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REVEAL (The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) provides current demographics of patients with group 1 pulmonary arterial hypertension (PAH) in the United States. [ABSTRACT FROM AUTHOR]

Background: The Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management (REVEAL Registry) was established to provide updated characteristics of patients with pulmonary arterial hypertension (PAH) and to improve diagnosis, treatment, and management.Methods: Fifty-four US centers enrolled consecutively screened patients with World Health Organization group I PAH who met expanded hemodynamic criteria of mean pulmonary arterial pressure (PAP) > 25 mm Hg at rest (30 mm Hg with exercise), pulmonary capillary wedge pressure (PCWP) or= 240 dynes x s x cm(-5). Patients meeting the traditional hemodynamic definition (PCWP Results: Between March 2006 and September 2007, 2,967 patients enrolled. Among 2,525 adults meeting traditional hemodynamic criteria, the mean age was 53 +/- 14 years, and 2,007 (79.5%) were women. The mean duration between symptom onset and diagnostic catheterization was 2.8 years, and 1,008 (41.3%) patients were treated with more than one pulmonary vascular-targeted medication. Compared with patients meeting the traditional hemodynamic definition of PAH, patients with a PCWP of 16 to 18 mm Hg were older, more obese, had a lower 6-min walk distance, and had a higher incidence of systemic hypertension, sleep apnea, renal insufficiency, and diabetes.Conclusions: Patients in the REVEAL Registry are older and more often female than in previous descriptions. Delays between symptom onset and diagnostic catheterization persist. Many treatment regimens are fundamentally empirical, and data will be required to determine outcomes, improve risk stratification, and develop and validate more precise prognostic tools. Patients with PCWP of 16 to 18 mm Hg differ in a number of important respects from those meeting the traditional hemodynamic definition of PAH. [ABSTRACT FROM AUTHOR]

Purpose: To determine the strength of clinical evidence for individual drugs as a cause of thrombocytopenia.Data Sources: All English-language reports on drug-induced thrombocytopenia.Study Selection: Articles describing thrombocytopenia caused by heparin were excluded from review. Of the 581 articles reviewed, 20 were excluded because they contained no patient case reports. The remaining 561 articles reported on 774 patients.Data Extraction: Two of the authors used a priori criteria to independently review each patient case report. Two hundred fifty-nine patient case reports were excluded from further review because of lack of evaluable data, platelet count of 100000 cells/microL or more, use of cytotoxic or nontherapeutic agents, occurrence of drug-induced systemic disease, or occurrence of disease in children. For the remaining 515 patient case reports, a level of evidence for the drug as the cause of thrombocytopenia was assigned. Data on bleeding complications and clinical course were recorded.Data Synthesis: The evidence supported a definite or probable causal role for the drug in 247 patient case reports (48%). Among the 98 drugs described in these reports, quinidine was mentioned in 38 case reports, gold in 11, and trimethoprim-sulfamethoxazole in 10. Of the 247 patients described in the case reports, 23 (9%) had major bleeding and 2 (0.8%) died of bleeding.Conclusions: Many reports of drug-induced thrombocytopenia do not provide evidence supporting a definite or probable causal relation between the disease and the drug. Future patient case reports should incorporate standard criteria to clearly establish the etiologic role of the drug. [ABSTRACT FROM AUTHOR]

This chapter about antithrombotic therapy for venous thromboembolic disease is part of the seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S-187S). Among the key recommendations in this chapter are the following: for patients with objectively confirmed deep vein thrombosis (DVT), we recommend short-term treatment with subcutaneous (SC) low molecular weight heparin (LMWH) or, alternatively, IV unfractionated heparin (UFH) [both Grade 1A]. For patients with a high clinical suspicion of DVT, we recommend treatment with anticoagulants while awaiting the outcome of diagnostic tests (Grade 1C+). In acute DVT, we recommend initial treatment with LMWH or UFH for at least 5 days (Grade 1C), initiation of vitamin K antagonist (VKA) together with LMWH or UFH on the first treatment day, and discontinuation of heparin when the international normalized ratio (INR) is stable and > 2.0 (Grade 1A). For the duration and intensity of treatment for acute DVT of the leg, the recommendations include the following: for patients with a first episode of DVT secondary to a transient (reversible) risk factor, we recommend long-term treatment with a VKA for 3 months over treatment for shorter periods (Grade 1A). For patients with a first episode of idiopathic DVT, we recommend treatment with a VKA for at least 6 to 12 months (Grade 1A). We recommend that the dose of VKA be adjusted to maintain a target INR of 2.5 (INR range, 2.0 to 3.0) for all treatment durations (Grade 1A). We recommend against high-intensity VKA therapy (INR range, 3.1 to 4.0) [Grade 1A] and against low-intensity therapy (INR range, 1.5 to 1.9) compared to INR range of 2.0 to 3.0 (Grade 1A). For the prevention of the postthrombotic syndrome, we recommend the use of an elastic compression stocking (Grade 1A). For patients with objectively confirmed nonmassive PE, we recommend acute treatment with SC LMWH or, alternatively, IV UFH (both Grade 1A). For most patients with pulmonary embolism (PE), we recommend clinicians not use systemic thrombolytic therapy (Grade 1A). For the duration and intensity of treatment for PE, the recommendations are similar to those for DVT. [ABSTRACT FROM AUTHOR]

Adjusted doses of oral warfarin sodium or fixed doses of subcutaneous low-molecular-weight heparin (LMWH) are the standard approaches for preventing venous thromboembolism following major orthopedic surgery of the legs. In recent years, new anticoagulants have been compared with either LMWH or warfarin. The optimal timing for the first dose of LMWH prophylaxis and of the new anticoagulants is controversial. Recent clinical trials of LMWH and of newer anticoagulants have provided new information on the relationship between the timing of the first anticoagulant dose and the efficacy and safety of thromboprophylaxis after major orthopedic surgery. These data on the optimal timing of initiating prophylaxis come from limited direct randomized comparisons of different timing with the same anticoagulant, subgroup analysis of large studies with a single anticoagulant, indirect comparisons across studies in systematic reviews, and single randomized trials comparing different anticoagulants. In the direct comparison of the same anticoagulant, preoperative initiation of the same regimen of LMWH (dalteparin) increased major bleeding, without improved antithrombotic efficacy compared to the early postoperative regimen. Fondaparinux, 2.5 mg, begun 6 h postoperatively is more effective and as safe as the currently approved regimens of enoxaparin begun either 12 h preoperatively, or 12 to 24 h postoperatively, in patients undergoing major orthopedic surgery. In a subgroup analysis of several large randomized trials, fondaparinux, 2.5 mg, begun < 6 h postoperatively was associated with increased major bleeding, without improved efficacy. The results of indirect comparisons also favor the use of a 6-h postoperative starting time for the first dose, while the single randomized trials comparing different anticoagulants performed to date are not helpful in establishing an optimal time for the first dose. The aggregate clinical research evidence supports the following general conclusions about the relationship between the timing of the first anticoagulant dose and the efficacy and safety of prophylaxis: (1) preoperative initiation is not required for good efficacy and, when begun within 2 h of surgery, increases major bleeding; (2) initiation at 6 h postoperatively is effective and not associated with increased major bleeding; (3) initiation < 6 h postoperatively increases major bleeding, without improved efficacy; thus, 6 h appears to be the threshold for early postoperative administration; and (4) initiation 12 to 24 h postoperatively may be less effective than initiation at 6 h, but further randomized trials comparing the same anticoagulant initiated at different times postoperatively (eg, 6 h vs 12 h) are required to establish definitively the optimal timing of the first anticoagulant dose. [ABSTRACT FROM AUTHOR]

Background: A fixed-dose regimen of rivaroxaban, an oral factor Xa inhibitor, has been shown to be as effective as standard anticoagulant therapy for the treatment of deep-vein thrombosis, without the need for laboratory monitoring. This approach may also simplify the treatment of pulmonary embolism.Methods: In a randomized, open-label, event-driven, noninferiority trial involving 4832 patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis, we compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding.Results: Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0; P=0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group (2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12; 95% confidence interval [CI], 0.75 to 1.68). The principal safety outcome occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard-therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P=0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P=0.003). Rates of other adverse events were similar in the two groups.Conclusions: A fixed-dose regimen of rivaroxaban alone was noninferior to standard therapy for the initial and long-term treatment of pulmonary embolism and had a potentially improved benefit-risk profile. (Funded by Bayer HealthCare and Janssen Pharmaceuticals; EINSTEIN-PE ClinicalTrials.gov number, NCT00439777.). [ABSTRACT FROM AUTHOR]

The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) has been designed to meet the need for current information about patients with pulmonary arterial hypertension (PAH). The main objectives of REVEAL are to better define and understand PAH and to assess the consequences of treatment strategies. REVEAL is collecting clinically relevant data from 3500 consecutively enrolled patients with confirmed PAH diagnoses. Outcomes will be evaluated longitudinally and compared according to the baseline classification of PAH. The primary outcome for group comparisons will be survival. Collected data include World Health Organization functional class, 6-minute walk distance, cardiopulmonary exercise testing, pulmonary function test results, hemodynamic measurements, functional status, hospitalizations, and death. REVEAL will be the richest source of data on patients with World Health Organization group I PAH. [ABSTRACT FROM AUTHOR]

Background:  About 7% of patients with cancer-associated venous thromboembolism (CAT) develop a recurrence during anticoagulant treatment. Identification of high-risk patients may help guide treatment decisions., Aim:  To identify clinical predictors and develop a prediction model for on-treatment recurrent CAT., Methods:  For this individual patient data meta-analysis, we used data from four randomized controlled trials evaluating low-molecular-weight heparin or direct oral anticoagulants (DOACs) for CAT (Hokusai VTE Cancer, SELECT-D, CLOT, and CATCH). The primary outcome was adjudicated on-treatment recurrent CAT during a 6-month follow-up. A clinical prediction model was developed using multivariable logistic regression analysis with backward selection. This model was validated using internal-external cross-validation. Performance was assessed by the c-statistic and a calibration plot., Results:  After excluding patients using vitamin K antagonists, the combined dataset comprised 2,245 patients with cancer and acute CAT who were treated with edoxaban (23%), rivaroxaban (9%), dalteparin (47%), or tinzaparin (20%). Recurrent on-treatment CAT during the 6-month follow-up occurred in 150 (6.7%) patients. Predictors included in the final model were age (restricted cubic spline), breast cancer (odds ratio [OR]: 0.42; 95% confidence interval [CI]: 0.20-0.87), metastatic disease (OR: 1.44; 95% CI: 1.01-2.05), treatment with DOAC (OR: 0.66; 95% CI: 0.44-0.98), and deep vein thrombosis only as an index event (OR: 1.72; 95% CI: 1.31-2.27). The c-statistic of the model was 0.63 (95% CI: 0.54-0.72) after internal-external cross-validation. Calibration varied across studies., Conclusion:  The prediction model for recurrent CAT included five clinical predictors and has only modest discrimination. Prediction of recurrent CAT at the initiation of anticoagulation remains challenging., Competing Interests: M.G. is an employee of Daiichi Sankyo. A.Y.Y.L. reports consulting fees and honoraria from Bayer AG, consulting fees and honoraria from LEO Pharma, consulting fees and honoraria from Pfizer, consulting fees from Servier, and honoraria from Bristol Myers Squibb. M.D.N. reports personal fees as an invited speaker from Bayer, Daiichi Sankyo, and Viatris, personal fees for advisory board membership from Leo Pharma, Janssen, and Pfizer, and institutional funding from Leo Pharma, all outside the submitted work. G.E.R. reports consultancy fees or honoraria from AMAG Pharma, Alnylam, Anthos Therapeutics, Bayer HealthCare Pharmaceuticals Inc., Bristol-Myers Squibb, Daiichi Sankyo Inc., Ionis, Janssen Global Services LLC, Pfizer, Regeneron, Sirius Pharmaceutical; honoraria from BMS, Pfizer, Daiichi Sankyo; DSMB or advisory board membership from Anthos Therapeutics, Janssen, Bristol-Myers Squibb, and Pfizer, leadership or fiduciary role in other board, society, committee or advocacy group of OU Health, and the National Blood Clot Alliance. P.W.K. reports research funding from Daiichi Sankyo and Roche diagnostics. H.R.B. reports research support from Sanofi-Aventis, Bayer HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Pfizer, Roche, IONIS, Boehringer Ingelheim, Eli Lilly, and Novartis. Consultant from Sanofi-Aventis, Bayer HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Pfizer, Roche, IONIS, Boehringer Ingelheim, Eli Lilly, and Novartis. Scientific advisory board from Sanofi-Aventis, Bayer HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Pfizer, Roche, IONIS, Boehringer Ingelheim, Eli Lilly, and Novartis. N.v.E. reports advisory board honoraria from Daiichi Sankyo, LEO Pharma, and Bayer, which were transferred to his institute. The other authors have nothing to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Cancer-associated thrombosis, with the incidence rising over the years, is associated with significant morbidity and mortality in patients with cancer. Recent advances in the treatment of cancer-associated venous thromboembolism (VTE) include the introduction of direct oral anticoagulants (DOACs), which provide a more convenient and effective option than low-molecular-weight heparin (LMWH). Nonetheless, important unmet needs remain including an increased risk of bleeding in certain patient subgroups such as those with gastroesophageal cancer, concerns about drug-drug interactions, and management of patients with severe renal impairment. Although DOACs are more convenient than LMWH, persistence can decline over time. Factor XI inhibitors have potential safety advantages over DOACs because factor XI appears to be essential for thrombosis but not hemostasis. In phase II trials, some factor XI inhibitors were superior to enoxaparin for the prevention of VTE after knee replacement surgery without increasing the risk of bleeding. Ongoing trials are assessing the efficacy and safety of factor XI inhibitors for the treatment of cancer-associated VTE., (© The Author(s) 2023. Published by Oxford University Press.)

Aims: Deciding to stop or continue anticoagulation for venous thromboembolism (VTE) after initial treatment is challenging, as individual risks of recurrence and bleeding are heterogeneous. The present study aimed to develop and externally validate models for predicting 5-year risks of recurrence and bleeding in patients with VTE without cancer who completed at least 3 months of initial treatment, which can be used to estimate individual absolute benefits and harms of extended anticoagulation., Methods and Results: Competing risk-adjusted models were derived to predict recurrent VTE and clinically relevant bleeding (non-major and major) using 14 readily available patient characteristics. The models were derived from combined individual patient data from the Bleeding Risk Study, Hokusai-VTE, PREFER-VTE, RE-MEDY, and RE-SONATE (n = 15,141, 220 recurrences, 189 bleeding events). External validity was assessed in the Danish VTE cohort, EINSTEIN-CHOICE, GARFIELD-VTE, MEGA, and Tromsø studies (n = 59 257, 2283 recurrences, 3335 bleeding events). Absolute treatment effects were estimated by combining the models with hazard ratios from trials and meta-analyses. External validation in different settings showed agreement between predicted and observed risks up to 5 years, with C-statistics ranging from 0.48-0.71 (recurrence) and 0.61-0.68 (bleeding). In the Danish VTE cohort, 5-year risks ranged from 4% to 19% for recurrent VTE and 1% -19% for bleeding., Conclusion: The VTE-PREDICT risk score can be applied to estimate the effect of extended anticoagulant treatment for individual patients with VTE and to support shared decision-making., Competing Interests: Conflict of Interest: Marc Carrier reports research funding from BMS, Leo Pharma, and Pfizer, and honoraria from Bayer, Sanofi, BMS, Leo Pharma, Servier and Pfizer. All fees are paid to his institution. Ander Cohen reports grants or contracts, consulting fees and payment or honoraria from Bayer AG, Daiichi Sankyo, BMS/Pfizer, and AstraZeneca. All fees were paid to his company. Alfredo Farjat was a full-time employee at Thrombosis Research Institute when he collaborated with this study. Akos Ference Pap is an employee of Bayer AG. Samuel Goldhaber reports grants or contracts from Bayer, Boston Scientific BTG EKOS, NHLBI, BMS, Janssen and Pfizer, consulting fees from Agile, Pfizer, Bayer, speaker fees from Lankenau Grand Rounds in Medicine, Bakken Symposium -University of Minnesota, The Brigham Board Review in Critical Care ‘Virtual Studio/Distance Learning’, New York Cardiovascular Symposium, Latin American Anticoagulation Series Conference, Jeresaty Symposium—Trinity Health of New England, Rutgers New Jersey Medical School Grand Rounds, SBACV Symposium—Brazil Society of Angiology and Vascular Medicine, Brigham-Sheba Collaboration on Thrombosis and Vascular Medicine and Philippine Society of Vascular Medicine Annual Convention. Michael Grosso is an employee of Daiichi Sankyo. Ajay Kakkar reports grants from Bayer AG, Sanofi SA, personal fees from Anthos Therapeutics, Bayer AG, Sanofi S.A. Karen Pieper reports consulting fees from Cryolife, J&J Pharmaceuticals, Artivion and Element Science. Gary Raskob reports consultancy fees or honoraria from AMAG Pharma, Anylam, Anthos Therapeutics, Bayer HealthCare Pharmaceuticals Inc., Bristol-Myers Squibb, Daiichi Sankyo Inc., Janssen Global Services LLC, Pfizer, and XaTrek; honoraria from BMS, Pfizer, Daiichi Sankyo; DSMB or advisory board membership from Anthos Therapetuics, Janssen, Bristol-Myers Squibb and Pfizer, leadership or fiduciary role in other board, society, committee or advocacy group of OU Health, stock or stock option ownership for AbbVie, Inc., Gilead Sciences Inc, GlaxoSmithKline, LLC., LLY, MRK, and Pfizer. Sam Schulman reports research grants, paid to his institution, from Octopharma, and consulting fees from Alexion, Bayer, Boehringer–Ingelheim, Sanofi, Daiichi Sankyo and Octopharma. Minggao Shi is an employee of Daiichi Sankyo. Phillip Wells reports grants and speaker fees from BMS/Pfizer, consulting fees from Anthos and speaker fees and consulting fees from Bayer Healthcare. All fees are paid to his institution. The other authors have nothing to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Patients with venous thromboembolism (VTE) are commonly classified by the presence or absence of provoking factors at the time of VTE to guide treatment decisions. This approach may not capture the heterogeneity of the disease and its prognosis., Objectives: To evaluate clinically important novel phenotypic clusters among patients with VTE without cancer and to explore their association with anticoagulant treatment and clinical outcomes., Methods: Latent class analysis was performed with 18 baseline clinical variables in 3062 adult patients with VTE without active cancer participating in PREFER in VTE, a noninterventional disease registry. The derived latent classes were externally validated in a post hoc analysis of Hokusai-VTE (n = 6593), a randomized trial comparing edoxaban with warfarin. The associations between cluster membership and anticoagulant treatment, recurrent VTE, bleeding, and mortality after initial treatment were studied., Results: The following 5 clusters were identified: young men cluster (n = 1126, 37%), young women cluster (n = 215, 7%), older people cluster (n = 1106, 36%), comorbidity cluster (n = 447, 15%), and history of venous thromboembolism cluster (n = 168, 5%). Patient characteristics varied by age, sex, medical history, and treatment patterns. Consistent clusters were evident on external validation. In Cox proportional hazard models, recurrence risk was lower in the young women cluster (hazard ratio [HR], 0.27; 95% CI, 0.12-0.61) compared with the comorbidity cluster, after adjusting for extended anticoagulation. The risk of bleeding was lower in young men, young women, and older people clusters (HR, 0.50; 95% CI, 0.38-0.66; HR, 0.23; 95% CI, 0.11-0.46; and HR, 0.55; 95% CI 0.41-0.73, respectively)., Conclusion: The heterogeneity of VTE cases extends beyond the distinction between provoked and unprovoked VTE., (Copyright © 2022 International Society on Thrombosis and Haemostasis. All rights reserved.)

Background Venous thromboembolism (VTE) often occurs after hospitalization in medically ill patients, but the population benefit-risk of extended thromboprophylaxis remains uncertain. Methods and Results The MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) study (NCT02111564) was a randomized double-blind trial that compared thromboprophylaxis with rivaroxaban 10 mg daily versus placebo for 45 days after hospital discharge in medically ill patients with a creatinine clearance ≥50 mL/min. The benefit-risk balance in this population was quantified by calculating the between-treatment rate differences in efficacy and safety end points per 10 000 patients treated. Clinical characteristics of the study population were consistent with a hospitalized medical population at risk for VTE. Treating 10 000 patients with rivaroxaban resulted in 32.5 fewer symptomatic VTE and VTE-related deaths but was associated with 8 additional major bleeding events. The treatment benefit was driven by the prevention of nonfatal symptomatic VTE (26 fewer events). There was no between-treatment difference in the composite of critical site or fatal bleeding. Conclusions Extending thromboprophylaxis with rivaroxaban for 45 days after hospitalization provides a positive benefit-risk balance in medically ill patients at risk for VTE who are not at high risk for bleeding. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT02111564.

This post hoc subgroup analysis examined efficacy and safety outcomes with extended thromboprophylaxis rivaroxaban compared with in-hospital enoxaparin in 2,078 patients from the MAGELLAN study who had a hospitalization for heart failure or a history of heart failure and a lower risk of bleeding. A significant 36% reduction in the composite endpoint of asymptomatic proximal deep vein thrombosis (DVT) in the lower extremity, symptomatic DVT in the lower extremity (proximal or distal), symptomatic nonfatal pulmonary embolism, and venous thromboembolism-related death was observed with rivaroxaban. Major bleeding was low in both groups and not significantly increased with rivaroxaban., Competing Interests: Conflict of Interest A.C.S. has received research grants and consulted for Janssen Research & Development, LLC, Bayer, Daiichi Sankyo, Portola, Boehringer Ingelheim, and ATLAS Group. G.E.R. has consulted for Janssen Research & Development, LLC and Bayer; has consulted and received honoraria for advisory boards from Anthos, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Novartis, Pfizer, Portola, and Tetherex. T.E.S. and Y.D.S. are employees of Bayer US LLC. W.L., J.A., and E.S.B. are employees of Janssen Research & Development, LLC. A.M. has no conflicts of interest to disclose., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background: Data on the population-based incidence of cancer-associated venous thromboembolism (VTE) from racially diverse populations are limited., Objective: To evaluate the incidence and burden of cancer-associated VTE, including demographic and racial subgroups in the general population of Oklahoma County-which closely mirrors the United States., Design: A population-based prospective study., Setting: We conducted surveillance of VTE at tertiary care facilities and outpatient clinics in Oklahoma County, Oklahoma, from 2012-2014. Surveillance included reviewing all imaging reports used to diagnose VTE and identifying VTE events from hospital discharge data and death certificates. Cancer status was determined by linkage to the Oklahoma Central Cancer Registry., Measurements: We used Poisson regression to calculate crude and age-adjusted incidence rates of cancer-associated VTE per 100 000 general population per year, with 95% confidence intervals (95% CI)., Results: The age-adjusted incidence (95% CI) of cancer-associated VTE among adults age ≥ 18 was 70.0 (65.1-75.3). The age-adjusted incidence rates (95% CI) were 85.9 (72.7-101.6) for non-Hispanic Blacks, 79.5 (13.2-86.5) for non-Hispanic Whites, 18.8 (8.9-39.4) for Native Americans, 15.6 (7.0-34.8) for Asian/Pacific Islanders, and 15.2 (9.2-25.1) for Hispanics. Recurrent VTE up to 2 years after the initial diagnosis occurred in 38 of 304 patients (12.5%) with active cancer and in 34 of 424 patients (8.0%) with a history of cancer &gt; 6 months previously., Conclusion: Age-adjusted incidence rates of cancer-associated VTE vary substantially by race and ethnicity. The relatively high incidence rates of first VTE and of recurrence warrant further assessment of strategies to prevent VTE among cancer patients., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background  The MARINER trial evaluated whether postdischarge thromboprophylaxis with rivaroxaban could reduce the primary outcome of symptomatic venous thromboembolism (VTE) or VTE-related death in acutely ill medical patients at risk for VTE. Although aspirin use was not randomized, approximately half of the enrolled patients were receiving aspirin at baseline. We hypothesized that thromboprophylaxis with once-daily rivaroxaban (10 mg or, if creatinine clearance was 30-49 mL/min, 7.5 mg) plus aspirin (R/A) would be superior to placebo without aspirin (no thromboprophylaxis [no TP]). Methods  We compared the primary and major secondary outcomes in the intention-to-treat population in four subgroups defined at baseline: (1) R/A ( N  = 3,159); (2) rivaroxaban alone ( N  = 2,848); (3) aspirin alone ( N  = 3,046); and (4) no TP ( N  = 2,966). Major bleeding (MB) and nonmajor clinically relevant (NMCR) bleeding were assessed in the safety population on treatment plus 2 days. Results  Patients on R/A had reduced symptomatic VTE and VTE-related death compared with no TP (0.76 vs 1.28%, p  = 0.042), and experienced less symptomatic VTE and all-cause mortality ( p  = 0.005) and all-cause mortality alone ( p  = 0.01) compared with no TP. Event incidences for rivaroxaban alone (0.91%) or aspirin alone (0.92%) were similar. MB was low in all groups but lowest in the no TP group. NMCR bleeding was increased with R/A compared with no TP ( p  = 0.009). Limitations  Aspirin use was not randomized. Conclusion  Extended postdischarge thromboprophylaxis with R/A was associated with less symptomatic VTE and VTE-related death compared with no TP in previously hospitalized medical patients at risk for VTE. NMCR bleeding was increased with R/A compared with no TP. These post hoc findings need confirmation in a prospective trial., Competing Interests: Conflict of Interest Alex C. Spyropoulos: Janssen Research & Development LLC, Bayer, Portola, Boehringer Ingelheim, Daiichi Sankyo, ATLAS group; Mark Goldin: Janssen Research & Development LLC; Walter Ageno: Janssen Research & Development LLC, Bayer, Portola, Daiichi Sankyo, Aspen, BMS, Pfizer, Sanofi, Leo Pharma; Gregory W. Albers: Janssen Research & Development LLC, Bayer; C. Greg Elliott: Janssen Research & Development LLC, Bayer; Jonathan L. Halperin: Janssen Research & Development LLC, Abbott, Bayer, Boehringer Ingelheim, National Institute of Health, ATLAS group, Johnson & Johnson, Ortho-McNeil-Janssen; William R. Hiatt: Janssen Research & Development LLC, Bayer, NIH; Gregory Maynard: Janssen Research & Development LLC; P. Gabriel Steg: Janssen Research & Development LLC, Bayer, Merck, Sanofi, Servier, Amarin, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Novartis, Regeneron, Lilly, AstraZeneca, Idorsia, Novo-Nordisk; Jeffrey I. Weitz: Janssen Research & Development LLC, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis, Merck, Novartis, Pfizer, Portola, Anthos, Servier; Theodore E. Spiro: Bayer U.S. LLC; Wentao Lu, Janssen Research and Development LLC; Jessica Marsigliano, Janssen Research and Development LLC; Gary E. Raskob: Janssen Research & Development LLC, Bayer, BMS, Daiichi Sankyo, Boehringer Ingelheim, Eli Lilly, Pfizer, Portola, Novartis, Anthos, Tetherex; Elliot S. Barnathan: Janssen Research & Development LLC., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background: Extended thromboprophylaxis has not been widely implemented in acutely ill medical patients because of bleeding concerns. The MAGELLAN (Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Medically Ill Patients Comparing Rivaroxaban With Enoxaparin) and MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) trials evaluated whether rivaroxaban compared with enoxaparin or placebo could prevent venous thromboembolism without increased bleeding. We hypothesized that patients with major bleeding but not those with nonmajor clinically relevant bleeding would be at an increased risk of all-cause mortality (ACM)., Methods: We evaluated all bleeding events in patients taking at least 1 dose of study drug and their association with ACM in 4 mutually exclusive groups: (1) no bleeding, or first event was (2) nonmajor clinically relevant bleeding, (3) major bleeding, or (4) trivial bleeding. Using a Cox proportional hazards model adjusted for differences in baseline characteristics associated with ACM, we assessed the risk of ACM after such events., Results: Compared with patients with no bleeding, the risk of ACM for patients with nonmajor clinically relevant bleeding was not increased in MARINER (hazard ratio, 0.43; P =0.235) but was increased in MAGELLAN (hazard ratio, 1.74; P =0.021). Major bleeding was associated with a higher incidence of ACM in both studies, whereas trivial bleeding was not associated with ACM in either study., Conclusions: Patients with major bleeding had an increased risk of ACM, whereas nonmajor clinically relevant bleeding was not consistently associated with an increased risk of death. These results inform the risk-benefit calculus of extended thromboprophylaxis in medically ill patients., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: MAGELLAN, NCT00571649. URL: https://www., Clinicaltrials: gov; Unique identifier: MARINER, NCT02111564.

Background: Factor XIa inhibitors for the prevention and treatment of venous and arterial thromboembolism may be more effective and result in less bleeding than conventional anticoagulants. Additional data are needed regarding the efficacy and safety of milvexian, an oral factor XIa inhibitor., Methods: In this parallel-group, phase 2 trial, we randomly assigned 1242 patients undergoing knee arthroplasty to receive one of seven postoperative regimens of milvexian (25 mg, 50 mg, 100 mg, or 200 mg twice daily or 25 mg, 50 mg, or 200 mg once daily) or enoxaparin (40 mg once daily). The primary efficacy outcome was venous thromboembolism (which was a composite of asymptomatic deep-vein thrombosis, confirmed symptomatic venous thromboembolism, or death from any cause). The principal safety outcome was bleeding., Results: Among the patients receiving milvexian twice daily, venous thromboembolism developed in 27 of 129 (21%) taking 25 mg, in 14 of 124 (11%) taking 50 mg, in 12 of 134 (9%) taking 100 mg, and in 10 of 131 (8%) taking 200 mg. Among those receiving milvexian once daily, venous thromboembolism developed in 7 of 28 (25%) taking 25 mg, in 30 of 127 (24%) taking 50 mg, and in 8 of 123 (7%) taking 200 mg, as compared with 54 of 252 patients (21%) taking enoxaparin. The dose-response relationship with twice-daily milvexian was significant (one-sided P<0.001), and the 12% incidence of venous thromboembolism with twice-daily milvexian was significantly lower than the prespecified benchmark of 30% (one-sided P<0.001). Bleeding of any severity occurred in 38 of 923 patients (4%) taking milvexian and in 12 of 296 patients (4%) taking enoxaparin; major or clinically relevant nonmajor bleeding occurred in 1% and 2%, respectively; and serious adverse events were reported in 2% and 4%, respectively., Conclusions: Postoperative factor XIa inhibition with oral milvexian in patients undergoing knee arthroplasty was effective for the prevention of venous thromboembolism and was associated with a low risk of bleeding. (Funded by Bristol Myers Squibb and Janssen Research and Development; AXIOMATIC-TKR ClinicalTrials.gov number, NCT03891524.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: In the Hokusai VTE Cancer study, the risk of major bleeding was 2.9% higher in the edoxaban group compared with the dalteparin group, mainly due to more gastrointestinal bleedings in patients with gastrointestinal cancer. The identification of risk factors for gastrointestinal bleeding may help to guide the use of DOACs in these patients., Objectives: To evaluate risk factors for gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban., Patients/methods: In this nested case-control study in patients with gastrointestinal cancer randomized to edoxaban in the Hokusai VTE Cancer study, cases (patients with clinically relevant gastrointestinal bleeding during treatment) were randomly matched to three controls (patients who had no gastrointestinal bleeding). Data for the 4-week period prior to bleeding were retrospectively collected. Odds ratios (ORs) were calculated in a crude conditional logistic regression model and a multivariable model adjusted for age, sex, and cancer type., Results: Twenty-four cases and 64 matched controls were included. In the multivariable analysis, advanced cancer, defined as regionally advanced or metastatic cancer (OR 3.6, 95% CI 1.01-12.6) and low hemoglobin levels (OR 4.8, 95% CI 1.5-16.0) were significantly associated with bleeding. There was no significant difference in patients with resected tumors (OR 0.4, 95% CI 0.1-1.4), or in patients on chemotherapy (OR 1.3, 95% CI 0.5-3.5)., Conclusion: Advanced cancer and low hemoglobin levels were associated with an increased risk of gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban. We were unable to identify other risk factors, mainly due to limited statistical power., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background Thromboprophylaxis extended after hospital discharge in medically ill patients currently is not recommended by practice guidelines because of uncertainty about the benefit for preventing major or fatal thromboembolic events, and the risk of bleeding. Methods and Results We assessed the benefit and risk of thromboprophylaxis with rivaroxaban 10 mg once daily extended for 25 to 45 days after hospitalization for preventing major thromboembolism in medically ill patients using the pooled data in 16 496 patients from 2 randomized trials, MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) and MAGELLAN (Multicenter, randomized, parallel-group efficacy and safety study for the prevention of venous thromboembolism in hospitalized medically ill patients comparing rivaroxaban with enoxaparin). The data from the MARINER trial were pooled with the data from the MAGELLAN trial in patients who were free of thrombotic or bleeding events up to the last dose of enoxaparin/placebo and who continued in the outpatient phase of thromboprophylaxis. The composite outcome of major thromboembolic events (symptomatic deep vein thrombosis, nonfatal pulmonary embolism, myocardial infarction, and nonhemorrhagic stroke) and all-cause mortality was used to assess benefit and was compared with the risk of the composite of fatal and critical site bleeding. The incidence of the composite efficacy outcome was 1.80% (148 of 8222 patients) in the rivaroxaban group, compared with 2.31% (191 of 8274 patients in the placebo group) (HR, 0.78 [95% CI, 0.63-0.97], P =0.024). Fatal or critical site bleeding events were infrequent and occurred in <0.1% of patients in both groups (rivaroxaban 0.09%; placebo 0.04%; HR, 2.36; P =0.214). Conclusions The results suggest a benefit for reducing major thromboembolic outcomes (number needed to treat: 197), with a favorable trade-off to fatal or critical site bleeding (number needed to harm: 2045). Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00571649 and NCT02111564.

Background: The long-term risk for recurrent venous thromboembolism (VTE) during extended anticoagulation for a first unprovoked VTE is uncertain., Objectives: To determine the incidence of recurrent VTE during extended anticoagulation of up to 5 years in patients with a first unprovoked VTE., Methods: MEDLINE, EMBASE, and the Cochrane CENTRAL were searched to identify randomized trials and prospective cohort studies reporting recurrent VTE among patients with a first unprovoked VTE who were to receive anticoagulation for a minimum of six additional months after completing ≥3 months of initial treatment. Unpublished data on number of recurrent VTE and person-years, obtained from authors of included studies, were used to calculate study-level incidence rate, and random-effects meta-analysis was used to pool results., Results: Twenty-six studies and 15 603 patients were included in the analysis. During 11 631 person-years of follow-up, the incidence of recurrent VTE and fatal pulmonary embolism per 100 person-years was 1.41 (95% CI, 1.03-1.84) and 0.09 (0.04-0.16), with 5-year cumulative incidences of 7.1% (3.0%-13.2%) and 1.2% (0.4%-4.6%), respectively. The incidence of recurrent VTE was 1.08 (95% CI, 0.77-1.44) with direct oral anticoagulants and 1.55 (1.01-2.20) with vitamin K antagonists. The case-fatality rate of recurrent VTE was 4.9% (95% CI, 2.2%-8.7%)., Conclusions: In patients with a first unprovoked VTE, the long-term risk of recurrent VTE during extended anticoagulation is low but not negligible. Thus, clinicians and patients should be aware of this risk and take appropriate and timely action in case of suspicion of recurrent VTE. Estimates from this study can be used to advise patients on what to expect while receiving extended anticoagulation, and estimate the net clinical benefit of extended treatment to guide long-term management of unprovoked VTE., (© 2021 International Society on Thrombosis and Haemostasis.)

Background: Although older patients are at increased risk for venous thromboembolism (VTE), thromboprophylaxis is underused because of bleeding concerns. The MARINER trial evaluated whether rivaroxaban reduced symptomatic postdischarge VTE in acutely ill medical patients., Objectives: We hypothesized that rivaroxaban would have a favorable benefit/risk profile in patients ≥75 years of age., Methods: Patients were randomized in a double-blind manner at hospital discharge to rivaroxaban (10 mg/day for creatinine clearance ≥50 ml/min; 7.5 mg/day for ≥30-<50 ml/min) or placebo for 45 days. Using a Cox proportional hazard model including treatment as a covariate, we compared the risk of the primary efficacy outcome (symptomatic VTE plus VTE-related death in the intention-to-treat population) and safety outcome (International Society on Thrombosis and Haemostasis major bleeding in the safety population) in the prespecified subgroups of patients ≥ and <75 years of age., Results: The primary event rate in patients ≥75 years of age was 2-fold higher than that in those <75 years. The incidence of the primary efficacy outcomes in both age groups was numerically lower with rivaroxaban than with placebo (≥75: 1.2% and 1.6%, HR 0.73, 95% CI 0.43-1.22; <75 0.6% and 0.8%, HR 0.78, 95% CI 0.46-1.32; interaction p-value for age group = .85). The incidence of major bleeding was low and similar in the two age and treatment groups (interaction p value for age group = .35)., Conclusion: Symptomatic VTE and VTE-related death occur frequently in older patients with acute medical illness. The benefit/risk profile of rivaroxaban in patients ≥75 years of age appears consistent with that observed in the general population., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain., Purpose: To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups., Data Sources: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021., Study Selection: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment., Data Extraction: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies., Data Synthesis: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs., Limitation: Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs., Conclusion: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE., Primary Funding Source: Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

Background: The role of factor XI in the pathogenesis of postoperative venous thromboembolism is uncertain. Abelacimab is a monoclonal antibody that binds to factor XI and locks it in the zymogen (inactive precursor) conformation., Methods: In this open-label, parallel-group trial, we randomly assigned 412 patients who were undergoing total knee arthroplasty to receive one of three regimens of abelacimab (30 mg, 75 mg, or 150 mg) administered postoperatively in a single intravenous dose or to receive 40 mg of enoxaparin administered subcutaneously once daily. The primary efficacy outcome was venous thromboembolism, detected by mandatory venography of the leg involved in the operation or objective confirmation of symptomatic events. The principal safety outcome was a composite of major or clinically relevant nonmajor bleeding up to 30 days after surgery., Results: Venous thromboembolism occurred in 13 of 102 patients (13%) in the 30-mg abelacimab group, 5 of 99 patients (5%) in the 75-mg abelacimab group, and 4 of 98 patients (4%) in the 150-mg abelacimab group, as compared with 22 of 101 patients (22%) in the enoxaparin group. The 30-mg abelacimab regimen was noninferior to enoxaparin, and the 75-mg and 150-mg abelacimab regimens were superior to enoxaparin (P<0.001). Bleeding occurred in 2%, 2%, and none of the patients in the 30-mg, 75-mg, and 150-mg abelacimab groups, respectively, and in none of the patients in the enoxaparin group., Conclusions: This trial showed that factor XI is important for the development of postoperative venous thromboembolism. Factor XI inhibition with a single intravenous dose of abelacimab after total knee arthroplasty was effective for the prevention of venous thromboembolism and was associated with a low risk of bleeding. (Funded by Anthos Therapeutics; ANT-005 TKA EudraCT number, 2019-003756-37.)., (Copyright © 2021 Massachusetts Medical Society.)