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The risk of recurrence after discontinuation of anticoagulation for a combined oral contraceptive (COC)-associated venous thromboembolism (VTE) is unclear. Therefore, we conducted a systematic review and meta-analysis to estimate the incidence of recurrent VTE among women with COC-associated VTE, unprovoked VTE and to compare the incidence of recurrent VTE between the two groups. The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase Classic +Embase and Medline ALL to July 2020 and citations from included studies were searched. Randomized controlled trials, prospective cohort studies and meta-analyses of these study types were selected. The analysis was conducted by random-effects model. Nineteen studies were identified including 1537 women [5828 person-years (PY)] with COC-associated VTE and 1974 women (7798 PY) with unprovoked VTE. Studies were at low risk of bias. The incidence rate of VTE recurrence was 1.22/100 PY [95% confidence interval (CI) 0.92-1.62, I 2  = 6%] in women with COC-associated VTE, 3.89/100 PY (95% CI 2.93-5.17, I 2  = 74%) in women with unprovoked VTE and the unadjusted incidence rate ratio was 0.34 (95% CI 0.26-0.46, I 2  = 3%). The recurrence risk in women after COC-associated VTE is low and lower than after an unprovoked VTE., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

No clinical prediction model has been specifically developed or validated to identify patients with unprovoked venous thromboembolism (VTE) who are at high risk of major bleeding during extended anticoagulation. In a prospective multinational cohort study of patients with unprovoked VTE receiving extended anticoagulation after completing ≥3 months of initial treatment, we derived a new clinical prediction model using a multivariable Cox regression model based on 22 prespecified candidate predictors for the primary outcome of major bleeding. This model was then compared with modified versions of 5 existing clinical scores. A total of 118 major bleeding events occurred in 2516 patients (annual risk, 1.7%; 95% confidence interval [CI], 1.4-2.1). The incidences of major bleeding events per 100 person-years in high-risk and non-high-risk patients, respectively, were 3.9 (95% CI, 3.0-5.1) and 1.1 (0.8-1.4) using the newly derived creatinine, hemoglobin, age, and use of antiplatelet agent (CHAP) model; 3.3 (2.6-4.1) and 1.0 (0.7-1.3) using modified ACCP score, 5.3 (0.6-19.2) and 1.7 (1.4-2.0) using modified RIETE score, 3.1 (2.3-3.9) and 1.1 (0.9-1.5) using modified VTE-BLEED score, 5.2 (3.3-7.8) and 1.5 (1.2-1.8) using modified HAS-BLED score, and 4.8 (1.3-12.4) and 1.7 (1.4-2.0) using modified outpatient bleeding index score. Modified versions of the ACCP, VTE-BLEED, and HAS-BLED scores help identify patients with unprovoked VTE who are at high risk of major bleeding and should be considered for discontinuation of anticoagulation after 3 to 6 months of initial treatment. The CHAP model may further improve estimation of bleeding risk by using continuous predictor variables, but external validation is required before its implementation in clinical practice., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background:  The long-term risk of major bleeding after discontinuing anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain., Objectives:  To determine the incidence of major bleeding up to 5 years after discontinuing anticoagulation for a first unprovoked VTE., Methods:  We searched MEDLINE, EMBASE, and Cochrane CENTRAL (from inception to January 2021) to identify relevant randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding after discontinuing anticoagulation in patients with a first unprovoked or weakly provoked VTE who had completed (IMAGE_)3 months of initial treatment. Unpublished data on major bleeding events and person-years were obtained from authors of included studies to calculate study-level incidence rates. Random-effects meta-analysis was used to pool results across studies., Results:  Of 1,123 records identified by the search, 20 studies (17 RCTs) and 8,740 patients were included in the analysis. During 13,011 person-years of follow-up after discontinuing anticoagulation, the pooled incidence of major bleeding ( n  = 41) and fatal bleeding ( n  = 7) per 100 person-years was 0.35 (95% confidence interval [CI]: 0.20-0.54) and 0.09 (95% CI: 0.05-0.15). The 5-year cumulative incidence of major bleeding was of 1.0% (95% CI: 0.4-2.4%). The case-fatality rate of major bleeding after discontinuing anticoagulation was 19.9% (95% CI: 10.6-31.1%)., Conclusion:  The risk of major bleeding once anticoagulants are discontinued in patients with a first unprovoked VTE is not zero. Estimates from this study can help clinicians counsel patients about the incremental risk of major bleeding with extended anticoagulation to guide decision making about treatment duration for unprovoked VTE., Competing Interests: M.C. reports receiving research support form Leo Pharma and BMS, and honoraria from Pfizer, Bayer, BMS, and Sanofi, outside the submitted work. S.S. reports receiving honoraria from Boehringer Ingelheim, Bayer HealthCare, Daiichi Sankyo, and Sanofi, and research support from Boehringer Ingelheim, Baxter, and Octapharma, outside the submitted work. J.I.W. reports receiving honoraria from Boehringer Ingelheim, Bayer, Daiichi Sankyo, Servier, Bristol-Myers Squibb, Janssen, Novartis, and Ionis Pharmaceuticals, and research support from Boehringer Ingelheim outside the scope of the submitted work. F.C. reports having received research grant support from Pfizer, honoraria for board memberships or symposia from Bayer and AstraZeneca, and travel support from Bayer, Daiichi Sankyo, Leo Pharma, Intermune, and Actelion, outside the submitted work. C.B. reports receiving lecture fees from Bayer HealthCare, Bristol Meyer Squibb, and Boehringer Ingelheim, outside the submitted work. G.A. reports personal fees from Bristol-Myers-Squibb, Pfizer, Bayer Healthcare, Boehringer Ingelheim, and Daiichi Sankyo, outside the submitted work. T.A.B. reports receiving personal fees from Bayer, Bayer Australia, Novo Nordisk, and GlaxoSmithKline, outside the submitted work. W.A.L. reports being an employee of Bayer HealthCare. G.P. reports advisory Board for Alfa-Wassermann, Daiichi-Sankyo, Pfizer, and Roche, and speaker fees from Werfen, outside the submitted work. B.H. reports receiving honoraria from Cornerstone Research Group for provision of methodologic advice related to systematic reviews and meta-analysis. P.P. reports receiving consultancy and lectures fees from Bayer Pharma, Sanofi, Daiichi-Sankyo, and Pfizer, outside the submitted work. H.R.B. reports receiving research support and consultancy fees from Sanofi-Aventis, Bayer HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Pfizer, Roche, Isis, Thrombogenics, and Boehringer Ingelheim, outside the submitted work. G.L.-G. holds the Chair on Diagnosis of Venous Thromboembolism at the Department of Medicine, University of Ottawa, and a Clinician-Scientist Award from the Heart and Stroke Foundation of Canada. M.R. is the McGill University Harry Webster Thorp Professor of Medicine. G.L.-G reports other support from Portola Pharmaceuticals, Boehringer Ingelheim, Pfizer, Bristol Myers Squibb, LEO Pharma, Daiichi Sankyo, Bayer, Sanofi, and bioMerieux, outside the submitted work. No other authors disclosed any competing interests., (Thieme. All rights reserved.)

Background: Post-thrombotic syndrome (PTS) is one of the most frequent complications of venous thromboembolism (VTE) leading to considerable morbidity and cost. Apart from appropriate anticoagulation, there is no drug or medical intervention that helps to prevent PTS. We conducted a multicenter randomized controlled trial to determine whether rosuvastatin can prevent PTS., Methods: 312 patients receiving standard anticoagulation for a newly diagnosed VTE were randomly allocated to adjuvant rosuvastatin 20 mg once daily for 180 days (n = 155) or no rosuvastatin (n = 157). At the last study visit (Day 180 ± 21), an independent observer who was blinded to study treatment performed a PTS assessment using the Villalta scale. The primary clinical outcome of the trial was mean Villalta score at Day 180. We also explored the presence of PTS as defined by Villalta score > 4 at Day 180. Patients mean age was 46.7 ± 10.8 years, 55.8% were female., Results: At Day 180, the Villalta score was 3.5 ± 0.3 in the rosuvastatin arm vs. 3.3 ± 0.3 in the control arm (p = 0.59), and presence of PTS (Villalta >4) was 29.7% in the rosuvastatin arm vs. 25.5% in the control arm (p = 0.41). Secondary analyses showed no difference between trial arms for presence of severe PTS at Day 180 (2.0% vs. 2.7%, p = 1) and for changes in Villalta score between baseline and Day 180 (-3.7 ± 4.4 vs. -4.0 ± 5.0, p = 0.59)., Conclusion: This randomized controlled pilot trial did not demonstrate efficacy of rosuvastatin to reduce Villalta score. Further studies with longer duration of exposure to rosuvastatin are needed., Trial Registration: ClinicalTrials.gov, number NCT02679664., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Statins may reduce the risk for recurrent venous thromboembolism (VTE); however, no randomized trials have explored this hypothesis. We performed a pilot randomized trial to determine feasibility of recruitment for a larger trial of secondary VTE prevention with rosuvastatin., Methods: Patients with a newly diagnosed symptomatic proximal deep vein thrombosis and/or pulmonary embolism, receiving standard anticoagulation, were randomly allocated to adjuvant rosuvastatin 20 mg once daily for 180 days or no rosuvastatin for 6 months., Results: Between November 2016 and December 2019, 3391 patients were assessed for eligibility in six centers. Of these patients, 1347 (39.7%) were eligible and approached for participation in the trial and 312 (23.1%) were randomized. The mean rate of randomization was 8.2 ± 4.3 patients per month. During follow-up, five recurrent VTE events were observed, three (1.9%) in the rosuvastatin group (two pulmonary embolism, one deep vein thrombosis), and two (1.3%) in the control group (two pulmonary embolism; P = 0.68). One major arterial event occurred in the rosuvastatin arm and none in the control arm (0.6% vs. 0%, P = 0.50)., Conclusion: This pilot trial supports the feasibility of a larger scale randomized controlled trial to determine the efficacy of adjuvant rosuvastatin for the secondary prevention of VTE., (© 2021 International Society on Thrombosis and Haemostasis.)

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: 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).

Deep vein thrombosis and pulmonary embolism, collectively defined as venous thromboembolism (VTE), are the third leading cause of cardiovascular death in the United States. Common genetic variants conferring increased varying degrees of VTE risk have been identified by genome-wide association studies (GWAS). Rare mutations in the anticoagulant genes PROC, PROS1 and SERPINC1 result in perinatal lethal thrombosis in homozygotes and markedly increased VTE risk in heterozygotes. However, currently described VTE variants account for an insufficient portion of risk to be routinely used for clinical decision making. To identify new rare VTE risk variants, we performed a whole-exome study of 393 individuals with unprovoked VTE and 6114 controls. This study identified 4 genes harboring an excess number of rare damaging variants in patients with VTE: PROS1, STAB2, PROC, and SERPINC1. At STAB2, 7.8% of VTE cases and 2.4% of controls had a qualifying rare variant. In cell culture, VTE-associated variants of STAB2 had a reduced surface expression compared with reference STAB2. Common variants in STAB2 have been previously associated with plasma von Willebrand factor and coagulation factor VIII levels in GWAS, suggesting that haploinsufficiency of stabilin-2 may increase VTE risk through elevated levels of these procoagulants. In an independent cohort, we found higher von Willebrand factor levels and equivalent propeptide levels in individuals with rare STAB2 variants compared with controls. Taken together, this study demonstrates the utility of gene-based collapsing analyses to identify loci harboring an excess of rare variants with functional connections to a complex thrombotic disease., (© 2020 by The American Society of Hematology.)

Introduction: Cell-free DNA (CFDNA) is the major structural component of neutrophil extracellular traps (NETs). CFDNA contributes to the prothrombotic potential of NETs by promoting thrombin generation and inhibiting fibrinolysis. Patients with venous thromboembolism (VTE) have elevated circulating nucleosomes (i.e. DNA-histone complexes). In this study, we investigated if CFDNA contributes to a procoagulant and an antifibrinolytic state in patients with unprovoked VTE., Materials and Methods: Plasma samples from patients with a first episode of unprovoked VTE were obtained from the D-Dimer Optimal Duration Study (DODS). We measured CFDNA plasma levels in 263 patients while on warfarin and 1-month after stopping. Thrombin generation assays and clot lysis assays were measured in patients after stopping warfarin. Comparisons were made with healthy controls., Results: CFDNA levels in VTE patients who stopped warfarin (5.53 μg/mL; 95%CI: 5.34-5.72) were higher than during warfarin therapy (3.11 μg/mL; 95%CI: 2.98-3.25; p < .001), and higher than in healthy controls (2.77 μg/mL; 95%CI: 2.42-3.11; p < .001). VTE patients had a procoagulant state as evidenced by a shorter lag time (30.8 min; 95%CI: 29.2-32.4) compared to controls (48.2 min; 95%CI :41.0-55.5; p < .001) and a greater endogenous thrombin potential (2656 nM∗min; 95%CI: 2479-2836) compared to healthy controls (1198 nM ∗ min; 95%CI: 793-1603). There was a higher proportion of clots generated from patient plasma that were resistant to lysis (43.7%) compared to healthy controls (46.3%; p < .05). CFDNA levels were not associated with enhanced thrombin generation or impaired fibrinolysis in VTE patients., Conclusion: CFDNA levels are elevated in patients with unprovoked VTE but do not correlate with the procoagulant or anti-fibrinolytic properties of patient plasma. This study suggests that additional factors in addition to CFDNA may contribute to the pathogenesis of VTE., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The most important decision in the long-term treatment of venous thromboembolism (VTE) is how long to anticoagulate. VTE provoked by a reversible risk factor, or a first unprovoked isolated distal deep vein thrombosis (DVT), generally should be treated for 3 months. VTE provoked by a persistent or progressive risk factor (eg, cancer), or a second unprovoked proximal DVT or PE, is generally treated indefinitely. First unprovoked proximal DVT or PE may be treated for 3 to 6 months or indefinitely. Male sex, presentation as PE (particularly if concomitant proximal DVT), a positive d-dimer test after stopping anticoagulation, an antiphospholipid antibody, low risk of bleeding, and patient preference favor indefinite anticoagulation. The type of indefinite anticoagulation is of secondary importance. Low-dose oral Xa inhibitors are convenient and are thought to have a lower risk of bleeding; they are less suitable if there is a higher risk for recurrence. For cancer-associated VTE, we now prefer full-dose oral Xa inhibitors over low-molecular-weight heparin, with gastrointestinal lesions being a relative contraindication. Graduated compression stockings are not routinely indicated after DVT, but are encouraged if there is persistent leg swelling or if a trial of stockings improves symptoms. Medications have a limited role in the treatment of postthrombotic syndrome. After PE, patients should have clinical surveillance for chronic thromboembolic pulmonary hypertension (CTEPH), with ventilation-perfusion scanning and echocardiography being the initial diagnostic tests if CTEPH is a concern. Patients with CTEPH and other symptomatic patients with extensive residual perfusion defects should be evaluated for endarterectomy, balloon pulmonary angioplasty, or vasodilator therapies., (© 2020 by The American Society of Hematology.)

Essentials Long-term recurrence risk after a first unprovoked VTE with negative d-dimer levels is uncertain. Anticoagulation was stopped if d-dimer was negative, and was continued if d-dimer was positive. Five years after stopping anticoagulants, recurrent VTE was 30% in men and 17% in women. Negative d-dimers do not justify stopping anticoagulants in most men but appear to in most women., Background: The long-term risk of recurrence in patients with a first unprovoked venous thromboembolism (VTE) who have negative d-dimer results is uncertain., Objectives: To determine this risk, including in subgroups based on sex., Patients and Methods: ln a prospective interventional cohort study of 410 patients with a first unprovoked VTE, anticoagulants were stopped if d-dimer was negative on therapy and 1 month after stopping therapy. Other patients remained on anticoagulant therapy. We previously reported findings after a mean of 2.2 years. The current report includes 3 years of additional follow-up in 293 of these patients., Results: During a median follow-up of 5.0 years, recurrent VTE after stopping therapy in response to negative d-dimer testing was 5.1% (95% confidence interval [CI], 3.6-6.5) per patient-year overall, 7.5% (95% CI, 5.5-10.0) in men, 3.8% (95% CI, 2.0-6.6) in women with VTE not associated with estrogens, and 0.4% (95% CI, 0.0-2.3) in women with VTE associated with estrogens (P < 0.001 for three-group comparison). Risk of recurrence at 5 years was 21.5% (95% CI, 16.4-26.5) overall, 29.7% (95% CI, 22.1-37.3) in men, 17.0% (95% CI, 8.1-25.9) in non-estrogen women, and 2.3% (95% CI, 0.0-6.8) in estrogen women., Conclusion: The long-term risk of recurrence in patients with a first unprovoked VTE who have negative d-dimer results is not low enough to justify stopping anticoagulant therapy in men, but appears to be low enough in women for many to choose stopping therapy (ClinicalTrials.gov; NCT00720915)., (© 2019 International Society on Thrombosis and Haemostasis.)

Background: Myocardial injury after non-cardiac surgery (MINS) increases the risk of cardiovascular events and deaths, which anticoagulation therapy could prevent. Dabigatran prevents perioperative venous thromboembolism, but whether this drug can prevent a broader range of vascular complications in patients with MINS is unknown. The MANAGE trial assessed the potential of dabigatran to prevent major vascular complications among such patients., Methods: In this international, randomised, placebo-controlled trial, we recruited patients from 84 hospitals in 19 countries. Eligible patients were aged at least 45 years, had undergone non-cardiac surgery, and were within 35 days of MINS. Patients were randomly assigned (1:1) to receive dabigatran 110 mg orally twice daily or matched placebo for a maximum of 2 years or until termination of the trial and, using a partial 2-by-2 factorial design, patients not taking a proton-pump inhibitor were also randomly assigned (1:1) to omeprazole 20 mg once daily, for which results will be reported elsewhere, or matched placebo to measure its effect on major upper gastrointestinal complications. Research personnel randomised patients through a central 24 h computerised randomisation system using block randomisation, stratified by centre. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary efficacy outcome was the occurrence of a major vascular complication, a composite of vascular mortality and non-fatal myocardial infarction, non-haemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism. The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01661101., Findings: Between Jan 10, 2013, and July 17, 2017, we randomly assigned 1754 patients to receive dabigatran (n=877) or placebo (n=877); 556 patients were also randomised in the omeprazole partial factorial component. Study drug was permanently discontinued in 401 (46%) of 877 patients allocated to dabigatran and 380 (43%) of 877 patients allocated to placebo. The composite primary efficacy outcome occurred in fewer patients randomised to dabigatran than placebo (97 [11%] of 877 patients assigned to dabigatran vs 133 [15%] of 877 patients assigned to placebo; hazard ratio [HR] 0·72, 95% CI 0·55-0·93; p=0·0115). The primary safety composite outcome occurred in 29 patients (3%) randomised to dabigatran and 31 patients (4%) randomised to placebo (HR 0·92, 95% CI 0·55-1·53; p=0·76)., Interpretation: Among patients who had MINS, dabigatran 110 mg twice daily lowered the risk of major vascular complications, with no significant increase in major bleeding. Patients with MINS have a poor prognosis; dabigatran 110 mg twice daily has the potential to help many of the 8 million adults globally who have MINS to reduce their risk of a major vascular complication [corrected]., Funding: Boehringer Ingelheim and Canadian Institutes of Health Research., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

It is uncertain whether antiphospholipid antibodies (APAs) increase the risk of recurrence after a first unprovoked venous thromboembolism (VTE). We tested for anticardiolipin antibodies, anti-β2 glycoprotein 1 antibodies, and lupus anticoagulant on 2 occasions ∼6 months apart in 307 patients with a first unprovoked VTE who were part of a prospective cohort study. We then determined if APAs were associated with recurrent thrombosis in the 290 patients who stopped anticoagulant therapy in response to negative D-dimer results. Compared with those without an APA, the hazard ratios for recurrent VTE were 1.8 (95% confidence interval [CI], 0.9-3.7; P = .09) in the 25.9% of patients with an APA on ≥1 occasions, 2.7 (95% CI, 1.1-.7; P = .03) in the 9.0% of patients with the same APA on 2 occasions, and 4.5 (95% CI, 1.5-13.0; P = .006) in the 3.8% of patients with 2 or 3 different APA types on either the same or different occasions. There was no association between having an APA and D-dimer levels. We conclude that having the same type of APA on 2 occasions or having >1 type of APA on the same or different occasions is associated with recurrent thrombosis in patients with a first unprovoked VTE who stop anticoagulant therapy in response to negative D-dimer tests. APA and D-dimer levels seem to be independent predictors of recurrence in patients with an unprovoked VTE. This trial was registered at www.clinicaltrials.gov as #NCT00720915., (© 2018 by The American Society of Hematology.)

Two new strategies for interpreting D-dimer results have been proposed: i) using a progressively higher D-dimer threshold with increasing age (age-adjusted strategy) and ii) using a D-dimer threshold in patients with low clinical probability that is twice the threshold used in patients with moderate clinical probability (clinical probability-adjusted strategy). Our objective was to compare the diagnostic accuracy of age-adjusted and clinical probability-adjusted D-dimer interpretation in patients with a low or moderate clinical probability of venous thromboembolism (VTE). We performed a retrospective analysis of clinical data and blood samples from two prospective studies. We compared the negative predictive value (NPV) for VTE, and the proportion of patients with a negative D-dimer result, using two D-dimer interpretation strategies: the age-adjusted strategy, which uses a progressively higher D-dimer threshold with increasing age over 50 years (age in years × 10 µg/L FEU); and the clinical probability-adjusted strategy which uses a D-dimer threshold of 1000 µg/L FEU in patients with low clinical probability and 500 µg/L FEU in patients with moderate clinical probability. A total of 1649 outpatients with low or moderate clinical probability for a first suspected deep vein thrombosis or pulmonary embolism were included. The NPV of both the clinical probability-adjusted strategy (99.7 %) and the age-adjusted strategy (99.6 %) were similar. However, the proportion of patients with a negative result was greater with the clinical probability-adjusted strategy (56.1 % vs, 50.9 %; difference 5.2 %; 95 % CI 3.5 % to 6.8 %). These findings suggest that clinical probability-adjusted D-dimer interpretation is a better way of interpreting D-dimer results compared to age-adjusted interpretation.

Introduction: For patients with a first unprovoked venous thromboembolism (VTE), the optimal duration of anticoagulation is a crucial clinical dilemma which has yet to be resolved. The decision to stop anticoagulant therapy (AT) after the initial 3-6 months or to continue AT indefinitely, is primarily governed by the long-term risk of recurrence when treatment is discontinued. This risk however, is not well established, hindering decision making., Methods and Analysis: We will conduct a systematic review and a meta-analysis of studies involving patients diagnosed with a first, symptomatic unprovoked VTE or VTE provoked by minor transient risk factors, who have completed at least 3 months of initial AT; and who were followed-up for standardised time intervals of 1, 2, 5, 10 and 20 years (±3 months) after stopping AT. We will search (from inception to January 2017) MEDLINE, Embase and the Cochrane library for randomised controlled trials and prospective observational studies. Two reviewers will conduct all screening and data collection independently. The primary outcome of the rate of recurrent VTE at the standardised time intervals will be calculated for each study from the total number of recurrent events and the corresponding number of patient-years of follow-up. We will use a random-effects model to pool study results and report a weighted estimate of the absolute rate of recurrent VTE (events per 100 patient-years) over standardised time intervals of 1, 2, 5, 10 and 20 years after discontinuing anticoagulants., Ethics and Dissemination: Ethical approval is not applicable for this study. Findings from this study will be disseminated through peer-reviewed journal publication as well as relevant national and international conference presentations., Prospero Registration Number: CRD42017056309., Competing Interests: Competing interests: MC reports receiving research support form Leo Pharma and BMS, and honoraria from Pfizer, Bayer, BMS, and Sanofi, outside the submitted work. SS reports receiving honoraria from Boehringer Ingelheim, Bayer HealthCare, Daiichi Sankyo and Sanofi, and research support from Boehringer Ingelheim, Baxter and Octapharma, outside the submitted work. FC reports having received research grant support from Pfizer, honoraria for board memberships or symposia from Bayer and AstraZeneca, and travel support from Bayer, Daiichi Sankyo, Leo Pharma, Intermune, and Actelion, outside the submitted work. PP reports receiving consultancy and lectures fees from Bayer Pharma, Sanofi, Daiichi-Sankyo and Pfizer, outside the submitted work. CB reports receiving lectures fees from Bayer HealthCare, Bristol Meyer Squibb and Boehringer Ingelheim, outside the submitted work. GA reports personal fees from Bristol-Myers-Squibb, Pfizer, Bayer Healthcare, Boehringer Ingelheim, and Daiichi Sankyo, outside the submitted work. HRB reports receiving research support and consultancy fees from Sanofi-aventis, Bayer HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Pfizer, Roche, Isis, Thrombogenics, and Boehringer Ingelheim, outside the submitted work. TAB reports receiving personal fees from Bayer, Bayer Australia, Novo Nordisk, and Glaxo Smith Klein, outside the submitted work. GP reports Advisory Board for Alfa-Wassermann, Daiichi-Sankyo, Pfizer and Roche, and speaker fees from Werfen, outside the submitted work. BH reports receiving honoraria from Cornerstone Research Group for provision of methodologic advice related to systematic reviews and meta-analysis. MAR reports receiving research support from Biomerieux, outside of the submitted work. All other authors (FK, AR, CK, SE, LP, ES and GAW) declare that they have no relevant competing interests., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The management of patients with venous thromboembolism (VTE) is a common clinical scenario that, for the most part, involves well‑established, evidence‑based treatment pathways. However, important unanswered clinical questions remain that are the focus of ongoing research. The aim of this narrative review is to provide a practical, case‑based approach to the following clinical scenarios in which therapeutic management pathways are less well established: How long to administer anticoagulation to patients with a first unprovoked VTE? How to manage complex patients with cancer‑associated VTE? When and how to treat patients with splanchnic vein thrombosis? When to use thrombolytic therapy for deep vein thrombosis?

The primary goal of diagnostic testing for venous thromboembolism (VTE) is to identify all patients who could benefit from anticoagulant therapy. Test results that identify patients as having a ≤2% risk of VTE in the next 3 months are judged to exclude deep vein thrombosis (DVT) or pulmonary embolism (PE). Clinical evaluation, with assessment of: (1) clinical pretest probability (CPTP) for VTE; (2) likelihood of important alternative diagnoses; and (3) the probable yield of D-dimer and various imaging tests, guide which tests should be performed. The combination of nonhigh CPTP and negative D-dimer testing excludes DVT or PE in one-third to a half of outpatients. Venous ultrasound of the proximal veins, with or without examination of the distal veins, is the primary imaging test for leg and upper-extremity DVT. If a previous test is not available for comparison, the positive predictive value of ultrasound is low in patients with previous DVT. Computed tomography pulmonary angiography (CTPA) is the primary imaging test for PE and often yields an alternative diagnosis when there is no PE. Ventilation-perfusion scanning is associated with less radiation exposure than CTPA and is preferred in younger patients, particularly during pregnancy. If DVT or PE cannot be "ruled-in" or "ruled-out" by initial diagnostic testing, patients can usually be managed safely by: (1) withholding anticoagulant therapy; and (2) doing serial ultrasound examinations to detect new or extending DVT., (© 2016 by The American Society of Hematology. All rights reserved.)

Background: The PeriOperative ISchemia Evaluation-2 (POISE-2) trial compared aspirin with placebo after noncardiac surgery., Methods: The authors randomly assigned 10,010 patients undergoing noncardiac surgery to receive 200 mg aspirin or placebo 2 to 4 h before surgery and then 100 mg aspirin daily or placebo daily for up to 30 days after surgery. Herein, the authors report the effect of aspirin on venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, as well as an updated pooled analysis of randomized trials of antiplatelet therapy for VTE prevention in noncardiac surgery patients., Results: Six thousand five hundred forty-eight patients (65.4%) received anticoagulant prophylaxis. VTE occurred in 53 patients (1.1%) allocated to aspirin and in 60 patients (1.2%) allocated to placebo (hazard ratio, 0.89; 95% CI, 0.61 to 1.28). Major or life-threatening bleeding occurred in 312 patients (6.3%) allocated to aspirin and in 256 patients (5.1%) allocated to placebo (hazard ratio, 1.22; 95% CI, 1.04 to 1.44). Concomitant use of anticoagulant prophylaxis did not modify the effect of aspirin on VTE or bleeding. Pooled analysis of the POISE-2 and Pulmonary Embolism Prevention trials demonstrated that symptomatic VTE occurred in 173 (1.3%) of 13,724 patients allocated to aspirin and in 246 (1.8%) of 13,730 patients allocated to placebo (odds ratio, 0.71; 95% CI, 0.56 to 0.89; heterogeneity P = 0.27; I = 17%); the impact of aspirin was very similar in those who did and did not receive pharmacologic prophylaxis. Pooled estimates for symptomatic VTE were similar to the pooled estimates for any deep vein thrombosis and pulmonary embolism from the POISE-2 trial, Pulmonary Embolism Prevention trial, and the Antiplatelet Trialists' Collaboration meta-analysis., Conclusions: Aspirin in the POISE-2 trial did not reduce VTE, but two thirds of patients received anticoagulant prophylaxis, there were few VTE events, and results were consistent with a wide range of aspirin effects. A pooled analysis of the randomized trials demonstrates evidence for the efficacy of aspirin for VTE prevention in hospitalized surgical patients.

Background: The rate of recurrent venous thromboembolism (VTE) in patients with a first unprovoked VTE who had a negative qualitative D-dimer test one month after stopping anticoagulant therapy was higher than expected in the D-dimer Optimal Duration Study (DODS)., Objectives: To determine whether quantitative D-dimer levels using a low threshold, age- and sex-specific thresholds, or repeated measurements, would improve identification of patients at low risk of recurrent VTE., Materials and Methods: D-dimer levels were quantified in banked samples from 307 patients in DODS who had a negative qualitative D-dimer test while on, and 1month after stopping, anticoagulant therapy and the rates of recurrent VTE were determined in patients with D-dimer levels below various predefined thresholds., Results: The rate (per patient year) of recurrent VTE was: 5.9% with D-dimer levels<250μg/l at one month; 5.2% with D-dimer levels between 250 and 499μg/l at one month; 5.0% with D-dimer levels less than predefined age- and sex-specific thresholds at one month; and 6.3% when D-dimer levels were <500μg/l at both one and 7months after stopping anticoagulant therapy. These rates are similar to the overall event rate of 6.3% in patients who stopped treatment., Conclusions: Among unprovoked VTE patients who had a negative qualitative D-dimer test during and after anticoagulant therapy, low D-dimer thresholds, age and sex-adjusted thresholds or repeated measurements, did not identify subgroups with a very low rate of recurrence., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Unlabelled: ESSENTIALS: It is not known if D-dimer testing alone can safely exclude pulmonary embolism (PE). We studied the safety of using a quantitative latex agglutination D-dimer to exclude PE in 808 patients. 52% of patients with suspected PE had a negative D-dimer test and were followed for 3 months. The negative predictive value of D-dimer testing alone was 99.8%, suggesting it may safely exclude PE., Background: Strategies are needed to exclude pulmonary embolism (PE) efficiently without the need for imaging tests. Although validated rules for clinical probability assessment can be combined with D-dimer testing to safely exclude PE, the rules can be complicated or partially subjective, which limits their use., Objectives: To determine if PE can be safely excluded in patients with a negative D-dimer without incorporating clinical probability assessment., Patients/methods: We enrolled consecutive outpatients and inpatients with suspected PE from four tertiary care hospitals. All patients underwent D-dimer testing using the MDA D-dimer test, a quantitative latex agglutination assay. PE was excluded in patients with a D-dimer less than 750 μg FEU L(-1) without further testing., Patients: with D-dimer levels of 750 μg FEU L(-1) or higher underwent standardized imaging tests for PE. All patients in whom PE was excluded had anticoagulant therapy withheld and were followed for 3 months for venous thromboembolism (VTE). Suspected events during follow-up were adjudicated centrally., Results: Eight hundred and eight patients were enrolled, of whom 99 (12%) were diagnosed with VTE at presentation. Four hundred and twenty (52%) patients had a negative D-dimer level at presentation and were not treated with anticoagulants; of these, one had VTE during follow-up. The negative predictive value of D-dimer testing for PE was 99.8% (95% confidence interval, 98.7-99.9%)., Conclusions: A negative latex agglutination D-dimer assay is seen in about one-half of patients with suspected PE and reliably excludes PE as a stand-alone test., (© 2015 International Society on Thrombosis and Haemostasis.)

Dabigatran was as effective as warfarin for the acute treatment of venous thromboembolism in the RE-COVER and RE-COVER II trials. We compared the incidence of bleeding with dabigatran versus warfarin in pooled data from these studies. The localisation, bleeding severity, and the impact of key factors on the incidence of bleeding, were compared between the dabigatran and warfarin treatment group. Altogether, 2553 patients received dabigatran and 2554 warfarin, each for a mean of 164 days. The incidence of any bleeding event was significantly lower with dabigatran (hazard ratio [HR] 0.70; 95% confidence interval [CI], 0.61-0.79), as was the incidence of the composite of MBEs and clinically relevant non-major bleeding events (HR 0.62; 95% CI, 0.50-0.76). The incidence of major bleeding events (MBEs) was also significantly lower with dabigatran in the double-dummy phase (HR, 0.60; 95%CI, 0.36-0.99) but not statistically different between the two treatment arms when the entire treatment period is considered (HR 0.73 95% CI, 0.48-1.11). Increasing age, reduced renal function, Asian ethnicity, and concomitant antiplatelet therapy were associated with higher bleeding rates in both treatment groups. The reduction in bleeding with dabigatran compared to warfarin was consistent among the subgroups and with a similar pattern for intracranial, and urogenital major bleeding. In conclusion, treatment of venous thromboembolism with dabigatran is associated with a lower risk of bleeding compared to warfarin. This reduction did not differ with respect to the location of bleeding or among predefined subgroups.

The efficacy and safety of dabigatran for treatment of venous thromboembolism (VTE) were demonstrated in two trials. It is unclear if the results pertain to patients with cancer and VTE. Data from two randomised trials comparing dabigatran and warfarin for acute VTE were pooled. Primary efficacy outcome was symptomatic recurrent VTE and related death from randomisation to the end of the treatment period. Safety outcomes were major, major and clinically relevant non-major, and any bleeding during the oral-only treatment period. Patients with active cancer (=within 5 years) at baseline or diagnosed during the study were analysed. Compared with 4,772 patients without cancer, recurrent VTE occurred more frequently in 335 patients with cancer at any time (hazard ratio [HR] 3.3; 95 % confidence interval [CI], 2.1-5.3) and more often in 114 with cancer diagnosed during the study compared to 221 with cancer at baseline (HR 2.6; 95 % CI, 1.1-6.2). There was no significant difference in efficacy between dabigatran and warfarin for cancer at baseline (HR 0.75; 95 % CI, 0.20-2.8) or diagnosed during the study (HR 0.63; 95 % CI, 0.20-2.0). Major bleeding (HR 4.1; 95 % CI, 2.2-7.5) and any bleeding (HR 1.5; 95 % CI, 1.2-2.0) were more frequent in patients with cancer than without, but with similar incidence in cancer with dabigatran or warfarin. In conclusion, in cancer patients, dabigatran provided similar clinical benefit as warfarin. VTE recurrence or bleeding were similar in patients on dabigatran or warfarin. The efficacy of dabigatran has not been assessed in comparison with low-molecular-weight heparin.

Background: Normal D-dimer levels after withdrawal of anticoagulant therapy are associated with a reduced risk for recurrence in patients with unprovoked venous thromboembolism (VTE) and may justify stopping treatment., Objective: To determine whether patients with a first unprovoked VTE and negative D-dimer test result who stop anticoagulant therapy have a low risk for recurrence., Design: Prospective management study with blinded outcome assessment. (ClinicalTrials.gov: NCT00720915)., Setting: 13 university-affiliated clinical centers., Patients: 410 adults aged 75 years or younger with a first unprovoked proximal deep venous thrombosis or pulmonary embolism who had completed 3 to 7 months of anticoagulant therapy., Intervention: Anticoagulant therapy was stopped if D-dimer test results were negative and was not restarted if results were still negative after 1 month., Measurements: Recurrent VTE during an average follow-up of 2.2 years., Results: In 319 patients (78%) who had 2 negative D-dimer results and did not restart anticoagulant therapy, rates of recurrent VTE were 6.7% (95% CI, 4.8% to 9.0%) per patient-year overall (42 of 319), 9.7% (CI, 6.7% to 13.7%) per patient-year in men (33 of 180), 5.4% (CI, 2.5% to 10.2%) per patient-year in women with VTE not associated with estrogen therapy (9 of 81), and 0.0% (CI, 0.0% to 3.0%) per patient-year in women with VTE associated with estrogen therapy (0 of 58) (P = 0.001 for the 3-group comparison)., Limitations: Imprecision in female subgroups. Results may not be generalizable to different D-dimer assays from the one used in the study., Conclusion: The risk for recurrence in patients with a first unprovoked VTE who have negative D-dimer results is not low enough to justify stopping anticoagulant therapy in men but may be low enough to justify stopping therapy in women., Primary Funding Source: Canadian Institutes of Health Research.

When counseling first-degree relatives of patients with venous thromboembolism (VTE), it is important to know whether factors other than thrombophilia influence their risk for thrombosis. We assessed the risk for VTE in 915 first-degree relatives of patients with provoked VTE, compared this with the risk in 1752 first-degree relatives of patients with unprovoked VTE, and then combined data from the 2 groups of relatives to identify predictors of thrombosis. There had been 123 VTEs in 2617 first-degree relatives (0.12 per 100 person-years). The risk for VTE in first-degree relatives was higher if the index cases had an unprovoked compared with a provoked VTE (odds ratio [OR], 2.38; 95% confidence interval [CI], 1.43-3.85), if the index case was younger (OR, 0.97 per year older; 95% CI, 0.96-0.99), and if an additional family member had VTE (OR, 2.71; 95% CI, 2.22-3.31). Among first-degree relatives of an index case with factor V Leiden or the prothrombin 20210A gene variant, the presence of these abnormalities also predicted thrombosis (OR, 4.42; 95% CI, 1.35-14.38). We conclude that thrombosis at a young age and unprovoked VTE predict VTE in first-degree relatives, and that the influence of these 2 factors is additive., (© 2014 by The American Society of Hematology.)

Background: Although venous thromboembolism (VTE) is an important cause of postoperative morbidity and mortality, there is still no consensus on the optimal strategy for VTE prevention after major surgery. The objective of this review was to determine the benefits and risks of thromboprophylaxis with both compression and anticoagulation, compared with either modality alone., Methods: A systematic review of MEDLINE, CENTRAL and Embase databases was performed to identify eligible randomized trials. The literature search and data extraction were carried out independently by two reviewers. Outcomes of interest were deep vein thrombosis (DVT), pulmonary embolism, bleeding, limb injury and mortality., Results: Twenty-five studies were eligible for inclusion. Adding compression to anticoagulation decreased the risk of DVT by 49 per cent (risk ratio (RR) 0·51, 95 per cent confidence interval 0·36 to 0·73). The corresponding funnel plot suggested publication bias and, overall, the evidence for this comparison was judged to be of low quality. Adding anticoagulation to compression decreased the risk of DVT by 44 per cent (RR 0·56, 0·45 to 0·69) while increasing the risk of bleeding (RR 1·74, 1·29 to 2·34). There was no suggestion of publication bias and the evidence for this comparison was judged to be of moderate quality., Conclusion: Combined compression and anticoagulation is more effective at preventing postoperative DVT than either modality alone. However, adding anticoagulation to compression increases the risk of bleeding, and the evidence that adding compression to anticoagulation reduces VTE risk is of low quality., (© 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.)

Introduction: Venous thromboembolism (VTE) is a major disease associated with short-term and long-term morbidity and mortality. Patients with a VTE provoked by surgery or immobilisation are at low risk of recurrence and do not require long-term anticoagulation; those with a VTE and metastatic cancer are at high risk of recurrence and require lifetime thromboprophylaxis. In those at intermediate risk of recurrence, it remains controversial whether prolonging anticoagulation and thus incurring treatment burden and bleeding risk is warranted., Methods and Analysis: We will conduct a systematic review and meta-analysis of randomised controlled trials enrolling patients with VTE at intermediate risk of recurrence and evaluating short-term anticoagulation (12 weeks to 9 months initial therapy) versus longer term anticoagulation (at least 6 months additional anticoagulation beyond the course of treatment in the shorter arm). Anticoagulation could consist of vitamin K antagonists or new oral anticoagulants. Outcomes of interest include recurrent non-fatal thrombosis (deep venous thrombosis and pulmonary embolism), major non-fatal bleeding and mortality. We will systematically search CINAHL, EMBASE, MEDLINE and the Cochrane Central Registry of Controlled Trials. Teams of two reviewers will, independently and in duplicate, screen titles and abstracts and complete full text reviews to determine eligibility, and subsequently abstract data and assess risk of bias in eligible trials. We will conduct meta-analyses to establish the effect of short-term versus long-term anticoagulation on the outcomes of interest and evaluate confidence in estimates (quality of evidence) using the GRADE (grading of recommendations, assessment, development and evaluation) approach., Ethics and Dissemination: Our review will facilitate evidence-based management of patients with unprovoked or recurrent VTE. For purposes of privacy and confidentiality, the systematic review will be limited to studies with deidentified data. The study will be disseminated by peer-review publication and conference presentation., Trial Registration Number: PROSPERO (CRD42014007620)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background & Aims: Guidelines for the management of venous thromboembolism (VTE) from the American College of Chest Physicians do not address patients with inflammatory bowel disease (IBD), a group with a high risk of both VTE and gastrointestinal bleeding. We present recommendations for the prevention and treatment of VTE in patients with IBD., Methods: A systematic literature search was performed to identify studies on VTE in IBD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Statements were developed through an iterative online platform, then finalized and voted on by a working group of adult and pediatric gastroenterologists and thrombosis specialists., Results: IBD patients have an approximately 3-fold higher risk of VTE compared with individuals without IBD, and disease flares further increase this risk. Anticoagulant thromboprophylaxis is recommended for IBD patients who are hospitalized with IBD flares without active bleeding and is suggested when bleeding is nonsevere. Anticoagulant thromboprophylaxis is suggested during moderate-severe IBD flares in outpatients with a history of VTE provoked by an IBD flare or an unprovoked VTE, but not otherwise. The recommended duration of anticoagulation after a first VTE is based on the presence of provoking factors. Specific suggestions are made for the prevention and treatment of VTE in pediatric and pregnant IBD patients., Conclusions: Using the American College of Chest Physicians' guidelines as a foundation, we have integrated evidence from IBD studies to develop specific recommendations for the management of VTE in this high-risk population., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Dabigatran and warfarin have been compared for the treatment of acute venous thromboembolism (VTE) in a previous trial. We undertook this study to extend those findings., Methods and Results: In a randomized, double-blind, double-dummy trial of 2589 patients with acute VTE treated with low-molecular-weight or unfractionated heparin for 5 to 11 days, we compared dabigatran 150 mg twice daily with warfarin. The primary outcome, recurrent symptomatic, objectively confirmed VTE and related deaths during 6 months of treatment occurred in 30 of the 1279 dabigatran patients (2.3%) compared with 28 of the 1289 warfarin patients (2.2%; hazard ratio, 1.08; 95% confidence interval [CI], 0.64-1.80; absolute risk difference, 0.2%; 95% CI, -1.0 to 1.3; P<0.001 for the prespecified noninferiority margin for both criteria). The safety end point, major bleeding, occurred in 15 patients receiving dabigatran (1.2%) and in 22 receiving warfarin (1.7%; hazard ratio, 0.69; 95% CI, 0.36-1.32). Any bleeding occurred in 200 dabigatran (15.6%) and 285 warfarin (22.1%; hazard ratio, 0.67; 95% CI, 0.56-0.81) patients. Deaths, adverse events, and acute coronary syndromes were similar in both groups. Pooled analysis of this study RE-COVER II and the RE-COVER trial gave hazard ratios for recurrent VTE of 1.09 (95% CI, 0.76-1.57), for major bleeding of 0.73 (95% CI, 0.48-1.11), and for any bleeding of 0.70 (95% CI, 0.61-0.79)., Conclusion: Dabigatran has similar effects on VTE recurrence and a lower risk of bleeding compared with warfarin for the treatment of acute VTE., Clinical Trial Registration Url: www.clinicaltrials.gov. Unique identifiers: NCT00680186 and NCT00291330.

Objective: The interaction of protein C (PC) with the endothelial PC receptor (EPCR) enhances activated PC generation. We performed targeted gene sequencing of the PC gene (PROC) and EPCR genes (PROCR) in patients with unprovoked venous thromboembolism (VTE) to determine whether mutations that impair PC-EPCR interactions are associated with an increased risk of VTE., Approach and Results: We sequenced exon 3 of PROC and exons 2 and 3 of PROCR (the exons that encode the protein-protein binding domains of PC and EPCR) in 653 patients with unprovoked VTE and in 627 healthy controls. Five single nucleotide variants, each in individual patients, were identified that result in abnormal PC (Arg9Cys, Val34Met, and Arg-1Cys) or abnormal EPCR proteins (Arg96Cys and Val170Leu). We did not detect any nonsynonymous coding variants in the controls. When the PC variants were expressed in human embryonic kidney 293 cells, all exhibited decreased synthesis, and 2 of the variants had reduced capacity for activated PC generation. When expressed on the surface of human embryonic kidney 293 cells, the EPCR variants showed reduced affinity for fluorescently labeled PC. In addition, the previously reported EPCR A3 haplotype, which promotes cellular shedding of EPCR, is over-represented in the patient group (P=0.001)., Conclusions: This is the first targeted DNA sequencing analysis of PROC and PROCR in a large group of patients with unprovoked VTE. Our data suggest that mutations that impair PC-EPCR interactions may be associated with an increased risk of VTE.

Laboratory evidence of antiphospholipid antibodies (APLA) in patients with a first episode of venous thromboembolism (VTE) is often considered an indication for indefinite anticoagulant therapy, but it is uncertain if this practice is justified. We performed a systematic review to determine whether the presence of APLA in patients with a first VTE is associated with an increased risk of recurrence. We searched PubMed, CINAHL, Cochrane, EMBASE, and Web of Knowledge through February 2012 and included prospective studies that met prespecified design criteria. There were 109 recurrent VTE in 588 patients with APLA and 374 recurrent VTE in 1914 patients without APLA (relative risk 1.41; 95% confidence interval [CI], 0.99 to 2.36). The unadjusted risk ratio for recurrent VTE after stopping anticoagulant therapy in patients with an anticardiolipin antibody was 1.53 (95% CI, 0.76-3.11), and with a lupus anticoagulant was 2.83 (95% CI, 0.83-9.64). All studies had important methodologic limitations and we judged the overall quality of the evidence as very low. Although a positive APLA test appears to predict an increased risk of recurrence in patients with a first VTE, the strength of this association is uncertain because the available evidence is of very low quality.

Background: Dabigatran, which is administered in a fixed dose and does not require laboratory monitoring, may be suitable for extended treatment of venous thromboembolism., Methods: In two double-blind, randomized trials, we compared dabigatran at a dose of 150 mg twice daily with warfarin (active-control study) or with placebo (placebo-control study) in patients with venous thromboembolism who had completed at least 3 initial months of therapy., Results: In the active-control study, recurrent venous thromboembolism occurred in 26 of 1430 patients in the dabigatran group (1.8%) and 18 of 1426 patients in the warfarin group (1.3%) (hazard ratio with dabigatran, 1.44; 95% confidence interval [CI], 0.78 to 2.64; P=0.01 for noninferiority). Major bleeding occurred in 13 patients in the dabigatran group (0.9%) and 25 patients in the warfarin group (1.8%) (hazard ratio, 0.52; 95% CI, 0.27 to 1.02). Major or clinically relevant bleeding was less frequent with dabigatran (hazard ratio, 0.54; 95% CI, 0.41 to 0.71). Acute coronary syndromes occurred in 13 patients in the dabigatran group (0.9%) and 3 patients in the warfarin group (0.2%) (P=0.02). In the placebo-control study, recurrent venous thromboembolism occurred in 3 of 681 patients in the dabigatran group (0.4%) and 37 of 662 patients in the placebo group (5.6%) (hazard ratio, 0.08; 95% CI, 0.02 to 0.25; P<0.001). Major bleeding occurred in 2 patients in the dabigatran group (0.3%) and 0 patients in the placebo group. Major or clinically relevant bleeding occurred in 36 patients in the dabigatran group (5.3%) and 12 patients in the placebo group (1.8%) (hazard ratio, 2.92; 95% CI, 1.52 to 5.60). Acute coronary syndromes occurred in 1 patient each in the dabigatran and placebo groups., Conclusions: Dabigatran was effective in the extended treatment of venous thromboembolism and carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo. (Funded by Boehringer Ingelheim; RE-MEDY and RE-SONATE ClinicalTrials.gov numbers, NCT00329238 and NCT00558259, respectively.).

Background: D-Dimer testing is sensitive but not specific for diagnosing deep venous thrombosis (DVT). Changing the use of testing and the threshold level for a positive test result on the basis of risk for DVT might improve the tradeoff between sensitivity and specificity and reduce the need for testing., Objective: To determine whether using a selective D-dimer testing strategy based on clinical pretest probability (C-PTP) for DVT is safe and reduces diagnostic testing compared with using a single D-dimer threshold for all patients., Design: Randomized, multicenter, controlled trial. Patients were allocated using a central automated system. Ultrasonographers and study adjudicators but not other study personnel were blinded to trial allocation. (ClinicalTrials.gov: NCT00157677), Setting: 5 Canadian hospitals., Patients: Consecutive symptomatic patients with a first episode of suspected DVT., Intervention: Selective testing (n = 860), defined as D-dimer testing for outpatients with low or moderate C-PTP (DVT excluded at D-dimer levels <1.0 µg/mL [low C-PTP] or <0.5 µg/mL [moderate C-PTP]) and venous ultrasonography without D-dimer testing for outpatients with high C-PTP and inpatients, or uniform testing (n = 863), defined as D-dimer testing for all participants (DVT excluded at D-dimer levels <0.5 µg/mL)., Measurements: The proportion of patients not diagnosed with DVT during initial testing who had symptomatic venous thromboembolism during 3-month follow-up and the proportion of patients undergoing D-dimer testing and ultrasonography., Results: The incidence of symptomatic venous thromboembolism at 3 months was 0.5% in both study groups (difference, 0.0 percentage point [95% CI, -0.8 to 0.8 percentage points]). Selective testing reduced the proportion of patients who required D-dimer testing by 21.8 percentage points (CI, 19.1 to 24.8 percentage points). It reduced the proportion who required ultrasonography by 7.6 percentage points (CI, 2.9 to 12.2 percentage points) overall and by 21.0 percentage points (CI, 14.2 to 27.6 percentage points) in outpatients with low C-PTP., Limitation: Results may not be generalizable to all D-dimer assays or patients with previous DVT, study personnel were not blinded, and the trial was stopped prematurely., Conclusion: A selective D-dimer testing strategy seems as safe as and more efficient than having everyone undergo D-dimer testing when diagnosing a first episode of suspected DVT., Primary Funding Source: Heart and Stroke Foundation of Ontario.

Purpose of Review: Deficiency of antithrombin, protein C, and protein S increases the risk of a first venous thromboembolism (VTE) by at least 10-fold and is rare (i.e., <0.5% of population), whereas factor V Leiden and the prothrombin G20210A gene increase this risk by 2-5-fold and are common (2-5% of whites). Antiphospholipid antibodies are considered acquired thrombophilic states. Testing for these abnormalities is widespread. This review will consider if the results of testing should influence how patients with VTE are treated., Recent Findings: There are no randomized trials that have compared testing for thrombophilia with no testing; consequently, current assessments of whether testing should influence treatment of VTE are based on indirect evidence. Observational studies indicate that anticoagulants are equally effective in patients with and without thrombophilia; therefore, the presence of thrombophilia should not influence the choice of anticoagulant or the intensity of therapy. A lupus anticoagulant, however, can complicate monitoring of vitamin K antagonist therapy. The risk of recurrent VTE after stopping anticoagulant therapy may be higher in patients with thrombophilia, but not enough to influence whether anticoagulants should be stopped at 3 months or continued indefinitely., Summary: Thrombophilia should rarely influence the treatment of VTE. Therefore, routine thrombophilia testing of patients with VTE is not indicated as a way to guide treatment decisions.

Four observations support that anticoagulant therapy for venous thromboembolism (VTE) has an 'active treatment' phase that is limited to about 3 months. First, <3 months of treatment is associated with a higher risk of recurrent VTE than treatment for 3 months or longer, suggesting that <3 months is inadequate therapy. Second, treatment for 3 months is associated with the same risk of recurrent VTE as treatment for 6 months or longer, suggesting that 3 months is adequate therapy. Third, the increase in recurrent VTE with too short a course of treatment is predominantly at the site of the initial thrombosis, suggesting reactivation of initial thrombosis. Fourth, the increase in recurrent VTE with too short a course of treatment occurs immediately after treatment is stopped and is short lived, again suggesting reactivation of initial thrombosis. Once the initial thrombosis has been adequately treated (i.e. the first phase of treatment), further anticoagulation serves as 'secondary prevention' of new, unrelated, episodes of thrombosis (i.e. the second phase of treatment). For most patients, therefore, anticoagulant therapy for VTE should be stopped at 3 months when the acute episode has completed treatment, or should be continued indefinitely as 'secondary prevention' if the risk of recurrence remains unacceptably high having completed 'active treatment'., (© 2012 International Society on Thrombosis and Haemostasis.)

Objective: To determine how length of anticoagulation and clinical presentation of venous thromboembolism influence the risk of recurrence after anticoagulant treatment is stopped and to identify the shortest length of anticoagulation that reduces the risk of recurrence to its lowest level., Design: Pooled analysis of individual participants' data from seven randomised trials., Setting: Outpatient anticoagulant clinics in academic centres., Population: 2925 men or women with a first venous thromboembolism who did not have cancer and received different durations of anticoagulant treatment., Main Outcome Measure: First recurrent venous thromboembolism after stopping anticoagulant treatment during up to 24 months of follow-up., Results: Recurrence was lower after isolated distal deep vein thrombosis than after proximal deep vein thrombosis (hazard ratio 0.49, 95% confidence interval 0.34 to 0.71), similar after pulmonary embolism and proximal deep vein thrombosis (1.19, 0.87 to 1.63), and lower after thrombosis provoked by a temporary risk factor than after unprovoked thrombosis (0.55, 0.41 to 0.74). Recurrence was higher if anticoagulation was stopped at 1.0 or 1.5 months compared with at 3 months or later (hazard ratio 1.52, 1.14 to 2.02) and similar if treatment was stopped at 3 months compared with at 6 months or later (1.19, 0.86 to 1.65). High rates of recurrence associated with shorter durations of anticoagulation were confined to the first 6 months after stopping treatment., Conclusion: Three months of treatment achieves a similar risk of recurrent venous thromboembolism after stopping anticoagulation to a longer course of treatment. Unprovoked proximal deep vein thrombosis and pulmonary embolism have a high risk of recurrence whenever treatment is stopped.

About half of patients with a first unprovoked proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) will have a recurrent venous thromboembolism (VTE) within 10 years if they stop treatment, and randomized trials have shown clear benefit from extended anticoagulant therapy in these patients. Although the risk of recurrence varies among patients with a first unprovoked proximal DVT or PE, and a number of factors can identify patients with a lower risk of recurrence, the safety of routinely stopping anticoagulant therapy based on the presence of these factors needs to be established in prospective studies before this is done in clinical practice. As isolated distal DVT is associated with about half the risk of recurrence of proximal DVT or PE, a first episode of unprovoked distal DVT does not justify extended anticoagulation. High risk for bleeding, and patient preference, are good reasons not to treat unprovoked proximal DVT or PE indefinitely. New anticoagulants, because they are easier to use and may be associated with less bleeding that vitamin K antagonists, have the potential to increase the proportion of patients with unprovoked VTE who are candidates for extended anticoagulant therapy.

Pulmonary embolism is the most common preventable cause of death in hospital patients and prevention of venous thromboembolism (VTE) is cost-saving in high-risk patients. Low-dose anticoagulation is very effective at preventing VTE but increases bleeding. Graduated compression stockings and intermittent pneumatic compression devices are also used to prevent VTE and do not increase bleeding, which makes their use appealing in patients who cannot tolerate bleeding, such as patients with acute stroke. Studies that evaluated mechanical methods of preventing VTE were small and mainly used asymptomatic deep vein thrombosis (DVT), detected using screening tests, as the study outcome. The recently published CLOTS Trial 1 (Clots in Legs Or sTockings after Stroke) compared thigh-level compression stockings with no stockings in about 2500 patients with stroke and immobility, and found that thigh-level stockings were not effective. Indirectly, the findings of this study question the ability of stockings to prevent VTE in other patient groups, including those after surgery. CLOTS 1 compared thigh-level and below-knee stockings in about 3000 patients with acute stroke. Given that thigh-level stockings were ineffective in CLOTS 1, it is surprising that they were more effective than below-knee stockings in CLOTS Trial 2. A possible explanation is that below-knee stockings increase DVT, although this seems unlikely. CLOTS 1 and CLOTS 2 question whether graduated compression stockings prevent VTE and suggest the need for further trials evaluating their efficacy in medical and surgical patients.

Treatment of venous thromboembolism (VTE) should be continued until the reduction of recurrent VTE that anticoagulation is expected to achieve no longer outweighs the increase in bleeding associated with therapy, or until the patient wants to stop treatment even if treatment is expected to be of benefit. Reversibility of risk factors for VTE is the most important factor that influences risk of recurrence and duration of therapy. VTE associated with a reversible risk factor (eg, surgery) is treated for 3 months; unprovoked VTE often benefits from indefinite therapy provided patients do not have risk factors for bleeding; and cancer-associated VTE is usually treated indefinitely. A systematic approach to managing warfarin therapy improves its efficacy, safety, and acceptability., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: We aimed to determine the risk of recurrence for symptomatic venous thromboembolism (VTE) provoked by different transient risk factors., Data Sources: MEDLINE, EMBASE, and Cochrane Collaboration Registry of Randomized Trials databases were searched., Study Selection: Prospective cohort studies and randomized trials of patients with a first episode of symptomatic VTE provoked by a transient risk factor and treated for at least 3 months were identified., Data Extraction: Number of patients and recurrent VTE during the 0- to 12-month and 0- to 24-month intervals after stopping therapy, study design, and provoking risk factor characteristics were extracted., Data Synthesis: Annualized recurrence rates were calculated and pooled across studies. At 24 months, the rate of recurrence was 3.3% per patient-year (11 studies, 2268 patients) for all patients with a transient risk factor, 0.7% per patient-year (3 studies, 248 patients) in the subgroup with a surgical factor, and 4.2% per patient-year (3 studies, 509 patients) in the subgroup with a nonsurgical factor. In the same studies, the rate of recurrence after unprovoked VTE was 7.4% per patient-year. The rate ratio for a nonsurgical compared with a surgical factor was 3.0 and for unprovoked thrombosis compared with a nonsurgical factor was 1.8 at 24 months., Conclusions: The risk of recurrence is low if VTE is provoked by surgery, intermediate if provoked by a nonsurgical risk factor, and high if unprovoked. These risks affect whether patients with VTE should undergo short-term vs indefinite treatment.

Purpose of Review: Hereditary and acquired risk factors contribute to the development of venous thromboembolism (VTE). Relatives of patients who have a hereditary predisposition to thrombosis ('hereditary thrombophilia') will have a heightened risk of VTE if they share the same thrombophilic abnormality. However, if patients do not have a currently recognized thrombophilia it cannot be assumed that their relatives have a normal risk of thrombosis; the patient and their relatives may have a yet to be discovered hereditary abnormality., Recent Findings: A recent study by our group suggests that the relatives of patients with unprovoked VTE at a young age (e.g. <45 years) have a substantially higher risk [odds ratio (OR) 3.3; 95% confidence interval (CI) 1.7-6.4] of developing VTE than the relatives of older patients with unprovoked VTE (e.g. >71 years). This effect occurred independently of whether patients had a currently recognized hereditary thrombophilia., Summary: Relatives of patients with unprovoked VTE have an increased risk of VTE. Testing for thrombophilia in the patients, and in the relatives of the patients who have a thrombophilia, allows the risk of thrombosis in the relatives to be estimated. Thrombosis at a young age appears to be an additional independent risk factor for a heightened risk of thrombosis in patients' relatives.

Background: Fatal bleeding is a serious consequence of anticoagulant therapy, but factors associated with fatal bleeding during the first 3 months of treatment of venous thromboembolism (VTE) are uncertain., Methods: Using data from RIETE, an ongoing registry of consecutive patients with acute VTE, we assessed risk factors for fatal bleeding among all patients. We then used this information to derive a clinical model that would stratify a patient's risk of fatal bleeding during the first 3 months of treatment., Results: Of 24 395 patients, 546 (2.24%) had a major bleed and 135 (0.55%) had a fatal bleed. The gastrointestinal tract was the most common site (40% of fatal bleeds), followed by intracranial bleeding (25%). Fatal bleeding was independently associated with the following factors at the time of VTE diagnosis: age >75 years (OR, 2.16), metastatic cancer (OR, 3.80), immobility > or = 4 days (OR, 1.99), a major bleed within the past 30 days (OR, 2.64), an abnormal prothrombin time (OR, 2.09), a platelet count < 100 x 10(9) L(-1) (OR, 2.23), creatinine clearance < 30 mL min(-1) (OR, 2.27), anemia (OR, 1.54), and distal deep vein thrombosis (OR, 0.39). INR at the time of bleeding is not known. A clinical prediction rule for risk of fatal bleeding that included nine baseline factors was derived. Fatal bleeding occurred in 0.16% (95% CI, 0.11-0.23) of the low-risk, 1.06% (95% CI, 0.85-1.30) of the moderate-risk, and 4.24% (95% CI, 2.76-6.27) of the high-risk category., Conclusions: Patient characteristics and laboratory variables can identify patients at high risk for fatal bleeding during treatment of VTE.

Background: The direct oral thrombin inhibitor dabigatran has a predictable anticoagulant effect and may be an alternative therapy to warfarin for patients who have acute venous thromboembolism., Methods: In a randomized, double-blind, noninferiority trial involving patients with acute venous thromboembolism who were initially given parenteral anticoagulation therapy for a median of 9 days (interquartile range, 8 to 11), we compared oral dabigatran, administered at a dose of 150 mg twice daily, with warfarin that was dose-adjusted to achieve an international normalized ratio of 2.0 to 3.0. The primary outcome was the 6-month incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths. Safety end points included bleeding events, acute coronary syndromes, other adverse events, and results of liver-function tests., Results: A total of 30 of the 1274 patients randomly assigned to receive dabigatran (2.4%), as compared with 27 of the 1265 patients randomly assigned to warfarin (2.1%), had recurrent venous thromboembolism; the difference in risk was 0.4 percentage points (95% confidence interval [CI], -0.8 to 1.5; P<0.001 for the prespecified noninferiority margin). The hazard ratio with dabigatran was 1.10 (95% CI, 0.65 to 1.84). Major bleeding episodes occurred in 20 patients assigned to dabigatran (1.6%) and in 24 patients assigned to warfarin (1.9%) (hazard ratio with dabigatran, 0.82; 95% CI, 0.45 to 1.48), and episodes of any bleeding were observed in 205 patients assigned to dabigatran (16.1%) and 277 patients assigned to warfarin (21.9%; hazard ratio with dabigatran, 0.71; 95% CI, 0.59 to 0.85). The numbers of deaths, acute coronary syndromes, and abnormal liver-function tests were similar in the two groups. Adverse events leading to discontinuation of the study drug occurred in 9.0% of patients assigned to dabigatran and in 6.8% of patients assigned to warfarin (P=0.05)., Conclusions: For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring. (ClinicalTrials.gov number, NCT00291330.), (Copyright 2009 Massachusetts Medical Society.)

Background: Factors that predict the risk of venous thromboembolism in the first-degree relatives of patients with unprovoked venous thromboembolism are uncertain but important for counseling. We aimed to identify risk factors for, and quantify the risk of, venous thromboembolism in first-degree relatives of patients (index case patients) with a first episode of unprovoked venous thromboembolism., Methods: In a cross-sectional study, using a standardized method and without knowledge of whether patients or their relatives had thrombophilia, we assessed the prevalence of previous venous thromboembolism in 1,916 first-degree relatives of 378 unselected patients with a first episode of unprovoked venous thromboembolism. Patient characteristics, and the presence of factor V Leiden or the G20210A prothrombin gene mutation in patients, were assessed as predictors of venous thromboembolism in patient's relatives., Results: There were 102 previous episodes of venous thromboembolism in the first-degree relatives (prevalence, 5.3%). Thrombosis at a young age in patients was the strongest predictor of venous thromboembolism in relatives, with an adjusted odds ratio (OR) for younger patients (ie, patients < 45 years of age when venous thromboembolism occurred; lowest quartile) compared with older patients (ie, patients > 71 years of age; highest quartile) of 3.27 (95% CI, 1.68 to 6.38). The presence of factor V Leiden or the G20210A prothrombin gene in patients was a weak independent predictor of venous thromboembolism in relatives (adjusted OR, 1.48; 95% CI, 0.94 to 2.33)., Conclusion: Unprovoked venous thromboembolism at a young age is associated with a substantially increased risk of venous thromboembolism in patients' families.