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Up to 10% of the >3 million Americans with atrial fibrillation will experience an acute coronary syndrome or undergo percutaneous coronary intervention. Therefore, concurrent indications for multiple antithrombotic agents is a common clinical scenario. Although each helps reduce thrombotic risk, their combined use significantly increases the risk of major bleeding events, which can be life threatening. In the past 5 years, a number of randomized clinical trials have explored different combinations of anticoagulation plus antiplatelet agents aimed at minimizing bleeding risk while preserving low thrombotic event rates. In general, shorter courses with fewer antithrombotic agents have been found to be effective, particularly when direct oral anticoagulants are combined with clopidogrel. Combined use of very low-dose rivaroxaban plus aspirin has also demonstrated benefit in atherosclerotic diseases, including coronary and peripheral artery disease. Use of proton pump inhibitor therapy while patients are taking multiple antithrombotic agents has the potential to further reduce upper gastrointestinal bleeding risk in select populations. Applying this evidence to patients with multiple thrombotic conditions will help to avoid costly and life-threatening adverse medication events.

Up to two-thirds of menstruating women experience abnormal uterine bleeding (AUB) when treated with oral anticoagulants. However, the true prevalence of AUB for specific agents remains uncertain, as many of these episodes, while interfering significantly with quality of life and overall health, are not captured by definitions of major bleeding (MB) or clinically relevant nonmajor bleeding (CRNMB) used in clinical trials. A 2017 systematic review determined that women taking rivaroxaban, but not edoxaban or apixaban, had a twofold higher risk of AUB than women taking warfarin. Since then, new data have become available from extension trials, cancer-associated venous thromboembolism trials, pediatric trials, and a few observational studies specifically examining AUB as an outcome. Reported rates of uterine CRNMB were low (around 1%) and similar for rivaroxaban and apixaban in all these studies, and no episodes of uterine bleeding meeting MB criteria were reported. Rates of AUB not meeting MB or CRNMB criteria were much higher, affecting up to 50% of women on rivaroxaban. Only 1 such study included women on apixaban, and no AUB was reported. In pediatric trials, 19% of girls experienced menorrhagia when treated with rivaroxaban. In conclusion, rates of uterine MB and CRNMB were low in all studies, but rates of other types of AUB not meeting these criteria ranged from 15.8% to 50%. We conclude that AUB is underreported due to the limitations of MB/CRNMB criteria despite its substantial impact on quality of life. We urge future investigators to include broader definitions of AUB to better capture the impact of this outcome in menstruating women treated with oral anticoagulants.

Heparin-induced thrombocytopenia (HIT) is a life-threatening complication associated with high medical costs. Factor Xa inhibitors gradually replace approved treatment with intravenous direct thrombin inhibitors despite their off-label indication, because of easier management and favorable economic profile. Whether they are cost-effective remains unclear. We evaluated the cost-effectiveness of approved and off-label anticoagulants in patients with suspected HIT, based on census data from the largest Swiss hospital between 2015 and 2018. We constructed a decision tree model that reflects important clinical events associated with HIT. Relevant cost data were obtained from the finance department or estimated based on the Swiss-wide cost tariff. We estimated averted adverse events (AEs) and incremental cost-effectiveness ratio as primary outcome parameters. We performed deterministic and probabilistic sensitivity analyses with 2000 simulations to assess the robustness of our results. In the base-case analysis, the total cost of averting 1 AE was 49 565 Swiss francs (CHF) for argatroban, 30 380 CHF for fondaparinux, and 30 610 CHF for rivaroxaban; after adjusting for 4Ts score: 41 152 CHF (argatroban), 27 710 CHF (fondaparinux), and 37 699 CHF (rivaroxaban). Fondaparinux and rivaroxaban were more clinically effective than argatroban, with AEs averted of 0.820, 0.834, and 0.917 for argatroban, fondaparinux, and rivaroxaban, respectively. Treatment with fondaparinux resulted in less cost and more AEs averted, hence dominating argatroban. Results were most sensitive to AE rates and prolongation of stay. Monte Carlo simulations affirmed our base-case analysis. This is the first cost-effectiveness analysis comparing argatroban with fondaparinux and rivaroxaban using primary data. Fondaparinux and rivaroxaban resulted in more averted AEs, but fondaparinux had greater cost savings. Fondaparinux could be a viable alternative to argatroban.

A 77-year-old man with atrial fibrillation and a CHA2DS2Vasc score of 6 for hypertension, age, diabetes, and previous stroke is brought to the emergency department with decreased level of consciousness. He is anticoagulated with rivaroxaban (a direct oral factor Xa inhibitor [FXaI]) and received his last dose about 4 hours before presentation. Urgent computed tomography of the head shows intracerebral hemorrhage. Because of his previous stroke, the patient’s family is concerned about treating the bleed with pharmacological agents that may increase the risk of stroke. What are the risks of thrombosis and mortality related to the use of prothrombin complex concentrates (PCCs) and andexanet alfa for patients with direct oral FXaI-associated major bleeding?

The direct oral anticoagulants (DOACs) have transformed the management of thrombotic disorders. Large clinical trials have demonstrated that DOACs can replace vitamin K antagonists (VKAs) in the 2 existing major indications for anticoagulation: the prevention of stroke in atrial fibrillation and the acute treatment and secondary prevention of venous thromboembolism (VTE); this literature is widely known. In this article, we will concentrate on the less well-discussed benefits of the use of DOACs—using low doses as primary and secondary prophylaxis in both venous and arterial thromboprophylaxis. The attractiveness of using a low-dose DOAC is that the bleeding risk seems to be slightly lower than with the standard dose and significantly lower than with VKAs so that they can be used safely for long periods, where previously, VKAs had risk/benefit ratios that did not permit this. We discuss in detail the extended use of low-dose DOACs in secondary VTE prevention. We also cover the utility of low-dose DOACs in the evolving fields of prevention of hospital-associated VTE in acutely ill medical patients, after total hip and knee replacement, and in cancer patients. To complete the indications, we briefly discuss the role of low-dose DOACs in the secondary prevention of arterial vascular events.

Both apixaban and rivaroxaban have been approved for use in acute venous thromboembolism (VTE). Although indirect comparison through network meta-analyses of randomized trials have been performed to compare the efficacy and safety of these agents, further comparison between these agents was lacking until recently. We sought to systematically review and carry out a meta-analysis of studies to further compare apixaban with rivaroxaban from multiple studies done in the real-world settings. Studies comparing rivaroxaban with apixaban in patients with acute VTE were identified through electronic literature searches of MEDLINE, EMBASE, Scopus, and the Cochrane library up to May 2019. Study-specific risk ratios (RRs) were calculated and combined using a random-effects model meta-analysis. In an analysis involving 24 041 patients, recurrent VTE within 6 months occurred in 56 of 4897 patients (1.14%) in the apixaban group and 258 of 19 144 patients (1.35%) in the rivaroxaban group (RR, 0.89; 95% confidence interval [CI], 0.67-1.19; P = .45). Clinically relevant major bleeding occurred in 85 of 11 559 patients (0.74%) in the apixaban group and 350 of 33 909 patients (1.03%) in the rivaroxaban group (RR, 0.73; 95% CI, 0.58-0.93; P = .01). Clinically relevant nonmajor bleeding occurred in 169 of 3417 patients (4.95%) in the apixaban group and 1094 of 12 475 patients (8.77%) in the rivaroxaban group (RR, 0.59; 95% CI, 0.50-0.70; P < .01). Apixaban shows equivalent efficacy in prevention of recurrent VTE but decreased risk of major and minor bleeding events compared with rivaroxaban.

Heavy menstrual bleeding (HMB) is a common complication of anticoagulation, affecting ∼70% of menstruating women receiving oral anticoagulants. The risk of HMB is lower with apixaban and/or dabigatran than with rivaroxaban. HMB can result in iron deficiency with or without anemia, increased need for medical interventions, decreased quality of life, and missed school/work. Mainstays of treatment include hormone therapies such as the levonorgestrel intrauterine system, subdermal implant, and other progesterone-based therapies, which can result in decreased blood loss and, in some cases, amenorrhea. Combined hormone therapies can be used while patients continue receiving anticoagulation and are also highly effective for decreasing menstrual blood loss. Rarely, procedure-based interventions such as endometrial ablation may be required. Patients should be evaluated for iron deficiency and anemia and offered supportive therapies as needed. Abbreviating the course of anticoagulation or skipping doses can increase the risk of recurrent venous thromboembolism by as much as fivefold, but switching oral anticoagulants may be considered. Awareness of HMB and careful history taking at each visit are crucial to avoid a missed diagnosis.

Guidelines provide differing recommendations regarding direct-acting oral anticoagulants vs low-molecular-weight heparin (LMWH) for treatment of cancer-associated thrombosis (CAT). This study was undertaken to evaluate the effectiveness and safety of rivaroxaban vs LMWH for treatment of CAT. Using US Surveillance, Epidemiology and End Results-Medicare–linked data from 2013 through 2016, we evaluated adults with active breast, lung, ovarian, or pancreatic cancer, who were admitted to the hospital or treated in the emergency department for CAT and were prescribed rivaroxaban or LMWH for outpatient anticoagulation. Patients with luminal gastrointestinal or genitourinary cancers were excluded. Rivaroxaban and LMWH users were 1:1 propensity score matched. Outcomes included the composite of recurrent thrombosis or major bleeding, each outcome separately, and mortality at 6 months, using an intent-to-treat approach. On-treatment analysis after 12 months was also performed. Proportional hazards models for the subdistribution of competing risk were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). We included 529 rivaroxaban- and 529 LMWH-treated patients with CAT. Rivaroxaban was not associated with differences in risk of the composite outcome (HR, 0.71; 95% CI, 0.41-1.22), major bleeding (HR, 1.01; 95% CI, 0.50-2.01), or mortality (HR, 0.87; 95% CI, 0.70-1.07) vs LMWH, but it reduced recurrent thrombosis (HR, 0.37; 95% CI, 0.15-0.95). On-treatment analysis at 12 months showed similar results. Rivaroxaban may be a reasonable alternative to LMWH for patients with CAT without gastrointestinal or genitourinary cancer.

The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) study prospectively evaluated a prespecified periprocedural-interruption strategy of direct oral anticoagulants (DOACs) among patients with atrial fibrillation. Logistic regression analyses were performed to identify clinical parameters associated with residual DOAC levels ≥30 ng/mL or ≥50 ng/mL. Patients undergoing low-bleed-risk procedures were more likely to have residual levels of ≥30 ng/mL and ≥50 ng/mL. For low-risk procedures, age ≥75 years, female sex, a creatinine clearance (CrCl)

As with any anticoagulant, factor Xa (FXa) inhibitors are associated with a risk of major bleeding. Andexanet alfa is a recombinant modified human FXa lacking enzymatic activity, developed for reversal of FXa inhibitor–induced anticoagulation. In two phase 2, randomized, double-blind, placebo-controlled, single-center studies, different regimens of andexanet alfa were administered to healthy volunteers after therapeutic anticoagulation with rivaroxaban or edoxaban, and multiple anticoagulation reversal and safety end points were evaluated. Andexanet alfa rapidly and effectively reversed anticoagulation with both rivaroxaban and edoxaban. Within 2 minutes after bolus, anti-FXa activity decreased significantly, with maximum decreases of ≈93% (P < .05) and ≈82% (P < .05), respectively, compared with placebo. The stoichiometric ratios of andexanet alfa:total anticoagulant at maximum reversal of anti-FXa activity ranged from 1:1 to 1.3:1 for rivaroxaban and 1.41:1 to 2.58:1 for edoxaban. Sustained normalization of thrombin generation for ≈2 hours and sustained decrease in unbound anticoagulant (maximum ≈80%) for up to ≈4 hours following completion of andexanet alfa administration, compared with placebo, were observed when andexanet was administered as a bolus or as a bolus followed by continuous infusion. Andexanet alfa was well tolerated, and there were no serious adverse events or thrombotic events. Andexanet alfa has been approved in the United States and Europe for reversal of anticoagulation in patients treated with rivaroxaban or apixaban who experience life-threatening or uncontrolled bleeding. These studies were registered with clinicaltrials.gov (#NCT03578146 and #NCT03551743).

Guidelines suggest using empiric low-molecular-weight heparin if the diagnostic workup of deep vein thrombosis (DVT) is expected to be delayed. The role of direct oral anticoagulants for deferred compression ultrasound imaging (CUS) in patients with suspected DVT remains unexplored. The main objective of the study was to assess the safety of deferring CUS with therapeutic doses of rivaroxaban. We prospectively included consecutive outpatients referred to the Emergency Department at Østfold Hospital, Norway, with suspected first or recurrent lower-extremity DVT between February 2015 and November 2018. Patients were discharged with rivaroxaban 15 mg twice daily while awaiting CUS within 24 hours if D-dimer level was ≥0.5 mg/L fibrinogen-equivalent units. The primary outcome was the rate of major bleeding incidents from study inclusion until DVT was confirmed and anticoagulation therapy continued, or otherwise up to 48 hours following administration of the last tablet of rivaroxaban. The secondary outcome was the rate of progressive DVT symptoms or symptoms or signs of pulmonary embolism between hospital discharge until venous thromboembolism was diagnosed. Six hundred twenty-four of 1653 patients referred with suspected DVT were included (37.7%; 95% confidence interval [CI], 35.4-40.1). DVT was diagnosed in 119 patients (19.1%; 95% CI, 16.1-22.3). There were no major bleeding incidents, yielding an observed major bleeding rate of 0% (1-sided 95% CI

Venous thromboembolism (VTE) is a common complication in ambulatory cancer patients receiving chemotherapy. Current clinical guidelines recommend against the use of routine primary thromboprophylaxis in unselected ambulatory cancer patients. The Khorana score is a risk assessment tool derived and prospectively validated for the identification of cancer patients at high risk of thrombotic complications. Recently, 2 randomized, controlled trials have assessed the use of low-dose direct oral Xa inhibitors, apixaban and rivaroxaban, for the prevention of cancer-associated thrombosis in ambulatory patients at intermediate to high risk of VTE (Khorana score ≥2). Taken together, these trials have shown that low-dose direct oral Xa inhibitors reduce the risk of VTE in this patient population without a significant increase in major bleeding. These results should encourage clinicians to consider the use of primary thromboprophylaxis in ambulatory cancer patients at intermediate to high risk of VTE who do not have any apparent risk factors for bleeding. The direct oral Xa inhibitors have also been assessed in the acute management of cancer-associated thrombosis. Current evidence suggests that these drugs are a convenient, effective, and safe option for the management of acute VTE in many cancer patients. Low-molecular weight heparin, however, may continue to be the treatment of choice depending on the presence of bleeding risk factors, the type of cancer, drug-drug interactions, and patient preferences.

Randomized clinical trials comparing direct oral anticoagulants (DOACs) to warfarin in cancer patients have not been performed. We evaluated the effectiveness and associated risk of DOACs vs warfarin, as well as comparisons of DOACs, in a large population of cancer patients with nonvalvular atrial fibrillation (AF). Using the MarketScan databases, we identified 16 096 AF patients (mean age, 74 years) initiating oral anticoagulant and being actively treated for cancer between 2010 and 2014. Anticoagulant users were matched by age, sex, enrollment date, and drug initiation date. Study end points were identified with diagnostic codes and included ischemic stroke, severe bleeding, other bleeding, and venous thromboembolism (VTE). Cox regression was used to estimate associations of anticoagulants with study end points. Compared with warfarin, rates of bleeding (hazard ratio [95% confidence interval]) were similar in rivaroxaban (1.09 [0.79, 1.39]) and dabigatran (0.96 [0.72, 1.27]) users, whereas apixaban users experienced lower rates (0.37 [0.17, 0.79]). Rates of ischemic stroke did not differ among anticoagulant users. Compared with warfarin, rate of VTE (hazard ratio [95% confidence interval]) was lower among rivaroxaban (0.51 [0.41, 0.63]), dabigatran (0.28 [0.21, 0.38]), and apixaban (0.14 [0.07, 0.32]) users. In head-to-head comparisons among DOACs, dabigatran users had lower rates of VTE than rivaroxaban users; apixaban users had lower rates of VTE and severe bleeding than rivaroxaban users. In this population of patients with AF and cancer, DOAC users experienced lower or similar rates of bleeding and stroke compared with warfarin users, and a lower rate of incident VTE.

Key Points Rivaroxaban was efficacious and safe in a child with protein C deficiency to prevent the recurrence of skin necrosis or venous thrombosis. The dosage of direct oral anticoagulants in children with thrombophilia is unclear; a thrombin generation assay may be useful to adjust it.

Introduction: Anticoagulation plays a crucial role in the treatment of splanchnic vein thrombosis (SVT), including thrombosis of the portal (PVT), mesenteric (MVT) and splenic (SpVT) veins. Rivaroxaban is a potential alternative to heparins and vitamin K antagonists (VKA) in these patients, but data to support its use are scant. Several recent guidelines highlighted the limited evidence available for the use of the direct oral anticoagulants in these patients. In addition, despite anticoagulation, SVT patients carry high risk of recurrent venous thromboembolic events. The aim of this study was to evaluate the safety and efficacy of rivaroxaban for the acute-phase treatment of SVT (first 3 months of treatment). Methods: RIVASVT-100 (NCT02627053) was a prospective cohort study of adult patients with a first episode of symptomatic, objectively diagnosed PVT, MVT or SpVT. Exclusion criteria were known liver cirrhosis, Budd-Chiari syndrome, previous or ongoing variceal bleeding, portal cavernoma, thrombocytopenia, severe renal failure, life expectancy 7 days, ongoing VKA treatment. Patients received rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily for a total of 3 months. Afterwards, the decision to continue any available anticoagulant drug was left to the discretion of the attending physicians. Follow-up was performed at 3 weeks, 2 months, 3 months and 6 months. Primary outcome was the occurrence of ISTH-defined major bleeding events during the 3 months of active treatment and up to 2 days after the end of study treatment. Secondary outcomes included death, clinically relevant non-major bleeding (CRNMB), recurrent SVT or symptomatic venous thromboembolism in other sites. We here report the results of the 3-month follow-up. Results: Between June 2015 and March 2021, 103 patients were enrolled from 18 participating centres. After excluding 3 patients who did not meet the criteria for eligibility, 100 patients were included in the analysis. Mean (SD) age was 54.4 (± 15.5) years; 64% were males. Overall, 74% of patients had PVT, 61% MVT and 48% SpVT; 53% of SVT occurred in multiple sites. The most common risk factors were abdominal inflammation/infection (26%), followed by solid cancer (9%), overt myeloproliferative neoplasms (9%) and oestrogen hormonal therapy (9%), while 43% of cases were unprovoked. The JAK2 V617F mutation was detected in 13 out of 50 tested patients (26%). Rivaroxaban was the sole anticoagulant agent used in 21% of patients, whereas the remaining received a combination of anticoagulants, which included low molecular weight heparin, unfractionated heparin or fondaparinux for a median of 5.0 days before transitioning to rivaroxaban. Three patients were lost to follow-up but known to be alive at the end of the study. At 3-month follow-up, 1 (1.0%) patient died due to a non-SVT related cause. Two patients (2.06%; 95% CI, 0.57-7.21) had major bleeding events (both gastrointestinal), while 3 patients (3.09%) had CRNMB. There were 2 recurrent SVT (2.06%) during rivaroxaban treatment, one of these occurred in a patient with metastatic solid cancer. The 6-month follow-up for the last enrolled patient is ongoing. Conclusions: Rivaroxaban appears to be safe and effective for the acute-phase treatment of SVT in non-cirrhotic patients. Disclosures Beyer-Westendorf: Bayer: Other: Personal fees; Daiichi Sankyo: Other: Personal fees; Pfizer: Other: Personal fees; Portola-Alexion: Other: Personal fees. Carrier: BMS: Honoraria, Research Funding; Leo Pharma: Honoraria, Research Funding; Bayer: Honoraria; Pfizer: Honoraria, Research Funding; Servier: Honoraria; Sanofi: Honoraria. Bertoletti: BMS: Honoraria, Other: Personal Fees; Pfizer: Honoraria, Other: Personal fees; Aspen: Other: Personal Fees; Bayer: Other: Personal Fees; Leo Pharma: Other: Personal Fee. Di Nisio: Bayer, Daiichi Sankyo, BMS-Pfizer, Leo Pharma, and Sanofi: Other: Personal fees. Ageno: Bayer: Research Funding; Bayer, Portola, Janssen, Aspen, Norgine, Sanofi.: Other: Advisory Board. OffLabel Disclosure: The use of rivaroxaban in splanchnic vein thrombosis is off label in most countries.

Introduction: CALLISTO, a comprehensive programme of research on cancer-associated thrombosis (CAT) , included 3 randomized trials of rivaroxaban versus low molecular weight heparin (LMWH) for the treatment of venous thrombosis in patients with solid and haematological cancers (SELECT-D, CASTA-DIVA and CONKO-11). A meta-analysis of these studies was conducted to improve the precision of current estimates of the efficacy and safety of rivaroxaban in this patient group and investigate how patient characteristics impact the treatment effects. Methods: The primary endpoint was the cumulative incidence of venous thromboembolism (VTE) recurrence at the end of the treatment period (≥3 months). Other endpoints included major bleeding (MB), a composite of MB or clinically relevant non-major bleeding (clinically relevant bleeding [CRB]) and deaths from any cause. All endpoints were assessed by 8 pre-defined subgroup analyses: age, gender, creatinine clearance, type of index VTE, index VTE localization, cancer localization, performance status and presence of metastases (Prospero submission 266227). Patient-level data were used in this analysis. The cumulative incidences of VTE recurrence, CRB were estimated using the Kalbfleisch and Prentice model, while the Kaplan-Meier model was used to estimate the incidence of death. Comparisons between rivaroxaban and LMWH for VTE recurrence, MB and CRB were assessed by sub-distribution hazard ratios (SubHR) and 95% confidence intervals (CI), whereas hazard ratios and 95% CIs were used for the all-cause death endpoint. The pooled treatment effect size of each study was estimated using fixed-effect and random-effects models. Results: When considering the prevention of VTE recurrence in the 3 randomized trials (N=804), an overall reduction of 48% was observed with rivaroxaban compared with LMWH (SubHR = 0.52, 95% CI 0.28─0.98). The estimation appeared to be homogeneous across subgroups of patients. In comparison with LMWH, rivaroxaban was associated with an increased risk of CRB (SubHR = 2.03, 95% CI 1.34─3.09), without significant difference in MB (SubHR = 1.24, 95% CI 0.60─2.57), and no difference was observed for death. Conclusions: This pooled analysis suggests that rivaroxaban may be an alternative treatment option for the prevention of VTE recurrence in cancer patients with VTE. The gain in statistical power has shown significant benefit, as well as some risk associated with rivaroxaban treatment in this complex patient population. The impact of patient characteristics on these treatment effects will be presented at the meeting. Disclosures Laporte: Bayer Healthcare: Other: personal fees and non-financial support; Pfizer: Other: non-financial support; LEO Pharma: Other: non-financial support. Marshall: Bayer: Research Funding. Young: BMS/Pfizer Alliance: Honoraria; Leo Pharma: Honoraria; Chugai: Honoraria; Bayer: Honoraria, Research Funding. Riess: Bristel Myers Squibb: Honoraria; Bayer: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; ASPEN: Honoraria; Leo Pharma: Honoraria; Pfizer: Honoraria. Sinn: BMS: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Pfizer: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Astra Zenica: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; MSD: Consultancy, Research Funding; Sanofi: Consultancy; Bayer: Research Funding. Girard: Bayer Healthcare: Other: Personal fees, Research Funding; LEO Pharma: Other: Perconal fees, Research Funding. Sanchez: BAYER: Other: reports grants, personal fees and non-financial suppor; BMS: Other: grants, personal fees and non-financial support; PFIZER: Other: personal fees and non-financial support; BOEHRINGER INGELHEIM: Other: personal fees and non-financial support; CHIESI: Other: personal fees; BOSTON SCIENTIFICS: Other: grants and personal fees.

Background The clinical benefit of extending prophylaxis for venous thromboembolism (VTE) beyond hospital discharge after laparoscopic surgery for cancer is unclear. The efficacy and safety of thromboprophylaxis with direct oral anticoagulants in cancer surgery is unexplored. Methods PROLAPS II is an investigator-initiated, prospective, randomized, double-blind study aimed at assessing the efficacy and safety of extended prophylaxis with rivaroxaban compared with placebo after laparoscopic surgery for colorectal cancer (NCT03055026). All patients received antithrombotic prophylaxis with low molecular-weight heparin for 7±2 days and were then randomized to receive rivaroxaban (10 mg once daily) or placebo for the following 3 weeks (up to day 28±2 from surgery). The primary study outcome was the composite of symptomatic objectively confirmed VTE, asymptomatic ultrasonography-detected deep vein thrombosis (DVT) or VTE-related death within 28±2 days from laparoscopic surgery. The primary safety outcome was ISTH-defined major bleeding. By assuming an 8% incidence of primary study outcome in patients randomized to placebo and a 60% reduction with rivaroxaban, 323 patients per group were necessary to show the superiority of rivaroxaban. Results. Patient recruitment in PROLAPS II study was preliminary closed in June 7 th, 2021 due to study drug expiry, after the inclusion of 577 patients. The main patients features are reported in the Table. Study results will be available after the last study patient will complete the 90-day follow-up (scheduled on September 7th, 2021) and will be ready to be presented at the ASH 2021 Congress. Conclusion PROLAPS II is the first study with an oral anti-Xa agent in cancer surgery. The study has the potential to improve clinical practice by assessing the clinical benefit of extending prophylaxis after laparoscopic surgery for colorectal cancer. Figure 1 Figure 1. Disclosures Becattini: Bayer HealthCare: Honoraria; Daiichi Sankyo: Honoraria; Bristol Myers Squibb: Honoraria. Dentali: Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Daiichi Sankyo: Honoraria; Bayer: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; Boehringer: Honoraria; Alfa Sigma: Honoraria. Agnelli: Bayer HealthCare: Honoraria; Daiichi Sankyo: Honoraria; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria.

Venous Thromboembolism (VTE) remains a significant cause of morbidity and mortality worldwide. Rivaroxaban, a direct oral factor Xa inhibitor, mediates anti-inflammatory and cardiovascular-protective effects besides its well-established anticoagulant properties, however, these remain poorly characterized. Extracellular vesicles (EVs) are important circulating messengers regulating a myriad of biological and pathological processes and may be highly relevant to the pathophysiology of VTE as they reflect alterations in platelet and endothelial biology. However, the effects of Rivaroxaban on circulating pro-inflammatory EVs in VTE patients remain unknown. We hypothesized that rivaroxaban's anti-inflammatory properties are reflected upon differential molecular profiles of circulating EVs. Single-episode VTE patients anticoagulated with 20 mg Rivaroxaban or warfarin at a target INR of 2.0-3.0, respectively, who had commenced therapy no sooner than 3 months previously were recruited following informed written consent at the Mater Misericordiae University Hospital, Dublin, Ireland. Patient data including age, sex, BMI, prevalent risk factors and comorbidities were collected. Patients on warfarin therapy had a time in therapeutic range of at least 55% and an INR in target range at time of blood sampling. Exclusion criteria included known pro-inflammatory conditions, active malignancy, recurrent VTE, antiphospholipid syndrome, bleeding or platelet function disorders, use of anti-platelet drugs, and thrombocytopenia. To address the hypothesis, we firstly used a combination of Nanoparticle Tracking Analysis (NTA) and flow cytometry to comprehensively characterise differences in the concentration and size of small (0-200 nm) and large (200-1000 nm) circulating EVs, respectively. Statistical analysis revealed a trend towards reduced levels of circulating small and large EVs in Rivaroxaban-treated VTE patients compared with matched warfarin controls. Moreover, small and large EVs measured in the patients plasma correlated strongly and highly significantly (r=0.804, p Collectively, we established that EV proteomic signatures are powerful biological sensors of Rivaroxaban's anti-inflammatory potential. Moreover, Rivaroxaban therapy may ameliorate endothelial dysfunction relative to warfarin. These findings are of translational relevance towards characterizing the anti-inflammatory and cardiovascular-protective mechanisms associated with Rivaroxaban therapy. Disclosures Kevane: Leo Pharma: Research Funding. Murphy: Bayer Pharma: Research Funding. Ni Ainle: Daiichi-Sankyo: Research Funding; Actelion: Research Funding; Leo Pharma: Research Funding; Bayer Pharma: Research Funding. Maguire: Bayer Pharma: Research Funding; Actelion: Research Funding.

BACKGROUND After a standard anticoagulation period (3-6 months), the risk of venous thromboembolism recurrence (RVTER) needs to be considered. Such risk is higher in unprovoked events and patients with persistent risk factor. The increase of D-dimer (DD) levels during the therapy seems to be strongly associated to RVTER. The use of rivaroxaban 10 mg/day and apixaban 2.5mg/12h as an extended therapy (ET) after the standard anticoagulation period has been proven to be an effective strategy to prevent recurrence without increasing bleeding events. AIM To assess the effectiveness and safety of reduced doses of rivaroxaban and apixaban as ET in patients with RVTER and to compare their DD levels with those of a control group on anticoagulant therapy at a standard dose. METHODS From April 2016 to June 2020, we included patients with venous thromboembolism (VTE) who received ET with rivaroxaban and apixaban with/at reduced doses. Dose reduction was performed following the clinical algorithm of our unit (Fig. 1). The DD values were determined using HemosIl D-Dimer HS-500 and the cut-off value was established at 500 µg/L DD levels were compared with a control group of 235 patients with VTE who received ET with standard doses of anticoagulation. DD levels were measured at the time of diagnosis (D1), initiation of treatment (D2) and 3 months after treatment (D3). RESULTS From a total of 116 patients (65.5% women), 77.6% (n=90) received rivaroxaban 10 mg/24h and 22.4% received apixaban 2.5 mg/12h as an ET. The mean duration of the initial anticoagulant therapy was 12 +/- 8.8 months. The mean DD value prior to the ET was 388 µg/L. In this group, 63.8% (n=74) was an unprovoked VTE and 17.2% (20) had hereditary thrombophilia. The mean of follow-up time was 6.9 +/- 8.3 months. No recurrences of VTE were observed during the follow-up and only one major bleeding event was reported in a high-bleeding risk patient. We observed a progressive decrease of DD levels from the VTE diagnosis to the last visit, with D1, D2, and D3 values of 987 µg/L ± 324, 388 µg/L ± 134, and 288 µg/L ± 98, respectively. There were no differences in d-dimer concentrations between patients with reduce doses of rivaroxaban or apixaban and the control group with standard doses (D1: 85.6% vs 81%, p =0.22; D2: 10.2% vs 8.0%, p =0.14; and D3: 9.1% vs 9.5%, p =0.18). CONCLUSIONS Our data indicated that an ET strategy with reduced doses of rivaroxaban or apixaban is effective and safe. We did not observe significant differences in DD levels at follow-up compared to the control group receiving a standard dose of anticoagulation. Further studies are needed in order to select and standardize dose reduction criteria in secondary prevention. Figure 1 Disclosures Campoy: boehringer ingelheim: Consultancy; Daiichi Sankyo: Speakers Bureau. Sierra:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead-Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Olivera:Daiichi Sankyo: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Boehringer Ingelheim: Consultancy, Speakers Bureau; BAYER: Consultancy.

Introduction: Thrombotic Antiphospholipid syndrome (TAPS) is an autoimmune condition where venous thromboembolism (VTE) and/or arterial thromboembolism (ATE) occurs in the presence of antiphospholipid antibodies (aPLs). TAPS is traditionally managed with long-term anticoagulation with vitamin K antagonists (VKA). Over the past decade, direct oral anticoagulants (DOACs) have been increasingly replacing VKAs as the oral anticoagulant of choice given their lower risk of bleeding, fixed dosing, and no requirement for routine monitoring. However, recent evidence has demonstrated inferiority of DOACs compared to VKAs in TAPS patients with high risk (triple positive) aPL profiles or previous arterial events. It remains unclear whether TAPS patients with low risk aPL profiles (single positive), and without previous ATE, can be treated effectively and safely with DOACs. Objectives: To assess the effectiveness and safety of DOACs at preventing recurrent VTE or ATE in TAPS patients with a low risk aPL profile, and without prior ATE. Methods: We conducted a retrospective review of all TAPS patients with a low risk aPL profile, without prior ATE, who were anticoagulated with a DOAC at two tertiary care hospitals in Toronto, Canada from January 2010 to July 2020. All patients with any positive aPL test results were first identified through the laboratory information system. This list was cross referenced with patients seen in specific thrombosis clinics and confirmed through individual electronic chart review. TAPS was defined as persistent (>12 weeks apart) lupus anticoagulant (LA) positivity, anti-cardiolipin titre (ACA) >40 GPL, or anti-2-glycoprotein 1 titre (a2GP1) >40 GPL, with a preceding thrombotic event. Patients were excluded if any of the aPLs were deemed to be simultaneously positive or if there was a history of previous ATE. a2GP1 was not systematically tested in all patients. Patient outcomes were assessed throughout the duration of anticoagulation with a DOAC. Recurrent VTE included deep vein thrombosis, pulmonary embolism, or VTE of atypical location, and required objective confirmation with appropriate diagnostic imaging. ATE included ischemic stroke, transient ischemic attack (TIA), myocardial infarction, or other systemic arterial embolism. Major bleeding (MB) and clinically relevant non major bleeding (CRNMB) were defined by International Society on Thrombosis and Hemostasis criteria. Results: 1195 patients were identified with at least one instance of single positive aPL who had been seen in one of the thrombosis clinics. Patients were excluded for the following reasons: 858 for non-persistent aPL positivity, 70 for simultaneous aPL positivity, 20 for a likely false positive LA due to DOAC therapy, 93 due to an absence of preceding VTE, 45 for history of previous ATE, and 59 due to no prior DOAC therapy. After exclusions, 50 patients were included in the analysis, encompassing 157.2 years of patient-follow up. The study population was comprised of 24 women and 26 men with a mean age of 49.6 (standard deviation (SD) 16.3)years at the start of DOAC therapy (Table 1). The mean duration of DOAC treatment was 37.7 (SD 23.8) months. Fifteen (30%) patients had prior diagnosis of systemic lupus erythematosus (SLE), while 4 (8%) had other systemic autoimmune disease diagnoses. Only 1 patient met criteria for obstetric APS, on the basis of 3 consecutive fetal losses before 10 weeks gestation. None of the patients had documented valvular disease or thrombocytopenia. All patients were treated initially with therapeutic dose rivaroxaban, although 6 (12%) patients were switched to therapeutic dose apixaban due to increased bruising or menorrhagia. Five patients on rivaroxaban and 3 patients on apixaban were switched to a reduced dose DOAC. No patient had recurrent VTE. One patient had a possible ATE as a TIA, presenting with an episode of loss of sight for 15 minutes while on reduced dose apixaban. None of the patients experienced MB. Two patients experienced CRNMB, both severe menorrhagia, one on therapeutic dose of rivaroxaban and the other patient on reduced dose of rivaroxaban. Conclusions: In our retrospective case series of 50 patients with TAPS, a low risk aPL profile and no previous ATE, DOACs were effective and safe in the secondary prevention of thrombotic events with no MB. Larger, prospective controlled studies are required to confirm these findings. Disclosures No relevant conflicts of interest to declare.

Background: The coronavirus disease pandemic of 2019 (COVID-19) has been associated with coagulopathy and an increased rate of thrombosis in adults. Medical practitioners have been prompted to consider prophylactic anticoagulation in special populations diagnosed with COVID-19. Patients with sickle cell disease (SCD) are predisposed to a hypercoagulable state. Despite the concern for development of venous thromboembolism (VTE) in these patients, there are no standardized guidelines for routine thromboprophylaxis in either adults or children with SCD. Thus, VTE management options are often extrapolated from guidelines for the general population. Methods: A cross-sectional electronic survey was distributed to pediatric and adult hematology oncology practitioners through 7 SCD specific interest groups. Pediatric and adult practitioners were defined as those who medically manage patients 0-21 years of age and >21 years of age respectively. We examined responses to survey questions focused on routine thromboprophylaxis practices in children and adults with SCD prior to the pandemic and in patients with SCD admitted with COVID-19. Chi-square analyses or Fisher's exact tests for small samples were used to compare proportions as needed. Results: The survey was distributed to approximately 2,550 providers. Of 93 total responses, 14% (N=13) only treat patients >21yo; 38.7% (N=36) only treat patients 0-21yo and 47.3% (N=44) treat both. Nearly all adult practitioners (96.6%) would recommend pharmacologic prophylaxis, mechanical prophylaxis or both for hospitalized adults, but only 76% of pediatric treaters would recommend any prophylaxis (PPX) in hospitalized children (p21yo patients, 51% preferred to use both pharmacologic and non-pharmacologic PPX, 25% preferred pharmacologic alone, with just 5.3% preferring non-pharmacologic PPX only. Enoxaparin was the most frequently used anticoagulant among both pediatric and adult practitioners [78% vs 89% respectively] (Figure 2). Direct oral anticoagulants (DOACS) were infrequently recommended (3.8% for SCD children and 10.9% for adults); of these, rivaroxaban was used most often. The most common indication for starting thromboprophylaxis for both 0-21yo and >21yo patients was history of prior VTE [81% and 81% respectively], followed by hip replacement [57% and 75% respectively]. In patients admitted with COVID-19, prophylactic anticoagulation was recommended for adults by 94% of treaters. There was a significant increase in the use of prophylactic anticoagulation in children with COVID-19 vs. those without (84% vs. 40%; p=.0001). Figure 3 shows extended thromboprophylaxis practices upon discharge for COVID related admissions. Almost half of respondents (46%) would not recommend any thromboprophylaxis for children on discharge; 37% would recommend either 2-4 weeks or >4weeks of post-discharge PPX. The majority of adult providers would recommend discharge thromboprophylaxis for adults with 2 weeks post discharge (33%), and 2-4 weeks (30%) being the most common regimens. Conclusion: This pilot survey describes the thromboprophylaxis practices used for adult and pediatric SCD patients by specialty practitioners. In general, practitioners were likely to prescribe pharmacologic thromboprophylaxis for adults while mechanical PPX was preferred for children. However, in the high-risk setting of COVID-19 infection, pediatric practitioners would modify their practice to include pharmacologic thromboprophylaxis. Interestingly, despite the long-term availability of direct oral anticoagulants in adults, and recent completion of pediatric studies, the most commonly used pharmacologic agent pre-COVID in adults and children was enoxaparin. Of note, this survey was conducted prior to release of the International Society on Thrombosis and Haemostasis guidelines regarding discharge PPX in COVID-19. (Spyropoulos AC, J Thromb Haemost, 2020) These results highlight the influence of COVID-19 on the use of pharmacologic thromboprophylaxis, specifically in the pediatric population. Due to frequent hospitalization, studies are needed to guide decision making surrounding VTE PPX for the adult and pediatric inpatient SCD population. Disclosures Davila: Spire Learning: Speakers Bureau; ATHN: Other: Grant Funding. Minniti:Bluebird bio: Consultancy, Research Funding; TauTona: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Emmaus: Consultancy, Research Funding; CLS Bering: Consultancy; Novartis: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding. Desai:Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; GBT, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ironwood Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Rockpointe Continuing Medical Education Company: Consultancy. O'Brien:Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Enoxaparin used as a form of thromboprophylaxis in children.

Background: There are currently four direct oral anticoagulants (DOACs) approved for the acute treatment and prevention of venous thromboembolism (VTE) in adults. Pediatric hematologists across the United States (US) are using DOACs for their patients based on extrapolated data from adult studies and recently published phase 3 pediatric-specific studies. (Brandao LR, et al. Blood, 2019 and Male C, et al. Lancet Haematol, 2020.) Because further data regarding DOAC use in children are needed, ATHN 15: Characterizing the Real-World Use of Direct Oral Anticoagulants in Pediatric Patients, was developed and is being sponsored by the American Thrombosis and Hemostasis Network (ATHN). The study is being conducted at ATHN-affiliated sites in the US and aims to characterize the real-world use of DOACs in children diagnosed with VTE. ATHN is a nonprofit network of over 140 federally funded hemophilia treatment centers (HTCs) that provides the infrastructure for clinical research and public health surveillance. Methods: Data being captured includes demographics, clinical characteristics, anticoagulation management, and treatment outcomes (bleeding and recurrent thrombosis) of patients Results: As of May 31, 2020, 76 patients from 9 sites have been enrolled (see Table 1 for demographics). Deep venous thrombosis (DVT) of the lower extremities or pelvis is the most prevalent VTE (n = 23, 30.26%), followed by DVT of the upper extremity or upper thorax and pulmonary embolism plus VTE (n = 22, 28.95 and n = 13, 17.1% respectively). 82.89% of patients did not have a history of prior VTE at the time of enrollment. Of the 15 patients with a radiologically confirmed anatomic anomaly, Paget Schroetter/Thoracic Outlet Syndrome and May-Turner Syndrome are the most common (n = 6, 40% and n = 4, 26.7%, respectively). Factor V Leiden heterozygosity, reported in 8 patients, is the most prevalent inherited thrombophilia. Forty-eight patients were identified as having a medical risk factor associated with their VTEs. Sixteen (33.3%) were classified as obese and another 13 (27.1%) had a hospital admission stay greater than 7 days and within 30 days prior to the VTE. At least one specific drug or environmental risk factor was reported in 44 patients. Concomitant use of hormonal contraception (currently taking/stopped within 4 weeks prior to VTE) and the presence of a central venous catheter (present at time of VTE or within 30 days prior to VTE) were the most commonly reported (n = 18, 40.9% and n = 15, 34.09%, respectively). Rivaroxaban is the most prescribed DOAC with 59.2% (n = 45) of patients using this agent. Apixaban and dabigatran use is also reported (n = 29; 38.2% and n = 2; 2.6% respectively). Of the 76 patients, 65 received a different anticoagulant prior to starting a DOAC. Enoxaparin and unfractionated heparin are most commonly prescribed prior to the institution of a DOAC regimen (n = 52, 80% and n = 17, 26.2%). Conclusions: Despite lack of an FDA-approved pediatric indication, hematologists in the US are already using DOACs for children with VTE. Most pediatric patients treated with a DOAC are older than 13 years of age, although we anticipate this will change as providers develop more comfort with these drugs. Interestingly, most of these patients were started on a different anticoagulation regimen prior to starting a DOAC. As enrollment continues, ATHN 15 will serve as a resource for pediatric hematologists to characterize the real-world use of DOACs in children. Further analysis will evaluate DOAC-specific utilization, efficacy and adverse events, including heavy menstrual bleeding. Disclosures Davila: Spire Learning: Speakers Bureau; ATHN: Other: Grant Funding. Corrales-Medina:Bayer: Consultancy; Takeda: Consultancy; Octapharma: Consultancy, Speakers Bureau. Raffini:XaTek: Other: Advisory Board; CSL Behring: Other: Advisory Board; HemaBiologics: Other: Advisory Board; Bayer: Other: Advisory Board; Roche: Other: Advisory Board. Thornburg:Sanofi Genzyme: Consultancy, Other: Data Safety Monitoring Board, Research Funding; NovoNordisk: Research Funding; Genentech: Speakers Bureau; Biomarin: Consultancy, Speakers Bureau; Bayer Pharmaceuticals: Research Funding; American Thrombosis and Hemostasis Network: Research Funding; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ironwood Pharmaceuticals: Consultancy, Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Spark Therapeutics: Consultancy. OffLabel Disclosure: Apixaban, Rivaroxaban, Dabigatran and Enoxaparin use in the pediatric population.

Background Oral anticoagulants are the recommended therapy for prophylaxis and treatment of venous thromboembolism and for stroke prevention among patients with non-valvular atrial fibrillation. Given their widespread use, clinicians must balance efficacy and anticoagulation associated bleeding risks. Intracranial hemorrhage (ICH) has been the most feared complication, as this form of bleeding has been associated with the greatest morbidity and mortality. Clinical trials suggest a lower incidence of ICH among patients prescribed the direct oral anticoagulants (DOACs) compared with vitamin K antagonists (VKAs). While reassuring, the clinical impact on functional outcomes once an anticoagulant-associated ICH does occur is needed. The aim of this study was to evaluate the role of anticoagulation use on in-hospital mortality rates, and functional outcomes among survivors presenting with ICH. Methods In this study, we present data from a retrospective chart review of patients who presented to The Ottawa Hospital, Ottawa, Canada with ICH between January 2016 and December 2017. Patients were identified from the Ottawa Hospital Data Warehouse using ICD-10 codes. Patient demographics, type of anticoagulant/antiplatelet agent and indication for therapy were collected. The primary outcome was in-hospital mortality rates among patients prescribed oral anticoagulants compared with those not anticoagulated or on antiplatelet therapy. A secondary outcome was functional assessment of survivors at hospital discharge using the modified Rankin Scale (mRS), a validated tool used widely in contemporary stroke research to measure the degree of disability after a neurological event. Results 1457 patients were identified in the Ottawa Hospital Data and 1331 patients with ICH were confirmed by manual review. 195 patients were on an oral anticoagulant, and the primary indication for anticoagulation was atrial fibrillation (Table 1). Intraparenchymal bleeding was most common among patients on DOACs, while patients on warfarin tended to have more subdural hematomas (Table 2). In-hospital mortality was 37.7% in DOAC-related ICH, 36.4% in warfarin-related ICH and 16.8% in patients not on an antithrombotic therapy. The average modified Rankin Scale (excluding death as a competing factor) at the time of discharge was 3.4 in DOAC-related ICH, 3.6 in warfarin-related ICH and 3.2 in patients not on an anticoagulant or antiplatelet (Table 3). The majority of patients with a DOAC-related ICH were on Apixaban or Rivaroxaban. The in-hospital mortality for patients on Apixaban (N=31) and Rivaroxaban (N=39) was 29.0% and 46.2%, respectively (Table 4). Conclusions In this cohort of patients presenting with ICH to a large academic hospital, the in-hospital mortality rate was higher in patients receiving oral anticoagulation compared to those not on anticoagulants. DOAC-related ICH tended to have similar in-hospital mortality when compared to warfarin; however, among survivors, functional outcomes at discharge tended to be more favourable in the DOAC cohort. Although the DOACs are reported in the literature to have an overall lower incidence of ICH, prospective studies are needed to understand the clinical impact when a bleeding event does occur. Disclosures Castellucci: Servier: Honoraria; Bayer: Honoraria; BMS-Pfizer: Honoraria; LEO Pharma: Honoraria.

Introduction: The Khorana Score (KS) is a validated tool to assess the risk of thrombosis in cancer patients, prior to initiation of chemotherapy. The AVERT and CASSINI studies evaluated prophylactic anticoagulation with apixaban or rivaroxaban for patients with KS of 2 or higher. Both studies demonstrated that while patients were taking prophylactic anticoagulant, the Hazard Ratio of cancer associated thrombosis was approximately 0.4. The NCCN and other societies are now recommending oral anticoagulant prophylaxis should be considered for up to 6 months, for patients with an intermediate or high-risk score of ≥2. Methods: We have developed a medical record tool, that identifies all MSKCC patients prior to initiation of a new chemotherapy regimen, captures the KS parameters, and generates the KS. Once fully implemented, it is anticipated that this tool and appropriate use of prophylactic anticoagulation, will reduce the burden of cancer associated thrombosis. To accurately document a potential reduction in rates of cancer associated thrombosis, we need to establish current baseline rates of cancer associated thrombosis via a contemporary verification of the KS, reflecting potential changes in oncology in the 12 years since the score was first published. We applied our KS capture tool to a 2-year period (10/17/2017 to 11/29/2019). 13,992 patients were identified with a new chemotherapy order, of whom 13,176 were found to have cancer and had complete parameters for the KS. We tracked all patients for 6 months, to identify possible episodes of Venous Thromboembolism (VTE). VTE episodes were identified by capturing the impressions of all contrast imaging studies, Doppler ultrasounds, and V/Q scans, combined with keyword and phrase computer identification, and manual review. To identify possible VTE events that occurred at an outside emergency department or hospital, we also queried new prescriptions for therapeutic doses of anticoagulants and ICD10 codes. In this analysis we focus on deep vein thrombosis (DVT) and pulmonary embolism (PE). Results: The 6-month rate of VTE (DVT or PE) was 6.4%. The VTE rate was 4.1% in the KS 0 cohort, and >18% for patients with a score of 4 or greater. We assessed the contribution of each parameter of the KS, in univariate analysis. Of the cancers assigned 2 points in the KS, pancreatic cancer had the highest VTE rate of 13.7%, but gastric/esophageal cancer did not have an increased rate. Of the cancers assigned 1 point, germ cell/testis, gynecologic, and lung cancer, also had increased risk of VTE, but bladder and non-Hodgkin lymphoma did not. Renal/urothelial cancers and cholangiocarcinoma/biliary tract cancers were also associated with high rates of VTE, although were not assigned points using the KS. Elevated BMI (≥35 kg/m2) was a weak risk factor. However, baseline anemia (11,000/mcL) and thrombocytosis (≥350,000/mcL) were all strong predictors of VTE rate. Conclusions: The purpose of this QA project was to provide contemporary data on baseline cancer associated thrombosis rates, anticipating implementation of a program of targeted primary thrombosis prophylaxis. It remains clear that the KS provides a valuable risk assessment tool, stratifying 6-month VTE risk from 4.1% to >18%. Cancer type is typically the parameter that gets the first consideration. And most of the cancers with 1 or 2 points did predict increased risk. We don't have an explanation as to why, gastric/esophageal cancers and non-Hodgkin lymphoma were not associated with increased risk, but this finding may reflect the stage of their treatment at which patients begin care at MSKCC. Renal/urothelial, and cholangiocarcinoma/biliary tract cancers are associated with a high risk of VTE, and one may choose to include them for consideration of prophylactic anticoagulation. The relative contribution of pre-chemotherapy blood counts has been questioned in the past, but in this cohort, they clearly contributed to appropriate risk assessment. These data will serve as baseline for future assessment of thrombosis risk reduction upon implementation of a program of targeted prophylactic anticoagulation. Table Disclosures Khorana: Leap: Research Funding; BMS: Honoraria, Research Funding; Merck: Research Funding; Array: Other: Research funding (to institution); Janssen: Honoraria; Bayer: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Medscape: Honoraria; Leo Pharma: Honoraria; Seattle Genetics: Honoraria; Pharmacyte: Honoraria; Pharmacyclics: Honoraria. Mantha:MJH Associates: Honoraria; Physicians Education Resource: Honoraria. Soff:Amgen: Research Funding; Amgen: Honoraria; Janssen Scientific Affairs: Honoraria; Dova Pharmaceuticals: Honoraria; Bristol-Myers Squibb, Pfizer: Honoraria; Janssen Scientific Affairs: Research Funding; Dova Pharmaceuticals: Research Funding.

Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.

The noninferiority of direct oral factor Xa (FXa) inhibitors (rivaroxaban, apixaban, and edoxaban) in treatment of atrial fibrillation were demonstrated compared with warfarin by several large clinical trials; however, subsequent meta-analyses reported a higher risk of major bleeding with rivaroxaban than with the other FXa inhibitors. In the present study, we first estimated the changes of prothrombin time (PT) in 5 randomized trials based on reported population pharmacokinetic and pharmacodynamic models and then carried out a model-based meta-analysis to obtain models describing the relationship between PT changes and the event rates of ischemic stroke/systemic embolism (SE) and of major bleeding. By using the models, we simulated the optimal therapeutic doses for each FXa inhibitor. It was suggested that dose reduction of rivaroxaban from the current 20 mg/d to 10 mg/d would decrease patient deaths from major bleeding (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.64-0.74) with little increase in those for ischemic stroke/SE (HR, 1.11; 95% CI, 1.07-1.20). The overall decrease in the mortality caused by both events was estimated as 5.81 per 10 000 patient-years (95% CI, 3.92-8.16), with an HR of 0.87 (95% CI, 0.83-0.91). For apixaban and edoxaban, no distinct change in the overall mortality was simulated by dose modification. This study suggested that the current dose of rivaroxaban might be excessive and would need to be reduced to decrease the excess risk of major bleeding.

Although the direct oral anticoagulants (DOACs) do not require routine monitoring and reduce bleeding compared with warfarin, there are special circumstances in which laboratory measurement or reversal of their anticoagulant effect may be indicated. The dilute thrombin time and ecarin-based assays are able to quantify dabigatran across a broad range of concentrations, but are not widely available. A normal thrombin time excludes clinically relevant levels and a normal activated partial thromboplastin time probably excludes excess levels of dabigatran. Factor Xa inhibitors may be quantified with an anti-Xa assay calibrated with drug-specific standards. A normal prothrombin time probably excludes excess levels of rivaroxaban and edoxaban, but not apixaban. Patients with minor and moderate DOAC-associated bleeding can be treated with supportive care and general hemostatic measures. Nonspecific reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate) are of unproven benefit, carry a risk of thrombosis, and should be reserved for severe bleeding. Specific reversal agents, such as idarucizumab (a monoclonal antibody fragment that binds dabigatran) and andexanet alfa (a recombinant factor Xa variant that binds factor Xa inhibitors but lacks coagulant activity), are in clinical development.

Introduction: Venous thromboembolic disease (VTE) is a common cause of morbidity and mortality in patients with cancer. Cancer associated thrombosis (CAT) is associated with poor prognosis, worse survival and increased care costs. Previous trials demonstrated the non-inferiority of DOACs to LMWH for the treatment of CAT, but there is concern for a possible increased incidence of bleeding, particularly in patients with gastrointestinal (GI) and urothelial (GU) cancers. Current guidelines suggest a preference for enoxaparin with these diagnoses. The aim of our study is to elucidate the safety of DOACs in the treatment of GI and GU cancer associated thrombosis at our institution. Methods: Retrospective chart review of patients with GI or GU cancer associated thrombosis who received either enoxaparin or DOACs (apixaban or rivaroxaban) was performed. The baseline characteristics, duration of anticoagulation (AC) and bleeding events (BEs) were compared between the two groups. The bleeding events were classified according to ISTH categories. Statistical analysis was done using R studio (V1.3.1056). Results: All patients from 01/2001 - 01/2020 with active GI or GU cancer and associated thrombosis who had received enoxaparin or a DOAC were included in the study. Of 262 patients reviewed, 206 (78.6 %) received a DOAC and 56 (21.4%) received enoxaparin. The baseline characteristics between the two groups are depicted in Table 1. Patients in the DOAC group had lower ECOG scores than those on enoxaparin: 79.7% of DOAC and 26.8% of enoxaparin patients had ECOG scores of 1-2. Patients on DOACs were less likely to have metastatic disease (58.7% vs. 78.6%) but were more likely to have additional risk factors for bleeding (p=0.004): 24 patients (11.7%) on DOACs were also on an antiplatelet agent (19 on aspirin, 5 on clopidogrel), compared to 4 patients (7.1%) in enoxaparin group (3 on aspirin, 1 on clopidogrel). Clot distribution was similar between the two groups. The majority of patients, 70.4% in the DOAC group and 73.2% in the enoxaparin group, had no BEs. There was no statistically significant difference in the cumulative incidence (CI) of bleeding between the DOAC and enoxaparin groups (p-value 0.65) Figure 1. In the DOAC group, 109 patients (52.9%) received apixaban and 97 patients (47.1%) received rivaroxaban. There were 26 (23.9%) and 35 (36.8%) BE in the apixaban and rivaroxaban subgroups respectively, Table 2. Of those on apixaban, 13/26 had GI bleeding (12 had underlying GI and 1 patient had GU cancer) and 10/26 had GU bleeding(all with underlying GU cancer). Of those on rivaroxaban 18/35 had GI bleeding (all with underlying GI cancer) and 11/35 had GU bleeding (6 patients had GU and 5 had GI cancer). Conclusion: Our study suggests that physician preferences play a major role in the choice of AC. Most physicians preferred DOACs even for patients with GI/GU cancers when patients had better ECOG scores and non-metastatic disease. However, these were also the same patients that were then more likely to have been exposed to additional risk factors for bleeding. BEs between DOACs and enoxaparin were similar and, between the DOACs, somewhat more favorable with apixaban than rivaroxaban. Randomized clinical trials, controlling for physician choice and bleeding risk factor, are necessary valid comparisons for the best choice of anticoagulation. Disclosures No relevant conflicts of interest to declare.

Background: There is limited data to guide prescribing of all available anticoagulants in obese patients, in particular those weighing > 150kg or with a BMI > 40kg/m2. We aimed to examine anticoagulant prescribing patterns in obese patients in Australia and New Zealand including choice of agent and dosing, determine whether patients with obesity achieve appropriate direct oral anticoagulant (DOAC) levels and evaluate the efficacy and safety of anticoagulation in obese patients. Methods: Patients with a BMI > 35kg/m2 or weight > 120kg receiving anticoagulant therapy are prospectively identified at 7 sites in Australia and New Zealand. Demographic data, indication for anticoagulation and choice of anticoagulant are collected at baseline. At follow-up visits, drug specific levels, dose adjustments and clinical progress (symptoms, imaging, recurrent thrombosis and adverse events) are recorded. Results: 155 patients have been recruited across seven sites (recruitment ongoing). The median age of patients was 53 (range 22-85) and 49% of patients were male. 77 (50%) of patients were anticoagulated for pulmonary embolus (PE) while 40% were anticoagulated for deep vein thrombosis (DVT) without PE. Initial anticoagulant prescribed was apixaban in 37 patients, dabigatran in 4 patients, rivaroxaban in 57 patients, low molecular weight heparin (LMWH) in 29 patients and warfarin in 28 patients (Table 1). A subset of patients initially received LMWH for 5-14 days prior to transition to a DOAC (rivaroxaban in 7, dabigatran in 6). There was cross-over between agents during the study period. Table 2 demonstrates median peak and trough DOAC levels. All peak apixaban levels and 25 of 37 (68%) peak rivaroxaban levels were within the therapeutic ranges published by the International Council for Standardization in Haematology (Gosselin, Thromb Haemost. 2018). Assessment of appropriate trough levels was limited by the limit of detection at different laboratories. 27 patients receiving enoxaparin had at least one peak Anti-Xa level (target peak 0.5-1.2U/ml). The median enoxaparin dose to achieve therapeutic peak Anti-Xa was 0.9mg/kg (range 0.52-1.3). 15 patients weighing > 150kg had a recorded peak Anti-Xa, 10 of these patients were prescribed a capped dose of 150mg BD (weight range 155-290kg) and nine had a therapeutic Anti-Xa and one had a supratherapeutic Anti-Xa measurement. One patient had a PE on apixaban 5mg twice daily (in the setting of suspected non-compliance), one patient had a new confirmed PE after 4 days of non-compliance with rivaroxaban 20mg daily and another patient had a confirmed recurrence on therapeutic warfarin. 1 patient had a PE when warfarin was withheld for emergency surgery. An equivocal recurrence occurred on enoxaparin with a supratherapeutic Anti-Xa (1.76 U.ml) and 1 DVT occurred on dabigatran for a cardiac indication (no drug level available). One patient had recurrent superficial thrombophlebitis on rivaroxaban 20mg daily (peak 301ng/L and trough Conclusion: There is limited data to guide prescribing of all anticoagulants in obese patients, in particular in patients weighing > 150kg or BMI > 40kg/m2. There is increasing use of DOACs in Australia and New Zealand in patients with obesity given the ease of administration and lack of monitoring required. Despite the recommendation to perform DOAC levels in this group of patients, interpretation of levels is difficult due to a lack of well validated therapeutic ranges with clinical correlation. Further data regarding the clinical utility of DOAC levels, appropriate dosing strategy for enoxaparin, and clinical outcomes in this population is required. Our registry provides data regarding drug levels in this population, prescribing characteristics and clinical outcome data. Disclosures No relevant conflicts of interest to declare.

Proteinuric glomerular diseases are a leading cause of chronic kidney disease (CKD). Both pre-CKD glomerular disease and established CKD are major risk factors for thrombosis. Glomerular capillary podocyte injury is a key determinant of CKD progression and results in massive proteinuria accompanied by an acquired hypercoagulopathy that drives thrombotic risk. Unfortunately, the routine use of anticoagulant prophylaxis during glomerular proteinuria (GP) remains controversial due to both a lack of agreement regarding indications and no randomized controlled trial data demonstrating both safety and efficacy. We have recently used rat glomerular disease models to reveal that: (1) Proteinuria is directly correlated with hypercoagulopathy and in vivo thrombosis and (2) Thrombin, the key effector enzyme of the coagulation system, directly injures podocytes during proteinuria. What is not yet known is the ability of direct oral anticoagulant (DOAC) therapy to improve these important CKD and thrombosis outcomes. Thus, the aim of the present study is to determine if DOACs simultaneously reduce podocytopathy and enable effective thromboprophylaxis during GP. We hypothesized that DOACs would simultaneously preserve podocyte function and reduce hypercoagulopathy, in a podocyte-specific rodent model of glomerular disease. We utilized the podocin promotor-human diphtheria toxin receptor (pDTR) transgenic rat model to induce highly specific podocyte injury following a single I.P. injection of 50 ng/kg diphtheria toxin (DT). DT-induced proteinuria was subsequently treated daily by oral gavage with 1) Dabigatran (20 mg/kg; Dabi), 2) Rivaroxaban (3 mg/kg; Riva), or 3) Sham (saline) and compared to healthy controls (n=3-6/group). Morning spot urine and citrated plasma samples were collected from each group at day 10 post-DT. Endogenous Thrombin Potential (ETP) was measured by Technothrombin TGA assay, without and with DOAC-Stop reagent. Glomeruli were isolated from the kidney, dissociated into single-cell suspensions and analyzed by flow cytometry following immunofluorescent antibody and TUNEL staining. Both Dabi and Riva significantly reduced proteinuria (Fig A) and podocytopathy (TUNEL positive podocyte fraction; Fig B), while concomitantly correcting elevated ETP levels (Fig C open symbols). Addition of DOAC-Stop (Fig C closed symbols) revealed an insignificant (P=0.18) trend toward partial ETP reduction, consistent with DOAC-mediated reduction of the underlying GP-mediated hypercoagulopathy (via indirect, antiproteinuric effects). In conclusion, dabigatran and rivaroxaban reduce proteinuria and enhance podocyte health in concert with alleviation of the acquired hypercoagulopathy in a podocyte-specific rodent model of glomerular disease. Overall these data suggest DOAC treatment as a novel approach to simultaneously reduce both podocytopathy and thrombotic co-morbidities during glomerular disease. Additional experiments using this model to determine DOAC efficacy on in vivo thrombosis are in progress. Results from these preclinical studies should inform subsequent randomized controlled DOAC trials that may transform care for patients with glomerular disease by mitigating their risk of both CKD progression and thrombosis. Disclosures No relevant conflicts of interest to declare.

Background: Assay parameters for anti-FXa activity assays for apixaban and rivaroxaban on the ACL TOP/TOP 50 analyzers have been modified to minimize the effect of sample dilution suitable for analyzing andexanet-containing samples with drug-specific calibrators [1].The modified assays showed a dose-dependent reversal of rivaroxaban and apixaban anti-FXa activity in andexanet-containing samples similar to the 96-well format anti-FXa activity assay used in the andexanet clinical studies. In the current study, further assay optimization and verification of analytical performance was performed for the modified apixaban and rivaroxaban assays. Methods: Calibration curves for the modified anti-FXa assays (apixaban, rivaroxaban) were further optimized to improve precision at 100 ng/mL. The calibration curves consisted of 5 dilution levels. The number of replicates at each level was increased from 3 to 4, and outlier removal was enabled to improve the % coefficient of variation (%CV). The limit of blank (LoB), detection (LoD) and quantitation (LoQ) for modified assays on the ACL TOP/TOP 50 were determined in accordance with the minimum requirements of two lots of calibrators and reagent, one instrument system, and three days in accordance with CLSI [2]. The linear ranges were tested for 3 lots of calibrators on 4 analyzers. The samples for the linearity tests consisted of a minimum of 9 to 11 levels extending below and above the anticipated linear range. A 5-day precision was performed with diluted controls encompassing the modified assay calibration range and andexanet-containing samples on a minimum of two analyzers with one lot of drug-specific calibrator to verify analytical performance. Results: Analytical performance with optimized calibration settings was evaluated with a minimum of 9 calibration curves generated with 3 calibrator lots and demonstrated improvement in the r2 and %CV at each level. The analytical parameters for the modified apixaban assay generated with 3 lots of calibrator and reagent on 4 analyzers are as follows: LoB of ~2.1 ng/mL, LoD of 3.5 ng/mL, and LoQ of 5.9 ng/mL. The analytical parameters for the modified rivaroxaban assay were generated with 2 lots of calibrators and reagents with a LoB of 2.3 ng/mL, and LoD of 3.6 ng/mL. Three lots of calibrators and reagents were used to generate an LoQ of 5.4 ng/mL. The linear range was determined to be 10-100 ng/mL and met the acceptance criteria for r2≥ 0.95 and slope of 0.90 - 1.10 for both assays. Conclusions: Results of this study demonstrate that modified apixaban and rivaroxaban LoQ and linearity meet the assay requirements. Modified test parameters will be user-defined on the ACL TOP/TOP 50 analyzers and can be used to measure apixaban or rivaroxaban levels when andexanet is present in the samples. References: Khan, A. et al. Blood(2019) 134 (Supplement1): 1153. American Society of Hematology- Modified Anti-FXa assays for measuring the residual activity of apixaban and rivaroxaban in andexanet alfa-containing samples on the ACL TOP Family® coagulation analyzers. CLSI EP17-A2.Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline - Second Edition.Wayne, PA: Clinical and Laboratory Standards Institute; 2012. Disclosures Lu: Portola Pharmaceuticals, Inc.:Current Employment.Bui:Portola Pharmaceuticals, Inc,:Current Employment.Conley:Portola Pharmaceuticals, Inc.:Current Employment.

Oral anticoagulants are commonly prescribed but high risk to cause adverse events. Skilled drug interaction management is essential to ensure safe and effective use of these therapies. Clinically relevant interactions with warfarin include drugs that modify cytochrome 2C9, 3A4, or both. Drugs that modify p-glycoprotein may interact with all direct oral anticoagulants, and modifiers of cytochrome 3A4 may interact with rivaroxaban and apixaban. Antiplatelet agents, nonsteroidal anti-inflammatory drugs, and serotonergic agents, such as selective serotonin reuptake inhibitors, can increase risk of bleeding when combined with any oral anticoagulant, and concomitant use should be routinely assessed. New data on anticoagulant drug interactions are available almost daily, and therefore, it is vital that clinicians regularly search interaction databases and the literature for updated management strategies. Skilled drug interaction management will improve outcomes and prevent adverse events in patients taking oral anticoagulants.

The incidence of venous thromboembolism (VTE) in adult patients with sickle cell disease (SCD) is high. However, overlapping features between the clinical presentation of VTE and SCD complications and a low index of suspicion for thrombosis can influence patient management decisions. VTE in SCD can therefore present management challenges to the clinical hematologist. Herein, we present 3 distinct clinical vignettes that are representative of our clinical practice with SCD patients. These vignettes are discussed with specific reference to the hypercoagulable state in SCD patients, recent VTE diagnosis and anticoagulant therapy guidelines from the general population, and evaluation of the risk of bleeding as a result of long-term exposure to anticoagulant therapy. We examine current diagnostic and treatment options, highlight limitations of the existing clinical prognostic models that offer personalized guidance regarding the duration of anticoagulation, and propose a clinical approach to guide the decision to extend anticoagulation beyond 3 months.

Anticoagulants such as unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and direct oral anticoagulants (DOACs) targeting thrombin (IIa) or factor Xa (FXa) are widely used in prevention and treatment of thromboembolic disorders. However, anticoagulant-associated bleeding is a concern that demands monitoring and neutralization. Protamine, the UFH antidote, has limitations, while there is no antidote available for certain direct FXa inhibitors. Improved antidotes in development include UHRA (Universal Heparin Reversal Agent) for all heparin anticoagulants; andexanet alfa (andexanet), a recombinant antidote for both direct FXa inhibitors and LMWHs; and ciraparantag (PER977), a small-molecule antidote for UFH, LMWHs, and certain DOACs. The binding affinities of these antidotes for their presumed anticoagulant targets have not been compared. Here, isothermal titration calorimetry (ITC) was used to determine the affinity of each antidote for its putative targets. Clotting and chromogenic FXa assays were used to characterize neutralization activity, and electron microscopy was used to visualize the effect of each antidote on clot morphology in the absence or presence of anticoagulant. ITC confirmed binding of UHRA to all heparins, and binding of andexanet to edoxaban and rivaroxaban, and to the antithrombin–enoxaparin complex. PER977 was found to bind heparins weakly, but not the direct FXa inhibitors studied. For UHRA and andexanet, an affinity at or below the micromolar level was found to correlate with neutralization activity, while no reversal activity was observed for the PER977/anticoagulant systems. Standard metrics of clot structure were found to correlate weakly with PER977’s activity. This is the first study comparing 3 antidotes in development, with each exerting activity through a distinct mechanism.

Rivaroxaban is an effective and safe alternative to warfarin in patients with atrial fibrillation and venous thromboembolism. We tested the efficacy and safety of rivaroxaban compared with warfarin in high-risk patients with thrombotic antiphospholipid syndrome. This is a randomized open-label multicenter noninferiority study with blinded end point adjudication. Rivaroxaban, 20 mg once daily (15 mg once daily based on kidney function) was compared with warfarin (international normalized ratio target 2.5) for the prevention of thromboembolic events, major bleeding, and vascular death in patients with antiphospholipid syndrome. Only high-risk patients triple positive for lupus anticoagulant, anti-cardiolipin, and anti-β2-glycoprotein I antibodies of the same isotype (triple positivity) were included in the study. The trial was terminated prematurely after the enrollment of 120 patients (59 randomized to rivaroxaban and 61 to warfarin) because of an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. There were 11 (19%) events in the rivaroxaban group, and 2 (3%) events in the warfarin group. Thromboembolic events occurred in 7 (12%) patients randomized to rivaroxaban (4 ischemic stroke and 3 myocardial infarction), whereas no event was recorded in those randomized to warfarin. Major bleeding occurred in 6 patients: 4 (7%) in the rivaroxaban group and 2 (3%) in the warfarin group. No death was reported. The use of rivaroxaban in high-risk patients with antiphospholipid syndrome was associated with an increased rate of events compared with warfarin, thus showing no benefit and excess risk. This trial was registered at www.clinicaltrials.gov as #NCT02157272.

In the last 4 years, 6 phase 3 trials including a total of 27,023 patients with venous thromboembolism (VTE) compared a direct oral anticoagulant (DOAC) with vitamin K antagonists (VKAs). To aid the clinician in assessing the amount of information, we address frequently raised clinical questions in a review of combined trial results. We included the phase 3 trials that compared dabigatran etexilate, rivaroxaban, apixaban, or edoxaban with VKA therapy in patients with acute symptomatic VTE. Recurrent VTE occurred in 2.0% of DOAC recipients compared with 2.2% in VKA recipients (relative risk [RR] 0.90, 95% confidence interval [CI] 0.77-1.06). Treatment with a DOAC significantly reduced the risk of major bleeding (RR 0.61, 95% CI 0.45-0.83). In parallel, intracranial bleeding, fatal bleeding, and clinically relevant nonmajor bleeding occurred significantly less in DOAC recipients. The efficacy and safety of DOACs were consistent in patients with pulmonary embolism, deep venous thrombosis, a body weight ≥100 kg, moderate renal insufficiency, an age ≥75 years, and cancer. In conclusion, DOACs and VKAs have similar efficacy in the treatment of acute symptomatic VTE, a finding that is consistent in key clinical subgroups. Treatment with a DOAC significantly reduces the risks of major bleeding.