Apixaban versus low molecular weight heparin in patients with cancer-associated venous thromboembolism: a systematic review and meta-analysis.

Background: The optimal treatment regimen for patients with cancer-associated venous thromboembolism (CA-VTE) remains unclear. Therefore, the authors sought to compare the outcomes of (VKAs) versus direct apixaban and low molecular weight heparin (LMWH) in patients with CA-VTE. Methods: MEDLINE, Embase, and Cochrane Central databases were searched for randomized controlled trials (RCTs) and observational studies comparing the efficacy and safety of apixaban and LMWH in patients with CA-VTE. Major bleeding, clinically relevant non-major bleeding (CRNMB), recurrence of pulmonary embolism (PE), deep venous thrombosis (DVT) and bleeding-related mortality were among outcomes of interest. Mantel-Haenszel weighted random-effects model was used to calculate relative risks (RRs) with 95% CIs. Results: The analysis included 12 011 patients from 3 RCTs and 2 observational studies. Compared to LMWH, apixaban significantly decreased the risk of major bleeding [RR 0.67 (95% CI 0.54, 0.83); P=0.0003, I2=0%] without significantly changing the risk of clinically relevant non-major bleeding [RR 0.96 (95% CI 0.64, 0.1.45); P=0.85, I2=57%]. Patients on apixaban had a noticeably reduced the risk of recurrence of PE than those taking LMWH, according to a meta-analysis [RR 0.56 (95% CI 0.32, 0.99); P=0.05, I2=0%]. There was no discernible difference between apixaban and LMWH in bleeding-related mortality events [RR 0.20 (95% CI 0.01, 4.18); P=0.30, I2=NA%], and recurrence of DVT [RR 0.60 (95% CI 0.22, 1.59); P=0.23, I2=32%]. Conclusion: Due to its lower risk of severe bleeding and reduced PE recurrence, apixaban may be a preferable treatment option for CA-VTE, but additional research is required to validate these conclusions and evaluate its long-term efficacy and safety.

Cerebral Vein Thrombosis and Direct Oral Anticoagulants: A Review.

Cerebral venous thrombosis (CVT) is a rare type of cerebrovascular event in which the thrombosis occurs in a vein of the cerebral venous system. The diagnosis could be challenging due to the great clinical variability, but the outcome is favourable in most cases, especially in the case of early diagnosis. Anticoagulant therapy is the core of CVT management and currently consists of heparin in the acute phase followed by vitamin K antagonists (VKAs) in the long term. The ideal duration of anticoagulant therapy is still unclear, and the same criteria for the treatment of extracerebral venous thromboembolism currently apply. In this paper, we reviewed the literature regarding the use of direct oral anticoagulants (DOACs) in CVT since in recent years a considerable number of studies have been published on the use of these drugs in this specific setting. DOACs have already been shown to be equally effective with VKAs in the treatment of venous thromboembolism. In addition to efficacy, DOACs appear to have the same safety profile, being, on the other hand, more manageable, as they do not require close monitoring with continuous personalised dose adjustments. In addition, a further advantage of DOACs over VKAs is the possibility of anticoagulant prophylaxis using a reduced dosage of the drug. In conclusion, although the use of DOACs appears from preliminary studies to be effective and safe in the treatment of CVT, additional studies are needed to include these drugs in the treatment of CVT.

Post-extraction bleeding in patients on direct oral anticoagulants.

Objectives: This study aimed to evaluate the association between use of direct oral anticoagulants (DOACs) and post-extraction bleeding and to quantify bleeding risk in patients receiving DOACs. Materials and Methods: The study included 293 patients who were taking DOACs and underwent tooth extraction (414 teeth). The patients were divided into those who had the extraction while taking DOACs and those who discontinued DOACs before the extraction. Bleeding complications were recorded and compared between the patient groups and types of DOACs. Results: Of the 293 patients, 12 patients (6.9%) had post-extraction bleeding. Post-extraction bleeding occurred in 12 of the 414 tooth extraction sites. Among the 246 patients who underwent dental extraction while continuing DOAC therapy, 12 patients (8.5%) had post-extraction bleeding. Among the 47 patients who underwent dental extraction after discontinuing the administration of DOACs, none reported post-extraction bleeding. There was no significant difference in the number of patients with post-extraction bleeding between the two groups (P=0.122). Conclusion: Continuing DOAC therapy during dental extraction does not increase post-extraction bleeding tendency. These results are consistent with those of previous studies.

Plasma apixaban concentrations and thrombin generation assay parameters in response to dose reduction for atrial fibrillation.

AIMS: To investigate plasma apixaban concentrations and thrombin generation assay (TGA) parameters across different apixaban doses in atrial fibrillation patients who had dose-reduction criteria for apixaban. METHODS: This observational study included 374 patients (mean age 75.6 ± 7.7 years, 54.8% female) with dose-reduction criteria for apixaban. The patients were divided into 3 groups: (i) on-label standard dose (5 mg twice daily, n = 166); (ii) on-label reduced dose (2.5 mg twice daily, n = 55); and (iii) off-label underdose (2.5 mg twice daily, n = 153). Apixaban concentrations determined via the anti-Xa assay and TGA parameters were compared at trough levels. RESULTS: The off-label underdose group exhibited significantly lower apixaban trough concentrations than the on-label reduced-dose and standard-dose groups (56.7 ± 42.9 vs. 83.7 ± 70.4 vs. 129.9 ± 101.8 ng/mL, all P < .001). Less than 70% of all patients fell within the expected range of apixaban concentrations. Proportions exceeding the upper limit of the expected range were significantly lower in the off-label underdose group (1.3%) than in the on-label reduced-dose (9.1%, P = .005) and standard-dose (12.7%, P < .001) groups. The TGA parameters showed the on-label standard-dose group displaying the lowest thrombogenic profiles. Lower creatinine clearance was the most significant predictor of higher apixaban concentrations. CONCLUSION: Off-label underdosed apixaban resulted in lower apixaban concentrations than both on-label standard and reduced-dose regimens. A considerable proportion of the patients exhibited apixaban concentrations outside the expected range, suggesting the potential benefits of plasma concentration monitoring. Further studies are needed to compare dosages directly, investigate the impact of plasma apixaban concentration monitoring and validate the current dose-reduction criteria.

Factor Xa Inhibitors Versus Vitamin K Antagonists in Atrial Fibrillation Patients with End-Stage Kidney Disease on Dialysis: A Meta-Analysis.

BACKGROUND: Atrial fibrillation (AF) is prevalent among patients with end-stage kidney disease (ESKD) undergoing dialysis, and both conditions are associated with a heightened risk of cardiovascular diseases. Anticoagulation is essential for preventing thromboembolic complications in these patients. This study aimed to evaluate the effects of factor Xa inhibitors compared to vitamin K antagonists (VKAs) for AF patients on dialysis. METHODS: A comprehensive search of PubMed and Embase databases was conducted to identify relevant studies published up to June 2024. Eligible studies compared factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) with VKAs in AF patients on dialysis, with primary outcomes of stroke or systemic embolism(SSE) and major bleeding. RESULTS: A total of 7 studies (3 randomized controlled trials and 4 observational cohorts) were included. For the RCTs, the use of factor Xa inhibitors was associated with a reduced risk of SSE compared to VKAs (odds ratio [OR] = 0.37, 95% confidence interval [CI]:0.15-0.93). There was no significant difference in the risk of major bleeding events between the two groups (OR = 0.65, 95%CI:0.32-1.33). Observational cohort studies yielded similar results with a decreased risk of SSE (hazard ratio [HR] = 0.74, 95%CI:0.57-0.96) and no significant difference in major bleeding (HR = 0.87, 95%CI:0.62-1.22). No differences in treatment effect between apixaban and rivaroxaban were observed for efficacy (p-interaction = 0.44) and safety (p-interaction = 0.21) outcomes. CONCLUSION: Factor Xa inhibitors, particularly apixaban and rivaroxaban, were associated with a lower risk of SEE without an increase in major bleeding, which might be convenient alternatives to VKAs in managing AF in patients with ESKD on dialysis.

Risk of Major Bleeding, Stroke/Systemic Embolism, and Death Associated With Different Oral Anticoagulants in Patients With Atrial Fibrillation and Severe Chronic Kidney Disease.

BACKGROUND: Patients with atrial fibrillation and severe chronic kidney disease have higher risks of bleeding, thromboembolism, and mortality. However, optimal anticoagulant choice in these high-risk patients remains unclear. METHODS AND RESULTS: Using deidentified electronic health records from the Optum Labs Data Warehouse, adults with atrial fibrillation and severe chronic kidney disease (estimated glomerular filtration rate <30 mL/min per 1.73 m2) initiating warfarin, apixaban, or rivaroxaban between 2011 and 2021 were included. Using inverse probability of treatment weighting, adjusted risks of major bleeding, stroke/systemic embolism, and death were compared among agents. A total of 6794 patients were included (mean age, 78.5 years; mean estimated glomerular filtration rate, 24.7 mL/min per 1.73 m2; 51% women). Apixaban versus warfarin was associated with a lower risk of major bleeding (incidence rate, 1.5 versus 2.9 per 100 person-years; subdistribution hazard ratio [sub-HR], 0.53 [95% CI, 0.39-0.70]), and similar risks for stroke/systemic embolism (incidence rate, 1.9 versus 2.4 per 100 person-years; sub-HR, 0.80 [95% CI, 0.59-1.09]) and death (incidence rate, 4.6 versus 4.5 per 100 person-years; HR, 1.03 [95% CI, 0.82-1.29]). Rivaroxaban versus warfarin was associated with a higher risk of major bleeding (incidence rate, 4.9 versus 2.9 per 100 person-years; sub-HR, 1.65 [95% CI, 1.10-2.48]), with no difference in risks for stroke/systemic embolism and death. Apixaban versus rivaroxaban was associated with a lower risk of major bleeding (sub-HR, 0.53 [95% CI, 0.36-0.78]). CONCLUSIONS: These real-world findings are consistent with potential safety advantages of apixaban over warfarin and rivaroxaban for patients with atrial fibrillation and severe chronic kidney disease. Further randomized trials comparing individual oral anticoagulants are warranted.

Outcomes of direct oral anticoagulants with aspirin vs warfarin with aspirin: a registry-based cohort study.

Background: For patients anticoagulated with direct oral anticoagulants (DOACs) or warfarin and on aspirin (ASA) for nonvalvular atrial fibrillation and/or venous thromboembolism, it is unclear if bleeding outcomes differ. Objectives: To assess bleeding rates for ASA with DOACs vs warfarin and one another. Methods: Registry-based cohort study of patients followed by a 6-center quality improvement collaborative in Michigan using data from 2009 to 2022. The study included adults on ASA with warfarin or DOACs for atrial fibrillation and/or venous thromboembolism without a recent myocardial infarction or heart valve replacement. Results: After propensity matching by anticoagulant class, we compared 2 groups of 1467 patients followed for a median of 18.0 months. Any bleeding and nonmajor bleeding was increased with DOACs + ASA compared with warfarin + ASA (32.2 vs 27.8 and 27.1 vs 22.9 events/100 patient-years; relative risks [RRs], 1.1 and 1.2; 95% CIs, 1.1-1.2 and 1.1-1.3, respectively). After matching by drug, patients on apixaban + ASA vs warfarin + ASA had more bleeding (31.2 vs 27.8 events/100 patient-years; RR, 1.1; 95% CI, 1.0-1.2) and nonmajor bleeding but less major bleeding (3.8 vs 4.7 events/100 patient-years; RR, 0.8; 95% CI, 0.6-1.0) and emergency room visits for bleeding. Patients on rivaroxaban + ASA vs warfarin + ASA had more bleeding (39.3 vs 26.3 events/100 patient-years, RR, 1.5; 95% CI, 1.3-1.6), nonmajor bleeding, and thrombosis. Patients on apixaban + ASA vs rivaroxaban + ASA had significantly less bleeding (22.5 vs 39.3/100 patient-years; RR, 0.6; 95% CI, 0.5-0.7), nonmajor bleeding, major bleeding (2.1 vs 5.5 events/100 patient-years; RR, 0.4; 95% CI, 0.2-0.6), emergency room visits for bleeding, and thrombotic events. Conclusion: Patients on DOAC + ASA without a recent myocardial infarction or heart valve replacement had more nonmajor bleeding but otherwise similar outcomes compared with warfarin + ASA. Patients treated with rivaroxaban + ASA experienced more adverse clinical events compared with warfarin + ASA or apixaban + ASA.

Risks of major bleeding and venous thromboembolism in patients undergoing total hip or total knee arthroplasty using therapeutic dosages of DOACs.

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.

Anticoagulation strategy for patients presenting with ischemic strokes while using a direct oral anticoagulant: A systematic review and meta-analysis.

BACKGROUND: While direct-acting oral anticoagulants (DOACs) have established efficacy in reducing the risk of ischemic stroke, they still leave a residual risk of stroke, which may be greater in practice (0.7-2.3%) than in controlled clinical trial settings. This meta-analysis examines four therapeutic approaches following a stroke in patients already on DOACs: continuing with the same DOAC, changing to a different DOAC, increasing the current DOAC dosage, or switching to a vitamin K antagonist (VKA), such as warfarin. METHODS: Systematic review of literature from the MEDLINE, Embase, and Cochrane databases, was conducted in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The analysis focused on six studies with varied patient demographics, examining as outcomes as recurrent ischemic stroke, intracranial hemorrhage, other bleeding events, and mortality. RESULTS: Six studies comprising 12,159 patients were included, all of them were observational. Patients who remained on their initial DOAC regimen had a lower risk of experiencing ischemic strokes (risk ratio (RR) 0.55; 95% confidence interval (CI) 0.43-0.70; p < 0.001; I2 = 0%), intracranial hemorrhage (RR 0.37; 95% CI 0.25-0.55; p < 0.001; I2 = 0%), and hemorrhagic events (RR 0.44; 95% CI 0.30-0.63; p < 0.001; I2 = 6%) compared to those who were switched to warfarin, with an increase in mortality rates (hazard ratio (HR) 1.85; 95% CI 1.06-3.24; p = 0.03; I2 = 84%). In contrast, neither changing to a different DOAC nor adjusting the dose proved to be more effective than the original regimen. CONCLUSION: Post-stroke adjustments to anticoagulation therapy-whether altering the drug or its dosage-do not yield additional benefits. In addition, the results suggest that warfarin may be less effective than DOACs for preventing stroke recurrence, bleeding complications, and death in this patient population.

The comparative efficacy and safety of factor Xa inhibitors and warfarin for primary thromboprophylaxis in multiple myeloma patients undergoing immunomodulatory therapy.

There are limited data on the optimal choice of anticoagulation in multiple myeloma (MM) patients receiving immunomodulatory drugs (IMiDs). We conducted a propensity score-matched cohort study using the TriNetX database to compare the efficacy and safety of factor Xa inhibitors and warfarin in this patient population. Compared to warfarin, factor Xa inhibitors had a similar risk of deep vein thrombosis (hazard ratio [HR]: 1.11 [95% CI: 0.50-2.46]) or pulmonary embolism (HR: 1.08 [95% CI: 0.59-2.00]). There were no differences in the risk of gastrointestinal or intracranial bleeding. Factor Xa inhibitor-treated patients had lower all-cause mortality (HR: 0.56 [95% CI: 0.36-0.86]) compared with warfarin. These data suggest that factor Xa inhibitors had similar safety and efficacy compared with warfarin for MM patients on IMiDs.

Andexanet Alfa versus Four-Factor Prothrombin Complex Concentrate for the Reversal of Factor Xa (FXa) Inhibitor-Associated Intracranial Hemorrhage: A Systematic Review of Retrospective Studies.

Background/Objectives: There are limited data on the risks and benefits of using Andexanet alfa (AA) compared with four-factor prothrombin complex concentrate (4F-PCC) for the reversal of factor Xa inhibitor-associated intracranial hemorrhage (ICH). Our aim was to describe a compilation of the information available in the literature to date. Methods: PubMed, Embase, Web of Science (Clarivate Analytics) and the Cochrane Central Register of Controlled Trials were searched until December 2023. Following the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)" guidelines, our systematic literature review included studies that were retrospective in design and evaluated both drugs to control bleeding and complications (death and thromboembolic events). Two researchers re-examined the studies for relevance, extracted the data and assessed the risk of bias. No meta-analyses were performed for the results. Results: In this limited patient sample, we found no differences between published articles in terms of neuroimaging stability or thrombotic events. However, some studies show significant differences in mortality, suggesting that one of the AAs may be superior to 4F-PCC. Conclusions: Our qualitative analysis shows that AA has a better efficacy profile compared with 4F-PCC. However, further studies monitoring these patients and a multicenter collaborative network dedicated to this topic are needed.

Selection criteria for anticoagulants: survey of Japanese cardiologists based on their daily clinical practice: the Selection DOAC study.

BACKGROUND: In patients with atrial fibrillation (AF), direct oral anticoagulants (DOACs) have been utilized as an alternative to warfarin, which is known to have several limitations. This study aimed to clarify the selection criteria for anticoagulants, considering both individual patient factors and the differences between various drugs. METHODS: This study conducted a web-based questionnaire from September 20, 2023 to October 3, 2023, among physicians who were members of a cardiology-specific website. RESULTS: In total, 172 respondents were enrolled in this study. Edoxaban was the most frequently selected anticoagulant (39.1%), followed by apixaban (32.7%) and rivaroxaban (16.8%). Logistic regression analysis revealed that increased concern for adherence enhanced the frequency of selecting edoxaban (odds ratio [OR] = 2.42; p = 0.047), with the opposite trend observed for dabigatran (OR = 0.404; p = 0.029). The selection of apixaban is related to whether the patient is able to maintain a regular lifestyle, including adherence to medication schedules (OR = 1.874; p = 0.031). Furthermore, detailing activities from a medical representative, especially regarding a new indication, were found to influence drug selection for rivaroxaban (OR = 2.422; p = 0.047). CONCLUSION: This study revealed that edoxaban is the most frequently selected anticoagulant. Although prescribing cardiologists select drugs based on background factors, adherence to medication and information from medical representatives were also crucial factors in the selection process.

Design and rationale for REVERXaL: A real-world study of patients with factor Xa inhibitor-associated major bleeds.

BACKGROUND: The prevalence of anticoagulation treatment is increasing as an aging global population faces a high burden of cardiovascular comorbidities. Direct oral anticoagulants, including factor Xa inhibitors (FXai), are replacing vitamin K antagonists as the most commonly prescribed treatment for reducing risk of thrombotic events. While the risk of FXai-associated spontaneous bleeds is established, less is understood about their management and the effect of treatment on clinical and patient-reported outcomes. The primary objectives of the REVERXaL study are to describe patient characteristics, health care interventions during the acute-care phase, in-hospital outcomes, and associations between timing of reversal/replacement agent administration and in-hospital outcomes. Secondary/exploratory objectives focus on clinical assessments and patient-reported outcome measures (PROMs) at 30 and 90 days. METHODS: REVERXaL is a multinational, observational study of hospitalized patients with FXai-associated major bleeds in Germany, Japan, the United Kingdom, and the United States. The study includes 2 cohorts of approximately 2000 patients each. Cohort A is a historic cohort for whom medical chart data will be collected from hospitalization to discharge for patients admitted for major bleeds during FXai use within 2 years prior to enrollment of Cohort B. Cohort B will prospectively enroll patients administered any reversal/replacement agent during hospitalization to manage FXai-associated major bleeds and will include the collection of clinical outcomes and PROMs data over 3 months. CONCLUSIONS: REVERXaL will generate insights on patient characteristics, treatment approaches, and associated outcomes in patients hospitalized with FXai-associated major bleeds. These data may inform clinical practice and streamline treatment pathways in this population. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; unique identifier: NCT06147830.

External validation of the Pulmonary Embolism-Syncope, Anemia, and Renal Dysfunction bleeding score for early major bleeding in patients with acute pulmonary embolism: from the COMMAND VTE Registry-2.

BACKGROUND: There is no established risk score for anticoagulant-related bleeding during the acute phase in patients with pulmonary embolism (PE). The PE-Syncope, Anemia, and Renal Dysfunction (PE-SARD) bleeding score was developed to predict early major bleeding but has not yet been fully externally validated. OBJECTIVES: To externally validate the PE-SARD bleeding score. METHODS: Using the COntemporary ManageMent AND outcomes in patients with Venous ThromboEmbolism (COMMAND VTE) Registry-2 database, which enrolled 5197 consecutive acute symptomatic venous thromboembolism patients among 31 centers in Japan between January 2015 and August 2020, we identified acute PE patients. We divided them into 3 groups by the score: high-risk (>2.5 points), intermediate-risk (1-2.5 points), and low-risk (0 points). The discriminating and calibration performances of the score for 30-day major bleeding were assessed. Subgroup analyses based on active cancer were also performed. RESULTS: Of 2781 eligible patients, the high-risk group accounted for 557 patients (20%), intermediate-risk group for 1412 (51%), and low-risk group for 812 (29%). Major bleeding occurred in 121 patients within 30 days. The cumulative 30-day incidence of major bleeding substantially increased in the higher risk categories by the score (high-risk group, 8.2% [95% CI, 5.9%-10.5%]; intermediate-risk group, 4.6% [95% CI, 3.5%-5.7%]; and low-risk group, 1.8% [95% CI, 0.8%-2.7%]). The discriminating power of the score was modest with a C statistic of 0.65 (95% CI, 0.61-0.70), with a good calibration performance with a score of <4 points, except for that in active cancer patients. CONCLUSION: The PE-SARD bleeding score had a modest discriminating performance with a limited calibration performance in acute PE patients without active cancer.

Anticoagulantes Orais Diretos versus Antagonistas da Vitamina K para Trombo Ventricular Esquerdo: Uma Metanálise com Análise Sequencial de Ensaios / Direct Oral Anticoagulants versus Vitamin K Antagonists for Left Ventricular Thrombus: A Meta-Analysis with Trial Sequential Analysis

Resumo Fundamento Os antagonistas da vitamina K (AVKs) são o tratamento de primeira linha recomendado para trombo ventricular esquerdo (TVE); entretanto, os anticoagulantes orais diretos (AODs) têm sido considerados uma terapia alternativa. Objetivos Avaliar a eficácia e a segurança dos AODs em comparação com a terapia com AVKs em pacientes com TVE. Métodos PubMed, Embase e Cochrane foram sistematicamente pesquisados em busca de ensaios clínicos randomizados ou estudos de coorte que comparassem AODs versus AVKs para TVE. As razões de risco (RR) foram calculadas para desfechos binários, com intervalos de confiança (IC) de 95%. A significância estatística foi definida como valor de p < 0,05. Resultados Foram incluídos um total de 4 ensaios clínicos randomizados e 29 estudos de coorte, com 4.450 pacientes designados para AODs ou AVKs. Não houve diferença significativa entre os grupos para acidente vascular cerebral ou eventos embólicos sistêmicos (AVC/EES) (RR 0,84; IC 95% 0,65 a 1,07; p = 0,157), acidente vascular cerebral (RR 0,73; IC 95% 0,48 a 1,11; p = 0,140), eventos embólicos sistêmicos (EES) (RR 0,69; IC 95% 0,40 a 1,17; p = 0,166), resolução do trombo (RR 1,05; IC 95% 0,99 a 1,11; p = 0,077), qualquer sangramento (RR 0,78; IC 95% 0,60 a 1,00; p = 0,054), sangramento clinicamente relevante (RR 0,69; IC 95% 0,46 a 1,03; p = 0,066), sangramento menor (RR 0,73; IC 95% 0,43 a 1,23; p = 0,234), sangramento maior (RR 0,87; IC 95% 0,42 a 1,80; p = 0,705) e mortalidade por todas as causas (RR 1,05; IC 95% 0,79 a 1,39; p = 0,752). Em comparação com AVKs, a rivaroxabana reduziu significativamente AVC/EES (RR 0,35; IC 95% 0,16 a 0,91; p = 0,029) e EES (RR 0,39; IC 95% 0,16 a 0,95; p = 0,037). Conclusões Os AODs tiveram uma taxa semelhante de eventos tromboembólicos e hemorrágicos, bem como de resolução do trombo, em comparação com os AVKs no tratamento de TVE. A terapia com rivaroxabana teve uma redução significativa nos eventos tromboembólicos, em comparação com os AVKs.

Abstract Background Vitamin K antagonists (VKAs) are the recommended first-line treatment for left ventricular thrombus (LVT); however, direct oral anticoagulants (DOACs) have been considered an alternative therapy. Objectives To evaluate the efficacy and safety of DOACs compared with VKAs therapy in patients with LVT. Methods PubMed, Embase, and Cochrane were systematically searched for randomized clinical trials or cohort studies that compared DOACs versus VKAs for LVT. Risk ratios (RRs) were computed for binary endpoints, with 95% confidence intervals (95% CIs). Statistical significance was defined as p value < 0.05. Results A total of 4 randomized clinical trials and 29 cohort studies were included, with 4,450 patients assigned to either DOACs or VKAs. There was no significant difference between groups for stroke or systemic embolic (SSE) events (RR 0.84; 95% CI 0.65 to 1.07; p = 0.157), stroke (RR 0.73; 95% CI 0.48 to 1.11; p = 0.140), systemic embolic (SE) events (RR 0.69; 95% CI 0.40 to 1.17; p = 0.166), thrombus resolution (RR 1.05; 95% CI 0.99 to 1.11; p = 0.077), any bleeding (RR 0.78; 95% CI 0.60 to 1.00; p = 0.054), clinically relevant bleeding (RR 0.69; 95% CI 0.46 to 1.03; p = 0.066), minor bleeding (RR 0.73; 95% CI 0.43 to 1.23; p = 0.234), major bleeding (RR 0.87; 95% CI 0.42 to 1.80; p = 0.705), and all-cause mortality (RR 1.05; 95% CI 0.79 to 1.39; p = 0.752). Compared with VKAs, rivaroxaban significantly reduced SSE events (RR 0.35; 95% CI 0.16 to 0.91; p = 0.029) and SE events (RR 0.39; 95% CI 0.16 to 0.95; p = 0.037). Conclusions DOACs had a similar rate of thromboembolic and hemorrhagic events, as well as thrombus resolution, compared to VKAs in the treatment of LVTs. Rivaroxaban therapy had a significant reduction in thromboembolic events, compared to VKAs.

Efficacy and Safety of Direct Oral Anticoagulants for Acute Treatment of Venous Thromboembolism in Older Adults: A Network Meta-Analysis of Randomised Controlled Trials.

OBJECTIVE: This systematic review and network meta-analysis aimed to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) in adults aged 75 and over undergoing acute venous thromboembolism (VTE) treatment. METHODS: PubMed, Embase and the CENTRAL were searched up to 25 December 2023. The incidence of VTE recurrence and bleeding events was assessed. Employing a frequentist network meta-analysis approach, interventions not directly compared could be indirectly assessed through the 95% confidence interval (CI), enhancing the interpretability of the search results. The surface under the cumulative ranking curves (SUCRA) was utilized to generate the relative ranking probabilities for each group. RESULTS: Our study, analysing 6 randomised controlled trials with 3665 patients, compares direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in adults aged 75 and over with acute venous thromboembolism. Edoxaban reduces VTE recurrence risk compared with VKAs (risk ratio [RR] .50, 95% CI 0.27 - .95), while apixaban significantly decreases bleeding risk compared with VKAs (RR .23, 95% CI 0.08 - .69), edoxaban (RR .28, 95% CI 0.09 - .86) and rivaroxaban (RR .28, 95% CI 0.09 - .86). Despite low overall evidence quality, apixaban consistently ranks highest for both efficacy and safety. Findings underscore the nuanced efficacy-safety balance in this population, emphasizing cautious interpretation due to evidence limitations. CONCLUSION: Apixaban emerges as a favourable choice for acute VTE treatment in the elderly, displaying reduced bleeding risk compared to other treatments while maintaining comparable efficacy. Future studies should explore diverse anticoagulants efficacy and safety in older populations. Additionally, clinical prediction models tailored to geriatric cohorts are crucial for guiding treatment duration decisions.

Minimally modified human blood coagulation factor X to bypass direct factor Xa inhibitors.

BACKGROUND: Direct oral factor (F)Xa inhibitors are widely used as alternatives to conventional vitamin K antagonists in managing venous thromboembolism and nonvalvular atrial fibrillation. Unfortunately, bleeding-related adverse events remain a major concern in clinical practice. In case of bleeding or emergency surgery, rapid-onset reversal agents may be required to counteract the anticoagulant activity. OBJECTIVES: The ability of FXa variants to bypass the direct oral FXa inhibitors was assessed. METHODS: Human FXa variants were generated through substitution of phenylalanine 174 (F174) for either alanine, isoleucine, or serine. FXa variants were stably expressed in HEK293 cells and purified to homogeneity using ion-exchange chromatography. RESULTS: F174-substituted human FX variants demonstrated efficacy in restoring thrombin generation in plasma containing direct FXa inhibitors (apixaban, rivaroxaban, edoxaban). Their ability to bypass the anticoagulant effects stems from a significantly reduced sensitivity for the direct FXa inhibitors due to a decrease in binding affinity determined using molecular dynamics simulations and free energy computation. Furthermore, F174 modification resulted in a partial loss of inhibition by tissue factor pathway inhibitor, enhancing the procoagulant effect of F174-substituted FX. Consequently, the F174A- and F174S-substituted FX variants effectively counteracted the effects of 2 widely used anticoagulants, apixaban and rivaroxaban, in plasma of atrial fibrillation and venous thromboembolism patients. CONCLUSION: These human FX variants have the potential to serve as a rescue reversal strategy to overcome the effect of direct FXa inhibitors in case of life-threatening bleeding events or emergency surgical interventions.

Evaluation of the Hemocompatibility of the Direct Oral Anticoagulant Apixaban in Left Ventricular Assist Devices: The DOAC LVAD Study.

BACKGROUND: Patients receiving left ventricular assist device (LVAD) support require long-term anticoagulation to reduce the risk of thromboembolic complications. Apixaban is a direct oral anticoagulant that has become first-line therapy; however, its safety in LVAD recipients has not been well described. OBJECTIVES: This study sought to investigate whether, in patients with a fully magnetically levitated LVAD, treatment with apixaban would be feasible and comparable with respect to safety and freedom from the primary composite outcome of death or major hemocompatibility-related adverse events (HRAEs) (stroke, device thrombosis, major bleeding, aortic root thrombus, and arterial non-central nervous system thromboembolism) as compared with treatment with warfarin. METHODS: The DOAC LVAD (Evaluation of the Hemocompatibility of the Direct Oral Anti-Coagulant Apixaban in Left Ventricular Assist Devices) trial was a phase 2, open label trial of LVAD recipients randomized 1:1 to either apixaban 5 mg twice daily or warfarin therapy. All patients were required to take low-dose aspirin. Patients were followed up for 24 weeks to evaluate the primary composite outcome. RESULTS: A total of 30 patients were randomized: 14 patients to warfarin and 16 patients to apixaban. The median patient age was 60 years (Q1-Q3: 52-71 years), and 47% were Black patients. The median time from LVAD implantation to randomization was 115 days (Q1-Q3: 56-859 days). At 24 weeks, the primary composite outcome occurred in no patients receiving apixaban and in 2 patients (14%) receiving warfarin (P = 0.12); these 2 patients experienced major bleeding from gastrointestinal sources. CONCLUSIONS: Anticoagulation with apixaban was feasible in patients with an LVAD without an excess of HRAEs or deaths. This study informs future pivotal clinical trials evaluating the safety and efficacy of apixaban in LVAD recipients. (Evaluation of the Hemocompatibility of the Direct Oral Anti-Coagulant Apixaban in Left Ventricular Assist Devices [DOAC LVAD]; NCT04865978).