Clinically Relevant Non-major Bleeding Research Articles

Bleeding Risk in Atrial Fibrillation and Thrombocytopenia: A Propensity Matched Cohort Study

Background: Anticoagulation is the major therapeutic strategy in the management of patients with atrial fibrillation (AF). Thrombocytopenia is a frequent coexisting condition that may predispose to bleeding in these patients. However, the risk of bleeding in patients with AF and thrombocytopenia has not been well studied. Moderate thrombocytopenia (<100,000/μL) was an exclusion criteria in the clinical trials used to approve non-vitamin K oral anticoagulants for stroke prophylaxis. Similarly, studies examining warfarin's safety and efficacy in AF have not included significant numbers of thrombocytopenic patients. This paucity of data describing the safety of oral anticoagulants in patients with AF and thrombocytopenia represents a major challenge in clinical practice. Present treatment guidelines do not include specific guidance for anticoagulation in patients with these coexisting conditions. Thus, the purpose of this study was to compare rates of bleeding among patients with and without thrombocytopenia who begin oral anticoagulation for AF. Methods: A propensity matched cohort study was designed to compare rates of bleeding among patients with thrombocytopenia who began oral anticoagulation for AF between 2015-2020 at a quaternary care hospital in Boston, MA against patients with AF starting anticoagulation in the absence of thrombocytopenia. The thrombocytopenic cohort was defined as having at least two platelet counts on separate days <100,000/μL in the period spanning the 12 weeks preceding the initiation of anticoagulation to 6 weeks following the initiation of anticoagulation. Patients with only one platelet count <100,000/μL were excluded. Individuals from the thrombocytopenic cohort were matched with patients (1:3 ratio) from the non-thrombocytopenic cohort using propensity matching on the basis of age, sex, CHA2DS2-VASc score, and anticoagulant agent used. Bleeding outcomes were determined by blinded manual chart review and verified by a second reviewer; all bleeding events were classified as per the International Society on Thrombosis and Haemostasis. The primary endpoint of the study was the cumulative incidence of clinically relevant bleeding, a composite of major bleeding and clinically relevant non-major bleeding (CRNMB), within one year of the initiation of anticoagulation. Results: The study population included 1,075 patients who started oral anticoagulation for AF (274 with thrombocytopenia, 801 controls). Overall, 38% of the cohort was female, with a median age of 72 years; 14.6% of the total cohort had cancer and 2.8% had liver disease at the time they began anticoagulation. The median CHA2DS2-VASc score was 3 (IQR 2-4). Warfarin (48.2%) and apixaban (39.6%) were the anticoagulants used in the majority of patients. Notably, the thrombocytopenic cohort included more patients with significant comorbidities, such as cancer (23.0% vs 11.7%), liver disease (4.7% vs. 2.1%), and kidney disease (12.8% vs. 7.5%). There were a total 219 bleeding events recorded, including 90 (41.1%) major bleeding events and 122 (55.7%) CRNMB events. (Table 1) The cumulative incidence of clinically relevant bleeding at 1 year was significantly higher (18.3%; 95% CI, 13.6-22.9) in those with thrombocytopenia at the time of starting anticoagulation compared with the control cohort (13.2%; 95% CI, 10.9-15.6) (P < 0.001, Gray test). Similarly, the cumulative incidence of major bleeding at 1 year was 10.1% (95% CI, 6.5-13.7) in those with thrombocytopenia compared with 5.2% (95% CI, 3.7-6.8) among controls (P < 0.001, Gray test). (Figure 1) Conclusions: Oral anticoagulation for AF in patients with thrombocytopenia at the time of starting anticoagulation significantly increased the risk of clinically relevant and major bleeding relative to patients with normal platelet counts. These findings support the need for further characterization of the risk-benefit profile of anticoagulation in this population to guide clinicians faced with this common clinical scenario. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Achieving Therapeutic Anti-Xa Levels Using Rivaroxaban for Venous Thromboembolism in a Morbidly Obese Patient with a BMI >70

Background: Anticoagulation (AC) is the cornerstone of treatment for venous thromboembolism (VTE). Direct oral anticoagulants (DOACs) have become the standard of care during the acute and extended phases of therapy for VTE, mostly due to their ease of use, efficacy, and safety profiles. There is a 9.2% prevalence of severe obesity (BMI>40) in Americans as of 2017-2020 with a 6.2-fold increased risk of VTE in obese individuals. The 2021 International Society on Thrombosis and Haemostasis (ISTH) guidelines recommend using standard dosages of DOACs in patients with a BMI >40 kg/m2 or weight >120 kg. Despite these recommendations, their use in severely obese individuals at extremes of weight like our patient with a BMI > 70 kg/m2 remains uncertain. Case Presentation Herein, we present a 38-year-old morbidly obese female with no significant past medical history who presented with an acute worsening of dyspnea on exertion saturating 60% on room air. The diagnosis of intermediate-high risk pulmonary embolism (PE) was made based on computed tomographic angiography (CTA) with right ventricular strain and elevated cardiac biomarkers. A concomitant proximal DVT from the left common femoral to the distal peroneal vein was also noted. The patient's weight was 243kg with a calculated BMI of 72.3 kg/m2. After the patient had received parenteral anticoagulation with heparin for 4 days, it was decided to switch to Rivaroxaban 15mg BID for 21 days followed by 20 mg daily. With a history of irregular menses, the patient developed heavy menstrual bleeding (HMB) following the initiation of rivaroxaban. Her hemoglobin remained stable with no blood transfusion requirements. However, this led to the decision to switch to rivaroxaban 20 mg PO daily earlier than planned due to a lack of improvement in menstrual bleeding which was considered to be clinically relevant non-major bleeding (CRNMB). Despite this switch, there was no effect on efficacy and the patient did not develop any signs or symptoms of VTE recurrence during her prolonged hospital stay with a significant improvement in her oxygenation levels and VTE symptomatology. In our patient, we demonstrated the use of rivaroxaban in a morbidly obese individual with a BMI>70 by achieving therapeutic anti-Xa levels. Figure 1 shows the therapeutic peak and trough anti-Xa levels throughout the patient's hospitalization. The highest Anti Xa level of 314 mcg/mL was reported on day 19 correlating with the patient's menorrhagia, which self-limited with the transition from rivaroxaban 15 mg twice daily to 20 mg daily. Discussion: Two pivotal clinical trials, the EINSTEIN-DVT/PE trials, where 14% of patients in both arms weighed >100 kg, showed that patients on rivaroxaban (15 mg BID for 3 weeks, followed by 20 mg once daily) vs those on enoxaparin followed by a vitamin K antagonist, had no significant difference in recurrence rates of VTE and bleeding rates [Moore KT, et Al. Influences of Obesity, Am J Med 2017]. A recent post-hoc analysis of the EINSTEIN DVT/PE trials also portrayed no correlation between weight/BMI and risk of recurrent VTE or bleeding in those who received rivaroxaban. Our case illustrates the attainment of therapeutic anti-Xa levels with no recurrent VTE in our morbidly obese patient. Despite her heavy menstrual bleeding, the bleeding was controlled once the switch to rivaroxaban 20mg daily was completed. Another study in which its heaviest participant at 172 kg, showed compelling evidence that morbid obesity has minimal influence on the safety and efficacy of rivaroxaban [Speed V, et al. Fixed dose rivaroxaban. JTH 2020]. This remains true for our patient at 243 kg. Conclusion: Our case demonstrates that standard doses of rivaroxaban for the treatment of DVT/PE in individuals with morbid obesity with BMI>70 kg/m2 can be effective, and safer for the initial phase of treatment for VTE and in prevention of VTE recurrence. It also portrays that increased dosages attempting to account for high bodyweight/fat can potentially result in major bleeding events. Despite the 2021 ISTH guidelines, further prospective studies and randomized controlled trials are warranted, to assess the safety and efficacy of DOACs in VTE, particularly in such challenging clinical scenarios like morbid obesity. Alongside clinical assessment, additional studies will be essential to evaluate the need for universal and external validation of anti-Xa levels in patients taking DOACs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Influence of primary cancer site on clinical outcomes of anticoagulation for associated venous thromboembolism

IntroductionThe outcome of anticoagulation for cancer-associated venous thromboembolism (Ca-VTE) differs according to cancer location, but data are limited and inconsistent. Materials and methodsPatients with acute venous thromboembolism (VTE) enrolled between 03/01/2013 and 04/30/2021 were followed prospectively to assess VTE recurrence, major bleeding (MB), clinically relevant non-major bleeding (CRNMB), and death. ResultsThere were 1702 (45.3 %) patients with Ca-VTE including: gastrointestinal (n = 340), pancreatic (n = 223), hematologic (n = 188), genitourinary (n = 163), lung (n = 139), ovarian (n = 109), breast (n = 97), renal (n = 75), prostate (n = 73), hepatobiliary (n = 70), brain (n = 57), and other cancers (n = 168); 2057 VTE patients had no cancer (NoCa-VTE). Hepatobiliary cancer had the highest VTE recurrence (all rates 100 person-years) of all cancers and higher compared to NoCa-VTE (13.69, p = 0.01), while the MB rate, although numerically higher (15.91), was not different (p = 0.09). Another 3 cancers had higher VTE recurrence but similar MB rates compared to NoCa-VTE: genitourinary [(9.59, p = 0.01) and (7.03, p = 1.0)], pancreatic [(9.74, p < 0.001) and (5.47, p = 1.00)], and hematologic [(5.29, p = 0.05) and (3.59, p = 1.0)]. Renal cancer had the highest rate of MB among all cancers and was higher than that of NoCa-VTE (16.49; p < 0.001), with no difference in VTE recurrence (1.62; p = 1.0). VTE recurrence and MB rates were not significantly different between NoCa-VTE and gastrointestinal, lung, breast, prostate, and brain cancers. CRNMB rates were similar and mortality higher in Ca-VTE patients, except for prostate and breast cancer, compared to NoCa-VTE. ConclusionsSignificant differences in clinical outcomes indicate that anticoagulation strategies may need to be tailored to the primary cancer location.

Anticoagulation and/or Antiplatelet in Thrombotic Antiphospholipid Syndrome with Previous Arterial Thromboembolism: A Retrospective Cohort

Introduction: Thrombotic antiphospholipid syndrome (TAPS) is a prothrombotic autoimmune disease associated with a high risk of arterial thromboembolism (ATE). While direct oral anticoagulants (DOAC) are inferior treatment in TAPS with ATE, the optimal antithrombotic regimen of vitamin K antagonists (VKA) and/or antiplatelet therapy (AP) remains unclear. Objectives: To assess the effectiveness and safety of VKA (target (t) international normalized ratio (INR) 2-3), VKA (t INR 2-3) with AP (including dual AP therapy), VKA (t INR >3), VKA (t INR >3) with AP, and AP alone at preventing recurrent thrombotic events in TAPS patients with previous ATE. Methods: This retrospective cohort study included adult TAPS patients with previous ATE assessed at two academic tertiary care centers in Toronto, Canada between April 1, 2011 to April 1, 2021. Included patients met Sydney criteria for TAPS and had a history of ATE (ischemic stroke (IS), transient ischemic attack (TIA), myocardial infarction (MI), or systemic embolism (SE)). At participating centers, patients with a thrombotic history suspicious for TAPS were screened for lupus anticoagulant, anti-cardiolipin antibodies, and/or anti-beta-2-glycoprotein 1 antibodies (anti-B2GP1) at the discretion of the treating physician. Testing for anti-B2GP1 was only available as a send away test. We excluded patients with a known cardioembolic source for their ATE including atrial fibrillation, patent foramen ovale, mechanical heart valves, Libman-Sacks endocarditis, those with initial ATE associated with catastrophic antiphospholipid syndrome (CAPS), and those treated with DOAC. Outcomes included both thrombotic and bleeding events. Recurrent thrombosis included both ATE and VTE. ATE included IS, TIA, MI, or SE. Bleeding events were categorized as major bleeding (MB) or clinically relevant non-major bleeding (CRNMB) as defined by International Society on Thrombosis and Haemostasis criteria. Outcomes were assessed during the time the particular antithrombotic regimen was used. If a single patient had multiple antithrombotic regimens, they were included in multiple groups for the time they used that particular antithrombotic regimen, defined as antithrombotic trials. Outcomes were calculated as the number of events per 100 patient years by antithrombotic regimen with 95% confidence intervals (CI) using Poisson's exact test. Statistical calculations were performed using SPSS. Results: From an initial 891 patients with at least one positive antiphospholipid antibody test, 120 patients met criteria for TAPS and had a previous ATE. 62 patients were excluded for the following reasons: 47 for a cardio-embolic source of ATE, 5 for absence of any follow up, 7 for use of DOAC, and 3 for CAPS in the absence of any other ATE. After exclusions, 58 patients with a total of 89 antithrombotic trials were included in the analysis with a cumulative follow up of 248.4 years. The study population comprised of thirty-one (53.4%) women with a mean age of 51 (Standard Deviation (SD) 12.9) years at the start of their initial antithrombotic trial. Twenty-three (39.7%) patients were known to have systemic lupus erythematosus (SLE) whereas seven (12.1%) patients had non-SLE autoimmune disorders. Thirty-four (58.6%) patients had baseline hypertension. The baseline characteristics are summarized in table 1. Overall, there were a total of 7 ATE and 1 VTE recurrences with a thrombotic rate of 3.2 per 100 patient-years (95% CI 1.4 to 6.3). The recurrence rates in the VKA (t INR 2-3), VKA (t INR 2-3) with AP, VKA (t INR >3) with AP, and AP alone were 3.3 (95% CI 0.9 to 8.4), 2.6 (95% CI 0.3 to 9.3), 0 (95% CI 0 to 18.8), and 6.8 (0.8 to 24.4) per 100 patient-years respectively. There were a total of 10 MB events including 4 intracranial bleeding (ICB), 1 gastrointestinal bleeding, and 5 other types of MB. ICB occurred in 3 patients on VKA (t INR 2-3) and 1 on VKA (t INR 2-3) with AP. Outcomes are summarized in table 2. Conclusions: This retrospective cohort of 58 patients with TAPS and a previous ATE demonstrated a numerically higher risk of recurrent thrombosis with AP alone and a numerically higher risk of MB with the combination VKA and AP. Study limitations include the small sample size, risk of selection bias, and retrospective design. Larger, prospective studies are needed to confirm our observations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Thrombocytopenia on Bleeding and Recurrent Thrombosis in Cancer Associated Thrombosis: A Post Hoc Analysis of Hokusai VTE Cancer Study

Background: Thrombosis and thrombocytopenia are both frequent complications in patients with active cancer. Thrombocytopenia can complicate decisions around anticoagulation in cancer associated thrombosis (CAT) but data to guide clinicians is limited. Much of the data on the safety and efficacy of anticoagulation in patients with CAT and thrombocytopenia have been retrospective, single-center, cohort studies. The benefit and risk of direct oral anticoagulants in cancer patients with acute venous thromboembolism (VTE) and thrombocytopenia is incompletely understood. The HOKUSAI VTE Cancer study was a randomized open-label, non-inferiority, phase III trial in CAT that compared dalteparin with edoxaban for at least 6 months. We conducted a post hoc analysis of this trial to investigate the impact of platelet count on bleeding and recurrent thrombosis. Methods: Patients with platelet counts less than 100,000/µL at specified time points (enrollment, day 31 or day 90) were compared with patients with platelet count > 100,000/µL on all three time points. The primary outcomes for these analyses was major bleeding; secondary outcomes were clinically relevant non-major bleeding (CRNMB), recurrent thrombosis and survival. Cumulative incidences of bleeding and thrombosis outcomes were calculated with death as a competing risk. Results: A total of 1045 patients were included in the analyses. , The median age was 65 years and 52% were male. Most common malignancies included colorectal (16%), lung (15%), genitourinary (13%), breast (12%), and hematologic malignancies (11%). Of patients with solid cancers, 53% had metastatic disease and 30% recurrent disease at enrollment. Qualifying thrombotic events included pulmonary embolism for 63% and isolated deep vein thrombosis in 37%. Thrombocytopenia (<100,000/µL) was present in 101 patients (9.6%) of the total cohort. Only 14 patients had a platelet count <50,000/µL at any of the three time points. For the overall trial period the rates of major bleeding were significantly higher in patients with platelet count <100,000/µL (11.9% vs. 4.8%, HR 2.5 P=0.004). (Table 1) Rates of CRNMB were similarly higher in patients with platelet count <100,000/ µL (21.8% vs. 11.9%, HR 1.93, P=0.005), however there was no significant difference in rates of recurrent VTE (11.9% vs. 9.2%, HR 1.28 P=0.42) or overall mortality (37.6% vs. 38%, HR 0.98, P=0.90). Cumulative incidence of major bleeding at 180 days was higher 8.9% (95% CI 3.4-14.5%) in patients with platelet count <100,000/ µL compared to 3.9% (95% CI 2.7-5.2%) in those higher than 100,000/µL. (Figure 1) Conclusion: In this post hoc analysis of a randomized controlled study in CAT, thrombocytopenia (<100,000/µL) was associated with an increased risk of major bleeding by two-fold. No difference in the risk of recurrent thrombosis was detected. These data highlight the importance of recognizing even mild thrombocytopenia as an important risk factor for bleeding in patients being anticoagulated for CAT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Prospective Randomized Study for Optimal Red Blood Cell Use Patients with Acute Myeloid Leukemia Receiving Dose Intensive Chemotherapy

Background: Although blood transfusion is fundamental throughout the course of hematologic malignancy, acute myeloid leukemia (AML) patients requiring intensive chemotherapy are left at the edges of patient blood management programs because current guidelines do not have established recommendations for a transfusion threshold in patients treated for hematological disorders nor for those with severe thrombocytopenia who are at risk of bleeding. Especially in the past 2 years, patient blood management programs gained more popularity with the spread of COVID-19. Due to blood inventory shortages, majority of the institutions lowered the hemoglobin (Hb) threshold to 7g/dL and this hit patients with hematologic malignancies especially hard. To close the gaps in inconsistencies of RBC transfusion care, we conducted a prospective trial focusing on newly diagnosed AML patients undergoing intensive chemotherapy. To the best of our knowledge, this is the first trial focusing on this unique subpopulation of patients. Also by doing so, we were able to shed some light on RBC transfusion optimization for patients with thrombocytopenia. Methods: This was a randomized trial of newly diagnosed AML diagnosed and treated between September 2018 and February 2022. Figure A outlines the study design. Patients were randomized into 4 groups using 2 by 2 factorial design, according to trigger (Hb 7 vs 8g/dL) and quantity (single-unit vs double-unit). In case patients became hemodynamically unstable due to major bleeding, severe infection, ischemic heart disease, stroke or any other compromising conditions, liberal RBC transfusion was allowed regardless of the grouping to ensure patients’ safety. Platelet transfusion was done liberally to maintain target platelet count between 10 - 20 x 109/L. Non-acute promyelocytic leukemia AML aged between 19 to 70 years old, undergoing cytarabine ± anthracycline chemotherapy were considered eligible for enrollment. The primary objective of the study was to compare the differences in the number of RBC units per case across the groups. The secondary outcomes included major bleeding and clinical relevant non-major bleeding (CRNM) according to ISTH, AML treatment outcomes according to International Working Group, platelet transfusion, RBC transfusion adherence rates (events of out of specification transfusion), transfusion related adverse events (AE), and infection complications Results: Initially 91 patients were randomized into 4 groups, but the protocol adherence rate was 90.1% (Figure B). As whole, patients received a median of 4 units of RBC (range 0-24) and AE rate associated with RBC transfusion was 16.9% (13/77). All 13 cases of AE were mild allergic and non-hemolytic reactions. There were no cases of fatal AEs such as anaphylaxis, acute hemolysis or transfusion-associated lung injury. Hemoglobin trigger did not affect the amount of RBC transfusion required during treatment. Patients receiving RBC transfusion at Hb < 7 g/dL used a median of 4 units of RBC (range 0-12), and those receiving transfusion at Hb < 8g/dL also used a median of 4 units of RBC (range 0-24) (P=0.305). The AE rates associated with RBC transfusion were similar between the 2 groups (P=0.286). As for platelet transfusion, there were no differences regards to transfusion frequency (P=0.256) or amount (P=0.258) between the 2 groups. Quantity of RBC per transfusion did not affect the total amount of RBC transfusion required during treatment. Patients receiving 2 units of RBC per transfusion used similar amount of RBC as patients receiving 1 unit of RBC per transfusion. There were no differences in platelet transfusion frequency (P=0.256) or amount (P=0.258) between the 2 groups. Overall, treatment outcomes did not differ across the 4 groups. There were 3 cases of major bleeding: 2 cases of gastrointestinal bleeding and 1 case of muscle hematoma. There was 1 case of CRNM: the patient had grade 1 epistaxis that did not require intervention. There were 4 deaths during the follow-up: 2 due to uncontrolled AML and 2 due to infection. Conclusion: This study establishes feasibility for restrictive RBC transfusion in AML patients undergoing chemotherapy. For stable patients without significant medical history, RBC transfusion can be safely initiated when Hb < 7g/dL and 1 unit is adequate. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Assessing the Relationship between Thrombosis and Immune-Related Adverse Events in Patients with Lung Cancer Treated with Immune Checkpoint Inhibitors

Introduction: Venous thromboembolisms (VTE) frequently occur in cancer patients, and the role of immune checkpoint inhibitors on thrombotic risk has been a rising concern for clinicians. Identifying pro-thrombotic risk factors could guide primary prophylaxis strategies in patients receiving immunotherapy. Immune checkpoint blockade can induce inflammatory side effects known as immune-related Adverse Events (irAE). Inflammatory states are known to be associated with a hypercoagulable state. It is not established whether patients treated with immunotherapy experience a higher risk of thrombotic events during periods of increased inflammation surrounding irAE occurrence. Similarly, while immune checkpoint inhibitors have been shown to be associated with increased bleeding events, it is not clear whether irAE occurrence affects incidence of hemorrhage. Our primary objective was to determine the association between irAE and thrombosis in patients with non-small cell lung cancer treated with immune checkpoint inhibitors in order to better elucidate potential risk factors for thrombosis in patients on immunotherapy. Our secondary objective was to evaluate the association between irAE and clinically significant bleeding events. Methods: We identified all patients with non-small cell lung cancer treated with pembrolizumab at an academic medical center between 2016 and 2021. Outcomes of interest were VTE and clinically relevant bleeding (a composite of major bleeding and clinically-relevant non-major bleeds). We collected information regarding concurrent chemotherapy use with immunotherapy, frequency and type of irAE, steroid use for treatment for irAE, and use of anticoagulation or antiplatelet agents. We used logistic regression to calculate the odds ratios (OR) and 95% confidence intervals (CI) of VTE and clinically-relevant bleeding among patients who had an irAE prior to the outcome of interest compared to those who did not. We calculated the odds of VTE associated with use of concurrent chemotherapy (vs. no concurrent chemotherapy). Results: Of 102 patients included, 46.1% were female, and average age at diagnosis was 66.8 ± 10.5 years. Thirty-four patients were treated with pembrolizumab alone, with the remainder receiving concurrent chemotherapy and/or targeted therapy with pembrolizumab. Overall, 21 patients experienced thrombotic events (20.6%), 7 (6.9%) experienced clinically-relevant bleeding events, and 28 (27%) experienced an irAE. (Table 1). Overall, occurrence of irAE was not associated with increased odds of VTE (OR: 1.07, 95% CI: 0.37-3.11, P=0.90). (Figure 1). Similarly, among those with an irAE, steroid treatment was not associated with increased odds of VTE (OR: 1.14, 95% CI: 0.17-7.69, P=0.89). The combination of chemotherapy with pembrolizumab did not result in a statistically significant increase in odds of VTE (OR: 1.37, 95% CI: 0.52-3.60, P=0.53). The odds of clinically-relevant bleeding was not statistically higher among those with an irAE (OR: 2.10, 95% CI: 0.44-10.0, P=0.35). Conclusions: The development of irAE in patients with NSCLC treated with pembrolizumab does not appear to predict the development of VTE. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Developing a Cancer-Associated Thrombosis Clinic: Two-Year Experience

Background: Cancer-associated thrombosis (CAT) is a common comorbidity in patients with cancer. Prior trials have demonstrated that direct oral anticoagulants (DOACs) and low-molecular weight heparins (LMWHs) are safe and effective for CAT management. Despite these data, treatment of CAT is complicated by consequences of both cancers and cancer-directed therapies that can impact anticoagulation options. Methods: We developed the Northwestern Medicine CAT clinic in April 2020 to improve care by streamlining referrals for evaluation and management of CAT by a non-malignant hematologist. Patients were referred for either acute management of new VTE or for ongoing management of previously known VTE. Goal time-to-appointment for acute referrals was within 24 hours and for ongoing management within two weeks. Initial evaluations were completed by advanced practice providers with review by an attending classical hematologist and clinical pharmacist. We manually reviewed electronic health records of patients seen in the CAT clinic since its inception. Data collected included demographic, cancer diagnosis and cancer-directed therapy, CAT clinic recommendations, and recurrent VTE, bleeding and death within 6 months of initial CAT clinic appointment. We used descriptive statistics to assess referral and treatment patterns. Results: One hundred twenty-two patients (N=122) were seen by CAT clinic clinicians between April 2020 - April 2022, including 63 (51%) in the first year. Patients had a median age of 63 years and 56.4% were female. Appointments occurred in nearly equal proportion via telehealth (50.8%) and in-office visits (49.2%) during these two years; however, 78% of visits were telehealth during the first year, and only 25.4% during the second. Forty-three (35.2%) referred for acute management were seen at a median time of two days, and the remainder for ongoing management were seen at a median time of 10 days. Referrals were predominantly for PE (25.4%), concurrent PE/DVT (23.0%), and proximal lower extremity DVT (18.9%); however, consults included thrombi of the cerebral, pulmonary, and splanchnic veins, as well as tumor thrombi, arterial thrombi, and need for primary prophylaxis. Tumor types were categorized into nine groups, with the largest proportion consisting of gastrointestinal (25.4%), gynecologic (17.2%), and hematologic (17.2%) malignancies (Figure 1). DOACs were recommended in 47.5%, and LMWHs in 41% (Figure 2), with a similar proportion of DOACs prescribed between year one (47.5%) and year two (47.6%). Primary reasons for choosing LMWHs over DOACs were perceived bleeding risk (40%), tumor type (22%), and prior DOAC failure (20%). Twelve (9.8%) patients were advised to stop anticoagulation, due to lack of indication for 11 (91.7%) and perceived bleeding risk for one (8.3%). Four were referred for inferior vena cava (IVC) filter retrieval. At the time of evaluation, 16 (13.1%) patients were noted to have platelet counts <150,000/µL, but none had platelet counts <50,000/µL. Within 6 months of initial evaluation, 11 (9.0%) patients developed progressive or recurrent VTE. Fourteen (11.5%) patients experienced bleeding: eight (57.1%) had major bleeding episodes as defined by the International Society on Thrombosis and Hemostasis, and six (42.9%) had clinically-relevant non-major bleeding. Among major bleeding events, six (75%) were gastrointestinal and two (25%) intraabdominal in origin, with no identified intracranial hemorrhages. Twenty (16.4%) died during the follow up period. Seventy-six (61.8%) patients were seen for a follow up visit after initial consultation. Conclusion: Building the CAT clinic led to improved access to classical hematologists with thrombosis expertise to manage CAT. Historical wait times for this specialty have exceeded 90 days, while those referred to the CAT clinic had a median time-to-appointment of only nine days. Highlighting the complexity of CAT management, more than 40% of patients were not treated with DOAC, primarily related to perceived bleeding risk. Four patients were identified for IVC filter removal, suggesting there may be additional benefits to non-malignant hematologists beyond anticoagulant management. Decisions regarding treatment of individual patients with CAT remain complex, and access to thrombosis specialists provides additional expertise to optimize care. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 11655: Direct Oral Anticoagulants Compared With Low Molecular Weight Heparin and Vitamin K Antagonists in the Management of Cancer-Associated Thrombosis: A Systematic Review and Network Meta-Analysis

Objective: Low molecular weight heparin (LMWH) has been established for the treatment of cancer-associated thromboembolism (CAT). Recent guidelines suggest Direct Oral Anti-Coagulants (DOACs) may have a role in the management of CAT, however these recommendations were conditional. This study aims to compare DOACs with LMWH and Vitamin K Antagonists (VKAs) in CAT. Methods: We conducted a meta-analysis of studies through a systematic search of four electronic databases (PubMed, Scopus, Web of Science, and Cochrane) published before January 25, 2022. Our criteria included studies in patients with all cancer types who received DOACs, VKAs, or LMWH for prevention or treatment of CAT. We analyzed outcomes including recurrent venous thromboembolism, major bleeding, clinically relevant non-major bleeding (CRNMB), and all-cause mortality. The quality assessment of the included RCTs was conducted through Cochrane Tool, while the quality of the included cohort studies was assessed by the NIH tool. The network meta-analysis was performed using the netmeta package in R software. Results: A total of 55 studies were included; 18 RCTs, and 37 cohort studies. DOACs (RR= 0.72, 95% CI [0.63; 0.83]) and LMWH (RR= 0.78, 95% CI [0.64; 0.94]) had a significantly lower risk of major bleeding than VKAs. There was also a significantly decreased risk of clinically relevant non-major bleeding (CRNMB) with LMWH than DOACs (RR= 0.63, 95% CI [0.55; 0.73]) and DOACs compared to VKA (RR= 0.83, 95% CI [0.72; 0.95]). With regards to recurrent venous thromboembolism risk (VTE), DOACs showed a significantly lower risk compared with either LMWH (RR=0.70, 95% CI [0.59; 0.83]) or VKA (RR=0.66, 95% CI [0.54; 0.80]). Conclusion: We conclude that DOACs are more effective in the management of CAT when compared to LMWH and VKA. DOACs and LMWH have significantly lower risk of major bleeding when compared to VKA. More research is needed to determine the best anticoagulation strategy for distinct types of cancers.

Abstract 13427: Bleeding in Morbidly Obese Patients Treated With Direct Oral Anticoagulants Compared to Warfarin: The Michigan Anticoagulation Quality Improvement Initiative Experience

Introduction: Direct Oral Anticoagulants (DOACs) have overtaken warfarin in the treatment of non-valvular Atrial Fibrillation (AF) and venous thromboembolism (VTE). However, there is very limited data that explores the safety of DOACs for patients that are morbidly obese (BMI &gt;40). Methods: In this multi-center retrospective study, we sought to use the Michigan Anticoagulation Quality Improvement registry (MAQI) to see how treatment of non-valvular AF or VTE with DOAC vs. warfarin affects bleeding in morbidly obese patients. Specifically, we compared average major, clinically relevant non-major (CRNM), and minor bleeding events per 100 patient years that were adjusted for statistically significant baseline characteristics (p&lt;0.05). Results: There were a total of 1028 patients with BMI &gt;40 included in the registry between June 2015 and September 2019. 434 patients were treated with DOACs, while 594 patients were treated with warfarin. Baseline characteristics between the two groups included age (61.5 vs 57.8, p&lt;0.001), gender (63.6% vs 61.1% female, p=0.42), race (76.5% vs 64.3% white, p&lt;0.001), and HAS-BLED score (2.3 vs 2.3, p=0.96). The DOAC treated group had a higher event rate of major (4.3 vs 3.7, p=0.006), CRNM (10.7 vs. 7.4, p=0.002), and minor bleeding (19.1 vs. 13.2 p&lt;0.001) compared to the warfarin treated group. Conclusions: There is a higher rate of major, CRNM, and minor bleeding in morbidly obese patients treated with DOAC compared to warfarin. Further studies to compare the two anticoagulants and understand bleeding drivers in this population are needed.

Abstract 14063: Eight Pharmacokinetic-Related Genetic Variants Were Not Associated With Bleeding From Direct Oral Anticoagulants in Non-Valvular Atrial Fibrillation Patients

Background. Atrial fibrillation (AF) is the leading cause of ischemic stroke and treatment has focused on reducing stroke risk through anticoagulation. Direct Oral Anticoagulants (DOACs) are the first-line guideline-recommended therapy in non-valvular AF since they are as effective and safer than warfarin. Although patients bleed less overall from DOACs, bleeding still is the main safety concern with this therapy. Previous studies have shown that genetic variants modify the function of metabolic enzymes or transporters involved in the pharmacokinetics (PK) of DOACs, which then affect DOAC plasma concentrations. However, whether those functional PK genetic variants are significantly associated with the risk of bleeding on DOACs is unknown. Aim. Assess the association of PK-related single nucleotide variants (SNVs) with the risk of bleeding from DOACs in non-valvular AF patients. Methods. 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. 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 (Table 1). Conclusion. SNVs that affect the function of PK genes were not significantly associated with major and CRNM bleeding from rivaroxaban or apixaban in 2,364 AF patients.

Outcomes in patients undergoing periprocedural interruption of warfarin or direct oral anticoagulants

BackgroundDifferences in clinical outcomes following a temporary interruption of warfarin or a direct oral anticoagulant (DOAC) for a surgical procedure are not well described. Differences in patient characteristics from practice‐based cohorts have not typically been accounted for in prior analyses. AimTo describe risk‐adjusted differences in postoperative outcomes following an interruption of warfarin vs DOACs. MethodsPatients receiving care at six anticoagulation clinics participating in the Michigan Anticoagulation Quality Improvement Initiative were included if they had at least one oral anticoagulant interruption for a procedure. Inverse probability of treatment weighting (IPTW) was used to balance baseline differences between the warfarin cohort and DOAC cohort. Bleeding and thromboembolic events within 30 days following the procedure were compared between the IPTW cohorts using the Poisson distribution test. ResultsA total of 525 DOAC patients were matched with 1323 warfarin patients, of which 923 were nonbridged warfarin patients and 400 were bridged warfarin patients. The occurrence of postoperative minor bleeding (10.8% vs. 4.7%, p < .001), major bleeding (2.9% vs. 1.1%, p = .01) and clinically relevant nonmajor bleeding (CRNMB) (6.5% vs. 3.0%, p = .002) was greater in the DOAC cohort compared with the nonbridged warfarin cohort. The rates of postoperative bleeding outcomes were similar between the DOAC and the bridged warfarin cohorts. ConclusionPerioperative interruption of DOACs, compared with warfarin without bridging, is associated with a higher incidence of 30‐day minor bleeds, major bleeds, and CRNMBs. Further research investigating the perioperative outcomes of these two classes of anticoagulants is warranted.

Safety and Efficacy of Rivaroxaban as Extended-Phase Anticoagulation in Patients with Cancer and Venous Thromboembolism: A Preliminary Data Analysis from the Mac Project.

Extended-phase anticoagulation with direct oral Xa inhibitors (OAXI) is suggested in patients with cancer-associated venous thromboembolism (CAT). We report on patients enrolled in the MAC (Monitoring AntiCoagulants) Project, given rivaroxaban as extended-phase anticoagulation after CAT. The primary efficacy outcome was the incidence of symptomatic recurrent VTE; the primary safety outcomes were incidence of major and non-major clinically relevant bleeding, adverse events, and all-cause mortality. The mean patients' follow-up was 19 months (SD 16); 64/604 (11%) had CAT. Recurrent VTE occurred in 9.3% and in 8.1% of patients with and without CAT (OR 1.2, 95% CI 0.5 to 2.9; p = 0.6). Major bleeding occurred in 4.7% and in 2.6%, respectively (OR = 1.8, 95% CI 0.5 to 6.6, p = 0.4), and non-major clinically-relevant bleeding in 4.7% and in 4.1% (OR = 1.2, 95% CI 0.3 to 3.9, p = 0.7). The relative figures for fatal haemorrhage and all-cause death were 1.6% versus 0%, and 1.6% versus 0.4%. Rivaroxaban appears to be effective and safe as extended-phase anticoagulation in patients with CAT. The mean treatment period was 3-times the standard 6-month course.

Bleeding and ischaemic events after first bleed in anticoagulated atrial fibrillation patients: risk and timing.

To determine the risk of subsequent adverse clinical outcomes in anticoagulated patients with atrial fibrillation (AF) who experienced a new bleeding event. Anticoagulated AF patients were followed in two prospective cohort studies. Information on incident bleeding was systematically collected during yearly follow-up visits and events were adjudicated as major bleeding or clinically relevant non-major bleeding (CRNMB) according to the International Society on Thrombosis and Haemostasis guidelines. The primary outcome was a composite of stroke, myocardial infarction (MI), or all-cause death. Time-updated multivariable Cox proportional-hazards models were used to compare outcomes in patients with and without incident bleeding. Median follow-up was 4.08 years [interquartile range (IQR): 2.93-5.98]. Of the 3277 patients included (mean age 72 years, 28.5% women), 646 (19.7%) developed a new bleeding, 297 (9.1%) a major bleeding and 418 (12.8%) a CRNMB. The incidence of the primary outcome was 7.08 and 4.04 per 100 patient-years in patients with and without any bleeding [adjusted hazard ratio (aHR): 1.36, 95% confidence interval (CI): 1.16-1.61; P < 0.001; median time between a new bleeding and a primary outcome 306 days (IQR: 23-832)]. Recurrent bleeding occurred in 126 patients [incidence, 8.65 per 100 patient-years (95% CI: 7.26-10.30)]. In patients with and without a major bleeding, the incidence of the primary outcome was 11.00 and 4.06 per 100 patient-years [aHR: 2.04, 95% CI: 1.69-2.46; P < 0.001; median time to a primary outcome 142 days (IQR: 9-518)], and 59 had recurrent bleeding [11.61 per 100 patient-years (95% CI: 8.99-14.98)]. The incidence of the primary outcome was 5.29 and 4.55 in patients with and without CRNMB [aHR: 0.94, 95% CI: 0.76-1.15; P = 0.53; median time to a composite outcome 505 days (IQR: 153-1079)], and 87 had recurrent bleeding [8.43 per 100 patient-years (95% CI: 6.83-10.40)]. Patients who had their oral anticoagulation (OAC) discontinued after their first bleeding episode had a higher incidence of the primary composite than those who continued OAC (63/89 vs. 159/557 patients; aHR: 4.46, 95% CI: 3.16-6.31; P < 0.001). In anticoagulated AF patients, major bleeding but not CRNMB was associated with a high risk of adverse outcomes, part of which may be explained by OAC discontinuation. Most events occurred late after the bleeding episode, emphasizing the importance of long-term follow-up in these patients.

Incidental pulmonary embolism in cancer and noncancer patients: Prospective cohort study.

Clinical picture and outcome of incidental pulmonary embolism (iPE) compared to symptomatic pulmonary embolism (sPE) remain unclear. Demographics, recurrent venous thromboembolism (VTE), mortality, major bleeding, and clinically relevant nonmajor bleeding (CRNMB) were compared between iPE and sPE patients who were followed prospectively at Mayo Thrombophilia Clinic (March 1, 2013 to August 1, 2020). Out of 3576 VTE patients, 1417 (39.6%) had PE: 562 (39.7%) iPE and 855 sPE. Patients with cancer were more likely to have iPE (400 iPE vs. 314 sPE) compared to those without cancer (162 iPE vs. 541 sPE). VTE recurrence rate (all per 100 person-years) was similar in all iPE and sPE patients (3.34 vs. 3.68, p=.50), with cancer (4.16 vs. 4.89, p=.370), and without cancer patients (0.89 vs. 2.80, p=.25). Higher mortality observed in all patients with iPE compared to sPE (46.45 vs. 23.47, p < .001) and with cancer (56.41 vs. 45.77, p=.03) became not significant after adjustment for age, antiplatelet therapy, metastases, and cancer location. Noncancer iPE patients had higher mortality (15.95 vs. 7.18, p=.006) even after adjustment (p=.05). The major bleeding rate was also higher in all patients iPE compared to sPE (7.10 vs. 3.68, p=.03), but not after adjustment (p=.974); higher major bleeding rate in noncancer patients (6.49 vs. 1.25, p=.007) remained significant after adjustment (.02). CRNMB rate was similar to iPE and sPE patients. iPE represents a more serious clinical condition compared to sPE as indicated by the higher mortality and major bleeding but these differences reflect underlying comorbidities rather than the seriousness of the embolic event.

Oral anticoagulation therapy in atrial fibrillation patients with advanced chronic kidney disease: CODE-AF Registry

Abstract Background and objectives 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 OAC among AF patients with advanced CKD or ESRD on dialysis. Methods 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 [eGFR] &amp;lt;3 0ml/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 group, 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. Results 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] 0.21, 95% confidence interval [CI] 0.05 to 0.95, p=0.042). In addition, the risk of composite adverse clinical outcome (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 0.32, 95% CI 0.11 to 0.96, p=0.043). Conclusion 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 outcome compared to no OAC. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Korean Healthcare Technology R&amp;D project funded by the Ministry of Health &amp; Welfare (HI15C1200, HC19C0130)

Frailty and outcomes in octogenarians with atrial fibrillation treated with edoxaban: ESCAPE study

Abstract Background Frailty is associated with significant morbidity and mortality among elderly adults. Whether frailty predicts adverse outcomes in patients treated with oral anticoagulants for stroke prevention in atrial fibrillation remains uncertain. Purpose To examine the impact of frailty in clinical outcomes in elderly patients with non-valvular atrial fibrillation treated with edoxaban. Methods This is an observational prospective single centre cohort study enrolling consecutive naïve to anticoagulation patients of age ≥80 years starting oral anticoagulation with edoxaban for stroke prevention in non-valvular atrial fibrillation and followed up for 2 years. At baseline, all patients were evaluated for frailty, comorbidities, medications, and stroke and bleeding risk factors. Frailty was assessed using the Survey of Health Ageing and Retirement in Europe Frailty Index (SHARE-FI) tool, a validated frailty measure centred on health resource utilisation, with the cohort stratified into non-frail, pre-frail and frail. The clinical outcomes were the cumulative incidence of stroke/systemic embolism, major bleeding, and clinically relevant non-major bleeding (CRNMB), and individual components part of the composite outcome. Results Among 160 patients who received edoxaban for stroke prevention in atrial fibrillation, 34% were frail, 20% pre-frail, 46% non-frail. The mean age of the cohort was 85±4 years and 58% were female. The mean CHA2DS2VASc score was 4±1. Mean Cockroft-Gault creatinine clearance (CrCl) was 52±17 mL/min, and edoxaban 30mg was administered to 59% of patients as per indications (weight ≤60 kg and/or, CrCl 15–50 ml/min). The follow up extended for 681±289 days. Primary endpoint occurred in 46 patients (28.7%; annualised rate 15.4%patient-years): 19 events occurred in non-frail, 9 in pre-frail, and 18 in frail patients (p=0.6). Stroke/systemic embolism occurred in 2.2%, major bleeding in 5.0%, and CRNM bleeding in 10.0% of patients. Frailty was not a predictor of the events part of the composite outcome (non-frail 5.4% vs pre-frail 0% vs frail 1.9%, p=0.27; non-frail 5.4% vs pre-frail 9.4% vs frail 1.9%, p=0.29; and non-frail 13.5% vs pre-frail 3.1% vs frail 9.3%, p=0.25; for stroke/systemic embolism, major bleeding, and CRNMB, respectively). Cumulative rate of events (Figure) did not differ in frail versus the rest (non-frail and pre-frail) of patients (p=0.521). Conclusions Frailty status was not a predictor of events among the elderly with atrial fibrillation treated with edoxaban. Anticoagulation with edoxaban is feasible in octogenarians even if frail. Funding Acknowledgement Type of funding sources: None.

D-dimer-driven versus standard prophylactic anticoagulation with fondaparinux in critically ill patients with COVID-19 and coagulopathy: an open-label, randomized controlled trial

Abstract Background Anticoagulation with fondaparinux (FPX) has shown benefit to improve clinical outcomes in hospitalized patients with COVID-19. However, optimal thromboprophylaxis dosing in critically ill patients remains unknown. Purpose To evaluate the effects of D-dimer-driven (DDD) FPX compared with standard prophylactic-dose (SPD) FPX in critically ill patients with COVID-19 and associated coagulopathy. Methods This was a single-center, open-label, two-arms, parallel-group, randomized controlled trial conducted between April 1, 2021 and Feb 28, 2022. The eligible COVID-19 patients who were critically ill (defined as a presence of critical care-level organ support at enrollment) and presented with coagulopathy were randomly assigned (1:1 ratio) to receive pragmatically defined regimens of either DDD FPX or SPD FPX throughout hospitalization. The primary efficacy outcome was a composite of all-cause mortality (ACM), acute myocardial infarction (MI), confirmed arterial (ATE) or venous thromboembolisms (VTE), assessed up to 30 days. The secondary efficacy outcomes were 30-day ACM, composite thrombotic events, progression to invasive mechanical ventilation (IMV) or ARDS, and acute kidney injury (AKI). The safety outcomes included major bleeding and clinically relevant non-major bleeding (CRNMB). Outcomes were blindly adjudicated and analysed on a 30-day intention-to-treat basis. Results During allocated period, 270 (58%) of 465 patients were eligible and were equally assigned to DDD and SPD groups. The baseline characteristics were well-matched between groups (all p&amp;gt;0.05). At 30 days, the primary efficacy outcome was met in 49 of 135 patients (36.3%) with DDD FPX versus 47 of 135 patients (34.8%) with SPD FPX (hazard ratio [HR], 1.32; 95% CI, 0.89–1.98; p=0.17). DDD group compared with SPD group revealed no significant difference in 30-day ACM (22.9% vs 31.8%; HR, 0.73; p=0.17). At 30 days, DDD group demonstrated no significant reduction in thromboembolism, i.e. acute MI (14.1% vs 11.8%; HR, 1.53; p=0.21); ATE (3.0% vs 3.0%; HR, 1.27; p=0.74); and VTE (2.2% vs 4.4%; HR, 0.69; p=0.59) when compared with SPD group. Among those not on IMV at randomization, DDD group showed no significant reduction in the proportion of patients meeting the need for IMV (18.5% vs 32.6%; HR, 0.72; p=0.18) or progression to ARDS (17.8% vs 27.4%; HR, 0.81; p=0.43). Allocation to DDD FPX had no significant effect on the proportion of patients experiencing AKI within 30 days (17.8% vs 14.8%; HR, 1.36; p=0.39). There was no significant difference between DDD and SPD groups in terms of major bleeding (2.2% vs 0%; HR, 8.35; p=0.35) or CRNMB (3.0% vs 2.2%; HR, 1.70; p=0.48) at 30 days. Conclusions In critically ill patients with COVID-19 and coagulopathy, D-dimer-driven anticoagulation with fondaparinux did not significantly improve clinical outcomes at 30 days as compared to standard prophylactic-dose. The risk of bleeding was not significantly increased in this trial. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Syarifah Ambami Rato Ebu Generał Hospital, Bangkalan, East Java, Indonesia

ABCL-104 Direct Oral Anticoagulants for the Treatment of Venous Thromboembolism in Patients With Hematological Malignancies

Data is needed on direct oral anticoagulants (DOACs) for the treatment of venous thromboembolism (VTE) in hematological malignancies (HM). Retrospective studies to date have lacked a control group and included patients with atrial fibrillation and/or VTE, but not VTE alone. Assess the incidence of VTE recurrence and bleeding in HM patients treated with low molecular weight heparin (LMWH) or DOACs for acute VTE. Retrospective cohort study. The study included subjects with active HM and newly diagnosed VTE treated as inpatients or outpatients in the hemato-oncology department at Rabin or Meir Medical Centers (1/2015-7/2021). Patients were indexed on the first day of anticoagulation for VTE and followed for 12 months. Type of anticoagulation at study index, classified as LMWH or DOAC. Composite of recurrent VTE, clot progression, major bleeding, or clinically relevant non-major bleeding (CRNMB). Cumulative incidence (95% confidence interval [CI]) was calculated for each anticoagulation group (LMWH, DOAC) and hazard ratios (HRs) were calculated using the Cox proportional-hazards model with death as a competing risk. A total of 143 HM patients treated with LMWH (96) or DOACs (47) for acute VTE were included. HM was lymphoma in 83 (58%). DOAC-treated patients were older and had more pulmonary embolisms and less splanchnic vein thrombosis. The 12-month cumulative incidence of the primary outcome was 24.2% (95% CI 15.9%-33.5%; n=22) in the LMWH group and 18.5% (8.5%-31.5%; n=8) in the DOAC group (HR 1.51 [0.695-3.297]). Two recurrent VTEs occurred (both in the DOAC group while off-treatment). Nine (9.4%) LMWH-treated patients and 1 (2.1%) DOAC-treated patient (HR 4.85 [0.64-36.56]) had major bleeding. There were 13 (13.5%) CRNMB cases in the LMWH group and 5 (10.6%) in the DOAC group (HR 1.44 [0.52-3.98]). This study generates the hypothesis that DOACs may be a safe and effective alternative to LMWH for VTE in patients with lymphoma or plasma cell dyscrasia. Larger prospective studies are needed to confirm these findings.

Superiority of Direct Oral Anticoagulants over Vitamin K Antagonists in Oncological Patients with Atrial Fibrillation: Analysis of Efficacy and Safety Outcomes.

Background and aim. Cancer and atrial fibrillation (AF) may be associated, and anticoagulation, either with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs), is necessary to prevent thromboembolic events by reducing the risk of bleeding. The log incidence rate ratio (IRR) and 95% confidence interval were used as index statistics. Higgin’s I2 test was adopted to assess statistical inconsistencies by considering interstudy variations, defined by values ranging from 0 to 100%. I2 values of less than 40% are associated with very low heterogeneity among the studies; values between 40% and 75% indicate moderate heterogeneity, and those greater than 75% suggest severe heterogeneity. The aim of this meta-analysis was to compare the safety and efficacy of VKAs and DOACs in oncologic patients with AF. Methods. A meta-analysis was conducted comparing VKAs to DOACs in terms of thromboembolic events and bleeding. A meta-regression was conducted to investigate the differences in efficacy and safety between four different DOACs. Moreover, a sub-analysis on active-cancer-only patients was conducted. Results. A total of eight papers were included. The log incidence rate ratio (IRR) for thromboembolic events between the two groups was −0.69 (p < 0.005). The meta-regression did not reveal significant differences between the types of DOACs (p > 0.9). The Log IRR was −0.38 (p = 0.008) for ischemic stroke, −0.43 (p = 0.02) for myocardial infarction, −0.39 (p = 0.45) for arterial embolism, and −1.04 (p = 0.003) for venous thromboembolism. The log IRR for bleeding events was −0.43 (p < 0.005), and the meta-regression revealed no statistical difference (p = 0.7). The log IRR of hemorrhagic stroke, major bleeding, and clinically relevant non-major bleeding between the VKA and DOAC groups was −0.51 (p < 0.0001), −0.45 (p = 0.03), and 0.0045 (p = 0.97), respectively. Similar results were found in active-cancer patients for all the endpoints except for clinically-relevant non-major bleedings. Conclusions. DOACs showed better efficacy and safety outcomes than VKAs. No difference was found between types of DOACs.