Publications by authors named "Patrick Mismetti"

137 Publications

Severe inflammation, acute kidney injury, and drug-drug interaction: triple penalty for prolonged elimination of apixaban in patients with COVID-19, a grand round.

Ther Drug Monit 2021 Apr 21. Epub 2021 Apr 21.

Laboratoire de Pharmacologie - Toxicologie - Gaz du Sang, CHU de Saint-Etienne, Saint Etienne, France Service de Médecine Intensive et Réanimation G, CHU de Saint-Etienne, Saint Etienne, France INSERM U1059, Dysfonctions Vasculaires et de L'Hémostase, Université de Lyon, Saint-Etienne, France Service de Médecine Vasculaire et Thérapeutique, CHU de Saint-Etienne, Saint Etienne, France Infectious Diseases Department, CHU de Saint-Etienne, Saint Etienne, France.

Abstract: Herein, we present a case of apixaban elimination prolonged by 450% in a patient with coronavirus disease 2019 due to multiple conditions, including drug-drug interaction, severe inflammation, and acute kidney injury. Therapeutic drug monitoring (TDM) was used to explain unusual routine coagulation assays. This grand round highlights the importance of dialog between the clinician and a TDM consultant for optimal patient care.
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http://dx.doi.org/10.1097/FTD.0000000000000899DOI Listing
April 2021

In memory of Professor Guy Meyer, 1957-2020.

Thromb Res 2021 04 14;200:A1-A2. Epub 2021 Mar 14.

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

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http://dx.doi.org/10.1016/j.thromres.2021.02.001DOI Listing
April 2021

Early venous thromboembolism is a strong prognostic factor in patients with advanced pancreatic ductal adenocarcinoma.

J Cancer Res Clin Oncol 2021 Mar 14. Epub 2021 Mar 14.

University Hospital of Saint-Etienne, Saint-Priest en Jarez, France.

Background: There are still controversial data regarding the prognostic value of Venous ThromboEmbolism (VTE) in advanced Pancreatic Ductal AdenoCarcinoma (PDAC) and thromboprophylaxis is poorly prescribed despite international recommendations.

Methods: Medical charts of patients consecutively treated for advanced PDAC from 2010 to 2019 were retrospectively reviewed. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method. Prognostic Factors were identified using a multivariate Cox's proportional hazard model. Early VTE was defined as VTE occurring within the three months following the PDAC diagnosis.

Results: A total of 174 patients were included (median age: 67 years; males: 55.2%; performance status (PS) 0-1: 88.5%) with metastatic disease in 74.7%. At baseline, Khorana score was high (≥ 3) in the vast majority of cases (93.7%). The cumulative incidences of VTE were 12.4% (95% CI 7.3-17.2) at 3 months, 20.4% (95% CI 13.9-26.4) at 6 months and 28.1% (95% CI 20.0-35.3) at 12 months. Patients who experienced early VTE had shorter PFS (3.8 months vs. 7.1 months; HR = 2.02; 95% CI 1.21-3.37; p = 0.006) and shorter OS (8.0 months vs. 14.1 months; HR = 2.42; 95% CI 1.37-4.30; p = 0.002) compared to the others, independently of prognostic factors such as PS, liver metastases, carcinomatosis, and chemotherapy regimen.

Conclusion: early VTE is a strong prognostic factor in advanced PDAC and occurs in about one in 10 patients.
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http://dx.doi.org/10.1007/s00432-021-03590-xDOI Listing
March 2021

Effects and Side Effects of Platelet Transfusion.

Hamostaseologie 2021 Apr 12;41(2):128-135. Epub 2021 Mar 12.

Department of Surgery and Anaesthesia, University of Otago, Wellington, New Zealand.

Aside from their canonical role in hemostasis, it is increasingly recognized that platelets have inflammatory functions and can regulate both adaptive and innate immune responses. The main topic this review aims to cover is the proinflammatory effects and side effects of platelet transfusion. Platelets prepared for transfusion are subject to stress injury upon collection, preparation, and storage. With these types of stress, they undergo morphologic, metabolic, and functional modulations which are likely to induce platelet activation and the release of biological response modifiers (BRMs). As a consequence, platelet concentrates (PCs) accumulate BRMs during processing and storage, and these BRMs are ultimately transfused alongside platelets. It has been shown that BRMs present in PCs can induce immune responses and posttransfusion reactions in the transfusion recipient. Several recent reports within the transfusion literature have investigated the concept of platelets as immune cells. Nevertheless, current and future investigations will face the challenge of encompassing the immunological role of platelets in the scope of transfusion.
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http://dx.doi.org/10.1055/a-1347-6551DOI Listing
April 2021

An epidemic of redundant meta-analyses.

J Thromb Haemost 2021 May 27;19(5):1299-1306. Epub 2021 Mar 27.

Unité de Recherche Clinique, Innovation, Pharmacologie, CHU Saint-Etienne, Hôpital Nord, Saint-Etienne, France.

Background: Meta-analyses are widely used to strengthen available evidence and obtain more precise estimates of treatment effect than any individual trial. Paradoxically, multiplication of meta-analyses on the same topic can lead to confusion as practitioners no longer benefit from a rapid and synthetic response. This phenomenon may appear disproportionate when the number of published meta-analyses exceeds the number of original studies.

Objectives: To describe an example of redundant meta-analyses published in the same area with the same randomized clinical trials (RCTs).

Methods: A systematic review was performed to identify all published meta-analyses of original RCTs that compared direct oral anticoagulants with low molecular weight heparins in cancer patients with venous thromboembolism (VTE). Forest plots were used to represent the meta-analyses results for efficacy (VTE recurrence) and safety (major bleeding) endpoints. An authors' network was constructed to explore the links between the authors of the published meta-analyses.

Results: In the past 3 years, four original RCTs were the subject of 20 published meta-analyses by 142 authors: five, four, and 11 meta-analyses pooled the data of two, three, and four RCTs, respectively. The results of meta-analyses were similar regarding the risks of VTE recurrence and major bleeding. The 11 meta-analyses of four RCTs were published within 6 months of the publication of the last RCT.

Conclusions: The epidemic proportions of such redundant literature and authorship could be moderated by developing "living" meta-analyses and encouraging authors of new RCTs to update the corresponding meta-analysis in the same paper as their original research.
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http://dx.doi.org/10.1111/jth.15280DOI Listing
May 2021

Recovery from acute kidney injury in patients with pulmonary embolism: A single-center study.

Thromb Res 2021 03 14;199:106-109. Epub 2021 Jan 14.

INSERM UMR 1059 SAINBIOSE, Université Jean-Monnet, Saint-Etienne, France; Service De Médecine Vasculaire Et Thérapeutique, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France; INSERM CIC 1408, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2020.12.020DOI Listing
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

Compared to randomized studies, observational studies may overestimate the effectiveness of DOACs: a metaepidemiological approach.

J Clin Epidemiol 2021 Feb 17;130:49-58. Epub 2020 Oct 17.

Unité de Recherche Clinique, Innovation, Pharmacologie, CHU Saint-Etienne, Hôpital Nord, F-42055 Saint-Etienne, France; SAINBIOSE U1059, Université Jean Monnet, University of Lyon, INSERM, F-CRIN INNOVTE Network, F-42023 Saint-Etienne, France. Electronic address:

Background And Objectives: Randomized controlled trials (RCTs) are criticized for including patients who are overselected. Health authorities consequently encourage "real-world" postmarketing cohort studies. Our objective was to determine the differences between RCTs and observational studies as regards their populations and efficacy/safety results.

Methods: A systematic review was conducted to identify RCTs and observational studies including patients with venous thromboembolism receiving direct oral anticoagulants or conventional treatment. Ratios of hazard ratio (RHR) comparing epidemiological studies (prospective and retrospective cohort studies and studies using living databases) with RCTs were computed.

Results: Six RCTs (27,121 patients) and twenty observational studies (248,971 patients) were identified and analyzed. Prospective cohort studies seemed to recruit patients who were no less selected than those of RCTs whereas other types of observational studies may reflect the population treated in real life. Among observational studies, prospective cohort studies yielded the most favorable estimates of treatment effect compared with RCTs. These studies were associated with a nonsignificant 33% increase in efficacy estimate (RHR 0.67, [95% CI, 0.39-1.18]) but no effect on safety estimate. Studies using living databases were associated with nonsignificant trends toward a greater effect on efficacy (RHR 0.82, [0.66-1.01]) and a smaller effect on safety (RHR 1.33, [0.96-1.84]).

Discussion: Overall, in this clinical setting, an exaggeration of the treatment efficacy estimate was seen with observational studies compared with RCTs.

Conclusions: As the presence of residual confounding cannot be excluded, these results should be interpreted cautiously.
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http://dx.doi.org/10.1016/j.jclinepi.2020.10.013DOI Listing
February 2021

Assessment of non-inferiority with meta-analysis: example of hypofractionated radiation therapy in breast and prostate cancer.

Sci Rep 2020 09 22;10(1):15415. Epub 2020 Sep 22.

SAINBIOSE U1059, Equipe DVH, Université Jean Monnet, Saint-Etienne, France.

The aim of this study was to propose a methodology for the assessment of non-inferiority with meta-analysis. Assessment of hypofractionated RT in prostate and breast cancers is used as an illustrative example. Non-inferiority assessment of an experimental treatment versus an active comparator should rely on two elements: (1) an estimation of experimental treatment's effect versus the active comparator based on a meta-analysis of randomized controlled trials and (2) the value of an objective non-inferiority margin. This margin can be defined using the reported effect of active comparator and the percentage of the active comparator's effect that is desired to be preserved. Non-inferiority can then be assessed by comparing the upper bound of the 95% confidence interval of experimental treatment's effect to the value of the objective non-inferiority margin. Application to hypofractionated RT in breast cancer showed that hypofractionated whole breast irradiation (HWBI) appeared to be non-inferior to conventionally fractionated RT for local recurrence. This was not the case for accelerated partial breast irradiation (APBI). Concerning overall survival, non-inferiority could not be claimed for either HWBI or APBI. For prostate cancer, the lack of demonstrated significant superiority of conventional RT versus no RT precluded any conclusion regarding non-inferiority of hypofractionated RT.
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http://dx.doi.org/10.1038/s41598-020-72088-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508968PMC
September 2020

Using 99mTc-(V)-DMSA to follow the vascular calcification process in vascular smooth muscle cells based on pit-1 expression.

Q J Nucl Med Mol Imaging 2020 Jun 15. Epub 2020 Jun 15.

INSERM U1059 Dysfonction Vasculaire et Hémostase, Université de Lyon, UJM-Saint-Etienne, Saint-Étienne, France.

Background: Vascular calcification is an established feature of atherosclerosis process. The sodium/phosphate transporter PiT-1 acts as a biosensor in vascular calcification of VSMCs. [99mTc]-Pentavalent dimercaptosuccinic acid (99mTc-(V)-DMSA) was mediated by PiT-1 transporter in tumoral cells and we propose its evaluation in a vascular calcification in vitro model. The aim of this study was to determine if 99mTc-(V)-DMSA can follow the vascular calcification process in vascular smooth muscle cells (VSMCs) based on PiT-1 expression.

Methods: From a rat aortic VSMC cell line (A7r5), we set up a model of calcification within 7 days using a calcifying medium containing a high inorganic phosphate concentration. Phosphocalcic deposits were monitored with Alizarin red and Von Kossa staining and with phase contrast microscopy. PiT-1 expression was evaluated with an immunofluorescence assay and osteopontin expression, with whole cell ELISA assay. 99mTc-(V)-DMSA uptake was measured in control and calcifying conditions and compared with optical microscopy evaluation.

Results: Under hyperphosphatemia conditions, the VSMC cells progressively overexpressed osteopontin protein, PiT-1 transporter, and synthetized mineralized matrix with phosphocalcic deposition. 99mTc-(V)-DMSA uptake was to 2.8+/-2.08%DA/mg-protein in control cells and 42+/-24%DA/mg-protein in calcified cells (p<0,001). PiT-1 inhibition with phosphonoformic acid completely reverse the calcium deposition as well as the 99mTc-(V)- DMSA uptake. These results demonstrated that 99mTc-(V)-DMSA in vitro uptake is mediated by PiT-1 transporter and follow the VSMC calcification process.

Conclusions: These preliminary in vitro results showed 99mTc-(V)-DMSA uptake follow the phospho-calcic deposition mediated by PiT-1 transporter. This radiotracer may have some potential to detect changes of VSMC metabolism occurring in the atherosclerosis process.
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http://dx.doi.org/10.23736/S1824-4785.20.03225-2DOI Listing
June 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

Severe renal impairment and risk of bleeding during anticoagulation for venous thromboembolism.

J Thromb Haemost 2020 07 11;18(7):1728-1737. Epub 2020 May 11.

Department of Internal Medicine, Hospital Germans Trias i Pujol, Badalona, Spain.

Background: Detection of severe renal impairment in patients with venous thromboembolism (VTE) is mandatory both for selecting anticoagulant therapy and for evaluating major bleeding risk, increased by severe renal impairment.

Objectives: To determine whether the Cockcroft and Gault (CG) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas identify severe renal impairment in the same VTE patients presenting the same risk of major bleeding.

Patients/methods: We compared clinical characteristics and outcomes during the first 3 months of anticoagulation between VTE patients in the RIETE registry with severe renal impairment according to the CG and/or CKD-EPI formula (estimated glomerular filtration rate <30 mL/min and <30 mL/min/1.73 m , respectively). The primary outcome was major bleeding.

Results: Up to October 2017, 41 796 patients were included in RIETE. Among the 4676 patients with severe renal impairment according to at least one of the formulas, this was not confirmed by the other formula in 1904 (40.7%). Major bleeding risk was increased in every patient subgroup with severe renal impairment vs patients without this condition (CG or CKD-EPI < 30: odds ratio [OR] = 2.26, 95% confidence interval [CI 2.01-2.53], only CG < 30: OR = 1.72, 95% CI [1.37-2.13], only CKD-EPI < 30: OR = 2.34, 95% CI [1.77-3.05], CG+CKD-EPI < 30: OR = 2.47, 95% CI [2.16-2.83], all vs CG+CKD-EPI > 30).

Conclusion: The CG and CKD-EPI formulas identify different subgroups of patients with severe renal impairment, leading to discordant results in 40.7% of these patients. Irrespective of the formula used for their identification, patients with severe renal impairment have a higher risk of major bleeding under anticoagulant therapy.
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http://dx.doi.org/10.1111/jth.14837DOI Listing
July 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

Rivaroxaban or Enoxaparin in Nonmajor Orthopedic Surgery.

N Engl J Med 2020 05 29;382(20):1916-1925. Epub 2020 Mar 29.

From the Department of Anesthesia and Critical Care, Groupe Hospitalo-Universitaire Assistance Publique-Hôpitaux de Paris Centre-Université de Paris, Hôpital Cochin (C.M.S., N.R.), Unité de Recherche Clinique, Innovation, Pharmacologie, Centre Hospitalier Universitaire de Saint-Etienne, Sainboise INSERM Unité 1059, Université Jean Monnet, and INSERM CIE1408 (S.L., B.D., E.P., P. Mismetti), French Clinical Research Infrastructure Network (F-CRIN), Investigation Network on Venous Thromboembolism (INNOVTE) (S.L., P.G., P. Mismetti), and Institut du Thorax Curie-Montsouris, Institut Mutualiste Montsouris (P.G.), Paris, INSERM Centre National de la Recherche Scientifique 5558, Université Claude Bernard, Université de Lyon, Lyon (M.C.), and the Department of Anesthesia and Critical Care, Polyclinique du Parc, Saint Saulve (D.D.) - all in France; the Department of Anesthesia and Critical Care, University Hospital Doctor Peset, Valencia (J.L.), and the Department of Anesthesia and Critical Care, Hospital Universitario Fundación de Alcorcón, Madrid (J.M.-M.) - both in Spain; Sektionsleiter Endoprothetik, Sana Klinikum Offenbach, Offenbach am Main, Germany (P. Mouret); and McGill University, Montreal (W.F.).

Background: Nonmajor orthopedic surgery of the lower limbs that results in transient reduced mobility places patients at risk for venous thromboembolism. Rivaroxaban may be noninferior to enoxaparin with regard to the prevention of major venous thromboembolism in these patients.

Methods: In this international, parallel-group, randomized, double-blind, noninferiority trial, we randomly assigned adult patients undergoing lower-limb nonmajor orthopedic surgery who were considered to be at risk for venous thromboembolism on the basis of the investigator's judgment to receive either rivaroxaban or enoxaparin. The primary efficacy outcome of major venous thromboembolism was a composite of symptomatic distal or proximal deep-vein thrombosis, pulmonary embolism, or venous thromboembolism-related death during the treatment period or asymptomatic proximal deep-vein thrombosis at the end of treatment. A test for superiority was planned if rivaroxaban proved to be noninferior to enoxaparin. For all outcomes, multiple imputation was used to account for missing data. Prespecified safety outcomes included major bleeding (fatal, critical, or clinically overt bleeding or bleeding at the surgical site leading to intervention) and nonmajor clinically relevant bleeding.

Results: A total of 3604 patients underwent randomization; 1809 patients were assigned to receive rivaroxaban, and 1795 to receive enoxaparin. Major venous thromboembolism occurred in 4 of 1661 patients (0.2%) in the rivaroxaban group and in 18 of 1640 patients (1.1%) in the enoxaparin group (risk ratio with multiple imputation, 0.25; 95% confidence interval, 0.09 to 0.75; P<0.001 for noninferiority; P = 0.01 for superiority). The incidence of bleeding did not differ significantly between the rivaroxaban group and the enoxaparin group (1.1% and 1.0%, respectively, for major bleeding or nonmajor clinically relevant bleeding; 0.6% and 0.7%, respectively, for major bleeding).

Conclusions: Rivaroxaban was more effective than enoxaparin in the prevention of venous thromboembolic events during a period of immobilization after nonmajor orthopedic surgery of the lower limbs. (Funded by Centre Hospitalier Universitaire de Saint-Etienne and Bayer; PRONOMOS ClinicalTrials.gov number, NCT02401594.).
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http://dx.doi.org/10.1056/NEJMoa1913808DOI Listing
May 2020

Monitoring of biological response to clopidogrel after treatment for non-cardioembolic ischemic stroke or transient ischemic attack.

Am J Transl Res 2019 15;11(9):5332-5337. Epub 2019 Sep 15.

University of Lyon, UJM - Saint-Etienne, Inserm Sainbiose U1089, Saint-Etienne F-42023, France.

Background And Purpose: Biological response to clopidogrel prescribed after a non-cardioembolic ischemic stroke or transient ischemic attack (TIA) has been little studied. The aim of our study (AAPIX) was to assess this response and investigate the agreement between different biological assays in revealing poor responders.

Methods: Patients hospitalized following a non-cardioembolic ischemic stroke or transient ischemic attack (TIA) and prescribed clopidogrel were consecutively included from September 2013 to November 2015 in the Stroke Center of Saint-Etienne Hospital. Blood was drawn after 5 to 8 days of standard-dose clopidogrel. Light transmission aggregometry (LTA) and flow cytometric assays, using vasodilator-stimulated phosphoprotein [VASP] and CD62P, were accomplished for all patients. Transmission electron microscopy (TEM) was performed for a poor clopidogrel-responder and for a patient with discordant platelet assay results (platelet reactivity index (PRI) >50% and maximum platelet aggregation <70%), after activation with adenosine diphosphate (ADP) 10 µM.

Results: 72 patients were included. According to LTA, VASP assay and CD62P test results, 65%, 71% and 0% of patients, respectively, had a low response to clopidogrel, indicating poor agreement between these assays. Images of ADP-activated platelet samples from a patient manifesting a low response to clopidogrel and from a patient with discordant platelet assay results showed an ultrastructural pattern typical of activation and a state of slight activation, respectively.

Conclusions: Platelet function results obtained using different assays for patients having experienced a non-cardioembolic ischemic stroke or TIA were discordant. Transmission electron microscopy could be useful in certain clinical contexts when platelet function assay results disagree.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789282PMC
September 2019

Direct Oral Anticoagulants for the Treatment of Cerebral Venous Thrombosis.

Cerebrovasc Dis 2019 3;48(1-2):32-37. Epub 2019 Sep 3.

Groupe d'Etude Multidisciplinaire sur les Maladies Thrombotiques (GEMMAT), Lyon, France,

Background: Cerebral venous thrombosis (CVT) is an uncommon neurological condition usually treated with heparin followed by oral vitamin K antagonists (VKAs). In patients with venous thromboembolism (VTE), compared to VKAs, direct oral anticoagulants (DOACs) offer several advantages. However, there is little data concerning their use in managing CVT.

Aims: This retrospective observational study pursued 2 objectives: (1) to investigate clinical characteristics of CVT patients treated with heparin + DOACs vs. heparin + standard treatment; (2) to compare clinical outcomes.

Methods: Consecutive CVT patients recruited from January 2016 to March 2018 in 2 French university hospitals (Lyon, Saint-Etienne), and treated with DOACs or VKAs were identified. Radiological evolution, VTE, hemorrhagic events, and antithrombotic medication were recorded. Functional outcome was assessed by the modified Rankin scale score and venous recanalization was assessed by magnetic resonance imaging.

Results: Overall, 41 patients were included: 25 (61%) received VKAs and 16 (39%) DOACs. We identified no clinical or radiological features explaining the physicians' preference for a specific anticoagulation treatment, and age, initial clinical presentation, radiological severity, and individual risk factors thus unlikely guided the choice of anticoagulant. No DOAC patient exhibited clinical or radiological thrombosis aggravation, and the thrombosis completely vanished in 6 (40%). Two of the VKA-treated patients (28.6%) demonstrated complete venous recanalization, whereas 3 others experienced clinical or radiological aggravation versus baseline. There was no major bleeding leading to hospitalization in both groups.

Conclusion: The collected data on DOAC efficacy and safety in CVT management appear encouraging, yet needs to be confirmed by larger prospective randomized clinical trials.
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http://dx.doi.org/10.1159/000502454DOI Listing
May 2020

Platelet Inflammatory Response to Stress.

Front Immunol 2019 28;10:1478. Epub 2019 Jun 28.

GIMAP-EA3064, Université de Lyon, Saint-Étienne, France.

Blood platelets play a central hemostatic role, (i) as they repair vascular epithelial damage, and (ii) they play immune defense roles, as they have the capacity to produce and secrete various cytokines, chemokines, and related products. Platelets sense and respond to local dangers (infectious or not). Platelets, therefore, mediate inflammation, express and use receptors to bind infectious pathogen moieties and endogenous ligands, among other components. Platelets contribute to effective pathogen clearance. Damage-associated molecular patterns (DAMPs) are danger signals released during inflammatory stress, such as burns, trauma and infection. Each pathogen is recognized by its specific molecular signature or pathogen-associated molecular pattern (PAMP). Recent data demonstrate that platelets have the capacity to sense external danger signals (DAMPs or PAMPs) differentially through a distinct type of pathogen recognition receptor (such as Toll-like receptors). Platelets regulate the innate immune response to pathogens and/or endogenous molecules, presenting several types of "danger" signals using a complete signalosome. Platelets, therefore, use complex tools to mediate a wide range of functions from danger sensing to tissue repair. Moreover, we noted that the secretory capacity of stored platelets over time and the development of stress lesions by platelets upon collection, processing, and storage are considered stress signals. The key message of this review is the "inflammatory response to stress" function of platelets in an infectious or non-infectious context.
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http://dx.doi.org/10.3389/fimmu.2019.01478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611140PMC
October 2020

Evaluation of the predictive value of the bleeding prediction score VTE-BLEED for recurrent venous thromboembolism.

Res Pract Thromb Haemost 2019 Jul 25;3(3):364-371. Epub 2019 May 25.

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

Introduction: VTE-BLEED is a validated score for identification of patients at increased risk of major bleeding during extended anticoagulation for venous thromboembolism (VTE). It is unknown whether VTE-BLEED high-risk patients also have an increased risk for recurrent VTE, which would limit the potential usefulness of the score.

Methods: This was a post hoc analysis of the randomized, double-blind, placebo-controlled PADIS-PE trial that randomized patients with a first unprovoked pulmonary embolism (PE) initially treated during 6 months to receive an additional 18-month of warfarin vs. placebo. The primary outcome of this analysis was recurrent VTE during 2-year follow-up after anticoagulant discontinuation, that is, after the initial 6-month treatment in the placebo arm and after 24 months of anticoagulation in the active treatment arm. This rate, adjusted for study treatment allocation, was compared between patients in the high- vs. low-risk VTE-BLEED group.

Results: In complete case analysis (n = 308; 82.4% of total population), 89 (28.9%) patients were classified as high risk; 44 VTE events occurred after anticoagulant discontinuation during 668 patient-years. The cumulative incidence of recurrent VTE was 16.4% (95% confidence interval [CI], 10.0%-26.1%; 14 events) and 14.6% (95% CI, 10.4%-20.3%; 30 events) in the high-risk and low-risk VTE-BLEED groups, respectively, for an adjusted hazard ratio of 1.16 (95% CI, 0.62-2.19).

Conclusion: In this study, patients with unprovoked PE classified at high risk of major bleeding by VTE-BLEED did not have a higher incidence of recurrent VTE after cessation of anticoagulant therapy, supporting the potential yield of the score for making management decisions on the optimal duration of anticoagulant therapy.
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http://dx.doi.org/10.1002/rth2.12214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611364PMC
July 2019

Comparative Real-Life Effectiveness and Safety of Dabigatran or Rivaroxaban vs. Vitamin K Antagonists: A High-Dimensional Propensity Score Matched New Users Cohort Study in the French National Healthcare Data System SNDS.

Am J Cardiovasc Drugs 2020 Feb;20(1):81-103

Bordeaux PharmacoEpi, INSERM CIC 1401 Université de Bordeaux, CHU de Bordeaux, 146 Rue Leo Saignat, 33076, Bordeaux, France.

Background: Clinical trials have indicated that the direct-acting oral anticoagulants dabigatran and rivaroxaban have better risk/benefit profiles than do vitamin K antagonists (VKAs) for stroke prevention in non-valvular atrial fibrillation (NVAF).

Objective: Our objective was to compare the 1-year real-life risk of major clinical events with dabigatran or rivaroxaban versus VKAs for NVAF.

Methods: This was a high-dimensional propensity score (hdPS)-matched cohort study of new users of dabigatran, rivaroxaban or VKAs for NVAF in the French national healthcare systems database in 2013 followed-up for 1 year [22]. Hazard ratios (HRs) with 95% confidence intervals (CIs) for clinical events and death were determined during exposure.

Results: In 2013, a total of 103,101 new anticoagulant users had definite NVAF: 44,653 VKA, 27,060 dabigatran, and 31,388 rivaroxaban. In matched populations, HRs were as follows for dabigatran versus VKAs (20,489 per group): stroke and systemic embolism (SSE) 0.75 (95% CI 0.63-0.88), clinically relevant bleeding (CRB) 0.58 (95% CI 0.51-0.66), hemorrhagic stroke (HS) 0.22 (95% CI 0.14-0.36), gastrointestinal bleeding (GIB) 0.98 (95% CI 0.80-1.19), acute coronary syndrome (ACS) 0.79 (95% CI 0.65-0.95), death 0.74 (95% CI 0.67-0.82), composite (any of the above) 0.71 (95% CI 0.66-0.76). For matched rivaroxaban versus VKA (23,053 per group) HRs were as follows: SSE 0.98 (95% CI 0.85-1.14), CRB 0.83 (95% CI 0.75-0.92), HS 0.65 (95% CI 0.49-0.87), GIB 1.08 (95% CI 0.90-1.30), ACS 0.84 (95% CI 0.71-1.00), death 0.77 (95% CI 0.71-0.84), composite 0.84 (95% CI 0.79-0.89). Numbers needed to treat to observe one fewer death were 49 ± 0.05 with dabigatran or rivaroxaban versus VKAs.

Conclusion: Consistent with results from clinical trials and other observational studies, dabigatran and rivaroxaban were at least as effective and safer than VKAs for the prevention of thromboembolic events in NVAF over 1 year in the French population.

Study Registration: European Medicines Agency EUPAS 13017 (www.encepp.eu) Clinicaltrials.gov id NCT02785354.
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http://dx.doi.org/10.1007/s40256-019-00359-zDOI Listing
February 2020

Predictors for Residual Pulmonary Vascular Obstruction after Unprovoked Pulmonary Embolism: Implications for Clinical Practice-The PADIS-PE Trial.

Thromb Haemost 2019 Sep 23;119(9):1489-1497. Epub 2019 Jun 23.

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 identify risk factors for residual pulmonary vascular obstruction after a first unprovoked pulmonary embolism (PE).

Methods:  Analyses were based on data from the double-blind randomized "PADIS-PE" trial that included 371 patients with a first unprovoked PE initially treated during 6 uninterrupted months; all patients underwent baseline ventilation-perfusion lung scanning at inclusion (i.e., after 6 months of anticoagulation). Each patient's pulmonary vascular obstruction indexes (PVOIs) at PE diagnosis and at inclusion were centrally assessed.

Results:  Among the 371 included patients, residual PVOI was available in 356 patients, and 150 (42.1%) patients had PVOI ≥ 5%. At multivariable analysis, age > 65 years (odds ratio [OR], 2.81, 95% confidence interval [CI], 1.58-5.00), PVOI ≥ 25% at PE diagnosis (OR, 3.53, 95% CI, 1.94-6.41), elevated factor VIII (OR, 3.89, 95% CI, 1.41-10.8), and chronic respiratory disease (OR, 2.18, 95% CI, 1.11-4.26) were independent predictors for residual PVOI ≥ 5%. Patients with ≥ 1 of these factors represented 94.5% (123 patients) of all patients with residual PVOI ≥ 5%.

Conclusion:  Six months after a first unprovoked PE, age > 65 years, PVOI ≥ 25% at PE diagnosis, elevated factor VIII, or chronic respiratory disease were found to be independent predictors for residual pulmonary vascular obstruction.

Clinical Trials Registration:  URL: http://www.controlled-trials.com. Unique identifier: NCT00740883.
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http://dx.doi.org/10.1055/s-0039-1692424DOI Listing
September 2019

Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system: Modeling and assessing interindividual variability.

J Thromb Haemost 2019 10 9;17(10):1670-1682. Epub 2019 Jul 9.

Laboratoire d'Hématologie Biologique, Centre Hospitalier Universitaire Pontchaillou, Rennes, France.

Background: Rivaroxaban is a direct factor Xa inhibitor with substantial inter-individual pharmacokinetic (PK) variability. Pharmacodynamic (PD) variability, especially assessed with thrombin generation (TG), has been less documented.

Objectives: (i) To assess TG parameter time profiles in healthy volunteers, with TG being studied under different conditions and (ii) to model the relationship between rivaroxaban concentrations and TG parameters and subsequently estimate interindividual variability.

Methods: Sixty healthy male volunteers (DRIVING-NCT01627665) received a single 40-mg rivaroxaban dose. Blood sampling was performed at baseline and 10 predefined time points over 24 h. The TG was investigated with the fully automated ST-Genesia system (Stago), using two tissue-factor (TF) concentrations, in the absence (-), or presence (+) of thrombomodulin (TM) for the lowest one. The PD models were built to characterize the relationships between plasma rivaroxaban concentrations and endogenous thrombin potential (ETP) or peak height induced by the lowest TF concentration.

Results: Thrombin generation parameter time profiles with the lowest TF concentration showed a good sensitivity to rivaroxaban, especially +TM (active protein C negative feedback). The relationship between rivaroxaban concentrations and TG parameters was modeled with a sigmoidal relation. Mean rivaroxaban concentrations halving the baseline value of ETP and peak height (-TM) (C ) were of 284 and 33.2 ng/mL, respectively: +TM, C declined to 19.4 and 13.8 ng/mL, reflecting a powerful inhibitory effect. The estimated C population coefficients of variation were of 12.2% (-TM) and 31.3% (+TM) with the peak height models, 34.8% (+TM) with the ETP model.

Conclusions: This low-rivaroxaban to moderate-rivaroxaban PD variability in healthy volunteers contrasts with the substantial PK variability and deserves to be studied in different patient settings.
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http://dx.doi.org/10.1111/jth.14541DOI Listing
October 2019

High tolerance of progressive elastic compression in peripheral arterial disease.

Vasa 2019 Aug 4;48(5):413-417. Epub 2019 Jun 4.

INSERM, U1059 Sainbiose, Université de Lyon, Saint-Étienne, France.

Theoretically progressive compression stockings, which produce a higher compression at the calf than at the ankle level, improve venous return flow without exacerbating peripheral arterial insufficiency (PAD). We aimed to evaluate the short-term tolerance of elastic progressive compression stockings on peripheral arterial vascularisation in patients with symptomatic PAD and associated mild venous insufficiency. Monocentric, prospective, open pilot study of 18 patients (acceptability study, 6 x 6 plan) evaluating the short-term tolerance of progressive compression stockings (18 ± 2 mmHg at calf and 8 ± 2 mmHg at ankle level) in patients with PAD (ankle brachial index ABI > 0.60 < 0.75) and chronic venous insufficiency (C1s-C4 stages of the CEAP classification). Day 15 tolerance was evaluated by a composite primary criteria comprising: no decrease > 15 % of ABI on each side, no decrease > 15 % of toe brachial index (TBI) on each side and no decrease > 25 % of the number of active plantar flexions performed while standing. The proportion of men was 77.8 %, mean age was 77.3 ± 7.5 years and no patient were diabetic. At inclusion, the mean low ABI was 0.60 ± 0.04 and the mean high ABI was 0.77 ± 0.18. The mean low TBI was 0.32 ± 0.09 and the mean high TBI 0.46 ± 0.15. The mean number of active standing plantar flexions was 33.0 ± 5.0. The majority of the patients were classified in CEAP C2s and C3 classes (class 2: 16.7 %, class C2s: 27.8 %, class C3: 44.4 %, class C4: 5.6 % and class C4s: 5.6 %). Poor tolerance occurred in no patient. By day 30, no patient had worsening of their arterial and venous symptoms. No adverse events occurred during the study. Conclusions: These results suggest a high tolerance of progressive elastic stockings (18 ± 2 mmHg at calf and 8 ± 2 mmHg at ankle level) in symptomatic PAD.
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http://dx.doi.org/10.1024/0301-1526/a000799DOI Listing
August 2019

Direct oral anticoagulants are associated with limited damage of endothelial cells of the blood-brain barrier mediated by the thrombin/PAR-1 pathway.

Brain Res 2019 09 20;1719:57-63. Epub 2019 May 20.

INSERM, U1059 Sainbiose, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France; Université de Lyon, Saint-Etienne F-42023, France.

Anticoagulant therapy presents iatrogenic effects such as intracerebral hemorrhage (ICH). The latest anticoagulants on the market, direct oral anticoagulants (DOACs) such as apixaban, dabigatran and rivaroxaban, are reported to cause less ICH than other anticoagulants. Next to the ICH area, the thrombin is accumulated and the blood-brain barrier (BBB) is opened. The effects of thrombin on the BBB are largely mediated by the protease activated receptor (PAR) family, especially the PAR-1 isoform. Our hypothesis is that DOACs may limit the effects of thrombin on endothelial cells (of the BBB) alteration by a mechanism probably involving PAR-1 activation. To test this hypothesis in vitro, we used HBEC-5i human brain endothelial cells as a human BBB model. The effects of thrombin under warfarin, heparin, rivaroxaban, apixaban, and dabigatran treatment on endothelial cells were then investigated by measuring of permeability and junction proteins: ZO-1 and VE-cadherin expressions and PAR-1 cleavage. Depending on the anticoagulant used, we observed three profiles of response of the endothelial cells after thrombin exposure: i) dabigatran treatment allowed maintaining the tightness of the endothelial monolayer; ii) other DOACs limited thrombin-induced alteration of the endothelial monolayer; and iii) pretreatment with warfarin and heparin did not protect from thrombin-induced BBB breakdown. Pretreatment with DOACs clearly limited the impact of thrombin on PAR-1 cleavage in our model, contrary to other anticoagulants, associated with ZO-1 and VE-cadherin expressions. In conclusion, DOACs seem to limit the alteration of the monolayer of endothelial cells of the BBB mediated by the thrombin/PAR-1 pathway.
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http://dx.doi.org/10.1016/j.brainres.2019.05.024DOI Listing
September 2019

Health-related quality of life and mortality in patients with pulmonary embolism: a prospective cohort study in seven European countries.

Qual Life Res 2019 Aug 4;28(8):2111-2124. Epub 2019 Apr 4.

Ramon y Cajal Hospital IRYCIS and Alcala de Henares University, Madrid, Spain.

Purpose: Little is known about the quality of life following pulmonary embolism (PE). The aim of the study was to assess the 12-month illness burden in terms of health-related quality of life (HrQoL) and mortality, in relation to differences in patient characteristics.

Methods: The PREFER in VTE registry, a prospective, observational study conducted in seven European countries, was used. Within 2 weeks following an acute symptomatic PE, patients were recruited and followed up for 12 months. Associations between patient characteristics and HrQoL (EQ-5D-5L) and mortality were examined using a regression approach.

Results: Among 1399 PE patients, the EQ-5D-5L index score at baseline was 0.712 (SD 0.265), which among survivors gradually improved to 0.835 (0.212) at 12 months. For those patients with and without active cancer, the average index score at baseline was 0.658 (0.275) and 0.717 (0.264), respectively. Age and previous stroke were significant factors for predicting index scores in those with/without active cancer. Bleeding events but not recurrences had a noticeable impact on the HrQoL of patients without active cancer. The 12-month mortality rate post-acute period was 8.1%, ranging from 1.4% in Germany, Switzerland, and Austria to 16.8% in Italy. Mortality differed between patients with active cancer and those without (42.7% vs. 4.7%).

Conclusion: PE is associated with a substantial decrease in HrQoL at baseline which normalizes following treatment. PE is associated with a high mortality rate especially in patients with cancer, with significant country variation. Bleeding events, in particular, impact the burden of PE.
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http://dx.doi.org/10.1007/s11136-019-02175-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620245PMC
August 2019

Effects of heparin and derivatives on podocytes: An in vitro functional and morphological evaluation.

J Cell Physiol 2019 Jan 26. Epub 2019 Jan 26.

INSERM, U1059, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France.

Unfractionated heparin (UFH) and low molecular heparin derivatives (LMWH) display numerous biological properties in addition to their anticoagulant effects. However, due to the physicochemical heterogeneity of these drugs, a better understanding concerning their effects on human cells is clearly needed. Considering that heparins are mainly excreted by the kidney, we focused our attention on the effect of UFH and LMWH on human podocytes by functional and morphological/phenotypic in vitro analyses. We demonstrated that these products differentially modulate the permeability of podocyte monolayer to albumin. The functional perturbations observed were correlated to significant cellular morphological and cytoskeletal changes, as well as a decrease in the expression of proteins involved in podocyte adherence to the extracellular matrix or intercellular interactions. This point confirms that UFH and the different LMWHs exert specific effects on podocyte permeability and underlines the need of in vitro tests to evaluate new biological nonanticoagulant properties of LMWH.
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http://dx.doi.org/10.1002/jcp.28191DOI Listing
January 2019

Six months two years of oral anticoagulation after a first episode of unprovoked deep-vein thrombosis. The PADIS-DVT randomized clinical trial.

Haematologica 2019 07 3;104(7):1493-1501. Epub 2019 Jan 3.

Départementde Médecine Interne et Pneumologie, CHU de Brest, Université de Bretagne Occidentale, EA 3878, CIC INSERM 1412, F-CRIN INNOVTE, Brest.

The optimal duration of anticoagulation after a first episode of unprovoked deep-vein thrombosis is uncertain. We aimed to assess the benefits and risks of an additional 18 months of treatment with warfarin placebo, after an initial 6 months of anticoagulation for a first unprovoked proximal deep-vein thrombosis. We conducted a multicenter, randomized, double-blind, controlled trial comparing an additional 18 months of warfarin with placebo in patients with a unprovoked proximal deep-vein thrombosis initially treated for 6 months (treatment period: 18 months; follow up after treatment period: 24 months). The primary outcome was the composite of recurrent venous thromboembolism or major bleeding at 18 months. Secondary outcomes were the composite at 42 months, as well as each component of the composite, and death unrelated to pulmonary embolism or major bleeding, at 18 and 42 months. All outcomes were centrally adjudicated. A total of 104 patients, enrolled between July 2007 and October 2013 were analyzed on an intention-to-treat basis; no patient was lost to follow-up. During the 18-month treatment period, the primary outcome occurred in none of the 50 patients in the warfarin group and in 16 out of 54 patients (cumulative risk, 29.6%) in the placebo group (hazard ratio, 0.03; 95% confidence interval: 0.01 to 0.09; <0.001). During the entire 42-month study period, the composite outcome occurred in 14 patients (cumulative risk, 36.8%) in the warfarin group and 17 patients (cumulative risk, 31.5%) in the placebo group (hazard ratio, 0.72; 95% confidence interval: 0.35-1.46). In conclusion, after a first unprovoked proximal deep-vein thrombosis initially treated for 6 months, an additional 18 months of warfarin therapy reduced the composite of recurrent venous thrombosis and major bleeding compared to placebo. However, this benefit was not maintained after stopping anticoagulation. .
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http://dx.doi.org/10.3324/haematol.2018.210971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601089PMC
July 2019

Comparative effectiveness of direct oral anticoagulants versus low-molecular weight heparins for the prevention of venous thromboembolism after total hip or knee replacement: A nationwide database cohort study.

Pharmacol Res 2019 03 21;141:201-207. Epub 2018 Dec 21.

Bordeaux Pharmacoepi, Inserm CIC1401, Bordeaux University, 33076, Bordeaux, France; INSERM U1219, Bordeaux, 33076, France.

Background: Venous thromboembolism (VTE) after total knee or hip replacement (TKR, THR) is usually prevented with low-molecular weight heparin (LMWH), and increasingly by direct oral anticoagulants (DOAC). The aim of the present study was to compare the benefit-risk and medical costs of DOAC vs. LMWH in a real-life setting.

Methods: All patients with THR or TKR in France between Jan-1st 2013 and Sep-30th 2014, discharged to home, were identified and followed-up for 3 months in the French nationwide claims database, SNDS. DOAC users were 1:1 matched with LWMH users on gender, age and propensity score. Relative risks (RR) of hospitalized VTE, hospitalized bleeding and death were estimated using quasi-Poisson models. Medical costs were calculated according to the societal perspective, including total cost for outpatient claims and national DRG costs for hospitalisations.

Results: Most DOAC users (≥ 98.8%) were matched to a LMWH patient. For the 63,238 matched THR patients, the 3-month absolute risk of VTE was 0.9‰ with DOAC and 2.5‰ with LMWH (RR = 0.35 [0.23 to 0.54]), of bleeding 1.8‰ and 2.1‰ (0.88 [0.62-1.25]), death 0.7‰ and 1.1‰ (0.68 [0.40-1.15]). For the 31,440 matched TKR patients, risks were 1.6‰ and 2.3‰ (0.69 [0.42-1.16]) for VTE, 2.4‰ and 3.8‰ (0.64 [0.43 to 0.97]) for bleeding, and 0.6‰ and 0.8‰ (0.69 [0.30-1.62]) for all-cause death. Mean medical costs were 28% and 21% lower with DOAC than LMWH for THR and TKR, respectively. This nationwide study found a very low risk of VTE, hospitalized bleeding and death after THR or TKR discharge in patients with VTE prevention in real-life setting, with better benefit-risk profiles of DOAC compared to LMWH, and associated cost savings.
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http://dx.doi.org/10.1016/j.phrs.2018.12.018DOI Listing
March 2019