The current “love affair” with recombinant factor 7a (rFVIIa) is growing. What started as a replacement therapy for factor 7 deficient patients has now become a near first line therapy for bleeding thought to be refractory. However recognize that the approved indications listed in the package insert only involve patients with hemophilia A and B, acquired hemophilia, and congenital FVII deficiency. The growing list of other uses is “off label.”
Aldouri reviewed the use of rFVIIa for controlling surgical bleeding in non hemophiliac patients (1). In one small open labeled study in post operative cardiac surgery patients, doses of 30 mcg/kg given every three hours for a maximum of four doses or until bleeding was controlled resulted in a marked decrease in blood loss despite prior failure of conventional measures. There have been similar positive results in patients with non cardiac surgical bleeding and in some trauma patients. The first reported use in a trauma patient was with doses of 60 mcg/kg given at hourly intervals.
Bowman et al reported on the use of rFVIIa to control post operative hemorrhage after complex cardiovascular surgery. They performed a retrospective chart review to identify 36 patients who received this drug. The criteria for use included: exclusion of all surgical causes of bleeding, failure to reverse coagulopathy with adequate pharmacologic and blood product replacement, correction of core body temperature to normal, adequate heparin reversal with protamine and chest tube drainage grater than 3 ml/kg/h or more for 2 hours or more. With the most commonly used dose of 90 mcg/kg, bleeding was controlled in 30 of the 36 patients. In 27 patients one dose was sufficient to achieve control.
The early positive experience in the use of rFVIIa led Martinwitz and collaborators (3) to develop dosing guidelines for its use in trauma patients. They suggested a dose (130 mcg/kg) that was about 30% greater than recommended for hemophiliacs. In an initial cohort of 36 patients cessation of bleeding was obtained in 26 (72%). Nine of the ten patients who did not respond exsanguinated in less than 24 hours. More recently Spinella and associates (4) suggested that early use of rFVIIa may decrease 24 hour mortality in combat casualties who required massive transfusion (> 10 units of red blood cells within 24 hours). The rFVIIa protocol called for an initial dose of 120 mcg/kg after the initial 4 – 6 units of RBC in patients with life threatening hemorrhage. The authors conducted a retrospective review of 124 patients 49 of whom received rFVIIa and 75 who did not. Twenty four hour mortality was 14% in the group that received rFVIIa and 35% in those who did not. Thirty day mortality was also significantly better in the treated group. They emphasize that rFVIIa alone is not adequate. They encourage aggressive correction of acidosis and hypocalcemia. They also emphasize the importance of adequate concentrations of platelets, fibrinogen and coagulation factors. Note that the results from combat casualties my not be directly applicable to trauma patients typically seen at HUP. Except for the cardiac surgery literature there is little that I could find that would apply directly to our trauma patients or other patients with uncontrolled intraoperative bleeding. Regardless of the findings in the studies just cited a local protocol calls for a dose of 90 mcg/kg (rounded to the nearest 1.2 mg) infused intravenously for ongoing, non surgical bleeding refractory to conventional therapy. Patients need to meet the following criteria: patients without known coronary artery disease or peripheral vascular disease; transfusion of greater than 10 units of red blood cells with an ongoing requirement and no evidence of surgical bleeding. The dose can be repeated in two hours if bleeding persists. However, Novo Nordisk has just stopped a phase 3 clinical trial of NovoSeven brand rFVIIa in blunt trauma patients. The reason for stopping the trial was an interim analysis that suggested the end point of improved 30 day mortality and morbidity could not be reached because of a much lower than expected mortality in the overall study groups. 535 patients out of a planned 1502 had been enrolled in a 24 country, randomized, double blind, placebo – controlled trial using three single doses of rFVIIa (200 mcg/kg followed by 100 and 100 mcg/kg). A recent review of the use of rFVIIa for the control of bleeding assessed the results of 17 randomized controlled trials (5). Some of the trials used rFVIIa in an attempt to reduce blood loss during surgery with high blood loss. Others were designed to examine the effect of rFVIIa on gastrointestinal bleeding, trauma or intracranial hemorrhage. The authors concluded that, at present, the benefits of rFVIIa to control bleeding have not been demonstrated and that the rate of thrombotic complication may be higher than many anticipated. What is clear from this study are the relatively few well controlled trials that have been done and that enthusiasm may be exceeding evidence.
From the package insert (2008), the risk of thrombotic adverse events is thought to be low. Patients with disseminated intravascular coagulation, advanced atherosclerotic disease, crush injury or septicemia may be at increased risk of developing thrombotic events. The drug is intended for intravenous bolus administration only. NovoSeven Coagulation Factor VIIa is supplied as a white, lyophilized powder. It should be used within three hours after reconstitution. It should be reconstituted using aseptic technique into the provided histidine diluent. The 1 mg vial should be reconstituted in 1.1 ml, and the 5.0 mg vial into 5.2 ml so that the final concentrations are 1.0 mg/ml. Do not inject the diluent directly onto the drug powder. Aim the needle so that the diluent goes down the vial wall. After adding the diluent, gently swirl the vial until all the material is dissolved. The reconstituted solution is clear. For surgery in hemophilia A or B patients the recommended dosing is 90 mcg/kg immediately before surgery and every 2 hours during surgery. After surgery the suggested dosing depends on the type of surgery. For minor procedures dose every 2 hours for 48 hours then every 2 - 6 hours; for major procedures dose every 2 hours for the first five days, then every 4 hours until healing has occurred.
Thrombosis after rFVIIa is of growing concern. O’Connell et al (6) reviewed the FDA adverse event file for the initial five years after drug licensure for US sales and found 431 submissions related to rFVIIa. The reports (N=168) described 185 thromboembolic events. Seventeen of the events occurred in patients with hemophilia while 151 occurred during unlabelled use, mostly for the treatment of active bleeding. The adverse events included cerebrobvascular accidents (N=39), acute myocardial infarction (N=34), other arterial thrombosis (N=26), pulmonary embolism (N=32), other venous thrombosis including DVT (N=42) and clotted devices (N=10). In 36 of 50 reported deaths, the probable cause of death was related to the thromboembolism. There is greater concern about the potential of thrombosis after rFVIIa in patients with implanted devices. Apostolidou et al (7) describes the acute formation of a left atrial thrombus (observed by TEE) within minutes after administration of rFVIIa (90 mcg/kg over 5 min) in a patient with a left ventricular assist device. Dr. Augoustides relates his concern (personal communication) that the thrombotic risk associated with rFVIIa may be higher in patients exposed to ECHMO, LVADs, or other clinical situations in which blood is being exposed to a foreign material under nonphysiologic flow conditions.
Ref 1) Aldouri M: The use of recombinant factor VIIa in controlling surgical bleeding in non-haemophiliac patients. Pathophysiol Haemost Thromb 2002;32(suppl 1):41-46. 2) Bowman LJ et al: Use of recombinant activated factor VII concentrate to control postoperative hemorrhage in complex cardiovascular surgery. Ann Thorac Surg 2008;85:1669-77. 3) Martinowtiz U et al: Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli multidisciplinary rFVIIa task force. J Thromb Haemost 2005;3:340-8. 4) Spinella PC et al: The effect of recombinant activated factor VII on mortality in combat-related casualties with severe trauma and massive transfusion. J Trauma 2008;64:286-294. 5) Birchall J et al: Evidence for the use of recombinant factor VIIa in the prevention and treatment of bleeding in patients without hemophilia. Transfusion Med Rev 2008;3:177-187. 6) O’Connell KA et al: Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006;295:293-298. 7) Apostolidou I et al: Acute left atrial thrombus after recombinant factor VIIa administration during left ventricular assist device implantation in a patient with heparin-induced thrombocytopenia. Anesth Analg 2008;106:404-8
David S. Smith, M.D., Ph.D.
The current “love affair” with recombinant factor 7a (rFVIIa) is growing. What started as a replacement therapy for factor 7 deficient patients has now become a near first line therapy for bleeding thought to be refractory. However recognize that the approved indications listed in the package insert only involve patients with hemophilia A and B, acquired hemophilia, and congenital FVII deficiency. The growing list of other uses is “off label.”
Aldouri reviewed the use of rFVIIa for controlling surgical bleeding in non hemophiliac patients (1). In one small open labeled study in post operative cardiac surgery patients, doses of 30 mcg/kg given every three hours for a maximum of four doses or until bleeding was controlled resulted in a marked decrease in blood loss despite prior failure of conventional measures. There have been similar positive results in patients with non cardiac surgical bleeding and in some trauma patients. The first reported use in a trauma patient was with doses of 60 mcg/kg given at hourly intervals.
Bowman et al reported on the use of rFVIIa to control post operative hemorrhage after complex cardiovascular surgery. They performed a retrospective chart review to identify 36 patients who received this drug. The criteria for use included: exclusion of all surgical causes of bleeding, failure to reverse coagulopathy with adequate pharmacologic and blood product replacement, correction of core body temperature to normal, adequate heparin reversal with protamine and chest tube drainage grater than 3 ml/kg/h or more for 2 hours or more. With the most commonly used dose of 90 mcg/kg, bleeding was controlled in 30 of the 36 patients. In 27 patients one dose was sufficient to achieve control.
The early positive experience in the use of rFVIIa led Martinwitz and collaborators (3) to develop dosing guidelines for its use in trauma patients. They suggested a dose (130 mcg/kg) that was about 30% greater than recommended for hemophiliacs. In an initial cohort of 36 patients cessation of bleeding was obtained in 26 (72%). Nine of the ten patients who did not respond exsanguinated in less than 24 hours. More recently Spinella and associates (4) suggested that early use of rFVIIa may decrease 24 hour mortality in combat casualties who required massive transfusion (> 10 units of red blood cells within 24 hours). The rFVIIa protocol called for an initial dose of 120 mcg/kg after the initial 4 – 6 units of RBC in patients with life threatening hemorrhage. The authors conducted a retrospective review of 124 patients 49 of whom received rFVIIa and 75 who did not. Twenty four hour mortality was 14% in the group that received rFVIIa and 35% in those who did not. Thirty day mortality was also significantly better in the treated group. They emphasize that rFVIIa alone is not adequate. They encourage aggressive correction of acidosis and hypocalcemia. They also emphasize the importance of adequate concentrations of platelets, fibrinogen and coagulation factors. Note that the results from combat casualties my not be directly applicable to trauma patients typically seen at HUP. Except for the cardiac surgery literature there is little that I could find that would apply directly to our trauma patients or other patients with uncontrolled intraoperative bleeding. Regardless of the findings in the studies just cited a local protocol calls for a dose of 90 mcg/kg (rounded to the nearest 1.2 mg) infused intravenously for ongoing, non surgical bleeding refractory to conventional therapy. Patients need to meet the following criteria: patients without known coronary artery disease or peripheral vascular disease; transfusion of greater than 10 units of red blood cells with an ongoing requirement and no evidence of surgical bleeding. The dose can be repeated in two hours if bleeding persists. However, Novo Nordisk has just stopped a phase 3 clinical trial of NovoSeven brand rFVIIa in blunt trauma patients. The reason for stopping the trial was an interim analysis that suggested the end point of improved 30 day mortality and morbidity could not be reached because of a much lower than expected mortality in the overall study groups. 535 patients out of a planned 1502 had been enrolled in a 24 country, randomized, double blind, placebo – controlled trial using three single doses of rFVIIa (200 mcg/kg followed by 100 and 100 mcg/kg). A recent review of the use of rFVIIa for the control of bleeding assessed the results of 17 randomized controlled trials (5). Some of the trials used rFVIIa in an attempt to reduce blood loss during surgery with high blood loss. Others were designed to examine the effect of rFVIIa on gastrointestinal bleeding, trauma or intracranial hemorrhage. The authors concluded that, at present, the benefits of rFVIIa to control bleeding have not been demonstrated and that the rate of thrombotic complication may be higher than many anticipated. What is clear from this study are the relatively few well controlled trials that have been done and that enthusiasm may be exceeding evidence.
From the package insert (2008), the risk of thrombotic adverse events is thought to be low. Patients with disseminated intravascular coagulation, advanced atherosclerotic disease, crush injury or septicemia may be at increased risk of developing thrombotic events. The drug is intended for intravenous bolus administration only. NovoSeven Coagulation Factor VIIa is supplied as a white, lyophilized powder. It should be used within three hours after reconstitution. It should be reconstituted using aseptic technique into the provided histidine diluent. The 1 mg vial should be reconstituted in 1.1 ml, and the 5.0 mg vial into 5.2 ml so that the final concentrations are 1.0 mg/ml. Do not inject the diluent directly onto the drug powder. Aim the needle so that the diluent goes down the vial wall. After adding the diluent, gently swirl the vial until all the material is dissolved. The reconstituted solution is clear. For surgery in hemophilia A or B patients the recommended dosing is 90 mcg/kg immediately before surgery and every 2 hours during surgery. After surgery the suggested dosing depends on the type of surgery. For minor procedures dose every 2 hours for 48 hours then every 2 - 6 hours; for major procedures dose every 2 hours for the first five days, then every 4 hours until healing has occurred.
Thrombosis after rFVIIa is of growing concern. O’Connell et al (6) reviewed the FDA adverse event file for the initial five years after drug licensure for US sales and found 431 submissions related to rFVIIa. The reports (N=168) described 185 thromboembolic events. Seventeen of the events occurred in patients with hemophilia while 151 occurred during unlabelled use, mostly for the treatment of active bleeding. The adverse events included cerebrobvascular accidents (N=39), acute myocardial infarction (N=34), other arterial thrombosis (N=26), pulmonary embolism (N=32), other venous thrombosis including DVT (N=42) and clotted devices (N=10). In 36 of 50 reported deaths, the probable cause of death was related to the thromboembolism. There is greater concern about the potential of thrombosis after rFVIIa in patients with implanted devices. Apostolidou et al (7) describes the acute formation of a left atrial thrombus (observed by TEE) within minutes after administration of rFVIIa (90 mcg/kg over 5 min) in a patient with a left ventricular assist device. Dr. Augoustides relates his concern (personal communication) that the thrombotic risk associated with rFVIIa may be higher in patients exposed to ECHMO, LVADs, or other clinical situations in which blood is being exposed to a foreign material under nonphysiologic flow conditions.
Ref 1) Aldouri M: The use of recombinant factor VIIa in controlling surgical bleeding in non-haemophiliac patients. Pathophysiol Haemost Thromb 2002;32(suppl 1):41-46. 2) Bowman LJ et al: Use of recombinant activated factor VII concentrate to control postoperative hemorrhage in complex cardiovascular surgery. Ann Thorac Surg 2008;85:1669-77. 3) Martinowtiz U et al: Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli multidisciplinary rFVIIa task force. J Thromb Haemost 2005;3:340-8. 4) Spinella PC et al: The effect of recombinant activated factor VII on mortality in combat-related casualties with severe trauma and massive transfusion. J Trauma 2008;64:286-294. 5) Birchall J et al: Evidence for the use of recombinant factor VIIa in the prevention and treatment of bleeding in patients without hemophilia. Transfusion Med Rev 2008;3:177-187. 6) O’Connell KA et al: Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006;295:293-298. 7) Apostolidou I et al: Acute left atrial thrombus after recombinant factor VIIa administration during left ventricular assist device implantation in a patient with heparin-induced thrombocytopenia. Anesth Analg 2008;106:404-8
David S. Smith, M.D., Ph.D.