Recombinant Activated Factor VII: Useful Department of Surgery Grand Rounds 11/8/10 David Mauchley MD
Hemostasis and Coagulation Traditional cascade model Two convergent pathways Series of proteolytic reactions Models PT (extrinsic) PTT (intrinsic) Cells to provide phospholipids (PTS)
Problems with Cascade Model Lack of factors VIII/IX in hemophiliacs Extrinsic production of Xa insufficient Deficiency of factor XII No bleeding despite elevated PTT Variability in bleeding severity Factor VIII/IX deficiency worse than XI Led to description of cell-based model
Cell-Based Model Concept that coagulation controlled by cellular components rather than proteins (factors) Occurs in three overlapping phases Tissue factor-bearing cells/platelets at center VIIa/TF complex initial step toward formation of clot Hoffman, et al. Throm Haemost. 2001
Recombinant Factor VIIa (rfviia) Developed in 1983 Hemophilia A FDA approval: 1999: bleeding in hemophiliacs 2005: surgery in hemophiliacs/factor VII deficiency Off-label uses Al-Ruzzeh et al. J Am Coll Surg. 2009
rfviia Considerations Pharmacologic doses 100x physiologic TF-dependent mechanism Factor X activation thrombin platelet activation Similar to natural factor VII TF-independent mechanism Binds activated platelets factor X activation without TF increased thrombin Ability to bypass factors VIII and IX in hemophiliacs Downregulate fibrinolytic system thrombin activation fibrinolysis inhibitor Very potent coagulant Al-Ruzzeh et al. J Am Coll Surg. 2009
Off-Label Use of rfviia Interest after report of treatment in trauma 1 19 yo male soldier, GSW to IVC, diffuse bleeding after repair of vessel, 60 µg/kg dose x 2 Report of success in treating post-surgical abdominal hemorrhage 2 2 pts who both underwent colectomy for GI bleed associated with Crohns both given 90 µg/kg dose x 2 1. Kenet G. Lancet. 1999 2. White B. Br J Haematol. 1999
Off-Label Use of rfviia Trauma 40% early deaths related to massive bleeding Cardiac Surgery Coagulopathy after cardiopulmonary bypass (CPB) Liver Transplantation Coagulopathy due to non-functioning liver
Rizoli et al. J Trauma. 2006 Retrospective review 242 pts 8 units PRBCs 12 hrs rfviia (38) vs. none (204) rfviia pts: Younger More penetrating trauma Lower platelets More acidotic Requiring more blood initially Trauma
Rizoli et al Multivariate analysis: Adjust for age, head injury score (AIS), ph Pts in rfviia group had higher predicted 24-hour survival and a trend toward overall survival
Trauma: Military Experience Spinella et al. J Trauma. 2008 Retrospective review admissions to combat hospital Dec 2003-Oct 2005 Elevated Injury Severity Score (>15) Massive transfusion ( 10 units PRBCs) 124/5,293 pts met qualifications 49 pts rfviia (40%)
Mortality decreased at: 12 hrs: (p=0.008) 6/49 (12%) rfviia+ 25/75 (33%) rfviia- 24 hrs: (p=0.01) 7/49 (14%) rfviia+ 26/75 (35%) rfviia- 30 days: (p=0.03) 15/49 (31%) 38/75 (51%) Trend toward fewer pts dying of hemorrhage Spinella et al
Trauma: RCT Two parallel studies: Blunt/penetrating trauma Multicenter: 32 hospitals worldwide Massive transfusion (>6 units PRBC in 4hrs) 3 doses rfviia or placebo Immediately after 8 th unit, 1hr and 3hrs after first dose 200 µg/kg, 100 µg/kg, 100 µg/kg Endpoints: transfusion requirements, mortality, serious outcomes Boffard et al. J Trauma. 2005
Trauma: RCT Results Boffard et al. J Trauma. 2005
Trauma: RCT Results PRBC transfusion requirements: Need for massive transfusion: Alive at 48 hrs >20 units Blunt NNT=5.4 Boffard et al. J Trauma. 2005
Trauma: RCT Results Adverse Events: Essentially equal Boffard et al. J Trauma. 2005
Trauma: Summary Retrospective studies suggest lower mortality with rfviia in military and civilian settings Prospective RCT suggest decrease in number of RBC transfusions No difference in thromboembolic events
Cardiac Surgery McCall et al 2006 Retrospective review post-cpb bleeding preventing chest closure 53 pts Valve or aortic surgery Median CPB=266 min Compared transfusion before and after rfviia Decrease significant for all types of products p<0.001 McCall et al. Can J Anesth. 2006
Cardiac Surgery: RCT Randomized double-blind placebo trial 24 consecutive pts. complicated cardiac surgery, 5 excluded 9 pts rfviia, 10 pts placebo 90 µg/kg dose given at termination of CBP Pts taken to ICU RBC transfused for Hgb<8.5 FFP, plt, cryo given per protocol Diprose et al. Br J Anaesth. 2005
Cardiac Surgery: RCT Results: Placebo group: 8 pts transfused total of 105 units rfviia group: 2 pts transfused total of 13 units No difference: Hospital length of stay Vent days ICU days Thromboembolic events Diprose et al. Br J Anaesth. 2005
Liver Transplant Randomized, placebocontrolled, DB trial Childs class B & C- transplant for cirrhosis rfviia: 60 µg/kg or 120 µg/kg Endpoint: # of units transfused at operation Lodge et al. Liver Transplantation. 2005
Liver Transplant
Liver Transplant Results: No difference in number of transfusions Fewer pts transfused in rfviia group No difference in adverse outcomes Thromboembolic events
Review of 35 RCT trials 26 involving pts with varying clinical conditions (n=4119) 9 involving healthy volunteers (n=349) Thromboembolic events evaluated
Levi et al
Levi et al
Summary rfviia is a potent procoagulant Use of rfviia leads to decreased number of transfusions in trauma, cardiac surgery, and liver transplantation There is the suggestion of improved mortality in battlefield trauma with rfviia use rfviia is safe to use in surgical patients