Low-dose Direct Oral Anticoagulants Research Articles

The Efficacy and Safety of DOACs in Inherited Antithrombin Deficiency: A Cohort Study from a Tertiary Referral Center.

Individuals with inherited antithrombin deficiency (IATD) have a high risk of venous thromboembolism (VTE). Most VTEs are managed with direct oral anticoagulants (DOACs), but the utility of DOACs in antithrombin deficiency (ATD) is unreported. Patients with IATD treated with DOAC were identified from our institutions' IATD registry. We assessed patients' characteristics, ATD type, and initial VTE characteristics, thrombosis recurrence and bleeding rates. Thirty-three patients received DOACs for 73 (38.5-111.5) months (median (interquartile range)). Prior to taking DOACs, 12 (36%) patients had VTE recurrence: these occurred after anticoagulation was ceased (4), nonadherence to VKA prior to DOAC use (3), or during heparin use in pregnancy (5). There were no VTE recurrences on standard-dose DOAC, except in a noncompliant patient receiving dabigatran. There was one recurrence with compliant DOAC use-a patient receiving rivaroxaban 10 mg. Six (18%) patients experienced clinically relevant bleeding, which was predominantly menorrhagia (5/6). One major bleeding event, intracranial hemorrhage, occurred in a patient receiving full-dose rivaroxaban who had refractory hypertension (0.5 events/100 patient-years). In this cohort, compliant DOAC users had an overall VTE recurrence rate of 0.5/100 patient-years, whereas with low-dose DOACs the event rate was 3.5/100 patient-years. Standard-dose DOACs appear efficacious and relatively safe in IATD.

Direct Oral Anticoagulants in Older and Frail Patients with Atrial Fibrillation: A Decade of Experience.

Both the prevalence of atrial fibrillation (AF) and its subsequent use of direct oral anticoagulants (DOACs) are rapidly increasing in patients of older age. In the absence of contra-indications, guidelines advocate anticoagulation based on the CHA2DS2-VASc score for all AF patients aged 75 and above. However, some practitioners are hesitant to prescribe anticoagulants to older and frail patients due to perceived elevated bleeding risks. This review delves into the comparative treatment outcomes of DOACs versus vitamin K antagonists (VKAs) in older patients with AF, particularly focusing on those of advanced age, frailty, increased risk of falling, chronic kidney disease (CKD), or with a history of major bleeding. Additionally, considerations on the use of off-label DOAC doses, the role of left atrial appendage (LAA) closure and future developments in factor XIa-inhibitors will be discussed. While strong evidence supports the use of DOACs in the vital older patients with nonvalvular AF, it remains scant in frail patient groups. There is some evidence from non-randomized studies suggesting that the effect of DOACs compared with VKAs is consistent between frail and nonfrail patients. However, recent findings from a single randomized trial showed increased bleeding risks but comparable thromboembolic outcomes in frail individuals switching from VKAs to DOACs. In patients with an increased risk of falling, data suggest no relevant interaction of increased risk of falling on the effectiveness and safety of DOACs compared with warfarin. Resuming oral anticoagulants in patients with Af after major bleeding seems to be beneficial. Off-label low-dose DOAC is often prescribed to patients who were underrepresented in larger randomized trails because of an elevated risk of bleeding or overexposure to DOACs, but its effect on clinical outcomes remains uncertain. DOACs are the recommended oral anticoagulant for vital older patients with AF. The scarcity of data backing DOAC use in frail individuals, those with renal impairments, or significant bleeding history underscores the necessity for further investigation. However, existing evidence suggests at least similar effectiveness and safety and potential benefits for DOACs in these patient subsets. Therefore, there is no reason to suggest these patients should be treated differently than the established guidelines regarding anticoagulation.

More early bleeds associated with high baseline direct oral anticoagulant levels in atrial fibrillation: the MAS study

AbstractTreatment with direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) is effective and safe. However, bleeding complications still occur. Whether DOAC level measurement may further improve treatment efficacy and safety is still an open issue. In the "Measure and See" study, venous blood was collected 15-30 days after DOAC initiation in patients with AF who were then followed up for 1 year to record the occurrence of major and clinically relevant nonmajor bleeding. DOAC plasma levels were measured in 1 laboratory, and results were kept blind to patients and treating doctors. Trough DOAC levels were assessed in 1657 patients (957 [57.7%] and 700 patients treated with standard and low-dose, respectively). Fifty bleeding events were recorded during 1606 years of follow-up (3.11% pt/yrs). Fifteen bleeding events (4.97% pt/yrs) occurred in patients with C-trough standardized values in the highest activity class (>0.50), whereas 35 events (2.69% pt/yrs) occurred in those with values in the 2 lower classes (≤0.50, P = .0401). Increasing DOAC levels and low-dose DOAC use were associated with increased bleeding risk in the first 3 months of treatment. Overall, 19% of patients receiving low doses had standardized values in the highest class. More bleeding occurred in patients on low (4.3% pt/yrs) vs standard (2.2% pt/yrs; P = .0160) dose DOAC. Early measurement of DOAC levels in patients with AF identified many individuals with high levels despite the low doses use and had more bleeding risk during the first 3 months of treatment. This trial was registered at www.ClinicalTrials.gov as #NCT03803579.

Apixaban versus warfarin for primary thromboprophylaxis in patients with multiple myeloma undergoing immunomodulatory treatment.

7548 Background: Immunomodulatory drugs (IMiDs) have been demonstrated to improve clinical outcomes in patients with multiple myeloma (MM), but are associated with an elevated risk of thromboembolism. Existing guidelines recommend low-dose direct oral anticoagulants as an alternative to warfarin for primary thromboprophylaxis in MM. However, the data comparing these two therapies are limited. We aim to compare the efficacy and safety of apixaban versus warfarin in patients with MM undergoing IMiD treatment. Methods: We conducted a retrospective propensity score-matched cohort study using the TriNetX Analytics Network database, which contains de-identified data from over 120 participating healthcare institutions. We included adult patients with MM who underwent IMiD treatment. Patients treated with apixaban were matched in a 1:1 ratio to those treated with warfarin using clinical variables a priori. The primary safety outcomes included all-cause mortality, intracranial hemorrhage, and gastrointestinal bleeding, while the primary efficacy outcomes included thromboembolic events including pulmonary embolism, deep venous thrombosis, and ischemic stroke within a 3-year period following IMiDs initiation. Results: We identified 448 patients on apixaban who were matched to patients on warfarin. In a Cox proportional hazard analysis, apixaban was associated with a 30% lower risk of all-cause mortality compared to warfarin (Hazard ratio (HR), 0.70 [95% CI: 0.56-0.88]).There was a tendency toward a reduced risk of gastrointestinal bleeding in patients treated with apixaban compared to warfarin (HR, 0.58 [95% CI: 0.31-1.08], log-rank p = 0.083). The risk of intracranial hemorrhage was similar between the two groups.The risks of thromboembolic events including pulmonary embolism, deep venous thrombosis, and ischemic stroke were comparable between the apixaban and warfarin cohorts. Conclusions: Apixaban was associated with a lower risk of all-cause mortality and a comparable risk of bleeding and thromboembolism compared with warfarin among MM patients undergoing immunomodulatory treatment. [Table: see text]

Efficacy of low-dose direct oral anticoagulants (DOACs) for venous thromboembolism prophylaxis in newly diagnosed multiple myeloma.

e19521 Background: The venous thromboembolism (VTE) risk is high in newly diagnosed multiple myeloma (NDMM) patients, especially within 6 months of beginning treatment and with the use of immunomodulatory-drug (IMiD)-based regimens. SAVED and IMPEDE VTE scores assess risk and NCCN guidelines recommend their use. Few studies have explored optimal thromboprophylaxis agent by risk category which has led to varied treatment strategies. We share our institutional experience using DOACs vs aspirin in NDMM patients and explore incidence of VTE, utility of SAVED and IMPEDE scores, and patient safety. Methods: We retrospectively analyzed outcomes of NDMM patients aged 18 and above from January 2018 to June 2022. Patients receiving anticoagulation for other indications or unable to safely take aspirin or DOACs were excluded. The primary outcome was incidence of VTE in the first 6 months of treatment. Secondary outcomes included patient and treatment factors contributing to VTE risk, comparison of VTE scoring calculators: SAVED vs IMPEDE VTE, and safety of low dose DOAC therapy. Fisher’s exact and Wilcoxon rank sum tests were used to compare patient characteristics between 6-month VTE status. Results: Of 347 NDMM patients that were included, 21% experienced VTE within 6 months. Of those who took aspirin, 20.2% had 6-month VTE. For DOACs, 21.4% taking apixaban and 21.7% taking rivaroxaban had 6-month VTE. There was no significant difference in VTE rate between DOAC or ASA groups (p=0.90). Patients with SAVED score ≥2 (p<0.0006) or prior VTE history (p<0.0001) had significantly higher 6-month VTE rates . Characteristics including age>80, sex, race, BMI>25, IMPEDE score, presence of high-risk cytogenetics, existing use of aspirin or low molecular weight heparin, or transplant status showed no significant difference in VTE rate. Conclusions: This is one of the largest retrospective studies examining efficacy and safety of DOACs in NDMM. Initial analysis showed no significant difference in 6-month VTE rate between NDMM patients treated with aspirin or DOAC therapy. SAVED score appears to delineate high risk VTE patients vs IMPEDE. Follow-up will assess 12-month, 18-month, and overall VTE rates. Bleeding events and analysis for additional high-risk correlates, such as choice of induction regimen, will be presented. This highlights the need for ongoing trials evaluating risk-assigned thromboprophylaxis in patients with MM. [Table: see text]

Primary prevention of venous thromboembolism in ambulatory cancer patients: recent advances and practical implications.

Venous thromboembolism (VTE) is a common complication in ambulatory cancer patients receiving anticancer therapies. Many patient-, cancer-, and treatment‑related factors along with specific biomarkers can be associated with an increased risk of VTE in patients with cancer. Risk assessment models, such as the Khorana score, serve as valuable tools to aid in the identification of patients with cancer who are at high risk of VTE. Two randomized controlled trials have evaluated the efficacy of primary thromboprophylaxis with low‑dose direct oral anticoagulants, apixaban and rivaroxaban, to reduce the risk of VTE in ambulatory patients with cancer who are at intermediate to high risk of VTE identified by the Khorana score. This narrative review summarizes the literature on the risk factors and risk assessment process for VTE, and the use of primary thromboprophylaxis in ambulatory cancer patients. We also outline important practical considerations for initiating primary thromboprophylaxis in this population.

(643) - High Incidence of Pulmonary Artery Thrombosis After Balloon Pulmonary Angioplasty in Patients with Chronic Thromboembolic Pulmonary Hypertension Receiving Low-Dose Direct Oral Anticoagulants

(643) - High Incidence of Pulmonary Artery Thrombosis After Balloon Pulmonary Angioplasty in Patients with Chronic Thromboembolic Pulmonary Hypertension Receiving Low-Dose Direct Oral Anticoagulants

One-year morbidity and mortality in patients treated with standard-dose and low-dose apixaban after acute large vessel occlusion stroke

Although low-dose direct oral anticoagulants (DOACs) are recommended for patients at high risk of bleeding complications, it remains unclear whether the dose reduction in real-world setting is also appropriate in patients after large-vessel occlusion (LVO) stroke. This study hypothesized that patients with atrial fibrillation (AF) and LVO receiving low-dose DOACs have an increased risk of ischemic and hemorrhagic events. The study aimed to assess 1 year morbidity and mortality in patients treated with standard-dose and low-dose apixaban after LVO stroke. A post hoc analysis was performed using the acute LVO registry data, which enrolled patients with AF and LVO who received apixaban within 14 days of stroke onset. The incidences of ischemic events (ischemic stroke, acute coronary syndrome, acute myocardial infarction, and systemic embolism), major bleeding events, and death from any cause were compared between patients receiving standard- and low-dose apixaban. Of 643 patients diagnosed with LVO, 307 (47.7%) received low-dose apixaban. After adjustment for clinically relevant variables, no significant differences were observed in the incidence of ischemic events (adjusted hazard ratio [aHR]: 2.12, 95% confidence interval [CI] 0.75–6.02), major bleeding events (aHR: 1.17, 95% CI 0.50–2.73), and death from any cause (aHR: 1.95, 95% CI 0.78–4.89) between patients receiving standard- and low-dose apixaban. No significant differences were observed in the incidence of ischemic events, major bleeding events, or death from any cause between patients with AF and LVO receiving standard- and low-dose apixaban.

Secondary Prophylaxis of Venous Thromboembolism (VTE) with Low Dose Apixaban or Rivaroxaban: Results from a Patient Population with More than 2 Years of Median Follow-up.

Direct oral anticoagulants (DOACs) are widely used for the treatment and secondary prophylaxis of venous thromboembolism (VTE). Nowadays, DOACs represent the gold standard for long-term anticoagulation, with low-intensity DOACs administration becoming increasingly used worldwide in such scenario. Albeit low-intensity apixaban and rivaroxaban are approved for clinical usage as secondary VTE prophylaxis, there are few literature data regarding their efficacy and safety with a long follow-up. The aim of our study was to evaluate the efficacy and safety of low-dose DOACs for VTE secondary prophylaxis in patients at high risk of VTE recurrence. We retrospectively evaluated patients who required long-term anticoagulant secondary prophylaxis to prevent recurrent VTE, treated with apixaban 2.5 mg BID or rivaroxaban 10 mg daily with a follow-up ≥ 12 months. The examined patients were 323. The median low-dose DOAC administration time was 25.40 months (IQR 13.93-45.90). Twelve (3.7%) VTE recurrences were observed; 21 bleeding events were registered (6.5%), including one episode of Major bleeding (MB) (0.3%), 8 Clinically relevant nonmajor bleeding (CRNMB) (2.5%) and 12 minor bleeding (3.7%). No statistically significant difference in the rate of VTE recurrence and/or bleeding events emerged between the rivaroxaban and apixaban groups. Patients included in the study for multiple episodes of VTE presented a significantly higher risk of a new VTE recurrence during low-intensity DOAC. Our data suggest that low-dose DOACs may be effective and safe in secondary VTE prophylaxis in patients at high risk of VTE recurrence; however, attention might be needed in their choice in such a scenario for patients who experienced multiple episodes of VTE.

Comparison of different direct oral anticoagulant regimens in atrial fibrillation patients with high bleeding risk

BackgroundThe optimal dose of direct oral anticoagulants (DOACs) to prevent ischemic stroke (IS) and systemic thromboembolism (STE) in atrial fibrillation (AF) patients with a predisposing bleeding risk remains unclear. ObjectiveThe purpose of this study was to compare the effectiveness and safety of different DOAC dosage regimens in AF patients with high bleeding risk but low thrombosis risk. MethodsThis retrospective observational study was conducted with the National Health Insurance claims database in Taiwan to include AF patients aged 20 up to 75 years, under DOAC therapy, with CHA2DS2-VASc score of 1 for males and 2 for females and HAS-BLED score ≥3. Standard-dose regimen was defined as dabigatran 300 mg, rivaroxaban 20 mg, apixaban 10 mg, or edoxaban 60 mg per day. Any other lower-dose regimen were defined as the low-dose regimen. The primary outcomes were IS and major bleeding (MB). The secondary outcomes were STE, gastrointestinal bleeding, intracranial hemorrhage, and cardiovascular death. ResultsA total of 964 patients were included (52.1% standard-dose regimen). Median HAS-BLED score was 3 [interquartile range 3–3]. Compared with standard-dose group, patients in the low-dose group had a significantly increased risk of IS (adjusted hazard ratio [aHR] 5.13; 95% confidence interval 1.37–19.22) and STE (aHR 3.14 [1.05–9.37]) but similar risk of MB (aHR 0.45 [0.12–1.67]). The risks of other hemorrhage and cardiovascular death were similar between the 2 dose groups. ConclusionAmong patients with a predominant bleeding risk but relatively low thrombosis risk, the low-dose DOAC regimen is not a more appropriate selection than standard-dose regimen.

Real-World Management Strategies of Anticoagulated Atrial Fibrillation Patients After a Clinically Significant Bleeding Episode

BackgroundSystemic anticoagulation for stroke prevention in patients with atrial fibrillation (AF) carries inherent bleeding risks, and determining whether and when to resume anticoagulation after significant bleeding is a common dilemma. We aimed to describe the clinical characteristics of AF patients discharged after a bleeding event, document real-life thromboembolic prevention strategy (TPS), and analyse their associated clinical outcomes. MethodsWe retrospectively reviewed the charts of anticoagulated AF patients admitted for bleeding from 2017 to 2019. ResultsA total of 140 patients were included, with a mean age of 78.6 years. Four discharge groups were defined: 75 patients (53.5%) had optimal anticoagulation (OA), 37 (26.4%) had a suboptimal antithrombotic regimen (SAR; low-dose direct oral anticoagulants without dose-reduction criteria or antiplatelet therapy), 10 (7.1%) were referred for left atrial appendage occlusion (LAAO), and 18 (12.9%) left without any TPS. All-cause mortality at 2 years was high (28.6%) but not statistically different between groups (P = 0.71). Patients discharged with a TPS (OA/SAR/LAAO referral) were more likely to be readmitted for bleeding at 2 years (34% vs 0%; P = 0.002), and those discharged without a TPS had higher rates of stroke (16.6% vs 1.4%; P = 0.003). SAR yielded readmission rates for bleeding similar to resumption of OA (27% vs 34.7%; P = 0.41) but was associated with high rates of death or readmission at 2 years. ConclusionsThis real-life cohort reveals that clinicians frequently downgrade or discontinue long-term thromboembolic protection after a bleeding event despite current guideline recommendations to the contrary, and downgrading resulted in bleeding risk similar to OA.

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 <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.

Usefulness of low-dose direct oral anticoagulants for peripheral deep vein thrombosis of the lower extremities in cancer patients with cancer bleeding lesions

Abstract Background Venous thromboembolism (VTE) is a frequent complication in cancer patients. VTE is often detected as asymptomatic peripheral deep vein thrombosis (DVT). Standard doses of anticoagulants are generally considered difficult to administer in cancer patients due to the high risk of bleeding. However, it has been reported that peripheral DVT worsening to proximal DVT in cancer patients due to increased coagulation tendency, and some strategy for peripheral DVT is required. And the adverse bleeding effects of DOACs have been reported to be dose-dependent. Purpose The aim of this study was to determine the optimal treatment strategy of peripheral DVT in patients with bleeding cancer lesions. In order to do this we compared no anticoagulation, low-dose direct oral anticoagulants (DOACs) and standard-dose DOACs in patients with and without bleeding cancer lesions. Methods A total of 224 consecutive patients with peripheral DVT of the lower extremities (excluding pulmonary thromboembolism or proximal DVT) were included from April 2019 to March 2020. Of these, 172 patients could be followed up by repeated ultrasound examinations for up to 2 years. We investigated retrospectively the change in ultrasound findings between first and second examinations (median interval 44 days). 163 patients were studied, excluding 9 patients who used warfarin or heparin. In 119 of these DOACs were applied, and 44 were without anticoagulation. If the treatment procedure had changed between the first and second ultrasound examinations main treatment procedure was selected and categorized. Results All the patients of low-dose and standard-dose DOACs groups had no major bleeding during follow up period. In the group with cancer bleeding lesion (n=45) there were 12 patients (70.1%) worsening DVT in the group without anticoagulation, 1 patient (4.3%) in the low-dose DOACs and 0 (0%) in the standard-dose DOACs group. There was significant worsening of DVT in the no anticoagulant group compared with low-dose DOACs (P<0.0001), but no significant difference between low-dose DOACs and standard-dose DOACs (P=0.63) in the group with bleeding (see Figure 1). In the group without cancer bleeding (n=118), worsening of DVT occurred in 16 patients (59.3%) without anticoagulation, in 6 patients (16.7%) with low-dose DOACs and in 4 patients (7.3%) with standard-dose DOACs. There was significant worsening of DVT in the no anticoagulant group compared with low-dose DOACs (P<0.0001), but no significant difference between the low-dose and standard-dose DOACs (P=0.16) in the group without bleeding (see Figure 2). Conclusion Low-dose DOACs were found to be as effective as standard-dose DOACs in treating peripheral DVT in cancer patients, with or without bleeding of the cancer lesion. Peripheral DVT treatment with low-dose DOACs can reduce worsening of DVT and should be one of the supportive treatments for the completion of cancer management.DVT in 3 groups with cancer bleedingDVT in 3 groups without cancer bleeding

Periprocedural management of direct oral anticoagulants in patients with atrial fibrillation and active cancer

BackgroundCancer and atrial fibrillation (AF) are common concurrent disorders. Direct oral anticoagulants (DOACs) are prescribed to prevent stroke in patients with AF. Patients with cancer often undergo invasive procedures for diagnostic or therapeutic purposes, necessitating interruption of anticoagulation. There are limited data to guide best periprocedural anticoagulation management practices in the setting of active cancer. ObjectivesTo describe patient characteristics, periprocedural management, and clinical outcomes in DOAC-treated patients with AF according to active cancer status. MethodsWe conducted descriptive and comparative analyses using data from the PAUSE study. Multivariable logistic regression was used to determine whether active cancer status was an independent risk factor for bleeding outcomes. Covariates were selected a priori based on biological rationale and preexisting knowledge. ResultsPatients with active cancer were older (P < .001), more likely to be thrombocytopenic (P = .026), have moderate renal dysfunction (P = .005), and more likely to receive low-dose DOAC therapy (P < .001). A greater proportion of patients with active cancer underwent a high-bleed-risk procedure (P < .001), with longer periprocedural DOAC-interruption intervals (P <.001) and lower preprocedural residual DOAC levels (P = .002). Active cancer was an independent predictor for surgical major bleeding (OR = 2.45; 95% CI, 1.08-5.14) after adjusting for study center, procedure category and bleed risk, thrombocytopenia, hypertension, and the use of a P2Y12 inhibitor. ConclusionsActive cancer status is associated with an increased risk of surgical major bleeding among DOAC-treated patients with AF undergoing interruption of anticoagulation for elective invasive procedures.

Assessing the Feasibility of Thromboprophylaxis with Apixaban in JAK2-Positive Myeloproliferative Neoplasm Patients: The Airport-MPN Trial

Introduction: Thrombosis is a major cause of mortality and morbidity in myeloproliferative neoplasms (MPN). In patients classified as high-risk for thrombosis, current guidelines recommend the use of cytoreduction therapy and low-dose aspirin (e.g., ASA 81 mg daily) to decrease the risk of thrombotic events. However, use of low-dose aspirin is based on limited evidence and is associated with a significant failure rate. Thromboprophylaxis with low-dose direct oral anticoagulants (e.g., apixaban 2.5 mg BID) is an appealing option in MPN, specifically when patients carry the JAK2 mutation, based on the pathophysiology of thrombus formation associated with this driver mutation. In other populations, thromboprophylaxis with a low-dose direct oral anticoagulant has been associated with a reduced risk of arterial and venous thrombotic complications, when compared to low-dose aspirin. Hence, we conducted a pilot trial to assess the feasibility of conducting a randomized controlled trial evaluating the efficacy and safety of apixaban (2.5 mg BID) compared to aspirin (81 mg daily) to prevent thrombotic complications in patients with JAK2-positive MPN (JAK2MPN). Methods: This was a multi-centre, prospective, open-label, blinded endpoint pilot trial (NCT04243122), conducted in three Canadian centers (Ottawa, Calgary, Sherbrooke). Adult patients with a confirmed diagnosis of polycythemia vera, JAK2-positive essential thrombocythemia or JAK2-positive pre-fibrotic myelofibrosis (per local clinical definitions) requiring low-dose aspirin for thromboprophylaxis were eligible. Both patients with an incident diagnosis of JAK2MPN (defined as diagnosed within 1 year) and patients with prevalent disease were targeted for recruitment. Exclusion criteria included a contraindication to thromboprophylaxis or the need for a specific anticoagulant or non-aspirin anti-platelet agent. Patients with a prior history of venous thromboembolism were eligible if they had completed a minimum of 6 months of anticoagulation therapy. Participants were randomized 1:1 to receive apixaban 2.5mg BID or aspirin 81mg daily, along with cytoreductive therapy (per guidelines). The study treatment duration was 6 months. Follow-up occurred at 3, 6 and 7 months after allocation of the study medication. The primary study outcome for feasibility was the monthly recruitment rate per study site over a 6-month follow-up period. Secondary outcomes included rates of thrombotic and bleeding complications. The total estimated sample size was 44 participants (22 per arm). Due to the COVID-19 pandemic, not all sites were able to start recruitment at the same time and the total recruitment period spanned over 24 months. Results: During this 24-month recruitment period, 93 JAK2MPN patients were screened for eligibility. Of these, 69 were eligible and 64% of eligible patients consented to participate. We therefore recruited 44 participants, for a recruitment rate of 0.8 patient per centre per month. Baseline characteristics of participants are presented in Table 1. A total of 29 prevalent cases and 15 incident cases were included. Secondary efficacy, safety, and feasibility outcomes (relating to thrombotic events, bleeding complications, and study compliance) will be available at the ASH Meeting, since all participants will have completed the 6-month treatment duration by October 2023. Discussion: Despite the challenges of the COVID-19 pandemic, we have recruited 100% of our target population. Given the chronicity of MPN, most outpatient clinics functioned remotely during the pandemic, precluding recruitment. Nevertheless, by adapting to the realities of the pandemic, we achieved our recruitment target demonstrating feasibility of a larger trial. The strategies adopted during this pilot trial to recruit participants, such as active screening of clinic lists for potential participants and direct communication with MPN specialists, will be applied to our larger scale trial. Conclusion: This pilot trial demonstrated the feasibility of conducting a large-scale trial evaluating the superiority of apixaban over aspirin for the thromboprophylaxis of JAK2MPN patients. As JAK2MPN are rare diseases, we have partnered with counterparts in France to conduct an international study on the efficacy and safety of direct oral anticoagulant thromboprophylaxis in JAK2MPN patients.

Extended Full Dose Versus Low Dose Direct Oral Anticoagulants in Cancer and Overweight Patients

Background: Reduced or low-dose direct oral anticoagulants (DOACs) have been studied in randomized control trials for the extended prevention of venous thromboembolism (VTE) after 6 months of treatment at full, therapeutic doses. The real-world effectiveness as well as utilization of this approach in clinical practice compared to continuing at therapeutic doses is unclear. Aims: Examine the effectiveness, safety and utilization of reduced-dose DOACs in cancer patients and overweight patients. Methods: Consecutive patients with VTE were identified using the Mayo Clinic VTE Registry from March 1st, 2013 to December 31st, 2021. Patients were followed prospectively for outcomes of VTE recurrence, death, major bleeding and clinically relevant non major bleeding (CRNMB) either in person or by survey. Patients with recurrent VTE or bleeding during the first 3 months were excluded from further analysis. After completion of anticoagulation treatment for 3 months with either rivaroxaban or apixaban, patients continuing anticoagulation were evaluated in a nested case-control study. Results: A total of 404 patients (283 (70%) on apixaban and 121 (30%) on rivaroxaban) were identified in the low dose DOAC and 3060 in the full dose anticoagulation group. Overall, the mean age was 60.7 years (SD 14.4), mean weight was 89.9 kg (SD 23.8) and 55.1% were males. Within the full cohort, patients with active cancer were less likely to be prescribed low dose DOACs (HR 0.56; 95%CI 0.42-0.73; p&amp;lt;0.001). However, low dose DOAC prescription was more likely in patients with pulmonary embolism alone (HR 1.48; 95%CI 1.21-1.80; p&amp;lt;0.001) or in combination with DVT (HR 1.54; 95%CI 1.25,1.90; p&amp;lt;0.001). Patients transitioned to low dose DOACs had similar age, sex and weight compared to the full dose anticoagulation group, however, fewer patients with weight ≥120 kg had reduced dosing (HR 0.68; 95%CI 0.46,0.99; p=0.046). The mean time to start of a low dose DOAC was 5.1 months overall, 5.4 months in cancer patients, and 3.6-4.9 months in non-cancer patients (Table 1). Non-cancer patients had significantly lower transition numbers in those ≥120kg (HR 0.62; 95%CI 0.40,0.97; p=0.038). In non-cancer patients In comparing weight, ≥120kg to &amp;lt;120kg, in the low dose group, only death was statistically different with higher risk in those ≥120kg (HR 6.44; 95%CI1.27,32.81; p=0.025). Cancer patients transitioned to low dose DOACs around 5 months on average with a median of 3.3 months. Apixaban continued to be the dominant DOAC used (78%) in the low dose group. The cancers with the most patients on low dose DOACs include lymphoma, prostate, melanoma, ovarian, and breast. There was no significant difference in VTE recurrence or death in the cancer group on different DOAC doses. Conclusion: Our results show that anticoagulant prescribers are not always waiting until 6 months to transition to low doses and low doses are being utilized in cancer patients despite lack of cancer-specific studies during the analyzed time period. Although the sample size limits the precision of this analysis, we did not find statistically significant increases in VTE recurrence with low dose DOACs in either cancer patients or with elevated body weight. We did find CRNMB but not MB was observed more frequently in weights above 120kg, possibly from unadjusted confounding in this unadjusted analysis.

Direct oral anticoagulants versus aspirin for primary thromboprophylaxis in patients with multiple myeloma undergoing outpatient therapy: A systematic review and updated meta-analysis.

Patients with multiple myeloma (MM) are at an elevated risk of venous thromboembolism (VTE), which is further increased for those undergoing anti-myeloma therapy. Current guidelines suggest low-dose direct oral anticoagulants (DOACs) as an alternative to aspirin for primary thromboprophylaxis in this population, but data comparing these two therapies are limited. We performed a systematic review and meta-analysis to compare DOACs with aspirin for primary thromboprophylaxis in individuals undergoing outpatient anti-myeloma therapy. Studies were selected when comparing DOACs versus aspirin for thrombotic and haemorrhagic outcomes. We included 10 randomised controlled trials and observational studies comprising 1026 patients with MM who received primary thromboprophylaxis with DOACs (n = 337) or aspirin (n = 689). DOAC thromboprophylaxis was associated with a significantly lower incidence of VTE compared with aspirin (OR 0.33; 95% CI 0.16-0.68; p < 0.001). Major, clinically relevant non-major and minor bleeding event rates did not differ significantly between groups. Overall, our meta-analysis suggests that DOACs may be a preferable option to aspirin for the prevention of MM-related thrombosis. However, these results should be interpreted in the context of heterogeneous baseline population characteristics and potential bias from including observational studies. Further research is needed to evaluate the optimal thromboprophylaxis strategy, particularly in high-risk individuals.

Low-dose apixaban or rivaroxaban as secondary prophylaxis of upper extremity deep vein thrombosis.

Upper extremity deep vein thrombosis (UEDVT) may occur without inciting factor or may be secondary to malignancy, surgery, trauma, central venous catheter or related to thoracic outlet syndrome (TOS). International guidelines recommend anticoagulant treatment for at least three months, in particular the use of vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). No data on extended anticoagulant therapy and reduced dose of DOACs have been reported in patients affected by UEDVT with persistent thrombotic risk (active cancer, major congenital thrombophilia) or without affected vein recanalization. In our retrospective observational study, including 43 patients, we treated secondary UEDVT with DOACs. In the acute phase of thrombosis (median time of 4 months), we used therapeutic dose of DOACs; the 32 patients with permanent thrombotic risk factors or without recanalization of the UEDVT were shifted to low-dose DOACs (apixaban 2.5mg twice daily or rivaroxaban 10mg daily). During therapy with full-dose DOACs, 1 patient presented recurrence of thrombosis; no thromboembolic events were observed during treatment with low-dose DOACs. During full-dose treatment, 3 patients presented minor hemorrhagic complications; no hemorrhagic events were observed during DOACs at low dose. We think our preliminary data could support the indication to extend the anticoagulation with dose reduction of DOACs in patients affected by UEDVT and no-transient thrombotic risk. These data should be confirmed in randomized controlled prospective study.

Safety outcomes of direct oral anticoagulants in older adults with atrial fibrillation: a systematic review and meta-analysis of (subgroup analyses from) randomized controlled trials

Balancing stroke prevention and risk of bleeding in patients with atrial fibrillation (AF) is challenging. Direct oral anticoagulants (DOACs) are by now considered standard of care for treating patients with AF in international guidelines. Our objective was to assess the safety of long-term intake of DOACs in older adults with AF. We included RCTs in elderly (≥ 65 years) patients with AF. A systematic search in MEDLINE and EMBASE was performed on 19 April 2022. For determination of risk of bias, the RoB 2 tool was applied. We pooled outcomes using random-effects meta-analyses. The quality of evidence was assessed using GRADE. Eleven RCTs with a total of 63,374 patients were identified. Two RCTs compared apixaban with either warfarin or aspirin, four edoxaban with either placebo, aspirin, or vitamin K antagonists (VKAs), two dabigatran with warfarin and three rivaroxaban with warfarin. DOACs probably reduce mortality in elderly patients with AF (HR 0.89 95%CI 0.77 to 1.02). Low-dose DOACs likely reduce bleeding compared to VKAs (HR ranged from 0.47 to 1.01). For high-dose DOACS the risk of bleeding varied widely (HR ranged from 0.80 to 1.40). We found that low-dose DOACs probably decrease mortality in AF patients. Moreover, apixaban and probably edoxaban are associated with fewer major or clinically relevant bleeding (MCRB) events compared to VKAs. For dabigatran and rivaroxaban, the risk of MCRB varies depending on dose. Moreover, subgroup analyses indicate that in the very old (≥ 85) the risk for MCRB events might be increased when using DOACs.Registration: PROSPERO: CRD42020187876.

NET CLINICAL BENEFIT OF A REDUCED DOSE OF DIRECT ORAL ANTICOAGULANTS IN NON-VALVULAR ATRIAL FIBRILLATION: A META-ANALYSIS OF RANDOMIZED TRIALS

Objective: To evaluate the net clinical benefit of a reduced dose of direct oral anticoagulants (DOACs) compared to warfarin in nonvalvular atrial fibrillation. Design and method: We searched three electronic databases covering the period until end-February 2021. All-cause death, non-fatal stroke/systemic embolism, and major bleeding events, with or without the inclusion of myocardial infarction, were used to define two different net clinical benefit outcomes. In addition, we evaluated different component outcomes of net clinical benefit as secondary outcomes. Finally, each outcome's risk ratios and 95% Confidence Intervals (CI) were calculated (random-effects model). Results: In the four randomized trials included (n = 29,779 patients), the net clinical benefit - with or without the inclusion of myocardial infarction - of low-dose DOACs, compared to warfarin, was a 12% (95% CI, 7%-16%) or a 10% (95% CI, 5%-13%) reduction of events, respectively. Compared to warfarin, the reduced dose of DOACs decreased death outcomes, major bleeding events, and hemorrhagic stroke, whereas all thrombotic outcomes were not different among the groups. Conclusions: DOACs at low doses present a more favorable net clinical benefit profile than warfarin.