Clinical Presentation and Outcomes of Patients With Cancer-Associated Isolated Distal Deep Vein Thrombosis.

PURPOSE: Patients with isolated distal deep vein thrombosis (DVT) have lower rates of adverse outcomes (death, venous thromboembolism [VTE] recurrence or major bleeding) than those with proximal DVT. It is uncertain if such findings are also observed in patients with cancer. METHODS: Using data from the international Registro Informatizado de la Enfermedad TromboEmbolica venosa registry, we compared the risks of adverse outcomes at 90 days (adjusted odds ratio [aOR]; 95% CI) and 1 year (adjusted hazard ratio [aHR; 95% CI]) in 886 patients with cancer-associated distal DVT versus 5,196 patients with cancer-associated proximal DVT and 5,974 patients with non-cancer-associated distal DVT. RESULTS: More than 90% of patients in each group were treated with anticoagulants for at least 90 days. At 90 days, the adjusted risks of death, VTE recurrence, or major bleeding were lower in patients with non-cancer-associated distal DVT than in patients with cancer-associated distal DVT (reference): aOR = 0.16 (0.11-0.22), aOR = 0.34 (0.22-0.54), and aOR = 0.47 (0.27-0.80), respectively. The results were similar at 1-year follow-up: aHR = 0.12 (0.09-0.15), aHR = 0.39 (0.28-0.55), and aHR = 0.51 (0.32-0.82), respectively. Risks of death, VTE recurrence, and major bleeding were not statistically different between patients with cancer-associated proximal versus distal DVT, both at 90 days: aOR = 1.11 (0.91-1.36), aOR = 1.10 (0.76-1.62), and aOR = 1.18 (0.76-1.83), respectively, and 1 year: aHR = 1.01 (0.89-1.15), aHR = 1.02 (0.76-1.35), and aHR = 1.10 (0.76-1.61), respectively. However, more patients with cancer-associated proximal DVT, compared with cancer-associated distal DVT, developed fatal pulmonary embolism (PE) during follow-up: The risk difference was 0.40% (95% CI, 0.23 to 0.58). CONCLUSION: Cancer-associated distal DVT has serious and relatively comparable outcomes compared with cancer-associated proximal DVT. The lower risk of fatal PE from cancer-associated distal DVT needs further investigation.

TILE pilot trial study protocol: Tinzaparin Lead-in to Prevent the Post-Thrombotic syndrome study protocol.

INTRODUCTION: The post-thrombotic syndrome (PTS) is a form of chronic venous insufficiency due to a prior ipsilateral deep venous thrombosis (DVT). This is a frequent complication that develops in 20%-50% of patients after a proximal DVT and is associated with significant healthcare, economic and societal consequences. In the absence of effective and well-tolerated treatment options for established PTS, effective preventative measures are needed. Anticoagulation itself reduces the risk of PTS, and low-molecular-weight heparin may reduce this further through anti-inflammatory properties targeting the initial acute inflammatory phase of DVT. METHODS AND ANALYSIS: The Tinzaparin Lead-In to Prevent the Post-Thrombotic syndrome pilot trial is an investigator-initiated, multicentre, open-label assessor-blinded trial that will randomise patients with first acute symptomatic common femoral or iliac DVT to receive either a 3-week lead-in course of tinzaparin, followed by rivaroxaban (experimental arm) or rivaroxaban alone (control arm). Its primary objectives are to assess: (1) proportion of PTS at 6 months using the Villalta scale and (2) study feasibility, which consists of (a) the proportion of screened patients eligible for the study, (2) the proportion of eligible patients recruited and (c) the proportion of recruited patients adherent to treatment (defined as at least 80% of drug taken). This study will determine the feasibility of a subsequent larger definitive trial. Secondary outcomes include change of quality of life scores, PTS severity, global improvement, patient satisfaction, bleeding, recurrent venous thromboembolism, leg pain, death and lost to follow-up. Target recruitment will be a total of 60 participants, recruited at 5-6 centres. ETHICS AND DISSEMINATION: Primary ethics approval was received from the Sunnybrook Health Sciences Center Research Ethics Board (approval ID 3315). Results of the study will be disseminated via peer-reviewed presentation at scientific conferences and open access publication. TRIAL REGISTRATION NUMBER: NCT04794569.

Implementation of the YEARS algorithm to optimise pulmonary embolism diagnostic workup in the emergency department.

BACKGROUND: Excessive use of CT pulmonary angiography (CTPA) to investigate pulmonary embolism (PE) in the emergency department (ED) contributes to adverse patient outcomes. Non-invasive D-dimer testing, in the context of a clinical algorithm, may help decrease unnecessary imaging but this has not been widely implemented in Canadian EDs. AIM: To improve the diagnostic yield of CTPA for PE by 5% (absolute) within 12 months of implementing the YEARS algorithm. MEASURES AND DESIGN: Single centre study of all ED patients >18 years investigated for PE with D-dimer and/or CTPA between February 2021 and January 2022. Primary and secondary outcomes were the diagnostic yield of CTPA and frequency of CTPA ordered compared with baseline. Process measures included the percentage of D-dimer tests ordered with CTPA and CTPAs ordered with D-dimers <500 µg/L Fibrinogen Equivalent Units (FEU). The balancing measure was the number of PEs identified on CTPA within 30 days of index visit. Multidisciplinary stakeholders developed plan- do-study-act cycles based on the YEARS algorithm. RESULTS: Over 12 months, 2695 patients were investigated for PE, of which 942 had a CTPA. Compared with baseline, the CTPA yield increased by 2.9% (12.6% vs 15.5%, 95% CI -0.06% to 5.9%) and the proportion of patients that underwent CTPA decreased by 11.4% (46.4% vs 35%, 95% CI -14.1% to -8.8%). The percentage of CTPAs ordered with a D-dimer increased by 26.3% (30.7% vs 57%, 95% CI 22.2% 30.3%) and there were two missed PE (2/2695, 0.07%). IMPACT: Implementing the YEARS criteria may safely improve the diagnostic yield of CTPAs and reduce the number of CTPAs completed without an associated increase in missed clinically significant PEs. This project provides a model for optimising the use of CTPA in the ED.

Exploring the Villalta scale to capture postthrombotic syndrome using alternative approaches: A subanalysis of the ATTRACT trial.

Background: Clinical trials that evaluated interventions to prevent postthrombotic syndrome (PTS) used the Villalta scale (VS) to define PTS, but there is a lack of consistency in its use. Objectives: This study aimed to improve the ability to identify patients with clinically meaningful PTS after DVT in participants of the ATTRACT trial. Methods: We conducted a post hoc exploratory analysis of 691 patients from the ATTRACT study, a randomized trial evaluating the effectiveness of pharmacomechanical thrombolysis to prevent PTS in proximal deep vein thrombosis. We compared 8 VS approaches to classify patients with or without PTS in terms of their ability to discriminate between those with poorer vs better venous disease-specific quality of life (Venous Insufficiency Epidemiological and Economic Study Quality of Life [VEINES-QOL]) between 6- and 24-months follow-up. The difference in the average area under the fitted curve of VEINES-QOL scores between PTS and no PTS ( Δ A U C ¯ ) were compared among approaches. Results: For any PTS (a single VS score ≥5), approaches 1 to 3 had similar Δ A U C ¯ (-21.2, -23.7, -22.0, respectively). Adjusting the VS for contralateral chronic venous insufficiency (CVI) or restricting to patients without baseline CVI (approaches 7 and 8) did not improve Δ A U C ¯ (-13.6, -19.9, respectively; P >.01). For moderate-to-severe PTS (a single VS score ≥10), approaches 5 and 6 requiring 2 positive assessments had greater but not statistically significant Δ A U C ¯ than approach 4, using one single positive assessment (-31.7, -31.0, -25.5, respectively; P >.01). Conclusion: A single VS score of ≥ 5 reliably distinguishes patients with clinically meaningful PTS as assessed by impact on QOL and is preferred because of greater convenience (only one assessment needed). Alternative methods to define PTS (ie, adjusting for CVI) do not improve the scale's ability to identify clinically meaningful PTS.

25 mm Hg versus 35 mm Hg elastic compression stockings to prevent post-thrombotic syndrome after deep vein thrombosis (CELEST): a randomised, double-blind, non-inferiority trial.

BACKGROUND: The optimal strength of compression needed to prevent post-thrombotic syndrome (PTS) after a proximal deep vein thrombosis (DVT) is debated. We aimed to assess whether 25 mm Hg elastic compression stockings (ECS) are non-inferior to 35 mm Hg ECS in preventing PTS after a DVT. METHODS: In this multicentre, double-blind, non-inferiority, randomised controlled trial, we enrolled adults (≥18 years) with a first ipsilateral proximal DVT attending 46 French vascular medicine hospital departments or private practices. Participants were randomly allocated (1:1, stratified by centre, age, and sex; with varying block sizes of two and four) to wear 25 mm Hg or 35 mm Hg ECS for 2 years. The primary outcome was the cumulative rate of PTS 2 years after inclusion, defined by a Villalta scale (≥5). Efficacy was assessed by intention-to-treat and in eligible participants who had complete primary outcome data. A per-protocol analysis was also conducted among compliant patients as a secondary outcome measure. Safety was assessed in all participants who used ECS at least once, and for which we have at least some tolerance information during follow-up. The margin for non-inferiority was 12·5%. This study is registered with ClinicalTrials.gov, NCT01578122, and has been completed. FINDINGS: Between June 28, 2012, and July 21, 2017, we enrolled 341 eligible participants who consented to randomisation. 233 (68%) were men and median age was 59 years (IQR 45-70). Collection of ethnicity and race as a routine research variable is not authorised in France. Median follow-up was 735 days (IQR 721-760). 249 (73%) had complete data at 2 years. For the primary analysis, 40 (31%) of 129 participants with complete data in the 25 mm Hg ECS group and 40 (33%) of 120 in the 35 mm Hg group had PTS (absolute difference -2·3% [90% CI -12·1 to 7·4], pnon-inferiority=0·0062; relative risk 0·93, 95% CI 0·65 to 1·33). Results remained similar after imputation of missing data in patients we were authorised to do so: the cumulative proportion of PTS was 45 (29%) of 154 in the 25 mm Hg ECS group versus 52 (35%) of 148 in the 35 mm Hg ECS group (relative risk 0·83, 95% CI 0·60 to 1·16). Absolute difference was -5·9%, (90% CI -14·7 to 2·9), p=0·0003 for non-inferiority. Adherence was optimal (>80% and modified GIRERD score of 0-2) for 75 (51%) of 146 patients assigned to 25 mm Hg ECS and for 56 (42%) of 134 patients assigned to 35 mm Hg ECS (p=0·11). Regarding major adverse events related to ECS, there were no between-group differences in rates of deep vein thrombosis (0 vs 1 [0·6%]), ipsilateral leg ulcer (0 vs 1 [0·6%]), infection (0 vs 0), or death (0 vs 0) between the 169 patients evaluated in the 25 mm Hg ECS group and the 159 patients in the 35 mm Hg ECS group. Two (1%) of 328 patients who ever wore ESC developed ECS-related serious adverse events, one distal DVT and one leg ulcer (both in the 35 mm Hg ECS group). In the 25 mm Hg group, 6 patients died, 14 had a venous thromboembolic recurrence (proximal DVT or pulmonary embolism), and 7 had a major bleed. In the 35 mm Hg group, 5 patients died, 10 had a venous thromboembolic recurrence (proximal DVT or pulmonary embolism), and 6 had a major bleed. INTERPRETATION: Although we did not reach the prespecified sample size, our results suggest that 25 mm Hg ECS are non-inferior to 35 mm Hg ECS in preventing PTS. Larger more powerful studies are needed. FUNDING: Laboratoires Innothera, France.

Development of an international standard set of outcome measures for patients with venous thromboembolism: an International Consortium for Health Outcomes Measurement consensus recommendation.

The International Consortium for Health Outcomes Measurement assembled an international working group of venous thromboembolism experts and patient representatives to develop a standardised minimum set of outcomes and outcome measurements for integration into clinical practice and potentially research to support clinical decision making and benchmarking of quality of care. 15 core outcomes important to patients and health-care professionals were selected and categorised into four domains: patient-reported outcomes, long term consequences of the disease, disease-specific complications, and treatment-related complications. The outcomes and outcome measures were designed to apply to all patients with venous thromboembolism aged 16 years or older. A measurement tool package was selected for inclusion in the core standard set, with a minimum number of items to be measured at predefined timepoints, which capture all core outcomes. Additional measures can be introduced to the user by a cascade opt-in system that allows for further assessment if required. This set of outcomes and measurement tools will facilitate the implementation of the use of patient-centred outcomes in daily practice.

Clinical Presentation and Short- and Long-term Outcomes in Patients With Isolated Distal Deep Vein Thrombosis vs Proximal Deep Vein Thrombosis in the RIETE Registry.

Importance: Insufficient data exist about the clinical presentation, short-term, and long-term outcomes of patients with isolated distal deep vein thrombosis (IDDVT), that is, thrombosis in infrapopliteal veins without proximal extension or pulmonary embolism (PE). Objective: To determine the clinical characteristics, short-term, and 1-year outcomes in patients with IDDVT and to compare the outcomes in unadjusted and multivariable adjusted analyses with patients who had proximal DVT. Design, Setting, and Participants: This was a multicenter, international cohort study in participating sites of the Registro Informatizado Enfermedad Tromboembólica (RIETE) registry conducted from March 1, 2001, through February 28, 2021. Patients included in this study had IDDVT. Patients with proximal DVT were identified for comparison. Patients were excluded if they had a history of asymptomatic DVT, upper-extremity DVT, coexisting PE, or COVID-19 infection. Main Outcomes and Measures: Primary outcomes were 90-day and 1-year mortality, 1-year major bleeding, and 1-year venous thromboembolism (VTE) deterioration, which was defined as subsequent development of proximal DVT or PE. Results: A total of 33 897 patients were identified with isolated DVT (without concomitant PE); 5938 (17.5%) had IDDVT (mean [SD] age, 61 [17] years; 2975 male patients [50.1%]), and 27 959 (82.5%) had proximal DVT (mean [SD] age, 65 [18] years; 14 315 male patients [51.2%]). Compared with individuals with proximal DVT, those with IDDVT had a lower comorbidity burden but were more likely to have had recent surgery or to have received hormonal therapy. Patients with IDDVT had lower risk of 90-day mortality compared with those with proximal DVT (odds ratio [OR], 0.47; 95% CI, 0.40-0.55). Findings were similar in 1-year unadjusted analyses (hazard ratio [HR], 0.52; 95% CI, 0.46-0.59) and adjusted analyses (HR, 0.72; 95% CI, 0.64-0.82). Patients with IDDVT had a lower 1-year hazard of VTE deterioration (HR, 0.83; 95% CI, 0.69-0.99). In 1-year adjusted analyses of patients without an adverse event within the first 3 months, IDDVT was associated with lower risk of VTE deterioration (adjusted HR, 0.48; 95% CI, 0.24-0.97). By 1-year follow-up, symptoms or signs of postthrombotic syndrome were less common in patients with IDDVT (47.6% vs 60.5%). Conclusions and Relevance: Results of this cohort study suggest that patients with IDDVT had a less ominous prognosis compared with patients with proximal DVT. Such differences were likely multifactorial, including the differences in demographics, risk factors, comorbidities, particularly for all-cause mortality, and a potential association of thrombus location with VTE deterioration and postthrombotic syndrome. Randomized clinical trials are needed to assess the optimal long-term management of IDDVT.

Prevention of the Postthrombotic Syndrome with Anticoagulation: A Narrative Review.

The postthrombotic syndrome (PTS) is chronic venous insufficiency secondary to a prior deep vein thrombosis (DVT). It is the most common complication of venous thromboembolism (VTE) and, while not fatal, it can lead to chronic, unremitting symptoms as well as societal and economic consequences. The cornerstone of PTS treatment lies in its prevention after DVT. Specific PTS preventative measures include the use of elastic compression stockings and pharmacomechanical catheter-directed thrombolysis. However, the efficacy of these treatments has been questioned by large randomized controlled trials (RCTs). So far, anticoagulation, primarily prescribed to prevent DVT extension and recurrence, appears to be the only unquestionably effective treatment for the prevention of PTS. In this literature review we present pathophysiological, biological, radiological, and clinical data supporting the efficacy of anticoagulants to prevent PTS and the possible differential efficacy among available classes of anticoagulants (vitamin K antagonists [VKAs], low molecular weight heparins [LMWHs] and direct oral anticoagulants [DOACs]). Data suggest that LMWHs and DOACs are superior to VKAs, but no head-to-head comparison is available between DOACs and LMWHs. Owing to their potentially greater anti-inflammatory properties, LMWHs could be superior to DOACs. This finding may be of interest particularly in patients with extensive DVT at high risk of moderate to severe PTS, but needs to be confirmed by a dedicated RCT.

MUFFIN-PTS trial, Micronized Purified Flavonoid Fraction for the Treatment of Post-Thrombotic Syndrome: protocol of a randomised controlled trial.

INTRODUCTION: After deep vein thrombosis, up to 50% of patients develop post-thrombotic syndrome (PTS). PTS is a chronic condition that reduces quality of life (QOL). Cornerstones of PTS treatment include the use of elastic compression stockings but this treatment is usually incompletely effective and is burdensome. Venoactive drugs have been reported to be effective to treat chronic venous insufficiency (CVI). However, the level of evidence supporting their use in CVI in general and in PTS in particular is low. METHODS AND ANALYSIS: The MUFFIN-PTS trial is an academic, publically funded, multicentre randomised placebo-controlled trial assessing the efficacy of micronised purified flavonoid fraction (MPFF, Venixxa), a venoactive drug, to treat PTS. Eighty-six patients with PTS (Villalta score (VS) ≥5) and experiencing at least two of the following PTS manifestations among daily leg heaviness, cramps, pain or oedema will be randomised to receive 1000 mg of oral MPFF or a similar appearing placebo for 6 months, in addition to their usual PTS treatment. Total study follow-up will be 9 months, with visits at inclusion/baseline, 3, 6 and 9 months. Primary outcome is the proportion of patients with improvement in VS in each group, where improvement is defined as a decrease of at least 30% in VS or a VS <5 in the PTS-affected leg. Main secondary outcomes include QOL and patient satisfaction. ETHICS AND DISSEMINATION: Primary ethics approval was received from Centre intégré universitaire de santé et de services sociaux (CIUSSS) West-Central Montreal Research Ethics Board. Results of the study will be disseminated via peer-reviewed publications and presentations at scientific conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03833024); Pre-results.

Significance and management of isolated distal deep vein thrombosis.

PURPOSE OF REVIEW: Management of isolated distal deep vein thrombosis (IDDVT) remains controversial. We summarize recent studies regarding the natural history of IDDVT as well as pertinent therapeutic trials. We also provide our management approach. RECENT FINDINGS: IDDVT is more commonly associated with transient risk factors and less often associated with permanent, unmodifiable risk factors than proximal DVT. IDDVT has a significantly lower risk of proximal extension and recurrence than proximal DVT. Cancer-associated IDDVT has a similar natural history to cancer-associated proximal DVT, with substantially less favourable outcomes than noncancer-associated IDDVT. Anticoagulant treatment reduces the risk of proximal extension and recurrence in IDDVT at the cost of increased bleeding risk. Intermediate dosing of anticoagulation may be effective for treating noncancer-associated IDDVT in patients without prior DVT. SUMMARY: IDDVT with a transient risk factor can be treated for 6 weeks in patients without a prior DVT. Unprovoked IDDVT in patients without malignancy can be treated for 3 months. Outpatients without malignancy or a prior DVT can be left untreated and undergo surveillance compression ultrasound in one week to detect proximal extension, but few patients opt for this in practice. Cancer-associated IDDVT should be treated analogously to cancer-associated proximal DVT.

Micronized purified flavonoid fraction for the treatment of chronic venous insufficiency, with a focus on postthrombotic syndrome: A narrative review.

INTRODUCTION: Postthrombotic syndrome (PTS) is a form of secondary chronic venous insufficiency (CVI) that occurs after deep vein thrombosis (DVT). Effective treatments for PTS are lacking. Micronized purified flavonoid fraction (MPFF) is a venoactive drug used in the treatment of CVI. OBJECTIVE: To determine whether MPFF is a good candidate to explore as a therapeutic agent for PTS. METHODS: We performed a narrative review in which we identified 14 systematic reviews, 33 randomized controlled trials, and 19 observational studies that discussed the use of MPFF in CVI, as well as studies that reported on the mechanistic action of MPFF in relation to the pathophysiology of PTS. RESULTS: MPFF targets a number of pathophysiologic components of PTS. Based on animal models and human studies investigating objective vascular and lymphatic measures, MPFF promotes venous recanalization after DVT, decreases venous remodeling and reflux, inhibits inflammatory processes, improves venous tone and stasis, improves lymphatic circulation, improves capillary hyperpermeability, and decreases tissue hypoxia. Furthermore, MPFF shows promise in improving clinical manifestations, quality of life, and objective venous parameters of CVI. Studies suggest good patient acceptability and tolerability with the use of MPFF in CVI. CONCLUSION: MPFF is a good candidate to explore as a potential therapy for PTS. Confirmatory high-quality studies are still needed to reinforce the evidence supporting the use of MPFF in CVI. Double-blind randomized controlled trials with clinical endpoints are needed to assess the clinical efficacy of MPFF in the treatment of PTS.

Initiation of anticoagulation in atrial fibrillation by primary care physicians: Results of a telephone survey.

BACKGROUND: Direct oral anticoagulants (DOACs) are prescribed for over 80% of patients who start anticoagulant therapy for a new diagnosis of atrial fibrillation (AF). Inappropriate DOAC prescriptions are associated with increased mortality. However, limited data exist as to what proportion of primary care physicians (PCPs) initiate anticoagulation in patients with new AF and the extent of their DOAC knowledge. MATERIAL AND METHODS: We conducted a telephone survey of randomly selected PCPs in Ontario, Canada. Our primary objective was to determine the percentage of PCPs who initiate anticoagulation in new AF patients and the proportion of patients they initiate on DOACs. Our secondary objectives were to assess PCPs' knowledge about DOACs and to identify educational opportunities to address any knowledge gaps. RESULTS: Our survey included 50 respondents. After making a new AF diagnosis, 66% of PCPs stated that they usually initiate anticoagulation themselves and 84% prescribed a DOAC at least 75% of the time. Potential DOAC knowledge gaps included: administration considerations, off-label dosing, concomitant use of acetylsalicylic acid (ASA) in stable coronary artery disease (CAD) and use in valvular AF. CONCLUSION: Most PCPs initiate anticoagulants for AF and prescribe DOACs for the vast majority of new patients. PCPs were well versed in certain aspects of DOAC prescribing, however, a number of knowledge gaps were identified. PCPs may benefit from targeted education in these areas to improve patient outcomes in AF.

Management of isolated distal deep-vein thrombosis with direct oral anticoagulants in the RIETE registry.

Isolated distal deep-vein thrombosis (DVT, infra-popliteal DVT without pulmonary embolism) is a common presentation of venous thromboembolism (VTE), but was an exclusion criterion from the pivotal trials that validated the use of direct oral anticoagulants (DOACs) for VTE management. Using data from the international RIETE registry, we analyzed and compared trends in DOACs prescription between January 2011 and June 2019 in patients with distal vs. proximal DVT. We also assessed DOACs' prescriptions and compared the outcomes (VTE recurrence, bleeding and death) of distal DVT patients treated with DOACs vs. those on vitamin K antagonists (VKAs). 2308 patients with distal DVT and 11,364 patients with proximal DVT were included in the current analysis. DOACs were more frequently prescribed in patients with distal than proximal DVT (25% vs. 16%, p < 0.001). DOACs use increased sharply during the observation period (P < 0.001 for trend). In 2018, 56% of patients with distal DVT received DOACs. Distal DVT patients treated with rivaroxaban or edoxaban received the dose recommended for VTE management in most (> 85%) cases. Patients treated with apixaban were older, more likely to have underlying conditions than patients treated with rivaroxaban and, in most cases (> 75%), did not receive the recommended 1-week loading dose for acute VTE management. Outcomes between distal DVT patients treated with VKAs or DOACs appeared to be similar. In patients with distal DVT, DOACs have become the most common anticoagulant regimen. Specific trials are needed to determine the optimal DOACs dose regimen for treatment of distal DVT.

Compression stockings to prevent postthrombotic syndrome: Literature overview and presentation of the CELEST trial.

Postthrombotic syndrome (PTS) is a burdensome and costly complication of deep vein thrombosis (DVT) that develops in 20%-40% of patients within 2 years after proximal DVT. In the absence of effective curative treatment, management of PTS relies on its prevention after DVT. The effectiveness of elastic compression stockings (ECS) to prevent PTS is uncertain. We present an overview of published studies assessing the efficacy of ECS to prevent PTS and present the protocol for the CELEST clinical trial. While previous open-label randomized trials have reported a 50% risk reduction in PTS in patients treated with >30 mm Hg ankle pressure ECS, a large double-blind trial reported no effect of ECS. We discuss the main potential limitations of these trials, including a placebo effect and suboptimal compliance to ECS. We present the protocol of the CELEST double-blind randomized trial comparing 2 years of high strength (ankle pressure 35 mm Hg) versus lower strength (ankle pressure 25 mm Hg) ECS in the prevention of PTS after a first acute symptomatic, unilateral, proximal DVT. The use of lower-strength ECS than that used in previous studies should favor compliance. CELEST may provide important evidence about the efficacy of ECS in the prevention of PTS after DVT. The results will be interpreted in the light of results from recent clinical trials assessing ECS for PTS prevention that reported that the duration of ECS use should be tailored to the individual, if ECS are efficacious in the prevention of PTS.

Epidemiology and 3-year outcomes of combined oral contraceptive-associated distal deep vein thrombosis.

BACKGROUND: Distal deep vein thrombosis (infrapopliteal DVT without proximal DVT or pulmonary embolism [PE]) generally shares the same triggering risks factors as proximal DVT. In women of childbearing age, a frequent triggering risk factor is the use of combined oral contraceptive (COC) pills. However, data on the epidemiology and long-term outcomes of COC-associated distal DVT are lacking. OBJECTIVES: To assess the epidemiology and long-term outcomes of COC-associated distal DVT. METHODS: Using data from the OPTIMEV (Optimisation de l'Interrogatoire dans l'évaluation du risque thrombo-Embolique Veineux [Optimization of Interrogation in the Assessment of Thromboembolic Venous Risk]) multicenter cohort study of patients with objectively confirmed venous thromboembolism (VTE) enrolled between 2004 and 2006, we assessed in nonpregnant or postpartum women aged ≤ 50 years without cancer or history of VTE (i) proportion of COC-associated distal DVTs among women with distal DVTs and among women with COC-associated VTEs (distal DVT, proximal DVT, or PE) and (ii) 3-year incidence of death, bleeding, and VTE recurrence. RESULTS: COC-associated distal DVTs (n = 54) represented 43.9% of all distal DVTs and 51.9% of COC-associated VTEs. All but one woman with a COC-associated distal DVT received therapeutic anticoagulation for a median of 3 months. At 3-year follow-up, all women with COC-associated distal DVTs were alive, and none had bled during anticoagulant treatment or had experienced a DVT or PE recurrence after stopping anticoagulants. Similar results were found in patients with COC-associated proximal DVT and PE: The VTE recurrence rate was 1.7% per patient-year (PY) and 0% PY, respectively, and there were no deaths or major bleeds in either group. CONCLUSIONS: Distal DVT was the most frequent clinical presentation of COC-associated VTE and had similarly favorable long-term outcomes as other COC-associated VTE.

Accuracy of contralateral Villalta score to assess for pre-existing chronic venous insufficiency in patients with unilateral deep vein thrombosis.

BACKGROUND: International guidelines recommend using the Villalta score (VS) to diagnose the postthrombotic syndrome (PTS). However, a high proportion of PTS detected with VS could just reflect the presence of preexisting primary venous insufficiency (PVI). Furthermore, it is unclear whether the contralateral VS (cl-VS) can be used to assess for preexisting PVI. OBJECTIVES: To estimate whether cl-VS can be used to assess for preexisting PVI, and to assess the proportion of PTS that could be attributable to preexisting PVI. METHODS: Subanalysis of the SOX multicenter randomized trial focusing on patients with a first unilateral proximal deep vein thrombosis (DVT) followed for up to 2 years. PVI was defined as a baseline cl-VS > 4, and PTS as VS > 4 in the leg ipsilateral to DVT starting 6 months after DVT. RESULTS: Among 680 patients, mean cl-VS remained stable over time: 1.23 (standard deviation [SD] ±2.49) at baseline and 1.17 (±2.20), 1.59 (±2.81), 1.54 (±2.50), 1.65 (±2.82), and 1.55 (±2.63) at the 1-, 6-, 12-, 18-, and 24-month visits, respectively. Baseline cl-VS and ipsilateral VS measured during follow-up were mildly correlated (Pearson correlation = 0.13-0.25). This association disappeared after subtracting the cl-VS measured at the same visit from the ipsilateral VS. Overall, 48.8% of patients developed PTS of whom 12.8% had baseline cl-VS > 4. CONCLUSION: In our study of patients with a first unilateral proximal DVT, the proportion of patients with PTS who had a cl-VS > 4 is modest. However, cl-VS appears to be stable over time. Its assessment could constitute a simple way of documenting preexisting PVI and help to classify patients as having PTS.

Prevention and Management of the Post-Thrombotic Syndrome.

The post-thrombotic syndrome (PTS) is a form of chronic venous insufficiency secondary to prior deep vein thrombosis (DVT). It affects up to 50% of patients after proximal DVT. There is no effective treatment of established PTS and its management lies in its prevention after DVT. Optimal anticoagulation is key for PTS prevention. Among anticoagulants, low-molecular-weight heparins have anti-inflammatory properties, and have a particularly attractive profile. Elastic compression stockings (ECS) may be helpful for treating acute DVT symptoms but their benefits for PTS prevention are debated. Catheter-directed techniques reduce acute DVT symptoms and might reduce the risk of moderate-severe PTS in the long term in patients with ilio-femoral DVT at low risk of bleeding. Statins may decrease the risk of PTS, but current evidence is lacking. Treatment of PTS is based on the use of ECS and lifestyle measures such as leg elevation, weight loss and exercise. Venoactive medications may be helpful and research is ongoing. Interventional techniques to treat PTS should be reserved for highly selected patients with chronic iliac obstruction or greater saphenous vein reflux, but have not yet been assessed by robust clinical trials.

Patient-reported reasons for and predictors of noncompliance with compression stockings in a randomized trial of stockings to prevent postthrombotic syndrome.

INTRODUCTION: Elastic compression stockings (ECSs) are used to treat symptoms of venous insufficiency. However, lack of patient compliance can limit their effectiveness. In a secondary analysis of the SOX Trial, a randomized trial of active vs. placebo ECSs worn for 2 years to prevent postthrombotic syndrome after deep vein thrombosis, we aimed to describe patient-reported reasons for nondaily use of ECS and to identify predictors of noncompliance during follow-up. METHODS: At each follow-up visit of the SOX Trial, patients were asked how many days per week they wore study stockings, and if not worn daily, to specify the reason(s). Reasons for nondaily use of ECSs were tabulated. Multiple logistic regression modeling was used to identify predictors of stocking noncompliance during follow-up (defined as use <3 days per week). RESULTS: Among the 776 patients who attended at least 1 follow-up visit, daily use of stockings at each visit was similar in the active and placebo ECS groups. Reasons for nondaily use of stockings was most frequently related to aversive aspects of stockings (~three-fourths of patients) and less often related to patient behaviors (~one-fourth of patients). In multivariate analyses, behavior-related and aversive aspect-related reasons for nondaily use of ECSs at the 1-month visit were significant predictors of noncompliance during follow-up (odds ratio [OR] = 4.41 [95% confidence interval, 2.12-9.17] and OR = 3.99 [2.62-6.08], respectively). CONCLUSIONS: Aversive aspects of ECSs and patient behaviors are important reasons for noncompliance. Improving the appeal and tolerability of ECS and education directed at modifying patient behaviors may improve compliance.

Pulmonary embolism home treatment: What GP want?

BACKGROUND: In routine clinical practice, in most countries, patients with pulmonary embolism (PE) are hospitalized for clinical surveillance and to start anticoagulant treatment. Clinical trials and guidelines suggest that patients with stable PE can be safely treated as outpatients. This shift in management may increase general practitioners' (GP) role in PE early management. However, GP opinion regarding PE home treatment has never been assessed. METHODS: Survey conducted in France among a random sample of 360 GP (564 contacted to reach targeted sample size) working in regions representative of national access to French healthcare system. Main objectives were to assess i) GP' acceptability to PE home treatment ii) GP' preferred outpatient pathway. RESULTS: 87% of GP were favorable to home treatment of stable PE if the medical report is immediately available when the patient is discharged from ER (100%), in the absence of social and medical facility isolation of the patient (99%) and if the patient (99%) and GP (76%) consented. Outpatient pathways should be collaborative, between GP and a thrombosis specialist, and should include specialized follow-up visits at one week (80%), 3-6 months (80%) and when anticoagulant treatment is stopped (97%). 61% of GP felt that direct oral anticoagulants (DOAC) should facilitate PE home treatment, which should improve patient's quality of life. CONCLUSION: The vast majority of interviewed GP are favorable to home treatment of stable PE if a formal outpatient pathway is established. DOAC are perceived as another key for the success of the development of PE home treatment.