Oral Anticoagulation in Patients with Chronic Liver Disease.

The administration of an anticoagulant in patients with liver disease (nonalcoholic steatohepatitis-NASH, nonalcoholic fatty liver disease-NAFLD, chronic hepatitis, or cirrhosis) who have an indication (atrial fibrillation, venous thrombosis, or pulmonary embolism) is challenging because there is an imbalance between thrombosis and bleeding. There is a need to focus our attention on preventing risk factors because diabetes, obesity, dyslipidemia, smoking, and sedentary behavior are risk factors for both NASH/NAFLD and AF, and these patients require anticoagulant treatment. Patients with advanced liver disease (Child-Pugh C) were excluded from studies, so vitamin K antagonists (VKAs) are still recommended. Currently, VKAs are recommended for other conditions (antiphospholipid syndrome, mitral valve stenosis, and mechanical valve prosthesis). Amongst the patients under chronic anticoagulant treatment, especially for the elderly, bleeding as a result of the improper use of warfarin is one of the important causes of emergency admissions due to adverse reactions. DOACs are considered to be efficient and safe, with apixaban offering superior protection against stroke and a good safety profile as far as major bleeding is concerned compared to warfarin. DOACs are safe in the Child-Pugh A and B classes (except rivaroxaban), and in the Child-Pugh C class are contraindicated. Given that there are certain and reliable data for chronic kidney disease regarding the recommendations, in liver function impairment more randomized studies must be carried out, as the current data are still uncertain. In particular, DOACs have a simple administration, minimal medication interactions, a high safety and effectiveness profile, and now a reversal agent is available (for dabigatran and idarucizumab). Patients are also statistically more compliant and do not require INR monitoring.

Effect of Rivaroxaban vs Enoxaparin on Major Cardiac Adverse Events and Bleeding Risk in the Acute Phase of Acute Coronary Syndrome: The H-REPLACE Randomized Equivalence and Noninferiority Trial.

Importance: Parenteral enoxaparin is a preferred anticoagulant used in the acute phase for patients with acute coronary syndrome (ACS). The safety and efficacy of short-term low-dose rivaroxaban in this clinical setting remain unknown. Objective: To compare the safety and efficacy of rivaroxaban vs enoxaparin in the acute phase of ACS. Design, Setting, and Participants: This multicenter, prospective, open-label, active-controlled, equivalence and noninferiority trial was conducted from January 2017 through May 2021 with a 6-month follow-up at 21 hospitals in China. Participants included patients with ACS missing the primary reperfusion window or before selective revascularization. Data were analyzed from November 2021 to November 2022. Interventions: Participants were randomized 1:1:1 to oral rivaroxaban 2.5 mg or 5 mg or 1 mg/kg subcutaneous enoxaparin twice daily in addition to dual antiplatelet therapy (DAPT; aspirin 100 mg and clopidogrel 75 mg once daily) for a mean of 3.7 days. Main Outcomes and Measures: The primary safety end point was bleeding events, as defined by the International Society on Thrombosis and Haemostasis, and the primary efficacy end point was major adverse cardiovascular events (MACEs), including cardiac death, myocardial infarction, rerevascularization, or stroke during the 6-month follow-up. Results: Of 2055 enrolled patients, 2046 (99.6%) completed the trial (mean [SD] age 65.8 [8.2] years, 1443 [70.5%] male) and were randomized to enoxaparin (680 patients), rivaroxaban 2.5 mg (683 patients), or rivaroxaban 5 mg (683 patients). Bleeding rates were 46 patients (6.8%) in the enoxaparin group, 32 patients (4.7%) in the rivaroxaban 2.5 mg group, and 36 patients (5.3%)in the rivaroxaban 5 mg group (rivaroxaban 2.5 mg vs enoxaparin: noninferiority hazard ratio [HR], 0.68; 95% CI, 0.43 to 1.07; P = .005; rivaroxaban 5 mg vs enoxaparin: noninferiority HR, 0.88; 95% CI, 0.70 to 1.09; P = .001). The incidence of MACEs was similar among groups, and noninferiority was reached in the rivaroxaban 5 mg group (HR, 0.60; 95% CI, 0.31 to 1.16, P = .02) but not in the rivaroxaban 2.5 mg group (HR, 0.68; 95% CI, 0.36 to 1.30; P = .05) compared with the enoxaparin group. Conclusions and Relevance: In this equivalence and noninferiority trial, oral rivaroxaban 5 mg showed noninferiority to subcutaneous enoxaparin (1 mg/kg) for patients with ACS treated with DAPT during the acute phase. Results of this feasibility study provide useful information for designing future randomized clinical trials with sufficient sample sizes. Trial Registration: ClinicalTrials.gov Identifier: NCT03363035.

Prolonged thromboprophylaxis with rivaroxaban after bariatric interventions: single centre experience.

BackgroundVenous thromboembolism (VTE) is common after bariatric surgery and extended prophylaxis is generally recommended. Low molecular weight heparin is the most commonly used agent but requires patients to be trained to self-inject and is expensive. Rivaroxaban is an oral daily formulation approved for VTE prophylaxis after orthopedic surgery. Efficacy and safety of rivaroxaban has been confirmed in major gastrointestinal resections by several observational studies. We report a single centre experience of using rivaroxaban as an agent for VTE prophylaxis in bariatric surgery. MethodsWe performed prospective cohort study assessing safety and efficacy of rivaroxaban as a medication for VTE prophylaxis in patients undergoing bariatric surgery in a single centre in Kyiv, Ukraine. Patients undergoing major bariatric procedure received perioperative prophylaxis of VTE with subcutaneous low molecular weight heparin and then were switched to rivaroxaban for total of 30 days starting on the 4th postoperative day. Thromboprophylaxis was performed in accordance with the VTE risks derived from the Caprini score. On the 3rd, 30th, 60th day after the operation, the patients underwent ultrasound examination of the portal vein, as well as the veins of the lower extremities. Telephone interviews were conducted 30 and 60 days after the surgery to evaluate the presence of complaints which may be characteristic for VTE as well as to assess compliance with the regimen and to assess patient satisfaction. Outcomes studies were incidence of VTE and adverse events related to rivaroxaban administration.Results110 patients were included in the study from July 2019 to May 2021. The average age of the patients was 43.6 years, the average preoperative BMI was 55 (35 to 75). One hundred and seven patients (97.3%) underwent laparoscopic intervention while three patients (2.7%) underwent laparotomy. Eighty-four patients underwent sleeve gastrectomy and twenty-six patients underwent other procedures, including bypass surgery. Average calculated risk of thromboembolic event was 5-6% based on Caprine index. All patients were treated with extended prophylaxis with rivaroxaban. The average follow-up period for patients was 6 months. There were no clinical or radiological evidence of thromboembolic complications in the study cohort. Overall complication rate was 7.2%, however, only one patient (0.9%) developed subcutaneous hematoma associated with rivaroxaban not requiring intervention. ConclusionExtended postoperative prophylaxis with rivaroxaban is safe and effective in preventing thromboembolic complications in patients undergoing bariatric surgery. It is preferred by patients and further studies should be considered to further evaluate its use in bariatric surgery.

Comparative Effectiveness and Safety of Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and Chronic Liver Disease: A Nationwide Cohort Study.

BACKGROUND: The benefit-risk profile of direct oral anticoagulants (DOACs) compared with warfarin, and between DOACs in patients with atrial fibrillation (AF) and chronic liver disease is unclear. METHODS: We conducted a new-user, retrospective cohort study of patients with AF and chronic liver disease who were enrolled in a large, US-based administrative database between January 1, 2011, and December 31, 2017. We assessed the effectiveness and safety of DOACs (as a class and individually) compared with warfarin, and between DOACs in patients with AF and chronic liver disease. The primary outcomes were hospitalization for ischemic stroke/systemic embolism and hospitalization for major bleeding. Inverse probability treatment weights were used to balance the treatment groups on measured confounders. RESULTS: Overall, 10 209 participants were included, with 4421 (43.2%) on warfarin, 2721 (26.7%) apixaban, 2211 (21.7%) rivaroxaban, and 851 (8.3%) dabigatran. The incidence rates per 100 person-years for ischemic stroke/systemic embolism were 2.2, 1.4, 2.6, and 4.4 for DOACs as a class, apixaban, rivaroxaban, and warfarin, respectively. The incidence rates per 100 person-years for major bleeding were 7.9, 6.5, 9.1, and 15.0 for DOACs as a class, apixaban, rivaroxaban, and warfarin, respectively. After inverse probability treatment weights, the risk of hospitalization for ischemic stroke/systemic embolism was significantly lower between DOACs as a class (hazard ratio [HR], 0.64 [95% CI, 0.46-0.90]) or apixaban (HR, 0.40 [95% CI, 0.19-0.82]) compared with warfarin, but not significantly different between rivaroxaban versus warfarin (HR, 0.76 [95% CI, 0.47-1.21]) or rivaroxaban versus apixaban (HR, 1.73 [95% CI, 0.91-3.29]). Compared with warfarin, the risk of hospitalization for major bleeding was lower with DOACs as a class (HR, 0.69 [95% CI, 0.58-0.82]), apixaban (HR, 0.60 [95% CI, 0.46-0.78]), and rivaroxaban (HR, 0.79 [95% CI, 0.62-1.0]). However, the risk of hospitalization for major bleeding was higher for rivaroxaban versus apixaban (HR, 1.59 [95% CI, 1.18-2.14]). CONCLUSIONS: Among patients with AF and chronic liver disease, DOACs as a class were associated with lower risks of hospitalization for ischemic stroke/systemic embolism and major bleeding versus warfarin. However, the incidence of clinical outcomes among patients with AF and chronic liver disease varied between individual DOACs and warfarin, and in head-to-head DOAC comparisons.

Effectiveness of different antithrombotic agents in combination with tranexamic acid for venous thromboembolism prophylaxis and blood management after total knee replacement: a prospective randomized study.

BACKGROUND: Tranexamic acid (TXA) has been widely applied in total knee arthroplasty (TKA) to significantly reduce perioperative blood loss and improve knee function recovery in patients after surgery. The choice of antithrombotic agents for venous thromboembolism (VTE) prevention after TKA is controversial. Therefore, this study aimed to compare the effects of different antithrombotic agents on patients after primary unilateral TKA in the context of applied TXA. METHODS: A total of 180 patients undergoing primary unilateral TKA from October 2020 to December 2021 were included in this study. All patients were given an intraoperative drip of 60 mg/kg TXA. Thereafter, patients were divided into three groups (n = 60 each). Baseline data were comparable among the three groups. The average follow-up time was 3.02 ± 0.09 months. Group 1 enrolled patients receiving oral rivaroxaban (RA) at 10 mg, Group 2 included patients who received subcutaneous Dalteparin sodium at 2500 IU, while Group 3 included patients taking oral aspirin (ASA) at 100 mg. Patients in all the three groups received treatment once a day for 30 days at 12 h postoperatively. The primary outcomes in this study were post-treatment drainage volume and thrombotic complication rate. The secondary outcomes included hematologic parameters, transfusion rate, intraoperative blood loss, total blood loss (TBL), and bleeding complication rate. RESULTS: The average drainage volume after treatment was significantly lower in Group 3 than in Group 1 and Group 2 (205.2 ± 69.0 vs 243.4 ± 72.5 vs 295.4 ± 72.5 ml, P < 0.001), and there was a significant difference between Group 1 and Group 2 (243.4 ± 72.5 mL vs 295.4 ± 72.5 mL, P < 0.001). The blood transfusion rate of Group 2 dramatically increased compared with Group 1 and Group 3 (20.0% vs 6.7% vs 5.0%, P = 0.01). The bleeding complication rate in Group 1 apparently increased relative to Group 2 and Group 3 (26.7% vs 10.0% vs 8.3%, P = 0.008). Besides, there was no significant difference in the thrombotic complication rate among the three groups. CONCLUSION: Under the background of TXA application, ASA, RA, and Dalteparin sodium were all effective on preventing VTE after TKA. In addition, ASA effectively reduced post-treatment Hemoglobin (Hb) loss, drainage volume, TBL, transfusion rate, and bleeding complications compared with RA and Dalteparin sodium. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2200060169). Date of Registration: 21/05/2022.

Multicenter experience with andexanet alfa for refractory pericardial bleeding during catheter ablation of atrial fibrillation.

INTRODUCTION: Pericardial bleeding is a rare but life-threatening complication of atrial fibrillation (AF) ablation. Patients taking uninterrupted oral anticoagulation (AC) may be at increased risk for refractory bleeding despite pericardiocentesis and administration of protamine. In such cases, andexanet alfa can be given to reverse rivaroxaban or apixaban. In this study, we aim to describe the rate of acute hemostasis and thromboembolic complications with andexanet for refractory pericardial bleeding during AF ablation. METHODS AND RESULTS: In this multicenter, case series, participating centers identified patients who received a dose of apixaban or rivaroxaban within 24 h of AF ablation, developed refractory pericardial bleeding during the procedure despite pericardiocentesis and administration of protamine and received andexanet. Eleven patients met inclusion criteria, with mean age of 73.5 ± 5.3 years and median CHA2 DS2 -VASc score 4 [3-5]. All patients received protamine and pericardiocentesis, and 9 (82%) received blood products. All patients received a bolus of andexanet followed, in all but one, by a 2-h infusion. Acute hemostasis was achieved in eight patients (73%) while three required emergent surgery. One patient (9%) experienced acute ST-elevation myocardial infarction after receiving andexanet. Therapeutic AC was restarted after a mean of 2.2 ± 1.9 days and oral AC was restarted after a mean of 2.9 ± 1.6 days, with no recurrent bleeding. CONCLUSION: In patients on uninterrupted apixaban or rivaroxaban, who develop refractory pericardial bleeding during AF ablation, andexanet can achieve hemostasis thereby avoiding the need for emergent surgery. However, there is a risk of thromboembolism following administration.

In rheumatic heart disease-associated AF, rivaroxaban increased adverse vascular outcomes vs. VKA at 3 y.

SOURCE CITATION: Connolly SJ, Karthikeyan G, Ntsekhe M, et al. Rivaroxaban in rheumatic heart disease-associated atrial fibrillation. N Engl J Med. 2022;387:978-88. 36036525.

Vitamin-K-antagonist phenprocoumon versus direct oral anticoagulants in patients with atrial fibrillation: a real-world analysis of German claims data.

OBJECTIVES: Direct oral anticoagulants (DOACs) were introduced based on randomised controlled trials (RCTs) comparing them to vitamin-K-antagonist (VKA) warfarin. In Germany, almost exclusively phenprocoumon is used as VKA. RCTs with phenprocoumon being absent we analysed the benefits and harms of DOACs and phenprocoumon for patients with atrial fibrillation (AF) in a real-world setting. DESIGN: In a retrospective observational cohort study, claims data covering inpatient and outpatient care from 2015 to 2019 were analysed by Cox regression and propensity score matching (PSM). SETTING: Data from a group of small-sized to medium-sized health insurance companies in Germany. PARTICIPANTS: We analysed datasets of 71 961 patients with AF and first prescription of phenprocoumon (n=20 179) or DOAC in standard dose (n=51 782). Patients with reduced dose of DOACs were excluded (n=21 724). OUTCOME MEASURES: Outcomes were thromboembolic events, major bleeding and death during a 12-month follow-up period. RESULTS: The regression analysis widely showed similarity between phenprocoumon and standard dose DOACs regarding effectiveness and safety. There were only three statistically significant differences: a lower bleeding risk with composite DOACs and apixaban (HR (95% CI) = 0.67 (0.59 to 0.76) and 0.54 (0.46 to 0.63), respectively) and a higher risk of death with rivaroxaban (1.21 (1.10 to 2.34)). The analysis after PSM was consistent with the first two results regarding composite DOACs and apixaban (number needed to treat, NNT 101 and 78) and showed a lower bleeding risk with rivaroxaban (NNT 156). Absolute differences were small. CONCLUSIONS: The small superiority or non-inferiority of DOACs over warfarin seen in the RCTs might not translate into relevant advantages of DOACs over phenprocoumon. To confirm the hypothesis, an RCT with phenprocoumon is needed. Next to the safety and effectiveness assessments other factors might also play a substantial role in the decision on the right OAC for stroke prevention.

Real world experience of efficacy and safety of rivaroxaban in paediatric venous thromboembolism.

INTRODUCTION: Paediatric clinical practice for treatment of venous thromboembolism (VTE) is based on extrapolation from adult trials with minimal data on anticoagulation efficacy and safety in children. Based on EINSTEIN-Jr clinical trial data, rivaroxaban was approved to treat VTE and prevent its recurrence in children of all ages. AIM: To report the safety and efficacy of rivaroxaban use in paediatric VTE and to present real-world data, specifically about very young children. METHODS: We conducted a retrospective observational study at Birmingham Children's Hospital. Data were collected from patients <16 years old who received rivaroxaban after its licensure in the period between March 2021 and June 2022. RESULTS: Rivaroxaban was used for treatment of acute VTE in 64 patients. Thrombosis was CVC-related in 26 patients, unprovoked in 3, while the rest had one or more risk factors for VTE. Safety and efficacy of rivaroxaban were assessed in 52 patients after excluding patients who were on current rivaroxaban treatment and those who were lost to follow up or stopped rivaroxaban due to intolerance. No bleeding events were reported, and recurrence of thrombosis occurred in only 3.6 %. About 35 % had normalised re-imaging, 40.3 % improved, 9.6 % were unchanged and 11.5 % stopped rivaroxaban without re-imaging. Rivaroxaban was used for secondary VTE prophylaxis in 6 patients in our cohort with no recurrence of thrombosis or bleeding reports. CONCLUSIONS: Our real-world experience confirmed that rivaroxaban was well tolerated, effective and safe. Further real-world data and observational studies are essential to investigate the use of rivaroxaban among different risk groups.

Effectiveness and Safety of Direct Oral Anticoagulants Among Patients with Non-valvular Atrial Fibrillation and Multimorbidity.

INTRODUCTION: In the USA, there is a steady rise of atrial fibrillation due to the aging population with increased morbidity. This study evaluated the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) among elderly patients with non-valvular atrial fibrillation (NVAF) and multimorbidity prescribed direct oral anticoagulants (DOACs). METHODS: Using the CMS Medicare database, a retrospective observational study of adult patients with NVAF and multimorbidity who initiated apixaban, dabigatran, or rivaroxaban from January 1, 2012 to December 31, 2017 was conducted. High multimorbidity was classified as having ≥ 6 comorbidities. Cox proportional hazard models were used to evaluate the hazard ratios of S/SE and MB among three 1:1 propensity score matched DOAC cohorts. All-cause healthcare costs were estimated using generalized linear models. RESULTS: Overall 36% of the NVAF study population had high multimorbidity, forming three propensity score matched (PSM) cohorts: 12,511 apixaban-dabigatran, 60,287 apixaban-rivaroxaban, and 12,567 dabigatran-rivaroxaban patients. Apixaban was associated with a lower risk of stroke/SE and MB when compared with dabigatran and rivaroxaban. Dabigatran had a lower risk of stroke/SE and a similar risk of MB when compared with rivaroxaban. Compared to rivaroxaban, apixaban patients incurred lower all-cause healthcare costs, and dabigatran patients incurred similar all-cause healthcare costs. Compared to dabigatran, apixaban patients incurred similar all-cause healthcare costs. CONCLUSION: Patients with NVAF and ≥ 6 comorbid conditions had significantly different risks for stroke/SE and MB when comparing DOACs to DOACs, and different healthcare expenses. This study's results may be useful for evaluating the risk-benefit ratio of DOAC use in patients with NVAF and multimorbidity.

Effectiveness and safety of low-dose versus standard-dose rivaroxaban and apixaban in patients with atrial fibrillation.

BACKGROUND: Low-dose direct oral anticoagulant (DOAC) use is quite prevalent in clinical practice, but evidence of its effectiveness and safety compared with high-dose DOAC in patients with atrial fibrillation (AF) remains limited. We aimed to assess the effectiveness and safety of low-dose and high-dose DOACs in patients with AF with similar baseline characteristics. METHODS: We used a cohort of hospitalized patients with a primary or secondary diagnosis of AF after discharge to the community, whose data were stored in the Quebec administrative databases, from 2011 to 2017. Older adults with AF newly prescribed with rivaroxaban (15 or 20 mg) or apixaban (2.5 mg or 5 mg) were classified as under treatment (UT) and intent to treat (ITT). We used an inverse probability treatment weighting study of new users of rivaroxaban and apixaban to address confounding by indication. The primary effectiveness outcome was ischemic stroke/systemic embolism (SE), while the primary safety outcome was major bleeding (MB). We used Cox proportional models to estimate the marginal hazard ratios (HRs). FINDINGS: A total of 1,722 and 4,639 patients used low-dose and standard-dose rivaroxaban, respectively, while 3,833 and 6,773 patients used low-dose and standard-dose apixaban, respectively. No significant difference was observed in the incidence of comparative stroke/SE and MB between low-dose and standard-dose rivaroxaban, except for the risk of acute myocardial infarction (AMI), which was increased with the low dose in the UT analysis. For apixaban, no difference was found in the bleeding rates, but the risk of stroke/SE (HR: 1.95; 95% confidence interval (CI): 1.38-2.76) and death (HR: 1.99; 95% CI: 1.46-2.70) were greater in the low-dose group than in the standard-dose group in the UT analysis. Similar results were observed for the ITT analysis. CONCLUSION: No significant differences were observed in the effectiveness or safety outcome between low-dose and standard-dose rivaroxaban, except for AMI. However, low-dose apixaban was associated with a greater risk of stroke/SE and death without a reduction in the bleeding rates.

Prescribing Patterns of Direct-Acting Oral Anticoagulants in Patients With Atrial Fibrillation and Chronic Kidney Disease: A Retrospective Cohort Analysis.

BACKGROUND: The association of patient and prescriber characteristics with use of warfarin versus direct-acting oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) and chronic kidney disease (CKD) is not well studied. METHODS: The 20% Centers for Medicare & Medicaid Services Parts A, B, and D claims data from 2010 to 2017 were used to identify patients with stage 3, 4, or 5 CKD and AF who received a DOAC (apixaban, dabigatran, rivaroxaban) or warfarin. Prescribers were categorized as cardiologists, primary care providers (PCPs), and others. Using logistic regression, we estimated odds ratios (ORs) for the association of baseline characteristics and prescriber specialty with first use of a DOAC, relative to warfarin. RESULTS: We identified 22,739 individuals with CKD who were newly initiated on oral anticoagulation for AF. New DOAC prescriptions increased from 490 in 2011 to 3261 in 2017, and displaced warfarin over time (1849, 2011; 945, 2017). By Q4 of 2014, cardiologists prescribed DOACs as initial treatment more frequently than warfarin, but non-cardiologists did not do so until 2015. As of 2017, apixaban was the most widely prescribed anticoagulant, comprising 56% and 50% of prescriptions by cardiologists and non-cardiologists, respectively. PCPs (OR 0.54, 0.51-0.58) and other providers (OR 0.55, 0.51-0.59) were less likely than cardiologists to prescribe DOACs. CONCLUSIONS: DOAC prescriptions, particularly apixaban, increased over time and gradually displaced warfarin. The total number of patients with AF and CKD receiving anticoagulation increased over time. Cardiologists increased DOAC prescriptions more rapidly than non-cardiologists.

Eligibility and Implementation of Rivaroxaban for Secondary Prevention of Atherothrombosis in Clinical Practice-Insights From the CANHEART Study.

Background The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial decreased major adverse cardiovascular events with very low-dose rivaroxaban and aspirin in patients with coronary artery disease and peripheral artery disease. We examined the eligibility and potential real-world impact of this strategy on the COMPASS-eligible population. Methods and Results COMPASS eligibility criteria were applied to the CANHEART (Cardiovascular Health in Ambulatory Care Research Team) registry, a population-based cohort of Ontario adults. We compared 5-year major adverse cardiovascular events and major bleeding rates stratified by COMPASS eligibility and by clinical risk factors. We applied COMPASS trial rivaroxaban/aspirin arm hazard ratios to estimate the potential impact on the COMPASS-eligible cohort. Among 362 797 patients with coronary artery disease or peripheral artery disease, 38% were deemed eligible, 47% ineligible, and 15% indeterminate. Among eligible patients, a greater number of risk factors was associated with higher rates of cardiovascular outcomes, whereas bleeding rates increased minimally. Over 5 years, applying COMPASS treatment effects to eligible patients resulted in a 2.4% absolute risk reduction of major adverse cardiovascular events and a number needed to treat of 42, and a 1.3% absolute risk increase of major bleeding and number needed to harm (NNH) of 77. Those with at least 2 risk factors had a 3.0% absolute risk reduction of major adverse cardiovascular events (number needed to treat =34) and a 1.6% absolute risk increase of major bleeding (number needed to harm =61). Conclusions Implementation of very-low-dose rivaroxaban therapy would potentially impact ≈$$ \approx $$2 in 5 patients with atherosclerotic disease in Ontario. Eligible individuals with ≥$$ \ge $$2 comorbidities represent a high-risk subgroup that may derive the greatest benefit-to-risk ratio. Selection of patients with high-risk predisposing factors appears appropriate in routine practice.

Safety of apixaban and rivaroxaban compared to warfarin after cardiac surgery.

BACKGROUND: Direct oral anticoagulants (DOACs) are frequently prescribed for the management of atrial fibrillation and venous thrombosis. There is a lack of published data on the utilization of DOACs in individuals who have undergone recent cardiac surgery. The purpose of this study was to evaluate the safety and efficacy of apixaban and rivaroxaban compared to warfarin in patients postcardiac surgery. METHODS: In this retrospective cohort study, patients were separated into a DOAC cohort or a warfarin cohort based on the agent they received after cardiac surgery. Patients could be included if they were ≥18 years of age and received or were discharged on either rivaroxaban, apixaban, or warfarin within 7 days after cardiac surgery. The primary outcome for the study was the rate of International Society on Thrombosis and Hemostasis (ISTH) major bleeding during hospitalization and for 30 days following discharge or until first follow-up appointment. RESULTS: There were a total of 194 patients included in the analysis, 97 in the DOAC cohort and 97 in the warfarin cohort. Four patients (4.1%) in the DOAC group experienced ISTH major bleeding, while 2 patients (2.1%) in the warfarin cohort experienced ISTH major bleeding (p = 0.68). No patients in the DOAC cohort experienced a thrombotic event, whereas 2 patients (2.1%) in the warfarin cohort experienced a thrombotic complication (p = 0.5). CONCLUSION: Apixaban and rivaroxaban demonstrated similar safety when compared to a matched cohort of warfarin patients. Larger prospective randomized studies are needed to confirm these findings.

Drug-drug interaction between dexamethasone and direct-acting oral anticoagulants: a nested case-control study in the National COVID Cohort Collaborative (N3C).

OBJECTIVE: The goal of this work is to evaluate if there is an increase in the risk of thromboembolic events (TEEs) due to concomitant exposure to dexamethasone and apixaban or rivaroxaban. Direct oral anticoagulants (DOACs), as well as corticosteroid dexamethasone, are commonly used to treat individuals hospitalised with COVID-19. Dexamethasone induces cytochrome P450-3A4 enzyme that also metabolises DOACs apixaban and rivaroxaban. This raises a concern about possible interaction between dexamethasone and DOACs that may reduce the efficacy of the DOACs and result in an increased risk of TEE. DESIGN: We used nested case-control study design. SETTING: This study was conducted in the National COVID Cohort Collaborative (N3C), the largest electronic health records repository for COVID-19 in the USA. PARTICIPANTS: Study participants were adults over 18 years who were exposed to a DOAC for 10 or more consecutive days. Exposure to dexamethasone was at least 5 or more consecutive days. PRIMARY AND SECONDARY OUTCOME MEASURES: Our primary exposure variable was concomitant exposure to dexamethasone for 5 or more days after exposure to either rivaroxaban or apixaban for 5 or more consecutive days. We used McNemar's Χ2 test and adjusted logistic regression to evaluate association between concomitant use of dexamethasone with either apixaban or rivaroxaban. RESULTS: McNemar's Χ2 test did not find a discernible association of TEE in patients concomitantly exposed to dexamethasone and a DOAC (χ2=0.5, df=1, p=0.48). In addition, a conditional logistic regression model did not find an increase in the risk of TEE (adjusted OR 1.15, 95% CI 0.32 to 4.18). CONCLUSION: This nested case-control study did not find evidence of an association between concomitant exposure to dexamethasone and a DOAC with an increase in risk of TEE. Due to small sample size, an association cannot be completely ruled out.

Efficacy and Safety Assessment of Rivaroxaban for the Treatment of Cerebral Venous Sinus Thrombosis in a Chinese Population.

We aimed to investigate the efficacy and safety of rivaroxaban for acute and long-term management of cerebral venous sinus thrombosis (CVST). This study reviewed CVST-diagnosed patients admitted to the First Affiliated Hospital of Guangxi Medical University from January 2015 to December 2020. The primary outcome was a composite of recurrent thrombosis or major bleeding events. The secondary efficacy outcomes included a disease recovery time (DRT) presenting the time from admission to the endpoint as recovery (the modified Rankin scale [mRS] score [0-1]) within 30 and 90 days, and length of hospital stay (LHS). Patients treated with rivaroxaban (38) and warfarin (45) were enrolled in the final analysis. The primary outcome had no significant difference (5.3% vs 11.1%, P = .576) between the 2 groups. The secondary efficacy outcome regarding the median 30-d DRT was 17 days (95% confidence interval [CI], 14.6-19.4) in the rivaroxaban group, compared with 26.0 days (95% CI, 16.8-35.2) in the warfarin group (hazard ratio, 1.806; 95% CI, 1.051-3.103; log-rank P = .026). Two groups have a significant difference in LHS (P = .041). Patients with cerebral edema, intracerebral hemorrhage, and mild/moderate disability (admission mRS score [2-3]) treated with rivaroxaban recovered faster than those with warfarin (log-rank P < .05). Patients with cerebral edema, intracerebral hemorrhage, and mild/moderate disability treated with rivaroxaban had a shorter recovery time than those treated with warfarin within 1 month from admission, indicating that rivaroxaban a promising convenient therapy for CVST, helping them speedily restore social functions.

Safety of direct oral anticoagulants in patients with advanced solid tumors receiving anti-VEGF agents: a retrospective study.

PURPOSE: Kinase inhibitors (KI) and antibodies targeting the VEGF pathway are approved in a broad spectrum of cancers and associated with an increased risk of bleeding and thromboembolic events (TE). The use of direct oral anticoagulants (DOACs) apixaban and rivaroxaban is increasing in cancer patients, but limited data are available for patients receiving anti-VEGF agents. METHODS: To assess safety of DOAC with concomitant anti-VEGF agents, a retrospective chart review of all patients receiving concomitantly DOAC and anti-VEGF agents was performed from 2013 to 2020 in our center. Data on demographics, safety, and time on treatment were collected. Main outcome was safety (bleeding and thromboembolic events). RESULTS: Of 92 patients (median age 66 years (IQR: 59-72)), 40 were treated with KI and 52 with bevacizumab. The most frequent primary tumor sites were colon/rectum (24%), kidney (21%), ovary (13%), lung (11%), soft tissue sarcoma (10%), and thyroid (9%); 2% had brain metastases. Apixaban 5 mg bid (n = 41) or rivaroxaban 20 mg daily (n = 51) were given for TE (65%), atrial fibrillation (32%), or other indications (3%). The median duration of concomitant treatment was 4.8 months (95%CI: 0.7-50.0) with bevacizumab and 11.7 months (95%CI: 0.1-53.8) with KI. Grade ≥ 3 bleeding events occurred in 5 patients (5%): 4 patients receiving bevacizumab (one grade 5 upper digestive tract bleeding and three grade 3 rectal or vaginal hemorrhages) and 1 patient under cabozantinib for kidney cancer with endobronchial metastasis (grade 3 hemoptysis). Grade ≥ 3 TE occurred in 8 patients (9%): 7 patients receiving bevacizumab (including one grade 5 pulmonary embolism), and one patient receiving sunitinib (grade 3 pulmonary embolism). Median time-to-event (bleeding or thrombotic event) was not reached (NR) (95%CI: 76.9-NR) for KI and 86.9 months (95%CI: 42.9-148.0) for bevacizumab. CONCLUSIONS AND RELEVANCE: In our experience, the use of DOAC was safe in selected patients treated with KI, but unclear with bevacizumab. More data are needed to endorse guidelines in this specific group of patients.

Rivaroxaban treatment for six weeks versus three months in patients with symptomatic isolated distal deep vein thrombosis: randomised controlled trial.

OBJECTIVE: To compare two different treatment durations of rivaroxaban in patients with symptomatic isolated distal deep vein thrombosis (DVT). DESIGN: Randomised, double blind, placebo controlled clinical trial. SETTING: 28 outpatient clinics specialising in venous thromboembolism. PARTICIPANTS: 402 adults (≥18 years) with symptomatic isolated distal DVT. INTERVENTIONS: After receiving standard dose rivaroxaban for six weeks, participants were randomly assigned to receive rivaroxaban 20 mg or placebo once daily for an additional six weeks. Follow-up was for 24 months from study inclusion. MAIN OUTCOMES MEASURES: The primary efficacy outcome was recurrent venous thromboembolism during follow-up after randomisation, defined as the composite of progression of isolated distal DVT, recurrent isolated distal DVT, proximal DVT, symptomatic pulmonary embolism, or fatal pulmonary embolism. The primary safety outcome was major bleeding after randomisation until two days from the last dose of rivaroxaban or placebo. An independent committee adjudicated the outcomes. RESULTS: 200 adults were randomised to receive additional rivaroxaban treatment and 202 to receive placebo. Isolated distal DVT was unprovoked in 81 (40%) and 86 (43%) patients, respectively. The primary efficacy outcome occurred in 23 (11%) patients in the rivaroxaban arm and 39 (19%) in the placebo arm (relative risk 0.59, 95% confidence interval 0.36 to 0.95; P=0.03, number needed to treat 13, 95% confidence interval 7 to 126). Recurrent isolated distal DVT occurred in 16 (8%) patients in the rivaroxaban arm and 31 (15%) in the placebo arm (P=0.02). Proximal DVT or pulmonary embolism occurred in seven (3%) patients in the rivaroxaban arm and eight (4%) in the placebo arm (P=0.80). No major bleeding events occurred. CONCLUSIONS: Rivaroxaban administered for six additional weeks in patients with isolated distal DVT who had an uneventful six week treatment course reduces the risk of recurrent venous thromboembolism, mainly recurrent isolated distal DVT, over a two year follow-up without increasing the risk of haemorrhage. TRIAL REGISTRATION: EudraCT 2016-000958-36; ClinicalTrials.gov NCT02722447.

Impact of increased kidney function on clinical and biological outcomes in real-world patients treated with Direct Oral Anticoagulants.

BACKGROUND AND PURPOSE: Renal excretion of direct oral anticoagulants (DOACs) varies depending on the drug. Hypothetically, an increased glomerular filtration rate (GFR) may lead to suboptimal dosing and a higher thromboembolic events incidence. However, real-world patient data do not support the theoretical risk. The aim is to analyse DOAC outcomes in patients with normal and high (≥90 mL/min) GFR, focusing on biological parameters and thrombotic/haemorrhagic events. METHODS: Observational prospective single-centre study and registry of patients on DOACs. Follow-up was 1,343 patient-years. A bivariate analysis was performed of baseline variables according to GFR (<90 mL/min vs ≥90 mL/min). Anti-Xa activity before and after drug intake (HemosIL, Liquid Anti-Xa, Werfen) was measured for edoxaban, apixaban, and rivaroxaban; diluted thrombin time for dabigatran (HEMOCLOT); and additionally, plasma concentrations in edoxaban (HemosIl, Liquid Anti-Xa suitably calibrated). RESULTS: 1,135 patients anticoagulated with DOACs were included and 152 patients with GFR ≥90 mL/min. Of 18 serious thrombotic complications during follow-up, 17 occurred in patients with GFR <90 mL/min, and 1 in a patient with GFR ≥90 mL/min. A higher incidence of complications was observed in patients with normal GFR, but the difference was not statistically significant (p>0.05). No statistically significant differences with clinical relevance were observed between the normal or supranormal groups in anti-Xa activity or in edoxaban plasma concentrations. CONCLUSIONS: There was no increased incidence of thrombotic/haemorrhagic complications in our patients treated with DOACs, including 66% treated with edoxaban, and patients with GFR ≥90 mL/min. Likewise, drug anti-Xa activity and edoxaban plasma concentration did not seem to be influenced by GFR.

Effectiveness and Safety of DOACs in Atrial Fibrillation Patients Undergoing Catheter Ablation: Results from the China Atrial Fibrillation (China-AF) Registry.

BACKGROUND: Direct oral anticoagulants (DOACs) have increasingly become an alternative to warfarin in atrial fibrillation (AF) patients. Nonetheless, data on the effectiveness and safety of DOACs in periprocedural of catheter ablation (CA) in real-world practice was relatively rare. METHODS AND RESULTS: 3385 AF patients underwent initial CA and never used oral anticoagulant before enrollment between April 2013 and December 2018 were involved from China Atrial Fibrillation (China-AF) Registry. Warfarin, rivaroxaban and dabigatran were used in 1896 (56.0%), 718 (21.2%), and 771 (22.8%) patients, respectively. Propensity score matching was used to balance covariates across study groups. No significant differences were observed in rivaroxaban-warfarin, dabigatran-warfarin and dabigatran-rivaroxaban cohort for thromboembolic (TE) and major bleeding (MB) incidence. Similar results were also revealed in low-dose rivaroxaban (RLD)-warfarin, low-dose dabigatran (DLD)-warfarin and DLD-RLD cohort. However, the risk of non-MB was higher not only on standard-dose of rivaroxaban but also on RLD when compared with warfarin and with DLD, respectively. CONCLUSIONS: In this study, the incidence of TE and MB were both comparable in standard- or low-dose DOACs versus warfarin and between the two DOACs, whereas the risk of non-MB was higher in rivaroxaban than in warfarin and in RLD than in DLD.