Injectable hemostatic adjuncts

FIinTIC-Study

Marc Maegele

Department for Trauma and Orthopedic Surgery(Director: Prof. Dr. Bertil Bouillon)

Cologne-Merheim Medical Center (CMMC)

Institute for Research in Operative Medicine(IFOM)

(Director: Prof. Dr. Edmund Neugebauer)

University of Witten/Herdecke

Campus Cologne-Merheim

Uncontrolled Bleeding is a Major Causeof Death in Trauma

(Patients dying in-hospital within the first 48 hours after trauma)

Sauaia et al., J Trauma 1995; 38: 185-193Evans et al., World J Surg 2010; 34: 1720-21

Exsanguination

10

20

30

40

Mor

talit

y <

48 h

ours

afte

r Tra

uma

in (%

)50

60

CNS CNS +Exsang.

Organfailure

Other

The Incidence of Acute Post-TraumaticCoagulopathy upon ER Admission

(25% of trauma patients are coagulopathic upon ER admission)

10

20

Trau

ma

Pat

ient

s in

(%) 3

0

40

BrohiJ Trauma

2003n=1,088

MacLeodJ Trauma

2003n=10,790

MaegeleInjury2007

n=8,724

RugeriJ Th Hem

2007n=88

25% !

The Clinical Significance of Acute Post-Traumatic Coagulopathy : Mortality

20

Mor

talit

y in

(%)

40

60

BrohiJ Trauma

2003n=1,088

MacLeodJ Trauma

2003n=10,790

MaegeleInjury2007

n=8,724

BrohiAnn Surg

2007n=208

x 4,6

normal coagulationcoagulopathy

Key Recommendations for the Management ofAcute Traumatic Hemorrhage: S3-Guideline

„Polytrauma“

Trauma-induced coagulopathy=

„own clinical entity“

Recommendation 23We recommend that

monitoring and measuresto support coagulation be

initiated as early aspossible (Grade 1C).

The current concept

Maegele et al. , Shock 2013

The role of fibrinogen

Primary haemostasis: Ligand between activated platelets GP receptor IIb/IIIa has a high affinity

to fibrinogen

Secondary haemostasis Precursor for fibrin formation Fibrinogen is the substrate of the

coagulation process

Mosesson et al. J Thromb Haemost 2005

Reasons for low fibrinogen

Bleeding Consumption Dilution (Hyper)fibrinolysis Hypothermia Acidosis

Schlimp CJ, Schöchl H. Haemostasiologie 2014

Normovolaemic hemodilution

McLoughlin et al. Anasth Anal 1996

10 20 30 40 50 60 70 80% Original blood volume exchanged

250

200

150

100

50

Platelets

FibrinogenFibrinogenFi

brin

ogen

[mg/

dL]

Plat

elet

s [1

09/L

]

Floccard et al. Injury 2012

Early coagulopathy in trauma:An on-scene and hospital admission study

On-scene coagulation factor concentrates as a function of injuryseverity

Fibrinogen: First factor to reach criticallevels during severe bleeding replaced

with plasma and fluids (Hippala et al., 1995)

Fibrinogen levels at Ermergency Roomadmission and mortality

N = 517

24-hours mortality 28-days mortality

Alive Dead

3.0

2.5

2.0

1.5

1.0

0.5

0.0

Fibr

inog

en le

vel (

g/L)

3.0

2.5

2.0

1.5

1.0

0.5

0.0

Fibr

inog

en le

vel (

g/L)

***

Alive Dead

***

Rourke et al. J Thromb Haemost 2012

Impact of fibrinogen levels on outcomeafter acute injury in patients with

massive transfusion

The role of Fibrinogen

Substate for clotting (coverted into fibrin by thrombin)!

Thrombin

The role ofFibrinogen

Maegele, Textbook of Surgery 2014 (in press)

Clotting interaction of platelets, fibrin, aFXIIIaFXIII, activated factor XIII; CFT, clot formation time; CT, clotting time; MA, maximum amplitude; MCF, maximum clot firmness

Fibrinogen: 835mg/dl

Absolute strength of the clot is reflected byamplitude in mm

Impact of fibrinogen on maximum clotfirmness / stability

Plotkin AJ, et al. J Trauma 2008;64:S64, Leemann H, et al. J Trauma 2010;69:1403Davenport R, et al. Crit Care Med 2011;39:2652, Tauber H, et al. Brit J Anaesth 2011;107:378

Schöchl H, et al. J Neurotrauma 2011;28:2033, Cotton BA, et al. J Trauma 2011;71:407Schöchl H, et al. Crit Care 2011;15:R265, Holcomb J, et al. Ann Surg 2012;256:476

Low MCF/MA is associated withincreased blood loss, blood transfusion

requirement and higher mortality

FIBTEM baseline 33% Dilution with Saline

Saline Dilution + FXIIISaline Dilution + Fibrinogen Saline Dilution + Fib + FXIII

FIBTEM examples of normal, salinediluted and substituted clots

Fibrinogen in the treatment of post-traumatic coagulopathy

Fries et al., Br J Anaesth 2005

Electronmicroscopic findings

Normal clotting Dilution

Diluted clot after administrationof fibrinogen

Schöchl et al. , Crit Care 2011

Coagulation parameters and their valuesto predict massive transfusion

.... what does the literature say ?

Spahn et al., Crit Care 2013

Substitution: Fib-Concentrate vs FFP vs Cryo

Prospective, randomised, controlled and double-blind Study, N = 60 patients Early administration of 50 mg/kg BW fibrinogen concentrate

versus placeboin bleeding trauma patients.

Assessment time points:Inclusion (at site of the accident) (T1)Immediately after trauma bay arrival (T2)after 3 hours (T3)after 9 hours (T4)after 24 hours (T5)after 48 hours (T6)after 1 week (T7)

Study design

1. Change in plasma coagulation2. Transfusion requirements/blood loss3. Thromboembolic complications4. Clinical endpoint/morbidity/LOS

Pilot /proof of concept study to investigatethe effect of early treatment with fibrinogenconcentrate on:

Study aim

Inclusion criteria:1.Trauma patient (Age 18-85 years)

2.Patients admitted to a FIinTIC study center

3.Patients with visible or suspected bleeding and state of shock

(RRsyst <110 mmHG)

4.Confirmed of bleeding after completed diagnostic procedures (CT)

Exclusion criteria1. Patients with history of or known thombembolic events

2. Patients with survivable trauma/deth at scene

3. Pregnancy

Number of patients:

60 patients (30 plazebo, 30 verum)

expected/calculated „drop out rate“: 50%

Patients per emergency vehicle/rescue helicopter:

9 patients in 2 years per center

Patienten per hospital

12 patients in 2 years per center

Further parameters:• Blood loss: documentation of (calculated) blood loss transfusion

requirements• Clinical endpoints• Volume requirement• Use of further coagulation products (coagulation factor

concentrates, antifibrinolytic agents, DDAVP, buffer therapy, …).

Primary endpoint: Fibrinogen polymerisation measure with the FIBTEM® MCF

Secondary endpoints: • Other ROTEM® and biological parameters• Number of thromboses at 7 days assessed by duplex ultrasound

Endpoints

FGTW: Fibrinogen concentrate, LFB France (1,5 g in

100 mL)

Dosage: 1x 50 mg/kg KG (1 package per 30 kg KG)

storage: room temperature

Temp range of -20 up to + 40 C0: 6 month

at room temperature: 3 years

Test substance

Austria

Active CenterInitiated but inactive CenterClosed CenterNew Initiated Center

H01Christophorus 1 Innsbruck PI: Dr. Marc Kaufmann

H03Christophorus 6 SalzburgPI: Dr. Bernhard Ziegler

H06Christophorus 14NiederöblarnPI: Dr. Christine Wimmer

H07Martin 2 Karres PI: Dr. Christian Niederwanger

H08NEF InnsbruckPI: Univ. Doz. Dr. MichaelBaubin

H11NAW VöcklabruckPI: Prim. Mag. Dr. Günther

H12Christophorus 5 ZamsPI: Dr. Manuel Mauerer

H13NEF TelfsPI: Dr. Markus Thaler

Austria

Germany

G01Cologne-Merheim Medical CenterDepartment for Trauma Surgery undOrthopedicsPI & National Coordinator:Prof. Dr. Marc Maegele

G03Federal Armed Forces MedicalCenter UlmDepartment of General, Visceral andThoracic SurgeryPI: Dr. Thorsten Hauer

Frankfurt / Kempten /Duisburg ???

Czech Republic

C01University Hospital Hradec KraloveDepartment for Anaesthesiology and Intensive CarePI & National Coordinator: Dr. Anatolij Truhlar

K01Christoph 06 Hradec Kralove PI: Dr. Anatolij Truhlar

DenmarkD01Aarhus UniversityHospitalDepartment ofAnaesthesiologyPI & NationalCoordinator:Dr. Christian Fenger-Eriksen

N01 / H1AkutlægehelikopterKarup LufthavnPI: Dr. Christian Fenger-Eriksen

Network

Project management (KKS Innsbruck): 74.000 €Statistics (Department of Biostatistics Innsbruck): 13.200 €Labelling (Pharmacy Salzburg): 4.000 €IMP Shipment (Salzburg): 2.000 €CRF-Print: 4.000 €Travel Costs: 10.000 €Monitoring and Pharmacovigilance: 108.000 €Employment of 2 labors: 172.000 €Total: 497.200 €

Actual Funding:LFB – unrestricted grant: 100.000€Coalition Warfare Grant/US Army 207.000€University Innsbruck: 200.000 €Total: 507.000 €

Kosten

TheCologneprotocol

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