Phase II Study Indicates that Fibrinogen Concentrate Given as a
First-Line Therapy Safely Reduces Need for Transfusion after Aortic
Surgery
MARBURG, Germany, Dec. 19, 2012 /PRNewswire/ -- Clinical study
results published today in the journal Anesthesiology showed
that human fibrinogen concentrate can significantly reduce the need
for blood transfusion when given as an intra-operative, targeted
first-line hemostatic therapy in bleeding patients undergoing
aortic replacement surgery.
The Phase II prospective study, performed by CSL Behring and
collaborators at the Hannover Medical School, Germany, enrolled 61 patients to assess the
ability of fibrinogen concentrate to improve clotting and reduce
the need for transfusion following elective aortic replacement
surgery with cardiopulmonary bypass (CPB). Patients who received
fibrinogen concentrate required fewer allogeneic blood product
transfusions than patients receiving placebo (a median of 2 units
in the fibrinogen concentrate group compared with 13 units in the
placebo (p<0.001)). In the fibrinogen concentrate group, 45
percent (13 out of 29 patients) avoided transfusion entirely,
whereas all 32 placebo patients required transfusion
(p<0.001).
A novel approach to dosing was used in the study. The group in
Hannover has developed and
validated a model for individualized dosing of fibrinogen
concentrate,[1],[2] based on measuring the firmness of
the fibrin-based clot, which is mainly dependent on plasma
fibrinogen levels.[3] Maximum clot firmness (MCF) of the
fibrin-based clot can be monitored using FIBTEM, a commercially
available thromboelastometry point-of-care test.
"Aortic replacement surgery puts patients at risk for
potentially life-threatening bleeding events because the surgery
depletes fibrinogen levels and delays clotting, which may require
extensive blood transfusion to restore a patient's clotting
ability," said Niels Rahe-Meyer,
M.D. Ph.D., of the Clinic for Anesthesiology and Intensive Care
Medicine, Hannover Medical School and lead author of the study.
"This is the largest study of its kind in patients undergoing
aortic replacement surgery and strongly indicates that proactive
treatment with fibrinogen concentrate may safely reduce the need
for transfusions, restore clotting ability, and consequently
protect aortic surgery patients from possible adverse events
associated with donor blood transfusion."
In the study, reported treatment-emergent adverse events were
similar in both groups and typical for patients undergoing cardiac
surgery, with the most common being fluid buildup around the lungs
(pleural effusion) and abnormal heart rhythm (atrial fibrillation).
None of the treatment-emergent adverse events were ascribed to
study medication or led to discontinuation from the study. The
study was not powered to compare mortality or morbidity between
groups.
"Fibrinogen concentrate has been well-characterized for the
treatment of specific inherited blood clotting disorders," said
Andrew Cuthbertson, CSL Chief
Scientist. "CSL Behring is committed to exploring the use of
fibrinogen concentrate in patients at high risk of bleeding,
particularly those in the hospital setting where fibrinogen has
been shown to be depleted by surgical procedures and where a quick
intervention is needed to improve clotting and prevent serious
bleeding events."
About the Study
The Phase II prospective, randomized,
double-blind, placebo-controlled, parallel-group, stratified
clinical study was conducted at the Hannover Medical School,
Hannover, Germany. The study
enrolled patients 18 years or older who were undergoing elective
aortic replacement surgery with cardiopulmonary bypass. Patients
were excluded from the study if they had undergone previous surgery
at the same aortic site, had a congenital or acquired coagulation
disorder, had a myocardial infarction or stroke in the previous two
months, or if they used aspirin, clopidogrel or vitamin K
antagonists before the surgery.
Before surgery, patients were randomized to receive either
fibrinogen concentrate or placebo. Study medication was
administered if clinically relevant bleeding occurred. Each 50 mL
syringe contained either 1 g fibrinogen concentrate
(Haemocomplettan® P, RiaSTAP®, CSL
Behring, Marburg, Germany) diluted
in 50 mL sterile water, or an equivalent volume of 0.9 percent
saline as placebo. Doses were determined from the MCF value of the
FIBTEM test, using a model developed in previous studies for
individualizing fibrinogen concentrate dosing.[1], [2]
The FIBTEM test was performed by point-of-care thromboelastometry
(ROTEM® device, TEM International, Munich, Germany), using blood samples taken 20
min before the end of cardiopulmonary bypass. The time taken to
obtain the MCF value was 15 min. The medications were administered
intravenously within five minutes after bleeding measurement.
The primary endpoint was the total number of units of allogeneic
blood components (red blood cells plus fresh frozen plasma plus
platelet concentrate) given to patients between administration of
study medication and 24 hours thereafter. Safety was evaluated by
treatment-emergent adverse events occurring within 10 days of
treatment, with follow-up for serious adverse events extended to 45
days.
About Acquired Bleeding and Fibrinogen
In addition to
bleeding caused by injury or a surgical intervention itself
(surgical bleeding), critical reduction in the level of coagulation
factors can lead to additional non-surgical bleeding complications
that can be difficult to control (e.g., coagulopathic bleeding).
Such patients can have critically low concentrations of many
coagulation factors. In general, it is necessary to replace the
missing coagulation factors in order to reverse the critical
condition. The first factor to be depleted is fibrinogen (also
called Factor I), a protein needed to form blood
clots.[4] Fibrinogen levels in plasma determine the
potential clotting ability and activity in the body. Diminished
concentrations of fibrinogen limit the body's ability to form a
clot. A simple blood test can detect the level of fibrinogen; the
normal range is 150–450 milligrams per deciliter.[5]
CPB-induced coagulopathy is complex. Fibrinogen is one of the
coagulation factors to be significantly depleted during CPB;
decreases in plasma level of 34 to 42 percent have been reported,
and can increase the risk of post-operative
bleeding.[4],[6]
For nearly a hundred years the approach to managing bleeding has
been simplistic; replacing loss of blood with blood. This currently
standard approach is empirical and not based on rigorous scientific
evidence. There is growing evidence that this may not be the most
effective or appropriate approach.
As a leader in the field of bleeding management for
anaesthetists, haematologists and other managers of coagulopathy,
CSL Behring is pioneering an evidence-based approach to management
of bleeding. The aim is to allow the anaesthetist and haematologist
to tailor the treatment to the precise needs of the patient. This
efficient method allows timely, adaptive and cost-effective
interventions that improve patient outcomes, by helping provide the
right factor at the right time to the right patient.
About fibrinogen concentrate [human]
CSL Behring manufactures a purified fibrinogen concentrate
marketed under the name Haemocomplettan® P which is
licensed for an acquired bleeding indication in the following
countries: Austria, Brazil, Bulgaria, Czech
Republic, Germany,
Hungary, Iran, Israel,
Kuwait, Netherlands, Portugal, Romania, Switzerland, Taiwan, and Turkey.
CSL Behring is conducting a Phase III study to further
investigate the utility of fibrinogen concentrate in complex
cardiovascular surgery. Its utility is also being investigated in a
range of other clinical indications, including liver disease,
postpartum haemorrhage and trauma, in which a critical reduction in
the level of coagulation factors can lead to additional
non-surgical bleeding complications.
In the United States,
fibrinogen concentrate is indicated for the treatment of acute
bleeding episodes in patients with congenital fibrinogen
deficiency, including afibrinogenaemia and hypofibrinogenaemia.
Afibrinogenaemia, or congenital fibrinogen deficiency, is a rare
and life-threatening disorder that results from a deficiency in
fibrinogen that prevents blood from clotting normally. This disease
is inherited and can occur in men and women.[7]
Approximately one in one million people in Western countries have
this disorder.[8]
About CSL Behring
CSL Behring is a leader in the
plasma protein therapeutics industry. Committed to saving lives and
improving the quality of life for people with rare and serious
diseases, the company manufactures and markets a range of
plasma-derived and recombinant therapies worldwide. CSL Behring
therapies are indicated for the treatment of coagulation disorders
including haemophilia and von Willebrand disease, primary immune
deficiencies, hereditary angioedema and inherited respiratory
disease. The company's products are also used in cardiac surgery,
organ transplantation, burn treatment and to prevent hemolytic
diseases in newborns. CSL Behring operates one of the world's
largest plasma collection networks, CSL Plasma. CSL Behring is a
subsidiary of CSL Limited (ASX: CSL), a biopharmaceutical company
headquartered in Melbourne,
Australia. For more information, visit
www.cslbehring.com.
Media Contacts:
Sheila A.
Burke
1020 First Avenue
PO Box 61501
King of Prussia, PA 19406
610-878-4209
sheila.burke@cslbehring.com
Etanjalie Ayala
Weber Shandwick
212-445-8225
eayala@webershandwick.com
[1] Rahe-Meyer N, et al. Bleeding management with fibrinogen
concentrate targeting a high-normal plasma fibrinogen level: A
pilot study. Br J Anaesth. 2009;102:785-92
[2] Rahe-Meyer N, et al. Thromboelastometry-guided
administration of fibrinogen concentrate for the treatment of
excessive intraoperative bleeding in thoracoabdominal aortic
aneurysm surgery. J Thorac Cardiovasc Surg.
2009;138:694-702
[3] Reinhofer M, et al. The value of rotation thromboelastometry
to monitor disturbed perioperative haemostasis and bleeding risk in
patients with cardiopulmonary bypass. Blood Coagul
Fibrinolysis. 2008;19:212-9
[4] Medline Plus. Fibrinogen.
http://www.nlm.nih.gov/medlineplus/ency/article/003650.htm
[5] Lowe GDO, et al. Ann Clin Biochem. 2004;41:430-40
[6] Blome M, et al. Relationship between factor XIII activity,
fibrinogen, haemostasis screening tests and post-operative bleeding
in cardiopulmonary bypass surgery. Thromb Haemost.
2005;93:1101-7.
[7] Medline Plus. Afibrinogenaemia.
http://www.nlm.nih.gov/medlineplus/ency/article/001313.htm
[8] Rare Bleeding Disorders Database.
http://www.rbdd.org/index.php?option=com_content&view=article&id=72
SOURCE CSL Behring