jr trakhir

8/11/2019 JR Trakhir

1/10

n engl j med 363;19 nejm.org november 4, 2010 1791

Thenew englandjournalofmedicineestablished in 1812 november 4, 2010 vol. 363 no. 19

Safety of Recombinant Activated Factor VIIin Randomized Clinical Trials

Marcel Levi, M.D., Jerrold H. Levy, M.D., Henning Friis Andersen, M.Sc., and David Truloff, D.V.M.

A bs t ra c t

From the Academic Medical Center, Uni-versity of Amsterdam, Amsterdam (M.L.);the Emory University School of Medi-cine, Atlanta (J.H.L.); and Novo Nordisk,Bagsvrd, Denmark (H.F.A., D.T.). Ad-dress reprint requests to Dr. Levi at theDepartment of Medicine (F-4), AcademicMedical Center, University of Amsterdam,Meibergdreef 9, 1105 AZ Amsterdam, theNetherlands, or at [email protected].

N Engl J Med 2010;363:1791-800.Copyright 2010 Massachusetts Medical Society.

Background

The use of recombinant activated factor VII (rFVIIa) on an off-label basis to treat

life-threatening bleeding has been associated with a perceived increased risk of throm-

boembolic complications. However, data from placebo-controlled trials are needed

to properly assess the thromboembolic risk. To address this issue, we evaluated the

rate of thromboembolic events in all published randomized, placebo-controlled

trials of rFVIIa used on an off-label basis.

Methods

We analyzed data from 35 randomized clinical trials (26 studies involving patients

and 9 studies involving healthy volunteers) to determine the frequency of thrombo-

embolic events. The data were pooled with the use of random-effects models to cal-

culate the odds ratios and 95% confidence intervals.

Results

Among 4468 subjects (4119 patients and 349 healthy volunteers), 498 had thrombo-

embolic events (11.1%). Rates of arterial thromboembolic events among all 4468

subjects were higher among those who received rFVIIa than among those who re-

ceived placebo (5.5% vs. 3.2%, P = 0.003). Rates of venous thromboembolic events

were similar among subjects who received rFVIIa and those who received placebo

(5.3% vs. 5.7%). Among subjects who received rFVIIa, 2.9% had coronary arterial

thromboembolic events, as compared with 1.1% of those who received placebo

(P = 0.002). Rates of arterial thromboembolic events were higher among subjects

who received rFVIIa than among subjects who received placebo, particularly among

those who were 65 years of age or older (9.0% vs. 3.8%, P = 0.003); the rates wereespecially high among subjects 75 years of age or older (10.8% vs. 4.1%, P = 0.02).

Conclusions

In a large and comprehensive cohort of persons in placebo-controlled trials of rFVIIa,

treatment with high doses of rFVIIa on an off-label basis significantly increased the

risk of arterial but not venous thromboembolic events, especially among the elderly.

(Funded by Novo Nordisk.)

The New England Journal of Medicine

Downloaded from nejm.org on January 8, 2011. For personal use only. No other uses without permission.

Copyright 2010 Massachusetts Medical Society. All rights reserved.


2/10

T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 363;19 nejm.org november 4, 20101792

Recombinant activated coagulation

factor VII (rFVIIa) (NovoSeven, Novo Nor-

disk) is approved for the treatment of bleed-

ing in patients with hemophilia A or B who have

inhibiting antibodies to coagulation factor VIII

or IX. Indications have been broadened to include

the treatment of episodes of bleeding and the

prevention of episodes of bleeding related to sur-gical or invasive procedures in patients with con-

genital and acquired hemophilia, factor VII defi-

ciency, or Glanzmanns thrombasthenia (the last

indication is approved only in Europe).

The mechanism of action of rFVIIa may offer

the potential for its use in preventing or treating

severe or life-threatening bleeding in patients with

other clinical conditions.1A growing number of

case reports and small, controlled or uncontrolled

studies have shown the successful use of rFVIIa

for various clinical indications other than the

treatment of hemophilia, including managementof severe traumatic injury, control of bleeding dur-

ing surgery and transplantation, treatment of in-

tracerebral hemorrhage, and management of

bleeding due to anticoagulation therapy.2Many

of the patients who have received rFVIIa for these

indications have been at high risk for death be-

cause of frank hemorrhaging, which was a pre-

requisite for the clinical trials.

The primary concern surrounding the use of

rFVIIa is its potential as a hemostatic agent to in-

duce thromboembolic events. It is administered

at doses that are up to 1000 times the physiologic

level and has a half-life of approximately 2.5

hours.3 Although rFVIIa acts by generation of

thrombin on thrombin-activated platelets and is

theoretically localized to the site of vessel-wall

injury, systemic activation of coagulation may

occur.4

An evaluation of 483 published studies (most-

ly uncontrolled and retrospective) of the use of

rFVIIa in patients with hemophilia, liver disease,

trauma or a condition requiring surgery, antico-

agulation reversal, and coagulation disordersshowed an incidence rate of thromboembolic

events of 1 to 2%.2OConnell et al.5described

168 reports of 185 rFVIIa-associated thromboem-

bolic events in the Adverse Event Reporting Sys-

tem of the Food and Drug Administration (FDA),

involving both approved and off-label uses of

rFVIIa. In 38% of these reported cases, however,

other hemostatic agents were used concomitantly

with rFVIIa. Most of the safety data on off-label

indications are retrospective and involve subjects

with a relatively high risk of adverse events, in-

cluding thrombosis, making interpretation of

these findings difficult.

We systematically analyzed rates of thrombo-

embolic events in 35 placebo-controlled trials (in-

volving 4468 persons) of off-label indications for

rFVIIa, including various coagulopathic states,coexisting conditions, and dosing algorithms. In

all these trials, rFVIIa was administered for the

treatment or prevention of bleeding.

Methods

Identification of Safety Data

To evaluate the profile of thromboembolic events

associated with the off-label use of rFVIIa, we used

data from two main types of clinical trials: 26 ran-

domized, placebo-controlled trials involving 4119

patients with various clinical conditions, and9 randomized, placebo-controlled trials involv-

ing 349 healthy volunteers. These trials included

both Novo Nordisk-sponsored trials (29 trials in-

volving 4064 patients and 263 healthy volunteers)

and investigator-initiated trials (6 trials involving

55 patients and 86 healthy volunteers). The inves-

tigator-initiated trials were identified through a

Medline search of randomized clinical trials (span-

ning the period from 1996 through 2008) with

the use of the terms rFVIIa, factor VIIa, ep-

tacog alfa, activated, or NovoSeven. The data

from the investigator-initiated trials were obtained

from the published studies, through direct con-

tact with the authors of the studies, or both (for

more details, see the Supplementary Appendix,

available with the full text of this article at NEJM

.org). These randomized, controlled clinical trials

were broadly categorized according to the under-

lying diagnosis. The resultant seven major catego-

ries of bleeding were spontaneous central nervous

system bleeding and bleeding due to advanced liver

disease, trauma, cardiac surgery, traumatic brain

injury, spinal surgery, and other conditions.The study was designed by the first author, and

the data were collected by all the authors. Data

analysis was performed by the first, second, and

last authors, and the statistical analysis was per-

formed by the third author. All authors vouch for

the data and the analysis. The first two authors

wrote the first draft of the manuscript and made

the decision to submit the manuscript for publi-

cation with the approval of all the authors.





3/10

Recombinant Activated Factor VII in Clinical Trials


Definition of Terms

All reported adverse events that were considered

to be possibly or probably thrombotic or embolic

in nature (on the basis of the use of standardized

terms in the Medical Dictionary for Regulatory Ac-

tivities [MedDRA]) were reviewed by the industry

authors and categorized as an arterial thrombo-

embolic event, a venous thromboembolic event, oran event that was not thromboembolic. Reports

of adverse events that used broad terms that may

have been suggestive of thromboembolic events

were reviewed. Cases in which clear evidence

showed that the event was not thrombotic in na-

ture were excluded. All thrombotic events were

confirmed by means of objective tests. Arterial

thromboembolic events were classified as coro-

nary, cerebrovascular, or other events. Coronary

events (MedDRA terms: [acute] myocardial infarc-

tion, silent myocardial infarction, unstable angina,

and increased troponin) were confirmed by meansof electrocardiographic studies, laboratory tests,

echocardiographic studies, or a combination of

these tests. Cerebrovascular events (MedDRA

terms: cerebral infarction, cerebellar infarction,

ischemic stroke, cerebrovascular accident, hemipa-

resis, lacunar infarction, thromboembolic stroke,

or ischemic cerebral infarction) were confirmed

by means of computed tomography (thereby ex-

cluding cerebral hemorrhage as a cause of the

symptoms). Other arterial thromboembolic events

(MedDRA terms: arterial thrombosis of the legs,

embolism, graft thrombosis, hepatic-artery occlu-

sion, hepatic-artery thrombosis, iliac-artery throm-

bosis, intestinal infarction, intestinal ischemia,

intracardiac thrombus, peripheral arterial occlu-

sive disease, renal-artery thrombosis, retinal-artery

embolism, splenic infarction, and vascular-graft

occlusion) were confirmed by means of vascular

imaging.

Venous thromboembolic events (MedDRA

terms: deep-vein thrombosis, graft thrombosis,

jugular-vein thrombosis, mesenteric-vein throm-

bosis, pelvic venous thrombosis, phlebitis, portal-vein thrombosis, pulmonary embolism, renal-vein

thrombosis, retinal-vein thrombosis, shunt occlu-

sion, subclavian-vein thrombosis, thrombophle-

bitis, superficial thrombophlebitis, thrombosis,

transverse sinus thrombosis, vena cava thrombo-

sis, venous thrombosis, and venous thrombosis of

the legs) were also confirmed by means of vascu-

lar imaging.

Dose Categories

A range of rFVIIa doses was administered across

the 35 trials. The data were categorized into one

of three dose groups: less than 80 g per kilogram

of body weight (low), 80 to 120 g per kilogram

(medium), or more than 120 g per kilogram

(high). This categorization of doses was chosen

because 80 to 120 g per kilogram approximatesthe 90-g-per-kilogram-dose recommended in the

prescribing information for treating episodes of

bleeding in patients with hemophilia A or B who

have inhibiting antibodies to coagulation factors

VIII or IX. In trials with crossover or multiple-dose

designs, the subject was assigned to the group ac-

cording to the highest dose received.

Statistical Analysis

The statistical analyses focused on the propor-

tion of subjects who had thromboembolic events,

arterial thromboembolic events, or venous throm-boembolic events. The statistical analyses were

primarily performed on data collected from ran-

domized, controlled clinical trials involving pa-

tients. The data from clinical trials involving

healthy volunteers are presented separately, with

the exception of Table 1, which shows rates of

thromboembolic events among all persons in the

35 trials.

For descriptive statistics, the rate of thrombo-

embolic events was defined as the number of pa-

tients with events as a proportion of the number

of patients who received a study drug. P values,

odds ratios, and 95% confidence intervals were

calculated with the use of logistic regression and

SAS software (version 9.2), with adjustment for

the type of bleeding, age, and rFVIIa treatment.

The type of bleeding and age were included be-

cause it was known that they are both predictors

of thromboembolic events.33-36 If a statistically

significant difference was observed between the

event rate among patients who received rFVIIa and

the rate among patients who received placebo,

additional analyses were performed according tothe type of adverse event, the type of bleeding,

and the age group. In addition, P values, model-

based odds ratios, and confidence intervals were

calculated only in subgroups in which there were

enough events (>10 events in total) for the analy-

sis to be meaningful.

The association of dose with the risk of a

thromboembolic event was also evaluated by





4/10



Table1.PopulationandDose-Grou

pDistributioninPlacebo-ControlledTrials

ofrFVIIa.*

PopulationandCause

ofBleeding

No.of

Studies

Mean

Age

Placebo

(N

=1653)

rFVIIa

(N

=2815)

Total

(N=4468)

rFVIIa,

120g/kg

(N=789)

Reference

yr

no.ofsubjects

no.ofsubjects(%)

no.ofsubjects

Patients

1536

2583

4119(92.2)

850

984

749

Spontaneouscentralnervous

system

bleeding

5

65.0

423

974

1397(31.3)

430

435

109

Mayeretal.6-9

Liverdisease

7

54.0

449

795

1244(27.8)

259

360

176

Boschetal.,1

0,11Carreno

eta

l.,1

2Lodgeetal.,1

3,14

Planinsicetal.,1

5S

hao

eta

l.16

Trauma

3

36.5

428

409

837(18.7)

0

0

409

Boffard

etal.17

Cardiacsurgery

3

45.4

114

153

267(6.0)

75

78

0

Diproseetal.,1

8E

kertetal.,1

9

Gilletal.20

Traumaticbraininjury

1

50.9

36

61

97(2.2)

12

25

24

Naraya

netal.21

Spinalsurgery

1

46.6

13

36

49(1.1)

24

12

0

Sachsetal.22

Othercauses

6

38.5

73

155

228(5.1)

50

74

31

Chuansumritetal.,2

3

Frie

derichetal.,2

4P

ihusch

eta

l.,2

5Raobaikadyetal.26

Healthyvolunteers

9

27.2

117

232

349(7.8)

90

102

40

Bijsterveldetal.,2

7,28

Erh

ardtsenetal.,2

9

Frid

bergetal.,3

0Friederich

eta

l.,3

1Wolztetal.32

*Referencesareprovidedforthetri

alsthathavebeenpublished.Theremainin

gdataareprovidedintheSupplementary

Appendix.Onestudyincludedchildrenyoungerthan1yearofage.

Studiesincludedpatientswithpro

statectomy,pelvicorpelvicacetabularfracturereconstruction,denguehemorrhagicfever,bleedingafterhematopoieticstem-celltransplantation(two

patients),andseverebleedingassociatedwithvitaminKantagonisttherapy.

Fourstudiesinvolvedhealthyvolu

nteerswhoreceivedanticoagulants(fonda

parinux,2

7i

draparinux,

28acenocoumarol,29

andwarfarin

30).Onestudyinvolvedperso

nswhohadreceivedthe

antiplateletagentclopidogrel,one

studyinvolvedpersonswhohadreceivedtissuefactorinhibitor(nematodeanticoagulantproteinc2),31onestudyinvolvedpersonswhohadreceiveda

thrombininhibitor(melagatran),32onestudywasapharmacokineticsstudy,31andonestudyinvolvedpersonswhohad

undergonepunchbiopsy.





5/10



means of logistic regression. Statistical analyses

were performed by means of logistic regression

with dose as a covariate. Since the administered

dose of rFVIIa varies according to the type of

bleeding being treated (with some types of bleed-

ing, such as trauma-related bleeding, requiring the

use of higher doses than other types, such as

spontaneous central nervous system bleeding), thedose given is confounded by the type of bleeding.

To minimize this problem, the analyses included

only studies in which patients had received a study

drug in at least two of the dose categories. Most

of the studies in which patients were randomly

assigned to at least two of the dose categories in-

volved spontaneous central nervous system bleed-

ing, which was associated with a higher event rate

than other indications. Therefore, the effect of the

dose was examined only among patients with this

type of bleeding.

Results

Demographic Characteristics of the Subjects

A total of 4468 subjects (1653 subjects who re-

ceived placebo and 2815 subjects who received

rFVIIa) were enrolled in 35 randomized clinical

trials encompassing various clinical scenarios.

Most of the subjects were patients with sponta-

neous central nervous system bleeding (31.3%),

advanced liver disease (27.8%), or trauma (18.7%)

(Table 1). Approximately 45% (2026) of the sub-

jects received either low doses of rFVIIa (


6/10



1 for types of bleeding other than central nervous

system bleeding, but they were not significant,

possibly because of the lower numbers of patients

for most of the other types of bleeding, as well

as a lower incidence of arterial thromboembolic

events in the placebo group (Table 5).

These analyses, however, do not account for the

various doses of rFVIIa that were used, which may

have had an effect on the risk of thromboembolic

events, especially in studies involving patients with

central nervous system bleeding. The rates of ar-

terial thromboembolic events were 5.4% among23 patients with spontaneous central nervous sys-

tem bleeding who received placebo, 6.0% among

26 patients who received less than 80 g of rFVIIa

per kilogram, 10.3% among 45 patients who re-

ceived 80 to 120 g of rFVIIa per kilogram, and

11.9% among 13 patients who received more than

120 g of rFVIIa per kilogram. When the dose

was considered as a covariate (adjusted for age) of

rates of arterial thromboembolic events among

patients with central nervous system bleeding who

received rFVIIa, this apparent dose-dependent ef-

fect of rFVIIa treatment was signif icant (P = 0.02).

Thromboembolic Events in Healthy Volunteers

Thromboembolic events were also analyzed in 349

healthy volunteers in f ive Novo Nordisk-sponsored

and four investigator-initiated placebo-controlled

trials. The rate of thromboembolic events was 0.9%

among both healthy volunteers who received

rFVIIa and healthy volunteers who received pla-

cebo. None of the thromboembolic events were

arterial in nature. All three venous thromboem-bolic events (two in healthy volunteers who received

rFVIIa and one in a healthy volunteer who received

placebo) were cases of phlebitis.

Discussion

This comprehensive study of the safety profile of

rFVIIa for off-label treatment of episodes of bleed-

ing involved 4468 subjects enrolled in 35 placebo-

controlled clinical trials. We found an increased

Table 3.Arterial Thromboembolic Events with a Rate Greater Than 0.5%.

VariablerFVIIa

(N = 2583)Placebo

(N = 1536)Odds Ratio(95% CI)* P Value

number (percent)

All arterial thromboembolic events 141 (5.5) 49 (3.2) 1.68 (1.202.36) 0.003

Coronary events 76 (2.9) 17 (1.1) 2.39 (1.394.09) 0.002

Acute coronary syndromes 57 (2.2) 11 (0.7)

Increased troponin level 19 (0.7) 6 (0.4)

Cerebrovascular events 45 (1.7) 20 (1.3) 1.27 (0.742.17) 0.39

Cerebral infarction 44 (1.7) 19 (1.2)

Hemiparesis 1 (


7/10



risk of arterial thromboembolic events among pa-

tients who received off-label rFVIIa as compared

with patients who received placebo for bleeding

episodes. The rate of coronary arterial thrombo-embolic events among the patients who received

rFVIIa was 2.6 times as high as the rate among

patients who received placebo. Age was also as-

sociated with an increase in the risk of arterial

thromboembolic events after rFVIIa treatment,

with an odds ratio of 2.4 among patients 65 years

of age or older and 3.0 among patients 75 years

of age or older. The rates of arterial thromboem-

bolic events were also higher among patients who

received higher doses of rFVIIa.

Abshire reviewed the efficacy and safety of

rFVIIa in patients with hemophilia who had con-

genital or acquired inhibitory antibodies against

factor VIII or IX; that study was based on data

from clinical trials and spontaneous postmarket-

ing surveillance reports.37With approximately

800,000 standard doses of rFVIIa administered

during the period from May 2003 through Decem-

ber 2006, a total of 30 thromboembolic events

were reported, 6 of which were fatal. Spontaneous

reports of 71 adverse events included 14 thrombo-

embolic events (20%), with 2 of 34 reported deaths

due to a thromboembolic event.37

Solicited reportsof 40 adverse events included 5 thromboembolic

events 12%), with 1 of 32 deaths due to a throm-

boembolic event. A comprehensive overview of

thrombotic adverse events, based on the Med-

Watch pharmacovigilance program, also showed

a low incidence of thrombotic complications as-

sociated with the use of rFVIIa (24.6 events per

100,000 infusions), although the risk of thrombo-

sis was higher among patients treated with rFVIIa

than among those treated with other hemostatic

agents.38As the authors of the overview correctly

state, differences in adverse-event reporting prac-

tices among the various compounds may have

contributed to the observed difference in the rateof thrombotic events. Taken together, the data

show that the use of rFVIIa for an approved in-

dication (i.e., the treatment of episodes of bleeding

in patients with hemophilia) is associated with a

rate of thromboembolic events of less than 1%.

OConnell et al.5 reviewed events from the

FDAs Adverse Event Reporting System during the

period from 1999 through 2005 and identified

185 thromboembolic events, the majority of which

occurred in patients with off-label indications for

rFVIIa. However, in this patient population, 38%

of the patients received other concomitant thera-

pies, and the study had the inherent limitations

of passive surveillance. In a systematic review of

all published and unpublished case reports, case

series, and clinical studies from 1996 through

2004 that focused on the efficacy and safety of

rFVIIa in patients with or without coagulation

disorders, including patients with trauma and

those who had undergone surgery, the incidence

rate of thrombosis was 1 to 2%.2The difference

between the rate of thromboembolic events re-

ported in that review and the results of the pooledanalysis presented here may be due to the fact

that the previous review included mostly patients

with congenital or acquired hemophilia or liver

failure, whereas the present review includes clini-

cal trials involving patients with other causes of

hemorrhage.

Our pooled analysis was conducted with a large

safety data set obtained from placebo-controlled

trials of rFVIIa. The inclusion of control groups

allowed for the proper evaluation of thromboem-

Table 4.All Arterial Thromboembolic Events, According to Age.

Age Group rFVIIa PlaceboOdds Ratio(95% CI)* P Value

no./total no. (%)


8/10



bolic events after the administration of rFVIIa.

Furthermore, the data presented in our analysis

were obtained from clinical trials involving pa-

tients with bleeding disorders other than hemo-

philia in order to establish a clear understanding

of the safety of rFVIIa in patients with various

types of bleeding. This design is important, be-

cause many of these patients also received multiple

transfusions that may have contributed to adverse

outcomes, especially in observational studies.39In

a previous study, we evaluated safety data obtained

from 13 clinical trials of rFVIIa in patients with

coagulopathy due to anticoagulant therapy, cirrho-

sis, or severe traumatic injury, and we reported

thromboembolic events in 23 of 430 patients who

received placebo (5.3%) and in 45 of 748 patientswho received active treatment (6.0%). No signifi-

cant differences were noted between patients who

received placebo and patients who received rFVIIa,

on the basis of data from individual trials or

pooled data (P = 0.57).40

The limitations of the current data set include

the relatively small individual study samples, dif-

ferences in indications (e.g., central nervous sys-

tem bleeding and bleeding from liver disease,

trauma, and other causes), and the fact that the

studies were conducted over a 12-year span. How-

ever, the wide scope of indications may be con-

sidered important, since subjects with or without

coagulopathies were evaluated. The variation in

dosing was taken into consideration by categoriz-

ing subjects into three dose groups. Confounding

factors such as age and sex were also taken into

consideration in the statistical analysis.

The data presented provide a systematic evalu-

ation of rates of thromboembolic events in place-

bo-controlled trials of rFVIIa. It is important to

note that central nervous system bleeding occurs

in an older population with an inherently in-

creased risk of thromboembolic events. Therefore,

risk-benefit considerations should be evaluated

before administering any hemostatic agent.Supported by Novo Nordisk.

Dr. Levy reports serving on a steering committee for NovoNordisk, and Drs. Andersen and Truloff report being employees

of and having equity interest in Novo Nordisk. No other poten-tial conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available withthe full text of this art icle at NEJM.org.

We thank the fol lowing Novo Nordisk employees: Brett Skol-

nick, Ph.D., Sheba Mathew, Ph.D., and Abha Chandra, Ph.D., forvaluable contributions made during the development of an ear-

lier version of the manuscript, and Ming Ying Ching, M.S.,Naum Khutoryansky, Ph.D., and Anders Rosholm, Ph.D., for

providing statistical support.

Table 5.All Arterial Thromboembolic Events, According to Cause of Bleeding.*

Cause of BleedingNo. ofStudies rFVIIa Placebo

Odds Ratio(95% CI) P Value Reference

no./total no. (%)

Spontaneous central nervous system

bleeding

5 84/974 (8.6) 23/423 (5.4) 1.67 (1.032.69) 0.04 Mayer et al.6-9

Advanced liver disease 7 23/795 (2.9) 6/449 (1.3) 2.19 (0.895.42) 0.09 Bosch et al.,10,11Carreno et al.,12Lodge et al.,13,14Planinsic et al.,15Shao et al.16

Trauma 3 19/409 (4.6) 15/428 (3.5) 1.39 (0.692.77) 0.36 Boffard et al.17

Cardiac surgery 3 9/153 (5.9) 4/114 (3.5) 1.59 (0.475.34) 0.45 Diprose et al.,18Ekertet al.,19Gill et al.20

Traumatic brain injury 1 2/61 (3.3) 1/36 (2.8) Narayan et al.21

Spinal surgery 1 1/36 (2.8) 0/13 Sachs et al.22

Other causes 6 3/155 (1.9) 0/73 Chuansumrit et al.,23

Friederich et al.,

24

Pihusch et al.,25Raobaikady et al.26

* References are provided for the trials that have been published. The remaining data are provided in the Supplementary Appendix. Odds ratios were calculated by means of logistic regression with adjustment for age. Odds ratios were not calculated in instances with very

few events. The percentage of thromboembolic events was calculated as the number of patients with events as a proportion of the number of patients

who received a study drug.





9/10



References

1. Hedner U. Factor VIIa and its poten-tial therapeutic use in bleeding-associated

pathologies. Thromb Haemost 2008;100:557-62.2. Levi M, Peters M, Bller HR. Efficacyand safety of recombinant factor VIIa for

treatment of severe bleeding: a systematic

review. Crit Care Med 2005;33:883-90.

3. Villar A, Aronis S, Morfini M, et al.Pharmacokinetics of activated recombinantcoagulation factor VII (NovoSeven) in chil-

dren vs. adults with haemophilia A. Hae-

mophil ia 2004;10:352-9.4. Hedner U. Mechanism of action of

factor VIIa in the treatment of coagulopa-thies. Semin Thromb Hemost 2006;32:

Suppl 1:77-85.5. OConnell KA, Wood JJ, Wise RP,Lozier JN, Braun MM. Thromboembolic

adverse events after use of recombinant hu-man coagulation factor VIIa. JAMA 2006;

295:293-8.6. Mayer SA, Brun NC, Begtrup K, et al.

Recombinant activated factor VII for acute

intracerebral hemorrhage. N Engl J Med2005;352:777-85.7. Mayer SA, Brun NC, Broderick J, et al.Safety and feasibility of recombinant fac-

tor VIIa for acute intracerebral hemorrhage.

Stroke 2005;36:74-9.8. Mayer SA, Brun NC, Broderick J, et al.

Recombinant activated factor VII for acuteintracerebral hemorrhage: US phase IIA

trial. Neurocrit Care 2006;4:206-14.9. Mayer SA, Brun NC, Begtrup K, et al.Efficacy and safety of recombinant activated

factor VII for acute intracerebral hemor-rhage. N Engl J Med 2008;358:2127-37.10. Bosch J, Thabut D, Bendtsen F, et al.

Recombinant factor VIIa for upper gastro-intestinal bleeding in patients with cir-

rhosis: a randomized, double-blind trial.Gastroenterology 2004;127:1123-30.11. Bosch J, Thabut D, Albillos A, et al.Recombinant factor VIIa for variceal bleed-

ing in patients with advanced cirrhosis:

a randomized, controlled trial. Hepatolo-gy 2008;47:1604-14.12. Carreno V, Messnern M, Arrieta J,Berthier A, Schelde P, DeMello G. The ef-

fect of recombinant factor VIIa (Novo-

Seven) on haemorrhage following dentalsurgery in patients with liver cirrhosis

a randomised placebo controlled study.Presented at the XVIII Congress of the

International Society on Thrombosis andHaemostasis, July 612, 2001:P2612.

13. Lodge JP, Jonas S, Jones RM, et al.

Efficacy and sa fety of repeated perioper-ative doses of recombinant factor VIIa in

liver transplantation. Liver Transpl 2005;11:973-9.14. Lodge JP, Jonas S, Oussoultzoglou E,

et al. Recombinant coagulation factor VIIain major liver resection: a randomized,

placebo-controlled, double-blind cl inicaltrial. Anesthesiology 2005;102:269-75.15. Planinsic RM, van der Meer J, Testa G,

et al. Safety and efficacy of a single bolusadministration of recombinant factor VIIa

in liver transplantation due to chronic liverdisease. Liver Transpl 2005;11:895-900.16. Shao YF, Yang JM, Chau GY, et al. Safetyand hemostatic effect of recombinant acti-

vated factor VII in cirrhotic patients under-

going partial hepatectomy: a multicenter,

randomized, double-blind, placebo-con-trolled trial. Am J Surg 2006;191:245-9.17. Boffard KD, Riou B, Warren B, et al.

Recombinant factor VIIa as adjunctive

therapy for bleeding control in severely in-jured trauma patients: two parallel ran-

domized, placebo-controlled, double-blindclinical trials. J Trauma 2005;59:8-15.18. Diprose P, Herbertson MJ, OShaugh-

nessy D, Gill RS. Activated recombinant fac-tor VII after cardiopulmonary bypass re-

duces allogeneic transfusion in complexnon-coronary cardiac surgery: randomized

double-blind placebo-controlled pilot study.Br J Anaesth 2005;95:596-602.

19. Ekert H, Brizard C, Eyers R, Cochrane

A, Henning R. Elective administration ininfants of low-dose recombinant activat-

ed factor VII (rFVIIa) in cardiopulmonarybypass surgery for congenital heart dis-

ease does not shorten time to chest clo-

sure or reduce blood loss and need fortransfusions: a randomized, double-blind,

parallel group, placebo-controlled study ofrFVIIa and standard haemostatic replace-

ment therapy versus standard haemostatic

replacement therapy. Blood Coagul Fibri-nolysis 2006;17:389-95.20. Gill R, Herbertson M, Vuylsteke A, et al.Safety and efficacy of recombinant activat-

ed factor VII: a randomized placebo-con-

trolled trial in the setting of bleeding aftercardiac surgery. Circulation 2009;120:21-7.21. Narayan RK, Maas AI, Marshall LF,Servadei F, Skolnick BE, Tillinger MN. Re-

combinant factor VIIA in traumatic intra-cerebral hemorrhage: results of a dose-

escalation clinical trial. Neurosurgery

2008;62:776-86.22. Sachs B, Delacy D, Green J, et al. Re-

combinant activated factor VII in spinalsurgery: a multicenter, randomized, dou-

ble-blind, placebo-controlled, dose-esca-

lation trial. Spine 2007;32:2285-93.23. Chuansumrit A, Wangruangsatid S,

Lektrakul Y, Chua MN, Zeta Capeding MR,Bech OM. Control of bleeding in children

with Dengue hemorrhagic fever usingrecombinant activated factor VII: a ran-

domized, double-blind, placebo-controlled

study. Blood Coagul Fibrinolysis 2005;16:549-55.24. Friederich PW, Henny CP, MesselinkEJ, et al. Effect of recombinant activated

factor VII on perioperative blood loss in

patients undergoing retropubic prostatec-tomy: a double-blind placebo-controlled

randomised trial. Lancet 2003;361:201-5.[Erratum, Lancet 2003;361:1138.]25. Pihusch M, Bacigalupo A, Szer J, et al.

Recombinant activated factor VII in treat-ment of bleeding complications following

hematopoietic stem cell transplantation.J Thromb Haemost 2005;3:1935-44.26. Raobaikady R, Redman J, Ball JA, Ma-loney G, Grounds RM. Use of activated

recombinant coagulation factor VII in pa-

tients undergoing reconstruction surgery

for traumatic fracture of pelvis or pelvisand acetabulum: a double-blind, random-ized, placebo-controlled trial. Br J Anaesth

2005;94:586-91.27. Bijsterveld NR, Moons AH, BoekholdtSM, et al. Ability of recombinant factor

VIIa to reverse the anticoagulant effectof the pentasaccharide fondaparinux in

healthy volunteers. Circulation 2002;106:

2550-4.28. Bijsterveld NR, Vink R, van Aken BE,

et al. Recombinant factor VIIa reversesthe anticoagulant effect of the long-acting

pentasaccharide idraparinux in healthyvolunteers. Br J Haematol 2004;124:653-8.

29. Erhardtsen E, Nony P, Dechavanne M,

French P, Biossel JP, Hedner U. The effectof recombinant factor VIIa (NovoSeven) in

healthy volunteers receiving acenocouma-rol to an International Normalized Ratio

above 2.0. Blood Coagul Fibrinolysis 1998;

9:741-8.30. Fridberg MJ, Hedner U, Roberts HR,

Erhardtsen E. A study of the pharmacoki-netics and safety of recombinant activated

factor VII in healthy Caucasian and Japa-

nese subjects. Blood Coagul Fibrinolysis2005;16:259-66.31. Friederich PW, Levi M, Bauer KA, etal. Ability of recombinant factor VIIa to

generate thrombin during inhibition of

tissue factor in human subjects. Circula-tion 2001;103:2555-9.32. Wolzt M, Levi M, Sarich TC, et al. Effectof recombinant factor VIIa on melagatran-

induced inhibition of thrombin generationand platelet activation in healthy volunteers.

Thromb Haemost 2004;91:1090-6.33. Abbott RD, Curb JD, Rodriguez BL, etal. Age-related changes in risk factor ef-

fects on the incidence of thromboembolicand hemorrhagic stroke. J Clin Epidemiol

2003;56:479-86.34. Heit JA. Venous thromboembolism:disease burden, outcomes and risk factors.

J Thromb Haemost 2005;3:1611-7.35. Rosendaal FR. Risk factors for venous

thrombotic disease. Thromb Haemost1999;82:610-9.

36. Samama MM. An epidemiologic study

of risk factors for deep vein thrombosis inmedical outpatients: the Sirius study.

Arch Intern Med 2000;160:3415-20.37. Abshire T. Safety update on recombi-

nant factor VIIa in the treatment of con-

genital and acquired hemophilia. SeminHematol 2008;45:Suppl:S3-S6.38. Aledort LM. Comparative thromboticevent incidence after infusion of recombi-

nant factor VIIa versus factor VIII inhibi-





10/10



tor bypass activity. J Thromb Haemost2004;2:1700-8.39. Murphy GJ, Reeves BC, Rogers CA,Rizvi SI, Culliford L, Angelini GD. In-

creased mortalit y, postoperative morbidi-ty, and cost after red blood cell transfu-

sion in patients having cardiac surgery.Circulation 2007;116:2544-52.40. Levy JH, Fingerhut A, Brott T, Lang-bakke IH, Erhardtsen E, Porte R J. Recom-

binant factor VIIa in patients with coagu-lopathy secondary to anticoagulant therapy,

cirrhosis, or severe traumatic injury: re-view of safety profile. Transfusion 2006;

46:919-33.Copyright 2010 Massachusetts Medical Society.

Paul Berman, M.D.



jr trakhir

Documents