The desperate need for good-quality clinical trials to evaluate the optimal source and dose of fibrinogen in managing bleeding

Recent interest in transfusion management of trauma patients has heightened expectation in the role of blood component therapy in improving patient outcome. Optimal transfusion support in supplementation with fibrinogen has not been defined by high-quality evidence. Current evidence comes mainly from case series and uncontrolled studies and does not support the superiority of one source of fibrinogen over another or the optimal schedule or dose for patient benefit. There are unanswered questions about safety, especially the effects on the risk of hospital-acquired venous thromboembolism, an important consideration in any therapy that alters the hemostatic balance. Studies of cost-effectiveness have not been considered in research. An international move to supplement fibrinogen more 'aggressively' without direct clinical evaluation beforehand represents a failed opportunity to improve our very limited understanding of optimal transfusion practice.


Abstract
Recent interest in transfusion management of trauma patients has heightened expectation in the role of blood component therapy in improving patient outcome. Optimal transfusion support in supplementation with fi brinogen has not been defi ned by high-quality evidence. Current evidence comes mainly from case series and uncontrolled studies and does not support the superiority of one source of fi brinogen over another or the optimal schedule or dose for patient benefi t. There are unanswered questions about safety, especially the eff ects on the risk of hospital-acquired venous thromboembolism, an important consideration in any therapy that alters the hemostatic balance. Studies of cost-eff ectiveness have not been considered in research. An international move to supplement fi brinogen more 'aggressively' without direct clinical evaluation beforehand represents a failed opportunity to improve our very limited understanding of optimal transfusion practice.
only three compared fi brinogen concentrate against FFP, and, in this case, plasma in combination with other products. As the authors indicate, RCTs do provide a more robust assessment, but no detail is presented in the quality assessment of the 15 RCTs of plasma or, crucially, the three RCTs of fi brinogen concentrate. Th e three trials of fi brinogen concentrate enroll 17, 10, and 10 patients into the intervention arm, and this must raise questions about confi dence intervals for the trial outcomes. Th e numbers of small studies not only may exaggerate the amount of evidence available but also, in the setting of RCTs, could compromise the ability of randomization to achieve equivalence of baseline characteristics. Studies comparing fi brinogen with FFP must also presume that evidence of eff ectiveness is known for one of the interventions, as the standard, but this is far from clear for FFP.
Th ere are a number of other issues to consider. Fibrinogen is not licensed to be given in acquired fi brinogen defi ciency in most countries. Are clinical trials being planned or undertaken to support the case for licensing? Th ere is no mention of cost-eff ectiveness or of the true risk-benefi t of giving potentially prothrombotic concentrates to patients (post-bleeding patients are at higher risk of hospital-acquired venous thromboembolism, and this is a major safety issue that has never been addressed).
Our view is that these data show that FFP and fi brino gen have never been adequately assessed in the manage ment of bleeding, and we would suggest that, until robust trial data emerge, the use of fi brinogen concentrate be confi ned to clinical trials. We are fearful that the danger of this review is that the message supports a move toward greater use of fi brinogen concentrate without proper evaluation fi rst.
Th e research into managing bleeding is littered with failure. Ian Chalmers, the guru of clinical trials, uses aprotinin as a scandalous example of ethical and clinical trial failure [5]. Eighty RCTs were performed to show that aprotinin reduced bleeding, but how was it ethical to randomly assign patients in the later trials when this antifi brinolytic had already been shown to work? And yet the even bigger failing was using the wrong endpointreducing bleeding or transfusion requirements -rather than reduction of premature death. After many years, the BART trial (Blood Conservation Using Antifi brinolytics in a Randomized Trial) addressed these concerns and showed that aprotinin, despite reducing bleeding, led to a higher mortality than other antifi brinolytics [6]. Th e future for studying blood components lies in pragmatic RCTs, with endpoints of mortality, which assess the rate of hospital-acquired thrombosis as well as reduction in bleeding. It has been said in the past that it is too diffi cult to do such studies in sick, bleeding patients, but CRASH-2 (Clinical Randomisation of an Antifi brinolytic in Signifi cant Haemorrhage), which randomly assigned 20,000 patients, shows that this is a fallacy [7].
Why are we, as a community of health professionals working to improve patient outcome in those with major bleeding, getting it so wrong and failing to undertake high-quality studies? Th is appears to be a common theme in the acute management of trauma hemorrhage, even though a recent systematic review identifi ed over 30 RCTs [8]. Is there a general lack of understanding, among health professionals in this fi eld, of how to weigh up and respond to defi ciencies in the scientifi c evidence? It would be ethically unacceptable and a moral tragedy for the greater use of diff erent sources of fi brinogen, whatever the cause, to slip into routine clinical practice without an adequate evidence base.