Drug Criteria & Outcomes
From battlefield to hospital: Researchers ponder broader role for drug designed to stop the bleeding
Implications for reducing blood shortages and costs
By Jonathan Byrd, Pharm. D. Candidate, Samford (AL) University McWhorter School of Pharmacy
In recent months different media outlets across the United States and Great Britain have reported on the use of an "unproven" drug being used on the battlefields of Iraq and Afghanistan. Media attention has been focused on NovoSeven® which is approved for uncontrolled bleeding episodes in hemophiliacs, but it has been used by field surgeons for those soldiers who are at risk for life-threatening bleeds.
Stateside, more and more surgeons and trauma physicians are using NovoSeven® in patients that need immediate surgery or are at risk for severe blood loss.1-2 In any severely injured patient, achieving hemostasis as quickly as possible is critical. Also, complications such as dilutional coagulopathies can occur when a patient receives large amounts of blood transfusion products and fluids in a trauma situation. The use of NovoSeven® could help reduce blood shortages, overall costs, and the amount of allogenic blood transfusions needed during surgery and emergent situations.
NovoSeven® is a blood derivative of recombinant factor VIIa which is derived from hamster cells and is FDA approved for use in patients with Hemophilia A or B with inhibitors to factor VIIa and factor IX who have uncontrolled bleeding. However, it has many off label uses in which its effects are being evaluated such as liver transplant, bone marrow transplant, CNS bleeds in thrombocytopenic patients, and patients who have severe bleeding after surgery. The mechanism of action involves the intrinsic pathway and stimulates the coagulation cascade which activates factor Xa prothrombin. The prothrombin then activates fibrin from fibrinogen to form a hemostatic plug. The usual dose given to patient is 90 mcg/kg (actual body weight) given as a slow bolus infusion over two to five minutes every two hours as needed to keep the patient hemodynamically stable. Patients who are hypersensitive to mouse, hamster, or bovine proteins should not receive this product.
Adverse events include fever, hemorrhage
Adverse events that are associated with NovoSeven® include fever, hemorrhage, decreased fibrinogen, and hypertension. Other rare occurrences include allergic reaction, disseminated intravascular coagulation, edema, bradycardia, pain, and vomiting. Patients with DIC, severe atherosclerotic disease, crush trauma, or septicemia are at increased risk for thrombotic events when given NovoSeven®. In December 2005, Novo Nordisk and the FDA released a "Dear Healthcare Professional" letter that suggested that there was an increased risk for arterial thromboembolic events such as an MI or stroke in non-hemophiliac patients that received the drug. NovoSeven® should be stored in the refrigerator until it is used, and it should be used within three hours of reconstitution.3
There have been many case reports and studies conducted over the last few years that have investigated the use of NovoSeven® in patients who do not have hemophilia but need immediate treatment for uncontrolled bleeding. In a case study, O'Neil et al. reported on a 24-year-old stab victim whose uncontrolled bleeding after surgical repair was stopped only by one dose of NovoSeven® with no adverse events reported.4 Kenet et al reported in another case study that a 19-year-old soldier who suffered hypovolemic shock, hypothermia, DIC, and ketoacidosis from a gun shot wound had his postsurgical hemorrhaging stopped by two doses of NovoSeven.5 Both of these patients had received various blood products that did not control the bleeding, and the main factor that controlled and stopped the bleeding was the administration of NovoSeven®. Vlot et al. reported on a 59-year-old man who had recurrent gastric postsurgical bleeding that did not resolve with standard treatments, but when given NovoSeven® the bleeding ceased and the amount of pRBCs was reduced.6
A randomized, double-blind, placebo-controlled trial conducted by Shao et al in 232 patients, investigated whether or not the use of Novoseven® in cirrhotic patients who are undergoing partial hepatectomy is safe and effective. Patients were randomized to receive a placebo (n=76), rFVIIa 50 mcg/kg (n=71), or rFVIIa 100 mcg/kg (n=74). The study measured the amount of blood transfusions needed by each study group during surgery and the first 48 hours after surgery. The results did not show a statistical difference in reducing the number of those requiring transfusion (p-value of 0.59). However, the trial illustrated that the safety of rFVIIa in this group of patients was not statistically different than that of the placebo. The adverse events reported in the study showed no difference between the three groups.7 Another study using Novoseven® to control surgical bleeding was conducted in patients undergoing cardiopulmonary bypass during non-coronary cardiac surgery. In this pilot study conducted by Diprose et al, twenty patients were randomized to receive either 90µg/kg of rFVIIa (n=10) or equivalent volume of NS (n=10) after cardiopulmonary bypass. Two patients in the treatment group received 13 units of allogeneic red cells and coagulation products compared with eight patients in the placebo group receiving 105 units of allogeneic red cells and coagulation products. The treatment and placebo group did not differ for the occurrence of adverse events. The investigators believe that this study has built upon previous trials' results and show that rFVIIa should be considered in patients who are likely to develop coagulopathies due to complex surgery. The investigators believe that this pilot study has shown that rFVIIa has potential usefulness in cardiac surgery but further trials are needed to explore the safety and efficacy.8 NovoSeven® could be approved for use in emergency and complicated surgical situations, if future studies show that it is efficacious and safe in the majority of patients that receive the medication.
Protocol to guide use
Currently Huntsville (AL) Hospital has a protocol for the use of NovoSeven. The patient who is eligible to receive NovoSeven® must be inpatients in the ICU, ER, or OR with prescribing physician's specialty in trauma, neurosurgery, cardiovascular surgery, cardiovascular anesthesiology, or hematology. The patient must have full code status with no advanced directive to withhold life-sustaining treatment. NovoSeven® should be used after standard blood management strategies have been used without successfully achieving hemodynamic stability. Standard protocol includes use of at least 10 units of FFP in < six hours, 10 units pRBCs in < six hours, 10 units of cryoprecipitate, 20 units of platelets or two units of pheresed platelets. Platelet level, PT, PTT, Hgb, Hct, and fibrinogen must be obtained at baseline prior to NovoSeven® administration. If the platelet count is less than 50,000, platelets must be given before the drug is administered. If fibrinogen levels < 100 mg/dL, then administer cryoprecipitate before administering the drug. Protamine use should be considered if the patient has received heparin. Hemodialysis can be given five hours after drug administration. The criteria for use of NovoSeven® includes indications for all patients with Hemophilia A or B, anticoagulation reversal for emergency situations, uncontrolled bleeding in trauma, surgery, or cirrhotic patients, or patients that have congenital platelets disorders.9 These patients receive the approved dose of 90 mcg/kg and are reevaluated after each dose.
To summarize, there has been recent news and controversy over the use of Novoseven® in patients who do not have hemophilia but are in need of treatment for severe hemorrhage. Through multiple case studies and limited clinical trials, NovoSeven® has been shown to be beneficial and safe in a majority of patients. Not only did this medication hemodynamically stabilized patients but it reduced the need and volume of blood transfusions. Through following hospital protocol and applying NovoSeven® use criteria correctly, cost of care can be reduced. Although not a first line agent, medical professionals should be watchful for any future exploits that may develop concerning the use of NovoSeven®.
References
- Baltimore Sun Web site. Available at: http://www.baltimoresun.com. Accessed January 3, 2007.
- ABC News Web site. Available at: http://abcnews.go.com. Accessed January 3, 2007.
- Lexi-Comp (Drugs and Specialties) [computer program]. Lexi-Comp; January 6, 2007.
- O'Neil PA, Bluth M, Gloster ES, et al. Successful use of recombinant activated factor VIIa for trauma-associated hemorrhage in a patient without preexisting coagulopathy. J Trauma. 2002; 52: 400-405.
- Kenet G, Walden R, Eldad A, Martinowitz U. Treatment of traumatic bleeding with recombinant factor VIIa. Lancet. 2000; 354: 1879.
- Vlot A, Ton E, Mackaay AJC, Kramer MHH, Gaillard CAJM. Treatment of a severely bleeding patient without preexisting coagulopathy with activated recombinant factor VII. Am J Med. 2000; 108: 421-422.
- Shao YF, Yang JM, Chau GY, et al. Safety and hemostatic effect of recombinant activated factor VII in cirrhotic patients undergoing partial hepatectomy; a mulitcentered, randomized, double-blind, placebo-controlled trial. Am J of Surgery. 2006; 191: 245-249.
- Diprose P, Herbertson MJ, O'Shaughnessy D, Gill RS. Activated recombinant factor VII after cardiopulmonary bypass reduces allogenic transfusions in complex non-coronary cardiac surgery: randomized double-blind placebo-controlled pilot study. Br J Anesth. 2005: 95; 596-602.
- Huntsville Hospital's Protocol for approval and dosing of Factor VIIa (NovoSeven®).
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