Ferric derisomaltose and tranexamic acid, combined or alone, for reducing blood transfusion in patients with hip fracture (the HiFIT trial): a multicentre, 2 × 2 factorial, randomised, double-blind, controlled trial.

BACKGROUND: Anaemia and blood transfusion are associated with poor outcomes after hip fracture. We evaluated the efficacy of intravenous iron and tranexamic acid in reducing blood transfusions after hip fracture surgery. METHODS: In this double-blind, randomised, 2 × 2 factorial trial, we recruited adults hospitalised for hip fractures in 12 medical centres in France who had preoperative haemoglobin concentrations between 9·5 and 13·0 g/dL. We randomly allocated participants (1:1:1:1), via a secure web-based service, to ferric derisomaltose (20 mg/kg intravenously) and tranexamic acid (1 g bolus followed by 1 g over 8 h intravenously at inclusion and 3 g topically during surgery), iron plus placebo (normal saline), tranexamic acid plus placebo, or double placebo. Unmasked nurses administered study drugs; participants and other clinical and research staff remained masked to treatment allocation. The primary outcome was the percentage of patients transfused during hospitalisation (or by day 30). The primary analysis included all randomised patients. This study is registered on ClinicalTrials.gov (NCT02972294) and is closed to new participants. FINDINGS: Of 413 patients (51-104 years old, median [IQR] 86 [78-91], 312 [76%] women, 101 [24%] men), 104 received iron plus tranexamic acid, 103 iron plus placebo, 103 tranexamic acid plus placebo, and 103 double placebo between March 31, 2017 and June 18, 2021 (study stopped early for efficacy after the planned interim analysis done on the first 390 patients included on May 25, 2021). Data for the primary outcome were available for all participants. Among patients on double placebo, 31 (30%) were transfused versus 16 (15%) on both drugs (relative risk 0·51 [98·3% CI 0·27-0·97]; p=0·012). 27 (26%) participants on iron (0·81 [0·50-1·29]; p=0·28) and 28 (27%) on tranexamic acid (0·85 [0·54-1·33]; p=0·39) were transfused. 487 adverse events were reported with similar event rates among the groups; among prespecified safety endpoints, severe postoperative anaemia (haemoglobin <8 g/dL) was more frequent in the double placebo group. Main common adverse event were sepsis, pneumonia, and urinary infection, with similar rates among all groups. INTERPRETATION: In patients hospitalised for hip fracture surgery with a haemoglobin concentration 9·5-13·0 g/dL, preoperative infusion of ferric derisomaltose plus tranexamic acid reduced the risk of blood transfusion by 50%. Our results suggest that combining treatments from two different pillars improves patient blood-management programmes. Either treatment alone did not reduce transfusion rates, but we might not have had the power to detect it. FUNDING: French Ministry of Health, HiFIT trial.

Impact of Skin Disinfection on Cutaneous Microbiota, before and after Peripheral Venous Catheter Insertion.

Introduction. Patients with invasive medical devices are at high risk for infection. Skin colonization is the initial stage of these infections, leading to the recommendation of practices requiring disinfection using antiseptics. Microbial communities playing a major role in skin health could be impacted by antiseptic procedures. Aim. To characterize and compare the bacterial communities of skin samples from patients before an antisepsis procedure, and after removal of the medical device itself, according to the nature of the antiseptic molecule (povidone iodine or chlorhexidine). Methods. The study focused on alterations in bacterial communities depending on the nature of the antiseptic procedure and type of intravascular device. After amplification of 16S rDNA, libraries (n = 498 samples) were sequenced using MiSeq platform. Results. Using an in-house pipeline (QIIME2 modules), while no alteration in skin microbiota diversity was associated with antiseptic procedure or PVC type, according to culture results (p < 0.05), alterations were at times associated with restricted diversity and higher dissimilarity (p < 0.05). Antiseptic procedures and PVC types were associated with the modification of specific bacterial representations with modulation of the Bacillota/Bacteroidota (Firmicutes/Bacteroidetes) ratio (modulation of C. acnes, Prevotella, Lagierella, and Actinomyces spp.) (p < 0.05). At baseline, the microbiota shows certain bacteria that are significantly associated with future PVC colonization and/or bacteremia (p < 0.05). All of these modulations were associated with altered expression of metabolic pathways (p < 0.05). Discussion. Finally, this work highlights the need to optimize the management of patients requiring intravascular devices, possibly by modulating the skin microbiota.

Cost-effectiveness analysis of bundled innovative devices versus standard approach in the prevention of unscheduled peripheral venous catheters removal due to complications in France.

The objective of the study was to perform a cost-effectiveness analysis of bundled devices (BDs) versus standard devices (SDs) for the prevention of unscheduled peripheral venous catheter (PVC) removal due to complication from a French investigator-initiated, open-label, single center, randomized-controlled, two-by-two factorial trial (CLEAN-3 study). A 14-day time non homogeneous semi-markovian model was performed to be fitted to longitudinal individual patient data from CLEAN-3 database. This model includes five health states and eight transitional events; a base case scenario, two scenario analyses and bootstrap sensitivity analyses were performed. The cost-effectiveness criterion was the cost per patient with unscheduled PVC removal avoided. 989 adult (age≥18 years) patients were analyzed to compare the BDs group (494 patients), and the SDs group (495 patients). The assessed intervention was a combination of closed integrated catheters, positive displacement needleless-connectors, disinfecting caps, and single-use prefilled flush syringes compared with the use of open catheters and three-way stopcocks for treatment administration. For the base case scenario, an unscheduled 1st PVC removal before discharge was significantly more frequent in the SDs group (235 patients (47.5%) in the SDs group and 172 patients (34.8%) in the BDs group, p = 0.00006). After adjustment for 1st catheter time, the number of patients with unscheduled PVC removal per day was of 16 (95%CI: 15; 18) patients (out of 100) in the BDs group and of 26 (95%CI: 24; 28) patients (out of 100) in the SDs group. The mean cost per patient (adjusted on catheter-time) was of €144 (95%CI: €135-€154) for patients in the SDs group versus €102 (95%CI: €95-€109) for patients in the BDs group; the mean saving per patient was of €42 (95%CI: €32-€54). As a consequence, the assessed BDs strategy was less costly and more effective than the SDs strategy. Trail registration: CLEAN-3 study is registered with ClinicalTrials.gov, NCT03757143.

Chlorhexidine plus alcohol versus povidone iodine plus alcohol, combined or not with innovative devices, for prevention of short-term peripheral venous catheter infection and failure (CLEAN 3 study): an investigator-initiated, open-label, single centre, randomised-controlled, two-by-two factorial trial.

BACKGROUND: Two billion peripheral venous catheters are sold globally each year, but the optimal skin disinfection and types of devices are not well established. We aimed to show the superiority of disinfection with 2% chlorhexidine plus alcohol over 5% povidone iodine plus alcohol in preventing infectious complications, and of closed integrated catheters, positive displacement needleless-connectors, disinfecting caps, and single-use prefilled flush syringes used in combination (innovation group) over open catheters and three-way stopcocks for treatment administration (standard group) in preventing catheter failure. METHODS: We did an open-label, randomised-controlled trial with a two-by-two factorial design, for which we enrolled adults (age ≥18 years) visiting the emergency department at the Poitiers University Hospital, France, and requiring one peripheral venous catheter before admission to the medical wards. Before catheter insertion, patients were randomly assigned (1:1:1:1) using a secure web-based random-number generator to one of four treatment groups based on skin preparation and type of devices (innovative devices or standard devices; 2% chlorhexidine plus alcohol or 5% povidone iodine plus alcohol). Primary outcomes were the incidence of infectious complications (local infection, catheter colonisation, or bloodstream infections) and time between catheter insertion and catheter failure (occlusion, dislodgment, infiltration, phlebitis, or infection). This study is registered with ClinicalTrials.gov, NCT03757143. FINDINGS: 1000 patients were recruited between Jan 7, and Sept 6, 2019, of whom 500 were assigned to the chlorhexidine plus alcohol group and 500 to the povidone iodine plus alcohol group (250 with innovative solutions and 250 with standard devices in each antiseptic group). No significant interaction was found between the two study interventions. Local infections occurred less frequently with chlorhexidine plus alcohol than with povidone iodine plus alcohol (0 [0%] of 496 patients vs six [1%] of 493 patients) and the same was observed for catheter colonisation (4/431 [1%] vs 70/415 [17%] catheters among the catheters cultured; adjusted subdistribution hazard ratio 0·08 [95% CI 0·02-0·18]). Median time between catheter insertion and catheter failure was longer in the innovation group compared with the standard group (50·4 [IQR 29·6-69·4] h vs 30·0 [16·6-52·6] h; p=0·0017). Minor skin reactions occurred in nine (2%) patients in the chlorhexidine plus alcohol group and seven (1%) patients in the povidone iodine plus alcohol group. INTERPRETATION: For skin antisepsis, chlorhexidine plus alcohol provides greater protection of peripheral venous catheter-related infectious complications than does povidone iodine plus alcohol. Use of innovative devices extends the catheter complication-free dwell time. FUNDING: Becton Dickinson.

Study protocol for a multicentre, 2×2 factorial, randomised, controlled trial evaluating the interest of intravenous iron and tranexamic acid to reduce blood transfusion in hip fracture patients (the HiFIT study).

INTRODUCTION: Blood transfusion and anaemia are frequent and are associated with poor outcomes in patients with hip fracture (HF). We hypothesised that preoperative intravenous iron and tranexamic acid (TXA) may reduce the transfusion rate in these patients. METHODS AND ANALYSIS: The HiFIT study is a multicentre, 2×2 factorial, randomised, double-blinded, controlled trial evaluating the effect of iron isomaltoside (IIM) (20 mg/kg) vs placebo and of TXA (intravenously at inclusion and topically during surgery) versus placebo on transfusion rate during hospitalisation, in patients undergoing emergency surgery for HF and having a preoperative haemoglobin between 95 and 130 g/L. 780 patients are expected. The primary endpoint is the proportion of patients receiving an allogenic blood transfusion of packed red blood cells from the day of surgery until hospital discharge (or until D30 if patient is still hospitalised). Enrolment started on March 2017 in 11 French hospitals. The study was stopped between July 2017 and August 2018 (because of investigation of serious AEs with IIM in Spain) and slowed down since March 2020 (COVID-19 crisis). The expected date of final follow-up is May 2022. Analyses of the intent-to-treat and per-protocol populations are planned. ETHICS AND DISSEMINATION: The HiFIT trial protocol has been approved by the Ethics Committee of Comité de Protection des Personnes Ouest II and the French authorities (ANSM). It will be carried out according to the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines. The results will be disseminated through presentation at scientific conferences and publication in peer-reviewed journals. The HiFIT trial will be the largest study evaluating iron and TXA in patients with HF. TRIAL REGISTRATION NUMBER: clinicalTrials.gov identifier: NCT02972294; EudraCT Number 2016-003087-40.

Skin antisepsis with chlorhexidine-alcohol versus povidone iodine-alcohol, combined or not with use of a bundle of new devices, for prevention of short-term peripheral venous catheter-related infectious complications and catheter failure: an open-label, single-centre, randomised, four-parallel group, two-by-two factorial trial: CLEAN 3 protocol study.

INTRODUCTION: Short peripheral intravenous catheters (PVCs) are the most frequently used invasive medical devices in hospitals. Unfortunately, PVCs often fail before the end of treatment due to the occurrence of mechanical, vascular or infectious complications, which prolongs hospitalisation and increases healthcare costs and mortality.Prevention of these complications is mainly based on the respect of hygiene rules and the use of biocompatible catheters. In critically ill patients, 2% chlorhexidine-alcohol is superior to 5% povidone iodine-alcohol for skin preparation before central venous and arterial catheters; whether this finding can be extended to PVC inserted in the wards remains speculative. Similarly, the use of new technologies such as catheters designed to minimise blood exposure, zero-reflux needleless connectors, disinfecting caps and flushing PVCs before and after each medication administration to maintain catheter patency are of theoretical interest to prevent PVC failure, but little scientific data support their routine use. METHODS AND ANALYSIS: The CLEAN 3 study is an open-label, single-centre, randomised, two-by-two factorial trial. One thousand patients visiting our emergency department and requiring hospital admission in the wards will be randomised to one of four strategies according to skin preparation and devices used. The two primary endpoints will be (1) the incidence of infectious complications related to the catheters (colonisation, local infection or bloodstream infection) and (2) the time between catheter insertion and catheter failure defined as any premature removal of PVC before end of treatment, other than for routine replacement. ETHICS AND DISSEMINATION: This protocol has been approved by an independent ethics committee and will be carried out according to the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines. The results of this study will be disseminated through presentation at scientific conferences and publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: EudraCT 2018-A02535-50; NCT03757143.