Early fibrinogen concentrate therapy for major haemorrhage in trauma (E-FIT 1): results from a UK multi-centre, randomised, double blind, placebo-controlled pilot trial.

BACKGROUND: There is increasing interest in the timely administration of concentrated sources of fibrinogen to patients with major traumatic bleeding. Following evaluation of early cryoprecipitate in the CRYOSTAT 1 trial, we explored the use of fibrinogen concentrate, which may have advantages of more rapid administration in acute haemorrhage. The aims of this pragmatic study were to assess the feasibility of fibrinogen concentrate administration within 45 minutes of hospital admission and to quantify efficacy in maintaining fibrinogen levels ≥ 2 g/L during active haemorrhage. METHODS: We conducted a blinded, randomised, placebo-controlled trial at five UK major trauma centres with adult trauma patients with active bleeding who required activation of the major haemorrhage protocol. Participants were randomised to standard major haemorrhage therapy plus 6 g of fibrinogen concentrate or placebo. RESULTS: Twenty-seven of 39 participants (69%; 95% CI, 52-83%) across both arms received the study intervention within 45 minutes of admission. There was some evidence of a difference in the proportion of participants with fibrinogen levels ≥ 2 g/L between arms (p = 0.10). Fibrinogen levels in the fibrinogen concentrate (FgC) arm rose by a mean of 0.9 g/L (SD, 0.5) compared with a reduction of 0.2 g/L (SD, 0.5) in the placebo arm and were significantly higher in the FgC arm (p < 0.0001) at 2 hours. Fibrinogen levels were not different at day 7. Transfusion use and thromboembolic events were similar between arms. All-cause mortality at 28 days was 35.5% (95% CI, 23.8-50.8%) overall, with no difference between arms. CONCLUSIONS: In this trial, early delivery of fibrinogen concentrate within 45 minutes of admission was not feasible. Although evidence points to a key role for fibrinogen in the treatment of major bleeding, researchers need to recognise the challenges of timely delivery in the emergency setting. Future studies must explore barriers to rapid fibrinogen therapy, focusing on methods to reduce time to randomisation, using 'off-the-shelf' fibrinogen therapies (such as extended shelf-life cryoprecipitate held in the emergency department or fibrinogen concentrates with very rapid reconstitution times) and limiting the need for coagulation test-based transfusion triggers. TRIAL REGISTRATION: ISRCTN67540073 . Registered on 5 August 2015.

Characterization of Moderate and Severe Asthma Exacerbations in the CAPTAIN Study.

BACKGROUND: Limited data exist on the relative impact of moderate and severe exacerbations on asthma control and impairment. OBJECTIVE: To explore data from the CAPTAIN trial to evaluate the relationship between first moderate or severe exacerbation and changes in lung function, symptoms, physical activity limitation scores, and short-acting ß2-agonist (SABA) usage to determine the clinical relevance of moderate events. METHODS: CAPTAIN was a phase IIIA 24- to 52-week, multicenter, international, randomized controlled trial evaluating efficacy and safety of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI in patients with uncontrolled asthma on inhaled corticosteroid/long-acting ß2-agonist. Outcomes reported include first postrandomization exacerbation event by severity (wk 1-52), frequency and duration of moderate and severe exacerbations, and time course of changes over ± 14-day peri-exacerbation period for lung function, symptoms, limitations, and SABA use. RESULTS: Of the intent-to-treat population (n = 2,436), 550 patients (23%) continued to 52 weeks. There were 529 moderate and 546 severe exacerbations. Lung function changes were similar, but symptom, physical activity limitation scores, and SABA use were higher, for severe versus moderate exacerbations. Lung function decline preceded increases in symptom, physical activity limitation scores, and SABA use, irrespective of exacerbation severity. Lung function variables, limitation scores, and SABA use returned to pre-exacerbation baseline after approximately 8 to 12 days for both exacerbation severities. CONCLUSIONS: Whereas severe events were associated with greater impact on symptoms, physical activity limitations, and SABA use, onset and time to resolution were generally similar for moderate and severe events. Both exacerbation severities represent clinically important deteriorations comprising clinical and functional changes.

Impact of Regional Organ Sharing and Allocation in the UK Northern Liver Alliance on Waiting Time to Liver Transplantation and Waitlist Survival.

BACKGROUND: In the United Kingdom, liver transplantation (LT) is undertaken in 7 supraregional centers. Until March 2018, liver grafts were offered to a center and allocated to a patient on their elective waiting list (WL) based on unit prioritization. Patients in Newcastle, Leeds, and Edinburgh with a United Kingdom Model for End-Stage Liver Disease (UKELD) score ≥62 were registered on a common WL and prioritized for deceased-donor liver allocation. This was known as the Northern Liver Alliance (NLA) "top-band scheme." Organs were shared between the 3 centers, with a "payback" scheme ensuring no patient in any center was disadvantaged. We investigated whether the NLA had improved WL survival and waiting time (WT) to transplantation. METHODS: Data for this study were obtained from the UK Transplant Registry maintained by National Health Service Blood and Transplant. This study was based on adult patients registered for first elective liver transplant between April 2013 and December 2016. Non-NLA centers were controls. The Kaplan-Meier method was used to estimate WL survival and median WT to transplant, with the log-rank test used to make comparisons; a Bonferroni correction was applied post hoc to determine pairwise differences. RESULTS: WT was significantly lower at NLA centers compared with non-NLA centers for top-band patients (23 versus 99 days, P < 0.001). However, WL survival was not significantly different for top-band patients (P > 0.999) comparing NLA with non-NLA centers. WL survival for nontop-band patients was no different (P > 0.999) comparing NLA with non-NLA centers. CONCLUSIONS: The NLA achieved its aim, providing earlier transplantation to patients with the greatest need. Nontop-band patients did not experience inferior survival.