOAC) are associated with a higher risk of bleeding. We completed a meta-analysis to determine whether DOAC therapy, compared to single anti-platelet, was associated with an increased risk of major haemorrhage, with a primary focus on intracranial haemorrhage (ICH). Methods We searched PubMed and Embase databases up to 7/2/2024. Randomised controlled trials (RCT) that compared DOAC therapy to single anti-platelet agents were included. Trials with follow-up less than 30 days, or sample size less than 200 were excluded. A random-effects meta-analysis model was used to report pooled treatment effects and 95% confidence intervals (CIs). The primary outcome was occurrence of ICH. Results A total of 9 RCTs were included (n=45,493). Overall, DOAC therapy was not associated with significantly higher odds of ICH compared to anti-platelet therapy (Odds ratio (OR) 1.14; 95% CI, 0.71-1.82), but there was heterogeneity among trials (I2 = 49.3). In an analysis by DOAC agent, the respective estimates for ICH risk were; Rivaroxaban (OR 2.05; 95% CI, 1.09-3.83); Dabigatran (OR 1.00; 95% CI, 0.61-1.64) and Apixaban OR 0.72; 95% CI, 0.44-1.17). DOAC therapy was associated with higher odds of major haemorrhage compared to aspirin (OR 1.39; 95% CI,1.07-1.80), with the following estimates by agent; Rivaroxaban (OR 1.91; 95% CI 1.22-3.00); Dabigatran (OR 1.21; 95% CI 0.86-1.69); Apixaban OR 1.09; 95% CI 0.73, 1.63). DOAC therapy was associated with higher odds of GI haemorrhage then control (OR 1.39; 95% CI,1.11, 1.73). Conclusion DOAC therapy was not associated with a significantly higher risk of ICH compared to anti-platelet therapy, but risks may differ among DOAC agents. DOAC therapy was associated with a higher risk of major haemorrhage, mostly related to GI haemorrhage.

Safety of Sofosbuvir-Based Direct-Acting Antivirals for Hepatitis C Virus Infection and Direct Oral Anticoagulant Co-Administration.

Background: Direct oral anticoagulants (DOACs) are recommended for the management of thrombosis prophylaxis, especially in patients with atrial fibrillation. As substrates of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein, they are implicated in potential drug-drug interactions. NS5A/NS5B inhibitors are direct-acting agents (DAAs) against the Hepatitis C Virus (HCV) infection that exert a mild inhibition of P-glycoprotein without effects on CYP3A4. A DOAC and NS5A/NS5B inhibitor co-administration may lead to an increased risk of bleeding. Real-world data on the concomitant use of DOACs and DAAs are scarce. On this purpose, we perform a retrospective analysis on the risk of vascular adverse events (bleeding and thrombosis) among HCV patients under DOAC/DAA therapy, even in advanced liver disease. Methods: Between May 2015 and April 2023, patients treated with sofosbuvir-based DAA regimens and DOACs were consecutively included in this study from 12 Italian medical centers. Baseline characteristics, especially concerning bleeding risk and liver function, were collected. The occurrence of bleeding events, classified as major and minor, was the primary endpoint. Secondary endpoints were the rate of any thrombotic events and/or the need for discontinuation of one or both treatments. Moreover, a cohort of patients, matched by demographic characteristics (age and sex), that switched to vitamin K antagonists (VKAs) during the antiviral treatment was compared with the DOAC/DAA group. Results: A total of 104 patients were included. Thirty-eight of them (36.5%) were cirrhotic. Atrial fibrillation was an indication for anticoagulation in almost all cases (76%). Rivaroxaban (35.6%) was the most used DOAC, followed by apixaban (26.9%), dabigatran (19.2%) and edoxaban (18.3%). Sofosbuvir/velpatasvir (78.8%) was the most prescribed DAA, and all patients were already on anticoagulant therapy before the start of DAAs. During concomitant DOAC/DAA treatment, no major bleeding events were recorded, while four minor bleeding events occurred, but none resulted in DAA or DOAC discontinuation. At univariate analysis, the only additional risk factor statistically related to bleeding events was the anticoagulant therapy (hazard ratio [HR]: 13.2, 95% confidence interval 1,6-109). Performing an evaluation by a LOGIT binomial analysis with demographic characteristics, the antiplatelet therapy remained statistically associated to bleeding events. No significant differences were found in the rate of clinically relevant bleeding when the main population was compared with the VKA-switched cohort. A single major bleeding event leading to anticoagulation and DAA discontinuation was reported in VKA-switched matched cohort. Conclusions: In our study, the concomitant use of NS5A/NS5B inhibitors with DOAC showed good safety, and the only risk factor associated with bleeding events was the concomitant antiplatelet therapy. These findings support the use of DOACs during sofosbuvir-based HCV treatment, even in advanced liver disease. Replacing DOACs with VKAs does not appear to be of clinical benefit.

Overview and Future Direction of Embolic Stroke of Undetermined Source from the Insights of CHALLENGE ESUS/CS Registry.

Cryptogenic stroke (CS) accounts for approximately one-fourth of acute ischemic strokes, with most cases derived from embolic etiologies. In 2014, embolic stroke of undetermined source (ESUS) was advocated and the efficacy of anticoagulant therapy was anticipated. However, 3 large-scale clinical trials failed to demonstrate the superiority of direct oral anticoagulants (DOACs) over aspirin, potentially due to the heterogeneous and diverse pathologies of ESUS, including paroxysmal atrial fibrillation (AF), arteriogenic sources such as nonstenotic carotid plaque and aortic complicated lesion (ACL), patent foramen oval (PFO), and nonbacterial thrombotic endocarditis (NBTE) related to active cancer.Transesophageal echocardiography (TEE) is one of the most effective imaging modalities for assessing embolic sources in ESUS and CS. The Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke (CHALLENGE ESUS/CS) registry is a multicenter registry that enrolled consecutive patients with CS who underwent TEE at 8 hospitals in Japan between April 2014 and December 2016. Their mean age was 68.7±12.8 years, and 455 patients (67.2%) were male. The median National Institutes of Health Stroke Scale (NIHSS) score was 2. Since 7 analyses have been conducted from each institution to date, novel and significant insights regarding embolic origins and pathophysiologies of ESUS and CS were elucidated from this multicenter registry. This review discusses the diagnosis and treatment of ESUS and CS, tracing their past and future directions. Meaningful insights from the CHALLENGE ESUS/CS registry are also referenced and analyzed.

Medical Management of Acute Stroke based on Japan Stroke Society Guidelines and the Japan Stroke Data Bank.

Stroke is a leading cause of death and disability in Japan, necessitating standardized treatment guidelines. The Japan Stroke Society (JSS) periodically revises its guidelines to incorporate new research. This review provides a short overview of acute stroke management based on JSS Guideline 2021 (revised 2023) and the Japan Stroke Data Bank (JSDB), and discusses future directions in stroke management. Acute stroke management emphasizes systemic support and complication management. Risk factor control during acute hospitalization is also crucial for preventing recurrent strokes in the chronic phase.In ischemic stroke, super-acute recanalization therapies, including intravenous thrombolysis and mechanical thrombectomy, are the most important and effective. Antiplatelet therapy, particularly aspirin and clopidogrel, is recommended for noncardiogenic stroke and high-risk transient ischemic attack. In cardioembolic stroke, early initiation of direct oral anticoagulants might be considered according to stroke severity.For brain hemorrhage, early blood pressure management is recommended. Specific reversal agents are advised for patients on anticoagulant therapy. Minimally invasive hematoma removal may improve outcomes for intracerebral hemorrhage.Subarachnoid hemorrhage treatments reported from Japan include intravenous drugs to prevent vasospasm.The JSDB revealed improvements in functional outcomes in patients with ischemic stroke over the past 20 years, although patients with hemorrhagic stroke showed no clear improvement. The evolving guidelines and research underscore the importance of stratified and timely intervention in stroke care.

Antithrombotic Strategies After Transcatheter Aortic Valve Replacement in Patients Without an Indication of Oral Anticoagulants: A Network Meta-Analysis of Randomized Controlled Trials.

Single-antiplatelet therapy (SAPT) has been a standard of care posttranscatheter aortic valve replacement with no clear evidence exist using direct oral anticoagulants (DOACs), vitamin K antagonists (VKA), or dual antiplatelet agents (DAPT); thus we aim to compare the safety and efficacy of the various antithrombotic strategies after transcatheter aortic valve replacement. We performed a network meta-analysis using a frequentist framework, pooling dichotomous outcomes using risk ratio (RR), and continuous data using mean difference, along with the corresponding 95% confidence interval (CI). Nine randomized controlled trials with 4193 patients were included, 567 patients were in the VKA group, 591 patients in the SAPT group, 1571 patients in the DAPT group, and 1464 patients in the DOACs group. Only DOAC showed a statistically significant higher risk of all-cause mortality [RR of 1.88 (95% CI: 1.07-3.28)] with no statistically significant difference between our arms in terms of mortality. For minor bleeding, DAPT had a significant higher risk with RR of 1.53 (95% CI: 1.04-2.25), while for major bleeding, DAPT and DOAC had a significant higher risk with RR of 2.36 (95% CI: 1.27-4.40) and 4.74 (95% CI: 2.05-10.92), respectively. There was no significant difference in terms of stroke and life-threatening bleeding. Moreover, only DOAC showed a significantly lower risk for valve thrombosis, when compared to other strategies [RR: 0.24 (95% CI: 0.13-0.46)]. Overall, SAPT had lower major bleeding events compared to other arms. There were no differences in the outcomes of stroke, myocardial infarction, or life-threatening bleeding outcomes. However, DOACs significantly reduced valve thrombosis compared to VKAs.

A new strategy for monitoring of direct oral anticoagulants in patients with cyanotic and complex congenital heart disease

BackgroundPatients with congenital heart disease (CHD) often require an oral anticoagulation. Vitamin K antagonists (VKA) are the standard treatment, however, an increased hematocrit in patients with secondary erythrocytosis due to cyanosis complicates the correct measurement of the international normalized ratio. Direct oral anticoagulants (DOAC) could be an alternative, but data on their efficacy and safety in complex and cyanotic CHD patients are scarce. This study proposes a new strategy of DOAC monitoring in these patients using D-dimers and DOAC trough levels. MethodsThis is a retrospective study including cyanotic and complex CHD patients requiring oral anticoagulation. Clinical, cardiac imaging and laboratory data were collected before and after start of DOAC. The new monitoring strategy consists of determination of D-dimers and DOAC trough levels at 1–4 weeks, 1–6 months, 6–12 months, >1 year after start of DOAC. ResultsEleven patients were included. For 10 patients D-dimers and DOAC trough levels were in target range. In one patient, D-dimers increased continuously after start of DOAC despite dose escalation, suggesting insufficient DOAC efficacy and finally requiring a switch to VKA. D-dimers subsequently decreased under VKA to the therapeutic range. In three patients, one thromboembolic and two minor bleeding complications occurred. No major complications were observed. ConclusionsWe propose a new strategy of monitoring of oral anticoagulation with DOAC and report its implementation in clinical routine. Highlighting the importance of pharmacokinetic and -dynamic monitoring, this strategy could improve safety and efficacy of DOAC in cyanotic and complex CHD which, however, requires a prospective validation.

Challenges in laboratory testing of patients suspected of antiphospholipid syndrome: practical implications for clinicians.

This paper focuses on the laboratory tests necessary for the diagnosis of antiphospholipid syndrome (APS). Diagnosis starts with the selection of patients suspicious of having APS. The timing related to the clinical event is important to avoid false classification of APS patients. For the interpretation of the test results of antiphospholipid antibodies (aPL) understanding of all pitfalls and interferences is necessary. Lupus anticoagulant (LA) measurement remains a complex procedure with many pitfalls and interferences. The effect of anticoagulant therapy, the main confounder of LA measurement, can be overcome by removal agents for direct oral anticoagulants (DOAC) or by considering assays as Taipan snake venom time / Ecarin clotting time not affected by antivitamin K therapy and anti-Xa DOAC. However, both procedures have limitations. Solid-phase assays for anticardiolipin antibodies (aCL) and anti-β2-glycoprotein 1 antibodies (aβ2GPI) show inter-assay differences. Diagnosis is based on the measurement of three groups of aPL: LA, aCL and aβ2GPI, of IgG and IgM isotype. This allows to make antibody profiles that helps in identifying patients at risk. Other aPL, such as antibodies against the domain I of β2GPI and anti-phosphatidylserine-prothrombin antibodies may be useful in risk stratification of APS patients and in some specific situations of patients with incomplete antibody profile, but are not needed for diagnosis. Laboratory diagnosis of APS remains challenging. To increase the diagnostic efficacy and reliability, an integrated interpretation of all results and an interpretative comment should be provided on the laboratory report. Therefore, a close interaction between clinical pathologists and clinicians is mandatory.

Thrombin generation to evaluate the complex hemostatic balance of hemophilia A plasma containing direct oral anticoagulant and supplemented by factor VIII

BackgroundThe incidence of cardiovascular diseases is increasing in persons with hemophilia A (HA). Therefore, anticoagulant therapy based on direct oral anticoagulants (DOACs) may be needed, despite the bleeding risk. In case of surgery or bleeding, such patients may be concomitantly treated with emicizumab (routine prophylaxis), factor (F)VIII products, and DOAC. Their concomitant presence constitutes a hemostatic challenge. Recent international guidelines stated that data are scarce on the hemostatic balance of plasma samples from patients with HA receiving emicizumab and DOAC. ObjectivesThe aim of this observational study was to assess the coagulation of FVIII-deficient plasma spiked with DOAC and emicizumab and to evaluate the effects of FVIII addition. MethodsProthrombin time, activated partial thromboplastin time, and thrombin generation (TG) using the calibrated automated thrombogram method were evaluated in aliquots of a commercial severe HA plasma supplemented with emicizumab (0, 12.5, 25, 50, and 100 ng/mL), DOAC (0, 50, 100, 200, and 400 ng/mL of apixaban, rivaroxaban, edoxaban, or dabigatran) and FVIII (0%, 5%, 15%, 50%, and 100%). ResultsDOAC rapidly induced a TG decrease. Emicizumab could counter this effect only for the lowest DOAC dose. FVIII addition to the FVIII-deficient plasma containing a DOAC and emicizumab improved TG and countered the anticoagulant effect of DOAC at ≤100 ng/mL. ConclusionOur findings indicate that FVIII can be safely used with emicizumab to counter the anticoagulant effect of DOAC at ≤100 ng/mL. The TG assay is an efficient tool to monitor plasma containing anti-FXa DOAC, but not dabigatran (anti-FIIa).