Clinically Relevant Non-major Research Articles

Milvexian vs apixaban for stroke prevention in atrial fibrillation: The LIBREXIA atrial fibrillation trial rationale and design.

Direct oral anticoagulants are the standard of care for stroke prevention in eligible patients with atrial fibrillation and atrial flutter; however, bleeding remains a significant concern, limiting their use. Milvexian is an oral Factor XIa inhibitor that may offer similar anticoagulant efficacy with less bleeding risk. LIBREXIA AF (NCT05757869) is a global phase III, randomized, double-blind, parallel-group, event-driven trial to compare milvexian with apixaban in participants with atrial fibrillation or atrial flutter. Participants are randomly assigned to milvexian 100 mg or apixaban (5 mg or 2.5 mg per label indication) twice daily. The primary efficacy objective is to evaluate if milvexian is noninferior to apixaban for the prevention of stroke and systemic embolism. The principal safety objective is to evaluate if milvexian is superior to apixaban in reducing the endpoint of International Society of Thrombosis and Hemostasis (ISTH) major bleeding events and the composite endpoint of ISTH major and clinically relevant nonmajor (CRNM) bleeding events. In total, 15,500 participants from approximately 1,000 sites in over 30 countries are planned to be enrolled. They will be followed until both 430 primary efficacy outcome events and 530 principal safety events are observed, which is estimated to take approximately 4 years. The LIBREXIA AF study will determine the efficacy and safety of the oral Factor XIa inhibitor milvexian compared with apixaban in participants with either atrial fibrillation or atrial flutter. ClinicalTrials.gov NCT05757869.

Oral anticoagulant safety in family practice: prognostic accuracy of Bleeding Risk Scores (from the CACAO study).

To assess bleeding risk of patients treated by oral anticoagulants, several scores have been constructed to assist physicians in the evaluation of the benefit risk. Most of these scores lack a strong enough level of evidence for use in family practice. To assess the predictive prognostic accuracy of 13 scores designed to assess the risk of major or clinically relevant non-major (CRNM) bleeding events in a French ambulatory cohort receiving Vitamin-K antagonists (VKA) or direct oral anticoagulants (DOACs) in a family practice setting. CACAO (Comparison of Accidents and their Circumstances with Oral Anticoagulants) was a multicentre prospective cohort of ambulatory patients prescribed oral anticoagulants. We selected patients from the cohort who had received an oral anticoagulant because of non-valvular atrial fibrillation (NVAF) and/or venous thromboembolism (VTE) to be followed during one year by their GP. The following scores were calculated: mOBRI, Shireman, Kuijer, HEMORR2HAGES, ATRIA, HAS-BLED, RIETE, VTE-BLEED, ACCP score, Rutherford, ABH-Score, GARFIEL-AF, and Outcomes Registry for Better InformedTreatment of Atrial Fibrillation (ORBIT). Prognostic accuracy was assessed by using receiver operating characteristic curves and c-statistics. During 1 year, 3,082 patients were followed. All of the scores demonstrated only poor to moderate ability to predict major bleeding or CRNM in NVAF patients on DOACs (c-statistic: 0.41-0.66 and 0.45-0.58), respectively. The results were only slightly better for patients prescribed VKA (0.47-0.66 and 0.5-0.55, respectively) in this indication. The results were also unsatisfactory in patients treated for VTE. None of the scores demonstrated satisfactory discriminatory ability when used in family practice. ClinicalTrials.gov NCT02376777.

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.

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.

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 < 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.

Efficacy and Safety of Different Doses of Rivaroxaban and Risk Factors for Bleeding in Elderly Patients with Venous Thromboembolism: A Real-World, Multicenter, Observational, Cohort Study.

Venous thromboembolism (VTE) consists of deep vein thrombosis (DVT) and pulmonary embolism (PE). Rivaroxaban is a direct oral anticoagulant (DOAC) inhibiting activated coagulation factorX (FXa), and exerts several advantages in the treatment of VTE compared to conventional therapy. However, the efficacy and safety of rivaroxaban in elderly patients with VTE was still poorly understood. The study was carried out using an observational and non-interventional approach. A total of 576 patients aged ≥ 60years with newly diagnosed VTE were included in the study. All patients received rivaroxaban with recommended treatment duration of ≥ 3months for secondary prevention. In addition, 535 elderly patients with various diseases except VTE were included in the study in a retrospective and randomized way. The total bleeding rate was 12.2% (70/576). Major bleeding and non-major clinically relevant (NMCR) bleeding occurred in 4 (0.69%) patients and 5 (0.87%) patients, respectively. The rate of recurrent VTE was 5.4%. The mean level of D-dimers was increased by 467.2% in the elderly patients with VTE compared with the elderly patients without VTE. The elderly patients with VTE receiving rivaroxaban at a dose of 10mg once daily (n = 134) had lower risk for bleeding (3.7% vs 14.7%; P = 0.001) and a similar rate of recurrent VTE (4.5% vs 5.7%; P = 0.596) as compared to the elderly patients with VTE receiving rivaroxaban at higher doses including 15mg once daily and 20mg once daily (n = 442). In addition, age, concomitant aspirin, hemoglobin, activated partial thromboplastin time (APTT), and rivaroxaban doses were independent predictive factors for bleeding events. The study suggested that a dose of 10mg once daily should be the priority in elderly patients with VTE receiving long-term rivaroxaban anticoagulation therapy in view of reduced bleeding risk.

Apixaban versus no anticoagulation for the prevention of venous thromboembolism in children with newly diagnosed acute lymphoblastic leukaemia or lymphoma (PREVAPIX-ALL): a phase 3, open-label, randomised, controlled trial

Paediatric patients with acute lymphoblastic leukaemia or lymphoma are at increased risk of venous thromboembolism resulting in increased mortality and morbidity. We hypothesised that apixaban, a direct oral anticoagulant, would safely reduce venous thromboembolism in this patient population. PREVAPIX-ALL was a phase 3, open-label, randomised, controlled trial conducted in 74 paediatric hospitals in 9 countries. Participants aged 1 year or older to younger than 18 years with newly diagnosed acute lymphoblastic leukaemia (pre-B cell or T cell) or lymphoblastic lymphoma (B cell or T cell immunophenotype) and a central venous line in place throughout induction were randomly assigned 1:1 to standard of care (SOC, ie, no systemic anticoagulation) or weight-adjusted twice-daily apixaban during induction. Randomisation was performed centrally and stratified by age (those <10 years or those ≥10 years). Participants weighing 35 kg or less were administered 2·5 mg twice daily of apixaban as a 2·5 mg tablet, 0·5 mg tablets, or 0·4 mg/mL oral solution, while those weighing more than 35 kg were administered weight-adjusted prophylactic doses using 0·5 mg tablets or the 0·4 mg/mL oral solution twice daily. Primary outcomes were assessed by a blinded central adjudication committee. The primary efficacy outcome for the intention to treat population was the composite of symptomatic or clinically unsuspected venous thromboembolism, the primary safety outcome was major bleeding, and secondary safety outcomes included clinically relevant non-major (CRNM) bleeding. Patients were screened for venous thromboembolism by ultrasound and echocardiogram at the end of induction. The trial was registered with ClinicalTrials.gov (NCT02369653) and is now complete. Between Oct 22, 2015, and June 4, 2021, 512 participants were randomly assigned and included in analyses (222 [43%] female and 290 [57%] male; 388 [76%] White, 52 [10%] Asian, 24 [5%] Black or African American, and 48 [9%] other races; and 122 [24%] Hispanic or Latino ethnicity). During a median follow-up period of 27 days (IQR 26-28), 31 (12%) of 256 patients on apixaban had a composite venous thromboembolism compared with 45 (18%) of 256 participants receiving SOC (relative risk [RR] 0·69, 95% CI 0·45-1·05; p=0·080). Two major bleeding events occurred in each group (RR 1·0, 95% CI 0·14-7·01; p=1·0). A higher incidence of CRNM bleeding, primarily grade 1 or 2 epistaxis, occurred in the apixaban group (11 [4%] of 256 participants) compared with the SOC group (3 [1%] of 256; RR 3·67, 95% CI 1·04-12·97, p=0·030). The most frequent grade 3-5 adverse events in both groups were thrombocytopenia (n=28 for the apixaban group and n=20 for the SOC group) or platelet count decreased (n=49 and n=45), anaemia (n=77 and n=74), febrile neutropenia (n=27 and n=20), and neutropenia (n=16 and n=17) or neutrophil count decreased (n=22 and n=25). Five deaths occurred, which were due to infection (n=3 in the SOC group), cardiac arrest (n=1 in apixaban group), and haemorrhagic cerebral sinus vein thrombosis (n=1 in the SOC group). There was one apixaban-related death (coagulopathy and haemorrhage after cardiac arrest of unknown cause). PREVAPIX-ALL is, to our knowledge, the first trial assessing primary thromboprophylaxis using a direct oral anticoagulant in paediatric patients with acute lymphoblastic leukaemia or lymphoma. No statistically significant treatment benefit was identified in participants receiving apixaban. Major and CRNM bleeding were infrequent overall, but a higher incidence of CRNM bleeding (primarily epistaxis in younger children) occurred in participants receiving apixaban. For patients deemed to be at particularly high risk of thrombosis, PREVAPIX-ALL provides encouraging safety data for the use of apixaban in clinical settings in which the potential benefits are thought to outweigh the risk of bleeding. Bristol Myers Squibb-Pfizer Alliance.

Efficiency and safety of dual pathway inhibition for the prevention of femoropopliteal artery restenosis in repeated endovascular interventions

ObjectiveThere is a lack of consensus regarding the optimal strategy for evaluating the efficiency and safety of dual-pathway inhibition (DPI) in preventing femoropopliteal restenosis in patients undergoing repeated endovascular interventions. Despite several therapeutic interventions available for preventing femoropopliteal restenosis post repeated endovascular interventions, the ideal strategy, particularly evaluating the efficacy and safety of DPI, remains a matter of debate. MethodsFrom January 2015 to September 2021, patients who underwent repeated endovascular interventions for femoropopliteal restenosis were compared with those who underwent DPI or dual antiplatelet therapy (DAPT) after surgery using a propensity score-matched analysis. The primary outcome was clinically driven target lesion revascularization (CD-TLR). The principal safety outcome was a composite of major bleeding and clinically relevant non-major (CRNM) bleeding. To further enhance the rigor, Kaplan-Meier plots, Cox proportional hazards modeling, and sensitivity analyses, as well as subgroup analyses were employed, reducing potential confounders. ResultsA total of 441 patients were included in our study, of whom 294 (66.7%) received DAPT and 147 (33.1%) received DPI, with 114 matched pairs (mean age, 72.21 years; 84.2% male). Cumulative probability of CD-TLR at 36 months in the DPI group (17%) trended lower than that in the DAPT group (32%) (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.26-0.78; P =.004). The cumulative probability of freedom from CD-TLR at 36 months in the DPI group was 83%. No significant difference was observed in the composite outcome of major or CRNM bleeding between the DPI and DAPT groups (HR, 1.26; 95% CI, 0.34 to 4.69; P = .730). The DPI group was associated with significantly lower rates of CD-TLR in the main subgroup analyses of diabetes (P = .001), previous smoking history (P = .008), longer lesion length (>10 cm) (P = .003), and treatment with debulking strategy (P = .003). ConclusionsIn our investigation focused on CD-TLR, we found that DPI exhibited a significant reduction in the risk of reintervention compared with other treatment modalities. This underscores the potential of DPI as a viable therapeutic strategy in preventing reinterventions. Moreover, our assessment of safety outcomes revealed that the bleeding risks associated with DPI were on par with DAPT, thereby not compromising patient safety. These findings pave the way for potential broader clinical implications, emphasizing the effectiveness and safety of DPI in the context of reducing reintervention risks.

Abstract 15688: Association of Cytochrome P450 2C19 Polymorphism With Ischemic and Bleeding Risk in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention

Introduction: CYP2C19 isoenzymes of cytochrome P450 impact the effect of clopidogrel. Guidelines recommend clopidogrel in addition to oral anticoagulation (OAC) in patients with atrial fibrillation (AF) after percutaneous coronary intervention (PCI). This study aimed to evaluate the association of CYP2C19 polymorphism with ischemic and bleeding risk in patients with AF undergoing PCI. Methods: Patients with AF and an indication for OAC were included in this two-center prospective cohort study up to 3 days after PCI. Carriers of ≥1 loss of function (LOF) allele CYP2C19*2 were classified as poor metabolisers (PM). Carriers of ≥1 gain of function allele (GOF) were defined as rapid metabolisers (RM). Normal metabolisers (NM) were defined as absence of LOF and GOF alleles. Primary outcome was defined as death, myocardial infarction, or stroke (MACE) at 6 months ±2 weeks. Secondary outcome was defined as non-major clinically relevant (NMCR) or major bleedings. Results: 283 patients were included in the study. Median age was 78 (interquartile range, IQR 72-82) years old and 204 (72%) were males. All patients received treatment with clopidogrel and OAC. 73 (26%) were PM, 108 (38%) were NM and 102 (36%) RM. The primary ischemic outcome occurred in 22 (8%) and the secondary outcome in 38 (13%) patients. PM status did not significantly associate with primary ischemic outcome (PM: 6 [8.2%] vs. NM+RM: 16 [7.6%]; odds ratio, OR 1.09 [95% confidence interval 0.41-2.89], p=0.805). RM status did not significantly associate with bleeding (RM: 14 [13.7%] vs. PM+NM: 24 [13.3%]; OR 1.04 [0.51-2.12], p=1.00). Bleeding rates tended to be lower for patients with PM status (major, NMCR, or minor bleeding: PM 12 [28.7%] vs. NM+RM 84 [40.0%]; 0.61 [0.34-1.07], p=0.09). Conclusions: This pilot study of patients with oral anticoagulation for atrial fibrillation and clopidogrel after PCI ruled out, with 95% confidence, a ≥3-fold increase of ischemic risk for carriers of ≥1 loss of function allele CYP2C19*2 compared with non-carriers. This study was underpowered to detect less pronounced associations. LOF-carrier status might protect from bleeding.

A prognostic score to identify women at increased risk for abnormal uterine bleeding during anticoagulation for venous thromboembolism

IntroductionLittle is known about the clinical characteristics of women at increased risk for abnormal uterine bleeding (UB) during anticoagulation for venous thromboembolism (VTE). MethodsWe used the RIETE registry to identify the baseline characteristics of women developing abnormal UB during anticoagulation. We used logistic regression analysis to identify independent predictors for abnormal UB. Then, we built a prognostic score to identify at-risk women. ResultsFrom March 2001 through October 2022, there were 54,372 women with VTE. During anticoagulation (median, 181 days), 318 (0.6%) developed abnormal UB (major bleeding = 88, clinically relevant non-major (CRNM) = 230). On multivariable analysis, women aged <50 years, weighing >70 kg, with uterine cancer, recent UB, anemia, estrogen-related VTE, or receiving rivaroxaban or apixaban were at increased risk for abnormal UB. Using the prognostic score, 42,273 women (78%) were at low-risk, 8,828 (16%) intermediate-, and 3,271 (6.1%) at high-risk for abnormal UB. Their rates of abnormal UB were: 0.28 (95%CI: 0.23–0.35), 1.32 (95%CI: 1.07–1.61) and 7.12 (95%CI: 5.98–8.41) bleeds per 100 patient-years, respectively. The c-statistic was 0.80 (95%CI: 0.77–0.83). The rates of major UB were: 0.06 (95%CI: 0.04–0.09), 0.43 (95%CI: 0.30–0.60) and 1.85 (95%CI: 1.31–2.53) per 100 patient-years, respectively (c-statistic: 0.84; 95%CI: 0.80–0.89). The rates of CRNM uterine bleeding were: 0.21 (95%CI: 0.17–0.26), 0.85 (95%CI: 0.65–1.08), and 5.02 (95%CI: 4.09–6.10) bleeds per 100 patient-years, respectively (c-statistic: 0.78; 95%CI: 0.75–0.82). ConclusionsUsing 7 variables easily available at admission, we built a prognostic score that reliably identified women with VTE at increased risk for abnormal UB during anticoagulation.

Comparative Bleeding Risk in Patients with Atrial Fibrillation with Cancer versus Without Cancer from Nationwide Prospective Cohort.

Comparison of the bleeding risk for long-term oral anticoagulation (OAC) in patients with nonvalvular atrial fibrillation (AF) with and without cancers has been inconsistent. This study aimed to clarify the differences in the bleeding risk in patients with AF with cancers and those without cancers during the long-term OAC.The CODE-AF prospective registry enrolled 5,902 consecutive patients treated for AF at 10 tertiary referral centers in Korea. Of the enrolled patients, 464 (7.8%) were diagnosed with cancers and were followed for all stroke and bleeding events (net composite events).The age, CHA2DS2-VASC, and HAS-BLED scores were similar between AF patients with and without cancers. Male population greatly comprised patients with AF with cancers. They were equally prescribed with direct OAC compared to those without cancers. The incidence rate for clinically relevant nonmajor (CRNM) bleeding events was higher in the patients with AF with cancers than in those without cancers (4.4 per 100 person-years versus 2.8 per 100 person-years, P = 0.023), and net composite events were also more frequent in patients with AF with cancers than in those without cancers (6.4 per 100 person-years versus 4.0 per 100 person-years, P = 0.004). Patients with AF with cancers showed a significantly higher rate of CRNM bleeding (hazard ratio [HR] 1.54, confidence interval [CI] 1.05-2.25, P = 0.002) than those without cancers.Based on the AF cohort, AF with cancers could face a significantly higher risk for CRNM bleeding events in the long-term OAC than those without cancers.

The clinical outcomes of different doses of rivaroxaban in patients with isolated distal deep vein thrombosis

ObjectiveIsolated distal deep vein thrombosis (IDDVT) is defined as thrombosis involving the infrapopliteal veins. The optimal anticoagulant therapy of IDDVT remains controversial. This study aimed to assess whether reduced dose of rivaroxaban was suitable in patients with IDDVT. MethodsConsecutive patients with acute IDDVT were identified by reviewing the venous thromboembolism (VTE) registry databases. Outcomes including VTE recurrence, major bleeding, clinically relevant non-major (CRNM) bleeding, and death. Patients were followed until the first occurrence of any outcomes or the study end date (December 31, 2018). Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed. ResultsA total of 1246 patients were divided into low-dose (10 or 15 mg/day; n = 716) and standard-dose (20 mg/day; n = 530) groups. The incidences of VTE recurrence, major bleeding, CRNM bleeding, and death between the two groups were 9.64% vs 5.66%, 1.68% vs 3.02%, 4.61% vs 8.68%, and 13.83% vs 10.75%, respectively. After the inverse probability of treatment weighting, HRs for standard-dose vs low-dose of VTE recurrence, major bleeding, CRNM bleeding, and death were 0.54 (95% CI, 0.35-0.84), 1.71 (95% CI, 0.80-3.67), 2.28 (95% CI, 1.40-3.74), and 1.30 (95% CI, 0.91-1.86), respectively. For the subgroup analysis, the interaction with anticoagulation duration and treatment was evident for VTE recurrence (P for interaction = .002), but not for major bleeding. Patients with residual vein thrombosis were associated with an increased risk of VTE recurrence (HR, 1.95; 95% CI, 1.29-2.95). The interaction between risk factors and residual vein thrombosis was evident for VTE recurrence (P for interaction = .085). ConclusionsStandard-dose rivaroxaban reduced the risk of VTE recurrence without increasing the risk of major bleeding in patients with IDDVT. Anticoagulant therapy for >1.5 months should be preferred over shorter durations. Residual vein thrombosis should be assessed as a predictor of recurrence in patients with IDDVT, especially for patients with non-transient factors.

Patrones y resultados del cambio de anticoagulantes orales directos en la fibrilación auricular no valvular: experiencia en la práctica clínica en España

AimsThe aim is to evaluate a management program for direct oral anticoagulants (DOACs) in non-valvular atrial fibrillation (NVAF) patients according to their profiles, appropriateness of dosing, patterns of crossover, effectiveness and safety.This is an observational and longitudinal prospective study in a cohort of patients attended in daily clinical practice in a regional hospital in Spain with 3-year a follow-up plan for patients initiating dabigatran, rivaroxaban or apixaban between Jan/2012 and Dec/2016. MethodsWe analyzed 490 episodes of treatment (apixaban 2.5, 9.4%; apixaban 5, 21.4%; dabigatran 75, 0.6%; dabigatran 110, 12.4%; dabigatran 150, 19.8%; rivaroxaban 15, 17.8% and rivaroxaban 20, 18.6%) in 445 patients. 13.6% of patients on dabigatran, 9.7% on rivaroxaban, and 3.9% on apixaban switched to other DOACs or changed dosing. ResultsApixaban was the most frequent DOAC switched to. The most frequent reasons for switching were toxicity (23.8%), bleeding (21.4%) and renal deterioration (16.7%). Inappropriateness of dose was found in 23.8% of episodes. Rates of stroke/transient ischemic attack (TIA) were 1.64/0.54 events/100 patients-years, while rates of major, clinically relevant non-major (CRNM) bleeding and intracranial bleeding were 2.4, 5, and 0.5 events/100 patients-years. Gastrointestinal and genitourinary bleeding were the most common type of bleeding events (BE). On multivariable analysis, prior stroke and age were independent predictors of stroke/TIA. Concurrent platelet inhibitors, male gender and age were independent predictors of BE. ConclusionThis study complements the scant data available on the use of DOACs in NVAF patients in Spain, confirming a good safety and effectiveness profile.

PO-05-165 COMPARATIVE BLEEDING RISK IN PATIENTS WITH ATRIAL FIBRILLATION WITH CANCER VERSUS WITHOUT CANCER FROM NATIONWIDE PROSPECTIVE COHORT: CODE-AF REGISTRY

Comparison of the bleeding risk for long-term oral anti-coagulation (OAC) in non-valvular atrial fibrillation (AF) patients with cancers and those without cancers has been yet inconsistent The purpose of this study was to clarify the differences in the bleeding risk in AF patients with cancers and those without cancers during the long-term OAC. The CODE-AF prospective registry enrolled 5,902 consecutive patients who were treated for AF at 10 tertiary referral centers in Korea. Of the enrolled patients, 464 (7.8%) patients were diagnosed with cancers and clinically followed for all stroke and bleeding (net composite events). The CODE-AF prospective registry enrolled 5,902 consecutive patients who were treated for AF at 10 tertiary referral centers in Korea. Of the enrolled patients, 464 (7.8%) patients were diagnosed with cancers and clinically followed for all stroke and bleeding (net composite events). The age, CHA2DS2-VASC and HAS-BLED scores were similar between AF patients with cancers and those without cancers. AF patients with cancers had a greater proportion of male, and were equally prescribed non-vitamin K OAC compared to those without cancers. Incidence rate for clinically relevant non-major (CRNM) bleeding events were observed to be higher in the AF patients with cancers than those without cancers (4.4 per 100 person-years vs. 2.8 per 100 person-years, P=0.023), and net composite events were also more frequently observed in the AF patients with cancers than those without cancers (6.4 per 100 person-years vs. 4.0 per 100 person-years, P=0.004). AF patients with cancers showed a significantly higher rate of CRNM bleeding (hazard ratio [HR] 1.54, confidence interval [CI] 1.05 – 2.25, P=0.002) compared with those without cancers. Based on AF prospecitve multicenter cohort, AF with cancers could face a significantly higher risk for CRNM bleeding events in the long-term OAC compared with those without cancers.

Patterns and outcomes of switching direct oral anticoagulants in non-valvular atrial fibrillation: A real-world experience from Spain

AimsThe aim is to evaluate a management program for direct oral anticoagulants (DOACs) in non-valvular atrial fibrillation (NVAF) patients according to their profiles, appropriateness of dosing, patterns of crossover, effectiveness and safety. This is an observational and longitudinal prospective study in a cohort of patients attended in daily clinical practice in a regional hospital in Spain with 3-year a follow-up plan for patients initiating dabigatran, rivaroxaban or apixaban between JAN/2012-DEC/2016. MethodsWe analyzed 490 episodes of treatment (apixaban 2.5 9.4%, apixaban 5 21.4%, dabigatran 75 0.6%, dabigatran 110 12,4%, dabigatran 150 19.8%, rivaroxaban 15 17.8% and rivaroxaban 20 18.6%) in 445 patients. 13.6% of patients on dabigatran, 9.7% on rivaroxaban, and 3.9% on apixaban switched to other DOACs or changed dosing. ResultsApixaban was the most frequent DOAC switched to. The most frequent reasons for switching were toxicity (23.8%), bleeding (21.4%) and renal deterioration (16.7%). Inappropriateness of dose was found in 23.8% of episodes. Rates of stroke/transient ischemic attack (TIA) were 1.64/0.54 events/100 patients-years, while rates of major, clinically relevant non-major (CRNM) bleeding and intracranial bleeding were 2.4, 5, and 0.5 events/100 patients-years. Gastrointestinal and genitourinary bleeding were the most common type of bleeding events (BE). On multivariable analysis, prior stroke and age were independent predictors of stroke/TIA. Concurrent platelet inhibitors, male gender and age were independent predictors of BE. ConclusionThis study complements the scant data available on the use of DOACs in NVAF patients in Spain, confirming a good safety and effectiveness profile.

External validation and updating of prediction models of bleeding risk in patients with cancer receiving anticoagulants

ObjectivePatients with cancer are at increased bleeding risk, and anticoagulants increase this risk even more. Yet, validated bleeding risk models for prediction of bleeding risk in patients with cancer are...

278 Eight Pharmacokinetic-related Genetic Variants Were Not Associated with Bleeding from Direct Oral Anticoagulants in Non-valvular Atrial Fibrillation Patients

OBJECTIVES/GOALS: Assess the association of PK-related single nucleotide variants (SNVs) with the risk of bleeding from DOACs in non-valvular AF patients. METHODS/STUDY POPULATION: A retrospective cohort study was carried out with 2,364 Caucasians with non-valvular AF and treated with rivaroxaban or apixaban. Patients were genotyped as part of the genomic biobank at the University of Michigan Health System. The primary endpoint was a composite of major and clinically relevant non-major (CRNM) bleeding. Cox proportional hazards regression with time-varying analysis assessed the association of 8 SNVs in 5 PK genes (ABCB1, ABCG2, CYP3A4, CYP3A5, CYP2J2) with the risk of bleeding from DOACs in unadjusted and covariate-adjusted models. Six tests were performed as 3 of the SNVs are in the same haplotype. P-values below the Bonferroni-corrected level of 8.33e-3 were considered statistically significant. RESULTS/ANTICIPATED RESULTS: A total of 412 (17.4%) major and CRNM bleeding events occurred over 2.27 ± 2.03 years of follow-up. None of the PK SNVs were significantly associated with bleeding risk on DOACs in both unadjusted and covariate-adjusted Cox regression models. DISCUSSION/SIGNIFICANCE: The effects of these eight genetic variants on exposure to DOACs may not be strong enough to translate into differences in clinical outcomes. Especially if the genetic inheritance underlying the risk of bleeding from DOACs is polygenic, reinforcing the need for further genomic studies on this subject.

Effectiveness and Safety of Apixaban vs Warfarin in Patients with Venous Thromboembolism with Risk Factors for Bleeding or for Recurrences.

Patients at increased risk of bleeding and recurrent VTE who develop venous thromboembolism (VTE) present challenges for clinical management. This study evaluated the effectiveness and safety of apixaban vs warfarin in patients with VTE who have risk factors for bleeding or recurrences. Adult patients with VTE initiating apixaban or warfarin were identified from five claims databases. Stabilized inverse probability treatment weighting (IPTW) was used to balance characteristics between cohorts for the main analysis. Subgroup interaction analyses were conducted to evaluate treatment effects among patients with and without each of the conditions that increased the risk of bleeding (thrombocytopenia and history of bleed) or recurrent VTE (thrombophilia, chronic liver disease, and immune-mediated disorders). A total of 94,333 warfarin and 60,786 apixaban patients with VTE met selection criteria. After IPTW, all patient characteristics were balanced between cohorts. Apixaban (vs warfarin) patients were at lower risk of recurrent VTE (HR [95% confidence interval (CI) 0.72 [0.67-0.78]), major bleeding (MB) (HR [95%CI] 0.70 [0.64-0.76]), and clinically relevant non-major(CRNM) bleeding (HR [95%CI] 0.83 [0.80-0.86]). Subgroup analyses showed generally consistent findings with the overall analysis. For most subgroup analyses, there were no significant interactions between treatment and subgroup strata on VTE, MB and CRNMbleeding. Patients with prescription fills for apixaban had lower risk of recurrent VTE, MB, and CRNM bleeding compared with warfarin patients. Treatment effects of apixaban vs warfarin were generally consistent across subgroups of patients at increased risk of bleeding/recurrences.

Oral Anticoagulation Therapy in Atrial Fibrillation Patients with Advanced Chronic Kidney Disease: CODE-AF Registry.

Advanced chronic kidney disease (CKD), including end-stage renal disease (ESRD) on dialysis, increases thromboembolic risk among patients with atrial fibrillation (AF). This study examined the comparative safety and efficacy of direct-acting oral anticoagulant (DOAC) compared to warfarin or no oral anticoagulant (OAC) in AF patients with advanced CKD or ESRD on dialysis. Using data from the COmparison study of Drugs for symptom control and complication prEvention of AF (CODE-AF) registry, 260 non-valvular AF patients with advanced CKD (defined as estimated glomerular filtration rate <30 mL/min per 1.73/m²) or ESRD on dialysis were enrolled from June 2016 to July 2020. The study population was categorized into DOAC, warfarin, and no OAC groups; and differences in major or clinically relevant non-major (CRNM) bleeding, stroke/systemic embolism (SE), myocardial infarction/critical limb ischemia (CLI), and death were assessed. During a median 24 months of follow-up, major or CRNM bleeding risk was significantly reduced in the DOAC group compared to the warfarin group [hazard ratio (HR) 0.11, 95% confidence interval (CI) 0.01 to 0.93, p=0.043]. In addition, the risk of composite adverse clinical outcomes (major or CRNM bleeding, stroke/SE, myocardial infarction/CLI, and death) was significantly reduced in the DOAC group compared to the no OAC group (HR 0.16, 95% CI 0.03 to 0.91, p=0.039). Among AF patients with advanced CKD or ESRD on dialysis, DOAC was associated with a lower risk of major or CRNM bleeding compared to warfarin and a lower risk of composite adverse clinical outcomes compared to no OAC. ClinicalTrials.gov (NCT02786095).

Early Time Courses of Recurrent Thromboembolism and Bleeding during Apixaban or Dalteparin Therapy for Patients with Cancer

Introduction The CARAVAGGIO trial was a multinational, randomised, investigator initiated, open-label with blind outcome assessment, noninferiority trial which demonstrated noninferiority of apixaban to dalteparin for treatment of cancer related venous thromboembolism (VTE) without an increased risk of major bleeding. In patients with acute VTE, the rates of recurrence and major bleeding are highest during the first weeks of anticoagulation (1). We sought to evaluate the efficacy and safety of apixaban during the initial high-risk phase of treatment in patients with cancer associated VTE. Specifically, we performed a pre-specified sub-analysis of the time courses of recurrence and bleeding, with the aim to determine the incidence after 7, 30 and 90 days of treatment with apixaban compared with dalteparin. Methods The study design and methods of the CARAVAGGIO trial (CARAVAGGIO; NCT03045406; https://clinicaltrials.gov/ct2/show/NCT03045406) have been described (2). Briefly, CARAVAGGIO compared the efficacy and safety of apixaban with dalteparin in consenting patients who had active cancer and a newly diagnosed symptomatic or incidental proximal lower-limb deep-vein thrombosis (DVT) or pulmonary embolism (PE). Eligible patients were randomly assigned to receive monotherapy with either apixaban or dalteparin for 6 months. The primary efficacy outcome was the incidence of objectively confirmed VTE. The primary safety outcome was major and clinically relevant non-major (CRNM) bleeding. Results The CARAVAGGIO study enrolled 1170 patients from 119 centres in eleven countries from April 2017 through June 2019); 1155 patients were included in the modified intention-to-treat analysis. The demographic and clinical characteristics of the patients were similar in the two treatment groups. Of the 78 recurrent VTE events 11 (14.1%) occurred in the first 7 days, 35 (44.8%) in the first 30 days and 63 (80.7%) in the first 90 days. Recurrent events occurred in 6 (1.0%) in the apixaban group and 5 (0.9%) in the dalteparin group (RR 1.21; 95% CI 0.37-3.93) by day 7, 15 (2.6%) in the apixaban group and 20 (3.5%) in the dalteparin group (RR 0.75; 95% CI 0.39-1.46) by day 30, and in 27 (4.7%) in the apixaban group and 36 (6.2%) in the dalteparin group (RR 0.75; 95% CI 0.46-1.23) by day 90. By 6 months, recurrent events occurred in 32 (5.6%) in the apixaban group and 46 (7.9%) in the dalteparin group (RR 0.70; 95% CI 0.45-1.08). (Table 1). During the six months of treatment, major and CRNM bleeding occurred in 70 patients who received apixaban (12.2%) and in 56 patients who received dalteparin (9.7%) (RR 1.26; 95% CI 0.90-1.75). Of the total 126 bleeding events, 24 (19.0%) occurred during the first 7 days; 58 (46.0%) during the first 30 days, and 89 (70.6%) during the first 90 days. Bleeding events occurred in 14 (2.4%) in the apixaban group and 10 (1.7%) in the dalteparin group (RR 1.40; 95% CI 0.63-3.14) by day 7, 30 (5.2%) in the apixaban group and 28 (4.8%) in the dalteparin group (RR 1.08; 95% CI 0.65-1.78) by day 30, and in 46 (8.0%) in the apixaban group and 43 (7.4%) in the dalteparin group (RR 1.07; 95% CI 0.72-1.60) by day 90. The Kaplan-Meier plot of time to recurrent VTE and major and CRNM bleeding is shown in figure 1. Conclusion The results of this sub-analysis of the CARAVAGGIO trial demonstrate no difference of oral apixaban to subcutaneous dalteparin at all time points. Specifically, there was no increase in recurrent VTE or bleeding events at 7 days, 30 days, 90 days and 6 months. This supports early initiation of oral anticoagulation. Oral versus subcutaneous anticoagulation has the advantage of ease of administration and outpatient delivery which may improve patients’ quality of life - an important consideration in patients with cancer. Reference 1. Raskob GE, Gallus AS, Sanders P, Thompson JR, Agnelli G, Buller HR, et al. Early time courses of recurrent thromboembolism and bleeding during apixaban or enoxaparin/warfarin therapy. A sub-analysis of the AMPLIFY trial. Thrombosis and haemostasis. 2016;115(4):809-16. 2. Agnelli G, Becattini C, Meyer G, Muñoz A, Huisman MV, Connors JM, et al. Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. New England Journal of Medicine. 2020;382(17):1599-607. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal