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Background: The Direct Oral Anticoagulant (DOAC) Score can predict bleeding risk in patients with atrial fibrillation taking DOACs; however, it lacks external validation. Therefore, this study aimed to assess the association between the DOAC Score and bleeding events in patients with atrial fibrillation who underwent transcatheter aortic valve replacement., Methods and Results: This retrospective multicenter cohort study included patients with atrial fibrillation who underwent transcatheter aortic valve replacement, as registered in a Japanese multicenter registry. The primary end point was the incidence of bleeding. Patients were categorized based on their DOAC Score: low and moderate- (≤7 points), high- (8-9 points), and very high-risk (≥10 points) groups. Among 1230 patients (mean age 84.6±5.1 years; 457 men), 465 (37.8%) received a vitamin K antagonist, and the remaining patients received DOACs. The low and moderate-, high-, and very high-risk groups included 380 (30.1%), 497 (40.4%), and 353 patients (28.7%), respectively. The 3-year cumulative incidence of all bleeding events was significantly different among the 3 groups (low and moderate risk: 6.6%, high risk: 6.9%, and very high risk: 14.0%; P <0.01). Multivariable Cox regression analysis revealed that significant increments in the DOAC Score were associated with a risk of all bleeding events at 3 years in the overall cohort (hazard ratio [HR], 1.22 [95% CI, 1.08-1.38]; P <0.01), in the DOAC cohort (HR, 1.20 [95% CI, 1.01-1.42]; P =0.04), and in the vitamin K antagonist cohort (HR, 1.25 [95% CI, 1.04-1.50]; P =0.02)., Conclusions: The DOAC Score was significantly associated with bleeding events in patients with atrial fibrillation after transcatheter aortic valve replacement, aiding in clinical decision-making for anticoagulant management., Registration: URL: https://center6.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000023585; Unique identifier: UMIN000020423.

Background: This study investigated drug-drug interactions in patients with atrial fibrillation taking both a direct oral anticoagulant (DOAC) and an antiarrhythmic drug., Methods and Results: Using data from the National Health Insurance database (2012-2018), we identified 78 805 patients with atrial fibrillation on DOACs, with 24 142 taking amiodarone, 8631 taking propafenone, 2784 taking dronedarone, 297 taking flecainide, 177 taking sotalol, and 42 772 on DOACs alone. Patients with bradycardia, heart block, heart failure, mitral stenosis, prosthetic valves, or incomplete data were excluded. Propensity score matching compared those taking both DOACs and antiarrhythmic drugs with those on DOACs alone. There was an increased risk of major bleeding in patients concomitantly taking DOACs with amiodarone when compared with matched patients taking DOACs alone (hazard ratio [HR],1.13 [95% CI, 1.04-1.23]; P =0.0044), particularly in patients taking dabigatran (HR, 1.19 [95% CI, 1.03-1.38]; P =0.0175). No significant difference in bleeding risk was found for propafenone, dronedarone, flecainide, or sotalol. The small sample sizes in the flecainide and sotalol groups limit interpretation. Notably, intracranial bleeding risk was higher in patients on DOACs and amiodarone, regardless of age. Additionally, patients <80 years old taking dabigatran with amiodarone or propafenone had a higher risk of gastrointestinal bleeding., Conclusions: Concomitant use of DOACs with amiodarone, but not dronedarone or propafenone, increases the risk of major bleeding, particularly intracranial bleeding. This study provides new evidence to guide clinicians to tailor concomitant anticoagulation and antiarrhythmic therapy for patients with atrial fibrillation.

Source Citation: Lopes RD, Granger CB, Wojdyla DM, et al. Apixaban vs aspirin according to CHA 2 DS 2 -VASc score in subclinical atrial fibrillation: insights from ARTESiA. J Am Coll Cardiol. 2024;84:354-364. 39019530., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Objective: The incidence of splanchnic vein thrombosis (SVT) is reported to be <25 times lower than that of deep vein thrombosis and pulmonary emboli, which occur in 70 to 270/100,000 cases in the general population. Current guidelines recommend initial treatment with therapeutic low-molecular-weight heparin followed by a transition to a vitamin K antagonist (VKA) or a direct oral anticoagulant (DOAC) in patients with cirrhosis who develop SVT without severe liver dysfunction. This, however, is based on observational data. This study aimed to evaluate the efficacy and safety of anticoagulant therapy in patients with cirrhosis who present with SVT and receive either a DOAC or a VKA., Methods: This multicenter retrospective cohort study was conducted from December 2021 to November 2022. Patients between the ages of 18 and 75 years with cirrhosis and acute SVT who received either a VKA or a DOAC between July 2019 and July 2021 were eligible for inclusion. The primary outcome was the efficacy of treatment, defined as a new thrombotic event. The secondary outcome was the safety of treatment, defined as the development of major bleeding. Readmission data were followed up at 6 and 10 months. Bivariate analysis was conducted to assess the relationship between the medication groups and each outcome and summarized as odds ratios (ORs) with 95% confidence intervals (CIs). Statistical significance was set at 5% for all of the comparisons., Results: A total of 80 patients from 50 hospitals were included in this study. Sixty-one patients (59.02% male) received DOACs and 19 (57.89% male) received a VKA. Of the patients who received DOACs, 41 (67.21%) received apixaban, one (1.64%) received dabigatran, and 19 (31.15%) received rivaroxaban. The results from the bivariate analysis revealed no significant differences between DOACs and warfarin for both the efficacy (OR 1.46, 95% CI 0.44-4.84, P = 0.53) and safety outcomes (OR 1.03, 95% CI 0.04-26.43, P = 1) at 10 months., Conclusions: The use of DOACs in patients with cirrhosis who present with SVT may be efficacious and safe compared with warfarin. The findings from our study may inform power analyses for well-conducted randomized trials to confirm these findings.

Background: The prospective, single-arm, observational, phase 4 ETNA-AF Europe study collected real-world data about safety, effectiveness and therapeutic adherence in European patients with non-valvular atrial fibrillation newly prescribed with edoxaban and followed up for 4 years., Methods: Overall, 13 164 patients were included in the full-analysis set, which means that they had at least one documentation after baseline at 4 years. The current paper reports about the 3329 Italian patients out of the whole European population., Results: In the Italian cohort, median age was 76.0 (69.0-82.0) years, with 57.4% of the patients being ≥75 years old. The CHA2DS2-VASc score was >4 in 586 (18.1%) patients. At baseline, 670 (20.8%) patients were classified as frail by the investigators. Edoxaban 30 mg/day was prescribed to 1013 (31.8%) patients: these were older, with more comorbidities and a lower estimated creatinine clearance compared with those receiving 60 mg/day. All-cause mortality was 4.1%/year and there were very low yearly rates of bleeding and thromboembolic events: major bleeding, 0.9%; intracranial hemorrhage, 0.2%; ischemic stroke, 0.3%; systemic embolism, <0.1%. These events were more frequent in patients ≥75 years or in patients with renal impairment or treated with edoxaban 30 mg/day. Advancing age was not associated with an increased incidence of intracranial bleeding., Conclusions: These findings confirm the favorable long-term safety and effectiveness profile of edoxaban in non-valvular atrial fibrillation patients treated in routine clinical care in Italy.

Direct oral anticoagulants (DOACs) are widely used for treatment and secondary prophylaxis of venous thromboembolism (VTE) and represent the gold standard for VTE secondary prophylaxis, with low-intensity DOACs administration becoming increasingly used worldwide in such scenario. Albeit widespread DOACs usage there are few literature data regarding their efficacy and safety in major thrombophilia carriers and almost no data is available for low intensity apixaban and rivaroxaban as secondary VTE prophylaxis in such patients. The aim of our study is to evaluate and confront the efficacy and safety of low-dose DOACs for VTE secondary prophylaxis, in major thrombophilia carriers vs patients at high risk of VTE recurrence for other reasons. We retrospectively evaluated patients who required long-term anticoagulant secondary prophylaxis to prevent recurrent VTE, treated with apixaban 2.5 mg BID or rivaroxaban 10 mg daily and that were screened for thrombophilia. The examined patients were 339. Baseline characteristics such as sex, age, obesity rate, smoking, number of previous VTEs and comorbidities (such as cardiovascular diseases, diabetes, mild CKD) were equally distributed in either group. The median low-dose DOACs administration time was 19.20 months (IQR 12.17-35.67). During low-dose DOACs treatment, 13 (3.8%) VTE recurrences were observed; 14 bleeding events were registered (4,1%), with no major bleeding (MB), 6 clinically relevant non major bleeding (CRNMB) (1.8%) and 8 minor bleeding (2.3%). No statistically significant difference in the rate of VTE recurrence and/or bleeding events emerged between major thrombophilia carriers and non-major thrombophilia carriers. In multivariate analysis increased risk of VTE recurrence was found for patients with cardiovascular comorbidities (HR 4.00 - p = 0.034) and for patients with more than one previous VTE episode (HR 5.14 - p = 0.034). Our data suggest that low-dose DOACs may be effective and safe in secondary VTE prophylaxis for carriers of major thrombophilia with no increase in VTE recurrence and/or bleeding risk., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Factor Xa inhibitor (FXaI)-associated bleeding events are common and associated with substantial morbidity. Systematic evaluation of widely available, effective, and affordable FXaI bleed management strategies is needed., Materials and Methods: We conducted a single-center retrospective cohort study of FXaI-treated patients presenting to a tertiary academic medical center from January 2018 to May 2019 who received 25-50 IU/kg 4F-PCC for either FXaI-associated major bleeding or urgent surgery. The primary outcome was hemostatic efficacy, and the safety outcome was the 30-day risk of thromboembolism., Results: PCC was used to treat FXaI-associated bleeding in 83 cases (79.1 %) and was given before urgent surgery in 22 cases (20.9 %). Sixty-six patients were on apixaban, 38 were on rivaroxaban and one patient was on edoxaban. Intracranial hemorrhage (ICH) and gastrointestinal bleeding accounted for most bleeds (74.7 %). Median interval between last DOAC intake and presentation to triage was 9 h [IQR 5.3-14.8] and median PCC dosing was 40.0 IU/kg [IQR 28.5-46.6]. Forty-two patients (40.0 %) had pre-PCC FXaI levels drawn with median FXaI levels of 114.5 ng/mL [IQR 70.0-175.0]. Effective hemostasis occurred in 66.7 % [95%CI 55.4-76.3] of patients receiving PCC for bleeding and surgical hemostasis was rated as normal in 95.5 % (95%CI 76.5-100.0) for patients having urgent surgery. The 30-day risk of thromboembolism was 7.6 % [95%CI 3.7-14.5] and 22.9 % [95%CI 15.8-31.8] of patients died., Conclusions: PCC for FXaI-associated bleeding was associated with hemostatic efficacy in two-thirds of patients and thromboembolic events were uncommon. PCC represents a promising treatment strategy for FXaI-associated bleeding., Competing Interests: Declaration of competing interest J.R. Shaw has received in-kind laboratory support from Diagnostica Stago. J.H. Levy serves on steering committees for Merck, Octapharma, Takeda, and Werfen. S. Schulman reports research grant funding from Octapharma and honoraria from Alexion, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Regeneron, Sanofi, and Takeda. D.M. Siegal has received honoraria paid indirectly to her institution from Astra Zeneca, BMS-Pfizer, Servier. D. Dowlatshahi has provided consultation to Astra Zeneca Canada. M. Carrier has received research funding from Leo Pharma and Pfizer, in addition to honoraria from BMS, Valeo Pharma, Leo Pharma, Sanofi and Servier. L. Castellucci's research institution has received honoraria from Bayer, BMS-Pfizer Alliance, The Academy for Continued Advancement in Healthcare Education, Amag Pharmaceutical, LEO Pharma, Sanofi, Valeo Pharma, and Servier., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Despite advancements in coronary artery disease (CAD) management, major adverse cardiovascular events persist. Vitamin K antagonists and direct oral anticoagulants present bleeding risks. Low-dose rivaroxaban (2.5 mg) is approved by the European Society of Cardiology and the US Food and Drug Administration for CAD. The survival advantage and risk-benefit profile of combining low-dose rivaroxaban with aspirin for CAD patients remain uncertain. This meta-analysis aims to compare the efficacy of low-dose rivaroxaban plus aspirin versus aspirin monotherapy in CAD patients., Methods: We systematically searched databases for randomized controlled trials exploring low-dose rivaroxaban with aspirin in CAD patients. Of the 6220 studies screened, five met the inclusion criteria. Primary outcomes included myocardial infarction, stroke, major bleeding events, and all-cause mortality. The analysis employed a fixed-effects model, calculating hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: Five randomized controlled trials involving 41,351 participants were included. Rivaroxaban (2.5 mg) significantly reduced all-cause mortality (HR, 0.88; 95% CI, 0.81-0.95; P = 0.002), myocardial infarction (HR, 0.81; 95% CI, 0.70-0.94; P = 0.006), and stroke (HR, 0.61; 95% CI, 0.49-0.76; P < 0.00001) compared to aspirin alone. However, it increased major bleeding risk (HR, 1.66; 95% CI, 1.40-1.97; P < 0.01). Meta-regression revealed no dose-dependent impact on all-cause mortality., Conclusion: Low-dose rivaroxaban demonstrates survival benefits and reduces myocardial infarction and stroke risks in CAD patients, albeit with an increased risk of major bleeding. Consideration of patient bleeding risk is crucial when adding rivaroxaban to antiplatelet therapy. Further research is warranted to compare its effectiveness and safety with dual antiplatelet therapy or P2Y12 inhibitors., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Direct oral anticoagulants (DOACs) have shown comparable efficacy and a superior safety profile in clinical trials for patients with venous thromboembolism (VTE). However, further study is needed to assess DOACs' effectiveness and safety compared to warfarin in a real-world context. Thus, this meta-analysis compares the effectiveness and safety of warfarin and DOACs in patients with VTE., Method: A systematic review of the literature using PubMed and EMBASE was conducted from inception until June 2024. We examined observational studies that compared safety and effectiveness between DOACs and warfarin when used in treating VTE and reported adjusted hazard ratios (HRs) and/or odds ratios (ORs) for recurrent VTE, major bleeding, clinically relevant non-major bleeding, gastrointestinal bleeding, intracranial hemorrhage, and death from any cause. We then estimated the pooled effect using the random-effects model for meta-analysis., Results: A total of 25 studies were included in the current meta-analysis. DOAC therapy was associated with significantly lower risks of recurrent VTE (HR 0.76, 95% confidence interval [CI] 0.69-0.85), major bleeding (HR 0.77, 95% CI 0.72-0.83), clinically relevant non-major bleeding (HR 0.82, 95% CI 0.77-0.88), and gastrointestinal bleeding (HR 0.75, 95% CI 0.68-0.83) compared to warfarin. However, no statistically significant difference was observed in all-cause mortality between the two groups (HR 0.96, 95% CI 0.83-1.10)., Conclusion: This meta-analysis found that DOACs are associated with a significant reduction in VTE recurrence in addition to the known favorable safety profile when compared to warfarin., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: In patients with atrial fibrillation (AF), the association between cancer and cardioembolic or bleeding risk during oral anticoagulant therapy still remains unclear., Purpose: We aimed to assess the impact of cancer present at baseline (CB) or diagnosed during follow-up (CFU) on bleeding events in patients treated with direct oral anticoagulants (DOACs) for non-valvular AF (NVAF) compared with patients without CB or CFU, respectively., Methods: All consecutive patients with NVAF treated with DOACs for stroke prevention were enrolled between January 2017 and March 2019. Primary outcomes were bleeding events or cardiovascular death, non-fatal stroke and non-fatal myocardial infarction, and the composite endpoint between patients with and without CB and between patients with and without CB., Results: The study population comprised 1170 patients who were followed for a mean time of 21.6 ± 9.5 months. Overall, 81 patients (6.9%) were affected by CB, while 81 (6.9%) were diagnosed with CFU. Patients with CFU were associated with a higher risk of bleeding events and major bleeding compared with patients without CFU. Such an association was not observed between the CB and no CB populations. In multivariate analysis adjusted for anemia, age, creatinine, CB and CFU, CFU but not CB remained an independent predictor of overall and major bleeding (hazard ratio [HR] 2.67, 95% confidence interval [CI] 1.8-3.89, p < 0.001; HR 3.02, 95% CI 1.6-3.81, p = 0.001, respectively)., Conclusion: During follow-up, newly diagnosed primitive or metastatic cancer in patients with NVAF taking DOACs is a strong predictor of major bleeding regardless of baseline hemorrhagic risk assessment. In contrast, such an association is not observed with malignancy at baseline. Appropriate diagnosis and treatment could therefore reduce the risk of cancer-related bleeding., (© 2024. The Author(s).)

Direct oral anticoagulants (DOACs) are the first-line anticoagulants for the secondary prevention of venous thromboembolism (VTE). However, patients with severe inherited thrombophilias represent a group in whom the efficiency and safety of DOACs is poorly studied. In this communication, we focus on the utility of DOACs in the secondary prevention of VTE in patients with severe thrombophilia. Current evidence is based only on cohort or single-center studies, and poor data are available on compliance of the patients in the studies. Analysis of the studies suggested that full-dose DOACs and vitamin K antagonists have a similar efficacy and bleeding risk in the secondary prevention of VTE in patients with thrombophilia, with a low hazard ratio for recurrent VTE calculated from cohort studies for DOAC vs warfarin, ranging from 0.3 to 0.75. We wish to highlight that treatment failure is greater in those with severe forms of protein S deficiency (below 20%) and possibly in antithrombin deficiency type II heparin-binding site homozygous Budapest 3. In summary, the current approach to using DOACs in patients with severe thrombophilia is dependent on clinical judgment and experience. Limited evidence suggests that for those with severe thrombophilias, full-dose DOACs have similar utility as vitamin K antagonists. We recommend caution in using low-dose DOACs due to lack of evidence. Ideally, large randomized multicenter studies are required to develop a reliable treatment algorithm., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. All rights reserved.)

Rivaroxaban is a new direct oral anticoagulant, and the same dose is recommended for older and young patients. However, recent real-world studies show that older patients may need dose adjustment to prevent major bleeding. At present, the evidence for dose adjustment in older patients is extremely limited with only a few reports on older atrial fibrillation patients. The aim of this study was to review the morbidity data of adverse events and bleeding events across all indications for older and young patients treated with the same dose of rivaroxaban to provide some support for dosage adjustment in older patients. The PubMed, EMBASE, ClinicalTrials, Cochrane and Web of Science databases were searched for randomized controlled trials (RCTs) published between January 1, 2005, and October 10, 2023. The primary outcomes were the morbidity of bleeding events and efficacy-related adverse events. Summary estimates were calculated using a random effects model. Eighteen RCTs were included in the qualitative analysis. The overall morbidity of primary efficacy endpoints was higher in older patients compared to the young patients (3.37% vs. 2.60%, χ 2  = 5.24, p = 0.022). Similarly, a higher morbidity of bleeding was observed in older patients compared to the young patients (4.42% vs. 6.03%, χ 2  = 13.22, p < 0.001). Among all indications, deep vein thrombosis, pulmonary embolism and atrial fibrillation were associated with the highest incidence of bleeding in older patients, suggesting that these patients may be most need dose adjustment. Patients older than 75 years may require extra attention to prevent bleeding. The same dose of rivaroxaban resulted in higher bleeding morbidity and morbidity of efficacy-related adverse events in older patients compared to the young patients. An individualized dose adjustment may be preferred for older patients rather than a fixed dose that fits all., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background:  Real-world data on clinical characteristics and outcomes related to the use of different direct oral anticoagulants (DOACs) for cancer-associated venous thromboembolism (VTE) is lacking., Methods:  The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive patients with acute symptomatic VTE from 31 centers in Japan from January 2015 to August 2020. Our study population comprised 1,197 patients with active cancer who were divided into the edoxaban ( N  = 643, 54%), rivaroxaban ( N  = 297, 25%), and apixaban ( N  = 257, 22%) groups., Results:  The cumulative 5-year incidence of recurrent VTE (9.3, 10.2, and 8.5%, respectively, p  = 0.82) and all-cause death (67.5, 66.8, and 63.8%, respectively, p  = 0.22) did not differ among the groups. Despite adjusting for confounders, the risks of recurrent VTE and all-cause death did not differ significantly among the groups. The cumulative 5-year incidence of major and clinically relevant bleeding was significantly lower in the rivaroxaban group than those in the other groups (22.6, 14.0, and 22.8%, p  = 0.04; and 37.6, 26.8, and 38.3%, p  = 0.01, respectively). After adjusting for confounders, in the rivaroxaban group, the risk for major bleeding was numerically lower (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.40-1.01) and that of clinically relevant all bleeding was significantly lower (HR: 0.67, 95% CI: 0.48-0.92) than those in the edoxaban group., Conclusion:  The risks of recurrent VTE and all-cause death did not differ significantly among the different DOACs ; however, the risk of bleeding events could differ, with a potentially lower risk of bleeding with rivaroxaban., Competing Interests: Y.Y. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo, and grant support from Bayer Healthcare and Daiichi-Sankyo. T.M. reports lecturer's fees from Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray; manuscript fees from Bristol-Myers Squibb and Kowa; advisory board for Sanofi. Y.N. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo. K.K. received lecture fees from Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo. N.I. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi-Sankyo. S.I. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi-Sankyo. Y.O. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo, and research funds from Bayer Healthcare and Daiichi-Sankyo. K.T. received significant research grant from AMI Co., Ltd., Bayer Yakuhin, Ltd., Bristol-Myers K.K., EA Pharma Co., Ltd., MOCHIDA PHARMACEUTICAL CO., LTD., and scholarship fund from AMI Co., Ltd., Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Edwards Lifesciences Corporation, Johnson & Johnson K.K., ONO PHARMACEUTICAL CO., LTD., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and honoraria from Amgen K.K., Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Kowa Pharmaceutical Co. Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., and belongs to the endowed departments donated by Abbott Japan Co., Ltd., Boston Scientific Japan K.K., Fides-one, Inc., GM Medical Co., Ltd., ITI Co., Ltd., Kaneka Medix Co., Ltd., NIPRO CORPORATION, TERUMO Co, Ltd., Abbott Medical Co., Ltd., Cardinal Health Japan, Fukuda Denshi Co., Ltd., Japan Lifeline Co., Ltd., Medical Appliance Co., Ltd., Medtronic Japan Co., Ltd. All other authors have reported that they have no relationships relevant to the contents of this article to disclose., (Thieme. All rights reserved.)

Background: Prophylactic dose of rivaroxaban is often used in treatment of isolated calf muscle vein thrombosis (ICMVT); nevertheless, its effect is less reported. This study aims to evaluate short-term outcomes in patients with ICMVT who received prophylactic dose of rivaroxaban or warfarin therapy., Methods: A retrospective analysis of 472 ICMVT patients who received 2 different treatment regimens was undertaken. Propensity score matching method was used to balance the confounding effect of baseline clinical data. Chi-squared test and logistic regression analysis were used to compare outcomes (venous thromboembolism events, bleeding events, complete clot resolution) according to the type of treatment regimens before and after propensity score matching. Univariate and multivariable analysis were used to investigate risk factors for incomplete clot resolution of ICMVT after propensity score matching., Results: 242 ICMVT patients received prophylactic dose of rivaroxaban (rivaroxaban group, RG), and 230 received warfarin (warfarin group, WG). After propensity score matching, 156 patients were included in each group; Venous thromboembolism (VTE) events occurred in 14 (9.0%) patients in the RG and 10 (6.4%) in the WG (P = 0.395); no major bleeding events occurred in each group, and clinically relevant nonmajor bleeding events occurred in 5 (3.2%) patients in the RG and 10 (6.4%) in the WG (P = 0.186); complete clot resolution at 3 months occurred in 80 (51.3%) patients in the RG and 100 (64.1%) in the WG (P = 0.022). Logistic regression analysis showed that there were no significant differences between RG and WG in VTE events (odds ratio 1.439, 95% confidence interval 0.619-3.347, P = 0.397) and clinically relevant nonmajor bleeding events (odds ratio 0.483, 95% confidence interval 0.161-1.449, P = 0.194); it revealed that complete clot resolution rate at 3 months was different in the 2 groups (odds ratio 0.589, 95% confidence interval 0.375-0.928, P = 0.022). Treatment regimens (prophylactic dose of rivaroxaban), thrombosis (maximum diameter >7 mm), and risk factors for VTE (nonsurgery risk factors, mainly referring to active malignancy) were risk factors for incomplete clot resolution of ICMVT (P < 0.05)., Conclusions: In this retrospective study with a short-term follow-up, ICMVT patients who received prophylactic dose of rivaroxaban had no significant differences in VTE and bleeding events compared to those who received warfarin therapy (the overall INR >2.0 for >50% of the time); but it was not conducive to complete clot resolution., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Limited data exist on the safety and effectiveness of using direct oral anticoagulants (DOACs) in patients with atrial fibrillation aged 80 years or more with and without low bodyweight (LBW)., Objectives: We aimed to evaluate the safety and effectiveness of using DOACs in this population compared with warfarin., Methods: This retrospective active comparator new-user cohort study included veteran patients with atrial fibrillation who were newly initiated on either warfarin or DOACs between January 1, 2015, and January 1, 2021. The primary outcome was incidence of major bleeding and ischemic stroke. All outcomes were compared between treatment groups in 2 propensity score-matched cohorts of patients aged 80 years older with (AW) and without LBW (age-only cohort). Cox proportional hazard models were used to estimate adjusted hazard ratios (aHRs)., Results: Matched AW and age-only cohorts included 493 and 11 909 patients, respectively, in each of the DOAC and warfarin exposure groups. Greater than 90% were male, with a mean age of ∼87 years. The rate of major bleeding was lower in the DOAC group compared with warfarin in both the AW (aHR, 0.63; 95% CI, 0.46-0.87) and age-only cohorts (aHR, 0.58; 95% CI, 0.49-0.77). A significantly lower rate of ischemic stroke occurred in the DOAC group compared with warfarin in the AW cohort (aHR, 0.62; 95% CI, 0.45-0.84) and age-only cohort (aHR, 0.63; 95% CI, 0.58-0.68)., Conclusion: DOAC use was associated with lower risk of major bleeding and ischemic stroke compared with warfarin in patients aged 80 years or older with and without LBW., Competing Interests: Declaration of competing interests There are no competing interests to disclose. The results of this study do not represent the views of the federal government or the Veterans Health Administration., (Published by Elsevier Inc.)

Background: After drug-coated balloon (DCB) treatment of the femoropopliteal artery in-stent restenosis (ISR), a certain proportion of patients also experience target lesion restenosis. The purpose of this study was to explore the efficacy and safety of rivaroxaban combined with aspirin in the treatment of ISR after DCB intervention., Methods: Patients who underwent DCB treatment for ISR after femoropopliteal artery intervention at our center from March 2017 to February 2022 were included consecutively. According to the drug treatment after DCB intervention of ISR, the patients were divided into rivaroxaban and aspirin group (RA Group) and dual antiplatelet therapy (DAPT) group. The outcomes of 2 groups during the 12-month follow-up after DCB intervention were compared., Results: A total of 92 patients were included in final analysis, with 43 in RA group and 49 in DAPT group. During 12-month follow-up, a total of 15 cases of recurrent ISR were detected, and the recurrence rate of ISR and clinically driven target lesion revascularization in the RA group were lower than those in the DAPT group (P < 0.05). The vascular patency rate in the RA group was higher than that in the DAPT group at 6 and 12 months of follow-up (P < 0.05). During the follow-up, there were no adverse events such as death, myocardial infarction, stroke, amputation, or major bleeding, and only a total of 5 cases of minor bleeding occurred., Conclusions: Compared with the standard DAPT regimen, rivaroxaban combined with aspirin can safely improve the follow-up outcome after DCB for femoropopliteal ISR., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, commonly used direct oral anticoagulant (DOAC), are widely used to prevent and treat stroke and venous thromboembolic events in patients with atrial fibrillation (AF). This study aimed to assess and compare reports of adverse events associated with rivaroxaban, apixaban, and edoxaban, including hemorrhagic and non-hemorrhagic events., Methods: Reporting odds ratio (ROR), proportional reporting ratio (PRR), Medications and Health Care Products Regulatory Agency (MHRA), and the information component (IC) were used to perform a risk assessment of adverse event reports in the FDA Adverse Event Reporting System (FAERS) database for the years 2018-2022., Results: Combined with disproportionality analysis in different backgrounds, the salient risks of the three-factor Xa inhibitors varied. Rivaroxaban had the most significant risk of hemorrhage, apixaban had a higher incidence and risk of death, cardiac and cerebral adverse events, and edoxaban showed a more prominent risk in the kidneys and urinary system., Conclusion: Hemorrhage is a common risk with factor Xa inhibitors, with rivaroxaban being the most significant. Apixaban and edoxaban also showed significant association with non-hemorrhagic adverse events, and increased attention to non-hemorrhagic adverse events is needed in clinical use.

Introduction: Deep vein thrombosis (DVT) is a medical condition characterized by forming a blood clot, or thrombus, in one of the deep veins, typically in the legs. It is a type of venous thromboembolism, which refers to the formation of blood clots in the veins. It is caused by Virchow's triad (stasis, hypercoagulation, and endothelial injury)., Objective: Our main objective is to explore the effectiveness and safety of rivaroxaban and edoxaban in treating lower extremity DVT., Methods: We conducted a retrospective study involving 406 patients subjected to DVT treatment using direct oral anticoagulants (edoxaban and rivaroxaban) at our hospital. We recruited adult patients (aged 18 years and more) diagnosed with lower extremity DVT and received treatment with either rivaroxaban or edoxaban as the primary anticoagulant therapy for DVT. We excluded patients who received treatment with other anticoagulant medications (warfarin and heparin) as the primary therapy for DVT., Results: The groups showed statistically significant differences in red blood cell count and hemoglobin levels, with the edoxaban group having high values. However, the 2 groups observed no statistically significant differences in creatinine clearance, white blood cell count, platelet count, C-reactive protein, and D-dimer levels. The difference in the incidence of pulmonary embolism between the 2 groups was statistically significant (P value < 0.001). The edoxaban group had fewer pulmonary embolism patients than the rivaroxaban group. The reduction in recurrent thrombosis was significantly higher in the rivaroxaban group compared to the edoxaban group. There were no significant differences in the major bleeding at various sites across the 2 treatment groups (P > 0.05)., Conclusions: Rivaroxaban's pharmacokinetic profile includes rapid absorption and a relatively short half-life. It means that once administered, rivaroxaban quickly reaches its peak concentration in the blood and is subsequently eliminated from the body within a relatively short period. Edoxaban's pharmacokinetic profile may include slower absorption and a longer half-life than rivaroxaban. It can result in a slower rate of achieving peak concentration and a more prolonged presence in the bloodstream. These results emphasize the need for careful consideration of anticoagulant therapy in patients with underlying cancer and underscore the importance of managing risks while providing adequate anticoagulation to prevent thrombotic events., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The COMPASS trial demonstrated that in patients with atherosclerotic diseases, low-dose rivaroxaban and aspirin provides greater protection against subsequent major adverse cardiovascular events (MACEs) than mono-antiplatelet therapy (MAPT) alone. Drug acceptance and adherence maximizes this benefit. We have assessed drug acceptance and adherence to the COMPASS drug regime in patients following carotid endarterectomy (CEA) for symptomatic carotid artery stenosis., Methods: Following CEA, the views of 63 patients on the COMPASS drug regime were assessed using the Beliefs about Medicine Questionnaire and drug adherence was determined using the Sidorkiewicz scoring system. These views were compared with those of 54 patients on MAPT. Side effects (bleeding and drug reactions) and new MACE were recorded., Results: Post-CEA patients on the COMPASS drug regimen had strong positive views on the necessity to take these drugs (necessity scale 19.6 ± 3.6). Although there were some concerns about the COMPASS drug regimen, these were not strongly held (concern cscale 11.8 ± 4.9) and the necessity-concerns differential was positive (7.8 ± 6.2). The Drug Adherence Score was "High" to "Good" (level of drug adherence 1.7 ± 1.0). The Beliefs about Medicine Questionnaire scales and Drug Adherence Score of post-CEA patients on the COMPASS drug regimen were similar to those on MAPT. The incidence of post-CEA MACE and side effects were similar for those on the COMPASS drug regimen and MAPT., Conclusions: Post-CEA patients on the COMPASS drug regimen had positive views on taking the drugs and drug adherence was high. We did not identify any patient-related barriers to the use of the COMPASS drug regimen to further reduce cardiovascular events., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Elderly with multimorbidity are at higher risk of accumulating direct oral anticoagulants (DOAC). The presence of renal insufficiency, an extreme age or weight, a limited functional reserve, and a polypharmacy that may interact with DOAC, lead to an increased risk of bleeding. A medication review and an evaluation of DOAC exposure in this population could help identify this risk and better manage it. This evaluation is conducted in collaboration with coagulation experts through calibrated measurement of anti-Xa (rivarobaxan, apixaban and edoxaban), along with D-dimers measurement as a potential tool to assess thrombo-hemorrhagic risk. In the event of DOAC accumulation, experts could then propose personalized intervention, such as a dose reduction or a switch to another DOAC., Competing Interests: les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

An 87-year-old woman receiving aspirin and apixaban with a history of large artery atherosclerotic stroke, and pulmonary embolism presented to the hospital for aphasia and right hemiplegia. A head CT scan showed 18-ml hematoma in the left thalamus. Low-dose Andexanet alfa was administered 84 minutes after the onset of stroke, and 10 hours and 24 minutes after the last dose of apixaban. Three hours later after admission, she had flaccid hemiplegia and became comatose. CT and CT angiography revealed occlusion of left internal carotid artery (ICA) and no evidence of hematoma expansion. Although repetitive mechanical thrombectomy resulted in recanalization (modified TICI 2b), carotid ultrasound revealed the occlusion of left ICA on next day. On day 7, she died of brain herniation following extensive cerebral infarction. It has been reported that some patients did experience thrombotic events after administration of Andexanet alfa. Our case illustrates that even large vessel occlusion might occur after intravenous injection of Andexanet alfa. Thus, careful follow-up, including cerebrovascular imaging, is required immediately after administration of Andexanet alfa.

Cancer-associated thrombosis (CAT) remains a challenging aspect of managing patients with cancer. This review discusses evidence regarding anticoagulants in the treatment of CAT, with particular emphasis on direct oral anticoagulants (DOAC). Apixaban, rivaroxaban and edoxaban have proven attractive alternatives to low-molecular weight heparins, and interactions with medical cancer treatment does not pose a major challenge. The majority of guidelines have endorsed the use of DOAC, and we highlight points to consider when choosing the optimal anticoagulant for the individual patient., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Introduction: The transition to or from direct oral anticoagulants (DOACs) is common in clinical practice., Areas Covered: A literature search was conducted on PubMed, Google Scholar, and UpToDate up to March 2024 for conditions and approaches for transitioning from one agent to the other. No randomized clinical trials were retrieved except for two studies regarding switching to DOAC in well-conducted vitamin K antagonist (VKA) therapy. A narrative review was conducted addressing the conditions for switching from one agent to the other, such as thromboembolic events and major bleeding during anticoagulation, development or worsening of kidney or liver failure, initiation of interfering drugs, adverse events such as allergic reactions, frailty, patients' preferences, and affordability. During transitions from one anticoagulant to the other, the risk of both thromboembolic and bleeding complications should be minimized. The current approaches for such transitions are derived from those employed in clinical trials evaluating DOAC and from product information., Expert Opinion: Many uncertainties remain regarding those circumstances requiring a change in anticoagulant strategies, as they lack evidence-based guidance. It can be envisaged that the problem of switching to and from DOAC will need additional studies especially addressing the conditions and the best approach to such transitions.

Background: Vitamin-K antagonists (VKAs) have widely been replaced by non-VKA oral anticoagulants (NOACs). This includes Austria, Germany and Switzerland, where as VKA, instead of warfarin, the much longer-acting phenprocoumon is used, which was not compared to NOACs in clinical trials., Methods: Using administrative data from a large German health insurance, we included all anticoagulation-naïve patients with a first prescription of a NOAC or VKA between 2012 and 2020. We analysed overall survival, major adverse cardiac and cerebrovascular events, major thromboembolic events and major bleeding., Results: Overall, 570,137 patients were included (apixaban: 26.9%, dabigatran: 4.6%, edoxaban: 8.8%, rivaroxaban: 39.1% and VKA: 20.7% of these 99.4% phenprocoumon). In the primary analysis using a 1:1 propensity score matching-cohort (PSM-cohort), a significantly higher overall mortality was found for apixaban, edoxaban and rivaroxaban (all p < 0.001) but not for dabigatran (p = 0.13) compared to VKA. In this PSM-cohort, 5-year mortality was 22.7% for apixaban versus 12.7% for VKA, 19.5% for edoxaban versus 11.4% for VKA, 16.0% for rivaroxaban versus 12.3% for VKA (all p < 0.001) and 13.0% for dabigatran versus 12.8% for VKA (p = 0.06). The observed effect was confirmed in sensitivity analyses using un-weighted and three different weighted Fine-Gray regression models on the basis of the entire cohort., Conclusions: In this large real-world analysis, apixaban, edoxaban and rivaroxaban, but not dabigatran, were associated with worse survival compared to VKA. These findings, consistent with a few other studies including phenprocoumon, cast profound doubts on the unreflected, general use of NOACs. Randomized trials should assess whether phenprocoumon might actually be superior to NOACs., (© 2024 BARMER Institut für Gesundheitssystemforschung and The Author(s). Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Objective: We aimed to evaluate the safety and efficacy of antithrombotic strategies by age in patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention in AUGUSTUS., Methods: Patients were stratified into 3 age groups: <65, 65-74, and ≥75 years. Outcomes of interest were major or clinically relevant non-major bleeding, major bleeding, death or rehospitalization, and ischemic events. Treatment effects of apixaban vs. vitamin K antagonist (VKA) and aspirin vs. placebo were assessed across age groups using Cox models., Results: Of 4614 patients, 1267 (27.5%) were <65, 1802 (39.0%) were 65-74, and 1545 (33.5%) were ≥75 years. Apixaban was associated with lower rates of major or clinically relevant non-major bleeding than VKA (<65: HR 0.69 [0.47-1.00]; 65-74: HR 0.57 [0.43-0.75]; ≥75: HR 0.81 [0.63-1.04]). Death or hospitalization occurred less often with apixaban, regardless of age. No differences were observed in rates of ischemic events between apixaban and VKA according to age. Aspirin was associated with higher rates of bleeding than placebo (<65: HR 1.67 [1.15-2.43]; 65-74: HR 2.32 [1.73-3.10]; ≥75: HR 1.69 [1.31-2.19]). Rates of death or rehospitalization and ischemic events were similar among patients receiving aspirin or placebo across age groups., Conclusions: Apixaban was associated with greater absolute reduction in bleeding than VKA in older age groups, reflecting their higher hemorrhagic risk. Aspirin increased bleeding in all age groups vs. placebo. Our findings support the use of apixaban plus a purinergic receptor P2Y 12 (P2Y 12 ) inhibitor without aspirin in patients with atrial fibrillation and recent acute coronary syndrome/percutaneous coronary intervention, regardless of age., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Patients with symptomatic lower extremity arterial disease (LEAD) are recommended to receive antiplatelet therapy, while direct oral anticoagulants (DOACs) are standard for stroke prevention in patients with atrial fibrillation (AF). For patients with concomitant LEAD and AF, data comparing dual antithrombotic therapy (an antiplatelet agent used in conjunction with a DOAC) vs. DOAC monotherapy are scarce. This retrospective cohort study, based on data from the Taiwan National Health Insurance Research Database, aimed to compare the efficacy and safety of these antithrombotic strategies., Methods: Patients with AF who underwent revascularisation for LEAD between 2012 - 2020 and received any DOAC within 30 days of discharge were included. Patients were grouped by antiplatelet agent exposure into the dual antithrombotic therapy and DOAC monotherapy groups. Inverse probability of treatment weighting was used to mitigate selection bias. Major adverse limb events (MALEs), ischaemic stroke or systemic embolism, and bleeding outcomes were compared. Patients were followed until the occurrence of any study outcome, death, or up to two years., Results: A total of 1 470 patients were identified, with 736 in the dual antithrombotic therapy group and 734 in the DOAC monotherapy group. Among them, 1 346 patients received endovascular therapy as the index revascularisation procedure and 124 underwent bypass surgery. At two years, dual antithrombotic therapy was associated with a higher risk of MALEs than DOAC monotherapy (subdistribution hazard ratio [SHR] 1.34, 95% confidence interval [CI] 1.15 - 1.56), primarily driven by increased repeat revascularisation. Dual antithrombotic therapy was also associated with a higher risk of major bleeding (SHR 1.43, 95% CI 1.05 - 1.94) and gastrointestinal bleeding (SHR 2.17, 95% CI 1.42 - 3.33) than DOAC monotherapy., Conclusion: In patients with concomitant LEAD and AF who underwent peripheral revascularisation, DOAC monotherapy was associated with a lower risk of MALEs and bleeding events than dual antithrombotic therapy., (Copyright © 2024 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Purpose: To report an incident of a breakthrough deep vein thrombosis (DVT) and potential example of a drug-drug interaction in a patient treated with edoxaban and rifabutin who was being treated for respiratory tuberculosis. Case: A 76-year-old male presented with anemia requiring transfusion and subsequent shortness of breath that was later diagnosed to be respiratory tuberculosis. He experienced a prolonged hospital stay due to persistently positive Mycobacterium tuberculosis respiratory samples and a complicated social situation that required continuous hospitalization for approximately five months. During his treatment the patient was transitioned from apixaban to edoxaban due to a drug-drug interaction with rifabutin. He subsequently had a DVT while on edoxaban after two months of therapy that would require him to transition to warfarin. Conclusion: This case represents an example of a potentially significant drug-drug interaction between edoxaban and rifabutin. Other direct oral anticoagulants (DOACs) exhibit a potential drug-drug interaction that limit their effectiveness when used with rifamycins. This report describes the first known case of a patient experiencing a DVT after prolonged edoxaban use in combination with rifabutin. Treatment with DOACs for patients taking concomitant cytochrome P450 (CYP) inducers such as rifabutin may be more complicated than previously believed., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: Bleeding after endoscopic submucosal dissection (ESD) for gastric tumors in patients taking antithrombotic drugs, in particular direct oral anticoagulants (DOACs), remains unresolved; therefore, we evaluated the risk factors for post-ESD bleeding and drug differences in patients taking DOACs., Methods: We included 278 patients taking antithrombotic drugs who underwent gastric ESD between January 2017 and March 2022. Antithrombotic drugs were withdrawn following the 2017 guidelines (Appendix on anticoagulants including DOACs). To further clarify differences in antithrombotic agents' effects, the peri-cancerous mucosa in the resected specimen was pathologically evaluated according to the Updated Sydney System. Multivariate analysis was performed to assess the risk of post-ESD bleeding., Results: The incidence of post-ESD bleeding in patients taking DOACs was 19.6% (10/51). Among patients taking antithrombotic drugs, DOACs were identified as a possible factor involved in post-ESD bleeding (odds ratio [OR] 4.92). Among patients taking DOACs, possible factors included resection length diameter ≥30 mm (OR 3.72), presence of neutrophil infiltration (OR 2.71), lesions occurring in the lower third of stomach (OR 2.34), and preoperative antiplatelet use (OR 2.22). Post-ESD bleeding by DOAC type was 25.0% of patients (4/16) receiving apixaban, in 20.0% (3/15) receiving edoxaban, in 21.4% (3/14) receiving rivaroxaban, and in none of those receiving dabigatran., Conclusions: The administration of DOACs was shown to be a possible factor involved in post-ESD bleeding, and risk factors for patients taking DOACs included neutrophil infiltration. The pharmacological differences in the effects of DOACs contributing to bleeding in gastric ulcers suggest comparatively less bleeding with dabigatran after ESD., (© 2024 Japan Gastroenterological Endoscopy Society.)

Background: The DOAC score has been recently proposed for bleeding risk stratification of patients with atrial fibrillation treated with direct oral anticoagulants (DOAC)., Objective: To compare the performance of HAS-BLED and DOAC score in predicting major bleeding events in a contemporary cohort of European AF patients treated with DOAC., Methods: We included patients derived from a prospective observational registry of European AF patients. HAS-BLED and DOAC scores were calculated as per the original schemes. Our primary endpoint was major bleeding events. Receiver operating characteristic (ROC) curves were used to compare the predictive ability of the scores., Results: A total of 2834 AF patients (median age [IQR] 69 [62-77] years; 39.6 % female) treated with DOAC were included in the analysis. According to the HAS-BLED score, 577 patients (20.4 %) were categorized as very low risk of bleeding, as compared to 1276 (45.0 %) according to DOAC score. A total of 55 major bleeding events occurred with an overall incidence of 1.04 per 100 patient-years. Both scores showed only a modest ability for the prediction of bleeding events (HAS-BLED area under the curve [AUC], 0.65, 95 % confidence interval [CI] 0.55-0.70; DOAC score AUC 0.62, 95 % CI 0.59-0.71, p for difference = 0.332]. At calibration analysis, the DOAC score showed modest calibration, especially for patients at high risk, when compared to HAS-BLED., Conclusion: In a contemporary cohort of DOAC-treated AF patients, both HAS-BLED and DOAC scores only modestly predicted the occurrence of major bleeding events. Our results do not support the preferential use of DOAC score over HAS-BLED., Competing Interests: Declaration of competing interest GB: reports small speaker fees from Bayer, Boehringer Ingelheim, Boston, BMS, Daiichi, Sanofi and Janssen outside the submitted work. GYHL: Consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Anthos. No fees are received personally. He is a National Institute for Health and Care Research (NIHR) Senior Investigator and co-PI of the AFFIRMO project on multimorbidity in AF (grant agreement No 899871), TARGET project on digital twins for personalised management of atrial fibrillation and stroke (grant agreement No 101136244) and ARISTOTELES project on artificial intelligence for management of chronic long term conditions (grant agreement No 101080189), which are all funded by the EU's Horizon Europe Research & Innovation programme. MP: Italian national Principal Investigator of the AFFIRMO project on multimorbidity in atrial fibrillation, which has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 899871. GFR: GFR reports consultancy for Boehringer Ingelheim and an educational grant from Anthos, outside the submitted work. No fees are directly received personally. The other authors do not have conflict of interests to report., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Direct oral anticoagulants (DOACs) have overtaken warfarin in the treatment of nonvalvular atrial fibrillation (AF) and venous thromboembolism (VTE). Limited data explore the safety of DOACs in obesity., Methods: This multicenter retrospective study between June 2015 and September 2019 uses the Michigan Anticoagulation Quality Improvement Initiative (MAQI 2 ) registry to compare DOACs and warfarin across weight classes (not obese: body mass index (BMI) ⩾ 18.5 and < 30; obese: BMI ⩾ 30 and < 40; severely obese: BMI ⩾ 40). Primary outcomes include major, clinically relevant nonmajor (CRNM), and minor bleeding events per 100 patient-years. Secondary outcomes include stroke, recurrent VTE, and all-cause mortality., Results: DOACs were prescribed to 49% of the 4089 patients with AF and 46% of the 3162 patients with VTE. Compared to patients treated with warfarin, those treated with DOACs had a higher estimated glomerular filtration rate across BMI categories regardless of indication. In the AF population, severely obese patients treated with DOACs had more major (3.4 vs 1.8, p = 0.004), CRNM (8.6 vs 5.9, p = 0.019), and minor bleeding (11.4 vs 9.9, p = 0.001). There was no difference in stroke or all-cause mortality. In the VTE population, both CRNM (7.5 vs 6.7, p = 0.042) and minor bleeding (19.3 vs 10.5, p < 0.001) events occurred at higher rates in patients treated with DOACs. There was no difference in recurrent pulmonary embolism, stroke, or all-cause mortality., Conclusion: There is a higher rate of bleeding in severely obese patients with VTE and AF treated with DOACs compared to warfarin, without a difference in secondary outcomes. Further studies to compare the anticoagulant classes and understand bleeding drivers in this population are needed., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Geoffery Barnes reports research funding from Boston Scientific; consulting for Pfizer, Bristol-Myers Squibb (BMS), Janssen, Bayer, AstraZeneca, Sanofi, Anthos, Abbott Vascular, and Boston Scientific; and he serves on the Board of Directors for the Anticoagulation (AC) Forum. Dr Scott Kaatz reports research funding from Janssen, BMS, Osmosis Research, National Institutes of Health, and Bayer; consulting for Janssen, Pfizer, BMS, AstraZeneca, Gilead, Phase Bio, Boston Scientific, Inari, and Anthos; and Board membership for AC Forum, National Blood Clot Alliance Medical and Scientific Advisory Board, and PERT Consortium. Dr James Froelich reports research funding from Blue Cross Blue Shield of Michigan and FMD Society of America. The remaining authors have no conflicts of interest.

About 1.5% of patients undergoing total hip (THA) or total knee arthroplasty (TKA) still develop postoperative venous thromboembolism (VTE), indicating that the current thromboprophylaxis strategy is not optimal. To evaluate the feasibility of therapeutic dosages of direct oral anticoagulants (DOACs) as thromboprophylaxis for high VTE risk patients, we determined the risks of major bleeding and VTE in patients who underwent THA/TKA and were treated with DOACs in therapeutic dosages for atrial fibrillation (AF). We conducted a registry-based cohort study from 2010 to 2018 in Denmark and included AF patients on therapeutic DOACs dose who underwent THA/TKA. AF patients were utilized as proxy since they have a life-long indication for therapeutic anticoagulant medication. The 49-days cumulative incidence (with death as competing risk) of major bleeding was assessed. The same was done for VTE at 49- and 90-days. 1,354 THA and TKA procedures were included. The 49-days cumulative incidence of major bleeding was 1.40% (95%Confidence Interval[CI] 0.88-2.14%). Most bleeding events occurred at the surgical site. The cumulative incidence of VTE at 49-days was 0.59% (95%CI 0.28-1.13%) and 0.74% (95%CI 0.38-1.32%) at 90-days. The incidence of major bleeding in THA/TKA patients on DOACs in therapeutic dosages was in line with previously reported incidences among THA/TKA patients on thromboprophylaxis dosages, while the incidence of VTE was relatively low. These data provide a solid basis for the design of randomized controlled trials to establish the safety and efficacy of therapeutic dosages of DOACs to prevent VTE in high-risk patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: It is uncertain whether prothrombin complex concentrate (PCC) improves hemostasis in patients on treatment with oral factor Xa-inhibitors (XaI) who require emergency surgery., Objectives: To evaluate whether, in patients with therapeutic levels of oral XaI, preoperative PCC prevents excessive bleeding during and after emergency surgery and is not associated with thrombotic complications., Methods: We conducted a prospective cohort study wherein a fixed 2000 IU dose of 4-factor PCC was given to patients taking oral XaI with plasma XaI levels of at least 75 ng/mL before the emergency surgery with an expected blood loss of at least 50 mL. Patients were followed for 30 days. The primary efficacy outcome was the incidence of normal or mildly abnormal surgical hemostasis, as assessed by the surgeon; primary safety outcome was the incidence of thromboembolic events within 7 days., Results: We included 20 patients, of which 50% were female, on apixaban (75%) or rivaroxaban (25%) with median XaI level of 128 ng/mL (range, 77-497 ng/mL). The median duration of surgery was 2 hours 42 minutes (range, 15 minutes to 8 hours 17 minutes). Normal or mildly abnormal hemostasis was observed in 16 patients (80%); 2 patients had moderately abnormal and 2 had severely abnormal hemostasis, 1 each of those was considered due to local or technical factors. There were 4 deaths (20%) secondary to underlying disease and 1 incidental pulmonary embolism in a patient with cancer., Conclusion: A fixed dose of PCC appears to control hemostasis in patients with therapeutic plasma levels of apixaban or rivaroxaban requiring emergency surgery., Competing Interests: Declaration of competing interests S.S. served on data safety monitoring boards for Alexion, Bayer, Boehringer-Ingelheim, Regeneron, and Sanofi; served on a steering committee for Octapharma; served on event adjudication for Daiichi Sankyo and Takeda. V.B. received honorarium from Bayer. F.G.’s institution received research funding from Novo Nordisk, Roche, Takeda, Bayer, Pfizer, BioMarin, and CSL. R.I. received honoraria for advisory boards for Aspen, LeoPharma, Sanofi, and Inari. P.L.G. is named on a patent, “Novel methods to measure protease inhibitors.” N.C., A.I., S.M., and J.I.W. have no relevant conflicts., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The currently approved direct oral anticoagulants (DOACs) are increasingly used in clinical practice. Although serious bleeding risks are lower with DOACs than with vitamin K antagonists, bleeding remains the most frequent side effect. Andexanet alfa and idarucizumab are the currently approved specific reversal agents for oral factor (F)Xa inhibitors and dabigatran, respectively. Our prior guidance document was published in 2016, but with more information available on the utility and increased use of these reversal agents and other bleeding management strategies, we have updated this International Society on Thrombosis and Haemostasis guidance document on DOAC reversal. In this narrative review, we compare the mechanism of action of specific and nonspecific reversal agents, review the clinical data supporting their use, and provide guidance on when reversal is indicated. In addition, we briefly discuss the reversal of oral FXIa inhibitors, a new class of DOACs currently under clinical development., Competing Interests: Declaration of competing interests J.H.L.: Participation on Advisory or Steering Committees for Grifols, Octapharma, Takeda, and Werfen. J.R.S.: In-kind laboratory support from Diagnostica Stago. L.A.C.: L.A.C.’s research institution has received honoraria from Bayer, BMS-Pfizer Alliance, The Academy for Continued Advancement in Healthcare Education, Amag Pharmaceutical, LEO Pharma, Sanofi, Valeo Pharma, and Servier. L.A.C. holds a Tier 2 Research Chair from the University of Ottawa. J.M.C.: Participation on Scientific Advisory Boards and consulting for Abbott, Anthos, BMS, Pfizer, Roche, Sanofi, and Werfen; research funding from CSL Behring to the institution. J.D.: Serves on advisory committees for Pfizer, Sanofi, Leo Pharma, Bristol-Myers Squibb, and Janssen. E.L-L.: Lecture honoraria and advisory fees from Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Portola, CSL Behring, Norgine, Roche, Leo, AstraZeneca, and Aspen; institutional research support from Bayer AG, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Werfen, and CSL Behring. B.R.: Consultant for AbocaSRL on medical devices; Advisory Committee for Bayer AG. C.M.S.: Advisory for Norgine Pharma. D.S.: Honoraria for educational presentations and advisory fees paid indirectly to research institute from AstraZeneca, BMS-Pfizer, Roche, Servier. D.S. is supported by a Tier 2 Canada Research Chair in Anticoagulant Management of Cardiovascular Disease. J.I.W.: Consultant or member of Advisory Boards or Steering Committees for Anthos, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson and Johnson, Merck, and Regeneron., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

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., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Patients with atrial fibrillation (AF) and concomitant moderate-to-severe mitral stenosis (MS) are listed as a contraindicated population to direct oral anticoagulant (DOAC) because of the traditional tenet of high stroke risk, despite scarce evidence. With accumulating data, we sought to conduct a systematic meta-analysis to preliminarily explore the efficacy and safety of DOAC versus warfarin in patients with AF and concomitant significant MS., Methods: We searched the Medline, Embase databases, and the Cochrane Library (assessed October 10th, 2022) for eligible studies. Risk ratios (RRs) and 95% confidence intervals (CIs) were synthesized in Stata 16.1 (StataCorp)., Results: In random-effects meta-analyses, DOACs demonstrated a similar risk of stroke or systemic embolism (RR 0.51; 95% CI 0.09-2.96), all-cause death (RR 0.81; 95% CI 0.35-1.87), major or clinically relevant non-major bleeding (RR 0.57; 95% CI 0.24-1.39), and silent cerebral ischemia (RR 1.01; 95% CI 0.64-1.58) when compared with warfarin., Conclusions: DOACs were similar to warfarin in the efficacy and safety profiles in patients with AF and concomitant significant MS. Future evidence is expected from other large trials., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The efficacy of factor Xa inhibitors in patients with atrial fibrillation (AF) and rheumatic heart disease (RHD) is unknown., Methods/results: The objective of this article was to conduct a comprehensive evaluation of the INVICTUS trial, an open-label randomized controlled study that compared vitamin K antagonists (VKA) to rivaroxaban in patients with AF and RHD while also considering the existing evidence from literature in this particular area of research., Conclusion: The findings of the INVICTUS trial indicated that rivaroxaban was found to be inferior in efficacy to VKA. However, it is important to note that the primary outcome of the trial was driven by sudden death and death caused by mechanical pump failure. As a result, it is necessary to approach the data from this study with caution, and it would be inappropriate to draw parallel conclusions for other causes of valvular AF. Particularly, the perplexing issue of how rivaroxaban could have contributed to both pump failure and sudden cardiac death requires further explanation. Additional data regarding changes in heart failure medication and ventricular function would be essential for proper interpretation., (© 2023. The Author(s).)

Background: Bariatric surgery (BS) induces significant changes in gastrointestinal anatomy, potentially influencing the pharmacokinetics of orally administered drugs such as rivaroxaban., Objectives: This phase 1 study aimed to assess the pharmacokinetics and safety of full-dose rivaroxaban in post-BS patients., Methods: The ABSORB (Rivaroxaban Pharmacokinetics and Pharmacodynamics After Bariatric Surgery and in Morbid Obesity) study was a single-center, nonrandomized, multiple-dose, parallel-design bioequivalence trial. Adult patients with stable weight after Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) were compared with subjects with class III obesity and healthy controls. Participants received 20 mg of rivaroxaban daily for 8 days., Results: Post-BS patients exhibited altered rivaroxaban pharmacokinetics, suggesting reduced absorption. Mean area under the concentration-time curve from time 0 to 24 hours after the first dose (RYGB, 1806.8 ng.h/mL; SG, 1648.9 ng.h/mL) was lower compared with that in controls (1893.5 ng.h/mL). At steady state, the area under the concentration-time curve values remained lower in BS groups (RYGB, 2129.9 ng.h/mL; SG, 1946.4 ng.h/mL) than in controls (2224.8 ng.h/mL). The maximum concentration after the first dose was lower in post-RYGB subjects (214.9 ng/mL) than in controls (264.1 ng/mL). This difference was less pronounced at steady state (RYGB, 256.9 ng/mL vs controls, 288.8 ng/mL). Neither BS group met bioequivalence criteria compared with controls, whereas the group with class III obesity met bioequivalence criteria compared with controls at steady state., Conclusion: Rivaroxaban displayed minor pharmacokinetic variations in post-BS patients. Given reported interindividual variability in the general population, these variations are unlikely to be of clinical significance. Our findings support rivaroxaban use in BS patients, emphasizing the need for further research in this area., Competing Interests: Declaration of competing interests J.T. reports personal fees from Sanofi and Viatris outside the submitted work. F.C. reports having received research grant support from Bristol Myers Squibb/Pfizer and Bayer and fees for board memberships or symposia from Bayer, Bristol Myers Squibb/Pfizer, Merck Sharp and Dohme, Sanofi, Leo Pharma, Janssen, and Astra Zeneca and has received travel support from Bayer, Bristol Myers Squibb/Pfizer, Merck Sharp and Dohme, Leo Pharma, Astra Zeneca, Sanofi, and Chiesi. The remaining authors have no known competing interests related to this work., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) is common in patients with chronic kidney disease (CKD) undergoing hemodialysis and in this patient population, management in terms of oral anticoagulation (OAC) presents unique challenges due to the increased risk of both thromboembolic events and bleeding complications. The attributable risk of AF for stroke may differ from patients without CKD, raising the question if OAC is indicated at all. Historically, vitamin K antagonists (VKA) have been the standard treatment for anticoagulation in AF; however, direct oral anticoagulants (DOACs) have emerged as an alternative therapeutic option, whereby data from prospective randomised trials with hemodialysis patients is limited resulting in great variability of practice and guideline recommendations. This review summarizes existing data sources regarding the use and benefit of oral anticoagulation with VKA and DOAC in hemodialysis patients., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The management of factor Xa (FXa) inhibitor-associated bleeding remains a clinical challenge. Massive bleeding is often associated with complex coagulopathy and, thus, the sole reversal of FXa inhibitors might not be sufficient to restore hemostasis, requiring instead a multimodal approach. Four-factor prothrombin complex concentrate (4F-PCC) is widely recognized as a viable treatment option for FXa inhibitor-associated bleeding. Here, we applied computational models to explore the effect 4F-PCC has on the coagulation cascade and restoration of thrombin generation in a system that simulates a patient that has received a FXa inhibitor. The coagulation model is largely based on a previously developed model with modifications incorporated from various other published sources. The model was calibrated and validated using data from a phase 3 clinical trial of vitamin K antagonist reversal with 4F-PCC. Using the parameters and initial conditions determined during the calibration and validation process, the prothrombin time (PT) test simulations predicted a PT of 11.4 seconds. The model successfully simulated the effects of rivaroxaban and apixaban on total thrombin concentration and showed that 4F-PCC increased thrombin generation in the presence of rivaroxaban or apixaban., Competing Interests: Competing Interests statement remains unchanged: M.H., research support from Sanofi and Takeda; advisory board for Sanofi and BPL. I.M., E.H., M.B., O.G., and A.R.S are employees of CSL This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no restrictions on sharing of data and/or materials., (Copyright: © 2024 Muir et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Clinical trials of direct oral anticoagulants (DOAC) are scarce and inconclusive in patients who are receiving dialysis, for whom DOAC are not labelled in Europe. In a French nationwide registry study of patients on chronic dialysis, we compared the effectiveness and safety of off-label DOAC use vs approved vitamin K antagonist (VKA)., Methods: Data on patients on dialysis were extracted from the French Renal Epidemiology and Information Network (REIN) registry and merged with data from the French national healthcare system database (Système National des Données de Santé, SNDS). Patients on dialysis who had initiated treatment with an oral anticoagulant between 1 January 2012 and 31 December 2020, were eligible for inclusion. The primary safety outcome was the occurrence of major bleeding events and the primary effectiveness outcome was the occurrence of thrombotic events. Using propensity score-weighted cause-specific Cox regression, we compared the safety and effectiveness outcomes for DOAC and VKA., Results: A total of 8954 patients received an oral anticoagulant (483 DOAC and 8471 VKA) for the first time after the initiation of dialysis. Over a median (interquartile range) follow-up period of 1.7 (0.8-3.2) years, 2567 patients presented a first thromboembolic event and 1254 patients had a bleeding event. After propensity score adjustment, the risk of a thromboembolic event was significantly lower in patients treated with a DOAC than in patients treated with a VKA {weighted hazard ratio (wHR) [95% confidence interval (CI)] 0.66 (0.46; 0.94)}. A non-significant trend toward a lower risk of major bleeding events was found in DOAC-treated patients, relative to VKA-treated patients [wHR (95% CI) 0.68 (0.41; 1.12)]. The results were consistent across subgroups and in sensitivity analyses., Conclusions: In a large group of dialysis patients initiating an oral anticoagulant, the off-label use of DOACs was associated with a significantly lower risk of thromboembolic events and a non-significantly lower risk of bleeding, relative to VKA use. This provides reassurance regarding the off-label use of DOACs in people on dialysis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Abstract: Treatment with direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) is effective and safe. However, bleeding complications still occur. Whether DOAC level measurement may further improve treatment efficacy and safety is still an open issue. In the "Measure and See" study, venous blood was collected 15-30 days after DOAC initiation in patients with AF who were then followed up for 1 year to record the occurrence of major and clinically relevant nonmajor bleeding. DOAC plasma levels were measured in 1 laboratory, and results were kept blind to patients and treating doctors. Trough DOAC levels were assessed in 1657 patients (957 [57.7%] and 700 patients treated with standard and low-dose, respectively). Fifty bleeding events were recorded during 1606 years of follow-up (3.11% pt/yrs). Fifteen bleeding events (4.97% pt/yrs) occurred in patients with C-trough standardized values in the highest activity class (>0.50), whereas 35 events (2.69% pt/yrs) occurred in those with values in the 2 lower classes (≤0.50, P = .0401). Increasing DOAC levels and low-dose DOAC use were associated with increased bleeding risk in the first 3 months of treatment. Overall, 19% of patients receiving low doses had standardized values in the highest class. More bleeding occurred in patients on low (4.3% pt/yrs) vs standard (2.2% pt/yrs; P = .0160) dose DOAC. Early measurement of DOAC levels in patients with AF identified many individuals with high levels despite the low doses use and had more bleeding risk during the first 3 months of treatment. This trial was registered at www.ClinicalTrials.gov as #NCT03803579., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: Several randomised controlled trials have demonstrated that novel oral anticoagulants are safer compared with vitamin K antagonists for the management of non-valvular atrial fibrillation (NVAF) to prevent thromboembolic events in the general population. There is a growing interest in the use of apixaban in patients with end-stage renal disease (ESRD) undergoing peritoneal dialysis (PD) but there is a lack of randomised data in this population., Methods and Analysis: APIDP2 is a prospective parallel, randomised, open-label, blinded endpoint trial involving patients with ESRD undergoing chronic PD who have NVAF. A total of 178 participants will be recruited from 20 French PD centres. Eligible patients will be randomly assigned to receive either apixaban at a reduced dose of 2.5 mg two times per day (dose determined with the previous pharmacokinetic study APIDP1) or dose-adjusted to international normalised ratio (INR) target (2-3) coumadin therapy. Anticoagulation to prevent thromboembolic events will be initiated or changed according to the randomisation for a duration of 1 year. The primary outcome is a major or clinically relevant non-major bleeding from randomisation up to month 12, assessed according to the International Society on Thrombosis and Haemostasis Score. Secondary outcomes encompass an efficacy composite criterion combining stroke or transient ischaemic attack (TIA), cardiovascular death and thrombosis including myocardial infarction cumulated at 12 months. Bleeding events will be also classified according to Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) and Thrombolysis In Myocardial Infarction (TIMI) criteria and pharmacodynamics outcomes will evaluate the time within the INR target range of 2-3 in the warfarin arm over 1 year, and anti-Xa apixaban activity in case of bleeding events and at 1 month, 6 months and 12 months of follow-up in the apixaban arm. To demonstrate that apixaban is safer than warfarin at 1 year, assuming two interim analyses after 60 and 118 patients, a bilateral alpha risk of 5% and a power of 80%, 178 patients are needed in this randomised trial (effect size found from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Study among patients with creatinine clearance 25-30 ml/min), that is, 89 patients per group., Ethics and Dissemination: The study has been approved by the ethics committee Comité de Protection des Personnes Sud Est III - Lyon - FRANCE, CT number 2023-507544-37-00. Written informed consent is required for each participant. Findings will be presented at scientific meetings and published in peer-reviewed journals., Trial Registration: ClinicalTrials.gov, NCT06045858; European Clinical Trial System, CT number 2023-507544-37-00., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients with thrombotic antiphospholipid syndrome (APS) are at high risk for recurrent thrombosis, and indefinite anticoagulation is recommended. Patients with APS merit indefinite anticoagulation, and vitamin K antagonists (VKAs) have historically been the standard treatment. Direct oral anticoagulants (DOACs) present an appealing alternative to VKAs. Due to their pharmacokinetic and pharmacodynamic characteristics, DOACs offer advantages over VKAs, namely the lack of need for laboratory monitoring, the usage of a fixed dosage, and the absence of significant interaction with dietary components and drugs. The efficacy and safety of DOACs in patients with APS have been studied in four phase II/III clinical trials (three with rivaroxaban and one with apixaban). These studies showed DOACs' inferiority compared to VKAs in preventing recurrent thrombosis. Recurrence was significantly greater in patients with arterial thrombotic events and a triple positivity for antiphospholipid antibodies. No differences were observed in the incidence of venous thromboembolism between both groups. Major bleeding was similar in patients treated with DOACs or VKAs. Several observational studies have reported similar results. This review aims to analyse the existing evidence on the efficacy and safety of DOACs for secondary prevention in patients with APS.

Background: Direct oral anticoagulants (DOACs) have complex dosing regimens and are often incorrectly prescribed. We evaluated a nationwide DOAC population management dashboard rollout whose purpose includes pharmacist review and correction of off-label dosing prescriptions., Methods and Results: Using data from Veterans Health Affairs, we identified all patients prescribed DOACs for atrial fibrillation or venous thromboembolism between August 2015 and December 2019. Sites were grouped on the basis of the timing of moderate-high usage of the DOAC population management tool dashboard. Effectiveness was defined as the monthly rate of off-label DOAC prescribing and the rate of clinical adverse events (bleeding, composite of stroke or venous thromboembolism). Implementation was evaluated as the percentage of off-label DOAC prescriptions changed within 7 days. Among the 128 652 patients receiving DOAC therapy at 123 centers, between 6.9% and 8.6% had off-label DOAC prescriptions. Adoption of the DOAC population management tool dashboard before July 2018 was associated with a decline in off-label dosing prescriptions (8.7%-7.6%). Only 1 group demonstrated a significant reduction in monthly rates of bleeding following implementation. All sites experienced a reduction in the composite of venous thromboembolism or stroke following dashboard adoption. There was no difference in the implementation outcome of DOAC prescription change within 7 days in any of the adoption groups., Conclusions: Early adoption of the DOAC population management tool dashboard was associated with decreased rates of off-label DOAC dosing prescription and reduced bleeding. Following adoption of the DOAC population management tool dashboard, all sites experienced reductions in venous thromboembolism and stroke events.

Background/aims: Early studies on direct oral anticoagulants (DOACs) reported a higher risk of gastrointestinal bleeding (GIB) compared with warfarin; however, recent studies have reported a reduced risk. Therefore, this study was designed to evaluate the risk of GIB in users of DOAC and warfarin., Methods: Using a common data model, we investigated the comparative risk of GIB in subjects from eight hospitals who were newly prescribed DOACs or warfarin. We excluded subjects who had a prior history of GIB or had been prescribed both medications. After propensity score matching, we analyzed 3,347 matched pairs of new DOAC and new warfarin users., Results: The risk of GIB in new DOAC users was comparable to that in new warfarin users (hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.65 to 1.40; p=0.808). New DOAC users had a similar risk of GIB to new warfarin users among older patients >65 years (HR, 1.00; 95% CI, 0.69 to 1.52; p=0.997) and in older patients >75 years (HR, 1.21; 95% CI, 0.68 to 2.10; p=0.509). In addition, the risk of GIB was not significantly different between two groups according to sex. We also found that the risk of GIB in DOAC users was 26% lower in edoxaban or apixaban subgroups compared to rivaroxaban or dabigatran subgroups (HR, 0.74; 95% CI, 0.69 to 1.00; p=0.049)., Conclusions: In real-world practice, the risk of GIB in new DOAC users is comparable to that in new warfarin users. In DOAC users, the risk of GIB was lower in edoxaban or apixaban subgroups than rivaroxaban or dabigatran subgroups.

This was an open-label, single-dose, phase I study to characterize the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of edoxaban in pediatric subjects from birth to 18 years at risk for venous thromboembolism (VTE). Children requiring anticoagulant therapy were enrolled into 5 age cohorts (0 to < 6 months (N = 12), 0.5 to < 2 years (N = 13), 2 to < 6 years (N = 13), 6 to < 12 years (N = 13), and 12 to < 18 years (N = 15)) receiving tablet or oral suspension of edoxaban at doses expected to be equivalent to 30 or 60 mg once daily (q.d.) in adult subjects with VTE. Sixty-six pediatric subjects were enrolled and completed the study. Edoxaban plasma concentration peaked between 1 and 3 hours and declined rapidly until 4-8 hours. The range of mean total apparent clearance across 5 age cohorts at low and high doses was 0.47 to 1.11 L/h/kg. The ranges of mean volume of central compartment and apparent peripheral volume were 2.31 to 3.59 L/kg and 1.92 to 4.14 L/kg, respectively. Across all age groups, the estimated median exposures were within the 0.5- to 1.5-fold of the median area under the plasma drug concentration-time curve (AUC) in adult subjects receiving corresponding doses (30 mg q.d. for low dose and 60 mg q.d. for high dose). In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time, and anti-Factor Xa activity) showed a linear PK-PD relationship and were in line with previous adult data. The results support further evaluation of the pediatric doses in larger pivotal trials., (© 2024 Daiichi Sankyo Inc. Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Background: The Vascular Outcomes Study of aspirin (ASA) Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for peripheral artery disease (PAD) trial demonstrated the superiority of ASA and low-dose rivaroxaban (Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial dosing) compared with ASA alone in reducing major adverse cardiovascular events and major adverse limb events. We studied the COMPASS discharge prescription patterns in patients with symptomatic PAD who have undergone revascularization in our institution, since the time of publication of the Vascular Outcomes Study of ASA Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD trial., Methods: All patients included in this study had documented lower-extremity atherosclerotic PAD and were eligible for COMPASS dosing. Revascularization strategies included endovascular (n = 299), suprainguinal bypass (n = 18), and infrainguinal bypass (n = 36)., Results: COMPASS prescription patterns for the composite of endovascular and surgical strategies demonstrated a consistently low rate over time, without a trend toward increasing use. COMPASS dosing was prescribed as often as antiplatelet monotherapy (33.4% COMPASS vs. 34.6% antiplatelet monotherapy). This low COMPASS prescription rate was driven by significantly lower COMPASS prescriptions following endovascular therapy compared to surgical bypass (28.8% endovascular vs. 59.3% surgical bypass). COMPASS prescriptions following surgical bypass showed better trends; half of suprainguinal bypass patients (50.0%) and two-thirds of infrainguinal bypass patients (63.9%) were discharged on COMPASS. Despite patients with chronic limb-threatening ischemia (CLTI) representing a high-risk limb presentation, COMPASS prescriptions were low (29.8%), as opposed to patients without CLTI, and did not show a trend toward increasing use. In patients who underwent reinterventions throughout the observation period, there was a low conversion rate from ASA alone to COMPASS (3/26, 11.5%)., Conclusions: In this observational study, one-third of patients were undertreated by prescription of antiplatelet monotherapy, indicating that there is significant room for medical optimization. This is especially true of patients undergoing endovascular treatment, including the high-risk subgroup of patients with CLTI. We highlight the importance of dual pathway antithrombotic therapy in patients eligible for COMPASS dosing to optimize best current evidence medical therapy., (Copyright © 2024 Elsevier Inc. All rights reserved.)