Publications by authors named "Guy Meyer"

162 Publications

Rivaroxaban vs Dalteparin in Cancer-Associated Thromboembolism: A Randomized Trial.

Chest 2021 Oct 8. Epub 2021 Oct 8.

F-CRIN INNOVTE Network, Saint-Etienne, France; Service de Médecine Vasculaire et Thérapeutique, CHU Saint-Etienne, Hôpital Nord, Saint-Etienne, France.

Background: Direct oral anticoagulants (DOACs) are an alternative to low-molecular-weight heparin for treating cancer-associated VTE.

Research Question: Is rivaroxaban as efficient and safe as dalteparin to treat patients with cancer-associated VTE?

Study Design And Methods: In a randomized open-label noninferiority trial, patients with active cancer who had proximal DVT, pulmonary embolism (PE), or both were assigned randomly to therapeutic doses of rivaroxaban or dalteparin for 3 months. The primary outcome was the cumulative incidence of recurrent VTE, a composite of symptomatic or incidental DVT or PE, and worsening of pulmonary vascular or venous obstruction at 3 months.

Results: Of 158 randomized patients, 74 and 84 patients were assigned to receive rivaroxaban and dalteparin, respectively. Mean age was 69.4 years, and 115 patients (76.2%) had metastatic disease. The primary outcome occurred in 4 and 6 patients in the rivaroxaban and dalteparin groups, respectively (both the intention-to-treat and per-protocol populations: cumulative incidence, 6.4% vs 10.1%; subdistribution hazard ratio [SHR], 0.75; 95% CI, 0.21-2.66). Major bleeding occurred in 1 and 3 patients in the rivaroxaban and dalteparin groups, respectively (cumulative incidence, 1.4% vs 3.7%; SHR, 0.36; 95% CI, 0.04-3.43). Major or clinically relevant nonmajor bleeding occurred in 9 and 8 patients in the rivaroxaban and dalteparin groups, respectively (cumulative incidence, 12.2% vs 9.8%; SHR, 1.27; 95% CI, 0.49-3.26). Overall, 19 patients (25.7%) and 20 patients (23.8%) died in the rivaroxaban and dalteparin groups, respectively (hazard ratio, 1.05; 95% CI, 0.56-1.97).

Interpretation: In this trial comparing rivaroxaban and dalteparin in the treatment of cancer-associated VTE, the number of patients was insufficient to reach the predefined criteria for noninferiority, but efficacy and safety results were consistent with those previously reported with DOACs. An updated meta-analysis of randomized trials comparing DOACs with low-molecular-weight heparin in patients with cancer-associated VTE is provided.

Trial Registry: ClinicalTrials.gov; No.: NCT02746185; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2021.09.037DOI Listing
October 2021

Reduced-Dose Intravenous Thrombolysis for Acute Intermediate-High-risk Pulmonary Embolism: Rationale and Design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial.

Thromb Haemost 2021 Sep 24. Epub 2021 Sep 24.

AP-HP, hôpital européen Georges-Pompidou, Service de Pneumologie et de Soins Intensifs, APHP.Centre - Université de Paris, Paris, France.

Intermediate-high-risk pulmonary embolism (PE) is characterized by right ventricular (RV) dysfunction and elevated circulating cardiac troponin levels despite apparent hemodynamic stability at presentation. In these patients, full-dose systemic thrombolysis reduced the risk of hemodynamic decompensation or death but increased the risk of life-threatening bleeding. Reduced-dose thrombolysis may be capable of improving safety while maintaining reperfusion efficacy. The Pulmonary Embolism International THrOmbolysis (PEITHO)-3 study (ClinicalTrials.gov Identifier: NCT04430569) is a randomized, placebo-controlled, double-blind, multicenter, multinational trial with long-term follow-up. We will compare the efficacy and safety of a reduced-dose alteplase regimen with standard heparin anticoagulation. Patients with intermediate-high-risk PE will also fulfill at least one clinical criterion of severity: systolic blood pressure ≤110 mm Hg, respiratory rate >20 breaths/min, or history of heart failure. The primary efficacy outcome is the composite of all-cause death, hemodynamic decompensation, or PE recurrence within 30 days of randomization. Key secondary outcomes, to be included in hierarchical analysis, are fatal or GUSTO severe or life-threatening bleeding; net clinical benefit (primary efficacy outcome plus severe or life-threatening bleeding); and all-cause death, all within 30 days. All outcomes will be adjudicated by an independent committee. Further outcomes include PE-related death, hemodynamic decompensation, or stroke within 30 days; dyspnea, functional limitation, or RV dysfunction at 6 months and 2 years; and utilization of health care resources within 30 days and 2 years. The study is planned to enroll 650 patients. The results are expected to have a major impact on risk-adjusted treatment of acute PE and inform guideline recommendations.
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http://dx.doi.org/10.1055/a-1653-4699DOI Listing
September 2021

Extended Anticoagulant Treatment with Full- or Reduced-Dose Apixaban in Patients with Cancer-Associated Venous Thromboembolism: Rationale and Design of the API-CAT Study.

Thromb Haemost 2021 Sep 17. Epub 2021 Sep 17.

INNOVTE-FCRIN, Saint-Etienne, France.

Cancer-associated thrombosis (CT) is associated with a high risk of recurrent venous thromboembolic (VTE) events that require extended anticoagulation in patients with active cancer, putting them at risk of bleeding. The aim of the API-CAT study (NCT03692065) is to assess whether a reduced-dose regimen of apixaban (2.5 mg twice daily [bid]) is noninferior to a full-dose regimen of apixaban (5 mg bid) for the prevention of recurrent VTE in patients with active cancer who have completed ≥6 months of anticoagulant therapy for a documented index event of proximal deep-vein thrombosis and/or pulmonary embolism. API-CAT is an international, randomized, parallel-group, double-blind, noninferiority trial with blinded adjudication of outcome events. Consecutive patients are randomized to receive apixaban 2.5 or 5 mg bid for 12 months. The primary efficacy outcome is a composite of recurrent symptomatic or incidental VTE during the treatment period. The principal safety endpoint is clinically relevant bleeding, defined as a composite of major bleeding or nonmajor clinically relevant bleeding. Assuming a 12-month incidence of the primary outcome of 4% with apixaban and an upper limit of the two-sided 95% confidence interval of the hazard ratio <2.0, 1,722 patients will be randomized, assuming an up to 10% loss in total patient-years (β = 80%; α one-sided = 0.025). This trial has the potential to demonstrate that a regimen of extended treatment for patients with CT beyond an initial 6 months, with a reduced apixaban dose, has an acceptable risk of recurrent VTE recurrence and decreases the risk of bleeding.
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http://dx.doi.org/10.1055/a-1647-9896DOI Listing
September 2021

Early switch to oral anticoagulation in patients with acute intermediate-risk pulmonary embolism (PEITHO-2): a multinational, multicentre, single-arm, phase 4 trial.

Lancet Haematol 2021 Sep 4;8(9):e627-e636. Epub 2021 Aug 4.

Internal and Subintensive Medicine Department, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy.

Background: Current guidelines recommend a risk-adjusted treatment strategy for the management of acute pulmonary embolism. This is a particular patient category for whom optimal treatment (anticoagulant treatment, reperfusion strategies, and duration of hospitalisation) is currently unknown. We investigated whether treatment of acute intermediate-risk pulmonary embolism with parenteral anticoagulation for a short period of 72 h, followed by a switch to a direct oral anticoagulant (dabigatran), is effective and safe.

Methods: We did a multinational, multicentre, single-arm, phase 4 trial at 42 hospitals in Austria, Belgium, France, Germany, Italy, Netherlands, Romania, Slovenia, and Spain. Adult patients (aged ≥18 years) with symptomatic intermediate-risk pulmonary embolism, with or without deep-vein thrombosis, were enrolled. Patients received parenteral low-molecular-weight or unfractionated heparin for 72 h after diagnosis of pulmonary embolism before switching to oral dabigatran 150 mg twice per day following a standard clinical assessment. The primary outcome was recurrent symptomatic venous thromboembolism or pulmonary embolism-related death within 6 months. The primary and safety outcomes were assessed in the intention-to-treat population. The study was terminated early, as advised by the data safety and monitoring board, following sample size adaptation after the predefined interim analysis on Dec 18, 2018. This trial is registered with the EU Clinical Trials Register (EudraCT 2015-001830-12) and ClinicalTrials.gov (NCT02596555).

Findings: Between Jan 1, 2016, and July 31, 2019, 1418 patients with pulmonary embolism were screened, of whom 402 were enrolled and were included in the intention-to-treat analysis (median age was 69·5 years [IQR 60·0-78·0); 192 [48%] were women and 210 [52%] were men). Median follow-up was 217 days (IQR 210-224) and 370 (92%) patients adhered to the protocol. The primary outcome occurred in seven (2% [upper bound of right-sided 95% CI 3]; p<0·0001 for rejecting the null hypothesis) patients, with all events occurring in those with intermediate-high-risk pulmonary embolism (seven [3%; upper bound of right-sided 95% CI 5] of 283). At 6 months, 11 (3% [95% CI 1-5]) of 402 patients had at least one major bleeding event and 16 (4% [2-6]) had at least one clinically relevant non-major bleeding event; the only fatal haemorrhage occurred in one (<1%) patient before the switch to dabigatran.

Interpretation: A strategy of early switch from heparin to dabigatran following standard clinical assessment was effective and safe in patients with intermediate-risk pulmonary embolism. Our results can help to refine guideline recommendations for the initial treatment of acute intermediate-risk pulmonary embolism, optimising the use of resources and avoiding extended hospitalisation.

Funding: German Federal Ministry of Education and Research, University Medical Center Mainz, and Boehringer Ingelheim.
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http://dx.doi.org/10.1016/S2352-3026(21)00203-9DOI Listing
September 2021

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

Eur Heart J 2021 08;42(33):3146-3157

F-CRIN, INNOVTE, Saint-Etienne, France.

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.
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http://dx.doi.org/10.1093/eurheartj/ehab373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408662PMC
August 2021

Second consensus document on diagnosis and management of acute deep vein thrombosis: updated document elaborated by the ESC Working Group on aorta and peripheral vascular diseases and the ESC Working Group on pulmonary circulation and right ventricular function.

Eur J Prev Cardiol 2021 Jul 13. Epub 2021 Jul 13.

Department of Cardiology, Dupuytren University Hospital and Inserm 1094, Tropical Neuroepidemiology, School of Medicine, 2 avenue martin Luther-King 87042 Limoges, France.

This consensus document is proposed to clinicians to provide the whole spectrum of deep vein thrombosis management as an update to the 2017 consensus document. New data guiding clinicians in indicating extended anticoagulation, management of patients with cancer, and prevention and management of post-thrombotic syndrome are presented. More data on benefit and safety of non-vitamin K antagonists oral anticoagulants are highlighted, along with the arrival of new antidotes for severe bleeding management.
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http://dx.doi.org/10.1093/eurjpc/zwab088DOI Listing
July 2021

Randomised trial of first-line bronchial artery embolisation for non-severe haemoptysis of mild abundance.

BMJ Open Respir Res 2021 06;8(1)

Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (URC-CRC-CRB), Hôpital St Antoine, Paris, France, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, Paris, France.

Background: Whereas first-line bronchial artery embolisation (BAE) is considered standard of care for the management of severe haemoptysis, it is unknown whether this approach is warranted for non-severe haemoptysis.

Research Question: To assess the efficacy on bleeding control and the safety of first-line BAE in non-severe haemoptysis of mild abundance.

Study Design And Methods: This multicentre, randomised controlled open-label trial enrolled adult patients without major comorbid condition and having mild haemoptysis (onset <72 hours, 100-200 mL estimated bleeding amount), related to a systemic arterial mechanism. Patients were randomly assigned (1:1) to BAE associated with medical therapy or to medical therapy alone.

Results: Bleeding recurrence at day 30 after randomisation (primary outcome) occurred in 4 (11.8%) of 34 patients in the BAE strategy and 17 (44.7%) of 38 patients in the medical strategy (difference -33%; 95% CI -13.8% to -52.1%, p=0.002). The 90-day bleeding recurrence-free survival rates were 91.2% (95% CI 75.1% to 97.1%) and 60.2% (95% CI 42.9% to 73.8%), respectively (HR=0.19, 95% CI 0.05 to 0.67, p=0.01). No death occurred during follow-up and no bleeding recurrence needed surgery.Four adverse events (one major with systemic emboli) occurred during hospitalisation, all in the BAE strategy (11.8% vs 0%; difference 11.8%, 95% CI 0.9 to 22.6, p=0.045); all eventually resolved.

Conclusion: In non-severe haemoptysis of mild abundance, BAE associated with medical therapy had a superior efficacy for preventing bleeding recurrences at 30 and 90 days, as compared with medical therapy alone. However, it was associated with a higher rate of adverse events.

Trial Registration Number: NCT01278199.
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http://dx.doi.org/10.1136/bmjresp-2021-000949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183216PMC
June 2021

Failure of the Ottawa Score to Predict the Risk of Recurrent Venous Thromboembolism in Cancer Patients: The Prospective PREDICARE Cohort Study.

Thromb Haemost 2021 Apr 20. Epub 2021 Apr 20.

F-CRIN INNOVTE network, Saint-Etienne, France.

Introduction:  Recurrent venous thromboembolism (VTE) despite curative anticoagulation is frequent in patients with cancer. Identifying patients with a high risk of recurrence could have therapeutic implications. A prospective study was designed to validate the Ottawa risk score of recurrent VTE in cancer patients.

Methods:  In a prospective multicenter observational cohort, adult cancer patients with a recent diagnosis of symptomatic or incidental lower limb deep vein thrombosis or pulmonary embolism (PE) were treated with tinzaparin for 6 months. The primary endpoint was the recurrence of symptomatic or asymptomatic VTE within the first 6 months of treatment. All clinical events were centrally reviewed and adjudicated. Time-to-event outcomes were estimated by the Kalbfleisch and Prentice method to take into account the competing risk of death. A C-statistic value of > 0.70 was needed to validate the Ottawa score.

Results:  A total of 409 patients were included and analyzed on an intention-to-treat basis. Median age was 68 years, 60.4% of patients had PE, and VTE was symptomatic in 271 patients (66.3%). The main primary sites were lung (31.3%), lower digestive tract (14.4%), and breast (13.9%) cancers. The Ottawa score was high (≥ 1) in 58% of patients. The 6-month cumulative incidence of recurrent VTE was 7.3% (95% confidence interval [CI]: 4.9-11.1) overall, and 5.0% (95% CI: 2.3-10.8) versus 9.1% (95%CI: 6.1-13.6) in the Ottawa low versus high risk groups, respectively. The C-statistic value was 0.60 (95% CI: 0.55-0.65).

Conclusion:  In this prospective cohort of patients with cancer receiving tinzaparin for VTE, the Ottawa score failed to accurately predict recurrent VTE.
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http://dx.doi.org/10.1055/a-1486-7497DOI Listing
April 2021

Venous thrombosis and predictors of relapse in eosinophil-related diseases.

Sci Rep 2021 03 18;11(1):6388. Epub 2021 Mar 18.

National Reference Center for Hypereosinophilic Syndromes, CEREO, France.

Eosinophils have widespread procoagulant effects. Eosinophilic cardiovascular toxicity mostly consists of endomyocardial damage or eosinophilic vasculitis, while reported cases of venous thrombosis (VT) are scarce. We aimed to report on the clinical features and treatment outcomes of patients with unexplained VT and eosinophilia, and to identify predictors of relapse. This retrospective, multicenter, observational study included patients aged over 15 years with VT, concomitant blood eosinophilia ≥ 1G/L and without any other moderate-to-strong contributing factors for VT. Fifty-four patients were included. VT was the initial manifestation of eosinophil-related disease in 29 (54%) patients and included pulmonary embolism (52%), deep venous thrombosis (37%), hepatic (11%) and portal vein (9%) thromboses. The median [IQR] absolute eosinophil count at VT onset was 3.3G/L [1.6-7.4]. Underlying eosinophil-related diseases included FIP1L1-PDGFRA-associated chronic myeloid neoplasm (n = 4), Eosinophilic Granulomatosis with Polyangiitis (n = 9), lymphocytic (n = 1) and idiopathic (n = 29) variants of hypereosinophilic syndrome. After a median [IQR] follow-up of 24 [10-62] months, 7 (13%) patients had a recurrence of VT. In multivariate analysis, persistent eosinophilia was the sole variable associated with a shorter time to VT relapse (HR 7.48; CI95% [1.94-29.47]; p = 0.015). Long-term normalization of eosinophil count could prevent the recurrence of VT in a subset of patients with unexplained VT and eosinophilia ≥ 1G/L.
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http://dx.doi.org/10.1038/s41598-021-85852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973521PMC
March 2021

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

JAMA 2021 Jan;325(1):59-68

Département de Médecine Interne et Pneumologie, Centre Hospitalo-Universitaire de Brest, Brest, France.

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.
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http://dx.doi.org/10.1001/jama.2020.23567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786241PMC
January 2021

Opinion and practice survey about the use of prognostic models in acute pulmonary embolism.

Thromb Res 2021 02 1;198:40-48. Epub 2020 Nov 1.

Department for Continuing Education Professional Development, University of Oxford, Oxford, United Kingdom; Northern Ireland Network for Trials Methodology Research, Queen's University Belfast, Belfast, United Kingdom.

Introduction: Methods for prognosis assessment and patient management in acute pulmonary embolism (PE) are much debated among physicians. We conducted an online survey to determine physician's attitudes and barriers towards the use of prognostic models when treating patients with acute PE.

Method: Physicians members of the French and the European scientific societies for emergency medicine or of a French thrombosis research network were reached by their respective scientific societies and invited to participate via email. The questionnaire was a mixture of close-ended with yes-no or multiple-choice options and a small number of open-ended questions.

Results: The survey included 461 respondents. The most commonly used prognostic tools were clinical judgment (36%) and prognostic models (29.5%). Prognostic models were used by 57% of respondents in more than half of all cases and prognostic indicators by 62% in addition to prognostic models. Affiliation group and type of hospital emerged as independent predictors for choosing prognostic models. Many (52%) reported lack of familiarity with the models and reported clinical judgment (60%) or hospital checklists (73%) as being as good as or better than prognostic models. The highest acceptable 30-day mortality rate limit for early discharge or outpatient management was deemed to be 1%, but few patients are discharged early or completely managed on an outpatient basis.

Conclusions: This survey provides new information for implementing knowledge translation strategies to improve prognostic risk assessment for acute PE patients, and highlights the need for considering the use of clinical judgment and hospital checklists in future clinical research.
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http://dx.doi.org/10.1016/j.thromres.2020.10.027DOI Listing
February 2021

Prevention of venous thromboembolism in ambulatory patients with cancer.

ESMO Open 2020 11;5(6):e000948

Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, Ontario, Canada.

Patients with cancer are at high risk of venous thromboembolic events, and this risk can be further increased in patients with certain cancer types and by cancer treatments. Guidelines on the prevention of cancer-associated thrombosis (CAT) recommend thromboprophylaxis for hospitalised patients; however, this is not routinely recommended for ambulatory patients receiving chemotherapy and is limited to specified high-risk patients. Identification of the ambulatory patients at risk of CAT who would most benefit from anticoagulant therapy is therefore critical to reduce the incidence of this complication. For patients receiving thromboprophylaxis for CAT, treatment options include low molecular weight heparin, acetylsalicylic acid, warfarin or direct oral anticoagulants (apixaban or rivaroxaban), dependent on the cancer type and cancer treatment regimen. This review discusses emerging clinical trial data and their potential clinical impact.
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http://dx.doi.org/10.1136/esmoopen-2020-000948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684816PMC
November 2020

Prevalence and characteristics of pulmonary embolism in 1042 COVID-19 patients with respiratory symptoms: A nested case-control study.

Thromb Res 2021 01 7;197:94-99. Epub 2020 Nov 7.

Université de Paris, France; Groupe Hospitalier Paris Saint-Joseph, F-75014 Paris, France; Department of Vascular Medicine, France; INSERM CRESS UMR 1153, F-75005 Paris, France.

Introduction: Coronavirus disease 2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders. Previous studies reported pulmonary embolism (PE) in severe COVID-19 patients. Aim of the study was to estimate the prevalence of symptomatic PE in COVID-19 patients and to identify the clinical, radiological or biological characteristics associated with PE.

Patients/methods: We conducted a retrospective nested case-control study in 2 French hospitals. Controls were matched in a 1:2 ratio on the basis of age, sex and center. PE patients with COVID-19 were compared to patients in whom PE was ruled out (CTPA controls) and in whom PE has not been investigated (CT controls).

Results: PE was suspected in 269 patients among 1042 COVID-19 patients, and confirmed in 59 patients (5.6%). Half of PE was diagnosed at COVID-19 diagnosis. PE patients did not differ from CT and CTPA controls for thrombosis risk factors. PE patients more often required invasive ventilation compared to CTPA controls (odds ratio (OR) 2.79; 95% confidence interval (CI) 1.33-5.84) and to CT controls (OR 8.07; 95% CI 2.70-23.82). PE patients exhibited more extensive parenchymal lesions (>50%) than CT controls (OR 3.90; 95% CI 1.54-9.94). D-dimer levels were 5.1 (95% CI 1.90-13.76) times higher in PE patients than CTPA controls.

Conclusions: Our results suggest a PE prevalence in COVID-19 patients close to 5% in the whole population and to 20% of the clinically suspected population. PE seems to be associated with more extensive lung damage and to require more frequently invasive ventilation.
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http://dx.doi.org/10.1016/j.thromres.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648521PMC
January 2021

Reperfusion therapies in pulmonary embolism-state of the art and expert opinion: A position paper from the "Unité de Soins Intensifs de Cardiologie" group of the French Society of Cardiology.

Arch Cardiovasc Dis 2020 Nov 22;113(11):749-759. Epub 2020 Sep 22.

Intensive Care Unit, Department of Cardiology, Hôpital Nord, AP-HM, Aix-Marseille Université, 13015 Marseille; Mediterranean Association for Research and Studies in Cardiology (MARS Cardio), 13000 Marseille, France; INSERM 1263, 1260, Centre for Cardiovascular and Nutrition Research (C2VN), INRA, 13385 Marseille, France. Electronic address:

Acute pulmonary embolism is a frequent cardiovascular emergency with an increasing incidence. The prognosis of patients with high-risk and intermediate-high-risk pulmonary embolism has not improved over the last decade. The current treatment strategies are mainly based on anticoagulation to prevent recurrence and reduce pulmonary vasculature obstruction. However, the slow rate of thrombus lysis under anticoagulation is unable to acutely decrease right ventricle overload and pulmonary vasculature resistance in patients with severe obstruction and right ventricle dysfunction. Therefore, patients with high-risk and intermediate-high-risk pulmonary embolism remain a therapeutic challenge. Reperfusion therapies may be discussed for these patients, and include systemic thrombolysis, catheter-directed therapies and surgical thrombectomy. High-risk patients require systemic thrombolysis, but may have contraindications as a result of the high risk of bleeding. In addition, intermediate-high-risk patients should not receive systemic thrombolysis, despite its high efficacy, because of prohibitive bleeding complications. Recently, percutaneous reperfusion techniques have been developed to acutely decrease pulmonary vascular obstruction with lower-dose or no thrombolytic agents and, thus, potentially higher safety than systemic thrombolysis. Some of these techniques improve key haemodynamic variables. Cardiac surgical techniques and venoarterial extracorporeal membrane oxygenation as temporary circulatory support may be useful in selected cases. The development of pulmonary embolism centres with multidisciplinary pulmonary embolism teams is mandatory to enable adequate use of reperfusion and improve outcomes. We aim to present the state of the art regarding reperfusion therapies in pulmonary embolism, but also to provide guidance on their indications and patient selection.
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http://dx.doi.org/10.1016/j.acvd.2020.06.002DOI Listing
November 2020

External validation of the YEARS diagnostic algorithm for suspected pulmonary embolism.

J Thromb Haemost 2020 12 23;18(12):3289-3295. Epub 2020 Oct 23.

Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.

Background: Validated diagnostic algorithms are used to manage patients with suspected pulmonary embolism (PE). The recently published YEARS study proposed a simplified diagnostic strategy to reduce the use of computed tomography pulmonary angiography.

Objectives: To externally validate this strategy in an independent cohort.

Methods: We analyzed data from three previous prospective cohort studies of outpatients with suspected PE. We retrospectively applied the YEARS algorithm. The three YEARS clinical criteria are: clinical signs of deep vein thrombosis, hemoptysis, and PE as the most likely diagnosis. If zero YEARS criteria are met, a D-dimer < 1000 ng/mL will rule out PE. If ≥1 YEARS criteria are met, a D-dimer < 500 ng/mL will rule out PE.

Results: Of the 3314 patients, 731 (22.1%) had PE. Applying the YEARS diagnostic algorithm, 1423 (42.9%) patients could have had PE ruled out without imaging. Of these patients, 17 (1.2%; 95% confidence interval 0.8-1.9) were diagnosed with PE at initial testing. All 17 had no YEARS item and a D-dimer < 1000 ng/mL. All 17 had a D-dimer level above their age-adjusted cutoff. Among the 272 patients with no YEARS criteria and a D-dimer < 1000 ng/mL but above their age-adjusted D-dimer cutoff, PE was diagnosed in 6.3% (17/272; 95% confidence interval 3.9-9.8).

Conclusion: We provide external validation of the YEARS diagnostic algorithm in an independent cohort. The rule appears to safely exclude PE. However, caution is required in patients with no YEARS item and a D-dimer < 1000 ng/mL but above their age-adjusted D-dimer cutoff.
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http://dx.doi.org/10.1111/jth.15083DOI Listing
December 2020

Long-Term Treatment of Cancer-Associated Thrombosis (CAT) Beyond 6 Months in the Medical Practice: USCAT, a 432-Patient Retrospective Non-Interventional Study.

Cancers (Basel) 2020 Aug 12;12(8). Epub 2020 Aug 12.

F-CRIN INNOVTE network, F-42055 Saint-Etienne, France.

Background: extended anticoagulant therapy beyond the initial 6 months is suggested in patients with cancer-associated thrombosis (CAT) and active cancer. Few data are available on patient management and outcomes on the period between 6 and 12 months after the venous thromboembolism (VTE) event.

Objectives: our objective was to document patient management and outcomes beyond 6 months and up to 12 months in CAT patients initially treated for 6 months with tinzaparin.

Methods: adult CAT patients with a cancer still alive at the end of an initial 6-month treatment period were eligible to participate in this retrospective non-interventional French multicenter study.

Results: a total of 432 patients aged 66.5 ± 12.7 years were available to participate in this study. Out of the patients included in the study, the anticoagulant treatment was maintained in 348 of 422 documented patients (82.5%) while it was discontinued in 74 (17.5%) patients (before the end or at the end of the initial 6-month treatment period). Between 6 and 12 months, 24 patients (5.7%) experienced VTE recurrence, while 21 (5.1%) patients had clinically relevant bleeding, 11 patients (2.7%) had major bleeding and 96 patients (22.3%) died, mostly from cancer. VTE recurrence was more frequent in patients with lung (14.3%) and colorectal cancer (6.0%) while major bleeding was more frequent in patients with colorectal cancer (6.0%).

Conclusion: clinical outcomes were consistent with previous observations and variable according to the type of cancer. Further clinical research is required to orient the management of patients with CAT beyond 6 months based on cancer-specific treatment strategies.
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http://dx.doi.org/10.3390/cancers12082256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463918PMC
August 2020

Management of acute pulmonary embolism 2019: what is new in the updated European guidelines?

Intern Emerg Med 2020 09 26;15(6):957-966. Epub 2020 May 26.

Respiratory Medicine Department, Hôpital Européen Georges Pompidou, APHP, Paris, France.

Pulmonary embolism (PE) is the third most frequent acute cardiovascular syndrome. Annual PE incidence and PE-related mortality rates rise exponentially with age, and consequently, the disease burden imposed by PE on the society continues to rise as the population ages worldwide. Recently published landmark trials provided the basis for new or changed recommendations included in the 2019 update of the European Society of Cardiology Guidelines (developed in cooperation with the European Respiratory Society). Refinements in diagnostic algorithms were proposed and validated, increasing the specificity of pre-test clinical probability and D-dimer testing, and thus helping to avoid unnecessary pulmonary angiograms. Improved diagnostic strategies were also successfully tested in pregnant women with suspected PE. Non-vitamin K antagonist oral anticoagulants (NOACs) are now the preferred agents for treating the majority of patients with PE, both in the acute phase (with or without a brief lead-in period of parenteral heparin or fondaparinux) and over the long term. Primary reperfusion is reserved for haemodynamically unstable patients. Besides, the 2019 Guidelines endorse multidisciplinary teams for coordinating the acute-phase management of high-risk and (in selected cases) intermediate-risk PE. For normotensive patients, physicians are advised to include the assessment of the right ventricle on top of clinical severity scores in further risk stratification, especially if early discharge of the patient is envisaged. Further important updates include guidance (1) on extended anticoagulation after PE, taking into account the improved safety profile of NOACs; and (2) on the overall care and follow-up of patients who have suffered PE, with the aim to prevent, detect and treat late sequelae of venous thromboembolism.
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http://dx.doi.org/10.1007/s11739-020-02340-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467952PMC
September 2020

Evaluation of Venous Thromboembolism Recurrence Scores in an Unprovoked Pulmonary Embolism Population: A Post-hoc Analysis of the PADIS-PE trial.

Am J Med 2020 08 22;133(8):e406-e421. Epub 2020 Apr 22.

Département de Médecine Interne et Pneumologie, Centre Hospitalo-Universitaire de Brest, Université de Bretagne Occidentale, and EA 3878, CIC INSERM 1412, Brest, France.

Background: We aimed to validate the Men Continue and HERDOO2 (HERDOO2), D-dimer, age, sex, hormonal therapy (DASH), and updated Vienna recurrent venous thromboembolism prediction models in a population composed entirely of first unprovoked pulmonary embolism, and to analyze the impact of the addition of the pulmonary vascular obstruction index (PVOI) on score accuracy.

Methods: Analyses were based on the double-blind, randomized PADIS-PE trial, which included 371 unprovoked pulmonary embolism patients initially treated for 6 months, successively randomized to receive an additional 18 months of warfarin or placebo, and subsequently followed-up for 2 years.

Results: The HERDOO2, DASH, and updated Vienna scores displayed C-statistics of 0.61 (95% CI 0.54-0.68), 0.60 (95% CI 0.53-0.66), and 0.58 (95% CI 0.51-0.66), respectively. Only the HERDOO2 score identified low recurrence risk patients (<3%/year) after anticoagulation was stopped. When added to either of the prediction models, PVOI measured at pulmonary embolism diagnosis, after 6 months of anticoagulation, or both, improved scores' C-statistics between +0.06 and +0.11 points and consistently led to identifying at least 50% of patients who experienced recurrence but in whom the scores would have indicated against extended anticoagulation.

Conclusions: In patients with a first unprovoked pulmonary embolism, the HERDOO2 score is able to identify patients with a low recurrence risk after treatment discontinuation. Addition of PVOI improves accuracy of all scores.

Clinical Trials Registration: URL: http://www.controlled-trials.com. Unique identifier: NCT00740883.
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http://dx.doi.org/10.1016/j.amjmed.2020.03.040DOI Listing
August 2020

Early detection of the existence or absence of the treatment effect: A cumulative meta-analysis.

J Clin Epidemiol 2020 08 13;124:24-33. Epub 2020 Apr 13.

Unité de Recherche Clinique, Innovation, Pharmacologie, CHU Saint-Etienne, Hôpital Nord, F-42055 Saint-Etienne, France; SAINBIOSE U1059, Université Jean Monnet, University Lyon, INSERM, F-CRIN INNOVTE Network, F-42023 Saint-Etienne, France; Service de Médecine Vasculaire et Thérapeutique, CHU Saint-Etienne, Hôpital Nord, F-40255, Saint-Etienne, France.

Objectives: An unexpected promising effect of low molecular weight heparins (LMWHs) on survival in patients with cancer was observed in early trials in post hoc subgroup analyses but not found in more recent trials. To highlight a possible regression over time toward the lack of the antitumoral effect of LMWHs, we performed a cumulative meta-analysis of survival data from randomized controlled trials (RCTs).

Study Design And Setting: Medical databases were searched to identify RCTs comparing, in patients with cancer, LMWHs with placebo or no treatment in patients free of venous thromboembolism (VTE), or to vitamin K antagonists in patients who experienced an acute VTE in overall survival. The cumulative hazard ratio (HR) was estimated after each study inclusion in chronological order.

Results: Twenty-three studies (12,970 patients) were included. The cumulative meta-analysis of the earlier trials showed a significant improvement in overall survival with LMWHs. This apparent benefit then gradually regressed over time toward an absence of the effect of LMWHs on survival (HR: 0.98 [95% confidence interval, 0.93; 1.03]).

Conclusion: Despite supportive experimental data and early clinical findings, the promising antitumoral effect of LMWHs in patients with cancer gradually vanished over time toward a lack of impact on overall survival. This result suggests 'p-hacking' and selective reporting of the positive results from post hoc subgroup analyses in the early studies.
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http://dx.doi.org/10.1016/j.jclinepi.2020.04.006DOI Listing
August 2020

Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer.

N Engl J Med 2020 04 29;382(17):1599-1607. Epub 2020 Mar 29.

From the Internal Vascular and Emergency Medicine-Stroke Unit, University of Perugia, Perugia (G.A., C.B., M.V.), Federazione delle Associazioni dei Dirigenti Ospedalieri Internisti (FADOI) Research Center, Milan (G.G.), the Department of Medicine, Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara (M.C.), the Department of Medicine, Buon Consiglio-Fatebenefratelli Hospital, Naples (A.F.), and Internal Medicine, Azienda Ospedale-Università, Padua (G.V.) - all in Italy; Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, and INNOVTE, Saint-Etienne (G.M.) - both in France; Instituto de Investigatión Sanitaria Gregorio Marañon, Universidad Complûtense, Madrid (A.M.); the Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands (M.V.H.); the Hematology Division, Brigham and Women's Hospital, and Harvard Medical School, Boston (J.M.C.); Guy's and St. Thomas' NHS Foundation Trust Hospital, King's College London, London (A.C.); the Department of Vascular Medicine, Darmstadt, and Center for Thrombosis and Hemostasis, University of Mainz, Mainz (R.B.) - both in Germany; the Institute of Hematology and Bone Marrow Transplantation Unit, Rambam Health Care Campus Technion, Israel Institute of Technology, Haifa (B.B.); the Departments of Pulmonary Circulation, Thromboembolic Diseases, and Cardiology, Center for Postgraduate Medical Education, Europejskie Centrum Zdrowia, Otwock, Poland (A.T.); the Surgical Oncology Department, Institut Português de Oncologia do Porto, Porto, Portugal (M.R.S.); and Cliniques Universitaires Saint-Luc, Brussels (C.L.).

Background: Recent guidelines recommend consideration of the use of oral edoxaban or rivaroxaban for the treatment of venous thromboembolism in patients with cancer. However, the benefit of these oral agents is limited by the increased risk of bleeding associated with their use.

Methods: This was a multinational, randomized, investigator-initiated, open-label, noninferiority trial with blinded central outcome adjudication. We randomly assigned consecutive patients with cancer who had symptomatic or incidental acute proximal deep-vein thrombosis or pulmonary embolism to receive oral apixaban (at a dose of 10 mg twice daily for the first 7 days, followed by 5 mg twice daily) or subcutaneous dalteparin (at a dose of 200 IU per kilogram of body weight once daily for the first month, followed by 150 IU per kilogram once daily). The treatments were administered for 6 months. The primary outcome was objectively confirmed recurrent venous thromboembolism during the trial period. The principal safety outcome was major bleeding.

Results: Recurrent venous thromboembolism occurred in 32 of 576 patients (5.6%) in the apixaban group and in 46 of 579 patients (7.9%) in the dalteparin group (hazard ratio, 0.63; 95% confidence interval [CI], 0.37 to 1.07; P<0.001 for noninferiority). Major bleeding occurred in 22 patients (3.8%) in the apixaban group and in 23 patients (4.0%) in the dalteparin group (hazard ratio, 0.82; 95% CI, 0.40 to 1.69; P = 0.60).

Conclusions: Oral apixaban was noninferior to subcutaneous dalteparin for the treatment of cancer-associated venous thromboembolism without an increased risk of major bleeding. (Funded by the Bristol-Myers Squibb-Pfizer Alliance; Caravaggio ClinicalTrials.gov number, NCT03045406.).
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http://dx.doi.org/10.1056/NEJMoa1915103DOI Listing
April 2020

Incidental venous thromboembolism, detected by chance, but still venous thromboembolism.

Eur Respir J 2020 02 6;55(2). Epub 2020 Feb 6.

Division of Respiratory Disease, APHP Centre, Université Paris Descartes, Université de Paris, Paris, France.

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http://dx.doi.org/10.1183/13993003.00028-2020DOI Listing
February 2020

Should oral anticoagulation be discontinued after 3 months in the setting of a first high-risk pulmonary embolism secondary to a major transient/reversible risk factor?

Eur Respir J 2020 01 30;55(1). Epub 2020 Jan 30.

Center for Thrombosis and Haemostasis, University Medical Centre Mainz, Mainz, Germany.

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http://dx.doi.org/10.1183/13993003.02323-2019DOI Listing
January 2020

Age-adjusted D-dimer cutoff for the diagnosis of pulmonary embolism: A cost-effectiveness analysis.

J Thromb Haemost 2020 04 28;18(4):865-875. Epub 2020 Feb 28.

Division of Angiology and Haemostasis, Faculty of Medicine and Geneva University Hospitals, Geneva, Switzerland.

Background: In patients with suspected pulmonary embolism (PE) and a non-high pretest probability, the use of an age-adjusted D-dimer cutoff (AADD, <500 ng/mL up to 50 years, then
Methods: We created a decision tree to compare the use of the AADD with the standard D-dimer cutoff. The model included short-term venous thromboembolism-related events and long-term complications, their associated morbidity/mortality, and costs. Probabilities were derived from published literature and the ADJUST-PE study, and costs from US estimates. The time horizon was lifetime, with a health care system perspective.

Results: Using the AADD cutoff, compared with the standard cutoff, was associated with a loss of 0.0001 quality-adjusted life-years (QALY) and an average cost reduction of $33.4. The decremental cost-effectiveness ratio (DCER) was +$282 881/lost QALY (95% confidence interval from +$43 209/lost QALY to a dominant strategy). The probability that the use of the AADD cutoff was either dominant or gained >$200 000/lost QALY was 79.4%. In sensitivity analyses, the DCER became <+$200 000/lost QALY only if, among patients with D-dimer below the AADD cutoff, the mortality of an undiagnosed PE was >6% or the prevalence of PE was >0.6%.

Conclusions: The AADD cutoff results in a clinically nonsignificant decrease in QALY but important costs reductions. It is a decrementally cost-effective innovation, with a potential of cost savings of >$80 million per year for the United States health care system.
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http://dx.doi.org/10.1111/jth.14733DOI Listing
April 2020

The 2019 ESC Guidelines on the Diagnosis and Management of Acute Pulmonary Embolism.

Eur Heart J 2019 Nov;40(42):3453-3455

ESC Task Force co-chairman, Respiratory Medicine Department, Hôpital Européen Georges Pompidou, Paris, France. Université Paris Descartes, 75006 Paris, France.

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http://dx.doi.org/10.1093/eurheartj/ehz726DOI Listing
November 2019

Peripheral arterial disease and systematic detection of circulating tumor cells: rationale and design of the DETECTOR prospective cohort study.

BMC Cardiovasc Disord 2019 09 13;19(1):212. Epub 2019 Sep 13.

Groupe Hospitalier Paris Saint Joseph, 185 rue Raymond Losserand, 75 014, Paris, France.

Background: Smoking is a strong risk factor for cancer and atherosclerosis. Cancer mortality, especially from lung cancer, overtakes cardiovascular (CV) death rate in patients with peripheral arterial disease (PAD). Only a few patients with lung cancer after PAD management may benefit from surgical excision. Circulating tumor cells (CTC) associated with low-dose chest CT (LDCT) may improve early cancer detection. This study focuses on a screening strategy that can address not only lung cancer but all tobacco-related cancers in this high-risk population.

Methods: DETECTOR Project is a prospective cohort study in two French University hospitals. Participants are smokers or former smokers (≥30 pack-years, quitted ≤15 years), aged ≥55 to 80 years, with atherosclerotic PAD or abdominal aortic aneurysm. After the first screening round combining LDCT and CTC search on a blood sample, two other screening rounds will be performed at one-year interval. Incidental lung nodule volume, volume doubling time and presence of CTC will be taken into consideration for adapted diagnostic management. In case of negative LDCT and presence of CTC, a contrast enhanced whole-body PET/CT will be performed for extra-pulmonary malignancy screening. Psychological impact of this screening strategy will be evaluated in population study using a qualitative methodology. Assuming 10% prevalence of smoking-associated cancer in the studied population, a total of at least 300 participants will be enrolled.

Discussion: Epidemiological data underline an increase incidence in cancer and related death in the follow-up of patients with PAD, compared with the general population, particularly for tobacco-related cancers. The clinical benefit of a special workup for neoplasms in patients with PAD and a history of cigarette smoking has never been investigated. By considering CTCs detection in this very high-risk selected PAD population for tobacco-induced cancer, we expect to detect earlier pulmonary and extra-pulmonary malignancies, at a potentially curable stage.

Trial Registration: The study was registered in the French National Agency for Medicines and Health Products Safety (No N° EUDRACT_ID RCB: 2016-A00657-44) and was approved by the ethics Committee for Persons Protection (IRB number 1072 and n° initial agreement 2016-08-02; ClinicalTrials.gov identifier NCT02849041).
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http://dx.doi.org/10.1186/s12872-019-1193-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743149PMC
September 2019

Outpatient Management of Patients With Pulmonary Embolism.

Ann Intern Med 2019 08;171(3):227

Leiden University Medical Center Leiden, the Netherlands (M.H.).

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http://dx.doi.org/10.7326/L19-0206DOI Listing
August 2019

The use of direct oral anticoagulants for primary thromboprophylaxis in ambulatory cancer patients: Guidance from the SSC of the ISTH.

J Thromb Haemost 2019 10 28;17(10):1772-1778. Epub 2019 Jul 28.

Department of Respiratory Disease, Hopital Europeen Georges Pompidou, AP-HP, INSERM CIC1418, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

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http://dx.doi.org/10.1111/jth.14564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773470PMC
October 2019
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