Publications by authors named "Silvy Laporte"

92 Publications

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.

Georges Pompidou European Hosp, Paris, 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 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 >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, VTE was symptomatic in 271 patients (66.3%). The main primary sites were lung (31.3%), digestive tract (18.3%) 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) vs 9.1% (95%CI: 6.1-13.6) in the Ottawa low vs 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

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

Prothrombotic hemostasis disturbances in patients with severe COVID-19: Individual daily data.

Data Brief 2020 Dec 10;33:106519. Epub 2020 Nov 10.

Université catholique de Louvain, CHU UCL Namur, Hematology Laboratory, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), Yvoir, Belgium.

This data article accompanies the manuscript entitled: "Prothrombotic Disturbances of hemostasis of Patients with Severe COVID-19: a Prospective Longitudinal Observational Cohort Study" submitted to by the same authors. We report temporal changes of plasma levels of an extended set of laboratory parameters during the ICU stay of the 21 COVID-19 patients included in the monocentre cohort: CRP, platelet count, prothrombin time; Clauss fibrinogen and clotting factors II, V and VIII levels, D-dimers, antithrombin activity, protein C, free protein S, total and free tissue factor pathway inhibitor, PAI-1 levels, von Willebrand factor antigen and activity, ADAMTS-13 (plasma levels); and of two integrative tests of coagulation (thrombin generation with ST Genesia) and fibrinolysis (global fibrinolytic capacity - GFC). Regarding hemostasis, we used double-centrifuged frozen citrated plasma prospectively collected after daily performance of usual coagulation tests. Demographic and clinical characteristics of patients and thrombotic and hemorrhagic complications were also collected from patient's electronic medical reports.
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http://dx.doi.org/10.1016/j.dib.2020.106519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654236PMC
December 2020

Prothrombotic disturbances of hemostasis of patients with severe COVID-19: A prospective longitudinal observational study.

Thromb Res 2021 01 24;197:20-23. Epub 2020 Oct 24.

Université catholique de Louvain, CHU UCL Namur, Hematology Laboratory, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), Yvoir, Belgium. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2020.10.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585359PMC
January 2021

Preventing venous thrombo-embolism after nonmajor orthopedic surgery.

Trends Cardiovasc Med 2020 Nov 2. Epub 2020 Nov 2.

Institut du Thorax Curie-Montsouris, Institut Mutualiste Montsouris, 75014 Paris, France; F-CRIN INNOVTE Network, Paris, France.

The venous thromboembolism risk is low to moderate in nonmajor orthopedic surgery. The literature is unconclusive. New emerging data are now available. The global patient risk has to be taken into account to determine the need for any prophylaxis.
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http://dx.doi.org/10.1016/j.tcm.2020.10.013DOI Listing
November 2020

Rivaroxaban or Enoxaparin in Nonmajor Orthopedic Surgery. Reply.

N Engl J Med 2020 10;383(17):1694

Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France.

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http://dx.doi.org/10.1056/NEJMc2028468DOI Listing
October 2020

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

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

Survival after hypofractionation in glioblastoma: a systematic review and meta-analysis.

Radiat Oncol 2020 Jun 8;15(1):145. Epub 2020 Jun 8.

SAINBIOSE U1059, Jean Monnet University, Saint-Etienne, France.

Background: Glioblastoma multiforme (GBM) has a poor prognosis despite a multi modal treatment that includes normofractionated radiotherapy. So, various hypofractionated alternatives to normofractionated RT have been tested to improve such prognosis. There is need of systematic review and meta-analysis to analyse the literature properly and maybe generalised the use of hypofractionation. The aim of this study was first, to perform a meta-analysis of all controlled trials testing the impact of hypofractionation on survival without age restriction and secondly, to analyse data from all non-comparative trials testing the impact of hypofractionation, radiosurgery and hypofractionated stereotactic RT in first line.

Materials/methods: We searched Medline, Embase and Cochrane databases to identify all publications testing the impact of hypofractionation in glioblastoma between 1985 and March 2020. Combined hazard ratio from comparative studies was calculated for overall survival. The impact of study design, age and use of adjuvant temozolomide was explored by stratification. Meta-regressions were performed to determine the impact of prognostic factors.

Results: 2283 publications were identified. Eleven comparative trials were included. No impact on overall survival was evidenced (HR: 1.07, 95%CI: 0.89-1.28) without age restriction. The analysis of non-comparative literature revealed heterogeneous outcomes with limited quality of reporting. Concurrent chemotherapy, completion of surgery, immobilization device, isodose of prescription, and prescribed dose (depending on tumour volume) were poorly described. However, results on survival are encouraging and were correlated with the percentage of resected patients and with patients age but not with median dose.

Conclusions: Because few trials were randomized and because the limited quality of reporting, it is difficult to define the place of hypofactionation in glioblastoma. In first line, hypofractionation resulted in comparable survival outcome with the benefit of a shortened duration. The method used to assess hypofractionation needs to be improved.
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http://dx.doi.org/10.1186/s13014-020-01584-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278121PMC
June 2020

Genesis of an emergency public drug information website by the French Society of Pharmacology and Therapeutics during the COVID-19 pandemic.

Fundam Clin Pharmacol 2020 Jun;34(3):389-396

Univ. Grenoble Alpes, CHU Grenoble Alpes, Grenoble, France.

On March 16, 2020, the French Society of Pharmacology and Therapeutics put online a national Question and Answer (Q&A) website, https://sfpt-fr.org/covid19 on the proper use of drugs during the COVID-19 pandemic. The working group 'Drugs and COVID-19' was composed of a scientific council, an editorial team, and experts in the field. The first questions were posted online during the first evening of home-confinement in France, March 17, 2020. Six weeks later, 140 Q&As have been posted. Questions on the controversial use of hydroxychloroquine and to a lesser extent concerning azithromycin have been the most consulted Q&As. Q&As have been consulted 226 014 times in 41 days. This large visibility was obtained through an early communication on Twitter, Facebook, traditional print, and web media. In addition, an early communication through the French Ministry of Health and the French National Agency for Medicines and Health Products Safety ANSM had a large impact in terms of daily number of views. There is a pressing need to sustain a public drug information service combining the expertise of scholarly pharmacology societies, pharmacovigilance network, and the Ministry of Health to quickly provide understandable, clear, expert answers to the general population's concerns regarding COVID-19 and drug use and to counter fake news.
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http://dx.doi.org/10.1111/fcp.12564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273039PMC
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

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

Indirect Comparison of the Efficacy and Safety of Alirocumab and Evolocumab: A Systematic Review and Network Meta-Analysis.

Eur Heart J Cardiovasc Pharmacother 2020 Apr 10. Epub 2020 Apr 10.

Sorbonne Université, ACTION study group, UMR_S 1166, Institut de Cardiologie, Pitié Salpêtrière Hospital (AP-HP), Paris, France.

Aims: Although alirocumab and evolocumab have both been associated with improved outcomes in patients with dyslipidemia or established atherosclerotic cardiovascular disease, data on their respective performances are scarce. This study aimed at providing an indirect comparison of the efficacy and safety of alirocumab versus evolocumab.

Methods And Results: We conducted a systematic review and network meta-analysis of randomized trials comparing alirocumab or evolocumab to placebo with consistent background lipid lowering therapy up to November 2018. We estimated the relative risk and the 95% confidence intervals using fixed effect model in a frequentist pairwise and network meta-analytic approach. A total of 30 trials, enrolling 59,026 patients were included. Eligibility criteria varied significantly across trials evaluating alirocumab and evolocumab. Compared with evolocumab, alirocumab was associated with a significant reduction in all-cause death (RR: 0.80; 95%CI: 0.66-0.97) but not in cardiovascular death (RR: 0.83; 95%CI: 0.65-1.05). This study did not find any significant differences in myocardial infarction (RR: 1.15; 95%CI: 0.99-1.34), stroke (RR: 0.96; 95%CI: 0.71-1.28) or coronary revascularization (RR: 1.13; 95%CI: 0.99-1.29) between the two agents. Alirocumab was associated with a 27% increased risk of injection site reaction compared to evolocumab; however, no significant differences were found in terms of treatment discontinuations, systemic allergic reaction, neurocognitive events, ophthalmologic events, or new-onset of or worsening of pre-existing diabetes.

Conclusion: Alirocumab and evolocumab share a similar safety profile except for injection site reaction. No significant differences were observed across the efficacy endpoints, except for all-cause death, which may be related to the heterogeneity of the studied populations treated with the two drugs.
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http://dx.doi.org/10.1093/ehjcvp/pvaa024DOI Listing
April 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

From single-arm studies to externally controlled studies. Methodological considerations and guidelines.

Therapie 2020 Jan - Feb;75(1):21-27. Epub 2019 Dec 16.

Bristol-Myers Squibb, 92500 Rueil-Malmaison, France.

Single-arm studies are sometimes used as pivotal studies but they have methodological limitations which prevent them from obtaining the high level of reliability as for a randomised controlled study which remains the gold standard in the evaluation of new treatments. The objective of this roundtable was to discuss the limitations of these single-arm studies, to analyse available and acceptable solutions in order to propose guidelines for their conduct and assessment. Single-arm studies themselves are intrinsically inappropriate for demonstrating the benefit of a new treatment because it is impossible to infer the benefit from a value obtained under treatment without knowing what it would have been in the absence of the new treatment. The implication is that comparison with other data is necessary. However this comparison has limitations due to (1) the post hoc choice of the reference used for comparison, (2) the confusion bias for which an adjustment approach is imperative and, (3) the other biases, measure and attrition among others. When these limitations are taken into account this should, first and foremost, lead to the conduct of externally controlled trials instead of single-arm trials as is proposed by the latest version of ICH E10. Moreover, the external control must be formalised in the study protocol with a priori selection of both the reference control and the formal method of comparison: test in relation to a standard, adjustment on individual data, a synthetic control group or matching-adjusted indirect comparisons (MAIC). Lastly, externally controlled studies must be restricted to situations where randomisation is infeasible. To be acceptable, these studies must be able to guarantee freedom from residual confusion bias, which is only truly acceptable if the observed effect is dramatic and the usual course of the disease is highly predicable.
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http://dx.doi.org/10.1016/j.therap.2019.11.007DOI Listing
December 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

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

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

Does obstructive sleep apnea affect exercise capacity and the hemodynamic response to exercise? An individual patient data and aggregate meta-analysis.

Sleep Med Rev 2019 06 14;45:42-53. Epub 2019 Mar 14.

SNA-EPIS Laboratory, University of Lyon, University Jean Monnet Saint-Etienne, EA 4607, France; Department of Clinical and Exercise Physiology, University Hospital of Saint-Etienne, France.

Obstructive sleep apnea (OSA) has been linked to altered cardiovascular response to exercise. A systematic review and individual patient data (IPD) meta-analysis were conducted to assess whether OSA patients present reduced exercise capacity. PubMed, Embase and Web of Science were searched until September 2018. Studies which performed sleep recording in both OSA patients and controls and measured maximal oxygen consumption (VO) via a maximal exercise test were included. IPD were provided for five trials upon the 18 eligible (N = 289) and a two-stage IPD meta-analysis model was used, allowing to standardize the apnea cutoff and adjust for confounders. IPD meta-analysis demonstrated that moderate to severe OSA patients had similar VO (mean difference: -1.03 mL·kg min; 95% CI: -3.82 to 1.76; p = 0.47) and cardiovascular response to exercise compared to mild or non-OSA patients. By contrast, aggregate data (AD) meta-analysis including the 13 trials for which IPD were unavailable (N = 605) revealed that VO was reduced in OSA patients compared to controls (mean difference: -2.30 mL·kg min; 95% CI: -3.96 to -0.63; p < 0.001) with high heterogeneity. In conclusion, IPD meta-analysis suggests that VO and the cardiovascular response to exercise are preserved in moderate to severe OSA patients while AD meta-analysis suggests lower VO in severe OSA.
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http://dx.doi.org/10.1016/j.smrv.2019.03.002DOI Listing
June 2019

Predicting the dose of vancomycin in ICU patients receiving different types of RRT therapy: a model-based meta-analytic approach.

Br J Clin Pharmacol 2019 06 7;85(6):1215-1226. Epub 2019 Apr 7.

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

Aim: Previous pharmacokinetic (PK) studies have proposed various dosing regimens for vancomycin in intensive care unit (ICU) patients undergoing renal replacement therapy (RRT), but all are restricted to specific RRT modalities. To be useful in practice, a population PK model would need to predict vancomycin clearance during any RRT modality. Development of such a model is feasible using meta-analysis of published summarized estimates of vancomycin PK parameters. Our aims were: (i) to develop and validate a population PK model for vancomycin that takes into account any RRT modalities, and (ii) to predict vancomycin dosing for RRT patients in ICU.

Methods: Vancomycin pharmacokinetics were assumed to be two-compartmental, total body clearance being the sum of non-RRT clearance and RRT-induced clearance. Drug disposition and non-RRT clearance parameters were estimated by systematic review and meta-analysis of previously published parameter estimates. The relationship between RRT-induced clearance and RRT flowrate settings was assessed using a model-based meta-analysis. Prediction performances of the PK model were assessed using external data.

Results: The meta-analyses of disposition parameters, non-RRT clearance and RRT-induced clearance included 11, 6 and 38 studies (84 RRT clearance measurements) respectively. The model performed well in predicting external individual PK data. Individual vancomycin concentrations during RRT were accurately predicted using Bayesian estimation based solely on pre-RRT measurements.

Conclusions: The PK model allowed accurate prediction of the vancomycin pharmacokinetics during RRT in ICU patients. Based on the model of RRT-induced clearance, an appropriate adjustment of the vancomycin dosing regimen could be proposed for any kind of flowrate settings.
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http://dx.doi.org/10.1111/bcp.13904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533443PMC
June 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

Role of platelet α2-adrenoreceptor in biological low response to Clopidogrel for patients with non cardioembolic ischemic stroke or transient ischemic attack.

Am J Transl Res 2018 15;10(8):2712-2721. Epub 2018 Aug 15.

Vascular and Therapeutic Medicine Department, Saint-Etienne University Hospital Center, North Hospital Saint-Etienne F-42055, France.

Background And Purpose: Low biological response to Clopidogrel prescribed after non cardioembolic ischemic stroke or transient ischemic attack (TIA) is a major clinical problem and could explain the recurrence of vascular events. Platelet α2-adrenoreceptors are involved in the high residual platelet reactivity in stable coronary artery disease patients on dual antiplatelet therapy. In the present study we investigated the impact of platelet α2-adrenoreceptors on ADP-induced platelet aggregation and on ADP-induced platelet membrane CD62P (P-selectin) expression, a marker of platelet activation on blood samples from patients hospitalized at the acute phase of a non cardioembolic ischemic stroke or TIA.

Methods: 72 consecutive patients were prospectively recruited over the course of two years in a monocentric study. Patients received a daily 75 mg-dose of Clopidogrel. ADP-induced platelet aggregation was measured alone, with low dose epinephrine or with atipamezole, a selective α blocker of α2-adrenoreceptors, by Light Transmittance Aggregometry (LTA). Platelet membrane expression of P-selectin was measured by flow cytometry with either ADP alone or combined with epinephrine.

Results: Epinephrine at low dose stimulated ADP-induced platelet membrane expression of CD62P whereas Atipamezole significantly inhibited 10 µM ADP-induced platelet aggregation.

Conclusions: Our study showed the role of platelet α2-adrenoreceptors in biological low response to Clopidogrel for patients hospitalized for a non-cardioembolic ischemic stroke or TIA. Atipamezole could improve the status of biological response to Clopidogrel.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129516PMC
August 2018

Benefit of Risk Score-Guided Prophylaxis in Pregnant Women at Risk of Thrombotic Events: A Controlled Before-and-After Implementation Study.

Thromb Haemost 2018 Sep 13;118(9):1564-1571. Epub 2018 Aug 13.

INSERM U1059, Saint-Etienne, France.

Background:  Management of pregnant women at risk of venous thromboembolism (VTE) and placental vascular complications (PVCs) remains complex. Guidelines do not definitively specify optimal strategies.

Objective:  Our objective was to evaluate the impact of employing risk score-driven prophylaxis strategies on VTE and PVC rates in at-risk pregnant women.

Materials And Methods:  This study, conducted in 21 French maternity units, compared VTE and PVC rates before and after implementation of a risk scoring system to determine prophylactic strategies.

Results:  A total of 2,085 pregnant women at risk of VTE or PVC were enrolled. Vascular events occurred in 190 (19.2%) patients before and 140 (13.0%) after implementation of risk score-driven prophylaxis (relative risk [RR] = 0.68 [0.55; 0.83]). The incidence of deep vein thrombosis during pregnancy was reduced (RR = 0.30 [0.14; 0.67]). PVC comprised mainly pre-eclampsia, occurring in 79 patients before and 42 patients after risk score implementation (RR = 0.52 [0.36; 0.75]). Post-partum haemorrhage occurred in 32 patients (3.2%) before and 48 patients (4.5%) after risk score implementation (RR = 1.38 [0.89; 2.13],  = 0.15).

Conclusion:  Use of a simple risk scoring system, developed by experts in VTE and PVC research to guide prophylaxis, reduced the risk of thrombotic events during pregnancy without any significant increase in bleeding risk.
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http://dx.doi.org/10.1055/s-0038-1668524DOI Listing
September 2018

Cancer-associated thrombosis in patients with implanted ports: a prospective multicenter French cohort study (ONCOCIP).

Blood 2018 08 6;132(7):707-716. Epub 2018 Jul 6.

INSERM, Centre d'Investigation Clinique 1408, Saint-Etienne, France.

The need to accurately identify cancer outpatients at high risk of thrombotic complications is still unmet. In a prospective, multicenter cohort study (ONCOlogie et Chambres ImPlantables [ONCOCIP]), consecutive adult patients with a solid tumor and implanted port underwent 12-month follow-up. Our primary objective was to identify risk factors for (1) catheter-related thrombosis, defined as ipsilateral symptomatic upper-limb deep-vein thrombosis with or without pulmonary embolism, and (2) venous thromboembolism other than catheter-related, defined as any symptomatic superficial- or deep-vein thrombosis (other than catheter-related) or pulmonary embolism, and incidental pulmonary embolism. All events were objectively confirmed and centrally adjudicated. Rate assessments integrated competing risk of death. Overall, 3032 patients were included (median age: 63 years; women: 58%). The most frequent cancer locations were breast (33.7%), lung (18.5%), and colorectal (15.6%), cancer being metastatic in 43.2% of patients. Most patients (97.1%) received chemotherapy. By 12 months, 48 (1.6%) patients had been lost to follow-up and 656 (24.6%) had died; 3.8% (n = 111) of patients had experienced catheter-related thrombosis, and 9.6% (n = 276) venous thromboembolism other than catheter-related. By multivariate analysis, use of cephalic vein for catheter insertion predicted catheter-related thrombosis, whereas ongoing antiplatelet therapy was protective; risk factors for venous thromboembolism other than catheter-related were advanced age, previous venous thromboembolism, cancer site, and low hemoglobin level or increased leukocyte count before chemotherapy. In conclusion, this large prospective cohort study showed a high rate of venous thromboembolism in patients with a solid tumor and implanted port. Risk factors for catheter-related thrombosis differed from those for venous thromboembolism not catheter-related. This trial was registered at www.clinicaltrials.gov as #NCT02025894.
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http://dx.doi.org/10.1182/blood-2018-03-837153DOI Listing
August 2018

Risk factors for recurrent venous thromboembolism after unprovoked pulmonary embolism: the PADIS-PE randomised trial.

Eur Respir J 2018 01 4;51(1). Epub 2018 Jan 4.

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

We aimed to identify risk factors for recurrent venous thromboembolism (VTE) after unprovoked pulmonary embolism.Analyses were based on the double-blind randomised PADIS-PE trial, which included 371 patients with a first unprovoked pulmonary embolism initially treated during 6 months who were randomised to receive an additional 18 months of warfarin or placebo and followed up for 2 years after study treatment discontinuation. All patients had ventilation/perfusion lung scan at inclusion ( at 6 months of anticoagulation).During a median follow-up of 41 months, recurrent VTE occurred in 67 out of 371 patients (6.8 events per 100 person-years). In main multivariate analysis, the hazard ratio for recurrence was 3.65 (95% CI 1.33-9.99) for age 50-65 years, 4.70 (95% CI 1.78-12.40) for age >65 years, 2.06 (95% CI 1.14-3.72) for patients with pulmonary vascular obstruction index (PVOI) ≥5% at 6 months and 2.38 (95% CI 1.15-4.89) for patients with antiphospholipid antibodies. When considering that PVOI at 6 months would not be available in practice, PVOI ≥40% at pulmonary embolism diagnosis (present in 40% of patients) was also associated with a 2-fold increased risk of recurrence.After a first unprovoked pulmonary embolism, age, PVOI at pulmonary embolism diagnosis or after 6 months of anticoagulation and antiphospholipid antibodies were found to be independent predictors for recurrence.
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http://dx.doi.org/10.1183/13993003.01202-2017DOI Listing
January 2018

Angiogenic factors for prediction of preeclampsia and intrauterine growth restriction onset in high-risk women: AngioPred study.

J Matern Fetal Neonatal Med 2019 Jan 22;32(2):248-257. Epub 2017 Sep 22.

a Department of Gynaecology and Obstetrics , University Hospital , Saint Étienne , France.

Objective: The study aimed to compare the level of two angiogenic factors, soluble fms-like tyrosine kinase-1 (sFlt1) and soluble endoglin (sEng), for the prediction of preeclampsia and intrauterine growth restriction in high-risk pregnant women.

Methods: A prospective multicenter cohort study of 200 pregnant patients was conducted between June 2008 and October 2010. sFlt1 and sEng were measured by enzyme-linked immunosorbent assay.

Results: Forty-five patients developed a placenta-mediated adverse pregnancy outcome. Plasma levels of sFlt1 and sEng were higher in patients who will experience a preeclampsia at 28, 32, and 36 weeks compared with patients with no complication. The same results were observed for intrauterine growth restriction. Plasma levels of sFlt1 and sEng were not significantly different for patients with preeclampsia compare to patients with intrauterine growth restriction. Patients with early pre-eclampsia (PE) had very high rates of angiogenic factors at 20, 24, and 28 weeks. Patients with late PE and early and late intrauterine growth retardation (IUGR) had high rates at 32 and 36 weeks.

Conclusion: In high-risk women, angiogenic factors are disturbed before the onset of preeclampsia and this is true for intrauterine growth restriction.
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http://dx.doi.org/10.1080/14767058.2017.1378325DOI Listing
January 2019