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1.  Use of activated recombinant factor VII for severe coagulopathy post ventricular assist device or orthotopic heart transplant 
Background
Ventricular assist devices(VAD) implantation/removal is a complex surgical procedure with perioperative bleeding complications occurring in nearly half of the cases. Recombinant activated factor VII (rFVIIa) has been used off-label to control severe hemorrhage in surgery and trauma. We report here our experience with rFVIIa as a rescue therapy to achieve hemostasis in patients undergoing orthotopic heart transplant (OHT) and/or VAD implantation.
Methods
A retrospective review was conducted from Jan 03 to Aug 05 for patients who received rFVIIa for the management of intractable bleeding unresponsive to standard hemostatic blood component therapy. Blood loss and the quantity of blood products, prior to, and for at least 12 hours after, administration of rFVIIa were recorded.
Results
Mean patient age was 53, (38–64 yrs), mean dose of rFVIIa administered was 78.3 μg/kg (24–189 μg/kg) in 1–3 doses. All patients received the drug either intraoperatively or within 6 hours of arrival in ICU. Mean transfusion requirements and blood loss were significantly reduced after rFVIIa administration (PRBC's; 16.9 ± 13.3 to 7.1 ± 6.9 units, FFP; 13.1 ± 8.2 to 4.1 ± 4.9 units, platelets; 4.0 ± 2.8 to 2.1 ± 2.2 units, p < 0.04 for all). 5 patients expired including 3 with thromboembolic cause. One patient developed a lower extremity arterial thrombus, and another deep vein thrombosis.
Conclusion
In this review, there was a significant decrease in transfusion requirement and blood loss after rFVIIa administration. Although, 5/17 developed thromboembolic complications, these patients may have been at higher risk based on the multiple modality therapy used to manage intractable bleeding. Nevertheless, the exact role of rFVIIa with respect to development of thromboembolic complications cannot be clearly determined. Further investigation is needed to determine rFVIIa's safety and its effectiveness in improving postoperative morbidity and mortality.
doi:10.1186/1749-8090-2-32
PMCID: PMC1939840  PMID: 17617902
2.  Intraoperative Use of Low-Dose Recombinant Activated Factor VII During Thoracic Aortic Operations 
The Annals of thoracic surgery  2012;93(6):1921-1929.
Background
Numerous studies have supported the effectiveness of recombinant activated factor VII (rFVIIa) for the control of bleeding after cardiac procedures; however safety concerns persist. Here we report the novel use of intraoperative low-dose rFVIIa in thoracic aortic operations, a strategy intended to improve safety by minimizing rFVIIa exposure.
Methods
Between July 2005 and December 2010, 425 consecutive patients at a single referral center underwent thoracic aortic operations with cardiopulmonary bypass (CPB); 77 of these patients received intraoperative low-dose rFVIIa (≤60 μg/kg) for severe coagulopathy after CPB. Propensity matching produced a cohort of 88 patients (44 received intraoperative low-dose rFVIIa and 44 controls) for comparison.
Results
Matched patients receiving intraoperative low-dose rFVIIa got an initial median dose of 32 μg/kg (interquartile range [IQR], 16–43 μg/kg) rFVIIa given 51 minutes (42–67 minutes) after separation from CPB. Patients receiving intraoperative low-dose rFVIIa demonstrated improved postoperative coagulation measurements (partial thromboplastin time 28.6 versus 31.5 seconds; p = 0.05; international normalized ratio, 0.8 versus 1.2; p < 0.0001) and received 50% fewer postoperative blood product transfusions (2.5 versus 5.0 units; p = 0.05) compared with control patients. No patient receiving intraoperative low-dose rFVIIa required postoperative rFVIIa administration or reexploration for bleeding. Rates of stroke, thromboembolism, myocardial infarction, and other adverse events were equivalent between groups.
Conclusions
Intraoperative low-dose rFVIIa led to improved postoperative hemostasis with no apparent increase in adverse events. Intraoperative rFVIIa administration in appropriately selected patients may correct coagulopathy early in the course of refractory blood loss and lead to improved safety through the use of smaller rFVIIa doses. Appropriately powered randomized studies are necessary to confirm the safety and efficacy of this approach.
doi:10.1016/j.athoracsur.2012.02.037
PMCID: PMC3718882  PMID: 22551846
3.  Recombinant factor VIIA is associated with an improved 24‐hour survival without an improvement in inpatient survival in massively transfused civilian trauma patients 
Clinics  2011;66(1):101-106.
OBJECTIVE:
To determine whether recombinant factor VIIa (rFVIIa) is associated with increased survival and/or thromboembolic complications.
INTRODUCTION:
Uncontrollable hemorrhage is the main cause of early mortality in trauma. rFVIIa has been suggested for the management of refractory hemorrhage. However, there is conflicting evidence about the survival benefit of rFVIIa in trauma. Furthermore, recent reports have raised concerns about increased thromboembolic events with rFVIIa use.
METHODS:
Consecutive massively transfused (≥ 8 units of red blood cells within 12 h) trauma patients were studied. Data on demographics, injury severity scores, baseline laboratory values and use of rFVIIa were collected. Rate of transfusion in the first 6 h was used as surrogate for bleeding. Study outcomes included 24‐hour and in‐hospital survival, and thromboembolic events. A multivariable logistic regression analysis was used to determine the impact of rFVIIa on 24‐hour and in‐hospital survival.
RESULTS:
Three‐hundred and twenty‐eight patients were massively transfused. Of these, 72 patients received rFVIIa. As expected, patients administered rFVIIa had a greater degree of shock than the non‐rFVIIa group. Using logistic regression to adjust for predictors of death in the regression analysis, rFVIIa was a significant predictor of 24‐hour survival (odds ratio (OR) =  2.65; confidence interval 1.26–5.59; p = 0.01) but not of in‐hospital survival (OR = 1.63; confidence interval 0.79–3.37; p = 0.19). No differences were seen in clinically relevant thromboembolic events.
CONCLUSIONS:
Despite being associated with improved 24‐hour survival, rFVIIa is not associated with a late survival to discharge in massively transfused civilian trauma patients.
doi:10.1590/S1807-59322011000100018
PMCID: PMC3044583  PMID: 21437444
Coagulopathy; Bleeding; Thromboembolic events; Hemorrhagic shock
4.  Salvage use of activated recombinant factor VII in the management of refractory bleeding following cardiac surgery 
Journal of blood medicine  2011;2:131-134.
Background:
Refractory post cardiopulmonary bypass (CPB) bleeding continues to cause concern for cardiac surgeons and intensivists. Massive postoperative hemorrhage following CPB is multifactorial and not fully understood, and it is also associated with increased mortality and morbidity. Activated recombinant factor VII (rFVIIa) has emerged as possible salvage medication in refractory post cardiac surgical bleeding. This observational study sought to identify the pattern of use of rFVIIa in cardiac surgery, its effectiveness, and risk.
Methods:
This study involved a retrospective case review of medical records of ten patients undergoing a variety of cardiac surgery procedures and who developed life-threatening bleeding during surgery or after surgery despite conventional medical therapy, including transfusion of blood and blood products, and received rFVIIa at a regional center between August 2007 and April 2009.
Results:
All ten patients received two consecutive doses of rFVIIa (average dose 65 μg/kg) at a 2-hour interval. Eight patients were re-explored due to massive postoperative bleeding or cardiac tamponade before receiving rFVIIa. Surgical sources of bleeding were not identified in any cases. A second re-exploration was carried out in two cases. Two patients (20%) died in ITU from problems not related to bleeding and thromboembolism. Blood loss was significantly reduced after administration of rFVIIa. Blood loss 6 hours prior to treatment was 1758.5 ± 163.9 mL and blood loss in the 6-hour period post treatment was 405.6 ± 50.5 mL (P < 0.05). Blood and blood products used in the 6-hour period before and after administration of rFVIIa were 19.6 ± 1.5U and 4.4 ± 0.6U, respectively (P < 0.05). No adverse reactions or thrombotic complications related to rFVIIa were noted.
Conclusion:
In our limited study, use of rFVIIa in refractory post surgical bleeding was significantly reduced blood loss and use of blood and blood products. We concluded that rFVIIa can be used satisfactorily and safely as a rescue therapy in the management of post cardiac surgical bleeding.
doi:10.2147/JBM.S21609
PMCID: PMC3262339  PMID: 22287872
cardiopulmonary bypass; CPB; refractory bleeding; rFVIIa
5.  Recombinant Factor VII Is Associated with Worse Survival in Complex Cardiac Surgical Patients 
The Annals of thoracic surgery  2014;98(2):618-624.
Background
Recombinant, activated factor VII(rFVIIa) decreases requirements for allogenic blood transfusion and chest re-exploration in cardiac surgical patients. Whether rFVIIa increases risk for postoperative adverse events is unclear. We tested whether rFVIIa administration was associated with increased mortality, neurologic and renal morbidity in cardiac surgical patients. Risk of thromboembolic complications and the dose-response of rFVIIa on mortality and morbidity was also evaluated.
Methods
Of 27,977 patients who had complex cardiac surgery, 164 patients(0.59%) received rFVIIa perioperatively. Using propensity-matching techniques, patients were matched to a maximum of 3 controls. Patients who received rFVIIa were compared with controls on risk of mortality, neurologic and renal morbidity and thromboembolic complications, including a composite of myocardial infarction, pulmonary embolism, and deep venous thrombosis. A corresponding “dose-response” analysis using multivariable logistic regression was also performed.
Results
Propensity techniques successfully matched 144 patients(88%) with 359 controls. Of patients who received rFVIIa, 40% experienced in-hospital mortality compared to 18% of controls(OR 2.82(1.64, 4.87);P<0.001). Furthermore, 31% of patients treated with rFVIIa vs 17% of controls experienced renal morbidity(OR 2.07(1.19, 3.62);P=0.002), however neurologic morbidity and thromboembolic complications were not different among groups. High-dose(>60mcg/kg) did not increase risk for mortality compared to treatment with low-dose rFVIIa(<60mcg/kg).
Conclusion
Administration of rFVIIa is associated with increased mortality and renal morbidity in cardiac surgery patients.
doi:10.1016/j.athoracsur.2014.04.126
PMCID: PMC4122638  PMID: 24968771
bleeding; blood transfusion; stroke
6.  Recombinant activated factor VII (rFVIIa) as salvage treatment for intractable hemorrhage 
Thrombosis Journal  2004;2:9.
Background
Recently, there has been an increased use of recombinant activated factor VII (rFVIIa) to promote hemostasis in various hemorrhagic conditions. The objective of this study was to determine the outcome of patients treated with rFVIIa who had intractable bleeding associated with cardiac surgery (CSP) or as a result of other causes (OBP).
Methods
The medical records of 40 consecutive patients treated with rFVIIa were retrospectively reviewed for blood product use before and after treatment. In all patients, rFVIIa was given only after all other measures to stop bleeding had failed. The number of transfused units of red cells (R), platelets (P), fresh frozen plasma (F), and cryoprecipitate (C) were determined both before and after administration of rFVIIa, and the results compared. Mortality at 4 hours and 30 days was assessed. Patients dying within 4 hours of rFVIIa administration were not evaluable for response. Patient characteristics were also assessed as risk factors for mortality.
Results
Twelve of 24 CSP survived for more than 4 hours. These 12 patients required an average of 17 units (U) of R, 18 U of P, 18 U of F and 15 U of C pre-treatment compared to an average of 6 U, 10 U, 9 U and 4 U of R, P, F and C respectively, post-treatment. These differences were statistically significant. For the OBP, 11 of 16 survived more than four hours. These 11 patients required an average of 10 U of R, 11 U of P, 14 U of F and 10 U of C pretreatment compared to an average of 1 U, 2 U, 2 U and 0 U of R, P, F, and C respectively, post-treatment. With the exception of C, there was a statistically significant decrease in blood product use following treatment with rFVIIa. Of the survivors in each group, 6 of 12 CSP and 2 of 11 OBP died between 3 and 30 days post-treatment from causes other than bleeding. Mortality at 30 days for CSP and OBP survivors was 50% and 18% respectively, whereas overall 30 day mortality was 75% for CSP and 44% for OBP.
Conclusions
rFVIIa is effective in decreasing blood product use and promoting hemostasis in patients with intractable bleeding associated with cardiac surgery and a variety of other causes.
doi:10.1186/1477-9560-2-9
PMCID: PMC535534  PMID: 15530167
7.  Recombinant coagulation factor VIIa—a novel haemostatic agent in scoliosis surgery? 
European Spine Journal  2005;15(6):944-952.
Astract
Spinal fusion surgery in children and adolescents with idiopathic scoliosis is often associated with severe haemorrhage. Recombinant coagulation factor VIIa (rFVIIa) has previously been shown to be an effective haemostatic treatment for severe bleeding associated with a variety of coagulopathic and non-coagulopathic indications. The aim of this retrospective study was to assess the safety and haemostatic efficacy of rFVIIa in a series of 26 consecutive adolescent patients with scoliosis (22 females; mean age 16.6 years) undergoing correctional surgery. A second series of 26 consecutive patients (20 females; mean age 16.2 years) who received standard therapy during surgery, represented historical controls. Blood loss, transfusion requirements, duration of surgery, and peri-operative measurements of coagulation parameters were compared between the two groups. Intra-operative and combined intra-operative and post-operative blood losses were significantly smaller in the rFVIIa-treatment group than in the historical controls (P=0.003 and 0.032, respectively); rFVIIa-treated patients also demonstrated significantly reduced blood loss per vertebral segment fused (P=0.032) and per hour of surgery (P<0.001). Intra-operative requirements for packed red blood cells were also significantly lower in the treatment group (P=0.042). Patients in the treatment group demonstrated rapid and maintained reduction of prothrombin time and international normalised ratio; values among rFVIIa-treated patients remained significantly lower than those in the control group at all time points evaluated (P<0.001). There were no deaths and no adverse events. These results suggest that rFVIIa is a safe and effective haemostatic agent for use during spinal fusion surgery in adolescent patients with idiopathic scoliosis; however, further research and randomised, placebo-controlled trials are needed to confirm these findings.
doi:10.1007/s00586-005-1004-5
PMCID: PMC3489422  PMID: 16133083
Bleeding; Haemostasis; Scoliosis; Surgery; RFVIIa
8.  Recombinant Activated Factor VII Significantly Reduces Transfusion Requirements in Cardiothoracic Surgery 
Drugs in R&D  2015;15(2):187-194.
Background
The off-label use of recombinant activated factor VII (rFVIIa) for intractable bleeding is associated with a risk of thrombotic events. The objective of this study was to evaluate the incidence and predictors of rFVIIa-related thrombotic events and its efficacy in the reduction of transfusion requirements during various surgeries.
Methods
Ninety-two cases received rFVIIa for uncontrollable bleeding despite medical and surgical hemostasis. The incidence and risk factors of thrombotic events were analyzed. Blood products transfused in the 24 h before and after rFVIIa injection were calculated. Subgroup analysis was performed to see which types of surgeries benefited most from rFVIIa.
Results
The main indication for rFVIIa administration was uncontrollable bleeding during cardiothoracic surgery followed by coagulopathy due to liver failure followed by neurosurgical procedures. Requirements of blood products after rFVIIa decreased significantly by 45 % (p = 0.012), 52 % (p = 0.0001), and 75 % (p = 0.0001) for red blood cells, plasma, and cryoprecipitate, respectively. Subgroup analysis showed that cardiothoracic surgery was the sole group that benefited from rFVIIa with a reduction in transfusion of red blood cells (p = 0.013), plasma (p = 0.0001), and cryoprecipitate (p = 0.0001). Thrombotic events occurred in 9.8 % of the cases mostly on the arterial side (89 %) and have not contributed to mortality.
Conclusion
rFVIIa can significantly reduce transfusion requirements when given for intractable bleeding during cardiothoracic surgery at the expense of thrombotic events in approximately one tenth of the cases. Further prospective studies are necessary to study if this effect of rFVIIa is translated to a favorable outcome.
Electronic supplementary material
The online version of this article (doi:10.1007/s40268-015-0093-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s40268-015-0093-9
PMCID: PMC4488183  PMID: 25862216
9.  Recombinant Activated Factor VII Significantly Reduces Transfusion Requirements in Cardiothoracic Surgery 
Drugs in R&D  2015;15(2):187-194.
Background
The off-label use of recombinant activated factor VII (rFVIIa) for intractable bleeding is associated with a risk of thrombotic events. The objective of this study was to evaluate the incidence and predictors of rFVIIa-related thrombotic events and its efficacy in the reduction of transfusion requirements during various surgeries.
Methods
Ninety-two cases received rFVIIa for uncontrollable bleeding despite medical and surgical hemostasis. The incidence and risk factors of thrombotic events were analyzed. Blood products transfused in the 24 h before and after rFVIIa injection were calculated. Subgroup analysis was performed to see which types of surgeries benefited most from rFVIIa.
Results
The main indication for rFVIIa administration was uncontrollable bleeding during cardiothoracic surgery followed by coagulopathy due to liver failure followed by neurosurgical procedures. Requirements of blood products after rFVIIa decreased significantly by 45 % (p = 0.012), 52 % (p = 0.0001), and 75 % (p = 0.0001) for red blood cells, plasma, and cryoprecipitate, respectively. Subgroup analysis showed that cardiothoracic surgery was the sole group that benefited from rFVIIa with a reduction in transfusion of red blood cells (p = 0.013), plasma (p = 0.0001), and cryoprecipitate (p = 0.0001). Thrombotic events occurred in 9.8 % of the cases mostly on the arterial side (89 %) and have not contributed to mortality.
Conclusion
rFVIIa can significantly reduce transfusion requirements when given for intractable bleeding during cardiothoracic surgery at the expense of thrombotic events in approximately one tenth of the cases. Further prospective studies are necessary to study if this effect of rFVIIa is translated to a favorable outcome.
Electronic supplementary material
The online version of this article (doi:10.1007/s40268-015-0093-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s40268-015-0093-9
PMCID: PMC4488183  PMID: 25862216
10.  Recombinant Factor VIIa Reduces Bleeding after Blunt Liver Injury in a Pig Model of Dilutional Coagulopathy under Severe Hypothermia 
PLoS ONE  2015;10(6):e0113979.
Background
Recombinant factor VIIa (rFVIIa) is registered for use in haemophilia with inhibitors and other rare bleeding disorders, but has also been used in various other clinical conditions to terminate life-threatening bleeding. Underlying conditions (e.g. coagulopathy) and dosing may affect treatment efficacy. The objective of the present study was to evaluate the impact of increasing doses of rFVIIa on blood loss and coagulation assays in haemodiluted and hypothermic pigs undergoing blunt liver injury.
Methods
A grade III blunt liver injury was induced in 28 pigs after 70% haemodilution and cooling to 32.6–33.4°C. Ten minutes after trauma, animals randomly received placebo or 90, 180 or 360 μg/kg rFVIIa. Global coagulation parameters, thromboelastometry (TEM) and plasma thrombin generation (TG) were determined at different time points during the observation period of 120 minutes.
Results
Total blood loss was significantly lower following 90 μg/kg rFVIIa (1206 [1138–1470] mL) relative to placebo (2677 [2337–3068] mL; p<0.05), with no increased effect with higher dose levels of rFVIIa. Following trauma and haemodilution, coagulation was impaired relative to baseline in both TEM and TG analysis. At 60 and 120 minutes after trauma, TEM variables improved in the rFVIIa-treated animals compared with the placebo group. Similarly, rFVIIa improved coagulation kinetics in TG. As was observed with blood loss, no significant effect between different rFVIIa dose levels was found in TEM or TG. Macro- and microscopic post-mortem examination did not reveal any signs of thromboembolic events.
Conclusion
Early administration of 90 μg/kg rFVIIa reduced blood loss in pigs undergoing blunt liver injury even after severe haemodilution and hypothermia, with no further effect of higher dose levels. Coagulation assays showed impaired coagulation in coagulopathic animals, with a dose-independent improvement in animals treated with rFVIIa.
doi:10.1371/journal.pone.0113979
PMCID: PMC4476676  PMID: 26098426
11.  Use of Activated Recombinant Factor VII in Severe Bleeding – Evidence for Efficacy and Safety in Trauma, Postpartum Hemorrhage, Cardiac Surgery, and Gastrointestinal Bleeding 
Background
Uncontrolled bleeding continues to be a major cause of mortality in trauma, cardiac surgery, postpartum hemorrhage and liver failure. The aim of this paper is to assess the evidence supporting the efficacy of activated recombinant factor VII (rFVIIa) administration in these settings.
Methods
Electronic literature search.
Results
Numerous retrospective trials have mostly shown a decrease in blood transfusion requirements with no increase in thromboembolic events (TEE), but major limitations in trial design make generalization difficult. In most retrospective reports rFVIIa has been administered as a last-ditch attempt to control bleeding, when acidosis, hypothermia and coagulation factor depletion may not allow optimal rFVIIa effect. Prospective randomized controlled trials have not shown any effect of rFVIIa on mortality or TEE, although some have shown a reduction in RBC requirement.
Conclusion
Stipulated transfusion protocols in prospective trials have reduced anticipated mortality among controls and make future trials for mortality effect unlikely in view of large sample size requirements. Establishment of these protocols and rapid hemostasis are likely to have greater benefits than administration of a single agent.
doi:10.1159/000338034
PMCID: PMC3364092  PMID: 22670132
Factor VII; Coagulation factors; Bleeding complication
12.  Safety of rFVIIa in hemodynamically unstable polytrauma patients with traumatic brain injury: post hoc analysis of 30 patients from a prospective, randomized, placebo-controlled, double-blind clinical trial 
Critical Care  2007;11(4):R85.
Background
Trauma is a leading cause of mortality and morbidity, with traumatic brain injury (TBI) and uncontrolled hemorrhage responsible for the majority of these deaths. Recombinant activated factor VIIa (rFVIIa) is being investigated as an adjunctive hemostatic treatment for bleeding refractory to conventional replacement therapy in trauma patients. TBI is a common component of polytrauma injuries. However, the combination of TBI with polytrauma injuries is associated with specific risk factors and treatment modalities somewhat different from those of polytrauma without TBI. Although rFVIIa treatment may offer added potential benefit for patients with combined TBI and polytrauma, its safety in this population has not yet been assessed. We conducted a post hoc sub analysis of patients with TBI and severe blunt polytrauma enrolled into a prospective, international, double-blind, randomized, placebo-controlled study.
Methods
A post hoc analysis of study data was performed for 143 patients with severe blunt trauma enrolled in a prospective, randomized, placebo-controlled study, evaluating the safety and efficacy of intravenous rFVIIa (200 + 100 + 100 μg/kg) or placebo, to identify patients with a computed tomography (CT) diagnosis of TBI. The incidences of ventilator-free days, intensive care unit-free days, and thromboembolic, serious, and adverse events within the 30-day study period were assessed in this cohort.
Results
Thirty polytrauma patients (placebo, n = 13; rFVIIa, n = 17) were identified as having TBI on CT. No significant differences in rates of mortality (placebo, n = 6, 46%, 90% confidence interval (CI): 22% to 71%; rFVIIa, n = 5, 29%, 90% CI: 12% to 56%; P = 0.19), in median numbers of intensive care unit-free days (placebo = 0, rFVIIa = 3; P = 0.26) or ventilator-free days (placebo = 0, rFVIIa = 10; P = 0.19), or in rates of thromboembolic adverse events (placebo, 15%, 90% CI: 3% to 51%; rFVIIa, 0%, 90% CI: 0% to 53%; P = 0.18) or serious adverse events (placebo, 92%, 90% CI: 68% to 98%; rFVIIa, 82%, 90% CI: 60% to 92%; P = 0.61) were observed between treatment groups.
Conclusion
The use of a total dose of 400 (200 + 100 + 100) μg/kg rFVIIa in this group of hemodynamically unstable polytrauma patients with TBI was not associated with an increased risk of mortality or with thromboembolic or adverse events.
doi:10.1186/cc6092
PMCID: PMC2206502  PMID: 17686152
13.  Recombinant activated factor VII in controlling bleeding in non-hemophiliac patients 
Annals of Saudi Medicine  2010;30(3):198-202.
BACKGROUND:
There have been recent reports on the successful use of recombinant factor VIIa (rFVIIa) in non-hemophiliac patients who have experienced heavy blood loss due to trauma with extensive organ damage and who have received multiple blood transfusions with hemostatic changes without success. The timing of administration, dosage, mortality, units of blood transfusion saved, risk of thrombotic events, and the risk/benefit ratio are still poorly defined.
PATIENTS AND METHODS:
We conducted a retrospective review of all medical records of patients who received rFVIIa between January 2003 and March 2008. Data collection included demographic characteristics, diagnosis, indications, comorbidities, and amount of blood products used with rFVIIa, dose of rFVIIa, mortality, and adverse events.
RESULTS:
We identified 45 patients, 27 (60%) males and 18 (40%) females, with a median age of 52 years. The median dose of rFVIIa was 40 μg/kg (range, 20-120 μg/kg). Five (11.1%) patients needed a second dose of rFVIIa (dose range of 20-85 μg/kg) whereas three patients (6.7%) needed a third dose of rFVIIa (dose range of 40-60 μg/kg). There was a marked and significant reduction in transfusion requirements for packed red blood cells (P=.0078). Overall transfusion requirements significantly decreased after the infusion of rFVIIa (P=.0323). Nineteen patients (42.2%) died and thrombosis was documented in 3 patients (6.7%).
CONCLUSION:
Use of rFVIIa should be based on sound clinical evidence to balance the risks, benefits, and cost if used among non-hemophiliacs. Prospective randomized studies are needed to investigate the efficacy and cost-effectiveness of rFVIIa for this indication and to allow a final assessment of the importance of this treatment.
doi:10.4103/0256-4947.62830
PMCID: PMC2886869  PMID: 20427935
14.  Cost effectiveness of recombinant factor VIIa for treatment of intracerebral hemorrhage 
BMC Neurology  2008;8:17.
Background
Phase I/II placebo-controlled clinical trials of recombinant Factor VIIa (rFVIIa) suggested that administration of rFVIIa within 4 hours after onset of intracerebral hemorrhage (ICH) is safe, limits ICH growth, and improves outcomes. We sought to determine the cost-effectiveness of rFVIIa for acute ICH treatment, using published Phase II data. We hypothesized that rFVIIa would have a low marginal cost-effectiveness ratio (mCER) given the poor neurologic outcomes after ICH with conventional management.
Methods
We performed an incremental cost-effectiveness analysis from the societal perspective, considering conventional management vs. 80 ug/kg rFVIIa treatment for acute ICH cases meeting Phase II inclusion criteria. The time frame for the analysis was 1. 25 years: data from the Phase II trial was used for 90 day outcomes and rFVIIa complications – arterial thromboembolic events (ATE). We assumed no substantial cost differences in care between the two strategies except: 1) cost of rFVIIa (for an 80 mcg/kg dose in an 80 kg patient, assumed cost of $6,408); 2) cost of ATE side effects from rFVIIa (which also decrease quality of life and increase the chance of death); and 3) differential monetary costs of outcomes and their impact on quality of life, including disposition (home vs. nursing home), and outpatient vs. inpatient rehabilitation. Sensitivity analyses were performed to explore uncertainty in parameter estimates, impact of rFVIIa cost, direct cost of neurologic outcomes, probability of ATE, and outcomes after ATE.
Results
In the "base case", treating ICH with rFVIIa dominates the usual care strategy by being more effective and less costly. rFVIIa maintained a mCER < $50,000/QALY over a wide range of sensitivity analyses. Sensitivity analyses showed that the cost of rFVIIa must exceed $14,500, or the frequency of ATE exceed 29%, for the mCER to exceed $50,000/QALY. Varying the cost and/or reducing the utility of health states following ATE did not impact results.
Conclusion
Based on data from preliminary trials, treating selected ICH patients with rFVIIa results in lower cost and improved clinical outcomes. This potential cost-effectiveness must be considered in light of the Phase III trial results.
doi:10.1186/1471-2377-8-17
PMCID: PMC2397434  PMID: 18489750
15.  The use of recombinant activated coagulation factor VII for spine surgery 
European Spine Journal  2004;13(Suppl 1):S83-S88.
This article focuses on our current understanding of the role of activated coagulation factor VII (FVIIa) in coagulation, the current evidence regarding the efficacy and safety of recombinant FVIIa (rFVIIa), and thoughts regarding the use of rFVIIa in spine surgery. rFVIIa is approved in many countries (including the European Union and the USA) for patients with hemophilia and inhibitors (antibodies) to coagulation factors VIII or IX. High circulating concentrations of FVIIa, achieved by exogenous administration, initiate hemostasis by combining with tissue factor at the site of injury, producing thrombin, activating platelets and coagulation factors II, IX and X, thus providing for the full thrombin burst that is essential for hemostasis. This “bypass” therapy has led some clinicians to use rFVIIa “off-label” for disorders of hemostasis other than hemophilia. Based on clinical experience, case reports and limited information from clinical trials, rFVIIa may be efficacious in states of decreased concentration of coagulation factors, thrombocytopenia, and at least some states of altered platelet function. The former two can occur intra-operatively during spinal surgery as a consequence of substantial blood loss and normal consumption. Preliminary reports have indicated that rFVIIa does not increase the perioperative incidence of thromboembolic events. However, full reports from large clinical trials regarding the efficacy and safety of rFVIIa in settings other than hemophilia have yet to appear in peer-reviewed publications. Until adequate data demonstrating safety and efficacy are fully reported, it would seem appropriate to reserve the use of rFVIIa in spinal surgery to those instances where conventional therapy cannot provide adequate hemostasis, and “rescue” therapy is required.
doi:10.1007/s00586-004-0736-y
PMCID: PMC3592181  PMID: 15160317
Blood loss; Coagulation; Coagulopathy; Hemostasis; Recombinant coagulation factor VIIa
16.  The utility of recombinant factor VIIa as a last resort in trauma 
Introduction
The use of recombinant factor VII (rFVIIa) as a last resort for the management of coagulopathy when there is severe metabolic acidosis during large bleedings in trauma might be deemed inappropriate. The objective of this study was to identify critical degrees of acidosis and associated factors at which rFVIIa might be considered of no utility.
Methods
All massively transfused (≥ 8 units of red blood cells within 12 hours) trauma patients from Jan 2000 to Nov 2006. Demographic, baseline physiologic and rFVIIa dosage data were collected. Rate of red blood cell transfusion in the first 6 hours of hospitalization (RBC/hr) was calculated and used as a surrogate for bleeding. Last resort use of rFVIIa was defined by a pH≤ 7.02 based on ROC analysis for survival. In-hospital mortality was analyzed in last resort and non-last resort groups. Univariate analysis was performed to assess for differences between groups and identify factors associates with no utility of rFVIIa.
Results
71 patients who received rFVIIa were analyzed. The pH> 7.02 had 100% sensitivity for the identification of potential survivors. All 11 coagulopathic, severely acidotic (pH ≤ 7.02) patients with high rates of bleeding (4RBC/hr) died despite administration of rFVIIa. The financial cost of administering rFVIIa as a last resort to these 11 severely acidotic and coagulophatic cases was $75,162 (CA).
Conclusions
Our study found no utility of rFVIIa in treating severely acidotic, coagulopathic trauma patients with high rates of bleeding; and thus restrictions should be set on its usage in these circumstances.
doi:10.1186/1749-7922-7-S1-S7
PMCID: PMC3424973  PMID: 23531130
17.  Evaluation of Recombinant Factor VIIa Treatment for Massive Hemorrhage in Patients with Multiple Traumas 
Annals of Laboratory Medicine  2012;32(2):145-152.
Background
Recent studies and case reports have shown that recombinant factor VIIa (rFVIIa) treatment is effective for reversing coagulopathy and reducing blood transfusion requirements in trauma patients with life-threatening hemorrhage. The purpose of this study is to evaluate the effect of rFVIIa treatment on clinical outcomes and cost effectiveness in trauma patients.
Methods
Between January 2007 and December 2010, we reviewed the medical records of patients who were treated with rFVIIa (N=18) or without rFVIIa (N=36) for life-threatening hemorrhage due to multiple traumas at the Emergency Department of Pusan National University Hospital in Busan, Korea. We reviewed patient demographics, baseline characteristics, initial vital signs, laboratory test results, and number of units transfused, and then analyzed clinical outcomes and 24-hr and 30-day mortality rates. Thromboembolic events were monitored in all patients. Transfusion costs and hospital stay costs were also calculated.
Results
In the rFVIIa-treated group, laboratory test results and clinical outcomes improved, and the 24-hr mortality rate decreased compared to that in the untreated group; however, 30-day mortality rate did not differ between the groups. Thromboembolic events did not occur in both groups. Transfusion and hospital stay costs in the rFVIIa-treated group were cost effective; however, total treatment costs, including the cost of rFVIIa, were not cost effective.
Conclusions
In our study, rFVIIa treatment was shown to be helpful as a supplementary drug to improve clinical outcomes and reduce the 24-hr mortality rate, transfusion and hospital stay costs, and transfusion requirements in trauma patients with life-threatening hemorrhage.
doi:10.3343/alm.2012.32.2.145
PMCID: PMC3289780  PMID: 22389882
Recombinant factor VIIa; Multiple trauma; Clinical outcome; Mortality rate; Treatment cost
18.  Recombinant activated factor VIIa for the treatment of bleeding in major abdominal surgery including vascular and urological surgery: a review and meta-analysis of published data 
Critical Care  2008;12(1):R14.
Background
The purpose of this study was to determine the role of recombinant activated factor VII (rFVIIa) in abdominal, vascular, and urological surgery.
Methods
We conducted meta-analyses of case series and placebo-controlled studies reporting on the treatment or prophylaxis of bleeding with rFVIIa regarding 'reduction or cessation of bleeding', 'mortality', and 'thromboembolism'.
Results
All case reports (n = 15 case reports and 17 patients) documented an effect of rFVIIa in the treatment of bleeding. A meta-analysis of 10 case series revealed a reduction or cessation of bleeding in 39 out of 50 patients after administration of rFVIIa (estimated mean effect 73.2%, 95% confidence interval [CI] 51.0% to 95.4%) and a mean probability of survival of 53.0% (95% CI 26.4% to 79.7%). Among the rFVIIa responders, 19 out of 29 patients (66%) survived versus 1 out of 10 rFVIIa nonresponders (P = 0.003). Six out of 36 patients from the case series had a thromboembolic complication (estimated mean probability 16.5%, 95% CI 1.2% to 31.8%). Compared with a meta-analysis of eight placebo-controlled studies, no increased risk of thromboembolism was seen after administration of rFVIIa.
Conclusion
The meta-analysis of case series showed that, in a mean of 73% patients, rFVIIa achieved at least a reduction of bleeding and that the probability of survival is increased in patients responding to rFVIIa. rFVIIa was not associated with an increased risk of thromboembolism compared with placebo.
doi:10.1186/cc6788
PMCID: PMC2374636  PMID: 18279513
19.  Intrapulmonary administration of recombinant activated factor VII in diffuse alveolar haemorrhage: a report of two case stories 
Cases Journal  2008;1:150.
Background
Diffuse alveolar haemorrhage (DAH) is a serious pulmonary complication characterised by a high mortality rate and the absence of specific treatment. The intrapulmonary administration of activated recombinant factor VII (rFVIIa) in DAH was recently published in six patients by Heslet et al with an efficient hemostatic effect. We describe two cases of DAH treated with intrapulmonary rFVIIa.
Methods
Two cases of DAH were admitted to the ICU after presenting abrupt desaturation, tachypnea, cough and haemoptysis, requiring orotracheal intubation and mechanical ventilation. The diagnosis was achieved by the bloody return during the bronchoalveolar lavage, during the procedure rFVIIa (50 μg/Kg in 50 ml of isotonic saline) was administered via the bronchoscope.
Results
Immediate cessation of bleeding was observed. Prior to intrapulmonary administration of rFVIIa, the FiO2 was 1, which was reduced to 0.4 24 hours later. Following the procedure, the haemostatic effect made blood transfusion superfluous. No thrombotic complications associated with administration of the drug were observed. After the intervention both cases progressed fast and was discharged from the ICU with no further episodes of bleeding.
Conclusion
1. Local intrabronchial deposition of DAH with rFVIIa has been shown to be effective in controlling life-threatening DAH. 2. In the case described above, no thrombotic complications were observed following the intrapulmonary administration of rFVIIa.
doi:10.1186/1757-1626-1-150
PMCID: PMC2551590  PMID: 18789132
20.  Recombinant activated factor VII as an adjunctive therapy for bleeding control in severe trauma patients with coagulopathy: subgroup analysis from two randomized trials 
Critical Care  2006;10(6):R178.
Introduction
We conducted a post-hoc analysis on the effect of recombinant factor VIIa (rFVIIa) on coagulopathic patients from two randomized, placebo-controlled, double-blind trials of rFVIIa as an adjunctive therapy for bleeding in patients with severe trauma.
Methods
Blunt and penetrating trauma patients were randomly assigned to rFVIIa (200 + 100 + 100 μg/kg) at 0, 1, and 3 hours after transfusion of 8 units of red blood cells (RBCs) or to placebo. Subjects were monitored for 48 hours post-dosing and followed for 30 days. Coagulopathy was retrospectively defined as transfusion of fresh frozen plasma (FFP) (>1 unit of FFP per 4 units of RBCs), FFP in addition to whole blood, and transfusion of platelets and/or cryoprecipitate.
Results
Sixty rFVIIa-treated and 76 placebo subjects were retrospectively identified as being coagulopathic. No significant differences were noted in baseline characteristics. The rFVIIa-treated coagulopathic subgroup consumed significantly less blood product: RBC transfusion decreased by 2.6 units for the whole study population (P = 0.02) and by 3.5 units among patients surviving more than 48 hours (P < 0.001). Transfusion of FFP (1,400 versus 660 ml, P < 0.01), platelet (300 versus 100 ml, P = 0.01), and massive transfusions (29% versus 6%, P < 0.01) also dropped significantly. rFVIIa reduced multi-organ failure and/or acute respiratory distress syndrome in the coagulopathic patients (3% versus 20%, P = 0.004), whereas thromboembolic events were equally present in both groups (3% versus 4%, P = 1.00).
Conclusion
Coagulopathic trauma patients appear to derive particular benefit from early adjunctive rFVIIa therapy.
doi:10.1186/cc5133
PMCID: PMC1794494  PMID: 17184516
21.  Bio-distribution of pharmacologically administered recombinant factor VIIa (rFVIIa) 
Summary
Background
Recent clinical studies suggest that the prophylactic use of recombinant factor VIIa (rFVIIa) markedly reduces the number of bleeding episodes in hemophilic patients with inhibitors. Given the short biological half-life of rFVIIa, it is unclear how rFVIIa could be effective in prophylactic treatment.
Objectives
To examine the extravascular distribution of pharmacologically administered rFVIIa to obtain clues on how rFVIIa could work in prophylaxis.
Methods
Recombinant mouse FVIIa tagged with AF488 fluorophore (AF488-FVIIa) was administered into mice via the tail vein. At different time intervals following the administration, mice were exsanguinated and various tissues were collected. The tissue sections were processed for immunohistochemistry to evaluate distribution of rFVIIa.
Results
rFVIIa, immediately following the administration, associated with the endothelium lining of large blood vessels. Within 1 h, rFVIIa bound to endothelial cells was transferred to the perivascular tissue surrounding the blood vessels and thereafter diffused throughout the tissue. In the liver, rFVIIa was localized to sinusoidal capillaries and accumulated in hepatocytes. In bone, rFVIIa was accumulated in the zone of calcified cartilage and some of it was retained there for a week. The common finding of the present study is that rFVIIa in extravascular spaces was mostly localized to regions that contain TF expressing cells.
Conclusions
The present study demonstrates that pharmacologically administered rFVIIa readily associates with the vascular endothelium and subsequently enters into extravascular spaces where it is likely to bind to TF and is retained for extended time periods. This may explain the prolonged pharmacological effect of rFVIIa.
doi:10.1111/j.1538-7836.2009.03696.x
PMCID: PMC2849270  PMID: 19943873
bio-distribution; endothelial cell protein C receptor; hemophilia; prophylaxis; rFVIIa; tissue factor
22.  Is recombinant activated factor VII effective in the treatment of excessive bleeding after paediatric cardiac surgery? 
A best evidence topic in paediatric cardiac surgery was written according to a structured protocol. The question addressed was whether recombinant activated factor VII was effective for the treatment of excessive bleeding after paediatric cardiac surgery. Altogether 150 papers were found using the reported search; 13 papers were identified that provided the best evidence to answer the question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these studies were tabulated. A total of 311 children experienced excessive bleeding following cardiac surgery that was refractory to the conventional methods of achieving haemostasis. One hundred and ninety-two patients received the rFVIIa while 116 were in control arm from five studies. The primary end-point was on chest tube drainage, the plasma prothrombin time, the activated partial thromboplastin time after the administration of rFVIIa and the secondary end-point was reduction of blood products transfusion. Thrombosis was a complication in 8 patients (4.2%); three deaths (1.6%) but not attributable to thromboembolic events following the use of rFVIIa. Most of the studies failed to clearly state the doses but the extracted doses ranged between 30 and 180 µg/kg/dose, the interval between doses ranged between 15 and 120 min with a maximum of four doses. However, most of the patients had 180 µg/kg/dose with interval between dose of 2 h and maximum of two doses with dosage moderated with respect to weight, prior coagulopathy and responsiveness. There were two randomized studies with good sample size. One showed no significant differences in the secondary end points between the two arms and noted no adverse complications. However, the rFVIIa was used prophylactically. The other observed that there were no increase in thromboembolic events rather rFVIIa was effective in decreasing excessive bleeding that may complicate cardiac surgery in children. In conclusion, the studies were in support of the notion that the use of rFVIIa was effective in decreasing excessive bleeding which may complicate paediatric cardiac surgery, and care should be exercised when using it in the children on ECMO circuit.
doi:10.1093/icvts/ivs309
PMCID: PMC3445385  PMID: 22811512
Recombinant activated factor VII; Excessive bleeding; Paediatric cardiac surgery
23.  Recombinant factor VIIa for uncontrollable bleeding in patients with extracorporeal membrane oxygenation: report on 15 cases and literature review 
Critical Care  2013;17(2):R55.
Introduction
Bleeding is the most frequent complication in patients receiving venoarterial or venovenous extracorporeal membrane oxygenation (ECMO). Recombinant activated factor VII (rFVIIa) has been used in these patients with conflicting results. We describe our experience with rFVIIa for refractory bleeding in this setting and review the cases reported in the literature.
Methods
Clinical characteristics, demographics, bleeding, thrombotic complications, mortality, and rFVIIa administration were retrospectively collected for analysis from the electronic charts of the 15 patients in our intensive care unit who received rFVIIa while being given ECMO from January 2006 to March 2011.
Results
Fifteen patients received rFVIIa for persistent bleeding under venoarterial (n = 11) or venovenous (n = 4) ECMO. Bleeding dramatically decreased in 14 patients, without a major thrombotic event, except in one patient in whom a major stroke could not be ruled out. Two circuits were changed within the 48 hours after rFVIIa administration for clots in the membrane and decreased oxygenation but without massive clotting. The mortality rate was 60%.
Conclusions
rFVIIa use for intractable hemorrhaging in patients receiving ECMO controlled bleeding, without major thrombotic events, and with 60% dying. Hence, its use warrants discussion, and clinicians should be aware of the possibility of potentially life-threatening systemic thrombosis, emboli, or circuit clotting. Whether rFVIIa can save the lives of such patients remains to be determined.
doi:10.1186/cc12581
PMCID: PMC4057417  PMID: 23531278
24.  The Australian and New Zealand Haemostasis Registry: ten years of data on off-licence use of recombinant activated factor VII 
Blood Transfusion  2015;13(1):86-99.
Background
Recombinant activated factor VII (rFVIIa) has been widely used as an off-licence pan-haemostatic agent in patients with critical bleeding. However, outside the trauma setting, there is relatively little high quality evidence on the risks and benefits of this agent. The Haemostasis Registry was established to investigate the extent of use, dosing, safety and outcomes of patients after off-licence rFVIIa treatment of critical bleeding.
Materials and methods
The Registry recruited non-haemophiliac patients treated with rFVIIa from 2000–2009 (inclusive) in Australia and New Zealand. Detailed information was gathered on patients’ demographics, context of bleeding, rFVIIa administration, laboratory results, blood component and other therapies, and outcomes. Outcome measures included subjectively assessed effect of rFVIIa on bleeding (response), adverse events (thromboembolic and other) and 28-day mortality.
Results
The registry included 3,446 cases in 3,322 patients (median [IQR] age 56 [33–70] years, 65% (n=2,147) male). Clinical indications included cardiac surgery (45%), other surgery (18%), trauma (13%), medical bleeding (6%), liver disease (6%), and obstetric haemorrhage (5%). The median [IQR] dose was 91 [72–103] μg/kg and 77% received a single dose. Reduction or cessation of bleeding was reported in 74% and 28-day survival was 71% but outcomes varied depending on clinical context. pH strongly correlated with outcome measures; 81% of patients with pH <7.1 died. Approximately 11% of patients had thromboembolic adverse events. In multivariate analysis, pH prior to administration and bleeding context were independently associated with reported response to rFVIIa and 28-day mortality.
Discussion
The Haemostasis Registry is the largest dataset of its kind and provides observational data on the off-licence use of rFVIIa over a 10-year period. It has been an invaluable resource for rigorously tracking adverse events and helping to inform clinical practice.
doi:10.2450/2014.0260-13
PMCID: PMC4317095  PMID: 24960661
Haemostasis Registry; rFVIIa; NovoSeven®; critical bleeding; haemostasis
25.  Recommendations on the use of recombinant activated factor VII as an adjunctive treatment for massive bleeding – a European perspective 
Critical Care  2006;10(4):R120.
Introduction
Our aim was to develop consensus guidelines for use of recombinant activated factor VII (rFVIIa) in massive hemorrhage.
Methods
A guidelines committee derived the recommendations using clinical trial and case series data identified through searches of available databases. Guidelines were graded on a scale of A to E (with A being the highest) according to the strength of evidence available. Consensus was sought among the committee members for each recommendation.
Results
A recommendation for the use of rFVIIa in blunt trauma was made (grade B). rFVIIa might also be beneficial in post-partum hemorrhage (grade E), uncontrolled bleeding in surgical patients (grade E), and bleeding after cardiac surgery (grade D). rFVIIa could not be recommended for use in the following: in penetrating trauma (grade B); prophylactically in elective surgery (grade A) or liver surgery (grade B); or in bleeding episodes in patients with Child–Pugh A cirrhosis (grade B). Efficacy of rFVIIa was considered uncertain in bleeding episodes in patients with Child–Pugh B and C cirrhosis (grade C). Monitoring of rFVIIa efficacy should be performed visually and by assessment of transfusion requirements (grade E), while thromboembolic adverse events are a cause for concern. rFVIIa should not be administered to patients considered unsalvageable by the treating medical team.
Conclusion
There is a rationale for using rFVIIa to treat massive bleeding in certain indications, but only adjunctively to the surgical control of bleeding once conventional therapies have failed. Lack of data from randomized, controlled clinical trials, and possible publication bias of the case series data, limits the strength of the recommendations that can be made.
doi:10.1186/cc5026
PMCID: PMC1750973  PMID: 16919168

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