BACKGROUND:Randomized trials have shown that direct oral anticoagulants (DOACs) are as effective as vitamin K antagonists (VKAs) for treating venous thromboembolism (VTE), with less major bleeding. Whether these findings apply to routine clinical practice remains uncertain. OBJECTIVES:To compare recurrent VTE and bleeding during anticoagulation in patients with symptomatic lower-limb deep vein thrombosis (DVT) treated with DOACs or VKAs, and to assess outcomes according to approximate eligibility for pivotal randomized trials. METHODS:We analyzed consecutive patients with symptomatic lower-limb DVT enrolled in the RIETE registry who received therapeutic-dose VKAs or DOACs. Follow-up was restricted to the treatment period. Outcomes were recurrent VTE, major bleeding, and clinically relevant non-major bleeding (CRNMB). Hazard ratios (HRs) were estimated using Cox proportional hazards models with inverse probability of treatment weighting. RESULTS:Among 24,728 patients (11,349 DOACs; 13,379 VKAs), DOACs were associated with lower risks of recurrent VTE (HR 0.71; 95%CI, 0.58-0.87) and major bleeding (HR 0.78; 95%CI, 0.63-0.97), but a higher risk of CRNMB (HR 1.35; 95%CI, 1.17-1.55). Median times to recurrent VTE, major bleeding, and CRNMB were 105, 88, and 81 days, respectively. Among patients approximating eligibility for randomized trials, DOACs were associated with lower risks of recurrent VTE and major bleeding, whereas no significant reduction was observed in trial-ineligible patients. CONCLUSIONS:In routine clinical practice, DOACs were associated with lower risks of recurrent VTE and major bleeding, but higher CRNMB rates than VKAs. Their safety advantage appeared more evident in patients with characteristics similar to those enrolled in pivotal randomized trials.

Based on current evidence, in most patients with an episode of venous thromboembolism (VTE) extended anticoagulation is generally recommended beyond the initial 3–6 months provided the bleeding risk is acceptably low [1]. Among factors that are expected to increase the risk of (major) bleeding complications is the elderly age. In a recent overview and meta-analysis of 27 prospective cohort and randomized clinical trials, older patients were found to exhibit a higher risk of major or clinically relevant bleeding complications, even with the use of the direct oral anticoagulants (DOAC) [2].

The decision as to prolong or discontinue anticoagulation beyond the first three months in patients with unprovoked venous thromboembolism (VTE) is generally made after a balance between the expected risk of recurrent VTE and that of major bleeding complications. Indeed, based on the results of recent comprehensive overviews and meta-analyses of several cohorts, the 5-year cumulative incidence of recurrent VTE after stopping anticoagulation is expected to achieve 25 % [ [1] Khan F. Rahman A. Carrier M. Kearon C. Weitz J.I. Schulman S. Couturaud F. Eichinger S. Kyrle P.A. Becattini C. Agnelli G. Brighton T.A. Lensing A.W.A. Prins M.H. Sabri E. Hutton B. Pinede L. Cushman M. Palareti G. Wells G.A. Prandoni P. Büller H.R. Rodger M.A. Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis. Br. Med. J. 2019; 366l4363 Google Scholar ], and that of major bleeding complications in candidates to extended anticoagulation with vitamin K antagonists (VKA) is as high as 6.3 %, the 95 % confidence intervals (CI) around this rate achieving 10 % [ [2] Khan F. Tritschler T. Kimpton M. Wells P.S. Kearon C. Weitz J.I. Büller H.R. Raskob G.E. Ageno W. Couturaud F. Prandoni P. Palareti G. Legnani C. Kyrle P.A. Eichinger S. Eischer L. Becattini C. Agnelli G. Vedovati M.C. Geersing G.J. Takada T. Cosmi B. Aujesky D. Marconi L. Palla A. Siragusa S. Bradbury C.A. Parpia S. Mallick R. Lensing A.W.A. Gebel M. Grosso M.A. Thavorn K. Hutton B. Le Gal G. Fergusson D.A. Rodger M.A. Long-term risk for major bleeding during extended oral anticoagulant therapy for first unprovoked venous thromboembolism: a systematic review and meta-analysis. Ann. Intern. Med. 2021; 174: 1420-1429 Crossref PubMed Scopus (38) Google Scholar ]. Although the rate of major bleeding complications is definitely lower among patients managed with direct oral anticoagulants (DOAC), it is not negligible, and the case-fatality rate is fully consistent with that observed in patients managed with VKA [ [2] Khan F. Tritschler T. Kimpton M. Wells P.S. Kearon C. Weitz J.I. Büller H.R. Raskob G.E. Ageno W. Couturaud F. Prandoni P. Palareti G. Legnani C. Kyrle P.A. Eichinger S. Eischer L. Becattini C. Agnelli G. Vedovati M.C. Geersing G.J. Takada T. Cosmi B. Aujesky D. Marconi L. Palla A. Siragusa S. Bradbury C.A. Parpia S. Mallick R. Lensing A.W.A. Gebel M. Grosso M.A. Thavorn K. Hutton B. Le Gal G. Fergusson D.A. Rodger M.A. Long-term risk for major bleeding during extended oral anticoagulant therapy for first unprovoked venous thromboembolism: a systematic review and meta-analysis. Ann. Intern. Med. 2021; 174: 1420-1429 Crossref PubMed Scopus (38) Google Scholar ].

When a patient on antiplatelet drugs for primary or secondary prevention of cardiovascular events develops a venous thromboembolic (VTE) episode, a conventional anticoagulation with old or novel antithrombotic agents becomes paramount. In such circumstances, clinicians are confronted with the challenge of combining anticoagulation with antiplatelet drugs, a combination that in carriers of atrial fibrillation has consistently been shown to be hazardous [1,2]. While it would be important to know whether this is also true in patients with VTE, there are data in favor and against an increase in the bleeding risk coming from treatment combination [3,4].

Venous thromboembolism (VTE) is one of the leading cardiovascular etiologies of maternal morbidity and mortality. Indeed, pulmonary embolism (PE) accounts for approximately 9% of pregnancy-related deaths. In addition, pregnancy-related deep-vein thrombosis (DVT) can lead to (severe) post-thrombotic syndrome [...]

Following the demonstration that thrombosis involving the superficial veins of the lower extremities (SVT) is a less benign disease than previously thought,1 several controlled studies have consistently shown that fondaparinux in preventive doses, low-molecular-weight heparins (LMWHs) in intermediate doses, and rivaroxaban in preventive doses are effective and safe strategies for preventing extension or recurrence of the disease, as well as progression to the deep vein system and migration to the pulmonary circulation.2-6 In all these clinical trials, patients with the thrombus head within 3 cm from the saphenous–femoral junction were not eligible for recruitment, as they were perceived as being at a higher risk of venous thromboembolic complications in the absence of an active drug, nor were they in studies addressing the treatment of deep vein thrombosis (DVT) because of the lack of involvement of the deep vein system. Accordingly, which is the most proper therapeutic conduct in these patients is unknown. International guidelines are elusive in this regard.7,8 Although most physicians end up managing these patients with therapeutic doses of anticoagulants because of the feared risk of progression to the deep vein system, as far as we know there is no evidence of treatment failure coming from the long-term follow-up of patients managed with lower doses. Here we report the findings from an international registry. The Computerized Registry of Patients with Venous Thromboembolism (RIETE) (ClinicalTrials.gov Identifier: NCT02832245) is a large prospective registry that has been enrolling patients with objectively confirmed VTE since 2001.9 The main objective of RIETE is to provide information to help physicians to improve their knowledge on the natural history of thromboembolic disease, including epidemiologic, diagnostic, prophylactic, and therapeutic information. All enrollees provide written or verbal informed consent according to the local ethics protocols of enrolling centers. The institutional review board at each enrolling center approves participation in RIETE for the site investigators and allows the entry of de-identified patient information into the RIETE database. Out of 1320 patients with isolated SVT (i.e., without simultaneous involvement of the deep venous system, as assessed by systematic bilateral ultrasonography) who were enrolled in the RIETE registry between March 2015 and June 2021, 374 (28.3%) had a thrombosis involving the most proximal tract of the greater saphenous with the thrombus head being within 3 cm from the saphenous–femoral junction. Of these patients, 227 (60.7%) were managed with full-dose LMWH or therapeutic doses of fondaparinux overlapped with and/or followed by vitamin K antagonists or direct oral anticoagulants. The remaining 147 patients (39.3%) were managed with preventive doses of fondaparinux or intermediate-dose LMWH. Table 1 illustrates the main demographic and clinical characteristics of the recruited patients, as well as the main risk factors of thrombosis, which were fully comparable between the two study No difference in outcome between therapeutic and preventive anticoagulation in patients with superficial vein thrombosis involving the saphenous–femoral junction

Patients with autoimmune disorders are at an increased risk of venous thromboembolism (VTE), but this association has not been consistently evaluated. We used the RIETE (Registro Informatizado Enfermedad Trombo Embólica) database to compare the rates of VTE recurrences, major bleeding, and death during the course of anticoagulation, according to the presence or absence of autoimmune disorders. Of 71 625 patients with VTE recruited in February 2018, 1800 (2.5%) had autoimmune disorders. Median duration of anticoagulant therapy was slightly longer in patients with autoimmune disorders (median, 190 vs 182 days; P = .001). On multivariable analysis, patients with autoimmune disorders had a similar risk of VTE recurrences (hazard ratio [HR]: 0.93; 95% confidence interval [CI]: 0.68-1.27) or major bleeding (HR: 1.07; 95% CI: 0.82-1.40) and a lower risk to die (HR: 0.66; 95% CI: 0.54-0.81) than those without autoimmune disorders. Patients with giant cell arteritis had the highest rates of major bleeding (8.6 events per 100 patient-years) and the lowest rate of recurrences (zero). In other subgroups, the rates of both events were more balanced. During anticoagulation, patients with or without autoimmune disorders had similar rates of VTE recurrences or major bleeding. However, there were some differences between subgroups of patients with autoimmune disorders.

Background: Proper risk stratification of patients for early mortality after cancer-associated thrombosis may lead to personalized anticoagulation protocols. Therefore, we aimed to derive and validate a scoring system to predict early mortality in this population. To this end, we selected patients with active cancer and thrombosis from the Computerized Registry of Patients with Venous Thromboembolism database. Methods: The main outcome was all cause mortality within the month following a thrombotic event. We used a simple random selection to split arc data in a derivation and a validation cohort. In the derivation cohort, we used recursive partitioning and binary logistic regression to identify groups at risk and to determine the likelihood of the primary outcome. The risk score was developed based on odds ratios from the final multivariate model, and then tested in the validation cohort. Results: In 10,025 eligible patients, we identified 6 predictors of 30-day mortality: leukocytosis >= 11.5x109/L; platelet count <= 160x109/L, metastasis, recent immobility, initial presentation as pulmonary embolism and Body Mass Index <18.5. The model divided the population into 3 risk categories: low (score 0-3), moderate (score 4-6), and high (score >= 7). The AUC for the overall score was 0.74, and using a cutoff >= 7 points, the model had a negative predictive value of 94.4%, a positive predictive value of 23.1%, a sensitivity of 73.3%, and a specificity of 64.6% in the validation cohort. Conclusions: Our validated risk model may assist physicians in the selection of patients for outpatient management, and perhaps anticoagulant, considering expanding anticoagulation options.

Real-life data from the RIETE study suggest only a few patients with pulmonary embolism at low risk of complications were treated at home or hospitalised for ≤5 days. Management of PE appeared quite variable in different countries.http://ow.ly/o2b230mD8EY

Background: The clinical outcomes during the course of anticoagulation in patients with venous thromboem-bolism (VTE) using statins remain controversial. Methods: We used the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry to compare the risk for VTE recurrences, major bleeding or death during anticoagulation, according to the use of statins at baseline. We used propensity score-matching (PSM) to adjust for confounding variables. Results: From February 2009 to January 2018, 32,062 VTE patients were included. Of these, 7,085 (22%) were using statins. Statin users were 10 years older (73 +/- 11 vs. 63 +/- 19 years, respectively) and more likely to have comorbidities or to be using antiplatelets or corticosteroids at baseline than non-users. During the course of anticoagulation (median, 177 days), 694 patients developed VTE recurrences, 848 bled and 3,169 died (fatal pulmonary embolism 176, fatal bleeding 121). Statin users had a similar rate of VTE recurrences (hazard ratio [HR]: 0.98; 95%CI: 0.82-1.17), a higher rate of major bleeding (HR: 1.29; 95%CI: 1.11-1.50) and a similar mortality rate (HR: 1.01; 95%CI: 0.93-1.10) than non-users. On PSM analysis, statin users had a significantly lower risk for death (HR: 0.62; 95%CI: 0.48-0.79) and a similar risk for VTE recurrences (HR: 0.98; 95%CI: 0.61-1.57) or major bleeding (HR: 0.85; 95%CI: 0.59-1.21) than non-users. Conclusions: During anticoagulation for VTE, patients using statins at baseline had a lower risk to die than nonusers.

Background: Little is known on the clinical characteristics, risk factors and outcomes during anticoagulation in young patients with acute venous thromboembolism (VTE). Methods: We used data from the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry to assess the clinical characteristics, risk factors and outcomes during anticoagulation in VTE patients aged 10-24 years. Data were separately analyzed according to initial presentation and gender. Results: Of 76,719 patients with VTE, 1571 (2.0%) were aged 10-24 years. Of these, 989 (63%) were women and 669 (43%) presented with pulmonary embolism (PE). Most women were using estrogens (680, 69%) or were pregnant (101, 10%), while 59% of men had unprovoked VTE. Women were more likely to present with PE (48% vs. 34%). The majority (87%) of PE patients had Sat O-2 levels >= 90% at baseline. The vast majority (97%) of PE patients were at low risk according to the PESI score, many (90%) at very low risk. During the course of anticoagulation (median, 192 days), 40 patients had VTE recurrences, 17 had major bleeding and 10 died (3 died of PE). Women had as many VTE recurrences as major bleeds (15 vs. 14 events), while men had many more VTE recurrences than major bleeding (25 vs. 3 events). Conclusions: VTE is associated with low risk of short-term mortality in young adults. Noticeable gender differences exist in the risk factor profile and the risk of VTE recurrences and major bleeding in the course of anticoagulation.

Background: Among patients presenting with pulmonary embolism (PE), those with diabetes are at increased risk to die than those without diabetes. The reasons have not been identified. We used the RIETE (Registro Informatizado Enfermedad Trombo Embolica) database to compare the mortality rate and the causes of death during anticoagulation in patients with PE according to the presence or absence of diabetes. Methods: A matched retrospective cohort study from consecutively enrolled patients in RIETE, from 179 hospitals in 24 countries. For each patient with diabetes we selected two patients with no diabetes matched by age, sex and year of diagnosis of the PE. Results: As of September 2017, there were 2010 PE patients with diabetes and two age-and-gender matched controls. Mean age was 74 +/- 11 years, 46% were men. Patients with diabetes were more likely to have comorbidities, to be using antiplatelets and to have more severe PE. During anticoagulation (median, 219 days), patients with diabetes had a higher mortality (hazard ratio [HR]: 1.45; 95% confidence intervals [CI]: 1.25-1.67) and a higher rate of arterial ischemic events (HR: 2.89; 95%CI: 1.71-4.94) than those without diabetes. On multivariable analysis, diabetes was not associated with an increased risk for death (HR: 1.26; 95%CI: 0.97-1.63). We also failed to find differences according to the use of antiplatelet drugs concomitantly. Conclusions: In our cohort of patients with PE, diabetes was not an independent predictor for death. The influence of arterial events or antiplatelet drugs (if any) was low.

Central diabetes insipidus (DI) is a rare disease characterized by the excretion of excessive volumes of dilute urine due to reduced levels of the antidiuretic hormone arginine vasopressin (AVP), caused by an acquired or genetic defect in the neurohypophysis. The aim of this study was to identify any autonomic dysfunction (AD) in patients with DI as a possible cofactor responsible for their reportedly higher mortality.

Whether popliteal vein incompetence (PVI) occurring after an episode of deep-vein thrombosis (DVT) of the lower extremities accounts for the development of the post-thrombotic syndrome (PTS) is controversial, as there is data in favor and against this association [ 1 Vedovetto V. Dalla Valle F. Milan M. Pesavento R. Prandoni P. Residual vein thrombosis and trans-popliteal reflux in patients with and without the post-thrombotic syndrome. Thromb. Haemost. 2013; 110: 854-855 Crossref PubMed Scopus (40) Google Scholar , 2 Prandoni P. Frulla M. Sartor D. Concolato A. Girolami A. Vein abnormalities and the post-thrombotic syndrome. J. Thromb. Haemost. 2005; 3: 401-402 Crossref PubMed Scopus (147) Google Scholar , 3 Roumen-Klappe E.M. den Heijer M. Janssen M.C. van der Vleuten T. Wollersheim H. The post-thrombotic syndrome: incidence and prognostic value of non-invasive venous examinations in a six-year follow-up study. Thromb. Haemost. 2005; 94: 825-830 PubMed Google Scholar , 4 Enden T. Haig Y. Kløw N.-E. Slagsvold C.E. Sandvik L. Ghanima W. et al. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis: a randomised controlled trial. Lancet. 2012; 379: 31-38 Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar , 5 Prandoni P. Kahn S.R. Post-thrombotic syndrome: prevalence, prognostication and need for progress. Br. J. Haematol. 2009; 145: 286-295 Crossref PubMed Scopus (200) Google Scholar ]. In addition, PVI is not infrequently found also in patients who do not have a history of DVT, especially in the presence of chronic venous insufficiency [ 6 Bergan J.J. Schmid-Schönbein G.W. Smith P.D.C. Nicolaides A.N. Boisseau M.R. Eklof B. Chronic venous disease. N. Engl. J. Med. 2006; 355: 488-498 Crossref PubMed Scopus (737) Google Scholar , 7 Gillet J.L. Perrin M.R. Allaert F.A. Clinical presentation and venous severity scoring of patients with extended deep axial venous reflux. J. Vasc. Surg. 2006; 44: 588-594 Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar ]. In order to test the plausibility of the association between PVI and the subsequent development of PTS, we assessed the prevalence of PVI in a consecutive series of patients with previous proximal DVT, and compared it with that detectable in the unaffected contralateral leg of the same subjects. The study was approved by the local Ethical Board. All recruited patients gave their written consent for participation in this investigation.

BACKGROUND: The association between deep vein thrombosis (DVT) and atherosclerosis is still controversial.METHODS: We examined the rate of subsequent symptomatic atherosclerosis in patients with unprovoked as compared to secondary DVT with a retrospectively follow-up of a cohort of patients who 14 years earlier had developed an episode of DVT not preceded by arterial cardiovascular events. We collected information on the development of coronary heart disease, ischemic stroke, peripheral artery disease or sudden otherwise unexplained death.RESULTS. We retrieved information from 138 patients with unprovoked and 123 with secondary DVT. The cumulative incidence of symptomatic atherosclerosis was 17 6% (95% CI, 8.3 to 26.0) in patients with unprovoked DVT, and 5.1% (95% CI. 0 0 to 10.7) in those with secondary DVT After adjusting for age, sex, smoking, hypertension, diabetes and dyslipidemia, the hazard ratio (HR) for development of symptomatic atherosclerosis among patients with unprovoked DVT as compared to those with secondary DVT was 2.89 (95% CI, 1.06 to 7.88; P=0.038).CONCLUSIONS. The risk of subsequent symptomatic atherosclerosis among patients with unprovoked DVT is approximately three times as high as that of patients with secondary events.

Background: Subgroup analyses from randomized trials suggested favorable results for the direct oral anticoagulants in fragile patients with venous thromboembolism (VTE). The frequency and natural history of fragile patients with VTE have not been studied yet.Objectives: To compare the clinical characteristics, treatment and outcomes during the first 3 months of anticoagulation in fragile vs non-fragile patients with VTE.Methods: Retrospective study using consecutive patients enrolled in the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry. Fragile patients were defined as those having age >= 75 years, creatinine clearance (CrCl) levels <= 50 mL/min, and/or body weight <= 50 kg.Results: From January 2013 to October 2016, 15 079 patients were recruited. Of these, 6260 (42%) were fragile: 37% were aged >= 75 years, 20% had CrCl levels <= 50 mL/min, and 3.6% weighed <= 50 kg. During the first 3 months of anticoagulant therapy, fragile patients had a lower risk of VTE recurrences (0.78% vs 1.4%; adjusted odds ratio [OR]: 0.52; 95% confidence intervals [CI]: 0.37-0.74) and a higher risk of major bleeding (2.6% vs 1.4%; adjusted OR: 1.41; 95% CI: 1.10-1.80), gastrointestinalbleeding (0.86% vs 0.35%; adjusted OR: 1.84; 95% CI: 1.16-2.92), haematoma (0.51% vs 0.07%; adjusted OR: 5.05; 95% CI: 2.05-12.4), all-cause death (9.2% vs 3.5%; adjusted OR: 2.02; 95% CI: 1.75-2.33), or fatal PE (0.85% vs 0.35%; adjusted OR: 1.77; 95% CI: 1.10-2.85) than the non-fragile.Conclusions: In real life, 42% of VTE patients were fragile. During anticoagulation, they had fewer VTE recurrences and more major bleeding events than the non-fragile.

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Non-steroidal anti-inflammatory drugs have been associated with an increased risk of venous thromboembolism. We report for the first time, the case of a patient who developed massive pulmonary embolism after a long period of treatment with high doses of ibuprofen. A 65-year-old woman was admitted with severe dyspnea while on treatment with high doses of ibuprofen for diffuse spine pain due to arthrosis. A spiral computed tomography showed a massive pulmonary embolism. No other explanation for the thromboembolic disorder was found. She was successfully treated with therapeutic doses of low-molecular-weight heparin followed by rivaroxaban. Ibuprofen was discontinued and replaced by tramadol. High-dose ibuprofen is likely to have accounted for the life-threatening thromboembolic disorder.