Milvexian for the Prevention of Venous Thromboembolism.

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.).

Novel horizons in anticoagulation: the emerging role of factor XI inhibitors across different settings.

Anticoagulants have long been fundamental in preventing and treating thromboembolic disorders, with a recent shift of focus towards direct oral anticoagulants, thanks to their ease of use, efficacy, and safety. Despite these advancements, bleeding complications remain a major concern with any anticoagulant, highlighting the need for safer drugs. Factor XI (FXI) inhibitors have emerged as promising agents in this regard, offering a novel approach by targeting upstream factors in the coagulation system. Phase 2 trials have shown encouraging outcomes, indicating a reduced bleeding risk compared to traditional anticoagulants, particularly in the context of cardiovascular disease management when combined with antiplatelet therapy. However, the variability in findings and limited efficacy data call for a cautious interpretation pending phase 3 trial insights. These trials are essential for validating the potential of FXI inhibitors to balance bleeding risk reduction and maintain anticoagulant efficacy. This review explores the pharmacology, potential indications, clinical data, and future directions of FXI inhibitors, providing a perspective on their evolving role in anticoagulant therapy. It also provides a detailed analysis of data from published clinical trials on FXI inhibitors in various indications. Preliminary data from ongoing trials is also outlined. As the field moves forward, a cautiously optimistic outlook can be expected, focusing on comprehensive data from phase 3 trials to define the role of FXI inhibitors in various clinical scenarios.

Six-week low-molecular-weight heparin versus 12-week warfarin for calf deep vein thrombosis: A randomized, prospective, open-label study.

Current guidelines suggest a 3-month anticoagulant treatment course for isolated distal deep vein thrombosis (IDDVT), but shorter durations of treatment are frequently prescribed in clinical practice. We investigated whether a 6-week treatment with low-molecular-weight heparin (LMWH) at intermediate dosage can be an effective and safe alternative to vitamin K antagonists (VKA) in patients with IDDVT (non-inferiority trial). In a multicenter, open-label, randomized trial, 260 outpatients with symptomatic IDDVT were randomly assigned to receive either LMWH followed by VKA for 12 weeks or LMWH 1 mg/kg subcutaneously twice a day for 2 weeks followed by 1 mg/kg subcutaneously once a day for 4 weeks. The follow-up was 6 months and the primary endpoint was the composite measure of recurrent venous thromboembolism (VTE) defined as: recurrence or extension of IDDVT, proximal DVT, and pulmonary embolism (PE). The study was stopped prematurely due to slow recruiting rates. The primary efficacy outcome occurred in 14 patients receiving LMWH (10.8%) and in five patients receiving VKA (3.8%); risk difference was 0.069 (95% CI: 0.006-0.132), hazard ratio 2.8 (95% CI: 1.04-7.55). There was one PE in the VKA group and one proximal DVT in the LMWH group. IDDVT recurrence was 10.0% in the LMWH group versus 3.1% in the VKA group (p = .024). Two patients had clinically relevant bleedings (1.6%) in the LMWH group versus one (0.8%) in VKA group (p = .56). In conclusion, VKA for 12 weeks seems superior to LMWH for 6 weeks in reducing the risk of VTE recurrences in our cohort of outpatients with IDDVT.

Updates in the Incidence, Pathogenesis, and Management of Cancer and Venous Thromboembolism.

Patients with cancer are at higher risk of developing venous thromboembolism (VTE) compared with the general population. This elevated risk is due to several risk factors and multiple, overlapping thrombotic and hemostatic pathophysiological pathways that are specific to this patient population. Hence, the management of cancer-associated VTE can be challenging for clinicians. Patients with cancer-associated VTE are at higher risk of both recurrent events despite anticoagulation and bleeding complications due to the anticoagulant regimens. Direct oral anticoagulants have recently been shown to be effective, safe, and more convenient than parenteral low-molecular-weight heparin for the management of cancer-associated VTE. Despite these recent advances in anticoagulant therapy, many unmet needs remain in these patients (increased risk of bleeding with specific cancer types, drug-drug interactions, liver dysfunction). Factor XI inhibitors are currently being assessed for the management of cancer-associated VTE and may help clinicians address these important knowledge gaps.

Reperfusion therapies in patients with acute ischaemic stroke and atrial fibrillation: data on safety and effectiveness from a multi-centre cohort study.

BACKGROUND: Intravenous thrombolysis (IVT) and/or endovascular therapy (EVT) are currently considered best practices in acute stroke patients. Data regarding the efficacy and safety of reperfusion therapies in patients with atrial fibrillation (AF) are conflicting as regards haemorrhagic transformation, mortality, and functional outcome. This study sought to investigate for any differences, in terms of safety and effectiveness, between AF patients with acute ischaemic stroke (AIS) treated and untreated with reperfusion therapies. METHODS: Data from two multicenter cohort studies (RAF and RAF-NOACs) on consecutive patients with AF and AIS were analyzed to compare patients treated and not treated with reperfusion therapies (IVT and/or EVT). Multivariable logistic regression analysis was performed to identify independent predictors for outcome events: 90-day good functional outcome and mortality. A propensity score matching (PSM) analysis compared treated and untreated patients. RESULTS: Overall, 441 (25.4%) were included in the reperfusion-treated group and 1,295 (74.6%) in the untreated group. The multivariable model suggested that reperfusion therapies were significantly associated with good functional outcome. Rates of mortality and disability were higher in patients not treated, especially in the case of higher NIHSS scores. In the PSM comparison, 173/250 patients (69.2%) who had received reperfusion therapies had good functional outcome at 90 days, compared to 146/250 (58.4%) untreated patients (p = 0.009, OR: 1.60, 95% CI:1.11-2.31). CONCLUSIONS: Patients with AF and AIS treated with reperfusion therapies had a significantly higher rate of good functional outcome and lower rates of mortality compared to those patients with AF and AIS who had undergone conservative treatment.

Cilostazol for peripheral arterial disease - a position paper from the Italian Society for Angiology and Vascular Medicine.

Cilostazol is a quinolinone-derivative selective phosphodiesterase inhibitor and is a platelet-aggregation inhibitor and arterial vasodilator for the symptomatic treatment of intermittent claudication (IC). Cilostazol has been shown to improve walking distance for patients with moderate to severe disabling intermittent claudication who do not respond to exercise therapy and who are not candidates for vascular surgical or endovascular procedures. Several studies evaluated the pharmacological effects of cilostazol for restenosis prevention and indicated a possible effect on re-endothelialization mediated by hepatocyte growth factor and endothelial precursor cells, as well as inhibiting smooth muscle cell proliferation and leukocyte adhesion to endothelium, thereby exerting an anti-inflammatory effect. These effects may suggest a potential effectiveness of cilostazol in preventing restenosis and promoting the long-term outcome of revascularization interventions. This review aimed to point out the role of cilostazol in treating patients with peripheral arterial disease, particularly with IC, and to explore its possible role in restenosis after lower limb revascularization.

Association of Bleeding Severity With Mortality in Extended Thromboprophylaxis of Medically Ill Patients in the MAGELLAN and MARINER Trials.

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.

The Diagnostic Role of Lung Ultrasound and Contrast-Enhanced Ultrasound in Pulmonary Embolism.

The diagnosis of pulmonary embolism (PE) relies essentially on a probabilistic approach that requires careful clinical assessments, targeted laboratory tests, and the use of appropriate imaging tools. Nowadays, the diagnostic gold standard is computed tomographic pulmonary angiography. Lung ultrasound (LUS) can play a role in the diagnosis of PE mainly by allowing the visualization of peripheral lung infarctions. Hypoechoic, pleural-based parenchymal consolidation is the most typical and common finding of pulmonary infarction. More than 85% of infarct lesions are wedge-shaped, extending to the pleural surface and are localized to where the patient complains of pleuritic chest pain. Contrast-enhanced ultrasound can be performed in addition to basic ultrasound examination to ascertain nonvascularization of the consolidation, thus confirming that the lesion is an infarct. The aim of this narrative review is to summarize the latest evidence on the application of LUS to the diagnosis of PE, focusing purely on thoracic/lung signs.

Anticoagulant therapy for splanchnic vein thrombosis: a systematic review and meta-analysis.

Treatment of splanchnic vein thrombosis (SVT) is challenging, and evidence to guide therapeutic decisions remains scarce. The objective of this systematic review and meta-analysis was to determine the efficacy and safety of anticoagulant therapy for SVT. MEDLINE, EMBASE, and clinicaltrials.gov were searched from inception through December 2019, without language restrictions, to include observational studies and randomized controlled trials reporting radiological or clinical outcomes in patients with SVT. Pooled proportions and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated in a random-effects model. Of 4312 records identified by the search, 97 studies including 7969 patients were analyzed. In patients receiving anticoagulation, the rates of SVT recanalization, SVT progression, recurrent venous thromboembolism (VTE), major bleeding, and overall mortality were 58% (95% CI, 51-64), 5% (95% CI, 3-7), 11% (95% CI, 8-15), 9% (95% CI, 7-12), and 11% (95% CI, 9-14), respectively. The corresponding values in patients without anticoagulation were 22% (95% CI, 15-31), 15% (95% CI, 8-27), 14% (95% CI, 9-21), 16% (95% CI, 13-20), and 25% (95% CI, 20-31). Compared with no treatment, anticoagulant therapy obtained higher recanalization (RR, 2.39; 95% CI, 1.66-3.44) and lower thrombosis progression (RR, 0.24; 95% CI, 0.13-0.42), major bleeding (RR, 0.73; 95% CI, 0.58-0.92), and overall mortality (RR, 0.45; 95% CI, 0.33-0.60). These results demonstrate that anticoagulant therapy improves SVT recanalization and reduces the risk of thrombosis progression without increasing major bleeding. The incidence of recurrent VTE remained substantial in patients receiving anticoagulation, as well. Effects were consistent across the different subgroups of patients. This trial was registered on the PROPERO database at (https://www.crd.york.ac.uk/prospero//display_record.php?ID=CRD42019127870) as #CRD42019127870.

Incidence and outcomes of splanchnic vein thrombosis after diagnosis of COVID-19 or COVID-19 vaccination: a systematic review and meta-analysis.

Coronavirus disease 2019 (COVID-19) and COVID-19 vaccination may cause splanchnic vein thrombosis (SVT), which is potentially fatal. The present study aims to pool the incidence and outcomes of SVT patients with COVID-19 or having received COVID-19 vaccines. The PubMed, EMBASE, and Cochrane databases were searched. Based on the data from cohort studies, meta-analyses were performed to evaluate the incidence of SVT in COVID-19 patients or people having received COVID-19 vaccines. Pooled proportions were calculated. Based on the individual data from case reports, logistic regression analyses were performed to identify factors associated with death in SVT patients. Odds ratios (ORs) were calculated. Among 654 papers initially identified, 135 were included. Based on 12 cohort studies, the pooled incidence of SVT in COVID-19 patients was 0.6%. Data were insufficient to estimate the incidence of SVT after COVID-19 vaccination. Based on 123 case reports, the mortality was 14% (9/64) in SVT patients with COVID-19 and 25% (15/59) in those who received COVID-19 vaccines. Univariate analyses demonstrated that age (OR = 1.061; p = 0.017), diabetes mellitus (OR = 14.00; p = 0.002), anticoagulation (OR = 0.098; p = 0.004), and bowel resection (OR = 16.00; p = 0.001) were significantly associated with death in SVT patients with COVID-19; and anticoagulation (OR = 0.025; p = 0.003) and intravenous immunoglobulin (OR = 0.175; p = 0.046) were significantly associated with death in SVT patients who received COVID-19 vaccines. Multivariate analyses did not identify any independent factor for death in both patients. SVT in COVID-19 patients and in subjects who received COVID-19 vaccines carries a high mortality, but may be improved by anticoagulation. PROSPERO Identifier CRD42022315254.

Optimal follow-up after acute pulmonary embolism: a position paper of the European Society of Cardiology Working Group on Pulmonary Circulation and Right Ventricular Function, in collaboration with the European Society of Cardiology Working Group on Atherosclerosis and Vascular Biology, endorsed by the European Respiratory Society.

This position paper provides a comprehensive guide for optimal follow-up of patients with acute pulmonary embolism (PE), covering multiple relevant aspects of patient counselling. It serves as a practical guide to treating patients with acute PE complementary to the formal 2019 European Society of Cardiology guidelines developed with the European Respiratory Society. We propose a holistic approach considering the whole spectrum of serious adverse events that patients with acute PE may encounter on the short and long run. We underline the relevance of assessment of modifiable risk factors for bleeding, of acquired thrombophilia and limited cancer screening (unprovoked PE) as well as a dedicated surveillance for the potential development of chronic thromboembolic pulmonary hypertension as part of routine practice; routine testing for genetic thrombophilia should be avoided. We advocate the use of outcome measures for functional outcome and quality of life to quantify the impact of the PE diagnosis and identify patients with the post-PE syndrome early. Counselling patients on maintaining a healthy lifestyle mitigates the risk of the post-PE syndrome and improves cardiovascular prognosis. Therefore, we consider it important to discuss when and how to resume sporting activities soon after diagnosing PE. Additional patient-relevant topics that require Focused counselling are travel and birth control.

Common Practice in the Treatment of Superficial Vein Thrombosis Involving the Sapheno-Femoral Junction: Results from a National Survey of the Italian Society of Angiology and Vascular Medicine (SIAPAV).

Background and Objectives: Prophylactic doses of low-molecular-weight heparins or fondaparinux showed their efficacy and safety for treatment of all superficial vein thrombosis (SVT) of the lower limbs, yet not for those extended to the last 3 cm of the great saphenous vein, close to the sapheno-femoral junction, or considered as a deep-vein thrombosis. Some experts suggest that these patients should be managed with full anticoagulant doses but evidence to support this recommendation is lacking, suggesting the need for a properly designed trial. Materials and Methods: Before starting a new trial, the Italian Society of Angiology and Vascular Medicine (SIAPAV) decided to verify the common therapeutic approaches for patients with an SVT in Italian vascular centers based on a hypothetical significant variation in each daily clinical practice. A standardized questionnaire of 10 questions was administered to all SIAPAV affiliates by means of the official Society website. Results: From 1 December 2022 to 20 January 2023 a total of 191 members (31.8%) answered the questionnaire, showing a detailed and a substantial heterogeneity in the therapeutic approach to SVT patients among experienced vascular physicians and angiologists. Detailed results are reported in the relative section. Conclusions: The therapeutic approach of SVT extended to the iuxta-femoral segment of the great saphenous vein is still a matter of debate, and data to support therapeutic strategies are lacking. The wide heterogeneity in the management of SVT patients, including those with more extended thrombosis, confirmed that a randomized controlled clinical trial investigating the efficacy and the safety of a tailored therapeutic regimen in this particular subgroup of patients is strongly warranted.

Profile of Patients with Isolated Distal Deep Vein Thrombosis versus Proximal Deep Vein Thrombosis or Pulmonary Embolism: RE-COVERY DVT/PE Study.

Isolated distal deep vein thrombosis (IDDVT) is presumed to be more benign than proximal DVT (PDVT) or pulmonary embolism (PE), suggesting a need for different management approaches. This subgroup analysis of the RE-COVERY DVT/PE global, observational study investigated patient characteristics, hospitalization details, and anticoagulant therapy in patients with IDDVT in real-world settings in 34 countries enrolled from January 2016 to May 2017. Data were analyzed descriptively according to the type and location of the index venous thromboembolism (VTE): IDDVT, PDVT ± distal DVT (DDVT), and PE ± DVT. Of the 6,095 eligible patients, 323 with DVT located outside the lower limb and no PE were excluded. Of the remaining 5,772 patients, 17.6% had IDDVT, 39.9% had PDVT ± DDVT, and 42.5% had PE ± DVT. IDDVT patients were younger and had fewer risk factors for VTE than the other groups. Other comorbidities were less frequent in the IDDVT group, except for varicose veins, superficial thrombophlebitis, and venous insufficiency. IDDVT patients were less likely to be diagnosed in an emergency department (22.3 vs. 29.7% for PDVT ± DDVT and 45.4% for PE ± DVT) or hospitalized for VTE (29.2 vs. 48.5% for PDVT ± DDVT and 75.0% for PE ± DVT). At hospital discharge or 14 days after diagnosis (whichever was later), non-vitamin K antagonist oral anticoagulants were the most commonly used anticoagulants (55.6% for IDDVT, 54.7% for PDVT ± DDVT, and 52.8% for PE ± DVT). Although differences in patient characteristics, risk factors, and clinical management were identified, anticoagulant treatment of IDDVT was almost equal to that of PDVT or PE. Prospective studies should investigate whether, in a global perspective, this is an appropriate use of anticoagulants.

Clinical significance of neutrophil extracellular traps biomarkers in thrombosis.

Neutrophil extracellular traps (NETs) may be associated with the development of thrombosis. Experimental studies have confirmed the presence of NETs in thrombi specimens and potential role of NETs in the mechanisms of thrombosis. Clinical studies also have demonstrated significant changes in the levels of serum or plasma NETs biomarkers, such as citrullinated histones, myeloperoxidase, neutrophil elastase, nucleosomes, DNA, and their complexes in patients with thrombosis. This paper aims to comprehensively review the currently available evidence regarding the change in the levels of NETs biomarkers in patients with thrombosis, summarize the role of NETs and its biomarkers in the development and prognostic assessment of venous thromboembolism, coronary artery diseases, ischemic stroke, cancer-associated thromboembolism, and coronavirus disease 2019-associated thromboembolism, explore the potential therapeutic implications of NETs, and further discuss the shortcomings of existing NETs biomarkers in serum and plasma and their detection methods.

Safety and effectiveness of dabigatran in routine clinical practice: the RE-COVERY DVT/PE study.

RE-COVERY DVT/PE is a two-phase, international, observational study of anticoagulant therapy in patients with deep vein thrombosis and/or pulmonary embolism (DVT/PE). The objective of the second phase was to compare the safety and effectiveness of dabigatran versus a vitamin K antagonist (VKA) over 1 year of follow-up. Primary safety and effectiveness outcomes were major or clinically relevant nonmajor bleeding events (MBE/CRNMBEs) and symptomatic recurrent venous thromboembolism (VTE) (including deaths related to recurrent VTE). To minimize bias due to unbalanced patient characteristics, only patients in an overlapping range of estimated propensity scores were included (analytic set), and propensity score weighting was applied to compare outcomes. Outcome analysis used an as-treated approach, censoring patients after they stopped or switched their initial anticoagulant. Overall, 3009 patients enrolled from 2016 to 2018 were eligible: 60% were diagnosed with DVT alone, 21% with PE alone, and 19% with DVT plus PE. The analytic set consisted of 2969 patients. The incidence rate in %/year (95% confidence interval [CI]) of MBE/CRNMBEs was 2.63 (1.79-3.74) with dabigatran versus 4.48 (3.23-6.06) with warfarin; hazard ratio 0.63 (95% CI 0.32-1.25). For symptomatic recurrent nonfatal or fatal VTE the incidence rate was 1.53 (0.91-2.42) with dabigatran versus 2.01 (1.21-3.14) with VKAs; hazard ratio 0.78 (95% CI 0.30-2.02). In conclusion, we found lower annualized rates of MBE/CRNMBEs with dabigatran than VKA, although the difference was not statistically significant. Annualized rates of symptomatic VTE or related mortality were similar with dabigatran and VKA. These observational results with 1 year of follow-up reflect those of the randomized clinical trials. Trial registration: ClinicalTrials.gov identifier NCT02596230, first registered November 4, 2015.

Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Systematic Review and Meta-analysis.

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).

Incidence Rates and Case-Fatality Rates of Cerebral Vein Thrombosis: A Population-Based Study.

Background and Purpose: Cerebral vein thrombosis (CVT) incidence is estimated to be >10 per 1 000 000 per year. Few population-based studies investigating case-fatality rates (CFRs) and pyogenic/nonpyogenic CVT incidence are available. We assessed trends in CVT incidence between 2002 and 2012, as well as adjusted in-hospital CFRs and incidence of hospital admissions for pyogenic/nonpyogenic CVT in a large Northwestern Italian epidemiological study. Methods: Primary and secondary discharge diagnoses of pyogenic/nonpyogenic CVT were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes 325, 671.5, and 437.6. Age, sex, vital status at discharge, length of hospital stay, and up to 5 secondary discharge diagnoses were collected. Concomitant presence of intracerebral hemorrhage (ICH) was registered, and comorbidities were assessed through the Charlson comorbidity index. Results: A total of 1718 patients were hospitalized for CVT (1147 females­66.8%; 810 pyogenic and 908 nonpyogenic CVT, 47.1% and 52.9%, respectively), with 134 patients (7.8%) experiencing a concomitant ICH. The overall incidence rate for CVT was 11.6 per 1 000 000 inhabitants with a sex-specific rate of 15.1 and 7.8 per 1 000 000 in females and males, respectively. CVT incidence significantly increased in women during time of observation (P=0.007), with the highest incidence being at 40 to 44 years (27.0 cases per 1 000 000). In-hospital CFR was 3%, with no difference between pyogenic/nonpyogenic CVT. Patients with concomitant ICH had a higher in-hospital CFR compared with patients without ICH (7.5% versus 2.7%; odds ratio, 2.96 [95% CI, 1.45­6.04]). In-hospital CFR progressively increased with increasing Charlson comorbidity index (P=0.003). Age (odds ratio, 1.03 [95% CI, 1.02­1.05]), Charlson comorbidity index ≥4 (odds ratio, 4.33 [95% CI, 1.29­14.52]), and ICH (odds ratio, 3.05 [95% CI, 1.40­6.62]) were independent predictors of in-hospital mortality. Conclusions: In a large epidemiological study, CVT incidence was found to be comparable to the one registered in population-based studies reported after the year 2000. CVT incidence increased among women over time. In-hospital CFR was low, but not negligible, in patients with concomitant ICH. Age, ICH, and a high number of comorbidities were independent predictors of in-hospital mortality. Pyogenic CVT was not a predictor of in-hospital CFR, although its high proportion was not confirmed by internal validation.

Risk Factors for Intracerebral Hemorrhage in Patients With Atrial Fibrillation on Non-Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention.

[Figure: see text].

Rivaroxaban for Thromboprophylaxis after Hospitalization for Medical Illness.

BACKGROUND: Patients who are hospitalized for medical illness remain at risk for venous thromboembolism after discharge, but the role of extended thromboprophylaxis in the treatment of such patients is a subject of controversy. METHODS: In this randomized, double-blind trial, medically ill patients who were at increased risk for venous thromboembolism on the basis of a modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score of 4 or higher (scores range from 0 to 10, with higher scores indicating a higher risk of venous thromboembolism) or a score of 2 or 3 plus a plasma d-dimer level of more than twice the upper limit of the normal range (defined according to local laboratory criteria) were assigned at hospital discharge to either once-daily rivaroxaban at a dose of 10 mg (with the dose adjusted for renal insufficiency) or placebo for 45 days. The primary efficacy outcome was a composite of symptomatic venous thromboembolism or death due to venous thromboembolism. The principal safety outcome was major bleeding. RESULTS: Of the 12,024 patients who underwent randomization, 12,019 were included in the intention-to-treat analysis. The primary efficacy outcome occurred in 50 of 6007 patients (0.83%) who were given rivaroxaban and in 66 of 6012 patients (1.10%) who were given placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.52 to 1.09; P=0.14). The prespecified secondary outcome of symptomatic nonfatal venous thromboembolism occurred in 0.18% of patients in the rivaroxaban group and 0.42% of patients in the placebo group (hazard ratio, 0.44; 95% CI, 0.22 to 0.89). Major bleeding occurred in 17 of 5982 patients (0.28%) in the rivaroxaban group and in 9 of 5980 patients (0.15%) in the placebo group (hazard ratio, 1.88; 95% CI, 0.84 to 4.23). CONCLUSIONS: Rivaroxaban, given to medical patients for 45 days after hospital discharge, was not associated with a significantly lower risk of symptomatic venous thromboembolism and death due to venous thromboembolism than placebo. The incidence of major bleeding was low. (Funded by Janssen Research and Development; MARINER ClinicalTrials.gov number, NCT02111564 .).

Survival and quality of life after early discharge in low-risk pulmonary embolism.

INTRODUCTION: Early discharge of patients with acute low-risk pulmonary embolism requires validation by prospective trials with clinical and quality-of-life outcomes. METHODS: The multinational Home Treatment of Patients with Low-Risk Pulmonary Embolism with the Oral Factor Xa Inhibitor Rivaroxaban (HoT-PE) single-arm management trial investigated early discharge followed by ambulatory treatment with rivaroxaban. The study was stopped for efficacy after the positive results of the predefined interim analysis at 50% of the planned population. The present analysis includes the entire trial population (576 patients). In addition to 3-month recurrence (primary outcome) and 1-year overall mortality, we analysed self-reported disease-specific (Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire) and generic (five-level five-dimension EuroQoL (EQ-5D-5L) scale) quality of life as well as treatment satisfaction (Anti-Clot Treatment Scale (ACTS)) after pulmonary embolism. RESULTS: The primary efficacy outcome occurred in three (0.5%, one-sided upper 95% CI 1.3%) patients. The 1-year mortality was 2.4%. The mean±sd PEmb-QoL decreased from 28.9±20.6% at 3 weeks to 19.9±15.4% at 3 months, a mean change (improvement) of -9.1% (p<0.0001). Improvement was consistent across all PEmb-QoL dimensions. The EQ-5D-5L was 0.89±0.12 at 3 weeks after enrolment and improved to 0.91±0.12 at 3 months (p<0.0001). Female sex and cardiopulmonary disease were associated with poorer disease-specific and generic quality of life; older age was associated with faster worsening of generic quality of life. The ACTS burden score improved from 40.5±6.6 points at 3 weeks to 42.5±5.9 points at 3 months (p<0.0001). CONCLUSIONS: Our results further support early discharge and ambulatory oral anticoagulation for selected patients with low-risk pulmonary embolism. Targeted strategies may be necessary to further improve quality of life in specific patient subgroups.