Reversal of Coagulopathy in Critically Ill Patients With Traumatic Brain Injury

7/27/2019 Reversal of Coagulopathy in Critically Ill Patients With Traumatic Brain Injury

1/13

Reversal of Coagulopathy in Critically Ill Patients WithTraumatic Brain Injury: Recombinant Factor VIIa is More

Cost-Effective Than PlasmaDeborah 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 dis-

ability after trauma. Coagulopathy is com-

mon in this patient population and requires

rapid reversal to allow for safe neurosurgi-

cal intervention and prevent worsening of

the primary injury. Typically reversal of co-

agulopathy 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 coagulopa-

thy. 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 theR 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, neurosur-

gical procedures, length of stay (LOS), dis-

charge disposition, and outcome data were

abstracted. Patients who received rFVIIa

for reversal of coagulopathy were com-

pared against those who did not receive

rFVIIa. t Tests were used to compare dif-

ferences between continuous variables,

and 2 analysis was used to compare cat-

egorical variables. A p value of


2/13

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.4,68

Coagulopathy in patients with TBI precludes safe neurosur-gical 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 correc-

tion 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 physio-

logic 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 ofplasma 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 nontrau-

matic neurosurgical emergencies.1836 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 approxi-mately US $1.00 per microgram. Complete reversal of co-

agulopathy 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.20,30,32,3742

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 ex-

tended our use to patients with coagulopathy and TBI. Given the

results of recent work from our institution demonstrating adecreased 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.

MATERIALS AND METHODSAfter 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 Jan-

uary 2002 and December 2007 with an anatomic TBI (head

Abbreviated Injury Scale, AIS score of4). Patients with any

other body region AIS score of3 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 coagulopa-

thy was chosen because this is the clinical value at which our

neurosurgeons request normalization in patients with TBI. Weare unaware of any data that support this practice, but given the

retrospective nature of this work, utilization of the clinical trig-

ger 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 non-

survivable at the time of neurosurgical consultation, and there-

fore 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 ac-

cording to an institutional protocol based on the Brain Trauma

Foundation Guidelines.43

Administration of rFVIIa for all pa-tients 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 coagu-

lopathy 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 ad-

ministered, laboratory values, blood product utilization,

LOS, discharge disposition, and outcome data were ab-

stracted. Neurosurgical procedures, including craniotomy, in-traventricular 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 of0.05 was con-

sidered significant for all statistical tests.

RESULTSDuring a 6-year period, there were 36,624 injured patientsadmitted to the R Adams Cowley STC, 2,997 with an anatomic

severe TBI (head AIS score of4). Of these patients, 1,671

were identified with a relatively isolated TBI (no other body

region AIS score of3). 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

The Journal ofTRAUMA Injury, Infection, and Critical Care

64 January 2009


3/13

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).

Baseline characteristics between the two groups were com-

pared. 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 differencein 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 neurosur-

gical procedures and a higher percentage of patients with pre-

injury 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). Thromboem-

bolic complications in the conventionally treated group in-

cluded two territorial cerebral infarctions (CI), one CI sec-

ondary to brain herniation, two suspected CIs, one cardiac

Fig. 1. Study population.

Table 1 Baseline Characteristics of All Patients

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

Mean Mean

Age (yr) 57.4 23.2 61.4 24.9 0.273ISS 24.0 7.2 26.7 8.0 0.024Predicted survival

(TRISS)0.77 0.25 0.75 0.23 0.586

RTS 6.56 1.67 6.60 1.50 0.858Admission GCS 10.6 4.9 10.2 4.4 0.574Admission INR 1.9 0.7 2.5 0.7 0.001

n % n % p

Male 71 64.0 43 63.2 0.914Blunt injury 106 95.5 65 95.6 0.975Head AIS

4 75 67.6 32 47.1 0.0075 36 32.4 36 52.9 0.007

Neurosurgicalintervention

41 36.9 48 70.6 0.001

Cause ofcoagulopathy

Warfarin 54 48.6 45 66.2 0.028TBI alone 46 41.4 21 30.9 0.161Cirrhosis 9 8.1 3 4.4 0.338

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

Reversal of Coagulopathy in TBI Patients

Volume 66 Number 1 65


4/13

thrombus, four myocardial infarctions, three patients with

myocardial ischemia manifested by elevated cardiac en-

zymes, 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 in-

farctions, one patient with myocardial ischemia, two deep

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 effective-

ness 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 co-

agulopathy. 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, respira-

tory 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

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

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

Table 2 Outcomes of All Patients

No rFVIIa(n 111)

rFVIIa(n 68)

p

Mean Mean

LOS (d) 11.7 13.9 11.8 10.1 0.976

ICU-LOS (d) 8.5 14.2 10 10.2 0.465Discharge GCS 13.2 2.6 11.9 2.6 0.006Discharge RLAS 5.9 2.0 5.2 2.0 0.036

n % n % p

Mortality 21* 18.9 18 26.5 0.517Thromboembolic complications 18 16.2 13 19.1 0.233

* 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.


66 January 2009


5/13

group (Fig. 7, A and B). In addition, blood product utili-

zation 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 signifi-

cant differences in the number of units of plasma trans-

fused in the first 24 hours of admission, as well as during

the entire hospitalization (Fig. 8). Functional outcome mea-

sures for survivors recorded at discharge were no different in the

two groups. Similarly, mortality and thromboembolic compli-

cation rates were not statistically different between the pa-tients 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 conven-

tional therapy alone and 13 were treated with rFVIIa. Baseline

characteristics were no different in the group that received con-

ventional therapy and the group that was treated with rFVIIa

(Table 6). Total mean charges and costs were not signifi-

cantly 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).

DISCUSSION

Coagulopathy occurs commonly in patients with TBI

and must be addressed rapidly to allow for safe neurosur-

gical intervention and prevent worsening of the primary

injury from ongoing hemorrhage. Recombinant factor VIIa

has been used in hemorrhaging trauma patients for many

years.18,4448 Numerous reports exist in the literature de-

scribing the successful use of rFVIIa in patients requiring

neurosurgical intervention2123,30,31,33,35 and for the pre-

vention of progression of injury in patients with nonsurgical

intracranial bleeds.10,27,28,33,34 Recombinant activated factorVII 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 pro-

spective, 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

Table 3 Comparison of Patients Requiring ICU Admission and Those Who Did Not

ICU (n 110) No ICU (n 69)p

Mean Mean

Age (yr) 55.8 23.9 63.9 23.0 0.027ISS 26.8 7.9 22.2 6.1 0.001

Predicted survival (TRISS) 0.70 0.26 0.86 0.18 0.001RTS 6.13 1.63 7.29 1.26 0.001

Admission GCS 8.8 4.6 13.1 3.8 0.001Admission INR 2.2 1.1 2.1 0.7 0.545LOS (d) 16.6 13.9 4.1 2.7 0.001Discharge GCS 11.2 2.8 14.6 1.0 0.001Discharge RLAS 4.5 1.8 7.1 1.2 0.001Total charges (US $) 92,814 76,944 19,161 14,074 0.001Total costs (US $) 65,274 54,205 13,025 9,308 0.001

n % n % p


4 56 50.9 51 73.9 0.003

5 54 49.1 18 26.1 0.003Neurosurgical intervention 77 70.0 12 17.4 0.001Cause of coagulopathy


Received rFVIIa 55 50.0 13 18.8 0.001Mortality 31* 28.2 8 13.0 0.001Thromboembolic complications 24 21.8 8 11.6 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.




6/13

conventional therapy alone took, on average, three times

longer to receive neurosurgical intervention.30 Despite the

potential benefit of rFVIIa in achieving quicker interven-

tion times, no statistically significant outcome differences

were appreciated in this small group of patients.

Cost-effectiveness of rFVIIa in patients with neuro-

surgical 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 dem-

onstrated a cost benefit for patients treated with rFVIIa. In

this study, we were able to demonstrate a significant eco-

nomic benefit of the use of rFVIIa for reversal of coagu-

lopathy in severely injured patients with TBI.

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

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

patients admitted to the ICU.

Table 4 Baseline Characteristics of Patients Admittedto the ICU

No rFVIIa(n 55)

rFVIIa(n 55)

p

Mean Mean


(TRISS)0.68 0.27 0.74 0.23 0.216


n % n % p


4 34 61.8 22 40.0 0.0245 21 38.2 33 60.0 0.024

Neurosurgical

intervention

33 60.0 44 80.0 0.024



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

Table 5 Outcomes for Patients Admitted to the ICU

No rFVIIa(n 55)

rFVIIa(n 55)

p

Mean Mean

Ventilator days 15.4 14.7 8.8 8.0 0.004LOS (d) 19.4 16.3 13.7 10.2 0.029ICU-LOS (d) 17.2 16 12.3 9.9 0.057Discharge GCS 11.5 2.9 11.0 2.7 0.454Discharge RLAS 4.6 1.9 4.5 1.8 0.909

n % n % p


* 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



68 January 2009


7/13

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 neurolog-

ically or physiologically compromised, using rFVIIa to re-

verse coagulopathy significantly decreases total charges and

costs of hospitalization. This was found to be true even

though the patients who received rFVIIa had a higher AIS

grade of brain injury and were more likely to require neuro-

surgical 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 sig-

nificant 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 Novo-

Seven available, is US $1,100.35. This is equivalent to ap-

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

ICU.

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

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 NotRequiring ICU Admission

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

Mean Mean


(TRISS)0.86 0.18 0.81 0.24 0.374


n % n % p


4 41 73.2 10 76.9 0.7855 15 26.7 3 23.1 0.791

Neurosurgicalintervention

8 14.2 4 30.7 0.161



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




8/13

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

increased risk of infections, organ dysfunction, and respira-

tory failure.13,5457 There is an increasing body of literature

that describes worse outcomes in patients who receive plasmaas 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 ran-

domized trials describes that the use of rFVIIa and the atten-

dant 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 dys-function. 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. Al-though there was no difference in functional outcome mea-

sures 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 func-

tional 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

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

admission.

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

Table 7 Outcomes for Patients Not Requiring ICUAdmission

No rFVIIa(n 56)

rFVIIa(n 13)

p

Mean Mean

LOS (d) 4.1 2.8 3.7 2.2 0.610Discharge GCS 14.5 1.0 14.7 0.5 0.545Discharge RLAS 7.0 1.3 7.4 0.9 0.395

n % n % p


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



70 January 2009


9/13

with rFVIIa simply recovered functional status sooner than

those patients treated with plasma. However, the retrospec-

tive nature of this work severely limits conclusions concern-

ing 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. Demon-

strating 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. De-

spite consistent concerns in the literature about the risk of

thromboembolic complications in patients treated with

rFVIIa,28,5961 no increase in the risk of thromboembolic

complications was demonstrated in this study.

As important as determining which patients with TBI ben-efit 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 mon-

itoring 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 evidenceof 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 sug-

gests 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 becompared 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 admis-

sion, 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 addi-

tional 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.

REFERENCES1. Shackford SR, Mackersie RC, Holbrook TL, et al. The epidemiology of

traumatic death. A population-based analysis. Arch Surg. 1993;128:571

575.

2. Langlois JA, Rutland-Brown W, Thomas KE. Traumatic Brain Injury in

the United States: Emergency Department Visits, Hospitalizations, and

Deaths. Atlanta, GA: Centers for Disease Control and Prevention, Nation

Center for Injury Prevention and Control; 2006.

3. Thurman D, Alverson C, Dunn K, Guerrero J, Sniezek JE.

Traumatic brain injury in the United States: a public health

perspective. J Head Trauma Rehabil. 1999;14:602615.

4. Cortiana M, Zagara G, Fava S, Seveso M. Coagulation abnormalities

in patients with head injury. J Neurosurg. 1986;30:133138.

5. Zehtabchi S, Soghoian S, Carmody K, et al. The association of

coagulopathy and traumatic brain injury in patients with isolated

head injury. Resuscitation. 2008;76:5256.

6. Stein SC, Smith DH. Coagulopathy in traumatic brain injury.

Neurocrit Care. 2004;1:479488.

7. Zygun DA, Kortbeek JB, Fick GH, Laupland KB, Doig CJ. Non-

neurologic organ dysfunction in severe traumatic brain injury. Crit

Care Med. 2005;33:654660.

8. Hulka F, Mullins R, Frank E. Blunt brain injury activates thecoagulation process. Arch Surg. 1996;131:923928.

9. Powner DJ, Hartwell EA, Hoots WK. Counteracting the effects of

anticoagulants and antiplatelet agents during neurosurgical

emergencies. Neurosurgery. 2005;57:823831.

10. May AK, Young JS, Butler K, Bassam D, Brady W. Coagulopathy in

severe closed head injury: is empiric therapy warranted? Am Surg. 1997;

63:233237.

11. Carrick MM, Tyroch AH, Youens CA, Handley T. Subsequent

development of thrombocytopenia and coagulopathy in moderate and

severe head injury: support for serial laboratory examination.

J Trauma. 2005;58:725730.

12. Cohen DB, Rinker C, Wilberger JE. Traumatic brain injury in

anticoagulated patients. J Trauma. 2006;60:553557.

13. Bochicchio GV, Napolitano L, Joshi M, Bochicchio K, Meyer W,

Scalea TM. Outcome analysis of blood product transfusion in

trauma patients: a prospective, risk-adjusted study. World J Surg.

2008;32:21852189.

14. Dara SI, Rana R, Afessa B, Moore SB, Gajic O. Fresh frozen

plasma transfusion in critically ill medical patients with

coagulopathy. Crit Care Med. 2005;33:26672671.

15. Etemadrezaie H, Baharvahdat H, Shariati Z, Lari SM, Shakeri

MT, Ganjeifar B. The effect of fresh frozen plasma in severe

closed head injury. Clin Neurol Neurosurg. 2007;109:166171.

16. Khan H, Belsher J, Yilmaz M, et al. Fresh-frozen plasma and

platelet transfusions are associated with development of acute lung

injury in critically ill medical patients. Chest.

2007;131:13081314.

17. Hedner U. Mechanism of action of factor VIIa in the treatment of

coagulopathies. Semin Thromb Hemost (Suppl). 2006;32:S77S85.18. Dutton RP, McCunn M, Hyder M, et al. Factor VIIa for correction

of traumatic coagulopathy. J Trauma. 2004;57:709719.

19. Srensen B, Johansen P, Nielsen GL, Srensen JC, Ingerslev J.

Reversal of the international normalized ratio with recombinant

activated factor VII in central nervous system bleeding during

warfarin thromboprophylaxis: clinical and biochemical aspects.

Blood Coagul Fibrinolysis. 2003;14:469477.

20. Roitberg B, Emechebe-Kennedy O, Amin-Hanjani S, Mucksavage J,

Tesoro E. Human recombinant factor VII for emergency reversal of

coagulopathy in neurosurgical patients: a retrospective comparative

study. Neurosurgery. 2005;57:832836.

21. Park P, Fewel ME, Garton HJ, Thompson BG, Hoff JT. Recombinant

activated factor VII for the rapid correction of coagulopathy in

nonhemophilic neurosurgical patients. Neurosurgery. 2003;53:3439.




10/13

22. Karadimov D, Binev K, Nachkov Y, Platikanov V. Use of activated

recombinant factor VII (Novoseven) during neurosurgery.

J Neurosurg Anesthesiol. 2003;15:330332.

23. Yusim Y, Perel A, Berkenstadt H, Attia M, Knoller N, Sidi A. The use of

recombinant factor VIIa (NovoSeven) for treatment of active or impending

bleeding in brain injury: broadening the indications. J Clin

Anesth. 2006;18:545551.

24. Freeman WD, Brott TG, Barrett KM, et al. Recombinant factor VIIafor rapid reversal of warfarin anticoagulation in acute intracranial

hemorrhage. Mayo Clin Proc. 2004;79:14955000.

25. Lin J, Hanigan WC, Tarantino M, Wang J. The use of recombinant

activated factor VII to reverse warfarin-induced anticoagulation in

patients with hemorrhages in the central nervous system: preliminary

findings. J Neurosurg. 2003;98:73740.

26. Brody DL, Aiyagari V, Shackleford AM, Diringer MN. Use of

recombinant factor VIIa in patients with warfarin-associated

intracranial hemorrhage. Neurocrit Care. 2005;2:263267.

27. White CE, Schrank AE, Baskin TW, Holcomb JB. Effects of

recombinant activated factor VII in traumatic nonsurgical intracranial

hemorrhage. Curr Surg. 2006;63:310317.

28. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII

for acute intracerebral hemorrhage. N Engl J Med. 2005;352:777785.29. Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of

recombinant activated factor VII for acute intracerebral hemorrhage.

N Engl J Med. 2008;358:21272137.

30. Stein DM, Dutton RP, Kramer ME, Handley C, Scalea TM. Recombinant

factor VIIa: decreasing time to neurosurgical intervention in patients with

severe traumatic brain injury. J Trauma. 2008;64:620628.

31. Bartal C, Freedman J, Bowman K, Cusimano M. Coagulopathic

patients with traumatic intracranial bleeding: defining the role of

recombinant factor VIIa. J Trauma. 2007;63:725732.

32. Hawryluk GW, Cusimano MD. The role of recombinant activated

factor VII in neurosurgery: hope or hype? J Neurosurg. 2006;

105:859868.

33. Stein DM, Dutton RP, Hess JR, Scalea TM. Low-dose recombinant

factor VIIa for trauma patients with coagulopathy. Injury. 2008;

39:10541061.34. Steiner T, Diringer MN, Schneider D, et al. Dynamics of

intraventricular hemorrhage in patients with spontaneous

intracerebral hemorrhage: risk factors, clinical impact, and effect of

hemostatic therapy with recombinant activated factor VII.

Neurosurgery. 2006;59:76774.

35. Uhrig L, Blanot S, Baugnon T, Orliaguet G, Carli PA, Meyer PG.

Use of recombinant activated factor VII in intractable bleeding

during pediatric neurosurgical procedures. Pediatr Crit Care Med.

2007;8:576579.

36. Zaaroor M, Soustiel JF, Brenner B, Bar-Lavie Y, Martinowitz U,

Levi L. Administration off label of recombinant factor-VIIa (rFVIIa)

to patients with blunt or penetrating brain injury without

coagulopathy. Acta Neurochir (Wein). 2008;150:663668.

37. Ganguly S, Spengel K, Tilzer LL, Oneal B, Simpson SQ.Recombinant factor VIIa: unregulated continuous use in patients

with bleeding and coagulopathy does not alter mortality and

outcome. Clin Lab Haematol. 2006;28:309312.

38. Loudon B, Smith MP. Recombinant factor VIIa as an adjunctive

therapy for patients requiring large volume transfusion: a

pharmacoeconomic evaluation. Intern Med J. 2005;35:463467.

39. Kissela BM, Eckman MH. Cost effectiveness of recombinant factor VIIa

for treatment of intracerebral hemorrhage. BMC Neurology. 2008;8:17.

40. Morris S, Ridley S, Munro V, Christensen MC. Cost effectiveness of

recombinant activated factor VII for the control of bleeding in patients with

severe blunt trauma injuries in the United Kingdom. Anaesthesia. 2007;

62:4352.

41. Rudisill CN, Hockman RH, DeGregory KA, Mutnick AH, Macik

BG. Implementing guidelines for the institutional use of factor VIIa

(recombinant): a multidisciplinary approach. Am J Health Syst

Pharm. 2006;63:16411646.

42. Ranucci M, Isgro G, Soro G, Conti D, De Toffol B. Efficacy and

safety of recombinant activated factor VII in major surgical

procedures. Arch Surg. 2008;143:296304.

43. Brain Trauma Foundation and AANS/CNS Joint Section on

Neurotrauma and Critical Care. Guidelines for the management of

severe traumatic brain injury. J Neurotrauma (Suppl). 2007;24:S1S106.44. Kenet G, Walden R, Eldad A, Martinowitz U. Treatment of traumatic

bleeding with recombinant factor VIIa. Lancet 1999;354:1879.

45. Harrison TD, Laskosky J, Jazaeri O, Pasquale MD, Cipolle M. Low-dose

recombinant activated factor VII results in less blood and blood product use

in traumatic hemorrhage. J Trauma. 2005;59:150154.

46. Boffard KD, Riou B, Warren B, et al. Recombinant factor VIIa as

adjunctive therapy for bleeding control in severely injured trauma

patients: two parallel randomized, placebo-controlled, double-

blind clinical trials. J Trauma. 2005;59:815.

47. Rizoli SB, Nascimento B, Osman F, et al. Recombinant activated

coagulation factor VII and bleeding trauma patients. J Trauma.

2006;61:14191425.

48. Perkins JG, Schreiber MA, Wade CE, Holcomb JB. Early versus late

recombinant factor VIIa in combat trauma patients requiring massivetransfusion. J Trauma. 2007;62:10951101.

49. Boulis N, Bobek M, Schmaier A, Hoff JT. Use of factor IX complex in

warfarin related intracranial hemorrhage. Neurosurgery. 1999;45:1113

1119.

50. Earnshaw SR, Joshi AV, Wilson MR, Rosand J. Cost-effectiveness

of recombinant activated factor VII in the treatment of intracerebral

hemorrhage. Stroke. 2006;37:27512758.

51. Traynor K. Budget-busting drug gets institutional oversight. Am J

Health-Syst Pharm. 2004;61:866867.

52. Galanaud JP, Pelletier-Fleury N, Logerot-Lebrun H, Lambert T.

Determinants of drug costs in the hospitalized patients with

haemophilia: impact of recombinant activated factor VII.

Pharmacoeconomics. 2003;21:699707.

53. Lyseng-Williamson KA, Plosker GL. Recombinant factor VIIa(Eptacog Alfa): a pharmacoeconomic review of its use in

haemophilia in patients with inhibitors to clotting factors VIII and

IX. Pharmacoeconomics. 2007;25:10071029.

54. Bulger EM, Jurkovich GJ, Nathens AB, et al. Hypertonic

resuscitation of hypovolemic shock after blunt trauma: a randomized

controlled trial. Arch Surg. 2008;143:139148.

55. Dellinger RP, Levy MM, Carlet JM, et al. Surviving sepsis

campaign: international guidelines for management of severe sepsis

and septic shock: 2008. Crit Care Med. 2008;36:296327.

56. Vincent JL, Baron JF, Reinhart K, et al. Anemia and blood transfusion in

critically ill patients. JAMA. 2002;288:

14991507.

57. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT study: anemia

and blood transfusions in the critically ill current clinical practicein the United States. Crit Care Med. 2004;32:3952.

58. Rizoli SB, Boffard KD, Riou B, et al. Recombinant activated factor

VII as an adjunctive therapy for bleeding control in severe trauma

patients with coagulopathy: subgroup analysis from two randomized

trials. Crit Care. 2006;10:R178.

59. Tawil I, Stein DM, Mirvis SE, Scalea TA. Post traumatic cerebral

infarction: incidence, outcome, and risk factors. J Trauma. 2008;64:849

853.

60. Thomas GO, Dutton RP, Hemlock B, et al. Thromboembolic

complications associated with factor VIIa administration. J Trauma.

2007;62:564569.

61. Narayan RK, Maas AIR, Marshall LF, Servadei F, Skolnick BE, Tillinger

MN. Recombinant factor VIIa in traumatic intracerebral hemorrhage: results

of a dose escalation trial. Neurosurgery. 2008;62:776788.


72 January 2009


11/13


12/13

the things that VIIa are supposed to do so why not show that

outcome data?

Dr. Lonnie Frei (Jackson, Mississippi): Im a big pro-

ponent 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 anINR of greater than 1.4. Yet your patient population who re-

ceived 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 advan-

tage persist?

Secondarily, one of the things that is not explained is the

fact that those patients who received Factor VIIa had a de-

creased 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 shouldsay 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, decreasedINR values per se dont necessarily reflect reversal of anti-

coagulation 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 pharmeco-economic point of view is the dose of Factor VIIa you use. If

the correction of anti-coagulation sought consists of achiev-

ing a normal INR I refer to this and the euboxia ap-

proach 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 some-

what 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

used were. Also, were you able to track differences in com-

plications 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, howquickly 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 coagulopa-

thy 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 appro-

priate. Certainly there are much better physiologic markers of

coagulopathy such as thromboelastography.

As far as concern about the short half-life of Recombi-

nant 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 anesthesi-

ologist 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 recommen-

dation as this is an entirely off-label indication.


74 January 2009


13/13

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 takea 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 ventilator-

free 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 accommodatethem.

And to address Dr. Hausers question, typically the dos-

ing 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.



Reversal of Coagulopathy in Critically Ill Patients With Traumatic Brain Injury

Documents

Transcript of Reversal of Coagulopathy in Critically Ill Patients With Traumatic Brain Injury