Nationwide Audit of Postoperative Mortality and Complications After Digestive Cancer Surgery: Will New Legal Thresholds be Sufficient?

BACKGROUND: French policymakers recently chose to regulate high-risk digestive cancer surgery (DCS). A minimum of five cases per year should be performed for each of the following types of curative cancer surgery: esophagus/esogastric junction (ECS), stomach (GCS), liver (LCS, metastasis included), pancreas (PCS), and rectum (RCS). This study aimed to evaluate the hypothetical beneficial effects of the new legal minimal volume thresholds on the rates of 90-day postoperative mortality (90POM) for each high-risk DCS. METHODS: This nationwide observational population-based cohort study used data extracted from the French National Health Insurance Database from 1 January 2015-31 December 2017. Mixed-effects logistic regression models were performed to estimate the independent effect of hospital volume. RESULTS: During the study period, 61,169 patients (57.1 % male, age 69.7 ±12.2 years) underwent high-risk DCS including ECS (n = 4060), GCS (n = 5572), PCS (n = 8598), LCS (n = 10,988), and RCS (n = 31,951), with 90POM of 6.6 %, 6.9 %, 6.0 %, 5.2 %, and 2.9 %, respectively. For hospitals fulfilling the new criteria, 90POM was lower after adjustment only for LCS (odds ratio [OR],15.2; 95 % confidence interval [CI], 9.5-23.2) vs OR, 7.6; 95 % CI, 5.2-11.0; p < 0.0001) and PCS (OR, 3.6; 95 % CI, 1.7-7.6 vs OR, 2.1; 95 % CI, 1.0-4.4; p<0.0001). With higher thresholds, all DCSs showed a lower adjusted risk of 90POM (e.g., OR, 0.38; 95 % CI, 0.28-0.51) for PCS of 40 or higher. CONCLUSION: Based on retrospective data, thresholds higher than those promulgated would better improve the safety of high-risk DCS. New policies aiming to further centralize high-risk DCS should be considered, associated with a clear clinical pathway of care for patients to improve accessibility to complex health care in France.

A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant.

Rare variants outside the classical coagulation cascade might cause inherited thrombosis. We aimed to identify the variant(s) causing venous thromboembolism (VTE) in a family with multiple relatives affected with unprovoked VTE and no thrombophilia defects. We identified by whole exome sequencing an extremely rare Arg to Gln variant (Arg89Gln) in the Microtubule Associated Serine/Threonine Kinase 2 (MAST2) gene that segregates with VTE in the family. Free-tissue factor pathway inhibitor (f-TFPI) plasma levels were significantly decreased in affected family members compared to healthy relatives. Conversely, plasminogen activator inhibitor-1 (PAI-1) levels were significantly higher in affected members than in healthy relatives. RNA sequencing analysis of RNA interference experimental data conducted in endothelial cells revealed that, of the 13,387 detected expressed genes, 2,354 have their level of expression modified by MAST2 knockdown, including SERPINE1 coding for PAI-1 and TFPI. In HEK293 cells overexpressing the MAST2 Gln89 variant, TFPI and SERPINE1 promoter activities were respectively lower and higher than in cells overexpressing the MAST2 wild type. This study identifies a novel thrombophilia-causing Arg89Gln variant in the MAST2 gene that is here proposed as a new molecular player in the etiology of VTE by interfering with hemostatic balance of endothelial cells.

Pulmonary Embolism and Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a frequent and devastating chronic respiratory disease. COPD is ranked among the top five causes of death worldwide. Patients with COPD suffer from persistent dyspnea, with periods of acute worsening, called exacerbations. Such exacerbations may be severe. In fact, one-third of COPD patients will be hospitalized because of an exacerbation. Hospitalization due to respiratory failure has been identified as a powerful predisposing risk factor for venous thromboembolism (VTE) for many years. Therefore, COPD is recognized as a moderate risk factor for VTE, with an odds ratio between 2 and 9, similar to other risk factors such as estrogen-containing contraceptives or (any) cancer. However, unlike other risk factors such as contraception, the presence of COPD can modify the initial presentation of VTE and worsen the short-term prognosis of patients who have acute pulmonary embolism (PE), particularly during a COPD exacerbation. It is not only that both stable COPD and acute exacerbations of COPD might increase the risk of VTE, but PE itself may mimic the symptoms of a COPD exacerbation. Hence, some authors have evaluated the prevalence of PE among COPD patients with acute worsening. This clinical review (1) gives an update on epidemiological data, clinical presentation, and prognosis of PE associated with COPD; (2) presents the results of the Prevalence de l'Embolie Pulmonaire chez les patients admis pour exacerbation de BPCO study, which aimed at determining the frequency of PE in COPD patients hospitalized for an acute exacerbation; (3) discusses the results of the Significance of Pulmonary Embolism in COPD Exacerbations study, the first randomized trial having compared the efficacy of a systematic search for PE versus routine care on admission for a COPD exacerbation; and (4) provides a selection of remaining unmet needs on the association between COPD and PE.

Predictors of Recurrent Venous Thromboembolism or Arterial Thrombotic Events during and after Anticoagulation for a First Venous Thromboembolism.

After first episodes of venous thromboembolism (VTE), patients are at increased risk of recurrent VTE and arterial thrombotic events (ATE) compared with the general population, two disorders that are influenced by anticoagulation. However, risk factors of these conditions occurring during and after anticoagulation are little described. Using cause-specific hazard regression models, we aimed to determine risk factors of the composite outcome recurrent VTE/ATE, and separately recurrent VTE or ATE, during and after anticoagulation in patients with first episodes of VTE from a prospective cohort. Hazard ratios (HRs) are given with 95% confidence intervals (CIs). A total of 2,011 patients treated for at least 3 months were included. A total of 647 patients had recurrent VTE/ATE (incidence: 4.69% per patient-years) during overall follow-up (median: 92 months). Of these events, 173 occurred during anticoagulation (incidence: 3.67% per patient-years). Among patients free of events at the end of anticoagulation, 801 had a post-anticoagulation follow-up ≥3 months; and 95 had recurrent VTE/ATE (incidence: 1.27% per patient-years). After adjustment for confounders, cancer-associated VTE (HR: 2.64, 95% CI: 1.70-4.11) and unprovoked VTE (HR: 1.95, 95% CI: 1.35-2.81) were the identified risk factors of recurrent VTE/ATE during anticoagulation (vs. transient risk factor-related VTE). Risk factors of recurrent VTE/ATE after anticoagulation included 50 to 65 years of age (vs. < 50, HR: 1.99, 95% CI: 1.04-3.81), older than 65 years (vs. < 50, HR: 5.28, 95% CI: 3.03-9.21), and unprovoked VTE (vs. transient risk factor-related VTE, HR: 2.06, 95% CI: 1.27-3.34). Cancer-associated VTE and unprovoked VTE are the main risk factors of recurrent VTE/ATE during anticoagulation, while older age and unprovoked VTE mainly predict the risk of these events after anticoagulation.

Risk for Recurrent Venous Thromboembolism in Patients With Subsegmental Pulmonary Embolism Managed Without Anticoagulation : A Multicenter Prospective Cohort Study.

BACKGROUND: The incidence of pulmonary embolism has been increasing, but its case-fatality rate is decreasing, suggesting a lesser severity of illness. The clinical importance of patients with pulmonary embolism isolated to the subsegmental vessels is unknown. OBJECTIVE: To determine the rate of recurrent venous thromboembolism in patients with subsegmental pulmonary embolism managed without anticoagulation. DESIGN: Multicenter prospective cohort study. (ClinicalTrials.gov: NCT01455818). SETTING: Eighteen sites between February 2011 and February 2021. PATIENTS: Patients with isolated subsegmental pulmonary embolism. INTERVENTION: At diagnosis, patients underwent bilateral lower-extremity venous ultrasonography, which was repeated 1 week later if results were negative. Patients without deep venous thrombosis did not receive anticoagulant therapy. MEASUREMENTS: The primary outcome was recurrent venous thromboembolism during the 90-day follow-up period. RESULTS: Recruitment was stopped prematurely because the predefined stopping rule was met after 292 of a projected 300 patients were enrolled. Of the 266 patients included in the primary analysis, the primary outcome occurred in 8 patients, for a cumulative incidence of 3.1% (95% CI, 1.6% to 6.1%) over the 90-day follow-up. The incidence of recurrent venous thromboembolism was 2.1% (CI, 0.8% to 5.5%) and 5.7% (CI, 2.2% to 14.4%) over the 90-day follow-up in patients with single and multiple isolated subsegmental pulmonary embolism, respectively. No patients had a fatal recurrent pulmonary embolism. LIMITATION: The study was restricted to patients with low-risk subsegmental pulmonary embolism. CONCLUSION: Overall, patients with subsegmental pulmonary embolism who did not have proximal deep venous thrombosis had a higher-than-expected rate of recurrent venous thromboembolism. PRIMARY FUNDING SOURCE: Heart and Stroke Foundation of Canada and French Ministry of Health Programme Hospitalier de Recherche Clinique.

Pregnancy-Adapted YEARS Algorithm for Diagnosis of Suspected Pulmonary Embolism.

BACKGROUND: Pulmonary embolism is one of the leading causes of maternal death in the Western world. Because of the low specificity and sensitivity of the d-dimer test, all pregnant women with suspected pulmonary embolism undergo computed tomographic (CT) pulmonary angiography or ventilation-perfusion scanning, both of which involve radiation exposure to the mother and fetus. Whether a pregnancy-adapted algorithm could be used to safely avoid diagnostic imaging in pregnant women with suspected pulmonary embolism is unknown. METHODS: In a prospective study involving pregnant women with suspected pulmonary embolism, we assessed three criteria from the YEARS algorithm (clinical signs of deep-vein thrombosis, hemoptysis, and pulmonary embolism as the most likely diagnosis) and measured the d-dimer level. Pulmonary embolism was ruled out if none of the three criteria were met and the d-dimer level was less than 1000 ng per milliliter or if one or more of the three criteria were met and the d-dimer level was less than 500 ng per milliliter. Adaptation of the YEARS algorithm for pregnant women involved compression ultrasonography for women with symptoms of deep-vein thrombosis; if the results were positive (i.e., a clot was present), CT pulmonary angiography was not performed. All patients in whom pulmonary embolism had not been ruled out underwent CT pulmonary angiography. The primary outcome was the incidence of venous thromboembolism at 3 months. The secondary outcome was the proportion of patients in whom CT pulmonary angiography was not indicated to safely rule out pulmonary embolism. RESULTS: A total of 510 women were screened, of whom 12 (2.4%) were excluded. Pulmonary embolism was diagnosed in 20 patients (4.0%) at baseline. During follow-up, popliteal deep-vein thrombosis was diagnosed in 1 patient (0.21%; 95% confidence interval [CI], 0.04 to 1.2); no patient had pulmonary embolism. CT pulmonary angiography was not indicated, and thus was avoided, in 195 patients (39%; 95% CI, 35 to 44). The efficiency of the algorithm was highest during the first trimester of pregnancy and lowest during the third trimester; CT pulmonary angiography was avoided in 65% of patients who began the study in the first trimester and in 32% who began the study in the third trimester. CONCLUSIONS: Pulmonary embolism was safely ruled out by the pregnancy-adapted YEARS diagnostic algorithm across all trimesters of pregnancy. CT pulmonary angiography was avoided in 32 to 65% of patients. (Funded by Leiden University Medical Center and 17 other participating hospitals; Artemis Netherlands Trial Register number, NL5726.).

Risk stratification for predicting recurrent venous thromboembolism after discontinuation of anticoagulation: a post hoc analysis of a French prospective multicentre study.

BACKGROUND: We aimed to validate and to refine current recurrent venous thromboembolism (VTE) risk classification. METHODS: We performed a post hoc analysis of a multicentre cohort including 1881 patients with a first symptomatic VTE prospectively followed after anticoagulation discontinuation. The primary objective was to validate the International Society of Thrombosis and Haemostasis (ISTH) risk classification in predicting recurrence risk. The secondary objective was to evaluate a refined ISTH classification based on the recurrence risk estimate for each individual risk factor. RESULTS: During a 4.8-year median follow-up after anticoagulation discontinuation, symptomatic recurrent VTE occurred in 230 patients (12.2%). Based on the ISTH classification, patients with unprovoked VTE or VTE with minor or major persistent risk factors had a 2-fold increased recurrence risk compared with those with VTE and major transient risk factors. Recurrence risk was not increased in patients with minor transient factors (hazard ratio (HR) 1.31, 95% CI 0.84-2.06). Individual risk factors analysis identified hormone-related VTE (pregnancy: HR 0.26, 95% CI 0.08-0.82; oestrogens: HR 0.25, 95% CI 0.14-0.47) and amyotrophic lateral sclerosis (HR 5.84, 95% CI 1.82-18.70). After reclassification of these factors as major transient for the former and major persistent for the latter, the modified ISTH classification allowed us to accurately discriminate between patients at low risk of recurrence (i.e. with major transient risk factors) and those at high risk of recurrence (i.e. without major transient risk factors). CONCLUSIONS: Among patients who stopped anticoagulation after a first VTE, a refined ISTH classification based on recurrence risk intensity of individual factors allowed discrimination between patients at low recurrence risk, including hormonal exposure in women, and patients at high recurrence risk.

Nebulised liposomal amphotericin-B as maintenance therapy in allergic bronchopulmonary aspergillosis: a randomised, multicentre trial.

BACKGROUND: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission. METHODS: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time to first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters. RESULTS: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) out of 65 patients in the nebulised liposomal amphotericin-B group and 38 (51.3%) out of 74 in the placebo group (absolute difference -0.6%, 95% CI -16.8- +15.6%; OR 0.98, 95% CI 0.50-1.90; p=0.95). The median (interquartile range) time to first severe clinical exacerbation was longer in the liposomal amphotericin-B group: 337 days (168-476 days) versus 177 days (64-288 days). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in the nebulised liposomal amphotericin-B group. CONCLUSIONS: In ABPA, maintenance therapy using nebulised liposomal amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research.

Cardiovascular Mortality after Venous Thromboembolism: A Meta-Analysis of Prospective Cohort Studies.

Many studies from current literature show that cardiovascular diseases in patients with venous thromboembolism (VTE) are more frequent than in the general population without VTE. However, data summarizing the impact of cardiovascular diseases on mortality of patients with VTE are lacking. In this systematic review and meta-analysis, we aimed to determine the frequency and incidence rate of cardiovascular death in patients with VTE. MEDLINE and EMBASE were searched from January 1, 2000 to February 28, 2021. Eligible studies were observational prospective cohort studies including patients with VTE and reporting all causes of death. Cardiovascular death was defined as deaths that result from new or recurrent pulmonary embolism, death due to acute myocardial infarction, sudden cardiac death or heart failure, death due to stroke, death due to cardiovascular procedures or hemorrhage, death due to ruptured aortic aneurysm or aortic dissection and death due to other cardiovascular causes. Random-effect models meta-analysis served to determine all pooled effect size of interest with their 95% confidence interval (CI). Thirteen observational studies enrolling 22,251 patients were identified and included. The mean/median age varied between 49 and 75 years. The proportion of men ranged from 38.3 to 53.2%. The overall pooled frequency of cardiovascular death in patients with VTE was 3.9% (95% CI: 2.5-5.6%), while the overall pooled frequency of all-cause mortality was 12.0% (95% CI: 9.1-15.4%). The pooled proportion of cardiovascular death among all causes of deaths in patients with VTE was 35.2% (95% CI: 22.2-49.3%). The pooled incidence rate of cardiovascular death was 1.92 per 100 patient-years (95% CI: 0-4.1). The frequency of cardiovascular death in patients with VTE was significantly higher than in patients without VTE (risk ratio: 3.85, 95% CI: 2.75-5.39). Based on this updated meta-analysis from 13 prospective cohort studies, cardiovascular death in patients with VTE is more frequent than in the general population without VTE.

Risk Factors for Major Adverse Cardiovascular Events and Major Adverse Limb Events after Venous Thromboembolism: A Large Prospective Cohort Study.

BACKGROUND: There is an increased risk of arterial events including major adverse cardiovascular events (MACE) and major adverse limb events (MALE) after venous thromboembolism (VTE). However, their risk factors remain little explored. METHODS: We aimed to determine the risk factors for MACE (acute coronary syndrome/stroke/cardiovascular death) and MALE (limb ischemia/critical limb ischemia/non-traumatic amputation/any limb revascularization) after VTE. Competing risk models (Fine-Gray) were used in a multicenter prospective cohort of 4,940 patients (mean age: 64.6 years and median follow-up: 64 months). RESULTS: MACE occurred in 17.3% of participants (2.35% per patient-years) and MALE in 1.7% (0.27% per patient-years). In multivariable analysis, the identified risk factors for MACE were the age of 50 to 65 years (vs. <50 years, hazard ratio [HR]: 2.00, 95% confidence interval [CI]: 1.38-2.91), age >65 years (vs. <50 years, HR 4.85, 95% CI: 3.35-7.02), pulmonary embolism + deep vein thrombosis (DVT) (vs. isolated-DVT, HR: 1.25, 95% CI: 1.02-1.55), unprovoked-VTE (vs. transient risk factor associated-VTE, HR: 1.29, 95% CI: 1.04-1.59), current tobacco use (vs. never, HR: 1.45, 95% CI: 1.07-1.98), hypertension (HR: 1.61, 95% CI: 1.30-1.98), past history of symptomatic atherosclerosis (HR: 1.52, 95% CI: 1.17-1.98), heart failure (HR: 1.71, 95% CI: 1.21-2.42), atrial fibrillation (HR: 1.55, 95% CI: 1.15-2.08), and vena cava filter insertion (HR: 1.46, 95% CI: 1.03-2.08). The identified risk factors for MALE were the age of 50-65 years (vs. <50 years, HR: 3.49, 95% CI: 1.26-9.65) and atrial fibrillation (HR: 2.37, 95% CI: 1.15-4.89). CONCLUSIONS: Risk factors for MACE and MALE after VTE included some traditional cardiovascular risk factors, patient's comorbidities, and some characteristics of VTE.

Association between obstructive sleep apnea and venous thromboembolism recurrence: results from a French cohort.

BACKGROUND: Growing evidence suggests the relationship between obstructive sleep apnea (OSA) and venous thromboembolism (VTE). Few studies focused on VTE recurrence risk associated with OSA after anticoagulation cessation. METHODS: In a prospective cohort study, patients with documented VTE, were followed for an indefinite length of time and VTE recurrence were documented and adjudicated. The primary outcome was recurrent VTE after anticoagulation discontinuation. Secondary outcomes included all-cause mortality and the clinical presentation of VTE. Univariable and multivariable analyses were performed to identify risk factors for recurrence and mortality. RESULTS: Among the 2109 patients with documented VTE included, 74 patients had moderate to severe OSA diagnosis confirmed by home sleep test or polysomnography. During a median follow-up of 4.8 (interquartile range 2.5-8.0) years recurrent VTE occurred in 252 patients (9 with OSA and 243 without OSA). The recurrence risk in the univariable and multivariable analysis was not increased in patients with OSA, regardless of the time of diagnosis (before or after index VTE or pooled). VTE phenotype was significantly more often PE with or without associated deep vein thrombosis in the first event and recurrence for OSA patients compared to non-OSA patients. The risk of death was not increased in the OSA population compared to non-OSA patients in multivariable analysis. CONCLUSIONS: In patients with OSA and VTE, the risk of all-cause mortality and VTE recurrence after anticoagulation discontinuation was not increased compared to non-OSA patients.

Risk of recurrent venous thromboembolism and bleeding in patients with interstitial lung disease: a cohort study.

Interstitial lung disease (ILD) encompasses various parenchymal lung disorders, which has the potential to increase the risk of venous thromboembolism (VTE). To evaluate, in patients with ILD and VTE, the risk of recurrent VTE during follow-up after stopping anticoagulation. This was a cohort of patients with a first VTE recruited between 1997 and 2015. The primary outcome was adjudicated fatal or nonfatal recurrent VTE after stopping anticoagulation. Main secondary outcomes were major or clinically relevant non-major bleeding under anticoagulation. Among 4314 patients with VTE, 50 had ILD diagnosed before VTE. Of these, anticoagulation was stopped in 30 patients after a median duration of 180 days and continued indefinitely in 20 patients. During a median follow-up of 27.8 months after anticoagulation discontinuation, recurrent VTE occurred in 15 on 30 patients (annual incidence of 19.2 events per 100-person-years [95%CI 12.0-29.3], case-fatality rate of 6.7% [95%CI 1.21-29.8]). The risk of recurrence was threefold higher when VTE was unprovoked and case-fatality rate of recurrence was increased by 3 when VTE index was PE. During the anticoagulant period, (median duration of 8.6 months), 6 patients had a major or clinically relevant bleeding (annual incidence of 7.3 events per 100-person-years [95%CI 3.4-15.1], case-fatality rate of 16.7% [95%CI 3.0-56.4]). In patients with ILD, the risk of recurrent VTE after stopping anticoagulation and the risk of bleeding under anticoagulation were very high. Our results suggest that anticoagulation should not be prolonged beyond 3-6 months of anticoagulation in most of cases.

Effect of neuromuscular electrical stimulation on exercise capacity in patients with severe chronic obstructive pulmonary disease: A randomised controlled trial.

OBJECTIVE: To compare strengthening by neuromuscular electrical stimulation versus cycle ergometer training during a pulmonary rehabilitation program, in patients with severe to very severe chronic obstructive pulmonary disease. DESIGN: A prospective randomized controlled study. SETTING: Two inpatient pulmonary rehabilitation centers. SUBJECTS: Patients with severe to very severe chronic obstructive pulmonary disease and multidimensional index to predict risk of death ≥5, were randomly assigned to receive neuromuscular electrical stimulation or cycle ergometer training during pulmonary rehabilitation. MAIN MEASURES: The primary endpoint was the change in exercise capacity using 1-min sit-to-stand test Secondary endpoints were the changes in exercise capacity using 6-min walk test, quadriceps strength, quality of life and dyspnea. RESULTS: 102 patients were included. After 3 weeks, 47 patients in the neuromuscular electrical stimulation group, and 45 in the cycle ergometer training group were able to be analyzed. No significant difference was seen in the evolution of exercise capacity using 1-min sit-to-stand test (3.3 ± 3.8 and 2.6 ± 4.1) and 6-min walk test (37.8 ± 58.4 and 33.1 ± 46.7), in the evolution of quadriceps strength and endurance (9.2 ± 12.9 and 6.6 ± 16.1; 9.0 ± 13.2 and 6.2 ± 17.0), in the evolution of quality of life (St George's Respiratory Questionnaire: -11.3 ± 11.7 and -8.1 ± 11.6; COPD Assessment Test: -5.7 ± 7.1 and -4.7 ± 7.0), or in the evolution of dyspnea using Dyspnea 12 (-5.5 ± 10.2 and -5.9 ± 8.5) except using modified medical research council scale (95% confidence interval: 0.48 [0.05; 0.91], p = 0.027). CONCLUSION: We found no significant difference between the two programs on exercise capacity, quadriceps strength and quality of life.

Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Systematic Review and Meta-analysis.

BACKGROUND: The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE: To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION: Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

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.

The Extent of Aspergillosis in Critically Ill Patients With Severe Influenza Pneumonia: A Multicenter Cohort Study.

OBJECTIVES: To determine the frequency and prognosis of invasive pulmonary aspergillosis in critically ill patients with severe influenza pneumonia. DESIGN: Retrospective multicenter cohort study. SETTING: Five French ICUs. PATIENTS: Patients with influenza admitted to ICU between 2009 and 2018. MEASUREMENTS AND MAIN RESULTS: Of the 524 patients admitted for severe influenza diagnosed with a positive airway reverse-transcriptase polymerase chain reaction test, 450 (86%) required mechanical ventilation. A lower respiratory tract sample yielded with Aspergillus (Asp+) in 28 patients (5.3%). Ten patients (1.9%) were diagnosed with putative or proven invasive pulmonary aspergillosis, based on the validated AspICU algorithm. A multivariate model was built to identify independent risk factors for Aspergillus-positive pulmonary culture. Factors independently associated with Aspergillus-positive culture were liver cirrhosis (odds ratio = 6.7 [2.1-19.4]; p < 0.01), hematologic malignancy (odds ratio = 3.3 [1.2-8.5]; p = 0.02), Influenza A(H1N1)pdm09 subtype (odds ratio = 3.9 [1.6-9.1]; p < 0.01), and vasopressor requirement (odds ratio = 4.1 [1.6-12.7]; p < 0.01). In-hospital mortality of Asp+ patients was 36% versus 21% in patients without Aspergillus-positive pulmonary culture (p = 0.09). CONCLUSIONS: In this large retrospective multicenter cohort of critically ill patients, putative invasive pulmonary aspergillosis according to AspICU algorithm was a relatively rare complication of influenza. Patients at higher risk of Aspergillus pulmonary colonization included those with liver cirrhosis, hematologic malignancy, H1N1pdm09 influenza A virus, and requiring vasopressors. Our results provide additional data on the controversial association between severe influenza and invasive pulmonary aspergillosis. Reaching a consensual definition of invasive pulmonary aspergillosis becomes mandatory and confers further prospective research.

Whole exome sequencing, a hypothesis-free approach to investigate recurrent early miscarriage.

RESEARCH QUESTION: Are there genetic determinants shared by unrelated women with unexplained recurrent early miscarriage (REM)? DESIGN: Thirty REM cases and 30 controls were selected with extreme phenotype among women from Eastern Brittany (France), previously enrolled in an incident case-control study on thrombophilic mutations. Cases and controls were selected based on the number of early miscarriages or live births, respectively. Peripheral blood was collected for DNA extraction at initial visit. The burden of low-frequency variants in the coding part of the genes was compared using whole exome sequencing (WES). RESULTS: Cases had 3 to 17 early miscarriages (20 cases: ≥5 previous losses). Controls had 1 to 4 live births (20 controls: ≥3 previous live births) and no miscarriages. WES data were available for 29 cases and 30 controls. A total of 209,387 variants were found (mean variant per patient: 59,073.05) with no difference between groups (P = 0.68). The top five most significantly associated genes were ABCA4, NFAM1, TCN2, AL078585.1 and EPS15. Previous studies suggest the involvement of vitamin B12 deficiency in REM. TCN2 encodes for vitamin B12 transporter into cells. Therefore, holotranscobalamin (active vitamin B12) was measured for both cases and controls (81.2 ± 32.1 versus 92.9 ± 34.3 pmol/l, respectively, P = 0.186). Five cases but no controls were below 50 pmol/l (P = 0.052). CONCLUSIONS: This study highlights four new genes of interest in REM, some of which belong to known networks of genes involved in embryonic development (clathrin-mediated endocytosis and ciliary pathway). The study also confirms the involvement of TCN2 (vitamin B12 pathway) in the early first trimester of pregnancy.

Management of patients with pulmonary mycobacteriosis in France: a multicenter retrospective cohort study.

BACKGROUND: Recent studies report very low adherence of practitioners to ATS/IDSA recommendations for the treatment of nontuberculous mycobacteria pulmonary disease (NTM-PD), as well as a great variability of practices. Type of management could impact prognosis. METHODS: To evaluate management and prognosis of patients with NTM-PD cases with respect to ATS recommendations, we conducted a multicenter retrospective cohort study (18 sentinel sites distributed throughout France), over a period of six years. We collected clinical, radiological, microbiological characteristics, management and outcome of the patients (especially death or not). RESULTS: 477 patients with NTM-PD were included. Respiratory comorbidities were found in 68% of cases, tuberculosis sequelae in 31.4% of patients, and immunosuppression in 16.8% of cases. The three most common NTM species were Mycobacterium avium complex (60%), M. xenopi (20%) and M. kansasii (5.7%). Smear-positive was found in one third of NTM-PD. Nodulobronchiectatic forms were observed in 54.3% of cases, and cavitary forms in 19.1% of patients. Sixty-three percent of patients were treated, 72.4% of patients with smear-positive samples, and 57.5% of patients with smear-negative samples. Treatment was in adequacy with ATS guidelines in 73.5%. The 2-year mortality was 14.4%. In the Cox regression, treatment (HR = 0.51), age (HR = 1.02), and M. abscessus (3.19) appeared as the 3 significant independent prognostic factors. CONCLUSION: These findings highlight the adequacy between French practices and the ATS/IDSA guidelines. Treatment was associated with a better survival.

Prevalence of Pulmonary Embolism Among Patients With COPD Hospitalized With Acutely Worsening Respiratory Symptoms.

IMPORTANCE: The prevalence of pulmonary embolism in patients with chronic obstructive pulmonary disease (COPD) and acutely worsening respiratory symptoms remains uncertain. OBJECTIVE: To determine the prevalence of pulmonary embolism in patients with COPD admitted to the hospital for acutely worsening respiratory symptoms. DESIGN, SETTING, AND PARTICIPANTS: Multicenter cross-sectional study with prospective follow-up conducted in 7 French hospitals. A predefined pulmonary embolism diagnostic algorithm based on Geneva score, D-dimer levels, and spiral computed tomographic pulmonary angiography plus leg compression ultrasound was applied within 48 hours of admission; all patients had 3-month follow-up. Patients were recruited from January 2014 to May 2017 and the final date of follow-up was August 22, 2017. EXPOSURES: Acutely worsening respiratory symptoms in patients with COPD. MAIN OUTCOMES AND MEASURES: The primary outcome was pulmonary embolism diagnosed within 48 hours of admission. Key secondary outcome was pulmonary embolism during a 3-month follow-up among patients deemed not to have venous thromboembolism at admission and who did not receive anticoagulant treatment. Other outcomes were venous thromboembolism (pulmonary embolism and/or deep vein thrombosis) at admission and during follow-up, and 3-month mortality, whether venous thromboembolism was clinically suspected or not. RESULTS: Among 740 included patients (mean age, 68.2 years [SD, 10.9 years]; 274 women [37.0%]), pulmonary embolism was confirmed within 48 hours of admission in 44 patients (5.9%; 95% CI, 4.5%-7.9%). Among the 670 patients deemed not to have venous thromboembolism at admission and who did not receive anticoagulation, pulmonary embolism occurred in 5 patients (0.7%; 95% CI, 0.3%-1.7%) during follow-up, including 3 deaths related to pulmonary embolism. The overall 3-month mortality rate was 6.8% (50 of 740; 95% CI, 5.2%-8.8%). The proportion of patients who died during follow-up was higher among those with venous thromboembolism at admission than the proportion of those without it at admission (14 [25.9%] of 54 patients vs 36 [5.2%] of 686; risk difference, 20.7%, 95% CI, 10.7%-33.8%; P < .001). The prevalence of venous thromboembolism was 11.7% (95% CI, 8.6%-15.9%) among patients in whom pulmonary embolism was suspected (n = 299) and was 4.3% (95% CI, 2.8%-6.6%) among those in whom pulmonary embolism was not suspected (n = 441). CONCLUSIONS AND RELEVANCE: Among patients with chronic obstructive pulmonary disease admitted to the hospital with an acute worsening of respiratory symptoms, pulmonary embolism was detected in 5.9% of patients using a predefined diagnostic algorithm. Further research is needed to understand the possible role of systematic screening for pulmonary embolism in this patient population.

Effect of a Pulmonary Embolism Diagnostic Strategy on Clinical Outcomes in Patients Hospitalized for COPD Exacerbation: A Randomized Clinical Trial.

Importance: Active search for pulmonary embolism (PE) may improve outcomes in patients hospitalized for exacerbations of chronic obstructive pulmonary disease (COPD). Objective: To compare usual care plus an active strategy for diagnosing PE with usual care alone in patients hospitalized for COPD exacerbation. Design, Setting, and Participants: Randomized clinical trial conducted across 18 hospitals in Spain. A total of 746 patients were randomized from September 2014 to July 2020 (final follow-up was November 2020). Interventions: Usual care plus an active strategy for diagnosing PE (D-dimer testing and, if positive, computed tomography pulmonary angiogram) (n = 370) vs usual care (n = 367). Main Outcomes and Measures: The primary outcome was a composite of nonfatal symptomatic venous thromboembolism (VTE), readmission for COPD, or death within 90 days after randomization. There were 4 secondary outcomes, including nonfatal new or recurrent VTE, readmission for COPD, and death from any cause within 90 days. Adverse events were also collected. Results: Among the 746 patients who were randomized, 737 (98.8%) completed the trial (mean age, 70 years; 195 [26%] women). The primary outcome occurred in 110 patients (29.7%) in the intervention group and 107 patients (29.2%) in the control group (absolute risk difference, 0.5% [95% CI, -6.2% to 7.3%]; relative risk, 1.02 [95% CI, 0.82-1.28]; P = .86). Nonfatal new or recurrent VTE was not significantly different in the 2 groups (0.5% vs 2.5%; risk difference, -2.0% [95% CI, -4.3% to 0.1%]). By day 90, a total of 94 patients (25.4%) in the intervention group and 84 (22.9%) in the control group had been readmitted for exacerbation of COPD (risk difference, 2.5% [95% CI, -3.9% to 8.9%]). Death from any cause occurred in 23 patients (6.2%) in the intervention group and 29 (7.9%) in the control group (risk difference, -1.7% [95% CI, -5.7% to 2.3%]). Major bleeding occurred in 3 patients (0.8%) in the intervention group and 3 patients (0.8%) in the control group (risk difference, 0% [95% CI, -1.9% to 1.8%]; P = .99). Conclusions and Relevance: Among patients hospitalized for an exacerbation of COPD, the addition of an active strategy for the diagnosis of PE to usual care, compared with usual care alone, did not significantly improve a composite health outcome. The study may not have had adequate power to assess individual components of the composite outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT02238639.