Fibrinogen is a natural blood protein involved in the coagulation process. Bleeding decreases the blood level, and low levels of this protein may increase bleeding even further, thereby increasing morbidity and mortality. Fibrinogen concentrate is widely used instead of traditional sources of fibrinogen, such as the blood products fresh frozen plasma and cryoprecipitate (a pooled concentrated plasma product), especially in some countries, despite the lack of adequate knowledge derived from previous research to support such an approach. In the present Cochrane systematic review, we set out to assess the benefits and harms of fibrinogen concentrate in patients with bleeding. We searched the databases to August 2013, we identified six randomized trials in cardiac and elective surgical settings that compared fibrinogen concentrate (248 participants) with placebo/other sources or no treatment. Additionally, we found 12 ongoing trials, but we were unable to retrieve any data from them. We could not identify beneficial effects of fibrinogen concentrate on patient survival. In our predefined outcomes, we identified a reduced proportion of patients requiring donor blood transfusion. We could not identify reduced blood loss or any harms or adverse events caused by treatment with fibrinogen concentrate. However, all trials were of low quality and were small, so evidence in support of fibrinogen concentrate in patients with bleeding remains weak.
In the six available RCTs of elective surgery, fibrinogen concentrate appears to reduce transfusion requirements, but the included trials are of low quality with high risk of bias and are underpowered to detect mortality, benefit or harm. Furthermore, data on mortality are lacking, heterogeneity is high and acute or severe bleeding in a non-elective surgical setting remains unexplored. Currently, weak evidence supports the use of fibrinogen concentrate in bleeding patients, as tested here in primarily elective cardiac surgery. More research is urgently needed.
Hypofibrinogenaemia is associated with increased morbidity and mortality, but the optimal treatment level, the use of preemptive treatment and the preferred source of fibrinogen remain disputed. Fibrinogen concentrate is increasingly used and recommended for bleeding with acquired haemostatic deficiencies in several countries, but evidence is lacking regarding indications, dosing, efficacy and safety.
We assessed the benefits and harms of fibrinogen concentrate compared with placebo or usual treatment for bleeding patients.
We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 8); MEDLINE (1950 to 9 August 2013); EMBASE (1980 to 9 August 2013); International Web of Science (1964 to 9 August 2013); CINAHL (1980 to 9 August 2013); LILACS (1982 to 9 August 2013); and the Chinese Biomedical Literature Database (up to 10 November 2011), together with databases of ongoing trials. We contacted trial authors, authors of previous reviews and manufacturers in the field.
We included all randomized controlled trials (RCTs), irrespective of blinding or language, that compared fibrinogen concentrate with placebo/other treatment or no treatment in bleeding patients, excluding neonates and patients with hereditary bleeding disorders.
Three review authors independently abstracted data; we resolved any disagreements by discussion. Our primary outcome measure was all-cause mortality. We performed subgroup and sensitivity analyses to assess the effects of fibrinogen concentrate in adults and children in terms of various clinical and physiological outcomes. We presented pooled estimates of the effects of intervention on dichotomous outcomes as risk ratios (RRs) and on continuous outcomes as mean differences, with 95% confidence intervals (CIs). We assessed the risk of bias through assessment of trial methodological components and the risk of random error through trial sequential analysis.
We included six RCTs with a total of 248 participants; none of the trials were determined to have overall low risk of bias. We found 12 ongoing trials, from which we were unable to retrieve any data. Only two trials provided data on mortality, and one was a zero event study; thus the meta-analysis showed no statistically significant effect on overall mortality (2.6% vs 9.5%, RR 0.28, 95% CI 0.03 to 2.33). Our analyses on blood transfusion data suggest a beneficial effect of fibrinogen concentrate in reducing the incidence of allogenic transfusions (RR 0.47, 95% CI 0.31 to 0.72) but show no effect on other predefined outcomes, including adverse events such as thrombotic episodes.