HPE CSL Managing Perioperative Bleeding handbook - Page 17

Pregnancy and post-partum red blood cells and plasma while no information was described on tranexamic acid and platelets. 25 Mallaiah et al compared two periods: a massive transfusion protocol blind strategy during the first period versus the use of an adapted dose of fibrinogen concentrate targeted by point of care diagnosis of hypofibrinogenemia during the second period. They demonstrated a significant reduction in the number of patients requiring more than 6 RBC and in overall blood product requirements, in maternal morbidity but not on hysterectomy rate. 26 The first prospective, double-blind, placebo-controlled, randomised study available – the FIB-PPH trial 27 – failed to show a difference between placebo and fibrinogen in terms of transfusion rate (21% compared with 22% in the placebo group) in normo-fibrinogenaemic patients (pregnancy and postpartum reference values: 4.5–5.5g). In this trial, patients were recruited in case of blood loss due to manual removal of placenta (≥500ml), manual exploration of the uterus after placental delivery (≥1000ml), or C-section (perioperative blood loss ≥1000ml). Patients were randomised to receive a single uniform dose of 2g fibrinogen or placebo systematically, that is, independently to the laboratory- or the point of care plasma fibrinogen level. There were limitations to the FIB-PPH trial: the patients enrolled were non- severe and normofibrinogenemic; the delay to administer the product was long (more than one hour after the diagnosis) and the population studied was mostly surgical bleeding (C-section and genital tract injury) as opposed to obstetrical bleeding that leads to coagulation defects. Bleeding probably stopped in a majority of patients with a limited need for transfusion and no need for invasive procedures in both groups. The selection of a non-severe population with a low rate of transfusion was mostly due to the difficulty in recruiting and obtaining informed consents during an ongoing bleeding; the primary endpoint took into account only the transfusion rate but not anaemia or haemoglobin drop in non-transfused patients. Despite the pioneering nature of the FIB-PPH trial, the scientific questions on efficacy, safety, timing and dose of fibrinogen concentrate in ongoing severe PPH with hypofibrinogenemia have not yet been answered. 27 Collins et al have published a randomised trial hypothesising that an early fibrinogen replacement, guided by thomboelastometric test, reduces transfusion need and bleeding in severe PPH. 28,29 They enrolled 55 women w ith hypofibrinogenemia attested by a <12mm FIBTEM A5 amplitude out of the 663 severe PPHs recruited. The 55 enrolled patients were blinded to fibrinogen or placebo. The median (25th–75th centile) measured blood loss was 1450ml (1200–1800ml) at enrolment and 1950ml (1500–2285ml) when the studied medication was infused. 29 The adjusted incidence rate ratio (IRR) (95% CI) for the number of allogeneic units transfused in the fibrinogen group compared with placebo was 0.72 (0.3–1.7; p=0.45). In pre- specified subgroup analyses, subjects who had a FIBTEM A5 <12mm at the time of randomisation and who received fibrinogen concentrate received a median of 1 (0–4.5) PRBC and had an additional 300ml (100–350ml) blood loss whereas those who received placebo also received 3 (0–6) units of allogeneic blood products and had 700ml (200–1550ml) additional blood loss (NS). There was one thrombotic event in each group. 29 The authors concluded that infusion of fibrinogen concentrate triggered by FIBTEM A5 <15mm did not improve outcomes in PPH. Pre-specified subgroup analyses suggested that fibrinogen replacement is not required if the FIBTEM A5 is>12mm or Clauss fibrinogen >2g/l, but an effect below these levels cannot be excluded. However, in this trial, as in the data of Wikkelso et al, 27 the recruitment of the coagulopathic patients was difficult and women were excluded if they declined transfusion, had prenatally diagnosed placenta accreta, had undergone an invasive procedure to control bleeding, or if there was a clinical suspicion of amniotic fluid embolism. Moreover, despite a clear protocol design, the use of FFP was encouraged in both groups and tranexamic acid was given at randomisation. This may be responsible for a confounding effect on bleeding reduction. 20,21 The ongoing double-blind, placebo- controlled RCT – the FIDEL trial – aims to assess the early administration of 3g fibrinogen concentrates versus placebo in more severe and ongoing PPH resistant to the first-line uterotonics. 30 The recruitment has been prolonged to achieve inclusion of 462 patients and a 90% beta risk. FIDEL is an efficacy trial. The primary efficacy variable is a binary composite endpoint (failure versus success). Failure is defined when a patient loses at least 4g/dl Hb, and/or requires the transfusion of at least two units of packed RBCs within 48 hours following the administration of investigational medicinal product. The Hb reference level is defined as the last Hb value recorded within the third trimester of pregnancy. To avoid or minimise bias and/or centre effect, the primary endpoint has been defined independently of therapeutic obstetrical interventions and/or clinical practices such as surgical ligation or embolisation. All centres currently use a French guidelines’ algorithm for PPH management. 31 The secondary objectives of this trial are to evaluate PPH evolution, hospitalpharmacyeurope.com 17