Pathogenic variants in HGF give rise to childhood-to-late onset primary lymphoedema by loss of function.

Developmental and functional defects in the lymphatic system are responsible for primary lymphoedema (PL). PL is a chronic debilitating disease caused by increased accumulation of interstitial fluid, predisposing to inflammation, infections and fibrosis. There is no cure, only symptomatic treatment is available. Thirty-two genes or loci have been linked to PL, and another 22 are suggested, including Hepatocyte Growth Factor (HGF). We searched for HGF variants in 770 index patients from the Brussels PL cohort. We identified ten variants predicted to cause HGF loss-of-function (six nonsense, two frameshifts, and two splice-site changes; 1.3% of our cohort), and 14 missense variants predicted to be pathogenic in 17 families (2.21%). We studied co-segregation within families, mRNA stability for non-sense variants, and in vitro functional effects of the missense variants. Analyses of the mRNA of patient cells revealed degradation of the nonsense mutant allele. Reduced protein secretion was detected for nine of the 14 missense variants expressed in COS-7 cells. Stimulation of lymphatic endothelial cells with these 14 HGF variant proteins resulted in decreased activation of the downstream targets AKT and ERK1/2 for three of them. Clinically, HGF-associated PL was diverse, but predominantly bilateral in the lower limbs with onset varying from early childhood to adulthood. Finally, aggregation study in a second independent cohort underscored that rare likely pathogenic variants in HGF explain about 2% of PL. Therefore, HGF signalling seems crucial for lymphatic development and/or maintenance in human beings and HGF should be included in diagnostic genetic screens for PL.

Factors associated with cellulitis in lymphoedema of the arm - an international cross-sectional study (LIMPRINT).

BACKGROUND: Lymphoedema is a globally neglected health care problem and a common complication following breast cancer treatment. Lymphoedema is a well-known predisposing factor for cellulitis, but few have investigated the risk factors for cellulitis in this patient cohort on an international level. The aim of this study was to identify the frequency of cellulitis in patients with lymphoedema of the arm, including potential risk factors for cellulitis. METHODS: An international, multi-centre, cross-sectional study including patients with clinically assessed arm lymphoedema. The primary outcome was the incidence of cellulitis located to the arm with lymphoedema within the last 12 months, and its potential associated risk factors. The secondary outcome was life-time prevalence of cellulitis. Adults with clinically-assessed arm lymphoedema/chronic oedema (all causes) and able to give informed consent were included. End-of-life-patients or those judged as not in the patient's best interest were excluded. Both univariable and multivariable analysis were performed. RESULTS: A total of 2160 patients were included from Australia, Denmark, France, Ireland, Italy, Japan, Turkey and United Kingdom. Secondary lymphoedema was present in 98% of the patients; 95% of these were judged as related to cancer or its treatment. The lifetime prevalence of cellulitis was 22% and 1-year incidence 11%. Following multivariable analysis, factors associated with recent cellulitis were longer swelling duration and having poorly controlled lymphoedema. Compared to having lymphoedema less than 1 year, the risk increased with duration: 1-2 years (OR 2.15), 2-5 years (OR 2.86), 5-10 years (OR 3.15). Patients with well-controlled lymphoedema had a 46% lower risk of cellulitis (OR 0.54, 95% CI 0.39-0.73, p < 0.001). More advanced stages of lymphoedema were associated with cellulitis even after adjustment for swelling duration and control of swelling by logistic regression (stage II OR 5.44, stage III OR 9.13, p = 0.002), demonstrated in a subgroup analysis. CONCLUSION: Patients with advanced arm lymphoedema are at particular risk of developing cellulitis. Prevention of lymphoedema progression is crucial. The results lend towards a positive effect of having well-treated lymphoedema on the frequency of cellulitis.

Ureteropelvic junction obstruction with primary lymphoedema associated with CELSR1 variants.

BACKGROUND: Primary lymphoedema (PL) is a chronic, debilitating disease caused by developmental and functional defects of the lymphatic system. It is marked by an accumulation of interstitial fluid, fat and tissue fibrosis. There is no cure. More than 50 genes and genetic loci have been linked to PL. We sought to study systematically cell polarity signalling protein Cadherin Epidermal Growth Factor Laminin G Seven-pass G-type Receptor 1 (CELSR1) variants linked to PL. METHODS: We investigated 742 index patients from our PL cohort using exome sequencing. RESULTS: We identified nine variants predicted to cause CELSR1 loss of function. Four of them were tested for nonsense-mediated mRNA decay, but none was observed. Most of the truncated CELSR1 proteins would lack the transmembrane domain, if produced. The affected individuals had puberty/late-onset PL on lower extremities. The variants had a statistically significant difference in penetrance between female patients (87%) and male patients (20%). Eight variant carriers had a kidney anomaly, mostly in the form of ureteropelvic junction obstruction, which has not been associated with CELSR1 before. CELSR1 is located in the 22q13.3 deletion locus of the Phelan-McDermid syndrome. As variable renal defects are often seen in patients with the Phelan-McDermid syndrome, CELSR1 may be the long-sought gene for the renal defects. CONCLUSION: PL associated with a renal anomaly suggests a CELSR1-related cause.

Correlation of nailfold capillaroscopy findings with history of digital ulcer on same finger: Results of SCLEROCAP study.

Systemic sclerosis may be complicated by digital ulcers. Nailfold capillaroscopy on one finger might reflect an increased risk of digital ulcer (DU). In the present study we studied the correlations between a history of ulcer and capillary findings on the finger. METHOD: This study is part of Sclerocap, a multicenter study aiming at validating prospectively the prognostic value of Maricq's and Cutolo's capillaroscopic classifications during a three-year longitudinal follow-up. A history of past or present digital ulcer was recorded at inclusion and nailfold capillaroscopy was performed. Elementary findings as well as Cutolo and Maricq's classifications were assessed. RESULTS: 387 patients were included in Sclerocap (327 females, 60 males) and 3096 fingers were examined by capillaroscopy at inclusion: 316 fingers (10%) belonging to 113 patients had a history of DU. Late Cutolo's stage was statistically correlated with a history of DU, both by univariate: OR 2.08 [1.09-3.96] and multivariate analysis: OR 1.97 [1.06-3.63]. Among the elemental abnormalities, only edema and decreased capillary density were correlated with a history of DU by multivariate analysis: respectively OR 1.92 [1.17-3.16] and 0.65 [0.49-0.85]. CONCLUSION: This cross-sectional study in a large cohort of patients with systemic sclerosis shows a correlation between a history of digital ulcer and edema, a decrease in capillary density and the late stage in Cutolo's classification. The extent of capillary abnormalities on one finger is associated with a history of local digital ulcer. Capillaroscopy might be used to predict the risk of DU but these results need first to be confirmed by prospective studies.

Triaging acute pulmonary embolism for home treatment by Hestia or simplified PESI criteria: the HOME-PE randomized trial.

AIMS: The aim of this study is to compare the Hestia rule vs. the simplified Pulmonary Embolism Severity Index (sPESI) for triaging patients with acute pulmonary embolism (PE) for home treatment. METHODS AND RESULTS: Normotensive patients with PE of 26 hospitals from France, Belgium, the Netherlands, and Switzerland were randomized to either triaging with Hestia or sPESI. They were designated for home treatment if the triaging tool was negative and if the physician-in-charge, taking into account the patient's opinion, did not consider that hospitalization was required. The main outcomes were the 30-day composite of recurrent venous thrombo-embolism, major bleeding or all-cause death (non-inferiority analysis with 2.5% absolute risk difference as margin), and the rate of patients discharged home within 24 h after randomization (NCT02811237). From January 2017 through July 2019, 1975 patients were included. In the per-protocol population, the primary outcome occurred in 3.82% (34/891) in the Hestia arm and 3.57% (32/896) in the sPESI arm (P = 0.004 for non-inferiority). In the intention-to-treat population, 38.4% of the Hestia patients (378/984) were treated at home vs. 36.6% (361/986) of the sPESI patients (P = 0.41 for superiority), with a 30-day composite outcome rate of 1.33% (5/375) and 1.11% (4/359), respectively. No recurrent or fatal PE occurred in either home treatment arm. CONCLUSIONS: For triaging PE patients, the strategy based on the Hestia rule and the strategy based on sPESI had similar safety and effectiveness. With either tool complemented by the overruling of the physician-in-charge, more than a third of patients were treated at home with a low incidence of complications.

Wounds in chronic leg oedema.

Wounds and chronic oedema are common disorders, but rarely studied together. The objective of this cross-sectional study was to investigate the point-prevalence and risk factors of wounds on the leg, in chronic leg oedema. Forty sites in nine countries were included. Of 7077 patients with chronic leg oedema, 12.70% had wounds. Independent risk factors were: peripheral arterial disease (odds ratio (OR) 4.87, 95% confidence intervals (CI) 3.63-6.52), cellulitis within the past 12 months (OR 2.69, 95% CI 2.25-3.21), secondary lymphoedema (OR 2.64, 95% CI 1.93-3.60), being male (OR 2.08, 95% CI 1.78-2.44), being over 85 years of age (OR 1.80, 95% CI 1.23-2.62), underweight (OR 1.79, 95% CI 1.14-2.79), bed bound (OR 1.79, 95% CI 1.01-3.16), chair bound (OR 1.52, 95% CI 1.18-1.97), diabetes (OR 1.47, 95% CI 1.23-1.77), and walking with aid (OR 1·41, 95% CI 1.17-1.69). 43.22% of those with wounds had clinically defined well-controlled oedema, associated with a significantly lower risk of wounds (OR 0.50, 95% CI 0.42-0.58, P < .001). Hard/fibrotic tissue (OR 1.71, 95% CI 1.19-2.48), and a positive Stemmers sign (OR 1.57, 95% CI 1.05-2.35) were associated with wounds. The study reinforces the importance of measures to control oedema, as controlled swelling was associated with a 50% lower risk of wounds.

Severe adverse events during sirolimus "off-label" therapy for vascular anomalies.

OBJECTIVES: Clinical studies have shown low toxicity and a favorable safety profile for sirolimus in vascular anomalies. Here, we describe severe adverse events (SAEs) observed during "off-label use" for vascular anomalies. METHODS: We performed a retrospective, multicenter chart review for SAEs during "off-label" sirolimus therapy for vascular anomalies and analyzed these cases by a predesigned workflow. RESULTS: We identified 17 SAEs in 14 patients diagnosed with generalized lymphatic anomaly (n = 4), Gorham-Stout disease (n = 2), central conducting lymphatic anomaly (n = 1), lymphatic malformation (n = 4), tufted angioma (n = 1), kaposiform hemangioendothelioma (n = 1), and venous malformation in a patient with CLOVES syndrome (n = 1). Three patients presented two SAEs each. The age at initiation of sirolimus therapy was under 2 years (n = 5), 2-6 years (n = 5), and older than 12 years (n = 4). SAEs occurred during the first 3 months of sirolimus therapy (n = 7), between 3 and 12 months (n = 7) and after 1 year of therapy (n = 3). The most frequent SAE was viral pneumonia (n = 8) resulting in one death due to a metapneumovirus infection in a 3 months old and a generalized adenovirus infection in a 28-month-old child. Sirolimus blood level at the time of SAEs ranged between 2.7 and 21 ng/L. Five patients were on antibiotic prophylaxis. CONCLUSIONS: Most SAEs are observed in the first year of sirolimus therapy; however, SAEs can also occur after a longer treatment period. SAEs are potentially life threatening, especially in early infancy. Presence of other risk factors, that is, underlying vascular anomaly or immune status, may contribute to the risk of SAEs. Sirolimus is an important therapeutic option for vascular anomalies, but patients and physicians need to be aware that adequate monitoring is necessary, especially in patients with complex lymphatic anomalies that are overrepresented in our cohort of SAEs.

Post-thrombotic syndrome.

Post-thrombotic syndrome (PTS) is a chronic venous insufficiency manifestation following an episode of deep-vein thrombosis (DVT). It is an important and frequent long-term adverse event of proximal DVT affecting 20-50% of patients. This position paper integrates data guiding clinicians in deciding PTS diagnosis, treatment and follow-up.

Correlation between capillaroscopic classifications and severity in systemic sclerosis: results from SCLEROCAP study at inclusion.

OBJECTIVES: We assessed the correlation between severity of systemic sclerosis (SSc) and current staging systems based on nailfold capillaroscopy. METHODS: SCLEROCAP is a multicenter prospective study including consecutive scleroderma patients who have a yearly routine follow-up with capillaroscopy and digital blood pressure measurement. Capillaroscopy images were read by two observers blinded from each other, then by a third one in the case of discordance. A follow-up of 3 years is planned. The present study assessed the correlation between severity of systemic sclerosis (SSc) and current staging systems based on nail fold capillaroscopy at enrollment in the SCLEROCAP study. Univariate and multivariate logistic regression analysis was performed for both the Maricq and Cutolo classifications. RESULTS: SCLEROCAP included 387 patients in one year. Maricq's active and Cutolo's late classifications were very similar. In multivariate analysis, the number of digital ulcers (OR for 2 ulcers or more, respectively 2.023 [1.074-3.81] and 2.596 [1.434-4.699]) and Rodnan's skin score >15 (OR respectively 32.007 [6.457-158.658] and 18.390 [5.380-62.865]) correlated with Maricq's active and Cutolo's late stages. Haemoglobin rate correlated with Cutolo's late stage (hemoglobin<100 vs. >120 g/dl: OR 0.223 [0.051-0.980]), and total lung capacity with Maricq's active one: increase in 10%: OR0.833 [0.717-0.969]. CONCLUSIONS: The correlations found between capillaroscopy and severity of SSc are promising before the ongoing prospective study definitively assesses whether capillaroscopy staging predicts complications of SSc. Only two capillaroscopic patterns seem useful: one involving many giant capillaries and haemorrhages and the other with severe capillary loss.

Communication with patients using negative wound pressure therapy and their adherence to treatment.

OBJECTIVE: The purpose of this study was to explore the challenges of communication between patients and health professionals, and patient adherence to treatment for hard-to-heal wounds when using negative wound pressure therapy (NPWT). METHODS: Face-to-face, semi-structured interviews were conducted with patients undergoing NPWT. Specific features of the NPWT device were the priority for discussion although other factors central to communication and adherence were also explored. RESULTS: A total of 24 patients took part in the study. Data saturation was achieved during the analysis. Patients required ongoing support to understand complex and often protracted treatment and this was particularly important when specialist technology was used. A distinction was highlighted between those who decided not to adhere with therapy and those who did so unintentionally. Participants faced difficulties in their communications with health professionals and in ensuring their needs were listened to and addressed. CONCLUSION: Further research is needed to achieve a better understanding of this distinction and to evaluate interventions which can sustain adherence behaviours. Further exploration of how to establish concordant patient/health professional communications is warranted.

Urgent need to clarify the definition of chronic critical limb ischemia - a position paper from the European Society for Vascular Medicine.

Chronic critical lower limb ischemia (CLI) has been defined as ischemia that endangers the leg. An attempt was made to give a precise definition of CLI, based on clinical and hemodynamic data (Second European Consensus). CLI may be easily defined from a clinical point of view as rest pain of the distal foot or gangrene or ulceration. It is probably useful to add leg ulcers of other origin which do not heal because of severe ischemia, and to consider the impact of frailty on adverse outcome. From a hemodynamic viewpoint there is no consensus and most of the existing classifications are not based upon evidence. We should thus propose a definition and then validate it in a prospective cohort in order to define the patients at major risk of amputation, and also to define the categories of patients whose prognosis is improved by revascularisation. From today's available data, it seems clear that the patients with a systolic toe pressure (STP) below 30 mmHg must be revascularised whenever possible. However other patients with clinically suspected CLI and STP above 30 mmHg must be evaluated and treated in specialised vascular units and revascularisation has to be discussed on a case by case basis, taking into account other data such as the WiFi classification for ulcers.In conclusion, many useful but at times contradictory definitions of CLI have been suggested. Only a few have taken into account evidence, and none have been validated prospectively. This paper aims to address this and to give notice that a CLI registry within Europe will be set up to prospectively validate, or not, the previous and suggested definitions of CLI.

Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling.

BACKGROUND: Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. METHODS: We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro. RESULTS: We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in EPHB4 in 5 families that cosegregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. CONCLUSIONS: We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1-related CM-AVM1 and also hereditary hemorrhagic telangiectasia. RASA1-encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.

Imbalance of the Vanin-1 Pathway in Systemic Sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and visceral organs and vascular alterations. SSc pathophysiology involves systemic inflammation and oxidative stress. Because the vanin-1 gene (vnn1) encodes an enzyme with pantetheinase activity that converts vasculoprotective pantethine into profibrotic pantothenic acid and pro-oxidant cystamine, we tested this pathway in the pathophysiology of SSc. Activation of the vanin-1/pantetheinase pathway was investigated in wild-type BALB/c mice with hypochlorous acid (HOCl)-induced SSc by ELISA and Western blotting. We then evaluated the effects of the inactivation of vnn1 on the development of fibrosis, endothelial alterations, and immunological activation in mice with HOCl- and bleomycin-induced SSc. We then explored the vanin-1/pantetheinase pathway in a cohort of patients with SSc and in controls. In wild-type mice with HOCl-induced SSc, the vanin-1/pantetheinase pathway was dysregulated, with elevation of vanin-1 activity in skin and high levels of serum pantothenic acid. Inactivation of the vnn1 gene in vnn1-/- mice with HOCl-induced SSc prevented the development of characteristic features of the disease, including fibrosis, immunologic abnormalities, and endothelial dysfunction. Remarkably, patients with diffuse SSc also had increased expression of vanin-1 in skin and blood and elevated levels of serum pantothenic acid that correlated with the severity of the disease. Our data demonstrate that vanin-1/pantetheinase controls fibrosis, vasculopathy, autoimmunity, and oxidative stress in SSc. The levels of vanin-1 expression and pantothenic acid determine SSc severity and can be used as markers of disease severity. More importantly, inhibition of vanin-1 can open new therapeutic approaches in SSc.

Reproducibility of capillaroscopic classifications of systemic sclerosis: results from the SCLEROCAP study.

Objectives: Subgroups of capillaroscopic scleroderma landscape have been correlated with stages of SSc: two groups for Maricq's classification (slow and active), and three for Cutolo's classification (early, active and late). We report inter- and intra-observer agreement for these classifications as a preliminary step in the multicentre prospective SCLEROCAP study, which aims to assess the classification and single capillaroscopic items as prognostic tools for SSc. Methods: SCLEROCAP included 385 patients. Agreement was studied in the first 100 patients, who were independently rated twice by two observers, blind to patients' characteristics; 30 of the patients were rated once by six observers. After consensus meetings, these ratings were held again. Kappa and intraclass correlation coefficients were used to assess agreement. Results: Interobserver agreement on 100 patients was moderate for Maricq and Cutolo classifications [κ 0.47 (0.28, 0.66) and 0.49 (0.33, 0.65), respectively], and became substantial after consensus meetings [0.64 (0.50, 0.77) and 0.69 (0.56, 0.81)]. Intra-observer agreement between two observers was moderate to substantial: κ 0.54 (0.33, 0.75) and 0.70 (0.57, 0.83) for Maricq's classification; 0.57 (0.38, 0.77) and 0.76 (0.65, 0.87) for Cutolo's. Thirty patients were rated once by each of six observers, and agreement was moderate to substantial: κ 0.57 ± 0.10 (Maricq) and 0.61 ± 0.12 (Cutolo). Agreement was substantial for bushy, giant capillaries and microhaemorrhages, moderate for capillary density and low for oedema, disorganization and avascular areas. Conclusion: The moderate reproducibility of Maricq and Cutolo classifications might hamper their prognostic value in SSc patients. Consensus meetings improve reliability, a prerequisite for better prognostic performances. A focus on giant capillaries, haemorrhages and capillary density might be more reliable.

Obstetric antiphospholipid syndrome: early variations of angiogenic factors are associated with adverse outcomes.

The prognostic value of angiogenic factors in newly pregnant women with obstetric antiphospholipid syndrome (oAPS) has not been documented. We observed 513 oAPS who experienced three consecutive spontaneous abortions before the 10th week of gestation or one fetal loss at or beyond the 10th week. We assessed the plasma concentrations of the proangiogenic factor placenta growth factor (PIGF) and of the antiangiogenic factor soluble fms-like tyrosine kinase-1 on the eve and on the 4th day of the low-molecular weight heparin-low-dose aspirin treatment. Placenta growth factor and fms-like tyrosine kinase-1 plasma concentrations showed marked increases. Treatment-associated variations of PIGF and of soluble fms-like tyrosine kinase-1 were antagonist risk factors for placenta-mediated complications (PMC) and for severe PMC, for fetal death, stillbirth and neonatal death. The ratio between PIGF increase and soluble fms-like tyrosine kinase-1 was a summary variable whose best cut-off values (1.944.10-2) had high negative predictive values for PMC (0.918) and may be used to help rule out the development of PMC in evolutive pregnancies after 19 completed weeks. The early variations of PIGF and soluble fms-like tyrosine kinase-1 concentrations in newly pregnant oAPS may help to detect patients at low risk of PMC. (clinicaltrials.gov identifier: 02855047).

Prevalence, Clinical Characteristics, and Risk Factors for Non-recording of Alcohol Use in Hospitals across Europe: The ALCHIMIE Study.

AIM: To determine the detection rates, clinical features, and risk factors for lack of registration of alcohol use in medical patients admitted in European hospitals. METHODS: A point-prevalence, cross-sectional, multicenter survey involving 2100 medical inpatients from 43 hospitals from 8 European countries. Patients were screened for current alcohol use, using standardized questionnaires. Alcohol use recording in medical records was assessed. RESULTS: Of the 2100, more than a half reported alcohol use. Significant differences were shown in the prevalence of drinking and the recording rates of alcohol use among the hospitals and countries involved. Overall, 346 patients (16%) fulfilled criteria for alcohol use disorder. Alcohol use was registered in 909 (43%) of medical records, with quantification in 143 (7%). Multivariate analysis showed that women (OR 1.49), older age patients (OR 1.23), patients from the Northern European countries (OR 4.79) and from hospitals with high local alcohol prevalence (OR 1.59) were more likely to have lack of alcohol use registration in their medical files. CONCLUSIONS: A considerable proportion of medical patients admitted in European hospitals fulfill criteria for alcohol use disorders. These patients are frequently overlooked during hospitalization and not appropriately registered in medical records. Women, older patients, and inpatients from European areas with high local alcohol use prevalence are at higher risk associated with a non-recording of alcohol use.

Clinical relevance of symptomatic superficial-vein thrombosis extension: lessons from the CALISTO study.

The clinical relevance of symptomatic extension of spontaneous, acute, symptomatic, lower-limb superficial-vein thrombosis (SVT) is debated. We performed a post hoc analysis of a double-blind trial comparing fondaparinux with placebo. The main study outcome was SVT extension by day 77, whether to ≤ 3 cm or > 3 cm from the sapheno-femoral junction (SFJ). All events were objectively confirmed and validated by an adjudication committee. With placebo (n = 1500), symptomatic SVT extension to ≤ 3 cm or > 3 cm from the SFJ occurred in 54 (3.6%) and 56 (3.7%) patients, respectively, inducing comparable medical resource consumption (eg, anticoagulant drugs and SFJ ligation); subsequent deep-vein thrombosis or pulmonary embolism occurred in 9.3% (5/54) and 8.9% (5/56) of patients, respectively. Fondaparinux was associated with lower incidences of SVT extension to ≤ 3 cm (0.3%; 5/1502; P < .001) and > 3 cm (0.8%; 12/1502; P < .001) from the SFJ and reduced related use of medical resources; no subsequent deep-vein thrombosis or pulmonary embolism was observed in fondaparinux patients. Thus, symptomatic extensions are common SVT complications and, whether or not reaching the SFJ, are associated with a significant risk of venous thromboembolic complications and medical resource consumption, all reduced by fondaparinux.

Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial.

IMPORTANCE: Although retrievable inferior vena cava filters are frequently used in addition to anticoagulation in patients with acute venous thromboembolism, their benefit-risk ratio is unclear. OBJECTIVE: To evaluate the efficacy and safety of retrievable vena cava filters plus anticoagulation vs anticoagulation alone for preventing pulmonary embolism recurrence in patients presenting with acute pulmonary embolism and a high risk of recurrence. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, blinded end point trial (PREPIC2) with 6-month follow-up conducted from August 2006 to January 2013. Hospitalized patients with acute, symptomatic pulmonary embolism associated with lower-limb vein thrombosis and at least 1 criterion for severity were assigned to retrievable inferior vena cava filter implantation plus anticoagulation (filter group; n = 200) or anticoagulation alone with no filter implantation (control group; n = 199). Initial hospitalization with ambulatory follow-up occurred in 17 French centers. INTERVENTIONS: Full-dose anticoagulation for at least 6 months in all patients. Insertion of a retrievable inferior vena cava filter in patients randomized to the filter group. Filter retrieval was planned at 3 months from placement. MAIN OUTCOMES AND MEASURES: Primary efficacy outcome was symptomatic recurrent pulmonary embolism at 3 months. Secondary outcomes were recurrent pulmonary embolism at 6 months, symptomatic deep vein thrombosis, major bleeding, death at 3 and 6 months, and filter complications. RESULTS: In the filter group, the filter was successfully inserted in 193 patients and was retrieved as planned in 153 of the 164 patients in whom retrieval was attempted. By 3 months, recurrent pulmonary embolism had occurred in 6 patients (3.0%; all fatal) in the filter group and in 3 patients (1.5%; 2 fatal) in the control group (relative risk with filter, 2.00 [95% CI, 0.51-7.89]; P = .50). Results were similar at 6 months. No difference was observed between the 2 groups regarding the other outcomes. Filter thrombosis occurred in 3 patients. CONCLUSIONS AND RELEVANCE: Among hospitalized patients with severe acute pulmonary embolism, the use of a retrievable inferior vena cava filter plus anticoagulation compared with anticoagulation alone did not reduce the risk of symptomatic recurrent pulmonary embolism at 3 months. These findings do not support the use of this type of filter in patients who can be treated with anticoagulation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00457158.