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Background: Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of morbidity and mortality worldwide., Methods: GARFIELD-VTE is a prospective, non-interventional observational study of real-world treatment practices. We aimed to capture the 36-month clinical outcomes of 10,679 patients with objectively confirmed VTE enrolled between May 2014 and January 2017 from 415 sites in 28 countries., Findings: A total of 6582 (61.6 %) patients had DVT alone, 4097 (38.4 %) had PE ± DVT. At baseline, 98.1 % of patients received anticoagulation (AC) with or without other modalities of therapy. The proportion of patients on AC therapy decreased over time: 87.6 % at 3 months, 73.0 % at 6 months, 54.2 % at 12 months and 42.0 % at 36 months. At 12-months follow-up, the incidences (95 % confidence interval [CI]) of all-cause mortality, recurrent VTE and major bleeding were 6.5 (7.0-8.1), 5.4 (4.9-5.9) and 2.7 (2.4-3.0) per 100 person-years, respectively. At 36-months, these decreased to 4.4 (4.2-4.7), 3.5 (3.2-2.7) and 1.4 (1.3-1.6) per 100 person-years, respectively. Over 36-months, the rate of all-cause mortality and major bleeds were highest in patients treated with parenteral therapy (PAR) versus oral anti-coagulants (OAC) and no OAC, and the rate of recurrent VTE was highest in patients on no OAC versus those on PAR and OAC. The most frequent cause of death after 36-month follow-up was cancer (n = 565, 48.6 %), followed by cardiac (n = 94, 8.1 %), and VTE (n = 38, 3.2 %). Most recurrent VTE events were DVT alone (n = 564, 63.3 %), with the remainder PE, (n = 236, 27.3 %), or PE in combination with DVT (n = 63, 7.3 %)., Interpretation: GARFIELD-VTE provides a global perspective of anticoagulation patterns and highlights the accumulation of events within the first 12 months after diagnosis. These findings may help identify treatment gaps for subsequent interventions to improve patient outcomes in this patient population., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexander G. G. Turpie: Honoraria from Bayer Pharma AG, Janssen. Sylvia Haas: Honoraria from Bayer Pharma AG, Bristol Myers Squibb, Daiichi-Sankyo, Pfizer, Portola, Sanofi. Walter Ageno: Honoraria from Boehringer Ingelheim, Bayer Pharma AG, Bristol Myers Squibb, Pfizer, Daiichi-Sankyo, Portola, Aspen, Sanofi. Research support from Bayer Pharma AG. Jeffrey I. Weitz: Research support from Canadian Institutes of Health Research, Heart and Stroke Foundation, and the Canadian Fund for Innovation. Honoraria from Alnylam, Anthos, Bayer Pharma AG, Boehringer-Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Ionis, Janssen, Merck, Novartis Pfizer, PhaseBio, and Servier. Samuel Z. Goldhaber: Research Support from Bayer Pharma AG, Boehringer-Ingelheim, BMS, BTG EKOS, Daiichi, Janssen, NHLBI, Thrombosis Research Institute. Consultancy fees from Bayer Pharma AG, Boehringer-Ingelheim. Shinya Goto: Research funding from Ono, Bristol Myers Squibb, Sanofi, and Pfizer. Personal fees from Thrombosis Research Institute and the American Heart Association. Renato D. Lopes: Research grants and personal fees from Bristol-Myers Squibb and Pfizer, personal fees from Boehringer Ingelheim and Bayer AG, research grants from Amgen Inc, GlaxoSmithKline, Medtronic PLC, and Sanofi Aventis. Chern-En Chiang: Honoraria from Astrazeneca, Boehringer Ingelheim, Daiichi-Sankyo, MSD, Novartis, Pfizer, and Sanofi. Harry Gibbs: Personal fees from Pfizer, Bayer, Boehringer Ingelheim. Peter Verhamme: Research support and honoraria from Bayer Healthcare, Boehringer, Daiichi-Sankyo, Anthos Pharmaceuticals, Portola, Leo-Pharma, BMS and Pfizer. Hugo ten Cate: research support from Bayer, consultant for Alveron. Shareholder Coagulation Profile. Second affiliation is Center of Thrombosis and Hemostasis (CTH), Gutenberg University Medical Center, Mainz, Germany. Juan Muntaner: Speaker fees from Bayer Pharma Latin America. Sebastian Schellong: Speaker fees from Bayer Pharma AG, Boehringer-Ingelheim, Bristol Meyer Squibb, Daiichi-Sankyo, Sanofi Aventis and Pfizer. Consultancy fees from Bayer Pharma AG, Boehringer-Ingelheim, Daiichi-Sankyo, Sanofi Aventis, Aspen and Pfizer. Paolo Prandoni: Personal fees from Bayer Pharma AG, Pfizer, Daiichi-Sankyo and Sanofi. Professor Ajay K Kakkar: Research grants from Bayer Pharma AG and Sanofi. Personal fees from Anthos Therapeutics, Bayer Pharma AG, Sanofi S.A, and Alfredo E. Farjat, Henri Bounameaux, Pantep Angchaisuksiri, Gloria Kayani, Eric Tse: None., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Inferior vena cava (IVC) thrombosis is a rare form of venous thromboembolism (VTE). The optimal treatment strategies and outcomes are unclear in patients with this presentation., Objective: We aimed to compare baseline characteristics, treatment patterns and 24-month outcomes in IVC thrombosis patients (n = 100) with lower extremity deep vein thrombosis (LEDVT) patients (n = 7629)., Methods: GARFIELD-VTE is a prospective, observational registry of 10 868 patients with objectively diagnosed VTE from 415 sites in 28 countries., Results: IVC thrombosis patients were younger (51.9 vs. 59.8 years), more frequently had active cancer (26.0% vs. 8.9%) or history of cancer (21.0% vs. 12.2%), and less frequently had recent trauma or surgery than LEDVT patients. IVC thrombosis was more frequently treated with parenteral anticoagulants alone (35.1% vs. 15.9%), whereas patients with LEDVT more commonly received vitamin K antagonists (32.0% vs. 25.8%) or direct oral anticoagulants (49.0% vs. 35.1%). Thrombolysis (11.0% vs. 3.6%) and surgical/mechanical interventions (4.0% vs. 1.4%) were more frequent in IVC thrombosis. At 24-months, the rate per 100 person-years (95% confidence interval) of all-cause mortality was higher in patients with IVC thrombosis than LEDVT (13.28 [8.57-20.58] vs. 4.91 [4.55-5.3]); the incidence of cancer-associated mortality was comparable as was the incidence of VTE recurrence (4.11 [1.85-9.15] vs. 4.18 [3.84-4.55]). Major bleeding was slightly higher in IVC thrombosis (2.03 [0.66-6.31] vs. 1.66 [1.45-1.89])., Conclusion: In summary, IVC thrombosis patients have higher all-cause mortality rates than those with LEDVT, a finding only partly attributable to malignancy., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: This is the 2nd update to the 9th edition of these guidelines. We provide recommendations on 17 PICO (Population, Intervention, Comparator, Outcome) questions, four of which have not been addressed previously., Methods: We generate strong and weak recommendations based on high-, moderate-, and low-certainty evidence, using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology., Results: The panel generated 29 guidance statements, 13 of which are graded as strong recommendations, covering aspects of antithrombotic management of VTE from initial management through secondary prevention and risk reduction of postthrombotic syndrome. Four new guidance statements have been added that did not appear in the 9th edition (2012) or 1st update (2016). Eight statements have been substantially modified from the 1st update., Conclusion: New evidence has emerged since 2016 that further informs the standard of care for patients with VTE. Substantial uncertainty remains regarding important management questions, particularly in limited disease and special patient populations., (Copyright © 2021. Published by Elsevier Inc.)

Background: This is the 2nd update to the 9th edition of these guidelines. We provide recommendations on 17 PICO (Population, Intervention, Comparator, Outcome) questions, four of which have not been addressed previously., Methods: We generate strong and weak recommendations based on high-, moderate-, and low-certainty evidence, using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology., Results: The panel generated 29 guidance statements, 13 of which are graded as strong recommendations, covering aspects of antithrombotic management of VTE from initial management through secondary prevention and risk reduction of postthrombotic syndrome. Four new guidance statements have been added that did not appear in the 9th edition (2012) or 1st update (2016). Eight statements have been substantially modified from the 1st update., Conclusion: New evidence has emerged since 2016 that further informs the standard of care for patients with VTE. Substantial uncertainty remains regarding important management questions, particularly in limited disease and special patient populations., (Copyright © 2021. Published by Elsevier Inc.)

Venous thromboembolism (VTE) is common in cancer patients and is an important cause of morbidity and mortality. The Global Anticoagulant Registry in the FIELD (GARFIELD)-VTE (ClinicalTrials.gov: NCT02155491) is a prospective, observational study of 10,684 patients with objectively diagnosed VTE from 415 sites in 28 countries. We compared baseline characteristics, VTE treatment patterns, and 1-year outcomes (mortality, recurrent VTE and major bleeding) in 1075 patients with active cancer, 674 patients with a history of cancer, and 8935 patients without cancer. Patients with active cancer and history of cancer were older than cancer-free patients, with median ages of 64.8, 68.9, and 58.4 years, respectively. The most common sites of active cancer were lung (14.5%), colorectal (11.0%), breast (10.6%), and gynaecological (10.3%). Active cancer patients had a higher incidence of upper limb and vena cava thrombosis than cancer-free patients (9.0% vs 4.8% and 5.1% vs 1.4%, respectively), and were more likely to receive parenteral anticoagulation as monotherapy than cancer-free patients (57.8% vs 12.1%), and less likely to receive DOACs (14.2% vs 50.6%). Rates of death, recurrent VTE, and major bleeding were higher in active cancer patients than in cancer-free patients, with hazard ratios (95% confidence intervals) of 14.2 (12.1-16.6), 1.6 (1.2-2.0) and 3.8 (2.9-5.0), respectively. VTE was the second most common cause of death in patients with active cancer or history of cancer. In patients with VTE, those with active cancer are at higher risk of death, recurrence, and major bleeding than those without cancer.

Background: Parenteral anticoagulants and vitamin K antagonists (VKAs) have constituted the cornerstone of venous thromboembolism (VTE) treatment. Meanwhile, direct oral anticoagulants (DOACs) provide physicians with an alternative. The Global Anticoagulant Registry in the FIELD (GARFIELD)-VTE observes real-world treatment practices., Objectives: Describe initial anticoagulation (AC) treatment patterns in VTE patients who received parenteral AC, VKAs, and/or DOACs within ±30 days of diagnosis., Methods: VTE patients were categorized into parenteral AC only, parenteral AC with transition to VKA, VKA only, parenteral AC with transition to DOAC, and DOAC only., Results: A total of 9647 patients were initiated on AC treatment alone. 4781 (49.6%) patients received DOACs ± parenteral ACs; 3187 (33.0%), VKA ± parenteral ACs; and 1679 (17.4%) parenteral ACs alone. Rivaroxaban was the most frequently used DOAC (79.4%). DOACs were more frequently used in North America/Australia (58.1%), Europe (52.2%), and Asia (47.6%) than in Latin America (29.7%) and the Middle East/South Africa (32.5%). In patients with suspected VTE, most received parenteral AC monotherapy (67.7%). Patients with deep vein thrombosis were more likely to receive DOACs alone than those with pulmonary embolism with or without deep vein thrombosis (36.2% vs 25.9%). Active cancer patients received parenteral AC alone (58.9%), with 25.5% receiving DOAC ± parenteral AC and 12.8% parenteral AC and VKA. A total of 46.5% of pregnant patients received parenteral AC monotherapy, 34.0% were treated with VKA ± parenteral AC, and 19.5% received a DOAC (± parenteral AC)., Conclusion: AC treatment patterns vary by patient population, geographic region and site of VTE. Guidelines for AC therapy are not always adhered to., (© 2019 International Society on Thrombosis and Haemostasis.)

Isolated distal deep vein thrombosis (IDDVT) represents up to half of all lower limb DVT. This study investigated treatment patterns and outcomes in 2,145 patients with IDDVT in comparison with those with proximal DVT (PDVT; n  = 3,846) and pulmonary embolism (PE; n  = 4,097) enrolled in the GARFIELD-VTE registry. IDDVT patients were more likely to have recently undergone surgery (14.6%) or experienced leg trauma (13.2%) than PDVT patients (11.0 and 8.7%, respectively) and PE patients (12.7 and 4.5%, respectively). Compared with IDDVT, patients with PDVT or PE were more likely to have active cancer (7.2% vs. 9.9% and 10.3%). However, influence of provoking factors on risk of recurrence in IDDVT remains controversial. Nearly all patients (IDDVT, PDVT, and PE) were given anticoagulant therapy. In IDDVT, PDVT, and PE groups the proportion of patients receiving anticoagulant therapy was 61.4, 73.9, and 81.1% at 6 months and 45.8, 54.7, and 61.9% at 12 months. Over 12 months, the incidence of all-cause mortality, cancer, and recurrence was significantly lower in IDDVT patients than PDVT patients (hazard ratio [HR], 0.61 [95% confidence interval [CI], 0.48-0.77]; sub-HR [sHR], 0.60 [95% CI, 0.39-0.93]; and sHR, 0.76 [95% CI, 0.60-0.97]). Likewise, risk of death and incident cancer was significantly (both p  < 0.05) lower in patients with IDDVT compared with PE. This study reveals a global trend that most IDDVT patients as well as those with PDVT and PE are given anticoagulant therapy, in many cases for at least 12 months., Competing Interests: S.S.: Speaker fees from Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Sanofi Aventis, and Pfizer; consultancy fees from Bayer Healthcare, Boehringer Ingelheim, Daiichi-Sankyo, Sanofi Aventis, Pfizer. S.Z.G.: Grants from BiO2 Medical, Boehringer-Ingelheim, Bristol-Myers Squibb, BTG EKOS, Daiichi-Sankyo, National Heart Lung and Blood Institute of the National Institutes of Health, Janssen, Thrombosis Research Group; personal fees (all consultancy less than $10k) from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, Portola, Zafgen. J.I.W.: Honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis, Janssen, Merck, Portola, Pfizer, Servier, Novartis. W.A.: Grants and personal fees from Bayer. Personal fees from Boehringer Ingelheim, Daiichi-Sankyo, BMS-Pfizer, Sanofi, Portola, Aspen, Stago, CSL Behring. H.B.: Grants and personal fees from Thrombosis Research Institute, London. Personal fees from Bayer Switzerland. A.G.G.T.: Personal fees from Bayer Pharma AG, Janssen. P.A.: None declared. S.H.: Honoraria from Aspen, Bayer Healthcare, BMS, Daiichi-Sankyo, Pfizer, Portola, Sanofi. S.G.: Research grant from Ono, Bristol-Myers Squibb, Sanofi, Pfizer. A.Z.: None declared. A.F.: None declared. J.D.N.: Honoraria from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Leo Pharma, Pfizer. G.K.: None declared. L.G.M.: Grants and personal fees from Bayer Healthcare, Boehringer Ingelheim, Pfizer, Daiichi-Sankyo. P.P.: Personal fees from Bayer Pharma, Pfizer, Daiichi-Sankyo, Sanofi, Rovi Pharmaceuticos. A.K.K.: Research grants from Bayer Healthcare. Personal fees from Bayer Healthcare, Boehringer-Ingelheim Pharma, Daiichi-Sankyo Europe, Sanofi SA, Janssen Pharma, Verseon Inc., Pfizer., (Georg Thieme Verlag KG Stuttgart · New York.)

Upper extremity deep vein thrombosis (UEDVT) is less common than lower extremity DVT (LEDVT) and consequently less well characterized. This study compared clinical characteristics and 1-year outcomes between 438 UEDVT patients and 7,602 LEDVT patients recruited in the GARFIELD-VTE registry. UEDVT patients were significantly more likely to have a central venous catheter than those with LEDVT (11.5% vs. 0.5%; p  < 0.0001), and had a higher rate of active cancer (16.2%) or recent hospitalization (19.4%) compared with LEDVT patients (8.7% and 11.2%, respectively). Nearly all patients with UEDVT and LEDVT were initiated on anticoagulant therapy, which was a direct oral anticoagulant in one-third individuals in both groups. At 3, 6, and 12 months, the proportion of UEDVT and LEDVT patients who were receiving anticoagulant therapy was 82.6 and 87.4%, 66.0 and 72.6%, and 45.7 and 54.6%, respectively. In the UEDVT and LEDVT groups, VTE recurrence rate was 4.0 (95% confidence interval [CI], 2.4-6.7) and 5.5 (95% CI, 4.9-6.1) per 100 person-years, respectively; major bleed was noted in 1.3 (95% CI, 0.6-3.2) and 1.6 (95% CI, 1.3-1.9) per 100 person-years and all-cause mortality in 9.7 (95% CI, 7.1-13.4) and 6.7 (95% CI, 6.1-7.3) per 100 person-years, respectively. Hence, risk of recurrence was similar in the two groups whereas all-cause mortality was significantly higher in the UEDVT group than the LEDVT group ( p  = 0.0338). This latter finding was likely due to the high prevalence of cancer in the UEDVT group., Competing Interests: W.A.: Grants and personal fees from Bayer. Personal fees from Boehringer Ingelheim, Daiichi-Sankyo, BMS-Pfizer, Sanofi, Portola, Aspen, Stago, and CSL Behring. S.H.: Honoraria from Aspen, Bayer Healthcare, BMS, Daiichi-Sankyo, Portola, and Sanofi. S.Z.G.: Grants from BiO2 Medical, Boehringer-Ingelheim, Bristol-Myers Squibb, BTG EKOS, Daiichi-Sankyo, National Heart Lung and Blood Institute of the National Institutes of Health, Janssen, and Thrombosis Research Group. Personal fees (all consultancy less than $10k) from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, Portola, and Zafgen. A.G.G.T.: Personal fees from Bayer Pharma AG and Janssen. J.I.W.: Honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis, Janssen, Merck, Portola, Pfizer, Servier, and Novartis. S.G.: Research grant from Ono, Bristol-Myers Squibb, Sanofi, and Pfizer. P.A.: None declared. J.D.N.: Honoraria from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Leo Pharma, and Pfizer. G.K.: None declared. A.F.: None declared. A.Z.: None declared. S.S.: Personal fees from Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Sanofi Aventis, and Pfizer. H.B.: Grants and personal fees from Thrombosis Research Institute, London. Personal fees from Bayer Switzerland. L.G.M.: Grants and personal fees from Bayer Healthcare, Boehringer Ingelheim, Pfizer, and Daiichi-Sankyo. P.P.: Personal fees from Bayer Pharma, Pfizer, Daiichi-Sankyo, Sanofi, and Rovi Pharmaceuticals. H.D.: Personal fees and per patient fees for trial recruitment from Bayer, Boerhinger Ingelheim and Bristol-Myers Squibb. Personal fees from Daiichi-Sankyo and Berlin-Chemie. A.K.K.: Research grants from Bayer Healthcare. Personal fees from Bayer Healthcare, Boehringer-Ingelheim Pharma, Daiichi-Sankyo Europe, Sanofi SA, Janssen Pharma, Verseon Inc., and Pfizer., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: The efficacy and safety of anticoagulant treatment is not established for patients with acute symptomatic deep vein thrombosis (DVT) of the calf. We aimed to assess whether therapeutic anticoagulation is superior to placebo in patients with symptomatic calf DVT., Methods: In this randomised, double-blind, placebo-controlled trial, we enrolled low-risk outpatients (without active cancer or previous venous thromboembolic disease) with a first acute symptomatic DVT in the calf from 23 university medical centres or community medical clinics in Canada, France, and Switzerland. We randomly assigned (1:1) patients to receive either the low-molecular-weight heparin nadroparin (171 UI/kg, subcutaneously, once a day) or placebo (saline 0·9%, subcutaneously, once a day) for 6 weeks (42 days). Central randomisation was done using a computer-generated randomisation list, stratified by study centre. Random allocation sequences of variable block size were centrally determined by an independent research clinical centre. Study staff, patients, and outcome assessors (central adjudication committee) were masked to group assignment. Numbered boxes of active drug or placebo were provided to pharmacies in identical packaging. All patients were prescribed compression stockings and followed up for 90 days. The primary efficacy outcome was a composite measure of extension of calf DVT to proximal veins, contralateral proximal DVT, and symptomatic pulmonary embolism at day 42 in the modified intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding at day 42. The trial was registered with ClinicalTrials.gov, number NCT00421538., Findings: Between Feb 1, 2008, and Nov 30, 2014, we screened 746 patients, enrolling 259 patients (50% of the prespecified sample size), before the trial steering committee terminated the trial because of expiry of study drug and slow recruitment. The intention-to-treat analysis population comprised 122 patients in the nadroparin group and 130 in the placebo group. There was no significant difference between the groups in the composite primary outcome, which occurred in four patients (3%) in the nadroparin group and in seven (5%) in the placebo group (risk difference -2·1%, 95% CI -7·8 to 3·5; p=0·54). Bleeding occurred in five patients (4%) in the nadroparin group and no patients in the placebo group (risk difference 4·1, 95% CI 0·4 to 9·2; p=0·0255). In the nadroparin group one patient died from metastatic pancreatic cancer and one patient was diagnosed with heparin-induced thrombocytopenia type 2., Interpretation: Nadroparin was not superior to placebo in reducing the risk of proximal extension or venous thromboembolic events in low-risk outpatients with symptomatic calf DVT, but did increase the risk of bleeding. Avoidance of systematic anticoagulation for calf DVT could have a substantial impact on individual patients and from a public health perspective., Funding: Swiss National Science Foundation, the Programme Hospitalier de Recherche Clinique in France, and the Canadian Institutes of Health Research., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: We update recommendations on 12 topics that were in the 9th edition of these guidelines, and address 3 new topics., Methods: We generate strong (Grade 1) and weak (Grade 2) recommendations based on high- (Grade A), moderate- (Grade B), and low- (Grade C) quality evidence., Results: For VTE and no cancer, as long-term anticoagulant therapy, we suggest dabigatran (Grade 2B), rivaroxaban (Grade 2B), apixaban (Grade 2B), or edoxaban (Grade 2B) over vitamin K antagonist (VKA) therapy, and suggest VKA therapy over low-molecular-weight heparin (LMWH; Grade 2C). For VTE and cancer, we suggest LMWH over VKA (Grade 2B), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C). We have not changed recommendations for who should stop anticoagulation at 3 months or receive extended therapy. For VTE treated with anticoagulants, we recommend against an inferior vena cava filter (Grade 1B). For DVT, we suggest not using compression stockings routinely to prevent PTS (Grade 2B). For subsegmental pulmonary embolism and no proximal DVT, we suggest clinical surveillance over anticoagulation with a low risk of recurrent VTE (Grade 2C), and anticoagulation over clinical surveillance with a high risk (Grade 2C). We suggest thrombolytic therapy for pulmonary embolism with hypotension (Grade 2B), and systemic therapy over catheter-directed thrombolysis (Grade 2C). For recurrent VTE on a non-LMWH anticoagulant, we suggest LMWH (Grade 2C); for recurrent VTE on LMWH, we suggest increasing the LMWH dose (Grade 2C)., Conclusions: Of 54 recommendations included in the 30 statements, 20 were strong and none was based on high-quality evidence, highlighting the need for further research., (Copyright © 2016 American College of Chest Physicians. All rights reserved.)

Recent advances in the management of patients with suspected VTE have both improved diagnostic accuracy and made management algorithms safer, easier to use and well standardised. These diagnostic algorithms are mainly based on the assessment of clinical pretest probability, D-dimer measurement and imaging tests, mainly represented by compression ultrasound (CUS) for suspected DVT and computed tomography pulmonary angiography (CTPA) or lung ventilation-perfusion scan for pulmonary embolism. These diagnostic algorithms allow a safe and cost-effective diagnosis for most patients with suspected VTE. In this review, we focus on the challenge of diagnosing VTE in special patient populations, such as elderly patients, pregnant women, or patients with a prior VTE. Some additional challenges are arising that might require adjustments to current diagnostic strategies, such as the reduced clinical suspicion threshold, resulting in a lower proportion of VTE among suspected patients; the overdiagnosis and overtreatment of VTE, especially regarding calf deep-vein thrombosis (DVT) and subsegmental pulmonary embolism (SSPE).

Background: Venous ultrasonography is the cornerstone of the diagnostic work-up in patients with suspected deep vein thrombosis (DVT). Significant variations exist in clinical practice between centers and/or countries, e.g. proximal vs. whole-leg ultrasound, serial tests vs. single test, and combination with clinical probability and D-dimer testing. Fewer data exist on the need for bilateral leg imaging., Objectives: To assess the yield of bilateral leg ultrasonography in patients with suspected DVT., Patients and Methods: This was a retrospective cohort study of consecutive patients with clinically suspected DVT. A single whole-leg ultrasound scan was performed in all patients. We extracted information on demographics, risk factors, clinical signs, pretest probability, side of clinical suspicion, and ultrasound results., Results and Conclusions: Among the 2804 included patients, 609 (21.8%) patients had a positive ultrasound finding. A total of 20 patients (0.8%; 95% confidence interval [CI] 0.5-1.2%) had a thrombus diagnosed in both the symptomatic leg and asymptomatic leg. Moreover, five patients (0.2%; 95% CI 0.1-0.5%) did not have a thrombus in the symptomatic leg but had a thrombus in the asymptomatic leg. Two of 2540 patients with unilateral symptoms had no proximal DVT in the symptomatic leg and a proximal DVT in the asymptomatic leg (0.08%; 95% CI 0.0-0.3%). In summary, systematic imaging of both legs in patients with suspected DVT has a very low yield, and therefore does not appear to be justified., (© 2015 International Society on Thrombosis and Haemostasis.)

Background: D-dimer testing to rule out deep vein thrombosis is less useful in older patients because of a lower specificity. An age-adjusted D-dimer cut-off value increased the proportion of older patients (>50 years) in whom pulmonary embolism could be excluded. We retrospectively validated the efficacy of this cut-off combined with clinical probability for the exclusion of deep vein thrombosis., Design and Methods: Five management study cohorts of 2818 consecutive outpatients with suspected deep vein thrombosis were used. Patients with non-high or unlikely probability of deep vein thrombosis were included in the analysis; four different D-dimer tests were used. The proportion of patients with a normal D-dimer test and the failure rates were calculated using the conventional (500 μg/L) and the age-adjusted D-dimer cut-off (patient's age x 10 μg/L in patients >50 years)., Results: In 1672 patients with non-high probability, deep vein thrombosis could be excluded in 850 (51%) patients with the age-adjusted cut-off value versus 707 (42%) patients with the conventional cut-off value. The failure rates were 7 (0.8; 95% confidence interval 0.3-1.7%) for the age-adjusted cut-off value and 5 (0.7%, 0.2-1.6%) for the conventional cut-off value. The absolute increase in patients in whom deep vein thrombosis could be ruled out using the age-adjusted cut-off value was largest in patients >70 years: 19% among patients with non-high probability., Conclusions: The age-adjusted cut-off of the D-dimer combined with clinical probability greatly increases the proportion of older patients in whom deep vein thrombosis can be safely excluded.

Pulmonary embolism is the third most common cause of death from cardiovascular disease after heart attack and stroke. Sequelae occurring after venous thromboembolism include chronic thromboembolic pulmonary hypertension and post-thrombotic syndrome. Venous thromboembolism and atherothrombosis share common risk factors and the common pathophysiological characteristics of inflammation, hypercoagulability, and endothelial injury. Clinical probability assessment helps to identify patients with low clinical probability for whom the diagnosis of venous thromboembolism can be excluded solely with a negative result from a plasma D-dimer test. The diagnosis is usually confirmed with compression ultrasound showing deep vein thrombosis or with chest CT showing pulmonary embolism. Most patients with venous thromboembolism will respond to anticoagulation, which is the foundation of treatment. Patients with pulmonary embolism should undergo risk stratification to establish whether they will benefit from the addition of advanced treatment, such as thrombolysis or embolectomy. Several novel oral anticoagulant drugs are in development. These drugs, which could replace vitamin K antagonists and heparins in many patients, are prescribed in fixed doses and do not need any coagulation monitoring in the laboratory. Although rigorous clinical trials have reported the effectiveness and safety of pharmacological prevention with low, fixed doses of anticoagulant drugs, prophylaxis remains underused in patients admitted to hospital at moderate risk and high risk for venous thromboembolism. In this Seminar, we discuss pulmonary embolism and deep vein thrombosis of the legs., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To assess the safety of using single complete compression ultrasonography in pregnant and postpartum women to rule out deep vein thrombosis., Design: Prospective outcome study., Setting: Two tertiary care centres and 18 private practices specialising in vascular medicine in France and Switzerland., Participants: 226 pregnant and postpartum women referred for suspected deep vein thrombosis., Methods: A single proximal and distal compression ultrasonography was performed. All women with a negative complete compression ultrasonography result did not receive anticoagulant therapy and were followed up for a three month period., Main Outcome Measures: Symptoms of venous thromboembolism, second compression ultrasonography or chest imaging, a thromboembolic event, and anticoagulant treatment., Results: 16 women were excluded, mainly because of associated suspected pulmonary embolism. Deep vein thrombosis was diagnosed in 22 out of the 210 included women (10.5%). 10 patients received full dose anticoagulation despite a negative test result during follow-up. Of the 177 patients without deep vein thrombosis and who did not receive full dose anticoagulant therapy, two (1.1%, 95% confidence interval 0.3% to 4.0%) had an objectively confirmed deep vein thrombosis during follow-up., Conclusions: The rate of venous thromboembolic events after single complete compression ultrasonography in pregnant and postpartum women seems to be within the range of that observed in studies in the non-pregnant population. These data suggest that a negative single complete compression ultrasonography result may safely exclude the diagnosis of deep vein thrombosis in this setting., Trial Registration: clinicaltrials.gov NCT00740454.

Background: This article addresses the treatment of VTE disease., Methods: We generated strong (Grade 1) and weak (Grade 2) recommendations based on high-quality (Grade A), moderate-quality (Grade B), and low-quality (Grade C) evidence., Results: For acute DVT or pulmonary embolism (PE), we recommend initial parenteral anticoagulant therapy (Grade 1B) or anticoagulation with rivaroxaban. We suggest low-molecular-weight heparin (LMWH) or fondaparinux over IV unfractionated heparin (Grade 2C) or subcutaneous unfractionated heparin (Grade 2B). We suggest thrombolytic therapy for PE with hypotension (Grade 2C). For proximal DVT or PE, we recommend treatment of 3 months over shorter periods (Grade 1B). For a first proximal DVT or PE that is provoked by surgery or by a nonsurgical transient risk factor, we recommend 3 months of therapy (Grade 1B; Grade 2B if provoked by a nonsurgical risk factor and low or moderate bleeding risk); that is unprovoked, we suggest extended therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy if bleeding risk is high (Grade 1B); and that is associated with active cancer, we recommend extended therapy (Grade 1B; Grade 2B if high bleeding risk) and suggest LMWH over vitamin K antagonists (Grade 2B). We suggest vitamin K antagonists or LMWH over dabigatran or rivaroxaban (Grade 2B). We suggest compression stockings to prevent the postthrombotic syndrome (Grade 2B). For extensive superficial vein thrombosis, we suggest prophylactic-dose fondaparinux or LMWH over no anticoagulation (Grade 2B), and suggest fondaparinux over LMWH (Grade 2C)., Conclusion: Strong recommendations apply to most patients, whereas weak recommendations are sensitive to differences among patients, including their preferences.

Background: According to the Comparison of Arixtra in Lower Limb Superficial Vein Thrombosis with Placebo (CALISTO) study, a recent randomized, controlled trial, prophylactic fondaparinux can prevent thrombotic complications following superficial vein thrombosis (SVT). The cost-effectiveness of this treatment remains to be determined., Methods: We developed a decision-tree model comparing fondaparinux 2.5 mg daily for 45 days vs no treatment of SVT. It included all clinical events associated with SVT, its treatment, its complications, and all respective quality-adjustment factors. Data were mainly derived from the CALISTO study and the published literature. Measured outcomes comprised clinical events (VTE, major hemorrhage, death), quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). The analysis was conducted using a lifetime time horizon from a health-care system perspective. We performed one-way and probabilistic sensitivity analyses to evaluate parameter uncertainty., Results: In 10,000 patients, we estimated that fondaparinux would prevent 123 VTE events and two deaths. On a per-patient basis, the incremental QALY compared with no treatment was 0.04 (1 day) at an incremental cost of $1,734, resulting in an ICER of $500,000 per QALY. This result remained robust in the one-way sensitivity analyses, with an ICER remaining > $100,000 per QALY throughout all ranges. Based on probabilistic sensitivity analyses, the probability that fondaparinux was cost-effective was 1% at a willingness-to-pay of $100,000 per QALY., Conclusions: Fondaparinux for 45 days does not appear to be cost-effective when treating patients with isolated SVT of the legs. A better value for money could be obtained in subgroups of patients with a higher incidence of VTE after SVT. Shorter durations of treatment should be further evaluated in future clinical studies.

Background: The risk of patients dying of pulmonary embolism (PE) or bleeding during the treatment of deep vein thrombosis (DVT), and whether these risks are influenced by patient age, has not been thoroughly studied., Methods: We used data from the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) to assess the risk of fatal PE and fatal bleeding in 16,199 patients with lower limb DVT (without symptomatic PE at the time of inclusion) during the 3 months after diagnosis, with patients categorized according to age., Results: During the 3 months of anticoagulant treatment, there were 31 fatal PEs (0.19%) and 83 fatal hemorrhages (0.51%). During the first 7 days of therapy, the frequency of fatal PEs was similar to that of fatal bleeding (12 vs 14 deaths, respectively; odds ratio [OR], 0.86; 95% confidence interval [CI], 0.39-1.87). However, from days 8 to 90, the frequency of fatal bleeding was greater than that of fatal PE (69 vs 19 deaths; OR, 3.64; 95% CI, 2.22-6.20). The higher frequency of fatal bleeding compared with fatal PE from days 8 to 90 appeared to be confined to patients who were aged ≥ 60 years. Multivariate analysis showed that patient age was independently associated with an increased risk of death from bleeding during the first 3 months: every 10 years the OR increased by 1.37 (95% CI, 1.12-1.67)., Conclusions: During the first week of treatment, the risk of fatal bleeding and fatal PE were similar. Then, particularly in patients who were aged ≥ 60 years, the risk of dying from bleeding exceeded the risk of dying from PE., (Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

We report a rare case of an isolated and unsuspected thrombosis in the right internal iliac vein. The presentation was atypical with regard to the clinical manifestations and the thrombus location. The patient was admitted for an acute abdominal pain in the right iliac fossa. The thrombosis was suspected on the basis of a portal-phase contrast-enhanced abdominal CT but the lack of a delayed phase did not allow confirmation. Contrast-enhanced ultrasound confirmed the diagnosis, by displaying a well-defined filling defect., (Copyright © 2011 Wiley Periodicals, Inc.)

Edoxaban is an oral direct factor Xa inhibitor that is currently undergoing investigation in phase III clinical trials for the prevention of stroke in patients with atrial fibrillation (AF) and for the prevention and treatment of venous thromboembolic events (VTE). Factor Xa is an attractive target for anticoagulant treatment, as it is the primary and rate-limiting source of amplification in the coagulation cascade. Edoxaban is a competitive inhibitor of factor Xa and has >10 000-fold greater selectivity for factor Xa relative to thrombin. In phase I clinical trials, the anticoagulant effects of edoxaban included dose-dependent increases in activated partial thromboplastin time and prothrombin time following single edoxaban doses of 10-150 mg and after multiple ascending doses (60 mg twice daily, 90 mg daily and 120 mg daily). The anticoagulant effects of edoxaban were rapid in onset (time to peak plasma concentration 1-2 hours) and sustained for up to 24 hours. Prolongation of bleeding time in 8% of subjects was >9.5 minutes (none of which appeared to be clinically significant) 2 hours after initial dosing, and was independent of edoxaban dose, formulation or dietary state. In general, plasma edoxaban concentrations were linearly correlated with coagulation parameters. Phase II clinical trials in patients with AF and VTE suggest that the edoxaban 30 mg once-daily and 60 mg once-daily regimens had a similar or better safety profile compared with dose-adjusted warfarin (international normalized ratio 2.0-3.0) in terms of bleeding events, and that edoxaban was not associated with hepatotoxicity. In addition, edoxaban was associated with statistically significant dose-dependent reductions in VTE after orthopaedic surgery compared with placebo or dalteparin sodium. Further clinical investigation of the efficacy and safety of once-daily edoxaban is being conducted in phase III clinical trials in comparison with warfarin in patients with AF in the phase III ENGAGE AF-TIMI 48 trial (NCT00781391), and in comparison with low-molecular weight heparin/warfarin in the prevention of recurrent VTE in patients with symptomatic deep vein thrombosis and/or pulmonary embolism in the HOKUSAI VTE trial (NCT00986154).

Thromboembolic disorders are among the major causes of morbidity and mortality, and anticoagulation remains the cornerstone of prevention and treatment of these disorders. Although effective, the well-established agents have significant drawbacks. Heparin, low molecular weight heparin, and fondaparinux must be given parenterally, which is inconvenient for long-term or home use. The orally administered vitamin K antagonists (such as warfarin) have a slow onset of action, thus requiring bridging therapy with a parenteral agent when immediate anticoagulation is needed (e.g. inpatients with acute deep vein thrombosis). Because vitamin K antagonists produce a variable anticoagulant response as a result of multiple drug-drug and food-drug interactions and genetic polymorphisms, frequent coagulation monitoring and dose adjustment are required to ensure a therapeutic level of anticoagulation, which is inconvenient for both patients and physicians. In the search for new agents to overcome the drawbacks associated with traditional agents, direct Factor Xa inhibitors (e.g. rivaroxaban, apixaban, and edoxaban) and direct thrombin inhibitors (e.g. dabigatran etexilate) have been developed and are undergoing late-stage clinical evaluation for the prevention and treatment of thromboembolic disorders. These new oral agents have already shown promise in large-scale clinical studies and data suggest that we have entered a new era with novel drugs that are closer than ever to the 'ideal anticoagulant'. Because these new oral agents have a rapid onset of action and can be given at fixed doses without the need for routine coagulation monitoring, they may simplify treatment paradigms and are expected to improve overall clinical outcome., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring., Methods: We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study., Results: The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin-vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11)., Conclusions: Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation. (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT00440193 and NCT00439725.).

Deep vein thrombosis (DVT) and pulmonary embolism (PE) cannot be diagnosed solely on a clinical basis owing to the lack of sensitivity and specificity of clinical signs and symptoms. Phlebography and pulmonary angiography are invasive and resource-demanding imaging modalities. Because the prevalence of DVT and PE is relatively low (typically 20% or less) among clinically suspected individuals, submitting all of them to imaging would not be cost-effective. Therefore, non-invasive diagnostic algorithms have been developed that include clinical probability assessment and D-dimer measurement. These initial steps allow the selection of patients who require non-invasive imaging: compression ultrasonography in cases of suspected DVT and multidetector computed tomography (CT) angiography in cases of suspected PE. This review gives a critical appraisal of the sequential steps of the diagnostic work-up in suspected DVT or PE.

Background: Compression ultrasonography (US) confined to the proximal veins is usually performed to detect deep vein thrombosis (DVT) in patients with suspected pulmonary embolism (PE). Recent studies suggested a limited yield of proximal US when multislice computed tomography (MSCT) was used., Objectives: To assess whether performing an additional distal vein US would increase the diagnostic yield of the test., Patients and Methods: Data of 855 consecutive outpatients included in a multicenter randomized controlled trial were analyzed. Patients were investigated by a sequential diagnostic strategy including clinical probability assessment, D-dimer measurement, proximal US and MSCT. Proximal US was completed by an examination of the distal veins, the result of which was not disclosed to the physician in charge of the patient., Results: US was positive in 21% of patients, of whom 10% (53/541) had proximal DVT and 11% (59/541) isolated distal DVT. Of the 59 patients with distal DVT, 21 (36%) had no PE on MSCT. Twenty of those 21 patients were not given anticoagulant therapy and had an uneventful follow-up. The diagnostic performance of distal US for the diagnosis of PE was as follows: sensitivity 22% [95% confidence interval (CI) 17-29]; specificity 94% (95% CI 91-96); positive likelihood ratio 3.9 (95% CI 2.4-6.4)., Conclusions: In patients with suspected PE, distal US has limited diagnostic performance, and its additional use only modestly increases the yield of US. Moreover, it carries a high false-positive rate, impeding the use of distal US as a confirmatory test for PE.

Purpose of Review: To discuss pros and cons of anticoagulant treatment in the presence of symptomatic distal deep vein thrombosis., Recent Findings: Available data are responsible for a lack of consensus regarding treatment of distal deep vein thrombosis., Summary: One standard diagnostic approach of suspected deep vein thrombosis consists of serial lower limb compression ultrasound of proximal veins. Studies evaluating compression ultrasound limited to the proximal veins performed on two occasions separated by 1 week showed good safety with a pooled estimate of the 3-month thromboembolic events rate of 0.6% (95% confidence interval: 0.4-0.9%) in untreated patients. However, performing two lower limbs compression ultrasound is cumbersome and expensive. Recently, studies using a single complete (proximal and distal) compression ultrasound showed a similar pooled estimate of the 3-month thromboembolic risk (0.3%, 95% confidence interval: 0.1-0.6%) but distal deep vein thrombosis accounted for as many as 50% of all diagnosed deep vein thrombosis in those series. Comparing these studies may suggest that systematically searching for calf deep vein thrombosis potentially doubles the number of patients given anticoagulant treatment without reducing the 3-month thromboembolic risk. Despite these data, many physicians still search for and treat distal deep vein thrombosis in the fear of proximal extension and of pulmonary embolism. However, robust data in favour of anticoagulation for distal deep vein thrombosis are limited. Randomized trials assessing the usefulness of anticoagulation in distal deep vein thrombosis are therefore urgently needed.

During the past 2 decades, the diagnostic and therapeutic approach to deep vein thrombosis (DVT) has greatly evolved. First, the assessment of the clinical probability has gained wide acceptance. Second, novel noninvasive diagnostic tools such as venous compression ultrasonography and D-dimer measurement have become available, drastically reducing the need for invasive tools such as phlebography. Third, new anticoagulant drugs, in particular low-molecular-weight heparins (LMWHs), have become available and have made DVT treatment a lot easier by allowing out-of-hospital management. Several diagnostic algorithms, based on the assessment of clinical probability, D-dimer measurement and venous compression ultrasonography, have shown to be safe in management studies. In addition to improvements in diagnostic algorithms and anticoagulant treatment, compression therapy by elastic stockings to diminish the prevalence of the postthrombotic syndrome has been validated in prospective studies.The dilemma of the need or no need for looking for and treating isolated calf DVT with anticoagulants remains a controversial issue, as do the optimal length and intensity of anticoagulation. In the near future, the emergence of several new, totally synthetic, orally active anticoagulant compounds, such as direct thrombin or factor Xa inhibitors that are presently being tested in clinical studies, could profoundly change the therapeutic approach to DVT.

The presence of a clot-- even asymptomatic-- in the proximal lower limb veins of a patient with clinically suspected pulmonary embolism (PE) provides evidence for venous thromboembolism and indicates anticoagulant therapy in such patients. We aimed at assessing the diagnostic performance of compression ultrasonography as compared to multi-slice computed tomography (MSCT) for the diagnosis of PE. We analyzed data from a large outcome management study that included consecutive outpatients referred to the emergency ward with clinically suspected PE. All high clinical probability patients, and all non-high clinical probability patients with a positive D-dimer test underwent both MSCT and CUS. Of the 756 included patients, 232 had PE ruled out on the basis of a negative D-dimer test, and 524 patients underwent both MSCT and CUS. PE was found in 187 out of the 511 patients with a conclusive MSCT. The sensitivity of CUS for the presence of PE on MSCT was 39% (95% confidence interval: 32 to 46%), and its specificity was 99% (95% CI:97 to 100%). Positive and negative likelihood ratios were 42.2 (95% CI: 13.5 to 131.9) and 0.6 (95% CI: 0.5 to 0.7), respectively. We conclude from that large study of unselected patients that CUS has high specificity but low sensitivity, for the diagnosis of PE at MSCT in suspected patients. It allows ruling in the diagnosis of PE without further invasive and/or expensive testing in suspected patients.

Background: Elevated plasma D-dimer and factor VIII coagulant activity (FVIIIc) may be associated with the risk of recurrent venous thromboembolism (VTE)., Objectives: To evaluate D-dimer and FVIIIc as risk factors for recurrent VTE and assess the efficacy of extended low-intensity warfarin (target International Normalized Ratio 1.5-2.0) in preventing recurrence by biomarker level., Patients and Methods: In the Prevention of Recurrent Venous Thromboembolism trial, 508 idiopathic VTE patients treated for > or = 3 months with full-intensity warfarin, and who had stopped warfarin for 7 weeks on average, were randomized to low-intensity warfarin or placebo and followed for 2.1 years for recurrent VTE. Prerandomization blood samples were analysed for D-dimer and FVIIIc., Results: One-third of participants had elevated baseline D-dimer (> or = 500 ng mL(-1)) and one-fourth, elevated FVIIIc (> or = 150 IU dL(-1)). Adjusting for other risk factors, the hazard ratios (HRs) for recurrent VTE with elevated D-dimer or FVIIIc were 2.0 [95% confidence interval (CI) 1.2-3.4] and 1.5 (95% CI 0.8-2.8), respectively. The association of elevated D-dimer with recurrence was larger among patients with one prior VTE (HR 3.2, 95% CI 1.3-8.0) than in patients with more than one event (HR 1.4, 95% CI 0.7-2.2). For patients with one prior VTE on placebo, the annual recurrence incidence was 10.9% with elevated D-dimer and 2.9% with normal values. Low-intensity warfarin was equally effective in recurrence risk reduction in those with normal or elevated biomarkers., Conclusions: Among patients with idiopathic VTE, measurement of D-dimer, but not FVIIIc, might be useful for risk stratification. The efficacy of extended low-intensity warfarin therapy did not vary by biomarker level.

The standard diagnostic approach of suspected deep vein thrombosis (DVT) is serial lower limb compression ultrasound (CUS) of proximal veins. Although it only assesses the proximal veins, withholding anticoagulant treatment in patients with a negative CUS on day one and after one week has been proven to be safe. However, in many centres, distal DVT is systematically screened for and treated by anticoagulants. The objectives of the review were 1) to evaluate the rate of extension of distal DVTs to proximal veins 2) to compare the safety of proximal limited CUS versus single complete CUS. We performed a MEDLINE search covering the period from January 1983 to January 2005 by using the key-words "calf vein thrombosis", "distal thrombosis" and "compression ultrasonography". English, German and French language original studies were retrieved. Moreover, references of retrieved articles were screened in order to detect missed pertinent articles. We pooled data of management studies where proximal or complete (i.e. proximal and distal) CUS were used, respectively. Studies evaluating CUS limited to the proximal veins showed a good safety profile with a pooled estimate of the 3-month thromboembolic rate of 0.6% (95% CI: 0.4-0.9%) in patients in whom anticoagulation was withheld. Studies using proximal and distal CUS showed a similar pooled estimate of the 3-month thromboembolic rate (0.4%, 95% CI: 0.1-0.6%) but distal DVT accounted for as many as 50% of all diagnosed DVTs in those series. Therefore, searching for distal DVT potentially doubles the number of patients given anticoagulant therapy and entails a risk of over-treatment. Data suggesting that anticoagulation is indicated for distal DVT are limited, and realizing distal CUS entails a risk of over-treatment. There is an urgent need for randomised trials assessing the usefulness of anticoagulant treatment in distal DVT.

Therapy for venous thromboembolism (VTE) currently involves a minimum of 3 months of anticoagulation. After cessation of therapy, however, recurrent venous thrombosis occurs at rates of 6 to 9% per year. Clinical trials have demonstrated the benefits of extending anticoagulation beyond 3 months for the prevention of recurrent VTE events. Despite this, many eligible patients do not receive the required thromboprophylaxis and the incidence of recurrent VTE remains too high for a preventable condition. A reason for failure to use prophylaxis is the fear of bleeding complications with current oral anticoagulants such as warfarin. Warfarin has an unpredictable pharmacokinetic profile and a variable dose-response relationship that requires frequent coagulation monitoring and dose adjustments to maintain a target intensity that is both safe and effective. Alternative strategies for long-term prophylaxis, which may potentially provide more consistent anticoagulant responses and reduce coagulation monitoring requirements, include the use of low-molecular-weight heparin (LMWH), treatment with warfarin at a lower intensity, and the introduction of novel anticoagulants. The long-term use of LMWH has been found to be a particularly favorable treatment option for cancer patients in whom it is difficult to control the intensity of anticoagulation. In clinical trials, LMWH significantly reduced the risk of recurrent VTE without increasing bleeding risk. The parenteral administration of the LMWHs, however, is a drawback for long-term use in the outpatient setting. A clinical trial assessing the efficacy and safety of long-term low-intensity warfarin treatment found this therapy to be better than placebo, but another study showed that conventional intensity warfarin was significantly more efficacious than low-intensity warfarin. New therapies in development that may offer improved safety-efficacy profiles are the synthetic pentasaccharides fondaparinux and idraparinux and the oral direct thrombin inhibitor ximelagatran. Parenterally administered fondaparinux has been shown to be as effective as LMWH for the acute treatment (5 to 7 days) of symptomatic deep vein thrombosis. Idraparinux, with once-weekly parenteral dosing, is currently being assessed in phase III clinical trials for the long-term secondary prevention of VTE. Ximelagatran is the first oral agent in the new class direct thrombin inhibitors. With a fast onset of action and oral administration, ximelagatran is a candidate for both acute and chronic therapy. The Thrombin Inhibitor in Venous Thromboembolism (THRIVE) clinical trial program has demonstrated that this agent has a favorable benefit-risk profile compared with standard therapy for the initial treatment (6 months) and secondary prevention (up to 18 months) of VTE. However, in a substantial proportion (6 to 13%) of patients given extended ximelagatran therapy, elevated serum transaminase enzymes developed, typically in the first 2 to 4 months of treatment. Even though these elevations usually abated without clinical sequelae whether or not treatment was continued, their clinical relevance remains unclear. In addition, locally reported coronary events occurred more frequently in ximelagatran-treated patients during the initial 6 months of treatment, the reason for which is yet unclear. The consistent anticoagulant response and fixed oral dosing without coagulation monitoring allows ximelagatran to overcome many of the limitations inherent to current treatment options for VTE treatment and secondary prevention, provided the problem of liver enzyme elevation and coronary events is resolved.

Background: Single-detector-row computed tomography (CT) has a low sensitivity for pulmonary embolism and must be combined with venous-compression ultrasonography of the lower limbs. We evaluated whether the use of D-dimer measurement and multidetector-row CT, without lower-limb ultrasonography, might safely rule out pulmonary embolism., Methods: We included 756 consecutive patients with clinically suspected pulmonary embolism from the emergency departments of three teaching hospitals and managed their cases according to a standardized sequential diagnostic strategy. All patients were followed for three months., Results: Pulmonary embolism was detected in 194 of the 756 patients (26 percent). Among the 82 patients with a high clinical probability of pulmonary embolism, multidetector-row CT showed pulmonary embolism in 78, and 1 patient had proximal deep venous thrombosis and a CT scan that was negative for pulmonary embolism. Of the 674 patients without a high probability of pulmonary embolism, 232 (34 percent) had a negative D-dimer assay and an uneventful follow-up; CT showed pulmonary embolism in 109 patients. CT and ultrasonography were negative in 318 patients, of whom 3 had a definite thromboembolic event and 2 died of possible pulmonary embolism during follow-up (three-month risk of thromboembolism, 1.7 percent; 95 percent confidence interval, 0.7 to 3.9). Two patients had proximal deep venous thrombosis and a negative CT scan (risk, 0.6 percent; 95 percent confidence interval, 0.2 to 2.2). The overall three-month risk of thromboembolism in patients without pulmonary embolism would have been 1.5 percent (95 percent confidence interval, 0.8 to 3.0) if the D-dimer assay and multidetector-row CT had been the only tests used to rule out pulmonary embolism and ultrasonography had not been performed., Conclusions: Our data indicate the potential clinical use of a diagnostic strategy for ruling out pulmonary embolism on the basis of D-dimer testing and multidetector-row CT without lower-limb ultrasonography. A larger outcome study is needed before this approach can be adopted., (Copyright 2005 Massachusetts Medical Society.)

Aim of the Study: To examine the frequency and adequacy of thromboprophylaxis in acutely ill medical patients hospitalized in eight Swiss medical hospitals., Methods: A cross-sectional study of 1372 patients from eight Swiss hospitals was carried out. After exclusion of patients (275) given therapeutic anticoagulation, 1097 patients were audited. The adequacy of thromboprophylaxis was assessed by comparison with predefined explicit criteria., Results: Of 1097 patients, 542 (49.4%) received thromboprophylaxis. According to the explicit criteria, 644 (58.7%) should have been on prophylaxis (P < 0.001, when compared with the rate observed). The rate of prevention differed widely between hospitals (from 29.4 to 88.6%) with no difference between teaching and nonteaching hospitals. According to the explicit criteria, a substantial proportion (44.9%) of the patients who should have been treated were not. Conversely, 41.3% of the patients were unnecessarily treated., Conclusions: Even though the appropriateness of the explicit criteria used could be challenged, our data suggest that the current practice is associated with important uncertainty leading to both overuse and underuse of thromboprophylaxis in patients hospitalized in medical wards. More efforts are urgently needed to develop new or endorse existing explicit, evidence-based criteria and guidelines for thromboprophylaxis in this population of patients.

Context: Ximelagatran, an oral direct thrombin inhibitor with a rapid onset of action and predictable antithrombotic effect, has the potential to be a simple therapeutic alternative to current standard treatment of acute venous thromboembolism., Objective: To compare the efficacy and safety of ximelagatran with standard enoxaparin/warfarin treatment for the prevention of recurrent venous thromboembolism., Design, Setting, and Patients: Randomized, double-blind, noninferiority trial (Thrombin Inhibitor in Venous Thromboembolism [THRIVE] Treatment Study) of 2489 patients with acute deep vein thrombosis, of whom approximately one third had concomitant pulmonary embolism. The study was conducted at 279 centers in 28 countries from September 2000 through December 2002., Interventions: Patients were randomized to receive 6 months of treatment with either oral ximelagatran, 36 mg twice daily, or subcutaneous enoxaparin, 1 mg/kg twice daily, for 5 to 20 days followed by warfarin adjusted to maintain an international normalized ratio of 2.0 to 3.0., Main Outcome Measures: Recurrent venous thromboembolism, bleeding, and mortality., Results: Venous thromboembolism recurred in 26 of the 1240 patients assigned to receive ximelagatran (estimated cumulative risk, 2.1%) and in 24 of the 1249 patients assigned to receive enoxaparin/warfarin (2.0%). The absolute difference between ximelagatran and enoxaparin/warfarin was 0.2% (95% confidence interval [CI], -1.0% to 1.3%). This met the prespecified criterion for noninferiority. Corresponding values for major bleeding were 1.3% and 2.2% (difference, -1.0%; 95% CI, -2.1% to 0.1%), and for mortality were 2.3% and 3.4% (difference, -1.1%; 95% CI, -2.4% to 0.2%). Alanine aminotransferase levels increased to more than 3 times the upper limit of normal in 119 patients (9.6%) and 25 patients (2.0%) receiving ximelagatran and enoxaparin/warfarin, respectively. Increased enzyme levels were mainly asymptomatic. Retrospective analysis of locally reported adverse events showed a higher rate of serious coronary events with ximelagatran (10/1240 patients) compared with enoxaparin/warfarin (1/1249 patients)., Conclusions: Oral ximelagatran administered in a fixed dose without coagulation monitoring, was as effective as enoxaparin/warfarin for treatment of deep vein thrombosis with or without pulmonary embolism and showed similar, low rates of bleeding. Increased levels of liver enzymes in 9.6% of ximelagatran-treated patients require regular monitoring; the mechanism requires further evaluation. Prospective assessment of coronary events in future studies is warranted.

Venous thromboembolic disease (VTE) is a frequent clinical problem during pregnancy and post-partum. Pulmonary embolism (PE) remains the most common cause of mortality during pregnancy and post-partum in western countries. In the majority of cases, DVT may be diagnosed by non-invasive tests such as clinical probability, D-dimer measurement and venous compression ultrasonography. In contrast, at least one irradiating invasive exam is necessary in suspected PE. The lung scan, the most validated diagnostic test for PE during pregnancy and fetal irradiation is quite low, in particular if only perfusion lung scan is used. Helical computed tomography (hCT) has widely replaced lung scan in the diagnostic approach of suspected pulmonary embolism. However, it has never been validated in pregnant women.

To evaluate the performances of a new D-dimer assay, Stratus CS D-dimer (Dade Behring, Newark, Delaware, USA), for the exclusion of venous thromboembolism and to determine the best cut-off values. This test relies on a sandwich enzyme-linked immunosorbent assay with a fluorogenic substrate in a radial partition immunoassay system in a dedicated device. It does not require laboratory staff and the results are available within 18 min. Two hundred and ninety-one frozen samples from patients suspected of either deep venous thrombosis (n = 137) or pulmonary embolism (n = 154) were measured and the results compared with the VIDAS D-dimer New assay. There were 37 deep venous thrombosis (27%) and 49 pulmonary embolism (32%) samples. Receiver-operating characteristic curve analysis indicated that the cut-off value could be set at either 300 or 400 ng/ml Fibrinogen Equivalent Units (FEU). The coefficient of variation determined with a lyophilized low-level control plasma (305 ng/ml FEU) was 6%. With a cut-off at 300 ng/ml FEU, the sensitivity, the specificity and the negative predictive value were 100% [95% confidence interval (CI), 95.8-100], 33.1% (95% CI, 26.8-40) and 100% (95% CI, 94.7-100), respectively. Raising the cut-off to 400 ng/ml FEU, the corresponding figures were 96.5% (95% CI, 90.1-99.3), 46.3% (95% CI, 39.4-53.2) and 96.9% (95% CI, 91.3-99.4), respectively. At 400 ng/ml, three results were false-negative, one with both devices and two with the Stratus D-dimer only. Stratus D-dimer appears to be suitable for the exclusion of venous thromboembolism in the emergency room setting., (Copyright 2004 Lippincott Williams and Wilkins)

Objective: Study of the uptake of new medical technologies provides useful information on the transfer of published evidence into usual practice. We conducted an audit of selected hospitals in three countries (Canada, France, and Switzerland) to identify clinical predictors of low-molecular-weight (LMW) heparin use and outpatient treatment, and to compare the pace of uptake of these new therapeutic approaches across hospitals., Design: Historical review of medical records., Setting and Participants: We reviewed the medical records of 3043 patients diagnosed with deep vein thrombosis (DVT) in five Canadian, two French, and two Swiss teaching hospitals from 1994 to 1998. Measures. We explored independent clinical variables associated with LMW heparin use and outpatient treatment, and determined crude and adjusted rates of LMW heparin use and outpatient treatment across hospitals., Results: For the years studied, the overall rates of LMW heparin use and outpatient treatment in the study sample were 34.1 and 15.8%, respectively, with higher rates of use in later years. Many comorbidities were negatively associated with outpatient treatment, and risk-adjusted rates of use of these new approaches varied significantly across hospitals., Conclusion: There has been a relatively rapid uptake of LMW heparins and outpatient treatment for DVT in their early years of availability, but the pace of uptake has varied considerably across hospitals and countries.

Purpose: To evaluate a diagnostic strategy for pulmonary embolism that combined clinical assessment, plasma D-dimer measurement, lower limb venous ultrasonography, and helical computed tomography (CT)., Methods: A cohort of 965 consecutive patients presenting to the emergency departments of three general and teaching hospitals with clinically suspected pulmonary embolism underwent sequential noninvasive testing. Clinical probability was assessed by a prediction rule combined with implicit judgment. All patients were followed for 3 months., Results: A normal D-dimer level (<500 microg/L by a rapid enzyme-linked immunosorbent assay) ruled out venous thromboembolism in 280 patients (29%), and finding a deep vein thrombosis by ultrasonography established the diagnosis in 92 patients (9.5%). Helical CT was required in only 593 patients (61%) and showed pulmonary embolism in 124 patients (12.8%). Pulmonary embolism was considered ruled out in the 450 patients (46.6%) with a negative ultrasound and CT scan and a low-to-intermediate clinical probability. The 8 patients with a negative ultrasound and CT scan despite a high clinical probability proceeded to pulmonary angiography (positive: 2; negative: 6). Helical CT was inconclusive in 11 patients (pulmonary embolism: 4; no pulmonary embolism: 7). The overall prevalence of pulmonary embolism was 23%. Patients classified as not having pulmonary embolism were not anticoagulated during follow-up and had a 3-month thromboembolic risk of 1.0% (95% confidence interval: 0.5% to 2.1%)., Conclusion: A noninvasive diagnostic strategy combining clinical assessment, D-dimer measurement, ultrasonography, and helical CT yielded a diagnosis in 99% of outpatients suspected of pulmonary embolism, and appeared to be safe, provided that CT was combined with ultrasonography to rule out the disease.