Non-major Bleeding Research Articles

A Novel Nomogram for Predicting Warfarin-Related Bleeding: A Retrospective Cohort Study.

Warfarin is a widely used anticoagulant, and bleeding complications are the main reason why patients discontinue the drug. Currently, there is no nomogram model for warfarin-associated bleeding risk. The aim of this study was to develop a risk-prediction nomogram model for warfarin-related major and clinically relevant non-major (CRNM) bleeding. A total of 280 heart disease outpatients taking warfarin were enrolled, 42 of whom experienced major or CRNM bleeding at the one-year follow-up. The Least Absolute Shrinkage and Selection Operator regression model was employed to identify potential predictors. Backward stepwise selection with the Akaike information criterion was used to establish the optimal predictive nomogram model. The receiver operating characteristic (ROC) curve, calibration plot, Hosmer-Lemeshow goodness-of-fit test, and decision curve analysis (DCA) were used to evaluate the performance of the nomogram. The nomogram consisted of four predictors: female (OR = 1.85; 95% CI: 0.91-3.94), TIA (OR = 6.47; 95% CI: 1.85-22.7), TTR (OR = 0.99; 95% CI: 0.97-1.00), and anemia (OR = 2.30; 95% CI: 1.06-4.84). The model had acceptable discrimination (area under the ROC curve = 0.68, 95% CI: 0.59-0.78), and was significantly better than the existing nine warfarin-related bleeding prediction scoring systems. The calibration plot and Hosmer-Lemeshow test (χ² = 7.557; P = .478) indicated well-calibrated data in the model. The DCA demonstrated good clinical utility. In this study, we developed a nomogram to predict the risk of warfarin-related major or CRNM bleeding. The model has good performance, allows rapid risk stratification of warfarin users, and provides a basis for personalized treatment.

Effectiveness and Safety of the Coadministration of Rifampin and Warfarin versus Direct Oral Anticoagulants: A Cohort Study.

Pharmacokinetic studies have shown that rifampin reduces the levels of oral anticoagulants during the initiation of coadministration, raising concerns about an increased thrombotic risk, but there are limited comparative clinical outcomes between rifampin and warfarin compared with direct oral anticoagulants (DOACs). This study aimed to evaluate the effectiveness and safety of concurrent use of rifampin and warfarin versus DOACs, with assessments of outcome-associated factors and oral anticoagulant (OAC) management quality. A total of 142 patients given rifampin plus warfarin (n = 56) or DOACs (n = 86) for over 7 days were included, and their clinical data and outcomes were compared. The median Charlson Comorbidity Index and HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly) score of the two groups were 2 and 3, respectively. The incidence rate of composite ischemic or thromboembolic events was 2.16 and 1.44 per 10,000 patient-days in the warfarin and DOAC groups, respectively, with an adjusted hazard ratio (HR) of 0.41 (95% confidence interval [CI] 0.02-7.34). The incidence rate of composite major bleeding or clinically relevant nonmajor bleeding events was 1.58 and 1.52 per 10,000 patient-days in the warfarin and DOAC groups, respectively, with an adjusted HR of 1.12 (95% CI 0.32-4.45). The risk of composite bleeding events increased with a higher HAS-BLED score (HR: 1.62, 95% CI: 1.02-2.63). Moreover, 34.3% of warfarin users maintained a percent time in therapeutic range of above 50%. Furthermore, 77.9% of DOAC users received appropriate dosing. No significant differences were observed in terms of the incidence of thrombotic or bleeding events between the two groups during coadministration. In addition, a higher HAS-BLED score was associated with a greater risk of bleeding events regardless of the class of OACs used. Finally, close monitoring of bleeding events should be considered.

Direct Oral Anticoagulants for Treating Acute Venous Thromboembolism in Children: Meta-Analysis of Randomized Controlled Trials.

Acute venous thromboembolism (VTE) in children presents unique challenges due to the limitations of standard anticoagulation therapies. Herein, we aimed to systematically review randomized controlled trials (RCTs) evaluating the efficacy and safety of direct oral anticoagulants (DOACs) in pediatric patients with acute VTE. PubMed and Embase databases were searched for RCTs comparing DOACs to standard anticoagulation in pediatric VTE patients. Efficacy outcomes included VTE recurrence and all-cause mortality, while safety outcomes comprised major bleeding and other adverse events. Three RCTs with 790 participants were included. When compared with standard anticoagulation, DOACs demonstrated a reduced risk of VTE recurrence (risk difference[RD] = -3%, 95% confidence interval[CI]: -6% to 0%, P = 0.04) and an increased risk of any adverse event (RD = 8%, 95% CI: 1% to 14%, P = 0.02). No significant differences were found in all-cause mortality, major bleeding, clinically relevant non-major bleeding, or total bleeding between the DOAC and control groups. DOACs, primarily dabigatran and rivaroxaban, are non-inferior to standard anticoagulants in reducing VTE recurrence in pediatric patients, with comparable safety profiles. Further research is essential to confirm these findings.

Evaluation of Clinical, Echocardiographic, and Therapeutic Characteristics, and Prognostic Outcomes of Coexisting Heart Failure among Patients with Atrial Fibrillation: The Jordan Atrial Fibrillation (JoFib) Study.

Atrial fibrillation (AF) is the most commonly encountered cardiac arrhythmia in clinical practice. Heart failure (HF) can occur concurrently with AF. We compared different demographic, clinical, and echocardiographic characteristics between patients with AF+HF and patients with AF only. Furthermore, we explored whether concurrent HF independently predicts several outcomes (all-cause mortality, cardiovascular mortality, ischemic stroke/systemic embolism (IS/SE), major bleeding, and clinically relevant non-major bleeding (CRNMB)). Comparisons between the AF+HF and the AF-only group were carried out. Multivariable Cox proportional hazard models were constructed for each outcome to assess whether HF was predictive of any of them while controlling for possible confounding factors. A total of 2020 patients were included in this study: 481 had AF+HF; 1539 had AF only. AF+HF patients were older, more commonly males, and had a higher prevalence of diabetes mellitus, dyslipidemia, coronary artery disease, and chronic kidney disease (p≤0.05). Furthermore, AF+HF patients more commonly had pulmonary hypertension and low ejection fraction (p≤0.001). Finally, HF was independently predictive of all-cause mortality (adjusted HR 2.17, 95% CI (1.66-2.85) and cardiovascular mortality (adjusted HR 2.37, 95% CI (1.68-3.36). Coexisting AF+HF was associated with a more labile and higher-risk population among Jordanian patients. Furthermore, coexisting HF independently predicted higher all-cause mortality and cardiovascular mortality. Efforts should be made to efficiently identify such cases early and treat them aggressively.

Turkish Real Life Atrial Fibrillation in Clinical Practice: TRAFFIC Study.

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia worldwide and is associated with an increased risk of thromboembolism, ischemic stroke, impaired quality of life, and mortality. The latest research that shows the prevalence and incidence of AF patients in Türkiye was the Turkish Adults' Heart Disease and Risk Factors study, which included 3,450 patients and collected data until 2006/07.The Turkish Real Life Atrial Fibrillation in Clinical Practice (TRAFFIC) study is planned to present current prevalence data, reveal the reflection of new treatment and risk approaches in our country, and develop new prediction models in terms of outcomes. The TRAFFIC study is a national, prospective, multicenter, observational registry. The study aims to collect data from at least 1900 patients diagnosed with atrial fibrillation, with the participation of 40 centers from Türkiye. The following data will be collected from patients: baseline demographic characteristics, medical history, vital signs, symptoms of AF, ECG and echocardiographic findings, CHADS2-VASC2 and HAS-BLED (1-year risk of major bleeding) risk scores, interventional treatments, antithrombotic and antiarrhythmic medications, or other medications used by the patients. For patients who use warfarin, international normalized ratio levels will be monitored. Follow-up data will be collected at 6, 12, 18, and 24 months. Primary endpoints are defined as systemic embolism or major safety endpoints (major bleeding, clinically relevant nonmajor bleeding, and minor bleeding as defined by the International Society on Thrombosis and Hemostasis). The main secondary endpoints include major adverse cardiovascular events (systemic embolism, myocardial infarction, and cardiovascular death), all-cause mortality, and hospitalizations due to all causes or specific reasons. The results of the 12-month follow-up of the study are planned to be shared by the end of 2023. The TRAFFIC study will reveal the prevalence and incidence, demographic characteristics, and risk profiles of AF patients in Türkiye. Additionally, it will provide insights into how current treatments are reflected in this population. Furthermore, risk prediction modeling and risk scoring can be conducted for patients with AF.

Prevention of symptomatic pulmonary embolism for gynecologic malignancies with preoperative asymptomatic venous thromboembolism: GOTIC-VTE trial.

In Japan, perioperative prophylaxis of pulmonary embolism (PE) in gynecologic cancer patients with preoperative asymptomatic venous thromboembolism (VTE) has not been well established yet. The GOTIC-VTE trial was a prospective, multi-center, single-arm clinical trial to investigate the prevention of postoperative symptomatic PE onset by seamless anticoagulant therapy from the preoperative period to 4 weeks after surgery instead of using intermittent pneumatic compression. Anticoagulant therapy was started immediately after asymptomatic VTE diagnosis and stopped preoperatively according to the rules of each institution. Unfractionated heparin administration was resumed within 12 hours postoperatively, and this was followed by the switch to low-molecular-weight heparin and subsequently, edoxaban; this cycle was continued for 28 days. Primary outcome was the occurrence of symptomatic PE in 28 days postoperatively. Secondary outcomes were the incidence of VTE-related events in 28 days and 6 months postoperatively and protocol-related adverse events. Between February 2018 and September 2020, 99 patients were enrolled; of these, 82 patients were assessed as the full analysis set, including 58 for ovarian cancer, fallopian tube, or peritoneal cancer; 21 for endometrial cancer; and 3 for cervical cancer. No symptomatic PE was observed within 28 days postoperatively; two patients had bleeding events (major bleeding and clinically relevant nonmajor bleeding) and three had grade 3 adverse events (increased alanine transaminase, aspartate aminotransferase, or gamma-glutamyl transferase). The multifaceted perioperative management for gynecologic malignancies with asymptomatic VTE effectively prevented postoperative symptomatic PE. JRCT Identifier: jRCTs031180124.

Oral Rivaroxaban Versus Warfarin After inferior Vena cava Filter Implantation: A Retrospective Cohort Study.

To assess the efficacy and safety of rivaroxaban compared to warfarin after inferior vena cava (IVC) filter implantation. This retrospective analysis includes data from 100 patients with deep vein thrombosis (DVT) who underwent IVC filter implantation due to a free-floating thrombus (n = 64), thrombus propagation (n = 8), or acute bleeding (n = 8) on therapeutic anticoagulation, catheter-directed thrombolysis (n = 8), or had previously implanted filter with DVT recurrence. Patients were treated with warfarin (n = 41) or rivaroxaban (n = 59) for 3-12 months. Symptomatic venous thromboembolism (VTE) recurrence and bleeding events were assessed at 12 months follow-up. Three (7.3%) cases of VTE recurrence without IVC filter occlusion occurred on warfarin and none on rivaroxaban. The only (2.4%) major bleeding occurred on warfarin. Three (5.1%) clinically relevant non-major bleedings were detected on rivaroxaban. No significant differences existed between groups when full and propensity scores matched datasets were compared. Rivaroxaban seems not less effective and safe than warfarin after IVC filter implantation.

Real-world Data on Treatment Patterns and Bleeding in Cancer-associated Thrombosis: Data from the TROLL Registry.

Background International guidelines are increasingly recommending direct oral anticoagulants (DOACs) as the first-line treatment for cancer-associated thrombosis (CAT). However, data regarding treatment patterns and adherence to guidelines in patients with CAT are scarce. Objectives This study aimed to explore anticoagulant treatment patterns in patients with CAT and to calculate the incidence rates of bleeding events. Methods Patients ≥18 years with active cancer and a first-time venous thromboembolism between 2005 and 2020 were identified through the Venous T hrombosis R egistry in Østf OL d Hospita L . Outcome measures were patterns of anticoagulant treatment during the study period and bleeding events. We calculated overall incidence rates per 100 person-years and 6- and 12-month cumulative incidence of major and clinically relevant nonmajor bleeding (CRNMB) during anticoagulant treatment. Results Median age of 842 CAT patients at the time of thrombosis was 69 years (interquartile range 61-77), and 443 (52.6%) were men. In total, 526 patients (62.5%) had pulmonary embolism and 255 (30.3%) had deep vein thrombosis. Low molecular weight heparin (LMWH) was prescribed to 713 (85.8%) patients, whereas 64 (7.7%) received DOACs and 54 (6.5%) received vitamin K antagonists as the initial anticoagulant treatment. Prescription of DOACs as initial treatment increased from 3.0% in 2013/2014 to 18.0% in 2019/2020. The incidence rate of major bleeding was 6.9 (95% confidence interval [CI] 5.2-9.2) and 10.1 (95% CI 8.0-12.9) in CRNMB. Conclusion Most patients were treated with LMWH. However, a gradual shift in treatment toward DOACs was observed. Overall, bleeding complications were rare and comparable to those reported in randomized trials.

Apixaban versus Aspirin for Embolic Stroke of Undetermined Source

BackgroundRivaroxaban and dabigatran were not superior to aspirin in trials of patients with embolic stroke of undetermined source (ESUS). It is unknown whether apixaban is superior to aspirin in patients with ESUS and known risk factors for cardioembolism.MethodsWe conducted a multicenter, randomized, open-label, blinded-outcome trial of apixaban (5 mg twice daily) compared with aspirin (100 mg once daily) initiated within 28 days after ESUS in patients with at least one predictive factor for atrial fibrillation or a patent foramen ovale. Cardiac monitoring was mandatory, and aspirin treatment was switched to apixaban in case of atrial fibrillation detection. The primary outcome was any new ischemic lesion on brain magnetic resonance imaging (MRI) during 12-month follow-up. Secondary outcomes included major and clinically relevant nonmajor bleeding.ResultsA total of 352 patients were randomly assigned to receive apixaban (178 patients) or aspirin (174 patients) at a median of 8 days after ESUS. At 12-month follow-up, MRI follow-up was available in 325 participants (92.3%). New ischemic lesions occurred in 23 of 169 (13.6%) participants in the apixaban group and in 25 of 156 (16.0%) participants in the aspirin group (adjusted odds ratio, 0.79; 95% confidence interval, 0.42 to 1.48; P=0.57). Major and clinically relevant nonmajor bleeding occurred in five and seven participants, respectively (1-year cumulative incidences, 2.9 and 4.2; hazard ratio, 0.68; 95% confidence interval, 0.22 to 2.16). Serious adverse event rates were 43.9 per 100 person-years in those given apixaban and 45.7 per 100 person-years in those given aspirin. The Apixaban for the Treatment of Embolic Stroke of Undetermined Source trial was terminated after a prespecified interim analysis as a result of futility.ConclusionsApixaban treatment was not superior to cardiac monitoring-guided aspirin in preventing new ischemic lesions in an enriched ESUS population. (Funded by Bristol-Myers Squibb and Medtronic Europe; ClinicalTrials.gov number, NCT02427126.)

Efficacy and Safety of Direct Oral Anticoagulants in Pediatric Venous Thromboembolism: A Systematic Review and Meta-Analysis.

To assess the efficacy and safety of direct oral anticoagulants (DOACs) in comparison to standard-of-care (SOC) anticoagulants in the management and prophylaxis of thromboembolic events in pediatric populations. A comprehensive search of electronic databases was conducted to identify relevant studies published between January 1, 2015, and December 18, 2022. A meta-analysis was undertaken to evaluate the effect of DOACs on clinically significant endpoints, employing trial-level data with harmonized endpoint definitions. The primary outcome was venous thromboembolism (VTE). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. The study was registered with INPLASY (2022120065). Three studies encompassing 934 subjects were included. The incidence of VTE was reduced in patients administered DOACs compared to those on SOC anticoagulants (OR 0.41 [95% CI 0.19-0.93], I²=0%, P = 0.03). No significant differences were observed between the DOAC and SOC groups in all-cause mortality (OR 0.50 [95% CI 0.07-3.59], I²=0%, P = 0.35) or serious adverse events (OR 0.75 [95% CI 0.50-1.12], I²=0%, P = 0.16). The risk of major bleeding (OR 0.50 [95% CI 0.13-1.87], I²=44%, P = 0.30) and clinically relevant non-major bleeding (OR 1.23 [95% CI 0.50-3.00], I²=0%, P = 0.65) exhibited no significant differences between the groups. DOACs are associated with a reduced risk of VTE in pediatric patients without increasing the risk of bleeding, all-cause mortality, or serious adverse events when compared to SOC anticoagulants. DOACs may be an alternative for the treatment and prevention of thromboembolic events in the pediatrics.

Management of edoxaban therapy and clinical outcomes in patients undergoing major or nonmajor surgery: a subanalysis of the EMIT-AF/VTE study

BackgroundOptimising periprocedural management of direct oral anticoagulation in patients with atrial fibrillation on chronic treatment undergoing major surgeries is an important aspect of balancing the risk of surgery-related bleeding with the risk of thromboembolic events, which may vary by surgery type.MethodsThis subanalysis of the prospective EMIT-AF/VTE programme assessed periprocedural-edoxaban management, according to physicians’ decisions, and bleeding and thromboembolic event rates in patients who underwent major vs. nonmajor surgeries. Edoxaban interruption and clinical outcomes were compared between major vs. nonmajor surgeries and between renal function subgroups (creatinine clearance [CrCL] ≤ 50 mL/min vs. > 50 mL/min).ResultsWe included 276 major and 512 nonmajor surgeries. The median pre- and postprocedural duration of edoxaban interruption in major vs. nonmajor surgeries was 4 vs. 1 days, whereas median duration of interruption for those with preprocedural-only and postprocedural-only interruption was 2 vs. 1 days and 2 vs. 0 days, respectively (P < 0.0001). Rates of all bleeding and clinically relevant nonmajor bleeding were numerically higher in major vs. nonmajor surgeries. Event rates (number of events per 100 surgeries) were low overall (< 6 events per 100 surgeries), independent of renal function subgroups.ConclusionIn this subanalysis of the EMIT-AF/VTE programme, periprocedural-edoxaban interruption was significantly longer in patients undergoing major vs. nonmajor surgery. This clinician-driven approach was associated with low rates of bleeding and thromboembolic events following both major and nonmajor surgeries.Trial registrationNCT02950168, registered October 31, 2016; NCT02951039, registered November 1, 2016.

Comparison of clinical outcomes among patients with isolated axial vs muscular calf vein thrombosis: A systematic review and meta-analysis

ObjectiveThrombi in the axial calf veins have quite different anatomical and physiological characteristics from that in the muscular calf veins, but their treatment was usually addressed in the same manner. We performed a meta-analysis of randomized and cohort studies to compare clinical outcomes among patients with isolated axial vs muscular calf deep vein thrombosis (DVT). MethodsRecurrent venous thromboembolism (VTE) was selected as the primary outcome. Resolution, proximal propagation of calf DVT, pulmonary embolism (PE), major bleeds, and clinically relevant non-major bleeds were separately analyzed as secondary outcomes. Data were pooled and compared with risk ratio (RR) and 95% confidence interval (CI). ResultsThirteen studies, consisting of 4889 patients, met the inclusion criteria and were included for analysis. A greater rate of recurrent VTE (FE model: RR, 1.23; 95% CI, 1.00-1.53; I2 = 29%), resolution (FE model: RR, 1.32; 95% CI, 1.01-1.72; I2 = 31%), proximal propagation (FE model: RR, 1.63; 95% CI, 1.10-2.41; I2 = 40%), and PE (FE model: RR, 2.79; 95% CI, 1.31-5.95; I2 = 0%) in the axial group compared with the muscular group. There was no difference in the pooled estimates for major bleeds (FE model: RR, 1.09; 95% CI, 0.61-1.95; I2 = 0%), and clinically relevant non-major bleeds (FE model: RR, 1.80; 95% CI, 0.93-3.48) in the axial and muscular arms. ConclusionsPatients with calf DVT limited to muscular veins might have a lower rate of recurrent VTE, resolution, proximal propagation, and PE vs those with axial calf vein involvement and exhibited similar safety outcomes.

Venous thromboembolism management in people with cystic fibrosis.

Rates of venous thromboembolism (VTE) are increasing in people with cystic fibrosis (PwCF). Providers treating VTE in PwCF have reported low confidence concerning anticoagulant drug selection, dose, duration, and drug-drug interactions. As there are currently no published reports regarding management of VTE in PwCF, our objective was to describe the management of VTE in PwCF. PwCF and VTE at the University of Utah Health were identified through electronic medical record searches. Patients were categorized into one of three treatment groups: warfarin, direct oral anticoagulant (DOAC), and low molecular weight heparin (LMWH). The primary outcome was episodes of major bleeding. Secondary outcomes included clinically relevant nonmajor (CRNM) bleeding. Nine PwCF with a total of 12 unique VTE episodes were included in the study, with all but one episode associated with a peripherally inserted central catheter (PICC). Of the 12 VTE cases, 25% were treated with warfarin, 50% with a DOAC, and 25% with LMWH. There were no episodes of major bleeding and only one episode of CRNM bleeding (Hemoptysis) in the LMWH group. All anticoagulant doses and durations generally followed guidelines for persons without CF. DOACs were the most common VTE treatment, at doses and duration consistent with guidelines for persons without CF, with no major or CRNM bleeding. VTE treatment in PwCF is generally consistent with guidelines for persons without CF with low rates of bleeding. DOACs are a potential option for treatment of VTE in PwCF, but more research is needed.

Event rates and risk factors for venous thromboembolism and major bleeding in a population of hospitalized adult patients with acute medical illness receiving enoxaparin thromboprophylaxis

BackgroundWe aimed to describe the event rates and risk-factors for symptomatic venous thromboembolism (VTE) and major bleeding in a population of hospitalized acutely ill medical patients. MethodsPatients ≥40 years old and hospitalized for acute medical illness who initiated enoxaparin prophylaxis were selected from the US Optum research database. Rates of symptomatic VTE and major bleeding at 90-days were estimated via the Kaplan-Meier (KM) method. Risk factors were identified via the Cox proportional hazards model. ResultsA total of 123,022 patients met the selection criteria. The KM rates of VTE and major bleeding at 90-days were 3.5 % and 2.2 %, respectively. Among subgroups, the risk of VTE varied from 3.0 % in patients with ischemic stroke to 6.9 % in patients with a cancer-related hospitalization, and the risk of major bleeding varied from 1.9 % in patients with inflammatory conditions to 3.6 % in patients with ischemic stroke. Key risk factors for VTE were prior VTE (HR=4.15, 95 % confidence interval [CI] 3.80–4.53), cancer-related hospitalization (HR=2.35, 95 % CI 2.10–2.64), and thrombophilia (HR=1.64, 95 % CI 1.29–2.08). Key risk factors for major bleeding were history of major bleeding (HR=2.17, 95 % CI 1.72–2.74), history of non-major bleeding (HR=2.46, 95 % CI 2.24–2.70), and hospitalization for ischemic stroke (2.42, 95 % CI 2.11–2.78). ConclusionThere is substantial heterogeneity in the event rates for VTE and major bleeding in acute medically ill patients. History of VTE and cancer related hospitalization represent profiles with a high risk of VTE, where continued VTE prophylaxis may be warranted.

A Comparison of Bleeding Events Among Patients on Apixaban, Rivaroxaban, and Warfarin for Atrial Fibrillation and/or Venous Thromboembolism

Introduction Apixaban and rivaroxaban are the most commonly used direct oral anticoagulants (DOACs) for atrial fibrillation (AF) and venous thromboembolism (VTE). Both have been compared to warfarin in landmark clinical trials. However, there are limited comparative efficacy data between these drugs in a real-world setting. We sought to assess patient characteristics and outcomes of apixaban, rivaroxaban, and warfarin in a non-trial based study cohort. Methods Retrospective registry-based cohort of adults starting apixaban, rivaroxaban, or warfarin therapy or switching between these anticoagulants for the indications of VTE and/or non-valvular AF. Through the Michigan Anticoagulation Quality Improvement Initiative (MAQI 2) collaborative of six anticoagulation clinics, warfarin treated patients were followed from January 2009 to June 2023. Four of these clinics contributed DOAC patient data from June 2011 to June 2023. Patients treated with other anticoagulants, with valvular AF, or with less than 3 months of follow-up were excluded. Propensity matched cohorts (apixaban versus warfarin [1:1], rivaroxaban versus warfarin [1:3], and apixaban versus rivaroxaban [1:1]) of patients were analyzed based on DOAC use at study enrollment, using 1:1-3:1 matching ratios. Patients were matched based on demographics, social history, comorbidities, medications, bleeding/thrombotic history, indication for anticoagulation, and follow-up. The primary outcome was any new bleeding event. Secondary outcomes included new episodes of thrombosis, bleeding event type (major, fatal, life threatening, central nervous system, and non-major bleeding), emergency room (ER) visits, hospitalizations, and death. Random chart audits were done to confirm the accuracy of the abstracted data. Event rates were compared using Poisson regression. Results Of 13,435 patients on OAC who met the study inclusion criteria (3,536 on apixaban, 1,395 on rivaroxaban, and 8,504 on warfarin), the average age was 66.7 years (standard deviation [SD] 14.9 years), 51.1% identified as male, most (58.0%) were on anticoagulation for AF, and the average follow-up was 28.2 months (SD 30.7 months). After propensity matching, 3,527 patients on apixaban were compared to 3,527 patients on warfarin. Any bleeding was similar between groups, but major bleeding was higher with warfarin (3.4 versus 4.7 events/100 patient years, p&amp;lt;0.001). Thrombotic event rates were higher with apixaban (2.6 versus 2.1 events/100 patient years, p=0.026), including the thrombotic subtype of other thrombosis (1.0 versus 0.5 events/100 patient years, p&amp;lt;0.001). Rates of ER visits and hospitalizations for bleeding were higher with warfarin. Mortality was higher with warfarin (3.7 versus 4.4 deaths/100 patient years, p=0.027). After propensity matching, 1,395 patients on rivaroxaban were compared to 4,185 patients on warfarin. Any bleeding and major bleeding were higher with rivaroxaban (37.9 versus 24.9 events/100 patient years, p&amp;lt;0.001; 4.7 versus 3.6 events/100 patient years, p=0.041 respectively). Thrombotic event rates were similar, aside from a higher rate of the thrombotic subtype of other thrombosis with rivaroxaban (1.0 versus 0.3 events/100 patient years, p=0.002). ER visits, hospitalizations, and mortality were similar between rivaroxaban and warfarin. After propensity matching, 1,395 patients on apixaban were compared to 1,395 patients on rivaroxaban. Any bleeding and major bleeding were higher with rivaroxaban (37.9 versus 25.7 events/100 patient years, p&amp;lt;0.001; 4.7 versus 2.6 events/100 patient years, p&amp;lt;0.001). Thrombotic event rates were similar. ER visits occurred more frequently on rivaroxaban (12.8 versus 10.1 events/100 patient years, p=0.003) as did patient mortality (3.5 versus 2.6 deaths/100 patient years, p=0.047). Conclusions For patients on oral anticoagulation for AF and/or VTE we observed that bleeding was highest with rivaroxaban, followed by warfarin, and then apixaban. Rates of thrombosis were higher with apixaban compared to warfarin, seemingly largely driven by “other” thrombotic events. Thrombotic event rates were otherwise similar between apixaban, rivaroxaban, and warfarin. We observed apixaban to be associated with lower mortality than rivaroxaban and warfarin. While these findings should be confirmed with randomized studies, they may have implications for anticoagulant selection.

Outcomes of Oral Anticoagulation with Concomitant NSAID Use: A Registry Based Cohort Study

Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs), available without a prescription, are some of the most commonly used drugs in the United States. For patients on oral anticoagulation (OAC), concomitant NSAID use can increase the risk of bleeding. Patients are often advised to avoid this drug combination, or else consider adding a proton pump inhibitor (PPI) or H2 receptor antagonists (H2RA) for gastroprotection when both NSAIDs and OAC are used. However, there are limited data on how NSAID use impacts thrombotic and hemorrhagic outcomes. Available data may be biased due to selection bias, confounding, misclassification, and variable NSAID exposure. We sought to determine the frequency of NSAID use among patients on OAC, the impact on clinical outcomes, and if gastroprotection may mitigate bleeding risk. We hypothesized that NSAIDs would increase bleeding risk without impacting thrombotic risk. We did not anticipate gastroprotection would mitigate this risk. Methods We conducted a retrospective registry-based cohort study of adults starting a direct oral anticoagulant (DOAC) or warfarin therapy for the indications of venous thromboembolism and/or non-valvular atrial fibrillation between June 2011 and June 2023. As part of the Michigan Anticoagulation Quality Improvement Initiative (MAQI 2), warfarin-treated patients were followed by six anticoagulation clinics, and four of the six clinics contributed data for patients on DOACs. Patients were excluded if they had a history of valvular AF, less than 3 months of follow-up, or on more than one antiplatelet drug. Two propensity matched cohorts (OAC alone vs. OAC+NSAID) of patients were analyzed based on NSAID use at the time of study enrollment, using a 4:1 matching ratio. Both prescribed and over the counter NSAIDs were included, potentially with the former being more frequently captured in the study registry. The primary outcome was any new bleeding event. Secondary outcomes included new episodes of arterial or venous thrombosis, bleeding event type (major, fatal, life threatening, central nervous system, and non-major bleeding), emergency room visits, hospitalizations, transfusions, and death. Random chart audits were done to confirm the accuracy of the abstracted data. Event rates were compared using Poisson regression. Results Of 12,083 patients on OAC, 449 (3.7%) were on concomitant NSAIDs. After propensity matching, we compared 1,796 patients on OAC to 449 patients on OAC+NSAIDs. Patient demographics, co-morbidities, indication for anticoagulation, history of bleeding or clotting, medications, and duration of follow-up were well-balanced after matching. Patients were followed for an average of 30 months (standard deviation 34.2 months). For patients on OAC alone vs. OAC+NSAIDs, bleeding event rates were similar: 25.1 (95% confidence interval [CI] 23.7-26.6) versus 24.3 (95% CI 21.4-27.3) bleeds per 100 patient years ( P=0.56). Rates of non-major, major, life-threatening, central nervous system, and fatal bleeding were also similar. Furthermore, rates of thrombosis, emergency room visits, hospitalizations, transfusion, and death were similar. A pre-defined subgroup analysis comparing patients on OAC+NSAIDs with gastrointestinal prophylaxis (PPIs or H2RAs, N=179) to patients on OAC+NSAIDs without gastrointestinal prophylaxis (N=270) also showed similar rates of bleeding and healthcare utilization. Conclusions Nearly 4% of patients were taking NSAIDs with OAC and outcomes were similar to patients on OAC alone. Study limitations include NSAIDs and gastroprotection were only reliably known at time of enrollment. In addition, the potential for unmeasured or unadjusted confounding inherent to observational studies. Further research is needed to determine if there is a “safe” level of NSAID use for patients on OAC and to better define the role of gastrointestinal prophylaxis.

Apixaban Is Effective and Safe in Reducing Venous Thromboembolism (VTE) in Obese Patients with Newly Diagnosed Pediatric Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma (ALL/LL) a Sub-Study Analysis of the Prevapix-ALL/Children's Oncology Group ACCL1333 Trial

Background: Pediatric patients with ALL/LL are at increased risk for VTE and obesity further increases VTE risk. Pediatric ALL/LL patients experiencing VTE have increased risk for mortality as compared to ALL/LL patients without VTE. Therefore, effective and safe pharmacologic VTE prevention options are urgently needed. The PREVAPIX-ALL trial was a multi-center, multinational, randomized, open-label, controlled trial assessing the safety and efficacy of primary prophylaxis using apixaban for the prevention of VTE in pediatric patients with ALL/LL. PREVAPIX-ALL was a collaboration between the Bristol Myers Squibb/Pfizer Alliance and the Children's Oncology Group. Patients with ALL/LL undergoing induction chemotherapy containing asparaginase therapy were randomized to either apixaban or standard of care (SOC - no anticoagulation). The objective of the current study was to separately analyze obese patients as a subgroup of the PREVAPIX-ALL trial. Aims: To assess the efficacy and safety of prophylactic apixaban vs. SOC for VTE prevention during induction chemotherapy in obese pediatric patients with ALL/LL. Methods: Obesity was defined as ≥ 95 th percentile for age and sex specific body mass index as per the Centers for Disease Control and Prevention childhood obesity definition. Patients newly diagnosed with ALL/LL, ages ≥ 1 to &amp;lt; 18 years, with a central venous line, and on induction chemotherapy with asparaginase were randomized to apixaban vs. SOC. Apixaban thromboprophylaxis was administered at a fixed dose per body weight until the end of induction when participants were screened for VTE. The primary efficacy outcome was a composite of symptomatic and asymptomatic VTE. The primary safety outcome was major bleeding, and the secondary safety outcome was a composite of major and clinically relevant non-major (CRNM) bleeding. Results: Out of 512 PREVAPIX-ALL participants, 498 (97.2%) were age 24 months or older with weight and height available. Of those, 82 were obese. Forty-two were randomized to apixaban and 40 were randomized to SOC (Table 1). For the primary efficacy outcome there was a statistically significant decrease in VTE events in the apixaban arm, 1/42 (2.4%) compared to the SOC arm 10/40 (25%) [RRR 91% (95% CI 3%, 99%) p 0.0067] (Table 2). No statistically significant difference was observed in bleeding between the two groups (Table 2). The mean apixaban exposure was similar among the obese and non-obese groups: obese apixaban mean exposure (SD) 23.4 days (5.55) and non-obese 23.5 days (6.44). No statistical difference was observed in the median steady-state area under the curve (AUC-TAU ng.h/mL) drug exposure between obese and non-obese categories stratified by age group on a linear scale: obese (n=38) 686.94 ng.h/mL (95% CI 397.8-1314.6) and non-obese (n=186) 663.50 ng.h/mL (95% CI 319.1-1090.9). Conclusion: Apixaban VTE prophylaxis in obese ALL/LL patients receiving asparaginase during induction chemotherapy resulted in a statistically significant 91% RRR in VTE compared to SOC. No statistical difference was observed in apixaban exposure days and AUC/TAU between obese and non-obese patients. Bleeding events were not increased in the apixaban arm as compared to SOC. Primary prophylaxis using apixaban safely reduces VTE in obese ALL/LL pediatric patients receiving induction chemotherapy containing asparaginase.

Discriminating Risk of Anticoagulant-Related Bleeding in Ambulatory Cancer Patients on Thromboprophylaxis

Introduction: Among patients taking anticoagulants, those with cancer have double the risk of major bleeding (MB). Because they also have a risk of VTE, two large randomized-control trials, AVERT and CASSINI, demonstrated effectiveness of low-dose direct oral anticoagulants (DOACs) for primary prevention of VTE in patients with cancer at high-risk for VTE based on a validated prediction model. Despite demonstrated efficacy, there is limited uptake of primary thromboprophylaxis in clinical practice. This apprehension may, in part, be due to concerns about the risk of bleeding. We aimed to determine the predictive performance of available risk prediction scores for anticoagulant-related bleeding in cancer patients randomized to thromboprophylaxis during participation in the AVERT randomized trial. Methods: Using patients in the modified intent-to-treat analysis in the AVERT randomized controlled trial, we conducted a post-hoc analysis to assess the performance of three available risk prediction scores for anticoagulant-related bleeding in 288 patients randomized to apixaban. We selected scores based on availability of candidate variables: RIETE, VTE Bleed, and Kuijer et al. scores. The primary outcome of interest was development of a MB or clinically relevant non-major bleed (CRNMB). A second analysis was conducted limiting the bleeding event to either a MB or a CRNMB that required a medical intervention. Each bleeding risk score was applied to the cohort with clinical point assignments as in the original papers (Table) . Using a Fine and Gray competing risk model, we tested the association between each score and development of first bleed following anticoagulant prescription. Patients were censored after a MB. The performance of each model was evaluated using time-dependent ROC (model discrimination) and Brier score (model calibration/discrimination). All analyses were conducted using R (4.2.3) and SAS (9.4) statistical software. Results: Between 2014 and 2018, 574 patients were randomized with 563 receiving at least one dose of study medication. A total of 288 patients received apixaban 2.5mg twice daily and 275 received placebo. The mean age was 61 years and mostly women (58.2%). Frequent cancers included: gynecologic (25.8%), lymphoma (25.3%), and pancreatic cancer (13.6%). The median duration of follow-up for the cohort was 183 days with adherence rates of 83.6% and 84.1% with apixaban and placebo respectively. There were 10 MBs and 18 CRNMBs when censoring patients at the time of first bleed. Of the 18 CRNMB events, 6 required a medical intervention. There was no significant association between each 1-point increase in the Kuijer et al. score and risk of MB+CRNMB (subdistribution hazard ratio (sHR) 0.97, p 0.85). However, for each 1-point increase in score in RIETE and VTE BLEED, there was a 72% (sHR 1.72, p &amp;lt;0.0001) and 26% (sHR 1.26, p 0.05) increase in risk of MB+CRNMB respectively. Discrimination of each score at 180 days was 0.69 for RIETE, 0.50 for Kuijer et al., and 0.61 for VTE BLEED. Results of calibration for each score was similar at 180 days was 0.056 for RIETE, 0.059 for Kuijer et al., and 0.058 for VTE BLEED. When limiting analyses to MB+CRNMB that required medical intervention, results remained consistent for the RIETE and Kuijer et al. scores, with a loss of association for the VTE BLEED score. Conclusions: Of the scores analyzed, the RIETE score performed best with moderate discrimination. There is a need to improve the performance of these scores. The ability to quantify risk of anticoagulant-related bleeding in patients who are candidates for primary thromboprophylaxis can allow providers and patients to make informed decisions about primary thromboprophylaxis based on the risk of VTE versus risk of anticoagulant-related bleeding.

Safety and Efficacy of Direct Oral Anticoagulants in Patients with Liver Cirrhosis: A Systematic Review and Meta-Analysis

Introduction Direct oral anticoagulants (DOACs) are widely used for treatment of venous thromboembolism (VTE) and stroke prophylaxis in patients with atrial fibrillation. Liver cirrhosis increases the risk of conditions necessitating anticoagulation, but also increases the risk of bleeding, complicating anticoagulation use. Traditionally, low molecular weight heparin (LMWH) or Vitamin K Antagonists (VKA) have been used in this patient population. However, VKA use can be complicated due to difficulty monitoring in the context of synthetic dysfunction and baseline INR abnormalities. DOACs have emerged as alternative agents, with less proposed reliance on hepatic elimination. Apixaban, rivaroxaban, edoxaban and dabigatran are eliminated by the liver at 75%, 65%, 50% and 20% respectively. However, safety data on DOACs in cirrhosis patients is limited due to historic exclusion from larger trials. Patients with severe Child-Pugh (CP) classes are notably underrepresented in major trials. Various guidelines currently classify CP class C (and sometimes B) as contraindications to DOACs. Methods A literature search of MEDLINE and Embase from inception to Jan 2023 identified randomized controlled trials (RCTs) and cohort studies comparing DOACs to LMWH/VKA in cirrhosis patients. Two independent reviewers screened and extracted data at title, abstract, and full-text. Patient characteristics, CP class, and anticoagulation regimens were extracted. The primary outcome was major bleeding per ISTH criteria. Secondary outcomes include clinically relevant non-major bleeding (CRNMB) and minor bleeding per ISTH criteria as a composite outcome, VTE incidence, and arterial thromboembolism (ATE) incidence. Results were stratified into two subgroups: CP B&amp;C Exclusive, and CP Unspecified (primary study did not report or stratify by CP class). A meta-analysis was conducted using the Mantel-Haenszel random-effects model and presented as odds ratios (OR) with corresponding 95% confidence intervals (CI). Results Of 794 articles screened, 21 articles (2 RCTs, 1 prospective cohort, 13 retrospective cohorts, 5 abstracts) were included for analysis (n = 5738). Overall, DOACs were associated with a lower risk of major bleeding compared to controls (OR=0.63 [0.45, 0.89], p&amp;lt;0.01). This result was consistent in the CP B&amp;C Exclusive subgroup (OR=0.42 [0.29, 0.62], p&amp;lt;0.01, 5 studies) but not in the CP Unspecified subgroup (OR=0.71 [0.48, 1.08], p=0.11, 13 studies). One large study (n=3213), Lawal 2023, weighed 20.1% in the CP B&amp;C Exclusive group, favoured DOACs in reduction of major bleeding (OR=0.37, 95%CI [0.24,0.57]). Removal of this study in a post-hoc sensitivity analysis led to no differences in major bleeding in the CP B&amp;C subgroup (OR=0.79, 95%CI [0.31,1.97]), CP Unspecified subgroup (OR=0.71, 95%CI [0.48,1.08]), or overall bleeding (OR=0.75, 95%CI [0.55,1.03]). For CRNMB and minor bleeding, DOACs did not differ from control overall or in any subgroups. DOACs significantly reduced the risk of VTE in the CP Unspecified subgroup and overall. The difference in VTE incidence was non-significant in the CP B&amp;C Exclusive subgroup, however the analysis only had two studies. The difference in ATE incidence in the overall sample and all subgroups was non-significant. Conclusion In this analysis comparing DOACs to LMWH/VKAs in patients with liver cirrhosis, DOACs were associated with a statistically significant reduction in the risk of major bleeding overall and in the more advanced subgroups (CP B&amp;C). The association between DOACs and the risk of CRNMB and minor bleeding was non-significant. Patients using DOACs had lower VTE incidence compared to those using LMWH/VKA, with no difference in ATE incidence. Limitations include the inability to stratify CP class B and C due to limited CP class C evidence, reducing confidence in our ability to differentiate a differing effect in these two groups. Furthermore, a single large study (Lawal 2023), heavily influenced the major bleeding outcome; its removal shifted the conclusion from favouring DOACs to non-significant differences. Nevertheless, these results provide reassurance on the safety profile of DOACs in comparison to LMWH/VKA in patients with cirrhosis, particularly in those with moderate to severe liver cirrhosis, a population of clinical uncertainty. There is no concerning evidence for future trials, which are much needed, to include this population.

Oral Anticoagulant Therapy in Patients with Philadelphia-Negative Myeloproliferative Neoplasms: A Real-Life Comparison between Vitamin K Antagonists and Direct Oral Anticoagulants

BACKGROUND Chronic myeloproliferative neoplasms (MPN) are characterized by an high risk of thrombosis and bleeding. Historically, vitamin K inhibitors (VKAs) have been the preferred oral anticoagulant therapy (OAT) for these patients (pts). However, nowadays, VKAs are being used less frequently, and direct oral anticoagulants (DOACs) are becoming more popular. Despite this trend, there is still limited evidence in the literature regarding the efficacy and safety of these drugs in the context of MPN. Specifically, there is a lack of data directly comparing VKAs and DOACs in a real-world clinical setting. AIMS The study aimed to conduct a real-world analysis comparing the efficacy and safety of DOACs and VKAs in patients with MPN. Both medications were prescribed for the treatment and secondary prevention of venous thromboembolism (VTE) or for the prevention of thrombosis in pts with atrial fibrillation (AF). The secondary endpoints were to assess the influence of common demographic, clinical, and hematological variables on the incidence of thrombotic events (TE) and bleeding events (BE) METHODS We conducted an observational retrospective monocentric study that enrolled all consecutive pts with MPN, followed at the MPN Clinic of the IRCCS Foundation S. Gerardo dei Tintori - Monza between 1993 and 2022, who received OAT with VKAs or DOACs for VTE or AF. For each pts, we collected demographic, clinical, biological, therapeutic, and hematological data. TE were categorized based on their type (arterial or venous) and location. BE were classified as minor, major, or clinically relevant non-major bleeding, according to the ISTH classification. Thrombosis-free survival (TFS) and bleeding-free survival (BFS) were assessed from the initiation of OAT until the occurrence of the first TE or BE, respectively, and estimated using Kaplan-Meier analysis. The other analyses were conducted using common statistical methods. Multivariable analyses included previously established risk factors for BE and TE. RESULTS A total of 156 pts were enrolled: 89 were women (57%). The median age was 69 years (range 25-92); 61 were affected by myelofibrosis, 35 by polycythemia vera, and 48 by essential thrombocythemia. 64 pts received OAT with VKAs (41%), and 92 with DOACs (59%). For 82 pts OAT was prescribed for AF (52.6%), and for 74 for VTE (47.4%). 17 pts treated with DOACs for VTE received a reduced-dose extended treatment (45.9%). The median exposure time to OAT was 5.8 years in the VKAs group (range 0.2-20 years) and 1.77 years in the DOACs group (range 0.2-10 years). After a median follow-up of 3,2 years, 14 TE were reported: 5 (35.7%) in the DOAC-treated group, of which 4 were arterial (80%), and 9 (64.3%) in the VKA-treated group (7 arterial - 77.8%). The incidence rate of TE was 2.11 thrombosis/pts/year in the VKAs group and 2.14 thrombosis/pts/year in the DOACs group. There were no significant differences in terms of TFS between the two groups, whether considering the entire population or analyzing the therapeutic indications separately (respectively p=0.72, p=0.53, p=0.55). Overall, there were 27 BE: 13 in the DOACs group (51.9%), 14 in the VKAs group (48.1%). Among these, we report 8 major BE, 4 in both groups. The incidence rate of BE was 5.6/pts/year in the DOACs group and 3.3/pts/year in the VKAs group. We did not observe significant differences in terms of BFS analyzing the whole population and the VTE group (respectively p=0.13 and p=0.75), while we found a trend for lower BFS in pts treated with DOACs for AF (p=0.08, Fig. 1). In a multivariate model, adjusted for time of exposition to OAT, age, gender and antiplatelet treatment, the risk of BE was associated solely with DOACs administration (hazard ratio 3.7, p=0.01) We found no significant differences in the risk of TE and BE when considering the various types of DOACs used. Moreover, 45 (28.8%) patients received concomitant antiplatelet therapy, and we found no significant differences in the risk of BE or TE compared to the other group (p=0.39 and p=0.41, respectively). CONCLUSIONS To our knowledge, this is the largest study investigating the safety and efficacy of DOACs compared to VKAs for the treatment and prevention of TE in pts with MPN and VTE or AF. Our findings suggest that DOACs are as effective as VKAs, but they appear to exhibit a trend towards a higher overall risk of BE, especially in the AF group. More data from prospective multicentric studies are necessary to validate our results.