Low plasma fibrinogen is a predictor for excessive bleeding and mortality risk in cardiac surgery patients (Kozek-Langenecker et al., 2017). Whilst the European Society of Anaesthesiology (ESA) guidelines on management of severe perioperative bleeding recommend a trigger level for fibrinogen supplementation of <1.5–2.0 g/L, there is no consensus on the trigger value specifically in a cardiac setting (Kozek-Langnecker et al., 2017). Studies on the management of perioperative bleeding identified a possible trigger value of 2.15 g/L (2–2.2 g/L) fibrinogen for patients experiencing a severe bleed versus 1.15 g/L as a predictive value for developing a severe bleed (Karkouti et al., 2013; Kindo et al., 2014; Ranucci et al., 2016). Target values in a perioperative setting have not been formally assessed however studies have aimed to achieve ROTEM-FIBTEM values of 22 mm that corresponds to 3.75 g/L (Rahe-Meyer et al., 2009; Ranucci et al., 2011; Solomon et al., 2011; Rahe-Meyer et al., 2013a). These studies were double blind randomized trials that assumed either that 4 g fibrinogen should increase plasma concentrations by 1 g/L, or that 1 g of fibrinogen should increase FIBTEM by 2 mm in an average weight person. Ranucci and colleagues identified target values of 2.8 g/L for non-bleeding patients and 3.75 g/L for patients with severe bleeds (Ranucci et al., 2016). They further confirmed that the expected dose to raise fibrinogen levels from 1.15 to 2.80 g/L or from 2.15 to 3.75 g/L is 6.8 g of fibrinogen concentrate or 22 units of cryoprecipitate.
The ESA guidelines on management of severe perioperative bleeding further recommend fibrinogen concentrate (FCH) infusion guided by viscoelastic haemostatic assay monitoring to reduce perioperative blood loss (Kozek-Langnecker et al., 2017). The recommendation is based mainly on the clinical trial and study data, outlined below, which indicate that FCH may reduce the need for allogeneic blood transfusion and is generally safe in a cardiac surgery setting.
A retrospective study to assess fibrinogen recovery parameters after administration of FCH to 39 patients with diffuse bleeding after weaning from cardiopulmonary bypass (CPB) during cardiac surgery found that FCH (mean dose = 6.5 g) increased plasma fibrinogen concentration to more than baseline levels (3.3 g/L, maximum clot firmness [MCF] of 15.5 mm), both on the day of infusion (1.9 to 3.6 g/L, MCF from 10.1 to 20.7 mm) and the following day (1.9 to 4.5 g/L, MCF from 10.1 to 22.3 mm) (Figure 13) (Solomon et al., 2010). Furthermore 90% of patients received no intraoperative transfusion of allogeneic blood products after administration of FCH, suggesting that FCH contributed to the correction of bleeding.
In a prospective study of patients with decreased preoperative platelet function undergoing coronary artery bypass graft (CABG), patients with bleeding received either FCH (n = 10) or allogeneic blood products (ABPs) (n = 19) to examine if FCH could help achieve haemostasis when platelet function is low (Solomon et al., 2012). FCH increased FIBTEM MCF (from 10.5 mm to 20.5 mm) and resulted in significantly reduced total transfusion requirement compared to haemostatic treatment with ABPs, indicating that fibrinogen supplementation helps to achieve haemostasis even when platelet function is low (Figure 14). No FCH related complications were observed and postoperative outcomes were comparable for FCH and ABP treated patients.
A randomised, single-centre, prospective, double-blinded, placebo-controlled clinical trial that investigated the intraoperative use of FCH in 59 patients undergoing complex cardiac surgery found that FCH may be sufficient to control perioperative bleeding in a cardiac surgery setting (Ranucci et al., 2015). They found that patients treated with FCH had a lower rate of ABP transfusion (odds ratio, 0.40; 95% confidence interval [CI], 0.19–0.84, P=0.015) and less postoperative bleeding (300 mL versus 355 mL, P=0.042), compared with placebo (Figure 15) (Ranucci et al., 2015).
A single-centre phase II clinical trial (NCT00701142) including 61 patients undergoing aortic replacement surgery treated patients with either FCH (n = 29) or placebo (n = 32) (Rahe-Meyer et al., 2013b). Avoidance of ABP transfusion was achieved in 13 of 29 (45%) patients in the FCH group, versus 0 of 32 patients in the placebo group (P<0.001), with fewer units needed in the FCH group (median 2 versus 13, P<0.001) (Figure 16). There was no observed safety concern in the FCH group during aortic surgery and the number of intensive care unit (ICU) and hospital-free days were comparable for the two study groups.
The findings of 2013 Rahe-Meyer study were not replicated in a larger Phase III randomised, multi-centre, clinical trial, REPLACE (NCT01475669) that looked at 152 patients undergoing complex cardiovascular surgery (Rahe-Meyer et al., 2013b; Rahe-Meyer et al., 2016). The administration of FCH (n = 78) was associated with an increased need for ABP transfusion compared to placebo (n = 74) (5 units versus 3 units, P=0.026) (Figure 17a). This was in line with a lower avoidance of ABPs for FCH treatment compared to placebo (15.4% versus 28.4%, P=0.047) (Figure 17b). This outcome was despite patients who were treated with fibrinogen concentrate achieving the target FIBTEM MCF of 22 mm compared to no increase for placebo patients.
In a meta-analysis of eight randomised clinical trials that included the REPLACE study, FCH supplementation was shown to significantly reduce ABP transfusion versus comparators (risk ratio, 0.64; 95% confidence interval [CI], 0.49–0.83; P=0.001), though no difference in risk mortality was identified (Li et al., 2018). This places doubt over the ABP transfusion result of the REPLACE study and possible limitations to the REPLACE study were identified. These include the clinical practice variance between centres and the use of 5-minute bleeding mass, rather than fibrinogen concentration to guide FCH administration. Furthermore, adherence to the transfusion algorithm was low, at 68% compared to 87% in their earlier Phase II clinical trial and similarly, 62% of patients did not fulfil the bleeding criteria, compared to 19% in the Phase II clinical trial (Rahe-Meyer et al., 2013b; Rahe-Meyer et al., 2016). These limitations were addressed in a post-hoc analysis of the phase III REPLACE trial, in which patients were stratified according to protocol adherence, pre-treatment fibrinogen levels and whether the patients were among the first three treated at their centre (Rahe-Meyer et al., 2019). The post-hoc analyses revealed that FCH was associated with a trend towards reduced ABP transfusion in treatment-adherent patients who were not among the first three patients to be treated at their centres and with pre-treatment fibrinogen levels of less than 2 g/L.
In an earlier, large, non-randomised, retrospective study on 1,075 patients with bleeding during complex cardiac surgery, data for FCH (264 patients) was compared to placebo (811 patients) (Bilecen et al., 2013). Intraoperative infusion of FCH did not significantly reduce blood loss or ABP transfusion in the intensive care unit (ICU) setting. It is important to note that the patients with a longer cardiopulmonary bypass time or more blood loss were more likely to receive FCH treatment at a low median FCH dose of 2 g, given as a relatively late intervention which may explain the attenuated haemostatic effect. A prospective, randomised trial is needed to better understand outcome. In a later trial study on 120 high-risk cardiac surgery patients with intraoperative bleeding, Bilecen and colleagues randomised patients to receive either FCH (n = 60) or placebo (n = 60), targeted to achieve a plasma fibrinogen level of 2.5 g/L (Bilecen et al., 2017). Whilst 24–hour blood loss was significantly lower for FCH compared to placebo, FCH did not significantly reduce the already modest intraoperative blood loss (50 mL versus 70 mL, P=0.19), with only 2 of 58 FCH-treated patients receiving transfusion compared to 4/59 patients treated with placebo. Unlike their earlier 2013 study, Bilecen and colleagues identified an increase in adverse events experienced by patients treated with FCH, including 2 deaths versus 0 in the placebo group (Bilecen et al., 2017).
There have also been many meta-analysis publications looking at the impact of fibrinogen concentrate on transfusion requirements and mortality in cardiac surgery patients, often including smaller, less rigorous studies. An early meta-analysis study looking at six small clinical trials for cardiac surgery found that there was no statistical impact of FCH treatment on mortality (2.6% vs 9.5%; risk ratio, 0.28; 95% CI 0.03 to 2.33); however, FCH reduced the need for further blood transfusion (risk ratio, 0.47; 95% CI 0.31 to 0.72) (Wikkelsø et al., 2013). A key conclusion from this meta-analysis was that the studies were small and of poor quality. A follow-on systemic review of seven randomised controlled trials (total of n = 268 patients), five of which involved cardiac surgery for both adult and paediatric cases, also reported a similar outcome for fibrinogen concentrate treatment (Lunde et al., 2014). Only two trials from this systemic review reported a significant reduction in mortality and five reported a significant reduction in transfusion requirements. A more recent meta-analysis of eight randomised controlled trials for a total of 597 adult cardiac patients found that using fibrinogen concentrate in the clinic did not affect all-cause mortality (risk ratio, 0.41; P=0.15) but reduced the need for allogeneic red blood cell transfusion (risk ratio, 0.64; P=0.001) (Li et al., 2018). Once again, the authors conclude that larger and better designed trials would help to confirm these findings.
There have been far fewer studies comparing fibrinogen concentrate to the alternative treatments, fresh frozen plasma (FFP) or cryoprecipitate, for acquired fibrinogen deficiency during cardiac surgery. In a small prospective randomised trial of 39 patients, Lance and colleagues compared FFP to partial replacement of FFP with fibrinogen concentrate and found that the latter increased clot formation (Lance et al., 2012). Another small study of 49 patients comparing FFP to fibrinogen concentrate for controlling perioperative bleeding in elective thoracic aortic aneurysm surgery found that fibrinogen concentrate decreased blood loss by 64% and the number of transfusion units by 58% compared to FFP (Yamamoto et al., 2014). In a prospective randomised study, Galas and colleagues compared fibrinogen concentrate (n = 30) to cryoprecipitate (n = 33) in children undergoing cardiac surgery if bleeding was associated with fibrinogen levels less than 1 g/L. They found that there was no significant difference between FCH and cryoprecipitate in measurements for 48-hour blood loss (320 mL vs 410 mL, P=0.672), need for ABP transfusion or in the increase in fibrinogen levels following administration (Galas et al., 2014).
FCH was found to be at least as safe as alternative treatments in a cardiac surgery setting (Galas et al., 2014; Fassl et al., 2015; Ranucci et al., 2015; Fominskiy et al., 2016; Rahe-Meyer et al., 2016). A longer-term retrospective analysis of bleeding patients undergoing cardiac surgery found no difference in 30 day or 1-year mortality or adverse outcomes in patients treated with FCH (n = 210) compared to patients treated without FCH (n = 781) (Fass et al., 2015) (Table 2).
Table 2. Risks associated with perioperative administration of fibrinogen concentrate (FCH); multivariate logistic regression. Hazard ratios (HR) for mortality and adverse outcome either 30 days or 1 year after fibrinogen concentrate (FCH) treatment (adapted from Fassl et al., 2015)
Fominskiy and colleagues carried out a meta-analysis of fourteen randomised controlled trials investigating the use of FCH in 1,035 surgical patients who were mostly cardiac surgery patients (Fominskiy et al., 2016). Whilst the studies were individually underpowered, the meta-analysis found no difference in the rates of thromboembolic events (TEE) between FCH and control groups, and a possible reduction in all-cause mortality (0.9% for FCH versus 3.5% for the control group, P=0.02).
Fibrinogen is not indicated for prophylactic treatment in the surgery setting, and there are few studies that address this application. During coronary artery bypass surgery, Karlsson and colleagues found that preoperative administration of FCH (2 g dose) reduced postoperative blood loss by 32% (565 +/- 150 vs. 830 +/- 268 ml/12 h, P=0.010) in a prospective randomised pilot study on a total of 20 patients (Karlsson et al., 2009). More studies are needed on the value of FCH as a prophylactic treatment in the cardiac surgery setting.
Altogether, it appears that fibrinogen concentrate is safe in a cardiac surgery setting and may result in a reduced need for transfusion of allogeneic blood products. However, since most studies to date are underpowered, more studies are needed, particularly to establish the effect of FCH on mortality, compared to other treatments. A new phase III, multi-centre, randomised trial (FIBRES trial) seeking to recruit 1200 cardiac surgery patients is currently underway with the aim of directly comparing fibrinogen concentrate to cryoprecipitate (Karkouti et al., 2018).
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