Clinically Relevant Non-major Bleeding Research Articles

Safety of direct oral anticoagulants in patients with atrial fibrillation aged 80 years and older: clinical risk factors

BACKGROUND: Direct oral anticoagulants (DOACs) are associated with bleeding, particularly in the geriatric population. Most studies focus on predicting major bleeding, but clinically relevant non-major bleeding (CRNMB) is equally important in practice. АIM: To assess the ability of clinical factors to predict the risk of CRNMB with the use of DOACs in patients with atrial fibrillation (AF) aged 80 years and older. MATERIALS AND METHODS: A total of 367 patients on DOACs with non-valvular AF aged 80 years and older were evaluated; the median age was 84 [82; 88] years. Key characteristics of the groups were analyzed, including gender, age, and body mass index. CHA2DS2-VASc and HAS-BLED scales were used to assess the risk of ischemic stroke and bleeding, respectively. Comorbidities, Charlson Comorbidity Index, and risk factors of chronic non-communicable diseases were considered. In addition, number of medications taken, physical examination data, history of atherosclerosis, and laboratory test results were collected. RESULTS: In univariate analysis, significant risk factors for the development of CRNMB with all DOACs included higher walking frequency (p=0.022), lower heart rate (p=0.08), and history of gastric and duodenal ulcer [odds ratio 5.34; 95% confidence interval (CI) 2.31–12.0; p 0.001]. In multivariate analysis, a model for predicting CRNMB was developed using age, type of DOAC, liver disease, acute cerebrovascular accident, history of gastric and duodenal ulcer as predictors. The resulting model had a predictive accuracy of 62.6% (95% CI 57.4–67.6), a sensitivity of 66.5% (95% CI 59.4–73.1), and a specificity of 58.2% (95% CI 50.4–65.7). CONCLUSION: The study identified specific modifiable, potentially modifiable, and non-modifiable risk factors for developing CRNMB in AF patients aged 80 years and over taking DOACs. An electronic system to support medical decision making, risk factor management, and public quality of life can be created using results of the study.

A Dynamic, D-dimer-based Thromboprophylaxis Strategy in Patients with COVID-19

Background COVID-19 pandemics increases venous thromboembolism (VTE) risk during hospitalization, despite prophylactic anticoagulation. Limited radiological diagnosis in pandemic requires a guided protocol for anticoagulant adjustment. Methods This retrospective cohort study was conducted at a single center as part of a quality improvement program evaluating the efficacy and safety of anticoagulation protocols. The study focused on implementing a guideline for anticoagulant dosing protocol based on dynamic changes in D-dimer levels in COVID-19 hospitalized patients. The dosing guideline allowed for dose escalation from standard prophylactic levels to escalated prophylactic or therapeutic levels, depending on the patient's risk profile for VTE. The primary endpoints included in-hospital survival comparing between fix and dynamic adjustment treatment groups. Secondary endpoints encompassed major and clinically relevant non-major bleeding (CRNMB) events, incidence of breakthrough thrombosis, length of hospitalization and ICU stay, days of mechanical ventilator use, and survival duration. Findings Among the 260 COVID-19-infected patients hospitalized between March 15th and June 15th, 2020. The patients received fixed anticoagulant dosage in 188, 72.3%) patients, while 72 (27.7%) were up-titrated according to the protocol. In-hospital survival at 30 days demonstrated superiority among patients whose anticoagulation was up-titrated to either escalated prophylactic or therapeutic (80.2%) compared to receiving fixed anticoagulant dosage (51.3%) (p=0.01). Bleeding events were significantly higher in up-titrate group (12.5%) compared to fixed anticoagulant dosage group (2.13%). Most of them are CRNMB. Conclusion A dynamic, D-dimer-based dose escalation of anticoagulation for hospitalized patients with COVID-19 holds promise in improving in-hospital mortality rates without a significant increase in fatal bleeding events.

Direct Oral Anticoagulants Versus Aspirin for Stroke Prevention After Embolic Stroke of Undetermined Source: An Updated Meta-Analysis of Randomized Controlled Trials.

Background: Four randomized controlled trials (RCTs) did not show a benefit of direct oral anticoagulant (DOAC) treatment compared with antiplatelet therapy for the prevention of recurrent strokes in patients with embolic stroke of undetermined source (ESUS). However, the balance between efficacy and safety in subgroups needs to be better defined. We aimed to assess the relative benefits of DOACs in key subgroups of adult patients with ESUS. Methods: We searched major databases (PubMed, Embase, CENTRAL, and Web of Science) for RCTs published from inception to 16 June 2024. The primary outcome was recurrent stroke, and the main safety outcomes were major bleeding and clinically relevant non-major bleeding (CRNB). We assessed the risk of bias using the Cochrane Risk of Bias tool 2. Results: We identified four RCTs, involving a total of 13,970 patients with ESUS. Compared to antiplatelet therapy, treatment with DOAC did not reduce the risk of recurrent stroke (RR 0.95, 95% CI 0.83-1.08, p = 0.45) or ischemic stroke (RR 0.92, 95% CI 0.80-1.05, p = 0.22) or increase major bleeding (RR 1.57, 95% CI 0.87-2.83; p = 0.14). DOAC treatment was associated with a significantly higher risk of CRNMB compared to aspirin (RR 1.52, 95% CI: 1.22-1.90; p = 0.0002). The subgroup analysis demonstrated that use of DOACs was associated with a significant protective effect in patients aged 75 or older (RR 0.76, 95% CI 0.60-0.97, p = 0.03) and when the time from index stroke to randomization was ≥8 days (RR 0.80, 95% CI 0.66-0.97, p = 0.02) in preventing recurrency of any type of stroke. Conclusions: Our meta-analysis showed lack of overall benefit of anticoagulation with DOAC compared to antiplatelet therapy for recurrent stroke prevention in adult patients with ESUS. However, the subgroup analyses suggest the possibility of interactions between age and timing of randomization since stroke and treatment with an DOAC in terms of recurrent stroke prevention. Further research toward tailoring the antithrombotic strategy according to patient characteristics is needed.

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

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

Impact of body weight and body mass index on clinical outcomes of edoxaban therapy in atrial fibrillation patients included in the ETNA-AF-Global registry

Abstract Background In atrial fibrillation (AF) patients (pts) receiving non-vitamin K antagonist oral anticoagulant therapy, extreme body weights, both obesity and low body weight, may impact clinical outcomes. Purpose To determine the impact of body weight and body mass index (BMI) on clinical outcomes in AF pts receiving edoxaban from the Global ETNA program (Europe [NCT02944019], Japan [UMIN000017011], Korea/Taiwan [NCT02951039], Hong Kong [NCT03247582] and Thailand [NCT03247569]). Methods ETNA-AF-Global, a multinational, prospective, observational study collected demographic and clinical outcomes data for AF pts receiving edoxaban. In this subanalysis, pts were categorised into the following body weight groups: ≤60kg, >60 to 80kg (reference body weight), >80 to ≤100kg and >100kg; and BMI groups: <18.5kg/m², ≥18.5 to <25.0kg/m² (reference BMI), ≥25.0 to <30.0kg/m², ≥30.0 to <40.0kg/m² and ≥40.0kg/m². Clinical outcomes at 2-year follow-up were compared across body weight and BMI groups. Results 26,805 pts were included in this analysis. Mean ± standard deviation body weight was 72.2 ± 18.1kg and mean BMI was 26.4 ± 5.0kg/m². 43.7% of pts were categorised into the >60 to 80kg reference body weight group. [other groups: ≤60kg, 28.1%; >80 to ≤100kg, 21.7%; >100kg, 6.5%] and 40.0% of pts into the ≥18.5 to <25.0kg/m² reference BMI group [other groups: <18.5kg/m², 3.0%; ≥25.0 to <30.0kg/m², 37.3%; ≥30.0 to <40.0kg/m², 18.0%; ≥40.0kg/m², 1.7%]. Clinical outcomes are shown in Fig. 1 as unadjusted hazard ratios vs. reference group according to weight and in Fig. 2 according to BMI. Among body weight groups, pts weighing ≤60kg had the highest annualised rates of any stroke or systemic embolic event (SEE; 1.24%), ischemic stroke (0.97%), all-cause death (3.96%), major bleeding events (1.49%), and major bleeding or clinical-relevant non-major (CRNM) bleeding events (3.45%). Pts in the reference body weight group had the lowest annualised rates of all-cause death (2.81%). Annualised rates of major bleeding, major bleeding or CRNM bleeding events and any stroke or SEE were lowest in pts weighing >100kg. Among BMI groups, annualised rates of all effectiveness and safety outcomes were highest in pts with a BMI <18.5kg/m². Pts in the ≥25.0 to <30.0kg/m² BMI group had the lowest annualised rates of all-cause death (2.85%) and pts in the ≥18.5 to <25.0kg/m² BMI group had the lowest annualised rates of CV death (0.73%). Conclusions In the Global ETNA-AF program, clinical outcomes varied between different body weight and BMI subgroups. These findings highlight the need to consider the clinical implications of low body weight and/or low BMI, as AF pts who belong to these categories may be at higher risk of adverse outcomes during long-term anticoagulant treatment.Figure 1.Figure 2.

Bleeding and Thrombotic Events in Hemodialysis Patients with Atrial Fibrillation on Anticoagulation and Antiplatelet Therapy: A 24-Month Cohort Study.

Background and Objectives: Patients undergoing chronic hemodialysis (HD) are predisposed to both thrombotic and bleeding complications due to the complex interplay of end-stage renal disease (ESRD), cardiovascular comorbidities, and the routine use of anticoagulant and antiplatelet therapies. This study aimed to investigate the incidence of bleeding and thrombotic events in chronic HD patients receiving anticoagulant and antiplatelet therapy, with a specific focus on those with atrial fibrillation (AF). Materials and Methods: A total of 224 patients, with 43 (19%) of them diagnosed with AF, were included in this single-center, observational cohort study conducted over 24 months. The cohort was divided into three groups: patients without anticoagulation, those on warfarin monotherapy, and those on combined warfarin and aspirin therapy. Bleeding events were classified as major, clinically relevant non-major bleeding (CRNMB), or minor bleeding, while thrombotic events included ischemic stroke, myocardial infarction, pulmonary embolism, and arteriovenous fistula thrombosis. Results: Overall, 35.7% of patients experienced a bleeding event, with major bleeding occurring in 9.4%. Patients with AF had significantly higher rates of major bleeding (18.6%) compared to those without AF (7.18%; p = 0.043), especially in the combined therapy group. Mortality due to bleeding was also higher in AF patients (14%). In contrast, thrombotic events occurred in 26.8% of patients, with AF patients experiencing significantly more events (48.8%) compared to non-AF patients (21.5%; p = 0.0006). The hazard ratio (HR) for major bleeding in patients on combined warfarin and aspirin therapy was 2.56 (p = 0.016), while the HR for thrombotic events was 2.34 (p = 0.0202). Conclusions: These findings highlight the increased risks of both bleeding and thrombosis in chronic HD patients with AF, particularly those on combined anticoagulation and antiplatelet therapy.

Patients treated with vitamin K oral anticoagulants in family practice: a new approach to bleeding risk assessment. An ancillary study by the CACAO prospective general practice cohort.

The ability of bleeding risk scores to predict major bleeding (MB) or clinically relevant nonmajor bleeding (CRNMB) remains a topic of contention, particularly in nonselected patients in family practice. In addition, the capacity to predict bleeding risk using simple variables has yet to be established. The main objective was to confirm that severe anemia was the most predictive factor for the estimation of bleeding risk in patients treated with vitamin K antagonists (VKAs). Secondary objectives were to test the capacity of different bleeding scores to detect high-risk patients. Subsequently, the impact of functional decline on bleeding incidence was explored. The CACAO study was a multicenter prospective cohort study of patients who, due to nonvalvular atrial fibrillation (NVAF) and/or venous thromboembolism (VTE), had been prescribed an oral anticoagulant by their general practitioner (GP) as a prophylactic measure. Patient characteristics were collected at the time of inclusion by GPs, who then monitored them in accordance with standard practice for one year. MB and CRNMB were the main outcomes for one year. By applying this approach, a total of 13 scores were analyzed. Aaemia was found to be strongly associated with MB (HR: 2.77, 95% CI: 1.2-6.36), with a particularly pronounced association observed in cases of severe anemia (HR: 12.9, 95% CI: 2.76-60.35). Twelve out of 27 MB cases were not identified by at least half of the scores. By contrast, functional decline was identified as a novel factor associated with MB (HR: 2.45, 95% CI: 1.13-5.31). Preexisting anemia is a major prognostic factor associated with the occurrence of bleeding. It seems relevant to suggest that functional decline should be considered by GPs when assessing bleeding risk.

Secondary prophylaxis of venous thromboembolism (VTE) with low dose apixaban or rivaroxaban in major-thrombophilia carriers.

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 2.5mg BID or rivaroxaban 10mg 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 19.20months (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.

Venous thromboembolism secondary prophylaxis in elderly people (over 75-year-old) with low-dose direct oral anticoagulants: single-center Italian experience

Nowadays, direct oral anticoagulants (DOACs) represent the gold standard for venous thromboembolism (VTE) treatment and VTE secondary prophylaxis; nevertheless, the percentage of elderly patients in major trials and literature data about DOACs usage for VTE secondary prophylaxis in the elderly are scant. Our retrospective study tried to evaluate low-dose DOACs efficacy and safety for elderly VTE secondary prophylaxis in a real-life setting. A cohort of 73 patients (≥ 75 years) considered at high risk of VTE recurrence was treated with apixaban 2.5 mg twice daily (b.i.d.) or rivaroxaban 10 mg daily as VTE secondary prophylaxis. The median low-dose DOACs administration time was 18.40 months. Three (4.1%) VTE recurrence events were observed, with four bleeding events registered (5.5%), including one major bleeding (MB) (1.4%) and two clinically relevant non major bleeding (CRNMB) (2.7%). Our data suggest that low-dose DOACs may be effective and well tolerated for secondary VTE prophylaxis in elderly patients at high risk of VTE recurrence.

A Dynamic, D-dimer-based Thromboprophylaxis Strategy in Patients with COVID-19.

COVID-19 pandemics increases venous thromboembolism (VTE) risk during hospitalization, despite prophylactic anticoagulation. Limited radiological diagnosis in pandemic requires a guided protocol for anticoagulant adjustment. This retrospective cohort study was conducted at a single center as part of a quality improvement program evaluating the efficacy and safety of anticoagulation protocols. The study focused on implementing a guideline for anticoagulant dosing protocol based on dynamic changes in D-dimer levels in COVID-19 hospitalized patients. The dosing guideline allowed for dose escalation from standard prophylactic levels to escalated prophylactic or therapeutic levels, depending on the patient's risk profile for VTE. The primary endpoints included in-hospital survival comparing between fix and dynamic adjustment treatment groups. Secondary endpoints encompassed major and clinically relevant non-major bleeding (CRNMB) events, incidence of breakthrough thrombosis, length of hospitalization and ICU stay, days of mechanical ventilator use, and survival duration. Among the 260 COVID-19-infected patients hospitalized between March 15th and June 15th, 2020. The patients received fixed anticoagulant dosage in 188, 72.3%) patients, while 72 (27.7%) were up-titrated according to the protocol. In-hospital survival at 30 days demonstrated superiority among patients whose anticoagulation was up-titrated to either escalated prophylactic or therapeutic (80.2%) compared to receiving fixed anticoagulant dosage (51.3%) (p=0.01). Bleeding events were significantly higher in up-titrate group (12.5%) compared to fixed anticoagulant dosage group (2.13%). Most of them are CRNMB. A dynamic, D-dimer-based dose escalation of anticoagulation for hospitalized patients with COVID-19 holds promise in improving in-hospital mortality rates without a significant increase in fatal bleeding events.

Bleeding events in patients with cancer: incidence, risk factors, and impact on prognosis in a prospective cohort study

AbstractHemostatic imbalances are frequent in patients with cancer. Although cancer-associated thrombotic complications have been well characterized, data on bleeding events in patients with cancer are sparse. Therefore, we aimed to investigate the incidence, risk factors, and impact on prognosis of bleeding events in patients with cancer initiating systemic anticancer therapies in a prospective cohort study, the Vienna Cancer, Thrombosis, and Bleeding Study. The primary study outcome was defined as clinically relevant bleeding (CRB), comprising major bleeding (MB) and clinically relevant nonmajor bleeding. In total, 791 patients (48% female), with median age of 63 years (interquartile range [IQR], 54-70), with various cancer types, 65.5% stage IV, were included. Over a median follow-up of 19 months (IQR, 8.7-24.0), we observed 194 CRB events in 139 (17.6%) patients, of which 42 (30.0%) were tumor related, 64 (46.0%) gastrointestinal, and 7 (5.0%) intracerebral. The 12-month cumulative incidence of first CRB and MB was 16.6% (95% confidence interval [CI], 13.7-19.6) and 9.1% (95% CI, 6.8-11.3), respectively, in the whole cohort, and 14.4% (95% CI, 11.2-17.5) and 7.0% (95% CI, 4.7-9.2), respectively, in those without anticoagulation. Patients with head and neck cancer had the highest risk of CRB. Lower baseline hemoglobin and albumin were associated with bleeding in patients without anticoagulation. Seven (5.0%) bleeding events were fatal, of which 6 occurred in patients without anticoagulation. Patients with CRB were at an increased risk of all-cause mortality (multivariable transition hazard ratio, 5.80; 95% CI, 4.53-7.43). In patients with cancer, bleeding events represent a frequent complication and are associated with increased mortality.

FEATURES OF DRUG-DRUG INTERACTIONS BETWEEN RIVAROXABAN AND P-GLYCOPROTEIN INHIBITOR DEPENDING ON CYP3A4/A5 GENE POLYMORPHISM IN PATIENTS 80 YEARS AND OLDER WITH NONVALVULAR ATRIAL FIBRILLATION

Abstract Introduction. Increased risk of bleeding associated with rivaroxaban administration is associated with polymorphism of genes involved in its biotransformation, as well as with the use of drugs that inhibit common metabolic pathways. However, the data are contradictory. Objective of the work.To study the features of drug-drug interactions between rivaroxaban and a P-glycoprotein inhibitor (using verapamil as an example) depending on the polymorphism of the CYP3A4 (rs35599367)and CYP3A5 (rs776746)genes in patients aged 80 years and older with non-valvular atrial fibrillation. Material and methods. A total of 128 patients (median age 87.5 years [83-90 years], 75% women) were examined. All patients underwent genotyping for the studied polymorphisms, determination of the minimum steady-state concentration of rivaroxaban (Cmin,ss), standardization of the minimum steady-state concentration of rivaroxaban per daily dose (Cmin,ss /D), determination of prothrombin time (PT) in plasma, and analysis of medical records for the presence of clinically relevant non-major bleeding (CRNMB). Results.Co-administration of rivaroxaban with verapamil compared with patients receiving rivaroxaban without calcium channel blockers in CYP3A4gene CC carriers resulted in higher values of Cmin,ss(73.8 [49-113.5] vs 40.5 [25.6-73.3] ng/ml), Cmin,ss /D (2.5 [1.7-4.0] vs 4.7 [2.9-7.7] ng/ml/mg), PT (14.8 [13.3-17.3] vs 14.0 [12.6-14.5] sec) and CRNMB (10/30 (33.3%) vs 6/45 (13.3%) cases), (p0.05). In carriers of the GG gene, CYP3A5resulted in higher values of Cmin,ss (74.7 [50.6-108.8] vs 40.2 [25.7-72.3] ng/ml), Cmin,ss /D 4.6 [3.0-7.3] vs 2.5 [1.7-4.0] ng/ml/mg), PT (14.6 [12.8-15.2] vs 14.0 [12.6-14.5] sec) and CRNMB (10/27 (37%) vs 5/40 (12.5%) cases), (p0.05). And in GA+AA carriers of the CYP3A5gene, it resulted in higher values of Cmin,ss (88.1 [5.5-88.1] vs 52.8 [25.0-77.2] ng/ml), Cmin,ss /D 5.7 [0.4-5.7] vs 3.5 [1.7-5.2] ng/ml/mg), (p0.05). In CT carriers of the CYP3A4 gene, the combined use of rivaroxaban with verapamil was not observed in our sample. Conclusions:Carriers of the homozygous wild-type CYP3A4/A5 genotype showed high pharmacokinetic variability to verapamil (a strong P-glycoprotein inhibitor and a moderate CYP3A4 inhibitor).

A Dynamic, D-dimer-based Thromboprophylaxis Strategy in Patients with COVID-19

Background COVID-19 pandemics increases venous thromboembolism (VTE) risk during hospitalization, despite prophylactic anticoagulation. Limited radiological diagnosis in pandemic requires a guided protocol for anticoagulant adjustment. Methods This retrospective cohort study was conducted at a single center as part of a quality improvement program evaluating the efficacy and safety of anticoagulation protocols. The study focused on implementing a guideline for anticoagulant dosing protocol based on dynamic changes in D-dimer levels in COVID-19 hospitalized patients. The dosing guideline allowed for dose escalation from standard prophylactic levels to escalated prophylactic or therapeutic levels, depending on the patient's risk profile for VTE. The primary endpoints included in-hospital survival comparing between fix and dynamic adjustment treatment groups. Secondary endpoints encompassed major and clinically relevant non-major bleeding (CRNMB) events, incidence of breakthrough thrombosis, length of hospitalization and ICU stay, days of mechanical ventilator use, and survival duration. Findings Among the 260 COVID-19-infected patients hospitalized between March 15th and June 15th, 2020. The patients received fixed anticoagulant dosage in 188, 72.3%) patients, while 72 (27.7%) were up-titrated according to the protocol. In-hospital survival at 30 days demonstrated superiority among patients whose anticoagulation was up-titrated to either escalated prophylactic or therapeutic (80.2%) compared to receiving fixed anticoagulant dosage (51.3%) (p=0.01). Bleeding events were significantly higher in up-titrate group (12.5%) compared to fixed anticoagulant dosage group (2.13%). Most of them are CRNMB. Conclusion A dynamic, D-dimer-based dose escalation of anticoagulation for hospitalized patients with COVID-19 holds promise in improving in-hospital mortality rates without a significant increase in fatal bleeding events.

Effectiveness and Safety of Extended Treatment Apixaban Versus Low-Molecular-Weight Heparin in Cancer-Associated Venous Thromboembolism.

Limited real-world evidence is available comparing the safety and effectiveness of apixaban and low-molecular-weight heparins (LMWHs) for preventing recurrent venous thromboembolism (VTE) in patients with active cancer receiving anticoagulation in an extended treatment setting. This study evaluated the risk of bleeding and recurrent VTE in patients with cancer-associated VTE who were prescribed apixaban or LMWH for ≥3 months. A US commercial claims database was used to identify adult patients with VTE and active cancer who initiated apixaban or LMWH 30 days following the first VTE diagnosis and had ≥3 months of continuous enrollment and 3 months of primary anticoagulation treatment. Patients were followed from the day after the end of primary anticoagulation treatment until the earliest of: date of disenrollment, discontinuation of index anticoagulant, switch to another anticoagulant, or end of the study period. Inverse-probability treatment weighting (IPTW) was used to balance treatment cohorts. Incidence rates (IRs) for the outcomes were calculated per 100 person-years (PY). Cox proportional hazard models were used to evaluate the adjusted risk of recurrent VTE, major bleeding (MB), and clinically relevant nonmajor bleeding (CRNMB). A total of 13,564 apixaban- and 2,808 LMWH-treated patients were analyzed. Post-IPTW, the treatment cohorts were balanced. Patients receiving apixaban had lower adjusted IRs for recurrent VTE (4.1 vs 9.6 per 100 PY), MB (6.3 vs 12.6), and CRNMB (26.1 vs 36.0) versus LMWH (P<.0001 for all comparisons) during the follow-up period. Patients on apixaban had a lower adjusted risk of recurrent VTE (hazard ratio [HR], 0.42; 95% CI, 0.34-0.53), MB (HR, 0.50; 95% CI, 0.41-0.61), and CRNMB (HR, 0.76; 95% CI, 0.68-0.85) versus LMWH. Extended anticoagulation treatment of ≥3 months with apixaban was associated with lower rates of recurrent VTE, MB, and CRNMB compared with LMWH in adults with cancer-associated VTE.

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

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. 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. The analysis included 12011 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%]. 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.

Direct oral anticoagulants in embolic stroke of undetermined source: an updated meta-analysis.

The efficacy and safety of direct oral anticoagulants (DOAC) in patients with embolic stroke of undetermined source (ESUS) remains unclear. We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCT) comparing DOACs versus aspirin in patients with ESUS. Risk ratios (RR) and 95% confidence intervals (CI) were computed for binary endpoints. Four RCTs comprising 13,970 patients were included. Compared with aspirin, DOACs showed no significant reduction of recurrent stroke (RR 0.95; 95% CI 0.84-1.09; p = 0.50; I2 = 0%), ischemic stroke or systemic embolism (RR 0.97; 95% CI 0.80-1.17; p = 0.72; I2 = 0%), ischemic stroke (RR 0.92; 95% CI 0.79-1.06; p = 0.23; I2 = 0%), and all-cause mortality (RR 1.11; 95% CI 0.87-1.42; p = 0.39; I2 = 0%). DOACs increased the risk of clinically relevant non-major bleeding(CRNB) (RR 1.52; 95% CI 1.20-1.93; p < 0.01; I2 = 7%) compared with aspirin, while no significant difference was observed in major bleeding between groups (RR 1.57; 95% CI 0.87-2.83; p = 0.14; I2 = 63%). In a subanalysis of patients with non-major risk factors for cardioembolism, there is no difference in recurrent stroke (RR 0.98; 95% CI 0.67-1.42; p = 0.90; I2 = 0%), all-cause mortality (RR 1.24; 95% CI 0.58-2.66; p = 0.57; I2 = 0%), and major bleeding (RR 1.00, 95% CI 0.32-3.08; p = 1.00; I2 = 0%) between groups. In patients with ESUS, DOACs did not reduce the risk of recurrent stroke, ischemic stroke or systemic embolism, or all-cause mortality. Although there was a significant increase in clinically relevant non-major bleeding, major bleeding was similar between DOACs and aspirin.

Safety and effectiveness of oral anticoagulants in patients with atrial fibrillation and stage 4 chronic kidney disease: a real-world experience

It is still uncertain whether direct oral anticoagulants (DOACs) perform better than vitamin K antagonists (VKAs) in subjects with non-valvular atrial fibrillation (NVAF) and advanced chronic kidney disease (CKD). The aim of the study was to compare safety and effectiveness of DOACs and VKAs in patients with NVAF and stage 4 CKD (creatinine clearance 15–29 mL/min). We searched the hospital databases of two academic centers to retrospectively identify patients with stage 4 CKD who were on treatment with DOACs or VKAs for NVAF. Safety was the primary outcome of the study and was assessed in terms of incidence of major bleeding (MB). Secondary outcomes were clinically relevant non-major bleeding (CRNMB) and death for any cause. A total of 176 patients (102 on DOACs and 74 on VKAs) were found and included in the analysis. The incidence rate of MB was not statistically different between groups (8.6 per 100 patients-year in the DOAC group and 5.6 per 100 patients-year in the VKA group). Rates of IS/SSE and CRNMB were statistically similar in the two treatment groups, as well. There were less deaths for any cause in the DOAC group than in the VKA group (8.6 and 15.8 per 100 patients-year, respectively), but the difference was not statistically significant. This study found no difference in terms of safety and effectiveness between patients with NVAF and stage 4 CKD treated with DOACs and VKAs. Larger prospective or randomized studies are needed to confirm these findings.

Incidence of acute Deep Vein Thrombosis in pediatric and adolescent orthopedic trauma hospitalized patients and effect of rivaroxaban treatment

ObjectiveDeep vein thrombosis (DVT) provoked by orthopedic trauma is increasing in pediatric hospitalized patients. The purpose of our study is to identify the prevalence of acute DVT in pediatric and adolescent orthopedic trauma hospitalized patients and focus on evaluating the anticoagulation strategies and the clinical outcomes after a confirmed acute DVT. MethodsPatients (age ≤18 years) with a confirmed acute DVT admitted for orthopedic trauma between September 2017 and December 2023 were included. Patients were classified into the non-anticoagulation (NA), the in-hospital anticoagulation (IHA), and the in-and-out-of-hospital anticoagulation (IOHA) groups based on their anticoagulation regimen. Efficacy outcomes were the venous thromboembolism (VTE) recurrence within 3 months and change in thrombus burden by repeat imaging at 2 weeks after discharge compared with baseline. Safety outcomes were major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) within 3 months. ResultsOf the 11,206 pediatric and adolescent orthopedic trauma inpatients, 94(median age,16 [15, 18] years) were diagnosed with acute DVT, with an incidence of 0.84 %, of which 8(8.5 %) received NA, 41(43.6 %) received IHA, and 45(47.9 %) received IOHA. After the diagnosis of DVT, of patients who received anticoagulation, 97.9 % were treated with rivaroxaban as an oral anticoagulant, and 71.7 % received an LMWH course of ≥5 days before starting rivaroxaban therapy. With a median anticoagulation course of 22(8, 37.3) days, the duration in the IOHA was significantly longer than the IHA (37 days vs. 8 days, p = 0.000). No patients experienced recurrent VTE and MB at 3 months, and 1 received IOHA had a CRNMB event (0 % vs. 0 % vs. 2.2 %, p = 1.000). Thrombus resolution was significantly higher in patients who received anticoagulation therapy (IOHA 91.1 % vs. IHA 80.5 % vs. NA 37.5 %, P = 0.002), and thrombus-no relevant change was significantly lower in patients who received the IOHA strategy compared with the other groups (4.4 % vs. 19.5 % vs. 62.5 %, P = 0.000). ConclusionsA rivaroxaban-predominant IOHA strategy significantly reduced the thrombotic burden without increasing the risk of bleeding for the treatment of DVT in adolescents with orthopedic trauma. Duration of anticoagulation therapy <6 weeks appears appropriate for adolescent orthopedic trauma-related DVT.

Off-Label Reduced Dose Apixaban in Older Adults With Atrial Fibrillation and Associated Outcomes.

Apixaban is commonly used to prevent stroke in older adults with nonvalvular atrial fibrillation (AF). Although its package insert has specific dose reduction criteria, providers may dose reduce outside of these parameters based on clinical scenarios. The primary objective was to determine the incidence of apixaban off-label reduced dosing, while secondarily determining the safety and efficacy outcomes associated with such dosing. A retrospective analysis of patients aged 65 and older with orders for apixaban for AF was institutional review board (IRB)-approved and conducted across 3 academic medical centers. Patients receiving off-label reduced-dose apixaban (ie, "underdosed") were matched to a cohort of patients dosed according to the package insert at the standard dosing (5 mg twice daily) using stratified random sampling. Secondary outcomes included 1-year incidence of major bleeding, clinically relevant non-major bleeding (CRNMB), stroke or transient ischemic attack (TIA), and mortality. The Fisher exact tests were used to compare between-group differences. Of the 1172 patients meeting initial inclusion criteria, 201 (17%) were dosed off-label, with 175 (15%) "underdosed." The 147 "underdosed" patients with documented follow-up were matched with 139 patients receiving standard Food and Drug Administration (FDA)-labeled dosing. There were no significant differences in incidence of stroke (2.7% vs 2.2%), major bleeding (0% vs 0.7%), and CRNMB (2.7% vs 1.4%) in the off-label reduced dosing versus standard dosing groups. All-cause mortality was higher in the off-label reduced-dose group (16 [10.9%] vs 2 [1.4%], P < 0.05). Older adults with nonvalvular AF are commonly prescribed lower-than-recommended doses of apixaban. However, no significant association was found between empiric off-label reduced dosing and stroke or bleeding outcomes.

Assessment of Temporary Warfarin Reversal in Patients With Left Ventricular Assist Devices: the KVAD Study*

Patients with left ventricular assist devices (LVADs) require interruption of warfarin for invasive procedures, but parenteral bridging is associated with many complications. Four-factor prothrombin complex concentrate (4F-PCC) can temporarily restore hemostasis in patients undergoing anticoagulation with warfarin. This pilot study evaluated the strategy of using variable-dose 4F-PCC to immediately and temporarily reverse warfarin before invasive procedures without holding warfarin in patients with LVADs. The duration of effect of 4F-PCC on factor levels and time to reestablish therapeutic anticoagulation post procedure were assessed. Adult patients with LVADs and planned invasive procedures were enrolled from a single center. Warfarin was continued uninterrupted. The 4F-PCC dose administered immediately pre-procedure was based on study protocol. International normalized ratio (INR)- and vitamin K-dependent factor levels were collected before and during the 48 hours after 4F-PCC administration. The use of parenteral bridging, International Society for Thrombosis and Haemostasis major and clinically relevant nonmajor bleeding (CRNMB) and thromboembolic events at 7 and 30 days were collected. In 21 episodes of 4F-PCC reversal, median baseline INR was 2.7 (IQR 2.2-3.2). The median dosage of 4F-PCC administered was 1794 units (IQR 1536-2130). At 24 and 48 hours post 4F-PCC administration, median INRs were 1.8 (IQR 1.7-2.0) and 2.0 (IQR 1.9-2.4). Two patients required postoperative bridging. One patient experienced major bleeding within 72 hours, and 2 experienced CRNMB within 30 days. There were no thromboembolic events. Baseline and post 4F-PCC vitamin K-dependent factor levels corresponded with changes in INR values. The median time to achieve therapeutic INR post-procedure was 2.5 days (IQR, 1-4). Administration of 4F-PCC for temporary reversal of warfarin for invasive procedures in patients with LVADs allowed for continued warfarin dosing with minimal use of post-intervention bridging, limited bleeding and no thromboembolic events.