A framework to characterise the reproducibility of meta-analysis results with its application to direct oral anticoagulants in the acute treatment of venous thromboembolism.

The number of meta-analyses of aggregate data has dramatically increased due to the facility of obtaining data from publications and the development of free, easy-to-use, and specialised statistical software. Even when meta-analyses include the same studies, their results may vary owing to different methodological choices. Assessment of the replication of meta-analysis provides an example of the variation of effect 'naturally' observed between multiple research projects. Reproducibility of results has mostly been reported using graphical descriptive representations. A quantitative analysis of such results would enable (i) breakdown of the total observed variability with quantification of the variability generated by the replication process and (ii) identification of which variables account for this variability, such as methodological quality or the statistical analysis procedures used. These variables might explain systematic mean differences between results and dispersion of the results. To quantitatively characterise the reproducibility of meta-analysis results, a bivariate linear mixed-effects model was developed to simulate both mean results and their corresponding uncertainty. Results were assigned to several replication groups, those assessing the same studies, outcomes, treatment indication and comparisons classified in the same replication group. A nested random effect structure was used to break down the total variability within each replication group and between these groups to enable calculation of an intragroup correlation coefficient and quantification of reproducibility. Determinants of variability were investigated by modelling both mean and variance parameters using covariates. The proposed model was applied to the example of meta-analyses evaluating direct oral anticoagulants in the acute treatment of venous thromboembolism.

Replication of systematic reviews: is it to the benefit or detriment of methodological quality?

OBJECTIVES: To perform an overview of the overlap of systematic reviews (SRs) assessing direct oral anticoagulants and characterize these reviews in terms of bias and methodological quality (PROSPERO: CRD42022316273). STUDY DESIGN AND SETTING: A PubMed-indexed search was performed from inception to January 31, 2022 to identify SRs evaluating direct oral anticoagulants in patients treated for an acute venous thromboembolism. The risk of bias of these SRs was assessed according to the Risk Of Bias In Systematic reviews tool. Redundancy was defined as overlap in terms of the type of population considered, the interventions compared, and the studies included. RESULTS: A total of 144 SRs were evaluated, of which 26 (18.1%) were classified as original, 87 (60.4%) as conceptual replications, and 31 (21.5%) as excessive replications. The risk of bias was high in 19 (73.1%) of the original SRs, 65 (74.7%) of the conceptual replications, and 21 (67.7%) of the excessive replications. Compared to the original SRs, the overall methodological quality was not improved in either conceptual or excessive replications. CONCLUSION: A large number of SRs was classified as replications; a fifth constituted excessive replications. The replications showed no improvement in overall methodological quality compared to the original SRs.

Impact of wearable device-based interventions with feedback for increasing daily walking activity and physical capacities in cardiovascular patients: a systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: To systematically review randomised controlled trials (RCTs) using a wearable physical activity monitoring device as an intervention to increase daily walking activity and improve physical capacities in patients with cardiovascular disease (CVD). DESIGN: Systematic review and meta-analysis of RCTs. DATA SOURCES: PubMed, Embase and Web of Science from inception to June 2022. ELIGIBILITY CRITERIA: Randomised controlled studies including patients with CVD over 18 years of age at the end of a cardiac rehabilitation programme comparing an intervention group using a wearable physical activity monitoring device with feedback with usual care or with a control group receiving no feedback on their physical activity and reporting a change in the daily number of steps and/or a change in the distance covered in the 6-minute walk test (6-MWT) or a change in peak oxygen uptake (V̇O2peak) as endpoints. RESULTS: Sixteen RCTs were included. The intervention of wearing a physical activity monitoring device with feedback significantly improved daily number of steps compared with controls (standardised mean difference (SMD) 0.85; 95% CI (0.42; 1.27); p<0.01). The effect was greater when the duration of the intervention was less than 3 months (SMD 1.0; 95% CI (0.18; 1.82); p<0.01) than when the duration of the intervention was 3 months or longer (SMD 0.71; 95% CI (0.27; 1.16); p<0.01), but no significant interaction was found between subgroups (p=0.55). 6-MWT distance and V̇O2peak showed only small effects (SMD 0.34; 95% CI (-0.11; 0.80); p=0.02 and SMD 0.54; 95% CI (0.03; 1.03); p=0.07, respectively). CONCLUSION: The use of wearable physical activity monitoring devices appears to help patients with CVD to increase their daily walking activity and thus their physical activity, particularly in the short term. PROSPERO REGISTRATION NUMBER: CRD42022300423.

Antithrombotic therapy and cardiovascular outcomes after transcatheter aortic valve implantation in patients without indications for chronic oral anticoagulation: a systematic review and network meta-analysis of randomized controlled trials.

AIMS: As the antithrombotic regimen that may best prevent ischaemic complications along with the lowest bleeding risk offset following transcatheter aortic valve implantation (TAVI) remains unclear, we aimed to compare the safety and efficacy of antithrombotic regimens in patients without having an indication for chronic oral anticoagulation. METHODS AND RESULTS: We conducted a PROSPERO-registered (CRD42021247924) systematic review and network meta-analysis of randomized controlled trials evaluating post-TAVI antithrombotic regimens up to April 2022. We estimated the relative risk (RR) and 95% confidence intervals (95% CIs) using a random-effects model in a frequentist pairwise and network metanalytic approach. We included seven studies comprising 4006 patients with a mean weighted follow-up of 12.9 months. Risk of all-cause death was significantly reduced with dual antiplatelet therapy (DAPT) compared with low-dose rivaroxaban + 3-month single antiplatelet therapy (SAPT) (RR 0.60, 95% CI 0.41-0.88), while no significant reduction was observed with SAPT vs. DAPT (RR 1.02, 95% CI 0.67-1.58) and SAPT and DAPT compared with apixaban or edoxaban (RR 0.60, 95% CI 0.32-1.14 and RR 0.59, 95% CI 0.34-1.02, respectively). SAPT was associated with a significant reduction of life-threatening, disabling, or major bleeding compared with DAPT (RR 0.45, 95% CI 0.29-0.70), apixaban or edoxaban alone (RR 0.45, 95% CI 0.25-0.79), and low-dose rivaroxaban + 3-month SAPT (RR 0.30, 95% CI 0.16-0.57). There were no differences between the various regimens with respect to myocardial infarction, stroke, or systemic embolism. CONCLUSION: Following TAVI in patients without an indication for chronic oral anticoagulant, SAPT more than halved the risk of bleeding compared with DAPT and direct oral anticoagulant-based regimens without significant ischaemic offset.

Management of Cancer-Associated Thrombosis in France: A National Survey among Vascular Disease and Supportive Care Specialists.

Low molecular weight heparins (LMWHs) are recommended by international guidelines for at least 6 months in patients with cancer-associated thromboembolism (CAT). Direct oral anticoagulants (DOACs) have been proposed as an alternative to LMWH. In clinical practice, the specialists in charge of CAT have to decide which anticoagulant to prescribe. An electronic survey tool, including vignettes and questions, was sent to members of the French Society of Vascular Medicine, the French-speaking association for supportive care in oncology and the Investigation Network On Venous Thrombo-Embolism. Among the 376 respondents, LMWHs were reported as the first choice by most specialists. The prescription of DOACs within the first 3 weeks of CAT diagnosis was highly dependent on the cancer site: 5.9%, 18.6% and 24.5% in patients with locally advanced colorectal, lung and breast cancer, respectively. The determinants were mostly related to cancer (site and stage or evolution) and to anticancer treatments. For 61% of physicians, some anticancer treatments were contraindications to DOACs. However, almost 90% of physicians considered switching to DOAC after a median 3-month period of LMWHs. In daily practice, LMWHs and DOACs are now considered by specialists of CAT; the decision is mostly driven by the site of cancer. The role of anticancer treatments in the decision remains to be investigated.

Adjusted versus fixed doses of LMWHs in trauma patients: A systematic review and meta-analysis.

PURPOSE: Venous thromboembolism (VTE) causes significant morbidity and mortality in patients with traumatic injuries, despite thromboprophylaxis. To decrease both thrombotic and bleeding risks, some authors suggest adjusting the thromboprophylactic doses of low-molecular-weight heparins (LMWH), in particular according to body weight at treatment initiation or to changes in anti-factor Xa level during treatment. Our objective was to estimate in trauma patients the efficacy and safety of such adjustments, compared with the conventional strategy of fixed-dose LMWH thromboprophylaxis. SOURCE: A systematic review and a meta-analysis were conducted to identify and assess randomised control trials and observational studies with prospective enrolment that included trauma patients and compared adjustment of LMWH thromboprophylaxis versus no adjustment. The primary and secondary endpoints were VTE and bleeding, respectively. The Odds Ratio (OR) and 95% Confidence Interval (95% CI) were calculated using the Mantel-Haenszel method. PRINCIPAL FINDINGS: Nine studies were included in the meta-analysis. No significant reduction in the risk of VTE was observed with adjusted doses of LMWH compared with fixed doses when considering only randomised control trials (OR 1.02 [95% CI, 0.09 to 11.6]) or all trials (OR 0.70 [95% CI, 0.34 to 1.42]). Similarly, there was no significant difference in bleeding risk (OR 1.36, 95% CI 0.59 to 3.10). CONCLUSION: This meta-analysis shows that, to date, there is no evidence to justify adjusting LMWH doses, in agreement with the recommendations of the American College of Chest Physicians.

Prevention of Atrial Fibrillation After Atrial Flutter Ablation With Ramipril (from the PREFACE Study).

The clinical efficacy of the inhibitors of the renin-angiotensin-aldosterone system (RAAS) as an upstream therapy for atrial fibrillation (AF) prevention is controversial. No study has itemized so far the role of RAAS inhibitors in AF prevention after atrial flutter (AFL) ablation. This trial aims to investigate the effect of ramipril compared with placebo on AF occurrence in patients hospitalized for AFL ablation without structural heart disease. The Prevention of Atrial Fibrillation by Inhibition Conversion Enzyme (ICE) After Radiofrequency Ablation of Atrial Flutter (PREFACE) trial was a prospective, multicenter, randomized, double-blind, double-dummy trial depicting the AF occurrence during a 12-month follow-up as the primary end point. A total of 198 patients hospitalized for AFL ablation were enrolled in the trial and randomized to placebo or ramipril 5 mg/day. Patients were followed up during 1 year after AFL ablation using 1-week Holter electrocardiogram at 3, 6, 9, and 12 months. The intention-to-treat population encompassed 97 patients in the ramipril group and 101 patients in the placebo group. The primary end point, such as AF occurrence during the 1-year follow-up, was not different between the 2 groups (p = 0.96). Secondary end points, including the occurrence of supraventricular arrhythmia (p = 0.50), heart failure, stroke, and death, were not different between the 2 groups. Safety outcome parameters, including serious adverse events leading to treatment disruption (p = 0.10), hypotension, impairment of renal function, and elevated serum potassium level, also were not different between the 2 groups. In conclusion, RAAS inhibition using ramipril does not reduce AF occurrence in patients facing AFL ablation during the 1-year follow-up.

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

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

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

INTRODUCTION: Recurrent venous thromboembolism (VTE) despite curative anticoagulation is frequent in patients with cancer. Identifying patients with a high risk of recurrence could have therapeutic implications. A prospective study was designed to validate the Ottawa risk score of recurrent VTE in cancer patients. METHODS: In a prospective multicenter observational cohort, adult cancer patients with a recent diagnosis of symptomatic or incidental lower limb deep vein thrombosis or pulmonary embolism (PE) were treated with tinzaparin for 6 months. The primary endpoint was the recurrence of symptomatic or asymptomatic VTE within the first 6 months of treatment. All clinical events were centrally reviewed and adjudicated. Time-to-event outcomes were estimated by the Kalbfleisch and Prentice method to take into account the competing risk of death. A C-statistic value of > 0.70 was needed to validate the Ottawa score. RESULTS: A total of 409 patients were included and analyzed on an intention-to-treat basis. Median age was 68 years, 60.4% of patients had PE, and VTE was symptomatic in 271 patients (66.3%). The main primary sites were lung (31.3%), lower digestive tract (14.4%), and breast (13.9%) cancers. The Ottawa score was high (≥ 1) in 58% of patients. The 6-month cumulative incidence of recurrent VTE was 7.3% (95% confidence interval [CI]: 4.9-11.1) overall, and 5.0% (95% CI: 2.3-10.8) versus 9.1% (95%CI: 6.1-13.6) in the Ottawa low versus high risk groups, respectively. The C-statistic value was 0.60 (95% CI: 0.55-0.65). CONCLUSION: In this prospective cohort of patients with cancer receiving tinzaparin for VTE, the Ottawa score failed to accurately predict recurrent VTE.

Management of acute venous thromboembolism in patients taking antiplatelet therapy.

BACKGROUND: Concomitant anticoagulant and antiplatelet therapy increases bleeding risk, but most data are derived from patients with atrial fibrillation. Patients with venous thromboembolism (VTE) may differ. OBJECTIVE: To study the management of patients diagnosed with acute VTE while receiving antiplatelet treatment. The primary outcome was the number of patients discharged with concomitant therapy. Secondary outcomes were clinically relevant bleeding, cardiovascular events, recurrent VTE and death during follow-up, according to discharge therapy. METHODS: We performed a post-hoc analysis of patients included in two prospective registries, sharing the same case report form, from 2007 to 2017. RESULTS: Among the 1694 identified patients, 254 (15.0%) were receiving antiplatelet treatment at VTE diagnosis, of whom 61 (24.0%) were discharged with concomitant anticoagulant and antiplatelet therapy. In multivariable analysis, age ≥ 80 years-old and the use of Direct Oral Anticoagulants for VTE therapy were associated with the decision to stop the antiplatelet, while having dual anti-platelet therapy at baseline, a history of coronaropathy or peripheral arterial disease were associated with concomitant anticoagulant and antiplatelet therapy. The decision to stop antiplatelet was associated with a non-significant 46% decrease in the risk of bleeding (OR 0.54 (0.16; 1.78)), and a non-significant 68% increase in the risk of cardiovascular events (OR 1.68 (0.44; 6.46)). CONCLUSION: At acute VTE diagnosis, over 15% of patients were receiving antiplatelet agents, of whom 24% were discharged with concomitant anticoagulant and antiplatelet therapy. This therapeutic decision may be associated with a lower risk of cardiovascular events, but an increased risk of bleeding.

Impact of a Visual Support Dedicated to Prognosis on Symptoms of Stress of ICU Family Members: A Before-and-After Implementation Study.

Family members commonly have inaccurate expectations of patient's prognosis in ICU. Adding to classic oral information, a visual support, depicting day by day the evolution of the condition of the patient, improves the concordance in prognosis estimate between physicians and family members. The objective of this study was to evaluate the impact of this tool on symptoms of anxiety/depression of family members. DESIGN: Bicenter prospective before-and-after study. SETTING: A nonacademic and a university hospital. SUBJECTS: Relatives of consecutive patients admitted in the two ICUs. INTERVENTIONS: In the period "before," family members received classic oral information, and in the period "after," they could consult the visual support in the patient's room. The primary endpoint was the Hospital Anxiety and Depression Scale score of relatives at day 5. Secondary outcomes were the prevalence of symptoms of anxiety (Hospital Anxiety and Depression Scale anxiety subscale score > 7) and depression (Hospital Anxiety and Depression Scale depression subscale score > 7) at day 5 and Hospital Anxiety and Depression Scale score at day 90. MEASUREMENTS AND MAIN RESULTS: A total of 140 patients and their referent family members were included (77 in period before and 63 after). Characteristics of patients of the two groups were similar regarding age, reason for admission, Simplified Acute Physiology Score II at admission, and Sequential Organ Failure Assessment score at day 5. At day 5, median Hospital Anxiety and Depression Scale score was 17 (9-25) before and 15 (10-22) after the implementation of the visual support (p = 0.43). The prevalence of symptoms of anxiety and depression was similar in the two groups (66.2% and 49.4% before and 68.3% and 36.5% after [not significant], respectively). At day 90, median Hospital Anxiety and Depression Scale score was 11 before (7-16) and 9 (5-16) after the implementation of the tool (p = 0.38). CONCLUSIONS: In this study, the use of a visual support tool dedicated to prognosis did not modify the level of stress of family members.

An epidemic of redundant meta-analyses.

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.

Reasons Influencing Long-Term Anticoagulant Treatment Beyond 6 Months for Cancer-Associated Thrombosis in USCAT, A 432-Patient Retrospective Non-Interventional Study.

Background and objectives: Few data are available about anticoagulation management beyond 6 months in patients with cancer associated thrombosis (CAT). Our objective was to describe anticoagulant treatment modalities up to 12 months. Methods: The management of the anticoagulant treatment beyond 6 months was described in this initially retrospective non-interventional French multicenter study in patients treated with low-molecular-weight heparins (LMWH) still alive at the end of an initial 6-month treatment period. Clinical outcomes, including venous thromboembolism, recurrence, bleeding and deaths have been published previously. Results: Among the 432 patients (mean age 66.5±12.7 years) included in the study, 332 were followed up to 12 months while 96 patients deceased before study end and 4 patients were lost-to-follow-up. At 6 months, anticoagulant therapy was stopped in 74 patients, 56 were switched to vitamin K antagonists (VKA) (16.1% [95%CI, 12.4%-20.4]), 30 to direct oral anticoagulants (DOAC) (8.6% [95%CI, 5.9%-12.1]). LMWHs were maintained in 256 patients (73.6% [95%CI, 68.6-78.1]). During the follow-up, LMWHs were definitively discontinued in 86 patients (33.7%), the main reason being a favorable course of the cancer (16 patients, 18.6%), or the thromboembolic disease (11 patients, 12.8%), whereas concern about bleeding risk was low (2 patients, 2.3%). Conclusion: Anticoagulation beyond 6 months and up to 12 months was in accordance with clinical practice guidelines suggesting that treatment should be continued as long cancer is active or in the absence of bleeding risk. Anticoagulant treatment discontinuation beyond 6 months was influenced by the favorable courses of both malignancy and thromboembolic disease, as well as patient's preference.

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

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.

Indirect comparison of the efficacy and safety of alirocumab and evolocumab: a systematic review and network meta-analysis.

AIMS: Although alirocumab and evolocumab have both been associated with improved outcomes in patients with dyslipidaemia 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 vs. 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 (RR) and the 95% confidence intervals (CIs) 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.

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

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 Thrombosis Research 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.

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

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.

Perinatal inflammation is associated with social and motor impairments in preterm children without severe neonatal brain injury.

OBJECTIVE: To test the association between exposure to perinatal inflammation - i.e. clinical chorioamnionitis or early-onset neonatal infection - in preterm children without severe neonatal brain injury and neurodevelopmental outcome at 30 months of corrected age (CA). DESIGN: Cross-sectional study from a French regional cohort of clinical follow-up (SEVE Network). PATIENTS: One hundred sixty-four surviving neonates without severe brain injury - namely, grade III and IV cerebral hemorrhage and cystic periventricular leukomalacia - and without late-onset neonatal inflammation exposure - namely, late-onset neonatal infection and necrotizing enterocolitis -, born at less than 33 weeks of gestational age from November 2011 to June 2015 and enrolled in the SEVE Network. MAIN OUTCOME MEASURE: Global developmental quotient (DQ) score of the revised Brunet-Lézine scale and its four indices measured by the same neuropsychologist at 30 months of CA. RESULTS: After multivariate analysis, exposure to perinatal inflammation was not found significantly associated with a modification of the global DQ score (coefficient -1.7, 95% CI -4.8 to 1.3; p = 0.26). Exposure to perinatal inflammation was associated with a decrease of the gross motor function DQ score (coefficient -6.0, 95% CI -9.9 to -2.1; p < 0.01) and a decrease of the sociability DQ score (coefficient -5.1, 95% CI -9.2 to -0.9; p = 0.02). Language and visuospatial coordination DQ scores were not affected by exposure to perinatal inflammation. CONCLUSION: Exposure to perinatal inflammation in preterm children without severe neonatal brain injury is independently associated with decreased motor and social abilities at 30 months of CA.

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

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.