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Introduction: Estimation of residual apixaban plasma concentrations may be requested in the management of emergencies. This study aims at assessing the performance of specific anti-Xa assays calibrated with apixaban on real-life samples with low apixaban plasma concentrations (®-Liquid Anti-Xa assay (STA ® LAX) and the low and normal procedures of the Biophen ®Direct Factor Xa Inhibitors (DiXaI) assay was tested on 134 blood samples, collected from patients on apixaban, wherefrom 74 patients received LMWH after apixaban cessation. The results were compared with the liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) measurements. Results: The Biophen ®DiXaI, Biophen ®DiXaI LOW, and STA ®LAX showed very good correlation with LC-MS/MS measurements in patients without LMWH administration (Spearman r.95,.99, and.98, respectively). Their limits of quantitation were defined at 48, 24, and 12 ng/mL, respectively. The Bland-Altman test measured mean bias (SD) at 5.6 (13.1), −2.5 (5.0), and −0.8 (6.1) ng/ml, respectively. The Spearman r of the Biophen ®DiXaI decreased to 0.64 in presence of low apixaban concentrations. The Spearman r of the Biophen ®DiXaI LOW and STA ®LAX decreased to 0.39 and 0.26, respectively, in presence of LMWH. Conclusions: The accuracy of the low methodologies (Biophen ®DiXaI LOW and STA ®LAX) is slightly improved for low apixaban plasma concentrations, compared with the normal procedure of Biophen ®DiXaI. The interference of LMWH on the low methodologies is measurable, however, less important than the previously reported interference of LMWH on rivaroxaban calibrated specific anti-Xa assays.

Background Guidelines recommend performing atrial fibrillation (AF) catheter ablation without interruption of a direct oral anticoagulants (DOACs) and to administer unfractionated heparin (UFH) for an activated clotting time (ACT) ≥300 seconds, by analogy with vitamin K antagonist (VKA). Nevertheless, pharmacological differences between DOACs and VKA, especially regarding ACT sensitivity and UFH response, prevent extrapolation from VKA to DOACs. Hypothesis The level of anticoagulation at the time of the procedure in uninterrupted DOAC-treated patients is unpredictable and would complicate intraprocedural UFH administration and monitoring. Methods This prospective study included interrupted DOAC-treated patients requiring AF ablation. Preprocedural DOAC concentration ([DOAC]), intraprocedural UFH administration, and ACT values were recorded. A cohort of DOAC-treated patients requiring flutter catheter ablation was considered to illustrate [DOAC] without DOAC interruption. Results Forty-eight patients underwent AF and 14 patients underwent flutter ablation, respectively. In uninterrupted DOAC-treated patients, [DOAC] ranged from ≤30 to 466 ng/mL. When DOAC were interrupted, from 54 to 218 hours, [DOAC] were minimal (maximum: 36 ng/mL), preventing DOAC-ACT interference. Anyway, ACT values were poorly correlated with UFH doses (R 2 = 0.2256). Conclusions Our data showed that uninterrupted DOAC therapy resulted in an unpredictable and highly variable initial level of anticoagulation before catheter ablation. Moreover, even with DOAC interruption preventing interference between DOAC, UFH, and ACT, intraprocedural UFH monitoring was complex. Altogether, our exploratory results call into question the appropriateness of transposing UFH dose protocols, as well as the relevance of ACT monitoring in uninterrupted DOAC-treated patients.

Aims Patients receiving direct oral anticoagulants (DOACs) frequently undergo elective invasive procedures. Their management is challenging. We aimed to determine the optimal duration of DOAC discontinuation that ensures a minimal anticoagulant effect during the procedure. Methods and results This prospective multicentre study included 422 DOAC-treated patients requiring an invasive procedure. Pre-procedural DOAC concentration ([DOAC]) and routine haemostasis assays were performed to determine i/the proportion of patients who achieved a minimal pre-procedural [DOAC] (≤30 ng/mL) according to the duration of DOAC discontinuation, ii/the predictors of minimal [DOAC] and, iii/the ability of routine assays to predict minimal [DOAC]. Lastly, we assessed the predictors of peri-procedural bleeding events. The duration of DOAC discontinuation ranged from 1 to 218 h and pre-procedural [DOAC] from ≤30 to 527 ng/mL. After a 49-72-h discontinuation, 95% of the [DOAC] were ≤30 ng/mL. A 72-h discontinuation predicted concentrations ≤30 ng/mL with 91% specificity. In multivariable analysis, duration of DOAC discontinuation, creatinine clearance

INTRODUCTION: Andexanet alfa is a recombinant modified factor Xa protein that has been developed to reverse factor Xa inhibitors. Since May 2018, the FDA has approved its utilization in patients treated with apixaban and rivaroxaban in case of life-threatening or uncontrolled bleeding. On 28 of February 2019, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a conditional marketing authorization for andexanet alfa in Europe. Area covered: The authors provide an overview of andexanet alfa development and its pharmacokinetic and pharmacodynamic properties. The results of the clinical phase III trial ANNEXA as well as current limitations related to andexanet alfa are also discussed. Expert opinion: Although phase I and II studies have proven that andexanet alfa can be effective in reversing the effect of factor Xa inhibitors, its efficacy in major bleeding patients has only been shown for apixaban and rivaroxaban, without any comparator group. Well-designed studies comparing the efficacy and safety of andexanet alfa to other reversal strategies are required to confirm preliminary data. The benefit of andexanet alfa in specific settings needs to be investigated and its use in clinical practice needs to be facilitated by the implementation of international guidelines.

The perioperative management of dabigatran is challenging, and recommendations based on activated partial thromboplastin time (aPTT) and thrombin time (TT) are unsatisfactory. Dedicated coagulation tests have limitations at plasma concentrations < 50 ng/ml. Therefore, a more sensitive test, which is available 24/7, is required. It was the aim of this study to investigate the performance of the Hemoclot Thrombin Inhibitors® LOW (HTI LOW) kit, a diluted thrombin time, and the STA® – ECA II (ECA-II) kit, a chromogenic variant of the ecarin clotting time, that were developed to measure low dabigatran concentrations, compared to reference dabigatran analysis by liquid chromatography tandem mass-spectrometry (LC-MS/MS). This study included 33 plasma samples from patients treated with dabigatran etexilate who had plasma concentrations < 200 ng/ml. HTI LOW and ECA-II were performed along with HTI, aPTT (STA®-C. K.Prest® and SynthasIL ®) and TT (STA® – Thrombin). All procedures were performed according to recommendations by the manufacturers. Linear (or curvilinear) correlations and Bland-Altman analyses were calculated. For free dabigatran concentrations < 50 ng/ml, the R2 of linear correlations were 0.69, 0.84 and 0.61, with HTI, HTI LOW and ECA-II, respectively. The R2 for TT, STA®-C. K.Prest® and SynthasIL® were 0.67, 0.42 and 0.15. For HTI, HTI LOW and ECA-II, Bland-Altman analyses revealed mean differences of –6 ng/ml (95 %CI: –25–14 ng/ml), 1 ng/ml (95 %CI: –18–19 ng/ml) and –1 ng/ml (95 %CI: –25–23 ng/ml), demonstrating that tests dedicated to measuring low concentrations are more accurate than HTI. In conclusion, the use of HTI LOW or ECA-II to assess low plasma dabigatran concentrations is supported by our findings.

Background The perioperative management of antiplatelet therapy in noncardiac surgery patients who have undergone previous percutaneous coronary intervention (PCI) remains a dilemma. Continuing dual antiplatelet therapy (DAPT) may carry a risk of bleeding, while stopping antiplatelet therapy may increase the risk of perioperative major adverse cardiovascular events (MACE). Methods Occurrence of Bleeding and Thrombosis during Antiplatelet Therapy In Non-Cardiac Surgery (OBTAIN) was an international prospective multicentre cohort study of perioperative antiplatelet treatment, MACE, and serious bleeding in noncardiac surgery. The incidences of MACE and bleeding were compared in patients receiving DAPT, monotherapy, and no antiplatelet therapy before surgery. Unadjusted risk ratios were calculated taking monotherapy as the baseline. The adjusted risks of bleeding and MACE were compared in patients receiving monotherapy and DAPT using propensity score matching. Results A total of 917 patients were recruited and 847 were eligible for inclusion. Ninety-six patients received no antiplatelet therapy, 526 received monotherapy with aspirin, and 225 received DAPT. Thirty-two patients suffered MACE and 22 had bleeding. The unadjusted risk ratio for MACE in patients receiving DAPT compared with monotherapy was 1.9 (0.93–3.88), P=0.08. There was no difference in MACE between no antiplatelet treatment and monotherapy 1.03 (0.31–3.46), P=0.96. Bleeding was more frequent with DAPT 6.55 (2.3–17.96) P=0.0002. In a propensity matched analysis of 177 patients who received DAPT and 177 monotherapy patients, the risk ratio for MACE with DAPT was 1.83 (0.69–4.85), P=0.32. The risk of bleeding was significantly greater in the DAPT group 4.00 (1.15–13.93), P=0.031. Conclusions OBTAIN showed an increased risk of bleeding with DAPT and found no evidence for protective effects of DAPT from perioperative MACE in patients who have undergone previous PCI.

Summary Background Enterobacteriaceae are recognized as leading pathogens of healthcare-associated infections. Aim To report the investigation of a nosocomial outbreak of extended-spectrum β-lactamase-producing Enterobacter cloacae affecting cardiothoracic surgery patients in a Belgian academic hospital. Methods Cases were defined based on epidemiological and microbiological investigations, including molecular typing using repetitive element-based polymerase chain reaction and multi-locus sequence typing. Case–control studies followed by field evaluations allowed the identification of a possible reservoir, and the retrospective assessment of human and financial consequences. Findings Over a three-month period, 42 patients were infected or colonized by CTX-M-15-producing E. cloacae strains that belonged to the same clonal lineage. Acquisition mainly occurred in the intensive care unit (N = 23) and in the cardiothoracic surgery ward (N = 16). All but one patient had, prior to acquisition, undergone a cardiothoracic surgical procedure, monitored by the same transoesophageal echocardiography (TOE) probe in the operating room. Despite negative microbiological culture results, the exclusion of the suspected probe resulted in rapid termination of the outbreak. Overall, the outbreak was associated with a high mortality rate among infected patients (40%) as well as significant costs (€266,550). Conclusion The outbreak was indirectly shown to be associated with the contamination of a manually disinfected TOE probe used per-operatively during cardiothoracic surgery procedures, because withdrawal of the putative device led to rapid termination of the outbreak.

Introduction Prevalence and 1-year impact of right ventricular systolic dysfunction (RVSD) early after lung transplantation (LTx), in a population without pulmonary hypertension (PHT), is not well documented. In this retrospective study, we hypothesized that, as after heart Tx, occurrence of early RVSD after LTx in those patients (pts) would be associated with impaired 1-year survival.¹ Methods After ICU admission of LTx pts, we routinely perform a comprehensive transoesophageal echocardiographic (TOE) to check pulmonary veins’ patency. After exclusion of pts transplanted for PHT and of pts under ECMO, we retrospectively reviewed RV systolic data acquired during this TOE. At the time of TOE, all pts were mechanically ventilated. RVSD was defined based on visual assessment (RV dilation and/or RV hypokinesia) and RV fractional area change (FAC) Results From January 2004 to March 2018, 166 LTx pts underwent comprehensive TOE in ICU. Indications for LTx were COPD in 117 pts (70.5%), fibrosis in 25 (15.1%), cystic fibrosis in 7 (4.2%), bronchiectasis in 7 pts (4.2%) and other indications in 10 (6.0%). RV visual assessment was reported as abnormal in 56/166 pts (33.7%). RV FAC was reported in 112 pts and was Discussion Based on this retrospective TOE and single-center experience, prevalence of early RVSD after LTx, in a population without PHT, ranges from 34 to 39%, depending on the used criteria (visual assessment or RV FAC). However, occurrence of early RVSD after LTx was not associated with impaired 1-year survival.

Dabigatran etexilate (DE), rivaroxaban, and apixaban are nonvitamin K antagonist oral anticoagulants (NOACs) that have been compared in clinical trials with existing anticoagulants (warfarin and enoxaparin) in several indications for the prevention and treatment of thrombotic events. All NOACs presented bleeding events despite a careful selection and control of patients. Compared with warfarin, NOACs had a decreased risk of intracranial hemorrhage, and apixaban and DE (110 mg BID) had a decreased risk of major bleeding from any site. Rivaroxaban and DE showed an increased risk of major gastrointestinal bleeding compared with warfarin. Developing strategies to minimize the risk of bleeding is essential, as major bleedings are reported in clinical practice and specific antidotes are currently not available. In this paper, the following preventive approaches are reviewed: improvement of appropriate prescription, identification of modifiable bleeding risk factors, tailoring NOAC's dose, dealing with a missed dose as well as adhesion to switching, bridging and anesthetic procedures. © 2014 Lessire Sarah et al.

The indications for rigid bronchoscopy for interventional pulmonology have increased and include stent placements and transbronchial cryobiopsy procedures. The shared airway between anesthesiologist and pulmonologist and the open airway system, requiring specific ventilation techniques such as jet ventilation, need a good understanding of the procedure to reduce potentially harmful complications. Appropriate adjustment of the ventilator settings including pause pressure and peak inspiratory pressure reduces the risk of barotrauma. High frequency jet ventilation allows adequate oxygenation and carbon dioxide removal even in cases of tracheal stenosis up to frequencies of around 150 min−1; however, in an in vivo animal model, high frequency jet ventilation along with normal frequency jet ventilation (superimposed high frequency jet ventilation) has been shown to improve oxygenation by increasing lung volume and carbon dioxide removal by increasing tidal volume across a large spectrum of frequencies without increasing barotrauma. General anesthesia with a continuous, intravenous, short-acting agent is safe and effective during rigid bronchoscopy procedures.

Introduction.We herein report our experience with new fully covered self-expanding metallic stents in the setting of inoperable recurrent benign tracheobronchial stenosis.Methods.Between May 2010 and July 2014, 21 Micro-Tech® FC-SEMS (Nanjing Co., Republic of Korea) were placed in our hospital in 16 patients for inoperable, recurrent (after dilatation), and symptomatic benign airway stenosis. Their medical files were retrospectively reviewed in December 2014, with focus on stent’s tolerance and durability data.Results.Twenty-one stents were inserted: 13 for posttransplant left main bronchus anastomotic stricture, seven for postintubation tracheal stenosis, and one for postlobectomy anastomotic stricture. Positioning was easy for all of them. Stents were in place for a mean duration of 282 days. The most common complications were granulation tissue development (35%), migration (30%), and sputum retention (15%). Fifty-five % of the stents (11/20) had to be removed because of various complications, without difficulty for all of them. None of the patients had life-threatening complications.Conclusion.Micro-Tech FC-SEMS were easy to position and to remove. While the rate of complications requiring stent removal was significant, no life-threatening complication occurred. Further studies are needed to better define their efficacy and safety in the treatment of benign airway disease.

Background Osteogenesis imperfecta is a genetic disorder of connective tissue causing mostly left-sided heart valves and aortic root pathologies, but a coronary artery involvement reflecting an increased sensitivity to cardiovascular risk factors is also suspected in this patient population. Case presentation We report a 38-year-old patient with an osteogenesis imperfecta and a typical presentation of an acute myocardial infarction. The coronary angiogram showed a coronary 3-vessel disease. The patient underwent a bypass grafting surgery with the internal mammary artery. The sternum was closed using four nitinol clips and had totally stabilized at 4 months with excellent bone healing. Conclusions With the successful clinical outcome in this patient severely affected by its osteogensis imperfecta, we underline the safe use of the LIMA, if precaution is taken towards the sternal bone, and its closure with nitinol clips.

Idarucizumab is a specific antagonist for dabigatran etexilate (DE). The recent market authorization of idarucizumab in Europe and the USA may reassure prescribers of DE, as it can increase the safety of the emergency management of patients taking this anticoagulant. However, idarucizumab use should be limited to specific indications to avoid unnecessary risks to patients and costs to healthcare systems. Areas covered: The authors provide an overview of idarucizumab development and its pharmacokinetic and pharmacodynamic properties. The results of the clinical phase III trial RE-VERSE AD and a review of recent case reports of idarucizumab use in emergency contexts are also discussed. Expert opinion: Although idarucizumab has shown clear efficacy in reversing dabigatran-induced coagulopathy, its overall effects on patient outcome have not been proven. Information regarding the clinical context in which patients on DE are admitted for emergency treatment, and accurate laboratory tests of dabigatran plasma level during reversal may inform selection and help with the follow-up of patients who may benefit from idarucizumab. Idarucizumab should be integrated into protocol for the emergency management of patients on DE. Furthermore, the benefit of idarucizumab in specific indications such as acute ischemic stroke should be investigated.

Direct oral anticoagulants (DOACs) have been licensed worldwide for several years for various indications. Each year, 10-15% of patients on oral anticoagulants will undergo an invasive procedure and expert groups have issued several guidelines on perioperative management in such situations. The perioperative guidelines have undergone numerous updates as clinical experience of emergency management has increased and perioperative studies including measurement of residual anticoagulant levels have been published. The high inter-patient variability of DOAC plasma levels has challenged the traditional recommendation that perioperative DOAC interruption should be based only on the elimination half-life of DOACs, especially before invasive procedures carrying a high risk of bleeding. Furthermore, recent publications have highlighted the potential danger of heparin bridging use when DOACs are stopped before an invasive procedure. As antidotes are progressively becoming available to manage severe bleeding or urgent procedures in patients on DOACs, accurate laboratory tests have become the standard to guide their administration and their actions need to be well understood by clinicians. This review aims to provide a systematic approach to managing patients on DOACs, based on recent updates of various perioperative guidance, and highlighting the advantages and limits of recommendations based on pharmacokinetic properties and laboratory tests., SCOPUS: re.j, info:eu-repo/semantics/published

Introduction Right ventricular (RV) diastolic dysfunction is known to be associated with increased mortality in heart failure or cardiac surgical patients (pts). However, after lung transplantation (LTx), the impact of early RV diastolic dysfunction on 1-year survival, in a population without pulmonary hypertension, is not well documented. Methods We routinely perform a comprehensive transoesophageal echocardiography (TOE) after ICU admission of LTx patients (pts) to check the pulmonary veins’ patency. After exclusion of pts transplanted for pulmonary hypertension and of pts under ECMO, we retrospectively reviewed the diastolic RV parameters acquired during this TOE. At that time, all pts were mechanically ventilated. RV diastolic function was explored by tricuspid peak early and late velocities (E and A waves) (pulsed-wave Doppler (PW) through the tricuspid valve), early diastolic peak velocity (Ea) of the lateral tricuspid annulus (PW-TDI), hepatic venous flow (HVF) pattern (PW Doppler), and characterized as normal or abnormal according to the algorithm validated by Shi et al. One-year survival status was recorded. Continuous variables are presented as median [interquartile range] and analysed with Mann-Whitney U test. Dichotomous variables are presented as numbers (%) and analysed with Chi-Squared test. Results From May 2008 to March 2018, RV diastolic data were available in 69 pts. Indications for LTx were COPD in 51 pts (73.9%), fibrosis in 12 (17.4%), bronchiectasis in 1 pt (1.5%) and other indications in 5 (7.2%). RV diastolic function was categorized as abnormal in 47pts. One-year survival rate was 72.3% (34/47) in the group with early RV diastolic dysfunction and 95.4% (1/22) in the group with normal RV diastolic function (P = 0.027). Discussion Based on these retrospective TOE data in this single-center experience, occurrence of early RV diastolic dysfunction after LTx seems to be associated with impaired 1-year survival. Further prospective data are needed to confirm these preliminary observations.

Objectives PIANO (Paediatric study of Intelence As an NNRTI Option; TMC125-C213; NCT00665847) assessed the safety/tolerability, antiviral activity and pharmacokinetics of etravirine plus an optimized background regimen (OBR) in treatment-experienced, HIV-1-infected children (≥ 6 to 95% adherent by questionnaire and 39% by pill count. Forty-one patients experienced virological failure (VF; time-to-loss-of-virological-response non-VF-censored algorithm) (29 nonresponders; 12 rebounders). Of 30 patients with VF with paired baseline/endpoint genotypes, 18 (60%) developed nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations, most commonly Y181C. Mean etravirine area under the plasma concentration–time curve over 12 h (AUC0–12h; 5216 ng h/mL) and C0h (346 ng/mL) were comparable to adult target values. Conclusions Results with etravirine 5.2 mg/kg bid (with OBR) in this treatment-experienced paediatric population and etravirine 200 mg bid in treatment-experienced adults were comparable. Etravirine is an NNRTI option for treatment-experienced paediatric patients.

The tolerability and immunogenicity of the hepatitis C virus E1 protein as a candidate vaccine was examined in a Phase I, single-arm study. Twenty healthy male volunteers were injected in the deltoid muscle at weeks 0, 3 and 6 with 20 μg recombinant E1 adsorbed on alum. A fourth (booster) dose was administered to 19 subjects at week 26. The candidate therapeutic vaccine was well tolerated. Three vaccine doses induced a clear humoral anti-E1 response that was boosted by a fourth dose. A strong, specific cellular immune response towards E1 was elicited in all vaccine recipients, which included a clear Th1 type response in all but one of the subjects.

New treatments are needed for chronic hepatitis C patients in whom viral clearance cannot be achieved. Thirty-five chronic hepatitis C patients (genotype 1) were randomized to receive 20 mug of recombinant HCV E1 (E1) (n = 26) or placebo (n = 9) intramuscularly at weeks 0, 4, 8, 12, and 24. Thirty-four then received open-label E1 vaccine at weeks 50, 53, 56, 59, 62, and 65. Twenty-four patients (12 men, 12 women; mean age, 52 y; 18 interferon-based treatment failures; mean baseline alanine aminotransferase [ALT] level, 118 IU/L) underwent a biopsy before and after 2 courses of E1, 17 months later. Liver histology was scored by 2 blinded pathologists according to the Ishak and Metavir systems. Postinjection reactions were similar to placebo (alum only). Nine of 24 patients (38%) had improvement of 2 points or more, 10 (41%) remained stable, and 5 (21%) showed worsening in total Ishak score. Nine patients (38%) improved both on Ishak and Metavir fibrosis scores. Plasma HCV-RNA levels remained unchanged, whereas ALT levels showed a trend toward a decrease during treatment. All but 3 patients developed a significant de novo E1-specific T-cell response. The increase in anti-E1 antibody levels correlated with the decrease in total Ishak score and with the relative decreases in both Ishak fibrosis score and ALT level (all P < or =.01). In conclusion, E1 therapeutic vaccination is well tolerated and the observed effects warrant further study.