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
[email protected]

Etanjalie Ayala
Weber Shandwick
212-445-8225
[email protected]

[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

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