Aetna considers RiaSTAP (human fibrinogen concentrate) medically necessary for the treatment of acute bleeding episodes in persons with congenital fibrinogen deficiency including afibrinogenemia and hypofibrinogenemia when both of the following criteria are met:

• Diagnosis of congenital fibrinogen deficiency has been confirmed by blood coagulation testing; and
• Poor response to cryoprecipitate in previous bleeding episodes.

Aetna considers RiaSTAP experimental and investigational for the treatment of the following indications (not an all inclusive list) because its effecriveness for these indications has not been established.

• Acquired hypofibrinogenemia
• Dysfibrinogenemia
• Obstetric hemorrhage including post-partum haemorrhage
• Post-operative hemorrhage
• Trauma-associated hemorrhage.

Fibrinogen, also known as Factor I, is synthesized in the liver and circulates in the blood with a normal plasma concentration of 250 to 400 mg/dL (2.5 to 4.0 g/L).  It plays an important role in clotting of the blood.  Diminished concentrations of fibrinogen limit the body's ability to form a clot.  Congenital fibrinogen deficiency (CFD) is a rare, potentially life-threatening bleeding disorder.  Individuals with CFD are unable to make sufficient amounts of fibrinogen.  There are 2 types of hereditary fibrinogen disorders: (i) type I deficiencies (quantitative defects) such as afibrinogenemia and hypofibrinogenemia -- with low or unmeasurable levels of immunoreactive protein; and (ii) type II deficiencies (qualitative defects) such as dysfibrinogenemia and hypodysfibrinogenemia -- with normal or altered antigen levels associated with reduced coagulant activity.  While dysfibrinogenemias are in most cases autosomal dominant disorders, type I deficiencies are generally inherited as autosomal recessive traits.  Patients affected by congenital afibrinogenemia or severe hypofibrinogenemia may experience bleeding manifestations varying from mild to severe (Asselta et al, 2006).

Congenital fibrinogen deficiency affects an estimated 1 person per 1,000,000, with an estimated prevalence of 150 to 300 people in the United States.  It is usually diagnosed at birth when newborns bleed from their umbilical cord site.  al-Mondhiry and Ehmann (1994) noted that diagnosis of congenital afibrinogenemia is usually established by demonstrating trace or absent immunoreactive fibrinogen in the plasma.  Patients with hypofibrinogenemia are usually asymptomatic, unless exposed to trauma.  Furthermore, Berube (2009) stated that disorders involving fibrinogen are rare but should be considered in any patient with a history of hemorrhage or thrombosis in whom most of the common causes have been ruled out.  Blood coagulation tests such as prothrombin time (PT) that is often reported as the International Normalized Ratio (INR), activated partial thromboplastin time (APTT), and thrombin clotting time (TCT) or thrombin time (TT) all require the production of a fibrin clot as an end point, and will be abnormally prolonged in patients with hypofibrinogenemia or afibrinogenemia.  Abnormal laboratory results in patients with afibrinogenemia will correct completely following administration of normal plasma or purified fibrinogen.  Accordingly, these tests are sensitive for the presence of a fibrinogen disorder, but lack specificity.

Verhovsek and colleagues (2008) provided examples of methods and findings for commonly used laboratory tests for afibrinogenemia and hypofibrinogenemia:

Individuals with CFD are advised to curtail physical activities because of risk of bleeding from minor trauma.  If bleeding occurs in the brain or other organs and is left untreated, it may lead to blood loss, organ damage and death.  The standard approach for replacement of fibrinogen in patients with CFD is cryoprecipitate; but more recently, a pasteurized human fibrinogen concentrate has become available.

In an open, multi-center, non-controlled, retrospective study, Kreuz and co-workers (2005) examined the effectiveness and tolerability of a pasteurized human fibrinogen concentrate in patients with CFD.  Hemostatic efficacy was assessed by laboratory investigation as well as clinical observation.  A total of 12 patients (afibrinogenemia, n = 8; hypofibrinogenemia, n = 3; dysfibrinogenemia combined with hypofibrinogenemia, n = 1) were included in the study.  Fibrinogen substitution was indicated for one of the following reasons: (i) to stop an ongoing bleed; (ii) as prophylaxis before surgery; or (iii) for routine prophylaxis to prevent spontaneous bleeding.  A total of 151 fibrinogen infusions were recorded.  The median single dosage was 63.5 mg/kg body weight of the drug for bleeding events or surgery and 76.9 mg/kg for prophylaxis.  The median total dose per event for bleeding events or surgery was 105.6 mg/kg.  Fibrinogen was administered in 26 bleeding episodes; 11 surgical operations; and 89 prophylactic infusions, of which 86 were received by 1 patient.  The median response (n = 8) was 1.5 mg/dL per substituted mg of fibrinogen per kg body weight (0.8 to 2.3).  The median in vivo recovery (n = 8) was 59.8 % (32.5 to 93.9).  Clinical efficacy was very good in all events with the exception of one surgical procedure, where it was moderate.  No intercurrent bleeding occurred during prophylaxis.  All but 1 infusion was well-tolerated; the patient, who was administered 86 prophylactic infusions, experienced an anaphylactic reaction after the 56th infusion.  In addition, one patient developed deep vein thrombosis and nonfatal pulmonary embolism with treatment for osteosynthesis after collum femoris fracture.  Fibrinogen substitution could not be excluded as a contributing factor in this high-risk patient.  The authors concluded that substitution with pasteurized human fibrinogen concentrate in patients with CFD is efficient and generally well tolerated.

Fenger-Eriksen and colleagues (2008) noted that patients experiencing massive hemorrhage are at high risk of developing coagulopathy through loss, consumption, and dilution of coagulation factors and platelets.  It has been reported that plasma fibrinogen concentrations may reach a critical low level relatively early during bleeding, calling for replacement fibrinogen therapy.  These researchers audited the effects of fibrinogen concentrate therapy on laboratory and clinical outcome in patients with massive hemorrhage.  They identified 43 patients over the previous 2 years to whom a fibrinogen concentrate had been administered as treatment for hypofibrinogenemia during serious hemorrhage.  Platelet count, plasma fibrinogen, activated partial thromboplastin time (APTT), prothrombin time (PT), D-dimer, and volume of blood lost were obtained from medical and laboratory records.  Numbers of units of red blood cells (RBC), fresh frozen plasma (FFP), and pooled platelet concentrates were recorded before and after fibrinogen substitution.  A significant increase in plasma fibrinogen concentration was observed after fibrinogen concentrate therapy.  Platelet counts and fibrin D-dimer values remained unchanged, whereas the APTT and PT improved significantly.  Requirements for RBC, FFP, and platelets were significantly reduced; blood loss decreased significantly.  The authors concluded that fibrinogen substitution therapy with a fibrinogen concentrate generally improved global laboratory coagulation results; and as supplementary intervention, appeared to reduce the requirements for RBC, FFP, and platelet substitution in this patient cohort.

On January 16, 2009, the Food and Drug Administration (FDA) licensed RiaSTAP (human fibrinogen concentrate) for the treatment of acute bleeding in patients with CFD.  RiaSTAP is a purified fibrinogen concentrate made from the plasma of healthy human donors that undergoes virus inactivation and removal for safety assurance.  It was developed under the FDA’s accelerated approval regulations for orphan drugs.  There have been more than 1,000,000 units sold worldwide (outside the United States, RiaSTAP is marketed under the trade name of Haemocomplettan).  RiaSTAP is indicated for the treatment of acute bleeding episodes in patients with CFD including afibrinogenemia and hypofibrinogenemia; it is not indicated for dysfibrinogenemia.

The licensing of RiaSTAP was based on a phase II, prospective, open-label, safety and pharmacokinetic study using maximum clot firmness (MCF) as a surrogate endpoint for hemostatic efficacy.  A total of 15 patients with afibrinogenemia achieved the target level of fibrinogen expected to prevent bleeding after they received 70 mg/kg body weight of the drug.  In addition, plasma from 14 of the 15 patients showed a highly significant (p < 0.0001) mean improvement in MCF from baseline to 1 hour post-infusion following RiaSTAP treatment.  The most serious adverse reactions that have been reported in clinical studies or through post-marketing surveillance following RiaSTAP treatment are allergic-anaphylactic reactions and thromboembolic episodes, including myocardial infarction, pulmonary embolism, deep vein thrombosis and arterial thrombosis.  The most common adverse reactions that have been reported after RiaSTAP therapy are allergic reactions and generalized reactions such as chills, fever, headache, as well as nausea and vomiting.

In addition to the treatment of CFD, human fibrinogen concentrate has also been employed in the management of other hypofibrinogenemic conditions such as acquired hypofibrinogenemia and post-operative hemorhage.  Clinical data for the use of human fibrinogen concentrate in acquired hypofibrinogenemic states are scarce.  Weinkove and Rangarajan (2008) evaluated the safety and effectiveness of Haemocomplettan in patients with acquired hypofibrinogenemia.  Demographical and pre-treatment clinical data of patients treated with Haemocomplettan were retrospectively reviewed.  Pre- and post-treatment fibrinogen levels, transfusion requirements, outcomes and adverse reactions were recorded.  A total of 30 adult patients who received Haemocomplettan for acquired hypofibrinogenemia (plasma fibrinogen concentration less than 1.5 g/L) were included in the study.  Causes of hypofibrinogenemia included placental abruption, disseminated intravascular coagulation as a result of massive blood loss and transfusion, liver failure and cardiac surgery.  Following a median dose of 4 g Haemocomplettan, median Clauss fibrinogen level rose from 0.65 to 2.01 g/L, with a median fibrinogen increment of 0.25 g/L per 1 g fibrinogen concentrate administered.  It was reporetd that 46 % of patients stopped bleeding with blood components and Haemocomplettan alone, and a further 29 % stopped bleeding with surgical or endoscopic intervention.  Inpatient mortality was 40 %; no venous thromboses were observed.  A total of 4 patients with massive perioperative hemorrhage and hypotension (including 3 post-cardiothoracic surgery) had arterial ischemic events, however, none of which was attributable to over-replacement of fibrinogen.  The cost of Haemocomplettan was comparable with that of cryo-precipitate.  The authors concluded that purified human fibrinogen concentrate appears effective in the management of acquired hypofibrinogenemia.

Bleeding diathesis after aortic valve operation and ascending aorta replacement (AV-AA) is usually managed with FFP and platelet concentrates.  In a pilot study, Rahe-Meyer et al (2009) compared hemostatic effects of conventional transfusion management and FIBTEM (thromboelastometry test)-guided fibrinogen concentrate administration.  A blood-product transfusion algorithm was developed with retrospective data from 42 elective patients (group A).  Two units of platelet concentrate were transfused after cardiopulmonary bypass, followed by 4 units of FFP if bleeding persisted, if platelet count was less than or equal to 100 x 10(3) microl(-1) when removing the aortic clamp, and vice versa if platelet count was greater than 100 x 10(3) microl(-1).  The trigger for each therapy step was greater than or equal to 60 g blood absorbed from the mediastinal wound area by dry swabs in 5 mins.  Assignment to two prospective groups was neither randomized nor blinded; group B (n = 5) was treated according to the algorithm, group C (n = 10) received Haemocomplettan/RiaSTAP before the algorithm-based therapy.  A mean of 5.7 (0.7) g fibrinogen concentrate decreased blood loss to below the transfusion trigger level in all group C patients.  Group C had reduced transfusion [mean of 0.7 (range of 0 to 4) units versus 8.5 (5.3) units in group A and 8.2 (2.3) units in group B] and reduced post-operative bleeding [366 (199) ml versus 793 (560) ml in group A and 716 (219) ml in group B].  The authors concluded that in this pilot study, FIBTEM-guided fibrinogen concentrate administration was associated with reduced transfusion requirements and 24-hr post-operative bleeding in patients undergoing AV-AA.

In a prospective randomised pilot study, Karlsson et al (2009) examined if prophylactic infusion of fibrinogen concentrate may reduce post-operative bleeding.  A total of 20 elective coronary artery bypass graft (CABG) patients with pre-operative plasma fibrinogen levels of less than 3.8 g/L were included in this study.  Patients were randomized to receive an infusion of 2 g fibrinogen concentrate (FIB group) or no infusion before surgery (control group).  Primary endpoint was safety with clinical adverse events and graft occlusion assessed by multi-slice computed tomography.  Pre-defined secondary endpoints were post-operative blood loss, blood transfusions, hemoglobin levels 24 hrs after surgery, and global hemostasis assessed with thromboelastometry, 2 and 24 hrs after surgery.  Infusion of 2 g fibrinogen concentrate increased plasma levels of fibrinogen by 0.6 +/- 0.2 g/L.  There were no clinically detectable adverse events of fibrinogen infusion.  Computed tomography revealed 1 sub-clinical vein graft occlusion in the FIB group.  Fibrinogen concentrate infusion reduced post-operative blood loss by 32 % (565 +/- 150 versus 830 +/- 268 ml/12 hrs, p = 0.010).  Hemoglobin concentration was significantly higher 24 hrs after surgery in the FIB group (110 +/- 12 versus 98 +/- 8 g/L, p = 0.018).  Prophylactic fibrinogen concentrate infusion did not influence global post-operative hemostasis as assessed by thromboelastometry.  The authors concluded that in this pilot study pre-operative fibrinogen concentrate infusion reduced bleeding after CABG without evidence of post-operative hypercoagulability.  They stated that larger studies are needed to ensure safety and confirm efficacy of prophylactic fibrinogen treatment in cardiac surgery.

Mercier and Bonnet (2010) reviewed the optimal use of blood products and clarified the indications for prohemostatic drugs in obstetric hemorrhage.  The literature emphasizes the usefulness of transfusing packed red blood cells, fresh frozen plasma and platelets earlier and in defined ratios to prevent dilutional coagulopathy during obstetric hemorrhage.  It seems reasonable to use blood products for transfusion earlier and in a 1: 1 fresh frozen plasma: red blood cell ratio during acute obstetric hemorrhage; however, this analysis is mainly based on trauma literature.  Fibrinogen concentrate should be added if the fibrinogen plasma level remains below 1.0 g/L and perhaps even as soon as it falls below 1.5 to 2.0 g/L; the addition of tranexamic acid (1 g) is cheap, likely to be useful and appears safe.  Data on the proactive administration of platelets are insufficient to recommend this practice routinely.  Presently, recombinant factor VIIa (60 to 90 microg/kg) is advocated only after failure of other conventional therapies, including embolization or conservative surgery, but prior to obstetric hysterectomy.  The authors stated that prospective randomized controlled trials are highly desirable to examine the use of clotting factors and other prohemostatic drugs for the management of obstetric hemorrhage.

Wikkelsoe and colleagues (2012) described the protocol of a randomized controlled trial (FIB-PPH trial) to examine the effects of fibrinogen concentrate as initial treatment for post-partum hemorrhage (PPH).  In this placebo-controlled, double-blind, multi-center trial, parturients with primary PPH are eligible following vaginal delivery in case of manual removal of placenta (blood loss [greater than or equal to] 500 ml) or manual exploration of the uterus after the birth of placenta (blood loss [greater than or equal to] 1,000 ml).  Caesarean sections are also eligible in case of peri-operative blood loss [greater than or equal to] 1,000 ml.  The exclusion criteria are known inherited hemostatic deficiencies, pre-partum treatment with anti-thrombotics, pre-pregnancy weight less than 45 kg or refusal to receive blood transfusion.  Following informed consent, patients will be randomly allocated to either early treatment with 2 g fibrinogen concentrate or 100 ml isotonic saline (placebo).  Hemostatic monitoring with standard laboratory coagulation tests and thrombo-elastography (TEG, functional fibrinogen and RapidTEG) is performed during the initial 24 hours.  Primary outcome is the need for blood transfusion.  To examine a 33 % reduction in the need for blood transfusion a total of 245 patients will be included.  Four university affiliated public tertiary care hospitals will include patients during a 2-year period.  Adverse events including thrombosis are assessed in accordance with International Conference on Harmonisation (ICH) - good clinical practice (GCP).  The authors concluded that a widespread belief in the benefits of early fibrinogen substitution in cases of PPH has led to increased off-label use.  The FIB-PPH trial is investigator-initiated and aims to provide an evidence-based platform for the recommendations of the early use of fibrinogen concentrate in PPH.

Schochl et al (2010) reported the treatment of major trauma using mainly coagulation factor concentrates.  This retrospective analysis included trauma patients who received greater than or equal to 5 units of red blood cell concentrate within 24 hours.  Coagulation management was guided by thromboelastometry (ROTEM).  Fibrinogen concentrate was given as first-line hemostatic therapy when maximum clot firmness (MCF) measured by FibTEM (fibrin-based test) was less than 10 mm.  Prothrombin complex concentrate (PCC) was given in case of recent coumarin intake or clotting time measured by extrinsic activation test (EXTEM) greater than 1.5 times normal.  Lack of improvement in EXTEM MCF after fibrinogen concentrate administration was an indication for platelet concentrate.  The observed mortality was compared with the mortality predicted by the trauma injury severity score (TRISS) and by the revised injury severity classification (RISC) score.  Of 131 patients included, 128 received fibrinogen concentrate as first-line therapy, 98 additionally received PCC, while 3 patients with recent coumarin intake received only PCC.  Twelve patients received FFP and 29 received platelet concentrate.  The observed mortality was 24.4 %, lower than the TRISS mortality of 33.7 % (p = 0.032) and the RISC mortality of 28.7 % (p > 0.05).  After excluding 17 patients with traumatic brain injury, the difference in mortality was 14 % observed versus 27.8 % predicted by TRISS (p = 0.0018) and 24.3 % predicted by RISC (p = 0.014).  The authors concluded that ROTEM-guided hemostatic therapy, with fibrinogen concentrate as first-line hemostatic therapy and additional PCC, was goal-directed and fast.  A favorable survival rate was observed.  Moreover, they stated that prospective, randomized trials to investigate this therapeutic alternative further appear warranted.

Wafaisade et al (2012) examined if blood component transfusion and hemostatic drug administration during acute trauma care have changed in daily practice during the recent years.  The multi-center trauma registry of the German Society for Trauma was retrospectively analyzed for primarily admitted patients older than 16 years with an Injury Severity Score greater than or equal to 16 who had received at least 5 red blood cell (RBC) units between emergency room arrival and intensive care unit admission.  Administration of FFP and platelet units has been documented since 2002, and use of hemostatic drugs since 2005.  From 2002 to 2009 (n = 2,813), the FFP:RBC ratio increased from 0.65 to 0.75 (p = 0.02) and the platelet:RBC ratio from 0.04 to 0.09 (p < 0.0001).  A constant increase was also observed regarding the overall use of hemostatic drugs (n = 1,811; 2005 to 2009) as these were administered to 43.4 % of the patients in 2005 and to 60.7 % in 2009 (p < 0.0001).  In particular, the administration of fibrinogen concentrate (2005: 17.0 %, 2009: 45.6 %; p < 0.0001) and recombinant factor VIIa (2005: 1.9 %, 2009: 6.3 %; p = 0.04) showed a marked increase.  However, mortality rates remained unchanged during the 8-year study period.  The authors concluded that therapy of bleeding trauma patients has changed in Germany during the recent years toward more aggressive coagulation support.  This development continues although grades of evidence are still low regarding most of the changes reported in this study.  They stated that randomized controlled trials are needed with respect to blood component therapy using pre-defined ratios and to the administration of hemostatic drugs commonly used for the severely injured.

RiaSTAP is available as single-use vials containing 900 to 1,300 mg lyophilized fibrinogen concentrate powder for reconstitution.  Actual fibrinogen potency for each lot is printed on vial label and carton.  The dosing of RiaSTAP is as follows (Israels, 2009; CSL Behring US Package Insert, 2009):

Adult:

• Administer intravenously, not to exceed injection rate of 5 ml/min.
• Dose (mg/kg) = (Target level [mg/dL] - measured level [mg/dL]) divided by 1.7; if fibrinogen level unknown, use 70 mg/kg body weight.
• Maintain target fibrinogen level of 100 mg/dL until hemostasis is obtained.

Pediatric:

• Data limited; clinical trials included 4 children less than 16 years of age.
• Children exhibited shorter half-life (69.9 +/- 8.5 hrs) and faster clearance (0.7 +/- 0.1 mg/L) than adults (half-life = 82.3 +/- 20.0 hrs; clearance = 0.53 +/- 0.1 mg/L), but limited number of children restricts statistical interpretation of these data.