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Meta-Analysis
. 2018 Dec 24;12(12):CD010649.
doi: 10.1002/14651858.CD010649.pub2.

Pro-coagulant haemostatic factors for the prevention and treatment of bleeding in people without haemophilia

Jez Fabes  1 , Susan J Brunskill, Nicola Curry, Carolyn Doree, Simon J Stanworth
Affiliations
Meta-Analysis

Pro-coagulant haemostatic factors for the prevention and treatment of bleeding in people without haemophilia

Jez Fabes et al. Cochrane Database Syst Rev. .

Abstract

Background: Some hospital patients may be at risk of or may present with major bleeding. Abnormalities of clotting (coagulation) are often recorded in these people, and the traditional management has been with transfusions of blood components, either to prevent bleeding (prophylactic) or to treat bleeding (therapeutic). There is growing interest in the use of targeted therapies with specific pro-coagulant haemostatic (causing bleeding to stop and to keep blood within a damaged blood vessel) factor concentrates in place of plasma.

Objectives: To assess the effects and safety of pro-coagulant haemostatic factors and factor concentrates in the prevention and treatment of bleeding in people without haemophilia.

Search methods: We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (2018, issue 3), MEDLINE (from 1948), Embase (from 1974), CINAHL (from 1938), PubMed (publications in process to 18 April 2018), PROSPERO, Transfusion Evidence Library (from 1950), LILACS (from 1980), IndMED (from 1985), KoreaMed (from 1934), Web of Science Conference Proceedings Citation Index (from 1990) and ongoing trial databases to 18 April 2018.

Selection criteria: We included RCTs that compared intravenous administration of a pro-coagulant haemostatic factor concentrate, either with placebo, current best or standard treatment, or another pro-coagulant haemostatic factor concentrate for prevention or treatment of bleeding. There was no restriction on the types of participants. We excluded studies of desmopressin, tranexamic acid and aminocaproic acid and use of pro-coagulant haemostatic factors for vitamin K over-anticoagulation.

Data collection and analysis: We followed standard Cochrane methodological procedures.

Main results: We identified 31 RCTs with 2392 participants and 22 ongoing trials. There were 13 therapeutic RCTs that randomised 1057 participants (range from 20 to 249 participants) and 18 prophylactic trials that randomised 1335 participants (range 20 to 479 participants). The pro-coagulant haemostatic factor concentrate was fibrinogen in 23 trials, Factor XIII in seven trials and pro-thrombin complex concentrates (PCC) in one trial.Seventeen trials had industrial funding or support, eight studies either did not declare their funding or were unclear about their source of funding and six studies declared non-industrial funding sources.Certainty in the evidence and included study biasOur certainty in the evidence, using GRADE criteria, ranged from very low to high across all outcomes. We assessed most outcomes as being of low certainty. Risks of bias were a concern in many of the RCTs; randomisation methodology was unclear in 15 RCTs, with allocation concealment unclear in 14 RCTs and at high risk of bias in five RCTs. The blinding status of outcome assessors was unclear in 13 RCTs and at high risk of bias in five RCTs, although most outcomes in these trials were objective and not prone to observer bias. Study personnel were often unblinded or insufficient information was available to assess their level of blinding (five RCTs were at unclear risk and seven at high risk of bias).Primary outcomesAll-cause mortality was reported by 21 RCTs, arterial thromboembolic events by 22 RCTs, and venous thromboembolic events by 21 RCTs.Fibrinogen concentrate: prophylactic trials with inactive comparator (nine RCTs)The trials had heterogeneous clinical settings and outcome time points, so we did not pool the data. Compared to placebo, there was no evidence that prophylactic fibrinogen concentrate reduced all-cause mortality (4 RCTs; 248 participants). Compared to inactive comparators there was low- to moderate-quality evidence that prophylactic fibrinogen concentrate did not increase the risk of arterial or venous thromboembolic complications (7 RCTs; 398 participants).Fibrinogen concentrate: prophylactic trials with active comparator (two RCTs)There was no mortality or incidence of thromboembolic events in these two RCTs (with 57 participants).Fibrinogen concentrate: therapeutic trials with inactive comparator (eight RCTs)The trials had heterogeneous surgical settings and outcome time points, so we pooled data for subgroups only. Compared to an inactive comparator, there was no evidence (quality ranging from low to high) that fibrinogen concentrate reduced all-cause mortality in actively bleeding participants (7 RCTs; 724 participants). Compared to inactive comparators there was no evidence that the use of fibrinogen concentrate in active bleeding increased arterial (7 RCTs; 607 participants) or venous (6 RCTs; 562 participants) thromboembolic events.Fibrinogen concentrate: therapeutic trials with active comparator (four RCTs)We did not pool the outcome data, as they were not measured at comparable time points. Compared to other active pro-coagulant agents, there was no evidence (very low to moderate quality) that fibrinogen concentrate reduced all-cause mortality in actively bleeding participants (4 RCTs; 220 participants). There was no evidence that fibrinogen concentrate increased the risk of arterial (3 RCTs; 126 participants) or venous (4 RCTs; 220 participants) thromboembolic events.FactorXIII: Prophylactic trials with inactive comparator (six trials)The trials were heterogeneous in their surgical settings and time points for outcome analysis, so we pooled data for subgroups only. Compared to an inactive comparator, there was no evidence that prophylactic Factor XIII reduced all-cause mortality (5 RCTs; 414 participants). There was no evidence (very low to low quality) of a difference in the arterial or venous event rate between Factor XIII and inactive comparators (4 trials; 354 participants).FactorXIII: therapeutic trials with inactive comparator (one trial)There was no mortality or incidence of thromboembolic events in this trial.Prothrombin complex concentrate (PCC): prophylactic trials with inactive comparator (one trial)There was no evidence (moderate quality) that PCC reduced all-cause mortality (1 trial; 78 participants). No thromboembolic complications were reported in this trial.

Authors' conclusions: The paucity of good-quality comparable evidence precludes the drawing of conclusions for clinical practice. Further research is required to determine the risk-to-benefit ratio of these interventions. The sample sizes of future RCTs would need to be greatly increased to detect a reduction in mortality or thromboembolic events between treatment arms. To improve consistency in outcome reporting, the development of core outcome sets is essential and may help address a number of the limitations identified in this review.

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Conflict of interest statement

Nicola Curry and Simon Stanworth were the chief investigators for the E‐FIT 1 trial which has been included in this review as Curry 2018.

Jez Fabes: None known.

Susan Brunskill: None known.

Carolyn Doree: None known.

Figures

1
1
Trial flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included trial. Thirty‐one trials are included in this review (Haas 2015 reports two trials).
See this image and copyright information in PMC

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References

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References to studies excluded from this review

ACTRN12615001293550p 2015 {published data only}
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    1. Refaai MA, Goldstein JN, Lee ML, Milling TJ Jr, Sarode R. Increased risk of volume overload with plasma compared to four‐factor prothrombin complex concentrate for the emergency reversal of vitamin K antagonist therapy. Academic Emergency Medicine. 2014; Vol. 21:5 (Suppl 1).
    1. Refaai MA, Goldstein JN, Milling TJ, Foehl H, Hug B, Sarode R. Correction of INR and coagulation factor levels in a randomized clinical trial of a four‐factor prothrombin complex concentrate (PCC‐4) versus plasma for urgent vitamin K antagonist reversal. Annals of Emergency Medicine. 2012; Vol. 60 (4s):S10.
Scherer 1994 {published data only}
    1. Scherer R, Gille A, Erhard J, Paar D, Kox WJ. [The effect of substitution with AT III‐ and PPSB‐concentrates in patients with terminal liver insufficiency]. [German] [Substitutionseffekt von AT III‐und PPSB‐Konzentraten bei patienten mit terminaler leberinsuffizienz]. Anaesthesist 1994;43(3):178‐82. - PubMed
TOP‐CLOT Trial {published data only}
    1. Trial of RiaSTAP Versus Cryoprecipitate to Lower Operative Transfusions (TOP‐CLOT). www.ClinicalTrials.gov, registry number (accessed 05.02.2018); study terminated (feasibility issues prevent completion of recruitment).
UMIN000022194 {published data only}
    1. Invasive intervention study on the safety of fibrinogen concentrate used in obstetric hemorrhage. UMIN‐CTR register: UMIN000022194 (accessed 05.02.2018).
UMIN000022666 {published data only}
    1. Application of fibrinogen concentrate (Fibrinogen HT) to uncontrollable massive bleeding. UMIN‐CTR registry: UMIN000022666 (accessed 05.02.2018).
van Aart 2006 {published data only}
    1. Aart L, Eijkhout H, Kamphuis JS, Dam M, Strengers PFW, Ploeger B. The use of prothrombin complex investigated [Gebruik van protrombinecomplex onderzocht [Dutch]. Pharmaceutisch weekblad 2001;136(3):84‐7.
    1. Aart L, Eijkhout HW, Kamphuis JS, Dam M, Schattenkerk ME, Schouten TJ, et al. Individualized dosing regimen for prothrombin complex concentrate more effective than standard treatment in the reversal of oral anticoagulant therapy: An open, prospective randomized controlled trial. Thrombosis Research 2006;118:313‐20. [PUBMED: 16182346] - PubMed

References to studies awaiting assessment

Siemens 2017 {published data only}
    1. Fibrinogen concentrate supplementation in the management of bleeding during paediatric cardiopulmonary bypass: a phase 1B/2A, open label dose escalation study. EudraCT Number: 2013‐003532‐68 (accessed 05.04.2018).
    1. Siemens K, Hunt BJ, Harris J, Nyman A, Perkins J, Murdoch IA, et al. Fibrinogen in paediatric cardiac surgery: the FIB‐CON trial. Transfusion Medicine. 2017; Vol. 27:19.

References to ongoing studies

ANZCTR12613001279718 {published data only}
    1. Prothrombinex‐VF vs Fresh Frozen Plasma for the treatment of bleeding post cardiopulmonary bypass. Australian New Zealand Clinical Trials Registry 12613001279718 (accessed 13 January 2016).
ANZCTR12614000691640 {published data only}
    1. The administration of fibrinogen concentrate (a component of blood involved in clotting process) to be given to those women who, after delivery of babies, develop severe bleeding to establish if this drug will prevent further blood loss or reduce the volume of blood loss. Australia New Zealand Clinical Trial Registry, number: ACTRN12614000691640 (accessed 13 January 2016).
EudraCT: 2010‐022923‐31 {published data only}
    1. A multicenter double‐blind, placebo controlled, randomized, pilot trial to assess the efficacy of pre‐hospital administration of Fibrinogen Concentrate (FGTW) in trauma patients, presumed to bleed (FI in TIC). EudraCT Identifier: 2010‐022923‐31 (accessed 20.4.18).
EudraCT: 2013‐003532‐68 {published data only}
    1. Fibrinogen concentrate supplementation in the management of bleeding during paediatric cardiopulmonary bypass: a phase 1B/2A, open label dose escalation study. EudraCT Identifier: 2013‐003532‐68 (accessed 13 January 2016).
EudraCT: 2013‐004484‐31 {published data only}
    1. Rivaroxaban and PCC: Prothrombin Complex Concentrate in patients with bleeding complications related to Rivaroxaban [Eine prospektive klinische Pilotstudie zur Untersuchung der Wirksamkeit von Prothrombin Komplex Konzentraten (Beriplex®) bei Patienten mit Blutungskomplikationen unter der Einnahme von Rivaroxaban (Xarelto®)]. EudraCT Identifier: 2013‐004484‐31 (accessed 13 January 2016).
NCT00994045 {published data only}
    1. Coagulopathy During Surgery for the Repair of Extent 4 Thoraco‐Abdominal Aortic Aneurysms ‐ Feasibility Study of the Use of Fibrinogen Concentrate by Infusion in Place of Fresh Frozen Plasma. ClinicalTrials.gov Identifier: NCT00994045 (accessed 05.02.2018).
NCT01539057 {published data only}
    1. The Efficacy of the Administration of Fibrinogen in Liver Transplantation (FibstudLT). ClinicalTrials.gov Identifier: NCT01539057 (accessed 13 January 2016).
NCT02155725 {published data only}
    1. Study on the Efficacy and Safety of a Therapeutic Strategy of PPH Comparing Early Administration of Human Fibrinogen vs Placebo in Patients Treated With IV Prostaglandins Following Vaginal Delivery. ClinicalTrials.gov Identifier: NCT02155725 (accessed 05.08.2018).
    1. Ducloy‐Bouthors A, Mignon A, Huissoud C, Grouin J, Mercier FJ. Fibrinogen concentrate as a treatment for postpartum haemorrhage‐induced coagulopathy: A study protocol for a randomised multicentre controlled trial. The fibrinogen in haemorrhage of DELivery (FIDEL) trial. Anaesthesia Critical Care and Pain Medicine 2016;35:293‐8. - PubMed
NCT02203968 {published data only}
    1. Fibrinogen in the Initial Resuscitation of Severe Trauma (FiiRST). ClinicalTrials.gov Identifier: NCT02203968 (accessed 13 January 2016).
NCT02253082 {published data only}
    1. Vasculopathic Injury and Plasma as Endothelial Rescue ‐ OCTAplas Trial (VIPER‐OCTA). ClinicalTrials.gov Identifier: NCT02253082 (accessed 13 January 2016).
NCT02299947 {published data only}
    1. Bloodtranfusions After Aortic Surgery (FIBTEG). ClinicalTrials.gov Identifier: NCT02299947 (accessed 13 January 2016).
NCT02344069 {published data only}
    1. Effect of Immediate, Pre‐emptive Fibrinogen Concentrate in Patients With Trauma Haemorrhage Needing Haemostatic Resuscitation ‐ a Randomized, Controlled, Double‐blinded Investigator‐initiated Pilot Trial. ClinicalTrials.gov Identifier: NCT02344069 (accessed 05.08.2018).
    1. Stensballe J, Sorensen AM, Steinmetz J, Henriksen HH, Lange T, Larsen CF, et al. Fibrinogen in trauma haemorrhage. Transfusion medicine. 2017; Vol. 27:19.
NCT02429453 {published data only}
    1. FFP Versus PCC in Traumatic Intracranial Hemorrhage. ClinicalTrials.gov Identifier: NCT02429453 (accessed 13 January 2016).
NCT02528708 {published data only}
    1. A Program to Evaluate Riastap® and FIBTEM® for the Early Control and Treatment of Postpartum Hemorrhage (PERFECT PPH). ClinicalTrials.gov Identifier: NCT02528708 (accessed 05.08.2018) currently suspended pending review to commence.
NCT02557672 {published data only}
    1. Prothrombin Complex Concentrate (PCC) Compared to Fresh Frozen Plasma (FFP) for Post‐cardiopulmonary Bypass Coagulopathy and Bleeding, a Prospective Randomized Trial at Large US Medical Center. ClinicalTrials.gov Identifier: NCT02557672 (accessed 05.02.2018).
NCT02745041 {published data only}
    1. Fibrinogen Concentrate vs Cryoprecipitate in Traumatic Haemorrhage: A Pilot Randomised Controlled Trial. ClinicalTrials.gov Identifier: NCT02745041 (accessed 05.08.2018).
    1. Winearls J, Wullschleger M, Wake E, Hurn C, Furyk J, Ryan G, et al. Fibrinogen Early In Severe Trauma studY(FEISTY): study protocol for a randomised controlled trial. Trials 2017;18:241. - PMC - PubMed
NCT02777424 {published data only}
    1. Prothrombin Complex Concentrate Versus Fresh Frozen Plasma to Correct Coagulation Disorders in Adult Neurosurgical Patients. ClinicalTrials.gov Identifier: NCT02777424 (accessed 05.08.2018).
NCT02822599 {published data only}
    1. The Role of Human Fibrinogen Concentrate (RiaSTAP) in Decreasing Blood Loss and the Need for Component Blood Therapy in Infants Undergoing Cardiopulmonary Bypass. ClinicalTrials.gov Identifier: NCT02822599 (accessed 05.02.2018).
NCT03014700 {published data only}
    1. Repurposing of Fibrinogen Concentrate as a Cost‐Effective and Safe Hemostatic Agent in Infants Undergoing Cardiac Surgery on Cardiopulmonary Bypass. ClinicalTrials.gov Identifier: NCT03014700 (accessed 05.02.2018).
NCT03037424 {published data only}
    1. Prospective, Multi‐center, Randomized, Active‐control, Non‐inferiority Study Comparing Fibrinogen Concentrate With Cryoprecipitate for the Treatment of Acquired Hypofibrinogenemia in Bleeding Adult Cardiac Surgical Patients. ClinicalTrials.gov Identifier: NCT03037424 (access 05.08.2018).
NCT03183479 {published data only}
    1. The Effects of Fibrinogen Concentrate Infusion on Perioperative Blood Loss and Allogeneic Blood Conservation in Patients Undergoing Scoliosis Surgery. ClinicalTrials.gov Identifier: NCT03183479 (accessed 05.02.2018).
NCT03218722 {published data only}
    1. Early Administration of Prothrombin Concentrate Complex in Patients With Acute Hemorrhage Following Severe Trauma (PROCOAG). ClinicalTrials.gov Identifier: NCT03218722 (accessed 20.4.18).

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