The Journal of TRAUMA Injury, Infection, and Critical Care

Reversal of Coagulopathy in Critically Ill Patients With Traumatic Brain Injury: Recombinant Factor VIIa is More Cost-Effective Than Plasma
Deborah M. Stein, MD, MPH, Richard P. Dutton, MD, MBA, Mary E. Kramer, RN, and Thomas M. Scalea, MD
Background: Traumatic brain injury (TBI) is the leading cause of death and disability after trauma. Coagulopathy is common in this patient population and requires rapid reversal to allow for safe neurosurgical intervention and prevent worsening of the primary injury. Typically reversal of coagulopathy is accomplished with the use of plasma. Recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) has become increasingly used off-label in patients with neurosurgical emergencies to rapidly reverse coagulopathy. We hypothesized that the use of rFVIIa in this patient population would prove to be cost-effective as well as demonstrate clinical benefit. Methods: The trauma registry at the R Adams Cowley Shock Trauma Center was used to identify all coagulopatic trauma patients admitted between January 2002 and December 2007 with relatively isolated TBI (head Abbreviated Injury Scale score of >4). The medical records of patients were reviewed and demographics, injury-specific data, medications administered, laboratory values, blood product utilization, neurosurgical procedures, length of stay (LOS), discharge disposition, and outcome data were
abstracted. Patients who received rFVIIa for reversal of coagulopathy were compared against those who did not receive rFVIIa. t Tests were used to compare differences between continuous variables, and 2 analysis was used to compare categorical variables. A p value of <0.05 was considered significant for all statistical tests. Results: During a 6-year period, there were 179 patients who met inclusion criteria. One hundred eleven patients (62.0%) were treated with conventional therapy alone whereas 68 (38.0%) received rFVIIa. Baseline characteristics between the two groups were similar except that Injury Severity Score and admission International normalized ratio were higher in the rFVIIa group and the rFVIIa group had a higher percentage of patients with head Abbreviated Injury Scale score of 5 injuries, patients who underwent neurosurgical procedures and patients with preinjury warfarin use. There was no difference in total charges between these groups (mean US $63,403 in the conventionally treated group vs. $66,086). When patients who required admission to the intensive care unit were analyzed (n 110, 50% received rFVIIa), total mean charges and costs were significantly lower in the group that received rFVIIa (mean US $108,900 vs. $77,907). Hospital LOS, days of mechanical ventilation, and plasma utilization were lower in the rFVIIa group. Mortality and thromboembolic complication rates were not different between the two groups. Conclusion: In this study, we were able to demonstrate a significant economic benefit of the use of rFVIIa for reversal of coagulopathy in severely injured patients with TBI. Not all patients with coagulopathy and an anatomic brain injury benefit, but in patients who are neurologically or physiologically compromised, using rFVIIa decreases total charges and costs of hospitalization. This decrease in overall cost is directly attributable to the significant decrease in LOS and decrease in the need for mechanical ventilation. This study demonstrates that in coagulopathic patients with TBI who require intensive care unit admission, rFVIIa is cost-effective and safe. Prospective studies are needed to confirm these findings and establish clinical effectiveness. Key Words: Trauma, Traumatic brain injury, Coagulopathy, rFVIIa, Cost-effectiveness.
J Trauma. 2009;66:6375.

raumatic brain injury (TBI) is the leading cause of death and disability after trauma.1 TBI is responsible for as many as 50,000 deaths each year and more than 235,000 hospitalizations.2 In patients who survive the acute injury, long-term morbidity is often profound with estimations of more than 5 million people currently living in the United States with long-term needs for assistance because of the functional disabilities from a TBI.3

Coagulopathy is common in patients with TBI.4 6 In several studies, coagulopathy in patients with TBI is associated with higher mortality rates than in noncoagulopathic patients.711 Coagulopathy may stem from a number of causes in this patient population. Hemorrhage from concomitant injuries may cause a dilutional coagulopathy or large volume crystalloid administration may contribute to a loss of available clotting factors. In addition, as the population continues to age, an increasing numPresented at the 67th Annual Meeting of the American Association for the Surgery of Trauma, September 24 27, 2008, Maui, Hawaii. R.P.D. serves as a paid consultant to NovoNordisk. Address for reprints: Deborah M. Stein, MD, MPH, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201; email: dstein@umm.edu. DOI: 10.1097/TA.0b013e318191bc8a

Submitted for publication August 20, 2008. Accepted for publication October 17, 2008. Copyright 2009 by Lippincott Williams & Wilkins From the R. Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, Maryland. Supported by research funding from NovoNordisk (to D.M.S. and T.M.S.).

Volume 66 Number 1

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The Journal of TRAUMA Injury, Infection, and Critical Care

ber of patients may be taking preinjury anticoagulants such as warfarin. Use of these medications is associated with a markedly higher mortality rate in injured patients.12 Even in the absence of these other factors, coagulopathy can occur as a direct result of brain injury. This is thought to be because of the release of tissue thromboplastin and activation of systemic fibrinolysis.4,6 8 Coagulopathy in patients with TBI precludes safe neurosurgical intervention and may result in worsening of the primary injury if left untreated. Coagulopathy in this patient population is typically reversed with the use of fresh frozen or thawed fresh plasma and vitamin K. This therapy may result in slow correction times and a delay in vital therapy. The volume of plasma required to normalize coagulation is variable and unpredictable, and simple replacement of clotting factors with plasma may not achieve normal coagulation in patients with significant physiologic dysfunction. In addition, not only can large volumes of plasma precipitate pulmonary edema in patients with cardiac dysfunction, a number of studies have also documented worse outcomes in patients who required large volume transfusions of plasma during acute care hospitalizations.1316 Recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) is a drug developed for treatment of hemophiliacs with inhibitors to factors VIII and IX.9,17 Recombinant factor VIIa has become increasingly used off-label in patients for both traumatic and nontraumatic neurosurgical emergencies.18 36 However, to date, no randomized prospective trial has been published describing efficacy in this patient population. A number of case series and retrospective studies have demonstrated effective use in coagulopathic patients with TBI.18,21,30,31,33,36 Recombinant activated factor VII is expensive, however, costing approximately US $1.00 per microgram. Complete reversal of coagulopathy with rFVIIa can thus cost up to US $10,000. Given the lack of high-quality evidence describing clinical effectiveness of this therapy, significant questions have been raised about the cost-effectiveness of the use of rFVIIa in these off-label clinical scenarios, especially in light of the frequency of its use in many hospitals.20,30,32,37 42 At the R Adams Shock Trauma Center (STC), we have used rFVIIa on an off-label basis since 2001. We began using this therapy initially for acute traumatic hemorrhage and extended our use to patients with coagulopathy and TBI. Given the results of recent work from our institution demonstrating a decreased time to neurosurgical intervention in coagulopathic patients with severe TBI and a trend toward a decreased length of stay (LOS),30 we hypothesized that the use of rFVIIa in this patient population would prove to be cost-effective as well as demonstrate clinical benefit. other body region AIS score of 3 were then excluded to limit the effect of hemorrhage and coagulopathy from significant concomitant injuries on the decision to use rFVIIa. All patients who were coagulopathic at admission (International normalized ratio, INR 1.4) were identified. This definition of coagulopathy was chosen because this is the clinical value at which our neurosurgeons request normalization in patients with TBI. We are unaware of any data that support this practice, but given the retrospective nature of this work, utilization of the clinical trigger for reversal of coagulopathy at our institution was chosen for the definition of coagulopathy for the purposes of this study. The medical records of patients were reviewed. Patients who died within 24 hours of admission and those that were deemed nonsurvivable at the time of neurosurgical consultation, and therefore no reversal of coagulopathy was attempted, were excluded. During the study period, the neurosurgical management of all patients was done by a single neurosurgical group and according to an institutional protocol based on the Brain Trauma Foundation Guidelines.43 Administration of rFVIIa for all patients at STC is requested by the attending surgeon, intensivist, or anesthesiologist, and requires approval from an institutional gatekeeper. Request for the use of rFVIIa for reversal of coagulopathy in patients with TBI was entirely at the discretion of the treating physician and was nonprotocolized. The gatekeepers monitor usage and recommend dosing based on the clinical status of the patient. The medical records of all study subjects were reviewed and demographics, injury-specific data, medications administered, laboratory values, blood product utilization, LOS, discharge disposition, and outcome data were abstracted. Neurosurgical procedures, including craniotomy, intraventricular catheter placement, fiberoptic pressure monitor placement, or subdural drain placement, were also recorded. Financial data were obtained from the Finance Office at the STC. Patients who met inclusion criteria for the study who received rFVIIa for reversal of coagulopathy were identified and compared against those who met inclusion criteria but did not receive rFVIIa. t Tests were used to compare differences between continuous variables, and 2 analysis was used to compare categorical variables. A p value of 0.05 was considered significant for all statistical tests.

RESULTS
During a 6-year period, there were 36,624 injured patients admitted to the R Adams Cowley STC, 2,997 with an anatomic severe TBI (head AIS score of 4). Of these patients, 1,671 were identified with a relatively isolated TBI (no other body region AIS score of 3). Of these, 302 were found to be coagulopathic at admission (INR 1.4). Upon review of the patients records, 76 patients with a LOS 24 hours were excluded, as were 47 patients in whom no attempt at reversal of coagulopathy was attempted because of nonsurvivability. One hundred seventy-nine patients were subsequently included for further analysis. One hundred eleven (62.0%) were treated with conventional therapy alone whereas 68 (38.0%) received rFVIIa January 2009

MATERIALS AND METHODS

After approval by the University of Maryland Institutional Review Board, the trauma registry at the R Adams Cowley STC was used to identify all trauma patients admitted between January 2002 and December 2007 with an anatomic TBI (head Abbreviated Injury Scale, AIS score of 4). Patients with any 64

Reversal of Coagulopathy in TBI Patients

Fig. 1. Study population.

Table 1 Baseline Characteristics of All Patients

No rFVIIa (n 111) Mean rFVIIa (n 68) Mean p

Age (yr) ISS Predicted survival (TRISS) RTS Admission GCS Admission INR Male Blunt injury Head AIS 4 5 Neurosurgical intervention Cause of coagulopathy Warfarin TBI alone Cirrhosis

57.4 24.0 0.77 6.56 10.6 1.9 n 71 106 75 36 41

23.2 7.2 0.25 1.67 4.9 0.7 % 64.0 95.5 67.6 32.4 36.9

61.4 26.7 0.75 6.60 10.2 2.5 n 43 65 32 36 48

24.9 8.0 0.23 1.50 4.4 0.7 % 63.2 95.6 47.1 52.9 70.6

0.273 0.024 0.586 0.858 0.574 0.001 p 0.914 0.975 0.007 0.007 0.001

54 46 9

48.6 41.4 8.1

45 21 3

66.2 30.9 4.4

0.028 0.161 0.338

ISS, Injury Severity Score; TRISS, Trauma Score, Injury Severity Score; RTS, Revised Trauma Score; GCS, Glasgow Coma Scale; PT, prothrombin time; INR, International normalized ratio; AIS, Abbreviated Injury Scale; TBI, traumatic brain injury.

for reversal of their coagulopathy (Fig. 1). Doses of rFVIIa administered ranged from 5.9 g/kg to 115 g/kg (mean 41.9 35.5, median 25.1). Volume 66 Number 1

Baseline characteristics between the two groups were compared. There were no differences in age, predicted survival (Trauma Score Injury Severity Score), admission revised trauma score, or admission Glasgow Coma Scale (GCS) in the two groups, whereas Injury Severity Score and admission INR were significantly higher in the rFVIIa group. There was no difference in sex distribution or mechanism of injury between the groups, but the rFVIIa group had a higher percentage of patients with head AIS score of 5 injuries (as compared with AIS score equal to 4), a greater frequency of patients who underwent neurosurgical procedures and a higher percentage of patients with preinjury warfarin use as the cause of their coagulopathy. Table 1 depicts the characteristics of these two groups. There was no significant difference in total hospital charges or costs between the two groups (Fig. 2). When stratified by cost center, pharmacy charges and costs were significantly higher in the group that received rFVIIa (Fig. 3, A and B). Outcome measures were also evaluated. Outcome data for the two groups are detailed in Table 2. LOS and intensive care unit LOS (ICU-LOS) were the same in the two groups, but functional outcome measures for survivors, such as discharge GCS and Rancho Los Amigos Cognitive Scale (RLAS), were higher in the conventionally treated patients. There was no difference in mortality rates (18.9% in the no rFVIIa group vs. 26.5% in the rFVIIa group, p 0.5) or thromboembolic complication rates (16.2% vs. 19.1%, p 0.6). Thromboembolic complications in the conventionally treated group included two territorial cerebral infarctions (CI), one CI secondary to brain herniation, two suspected CIs, one cardiac 65

The Journal of TRAUMA Injury, Infection, and Critical Care

Table 2 Outcomes of All Patients
No rFVIIa (n 111) Mean rFVIIa (n 68) Mean p

LOS (d) ICU-LOS (d) Discharge GCS Discharge RLAS Mortality Thromboembolic complications

11.7 13.9 8.5 14.2 13.2 2.6 5.9 2.0 n % 21* 18 18.9 16.2

11.8 10.1 0.976 10 10.2 0.465 11.9 2.6 0.006 5.2 2.0 0.036 n % p 18 13 26.5 0.517 19.1 0.233

Fig. 2. Total charges and costs for all patients.

* Withdrawal of care in 13 of 21 patients. Withdrawal of care in 16 of 18 patients. LOS, length of stay; ICU, Intensive Care Unit; GCS, Glasgow Coma Scale; RLAS, Rancho Los Amigos Cognitive Scale.

Fig. 3. (A) Charges for all patients. (B) Costs for all patients.

thrombus, four myocardial infarctions, three patients with myocardial ischemia manifested by elevated cardiac enzymes, two deep venous thromboses, and five pulmonary emboli. In the 68 patients in the rFVIIa group, there were one territorial CI, three CIs secondary to brain herniation, two suspected CIs, one cardiac thrombus, three myocardial infarctions, one patient with myocardial ischemia, two deep 66

venous thromboses, one pulmonary emboli, and one patient with a sagittal sinus thrombosis. When the patient populations included for analysis were examined in detail, it was realized that there were a large percentage of patients who had a head AIS score of 4 or 5 injury on CT, but were not physiologically or neurologically compromised. These patients had markedly different baseline characteristics and outcomes than patients who required ICU admission (Table 3). Therefore, to better evaluate the effectiveness and potential cost benefit in patients who had significant neurologic or physiologic sequelae of their injuries, patients who required admission to the ICU were analyzed separately. There were 110 patients (61.4%) who required ICU admission. Fifty-five (50%) received conventional therapy alone and 55 received rFVIIa. Baseline characteristics of these two groups are shown in Table 4. The group that received rFVIIa had a higher mean admission INR, a higher percentage of AIS score of 5 head injuries, more neurosurgical interventions, and was more likely to have preinjury warfarin use as the primary cause of their coagulopathy. Admission Injury Severity Score, predicted survival, revised trauma score, and admission GCS were no different between the two groups. For patients requiring ICU admission, total mean charges and costs were significantly lower in the group that received rFVIIa (Fig. 4). When analyzed by cost center, hospital (bed), laboratory, blood bank, respiratory service and rehabilitation service charges, and costs were less in the group that received rFVIIa (Fig. 5, A and B). When outcome measures were evaluated, total days of mechanical ventilation and LOS were significantly lower in the rFVIIa group (Table 5). Charges and costs per day of hospitalization were analyzed to determine the effect of LOS on total charges and costs. A nonsignificant increase in charges and cost per day of admission was noted in the group that received rFVIIa (Fig. 6). When charges and costs per day were stratified by cost center, pharmacy charges and costs were significantly higher in the rFVIIa January 2009

Reversal of Coagulopathy in TBI Patients

Table 3 Comparison of Patients Requiring ICU Admission and Those Who Did Not
ICU (n 110) Mean Mean No ICU (n 69) p

Age (yr) ISS Predicted survival (TRISS) RTS Admission GCS Admission INR LOS (d) Discharge GCS Discharge RLAS Total charges (US $) Total costs (US $) Male Blunt injury Head AIS 4 5 Neurosurgical intervention Cause of coagulopathy Warfarin TBI alone Cirrhosis Received rFVIIa Mortality Thromboembolic complications

55.8 26.8 0.70 6.13 8.8 2.2 16.6 11.2 4.5 92,814 65,274 n 72 103 56 54 77 52 51 6 55 31* 24

23.9 7.9 0.26 1.63 4.6 1.1 13.9 2.8 1.8 76,944 54,205 % 65.4 93.6 50.9 49.1 70.0 47.3 46.4 5.4 50.0 28.2 21.8

63.9 22.2 0.86 7.29 13.1 2.1 4.1 14.6 7.1 19,161 13,025 n 41 67 51 18 12 47 16 5 13 8 8

23.0 6.1 0.18 1.26 3.8 0.7 2.7 1.0 1.2 14,074 9,308 % 59.4 97.1 73.9 26.1 17.4 68.1 23.2 8.7 18.8 13.0 11.6

0.027 0.001 0.001 0.001 0.001 0.545 0.001 0.001 0.001 0.001 0.001 p 0.419 0.299 0.003 0.003 0.001 0.007 0.002 0.390 0.001 0.001 0.085

* Withdrawal of care in 22 of 31 patients. Withdrawal of care in 7 of 8 patients. ISS, Injury Severity Score; TRISS, Trauma Score Injury Severity Score; RTS, Revised Trauma Score; GCS, Glasgow Coma Scale; PT, prothrombin time; INR, International normalized ratio; AIS, Abbreviated Injury Scale; TBI, traumatic brain injury; LOS, length of stay; GCS, Glasgow Coma Scale; RLAS, Rancho Los Amigos Cognitive Scale.

group (Fig. 7, A and B). In addition, blood product utilization was examined for the groups who required ICU admission. There were significant differences in total units of red blood cells (RBC) and platelets administered during hospitalization between the two groups as well as significant differences in the number of units of plasma transfused in the first 24 hours of admission, as well as during the entire hospitalization (Fig. 8). Functional outcome measures for survivors recorded at discharge were no different in the two groups. Similarly, mortality and thromboembolic complication rates were not statistically different between the patients that received rFVIIa and those that were treated with conventional therapy alone (Table 5). The group that did not require ICU admission was similarly analyzed. Fifty-six patients (81.1%) were treated with conventional therapy alone and 13 were treated with rFVIIa. Baseline characteristics were no different in the group that received conventional therapy and the group that was treated with rFVIIa (Table 6). Total mean charges and costs were not significantly different between the groups (Fig. 9), but pharmacy charges and costs were significantly higher in the rFVIIa group (Fig. 10, A and B). In terms of outcome variables, no differences were noted between the two groups (Table 7). Volume 66 Number 1

DISCUSSION
Coagulopathy occurs commonly in patients with TBI and must be addressed rapidly to allow for safe neurosurgical intervention and prevent worsening of the primary injury from ongoing hemorrhage. Recombinant factor VIIa has been used in hemorrhaging trauma patients for many years.18,44 48 Numerous reports exist in the literature describing the successful use of rFVIIa in patients requiring neurosurgical intervention2123,30,31,33,35 and for the prevention of progression of injury in patients with nonsurgical intracranial bleeds.10,27,28,33,34 Recombinant activated factor VII has also been successfully used as an effective reversal agent in patients with neurosurgical emergencies who were taking preadmission warfarin.19,25,26,30,33 However, no prospective, randomized trial examining the effectiveness of rFVIIa in patients with TBI has been conducted. Reversal of coagulopathy with conventional therapy takes time and may delay neurosurgical intervention.30 In one study, it was demonstrated that the rate of correction of the INR with plasma and vitamin K is only 0.18 INR/h.49 Recent data from our institution demonstrated that coagulopathic patients with severe TBI treated with 67

The Journal of TRAUMA Injury, Infection, and Critical Care

Table 4 Baseline Characteristics of Patients Admitted to the ICU
No rFVIIa (n 55) Mean rFVIIa (n 55) Mean p

Age (yr) ISS Predicted survival (TRISS) RTS Admission GCS Admission INR Male Blunt injury Head AIS 4 5 Neurosurgical intervention Cause of coagulopathy Warfarin TBI alone Cirrhosis

51.7 26.3 0.68 6.49 8.2 1.9 n 36 52 34 21 33

22.3 8.1 0.27 1.50 4.8 0.8 % 65.5 94.5 61.8 38.2 60.0

59.7 27.1 0.74 6.69 9.7 2.5 n 36 51 22 33 44

25.1 7.7 0.23 1.40 4.3 1.3 % 65.5 92.7 40.0 60.0 80.0

0.078 0.595 0.216 0.554 0.080 0.004 p 1.000 0.700 0.024 0.024 0.024

17 32 5

30.9 58.2 9.1

35 19 1

63.6 34.5 1.8

0.001 0.014 0.095

ISS, Injury Severity Score; TRISS, Trauma Score Injury Severity Score; RTS, Revised Trauma Score; GCS, Glasgow Coma Scale; PT, prothrombin time; INR, International normalized ratio; AIS, Abbreviated Injury Scale; TBI, traumatic brain injury.

Fig. 5. (A) Charges for patients admitted to the ICU. (B) Costs for patients admitted to the ICU.

Table 5 Outcomes for Patients Admitted to the ICU

No rFVIIa (n 55) Mean rFVIIa (n 55) Mean p

Fig. 4. Total charges and costs for patients admitted to the ICU.

Ventilator days LOS (d) ICU-LOS (d) Discharge GCS Discharge RLAS Mortality Thromboembolic complications

15.4 19.4 17.2 11.5 4.6 n 15* 11

14.7 16.3 16 2.9 1.9 % 27.3 20.0

8.8 13.7 12.3 11.0 4.5 n 16 12

8.0 10.2 9.9 2.7 1.8 %

0.004 0.029 0.057 0.454 0.909 p

conventional therapy alone took, on average, three times longer to receive neurosurgical intervention.30 Despite the potential benefit of rFVIIa in achieving quicker intervention times, no statistically significant outcome differences were appreciated in this small group of patients. Cost-effectiveness of rFVIIa in patients with neurosurgical emergencies remains a topic of considerable debate.23,30,32,39,50,51 Several reports have been published attempting to address the issue of cost-effectiveness in patients treated both on-label and off-label with rFVIIa.38,39,40,50,52,53 Generally, these studies have dem68

29.1 0.834 21.8 0.817

* Withdrawal of care in 8 of 15 patients. Withdrawal of care in 14 of 16 patients. LOS, length of stay; ICU, Intensive Care Unit; GCS, Glasgow Coma Scale; RLAS, Rancho Los Amigos Cognitive Scale.

onstrated a cost benefit for patients treated with rFVIIa. In this study, we were able to demonstrate a significant economic benefit of the use of rFVIIa for reversal of coagulopathy in severely injured patients with TBI. January 2009

Reversal of Coagulopathy in TBI Patients

Fig. 6. Total charge and cost per day for patients admitted to the ICU.

Fig. 8. Blood product use in patients admitted to the ICU.

Table 6 Baseline Characteristics of Patients Not Requiring ICU Admission

No rFVIIa (n 56) Mean rFVIIa (n 13) Mean p

Age (yr) ISS Predicted survival (TRISS) RTS Admission GCS Admission INR Male Blunt injury Head AIS 4 5 Neurosurgical intervention Cause of coagulopathy Warfarin TBI alone Cirrhosis

62.9 21.8 0.86 7.28 13.0 2.0 n 35 54 41 15 8

22.9 5.4 0.18 1.23 3.8 0.6 % 62.5 96.4 73.2 26.7 14.2

68.5 24.6 0.81 7.12 12.4 2.4 n 6 13 10 3 4

23.6 9.3 0.24 1.57 4.5 0.9 % 46.1 100.0 76.9 23.1 30.7

0.438 0.142 0.374 0.697 0.604 0.050 p 0.282 0.490 0.785 0.791 0.161

37 14 4

66.1 25.0 7.1

10 2 1

76.9 15.4 7.7

0.454 0.463 0.940

ISS, Injury Severity Score; TRISS, Trauma Score Injury Severity Score; RTS, revised trauma score; GCS, Glasgow Coma Scale; PT, prothrombin time; INR, International normalized ratio; AIS, Abbreviated Injury Scale; TBI, traumatic brain injury.

Fig. 7. (A) Charge per day for patients admitted to the ICU. (B) Cost per day for patients admitted to the ICU.

Not all patients with coagulopathy and an anatomic brain injury will necessarily benefit from rFVIIa administration, but we have clearly shown that in patients who are neurologically or physiologically compromised, using rFVIIa to reverse coagulopathy significantly decreases total charges and costs of hospitalization. This was found to be true even Volume 66 Number 1

though the patients who received rFVIIa had a higher AIS grade of brain injury and were more likely to require neurosurgical intervention than patients who had reversal of their coagulopathy with plasma alone. This decrease in overall cost is directly attributable to the clinically and statistically significant decrease in LOS, as charges and costs per day were comparable in the two groups. The increase in pharmacy costs with the use of rFVIIa is directly offset by the decrease in LOS. In addition, the utilization of fewer blood products contributes to the cost savings as well. At our institution, the cost of a single 1.2-mg vial, the smallest dose-vial of NovoSeven available, is US $1,100.35. This is equivalent to ap69

The Journal of TRAUMA Injury, Infection, and Critical Care

Table 7 Outcomes for Patients Not Requiring ICU Admission
No rFVIIa (n 56) Mean rFVIIa (n 13) Mean p

LOS (d) Discharge GCS Discharge RLAS Mortality Thromboembolic complications

4.1 14.5 7.0 n 6* 7

2.8 1.0 1.3 % 10.7 12.5

3.7 14.7 7.4 n 2 1

2.2 0.5 0.9 % 15.3 7.8

0.610 0.545 0.395 p 0.788 0.642

Fig. 9. Total charges and costs for patients not requiring ICU admission.

Withdrawal of care in 5 of 6 patients. Withdrawal of care in 2 of 2 patients. LOS, length of stay; ICU, Intensive Care Unit; GCS, Glasgow Coma Scale; RLAS, Rancho Los Amigos Cognitive Scale.

Fig. 10. (A) Charges for patients not requiring ICU admission. (B) Costs for patients not requiring ICU admission.

proximately 9 units of administered plasma. Even if the cost of rFVIIa is not directly offset by the savings in units of plasma administered, the reduction in ventilator days and LOS clearly compensates for the cost of the drug. The direct cause of the decrease in LOS and subsequent charges and costs in the population of patients who required ICU admission and received rFVIIa cannot be analyzed in this retrospective study, but hypotheses can be generated. It has been well known for years that administration of red blood cells is associated with worse outcomes because of an 70

increased risk of infections, organ dysfunction, and respiratory failure.13,54 57 There is an increasing body of literature that describes worse outcomes in patients who receive plasma as well.1316 Many of these studies describe an increase in respiratory failure and acute lung injury or acute respiratory distress syndrome (ARDS) with the administration of plasma. At least one publication of subgroup analysis from two randomized trials describes that the use of rFVIIa and the attendant decrease in transfusion requirements were associated with a lower rate of organ failure and ARDS.58 In this current study, the number of units of plasma transfused in both the first 24 hours as well as throughout the hospitalization was significantly lower in the rFVIIa group. Perhaps, this directly resulted in a decrease in the need for days of mechanical ventilation because of a lower incidence of respiratory dysfunction. The total number of units of packed RBC and platelets transfused were not different in the first 24 hours of hospitalization, but were lower for the entire LOS. Whether the decrease in the number of packed RBC and platelets transfused in the rFVIIa group is a cause or an effect of a shorter LOS is unknown. Whatever the cause, the use of rFVIIa for reversal of coagulopathy in patients with TBI who required ICU admission was clearly associated with fewer days of mechanical ventilation, a shorter hospital LOS, and a decrease in overall charges and costs of hospitalization. In addition to the economic benefit demonstrated here, there may be a benefit in functional outcome as well. Although there was no difference in functional outcome measures between the two groups that required ICU admission, these measures were evaluated at hospital discharge. The fact that LOS was shorter in the rFVIIa means that these measures were recorded days earlier in the rFVIIa groups. As functional outcome is an exquisitely time-sensitive measure, it may be expected that if measured at the same time points after injury, patients who received rFVIIa for reversal of their coagulopathy might have better functional outcome scores than those who were treated with conventional therapy alone. Alternatively, because of the frequency of plateaus in functional recovery after TBI, perhaps the group treated January 2009

Reversal of Coagulopathy in TBI Patients

with rFVIIa simply recovered functional status sooner than those patients treated with plasma. However, the retrospective nature of this work severely limits conclusions concerning functional outcome. Importantly, there was no difference in mortality in the groups evaluated in this study, despite the fact that patients in the rFVIIa group had more severe anatomic injury and were more likely to require neurosurgical intervention. Demonstrating a mortality benefit with the use of rFVIIa in severely injured patients with TBI is likely to require hundreds of patients and is impractical in a retrospective study of this size. The baseline rate of thromboembolic complications was high in the severely injured patients presented in this study. Despite consistent concerns in the literature about the risk of thromboembolic complications in patients treated with rFVIIa,28,59 61 no increase in the risk of thromboembolic complications was demonstrated in this study. As important as determining which patients with TBI benefit from the use of rFVIIa is determining which subset of patients do not benefit. In our institution, admission to the ICU is dictated by the need for intracranial pressure monitoring, the need for mechanical ventilation, or the need for vasoactive medication infusion. Other patients who simply need close monitoring with serial neurologic examinations for their TBI are often admitted to our Neurotrauma Intermediate Care Unit. In the group not requiring ICU admission, patients were typically administered plasma or rFVIIa and admitted to the Intermediate Care Unit and discharged to home within a few days. Use of rFVIIa in these patients demonstrated no clear benefit, but also did not demonstrate any evidence of worse outcome or increase in cost. Low numbers of patients in this subset may have limited our ability to draw conclusions about the use of rFVIIa. There are several important and obvious limitations to this study. First, the retrospective design does not allow for the determination of cause and effect but rather only suggests the identification of associations. In this retrospective study, there is clearly a selection bias in who receives rFVIIa and who gets treated with conventional therapy based on the patients degree of coagulopathy, the perceived urgency of reversal, and the patients clinical status. The study design also limits the type of clinical information that could be compared between the two groups because of the consistency of documented information. Despite its limitations, this study has clearly demonstrated that in coagulopathic patients with TBI who require ICU admission, patients selected to receive rFVIIa demonstrated greater cost-effectiveness of care, decreases in ventilator days, and a shorter hospital LOS. In addition, we have provided an additional evidence that rFVIIa is safe in this patient population. Prospective studies in this patient population are sorely needed to confirm these findings and to establish clinical effectiveness to ultimately improve outcome in patients with severe TBI. Volume 66 Number 1

REFERENCES
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Reversal of Coagulopathy in TBI Patients DISCUSSION

Dr. Alex B. Valadka (Houston, Texas): What are some of the obvious problems with this? Well, as Dr. Stein mentioned, its a retrospective registry based study with all the problems inherent with that. It seems as if the decision to use Factor VIIa was arbitrary and not very well protocolized, depended more on what the individual neurosurgeon and other surgeons wanted to do. She used an INR greater than or equal to 1.4 which may be a reasonable choice but, again, that seemed to be based more on common practice than on any solid data or any good physiologic basis. Its important to note, also, that the authors do have a financial relationship with the company that makes the product discussed here. And in this era of growing awareness of the problems of conflict of interest we need to keep that in mind. Also, the groups are really not very comparable. Factor VIIa was used more often in the people whose CT scans seemed to be worse and those who were actually undergoing cranial procedures and in those who were taking Warfarin. But I think it actually works to their favor because those were the sicker patients and in spite of that they seemed to have outcomes that were as good as or better than the others. Now in terms of looking at the big picture, too, it is worth keeping in mind that no one has ever shown that treating coagulopathy after a head injury improves outcome. As a matter of fact the company that makes this drug has tried to do some other studies looking at this in a prospective manner and theyve not been able to show any benefit. Im not sure why. I think perhaps they were asking the wrong question or didnt design their studies well. So we need to keep in mind that perhaps were treating more of an epi-phenomenon; were treating a symptom and not the real disease. Another possibility is that there are certainly some patients who really need this to prevent intracranial hemorrhages from expanding but they tend to get lost in the background noise if we enroll every single patient. So although certainly I treat coagulopathic patients, we need to keep in mind that we dont quite understand why were doing this. And on a personal note, too, one of their justifications for doing this study was that coagulopathic patients often get their neurosurgical treatment delayed. And that certainly is conventional wisdom. But I have often taken a contrarian point of view. If someone needs a craniotomy I just take them to the OR and dont worry about the coags. My thought process is that if they have a mass lesion in their head, by the time I get them to the OR, get them positioned, shaved, prepped, draped and opened there should be enough time for our anesthesia colleagues to either get Volume 66 Number 1 them VIIa or FFP, whatever it takes to get the coagulopathy under control. And at least I can see what is bleeding and try to stop it. I am not quite so brave when patients need a ventriculostomy because I cant see what is bleeding and Im afraid I may cause a bleed that I wont be able to stop. So Ive said a lot of bad things so far so do I really think this study is all that bad? The answer is no, I actually like the study quite a bit. Weve heard a lot at this meeting about the problems associated with transfusion, whether its immune-based phenomena like transfusion related acute lung injury, other immune effects, or even a volume overload in many of these elderly patients on Coumadin. So it makes perfect sense to me, we need to find a better way to do this as opposed to giving unit after unit of FFP to these people. Our biggest objection to using Factor VIIa in our hospital has always been the cost. And we have some good data here showing costs really may not be the issue. I especially like the slide showing that although your pharmacy costs may be higher, overall costs are lower. And we need to get our hospital administrators to realize that even though the pharmacy may be increasing, theyre actually gaining in the big picture and most importantly patients are doing well. So I have just a couple of questions for them. One is did they ever consider using thromboelastograms or other measures of coagulopathy instead of INR which may not be the most appropriate test for this? And, secondly, and I apologize, we didnt discuss this when we spoke earlier at this meeting, are they concerned at all about their relatively short half-life of Factor VIIa and just giving one dose may not be enough and other patients may need subsequent doses down the line? But overall I really enjoyed this paper. I think it certainly represents the future. Dr. Gregory J. Jurkovich (Seattle, Washington): It would appear that the criteria for use of Factor VIIa in the institution is indiscriminate. It seems unclear to me why Factor VIIa would be utilized in some patients with a traumatic brain injury that was never admitted to the ICU. Could you please comment on the indications for use of VIIa and how closely your institution follows the recommended guidelines, both by the manufacturer and by the Israelis and by the prospective randomized study for the presence of other clotting factors that, and temperature and Ph that needs to be in existence for VIIa to be effective. Number 2, it strikes me that if you had a hypothesis that VIIa was supposed to reverse the coagulopathy, why not show us the data on that effectiveness? What in fact were the time to change in coagulation parameters? What was the time to reversal of the anticoagulation? And, finally, were there any changes documented changes in imaging in traumatic brain injury hemorrhage? These are 73

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the things that VIIa are supposed to do so why not show that outcome data? Dr. Lonnie Frei (Jackson, Mississippi): Im a big proponent of VIIa. Ive used it many times in the past. But it is without a doubt without problems, including its cost. One of the things that I found interesting was the INR that you picked to choose and stratify your patients which was an INR of greater than 1.4. Yet your patient population who received Factor VIIa on average had an INR that was 2.4. Would it be advantageous to take a look at the amount of FFP that would be required to treat these patients who have INRs just slightly above 1.4 as opposed to those patients who have the higher INR and would there, would the cost advantage persist? Secondarily, one of the things that is not explained is the fact that those patients who received Factor VIIa had a decreased length of stay and ventilator days. I think Factor VIIa is a great product for coagulation. Does it have other properties that we dont know about or and I realize that thats probably not the case but in fact to what do you attribute the decreased length of stay and the decreased ventilator days in that patient population? Dr. Carl J. Hauser (Boston, Massachusetts): I should say up front that I am a consultant for Novo Nordisk and that I co-chair the Steering Committee of the current Factor VIIa trauma trial, although I hope it doesnt color my comments. I thought this was a very nice study and I congratulate the authors. This is an area where there is a lot of smoke and not much light. There are a couple of difficulties with interpreting the clinical data, as the authors know very well. First, decreased INR values per se dont necessarily reflect reversal of anticoagulation after Factor VIIa use. They simply reflect the presence of VIIa in the plasma. Second, fresh frozen plasma per se cannot correct an INR of 1.4. In fact, an INR of up to 1.5 is considered normal by just about everyone except neurosurgeons. Third, FFP can only correct a truly elevated INR down to about 1.6 or 1.7. Treating past that with FP is of no proven value, wasteful and potentially dangerous. There was a great article on this by Holland and Brooks in the American Journal of Clinical Pathology in 2006 that anyone who thinks otherwise should read. That said, I think the key issue from a pharmecoeconomic point of view is the dose of Factor VIIa you use. If the correction of anti-coagulation sought consists of achieving a normal INR I refer to this and the euboxia approach it can be done with very, very small amounts of Factor VIIa. You dont need to use the 90 micrograms per kilogram dose, a half or a third of that will do just fine. Thats usually $1,200 or $2,400 worth which, as the authors point out, is probably a bargain. The VIIa stroke trials suggest higher doses may be marginally more effective but at somewhat higher risk of complications. So Id like to know what dose the authors used or what the range of doses that the group of users in their institution 74 used were. Also, were you able to track differences in complications at different doses? Dr. Bryan A. Cotton (Nashville, Tennessee): First of all, Dr. Stein, fantastic study. Congratulations on your work. Two quick questions. One, did you look at the time to death in two different groups to see if there were: 1, different causes and 2, how quickly they were dying? And on that same note did you consider looking at actually ventilator-free days versus just straight ventilator days, looking more, again, as a better surrogate for time on the ventilator? Dr. Bijan S. Kheirabadi (San Antonio, Texas): I would just like to know in this patient, was the fibrinogen level was also decreased or whether giving Factor VIIa actually can reverse in that situation? Dr. Deborah M. Stein (Baltimore, Maryland): First of all, let me thank you very much for your comments and questions and, Dr. Valadka, for spending some time with me this morning. Let me address the issues of our definition of coagulopathy that a couple of people have asked about. The reason we chose an INR of less than or equal to 1.4 is simply because thats what our neurosurgeons insist that we correct to. They want it below 1.4. Where that comes from, nobody knows. Nobody can explain it to me but thats what they want. And, you know, for the purpose of a retrospective study using a level that we clinically treat is what we felt was most appropriate. Certainly there are much better physiologic markers of coagulopathy such as thromboelastography. As far as concern about the short half-life of Recombinant Factor VIIa, we do typically concomitantly administer some plasma in these patients. But typically, if you want to acutely reverse their coagulopathy in order to normalize them, for example reverse their coagulopathy associated with Coumadin use, typically one dose is all thats really needed. And we do see consistently lower INRs thereafter. In terms of Dr. Valadkas comments about not waiting to correct their coagulopathy and taking the patient right to the operating room, I could not agree with him more. I think that may be the real benefit of the use of Recombinant Factor VIIa. At our institution it takes about an hour for us to get plasma from the time the patient gets typed. Typically this drug can be given, a simple syringe, en route to the operating room and I think that that actually is one of the real benefits of the use of this approach. In terms of Dr. Jurkovichs question about indiscriminate use of Recombinant Factor VIIa, this was non-protocolized. The decision to administer Recombinant Factor VIIa is left to the discretion of the attending trauma surgeon or anesthesiologist with gatekeeper approval. I do agree that it would be nice to have a protocol. We dont have one currently and its certainly not based on any manufacturer or label recommendation as this is an entirely off-label indication. January 2009

Reversal of Coagulopathy in TBI Patients

We did not look at changes in imaging or reversal of coagulopathy in terms of the INR for the purposes of this study we did do that in our previous work because in this study we really wanted to focus on the cost, potential cost-effectiveness. In terms of Dr. Freis question about stratifying the patients by their initial INR. I think thats a wonderful idea. It certainly is something Im very happy to go back and take a look at our data and do. Why the length of stay was lower, why ventilator days were lower? I think its not necessarily the benefit of Factor VII but really what youre doing is reducing the amount of plasma. The one thing I want to make very clear is I dont think that Recombinant Factor VIIa is a silver bullet to treat traumatic brain injury. What I think it allows us to do is use less plasma which I think is intrinsically bad for patients with traumatic brain injury. In reference to Dr. Cottons question about timing of death. There was no difference in timing of death in those patients. We didnt look at ventilator free days because at our institution once the patients are off the ventilator, they typically leave the hospital within 48 hours. That really doesnt allow us to do much of a comparison of ventilatorfree days because even though they are recently off of the ventilator, they tend to stay within our system to one of our local rehabilitation centers that can accommodate them. And to address Dr. Hausers question, typically the dosing regimen that we use for simple reversal of coagulopathy for patients with traumatic brain injury is usually a single 1.2 milligram dose. That costs about $1,200. I dont off-hand remember the upper limit of the range of dosing in this study, but the mean dose was 60 micrograms per kilogram. And in terms of the last question we did not evaluate fibrinogen levels for the purposes of this study but it would be an interesting question to go back and look at.

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