BACKGROUND:Apixaban and rivaroxaban are the oral anticoagulants most frequently used to treat acute venous thromboembolism. However, uncertainty remains about the difference in bleeding risk between the two medications. METHODS:In an international trial with a prospective, randomized, open-label, blinded end-point design, we assigned, in a 1:1 ratio, eligible patients with acute symptomatic pulmonary embolism or proximal deep-vein thrombosis to receive apixaban or rivaroxaban for 3 months. Apixaban was given at a dose of 10 mg twice daily for 7 days followed by 5 mg twice daily, and rivaroxaban was given at a dose of 15 mg twice daily for 21 days followed by 20 mg daily. The primary outcome was clinically relevant bleeding, a composite of major bleeding or clinically relevant nonmajor bleeding, as defined according to the International Society on Thrombosis and Haemostasis, during the 3-month trial period. Secondary outcomes included death from any cause. RESULTS:A total of 2760 patients underwent randomization: 1370 to the apixaban group and 1390 to the rivaroxaban group. A primary-outcome event occurred in 44 of 1345 patients (3.3%) in the apixaban group and 96 of 1355 patients (7.1%) in the rivaroxaban group (relative risk, 0.46; 95% confidence interval [CI], 0.33 to 0.65; P<0.001). Death from any cause occurred in 1 patient (0.1%) in the apixaban group and in 4 patients (0.3%) in the rivaroxaban group (relative risk, 0.25; 95% CI, 0.03 to 2.26). Serious adverse events unrelated to bleeding or venous thrombosis occurred in 36 patients (2.7%) in the apixaban group and in 30 patients (2.2%) in the rivaroxaban group. CONCLUSIONS:Among patients with acute venous thromboembolism, the risk of clinically relevant bleeding was significantly lower with apixaban than with rivaroxaban during the 3-month treatment period. (Funded by the Canadian Institutes of Health Research and others; COBRRA ClinicalTrials.gov number, NCT03266783.).

Isolated distal deep venous thrombosis (iDDVT) is an infra-popliteal DVT without pulmonary embolism (PE). It is a common condition, but its management remains debated. We conducted a survey distributed by email to the members of the French Society of Vascular Medicine, Thrombosis Canada, the Swiss Society of Angiology and INVENT-VTE research networks; Our objectives were to determine how healthcare professionals specialized in thrombosis manage iDDVT and to obtain experts input on the design of a future clinical trial. Participants were asked how they diagnosed and managed iDDVT and what should be the treatment arms of a future clinical trial on iDDVT management. 472 thrombosis specialists answered the questionnaire, mainly from France ( n = 337), Canada ( n = 61) and Switzerland ( n = 28). Overall, 87.9% ( n = 405) of respondents stated that their center always performed whole leg ultrasound in case of suspected DVT and that they managed patients with iDDVT usually at least once a week in 50.3% ( n = 229) of cases. In 91.0% ( n = 415) of cases respondents treated patients with iDDVT with anticoagulation more than 75% of time, with therapeutic doses and for a duration of 3 months in 90.2% ( n = 406) and 74.7% ( n = 334) of cases respectively. Most respondent managed muscular and deep-calf vein DVT similarly. More than 60% of respondents favored future trials comparing prophylactic versus therapeutic anticoagulation. Our real-world, international, practice survey of healthcare professionals shows that almost all respondents always conduct whole leg ultrasonography in case of suspected DVT and that they treat iDDVT with therapeutic anticoagulation usually for 3 months.

BACKGROUND:Diagnosing venous thromboembolism (VTE) in patients with previous VTE is challenging. Only approximately 15% of these patients have a VTE recurrence ruled out without imaging, as compared with >30% in patients with a suspected first episode. Clinical decision rules (CDRs) are not well studied in this population. The aim was to assess the performance of existing CDRs (Wells and Geneva scores) in these patients. METHODS:This international prospective multicenter observational cohort study of outpatients with suspected VTE recurrence was conducted in 8 sites (November 2014-January 2019) (clinicaltrials.gov: NCT02297373). The primary outcome was the performance of CDRs. Secondary outcome included the diagnostic yield of D-dimers. Suspected recurrent VTE were adjudicated. Follow-up was 3 months. RESULTS:In total, 723 patients were included. Among patients with suspected isolated deep venous thrombosis (DVT), 4 of 67 patients (6.0%), 39 of 186 patients (21.0%), and 65 of 148 patients (43.9%) had recurrent VTE in the low, moderate, and high probability groups, respectively. Among patients with suspected isolated pulmonary embolism, 11 of 83 patients (13.3%), 56 of 160 patients (35.0%), and 12 to 25 patients (48.0%) had VTE recurrence in the low, moderate, and high probability groups (Wells), respectively. In patients with suspected isolated DVT and negative D-dimers, 2 of 65 patients, 3.1% (95% CI: 0.4%-10.7%) in the low and moderate probability groups had recurrent VTE at enrollment. In patients with suspected pulmonary embolism ± DVT and negative D-dimers, no recurrent VTE was diagnosed: 0 of 82, 0.0% (95% CI: 0.0%-4.4%). CONCLUSION:CDRs were able to characterize patients with increasing VTE prevalence. The efficiency and safety in ruling out recurrent VTE without imaging were lower than for suspected first VTE.

Background Guidelines recommend extended anticoagulation after a first unprovoked venous thromboembolism (VTE) for individuals at low risk of bleeding. However, racial disparities in bleeding risks during extended treatment remain understudied. Objectives To compare risks of anticoagulant-associated bleeding and performance of a risk assessment model by racial group during extended VTE treatment. Methods We analyzed 2 prospective cohorts of patients (223 Black participants and 4314 White participants) with a first unprovoked/weakly provoked VTE who continued anticoagulation after ≥3 months of initial treatment. Primary outcome was adjudicated International Society on Thrombosis and Haemostasis-defined major bleeding. Secondary outcomes included intracranial hemorrhage, fatal bleeding, and clinically relevant nonmajor bleeding. We determined incidence and hazard ratios (HRs) by race, then adjusted for bleeding risk factors that included the Creatinine, Hemoglobin, Age, antiPlatelet model. Results Black participants had higher prevalence of bleeding risk factors and a 1.9-fold higher risk of major bleeding (HR, 1.87; 95% CI, 1.04-3.36) compared with White participants. Adjustment attenuated racial difference for major bleeding but not intracranial hemorrhage (adjusted HR, 2.35; 95% CI, 1.23-4.48). Among those classified as low risk by Creatinine, Hemoglobin, Age, antiPlatelet model, Black participants had numerically higher major bleeding incidence than White participants (2.5 vs 1.1 per 100 person-years). We did not observe racial disparities in fatal bleeding or clinically relevant nonmajor bleeding. Conclusion Black individuals on extended anticoagulation have higher risk of major bleeding compared with White individuals. This effect appears to persist in those classified as low risk for bleeding. Risk assessment models for anticoagulant-associated bleeding that are generalizable to racialized populations are needed.

Background:The Villalta Scale (VS) to diagnose postthrombotic syndrome (PTS) consists of 5 patient-reported leg symptoms and 6 clinician-rated leg signs. It is unknown how the scale performs across racial groups. Objectives:Our study explored if there were differences in VS scores, particularly clinician-rated signs components, according to self-reported race. Methods:Exploratory analysis of the ATTRACT trial, a randomized controlled trial conducted at 56 US sites that investigated pharmacomechanical catheter-directed thrombolysis to prevent PTS after proximal deep vein thrombosis (DVT). At the 6-month visit after randomization, we compared self-reported Black (n = 123) and White (n = 541) participants for mean total VS score, VS symptoms score, VS signs score, individual signs scores, and correlation coefficients between VS signs and VS symptoms scores and between VS signs and Venous Insufficiency Epidemiological and Economic Study Quality of Life (VEINES-QOL) scores (a self-reported venous disease-specific quality of life measure). Results:Mean total VS score (4.67 vs. 4.12, P = .54),VS signs score (1.66 vs. 2.00, P = .07), and VS symptoms score (2.83 vs. 2.04, P = .10) were similar between Black and White participants. The mean score for one individual VS sign, venous ectasia, was lower in Black vs. White participants (0.24 vs. 0.63, P< .01). There was similar, modest correlation in Black and White participants between VS signs and VS symptoms scores (r black = 0.19; r white = 0.23) and between VS signs and VEINES-QOL scores (r black = -0.32; r white = -0.30). Results were adjusted for ATTRACT trial treatment group, age, sex, body mass index, DVT extent, hypertension, diabetes, dyslipidemia, and congestive heart failure. Conclusion:The findings suggest that some differences in VS scores exist according to self-reported race. It is unclear whether these reflect clinicians' underrating of some VS signs and/or differences in PTS severity. Further work is needed to understand how the VS performs across racial groups.

Introduction:Up to 50% of pulmonary embolism (PE) patients have perfusion defects or residual vascular obstruction during follow-up despite adequate anticoagulant treatment, and a similar percentage experience chronic functional limitations and/or dyspnoea post-PE. We aimed to evaluate the association between pulmonary perfusion defects or residual vascular obstruction and functional recovery after PE.Methods:We performed a systematic review and meta-analysis including studies assessing both the presence of perfusion defects or residual vascular obstruction and functional recovery (i.e.persistent symptoms, quality of life, exercise endurance). An odds ratio was pooled for perfusion defects or residual vascular obstruction and persistent symptoms using a random-effect model.Results:12 studies were included totalling 1888 PE patients; at a median of 6 months after PE (range 2–72 months), 34% had perfusion defects or residual vascular obstruction and 37% reported persistent symptoms. Among patients with perfusion defects or residual vascular obstruction, 48% (95% CI 37–60%, I2=82%) remained symptomatic during follow-up, compared to 34% (95% CI 20–51%, I2=96%) of patients without such defects. Presence of perfusion defects or residual vascular obstruction was associated with persistent symptoms (OR 2.15, 95% CI 1.66–2.78; I2=0%, τ=0). Notably, there was no association between these defects and quality of life or cardiopulmonary exercise test parameters.Conclusion:While the odds of having persistent symptoms was higher in patients with perfusion defects or residual vascular obstruction after acute PE, a significant proportion of these patients reported no limitations. A possible causality between perfusion defects or residual vascular obstruction and residual functional limitation therefore remains to be proven.

Background: We aimed to describe the event rates and risk-factors for symptomatic venous thromboembolism (VTE) and major bleeding in a population of hospitalized acutely ill medical patients. Methods: Patients >= 40 years old and hospitalized for acute medical illness who initiated enoxaparin prophylaxis were selected from the US Optum research database. Rates of symptomatic VTE and major bleeding at 90-days were estimated via the Kaplan-Meier (KM) method. Risk factors were identified via the Cox proportional hazards model. Results: A total of 123,022 patients met the selection criteria. The KM rates of VTE and major bleeding at 90-days were 3.5 % and 2.2 %, respectively. Among subgroups, the risk of VTE varied from 3.0 % in patients with ischemic stroke to 6.9 % in patients with a cancer-related hospitalization, and the risk of major bleeding varied from 1.9 % in patients with inflammatory conditions to 3.6 % in patients with ischemic stroke. Key risk factors for VTE were prior VTE (HR=4.15, 95 % confidence interval [CI] 3.80-4.53), cancer-related hospitalization (HR=2.35, 95 % CI 2.10-2.64), and thrombophilia (HR=1.64, 95 % CI 1.29-2.08). Key risk factors for major bleeding were history of major bleeding (HR=2.17, 95 % CI 1.72-2.74), history of non-major bleeding (HR=2.46, 95 % CI 2.24-2.70), and hospitalization for ischemic stroke (2.42, 95 % CI 2.11-2.78). Conclusion: There is substantial heterogeneity in the event rates for VTE and major bleeding in acute medically ill patients. History of VTE and cancer related hospitalization represent profiles with a high risk of VTE, where continued VTE prophylaxis may be warranted.

BACKGROUND:The optimal management of patients with intermediate-risk pulmonary embolism (PE), who have right heart dysfunction (determined by a combination of imaging and cardiac biomarkers) but a normal blood pressure, is uncertain. These patients suffer from reduced functional capacity and a lower quality of life over the long-term, despite use of anticoagulant therapy. Catheter-directed therapy (CDT) is a promising treatment for acute PE that rapidly removes thrombus and potentially improves cardiac dysfunction. However, CDT has risk and is costly, and it is not known whether it improves long-term cardiorespiratory fitness and/or quality of life compared with anticoagulation alone. METHODS:We are therefore conducting an open-label, assessor-blinded, multicenter randomized trial, the Pulmonary Embolism: Thrombus Removal with Catheter-Directed Therapy (PE-TRACT) Study, to compare CDT plus anticoagulation (CDT group) with anticoagulation alone (No-CDT group) in 500 patients with intermediate-risk PE. The primary study hypothesis is that CDT will increase the peak oxygen uptake (peak VO2) with cardiopulmonary exercise testing at 3 months and reduce New York Heart Association (NYHA) Class at 12 months compared with No-CDT. These 2 primary efficacy outcomes will be analyzed sequentially using a "gatekeeping" procedure; for NYHA class to be compared, peak oxygen consumption must first be shown to be significantly increased by CDT. Safety and cost-effectiveness will also be assessed. CONCLUSION:When completed, PE-TRACT will provide important evidence regarding the benefits and risks of CDT to treat intermediate-risk PE compared with anticoagulation alone. TRIAL REGISTRATION:clinicaltrials.gov: NCT05591118.

Background:Clinical trials suggest that therapeutic-dose heparin may prevent critical illness and vascular complications due to COVID-19, but knowledge gaps exist regarding the efficacy of therapeutic heparin including its comparative effect relative to intermediate-dose anticoagulation. Objectives:The authors performed 2 complementary secondary analyses of a completed randomized clinical trial: 1) a prespecified per-protocol analysis; and 2) an exploratory dose-based analysis to compare the effect of therapeutic-dose heparin with low- and intermediate-dose heparin. Methods:Patients who received initial anticoagulation dosed consistently with randomization were included. The primary outcome was organ support-free days (OSFDs), a combination of in-hospital death and days free of organ support through day 21. Results:Among 2,860 participants, 1,761 (92.8%) noncritically ill and 857 (89.1%) critically ill patients were treated per-protocol. Among noncritically ill per-protocol patients, the posterior probability that therapeutic-dose heparin improved OSFDs as compared with usual care was 99.3% (median adjusted OR: 1.36; 95% credible interval [CrI]: 1.07-1.74). Therapeutic heparin had a high posterior probability of efficacy relative to both low- (94.6%; adjusted OR: 1.26; 95% CrI: 0.95-1.64) and intermediate- (99.8%; adjusted OR: 1.80; 95% CrI: 1.22-2.62) dose thromboprophylaxis. Among critically ill per-protocol patients, the posterior probability that therapeutic heparin improved outcomes was low. Conclusions:Among noncritically ill patients hospitalized for COVID-19 who were randomized to and initially received therapeutic-dose anticoagulation, heparin, compared with usual care, was associated with improved OSFDs, a combination of in-hospital death and days free of organ support. Therapeutic heparin appeared superior to both low- and intermediate-dose thromboprophylaxis.

PURPOSE:Venous thromboembolism (VTE) is a common complication of critical illness. Sex- or gender-based analyses are rarely conducted and their effect on outcomes is unknown. We assessed for an effect modification of thromboprophylaxis (dalteparin or unfractionated heparin [UFH]) by sex on thrombotic (deep venous thrombosis [DVT], pulmonary embolism [PE], VTE) and mortality outcomes in a secondary analysis of the Prophylaxis for Thromboembolism in Critical Care Trial (PROTECT).METHODS:We conducted unadjusted analyses using Cox proportional hazards analysis, stratified by centre and admission diagnostic category, including sex, treatment, and an interaction term. Additionally, we performed adjusted analyses and assessed the credibility of our findings.RESULTS:Critically ill female (n = 1,614) and male (n = 2,113) participants experienced similar rates of DVT, proximal DVT, PE, any VTE, ICU death, and hospital death. In unadjusted analyses, we did not find significant differences in treatment effect favouring males (vs females) treated with dalteparin (vs UFH) for proximal leg DVT, any DVT, or any PE, but found a statistically significant effect (moderate certainty) favouring dalteparin in males for any VTE (males: hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52 to 0.96 vs females: HR, 1.16; 95% CI, 0.81 to 1.68; P = 0.04). This effect remained after adjustment for baseline characteristics (males: HR, 0.70; 95% CI, 0.52 to 0.96 vs females: HR, 1.17; 95% CI, 0.81 to 1.68; P = 0.04) and weight (males: HR, 0.70; 95% CI, 0.52 to 0.96 vs females: HR, 1.20; 95% CI, 0.83 to 1.73; P = 0.03). We did not identify a significant effect modification by sex on mortality.CONCLUSIONS:We found an effect modification by sex of thromboprophylaxis on VTE in critically ill patients that requires confirmation. Our findings highlight the need for sex- and gender-based analyses in acute care research.

We invite you to attend International Society on Thrombosis and Haemostasis (ISTH) 2023 Congress from June 24 to 28, 2023, in Montréal, a friendly, reasonably priced multicultural city with an air of sophistication and excitement. The ISTH Congress is the most important international meeting in the field of thrombosis, hemostasis, and vascular biology. It offers new research, continuing education, and opportunities to make connections with colleagues from around the world. The theme of ISTH 2023 is “Investing in ISTH’s future: Early career investigators.” Early career investigators have been involved in planning the congress and will be spotlighted in various sessions. The 24 Scientific and Standardization Committee sessions will present ongoing work and the latest research on bleeding and thrombotic disorders. Additional congress highlights include presentations by 4 world-renowned plenary speakers, 28 State-of-the-Art sessions, 80 oral communication sessions, hundreds of poster presentations, and the not-to-be-missed late-breaking trials sessions. See you in Montréal—we cannot wait to welcome you!

Introduction: While several risk stratification tools have been developed to predict the risk of recurrence in patients with an unprovoked venous thromboembolism (VTE), only 1 in 4 patients are categorized as low-risk. Rather than a one-time measure, serial D-dimer assessment holds promise to enhance the prediction of VTE recurrence after oral anticoagulant (OAC) cessation.Methods: Using the REVERSE cohort, we compared VTE recurrence among patients with normal D-dimer levels (<490 ng/mL among males under age 70, <500 ng/mL in others) at OAC cessation and 1-month follow-up, to those with an elevated D-dimer level at either timepoint. We also evaluated VTE recurrence based on absolute increase in D-dimer levels between the two timepoints (e.g., Delta D-dimer) according to quartiles.Results: Among 214 patients with serial D-dimer levels measured at OAC cessation and 1-month follow-up, an elevated D-dimer level at either timepoint was associated with a numerically higher risk of recurrent VTE than patients with normal D-dimer levels at both timepoints (6.9 % vs. 4.2 % per year, hazard ratio 1.6; 95 % CI 0.9-2.7). Among women with <2 HERDOO2 criteria, a normal D-dimer level at both timepoints predicted a very low risk of recurrent VTE during follow-up (0.8 % per year, 95 % CI 0.1-2.8). Irrespective of baseline value, recurrent VTE risk was only 3 % per year (95 % CI 1.4-5.6) among patients in the lowest Delta D-dimer quartile.Conclusion: Serial normal D-dimer levels have the potential to identify patients at a low risk of recurrent VTE. In addition, Delta D-dimer, irrespective of its elevation above cutoff threshold, may predict recurrent VTE.

The 2015 Research Consensus Panel (RCP) on submassive pulmonary embolism (PE) set priorities for research in submassive PE and identified a rigorous randomized trial of catheter-directed therapy plus anticoagulation versus anticoagulation alone as the highest research priority. This update, written 8 years after the RCP was convened, describes the current state of endovascular PE practice and the Pulmonary Embolism-Thrombus Removal with Catheter-Directed Therapy trial, the main output from the RCP.

Background: Thrombophilia predisposes to venous thromboembolism (VTE) because of acquired or hereditary factors. Among them, it has been suggested that gene mutations of the factor V Leiden (FVL) or prothrombin G20210A mutation (PGM) might reduce the risk of bleeding, but little data exist for patients treated using anticoagulants.Objectives: To assess whether thrombophilia is protective against bleeding.Methods: This multicentre, multinational, prospective cohort study evaluated adults receiving long-term anticoagulants after a VTE event. We analyzed the incidence of major bleeding as the primary outcome, according to the genotype for FVL and PGM (wild-type and heterozygous/homozygous carriers).Results: Of 2260 patients with genotype testing, during a median follow-up of 3 years, 106 patients experienced a major bleeding event (17 intracranial and 7 fatal). Among 439 carriers of FVL, 19 experienced major bleeding and there were no differences between any mutation vs wild-type (hazard ratio [HR], 0.89 [0.53-1.49]; p = .66). The comparison of major bleeding events between the 158 patients with any-PGM muta-tion (heterozygous or homozygous) vs wild-type also showed a nonstatistically signif-icant difference with HR of 0.53 (0.19-1.43), p = .21. However, multivariate analysis demonstrated that major bleeds or clinically relevant nonmajor bleeding were statis-tically less likely for patients with either FVL and/or PGM compared with patients with both wild-type factor V and prothrombin genes (HR, 0.73; 95% CI = 0.55-0.97; p = .03).Conclusion: This study demonstrates that thrombophilia, defined as the presence of either FVL or the prothrombin G20210A mutation, is related with a lower rate of major/clinically relevant nonmajor bleeding while on anticoagulants in the extended treatment for VTE.

BACKGROUND:We previously determined good agreement and high specificity of the International Society on Thrombosis and Haemostasis (ISTH) definition of pulmonary embolism (PE)-related death among an expert central adjudication committee (CAC). CACs are often composed of experts in the corresponding research field. Involving physician trainees in CACs would allow investigators to divide the workload and foster trainees' research experience.OBJECTIVE:To evaluate the accuracy of the ISTH definition of PE-related death for PE- versus non-PE-related deaths as confirmed by autopsy and its interrater agreement among physician trainees.METHODS:This retrospective autopsy cohort included all patients with PE-related deaths between January 2010 and July 2019 as well as patients who died in 2018 from a cause other than PE at the New York-Presbyterian Hospital. Based on premortem clinical summaries, two physician trainees independently determined the cause of death using the ISTH definition of PE-related death. We calculated the sensitivity and specificity of the ISTH definition to identify autopsy-confirmed PE-related death and its interrater agreement.RESULTS:Overall, 126 death events were adjudicated (median age, 68 years; 60 [48%] women), of which 29 (23%) were due to PE, as confirmed by autopsy. Sensitivity and specificity of the ISTH definition for autopsy-confirmed PE-related death was 48% (95% CI, 29-67) and 100% (95% CI, 96-100), respectively. Interrater reliability for PE-related death was good (percentage agreement, 93%; 95% CI, 87-96, Cohen's Kappa, 0.67; 95% CI, 44-85).CONCLUSION:Our findings are consistent with our previous validation study. They further support the use of the ISTH definition of PE-related death and revealed high agreement between adjudicators with varied experience.

Despite guideline recommendations for long-term anticoagulation after the first diagnosis of unprovoked venous thromboembolism (VTE), benefits and harms associated with this approach remain unclear among older adults at risk of non VTE-related mortality. While death is a competing event to recurrent VTE, competing risk methods have not been used in determining VTE recurrence rates following anticoagulant discontinuation in unprovoked VTE. We sought to evaluate the risk of recurrent VTE by age strata among patients with first unprovoked VTE after anticoagulant cessation, accounting for all-cause mortality as a competing risk.

We invite you to attend International Society on Thrombosis and Haemostasis (ISTH) 2023 Congress from June 24 to 28, 2023, in Montréal, a friendly, reasonably priced multicultural city with an air of sophistication and excitement. The ISTH Congress is the most important international meeting in the field of thrombosis, hemostasis, and vascular biology. It offers new research, continuing education, and opportunities to make connections with colleagues from around the world. The theme of ISTH 2023 is "Investing in ISTH's future: Early career investigators." Early career investigators have been involved in planning the congress and will be spotlighted in various sessions. The 24 Scientific and Standardization Committee sessions will present ongoing work and the latest research on bleeding and thrombotic disorders. Additional congress highlights include presentations by 4 world-renowned plenary speakers, 28 State-of-the-Art sessions, 80 oral communication sessions, hundreds of poster presentations, and the not-to-be-missed late-breaking trials sessions. See you in Montréal-we cannot wait to welcome you!