Download Clinical Policy Bulletin: Clotting Factors

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Clotting Factors
Clinical Policy Bulletin: Clotting Factors
Revised April 2014
Number: 0131
Policy
I. Aetna considers anti-hemophilic factor (factor VIII), factor IX (e.g., BeneFIX, and Rixubis), and Humate-P or medically
necessary to prevent or treat hemorrhagic complications in adults and children with hemophilia A, B or von
Willebrand's disease according to the following criteria and limitations:
A. Standard dose therapy (dose until bleeding stops or up to 14 days after surgery) when both of the fol criteria
are met:
1. Member has a diagnosis of hemophilia A, hemophilia B, or von Willebrand's disease (only Hu
Alphanate may be used in von Willebrand’s disease); and
2. Member is hemorrhaging or physical trauma such as surgery is anticipated (secondary short-t
prophylaxis).
B. Continuous (long-term) prophylactic therapy when either of the following criteria is met:
1. Primary prophylactic therapy: Member has severe hemophilia A or hemophilia B (less than 1 factor
(less than 0.01 IU/ml)); or
2. Secondary prophylactic therapy: Member has hemophilia A or hemophilia B (regardless of no
levels) and has documented history of 2 or more episodes of spontaneous bleeding into joints
C. High-dose immune tolerance induction (dosing continues beyond 14 days) when all of the following c met:
1. Anti-hemophilic factor or Factor IX survival and recovery of anti-hemophilic factor levels after i
abnormal (see D, 1, below); and
2. Attempts to lower antibody levels with either immunosuppressant or corticosteroids have been
unsuccessful; and
3. Member has a diagnosis of hemophilia A or hemophilia B; and
4. Member has inhibitors (anti-factor VIII:c or IX:c antibodies).
D. Limits applicable to immune tolerance induction:
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1. Continued immune tolerance induction is no longer considered medically necessary when all o
following criteria are met:
a. Anti-hemophilic factor or factor IX survival after infusion is normal (6-hr level at least 46 min
level); and
b. Inhibitor levels become undetectable; and
c. Recovery of anti-hemophilic factor or factor IX levels after infusion are normal (defined
85 % of the expected for individuals without inhibitors);
2. Cases in which members are on immune tolerance induction for 6 months or more may be ref review
of medical necessity to determine whether continued immune tolerance therapy is me necessary.
Aetna considers anti-hemophilic factor (factor VIII), factor IX and Humate-P or Alphanate experimental and
investigational for all other indications because their effectiveness for indications other than the ones listed a not
been established.
II. Aetna considers recombinant factor VIII Fc fusion protein (Eloctate) medically necessary to prevent or treat
hemorrhagic complications in adults and children with hemophilia A according to the following criteria and li
A. Standard dose therapy (dose until bleeding stops or up to 14 days after surgery) when both of the fol criteria
are met:
1. Member has a diagnosis of hemophilia A; and
2. Member is hemorrhaging or physical trauma such as surgery is anticipated (secondary short-t
prophylaxis).
B. Continuous (long-term) prophylactic therapy when either of the following criteria is met:
1. Primary prophylactic therapy: Member has severe hemophilia A (less than 1 % of normal facto
0.01 IU/ml)); or
2. Secondary prophylactic therapy: Member has hemophilia A (regardless of normal factor level
documented history of 2 or more episodes of spontaneous bleeding into joints.
III. Aetna considers recombinant factor VIIa (rFVIIa, NovoSeven RT) medically necessary for the prevention of surgical
interventions or invasive procedures and for the control of bleeding events in members with any of t indications:
A. Members with hemophilia A or hemophilia B who have developed inhibitor antibodies to factor VIII or or
B. Members with acquired hemophilia or congenital FVII deficiency; or
C. Members with Glanzmann's thrombasthenia with antibodies to glycoprotein IIb-IIIa and/or human leu antigen
(HLA), and with past or present refractoriness to platelet transfusions.
Aetna considers rFVIIa experimental and investigational for all other indications including prevention unrelated
to hemophilia or factor deficiency (e.g., in persons undergoing cardiac surgery, liver transp vascular surgery, or
prostatectomy); or treatment of bleeding unrelated to hemophilia or factor deficie trauma, acute coronary
syndromes, acute spontaneous intracerebral hemorrhage, acute variceal ble gastrointestinal bleeding
secondary to Crohn's disease, and intracranial bleeding from traumatic brai
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stroke, not an all-inclusive list).
IV. Aetna considers human anti-thrombin III (Thrombate III) medically necessary for the treatment of persons w
hereditary anti-thrombin III deficiency in connection with thrombo-embolism, obstetrical procedures, or surgi
procedures.
Aetna considers human anti-thrombin III experimental and investigational for all other indications including it in
critically ill individuals.
V. Aetna considers factor eight inhibitor bypassing activity (FEIBA) (Febia NF) anti-inhibitor coagulant complex necessary in
persons with hemophilia A and B with inhibitors for the control and prevention of bleeding epis perioperative
management, and routine prophylaxis to prevent or reduce the frequency of bleeding episodes
Aetna considers FEIBA experimental and investigational for all other indications (e.g., reversal of anticoagu associated
coagulopathy, rescue treatment of coagulopathy after cardiac surgery; prevention and treatment in non-hemophilic
persons with acquired inhibitors, not an all-inclusive list) because its effectiveness for indi other than the ones listed
above has not been established.
VI. Aetna considers factor XIII concentrate [Human] (Corifact) medically necessary for the prevention of bleedin the perioperative management of surgical bleeding in persons with congenital factor XIII deficiency.
Aetna considered factor XIII concentrate experimental and investigational for all other indications because it
effectiveness for indications other than the one listed above has not been established.
VII. Aetna considers recombinant coagulation factor XIII A-subunit (Tretten) medically necessary for routine prop bleeding
in persons with congenital factor XIII A-subunit deficiency.
Coagulation factor XIII A-subunit is considered experimental and investigational for persons with congenital
-subunit deficiency and for all other indications.
VIII. Aetna considers von Willebrand factor/coagulation factor VIII complex (Wilate®) medically necessary for the of
spontaneous and/or trauma-induced bleeding episodes in individuals with severe von Willebrand disease individuals
with mild or moderate VWD when there is failure, contraindication or intolerance to desmopressi
Aetna considers von Willebrand factor/coagulation factor VIII complex (Wilate®) experimental and investiga
individuals with hemophilia A; and for the prophylaxis of spontaneous bleeding episodes, or the prevention o bleeding
during and after surgery in individuals with VWD.
IX. Aetna considers prothrombin complex concentrate (human) (Kcentra) medically necessary for urgent revers acquired
coagulation factor deficiency induced by vitamin K antagonist (e.g., warfarin) therapy in adults with major bleeding.
Aetna considers prothrombin complex concentrate (human) experimental and investigational for reversal of
coagulation in persons without acute major bleeding; and trauma-induced hemorrhage because its effective these
indications has not been established.
X. Aetna considers recombinant factor IX fc fusion protein (rFIXFc) (Alprolix) medically necessary for persons d with
hemophilia B (endogenous factor IX level of ≤2 IU per deciliter, or ≤2% of normal levels) for the followin indications: 1)
control and prevention of bleeding episodes, 2) perioperative management, and 3) routine pro prevent or reduce the
frequency of bleeding episodes.
A. Standard dose therapy (dose until bleeding stops or up to 14 days after surgery) when both of the fol criteria
are met:
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1. Member has a diagnosis of hemophilia B; and
2. Member is hemorrhaging or physical trauma such as surgery is anticipated (secondary short-t
prophylaxis).
B. Continuous (long-term) prophylactic therapy when either of the following criteria is met:
1. Primary prophylactic therapy: Member has severe hemophilia B (less than 1 % of normal facto
0.01 IU/ml)); or
2. Secondary prophylactic therapy: Member has hemophilia B (regardless of normal factor levels
documented history of 2 or more episodes of spontaneous bleeding into joints.
Aetna considers rFIXFc experimental and investigational for induction of immune tolerance in with
hemophilia B and for all other indications.
Note: This policy applies only to clotting factor products available through pharmaceutical suppliers. Cryoprecipitat factors
are available only through blood banks and have slightly different indications.
Background
Hemophilia and von Willebrand's disease are the most common congenital bleeding disorders. Hemophilia refers bleeding
disorders in which there is a deficiency (activity level of 35 % or less) of either factor VIII (hemophilia A, cl hemophilia) or
factor IX (hemophilia B, Christmas disease). In general, administration of anti-hemophilic factor is in hemophilia when a
bleeding episode arises (demand treatment) or when bleeding is anticipated or likely (prophyla treatment).
Primary prophylactic therapy may be indicated for patients with severe hemophilia A or hemophilia B who have les of normal
factor (less than 0.01 IU/ml; National Hemophilia Foundation, 2001). Primary prophylactic therapy shoul instituted early,
prior to the onset of frequent bleeding, with the aim of keeping the trough factor or VIII or factor IX l
1 % between doses (National Hemophilia Foundation, 2001). In some cases, continuous prophylactic therapy ma indicated in
persons with hemophilia A or hemophilia B that is not severe (i.e., hemophiliacs with more than 1 % of factor levels) who
have repeated episodes of spontaneous bleeding.
Short-term prophylactic treatment is given to patients before they undergo surgical procedures or engage in activiti carry a
high risk of provoking a bleed. It may also be given to break the cycle of frequent bleeding into specific join joints). Potential
harm, including the risk of hepatitis B, hepatitis C and HIV infection, has now been minimized thro inactivation of plasmaderived coagulation-factor concentrates and through the use of recombinant clotting factor c and other non-plasma-derived
hemostatic agents. Currently, cryoprecipitate does not undergo viral inactivation pro
Immune tolerance induction is designed to overcome the effects of anti-hemophilic factor or factor IX inhibitors in c
hemophiliac patients, thus restoring effectiveness of antihemophilic factor or factor IX therapy to resolve active ble these
patients. It consists of administration of very high doses of anti-hemophilic factor or factor IX over an extend time.
A number of different immune tolerance therapy regimens have been developed using replacement factor VIII or fa produce
long-term inhibitor suppression or eradication. These protocols utilize various doses of replacement facto factor IX with or
without additional therapies.
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There are a number of established protocols for immune tolerance induction; these regimens differ in dose and dur therapy
(Stachnik, 2003). The North American Immune Tolerance Registry was established in 1993 to assess the protocols used for
immune tolerance therapy in the United States and Canada (Stachnik, 2003; Kroner, 1999; DiM Kroner, 1999). Based on a
survey of 168 centers that provide medical care to hemophilia patients, many clinicians America (about 50 %) use 100 to 200
U/kg of replacement factor VIII daily for immune tolerance therapy. In gener duration of treatment is shorter when using
higher doses of factor VIII. For doses of factor VIII over 50 U/kg daily, treatment time was between 6 and 7 months;
however, with lower doses of factor VIII (less than 50 U/kg daily), the duration of treatment was nearly 19 months. Highest
success rates were found among patients who had a history maximum inhibitor titers (less than 50 Bethesda Units).
Immune tolerance induction is not successful in all patients -- approximately 20 % to 30 % fail to respond (Stachnik Although
the duration of treatment varies among the immune tolerance protocols, most clinicians would agree that who has not
responded as expected after 12 to 24 months of treatment is unlikely to respond with further treatmen induction tolerance,
although occasionally successful, generally is not effective (Stachnik, 2003). For these patient episodes can usually be
controlled using bypassing agents, including factor IX complex (prothrombin complex con PCCs), recombinant factor VIIa
(rFVIIa, NovoSeven RT), or activated anti-inhibitor coagulant complexes (AICCs or
In view of the increasing safety of clotting-factor concentrates, long-term prophylactic therapy in the form of factor
at least 3 times a week or factor IX infusion at least twice a week to prevent hemarthrosis in severely affected patie gaining
acceptance, especially in the treatment of infants and children. It has been shown that increasing in-vivo c factor levels to
more than 1 % activity (usually accomplished by giving 25 to 40 U/kg of factor VIII 3 times a week o U/kg of factor IX twice a
week) is sufficient to prevent most spontaneous joint bleeds and preserve joint function.
von Willebrand's disease is typically mild and it generally exhibits an autosomal dominant pattern of inheritance.
A
hemophilic factor/von Willebrand factor complex (Humate-P) is indicated for use in adult patients for treatment and of
bleeding in hemophilia A and in adult and pediatric patients for treatment of spontaneous and trauma-induced bl episodes in
severe von Willebrand disease and in mild and moderate von Willebrand disease where use of desmo known or suspected to
be inadequate. In April 2007, the U.S. Food and Drug Administration (FDA) approved Hum the prevention of excessive
bleeding during and after surgery in certain patients with mild-to-moderate and severe Willebrand disease.
Recombinant antihemophilic factor -- plasma/albumin free method (rAHF-PFM) (Advate, Baxter Healthcare, Westl CA) is
produced using a protein-free manufacturing process. Based on clinical studies submitted to the FDA comp PFM to a standard
recombinant antihemophilic factor (rAHF) (Recombinate, Baxter Healthcare), the FDA has conc rAHF-PFM is therapeutically
equivalent to rAHF. Human or animal plasma proteins or albumin are used in the cell process of rAHF, with the theoretical
risk of transmission viruses, prions or other pathogens (Schesinger and Ragn Adis, 2003). The Medical and Scientific Advisory
Council (MASAC) of the National Hemophilia Foundation has rec that "all efforts should be made to remove human albumin
from recombinant factor VIII products" and that "increase should be made to eliminate human and bovine proteins from the
manufacturing process of recombinant products. there are no documented episodes of transmission of HIV, West Nile Virus,
Creutzfeld-Jacob Disease or other suc pathogens from rAHF products currently on the market.
Case reports have been published on the successful use of rFVIIa in patients with Glanzmann's thrombasthenia, w inherited
hemorrhagic disorder characterized by a severe reduction in, or absence of, platelet aggregation in respo multiple physiologic
agonists due to qualitative or quantitative abnormalities of platelet glycoprotein IIb-IIIa. The E Medicine’s Agency (EMEA) has
approved rFVIIa for use in persons with Glanzmann’s thrombasthenia with antibod glycoprotein IIb-IIIa and/or human
leukocyte antigen (HLA), and with past or present refractoriness to platelet trans scientific discussion prepared by the EMEA
(2005) states that the clinical experience with the treatment of patients Glanzmann’s thrombasthenia with rFVIIa is based on
data from a clinical trial (n = 4), an International Registry on Recombinant Factor VIIa and Congenital Platelet Disorders (n =
59), and 10 published case reports. Most of the re clinical experience with the use of rFVIIa in persons with Glanzmann’s
thrombasthenia is in patients without anti-gl
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antibodies and platelet refractoriness. The EMEA analyzed the efficacy data for persons with anti-glycoprotein IIb/ anti-HLA
antibodies and platelet refractoriness. Seventeen patients with from the International Registry and 2 patie independently
published case reports were identified, with a total of 40 evaluable bleeding episodes. The EMEA s discussion reports that
rFVIIa was effective for bleeding prophylaxis in 18 (95 %) of 19 evaluable (minor plus major procedures. The EMEA states that
rFVIIa was effective in stopping 28/40 (70 %) of the evaluable bleeding episode similar as the efficacy of rFVIIa in bleeding
episodes reported in Glanzmann’s thrombasthenia patients generally. scientific discussion states that 3 recurrent bleedings
(3/40, 8 %) could be successfully treated with additional dose (but in 1 case a concomitant platelet transfusion was given).
There is a lack of reliable evidence of the effectiveness of rFVIIa for non-hemophilic indications. Levi and colleagu performed
a systematic review on the safety and effectiveness of rFVIIa in patients with or without coagulation dis They concluded that
more randomized controlled clinical trials are needed to evaluate the safety and effectiveness for patients without a preexistent coagulation disorder and with severe bleeding. In the meantime, off-labeled use may be considered in patients with
life-threatening bleeding. This is in agreement with the observations of Lam et who stated that until further prospective
controlled data are available, it is recommended that conventional interven prevention and control of hemorrhage in nonhemophiliac patients should remain the standard of care. More recen O’Connell and colleagues (2006) reported that the use
of rFVIIa is associated with severe adcerse events (AEs) e when it is used for off-labeled indications. They analyzed 431
incidents of AEs reported to the FDA during the first after the approval of NovoSeven. They noted that most reported
thromboembolic AEs followed the use of the drug labeled indications (n = 151) and occurred in the arterial and venous
systems, often resulting in serious morbidity a mortality. The majority of complications occurred within 24 hours of taking
the drug. These investigators conclude randomized controlled studies are needed to ascertain the safety and effectiveness of
rFVIIa in patients without he
A number of studies have found that hemostatic therapy with rFVIIa may reduce growth of hematoma but does not survival
or functional outcome after intra-cerebral hemorrhage. In a prospective, randomized, placebo-controlled, d escalation study,
Narayan and colleagues (2008) evaluated the safety and preliminary effectiveness of rFVIIa to li intra-cerebral hemorrhage
(tICH) progression. Patients were enrolled if they had tICH lesions of at least 2 ml on a computed tomographic scan obtained
within 6 hours of injury. Recombinant factor VIIa or placebo was administere hours of the baseline computed tomographic
scan but no later than 7 hours after injury. Computed tomographic sc repeated at 24 and 72 hours. Five escalating dose tiers
were evaluated (40, 80, 120, 160, and 200 microg/kg rFVI evaluations and AEs were recorded until day 15. No significant
differences were detected in mortality rate or numb of AEs among treatment groups. Asymptomatic deep vein thrombosis,
detected on routinely performed ultrasound was observed more frequently in the combined rFVIIa treatment group (placebo,
3 %; rFVIIa, 8 %; not significant). significant trend for rFVIIa dose-response to limit tICH volume increase was observed
(placebo, 21.0 ml; rFVIIa, 10 authors concluded that in this first prospective study of rFVIIa in tICH, there appeared to be a
trend toward less he progression in rFVIIa-treated patients (80 to 200 microg/kg) compared with that seen in placebo-treated
patients. T stated that the potential significance of this biological effect on clinical outcomes and the significance of the
somew incidence of ultrasound-detected deep vein thromboses in the rFVIIa-treated group need to be examined in a large
prospective randomized clinical trial.
Mayer et al (2008) carried out a phase 3 trial to evaluate whether rFVIIa reduces growth of hematoma and improve and
functional outcomes in patients with ICH. A total of 841 patients were randomly assigned to receive placebo (n microg of
rFVIIa per kilogram of body weight (n = 276), or 80 microg of rFVIIa per kilogram (n = 297) within 4 hours onset of stroke. The
primary end point was poor outcome, defined as severe disability or death according to the m Rankin scale 90 days after the
stroke. Treatment with 80 microg of rFVIIa per kilogram resulted in a significant red growth in volume of the hemorrhage.
The mean estimated increase in volume of the ICH at 24 hours was 26 % in group, as compared with 18 % in the group
receiving 20 microg of rFVIIa per kilogram (p = 0.09) and 11 % in the g receiving 80 microg (p < 0.001). The growth in volume
of ICH was reduced by 2.6 ml (95 % confidence interval [C
5.5; p = 0.08) in the group receiving 20 microg of rFVIIa per kilogram and by 3.8 ml (95 % CI: 0.9 to 6.7; p = 0.009) group
receiving 80 microg, as compared with the placebo group. Despite this reduction in bleeding, there was no s difference among
the 3 groups in the proportion of patients with poor clinical outcome (24 % in the placebo group,
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group receiving 20 microg of rFVIIa per kilogram, and 29 % in the group receiving 80 microg). The overall frequen
thromboembolic serious AEs was similar in the 3 groups; however, arterial events were more frequent in the group
80 microg of rFVIIa than in the placebo group (9 % versus 4 %, p = 0.04). The authors concluded that hemostatic rFVIIa
reduced growth of the hematoma but did not improve survival or functional outcome after ICH. Whether this effect can
translate to clinical benefit in a subgroup of patients at high risk for active bleeding, either by treatment w earlier time
window or by demonstration of intra-hematomal contrast extravasation after CT angiography deserves study.
A randomized controlled study found no effect of rFVIIa on a primary composite endpoint of failure to control 24-hr bleeding,
failure to control rebleeding or death in patients with advanced cirrhosis. In a randomized controlled stud and associates
(2008) evaluated the safety and effectiveness of rFVIIa in patients with advanced cirrhosis and acti bleeding. At 31 hospitals
in an emergency setting, 256 patients (Child-Pugh greater than 8; Child-Pugh B = 26 %, were randomized equally to: placebo;
600 microg/kg rFVIIa (200 + 4x 100 microg/kg); or 300 microg/kg rFVIIa (200 microg/kg). Dosing was intravenous at 0, 2, 8,
14, and 20 hrs after endoscopy, in addition to standard vasoactive, antibiotic, and endoscopic treatment. The primary
composite endpoint consisted of failure to control 24-hr bleedin to prevent re-bleeding or death at day 5. Secondary
endpoints included AEs and 42-day mortality. Baseline chara were comparable between groups. Administration of rFVIIa had
no significant effect on the composite endpoint co placebo (p = 0.37). There was no significant difference in 5-day mortality
between groups; however, 42-day morta significantly lower with 600 microg/kg rFVIIa compared with placebo (odds ratio
0.31, 95 % CI: 0.13 to 0.74), and b related deaths were reduced from 12 % (placebo) to 2 % (600 microg/kg). A marked
heterogeneity in the failure ra treatment groups was observed across participating centers. Adverse events, including overall
thromboembolic ev comparable between groups. The authors concluded that treatment with rFVIIa had no significant effect
on the pri composite endpoint compared with placebo. Thus, decision on the use of rFVIIa in acute variceal bleeding should
considered, because results of this study do not support the routine use of rFVIIa in this setting.
A Cochrane systematic evidence review (Marti-Carvajal et al, 2007) concluded that they found no evidence that rFV reduces
the risk of death in patients with liver disease and upper gastrointestinal bleeding. "More randomised clini having low risk of
bias are necessary in order to determine the role of human recombinant factor VIIa in clinical pra
An assessment by the Canadian Coordinating Office for Health Technology Assessment (Selin and Tejani, 2006) r rFVIIa is
increasingly used to control bleeding in non-hemophilic patients during surgery, or during treatment for se or ICH. The
assessment noted that there is potential for non-hemophilic use of rFVIIa, particularly if clinical and co effectiveness are
established. The assessment concluded that adequately powered randomized controlled trials a to clarify the efficacy and
safety of rFVIIa for non-bleeding disorder indications. The assessment noted that phase ICH and trauma are underway.
A randomized controlled clinical study found that propylactic use of rFVIIa did not decrease perioperative blood los with
normal hemostasis undergoing surgical repair of traumatic pelvic-acetabular fracture. In a double-blind, rando placebocontrolled trial, Raobaikady and associates (2005) examined the clinical value of rFVIIa in patients underg reconstruction
surgery for traumatic fracture of pelvis or pelvis and acetabulum (n = 48). Patients were randomized an intravenous bolus
injection of rFVIIa 90 microg/kg or placebo as add-on therapy at the time of the first skin incis patients also received intraoperative salvaged red blood cells (RBC). There was no significant difference in the to of peri-operative blood loss, the
primary outcome variable, between the rFVIIa and placebo groups. In addition, th differences between the 2 groups in the
total volume of blood components, including salvaged RBC transfused, nu patients requiring allogeneic blood components,
total volume of fluids infused, total operating time, time taken after intensive care unit to reach normal body temperature
and acid-base status, and time spent in hospital. No advers particular thromboembolic events, were reported in either group.
The authors concluded that in patients with norm hemostasis undergoing repair surgery of traumatic pelvic-acetabular
fracture, the prophylactic use of rFVIIa does n the volume of peri-operative blood loss.
A review found that the evidence does not support the use of rFVIIa to prevent or control excessive bleeding after surgery.
Hardy and co-workers (2009) noted that excessive bleeding is a common and morbid problem after cardia
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There is no doubt a need for an effective and safe hemostatic agent in order to minimize transfusions and avoid su
intervention for hemostasis. Recombinant activated factor VII is being used (off-label) increasingly after cardiac su prevent or
to control hemorrhage, but its efficacy and safety remain unclear. Several case reports, case series and would tend to
support the use of rFVIIa to control excessive bleeding after cardiac operations. On the contrary, 2 r controlled trials have
produced negative results whereas a 3rd has not been published yet. Adverse thrombotic ev been reported with increasing
frequency. The authors concluded that at present, the generalized use of rFVIIa to control excessive bleeding after cardiac
surgery can not be recommended.
Analaysis of a large cohort of persons in placebo-controlled trials of rFVIIa found that treatment with high doses of an offlabel basis significantly increased the risk of arterial thromboembolic events. Levi and colleagues (2010) eva rate of
thromboembolic events in all published randomized, placebo-controlled trials of rFVIIa used on an off-label non-hemophilia).
These investigators analyzed data from 35 randomized clinical trials (26 studies involving patien studies involving healthy
volunteers) to determine the frequency of thromboembolic events. The data were pooled use of random-effects models to
calculate the odds ratios and 95 % CI. Among 4,468 subjects (4,119 patients and healthy volunteers), 498 had
thromboembolic events (11.1 %). Rates of arterial thromboembolic events among all subjects were higher among those who
received rFVIIa than among those who received placebo (5.5 % versus 3.2
0.003). Rates of venous thromboembolic events were similar among subjects who received rFVIIa and those who placebo (5.3
% versus 5.7 %). Among subjects who received rFVIIa, 2.9 % had coronary arterial thromboembolic e compared with 1.1 % of
those who received placebo (p = 0.002). Rates of arterial thromboembolic events were hi subjects who received rFVIIa than
among subjects who received placebo, particularly among those who were 65 y or older (9.0 % versus 3.8 %, p = 0.003); the
rates were especially high among subjects 75 years of age or older (1 versus 4.1 %, p = 0.02). The authors concluded that in a
large and comprehensive cohort of persons in placebo-c trials of rFVIIa, treatment with high doses of rFVIIa on an off-label
basis significantly increased the risk of arterial bu venous thromboembolic events, especially among the elderly.
In an editorial that accompanied the afore-mentioned study, Aledort (2010) stated that "[t]his article uniquely prese the offlabel use of rFVIIa in a variety of clinical conditions, and it specifically addresses the incidence of thromboem events. In
patients with bleeding disorders, the challenge is to establish hemostasis without incurring thromboemb Clinical trials are put
in place to evaluate the safety and efficacy of new agents. Data and safety monitoring boards independent entities, are
charged with the responsibility of determining the safety of drugs in a given clinical trial. I determines that the data
demonstrate that the risk outweighs the benefit, the trial may be halted, but the reasons fo the trial may not be widely
promulgated. Even if trials are not discontinued, regulators, such as the Food and Drug Administration or the European
Medicines Agency, when reviewing a portfolio of information about a drug, may not label indication because of adverse
events; however, the data on the adverse events often do not reach the public Therefore, patients and health care
professionals may have no way to learn about adverse events associated with use".
Furthermore, the editorialist stated that "[t]he authors appropriately warn readers that these data warrant scrutiny w is used
on an off-label basis. The thrombotic sequelae reported here are not inconsequential. The risk is particula among older
patients. This article should serve as a template for pharmaceutical companies to report all studies in use of a given drug, onlabel and off-label, so that physicians can fully appreciate the benefit and risks when makin therapeutic decisions".
The Canadian Agency for Drugs and Technologies in Health's technology assessment on rFVIIa for the prevention unrelated to
hemophilia (Murphy et al, 2010) concluded that "no consistent benefit of rFVIIa therapy was detected a studies evaluating the
prevention of bleeding in patients undergoing prostatectomy, liver transplantation, or cardiac The risk of adverse events after
the prophylactic use of rFVIIa in surgical patients is unknown. No conclusions can on the effectiveness or safety of using rFVIIa
in the prevention of bleeding in patients who have received supra-the doses of anticoagulant agents. When used for
prevention of bleeding, no specific method is available to monitor th effectiveness of rFVIIa".
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Mannucci et al (2010) stated that the main cause of the hemostasis defects and related bleeding complications in p acute
coronary syndromes (ACS) are the intake of multiple anti-thrombotic drugs, alone or concomitantly with inva procedures such
as coronary angiography and percutaneous coronary intervention (PCI). Anti-thrombotic drugs th several phases of
hemostasis (platelet function, coagulation, and fibrinolysis) are causing bleeding particularly in e patients, in those who are
under-weight and with co-morbidities such as renal insufficiency, diabetes, hypertension malignancy. Identification of
patients at high risk of bleeding is the most important preventive strategy, because th and dosages of drugs may to some
extent be tailored to the degree of risk. Transfusions of blood products, which become necessary in patients with major
bleeding, should be used with caution, because they are associated with cardiovascular events. To reduce the need of
transfusion, the hemostatic drugs that decrease blood loss and trans requirements in cardiac surgery (anti-fibrinolytic amino
acids, desmopressin, and rFVIIa) might be considered. Ho efficacy of these drugs in the control of bleeding complications is
not unequivocally established in ACS and there is for an increased risk of thrombosis. The authors concluded that evidencebased recommendations for the manag bleeding in patients with ACS are currently lacking, so that prevention through
accurate assessment of the individu most valid strategy.
A Cochrane review found no reliable evidence from randomized controlled clincial trials to support the effectivenes
hemostatic drugs in reducing mortality or disability in patients with traumatic brain injury. Perel et al (2010) evaluat effects of
hemostatic drugs on mortality, disability and thrombotic complications in patients with traumatic brain inju These
investigators included published and unpublished randomized controlled trials comparing hemostatic drugs fibrinolytics:
aprotinin, tranexamic acid (TXA), aminocaproic acid or rFVIIa) with placebo, no treatment, or other tre patients with acute TBI.
Two review authors independently examined all electronic records, and extracted the data judged that there was clinical
heterogeneity between trials so they did not attempt to pool the results of the included results are reported separately. Two
trials were included; one was a post-hoc analysis of 30 TBI patients from a ra controlled trial of rFVIIa in blunt trauma patients.
The risk ratio for mortality at 30 days was 0.64 (95 % CI: 0.25 to 1 rFVIIa compared to placebo. This result should be
considered with caution as the subgroup analysis was not pre- the trial. The other trial evaluated the effect of rFVIIa in 97 TBI
patients with evidence of intra-cerebral bleeding in tomography (CT) scan. The corresponding risk ratio for mortality at the
last follow-up was 1.08 (95 % CI: 0.44 to 2 quality of the reporting of both trials was poor so it was difficult to assess the risk of
bias. The authors concluded th no reliable evidence from randomized controlled trials to support the effectiveness of
hemostatic drugs in reducing disability in patients with TBI. New randomized controlled trials assessing the effects of
hemostatic drugs in TBI p should be conducted. These trials should be large enough to detect clinically plausible treatment
effects.
Human AT III (Thrombate III) is indicated for the treatment of patients with hereditary AT III deficiency in connection surgical
or obstetrical procedures, or when they suffer from thromboembolism.
Rogers (2009) stated that anti-thrombin (AT) functions as a potent natural anticoagulant and serine protease inhibi inactivates
many enzymes in the coagulation cascade. Antithrombin also possesses anti-inflammatory properties, which are mediated by
its actions as an anti-coagulant. Hereditary AT deficiency is a rare, under-recognised medi that is associated with inadequate
endogenous anti-coagulation thought to result from impaired inhibition of serine coagulation factors. Inherited as an
autosomal dominant trait, congenital AT deficiency typically reduces functiona to 40 to 60 % of normal. As a result,
individuals with hereditary AT deficiency have a greater than or equal to 50 % of venous thromboembolism (VTE). Specifically,
AT deficiency is associated with a 3- to 7-fold higher risk of VTE with other thrombophilias. Thus, maintaining adequate levels
of AT during high-risk periods is an important treatme Long-term anti-coagulant thrombo-prophylaxis is not recommended in
asymptomatic patients with AT deficiency b the increased risk of hemorrhage. However, treatment guidelines recommend
short-term thromboprophylaxis in hi clinical settings, including surgery, trauma, and management of pregnancy, labor, and
delivery. The goal of treatm patients with hereditary AT deficiency is an initial increase in AT activity to greater than or equal
to 120 % of norma followed by maintenance of AT activity at greater than or equal to 80 % of normal levels. Plasma-derived
AT, hepa frozen plasma, and human recombinant AT are treatment options for individuals with hereditary AT deficiency.
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Tiede et al (2008) stated that during surgery and childbirth, patients with hereditary AT deficiency are at high risk fo
thrombosis, and heparin prophylaxis may not be sufficiently effective. In these patients, exogenous AT may be use association
with heparin. A recombinant human AT has been developed. In a phase III multi-center study, these i assessed the safety and
effectiveness of prophylactic intravenous administration of AT alfa to hereditary AT deficie in high risk situations, including
elective surgery, childbirth, or cesarean section. Anti-thrombin alfa was administer and during the high risk period for
restoration and maintenance of AT activity at 100 % of normal. Heparin, low-mo weight heparin, and/or vitamin K antagonists
were used according to standard of care. The primary efficacy endpo incidence of acute deep vein thrombosis (DVT) from
baseline up to day 30 post dosing as assessed by independe review of duplex ultrasonograms and/or venograms. Safety was
assessed based on AEs and laboratory evaluatio surgical and 9 obstetrical hereditary AT deficiency patients received AT alfa
for a mean period of 7 days. No clinica DVT occurred. Central review of ultrasonograms identified signs of acute DVT in 2 out
of 13 evaluable patients. N related AEs were reported. No patient developed anti-AT alfa antibodies. The authors concluded
that these finding suggested that AT alfa is a safe and effective alternative to human plasma-derived AT for treating hereditary
AT de patients at high risk for thromboembolic events.
A Cochrane review concluded that AT III can not be recommended for critically ill patients based on the available e Afshari et
al (2008) noted that AT III is an anti-coagulant with anti-inflammatory properties but the efficacy and any effects of AT III
supplementation in critically ill patients are unknown. These researchers evaluated the benefits an AT III in critically ill
patients. They searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The C Library); MEDLINE; EMBASE;
Science Citation Index Expanded; International Web of Science; CINAHL; LILACS; Chinese Biomedical Literature Database (up
to November 2006); and contacted authors and manufacturers in the included all randomized clinical trials, irrespective of
blinding or language, that compared AT III with no interventio
in critically ill patients. The primary outcome measure was mortality. These investigators each independently abst and
resolved any disagreements by discussion. They presented pooled estimates of the intervention effects on di outcomes as
relative risks (RR) with 95 % CI; performed subgroup analyses to assess risk of bias, the effect of AT different populations
(sepsis, trauma, obstetric, and pediatric patients), and the effect of AT III in patients with or wi use of concomitant heparin.
They assessed the adequacy of the available number of participants and performed a sequential analysis to establish the
implications for further research. These researchers included 20 randomized t total of 3,458 participants; 13 of these trials
had high risk of bias. When they combined all trials, AT III did not stati significantly reduce overall mortality compared with
the control group (RR 0.96, 95 % CI: 0.89 to 1.03; no heteroge between trials). A total of 32 subgroup and sensitivity analyses
were carried out. Analyses based on risk of bias, d populations, and the role of adjuvant heparin gave insignificant
differences. Anti-thrombin III reduced the multi-org score among survivors in an analysis involving very few patients. It
increased bleeding events (RR 1.52, 95 % CI:
1.78). The authors concluded that AT III can not be recommended for critically ill patients based on the available e The
authors stated that a randomized controlled trial of AT III, without adjuvant heparin, with prespecified inclusion good bias
protection is needed.
Anti-inhibitor coagulant complex, factor eight inhibitor bypassing activity-vapor heated (FEIBA VH), is indicated for of
spontaneous bleeding episodes or to cover surgical interventions in hemophilia A and hemophilia B patients with In addition,
the use of FEIBA VH has been described in a few non-hemophiliacs with acquired inhibitors to factors XII.
The development of inhibitory antibodies to factor VIII is a serious complication of hemophilia. Two hemostatic age different
bypassing mechanisms have been used in the treatment of patients with inhibitors: (i) rFVIIa and (ii) activ prothrombin
complex concentrate (APCC). Berntorp (2009) noted that the bypassing agents FEIBA anti-inhibitor c complex and rFVIIa have
been established as safe and effective therapies for treating bleeding episodes in hemop patients with inhibitors. However,
the efficacy of each bypassing agent can vary, and neither agent is universally e The reasons for such variability have yet to be
confirmed, but may involve patient-specific factors and the mechani action and pharmacokinetic profiles of these 2 agents.
Gomperts et al (2008) noted that FEIBA VH and rFVIIa are available to circumvent the need for factor FVIII in hemophilia A
patients with inhibitors, yet their hemostatic efficac
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unpredictable. As the results of the FEIBA NovoSeven study illustrated, patients may respond better to one bypas than the
other. Furthermore, guidelines from an expert panel reflect that responsiveness to bypassing therapy may from one bleed to
the next in the same patient and even from hour to hour during the course of a single bleeding e findings underscored the
need to have both bypassing products available to treat bleeding episodes in inhibitor pat frequently evaluate the efficacy of
hemostasis during the course of a bleeding event, and to switch products early i response to treatment is unsatisfactory.
A cost-effectiveness analysis found that a rFVIIa regimen appears to be a less expensive treatment option in inhibi with minorto-moderate bleeds. Joshi et al (2006) compared the cost-effectiveness of 3 treatment regimens using APCC (FEIBA vapor
heated), for home treatment of minor-to-moderate bleeds in hemophilia patients with inhibitor regimens consisting of 1st-,
2nd-, and 3rd-line treatments were: rFVIIa-rFVIIa-rFVIIa; APCC-rFVIIa-rFVIIa; and APC rFVIIa. Patients not responding to 1stline treatment were administered 2nd-line treatment, and those failing 2nd-li
3rd-line treatment. Using literature and expert opinion, the model structure and base-case inputs were adapted to from a
previously published analysis. The percentage of evaluable bleeds controlled with rFVIIa and APCC were from published
literature. Drug costs (2005 US$) based on average wholesale price were included in the base-cas Uni-variate and
probabilistic sensitivity analyses (2nd-order Monte Carlo simulation) were conducted by varying th
-bleeding rates, patient weight, and dosing to ascertain robustness of the model. In the base-case analysis, the av per
resolved bleed using rFVIIa as 1st-, 2nd-, and 3rd-line treatment was $28,076. Using APCC as 1st-line and rF and 3rd-line
treatment resulted in an average cost per resolved bleed of $30,883, whereas the regimen using APC and 2nd-line, and rFVIIa
as 3rd-line treatment was the most expensive, with an average cost per resolved bleed of Cost offsets occurred for the rFVIIaonly regimen through avoidance of 2nd and 3rd lines of treatment. In probabili sensitivity analyses, the rFVIIa-only strategy
was the least expensive strategy more than 68 % of the time. The au concluded that the management of minor-to-moderate
bleeds extends beyond the initial line of treatment, and shou the economic impact of re-bleeding and failures over multiple
lines of treatment. In the majority of cases, the rFVII regimen appears to be a less expensive treatment option in inhibitor
patients with minor-to-moderate bleeds over 3 treatment.
Steen Carlsson et al (2008) compare cost and outcome of APCC and rFVIIa in the treatment of joint bleeds. The a were based
on the FENOC (FEIBA NovoSeven Comparative Study) cross-over study where 48 patients used APC rFVIIa to treat 2 joint
bleeds. Incremental cost-effectiveness ratios were calculated for 3 outcome measures and th in cost was analyzed using 2
alternative regression methods. Results were subjected to sensitivity analyses. Key determinants of cost were prescribed
dose, body weight and treatment in addition to protocol. The cost of APCC w average lower than rFVIIa. At all but one timepoint, patients rated slightly higher (but not statistically significantly) percentages of treatment efficacy and stopping of the
bleed by APCC. The reported reduction in pain from start of up to 48 hours varied considerably among individuals. The
different relative prices in the U.S., Turkey and Sweden but did not reverse the main results. The authors concluded that the
cost per episode was significantly lower for A large individual-level variation in reduction of pain supports decisions that
consider the individual patient's experien accept trade-offs between cost and reduction in pain rather than focusing on cost
only.
In an unified Bayesian meta-regression model, Treur et al (2009) analyzed the published efficacy of rFVIIa and/or A
-demand treatments for joint bleeds in hemophilia patients with inhibitors. A systematic search was carried out to i studies
reporting on dosage and efficacy of rFVIIa and APCC in the treatment of joint bleeds in the target patient p Data were
abstracted and included in the model and adjusted for potential sources of heterogeneity. Pooled effica typical rFVIIa and
APCC regimens were estimated. A total fo 17 studies, collectively reporting on more than 2,000 bleeds, were included.
Medication type combined with dosage was the only significant explanatory parameter. Th predicts that a typical regimen of
90 microg kg(-1) rFVII repeated every 3 hours if needed results in cumulative join resolution of 66 %, 88 % and 95 % after 12,
24 and 36 hours, respectively. In comparison, a typical regimen of 75
APCC repeated every 12 hours if needed results in cumulative joint bleed resolution of 39 %, 62 % and 76 %, resp These
differences were statistically significant and were also robust in sensitivity analyses. This analysis suggeste typical rFVIIa
regimen will resolve joint bleeds more effectively than a typical APCC regimen after 12, 24 and 36 ho
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Congenital factor XIII deficiency is rare and affects 1 out of every 3 to 5 million people in the United States. It is as with a
tendency for severe bleeding, a risk for spontaneous abortion, and a high rate of spontaneous intra-cranial hemorrhage. The
clinical severity of this deficiency requires regular prophylaxis from the time of diagnosis. Accor replacement material can be
infused at intervals as long as every 20 to 30 days. Three types of factor XIII-contain are available: fresh-frozen plasma (FFP;
preferably virus-inactivated), cryoprecipitate, and a pasteurized plasma co (Fibrogammin-P, Dade-Behring). The pasteurized
concentrate and virus-inactivated FFP, when available, are pref cryoprecipitate (Lovejoy et al, 2006; Mannucci et al, 2010).
On February 17, 2011, the FDA approved Corifact (factor XIII concentrate [Human]), derived from the pooled plasm healthy
donors, via orphan-drug designation for the prevention of bleeding in people with congenital factor XIII defi FDA approved
Corifact based on results of a clinical study of 14 people, including children, with congenital factor X deficiency. The most
common side effects observed were hypersensitivity reactions (allergy, rash, pruritus, and er chills, fever, arthralgia,
headache, elevated thrombin-antithrombin levels, and an increase in hepatic enzymes. It p can cause adverse events from
abnormal clotting if doses higher than the labeled dose are given to patients.
The U.S. Food and Drug Administration approved recombinant coagulation factor XIII A-subunit (Tretten, Novo No use in the
routine prevention of bleeding in adults and children who have a congenital Factor XIII A-subunit deficie received orphan-drug
designation for this use by the FDA because it is intended for treatment of a rare disease or condition. Congenital Factor XIII
deficiency is a rare genetic disorder. Factor XIII is composed of two subunits, A an XIII deficiency is usually caused by a
deficiency of the A-subunit.
Tretten is a recombinant analogue of the human Factor XIII A-subunit that is produced in yeast cells and then furth It is a
sterile freeze-dried-powder to be reconstituted with diluent and injected intravenously. Tretten can be admini physician or
be self-administered. The effectiveness of coagulation factor XIII A-subunit was studied in 77 patients congenital Factor XIII Asubunit deficiency. The study found that coagulation factor XIII A-subunit was effective in p bleeding in 90 percent of the
patients when given monthly. Among the side effects reported in this study were hea in the extremities and pain at injection
site. No individual in the trial developed abnormal clots.
The FDA-approved labeling for Tretten states that the dose for routine prophylaxis for bleeding in patients with con factor XIII
(FXIII) A-subunit deficiency is 35 international units (IU) per kilogram body weight once monthly to achiev trough level of FXIII
activity at or above 10% using a validated assay. The labeling states that dose adjustment sho considered if adequate
coverage is not achieved with the recommended 35 IU/kg dose.
Logan et al (2011) stated that rFVIIa is increasingly used for off-label indications. In a retrospective database analy
investigators estimated patterns of off-label rFVIIa use in U.S. hospitals. Data were extracted from the Premier Pe database
(Premier, Charlotte, NC), which contains discharge records from a sample of academic and non-academ hospitals. A total of
12,644 hospitalizations for patients who received rFVIIa during a hospital stay were analyzed. diagnoses and patient
dispositions from 1 January 2000 to 31 December 2008 were reviewed. Statistical weights f hospital were used to provide
national estimates of rFVIIa use. From 2000 to 2008, off-label use of rFVIIa in hospi increased more than 140-fold, such that
in 2008, 97 % (95 % CI: 96 % to 98 %) of 18,311 in-hospital uses were off contrast, in-hospital use for hemophilia increased
less than 4-fold and accounted for 2.7 % (CI: 1.9 % to 3.5 %) of u
2008. Adult and pediatric cardiovascular surgery (29 % CI: 21 % to 33 %), body and brain trauma (29 % CI: 19 % and
intracranial hemorrhage (11 % CI: 7.7 % to 14 %) were the most common indications for rFVIIa use. Across a indications, inhospital mortality was 27 % (CI: 19 % to 34 %) and 43 % (CI: 26 % to 59 %) of patients were discha home. The authors
concluded that off-label use of rFVIIa in the hospital setting far exceeds use for approved indic These patterns raise concern
about the application of rFVIIa to conditions for which strong supporting evidence is l
Yank et al (2011) evaluated the benefits and harms of rFVIIa use for 5 off-label, in-hospital indications: (i) cardiac s ICH, (iii)
liver transplantation, (iv) prostatectomy, and (v) trauma. A total of 10 databases (including PubMed, EMBA the Cochrane
Library) queried from inception through December 2010. Articles published in English were analyzed reviewers independently
screened titles and abstracts to identify clinical use of rFVIIa for the selected indications a
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all randomized, controlled trials (RCTs) and observational studies for full-text review. Two reviewers independently study
characteristics and rated study quality and indication-wide strength of evidence. A total of 16 RCTs, 26 com observational
studies, and 22 non-comparative observational studies met inclusion criteria. Identified comparators limited to placebo
(RCTs) or usual care (observational studies). For ICH, mortality was not improved with rFVIIa u range of doses. Arterial
thrombo-embolism was increased with medium-dose rFVIIa use (risk difference [RD], 0.03
0.01 to 0.06]) and high-dose rFVIIa use (RD, 0.06 [CI: 0.01 to 0.11]). For adult cardiac surgery, there was no mort difference,
but there was an increased risk for thrombo-embolism (RD, 0.05 [CI: 0.01 to 0.10]) with rFVIIa. For bod there were no
differences in mortality or thrombo-embolism, but there was a reduced risk for the acute respiratory syndrome (RD, -0.05 [CI:
-0.02 to -0.08]). Mortality was higher in observational studies than in RCTs. The authors that limited available evidence for 5
off-label indications suggested no mortality reduction with rFVIIa use. For som indications, it increases thrombo-embolism.
In an editorial that accompanied the afore-mentioned studies, Avorn and Kesselheim (2011) stated that overall, Ya workers
found no evidence that rFVIIa reduced mortality for any off-label use; however, it did increase the risk for t embolism. Their
findings are compatible with other recent studies. The editorialists noted that "[a]llowing physicia to choose medications is
appealing, but not when it results in unhelpful, dangerous, and costly decisions. With suc compelling data in place about the
runaway use, uselessness, and risk for this expensive treatment, what can be d reduce it? First, if evidence should emerge
that the manufacturer played a role in building a market for the unautho increasingly implausible prescribing of its product,
both civil and criminal responses will probably be brought to bea occurred for many other instances of corporate-sponsored
drug misuse. Second, rFVIIa is used in hospitals, which providing organizational oversight to protect patients, as well as the
institutions’ own pharmacy budgets. In hospit such use continues, existing quality assurance, patient safety, and riskmanagement groups will surely want to look these practices. Although off-label prescribing by physicians is not illegal,
physicians who persist in such use in th clear evidence of inutility and harm could be subject to civil action by the affected
patients or their heirs".
Koncar et al (2011) examined the influence of rFVIIa on the treatment of intractable peri-operative bleeding in vasc when
conventional hemostatic measures are inadequate. There were 2 groups of patients: the NovoSeven group
10 patients with ruptured abdominal aortic aneurysms (RAAAs) and 14 patients operated on due to thoraco-abdom
aneurysms (TAAAs); the control group (group C), 14 patients with RAAAs and 17 patients with TAAAs. All patient intractable
hemorrhage refractory to conventional hemostatic measures, while patients from group N were addition with rFVIIa. Postoperative blood loss was significantly lower in group N treated with rFVII (p < 0.0001). Post-oper administration of packed
red blood cells, fresh frozen plasma, and platelets was lower in patients from group N, (p Successful hemorrhage arrest was
reported in 21 patients (87.5 %) treated with rFVIIa, and in 9 patients (29.03 %) (p < 0.001). Thirty-day mortality in these 2
groups significantly differed. The mortality rate was 12.5 % (3 patients) and 80.65 % (25 patients) in group C (p < 0.0001).
The authors concluded that these findings suggested that rFVI a role in controlling the intractable peri-operative and postoperative bleeding in surgical patients undergoing a rep RAAAs and TAAAs. They stated that prospective randomized trials
are necessary to further confirm the efficacy a effectiveness of rFVIIa in these patients.
Witmer et al (2011) described the off-label use of rFVIIa in tertiary care pediatric hospitals across the United States assess
thrombotic events. A retrospective multi-center cohort study using the Pediatric Health Information System administrative
database was performed. Children 18 years of age or younger who received rFVIIa between 2000 a were included. A label
admission was defined as an admission with an International Classification of Diseases dia code for hemophilia or factor VII
deficiency; admissions without these codes were classified as off-label. There we rFVIIa admissions, representing 3,764
individual subjects; 74 % (3,655) of the admissions were off-label. There wa increase in the annual rate of off-label admissions
from 2000 to 2007 (from 2 to 20.8 per 10,000 hospital admissio
0.001). The mortality rate in the off-label group was 34 % (1,258/3,655). Thrombotic events occurred in 10.9 % (3 the offlabel admissions. The authors concluded that off-label use of rFVIIa in hospitalized children is increasing ra despite the
absence of adequate clinical trials demonstrating safety and efficacy. Thrombotic events are common mortality is high
among patients receiving off-label rFVIIa. They stated that further studies are warranted to determ these adverse events are
attributable to rFVIIa.
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In a Cochrane review, Lin et al (2011) evaluated the effectiveness of rFVIIa when used therapeutically to control ac bleeding,
or prophylactically to prevent (excessive) bleeding in patients without hemophilia. These investigators se Cochrane Injuries
Group Specialized Register, CENTRAL, MEDLINE, EMBASE and other specialized databases u February 2009. Randomized
controlled trials comparing rFVIIa with placebo, or one dose of rFVIIa with another, i population (except hemophilia) were
included in this study. Outcomes were mortality, blood loss or control of bleed transfusion requirements, number of patients
transfused and thrombo-embolic adverse events. Two authors indep assessed potentially relevant studies for inclusion,
extracted data and examined risk of bias. They considered prop and therapeutic rFVIIa studies separately. A total of 25 RCTs
were included: 24 were placebo-controlled double-b and 1 compared different doses of rFVIIa. Fourteen trials involving 1,137
participants examined the prophylactic u
713 received rFVIIa. There was no evidence of mortality benefit (RR 1.06; 95 % CI: 0.50 to 2.24). There was decr blood loss
(WMD -272 ml; 95 % CI: -399 to -146) and decreased red cell transfusion requirements (WMD -243 ml;
393 to -92) with rFVIIa treatment; however these values were likely over-estimated due to the inability to incorporat trials
showing no difference of rFVIIa treatment compared to placebo. There was a trend in favor of rFVIIa in the n participants
transfused (RR 0.91; 95 % CI: 0.82 to 1.02). But there was a trend against rFVIIa with respect to thro adverse events (RR 1.32;
95 % CI: 0.84 to 2.06). Eleven trials involving 2,366 participants examined the therapeu rFVIIa; 1,507 received rFVIIa. There
were no outcomes where any observed advantage, or disadvantage, of rFVII placebo could not have been observed by chance
alone. There was a trend in favor of rFVIIa for reducing mortality
95 % CI: 0.77 to 1.03). However, there was a trend against rFVIIa for increased thrombo-embolic adverse events
5% CI: 0.93 to 1.58). The authors concluded that the effectiveness of rFVIIa as a more general hemostatic drug, e
prophylactically or therapeutically, remains unproven.
They stated that the use of rFVIIa outside its current license
indications should be restricted to clinical trials.
Wilate is a human plasma-derived, sterile, purified, double virus inactivated von Willebrand factor/coagulation facto Complex
(human). It is indicated for the treatment of spontaneous and/or trauma-induced bleeding episodes in ind with severe von
Willebrand disease (VWD) or individuals with mild or moderate VWD when there is failure, contrai intolerance to
desmopressin. It is not indicated for individuals with hemophilia A; and for the prophylaxis of sponta bleeding episodes, or the
prevention of excessive bleeding during and after surgery in individuals with VWD. The m common adverse reactions to
treatment with Wilate in patients with VWD have been urticaria and dizziness. The adverse reactions to treatment with Wilate
in patients with VWD have been hypersensitivity reactions.
An UpToDate review on “Factor VIII and factor IX inhibitors in patients with hemophilia” (Hoots and Shapiro, 2012a mention
the use of von Willebrand factor/coagulation factor VIII complex (Wilate). Moreover, an UpToDate review “Treatment of
hemophilia” (Hoots and Shapiro, 2012b) states that “Humate P, one of these products, contains both and von Willebrand
factor, and is mainly used for the treatment of von Willebrand disease. It is not a preferred age treatment of patients with
hemophilia A who do not have inhibitors”.
Franchini et al (2013) summarized the current knowledge on treatment strategies for hemophilia B, focusing on rec FIX (rFIX)
products either clinically used or in development. There is only 1 rFIX product that is licensed to treat he patients. From the
analysis of the literature data presented in this review, the authors concluded that this rFIX pro demonstrated an excellent
safety profile and excellent clinical effectiveness for halting and preventing bleeds in he patients. While prophylaxis has
emerged as the best therapeutic strategy for such patients because of its ability to hemophilic arthropathy, and to improve
patients' quality of life, the pharmacokinetically tailored dosing of rFIX is an point when planning hemophilia B treatment, as
it allows optimization of the factor concentrate usage.
Windyga et al (2014) stated that BAX326 is a rFIX manufactured without the addition of any materials of human or origin, and
with 2 viral inactivation steps (solvent/detergent treatment and 15 nm nano-filtration). The aim of this pr trial was to
investigate the pharmacokinetics, hemostatic efficacy and safety of BAX326 in previously treated patie to 65 years with
severe or moderately severe hemophilia B. BAX326 was safe and well-tolerated in all 73 treated s adverse events considered
related to treatment (2.7 % incidence, all non-serious) were transient and mild, and no hypersensitivity reactions, inhibitor
formation or thrombotic events were observed. Pharmacokinetic (PK) equivale between BAX326 and a licensed rFIX was
confirmed in terms of the ratio of geometric mean AUC0-72 h per dose.
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weekly prophylaxis [mean duration 6.2 (+/- 0.7) months; 1.8 (+/- 0.1) infusions per week, 49.5 (+/- 4.8) IU kg-1 per was
effective in preventing bleeding episodes, with a significantly lower (79 %, p < 0.001) annualized bleed rate (4 compared to an
on-demand treatment in a historical control group (20.0); 24 of 56 subjects on prophylaxis (43 %) d throughout the study
observation period. Of 249 total acute bleeds, 211 (84.7 %) were controlled with 1 to 2 infusi BAX326. Hemostatic efficacy at
resolution of bleed was rated excellent or good in 96.0 % of all treated bleeding ep The authors concluded that these findings
indicated that BAX326 is safe and effectives in treating bleeds and routi prophylaxis in patients aged 12 years and older with
hemophilia B.
On June 27, 2013, the FDA approved Rixubis [Coagulation Factor IX (Recombinant)] for use in people with hemop are 16 years
of age and older. Rixubis is indicated for the control and prevention of bleeding episodes, peri-operat extending from the
time of hospitalization for surgery to the time of discharge) management, and routine use to pre reduce the frequency of
bleeding episodes (prophylaxis). Rixubis is a purified protein produced by recombinant DN technology. It does not contain
human or animal proteins. It is supplied in single-use vials of freeze-dried powder administered by intravenous injection after
reconstitution with sterile water for injection. When used for the routine of bleeding episodes, it is administered twiceweekly. The effectiveness of Rixubis was evaluated in a multi-center which a total of 73 male patients between 12 and 65
years of age received Rixubis for routine prophylaxis or as ne response to symptoms of bleeding (on-demand). Overall,
patients in the prophylaxis study had a 75 % lower annu rate when compared to patients who have historically received ondemand treatment. An additional study in a ped population is currently ongoing. Although serious side effects including
anaphylaxis can occur, the most common observed in patients in clinical studies were dysgeusia, pain in an extremity, and
atypical blood test results.
An UpToDate review on “Treatment of hemophilia” (Hoots, 2013) states that “Recombinant human factor IX has be
genetically engineered by insertion of the human factor IX gene into a Chinese hamster ovary cell line. It has been be safe
and effective in the treatment of patients with previously treated and previously untreated hemophilia B, wit of 16 to 17
hours. The product has no added albumin, giving it a theoretical advantage over plasma-derived conce The volume of
distribution of recombinant factor IX is larger than that for plasma-derived factor IX, with a more pron increase in infants and
children. Available products include BeneFIX and Rixubis, which was licensed by the US F Drug Administration in 2013”.
The U.S. Food and Drug Administration approved Alprolix (Biogen Idec, Cambridge, MA), Coagulation Factor IX
(Recombinant), Fc Fusion Protein, for use in adults and children who have hemophilia B to help control and preven episodes,
manage bleeding during surgical procedures, and prevent or reduce the frequency of bleeding episodes (prophylaxis). Alprolix
is designed to require less frequent injections when used to prevent or reduce the frequency Alprolix consists of the Factor IX
molecule linked to a protein fragment, Fc, to make the product last longer in circul Alprolix received orphan-drug designation
for this use by the FDA because it is intended for treatment of a rare dis condition.
The safety and efficacy of Alprolix were evaluated in a multi-center clinical trial that compared each of two prophyla
treatment regimens to on-demand treatment. Powell, et al. (2013) conducted a phase 3, nonrandomized, open-lab the
safety, efficacy, and pharmacokinetics of Alprolix for prophylaxis, treatment of bleeding, and perioperative hem
123 previously treated male patients. All participants were 12 years of age or older and had severe hemophilia B (e factor IX
level of ≤2 IU per deciliter, or ≤2% of normal levels). The study included four treatment groups: group 1 re weekly doseadjusted prophylaxis (50 IU of Alprolix per kilogram of body weight to start), group 2 received interval- prophylaxis (100 IU
per kilogram every 10 days to start), group 3 received treatment as needed for bleeding episod
100 IU per kilogram), and group 4 received treatment in the perioperative period. A subgroup of group 1 underwen
comparative sequential pharmacokinetic assessments of recombinant factor IX and Alprolix. The primary efficacy was the
annualized bleeding rate, and safety end points included the development of inhibitors and adverse events compared with
recombinant factor IX, Alprolix exhibited a prolonged terminal half-life (82.1 hours) (P<0.001). The annualized bleeding rates
in groups 1, 2, and 3 were 3.0, 1.4, and 17.7, respectively. In group 2, 53.8% of participa dosing intervals of 14 days or more
during the last 3 months of the study. In groups 1, 2 and 3, 90.4% of bleeding resolved after one injection. Hemostasis was
rated as excellent or good during all major surgeries. No inhibitors w
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detected in any participants receiving Alprolix; in groups 1, 2, and 3, 73.9% of participants had at least one adverse serious
adverse events occurred in 10.9% of participants. These events were mostly consistent with those expecte general population
of patients with hemophilia. The authors concluded that prophylactic Alprolix, administered ever weeks, resulted in low
annualized bleeding rates in patients with hemophilia B.
One IU of Alprilox per kg body weight increases the circulating level of Factor IX by 1%. The recommended dose f prophylaxis
is 50 IU/kg once weekly or 100 IU/kg once every 10 days, with dosing regimen adjusted based upon in response. For control
of minor and moderate bleeding episodes (for example, uncomplicated hemarthoses, superf bleeding (except iliopsoas)
without neurovascular compromise, superficial soft tissue bleeding, bleeding of mucous membranes) requires a circulating
factor IX level of 30 to 60 IU/dL or 30 to 60 percent of normal). For control of ma (for example, iliopsoas and deep muscle
bleeding with neurovascular injury, or substantial blood loss; pharyngea, retropharyngeal, retroperitoneal or CNS bleeding)
requires a circulating factor IX level of 80 to 100 IU/dL or 80 to 1 of normal. For minor surgery (including uncomplicated
dental extraction), the required circulating Factor IX level is IU/dL or 50 to 80% normal. For major surgery, the required
circulating Factor IX level is 60 to 100 IU/dL or 60 to 10 normal.
Patients receiving chronic anti-coagulation therapy with warfarin and other vitamin K antagonist (VKA) anti-coagula prevent
blood clotting in conditions such as atrial fibrillation or the presence of an artificial heart valve sometimes d acute bleeding.
Hickey et al (2013) determined adverse event frequency after urgent reversal with frozen plasma v prothrombin complex
concentrate (PCC) -- Octaplex. This natural before-after retrospective cohort study in 2 tertia emergency departments
compared anti-coagulation reversal with frozen plasma (September 2006 to August 2008) Octaplex (September 2008 to
August 2010), without other system changes. These researchers included adult pat warfarin with an international normalized
ratio (INR) of greater than or equal to 1.5 who received frozen plasma or O The primary outcome was serious adverse events
(death, ischemic stroke, myocardial infarction, heart failure, ven thromboembolism, or peripheral arterial thromboembolism)
within 7 days. Secondary outcomes included time to IN hospital length of stay, and red blood cells transfused within 48 hours.
They included 149 patients receiving frozen and 165 receiving Octaplex. The incidence of serious adverse events for the frozen
plasma group was 19.5 % com
9.7 % for the Octaplex group (p = 0.014; relative risk, 2.0; 95 % CI: 1.1 to 3.5). This remained significant after adju baseline
history and reason for treatment (p = 0.038; adjusted relative risk, 1.85; 95 % CI: 1.03 to 3.3) in multi-varia regression analysis.
Median INR reversal was 11.8 hours with frozen plasma and 5.7 hours with Octaplex (p < 0.0 red cell transfusion was 3.2 with
frozen plasma and 1.4 with Octaplex (p < 0.0001). The authors concluded that Oc urgent reversal of warfarin resulted in
faster reversal and lower red cell transfusion requirement with fewer adverse than frozen plasma.
Hanke et al (2013) noted that the rapid reversal of the effects of VKA is often required in cases of emergency surge
threatening bleeding, or during bleeding associated with high morbidity and mortality such as intra-cranial hemorrh
Increasingly, 4-factor PCCs (4F-PCC) containing high and well-balanced concentrations of vitamin K-dependent c factors are
recommended for emergency oral anti-coagulation reversal. Both the safety and effectiveness of such are currently in focus,
and their administration is now expanding into the critical care setting for the treatment of life bleeding and coagulopathy
resulting either peri-operatively or in cases of acute trauma. After 15 years of clinical u of a pharmaco-vigilance report
(February 1996 to March 2012) relating to the 4F-PCC Beriplex P/N (CSL Behring, Germany) were analyzed and were
presented here. Furthermore, a review of the literature with regard to the safet effectiveness of 4F-PCCs was performed.
Since receiving marketing authorization (February 21, 1996), approxima
647,250 standard applications of Beriplex P/N have taken place. During this time, 21 thromboembolic events judg possibly
related to Beriplex P/N administration have been reported, while no incidences of viral transmission or hep induced
thrombocytopenia were documented. The low risk of thromboembolic events reported during the observa (1 in
approximately 31,000) is in line with the incidence observed with other 4F-PCCs. The authors concluded that
4F-PCCs have proven to be well-tolerated and highly effective in the rapid reversal of VKA.
Sarode et al (2013) performed a prospective clinical trial to compare non-activated 4F-PCC with plasma for urgent reversal.
In this phase IIIb, multi-center, open-label, non-inferiority trial, non-surgical patients were randomized to
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(containing coagulation factors II, VII, IX, and X and proteins C and S) or plasma. Primary analyses examined whe PCC was
non-inferior to plasma for the co-primary end-points of 24-hour hemostatic efficacy from start of infusion correction (less
than or equal to 1.3) at 0.5 hour after end of infusion. The intention-to-treat efficacy population com patients (4F-PCC, n = 98;
plasma, n = 104). Median (range) baseline INR was 3.90 (1.8 to 20.0) for the 4F-PCC g
3.60 (1.9 to 38.9) for the plasma group. Effective hemostasis was achieved in 72.4 % of patients receiving 4F-PC
65.4 % receiving plasma, demonstrating non-inferiority (difference, 7.1 % [95 % CI: -5.8 to 19.9]). Rapid INR reduc achieved in
62.2 % of patients receiving 4F-PCC versus 9.6 % receiving plasma, demonstrating 4F-PCC superiorit (difference, 52.6 % [95 %
CI: 39.4 to 65.9]). Assessed coagulation factors were higher in the 4F-PCC group than i plasma group from 0.5 to 3 hours after
infusion start (p < 0.02). The safety profile (adverse events, serious advers thromboembolic events, and deaths) was similar
between groups; 66 of 103 (4F-PCC group) and 71 of 109 (plasm patients experienced greater than or equal to 1 adverse
event. The authors concluded that 4F-PCC is an effective to plasma for urgent reversal of VKA therapy in major bleeding
events, as demonstrated by clinical assessments of and laboratory measurements of INR and factor levels.
On April 29, 2013, the FDA approved Kcentra (prothrombin complex concentrate, human) for the urgent reversal o
coagulation factor deficiency induced by VKA (e.g., warfarin) therapy in adult patients with acute major bleeding. K not
indicated for urgent reversal of VKA anti-coagulation in patients without acute major bleeding. The FDA approv Kcentra was
based on a study of 216 patients who had been receiving VKA anti-coagulation and who had acute m bleeding along with a
clotting test value indicative of anti-coagulant use. Kcentra was demonstrated to be similar t terms of the ability to stop acute
major bleeding. Kcentra is made from the pooled plasma of healthy donors. It is p in a way to minimize the risk of
transmitting viral and other diseases.
Ferreira and DeLosSantos (2013) stated that PCC is an inactivated concentrate of factors II, IX, and X, with variab of factor VII.
Guidelines recommend the use of PCC in the setting of life-threatening bleeds, but little is known on t effective dosing
strategies and how the presenting international normalized ratio affects response to therapy. Thes investigators high-lighted
available data on monitoring techniques, address shortcomings of currently available dat reversal of life-threatening and
critical bleeds with PCC, and how this product compares to other therapeutic option critically ill patients. Prothrombin
complex concentrate has been identified as a potential therapy for critically bleed but patient-specific factors, product
availability, and current data should weigh the decision to use it. Most data exi patients experiencing VKA-induced bleeding,
more specifically, those with intra-cranial hemorrhage. Prothrombin c concentrate has also been studied in trauma-induced
hemorrhage; however, it remains controversial, as its potenti have the abilities to become flaws in this setting. The authors
concluded that health care professionals must rema the differences in products and interpret how 3- versus 4-factor products
may affect patients, and interpret literatur accordingly. The clinician must be cognizant of how to progress when treating a
bleeding patient, propose a suppo scheme, and address the need for appropriate factor VII supplementation. At this point,
PCC cannot be recomme
-line therapy in patients with traumatic hemorrhage, and should be reserved for refractory bleeding until more data
available.
The National Institute for Health and Clinical Excellence’s clinical guideline on “Acute upper gastrointestinal bleedin
Management” (NICE, 2012) recommended PCC to patients who are taking warfarin and actively bleeding.
Dewhirst (2013) performed a short-cut review to establish whether rFVIIa improves survival and functional outcom
spontaneous intracranial hemorrhage. A total of 92 papers were found using the reported searches, of which 2 pre best
evidence to answer the clinical question. The author, date and country of publication, patient group studied, s relevant
outcomes, results and study weaknesses of these best papers were tabulated. The authors concluded tha evidence does not
support the use of rFVIIa in acute spontaneous intracranial hemorrhage.
Awad and Cocchio (2013) stated that PCC products are emerging as alternative strategies for reversing anticoagu
pharmacotherapy. Factor eight inhibitor bypassing activity (FEIBA, or anti-inhibitor coagulant complex) is an activa (aPCC).
Although FEIBA is approved by the FDA to control spontaneous bleeding episodes and to prevent bleedin surgical
interventions in hemophilia A and hemophilia B patients with inhibitors to factor VIII, recent data have sug the product may
be used off-label as an anticoagulant-reversal agent. These researchers evaluated the safety and
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effectiveness of aPCC products in reversing anticoagulant pharmacotherapy. They searched online databases for language
publications that discussed this topic. The EMBASE, MEDLINE, and International Pharmaceutical Abstr databases were used.
These researchers evaluated all articles published in the English language identified from th sources. They included studies
conducted in human subjects and in in-vitro and in-vivo models in this review. Cur published evidence suggested that the use
of an aPCC, compared with fresh-frozen plasma, is associated with a s faster correction of supra-therapeutic INRs secondary
to warfarin therapy. Conflicting evidence exists regarding th aPCCs to reverse the prolonged bleeding times caused by the
anticoagulant agents including dabigatran etexilate rivaroxaban (Xarelto), apixaban (Eliquis), and fondaparinux (Arixtra). The
authors concluded that the theoretical ri thrombosis associated with PCC products must be carefully considered before they
are administered to patients w coagulation therapy. The use of aPCCs to reverse the anticoagulant effects of warfarin,
dabigatran, or rivaroxaban limited because of the lack of safety and effectiveness data in humans. Moreover, the safety of
aPCCs in off-label has not been adequately assessed.
Stewart and Pettit (2013) summarized their experiences with FEIBA for the reversal of warfarin-related bleeding in community
hospital. A protocol was put in place in March of 2011, which outlined the use of FEIBA for the emerge of warfarin-related
coagulopathy. A fixed low-dose was given based on INR. For an INR less than 5.0, 500 U of F administered’ for an INR greater
than or equal to 5.0, 1,000 U of FEIBA was given. Intravenous vitamin K was give concurrently regardless of INR. A total of 16
patients were treated with FEIBA per the protocol. Average patient a years. Intracranial hemorrhage was the most common
indication for reversal. Mean pre-treatment INR was 3.56 ( mean post-treatment INR was 1.16 (1.01 to 1.32). Two of the
patients required a second 500-U dose, per the proto INR that had not yet normalized. Bleeding appeared clinically controlled
in 93 % of cases; 87 % of patients survive discharge. There were no signs or symptoms of thrombosis in any of the cases. The
authors concluded that emer reversal of warfarin utilizing a fixed low-dose of FEIBA appears to be effective, consistent, and
safe. Moreover, th that further comparator studies with other reversal agents are needed.
Cabral and colleagues (2013) evaluated the safety and effectiveness of a PCC-based protocol in patients with warf associated
ICH, sub-dural hematoma (SDH), or sub-arachnoid hemorrhage (SAH). This was a retrospective case- review of patients
treated with an institution-approved warfarin reversal protocol. Patients with ICH and known war with an INR greater than
1.4 received FFP, vitamin K (phytonadione), and weight-based, 3-factor PCC (Profilnine( based on the initial INR.
Demographic and clinical information, the degree of and time to INR normalization, and a events were recorded. The 30
study patients included 19 with primary ICH, 7 with SDH, and 4 with SAH. The me
72.8 (± 11) years, including 11 (37 %) patients greater than or equal to 80 years old. The median presenting INR w
(IQR 2 to 3.3) and post-treatment INR was 1.4 (IQR 1.3 to 1.5, Z score 6.4, p < 0.001). Median time from PCC ad
to the first follow-up INR was 95 (IQR 50 to 140) mins. No patient's INR increased by more than 0.3 over 72 hrs. N patients
(30 %) underwent neurosurgical procedures after PCC administration and no procedure-related bleeding was noted. Adverse
events included 3 instances of early hematoma expansion, 1 ischemic stroke in a patient with endocarditis on post-PCC day 1,
1 pulmonary embolism 5 weeks after PCC treatment, and 1 coronary in-stent thro days after PCC treatment. Six patients died
prior to hospital discharge of anticipated complications of their initial e none from identifiable thrombotic complications of
PCC. The authors concluded that a 3-factor PCC preparation ( SD), administered with FFP and vitamin K to patients with acute
warfarin-associated intracranial bleeding is a reas approach to urgent warfarin reversal. Moreover, they stated that
randomized, prospective trials are needed to verif and clinical effectiveness of PCC administration in this population.
Song et al (2013) reported their initial experience with the PCC FEIBA for the rescue treatment of coagulopathy an threatening
bleeding after cardiac surgery. A total of 25 patients who underwent cardiac surgery with coagulopath threatening bleeding
refractory to conventional treatment received FEIBA as rescue therapy at the authors’ instituti cohort represented
approximately 2 % of patients undergoing cardiac surgery in the authors’ university-based prac the study. The patients were
at high risk for post-operative coagulopathy with nearly all patients having at least 2 r for this. Aortic root replacement
(Bentall or valve-sparing procedure) and heart transplant with or without left ventri device explant were the most common
procedures. The mean FEIBA dose was 2,154 units. The need for fresh fro and platelet transfusion decreased significantly
after FEIBA administration (p = 0.0001 and p < 0.0001). The mean
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decreased from 1.58 to 1.13 (p < 0.0001). Clinical outcomes were excellent. No patient returned to the operating
exploration. There was no hospital mortality and all patients were discharged home. One patient who had a centra transvenous pacemaker developed an upper extremity DVT. The authors concluded that their initial experience w administration
for the rescue treatment of post-operative coagulopathy and life-threatening bleeding has been favo Moreover, they stated
that further studies are indicated to confirm its safety and effectiveness; and determine spe indications for its use in patients
undergoing cardiac surgery.
The U.S. Food and Drug Administration (FDA) has approved Eloctate [Antihemophilic Factor (Recombinant), Fc Fu Protein] for
the control and prevention of bleeding episodes, perioperative (surgical) management and routine prop adults and children
with hemophilia A (Biogen Idec, 2014). Eloctate reduces the frequency of bleeding episodes wi prophylactic infusions every
three to five days, offering people with hemophilia A the potential to extend the interva prophylactic infusions. Eloctate was
developed by fusing B-domain deleted factor VIII to the Fc portion of immunog subclass 1 (IgG1) which enables Eloctate to
prolong the time the therapy remains in the body.
The recommended starting prophylactic regimen for Eloctate is 50 IU/kg every four days. Based on clinical respon regimen
may be adjusted in the range of 25 to 65 IU/kg and every three to five days (Biogen Idec., 2014).
In clinical trials, Eloctate was effective for both routine prophylaxis and to treat acute bleeding episodes with a favo and
tolerability profile (Biogen Idec, 2014). The approval of Eloctate is based on results from the global, Phase 3 A clinical study, as
well as interim pharmacokinetic and safety data from the Phase 3 Kids A-LONG study.
The A-LONG study was an open-label, multi-center study that examined the efficacy, safety and pharmacokinetics in 165
previously treated males 12 years of age and older with severe hemophilia A (Biogen Idec, 2014). Results s adults and
adolescents with severe hemophilia A achieved a statistically significant reduction of bleeding episodes the study’s
prophylaxis arms, relative to the on-demand treatment arm. In addition, 98 percent of bleeding episode controlled with one
or two Elocttate infusions.
The study evaluated individualized and weekly prophylaxis to reduce or prevent bleeding episodes, and on-deman treat
bleeding episodes (Biogen Idec, 2014). In the individualized arm, each study participant started on a twice-we regimen.
Participants’ pharmacokinetic parameters were used to guide adjustments to dosing interval (every three days), and dose (25
to 65 IU/kg) to target a minimum factor VIII level of 1 to 3 IU/dL or higher as needed to mainta breakthrough bleeding
episodes. In the study, the dose in the weekly prophylaxis arm was 65 IU/ kg/week. The ov annualized bleeding rates (ABR),
or projected number of bleeding episodes per year, reported in the study were 1. individualized prophylaxis arm, 3.6 for the
weekly prophylaxis arm and 33.6 for the on-demand arm.
No participants in the A-LONG study developed inhibitors to Eloctate (Biogen Idec, 2014). One participant had a tra positive
neutralizing antibody test result, which was not confirmed upon repeat testing. There were no reports of se vascular clots or
serious allergic reactions. Across the routine prophylaxis and on-demand therapy arms, adverse r were reported in 5.5
percent of participants. Adverse reactions included arthralgia, malaise, upper abdominal pain, abdominal pain, angiopathy,
bradycardia, chest pain, cough, dizziness, dysgeusia, cold and heat intolerance, head hypertension, joint swelling, myalgia,
procedural hypotension and rash. Each event occurred in two or fewer study Two participants were withdrawn from the study
due to adverse reactions: one participant due to rash and one due arthralgia.
The pediatric indication for Eloctate is supported by interim safety and pharmacokinetic results in 38 boys ages tw old from
the Phase 3 Kids A-LONG study (Biogen Idec, 2014). These data showed that Eloctate was generally wel and no inhibitors were
detected. The relative increase in half-life seen with Eloctate was consistent with findings in adolescents. In comparison with
adolescents and adults, children two to five years old have a shorter half-life and h clearance of hemophilic factors (adjusted
for body weight); therefore, a higher dose or more frequent dosing may b this age group. In April 2014, Biogen Idec and
Swedish Orphan Biovitrum (Sobi) reported positive top-line results fr completed Kids A-LONG study, which confirmed and
expanded upon the interim data. Common adverse reactions of greater than or equal to 1 percent) reported in the A-LONG
study were arthralgia and malaise.
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CPT Codes / HCPCS Codes / ICD-9 Codes
Other CPT codes related to the CPB:
85002
85335
85610 - 85611
85730 - 85732
96365 - 96379
99601
+ 99602
Other HCPCS codes related to the CPB:
S9345
Home infusion therapy, antihemophilic agent infusion therapy (e.g., factor VIII); administ services,
professional pharmacy services, care coordination, and all necessary supplies equipment (drugs
and nursing visits coded separately), per diem
Anti-hemophilic factor (factor VIII), factor IX and Humate-P or Alphanate:
Other CPT codes related to the CPB:
85240
85244
85245
85246
85247
85250
HCPCS codes covered if selection criteria are met:
C9133
Factor ix (antihemophilic factor, recombinant), rixibus, per i.u.
J7180
Injection, factor XIII (antihemophilic factor, human), 1 I.U.
J7183
Injection, Von Willebrand factor complex (human), wilate, 1 I.U. VWF:RCO J7185
Injection, Factor VIII (Antihemophilic Factor, recombinant) (Xyntha), per I.U.
J7186
Injection, antihemophilic factor VIII / von Willebrand factor complex (human), per factor V J7187
Injection, von Willebrand factor complex (Humate-P), per IU vWF-RCO
J7190 - J7192
Hemophilia clotting factor VIII
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Clotting Factors
J7193 - J7195
Hemophilia clotting factor IX
ICD-9 codes covered if selection criteria are met:
286.0
Congenital factor VIII disorder [Hemophilia A]
286.1
Congenital factor IX disorder [Hemophilia B]
286.4
von Willebrand's disease
Recombinant factor VIII Fc fusion protein (Eloctate): No
specific code
ICD-9 codes covered if selection criteria are met:
286.0
Congenital factor VIII disorder [Hemophilia A]
Recombinant factor VIIa (rFVIIa, NovoSeven):
Other CPT codes related to the CPB:
85230
HCPCS codes covered if selection criteria are met:
J7189
Factor VIIa (antihemophilic factor, recombinant) per 1 mcg
Q2023
Injection, factor viii (antihemophilic factor, recombinant) (Xyntha), per i.u.
ICD-9 codes covered if selection criteria are met:
286.0
Congenital factor VIII disorder [Hemophilia A]
286.1
Congenital factor IX disorder [Hemophilia B]
286.3
Congenital deficiency of other clotting factors
286.52
Acquired hemophilia
287.1
Qualitative platelet defects [Glanzmann's thrombasthenia with antibodies to glycoprotein
and/or human leukocyte antigen (HLA), refractory to platelet infusions]
ICD-9 codes not covered for indications listed in the CPB:
411.1
Intermediate coronary syndrome
411.81
Acute coronary occlusion without myocardial infarction
430 - 438.9
Cerebrovascular disease [including treatment of acute spontaneous intracerebral hemo
unrelated to hemophilia]
456.0 - 456.21
Esophageal varices
555.0 - 555.9
Regional enteritis [Crohn's disease]
800.00 - 804.99
Fracture of skull [with intracranial bleeding]
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850.00 - 854.19
Intracranial injury, excluding those with skull fracture [with intracranial bleeding]
998.11
Hemorrhage complicating a procedure [not covered for peri-operative bleeding in vascu as well
as trauma]
Human anti-thrombin III (Thrombate III):
Other CPT codes related to the CPB:
85300
85301
HCPCS codes covered if selection criteria are met:
J7197
Anti-thrombin III (human) [Thrombate III]
ICD-9 codes covered if selection criteria are met:
289.81
Primary hypercoagulable state [anti-thrombin III deficiency] [covered in connection with
embolism, obstetrical procedures, or surgical procedures only]
Recombinant factor IX fc fusion protein (rFIXFc) (Alprolix): No
specific code
ICD-9 codes covered if selection criteria are met:
286.1
Congenital factor IX disorder [Hemophilia B]
Factor VIII inhibitor bypassing activity (FEIBA) anti-inhibitor coagulant complex:
Other HCPCS codes related to the CPB: J7198
Antiinhibitor, per IU
ICD-9 codes covered if selection criteria are met:
286.0
Congenital factor VIII disorder [Hemophilia A]
286.1
Congenital factor IX disorder [Hemophilia B]
286.2
Congenital factor XI deficiency
286.3
Congenital deficiency of other clotting factors [acquired inhibitors to Factors VIII, XII]
964.2
Poisoning by anticoagulants [not for use for reversal of anticoagulant-associated coagu rescue
treatment of coagulopathy after cardiac surgery]
997.1
Cardiac complications [rescue treatment of coagulopathy after cardiac surgery]
ICD-9 codes not covered for indications listed in the CPB:
286.52
Acquired hemophilia [non-hemophiliac persons with acquired inhibitors to factors VIII, X
Corifact (factor XIII concentrate [Human]):
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Clotting Factors
Other CPT codes related to the CPB:
85290
85291
Other HCPCS codes related to the CPB: J7198
Antiinhibitor, per IU
J7199
Hemophilia clotting factor, not otherwise classified
ICD-9 codes covered if selection criteria are met:
286.3
Congenital deficiency of other clotting factors [factor XIII]
Recombinant coagulation factor XIII A-subunit (Tretten): No
specific code
HCPCS codes covered if selection criteria are met:
C9134
Factor XIII (antihemophilic factor, recombinant), Tretten, per 10 I.U.
ICD-9 codes covered if selection criteria are met:
286.3
Congenital deficiency of other clotting factors [congenital factor XIII A-subunit deficiency
von Willebrand factor/coagulation factor VIII complex (Wilate®):
HCPCS codes covered if selection criteria are met:
J7183
Injection, Von Willebrand factor complex (human), wilate, 1 I.U. VWF:RCO
Other HCPCS codes related to the CPB:
J2597
Injection, desmopressin, acetate, per 1 mcg
ICD-9 codes covered if selection criteria are met:
286.0
Congenital factor VIII disorder [not covered for Hemophilia A]
286.4
von Willebrand's disease [not covered for prophylaxis of spontaneous bleeding episode
ICD-9 codes not covered for indications listed in the CPB:
674.30, 674.32, 674.34 Other complication of obstetrical surgical wounds [prevention of excessive bleeding dur after
surgery in individuals with VWD]
998.11
Hemorrhage complicating a procedure [prevention of excessive bleeding during and aft in
individuals with VWD]
Prothrombin complex concentrate (human) (Kcentra):
HCPCS codes covered if selection criteria are met:
C9132
Prothrombin complex concentrate (human), Kcentra, per i.u. of Factor IX activity
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Clotting Factors
ICD-9 codes covered if selection criteria are met:
286.7
Acquired coagulation factor deficiency
E934.2
Anticoagulants causing adverse effect in therapeutic use [e.g. Warfarin therapy]
The above policy is based on the following references:
1. United States Pharmacopeial Convention, Inc. (USPC). USP Dispensing Information. Volume I -- Drug Infor the Health
Care Professional. 18th ed. Rockville, MD: USPC; 1998.
2. Mosby-Year Book, Inc. Mosby's GenRx: The Complete Reference for Generic and Brand Drugs. 8th ed. St. Mosby;
1998.
3. American Society of Health-System Pharmacists, Inc. American Hospital Formulary Service Drug Informatio
Bethesda, MD: American Society of Health-System Pharmacists; 1998.
4. Medical Economics, Inc. Physicians' Desk Reference. 52nd ed. Montvale, NJ: Medical Economics Data Cor
1998.
5. Lusher JM. Considerations for current and future management of haemophilia and its complications. Haemo
1991;1:1-20.
6. DiMichele D. Hemophilia 1996: New approaches to an old disease. Pediatr Clin North Am. 1996;43:709-73
7. Association of Hemophilia Clinic Directors of Canada. Hemophilia and von Willebrand's disease: 1. Diagnos
comprehensive care and assessment. CMAJ. 1995;153:19-25.
8. Bray GL, Comperts ED, Courter S, et al. A multicenter study of recombinant Factor VIII (Recombinate): Saf and
9.
inhibitor risk in previously untreated patients with hemophilia A. Blood. 1994;83:2429-2435.
Nilsson IM, Berntorp E, Löfqvist T, et al. Twenty-five years' experience of prophylactic treatment in severe h
A and B. J Intern Med. 1992;232:25-32.
10.
Carlsson M, Berntorp E, Bjorkman S, et al. Pharmacokinetic dosing in prophylactic treatment of hemophilia
Haematol. 1993;31:247-252.
11.
Brackmann HH, Eickhoff HJ, Oldenburg J, et al. Long-term therapy and on-demand treatment of children an
12.
adolescents with severe haemophilia A: 12 years of experience. Haemostasis. 1992;22:251-258.
Berntorp E, Nilsson IM. Use of a high-purity Factor VIII concentrate (Hemate P) in von Willebrand's disease
1989;56:212-217.
13.
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Clotting Factors
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