Intervention Review

You have free access to this content

Fibrinogen concentrate in bleeding patients

  1. Anne Wikkelsø1,*,
  2. Jens Lunde2,
  3. Mathias Johansen3,
  4. Jakob Stensballe4,
  5. Jørn Wetterslev5,
  6. Ann Merete Møller6,
  7. Arash Afshari7,8

Editorial Group: Cochrane Anaesthesia, Critical and Emergency Care Group

Published Online: 29 AUG 2013

Assessed as up-to-date: 9 AUG 2013

DOI: 10.1002/14651858.CD008864.pub2


How to Cite

Wikkelsø A, Lunde J, Johansen M, Stensballe J, Wetterslev J, Møller AM, Afshari A. Fibrinogen concentrate in bleeding patients. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD008864. DOI: 10.1002/14651858.CD008864.pub2.

Author Information

  1. 1

    University of Copenhagen Herlev Hospital, Department of Anaesthesiology, Herlev, Denmark

  2. 2

    Rigshospitalet, Copenhagen University Hospital, Juliane Marie Centre - Anaesthesia and Surgical Clinic Department 4013, Copenhagen, Denmark

  3. 3

    Rigshospitalet, Copenhagen University Hospital, Department of Anaesthesiology, Centre of Neuroanaesthesia, Copenhagen, Denmark

  4. 4

    Copenhagen University Hospital, Rigshospitalet, Department of Anaesthesiology, Centre of Head and Orthopaedics & Section for Transfusion Medicine, Capital Region Blood Bank, Copenhagen, Denmark

  5. 5

    Rigshospitalet, Copenhagen University Hospital, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Copenhagen, Denmark

  6. 6

    University of Copenhagen Herlev Hospital, The Cochrane Anaesthesia Review Group, Rigshospitalet & Department of Anaesthesiology, Herlev, Denmark

  7. 7

    Hôpitaux Universitaires de Genève, Pediatric and Neonatal Intensive Care Service, Geneva, Switzerland

  8. 8

    Rigshospitalet, Copenhagen University Hospital, Juliane Marie Centre, Department of Anaesthesiology, Copenhagen, Denmark

*Anne Wikkelsø, Department of Anaesthesiology, University of Copenhagen Herlev Hospital, Herlev, Denmark. wikkelso@gmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 29 AUG 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Cui 2010

MethodsTwo-group parallel RCT, single centre

Overall study quality: high risk of bias

Sample size calculation: none reported

Funding: not stated


Participants40 participants randomly assigned, of which 31 received intervention (17 in fibrinogen group)

Inclusion criteria: cyanotic paediatric patients diagnosed with transposition of the great arteries (TGA) or double-outlet right ventricle (DORV); the operation that the patients underwent was arterial switch operation (ASO) or double roots transplantation (DRT). Hematocrit higher than 54% before operation

Exclusion criteria: history of blood disease; anticoagulation treatment before surgery; medication that affects haemostasis (such as prostaglandin E1); difficult sternal closure caused by anatomical or surgical reasons


InterventionsIntervention: fibrinogen (0.5 to 1 g) administration combined with traditional transfusion guided by thrombelastography (TEG, Haemoscope Corp)

The type of fibrinogen substitution is not specifically described

Control: traditional transfusion guided by clinical experience


OutcomesNo primary outcome is stated

Closure time, transfusion at closure (FFP/PLT), transfusion requirements at ICU (FFP/PLT/RBC), chest tube drainage (1,6,24 hours) and total transfusion requirements (FFP/PLT/RBC*)

*RBC at closure time was not assessed because residuals of blood were present in the CPB machine


NotesCountry: China

We have converted the missing standard deviation in accordance with recommendations stated in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 7.7.3.5

We used mean body weight for each group to calculate transfused amount, when outcome was reported in mL/kg

Letter to author 2 March 2012, repeated 23 May 2012. No reply received

Authors' conclusion: "The present study suggests that fibrinogen might be a better haemostatic agent for paediatric patients with severely cyanotic CCHD than FFP. This new therapy method could reduce the use of allogeneic blood products and shorten the operative recovery period. In addition, TEG is effective for blood protection"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated

Allocation concealment (selection bias)Unclear riskNot stated

Incomplete outcome data (attrition bias)
All outcomes
High risk22.5% excluded (9/40), not accounted for

Selective reporting (reporting bias)Unclear riskNot stated

Other biasHigh riskSample size not stated, funding not stated, baseline parameters are provided, but it is unclear if they include the excluded patients, and if the exclusions influence baseline balance. A small study and operative recovery data show very large differences between small trial groups, suggesting that the intervention group might have consisted of healthier individuals overall

Blinding of participants and personnel (performance bias)
All outcomes
High riskNot described. The intervention would be difficult to blind, so we expect this to be provided without blinding of personnel. It may be blinded to participants

Blinding of outcome assessment (detection bias)
All outcomes
High riskNot described (see above)

Fenger-Eriksen 2009a

MethodsTwo-group parallel RCT

Funding: The study was supported by an unrestricted research grant from CSL Behring, the University of Aarhus Research Foundation and the A. P. Møller and Hustru Chastine McKinney Møllers Foundation

Overall study quality: high risk of bias

Sample size calculation: yes, based on 10% change in maximum clot strength


Participants21 participants randomly assigned; 20 participants received intervention (10 in fibrinogen group)

Inclusion criteria: Patients older than 17 years of age suffering from localized bladder cancer and admitted for radical cystectomy. Furthermore, perioperative dilution with hydroxyethyl starch (HES) to a 30% reduction in hematocrit level

Exclusion criteria: 1: Presence of coagulation disorders defined as abnormal values of platelet count, PT, APTT, fibrinogen, antithrombin or D-dimer; 2: Treatment with oral vitamin K antagonists; 3: Intake of non-steroid anti-inflammatory drugs within 2 days before surgery; 4: Renal or hepatic dysfunction; 5: Ischaemic heart disease; 6: Pregnancy; 7: Known hypersensitivity to HES


InterventionsIntervention: fibrinogen concentrate, Haemocomplettan, CSL Behring (dosage 45 mg/kg)

Control: placebo in equivalent volume (isotonic saline 2.25 mL/kg)


OutcomesPrimary: whole-blood maximum clot firmness as determined by thromboelastometry (ROTEM, thromboelastometry, Pentafarm, Munich, Germany)

Secondary: other thromboelastometric variables; platelet function; thrombin generation; bleeding and perioperative and postoperative blood product requirements


NotesLetter to author sent 2 March 2012. Reply received 13 March 2012, additional data were provided


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskShuffling of cards (additional information)

Allocation concealment (selection bias)Low riskRandomly assigned using the closed envelope principle

Incomplete outcome data (attrition bias)
All outcomes
Low riskAccording to published article, one participant was excluded after randomization because of an interrupted operation. Participant did not receive intervention. Data from this participant were not included in the analysis (no intention-to-treat analysis). (additional information) Exclusion was due to "Spread of cancer, so it was not possible to perform planned cystectomy hence the operation was interrupted". No available data on this participant regarding outcomes of this review

Selective reporting (reporting bias)Low riskCompared with the official description on clinicaltrials.gov. NCT00493272

Other biasHigh riskUnrestricted funding from CSL Behring. Very small sample size aimed to assess a surrogate outcome. Baseline imbalance described but analysis not provided

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"The study medicine was prepared and administered by a second person; thus, the study staff was blinded to infusion of the drug vehicle and to patients participating in the study"

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Allocation concealment was sustained until all recruitment, data collection, transfusion requirement data and laboratory analyses were complete". Statistician was not blinded (additional information)

Galas 2012

MethodsRandomized double-blinded parallel-assigned single-centre clinical trial

Data from abstract. No additional information available

Funding: not stated

Overall study quality: high risk of bias

Sample size calculation: not stated


Participants63 participants completed the study (30 in fibrinogen group)

Mean age, 3 years and 5 months; mean weight, 6.7 kg

Inclusion criteria: children (< 15 years) receiving cardiac surgery with cardiopulmonary bypass, clinically important intraoperative bleeding and hypofibrinogenaemia (fibrinogen level < 1 g/L or TEG < 7 mm)

Exclusion criteria: previous coagulopathy (clinical history or INR > 1.5); low platelet count (lower than 100.000); product allergy; urgent procedures; active infection


InterventionsIntervention group: fibrinogen concentrate (60 mg/kg body weight) (RiaSTAP®/CSL Behring)

Median doses were 504 mg fibrinogen concentrate

Control group: cryoprecipiate (10 mL/kg body weight)

Median doses were 402 mg cryoprecipitate


OutcomesPrimary outcome measures: number of patients not receiving any allogeneic blood products (intraoperative until hospital discharge). Transfusional requirements were based on clinical judgement

Secondary outcome measures: haemostatic tests, length of ICU stay, clinical complications (renal failure, respiratory failure, sepsis, myocardial ischemias, stroke), transfusion requirements, mechanical ventilation free-days, length of hospital stay, vasopressors free-days, perioperative bleeding


NotesEstimated enrolment: 80 participants. Finished. Data submitted for publication. Abstract available International Symposium on Intensive Care and Emergency Medicine 2012

Collaborator: CSL Behring

Contacted 4 April 2012. Reply received 8 April 2012. No additional information provided

Participating hospitals: (Brazil) Incor - Heart Institute - University of Sao Paulo


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated

Allocation concealment (selection bias)Unclear riskNot stated

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated

Selective reporting (reporting bias)High riskInclusion criteria changed from < 18 years to < 15 years compared with trial registration (NCT01187225)

"Reoperation due to bleeding" not stated as secondary outcome in trial registration (NCT01187225)

Other biasUnclear riskSample size not stated, funding not stated, baseline imbalance not described

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated

Karlsson 2009

MethodsSingle-center parallel-group RCT, pilot study

Funding: The study was supported by the Swedish Heart & Lung Foundation, CSL Behring, Marburg, Germany, and Sahlgrenska University Hospital

Overall study quality: high risk of bias

Sample size calculation: pilot study: sample size was determined in agreement with the Regional Research Ethics Committee and the Swedish Medical Products Agency


Participants20 participants randomly assigned (10 in fibrinogen group)

Inclusion criteria: elective CABG patients with plasma fibrinogen < 3.8 g/L

Exclusion criteria: known kidney/liver disease, bleeding disorder and a surgical source of bleeding at acute re-exploration


InterventionsIntervention: preoperative infusion of 2 g fibrinogen concentrate (Haemocomplettan, CSL Behring)
Control: no treatment


OutcomesPrimary: clinical adverse events and graft occlusion assessed by multi-slice computed tomography 3 to 4 days after surgery

Secondary: postoperative blood loss, blood transfusions, haemoglobin levels 24 hours after surgery, and global haemostasis assessed with thromboelastometry, 2 and 24 hours after surgery and clinical adverse events


NotesCountry: Sweden

Letter to author 14 March 2012. Reply by phone 29 May 2012

Provided additional data on mortality (6 year follow-up), ICU stay, mechanical ventilation and length of stay

Authors' conclusion: "In summary, the results of this pilot study indicate that prophylactic treatment with fibrinogen concentrate in cardiac surgery patients is feasible and reduces postoperative bleeding.
Further prospective, randomized, placebo-controlled studies with sufficient statistical power are necessary to ensure safety, confirm efficacy, and to determine cost-effectiveness of fibrinogen prophylaxis in cardiac surgery"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskShuffling of cards (additional information)

Allocation concealment (selection bias)Low riskRandom assignment was conducted using unmarked envelopes

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data. All 20 randomly assigned participants were described

Selective reporting (reporting bias)Low riskProtocol not available. Apparently free of selective reporting

Other biasHigh riskUnrestricted funding from CSL Behring. Apparently without baseline imbalance but with a very small sample size because it was a pilot study

Blinding of participants and personnel (performance bias)
All outcomes
High riskQuote: "Only the study coordinator was informed about group assignment, that is neither the operating surgeon, the operating room staff, anaesthesiologists nor the staff at the intensive care unit, was informed."

Fibrinogen was administered after induction of anaesthesia as an infusion during 5 minutes in a central venous catheter line, meaning that anaesthetic personnel at the operation theatre were not completely blinded (additional information). Pharmacist randomly assigned and dispensed the medicine

Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of postoperative bleeding: This was assessed by ICU nurses, who were not informed of group assignment

Lance 2011

MethodsSingle-centre, parallel-group RCT

Funding: The study group received unrestricted grants from CSL Behring

Overall study quality: high risk of bias

Sample size calculation: yes, based on 10% reduction in blood loss


Participants52 participants randomly assigned, of which 43 received intervention (22 in fibrinogen group)

Patients with massive bleeding requiring less than 4 FFP were excluded after randomization

Inclusion criteria: Major surgery (cardiovascular, abdominal, and orthopaedic spine surgery) with expected duration of operation exceeding 120 minutes. Patients requiring massive transfusion (defined as "prolonged blood loss of > 150 ml/hour or > 1.5 ml/kg/20 min, or acute blood loss of > 700 ml at once") during or after surgery

Exclusion criteria: age younger than 18, active HIV infection, known coagulation abnormalities, deep hypothermia with circulatory arrest or preoperative need of transfusion


InterventionsIntervention: haemostatic transfusion with 2 units FFP plus 2 g fibrinogen concentrate (Haemocomplettan®)

Control: haemostatic transfusion with 4 units FFP

Haemostatic therapy to stop bleeding was started on the basis of clinical decision

Comment: 25 participants (13 in fibrinogen group and 12 in control group) received heparin (150 to 300 mg/kg) as the result of extracorporal circulation


OutcomesAccording to protocol, primary outcome was blood loss: "Primary endpoint is the amount of blood loss (expressed in ml per time unit) and the further use of blood products. As secondary endpoints, the levels of thrombin generation and thromboelastografische provisions compared with conventional coagulation tests"

In article: bleeding arrest after intervention, fibrin clot formation (measured by whole-blood thromboelastometry and thrombin generation), adverse events

Participants were followed up to 30 days or at least until discharge


NotesCountry: the Netherlands

Letter to author 6 March 2012. Reply received 3 April 2012 and 22 June

Authors' conclusion: "In conclusion, this trial showed a similar effect of 2 g fibrinogen additive to 2 units FFP compared with transfusion of 4 units FFP on haemostasis. The transfused fibrinogen had an important contribution to fibrin clot formation in thromboelastometry analysis, while the transfused 4 units FFP more increased thrombin generation and fibrinogen levels remained lower. We hence postulate that transfused FFP and fibrinogen are both relevant for early haemostasis and that both should be combined in massive haemorrhage protocols. These results argue for a larger-scale follow-up study, where the effects are determined of supplementing fibrinogen concentrate together with a standard dose of FFP. Herein, a pro-haemostatic effect of fibrinogen is expected on top of the effect of normalization of other coagulation factors."


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskShuffling of cards (additional information)

Allocation concealment (selection bias)Low riskClosed envelope method

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo intention-to-treat analysis, 9/52 (17%) patients were excluded after randomization because an inadequate amount of FFP was transfused; no data available on these

Selective reporting (reporting bias)High riskIn protocol, authors state blood loss and transfusions as primary outcome (with sample size calculated on reduction in blood loss). In publication, authors describe arrest of bleeding instead

Other biasHigh riskTwo of authors (not primary author) hold an unrestricted grant from CSL Behring. Three persons from CSL Behring are acknowledged for "stimulating discussions". Sample size provided. Apparently without baseline imbalance but with no data on exclusions.

Blinding of participants and personnel (performance bias)
All outcomes
High riskInclusion was based on clinical decision, with the attending anaesthesiologist not blinded to the study intervention

(additional information): "Patients and surgeons were not aware of group. Only the attending anaesthesiologist received the products and transfused them- so she/he was aware of the treatment group, but lab-parameters were taken from researchers and worked up by analysts who did not know the groups. Registration of bleeding and further treatment was done by researchers"

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskSee above

Rahe-Meyer 2013

MethodsSingle-centre parallel-group RCT

Data from publication and additional information provided by authors

Funding: CSL Behring supported the trial

Overall study quality: high risk of bias

Sample size calculation: not stated


Participants61 randomly assigned, of which 29 received fibrinogen concentrate

Inclusion criteria:

Age > 18 years and elective thoracic or thoracoabdominal aortic replacement surgery involving cardiopulmonary bypass (CPB) (aortic valve operations with root/ascending aorta replacement (thoracic aortic aneurysm) with or without aortic bow replacements and thoracoabdominal replacements (thoracoabdominal aortic aneurysm)) and clinically relevant bleeding (defined as bleeding of 60 to 250 g into the surgical site within 5 minutes after CPB and completion of surgical haemostasis)

Exclusion criteria:

  • Positive pregnancy test, pregnancy or lactation
  • Women of childbearing age not using a medically approved method of contraception during the study
  • Previous aortic replacement at the same aortic site (re-do surgeries)
  • Undergoing an emergency operation
  • Proof or suspicion of a congenital or acquired coagulation disorder (e.g. VWD, via severe liver disease)
  • Myocardial Infarction (MI) or apoplexy in the 2 months before study surgery
  • ASA administration in the 3 days preceding study surgery, and a pathological (< 74.5 U) ASPI Multiplate® test immediately before surgery began
  • Clopidogrel administration in the 5 days preceding study surgery, and a pathological (< 31.1 U) ADP/PG Multiplate® test immediately before surgery began
  • Tirofiban administration in the 2 days preceding study surgery, and a pathological (< 94.1 U) TRAP Multiplate® test immediately before surgery began
  • Phenprocoumon administration in the 5 days preceding study surgery, and an INR > 1.28 immediately before surgery began
  • Participation in another clinical study in the 4 weeks preceding aortic replacement
  • Sensitivity to any of the components of study medication, or to MPs with a similar chemical structure to any of the components of study medication
  • Any indication that the restrictions or procedures of the study may not be adhered to (e.g. an uncooperative attitude)
  • Any indication that the study restrictions, procedures, or consequences therein have not been considered or understood, such that informed consent cannot be convincingly given
  • Multiple morbidities, with a notably constrained remaining length of life


InterventionsIntervention: Fibrinogen concentrate (Haemocomplettan P®/CSL Behring). Individualized dose using maximum amplitude of ROTEM/FIBTEM measurements before the end of CPB. Median dose given was 8 g (range, 3 to 12 g).

Control: placebo (saline 0.9%) same volume


OutcomesPrimary outcome: total allogenic transfusion requirements in the 24 hours post administration phase

Transfusion therapy in both groups was guided by algorithm based on postoperative blood drainage and platelet count

Secondary outcomes:

Intensive care length of stay, number of allogenic units transfused, mortality and adverse events and re-operation due to persistent bleeding


NotesCountry: Germany

Letter to author: sent 8 April 2012: reply with additional data received 18 April 2012

Authors' conclusion: "Hemostatic therapy with fibrinogen concentrate
in patients undergoing aortic surgery significantly reduced the transfusion of allogeneic blood products. Larger multicenter studies are necessary to confirm the role of fibrinogen concentrate in the management of perioperative bleeding in patients with life-threatening coagulopathy"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated. 1:1 with blocks of 4

Allocation concealment (selection bias)Low riskClosed opaque envelopes

Incomplete outcome data (attrition bias)
All outcomes
Low riskOne participant in placebo/control group died before 24 hours and is not included in primary outcome analysis. One participant in fibrinogen group and 4 participants in control group did not have data on length of stay. Intention-to-treat analyses were used to assess adverse events

Selective reporting (reporting bias)Low riskCompared with clinical registration NCT00701142, apparently free of bias

Other biasHigh risk(Additional information provided by author): "CSL Behring funded the trial. Sponsor participated in study design but was not involved with data collection. Data analysis was performed independently by a contract research organization funded by the study sponsor. The sponsor paid for the services of biometrics service providers and medical writing support. The clinical study report was written by medical writing vendor funded by the sponsor." Apperently free of baseline imbalance

Blinding of participants and personnel (performance bias)
All outcomes
Low riskRandomization and dispensation of trial medication were performed by the local hospital pharmacy, and medication was delivered to the operation theatre in syringes blinded to personnel

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOnly pharmacists dispensing the medicine and randomly assigning participants were unblinded and had no participant contact

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Bell 2010Case report, obstetrical setting

Six cases characterized by significant (> 1500 mL) peripartum blood loss and severe acquired hypofibrinogenaemia. Patients were treated with fibrinogen concentrate (mean dose, 3.16 g) along with allogeneic blood products (PLT, FFP, RBC)

Findings: rapid normalization of coagulation parameters and improved haemorrhage

Reason for exclusion: non-RCT

Danes 2008Retrospective cohort study, non-controlled, single centre, mixed patient population

Patients given fibrinogen concentrate according to pharmacy-dispensing records were included, receiving a median dose of 4 g

The cohort consisted of 69 participants suffering from various forms of acquired severe hypofibrinogenaemia with life-threatening consumptive thrombo-haemorrhagic disorders (surgery, trauma and digestive haemorrhage) (43 participants), or with underlying disease states that limit fibrinogen synthesis (hepatic dysfunction, haematological malignancies) (26 participants)

Findings: improved coagulation after treatment. Acute fibrinogen deficiency probably related to mortality

Reason for exclusion: non-RCT

Glover 2010Case report, obstetrical setting

One patient suffering major antenatal obstetrical haemorrhage with DIC and severe hypofibrinogenaemia. Treated with fibrinogen concentrate (4 g) in combination with RBC and FFP transfusion

Findings: Emphasis on early and timely monitoring of coagulation and rapid administration and availability of fibrinogen substitution

Reason for exclusion: non-RCT

Guasch 2008Prospective observational cohort, non-controlled (descriptive), single centre, obstetrical setting

124 women admitted for postpartum haemorrhage. Treatment was provided with RBCs (96.8%), prothrombin complex concentrate (7.25%), recombinant factor VIIa (3.2%) and fibrinogen concentrate (49.2%)

Findings: Use of fibrinogen concentrate is common and provides good results

Reason for exclusion: non-RCT

Haas 2008Retrospective non-controlled study, single centre, craniofacial surgery, children

Nine children undergoing major craniofacial surgery with massive blood loss. Thromboelastometry-guided assessment of coagulopathy and guided administration of fibrinogen concentrate (30 mg/kg)

Findings: no need for PLT and FFP. Fibrinogen concentrate effectively improved fibrinogen polymerisation and total cloth strength

Reason for exclusion: non-RCT

Mittermayr 2007Randomized clinical trial, placebo-controlled, single centre, orthopaedic spine surgery

Intervention: three groups receiving modified gelatin solution, hydroxyethyl starch 130/0.4 or Ringer lactate

Fibrinogen concentrate (Hemocomplettan®) was administered (30 mg/kg) to all three groups when fibrin polymerisation was critically decreased as evaluated by thromboelastometry (ROTEM)

Population: 61 patients undergoing spine surgery of more than three segments with an expected duration of surgery of longer than 3 hours

Outcomes: allogeneic blood products transfused; estimated intraoperative blood loss; maximum clot firmness measured by FIBTEM

Findings: fibrin/fibrinogen polymerisation is disturbed because of dilution, especially in participants receiving hydroxyethyl starch 130/0.4. This effect may be reversed by fibrinogen concentrate

Reason for exclusion: Fibrinogen concentrate was not given in accordance with randomization. In this trial, it served as a rescue treatment to correct dilutional coagulopathy and was given to all three groups

Morrison 2011Case report, elective vascular surgery

Three patients undergoing elective type IV thoracoabdominal aortic aneurysm treatment. Patients were treated with continuous infusion of fibrinogen concentrate (mean dose, 13.3 g) guided by FIBTEM maximum clot firmness

Findings: despite blood loss of up to 11 L, no need for FFP and cryoprecipitate transfusion

Reason for exclusion: non-RCT

Rahe-Meyer 2009Prospective interventional cohort study non-randomized and non-blinded, single centre, elective aortic valve operation and ascending aorta replacement surgery

Fifteen participants included: standard treatment algorithm based on ROTEM (group with five participants) compared with a group receiving fibrinogen concentrate before standard treatment targeting ROTEM/FIBTEM CF > 22 mm (group with ten participants). Increased risk of all types of bias

Findings: FIBTEM-guided fibrinogen concentrate administration was associated with reduced transfusion requirements and 24 hour postoperative bleeding

Reason for exclusion: non-RCT

Rahe-Meyer 2009aProspective interventional cohort study with a retrospective control group, single centre, elective thoracoabdominal aortic aneurysm surgery

Retrospective control group (12 participants) with perioperative clinically relevant diffuse bleeding after weaning from cardiopulmonary bypass treated with allogeneic blood products according to predetermined algorithm

Prospective intervention group (6 participants) treated with fibrinogen concentrate guided by thromboelastometry (ROTEM), in addition to the algorithm

Findings: administration of 7.8 ± 2.7 g of fibrinogen concentrate established haemostasis, completely avoiding intraoperative transfusion of FFP and PLT. Lower 24 hour drainage volume in fibrinogen group

Reason for exclusion: non-RCT

Schöchl 2010aCase report, trauma setting

A severely injured patient with multiple trauma with massive blood loss. Patient receiving haemostatic therapy with coagulation factor concentrates, guided by thromboelastometry (ROTEM) Initial therapy consisted of fibrinogen concentrate

Findings: suggest successful haemostatic treatment with fibrinogen concentrate and prothrombin complex concentrate, minimizing the need for allogeneic blood products

Reason for exclusion: non-RCT

Schöchl 2010bRetrospective noncontrolled cohort study, single centre, trauma setting

The cohort consists of 128 trauma patients receiving at least five units of RBC within the first 24 hours after arrival at trauma centre. Patients who died in the first hour after admission and patients who received no haemostatic therapy within the first 24 hours were excluded. Evaluation of goal-directed coagulation management using thromboelastometry (ROTEM) with guided administration of fibrinogen concentrate and prothrombin complex concentrate

Findings: Thromboelastometry was rapid and reliable for diagnosing coagulopathy and guiding transfusion of concentrates. First-line fibrinogen concentrate and prothrombin complex concentrate seemed efficacious and quick to administer

Reason for exclusion: non-RCT

Solomon 2010Retrospective noncontrolled study, single centre, cardiovascular surgery

Aimed to assess fibrinogen recovery parameters after administration of fibrinogen concentrate. 39 patients with diffuse bleeding in relation to cardiovascular surgery and treated with fibrinogen concentrate. Patients with concomitant administration of FFP or with non-elective or emergency intervention, age younger than 18 and terminal illness were excluded. Dosing of fibrinogen concentrate was guided by FIBTEM thromboelastometry

Findings: Fibrinogen concentrate effectively increased plasma fibrinogen level. Suggests a favourable survival

Reason for exclusion: non-RCT

Thorarinsdottir 2010Retrospective non-controlled study, single centre, mixed patient population

37 patients receiving fibrinogen concentrate were identified using hospital database. If repeated dosage was necessary as well as recombinant factor VIIa, patients were excluded. Fibrinogen was administered when standard treatment was deemed to have failed to control the bleeding, aiming to maintain fibrinogen level above 1.5 g/L

Findings: Administration of fibrinogen in the context of severe haemorrhage was associated with increased fibrinogen concentration. A significant decrease in RBC transfusions was identified after fibrinogen administration (but no control group)

Reason for exclusion: non-RCT

Weinkove 2007Retrospective non-controlled cohort study, single centre, mixed patient population

30 patients receiving fibrinogen concentrate in treatment of acquired hypofibrinogenaemia

Findings: Fibrinogen concentrate is well suited for fibrinogen substitution

Reason for exclusion: non-RCT

 
Characteristics of studies awaiting assessment [ordered by study ID]
Galas 2012a

Methods

Participants

Interventions

Outcomes

NotesNeed full paper review, but apparently secondary publication of Galas 2012

Rahe-Meyer 2011a

Methods

Participants

Interventions

Outcomes

NotesNeed full paper review, but apparently not RCT

Rahe-Meyer 2012

Methods

Participants

Interventions

Outcomes

NotesNeed full paper review, but apparently publication of Rahe-Meyer 2013

Rahe-Meyer 2013a

Methods

Participants

Interventions

Outcomes

NotesNeed full paper review, but apparently secondary publication of Rahe-Meyer 2013

Solomon 2012

Methods

Participants

Interventions

Outcomes

NotesNeed full paper review, but apparently secondary publication of Rahe-Meyer 2013

 
Characteristics of ongoing studies [ordered by study ID]
Fries 2011

Trial name or titleFibrinogen Concentrate (FGTW) in Trauma Patients, Presumed to Bleed (FI in TIC)

MethodsRandomized double-blind parallel-assigned multicentre clinical trial

ParticipantsInclusion criteria: adult trauma patients > 18 years, with major or occult bleeding, indicating shock and need of volume replacement therapy

Exclusion criteria: penetrating trauma. Solely head injury. Hemodynamic instability (patient has to be excluded if haemodynamic stabilisation (SBP below 90 mmHg and HR more than 100 per min) is not achieved after 15 minutes of resuscitation management in spite of volume therapy and administration of catecholamines). Patient with inevitable lethal course as evaluated by emergency physician. Need for CPR on the scene. Deep hypothermia (below 30°C). Obviously pregnant women. Known recent history of thromboembolic events within the last 6 months. Patients receiving anticoagulant therapy

InterventionsIntervention group: infusion of 50 mg/kg body weight fibrinogen concentrate (FGTW/Clottafact®-LFB)-one vial for each 30 kg body weight, estimated by the emergency physician:

Body weight: < 30 kg/30 to 60 kg/60 to 90 kg/> 90 kg

No. of vials: 1 vial (100 mL)/2 vials (200 mL)/3 vials (300 mL)/4 vials (400 mL)

Fibrinogen (if applicable): 1.5 g/3 g/4.5 g/6 g

Control group: placebo (a buffer substance consisting of mannitol/sucrose/sodium chloride/polysorbate 80)

Infusion of one vial including 100 mL for each 30 kg body weight

The flow rate should not exceed 100 mL within 5 minutes

OutcomesPrimary outcome measure: change in the fibrinogen polymerisation measured with FIBTEM® MCF at average 60 min (arrival at hospital) post infusion

Further measurements and investigations will be done until 7 days after the hospital admission and final at 30 days

Starting dateOctober 2011

Contact informationPamela Schech, pamela.schech@i-med.ac.at

NotesEstimated enrolment: 60 participants, by 22 May, 6 participants included. The study is currently recruiting participants

Participating hospitals: (Austria) Medical University Innsbruck, Emergency Hospital Salzburg, PMU Salzburg, Regional Hospital Vöcklabruck, Medical University Graz

Contacted 3 April 2012 and again 22 May 2012; reply 22 May 2012

Funding: US Department of Defence. LFB provides medicine and placebo-drug together with unrestricted grant

Haas 2012

Trial name or titleFibrinogen for Treatment of Pediatric Dilutional Coagulopathy: FibPaed Study

MethodsRandomized single-blinded parallel-assigned single-centre clinical trial

ParticipantsInclusion criteria: children aged 6 months to 17 years scheduled for elective scoliosis surgery or major craniofacial surgery presenting with intraoperative hypofibrinogenaemia according to definition of treatment groups

Exclusion criteria: preexisting congenital or acquired coagulation disorder. Medical history of estimated increased bleeding tendency. Ongoing coagulation therapy. Clinical signs or diagnosis of acute thromboembolism. Intolerance of study drug. Pregnant or lactating women. Participation in another clinical trial

InterventionsIntervention group: fibrinogen concentrate (Haemocomplettan P, CSL Behring, 30 mg/kg body weight) over 15 min

Repetition if hourly intraoperative ROTEM measurements revealed hypofibrinogenaemia according to treatment group definition (administration of fibrinogen concentrate if ROTEM FIBTEM revealed MCF < 13 mm)

Control group: fibrinogen concentrate (Haemocomplettan P, CSL Behring, 30 mg/kg body weight) over 15 min

Repetition if hourly intraoperative ROTEM measurements revealed hypofibrinogenaemia according to treatment group definition (administration of fibrinogen concentrate if ROTEM FIBTEM revealed MCF < 8 mm)

OutcomesPrimary outcome measures: total amount of transfused red cell concentrate at 24 hours after start of surgery

Secondary outcome measures: coagulation measurements, length of stay on paediatric intensive care unit, additional transfusion/blood product requirements, occurrence of rebleeding, surgical revision, occurrence of (severe) adverse events

Starting dateJanuary 2012

Contact informationThorsten Haas, MD, thorsten.haas@kispi.uzh.ch

NotesEstimated enrolments: 60 participants. The study is currently recruiting participants

Collaborator/funding: independent

Contacted 4 April; reply 4 April 2012

Participating hospitals: (Switzerland) University Children's Hospital, Zurich

Innerhofer 2012

Trial name or titleRETIC Trial: Reversal of Trauma Induced Coagulopathy Using Coagulation Factor Concentrates or Fresh Frozen Plasma

MethodsSingle-centre parallel open-label randomized trial

ParticipantsSeverely traumatized patients (ISS > 15) admitted to emergency department with obvious bleeding and/or at risk for significant haemorrhage will be screened by rotational thromboelastometry (ROTEM) assays during ED treatment and subsequent surgical/radiological interventions for having coagulopathy

Inclusion criteria:

  • Male and female patients ≥ 18 years and ≤ 80 years
  • Major trauma (ISS > 15)
  • Clinical signs of ongoing bleeding or at risk for significant haemorrhage as assessed and judged by the ED team in charge of the patient
  • Presence of coagulopathy defined by ROTEM assays as follows: patients with concomitant decreased fibrinogen polymerisation (ROTEM® FIBTEM A10 < 7 mm after 10 min). Patients with concomitant decreased coagulation factor levels (ROTEM® EXTEM CT > 90 s)


Exclusion criteria:

  • Lethal injury
  • CPR on the scene
  • Isolated brain injury, burn injury
  • Avalanche injury
  • Administration of FFP or coagulation factor concentrates before ED admission
  • Delayed (> 6 hours after trauma) admittance to ED
  • Known use of oral anticoagulants or platelet aggregation inhibitors within 5 days before injury
  • Known history of severe allergic reaction to plasma products
  • Known history of congenital haemostasis disturbance, IgA or protein C deficiency
  • Patients with a history of thromboembolic events or heparin-induced thrombocytopenia (HIT) type 2 within the past year
  • Patients with body weight < 45 kg and > 150 kg
  • Patients known to be pregnant
  • Jehova's Witness
  • Known participation in another clinical trial
  • Patient with known refusal of participation in this clinical trial

InterventionsIntervention group: receives fibrinogen concentrate and/or prothrombin complex concentrate (PCC) and/or FXIII concentrate

If FIBTEM A10 < 7 mm: fibrinogen concentrate (RiaSTAP®/CLS Behring) dose at 50 mg/kg body weight intravenously as single dose or repeated, each single vial (1 g) over 5 min

If EXTEM CT > 90 s and FIBTEM A10 > 7 mm: prothrombin complex concentrate dose at 20 IE/kg body weight PCC intravenously as single dose or repeated, each single dose over 10 min

If FXIII decreases below 60% as detected by laboratory measurements: FXIII concentrate dose at 20 IU/kg body weight Fibrogammin® P administered with the second dose of fibrinogen concentrate (100 mg/kg) intravenously as single dose or repeated, each single dose over 10 min

Control group: fresh frozen plasma (FFP) blood type 0, A, B and AB

If FIBTEM A10 < 7 mm and/or EXTEM CT > 90 s: fresh frozen plasma dose of 15 mL/kg body weight intravenously as single dose or repeated, each single U (200 mL) over 5 min

Additional treatment/rescue treatment: Treatment failure will be registered if bleeding persists and ROTEM parameters do not improve after two times dosages of study drug. In these cases, haemostatic rescue therapy will be administered. CFC (fibrinogen concentrate and/or PCC, and/or FXIII concentrate) will be administered to participants randomly assigned to receive FFP, and FFP will be administered to participants in the CFC group. In cases unresponsive to comprehensive treatment or normal ROTEM combined with diffuse bleeding, other haemostatic medications can be administered (e.g. rFVIIa, DDAVP, VWF/FVIII concentrate) as judged by the anaesthetist in charge. The need for and type of any rescue therapy will be documented, and ROTEM will be performed thereafter

OutcomesMultiple organ failure (MOF) until 24 h on ICU

Difference between treatment groups in MOF as assessed by the Sequential Organ Failure Assessment score (SOFA)

Starting dateMarch 2012

Contact informationPetra Innerhofer, MD, petra.innerhofer@uki.at

NotesEstimated enrolment: 200 participants. The study is currently recruiting participants

Participating hospital: University Hospital Innsbruck

Contacted 3 April 2012; reply 3 April 2012

Relation to the industry: independent

Jeppsson 2010

Trial name or titleFibrinogen and Bleeding After Cardiac Surgery (Fibro-3)

MethodsRandomized double-blind placebo-controlled parallel-assigned single-centre study

ParticipantsInclusion criteria: adults 18 to 85 years eligible for first-time coronary artery bypass (CABG) surgery with a preoperative fibrinogen plasma concentration less than 3.8 g/L

Exclusion criteria: patients undergoing re-do surgery. Clinical or laboratory signs of bleeding disorder, liver disease or other significant disease/condition, which in the investigators' judgment interferes with haemostasis. Any medications with agents that may interfere with haemostasis within 14 days before study start. Clopidogrel and warfarin are withdrawn at least 24 hours before surgery. Oral aspirin is allowed as co-medication. Administration of other investigational drugs within eight weeks before the pre-entry examination. Pregnant or lactating women

InterventionsIntervention group: fibrinogen concentrate 2 g (RiaSTAP®, CSL Behring) in 100 mL sterile water

Control group: (placebo) saline 100 mL

Administration during a period of 15 minutes after induction of anaesthesia and before start of surgery. Pharmacist randomly assigns and dispenses the medicine

OutcomesPrimary outcome measures: to evaluate safety of prophylactic fibrinogen infusion in patients with fibrinogen levels in the lower normal range undergoing cardiac surgery (2 years' follow-up)

Blood loss at first 12 postoperative hours

Secondary outcome measures: transfusion requirements at 7 days. Biomarkers of coagulation, fibrinolysis and platelet function and pharmacoeconomic analysis

Starting dateApril 2009

Contact informationContact: Anders Jeppsson, MD, PhD, anders.jeppsson@vgregion.se

NotesSame group behind Karlsson 2009

Estimated enrolment: 60 participants. The study is currently recruiting participants

Contacted 14 March 2012 and again 22 May 2012; reply by phone 29 May 2012

Participating hospitals: Cardiothoracic Surgery Unit, Sahlgrenska University Hospital

Funding/relation to the industry: independent

Kwapisz 2012

Trial name or titleProspective Double Blinded Randomized Control Study of the Use of Fibrinogen in High-Risk Cardiac Surgery

MethodsRandomized double-blind placebo-controlled parallel-assigned single-centre study

ParticipantsInclusion criteria: adults, elective complex cardiac surgical procedures (double procedures re-do sternotomies, thoraco-abdominal aortic aneurysm, aortic root)

Participants will be randomly assigned after protamine administration. Surgeon and anaesthetist have to agree on diffuse, non-surgical bleeding

Exclusion criteria: any known congenital or preexisting bleeding disorder, preexisting abnormal fibrinogen level (normal: 1.8 to 4.7 g/L), severe liver disease (alanine aminotransferase or aspartate aminotransferase > 150 U/L), inability to provide informed consent, emergency surgery, pregnancy or nursing, younger than 18 years, intake of anti-platelet drugs within three days preoperatively (low-dose ASA is allowed), allergy to concentrated fibrinogen or other components in the product, anaemia (Hgb < 110), diagnosed deep vein thrombosis (DVT), pulmonary embolism, acute stroke

InterventionsIntervention group: fibrinogen concentrate (Haemocomplettan P®/CSL Behring) infused according to a haemostatic algorithm based on FIBTEM (MCF, maximum clot firmness)

Control group: intravenous saline

All syringes and tubing will be covered. A study nurse who is not involved in treatment of the participant will prepare the syringes

OutcomesPrimary outcome measure: the number of used blood products, including packed red cells, fresh frozen plasma, platelets and cryoprecipitate within 48 hours after surgery

Secondary outcome measures: (one-year follow-up) fibrinogen levels, TEG (R-value, K-value, angle), CVICU stay, hospital stay, in-hospital mortality, haemoglobin, adverse events (anaphylaxis, stroke, myocardial infarction, pulmonary embolism, and deep vein thromboembolism) and usage of factor VII concentrate and prothrombin complex concentrate

Starting dateNot yet recruiting

Contact informationMyron M Kwapisz, MD, myron.kwapisz@gmail.com, Heather E Mingo, RN, PhDc, heather.mingo@cdha.nshealth.ca

NotesInformation is based on clinical trials registration and contact with authors

Estimated enrolment: 40 participants. Currently awaiting IRB approval

Participating hospital: Halifax, Nova Scotia, Canada, B3H3A7

Funding/relation to the industry: collaborates with CSL Behring

Contacted 20 March 2013; reply 22 March 2013

Nierich 2011

Trial name or titleHaemocomplettan® P During Elective Complex Cardiac Surgery

MethodsRandomized double-blind parallel-assigned single-centre clinical trial

ParticipantsInclusion criteria: adults (> 18 years) undergoing elective complex cardiac surgery with clinically relevant non-surgical microvascular bleeding after removal of cardiopulmonary bypass.

Exclusion criteria: positive pregnancy test, pregnancy or lactation. Proof or suspicion of a congenital or acquired coagulation disorder. Emergency operation. Clopidogrel use in the 5 days preceding surgery. INR > 1.4 if on Coumadin

InterventionsIntervention group: fibrinogen concentrate (Haemocomplettan P®/CSL Behring)

Dose: study medication will be individually determined on the basis of plasma fibrinogen concentrations (measured with Clauss method during the reperfusion period on CPB) and body weight. Intravenous infusion within 10 minutes

Control group: human albumin with concentration 200 g/L

Study bottles of 50 mL will be diluted with saline and will contain 2 g in total. This concentration resembles the total protein load in the bottles with Haemocomplettan® P

OutcomesPrimary outcome measure: perioperative blood loss within 12 hours (measured as blood loss in mL between infusion of study medication and closure of chest)

Secondary outcome measures: postoperative blood loss (measured as blood loss at the ICU between closure of chest and 1st hour and 6th hour and after 24 hours). Postoperative transfusion requirements within 24 hours after closure of chest. Major clinical events: mortality at 30 days post-surgery, MACE (major adverse cardiac event), cerebrovascular accident/ transient ischaemic attack, renal insufficiency or failure, venous thromboembolism/pulmonary embolism, allergic or other systemic reaction to study medication

Starting dateFebruary 2011

Contact informationMarga Hoogendoorn, MSc, m.e.hoogendoorn@isala.nl

NotesEstimated enrolment: 120 participants. The study is currently recruiting participants

Participating hospitals: (Netherlands) Isala Klinieken, Zwolle, Overijssel

Funding/relation to the industry: investigator initiated but receives study medication from industry

Contacted 4 April 2012 and again 22 May 2012; reply 22 May 2012

Nimmo 2009

Trial name or titleFibrinogen as an Alternative to Fresh Frozen Plasma in Aortic Surgery

MethodsRandomized single-blinded parallel-assigned single-centre clinical trial

ParticipantsInclusion criteria: patients > 18 years undergoing elective thoracoabdominal aneurysm repair

Exclusion criteria: previous aortic surgery (re-do surgery). Emergency surgery. Pregnancy. Females of child-bearing age (younger than 45 years) not using medically approved method of contraception. Congenital or acquired coagulopathy. Known allergy to study drug

InterventionsIntervention group: fibrinogen concentrate (Haemocomplettan P®/CSL Behring) administered initially at 2 g per hour by continuous infusion. This rate will be adjusted in response to the clinical picture and results of point-of-care coagulation tests. The infusion will be used intraoperatively

Control group: fresh frozen plasma (dose not described)

OutcomesPrimary outcome measures: pattern of coagulation disturbance intraoperatively and up to 24 hours postoperatively

Secondary outcome measures: proportion of participants in the fibrinogen group requiring FFP during operation. Number of FFP units transfused-during surgery and up to 24 hours after surgery. Numbers of platelet and red blood cell units transfused-during surgery and up to 24 hours after surgery

Starting dateOctober 2009

Contact informationAlastair Nimmo, MBChB, a.nimmo@ed.ac.uk, University of Edinburgh

NotesEstimated enrolment: 20 participants. Apparently not yet recruiting but registered in 2009

Collaborators: NHS Lothian and CSL Behring

Participating hospitals: (United Kingdom) The Royal Infirmary of Edinburgh

Funding/relation to the industry: yes, collaborates with CSL Behring

Contacted 4 April 2012 and again 22 May 2012; no reply received

Ranucci 2011

Trial name or titleThe ZEro PLASma Trial (ZEPLAST): Avoidance of Fresh Frozen Plasma in Cardiac Surgery

MethodsProspective randomized double-blind comparative parallel-assigned single-centre clinical trial

ParticipantsInclusion criteria:

  • Combined cardiac operation with expected cardiopulmonary bypass(CPB) duration > 90 minutes
  • At least one additional risk factor within the following: age > 65 years; non-elective surgery; serum creatinine > 1.36 mg/dL; re-do operation


Exclusion criteria:

  • Age < 18 years
  • Patients receiving thienopyridines
  • Known coagulopathy
  • Known autoimmune disorders
  • Participation in another RCT
  • Pregnancy
  • Emergency operation
  • Baseline HCT < 35%
  • Baseline antithrombin < 80%
  • BSA < 1.7 m2


Withdrawal/additional exclusion criterion (exclusion following randomization):

  • Lowest HCT on CPB < 23%
  • Transfusions during CPB


Participants randomly assigned and not withdrawn will be given the investigational/place drugs in accordance with allocation

All participants randomly assigned and not withdrawn will be tested 20 minutes before removal of aortic cross-clamping with a thromboelastometric fibrinogen test ROTEM®/FIBTEM

InterventionsIntervention group: fibrinogen concentrate (Haempcpmplettan P®/CSL Behring) and prothrombin complex concentrate (PCC) (Confidex®/CSL Behring)

Dose fibrinogen: According to the formula based on ROTEM®/FIBTEM test: (22 [mm] − MCF [mm]) * body weight [kg]/140 [m] = whole g fibrinogen

Co-intervention: After 15 min from study drug administration and in the presence of ongoing microvascular bleeding: ROTEM®/EXTEM - prolonged CT time (> 80 seconds): PCC at a weight-based dose of 7 U/kg body weight

Control group: (placebo) saline

Study drugs or placebo has to be administered after protamine

OutcomesPrimary outcome measures: avoidance of allogeneic blood product transfusion within 30 days (packed red cells, FFP, platelet concentrates, cryoprecipitates)

Secondary outcome measures: reduction in allogeneic blood product transfusions within 30 days

Starting dateNovember 2011

Contact informationMarco Ranucci, MD, cardioanestesia@virgilio.it,

NotesEstimated enrolment: 120 participants. 16 included by 4 April 2012

Participating hospitals: (Italy) IRCCS Policlinico San Donato

Funding/relation to the industry: collaborates with CSL Behring

Contacted 4 April 2012; reply 4 April 2012

Sabate 2012

Trial name or titleThe Efficacy of the Administration of Fibrinogen in Liver Transplantation (FibstudLT)

MethodsRandomized placebo-controlled double-blind parallel-assigned multi-centre clinical trial

ParticipantsInclusion criteria: patients who are candidates for liver transplantation with a value of pretransplant plasma fibrinogen less than 2.9 g/L

Exclusion criteria: Patients with a value of fibrinogen in the 24 hours before the intervention greater than 2.9 g/L, known history of thromboembolic events in 30 days, known or suspected pregnancy, previous randomization in this trial, known or suspected allergy to trial products or related products, known presence of congenital bleeding disorder, patients treated with aspirin or warfarin. The following indications for transplantation: familial polyneuropathy, acute liver failure, biliary cirrhosis and sclerosing cholangitis, Budd-Chiari syndrome. Heart beating donors and living donors

InterventionsIntervention group: fibrinogen concentrate (RiaSTAP®/CSL Behring) will be administered until an expected plasmatic value of 2.9 g/L is achieved: The dose calculated as 1 g of fibrinogen to obtain an increase in plasma fibrinogen value of 0.29 g/L to reach a final value of 2.9 g/L

Control group: (placebo) saline in same volume

Administration before surgery starts, intravenous infusion for 10 minutes

OutcomesPrimary outcome measures: percentage of participants requiring transfusion of packed red blood cells during the procedure

Secondary outcome measures: Percentage of participants requiring intraoperative blood products other than red cell concentrates, number of units of fresh frozen plasma transfused during surgery, number of platelet units transfused during surgery, grams of fibrinogen administered during surgery, operative outcome until 4 weeks' follow-up, operative mortality, liver graft survival. Thrombotic complications of all types and causes. Liver transplantation outcome at follow-up 1 year

Starting dateMarch 2012

Contact informationAntoni Sabate, MD, asabatep@bellvitgehospital.cat

NotesEstimated enrolment: 132 participants. The study is currently recruiting participants

Participating hospitals: (Spain) Hospital de Cruces, Bilbao, Vizcaya, Hospital Universitari de Bellvitge, Barcelona, Hospital Clinic, Barcelona, Hospital Virgen de la Arrixaca, Murcia, Hospital Virgen del Rocio, Sevilla

Funding/relation to the industry: independent of industry with institutional and governmental support

Contacted 4 April 2012; reply 20 April 2012

Tanaka 2011

Trial name or titleRiaSTAP vs. Conventional Transfusion in Patients Having Heart Valve Surgery (RiaCT)

MethodsRandomized parallel-assigned single-centre clinical trial

ParticipantsInclusion criteria: adults 18 to 85 years undergoing planned cardiopulmonary bypass (CPB) for combined coronary artery bypass grafting and valve replacement/repair surgery, single valve replacement surgery, mitral valve repair surgery or double valve surgery (aortic and mitral). Presence of clinically relevant microvascular bleeding after protamine administration

Patients should fulfil the following parameters before the study intervention: body temperature > 35.0°C, blood pH > 7.2, Hb > 7.0 mg/dL, activated clotting time (ACT) < 155 seconds, CPB time > 60 minutes and evidence of significant microvascular bleeding

Exclusion criteria: replacement of aorta, planned valve replacement without median sternotomy, previous valve replacement surgery (previous CABG acceptable), history or suspicion of a congenital or acquired coagulation disorder such as haemophilia, von Willebrand disease, and liver disease, haemodialysis dependent renal failure, liver dysfunction (aspartate aminotransferase (AST) or alanine aminotransferase (ALT) increased ≥ 2-fold above the upper limit of local laboratory normal ranges), known allergy/anaphylaxis to fibrinogen concentrate or apheresis platelet units, clopidogrel administration within 5 days of surgery, Coumadin (warfarin) administration within 5 days of surgery, participation in another clinical study in the 4 weeks preceding surgery, any indication that a potential participant did not comprehend the study restrictions, procedures, or consequences (therein an informed consent cannot be convincingly given), life expectancy less than 48 hours

InterventionsIntervention group: fibrinogen concentrate (RiaSTAP®/CSL Behring) 4 g IV

Control group: a single apheresis platelet unit

Administration within 30 minutes of ACT < 155 seconds and post CPB

OutcomesPrimary outcome measures: pattern of coagulation disturbance intraoperatively and up to 24 hours postoperatively

Secondary outcome measures: proportion requiring FFP or platelets during or after surgery. Number of FFP, RBC and platelet units transfused during surgery and up to 24 hours after surgery and intraoperative blood loss

Starting dateJanuary 2011

Contact informationKathy F Egan, BSN, RN, kfegan@emory.edu

NotesEstimated enrolment: 60 participants. The study is currently recruiting participants, 14 included by 4 April

Participating hospitals: (United States) Emory University Hospital, Atlanta, Georgia

Funding/relation to industry: collaborates with CSL Behring

Contacted 4 April 2012; reply received 4 April 2012

Wikkelsoe 2011

Trial name or titleFibrinogen Concentrate as Initial Treatment for Postpartum Haemorrhage: A Randomized Clinically Controlled Trial (FIB-PPH)

MethodsRandomized placebo-controlled double-blind parallel-assigned multi-centre clinical trial

ParticipantsInclusion criteria: parturients > 18 years developing postpartum haemorrhage (PPH), defined as bleeding from uterus and/or the birth canal within 24 hours postpartum. If vaginal birth: indication of one of the following procedures at the operation theatre with anaesthetic assistance: (a) estimated blood loss ≥ 500 mL and indication of manual removal of placenta or (b) indication of manual exploration of the uterus due to continuous bleeding after the birth of placenta. If birth by caesarean section: perioperative blood loss ≥ 1000 mL

Exclusion criteria: known inherited deficiencies of coagulation, anti-thrombotic treatment prepartum due to increased risk of thrombosis, patients with a prepregnancy body weight < 45 kg. Refuse to receive blood transfusion

InterventionsIntervention group: intravenous administration of 2 g fibrinogen concentrate (Haemocomplettan, CSL Behring)

Control group: intravenous administration of isotonic saline in equivalent volume: 100 mL

OutcomesPrimary outcome measures: incidence of transfusion with allogenic blood products during hospital stay or until 6 weeks postintervention

Secondary outcome measures: severe PPH, defined as: "Decrease of haemoglobin (Hb) of > 2.5 mmol/L, transfusion of at least 4 red blood cell (RBC) units, haemostatic intervention (angiographic embolization, surgical arterial ligation or hysterectomy) or death, Estimated blood loss, total amount of blood transfused, the development of re-bleeding defined as bleeding re-occurring after primary haemostasis and requiring surgical procedures or intervention, haemoglobin level below 3,6 mmol/L." Side effects including thromboembolic complications (Safety measures/Potential known side effects): fever, headache, nausea, vomiting, allergic reactions, anaphylaxis and thromboembolic complications (deep venous thrombosis, acute myocardial infarct and lung embolus). All suspected unexpected serious adverse reactions will also be reported in accordance with the Good Clinical Practice (GCP) and the Danish Medicines Agency guidelines on follow-up until 6 weeks postintervention

Starting dateMay 2011

Contact informationAnne Juul Wikkelsoe, MD, wikkelso@gmail.com

NotesEstimated enrolment: 245 participants. Completed. No data available yet (August 2013).

Participating hospitals: (Denmark)

Rigshospitalet, Copenhagen University Hospital Denmark, Herlev Hospital, Copenhagen University Hospital, Hvidovre Hospital, Copenhagen University Hospital, Hillerød Hospital, Copenhagen University Hospital

Funding/relation to industry: independent

Collaborators: Haemonetics Corporation (provides TEG® assays)

 
Comparison 1. Fibrinogen concentrate versus any comparator

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mortality longest follow-up2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 2 ICU stay (hours)3112Mean Difference (IV, Fixed, 95% CI)-9.87 [-20.67, 0.93]

 3 Duration of mechanical ventilation (hours)251Mean Difference (IV, Random, 95% CI)-27.29 [-89.73, 35.16]

 4 Stay in hospital (days)3107Mean Difference (IV, Random, 95% CI)-2.28 [-7.04, 2.48]

 5 Incidence of allogenic blood transfusion (types of comparison)5207Risk Ratio (M-H, Random, 95% CI)0.47 [0.31, 0.72]

    5.1 Fibrinogen versus placebo/no treatment
240Risk Ratio (M-H, Random, 95% CI)0.27 [0.09, 0.80]

    5.2 Fibrinogen versus FFP/cryoprecipitate
163Risk Ratio (M-H, Random, 95% CI)0.29 [0.15, 0.56]

    5.3 Fibrinogen in combination with FFP versus placebo/no treatment/usual treatment
143Risk Ratio (M-H, Random, 95% CI)0.78 [0.41, 1.49]

    5.4 Fibrinogen as part of transfusion algorithm versus placebo or no treatment
161Risk Ratio (M-H, Random, 95% CI)0.56 [0.40, 0.77]

 6 Incidence of allogenic blood transfusion (cardiac vs non-cardiac)5207Risk Ratio (M-H, Random, 95% CI)0.47 [0.31, 0.72]

    6.1 Cardiac surgery
3144Risk Ratio (M-H, Random, 95% CI)0.42 [0.24, 0.76]

    6.2 Non-cardiac surgery
263Risk Ratio (M-H, Random, 95% CI)0.50 [0.17, 1.53]

 7 Incidence of allogenic blood transfusion (pediatric vs adult)5207Risk Ratio (M-H, Random, 95% CI)0.47 [0.31, 0.72]

    7.1 Paediatric studies
163Risk Ratio (M-H, Random, 95% CI)0.29 [0.15, 0.56]

    7.2 Adult studies
4144Risk Ratio (M-H, Random, 95% CI)0.57 [0.43, 0.75]

 8 Incidence of allogenic blood transfusion (high dose > 50 mg/kg vs low dose)5207Risk Ratio (M-H, Random, 95% CI)0.47 [0.31, 0.72]

    8.1 High-dose studies (> 50 mg/kg)
2124Risk Ratio (M-H, Random, 95% CI)0.42 [0.21, 0.86]

    8.2 Low-dose studies (≤ 50 mg/kg)
383Risk Ratio (M-H, Random, 95% CI)0.51 [0.23, 1.14]

 9 Re-operation due to persistent bleeding2124Risk Ratio (M-H, Random, 95% CI)0.68 [0.01, 36.71]

 10 Incidence of RBC transfusion longest follow-up292Risk Ratio (M-H, Random, 95% CI)0.81 [0.32, 2.02]

 11 Thrombotic episodes (arterial and venous graft occlusion, pulmonary embolus, deep venous thrombosis)3124Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.27, 3.97]

 12 Complications not specific to trial intervention (pleural effusion, abdominal ischaemia and other serious adverse events)2104Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.45, 3.44]

 13 Blood loss/drainage, longest follow-up251Mean Difference (IV, Random, 95% CI)-89.37 [-406.05, 227.32]

 14 Blood loss/Drainage (24 hours) mL/kg/h292Mean Difference (IV, Random, 95% CI)-32.34 [-176.45, 111.76]

 
Comparison 2. Fibrinogen versus placebo or no treatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Incidence of allogenic blood transfusion (cardiac vs non-cardiac)240Risk Ratio (M-H, Fixed, 95% CI)0.27 [0.09, 0.81]

    1.1 Cardiac surgery
120Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.04, 2.69]

    1.2 Non-cardiac surgery
120Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.07, 0.90]

 
Summary of findings for the main comparison. Fibrinogen concentrate versus any comparator for patients with bleeding

Fibrinogen concentrate versus any comparator for patients with bleeding

Patient or population: bleeding patients or at risk of severe bleeding
Settings: in-hospital care, operative setting, intensive care or trauma
Intervention: fibrinogen concentrate
Comparison: any comparator

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Any comparatorFibrinogen concentrate

MortalityStudy populationRR 0.28
(0.03 to 2.33)
81
(2 studies)
⊕⊝⊝⊝
very low1,2,3

95 per 100027 per 1000
(3 to 222)

Moderate

63 per 100018 per 1000
(2 to 147)

Incidence of allogenic blood transfusion
Proportion of participants transfused with RBC, FFP, PLT and/or cryo
Study populationRR 0.47
(0.31 to 0.72)
207
(5 studies)
⊕⊝⊝⊝
very low1,4,5,6

764 per 1000359 per 1000
(237 to 550)

Moderate

800 per 1000376 per 1000
(248 to 576)

Thrombotic episodes (arterial and venous graft occlusion, pulmonary embolus, deep venous thrombosis)
Proportion with event
Study populationRR 1.03
(0.27 to 3.97)
124
(3 studies)
⊕⊝⊝⊝
very low1,3,5,6

48 per 100049 per 1000
(13 to 189)

Moderate

48 per 100049 per 1000
(13 to 191)

Intensive care unit (ICU) stay
Duration of stay (hours)
The mean intensive care unit (ICU) stay ranged across control groups from
25 to 173 hours
The mean intensive care unit (ICU) stay in the intervention groups was
9.87 lower
(20.67 lower to 0.93 higher)
112
(3 studies)
⊕⊝⊝⊝
very low1,3,4,6

Re-operation due to persistent bleeding
Events during admission
Study populationRR 0.68
(0.01 to 36.71)
124
(2 studies)
⊕⊝⊝⊝
very low3,4,6

108 per 100073 per 1000
(1 to 1000)

Moderate

107 per 100073 per 1000
(1 to 1000)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1One trial was a small pilot study without complete blinding of personnel and industry supported. Other trial was Industry sponsored.
2One trial was a zero event trial.
3Few participants and very few events.
4One trial with "high risk" or "unclear risk" in all aspects.
5Included trials biased by industry support, small sample sizes, selective reporting and insufficient blinding.
6Differing comparator, population (prophylactic against bleeding and with bleeding) and children/adults.